Protoporphyrinogen oxidase inhibitors

Abstract

The present invention relates to protoporphyrinogen oxidase inhibitors of general formula (I), where the variables are defined herein. The invention features processes and intermediates for preparing the benzoxazinones of formula (I), compositions containing them, and their use as herbicides (i.e., for controlling harmful plants). The invention also features a method for controlling undesirable vegetation, comprising applying a herbicidally effective amount of at least one benzoxazinones of formula (I) to a plant, its seeds, and / or its habitat. [Formula 1] JPEG2024535847000122.jpg49169

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 244,586, filed September 15, 2021, U.S. Provisional Patent Application No. 63 / 299,855, filed January 14, 2022, and U.S. Provisional Patent Application No. 63 / 400,365, filed August 23, 2022, each of which is incorporated by reference in its entirety herein.

[0002] The present invention relates to protoporphyrinogen IX oxidase (PPO) inhibitors useful as herbicides. In particular, the present invention relates to certain benzoxazinone compounds, including, for example, 5-tetrafluorophenylbenzoxazinone and 6-pentafluorophenylbenzoxazinone, 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. Upon exposure to light, protoporphyrin IX can induce the formation of singlet oxygen and other reactive oxygen species in the cytosol, 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 approximately 30 species are currently 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 These include molecules from many different structural classes, including cyclic nucleotides (Ed., Vol 1: Herbicides, (2012) Wiley-VCH, Weinheim, Germany). 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, since such resistant weeds are becoming more and more prevalent and therefore weed control by herbicide application is no longer effective, causing great problems for farmers. Resistance to PPO herbicides has been slow to evolve (about 40 years since the 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 waterhemp (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 98Leu substitutions confer PPO resistance in waterhemp [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] In some aspects, novel PPO inhibitors with high herbicidal activity even at low application rates are provided herein. In some embodiments, improved leaf and root penetration, improved translocation, improved spectrum and selectivity are achieved by the benzoxazinones of the present invention as defined below, and their agriculturally suitable salts and formulations.

[0008] Thus, in one embodiment, a benzoxazinone having formula I: [ka] or a salt thereof (wherein rings A and R 1 ~R 8 is as defined herein. In some embodiments, ring A comprises at least four F atom substituents.

[0009] In certain embodiments, a benzoxazinone having formula II: [ka] or a salt thereof, wherein R 1 ~R 4 is as defined herein.

[0010] In certain embodiments, a benzoxazinone having formula III: [ka] or a salt thereof, wherein R 1 ~R 4 is as defined herein.

[0011] In certain embodiments, a benzoxazinone having formula IV: [ka] or a salt thereof, wherein R 1 ~R 4 is as defined herein.

[0012] 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, III, or IV, 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.

[0013] In yet another aspect, processes for producing the above-identified compounds, salts, and compositions are also provided.

[0014] 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.

[0015] 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.

[0016] The present application can be understood by reference to the following description in conjunction with the accompanying drawings. [Brief description of the drawings]

[0017] [Figure 1] 1A and 1B show the growth inhibition rate, necrosis upon application, xylem mobility, and phloem mobility of the compounds of the present invention versus known compounds. In FIG. 1A, two 6-plant trays are represented for each compound. The plants on the left side of the tray were treated with a penetrant (COC) and the plants on the right side were treated without a COC. In FIG. 1B, the effect of 3×2 μL drops without penetrant on the adaxial surface of emerged foxtail leaves is shown for Compound 2, Compound 920-4, and Compound 920-6. [Figure 2A] FIG. 1 is a photograph showing Compound 2 (60 g ai / ha) PPO dG210 mutant Tall Waterhemp (Amaranthus tuberculatus) residue control. [Figure 2B] FIG. 1 is a photograph showing Flumioxazin (70 g ai / ha) PPO dG210 resistant Tall Waterhemp (Amaranthus tuberculatus) residual control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Benzoxazinone Compounds In one embodiment, a benzoxazinone having formula I: [ka] or a suitable salt thereof, wherein R 1 is H or, optionally, R 1a wherein each of said alkyl, said phenyl, or said benzyl is optionally substituted with up to three halo atoms, OH groups, or O-alkyl groups; R 1a teeth, [ka] and Each R 1b are independently H, alkyl, or cyclopropyl; R 2 and R 3 Each of is independently H, Cl, F, alkyl, or R 2 and R 3 is, together with the intervening carbon, cyclopropyl; R 4 is H or F, R 5 is H or F, R 6 and R 7 each independently is halo, H, alkyl, alkenyl, OH, O-alkyl, O-cyclopropyl, OCH 2 CCH, NHCH 2 Ph, N(R x ) 2 or S-(alkyl); The alkyl is optionally substituted with at least one -OH; R 8 is H or halo, Each R x are independently H, alkyl, or C(O)alkyl; Ring A contains at least four halo substituents.

[0019] In some of the above-mentioned variations, R 1 is H or, optionally, R 1a C replaced with 1~4 alkyl, phenyl, or benzyl, each of which optionally contains up to three F atoms, OH groups, or OC 1~4 is substituted with an alkyl group, R 1a teeth, [ka] and Each R 1b are independently H, C 1~4 alkyl, or cyclopropyl; R 2 and R 3 each independently is H, Cl, F, CH 3 or R 2 and R 3 is, together with the intervening carbon, cyclopropyl; R 4 is H, Cl, or F, R 5 is H or F, R 6 and R 7 each independently represents F, H, C 1~2 Alkyl, alkenyl, OH, OC 1~2 Alkyl, O-cyclopropyl, OCH 2 CCH, NHCH 2 Ph, N(R x ) 2 , or SCH 3 and C 1~2 The alkyl is optionally substituted with at least one -OH; R 8 is H or F, Each R x are independently H, CH 3 , or C(O)CH 3 and Ring A contains at least four F atom substituents.

[0020] In one embodiment, R of the compound of formula I 2 , R 3 , and R 4 Each of is F. In another embodiment, R 2 , R 3 , and R 4 Each of is F and R 1 CH 2 CCH (i.e., R 1a C replaced with 1~4 is alkyl, R 1a teeth [ka] and R 1b is H).

[0021] In some variations, R 2 and R 3 each independently is H, F, CH 3 or R 2 and R 3 together with the intervening carbon is cyclopropyl.

[0022] In some variations, R 4 and R 5 Each of is independently H or F.

[0023] In another further embodiment, R of the compound of formula I 2 and R 3 is H, and each of R 4 is F.

[0024] In one embodiment, R of the compound of formula I 2 and R 3 Each of is F and R 4 and R 5 Each of is H.

[0025] In one particular variant, R 6 and R 7each independently represents C optionally substituted with F, H, OH 1~2 Alkyl, alkenyl, OH, OC 1~2 Alkyl, O-cyclopropyl, OCH 2 CCH, NHCH 2 Ph, N(R x ) 2 , or SCH 3 In one variation, R 6 and R 7 each independently represents F, H, C 1~2 Alkyl, alkenyl, OH, OC 1~2 Alkyl, N(R x ) 2 , N(R x )C(O)CH 3 , or SCH 3 It is.

[0026] In some variations, each R x are independently H or CH 3 It is.

[0027] In another embodiment, the present invention provides a compound of formula II: [ka] or a salt thereof.

[0028] In a further embodiment, R of the compound of formula II 2 , R 3 , and R 4 Each of R is F. In another embodiment, R of the compound of formula II is 2 , R 3 , and R 4 Each of is F and R 1 CH 2 CCH (i.e., R 1a C replaced with 1~4 is alkyl, R 1a teeth [ka] and R1b is H).

[0029] In another further embodiment, R of the compound of formula II 2 and R 3 is H, and each of R 4 is F.

[0030] In another embodiment, the present invention provides a compound of formula II: [ka] or a salt thereof.

[0031] In a further embodiment, R of the compound of formula III 2 , R 3 , and R 4 Each of R is F. In another embodiment, R of the compound of formula III is 2 , R 3 , and R 4 Each of is F and R 1 CH 2 CCH (i.e., R 1a C replaced with 1~4 alkyl, where R 1a teeth [ka] and R 1b is H).

[0032] In another further embodiment, R of the compound of formula III 2 and R 3 is H, and each of R 4 is F.

[0033] In another embodiment, the present invention provides a compound of formula IV: [ka] or a salt thereof.

[0034] In a further embodiment, R of the compound of formula IV 2 , R 3 , and R 4 Each of is F. In another embodiment, in the compound of formula IV, 2 , R 3 , and R 4 Each of is F and R 1 CH 2 CCH (i.e., R 1a C replaced with 1~4 is alkyl, R 1a teeth [ka] and R 1b is H).

[0035] In another further embodiment, R of the compound of formula IV 2 and R 3 is H, and each of R 4 is F.

[0036] In one embodiment, the compound of formula (I) is 6-pentafluorophenylbenzoxazinone.

[0037] 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.

[0038] In some embodiments, a compound selected from the compounds listed in Table 1 below, or a salt thereof (including agriculturally suitable salts thereof) is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0039] In some variations, compounds 1-53 or 56-68, or salts thereof, including agriculturally suitable salts thereof, are provided. In some variations, compounds 1-29, or salts thereof, including agriculturally suitable salts thereof, are provided. In some variations, compounds 1-62, or salts thereof, including agriculturally suitable salts thereof, are provided. In one variation, compound 2, or salts thereof, including agriculturally suitable salts thereof, are provided. In another variation, compound 37, or salts thereof, including agriculturally suitable salts thereof, are provided. In another variation, compound 52, or salts thereof, including agriculturally suitable salts thereof, are provided.

[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 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, C 2 Alkoxyalkyl is CH 3 OCH 2 - represents C 3 Alkoxyalkyl is, for example, CH3 CH(OCH 3 )-, CH 3 OCH 2 CH 2 - or CH 3 CH 2 OCH 2 - represents C 4 Alkoxyalkyl is CH 3 CH 2 CH 2 OCH 2 - and CH 3 CH 2 OCH 2 CH 2 - represents the various isomers of alkyl groups substituted with alkoxy groups containing a total of four carbon atoms, including, for example, -.

[0051] When a compound is substituted with a substituent having a subscript indicating the number of such substituents is greater than one, the substituents (if they are greater than one) may 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~j When a variable is depicted as "i" or "unsubstituted," the number of substituents may be selected from the integers between "i" and "j," inclusive. When a group includes a substituent that 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 depicted as being optionally attached to a position, a hydrogen may be at that position even if it is not recited 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 incorporates any free valency.

[0052] Unless otherwise specified, a "ring" or "ring system" as a component of the compounds of the invention is carbocyclic or heterocyclic.

[0053] "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.

[0054] The term "non-aromatic ring system" denotes a carbocyclic or heterocyclic ring system which may be fully saturated, partially or fully unsaturated, provided that none of the rings in the ring system are aromatic.

[0055] 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.

[0056] The term "acceptable salt" or "salt" 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, and the ions of transition metals, preferably manganese, copper, zinc and iron, additionally ammonium and ions in which one to four hydrogen atoms are present, such as C 1 ~C 4 -Alkyl, Hydroxy-C 1 ~C 4 -Alkyl, C 1 ~C 4 -Alkoxy-C 1 ~C 4 -Alkyl, Hydroxy-C 1 ~C 4 -Alkoxy-C 1 ~C4 - substituted ammonium ions, which are replaced by alkyl, phenyl or benzyl - preferably ammonium, methylammonium, isopropylammonium, dimethylammonium, diethylammonium, diisopropylammonium, trimethylammonium, triethylammonium, tris(isopropyl)ammonium, heptylammonium, dodecylammonium, tetradecylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium (olamine salt), 2-(2-hydroxyeth-1-oxy)eth-1-ylammonium (diglycolamine salt), di(2-hydroxyeth-1-yl)ammonium (diolamine salt), tris(2-hydroxyethyl)ammonium (trolamine salt), tris(2-hydroxypropyl)ammonium, benzylmethylammonium, benzyltriethylammonium, N,N,N-trimethylethanolammonium (choline salt), further phosphonium ions, sulfonium ions, preferably tri(C) ions such as trimethylsulfonium. 1 ~C 4 alkyl)sulfonium and sulfoxonium ions, preferably tri(C 1 ~C 4 -alkyl)sulfoxonium, and finally the salts of polybasic amines such as N,N-bis(3-aminopropyl)methylamine and diethylenetriamine.

[0057] The anions of useful acid addition salts are primarily chloride, bromide, fluoride, iodide, hydrogen sulfate, methyl sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and also C 1 ~C 4 anions of alkanoic acids - preferably formate, acetate, propionate and butyrate.

[0058] As used herein, the terms "undesirable vegetation" and "harmful plants" are synonymous.

[0059] 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, AR Katritzky and CW Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, AR Katritzky, CW Rees and EFV Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

[0060] 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 can have the same chemical composition, but can differ in composition due to the presence or absence of co-crystallized water or other molecules that can 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 accomplished by methods known to those skilled in the art, including, for example, crystallization using a selected solvent and temperature. For a comprehensive discussion of polymorphism, see R. Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0061] 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.

[0062] Furthermore, the present invention features processes and intermediates for preparing the compounds of the present invention. These compounds can be prepared by general methods known in the art of synthetic organic chemistry. One or more of the following methods and variations, as described in Schemes 1a, 1b, and 2, can be used.

[0063] In one general example, compounds of formula I can be prepared as shown in Scheme 1a. [ka]

[0064] Thus, compounds of formula c can be prepared by reaction of compounds of formula a (wherein X is Br or I) with substituted phenyls of formula b using cross-coupling reaction conditions with the aid of metal catalysts, as shown in Scheme 1a, step 1. Suitable catalysts include Pd(OAc) in combination with 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos). 2 As shown in step 2 of scheme 1a, a compound of formula d can be prepared by demethylating the aryl methyl ether of a compound of formula c under acidic conditions. In one embodiment, a Lewis acid such as boron tribromide can be used. As shown in step 3 of scheme 1a, a compound of formula e can be prepared by reduction of the nitro group of a compound of formula d. Several methods for this are known to those skilled in the art, including the use of catalytic hydrogenation, sodium sulfide, or sodium hydrosulfite. As shown in step 4 of scheme 1a, a compound of formula g can be prepared by condensing the amino group of a compound of formula e with a suitable haloacetate of formula f under basic conditions in an organic solvent. In one embodiment, the base is a trialkylamine such as triethylamine or diisopropylethylamine. As shown in step 5 of scheme 1a, a benzoxazinone of formula h (a compound of formula I, where R 1 Compounds of formula I, where R is H, can be prepared via intramolecular ring closure between the phenolic hydroxyl group of compounds of formula g and an N-acyl halide in a suitable polar organic solvent such as DMF or DMSO. As shown in Scheme 1a, step 6, compounds of formula I, where R is H, can be prepared via intramolecular ring closure between the phenolic hydroxyl group of compounds of formula g and an N-acyl halide in a suitable polar organic solvent such as DMF or DMSO. 1 can be, for example, optionally substituted C 1~4A benzoxazinone amino group of a compound of formula h, where the benzoxazinone amino group is an alkyl halide of formula i, can be formed by reacting the benzoxazinone amino group of a compound of formula h with an alkyl or aryl halide of formula i under conditions suitable for bond formation. Alternatively, a compound of formula h can be reacted with a boronic acid of formula j using a Chan-Lam type coupling to form a compound of formula I.

[0065] In another general example, compounds of formula I can be prepared as shown in Scheme 1b. [ka]

[0066] Thus, a phenylboronic acid (wherein R=H) or a phenylboronate (e.g., where -B(OR) 2 (wherein represents a pinacol ester) can be coupled to a suitably substituted phenyl bromide or phenyl iodide in a Suzuki-Miyaura type reaction using a suitable catalyst to produce a compound of formula c (step 1). This can also be achieved under similar conditions by reacting a compound of formula k with compound m (step 2). The compound of formula c can then be converted to a compound of formula I using steps similar to steps 2-6 described in Scheme 1. Alternatively, a compound of formula n can be reacted with a compound of formula o (step 3) or a compound of formula p can be reacted with a compound of formula q under Suzuki conditions (step 4) to produce a compound of formula I.

[0067] In yet another general embodiment, compounds of formula I can be prepared as shown in Scheme 2. [ka]

[0068] Thus, as shown in Scheme 2, Step 1, a fluorinated phenyl compound of formula r, where L is a leaving group such as Br, I, or OTf (triflate), can be reacted with a compound of formula s, where M 1is an alkali metal such as Li, or MgBr as found in Grignard reagents, to produce a compound of formula v. Alternatively, as shown in Scheme 2, step 2, a compound of formula t, where L is a leaving group such as Br or I, is reacted with a compound of formula u under conditions suitable for Cu-mediated aryl-aryl cross-coupling known to those skilled in the art to produce a compound of formula v. As shown in Scheme 2, step 3, a compound of formula v can then be nitrated, followed by steps 2-6 of Scheme 1a to produce a compound of formula I.

[0069] In one aspect, the following: deprotecting the compound of formula (c) or a salt thereof to obtain a compound of formula (d) or a salt thereof; [ka] reducing a compound of formula (d) or a salt thereof to obtain a compound of formula (e) or a salt thereof; [ka] reacting a compound of formula (e) or a salt thereof with a compound of formula (f) or a salt thereof to obtain a compound of formula (g) or a salt thereof; [ka] cyclizing the compound of formula (g) or a salt thereof to obtain a compound of formula (h) or a salt thereof; [ka] reacting a compound of formula (h) or a salt thereof with a compound of formula (i) or a salt thereof to obtain a compound of formula (I) or a salt thereof [ka] (In the formula, Y is X or B(OH) 2 and X is Br or I; R 1 ~R 8 and Ring A is as defined herein for Formula (I), a process for preparing a compound of Formula (I) as described herein, or a salt thereof, is provided.

[0070] In some embodiments, the compound of formula (c) or a salt thereof is prepared by a process comprising reacting a compound of formula (a) or a salt thereof with a compound of formula (b) or a salt thereof to obtain a compound of formula (c) or a salt thereof. [ka]

[0071] In some embodiments, the compound of formula (c) or salt thereof is prepared by a process comprising reacting a compound of formula (a) or salt thereof with a compound of formula (j) or salt thereof to obtain a compound of formula (c) or salt thereof; [ka] wherein R is H or phenyl.

[0072] In some embodiments, the compound of formula (c) or a salt thereof is prepared by a process comprising reacting a compound of formula (k) or a salt thereof with a compound of formula (m) or a salt thereof to obtain a compound of formula (c) or a salt thereof. [ka]

[0073] In some embodiments, the compound of formula (c) or salt thereof is prepared by a process comprising reacting a compound of formula (v) or salt thereof to obtain a compound of formula (c) or salt thereof. [ka]

[0074] In some embodiments, the compound of formula (v) or salt thereof is prepared by a process comprising reacting a compound of formula (r) or salt thereof with a compound of formula (s) or salt thereof to obtain a compound of formula (v) or salt thereof; [ka] In the formula, L is Br, I, or OTf; M 1 is an alkali metal.

[0075] In some embodiments, the compound of formula (v) or salt thereof is prepared by a process comprising reacting a compound of formula (t) or salt thereof with a compound of formula (u) or salt thereof to obtain a compound of formula (v) or salt thereof; [ka] In the formula, L is Br, I, or OTf; M 2 is an alkali metal.

[0076] In one aspect, there is provided a method of preparing a compound of formula (I) or a salt thereof, comprising reacting a compound of formula (p) or a salt thereof with a compound of formula (q) or a salt thereof to form a compound of formula (I) or a salt thereof; [ka] During the ceremony, R is H or phenyl; X is Br or I; R 1 ~R 8 and ring A are as defined herein for formula (I).

[0077] In one aspect, there is provided a method of preparing a compound of formula (I) or a salt thereof, comprising reacting a compound of formula (n) or a salt thereof with a compound of formula (o) or a salt thereof to form a compound of formula (I) or a salt thereof; [ka] During the ceremony, R is H or phenyl; X is Br or I; R 1 ~R 8 and ring A are as defined herein for formula (I).

[0078] In another aspect, there is provided a compound of formula (a), or a salt thereof: [ka] In the formula, X is Br or I, and R 4 is as defined in formula (I).

[0079] In another aspect, there is provided a compound of formula (b), or a salt thereof: [ka] In the formula, R 6 ~R 8 and ring A is as defined in formula (I).

[0080] In another aspect, there is provided a compound of formula (c), or a salt thereof: [ka] In the formula, R 4 ~R 8 and ring A is as defined in formula (I).

[0081] In one embodiment, the compound of formula (c) is [ka] It is.

[0082] In another aspect, there is provided a compound of formula (d), or a salt thereof: [ka] In the formula, R 4 ~R 8 and ring A is as defined in formula (I).

[0083] In one embodiment, the compound of formula (d) is [ka] It is.

[0084] In another aspect, there is provided a compound of formula (e), or a salt thereof: [ka] In the formula, R 4 ~R 8 and ring A is as defined in formula (I).

[0085] In one embodiment, the compound of formula (e) is [ka] It is.

[0086] In another aspect, there is provided a compound of formula (f), or a salt thereof: [ka] In the formula, R 2 and R 3 is as defined in formula (I).

[0087] In another aspect, there is provided a compound of formula (g), or a salt thereof: [ka] In the formula, R4 ~R 8 and ring A is as defined in formula (I).

[0088] In one embodiment, the compound of formula (g) is [ka] It is.

[0089] In another aspect, there is provided a compound of formula (h), or a salt thereof: [ka] In the formula, R 2 ~R 8 and ring A is as defined in formula (I).

[0090] In another aspect, there is provided a compound of formula (i), or a salt thereof: [ka] In the formula, Y is X or B(OH) 2 X is Br or I, and R 1 is as defined in formula (I).

[0091] In another aspect, there is provided a compound of formula (j), or a salt thereof: [ka] In the formula, R 6 ~R 8 and ring A is as defined in formula (I).

[0092] In another aspect, there is provided a compound of formula (k), or a salt thereof: [ka] In the formula, R 4 and R 5is as defined in formula (I).

[0093] In another aspect, there is provided a compound of formula (m), or a salt thereof: [ka] In the formula, R 6 ~R 8 and ring A is as defined in formula (I).

[0094] In another aspect, there is provided a compound of formula (n), or a salt thereof: [ka] In the formula, X is Br or I, and R 1 ~R 5 is as defined in formula (I).

[0095] In one embodiment, the compound of formula (n) is [ka] It is.

[0096] In another aspect, there is provided a compound of formula (o), or a salt thereof: [ka] where R is H or phenyl, and R 6 ~R 8 and ring A is as defined in formula (I).

[0097] In another aspect, there is provided a compound of formula (p), or a salt thereof: [ka] where R is H or phenyl, and R 1 ~R 5is as defined in formula (I).

[0098] In another aspect, there is provided a compound of formula (q), or a salt thereof: [ka] In the formula, X is Br or I, and R 6 ~R 8 and ring A is as defined in formula (I).

[0099] In another aspect, there is provided a compound of formula (r), or a salt thereof: [ka] In the formula, L is Br, I, or OTf; R 6 ~R 8 and ring A is as defined in formula (I).

[0100] In another aspect, there is provided a compound of formula (s), or a salt thereof: [ka] In the formula, M 1 is an alkali metal, and R 1 , R 4 , and R 5 is as defined in formula (I).

[0101] In another aspect, there is provided a compound of formula (t), or a salt thereof: [ka] In the formula, L is Br, I, or OTf; R 4 ~R 5 is as defined in formula (I).

[0102] In another aspect, there is provided a compound of formula (u), or a salt thereof: [ka] In the formula, M 2 is an alkali metal, and R 6 ~R 8 and ring A is as defined in formula (I).

[0103] In another aspect, there is provided a compound of formula (v), or a salt thereof: [ka] In the formula, R 4 ~R 8 and ring A is as defined in formula (I).

[0104] Any of the embodiments and variations described herein for formula (I) also apply to intermediates of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s), (t), (u) or (v).

[0105] 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, R. C, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd Ed., Wiley- VCH, New York, 1999.

[0106] It is recognized that some of the reagents and reaction conditions described above for preparing the compounds of the invention may not be compatible with certain functional groups present in the intermediates. In these cases, incorporating protection / deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. 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, 2001). nd 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 invention. Those skilled in the art will also recognize that in order to prepare the compounds of the invention, 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] Liquid formulations include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions, oil-in-water emulsions, flowable concentrates and / or suspoemulsions), etc., which may optionally be 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.

[0111] 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.

[0112] Sprayable formulations are typically made up with a suitable vehicle before spraying. Such liquid and solid formulations are formulated to be easily diluted with the spray vehicle, usually water, but sometimes with another suitable vehicle, such as an aromatic or paraffinic hydrocarbon or vegetable oil. 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 vehicle for foliar treatment by aerial or ground application, or for application to the growing environment of the plant.

[0113] Liquid and dry formulations can be metered directly into a drip irrigation system or metered into furrow within the plantings.

[0114] 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]

[0115] 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.

[0116] 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; acetates, such as isoamyl acetate, 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 C glycerol esters) 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. 6 ~C 22Liquid diluents also 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.

[0117] The solid and liquid formulations of the present disclosure often contain one or more surfactants.When added to liquid, surfactants (also known as "surface active agents") generally modify, and most often reduce, the surface tension of liquid.Depending on the nature of the hydrophilic and lipophilic groups in the surfactant molecule, surfactants can be useful as wetting agents, dispersing agents, emulsifying agents, or antifoaming agents.

[0118] Surfactants can be classified as nonionic, anionic, or cationic. Nonionic surfactants useful in the formulations of the 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 polymers 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.

[0119] 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 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 ether sulfates; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyl taurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzene. Included are sulfosuccinates and derivatives thereof, such as the sulfonates of condensed naphthalenes; the sulfonates of naphthalene and alkyl naphthalenes; the sulfonates of fractionated petroleum; the sulfonates of sulfosuccinates; and the dialkyl sulfosuccinates.

[0120] 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.

[0121] 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 AS Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.

[0122] 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.

[0123] 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 Application Publication No. 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. Pat. 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 US Pat. No. 3,299,566.

[0124] 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 Publications, Richmond, UK, See also 2000.

[0125] 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.

[0126] In some variations, provided herein are methods for controlling undesirable vegetation comprising applying a compound of formula I, II, III or IV, or a salt thereof (including agriculturally suitable salts thereof). In some variations, the compound is applied at a low application rate. In one particular variation, 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.

[0127] 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.

[0128] In certain variations, application of the compound with the above application rate provides residual control. The compounds described herein can be used as pre-emergence herbicides that can be applied after planting of the crop but before crop and / or weed emergence. Herbicides considered pre-emergence can also be referred to as herbicides that provide "residual control" and provide extended control of emergent or newly emerged weeds.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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 (Zinc Fingers, ZFNs) capable of sequence-specific DNA cleavage, TALENs, CRISPR-Cas9, CRISPER-Cpf1, meganucleases, and CAS9 nickases, as well as target-AIDs created by modifying the aforementioned tools.

[0139] 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 the 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 quality (e.g., with increased or decreased content or altered composition) of products (e.g., starch, amino acids, and fatty acids), reproductive trait-modified plants, abiotic stress-tolerant plants, and plants with modified traits related to growth or yield.

[0140] 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.

[0141] 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 gene, 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)".

[0142] 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®".

[0143] In another embodiment, oxynil herbicide-resistant plants are known. For example, bromoxynil-resistant transgenic plants in which the nitrilase gene (bxn) is introduced from an 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®".

[0144] ALS herbicide-resistant plants are also known. Examples include carnations (Dianthus caryophyllus) obtained by introducing the ALS herbicide resistance 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 the ALS herbicide resistance ALS gene (als) from Arabidopsis thaliana has been introduced is commercially available under the trade name "CDC Triffid Flax", and corn (Zea mays L.) with sulfonylurea herbicide resistance and imidazolinone herbicide resistance into which the ALS herbicide resistance ALS gene (zm-hra) from corn has been introduced is commercially available under the trade name "Optimum (registered trademark)". GAT™), imidazolinone herbicide tolerant soybean introduced with the ALS herbicide resistance gene (csr1-2) from Arabidopsis thaliana is commercially available under the trade name "Cultivance™", and sulfonylurea herbicide tolerant soybean introduced with the ALS herbicide resistance gene (gm-hra) from soybean (Glycine max) is 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.

[0145] 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.

[0146] 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."

[0147] 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®."

[0148] 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" and "Roundup Ready® Rice"; "Roundup 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).

[0149] 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.

[0150] Examples of plants that have been given herbicide resistance by genome editing technology include canola "SU Canola" that is resistant to sulfonylurea herbicides, which uses rapid trait development technology (Rapid Trait Development System, RTDS). RTDS corresponds to oligonucleotide-directed mutagenesis of genome editing technology, and RTDS allows for the introduction of mutations into the DNA of plants without cleaving the DNA, via gene repair oligonucleotides (GRON), 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).

[0151] 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.

[0152] 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).

[0153] 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.

[0154] 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 tolerant to glyphosate and glufosinate; Enlist™ 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; Enlist E3™ and Enlist™ Roundup™ corn tolerant to glyphosate, glufosinate, and 2,4-D. Enlist Roundup Ready 2Yield; Enlist Roundup Ready 2Yield, a genetically modified corn tolerant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; Enlist Roundup Ready 2Yield, a genetically modified corn tolerant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; Bollgard II XtendFlex Cotton, a genetically modified cotton tolerant to dicamba, glyphosate, and glufosinate; and Enlist Cotton, a genetically modified cotton tolerant 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.

[0155] Examples of commercially available plants that are provided with herbicide tolerance and pest resistance include glyphosate tolerant, pine moth resistant corn "YieldGard Roundup Ready®" and "YieldGard Roundup Ready® 2"; glufosinate tolerant, pine moth resistant corn "Agrisure® CB / LL"; glyphosate tolerant, corn rootworm resistant corn "Yield Gard® VT Rootworm / RR2"; glyphosate tolerant, corn rootworm and pine moth resistant corn "Yield Gard® VT Triple"; "Herculex® I" 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); "YieldGard® Corn Rootworm / Roundup®" 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).

[0156] 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.

[0157] 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.

[0158] 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 15~1,000g per 10,000m 215-100g per 10,000m 2 15-75g per 10,000m 2 Each serving weighs 15 to 60 grams.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] Specific examples of weed species controlled by the present compositions include, but are not limited to, the weed species listed below.

[0168] Urticaceae weeds to be controlled include Urtica urens.

[0169] 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.

[0170] Portulacaceae weeds controlled include Portulaca oleracea.

[0171] Caryophyllaceae weeds controlled include Stellaria media, Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum, Spergula arvensis, and Silene gallica.

[0172] Weeds in the Garland family that are controlled include Mollugo verticillate.

[0173] Chenopodiaceae weeds controlled include Chenopodium album, Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplex spp.

[0174] 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.

[0175] Papaveraceae weeds controlled include Papaver rhoeas, Papaver dubium, and Argemone Mexicana.

[0176] 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.

[0177] Capparaceae weeds controlled include Cleome affinis.

[0178] Leguminous weeds controlled include Aeschynomene indica, Aeschynomene rudis, 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.

[0179] Oxalid weeds controlled include Oxalis, Oxalis strica, and Oxalis oxyptera.

[0180] Geranium weeds controlled include Geranium carolinense and Erodium cicutarium.

[0181] 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.

[0182] Malvaceae weeds controlled include Abutilon theophrasti, Sida rhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sida santaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrum coromandelianum.

[0183] Onagraceae weeds controlled include Ludwigia epilobioides, Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenothera laciniata.

[0184] Sterculiaceae weeds controlled include Waltheria indica.

[0185] Violet weeds controlled include Viola arvensis and Viola tricolor.

[0186] Cucurbitaceae weeds controlled include Sichyos angulatus, Echinocystis lobata, and Momordica charantia.

[0187] Lythraceae weeds controlled include Ammannia multiflora, Ammannia auriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica.

[0188] The Lycopersicon esculentum weeds controlled include Elatine triandra and Elatine californica.

[0189] Umbelliferous weeds controlled include Oenanthe javanica, Daucus carota, and Conium maculatum.

[0190] The Araliaceae weeds controlled include Hydrocotyle sibthorpioides and Hydrocotyle ranunculoides.

[0191] Pine algae weeds controlled include Ceratophyllum demersum.

[0192] The Cabomba family weeds controlled include Cabomba caroliniana.

[0193] Weeds of the family Myriophyllum family that are controlled include Myriophyllum aquaticum, Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllum heterophyllum.

[0194] Sapindaceae weeds controlled include Cardiospermum halicacabum.

[0195] Primulaceae weeds controlled include Anagallis arvensis.

[0196] Asclepiadaceae weeds controlled include Asclepias syriaca and Ampelamus albidus.

[0197] Rubiaceae weeds controlled include Galium aparine, Galium spurium var. echinospermon, Spermacoce latifolia, Richardia brasiliensis, and Borreria alata.

[0198] 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.

[0199] Purple flowering weeds controlled include Myosotis arvensis.

[0200] Lamiaceae weeds controlled include Lamium purpureum, Lamium amplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta, Leonurus sibiricus, and Stachys arvensis.

[0201] 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.

[0202] Scrophulariaceae weeds controlled include Veronica hederaefolia, Veronica persica, Veronica arvensis, Lindernia procumbens, Lindernia dubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum, and Gratiola japonica.

[0203] Plantago family weeds controlled include Plantago asiatic, Plantago lanceolata, Plantago major, and Callitriche palustris.

[0204] 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.

[0205] Alismataceae weeds controlled include Sagittaria pygmaea, Sagittaria trifoli, Sagittaria sagittifolia, Sagittaria montevidensis, Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica.

[0206] Weeds in the Saxifraga family that are controlled include Limnocharis flava.

[0207] Hydrophila weeds controlled include Limnobium spongia, Hydrilla verticillata, and Najas guadalupensis.

[0208] Araceae weeds controlled include Pistia stratiotes.

[0209] Duckweed weeds controlled include Lemna aoukikusa, Spirodela polyrhiza, and Wolffia spp.

[0210] The Potamogeton family species controlled include Potamogeton distinctus, Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata.

[0211] Liliaceae weeds controlled include Allium canadense, Allium vineale, and Allium macrostemon.

[0212] Weeds of the Pontederiaceae family that are controlled include the genera Eichhornia crassipes, Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis.

[0213] Daylily weeds controlled include Commelina communis, Commelina bengharensis, Commelina erecta, and Murdannia keisak.

[0214] 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.

[0215] 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.

[0216] Equisetum weeds controlled include Equisetum arvense and Equisetum palustre.

[0217] Sophora weeds controlled include Salvinia natans.

[0218] Azolla weeds controlled include Azolla japonica and Azolla imbricata.

[0219] Marsilea family weeds controlled include Marsilea quadrifolia.

[0220] Other weeds controlled include Pithophora, Cladophora, Bryophyta, Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, and suckers of perennial crops (e.g., pome fruits, nuts, citrus, hops, grapes).

[0221] 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 causing reduced sensitivity due to non-target site mutation include increased metabolism, impaired absorption, translocation dysfunction, and excretion outside the system. Examples of factors causing 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.

[0222] 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 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.

[0223] 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.

[0224] 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.

[0225] combination In certain embodiments, weed control efficacy is demonstrated by using a compound of formula I in combination with certain compounds.

[0226] Therefore, the present invention is characterized by the following herbicide composition: [1] 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).

[0227] The present invention also relates to a compound in which [2]B-1 is 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, foramsulfuron, halosulfuron, halosulfuron-methyl, imazosulfuron, mesosulfuron, mesosulfuron-methyl, metazosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, primisulfuron-methyl Propyrisulfuron, pyrazosulfuron, pyrazosulfuron-ethyl, rimsulfuron, sulfometuron, sulfometuron-methyl, sulfosulfuron, trifloxysulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, cinosulfuron, ethametsulfuron, ethametsulfuron-methyl, iodosulfuron, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, metsulfuron, metsulfuron-methyl, prosulfuron, thifensulfuron, the group consisting of thifensulfuron-methyl, triasulfuron, tribenuron, tribenuron-methyl, triflusulfuron, triflusulfuron-methyl, tritosulfuron, bencarbazone, flucarbazone, flucarbazone sodium salt, propoxycarbazone, propoxycarbazone sodium salt, thiencarbazone, thiencarbazone-methyl, cloransulam, cloransulam-methyl, diclosulam, florasulam, 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 their agriculturally acceptable salts and derivatives thereof);

[0228] 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);

[0229] 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);

[0230] 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: 140 0904-50-8), 2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide (CAS Registry Number: 1361139-71-0), and 4-(4-fluorophenyl)-6-[2-hydroxy-6-oxo-1-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);

[0231] B-5 is the group consisting of diflufenican, picolinafen, beflubutamid, norflurazon, fluridone, flurochloridone, and flutamone (including their agriculturally acceptable salts and derivatives);

[0232] 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, siduron simazine, atrazine, propazine, cyanazine, ametryn, simetryn, dimethametryn, prometryn, terbumeton, terbuthylazine, terbutryn, trietazine, hexazinone, metamitron, metribuzin, amicarbazone, bromacil, lenacil, terbacil, chloridazon, desmedipham, and phenmedipham (including their agriculturally acceptable salts and derivatives);

[0233] 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);

[0234] B-8 is the group consisting of trifluralin, pendimethalin, ethalfluralin, benfluralin, oryzalin, prodiamine, butamiphos, dithiopyr, and thiazopyr (including their agriculturally acceptable salts and derivatives);

[0235] 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, isooctyl ester, methyl ester, potassium salt, sodium salt, trolamine salt, and choline salt). xyl ester, isobutyl salt, potassium salt, choline salt), dichlorprop and its salts or esters (butotyl salt, dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, methyl ester, potassium salt, sodium salt, and choline salt), dichlorprop-P, dichlorprop-P dimethylammonium, triclopyr and its salts or esters (butotyl ester, 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, the group consisting of tris(2-hydroxypropyl)ammonium salt, choline salt), clopyralid and its salts (olamine salt, potassium salt, triethylammonium salt, choline salt), clomeprop, aminocyclopyrachlor, halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen-benzyl (including their agriculturally acceptable salts and derivatives);

[0236] B-10 is a group consisting of glyphosate, glyphosate-isopropylammonium salt, glyphosate-trimesium salt, glyphosate-ammonium salt, glyphosate-diammonium salt, glyphosate-dimethylammonium salt, glyphosate-monoethanolamine salt, glyphosate-sodium salt, glyphosate-potassium salt, and glyphosate-guanidine salt (including agriculturally acceptable salts and derivatives thereof);

[0237] B-11 is the group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, glufosinate-P-sodium salt, and baylaphos (including agriculturally acceptable salts and derivatives thereof);

[0238] 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, methyldimuron, bromobutide, dimuron, cumyluron, diflufenzopyr, diflufenzopyr-sodium salt, etobenzanide, tridiphane, amirol, 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), 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).

[0239] The present invention also features the herbicidal composition according to [1] or [2], wherein the safener group C is the group consisting of enoxacor, 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.

[0240] In one embodiment, the present invention includes the herbicide composition of [1], wherein [4]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).

[0241] In another embodiment, the present invention includes the herbicide composition according to [1], wherein [5]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).

[0242] In another embodiment, the present invention comprises the herbicidal 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.

[0243] In another embodiment, the present invention relates to a compound selected from the group consisting of [7]B-4, 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)-3-(methylthio)-4-(trifluoromethyl)-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, The herbicide composition according to [1] is a herbicide composition comprising the group consisting of 4-triazine-3,5-(2H,4H)-dione (CAS registration number 1353870-34-4) (including agriculturally acceptable salts and derivatives thereof).

[0244] In another embodiment, the present invention includes the herbicidal composition according to [1], wherein -[8]B-5 is the group consisting of nofurazan and fluridone (including their agriculturally acceptable salts and derivatives thereof).

[0245] 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).

[0246] 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).

[0247] 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).

[0248] 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).

[0249] 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).

[0250] 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).

[0251] In another embodiment, the present invention includes the herbicidal 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 agriculturally acceptable salts and derivatives thereof).

[0252] 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).

[0253] 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.

[0254] 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.

[0255] In another embodiment, the present invention includes the method of

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

[0256] The present invention also features

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

[16] for controlling weeds.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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 the compound of formula I with pyrithiobac (1:0.1 to 1:20); A combination of the compound of formula I with pyrithiobac-sodium salt (1:0.1 to 1:20); A combination of the compound of formula I with chlorimuron-ethyl (1:0.1 to 1:20); A combination of the compound of formula I with foramsulfuron (1:0.1 to 1:20), A combination of the compound of formula I and halosulfuron-methyl (1:0.1 to 1:20); A combination of the compound of formula I with nicosulfuron (1:0.1 to 1:20), A combination of the compound of formula I with primisulfuron-methyl (1:0.1 to 1:20); A combination of the compound of formula I with rimsulfuron (1:0.1 to 1:20), A combination of the compound of formula I with trifloxysulfuron sodium salt (1:0.1 to 1:20), A combination of the compound of formula I with chlorsulfuron (1:0.1 to 1:20); A combination of the compound of formula I with iodosulfuron-methyl-sodium (1:0.1 to 1:20), A combination of the compound of formula I with iofensulfuron-sodium (1:0.1 to 1:20); A combination of the compound of formula I with metsulfuron-methyl (1:0.1 to 1:20), A combination of the compound of formula I with prosulfuron (1:0.1 to 1:20), A combination of the compound of formula I with thifensulfuron-methyl (1:0.1 to 1:20); A combination of the compound of formula I with tribenuron-methyl (1:0.1 to 1:20), A combination of the compound of formula I with thiencarbazone-methyl (1:0.1 to 1:20); A combination of the compound of formula I with cloransulam-methyl (1:0.1 to 1:20), Combinations of the compound of formula I with flumetsulam (1:0.1 to 1:20), A combination of the compound of formula I with imazamethabenz-methyl (1:0.1 to 1:20); A combination of the compound of formula I with imazamox ammonium salt (1:0.1 to 1:20), A combination of the compound of formula I with imazapine ammonium salt (1:0.1 to 1:20), A combination of the compound of formula I with imazapyr-isopropylammonium salt (1:0.1 to 1:20); A combination of the compound of formula I with imazaquin-ammonium salt (1:0.1 to 1:20), A combination of a compound of formula I with imazethapyr-ammonium salt (1:0.1 to 1:20); A combination of the compound of formula I with fenoxaprop-ethyl (1:0.1 to 1:20); A combination of the compound of formula I with fenoxaprop-p-ethyl (1:0.1 to 1:20); A combination of the compound of formula I with fluazifop-butyl (1:0.1 to 1:20), A combination of the compound of formula I with fluazifop-p-butyl (1:0.1 to 1:20), A combination of the compound of formula I with quizalofop-ethyl (1:0.1 to 1:20), A combination of the compound of formula I with quizalofop-p-ethyl (1:0.1 to 1:20), A combination of the compound of formula I with clethodim (1:0.1 to 1:20); A combination of the compound of formula I with sethoxydim (1:0.1 to 1:20); A combination of the compound of formula I with carfentrazone-ethyl (1:0.1 to 1:20); A combination of the compound of formula I with saflufenacil (1:0.1 to 1:20), A combination of the compound of formula I with sulfentrazone (1:0.1 to 1:30), A combination of the compound of formula I with pyraflufen-ethyl (1:0.1 to 1:30); A combination of the compound of formula I with fluthiacet-methyl (1:0.1 to 1:20); A combination of the compound of formula I with flufenpyr-ethyl (1:0.1 to 1:20); A combination of the compound of formula I with flumiclorac-pentyl (1:0.1 to 1:20); A combination of the compound of formula I with flumioxazin (1:0.1 to 1:20), A combination of the compound of formula I with oxyfluorfen (1:0.1 to 1:30); A combination of the compound of formula I and acifluorfen-sodium salt (1:0.1 to 1:30); A combination of the compound of formula I with fomesafen sodium salt (1:0.1 to 1:30), A combination of the compound of formula I with lactofen (1:0.1 to 1:30); A combination of the compound of formula I with thiaphenacyl (1:0.1 to 1:20), A combination of the compound of formula I 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); Combinations of compounds of formula I with bicyclopyrone (1:0.1 to 1:20); A combination of the compound of formula I with mesotrione (1:0.1 to 1:20), A combination of the compound of formula I with tembotrione (1:0.1 to 1:20), A combination of the compound of formula I with isoxaflutole (1:0.1 to 1:20); A combination of the compound of formula I with fenquinotrione (1:0.1 to 1:20); Combinations of compounds of formula I with topramezone (1:0.1 to 1:20), A combination of the compound of formula I with torpiralate (1:0.1 to 1:20), A combination of the compound of formula I with lancotrione sodium salt (1:0.1 to 1:20), A combination of the compound of formula I and 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide (CAS Registry Number: 1400904-50-8) (1:0.1 to 1:20), A combination of the compound of formula I and 2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide (CAS Registry Number: 1361139-71-0) (1:0.1 to 1:20); A combination of the compound of formula I 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) (1:0.1 to 1:20), A combination of the compound of formula I with norflurazon (1:0.1 to 1:20), Combination of the compound of formula I with fluridone (1:0.1 to 1:20), Combinations of compounds of formula I with bentazone (1:1 to 1:50), A combination of the compound of formula I with bromoxynil octanoate (1:1 to 1:50), A combination of the compound of formula I with diuron (1:1 to 1:50), Combinations of compounds of formula I with linuron (1:1 to 1:50), Combinations of the compound of formula I with fluometuron (1:1 to 1:50); A combination of a compound of formula I with simazine (1:1 to 1:50); A combination of a compound of formula I with atrazine (1:1 to 1:50); A combination of the compound of formula I with ametryn (1:1 to 1:50), Combination of the compound of formula I with prometryne (1:1 to 1:50), Combinations of compounds of formula I with metribuzin (1:1 to 1:50), A combination of a compound of formula I with alachlor (1:1 to 1:50); A combination of the compound of formula I with acetochlor (1:1 to 1:50); Combinations of compounds of formula I with metolachlor (1:1 to 1:50); A combination of the compound of formula I with S-metolachlor (1:1 to 1:50), A combination of a compound of formula I with dimethenamid (1:1 to 1:50), A combination of a compound of formula I with dimethenamid-P (1:1 to 1:50), A combination of the compound of formula I with pyroxasulfone (1:0.1 to 1:20), A combination of the compound of formula I and flufenacet (1:0.1 to 1:20), Combinations of compounds of formula I with trifluralin (1:1 to 1:50), A combination of the compound of formula I with pendimethalin (1:1 to 1:50), A combination of the compound of formula I with ethalfluralin (1:1 to 1:50), A combination of the compound of formula I with 2,4-DB (1:1 to 1:50), A combination of a compound of formula I with fluroxypyr (1:1 to 1:50), Combinations of compounds of formula I with fluroxypyr-meptyl (1:1 to 1:50); Combinations of compounds of formula I with clopyralid-olamine salt (1:1 to 1:50), A combination of the compound of formula I with clopyralid potassium salt (1:1 to 1:50), A combination of the compound of formula I with clopyralid triethylammonium salt (1:1 to 1:50), A combination of the compound of formula I with halaxifene (1:0.1 to 1:20); A combination of the compound of formula I with haloxifen-methyl (1:0.1 to 1:20); Combinations of compounds of formula I with florpiraxifen (1:0.1 to 1:20); A combination of the compound of formula I with florpyrauxifen-benzyl (1:0.1 to 1:20); A combination of a compound of formula I with glyphosate (1:1 to 1:50); A combination of the compound of formula I with glyphosate-isopropylammonium salt (1:1 to 1:50); A combination of a compound of formula I with glyphosate-ammonium salt (1:1 to 1:50); A combination of the compound of formula I with glyphosate-dimethylamine salt (1:1 to 1:50); A combination of a compound of formula I with glyphosate monoethanolamine salt (1:1 to 1:50); A combination of a compound of formula I with glyphosate-potassium salt (1:1 to 1:50); A combination of a compound of formula I with glyphosate-guanidine salt (1:1 to 1:50); A combination of the compound of formula I with glufosinate (1:1 to 1:50); A combination of the compound of formula I with glufosinate-ammonium salt (1:1 to 1:50); A combination of the compound of formula I with glufosinate-P (1:1 to 1:50); A combination of the compound of formula I with glufosinate-P-sodium salt (1:1 to 1:50); A combination of a compound of formula I with EPTC (1:1 to 1:50); Combinations of compounds of formula I with diflufenzopyr (1:1 to 1:50); A combination of the compound of formula I with diflufenzopyr-sodium salt (1:1 to 1:50), A combination of a compound of formula I with clomazone (1:1 to 1:50), A combination (1:1 to 1:50) of the compound of formula I and 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9), A combination of the compound of formula I and (3S,4S)--N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]--3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8) (1:1 to 1:50); A combination of the compound of formula I with cinmethylin (1:1 to 1:50); A combination of the compound of formula I with MSMA (1:1 to 1:50), A combination of a compound of formula I with paraquat (1:1 to 1:50); A combination of the compound of formula I with paraquat-dichloride (1:1 to 1:50); A combination of the compound of formula I with diquat (1:1 to 1:50); A combination of a compound of formula I with diquat-dibromide (1:1 to 1:50); Combination of the compound of formula I with benoxacor (1:0.1 to 1:20), A combination of a compound of formula I with cyprosulfamide (1:0.1 to 1:20), or Combinations of compounds of formula I with isoxadifen-ethyl (1:0.1 to 1:20).

[0269] 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.

[0270] 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

[0271] 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.

[0272] 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 +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" stands for single atomic mass unit, or electrospray ionization (ES+). Example 1. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 1) and 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 2) [ka]

[0273] As shown in Scheme 3, Step 1, a degassed mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3.0 g, 12.0 mmol) in isopropyl acetate (50 mL) was treated with Pd(OAc)2 (269 mg, 1.2 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 985 mg, 2.4 mmol) and K under a nitrogen atmosphere. 2 CO 3 (3.3 g, 24.0 mmol) was added. The resulting mixture was stirred at room temperature for 5 min, followed by the addition of a solution of pentafluorobenzene (4.0 g, 24.0 mmol) in isopropyl acetate (10 mL). The resulting mixture was stirred at 80 °C for 16 h under nitrogen, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-40% ethyl acetate in petroleum ether) to give 2,2',3,4,5,6-hexafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1001, 2.6 g, 64% yield) as a reddish solid. (C 13 H 5 F 6 NO 3 ) GCMS calculated value: 337.0; measured value: 337.0.

[0274] As shown in Scheme 3, Step 2, to a stirred mixture of 2,2',3,4,5,6-hexafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (2.6 g, 7.71 mmol) in DCM (50 mL) was added boron tribromide (7.7 g, 30.84 mmol) dropwise at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h and then allowed to warm slowly to room temperature over 16 h. The reaction was diluted with water and extracted with DCM. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1002, 2.4 g, crude) as a yellow solid. (C 12 H 3 F 6 NO 3 )[M-1] - MS(ESI) calculated for, 322.0; found, 322.1. This material was used in the subsequent step without further purification.

[0275] As shown in Scheme 3, Step 3, to a stirred solution of 2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-ol (2.4 g, 7.42 mmol) in EtOH (20 mL) was added a solution of sodium hyposulfite (6.4 g, 37.1 mmol) in water (20 mL). The resulting mixture was refluxed for 1 h, cooled to room temperature, concentrated under reduced pressure, 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 to give 5-amino-2,2',3',4',5',6'-hexafluoro-[1,1'-biphenyl]-4-ol (compound 1003, 2.0 g, crude) as a yellow solid. (C 12 H 5 F 6 NO) [M-1] - MS(ESI) calculated for, 292.1; found, 292.1. This material was used in the subsequent step without further purification.

[0276] As shown in Scheme 3, Step 4, to a solution of 5-amino-2,2',3',4',5',6'-hexafluoro-[1,1'-biphenyl]-4-ol (1.0 g, 3.41 mmol) in EtOAc (10 mL) was added 2-bromo-2,2-difluoroethyl acetate (690 mg, 3.41 mmol) and triethylamine (345 mg, 3.41 mmol). The mixture was stirred at 70° C. for 1 h, cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-50% ethyl acetate in petroleum ether) to give 2-bromo-2,2-difluoro-N-(2',3',4',5',6,6'-hexafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1004, 800 mg, 52% yield) as a yellow solid. (C 14 H 4 BrF 8 NO 2 )[M-1] + MS(ESI) calculated for, 450.1; found, 450.1.

[0277] As shown in Scheme 3, Step 5, to a stirred solution of 2-bromo-2,2-difluoro-N-(2',3',4',5',6,6'-hexafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (600 mg, 1.33 mmol) in DMF (6 mL) was added K 2 CO 3 (276 mg, 2.00 mmol) was added. The mixture was stirred at 50° C. 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 flash chromatography (0-20% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1, 320 mg, 64% yield) as a yellow solid. (C 14 H 3 F 8 NO 2)[M-1] - MS(ESI) calculated for, 368.1; found, 368.1.

[0278] As shown in Scheme 3, Step 6, a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.54 mmol) in DMF (2 mL) was treated with K 2 CO 3 (74 mg, 0.54 mmol) and 3-bromoprop-1-yne (70 mg, 0.54 mmol) were added. The mixture was stirred at room temperature 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 flash chromatography (0-30% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 2, 120 mg, 54% yield) as an off-white solid. (C 17 H 5 F 8 NO 2 GCMS calculated value for 407.0; measured value, 407.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.81-7.67(m,2H),4.88(s,2H),3.45(s,1H); 19 F-NMR (400 MHz, DMSO-d 6 )δ-74.85,-115.56,-140.50,-153.03,-162.01.

[0279] The following compounds were prepared by a procedure similar to that of step 6 of scheme 3 by reacting compound 1 with the appropriate alkyl halide or alkyl triflate: 2,2,7-Trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 5, 24 mg, 23% yield) as a white solid: (C 15 H5 F 8 NO 2 ) GCMS calculated value: 383.0, measured value: 383.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.87-7.62(m,2H),3.43(s,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.05,-116.55,-140.32,-153.34,-162.15; 4-Benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 10, 26.3 mg, 30% yield) as a white solid: (C 21 H 9 F 8 NO 2 ) GCMS calculated value: 459.1; measured value: 459.0; 1 H-NMR (400MHz, methanol-d 4 )δ7.42-7.37(m,4H),7.35-7.31(m,3H),5.33(s,2H); 19 F-NMR (376MHz, methanol-d 4 )δ-78.80,-116.83,-142.52,-155.24-164.83; 4-Allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 11, 29.6 mg, 44% yield) was obtained as a white solid. 17 H 7 F 8 NO 2 GCMS calculated value for 409.0; measured value, 409.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.79-7.74(m,1H),7.62(d,J=6.4Hz,1H),5.88(m,1H),5.27-5.14(m,2H),4.68-4.62(m,2H); 19 F-NMR (376MHz, DMSO-d 6)δ-74.67,-116.18,-140.50,-153.27,-162.03; 4-Ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 12, 28.0 mg, 43% yield) as a white solid: (C 16 H 7 F 8 NO 2 ) GCMS calculated value: 397.0; measured value: 397.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.80(d,J=6.4Hz,1H),7.78-7.72(m,1H),4.05(m,2H),1.19(t,J=7.2Hz,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.60,-116.48,-140.36,-153.44,-162.15; 2,2,7-Trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 13, 25 mg, 32% yield) as a white solid: (C 17 H 9 F 8 NO 2 GCMS calculated value for 411.1; measured value, 411.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.82-7.72(m,2H),3.98(t,J=7.2Hz,2H),1.65-1.59(m,2H),0.91(t,J=6.8Hz,3H); 19 F-NMR (400MHz, DMSO-d 6 )δ-74.70,-116.40,-140.10,-153.46,-162.12; 4-(3-cyclopropylprop-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 14, 28 mg, 33% yield) as a white solid: (C 20 H 9 F 8 NO2 GCMS calculated value for 447.1; measured value, 447.1; 1 H-NMR (400MHz, DMSO-d 6) δ7.76(d,J=9.6Hz,1H),7.71(d,J=6.4Hz,1H),4.80(s,2H),1.32-1.24(m,1H),0.80-0.69(m,2H),0.58-0.50(m,2H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.72,-115.70,-140.77,-153.12,-162.06; 4-(but-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 18, 31.0 mg, 37% yield) as a white solid: (C 18 H 7 F 8 NO 2 ) GCMS calculated value: 421.0; measured value: 421.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.78-7.73(m,2H),4.83-4.78(m,2H),1.78(s,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.68,-115.65,-140.58,-153.09,-161.96; 2,2,7-Trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 19, 250 mg, 72% yield) as a white solid: (C 18 H 9 F 8 NO 2 ) GCMS calculated value: 423.0; measured value: 423.0. 1 H-NMR (400MHz, DMSO-d 6 )δ7.77(d,J=9.6Hz,1H),7.53(d,J=6.4Hz,1H),4.92-4.88(m,1H),4.72-4.66(m,1H),4.56(s,2H),1.75(d,J=1.2Hz,3H);19 F-NMR(376MHz,DMSO-d6)δ-75.05,-116.00,-140.57,-153.23,-162.01; 2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 20, 58 mg, 39% yield) was obtained as a white solid. 16 H 4 F 11 NO 2 GCMS calculated value for 451.0; measured value, 451.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.97(d,J=6.4Hz,1H),7.80(d,J=9.2Hz,1H),5.08-4.97(m,2H); 19 F-NMR (400 MHz, DMSO-d 6 )δ-67.95,-75.15,-115.30,-140.49,-152.81,-161.86; 2,2,7-Trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 23, 89 mg, 66% yield) as a white solid: (C 21 H 8 F 9 NO 2 )[M+1] + MS(ESI) calculated for: 478.2; found: 477.9; 1 H-NMR(400MHz,DMSO-d6)δ7.78(d,J=9.6Hz,1H),7.65(d,J=6.4Hz,1H),7.43-7.33(m,1H),7.33-7.21(m,2H),7.18-7.16(m,1H),5.32(s,2H); 19 F-NMR(400MHz,DMSO-d6)δ-74.91,-115.69,-117.44,-140.68,-153.15,-162.02; 2,2,7-Trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 24, 34.1 mg, 15% yield) as a pale yellow solid: (C 17 H 9 F 8 NO 2 GCMS calculated value for 411.0; measured value, 411.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.72-7.62(m,2H),5.41-5.30(m,1H),1.39(d,J=6.4Hz,6H); 19 F-NMR(400MHz,DMSO-d6)δ-67.27,-112.83,-140.84,-153.73,-162.21. Example 2. Preparation of 7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 3) and 7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 4) [ka]

[0280] As shown in Scheme 4, Step 1, dimethoxyethane (DME, 2.5 mL) and H 2 To a solution of 5-amino-2,2',3',4',5',6'-hexafluoro-[1,1'-biphenyl]-4-ol (500 mg, 1.70 mmol) in 2HO (2.5 mL) was added NaHCO 3 (429 mg, 5.11 mmol) and chloroacetyl chloride (288 mg, 2.55 mmol) were added. The mixture was stirred at 15° C. for 30 min and then heated to 80° C. for 12 h. After cooling, the suspension was filtered and the collected solid was washed with water and dried under vacuum to give 7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 3, 350 mg, 60% yield) as a brown solid. 14 H5 FNO 2 [MH] - MS(ESI) calculated for = 332.0, found, 332.0; 1 H-NMR (400MHz, DMSO-d 6 )δ10.93(s,1H),7.18(d,J=10.4Hz,1H),6.96(d,J=7.2Hz,1H),4.71(s,2H); 19 F-NMR (400MHz, DMSO-d6) δ -119.20, -141.34, -154.32, -162.26.

[0281] As shown in Scheme 4, Step 2, a solution of 7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg, 0.18 mmol) in DMF (1 mL) was treated with K 2 CO 3 (27 mg, 0.19 mmol) and 3-bromoprop-1-yne (23 mg, 0.19 mmol) were added at room temperature under nitrogen. The mixture was stirred at room temperature for 8 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative reverse phase HPLC using the following conditions - Column: XBridge Prep OBD C18 column, 30×150 mm 5 um, Mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile, gradient: 45B to 75B, 7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 4, 23 mg, 20% yield) was obtained as a white solid. (C 17 H 7 F 6 GCMS calculated value for NO: 371.0, measured value: 371.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.43(d,J=6.8Hz,1H),7.28(d,J=9.6Hz,1H),4.86(s,2H),4.75(s,2H),3.30(s,1H); 19F NMR (400MHz, DMSO-d 6 )δ-118.25,-140.71,-153.89,-162.21. Example 3. Preparation of 7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 6) and 7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 7) [ka]

[0282] As shown in Scheme 5, Step 1, a solution of 2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-ol (500 mg, 1.54 mmol) in acetonitrile (5 mL) was treated with ethyl 2-bromo-2-methylpropanoate (362 mg, 1.85 mmol) and K 2 CO 3 (427 mg, 3.09 mmol) was added. The resulting solution was stirred at 80 °C for 2 h before being concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5-35% acetonitrile in water) to give ethyl 2-([2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-yl]oxy)-2-methylpropanoate (compound 1005, 390 mg, 52% yield) as a yellow solid. 1 H-NMR (400MHz, DMSO-d 6 )δ8.34(d,J=8.4Hz,1H),7.18(d,J=6.8Hz,1H),4.20(m,2H),1.62(s,6H),1.19(t,J=7.2Hz,3H).

[0283] As shown in step 2 of Scheme 5, to a solution of ethyl 2-([2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-yl]oxy)-2-methylpropanoate (100 mg, 0.22 mmol) in acetic acid (1 mL) was added iron powder (63 mg, 1.14 mmol). The resulting mixture was stirred at 60 °C for 16 h, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (20-70% acetonitrile in water) to give 7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 6, 35 mg, 40% yield) as a white solid. C 16 H 9 F 6 NO 2 [MH] - MS(ESI) calculated for: 360.1; found: 360.0; 1 H-NMR (400MHz, DMSO-d 6 )δ10.88(s,1H),7.16(d,J=10.4Hz,1H),6.97(d,J=6.8Hz,1H),1.47(s,6H); 19 F-NMR (400MHz, DMSO-d 6 )δ-118.85,-141.24,-154.31,-162.25.

[0284] As shown in Scheme 5, Step 3, a solution of 7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.27 mmol) in DMF (2 mL) was treated with K 2 CO 3(42 mg, 0.31 mmol) and propargyl bromide (36 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by reverse-phase flash chromatography (5% to 40% acetonitrile in water) to give 7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 7, 35 mg, 30% yield) as a white solid. (C 19 H 11 F 6 NO 2 ) GCMS calculated value: 399.0; measured value: 399.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.43(d,J=6.4Hz,1H),7.25(d,J=10.4Hz,1H),4.75(s,2H),3.30(s,1H),1.49(s,6H); 19 F-NMR (400 MHz, DMSO-d 6 )δ-117.89,-140.62,-153.97,-162.25. Example 4. Preparation of 7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropane]-3(4H)-one (Compound 9) [ka]

[0285] As shown in Scheme 6, step 1, to a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (102 mg, 4.30 mmol) in THF (5 mL) at 0° C. under nitrogen atmosphere was added NaH (60% oil dispersion, 206 mg, 5.16 mmol) in portions. The mixture was stirred at room temperature for 10 min, followed by the addition of 15-crown-5 (94 mg, 0.43 mmol) and methyl 1-hydroxycyclopropane-1-carboxylate (500 mg, 4.30 mmol). The mixture was stirred at room temperature for 16 h, cooled to 0° C., diluted with water at 0° C., and extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-35% ethyl acetate in petroleum ether) to give methyl 1-(4-bromo-5-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate (compound 1006, 500 mg, 33% yield) as a yellow solid. 11 H 9 BrFNO 5 GCMS calculated value for: 332.9; measured value: 332.9.

[0286] As shown in Scheme 6, Step 2, a solution of 1,2,3,4,5-pentafluorobenzene (503 mg, 2.99 mmol) in isopropyl acetate (5 mL) under a nitrogen atmosphere was treated with K 2 CO 3 (413 mg, 2.99 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, 122 mg, 0.29 mmol) and Pd(OAc). 2(33 mg, 0.15 mmol) was added. The mixture was stirred at room temperature for 5 min, then methyl 1-(4-bromo-5-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate (500 mg, 1.49 mmol) was added. The mixture was stirred at 80° C. for 12 h under nitrogen atmosphere, cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-20% ethyl acetate in petroleum ether) to give methyl 1-((2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-yl)oxy)cyclopropane-1-carboxylate (compound 1007, 400 mg, 71% yield) as a brown oil. C 17 H 9 F 6 NO 5 GCMS calculated value for = 421.0, measured value, 421.0.

[0287] As shown in Scheme 6, step 3, to a solution of methyl 1-((2,2',3',4',5',6'-hexafluoro-5-nitro-[1,1'-biphenyl]-4-yl)oxy)cyclopropane-1-carboxylate (200 mg, 0.47 mmol) in acetic acid (1 mL) was added iron powder (132 mg, 2.37 mmol). The mixture was stirred at 60° C. for 12 hours. The suspension was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified using the following conditions - Waters XBridge C18 column (30 mm x 150 mm, 5 um, 130 Angstroms), mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile, gradient: 55% to 66% B / A, to give 7-fluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-spiro[1,4-benzoxazine-2,1'-cyclopropane]-3-one (compound 8, 100 mg, 58% yield) as a white solid. 16 H 7 F 6 NO 2)[M-1] - MS(ESI) calculated for: 358.0; found: 358.0; 1 H-NMR (400MHz, DMSO-d 6 )δ11.02(s,1H),7.12(d,J=10.4Hz,1H),6.99(d,J=6.8Hz,1H),1.35-1.29(m,2H),1.29-1.23(m,2H); 19 F-NMR (400 MHz, DMSO-d 6 )δ-118.92,-141.27,-154.15,-162.24.

[0288] As shown in Scheme 6, Step 4, a solution of 7-fluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-spiro[1,4-benzoxazine-2,1′-cyclopropane]-3-one (50 mg, 0.13 mmol) in DMF (1 mL) was treated with K 2 CO 3 (21 mg, 0.15 mmol) and propargyl bromide (18 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was purified by preparative reverse phase HPLC using the following conditions: Waters SunFire C18 column (30 mm x 150 mm, 5 um); mobile phase A: water (0.1% TFA); mobile phase B: acetonitrile; gradient: ranging from 50% B / A to 90% B / A to give 7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (compound 9, 21 mg, 37% yield) as a white solid. 19 H 9 F 6 NO 2 GCMS calculated value for: 397.0; measured value: 397.0; 1 H-NMR (400MHz, methanol-d 4 )δ7.37(d,J=6.4Hz,1H),6.99(d,J=9.6Hz,1H),4.78(d,J=2.4Hz,2H),2.76(t,J=2.4Hz,1H),1.48-1.39(m,2H),1.38-1.32(m,2H); 19F-NMR (400MHz, DMSO-d6) δ -119.24, -142.60, -157.13, -165.16. Example 5. Preparation of 2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 15) and 2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 16) [ka]

[0289] As shown in Scheme 7, Step 1, a degassed mixture of 4-bromo-1-methoxy-2-nitrobenzene (2.0 g, 8.62 mmol) in isopropyl acetate (10 mL) was treated under nitrogen with Pd(OAc) 2 (190 mg, 0.86 mmol), Sphos (700 mg, 1.72 mmol), and K 2 CO 3 (2.4 g, 17.2 mmol) was added. The mixture was stirred at room temperature for 5 min and a solution of pentafluorobenzene (2.9 g, 17.24 mmol) in isopropyl acetate (10 mL) was added. The resulting mixture was stirred at 80 °C for 16 h under nitrogen, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 45% ethyl acetate in petroleum ether) to give 2,3,4,5,6-pentafluoro-4'-methoxy-3'-nitro-1,1'-biphenyl (compound 1008, 1.7 g, 54% yield) as a brown solid. (C 13 H 6 F 5 NO 3 ) GCMS calculated value: 319.0; measured value: 319.0.

[0290] As shown in Scheme 7, step 2, to a stirred solution of 2,3,4,5,6-pentafluoro-4-methoxy-3-nitro-1,1-biphenyl (1.3 g, 4.1 mmol) in DCM (10 mL) was added boron tribromide (5.1 g, 20.4 mmol) dropwise under nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 2 h, then warmed to room temperature and stirred for an additional 16 h. The reaction was diluted with water, extracted with DCM, and the combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2′,3′,4′,5′,6′-pentafluoro-3-nitro-[1,1′-biphenyl]-4-ol (compound 1009, 1.2 g, crude) as a yellow solid. (C 12 H 4 F 5 NO 3 )[M-1] - MS(ESI) calculated for, 304.0; found, 303.8. This material was used as is in subsequent reactions.

[0291] As shown in Scheme 7, step 3, to a stirred solution of 2',3',4',5',6'-pentafluoro-3-nitro-[1,1'-biphenyl]-4-ol (1.3 g, 4.2 mmol) in EtOH (6 mL) was added a solution of sodium hyposulfite (3.6 g, 20.8 mmol) in water (6 mL). The mixture was stirred under reflux for 1 h, cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting mixture 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 3-amino-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1010, 400 mg, crude) as a yellow solid. (C 12 H 6 F 5 NO) [M-1] - MS(ESI) calculated for, 274.0; found, 274.1. This material was used as is in subsequent reactions.

[0292] As shown in step 4 of scheme 7, to a solution of 3-amino-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (169 mg, 0.61 mmol) in ethyl acetate (2 mL) was added 2-bromo-2,2-difluoroethyl acetate (140 mg, 0.69 mmol) and TEA (70 mg, 0.69 mmol). The mixture was stirred at 50°C for 2 h, 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, and concentrated under reduced pressure to give 2-bromo-2,2-difluoro-N-(2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1011, 350 mg, crude) as a brown oil. (C 14 H 5 BrF 7 NO 2 )[M-1] - MS(ESI) calculated for, 429.9; found, 431.9. This material was used as is in subsequent reactions.

[0293] As shown in Scheme 7, Step 5, to a stirred solution of 2-bromo-2,2-difluoro-N-(2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (268 mg, 0.62 mmol) in DMF (3 mL) was added K 2 CO 3 (129 mg, 0.93 mmol) was added. The mixture was stirred at 50° C. for 16 h, 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 30% ethyl acetate in petroleum ether) to give 2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 15, 25 mg, 12% yield) as a white solid. (C 14 H 4 F 7 NO 2 )[M-1] -MS(ESI) calculated for: 350.0; found: 350.0; 1 H-NMR (400MHz, DMSO-d 6 )δ12.15(b,1H),7.49(d,J=8.4Hz,1H),7.33-7.23(m,1H),7.21(d,J=2.0Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.08,-143.46,-155.67,-162.52.

[0294] As shown in Scheme 7, Step 6, to a stirred solution of 2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (78 mg, 0.22 mmol) in DMF (1 mL) was added 3-bromoprop-1-yne (29 mg, 0.24 mmol) and K 2 CO 3 (37 mg, 0.27 mmol) was added. The mixture was stirred at room temperature 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 60% acetonitrile in water) to give 2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 16, 30 mg, 35% yield) as a white solid. 1 H-NMR (400MHz, methanol-d 4 )δ7.67-7.57(m,1H),7.48-7.44(m,1H),7.42-7.36(m,1H),4.92(d,J=2.4Hz,2H),2.91-2.81(m,1H); 19 F-NMR (376MHz, methanol-d 4 )δ-78.89,-145.03,-157.96,-165.12. Example 6. Preparation of 6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one (Compound 21) and 6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 22) [ka]

[0295] As shown in Scheme 8, Step 1, DME (25 mL) and H 2 3-Amino-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (5.0 g, 18.2 mmol) and NaHCO in O (25 mL). 3 To a stirred solution of 2,4-dihydro-1,4-benzoxazin-3-one (4.5 g, 54.5 mmol) was added dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature 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, concentrated under reduced pressure and purified by flash chromatography (10% to 60% ethyl acetate in petroleum ether) to give 6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one (compound 21, 3.4 g, 57% yield) as a brown solid. (C 14 H 6 F 5 NO 2 )[M-1] - MS(ESI) calculated for, 315.2; found, 314.0; 1 H-NMR (400MHz, DMSO-d 6 )δ10.89(s,1H),7.13(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),7.00(s,1H),4.67(s,2H); 19 F-NMR (400MHz, DMSO-d 6 )δ-143.63,-156.62,-162.75.

[0296] As shown in Scheme 8, Step 2, to a stirred solution of 6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one (100 mg, 0.32 mmol) in DMF (1 mL) was added Cs 2 CO 3 (124 mg, 0.38 mmol) and propargyl bromide (45 mg, 0.38 mmol) were added. The resulting mixture was stirred at room temperature for 16 h and then purified by preparative HPLC using the following conditions - Column: X Bridge Shield RP18 OBD column, 19 mm x 250 mm, 10 μm; Mobile phase A: Water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile; gradient: 75% B / A to 80% B / A, then 80% B / A, affording 6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 22, 39 mg, 34%) as a white solid. (C 17 H 8 F 5 NO 2 )[M+1] + MS(ESI) calculated for: 354.0; found: 354.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.42(s,1H),7.22(d,J=7.2Hz,2H),4.93-4.70(m,4H),3.30(d,J=6.4Hz,1H); 19 F-NMR (400MHz, DMSO-d 6 )δ-143.06,-156.10,-162.69. Example 7. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 17) [ka]

[0297] As shown in Scheme 9, to a stirred solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 0.81 mmol) and phenylboronic acid (594 mg, 4.87 mmol) in THF (3 mL) was added 2-[bis(2-hydroxyethyl)amino]ethanol (986 mg, 9.75 mmol) and copper(II) acetate (118 mg, 0.65 mmol) under nitrogen. The mixture was stirred at 60° C. for 16 h, 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 reverse-phase flash chromatography (30% to 80% acetonitrile in water) and then further purified under the following conditions - Column: X Bridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, Mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile, gradient: 51% B / A to 73% B / A, then 73% B / A, to give 2,2,7-trifluoro-6-(perfluorophenyl)-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 17, 23 mg, 35%) as a white solid. (C 20 H 7 F 8 NO 2 GCMS calculated value for 445.0; measured value, 445.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.87-7.80(m,1H),7.70-7.58(m,3H),7.56-7.47(m,2H),6.63(d,J=6.4Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-73.83,-116.15,-141.22,-153.75,-162.19. Example 8. Preparation of 7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 25), (R)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 26), and (S)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 27) [ka]

[0298] As shown in Scheme 10, Step 1, 5-amino-2,2',3',4',5',6'-hexafluoro-[1,1'-biphenyl]-4-ol (100 mg, 0.34 mmol) and NaHCO in DME (1.5 mL) and water (1.5 mL). 3 (86 mg, 1.02 mmol) was added 2-chloropropanoyl chloride (65 mg, 0.51 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The residue was dissolved in DMF (3 mL) and K 2 CO 3 (94 mg, 0.68 mmol) was added and the resulting mixture was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (10% to 60% acetonitrile in water) to give 7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 25, 38 mg, 32% yield) as a white solid. (C 14 H 3 F 8 NO 2 )[M-1] - MS(ESI) calculated for, 346.2; found, 346.2; 1H-NMR (400MHz, DMSO-d 6 )δ10.87(s,1H),7.18(d,J=10.4Hz,1H),6.97(d,J=7.2Hz,1H),4.89-4.80(m,1H),1.51-1.45(m,3H).

[0299] As shown in Scheme 10, Step 2, 7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (390 mg, 1.12 mmol), K 2 CO 3 To a stirred mixture of 1,2-dichloro-2,4-diphenyl-1,2-tetrafluoroethane (310 mg, 2.25 mmol) was added propargyl bromide (401 mg, 3.37 mmol). The resulting mixture was stirred at 80° C. for 4 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give racemic 7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 69% yield) as a brown-yellow oil.

[0300] As shown in step 3 of Scheme 10, racemic 7-fluoro-2-methyl-6-(2,3,4,5,6-pentafluorophenyl)-4-(prop-2-yn-1-yl)-2H-1,4-benzoxazin-3-one (150 mg) was resolved by chiral preparative HPLC using the following conditions - column: CHIRALPAK AD-H, 2×25 cm, 5 μm, mobile phase A: hexane, mobile phase B: 1:1 MeOH / EtOH, gradient: 5% B / A to 5% B / A to give (R)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 26, 26 mg, 18% yield) as a white solid. (C 18 H 9 F 6 NO 2 )[M+1]+ MS(ESI) calculated for, 386.1; found, 386.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.44(d,J=6.8Hz,1H),7.27(d,J=10.0Hz,1H),4.96(q,J=6.8Hz,1H),4.77-4.72(m,2H),3.28(s,1H),1.51(d,J=6.8Hz,3H); 19 F-NMR (377MHz, DMSO-d 6 ) δ -118.05, -140.67, -154.00, -162.27. Also collected at longer retention times was (S)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 27, 35 mg, 23% yield) as a white solid. (C 18 H 9 F 6 NO 2 )[M+1] + MS(ESI) calculated for 386.1; found, 386.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.43(d,J=6.8Hz,1H),7.28(d,J=10.0Hz,1H),4.96(q,J=6.8Hz,1H),4.75(s,2H),3.28(s,1H),1.50(d,J=6.8Hz,3H); 19 F-NMR (377MHz, DMSO-d 6 )δ-118.04,-140.67,-153.97,-162.25. Example 9. Preparation of (S)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 28) and (R)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 29) [ka]

[0301] As shown in Scheme 11, Step 1, (R)-but-3-yn-2-ol (200 mg, 2.86 mmol), 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (703 mg, 1.90 mmol) and PPh in THF (5 mL). 3 To a stirred solution of (749 mg, 2.86 mmol) diisopropyl azodicarboxylate (DIAD, 578 mg, 2.86 mmol) was added dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum and purified by preparative TLC (1:10 EtOAc / petroleum ether) to give (S)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 28, 73 mg, 9% yield) as a white solid. (C 18 H 7 F 8 NO 2 GCMS calculated value for 421.0; measured value, 421.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.96(d,J=6.4Hz,1H),7.84-7.74(m,1H),5.98-5.86(m,1H),3.68(d,J=2.4Hz,1H),1.64(d,J=7.2Hz,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.63,-77.16,-115.34,-140.69,-153.45,-162.12.

[0302] Similarly, as shown in Scheme 11, Step 2, using a procedure similar to that described in Step 1, but using (S)-butyl-3-yn-2-ol instead of (R)-butyl-3-yn-2-ol, (R)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 29, 49 mg, 21% yield) was produced as a white solid: (C 18 H 7 F 8 NO 2 GCMS calculated value for 421.0; measured value, 421.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.96(d,J=6.4Hz,1H),7.80(d,J=9.6Hz,1H),5.97-5.87(m,1H),3.69(d,J=2.4Hz,1H),1.64(d,J=7.2Hz,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.75,-77.34,-115.34,-140.91,-153.37,-162.17. Example 10. Preparation of 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 30) and 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 31) [ka]

[0303] As shown in Scheme 12, Step 1, to a stirred solution of 2-bromo-1,3-difluoro-5-methoxybenzene (20.0 g, 90.1 mmol) in anhydrous THF (200 mL) under a nitrogen atmosphere, n-BuLi (2.5 M in hexanes, 39.6 mL, 99.1 mmol) was added dropwise at −78° C. After the addition was complete, stirring was continued at −78° C. for 15 min, and hexafluorobenzene (25.1 g, 135.1 mmol) was added dropwise at −78° C. The resulting mixture was allowed to warm to room temperature, stirred under nitrogen 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 flash chromatography (0% to 10% ethyl acetate in petroleum ether) to give 2,2',3,4,5,6,6'-heptafluoro-4'-methoxy-1,1'-biphenyl (9.0 g, 26% yield) as a white solid. (C 13 H 5 F 7 GCMS calculated for O: 310.0; found: 310.0.

[0304] As shown in Scheme 12, Step 2, DCM (20 mL) and concentrated H 2 SO 4 To a stirred solution of 2,2',3,4,5,6,6'-heptafluoro-4'-methoxy-1,1'-biphenyl (8.0 g, 25.8 mmol) in 1,2-dichloro-1,3-difluorophenyl (1,2-dichloro-1,3-difluorophenyl) (80 mL) was added KNO in portions at 0 °C. 3 (2.6 g, 25.8 mmol) was added. The resulting solution was stirred at 20° C. under nitrogen 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 flash chromatography (0% to 25% ethyl acetate in petroleum ether) to give 2,2′,3,4,5,6,6′-heptafluoro-4′-methoxy-3′-nitro-1,1′-biphenyl (compound 1012, 5.5 g, 54% yield) as a yellow solid. (C 13 H 4 F 7 NO 3 ) GCMS (ESI) calculated: 355.0; found: 355.0.

[0305] As shown in Scheme 12, Step 3, to a stirred solution of 2,2',3,4,5,6,6'-heptafluoro-4'-methoxy-3'-nitro-1,1'-biphenyl (5.5 g, 15.5 mmol) in DCM (70 mL) under a nitrogen atmosphere was added BBr 3 (19.4 g, 77.4 mmol) was added dropwise at 0° C. The solution was stirred under nitrogen at 0° C. for 2 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,2′,3′,4′,5′,6,6′-heptafluoro-3-nitro-[1,1′-biphenyl]-4-ol (compound 1013, 4.9 g, crude) as a yellow oil. (C 12 H 2 F 7 NO 3 )[M-1] - MS(ESI) calculated for, 339.9; found, 339.9. This material was used as is in subsequent reactions.

[0306] As shown in Scheme 12, Step 4, EtOH (30 mL) and H 2 To a stirred solution of 2,2',3',4',5',6,6'-heptafluoro-3-nitro-[1,1'-biphenyl]-4-ol (4.9 g, 14.4 mmol) in O (30 mL) was added Na 2 S 2 O 4 (12.5 g, 71.8 mmol) was added portionwise at 20° C. The resulting mixture was stirred at 100° C. under nitrogen 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 flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 3-amino-2,2′,3′,4′,5′,6,6′-heptafluoro-[1,1′-biphenyl]-4-ol (compound 1014, 3.9 g, 78% yield) as a yellow solid. (C 12 H 4 F 7 NO) [M+1] +MS(ESI) calculated for, 312.0; found, 311.9.

[0307] As shown in Scheme 12, Step 5, to a stirred solution of 3-amino-2,2',3',4',5',6,6'-heptafluoro-[1,1'-biphenyl]-4-ol (3.9 g, 12.5 mmol) and TEA (2.5 g, 25.1 mmol) in EtOAc (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.1 g, 25.1 mmol) in portions at 20° C. The resulting mixture was stirred under nitrogen at 50° C. for 16 h, 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 vacuum, and purified by reverse-phase flash chromatography (5% to 70% acetonitrile in water) to give 2-bromo-2,2-difluoro-N-(2,2',3',4',5',6,6'-heptafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1015, 1.5 g, 17% yield). (C 14 H 3 BrF 9 NO) [M-1] - MS(ESI) calculated for, 465.9; found, 465.8.

[0308] As shown in Scheme 12, Step 6, to a stirred solution of 2-bromo-2,2-difluoro-N-(2,2',3',4',5',6,6'-heptafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (1.0 g, 2.1 mmol) in DMF (10 mL) was added K 2 CO 3(591 mg, 4.27 mmol) was added portionwise at 20° C. The resulting mixture was stirred at 50° C. under nitrogen 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 flash chromatography (0% to 20% ethyl acetate in petroleum ether) to give 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 30, 590 mg, 71% yield) as a yellow solid. (C 14 H 2 F 9 NO 2 )[M-1] - MS(ESI) calculated for, 385.9; found, 385.9; 1 H-NMR (400MHz, DMSO-d 6 )δ12.53(s,1H),7.63(d,J=9.6Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-76.31,-116.25,-124.01,-139.00,-151.21,-161.25.

[0309] As shown in Scheme 12, Step 7, to a stirred solution of 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.13 mmol) in DMF (1 mL) was added propargyl bromide (17 mg, 0.14 mmol) and K 2 CO 3 (20 mg, 0.14 mmol) was added at 20° C. The resulting solution was stirred under nitrogen at 20° C. for 16 h and then purified by reverse phase preparative HPLC using the following conditions - column: Xselect CSH C18 OBD column 30×150 mm 5 μm; gradient: 60% to 72% acetonitrile / 0.1% aqueous formic acid to give 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 31, 28 mg, 51% yield) as a white solid. (C17 H 4 F 9 NO 2 GCMS calculated value for 425.0; measured value, 425.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.80(d,J=9.2Hz,1H),4.82(d,J=2.8Hz,2H),3.46(s,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-78.21,-112.89,-117.49,-138.75,-150.73,-161.14. Example 11. Preparation of 4-(3,3-difluoroallyl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 32) [ka]

[0310] As shown in Scheme 13, to a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 1.35 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 49 mg, 1.22 mmol) portionwise under nitrogen atmosphere at 0° C. The mixture was stirred at 0° C. for 30 min under nitrogen atmosphere, then 3-bromo-3,3-difluoroprop-1-ene (255 mg, 1.65 mmol) was added dropwise at 0° C. The mixture was warmed to room temperature, stirred under nitrogen 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 55% acetonitrile in water) to give 4-(3,3-difluoroallyl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 32, 200 mg, 40% yield) as a white solid. (C 17 H 5 F 10 NO 2GCMS calculated value for 445.0; measured value, 445.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.76(d,J=9.6Hz,1H),7.65(d,J=6.4Hz,1H),4.94-4.76(m,1H),4.72-4.63(m,2H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.97,-85.19,-115.92,-140.67,-153.18,-162.08. Example 12. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-phenethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 33) [ka]

[0311] As shown in Scheme 14, a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.54 mmol) and (2-bromoethyl)benzene (150 mg, 0.81 mmol) in acetonitrile (2 mL) was added with K 2 CO 3 (150 mg, 1.08 mmol) and NaI (41 mg, 0.27 mmol) were added at 20° C. The resulting solution was stirred at 80° C. for 16 h, 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 25% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-6-(perfluorophenyl)-4-phenethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 33, 200 mg, 74% yield) as a white solid. (C 22 H 11 F 8 NO 2 )[M+1] + MS(ESI) calculated for: 474.0; found: 474.0; 1H-NMR (400MHz, methanol-d 4 )δ7.37(m,2H),7.26-7.16(m,5H),4.33(t,J=7.2Hz,2H),3.03(t,J=7.2Hz,2H); 19 F-NMR (376MHz, methanol-d 4 )δ-79.18,-117.29,-142.37,-156.38,-164.90. Example 13. Preparation of 2,2,7-trifluoro-4-(2-methylbut-3-yn-2-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 34) and 2,2,7-trifluoro-4-(3-methylbut-1,2-dien-1-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 35) [ka]

[0312] As shown in Scheme 15, a stirred solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 0.81 mmol) and 2-methylbut-3-yn-2-ol (342 mg, 4.07 mmol) in tetrahydrofuran (4 mL) was treated with PPh at 23 °C under nitrogen. 3(1.1 g, 4.07 mmol) and DIAD (822 mg, 4.07 mmol) were added sequentially. The resulting solution was stirred at 80° C. under nitrogen for 16 hours, 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 reverse-phase flash chromatography (5%-65% acetonitrile / water) to give a mixture of compounds. The crude mixture was further purified by reverse phase preparative HPLC using the following conditions - column: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 μm; gradient: 80% to 90% MeOH / 0.1% formic acid in water to give 2,2,7-trifluoro-4-(2-methylbut-3-yn-2-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 34, 25.3 mg, 7% yield) as a yellow semi-solid. (C 19 H 9 F 8 NO 2 GCMS calculated value for 435.0; measured value, 435.1; 1 H-NMR (400MHz, DMSO-d 6 )δ8.02(d,J=6.8Hz,1H),7.79(d,J=9.2Hz,1H),3.89(s,1H),1.99(s,6H); 19 F-NMR (377MHz, DMSO-d 6 ) δ -78.25, -114.71, -140.13, 153.50, -162.20. The later eluted compound was 2,2,7-trifluoro-4-(3-methylbut-1,2-dien-1-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 35, 81.5 mg, 22% yield) recovered as a white semi-solid: (C 19 H 9 F 8 NO 2 GCMS calculated value for 435.0; measured value, 435.0; 1 H-NMR (400MHz, DMSO-d 6)δ7.78(d,J=9.6Hz,1H),7.68(d,J=6.4Hz,1H),6.48(s,1H),1.81(s,6H); 19 F-NMR (377MHz, DMSO-d 6 )δ-74.90,-115.58,-140.75,153.23,-162.07. Example 14. Preparation of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 36) and 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 37). [ka]

[0313] As shown in Scheme 16, Step 1, a mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (20.0 g, 80.0 mmol), 1,2,3,5-tetrafluorobenzene (36.0 g, 24.0 mmol), K 3 PO 4 A solution of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1016, 11.0 g, 38% yield) was stirred at 90°C for 16 hours under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by reverse phase flash column chromatography (5% to 52% acetonitrile / water) to give 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1016, 11.0 g, 38% yield) as a pale yellow solid. 13 H 6 F 5 NO 3 GCMS calculated value for: 319.0; measured value: 319.0.

[0314] As shown in Scheme 16, step 2, to a stirred mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1.0 g, 3.13 mmol) in DCM (10 mL) was added boron tribromide (3.9 g, 15.7 mmol) dropwise under nitrogen atmosphere at 0° C. The mixture was stirred at 0° C. for 3 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 to give 2,2',3',4',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1017, 790 mg, 74% yield) as a brown solid. (C 12 H 4 F 5 NO 3 )[M-1] - MS(ESI) calculated for: 304.0; found: 303.9.

[0315] As shown in step 3 of Scheme 16, sodium hyposulfite (2.0 g, 12.94 mmol) was added to a stirred solution of 2,2',3',4',6-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (790 mg, 2.58 mmol) in water (5 mL) and EtOH (5 mL). The resulting mixture was stirred at 100 °C for 2 h, cooled to room temperature, 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 purified by flash chromatography (0% to 25% ethyl acetate / petroleum ether) to give 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1018, 580 mg, 59% yield) as a yellow solid. (C 12 H 6 F 5 NO) [M-1] - MS(ESI) calculated for, 274.0; found, 274.0.

[0316] As shown in step 4 of scheme 16, to a solution of 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (580 mg, 2.10 mmol) and triethylamine (427 mg, 4.21 mmol) in EtOAc (5 mL) was added 2-bromo-2,2-difluoroethyl acetate (856 mg, 4.21 mmol). The resulting mixture was stirred at 80°C for 2 hours, cooled to room temperature, 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 to give 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1019, 800 mg, 75% yield) as a brown oil. (C 14 H 5 BrF 7 NO 2 )[M-1] - MS(ESI) calculated for, 429.9; found, 430.0.

[0317] As shown in Scheme 16, Step 5, 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (870 mg, 2.01 mmol) and K in DMF (10 mL) were added. 2 CO 3 A stirred solution of (417 mg, 3.02 mmol) was stirred at 50° C. for 2 h, cooled to room temperature, 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 purified by reverse-phase flash chromatography (5% to 80% acetonitrile / water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 36, 250 mg, 31% yield) as a brown solid. (C 14 H 4 F 7 NO 2 )[M-1] -MS(ESI) calculated for: 350.0; found: 350.2; 1 H-NMR (400MHz, DMSO-d 6 )δ12.14(s,1H),7.71-7.65(m,1H),7.62(d,J=9.6Hz,1H),7.20(d,J=6.4Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.34,-115.87,-116.95,-131.54,-134.11,-164.81.

[0318] As shown in Scheme 16, Step 6, 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.28 mmol) and K in DMF (1 mL) were added. 2 CO 3 (79 mg, 0.57 mmol) was added propargyl bromide (68 mg, 0.57 mmol). The resulting mixture was stirred at 25° C. for 16 h and then purified by reverse-phase flash chromatography (5% to 70% acetonitrile / water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 37, 47 mg, 42% yield) as a white solid. (C 17 H 6 F 7 NO 2 ) GCMS calculated value: 389.0, measured value: 389.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.82-7.70(m,3H),4.88(d,J=2.4Hz,2H),3.43(t,J=2.4Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.99,-115.19,-115.78,-131.27,-133.64,-164.84. Example 15. Preparation of 6-bromo-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 1024) [ka]

[0319] As shown in step 1 of Scheme 17, Zn powder (39.5 g, 0.6 mol) was added in portions to a solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (30.0 g, 0.12 mol) in MeOH (300 mL) and acetic acid (30 mL, 0.52 mol) at 0° C. The resulting solution was then stirred at 20° C. for 16 h, filtered, 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. The residue was purified by flash chromatography (0% to 50% ethyl acetate / petroleum ether) to give 5-bromo-4-fluoro-2-methoxyaniline (compound 1020, 27.0 g, 78% yield) as a yellow solid. (C 7 H 7 BrFNO) [M-1] - MS(ESI) calculated for, 218.0; found, 218.0.

[0320] As shown in Scheme 17, Step 2, a solution of 5-bromo-4-fluoro-2-methoxyaniline (27.0 g, 122.70 mmol) in DCM (270 mL) was treated with BBr 3 (154 g, 614 mmol) was added portionwise at 0° C. The resulting solution was stirred at 20° C. for 16 h, diluted by slow addition of ice / 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 60% ethyl acetate / petroleum ether) to give 2-amino-4-bromo-5-fluorophenol (compound 1021, 25.0 g, 89% yield) as a brown solid. (C 6 H 5 BrFNO) [M-1]- MS(ESI) calculated for: 204.0; found: 204.0.

[0321] As shown in Scheme 17, step 3, to a solution of 2-amino-4-bromo-5-fluorophenol (18.0 g, 87.4 mmol) and 2-bromo-2,2-difluoroethyl acetate (35.5 g, 175 mmol) in EtOAc (180 mL) was added triethylamine (17.6 g, 175 mmol) at 20° C. The resulting solution was stirred at 50° C. for 2 h, 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 40% ethyl acetate / petroleum ether) to give 2-bromo-N-(5-bromo-4-fluoro-2-hydroxyphenyl)-2,2-difluoroacetamide (compound 1022, 11.0 g, 31% yield) as a brown solid. (C 8 H 4 Br 2 F 3 NO 2 )[M-1] - MS(ESI) calculated for: 360.0; found: 360.0.

[0322] As shown in Scheme 17, Step 4, a solution of 2-bromo-N-(5-bromo-4-fluoro-2-hydroxyphenyl)-2,2-difluoroacetamide (7.0 g, 19.3 mmol) in DMF (70 mL) was treated with K 2 CO 3 (5.3 g, 38.6 mmol) was added at 20° C. The resulting solution was stirred at 50° C. for 16 h, 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 30% ethyl acetate / petroleum ether) to give 6-bromo-2,2,7-trifluoro-4H-1,4-benzoxazin-3-one (compound 1023, 4.0 g, 66% yield) as a brown solid. (C 8 H 3 BrF3 NO 2 )[M-1] - MS(ESI) calculated for, 280.0; found, 280.0.

[0323] As shown in Scheme 17, Step 5, a solution of 6-bromo-2,2,7-trifluoro-4H-1,4-benzoxazin-3-one (2.0 g, 7.09 mmol) in DMF (20 mL) was treated with p-methoxybenzyl chloride (1.6 g, 10.7 mmol) and K 2 CO 3 (1.9 g, 14.2 mmol) was added at 20° C. The resulting solution was stirred at 20° C. 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 flash column chromatography (0% to 30% ethyl acetate / petroleum ether) to give 6-bromo-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one (compound 1024, 2.5 g, 78% yield) as a yellow solid. (C 16 H 11 BrF 3 NO 3 ) GCMS calculated value: 401.0; measured value: 401.0. Example 16. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 38) [ka]

[0324] As shown in Scheme 18, Step 1, 2,3,4,6-tetrafluorophenylboronic acid (1.0 g, 5.15 mmol) in acetic acid (2 mL) and water (2 mL), H 2 O 2A mixture of (30%) (877 mg, 25.8 mmol) was stirred at 25° C. under nitrogen atmosphere for 16 hours, 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 to give 2,3,4,6-tetrafluorophenol (compound 1025, 800 mg) as a colorless oil. (C 6 H 2 F 4 O) [M-1] - MS(ESI) calculated for: 165.0; found: 165.0. This material was used as is in subsequent reactions.

[0325] As shown in Scheme 18, Step 2, 2,3,4,6-tetrafluorophenol (800 mg, 4.81 mmol) in DMF (4 mL), K 2 CO 3 To a stirred mixture of 1.0 g (7.23 mmol) of benzyl bromide (0.90 g, 5.63 mmol) was added dropwise at 25° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. under nitrogen for 16 h, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 78% acetonitrile / water) to give 2-(benzyloxy)-1,3,4,5-tetrafluorobenzene (compound 1026, 480 mg, 38% yield) as a colorless oil. (C 13 H 8 F 4 GCMS calculated for O: 256.1; found: 256.0.

[0326] As shown in Scheme 18, Step 3, 2-(benzyloxy)-1,3,4,5-tetrafluorobenzene (669 mg, 2.61 mmol), 6-bromo-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one (700 mg, 1.74 mmol) and K in dioxane (2 mL) were added. 2 CO 3(481 mg, 3.48 mmol) of bis(adamantan-1-yl)(butyl)phosphane (62 mg, 0.17 mmol) and chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II) (116 mg, 0.17 mmol) were added at 20 °C. The mixture was stirred under nitrogen at 110° C. for 16 hours, cooled to room temperature, and purified by flash chromatography (0% to 20% ethyl acetate / petroleum ether), then further purified by reverse-phase flash chromatography (5% to 84% acetonitrile / water) to give 6-[3-(benzyloxy)-2,4,5,6-tetrafluorophenyl]-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one (compound 1027, 400 mg, 39% yield) as a brown solid. (C 29 H 18 F 7 NO 4 ) GCMS calculated value: 577.1; measured value: 577.1.

[0327] As shown in step 4 of Scheme 18, to a stirred mixture of 6-[3-(benzyloxy)-2,4,5,6-tetrafluorophenyl]-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one (440 mg, 0.76 mmol) in methanol (10 mL) was added Pd / C (48.6 mg, 0.45 mmol) under a nitrogen atmosphere. The atmosphere was evacuated and filled with hydrogen three times, then stirred under hydrogen atmosphere at 25° C. for 2 h. After this time, the hydrogen atmosphere was removed, the mixture was filtered, and the filter cake was washed with MeOH. The filtrate was collected and concentrated under reduced pressure to give 2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one (compound 1028, 380 mg, 95% yield) as a brown solid. (C 22 H 12 F 7 NO 4 )[M-1] -MS(ESI) calculated for, 486.1; found, 485.9.

[0328] As shown in Scheme 18, Step 5, to a stirred mixture of 2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one (340 mg, 0.69 mmol) in DMF (3 mL) was added methyl iodide (119 mg, 0.84 mmol) and K 2 CO 3 (145 mg, 1.04 mmol) was added at 25° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. under nitrogen atmosphere for 2 hours, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5%-28% acetonitrile / water) to give 2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one (compound 1029, 300 mg, 85% yield) as a colorless oil. (C 23 H 14 F 7 NO 4 ) GCMS calculated value: 501.1; measured value: 501.1.

[0329] As shown in Scheme 18, Step 6, to a mixture of 2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one (300 mg, 0.59 mmol) in DCM (2 mL) was added trifluoromethanesulfonic acid (898 mg, 6.0 mmol) and TFA (682 mg, 6.0 mmol). The resulting mixture was stirred at 20° 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%-55% acetonitrile / water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-4H-1,4-benzoxazin-3-one (compound 1030, 200 mg, 83% yield) as a yellow oil. (C 15 H 6 F 7 NO 3 )[M-1] - MS(ESI) calculated for, 381.0; found, 381.0.

[0330] As shown in Scheme 18, Step 7, 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-4H-1,4-benzoxazin-3-one (180 mg, 0.47 mmol), propargyl bromide (84.2 mg, 0.71 mmol), and K were dissolved in DMF (1 mL). 2 CO 3 A mixture of (131 mg, 0.94 mmol) was stirred at 25° C. under nitrogen atmosphere for 2 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 64% acetonitrile / water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one (compound 38, 150 mg, 80% yield) as a yellow oil. (C18 H 8 F 7 NO 3 GCMS calculated value for 419.0; measured value, 419.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.7-7.71(m,2H),4.88(d,J=2.4Hz,2H),4.02(s,3H),3.44(s,1H); 19 F NMR (377MHz, DMSO-d 6 )δ-74.94,-115.60,-134.37,-142.53,-148.47,-163.57. Example 17. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 39) [ka]

[0331] As shown in Scheme 19, Step 1, to a stirred solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (10.0 g, 40.0 mmol) in dioxane (100 mL) was added 2,3,5,6-tetrafluoroanisole (10.8 g, 60.00 mmol), chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II) (1.3 g, 2.0 mmol), bis(adamantan-1-yl)(butyl)phosphane (0.70 g, 2.0 mmol), and K 2 CO 3(11.1 g, 80.0 mmol) was added. 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 10% ethyl acetate / petroleum ether) to give 2,2′,3,5,6-pentafluoro-4,4′-dimethoxy-5′-nitro-1,1′-biphenyl (compound 1031, 10.0 g, 72% yield) as a yellow solid. (C 14 H 8 F 5 NO 4 ) CGMS calculated value: 349.0; actual value: 349.0.

[0332] As shown in Scheme 19, Step 2, to a stirred solution of 2,2',3,5,6-pentafluoro-4,4'-dimethoxy-5'-nitro-1,1'-biphenyl (5.0 g, 14.3 mmol) in DCM (100 mL) was added BBr 3 (17.9 g, 71.6 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 20° C. under nitrogen atmosphere for 2 h, quenched with MeOH at 0° C., diluted with water, extracted with ethyl acetate, and the combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 5% MeOH / DCM) to give 2,2',3,5,6-pentafluoro-5'-nitro-[1,1'-biphenyl]-4,4'-diol (compound 1032, 4.0 g, 87% yield) as a yellow solid. (C 12 H 4 F 5 NO 4 )[M-1] - MS(ESI) calculated for: 320.0; found: 320.0.

[0333] As shown in step 3 of Scheme 19, to a stirred solution of 2,2',3,5,6-pentafluoro-5'-nitro-[1,1'-biphenyl]-4,4'-diol (4.5 g, 14.01 mmol) in MeOH (50 mL) was added Pd / C (450 mg, 4.23 mmol) under nitrogen atmosphere. The atmosphere was replaced with hydrogen and the resulting mixture was stirred at 20° C. for 2 h under hydrogen atmosphere. After removing the hydrogen atmosphere, the mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 5'-amino-2,2',3,5,6-pentafluoro-[1,1'-biphenyl]-4,4'-diol (compound 1033, 4.0 g, 98% yield) as a dark green solid. (C 12 H 6 F 5 NO 2 )[M-1] - MS(ESI) calculated for, 290.0; found, 290.0.

[0334] As shown in Scheme 19, Step 4, to a stirred solution of 5'-amino-2,2',3,5,6-pentafluoro-[1,1'-biphenyl]-4,4'-diol (4.0 g, 13.7 mmol) in MeOH (40 mL) was added 2-bromo-2,2-difluoroethyl acetate (8.4 g, 41.21 mmol) and triethylamine (4.2 g, 41.2 mmol). The resulting mixture was stirred at 50° C. for 16 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 7% MeOH / DCM) to give 2-bromo-2,2-difluoro-N-{2',3',5',6,6'-pentafluoro-4,4'-dihydroxy-[1,1'-biphenyl]-3-yl}acetamide (compound 1034, 3.3 g, 53% yield) as a yellow solid. (C 14 H 5 BrF 7 NO 3 )[M-1] - MS(ESI) calculated for: 446.0; found: 446.0.

[0335] As shown in Scheme 19, Step 5, to a stirred solution of 2-bromo-2,2-difluoro-N-{2',3',5',6,6'-pentafluoro-4,4'-dihydroxy-[1,1'-biphenyl]-3-yl}acetamide (3.3 g, 7.37 mmol) in DMF (20 mL) was added K 2 CO 3 (1.5 g, 11.05 mmol) was added. The resulting mixture was stirred at 50° C. under nitrogen atmosphere for 2 h, cooled to room temperature, 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 flash column chromatography (5% to 50% acetonitrile / water) to give 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-4H-1,4-benzoxazin-3-one (compound 1035, 1.5 g, 56% yield) as a yellow solid. (C 14 H 4 F 7 NO 3 )[M-1] - MS(ESI) calculated for: 366.0; found: 366.0.

[0336] As shown in step 6 of Scheme 19, to a stirred mixture of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-4H-1,4-benzoxazin-3-one (50 mg, 0.14 mmol) in DMF (2 mL) was added propargyl bromide (16.2 mg, 0.14 mmol) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 h under nitrogen atmosphere, diluted with water, and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 28% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one (compound 39, 26 mg, 51% yield) as an off-white solid. (C 17 H 6 F7 NO 3 )[M-1] - MS(ESI) calculated for: 404.0; found: 403.9; 1 H-NMR (400MHz, DMSO-d 6 )δ11.94(s,1H),7.74-7.68(m,2H),4.88(d,J=2.4Hz,2H),3.43(t,J=2.4Hz,1H). 19 F-NMR (377MHz, DMSO-d 6 ) δ -75.03, -115.61, -143.82, -161.43. Chromatographic purification also resulted in the isolation of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-(prop-2-yn-1-yloxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 67): (C 17 H 6 F 7 NO 3 )[M-1] - MS(ESI) calculated for 404.0, found 403.9; 1 H-NMR (400MHz, DMSO-d 6 )δ12.08(s,1H),7.67-7.64(m,1H),7.28-7.22(m,1H),5.08(s,2H),3.81(s,1H). 19 F-NMR (377MHz, DMSO-d 6 ) δ -75.23, -116.77, -142.59, -155.59 and 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(prop-2-yn-1-yloxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 68) (C 20 H 8 F 7 NO 3 ) GCMS calculated value: 443.0, measured value: 443.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.86-7.67(m,2H),5.10(s,2H),4.88(s,2H),3.81(s,1H),3.45(s,1H); 19F-NMR (376MHz, DMSO-d 6 )δ-74.86,-115.59,-141.92,-155.51. Example 18. Preparation of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 40) and 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 41) [ka]

[0337] As shown in Scheme 20, Step 1, dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane (Sphos, 990 mg, 2.40 mmol), Pd(OAc) in isopropyl acetate (20 mL) 2 (270 mg, 1.20 mmol), and K 2 CO 3 To a stirred mixture of 2,2',3,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1036, 1.5 g, 35% yield) was added 1,2,4,5-tetrafluorobenzene (3.6 g, 24.0 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min under nitrogen atmosphere and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3.0 g, 12.0 mmol) in isopropyl acetate (10 mL) was added dropwise over 0.5 h at 80 °C. The mixture was stirred at 80 °C for an additional 2 h, the volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (0% to 40% EtOAc / petroleum ether) to give 2,2',3,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1036, 1.5 g, 35% yield) as a purple solid. (C 13 H 6 F 5 NO 3 GCMS calculated value for 319.0; measured value, 319.0

[0338] As shown in Scheme 20, Step 2, to a mixture of 2,2',3,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1.5 g, 4.69 mmol) in DCM (15 mL) at -78 °C was added BBr 3 (5.8 g, 23.49 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 3 h under nitrogen atmosphere, diluted with water at room temperature, and then diluted with CH 2 Cl 2 The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure to approximately 20% volume, filtered again, and the filtrate was concentrated under reduced pressure to give 2,2',3',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1037, 1.3 g) as a brown solid. (C 12 H 4 F 5 NO 3 )[M-1] - MS(ESI) calculated for, 304.0; found, 304.0. This material was used in the subsequent step without further purification.

[0339] As shown in Scheme 20, Step 3, EtOH (10 mL) and H 2 To a stirred solution of 2,2',3',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (1.4 g, 4.58 mmol) in 2O (3 mL) was added sodium thiosulfate (3.9 g, 22.91 mmol) in portions. The resulting mixture was stirred at 100° C. for 1 h under nitrogen atmosphere, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5-amino-2,2',3',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1038, 1.2 g) as a yellow solid. (C 12 H 5 F 6 NO) [M-1] - MS(ESI) calculated for, 292.1; found, 292.1. This material was used as is in subsequent reactions.

[0340] As shown in Scheme 20, Step 4, to a solution of 5-amino-2,2',3',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (500 mg, 1.81 mmol) and triethylamine (184 mg, 1.81 mmol) in EtOAc (5 mL) was added 2-bromo-2,2-difluoroethyl acetate (369 mg, 1.81 mmol). The resulting mixture was stirred at 80° C. for 5 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 38% EtOAc / petroleum ether) to give 2-bromo-2,2-difluoro-N-(2',3',5',6,6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1039, 300 mg, 38% yield) as a brown solid. (C 14 H 5 BrF 7 NO 2 )[M+1] + MS(ESI) calculated for, 431.9; found, 431.9.

[0341] As shown in Scheme 20, Step 5, a solution of 2-bromo-2,2-difluoro-N-[2',3',5',6,6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl]acetamide (500 mg, 1.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 178 mg, 1.16 mmol) in toluene (5 ml) was stirred at 80° C. for 2 hours 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 30% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 40, 230 mg, 55% yield) as a brown solid. (C 14 H 4 F 7NO 2 )[M-1] - MS(ESI) calculated for: 350.0; found: 350.0; 1 H-NMR (400MHz, DMSO-d 6 )δ12.20(s,1H),8.07(m,1H),7.70-7.62(m,1H),7.24(d,J=6.4Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.21,-116.80,-138.87,-141.58.

[0342] As shown in Scheme 20, Step 6, 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-4H-1,4-benzoxazin-3-one (50 mg, 0.14 mmol) and K in DMF (1 mL) were added. 2 CO 3 To a solution of (22 mg, 0.15 mmol) was added propargyl bromide (19 mg, 0.15 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 h and then purified by reverse phase HPLC (53%-68% acetonitrile / 10 mM NH 4 HCO 3 aqueous solution) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 41, 42.1 mg, 75% yield) as a yellow oil. 17 H 6 F 7 NO 2 ) GCMS calculated value: 389.0; measured value: 389.0; 1 H-NMR (400MHz, DMSO-d 6 )δ8.18-8.05(m,1H),7.83-7.74(m,2H),4.87(d,J=2.4Hz,2H),3.45(t,J=2.4Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.83,-115.67,-138.83,-141.01. Example 19. Preparation of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 42) and 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 43) [ka]

[0343] As shown in Scheme 21, Step 1, to a stirred mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1.0 g, 3.13 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 6.27 mmol, 1 M in THF) dropwise under nitrogen atmosphere at -78°C. The resulting mixture was stirred at -78°C for 30 minutes and methyl iodide (0.7 g, 4.70 mmol) was added under nitrogen atmosphere at -78°C. The mixture was stirred under nitrogen atmosphere at -78°C for 4 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 50% ethyl acetate / petroleum ether) to give 2,2',3,4,6-pentafluoro-4'-methoxy-5-methyl-5'-nitro-1,1'-biphenyl (compound 1040, 800 mg, 77% yield) as a yellow solid. (C 14 H 8 F 5 NO 3 ) GCMS calculated value: 333.0; measured value: 333.0.

[0344] As shown in step 2 of Scheme 21, to a stirred mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5-methyl-5'-nitro-1,1'-biphenyl (800 mg, 2.40 mmol) in DCM (20 mL) was added boron tribromide (3.7 g, 12.00 mmol) dropwise under nitrogen atmosphere at 0°C. The resulting mixture was stirred at 0°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 flash chromatography (0% to 50% ethyl acetate / petroleum ether) to give methyl 2-(6-amino-2,2,7-trifluoro-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 1041, 710.0 mg, 93% yield) as a yellow oil. (C 13 H 6 F 5 NO 3 )[M-1] - MS(ESI) calculated for, 318.0; found, 318.0.

[0345] As shown in Scheme 21, Step 3, to a stirred mixture of 2,2',3',4',6'-pentafluoro-5'-methyl-5-nitro-[1,1'-biphenyl]-4-ol (710 mg, 2.22 mmol) in acetic acid (0.2 mL) and MeOH (20 mL) was added zinc powder (727 mg, 11.1 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 h, filtered, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with NaHCO 3 The extract was washed with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 50% ethyl acetate / petroleum ether) to give 5-amino-2,2',3',4',6'-pentafluoro-5'-methyl-[1,1'-biphenyl]-4-ol (compound 1042, 560 mg, 87% yield) as a brown solid. (C 13 H 8 F 5 NO) [M-1] - MS(ESI) calculated for, 288.0; found, 288.0.

[0346] As shown in Scheme 21, Step 4, to a stirred mixture of 5-amino-2,2',3',4',6'-pentafluoro-5'-methyl-[1,1'-biphenyl]-4-ol (600 mg, 2.08 mmol) in ethyl acetate (15 mL) was added 2-bromo-2,2-difluoroethyl acetate (632 mg, 3.11 mmol) and triethylamine (420 mg, 4.15 mmol). The resulting mixture was stirred at 50° C. for 16 h under a 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 50% ethyl acetate / petroleum ether) to give 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-5'-methyl-[1,1'-biphenyl]-3-yl)acetamide (compound 1043, 550 mg, 59% yield) as a brown solid. (C 15 H 7 BrF 7 NO 2 )[M-1] - MS(ESI) calculated for, 444.0; found, 444.0.

[0347] As shown in Scheme 21, Step 5, to a stirred mixture of 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-5'-methyl-[1,1'-biphenyl]-3-yl)acetamide (550 mg, 1.23 mmol) in DMF (10 mL) was added K 2 CO 3(511 mg, 3.70 mmol) was added. The resulting mixture was stirred at 80° C. for 2 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 50% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 42, 360 mg, 80% yield) as a brown solid. (C 15 H 6 F 7 NO 2 )[M-1] - MS(ESI) calculated for: 364.0; found: 364.0; 1 H-NMR (400MHz, DMSO-d 6 )δ12.17(s,1H),7.64(d,J=9.6Hz,1H),7.18(d,J=6.4Hz,1H),2.24(s,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.25,-116.88,-120.24,-135.31,-138.86,-165.49.

[0348] As shown in Scheme 21, Step 6, to a stirred solution of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (180.0 mg, 0.49 mmol) in DMF (6 mL) was added propargyl bromide (70.4 mg, 0.59 mmol) and K 2 CO 3(204.4 mg, 1.48 mmol) was added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 50% acetonitrile / water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 43, 148.0 mg, 75% yield) as a colorless oil. (C 18 H 8 F 7 NO 2 GCMS calculated value for 403.0; measured value, 403.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.77-7.69(m,2H),4.88(s,2H),3.45-3.43(m,1H),2.28-2.23(m,3H); 19 F-NMR (400 MHz, DMSO-d 6 )δ-74.98,-115.72,-119.75,-134.88,-138.34,-165.51. Example 20. Preparation of 4-benzyl-2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 44) [ka]

[0349] As shown in Scheme 22, 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.14 mmol) and K in DMF (1 mL) were added. 2 CO 3To a mixture of (39 mg, 0.28 mmol) was added benzyl bromide (29 mg, 0.17 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 h and then purified by reverse phase HPLC (60%-72% acetonitrile / 10 mM NH 4 HCO 3 aqueous solution) to give 4-benzyl-2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 44, 43 mg, 68% yield) as a white solid. 21 H 10 F 7 NO 2 GCMS calculated value for 441.1; measured value, 441.1; 1 H-NMR (400MHz, DMSO-d 6 )δ8.07(m,1H),7.78-7.75(m,1H),7.73-7.68(m,1H),7.39-7.26(m,5H),5.28(s,2H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.87,-115.89,-138.90,-141.20. Example 21. Preparation of 2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 45) and 2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 46) [ka]

[0350] As shown in Scheme 23, Step 1, a degassed mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (3.0 g, 9.40 mmol) in DMF (30 mL) was treated with CuCl under an oxygen atmosphere. 2(0.6 g, 4.70 mmol) and t-BuOLi (1.5 g, 18.80 mmol) were added. The mixture was stirred at 37° C. for 24 hours at 37° C. for 24 hours. 2 The mixture was stirred at room temperature under atmospheric pressure for 16 hours, diluted with water, acidified to pH 2-4 with formic acid, 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 reverse-phase flash chromatography (30%-50% acetonitrile / water) to give 2,2',4,5,6-pentafluoro-4'-methoxy-5'-nitro-[1,1'-biphenyl]-3-ol (compound 1044, 850 mg, 25% yield) as a yellow solid; (C 13 H 6 F 5 NO 4 )[M-1] - MS(ESI) calculated for: 334.0; found: 334.0.

[0351] As shown in Scheme 23, step 2, to a solution of 2,2',4,5,6-pentafluoro-4'-methoxy-5'-nitro-[1,1'-biphenyl]-3-ol (850 mg, 2.54 mmol) in DCM (10 mL) was added boron tribromide (3.2 g, 12.7 mmol) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 3 h under nitrogen atmosphere, warmed to room temperature, and then stirred for an additional 2 h. The mixture 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 2,2',4,5,6-pentafluoro-5'-nitro-[1,1'-biphenyl]-3,4'-diol (compound 1045, 850 mg, 78% yield) as a yellow solid. (C 12 H 4 F 5 NO 4 )[M-1] - MS(ESI) calculated for, 320.0; found, 319.8.

[0352] As shown in Scheme 23, Step 3, ethanol (9 mL) and H 2To a solution of 2,2',4,5,6-pentafluoro-5'-nitro-[1,1'-biphenyl]-3,4'-diol (850 mg, 2.70 mmol) in 2O (3 mL) was added sodium hyposulfite (2.4 g, 14.01 mmol). The resulting mixture was stirred at 100°C for 2 h, 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, and concentrated under reduced pressure to give 5'-amino-2,2',4,5,6-pentafluoro-[1,1'-biphenyl]-3,4'-diol (compound 1046, 850 mg) as a yellow solid. (C 12 H 6 F 5 NO 2 )[M-1] - MS(ESI) calculated for, 290.0; found, 289.9. This material was used as is in subsequent reactions.

[0353] As shown in Scheme 23, Step 4, to a mixture of 5'-amino-2,2',4,5,6-pentafluoro-[1,1'-biphenyl]-3,4'-diol (850 mg, 2.92 mmol) in ethyl acetate (10 mL) was added triethylamine (325 mg, 3.21 mmol) and ethyl 2-bromo-2,2-difluoroacetate (652 mg, 3.21 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 50° C. under nitrogen for 3 h, 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, and concentrated under reduced pressure to give 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4,5'-dihydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1047, 950 mg, crude) as a yellow oil. (C 14 H 5 BrF 7 NO 3 )[M-1] - MS(ESI) calculated for, 445.9; found, 445.9.

[0354] As shown in Scheme 23, Step 5, a mixture of 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4,5'-dihydroxy-[1,1'-biphenyl]-3-yl)acetamide (950 mg, 2.12 mmol) in DMF (10 mL) was treated with K 2 CO 3 (879 mg, 6.36 mmol) was added. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere, cooled to room temperature, diluted with water, acidified to pH 1-3 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 flash chromatography (20%-60% acetonitrile / water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1048, 150 mg, 19% yield) as a brown-yellow solid. (C 14 H 4 F 7 NO 3 )[M-1] - MS(ESI) calculated for: 366.0; found: 366.0; 1 H-NMR (400MHz, DMSO-d 6 )δ12.14(s,1H),11.03(s,1H),7.63(d,J=9.6Hz,1H),7.17(d,J=6.8Hz,1H); 19 F-NMR (376MHz, DMSO-d6) δ -75.27, -116.82, -138.63, -150.19, -152.90, -165.02.

[0355] As shown in Scheme 23, Step 6, to a solution of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.41 mmol) and triethylamine (54 mg, 0.53 mmol) in DCM (1 mL), MeOH (0.1 mL) and acetonitrile (1 mL) was added trimethylsilyldiazomethane (0.49 mL, 2 M in hexanes) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (20% to 40% acetonitrile / water) to give 2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 45, 31 mg, 20% yield) as a yellow oil. (C 16 H 8 F 7 NO 3 ) GCMS calculated value: 395.0; measured value: 395.1; 1 H-NMR (400MHz, DMSO-d 6 ) δ 7.85-7.65 (m, 2H), 4.02 (s, 3H), 3.42 (s, 3H). Also isolated was 2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 46, 6.7 mg, 4%) as a yellow oil: (C 15 H 6 F 7 NO 3 ) GCMS calculated value: 380.0; measured value: 379.9; 1 H-NMR (300MHz, DMSO-d 6 )δ7.79-7.66(m,2H),3.63(s,3H). Example 22. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 47) [ka]

[0356] As shown in Scheme 24, step 1, to a stirred mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1.0 g, 3.13 mmol) in DMF (10 mL) was added t-BuOLi (0.30 g, 3.76 mmol) and iodine (0.80 g, 3.13 mmol). The mixture was stirred at 80° C. for 2 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 reverse-phase flash chromatography (0% to 70% acetonitrile / water) to give 2,2',3,4,6-pentafluoro-5-iodo-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1049, 660 mg, 47% yield) as a yellow solid. (C 13 H 5 F 5 INO 3 ) GCMS calculated value: 444.9; measured value: 444.9.

[0357] As shown in Scheme 24, step 2, to a stirred mixture of 2,2',3,4,6-pentafluoro-5-iodo-4'-methoxy-5'-nitro-1,1'-biphenyl (660 mg, 1.48 mmol) in DCM (15 mL) was added boron tribromide (1.8 g, 7.41 mmol) dropwise under nitrogen atmosphere at 0°C. The resulting mixture was stirred at 0°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 flash chromatography (0% to 15% ethyl acetate / petroleum ether) to give 2,2',3',4',6'-pentafluoro-5'-iodo-5-nitro-[1,1'-biphenyl]-4-ol (compound 1050, 580 mg, 90% yield) as a brown oil. (C 12 H 3 F 5 INO 3 )[M-1] -MS(ESI) calculated for, 430.0; found, 430.0.

[0358] As shown in Scheme 24, Step 3, to a stirred mixture of 2,2',3',4',6'-pentafluoro-5'-iodo-5-nitro-[1,1'-biphenyl]-4-ol (580 mg, 1.32 mmol) in EtOAc (20 mL) was added SnCl 2 (1.3 g, 7.14 mmol) was added. The mixture was stirred at 70° C. for 2 h under nitrogen atmosphere, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with 1 M HCl and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 35% ethyl acetate / petroleum ether) to give 5-amino-2,2′,3′,4′,6′-pentafluoro-5′-iodo-[1,1′-biphenyl]-4-ol (compound 1051, 330 mg, 56% yield) as a yellow solid. (C 12 H 5 F 5 INO) [M-1] - MS(ESI) calculated for, 400.0; found, 400.0.

[0359] As shown in Scheme 24, Step 4, to a stirred mixture of 5-amino-2,2',3',4',6'-pentafluoro-5'-iodo-[1,1'-biphenyl]-4-ol (280 mg, 0.69 mmol) in THF (10 mL) was added bromodifluoroacetyl chloride (203 mg, 1.04 mmol) and triethylamine (141 mg, 1.39 mmol). The mixture was stirred at 100° C. under nitrogen atmosphere for 1 h, 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 column chromatography (0% to 35% ethyl acetate / petroleum ether) to give 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-5'-iodo-[1,1'-biphenyl]-3-yl)acetamide (compound 1052, 340 mg, 87% yield) as a yellow solid. (C 14 H 4 BrF 7 INO 2 )[M-1] - MS(ESI) calculated for: 556.0; found: 556.0.

[0360] As shown in Scheme 24, Step 5, to a stirred mixture of 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-5'-iodo-[1,1'-biphenyl]-3-yl)acetamide (310 mg, 0.56 mmol) in DMF (10 mL) was added K 2 CO 3 (230 mg, 1.66 mmol) was added. The mixture was stirred at 80° C. for 2 h, 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 column chromatography (0% to 35% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-iodophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1053, 200 mg, 75% yield) as a yellow oil. (C14 H 3 F 7 INO 2 )[M-1] - MS(ESI) calculated for, 476.0; found, 476.0.

[0361] As shown in Scheme 24, Step 6, dioxane (5 mL) and H 2 To a stirred mixture of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-iodophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.21 mmol) in 2O (0.5 mL) was added 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39 mg, 0.25 mmol), Pd(dppf)Cl 2 (15 mg, 0.02 mmol) and K 3 PO 4 (133 mg, 0.63 mmol) was added. The mixture was stirred at 80° 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 preparative-TLC (1:5 EtOAc / petroleum ether) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1054, 70 mg, 88% yield) as a yellow oil. (C 16 H 6 F 7 NO 2 )[M-1] - MS(ESI) calculated for, 376.0; found, 376.0.

[0362] As shown in Scheme 24, Step 7, to a stirred solution of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg, 0.16 mmol) in DMF (3 mL) was added propargyl bromide (23 mg, 0.19 mmol) and K 2 CO 3(66 mg, 0.48 mmol) was added. The resulting mixture was stirred at room temperature 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 flash column chromatography (0% to 15% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 47, 37 mg, 56% yield) as a light oil. (C 19 H 8 F 7 NO 2 GCMS calculated value for 415.0; measured value, 415.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.76-7.74(m,2H),6.78-6.66(m,1H),6.05(d,J=17.6Hz,1H),5.81(d,J=11.6Hz,1H),4.87(s,2H),3.44(s,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.96,-115.67,-119.12,-135.03,-135.41,-164.64. Example 23. Preparation of 6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 48) [ka]

[0363] As shown in Scheme 25, step 1, to a stirred mixture of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.21 mmol) in MeOH (2 mL) and THF (2 mL) was added Pd / C (10%, 20 mg) under nitrogen. The atmosphere was replaced with hydrogen and the mixture was stirred at room temperature for 4 h. After removing the hydrogen atmosphere, the solids were filtered off through a Celite pad, the filtrate was collected and the volatiles were removed under reduced pressure to give 6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1055, 50 mg, 60% yield) as a brown oil. (C 16 H 8 F 7 NO 2 )[M-1] - MS(ESI) calculated for, 378.0; found, 378.0.

[0364] As shown in Scheme 25, Step 2, to a stirred solution of 6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.13 mmol) in DMF (2 mL) was added propargyl bromide (19 mg, 0.15 mmol) and K. 2 CO 3 (55 mg, 0.39 mmol) was added. The resulting mixture was stirred at 25° C. under nitrogen atmosphere for 2 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash column chromatography (20% to 70% acetonitrile / water) to give 6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 48, 13 mg, 24% yield) as a colorless oil. (C 19 H 10 F 7 NO 2GCMS calculated value for 417.1; measured value, 417.0; 1 H-NMR (400MHz, methanol-d 4 )δ7.59-7.57(m,1H),7.40-7.36(m,1H),4.91~4.89(m,2H),2.87(s,1H),2.88-2.77(m,2H),1.29-1.24(m,3H); 19 F-NMR (376MHz, methanol-d 4 )δ-78.88,-116.82,-123.84,-139.44,-139.86,-167.94. Example 24. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylthio)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 49) [ka]

[0365] As shown in Scheme 26, to a stirred solution of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.49 mmol) in dioxane (3 mL) was added sodium thiomethoxide (34.0 mg, 0.49 mmol). The resulting mixture was stirred at 20° 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 flash chromatography (0% to 10% ethyl acetate / petroleum ether) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylthio)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 49, 40 mg, 19% yield) as a white solid. (C 18 H 8 F 7 NO 2 GCMS calculated value for S: 435.0; found value: 434.9; 1H-NMR (400 MHz, chloroform-d) δ 7.32 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.82 (d, J = 2.4 Hz, 2H), 2.62 (s, 3H), 2.39 (s, 1H); 19 F-NMR (376 MHz, chloroform-d) δ -77.00, -113.18, -134.54, -140.64. Example 25. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 50) [ka]

[0366] As shown in Scheme 27, to a stirred solution of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.12 mmol) in DMF (2 mL) was added methyl iodide (21 mg, 0.15 mmol) and K 2 CO 3 (26 mg, 0.18 mmol) was added. The mixture was stirred at room temperature 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, purified by preparative-TLC (25% EtOAc / petroleum ether) and further purified by reverse-phase flash chromatography using (5% to 60% acetonitrile in water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 50) (13 mg, 25% yield) as a white solid. (C 18 H 8 F 7 NO 3 )[M+1] + MS(ESI) calculated for, 420.0; found 420.0;1 H-NMR (400MHz, DMSO-d 6 )δ7.87-7.64(m,2H),4.88(s,2H),4.15(s,3H),3.38(s,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.92,-115.62,-142.27,-157.65. Example 26. Preparation of 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 51) [ka]

[0367] As shown in Scheme 28, Step 1, a solution of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1.0 g, 2.72 mmol) in DMF (10 mL) was treated with K 2 CO 3 (1.1 g, 8.16 mmol) and 4-methoxybenzyl chloride (1.0 g, 6.8 mmol) were added. The mixture was stirred at 20° C. under nitrogen atmosphere for 2 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-(((4-methoxybenzyl)oxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1056, 804 mg, 48% yield) as a white solid. (C 30 H 20 F 7 NO 5 )[M-1] - MS(ESI) calculated for, 606.0; found 606.2.

[0368] As shown in Scheme 15, step 2, to a solution of 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-((4-methoxybenzyl)oxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (804 mg, 1.41 mmol) in methanol (10 mL) was added Pd / C (161 mg, 20 wt / wt%) under nitrogen atmosphere. The atmosphere was replaced with hydrogen gas and the mixture was stirred under hydrogen at 20° C. for 2 h. The hydrogen was removed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1057, 750 mg, crude) as a yellow solid. (C 22 H 12 F 7 NO 4 )[M-1] - MS(ESI) calculated for: 486.0; found: 486.1

[0369] As shown in Scheme 15, Step 3, a solution of 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.44 mmol) in DMF (3 mL) was treated with iodoethane (84 mg, 0.53 mmol) and K 2 CO 3 (93 mg, 0.66 mmol) was added. The mixture was stirred at 20° C. under nitrogen atmosphere for 1 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 50% ethyl acetate in petroleum ether) to give 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1058.160 mg, 97% yield) as a yellow solid. (C 24 H16 F 7 NO 4 )[M-1] - MS(ESI) calculated for, 514.1; found 514.0.

[0370] As shown in Scheme 15, Step 4, to a solution of 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.29 mmol) in DCM (2 mL) was added trifluoroacetic acid (332 mg, 2.91 mmol) and trifluoromethanesulfonic acid (437 mg, 2.91 mmol). The mixture was stirred under nitrogen atmosphere at 20° C. for 1 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 70% ethyl acetate in petroleum ether) to give 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1059, 70 mg, 60% yield) as a yellow oil. (C 16 H 8 F 7 NO 3 )[M-1] - MS(ESI) calculated for, 394.0; found 394.0.

[0371] As shown in Scheme 15, Step 5, a solution of 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (68 mg, 0.17 mmol) in DMF (2 mL) was treated with K 2 CO 3(48 mg, 0.34 mmol) and propargyl bromide (31 mg, 0.25 mmol) were added. The mixture was stirred at 20° 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 70% acetonitrile in water) to give 6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 51, 59 mg, 78% yield) as a white solid. (C 19 H 10 F 7 NO 3 GCMS calculated value for 433.0; measured value, 433.1; 1 H-NMR (400MHz, DMSO-d 6 )δ7.80-7.72(m,2H),4.88(d,J=2.4Hz,2H),4.40(q,J=7.2Hz,2H),3.45(s,1H),1.39(t,J=7.2Hz,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.88,-115.55,-142.21,-156.98. Example 27. Preparation of 7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 52) [ka]

[0372] As shown in Scheme 29, Step 1, DME (1.5 mL) and H 2 A solution of 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (250 mg, 0.91 mmol) in 2HO (1.5 mL) was added to NaHCO at room temperature under a nitrogen atmosphere. 3(229 mg, 2.73 mmol) was added followed by dropwise addition of chloroacetyl chloride (154 mg, 1.36 mmol) at 0° C. The reaction was stirred at room temperature for 3 h and concentrated under reduced pressure to give 2-chloro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide (compound 1060, 250 mg, crude) as a brown solid. (C 14 H 7 ClF 5 NO 2 )[M-1] - MS(ESI) calculated for: 350.0; found: 350.0. This material was used as is in subsequent reactions.

[0373] As shown in Scheme 29, Step 2, 2-chloro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (250 mg, 0.71 mmol) and K in DMF (3 mL) were added. 2 CO 3 A mixture of (198 mg, 1.42 mmol) was stirred at 50° C. for 1 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 7-fluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1061, 210 mg, 94% yield) as a yellow solid. (C 14 H 6 F 5 NO 2 )[M-1] - MS(ESI) calculated for: 314.0; found: 314.0.

[0374] As shown in Scheme 29, Step 3, 7-fluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.16 mmol) and K in DMF (1 mL) were added. 2CO 3 To a stirred mixture of 5-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 52, 27 mg, 48% yield) was added propargyl bromide (23 mg, 0.19 mmol). The mixture was stirred at room temperature under nitrogen for 2 h and then purified by reverse-phase flash chromatography (5% to 65% acetonitrile in water) to give 7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 52, 27 mg, 48% yield) as a white solid. (C 17 H 8 F 5 NO 2 )[M+1] + MS(ESI) calculated for: 354.0; found: 354.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.77-7.67(m,1H),7.40(d,J=6.8Hz,1H),7.23(d,J=9.6Hz,1H),4.84(d,J=1.2Hz,2H),4.75(d,J=2.4Hz,2H),3.33(s,1H); 19 F-NMR (377MHz, DMSO-d6) δ -115.26, -118.50, -132.08, -133.75, -165.01. Example 28. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 53) [ka]

[0375] As shown in Scheme 30, Step 1, a degassed solution of 6-bromo-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300.0 mg, 0.74 mmol) in toluene (5 mL) and water (1 mL) was added at 20 °C with 2,3,4,5-tetrafluorophenylboronic acid (434 mg, 2.23 mmol), XPhos Pd G3 (126 mg, 0.14 mmol), XPhos (71 mg, 0.14 mmol), Ag 2 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1062, 20 mg, 5% yield) was added as a yellow solid. (C 22 H 12 F 7 NO 3 ) GCMS calculated value 471.0, found value 471.0; 1 H-NMR (400MHz, methanol-d4) δ 7.31-7.28 (m, 2H), 7.29-7.19 (m, 2H), 7.18-7.06 (m, 1H), 6.95-6.83 (m, 2H), 5.26 (s, 2H), 3.76 (s, 3H); 19 F-NMR (376MHz, methanol-d 4 )δ-78.77,-78.85,-118.25,-141.39,-141.46,-158.09.

[0376] As shown in Scheme 30, Step 2, a solution of 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.11 mmol) in DCM (2.5 mL) was treated with TFA (121 mg, 1.06 mmol) and CF 3 SO 3 H (159 mg, 1.06 mmol) was added. The resulting mixture was stirred at 20° C. for 2 h, after which the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (0% to 26% ethyl acetate in petroleum ether) and further purified by preparative HPLC using the following conditions - column: XSelect CSH C18 OBD column 30×150 mm 5 μm; mobile phase A: ACN, mobile phase B: water (0.1% formic acid); flow rate: 60 mL / min, gradient: 53% B to 63% B in 10 min, then 63% B, to give 2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1063, 11 mg, 28% yield) as an off-white solid. (C 14 H 4 F 7 NO 2 )[M-1] - MS(ESI) calculated for 350.0, found 349.9; 1 H-NMR (400MHz, DMSO-d 6 )δ7.71-7.56(m,2H),7.14(d,J=6.9Hz,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.54,-118.23,-139.87,-140.13,-155.38,-155.84.

[0377] As shown in Scheme 30, Step 3, a solution of 2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (70 mg, 0.20 mmol) in DMF (2 mL) was treated with propargyl bromide (36 mg, 0.30 mmol) and K 2 CO3 (55 mg, 0.39 mmol) was added. The resulting mixture was stirred at 20° C. for 16 h and then purified by reverse-phase flash chromatography (5% to 60% acetonitrile in water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 53, 33 mg, 41% yield) as a colorless oil. (C 17 H 6 F 7 NO 2 ) CGMS calculated value 389.0, actual value 389.1; 1 H-NMR (400MHz, CD 3 OD) δ7.61-7.55(m,1H),7.44-7.33(m,2H),4.93(s,2H),3.32(s,1H); 19 F-NMR (376MHz, CD 3 OD) δ-78.93,-117.98,-141.37,-141.54,-157.99,-158.37. Example 29. Preparation of 7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 54) [ka]

[0378] As shown in Scheme 31, Step 1, a mixture of 1,2,3,4-tetrafluorobenzene (3 equiv.), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 equiv.), Pd(OAc 2 ) (0.1 equivalents), di-tert-butylmethylphosphine (0.1 equivalents), and K 2 CO 3(1 equiv.) is heated to 90° C. for 16 h, cooled to room temperature, diluted with water, and extracted with EtOAc. The combined extracts are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by reverse-phase flash chromatography to give 2,2′,3,4,5-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (compound 1064).

[0379] As shown in step 2 of scheme 31, to a stirred mixture of 2,2',3,4,5-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1 eq) in DCM, boron tribromide (5 eq) is added dropwise at 0°C under nitrogen atmosphere. The mixture is stirred at 0°C for 3 hours, diluted with water and extracted with dichloromethane. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,2',3',4',5'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1065).

[0380] As shown in step 3 of scheme 31, to a stirred solution of 2,2',3',4',5'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (1 eq.) in 1:1 water / EtOH is added sodium thiosulfate (5 eq.). The resulting mixture is stirred at 100°C for 2 hours, cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography to give 5-amino-2,2',3',4',5'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1066).

[0381] As shown in Scheme 31, Step 4, 1:1 DME / H 2 A solution of 5-amino-2,2',3',4',5'-pentafluoro-[1,1'-biphenyl]-4-ol (1 equiv.) in 20O was diluted with NaHCO at room temperature under a nitrogen atmosphere. 3(3 eq.) is added followed by dropwise addition of chloroacetyl chloride (1.5 eq.) at 0° C. The reaction is stirred at room temperature for 3 hours and concentrated under reduced pressure to give 2-chloro-N-(2′,3′,4′,5′,6-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide (compound 1067).

[0382] As shown in Scheme 31, Step 5, 2-chloro-N-(2',3',4',5',6-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (1 equivalent) and K in DMF (3 mL) were added. 2 CO 3 The mixture of (2 equiv.) is stirred at 50° C. under nitrogen for 1 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography to give 7-fluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1068).

[0383] As shown in Scheme 31, Step 6, 7-fluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1 equivalent) in DMF and K 2 CO 3 (1.5 eq.) is added to a stirred mixture of propargyl bromide (1.2 eq.). The mixture is stirred at room temperature under a nitrogen atmosphere for 2 hours and then purified by reverse phase flash chromatography to give 7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 54). Example 30. Preparation of 2,2-dichloro-7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 55) [ka]

[0384] As shown in Scheme 32, Step 1, chlorine gas (approximately 2 equivalents) is added to PCl 3 Introduce into a stirred suspension of 7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1 eq.) in 2,2-dichloro-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (6 eq.). After 2 hours at room temperature, remove volatiles via distillation at atmospheric pressure to obtain 2,2-dichloro-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1069).

[0385] As shown in Scheme 32, Step 2, a solution of 2,2-dichloro-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (1 equiv.) in DMF was heated under nitrogen at room temperature with K 2 CO 3 (1.05 equiv.) and 3-bromoprop-1-yne (1.05 equiv.). The mixture is stirred at room temperature for 8 hours, diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative reverse phase HPLC to give 2,2-dichloro-7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 55). Example 31. Preparation of 7-chloro-2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 56) [ka]

[0386] As shown in Scheme 33, Step 1, n-BuLi (2.5 M in hexanes, 1.1 eq) is added dropwise at −78° C. to a stirred solution of 1-bromo-2-chloro-4-methoxybenzene (1 eq) in anhydrous THF (200 mL) under nitrogen atmosphere. After the addition is complete, stirring is continued at −78° C. for 15 min, and hexafluorobenzene (1.5 eq) is added dropwise at −78° C. The resulting mixture is heated to room temperature, stirred under nitrogen for 2 h, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography to give 2′-chloro-2,3,4,5,6-pentafluoro-4′-methoxy-1,1′-biphenyl (compound 1070).

[0387] As shown in Scheme 33, Step 2, a solution of 2'-chloro-2,3,4,5,6-pentafluoro-4'-methoxy-1,1'-biphenyl in nitric acid is stirred at 50°C for 4 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography to give 2'-chloro-2,3,4,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (Compound 1071).

[0388] As shown in Scheme 33, Step 3, a solution of 5-bromo-4-chloro-2-methoxyaniline (1 equiv.) in DCM is treated with BBr 3 (5 equiv.) is added portionwise at 0° C. The resulting solution is stirred at 20° C. for 16 h, diluted by slow addition of ice / water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography to give 2-chloro-2′,3′,4′,5′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (compound 1072).

[0389] As shown in Scheme 33, step 4, to a solution of 2-chloro-2',3',4',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (1 eq.) in MeOH and acetic acid (4 eq.) is added Zn powder (5 eq.) portionwise at 0° C. The resulting solution is stirred at 20° C. for 16 hours, filtered, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography to give 5-amino-2-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1073).

[0390] As shown in Scheme 33, step 5, to a solution of 5-amino-2-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (1 eq.) and 2-bromo-2,2-difluoroethyl acetate (2 eq.) in MeOH (180 mL) is added triethylamine (2 eq.) at 20° C. The resulting solution is stirred at 50° C. for 2 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 40% ethyl acetate / petroleum ether) to give 2-bromo-N-(6-chloro-2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-2,2-difluoroacetamide (compound 1074).

[0391] As shown in Scheme 33, Step 6, a solution of 2-bromo-N-(6-chloro-2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-2,2-difluoroacetamide (1 equivalent) in DMF is treated with K 2 CO 3(2 equiv.) is added at 20° C. The resulting solution is stirred at 50° C. for 16 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography to give 7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1075).

[0392] As shown in Scheme 33, Step 7, a solution of 7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.13 mmol) in DMF (1 mL) was treated with K 2 CO 3 (1.5 eq.) is added and the mixture is stirred at 25° C. for 10 min, followed by dropwise addition of propargyl bromide (1.5 eq.) at room temperature. The mixture is stirred at room temperature for 2 h, followed by purification by preparative reverse phase HPLC to give 7-chloro-2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 56). Example 32. Preparation of 6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 57) and N-acetyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide (Compound 58) [ka]

[0393] As shown in step 1 of Scheme 34, to a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (380 mg, 1.03 mmol) in THF (4 mL) was added benzylamine (441 mg, 4.11 mmol). The reaction mixture was stirred at 80° 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 reverse-phase flash chromatography (5% to 60% acetonitrile in water) to give 6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1076, 220 mg, 42% yield) as a yellow solid. (C 21 H 11 F7N 2 O 2 )[M+1] + MS(ESI) calculated for: 457.1, found: 457.1.

[0394] As shown in Scheme 34, step 2, to a solution of 6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.22 mmol) in MeOH (5 mL) was added Pd / C (12 mg, 0.11 mmol) under nitrogen. The nitrogen atmosphere was replaced with hydrogen and the resulting solution was stirred at 65 °C for 3 h. The suspension was cooled, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (5% to 53% acetonitrile in water) to give 6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1077, 70 mg, 87% yield) as a yellow solid. (C 14 H 5 F 7 N 2 O 2 )[M+1] +MS(ESI) calculated value for: 367.0, found value: 367.0.

[0395] As shown in Scheme 34, Step 3, a solution of 6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.13 mmol) in DMF (1 mL) was treated with K 2 CO 3 (28 mg, 0.20 mmol) was added and the mixture was stirred at 25° C. for 10 min, followed by dropwise addition of propargyl bromide (24 mg, 0.20 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and then purified by preparative HPLC using the following conditions - column: Xselect CSH C18 OBD column 30×150 mm 5 μm; mobile phase A: ACN, mobile phase B: water (0.1% FA), gradient: 54% B to 62% B in 10 min, then 62% B, to give 6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 57, 20 mg, 35% yield) as a white solid. (C 17 H 7 F 7 N 2 O 2 ) GCMS calculated value 404.0, measured value 404.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.76-7.50(m,2H),6.33(s,2H),4.89(d,J=2.4Hz,2H),3.43(s,1H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.13,-115.56,-144.93,-161.62.

[0396] As shown in Scheme 34, Step 4, to a stirred mixture of 6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (20 mg, 0.05 mmol) and DIEA (6.4 mg, 0.05 mmol) in THF (1 mL) was added acetyl chloride (4 mg, 0.05 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by adding water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (1 mL), applied to a C-18 column, and purified by reverse-phase flash chromatography (5% to 65% acetonitrile in water) to give N-acetyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide (compound 58, 8 mg, 34% yield) as a yellow oil. (C 21 H 11 F 7 N 2 O 4 )[M+1] + MS(ESI) calculated for 89.1, found 489.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.89(d,J=6.4Hz,1H),7.86-7.74(m,1H),4.88(d,J=2.4Hz,2H),3.50(s,1H),2.44(s,6H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.64,-115.17,-140.00,-145.66. Example 33. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 59) and N-methyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide (Compound 60) [ka]

[0397] As shown in Scheme 35, Step 1, a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.49 mmol) in methylamine (2 M in THF) (3 mL) was stirred at 80° C. for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC using the following conditions: X Bridge Prep Phenyl OBD column (19 × 250 mm, 5 μm); mobile phase A, water (0.1% formic acid), mobile phase B, ACN; flow rate: 25 mL / min, gradient: 55% B to 75% B in 10 min, then 75% B, wavelength: 254 nm, to yield 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 59, 105 mg, 51% yield) as a white solid: (C 18 H 9 F 7 N 2 O 2 )[M-1] - MS(ESI) calculated for 417.0, found 417.0; 1 H-NMR (400MHz, DMSO-d 6)δ7.76-7.58(m,2H),6.36-6.21(m,1H),4.88(d,J=2.4Hz,2H),3.48(s,1H),3.11-2.96(m,3H); 19 F-NMR (377MHz, DMSO-d 6 )δ-75.10,-115.55,-144.56,-161.54.

[0398] As shown in Scheme 35, Step 2, to a solution of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (40 mg, 0.10 mmol) in THF (2 mL) was added acetyl chloride (15 mg, 0.19 mmol) and DIEA (25 mg, 0.19 mmol) at 0° C. The resulting solution was stirred at 80° C. under a nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 55% acetonitrile in water) to give N-methyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide (compound 60, 30 mg, 68% yield) as a white solid. (C 20 H 11 F 7 N 2 O 3 )[M+1] + MS(ESI) calculated for 461.0, found 461.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.91-7.68(m,2H),4.88(d,J=2.4Hz,2H),3.53-3.39(m,3H),3.19(s,1H),2.35-1.90(m,3H); 19 F-NMR (376MHz, DMSO-d 6 )δ-74.74,-115.35,-141.16,-145.4. Example 34. Preparation of 6-(4-(dimethylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 61) [ka]

[0399] As shown in Scheme 36, a solution of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.25 mmol) in methylamine (2M in THF) (3 mL) was stirred at 80° C. for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (5% to 60% acetonitrile in water) to give 6-(4-(dimethylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 61) (56 mg, 53% yield) as a white solid. (C 19 H 11 F 7 N 2 O 2 )[M+1] + MS(ESI) calculated for 433.0, found 432.9; 1 H-NMR (400MHz, DMSO-d 6 )δ7.80-7.60(m,2H),4.88(d,J=2.4Hz,2H),3.50-3.42(m,1H),3.06-2.93(m,6H); 19 F-NMR (377MHz, DMSO-d 6 )δ-74.97,-115.58,-143.29,-151.61. Example 35. Preparation of 6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 62) [ka]

[0400] As shown in Scheme 37, to a stirred solution of 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.27 mmol) in THF (1.5 mL) was added phenylmethanamine (116 mg, 1.08 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 16 h under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was applied to a C18 column and purified by reverse-phase flash chromatography (5% to 65% acetonitrile in water), then further purified by preparative HPLC using the following conditions: Column: XSelect CSH F-phenyl OBD column, 19 x 250 mm, 5 μm, Mobile phase A = water (0.05% formic acid), Mobile phase B = ACN, Flow rate = 25 mL / min, eluted with 60% B, to give 6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 62, 29.5 mg, 24% yield) as a white solid. (C 21 H 11 F 7 N 2 O 2 )[M+1] + MS(ESI) calculated for 457.1, found 457.1; 1 H-NMR (400MHz, DMSO-d 6 )δ12.09(br,1H),7.57(d,J=9.6Hz,1H),7.36-7.34(m,4H),7.30-7.21(m,1H),7.12(d,J=6.8Hz,1H),6.99(s,1H),4.54(d,J=6.0Hz,2H); 19 F-NMR (376MHz, DMSO-d 6 )δ-75.38,-116.61,-144.64,-144.70,-159.97. Example 36. Preparation of 6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 63) and 6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 64) [ka]

[0401] As shown in step 1 of scheme 38, to a solution of cyclopropanol (63 mg, 1.08 mmol) in DMF (2 mL) was added NaH (43 mg, 1.08 mmol, 60%) at 0° C. The reaction mixture was stirred at 0° C. for 30 min under nitrogen atmosphere and 2,2,7-trifluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-1,4-benzoxazin-3-one (200 mg, 0.54 mmol) in DMF (1 mL) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 20° C. for 2 h under nitrogen atmosphere and subsequently the reaction was quenched with water at 0° C. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 26% ethyl acetate in petroleum ether) and further purified by reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give 6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 63, 70.0 mg, 35% yield) as a white solid. (C 17 H 8 F 7 NO 3 )[M-1] - MS(ESI) calculated for 406.0, found 405.9; 1 H-NMR (400MHz, methanol-d 4)δ7.31(d,J=9.6Hz,1H),7.16(d,J=6.4Hz,1H),4.47-4.39(m,1H),0.96-0.89(m,2H),0.81-0.72(m,2H); 19 F-NMR (376MHz, methanol-d 4 )δ-78.94,-117.66,-144.45,-158.76.

[0402] As shown in Scheme 38, Step 2, to a stirred solution of 6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (70 mg, 0.17 mmol) in DMF (1 mL) was added K 2 CO 3 (36 mg, 0.26 mmol) and propargyl bromide (25 mg, 0.20 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours, quenched with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (5% to 68% acetonitrile in water) to give 6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 64, 23 mg, 29% yield) as a white solid. (C 20 H 10 F 7 NO 3 ) GCMS calculated value 445.0, found value 445.0; 1 H-NMR (400MHz, DMSO-d 6 )δ7.88-7.59(m,2H),4.87(d,J=2.4Hz,2H),4.51~4.42(m,1H),3.46-3.43(m,1H),0.94-0.88(m,2H),0.81-0.73(m,2H); 19 F-NMR (377MHz, DMSO-d6) δ -74.89, -115.55, -141.88, -156.42. Example 37. Preparation of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 65) and 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 66) [ka]

[0403] As shown in Scheme 39, Step 1, to a solution of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (3.5 g, 10.92 mmol) and 12 mmol equivalents of oxirane in THF (45 mL) was added lithium hexamethyldisilazide (27.4 mL, 27.37 mmol) dropwise at -78°C. After the addition was complete, the resulting mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 12 hours. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (0% to 50% ethyl acetate in petroleum ether) to give 2-(2,2',4,5,6-pentafluoro-4'-methoxy-5'-nitro-[1,1'-biphenyl]-3-yl)ethan-1-ol (compound 1078, 1.7 g, 42% yield) as a yellow oil. (C 15 H 10 F 5 NO 4 ) GCMS calculated value: 363.1, measured value: 363.1

[0404] As shown in Scheme 39, Step 2, a solution of 2-(2,2',4,5,6-pentafluoro-4'-methoxy-5'-nitro-[1,1'-biphenyl]-3-yl)ethan-1-ol (1.7 g, 4.6 mmol) in DCM (15 mL) was treated with BBr 3(2.2 mL, 23.0 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 2 hours under nitrogen atmosphere. The reaction mixture was quenched by the addition of 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. The residue was purified by silica gel column chromatography (0%-30% ethyl acetate in petroleum ether) to give 2,2′,3′,4′,6′-pentafluoro-5′-(2-hydroxyethyl)-5-nitro-[1,1′-biphenyl]-4-ol (compound 1079, 690 mg, 42% yield) as a yellow solid. (C 14 H 8 F 5 NO 4 )[M-1] - MS(ESI) calculated for: 348.0, found: 348.0.

[0405] As shown in Scheme 39, Step 3, to a stirred solution of 2,2',3',4',6'-pentafluoro-5'-(2-hydroxyethyl)-5-nitro-[1,1'-biphenyl]-4-ol (690 mg, 1.97 mmol) in AcOH (0.5 mL) and MeOH (5 mL) was added Zn dust (642.5 mg, 9.88 mmol) in portions under nitrogen at 0° C. The resulting mixture was stirred at 25° C. for 2 h under nitrogen, quenched by the addition of water, extracted with ethyl acetate, and purified with saturated NaHCO 3 The mixture was washed three times with hexanes. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 50% ethyl acetate in petroleum ether) to give 5-amino-2,2',3',4',6'-pentafluoro-5'-(2-hydroxyethyl)-[1,1'-biphenyl]-4-ol (compound 1080, 450 mg, 71% yield) as a yellow solid. (C 14 H 10 F 5 NO 2 )[M-1] - MS(ESI) calculated value for: 318.1, found value: 318.1.

[0406] As shown in Scheme 39, Step 4, to a stirred solution of 5-amino-2,2',3',4',6'-pentafluoro-5'-(2-hydroxyethyl)-[1,1'-biphenyl]-4-ol (450 mg, 1.41 mmol) and methyl 2-bromo-2,2-difluoroacetate (346 mg, 1.83 mmol) in MeOH (5 mL) was added TEA (143 mg, 1.41 mmol) at 25° C. under nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 2 h under nitrogen atmosphere. The resulting reaction mixture was cooled to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 30% ethyl acetate in petroleum ether) to give 2-bromo-2,2-difluoro-N-(2',3',4',6,6'-pentafluoro-4-hydroxy-5'-(2-hydroxyethyl)-[1,1'-biphenyl]-3-yl)acetamide (compound 1081, 110 mg, 16% yield) as a yellow oil. (C 16 H 9 BrF 7 NO 3 )[M-1] - MS(ESI) calculated for, 474.1; found 474.1.

[0407] As shown in Scheme 39, Step 5, a stirred solution of 2-bromo-2,2-difluoro-N-[2',3',4',6,6'-pentafluoro-4-hydroxy-5'-(2-hydroxyethyl)-[1,1'-biphenyl]-3-yl]acetamide (110 mg, 0.23 mmol) in DMF (1 mL) was incubated at 25 °C under a nitrogen atmosphere with K 2 CO 3(64 mg, 0.46 mmol) was added. The resulting mixture was stirred at 50° C. under nitrogen atmosphere for 2 h and then purified by reverse-phase flash chromatography (0-66% ACN in water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 65, 70.0 mg, 77% yield) as a yellow solid. (C 16 H 8 F 7 NO 3 )[M-1] - MS(ESI) calculated for 394.0, found 393.9; 1 H-NMR (400MHz, DMSO-d 6 )δ7.02-6.99(m,1H),6.76-6.75(m,1H),4.98-4.84(m,1H),3.61-3.58(t,J=6.4Hz,2H),2.84(t,J=6.8Hz,2H); 19 F-NMR (377MHz, DMSO-d6) δ -72.13, -120.85, -125.77, -137.97, -138.05, -166.14.

[0408] As shown in Scheme 39, Step 6, 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (30 mg, 0.07 mmol) and K in DMF (1 mL) were added. 2 CO 3 To a stirred solution of 3-bromoprop-1-yne (11 mg, 0.09 mmol) under nitrogen atmosphere at 25 °C was added 3-bromoprop-1-yne (11 mg, 0.09 mmol). The resulting mixture was stirred under nitrogen atmosphere at 25 °C for 2 h, applied to a C18 column, and purified by reverse phase flash chromatography (0% to 70% ACN in water) to give 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)one (compound 66, 7 mg, 20% yield) as a white solid.1 H-NMR (400MHz, DMSO-d 6 )δ7.77-7.67(m,2H),4.98-4.84(m,3H),3.62(t,J=6.4Hz,2H),3.48-3.40(m,1H),2.87(t,J=6.8Hz,2H); 19 F-NMR (377MHz, DMSO-d 6 )δ-75.02,-115.61,-120.43,-135.10,-137.54,-165.54.

[0409] Biological Examples Example B1. Testing the herbicidal activity of the compounds of the invention Protoporphyrinogen oxidase (PPO) inhibition was monitored by the change in fluorescence (excitation = 550 nm, emission = 625 nm) during the conversion of protoporphyrinogen IX (PPGIX) to protoporphyrin IX (PPIX) by PPO.

[0410] Cloning of pET28b_PPO_CHis The coding sequence of AmPPO was optimized for E. coli expression and assembled from synthetic oligonucleotides. The 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).

[0411] Protoporphyrinogen oxidase (AmPPO) expression in Amaranthus tuberculatus 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 per 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 for 4-6 hours and at 18°C ​​for an additional 40-48 hours with shaking at 230 rpm. The culture was harvested and centrifuged. The resulting AmPPO enzyme-containing cell pellet was frozen and stored at -80°C for future use.

[0412] Mutant AmPPO ΔG210 PPO expression The same procedure used for the production of 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.

[0413] Purification of AmPPO and mutant ΔG210-AmPPO Detergent solution was prepared by mixing together: 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-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 pellets, which were 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.

[0414] 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.

[0415] 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 is unstable and needs to be protected from light and used within 3 hours.

[0416] 384-well, clear-bottom plates were used for the assay (black plates are preferred for fluorescence assays). 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 as 1.2 μL droplets into wells of the plate. 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 where Buffer A was 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 gently mixed 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 zeroaverage The dose-response model was calculated using a nonlinear regression sigmoidal dose-response model (GraphPad Prism, variable slope) with the curve tops constrained to be .

[0417] Compounds 1-38 and 40-52 each had an IC 50 had.

[0418] Example B2. Testing the post-emergence herbicidal activity of compounds of the invention Selected compounds of the present invention were screened against Amaranthus retroflexus (AMARE), Setaria italica (SETIT), and Kochia / Bassia scoparia (KCHSC) at a concentration of 100 ppm.

[0419] Therefore, PPO-susceptible weed seeds were sown in quadrants into 5” × 5” pots containing Miracle-Gro potting mix (Soctts Miracle-Gro Company, Marysville, OH, USA) and grown under appropriate growth conditions (a 16 / 8-h photoperiod day / night and 300 μmol m 2 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.

[0420] 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. -1Plants were treated with test compound solutions in a laboratory spray chamber equipped with 8003 flat fan nozzles calibrated to deliver 100% of the weed growth rate. Plants were returned to the growth chamber and evaluated for percent visual damage compared to TC 7 days after treatment (DAT). For the data presented in Table 3, A represents percent control, with 100% control indicating complete inhibition of weed growth.

[0421] Representative compounds 2, 37, and 52 exhibited excellent herbicidal activity against weed species at parts per million (PPM) concentrations, as shown in Table 3. [Table 3]

[0422] Example B3. Leaf penetration and translocation studies with and without crop oil concentrate adjuvant (COC). Selected compounds of the present invention, along with compounds 920-4 and 920-6 from Japanese Patent Application No. 06321920, were tested for leaf penetration, translocation, and herbicidal activity in grass weeds when applied with or without an adjuvant to increase the epidermal penetration of the compounds. [ka]

[0423] Four to five PPO-susceptible foxtail millet seeds (Ernst Conservation Seeds, Meadville, PA) were sown into each of 1.5 × 1.5 inch 6-cell plug inserts containing Miracle-Gro™ planting mix (Scotts Miracle-Gro Company, Marysville, OH, USA) and grown under appropriate growth conditions (photoperiod 16 / 8 h day / night and 300 μmol m supplemented with LED lamps). -2 s -1The plants were grown in a Conviron growth chamber with 250 / s light intensity and 26 / 22°C temperature. The relative humidity in the growth chamber was maintained at approximately 65%. Plants were grown to the 1-2 leaf stage (one expanded leaf and one emerged leaf) and thinned to one plant per cell.

[0424] Test compounds were formulated in 25% acetone, 0.1% Tween-20, and 2.5% ammonium sulfate (AMS) to a final concentration of 1.5 mM with or without the addition of 1% v / v crop oil concentrate (COC, Agridex). A total of 6 μL was applied as 3×2 μL droplets onto the adaxial surface of emerged foxtail leaves for each of the two compound solutions (with and without COC). Six replicate plants were treated with each compound. A treatment consisting of the above formulation excluding the active compound was applied as a treatment control (TC). Plants were returned to the growth chamber and evaluated 7 days after treatment for overall % visual damage compared to TC. Plants were evaluated for rapid necrosis at the site of droplet application, indicative of PPO inhibition apically to the site of droplet application, and basophilically to the site of droplet application, to estimate the mobility of the compound in the general, xylem, and phloem, respectively. In general, compounds with necrosis only at the site of action appeared to be less mobile, whereas necrosis of emerging leaves indicated symplastic phloem movement and necrosis from the leaf base to the tip only on applied leaves indicated apoplastic xylem movement.

[0425] The data shown in Table 4 is for the TC treatment where the percent plant and leaf damage was considered to be 0%. "A" represents the percentage of leaf or plant damage between 80-100%, "B" represents the percentage of leaf or plant damage between 20-80%, and "C" represents the control percentage below 20%.

[0426] As can be seen in Table 4, compounds no. 2, 37, and 52 of the present invention surprisingly showed significantly improved leaf translocation compared to compounds 920-4 and 920-6. [Table 4]

[0427] Compounds 920-4 and 920-6 were also evaluated for herbicidal activity as described above in Example 34 and compared to compounds of the present invention as shown in Table 5. An unexpected improvement in the herbicidal activity of the compounds of the present invention was observed. [Table 5]

[0428] Example B4. Control of PPO-resistant weeds carrying the dG210 mutation A field experiment was conducted to evaluate the efficacy of compound 2 in controlling PPO dG210 mutant tall waterhemp (Amaranthus tuberculatus) populations. The field location was selected due to past documentation of several commercially available PPO herbicides failing to control this weed population. The field was prepared by standard conventional tillage methods and different herbicide treatments were applied using a backpack carbon dioxide pressure sprayer at a volume of 190 L / ha. Soybean at the pre-emergence stage (1 day after planting) was applied in 10 m long x 3 m wide plots arranged in a randomized complete block layout with four replicates. Herbicides were surface applied to soil without vegetation.

[0429] Herbicide treatments included Compound 2, formulated as a 10% emulsifiable concentrate, as well as the following commercial herbicides: Flumioxazin 51, a 51% wettable granule formulation of Flumioxazin (RedEagle International LLC), Zidua SC, a 41% suspension concentrate formulation of Pyroxasulfone (BASF Corporation), and Spartan, a 40% dry flowable formulation of Sulfentrazone (FMC Corporation).

[0430] The emergence and development of different weed species was evaluated 4 weeks after herbicide application and quantified as the growth control percentage relative to the untreated control treatment. No control is equal to 0% and complete control is equal to 100%. Table 6 shows the degree of control for various herbicide treatments and the significantly improved bioactivity of compound 2 compared to flumioxazin, sulfentrazone, and pyroxasulfone. The data in the table show that compound 2 was more effective in resistant weed control than other commercial herbicides investigated in the experiment. Also see Figure 2A and Figure 2B. [Table 6]

[0431] Further embodiments of the invention are evident from the claims, the description and the examples. It is to be understood that the above-mentioned and below-mentioned features of the subject matter of the invention can be applied not only in the combination given in each particular case but also in other combinations, without departing from the scope of the invention.

Claims

1. Compounds of Formula I: 【Chemical 1】 or a salt thereof, wherein R １ is H, or optionally R １ａ C substituted with １～４ alkyl, phenyl, or benzyl, each of said alkyl, said phenyl, or said benzyl optionally containing up to three F atoms, OH groups, or OC １～４ is substituted with an alkyl group, R １ａ but, 【Chemistry 2】 and Each R １ｂ However, independently, H, C １～４ alkyl, or cyclopropyl; R ２ and R ３ each independently selected from H, Cl, F, CH ３ or R ２ and R ３ together with the intervening carbon is cyclopropyl; R ４ is H, Cl or F, R ５ is H or F, R ６ and R ７ each independently selected from F, H, C optionally substituted with OH １～２ Alkyl, alkenyl, OH, OC １～２ Alkyl, O-cyclopropyl, OCH ２ CCH, NHCH ２ Ph, N(R ｘ ) ２ , or SCH ３ and R ８ is H or F, Each R ｘ However, independently, H, CH ３ , or C(O)CH ３ and The compound or a salt thereof, wherein ring A contains at least four F atom substituents.

2. The compound of claim 1 having formula II: 【Chemistry 3】 Or its salt.

3. The compound of claim 1 having formula III: 【Chemistry 4】 Or its salt.

4. The compound of claim 1 having formula IV: 【Chemistry 5】 Or its salt.

5. R ２ , R ３ , and R ４ 2. The compound of claim 1, wherein each of is F, or a salt thereof.

6. R ２ and R ３ each of which is H, and R ４ The compound according to claim 1, or a salt thereof, wherein is F.

7. R ２ , R ３ , and R ４ Each of the is F and R １ But CH ２ 2. The compound of claim 1, wherein CCH, or a salt thereof.

8. A compound selected from the following compounds or salts thereof: 【Chemistry 6】 【change】 【change】 【change】 【change】

9. The compound is 【Chemistry 7】 or a salt thereof.

9. The compound of claim 8, wherein:

10. The compound is 【Chemistry 8】 or a salt thereof.

9. The compound of claim 8, wherein:

11. The compound is 【Chemistry 9】 or a salt thereof.

9. The compound of claim 8, wherein:

12. 1. An agricultural composition comprising: A compound according to any one of claims 1 to 11 or a salt thereof and at least one additional ingredient that functions as a carrier.

13. The composition of claim 12, wherein the at least one additional component is a surfactant or a diluent.

14. 13. The composition of claim 12, wherein the composition is a herbicide composition.

15. 12. A method for controlling undesirable vegetation, comprising contacting the undesirable vegetation or its environment with a herbicidally effective amount of a compound, or salt thereof, according to any one of claims 1 to 11.

16. 16. The method of claim 15, wherein the undesirable vegetation comprises weeds.

17. 16. The method of claim 15, wherein the undesirable vegetation comprises protoporphyrinogen IX oxidase (PPO) inhibitor-resistant weeds.

18. The method of claim 17, wherein the PPO inhibitor-resistant weed has a dG210 mutation.

19. The compound or the composition is 10,000 m ２ 16. The method of claim 15, wherein the method is applied at a rate of 1 to 100 g per 1000 ml of water.

20. 16. The method of claim 15, wherein contacting the undesirable vegetation or its environment with the compound or composition results in post-emergence and / or pre-emergence control of the undesirable vegetation.

21. 16. The method of claim 15, wherein the undesirable vegetation is controlled by at least 60%.

22. 16. The method of claim 15, wherein the undesirable vegetation is controlled in fields of corn, soybeans, wheat and / or cotton.

23. A process for preparing a compound of formula (I) according to any one of claims 1 to 11, or a salt thereof, comprising: i) deprotecting a compound of formula (c), or a salt thereof, to obtain a compound of formula (d), or a salt thereof; 【Chemistry 10】 ii) reducing the compound of formula (d), or a salt thereof, to obtain a compound of formula (e), or a salt thereof; 【Chemistry 11】 iii) reacting a compound of formula (e), or a salt thereof, with a compound of formula (f), or a salt thereof, to obtain a compound of formula (g), or a salt thereof; 【Chemistry 12】 iv) cyclizing the compound of formula (g), or a salt thereof, to obtain a compound of formula (h), or a salt thereof; 【Chemistry 13】 v) reacting a compound of formula (h), or a salt thereof, with a compound of formula (i), or a salt thereof, to obtain a compound of formula (I), or a salt thereof; 【Chemistry 14】 wherein Y is X or B(OH) ２ and X is Br or I; R １ ~R ８ and ring A is as defined in formula (I).

24. A method for preparing a compound of formula (I) or a salt thereof according to any one of claims 1 to 11, comprising reacting a compound of formula (p), or a salt thereof, with a compound of formula (q), or a salt thereof, to form a compound of formula (I), or a salt thereof; 【Chemistry 15】 During the ceremony, R is H or phenyl; X is Br or I; R １ ~R ８ and ring A is as defined in formula (I).

25. A method for preparing a compound of formula (I) or a salt thereof according to any one of claims 1 to 11, comprising reacting a compound of formula (n), or a salt thereof, with a compound of formula (o), or a salt thereof, to form a compound of formula (I), or a salt thereof; 【Chemistry 16】 During the ceremony, R is H or phenyl; X is Br or I; R １ ~R ８ and ring A is as defined in formula (I).

26. A compound of formula (c), (d), (e), (g), (h), or (v): 【Chemistry 17】 or a salt thereof, wherein R is H or phenyl; X is Br or I; R ２ and R ３ each independently selected from H, Cl, F, CH ３ or R ２ and R ３ together with the intervening carbon is cyclopropyl; R ４ is H, Cl or F, R ５ is H or F, R ６ and R ７ each independently selected from F, H, C optionally substituted with OH １～２ Alkyl, alkenyl, OH, OC １～２ Alkyl, O-cyclopropyl, OCH ２ CCH, NHCH ２ Ph, N(R ｘ ) ２ , or SCH ３ and R ８ is H or F, Each R ｘ However, independently, H, CH ３ , or C(O)CH ３ and The compound or a salt thereof, wherein ring A contains at least four F atom substituents.

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