Protoporphyrinogen oxidase inhibitors

Abstract

The present invention relates to protopoiyphyrinogen oxidase inhibitors of general formula (I), the variables of which are defined herein. The present invention features processes and intermediates for preparing the compounds of formula (I), compositions containing them, and their use as herbicides (i.e., for controlling undesirable vegetation). The present invention also features a method for controlling undesirable vegetation, comprising applying a herbicidally effective amount of at least one benzoxazinone of formula (I) to a plant, its seeds, and / or its environment. [Formula 1] JPEG2025503676000073.jpg31169

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 299,862, filed January 14, 2022, which is incorporated by reference herein in its entirety.

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

[0003] Herbicides that inhibit protoporphyrinogen oxidase (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 oxidation of protoporphyrinogen IX to protoporphyrin IX, the final common step in chlorophyll and heme biosynthesis [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 then leaks into the cytosol and 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 disruption, 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, chlorophthalim, N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide)]; phenylpyrazoles (e.g., TNPP-ethyl, ethyl 2-[1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy]propionate, M&B 39279); pyridine derivatives (e.g., LS82-556); and fenopyruvate and its O-phenylpyrrolidino and piperidinocarbamate analogs (Kramer W., ed. Modern Crop Protection Compounds, 2004). nd These compounds include molecules from many different structural classes, including benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-10, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone-14, benzophenone-15, benzophenone-16, benzophenone-17, benzophenone-18, benzophenone-19, benzophenone-20, benzophenone-21, benzophenone-22, benzophenone-23, benzophenone-24, benzophenone-25, benzophenone-26, benzophenone-27, benzophenone-28, benzophenone-39, benzophenone-40, benzophenone-41, benzophenone-42, benzophenone-43, benzophen

[0005] However, the herbicidal properties of these known compounds against harmful plants are not always completely satisfactory. Herbicide-resistant weeds present a serious problem for efficient weed control, because such resistant weeds are becoming more and more prevalent, and therefore weed control by applying herbicides is no longer effective, causing great problems for farmers. Resistance to PPO herbicides has evolved slowly (approximately 40 years since their first commercialization) and has been identified in 13 weed species to date [Heap I, The International Survey of Herbicide Resistant Weeds. Available online: http: / / www.weedscience.org / (October 2019)]. The first weed to evolve resistance to PPO herbicides was 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 98 Leu substitutions confer PPO resistance in water ragweed [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].

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

[0007] Thus, in one aspect, a benzoxazinone having the 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.

[0008] In certain embodiments, a benzoxazinone having formula (II): [ka] or a salt thereof (wherein R 1 ~R 4 is as defined elsewhere herein) is provided.

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

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

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

[0012] In another aspect, agricultural compositions (which in some variations include herbicide compositions) are also provided that comprise a herbicidally effective amount of a compound of Formula (I), (II), (III), (IV), or (V), 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 comprises 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 of Table 1, or a salt thereof.

[0015] In yet another aspect, there is also provided a method for controlling undesirable vegetation growth comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, a salt thereof, or a composition comprising a compound of the invention as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0016] Benzoxazinone compounds In one aspect, a benzoxazinone having formula (I): [ka] or a suitable salt thereof, wherein R 1 is C 1~6 Alkyl, C 3~4 Alkenyl, C 3~4 Alkynyl, cyclopropyl, CH2C 3~6 Cycloalkyl, phenyl or C 1~2 alkylphenyl, each of which is C(O)R 1a or CH2C(O)R 1a each optionally substituted with up to three F or Cl atoms, and each C 1~6 Alkyl may also optionally be represented by -OR 1b is replaced by R 1a is OR 1b , CH2OC(O)C 1~4 Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1~4 Alkyl, or NHOR 1b and Each R 1b are independently H, C 3~6 Cycloalkyl, CH2 phenyl, or C 1~4 alkyl, optionally substituted with up to three F or Cl atoms; R 1c is H or optionally C(O)OR 1b C replaced with 1~4 alkyl, or R 1b and R 1ctogether with the intervening nitrogen atom, form a 4-6 membered heterocyclic ring, optionally containing additional atoms or groups selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b and is substituted with one or more groups selected from R 2 and R 3 each of which is H, F, or R 2 and R 3 together with the intervening carbon is cyclopropyl; R 4 is H, F, CH3, or Cl, R 5 is H or F, R 6 and R 7 each is independently F, H, CH3, CF3, or OCH3; R 8 is H or F, wherein ring A contains at least four F atom substituents.

[0017] In another embodiment, a benzoxazinone having formula (I): [ka] or a suitable salt thereof, wherein R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, CHcycloalkyl, phenyl, or alkyl-phenyl, each of which is C(O)R 1a or CH2C(O)R 1a each optionally substituted with up to three F or Cl atoms, and each alkyl also optionally substituted with -OR 1b is replaced by R 1a is OR 1b , CH2OC(O) alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2 alkyl, or NHOR 1b and Each R 1b are independently H, cycloalkyl, CHphenyl, or alkyl optionally substituted with up to three F or Cl atoms; R 1c is H, or optionally C(O)OR 1b or R 1b and R 1c and is alkyl substituted with, and together with the intervening nitrogen atom, forms a 4-6 membered heterocyclic ring, optionally containing additional atoms or groups selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b and is substituted with one or more groups selected from R 2 and R 3 each of which is H, F, or R 2 and R 3 together with the intervening carbon is cyclopropyl; R 4 is H, F, CH3, or Cl, R 5 is H or F, R 6 and R 7 each is independently F, H, CH3, CF3, or OCH3; R 8 is H or F, wherein ring A contains at least four F atom substituents.

[0018] In another embodiment, a benzoxazinone having formula (I): [ka] or a suitable salt thereof, wherein R 1 is C 1~6 Alkyl, C 3~4Alkenyl, C 3~4 Alkynyl, cyclopropyl, phenyl, or C 1~2 alkylphenyl, each of which is —C(O)R 1a or -CH2C(O)R 1a each optionally substituted with up to three halogens, and each C 1~6 Alkyl is optionally represented by -OR 1b is replaced by R 1a -OR 1b , -C(O)R 1b , CH2OC(O)C 1~4 Alkyl, CF3, -N(R 1b )(R 1c ), -ON(R 1b )(R 1c ), -NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1~4 Alkyl, or -NHOR 1b and Each R 1b are independently H, cyclopropyl, or C optionally substituted with up to three halogens. 1~4 is alkyl, R 1c optionally contains an additional heteroatom selected from N, O, or S, and optionally -C(O)OR 1b and -C(O)R 1b and, together with the intervening nitrogen atom, -C(O)OR, which form a 4- to 6-membered heterocyclic ring substituted with one or more groups selected from 1b or R 1b and R 1c optionally substituted with H or C 1~4 is alkyl, R 2 and R 3 is H, F, Cl, CH3, or R 2 and R 3 together with the intervening carbon is cyclopropyl; R 4 is H, F, or Cl, R 5 is H or F, R 6 and R 7 Each of these independently represents F, H, C 1~2 Alkyl, alkenyl, CF3, -OH, -OC 1~2 alkyl, or -SCH3; R 8 is H or F, wherein ring A contains at least four F atom substituents.

[0019] In one embodiment, R 2 , R 3、 and R 4 Each of is F.

[0020] In another embodiment, R 2 and R 3 is H and R 4 is F.

[0021] In another embodiment, R 1 is -C(O)R 1a C replaced with 1~6 alkyl, and R 1a -OR 1b or -N(R 1b )(R 1c In one embodiment, R 1 is -C(O)R 1a C replaced with 1~2 alkyl, and R 1a -OR 1b or -N(R 1b )(R 1c )

[0022] In another embodiment, R 1 is -C(O)R 1a C replaced with 1~6 alkyl, and R 1a -OR 1b In another embodiment, R 1 is -CH(CH3)C(O)R 1a and R 1a -OR 1bis.

[0023] In one embodiment, R 1 is C substituted with -C(O)OH 1~6 In one embodiment, R 1 is -C(O)OC 1~4 Alkyl-substituted C 1~6 In one embodiment, R 1 is C substituted with -C(O)OCH3 1~6 In one embodiment, R 1 teeth, [ka] is.

[0024] In another embodiment, R 1 is -C(O)R 1a C replaced with 1~6 alkyl, and R 1a is -N(R 1b )(R 1c In one embodiment, R 1 teeth, - C(O)R 1a is methyl substituted with R 1a is -N(R 1b )(R 1c )

[0025] In one embodiment, R 1 is -C(O)N(R 1b )(R 1c ) replaced by C 1~6 alkyl, and R 1b is C 1~4 alkyl, and R 1c is optionally C(O)OR 1b C replaced with 1~4 In one embodiment, R 1 teeth, [ka] is.

[0026] In one embodiment, R 1 is -C(O)N(R 1b )(R 1c ) replaced by C 1~6 alkyl, and R 1b and R 1c together with the intervening nitrogen atom, form a 4-6 membered heterocyclic ring, optionally containing additional atoms or groups selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b In one embodiment, R 1 is -C(O)N(R 1b )(R 1c ) replaced by C 1~6 alkyl, and R 1b and R 1c together with the intervening nitrogen atom form an azetidine ring, optionally with —C(O)OR 1b and -C(O)R 1b In one embodiment, R 1 teeth, [ka] is.

[0027] In one embodiment, the present invention provides a benzoxazinone having formula (II): [ka] or a salt thereof (including agriculturally suitable salts thereof).

[0028] In a further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0029] In another further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0030] In one embodiment, the present invention provides a benzoxazinone having formula (III): [ka] or a salt thereof (including agriculturally suitable salts thereof).

[0031] In a further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0032] In another further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0033] In one embodiment, the present invention provides a benzoxazinone having formula (IV); [ka] or a salt thereof (including agriculturally suitable salts thereof).

[0034] In a further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0035] In another further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0036] In one embodiment, the present invention provides a benzoxazinone having formula (V): [ka] or a salt thereof (including agriculturally suitable salts thereof).

[0037] In a further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0038] In another further embodiment, R 2 , R 3 , and R 4 Each of is F.

[0039] In some variations of the foregoing, the salt may be an agriculturally suitable salt. In certain variations, the agriculturally suitable salt is a salt that exhibits herbicidal activity or that is or can be converted in plants, water, or soil to a compound or salt that has herbicidal activity.

[0040] In some embodiments, a compound selected from the compounds listed in Table 1 below, or a salt thereof (an agriculturally suitable salt thereof) is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0041] In some variations, compounds 8-11, or salts thereof (including agriculturally suitable salts thereof), are provided. In some variations, compounds 76-79, or salts thereof (including agriculturally suitable salts thereof), are provided. In some variations, compounds 80-81, or salts thereof (including agriculturally suitable salts thereof), are provided. In some variations, compounds 86-87, or salts thereof (including agriculturally suitable salts thereof), are provided. In some variations, compounds 162-165, or salts thereof (including agriculturally suitable salts thereof), are provided.

[0042] In another aspect, the invention features an agricultural composition that includes a compound of the invention, or a salt thereof, and at least one additional ingredient that functions as a carrier.

[0043] In one embodiment, at least one additional component of the agricultural composition is a surfactant or a diluent.

[0044] In another embodiment, the composition is a herbicide composition.

[0045] In another aspect, the invention features a method for controlling undesirable vegetation, the method comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, or an agriculturally acceptable salt thereof.

[0046] In one embodiment, the undesirable vegetation includes weeds. In a further embodiment, the undesirable vegetation includes protoporphyrinogen IX oxidase (PPO) inhibitor-resistant weeds. In yet another embodiment, the PPO inhibitor-resistant weeds have a dG210 mutation.

[0047] In one embodiment, the compound or composition of the present invention is 2 It is applied at a rate of 1 to 100g per dose.

[0048] In one embodiment, contacting undesirable vegetation or its environment with a compound or composition of the present invention results in post-emergence control of the undesirable vegetation. In a further embodiment, the undesirable vegetation is controlled by at least 60%. In another embodiment, the undesirable vegetation is controlled by at least 80%. In yet another embodiment, the undesirable vegetation is controlled by at least 90%.

[0049] In one embodiment, contacting undesirable vegetation or its environment with a compound or composition of the present invention results in pre-emergence control of undesirable vegetation. In a further embodiment, undesirable vegetation is controlled by at least 60%. In another embodiment, undesirable vegetation is controlled by at least 80%. In yet another embodiment, undesirable vegetation is controlled by at least 90%.

[0050] 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.

[0051] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When recited in a claim, such 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; other elements are not excluded from the claim as a whole.

[0052] 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).

[0053] Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended regarding 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.

[0054] 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.

[0055] As referred to herein, the term "broadleaf" used alone or in terms such as "broadleaf weed" means a dicotyledonous plant (dicot) or dicotyledon, a term used to describe a group of angiosperms characterized by an embryo with two cotyledons.

[0056] 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.

[0057] "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the different butoxy, pentoxy and hexyloxy isomers.

[0058] "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0059] 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.

[0060] 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 1~4Alkylsulfonyl refers to methylsulfonyl to butylsulfonyl, C2 alkoxyalkyl refers to CH3OCH2-, C3 alkoxyalkyl refers to, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CHOCH2-, and C4 alkoxyalkyl refers to the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples of which include CH3CH2CH2OCH2- and CH3CHOCH2CH2-.

[0061] 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, subscripts may represent ranges, e.g., (R) i~j When a variable is designated "i" or "j," the number of substituents may be selected from the integers between "i" and "j," inclusive. When a group includes a substituent that may be, for example, hydrogen (H), it is recognized that if this substituent is designated as hydrogen, this is equivalent to the group being unsubstituted. When a variable is designated as being optionally attached to a position, a hydrogen may be at that position even if it is not listed in the definition of the variable. When one or more positions on a group are referred to as "unsubstituted" or "unsubstituted," a hydrogen atom is attached in a manner that captures any free valency.

[0062] "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.

[0063] 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.

[0064] The term "optionally substituted" in reference 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.

[0065] The term "acceptable salts" or "salts" in relation to the compounds of the present invention includes cations or anions. Preferred cations are ions of alkali metals, preferably lithium, sodium and potassium, ions of alkaline earth metals, preferably calcium and magnesium, and ions of transition metals, preferably manganese, copper, zinc and iron, as well as ammonium and substituted ammonium in which one to four hydrogen atoms are replaced by C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl - preferably ammonium, methylammonium, isopropylammonium, dimethylammonium, diethylammonium, diisopropylammonium, trimethylammonium, triethylammonium, tris(isopropyl)ammonium, heptylammonium, dodecylammonium, tetradecylammonium, tetramethylammonium, Tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium (olamine salts), 2-(2-hydroxyeth-1-oxy)eth-1-ylammonium (diglycolamine salts), di(2-hydroxyeth-1-yl)ammonium (diolamine salts), tris(2-hydroxyethyl)ammonium (trolamine salts), tris(2-hydroxypropyl)ammonium, benzyltomethylammonium, benzyltriethylammonium, N,N,N-trimethylethanolammonium (choline salts), further phosphonium ions, sulfonium ions, preferably tri(C1-C4 alkyl)sulfonium, such as trimethylsulfonium, and sulfoxonium ions, preferably tri(C1-C4 alkyl)sulfoxonium, and finally the salts of polybasic amines such as N,N-bis(3-aminopropyl)methylamine and diethylenetriamine.

[0066] Useful anions of acid addition salts are primarily chloride, bromide, fluoride, iodide, hydrogensulfate, methylsulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and also anions of C1-C4 alkanoic acids, preferably formate, acetate, propionate, and butyrate.

[0067] As used herein, the terms "undesirable vegetation" and "harmful plants" are synonymous.

[0068] Preparation of 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, A.R. Katrittzky and C.W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky, C.W. Rees and E.F.V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

[0069] The compounds of the present invention can exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Stereoisomers are isomers that have identical constitution but differ in the spatial arrangement of their atoms, 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 rotational barrier is high enough to allow for the isolation of isomeric species. Those skilled in the art will appreciate that one stereoisomer may be more active and / or exhibit beneficial effects when enriched relative to or separated from other stereoisomer(s). In addition, those skilled in the art will know how to separate, enrich, and / or selectively prepare such stereoisomers. The compounds of the present invention may exist as a mixture of stereoisomers, as individual stereoisomers, or in 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; therefore, the formulas of the present invention encompass 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 mixtures 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 have 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, which 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 appreciate 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. The preparation and isolation of specific polymorphs of the compounds of the present invention can be achieved by methods known to those skilled in the art, including, for example, crystallization using selected solvents and temperatures. For a comprehensive discussion of polymorphism, see R. Hilfiker, Ed., Polymorphism in Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0070] Those skilled in the art will recognize that salts of chemical compounds share the biological utility of their corresponding non-salt forms because, under environmental and physiological conditions, they exist in equilibrium with their corresponding 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 phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine, or ammonia, or with amides, hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium, or barium.

[0071] 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 1 and 2, can be used.

[0072] In one general example, compounds of formula (I) can be prepared as shown in Scheme 1. [ka]

[0073] Thus, as shown in Scheme 1, Step 1, compounds of formula (c) can be prepared by reacting compounds of formula (a) (wherein X is a leaving group such as Br, I, or OTf) with substituted phenyls of formula (b) using metal-catalyzed cross-coupling reaction conditions. Suitable catalysts include palladium catalysts such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) or chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II) and / or Pd(OAc)2 in combination with bis(adamantan-1-yl)(butyl)phosphine. As shown in Scheme 1, Step 2, compounds of formula (d) can be prepared by demethylating the aryl methyl ether of compounds of formula (c) under acidic conditions. In one example, a Lewis acid such as boron tribromide can be used. As shown in Step 3 of Scheme 1, compounds of formula (e) can be prepared by reduction of the nitro group of compounds of formula (d). Several methods for this, including catalytic hydrogenation, metallic zinc, or the use of sodium hydrosulfite, are known to those skilled in the art. As shown in Step 4 of Scheme 1, compounds of formula (g) can be prepared by condensing the amino group of compounds of formula (e) with compounds of formula (f) under basic conditions in an organic solvent, where L is a suitable leaving group such as an alkoxy group or a halogen atom. In one embodiment, the base is a non-nucleophilic base such as triethylamine or diisopropylethylamine. As shown in Step 5 of Scheme 1, benzoxazinones of formula (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 Step 6 of Scheme 1, compounds of formula (I) (wherein R 1 For example, -C(O)R 1a C replaced with 1~4A compound of formula (I), where R is an alkyl group, 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. 1a is OH) can be converted to other compounds of formula (I), e.g., where R 1a is -N(R 1b )(R 1c ), -NHN(R 1b )(R 1c ), -NHS(O)N(R 1b )2, or -NHOR 1b ) can be further prepared.

[0074] In another general example, compounds of formula (I) can also be prepared as shown in Scheme 2. [ka]

[0075] Thus, as shown in Scheme 2, Step 1, a phenylboronic acid of formula j (where R = H) or a phenylboronic acid (e.g., -B(OR)2 represents a pinacol ester) can be coupled to a suitable substituted phenyl bromide or phenyl iodide of formula (a) (where X is Br or I) in a Suzuki-Miyaura-type reaction using a suitable metal 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). Compounds of formula (I) can then be produced using steps similar to Steps 2-5 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).

[0076] In one aspect, reacting a protected phenyl bromide or phenyl iodide of formula (a) with a fluorinated phenyl of formula (b) using a catalytic promoter of a metal such as palladium to produce a biphenyl of formula (c), wherein R 4 From R 8 is as described elsewhere herein, and ring A contains 4 or 5 fluorine atoms; [ka] removing the protecting group of the biphenyl compound of formula (c) to produce a phenol of formula (d); [ka] reducing the nitro group of the compound of formula (d) to form an amine of formula (e); [ka] alkylating an amine of formula (e) with a compound of formula (f) using a non-nucleophilic base, wherein L is a suitable leaving group such as an alkoxy or halogen atom, to form a compound of formula (g); [ka] treating a compound of formula (g) with a suitable base such as K2CO3 using heat to produce a benzoxazinone of formula (h); [ka] and alkylating the amide of the benzoxazinone of formula (h) to form a compound of the invention of formula (I) (wherein R 2 and R 3 is a H or F atom, and R 1 , R 4 , R 5 , R 6 , R 7 , and R 8are as described elsewhere herein), [ka]

[0023] There is provided a process for preparing a compound of formula (I) or a salt thereof as described herein, comprising:

[0077] In one embodiment, a compound of formula (c) is formed by reacting a compound of formula (a) with a boronate or boronic acid of formula (j) in a Suzuki-Miyaura type reaction using a suitable metal catalyst. [ka]

[0078] In another embodiment, compounds of formula (c) are formed by the reaction of a boronate or boronic acid of formula (m) with a fluorinated phenyl bromide or fluorinated phenyl iodide of formula (m) in a Suzuki-Miyaura type reaction using a suitable metal catalyst. [ka]

[0079] In another aspect, there is provided a process for preparing a compound of formula (I) or a salt thereof described herein, comprising: A method is provided in which a compound of formula (n), in which X is a leaving group such as bromide, iodide, or tosylate, is reacted with a fluorinated phenyl boronate or boronic acid in a Suzuki-Miyaura type reaction using a suitable metal catalyst. [ka]

[0080] In yet another aspect, there is provided a process for preparing a compound of formula (I) described herein, or a salt thereof, comprising: A method is provided in which a fluorinated phenyl compound of formula (q), where X is a leaving group such as bromide, iodide, or tosylate, is reacted with a boronate or boronic acid of formula (p) in a Suzuki-Miyaura type reaction using a suitable metal catalyst. [ka]

[0081] Any of the embodiments and variations described herein for compounds of formula (I) also apply to intermediates of formula (c), (d), (e), (g), (h), (n), or (p). In some aspects, intermediates of formula (c), (d), (e), (g), (h), (n), or (p): [ka] or salts thereof (including agriculturally suitable salts thereof) are provided.

[0082] Those skilled in the art will recognize that various functional groups can be converted into other functional groups to provide different compounds of the present 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, 2002. nd Ed., Wiley-VCH, New York, 1999.

[0083] It is also recognized that some of the reagents and reaction conditions described above for preparing the compounds of the present invention may not be compatible with certain functional groups present in the intermediates. In these cases, incorporating 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, 2nd ed.; Wiley: New York, 1991). Those skilled in the art will recognize that in some cases, after the introduction of a given reagent as shown in any individual scheme, it may be necessary to perform additional routine synthetic steps not detailed in order to complete the synthesis of the compounds of the present invention. Those skilled in the art will also recognize that it may be necessary to perform combinations of steps shown in the above schemes in an order other than that implied by the details presented in order to prepare the compounds of the present invention.

[0084] Those skilled in the art will also recognize that the compounds of the present invention, and the intermediates described herein, can be subjected to a variety of electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.

[0085] composition In certain embodiments, the compounds of the present disclosure, including agriculturally suitable salts thereof, can be used as herbicidal 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 be consistent with the physical properties of the active ingredient, the mode of application, and environmental factors such as soil type, moisture, and temperature.

[0086] In some variations, the compositions provided herein are herbicides. In some variations, the compositions contain compounds of the present disclosure that control or modify plant growth. In certain variations, the compositions contain a herbicidally effective amount of the compound, and such an amount of the compound can produce a control or modify effect on plant growth. Control or modify effect includes any deviation from natural occurrence, such as killing, delaying, leaf withering, bleaching, dwarfing, etc.

[0087] Liquid formulations include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions, oil-in-water emulsions, flowable concentrates, and / or suspoemulsions), 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.

[0088] Common types of solid formulations include dusts, powders, granules, pellets, prills, pastilles, tablets, and filled films (including seed coatings), which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film-forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredients can be (micro)encapsulated and further formed into suspensions or solid formulations. 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 primarily used as intermediates for further formulation.

[0089] Sprayable formulations are typically increased in a suitable medium before spraying. Such liquid and solid formulations are formulated to be easily diluted with the spray medium, usually water, but sometimes another suitable medium such as 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 medium for foliar treatment by aerial or ground application, or for application to plant growth media.

[0090] Liquid and dry formulations can be metered directly into a drip irrigation system or metered into the furrow within the plantings.

[0091] Formulations typically contain effective amounts of active ingredient, diluent, and surfactant within the following approximate ranges, shown in Table 2, totaling 100% by weight: [Table 2]

[0092] Examples of solid diluents include 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.

[0093] Liquid diluents include, for example, water; N,N-dimethylalkanamides (e.g., N,N-dimethylformamide); limonene; dimethyl sulfoxide; N-alkylpyrrolidones (e.g., N-methylpyrrolidinone); alkyl phosphates (e.g., triethyl phosphate); ethylene glycol; triethylene glycol; propylene glycol; dipropylene glycol; polypropylene glycol; propylene carbonate; butylene carbonate; paraffins (e.g., white mineral oil, ordinary paraffin, isoparaffin); alkylbenzenes; alkylnaphthalenes; glycerin; glycerol triacetate; sorbitol; aromatic hydrocarbons; dearomatized aliphatics; alkylbenzenes; alkylnaphthalenes; ketones such as cyclohexanone, 2-heptanone, isophorone, and 4-hydroxy-4-methyl-2-pentanone; isoacetate. acetates such as methyl, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate, and isobornyl acetate; alkylated lactate esters, dibasic esters, alkyl and aryl benzoates, and other esters such as gamma-butyrolactone; and alcohols which may be linear, branched, saturated, or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol, cresol, and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C8), such as vegetable seed and fruit oils (e.g., olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grape seed, safflower, cottonseed, soybean, rapeseed, coconut, and palm kernel oils), fats of animal origin (e.g., beef tallow, pork fat, lard, cod liver oil, fish oil), and mixtures thereof. 22Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated), which can be obtained by hydrolysis of glycerol esters from plant and animal sources and purified by distillation. Typical liquid diluents are described in C. Marsden & S. Mann, Solvents Guide, Cleaver-Hume Press, London, 1963.

[0094] Surfactants can be classified as nonionic, anionic, or cationic. Nonionic surfactants useful in the formulations of the present invention include, but are not limited to, alcohol alkoxylates, such as alcohol alkoxylates (which may be branched or linear) based on natural and synthetic alcohols prepared from alcohols and ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof; amine ethoxylates, alkanolamides, and ethoxylated alkanolamides; alkoxylated triglycerides, such as ethoxylated soybean oil, castor oil, and rapeseed oil; alkylphenol alkoxylates (prepared from phenol and ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof), such as octylphenol ethoxylate, nonylphenol ethoxylate, dinonylphenol ethoxylate, and dodecylphenol ethoxylate; block polymers prepared from ethylene oxide or propylene oxide, and reverse block copolymers in which the end blocks are prepared from propylene oxide. ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenols (including those prepared from ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters, and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd PEG (polyethylene glycol) resins, graft or comb polymers, and star polymers; polyethylene glycol (PEG); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar derivatives such as sucrose esters, alkyl polyglycosides, and alkyl polysaccharides.

[0095] 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 tridecyl benzene. Included are sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkylnaphthalenes; sulfonates of fractionated petroleum; sulfosuccinates; and sulfosuccinates and derivatives thereof, such as dialkyl sulfosuccinates.

[0096] 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.

[0097] Also useful in the formulations of the present invention are mixtures of nonionic and anionic surfactants, or mixtures of nonionic and cationic surfactants. Nonionic, anionic, and cationic surfactants, and their recommended uses, are disclosed in various published references, including McCutcheon's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A.S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.

[0098] 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 also function as solid diluents, liquid diluents, or surfactants. Such formulation aids and additives may control: pH (buffering agents), foaming during processing (antifoaming agents such as polyorganosiloxanes), active ingredient settling (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobial agents), product freezing (antifreeze), color (dye / pigment dispersions), washout (film-forming agents or spreading agents), evaporation (evaporation inhibitors), and other formulation attributes. Film-forming agents 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.

[0099] 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 milling 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 upon dilution 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. Aqueous slurries can be made into finished suspension concentrates (see, e.g., U.S. Pat. No. 3,060,084) or can be further processed by spray drying to form water-dispersible granules. Dry formulations typically require a dry milling process to produce average particle diameters in the range of 2 microns to 10 microns. Dusts and powders can be prepared by blending and usually milling (such as with a hammer mill or 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 Patent No. 3,299,566.

[0100] For more information on formulation techniques, see T. S. Woods, "The Formulator's Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. U.S. Patent No. 3,235,361, column 6, lines 16-7, line 19, and Examples 10-41; U.S. Patent No. 3,309,192, column 5, lines 43-7, line 62, and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167, and 169-182; U.S. Patent No. 2,891,855, column 3, lines 66-5, line 17, and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp. 81-96; Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in Formulation Technology, PJB See also, J.P. Gerhardt, J.P. Publications, Richmond, UK, 2000.

[0101] 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 broad-spectrum pre-emergence and / or post-emergence weed control utility in areas where complete control of all vegetation is desired, such as fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, airports, riverbanks, irrigation, and around other waterways, billboards, and around highway and railroad structures.Many of the compounds of the present disclosure are useful for selective control of grasses and broadleaf weeds in crop / weed mixtures by selective metabolism in the crop relative to the weeds, or by selective activity at the locus of physiological inhibition in the crop and the 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.

[0102] In some variations, provided herein are methods for controlling undesirable vegetation comprising applying a compound of Formula (I), (II), (III), (IV), or (V), 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 10,000ml 2 2-5,000g per 10,000ml 2 5-2,000g per 10,000ml 2 1-1000g per 10,000ml 2 1-500g per 10,000ml 2 1-100g per 10,000ml 2 1-75g per 10,000ml 2 15-1000g per 10,000ml 2 15-100g per 10,000ml2 15-75g per 10,000ml 2 In certain variations of the foregoing, application of the compounds at the above rates results in post-emergence control of undesirable vegetation and / or pre-emergence control of undesirable vegetation.

[0103] In certain variations, application of the compound, including the aforementioned application rates, results in burndown. In one variation, burndown refers to when a herbicide is used to reduce the presence of weeds at the time of treatment. Burndown is often used in minimum or no-till fields because weeds cannot be controlled by drilling the soil. Burndown applications can be used after harvest and / or before crop emergence. Burndown can be useful against weeds that emerge during the growing season.

[0104] In certain variations, application of the compounds, including the aforementioned application rates, provides residual control. The compounds described herein can be used as pre-emergence herbicides, which 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 emerging or newly emerged weeds.

[0105] 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 foregoing, the undesirable vegetation is a weed. In one variation, the undesirable vegetation is a PPO inhibitor-resistant weed.

[0106] 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, forage 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 herein include corn, soybean, wheat, and cotton fields.

[0107] Examples of vegetable fields that can be treated with the compound of the present invention include fields where Solanaceae vegetables (eggplant, tomato, bell pepper, chili pepper, potato, etc.) are grown, fields where Cucurbitaceae vegetables (cucumber, pumpkin, zucchini, watermelon, melon, etc.) are grown, fields where Brassicaceae vegetables (radish, turnip, wasabi, kohlrabi, Chinese cabbage, cabbage, mustard greens, broccoli, cauliflower, etc.) are grown, fields where Asteraceae vegetables (burdock, chrysanthemum, almond, etc.) are grown, and fields where Asteraceae vegetables (burdock, chrysanthemum, almond, etc.) are grown. These include fields for growing vegetables of the lily family (such as leeks, onions, garlic, and asparagus), fields for growing vegetables of the Apiaceae family (such as carrots, parsley, celery, and parsnips), fields for growing vegetables of the Chenopodiaceae family (such as spinach and chard), fields for growing vegetables of the Lamiaceae family (such as perilla, mint, basil, and lavender), strawberry fields, sweet potato fields, yam fields, and taro fields.

[0108] 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 (Satsuma mandarins, oranges, lemons, limes, grapefruits, etc.), nuts (chestnuts, walnuts, hazelnut trees, almonds, pistachios, cashew trees, macadamia trees, etc.), berries (grapes, blueberries, cranberries, blackberries, raspberries, etc.), persimmons, olives, and loquats.

[0109] Examples of non-crop land in the present invention include sports fields, vacant lots, railroad verges, parks, parking lots, road verges, dry riverbeds, land under power lines, residential areas, and industrial areas.

[0110] The crops cultivated in the crop fields of the present invention are not limited as long as they are varieties that are commonly cultivated as crops.

[0111] The above-mentioned plant varieties can be plants that can be produced by natural crossbreeding, 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 substances toxic to pests, reduced susceptibility to diseases, increased potential yield, improved resistance to biotic and abiotic stress factors, accumulation of substances, and improved storability and processability.

[0112] F1 hybrid plants are first-generation hybrids obtained by crossing two different strain varieties and generally possess heterosis, which means that they have traits superior to those of either parent.Transgenic plants contain foreign genes introduced from another organism, such as a microorganism, and possess traits that are not readily obtainable by crossbreeding, mutagenesis, or natural recombination in their natural environment.

[0113] Techniques for producing the above-mentioned plants include, for example, conventional breeding, genetic engineering, genomic breeding, novel breeding, and genome editing. Conventional breeding techniques are used to obtain plants with desired characteristics through mutation or crossbreeding. Genetic engineering techniques include techniques for conferring 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 conferring new or improved characteristics by silencing another gene present in the plant. Genomic breeding techniques use genomic information to improve breeding efficiency. Examples of genomic breeding techniques include DNA marker (also called genomic marker or gene marker) breeding and genomic selection. For example, DNA marker breeding is a method of selecting offspring possessing a targeted useful trait gene from a large number of crossbreeding progeny using DNA markers, which are DNA sequences that function as markers for the location of specific useful trait genes on the genome. In this method, the hybrid offspring, when they are seedlings, are analyzed using DNA markers, effectively shortening the time required for breeding.

[0114] Genomic selection is a technique that creates a predictive formula based on previously obtained phenotype and genomic information, and predicts characteristics from the formula and genomic information without evaluating the phenotype. This technique can contribute to improving breeding efficiency. The term "new breeding techniques" is a general term for plant 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 to GM rootstock or scion, reverse crossing, agroinfiltration, and seed production technology (SPT). Genome editing technology is a technique for sequence-specifically converting genetic information, which can be used to delete base sequences, replace amino acid sequences, or introduce foreign genes. Examples of tools include sequence-specific genome modification technologies such as zinc finger nucleases (ZFNs), which are 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.

[0115] Examples of the above-mentioned plants include plants listed in the database of genetically modified crops (GM Approval Database) registered on the electronic information site of the International Service for Acquisition of Agri-biotech Applications (ISAAA) (http: / / www.isaaa.org / ). More specific examples are herbicide-resistant plants, pest-resistant plants, disease-resistant plants, plants with modified product (e.g., starch, amino acids, and fatty acids) quality (e.g., with increased or decreased content or altered composition), reproductive trait-modified plants, abiotic stress-tolerant plants, and plants with modified growth- or yield-related traits.

[0116] Herbicide resistance mechanisms include reduced affinity between the herbicide and its target, rapid drug metabolism (degradation, modification, etc.) by expressed enzymes that inactivate the herbicide, or inhibition of herbicide uptake or translocation within the plant. Examples of plants conferred herbicide resistance through genetic engineering include plants conferred tolerance to 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors such as isoxaflutole and mesotrione, acetolactate synthase (ALS) inhibitors such as imazethapyr-containing imidazolinone herbicides and thifensulfuron-methyl-containing sulfonylurea herbicides, 5-enolpyruvylshikimate-3-phosphate synthase (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, soybeans, rice, rapeseed, sugar beet, sugarcane, grapes, lentils, sunflowers, alfalfa, apples, drupes, coffee, tea, strawberries, turf, tomatoes, potatoes, cucumbers, and vegetables such as lettuce, and more preferred herbicide-tolerant transgenic plants are cereals such as wheat, barley, rye, and oats, soybeans, rice, grapes, tomatoes, potatoes, and apples.

[0117] In one embodiment, to obtain a glyphosate herbicide-tolerant plant, one or more genes are introduced from the following: glyphosate-tolerant EPSPS gene from Agrobacterium tumefaciens strain CP4 (CP4 epsps); glyphosate-metabolizing enzyme genes (gat4601, gat4621) from Bacillus licheniformis, whose metabolic activity of the glyphosate-metabolizing enzyme (glyphosate N-acetyltransferase) gene is enhanced by shuffling technology; glyphosate-metabolizing enzyme (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 with 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 with a glyphosate-tolerant mutation derived from corn are commercially available under trade names such as "GlyTol (registered trademark)."

[0118] In another example, to obtain a glufosinate herbicide-tolerant plant, one or more genes are introduced from Streptomyces hygroscopicus, a glufosinate-metabolizing enzyme, the phosphinothricin N-acetyltransferase (PAT) gene (bar), Streptomyces viridochromogenes, a glufosinate-metabolizing enzyme, the phosphinothricin N-acetyltransferase (PAT) enzyme gene (pat), and Streptomyces viridochromogenes strain Tu494, a synthetic pat gene (pat syn). Examples of plants include Argentine canola (Brassica napus), chicory (Cichorium intybus), cotton (Gossypium hirsutum L.), corn (Zea mays L.), Poland 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 containing glufosinate-metabolizing enzymes (bar) derived from Streptomyces hygroscopicus and Streptomyces viridochromogenes are commercially available under the trade names "LibertyLink®," "InVigor®," or "WideStrike®."

[0119] In another example, oxynil herbicide-tolerant plants are known. For example, a bromoxynil-tolerant transgenic plant is introduced into which the nitrilase gene (bxn) is derived from an oxynil herbicide-metabolizing enzyme from Klebsiella pneumoniae subsp. ozaenae. Key examples of plants include 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®."

[0120] ALS herbicide-resistant plants are also known. Examples include carnations (Dianthus caryophyllus) obtained by introducing the ALS herbicide-resistant ALS gene (surB) from tobacco (Nicotiana tabacum) as a selection marker 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-resistant ALS gene (als) derived from Arabidopsis thaliana has been introduced is commercially available under the trade name "CDC Triffid Flax," and corn (Zea mays) into which the ALS herbicide-resistant ALS gene (zm-hra) from corn has been introduced to exhibit tolerance to sulfonylurea herbicides and imidazolinone herbicides. Soybean tolerant to imidazolinone herbicides, which incorporate the ALS gene (csr1-2) derived from Arabidopsis thaliana, is commercially available under the trade name "Cultivance®." Soybean tolerant to sulfonylurea herbicides, which incorporate the ALS gene (gm-hra) derived from soybean (Glycine max), is commercially available under the trade names "Treus®," "Plenish®," and "Optimum® GAT®." Cotton also contains the ALS gene (S4-HrA) derived from tobacco (Nicotiana tabacum cv. Xanthi).

[0121] HPPD herbicide-tolerant plants are also known. One example is soybean into which the mesotrione-tolerant HPPD gene (avhppd-03) derived from oat (Avena sativa) and the phynothricin N-acetyltransferase (PAT) enzyme gene (pat) have been simultaneously introduced. Another example is mesotrione-tolerant soybean into which the glufosinate-metabolizing enzyme derived from Streptomyces viridochromogenes has been introduced.

[0122] In another example, examples of 2,4-D-tolerant plants include corn introduced with the aryloxyalkanoate dioxygenase gene (aad-1) for the 2,4-D metabolic enzyme derived from Sphingobium herbicidovorans, which is commercially available under the trade name "Enlist (registered trademark) corn," and soybeans and cotton introduced with the aryloxyalkanoate dioxygenase gene (aad-12) for the 2,4-D metabolic enzyme derived from Delftia acidovorans, which are commercially available under the trade name "Enlist (registered trademark) soybeans."

[0123] In another example, dicamba-tolerant plants include soybean and cotton introduced with a dicamba monooxygenase gene (dmo) containing 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, and are commercially available under the trade name "Genuity® Roundup Ready™ 2 Xtend®."

[0124] 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® Canola"; glyphosate-tolerant rice "Roundup Ready® Rice ... Ready® Rice; glufosinate-tolerant corn "Roundup Ready® 2," "LibertyLink®," "Herculex® 1," "Herculex® RW," "Herculex® Xtra," "Agrisure® GT / CB / LL," "Agrisure® CB / LL / RW," and "Bt10"; glufosinate-tolerant cotton "FiberMax™ LibertyLink™"; glufosinate-tolerant canola "InVigor®"; glufosinate-tolerant rice "LibertyLink® Rice" (manufactured by Bayer AG); bromoxynil-tolerant cotton "BXN"; bromoxynil-tolerant canola "Navigator®" and "Compass®"; and glufosinate-tolerant canola "InVigor®."Additional herbicide-modified plants are widely known, and examples of 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. Patent 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, soybeans, and other crops that are tolerant 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, and examples of rice 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., US2003 / 0217381 and WO200520673), and examples include rice that is tolerant to HPPD inhibitor herbicides (e.g., isoxaflutole). 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 oxazole herbicides, triketone herbicides such as sulcotrione or mesotrione, pyrazole herbicides such as pyrazophosphates, or diketonitriles, which are breakdown products of isoxaflutole (see, e.g., WO2004 / 055191, WO199638567, WO1997049816, and U.S. Pat. No. 6,791,014).

[0125] Examples of plants that have been conferred herbicide tolerance by classical or genomic breeding techniques include rice "Clearfield® Rice," wheat "Clearfield® Wheat," sunflower "Clearfield® Sunflower," lentil "Clearfield® Lentil," and canola "Clearfield® Canola" (manufactured by BASF SE) that are tolerant to imidazolinone ALS inhibitor herbicides such as imazethapyr or imazamox; soybean "STS® Soybean" that is tolerant to sulfonyl ALS inhibitor herbicides such as thifensulfuron-methyl; sethoxydim-tolerant corn "SR® Maize" and "Poast" that are tolerant to acetyl-CoA carboxylase inhibitors such as trione oxime herbicides or aryloxyphenoxypropionic acid herbicides. "Provisia™ Rice", rice tolerant to acetyl-CoA carboxylase inhibitors such as quizalofop; and "Triazine-Tolerant Canola", canola tolerant to PSII inhibitors.

[0126] Examples of plants conferred herbicide tolerance using genome editing include the sulfonylurea herbicide-tolerant canola "SU Canola®," which was developed using the Rapid Trait Development System (RTDS®). RTDS® corresponds to the oligonucleotide-directed mutagenesis genome editing technology, which allows for the introduction of mutations into plant DNA without DNA cleavage via gene repair oligonucleotides (GRONs), i.e., chimeric oligonucleotides of DNA and RNA. Other examples of plants include maize, which has been conferred herbicide tolerance and reduced phytic acid content by deleting the endogenous IPK1 gene using zinc finger nucleases (see, e.g., Nature 459, 437-441 2009), and rice, which has been conferred herbicide tolerance using CRISPR-Cas9 (see, e.g., Rice 7, 5 2014).

[0127] In the present invention, examples of crops that are tolerant to a specific PPO inhibitor include crops that have been genetically engineered to have a PPO with reduced affinity for the inhibitor. Alternatively, the crop may have, alone or in combination with the above-mentioned PPO, a substance that detoxifies and decomposes the PPO inhibitor via cytochrome P450 monooxygenase. Resistant crops are described 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, pp. 277-285.

[0128] 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, pp. 412-416).

[0129] The above-mentioned plants include lines that have been imparted with two or more traits from among the above-mentioned abiotic stress tolerance, disease resistance, herbicide tolerance, pest resistance, growth traits, yield traits, nutrient uptake, product quality, and reproduction traits using genetic engineering techniques, classical breeding techniques, genomic breeding techniques, new breeding techniques, genome editing techniques, etc., as well as lines that have been imparted with two or more traits from the characteristics of parent lines by crossbreeding plants with the same or different traits.

[0130] Examples of commercially available plants that are conferred tolerance to two or more herbicides include "GlyTol™ LibertyLink™" and "GlyTol™ LibertyLink™" cotton, which are tolerant to glyphosate and glufosinate; "Roundup Ready™ LibertyLink™ Corn," which is tolerant to glyphosate and glufosinate; "Enlist™ Soybean," which is tolerant to glufosinate and 2,4-D; "Genuity® Roundup Ready™ 2 Xtend™," which is tolerant to glyphosate and dicamba; "OptimumGAT™," which is tolerant to glyphosate and an ALS inhibitor; and "Enlist E3™" and "Enlist™ Roundup™," which are genetically modified soybeans that are tolerant to glyphosate, glufosinate, and 2,4-D. Ready® 2Yield; Enlist™ Roundup Ready® Corn 2, a genetically modified corn that is tolerant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; Enlist™ Roundup Ready® Corn 2, a genetically modified corn that is tolerant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; Bollgard II® XtendFlex™ Cotton, a genetically modified cotton that is tolerant to dicamba, glyphosate, and glufosinate; and Enlist™ Cotton, a genetically modified cotton that is tolerant to glyphosate, glufosinate, and 2,4-D herbicides. Additionally, 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.

[0131] Examples of commercially available plants that are conferred 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 "YieldGard® VT Rootworm / RR2"; glyphosate-tolerant, corn rootworm- and pine moth-resistant corn "Yield Gard® VT Triple; Herculex® I corn, which is 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, which is tolerant to glyphosate and resistant to corn rootworm. "Ready® 2"; "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" 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, bollworm larvae, and armyworm larvae).

[0132] In the present invention, the composition of the present invention is applied to a place where weeds are growing or may grow. Examples of methods for applying the composition include spraying the composition onto the soil and spraying the composition onto the weeds.

[0133] In some variations, the application rate of the compositions of the present invention is generally 10,000 m of total amount of compounds of formula (I), (II), (III), (IV) or (V), or salts thereof (including agriculturally suitable salts thereof). 2 1-10,000g per 10,000ml 2 2-5,000g per 10,000ml 2 5-2000g per 10,000ml 2 1-1000g per 10,000ml 2 1-500g per 10,000ml 2 1-100g per 10,000ml 2 1-75g per 10,000ml 2 15-1000g per 10,000ml 2 15-100g per 10,000ml 2 15-75g per 10,000ml 2 Each serving weighs 15 to 60g.

[0134] In one variant, the application rate of the composition of the present invention is a total amount of a compound of formula (I), (II), (III), (IV) or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener group C, generally in an amount of 10,000 m 2 1-10,000g per 10,000ml 2 2-5,000g per 10,000ml 2 5-2,000g per 10,000ml 2 1-1,000g per 10,000ml 2 1-500g per 10,000ml 2 1-100g per 10,000ml 2 1-75g per 10,000ml 215-1000g per 10,000ml 2 15-100g per 10,000ml 2 15-75g per 10,000ml 2 Each serving weighs 15 to 60g.

[0135] In this method, the adjuvant can be mixed into the composition of the present invention and then applied. The type of adjuvant is not particularly limited, and examples of adjuvants include oil-based adjuvants such as Agri-Dex (registered trademark) and methylated rapeseed oil (MSO), nonionic adjuvants (polyoxyethylene esters or ethers) such as Induce, anionic adjuvants (substituted sulfonates) such as Gramine S, cationic adjuvants (polyoxyethylene amines) such as Genamin (registered trademark) T200BM, and organic silicones such as Silwet (registered trademark) L77.

[0136] 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.

[0137] The period for applying the composition of the present invention is not particularly limited, but is usually in the range of 5:00 AM to 9:00 PM, and the photon flux density is usually 10 to 2,500 μmol / m 2 / s.

[0138] When the composition of the present invention is applied to a crop field, it can be applied before sowing the crop seeds, at the same time as sowing the crop seeds, and / or after sowing the crop seeds. That is, the application frequency of the composition of the present invention is once before sowing the crop seeds, at the same time as sowing, or after sowing, twice excluding before sowing, excluding at the same time as sowing, or excluding after sowing, or three times at all timings.

[0139] When the composition of the present invention is applied before sowing the crop seeds, it is applied from 50 days before to just before sowing, preferably from 30 days before to just before sowing, more preferably from 20 days before to just before sowing, and even more preferably from 10 days before to just before sowing.

[0140] 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, the seed drill and the sprayer are integrated with each other.

[0141] In applying the composition of the present invention to a cultivated area, a compound or compounds of formula (I), (II), (III), (IV), or (V) and at least one additional compound selected from the group consisting of herbicide compound group B and safener group C are typically mixed with a carrier such as a solid carrier or a liquid carrier, and formulation adjuvants such as surfactants are added as needed 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, with emulsifiable concentrates being more preferred. Furthermore, a formulation containing a compound of formula (I), (II), (III), (IV), or (V) alone as the 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 the active ingredient. Furthermore, a formulation containing the composition of the present invention as the active ingredient and a formulation containing another herbicide as the active ingredient may be used in combination.

[0142] Examples of methods for applying the composition of the present invention to a cultivated area include spraying it onto the soil of the cultivated area and spraying the composition of the present invention onto 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, and more preferably 140 to 300 L / ha.

[0143] Specific examples of weed species controlled by the present compositions include, but are not limited to, the weed species listed below.

[0144] Weeds in the nettle family that should be controlled include Urtica urens.

[0145] 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.

[0146] Portulacaceae weeds controlled include Portulaca oleracea.

[0147] Caryophyllaceae weeds controlled include Stellaria media, Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum, Spergula arvensis, and Silene gallica.

[0148] Weeds in the Garlic family that are controlled include Mollugo verticillate.

[0149] Chenopodiaceae weeds controlled include Chenopodium album, Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplex spp.

[0150] 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.

[0151] Papaveraceae weeds controlled include Papaver rhoeas, Papaver dubium, and Argemone Mexicana.

[0152] 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.

[0153] Capparaceae weeds controlled include Cleome affinis.

[0154] Leguminous weeds controlled include Aeschynomene indica, Aeschynomene rudis, Sesbania exaltata, Cassia obtusifolia, Cassia occidentalis, Desmodium adscendens, Desmodium illinoense, Trifolium repens, Pueraria lobata, Vicia angustifolia, Indigofera hirsuta, Indigofera truxillensis, and Vigna sinensis.

[0155] Oxalid weeds controlled include Oxalis, Oxalis strica, and Oxalis oxyptera.

[0156] Geraniaceae weeds controlled include Geranium carolinense and Erodium cicutarium.

[0157] 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.

[0158] Malvaceae weeds controlled include Abutilon theophrasti, Sida rhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sida santaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrum coromandelianum.

[0159] Onagraceae weeds controlled include Ludwigia epilobioides, Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenothera laciniata.

[0160] Sterculiaceae weeds controlled include Waltheria indica.

[0161] Violaceous weeds controlled include Viola arvensis and Viola tricolor.

[0162] Cucurbitaceous weeds controlled include Sicyos angulatus, Echinocystis lobata, and Momordica charantia.

[0163] Lythrum weeds controlled include Ammannia multiflora, Ammannia auriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica.

[0164] Weeds in the Chickweed family controlled include Elatine triandra and Elatine californica.

[0165] Umbelliferous weeds controlled include Oenanthe javanica, Daucus carota, and Conium maculatum.

[0166] Weeds in the Pine Algae family that are controlled include Ceratophyllum demersum.

[0167] Weeds in the Cabomba family that are controlled include Cabomba caroliniana.

[0168] Weeds of the family Myriophyllumaceae that may be controlled include Myriophyllum aquaticum, Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllum heterophyllum.

[0169] Sapindaceae weeds controlled include Cardiospermum halicacabum.

[0170] Primrose weeds controlled include Anagallis arvensis.

[0171] Asclepiad weeds controlled include Asclepias syriaca and Ampelamus albidus.

[0172] Rubiaceae weeds controlled include Galium aparine, Galium spurium var. echinospermon, Spermacoce latifolia, Richardia brasiliensis, and Borrelia alata.

[0173] 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.

[0174] Boraginaceae weeds controlled include Myosotis arvensis.

[0175] Lamiaceae weeds controlled include Lamium purpureum, Lamium amplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta, Leonurus sibiricus, and Stachys arvensis.

[0176] 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.

[0177] Scrophulariaceae weeds controlled include Veronica hederaefolia, Veronica persica, Veronica arvensis, Lindernia procumbens, Lindernia dubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum, and Gratiola japonica.

[0178] Plantaginaceae weeds controlled include Plantago asiatica, Plantago lanceolata, Plantago major, and Callitriche palustris.

[0179] 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.

[0180] Weeds in the Alismaceae family that may be controlled include Sagittaria pygmaea, Sagittaria trifolia, Sagittaria sagittifolia, Sagittaria montevidensis, Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica.

[0181] Weeds in the yellow arrowhead family that are controlled include Limnocharis flava.

[0182] Hydrocharid weeds controlled include Limnobium spongia, Hydrilla verticillata, and Najas guadalupensis.

[0183] Araceae weeds controlled include Pistia stratiotes.

[0184] Duckweed weeds controlled include Lemna aoukikusa, Spirodela polyrhiza, and Wolffia spp.

[0185] Potamogeton species controlled include Potamogeton distinctus, Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata.

[0186] Liliaceae weeds controlled include Allium canadense, Allium vineale, and Allium macrostemon.

[0187] Weeds of the Pontederiaceae family that are controlled include the genera Eichhornia crassipes, Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis.

[0188] Daylily weeds controlled include Commelina communis, Commelina bengharensis, Commelina erecta, and Murdannia keisak.

[0189] 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.

[0190] 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 nipponicus, Schoenoplectiella triqueter, Bolboschoenus koshevnikovii, and Bolboschoenus fluviatilis.

[0191] Equisetum weeds controlled include Equisetum arvense and Equisetum palustre.

[0192] Salviniaceae weeds controlled include Salvinia natans.

[0193] Azollaceae weeds controlled include Azolla japonica and Azolla imbricata.

[0194] Marsilea weeds controlled include Marsilea quadrifolia.

[0195] Other weeds controlled include Pithophora, Cladophora, Bryophyta, Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, and suckers of perennial crops (e.g., pome fruits, nuts, citrus, hops, grapes).

[0196] The intraspecific mutations of the above-mentioned weeds to be controlled are not particularly limited. That is, weeds include weeds with reduced sensitivity to a specific herbicide. The reduced sensitivity can be due to a mutation at the target site (target site mutation) or any factor other than a mutation at the target site (non-target site mutation). Examples of factors that reduce sensitivity due to non-target site mutation include increased metabolism, impaired absorption, impaired transport, and excretion from the system. Examples of factors that increase metabolism include increased activity of metabolic enzymes such as cytochrome P450 monooxygenase, aryl acylamidase, esterase, or glutathione S-transferase. Examples of excretion from the system include transport to the vacuole by ABC transporters. Examples of weeds having reduced susceptibility due to mutations 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 mutations at the target site 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.

[0197] Similarly, examples of weeds with reduced susceptibility due to mutations at the target site include PPO inhibitor-resistant weeds with one or more mutations in PPO selected from the group consisting of Arg128Leu mutation, Arg128Met mutation, Arg128Gly mutation, Arg128His mutation, Gly210 deletion mutation, and Gly399Ala mutation. The term "PPO" refers to protoporphyrinogen oxidase. Weeds typically have PPO1 and PPO2 in their PPOs, and the above-mentioned mutations may be present in either or both PPO1 and PPO2. It is preferable for weeds to have a mutation in PPO2. For example, the term "Arg128Met" means that the mutation is present in the 128th amino acid (the number is standardized to the PPO2 of Amaranthus palmeri). In Ambrosia artemisiaefolia PPO2, the mutation corresponds to a mutation at amino acid 98 (Rousonelos, et al., Weed Science (2012) Vol. 60, pp. 335-344) and is known as Arg98Leu, where Arg98 is equivalent to Arg128 according to the present invention. The Arg128Met mutation and Arg128Gly mutation in the PPO of the weeds controlled by the present invention are known in Amaranthus palmeri (Giacomini, et al., Pest Management Science (2017) Vol. 73, pp. 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 to these. That is, other weeds having amino acid mutations are similarly controlled.Not only Amaranthus palmeri having the Arg128Leu mutation, Arg128Met mutation, Arg128Gly mutation, Arg128His mutation, Gly210 deletion mutation, or 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.

[0198] 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, glyphosate-resistant weeds with one or both mutations, such as Eleusine indica, Lolium multiflorum, Lolium rigidum, Digitaria insularis, waterhemp, and Echinochloa colona, ​​are effectively controlled. Similarly, examples of weeds with reduced susceptibility due to target sites include weeds with an increased number of copies of the EPSP gene, and glyphosate-resistant weeds with mutations, such as Amaranthus palmeri, waterhemp, and Kochia scoparia. Conyza canadensis, Conyza smatrensis, and Conyza bonariensis, which are resistant to glyphosate due to ABC transporters, are also effectively controlled.

[0199] In the cultivation of the present invention, plant nutrition management can be carried out in the same manner as in conventional crop cultivation. The pollination system can be based on precision agriculture or a conventional uniform system. In addition, nitrogen-fixing bacteria or symbiotic bacteria can be inoculated in combination with seed treatment.

[0200] combination In certain embodiments, weed control efficacy is demonstrated by using a compound of formula (I), (II), (III), (IV), or (V) in combination with a specific compound.

[0201] Accordingly, the present invention features (i) a herbicide composition comprising a compound of formula (I), (II), (III), (IV), or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C, wherein the weight ratio of the compound of formula (I), (II), (III), (IV), or (V) to the at least one compound selected from the group consisting of herbicide compound group B and safener compound 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 herbicide, 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).

[0202] The present invention also features a herbicidal composition according to (ii)(i), 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, thifensulfuron-methyl, triasulfuron, tribenuron, tribenuron-methyl, triflusulfuron, triflusulfuron-methyl, tritosulfuron, benca the group consisting of rubazone, flucarbazone, flucarbazone sodium salt, propoxycarbazone, propoxycarbazone sodium salt, thiencarbazone, thiencarbazone-methyl, cloransulam, cloransulam-methyl, diclosulam, florasulam, flumetsulam, metosulam, penoxsulam, piroxsulam, 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); B-2 is the group consisting of clodinafop, clodinafop-propargyl, cyhalofop, cyhalofop-butyl, diclofop, diclofop-methyl, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fluazifop, fluazifop-butyl, fluazifop-P, fluazifop-P-butyl, haloxyfop, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-methyl, metamifop, propaxaxafop, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, alloxydim, clethodim, sethoxydim, tepriraloxydim, tralkoxydim, and pinoxaden (including their agriculturally acceptable salts and derivatives); B-3 is azafenidin, oxadiazon, oxadiargyl, carfentrazone, carfentrazone-ethyl, saflufenacil, cinidon, cinidon-ethyl, sulfentrazone, pyraclonil, pyraflufen, pyraflufen-ethyl, butafenacil, fluazolate, fluthiacet, fluthiacet-methyl, flufenpyr, flufenpyr-ethyl, flumiclorac, flumiclorac-pentyl, flumioxazin, pentoxazone, oxyfluorfen, aciflufen, acifluorfen-sodium salt , aclonifen, chlormethoxynil, chlornitrofen, nitrofen, bifenox, fluoroglycofen, fluoroglycofen-ethyl, fomesafen, fomesafen-sodium salt, lactofen, thiafenacil, and ethyl [3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetate (including their agriculturally acceptable salts and derivatives); B-4 is benzobicyclon, bicyclopyrone, mesotrione, sulcotrione, tefuryltrione, tembotrione, isoxaclorthole, 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); B-5 is the group consisting of diflufenican, picolinafen, beflubutamid, norflurazon, fluridone, flurochloridone, and flutamone (including their agriculturally acceptable salts and derivatives); B-6 is the group consisting of ioxynil, ioxynil-octanoate, bentazone, pyridate, bromoxynil, bromoxynil-octanoate, chlorotoluron, dimefuron, diuron, linuron, fluometuron, isoproturon, isouron, tebuthiuron, benzthiazuron, methabenzthiazuron, propanil, metobromuron, metoxuron, monolinuron, siduron simazine, atrazine, propazine, cyanazine, ametryn, simetryn, dimethametryn, prometryn, terbumeton, terbuthylazine, terbutryn, trietazine, hexazinone, metamitron, metribuzin, amicarbazone, bromacil, lenacil, terbacil, chloridazon, desmedipham, and phenmedipham (including their agriculturally acceptable salts and derivatives); B-7 is the group consisting of propachlor, metazachlor, alachlor, acetochlor, metolachlor, S-metolachlor, butachlor, pretilachlor, thienylchlor, indanofan, cafenstrole, fentrazamide, dimethenamid, dimethenamid-P, mefenacet, pyroxasulfone, fenoxasulfone, naproanilide, napropamide, anilofos, flufenacet, and ifencarbazone (including their agriculturally acceptable salts and derivatives); B-8 is the group consisting of trifluralin, pendimethalin, ethalfluralin, benfluralin, oryzalin, prodiamine, butamiphos, dithiopyr, and thiazopyr (including their agriculturally acceptable salts and derivatives); B-9 is 2,4-DB [4-(2,4-dichlorophenoxy)butyric acid] and its salts or esters (dimethylammonium salt, isooctyl ester, and choline salt), MCPA and its salts or esters (dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, sodium salt, and choline salt), MCPB, mecoprop and its salts or esters (dimethylammonium salt, diolamine salt, etadyl ester, 2-ethylhexyl ester, isooctyl ester, methyl ester, potassium salt, sodium salt, trolamine salt, choline salt), mecoprop-P and its salts or esters (dimethylammonium salt, 2-ethylhexyl ester, isobutyl salt, potassium salt, choline salt), dichlorprop and its salts or esters (butoctyl salt, dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, the group consisting of triclopyr and its salts or esters (butotyl ester, triethylammonium salt), fluroxypyr, fluroxypyr meptyl, picloram and its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt, choline salt), quinclorac, quinmelac, aminopyralid and its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt, choline salt), clopyralid and its salts (olamine salt, potassium salt, triethylammonium salt, choline salt), clomeprop, aminocyclopyrachlor, halauxifen, halauxifen-methyl, florpyrauxifen, florpyrauxifen-benzyl (including their agriculturally acceptable salts and derivatives); B-10 is the group consisting of glyphosate, glyphosate-isopropylammonium salt, glyphosate-trimesium salt, glyphosate-ammonium salt, glyphosate-diammonium salt, glyphosate-dimethylammonium salt, glyphosate-monoethanolamine salt, glyphosate-sodium salt, glyphosate-potassium salt, and glyphosate-guanidine salt (including agriculturally acceptable salts of each and derivatives thereof); B-11 is the group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, glufosinate-P-sodium salt, and baylaphos (including agriculturally acceptable salts and derivatives thereof); B-12 is not a steroid, and is not a steroid. It is not a steroid, but it is a steroid that can be used to treat a wide range of conditions, including: isoxaben, dichlobenil, methiozolin, diallate, butyrate, triallate, chlorpropham, asuram, fenisofaam, benthiocarb, molinate, esprocarb, pyributicarb, prosulfocarb, orbencarb, EPTC, dimepiperate, swabs, difenoxuron, methyldimuron, bromobutide, daimuron, cumyluron, diflufenzopyr, diflufenzopyr-sodium salt, etobenzanide, tridiphane, amylol, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CAS 10141-10-1). The group consisting of (3S,4S)-N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (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, benfresate, ACN, dalapon, chlorthiamid, flupoxam, bensulide, paraquat, paraquat dichloride, diquat, diquat dibromide, MSMA, indaziflam, and triaziflam (including their agriculturally acceptable salts and derivatives).

[0203] The present invention also features (iii) the herbicide composition according to (i) or (ii), wherein the safener group C is the group consisting of benoxacor, cloquintocet, chometrinil, cyprosulfamide, diclomid, dicyclonone, dietholic acid, fenchlorazole, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen, mefenpyr, mephenate, naphthalic anhydride, oxabetrinil, 4-(dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane, 2,2,5-trimethyl-3-(dichloroacetyl)-1,3-oxazolidine, and N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.

[0204] In one embodiment, the present invention comprises the herbicide composition of (i), wherein (iv) B-1 is the group consisting of pyrithiobac, pyrithiobac-sodium salt, chlorimuron-ethyl, foramsulfuron, halosulfuron-methyl, nicosulfuron, primisulfuron-methyl, rimsulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, iodosulfuron-methyl-sodium, iofensulfuron sodium, metsulfuron-methyl, prosulfuron, thifensulfuron-methyl, tribenuron-methyl, thiencarbazone-methyl, cloransulam-methyl, flumetsulam, imazamethabenz-methyl, imazamox-ammonium salt, imazapic-ammonium salt, imazapyr-isopropylammonium, imazaquin-ammonium salt, and imazethapyr-ammonium salt (including agriculturally acceptable salts and derivatives thereof).

[0205] In another embodiment, the invention includes the herbicide composition of (i), wherein (v) B-2 is the group consisting of fenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl, fluazifop-P-butyl, quizalofop-ethyl, quizalofop-P-ethyl, clethodim, and sethoxydim (each including an agriculturally acceptable salt and a derivative thereof).

[0206] In another embodiment, the present invention includes the herbicide composition of [1], wherein [6]B-3 is the group consisting of carfentrazone-ethyl, saflufenacil, sulfentrazone, pyraflufen-ethyl, fluthiacet-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).

[0207] In another embodiment, the present invention relates to a compound selected from the group consisting of bicyclopyrone, mesotrione, tembotrione, isoxaflutole, fenquinotrione, topramezone, tolpyralic 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 The herbicide composition according to [1] is a herbicide of the group consisting of 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexen-1-yl)carbonyl]-2-methyl-1,2,4-triazine-3,5-(2H,4H)-dione (CAS Registry Number 1353870-34-4) (including agriculturally acceptable salts and derivatives thereof).

[0208] In another embodiment, the present invention includes the herbicide composition according to [1], wherein -[8]B-5 is the group consisting of nofurazan and fluridone (including agriculturally acceptable salts and derivatives thereof).

[0209] 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).

[0210] 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 agriculturally acceptable salts and derivatives thereof).

[0211] 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 a derivative thereof).

[0212] 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).

[0213] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[13] B-10 is 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 of each and derivatives thereof).

[0214] 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 of each and derivatives thereof).

[0215] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[15] B-12 is the group consisting of EPTC, diflufenzopyr, diflufenzopyr sodium salt, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9), (3S,4S)—N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8), cinmethylin, MSMA, paraquat, paraquat dichloride, diquat, and diquat dibromide (including agriculturally acceptable salts and derivatives thereof).

[0216] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[16] safener group C is the group consisting of benoxacor, cyprosulfamide, and isoxadifen-ethyl (including agriculturally acceptable salts and derivatives thereof).

[0217] The invention also features a method for controlling weeds

[18] , comprising the steps of simultaneously or sequentially applying a compound of formula (I), (II), (III), (IV), or (V) 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 will grow.

[0218] In one embodiment, the present invention encompasses the method of

[19] , wherein the compound of Formula (I), (II), (III), (IV), or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C are used in a weight ratio of 1:0.1 to 1:50.

[0219] In another embodiment, the present invention includes the method of claim

[18] or

[19] , wherein the location where the weeds are growing or will grow is a crop field.

[0220] The present invention also features

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

[16] for controlling weeds.

[0221] The herbicidal composition according to the present invention also comprises a compound of formula (I), (II), (III), (IV), or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener group C.

[0222] 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 location 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 can be applied before, simultaneously with, and / or after sowing crop seeds.

[0223] The method includes the step of simultaneously or sequentially applying a compound of formula (I), (II), (III), (IV), or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C to a location where weeds are growing or are likely to grow. In the case of sequential application, the order of application is not particularly limited.

[0224] The composition of the present invention is generally a formulation prepared by mixing a compound of formula (I), (II), (III), (IV), or (V) 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 optionally adding formulation adjuvants such as surfactants. 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.

[0225] The total content of the compound of formula (I), (II), (III), (IV), or (V) and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C in the composition is in the range of 0.01 to 90% by weight, preferably 1 to 80% by weight.

[0226] Hereinafter, when at least one compound selected from the group consisting of herbicide compound group B is a salt (for example, glyphosate potassium salt), the weight of the at least one compound is expressed in terms of acid equivalent.

[0227] In the composition of the present invention, the mixing ratio of the compound of formula (I), (II), (III), (IV), or (V) to at least one compound selected from the group consisting of herbicide compound group B and safener C is within the range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50, by weight.

[0228] In this method, the ratio of the application rate of the compound of formula (I), (II), (III), (IV), or (V) to at least one compound selected from the group consisting of herbicide compound group B and safener compound group C is within the weight ratio range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50.

[0229] In some variations, the mixing ratio of the compound of Formula (I), (II), (III), (IV), or (V) to at least one compound selected from the group consisting of herbicide compound group B and safener compound group C in the compositions 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.

[0230] In some variations, the ratio of the application rate of the compound of Formula (I), (II), (III), (IV), or (V) to at least one compound selected from the group consisting of herbicide compound group B and safener group C in the method comprises 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.

[0231] 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.

[0232] In the present compositions and methods, particularly preferred examples of combinations of a compound of formula (I), (II), (III), (IV), or (V) with at least one compound selected from the group consisting of herbicide compound group B and safener group C, and ranges of weight ratios thereof, include, but are not limited to, the following combinations and ranges: a combination of a compound of formula (I), (II), (III), (IV) or (V) with pyrithiobac (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with pyrithiobac sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with chlorimuron-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with foramsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), or (IV) with halosulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with nicosulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with primisulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with rimsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with trifloxysulfuron sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with chlorsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with iodosulfuron-methyl-sodium (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV) or (V) with iofensulfuron sodium (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with metsulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with prosulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with thifensulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with tribenuron-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV) or (V) with thiencarbazone-methyl (1:0.1 to 1:20), a combination of a compound of formula (I), (II), (III), (IV) or (V) with cloransulam-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with flumetsulam (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazamethabenz-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazamox ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazapic ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazapyr-isopropylammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazaquin-ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with imazethapyr-ammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV) or (V) with fenoxaprop-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fenoxaprop-p-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fluazifop-butyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fluazifop-p-butyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with quizalofop-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with quizalofop-p-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with clethodim (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with sethoxydim (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with carfentrazone-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with saflufenacil (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with sulfentrazone (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with pyraflufen-ethyl (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fluthiacet-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with flufenpyr-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with flumiclorac-pentyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with flumioxazin (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with oxyfluorfen (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with acifluorfen sodium salt (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fomesafen sodium salt (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with lactofen (1:0.1 to 1:30); a combination of a compound of formula (I), (II), (III), (IV) or (V) with thiafenacil (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with ethyl [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridin-2-yl)oxy]acetate (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with bicyclopyrone (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with mesotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with tembotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with isoxaflutole (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fenquinotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with topramezone (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with tolpyralate (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with lancotrione sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide (CAS Registry Number: 1400904-50-8) (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with 2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide (CAS Registry Number: 1361139-71-0) (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) 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 a compound of formula (I), (II), (III), (IV) or (V) with norflurazon (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fluridone (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with bentazon (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), or (IV) with bromoxynil octanoate (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with diuron (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with linuron (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with fluometuron (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with simazine (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with atrazine (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with ametryn (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with prometryne (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV) or (V) with metribuzin (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with alachlor (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with acetochlor (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV) or (V) with metolachlor (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with S-metolachlor (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with dimethenamide (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with dimethenamide-P (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with pyroxasulfone (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with flufenacet (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with trifluralin (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with pendimethalin (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with ethalfluralin (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with 2,4-DB (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV) or (V) with fluroxypyr (1:1 to 1:50), A combination of a compound of formula (I), (II), (III), (IV) or (V) with fluroxypyr-meptyl (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with clopyralid-olamine salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with clopyralid potassium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with clopyralid triethylammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with halaxifene (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with haluxifen-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with florpiruxifen (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with florpiruxifen-benzyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-isopropylammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-ammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-dimethylamine salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-monoethanolamine salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-potassium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glyphosate-guanidine salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glufosinate (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glufosinate-ammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glufosinate-P (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with glufosinate-P-sodium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with EPTC (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with diflufenzopyr (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with diflufenzopyr sodium salt (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with clomazone (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9) (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) and (3S,4S)—N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8) (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with cinmethyline (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV) or (V) with MSMA (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with paraquat (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with paraquat dichloride (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with diquat (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with diquat-dibromide (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV) or (V) with benoxacor (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV) or (V) with cyprosulfamide (1:0.1 to 1:20); or Combinations of compounds of formula (I), (II), (III), (IV) or (V) with isoxadifen-ethyl (1:0.1 to 1:20).

[0233] The composition of the present invention may be applied to a field where crop seeds have been sown or are to be sown before, simultaneously with, and / or after sowing crop seeds treated with one or more compounds selected from the group consisting of insecticide compounds, nematicide compounds, fungicide compounds, and the like.

[0234] In some embodiments, the composition can be used in combination with another insecticidal active compound. Examples of insecticide compounds, nematicide compounds, and fungicide compounds that can be used in combination with the composition include neonicotinoid compounds, diamide compounds, carbamate compounds, organophosphorus compounds, biological nematicide compounds, other insecticide and nematicide compounds, azole compounds, strobilurin compounds, metaxyl compounds, SDHI compounds, and other fungicide compounds and plant growth regulators. [Example]

[0235] 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.

[0236] Compound synthesis and characterization. The steps of the following examples 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 used to determine the isotopic abundance of the molecule, where the H is present in the molecule, with the highest isotope abundance. +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 (molecular weight of 1), observed using liquid chromatography coupled to a mass spectrometer (LCMS) using atmospheric pressure chemical ionization (AP+), or electrospray ionization (ES+), where "amu" represents a single atomic mass unit.

[0237] Example 1 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 1) and 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 2) [ka] As shown in Scheme 3, 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), KPO (33.9 g, 160 mmol), chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-aminato-1,1-biphenyl-2-yl]palladium(II) (2.7 g, 4.0 mmol), and bis(adamantan-1-yl)(butyl)phosphane (1.4 g, 4.0 mmol) in dioxane (150 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The solvent was removed under reduced pressure and the residue was purified by reverse-phase flash chromatography (5% to 52% acetonitrile in water) to give 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1001, 11.0 g, 38% yield) as a pale yellow solid: GCMS calculated C 13 H6F5NO3=319.0, actual measured value 319.0.

[0238] As shown in Scheme 3, 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 at 0 °C under a nitrogen atmosphere. 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 1002, 790 mg, 74% yield) as a brown solid: MS (ESI) calculated C 12 H4F5NO3[M-1] - =304.0, actual value 303.9.

[0239] As shown in Scheme 3, Step 3, 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) was added sodium hyposulfite (2.0 g, 12.94 mmol). The resulting mixture was stirred at 100 °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. The residue was purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to afford 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1003, 580.0 mg, 59% yield) as a yellow solid: MS (ESI) calculated value C 12 H6F5NO[M-1] - =274.0, actual value 274.0.

[0240] As shown in Scheme 3, Step 4, to a solution of 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (580 mg, 2.10 mmol) and TEA (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 1004, 800 mg, 75% yield) as a brown oil: MS (ESI) calculated C 14 H5BrF7NO2[M-1] - =429.9, actual value 430.0.

[0241] As shown in Scheme 3, Step 5, a stirred solution of 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 K2CO3 (417 mg, 3.02 mmol) in DMF (10 mL) was stirred at 50 °C for 2 h, cooled to room temperature, diluted with water, and extracted with DCM. 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 in water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1005, 250 mg, 31% yield) as a brown solid: MS (ESI) calculated C 14 H4F7NO2[M-1] - =350.0, actual value 350.2; 1H-NMR(400 MHz,DMSO-d6)δ 12.14(s,1H),7.71-7.65(m,1H),7.62(d,J=9.6 Hz,1H),7.20(d,J=6.4 Hz,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.34, -115.87, -116.95, -131.54, -134.11, -164.81.

[0242] As shown in Scheme 3, Step 6, to 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 added KCO (112 mg, 0.81 mmol) and methyl 2-bromoacetate (109 mg, 0.81 mmol). The mixture was stirred at room temperature 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, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 1, 80 mg, 33% yield) as an off-white solid: GCMS calculated C 17 H7F8NO4=441.0, measured value 441.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.81-7.79 (m, 2H), 4.89 (s, 2H), 3.72 (s, 3H).

[0243] As shown in Scheme 3, Step 7, to a solution of methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (50 mg, 0.11 mmol) in THF (1.5 mL) and water (0.5 mL) was added lithium hydroxide (17 mg, 0.45 mmol). The resulting mixture was stirred at room temperature for 16 hours, acidified to pH 2-3 with formic acid, and then purified by reverse-phase preparative HPLC (55%-85% acetonitrile / 0.05% aqueous TFA) to give 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 2, 32 mg, 66% yield) as a white solid: MS (ESI) calculated C 16 H5F8NO4[M-1] - =427.0, actual value 425.8; 1 H-NMR (400 MHz, DMSO-d6) δ 13.74 (br, 1H), 7.79-7.74 (m, 2H), 4.74 (s, 2H).

[0244] Use of the appropriate alkylating agent in a transformation similar to that described in Scheme 3, followed by any subsequent synthetic manipulations or purification, led to the preparation of the following compounds.

[0245] Alkylation of compound 1005 with 4-bromo-2-(bromomethyl)-N,N-diethylbenzamide produced 4-bromo-N,N-diethyl-2-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide (compound 3): MS(ESI) calculated C 26 H 17 BrF8N2O3[M+H] + =637.03 and 639.06, actual values ​​637.05 & 639.05; 1H-NMR(400 MHz, methanol-d4)δ 7.66-7.56(m,1H),7.53(d,J=6.4 Hz,1H),7.46-7.36(m,2H),7.26(d,J=8.0 Hz,1H),5.22(b,2H),3.62-3.52(m,2H),3.28-3.24(m,2H),1.30(t,J=7.2 Hz,3H),1.15(t,J=7.2 Hz,3H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.10, -116.69, -142.42, -156.45, -164.98.

[0246] Alkylation of compound 1005 with methyl 2-(bromomethyl)benzoate produced methyl 2-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate (compound 4): GCMS calculated C 23 H 11 F8NO4=517.1, measured value 517.1; 1 H-NMR(400 MHz,DMSO-d6)δ 8.09-7.99(m,1H),7.85-7.80(m,1H),7.62-7.52(m,1H),7.50-7.40(m,2H),7.10-7.03(m,1H),5.59(s,2H),3.88(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.27, -115.88, -140.66, -153.34, -162.09, which was subsequently treated with 4 M HCl / dioxane at 100 °C to give 2-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid (compound 5); MS (ESI) calculated C 22 H9F8NO4[M-1] - =502.0, actual value 502.1; 1H-NMR(400 MHz,DMSO-d6)δ 13.27(s,1H),8.06-8.01(m,1H),7.85-7.78(m,1H),7.60-7.32(m,3H),7.08-6.98(m,1H),5.61(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.35, -115.97, -140.66, -153.52, -162.15.

[0247] Alkylation of compound 1005 with methyl 4-bromobutanoate produced methyl 4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (compound 16): GCMS calculated C 19 H 11 F8NO4=469.1, measured value 469.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.80(d,J=6.4 Hz,1H),7.73(d,J=9.6 Hz,1H),4.05(t,J=7.2 Hz,2H),3.55(s,3H),2.44(t,J=7.2 Hz,2H),1.92-1.82(m,2H); 19 F-NMR (376 MHz, DMSO-d) δ −74.29, −116.41, −140.32, −153.33, −162.08, which after treatment with LiOH in THF / HO produced 4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 17): MS(ESI) calculated C 18 H9F8NO4[M-1] - =454.0, actual value 453.9; 1 H-NMR(400 MHz,DMSO-d6)δ 12.20(s,1H),7.82(d,J=6.4 Hz,1H),7.79-7.73(m,1H),4.06-3.99(m,2H),2.39-2.33(m,2H),1.88-1.79(m,2H); 19F-NMR (376 MHz, DMSO-d6) δ -74.27, -116.44, -140.33, -153.37, -161.96.

[0248] Compound 1005 was alkylated with methyl 2-hydroxy-2-methylpropanoate under Mitsunobu conditions using triphenylphosphine and diisopropyl azodicarboxylate to produce 2-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 18): GCMS calculated C 19 H 11 FNO = 469.0, found 469.0, which was then treated with BBr in DCM at 0 °C to produce 2-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 19), which was isolated as its ring-closed tautomer, [4,4,7-trifluoro-3a-hydroxy-1,1-dimethyl-8-(perfluorophenyl)-3a,4-dihydrobenzo[b]oxazolo[3,2-d][1,4]oxazin-2(1H)-one]: MS(ESI) calculated C 18 H9F8NO4[M-1] - =454.0, actual value 454.0; 1 H-NMR(400 MHz,DMSO-d6)δ 9.47(d,J=4.0 Hz,1H),8.13(d,J=7.2 Hz,1H),7.75-7.65(m,1H),1.64(s,3H),1.42(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -82.17, -97.78, -112.87, -141.03, -153.57, -162.13.

[0249] Alkylation of compound 1005 with methyl 2-hydroxy-2-methylpropanoate in DMF at 80° C. produced methyl 1-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)cyclopropane-1-carboxylate (compound 20): GCMS calculated C 19 H9F8NO4=467.0, measured value 467.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.76(d,J=9.6 Hz,1H),7.70(d,J=6.4 Hz,1H),3.66(s,3H),1.99-1.82(m,2H),1.76-1.68(m,1H),1.33-1.22(m,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -69.26, -83.76, -115.96, -140.56, -153.91, -162.32.

[0250] Alkylation of compound 1005 with tert-butyl 2,4-dibromobutanoate in DMF at 80° C. gave tert-butyl 1-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)cyclopropane-1-carboxylate, which was subsequently treated with trifluoroacetic acid in DCM at 25° C. to give 1-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)cyclopropane-1-carboxylic acid (compound 21): MS (ESI) calculated C 18 H7F8NO4[M-1] - =452.0, actual value 452.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.25(s,1H),7.75(d,J=9.6 Hz,1H),7.62(d,J=6.4 Hz,1H),1.91-1.76(m,2H),1.62-1.55(m,1H),1.21-1.14(m,1H); 19F-NMR (376 MHz, DMSO-d6) δ -69.65, -82.53, -116.27, -140.53, -154.03, -162.30.

[0251] Alkylation of compound 1005 with methyl 3-(bromomethyl)benzoate produced methyl 3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate (compound 24): GCMS (ESI) calculated C 23 H 11 F8NO4=517.1, actual value 517.0; 1 H-NMR(400 MHz,DMSO-d6),δ 7.99(s,1H),7.90(d,J=7.6 Hz 1H),7.79-7.71(m,2H),7.60-7.50(m,2H),5.36(s,2H),3.85(s,3H); 19 F-NMR (400 MHz, DMSO-d), δ −74.80, −115.66, −140.64, −153.12, −162.06, which, when treated with LiOH in THF / HO, then produced 3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid (compound 25); MS (ESI) calculated C 22 H9F8NO4[M-1] - =502.0, actual value 502.2; 1 H-NMR(400 MHz,DMSO-d6),δ 13.09(s,1H),7.96-7.84(m,2H),7.79-7.74(m,1H),7.68(d,J=6.4 Hz,1H),7.50-7.43(m,2H),5.31(s,2H); 19 F-NMR (400 MHz, DMSO-d6), δ-74.86,-115.67,-140.58,-153.17,-161.98.

[0252] Alkylation of compound 1005 with methyl 4-(bromomethyl)benzoate produced 4-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate (compound 26): GCMS calculated C 23 H 11 F8NO4=517.0, measured value 517.0; 1 H-NMR(400 MHz,DMSO-d6)δ 8.12-7.92(m,2H),7.90-7.76(m,1H),7.60-7.46(m,1H),7.44-7.32(m,2H),5.35(s,2H),3.83(s,3H); 19 F-NMR (400 MHz, DMSO-d) δ −74.64, −115.66, −140.65, −153.20, −162.01, which after treatment with LiOH in THF / HO produced 4-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid (compound 27); MS (ESI) calculated C 22 H9F8NO4[M-1] - =502.0, actual value 502.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.96-7.86(m,2H),7.83-7.73(m,1H),7.64-7.61(m,1H),7.46-7.41(m,2H),5.35(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.61, -115.65, -140.61, -153.19, -161.98.

[0253] Alkylation of compound 1005 with 4-bromobut-2-yn-1-ol yielded 2,2,7-trifluoro-4-(4-hydroxybut-2-yn-1-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, followed by 3-oxo-1λ 5-benzo[d][1,2]iodaoxol-1,1,1(3H)-triyl triacetate (Dess-Martin reagent) in portions at 20 °C to give 4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)but-2-ynal, which was subsequently oxidized with NaClO to give 4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)but-2-ynoic acid (compound 28): 1 H-NMR(400 MHz,DMSO-d6)δ 7.80(d,J=9.6 Hz,1H),7.70(d,J=6.4 Hz,1H),4.86(s,2H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.83, -115.66, -140.16, -153.01, -161.86.

[0254] Compound 1005 was alkylated with methyl acrylate using cesium carbonate as a base in acetonitrile at 80° C. to produce methyl 3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 45): GCMS calculated C 18 H9F8NO4=455.0, actual value 455.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.84(d,J=6.4 Hz,1H),7.74(d,J=9.6 Hz,1H),4.26(t,J=7.6 Hz,2H),3.59(s,3H),2.70(d,J=7.6 Hz,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.53, -116.30, -140.19, -153.28, -162.10, which after treatment with trimethylstannanol in dichloroethane at 80 °C yielded 3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 46). MS (ESI) calculated C17 H7F8NO4[M-1] - =440.0, actual value 440.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.83(d,J=6.4 Hz,1H),7.71(d,J=9.6 Hz,1H),4.17(t,J=7.6 Hz,2H),2.46(t,J=7.6 Hz,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.69, -116.49, -140.31, -153.57, -162.20.

[0255] Compound 1005 was alkylated with methyl 3-bromo-2,2-difluoropropanoate using cesium carbonate as a base in acetonitrile at 80 °C to produce 2,2-difluoro-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 47): MS (ESI) calculated C 17 H5F 10 NO4[M-1] - =476.0, actual value 475.9; 1 H-NMR (400 MHz, methanol-d₄) δ 7.69 (d, J = 6.4 Hz, 1H), 7.37 (m, 1H), 4.75-4.66 (m, 2H). 19 F-NMR (377 MHz, methanol-d4) δ −79.17, −108.24, −117.50, −142.15, −156.59, −165.05, which upon treatment with methanol and catalytic amount of sulfuric acid at 80 °C subsequently produced methyl 2,2-difluoro-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 48): GCMS calculated C 18 H7F 10 NO4 = 491.0, actual value 491.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.88(d,J=6.4 Hz,1H),7.79(d,J=9.4 Hz,1H),4.96-4.83(m,2H),3.85(s,3H);19 F-NMR (377 MHz, DMSO-d6) δ -75.39, -107.64, -115.36, -140.50, -152.77, -161.80.

[0256] Alkylation of compound 1005 with methyl 3-(bromomethyl)-2-fluorobenzoate produced methyl 2-fluoro-3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate (compound 53): MS(ESI) calculated C 23 H 10 F9NO4[M+1] + =536.1, actual value 536.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.85-7.73(m,2H),7.66(d,J=6.4 Hz,1H),7.53-7.47(m,1H),7.29(d,J=7.6 Hz,1H),5.35(s,2H),3.86(s,3H); 19 F-NMR (376 MHz, DMSO-d) δ −74.55, −114.65, −115.69, −140.58, −153.14, −162.06, which after treatment with trimethylstannanol in DCM at 80 °C yielded 2-fluoro-3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid (compound 54); MS (ESI) calculated C 22 H8F9NO4[M+1] + =521.0, actual value 521.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.35(br,1 H),7.81-7.78(m,2H),7.42-7.40(m,1H),7.35-7.30(m,1H),7.25-7.22(m,1H),5.33(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.61, -115.28, -140.53, -153.21, -162.01.

[0257] Arylation of compound 1005 with 3-bromobenzoate using Cu(OAc)2 and triethylamine in pyridine at 80 °C produced methyl 3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)benzoate (compound 55, 60 mg, 11% yield) as a pale yellow solid: MS (ESI) calculated C 22 H9F8NO4[M+1] + =504.0, actual value 503.9; 1 H-NMR(400 MHz,DMSO-d6)δ 8.16(s,1H),8.14(s,1H),7.86-7.77(m,3H),6.71(d,J=6.4 Hz,1H),3.88(s,3H); 19 F-NMR (400 MHz, DMSO-d6) δ −72.08, −74.99, −116.16, −140.92, −153.95, −162.36, which was subsequently treated with 4 M HCl / dioxane at 100 °C to produce 3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)benzoic acid (compound 56, 29 mg, 17% yield) as a white solid: MS (ESI) calculated C 21 H7F8NO4[M-1] - =487.0, actual value 487.4; 1 H-NMR(400 MHz,DMSO-d6)δ 13.38(s,1H),8.29-8.01(m,2H),7.98-7.74(m,3H),6.71(d,J=6.4 Hz,1H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.70, -116.17, -140.98, -153.99, -162.32.

[0258] Alkylation of compound 1005 with 2-bromoacetamide produced 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 83): MS(ESI) calculated C 16H6F8N2O3[M+1] + =427.0, actual value 427.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.76(d,J=9.6 Hz,2H),7.55(d,J=6.4 Hz,1H),7.38(s,1H),4.64(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.38, -116.33, -140.34, -153.27, -162.18.

[0259] Alkylation of compound 1005 with 2-bromo-N,N-dimethylacetamide produced N,N-dimethyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 90): MS(ESI) calculated C 18 H 10 F8N2O3[M+1] + =454.0, actual value 454.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.77(d,J=9.6 Hz,1H),7.62(d,J=6.4 Hz,1H),4.94(s,2H),3.08(s,3H),2.85(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.38, -116.33, -140.34, -153.27, -162.18.

[0260] Alkylation of compound 1005 with methyl 2-(bromomethyl)acrylate produced methyl 2-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)acrylate (compound 100): GCMS calculated C 19 H9F8NO4=467.0, measured value 467.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.78(d,J=9.6 Hz,1H),7.64(d,J=6.4 Hz,1H),6.20(s 1H),5.53(s 1H),4.82(s,2H),3.74(s,3H);19 F-NMR (376 MHz, DMSO-d6) δ -74.40, -116.05, -140.35, -153.33, -162.05, which after sequential treatment with osmium tetroxide and sodium periodate yielded methyl 2-oxo-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 101). MS(ESI) calculated C 18 H7F8NO5[M-1] - =468.0, actual value 467.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.80(d,J=9.6 Hz,1H),7.74(d,J=6.4 Hz,1H),5.35(s,2H),3.87(s,3H); 19 F-NMR (377 MHz, DMSO-d) δ -75.32, -115.72, -140.12, -152.80, -161.71, which after treatment with trimethylstannanol in DCE at 0 °C yielded 2-2-oxo-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 102); MS (ESI) calculated C 17 H5F8NO5[M-1] - =454.0, actual value 453.8; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79(d,J=9.6 Hz,1H),7.73(d,J=6.4 Hz,1H),5.31(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.23, -115.87, -140.19, -153.00, -161.93.

[0261] Alkylation of compound 1005 with methyl 2-(2-bromoethyl)benzoate produced 2-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoate (compound 105): GCMS calculated C 24 H13 F8NO4=531.1, measured value 531.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.87-7.79(m,2H),7.73(d,J=9.6 Hz,1H),7.53-7.47(m,1H),7.38-7.24(m,2H),4.34-4.24(m,2H),3.74(s,3H),3.30-3.23(m,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.83, -116.24, -140.21, -153.06, -162.13, which after treatment with 4 M HCl / dioxane at 100 °C yielded 2-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoic acid (compound 106): MS (ESI) calculated C 23 H 11 F8NO4[M-1] - =516.1, actual value 515.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.90-7.87 (m, 1H), 7.74-7.73 (m, 1H), 7.33-7.24 (m, 4H), 4.38 (t, J = 7.6 Hz, 2H), 3.39-3.37 (m, 2H); 19 F-NMR (377 MHz, methanol-d4) δ -78.60, -117.64, -142.27, -156.57, -164.86.

[0262] Alkylation of compound 1005 with methyl 4-(2-bromoethyl)benzoate produced 4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoate (compound 128): GCMS calculated C 24 H 13 F8NO4=531.1, measured value 531.1; 1H-NMR(400 MHz,DMSO-d6)δ 7.82(d,J=8.0 Hz,2H),7.71(d,J=9.6 Hz,1H),7.65(d,J=6.4 Hz,1H),7.35(d,J=4.0 Hz,2H),4.35-4.28(m,2H),3.84(s,3H),3.06-3.00(m,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.19, -116.19, -140.30, -153.36, -162.09, which after treatment with 4 M HCl / dioxane at 100 °C yielded 4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoic acid (compound 129); MS (ESI) calculated C 23 H 11 F8NO4[M-1] - =516.1, actual value 516.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.82(s,1H),7.86-7.79(m,2H),7.74-7.65(m,2H),7.38-7.28(m,2H),4.31(t,J=7.2 Hz,2H),3.02(t,J=7.2 Hz,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.14, -116.18, -140.28, -153.27, -162.01.

[0263] Alkylation of compound 1005 with methyl 2-(3-((tosyloxy)methyl)cyclobutyl)acetate (which in turn was produced by tosylation of methyl 2-(3-(hydroxymethyl)cyclobutyl)acetate) gave methyl 2-(3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)cyclobutyl)acetate, which was purified by preparative HPLC (10% iPrOH / hexanes) to give methyl 2-(((1r,3r)-3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)cyclobutyl)acetate (compound 136): GCMS (ESI) calculated C 22 H 15 F8NO4=509.0, actual value 509.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.77(d,J=6.4 Hz,1H),7.73(d,J=9.6 Hz,1H),4.06(d,J=6.8 Hz,2H),3.55(s,3H),2.53-2.49(m,1H),2.40-2.28(m,3H),2.16-2.05(m,2H),1.58-1.47(m,2H); 19 F-NMR (377 MHz, DMSO-d6) δ −74.85, −116.34, −140.29, −153.44, −162.14, which after treatment with trimethylstannanol in dichloroethane at 65 °C gave 2-((1r,3r)-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)cyclobutyl)acetic acid (compound 138): MS (ESI) calculated C 21 H 13 F8NO4[M-1] - =494.1, actual value 494.0; 1H-NMR(400 MHz,DMSO-d6)δ 11.85(b,1H),7.79(d,J=6.4 Hz,1H),7.73(d,J=9.6 Hz,1H),4.17(d,J=7.6 Hz,2H),2.75-2.57(m,2H),2.36(d,J=7.6 Hz,2H),1.98-1.84(m,2H),1.80-1.63(m,2H); 19 F-NMR (376 MHz, DMSO-d) δ -74.75, -116.31, -140.28, -153.48, -162.11, and GCMS (ESI) calculated C for methyl 2-((1s,3s)-3-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)cyclobutyl)acetate (compound 137). 22 H 15 F8NO4=509.0, actual value 509.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.77(d,J=6.4 Hz,1H),7.73(d,J=9.6 Hz,1H),4.06(d,J=6.8 Hz,2H),3.55(s,3H),2.53-2.49(m,1H),2.40-2.28(m,3H),2.16-2.05(m,2H),1.58-1.47(m,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.78, -116.30, -140.28, -153.49, -162.14, which after treatment with trimethylstannanol in dichloroethane at 65 °C yielded 2-((1s,3s)-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)cyclobutyl)acetic acid (compound 139). MS (ESI) calculated C 21 H 13 F8NO4[M-1] - =494.1, actual value 493.9; 1H-NMR(400 MHz,DMSO-d6)δ 11.87(s,1H),7.80-7.69(m,2H),4.06(d,J=6.8 Hz,2H),2.41-2.28(m,1H),2.27-2.18(m,3H),2.16-2.05(m,2H),1.57-1.44(m,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.86, -116.34, -140.28, -153.44, -162.11.

[0264] Alkylation of compound 1005 with methyl 4-bromo-2,2-dimethylbutanoate produced methyl 2,2-dimethyl-4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (compound 140): GCMS calculated C 21 H 15 F8NO4=497.1, measured value 497.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.76(d,J=9.6 Hz,1H),7.63(d,J=6.4 Hz,1H),4.08-3.93(m,2H),3.54(s,3H),1.94-1.73(m,2H),1.20(s,6H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.75, -115.99, -140.67, -153.01, -161.97, which upon treatment with 4 M HCl / dioxane at 100 °C yielded 2,2-dimethyl-4-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 141); MS (ESI) calculated C 20 H 13 F8NO4[M-1] - =482.1, actual value 481.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 6.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 4.25-3.99 (m, 2H), 1.98-1.80 (m, 2H), 1.30 (s, 6H); 19F-NMR (377 MHz, methanol-d4) δ -78.37, -117.33, -142.47, -156.50, -164.75.

[0265] Compound 1005 was alkylated with methyl 3-(2-hydroxymethyl)benzoate under Mitsinobu conditions using triphenylphosphine and diisopropyl azodicarboxylate to produce methyl 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoate (compound 142): MS (ESI) calculated C 24 H 13 F8NO4[M+1] + =532.0, actual value 532.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.84-7.66(m,4H),7.48-7.35(m,2H),4.30(t,J=7.2 Hz,2H),3.83(s,3H),3.01(t,J=7.2 Hz,2H); 19 F-NMR (400 MHz, DMSO-d6) δ -75.25, -116.23, -140.20, -153.37, -162.09, which, when treated with 4 M HCl / dioxane at 100 °C, subsequently produced 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)benzoic acid (compound 143): MS (ESI) calculated C 23 H 11 F8NO4[M-1] - =516.1, actual value 516.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.78(b,1H),7.79-7.68(m,4H),7.45-7.32(m,2H),4.30(t,J=7.2 Hz,2H),3.01(t,J=7.2 Hz,2H); 19 F-NMR(400 MHz,DMSO-d6)δ-75.19,-116.25,-140.23,-153.27,-162.01.

[0266] Alkylation of compound 1005 with 3-chloro-2-oxopropyl acetate produced 2-oxo-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propyl acetate (compound 144): MS (ESI) calculated C 19 H9F8NO5[M-1] - =482.0, actual value 482.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79(d,J=9.6 Hz,1H),7.53(d,J=6.4 Hz,1H),5.15(s,2H),5.05(s,2H),2.09(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.04, -115.85, -140.13, -152.83, -161.82.

[0267] Alkylation of compound 1005 with 3-bromo-3,3-difluoroprop-1-ene, after deprotonation of the benzoxazinone amide hydrogen with NaH in DMF at 0 °C, yielded 4-(3,3-difluoroallyl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one: GCMS calculated C 17 H5F 10 NO2 = 445.0, actual value 445.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.76(d,J=9.6 Hz,1H),7.65(d,J=6.4 Hz,1H),4.94-4.76(m,1H),4.72-4.63(m,2H); 19 F-NMR (376 MHz, DMSO-d) δ −74.97, −85.19, −115.92, −140.67, −153.18, −162.08, which was subsequently reacted with OsO and NaIO to produce 2-hydroxy-3-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 149): MS (ESI) calculated C 17 H7F8NO5[M-1]- =456.0, actual value 455.9; 1 H-NMR(400 MHz,DMSO-d6)δ 12.90(s,1H),7.84(d,J=6.4 Hz,1H),7.74(d,J=9.6 Hz,1H),5.81(s,1H),4.35-4.23(m,2H),4.19-4.17(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ -73.94, -77.07, -116.34, -140.33, -153.26, -162.03.

[0268] Alkylation of compound 1005 with methyl 2-(4-(bromomethyl)phenyl)acetate produced methyl 2-(4-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)phenyl)acetate (compound 156): GCMS calculated C 24 H 13 F8NO4=531.0, actual value 531.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.78-7.68(m,2H),7.31-7.21(m,4H),5.26(s,2H),3.65(s,2H),3.59(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.86, -115.76, -140.54, -153.20, -162.00, which was subsequently treated with 4 M HCl / dioxane at 100 °C to yield 2-(4-((2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)phenyl)acetic acid (compound 157); MS (ESI) calculated C 23 H 11 F8NO4[M-1] - =516.0, actual value 516.0.1; 1 H-NMR(400 MHz,DMSO-d6)δ 12.42(br,1H),7.78-7.70(m,2H),7.27-7.22(m,4H),5.31(s,2H),3.63(s,2H); 19F-NMR (377 MHz, DMSO-d6) δ -74.90, -115.75, -140.50, -153.20, -162.04.

[0269] Example 2. Methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (Compound 8), methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (Compound Preparation of Compound 9), (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (Compound 10), and (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (Compound 11) [ka] As shown in Scheme 4, Step 1, a mixture of 2,2,7-trifluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-1,4-benzoxazin-3-one (Compound 1005, 500 mg, 1.35 mmol), methyl (S)-2-(tosyloxy)propanoate (525 mg, 2.03 mmol), and KCO (374 mg, 2.70 mmol) in DMF (5 mL) was stirred at 80 °C for 16 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 60% ACN in water) to give methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 1006) as a racemic mixture, as shown by chiral HPLC.

[0270] As shown in Scheme 4, Step 2, racemic compound 1006 was separated into its respective enantiomers by preparative chiral HPLC using the following conditions - column: Chiralpak® AD-H, 2×25 cm, 5 um, eluted with 5% (1:1 EtOH / DCM) / hexanes (0.2% diethylamine) to give methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 9, 12 mg, 2% yield) as a yellow oil: GCMS calculated C 18 H9F8NO4=455.0, measured value 455.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.54 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.41-5.31 (m, 1H), 3.76 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -78.76, -81.33, -116.49, -142.50, -155.12, -164.78. Also with a longer retention time, methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 8) was collected as a yellow oil: GCMS calculated C 18 H9F8NO4=455.0, measured value 455.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.86-7.76 (m, 2H), 5.51-5.41 (m, 1H), 3.67 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -76.05, -115.42, -140.28, -152.93, -161.96.

[0271] As shown in Scheme 4, Step 3, a solution of methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (50 mg, 0.11 mmol) in 4 M HCl / dioxane (1 mL) was stirred at 100 °C for 48 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC (40% to 70% acetonitrile / 0.5% HCl in water) to afford (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 10, 12 mg, 24% yield) as a white solid: MS (ESI) calculated C 17 H7F8NO4[M-1] - =440.0, actual value 440.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.87-7.79(m,2H),5.37-5.27(m,1H),1.52(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO) δ -75.12, -115.76, -140.36, -153.04, -162.02.

[0272] As shown in Step 4 of Scheme 4, a solution of methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (70 mg, 0.15 mmol) in 4 M HCl / dioxane (1 mL) was stirred at 100 °C for 48 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC (45% to 75% acetonitrile / 0.5% aqueous HCl) to afford (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 11, 19 mg, 28% yield) as a white solid: MS (ESI) calculated C 17 H7F8NO4[M-1] - =440.0, actual value 440.0; 1H-NMR(400 MHz,DMSO-d6)δ 7.84-7.76(m,2H),5.33(m,1H),1.53(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO) δ-76.18,-115.73,-140.03-140.61,-153.03,-162.03.

[0273] Using the appropriate alkylating agent in a similar transformation as described in Scheme 4, Step 1, followed by any subsequent synthetic manipulations or purification, the following compounds were prepared.

[0274] Alkylation of compound 1005 with ethyl 2-bromopropanoate followed by chiral HPLC purification of the product gave ethyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 35): MS(ESI) calculated C 19 H 11 F8NO[M-1] - =468.0, actual value 468.0; 1 H-NMR (400 MHz, methanol-d4)δ 7.53(d,J=6.4 Hz,1H),7.45(d,J=9.2 Hz,1H),5.35-5.30(m,1H),4.32-4.13(m,2H),1.66(d,J=7.2 Hz,3H),1.22(t,J=7.2 Hz,3H); 19 F-NMR (400 MHz, methanol-d4) δ -79.75, -116.51, -142.49, -156.12, -164.77, and MS (ESI) calculated value C yielded ethyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 36). 19 H 11 F8NO[M-1] - =468.0, actual value 468.0; 1H-NMR(400 MHz, methanol-d4)δ 7.53(d,J=6.4 Hz,1H),7.44(d,J=9.2 Hz,1H),5.35-5.30(m,1H),4.29-4.15(m,2H),1.66(d,J=7.2 Hz,3H),1.23(t,J=7.2 Hz,3H); 19 F-NMR (400 MHz, methanol-d4) δ -79.75, -116.51, -142.48, -156.15, -164.77.

[0275] Reaction of racemic compound 1006 with trimethylstannanol in dichloroethane at 80 °C yielded 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid, followed by esterification with isopropanol (catalytic HSO, 80 °C) and chiral HPLC purification to give isopropyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 37): MS(ESI) calculated C 20 H 13 F8NO4[M-1] - =482.1, actual value 482.0; 1 H-NMR (400 MHz, methanol-d4)δ 7.53(d,J=6.0 Hz,1H),7.45(d,J=9.2 Hz,1H),5.29-5.17(m,1H),5.13-5.05(m,1H),1.65(d,J=7.2 Hz,3H),1.24(d,J=6.0 Hz,3H),1.17(d,J=6.0 Hz,3H); 19 F-NMR (377 MHz, methanol-d4) δ -80.05, -116.55, -142.65, -156.10, -164.76, and isopropyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 38) were produced: MS (ESI) calculated C 20 H 13 F8NO4[M-1] -=482.1, actual value 482.0; 1 H-NMR (400 MHz, methanol-d4)δ 7.53(d,J=6.0 Hz,1H),7.45(d,J=9.2 Hz,1H),5.29-5.17(m,1H),5.13-5.05(m,1H),1.65(d,J=7.2 Hz,3H),1.24(d,J=6.0 Hz,3H),1.17(d,J=6.0 Hz,3H); 19 F-NMR (377 MHz, methanol-d4) δ -80.05, -116.55, -142.65, -156.10, -164.76.

[0276] Alkylation of compound 1005 with methyl 2-bromobutanoate followed by chiral HPLC purification produced methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (compound 49): MS(ESI) calculated C 19 H 11 F8NO4[M+1] + =469.0, actual value 469.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.85(t,J=8.6 Hz,2H),5.43-5.40(m,1H),3.67(s,3H),2.26-2.15(m,1H),2.14-2.04(m,1H),0.86(t,J=7.5 Hz,3H); 19 F-NMR (400 MHz, DMSO-d6) δ −76.90, −115.11, −140.85, −152.99, −162.09, which after treatment with trimethylstannanol in dichloroethane at 65 °C gave (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 51): MS (ESI) calculated C 18 H9F8NO4[M-1] - =454.0, actual value 454.3; 1H-NMR(400 MHz,DMSO-d6)δ 7.74-7.70(m,1H),7.60(s,1H),5.09-5.05(m,1H),2.24-2.13(m,1H),2.02-1.90(m,1H),0.79(t,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -72.17, -79.32, -116.12, -140.75, -153.18, -161.97, and methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (compound 50) were produced: GCMS calculated C 19 H 11 F8NO4=469.0, actual value 469.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.87-7.83(m,2H),5.43-5.40(m,1H),3.67(s,3H),2.26-2.016(m,1H),2.14-2.04(m,1H),0.86(t,J=7.6 Hz,3H); 19 F-NMR (400 MHz, DMSO-d) δ −76.90, −115.11, −140.85, −152.99, −162.09, which after treatment with trimethylstannanol in dichloroethane at 65 °C yielded (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 52); MS (ESI) calculated C 18 H9F8NO4[M-1] - =454.0, actual value 454.2; 1 H-NMR(400 MHz,DMSO-d6)δ 7.71(d,J=9.6 Hz,1H),7.44(d,J=6.4 Hz,1H),5.02-4.87(m,1H),2.29-2.12(m,1H),1.93-1.73(m,1H),0.86-0.66(m,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -72.92, -79.32, -116.12, -140.75, -153.18, -161.97.

[0277] Alkylation of compound 1005 with methyl 2-bromopentanoate produced racemic methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate, which was then converted to the respective enantiomers, methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate (compound 115): MS(ESI) calculated value C 20 H 13 F8NO4[M-1] - =482.0, actual value 481.9; 1 H-NMR(400 MHz,CD3OD)δ 7.50-7.44(m,2H),5.44-5.41(m,1H),3.50(s,3H),2.29-2.12(m,2H),1.42-1.27(m,2H),0.94(d,J=6.4 Hz,3H); 19 F-NMR (376 MHz, CD3OD) δ -80.95, -116.29, -143.04, -156.11, -164.74, and resolved into methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate (compound 116): MS (ESI) calculated C 20 H 13 F8NO4[M-1] - =482.0, actual value 481.9; 1 H-NMR(400 MHz,CD3OD)δ 7.50-7.44(m,2H),5.44-5.41(m,1H),3.50(s,3H),2.29-2.12(m,2H),1.42-1.27(m,2H),0.94(d,J=6.4 Hz,3H); 19 F-NMR (376 MHz, CD3OD) δ -80.95, -116.29, -143.04, -156.11, -164.74.

[0278] The enantiomers of racemic methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate were hydrolyzed and subsequently purified by chiral HPLC to give (S)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoic acid (compound 117): MS(ESI) calculated C 19 H 11 F8NO4[M-1] - =468.0, actual value 467.9; 1 H-NMR(400 MHz,CD3OD)δ 7.48-7.43(m,2H),5.43-5.40(m,1H),2.31-2.05(m,2H),1.44-1.25(m,2H),0.95(d,J=6.4 Hz,3H); 19 F-NMR (376 MHz, CD3OD) δ -79.22, -81.60, -116.59, -142.52, -156.17, -164.77, and (R)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoic acid (compound 118) were produced: MS (ESI) calculated value C 19 H 11 F8NO4[M-1] - =468.0, actual value 467.9; 1 H-NMR(400 MHz,CD3OD)δ 7.48-7.43(m,2H),5.43-5.40(m,1H),2.31-2.05(m,2H),1.44-1.25(m,2H),0.95(d,J=6.4 Hz,3H); 19 F-NMR (376 MHz, CD3OD) δ -78.75, -81.50, -116.62, -142.65, -156.18, -164.77.

[0279] Alkylation of compound 1005 with methyl 2-bromo-4-methylpentanoate, followed by HPLC chiral separation, produced methyl (S)-4-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate (compound 122): MS(ESI) calculated C 21 H 15 F8NO4[M-1] - =496.0, actual value 496.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.89-7.81(m,2H),5.55-5.47(m,1H),3.68(s,3H),2.11-1.99(m,2H),1.53-1.38(m,1H),0.85(d,J=6.4 Hz,6H); 19 F-NMR (376 MHz, DMSO-d6) δ −77.14, −114.97, −140.69, −152.91, −161.91, which after treatment with trimethylstannanol in dichloroethane at 65 °C gave (S)-4-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoic acid (compound 124): MS (ESI) calculated C 20 H 13 F8NO4[M-1] - =482.0, actual value 482.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.35(s,1H),7.84-7.80(m,2H),5.42-5.35(m,1H),2.12-1.95(m,2H),1.50-1.38(m,1H),0.88-0.80(m,6H); 19 F-NMR (400 MHz, DMSO-d6) δ -76.19, -115.09, -140.83, -152.98, -161.91, and methyl (R)-4-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoate (compound 123): MS (ESI) calculated value C 21 H 15F8NO4[M-1] - =496.0, actual value 496.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.92-7.81(m,2H),5.52-5.49(m,1H),3.68(s,3H),2.12-1.99(m,2H),1.52-1.39(m,1H),0.84(d,J=6.4 Hz,6H); 19 F-NMR (376 MHz, DMSO-d) δ −77.14, −114.97, −140.69, −152.92, −161.92; which, after treatment with trimethylstannanol in dichloroethane at 65 °C, yielded (R)-4-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pentanoic acid (compound 125); MS (ESI) calculated C 20 H 13 F8NO4[M-1] - =482.0, actual value 482.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.38(b,1H),7.92-7.82(m,2H),5.43-5.39(m,1H),2.10-1.99(m,2H),1.47-1.38(m,1H),0.84(d,J=1.6 Hz,6H); 19 F-NMR (400 MHz, DMSO-d6) δ -75.90, -115.35, -140.72, -153.06, -162.00.

[0280] Alkylation of compound 1005 with methyl 2-hydroxy-3-methylbutanoate under Mitsunobu conditions (PPh3, diisopropyl azodicarboxylate, 0°C) afforded racemic methyl 3-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate, which was hydrolyzed by treatment with trimethylstannanol (dichloroethane, 65°C) and then separated by chiral HPLC to give (S)-3-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 150): MS(ESI) calculated C 19 H 11 F8NO4[M-1] - =468.0, actual value 467.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.32(s,1H),7.90-7.80(m,2H),4.93(d,J=9.6 Hz,1H),2.67-2.65(m,1H),1.25-1.15(m,3H),0.75(d,J=6.8 Hz,3H); 19 F-NMR (377 MHz, DMSO-d) δ -77.29, -153.20, -140.73, -153.13, -161.92, and (R)-3-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoic acid (compound 151) were produced: MS (ESI) calculated value C 19 H 11 F8NO4[M-1] - =468.0, actual value 468.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.34(s,1H),7.88-7.78(m,2H),4.92(d,J=9.6 Hz,1H),2.69-2.59(m,1H),1.25-1.15(m,3H),0.79-0.69(m,3H); 19F-NMR (377 MHz, DMSO-d6) δ -77.28, -115.20, -140.73, -153.16, -162.93.

[0281] Esterification of Compound 150 and Compound 151 with trimethylsilyldiazomethane gave methyl (S)-3-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (Compound 152), respectively: MS(ESI) calculated value C 20 H 13 F8NO4[M-1] - =482.1, actual value 481.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.90-7.72(m,2H),5.09(d,J=9.6 Hz,1H),3.64(s,3H),2.68(t,J=8.8 Hz,1H),1.20(d,J=6.4 Hz,3H),0.77(d,J=6.8 Hz,3H); 19 F-NMR (377 MHz, DMSO-d) δ -76.66, -114.86, -140.50, -153.03, -161.95, and MS (ESI) calculated C for methyl (R)-3-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate (compound 153). 20 H 13 F8NO4[M-1] - =482.1, actual value 482.0; 1 H-NMR(400 MHz,DMSO-d6)δ 8.02-7.84(m,2H),5.09(d,J=9.2 Hz,1H),3.64(s,3H),2.77-2.60(m,1H),1.20(d,J=6.4 Hz,3H),0.77(d,J=6.8 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -77.33, -114.86, -140.04, -153.05, -161.95.

[0282] Alkylation of compound 1005 with methyl 2-bromo-2-methoxyacetate yields racemic methyl 2-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate, which can be separated into its enantiomers by chiral HPLC to give methyl (S)-2-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 185): GCMS calculated C 18 H9F8NO5=471.0, measured value 471.0; 1 H-NMR(400MHz,DMSO-d6)δ 7.85(d,J=9.4 Hz,1H),7.48(d,J=6.4 Hz,1H),7.11(s,1H),6.63(s,1H),3.69(s,3H),3.47(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.79, -114.28, -140.38, -142.19, -152.80, -161.54, and methyl (R)-2-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 186) were produced: GCMS calculated C 18 H9F8NO5=471.0, measured value 471.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.85(d,J=9.4 Hz,1H),7.48(d,J=6.4 Hz,1H),6.63(s,1H),3.69(s,3H),3.47(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.79, -114.28, -140.38, -142.25, -152.80, -161.54.

[0283] Compounds 185 and 186 were each treated with trimethylstannanol in DCE at 65° C. to give (S)-2-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 187), respectively: MS(ESI) calculated value C 17 H7F8NO5[M-1] - =456.0, actual value 455.9; 1 H-NMR(400 MHz,DMSO-d6)δ 14.05(br,1H),7.84(d,J=9.6 Hz,1H),7.55(d,J=6.4 Hz,1H),6.47(s,1H),3.45(s,3H); 19 F-NMR (377 MHz, DMSO-d) δ −76.92, −114.47, −140.61, −141.55, −152.69, −161.67, and (R)-2-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 188) were produced: MS (ESI) calculated value C 17 H7F8NO5[M-1] - =456.0, actual value 455.9; 1 H-NMR(400 MHz,DMSO-d6)δ 14.05(br,1H),7.84(d,J=9.6 Hz,1H),7.55(d,J=6.4 Hz,1H),6.47(s,1H),3.45(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -76.92, -114.47, -140.61, -141.55, -152.69, -161.67.

[0284] Example 3. Preparation of 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-((trifluoromethyl)sulfonyl)acetamide (Compound 12) [ka] As shown in Scheme 5, to a solution of 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 2, 70 mg, 0.16 mmol) in DMSO (1 mL) was added triethylamine (50 mg, 0.49 mmol), trifluoromethanesulfonamide (29 mg, 0.20 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetrafluoronium tetrafluoroborate (TBTU, 79 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 h and then purified by reverse-phase preparative HPLC (40%-60% acetonitrile / 10 mM aqueous NH4HCO3) to give 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-((trifluoromethyl)sulfonyl)-acetamide (compound 12, 25 mg, 25% yield) as a white solid: MS(ESI) calculated (C 17 H5F 11 N2O5S)[M-1] - =557.0, actual value 556.8; 1 H-NMR(400 MHz,DMSO-d6)δ 7.70(d,J=9.4 Hz,1H),7.40(d,J=6.4 Hz,1H),4.54(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.41, -78.01, -116.34, -140.37, -153.14, -162.06.

[0285] As shown in Scheme 5, reaction of compound 2 with an appropriate amine, followed by any subsequent synthetic manipulations or purification, led to the preparation of the following compounds.

[0286] After activation with TBTU, compound 2 was condensed with methanesulfonamide to give N-(methylsulfonyl)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 13): MS(ESI) calculated C17 H8F8N2O5S[M-1] - =503.0, actual value 502.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.61-7.18 (m, 2H), 4.69 (d, J = 4.0 Hz, 2H), 2.99-3.15 (m, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -77.87, -117.62, -142.25, -156.47, -164.96.

[0287] Condensation of compound 2 with isopropyl(methyl)sulfonamide after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) yielded N-(N-isopropyl-N-methylsulfamoyl)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 14): MS(ESI) calculated C 20 H 15 F8N3O5S[M-1] - =560.1, actual value 559.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.54-7.23 (m, 2H), 4.73 (s, 2H), 4.10 (s, 1H), 2.73 (s, 3H), 1.08 (d, J = 6.8 Hz, 6H); 19 F-NMR (400 MHz, methanol-d4) δ -78.39, -117.29, -142.09, -156.27, -164.90.

[0288] Condensation of compound 2 with dimethyl(sulfamoyl)amine after EDCI activation produced N-(N,N-dimethylsulfamoyl)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 15): MS (ESI) calculated C 18 H 11 F8N3O5S[M-1] - =532.0, actual value 531.9; 1H-NMR(400 MHz,DMSO-d6)δ 11.94(s,1H),7.78(d,J=9.6 Hz,1H),7.72(d,J=6.4 Hz,1H),4.80(s,2H),2.75(s,6H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.89, -115.95, -140.29, -152.91, -161.94.

[0289] After EDCI activation, compound 2 was condensed with 1,1-dimethylhydrazine to produce N',N'-dimethyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetohydrazide (compound 57): MS(ESI) calculated C 19 H9F8N3O2[M+1] + =470.1, actual value 470.1; 1 H-NMR (400 MHz, methanol-d4) δ 7.52-7.25 (m, 2H), 5.09 (s, 1H), 4.70 (s, 1H), 2.64 (s, 3H), 2.55 (s, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -78.50, -117.05, -142.39, -156.33, -164.99.

[0290] After activation with carbonyldiimidazole (CDI), compound 2 was condensed with O-methylhydroxylamine to give N-methoxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 58): MS(ESI) calculated C 17 H8F8N2O4[M-1] - =455.0, actual value 455.0; 1 H-NMR(400 MHz,DMSO-d6)δ 11.54(s,1H),7.78(d,J=9.2 Hz,1H),7.63(d,J=6.4 Hz,1H),4.62(s,2H),3.59(s,3H); 19F-NMR (400 MHz, DMSO-d6) δ -74.85, -115.97, -140.39, -153.02, -161.95.

[0291] Compound 2 after EDCI activation was condensed with tert-butyl 1-methylhydrazine-1-carboxylate to produce tert-butyl 1-methyl-2-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)hydrazine-1-carboxylate: MS(ESI) calculated C 22 H 17 F8N3O5[M-1] - = 554.1, found 554.0, which after treatment with trifluoroacetic acid in DCM at 0 °C yielded N'-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetohydrazide (compound 59): MS (ESI) calculated C 17 H9F8N3O3[M+1] + =456.0, actual value 456.1; 1 H-NMR (400 MHz, DMSO-d6) δ 9.70 and 8.96 (s, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.57-7.23 (m, 1H), 4.90 and 4.64 (s, 3H), 2.52-2.50 (m, 1H), 2.41 (s, 2H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.18, -116.29, -140.43, -153.15, -162.00.

[0292] After EDCI activation, compound 2 was condensed with O-benzylhydroxylamine to produce N-(benzyloxy)-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 70): MS(ESI) calculated C 23 H 12 F8N2O4=533.0, measured value 533.0; 1H-NMR (400 MHz, CDCl3) δ 8.08 and 8.55 (br, 1H), 7.36-7.34 (m, 6H), 7.19-7.14 (m, 1H), 4.94 (s, 2H), 4.80-4.42 (m, 2H); 19 F-NMR (400 MHz, DMSO-d) δ −76.88, −113.22, −139.62, −152.10, −160.91, which, after treatment with hydrogen and Pd / C, produced N-hydroxy-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 71); MS (ESI) calculated C 16 H6F8N2O4=443.0, measured value 443.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.42-7.18 (m, 2H), 4.72 (s, 2H); 19 F-NMR (400 MHz, methanol-d4) δ -78.20, -117.13, -142.27, -156.25, -164.85.

[0293] After EDCI activation, condensation of compound 2 with methyl (2S)-pyrrolidine-2-carboxylate from the hydrochloride salt gave methyl (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)-D-prolinate (compound 72): MS(ESI) calculated (C 22 H 14 F8N2O5)[M+1] + ,539.0, Actual value 539.1; 1 H-NMR (400 MHz, methanol-d4) δ 7.43-7.30 (m, 2H), 5.22-5.11 (m, 1H), 4.95-4.74 (m, 1H), 4.58-4.46 (m, 1H), 3.89-3.42 (m, 5H), 2.45-2.22 (m, 1H), 2.16-1.92 (m, 3H); 19F-NMR (377 MHz, DMSO-d6) δ -78.12, -117.40, -142.50, -156.38, -165.11, which after treatment with 4 M HCl in dioxane at 100 °C yielded (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)-D-proline (compound 73): MS (ESI) calculated C 21 H 12 F8N2O5[M+1] + =525.0, actual value 525.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.52-7.44 (m, 1H), 7.40-7.34 (m, 1H), 5.18-5.07 (m, 1H), 4.64-4.43 (m, 2H), 3.86-3.68 (m, 1H), 3.63-3.45 (m, 1H), 2.39-2.00 (m, 3H), 1.95-1.81 (m, 1H); 19 F-NMR (376 MHz, methanol-d4) δ -78.99, -117.57, -141.27, -156.71, -165.08.

[0294] After activation as the acyl chloride via treatment with oxalyl chloride at 0 °C, condensation of compound 2 with methyl L-prolinate gave methyl (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)-L-prolinate (compound 74): MS(ESI) calculated C 22 H 14 F8N2O5[M+1] + =539.0, actual value 539.1; 1 H-NMR (400 MHz, methanol-d4) δ 7.42-7.37 (m, 1H), 7.34 (d, J = 10.4 Hz, 1H), 5.20-5.13 (m, 1H), 4.89-4.75 (m, 1H), 4.60-4.46 (m, 1H), 3.89-3.50 (m, 5H), 2.42-2.23 (m, 1H), 2.15-1.73 (m, 3H); 19F-NMR (400 MHz, DMSO-d6) δ −77.91, −117.40, −142.37, −156.44, −165.11, which, after treatment with 4 M HCl in dioxane at 100 °C, yielded (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)-L-proline (compound 75): MS (ESI) calculated C 21 H 12 F8N2O5[M+1] + =525.0, actual value 525.1; 1 H-NMR (400 MHz, methanol-d4) δ 7.46-7.29 (m, 2H), 5.20-5.08 (m, 1H), 4.65-4.44 (m, 1H), 3.89-3.71 (m, 1H), 3.64-3.45 (m, 2H), 2.42-2.24 (m, 1H), 2.17-1.78 (m, 3H); 19 F-NMR (400 MHz, DMSO-d6) δ -77.95, -117.37, -142.35, -156.61, -164.96.

[0295] Condensation of compound 2 with methyl 3-(methylamino)propanoate after activation with n-propanephosphonic anhydride (T3P) and DIEA produced methyl 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoate (compound 80): MS(ESI) calculated C 21 H 14 F8N2O5[M+1] + =527.0, actual value 527.1; 1 H-NMR(400 MHz,CDCl3)δ 7.39-6.84(m,2H),5.17 and 4.77(s,2H),3.71-3.65(m,2H),3.58(s,3H),3.18 & 2.92(s,3H),2.82-2.49(m,2H); 19F-NMR (376 MHz, CDCl) δ −76.84, −114.40, −139.43, −152.94, −161.57, which, after treatment with trimethylstannanol in DCE at 80 °C, gave 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoic acid (compound 81; MS(ESI) calculated C 20 H 12 F8N2O5[M-1] - =511.0, actual value 511.0; 1 H-NMR(400 MHz,CDCl3)δ 7.21-6.83(m,2H),5.05 and 4.79(s,2H),3.75-3.62(m,2H),3.20 & 2.95(s,3H),2.80-2.55(m,2H); 19 F-NMR (376 MHz, CDCl3) δ -76.94, -114.12, -139.69, -152.73, -161.42.

[0296] After activation with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and DIEA, compound 2 was condensed with methanamide to give N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 82): MS(ESI) calculated C 17 H8F8N2O3[M-1] - =439.0, actual value 438.9; 1 H-NMR(400 MHz,DMSO-d6)δ 8.22(d,J=5.2 Hz,1H),7.77-7.74(d,J=9.6 Hz,1H),7.57-7.55(d,J=6.4 Hz,1H),4.65(s,2H),2.63-2.60(d,J=4.4 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.32, -116.21, -140.44, -153.18, -162.01.

[0297] After EDCI activation, compound 2 was condensed with methyl 2-(methylamino)acetate, hydrochloride to give methyl N-methyl-N-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)glycinate (compound 84): MS (ESI) calculated C 20 H 12 F8N2O5[M+1] + =513.1, actual value 513.1; 1 H-NMR (400 MHz, methanol-d4) δ 7.42-7.37 (m, 1H), 7.32 (d, J = 6.4 Hz, 1H), 5.09 (s, 2H), 4.37 and 4.18 (s, 2H), 3.79 and 3.69 (s, 3H), 3.24 (s, 2H), 2.97 (s, 1H); 19 F-NMR (377 MHz, methanol-d₄) δ −78.11, −117.40, −141.93, −156.57, −165.08, which, after treatment with trimethylstannanol in DCE at 80 °C, yielded N-methyl-N-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)glycine (compound 85): MS(ESI) calculated (C 19 H 10 F8N2O5)[M-1] - =497.0, actual value 497.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.54-7.46 (m, 1H), 7.38-7.35 (m, 1H), 5.06 & 4.95 (s, 2H), 4.11 (s, 2H), 3.32 and 2.98 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -78.25, -117.82, -142.18, -156.93, -165.11.

[0298] After activation as the acyl chloride by treatment with oxalyl chloride at 0 °C, condensation of compound 2 with methyl azetidine-3-carboxylate gave methyl 1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)azetidine-3-carboxylate (compound 86): MS (ESI) calculated for (C 21 H 12 F8N2O5[M+1] + =525.2, actual value 525.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.77(d,J=9.2 Hz,1H),7.60(d,J=6.4 Hz,1H),4.74(s,2H),4.52-4.47(m,2H),4.09-3.95(m,2H),3.68(s,3H),3.62-3.48(m,1H); 19 F-NMR (376 MHz, DMSO-d6) δ −75.15, −115.98, −140.28, −152.95, −161.81, which, after treatment with trimethylstannanol in DCE at 80 °C, yielded 1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)azetyl-3-carboxylic acid (compound 87); MS(ESI) calculated C 20 H 10 F8N2O5[M+1] + =511.0, actual value 511.1; 1 H-NMR(400 MHz,DMSO-d6)δ 12.82(s,1H),7.77(d,J=9.6 Hz,1H),7.61(d,J=6.4 Hz,1H),4.74(s,2H),4.51-4.42(m,1H),4.42-4.34(m,1H),4.13-4.03(m,1H),3.98-3.90(m,1H),3.56-3.44(m,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.13, -116.03, -140.29, -152.92, -161.81.

[0299] After HATU and DIEA activation, condensation of compound 2 with methyl piperidine-4-carboxylate gave methyl 1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)piperidine-4-carboxylate (compound 88): MS (ESI) calculated C 23 H 16 F8N2O5[M+1] + =553.0, actual value 553.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.78(d,J=9.6 Hz,1H),7.57(d,J=6.4 Hz,1H),5.08-4.93(m,2H),4.16-4.13(m,1H),3.89-3.85(m,1H),3.63(s,3H),3.23-3.19(m,1H) ,2.82-2.80(m,1H),2.73-2.61(m,1H),1.96-1.82(m,2H),1.70-1.56(m,1H),1.43-1.32(m,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.65, -116.09, -140.56, -153.04, -161.82, which, after treatment with 4 M HCl / dioxane at 90 °C, yielded 1-(2-(2,2-7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[1,4-oxazinyl][oxazine-4])acidyl-4-carboxylic acid (compound 89): MS (ESI) calculated C 22 H 14 F8N2O5[M+1] + =539.1, actual value 539.1; 1 H-NMR(400 MHz,DMSO-d6)δ 12.29(s,1H),7.78(d,J=9.6 Hz,1H),7.57(d,J=6.4 Hz,1H),5.09-4.92(m,2H),4.18-4.08(m,1H),3.85(t,J=10.2 Hz,1H),3.24-3.15(m,1H),2.84-2.76(m,1H),2.59-2.53(m,1H),1.94-1.80(m,2H),1.66-1.55(m,1H),1.42-1.32(m,1H); 19F-NMR (376 MHz, DMSO-d6) δ -75.00, -116.11, -140.56, -152.93, -161.76.

[0300] Condensation of compound 2 with methyl 2-aminoacetate after HATU and DIEA activation produced methyl (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)glycinate (compound 91): MS (ESI) calculated C 19 H 10 F8N2O5[M+1] + =499.0, actual value 499.1; 1 H-NMR(400 MHz,DMSO-d6)δ 8.86-8.78(m,1H),7.77(d,J=9.6 Hz,1H),7.48(d,J=6.4 Hz,1H),4.76(s,2H),3.90(d,J=6.0 Hz,2H),3.59(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ v 74.63, −116.16, −140.22, −153.24, −162.14, which after treatment with 4 M HCl / dioxane at 100 °C yielded (2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)glycine (compound 92): MS (ESI) calculated C 18 H8F8N2O5[M+1] + =485.0, actual value 485.1; 1 H-NMR(400 MHz,DMSO-d6)δ 12.56(s,1H),8.75-8.68(m,1H),7.77(d,J=9.6 Hz,1H),7.48(d,J=6.4 Hz,1H),4.74(s,2H),3.80(d,J=5.6 Hz,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.59, -116.10, -140.33, -153.20, -161.96.

[0301] After HATU and DIEA activation, condensation of compound 2 with methyl 3-aminopropanoate produced methyl 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoate (compound 94): MS(ESI) calculated C 20 H 12 F8N2O5[M+1] + =513.0, actual value 513.2; 1 H-NMR(400 MHz,DMSO-d6)δ 8.46-8.40(m,1H),7.77(d,J=9.6 Hz,1H),7.49(d,J=6.4 Hz,2H),4.65(s,3H),3.56(s,3H),2.48-2.43(m,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.55, -116.14, -140.40, -153.21, -162.03, which after treatment with trimethylstannanol in DCE at 80 °C yielded 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetide)propanoic acid (compound 95). MS (ESI) calculated C 19 H 10 F8N2O5[M+1] + =499.0, actual value 499.1; 1 H-NMR(400 MHz,DMSO-d6)δ 8.44-8.41(m,1H),7.77(d,J=9.6 Hz,1H),7.50(d,J=6.4 Hz,1H),4.65(s,2H),3.28-3.24(m,2H),2.31(t,J=6.8 Hz,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.57, -119.18, -140.45, -153.10, -161.96.

[0302] After HATU and DIEA activation, condensation of compound 2 with N-methyl-1-phenylmethanamine gave N-benzyl-N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 96). MS(ESI) calculated C 24 H 14 ClF8N2O3[M+1] + =531.0, actual value 531.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79(d,J=9.2 Hz,1H),7.67(d,J=6.4 Hz,1H),7.47-7.36(m,1H),7.36-7.26(m,3H),7.22(d,J=7.2 Hz,1H),5.12-4.95(m,2H),4.73-4.47(m,2H),3.04(s,2H),2.85(s,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.09, -116.12, -140.28, -152.90, -161.84.

[0303] After HATU and DIEA activation, condensation of compound 2 with N,O-dimethylhydroxylamine hydrochloride gave N-methoxy-N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 97): MS(ESI) calculated C 18 H 10 F8N2O4[M+1] + =471.0, actual value 471.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.78(d,J=9.6 Hz,1H),7.70(d,J=6.4 Hz,1H),4.99(s,2H),3.82(s,3H),3.15(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.46, -116.06, -140.24, -153.20, -161.99.

[0304] Condensation of compound 2 with N-methylhydroxylamine after activation with propanephosphonic anhydride (T3P) and triethylamine produced N-hydroxy-N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 98, 30 mg, 29% yield) as a white solid: MS (ESI) calculated C 17 H8F8N2O4[M-1] - =455.0, actual value 454.9; 1 H-NMR(400 MHz,DMSO-d6)δ 10.24(s,1H),7.77(d,J=9.6 Hz,1H),7.54(d,J=6.4 Hz,1H),4.93(s,2H),3.14(s,3H); 19 F-NMR (400 MHz, DMSO-d6) δ -75.23, -116.16, -140.27, -153.23, -162.02.

[0305] After HATU and DIEA activation, condensation of compound 2 with phenylmethanamine produced N-benzyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 99): MS (ESI) calculated C 23 H 12 ClF8N2O3[M+1] + =517.1, actual value 517.1; 1 H-NMR(400 MHz,DMSO-d6)δ 8.80(s,1H),7.78(d,J=9.6 Hz,1H),7.57(d,J=6.4 Hz,1H),7.36-7.21(m,5H),4.71(s,2H),4.30(d,J=5.6 Hz,3H); 19 F-NMR(376 MHz,DMSO-d6)δ-74.26,-116.15,-140.28,-153.09,-161.98; After HATU and DIEA activation, condensation of compound 2 with methyl (R)-thiomorpholine-3-carboxylate produced methyl (R)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)thiomorpholine-3-carboxylate (compound 107): MS(ESI) calculated C 22 H 14 F8N2O5S[M-1] - =569.0, actual value 568.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.84-7.74(m,1H),7.46-7.34(m,1H),5.47-5.26(m,2H),5.04-4.88(m,1H),4.59- 4.16(m,1H),3.68(s,3H),3.16-2.98(m,1H),2.93-2.73(m,2H),2.70-2.53(m,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.04, -76.77, -115.88, -140.29, -152.70, -161.85, which after treatment with trimethylstannanol in DCE at 80 °C yielded (R)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetylethylfoline-3-carboxylic acid (compound 108); MS (ESI) calculated C 21 H 12 F8N2O5S[M-1] - =555.0, actual value 554.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.10(s,1H),7.82-7.74(m,1H),7.46-7.35(m,1H),5.34-5.05(m,2H),4. 95-4.55(m,1H),4.18-3.44(m,2H),3.08-2.77(m,3H),2.66-2.55(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.17, -76.76, -115.89, -140.52, -152.96, -161.69.

[0306] After HATU and DIEA activation, condensation of compound 2 with methyl (S)-piperidine-2-carboxylate gave methyl (S)-1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)piperidine-2-carboxylate (compound 109): MS (ESI) calculated (C 23 H 16 F8N2O5)[M+1] + =553.0, actual value 553.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79(d,J=8.4 Hz,1H),7.42-7.37(m,1H),5.28-4.90(m,3H),4.91-4.75(m,1H),4.27-3.79( m,1H),3.64(s,3H),3.28-3.12(m,1H),2.26-2.15(m,1H),1.73-1.48(m,4H); 19 F-NMR (376 MHz, DMSO-d) δ -73.49, -77.37, -115.96, -140.28, -152.73, -161.93, which after treatment with trimethylstannanol in DCE at 80 °C yielded (S)-1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzone[1,4]oxazin-4-yl)acetyl-piperidine-2carboxylic acid (compound 110): MS(ESI) calculated (C 22 H 14 F8N2O5)[M+1] + =539.0, actual value 539.1; 1 H-NMR(400 MHz,DMSO-d6)δ13.02(s,1H),7.78(d,J=9.6 Hz,1H),7.45-7.30(m,1H),5.31-5.13(m,1H),5.06-4.63(m,2H),4.33-3.79(m,1H),3.29 -3.16(m,1H),2.24-2.07(m,1H),1.69-1.66(m,2H),1.61-1.45(m,1H),1.40-1.17(m,2H); 19F-NMR (376 MHz, DMSO-d6) δ -74.96, -77.26, -116.01, -140.54, -153.04, -161.65.

[0307] After HATU and DIEA activation, condensation of compound 2 with methyl (R)-thiomorpholine-3-carboxylate 1,1-dioxide gave methyl (R)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)thiomorpholine-3-carboxylate 1,1-dioxide (compound 119): MS(ESI) calculated C 22 H 14 F8N2O7S[M-1] - =601.0, actual value 600.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.83-7.73(m,1H),7.51-7.25(m,1H),5.82-5.46(m,1H),5.46-5.11(m,2H),5.10-4.7 0(m,1H),4.59-3.78(m,2H),3.73-3.64(m,3H),3.64-3.50(m,2H),3.22-3.20(m,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.24, -76.79, -115.78, -140.24, -152.63, -161.86, which was treated with trimethylstannanol in DCE at 80 °C, followed by chiral preparative HPLC to give (R)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[1,4]oxazine-4-acetylacyl)thiomorpholine-3-carboxylic acid 1,1-dioxide (120) compound: MS(ESI) calculated C 21 H 12 F8N2O7S[M-1] - =587.0, actual value 587.0; 1H-NMR(400 MHz,DMSO-d6)δ 7.80-7.77(m,1H),7.51-7.21(m,1H),5.50-5.06(m,2H),4.73-4.69(m,2H),4.59-3.33(m,4H),3.23-3.13(m,2H); 19 F-NMR (376 MHz, DMSO-d) δ -74.20, -76.69, -116.10, -140.40, -153.10, -161.79, and (S)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)thiomorpholine-3-carboxylic acid 1,1-dioxide (compound 121) were produced. MS (ESI) calculated for (C 21 H 12 F8N2O7S[M-1] - =587.0, actual value 587.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.80-7.77(m,1H),7.51-7.21(m,1H),5.50-5.06(m,2H),4.73-4.69(m,2H),4.59-3.33(m,4H),3.23-3.13(m,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.20, -76.70, -115.84, -140.48, -153.10, -161.99.

[0308] After HATU and DIEA activation, condensation of compound 2 with methyl (S)-morpholine-3-carboxylate gave methyl (S)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)morpholine-3-carboxylate (compound 126): MS(ESI) calculated C 22 H 14 F8N2O6[M-1] - =553.0, actual value 552.9; 1H-NMR(400 MHz,DMSO-d6)δ 7.85-7.71(m,1H),7.46-7.25(m,1H),5.40-5.13(m,1H),4.96-4.69(m,2H),4.37-4.1 6(m,1H),4.04-3.84(m,1H),3.84-3.71(m,1H),4.27-3.66(m,4H),3.62-3.32(m,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -73.29, -77.14, -115.91, -140.40, -152.76, -161.87, which after treatment with trimethylstannanol in DCE yielded (S)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)morpholine-3-carboxylic acid (127). MS (ESI) calculated C 21 H 12 F8N2O6[M-1] - =538.9, actual value 538.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.56-7.27 (m, 2H), 5.38-5.28 (m, 1H), 4.82-4.75 (m, 1H), 4.63-4.45 (m, 1H), 4.43-4.40 (m, 1H), 3.99-3.82 (m, 1H), 3.79-3.48 (m, 3H), 3.10-3.04 (m, 1H); 19 F-NMR (377 MHz, methanol-d4) δ -76.19, -79.90, -117.49, -142.25, -156.58, -164.92.

[0309] After HATU and DIEA activation, compound 2 was condensed with 1-(tert-butyl) 3-methyl(S)-piperazine-1,3-dicarboxylate to produce 1-(tert-butyl) 3-methyl(S)-4-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)piperazine-1,3-dicarboxylate. LCMS calculated C 27 H 23 F8N3O7,[M+1]- = 654.1, found 654, which was treated with TFA in DCM to give methyl (S)-1-(2-(2,2,7 - Trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)piperazine-2-carboxylate (compound 145) was produced: MS (ESI) calculated C 22 H 15 F8N3O5[M+1] + =554.1, actual value 554.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79-7.77(m,1H),7.38-7.33(m,1H),5.32-5.23(m,1H),4.88-4.82(m,2H),4.02-3.99(m,1H),3.75-3.72(m,1H), 3.66-3.60(m,2H),3.44-3.41(m,1H),3.26-3.25(m,2H),2.88-2.85(m,1H),2.75-2.71(m,1H),2.68-2.60(m,1H); 19 F-NMR (400 MHz, DMSO-d6) δ −76.9, −115.9, −140.63, −153.06, −161.90, which, after treatment with trimethylstannanol in DCE at 80 °C, yielded (S)-1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[1,4-oxazin-4-yl])acetyl)piperazine-2-carboxylic acid (compound 148): MS(ESI) calculated C 21 H 13 F8N3O5[M+1] + =540.0, actual value 540.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.90-7.88(m,1H),7.78-7.76(m,1H),5.26-5.22(m,1H),4.89-4.84(m,1H),4.50-4.46(m,1H), 4.05-4.03(m,1H),3.74-3.72(m,1H),3.56-3.52(m,1H),2.97-2.92(m,2H),2.87-2.83(m,2H); 19F-NMR (400 MHz, DMSO-d6) δ −70.99, −78.37, −116.32, −140.23, −153.41, −162.0, or after treatment of compound 145 with acetyl chloride and triethylamine in DCM, methyl (S)-4-acetyl-1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzonzene[b][1,4]oxazin-4-yl)acetyl)piperazine-2-carboxylate (compound 146) was produced: MS (ESI) calculated C 24 H 17 F8N3O6[M+1] + =596.1, actual value 596.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79(d,J=9.6 Hz,1H),7.47-7.28(m,1H),5.34-5.24(m,1H),5.12-4.79(m,2H),4.43-4.05(m,2H),3.99-3.76(m,1H),3.65(d,J=9.6 Hz,2H),3.59-3.47(m,2H),3.10-2.78(m,1H),2.71-2.53(m,1H),2.07-2.00(m,3H); 19 F-NMR (377 MHz, DMSO-d6) δ −73.82, −76.98, −115.87, −140.14, −152.73, −161.87, which, after treatment with trimethylstannanol in DCE at 80 °C, yielded (S)-4-acetyl-1-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[1,4-oxazin-4-yl]acetyl)-2-carboxylic acid (compound 147): MS(ESI) calculated C 23 H 15 F8N3O6[M-1] - =580.1, actual value 580.0; 1H-NMR(400 MHz,DMSO-d6)δ 13.08(b,1H),7.78(d,J=9.6 Hz,1H),7.46-7.20(m,1H),5.46-5.18(m,1H),5.04-4.55(m,2H),4.40-4.03(m,2H),3.98 -3.73(m,1H),3.64-3.43(m,1H),3.15-2.85(m,1H),2.71-2.53(m,1H),2.08-1.93(m,3H); 19 F-NMR (400 MHz, DMSO-d6) δ -73.81, -76.52, -115.94, -140.60, -153.06, -161.50.

[0310] Example 4 Preparation of methyl (S)-3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (Compound 130) and methyl (R)-3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (Compound 131) [ka] As shown in Scheme 6, Step 1, a mixture of methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (Compound 1006, 720 mg, 1.58 mmol) and trimethylstannanol (141 mg, 1.90 mmol) in dichloroethane (8 mL) was stirred at 80° C. for 16 hours, cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 60% ethyl acetate in petroleum ether) to give racemic 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 1007, 103 mg, 14% yield) as a white solid: MS (ESI) calculated C 17 H7F8NO4[M+1] - =440.0, actual value 439.4; 1 H-NMR(400 MHz,DMSO-d6)δ 13.26(s,1H),7.79(t,J=6.8 Hz,2H),5.33(d,J=7.2 Hz,1H),1.53(d,J=7.2 Hz,3H); 19 F-NMR (400 MHz, DMSO-d6) δ -75.96, -115.72, -140.33, -153.07, -162.04.

[0311] As shown in Scheme 6, Step 2, to 2-[2,2,7-trifluoro-3-oxo-6-(2,3,4,5,6-pentafluorophenyl)-1,4-benzoxazin-4-yl]propanoic acid (300 mg, 0.68 mmol) in DMF (6 mL) was added methyl 3-aminopropanoate (18 mg, 0.17 mmol), DIEA (44 mg, 0.34 mmol), and HATU (54 mg, 0.14 mmol). The resulting mixture was stirred under nitrogen atmosphere 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, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 69% acetonitrile in water) to give racemic methyl 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (compound 1008, 21 mg, 33% yield) as a white solid: MS (ESI) calculated C 21 H 14 F8N2O5[M-1] - =525.1, actual value 524.9. 1 H-NMR(400 MHz, methanol-d4)δ 7.44-7.39(m,2H),5.46(d,J=7.2 Hz,1H),3.61(s,3H),3.45-3.42(m,2H),2.47(t,J=2.4 Hz,2H),1.63(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, methanol-d4) δ -78.99, -116.76, -142.50, -156.28, -164.78.

[0312] As shown in Scheme 6, Step 3, racemic methyl 3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (70 mg) was separated by preparative chiral HPLC using the following conditions—Column: CHIRAL ART Cellulose-SC, 2×25 cm, 5 μm, eluted with 50% iPrOH / hexane to give methyl (R)-3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (Compound 131, 28 mg) as a white solid: MS (ESI) calculated C 21 H 14 F8N2O5[M+1] + =527.1, actual value 527.0; 1 H-NMR(400 MHz,DMSO-d6)δ 8.31(t,J=6.4 Hz,1H),7.77(d,J=8.8 Hz,1H),7.46(d,J=6.4 Hz,1H),5.32-5.30(m,1H),3.53(s,3H),3.27-3.24(m,2H),2.40-2.35(m,2H),1.50(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.53, -115.94, -140.73, -153.20, -162.04. Also recovered at longer retention times was methyl (S)-3-(2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (compound 130, 28 mg) as a white solid: MS (ESI) calculated C 21 H 14 F8N2O5[M+1] + =527.1, actual value 527.0; 1H-NMR(400 MHz,DMSO-d6)δ 8.31(t,J=6.4 Hz,1H),7.77(d,J=8.8 Hz,1H),7.46(d,J=6.4 Hz,1H),5.32-5.30(m,1H),3.53(s,3H),3.27-3.24(m,2H),2.40-2.35(m,2H),1.50(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.53, -115.94, -140.73, -153.20, -162.04.

[0313] Compound 1007 was reacted with methyl 3-(methylamino)propanoate under HATU coupling conditions in Step 2 of Scheme 6 to give racemic methyl 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate: MS(ESI) calculated C 22 H 16 F8N2O5[M+1] + = 541.1, found 541.0; separation into its enantiomers by chiral HPLC gave methyl (S)-3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoate (compound 132): MS (ESI) calculated C 22 H 16 F8N2O5[M+1] + =541.1, actual value 541.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.82-7.74(m,2H),5.73-5.65(m,1H),3.67-3.58(m,1H),3.55 and 3.49(s,3H),3.38(t,J=6.8 Hz, 1H), 2.83 and 2.78 (s, 3H), 2.47-2.30 (m, 2H), 1.52-1.42 (m, 3H); 19F-NMR (377 MHz, DMSO-d) δ −74.09, −77.52, −115.08, −140.85, −152.78, −161.78, which was subsequently hydrolyzed with trimethylstannanol in DCE at 80 °C to yield (S)-3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (134); MS(ESI) calculated C 21 H 14 F8N2O5[M+1] + =527.1, actual value 527.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.30(b,1H),7.88-7.72(m,2H),6.03-5.57(m,1H),3.62-3.36(m,2H),2. 84 and 2.78(s,3H),2.60-2.51(m,1H),2.38-2.25(m,1H),1.49-1.24(m,3H); 19 F-NMR (377 MHz, DMSO-d) δ -73.87, -76.68, -115.09, -140.82, -152.76, -161.74, and methyl (R)-3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 133) were also produced: MS(ESI) calculated C 22 H 16 F8N2O5[M+1] + =541.1, actual value 541.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.82-7.72(m,2H),5.75-5.65(m,1H),3.66-3.56(m,1H),3.55-3.52(m,1H),3.50-3.4 3(m,2H),3.42-3.34(m,1H),2.83 and 2.78(s,3H),2.48-2.29(m,2H),1.52-1.42(m,3H); 19F-NMR (377 MHz, DMSO-d6) -74.11, -77.52, -115.10, -140.85, -152.79, -161.78. This was prepared using trimethylstannanol in DCE at 80 °C to produce (R)-3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanamido)propanoic acid (compound 135): MS (ESI) calculated C 21 H 14 F8N2O5[M+1] + =527.1, actual value 527.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.23(b,1H),7.83-7.72(m,2H),5.90-5.67(m,1H),3.57-3.51(m,1H),3. 49-3.34(m,1H),2.84 and 2.78(s,3H),2.43-2.22(m,2H),1.52-1.42(m,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -74.19, -77.39, -115.07, -140.82, -152.84, -161.78.

[0314] Example 5 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 64) and 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 65) [ka] As shown in Scheme 7, Step 1, a solution 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), KPO (33.9 g, 160 mmol), chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-aminato-1,1-biphenyl-2-yl]palladium(II) (2.7 g, 4.0 mmol), and bis(adamantan-1-yl)(butyl)phosphane (1.4 g, 4.0 mmol) in dioxane (150 mL) was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by reverse-phase flash chromatography (5% to 52% acetonitrile in water) to give 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1009, 11.0 g, 38% yield) as a pale yellow solid: GCMS calculated C 13 H6F5NO3=319.0, actual measured value 319.0.

[0315] As shown in Scheme 7, 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 at 0 °C under a nitrogen atmosphere. 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 1010, 790 mg, 74% yield) as a brown solid: MS (ESI) calculated C 12 H4F5NO3[M-1] - =304.0, actual value 303.9.

[0316] As shown in Scheme 3, Step 7, 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 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. The residue was purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to afford 5-amino-2,2',3',4',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1011, 580 mg, 59% yield) as a yellow solid: MS (ESI) calculated value C 12 H6F5NO[M-1] - =274.0, actual value 274.0.

[0317] As shown in Scheme 7, Step 4, 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 ethyl 2-bromo-2,2-difluoroacetate (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 1012, 800 mg, 75% yield) as a brown oil: MS (ESI) calculated C 14 H5BrF7NO2[M-1] - =429.9, actual value 430.0.

[0318] As shown in Scheme 7, Step 5, a stirred solution of 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 K2CO3 (417 mg, 3.02 mmol) in DMF (10 mL) 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 in water) to give 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1013, 250 mg, 31% yield) as a brown solid: MS (ESI) calculated C 14 H4F7NO2[M-1] - =350.0, actual value 350.2; 1 H-NMR(400 MHz,DMSO-d6)δ 12.14(s,1H),7.71-7.65(m,1H),7.62(d,J=9.6 Hz,1H),7.20(d,J=6.4 Hz,1H); 19 F-NMR(376 MHz,DMSO-d6)δ-75.34,-115.87,-116.95,-131.54,-134.11,-164.81.

[0319] As shown in Scheme 7, Step 6, to a stirred mixture of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (450 mg, 1.28 mmol) in DMF (3 mL) was added KCO (354 mg, 2.56 mmol) and methyl 2-bromoacetate (294 mg, 1.92 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 25 °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. The residue was purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 64, 54 mg, 9% yield) as a white solid: GCMS calculated C 17 H8F7NO4=423.0, measured value 423.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.45-7.35 (m, 2H), 7.39-7.21 (m, 1H), 4.90 (s, 2H), 3.79 (s, 3H); 19 F-NMR (377 MHz, methanol-d4) δ -79.00, -117.03, -133.42, -135.32, -167.69.

[0320] As shown in Scheme 7, Step 7, to a stirred mixture of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (340 mg, 0.80 mmol) in DCE (2 mL) was added trimethylstannanol (292 mg, 1.60 mmol). The resulting mixture was stirred at 65 °C for 16 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 65, 52 mg, 15% yield) as a yellow semi-solid: MS (ESI) calculated C 16 H6F7NO4[M-1] - =408.0, actual value 407.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.80-7.68(m,3H),4.72(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.44, -115.12, -116.31, -131.44, -133.46, -165.01.

[0321] Alkylation of compound 1013 with methyl 2-bromopropanoate using cesium carbonate in acetonitrile at 65 °C produced racemic methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate, followed by its enantiomer, methyl (2S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 76): GCMS calculated C 18 H10 F7NO4=437.0, measured value 437.0; 1 H-NMR (400 MHz, methanol-d4)δ 7.49(d,J=6.4 Hz,1H),7.39(d,J=9.2 Hz,1H),7.33-7.26(m,1H),5.37(q,J=7.2 Hz,1H),3.76(s,3H),1.65(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, methanol-d4) δ -78.57, -81.67, -116.96, -117.45, -133.25, -135.67, -167.60, and methyl (2R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 77). GCMS calculated C 18 H 10 F7NO4=437.0, measured value 437.0; 1 H-NMR(400 MHz, methanol-d4)δ 7.48(d,J=6.4 Hz,1H),7.40(d,J=9.6 Hz,1H),7.33-7.26(m,1H),5.37(q,J=7.2 Hz,1H),3.76(s,3H),1.65(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, methanol-d₄) δ −78.55, −81.68, −116.62, −117.45, −133.21, −135.64, −167.60, which were each subsequently treated with trimethylstannanol in DCE at 65 °C to give (2S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 78): MS (ESI) calculated C 17 H8F7NO4[M-1] - =422.0, actual value 422.1; 1 H-NMR(400 MHz,DMSO-d6)δ 13.18(s,1H),7.81-7.73(m,3H),5.33(d,J=6.8 Hz,1H),1.53(d,J=7.2 Hz,3H); 19F-NMR (376 MHz, DMSO-d) δ -75.96, -115.12, -115.90, -131.26, -133.49, -164.94, and MS (ESI) calculated values ​​for (2R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 79) were obtained. 17 H8F7NO4)[M-1] - =422.0, actual value 421.8; 1 H-NMR (400 MHz, methanol-d4) δ 7.46 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31-7.25 (m, 2H), 5.41-5.35 (m, 1H), 1.65 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -75.52, -82.02, -116.89, -133.30, -135.38, -167.62.

[0322] After activation using EDCI and triethylamine, compound 65 was condensed with dimethyl(sulfamoyl)amine to produce N-(N,N-dimethylsulfamoyl)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (compound 93): MS(ESI) calculated C 18 H 12 F7N3O5S[M-1] - =514.0, actual value 514.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.43-7.38 (m, 2H), 7.33-7.23 (m, 1H), 4.84 (s, 2H), 2.89 (s, 6H); 19 F-NMR (400 MHz, methanol-d4) δ -78.71, -116.65, -117.03, -133.31, -135.13, -167.65.

[0323] After activation using HATU and DIEA, methyl 3-(methylamino)propanoate was condensed with compound 65 to produce methyl 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoate (compound 162): MS(ESI) calculated C 21 H 15 F7N2O5[M+1] + =509.1, actual value 509.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.79-7.69(m,2H),7.57-7.47(m,1H),5.07(s,1H),4.93(s,1H),3.64(t,J=6.4 Hz,1H),3.54(d,J=6.4 Hz,4H),3.08(s,2H),2.80(s,1H),2.75(t,J=6.4 Hz,1H),2.49(d,J=7.6 Hz,1H); 19 F-NMR (377 MHz, DMSO-d) δ −75.69, −115.46, −116.02, −131.50, −133.71, −164.87, which, after treatment with trimethylstannanol in DCE at 65 °C, yielded 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) azidoamido)propanoic acid (compound 163): MS (ESI) calculated C 20 H 13 F7N2O5[M+1] + =495.1, actual value 495.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.29(s,1H),7.78-7.68(m,2H),7.58-7.48(m,1H),5.08(s,1H),4.93(s,1H),3.64-3. 56(m,1H),3.47-3.46(m,1H),3.09 and 2.82(s,3H),2.65-2.54(m,1H),2.48-2.45(m,1H); 19F-NMR(377 MHz,DMSO-d6)δ-75.29,-115.15,-116.47,-131.33,-133.65,-164.78.

[0324] After activation using HATU and DIEA, compound 65 was condensed with methyl azetidine-3-carboxylate to produce methyl 1-(2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)azetidine-3-carboxylate (compound 164): MS(ESI) calculated C 21 H 13 F7N2O5[M+1] + =507.1, actual value 507.0; 1 H NMR(400 MHz,DMSO-d6)δ 7.82-7.68(m,2H),7.59(s,1H),4.74(s,2H),4.44-4.54(m,1H),4.30-4.43( m,1H),4.06-4.16(m,1H),3.92-4.05(m,1H),3.69(s,3H),3.57-3.68(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ −74.75, −115.01, −116.27, −131.22, −133.50, −164.76, which, after treatment with trimethylstannanol in DCE at 65 °C, yielded 1-(2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)acetidine-3-carboxylic acid (compound 165); MS (ESI) calculated C 20 H 11 F7N2O5[M-1] - =491.1, actual value 491.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.83(b,1H),7.68-7.84(m,2H),7.60(s,1H),4.74(s,2H),4.46-4.54(m,1H) ,4.35-4.53(m,1H),4.07-4.17(m,1H),3.82-3.98(m,1H),3.48-3.63(m,1H);19 F-NMR(377 MHz,DMSO-d6)δ-75.23,-115.04,-116.29,-131.18,-133.49,-164.75.

[0325] Example 6 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 6) and 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 7) [ka] As shown in Scheme 8, Step 1, to a stirred mixture of dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane (Sphos, 990 mg, 2.40 mmol), Pd(OAc) (270 mg, 1.20 mmol), and KCO (3.3 g, 24.0 mmol) in isopropyl acetate (20 mL) was added 1,2,4,5-tetrafluorobenzene (3.6 g, 24.0 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 10 minutes, 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 hours at 80 °C. The resulting mixture was stirred at 80° C. for an additional 2 h, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0% to 40% EtOAc in petroleum ether) to give 2,2′,3,5,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (compound 1014, 1.5 g, 35% yield) as a purple solid: GCMS calculated C 13 H6F5NO3=319.0, actual value 319.0.

[0326] As shown in Scheme 8, 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 (5.8 g, 23.5 mmol) dropwise. The resulting mixture was stirred under a nitrogen atmosphere at -78 °C for 3 hours, diluted with water, and extracted with CHCl. ​​The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure to approximately 20% volume. The filtrate was concentrated under reduced pressure to give 2,2',3',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1015, 1.3 g, crude) as a brown solid: MS (ESI) calculated C 12 H4F5NO3[M-1] - = 304.0, found 304.0. This material was used in the subsequent step without further purification.

[0327] As shown in Scheme 8, Step 3, 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 EtOH (10 mL) and HO (3 mL) was added sodium hyposulfite (3.9 g, 22.91 mmol) in portions. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour, 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 1016, 1.2 g) as a yellow solid: MS (ESI) calculated C 12 H5F6NO[M-1] - =292.1, found 292.1. This material was used as is in subsequent reactions.

[0328] As shown in Scheme 8, 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 ethyl 2-bromo-2,2-difluorodifluoroacetate (369 mg, 1.81 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 5 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, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 38% EtOAc in 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 1017, 300 mg, 38% yield) as a brown solid: MS (ESI) calculated C 14 H5BrF7NO2[M+1] + =431.9, actual value 431.9.

[0329] As shown in Scheme 8, 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 a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1018, 230 mg, 55% yield) as a brown solid: MS (ESI) calculated C 14 H4F7NO2[M-1] - =350.0, actual value 350.0;1 H-NMR(400 MHz,DMSO-d6)δ 12.20(s,1H),8.07(m,1H),7.70-7.62(m,1H),7.24(d,J=6.4 Hz,1H); 19 F-NMR(376 MHz,DMSO-d6)δ-75.21,-116.80,-138.87,-141.58.

[0330] As shown in Scheme 8, Step 6, to a solution of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.14 mmol) in DMF (1 mL) was added KCO (59 mg, 0.42 mmol) and methyl 2-bromoacetate (26 mg, 0.17 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC [55%-68% acetonitrile / water (10 mM NH4HCO3)] to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 6, 10 mg, 16% yield) as an off-white solid: GCMS calculated C 17 H8F7NO4=423.0, measured value 423.0; 1 H-NMR(400 MHz,DMSO-d6)δ 8.11(s,1H),7.86-7.75(m,2H),4.88(s,2H),3.71(s,3H); 19 F-NMR (376 MHz, CDCl3) δ -75.03, -112.96, -137.17, -139.25.

[0331] As shown in Scheme 8, Step 7, to a solution of methyl 2-(2,2,7-trifluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (460 mg, 1.08 mmol) in DCE (5 mL) was added trimethystyltannanol (394 mg, 2.17 mmol) in portions at 20 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue purified by reverse-phase flash chromatography (5% to 70% acetonitrile in water) to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 7, 228 mg, 51% yield) as a white solid: MS (ESI) calculated C 16 H6F7NO4[M-1] - =408.0, actual value 408.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.41(s,1H),8.17-8.03(m,1H),7.90-7.63(m,2H),4.77(s,2H); 19 F-NMR(376 MHz,DMSO-d6)δ-75.44,-116.08,-139.00,-140.86.

[0332] Compound 1018 was alkylated with methyl 2-bromopropanoate using potassium carbonate in DMF at 25° C. to produce racemic methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate, followed by its enantiomer, methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 66): GCMS calculated C18 H 10 F7NO4=437.0, measured value 437.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.67-7.54 (m, 2H), 7.44 (d, J = 9.2 Hz, 1H), 5.42-5.32 (m, 1H), 3.76 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, methanol-d4) δ -78.72, -81.35, -116.49, -140.98, and the resulting product was methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 67). GCMS calculated value C 18 H 10 F7NO4=437.0, measured value 437.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.67-7.54 (m, 2H), 7.44 (d, J = 9.2 Hz, 1H), 5.42-5.32 (m, 1H), 3.76 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, methanol-d₄) δ −78.72, −81.35, −116.49, −140.98, each of which was subsequently treated with trimethylstannanol in DCE at 65 °C to give (S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 68); MS (ESI) calculated C 17 H8F7NO4[M-1] - =422.0, actual value 421.9; 1 H-NMR(400 MHz,DMSO-d6)δ 8.14-8.05(m,1H),7.72(d,J=9.6 Hz,1H),7.61-7.43(m,1H),5.19-5.12(m,1H),1.45(d,J=7.2 Hz,3H); 19F-NMR (376 MHz, DMSO-d) δ −72.60, −78.91, −116.65, −138.72, −141.95, and MS (ESI) calculated C provided (R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 69). 17 H8F7NO4[M-1] - =422.0, actual value 421.9; 1 H-NMR(400 MHz,DMSO-d6)δ 8.16-8.02(m,1H),7.70(d,J=9.6 Hz,1H),7.43(d,J=6.4 Hz,1H),5.11(d,J=7.6 Hz,1H),1.44(d,J=7.2 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -71.89, -79.60, -116.89, -138.64, -142.29.

[0333] Example 7 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 158) and 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 159) [ka] As shown in Scheme 9, Step 1, 1,2,3,4-tetrafluorobenzene (3 equivalents), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 equivalent), Pd(OAc) (0.1 equivalents), di-tert-butylmethylphosphine (0.1 equivalents), and KCO (1 equivalent) in dioxane are heated to 90 °C for 16 hours, 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 1019).

[0334] As shown in Scheme 9, Step 2, to a stirred mixture of 2,2',3,4,5-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (1 equivalent) in DCM is added boron tribromide (5 equivalents) dropwise at 0°C under a 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 1020).

[0335] As shown in Scheme 9, Step 3, to a stirred solution of 2,2',3',4',5'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (1 equivalent) in 1:1 water / EtOH is added sodium hyposulfite (5 equivalents). 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 1021).

[0336] As shown in Scheme 9, Step 4, to a stirred solution of 5-amino-2,2',3',4',5'-pentafluoro-[1,1'-biphenyl]-4-ol (1 equivalent) and TEA (2 equivalents) in EtOAc is added ethyl 2-bromo-2,2-difluoroacetate (2 equivalents) in portions at 20°C. The resulting mixture is stirred at 50°C for 16 hours under nitrogen, 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 in vacuo, and purified by reverse-phase flash chromatography to give 2-bromo-2,2-difluoro-N-(2',3',4',5',6-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)acetamide (compound 1022).

[0337] As shown in Scheme 9, 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 (1 equivalent) in DMF is added KCO (2 equivalents) portionwise at 20°C. The resulting mixture is stirred under nitrogen at 50°C for 2 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 2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1023).

[0338] As shown in Scheme 9, Step 6, to a stirred solution of 2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1 equivalent) and methyl 2-bromoacetate (1.2 equivalents) in DMF is added KCO (2 equivalents) at room temperature under a nitrogen atmosphere. The mixture is stirred at room temperature for 2 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 reverse-phase preparative HPLC to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 158): GCMS calculated C 17 H8F7NO4=423.0, measured value 423.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.81-7.63(m,3H),4.96(s,2H),3.73(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -76.04, -82.16, -116.48, -139.33, -155.52, -156.00.

[0339] As shown in Scheme 9, Step 7, to a stirred mixture of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (1 equivalent) in DCE is added trimethylstannanol (2 equivalents). The resulting mixture is stirred at 65 °C under a nitrogen atmosphere for 16 hours, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers 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-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 159): MS (ESI) calculated C 16 H6F7NO4[M-1]- =408.0, actual value 407.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.40(b,1H),7.78-7.60(m,3H),4.83(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.88, -82.09, -116.77, -139.39, -155.63, -156.00.

[0340] Condensation of compound 159 with methyl 3-(methylamino)propanoate after activation using N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) produced methyl 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoate (compound 166): MS (ESI) calculated C 21 H 15 F7N2O5[M+1] + =509.1, actual value 509.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.74-7.59(m,2H),7.48-7.38(m,1H),5.12(s,1H),4.99(s,1H),3.65(t,J=6.4 Hz,1H),3.58-3.57(m,1H),3.38(s,3H),3.09 and 2.78(s,3H),2.75-2.65(m,1H),2.48-2.46(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ −75.68, −117.21, −139.43, −155.16, −156.00. After treatment with trimethylstannanol in DCE at 65 °C, 3-(N-methyl-2-(2,2,7-trifluoro-3-oxo-6(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamido)propanoic acid (compound 167) was obtained: MS (ESI) calculated value C 20 H 13 F7N2O5[M+1] +=495.0, actual value 494.9; 1 H-NMR(400 MHz,DMSO-d6)δ 12.36(s,1H),7.73-7.59(m,2H),7.44(t,J=6.4 Hz,1H),5.13(s,1H),4.98(s,1H),3.68-3.58(m,1H),3.49(t,J=7.2 Hz,1H),3.10(s,2H),2.82(s,1H),2.66-2.62(m,1H),2.43-2.38(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.66, -117.23, -139.40, -155.33, -155.88.

[0341] After activation using N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI), condensation of compound 159 with methyl azetidine-3-carboxylate produced methyl 1-(2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetyl)azetidine-3-carboxylate (compound 168): MS (ESI) calculated C 21 H 13 F7N2O5[M+1] + =507.1, actual value 507.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.68(m,2H),7.49(d,J=6.4 Hz,1H),4.80(s,2H),4.50(t,J=8.8 Hz,1H),4.46-4.37(m,1H),4.12(t,J=9.2 Hz,1H),3.97-3.95(m,1H),3.69(s,3H),3.62 3.60(m,1H); 19F-NMR (377 MHz, DMSO-d6) δ -75.63, -116.95, -139.36, -155.19, -155.74, -155.81, which after treatment with trimethylstannanol in DCE at 80 °C yielded 1-(2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,5-tetrafluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetin-3-carboxylic acid (169). MS (ESI) calculated C 20 H 11 F7N2O5[M+1] + =493.1, actual value 493.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.78(br,1H),7.70-7.64(m,2H),7.50(d,J=6.4 Hz,1H),4.80(s,2H),4.47(d,J=8.4 Hz,1H),4.40-4.36(m,1H),4.08(t,J=9.6 Hz,1H),3.96-3.92(m,1H),3.48-3.41(m,1H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.61, -116.98, -139.37, -155.18, -155.70, -155.81.

[0342] Example 8 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 103) and 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 104) [ka] As shown in Scheme 10, Step 1, to a solution of 2-amino-4-bromo-5-fluorophenol (18.0 g, 87.4 mmol) and methyl 2-bromo-2,2-difluoroacetate (550 mg, 2.91 mmol) in EtOAc (180 mL) was added triethylamine (17.6 g, 175 mmol) at 20° C. The resulting solution was then stirred at 50° C. for 2 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, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 40% ethyl acetate in petroleum ether) to give 2-bromo-N-(5-bromo-4-fluoro-2-hydroxyphenyl)-2,2-difluoroacetamide (compound 1024, 11.0 g, 31% yield) as a brown solid: MS (ESI) calculated C8H4Br2F3NO2[M-1] - =360.0, actual value 360.0.

[0343] As shown in Scheme 10, Step 2, to 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 added K2CO3 (5.3 g, 38.6 mmol) 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, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 6-bromo-2,2,7-trifluoro-4H-1,4-benzoxazin-3-one (compound 1025, 4.0 g, 66% yield) as a brown solid: MS (ESI) calculated CH3BrF3NO2 [M-1]. - =280.0, actual value 280.0.

[0344] As shown in Scheme 10, Step 3, to 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 added p-methoxybenzyl chloride (1.6 g, 10.7 mmol) and K2CO3 (1.9 g, 14.2 mmol) 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, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 6-bromo-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1026, 2.5 g, 78% yield) as a yellow solid: GCMS calculated C 16 H 11 BrF3NO3 = 401.0, Measured value = 401.0.

[0345] As shown in Scheme 10, Step 4, to a solution of 6-bromo-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one (compound 1021, 2.0 g, 4.97 mmol) and 2,3,5,6-tetrafluoroanisole (1.3 g, 7.44 mmol) in dioxane (10 mL) was added chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II) (CataCXium A Pd G2, 300 mg, 0.50 mmol), bis(adamantan-1-yl)(butyl)phosphane (CataCXium A, 200 mg, 0.50 mmol), and KCO (1.4 g, 9.95 mmol). The mixture was stirred under nitrogen at 110° C. 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, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 60% acetonitrile in water) to give 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1027, 680 mg, 25% yield) as a yellow solid: GCMS calculated C 23 H 14 F7NO4=501.1, actual measured value 501.0.

[0346] As shown in Scheme 10, Step 5, to a solution of 2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (640 mg, 1.28 mmol) in DCM (10 mL) was added trifluoromethanesulfonic acid (1.9 g, 12.77 mmol) and trifluoroacetic acid (1.4 g, 12.77 mmol). The mixture was stirred at 25° 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. The residue was purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to give 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1028, 420 mg, 78% yield) as a colorless oil: GCMS calculated C 15 H6F7NO3=381.0, actual measured value 381.0.

[0347] As shown in Scheme 10, Step 6, to a stirred solution of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 1028, 100 mg, 0.26 mmol) and DMF (2 mL) was added methyl 2-bromoacetate (60.2 mg, 0.39 mmol) and KCO (73 mg, 0.52 mmol). The mixture was stirred at 20 °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. The residue was purified by reverse-phase flash chromatography (5% to 40% acetonitrile in water) to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 103, 100 mg, 84% yield) as a white solid: GCMS calculated C 18 H 10F7NO5=453.0, actual value 453.0. 1 H-NMR(400 MHz,DMSO-d6)δ 7.85-7.69(m,2H),4.88(s,2H),4.13(s,3H),3.72(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.60, -115.73, -142.07, -157.69.

[0348] As shown in Scheme 10, Step 7, to a stirred solution of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (60 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) was added trimethylstannane (48 mg, 0.26 mmol). The mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere, diluted with water, acidified to pH=4 with 1 M HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 104, 30 mg, 52% yield) as a white solid: MS (ESI) calculated C 17 H8F7NO5[M-1] - =438.0, actual value 438.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.48-7.27 (m, 2H), 4.85 (s, 2H), 4.16 (s, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -78.85, -117.01, -144.43, -160.22.

[0349] Alkylation of compound 1028 with methyl 2-bromopropanoate followed by separation of the resulting enantiomers by chiral HPLC gave methyl (S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 111). GCMS calculated C 19 H 12 F7NO5=467.0, actual value 467.1; 1 H-NMR (400 MHz, chloroform-d) δ 7.21-7.12 (m, 1H), 6.91 (d, J = 6.0 Hz, 1H), 5.54-5.45 (m, 1H), 4.21-4.11 (m, 3H), 3.77 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, chloroform-d) δ -76.23, -79.97, -113.45, -142.28, -157.23, and methyl (R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 112) were produced. GCMS calculated C 19 H 12 F7NO5=467.0, actual value 467.1; 1 H-NMR (400 MHz, chloroform-d) δ 7.21-7.12 (m, 1H), 6.91 (d, J = 6.4 Hz, 1H), 5.55-5.45 (m, 1H), 4.23-4.09 (m, 3H), 3.77 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, chloroform-d) δ −76.23, −79.97, −113.45, −142.28, −157.23. Compounds 111 and 112 were each treated with trimethylstannanol in DCE at 80° C. to give (S)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 113), respectively: MS (ESI) calculated value C 18H 10 F7NO5[M-1] - =452.0, actual value 451.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.22(s,1H),7.80-7.72(m,2H),5.38-5.28(m,1H),4.14(s,3H),1.53(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.98, -118.78, -142.14, -151.73, and (R)-2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 114) were obtained. MS (ESI) calculated C 18 H 10 F7NO5[M-1] - =452.0, actual value 451.9; 1 H-NMR(400 MHz,DMSO-d6)δ 7.80-7.72(m,2H),5.38-5.28(m,1H),4.14(s,3H),1.65-1.33(m,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.70, -115.85, -142.19, -157.72.

[0350] Example 9 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 60) and 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 61) [ka] As shown in Scheme 11, Step 1, to a stirred mixture of 2,2',3,4,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (Compound 1009, 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 at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C for 30 minutes, and methyl iodide (0.7 g, 4.70 mmol) was added under a nitrogen atmosphere at -78°C. The resulting mixture was stirred at -78°C for 4 hours under nitrogen, 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 in petroleum ether) to give 2,2',3,4,6-pentafluoro-4'-methoxy-5-methyl-5'-nitro-1,1'-biphenyl (compound 1029, 800 mg, 77% yield) as a yellow solid: GCMS calculated C 14 H8F5NO3=333.0, actual measured value 333.0.

[0351] As shown in Scheme 11, Step 2, 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 at 0°C under a nitrogen atmosphere. The resulting mixture was stirred 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. The residue was purified by flash chromatography (0% to 50% ethyl acetate in 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 1030, 710 mg, 93% yield) as a yellow oil: MS (ESI) calculated C 13 H6F5NO3[M-1] - =318.0, actual value 318.0.

[0352] As shown in Scheme 11, Step 3, zinc powder (727 mg, 11.12 mmol) was added 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solids were filtered, and the resulting solution was diluted with water. The aqueous solution was extracted with ethyl acetate, and the combined organic layers were washed with NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to give 5-amino-2,2',3',4',6'-pentafluoro-5'-methyl-[1,1'-biphenyl]-4-ol (compound 1031, 560 mg, 87% yield) as a brown solid: MS (ESI) calculated C 13 H8F5NO[M-1] - =288.0, actual value 288.0.

[0353] As shown in Scheme 11, 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 MeOH (15 mL) was added ethyl 2-bromo-2,2-difluoroacetate (632 mg, 3.11 mmol) and triethylamine (420 mg, 4.15 mmol). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours and then diluted with water. The aqueous solution 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 flash chromatography (0% to 50% ethyl acetate in 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 1032, 550 mg, 59% yield) as a brown solid: MS (ESI) calculated C 15 H7BrF7NO2[M-1] - =444.0, actual value 444.0.

[0354] As shown in Scheme 11, 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 K2CO3 (511 mg, 3.70 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 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, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 50% ethyl acetate in 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 1033, 360 mg, 80% yield) as a brown solid: MS (ESI) calculated C 15 H6F7NO2[M-1] - =364.0, actual value 364.0; 1 H-NMR(400 MHz,DMSO-d6)δ 12.17(s,1H),7.64(d,J=9.6 Hz,1H),7.18(d,J=6.4 Hz,1H),2.24(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.25, -116.88, -120.24, -135.31, -138.86, -165.49.

[0355] As shown in Scheme 11, Step 6, to a solution of 2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (40 mg, 0.11 mmol) in DMF (2 mL) was added 2-bromomethyl acetate (25 mg, 0.16 mmol) and KCO (45 mg, 0.33 mmol) under a nitrogen atmosphere at 20° C. The resulting solution was stirred at 20° 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, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (10% to 50% acetonitrile in water) to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 60, 30 mg, 75% yield) as a colorless oil: GCMS calculated C 18 H 10 F7NO4=437.0, measured value 437.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.42-7.35 (m, 2H), 4.90 (s, 2H), 3.78 (s, 3H), 2.28 (s, 3H); 19 F-NMR (377 MHz, methanol-d4) δ -79.05, -116.98, -121.84, -137.66, -140.46, -168.48.

[0356] As shown in Scheme 11, Step 7, to a stirred solution of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (90 mg, 0.21 mmol) in DCE (5 mL) was added trimethylstannanol (74 mg, 0.41 mmol). The resulting mixture was stirred at 65 °C under a nitrogen atmosphere for 16 h, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10% to 50% acetonitrile in water) to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 61, 25 mg, 28% yield) as a white solid: MS (ESI) calculated C 17 H8F7NO4[M-1] - =422.0, actual value 421.9; 1 H-NMR (400 MHz, methanol-d4) δ 7.30 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 4.58 (s, 2H), 2.27 (s, 3H); 19 F-NMR (377 MHz, methanol-d4) δ -77.44, -118.12, -121.58, -137.89, -140.14, -168.62.

[0357] Example 10 Preparation of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 62) and methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 63) [ka] As shown in Scheme 12, Step 1, to a solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3.0 g, 11.99 mmol) and 1,2,4,5-tetrafluoro-3-(trifluoromethyl)benzene (3.9 g, 17.99 mmol) in dioxane (70 mL) was added chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A Pd G2, 400 mg, 0.60 mmol), di(1-adamantyl)-n-butylphosphine (cataCXium A, 220 mg, 0.60 mmol), and K2CO3 (3.3 g, 23.99 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 90 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 13% ethyl acetate in petroleum ether) to give 2,2',3,5,6-pentafluoro-4'-methoxy-5'-nitro-4-(trifluoromethyl)-1,1'-biphenyl (compound 1034, 3.3 g, 63% yield) as a yellow oil: GCMS calculated C 14 H5F8NO3=387.0, actual measured value 387.0.

[0358] As shown in Scheme 12, Step 2, to a solution of 2,2',3,5,6-pentafluoro-4'-methoxy-5'-nitro-4-(trifluoromethyl)-1,1'-biphenyl (3.1 g, 8.00 mmol) in DCM (20 mL) was added BBr3 (10.0 g, 40.03 mmol) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 3 h under a nitrogen atmosphere. The resulting mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 19% ethyl acetate in petroleum ether) to give 2,2',3',5',6'-pentafluoro-5-nitro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-ol (compound 1035, 1.9 g, 54% yield) as a black solid: MS (ESI) calculated C13 H3F8NO3[M-1] - =372.0, actual value 372.1.

[0359] As shown in Scheme 12, Step 3, to a solution of 2,2',3',5',6'-pentafluoro-5-nitro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-ol (1.8 g, 4.82 mmol) in HO (10 mL) and EtOH (10 mL) was added sodium hypophosphite (2.1 g, 24.12 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 18% ethyl acetate in petroleum ether) to give 5-amino-2,2',3',5',6'-pentafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-ol (compound 1036, 1.4 g, 78% yield) as a brown solid: MS (ESI) calculated C 13 H5F8NO[M-1] - =342.0, actual value 342.0.

[0360] As shown in Scheme 12, Step 4, to a solution of 5-amino-2,2',3',5',6'-pentafluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-ol (1.1 g, 3.40 mmol) and triethylamine (690 mg, 6.81 mmol) in THF (25 mL) was added bromodifluoroacetyl chloride (790 mg, 4.09 mmol) dropwise at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours, diluted with water, and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-bromo-2,2-difluoro-N-[2',3',5',6,6'-pentafluoro-4-hydroxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]acetamide (compound 1037, 1.0 g, 54% yield) as a brown oil: MS (ESI) calculated C 15 H4BrF 10NO2[M-1] - =497.9, actual value 498.0.

[0361] As shown in Scheme 12, Step 5, a mixture of 2-bromo-2,2-difluoro-N-[2',3',5',6,6'-pentafluoro-4-hydroxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]acetamide (1.7 g, 3.39 mmol) and K2CO3 (940 mg, 6.79 mmol) in DMF (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 3 hours. The resulting mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 36% acetonitrile in water) to give 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1038, 600 mg, 41% yield) as a white solid: MS(ESI) calculated C 15 H3F 10 NO2[M-1] - =418.0, actual value 418.2; 1 H-NMR(400 MHz,DMSO-d6)δ 12.24(s,1H),7.72-7.70(d,J=9.6 Hz,1H),7.30-7.28(d,J=6.8 Hz,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -55.60, -74.99, -116.42, -139.04, -141.63.

[0362] As shown in Scheme 12, Step 6, to a stirred solution of 2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.48 mmol) in DMF (4 mL) was added methyl 2-bromoacetate (110 mg, 0.72 mmol) and KCO (132 mg, 0.95 mmol). The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 62, 200 mg, 85% yield) as a colorless oil: GCMS calculated C 18 H7F 10 NO4=491.0, actual measured value 491.0.

[0363] As shown in Scheme 12, Step 7, to a stirred solution of methyl 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (180 mg, 0.37 mmol) in DCE (4 mL) was added trimethylstannanol (133 mg, 0.73 mmol). The resulting mixture was stirred at 65 °C for 16 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 2-(2,2,7-trifluoro-3-oxo-6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 63, 80 mg, 46% yield) as a white solid: MS (ESI) calculated C 17 H5F 10 NO4[M-1] - =476.0, actual value 476.3; 1 H-NMR(400 MHz,DMSO-d6)δ 7.82(d,J=9.6 Hz,2H),4.74(s,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -55.64, -75.33, -115.46, -138.07, -141.59.

[0364] Example 11 Preparation of methyl 2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 39) and 2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 40) [ka] As shown in Scheme 13, Step 1, to a degassed mixture of 4-bromo-1-methoxy-2-nitrobenzene (2.0 g, 8.62 mmol) in isopropyl acetate (10 mL) was added Pd(OAc) (190 mg, 0.86 mmol), Sphos (700 mg, 1.72 mmol), and KCO (2.4 g, 17.2 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 minutes, 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 hours 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 1039, 1.7 g, 54% yield) as a brown solid: GCMS calculated C 13 H6F5NO3=319.0, actual measured value 319.0.

[0365] As shown in Scheme 13, 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 at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. 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 1040, 1.2 g, crude) as a yellow solid: MS (ESI) calculated C 12 H4F5NO3[M-1] - =304.0, found 303.8. This material was used directly in subsequent reactions.

[0366] As shown in Scheme 13, 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 hour, 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 1041, 400 mg, crude) as a yellow solid: MS (ESI) calculated C 12 H6F5NO[M-1] - =274.0, found 274.1. This material was used directly in subsequent reactions.

[0367] As shown in Scheme 13, Step 4, to a stirred solution of 3-amino-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (5.0 g, 18.2 mmol) and NaHCO (4.5 g, 54.5 mmol) in DME (25 mL) and HO (25 mL) was added chloroacetyl chloride (3.1 g, 27.25 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (10% to 60% ethyl acetate / petroleum ether) to give 6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1042, 3.4 g, 57% yield) as a brown solid: MS (ESI) calculated C 14 H6F5NO2[M-1] - =315.2, actual value 314.0; 1H-NMR(400 MHz,DMSO-d6)δ 10.89(s,1H),7.13(d,J=8.4 Hz,1H),7.06(d,J=8.4 Hz,1H),7.00(s,1H),4.67(s,2H); 19 F-NMR (400 MHz, DMSO-d6) δ -143.63, -156.62, -162.75.

[0368] As shown in Scheme 13, Step 5, a solution of 6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.63 mmol) and KCO (105 mg, 0.76 mmol) in DMF (4.0 mL) was stirred at 80 °C under a nitrogen atmosphere 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. The residue was purified by flash chromatography (0% to 10% methanol in dichloromethane) to give methyl 2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 39, 29 mg, 11% yield) as a red solid: MS (ESI) calculated C 17 H 10 F5NO4[M+1] + =388.0, actual value 388.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.31(s,1H),7.24-7.13(m,2H),4.83(s,2H),4.76(s,2H),3.69(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -142.89, -156.29, -162.85.

[0369] As shown in Scheme 13, Step 6, to a solution of methyl 2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (110 mg, 0.28 mmol) in DCE (3 mL) was added trimethylstannanol (103 mg, 0.56 mmol). The resulting solution was stirred at 80 °C for 2 h, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give 2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 40, 75 mg, 69% yield) as a white solid: MS (ESI) calculated C 16 H8F5NO4[M-1] - =372.2, actual value 372.2; 1 H-NMR(400 MHz,DMSO-d6)δ 7.15(d,J=2.4 Hz,2H),7.09(d,J=2.4 Hz,2H),4.69(s,2H),4.07(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -143.12, -156.42, -162.72.

[0370] Alkylation of compound 1042 with methyl 2-bromopropanoate followed by separation of the resulting enantiomers by chiral HPLC gave methyl (S)-2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 41): MS(ESI) calculated C 18 H 12 F5NO4[M+1] + =401.0, actual value 402.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.22-7.15 (m, 3H), 5.31-5.23 (m, 1H), 4.83 (s, 1H), 4.68 (d, J = 1.2 Hz, 1H), 3.74 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H);19 F-NMR (377 MHz, methanol-d4) δ -145.36, -158.85, -165.37, and MS (ESI) calculated for (C 18 H 12 F5NO4[M+1] + =401.0, actual value 402.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.24-7.14 (m, 3H), 5.30-5.23 (m, 1H), 4.83 (s, 1H), 4.69 (d, J = 1.2 Hz, 1H), 3.74 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H); 19 F-NMR (377 MHz, methanol-d4) δ -145.37, -158.86, -165.38. Compounds 41 and 42 were each treated with trimethylstannanol in DCE at 80 °C to give (S)-2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 43), respectively: MS (ESI) calculated value C 17 H 10 F5NO4[M-1] - =386.0, actual value 386.1; 1 H-NMR(400 MHz,DMSO-d6)δ 7.14-7.03(m,3H),5.15-5.09(m,1H),4.71-4.60(m,2H),1.36(d,J=7.2 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -143.52, -156.23, -162.57, and (R)-2-(3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 44) ​​was produced as a white solid. MS (ESI) calculated value C 17 H 10 F5NO4[M+1] + =388.1, actual value 388.0; 1H-NMR(400 MHz,DMSO-d6)δ 7.29-7.03(m,3H),5.15-5.11(m,1H),4.70(s,2H),1.42(d,J=7.2 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -143.24, -156.23, -162.67.

[0371] Similar to the procedure shown in Scheme 3, compound 1041 was reacted with ethyl 2-bromo-2,2-difluoroacetate and then cyclized to produce 2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one. Alkylation of this material with methyl 2-bromoacetate produced methyl 2-(2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 29): GCMS calculated C 17 H8F7NO4=423.0, measured value 423.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.68(s,1H),7.62(d,J=8.4 Hz,1H),7.42(d,J=8.4 Hz,1H),4.92(s,2H),3.72(s,3H); 19 F-NMR (400 MHz, DMSO-d6) δ −75.61, −142.53, −155.30, −162.56, which, after treatment with 4 M HCl in dioxane at 100 °C, yielded 2-(2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 30): MS (ESI) calculated C 16 H6F7NO4[M-1] - =408.0, actual value 408.1; 1 H-NMR(400 MHz,DMSO-d6)δ 13.34(br,1H),7.62-7.59(m,2H),7.41-7.39(d,J=8.0 Hz 1H),4.77(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.45, -142.51, -155.43, -162.65.

[0372] Example 12 Preparation of methyl 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 154) and 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 155) [ka] As shown in Scheme 14, 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 was added n-BuLi (2.5 M in hexanes, 39.6 mL, 99.1 mmol) 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 warmed 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 (compound 1043, 9.0 g, 26% yield) as a white solid: GCMS calculated C 13 H5F7O=310.0, actual value 310.0.

[0373] As shown in Scheme 14, Step 2, 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 DCM (20 mL) and concentrated H2SO4 (80 mL) was added KNO3 (2.6 g, 25.8 mmol) portionwise at 0 °C. The resulting solution was stirred under nitrogen 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 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 1044, 5.5 g, 54% yield) as a yellow solid: GCMS (ESI) calculated C 13 H4F7NO3=355.0, actual measured value 355.0.

[0374] As shown in Scheme 14, 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 BBr3 (19.4 g, 77.4 mmol) 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 1045, 4.9 g, crude) as a yellow oil: MS (ESI) calculated C 12 H2F7NO3[M-1] - =339.9, found 339.9. This material was used as is in subsequent reactions.

[0375] As shown in Scheme 14, Step 4, 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 EtOH (30 mL) and HO (30 mL) was added NaSO (12.5 g, 71.8 mmol) in portions at 20° C. The resulting mixture was stirred under nitrogen at 100° 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 30% ethyl acetate in petroleum ether) to give 3-amino-2,2',3',4',5',6,6'-heptafluoro-[1,1'-biphenyl]-4-ol (compound 1046, 3.9 g, 78% yield) as a yellow solid: MS (ESI) calculated C 12 H4F7NO[M+1] + =312.0, actual value 311.9.

[0376] As shown in Scheme 14, 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 at 50° C. for 16 hours under nitrogen, 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 in vacuo, 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 1047, 1.5 g, 17% yield): MS (ESI) calculated C 14 H3BrF9NO[M-1] - =465.9, actual value 465.8.

[0377] As shown in Scheme 14, 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 K2CO3 (591 mg, 4.27 mmol) in portions at 20° C. The resulting mixture was stirred under nitrogen at 50° 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 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 1048, 590 mg, 71% yield) as a yellow solid: MS (ESI) calculated C 14 H2F9NO2[M-1] - =385.9, actual value 385.9; 1 H-NMR(400 MHz,DMSO-d6)δ 12.53(s,1H),7.63(d,J=9.6 Hz,1H); 19 F-NMR (376 MHz, DMSO-d6) δ -76.31, -116.25, -124.01, -139.00, -151.21, -161.25.

[0378] As shown in Scheme 14, Step 7, to a stirred solution of 2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.52 mmol) and methyl 2-bromoacetate (95 mg, 0.62 mmol) in DMF (2 mL) was added KCO (143 mg, 1.03 mmol) at room temperature under a nitrogen atmosphere. 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 preparative HPLC using the following conditions - Column: XBridge Prep Phenyl OBD column, 19 x 250 mm, 5 μm, Gradient: 55% to 75% acetonitrile / 10 mM aqueous NH4HCO3 to give methyl 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 154, 179 mg, 74% yield) as a brown oil: GCMS calculated C 17 H6F9NO4=459.0, measured value 459.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.83(d,J=9.2 Hz,1H),4.88(d,J=5.2 Hz,2H),3.72(s,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -76.32, -112.93, -120.76, -138.80, -150.69, -161.11.

[0379] As shown in Scheme 14, Step 8, to a stirred solution of methyl 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (32 mg, 0.07 mmol) in DCE (1 mL) was added trimethylstannanol (25 mg, 0.14 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C under a nitrogen atmosphere overnight, cooled to room temperature, diluted with water, acidified to pH 4-5 with 2 M HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC using the following conditions—Column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm, Gradient: 54% to 64% B acetonitrile / 0.1% aqueous formic acid—to afford 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 155, 9.2 mg, 31% yield) as a white solid: MS (ESI) calculated C 16 H4F9NO4[M-1] - =444.0, actual value 443.8; 1 H-NMR(400 MHz,DMSO-d6)δ 13.46(s,1H),7.84-7.76(m,1H),4.72(d,J=5.2 Hz,2H); 19 F-NMR (376 MHz, DMSO-d6) δ -76.10, -113.39, -120.19, -138.82, -150.82, -161.17.

[0380] Compound 1048 was alkenylated with propiolic acid methyl ester using PPh3, HOAc in toluene at 110 °C to produce methyl 2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acrylate (compound 178): MS (ESI) calculated C 18 H6F9NO4[M-1] - =458.0, actual value 458.0; 1H-NMR(400 MHz,DMSO-d6)δ 7.89-7.82(m,1H),6.83-6.77(m,1H),6.52(d,J=1.6 Hz,1H),3.79(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -77.37, -112.97, -118.18, -138.91, -150.93, -161.12.

[0381] Hydrogenation of compound 178 using Pd(OH)2 / C as catalyst followed by separation of the resulting enantiomeric mixture by chiral HPLC gave methyl (S)-2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 174): GCMS calculated C 18 H8F9NO4=473.0, measured value 473.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.85(d,J=9.6 Hz,1H),5.39-5.51(m,1H),3.67(s,3H),1.60(d,J=7.2 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.01, -84.05, -112.32, -116.94, -138.74, -150.65, -161.11, and methyl (R)-2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 175) were produced: GCMS calculated C 18 H8F9NO4=473.0, measured value 473.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.86(d,J=9.6 Hz,1H),5.40-5.50(m,1H),3.67(s,3H),1.60(d,J=7.2 Hz,3H); 19F-NMR (377 MHz, DMSO-d6) δ −75.01, −84.05, −112.32, −116.93, −138.74, −150.65, −161.11. Hydrolysis of compounds 174 and 175 with trimethylstannanol in DCE at 80 °C gave (S)-2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 177): MS (ESI) calculated C 17 H6F9NO4[M-1] - =458.0, actual value 458.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.26(b,1H),7.84(d,J=9.2 Hz,1H),5.35-5.48(m,1H),1.58(d,J=7.2 Hz,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -84.14, -112.85, -115.94, -138.71, -150.67, -161.12, and (R)-2-(2,2,5,7-tetrafluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 176) were obtained. MS (ESI) calculated C 17 H6F9NO4[M-1] - =458.0, actual value 458.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.26(s,1H),7.87-7.80(m,1H),5.41-5.31(m,1H),1.61-1.55(m,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -84.14, -112.85, -115.94, -138.71, -150.67, -161.12.

[0382] Example 13 Preparation of methyl 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 160) and 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 161) [ka] As shown in Scheme 15, Step 1, n-BuLi (2.5 M in hexanes) was added dropwise to a stirred solution of 1-bromo-2-chloro-4-methoxybenzene in anhydrous THF at −78°C under a nitrogen atmosphere. After the addition was complete, stirring was continued at −78°C for 15 minutes, and hexafluorobenzene was added dropwise at −78°C. The resulting mixture was heated to room temperature, stirred under nitrogen 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 10% ethyl acetate in petroleum ether) to give 2′-chloro-2,3,4,5,6-pentafluoro-4′-methoxy-1,1′-biphenyl (compound 1049).

[0383] As shown in Scheme 15, Step 2, to a stirred solution of 2'-chloro-2,3,4,5,6-pentafluoro-4'-methoxy-1,1'-biphenyl in DCM (20 mL) and concentrated H2SO4 (80 mL) was added KNO3 portionwise at 0 °C. The resulting solution was stirred under nitrogen 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 chromatography (0% to 25% ethyl acetate in petroleum ether) to give 2'-chloro-2,3,4,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl (compound 1050).

[0384] As shown in Scheme 15, Step 3, BBr3 was added dropwise to a stirred solution of 2'-chloro-2,3,4,5,6-pentafluoro-4'-methoxy-5'-nitro-1,1'-biphenyl in DCM under a nitrogen atmosphere 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-chloro-2',3',4',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol (compound 1051). This material was used directly in the subsequent reaction.

[0385] As shown in Scheme 15, Step 4, Zn dust was added portionwise to a stirred solution of 2-chloro-2',3',4',5',6'-pentafluoro-5-nitro-[1,1'-biphenyl]-4-ol in MeOH / HOAc. The resulting mixture was stirred under nitrogen at 25 °C, 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 5-amino-2-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol (compound 1052).

[0386] As shown in Scheme 15, Step 5, to a stirred solution of 5-amino-2-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-4-ol and TEA in EtOAc was added ethyl 2-bromo-2,2-difluoroacetate in portions at 20 °C. The resulting mixture was stirred at 50 °C for 16 hours under nitrogen, 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 in vacuo, and purified by reverse-phase flash chromatography to give 2-bromo-N-(6-chloro-2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-2,2-difluoroacetamide (Compound 1047).

[0387] As shown in Scheme 15, Step 6, to a stirred solution of 2-bromo-N-(6-chloro-2',3',4',5',6'-pentafluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-2,2-difluoroacetamide in DMF was added KCO portionwise at 20 °C. The resulting mixture was stirred under nitrogen at 50 °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, concentrated under reduced pressure, and purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to give 7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1054).

[0388] As shown in Scheme 14, Step 7, to a stirred solution of 7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.51 mmol) and methyl 2-bromoacetate (95 mg, 0.62 mmol) in DMF (5 mL) was added KCO (143 mg, 1.0 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 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 90% acetonitrile in water) to give methyl 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 160, 38 mg, 16% yield): GCMS calculated C 17 H7ClF7NO4 = 457.0, measured value 457.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.97(s,1H),7.81(s,1H),4.88(s,2H),3.72(s,3H); 19F-NMR (377 MHz, DMSO-d6) δ -75.31, -139.72, -153.03, -162.02.

[0389] As shown in Scheme 14, Step 8, to a stirred solution of methyl 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (50 mg, 0.10 mmol) in DCE (2 mL) at room temperature under a nitrogen atmosphere was added trimethylstannanol (40 mg, 0.21 mmol). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 95% acetonitrile in water) to give 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 161, 21 mg, 43% yield): MS (ESI) calculated C 16 H5ClF7NO4[M-1] - =442.0, actual value 441.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.57(b,1H),7.94(s,1H),7.76(s,1H),4.72(s,2H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.12, -139.78, -153.25, -162.17.

[0390] Alkylation of 7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1054) with methyl 2-bromopropanoate followed by separation of the resulting enantiomeric mixture by chiral HPLC gave methyl (S)-2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 170): GCMS calculated C 18 H9ClF7NO4 = 471.0, measured value 471.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.97(s,1H),7.82(s,1H),5.35-5.54(m,1H),3.67(s,3H),1.55(d,J=6.8 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.67, -139.73, -153.01, -162.08, and methyl (R)-2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 171) were produced: GCMS calculated C 18 H9ClF7NO4 = 471.0, measured value 471.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.98(s,1H),7.82(s,1H),5.34-5.52(m,1H),3.67(s,3H),1.55(d,J=6.8 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ −75.67, −139.73, −153.01, −162.07. Compounds 170 and 171 were each hydrolyzed with trimethylstannanol in DCE at 80 °C to give (S)-2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 172): MS (ESI) calculated C 17 H7ClF7NO4[M-1] - =456.0, actual value 455.9; 1H-NMR(400 MHz,DMSO-d6)δ 13.22(s,1H),7.96(s,1H),7.81(s,1H),5.36-5.26(m,1H),1.54(d,J=6.8 Hz,3H); 19 F-NMR (376 MHz, DMSO-d) δ -77.12, -139.78, -153.10, -162.17, and (R)-2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 173) were produced: MS (ESI) calculated C 17 H7ClF7NO4[M-1] - =456.0, actual value 455.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.26(b,1H),7.96(s,1H),7.81(s,1H),5.32-5.50(m,1H),1.54(d,J=6.8 Hz,3H); 19 F-NMR (376 MHz, DMSO-d6) δ -73.90, -77.66, -139.78, -153.10, -162.17.

[0391] Example 14 Preparation of methyl 2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (Compound 160) and 2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (Compound 161) [ka] As shown in Scheme 16, Step 1, n-BuLi (2.5 M in hexanes) was added dropwise to a stirred solution of 1-bromo-4-methoxy-2-methylbenzene in anhydrous THF at −78°C under a nitrogen atmosphere. After the addition was complete, stirring was continued at −78°C for 15 minutes, and hexafluorobenzene was added dropwise at −78°C. The resulting mixture was heated to room temperature, stirred under nitrogen 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 10% ethyl acetate in petroleum ether) to give 2,3,4,5,6-pentafluoro-4'-methoxy-2'-methyl-1,1'-biphenyl (compound 1055).

[0392] As shown in Scheme 16, Step 2, to a stirred solution of 2,3,4,5,6-pentafluoro-4'-methoxy-2'-methyl-1,1'-biphenyl in DCM (20 mL) and concentrated H2SO4 (80 mL) was added KNO3 portionwise at 0 °C. The resulting solution was stirred under nitrogen 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 chromatography (0% to 25% ethyl acetate in petroleum ether) to give 2,3,4,5,6-pentafluoro-4'-methoxy-2'-methyl-5'-nitro-1,1'-biphenyl (compound 1056).

[0393] As shown in Scheme 16, Step 3, BBr3 was added dropwise to a stirred solution of 2,3,4,5,6-pentafluoro-4'-methoxy-2'-methyl-5'-nitro-1,1'-biphenyl in DCM (70 mL) under a nitrogen atmosphere 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',3',4',5',6'-pentafluoro-2-methyl-5-nitro-[1,1'-biphenyl]-4-ol (compound 1057). This material was used directly in the subsequent reaction.

[0394] As shown in Scheme 16, Step 4, to a stirred solution of 2',3',4',5',6'-pentafluoro-2-methyl-5-nitro-[1,1'-biphenyl]-4-ol in EtOH and HO was added NaSO portionwise at 20 °C. The resulting mixture was stirred under nitrogen at 100 °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 30% ethyl acetate in petroleum ether) to give 5-amino-2',3',4',5',6'-pentafluoro-2-methyl-[1,1'-biphenyl]-4-ol (compound 1058).

[0395] As shown in Scheme 16, Step 5, to a stirred solution of 5-amino-2',3',4',5',6'-pentafluoro-2-methyl-[1,1'-biphenyl]-4-ol and TEA in EtOAc was added ethyl 2-bromo-2,2-difluoroacetate in portions at 20 °C. The resulting mixture was stirred at 50 °C for 16 hours under nitrogen, 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 in vacuo, and purified by reverse-phase flash chromatography to give 2-bromo-2,2-difluoro-N-(2',3',4',5',6'-pentafluoro-4-hydroxy-6-methyl-[1,1'-biphenyl]-3-yl)acetamide (Compound 1059).

[0396] As shown in Scheme 16, Step 6, to a stirred solution of 2-bromo-2,2-difluoro-N-(2',3',4',5',6'-pentafluoro-4-hydroxy-6-methyl-[1,1'-biphenyl]-3-yl)acetamide) in DMF was added KCO portionwise at 20 °C. The resulting mixture was stirred under nitrogen at 50 °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, concentrated under reduced pressure, and purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to give 2,2-difluoro-7-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 1060).

[0397] As shown in Scheme 16, Step 7, to a stirred solution of 2,2-difluoro-7-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.24 mmol) and methyl 2-bromoacetate (50 mg, 0.32 mmol) in DMF (2.5 mL) was added KCO (57 mg, 0.41 mmol) at room temperature under a nitrogen atmosphere. 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 78% acetonitrile / water) to give methyl 2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (compound 179, 38 mg, 30% yield): GCMS calculated C 18 H 10 F7NO4=437.0, measured value 437.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.52(d,J=4.8 Hz,2H),4.86(s,2H),3.70(s,3H),2.16(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.60, -140.51, -155.08, -162.39.

[0398] As shown in Scheme 16, Step 8, to a stirred solution of methyl 2-(7-chloro-2,2-difluoro-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate (100 mg, 0.22 mmol) in DCE (3 mL) at room temperature under a nitrogen atmosphere was added trimethyltin chloride (91 mg, 0.48 mmol). The resulting mixture was stirred at 65 °C under a nitrogen atmosphere for 5 h, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 53% acetonitrile / water) to give 2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetic acid (compound 180, 52 mg, 52% yield): MS (ESI) calculated C 17 H8F7NO4[M-1] - =422.0, actual value 421.9; 1 H-NMR(400 MHz,DMSO-d6)δ 13.36(s,1H),7.49(d,J=2.7 Hz,2H),4.74(s,2H),2.16(s,3H); 19 F-NMR (377 MHz, DMSO-d6) δ -75.44, -140.54, -155.25, -162.50.

[0399] Alkylation of 2,2-difluoro-7-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 1060) with methyl 2-bromopropanoate, followed by separation of the resulting enantiomeric mixture by chiral HPLC, gave methyl (S)-2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 181): MS(ESI) calculated C 19 H 12 F7NO4[M+1]+ =452.1, actual value 452.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.54(d,J=8.0 Hz,2H),5.41(d,J=7.2 Hz,1H),3.66(s,3H),2.17(s,3H),1.54(d,J=6.8 Hz,3H); 19 F-NMR (377 MHz, DMSO-d) δ -76.52, -140.40, -155.04, -162.44, and MS (ESI) calculated C for methyl (R)-2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoate (compound 182). 19 H 12 F7NO4[M+1] + =452.1, actual value 452.0; 1 H-NMR(400 MHz,DMSO-d6)δ 7.54(d,J=8.0 Hz,2H),5.46-5.38(m,1H),3.66(d,J=2.4 Hz,3H),2.17(s,3H),1.59-1.49(m,3H); 19 F-NMR (377 MHz, DMSO-d6) δ −76.33, −140.52, −154.99, −162.38. Compounds 181 and 182 were each hydrolyzed with trimethylstannanol in DCE at 80 °C to give (S)-2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 183): MS (ESI) calculated C 18 H 10 F7NO4[M-1] - =436.0, actual value 436.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.21(b,1H),7.58-7.40(m,2H),5.32-5.50(m,1H),2.16(s,3H),1.51(d,J=6.8 Hz,3H); 19F-NMR (377 MHz, DMSO-d) δ -75.62, -77.45, -140.51, -155.05, -162.41, and (R)-2-(2,2-difluoro-7-methyl-3-oxo-6-(perfluorophenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propanoic acid (compound 184) were produced: MS (ESI) calculated value C 18 H 10 F7NO4[M-1] - =436.0, actual value 436.0; 1 H-NMR(400 MHz,DMSO-d6)δ 13.22(s,1H),7.52(d,J=...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a salt thereof, wherein R １ But, C １～６ Alkyl, C ３～４ Alkenyl, C ３～４ Alkynyl, cyclopropyl, CH ２ C ３～６ Cycloalkyl, phenyl or C １～２ alkyl-phenyl, each of which is C(O)R １ａ or CH ２ C(O)R １ａ each optionally substituted with up to three F or Cl atoms; １～６ Alkyl may also be optionally represented by -OR １ｂ is replaced by R １ａ But, OR １ｂ , C.H. ２ O.C.(O)C １～４ Alkyl, C(O)OR １ｂ , N(R １ｂ ) (R １ｃ ), ON(R １ｂ ) (R １ｃ ), N.H.N. １ｂ ) (R １ｃ ), NHS (O) ２ N (R １ｂ ) ２ , N.H.S. (O) ２ C １～４ Alkyl, or NHOR １ｂ and Each R １ｂ However, independently, H, C ３～６ Cycloalkyl, CH ２ Phenyl, or C １～４ alkyl, optionally substituted with up to three F or Cl atoms; R １ｃ is H or optionally C(O)OR １ｂ C substituted with １～４ alkyl or R １ｂ and R １ｃ together with the intervening nitrogen atom form a 4-6 membered heterocycle, optionally including N, O, S, S(O) ２ and optionally containing an additional atom or group selected from -C(O)OR １ｂ and -C(O)R １ｂ and is substituted with one or more groups selected from R ２ and R ３ Each of is H, F, or R ２ and R ３ together with the intervening carbon is cyclopropyl; R ４ But H, F, CH ３ or Cl, R ５ is H or F, R ６ and R ７ each independently represents F, H, CH ３ , C.F. ３ , or OCH ３ and R ８ is H or F, The compound or a salt thereof, wherein Ring A contains at least four F atom substituents.

2. R ２ , R ３ , and R ４ Each of the following is F, or a salt thereof:

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

4. R １ But -C(O)R １ａ C substituted with １～６ alkyl, R １ａ But, -OR １ｂ Or -N(R １ｂ ) (R １ｃ 2. The compound of claim 1, or a salt thereof.

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

6. R ２ , R ３ , and R ４ Each of the following is F, or a salt thereof:

7. R １ But -C(O)R １ａ C substituted with １～６ alkyl, R １ａ But, -OR １ｂ Or -N(R １ｂ ) (R １ｃ 6. The compound according to claim 5, or a salt thereof,

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

9. R ２ , R ３ , and R ４ Each of the following is F, or a salt thereof:

10. R １ But -C(O)R １ａ C substituted with １～６ alkyl, R １ａ But, -OR １ｂ Or -N(R １ｂ ) (R １ｃ 9. The compound according to claim 8, or a salt thereof.

11. The compound of claim 1 having the formula (IV): 【Chemistry 4】 Or its salt.

12. R ２ , R ３ , and R ４ Each of the following is F, or a salt thereof:

13. R １ But -C(O)R １ａ C substituted with １～６ alkyl, R １ａ But, -OR １ｂ Or -N(R １ｂ ) (R １ｃ 12. The compound of claim 11, or a salt thereof.

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

15. R ２ , R ３ , and R ４ Each of the following is F, or a salt thereof:

16. R １ But -C(O)R １ａ C substituted with １～６ alkyl, R １ａ But, -OR １ｂ Or -N(R １ｂ ) (R １ｃ 15. The compound of claim 14, or a salt thereof.

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

18. 18. An agricultural composition comprising a compound according to any one of claims 1 to 17, or a salt thereof, and at least one additional ingredient which acts as a carrier.

19. 20. The composition of claim 18, wherein the at least one additional component is a surfactant or a diluent.

20. 20. The composition of claim 18 or 19, wherein the composition is a herbicide composition.

21. 21. A method for controlling undesirable vegetation, comprising contacting said vegetation or its environment with a herbicidally effective amount of a compound according to any one of claims 1 to 17, a salt thereof, or a composition according to any one of claims 18 to 20.

22. 22. The method of claim 21, wherein the undesirable vegetation comprises weeds.

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

24. The method of claim 23, wherein the PPO inhibitor-resistant weed has a dG210 mutation.

25. The compound or composition is 10,000 m ２ 25. The method according to any one of claims 21 to 24, applied at a rate of 1 to 100 g per unit area.

26. A method according to any one of claims 21 to 25, which results in a post-emergence control of said undesirable vegetation by contacting said undesirable vegetation or its environment with said compound or said composition.

27. A method according to any one of claims 21 to 26, which results in a pre-emergence control of said undesirable vegetation by contacting said undesirable vegetation or its environment with said compound or said composition.

28. The method of any one of claims 21 to 27, wherein the undesirable vegetation is controlled by at least 60%.

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