Title of Invention

METHOD FOR CONTROLLING PARTICULAR INSECT PESTS BY APPLYING ANTHRANILAMIDE COMPOUNDS

Abstract

This invention pertains to a method for controlling lepidoptern , homopteran, hemipteran, thysanopteran and coleopteran insect pests comprising contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, its N-oxide or an agriculturally suitable salt thereof wherein A and B and R1 through R8 are as defined in the disclosure. This invention further relates to a bezoxazinone compound of Formula (10), wherein R4, through R8 are as defined in the disc losure, useful for preparation of a compound of Formula I.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] "METHOD FOR CONTROLLING PARTICULAR INSECT PESTS BY APPLYING ANTHRANILAMIDE COMPOUNDS" E.I. DU PONT DE NEMOURS AND COMPANY, a Corporation organized and existing under the laws of the State of Delaware, U.S.A., of 1007 Market Street, Wilmington, Delaware 19898, United States of America The following specification particularly describes and ascertain the nature of the invention and the manner in which it is to be performed :- WO 03/015518 PCT/US02/25613 TITLE METHOD FOR CONTROLLING PARTICULAR INSECT PESTS BY APPLYING ANTHRANTLAMLDE COMPOUNDS BACKGROUND OF THE INVENTION This invention relates to a method of use for controlling invertebrate pests in both agronomic and nonagronornic environments of certain anthranilamides, their TV-oxides, agriculturally suitable salts and compositions. The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different modes of action. NL 920207S discloses JV-acyl anthranilic acid derivatives of Formula i as insecticides wherein, niter alia, X is a direct bond; Y is H or C1-C6 alkyl; Z is NH2, NH(C1-C3 alkyl) or N(CrC3 alkyl)2: and R1 through R9 are independently H, halogen, C1-C6 alkyl, phenyl, hydroxy, C1-C6 alkoxy or C1-C7 acyloxy. SUMMARY OF THE INVENTION This invention pertains to a method for controlling lepidopteran, homopteran, hemipteran, thysanopteran and coleopteran insect pests comprising contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, its TV-oxide or an agriculturally suitable salt thereof 10 15 20 25 wherein ■ A and B are independently 0 or S; R1 is H, C1-C6 alkyl, C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl; R2isHorC1-C6 alkyl; R3 is H; C1-C6 alkyl, C2-C6 alkenyi, C2-C6 alkynyl, or C3-C6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, N02, hydroxy, C1-C4 alkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C2-C6 alkoxycarbonyl, C2-Cg alkylcarbonyl, C3-C6 trialkylsilyl, phenyl, phenoxy, 5-membered heteroaromatic rings, and 6-memberedheteroaromatic rings; each phenyl, phenoxy, 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring optionally substituted with one to three substituents independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyi," C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4haloalkyl, C2-C4 haloalkenyl, C9-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, N02, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 aikylamino, C2-C8 cHaJkylamino, C3-C5 cycloalkylarnino, C4-C8 (alkyl)(cycloalkyl)amino, C2-C4 alkylcarbonyl, C2-C6alkoxycarbonyl, C2-C6 alkylamin0carbonyl, C3-C8 dialkylaminocarbonyl and C3-C5 trialkylsilyl- C1-C4 alkoxy; C4-C4 aikylamino; C2-C8 dialkylamino; C3-C5 cycloalkylamino; C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl; R4 is H, C1-C6 alkyl, C1-C6 alkenyi, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, CN, halogen, C1-C4 alkoxy, C1-C4 haloalkoxy orN02; WO 03/015518 PCT/US02/25613 R5 is H, CrC6 alkyl, CrC6 haloalkyl, C1-C4 alkoxyalkyl, C1-C4 hydroxy alkyl C(O)Rl0, C02R10, C(O)NRl0R11, halogen, C1-C4 alkoxy, C1-C4 haloalkoxy, NR10R11, N(Rn)C(0)R10, N(Rn)C02R10 or S(0)nRl2; R6 is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, C1-C4 alkoxy or C1-C4 5 haloalkoxy; R7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenid, C2-Cg haloalkyn3"l or C3-C6 halocycloalkyl; or R7 is a phenyl ring, a benzyl ring, a 5- or 6-memberedheteroaromatic ring, a naphthyl ring system or an aromatic S-, 9- or 10-membered fused heterobicyclic 10 ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R9; R8 is H, C1-C6alkyl, C1-C6 haloalkyl, halogen, C1-C4alkoxy or C1-C4 haloalkoxy; each R9 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C.6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-€4 haloalkynyl, C3-C5 15 halocyclbalkyl, halogen, CN, N02, Cr-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C]-C4 alkylamino, C2-Cg dialkylamino, C3-C6 cydoalkylamino, C4-Cg (alkyl)(cycloalkyl)amino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl C2-C6 alkylarninocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsiryi; 20 Rl10 is H, C1-C4 alkyl or C1-C4 haloalkyl; 10 Rn.isH or C1-C4 alkyl; R12 is C1-Q 4 allcyl or C1-C4. haloalkyl; and n is 0,1 or 2. This invention also relates to such a method wherein an invertebrate pest or its 25 environment is contacted with a composition comprising a biologically effective amount of a compound of Formula I or a composition comprising a compound of Formula I and a biologically effective amount of at least one additional biologically active compound. This invention further relates to abenzoxazinone compound of Formula 10 30 wherein WO 03/015518 PCT/US02/25613 4 are defined as aboved in Formula I. The compound of Formula 10 is useful as a synthetic intermediate for preparing a compound of Formula I. DETAILS OF THE INVENTION 5 In the above recitations, the term "alkyl", used either alone or in compound words such as "alkyltliio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, penryl or hexyl isomers. " Alkenyl" includes straight-chain or branched alkenes such as 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl 10 and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as 1-propynyl, 2-propynyl and. the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-h.exadiynyl. "Alkoxy" includes, for example, methoxy, ethox3", 77-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution 15 on alkyl. Examples of "alkoxyalkyl" include CH3 OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and. cyclohexyl. 20 The term "heterocyclic ring" or heterocyclic ring system" denotes rings or ring systems in which at least one ring atom is not carbon and. comprises 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. The heterocyclic ring can be attached through any available carbon 25 or nitrogen by replacement of hydrogen on said carbon or nitrogen. The term "aromatic ring system" denotes fully unsaturated carbocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic (where aromatic indicates that the Hiickel rule is satisfied for the ring system). The term "heteroaromatic ring" denotes fully aromatic rings in which at least one"ring atom is not carbon and comprises 1 to 4 heteroatoms independently 30 selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs (where aromatic indicates that the Hiickel rule is satisfied). The heterocyclic ring can be attached through any available carbon or nitrogen by replacement of hydrogen on said carbon or nitrogen. The term "aromatic heterocyclic ring system" includes fully 35 aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Hiickel rule is satisfied). The term "fused heterobicyclic ring system" includes a ring system comprised of two fused rings in which at least one ring atom is not carbon and can be aromatic or non aromatic, as defined above. WO 03/015518 PCT/US02/25613 5 The term, "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound, words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyT include F3C, C1CH2, CF3CH9 and 5 CF3CCI2. The terras "haloalkenyl", "haloalkynjT", "haloalkoxy", and the like, are defined analogously to the terra "haloalkyl". Examples of "haloalkenyl" include (Cl)2OCHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HOCCHCL CF3C=C, CCI3 C^C and FCH2OCCH2. Examples of "haloalkoxy" include CF3 O, CC13 CH20, HCF2CH2CH20 and CF3CH20. 10 The total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from 1 to 8. For example, C1-04 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH30CH2; C3 alkoxyalkyl designates, for example, CH3CH(OCH3), CH3OCH2CH2 or CH3CH2OCH2; and C4 alkox3^alkyl designates the various isomers of an alkyl group substituted with an alkoxy 15 group containing a total of four carbon atoms, examples including CHL3CH2CH2OCH2 and CH3CH2OCH2CH2. In the above recitations, when a compound of Formula I comprises a heterocyclic ring, all substituents are attached to this ring through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. The term "optionally substituted with one to three substituents" indicates that one to 20 three of the available positions on the group may be substituted. When a group contains a substituent which can be hydrogen, for example R6, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. Compounds of Formula I can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One 25 skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the compounds of Formula I may be present as a mixture of stereoisomers, individual 30 stereoisomers, or as an optically active form. Similarly, compounds of Formula 10 can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the ait will appreciate that one stereoisomer of a compound of Formula 10 may be more useful in preparing a specific stereoisomer of Formula I. Additionally, the skilled artisan knows how to separate, 35 enrich, and/or to selectively prepare said stereoisomers. Accordingly, the compounds of Formula 10 may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. WO 03/015518 PCT/US02/25613 The salts of the compounds of Formula I include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. 5 As noted above, R7 is (among others) a phenyl, a benzyl, a 5- or 6-membered heteroaromatic ring, a naphthyl ring system or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R9. The term "optionally substituted" in connection with these R7 groups refers to groups which are unsubstituted or have at least one 10 non-hydrogen substituent that does not extinguish the invertebrate pest control activity possessed by the unsubstituted analog. Note also that J-l through J-4 below denote 5- or 6-membered heteroaromatic rings. An example of a phenyl ring optionally substituted with 1 to 3 R9 is the ring illustrated as J-5 in Exhibit 1, wherein r is an integer from 0 to 3. An example of a benzyl ring optionally substituted with 1 to 3 R9 is the ring illustrated as J-6 in 15 Exhibit 1, wherein r is an integer from 0 to 3. An example of a naphthyl ring system optionally substituted with 1 to 3 R9 is illustrated as J-59 in Exhibit 1, wherein r is an integer from 0 to 3. Examples of a 5- or 6-membered heteroaromatic ring optionally substituted with 1 to 3 R9 include the rings J-7 through J-58 illustrated in Exhibit 1 wherein r is an integer from 0 to 3. Note that J-7 through J-26 are examples of J-l, J-27 through J-41 are 20 examples of J-2, and J-46 through J-58 are examples of J-3 and J-4. The nitrogen atoms that require substitution to fill then valence are substituted with H or R9. Note that some J groups -can only be substituted with less than 3 R9 groups (e.g. J-19, J-20, J-23 through J-26 and J-37 through J-40 can only be substituted with one R9). Examples of aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems optionally substituted with 1 to 3 R9 include 25 J-60 through J-90 illustrated in Exhibit 1 wherein r is an integer from 0 to 3. Although R9 groups are shown in the structures J-5 through J-907 it is noted that they do not need to be present since they are optional substituents. Note that when the attachment point between (R9)r and the J group is illustrated as floating, (R9)r can be attached to any available carbon atom of the J group. Note that when the attachment point on the J group is illustrated as 30 floating, the J group can be attached to the remainder of Formula I through any available carbon of the J group by replacement of a hydrogen atom. 10 WO 03/015518 PCTAJS02/25613 ( 11 W, X, Y and Z are independently N, CH or CR9, provided that in J-3 and J-4 at least one of W, X, Y or Z is N. Preferred 2. Methods of Preferred 1 wherein R1andR2areallH; 5 R3 is C1-C4 alkyl optionally substituted with halogen, CN, OCH3 or S(0)pCH3; . R4 group is attached at position 2; R4 is C% CF3, OCF3, OCHF2, CN or halogen; R5 is H, CH3 or halogen,- 10 R6 is C% CF3 or halogen; R7 is phenyl or 2-pyridinyl, each optionally substituted; and p is 0, 1 or 2. Preferred 3. Methods of Preferred 2 wherein R3 is C1-C4 alkyl and R6 is CF3. Preferred 4. A compound of Preferred 2 wherein R3 is C1-C4 alkyl and R6 is CI or Br. 15 Preferred compounds of Formula 10 are: Preferred A. Compounds of Formula 10 wherein R7 is a phenyl ring or a 5- or 6-membered heteroaromatic ring selected from the group consisting of independently s elected from R9 QisO,S,NHorNR9;and W, X, Y and Z are independently N, CH or CR9, provided that in J-3 and J-4 at least one of W, X, Y or Z is N. Preferred B. Compounds of Preferred A wherein Rs is H; R4 group is attached at position 2; R.4.JS CH3, CF3) OCF3, OCF£F2, CN or halogen; R5 is H, CH3 or halogen; R6 is CH3, CF3 or halogen; and R7 is phenyl or 2-pyridinyl, each optionally substituted. Preferred C. Compounds of Preferred B wherein R6 is CF3. Prefen-ed D. Compounds of Preferred B wherein Rg is CI or Br. WO 03/015518 PCT/US02/25613 Of note are compounds of Formula 10 wherein R4 is at the 2 position and is CH3, CI or Br: R5 is at the 4 position and is F, CI, Br, I or CF3: R6 is CF3, CI or Br; R7 is 3-C1-2-pyridinyl or 3-Br-2-pyridhryl; andR8 is H. One or more of the following methods and variations as described in Schemes 1-22 can be used to prepare the compounds of Formula I. The definitions of A, B and R1 through R9 in the compounds of Formulae 2-40 below are as defined above in the Summaiy of the Invention unless indicated otherwise. Compounds of Formulae Ia-d, 2a-d, 3a, 4a-d, 5a-b, 17a-c, 18a and 32a-b are various subsets of the compounds of Formula I, 2, 3, 4, 5, 17, 18 and 32. In the schemes, Het is the moiety shown below: 10 A typical method for preparation of a compound of Formula la is described in Scheme 1. Scheme 1 la (A is O) Ib(AisS) 15 The method of Scheme 1 involves coupling of an amine of Formula 2 with an acid chloride of Formula 3 in the presence of an acid scavenger to provide the compound of Formula la. Typical acid scavengers include amine bases such as triethylamitie, Ar,iV"-diisopropylethylairiine and pyridine; other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium 20 carbonate. In certain instances it is useful to use polymer-supported acid scavengers such as polymer-bound i^A^diisopropylemylamine and polymer-bound 4-(dimemylamino)pyridine. The coupling can be run in a suitable inert solvent such as tetxahydrofuran, dioxane, dietbylether or dichloromethane to afford the anilide of Formula la. WO 03/1115518 PCT/US02/25613 13 A ibioamide of Formula lb can be obtained in a subsequent step from the corresponding amide of Formula la by treatment with one of a variety of standard thio transfer reagents including phosphorus pentasulfide and Lawesson"s reagent (2,4-bis(4-methoxyphenyl)-l,3-dithia-234-diphosphetane-234-disulfide). As shown in Scheme 2, an alternate procedure for the preparation of compounds of Formula la involves coupling of an amine of Formula 2 with an acid of Formula 4 in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC), l,l"-carbonyl-diimidazole, bis(2-oxo-3-oxazohdmyl)phosphinic chloride or benzotriazoH-yloxy-tris-(dimemylarnmo)phosphoniumhexafluorophosphate. Scheme 2 10 Polymer-supported reagents are again useful here, such as polymer-bound cyclohexylcarbodiimide. The coupling can be run in a suitable inert solvent such as dichloromethane or N, Af-dimemylformamide. The synthetic methods of Schemes 1 and 2 are 15 just representative examples of a wide vaiiety of coupling methods useful for the preparation of Formula I compounds; the synthetic Eterature is extensive for this type of coupling reaction. One skilled in the art will also realize that acid chlorides of Formula 3 may be prepared from acids of Formula 4 by numerous well-known methods. For example, acid chlorides of 20 Formula 3 are readily made from carboxylic acids of Formula 4 by reacting the carboxylic acid 4 with thionyl chloride or oxalyl chloride in an inert solvent such as toluene or dichloromethane in the presence of a catalytic amount of iN,N"-dimethylformamide. As shown in Scheme 3, amines of Formula 2a are typically available from the corresponding 2-nitrobenzamides of Fonnula 5 via catalytic hydrogenarion of the nitro 25 group. Scheme 3 WO 03/015518 PCT/US02/25613 10 14 Typical procedures involve reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum oxide and in hydroxylic solvents such as ethanol and isopropanol. Amines of Formula 2a can also be prepared by reduction with zinc in acetic acid These procedures are well documented in the chemical literature. R1 substituents such as C1-C6alkyl can be introduced at this stage through well known methodologies including either direct alkylation or through the generally preferred method of reductive alkylation of the amine. As is further shown in Scheme 3, a commonly employed procedure is to combine the amine 2a with an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride to produce the Formula 2b compounds where R1 isC1-C6 alkyl. Scheme 4 shows that compounds of Formula Ic can be alkylated or acylated with a suitable alkylating or acylating agent such as an alkyl halide, alkyl chloroformate or acyl chloride in the presence of a base such as sodium hydride or n-buryllithium in an inert solvent such as tetrahydrofuran or N,Ndimethylformamide to afford anilides of Formula Id wherein R1 is other than hydrogen. 15 20 The intermediate amides of Formula 5a are readily prepared from commercially available 2-nitrobenzoic acids. Typical methods for amide formation can be used. As shdwn in Scheme 5, these methods include direct dehydrative coupling of acids of Formula 6 with amines of Formula 7 using for example DCC, and conversion of the acids to activated forms such as the acid chlorides or anhydrides and subsequent coupling with amines to form amides of Formula 5a. WO 03/015518 PCT/US02/25613 15 Alkyl chloroformates, such as ethyl chloroformate or zsopropyl chloroformate, are especially useful reagents for this type of reaction involving activation of the acid. The chemical literature is extensive regarding methods for amide formation. Amides of Formula 5a are readily converted to thioamides of Formula 5b by using commercially available thio transfer reagents such as phosphorus pentasulfide and Lawesson"s reagent. Intermediate anthranilic amides of Formula 2c or 2d may also be prepared from isatoic anhydrides of Formula 8 or 9, respectively, as shown in Scheme 6. Scheme 6 2d (R1 is other than H) 10 Typical procedures involve combination of equimolar amounts of the amine 7 with the isatoic anhydride in polar aprotic solvents such as pyridine and N,N-dimethylformamide at temperatures ranging from room temperature to 100 °C. R1 substituents such as alkyl and substituted alkyl may be introduced by the base-catalyzed alkylation of isatoic anhydride 8 with known alkylating reagents R1-Lg (wherein Lg is a nucleophilic displaceable leaving 15 group such as halide, alkyl or aryl sulfonates or alkyl sulfates) to provide the alkyl substituted intermediate 9. Isatoic anhydrides of Formula 8 may be made by methods described in Coppola, Synthesis 1980,505-36. . As shown in Scheme 7, an alternate procedure for the preparation of specific compounds of Formulaic involves reaction of an amine 7 with a benzoxazinone of 20 Formula 10." 16 10 The reaction of Scheme 7 can be run neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, pyridine, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. The general reaction of benzoxazrnones with amines to produce anthranilamides is well documented in the chemical literature. For a review of benzoxazinone chemistry see Jakobsen et al., Biorganic and Medicinal Chemistiy 2000,8, 2095-2103 and references cited therein. See also Coppola, 1 Heterocyclic Chemistiy 1999, 36, 563-588. Benzoxazinones of Formula 10 can be prepared by a variety of procedures. Two procedures that are especially useful are detailed in Schemes 8-9. In Scheme 8, a benzoxazinone of Formula 10 is prepared directly via coupling of a pyrazolecarboxylic acid of Formula 4a with an anthranilic acid of Formula 11. Scheme 8 15 20 This involves sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 4a, followed by the addition of an anthranilic acid of Formula 11, followed by a second addition of tertiary amine and methanesulfonyl chloride. This procedure generally affords good yields of the benzoxazinone and is illustrated with greater detail in Examples 6 and 8. Scheme 9 depicts an alternate preparation for benzoxazinones of Formula 10 involving coupling of a pyrazole acid chloride of Formula 3a with an isatoic anhydride of Formula 8 to provide the Formula 10 benzoxazinone directly. 10 3a Solvents such as pyridine or pyiidine/acetonitrile are suitable for this reaction. The acid chlorides of Formula 3a are available from the corresponding acids of Formula 4a by a variety of synthetic methods such as chlorination withthionyl chloride or oxalyl chloride. Isatoic anhydrides of Formula 8 can be prepared from isatins of Formula 13 as outlined in Scheme 10. Scheme 10 15 Isatins of Formula 13 are obtained from aniline derivatives of Formula 12 using methods known in the literature. Oxidation of isatin 13 with hydrogen peroxide generally affords good yields of the corresponding isatoic anhydride 8 (Angew. Chem. Int. Ed. Engl. 1980,19, 222-223). Isatoic anhydrides are also available from the anthranilic acids 11 via many known procedures involving reaction of 11 with phosgene or a phosgene equivalent. The syntheses of representative acids of Formula 4 are depicted in Schemes 11-16. Syntheses of pyrazoles of Formula 4a are shown in Scheme 11. 20 WO 03/015518 PCT/US02/25613 18 The synthesis of compounds of Formula 4a in Scheme 11 involves as the key step introduction of the R7 substituent via alkylation or arylation of the pyrazole of Formula 14 with compounds of Formula 15 (wherein Lg is a leaving group as defined above). Oxidation of the methyl group affords the pyrazole carboxylic acid. Some of the more preferred R6 groups include haloalkyl. Synthesis of pyrazoles of Formula 4a is also shown in Scheme 12. 10 15 These acids may be prepared via metallation and carboxylation of compounds of Formula 18 as the key step. The R7 group is introduced in a manner similar to that of Scheme 11, i.e. via alkylation or arylation with a compound of Formula 15. Representative R6 groups include e.g. cyano, haloalkyl and halogen. This procedure is particularly useful for preparing l-(2-pyridinyl)pyrazolecarboxylic acids of Formula 4b as shown in Scheme 13. Scheme 13 R.6 R8 20 Reaction of a pyrazole of Formula 17 with a 2,3-dih.alopyridine of Formula 15a affords good yields of the 1-pyridylpyrazole of Formula 18a with good..specificity for the desired regiochemistry. Metallation of 18a with lithium diisopropyiamide (LDA) followed by quenching of the lithium salt with carbon dioxide affords the l-(2-pyridinyl)pyrazole-carboxylic acid of Formula 4b. Additional details for these procedures are provided in Examples 1, 3, 6, 8 and 10. The synthesis of pyrazoles of Formula 4c is described in Scheme 14. Scheme 14 involves reaction of an optionally substituted phenyl hydrazine of Formula 19 with a ketopyruvate of Formula 20 to yield pyrazole esters of Formula 21. Hydrolysis of the esters affords the pyrazole acids of Formula 4c. This procedure is particularly useful for the preparation of compounds in which R7 is optionally substituted phenyl and R6 is haloalkyl. An alternate synthesis of pyrazole acids of Formula 4c is described in Scheme 15. 10 The method of Scheme 15 involves 3+2 cycloaddition of an appropriately substituted irninohalide 22 with either substituted propiolates of Formula 23 or acrylates of Formula 25. Cycloaddition with an acrylate requires additional oxidation of the intermediate pyrazoline to the pyrazole. Hydrolysis of the esters affords the pyrazole acids of Formula 4c. Preferred imrnohalides for this reaction include the hifiuorornethyl iminochloride of Formula 26 and 15 the iminodibromide of Formula 27. Compounds such as 26 are known (J. Heterocycl Chem. 1985, 22(Z). 565-8). Compounds such as 27 are available by known methods {Tetrahedron Letters 1999, 40, 2605). These"procedures are particularly useful for the preparation of compounds where R7 is optionally substituted phenyl andR6 is haloalkyl or bromo. The starting p3Tazoles of Formula 17 are known compounds or can be prepared 5 according to known methods. The pyrazole of Formula 17a (the compound of Formula 17 wherein R6 is CF3 and R8 is H) can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). The pyrazoles of Formula 17c (compounds of Formula 17 wherein R6 is CI or Br and R8 is H) can also be prepared by literature procedures (Chem. Ber. 1966, 99(10), 3350-7). A useful alternative method for the preparation of compound 17c is 10 depicted in Scheme 16. fn the method of Scheme 16, metallation of the sulfamoyl pyrazole of Formula 28 with 77-butyllithium followed by direct halogenation of the anion with either hexachloroethane 15 (for R6 being C1) or 1,2-dibromotetrachloro ethane (for R6 being Br) affords the haiogenated derivatives of Formula 29. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature proceeds cleanly and in good yield to afford the pyrazoles of Formula 17c. One skilled in the art will recognize that Formula 17c is a tautomer of Formula 17b. Further experimental details for these procedures are described in Examples 8 and 10. Pyrazolecarboxylic acids of Formula 4d wherein R6 is H, Cj-Cg alkyl or CrC6 haloalkyl can be prepared by the method outlined in Scheme 17. 4d Reaction of a compound of Formula 30 wherein R13 is C1-C4 alkyl with a suitable base in a suitable organic solvent affords the cyclized product of Formula 31 after neutralization with ■ an acid such as acetic acid. The suitable base can be, for example but not limitation, sodium hydride, potassium r-butoxide, dirnsyl sodium (CH3S(0)CH2_ Na+), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or 2-?e;f-butylimmo-2-oUemylarnko-l,3-dimethyl-perhydi""o-l,3,2-diazaphosphonine. The suitable organic solvent can be, for example but not limitation, acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide, or N,N -dimethylfonnamide. The cyclization reaction is usually conducted in a temperature range from about 0 to 120 °C. The effects of solvent, base, temperature and addition time are all interdependent, and choice of reaction conditions is important to mirrrmize the formation of byproducts. A preferred base is teh"abutylammomum fluoride. Dehydration of the compound of Formula 31 to give the compound of Formula 32, followed by converting the carboxyiic ester function to carboxylic acid, affords the compound of Formula 4d. The dehydration is effected by treatment with a catalytic amount of a suitable acid. This catalytic acid can be, for example but not limitation, sulfuric acid. The reaction is generally conducted using an organic solvent. As one skilled in the art will realize, dehydration reactions may be conducted in a wide variety of solvents in a temperature range generally between about 0 and 200 °C, more preferably between about 0 and 100 °C. For the dehydration in the method of Scheme 17, a solvent comprising acetic acid and temperatures of about 65 °C are preferred. Carboxylic ester compounds can be converted to carboxyiic acid compounds by numerous methods including nucleophihc WO 03/015518 PCT/US02/25612 10 22 cleavage under anhydrous conditions or hydro lytic methods involving the use of either acids or bases (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, inc., New York, 1991, pp. 224-269 for a review of methods). For the method of Scheme 17, base-catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal (such as lithium, sodium or potassium) hydroxides. For example, the ester can be dissolved hi a mixture of water and an alcohol such as ethanol Upon treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to provide the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of Formula 4d. The carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Compounds of Fonnula 30 can be prepared by the method outlined in Scheme 18. Scheme 18 15 20 25 wherein R6 is H, C1-C6 alkyl or C1-C6 haloalkyl and R13 is C1--C4alkyl. Treatment of a hydrazine compound of Formula 33 with a ketone of Formula 34 in a solvent such as water, methanol or acetic acid gives the hydrazone of Formula 35. One skilled in the ait will recognize that this reaction may require catalysis by an optional acid and may also 1 t require elevated temperatures depending on the molecular substitution pattern of the hydrazone of Formula 35. Reaction of the hydrazone of Fonnula 35 with the compound of Fonnula 36 in a suitable organic solvent such as, for example but not limitation, dichloromethane or tetrahydrofuran in the presence of an acid scavenger such as iriemylaroine provides the compound of Formula 30. The reaction is usually conducted at a temperature between about 0 and 100 °C. Further experimental details for the method of Scheme 18 are illustrated in Example 17. Hydrazine compounds of Formula 33 can be prepared by standard methods, such as by contacting the corresponding halo compound of Formula 15a with hydrazine. Pyrazolecarboxylic acids of Formula 4d wherein R6 is halogen can be prepared by the method outlined in Scheme 19. 23 wherein R13 is C1-C4 alfcyl. Oxidization of the compound of Formula 37 optionally in the presence of acid to give the 5 compound of Formula 32 followed by conversion of the carboxylic ester junction to the carboxylic acid provides the compound of Formula 4d, The oxidizing agent can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. To obtain complete conversion, at least one equivalent of oxidizing agent versus the compound of Formula 37 10 should be used, preferably between about one to two equivalents. This oxidation is typically carried out in the presence of a solvent. The solvent can be an ether, such as tetrahydrofuran, p-dioxane and the like, an organic ester, such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic such as N,N,-dimethylformamide, acetonitrile and the like. Acids suitable for use in the oxidation step include inorganic acids, such as sulfuric acid, 15 phosphoric acid and the like, and organic acids, such as acetic acid, benzoic acid and-the like. The acid, when used, should be used in greater than 0.1 equivalents versus the compound of Formula 37. To obtain complete conversion, one to five equivalents of acid can be used. The preferred oxidant is potassium persulfate and the oxidation is preferably carried out in the presence of sulfuric acid. The reaction can be carried out by mixing the 20 compound of Formula 37 in the desired solvent and, if used, the acid. The oxidant can then . be added at a conyenient rate. The reaction temperature is typically varied from as low as about 0 °C up to the boiling point of the solvent in order to obtain a reasonable reaction time to complete the reaction, preferably less than 8 hours. The desired product, a compound of Formula 32 can be isolated by methods known to those skilled in the art, including 25 crystallization, extraction and distillation. Methods suitable for converting the ester of Formula 32 to the carboxylic acid of Formula 4d are already described for Scheme 17. Further experimental details for the method of Scheme 19 are illustrated in Examples 12 and 13. Compounds of Formula 37 can be prepared from corresponding compounds of 30 Formula 38 as shown in Scheme 20. WO 03/015518 PCT/US02/25613 Scheme 20 wherein R13 is C1-C4 alkyl and R6 is halogen. Treatment of a compound of Formula 38 with ahalogenating reagent, usually in the presence 5 of a solvent, affords the corresponding halo compound of Formula 37. Halogenatrng reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. To obtain complete conversion, at least 0.33 equivalents of phosphorus 10 oxyhalide versus the compound of Formula 38 (i.e. the mole reatio of phosphorus oxyhalide to Formula 18 is at least 0.33) should be used, preferably between about 0.33 and 1.2 equivalents. To obtain complete conversion, at least 0.20 equivalents of phosphorus pentahalide versus the-compound of Formula 38 should be used, preferably between about 0.20 and 1.0 equivalents. Compounds of Formula 38 wherein R13 is C1-C4 alkyl are 15 preferred for this reaction. Typical solvents for this halogenation include halogenated alkanes, such as dichloromethane, chloroform, chiorobutane and the like, aromatic solvents, such as benzene, xylene, chlorobenzene and the like, ethers, such as tetrahydrofuran, p-dioxane, diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like. Optionally, an organic base, such as triethylamine, 20 pyridine, N,N-dimethylani 1 ine or the like, can be added. Addition of a catalyst, such as N,N-dimethylformamide, is also an option. Preferred is the process in which the solvent is acetonitrile and a base is absent. Typically, neither a base nor a catalyst is required when acetonitrile solvent is used. The preferred process is conducted by mixing the compound of Formula 38 in acetonitrile. The halogenating reagent is then added over a convenient time, 25 and the mixture is then held at the desired temperature until the reaction is complete. The reaction temperature is typically between 20 °C and the boiling point of acetonitrile, and the reaction time is typically less than 2 hours. The reaction mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide and the like, or an organic base, such as sodium acetate. The desired product, a compound of Formula 37, can be WO 03/015518 PCT/US02/25613 I. 25 isolated by methods known to those skilled in the art. including crystallization, extraction and distillation. Alternatively, compounds of Formula 37 wherein R6 is halogen can be prepared by treating the corresponding compounds of Formula 37 wherein R6 is a. different halogen (e.g., 5 CI for making Formula 37 wherein R3 is Br) or a sulfonate group such as P-toluenesulfonate, benzenesulfonate and methanesulfonate with the appropriate hydrogen halide. By this method the R6 halogen or sulfonate substituent on the Formula 37 starting compound is replaced with, for example, Br or CI from hydrogen bromide or hydrogen chloride, respectively. The reaction is conducted in a suitable solvent such as dibrornomethane, 10 dichloromethane or acetonitrile. The reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel. When R6in the starting compound of Formula 37 is a halogen such as CI, the reaction is preferably conducted in such a way that the hydrogen halide generated from the reaction is removed by sparging or other suitable means. The reaction can be conducted between about 0 and 100 °C, most 15 conveniently near ambient temperature (e.g., about 10 to 40 °C), and more preferably between about 20 and 30 °C. Addition of a Lewis acid catalyst (such as aluminum tribromide for preparing Formula 37 wherein R6 is Br) can facilitate the reaction. The product of Formula 37 is isolated by the usual methods known to those skilled in the art, including extraction, distillation and crystallization. Further details for this process are 20 illustrated in Example 14. Starting compounds of Formula 37 wherein R6 is CI or Br can be prepared from corresponding compounds of Formula 38 as already described. Starting compounds of Formula 37 wherein R6 is a sulfonate group can likewise be prepared from corresponding compounds of Formula 38 by standard methods such as treatment with a sulfonyl chloride 25 (e.g., jD-loluenesulfonyl chloride) and base such as a tertiary amine (e.g., hiemylamrne) in a suitable solvent such as dichloromethane; further details for this process are illustrated in Example 15. Pyrazolecarboxylic acids of Formula 4d wherein R6 is C2-C4 alkoxy or C1-C4 haloalkoxy can also be prepared by the method outlined in Scheme 21. WO 03/015518 PCT/US02/25613 26 wherein R13 is C1-C4 alkyl, andX is a leaving group. I11 this method, instead of being halogenated as shown in Scheme 20, the compound of Formula 33 is oxidized to the compound of Formula 32a. The reaction conditions for this oxidation are as already described for the conversion of the compound of Formula 37 to the 5 compound of Formula 32 in Scheme 19. The compound of Formula 32a is then alkylated to form the compound of Formula 32b by contact with an alkylating agent CF3CH2X (39) in the presence of a base. In the alkylating agent 39, X is a nucleophilic reaction leaving group such as halogen (e.g., Br, I), OS(0)2CH3 (methanesulfonate), OS(0)2CF3, OS(0)2Ph.-j7-CH3 (p-toluenesulfonate), and 10 the like; methanesulfonate works well. The reaction is conducted in the presence of at least one equivalent of a base. Suitable bases include inorganic bases, such as alkali metal (such as lithium, sodium or potassium) carbonates and hydroxides, and organic bases, such as triethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conducted in a solvent, which can comprise alcohols, such as methanol and 15 ethanol, halogenated alkanes, such as dichloromethane, aromatic solvents, such as benzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, and polar aprotic solvents, such as acetonitrile, such as such as acetonitrile, N,N-dimethylformamide, and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as base and acetonitrile as solvent are preferred. The reaction is generally conducted between 20 about 0 and 150 °C, with most typically between ambient temperature and 100 °C. The product of Formula 32b can be isolated by conventional techniques such as extraction. The ester of Formula 32b can then be converted to the carboxylic acid of Formula 4d by the methods already described for the conversion of Formula 32 to Formula 4d in Scheme 17. Further experimental details for the method of Scheme 21 are illustrated in Example 16. 25 Compounds of Formula 38 can be prepared from compounds of Formula 33 as outlined in Scheme 22. Scheme 22 NH -1 33 30 In this method, a hydrazine compound of Formula 33 is contacted with a compound of Formula 40 (a fumarate ester or maleate ester or a mixture thereof may be used) in the presence of a base and a solvent. The base is typically a metal alkoxide salt, such as sodium WO 03/015518 PCT/USO.2/25613 27 methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-buioxide, Hthium tert-bvtoxide, and the like. Greater than 0.5 equivalents of base versus the compound of Formula 33 should be used, preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalents of the compound of Formula 40 should be used, preferably 5 between 1.0 to 1.3 equivalents. Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, A^,iV-dimethylformamide, dimethyl sulfoxide and the like. Preferred solvents are alcohols such as methanol and ethanol. It is especially preferred that the alcohol be the same as that making up the furnarate or maleate ester and the alkoxide base. The reaction is typically conducted by mixing the compound of Formula 10 33 and the base in the solvent. The rnixture can be heated or cooled to a desired temperature and the compound of Formula 40 added over a period of time. Typically reaction temperatures are between 0 °C and the boiling point of the solvent used. The reaction may be conducted under greater than atmospheric pressure in order to increase the boiling point of the solvent. Temperatures between about 30 and 90 °C are generally preferred. The 15 addition time can be as quick as heat transfer allows. Typical addition times are between 1 minute and 2 hours. Optimum reaction temperature and addition time vary depending upon the identities of the compounds of Formula 33 and Formula 40. After addition, the reaction mixture can be held for a time at the reaction temperature. Depending upon the reaction temperature, the required hold time may be from 0 to 2 hours. Typical hold times 20 are 10 to 60 minutes. The reaction mass then can be acidified by adding an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid and the like. Depending on the reaction conditions and the means of isolation, the -CO9R13 ■function on the compound of Formula 38 may be hydrolyzed to -C02H; for example, the presence of water in the reaction mixture can promote such hydrolysis. If the carboxylic 25 acid (-CO2H) is formed, it can be converted back to -C02R13 wherein R13 is C1-C4 alkyl using esterification methods well-known in the art. The desired product, a compound of Formula 38, can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation. It is recognized that some reagents and reaction conditions described above for 30 preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be"apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.: Wuts, P. G. M. Protective Groups in 35 Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the WO 03/015518 PCT/US02/25613 28 ait will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I. It is believed that one skilled in the art using the preceding description can prepare 5 compounds of Formula I of the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in 10 ppm downfield from tetramethylsilane; s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, dd means doublet of doublets, dt means doublet of triplets, br s means broad singlet. EXAMPLE 1 Preparation of 2-[l-Emvl-3-trifluorome1faylpvrazol-5-ylcarbamoyl]-3-methvl-JV"-fl- 15 methylethvDbenzamide Step A: Preparation of 3-Memyl-A^-(l-me%lethyl)-2-mtroben2amide A solution of 3-methyl-2-nirrobenzoic acid (2.00 g, 11.0 mmol) and triethylamiae (1.22 g, 12.1 mmol) in 25 mL of methylene chloride was cooled to 10 °C. Ethyl chloroformate was carefully added and a solid precipitate formed. After stirring for 20 30 minutes isopropylamine (0.94 g, 16.0 mmol) was added and a homogeneous solution resulted. The reaction was stirred for an additional hour, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to afford 1.96 g of the desired intermediate as a white solid melting at 126-128 °C. 25 StepB: Preparation of 2-Ammo-3-memyl-N-(l-memylemyl)benzamide The 2-nitrobenzamide of Step A (1.70 g, 7.6 mmol) was hydrogenated over 5% Pd/C in 40 mL of ethanol at 50 psi. When -the uptake of hydrogen ceased the reaction was filtered through Celite® diatomaceous filter aid and the Celite® was washed with ether. The filtrate 30 was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151 °C. lH NMR (CDC13) 8 1.24 (dd, 6H), 2.16 (s, 3H), 4.25 (m, 1H), 5.54 (br s, 2H), 5.85 (br s, 1H), 6.59 (t, 1H), 7.13 (d, 1H), 7.17 (d, 1H). Step C: Preparation of l-Ethyl-3-triffaoromethylpyrazol-5-yl carboxylic acid 35 To a mixture of 3-tafluoromethylpyrazole (5 g, 37 mmol) and powdered potassium carbonate (10 g, 72 mmol) stirring in 30 mL of 7Y,N,Ndimemylformarnide, iodoethane (8 g, VO 03/015518 PCT/US02/25613 29 51 mmol) was added dropwise. After a mild exotherm, the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between 100 mL of diethyl ether and 100 mL of water. The ether layer was separated, washed with water (3X) and brine,-and. dried over magnesium sulfate. Evaporation of solvent in vacuo gave 4 g of oil. 5 To 3.8 g of this oil stirring in 40 mL of tetrahydrofnran under nitrogen in a dry ice/acetone bath, 17 mL of a 2.5 M solution of /i-butyllithium in tetrahydrofuran (43 mmol) was added dropwise and the solution stirred for 20 rnimites at -78 °C. An excess of gaseous carbon dioxide was bubbled into the stirred solution at a moderate rate for 10 minutes. After addition of carbon dioxide, the reaction was allowed to slowly reach room temperature and 10 stirred overnight. The reaction mixture was partitioned between diethyl ether (100 mL) and 0.5 N" aqueous sodium hydroxide (100 mL). The basic layer was separated and acidified with concentrated hydro chloric acid to a pH of 2-3. The aqueous mixture was extracted with ethyl acetate (100 mL) and the organic extract washed with water and brine and dried over magnesium sulfate. The oily residue, which remained after evaporating the solvent in vacuo, 15 was triturated to a solid from a small amount of 1-chlorobutane. After filtering and drying, a slightly impure sample of l-ethyl-3-trifiuoromethyl-pyrazol-5-yl carboxylic acid (1.4 g) was obtained as a broad-melting solid. 1HNMR (CDC13) 5 1.51 (t, 3H), 4.6S (q, 2H), 7.23 (s, 1H), 9.S5 (br s, IB). Step D: Preparation of 2-[l -Ethyl-3-hifluoromethylpyrazol-5-yl carbamoyl]-3-methyl- 20 i\A(l-memylemyl)benzamide To a solution of l-ethyl-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (i.e. the product of Step C) (0.5 g, 2.4 mmol) stirring in 20 mL of methylene chloride, oxalyl chloride (1.2 mL, 14 mmol) was added. Upon addition of 2 drops of Ar,i\^-dimethylformamide, foaming and bubbling occurred. The reaction mixture was heated at reflux for 1 hr"as a 25 yellow solution. After cooling, the solvent was removed in vacuo and the resulting residue dissolved in 20 mL of tetrahydrofuran. To the stirred solution, 2-ammo-3-methyl-/V-(l-metliylethyl)benzamide (i.e. the product of Step B) (0.7 g, 3.6 mmol) was added followed by the dropwise addition of iXiV-dnsopropylethylamine (3 mL, 17 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between ethyl acetate 30 (100 mL) and 17V aqueous hydrochloric acid (75 mL). The separated organic layer was washed with water and brine and dried over magnesium sulfate. Evaporating in vacuo gave a. white solid residue, which on purification by flash column chromatography on silica gel (2:1 hexanes/ethyl acetate) afforded 0.5 g of the title compound, a compound of the present invention, melting at 223-226 °C. 35 1HNMR (DMSO-d6) 8 1.06 (d, 6H), 1.36 (t, 3H), 2.45 (s, 3H), 3.97 (m, 1H), 4.58 (q, 2H), 7.43-7.25 (m, 3H), 7.45 (s, 1H), 8.05 (d, 1H), 10.15 (s, 1H). WO 03/015518 PCT7US02/25613 30 EXAMPLE 2 Preparation of A-[2-Methyl-6-[["(l-raemylethyl)ammo]carbonvl]phenvfl-1 -phenyl-3-(trifhioromemvl)-1 H-pyi"azole-5-carboxainide Step A: Preparation of 2-Memyl-l-phenyl-4-(ttifluoromethyl)~li?"-pyrazole 5 A solution of l,l,l-uifluoropentane-2,4-dione (20.0 g, 0.130 mole) in glacial acetic acid (60 rnL) was cooled to 7 °C using an ice/water bath. Phenylhydrazine (14.1 g, 0.130 mole) was added dropwise over a period of 60 minutes. The reaction mass temperature increased to 15 °C during the addition. The resulting orange solution was held under ambient conditions for 60 minutes. The bulk of the acetic acid was removed by stripping on 10 a rotary evaporator at a bath temperature of 65 °C. The residue was.dissolved in methylene chloride (150 mL). The solution was washed with aqueous sodium bicarbonate (3 g in 50 rnL of water). The purple-red organic layer was separated, treated with activated charcoal (2 g) and MgSO4 then filtered. Volatiles were removed on a rotary evaporator. The crude product consisted of 28.0 g of a rose-colored oil, which contained ~S9% the desired product 15 and 11% l-phenyl-5-(trifl.uoromethyl)-3-methylpyrazole. iHNMR (DUSO-d6) 5 2.35 (s, 3H), 6.76 (s, IB), 7.6-7.5 (m, 5H). StepB: Preparation of l-Phenyl-3-(trifluoromethyl)-liy-p3Tazole-5-carboxylic acid A sample of crude 2-methyl-l-phenyl-4-(trifluoromethyl)-li?-pyrazole (i.e. the product of Step A) (-89%, 50.0 g, 0.221 mole) was mixed with water (400 mL) and 20 cetyltrimethylammonium chloride (4.00 g, 0.011 mole). The mixture was heated to 95 °C. Potassium permanganate was added in 10 equal portions, spaced at ~8 minute intervals. The reaction mass was maintained at 95-100 °C during this period. After the last portion was added, the mixture was held for -15 minutes at 95-100 °C. whereupon the purple, permanganate color had been discharged. The reaction mass was filtered while hot (~75 °C) 25 through a 1-cm bed of Celite® diatomaceous filter aid in a 150-mL coarse glass frit funnel. The filter cake was washed with warm (-50 °C) water (3xl00mL). The combined filtrate and washings were extracted with ether (2x100 mL) to remove a small amount of yellow, water-insoluble material. The aqueous layer was purged with nitrogen to remove residual ether. The clear, colorless alkaline solution was acidified by adding concentrated 30 hydrochloric acid dropwise until the pH reached -1.3 (28 g, 0.28 mole). Gas evolution was vigorous during the first two-thirds of the addition. The product was collected via filtration, washed with water (3x40 mL), then dried overnight at 55 °C in vacuo. The product consisted of 11.7 g of a white, crystalline powder, which was essentially pure based upon NMR. 35 *HNMR (CDC13) 8 7.33 (s, 1H), 7.4-7.5 (m, 5H). . WO 03/015518 PCT/US02/25613 31 Step C: Preparation of l-Phenyl-3-(trifl.uoromethyl)-li?-pyi"azole-5-carbon.yl chloride A sample of crude l-phenyl-3-(uifluoromemyl)p5Ta2ole-5-carboxyiic acid (i.e. the product of Step B) (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45 mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol), followed by N,N- 5 dimethylformamide (0.010 mL, 0.13 mmol). Off-gassing began shortly after adding the iV,7V-dimethylformamide catalyst. The reaction mixture was stirred for -20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by stripping the reaction mixture on a rotary evaporator at a bath temperature of 55 °C. The product consisted of 4.43 g of a light-yellow oil. The only impurity observed by .10 lE NMR was 7V3iV-dimerhylfonnamide. 1HNMR (CDC13) 5 7.40 (m, 1H), 7.42 (s, 1H), 7.50-7,53 (m, 4H). Step D: Preparation of iV-[2-Methyl-6-[[(l -methylethyl)amino]carbonyl]phenyl]-l- phenyl-3-(trifluoromethyl)-lff-pyrazole-5-carboxamide A sample of 3-methylisatoic anhydride (0.30 g, 1.7 mmol) partially dissolved in 15 pyridine (4.0 mL) was treated with l-phenyl-3-(trifluoromethylpyi-azole)-5-carboxyl chloride (i.e. the product of Step C) (0.55 g, 1.9 mmol). The mixture was heated to ~95°C for a period of 2 hours. The resulting orange solution was cooled to 29 °C, then was treated with isopropylamine (1.00 g, 16.9 mmol). The reaction mass exothermically warmed to 39 °C. It was further heated to 55 °C for a period of 30 minutes, whereupon much precipitate formed. 20 The reaction mass was dissolved in dichloromethane (150 mL). The solution was washed with aqueous acid (5 mL of cone. HC1 in 45 mL of water), then with aqueous base (2 g sodium carbonate in 50 mL of water). The organic layer was dried over MgSO/j., filtered, then concentrated on a rotary evaporator. Upon reduction to ~4 mL, product crystals had formed. The slurry was diluted with -10 mL of ether, whereupon more product precipitated. 25 The product was isolated by filtration, washed with ether (2x10 mL), then washed with water (2x50 mL). The wet cake was dried for 30 minutes at 70 °C in vacuo. The product, a compound of the present invention, consisted of 0.52 g of an off-white powder melting at 260-262 °C. JHNMR (DMSO-rf6) 5 1.07 (d, 6H), 2.21 (s, 3H), 4.02 (octet, 1H), 7.2-7.4 (m, 3H), 7.45-7.6 30 (m, 6H), 8.10 (d, 1H), 10.31 (s, 1H). WO 03/015518 PCT/US02/25613 32 EXAMPLE 3 Step A: Preparation of 3-Trifluoromemyl-2-[3-(trifmoromerhyl)-lif-pyrazol-1- 5 yl]pyridine A mixture of 2-cchoro-3-trifluoromemylpyridine (3.62 g., 21 mmol), 3-trifluoro-methylpyrazole (2.7 g., 20 mmol), and potassium carbonate (6.0 g, 43 mmol) were heated at 100 °C for 18 h. The cooled reaction mixture was added to ice/water (100 mL). The mixture was extracted twice with ether (100 mL) and the combined ether extracts were JO washed twice with water (100 mL). The organic layer was dried with magnesium sulfate and concentrated to an oil. Chromatography on silica gel with hexanes:ethyl acetate (8:1 to 4:1) as eluent gave the title compound (3.5 g) as an oil. 1HNMR (CDC13) § 6.75 (m, 1H), 7.5 (m, 1H), 8.2 (m? 2H), 8.7 (m, IB). Step B: Preparation of 3 -(Trifluoromethyl)-1 -[3-(trifhioromethyl)-2-pyridinyl]- \H- 15 pyrazole-5-carboxylic acid A mixture of the title compound of Example 3, Step A (3.4 g, 13 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to -70 °C. Lithium diisopropylamide (2N in heptane/tetrahydrofuran, (Aldrich) 9.5 mL, 19 mmol) was added and the resulting dark mixture was stirred for 10 minutes. Dry carbon dioxide was bubbled through the mixture for 20 15 minutes. The rnixture was allowed to warm to 23 °C and treated with water (50 mL) and IN sodium hydroxide (10 mL). The aqueous mixture was extracted with ether (100 mL) and then ethyl acetate (100 mL). The aqueous layer was acidified with 6N hydrochloric acid to pH 1-2 and extracted twice with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated to give the title compound (1.5 g). 25 1HLNMR (CDCI3) 5 7.6 (m, 1H), 7.95 (m, 1H), 8.56 (m, 1H), 8."9(m, 1H), 14.2 (br, 1H) Step C: Preparation of 7y-[2-Memyl-6-[[(l-memylethyl)amino]carbonyl]phenyl]-3- (uifiuoromethyl)-1 -[3-(trifiuoromethyl)-2-pyridinyl]- lfT-pyrazole-5- carboxamide A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title 30 compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g5 2.1 mmol) in acetonitrile (13 mL) was treated with triethylamhie (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 17Y hydrochloric acid. The ethyl acetate layer was washed successively with IN hydrochloric acid (50 mL), IN sodium 35 hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column WO 03/015518 PCT/US02/25613 chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g), a compound of the present invention, was isolated as a white solid, m.p. 227-230 °C. !H NMR (CDC13) 5 1.2 (ni. 6H), 4.15 (m, 1H), 5.9 (br d, IB), 7.1 (rn, 1H), 7.2 (m, 2H), 7.4 5 (s, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.74 (m, 1H), 10.4 (br, 1H). EXAMPLE 4 Preparation of 1 -(3-Chloro-2-pvridmylViY-f 2-methyl-6-iTf 1 -methvlethyDamino]carbonyl]-phenvl]-3-fhifluoromethyl)-lff-pyrazole-5-carboxamide Step A: Preparation of 3-CMorQ-2-[3-(trifIuoromethyl)-l.ff-pyrazol-l -yljpyridine ^10 To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-(trifluoromethyl)- pyrazole (83 g, 0.61 mol) in dry 7V,iV-dimethylfoiinamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125 °C over 48 hours. The reaction was cooled to 100 °C and filtered through Celite© diatomaceous filter aid to remove solids. iV^JV-Dmiemylformamide and excess dichloropyridine were removed by 15 distillation at atmospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141 °C, 7 mm) afforded the desired intermediate as a clea" yellow oil (113.4 g). 1HNMR(CDC13) 5 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H). Step B: Preparation of l-(3-Chloro-2-pyiidmyl)-3-(tiifluoromethyl)-l/r"--pyrazole-5- carboxylic acid 20 To a solution of 3-cMoro-2-[3-(trifluoromethyl)-liy-pyrazol-l-yl]pyridine (i.e. the product of Step A) (105.0 g, 425 mmol) in dry tetrahydrofuraii (700 mL) at -75 °C was added via cannula a -30 °C solution of Hthium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deep red solution was stirred for 15 minutes, after which time carbon dioxide was bubbled through at -63 °C until the solution became pale yellow 25 and the exotheimicity ceased. The reaction was stirred for an additional 20 minutes and then quenched with water (20 mL). The solvent was removed under reduced pressure, and the reaction mixture partitioned between ether and Q.5N aqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3x), filtered through Celite® diatomaceous filter aid to remove residual solids, and then acidified to a pH of approximately 4, at which 30 point an orange oil formed. The aqueous mixture was stirred vigorously and additional acid was added to lower the pH to 2.5-3. The orange oil congealed into a granular solid, which. was filtered, wasned successively with water and IN hydrochloric acid, and dried under vacuum at 50 °C to afford the title product as an off-white solid (130 g). (Product from another run following similar procedures melted at 175-176 °C.) 35 iHNMR (DMSO-45) 5 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H). WO 03/015518 - , . PCT/US02/25613 34 Step C: Preparation of 8-Methyl-2ff-3. l-benzoxazine-2,4(liy)-dione To a solution of 2-ammo-3-methylbenzoic acid (6 g) in dry 1,4-diosane (50 roL) was added dropwise a solution of trichloromethyl chloroformate (8 mL) in dry 1,4-dioxane (25 mL), with ice-water cooling to keep the reaction temperature below 25 °C. A white 5 precipitate began to form during the addition. The reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and washed with 1,4-dioxane (2x20 mL) and hexane (2x15 mL) and air-dried to yield 6.51 g of off-white solid. 1HNMR (DMSO-d6) 8 2.33 (s, 3H), 7.18 (t, 1H), 7.59 (d, 1H), 7.78 (d, 1H), 11.0 (br s, 1H). 10 Step D: Preparation of 2-[l-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-lH-pyrazol- 5-yi]-8-methyl-H-3,1 -benzoxazin-4-one To a suspension of the carboxylic acid product prepared as in Step B (146 g, 500 mmoi) in dichloromethane (approximately 2 L) was added A^-dimethylformainide (20 drops) and oxalyl chloride (67 mL, 750 mmol) in approximately 5-niL portions over 15 approximately 2 h. Vigorous gas evolution occurred during the addition. The reaction mixture was "stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to provide the crude acid chloride as an opaque orange mixture. This material was taken up in dichloromethane, filtered to remove some solids and then reconcentrated and used without further purification. The crude acid chloride was dissolved in acetonitrile (250 20 mL) and added to a suspension of the product from Step C in acetonitrile (400 mL). Pyridine (250 mL) was added, the mixture was stirred for 15 min at room temperature, then warmed to reflux for 3 h. The resulting mixture was cooled to room temperature and stirred overnight to provide a solid mass. Additional acetonitrile was added and the mixture was mixed to form a thick slurry. The solids were collected and washed with cold acetonitrile. 25 The solids were air-dried and the dried in vacuo at 90 °C for 5 h to yield 144.8 g of fluffy white solid. 1H NMR (CDC13) 8 1.84 (s, 3H), 7.4 (t, 1H), 7.6 (m5 3H), 8.0 (dd, IB), 8.1 (s, 1H), 8.6 (d, IB). Step E: Preparation of l-(3-CMoro-2-pyiidinyl)-7y-[2-methyl"6-[[(l-methylethyl)- 30 arrn^o]carbonyl]phenyl]-3-(trifluoromemyl)-lff-pyrazole-5-carboxarmde To a suspension of the benzoxazinone product of Step D (124 g, 300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine (76 mL, 900 mmol) at room temperature. The temperature of the reaction mixture rose and the suspension thinned during the addition. The reaction mixture was then warmed to reflux for 1.5 n. A new suspension 35 formed The reaction rnixture was cooled to room temperature and diethyl ether (1.3 L) was added and the mixture stirred at room temperature overnight. The solids were collected and washed with ether. The solids were air-dried and then dried in vacuo at 90 °C for 5 h to WO 03/015518 FCT/US02/256I3 35 yield 122 g of the title compound, a compound of the present invention, as a fluffy white solid, melting at 194-196 °C. 1HNMR (CDC13) 3 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, Iff), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, ffl), 7.8 (d, 1H), 8.5 (d, IB), 10.4 (s, 1H). 5 EXAMPLE 5 Alternate preparation of l-(3-chloro-2-pvridmyl)-/y-[2-memyl-6-[[fl-memvlemyDarnrno1- carbonvllphenyl]-3-(trifiuoromemyl)-lg-pyL-a2ole-5-carboxarnide To a solution of the carboxylic acid product prepared as in Example 4, Step B (28 g, 96 mmol) in dichloromethane (240 mL) was added nN,N-dmiethylformamide (12 drops) and 10 oxalyl chloride (15.8 g, 124 mmol). The reaction mixture was stirred at room temperature until gas evolution ceased (approximately 1.5 h). The reaction mixture was concentrated in vacuo to provide the crude acid chloride as an oil that was used without further purification. The crude acid chloride was dissolved in acetonitrile (95 mL) and added to a solution of the benzoxazin-2,4-dione prepared as in Example 4, Step C in acetonitrile (95 mL). The 15 resulting mixture was stirred at room temperature (approximately 30 min). Pyridine (95 mL) was added and the mixture heated to about 90 °C (approximately 1 h). The reaction mixture was cooled to about 35 °C and isopropylamine (25 mL) was added. The reaction mixture exothermically warmed during the addition and then was maintained at about 50 °C (approximately 1 h). The reaction mixture was then poured into ice water and stirred. The 20 resulting precipitate was collected by filtration, washed with water and dried in vacuo overnight to provide 37.5 g of the title compound, a compound of the present invention, as a tan solid. 1H NMR (CDCI3) 8 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 10.4 (s, 1H). 25 . EXAMPLE 6 Step A: Preparation of 2-Amino-3-methyl-5-chlorobenzoic acid To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g," 99.2 mmol) in 30 iV,A^dhnethylformamide (50 mL) was added NcHorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100 °C for 30 minutes. The heat was"removed, the reaction was cooled to room temperature and let stand overnight. The reaction mixture was then slowly poured into ice-water (250 mL) to precipitate a white solid. The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The 35 ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure WO 1)3/015518 PCT/US02/25613 36 and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g). 1HNMR (DMSO-d6) 8 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H). Step B: Preparation of 3-chloro-2-[3-(trifluorornethyl)-lZf-pyrazol-l-yl]p}Tidffl.e 5 To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethyl pyrazole (83 g, 0.61 mo 1) in diy N,N-dimemylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125 °C over 48 hours. The reaction was cooled to 100 °C and filtered through Celite® diatornaceous filter aid to remove solids. iV,iV-Dimethylfonnamide and excess dichloropyridine were removed by distillation at 10 atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141 °C, 7 mm) afforded the title compound as a clear yellow oil (113.4 g). 1HNMR(CDC13) 5 6.7S (s, IE), 7.36 (t, IB), 7.93 (d, IE), 8.15 (s, 1H), 8.45 (d, 1H). Step C: Preparation of l-(3-ChJoro-2-pyridmyl)-3 carboxylic acid 15 To a solution of the pyrazole product from Step B (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL) at -75 °C was added via cannula a -30 °C solution of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deep red solution was stilted for 15 minutes, after which time carbon dioxide was bubbled through at -63 °C until the solution became pale yellow and the exothermicity ceased. The reaction was stirred for 20 an additional 20 minutes and then quenched with water (20 mL). The solvent was removed under reduced pressure, and the reaction mixture was partitioned between ether and 0.5 N iqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3x), altered through Celite® diatornaceous filter aid to remove residual solids, and then acidified ;o a pH of approximately 4, at which point an orange oil formed. The aqueous mixture was 25 stirred vigorously and additional acid was added to lower the pH to 2.5-3. The orange oil congealed into a granular solid, which was filtered, washed successively with water and IN hydrochloric acid, and dried under vacuum at 50 °C to afford the title product as an off-white solid (130 g). (Product from another run following similar procedure melted at 175-176 °C.) 1HNMR (DMSO-rf6) S 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H). 30 Step D: Preparation of 6-chloro-2-[l-(3-chloro-2-pyridinyl)-3-(tiiiluoromethyl)-li7- pyrazol-5-yl]-8-methyl-477-3.1 -benzoxazin-4-one To a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in acetonitrile (75 mL) was added dropwise a mixture of the carboxylic acid product from Step C (7.5 g, 27.0 mmol) and triefhylamine (3.75 mL, 27.0 mmol) in acetonitrile (75 mL) at 0-5 °C. The reaction 35 temperature was then maintained at 0 °C throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-chlorobenzoic acid from Step A (5.1g, 27.0 rnrnol) was added and stirring was continued for an additional 5 minutes. A solution of WO 03/015518 PCT/US02/25(5]3 taethylaniine (7.5 mL, 54.0 mmol) in acetonitiile (15 mL) was then added drop wise, and the reaction mixture was stirred 45 minutes, followed by the addition of methanesulfonyl chloride (2.2 mL, 28.3 mmol). The reaction mixture was then warmed to room temperature and stirred overnight. Approximately 75 mL of water was then added to precipitate 5.8 g of 5 a yellow solid. An additional 1 g of product was isolated by extraction from the filtrate to provide a total of 6.8 g of the title compound as a yellow solid. 1HNMR(CDC13) 5 1.83 (s, 3H), 7.50 (s, IH), 7.53 (m, 2H), 7.99 (m, 2H), 8.58 (d, IH). Step E: Preparation of N-[4-Cliloro-2-memyl-6-[[(l-methylemyl)arrrko]carbonyl]- phenyl]-l-(3-chloro-2"pyridinyl)-3-(trifluoromethyl)-lH-pyrazole- 10 5-carboxamide To a solution of the benzoxazinone product of Step D (5.0 g, 11.3 mmol) in tetrahydrofuran (35 mL) was added" dropwise isopropylamine (2.9 mL, 34.0 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was then warmed until all solids had dissolved and stirred an additional five minutes, at which point thin layer 15 chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel, followed by trituration with ether/hexane to afford the title compound, a compound of the present invention, as a solid (4.6 g), melting at 195-196 °C. lK NMR (CDC13) 5 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, IH), 5.95 (br d, IH), 7.1-7.3 (m, 20 2H), 7.39 (s, IH), 7.4 (m, IH), 7.84 (d, IH), 8.50 (d, IH), 10.24 (br s, IH). EXAMPLE 7 Preparation of N-[4-Chloro-2-methyl-6-[(methylamino)cai-bonyl]phenyl]--l-(3-chloro-2- pyridmyl)-3-(1iifhoromemyl)-lif-pyrazole-5-carboxamide To a solution of the benzoxazinone product of Example 6, Step D (4.50 g, 10.18 25 mmol) in tetrahydrofuran (THF; 70 mL) was added memylamiue (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for " 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 4.09 g of the title compound, a compound of the present invention, as a white solid melting at 185-186 °C. 30 . 1HNMR CDMSO-d6) 5 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, IH), 7.46 (dd, IH), 7.65 (dd, IH), 7.74 (s, IH), 8.21 (d, IH), 8.35 (br q, IH), 8.74 (d, IH), 10.39 (s, IH). WO 03/0155 J 8 PCT/US02/25613 38 EXAMPLE 8 Prepration of 3-Chloro-N-[4-chloro-2-methv]-6-[[(1-methlethvl)amino lcarbonvl]pheny]- (3-chloro-2-pvrazole-5-carboxamide Step A: Preparation of 3-CUoro-N,N--dimethyl-lif-pyrazole-l-siilfonamide 5 To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at -78 °C was added dropwise a solution of 2.5. M 72-butylffihium (472 mL, 1.18 mol) in hexane while maintaining the temperature below -65 °C. Upon completion of the addition the reaction mixture was maintained at -78 °C for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) 10 in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at -78 °C, wanned to -20 QC and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4x500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product 15 compound as a yellow oil (160 g). 1HNMRCCDCy 5 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, IB). Step B: Preparation of 3-Chloropyrazole To trifluoroacetic acid (290 mL) was added dropwise the chloropyrazole product (160 g) from Step A, and the reaction mixture was stirred at room temperature for 1.5 hours 20 and then concentrated at reduced pressure. The residue was taken up in hexane, insoluble solids were filtered off, and the hexane was concentrated to afford the crude product as an oil. The crude product was further purified by chromatography on. silica gel using ether/hexane (40:60) as eluent to afford the title product as a yellow oil (64.44 g). 1HNMR (CDC13) 5 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H). 25 Step C: Preparation of 3-Chloro-2-(3-chloro-liy-pyrazol-l-yl)pyridine To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformarnide (400 mL) was added potassium carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100 °C for 36 hours. The reaction mixture was cooled to room temperature and slowly poured 30 into ice water. The precipitated solids were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g). 1HNMR (CDCI3) 5 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.41 (d, Iff). Step D: Preparation of 3-CbIoro-l-(3-chloro-2-pyridinyl)-lir-pyrazole-5-carboxylic acid To a solution of the pyrazole product from Step C (39.75 g, 186 mmol) in dry tetrahydrofuran (400 mL) at -78 °C was added dropwise a solution of 2.0 M lithinm 5 diisopropylamide (93 mL, 186 mmol) in tetrahydrofuran. Carbon dioxide was bubbled through the amber solution for 14 minutes, after which time the solution became pale brownish-yellow. The reaction was made basic with IN aqueous sodium hydroxide solution and extracted with ether (2x500 mL). The aqueous extracts were acidified with 6 N hydrochloric acid and extracted with ethyl acetate (3x500 mL).- The ethyl acetate extracts 10 were dried over magnesium sulfate and concentrated to afford the title product as an off-white solid (42.96 g). (Product from another run following similar procedure melted at 198-199 °C.) 1HNMR (DMSO-d6) 5 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51 (d, 1H). Step E: Preparation of 6-Chloro-2-[3-chIoro-l-(3-chloro-2-pyridinyl)-IH-pyxazol- 15 5-yl]-8-methyl-4H-3,1 -benzoxazin-4-one To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of the carboxylic acid product from Step D (15.0 g, 58.16 mmol) and triethylamine (5.88 g58.16 mmol) in acetonitrile (150 mL) at -5 °C. The reaction mixture was then stirred for 30 minutes at 0 °C. Then, 2-ammo-3-methyl-5-20 chlorobenzoic acid from Example 6, Step A (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triemylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10 °C. The reaction mixture was stirred 60 minutes at 0 °C, and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room 25 temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g). 1HNMR(CDCl3 5 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d, 2H), 8.56 (d, 1H). Step F: Preparation of 3-chloro-iV-[4-chloro-2-methyl-6-[[(l-methylethyl)amino]- 30 carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-liy-pyrazole-5-carboxamide To a solution of the benzoxazinone product of Step E (6.21 g, 15.21 mmol) in tetrahydrofuran (100 mL) was added isopropylamine (4.23 g, 72.74 mmol) and the reaction mixture was then heated to 60 °C, stirred for 1 hour and then cooled to room temperature. The tehahydrofuran solvent was evaporated under reduced pressure, and the residual solid 35 was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (5.05 g) melting at 173-175 °C. WO 03/015518 PCT/US02/25613 40 !H NMR (CDCI3) 5 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97 (d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83 (d, IB), 8.43 (d, 1H), 10.15 (far s, 1H). EXAMPLE 9 Preparation of 3-Chloro-iV"-[4-cUoro-2-methyl-6-[(metiiylammo)carbonyl]phenyl]-l-(3- 5 chlorO"2-pyridinyl)-lir-pyrazole-5-carboxamide To a solution of the benzoxazinone product of Example 8, "Step E (6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60 °C, stirred for 1 hour and then cooled to room temperature. The tefrahydrofuran solvent was evaporated under reduced 10 pressurej and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (4.57 g) melting at 225-226 °C. iHNMR (CDCI3) 8 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, 1H), 7.06 (s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m, 1H), 7.83 (d, 1H), 8.42 (d, 1H), 10.08 (br s, 1H). 15 EXAMPLE 10 Preparation of 3-Bromo-7V"44-chloro-2-me&yl-6-[[(l-memvlemyl^rnirinlcarbonvllDhenvl1" l-(3-cfaloro-2-pyridinyl)-lif-pyrazole-5-carboxamide . Step A: Preparation of 3-Bromo-7y^-dimethyl-ljy-pyrazole-l-sulfonarnide To a solution of 7V-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry 20 tetrahydrofuran (500 mL) at -78 °C was added dropwise a solution of n-butyllifhium (2.5 M in hexane, 105.5 mL,-0.264 mol) while mamtaining the temperature below -60 °C. A thick solid formed during the addition. Upon completion of the addition the reaction mixture was maintained for an additional 15 minutes, after which time a solution of 1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150 mL) was added dropwise while 25 maintaining the temperature below -70 °C. The reaction mixture turned a clear orange; stirring was continued for an additional 15 minutes. The -78 °C bath was removed and the reaction was quenched with water (600 mL). The reaction mixture was ■ extracted with methylene chloride (4x), and the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using 30 methylene chloride/hexane (50:50) as eluent to afford the title product as a clear colorless oil (57.04 g). iHNMR (CDCI3) 8 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H). StepB: Preparation of 3-Bromopyrazole To trifmoroacetic acid (70 mL) was slowly added the bromopyrazole product (57.04 g) 35 from Step A. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated at reduced pressure. The residue was taken up in hexane, insoluble solids were WO 03/015518 PCT/US02/25613 41 filtered off. and the hexane was evaporated to afford the crude product as an oil. The crude product was further purified by chromatography on silica gel using ethyl acetate/dichloromethane (10:90) as eluent to afford an oil. The oil was taken up in dichlorornethane, neutralized with aqueous sodium bicarbonate solution, extracted with 5 methylene chloride (3x), dried over magnesium sulfate and concentrated to afford the title " product as a white solid (25.9 g), ni.p. 61-64 °C. 1HNMR (CDC13) 5 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H). Step C: Preparation of 2-(3-Bromo-lH-pyrazol-l-yl)-3-cWorapyridine To a mixture of 2,3-dichloropyridfne (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the 10 product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125 °C for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2x100 mL). The solid filter cake was taken up in methylene ■ 15 chloride and washed sequentially with water, IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 br. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be 20 > 94 % pure by NMR. This material was used without further purification in Step D. 1HNMR (CDCI3) 5 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05 (s, 1H), 8.43 (d, 1H). Step D: Preparation of 3-Bromo-l-(3-chloro-2-pyridrriyl)-li?-pyrazole-5-carboxyHc acid To a solution of the pyrazole product from Step C (30.4 g, 118 mmol) in dry 25 tetrahydrofuran (250 mL) at -76 °C was added dropwise a solution of lithium diisopropyl-amide (118 mmol) in tetrahydrofuran at such a rate as to maintain the temperature below -71 °C. The reaction mixture was stirred for 15 minutes at -76 °C, and carbon dioxide was then bubbled through for 10 minutes, causing wanning to -57 °C. The reaction rnixture was warmed to -20 °C and quenched with water. The reaction mixture was concentrated and 30 then taken up in water (1 L) and ether (500 mL), and then aqueous sodium hydroxide solution (1 N, 20 mL) was added. The aqueous extracts were washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered, washed with water and dried to afford the title product as a tan solid (27.7 g). (Product from another run following similar procedure melted at 200-201 °C.) 35 1HNMR (DMSO-dg) 5 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, IE), 8.56 (d, 1H). WO 03/015518 PCT/US02/25613 42 Step E: Preparation of 2-[3-Bromo-l-(3-chloro-2-p5ildinyl)-li7-pyrazol-5-3d]- 6-chloro-8-methyl-4H-3,l-benzoxazin-4-one A procedure analogous to that of Example 6, Step D was used to convert the pyrazolecarboxylic acid product from Example 10, Step D (1.5 g, 4.96 mmol) and 2-amino-5 3-methyl-5-chlorobenzoic acid (0.92 g, 4.96 mmol) to the title product as a solid (1.21 g). 1HNMR (CDC13) 5 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d, 1H), 8.04 (m, 1H), 8.25 (s, 1H), 8.26 (d, 1H). Step F: Preparation of 3-Bromo-7Y-[4-chloro-2-memyl-6-[[(l-memylemyl)arnino]- carbony ljphenyl]-1 -(3-chloro-2-pyridirryi)- lff-pyrazole-5-carboxamide 10 To a solution of the benzoxazinone product of Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 mL, 1.42 mmol), and the reaction mixture was heated to 60 °C for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the 15 present invention, as a solid (150 mg), m.p. 159-161 °C. lS NMR (CDCI3) 5 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99 (m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41 (d, 1H). EXAMPLE 11 Preparation of 3-Bromo-N"-[4-chloro-2-memyl-6-[(methylamino)carbonylJphenyl]-1 -(3- 20 chloro-2"pyridinyl)--lff-pyrazole--5-carboxamide To a solution of the benzoxazinone product of Example 10, Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamme (2.0 M solution in THE, 0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60 °C for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the 25 residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (40 mg), m.p. 162-164 °C. lS NMR (CDCI3) 52.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, IS), 7.10 (s, IS), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, l"H), 8.45 (d, 1H). The following Example 12 illustrates an alternative preparation of 3-chloro-l-(3-50 chloro-2-pyridinyl)-l/f-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-cMoro-iV-[4-chloro-2-memyl-6-[[(l-memylemyl)ammo]carbonyl]phenyl]-l-(3--chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide and 3-chloro-iV-[4-chloro-2-methyl-6-[(memylamiao) carbonyl]phenyl]-1 -(3 -chloro-2-pyridinyl)- Lff-pyrazole-5-carboxamide, by further steps illustrated in. Examples 8 and 9. WO 03/015518 PCT/US02/25613 43 EXAMPLE 12 Preparation of 3-chloro-1 -(3-chloro-2-pvridinv)-H-pvrazole-5-carboxyiic acid Step A: " Preparation of Ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3- pyrazolidinecarboxylate (alternatively named ethyl 1 -(3-chloro-2-pyridinyl)- 5 3-pyrazolidinone-5-carboxylate) A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 rnL) and an ethanolic solution of sodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83 °C. It was then treated with 3-chloro-2(li?)-pyridinone 10 hydrazone (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65 °C, the reaction mixture 15 was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28 °C. The slurry was held at about 2 °C for 2 hours. The product was isolated via filtration, washed with aqueous ethanol (40%, 3 x 50 mL), and then air-dried on the filter for about 1 hour. The title product 20 compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by 1HNMR. lH NMR (DMSO-ig) 8 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18 (s, 1H). Step B: Preparation of Ethyl 3-cMoro-l-(3-cUoro-2-pyridinyl)-4,5-dihydro- 25 , lH-pyrazole-5-carboxylate (alternatively named ethyl l-(3-chloro- 2-pyridkyl)-3-chloro-2-pyrazoline-5-carboxyiate) To a 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged acetonitrile (1000 mL), ethyl 2-(3-chloro-2-pyridinyl)-5--oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (91.0 g, 0.337 mol) 30 and phosphorus oxycbloride (35.0 mL, 0.375 mol). Upon adding the phosphorus oxychloride, the mixture self-heated from 22 to 25 °C and a precipitate formed. The light-yellow slurry was heated to reflux at 83 °C over a period of 35 rninutes, whereupon the precipitate dissolved. The resulting orange solution was held at reflux for 45 minutes, whereupon it had become black-green. The reflux condenser was replaced with a distillation 35 head, and 650 mL of solvent was removed by distillation. A second 2-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (130 g, 1.55 mol) and water (400 mL). The concentrated reaction mixture was added to the sodium WO 03/015518 PCT/US02/25613 44 bicarbonate slurry over a period of 15 rninutes. The resulting, two-phase mixture was stirred vigorously for 20 rninutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (250 mL) and then was stirred for 50 minutes. The mixture was treated with Celite® 545 diatomaceous earth filter aid (11 g) and then filtered to remove a 5 black, tarry substance that inhibited phase separation. Since the filtrate was slow to separate into distinct phases, it was diluted with dichloromethane (200 mL) and water (200 mL) and treated with more Celite® 545 (15 g). The mixture was filtered, and the filtrate was transferred to a separatory funnel. The heavier, deep green organic layer was separated. A rag layer (50 mL) was refiltered and then added to the organic layer. The organic solution 10 (800 mL) was treated with magnesium sulfate (30 g) and silica gel (12 g), and the slurry was stirred magnetically for 30 rninutes. The slurry was filtered to remove the magnesium sulfate and silica gel, which had become deep blue-green. The filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated on a rotary evaporator. The product consisted of dark amber oil (92.Q g, 93% yield). The only appreciable impurities 15 observed by 1H NMR were 1% starting material and 0.7% acetomtrile. lH NMR (DMSO-d6) 5 1.15 (t, 3H), 3.26 (dd, IB), 3.5S (dd, 1H), 4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, IH). Step C: Preparation of Ethyl 3-chloro- l-(3-chloro-2-pyridhiyl)- lH-pyrazole- 5-carboxylate (alternatively named ethyl l-(3-chioro-2-pyridinyi)- 20 3-chloropyrazole-5"Carboxylate) A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with ethyl 3-chloro-l-(3-chloro-2-pyridinyl)-4,5-dihydro-lH-p5Tazole-5-carboxylate (Le. the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitfile (1000 mL) and sulfuric acid (98%, 35.0 mL, 0.661 mol). The 25 mixture self-heated from 22 to 35 °C upon adding the sulfuiic acid. After being stirred for several minutes, the mixture was treated with potassium persulfate (140 g, 0.518 mol). The slurry was heated to reflux at 84 °C for 4.5 hours. The resulting orange slurry while still warm (50-65 °C) was filtered to remove a fine, white pi"ecipitate. The filter cake was washed with acetonitrile (50 mL). The filtrate was concentrated to about 500 mL on a rotary 30 evaporator. A second 2-L four-necked flask equipped with a mechanical stirrer was charged with water (1250 mL). The concentrated reaction mass was added to the water over a period of about 5 minutes. The product was isolated via filtration, washed with aqueous acetonitrile (25%, 3 x 125 mL), washed once with water (1QQ mL), and then dried overnight in vacuo at room temperature. The product consisted of a crystalline, orange powder (79.3 g, 82% 35 yield). The only appreciable impurities observed by 1H NMR were about 1.9% water and 0.6% acetonitrile. 1HMR. (DMSO-rf6) 8 1.09 (t 3K), 4.16 (q, 2H), 7.31 (s, 1H),.7.71 (dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H). WO 03/015518 PCT/US02/25613 45 Step D: Preparation, of 3-Chloro-l-(3-cifaloro-2-pyridinyl)-lif-pyrazole-5-carboxylic acid (alternatively named 1 -(3-chloro-2-pyridinyl)-3-chloropyrazole- " 5-carboxylic acid) A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen 5 inlet was charged with ethyl 3-chloro-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylate (i.e. the product of Step C) (97.5% pure, 79.3 g, 0.270 mol), methanol (260 mL), water (140 mL) and sodium hydroxide pellets (13.0 g, 0.325 mol). Upon adding the sodium hydroxide the mixture self-heated from 22 to 35 °C, and the starting material began to dissolve. After being stirred for 45 minutes under ambient conditions, all of the starting 10 material had dissolved. The resulting deep orange-brown solution was concentrated to about 250 mL on a rotary evaporator. The concentrated reaction mixture was then, diluted with. water (400 mL). The aqueous solution was extracted with ether (200 mL). Then the aqueous layer was transferred to a 1-L Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol) 15 over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2 x 200 mL), cover washed once with water (100 mL) and then air-dried on the filter for 1.5 hours. The product consisted of a crystalline, light brown powder (58.1 g, 83% yield). About 0.7% ether was the only appreciable impurity observed by 1HNMR.. 1H NMR (DMSO-d6) 8 7.20. (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56 (d, 1H), 13.95 (br s, 20 1H). The following Example 13 illustrates an alternative preparation of 3-bromo-l-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-bromo-N-[4-cmoro-2-memyl-6-[[(l-methylethy)amino]carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide and 3-bromo-7Y-[4-chloro-2-methyl-6-25 [(memylammo)cmbonyl]phenyl]-l-(3-chloro-2-pyridmyl)-lH-pyrazole-5-carboxamide, by further steps illustrated in Examples 10 and 11. EXAMPLE 13 Preparation" of 3 -Bromo-1 -(3-chloro-2-pvridin VI)-1H-pyrazole-5-carboxvlic acid Step Al: Preparation of Ethyl 3-bromo-1 -(3-chloro-2-pyridin.yl)~4,5-dihydro- 30 1H-pyrazole-5-carboxylate (alternatively named ethyl l-(3-chloro- 2-pyridmyl)-3-bromo-2-pyrazoline-5-carboxylate) using phosphorus oxybromide A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (400 mL), ethyl 2-(3-chloro-2- 35 pyiidinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83 °C over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The 5 concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was 10 transfeired to a separatory funnel. The brown organic layer (400 mL) was separated and i then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the 15 filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile. lE NMR (DMSO-d6) 8 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H). 20 Step A2: Preparation of Ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-4,5-dihydro- lH-pyrazole-5-carboxylate using phosphorus pentabromide A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux | condenser, and nitrogen inlet was charged with acetonitrile (330 mL), ethyl 2-(3-chloro-2- pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (52.0 g, 25 0.193 mol), and phosphorus pentabromide (41.0 g, 0.0952 mol). The orange slurry was heated to reflux at 84 °C over a period of 20 minutes. The resulting brick-red mixture was held at reflux for 90 minutes, at which time- a dense tan crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (220 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer 30 was charged with sodium bicarbonate (40 g, 0.48 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting, two-phase mixture was stirred vigorously for 10 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 10 minutes. The mixture was treated with Celite® 545 diatomaceous 35 filter aid (5 g) and then filtered to remove a purple, tarry substance. The filter cake was washed with dichloromethane (50 inL). The filtrate was transferred to a separatory funnel. The purple-red organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.2 g). The slurry was stirred WO 03/015518 PCT/US02/256J3 47 magnetically for 40 minutes. The slurry was filtered to remove the magnesium sulfate and charcoal. The filtrate was concentrated on a rotary evaporator. The product consisted of a dark amber oil (61.2 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H. NMR was 0.7% acetonitrile. 5 1HNMR (DMSO-d6) 5 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, IH), 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d,1H), 8.12 (d, 1H). Step B: Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyiidinyl)-1H-pyrazole- 5-carboxy.late (alternatively named ethyl l-(3-chloro-2-pyridinyl)- 3-bromopyrazole-5-carboxylate) 10 A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-4,5-dihyadro-1H-pyrazoIe-5-carboxylate (i.e. the product of Steps Al and A2) (40.2 g, 0.121 mol), acetonitrile (300 mL) and sulfuric acid (98%, 13.0 mL, 0.245 mol). The mixture self-heated from 22 to 36 °C upon adding the sulfuric acid. After being stirred for several 15 minutes, the mixture was treated with potassium persulfate.(48.0 g, 0.178 mol). The slmxy was heated to reflux at 84 °C for 2 hours. The resulting orange slurry while still warm (50-65 °C) was filtered to remove a white precipitate. The filter cake was washed with acetonitrile (2 x 50 mL). The filtrate was concentrated to about 200 mL on a rotary evaporator. A second 1-L four-necked flask equipped with a mechanical stirrer was charged 20 with water (400 mL). The concentrated reaction mass was added to the water over a period of about 5 minutes. The product was isolated via filtration, washed sequentially with aqueous acetonitrile (20%, 100 mL) and water (75 mL), and was then air-dried on the filter for 1 hour. The product consisted of a crystalline, orange powder (36.6 g, 90% yield). The only appreciable impurities observed by !R NMR were about 1% of an unknown and 0.5% 25 acetonitrile. 1HNMR (DMSO-d6) 5 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72 (dd, 1H), 8.39 (d,1H), 8.59 (d, IH). Step C: Preparation of 3-Bromo-l-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternatively named l-(3-chloro~2-pyridinyl)-3-bromopyrazole- 30 5-carboxylic acid) A 300-mL four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-lH"-pyrazole-5-carboxylate (i.e: the product of Step B).(98.5% pure, 25.0 g, 0.0756 mol), methanol (75 mL), water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Upon adding 35 the sodium hydroxide the mixture self-heated from 29 to 34 °C and the starting material began to dissolve. After being stirred for 90 minutes under ambient conditions, all of the starting material had dissolved. The resulting dark orange solution was concentrated to . WO 03/015518 PCT/US02/25613 48 about 90 mL on a rotary evaporator. The concentrated reaction mixture was then diluted with water (160 mL). The aqueous solution was extracted with ether (100 mL). Then the aqueous layer was transferred to a 500-mL Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated drop-wise with concentrated hydrochloric acid (8.50 g, 5 0.0839 mol) over a period of about 10 minutes. The product was isolated via filtration, res lurried with water (2 x 40 mL), cover washed once with"water (25 mL), and then air-dried on the filter for 2 hours. The product consisted of a crystalline, tan powder (20.9 g, 91% yield). The only appreciable impurities observed by 1H NMR were about 0.8% of an unknown and 0.7% ether. 10 lH NMR {DMSO-d6) 5 7.25 (s,1H), 13.95 (br s, 1H), 8.56 (d,1IH), 8.25 (d, 1H), 7.68 (dd, 1H). The following Example 14 illustrates an alternative preparation of ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-4,5-dihydro-lH-pyrazole-5-cai-boxylate, which can be used to prepare, for example, ethyl 3-bromo-l-(3-chloro-2-pyxidin.yl)-1H-pyrazole-5-carboxylate (i.e. product 15 of Example 13, Step B). EXAMPLE 14 Preparation of Ethyl 3-bromo- l-(3-chloro-2-p3yridiny1)-4,5-dihydro- lH-pyrazole-5-carboxylate from ethyl 3-chloro-l-(3-chloro-2-pyridinyl)-45-dih.ydro-1H-pyrazole-5- carbox37late using hydrogen bromide 20 Hydrogen bromide was passed through a solution of ethyl 3-chloro-l-(3-cbloro-2- pyridinyl)-4,5-dihydro-lH-pyrazole-5-caiboxylate (i.e. product of Example 12, Step B) (8.45 g, 29.3■ mmol) in dibromomethane (85 mL). After 90 minutes the gas flow was terminated, and the reaction mixture was washed with aqueous sodium bicarbonate solution (100 mL). The organic phase was dried and evaporated under reduced pressure to give the 25 title product as an oil (9.7 g, 99% yield), which crystallized on standing. 1HfNMR (CDC13) 5 1.19 (t, 3H), 3.24 (1/2 of AB in ABX pattern, J = 9.3, 17.3 Hz, IH), 3.44 (1/2 of AB in ABX pattern, J= 11.7, 17.3 Hz, IH), 4.1S (q, 2H), 5.25 (X of ABX, IH, J = 9.3, 11.9 Hz), 6.85 (dd, J- 4.7, 7.7 Hz, IH), 7.65 (dd, J= 1.6, 7.8 Hz, IH), 8.07 (dd, /= 1.6,4.8 Hz, IH). " 30 The following Example 15 illustrates the preparation of ethyl l-(3-chloxo-2-pyridinyl)- 4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate5 which can be used to prepare ethyl 3-bromo-l-(3-chloro-2-pyxidiriyl)-4,5"-dihydro-lHpyrazole-5-carboxylate by procedures similar to that described in Example 14. WO 03/0155] 8 PCT/US02/25613 49 EXAMPLE 15 Preparation of ethyl 1 -(3 -chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)snlfonyl]oxy]-1H-pyrazole-5-cai"boxylate Triethylamine (3.75 g, 37.1 mmol.) was added dropwise to a mixture of ethyl 2-(3-5 chloro-2-pyiidinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (10.0 g, 37.1 mmol) and ,p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0 °C Further portions of ;p-tomenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm, to room temperature and was stirred overnight. The mixture was then 10 diluted with dichloromethane (200 mL) and washed with water (3 x 70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100 °C. TR (nujol) v 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 15 868, 845 cm4. 1HNMR (CDC13) 8 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (1/2 of AB in ABX pattern, /= 17.3, 9 Hz, 1H), 3.33 (1/2 of AB in ABX pattern, J"= 17.5,11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (X of ABX, J= 9, U.S Hz, 1H), 6.79 (dd, J= 4.6, 7.7 Hz, 1H), 7.36 (d, J= 8.4 Hz, 2H), 7.56 (dd, /= 1.6, 7.8 Hz, 1H), 7.95 (d, J= 8.4 Hz, 2H), 8.01 (dd, /= 1.4,4.6 Hz, 1H). 20 EXAMPLE 16 Preparation of N-[4-chloro-2-metnvl-6-r(methylammo)carbonyl]phenyl]-l-(3-chloro-2-p yridinyl)-3 -(2.2.2-trifluoro ethoxvV l.ff-pvrazole-5-carboxamide Step A: Preparation of Ethyl l-(3-chloro-2-pyridinyl)-2,3-dihydi-o-3-oxo-lH pyrazole-5-carboxylate 25 . To a suspension of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-p}"razolidinecai",boxylate (i.e. product of Example 12, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200 mL) was added sulfuric acid (20 g, 200 mmol) in one portion. The reaction mixture thinned to form a pale green, nearly clear solution before thickening again to form a pale yellow suspension. Potassium persulfate (33 g, 120 mmol) was added in one portion, and then the 30 " reaction mixture was heated at gentle reflux for 3.5 hours. After cooling using an ice bath, a precipitate of white solid was removed by filtration and discarded. The filtrate was diluted with water (400 mL) and then extracted three times with ethyl ether (700 mL. total). Concentration of the combined ether extracts to a reduced volume (75 mL) caused precipitation of an off-white solid (3.75 g), which was collected by filtration. The ether 35 mother liquor was further concentrated to yield a second crop of an off-white precipitate (4.2 g), which was also collected by filtration. An off-white solid also precipitated from the WO 03/015518 PCT/US02/25613 50 aqueous phase; this solid (4.5 g) was collected by filtration to provide a combined total of 12.45 g of the title compound. 1HNMR (DMSO-d6) 5 L06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t, 1H), 8.19 (d, 1H), 8.5 (d,lH),l0.6(s,lH). 5 StepB: Preparation of Ethyl l-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)- 1H-pyrazole-5-carboxylate To a suspension of ethyl l-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-caiboxylate (i.e. product of Step A) (0.8 g, 3 rnmol) stirred in dry acetonitrile (15 mL) at -5 °C was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 10 15 minutes at 20 °C. The stirred suspension was then cooled to 5 °C, and 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (0.8 g; 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated to reflux, at which time thin layer chromatography showed the reaction to be complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl ether. The ether extract was dried 15 over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a pale yellow oil. lHNMR (CDC13) 5 1.21 (t, 3H), 4.20 (q, 2H), 4.63 (q, 2H), 6.53 (s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H). Step C: Preparation of l-(3-Chloro-2-pyiidinyl)-3-(2,2,2-trifluoroerhoxy)-- 20 liy-pyrazole-5-carboxylic acid To a stirred solution of ethyl l-(3-chloro-2-pyridinyl)-3-(2,2,2-trifruoroethoxy)-1H-pyrazoie-5-carboxylate (i.e. product of Step B) (0.92 g, 2.8 mmol) in methanol (15 mL) was added water (5 mL), which caused the reaction mixture to become cloudy. An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) was added dropwise, and the reaction 25 mixtm-e was stiixed at room temperature for 30 minutes, during which time the reaction mixture became again, clear. Water (20 mL) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 using concentrated hydrochloric acid and then extracted with ethyl acetate (50 mL). The ethyl acetate extract, which was washed with water (20 mL) and brine (20- mL), dried over 30 magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0.8 g). 1HNMR (DMSO-d6) 5 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d, 1H), S.55 (d, 1H), 13.7 (bs, 1H). Step D: Preparation of 6-CMoro-8-methy 2H-3,l-benzoxazme-2,4(1Hf)-dione 35 To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 6, Step A) (97 g, 520 mmol) stirred in dry dioxane (750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise. The reaction mixture WO 03/015518 PCT/TJS02/25613 51 exothermically warmed slowly to 42 °C, and the solid almost completely dissolved before a thick suspension formed again. After the suspension was stirred at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether, and dried to yield the title"product compound, obtained as a white solid (98 g). 5 1HNMR (DMSO-d6) 5 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H), 11.2 (s, 1H). Step E: Preparation of 6-Chloro-2-[l-(3-chloro-2-pyi-idinyl)-3-(2,2,2-trifluoroethoxy)- liy-pyrazol-5-yl]-8-methyl-4H-3,l-benzoxazin-4-one To a suspension of l-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 gs 24 mmol) stirred in dichloromethane 10 (100 mL) was added N,N-dimethylforaamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added drop wise over a period of 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The isolated acid chloride was dissolved in dry acetonitrile (10 mL) and added to a suspension of 6-chloro-8~methyl-2/T-3,l-benzoxazine-2,4(lH)-dione (i.e. product of Step D) (4.9 g, 23 mmol) stirred in dry 15 acetonitrile (14 mL). Pyridine (10 mL) was added, and the solution heated at reflux 6 hours. After cooling using an ice bath, a precipitate of white solid (9.15 g) was collected. The 1H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-chloro-8-memyl-2H-3l-benzoxazme-2,4(lH)-dione starting material A small portion of the collected precipitate was recrystallized from acetonitrile to yield the 20 pure title product melting at 178—180 °C. !H NMR (DMSO-d6) 81.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7 (t, 1H), 7.75 (s, Iff),.7.9 (s, Iff), 8.3 (d, 1H), S.6 (d, Iff). Step F: Preparation of iVL[4-clnoro-2-memyl-6-[(memylainino)carbonyl]phenyl]- l-(3-chloro-2-pyridinyl)-3-(2J2,2~trifluoroethoxy)1H-pyra2ole-25 5-carboxamide To a suspension of the 6-chloro-2-[l-(3-cMoro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)--1H-pyrazol-5-yl]-8-methyl-4H-3,l-benzoxazhi-4-one (i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) in tetrah-ahydrofuran (15 mL), memylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 30 45 minutes. Thin layer chromatography then showed the reaction to be complete. Ethyl ether (100 mL) was added, and the reaction mixture was stirred for 2 hours while a precipitate formed. The precipitate was collected by filtration and then recrystallized "from acetonitrile to yield a white solid (0.82 g). A second crop of white solid (0.35 g) precipitated from the acetonitrile mother liquor and was collected by filtration. The initial 35 emer/tetrahydrofuran mother liquor was concentrated to dryness, and the residual solid was recrystallized from acetonitrile to yield a third crop of white solid (0.95 g). The three crops WO 03/015518 PCT/US02/25613 52 were combined, totaling 2.12 g (after drying) of the title compound, a compound of the present invention, isolated as a white solid, melting at 195-197 °C. • 1HNMR (CDC13) 5 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.S (d, IH), 8,45 (d, 1H), 10.0 (s, IH). 5 The Mowing Example 17 illustrates an alternative preparation of l-(3-cbloro-2- pyridinyl)-3-(tiifluoromethyl)-lH-pyrazole-5-car-boxylic acid, which can be used to prepare, for example, l-(3-chloro-2-pyridinyl)-IV-[2-methy1-6-[[(1-methylethy1)amino ]carbony phenyl]-3-(hifluoromemyl)-li//-pyrazole-5-carboxamide3 by further steps illustrated in Examples 4. , 10 EXAMPLE 17 Preparation of l-G-chloro-2-i>vridinvlV3-ftLifluoromethvlVlff-pvi-azole-S-carboxvlic acid Step A: Preparation of 3~chloro-2(l^)-pyridinone (2,2,2-trifiuoro- l-mefnyletriylidene)hydrazone ^__ 1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to 3-chloro-2(lif)-pyridinone 15 hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25 °C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl acetate (100 rnL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) 20 gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5 °C (after ciystallization from ethyl acetate/hexanes). IR (nujol) v 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196, 1158, 1100, 1032, 992, 800 cmr1. iHNMR^DC^) 5 2.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-S.32 (m, 2H). 25 MS m/z 237 (M+). Step B: Preparation of ethyl hydrogen ethanedioate (3-chloro- 2-p5Tidinyl)(2,2,2-tiifluoro-l"methylethyhdeGe)hydra2ide (alternatively named ethyl hydrogen ethanedioate (3-chloro-2-pyridinyl)(2,2,2-trifluoro- l-me&5dethylidene)hydrazine) 30 Triethylamine (20.81 g, 0.206 mol) was added to 3-chloro-2(lfl>-pyridiiione (2,2,2- trifiuoro-l-mernylethylidene)liydrazone (i.e. the product of Step A) (32.63 g, 0.137 mol) in dichloromerhane (68 mL) at 0 °C. Ethyl chlorooxoacetate (18.75 g, 0.137 mol) in dicHoromethane (69 mL) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to 25 °C over about 2 hours. The mixture was cooled to 0 CC and a further 35 portion of ethyl chlorooxoacetate (3.75 g, 27.47 mmol) in dicHoromethane (14 mL) was added dropwise. After about an additional 1 hour, the mixture was diluted with dicHoromethane (about 450 mL), and the mixture was washed with water (2 x 150 mL). WO 03/015518 PCT/US02/25613 53 The organic layer was dried and evaporated. Chromatography on silica gel (eluted with 1:1 ethyl acetate-hexanes) gave the product as a solid (42.06 g, 90% yield), m.p. 73.0-73.5 °C (after crystallization from ethyl acetate/hexanes). IR(nujol) v 1751, 1720, 1664,1572,1417,1361, 1330, 1202, 1214,1134,1137,1110, 1004, 5 1043, 1013, 942, 807, S36 cm"1. 1HNMR (DMSCWg, 115 °C) 1.19 (t, 3H), 1.72 (brs, 3H), 4.25 (q, 2H), 7.65 (dd, /= S.3, 4.7 Hz, 1H), 8.20 (dd, J= 7.6, 1.5 Hz, 1H), 8.55 (d, /= 3.6 Hz, 1H). MSm/z337(M+). StepC: Prepai-ation of ethyl l-(3-chlorO"2-pyiidinyl)-4,5-dihydro-5-hydroxy- 10 3-(nifruoromethyl)- lH-pyrazole-5-carboxylate Ethyl hydrogen ethanedioate (3-chloro-2-pyridinyl)(2,2,2-tiifluoro-l-methyl-ethylidene)hydrazide (i.e. the product of Step B) (5 g, 14.8 rnrnol) in dimethyl sulfoxide (25mL) was added to tetrabutylarnmonium fluoride hydrate (10 g) in dimethyl sulfoxide (25 mL) over 8 hours. When the addition was complete, the mixture was poured into acetic 15 acid (3.25 g) in water (25 mL). After stirring at 25 °C overnight, the rnixture was then extracted with toluene (4 x 25 mL), and the combined toluene extracts were washed with water (50 mL), dried and evaporated to give a solid. Chromatography on silica gel (eluted with 1:2 ethyl acetate-hexanes) gave the product as a solid (2.91 g, 50% yield, containing about 5% of 3-chloro-2(1H)-pyaidrnone (2,2,2-trifiuoro-l-methylethylidene)hydrazone), 20 m.p. 78-78.5 °C (after recrystallization from ethyl acetate/hexanes). IR (nujol) v 3403, 1726, 1618, 1582, 1407, 1320, 1293, 1260,1217, 1187,1150, 1122, 1100, -1067, 1013,873,829 cm-1. 1HNMR (CDC13) 5 1.19 (s, 3H), 3.20 (1/2 of ABZ pattern, J = 18 Hz, 1H), 3.42 (1/2 of ABZ partem, J= 18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, /= 7.9,4.9 Hz, IB), 7.74 (dd, /= 7.7, 25 1.5 Hz, 1H), 8.03 (dd, J= 4.7, 1.5 Hz, 1H). MS m/z 319 (M+). StepD: Preparation of ethyl l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)- 1H;pyrazole-5-cafboxylate Sulfuric acid (concentrated, 2 drops) was added to ethyl l-(3-chloro-2-pyridinyl)- 30 4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-lH-pvrazole-5-carboxylate (i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) and the mixture was warmed to 65 °C for about 1 hour. The mixture was allowed to cool to 25 °C and most of the acetic acid was removed under" reduced pressure. The mixture was "partitioned between saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (100 mL). The aqueous layer was 35 further extracted with ethyl acetate (100 mL), The combined organic extracts were dried and evaporated to give the product as an oil (0.66 g, 77% yield). WO 03/015518 PCT/US02/256I3 IR. (neat) v 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277, 1236, 1135, 1082, 1031, 973, 842, 802 cm-1. 1HNMR (CDC13) 5 1.23 (t, 3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd, J= 8.1, 4.7 Hz, 1H), 7.94 (dd, J= 6.6,2 Hz, 1H), 8.53 (dd, J= 4.7,1.5 Hz, 1H). 5 ,MSm/z319(M+). Step E: Preparation of l-(3-chloro-2--pyridmyl)-3-(tiifluoromediyl)"1H-pyrazole- 5-carboxylic acid Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl l-(3-chloro-2-pyridinyl)--3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of 10 Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was" acidified with concentrated hydrochloric acid and was extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried and evaporated to give the product as a solid (0.53 g_, 93% 15 yield), m.p. 178-179 °C (after crystallization from hexanes-ethyl acetate). IR (nujol) v 1711, 15S6, 1565, 1550, 1440, 1425, 1292, 1247, 1219, 1170, 1135,1087, 1059, 1031,972,843,816 cm-1. iHNMR (DMSOd6) 5 7.61 (s, IK), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H). . Examples 18 and 19 illustrate alternatives to reaction conditions described in Example 20 10, Step E and Example 8, Step E, respectively. EXAMPLE 18 Preparation of 2-[3-bromo-l 4H-3, l-benzoxazin-4-one Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile 25 (10 mL), and the mixture was cooled to -5 °C. A solution of 3-bromo-l-(3-chloro-2-pyridmyl)-lH-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 10, Step D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at -5 to" 0 °C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 30 2-amino--3-methyl-5-chlorobenzoic acid (i.e. the product of Example 6 Step A) (1/86 g, 10 mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at -5 to 0 °C, and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of -5 to 0 °C. The reaction mixture was stirred 35 15 minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3*3 WO 03/015518 PCT/US02/25613 55 mL), then with acetonitrile (2 * 3 mL), and dried under nitrogen to afford the title product as a light yellow powder. 4.07 g (90.2% crude yield), melting at 203-205 °C. HPLC of the • product using a Zorbax© RX-C8 chromatography column (4.6 mm x 25 cm, eluent 25-95% acetonitrile/ pH 3 water) showed a major peak corresponding to the title compound and 5 having 95.7% of total chromatogram peak area. 1H NMR (DMSO-d6) 5 1.72 (s, 3H) 7.52 (s, 1H), 7.72-7.78 (m, 2H), 7.S8 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H). EXAMPLE 19 Preparation of 6-cMoro-2-[3-chloro-l-(3-cmoro-2-pyridmyl)-lif-pyrazol-5-yl]-8-methyl- 10 4,H-3,l-benzoxazrn-4-one Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetomtrile (10 mL), and the mixture was cooled to -5°C. A solution of 3-chioro-l-(3-chloro-2-pyridinyl)-lH-pyra2ole-5-carboxylic acid (i.e. the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) 15 was added dropwise over 5 minutes at -5 to 0 °C. A sluny formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-arnino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 6, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at -5 to 0 °C. The mixture was stirred 15 minutes at -5 to 0 °C, 20 and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at -5 to 0 °C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3x3 rnL), then with 25 acetonitrile (2 x 3 rnL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201 °C. HPLC of the product using a Zorbax® RX-CS chromatography column (4.6 mm x 25 cm, eluent 25-95% acetonitrile/ pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area. 30 lH NMR (DMSO-d6) 5 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H), 7.87 (m, 1H), 8.37 (dd, llHi,S.62(dd, 1H). By the procedures described herein together with methods known in the art, the following compounds of Table 1 can be prepared. The following abbreviations are used in the Tables which follow: rmeans tertiary, s means secondary, n means normal, i means iso, 35 Me means methyl, Et means ethyl, Pr means propyl, z"-Pr means isopropyl, and Bu means buty1. PCT/US02/25613 WO 03/015518 PCT/US02/25613 n- 60 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613. WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/2513 67 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 vru uj/ujrois PCT/US02/25613 PCT/US02/25613 WO 03/015518 PCT/US02/25613 83 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT7US02/25613 WO 03/015518 PCT/US02/25613 WO 03/0.15518 PCT/US02/25613 Formulation/Utility Compounds of this mvertfion will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient mode of apphcation and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, can be thickened into gels. Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Spray able formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation. The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges that add up to 10.0 percent by weight. Weight Percent Active Ingredient Diluent Surfactant Water-Dispersible and Water-soluble 5-90 0-94 1-15 Granules, Tablets and Powders. Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (including Emulsifiable Concentrates) Dusts 1-25 70-99 0-5 Granules and Pellets 0.01-99 5-99.99 0-15 High Strength Compositions 90-99- 0-10 0-2 Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Caniers, 2nd Ed., Borland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon "s Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity. Surfactants include, for example, polyethoxylated alcohols, polyethoxylated "Jkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl WO 03/015518 PCT/US02/25613 90 sulfates, alkylbenzene sulfonates, organosilicones,N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropyleneblock copolymers. Solid diluents include, for example, clays such as bentonite, montinorulonite, attapulgite and kaolin, starch, sugar, silica, talc, 5 diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water,N,N-dimethylformamide, dimethyl sulfoxide, iV-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as 10 cyclohexanone, 2-heptanbne, isophorone and 4-hydroxy-4~methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuiyl alcohol. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for 15 example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Peny"s Chemical Engineer"s Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and PCT Publication WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. 20 Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566. For further information regarding the art of formulation, see T. S. Woods, "The 25 Formulator"s Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistiyand Biqscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 andExamples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 30 andExamples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166,167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; andHance et al, Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989, In the following Examples, all percentages are by weight and all formulations are 35 prepared in conventional ways. Compound numbers refer to compounds in Index Table A. WO 03/015518 PCT/US02/25613 91 10 Compound 214 " 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example C Extruded Pellet 15 Compound 214 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alicylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. 20 Example D Emulsifiable Concentrate Compound 214 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% 25 , isophorone 70.0%. Example E Granule Compound 214 0.5% cellulose 2.5% 30 lactose 4.0%. comrneal " 93.0%. Compounds of this invention are characterized by favorable metabolic and/or soil residual patterns and exhibit activity controlling a spectrum of agronomic and non-agronomic invertebrate pests. (In the context of this disclosure "invertebrate pest control" 35 means inhibition of invertebrate pest development (including mortality) that causes significant reduction in feeding or other injury or damage caused by the pest; related WO 03/015518 PCT/US02/25613 92 expressions are defined analogously.) As referred to in this disclosure, the term "invertebrate pest" includes arthropods, gastropods and nematodes of economic importance as pests. The term, "arthropod" includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans. The term "gastropod" includes snails, slugs and other 5 Stylommatophora. The term "nematode" includes all of the helminths, such as: roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes (Tematoda), Acanthocephala, and tapeworms (Cestoda), Those skilled in the art will recognize that not all compounds are equally effective against all pests. Compounds of this invention display activity against economically important agronomic, forest, greenhouse, nursery, 10 ornamentals, food and fiber, public and animal health, domestic and commercial structure, household, and stored product pests. These include larvae of the order Lepidoptera, such as armyworms, cutworms, loopers, and heliothines in the family Noctuidae (e.g., fall armyworm (Spodopterafugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hiibner), black cutworm (Agrotis ipsilon Hufnagel), cabbage looper (Trichqplusia ni 15 Hiibner), tobacco budworm (Heliothis virescens Fabricius)); borers, casebearers, webworms, coneworms, cabbageworms and slceletonizers from the family Pyrahdae (e.g., European com borer (Ostrinia mibilalis Hiibner), navel orangeworm (Amyelois transitella Walker), corn root webworm (Crambus caliginosellus Clemens), sod webworm (Herpetogramma licarsisalis Walker)); leafrollers, budworms, seed worms, and fruit worms in the family 20 Tortricidae (e.g., codling moth (Cydia pomonella Linnaeus), grape berry moth (Endopiza viteana Clemens), oriental fruit moth (Grapholita molesta Busck)); and many other economically important lepidoptera (e.g., diamondback moth (Plutella xylostella Linnaeus), pink bollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantria dispar Linnaeus)); nymphs and adults of the order Blattodea including cockroaches from the 25 families Blattellidae and Blattidae (e.g., oriental cockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatella asahinai Mizukubo), German cockroach (Blattella germcmica Linnaeus), brownbanded cockroach (Supella longipalpa Fabricius), American cockroach (Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeira cockroach (Leucophaea maderae Fabricius)); foliar feeding larvae and adults of the 30 . order Coleoptera including weevils from the families Anthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptrus oryzophilus Kuschel), granary weevil (Sitophilus granarius Linnaeus), rice weevil (Sitophilus oiyzae Linnaeus)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafminers in the family Chrysomelidae (e.g., Colorado potato 35 beetle (Leptinotarsa decemlineata Say), western corn rootworm (Diabrotica virgifera virgiferaLeConte)); chafers and other beetles from the family Scaribaeidae (e.g., Japanese beetle (Popilliajaponica Newman) and European chafer (Rhiizofroguns majatis Razoumowsky)); carpet beetles from the family Dermestidae: wireworms from the family Elateridae; bark beetles from the family Scolytidae and flour beetles from the family Tenebrionidae. In addition it includes: adults and larvae of the order Dermaptera including earwigs from the family Forficulidae (e.g., European earwig (Forficula auricularia Linnaeus), black earwig {Chelisoches mono Fabricius)); adults and nymphs of the orders 5 Hemiptera and Homoptera such as, plant bugs from the family Miridae, cicadas from the family Cicadidae, leafhoppers (e.g. Empoasca spp.), from the family Cicadellidae, . planthoppers from the families Fulgoroidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae. whiteflies from the family Aleyrodidae, aphids from the family Aphididae, phylloxera from the family Phylloxeridae, mealybugs 10 from the family Pseudococcidae, scales from the families Coccidae, Diaspididae and Margarodidae, lace bugs from the family Tfngidae, stink bugs from the family Pentatomidae, cinch bugs (e.g., Blissus spp.) and other seed bugs from the family Lygaeidae, spitflebugs from the family Cercopidae squash bugs from the family Coreidae, and red bugs and cotton stainers from the family Pyrrhocoridae. Also included are adults and larvae of the order 15 Acari (mites) such as spider mites and red mites in the family Tetranychidae (e.g., European red mite {Panonychus ulmi Koch), two spotted spider mite {Tetranychus urticae Koch), McDaniel mite {Tetranychus mcdanieli McGregor)), flat mites in the family Tenuipalpidae (e.g., citrus flat mite {Brevipalpus lewisi McGregor)), rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, 20 i.e. dust mites in the family Epiderrnoptidae, follicle mites in the family Demodicidae, grain mites in the family Glycyphagidae, ticks in the order Ixodidae (e.g., deer tick {Ixodes scapularis Say), Australian paralysis tick {Ixodes holocyclus Neumann), American dog tick {Dermacentor variabilis Say), lone star tick {Amblyomma amencanum Linnaeus) and scab and itch mites in the families Psoroptidae, Pyemotidae, and Sarcoptidae; adults and 25 irnmatures of the order Orthoptera including grasshoppers, locusts and crickets (e.g., migratory grasshoppers (e.g., Melanophis sanguinipes Fabricius, M. differentialis Thomas), American grasshoppers (e.g., Schistocerca americana Drury), desert locust {Schistocerca gregaria Forskal), migratory locust {Locusta migratoria Linnaeus), house cricket {Acketa domesticus Linnaeus), mole crickets {Gryllotalpa spp.)); adults and irnmatures of the order 30 Diptera including leafminers, midges, fruit flies (Tephritidae), frit flies (e.g., Oscinellafrit Linnaeus), soil maggots, house flies (e.g., Musca domestica Linnaeus), lesser house flies (e.g., Fannia canicularis Linnaeus, F.femoralis Stein), stable flies (e.g., Stomoxys calcitrans Linnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp., Phonnia spp.), and other muscoid fly pests, horse flies (e.g., Tabanus spp.), botflies (e.g., Gastrophilus spp., Oestrus 35 spp.), cattle grubs (e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g., Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g., Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimalium spp,, Simulium spp.), biting midges, sand flies, sciarids, and other Nematocera; adults and irnmatures of the order WO 03/015518 PCT/US02/25613 94 Thysanoptera including onion thrips (Thrips tabaci Lindeman) and other foliar feeding thrips; insect pests of the order Hymenoptera including ants (e.g., red carpenter ant (Camponotus fermgineus Fabricius), black carpenter ant (Camponotus pennsylvaniciis De Geer), Pharaoh ant (Monomoriwnpharaonis Linnaeus), little fire ant (Wasmannia 5 auropunctata Roger), fire ant {Solenopsis geminata Fabricius), red imported fire ant (Solenopsis invicta Buren), Argentine ant (Jridomyrmex humilis Mayr), crazy ant (Paratrechina longicornis Latreille), pavement ant (Tetramorium caespitwn Linnaeus), cornfield ant (Lasius alienus Forster), odorous house ant (Tapinoma sessile Say)), bees (including carpenter bees), hornets, yellow jackets and wasps; insect pests of the order 10 Isoptera including the eastern subterranean termite {Reticulitermes flavipes Kollar), western subterranean termite {Reticulitermes hespems Banks), Formosan subterranean termite (Coptotermes formosanus Shiraki), West Indian drywood termite (Incisitermes immigrans Snyder) and other termites of economic importance; insect pests of the order Thysanura such as silverfish (Lepisma saccharina Linnaeus) and ftrebrat {Thermobia domestica Packard); 15 insect pests of the order Mallophaga and including the head louse (Pediculus humanns capitis De Geer), body louse (Pediculus humanus humanus Linnaeus), chicken body louse (Menacanthus stramineus Nitszch), dog biting louse (Trichodectes canis De Geer), fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicola ovis Schrank), short-nosed cattle louse (Haematopinus ewystemus Nitzsch), long-nosed cattle louse {Linognathus vituli 20 Linnaeus) and other sucking and chewing parasitic lice that attack man and animals; insect pests of the order Siphonoptera including the oriental rat flea (Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felis Bouche), dog flea (Ctenocephalides canis Curtis), hen flea {Ceratophyllus gallinae Schrank), sticktight flea (Echidnophaga gallinacea Westwood), human flea (Pidex irritans Linnaeus) and other fleas afflicting mammals and 25 birds. Additional arthropod pests covered include; spiders in the order Araneae such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Lafrodectus mactans Fabricius), and centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleopti-ata Linnaeus). Activity also includes members of the Classes Nematoda, Cestoda, Trematoda, and Acanthocephala including economically 30 important members of the orders Strongylida, Ascaridida, Oxyurida, Rhabditida, Spirurida, and Enoplida such as but not limited to economically important agricultural pests (i.e. root knot nematodes in the genus Meloidogyne, lesion nematodes in the genus Pratylenchus, stubby root nematodes in the genus Trichodoms, etc.) and animal and human health pests (i.e. all economically important flukes, tapeworms, and roundworms, such as Strongylus 35 vulgaris in horses, Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilana immitis Leidy in dogs, Anoplocephalapeifoliata in horses, Fasciola hepatica Linnaeus in ruminants, etc.). WO 03/015518 PCT/US02/25613 95 Compounds of the invention show particularly high activity against pests in the order Lepidoptera (e.g., Alabama argillacea Hubner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo siippressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice 5 leaf roller), Crambus caligmosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydiapomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm), Earias vittella Fabricius (spotted bollworm), Helicoveipa armigera Hubner (American bollworm), Helicoveipa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogramma licarsisalis Walker (sod 10 webworm), Lobesia botrana Denis & Schiffennuller (grape berry moth), Pectinophora ■ gossypiella Saunders (pink bollworm), Phyllocnistis ciP"ella Stainton (citrus leafininer), Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diarnondback moth), Spodoptera exigua Hubner (beet armyworrn), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), 15 Spodoptera frugiperda J. E. Smith (fall armyworrn), Trichoplnsia ni Hubner (cabbage . looper) and Tula absohtta Meyrick (tomato leafininer)). Compounds of the invention also have commercially significant activity on members from the order Homoptera including: Acynhisiphonpisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphispomi 20 De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphonfragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kmdjumov/Mordvilko (Russian wheat aphid), Dysaphisplantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pnaii Geoffxoy (mealy plum aphid), Lipaphis eiysimi Kaltenbach (turnip 25 aphid), Metopolophium dhrhodum Walker (cereal aphid), Macrosipum euphorbiae Thomas (pqtato aphid), Myzuspersicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (corn leaf aphid), Rhopalosiphum padi Linnaeus (bird cherry-oat aphid), Schizaphis grammwn Rondani (greenbug), Sitobion avenae Fabricius (English 30 grain aphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid), and Toxoptera citiicida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii Bellows & Pexring (silverie&f whitefly), Dialeurodes citri Ashmead (citrus whitefly) a&d 35 Trialeurodes vaporariomm Westwood (greenhouse whitefly); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephoteitix nigropictus Stal (rice leafhopper), Nilapan>ata lugens Stal (brown planthopper). WO 03/015518 PCT/US02/25613 96 Peregrinns maidis Ashmead (com planthopper), Sogatellafurcifera Horvath (white-backed planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocybapomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Iceiyapurchasi Maskell (cottony cushion scale), 5 Ouadraspidiotuspemiciosus Comstock (San Jose scale); Planococcus citri Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsyllapyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmon psylla). These compounds also have activity on members from the order Hemiptera including: Acrostemum hilore Say (green stink bug), Anas a tristis De Geer (squash bug), Blissus leucoptems leucopterus Say (chinch. 10 bug), Coiythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-Schaffer (cotton stainer), Enchistus servus Say (brown stink bug), Euchishis variolarius Palisot de Beauvois (one-spotted stink bug), Graptdsthetus spp. (complex of seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezara viridula Linnaeus (southern 15 green stink bug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cotton fleahopper). Other insect orders controlled by compounds of the invention include Thysanoptera (e.g., Frankliniella occidentalis Pergande (western flower thrip), Scirthothrips citri Moulton (citrus thrip), , Sericothrips variabilis Beach (soybean thrip), and Thrips tabaci Lindeman (onion thrip); and 20 the order Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius). Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including insecticides, fungicides, nematocides, bactericides, 25 acaricides, growth regulators such as rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural utility. Thus compositions of the present invention can further comprise a biologically effective amount of at least one additional biologically 30 active compound or agent. Examples of such biologically active compounds or agents with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron. chlorpyrifos, chlorpyrifos -methyl, chromafenozide, clothianidin, cyflutmin, beta-cyfluthrin, cyhalothrin, 35 lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, o^afenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan. emamectin, endosulfan, esfenvalerate, ethiprole. fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fiuvalinate, flufenerim (UR-50701). flufenoxuron, fonophos. halofenozide, WO 03/015518 PCT/US02/25613 97 hexaflumuron, imidacloprid, indoxacarb. isofenphos, lufenuron, malathiott, metaldehyde, methamidophos. methidatbion, methomyl, methoprene. methoxychlor, monocrotoplios, methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl, paratbion, parathion-metbyl, permethrin, phorate. phosalone, phosmet, phosphamidon, pirimicarb, 5 profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos, tebufeaozide, teflubenzuron, teflutmin, terbufos, tetrachloi^inphos, tbiacloprid, tbiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichiorfon and tiflumuron; fungicides such as acibenzolar, azoxystrobin, benomyl, blasticidin-S, Bordeaux mixture (nibasic copper sulfate), bromuconazole, carpropamid, captafol, captan, 10- carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cyfmfenamid, cymoxanil, cyproconazole, cyprodinil, (^-3,5-dicbIoro-7y-(3-chloro-l-etiLyl-l-methyl-2-oxopropyl)-4-methylberrzamide (RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole, (!S)~3,5-dmyd^-o-5-memyl-2-(memyltMo)-5-pbenyl-3-(pbenylarrrino)-4i?-imidazol-4-one (RP 407213), dimethomorph, dimoxystrobin, dmiconazole, diniconazole-M, 15 dodine, edifeuphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorph, fentiri acetate, fentin hydroxide, fluazinam, fludioxonil, ffumetover (RPA 403397), flumorf/flumorlin (SYP-L190), fluoxastrobin (HEC 5725), fiuquinconazole, flusilazole, fhitolanil, flntriafol, folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658), hexaconazole, ipconazole, iprobenfos, 20 iprodione, isoprothiolane, kasugarnycin, lores oxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin (SSF-126), metrafenone (AC 375839), myclobutanil, neo-asozin (ferric methanearsonate), nicobifen • (B AS 510), orysastrobin, oxadixyl, penconazole, pencycnron, probenazole, prochloraz, propamocarb, propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU 6476), " ) 25 pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spnoxamine, stdfur, tebjiconazole, tetraconazole, thiabendazole, thifluzamide, thiopbanate-methyl, thiram, tiadinil, tiiadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin and vinclozolin; nematocides such, as aldicarb, oxamyl and fenarniphos; bactericides such as streptomycin; acaricides such as amitraz, cninomethionat, chlorobenzilate, cyhexatin, 30 dicofol, dienocblor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexyfhiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis including ssp. aizawai and kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi. A general reference for these agricultural protectants is The Pesticide Manual, 12th 35 Edition, C. D. S. Tomiin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2000. Preferred insecticides and acaricides for mixing with compounds of this invention include pyrethroids such as cypermethrin, cyhalothrin, cyfluthrin and beta-cyfiuthrin, WO 03/015518 PCT/US02/25613 98 esfenvalerate, fenvalerate and tialomethrin.; carbamates such as fenothicarfy methomyl, oxaniyl and thiodicarb; neonicotinoids such as clothianidin,. imidacloprid and thiacloprid, neuronal sodium channel blockers such as indoxacarb, insecticidal macrocyclic lactones such as spinosad, abamectin, avermectin and emamectin; y-ammobutyric acid (GAB A) 5 antagonists such as endosulfan, ethiprole and fipronil; insecticidal ureas such as flufenoxuron and trifiumuron, juvenile hormone mimics such as diofenolan and pyriproxyfen; pymetrozine; and amitraz. Preferred biological agents for mixing with compounds of this invention include Bacillus thuringiensis arid Bacillus thuringiensis delta endotoxin as well as naturally occurring and genetically modified viral insecticides including 10 members of the family Baculoviridae as well as entomophagous fungi. Most preferred mixtures include a mixture of a compound of this invention with cyhalothrin; a mixture of a compound of this invention with beta-cyfluthrin; a mixture of a compound of this invention with esfenvalerate; a mixture of a compound of this invention with methomyl; a mixture of a compound of this invention with imidacloprid; a mixture of a 15 compound of this invention with thiacloprid; a mixture of a compound of this invention with indoxacarb; a mixture of a compound of this invention with abamectin; a mixture of a compound of this invention with endosulfan; a mixture of a compound of this invention with ethiprole; a mixture of a compound of this invention with fipronil; a mixture of a compound of this invention with flufenoxuron; a mixture of a compound of this invention with 20 pyriproxyfen; a mixture of a compound of this invention with pymetrozine; a mixture of a compound of this invention with amitraz; a mixture of a compound of this invention with Bacillus thuringiensis and a mixture of a compound of this invention with. Bacillus thuringiensis delta endotoxin. " In certain instances, combinations with other invertebrate pest control compounds or 25 agents having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management. Thus, compositions of the present invention can further comprise an biologically effective amount of at least one additional invertebrate pest control compounds or agents having a similar spectrum of control but a different mode of action. Contacting a plant genetically modified to express a plant 30 protection compound (e.g., protein) or the locus of the plant with a biologically effective amount of a compound of invention can also provide a broader spectrum of plant protection and be advantageous for resistance management. Invertebrate pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the 35 compounds of this mvention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. Thus, the present invention further comprises a method for the control of foliar- and soil-inha"biting invertebrates and protection WO 03/015518 PCT/OS02/25613 99 of agronomic and/or nonagronomic crops, comprising contacting the invertebrates or their environment with a biologically effective amount of one or more of the compounds of the invention, or with a composition comprising at least one such compound or a composition comprising at least one such compound and an effective amount of at least one additional 5 biologically active compound or agent. A preferred method of contact is by spraying. Alternatively, a granular composition comprising a compound of the invention can be applied to the plant foliage or the soil. Compounds of this invention are effective in delivery through plant uptake by contacting the plant with a composition comprising a compound of this invention applied as a soil drench of a liquid formulation, a granular formulation to the 10 soil, a nursery box treatment or a dip of transplants. Other methods of contact include application of a compound or a composition of the invention by direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, Joggers, furnigants, aerosols, dusts and many others. The compounds of this invention can be incorporated into baits that are consumed by 15 the invertebrates or within devices such as traps and the like. Granules or baits comprising between 0.01-5% active ingredient, 0.05-10% moisture retaining agent(s) and 40-99% vegetable flour are effective in controlling soil insects at very low application rates, particularly at doses of active ingredient that are lethal by ingestion rather than by direct contact. 20 The compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil 25 concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butpxide often enhance compound efficacy. The rate of application required for effective control (i.e. "biologically effective amount") will depend on such factors as the species of invertebrate to be controlled, the pest"s life cycle, life stage, its size, location, time of year, host crop or animal, feeding 30 behavior, mating behavior, ambient moisture, temperature, and the like. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.0001 kg/hectare may be sufficient or as much as 8 kg/hectare may be required. For nonagronomic applications, effective use rates will range from about 1.0 to 50 mg/square meter but as little as 35 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required. One skilled in the art can easily determine the biologically effective amount necessary for the desired level of invertebrate pest control. WO 03/015518 PCT/US02/25613 100 The following Tests in the Biological Examples of the Invention demonstrate the efficacy of methods of the invention for protecting plants from specific arthropod pests. "Control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to these species. See Index Table A for compound descriptions. The following abbreviations are used in the Index Table which follows: t is tertiary, n is normal, i is iso, s is secondary, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; accordingly /-Pr is isopropyl, s-Bu is secondaiy butyl, etc. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. INDEX TABLE A RS R WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 102 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 107 WO 03/015518 PCT/US02/25613 108 WO 03/015518 PCT/US02/25613 WO 03/015518 PCTAJS02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 112 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 120 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 WO 03/015518 PCT/US02/25613 through a SUJ2 atomizer nozzle with 1/8 JJ custom body (Spraying Systems Co.) positioned 1.27 cm (015 inches) above the top of each test unit. All experimental compounds in this screen were sprayed at 50 ppm and replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 hour and then a black, screened cap 5 was placed on top. The test units were held for 6 days in a growth chamber at 25 °C and 70% relative, humidity. Plant feeding damage was then visually assessed. Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 5, 11, 18, 19, 24, 28, 30, 32, 33, 34, 37, 38, 39, 40, 45, 46, 47, 48, 56, 57, 58, 59, 63, 64, 75, 76, 77, 78, 79, 84, 85, 86, 87, 91, 93, 94, 95, 96, 97, 98, 99, 10 108, 113, 114, 116, 115, 117,118, 119, 120, 121,122, 123, 124, 125, 126, 127, 128, 129, 130, 133, 135, 136, 141, 142, 143, 144, 145, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 160, 161, 164, 165,166, 168, 169,170, 174,176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193,194,195, 196, 197,198,199, 200, 201,202, 207, 208, 209, 210,211, 212, 213, 214, 218,219,220, 221, 222,224, 229, 230, 15 231, 232, 233, 234, 236, 237,238, 244, 246, 247, 250, 257,258, 259, 267,268, 270, 271, 272, 273, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,287, 288, 289, 290, 291, 292, ■ 293,294, 295, 297, 298,299, 300, 301, 302, 305, 306, 307, 309, 313, 314,315, 316, 319, 320, 321, 322, 324, 325, 326,327, 328, 329, 330, 335, 336, 338, 339, 341, 344, 345, 346, 347, 348, 349, 351, 352, 356, 364, 365, 366,367, 370, 371, 372, 373, 374, 376,377, 384, 20 387, 388, 390, 391, 392, 393,394, 395, 396, 401, 402, 404, 405, 406, 407, 409,410, 411, 412, 413, 414, 415, 416, 417,418, 419,420, 421, 422, 423, 424, 426, 428, 429, 430, 431, 432, 433, 434, 446, 449,453,454, 456, 457, 458,459, 460,461, 462, 463, 468,469, 470, 471,472, 473, 474, 475, 476,477, 478,479,481,482, 483,484, 486, 487, 488,489, 494, 497, 499, 500, 501, 502, 505, 506, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 25 523, 524, 526, 527, 528, 529,530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 55^, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 611, 612, 613, 615, 616, 30 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639,"640, 641, 642, 643, 644, 645, 647, 648, 649, 650, 651, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668,-669, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702,703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 35 716, 717, 718, 719, 720, 721, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 759, 762, 763, 766, 767, 768, 769, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 787, 790, 791, 792, 793, 794, 795, 796, 797, 798, 801, WO 03/015518 PCT/US02/25613 129 804, 809, 810, 811, 812, 813, 814, 815, 816, 817, SIS, 820, 821, 822, 823, 824, 825, 826, 829, 830, 831, 832 and 833. TESTB For evaluating control of tobacco budworm (Heliothis vires cens) the test unit consisted 5 of a small open container with a 6-7 day old cotton plant inside. This was pre-infested with 8 2-day-old larvae on a piece of insect diet by use of a core sampler as described for Test A. Test compounds were formulated and sprayed at 50 ppm as described for Test A. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test A. 10 Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 8, 11, 18, 24, 28, 30, 32, 33, 34, 37, 39, 46, 47, 48, 53, 56, 57, 58, 59, 60, 74, 75, 76, 77, 78, 79, 80, 82, 84, 85, 86,87, 88, 91, 93, 94, 95, 96, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 141, 142, 143, 145, 147, 150, 151, 153, 154, 155, 156, 158, 160, 161, 164, 165, 166, 168, 169, 170, 171, 174, 176, 177, 15 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 189,190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 207, 208, 209, 210, 211, 212, 213, 214, 216, 218, 219, 220, 221, 222, 223, 224, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 244, 246, 247, 250, 257, 258, 267, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298„299, 300, 301, 20 302, 304, 305, 306, 307, 309, 313, 314, 315, 316, 319, 320, 321, 322, 324, 325, 326, 327, 328, 336, 338, 339, 341, 345, 346, 348, 353, 356, 357, 364, 366, 367, 370, 371, 372, 373, 374, 377, 381, 383, 384, 385, 387, 388, 390, 391, 392, 393, 394, 395, 397, 399, 401, 402, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 428, 429, 430, 431, 432, 433, 434, 444, 445, 446, 447, 449, 453, 454, 456, 457, 25 458, 459, 460, 461, 462, 468, 469, 470, 471, 472, 474, 473, 475, 476, 477, 478, 479, 481, 482, 483, 484, 486, 487, 488, 489, 494, 497, 499, 500, 501, 502, 506, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 53S, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, ■ 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 30 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 600, 601, 602, 603, 605, 608, 609, 611, 612, 613, 614, 615, 616, 619, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 649, 650, 651, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 35 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 716, 717, 718, 719, 720, 721, 724, 725, 726, 727, 728, 729, 730, WO 03/015518 PCT/US02/25613 130 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 742, 743, 745, 746, 747, 748, 749, 750, 751,752, 753, 754 and 755. TEST C For evaluating control of beet armyworm {Spodoptera exigua) the test unit consisted of 5 a small open container with a 4-5-day-old com (maize) plant inside. This was pre-infested with 10-15 1-day-old larvae on a piece of insect diet by use of a core sampler as described for Test A. Test compounds were formulated and sprayed at 50 ppm as described for Test A; The applications were replicated three times. After spraying, the test units were maintained in a 10 growth chamber and then visually rated as described for Test A. Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 5, 8,11, 18, 19, 24, 28, 30, 32, 33, 34, 37, 38, 39, 46,47, 48, 53, 56, 57, 58, 59, 60, 63, 64, 74, 75, 76, 77, 78, 79, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 96, 97, 98, 99, 101, 102, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 15 127, 128, 129, 130, 133, 135, 136, 137, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 160, 161, 164, 165, 166, 168, 169, 170, 174, 176, 177, 178, 179, 180, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 195, 196, 197, 198, 199, 201, 202, 207, 208, 209, 210, 211, 212, 214, 218, 219, 221, 224, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 244, 246, 247, 250, 257, 258, 267, 270, 271, 272, 273, 20 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 297, 298, 299, 300, 301, 302, 304, 305, 307, 309, 313, 314, 315, 316, 319, 320, 321, 322, 324, 325, 326, 327, 328, 330, 336, 338, 339, 341, 343, 344, 345, 346, 347, 348, 351, 352, 356, 364, 365, 366, 367, 370, 371, 372, 373, 374, 376, 377, 380, 384, 385, 387, 388, 389, 390, 391, 392, 393, 394, 395, 401, 402, 404, 405, 406, 407, 409, 410, 413, 25 414, 418, 420, 422, 423, 424, 428, 429, 430, 431, 432, 433, 434, 449, 453, 454, 456, 457, 458, 459, 460, 461, 462, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 481, 482, 483, 484, 486, 487, 488, 494, 497, 499, 500, 501, 502, 506, 512, 5.13, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 30 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 595, 596, 597, 598, 600, 601, 603, 605, 606, 607, 608, 609, 611, 612, 613, 614, 616, 619, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633; 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 650, 651, 655, 656, 657, 658, 35 659, 660, 661, 662, 663, 664, 665, 666, 667, 669, 671, 672, 673, 674, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 719, 720, WO 03/015518 PCT/US02/25613 131 721, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754 and 755. TESTD For evaluating control of green peach aphid (Myzus persicae) through contact and/or 5 systemic means, the test unit consisted of a small open container with a 12—15-day-old radish plant inside. This was pre-infested by placing on a leaf of the test plant 30-40 insects on a piece of leaf excised from a cultui"e plant (cut-leaf method). The larvae moved onto the test plant as the leaf piece desiccated. After pre-infestation, the soil of the test unit was covered with a layer of sand. 10 Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionic surfactant containing alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), unless otherwise indicated. The formulated compounds were applied in 1 mL of liquid through a SUJ2 atomizer nozzle with 1/8 JJ custom body (Spraying Systems Co.) positioned 15 1.27 cm (0.5 inches) above the top of each test unit. AH experimental compounds in this " screen were sprayed at 250 ppm and replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 hour and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 19-21 °C and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality. 20 Of the compounds tested, the following resulted in at least 80% mortality: 283, 297, 370, 371, 372, 388, 431, 434, 469, 470, 472, 473, 474, 476, 479, 486, 494, 497, 499, 500, 501, 502, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 565, 566, 567, 569, 571, 575, 576, 577, 578, 579, 580, 582, 584, 590, 596, 597, h5 601, 602, 603, 604, 609, 611, 614, 619, 620, 621, 624* 625, 626, 627, 629, 630, 631, 633, 638, 639, 640, 641, 642, 643, 644, 645, 650, 651, 655, 656, 657, 661, 664, 669, 671, 672, 673, 674, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 691, 698, 699, 703, 70S, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 771, 776, 779, 780, 781, 783, 30 784, 787, 793, 809, 810, 811, 812, 821, 822, 823, 824, 825, 826, 830, 831, 832 and 833. TESTE For evaluating control of cotton melon aphid (Aphis gossypif) through contact and/or systemic means, the test unit consisted of a small open container with a 6-7-day-old cotton plant inside. This was pre-infested with 30-40 insects on a piece of leaf according to the 35 cut-leaf method described for Test D, and the soil of the test unit was covered with a layer of sand. WO 03/015518 PCT/US02/25613 132 Test compounds were formulated and sprayed at 250 ppm as described for Test D. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test D. Of the compounds tested, the following resulted in at least 80% mortality: 370, 371, 5 372, 388, 431, 470, 472, 474, 476, 486, 494, 497, 500, 501, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 566, 567, 568, 575, 576, 577, 57S, 579, 582, 596, 601, 602, 603, 604, 609, 611, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 638, 639, 640, 641, 642, 643, 644, 655, 656, 657, 661, 672, 673, 679, 681, 686, 10 687, 691, 698, 699, 703, 704, 706, 708, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 771, 774, 776, 777, 779, 780, 783, 784, 787, 791, 793, 794, 809, 811, 812, 821,822,823, 825 and 826. 15 TESTF For evaluating control of com planthopper (Peregrines maidis) through contact and/or systemic means, the test unit consisted of a small open container with a 3-4 day old corn (maize) plant (spike) inside. White sand was added to the top of the soil prior to application. Test compounds were formulated and sprayed at 250 ppm and replicated three times as 20 described for Test D. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with 10-20 corn planthoppers (18 to 20 day old) nymphs) by sprinkling them onto the sand with a salt shaker. A black, screened cap was placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 19-21 °C and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality. 25 Of the compounds tested, the following resulted in at least 80% mortality: 370, 371, 372, 388, 431, 469, 470, 472, 474, 476, 486, 489, 494, 497, 500, 501, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 566, 561, 568, 575, 576, 577, 578, 57£, 582, 596, 601, 602, 603, 604, 609, 611, 620, 621, 624, 625, 626, 627, 30 628, 629, 630, 631, 638, 639, 640, 641, 642, 643, 644, 655, 656, 657, 661, 672, 673, 679, 681, 686, 687, 691, 698, 699, 703, 704, 706, 708, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 771, 774, 776, 777, 779, 780, 781, 783, 784, 787, 791, 793, 794, 809, 811, 812, 814, 821, 822, 823, 825 and 826. 35 TESTG For evaluating control of potato leafhopper (Empoasca fabae Harris) through contact and/or systemic means, the test unit consisted of a small open container with a 5-6 day old Longio bean plant (primary leaves emerged) inside. White sand was added to the top of the WO 03/015518 PCT/US02/25613 133 soil and one of the primary leaves was excised prior to application. Test compounds were formulated and sprayed at 250 ppm and replicated three times as described for Test D. After spraying, the-test units were allowed to dry for 1 hour before they were post-infested with 5 potato leafhoppers (18 to 21 day old) adults). A black, screened cap is placed on the top of 5 the cylinder. The test units were held for 6 days in a growth chamber at 19-21 °C and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality. Of the compounds tested, the following resulted in at least 80% mortality. 200, 233, 236, 283, 313, 316, 324, 370, 371, 372, 434, 456, 457, 469, 470, 471, 472, 473, 474, 475, 476, 482, 486, 494, 497, 499, 500, 501, 502, 506, 512, 514, 515, 516, 517, 518, 519, 520, ■ 10 530, 531, 533, 534, 536, 537, 538, 539, 542, 543, 544, 549, 550, 551, 553, 554, 555, 557, 558, 559, 560, 561, 562, 563, 564, 566, 567, 568, 575, 576, 577, 578, 579, 5S2, 584, 601, 603, 609, 611, 614, 619, 621, 625, 626, 629, 630, 631, 632, 633, 634, 639, 640, 641, 643, 644, 655, 656, 657, 662, 664, 672, 678, 679, 680, 68 L 682, 683, 685, 686, 687, 703, 706, 708, 710, 719, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 742, 743, 15 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 766, 771, 776, 777, 779, 780, 781, 784, 787, 793, 794, 796, 809, 810, 811, 812, 814, 821, 822, 824, 825, 826, 828, S31, 832 and 833. TESTH For evaluating control of silverleaf whitefly (Bemisia tabad), the test unit consisted of 20 a 14-21-day-old cotton plant grown in Redi-earth® media (Scotts Co.) with at least two true leaves infested with 2nd and 3rd instar nymphs on the underside of the leaves. Test compounds were formulated in no more than 2 mL of acetone and then diluted with water to 25-30 mL. The formulated compounds were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Plants were sprayed to run- 25 off on a turntable sprayer. All experimental compounds in this screen were sprayed at 250 ppm and replicated-three times. After spraying of the test compound, the test units were held for 6 days in a growth chamber at 50-60% relative humidity and 28 °C daytime and 24 °C nighttime temperature. Then the leaves were removed and the dead and live nymphs were counted to calculate percent mortality. 30 Of the compounds tested, the following resulted in at least 80% mortality: 494, 497, 499, 500, 501, 502, 506, 512, 513, 514, 515, 516, 517, 518, 520, 523, 530, 531, 532, 533, 534, 535, 536, 537, 538, 540, 542, 543, 544, 549, 550, 551, 553, 554, 555, 557, 560, 575, 576"; 577, 578, 579, 601, 620,625, 629f; 641, 673, 686,691 and703/ TEST I 35 For evaluating soil systemic control of tobacco budworm (Heliothis vires cem), cotton plants were grown in sassafras soil in 15-cm pots in alumhxum trays. When the plants reached square stage (bud formation on the plant) the plants were treated with the test compounds. WO 03/015518 PCT/US02/25613 134 Test compounds were formulated in 0.25 mL of acetone and then diluted with water to provide solutions of 10 ppm. Ten mL of the treatment solutions was added to the pots weekly for four weeks, with four replicates of each treatment rate. One day after the second, third and fourth treatments, 35-50 first instar Heliothis virescens larvae were brushed on 5 each plant with paintbrushes and placed on the terminal area, squares, and bolls. Five days after the last infestation with larvae the plants were rated for damage. Of the compounds tested, the following provided excellent levels of plant protection at 10 ppm (10% or less feeding damage) with excellent protection of squares and bolls including no or minimal sepal demage: 214, 283 and 520. 10 TEST J Test H followed an alternative protocol for evaluating soil systemic control of tobacco budworm {Heliothis virescens). Cotton plants were grown in sassafras soil in 15-cm pots under greenhouse conditions. When the plants reached square stage (bud formation on the plant) the soil surface was treated with the test compounds. 15 Test compounds were formulated in 0.25 mL of acetone and then diluted with water. Ten mL of treatment solution containing 3 mg of compound was added to the soil surface of each pot. The plants were watered the next day and each day following as needed. At 1, 2 and 4 days after treatment, leaves were excised for evaluation. Two sets of leaves were selected from each plant: upper leaves at approximately second node from terminal and with 20 area greater than 25 cm2 and lower leaves at approximately third node from bottom and with area greater than 25 cm2. The excised leaves were cut into 3 cm x 2 cm sections and placed into test trays made of high-impact styrene consisting of sixteen contiguous wells, each 6 cm wide, 4 cm long and 3 cm deep, with a clear plastic lid molded so that it locked into each well by friction. Solidified agar was placed into the bottom of each well to maintain 25 moisture for plant material. One second instar tobacco budworm was placed into each well with plant material; wells were sealed and held at 25 °C and provided with 16 hours of light per day Of the compounds tested, the following compounds provided excellent levels of mortality (greater fhan 70% mortality) on upper leaves excised at 4 days after treatment at 30 the test rate: 497, 530 and 543. TEST K For evaluating soil systemic control of fall armyworm (Spodopterafrugiperda), corn (maize) plants (Pioneer #3394) were grown in small pots for 5 days until they were at least 4 cm tall and the first leaf was uxrforling. 35 Test compounds were dissolved in 0.25 mL of acetone and diluted with water provide solutions of 1, 10, 50 and 200 ppm. One mL of the test solution was applied by pipette to the surface of the soil in each pot, with eight plants for each compound/rate. The pots were covered and held at 25 °C with 16 hours of light per day. The plants were watered the next WO 03/015518 PCT/US02/25613 135 ay and each day following as needed. After 6 days, the plant matter above the first leaf was excised and cut into 3-cm lengths. Each test unit was a high-impact styrene tray (Supplier: Clearpack Company, 11610 Copenhagen Court, Franklin Park, IL 60131) consisting of sixteen contiguous wells each 6 cm wide. 4 cm long and 3 cm deep, with a clear plastic lid 5 molded so that it locks into each well by friction. Solidified agar (2 to 4 mL) was placed onto the bottom of each well to maintain moisture in the wells during the test. Each 3-cm length of com plant matter was placed into a tray such that the plant matter was contained within two wells. One second-instar fall arrnyworm (Spodoptera frugiperda) larva was placed in each well, the tray was covered and then the test units were held at at 25 °C with 10 16 hours of light pet day. Mortality was observed after four days. LC90 concentrations (test compound concentrations giving 90% kill of the larvae) were calculated based on probit analysis (log linear regression) using a general linearized model (GLIM) of the SAS statistical computer analysis product of SAS Institute (Gary, NC, U.S.A.). Of the compounds tested, the following provided excellent levels of mortality, with 15 LC90 values of 10 ppm or less: 200, 202, 313, 494, 497, 500, 513, 515, 516, 518, 520, 531, 533, 535, 538, 542, 543 and 544. TESTL For evaluating soil systemic control of Colorado potato beetle (Leptinotarsa decemlineata), transplanted tomato plants were grown in 6-cm pots for 5 days until they 20 were at the two true leaf stage. Test compounds were dissolved in 0.25 mL of acetone and diluted with water provide solutions of 5 ppm. Five mL of the appropriate test solution was applied by pipette to the surface of the soil in each pot, followed by 5 mL of water, with eight plants for each compound/rate. The pots were covered and held at 25 °C with 16 hours of fight per day. 25 The plants were watered the next day and each day following as needed. After 4 days, one leaf from each plant was excised and placed into a wefi of a test tray as des cribed in Test H. One 5-day old Colorado potato beetle (Leptinotarsa decemlineata) was placed in each well, the tray was covered and then the test units were held at at 25 °C with 16 hours of fight per day. Mortality was observed after four days. 30 Of the compounds tested, the following provided excellent levels of mortality and feeding inhibition at 5 ppm: 214. TESTM For evaluating control of boll weevil (Anthonomus g. grandis), .samples of the test compounds were dissolved in 1 mL of acetone. This solution was then diluted to 100 mL 35 total volume using an aqueous 500 ppm solution of Ortho X-77™ surfactant. Serial dilutions were made to obtain 50 mL of 50 ppm concentration. WO 03/015518 PCT/US02/25613 136 The diluted solutions of the test compounds were sprayed to run-off on three-week-old cotton plants. The plants were placed on a rotating turntable sprayer (10 rpm). Test solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Sprayed and dried plants were incased in a plastic cylinder. Twenty weevils 5 were placed in each cylinder containing a whole cotton plant. At three days after infestation a feeding damage rating was taken. Of the compounds tested, the foEowing provided excellent levels of plant protection at 50 pprn (10% or less feeding damage): 530 and 531. TESTN 10 For evaluating control of thrips (Frahkliniella sp.), samples of the test compounds were dissolved in 1 roL of acetone. This solution was then diluted to 100 mL total volume using an aqueous 500 ppm solution of Ortho X-77™ surfactant. Serial dilutions were made to obtain 50 mL of 10 ppm concentration. The diluted solutions of the test compounds were sprayed to run-off on three-week-old 15 cotton or soybean plants infested with thrips. The plants were placed on a rotating turntable sprayer (10 rpm). Test solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Sprayed and dried plants were incased in a plastic cylinder. At four days after application the total number of dead thrips was recorded. Of the compounds tested, the following resulted in at least 90% mortality at 10 ppm: 20 542. TEST O Test O followed an alternative protocol for evaluating control of Colorado potato beetle (Leptinotarsa decemlineate). Several hours prior to spraying, 5 mg (100% active | ingredient, ai) of the test compounds were dissolved in 1 mL of acetone. Using the aqueous 25 solution of 500 ppm of Ortho X-77™, the sample botde was rinsed and added to the test i compounds. This sample solution was then brought to 100 mL with the aqueous solution. Serial dilutions are made to obtain 50 mL of 10 ppm. Formulated experimental compounds were sprayed to run-off on three week old potato or tomato plants. The plants were placed on a rotating turntable sprayer (10 rpm). Test 30 solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 KPa). Once the plants were dried, leaves were excised from the treated plant. The leaves were cut, and then the pieces were placed singly into a 5.5 cm-by-3.5 cm cell of a sixteen-well plastic tray. Each cell contained a 2.5 square of moistened chromatography paper to prevent desiccation. One second instar larvae was placed in each cell. At three 35 days after infestation total number of dead Colorado potato beetles was recorded. Of the compounds tested, the following resulted in at least 90% mortality at 10 ppm: 497, 500, 530, 543, 544, 558, 562 and 684. WO 03/015518 PCT/US02/25613 137 TESTP Seventy-eight cotton plants were grown in the greenhouse with natural lighting in Sassafras soil in six inch pots. "When six true leaves were on the plant (approximately 36 cm tall) the soil was drenched with a solution of Compound 497, 500, 530, 531 or 543. Each of the 5 compounds was dissolved in 2 mL of acetone, and distilled water was added to make 300 ppm solutions of each of the compounds. The pots were divided into six groups (13 plants / treatment), and 10 mL of each solution was applied over the soil surface of each group with one group left untreated. The plants were arranged in the greenhouse: in a randomized block design. Each treatment was divided into three groups for sampling at 24, 48, and 96 hours. Leaves were taken from the base and tenninal of the plants. The leaves from the third node and the tenninal leaves greater than 15 cm2 were sampled per plant One clipped leaf from each plant was cut into four pieces and each piece was placed into an well with one second-instar larvae of Heliothis virescens (tobacco budworm). Larval mortality (%M) was recorded 96 hours after sampling. The percentage of leaf feeding (%FF) was also recorded. Consumption of the leaf in the well was reported as 0 - 100% (0 equals no feeding). Results are listed in Table P. TABLE? Percent Larval Mortality and Feeding of Cotton Leaves Over Time WO 03/015518 PCTAJS02/25613 13S substance as indicated in the foRowing table. Approximately 1 gram of bait was placed into " each test cage. Ten German cockroaches (Blatella germanica) were then placed into each cage, and provided water via a saturated cotton ball. The cages were held indoors, with indirect sunlight, and temperatures ranging from 22 to 31 °C. Four test replicates were set 5 up per rate. Evaluations were conducted 1, 2, 3, 5, and 7 days after treatment (DAT) by counting and removing the killed roaches found in each cage. TABLEO German Cockroach Bait Test TESTR 10 For evaluating control of fire ant (Solenopsis xyloni), Compound 531 was mixed with water and then mixed into a slurry with equal amounts (by weight) of Niban granular bait with no active ingredient (supplied by Nisus Corp.). The mixture was air dried, leaving a dry granular bait with final concentration of the test substance as indicated in the following table. The baits were uniformly sprinkled onto the sand substrate in each test cage. Fifty 15 field-collected southern fire ants (Solenopsis xyloni) were then placed into each cage and provided water via a saturated cotton ball. The cages were held indoors with indirect sunlight and temperatures ranging from 22 to 31 °C. Four test replicates were set up per rate. Evaluations were conducted at 1,3, 7,10, and 14 days after treatment (DAT) by counting and removing the killed ants found in each cage. 20 TABLE R Fire Ant Bait Test Average of Killed Fire Ants Rate 1DAT 3 DAT 7 DAT 10 DAT 14 DAT untreated 0.8 1.3 3.5. 5.5 J 8.5 400 ppm 0.5 1.3 40.5 50 50 2,000 ppm 1 43 49.8 50 10,000 ppm 0 2.3 " 42.8 50 50 We claim: 1. A method for controlling lepidopteran, homopteran, hemipteran, thysanopteran and coleopteran insect pests, comprising: contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, anN-oxide or an agriculturally suitable salt thereof of the kind as herein described. wherein A and B are independently 0 or S. R1 is H. C1-Ce alkyl, C2-C¬ alkoxycarbonyl or C2-C6 alkylcarbony R2isH or C1-C6 alkyl; R3 is H; Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfmyl, C1-C4 alkylsulfonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyl, C3-C6 ttialkylsilyt, phenyl, phenoxy, 5-membered heteroaromatic rings, and 6- membered heteroaromatic rings; each phenyl, phenoxy, 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring optionally substituted with one to three substituents 20 independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfmyl, C1-C4 allcylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C4-C8 (alkyl)(cycloalkyl) amino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl and C3-C5 trialkylsilyl; C1-C4 alkoxy; C1-C4 alkylamino, C2-C8 dialkylamino; C3-Ce cycloalkylamino; C2-C6 alkoxycarbonyl or C2-C6 alcylcarbonyl; 3. ^he method as claimed in Claim 2 wherein R\R2andR8areaHH.; R3 is d-C4 alkyl optionally substituted with halogen, CN, OCH3 or S(0)pCH3; R4 group is attached at position 2; R4 is CH3, CF3, OCF3, OCHF2, CN or halogen; Rs is H.CH3 or halogen; R6 is CH3, CF3 or halogen; R7 is phenyl or 2-pyridinyl, each optionally substituted; and p is 0,1 or 2. 4. The method as claimed in Claim 3 wherein R is C1-C4 alkyl and R is CF3. 5. The method as claimed in Claim 3 wherein R3 is C1 -C4 alkyl and R6 is CI or Br. 6. A method for preparing a synergistic composition comprising adding a biologically effective amount of compound of formula I as claimed in claim 1 to at least one biologically active compound or agent. 7. The method as claimed in Claim 6 wherein the at least one biologically active compound or agent is" selected torn arthropodicides of the group consisting of pyrethroids, carbamates, neonicotinoids, neuronal sodium channel blockers, insecticidal macrocyclic lactones, aminobutyric acid (GABA) antagonists, insecticidal ureas and juvenile hormone mimics. 8. The method as claimed in Claim 6 wherein the at least one biologically active compound or agent is selected from the group consisting of abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos- methyl, chromafenozide, clothianidin, cyfluthrin, beta- cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, diftubenzuron, dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate, f pronil, florucamid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), fluienoxuron, fonophos, halofenozide, hexaflumuron, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, rnetaldebyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirunicarb, profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbutos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon and triflumuron, aldicarb, oxamyl, fenamiphos, arnitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fentutatin oxide, fenpropat in, fenpyroximate, hexythiazox, propargite, pyridaben, tebutenpyrad; and biological agents such as Bacillus thuri7 giensis including ssp. aizawai and kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi. 9. The method as claimed in Claim 6 wherein the at least one biologically active compound or agent is selected from the group consisting of cypermethrin, cyhalothrin, cyfluthrin and beta-cyfluthrin, esfenvalerate, fenvalerate, tralomethrin, fenothicarb, methomyl, oxarayl, thiodicarb, clothianidin, imidacloprid, thiacloprid, indoxacarb, spinosad, abamectin, avermectin, emamectin, endosulfan, ethiprole, fipronil, flufenoxuron, triflumurpn, diofenolan, pyriproxyfen, pymetrozine, amitraz, Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin and entomophagous fungi. 10. The method as claimed in Claim 1 wherein at least one of the insect pests controlled is selected from the group consisting of Alabama argillacea Hubner (cotton leaf wonn), Archips argyrospila WaLker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo suppressalis WaLker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm)" Earias vittella Fabricius (spotted bollworm), Helicoverpa armigera Huhner (American bollworm), Helicoverpa zea Boddie (com earworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogramma licarsisalis Walker (sod webworm), Lobesia botrana Denis & Schiffermutler (grape berry moth), Pectinophora gossypiella Saunders (pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer), Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diamondback moth), Spodoptera exigua Hubner (beet armyworm), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperda J. E. Smith (fall armyworm), Trichoplusia ni Hubuer (cabbage looper) and Tura absoluta Meyrick (tomato leafminer), Acyrthisiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gosspii Glover (cotton aphid, melon aphid), Aphis pomi De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paasermi (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy (mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophiurn di -hodum Wall er (cereal aphid), Macrosipum euphorbiae Thomas (potato aphid), Myzas persicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (corn leaf aphid), Rhopalosiphun padi Linnaeus (bird cherry-oat aphid), Schizaphis graminun Rondani (greenbug) , Sitobion avenae Fabricius (English grain aphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid), and Toxoptera citricida Kirkaldy (brown citrus aphid), Adelges spp, (adelgids); Phylloxera devastatrix Pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes cit i Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhouse whitefly); jgmpoascafabae Harris (potato leafhopper), Laodelphuxshiatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafLopper), Nephotettix nigropictus Stal (rice leafhopper), Milaparvata lugens Stal (brown planthopper), Peregrinus inaidis Ashmead (com planthopper), Sogatella furcifera Horvath ("bite- backed planthopper) ", Sogatodes orizicola Muli (rice delphacid), Typhlocyba pomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotus perrdciosus Comstock (San Jose scale); Planococcus citri Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola Foerster (pear psylla), Trioza diospyri Ashmead (pe.rsimmon psylla), Acroster zum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturell" s Her icll-Schaffer (cotton stainer), Euchistus serrus Say (brown stink bug), Euchistus var.iolarius Palisot de Beauvois (one- spotted shnk bug), Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezara viridula Linnaeus (southern green stink bug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug), PseudatomosceUs seriatus Reuter (cotton fleahopper), Frankliniella occidentalis Pergande (western flower rip), Scirthothrips citri Moulton (citrus thrip), Sericothrips variabilis Beach (soybean thrip), and Thrips tabaci Lindeman (onion thrip), Leptinotarsa decenlineata Say (Colorado potato beetle), Epilachna varivestis Muls ant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius).

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