| Title of Invention | ARTHROPODICIDAL ANTHRANILAMIDES |
|---|---|
| Abstract | This invention provides compounds of Formula (1), their N-oxides and agriculturally suitable salts wherein R1, R2, R3, R4a, R4b and R5 are as defined in the disclosure.Also disclosed are methods for controlling invertebrate pests comprising contacting the invertebrate pests or their environment with a biologically effective amount of a compound of Formula 1 or a composition comprising a compound of Formula 1. |
| Full Text | FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] "ARTHROPODICIDAL ANTHRANILAMIDES" 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 :- Granted 6-9-2005 WO 03/015519 PCT/US02/25615 TITLE ARTHROPODiCIDAL ANTHRANILAMIDES BACKGROUND OF THE INVENTION This invention relates to certain anthranilamides, their iV-oxides, agriculturally suitable salts and compositions, and methods of their use for control of invertebrate _Bgsis_sxich-aff arthropods in both agronomic and nonagronomic environments. The control of invertebrate pests such as arthropods 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 which are more effective, less costly, less toxic, environmentally safer or have different modes of action. NL 9202078 discloses vV~acyl anthranilic acid derivatives of Formula i as insecticides wherein, mt€f alia, X is a direct bond; Y is H or C1-C6 alkyl; % is NH2, NH(C1-C3 alkyl) or N(C1-C3 alkyl)2; and R1 through R9 are independently H, halogen, C1-C8 alkyl, phenyl, hydroxy, C1-C8 alkoxy or C1-C7 acyloxy. SUMMARY OF THE INVENTION This invention pertains to a compound of Formula 1, its iV-oxide or an agriculturally suitable salt of the compound 2 A"O 03/015519 PCT/US02/25615 wherein R1is CH3FCl or Br; R2 is F, CI, Br, I or CF3; 5 R3 is CF3, CI, Br or OCH2CF3; R4aisC1-C4alkyl; R4b is H or CH3; and R5 is CI or Br. This invention also pertains to a composition for controlling an invertebrate pest 10 comprising a biologically effective amount of a compound of Formula 1 and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. This invention also pertains to a composition comprising a biologically effective amount of a compound of Formula 1 and an effective amount of at least one additional biologically active compound or agent. 15 This invention also pertains to a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1 (e.g., as a composition described herein). This invention also relates to such method wherein the invertebrate pest or its environment is contacted with a biologically effective amount of a compound of Formula 1 or a composition comprising a 20 compound of Formula 1 and a biologically effective amount of at least one additional compound or agent for controlling invertebrate pests. This invention further relates to a benzoxazinone compound of Formula 2 R3 3 WO 03/015519 PCT/US02/25615 wherein RHsCH3,F,Cl or Br; R2isF,Cl,Br,I or CF3; R3 is CF3, CI, Br or OCH2CF3; and R5 is CI or Br; which is useful as a synthetic intermediate for preparing a compound of Formula 1. This invention also relates to a pyrazolecarboxylic acid compound of Formula 4 R3 wherein 10 R3 is CF3, Cl, Br or OCH2CF3; and R5 is CI or Br; which is useful as a synthetic intermediate for preparing a compound of Formula 1. DETAILS OF THE INVENTION In the above recitations, the term "alkyl", used either alone or in compound words such 15 as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, /z-propyl, z"-propyl, or the different butyl isomers. One skilled in the art will appreciate that not all nitrogen containing heterocycles can form iV-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form iV-oxides. One skilled in the art will also 20 recognize that tertiary amines can form iV-oxides. Synthetic methods for the preparation of iV-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and 7rc-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as f-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. 25 These methods for the preparation of JV-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive"Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic 30 Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky 4 WO 03/015519 PCT/US02/25615 4 and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392,"A. R. Katritzky and A. J. Boulton, Eds., Academic Press. Compounds of this invention can exist as one or more stereoisomers. The various 5 stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present 10 invention comprises compounds selected from Formula 1, iV-oxides and agriculturally suitable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, 15 butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. Preferred compounds for reasons of cost, ease of synthesis and/or biological efficacy are: Preferred 1 Compounds of Formula 1 wherein R4a is Ci-C4 alkyl and R4b is H; or 20 R4aisCH3andR4bisCH3. Preferred 2 Compounds of Preferred 1 wherein R5 is CI. Preferred 3 Compounds of Preferred 2 wherein R4* is CH3, CH2CH3, CH(CH3)2 orC(CH3)3. Preferred 4 Compounds of Preferred 3 wherein R2 is CI or Br. 25 Preferred 5 Compounds of Preferred 4 wherein R1 is CH3. Preferred 6 Compounds of Preferred 4 wherein R1 is CI. Preferred 7 Compounds of Formula 1 wherein R1 is CH3, CI or Br; R2 is F, CI, Br, I or CF3; R3 is CF3; CI or Br; R4* is CrC4 alkyl; R4b is H; and R5 is CI or Br. 30 Specifically preferred is a compound of Formula 1 selected from the group consisting of: the compound of Formula 1 wherein R1 is CH3, R2 is Br, R3 is CF3, R4a is CH(CH3)2? R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is Br, R3 is CF3, R4a is CH3, 35 R4bisH, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is Br, R3 is Br, R4a is CH(CH3)2, R4b is H, and R5 is CI; 5 WO 03/015519 PCT/US02/25615 the compound of Formula 1 wherein Rl is CH3, R2 is Br, R3 is Br, R4a is CH3, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is Br, R3 is CI, R4a is CH(CH3)2, R4b is H, and R5 is CI; 5 the compound of Formula 1 wherein R1 is CH3, R2 is Br, R3 is CI, R4a is CH3, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is CF3, R4a is CH(CH3)2, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is CF3, R4a is CH3, 10 R4bis H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is Br, R4a is CH(CH3)2, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is Br, R4a is CH3, R4b is H, and R5 is CI; 15 the compound of Formula 1 wherein R1 is CH3,R2 is CI, R3 is CI, R4a is CH(CH3)2, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is CI, R4a is CH3, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is OCH2CF3, R4a is 20 CH(CH3)2, R4b is H, and R5 is CI; the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is OCH2CF3, R4ais CH3,R4bisH,andR5isCl; the compound of Formula 1 wherein R1 is CI, R2 is CI, R3 is Br, R4a is CH3, R4b is H, and R5 is CI; and 25 the compound of Formula 1 wherein R1 is CH3, R2 is CI, R3 is OCH2CF3, R4a is CH3sR4bisH,andR5 isCl. The preferred compositions of the present invention are those which comprise the above preferred compounds. The preferred methods of use are those involving the above preferred compounds. 30 Of note are compounds of Formulae 1, 2 and 4 wherein R1 is CH3, CI or Br; R2 is F, CI, Br, I or CF3; R3 is CF3, Cl or Br; R4a is C1-C4 alkyl; R4b is H; and R5 is CI or Br. The compounds of Formula 1 can be prepared by one or more of the following methods and variations as described in Schemes 1-11. The definitions of R1, R2, R3, R4a3 R4b andR5 in the compounds of Formulae 1-24 below are as defined above in the Summary 35 of the Invention unless indicated otherwise. Compounds of Formula 1 can be prepared by the reaction of.benzoxazinones of Formula 2 with C1-C4 alkyl amines as outlined in Scheme 1. 6 WO 03/015519 PCT/US02/25615 Scheme 1 R2/^^^\ C(0)NR4aR4b 2 1 The reaction can be run neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. The general reaction of benzoxazinones 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 Chemistry 2000, 8, 2095-2103 and references cited within. See also G. M. Coppola, J. Heterocyclic Chemistiy 1999, 36, 563-588. Benzoxazinones of Formula 2 can be prepared by a variety of methods. Two methods that are especially useful are detailed in Schemes 2-3. In Scheme 2, a benzoxazinone of Formula 2 is prepared directly via coupling of a pyrazolecarboxylic acid of Formula 4 with an antliranilic acid of Formula 3. Scheme 2 tertiary amine 4. MeS(0)2a 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 4, followed by the addition of an anthranilic acid of Formula 3, followed by a second addition of tertiary 7 WO 03/015519 PCT/US02/25615 amine and methanesulfonyl chloride. This method generally affords good yields of the benzoxazinone and is illustrated with greater detail in Example 1. Scheme 3 depicts an alternate preparation for benzoxazinones of Formula 2 involving coupling of a pyrazole acid chloride of Formula 6 with an isatoic anhydride of Formula 5 to provide the Formula 2 benzoxazinone directly. Scheme 3 + Solvents such as pyridine or pyridine/acetonitrile are suitable for this reaction. The acid chlorides of Formula 6 are available from the corresponding acids of Formula 4 by known 10 methods such as chlorination with thionyl chloride or oxalyl chloride. Anthranilic acids of Formula 3 are available by a variety of known methods. Many of these compounds are known. As shown in Scheme 4, anthranilic acids containing an R2 substituent of chloro, bromo or iodo can be prepared by direct halogenation of an unsubstituted anthranilic acid of Formula 7 with iV-chlorosuccinimide (NCS), 15 iV-bromosuccinimide (NBS) or iV-iodosuccinimide (NIS) respectively in solvents such as N,N-dimethylformamide (DMF) to produce the corresponding substituted acid of Formula 3. Scheme 4 20 Preparation of the isatoic anhydrides of Formula 5 can be achieved from isatins of Formula 9 as outlined in Scheme 5. 8 WO 03/015519 PCT/US02/25615 Scheme 5 10 Isatins of Formula 9 are available from aniline derivatives of Formula 8 following literature procedures such as F. D. Popp, Adv. Heterocycl. Chem. 1975,18, 1-58 and J. F. M. Da Silva et al., Journal of the Brazilian Chemical Society 2001,12(3), 273-324. Oxidation of isatin 9 with hydrogen peroxide generally affords good yields of the corresponding isatoic anhydride 5 (G. Reissenweber and D. Mangold, Angew. Chem, Int. Ed. Engl. 1980, 19, 222-223). Isatoic anhydrides are also available from the anthranilic acids 3 via many known procedures involving reaction of 3 with phosgene or a phosgene equivalent. Pyrazolecarboxylic acids of Formula 4 can be prepared by the method outlined in Scheme 6. Scheme 6 15 20 Reaction of pyrazole 10 with a 2,3-dihalopyridme of Formula 11 affords good yields of the 1-pyridylpyrazole 12 with good specificity for the desired regiochemistry. Metallation of 12 with lithium diisopropylamide (LDA) followed by quenching of the lithium salt with carbon dioxide affords the pyrazolecarboxylic acid of Formula 4. Additional procedural details for this method are provided in Examples 1, 3 and 5. The starting pyrazoles 10 wherein R3 is CF3, C1 or Br are known compounds. Pyrazole 10 wherein R3 is CF3 is commercially available. Pyrazoles 10 wherein R3 is C1 or Br can be prepared by literature procedures (H. Reimlinger and A. Van Overstraeten, Chem. Ber. 1966, 99(10), 3350-7). A useful alternative method for the preparation of 10 wherein R3 is C1 or Br is depicted in Scheme 7. 9 WO 03/015519 PCT/US02/25615 ^-Metallation of the sulfamoyl pyrazole 13 with /z-butyllithiuni followed by direct halogenation of the anion with either hexachloroethane (for R3 being CI) or 1,2-dibromo-5 tetrachloroethane (for R3 being Br) affords the halogenated derivatives 14j Removal of the sulfamoyl group with triffuoroacetic acid (TFA) at room temperature proceeds cleanly and in good yield to afford" the pyrazoles 10 wherein R3 is CI or Br respectively. Further experimental details for this method are described in Examples 3 and 5. As an alternative to the method illustrated in Scheme 6, pyrazolecarboxylic acids of \ 15 16 17 r Reaction of a compound of Formula 15 wherein R6 is C1-C4 alkyl with a suitable base in a suitable organic solvent affords the cyclized product of Formula 16 after neutralization with 15 an acid such as acetic acid. The suitable base can be, for example but not limitation, sodium hydride, potassium /-butoxide, dimsyl sodium (CH3S(0)CH2e Naffi), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)arnmonium fluorides or hydroxides, or 2-tert-butylimino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphonine. The suitable organic solvent can be, for example but not 20 limitation, acetone, acetomtrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide, or N,N-dimethylformamide. 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 minimize the formation of byproducts. A preferred base is tetrabutylammonium fluoride. 10 VO 03/015519 PCT/US02/25615 10 Dehydration of the compound of Formula 16 to give the compound of Formula 17, followed by converting the carboxylic ester function to carboxylic acid, affords the compound of Formula 4. 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 conducte4 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 100oC\ FSV THE dehydration in 222 the method of Scheme B, 3 solvent comprising "seetic acid and temperatures of about 65 °C are preferred. Carboxylic ester compounds can be converted to carboxylic acid compounds by numerous methods including nucleopbilic cleavage under anhydrous conditions or hydrolytic 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 8, 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 in 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 ^cid3 yields the carboxylic acid of Formula 4. The carboxylic acid can be isolated by methods known to those skilled in the art, including crystalhzation, extraction and distillation. Compounds of Formula 15 can be prepared by the method outlined in Scheme 9. 20 wherein R3 is CF3 and R6 is C1-C4 alkyl. Treatment of a hydrazine compound of Formula 18 with a ketone of Formula 19 in a solvent such as water, methanol or acetic acid gives the hydrazone of Formula 20. One skilled in the art will recognize that this reaction may require catalysis by an optional acid and may also require elevated temperatures depending on the molecular substitution pattern of the hydrazone of Formula 20. Reaction of the hydrazone of Formula 20 with the compound of 11 WO 03/015519 PCT/US02/25615 11 Formula 21 in a suitable organic solvent such as, for example but not limitation, dichloromethane or tetrahydrofuran in the presence of an acid scavenger such as triethylarnine provides the compound of Formula 15. The reaction is usually conducted at a temperature between about 0 and 100 °C. Further experimental details for the method of 5 Scheme 9 are illustrated in Example 7. Hydrazine compounds of Formula 18 can be prepared by standard methods, such as by contacting the corresponding halo compound of Formula 11 with hydrazine. As an alternative to the method illustrated in Scheme 6, pyrazolecafboxylic acids of Formula 4 wherein R3 is CI or Br can also be prepared by the method outlined in Scheme 10. 10 Scheme 10 K-V R3_ 22 17 wherein R6 is C1-C4 alkyl. Oxidization of the compound of Formula 22 optionally in the presence of acid to give the compound of Formula 17 followed by conversion of the carboxylic ester function to the 15 carboxylic acid provides the compound of Formula 4. 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 22 should be used, preferably, between about one to two equivalents. This oxidation is typically 20 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 iVJV-dimethylformamide, acetonitrile and the like. Acids suitable for use in the oxidation step include inorganic acids, such as sulfuric acid, phosphoric acid and the like, and organic acids, such as acetic acid, benzoic acid and the 25 like. The acid, when used, should be used in greater than 0.1 equivalents versus the compound of Formula 22. 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 compound of Formula 22 in the desired solvent and, if used, the acid. The oxidant can then 30 be added at a convenient rate. The reaction temperature is typically varied from as low as 12 WO 03/015519 PCT/US02/25615 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 17 can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Methods suitable for converting the ester of Fonnula 17 to the carboxylic acid of Formula 4 are already described for Scheme 8. Further experimental details for the method of Scheme 10 are illustrated in Examples 8 and 9. Compounds of Formula 22 can be prepared from corresponding compounds of Formula 23 as shown in Scheme 11. Scheme 11 10 23 22 wherein R6 is C1-C4 alkyl. 15 20 25 30 Treatment of a compound of Formula 23 with a halogenating reagent, usually in the presence of a solvent, affords the corresponding halo compound of Fonnula 22. Halogenating reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphophoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. To obtain complete conversion, at least 0.33 equivalents of phosphorus oxyhalide versus the compound of Formula 23 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 23 should be used, preferably between about 0.20 and 1,0 equivalents. Compounds of Formula 23 wherein R6 is C1-C4 alkyl are preferred for this reaction. Typical solvents for this halogenation include halogenated alkanes, such as dichloromethane, chloroform, chlorobutane 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, pyridine, N,N-dimethylaniline 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 13 WO 03/015519 . PCT/US02/25615 . 13 the compound of Formula 23 in acetonitrile. The halogenating reagent is then added over a convenient time, 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 5 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 22, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Alternatively, compounds of Formula 22 wherein R3 is Br or CI can be prepared by 10 treating the corresponding compounds of Formula 22 wherein R3 is a different halogen (e.g., CI for making Formula 22 wherein R3 is Br) or a sulfonate group such as^-toluenesulfonate, benzenesulfonate and methanesulfonate with hydrogen bromide or hydrogen chloride, respectively. By this method the R3 halogen or sulfonate substituent on the Formula 22 starting compound is replaced with Br or CI from hydrogen bromide or hydrogen chloride, 15 respectively. The reaction is conducted in a suitable solvent such as dibromomethane, dichloromethane or acetonitrile. The reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel. When R3 in the starting compound of Formula 22 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 20 other suitable means. The reaction can be conducted between about 0 and 100 °C, most 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 22 wherein R3 is Br) can facilitate the reaction. The product of Formula 22 is isolated by the usual methods known to those skilled in the art, 25 including extraction, distillation and crystallization. Further details for this process are illustrated in Example 10. Starting compounds of Formula 22 wherein R3 is CI or Br can be prepared from corresponding compounds of Formula 23 as already described. Starting compounds of Formula 22 wherein R3 is a sulfonate group can likewise be prepared from corresponding 30 compounds of Formula 23 by standard methods such as treatment with a sulfonyl chloride (e.g.,p-toluenesulfonyl chloride) and base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane; further details for this process are illustrated in Example 11. As an alternative to the method illustrated in Scheme 6, pyrazolecarboxylic acids of 35 Formula 4 wherein R3 is OCH2CF3 can also be prepared by the method outlined in Scheme 12. 14 WO 03/015519 PCT/US02/25615 14 Scheme 12 wherein R6 is C1-C4 alkyl, and X is a leaving group. In this method, instead of being halogenated as shown in Scheme 11, the compound of 5 Formula 23 is oxidized to the compound of Formula 17a. The reaction conditions for this oxidation are as already described for the conversion of the compound of Formula 22 to the compound of Formula 17 in Scheme 10. The compound of Formula 17a is then alkylated to form the compound of Formula 17b by contact with an alkylating agent CF3CH2X (24) in the presence of a base. In the 10 alkylating agent 24, X is a nucleophilic reaction leaving group such as halogen (e.g., Br, I), OS(0)2CH3 (methanesulfonate), OS(0)2CF3, OS(0)2Ph-£-CH3 (p-toluenesulfonate), and 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 15 triemylamine, 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 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, iV^-dimethylformamide, and the like. Alcohols 20 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 about 0 and 150 °C, with most typically between ambient temperature and 100 °C. The product of Formula 17b can be isolated by conventional techniques such as extraction. The ester of Formula 17b can then be converted to the carboxylic acid of Formula 4 by the 25 methods, already described for the conversion of Formula 17 to Formula 4 in Scheme 8. Further experimental details for the method of Scheme 12 are illustrated in Example 12. Compounds of Formula 23 can be prepared from compounds of Formula 18 as outlined in Scheme 13. 15 WO 03/015519 PCT/US02/25615 base ^ 23 18 wherein R6 is C1-C4 alkyL In this method, a hydrazine compound of Formula 18 is contacted with a compound of Formula 25 (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 methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxi&e, lithium tert-bntoxide, and the like. Greater than 0.5 equivalents of base versus the compound of Formula 18 should be used, preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalents of the compound of Formula 25 should be used, preferably between 1.0 to 1.3 equivalents. Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, 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 fumarate or maleate ester and the alkoxide base. The reaction is typically conducted by mixing the compound of Formula 18 and the base in the solvent. The mixture can be heated or cooled to a desired temperature and the compound of Formula 25 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 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 18 and Formula 25. 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 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 -C02R6 function on the compound of Formula 23 may be hydrolyzed to -C02H; for example, the presence of water in the reaction mixture can promote such hydrolysis. If the carboxylic acid (-C02H) is formed, it can be converted back to -CO2R6 wherein R6 is C1-C4 alkyl using esterification methods well-known in the art. The desired product, a compound of WO 03/015519 PCT/US02/25615 Formula 23, 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 preparing compounds of Formula 1 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, T. W. Greene and P. G. M. Wuts, Protective Groups In Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as 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 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1. It is believed that one skilled in the art using the preceding description can utilize 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. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. 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 ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "dd" means doublet of doublets, "dt" means doublet of triplets, and "br s" means broad singlet. EXAMPLE 1 Preparation of 7Vr-[4-chloro-2-methyl-6-[[(l-methylethyl)amino]carbonyl]phenyl]-l-(3-cMoro-2-pyridmyl)-3-(trifluoromemyl)-li7-pyrazole-5-carboxamide 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 rnmol) in N,N-dimethylformarnide (50 mL) was added N-chlorosuccinimide (13.3 g, 99.2 rnmol) 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 WO 03/015519 PCT/US02/25615 17 ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g). 1H NMR (DMSO-d6) 6 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H). 5 Step B: Preparation of 3-chloro-2-[3-(trifluoromemyl)-liy-pyrazol-l-yl]pyridine To a mixture of 2,3-dichloropyridme (99.0 g, 0.67 mol) and 3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide (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 10 remove solids. TV^-Dimethylformamide and excess dichloropyridine were removed by distillation at atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141 °C, 7 mm) afforded the desired intermediate as a clear yellow oil (113.4 g). !HNMR (CDC13) 5 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H). Step C: Preparation of 1 -(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-liJ-pyrazole- 15 5-carboxylic acid To a solution of 3-cMoro-2-[3-(trifluoromemyl)-lif-pyrazol-l-yl]pyridine (i.e. 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 stirred for 15 minutes, after which 20 time carbon dioxide was bubbled through at -63 °C until the solution became pale yellow and the exothermicity 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 0.5 N aqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3x), filtered through Celite® diatomaceous 25 filter aid to remove residual solids, and then acidified to a pH of approximately 4, at which 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, washed successively with water and 1 N hydrochloric acid, and dried under vacuum at 50 °C to afford the title product as an off-white solid (130 g). (Product from 30 another run following similar procedure melted at 175-176 °C.) 1H NMR (DMSO-d6) 8 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H). Step D: Preparation of 6-chloro-2-[ 1 -(3-chloro-2-pyridinyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]-8-methyl-4H-3,l-benzoxa2in-4-one To a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in acetonitrile (75 mL) 35 was added dropwise a mixture of l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-liy-pyrazole- 5-carboxylic acid (i.e. the carboxylic acid product of Step C) (7.5 g, 27.0 mmol) and triemylamine (3.75 mL, 27.0 mmol) in acetonitrile (75 mL) at 0-5 °C. The reaction 18 WO 03/015519 PCT/US02/25615 18 temperature was then maintained at 0 °C throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-mefhyl-5-chlorobenzoic acid (i.e. the product from Step A) (5.1 g, 27.0 mmol) was added and stirring was continued,for an additional 5 minutes. A solution of triethylamine (7.5 mL, 54.0 mmol) in acetonitrile (15 mL) was then added 5 dropwise, 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 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. 10 !H NMR (CDC13) 5 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m, 2H), 7.99 (m, 2H), 8.58 (d, 1H). Step E: Preparation of i\^44-chloro-2-methyl-6-[[(l--methylethyl)amino]carbonyl]- phenyl]-l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-li^-pyrazole- 5-carboxamide To a solution of 6-chloro-2-[l-(3-cWoro-2-pyridinyl)-3-(trifluoromethyl)-li/"--pyrazol- 15 5-yl]-8-methyl-4_7-3,l-benzoxazm-4-one (i.e. the benzoxazinone product of Step D) (5.0 g, 11.3 rnmol) 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 chromatography on silica gel confirmed completion of the reaction. The 20 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. *H NMR (CDCI3) 5 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95 (br d, 1H), 7.1-7.3 (m, 25 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H), 8.50 (d, 1H), 10.24 (br s, 1H). EXAMPLE 2 Preparation of Ar-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1 -(3-chloro- 2-pyridmyl)-3-(Mfluoromemyl)-l//"-pyrazole-5-carboxamide To a solution of 6-cHoro-2-[l-(3-cHoro-2-pyridinyl)-3-(trifluoromethyl)-l__"-pyrazol- 30 5-3"l]-8-methyl-4i_"-3,l-benzoxazin-4-one (i.e. the benzoxazinone product of Example 1, Step D) (4.50 g, 10.18 mmol) in tetrahydrofuran (THE; 70 mL) was added methylamine (2.0 M solution in THE, 15 mL, 30.0 mmol) dropwise arid 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 35 of the title compound, a compound of the present invention, as a white solid melting at 185-186°C. 19 WO 03/015519 PCT7US02/25615 .( 1H NMR (DMSO- EXAMPLE 3 Preparation of 3-chloro-iV:-[4-chloro-2-methyl-6-[[(l-rnethylethyl)ammo]carbonyl]phenyl]- 5 1 -(3-chloro-2-pyridinyl)- li?-pyrazole-5-carboxamide Step A: Preparation of 3-chloro-.A/rAMimethyl-lifepyrazole-1 -sulfonamide To a solution of W-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at -78 °C was added dropwise a solution of 2.5 M n-butyl- lithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below 10 -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) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at -78 °C, warmed to -20 °C and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4 x 500 mL); the organic extracts were dried 15 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 compound as a yellow oil (160 g). *H NMR (CDC13) 8 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, 1H). Step B: Preparation of 3 -chloropyrazole 20 To trifmoroacetic acid (290 mL) was added dropwise 3-chloro-AyV-dimethyl- li7-pyrazole-l-sulfonamide (i.e. the chloropyrazole product of Step A) (160 g), and the reaction mixture was stirred at room temperature for 1.5 hrs 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 25 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). lH NMR (CDCI3) 8 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H). Step C: Preparation of 3 -chloro-2-(3 -chloro- lff-pyrazol-1 -yl)pyridine To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. 30 the product of Step B) (64.44 g, 0.629 mol) in iV^V-dimethylformamide (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 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 35 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). 20 WO 03/015519 PCT/US02/25615 1H NMR (CDCI3) 5 6.43 (s, 1H), 7.26 (m, IH), 7.90 (d, IH), 8.09 (s, IH), 8.41 (d, 1H). Step D: Preparation of 3-cUoro4-(3-crdoro-2-pyridinyl)-lF-pyrazole-5-carboxylic acid To a solution of 3-chloro-2-(3-chloro-li7-pyrazol-l-yl)pyridine (i.e. the pyrazole product of Step C) (39.75 g, 186 mmol) in dry tetrahydrofuran (400 mL) at -78 °C was added dropwise a solution of 2.0 M lithium 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 1 N aqueous sodium hydroxide solution and extracted with ether (2 x 500 mL). The aqueous extracts were acidified with 6 N hydrochloric acid and extracted with ethyl acetate (3 x 500 mL). The ethyl acetate extracts 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 a similar procedure melted at 198-199 °C.) *H NMR (DMSO-d6) 5 6.99 (s, IH), 7.45 (m, IH), 7.93 (d, IH), 8.51 (d, IH). Step E: Preparation of 6-chloro-2-[3-chloro-l-(3-chloro-2-pyridinyl)-lif-pyrazol- 5-yl]-8-methyl-4#-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 S-chloro-l-fS-chloro^-pyridiny^-l^-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of StepD) (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at -5 °C. The reaction mixture was then stirred for 30 minutes at 0 °C. Then, 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, Step A) (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of tnemylamine (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 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). 1H NMR (CDCI3) 6 1.81 (s, 3H), 7.16 (s, IH), 7.51 (m, 2H), 7.98 (d, 2H), 8.56 (d, IH). Step F: Preparation of 3-chloro-N-[4-crdoro-2-memyl-6-[[(l-memylethyl)arriino]- carbonyl]phenyl] -1 -(3 -chlQro-2-pyridinyl)- lH-pyrazole-5-carboxamide To a solution of 6-chloro-2-[3-chloro-l-(3-chloro-2-pyridinyl)-lH-pyrazol-5-yl]-8-methyl-4i7-3,l-benzoxazin-4-one (e.g, 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 tetrahydrofuran solvent was evaporated under reduced pressure, and the 21 WO 03/015519 PCT/US02/25615 . 21 residual solid 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. 1H NMR (CDC13) 6 1.23 (d, 6H), 2.18 (s, 3H)3 4.21 (m5 1H), 5.97 (d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83 (d, 1H), 8.43 (d, 1H), 10.15 (br s, 1H). 5 EXAMPLE 4 Preparation of 3-GhlorO-^[4- EXAMPLE 5 Preparation of 3-bromo-iV-[4-chloro-2-methyl-6-[[(l-methylethyl)amino]carbonyl]phenyl]- 20 1 -(3-chloro-2-pyridinyl)- li7~pyrazole-5-carboxarnide Step A: Preparation of 3 -bromo-iVffi-dimethyl- li7-pyrazole-1 -sulfonamide To a solution of iV-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry tetrahydrofuran (500 mL) at -78 °C was added dropwise a solution of «-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintaining the temperature below -60 °C. A thick 25 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 maintaining the temperature below -70 °C. The reaction mixture turned a clear orange; stirring Avas continued for an additional 15 minutes. The -78 °C bath was removed and the 30 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 methylene chloride-hexane (50:50) as eluent to afford the title product as a clear colorless oil (57.04 g). 35 1H NMR (CDCI3) 5 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H). 22 WO 03/015519 PCT/US02/25615 step B: Preparation of 3-bromopyrazole To trifluoroacetic acid (70 mL) was slowly added 3-bromo-i\yV-dimethyl-li7-pyrazole-1 -sulfonamide (i.e. the bromopyrazole product of Step A) (57.04 g). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated at reduced 5 pressure. The residue was taken up in hexane, insoluble solids were 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 dichloromethane, neutralized with aqueous sodium bicarbonate solution, extracted with methylene chloride (3x), dried over magnesium 10 sulfate and concentrated to afford the title product as a white solid (25.9 g), m.p. 61-64 °C. *H NMR (CDC13) 8 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H). StepC: Preparation of 2-(3-bromo-lJfir-pyrazol-l-yl)-3-chloropyridine To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry A^JV-dimethylformamide (88 mL) was added 15 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 chloride and washed sequentially with water, IN hydrochloric acid, saturated aqueous 20 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 hr. 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 > 94 % pure by NMR. This material was used without further purification in Step D. 25 1H NMR (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-pyridinyl)-liy-pyrazole-5-carboxylic acid To a solution of 2-(3-bromo-lJH"-pyrazol-l-yl)-3-chloropyridme (i.e. the pyrazole product of Step C) (30.4 g, 118 mmol) in dry tetrahydrofuran (250 mL) at -76 °C was added 3 0 dropwise a solution of lithium diisopropylamide (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 warming to -57 °C. The reaction mixture was warmed to -20 °C and quenched with water. The reaction mixture was concentrated and then taken up in water (1 L) and ether (500 mL), 35 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 23 WO 03/015519 PCT/US02/25615 23 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.) 1H NMR (DMSO-dg) 5 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d, 1H). Step E: Preparation of 2-[3-bromo-l-(3-chIoro-2-pyridinyl)-li7-pyrazol-5-yl]- 5 6-chloro-S-rnetb.yl-4.fl-3,1 -benzoxazin-4-one A procedure analogous to that of Example 1, Step E was used to convert 3-bromo- l-(3-chloro-2-pyridinyl)-li?-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step D) (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (0.92 g, 4.96 mmol) to the title product as a solid 10 (1.21 g). *H NMR (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-iV-[4-chloro-2-methyl-6-[[(l-methylethyl)amino]- carbonyljphenyl]-1 -(3-chloro-2-pyridmyl)-lff-pyrazole-5-carboxamide 15 To a solution of "2-[3-bromo-l-(3-chloro-2-pyridinyl)-lJfir-pyrazol-5-yl]-6-chloro-8- methyl-4fl-3,l-benzoxazin-4-one (i.e. 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 20 was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (150 mg), m.p. 159-161 °C. *H NMR (CDCI3) 8 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 6 25 Preparation of 3-bromo-7Y-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]- 1 -(3-chloro-2-pyridinyl)-1 ff-pyrazole-5-carboxamide To a solution of 2-[3-bromo-l-(3-cMoro-2-pyridinyl)-l/T--pyrazol:-5-yl]-6-chloro-8-methyl-4#-3,l-benzoxazin-4-one (i.e. the benzoxazinone product of Example 5, Step E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 30 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 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. 2H NMR (CDCI3) 5 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 35 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H). 24 WO 03/015519 PCT/US02/25615 The following Example 7 illustrates an alternative preparation of l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-li^pyrazole-5-carboxylic acid, which can be used to prepare, for example, N-[4-chloro-2-rnethyl-6-[[(l-methylethyl)amino]carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-liy-pyrazole-5-carboxamide and JV"-[4-chloro~2-rnethyl-5 6-[(me%laniino)carbonylJphenyl]4-(3-chloro-2-pyridinyl)"3-(Mfluorome%l)-liir-pyrazole-5-carboxamide, by further steps illustrated in Examples 1 and 2. EXAMPLE 7 Preparation of l-(3-cMoro-2-pyridmyl)-3-(trifluoromethyl)"l^-pyrazole-5-carboxylic acid Step A: Preparation of 3-chloro-2(l.#)-pyridinone (2,2,2-trifluoro- 10 1 -methyl ethylidene)hydrazone 1,1,1-Trifiuoroacetone (7.80 g, 69.6 mmol) was added to 3-cUoro-2(l.#)-pyridinone hydrazone. (alternatively named (3-chloro-pyridm-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20- 25 °C. After the addition was complete, tire mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl 15 acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5 °C (after crystallization from ethyl acetate/hexanes). IR (nujol) v 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196, 1158, 1100, 1032, 992, 20 800 cnr*. XHNMR (CDC13) 5 2.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-8.32 (m, 2H). MS m/z 237 (M+). Step B: Preparation of ethyl hydrogen ethanedioate (3-chloro- 2-pyridinyl)(2,2,2-trifluoro-1 -methylethylidene)hydrazide (alternatively 25 named ethyl hydrogen ethanedioate (3-chloro-2-pyridmyl)(2,2,2-trifluoro- 1 -methylethylidene)hydrazine) Triethylamine (20.81 g, 0.206 mol) was added to 3-chloro-2(lii0-pyridinone (2,2,2-trifluoro-l-methylethylidene)hydrazone (i.e. the product of Step A) (32.63 g, 0.137 mol) in dichloromethane (68 mL) at 0 °C. Ethyl chlorooxoacetate (18.75 g, 0.137 mol) in 30 dichloromethane (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 °C and a further portion of ethyl chlorooxoacetate (3.75 g, 27.47 mmol) in dichloromethane (14 mL) was added dropwise. After about an additional 1 hour, the mixture was diluted with dichloromethane (about 450 mL), and the mixture was washed with water (2 x 150 mL). 35 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). 25 WO 03/015519 PCT/US02/25615 IR(nujol)v 1751, 1720, 1664, 1572,1417, 1361, 1330, 1202, 1214, 1184,1137, 1110, 1004, 1043,1013,942,807,836 cm-1. 1H NMR (DMSCW6, 115 °C) 1.19 (t, 3H), 1.72 (br s, 3H), 4.25 (q, 2H), 7.65 (dd, /= 8.3, 4.7 Hz, IH), 8.20 (dd, /= 7.6,1.5 Hz, IH), 8.55 (d,/= 3.6 Hz, IH). 5 MS m/z 337 (M+). Step C: Preparation of ethyl 1 -(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy- 3 -(trifluoromethyl)- lff-pyrazole-S-carboxylate Ethyl hydrogen ethanedioate (3-chloro-2^pyridinyl)(2,2,2-trifluoro~l-methyl- ethylidene)hydrazide (i.e. the product of Step B) (5 g, 14.8 mmol) in dimethyl sulfoxide 10 (25mL) was added to tetrabutylammonium fluoride hydrate (10 g) in dimethyl sulfoxide (25 mL) over 8 hours. When the addition was complete, the mixture was poured into acetic acid (3.25 g) in water (25 mL). After stirring at 25 °C overnight, the mixture 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 15 with 1:2 ethyl acetate-hexanes) gave the product as a solid (2.91 g, 50% yield, containing about 5% of 3-cWoro-2(lJ^-pyridinone (2,2,2-trifluoro-l-methylethylidene)hydrazone), 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. 20 *HNMR (CDC13) 5 1.19 (s, 3H), 3.20 (1/2 of ABZ pattern,/= 18 Hz, IH), 3.42 (1/2 of ABZ pattern, J= 18 Hz, IH), 4.24 (q, 2H), 6.94 (dd, J= 7.9, 4.9 Hz, IH), 7.74 (dd, /- 7.7, 1.5 Hz, IH), 8.03 (dd, 7=4.7,1.5 Hz, IH). MS m/z 319 (M+). StepD: Preparation of ethyl l-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)- 25 l.ff-pyrazole-5-carboxylate Sulfuric acid (concentrated, 2 drops) was added to ethyl l-(3-chloro-2-pyridinyl)- 4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-liy-pyrazole-5-carboxylate (i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) and the mixture was wanned to 65 °C for about 1 hour. The mixture was allowed to cool to 25 °C and most of the acetic acid was 30 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 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). IR (neat) V 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277, 1236,1135, 1082, 1031, 35 973,842,802 cm-1. iHNMR (CDCI3) 8 1.23 (t; 3H), 4.25 (q, 2H), 7.21 (s, IH), 7.48 (dd, J= 8.1, 4.7 Hz, IH), 7.94 (dd, J= 6.6, 2 Hz, IH), 8.53 (dd, J= 4.1,1.5 Hz, IH) 26. WO 03/015519 PCT/US02/25615 26 MS m/z 319 (M+). Step E: Preparation of l-(3-chloro-2-pyridmyl)-3-(triflrioromethyl)-li?-pyrazole- 5-carboxylic acid . _____„ Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 5 l-(3-cmoro-2-pyridinyl)-3-(trifluoromethyl)-li7-pyrazole-5-carboxylate (i.e. the product of 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 (3x20mL). The 10 combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), m.p. 178-179 °C (after crystallization from hexanes-ethyl acetate). IR(nujol)v 1711, 1586,1565, 1550, 1440, 1425, 1292, 1247, 1219, 1170, 1135, 1087, 1059, 1031,972,843,816 cm-1. *H NMR (DMSO-J6) 6 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H). 15 The following Example 8 illustrates an alternative preparation of 3-chloro-l-(3-chloro- 2-pyridmyl)-l-#-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-cMoro-A^[4-cHoro-2-memyL6-[[(l-methylethyl)amino]carbonyl]phenyl]-l-(3--chloro-2-pyridinyl)-l#-pyrazole-5-carboxamide and 3-chloro-iV-[4-chloro-2-methyl-6-[(methyl-amino)carbonyl]phenyl]-l -(3-cMoro-2-pyridinyl)-liy-pyrazole-5-carboxamide, by further 20 steps illustrated in Examples 3 and 4. EXAMPLE 8 Preparation of 3-chloro-1 -(3-chloro-2-pyridinyl)-1 i7-pyrazole-5-carboxylic acid Step A: Preparation of ethyl 2-(3-cHoro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (alternatively named ethyl l-(3-chloro-2-pyridinyl)-3-pyrazolidinone- 25 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 mL) 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(l#)-pyridinone 30 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 °C5 the reaction mixture 35 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 27 WO 03/015519 PCT/US02/25615 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 compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by JH NMR. }H NMR (DMSOrfg) 5 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-chloro-2-pyridinyl)-4,5-dihydro- l.ff-pyrazole-5-carboxylate (alternatively named ethyl l-(3-chloro- 2-pyridinyl)-;3-chloro-2-pyrazoline-5-carboxylate) 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) and phosphorus oxychloride (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 minutes, 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 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 bicarbonate slurry over a period of 15 minutes. The resulting, two-phase mixture was stirred vigorously for 20 minutes, 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 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 (800 mL) was treated with magnesium sulfate (30 g) and silica gel (12 g), and the slurry was stirred magnetically for 30 minutes. 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 (92.0 g, 93% yield). The only appreciable impurities observed by *H NMR were 1% starting material and 0.7% acetonitrile. iHNMR (DMSO- 28. WO 03/015519 PCT/US02/25615 28 Step C: Preparation of ethyl 3-chloro-l-(3-chloro-2-pyiidinyl)-li?-pyra2ole- 5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)- 3-chloropyrazole-5-carboxylate) A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux 5 condenser, and nitrogen inlet was charged with ethyl 3-chloro-l-(3-chloro-2-pyridinyl)-4,5-dihydro-l#-pyrazole-5-carboxylate (i.e. the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitrile (1000 mL) and sulfuric acid (98% 35.0 mL, 0,661 mol). The mixture self-heated from 22 to 35 °C upon adding the sulfuric acid. After being stirred for .several minutes, the mixture was treated with potassium persulfate (140 g, 0.518 mol). The 10 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 precipitate. The filter cake was washed with acetonitrile (50 mL). The filtrate was concentrated to about 500 mL on a rotary 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 15 of about 5 minutes. The product was isolated via filtration, washed with aqueous acetonitrile (25%, 3 x 125 mL), washed once with water (100 mL), and then dried overnight in vacuo at room temperature. The product consisted of a crystalline, orange powder (79.3 g, 82% yield). The only appreciable impurities observed by *H NMR were about 1.9% water and 0.6% acetonitrile. 20 lH NMR (DMSO-d6) 8 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71 (dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H). Step D: Preparation of 3-chloro-l-(3-cMoro-2-pyridinyl)-lJ7-pyrazole-5-carboxylic acid (alternatively named l-(3-chloro-2-pyridinyl)-3-chloropyrazole- 5-carboxylic acid) 25 A 1 -L four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-chloro-l-(3-chloro-2-pyridinyl)-lZr-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 30 dissolve. After being stirred for 45 minutes under ambient conditions, all of the starting -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. 35 The solution was treated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol) 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 29 WO 03/015519 PCT/US02/25615 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 jH NMR. !H NMR (DMSO-d6) 5 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56 (d, 1H), 13.95 (br s, 1H). 5 The following Example 9 illustrates an alternative preparation of 3-bromo-1 -(3-chloro- 2-pyridinyl)-l#-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-bromo-iV"-[4-cMoro-2-methyl-6-[[(l-methylethyl)arnino]carbonyl]phenylj-l-(3-chloro-2-pvridinyl)-lif-pyrazole-5-carboxamide and 3-bromo-iV-[4-chloro-2-methyl-6-[(methyl-amino)carbonyl]phenyl]-l-(3-cliloro-2-pyridmyl)-lif-pyrazole-5-carboxamide, by further 10 steps illustrated in Examples 5 and 6. EXAMPLE 9 Preparation of 3-bromo-1 -(3-chloro-2-pyridmyl)-lH-pyrazole-5-carboxylic acid Step Al: Preparation of ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-4,5-dihydro- li/-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro- 15 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-pyridinyl)-5-oxo-3-pyrazoIidinecafboxylate (i.e. the product of Example 8, Step A) (50.0 g, 20 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 25 was charged with sodium bicarbonate (45 g, 0.54 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 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 30 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 rninutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and 35 stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil WO 03/015519 PCT/US02/25615 30 (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by lB. NMR was 0.3% acetonitrile. !H NMR (DMSO-d6) 5 1.15 (t, 3H), 3.29 (dd, 1H)5 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H). Step A2: Preparation of ethyl 3-bromo-l-(3-cMoro-2-pyridinyl>4,5-dihydro- l.ff-pyrazole-5-rcarboxylate 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 8, Step A) (52.0 g, 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 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 filter aid (5 g) and then filtered to remove a purple, tarry substance. The filter cake was washed with dichloromethane (50 mL). The filtrate was transferred to a separatory flannel. 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 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 !H NMR was 0.7% acetonitrile. *H NMR (DMSO-4) 5 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). Step B: Preparation of.ethyl 3-bromo-l-(3-cMoro-2-pyridhyl)-l#-pyrazole- 5-carboxylate (alternatively named ethyl l-(3-chloro-2-pyridinyl)- 3-bromopyrazole-5-carboxylate) 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-dihydro-liJ-pyrazole-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 31 WO 03/015519 PCT/US02/25615 31 minutes, the mixture was treated with potassium persulfate (48.0 g, 0.178 mol). The slurry 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 5 evaporator. A second 1-L four-necked flask equipped with a mechanical stirrer was charged 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 10 only appreciable impurities observed by *H NMR were about 1% of an unknown and 0.5% acetonitrile. 1H NMR (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, 1H). Step C: Preparation of 3-bromo-l-(3-chloro-2-pyridinyl)-lif-pyrazole-5-carboxylic 15 acid (alternatively named 1 -(3-chloro-2-pyridinyl)-3-bromopyrazole- 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)-l#-pyrazole-5-carboxylate (i.e. the product of Step B) (98.5% pure, 25.0 g, 0.0756 mol), methanol 20 (75 mL), water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Upon adding 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 about 90 mL on a rotary evaporator. The concentrated reaction mixture was then diluted 25 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 dropwise with concentrated hydrochloric acid (8.50 g, 0.0839 mol) over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2 x 40 mL), cover washed once with water (25 mL), and then air-dried 30 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 *H NMR were about 0.8% of an unknown and 0.7% ether. 1H NMR (DMSO-d6) 8 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H). 35 The following Example 10 illustrates an alternative preparation of ethyl 3-bromo-1 -(3- cMoro-2-pyridinyl)-4,5-dihydro-li7-pyrazole-5-carboxylate, which can be used to prepare, 32 WO 03/015519 PCT/US02/25615 for example, ethyl 3-bromo-l-(3-chloro-2-pyridinyl)-liy-pyrazole-5-carboxylate (i.e. product of Example 9, Step B). EXAMPLE 10 Preparation of ethyl 3-bromo-l-(3-cWoro-2-pyridinyl)-4,5-dfhydro-li?-pyrazole-5- 5 carboxylate from ethyl 3-cHoro-l-(3-(^oro-2-pyridiriylH,5-dihydK)-lJy-pyrazole-5- carboxylate using hydrogen bromide Hydrogen bromide was passed through a solution of ethyl 3-chloro~l-(3-chloro-2- pyridinyl)4,5-dwydro-li7-pyrazole-5-carboxylate (i.e. product of Example 8, Step B) (8.45 g, 29.3 mmol) in dibromomethane (85 mL). After 90 minutes the gas flow was 10 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 title product as an oil (9.7 g, 99% yield), which crystallized on standing. *H NMR (CDC13) 5 1.19 (t, 3H), 3.24 (1/2 of AB in ABX pattern, /= 9.3, 17.3 Hz, 1H), 3.44 (1/2 of AB in ABX pattern, J= 11.7, 17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (X of ABX, 1H, 15 /= 9.3, 11.9 Hz), 6.85 (dd, J= 4.7, 7.7 Hz, 1H), 7.65 (dd, /= 1.6, 7.8 Hz, 1H), 8.07 (dd, 7=1.6, 4.8 Hz, 1H). The following Example 11 illustrates the preparation of ethyl l-(3-chloro-2-pyridmyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-liy-pyrazole-5-carboxylate, which can be used to prepare ethyl 3-bromo-l-(3-cMoro-2-pyridinyl)-4,5-dihydro-l^/-pyrazole-5-20 carboxylate by procedures similar to that described in Example 10. EXAMPLE 11 Preparation of ethyl 1 -(3 -chloro-2-pyridinyl)-455-dihydro- 3-[[(4-methylphenyl)sulfonyl]oxy]-li7-pyrazole-5-carboxylate Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-25 chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 8, Step A) (10.0 g, 37.1 mmol) and/i-tomenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0 °C. Further portions of jp-toluenesulfonyl 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 diluted with 30 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. IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 868, 845 cm-l. 35 1H NMR (CDCI3) 5 1.19 (t 3H), 2.45 (s, 3H), 3.12 (1/2 of AB in ABX pattern, J= 17.3, 9 Hz, 1H), 3.33 (1/2 of AB in ABX pattern, /= 17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (X of WO 03/015519 PCT/US02/25615 33 ABX, J = 9, 11.8 Hz, 1H), 6.79 (dd, J= 4.6, 7.7 Hz, IB), 7.36 (d, /= 8.4 Hz, 2H), 7.56 (dd, J 1.6, 7.8 Hz, 1H), 7.95 (d, /= 8.4 Hz, 2H), 8.01 (dd, /= 1.4,4.6 Hz, 1H), EXAMPLE 12 Preparation of AN44-cWoro-2-methyl-64(methylamirio)carbonyl]phenyl]-1 -(3-chloro- 5 2-pyridinyl)-3-(2,2,2-trifluoroethoxy)- lH-pyrazole-5-carboxamide Step A: Preparation of ethyl l-(3-chloro-2-pyridinyl)-2,3-dihydro-3^xo-l^-pyrazpl&- 5-carboxylate To a suspension of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. product of Example 8, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200 mL) 10 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 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 15 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 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 20 aqueous phase; this solid (4.5 g) was collected by filtration to provide a combined total of 12.45 g of the title compound. lE NMR (DMSO-d6) 5 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t, 1H), 8.19 (d, 1H), 8.5 (d, 1H), 10.6 (s, 1H). Step B: Preparation of ethyl 1 -(3-chloro-2-pyridinyl)-3-(2,2,2-trifiuoroethoxy)- 25 l/f-pyrazole-5-carboxylate To a suspension of ethyl l-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-l//-pyrazole-5-carboxylate (i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 mL) at -5 °C was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 15 minutes at 20 °C. The stirred suspension was then cooled to 5 °C, and 2,2,2-trifluoro- 30 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 over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a 35 pale yellow oil. JHNMR (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). 34 WO 03/015519 PCT/US02/25615 34 Step C: Preparation of 1 -(3-chloro-2-pyridinyl)-3-(2,2,2-trifiuoroethoxy)- liJ-pyrazole-5-carboxylic acid - To a stirred solution of ethyl l-(3-chloro-2-pyridinyl)-3-(252,2-trifluoroethoxy)-l#-pyrazole-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 mixture was stirred 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 magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0-8 g). 1HNMR (DMSO-J6) 5 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d, iH), 8.55 (d, 1H), 13.7 (bs, 1H). StepD: Preparation of 6-chloro-8-methyl-2ff-3,1 -benzoxazine-2,4(l.fl)-dione To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 1, 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 exothermicarly 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 etnyl ether, and dried to yield the title product compound, obtained as a white solid (98 g). iHNMR (DMSO-d6) 5 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H)S 11.2 (s, 1H). Step E: Preparation of 6-cMoro-2-[l-(3-cMoro-2-pyridinyl)-3-(2,2,2-trifiuoroethoxy)- 1 ff-pyrazol-5-ylJ -8-methyl-4i?"-3,1 -benzoxazin-4-one To a suspension of l-(3-cMoro-2-pyridmyl)-3-(2,2,2-trifluoroethoxy)-l^"-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 g, 24 mmol) stirred in dichloromethane (100 mL) was added A^V-dimemylformamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added dropwise 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#-3,l-benzoxazine-2,4(l.#)-dione (i-e- product of Step D) (4.9 g, 23 mmol) stirred in dry 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 *H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-cMoro-S-memyl-2#-3,l-benzoxazine-254(li?)-dione starting material. A 35 WO 03/015519 PCT/US02/25615 small portion of the collected"precipitate was recrystallized from acetonitrile to yield the pure title product melting at 178-180 °C. !H NMR (DMSO-i6) 6 1.72 (s, 3H), 4.96 (q, 2H)5 7.04 (s, 1H), 7.7 (t, 1H), 7.75 (s, 1H), 7.9 (s, 1H), 8.3 (d, 1H), 8.6 (d, 1H). 5 Step F: Preparation of 7V-[4-chloro-2-metliyl-6-[(metliylamino)carbonyl]phenyl]- l-(3-cMoro-2-pyridinyl)-3--(2,252-trifluoroetrioxy)-li/-pyrazole- 5-carboxamide " __ To a suspension of the 6-cmoro-241-(3-chloxo-2-pyridmyl)-3-(2,2>triflvioioetrioxy)-l^-pyrazol-5-yI]-8-methyl-4i7-3,l-benzoxazin-4-one (i.e. precipitate product of Step E) 10 (3.53 g, 7.5 mmol) in tetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 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 15 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 ether/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 were combined, totaling 2.12 g (after drying) of the title compound, isolated as a white solid, 20 melting at 207-208 °C. 1HNMR (CDC13) 8 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s, 1H), 7.2 (s, IB), 1.25 (s, 1H), 7.35 (t, M), 7.8 (d, 1H), 8.45 (d, IE), 10.0 (s, 1R). Examples 13 and 14 illustrate alternatives to reaction conditions described in Example 5, Step E and Example 3, Step E, respectively. 25 EXAMPLE 13 Preparation of 2-[3-bromo4-(3-cMoro-2-pyridmyl)-l/^pyrazol-5-yl]-6-chloro-8-methyl- 4H-3,1 -benzoxazin-4-one Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 rnmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to -5 °C. A solution of 3-bromo-l-(3-chloro- 30 2-pyridinyl)-l_y-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, 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 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (1.86 g, 35 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 36 WO 03/015519 PCT/US02/25615 36 "dropwise over 5 minutes at a temperature of -5 to 0 °C. The reaction mixture was stirred 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> 5 mL), then with acetonitrile (2x3 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 Zofbax® 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 having 95.7% of total chromatogram peak area. 10 IH NMR (DMS(W6) 5 1.72 (s, 3H) 7.52 (s, IH), 7.72-7.78 (m, 2H), 7.88 (m, IH), 8.37 (dd, IH), 8.62 (dd, IH). EXAMPLE 14 Preparation of 6~chloro-2-[3-chloro- l-(3-chloro-2-pyridinyl)-lijT-pyrazol-S-yij-S-methyl- 4/7-3, l-benzoxazin-4-one - ■ "_ 15 Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 rnmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to -5 °C. A solution of 3-chloro-l-(3-chloro-2-pyridinyl)-li/-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (2.58 g, 10 rnmol) 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 20 mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, 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, and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was 25 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 mL), then with acetonitrile (2x3 mL), and dried under nitrogen to afford the title product as a pale yellow 30 powder, 3.83 g (94.0% crude yield), melting at 199-201 °C. HPLC of the product using a Zorbax® KK.-CS chromatography column (4.6 mm * 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. JH MMR (DMSO-rf6) 5 1.72 (s, 3H), 7.48 (s, IH), 7.74-7.80 (m, 2H), 7.87 (m, IH), 8.37 35 (dd, IH), 8.62 (dd, IH). 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 WO 03/035519 PCT/US02/256J5 37 the Tables which follow: t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, /-Pr means isopropyl, and Bu means butyl. TABLE 1 ■^^^^^ c(0)NR4aR4b Ri R2 R1 g4a R^ R5 Ri R2 R! R4a R4b R! CH3 F CF3 Me H Cl Cl F CF3 Me H Cl CH3 F CF3 Et H Cl Cl F CF3 Et H Cl CH3 F CF3 /-Pr H Cl Cl F CF3 /-Pr H Cl CH3 F CF3 t-Bn H Cl Cl F CF3 t-Bn H Cl CH3 . F CF3 Me Me Cl Cl F CF3 Me Me Cl CH3 F CF3 Me H Br Cl F CF3 Me H Br CH3 F CF3 Et H Br Cl F CF3 Et H Br CH3 F CF3 /-Pr H Br Cl F CF3 /-Pr H Br CH3 F CF3 t-Bn H Br Cl F CF3 /-Bu H Br CH3 F CF3 Me Me Br Cl F CF3 Me Me Br CH3 F CI Me \ H Cl Cl F Cl Me H Cl CH3 F CI Et H Cl Cl F Cl Et H Cl CH3 F CI /-Pr H Cl Cl F Cl /-Pr H Cl CH3 F ci t-Bn H Cl Cl F Cl /-Bu H Cl CH3 F CI Me Me Cl Cl F Cl Me Me ci CH3 F CI Me H Br Cl F Cl Me H Br CH3 F CI Et H Br Cl F Cl Et H Br CH3 F a /-Pr H Br Cl F Cl /-Pr H Br CH3 F Cl /-Bu H Br Cl F Cl t-Bn H Br CH3 F Cl Me Me Br Cl F Cl Me Me Br CB3 F Br Me S Cl | a F Br Me H Cl CH3 F Br Et H Cl Cl F Br Et H Cl CH3 F Br /-Pr H Cl Cl F Br /-Pr H Cl CH3 F Br t-Bn H Cl Cl F Br /-Bu H Cl 38 WO 03/015519 PCT/US02/25615 " Rl R2 R3 R4a R4b . R5 El R2 Rl g4a R4b E! CH3 F Br Me Me Cl Cl F Br Me Me Cl CH3 F Br Me H Br Cl F Br Me H Br CH3 F Br Et H Br Cl F Br Et H Br CH3 F Br z"-Pr H Br Cl F Br z"-Pr H Br CH3 F Br t-Bu -H Br Cl F Br Z"-Bu H Br CH3 F Br Me Me Br Cl F Br Me ■ Me Br CH3 ,F OCH2CF3 Me H Cl Cl F OCH2CF3 Me H Cl CH3 F OCH2CF3 Et H Cl Cl F OCH2CF3 Et H Cl CH3 F OCH2CF3 z-Pr H Cl Cl F OCH2CF3 z"-Pr H ci CH3 F OCH2CF3 t-Bu H Cl Cl F OCH2CF3 t-Bu H Cl CH3 F OCH2CF3 Me Me Cl Cl F OCH2CF3 Me Me Cl CH3 F OCH2CF3 Me H Br Cl F OCH2CF3 Me H Br CH3 F OCH2CF3 Et H Br Cl F OCH2CF3 Et H Br CH3 F OCH2CF3 z"-Pr H Br Cl F OCH2CF3 z"-Pr H Br CH3 F OCH2CF3 t-Bu H Br Cl F OCH2CF3 t-Bu H Br CH3 . F OCH2CF3 Me Me Br Cl F OCH2CF3 Me Me Br CH3 CI CF3 Me H Cl Cl Cl CF3 Me H Cl CH3 CI CF3 Et H Cl Cl Cl CF3 Et H Cl CH3 CI CF3 z"-Pr H Cl Cl Cl CF3 z"-Pr H Cl CH3 CI CF3 t-Bu H Cl Cl Cl CF3 t-Bu H Cl CH3 CI CF3 Me Me Cl Cl Cl CF3 Me Me Cl CH3 CI CF3 Me H Br Cl Cl CF3 Me H Br CH3 CI CF3 Et H Br Cl Cl CF3 . Et H Br CH3 CI CF3 z"-Pr H Br Cl Cl CF3 . z-Pr H Br CH3 CI CF3 t-Bu H Br Cl Cl CF3 t-Bu H Br CH3 CI CF3 Me Me Br Cl Cl CF3 Me Me Br CH3 CI CI Me H Cl Cl Cl Cl Me H Cl CH3 CI CI Et H Cl Cl Cl Cl Et H Cl CH3 CI CI z"-Pr H Cl Cl Cl Cl z"-Pr H Cl CH3 CI CI t-Bu H Cl Cl Cl Cl t-Bu H Cl CH3 CI CI Me Me Cl Cl Cl Cl Me Me Cl CH3 CI a Me H Br Cl Cl Cl Me H Br CH3 CI c\ Et H Br Cl Cl Cl Et H Br CH3 CI Cl z"-Pr H Br Cl Cl Cl z-Pr H Br CH3 CI Cl t-Bu H Br Cl Cl Cl t-Bu H Br CH3 CI ci Me Me Br Cl Cl Cl Me Me Br CH3 Cl Br Me H Cl Cl Cl Br Me H Cl y WO 03/015519 PCT/US02/25615 39 RI R2 R3 B^ R4b & R* R2 El g4a R4b ll CH3 CI Br Et H CI CI CI Br Et H CI CH3 CI Br /-Pr H CI CI ci Br /-Pr H CI CH3 CI Br r-Bu H CI CI CI Br t-Bu H CI CH3 CI Br Me Me CI CI CI " Br Me Me CI CH3 CI Br Me H Br CI CI Br Me H Br CH3 CI Br Et H Br CI CI Br Et H Br CH3 CI Br /-Pr H Br CI CI Br /-Pr H Br CH3 CI Br t-Bu H Br CI CI Br t-Bu H Br CH3 CI Br Me Me Br CI CI Br Me Me Br CH3 CI OCH2CF3 Me H CI CI CI OCH2CF3 Me H CI CH3 CI OCH2CF3 Et H CI CI CI OCH2CF3 Et H CI CH3 CI OCH2CF3 /-Pr H CI CI CI OCH2CF3 /-Pr H CI CH3 CI OCH2CF3 *-Bu H CI CI CI OCH2CF3 t-Bu H CI CH3 CI OCH2CF3 Me Me CI CI CI OCH2CF3 ■ Me Me CI CH3 CI OCH2CF3 Me H Br CI CI OCH2CF3 Me H Br CH3 CI OCH2CF3 Et H Br CI CI OCH2CF3 Et H Br CH3 CI OCH2CF3 /-Pr H Br CI CI OCH2CF3 /-Pr H Br CH3 CI OCH2CF3 t-Bu H Br CI CI OCH2CF3 t-Bu H Br CH3 CI OCH2CF3 . Me Me Br CI CI OCH2CF3 Me Me Br CH3 Br CF3 Me H CI CI Br CF3 Me H CI cn3 Br CF3 Et H CI CI Br CF3 Et H CI CH3 Br CF3 /-Pr H CI CI Br CF3 /-Pr H CI CH3 Br CF3 t-Bu H CI CI Br CF3 r-Bu H CI CH3 Br CF3 Me Me CI CI Br CF3 Me Me CI CH3 Br CF3 Me H Br CI Br CF3 Me H Br CH3 Br CF3 Et H Br CI Br CF3 Et H Br CI{3 Br CF3 /-Pr H . Br CI Br. CF3 /-Pr H Br CH3 Br CF3 t-Bu H Br CI Br CF3 t-Bu H Br CH3 Br CF3 Me Me Br CI Br CF3 Me Me Br CFi3 Br CI Me H CI CI Br CI Me H CI cu3 Br CI Et H CI CI Br CI Et xi CI CH3 Br CI i-Pi H CI CI Br CI /-Pr H CI CR3 Br CI t-Bu H CI CI Br CI t-Bu H CI cn3 Br CI Me Me CI CI Br CI Me Me CI CR3 Br CI Me H Br CI Br CI Me H Br CH3 Br CI Et H Br CI Br CI Et H Br CH3 Br CI /-Pr H Br CI Br CI /-Pr H Br V40 WO 03/015519 PCT/US02/25615 40 Rl R^ R! P> Rl! E£ Rl R2 R! Rif E^ Rl CH3 Br CI t-Bu H Br CI Br Cl r-Bu H Br CH3 Br CI Me Me Br CI Br Cl Me Me Br CH3 Br Br Me H CI CI Br Br Me H Cl CH3 Br Br Et H CI CI Br Br Et H Cl CH3 Br Br z"-Pr H CI CI Br Br z"-Pr XI . Cl CH3 Br Br t-Bu H CI CI Br Br t-Bu H Cl CH3 Br Br Me Me CI CI Br Br Me Me Cl CH3 Br Br Me H Br CI Br Br Me H Br CH3 Br Br Et H Br CI Br Br Et H Br CH3 Br Br z-Pr H Br CI Br Br z-Pr H Br CH3 Br Br t-Bu H Br CI Br Br t-Bu H Br CH3 Br Br Me Me Br CI Br Br Me Me Br CH3 Br OCH2CF3 Me H CI CI Br OCH2CF3 Me H Cl CH3 Br OCH2CF3 Et H CI CI Br OCH2CF3 Et H Cl CH3 Br OCH2CF3 z"-Pr H CI CI Br OCH2CF3 z-Pr H Cl CH3 Br OCH2CF3 t-Bu H CI CI Br OCH2CF3 *-Bu H Cl CH3 Br OCH2CF3 Me Me CI CI Br OCH2CF3 Me Me Cl CH3 Br OCH2CF3 Me H Br a Br OCH2CF3 Me H Br CH3 Br OCH2CF3 Et H Br Cl Br OCH2CF3 Et H Br CH3 Br OCH2CF3 z-Pr H Br Cl Br OCH2CF3 z"-Pr H Br CH3 Br OCH2CF3 t-Bu H Br Cl Br OCH2CF3 t-Bu H Br CH3 Br OCH2CF3 Me Me Br Cl Br OCH2CF3 Me Me Br CH3 CF3 Me H CI Cl CF3 Me H Cl CH3 CF3 Et H CI Cl CF3 Et H Cl CH3 CF3 z"-Pr H CI Cl " CF3 z-Pr H Cl CH3 CF3 t-Bu H CI Cl CF3 t-Bu H Cl CH3 CE3 Me Me CI Cl CF3 Me Me Cl CH3 CF3 Me H Br Cl CH3 CF3 z"-Pr H Br Cl CF3 z"-Pr H Br CH3 CF3 t-Bu H Br Cl CF3 t-Bu H Br CH3 CF3 Me Me Br a CF3 Me Me Br CH3 CI Me H CI Cl Cl Me H Cl CH3 CI Et H CI Cl Cl Et H Cl CH3 CI z"-Pr H CI Cl Cl z"-Pr H Cl CH3 CI t-Bu H CI Cl Cl z-Bu H Cl CH3 CI Me Me CI Cl Cl Me Me Cl Ml WO 03/015519 PCT/US02/25615 . 42 Rl R2 Si R4a Rib El- Rl EH El g4a R^ El CH3 CF3 CI z-Pr H CI CI CF3 CI z-Pr H CI CH3 CF3 CI t-Bu H CI CI CF3 CI t-Bu H CI CH3 CF3 CI Me Me CI CI CF3 CI Me Me CI CH3 CF3 CI Me H Br CI CF3 CI Me H Br CH3 CF3 CI Et H Br CI CF3 CI Et H Br CH3 CF3 CI i-Pr H Br CI ,CF3 CI z-Pr H Br CH3 CF3 CI f-Bu H Br CI CF3 CI z"-Bu H Br CH3 CF3 CI Me Me Br CI CF3 CI Me Me Br CH3 CF3 Br Me H CI CI CF3 Br Me H CI CH3 CF3 Br Et H CI CI CF3 Br Et H CI CH3 CF3 Br z-Pr H CI CI CF3 Br z"-Pr H CI CH3 CF3 Br z"-Bu H CI CI CF3 Br f-Bu H CI CH3 CF3 Br Me Me CI CI CF3 Br Me Me CI CH3 CF3 Br Me H Br CI CF3 Br Me H Br CH3 CF3 Br Et H Br CI CF3 Br Et H Br CH3 CF3 Br i-Pr H Br CI CF3 Br z-Pr H Br CH3 CF3 Br t-Bu H Br CI CF3 Br t-Bu H Br CH3 CF3 Br Me Me Br CI CF3 Br Me Me Br CH3 CF3 OCH2CF3 Me H CI CI CF3 OCH2CF3 Me H CI CH3 CF3 OCH2CF3 Et H CI CI CF3 OCH2CF3 Et H CI CH3 CF3 OCH2CF3 /-Pr H CI CI CF3 OCH2CF3 z-Pr H CI CH3 CF3 OCH2CF3 f-Bu H CI CI CF3 OCH2CF3 z"-Bu H CI CH3 CF3 OCH2CF3 Me Me CI CI CF3 OCH2CF3 Me Me CI CH3 CF3 OCH2CF3 Me H Br CI CF3 OCH2CF3 Me H Br CH3 CF3 OCH2CF3 Et H Br CI CF3 OCH2CF3 Et H Br CH3 CF3 OCH2CF3 z-Pr H Br CI CF3 OCH2CF3 z-Pr H Br CH3 CF3 OCH2CF3 t-Bu H Br CI CF3 OCH2CF3 t-Bu H Br CH3 CF3 OCH2CF3 Me Me Br CI CF3 OCH2CF3 Me Me Br C% CI CI zz-Pr H a CI CI CI zz-Pr H CI CH3 CI CI ZZ-Bu H CI CI CI CI zz-Bu H CI CH3 CI CI 5-Bu H CI CI CI CI j-Bu H CI CH3 CI CI z"-Bu H CI CI CI CI z"-Bu H CI CH3 CI CI Et Me CI CI CI CI Et Me CI F F CF3 Me H CI Br F CF3 Me H CI F F CF3 Et H CI Br F CF3 Et H CI F F CF3 z-Pr H CI Br F CF3 z-Pr H CI F F CF3 z"-Bu H CI Br F CF3 t-Bu H CI M"b WO 03/015519 PCT/US02/25615 45 ^ WO 03/015519 R1 R2 R3 R4a R4b R! F OCH2CF3 i-Pi H CI F OCH2CF3 t-Bu H CI F OCH2CF3 Me Me CI F OCH2CF3 Me H Br F OCH2CF3 Et H Br F OCH2CF3 /-Pr H Br F OCH2CF3 t-Bu H Br F OCH2CF3 Me Me Br F CF3 CF3 Me H CI F CF3 CF3 Et H CI F CF3 CF3 /-Pr H CI F CF3 CF3 t-Bu H CI F CF3 CF3 Me Me CI F CF3 CF3 Me H Br F CF3 CF3 Et H Br F CF3 CF3 /-Pr H Br F CF3 CF3 t-Bu H Br F CF3 CF3 Me Me Br F CF3 CI Me H CI F CF3 CI Et H CI F CF3 CI /-Pr H CI F CF3 CI t-Bu H CI F CF3 CI Me Me CI. F CF3 CI Me H Br F CF3 CI Et H Br F CF3 CI /-Pr H Br F CF3 CI t-Bu H Br F CF3 CI Me Me Br F CF3 Br Me H ci F CF3 Br Et H Cl F CF3 Br z-Pr H Cl F CF3 Br t-Bu H Cl F CF3 Br Me Me Cl F CF3 Br Me H Br F CF3 Br Et H Br F CF3 Br z"-Pr H Br F CF3 Br t-Bu H Br PCT/US02/25615 47 R1 R2 R3 R4a R4b R5 Br OCH2CF3 z"-Pr H Cl Br OCH2CF3 t-Bu H Cl. Br OCH2CF3 Me Me Cl Br OCH2CF3 Me H Br Br OCH2CF3 Et H Br Br OCH2CF3 /-Pr H Br Br OCH2CF3 t-Bu H Br Br OCH2CF3 Me Me Br Br CF3 CF3 Me H Cl Br CF3 CF3 Et H Cl Br CF3 CF3 z"-Pr H Cl Br CF3 CF3 t-Bu H Cl Br CF3 CF3 . Me Me Cl Br CF3 CF3 Me H Br Br CF3 CF3 Et H Br Br CF3 CF3 /-Pr H Br Br CF3 CF3 t-Bu H Br Br CF3 CF3 Me Me Br Br CF3 Cl Me H Cl Br CF3 Cl Et H Cl Br CF3 Cl z"-Pr H Cl Br CF3 Cl t-Bu H Cl Br CF3 Cl Me Me Cl Br CF3 Cl Me H Br Br CF3 Cl Et H Br Br CF3 Cl z"-Pr H Br Br CF3 Cl t-Bu H Br Br CF3 Cl Me Me Br Br CF3 Br Me H Cl Br CF3 Br Et H Cl Br CF3 Br z"-Pr H Cl Br CF3 Br t-Bu H Cl Br CF3 Br Me Me Cl Br CF3 Br Me H Br Br CF3 Br Et H Br Br CF3 Br z"-Pr H Br Br CF3 Br t-Bu H Br 48 WO 03/015519 PCT/US02/25615 48 Rl Rl R3 R4a! R4b R5 Rl R2 R3 R4a R4b R5 F CF3V Br Me Me Br Br CF3 Br Me Me Br F CF3 OCH2CF3 Me H CI Br CF3 OCH2CF3 Me H CI F CF3 OCH2CF3 Et H CI Br CF3 OCH2CF3 Et H CI F CF3 OCH2CF3 z"-Pr H CI Br CF3 OCH2CF3 z"-Pr H CI F CF3 OCH2CF3 t-Bu H CI Br CF3 OCH2CF3 Z-Bu H CI F CF3 OCH2CF3 Me Me CI Br CF3 OCH2CF3 Me Me CI F CF3 OCH2CF3 Me H Br Br CF3 OCH2CF3 Me H Br F CF3 OCH2CF3 Et H Br Br CF3 OCH2CF3 Et H Br F CF3 OCH2CF3 z"-Pr H Br Br CF3 OCH2CF3 z"-Pr H Br F CF3 OCH2CF3 Z-Bu H Br Br CF3 OCH2CF3 Z-Bu ri Br F CF3 OCH2CF3 Me Me Br Br CF3 OCH2CF3 Me Me Br As shown in Scheme 1 and further illustrated in Examples 1-10, the benzoxazines of Formula 2 such as those listed in Table 2 are useful for preparing the compounds of Formula 1, including those listed in Table 1. TABLE 2 Rl R2 R3 R5 Rl R2 R3 R5 CH3 F CF3 CI CI F CF3 CI CH3 F CF3 Br CI F CF3 Br CH3 F CI CI CI F CI CI CH3 F CI Br CI F CI Br CH3 F Br CI CI F Br CI CH3 ■ F Br Br CI F Br Br CH3 F OCH2CF3 CI CI F OCH2CF3 CI CH3 F OCH2CF3 Br CI F OCH2CF3 Br CH3 CI CF3 CI CI CI CF3 CI CH3 CI CF3 Br CI CI CF3 Br CH3 CI CI CI CI CI CI CI 49 PCT/US02/256J5 R2 R3 R5 R1 R2 R3 R5 CI Cl Br Cl Cl Cl Br Cl Br Cl CI Cl Br Cl Cl Br Br Cl Cl Br Br Cl OCH2CF3 Cl Cl Cl OCH2CF3 Cl Cl OCH2CF3 Br Cl Cl OCH2CF3 Br Br CF3 Cl Cl Br CF3 Cl Br CF3 Br Cl Br CF3 Br Br Cl Cl Cl Br Cl Cl Br Cl Br Cl Br Cl Br Br Br Cl Cl Br Br Cl Br Br Br Cl Br Br Br Br OCH2CF3 Cl Cl Br OCH2CF3 Cl Br OCH2CF3 Br Cl Br OCH2CF3 Br CF3 Cl Cl CF3 Cl CF3 Br Cl CF3 Br Cl Cl ■ Cl Cl Cl Cl Br Cl Cl Br Br Cl Cl Br Cl Br Br Cl, Br Br OCH2CF3 Cl Cl OCH2CF3 Cl OCH2CF3 Br Cl OCH2CF3 Br CF3 CF3 Cl Cl CF3 CF3 Cl CF3 CF3 Br Cl CF3 CF3 Br CF3 Cl Cl Cl CF3 Cl Cl CF3 Cl Br Cl CF3 Cl Br CF3 Br Cl Cl CF3 Br Cl CF3 Br Br Cl CF3 Br Br CF3 OCH2CF3 Cl Cl CF3 OCH2CF3 Cl CF3 OCH2CF3 Br Cl CF3 OCH2CF3 Br F CF3 Cl Br F CF3 Cl F CF3 Br Br F CF3 Br F Cl Cl Br F Cl Cl F Cl Br Br F Cl Br F Br Cl Br F Br Cl F Br Br Br F Br Br F OCH2CF3 Cl Br F OCH2CF3 Cl F OCH2CF3 Br Br F OCH2CF3 Br 50 WO 03/015519 PCT/US02/25615 50 R1 R2 R3 R5 R1 R2 R3 R5 F CI CF3 CI Br CI CF3 CI F CI CF3 Br Br CI CF3 Br F CI CI CI Br CI CI CI F CI CI Br Br CI CI Br F CI Br CI Br CI Br CI F CI Br Br Br CI Br Br F CI OCH2CF3 CI Br CI OCH2CF3 CI F CI OCH2CF3 Br Br CI OCH2CF3 Br F Br CF3 CI Br Br CF3 CI F Br CF3 Br Br Br CF3 Br F Br CI CI Br Br CI CI F Br CI Br Br Br CI Br F Br Br CI Br Br Br CI F Br Br Br Br Br Br Br F Br OCH2CF3 CI Br Br OCH2CF3 CI F Br OCH2CF3 Br Br Br OCH2CF3 Br F CF3 CI Br CF3 CI F CF3 Br Br CF3 Br F x C1 CI Br CI CI F CI Br Br CI Br F Br "CI Br Br CI F Br Br Br Br Br F OCH2CF3 CI Br OCH2CF3 CI F OCH2CF3 Br Br OCH2CF3 Br F CF3 CF3 CI Br CF3 CF3 CI F CF3 CF3 Br Br CF3. CF3 Br F CF3 CI CI Br CF3 CI CI F CF3 CI Br Br CF3 CI Br F CF3 Br CI Br CF3 Br CI F CF3 Br Br Br CF3 Br Br F CF3 OCH2CF3 CI Br CF3 OCH2CF3 CI F CF3 OCH2CF3 Br Br CF3 OCH2CF3 Br As shown in Scheme 2 and further illustrated in Examples 1-10, the pyrazolecarboxylic acids of Formula 4 such as those listed in Table 3 are useful in preparing the compounds of Formula 1, including those listed in Table 1. 51 WO 03/015519 - PCT/US02/25615 Rl R5 R3 R5 OCH2CF3 Cl Br Br CF3 Br OCH2CF3 Br CI Br R3 R5 CF3 CI CI CI Br CI Formulation/Utility Compounds of this invention will generally be used as a formulation or composition 5 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 application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, 10 emulsions (including microemulsions and/or suspoemulsions) and the like which optionally 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 15 ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Sprayable 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 20 and surfactant within the following approximate ranges that add up to 100 percent by weight. 52 WO 03/015519 PCT/US02/25615 Weight Percent Active Ineredient Diluent Surfactant Water-Dispersible and Water-soluble Granules, Tablets and Powders. 5-90 0-94 1-15 Suspensions, Emulsions, Solutions (including Emulsifiable Concentrates) 5-50 40-95 0-15 Dusts Granules and Pellets 1-25 0.01-99 70-99 5-99.99 0-5 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 Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Giride, 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 foanij caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity. Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, AyV-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxy-ethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, 7\yV-dimethylformamide, dimethyl sulfoxide, JV-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, rang, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol, benzyl and tetrahydrofurfuryl 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 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 53 WO 03/015519 PCT/US02/25615 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. 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 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 Formulator"s Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., 10 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 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed 15 Confrol as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance 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 prepared in conventional ways. Compound numbers refer to compounds in Index Table A. Example A 20 Wettable Powder Compound 2 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% 25 montmorillonite (calcined) 23.0%. Example B Granule Compound 10 10.0% attapulgite granules (low volatile matter, 30 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example C Extruded Pellet Compound 20 25.0% anhydrous sodium sulfate 10.0% 35 crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. 54 VO 03/015519 PCT/US02/25615 Example D Emulsifiable Concentrate Compound 33 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%. 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" means inhibition of invertebrate pest development (including mortality) that causes significant reduction in feeding or other injury or damage caused by the pest; related 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 Stylommatophora. The term "nematode" includes all of the helminths, such as: roundwonns, 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 actmty against economically important agronomic and nonagronomic pests. The term "agronomic" refers to the production of field crops such as for food and fiber and includes the growth of cereal crops (e.g., wheat, oats, barley, rye, rice, maize), soybeans, vegetable crops (e.g., lettuce, cabbage, tomatoes, beans), potatoes, sweet potatoes, grapes, cotton, and tree fruits (e.g., pome fruits, stone fruits and citrus fruits). The term "nonagronomic" refers to other horticultural (e.g., forest, greenhouse, nursery or ornamental plants not grown in a field), public (human) and animal health, domestic and commercial structure, household, and stored product applications or pests. For reason of invertebrate pest control spectrum and economic importance, protection (from damage or injury caused by invertebrate pests) of agronomic crops. of cotton, maize, soybeans, rice, vegetable crops, potato, sweet potato, grapes and tree fruit by controlling invertebrate pests are preferred embodiments of the invention. Agronomic or nonagronomic pests include larvae of the order Lepidoptera, such as armyworms, cutworms, loopers, and heliothines in the family Noctuidae (e.g., fall armyworm {Spodoptera fiigiperda J. E. Smith), beet arrnyworrn (Spodoptera exigua Htibner), black cutworm (Agrotis ipsilon Hufnagel), cabbage looper (Trichoplusia ni Hxibner), tobacco budworm (Heliothis virescens Fabricius)); borers, casebearers, webworms, coneworms, cabbageworms and skeletonizers from the family Pyralidae (e.g., European corn borer (Ostrinia nubilalis Htibner), navel orangeworm (Amyelois transnsitella Walker), corn root webworm {Crambus caliginosellus Clemens), sod webworm (Herpetogramma 55 WO 03/015519 PCT/US02/25615 licarsisalis Walker)); leafrollers, budworms, seed worms, and fruit worms in the family 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), 5 pink bollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantria dispar Linnaeus)); nymphs and adults of the order Blattodea including cockroaches from the families Blattellidae and Blattidae (e.g., oriental cockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatella asahinai Mizukubo), German cockroach (Blattella germanica Linnaeus), browribanded cockroach (Supella longipalpa Fabricius), American cockroach 10 (Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeira cockroach (Lencophaea maderae Fabricius)); foliar feeding larvae and adults of the order Coleoptera including weevils from the families Anthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptiiis ojyzophilus Kuschel), granary weevil (Sitophilus granarius Linnaeus), rice 15 weevil {Sitophihis oiyzae Linnaeus)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafrniners in the family Chrysomelidae (e.g., Colorado potato beetle (Leptinotarsa decemlineata Say), western corn rootworm (Diabrotica virgifera virgifera LeConte)); chafers and other beetles from the family Scaribaeidae (e.g., Japanese beetle (Popillia japonica Newman) and European chafer (Rhizofrogus majalis 20 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, agronomic and nonagronomic pests include: 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)); 25 adults and nymphs of the orders Hemiptera and Homopfera such as, plant bugs from the family Miridae, cicadas from the family Cicadidae, leafhoppers (e.g. Empoas"ca spp.) from the family Cicadellidae, planthoppers from the families Fulgoroidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae, whitefJies from the family Aleyrodidae, aphids from the family Aphididae, phylloxera from the family 30 Phylloxeridae, mealybugs from the family Pseudococcidae, scales from the . families Coccidae, Diaspididae and Margarodidae, lace bugs from the family Tingidae, stink bugs from the family Pentatomidae, cinch bugs (e.g., Blissus spp.) and other seed bugs from the family Lygaeidae, spittlebugs from the family Cercopidae squash bugs from the family Coreidae, and red bugs and cotton stainers from the family Pyrrhocoridae. Also included are 35 adults and larvae of the order 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 WO 03/015519 PCT/US02/25615 bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e. dust mites in the family Epidermoptidae, 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 5 Neumann), American dog tick (Dermacentor variabilis Say), lone star tick (Ambfyomma americanum Linnaeus) and scab and itch mites in the families Psoroptidae, Pyerhotidae, and Sarcoptidae; adults and immatures of the order Orthoptera including grasshoppers, locusts arid crickets (e.g., migratory grasshoppers (e.g., Melanoplus sanguinipes Fabricius, M. differentialis Thomas), American grasshoppers (e.g., Schistocerca americana Drury), desert 10 locust (Schistocerca gregaria Forskal), migratory locust (Locusta migratoria Linnaeus), house cricket (Acheta domesticus Linnaeus), mole crickets (Gryllotalpa spp.)); adults and immatures of the order Diptera including leafminers, midges, fruit flies (Tephritidae), frit flies (e.g., Oscinella frit Linnaeus), soil maggots, house flies (e.g., Musca domestica Linnaeus), lesser house flies (e.g., Fannia canicularis Linnaeus, F. femoralis Stein), stable 15 flies (e.g., Stomox)>s calcitrans Linnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp., Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanus spp.), bot flies (e.g., Gasfrophilus spp.. Oestrus spp.), cattle grubs (e.g., Hypbderma 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., Prosimulium spp., Simulium 20 spp.), biting midges, sand flies, sciarids, and other Nematocera; adults and immatures of the order 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 feirugineus Fabricius), black carpenter ant (Camponotus pennsylvanicus De Geer), Pharaoh ant (Monomorium pharaonis Linnaeus), little fire ant (Wasmannia 25 auropunctata Roger), fire ant (Solenopsis geminata Fabricius), red imported fire ant (Solenopsis invicta Buren), Argentine ant (Iridomyrmex humilis Mayr), crazy" ant (Paratrechina longicornis Latreille), pavement ant (Tetramorium caespitum 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 30 Isoptera including the eastern subterranean termite (Reticulitermes flavipes Kollar), western subterranean termite (Reticulitermes hesperus 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 firebrat (Thermobia domestica Packard); 35 insect pests of the order Mallophaga and including the head louse (Pediculus humanus 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 57 WO 03/015519 PCT/US02/25615 cattle louse {Haematopinus eurysternus Nitzsch), long-nosed cattle louse {Linognathus vituli 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 (Ctenocephalid.es felis Bouche), dog flea (Ctenocephalides canis Curtis), hen flea (Ceratophyllus gallinae Schrank), sticktight flea (Echidnopliaga gallinacea Westwood), human flea (Pidex irritans Linnaeus) and other fleas afflicting mammals and 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 (Latrodectus mactans Fabricius), and centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleopfrata Linnaeus). Compounds of the present invention also have activity on members of the Classes Nematoda, Cestoda, Trematoda, and Acanthocephala including economically 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 Meloidogyme, lesion nematodes in the genus Pratylenchiis, stubby root nematodes in the genus Trichodorus, etc.) and animal and human health pests (i.e. all economically important flukes, tapeworms, and roundworms, such as Stronglus vidgaris in horses, Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilaria immitis Leidy in dogs, Anoplocephala perfoliata in horses, Fasciola hepatica Linnaeus in ruminants, etc). Compounds of the invention show particularly high activity against pests in the order Lepidoptera (e.g., Alabama argillacea Hiibner (cotton leaf worm), 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 catiginosellus 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 arniigera Hiibner (American bollworm), Helicoverpa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogramma licarsisalis Walker (sod webworm), Lobesia botrana Denis & Schiffermiiller (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 Hiibner (beet armyworrn), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperda J. E. Smith (fall armyworrn), Trichoplusia m Hubner (cabbage looper) and Tuta absoluta MejTick (tomato leafminer)). Compounds of the invention also have commercially significant activity on members from the order Homoptera including: Acyrthisiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi 58 WO 03/015519 PCT/US02/25615 De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerel1 (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), 5 Hyaloptems pruni Geoffroy (mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophium dirrhodum Walker (cereal aphid), Macrosipum euphorbiae Thomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (com leaf aphid), Rhopahsiphwn padi Linnaeus (bird cherry-10 oat aphid), Schizaphis graminum Rondani (greenbug), Sitobion avenae Fabricius (English 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 devastatiix Pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii 15 Bellows & Perring (silverleaf whitefly), Dialeurodes citri Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhouse whitefly); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stal (rice leafhopper), Nilaparvata lugens Stal (brown planthopper), 20 Peregrinus maidis Ashmead (corn planthopper), Sogatella furcifera Horvath (white-backed planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocyba pomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotus perniciosus Comstock (San Jose scale); Planococcus citri Risso (citrus 25 mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmon psylla). These compounds also have activity on members from the order Hemiptera including: Acrostemum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Coiythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato 30 bug), Dysdercus suturellus Herrich-Schaffer (cotton stainer), Euchistus servus Say (brown stink bug), Euchistus variolarius Palisot de Beauvois (one-spotted stink 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 35 (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 WO 03/015519 PCT/US02/25615 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 Limonhis). Compounds of this invention can also be mixed with one or more other biologically 5 active compounds or agents including insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators such as rooting stimulants, chemosterilants, semiocheimcals, 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 the present invention also pertains to a 10 composition comprising a biologically effective amount of a compound of Formula 1 and an effective amount of at least one additional biologically active compound or agent and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. 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 15 (S-1955), avermectin, azadirachtin, azinphos-methyl, bifehthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrm, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycarb, 20 fenpropathrin, fenvalerate, fipronil, flonicaniid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron, irnidacloprid, indoxacarh, isofenphos, lufehuron, malathion, metaldehyde, methamidopnos, methidathion, methomyl, methoprene, methoxychlor, monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, 25 phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine, pyridalyi, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos, tebufenozide, tefiubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralometlirin, trichlorfon and triflumuron; fungicides such as acibenzolar, azoxystrobin, behomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), 30 bromuconazole, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, (S)~3,5-dichloro-^-(3-chloro-1 -ethyl-1 -methyl-2-oxopropyl)-4-methylbenzamide (KH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole, (S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one (RP 407213), dimethomorph, 35 dimoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil, flumetover (RPA 403397), flumorf/flumorlin (SYP-L190), fluoxastrobin (HEC 5725), 60 WO 03/015519 PCT/US02/25615 fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658), hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, kresoxim-metlryl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrdbin (SSF-126), metrafenone (AC375839), 5 myclobutanil, neo-asozin (ferric methanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU6476), pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thirain, tiadinil, triadimefon, triadimenol, 10 tricyclazole, trifloxystrobin, triticonazole, validamycin and vinclozolin; nematocides such as aldicarb, oxamyl and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis including 15 ssp. aizawai and Icurstaki, Bacillus thuringiensis delta endotoxin, baculoviras, and entomopathogenic bacteria, virus and fungi. Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis toxin). The effect of the exogenously applied invertebrate pest control compounds of this invention may be synergistic with the 20 expressed toxin proteins. A general reference for these agricultural protectants is The Pesticide Manual, 12th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2000. Preferred insecticides and acaricides for mixing with compounds of this invention 25 include pyrethroids such ars cypermethrin, cyhalothrin, cyfluthrin, beta-cyfluthrin, esfenvalerate, fenvalerate and tralomethrin; carbamates such as fenothicarb, methomyl, oxamyl and thiodicarb; neonicotinoids such as clothianidin, imidacloprid and thiacloprid; neuronal sodium channel blockers such as indoxacafb; insecticidal macrocyclic lactones such as spinosad, abamectin., avermectin and emamectin; y-aminobutyric acid (GABA) 30 antagonists such as endosulfan, ethiprole and fipronil; insecticidal ureas such as flufenoxuron and triflumuron; juvenile hormone mimics such as diofenolan and pyriproxyfen; pymetrozine; and amitraz. Preferred biological agents for mixing with compounds of this invention include Bacillus thuringiensis and Bacillus thuringiensis delta endotoxin as well as naturally occurring and genetically modified viral insecticides including 35 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 61 WO 03/015519 PCT/US02/25615 with methomyl; a mixture of a compound of this invention with imidacloprid; a mixture of a 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 abarnectin; 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 flufenoxurdn; a mixture of a compound of this invention with pyriproxyfen; a mixture of a compound of this invention with pymetrozine; a mixture of a compound of mis invention with amitraz; a mixture of a compound of mis 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 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 a biologically effective amount of at least one additional invertebrate pest control compound or agent having a similar spectrum of control but a different mode of action. Contacting a plant genetically modified to express a plant 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 in agronomic and nonagronomic applications by applying one or more of the compounds of this invention, 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 controlling an invertebrate pest, comprising contacting the invertebrate pest or its 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 with a composition comprising at least one such compound and an effective amount of at least one additional biologically active compound or agent. Examples of suitable compositions comprising a compound of the invention and an effective amount of at least one additional biologically active compound or agent include granular compositions wherein the additional biologically active compound or agent is present on the same granule as the compound of the invention or on granules separate from those of the compound of this invention. 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 also effectively delivered 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 soil, a nursery box 62 WO 03/015519 PCT/US02/25615 62 treatment or a dip of transplants. Compounds are also effective by topical application of a composition comprising a compound of this invention to the locus of infestation, Other methods of contact include application of a compound or a composition of the invention by direct and residual sprays, aerial sprays, gels, seed coatings, microencapsulations, systemic 5 uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others. The compounds of this invention may also be impregnated into materials for fabricating invertebrate control devices (e.g., insect netting). The compounds of this invention can be incorporated into baits that are consumed by the invertebrates or within devices such as traps and the like. Granules or baits comprising 10 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. The compounds of this invention can be applied in their pure state, but most often 15 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 concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl 20 butoxide 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 behavior, mating behavior, ambient moisture, temperature, and the like. Under normal 25 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 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required. 30 One skilled in the art can easily determine the biologically effective amount necessary for the desired level of invertebrate pest control. The following Tests in the Biological Examples of the Invention demonstrate the control efficacy of compounds of this invention on specific pests. "Control efficacy" represents inhibition of arthropod development (including mortality) that causes significantly 35 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, Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; accordingly 63 WO 03/015519 PCT/US02/25615 63 /-Pr is isopropyl, s-Bu. is secondary butyl, etc. The abbreviation "Ex." stands for "Exampler and is followed by a number indicating in which example the compound is prepared. INDEX TABLE A R3 Compound Rl R2 R3 R4a R4b R5 m.p.(°C) 1 Me Br CF3 z"-Pr H CI 197-198 2 (Ex. 1) Me CI CF3 z-Pr H CI 195-196 3 Me CI CF3 t-Bv H CI 223-225 4 (Ex. 2) Me CI CF3 Me H CI 185-186 / 5 Br Br CF3 z-Pr H CI 192-193 6 Br Br CF3 f-Bu H CI 246-247 7 Br Br CF3 Me H CI 162-163 8 Br Br CF3 Et H CI 188-189 9 CI CI CF3 z-Pr H CI 200-201 10 CI CI CF3 t-BM H CI 170-172 11 CI CI CF3 Me H CI 155-157 12 ci. CI CF3 Et H CI 201-202 13 Me Br CF3 t-Bu H CI 247-248 14 Me Br CF3 Et H CI 192-193 15 Me F CF3 z"-Pr H CI 179-180 16 "Me Br Br z-Pr H CI 185-187 17 Me CF3 CF3 /-Pr H CI 235-236 18 Me CF3 CF3 Et H CI 216-217 19 Me I CF3 f-Pr H CI 188-189 20 (Ex. 6) Me CI Br Me H CI 162-164 21 Me CI Br t-Bu •H CI 159-161 22 Br Br Br z-Pr H CI 162-163 23 Br Br Br Me H CI 166-168 24 Br Br Br /-Bu H CI 210-212 25 CI CI Br i-Pr H CI 188-190 64 WO 03/015519 PCT/US02/25615 64 Compound Rl R2 R3 R4a R4b R5 m.p. (°C) 26 CI CI Br r-Bu H CI 179-180 27 (Ex. 5) Me CI Br z-Pr H CI 159-161 28 CI CI CF-i z-Pr H CI 200-202 29 CI Br CF3 t-Bu H CI 143-145 30 CI Br CF3 Me H CI 171-173 31 Me Br Br Me H CI 147-149 39 33 (Ex. 3) Me Me Br CI CF, CI Me z-Pr H H a c 222-223 173-175 34 (Ex. 4) Me CI CI Me H ci 225-226 35 Me CI CI r-Bu H ci 163-165 36 Me Br CI z-Pr H CI 152-153 37 Me Br CI Me H CI 140-141 38 Me Br Br t-Bu H CI 215-221 39 Me CFq Me H CI 199-200 40 Me CF3 CF3 f-Bu H CI 148-149 41 Me CI CI Et H CI 199-200 42 Br Br CI z-Pr H CI 197-199 43 Br Br CI Me H CI 188-190 44 Br Br CI /-Bu H CI 194-196 45 Br Br CI Et H CI 192-194 46 CI CI CI z-Pr H CI 197-199 47 CI CI CI Me H CI 205-206 48 CI CI CI t-Bu H CI 172-173 49 CI CI CI Et H CI 206-208 50 Me Br /-Bu H CI 124-125 51 Br Br Br Et H CI 196-197 52 CI CI Br Me H CI 245-246 53 CI CI Br Et H CI 214-215 54 Me Br Br Et H CI 194-196 55 Me Br Me H CI 229-230 56 Me Br z-Pr H CI 191-192 57 Me CF3 CF3 Me H CI 249-250 58 59 60 61 Me Me Me Me CI CI CF3 CT3 CF3 Br Et Et t-Bu Et H H H H CI CI CI CI 163-164 199-200 242-243 194-195 65 WO 03/015519 PCT/US02/256I5 65 Compound "62 Rl Me R3 CF3 R4a Me R4b H R5 CI m.p.(eC) 213-214 63 Me CF3 Et H CI 212-213 64 Me CF3 f-Bu H CI 142-143 65 Me Br Me H CI 214-215 66 Me Br Et H CI 205-205 67 Me Br i-Pr H CI 206-208 68 Me CI z"-Pr H CI 184-185 69 Me CI Me H CI 180-182 70 Me CI Et H CI 163-165 71 Me Br CI Et H CI 192-194 72 Me CI Me H CI 233-234 73 Me CI Et H CI 196-197 74 Me CI i-Pr H CI 189-190 75 Me CI t-Bu H CI 228-229 76 Me Br CI t-Bu H CI 224-225" 77 Br Br CI Me Me CI 153-155 78 Me Br CF3 Me Me CI 207-208 79 CI CI CI Me Me CI 231-232 80 Br Br Br Me Me CI 189-190 81 CI Cl Br Me Me Cl 216-218 82 Cl Cl CF3 Me Me Cl 225-227 83 Me Br OCH2CF3 i-Pr H Cl 213-215 84 Me Br OCH2CF3 Me H Cl 206-208 85 Me Cl OCH2CF3 f-Pr H Cl 217-218 86 Me Cl OCH2CF3 Et H Cl 205-207 87 (Ex. 10) Me Cl OCH2CF3 Me H Cl 207-208 Me Br OCH2CF3 Et H Cl 208-211 89 Me Br OCH2CF3 t-Bu H Cl 213-216 90 Br Br CF3 Me Me Cl 228-229 91 Cl Br CF3 Me Me Cl 238-239 92 Cl OCH2CF3 z"-Pr H Cl 232-235 93 Cl Cl OCH2CF3 Me H Cl 192-195 94 Cl Cl OCH2CF3 Me Me Cl 132-135 95 96 97 Br Br Br Br Br Br OCH2CF3 OCH2CF3 OCH2CF3 i-Pr Me Me H H Me Cl Cl Cl 225-227 206-208 175-177 66 PCT/US02/25615 66 Compound Rl R2 R3 R4a R4b R5 m.p. (°C) 98 CI Br Br Me Me CI 237-238 99 CI Br CI Me H CI 228-229 100 CI Br CI Me Me Cl 236-237 101 CI Br Br Me H CI 226-227 102 CI F CF3 Me Me CI 215-216 103 CI F CF3 Me H CI 219-220 104 Br F Br Me Me a 235-236 105 Br F Br Me H Cl 238-239 106 Br F Br /-Pr H Cl 236-237 107 Br F CI Me Me Cl 246-247 108 Br F CI Me H Cl 233-234 109 Br F CI i-Pr H Cl 153-154 110 Me " F CI Me Me Cl 242-243 111 CI F Br Me Me Cl 245-246 112 CI F Br Me H Cl 217-218 113 CI F Br /-Pr H Cl 168-169 114 CI F CI Me Me Cl 239-240 115 CI F CI Me H Cl 248-249 116 CI F CI /-Pr H Cl 169-170 117 Br F CF3 Me Me Cl 191-192 118 Br F CF3 Me H Cl 228-229 119 Br F CF3 i-Pr H Cl 224-226 120 Br CI Br Me Me Cl 188-189 121 Br CI Br Me H Cl 248-249 122 Br CI " Br /-Pr H Cl 252-253 123 Br CI CI Me Me Cl 147-148 124 Br CI CI Me H Cl 249-250 125 Br CI CI /-Pr H Cl 239-240 126 Br CI CF3 Me Me Cl 200-201 127 Br CI CF3 Me H Cl 158-159 128 Br CI CF3 /-Pr H Cl 250-250 129 Me CI Cl Me Me Cl 232-233 130 Me CI Br Me Me Cl 210-211 131 F F Br Me H Cl 197-198 132 F F Br Me Me Cl 218-222 133 F CI Br Me H Cl 203-204 67 WO 03/015519 PCT/US02/25615 67 Compound Rl R2 R3 R4a R4b R5 m.p. (°C) 134 F CI Br Me Me CI 226-227 135 F CI Br . f-Pr H CI 207-208 136 F CI CI Me H CI 211-212 137 F CI CI Me Me CI 237-238 Z3S F F CI Me H CI 159-160 139 F F cI Me Me CI 225-226 140 F F CI z-Pr H CI 201-202 141 F Br Br Me H CI 209-210 142 F Br Br Me Me CI 225-226 143 F Br Br z-Pr H CI 208-209 144 F Br CI Me H .ci 209-210 145 F Br ci Me " Me CI 244-245 146 F Br CI i-Pr H CI 207-208 147 F Br OCH2CF3 Me H CI 210-211 148 F Br OCH2CF3 Me Me CI 204-206 BIOLOGICAL EXAMPLES OF THE INVENTION TESTA For evaluating control of diamondback moth {Plutella xylostella) the test unit consisted of a small open container with a 12-14-day-old radish plant inside. This was pre-infested 5 with 10-15 neonate larvae on a piece of insect diet by use of a core sampler to remove a plug from a sheet of hardened insect diet having many larvae growing on it and transfer the plug containing larvae and diet to the test unit. The larvae moved onto the test plant as the ditt plug dried out. Test compounds were formulated using a solution containing 10% acetone, 90% water 10 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 1.27 cm (0.5 inches) above the top of each test unit. All experimental compounds in this 15 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 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 20 (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7, 8, 9, 1=0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 68 WO 03/015519 PCTAJS02/25615 68 .45,46, 47,48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93,94, 95,96, 97, 98, 99,100, 101,102,103, 104, 105, 106, 107,108,109, 110, 111, 112, 113,114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127,.128, 129, 130, 131, 132, 133, 5 134,135,136,137. TESTB For evaluating control of fall armyworm (Spodoptera frugiperda) the test unit consisted of a small open container with a 4-5-day-old corn (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 10 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. Of the compounds tested, the following provided excellent levels of plant protection 15 (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20,21,22,23,24, 25,26,27, 28,29, 30,31, 32, 33,34, 35, 36, 37, 38, 39,40,41, 42, 43,44, 45,46, 47,48,49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82s 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 20 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132; 133, 134,135,136,137. TESTC For evaluating control of tobacco budworm (Heliothis virescens) the test unit consisted of a small open container with ei 6-7 day old cotton plant inside. This was pre-infested with 25 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. Of the compounds tested, the following provided excellent levels of plant protection 30 (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22,23,24, 25, 26,27,28,29, 30,31, 32, 33,34, 35, 36, 37, 38, 39,40,41,42, 43, 44, 45,46, 47,48,49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 61, 68, 69, 70,71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 35 115,116,117,119,120,121,122,123,124,125,126,127,128,129. 69 WO 03/015519 PCT/US02/25615 TEST D For evaluating control of beet armyworm (Spodoptera exigiia) tire test unit consisted of a small open container with a 4-5-day-old com 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. 5 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. Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 10 20,21,22,23,24,25, 26,27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41,42, 43,44, 45, 46,47,48,49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72,73,74,75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 100 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117,119,120,121,122, 123, 124,125, 126,127, 128, 129. 15 TEST E For evaluating control of green peach aphid (Myzus persicae) through contact and/or 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 culture plant (cut-leaf method). The larvae moved onto the 20 test plant as the leaf piece desiccated. After pre-infestation, the soil of the test unit was covered with a layer of sand. 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, 25 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 1.27 cm (0.5 inches) above the top of each test unit; All 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 30 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. Of the compounds tested, the following resulted in at least 80% mortality: 1,2,3,4,5, 6, 7, 8,10,11, 12, 13, 14, 16,20, 21, 22, 23, 25,26, 27,28, 29, 31, 32, 33, 36, 38, 39,41,42, 43,45,46, 47,49, 51, 52, 54, 55, 56, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 69, 72, 74,77,78, 35 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 93, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108,109, 111, 112, 113,114,115, 116,126,127,128,131, 135. 70 I WO 03/015519 PCT/OS02/25615 70 TE5T F For evaluating control of cotton melon aphid (Aphis gossypii) 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 5 cut-leaf method described for Test E, and the soil of the test unit was covered with a layer of sand. Test compounds were formulated and sprayed at 250 ppm as described for Test E. 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 E. tO Of the compounds tested, the following resulted in at least 80% mortality: 1, 2, 4, 5, 7, 8,10, 11, 12, 13, 14, 16, 20, 21, 22, 23, 25, 26, 27, 28, 29, 31, 32, 33, 34, 36, 38, 39, 42, 43, 45,46,47,49, 51, 52, 53, 54, 55, 56, 58, 59, 62, 63, 65, 66, 67, 77, 78, 79, 80, 81, 82, 87, 88, ) 90, 91, 93, 94, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114,115,116,117,119,120,121, 122,123,124, 125,126,127,128,131,133,135,136. 15 TEST G For evaluating control of silverleaf whitefly (Bemisia tabaci), the test unit consisted of 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 20 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¬off on a turntable sprayer (patent application EP-1110617-A1). 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 25 humidity and 28 °C daytime and 24 °C nighttime temperature. Then the leaves were removed and then dead and live nymphs were counted to calculate percent mortality. Of the compounds tested, the following resulted in at least 80% mortality: 1,2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14, 16,19, 20,21, 22, 23, 24,25, 26, 27, 29, 31, 32, 33, 34, 39, 42, 43,45, 46,47,49, 51, 52,53, 54, 55, 56, 59, 77, 78, 79, 80, 81, 82, 87, 90, 93. 30 TEST H For evaluating soil systemic control of tobacco budworm (Heliothis virescens), cotton plants were grown in sassafras soil in 15-cm pots in aluminum trays. When the plants reached square stage (bud formation on the plant) the plants were treated with the test compounds. 35 Test compounds were formulated in 0.25 mL of acetone and then diluted with water to provide solutions of 1, 5, 10 and 50 ppm. 10 mL of the treatment solutions were added to the pots weekly for four weeks, with four replicates of each treatment rate. One day after the 71 second, third and fourth treatments, 35-50 first instar Heliothis virescens larvae were brushed on 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 5 (10% or less feeding damage): 16. Of the compounds tested, the following also provided excellent protection of squares and bolls at 10 ppm, with no feeding or minimal sepal damage: 16. TEST I Test I followed an alternative protocol for evaluating soil systemic control of tobacco 10 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. 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 15 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 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 20 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 moisture for plant material. One second instar tobacco budworm was placed into each well with plant material; cells were sealed and held at 25 °C and provided with 16 hours of light 25 per day. For leaves excised at 1, 2, and 4 days mortality was observed 4 days after treatment with one second instar todacco budworm. Of the compounds tested, the following compounds provided excellent levels of mortality (greater than 70% mortality) on upper leaves excised at 4 days after treatment at the test rate: 2,27,33. 30 TEST J For evaluating soil systemic control of fall armyworm (Spodoptera frugiperda), corn (maize) plants (Eioneer #3394) were grown in small pots for 5 days until they were at least 4 cm tall and the first leaf was Unfurling. Test compounds were dissolved in 0.25 mL of acetone and diluted with water to 35 provide solutions of 1, 10, 50 and 200 ppm. 1 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 72 WO 03/015519 PCT/TJS02/25615 72 next day 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: Cleaxpack 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 5 clear plastic lid molded so.that it locked 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 corn plant matter was placed into a tray such that the plant matter was contained within two wells. One second-instar fall armyworm (Spodoptera frugiperda) larva was placed in each well, the tray was covered and then the test units were held at 25 °C 10 with 16 hours of light per 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 (Cary, NC, U.S.A.). Of the compounds tested, the following provided excellent levels of mortality, with 15 LC90 values of 10 ppm or less: 1,2, 4,9, 11,12, 14, 16, 20, 22, 24, 31, 32, 33, 34. TEST K For evaluating control of Colorado potato beetle (Leptinotarsa decemlineate), 5 mg samples of the test compounds were dissolved in 1 mL of acetone. This solution was then diluted to 100 mL total volume using an aqueous 500 ppm solution of Ortho X-77™ 20 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 potato or tomato 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). After each treated plant had dried, leaves were excised from the treated 25 plant. The leaves were cut into pieces, which were placed singly into 5.5 cm-by-3.5 cm cells of a sixteen-cell plastic tray. Each cell contained a 2.5-cm square of moistened chromatography paper to prevent desiccation. One second instar larvae was placed in each cell. At three days after infestation the total number of dead Colorado potato beetles was recorded. 30 Of the compounds tested, the following resulted in at least 90% mortality at 10 ppm: 2,4,27,33,34,41,61,85. TESTL 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. 73 WO 03/015519 PCT/US02/25615 73 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 following provided excellent levels of plant protection at 50 ppm (10% or less feeding damage): 20,27. TESTM 10 For evaluating control of thrips (Frankliniella sp.), samples of the test compounds were dissolved in 1 mL 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 32. 74 We claim: 1. A process for preparing a compound of formula 1 by reacting a benzoxazinone of formula 2 with an C1-C4 alkyl amine or dimethylamine. \\VULCAN\Patent Docs\ARCHANA\Dupont\Gmntedprocess claims DUPONT 13813(P-6).doc A process as claimed in claim 1 wherem said benzoxazinone of formula 2 is prepared by coupling of a pyrazolecarboxylic acid of formula 4 with an anthranilic acid of formula 3. tertiary amine 4. MeS(0)2d 3. A process as claimed in claim 2 wherein said coupling reaction comprising sequential addition of methanesulfonyl chloride in the presence of a tertiary amine to a pyrazolecarboxylic acid of formula 4, followed by the addition of an anthranilic acid of formula 3, followed by a second addition of methanesulfonyl chloride and a tertiary amine. 4. A process as claimed in claim 3 wherein said tertiary amine is triethylamine or pyridine. 5. A process as claimed in claim 1 wherein said benzoxazinone of formula 2 is prepared by coupling a pyrazole acid chloride of formula 6 with an isatoic anhydride of formula 5. \\VULCAN\Patent Docs\ARCHANA\Dupont\Grantedprocess claims DUPONT 13813(P-6).doc 6. A process as claimed in claim 5 wherein said reaction is carried out in the presence of an organic solvent. 7. A process as claimed in claim 5 wherein said pyrazole acid chloride of formula 6 is prepared by chlorination of a pyrazolecarboxylic acid of formula 4 with thionyl chloride or oxalyl chloride. 8. A process as claimed in claim 2 wherein the anthranilic acid of formula 3, wherein R2 is chloro, bromo or iodo, is prepared by halogenation of an unsubstituted anthranilic acid of formula 7 with an TV-halosuccinimide in an organic solvent A process as claimed in claim 5 wherein said isatoic anhydride of formula 5 is prepared from oxidation of an isatin of formula 9 with hydrogen peroxide. 10. A process as claimed in claim 5 wherein said isatoic anhydride of formula 5 \\VULCAN\Patent Docs\ARCHANA\Dupont\Grantedprocess claims DUPONT 13813(P-6).doc is prepared by reacting an anthranilic acid of formula 3 Rl with phosgene or a phosgene equivalent. 11. A process as claimed in claim 2 wherein said pyrazolecarboxylic acid of formula 4 is prepared by - reacting pyrazole 10 with a 2,3-dihalopyridine of formula 11 to obtain 1-pyridylpyrazole of formula 12 in the presence of a base, and - metallation of said 1-pyridylpyrazole of formula 12 with lithium diisopropylamide, - followed by quenching of the lithium salt with carbon dioxide to obtain the pyrazolecarboxylic acid of formula 4. \WULCAN\Patent Docs\ARCHANA\Dupont\Grcmted process claims DUPONT 13813(P-6)-doc 12. A process as claimed in claim 11 wherein pyrazole of formula 10, wherein R is C1 or Br, is prepared by - metallation of the sulfamoyl pyrazole of formula 13 with n-butyllithium followed by direct halogenation of the anion with either hexachloroethane (for R being CI) or 1,2-dibromo-tetrachloroethane (R3 being Br) to afford the halogenated compound of formula 14, and - removal of the sulfamoyl group with trifluoroacetic acid at room temperature to afford the pyrazole of formula 10. \\VULCAN\Patent Doc$\ARCHANA\Pupont\Grantedprocess claims DUPONT 13813(P-6).doc A process as claimed in claim 2 wherein the pyrazolecarboxylic acid of formula 4, wherein R3 is CF3, is prepared by - reacting a compound of formula 15 wherein R6 is C1-C4 alkyl with a suitable base in a suitable organic solvent, - neutralizing with an acid to afford a compound of formula 16, - dehydrating the compound of formula 16 to obtain a compound of formula 17, and - converting the carboxylic ester of formula 17 to the carboxylic acid of formula 4 by nucleophilic cleavage or hydrolysis. A process as claimed in claim 13 wherein said suitable base is sodium hydride, potassium t-butoxide, dimsyl sodium, alkali metal carbonates or hydroxides, tetraalkyl ammonium fluorides or hydroxides, or 2-tert-butylimino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphonine. A process as claimed in claim 13 wherein said suitable organic solvent is acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide or N,N-dimethylformamide. A process as claimed in claim 13 wherein a compound of formula 15 is prepared by WVULCANXPatent Docs\ARCHANA\Dupont\Grantedprocess claims DUPONT 13813(P-6).doc treating a hydrazine compound of formula 18 with a ketone of formula 19 in a protic solvent to afford a hydrazone of formula 20, and reacting the hydrazone of formula 20 with a compound of formula 21 in an organic solvent in the presence of an acid scavenger to obtain the compound of formula 15. O R3v. .CH3 solvent 18 JL. Y 17. A process as claimed in claim 2 wherein said pyrazolecarboxylic acid of formula 4, wherein R is CI or Br, is prepared by conversion - reacting a compound of formula 22 with an oxidizing agent to afford a compound of formula 17, and - converting the carboxylic ester of formula 17 to the carboxylic acid of formula 4 by nucleophilic cleavage or hydrolysis. 22 17 18. A process as claimed in claim 17 wherein the oxidizing agent is hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate or potassium permanganate. 19. A process as claimed in claim 17 wherein the compound of formula is 22 is prepared by treating a compound of formula 23 wherein R C1-C4 alkyl with a halogenating reagent in the presence of a solvent. \\VULCAN\Patent Docs\ARCHANA\Dupont\Granted process claims DUPONT 13813(P-6).doc halogenation■ 23 22 20. 21. A process as claimed in claim 19 wherein the halogenating agent is phosphorous oxyhalides, phosphorous trihalides, phosphorous pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl chloride or phosgene. A process as claimed in claim 2 wherein the pyrazolecarboxylic acid of formula 4, wherein R3 is OCH2CF3, is prepared by - oxidizing a compound of formula 23 wherein R6 is C1-C4 alkyl to obtain a compound of formula 17a, - alkylating the compound of formula 17a by contacting said compound with an alkylating agent of formula 24 in the presence of at least one equivalent of a base to afford a compound of formula 17b, and - converting the carboxylic ester of formula 17b to the carboxylic acid of formula 4 by nucleophilic cleavage or hydrolysis. 23 17a 17b 22. A process as claimed in claim 19 or 21 wherein the compound of formula 23 is prepared by contacting a hydrazine of formula 18 with a compound of formula 25 in the presence of a base and a solvent. \\VULCAN\Patent Docs\ARCHANA\Dupont\Grantedprocess claims DUPONT 13813(P-6).doc + R6O2CCH=CHC02R6 25 base 23 18 Dated this 8th January day of 2005 Shanti Kumar Anand and Anand, Advocates Attorneys for the applicants \\VULCAN\Patent Does\ARCHANA\Dupont\Granted process clains DUPONT 138l3(P-6).doc FORM 1A THE PATENTS ACT, 1970 [39 OF 1970] APPLICATION CORRESPONDING TO AN INTERNATIONAL APPLICATION FOR GRANT OF A PATENT [See Sections 7(1A); Rule 20(1) ] We, 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 hereby declare - [a] that we are in possession of "ARTHROPODICIDALANTHRANILAMIDES" an invention titled: [b] that our application in India is based on the International application under PCT application No. PCT/US02/25615 dated 13,8.2002; further declare that the inventor[s] for the said invention are GEORGE PHILIP LAHM, of 148 Fairhill Drive, Wilmington, DE 19808, USA; THOMAS PAUL SELBY, of 116 Hunter Court, Wilmington, DE 19808, USA and THOMAS MARTIN STEVENSON, of 103 Iroquois Court, Newark, DE 19702, USA, all US citizens, We, claim the priority from the application[s] filed in convention country[ies], particulars of which are as follows : [a] U.S.A, U.S.A. and U.S.A [b] 60/311,919, 60/324,128 AND 60/369,661 [c] 13.8.2001, 21.9.2001 AND 2.4.2002 [d] GEORGE PHILIP LAHM, THOMAS PAUL SELBY and THOMAS MARTIN STEVENSON [e] "ARTHROPODICIDAL ANTHRANILAMIDES" and declare that above application or each of the above applications was the first application(s) in a convention country in respect of our invention. That we are the assignees of the applicants in the convention country. That our address for service in India is: REMFRY & SAGAR, Attorneys-at-Law, Gresham Assurance House 1 Sir P.M. Road MUMBAI 400 001 Tele + Fax : [022] 266 0907 8-1-2004 Following declaration is given by the applicants in the convention country: We, GEORGE PHILIP LAHM, of 148 Fairhill Drive, Wilmington, DE 19808, USA; THOMAS PAUL SELBY, of 116 Hunter Court, Wilmington, DE 19808, USA and THOMAS MARTIN STEVENSON, of 103 Iroquois Court, Newark, DE 19702, USA, all US citizens, the applicants in the convention country declare that the applicants herein are our assignee. GEORGE PHILIP LAHM THOMAS PAUL SELBY i THOMAS MARTIN STEVENSON That to the best of our knowledge, information and belief the facts and matters stated herein are correct and that there is no lawful ground of objection to the grant of patent to us on this application. Following are the attachment with the application: (a) Complete specification in confirmation with the International application/as amended before the IPEA, if any. [b] Statement and undertaking on Form 3 [c] Declaration as to inventorship on Form 5 [d] A copy of the published International application [e] Fee Rs. 9000 by cheque We request that a patent may be granted to us for the said invention. Dated this 7/1/2004 E.I. DU PONT DE NEMOURS 8B COMPANY B. KOMBI OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS] THE CONTROLLER OF PATENTS, THE PATENT OFFICE, Mumbai |
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15-mumnp-2004-cancelled pages(16-5-2005).pdf
15-mumnp-2004-claims(8-1-2004).pdf
15-mumnp-2004-claims(amended)-(16-5-2005).pdf
15-MUMNP-2004-CLAIMS(AMENDED)-(6-9-2005).pdf
15-mumnp-2004-claims(gramted)-(06-09-2005).pdf
15-mumnp-2004-claims(granted)-(06-09-2005).doc
15-mumnp-2004-claims(granted)-(27-12-2007).pdf
15-mumnp-2004-correspondence 1(13-01-2005).pdf
15-mumnp-2004-correspondence 1(ipo)-(18-05-2004).pdf
15-mumnp-2004-correspondence 2(16-05-2005).pdf
15-mumnp-2004-correspondence 2(ipo)-(05-09-2005).pdf
15-mumnp-2004-correspondence 3(28-07-2007).pdf
15-mumnp-2004-correspondence 3(ipo)-(12-03-2007).pdf
15-mumnp-2004-correspondence(ipo)-(21-1-2008).pdf
15-mumnp-2004-description(complete)-(8-1-2004).pdf
15-mumnp-2004-description(granted)-(27-12-2007).pdf
15-mumnp-2004-form 1(12-3-2004).pdf
15-mumnp-2004-form 1(16-05-2005).pdf
15-mumnp-2004-form 1(18-05-2005).pdf
15-mumnp-2004-form 1(8-1-2004).pdf
15-mumnp-2004-form 13(13-04-2005).pdf
15-mumnp-2004-form 13(16-05-2005).pdf
15-mumnp-2004-form 13(23-03-2004).pdf
15-mumnp-2004-form 19(20-04-2004).pdf
15-mumnp-2004-form 2(complete)-(8-1-2004).pdf
15-mumnp-2004-form 2(gramted)-(06-09-2005).pdf
15-mumnp-2004-form 2(granted)-(06-09-2005).doc
15-mumnp-2004-form 2(granted)-(27-12-2007).pdf
15-mumnp-2004-form 2(title page)-(complete)-(8-1-2004).pdf
15-mumnp-2004-form 2(title page)-(granted)-(27-12-2007).pdf
15-mumnp-2004-form 3(02-04-2004).pdf
15-mumnp-2004-form 3(11-06-2004).pdf
15-mumnp-2004-form 3(13-01-2005).pdf
15-MUMNP-2004-FORM 3(15-6-2004).pdf
15-mumnp-2004-form 3(16-05-2005).pdf
15-mumnp-2004-form 3(20-04-2004).pdf
15-mumnp-2004-form 3(25-08-2004).pdf
15-MUMNP-2004-FORM 3(30-8-2004).pdf
15-MUMNP-2004-FORM 3(4-3-2004).pdf
15-MUMNP-2004-FORM 3(6-4-2004).pdf
15-mumnp-2004-form 3(8-1-2004).pdf
15-mumnp-2004-form 5(08-01-2004).pdf
15-mumnp-2004-form-pct-ipea-409(08-01-2004).pdf
15-mumnp-2004-general power of attorney(15-5-2005).pdf
15-MUMNP-2004-GENERAL POWER OF ATTORNEY(16-5-2005).pdf
15-mumnp-2004-petition under rule 137(16-05-2005).pdf
15-MUMNP-2004-PETITION UNDER RULE 137(16-5-2005).pdf
15-mumnp-2004-power of attorney(08-01-2004).pdf
15-MUMNP-2004-POWER OF AUTHORITY(8-1-2004).pdf
| Patent Number | 213332 | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 15/MUMNP/2004 | ||||||||||||||||||||||||
| PG Journal Number | 04/2008 | ||||||||||||||||||||||||
| Publication Date | 25-Jan-2008 | ||||||||||||||||||||||||
| Grant Date | 27-Dec-2007 | ||||||||||||||||||||||||
| Date of Filing | 08-Jan-2004 | ||||||||||||||||||||||||
| Name of Patentee | E.I. DU PONT DE NEMOURS AND COMPANY | ||||||||||||||||||||||||
| Applicant Address | 1007 MARKET STREET, WILMINGTON, DELAWARE 19898, UNITED STATES OF AMERICA. | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A01N 43/56, C07D 401/04, C07D 413/14 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/US02/25615 | ||||||||||||||||||||||||
| PCT International Filing date | 2002-08-13 | ||||||||||||||||||||||||
PCT Conventions:
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