IL169529A

Cyano anthranylamides, insecticidal compositions and devices comprising them and methods of use thereof

Abstract

This record has no abstract on file.

IL169529A, drawing sheet 1 — Sheet 1 of 34

Term

No projected expiry on record.

15 claims: 1 independent, 14 dependent

1
A compound of Formula 1, an A-oxide or a salt thereof wherein:R1 is Me, Cl, Br orF;R2 is F, Cl, Br, C!-C4 haloalkyl or C1-C4 haloalkoxy;R3 is F, ClorBr;R4 is H;C1-C4 alkyl, C3-C4 alkenyl, C3-C4 alkynyl, C3-C5 cycloalkyl, or C4-C6 cycloalkylalkyl, each optionally substituted with one substituent selected from the group consisting of halogen, CN, SMe, S(O)Me, S(O)2Me, and OMe;R5 is H or Me;R6 is H, For Cl;and R7 is H, For Cl, provided that when R1 is Me, R2 is CF3, R3 is Cl, and R5, R6 and R7 are H, R4 is other than z-Pr.
2
The compound of Claim 1 wherein R1 is Me or Cl;R2 is Cl, Br, CF3, OCF2H, OCF3 or OCH2CF3;and R4 is H, Me, Et, z-Pr, ί-Bu, CH2CN, CH(Me)CH2SMe or C(Me)2CH2SMe.
3
The compound of Claim 2 wherein:R2 is Cl, Br, CF3 or OCH2CF3;R4 is H, Me, Et or z-Pr;and R5 is H.
4
A composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of Claim 1 and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said composition optionally further comprising an effective amount of at least one additional biologically active compound or agent. . 5. ׳The composition of.Claim 4 wherein the at least.one.additional biologically- -. active compound or agent is selected from an insecticides of the group consisting of a pyrethroid, a carbamate, a neonicotinoid, a neuronal sodium channel blocker, an insecticidal macrocyclic lactone, a y—aminobutyric acid (GABA) antagonist, an insecticidal urea, a 5 juvenile hormone mimic, a member οι Bacillus thuringiensis, a Bacillus thuringiensis delta endotoxin, and a naturally occurring or a genetically modified viral insecticide.
5
6. The composition of Claim 4 wherein the at least one additional biologically active compound or agent is selected, from the group consisting of abamectin, acephate, acetarmprid., acetoprole, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, 10 bifenthrin, bifenazate, bistrifluron, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, cblorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, diflub enzuron, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycafb, fenpropathrin, fenvalerate, fipronil, 15 flonicamid, flucythiinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, gammacHaTotbrin, halofenozide, hexaflumuron, imidacloprid, indoxacafb, isofenphos, lufenuron, _ m a 1 athi on, m etal dehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthnn, monocrotophos, methoxyfenozide, .noyaluron,.noviflumuron (XDE-007), oxamyl, parathipn, parathion-methyl, permethrin,. 20 phorate, phosalone,phosmet, phosphamidon, pirimicarb, profenofos.pro fluthrin, protrifenbute, pymefrozine, pyridalyl, pynproxyfen, rotenone, S.l 812 (Valent) spinosad, spiromesifen (BSN 2060), sulprofos, tebufenozide, tefhibenzuron, tefluthxin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, trichlorfon and triflumuron, aldicarb, fenamiphos, amitraz, cbinomethionat, 25 chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fmpyroximate, hexythiazox, propargite, pyridaben, tebufenpyrad, Bacillus thuringiensis aizawai, Bacillus thuringiensis kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, entomopathogenic virus and entomopaihogenic fungi.
6
7. The composition of Claim 4 wherein the at least one additional biologically 30 active compound or agent is selected from the group consisting of acetamiprid, cypermethrin, cyhalothrin, c^frutbrin and beta-cyfluthrin, esfenvalerate, fenvalerate, tralomethrin, fenothicarb, methomyl, oxamyl, thiodicarb, clothiamdin, imidacloprid, thiacloprid^ indoxacafb, spinosad, abamectin, avermectin, emamectin, endosulfan, ethiprole, fipronil flufenoxuron, triflumuron, diofenolan, pyriproxyfen, pymetrozine, amitraz, Bacillus 35 thuringiensis aizawai, Bacillus thuringiensis kurstaki, Bacillus thuringiensis delta endotoxin and entomophagous fungi.
7
8. A method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Claim 1.
8
9. A method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a composition of Claim 4.
9
10. The method of Claim 8 or Claim 9 wherein the invertebrate pest is a cockroach, an ant or a termite which is contacted by the compound by consuming a bait composition comprising the compound.
10
11. The method of Claim 8 or Claim 9 wherein the invertebrate pest is a mosquito, a black fly, a stable, fly, a deer fly, a horse fly, a wasp, a yellow jacket, a hornet, a tick, a spider, an ant, or a gnat which is contacted by a spray composition comprising the compound dispensed from a spray container.
11
12. A spray composition, comprising:(a) a compound of Claim 1;and (b) a propellant.
12
13. A bait composition, comprising:(i) a compound of Claim 1;(ii) one or more food materials;(c) optionally an attractant;and (d) optionally a humectant.
13
14. A device for controlling an invertebrate pest, comprising:(a) the bait composition of Claim 13;and (b) a housing adapted to receive the bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.
14
15. The method of Claim 9 wherein a plant is contacted with the composition applied as a soil drench of a liquid formulation.
15
16. The composition of Claim 4 in the form of a soil drench liquid formulation.

Independent claims15

946 paragraphs in 21 sections, as filed

FIELD OF THE INVENTION

This invention relates to certain anthranilamides, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, including those uses listed below, and a method of their use for controlling invertebrate pests in both agronomic and nonagronomic environments.

BACKGROUND OF THE INVENTION

The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer.

The control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different modes of action.

WO 01/070671, corresponding to IL 151267, discloses N-acyl anthranilic acid derivatives of Formula i as arthropodicides

i wherein, inter alia, A and B are independently O or S; J is an optionally substituted phenyl ring, 5&#1470;or 6-membered heteroaromatic ring, naphthyl ring system or an aromatic 8-, 9-or 10membered fused heterobicyclic ring system; R1 and R3 are independently H or optionally substituted C1-C6 alkyl; R2 is H or C1-C6 alkyl; each R4 is independently H, C1-C6 alkyl, C!C6 haloalkyl, halogen or CN; and n is 1 to 4.

STATEMENT IN ACCORDANCE WITH COMMISSIONER’S CIRCULAR 23(P)

Inasmuch as the invention is defined in the appended claims, it will be apparent that the portions of the present specification, which fall outside the scope of the claims, do not relate directly to the claimed invention. This Notice is not meant to disclaim any legitimate rights to which the Patentee is legally entitled, especially any rights in accordance with Section 49 of the Israel Patent Law.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula 1, their N-oxides or salts thereof

wherein:

R1 is Me, Cl, Br or F;

R2 is F, Cl, Br, C1-C4 haloalkyl or C1-C4 haloalkoxy;

R3 is F, Cl or Br;

R4 is H; C1-C4 alkyl, C3-C4 alkenyl, C3-C4 alkynyl, C3-C5 cycloalkyl, or C4-C6 cycloalkylalkyl, each optionally substituted with one substituent selected from the group consisting of halogen, CN, SMe, S(O)Me, S(O)2Me, and OMe;

R5 is H or Me;

R6 is H, For Cl; and

R7 is H, F or Cl, provided that when R1 is Me, R2 is CF3, R3 is Cl, and R5, R6 and R7 are H, R4 is other than z-Pr.

The present invention also relates to a composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula 1 and at least one additional component selected from the group consisting of a surfactant, a solid diluent and liquid diluent and optionally an effective amount of at least one additional biologically active compound or agent.

The present invention also relates to a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of the aforementioned compound or composition.

The present invention further relates to a spray composition comprising a compound of Formula 1 and a propellant, and a bait composition comprising a compound of Formula 1, one or more food materials, and optionally an attractant or humectant.

The present invention also relates to a device for controlling an invertebrate pest comprising the aforementioned bait composition and a housing having at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.

ADDITIONAL ASPECTS OF THE APPLICATION

This invention pertains to compounds of Formula 1, their N-oxides or salts thereof

wherein:

R1 is Me, Cl, Br or F;

R2 is F, Cl, Br, C1-C4 haloalkyl or C1-C4 haloalkoxy;

R3 is F, Cl or Br;

R5 is H or Me;

R6 is H, For Cl; and

R7 is H, F or Cl.

This invention also pertains to a composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula 1 and at least one additional component selected from the group consisting of a surfactant, a solid diluent and liquid diluent and optionally an effective amount of at least one additional biologically active compound or agent.

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 a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a composition comprising a biologically effective amount of a compound of Formula 1 and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said composition optionally further comprising an effective amount of at least one additional biologically active compound or agent.

.This .mventipnforfoerpectainsjQ^^ray composition co^rismg^w^oimd of Formula 1 and. a propellant, and. to a bait composition comprising a compound of Formula 1, one or more food materials, an optional attractant, and an optional humectant. This invention also pertains to a device for controlling an invertebrate pest comprising said bait 5 composition and a housing adapted to receive the bait composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.

10 DETAILS OF THE INVENTION

In the above recitations, the term “allcyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, z-propyl, or the different butyl isomers. The term halogen , either alone or in compound words such as “haloalkoxy”, includes fluorine, chlorine, bromine or iodine.

Further, when used in compound words such as “haloalkyl”, or ‘haloalkoxy”, said alkyl or alkoxy may be partially or folly substituted with halogen atoms which may be the same or . different. Examples of “haloalkyl” include F3C, C1CH2, CF3CH2 ard CF3CC12. Examples of “haloalkoxy” include CF3O, Η&#971;Ρ2θ&#1470; CC13CH2O, HCF2CH2CH2O and CF3CH2O.

One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form V-oxides since the nitrogen requires an available lone pair for oxidation to the oxide;

:p F one skilled in the art vrill recognize those nitrogen-containing heterocycles which can form V-oxides. One skilled in the art will also recognize that tertiary amines can form V-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 25 amines with peroxy acids such as peracetic and zzz-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as &#943;-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. These methods for the preparation of A/-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., 30 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 Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler andB. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9. pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and 35 G. W. H. Cheeseman and E. S. G. Werstiuk in. Advances in Heterocyclic Chemistry, vol.

&#1505;&#1502;Q_392, A. R. Katritzky and A. J. Boulton,Eds., Academic Press.

Compounds of this invention can exist as one or more stereoisomers. The various 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 invention comprises compounds selected from Formula 1, .V-oxid.es and 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, 10 butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. In the compositions and methods of this invention, the salts of the compounds of the invention are preferably suitable for the agronomic and/or nonagronomic uses described herein.

Of note are compounds of Formula I wherein

R4 is H or Cj-C4 alkyl optionally substituted with one substituent selected from the group consisting of CN, SMe and OMe;

R5 is H or Me;.

R0 is H; and

R7isH. '’.

Preferred compounds for reasons of cost, ease of synthesis and/or biological efficacy . are:.: .&#1524;y. Ecv &#1470;

Preferred !.Compounds of Formula 1 wherein

R1 is Me or Cl;

R2 is Cl, Br, CF3, OCF2H, OCF3 or OCH2CF3; and

R4 is H, Me, Et, z-Pr, t-Bu, CH2CN, CH(Me)CH2SMe or C(Me)2CH2SMe.

Preferred 2. Compounds of Preferred 1 wherein

R2 is ci, Br, CF3 or OCH2CF3;

R4 is H, Me, Et or z-Pr, and

R5 is H.

Of note are compounds of Preferred 1 and Preferred 2 wherein R6 is H; and R7 is H.

The preferred compositions of the present invention are those, which comprise the above preferred compounds. The preferred methods of use are those involving the abovepreferred compounds.

The compounds of Formula 1 can be prepared by one or more of the following methods and variation as described in Schemes 1- 20. The definitions of R1, R2, R3&#1470; R4&#1470; and R5 in the compounds of Formulae 1—24 below are as denned above in the Summary of the Invention unless indicated otherwise.

' 5 ,

.,.Compounds.of Foimula.l. can be.prepared by. the reaction ofbenzpx^mones of_ &#1523; Formula 2 with, an amine of Formula HNR.4r5 as outlined in Scheme 1. This reaction can be &#1495;&#1493;&#1495;&#1497; neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, dioxane, toluene, 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 an.thran1 &#1493; amides 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 Chemistry 1999,36, 563—588.

Scheme 1

Compnimds of Formula 1 can also be prepared from haloanthranihc diamides of Formula 3 (wherein X is halogen, preferably iodine or bromine) by the coupling method shown in Scheme 2. Reaction of a compound of Formula 3 with a metal cyanide (e.g.

cuprous cyanide, zinc cyanide, or potassium cyanide), optionally with or without a suitable palladium catalyst [e.g. tefrakis(friphenylphosphine)palladium(0) or dichlorobis(triphenylphosphine) palladium(!!)] and optionally with or without a metal halide (e.g. cuprous iodide, zinc iodide, or potassium iodide) in a suitable solvent such as acetonitrile, N, V-dimethylformamide or V-methylpyrrolidinone, optionally at temperatures ranging from room temperature to the reflux temperature of the solvent, affords compounds of Formula 1. The suitable solvent can also be tetrahydrofuran or dioxane when palladium catalyst is used in the coupling reaction.

PCI7US2004/003568

(X is Halogen)

Cyanobenzoxazinones of Formula 2 can be prepared by the method outlined in

Scheme 3. Reaction of a halobenzoxazinone of Formula 4 (wherein X is halogen, preferably iodine or bromine) with a metal cyanide using a similar coupling method as described above for Scheme 2 (optionally with or without a palladium catalyst and optionally with or without a metal halide present) affords a compound of Formula 2.

Cyanobenoxazinones of Formula 2 can also be prepared, by the method detailed in

Scheme 4 via coupling of a pyrazole carboxylic acid of Formula 5 with a cyano anthranilic acid of Formula 6. This reaction involves sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazole carboxylic acid of Formula 5, followed by the addition of cyanoanthranilic acid of Formula 6, followed

Scheme 5 depicts another method for preparing benzoxazinones of Formula 2 involving coupling an isatoic anhydride of Formula 7 with a pyrazole acid chloride of Formula S. Solvents such as pyridine or pyridine/acetonitrile are suitable for this reaction.

The acid chlorides of Formula S are available from the corresponding acids of Formula 5 by known methods such as chlorination with thionyl chloride or oxalyl chloride.

pyridine^

MeCN

As shown in Scheme 6, halo anthranilic dia1md.es of Formula 3 can be prepared by the reaction of benzoxazinones of Formula 4, wherein X is halogen, with an amine of Formula 5 HNR4R5 &#1511; sing a similar method as described above for Scheme 1. Conditions for this reaction are similar to those specified in Scheme 1.

Scheme 6 r2

X is halogen 3

As shown in Sob erne 7, halobenzoxazinones of Formula 4 (wherein X is halogen) can 10 be prepared via direct coupling of a pyridylpyrazole carboxylic acid of Formula 5 with a halo anthranilic acid of Formula 9 (wherein X is halogen) by a similar method as described above for Scheme 4. This reaction involves sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 5, followed by the addition of a haloanthranilic acid of Formula 9, followed 15 by a second addition of tertiary amine and methanesulfonyl chloride. This method generally affords good yields of the benzoxazinone.

4)MeS(O)2Cl

As shown in Scheme 8, a halobenzoxazinone of Formula 4 can also be prepared via coupling an isatoic anhydride of Formula 10 (wherein X is halogen) with a pyrazole acid 5 chloride of Formula 8 by a similar method as described above for Scheme 5.

Scheme 8

R2

Cyanoanthranilic acids of Formula 6 can be prepared from haloanthranilic acids of Formula 9 as outlined in Scheme 9. Reaction of a haloanthranilic acid of Formula 9 (wherein X is halogen) with ametal cyanide using the same coupling procedure described above for Scheme 2 (optionally with or without a palladium catalyst and optionally with or without a metal halide present) affords a compound of Formula 6.

Scheme 9

NH׳-> metal cyanide ______solvent________

Pd Catalyst (optional)

COnH metal halide (optional) Nc

X is halogen

.As illustrated in Scheme-10, cyanoisatoic anhydrides of Formula 7 can be prepared from cyano anthranilic acids of Formula 6 by reaction with phosgene (or a phosgene equivalent such as triphosgene) or an alkyl chloroformate (e.g. methyl cbloroformate) in a suitable solvent such as toluene or tetrahydro furan.

Scheme 10

As shown in Scheme 11, haloanthranilic acids of Formula 9 can be prepared by direct halogenation of an unsubstituted anthranilic acid of Formula 11 with N-chlorosuccmimide (NCS), V-bromosuccinimide (NBS) or N-iodosuccinimide (NTS) respectively in solvents such as Ν,Ν-dimethylfoimamide (DMF) to produce the corresponding halogen-substituted acid of Formula 9.

Scheme 11

As illustrated in Scheme 12, haloisatoic anhydrides of Formula 10 can be prepared from haloanthranilic acids of Formula 9 by reaction with phosgene (or a phosgene equivalent such as triphosgene) or an alkyl cbloroformate, e.g. methyl chloroformate, in a suitable solvent such as toluene or tetrahydrofuran.

Scheme 12

O

Pyridylpyrazole carboxylic acids of Formula 5 can be prepared oy the method outlined in Scheme 13. Reaction of pyrazole 12 with a 2-halopyridine of Formula 13 in the presence of a suitable base such as potassium carbonate in a solvent such as ΛζΝ-dimethylformamide or acetonitrile affords good yields of the 1-pyridylpyrazole 14.with good specificity for the desiredregiochemistry.-MetaUationof.l4wi&titbit11n diisopropylamide (LDA.; followed by quenching of the lithium salt with carbon dioxide affords the pyrazole carboxylic acid of

Formulas.

Scheme 13

The starting pyrazole12 &#1470; wherein R2 is CF3, Cl or Br are known compounds. Pyrazole 12 wherein R2 is CF3 can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). Pyrazoles 12 wherein R2 is Cl or Br can also be prepared by literature procedures (H. Reimlinger and A Van Overstraeten, Chem. Her. 1966,99(10), 3350-7). A useful alternative method for the preparation of 12 wherein R2 is Cl or Br is depicted m ! Scheme 14. Metallation of the sulfamoyl pyrazole 15 with &#1524;-butylhtHim followed by direct halogenation of the anion with either hexachloroethane (for R2 being Cl) or 1 ^-dibromotetrachloroethane (for R2 being Br) affords the halogenated derivatives 16 (where R-is Cl or . Br) Removal of the sulfamoyl group with trifluoroacetic acid (TF A) at room temperature proceeds cleanly and in good yield to afford thepyrazoles 12 whereinR2 is Cl or Br respectively.

Scheme 14

1) n-BuLi, solvent 1/ TFA 12 / 2)^0120(¾£2 κ &#1503;

I SOsNMe,

SC^NMe?

As an alternative to the method illustrated in Scheme 13, pyrazolecarboxylic acids of &#1505;&#1497; Formula 5 whereinR2 is CF3 can also be prepared by the method outlined in Scheme 15.

Reaction of a compound of Formula 17 (wherein Rs is CrC4 alkyl) with a suitable base m a suitable organic solvent affords the cyclized product of Formula 18 after neutralization with an acid.&#1523; such as acetic acid.

The suitable base can be, for example but not limited to, sodium hydride, potassium tbutoxide, flimsy! sodium (CH3S(O)CH2&#1470;Na+), alkali metal (such as lithium, sodium or 5 potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or 2-te7tibutyli1nino dietoyla1nino-l,3-dimetoyl-perhydro-l,3,2diazaphosphonine. The suitable organic solvent can be, for example but not limited to, acetone, acetonitrile, tetrahydro furan, dichloromethane, dimethylsulfoxide, or NW&#1470; dimetoylformamide. The cyclization reaction is usually conducted in a temperature range 10 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 toe formation of .

' byproducts. A preferred base is tefrabutyla^ ::: Λ ’ Dehydration of toe compound of Formula 18 to give toe compound of Formula 19, followed by hydrolysis of toe carboxylic ester function to carboxylic acid, affords toe compound of Formula 5. The dehydration is accomplished by treatment with a catalytic amount of a suitable acid. This catalytic acid can be, for example but not limited to, sulfone acid. The reaction is generally conducted using an organic solvent. As one skilled m toe art will realize, dehydration reactions may be conducted in a :vide variety of solvents, e.g. acetic acid, in a temperature range generally between about 0 and 200 °C, more preferably between about 0 and 100 °C. Carboxylic esters of Formula 19 can be converted to carboxylic acids of Formula 5 by numerous methods including nucleophilic cleavage under anhydrous renditions or hydrolytic methods involving toe 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 toe method of 25 Scheme 15, base-catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal (such as lithium, sodium or potassium) hydroxides. For example, toe ester can be . dissolved in a mixture of water and an alcohol such as ethanol. Upon treatment with soaium hydroxide or potassium hydroxide, .toe ester is saponified to provide toe sodium or potassium

PCT7US2004/003568 salt ofthe carboxyhcacii-Acicfification-witfr^ &#1523;:

sulfuric acid, yields the carboxylic acid of Formula 5.

Compounds of Formula 17 wherein R2 i&#1470; CF3 can be prepared by the method outlined m Scheme 16. Treatment of a hydrazine compound of Formula20 with a ketone of Formula CH3COR2 in a solvent such as water, methanol or acetic acid gives the hydrazone of Formula 21.

.NH?

R&#1524;

R3

wherein R2 is CF3 and is C4-C4 alkyl

-One skilled in the art will recognize fliat this reaction may &#1504; optional acid and mdyffit require elevated temperatures depending on the molecular.

substitutionpattemofthehydrazoneofFormula-21, Reactionofthehydrazoneof. Formula 21 with an alkyl chlorooxalate in a suitable organic solvent such as, for examp &#1470;. not limited to, dicbloromethane or tetrahydroforan in the presence of an acid scavenger sue as triethylamine provides the compound of Formula 17. The reaction is usuaRy conducted a temperature between about 0 and 100 °C. Hydrazine compounds of Formula -0 can be prepared by standard methods, such as byreaction ofthe corresponding halopyn

Formula 13 with hydrazine.

As an alternative to the method illustrated in Scheme 13, pyrazolecarboxyhc ac _ Formula 5 wherein R2 is Cl or Br can also be prepared by 4&#1470; method outlined m Scheme 1 ,&#1523;. Oxidation ofthe compound of Formula 22, optionally m the presence of aci , gires compound of Formula 19, wheremR2 is Cl orBr. Hydrolysis ofthe carboxylic ester function to the carboxylic acid provides the compound of Formula 0.

19 &#1470; 22 wherein R8 is C!-C4 alkyl

The oxidizing agent for converting a compound of Formula 22 to a compound of Formula 19 can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium

5. persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. To obtain complete conversion, at least one equivalent of oxidizing agent

2 . versus the compound of Formula 22 should be used, preferably between about one to. two; , &#1524;equivalents. This oxidation is typically carried out in the presence of a solvent. The solvent : can be an ether, such as tetrahydrofuran, ^-dioxane and the like, an orgamc ester, such as . , ethyl -acetate,, dimethyl carbonate, and the like, or a polar aprotic organic such as MA- 0; dimethylformamide, acetonitrile and the like, Acids suitable for use in the oxidation step

I include inorganic acids, such as sulfuric acid, phosphoric acid and the like,, and organic acids, such as acetic acid, benzoic acid and the like. One to five equivalents of acid can be used. The preferred oxidant is potassium persulfate and the oxidation is preferably earned 15 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 be added at a convenient rate. The reaction temperature is typically varied from as low as about 0 °C up to the boiling point of the solvent in order to obtain a reasonable reaction time to complete the reaction. Methods suitable for converting the ester of Formula 19 to the carboxylic acid of Formula 5 are already described for Scheme 15.

Compounds of Formula 22, wherein R2 is halogen and R8 is alkyl, can be prepared from the corresponding compounds of Formula 23 as shown in Scheme 18.

Treatment of a compound of Formula 23 with a halogenating reagent, usually in the presence of a solvent, affords the corresponding halo compound of Formula 22.

Halogenating reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. To obtain complete conversion, at least 0.3 3 equivalents of phosphorus pxyhalide 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. 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 15 like, ethers, such as tetrahydro foran, p-dioxane, diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, ΝΛ-dimethylformamide, and the like. Optionally, an organic base, such as methylamine, pyridine, N,V-dimethylaniline or the like, can be added. Addition of a catalyst, such as ΛζΝ-dimethylforniamide, is also an option. Preferred is the process in which the solvent is acetonitrile and a base is absent. Typically, neither a base nor 20 a catalyst is required when acetonitrile solvent is used. The preferred process is conducted by mixing 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 25 mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide and the like, or an organic base, such as sodium acetate. The desired product 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 R2 is Br or Cl can be prepared by 30' treatins the corresponding compounds of Formula 22 wherein R- is a.different halogen (e.g.,

Cl for m airing Formula 22 wherein R^ is Br) or a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate with hydrogen bromide or hydrogen chloride, respectively. By this method the R2 halogen or sulfonate substituent on the compound of Formula 22 is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. The reaction is conducted in a suitable solvent such as dibromomethane, dichloromethane, acetic acid, ethyl acetate or acetonitrile. The reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel. The halogenating reagent can be added in the form of a gas to the reaction mixture containing the Formula 23 compound and solvent. When R2 in the starting compound of Formula 22 is a halogen such as Cl, the reaction is preferably conducted in such a way that sparging or other suitable means removes the hydrogen halide generated from the reaction. Alternatively, the halogenating reagent can first be dissolved in an inert solvent in which it is highly soluble (such as acetic acid) before contacting the compound of Formula 23 either neat or in solution. 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 R2 is Br) can facilitate the reaction. The product of Formula 22 is. isolatedby the usual methods known to those skilled in the art, including extraction,

- distillation and crystallization.;.

Starting compounds of Formula 22 wherein R2 is a sulfonate group can be prep ared fi&#1470;nm corresponding 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.

As an alternative to the method illustrated in Scheme 13, pyrazolecarboxylic acids of

Formula 5 wherein R2 is haloalkoxy can also be prepared by the method outlined in Scheme 19. A compound of Formula 23 is oxidized to a compound of Formula 24. The reaction conditions for this oxidation are as described for the conversion of the compound of Formula 22 to the compound of Formula 19 in Scheme 17.

Scheme 19

hydrolysis

-----&#9658;

8 wherein R is haloalkoxy and R is C!-C4 alkyl

The intermediate of Formula 24 is then alkylated to form a compound of Formula 19 (wherein R2 is haloalkoxy) by reaction with an appropriate haloalkylating agent such as a haloalkyl halide or sulfonate. 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, hydroxides and hydrides or organic bases, such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec 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, ΛζΑ-dimethylformamide, and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as base and ΛζΑ-dimethylformamide or acetonitrile as solvent are preferred. The reaction is generally conducted between 0 and 150 °C, most typically between ambient temperature and 100 °C. The ester of Formula 24 can then be converted to the carboxylic acid of Formula 5 by the methods already described for the conversion of a compound of Formula 19 to a compound of Formula 5 in Scheme 15.

Compounds of Formula 23 can be prepared from compounds of Formula 20 as outlined in Scheme 20. In this method, a hydrazine compound of Formula 20 is allowed to react with a compound of Formula 25 (a fumarate ester or maleate ester or a mixture thereof can be used) in the presence of a base and a solvent.

Scheme 20

The base used, in Scheme 20 is typically a metal alkoxide salt, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium ie7&#1470;t-butoxide, lithium ie7T-butoxide, and the like. Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, AW-dimethyl-.

formamide, 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 tiae film Pirate or maleate ester and the alkoxide base. The reaction is typically conducted hy rniying the compound of Formula 20 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() °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 reaction can then be acidified by adding an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfone acid and the like. The desired product of Formula 23 can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.

It is rooo gnized 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 G1 oups 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 derail 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 anurder other than that implied by the particular..

sequence presented to prepare the compounds of Formula 1.

Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its follest extent. The following Examples 5 are, therefore, to be construed as merely illustrative, and not limiting of the disclosure m any way whatsoever. Steps in the following Examples illustrate a procedure for each step m 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.

15 EXAMPLE 1

Potior, of !-(S^liloro^-pvii^invyy-r^-cyano-^-Tnfi/hv^-y^aminnoafbonv^phsPYll.^&#1470; . — ftrifluoromethvB-lg-pvrazole carboxamidg.

Step A: Preparation of 2-amino methvl iodobenzoic acid

To a solution of 2-an!mo methylbenzoic acid (Aldrich, 5 g, 33 mmol) in

MV-dimethylformamide (30 mL) was added Miodosuccmimide (7.8 g, 3/7 mmol), and the &#1470; reaction ntixture was suspended in a 75 °C. oil bath overnight The heat was removed and the reaction mixture was then slowly poured into ice-water (100 mL) to precipitate a light grey solid. The solid was filtered and washed four times with water and then placed ma vacuum oven at 70 °C to dry overnight. The desired intermediate was isolated as a light grey solid (8.S g).

1H NMR (DMSO-dg): δ 7.86 (d,lH), 7.44 (d,lH), 2.08 (s,3H).

Step B: Preparation of 3-chloro r3-(trifluoromethyn&#1470;l g-pvrazol-l-vllpvndine

To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-(trifluoromethyl)&#1470; pyrazole (83 g, 0.61 mol) in dry ;vJV-dimethylformamide (300 mL) was added potassium 30 carbonate (166.0 g, 1.2mol) and the reaction was then heated to 110-125 °C over 48 hours.

The reaction was cooled to 100 °C and filtered through Celite® diatomaceous filter aid to remove solids. ^V-Dimerhylformamide and excess dichloropyridine were removed by distillation at.atmospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141 °C, 7 mm) afforded 113.4 g of the desired intermediate as a clear yellow oil. 35 1HNMR(CDC13): δ 8.45 (d,lH), 8.15 (s, 1Ξ), 7.93 (d,lH), 7.36 (tiH), 6.78 (s,lH).

Step C: Preparation of .l-(3-chloro pvridinyl) (trifluoromethvl)-lZZ&#1470;-pyrazole- :

5-carboxylic acid.

To a solution of 3-chloro [3-(trifIuoromethyl)-12?-pyrazol-l-yl]pyridine (i.e. the pyrazole product from Step B) (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL) at

°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 time carbon dioxide was bubbled through at —63 °C until the solution became pale yellow and the exothennicity ceased. The reaction was stirred for an additional 20 minutes and then gnencheri 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 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 130 g of the title product as an off-white solid. Product from another rim following a similar procedure melted at 175—176 °C.

1H NMR (DMSO-cfg): δ 7.61 (s,lH),7.76 (dd,lH), 8.31 (d,lH), 8.60 (d,lEQ.

Step D: Preparation of 2&#1470;r1-('3-chloro c\'T1dmvD (trifluoromethvB)-12f-O&#1470;vTazol &#1470; .-. ------ vll iodo methvl-4ZL3.1-benzoxazin one v- . it:;' : x : &#1470; &#1470;&#1470; &#1523; '' η:&#1470;:- To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) in acetonitrile - - -.

(50rnT) was added dropwise a mixture of l-(3-chloro pyridinyl) (trifluoromethyl)-lEL pyrazole cafboxylic acid (i.e. the carboxylic acid product of Step C) (10.0 g, 34.1&#1490; mmol) and tri ethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at —5 °C. The reaction temperature was then maintained at 0 °C throughout successive addition of reagents. After stirring for 20 minutes, 2-amino methyl iodobenzoic acid (i.e. the product from Step A) (9.51 g, 34.31 mmol) was added and stirring was continued for an additional 10 minutes. A solution of tri ethyl amine (9.56 mL, 68.62 mmol) in acetonitrile (15 mL) was then added dropwise, and the reaction mixture was stirred 30 minutes, followed by the addition of.

methanesulfonyl chloride (2.91 mL, 37.74 mmol). The reaction mixture was then warmed to room temperature and stirred 2 hours. The solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 8 .53 g of the title compound as a yellow solid.

1H NMR (CDC13): δ 8.59 (dd,lH), 8.35 (d,lH), 7.97 (dd,lH), 7.86 (d,lH), •7.49 (m,2H), 1.79 35 (s,3H).

Sten R Preparation of S u u / ;. &#1497; uuicu.1 Suu7 -.---&#1497; &#1497; Η-^Λ-S^ _ vl1 cvano methvl-4g-3.1-benzoxazin one

To a solution of i-tl^Uoro^-pyridinyW iodo methyl-4ff-3,Lbenzoxazm one (i.e. the benzoxazinone product of Step D) (500 mg 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(!) iodide (180 mg,

094 nmol), tetrakis(triphenyphosphn1e)palladium(0) (5.4 mg, 0.047 nmol) and copper® cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper® cyanide (420 mg, 4.7 mmol), copper® iodide (107 mg, 0.56 mmol) and tetrakis(triphenyphosphine)palladiu1n(0) (32 mg, ._ .

mmol) were added and the reflux was continued for 1 hour. The reaction mxtrne turned black in color, at which point thin layer chromatography on silica gel confirmed cample on of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dned (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude

20&#1470; (S.3H). '&#1524;“' &#1470;I7•• :'.“.&#1470;''*.- &#1470;. Z I.;.':I.

0.^puyi- -supremrationofl-r3-chloro-210Yridim1W14^Yano---n1ethvlr6: <'aminnc3rb0nvl)nbRnvll (trifluoro1nethvl)'-lff-ps'razole carboxannJ^

To a&#1470;solution:of 2-[l-(3-ci11orp pyTidinyl)-3.-(trifluoromethyprlii&#1470;pyrazol&#1470;5&#1470;&#1470;yl]^6-.

cyano methyl-4ff-3,l-b1&#1470;&#1470;zoxazm-4um&#1470; (i.e. the cyanobenzoxazmone product of Step E) (200 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydmxid (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for ve minutes, af whichpomt to layer chromatography on silica gel confirmed completion of ft&#1470; reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, an e residual solid was purified by chromatography on silica gel to afford 62 mg 0 e compound, a compound of the present invention, as a solid melting at &#1524; 00&#1524;

Iff NIiffi.(CDCl,): 5 10.65 (s,l®,S.43(dd,l®, 7.9 (dd,lH), 7.67 (s, ®, &#1489;&#1501; (m,lH), 7.25 (s,lH), 6.21 (bs,lH), 5.75 (bs,lH), 2.26 (s,3H).

EXAMPLE 2&#1470;

20-&#1470;

Preparation of Ι/β-οΜοΓΟ^-ηνπ&#940;&#943;ηνη-Μ-Γ^ν^ο-Ζ-Εβ&#943;&#943;ιγΙ^ r(wethvlaTT1mo)carbonylfohenyl1 itrifl.uoromethvl)-lg-pvrazo1e carboxam1de

Ster1 Preparation of l-(3-chloro pvrid.myl)-M-r4-iodo methyl-6r rtmethvlaTriinoIcarbonyllnhenvn5-cafboxamide

To a solution of 2-[l-(3-cbloro py1idinyl) (trifluorometl1yl)-Ui-pyrazol yl]-6iodo-S-metl1yl-4.H'-3,l-benzoxazm one (i.e. the benzoxazmone product of Example 1, Step D) (500 mg, 0.94 mmol) intetrahytoftan (15 mL) was added topwise methylamme (2.0 M solution in THF, 1.4 mL, 2.8 mmol) and the reaction mixture was stirred for 3 hours, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahytofiiran solvent was evaporated under reduced pressure and the restdual solid was purified by cbromaiography on silica gel to afford 400 mg ofthe title compound as a yellow solid. _ z

&#938;Η NMR (CDC13): δ 10.25 (s,lH), 8.45 (dd,lH), 7.85 (dd,lH), 7.55 (s,lH)7.50 &#1470; (sJH), 7.46 (s,lH), 7.40 6.15 (d,lH), 2.93 (d.3H): 2.12 (s,3H). &#1470; / &#1470;

Step B: Preparation of l-(3-cMoro pvridinvL-A2-J4-cvano methvl-6z ? r(rnethvlarnino3carbonvllphenvl1- 3-(triflu0r0TnethYB-lj7&#1470;-pvraz01eI .

5-carboxarnide ; To a solution of l-(3-chloro-2&#1470;pwdmyl)-.¥-r4-iodo me±yl-6r(methyiantoo)cazbonyl]phenyl] (trifluoromethyl)-LH'-pyrazole carbOxamide (Le. the diamide product of Step X) (« Ο mg, 0.72 mmol) in tetrahytofuran (8 mL) was added copper(!) iodide (24mg, 0.126 mmol), tetrakis(triphenyphosphine)paUadium(0) (70 mg, 0 060 mmol) and copper© cyanide (640 mg, 7.2 mmol) sequentially at room temperature. The r*w-ti™ mixture was heated at reflux for 4.5 hours. Thin layer chromatography on silica &#1470;el confitmed completion ofthe reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Cehte®, Mowed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MsSO4) and concentrated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 114 mg of the title compound, a compound ofthe present invention, as awhile solid, melting at 214-^16 C. &#1524; . &#943;&#904;η 1H NMR (CDC13): δ 10.70 (s,!H), 8.46 (dd,lH), 7.87 (dd,lH), 7.:7 (s,2H), . (m, H),

7.31 (s.lH), 6.35 (d,lH), 2.98 (d,3H), 2.24 (s,3H).

.;.- ; ;&#1497;.EXAMPLES..-..-.~. \.:.

Preparation

Γ (methvlammo)carbonvllphenyll&#1470;lff-pwazole-5&#1470;carboxam1de . Step A: _____Preparation of3-chloro-ffff&#1470;dimethvl-lff-PYrazole-l-suKonam1de

To a solution of A^-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-butyllithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below -65 °C. Upon completion of the addition the reaction mixture was maintained at -78 °C for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydro furan (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 over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford 160 g of the title product compound as_ a yellow oil.

1H NMR (CDC13): δ 7.61 (s,lH), 6.33 (s,lH), 3.07 (d,6H). &#1470; ?w ^&#1470; : step b: ' Preparation of 3-chloropvraz01e' : .7.•^.-. '.-.'&#1470;&#1470; ;‘ .'&#1523; &#1470; &#1491; To tnfluoroacetic acid (290 mL) was added dropwise S-clLoro-ALXdimethylIff-pyrazole 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 ±e crude product as an oil. The crude product was further purified by chromatography on silica gel using ether/hexane (40:60) as eluent to afford 64.44 g of the title product as a yellow oil.

1H NMR (CDCI3): δ 6.39 (s,lH), 7.66 (s,lH), 9.6 (brs,lH).

Step C: Preparation of 3-chloro (3-chloro-lff-p-STazol-l-vfinyridine

To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in ffff-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 sohds were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford 39.75 g of the title product as a white solid.

1HNMRXCDCIs): δ 6.43 (s,lH), 7.26 (m,lH), 7.90 (d,lH), 8.09 (s,lH), 8.41 (d,lH).

- . step D: - &#1497; &#1497; &#1523; Preparation of3-chloro chloro nvridinyl)-lg-pyrazole carboxyhc;.

acid

To a solution of 3-chloro (3-chloro-lH-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 1N aqueous sodium hydroxide solution and extracted with ether (2x500 mL). The aqueous extracts were acidified with 6 N hydrochloric acid followed by extraction with ethy!

acetate (3x500 mL). The ethyl acetate extracts were dried over magnesium sulfate and concentrated to afford 42.96 g of the title product as an off-white solid. Product from another run following the same procedure melted at 198-199 °C.

1H NMR (DMSO&#1470;d0): δ 6.99 (s,lH), 7.45 (m,lH), 7.93 (d,lH), 8.51 (d,lH).

Sten E: Preparation of 2-r3-chloro4-(3-cbloro pyridinyl)-ljTpyragol yl1 iodo2

8-methyl-4ff-3.1 -benzoxazin one

To a solution of methanesulfonyl chloride (0.63 mL, 8.13 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-cNoro-l-(3-cl11oro pyridinyl)-17T-pyrazole-5carboxylic acid. (i.e. the carboxyhc acid product of Step D) (2.0 g, 7.75 mmol) and triethylamine (1.08 ml, 7.75’mmol) in acetonitrile (5 mL) at 0 °C. The reactionmixture was 20 . then stirred for 15 minutes at 0 °C. Then, 2-amino methyl iodobenzo1c acid (1.e. the . product from Example 1, Step A) (2.14 g, 7.75 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (2.17 mL, 15.15 mmol) in θ acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5 °C.

The reaction mixture was stirred 40 minutes at 0 °C, and then methanesulfonyl chloride (0.63 mL, 8.13 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight The reaction mixture was then diluted with water . (50 mL), and extracted with ethyl acetate (3x50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1x20 mL) and brine (1x20 mT,); dried (MgS O4) and concentrated to afford 3.18 g of the title product as a crude yellow 1H NMR (CDCI3): δ S.55 (dd,lH), 8.33 (s,lH), 7.95 (dd,lH), 7.82 (d,lH), 7.45 (m,lH), 7.10 (s,lH), 1.77 (s,3H).

Ster) Preparation of 2-r3-chloro-l-i3-chloro ovndinvl)-L?TovrazoL5-vll-6cvano methyl-4ff-3.1 -benzoxazin one

To a solution of 2-[3-chloro-l-(3-chloro pyridinyl)-lfi&#1470;-pyrazol yl] 1odo-8methyl-42T-3,l&#1470;benzoxazin one (i.e. the benzoxazinone product of Step E) (600 mg, 1.2 mmol) intetrahydrofuran (15 mL) was added copper(I) iodide (137 mg, 0.72 mmol), tetraltis(triphenyphosphine)palladium(0) (416 mg,.0.36 mmol) and copper(!) cyanide (860 mg, 9.6 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 397 mg of the title compound as a crude yellow solid.

1H NMR (CDC13): δ 8.50 (q,lH), 8.22 (d,lH), 7.90 (dd,lH), 7.67 (d,lH), 7.45 (m,lH), 7.15 (s,lH), 1.79 (s,3H).

Step _______Preparation of 3-chloro-l-(3-chloro pvridinvl)-/V&#1470;r4-cyano methvl-6r(methvlamino)carbonvl&#1470;|phenvl&#1470;|-lf/-pyrazole carboxamide

To a solution of 2-[3-chloro-l-(3-chloro pyridinyl) pyrazol yl] cyano8-methyl-4H-3,l-benzoxazin one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140 °C.

1H NMR (CDCI3): δ 10.55 (s,lH), 8.45 (dd,lH), 7.85 (dd,lH), 7.55 (d,2H), 7.40 (m,lH), 6.97 (d,lH), 6.30 (d,lH), 2.98 (d,3H), 2.24 (d,3H).

EXAMPLE

Preparation

3-chloro-l-(3-chloro pvridinvl)-N-r4-cvano methvl (aminocarbonvl)phenvl&#1470;l-177pyrazole carboxamide

To a solution of 2-[3-chloro-l-(3-chloro-2&#1470;pyridinyl)-lH-pyrazol yl] cyano8-methyl 3,l-benzoxazin one (i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 55 mg of the title compound, a compound of the present invention, as a white solid that decomposes in the melting apparatus above 255 °C.

1HNMR (CDC13): δ 10.50 (s,lH), 8.45 (dd,lH), 7.85 (dd,lH), 7.66 (d,lH), 7.61 (s,lH), 7.41 (m,lH), 6.95 (s,lH), 6.25 (bs,lH), 5.75 (bs,lH), 2.52 (s,3H).

.-..-..-.. example5&#1523; 2))ZZZIZZZZZZZZZ. Z.Z.

Preparation 0f3-br0m0-l-(3-chl0r0-?-pyridinYl)-JV4]-&#1470;-cyan022^efoylr6c rCme&vlaminoJcarbonyllphenvlI-lff-pyrazole-fi-cafboxamide

Step A: Preparation of 3-bromo-NW-dimethvl-lg-PVrazole-l-sulfonamide

To a solution of ΛξΝ-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry tetrahydrofuran (500 mL) at -78 °C was added dropwise a solution of n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintaining the temperature below-60 °C. A thick solid formed during the addition. Upon completion of the addition the reaction mixture was maintained for an additional 15 minutes, after which time a solution of 1,2-dibromo10 tetrachloro ethane (90 g, 0.276 mol) in tetrahydroforan (150 mL) was added dropwise while wainteining the temperature below -70 °C. The reaction mixture turned a clear orange; stirring was continued for an additional 15 minutes. The -78 °C bath was removed and the reaction was quenched with water (600 mL). The reaction mixture was extracted with methylene chloride (4x), and the organic extracts were dried over magnesium sulfate and.

concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride-hexane (50:50) as eluent to afford 57.04 g of the title product as clear colorless oil. &#1470; &#1524; : &#1470;/ &#1470; . -.

1H(CDCh): δ 3.07 (<L6H), 6.44 (m,lH), 7.62 (m,lH).

Step PS: Preparation of 3-bromopyrazole

To trifluoro acetic acid (70 mL) wasslowly added 3&#1470;bromo-.VJV dimethyl Iff .

r of Step A) (57.04 g). The reaction .&#1491; !riixtere was stimed at room temperature for 30 minutes and then concentrated at reduced pressure. The residue was taken up in hexane, insoluble solids were filtered oft) 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 sulfate and concentrated to afford 25.9 g of the title product as a white solid, m.p. 61-64 °C. 1H M4R (CDCI3): δ 6.37 (d,lH), 7.59 (d,lH), 12.4 (br s,lH).

3q step c-_______Preparation of 2-(3-bromo-lg-pvrazol-1 -yl) chloropvridine

To amixture of 2,3-dichloropyndine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry ΛζΝ-dhnethylfoimamide (88 mL) was added potassium carbonate (48-.0 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 ic״ water^ 35 (800mL). A precipitate-formed. The precipitated solids were stirred for 1.5 h, filtered ana washed with water (2x100 mL). The solid filter cake was taken up in methylene chlonde and washed sequentially with water; IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried, over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solidwas 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.

1HNMR (CDCI3): δ 6.52 (s,lH), 7.30 (dd,lH), 7.92 (d,lH), 8.05 (s,lH), 8.43 (d,lH).

Step _______Preparation of 3-bromo-l-(3-chloro pyndinyl)-17F-p&#1470;vrazole carboxylic acid

To a solution of 2-(3-bromo-12T-pyrazol-l-yI) chloropyridine (i.e. the pyrazole product of Step C) (30.4 g, 118 mmol) in dry tetrahydrofuran (250 mL) at-76 °C was added 10 dropwise a solution of lithium diisopropylamide (118 mmol) in tetrahydro furan 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), 15 and then aqueous sodinrn hydroxide solution (1 N, 20 mL) was added.The aqueous extracts were washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered,- washed with water and dried to afford 27.7 g of the title product as a tan solid. Product from another run follo&#1470;wing similar procedure melted at200—201 °C. 1HNMR (DMSO-J6): δ 7.25 (s,lH), 7,68 (dd,lH), S.24 (d,lH), 8.56 (d,lH).

Step E: Preparation of 2-r3-bromo-l3)&#1470;-chloro p5ridinyl)-17?-pvrazol vl1 iodo8-metl1vI-4.ff-3. l-benzoxazm one.,/./ _ w

To_a solution of methanesulfonyl chloride (0.54 ml, 6.94 nrmol) m acetonitrile (15 mL) was added dropwise a mixture of 3-bromo-l-(3-chloro pyridinyl)-12i-pyrazole-5carboxylic acid (i.e. the carboxylic acid product of Step D) (2.0 g, 6.6 mmol) and 25 triethylamine (0.92 ml, 6.6 mmol) in acetonitrile (5 mL) at 0 °C. The reaction mixture was then stirred for 15 minutes at 0 °C. Then, 2-amino methyl iodobenzoic acid (i.e. the product from Example 1, Step A) (1.8 g, 6.6 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (1.85 mL, 13.2 mmol) in acetonitrile (5 ml.) was then added dropwise while keeping the temperature below 5 °C. Tire reaction 30 mixture was stirred 40 minutes at 0 °C, and then methanesulfonyl chloride (0.54 ml, 6.94 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight.- The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1x20 mL) and brine (1x20 mL), dried (MgSO4) and 35 concentrated to afford 2.24 g of the title product as a erode yellow solid.

1HNMR (CDCL): δ 8.55 (dilH), 8.33 (d,lH), 7:95 (dd,lH), 7.85 (s,lH), 7.45 (m,lH), 7.25 (s,lH), 1.77 (s,3H).

:.Step.F: &#1510; &#1510; Preparation of 2-r3-br01n0rl-(3rchl0r0 pvndinvl')-lH-pvraz01 vl1 .

cyano methyl-4H-3.1 -benzoxazin one

To a solution of 2-[3-bromo-l-(3-chloro pyridinyl)-U?-pyrazol yl] iodo8&#1470;methyl-4M-3,l-benzoxazin one (i.e. the benzoxazinone product of Step E) (600 mg,

1.1 mmol) in tetrahydrofuran (15 mL) was added copper(!) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(!) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing throe times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSC>4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.

1H NMR (CDC13): δ 8.55 (m,lH), 8.31 (d>lH), 7.96 (dd,lH), 7.73 (s,lH), 7.51 (m,lH), 7.31 15 (s,lH), 1.86 (s,3H). ך ' '.

Step G: Preparation of 3-bromo-l-(3-chloro pvridinvD2&#1470;V&#1470;&#1470;r4-cvano methyl=6= r(methvlamino')carbonvl1phenvl&#1470;l-127'-pvrazole carboxam1de

To a solution of 2’-[3-bromo-l-(3-chloro pyridinyl>l;S’-pyrazol yl] cyano-8methyl-4H-3,l-benzoxazm one (i.e. the cyanobenzoxazinone product of Step F) (100 mg, 20 0 77 mmol) m tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in ,

THF, 0.5 mL, 1.0 mmol) and the reaction-mixture was stirred for 5 minutes, at which point thin layer chromatography on sihca gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the 25 present invention, as a white solid (41 mg), which decomposed in the melting apparatus above 180 °C.

1HNMR (CDC13): δ 10.55 (s,lH), 8.45 (dd,lH), 7.85 (dd,lH), 7.57 (s,2H), 7.37 (m,lH), •7.05 (s,lH), 6.30 (d,lH), 2.98 (d,3H), 2.24 (s,3H).

EXAMPLE

Prer> aration of 3 -bromo (3 -chloro-2־PYndinvll--V~r4-cyano methvl-6(aminocarbonvllphenvll- -l.H-pvrazole cafboxamide

To a solution of 2-[3-bromo-l-(3-chloro pyridinyl)-LH-pyrazol5&#1470;-yl] cyano-8methyl-4H-3,l-benzoxazin one (i.e. the cyanobenzoxazinone product of Example 5, Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium 35 hydroxide (0.5 mL., 12.8 mmol) at room temperature. The reaction mixture was then stirred, for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (6&#1499; mg), with a..

melting point above 255 °C.

1HNMR (CDC13): δ 10.52 (s, IB), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.65(s,lH), 7.60 (s,lH), 7.40 (m,lH), 7.05 (s,lH), 6.20 (bs,lH), 5.75 (bs,lH), 2.25 (s,3H).

5 EXAMPLE 7

Preparation

Γ (methvlaminokarbonyllphenyll-lH-pyrazole cafboxamide

Step A:______Preparation of 2-amino chloro iodobenzoic acid

To a solution of 2-amino chlorobenzoic acid (Aldrich, 5 g, 29.1 mmol) in

A/W-dimethylformamide (30 mL) was added W-iodosuccinimide (5.8 g, 26 mmol) and the reaction mixture was heated at 60 °C overnight. The heat was removed and the reaction mixture was then slowly poured into ice-water (100 mL) to precipitate a tight brown solid. The solid was filtered and washed four times with water and then placed in a vacuum oven at 70 °C to dry overnight. The desired intermediate was isolated as a tight brown solid (7.2 g).

1HNMR (DMSO&#1470;d): δ 7.96 (d,lH), 7.76 (t,lH).

Step B: .&#1470;. Preparation of 8-chloro2&#1470;-r3-chloro-l-(3-chloro pvridinyl)-lH-pyrazpl.: 5_v1y6-iodo-4g-3.1-benzoxazin one !&#1523;

To a solution of methanesulfonyl chloride (0.31 mL, 4.07 mmol) in acetonitrile .10) &#1470;&#1470; mL) was added dropwise a mixture of 3-chloro-l-(3-chloro pyridinyl)&#1470;lEf-pyrazole-520 carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (1.0 g, 3.87 mmol) and triethylamine (0.54 mL, 3.87 mmol) in acetonitrile (5 mL) at 0 °C. The reaction mixture was then stirred for 15 minutes at 0 °C. Then, 2-amino chloro iodobenzoic acid (i.e. the product from Step A) (1.15 g, 3.87 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (1.08 mL, 7.74 mmol) m acetonitrile (5 mT.) was then added dropwise while keeping the temperature below 5 °C. The reaction mixture was stirred 40 minutes at 0 °C, and then methanesulfonyl chloride (0.31 mL, 4.07 mmol) was added. The reaction mixture was then wanned to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1x20 mL) and brine (1x20 mL), dried (MgSO4) and concentrated under reduced pressure. The residual solid was purified, by chromatography on silica gel to afford 575 mg of the title compound as a crude yellow solid.

1H NMR (CDC13): δ 8.55 (q, 1H), 8.39 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.45 (m, 1Ξ), 7.19(5,1H).

Sten C:_______Preparation of S-chloro r3-chloro-l-i3-chloro pvridinylVl-H-pvrazol5-vll cvano-4j?-3. l-benzoxazin one

To a solution of S-chloro [3-chloro&#1470;l-(3-chloro pyridinyl)-12?-pyrazol yl]-6iodo-4if-3,l&#1470;benzoxazin one (i.e. the benzoxazinone product of Step B) (575 mg, 1.1 nimbi) &#1493;&#1493;&#1491; tetrahydrofuran. (15.ml.) was added copp_er(I)_ iptodeJ84tymg,0.44 mntel),.

tetrakis(ttiphenyphosphine)palladium(0) (255 mg, 0.22 mmol) and copper(!) cyanide (500 mg, 5.5 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 ml.) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 375 mg ofthe title compound as a crude yellow solid.

IfiL NMR (CDC13): δ 8.55 (q, 1H), 8.36 (d, 1H), 7.95 (m, 2H), 7.5 (m, 1H).

Step D: Preparation of 3-chloro-l&#1470;3)&#1470;chloro2&#1470;-pvridinvl)-N&#1470;&#1470;F2-chloro^&#1470;cyangz6z

Γ (methvlaminolcarbonyllphenyll- 127-p vrazole carboxamide

To a solution of 8-chloro3]-2&#1470;-chloro-l-(3-chloro pyridinyl) pyrazol5&#1470;-yl]-6cyano-4J7-3,l-benzoxazin one (i.e. the cyanobenzoxazdnone product of Step C) (187 mg, 15 0.446 mmol) in tetrahydrofuran (5 ml.) was added dropwise methylamine (2.0 M solution in

THF, 0.5 ml,, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion ofthe reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 49 mg of the title compound, a compound 20 of the present invention, as a white solid that melted at 197-200 C. — -. -. :

. 1H NMR (CDCI3): δ 10.05 (bs,lH), 8.45 (q,lH), 7.85 (dd,lH), 7.70 (d,lH), 7.59 (d,lH), . 7.38 (m,lH), 7.02 (s,lH), 6.35 (d,lH), 2.94 (d,3H).

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 25 the Tables which follow: t means tertiary, 5 means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, z-Pr means isopropyl, Bu means butyl and CN is cyano.

Table 1

<td> Me</td><td colspan="2"> OCFoH F</td><td> H</td><td> Ξ</td>

Table

Table 3

Componndslf this invention will generally be.used as a formulation or composition «th acanier suitable for agronomic or nona^onomic use comprising at least one of a diluent a solid diluent or a surfactant The formulation or composition mgredrmte 4 selectedtobe consistent with the physical properties <&#1470;f the active mgredient, mode of . apptication md mvironmenM factore such as soil type, moisture and temperature- Us fommlations include Hquids^assolutions (including emulsifiable ; g &#1523; siispetiSioimi’emulsioim (includingmicroemulsions.and(or snsppemulslo11s).a11d:the hk which optionitiy can be'xickened into geis. t.'setd fomndaiions further mciude soiids &#1524; : as dusts, powders, granules, pellets, tablets, films, md the like which cm &#1470; water-dispersible (“wettable”) or water-soluble. Active ingredient can be the entire formulation of active ingredient can be encapsulated (or overcoat

Encapsulation cm control or delay release of the active ingredient Sprayable formulations cm extended in suitable media and used at spray volumes from about one ^several hundred liters per hectare. High-strength compositions are primarily used as mtermedia for further &#1470;ffeotive ^nuts of active ingredient, ditoem and surfactant witbin the following approximate ranges that add up to 100 peicent y w1&#1470;

<td colspan="2" rowspan="2"> Active Ingredient</td><td colspan="2"> Weight Percent__________________________'</td>

<td> Diluent</td><td> Surfactant</td>

<td> Water-Dispersible and Water-soluble Granules, Tablets and Powders.</td><td> 5-90</td><td> 0-94</td><td> 1-15</td>

<td> Suspensions, Emulsions, Solutions (including Emulsifiable Concentrates)</td><td> 5-50</td><td> 40-95</td><td> 0-15</td>

<td> Dusts</td><td> 1-25</td><td> 70-99</td><td> 0-5</td>

<td> Granules and Pellets</td><td> 0.01-99</td><td> 5-99.99</td><td> U—13</td>

<td> High. Strength Compositions</td><td> 90-99</td><td> 0-10</td><td> 0-2</td>

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 Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon‘s Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New

Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co Tnr y New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.

Surfactants; include, for example, polyethoxylated alcohols, polyethoxylated alkydphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl : sulfates, alkylbenzene sulfonates, organosilicones, TO-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/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, A^-dimethylfomiamide, dimethyl sulfoxide, Y-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkydbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, com, peanut, cotton-seed, soybean, rape-seed and coconut, fatty&#1470;&#1523; acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy methyl pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurforyl 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 25 flxampU U.S. 3,060,084. Granules and pellets can be prepared by spraying the active matflrial upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration”, Chemical Engineering, December 4, 1967, pp 147-48, Perry ’s Chemical

<td></td><td> 38 Ed., 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 inU.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.</td>

<td> 5</td><td> 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 Modem Agriculture” in Pesticide Chemistry and Bioscience, The Food—Environment Challenge, T. Brooks and T. R. Roberts, Eds.,</td>

<td> 10</td><td> Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal S ociety 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 14־; Klingman, Weed</td>

<td> 15</td><td> Control 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.</td>

<td></td><td> ~ j In the following Examples, all percentages are by weight and all formulations are</td>

<td></td><td> prepared in conventional ways. Compound numbers refer to compounds in Index Table A.</td>

<td></td><td> . . __ _ Example A . ' ;</td>

<td> 20-</td><td> .. . Wettable Powder Compound 1 65.0% - dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0 /0 - sodium silicoaluminate 6.0%</td>

<td> 25</td><td> montmorillonite (calcined) 23.0/0. Example Granule Compound 1 ' 1θ.θ0//° attapulgite granules (low volatile matter,</td>

<td> 30</td><td> 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example Extruded Pellet Compound 1 25.0% anhydrous sodium sulfate 10.0%</td>

<td> 35</td><td> crude calcium ligninsulfonate 5.0% sodium־ alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.</td>

<td></td><td> -- .......־־־........................... .</td><td> ... . Example .......</td><td> - .... —---------------------</td>

<td></td><td> Emulsifiable Concentrate</td><td></td><td></td>

<td></td><td> Compound 1</td><td></td><td> 20.0%</td>

<td></td><td> blend of oil soluble sulfonates</td><td></td><td></td>

<td> 5</td><td> and polyoxyethylene ethers</td><td></td><td> 10.0%</td>

<td></td><td> isophorone</td><td></td><td> 70.0%.</td>

<td></td><td></td><td> Example E</td><td></td>

<td></td><td> Granule</td><td></td><td></td>

<td></td><td> Compound 1</td><td></td><td> 0.5%</td>

<td> 10</td><td> cellulose</td><td></td><td> 2.5%</td>

<td></td><td> lactose</td><td></td><td> 4.0%</td>

<td></td><td> cornmeal</td><td></td><td> 93.0%.</td>

Compounds of this invention are characterized by favorable metabolic and/or soil residual patterns and exhibit activity controlling a spectrum of agronomic and non15. agronomic invertebrate pests. Compounds of this invention are also characterized by :&#1497; favorable foliar and or soil-applied systemicity in plants exhibiting translocation to protect foliage'arid:other plant parts not directlycontacted with insecticidal, compositions comprising .

. :.the present compounds. (In the context of this disclosure invertebrate pest control means . mtiihitioTi of invertebrate pest development (including mortality) that causes significant rerinctinn in feeding or other injury of 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: roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes (Trematoda), Acanthocephala, and tapeworms (Cestoda). Those skilled in the art will recognize that not all compounds are equally effective against, all pests. Compounds of this invention display activity against economically important agronomic 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,, cabbase, 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), turf (r.nmmprci31, golf, residential, recreational, etc.), wood products, public (human) and animal bs31 th. domssric and commercial structure, household, and stored.product applications or pests. For reason of invertebrate pest control spectrum and&#1523; economic importance, protection (from damage or injury caused by invertebrate pests) of agronomic crops of cotton, maize, &#1470; 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 hehothines in the family Noctuidae (e.g., fall armyworm (Spodopterafugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hubner), black cutworm (Agrotis ipsilon Hufnagel), cabbage looper (Trichoplusia ni Hubner), tobacco budworm (Heliothis virescens Fabricius)); borers, casebearers, webwonns, coneworms,. cabbageworms and skeletonizers from the family Pyrahdae (e.g., European com borer (Ostrinia nubildlis Hubner), navel orangewonn (Amyelois transitella Walker), com root webworm (Crambus caliginosellus Clemens), sod webworm (Hetpetog-amma licarsisalis Walker)); leafrollers, budwonns, seed worms, and fruit worms in the family Tortricidae (e.g., codling moth (Cydiapomonella Linnaeus), grape berry moth (Endopiza viteana. Clemens), oriental fruit moth (Grapholita molesta Busck)); and many other economically important lepidoptera (e.g., diamondback moth (Plutella xylostella Linnaeus), pink bollwonn (Pectinophora gossypiella Saunders), gypsy moth (Lynianti-ia dispar Linnaeus)); nymphs and adults of the order Blattodea including cockroaches from the families Blattellidae and Blattidae (e.g., oriental cockroach (Blatta o7&#1470;ze72r<2Zfr Linnaeus), Asian cockroach (5Ζα&#943;β/Ζα hdizukubo), German cockroach “ &#1523; ’ &#1470;: (Blattella germanica Linnaeus), brownbanded cockroach (Supella longipalpa Fabricius),

American cockroach (Periplan eta americana&#1470;Lvxna.eOsl). brown cockroach (Periplaneta b7&#1470;wzz7ieaBurmeister)&#1470; Madeirn cockroach (Leucophaea maderae Fabricius));&#1470; foliar feeding larvae and adults of the order Coleoptera including weevils from the families Anthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Antlionomus grandis Boheman), rice water weevil (Lissorhoptrus oryzophilus Kuschel), granary weevil (Sitophilus granarius

Linnaeus), rice weevil (Sitophilus oryzae Linnaeus)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafminers in the family Chrysomelidae (e.g., Colorado potato beetle (Leptinotarsa decemlineata Say), western com rootworm (Diabrotica virgifera virgifera LeConte)); chafers and other beetles from the family Scaribaeidae (e.g., Japanese beetle (Popillia japonica Newman) and European chafer (Rhizotrogus majalis

Razoumowsky)); carpet beetles from the family Dermestidae; wirewonns 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 Dennaptera including earwigs from the family Forfimilidae (e.g., European earwig (Forficula auricularia Linnaeus), black earwig (Chelisoches morio Fabricius)); adults and nymphs of the orders Hemiptera and Homoptera such, as, plant bugs from the family Miridae, cicadas from the family Cicadiflae leafhoppers (e.g. Empoasca spp.) from the family Cicadellidae, planthoppers from the families Fulgoroidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae, whiteflies from. the family Aleyrodidae,.aphids from. the.family Aphididae, phylloxera from the family &#1470; Phyfloxeridae, mealybugs from the family Pseudococcidae, scales from the families .

Coccidae. Diaspididae and Margarodidae, lace bugs from the family Tingidae, stink bugs from the family Pentetomidae, 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 Pyirhocoridae. Also included as a gronomic and non-a gronnmic pests are adults and larvae of the order Acari (mites) such as spider mites and red mites in the family Tetranychidae (e.g., European red mite fPanonychus ulmi Koch), two spotted spider mite (Tetranychus urticae Koch), McDaniel mite .10 (Tetranychus mcdanieli NLcGrcgpr)), flat mites in the family Tenuipalpidae (e.g., citrus flat mite (Brevipalpus lewisi McGregor)), rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e. dust mites in the family Epidennoptidae, 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 liolocyclus Neumann), American dog tick (Dermacentor v'ariabilis Say), lone star tick (Amblyomma dmericaniim Linnaeus) and scab and itch mites in the families Psnrnptida.ej Pyemotidae. and Sarcoptidae: adults and immatures of the order ’1Orthoptefa includin.g grasshoppers, locusts and crickets (e.g., migratory grasshoppers (e.g.,

Melanoplus sangAnipes Tdodcvas, M. differentialis Thomas), American grasshoppers (e.g.,

Schistocerca Dniryj.desert locust (Schistocerca gregaria Forskal), migrator}&#1523;

- - locust (Locusta 1nig1-atoriaEhmaevH),}yasIi. locust (/,onocerus spp.), house cricket (Acheta 1 domesticus Lumaeus), mole crickets (Π/ν/Ζο&#943;αΖρα spp.)); adults and immatures of the order. &#1470; Diptera including leafinmers, 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 flies (e.g., Stomoxys 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., Gastrophilus spp., Oestrus spp.), cattle grubs (e.g. Hypoderma spp.), deer flies (e.g., Clirysops spp.), keds (e.g., Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g., Aed.es spp.,

Anopheles spp., Culex spp.), black flies (e.g., Prosimuliiim spp., Simulium spp.), biting midges, sand flies, sciarids, and other Nematocera; adults and. immatures of the order Thysanoptera including onion thrips (Thrips tabaci Lindeman), flower thnps (Frankliniella spp.), and other foliar feeding thrips; insect pests of the order Hymenoptera including ants (e.g., red carpenter ant (Camponotus ferrugiizeus Fabricius), black carpenter ant (Camvonotuspennsylvanicus De Geer), Pharaoh ant (Monomorzumpharaonis Linnaeus), little fire ant (Wasmannia.auropunctata Roger), fire ant (Solenopsis geminata rabricius), red imported fire ant (Solenopsis invicta Buren), Argentine ant (Iridomyrmex humilis Mayr), crazy ant (Paratrechina longicornis Latreille), pavement ant (Tefrainoriwn caespitum

. Linnaeus), cornfield ant (Lasius alienus Forster), odorous house ant (Thpmoma sessile Say)), bees (including carpenter bees), hornets, yellow jackets, wasps, and sawflies (Neodiprion spp.; Cephas spp.); insect pests of the order Isoptera including the eastern subterranean termite (Reticuliterm.es flavipes Kollar), western subterranean termite (Reticulitermes hesperus Ranks), Formosan subterranean termite (Coptoterm.es fonnosanus Shiraki), West Indian drywood termite (Incisitennes tmmigrans Snyder) and other termites of economic importance; insect pests ofthe order Thysanura such as silverfish (Lepisma saccharina Linnaeus) and firebrat (Thermobia domestica Packard); insectpests ofthe order Mallophaga and including the head louse (Pediculus humanus capitis De Geer), body louse (Pediculus 10&#1523; humanus humanus Linnaeus), chicken body louse (Menacanthus stramineus Nitszch), dog biting louse (Trichodectes cams De Geer), fluff louse (Goniocotes gallinae De Geer), sheep bod}&#1523;. louse (Bovicola ovis Schrank), short-nosed cattle louse (Haematopinus eurystemus Nitzsch), long-nosed cattle louse (Linognathus vituli Linnaeus) and othersucking and chewing parasitic lice that attack man and animals; insect pests of the order Siphonoptera including the oriental rat flea (Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felislouche), fiog fiez (Ctehocephalides canis C\rr)0s),}1&i1f!Le3.(Ce1‘atophyllus gallmae Schrank), sticktight ffe& (Echidnophaga gallinacea Westwood), human flea (Pulex irrttans : Γ inn a bn s) arid nth er fl en a affli cting m amm al s an d birds. Additional invertebrate pests ‘ covered include: spiders in the order Ararieae such asthe brown recluse spider (Loxosceles 20 reclusa Gertsch & Mulaik)and the black widow spider (Latrodectus mactans Fabricius), and ::' :. centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleoptrata &#1470; Linnaeus). Compounds ofthe present invention also have activity on members ofthe Classes Nematoda, Cestoda, Trematoda, arid Acanthocephala including economically important members ofthe orders Strongylida, Ascaridida, Oxyunda, Rhabditida, Spirurida, 25 and Enoplida such as but not limited to economically important agricultural pests (i.e. root knot nematodes in the genus Meloidogyne, lesion nematodes in the genus Pratylenchus, stubby root nematodes in the genus Trichodorus, etc.) and animal and human health pests (i.e. all economically important flukes, tapeworms, and roundworms, such as Strongylus vulgaris in horses, Toxocara canis in dogs, Haemonchus coniortus in sheep, Dirofilana 30 immitis Leidy in dogs, Anoplocephalaperfoliata 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 Hubner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips 35 species, Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (com root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydiapomonella Linnaeus (codling moth), Earias insulana&#1523; Boisduval (spiny bollworm), Earias vittella Fabricius (spotted tyofF^orrd),.Helicoverpa.

. armigera Hubner (American bollwonn), Helicoverpa zea Boddie (com earworm), Heliothisvires cens Fabricius (tobacco budworm), Heipetogrammalicarsisalis Walker (sod webwonn), Lobesia botrana Denis & Schiffermuller (grape berry moth), Pectinophora gossypiella Saunders (pink bollwonn), Phyllocnistis citrella Stainton (citrus leafininer),

Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diamondback moth), Spodoptera exigua Hubner (beet armyworm), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera fi-ugiperda J. E. Smith (fall armyworm), Trichoplusia ni Hubner (cabbage looper) and Tuta absoluta Meyrick (tomato leafininer)). Compounds of the invention also

10. 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 De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphonfragaefolii Cockerell (strawberry aphid),

Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserirn (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pruni GexAsroy (mealy plum, aphid), Lzpap/zzk eiysimi Kaltenbach (turnip : . aphid), Metopolophium dirrhodum Walker (cereal aphid), Macrosipinn 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), Rhopalosiphumpadi Linnaeus (bird cherryoat aphid), Schizaphis grdminum Rondani (greenbug), Sitobion avenae Fabricius (English grain aphid), 77zez70i2p7zz5 maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolom.be (black citrus aphid), and Toxoptera cttricida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix Pergande (pecan phylloxera);

Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes citri Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhouse whitefly); Empoasca fabae Hams (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper)&#1524; Macrolestes 30 quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper),

Nephotettix nigropictus Stal (rice leafhopper), Nilaparvata lugens Stal (brown planthopper), Peregrinus maidis Ashmead (com planthopper), Sogatella furcifera Horvath (white-backed, planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocybapomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidadaseptendecim

Linnaeus (periodical cicada); Iceryapurchasi Maskell (cottony cushion scale), Quadraspidiotus perniciosus Comstock (San Jose scale); Plano coccus citri. Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsyllapyricola Foerster (pearpsylla), Trioza diospyri Ashmead (persimmon psylla). These compounds also have &#1470; activity on members from the order EEemiptera including: 2417-6½½ &#1502;7»7&#1491;67?5&#1505;&#1470;7&#1513; Say(green ~ stink bug), Anasa tristis De Geer (squash, bug), Blissus leucoptems leucopterus Say (chinch bug), Corvtliuca gossypii Fabiicius (cotton lace bug), Cyrtppeltis modesta Distant (tomato 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), Oebaluspugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cotton fleahopper). Other insect orders controlled by compounds of the invention include Thysanoptera (e.g., Fr'ankliniella occidentdlis Pergande (western flower thrip), Scirthothrips citri Moulton (citrus thrip), Sericothrips variabilis Beach (soybean thrip), and Thrips tabaci Lindeman (onion timp), and the order Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potato beetle),

Epilaclma varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes,

Athous or Limonius&#1470;).

Compounds of this mvention can also be mixed with one or more other biologically active compounds or agents including insecticides, fungicides, nematocides, bactericides, ־ > '' acaricides, growth regulators such as rooting stimulants, chemosterilants,־ semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds .;

or entomopafhogenic bacteria, virus or fungi to form a multi-component pesticide giving an.

- even broader spectrum of agronomic and non-agronomic utility. Thus the present 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 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, acetoprole, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifemazats, bistrifluron, buprofezin, cafbofuran, chlorfenapyf, chlorfluazuron, chlorpyrifos, chlorp jrifos-methyl, chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fLuvalinate, flufenerim (UR-50701), flufenoxuron, gamma-chalothrin, halofenozide, hexaflumuron. imidacloprid, indoxacarb, isofenphos. lufenuron, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, monocrotophos, methoxyfenozide, novaluron, noviflwnuion (XDE-007), oya-rnyi, parathion, parathion-methyl,permethrin, phorate, phosalone, phosmet, phosphamidon, pin-mi carb, profenofos, profLutbrin,.protrifenbute, pymetrozine; pyridalyl, pyriproxyfen, rotenone,. S1812 (Valent) spinosad, spiromesifen (BSN-2060), sulprofos,tebiffenozideTteflubenffnon,!^ ---.

thiamethoxam. thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, trichlorfon and triflumuron; fungicides such as acibenzolar, S-methyl, azoxystrobin, benalazy-M, benthiavalicarb, benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), boscalid, bromn con azols, buthiobate, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, clotrimazole, copper oxychloride, copper salts, cymoxanil, cyazofamid, cyflufenamid, cyproconazole, cyprodinil, diclocymet, diclomezine, dicloran, difenoconazole, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, &#1470; epoxiconazole, ethaboxam, famoxadone, fenarimol, fenbuconazole, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenproprmorph, fentin acetate, fentin hydroxide, fluazinam, fLudioxonil, flumorph, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, fhrtriafol, folpet, fosetyl-aluminum, feralaxyl, furametapyr, guazatine, hexaconazole, hymexazol, imazalil, imibenconazole, iminoctadine, ipconazole, iprobenfos,. iprodione, iprovalicarb, isoconazole, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepanapyrim, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, m etra fen on e, mi con azol e. myclobutanik neo-asozin (ferric methanearsonate), nuarimol, oryzastrobin, oxadixyl, oxpoconazole, penconazole, pencycuron, picobenzamrd, picoxystrobin, probenazole, prochloraz, propamocafb, propiconazole, prqquinazid, prothioconazole, pyraclostrobin, pyrimethanil, pyrifenox, pyroquilon, quinoxyfen, . silthiofam, simeconazole, sipconazole, spiroxamine, sulfur, tebuconazole, tetraconazole, tiadinil, thiabendazole, tbifluzamide.thiophanate-methyl, thiram, tolylfluanid, triadimefon, triadimenol, triarimol, tricyclazole, trifloxystrobin, &#1470;triflumizole, triforine, triticonazole, nniconazole, validamycin, vinclozolin and zoxarmde; 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, hex^fhiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis including ssp. avzawai and fcurstald, Bacillus thuringiensis delta endotoxin, baculovirus, 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 nomponnds of this invention may be synergistic with the 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 &#1470;with compounds of dais invention include pyrethroids such as acetamiprid, cypennethrin, cyhalothrin, cyfluthrin, beta cyfluthriu, esfenvalerate, fenvalerate and tralomethrin; carbamates such as fenotiucarb,.

&#1470;&#1470;&#1470;.methomS^^^andtto^..

thiacloprid; neuronal sodium channel blockers such as indoxacarb; insecticidal macrocyclic lactones such as spinosad, abamectin, avermectin and emamectin; γ-ammobutyric acid (GABA) antagonists such as endosulfan, ethiprole and fipronil; insecticidal ureas such as&#1470; 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 natiirally occurring and genetically modified viral insecticides including 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-cyfiuthrin; a mixture of a compound of this invention with esfenvalerate; a mixture of a compound of this invention with methomyl; a mixture of a compound of this invention with imidacloprid; a mixture of a 15&#1470; compound of this invention with thiacloprid; a mixture of a compound of this invention with indoxacarb; a.mixture of a compound of this invention with abamectin, amixture of a &#1470; compound of this invention with, endosulfan; amixture of a compound of this invention with &#1470; ethiprole; amixtmeofacompoundof this invention withfipronil; amixtm of this invention with flufenoxuron; a mixture of a compound of this invention mth /' pyriproxyfen; a mixture of acompound of th|inyentionw^ .

compound of this invention with amitraz; a mixture of a compound of this invention w! ;

Bac&sthiriS^ compound of this invention with 5acz7Ius delta endotoxin.

In certain instances, combinations with other invertebrate pest control compounds or 25 agents having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management. Thus, compositions of the present invention can further comprise abiologically 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 30 protection compound (e.g., protein) or the locus of the plant with a biologically effective, amount of a compound of invention can also provide abroader spectrum of plant protection and. be advantageous for resistance management.

Invertebrate pests are controlled in agronomic and nonagronomic applications by aoplyine one or more of the compounds of this invention, in an effective amount, to the 35 environment of the pests including the agronomic and/or nonagronomic locus ofmrestanon, to the area to be protected, or directly on the pests to be controlled. Thus, the present invention furdier comprises a method for the control of invertebrates in agronomrc ano/or nonagronomic applications, comprismg contacting the invertebrates or their environment with a biologically effective amount of one or more of the compounds of the invention, or with a composition comprising at least one such compound or a composition comprising at least one such compound and an effective amount of at least one additional biologically active compound or agent. Examples of suitable compositions comprising a compound of 5 the invention and an effective amount of at least one additional biologically active compound or agent include granular compositions wherein the additional biologically active c-ompnuud 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 10 comprising a compound of the invention can be applied to the plant foliage or the soil.

Cn-mpnunds 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 treatment, or a dip of transplants. Compounds are also effective by topical application of a.15 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. j.uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others. The compounds of this invention may also&#1524;bp,impregnated into materials for fabricating.

,.j 20 invertebrate control devices (e.g. insect netting),

- - A compound of this invention can be incorporated into a bait composition that is, . : consumed by an invertebrate pest or used within devices such as traps, bait stations, and the guch a bait composition can be in the form of granules which comprise (a) an active ingredient, namely a compound of Formula 1, anN-oxide, or salt thereof, (b) one or more 25 food materials, (c) optionally an attractant, and (d) optionally one or more humectants. Of nets granules or bait compositions which comprise between about 0.001-5% active ingredient: about 40-99% food material and/or attractant; and optionally about 0.05-10% bn-mec-tants., are effective in controlling soil invertebrate pests at very low application rates, particularly at doses of active ingredient that are lethal by ingestion rather than by direct 30 contact. Of note some food materials will function both as a food, source and an. attractant.

Food materials include carbohydrates, proteins and lipids. Examples of food materials are vegetable flour, sugar, starches, animal fat, vegetable oil, yeast extracts and milk solids. Examples of attractants are odorants and flavorants, such as fruit or plant extracts, perfume, or other animal or plant component, pheromones or other agents known to attract a target 35 invertebrate pest. Examples of humectants, i.e. moisture, retaining agents, are glycols and other polyols, glycerine and sorbitol. Of note is abait composition (and. a method, utilizing such a bait composition) used to control invertebrate pests including individually or in. cembmariems ants, termites, and cockroaches. A device for controlling an invertebrate pest ; 48 can comprise the present bait composition and a housing adapted to receive the bait

. — - &#1470; —.—————.—.—-.-.«-,&#1497;--—-—.---.-.«----—--.-----.----.-.«-«------.-.-—.— _____ composition, wherein the housing has at least one opening sized to permit the invertebrate pest to pass through the opening so the invertebrate pest can gain access to the bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the invertebrate pest.

The compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil c.nric.entratioris, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy. For nonagronomic uses such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a p-n-mp or by releasing it from a pressurized container, e.g. a pressurized aerosol spray can.

Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions thus can further comprise propellants, foaming agents, etc. as

- the case may be. Of note is a spray composition comprising a compoundOr composition of -: : the present invention arid a propellant.'Representative propellants include, but are not ;7 limited to, methane,.ethane,.propane, iospropane,butane, isobutane, butene, pentane, vs 20 iospentane, neopentane, pentene, hydrofluorocarbons, chlorofluoroacarbons, dimethyl ether, -:; ;,. - . and mixtures of the foregoing. Of note is a spray composition (and a method utilizing such a &#1470; spray composition dispensed from a spray container) used.to control an invertebrate pest including individually or in combinations mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like.

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 σ&#912;το.πτη stances, 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 tittle as 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may he required. One tikritied in the art can easily HeteTmine the biologically effective amount necessary for the desired level of invertebrate pest control.

The following TESTS demonstrate the control efficacy of compounds of this invention on specific pests. “Control efficacy” represents inhibition of invertebrate pest development (including mortality) that causes significantly reduced feeding. The pest control protection afforded. by.the compounds.is not limited, however,, to these, species. See .Index Table. A, B. and C for compound descriptions. The following abbreviations are used in the Index Tables which follow: i is iso, t is tertiary, Me is methyl, Et is ethyl, Pr is propyl, z&#1470;Pr is. isopropyl, c-Pr is cyclopropyl, Bu is butyl, and CN is cyano. The abbreviation &#904;χ. stands for “Example” and is followed by a number indicating in which example the compound is prepared.

' N\R4Z r5

<td> Compound</td><td> Έ.</td><td></td><td> r3</td><td> Έ/////</td><td> r5</td><td> m.n. (°O</td>

<td> ComDOtmd</td><td> R1...</td><td> .......R2......</td><td> . R3....</td><td> ...............R4......-....</td><td> ...R5...</td><td> m.e. (°C)</td>

<td> Compound</td><td> rL. ...</td><td> R! . .</td><td> ...R2</td><td> / ' ־' Ή4 ־־ -...........</td><td> g?,......</td><td> m.p.rnC)</td>

<td></td><td> Me yte.:</td><td> Br</td><td> c.</td><td> • CHCCHsXCH^SMe</td><td> :H -,</td><td> 188-190</td>

*See Index Table C for NMR. data.

INDEX TABLE B..

[Γ

Rl R3

l./

<td> Compound</td><td> r!</td><td></td><td> R3</td><td> R3</td><td></td><td> R4</td><td></td><td> R^</td><td> rZ</td><td> m.p, (°C)</td>

INDEX TABLE C

Cmpd No. Ij! Data (CDCI3 solution unless indicated otherwise)____________ ~ (CDC13) 10.55 (s, IH), 8.45 (d, IH), 7.85 (dd, IH), 7.55 (s, 2H), 7.40 (dd,

1H), 6.97 (s, IH), 6.30 (b q,.lH), 2.98 (d, 3Ξ), 2.24 (s, 3H) (CDC13) 10.55 (s, IH), 8.45 (d, IH), 7.85 (dd, IH), 7.57 (m, 2Ξ), 7.37 &#1499; (dd, IH), 7.05 (s, 1Ξ), 6.30 (b q, IH) 2.98 (d, 3H), 2.24 (s, 3H) (CDC13) 10.10 (br s, IH), 8.38 (d, IH), 7.75 (s, 1Ξ), 7.65 (s, IH), 7.00 (m, 1Ξ), 7.34 (m, IH), 7.10 (s, IH), 6.58 (b q, IE) 2.96 (s, 3B) &#1500; (CDC13) 10.12 (s, IE), 8.56 (d, IH), 7.85 (d, IH), 7.58 (m, 2Ξ), 7.40 (dd, 24 IH), 6.97 (s, IB), 6.00 (b d, 1Ξ) 4.22 (m, 1Ξ), 2.25 (s, 3Ξ), 1.26 (d, 6B) (CDCL3) 10.60 (s, IB), 8.47 (d, IH), 7.85 (dd, IB), 7.56 (s, 2Ξ), 7.39 (dd,

IB), 7&#908;6 (s, IH), 6.04 (b d, IH) 4.20 (m, IH), 2.24 (s, 3H), 1.26 (s, 6H)

.. Cmpd No. NMRData (CDCI3 solution unless indicated otherwise) &#1470;.

' 33 ((ΞΓ&#940;371^ (s, 2H). 7.39 (m,

1H), 6.97 (s, IB), 6.20 (b t, IB) 3.46 (m, 2H), 2.25 (s, 3B), 125 (t, 3H) 35 . (CDC13) 10.60 (s, IB), 8.46 (d, IB), 7.85 (d, 1H), 7.57 (s,2H), 7:38 (m,

IB), 7.05 (s, IB), 6.25 (b t, IB) 3.46 (m, 2H), 2.24 (s, 3H), 1.25 (t, 3H) 41 (CDCI3) 10.40 (s, IB), 8.47 (d, IB), 7.85 (d, IB), 7.50 (s, 2H), 7.37 (dd, • IB), '6.63 (s, IB), 5.97 (s, IB) 4.68(¾ 2B), 1.42(8, 9H)

BIOLOGICAL EXAMPLES OF THE INVENTION

TESTA

For evaluating control of diamondback moth. (Plutella xylostelld) the test unit consisted of a small open container with a 12—14-day-old radish plant inside. This was pre-mfested with 10—15 neonate larvae on apiece 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 5 containing larvae and diet to the test unit. The larvae moved onto the test plant as the diet plug dried, out.' . Test compounds were formulated using a solution containing 10% acetone, 90% water a!1d 300 ppm X-7'?® Spreader Lo-Foam Fommla non-ionic surfactant containing : &#1524;.&#1470;&#1524; u alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc. 10 Greeley, Colorado, USA). The formulatedcompoundswereapplied inlmL. of liquid .

i :fbrnngb a ST ΓΓ2 atomizer nozzle with 1/8 JJ custom body (Spraying Systems Co. Wheaton, Illinois, USA) positioned. 1.27 cm (0.5. inches) above the top of each test unit. All.;.<

experimental compounds in these tests were sprayed at 50 ppm 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 based on foliage consumed.

Of the compounds tested the following provided very good to excellent levels of plant protection (20% 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, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,

75, 76, 77, 78,79, 80, 81, 82, 83, 84,.88, 89, 90, 91, 92, 94, 95, 96, 97, 98, 99,100, 101,102,

103,106,108,109,110, 111 and 112.

TESTS

For evaluating control of fall armyworm (Spodoptera frugiperdd) the test unit consisted of a small open container -with a 4—5-day-old com (maize) plant inside. This was pm-infested, (using a core sampler) with 10—15 1-day-old larvae on a piece of insect, diet.

&#943;

. 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 (20% or less feeding damage): 1, 2, 3,4, 5, 6,7, 8, 9,10,11, .12, 13,14,15,16,17, 18,20,

21,22, 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, 63, 64, 65, 66, 67, 68, 70, 73,74, 76, 78, 88, 91, 92, 94, 95,96, 98, 99,100,101, 102,103,106,109,110, 111 and 112.

TESTC ' 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 aphids on apiece of leaf excised from a culture plant (cut-leaf method). The larvae moved onto the . test plant as the leaf piece desiccated. After pre-mfestaiion, 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,

Jhc.). &#1493;&#1497;&#1491; e fn-rmul ate ^compounds &#1470;were applied in 1 mL of liquid through a SUJ2 atomizer .'20 nozzle with 1/8 JJ custom body (Spraying Systems Co.) positioned 1.27 cm (0.5 inches) '

abov&thbiOpbf eacfrltesftihitri^^em^ screen were sprayed at .:::. :::: . 250 ppm, replicated three times. After spraying of the&#1523; formulated test compound, each test unit was allowed to dry for 1 hour and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 19-21 °C and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12,13,14,15,16,17,18,19,20, 21,22,23, 24,25,26,27,-28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38,40,41,43, 44,46, 47, 48,49, 50, 51, 52, 53, 55, 56, 63, 65, 66, 67, 68, 69, 70, 73, 74,. 76, 78, 88, 89,90, 91, 92, 94, 95, 96, 98, 99, 100, 101, 102, 103, 106, 108, 30 109,110, 111 and 112.

TESTD

For evaluating control of potato leafhopper (Empoasca fabae Hams) through contact and/or .systemic means, the test unit consisted of a small open container with, a 5-6 day old Longio bean plant (primary leaves emerged) inside. White sand was added to the top of the 35 soil and one of the primary leaves was excised prior to application. Test compounds wereformulated and sprayed at 250 ppm and replicated three times as described for Test C. At&#1523;. n? spraying, the test units were allowed to dry fori hour before they were post-infested.with.

.- 5 potato leafhoppers (18 to 21. day old adults). -A black screcned cap was Placed top of the cylinder. The test units were held for 6 days in a growth chamber at 19-21&#1470; °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, 3, 4, 5, 6, •5 . 8,10,12,16,17,18,19,20,21, 22,23,24,25,26,27,28,29,32, 33, 34,35,37,38, 40,41,

,95 ,94 ,90 ,89 ,88 ,76 ,73 ,70 ,68 ,67 ,66 ,63 ,56 ,55 ,54 ,53 ,52 ,51 ,50 ,49 ,48 &#1470;47 &#1470;46 ,44 &#1470;43

99, 101, 103, 106, 108, 109,110, 111 and 112.

TESTE

For evaluating control of cotton melon aphid (Aphis gossypii) through contact and/or 10 systemic means, the test unit consisted of a small open container with a 6 day-old cotton plant inside. This was pre-infested with 30-40 insects on apiece of leaf according to the cut-leaf method described for Test C, 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 D.

The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test D.

Of the compounds tested, the following resulted in at least 80% mortality: 1, 2, 3, 4, 5, /. 6, 7/8, 9,10,11,12,13,14,15, 16’ 17’ Is’ 1933 ’2 3 295 ’27 ’26 255’24’22’21 &#1470;20&#1470; ’ : .35, 36,.37, 38, 39, 40,41, 42, 43, 44, 46,47,48, 49, 50, 51, 52, 53, 55, 56, 63, 69, 71, 72, 74, 20 76, 78, 79, 81, 84, 88,.89, 90, 91, 92, 95, 96,97, 98, 99,.100,101, 102, 103,106,108, 109,

110, 111 and 112.

. testf ;': &#1523; &#1497;&#1497;.:.&#1491;&#1497;:&#1524;’&#1523;&#1523;&#1524;' φφ /7//7 &#1523; For evaluating control of com planthopper (Peregrinus maidis)through contact and/or systemic means, the test unit consisted of a small open container with a 3-4 day old com .

(maize) plant (spike) inside. White sand was added to the top of the soil prior to application. Test compounds were formulated and sprayed at 250 ppm and replicated three times as described for Test C. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with 10-20 com planthoppers (18- to 20-day old nymphs) by sprinkling them onto the sand with a salt shaker. A black, screened cap was placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 19-21 °C and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 1, 2, 3,4, 5, 6, 7, 8,10,11, 12, 13, 18, 20,24, 25, 26, 27,28, 29, 32, 33, 35, 37, 38, 39, 40, 41, 43, 45, 46, 47, 48, 49, 50, 51, 53, 56, 88, 89, 90, 91, 94, 95, 108 and 109.

35 ’ ’ 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.

. 56 . &#1470; Test compounds were'formulated in no morethan 2 mL. of acetone and then diluted with water to 25—30 ml&#1470;,. The formulated compounds were applied using a flat fan airassisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Plants were sprayed to runoff on a turntable sprayer. All experimental compounds in this screen were sprayed at 250 ppm and replicated three times. After spraying of the test compound, the test units were held for 6 Hays in a growth ch amber at 50—60% relative humidity and 28 °C daytime and 24 C nighttime temperature. Then the leaves were removed and the dead and live nymphs were counted to calculate percent mortality. &#1470;

Of the compounds tested, the following resulted in at least 80% mortality: 2, 3, 4, 5, 7, 10 8, 9, 10, 24, 25, 26, 27, 28, 30, 32, 33, 34, 35, 38,41, 46,48, 49, 51, 52, 53, 66, 67, 70, 73,

88,92 and 98.

TESTS

For evaluating movement of compounds in plants and control of green peach aphid (Myzuspersicae) and potato leafhopper (Empoascafabae) after foliar movement of 15 compound through the plant, the test unit consisted of a small open container with a 12-15Hay-old radish plant (for green peach aphid test) or 5-6 day old Longio bean plant (for potato leafhopper test). &#1470; .// :

Test nomponrids were formulated using a solution containing 10% acetone, 90% water and 600 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing w /&#1523; 20 alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries,. Tnr.). The formulated compounds were applied in 20 microfiters by pipet to two larger. photosynthetically active leaves. All experimental compounds in this screen were applied at 1000 ppm, and the tests were replicated three times. After applying the formulated test compounds, the soil of each test unit was covered with a layer of sand and each test unit was 25 allowed to dry for 1 hr and then a black, screened cap was placed on top. The test units were held in a growth chamber at about 20 °C and 50-70% relative humidity.

After 2 days, the treated leaves were covered on all sides with, a fine plastic mesh, but with the leaf petiole intact and still attached to the plant to allow normal vascular movement and photosynthesis. The plants were then infested with 20-30 aphids (radish) or 20 leafhoppers (bean) and held in the growth chamber for 8 additional days. Each test unit was then yianally assessed for mortality of the insects, which had contacted and fed on the untreated plant tissues.

Results of green peach, aphid mortality (% GPA M) and potato leafhopper mortality (% PLH M) are listed in Table A.

.TABLE A.-.

Percent Insect Mortality

<td> Compound</td><td> %PLHM</td><td> %GPAM</td>

<td></td><td> TESTI</td><td></td>

For evaluating movement of compounds in plants and control of green peach aphid (Myzus persicae) and potato leafhopper (Empoascafabae) after xylem movement of compound from soil application up throu^i roots into foliage, the test unit consisted of a small open container with a 12 day-old radish plant (for green peach aphid test) or 5-6day-old Longio bean plant (for potato leafhopper test). , ; T6st compounds were ' and 600 ppm X-77® Spreader Lo-Foam Formula non-ionic surfactant containing &#1497; &#1497;' alkylarylpolyoxyethylene, free fatty&#1523; acids, glycols and isopropanol (Loveland Industries, ; Inc). The formulated compounds were applied in 1 mL of solution by pipet to the soil at the base of the plant. All experimental compounds in this screen were applied at 1000 ppm, .

and the tests were replicated three times. After applying the formulated test compounds, each test unit was allowed to dry for 1 h. The soil of each test unit was covered with a layer of sand and then a black, screened cap was placed on top. The test units were held m a growth chamber at about 20 °C and 50-70% relative humidity.

After 2 days, the plants were then infested with 20-30 aphids (radish) or 20 leafhoppers 20 (bean) and held in the growth chamber for 5 additional days. Each test unit was then visually assessed for mortality ofthe insects, which had contacted and fed on the untreated plant foliage.

Results of green peach aphid mortality (% GPA. M) and potato leafhopper mortality&#1523; (% PLH hi) are listed in Table B.

95 TABLE B

Percent Insect Mortality

Compound . %PLHM %GPAM

10064

5664

9540

10059

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Document	Office	Kind	Date
44325603	United States of America	P	2003-01-28
2004003568	United States of America	W	2004-01-21

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AU2004207848A1	Australia	A1	2004-08-12
CA2512242A1	Canada	A1	2004-08-12
WO2004067528A1	World Intellectual Property Organization (WIPO)	A1	2004-08-12
WO2004067528B1	World Intellectual Property Organization (WIPO)	B1	2004-10-07
TW200505897A	Taiwan Province of China	A	2005-02-16
AR042943A1	Argentina	A1	2005-07-06
MXPA05007924A	Mexico	A	2005-09-30
HRP20050745A2	Croatia	A2	2005-10-31
MA27622A1	Morocco	A1	2005-11-01
EP1599463A1	European Patent Office (EPO)	A1	2005-11-30
MD20050219A	Republic of Moldova	A	2005-11-30
BRPI0406709A	Brazil	A	2005-12-20
RU2005127049A	Russian Federation	A	2006-01-27
JP2006028159A	Japan	A	2006-02-02
PL378413A1	Poland	A1	2006-04-03
JP3764895B1	Japan	B1	2006-04-12
EG23536A	Egypt	A	2006-04-19
JP3770500B2	Japan	B2	2006-04-26
US2006111403A1	United States of America	A1	2006-05-25
JP2006515602A	Japan	A	2006-06-01
CN1829707A	China	A	2006-09-06
ZA200505310B	South Africa	B	2006-09-27
JP2006290862A	Japan	A	2006-10-26
KR20070036196A	Republic of Korea	A	2007-04-02
TNSN05182A1	Tunisia	A1	2007-06-11
US7247647B2	United States of America	B2	2007-07-24
RS20050582A	Serbia	A	2007-09-21
US2007264299A1	United States of America	A1	2007-11-15
NZ541112A	New Zealand	A	2008-01-31
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US7875634B2	United States of America	B2	2011-01-25
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EP1599463B1	European Patent Office (EPO)	B1	2013-06-05
US8475819B2	United States of America	B2	2013-07-02
EP2264022B1	European Patent Office (EPO)	B1	2013-07-24
US2013189228A1	United States of America	A1	2013-07-25
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2012-05-31	Patent grantedGrantedFF	FF

Cyano anthranylamides, insecticidal compositions and devices comprising them and methods of use thereof

Abstract

Term

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

ADDITIONAL ASPECTS OF THE APPLICATION

10 DETAILS OF THE INVENTION

PCI7US2004/003568

R2

O

R3

15 EXAMPLE 1

EXAMPLE

EXAMPLE

5 EXAMPLE 7

INDEX TABLE C

BIOLOGICAL EXAMPLES OF THE INVENTION

TESTA

TESTS

TESTD

TESTE

TESTS

95 TABLE B

Priority claims2

Members71

Over the term

Events

Numbers

Titles

Classification