Cyano anthranilamide insecticides

DESCRIPTION

CYAN-ANTRANYLAMIDE-BASED INSECTICIDES

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION Invertebrate pest control is extremely important for achieving high crop efficiency. Damage by invertebrate pests to growing and stocked agronomic crops can cause significant reduction in productivity and thus result in increased consumer costs. 0 Control of invertebrate pests in the forest, greenhouse, ornamental, nursery, stored food and fiber products, livestock, family homes, and animal and public health is also important. Many products are commercially available for these purposes, but there is still a need for new compounds that are more

ΡΕ1599463

<td>effective,</td><td>any less</td><td>expensive,</td><td>any less</td><td>toxic, safe</td>

<td>point of</td><td>View</td><td>environmental or</td><td>have</td><td>different modes of</td>

<td>action.</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">WO 01/070671 discloses</td><td colspan="2">N-acyl acid derivatives</td>

anthranilic formula I for arthropod control.

<img file="PT1599463E_D0001.tif" />

wherein, inter alia, A and B are independently 0 or S; J is an optionally substituted phenyl ring, 5 or 6 sided heteroaromatic ring, naphthyl ring or an 8, 9 or 10 sided fused heterobicyclic ring; R¹ and R³ are independently H or Οχ-Οβ optionally substituted alkyl; R₂ is H or Οχ — C6 alkyl; each R⁴ is regardless

<td>H, Cx-Cg</td><td>alkyl,</td><td>Οχ — C is haloalkyl,</td><td>halogen or</td><td>CN; en is</td>

<td>1 or 4.</td><td>SUMMARY</td><td>OF THE INVENTION</td><td></td><td></td>

<td>1, yours</td><td colspan="2">This invention concerns N-oxides or salts thereof.</td><td>the compound</td><td>Formula</td>

ΡΕ1599463 where

<img file="PT1599463E_D0002.tif" />

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's me,

R¹ it's Cl,

R¹ it's Cl,

R² is Cl and R⁴ it's me; or

R² is Cl and R⁴ is Et; or

R² is Cl and R⁴ is i-Pr; or

R² it's Br and R⁴ it's me; or

R² it's Br and R⁴ is Et; or

R² it's Br and R⁴ is i-Pr; or

R² is CF₃ and R⁴ it's me; or

R² is CF₃ and R⁴ is Et; or

R² is Cl and R⁴ it's me; or

R² is Cl and R⁴ is Et; or

ΡΕ1599463

R¹ it's Cl,

R¹ it's Cl,

R¹ it's Cl,

R¹ it's Cl,

R¹ it's Cl,

R¹ it's Cl,

R¹ it's Cl,

R² it's Cl

R² it's Br

R² it's Br

R² it's Br

R² is CF₃

R² is CF₃

R² is CF₃ and R⁴ is and R⁴ is and R⁴ is and R⁴ is and R⁴ is and R⁴ is and R⁴ is i-Pr; or

Me; or

Et; or i-Pr; or

Me; or

Et; or i-Pr.

This invention also relates to an invertebrate pest control 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 and optionally an effective amount of at least one additional active compound or biologically active agent.

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 compound of Formula 1 (eg, as a composition described herein). This invention also relates to a method for controlling a pest.

No. 1599463 of invertebrates 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 biologically active compound or agent.

This 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, an optional attractant, and an optional humectant. This invention also relates to a device for controlling an invertebrate pest comprising said bait composition and a box adapted to receive said bait composition. wherein the box has at least one opening of a size that allows the invertebrate pest to pass through the opening so that the invertebrate pest can gain access to the bait composition from a location outside the box and wherein the box is further adapted to be placed on or near the potential or known site of invertebrate pest activity.

DETAILS OF THE INVENTION

An art expert will appreciate that not everyone

991599463 nitrogen containing heterocycles may form A-oxides since nitrogen requires an electron pair available for oxidation of the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles that may form oxides. One skilled in the art will also recognize that tertiary amines may form A-oxides. Synthetic methods for the preparation of heterocycle A-oxides and tertiary amines are well known to those skilled in the art including oxidation of heerocycles and tertiary amines with peroxyacids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of A-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist in Comprehensive Organic Synthesis, vol 7, pp 748-750, SV Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol 3, pp 18-20, AJ Boulton and A. McKillop, Eds., Pergamon Press; MR Grimmett and BRT Keene in Advances in Heterocyclic Chemistry, vol 43, pp 149-161, AR Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol 9, pp 285-291, AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESG Werstiuk in Advances in Heterocyclic Chemistry, vol 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

Compounds of this invention may exist as one or

1599463 plus 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 have beneficial effects when enriched relative to other stereoisomer (s) or when separated from other stereoisomer (s). Additionally, the skilled person knows how to separate, enrich, and / or selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula 1, A-oxides and salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

Salts of the compounds of the invention include acid addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4toluenesulfonic acids or valeric. In the compositions and methods of this invention, salts of the compounds of the invention are preferably suitable for the agronomic and / or non-agronomic uses described herein.

The compounds of Formula 1 may be prepared by one or more of the following methods and variations as described in Schemes 1-20. The definitions of R¹, R² and R⁴ in the compounds of Formula 1-24 below are as defined above in the

ΡΕ1599463

Summary of the Invention Unless otherwise indicated, R³ is Cl and R⁵, R⁶ and R⁷ are each H.

The compounds of Formula 1 may be prepared by reacting benzoxazinones of Formula 2 with an amine of Formula HNR⁴R⁵ as outlined in Scheme 1. This reaction may be carried out singly or in a variety of suitable solvents including tetrahydrofuran, ethyl ether, dioxane, toluene, dichloromethane or chloroform with optimum temperatures ranging from room temperature to solvent reflux temperature. The general reaction of benzoxazinone with amines to produce anthranilamides is well documented in the chemical literature. For a review of benzoxazinone chemistry see Jakobsen et al., Biorganic and Meciinal Chemistry 2000, 8, 2095-2103 and references cited af. See also GM Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

Scheme 1

<img file="PT1599463E_D0003.tif" />

Compounds of Formula 1 may also be prepared from halo anthranilic 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 (eg cuprous cyanide, zinc cyanide or potassium cyanide), optionally with or without a suitable palladium catalyst [eg tetrakis (triphenylphosphine) palladium (0) or dichlorobis (triphenylphosphine) palladium (II)] and optionally with or without metal halide (eg cuprous iodide, zinc iodide, or potassium iodide) in a suitable solvent such as acetonitrile, N, N- Dimethylforamide or N-methylpyrrolidinone at temperatures ranging from room temperature to reflux temperature of the solvent yields compounds of Formula 1. Suitable solvent may also be tetrahydrofuran or dioxane when the palladium catalyst is used in the coupling reaction.

Scheme 2

<img file="PT1599463E_D0004.tif" />

3 (X is halogen) J

<img file="PT1599463E_D0005.tif" />

Cyanobenzoxaziones of Formula 2 may be

1599463 prepared by the method outlined in Scheme 3. The reaction of a halobenzoxazione of Formula 4 (wherein X is halogen, preferably iodine or bromine) with a metal cyanide using a similar coupling method as described above in Scheme 2 (optionally with or without a palladium catalyst and optionally with or without a metal halide present) yields a compound of Formula 2.

Scheme 3

<img file="PT1599463E_D0006.tif" />

Cyanobenoxazinones of Formula 2 may also be prepared by the method detailed in Scheme 4 via coupling of a Formula 5 pyrazole carboxylic acid with a Formula 6 cyanoanthranic acid. This reaction involves sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a Formula 5 pyrazole carboxylic acid, followed by the addition of Formula 6 cyanoanthanflamic acid, followed by the second addition of tertiary amine and methylene chloride. methanesulfonyl.

ΡΕ1599463

Scheme 4

<img file="PT1599463E_D0007.tif" />

<img file="PT1599463E_D0008.tif" />

Scheme 5 represents another method for preparing Formula 2 benzoxazions involving coupling of an Isatoic anhydride of Formula 7 with a pyrazole acid chloride of Formula 8. Solvents such as pyridine or pyridine / acetonitrile are suitable for this reaction. Acid chlorides of Formula 8 are available from the corresponding acids of Formula 5 by known methods such as chlorination with thionyl chloride or oxalyl chloride.

<img file="PT1599463E_D0009.tif" />

<img file="PT1599463E_D0010.tif" />

pyridine

MeCN

As shown in Scheme 6, Formula 3 haloanΡΕ1599463 tranylic diamides can be prepared by the reaction of Formula 4 benzoxazinones, wherein X is halogen, with a Formula HNR amine⁴R⁵ using a method similar to that described above for Scheme 1. The conditions for this reaction are similar to those specified in Scheme 1.

Scheme 6

<img file="PT1599463E_D0011.tif" />

As shown in the Halobenzoxazinones Scheme of

Formula 4 (wherein X is halogen) may 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 method similar to

<td>described</td><td>above</td><td>to</td><td>Scheme</td><td> 4 .</td><td>It is</td><td colspan="2">reaction involves</td>

<td>addition</td><td colspan="2">sequential</td><td>chloride</td><td>in</td><td colspan="2">methanesulfonyl</td><td>at</td>

<td>presence</td><td>of a</td><td>the mine</td><td>tertiary</td><td>such</td><td>how</td><td>triethylamine</td><td>or</td>

<td>pyridine</td><td>to one</td><td>acid</td><td colspan="3">pyrazolecarboxylic</td><td>Formula</td><td> 5.</td>

Followed by the addition of a halo anthranilic acid of Formula 9, followed by the second addition of tertiary amine and methanesulfonyl chloride. This method generally produces good yield of benzoxazinone.

ΡΕ1599463

Scheme 7

<img file="PT1599463E_D0012.tif" />

R2

<img file="PT1599463E_D0013.tif" />

4) MeSCO ^ Cl

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

Scheme 8

<img file="PT1599463E_D0014.tif" />

X is halogen

<img file="PT1599463E_D0015.tif" />

pyridine

MeGN *

ΡΕ1599463

Cyanoanthranilic acids of Formula 6 may be prepared from haloantranilic acids of Formula 9 as outlined in Scheme 9. Reaction of a haloantranilic acid of Formula 9 (where X is halogen) with a metal 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) yields a compound of Formula 6.

Scheme 9

K¹

<img file="PT1599463E_D0016.tif" />

X is halogen solvent metal cyanide

--->

Pd catalyst (optional) metal halide (optional)

Laughs

<img file="PT1599463E_D0017.tif" />

As illustrated in Scheme 10, Formula 7 cyanoisatoic anhydrides can be prepared from Formula 6 cyanoanthranic acids by reaction with phosgene (or phosgene equivalent such as triphosgene) or an alkyl chloroformate (eg methyl chloroformate) in a suitable solvent such as as toluene or tetrahydrofuran.

ΡΕ1599463

Figure 10

<img file="PT1599463E_D0018.tif" />

<img file="PT1599463E_D0019.tif" />

As shown in Scheme 11, halo anthranilic acids of Formula 9 may be prepared by direct halogenation of an unsubstituted anthranilic acid of Formula 11 with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) respectively in solvents. such as N, V-dimethylformamide (DMF) to yield the corresponding halogen substituted acid of Formula 9.

Scheme 11

<img file="PT1599463E_D0020.tif" />

Rl r!

<img file="PT1599463E_D0021.tif" />

As shown in Scheme 12, haloisatoic anhydrides of Formula 10 may be prepared from halo anthranilic acids of Formula 9 by reaction with phosgene (or a phosgene equivalent such as triphosgene) or an alkyl chloroformate, eg methyl chloroformate, in a suitable solvent. such as toluene or tetrahydrofuran.

ΡΕ1599463

Figure 12

<img file="PT1599463E_D0022.tif" />

Pyridylpyrazole carboxylic acids of Formula 5 may be prepared by 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 N, A-diethylformamide or acetonitrile yields good yields of 1-pyridylpyrazole 14 with good specificity for the desired regio-chemistry. Metallation of 14 with lithium diisopropylamide (LDA) followed by blocking the lithium salt with carbon dioxide yields the pyrazole carboxylic acid of Formula 5.

Figure 13

<img file="PT1599463E_D0023.tif" />

r7

ΡΕ1599463

The starting pyrazoles 12 where R² CF3, Cl or Br are known compounds. Pyrazole 12 where R² is CF 3 may be prepared by literature procedures (J. Fluorine Chem. 1991, 53 (1), 61-70). Pyrazoles 12 where R² is Cl or Br may also be prepared by literature procedures (H. Reimlinger and A. Van Overstraeten, Chem. Ber. 1966, 99 (10), 3350-7). A useful alternative method for the preparation of 12 wherein R² is Cl or Br is represented in Scheme 14. Metallation of sulfamoylpyrazole 15 with n-butyllithium followed by direct halogenation of the anion with hexachloroethane (for R² where Cl) or 1,2dibromotetrachloroethane (for R² where Br) produces halogenated derivatives 16 (where R² is Cl or Br). Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature proceeds cleanly and in good yield to produce pyrazoles 12 wherein R² is Cl or Br respectively.

Scheme 14

<img file="PT1599463E_D0024.tif" />

As an alternative to the method illustrated in

Scheme 13, pyrazolecarboxylic acids of Formula 5 wherein

ΡΕ1599463

R² and CF3 may also be prepared by the method outlined in Scheme 15. The reaction of a compound of Formula 17 (wherein R⁸ is C4-C₄ alkyl) with a suitable base in a suitable organic solvent produces the cyclized product of Formula 18 upon neutralization with an acid such as acetic acid.

Figure 15

<img file="PT1599463E_D0025.tif" />

18

Suitable base may be, for example, but not limited to, sodium hydride, potassium t-butoxide, sodium dimsil (CH₃S (0) CH2-Na⁺), alkali metal carbonates or hydroxides (such as lithium, sodium or potassium), tetralkyl fluorides or hydroxides (such as methyl, ethyl or butyl) ammonium, or 2-tert-butylimino-2-diethylamino1,3-dimethyl-perhydro -1,3,2-diazaphosphonin. Suitable organic solvent may be, for example, but not limited to acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, or N, N-dimethylformamide. The cyclization reaction is usually conducted within a temperature range of from about 0 to 120 ° C. The effects of solvent, base, temperature and addition time are all interdependent, and the choice of reaction conditions is important to minimize the formation of by-products. A preferred base is tetrabutylammonium fluoride.

Dehydration of the compound of Formula 18 to give the compound of Formula 19, followed by hydrolysis of the carboxylic ester function, yields the compound of Formula 5. Dehydration is accomplished by treatment with a catalytic amount of a suitable acid. Catalytic acid may be, for example but not limited to sulfuric acid. The reaction is generally conducted using an organic solvent. As one skilled in the art will understand, dehydration reactions may be conducted in a wide variety of solvents, eg acetic acid, in a temperature range generally between about 0 and 200 ° C, more preferably between about 0 and 100 ° C. Carboxylic ester of Formula 19 can be converted to carboxylic acid of Formula 5 by a number of methods including nucleophilic cleavage under anhydrous conditions or hydrolytic methods involving the use of either acids or bases (see TW Greene and PGM Wutts, Protective Groups in Organic Synthesis, 2).^The ed., John Wiley &amp; Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). For the method of Scheme 15, base catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal hydroxides (such as lithium, sodium and potassium). For example, the ester may be dissolved in a mixture of water and an alcohol such as ethanol. Upon treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to provide

ΡΕ1599463 is the sodium or potassium salt of carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of Formula

5.

Compounds of Formula 17 wherein R² is CF₃ may be prepared by the method outlined in Scheme 16. Treatment of a Formula 20 hydrazine compound with a Formula CH ketone₃COLOR² in a solvent such as water, methanol or acetic acid gives the hydrazone of Formula 21.

Scheme 16

<img file="PT1599463E_D0026.tif" />

One skilled in the art will recognize that this reaction may require catalysis by an optional acid and may also require elevated temperatures depending on the molecular substitution pattern of the Formula 21 hydrazone. Reaction of the Formula 21 hydrazone with an alkyl chloro oxalate in a suitable organic solvent such as

For example, but not limited to dichloromethane or tetrahydrofuran in the presence of an acid scavenger such as triethylamine provides the compound of Formula 17. The reaction is usually conducted at a temperature between about 0 and 100 ° C. Hydrazine compounds of Formula 20 may be prepared by standard methods, such as reacting the corresponding halopyridine of Formula 13 with hydrazine.

As an alternative to the method illustrated in Scheme 13, pyrazolecarboxylic acids of Formula 5 wherein R is² and Cl may also be prepared by the method outlined in Scheme 17. Oxidation of a compound of Formula 22, optionally in the presence of acid, gives the compound of Formula 19, wherein R² is Cl or Br. Hydrolysis of the function of carboxylic ester to carboxylic acid affords the compound of Formula 5.

Scheme 17

<img file="PT1599463E_D0027.tif" />

R?

R7

R⁷ where R⁸ is Ci-C₄ alkyl.

An oxidizing agent for converting a compound of Formula 22 to a compound of Formula 19 may be hydrogen peroxide, organic peroxides, potassium persulphate, sodium persulphate, ammonium persulphate, potassium monopersulphate (eg, Oxone®) or potassium permanganate. For complete conversion, at least one equivalent of oxidizing agent versus the compound of Formula 22, preferably about one to two equivalents, should be used. This oxidation is typically performed in the presence of a solvent. The solvent may be an ether, such as tetrahydrofuran, p-dioxane and the like, an organic ester, such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic such as N, N-dimethylformamide, acetonitrile and the like. Suitable acids for use in the oxidation step include inorganic acids such as sulfuric acid, phosphoric acid and the like, and organic acids such as acetic acid, benzoic acid and the like. One to five acid equivalents may be used. The preferred oxidant is potassium persulfate and oxidation is preferably carried out in the presence of sulfuric acid. The reaction may be carried out by mixing the compound of Formula 22 in the desired solvent and, if used, with the acid. 0 Oxidant can then be added at a convenient rate. The reaction temperature is typically varied from as low as about 0 ° C to the boiling temperature of the solvent to obtain a reasonable reaction time to complete the reaction. Suitable methods for converting the ester of Formula 19 to carboxylic acid of Formula 5 are already described for Scheme 15.

ΡΕ1599463

Compounds of Formula 22, wherein R² is halogen and R⁸ is C 1 -C 4 alkyl, may be prepared from the corresponding compounds of Formula 23 as shown in Scheme 18.

Scheme 18

<img file="PT1599463E_D0028.tif" />

Treatment of a compound of Formula 23 with a halogenation reagent, usually in the presence of a solvent, yields the corresponding halo compound of Formula 22. Halogenation reagents that may be used include phosphorus oxyhalides, phosphorus trihalides, pentahalides phosphorus, thionyl chloride, dihalotrialkylphosphorans, dihalodiphenylphosphorans, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. For complete conversion, at least 0.33 equivalents of phosphorus oxyhalide versus the compound of Formula 23, preferably from about 0.33 to 1.2, should be used.

ΡΕ1599463

4 equivalent. For complete conversion, at least 0.20 equivalents of phosphorus pentahalide should be used versus the compound of Formula 23, preferably from about 0.20 to 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 like, ethers such as tetrahydrofuran, p-dioxane, ethyl ether and the like, and polar aprotic solvents such as acetonitrile, A, A-dimethylformamide, and the like. Optionally, an organic base such as triethylamine, pyridine, N, A-dimethylaniline or the like may be added. Addition of a catalyst, such as N, A-dimethylformamide, is also an option. Preferred is the process in which the solvent is acetonitrile and the base is absent. Typically, neither the base nor the catalyst is required when the acetonitrile solvent is used. The preferred process is conducted by mixing the

<td>composed of</td><td>Formula 23</td><td>in</td><td>acetonitrile.</td><td> 0</td><td>reagent</td><td>in</td>

<td>halogenation</td><td colspan="3">is then added over</td><td>one</td><td>interval</td><td>in</td>

<td colspan="2">convenient time, and the</td><td colspan="2">mixture is then</td><td colspan="3">maintained at</td>

<td colspan="2">desired temperature up to</td><td>The</td><td colspan="2">reaction be</td><td>complete.</td><td>THE</td>

<td>temperature</td><td>reaction</td><td>it is</td><td>typically</td><td colspan="2">between 20 ° C and</td><td>The</td>

<td>temperature</td><td>boiling</td><td>of</td><td>acetonitrile,</td><td>and</td><td>the time</td><td>in</td>

reaction is typically less than 2 hours. The reaction mass is then neutralized with an inorganic base such as sodium bicarbonate, sodium hydroxide and the like or an organic base such as sodium acetate. The desired product of Formula 22 may be isolated by methods

No. 1599463 known to those skilled in the art, including crystallization, extraction and distillation.

Alternatively, compounds of Formula 22 wherein R² is Br or Cl may be prepared by treating the corresponding compounds of Formula 22 wherein R is² is a different halogen (eg, Cl to make Formula 22 where R² is Br) or a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate with hydrogen bromide or hydrogen chloride, respectively. By this method halogen R² or sulfonate substituent on the compound of Formula 22 is substituted 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 may be conducted at or near atmospheric pressure or above atmospheric pressure in a pressurized vessel. 0 The halogenation reagent may be added as a gas to the reaction mixture containing the compound of Formula 23 and solvent. When R² In the starting compound of Formula 22 is a halogen such as Cl, the reaction is preferably conducted such that washing or other suitable means removes the hydrogen halide generated in the reaction. Alternatively, the halogenating reagent may first be dissolved in an inert solvent in which it is highly soluble (such as acetic acid) prior to contacting the compound of Formula 23 either alone or in solution. The reaction may be conducted at about 0 to 100 ° C, more than

991599463 is conveniently close to room temperature (eg, about 10 to 40 ° C), more preferably about 20 to 30 ° C. Addition of a Lewis acid catalyst (such as aluminum tribromide to prepare Formula 22 wherein R²⁺ is Br) may facilitate the reaction. The product of Formula 22 is isolated by the usual methods known to those skilled in the art, including extraction, distillation and crystallization.

Formula 22 starting compounds wherein R² is a sulfonate group may be prepared from the corresponding compounds of Formula 23 by standard methods such as treatment with a sulfonyl chloride (eg, ptoluenesulfonyl chloride) and base such as tertiary amine (eg, triethylamine) in a suitable solvent such as dichloromethane .

It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In such cases, incorporation of protection / deprotection sequences or functional group interconversions in the synthesis will assist in obtaining the desired products. The use and choice of protecting groups will be apparent to those skilled in the chemical synthesis (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2^The ed .; Wiley, New York, 1991). One skilled in the art will recognize that in some cases, upon introduction of a given reagent as depicted in any individual scheme, it may be necessary to complete the synthesis of compounds of

ΡΕ1599463

Formula 1, perform additional routine synthetic steps not described in detail. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented for preparing the compounds of Formula 1.

Without further elaboration, it is believed that one skilled in the art using the foregoing description may utilize the present invention to its fullest extent. The following Examples are therefore construed as illustrative only, and not limiting the disclosure in any way. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not necessarily have to be prepared by a particular preparative route whose procedure is described in the other Examples or Steps. Percentages are by mass except for chromatographic solvent mixtures or where indicated. Parts and percentages for chromatography solvent mixtures are by volume unless otherwise indicated. Specters⁴1 H NMR reported in ppm from tetramethylsilane; s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, dd means doublet doublet, dt means triplet doublet, and 1 s means broad singlet.

ΡΕ1599463

EXAMPLE 1 (Reference)

Preparation of 1- (3-Chloro-2-pyridinyl) -N- [4-cyano2-methyl-6- (aminocarbonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazolo-5-carboxamide

Step A: Preparation of 2-Amino-3-Methyl-5iodobenzoic Acid

To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 5g, 33 mmol) in N, N-dimethylformamide (30 mL) was added N-iodosuccinimide (7.8 g, 34.7 mmol), and the mixture The reaction mixture was suspended in an oil bath at 75 ° C overnight. The heat was removed and the reaction mixture was then slowly poured into ice-water (100 mL) to precipitate a light gray 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 light gray solid (8.8 g).

⁴1 H NMR (DMSO-Ch): δ 7.86 (d, 1H), 2.08 (s, 3H).

Step B: Preparation of 3-Chloro-2- [3- (trifluoromethyl) -1A-pyrazol-1-yl] pyridine

To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3- (trifluoromethyl) pyrazole (83 g, 0.61 mol) in dry N, N-dimethylformamide (300 mL) was added. carbonate

ΡΕ1599463

<td rowspan="2">potassium heated to</td><td rowspan="2">(166.0 110-125 ° C</td><td rowspan="2">D, to</td><td rowspan="2">1.2 mol) long</td><td rowspan="2">and 48</td><td colspan="3">the reaction was then</td>

<td>hours</td><td>THE</td><td>reaction was</td>

<td>cooled</td><td>at 100 ° C</td><td>and</td><td>filtered</td><td colspan="2">through</td><td>in</td><td>filter</td>

<td>diatoms</td><td>Celite®</td><td colspan="3">to remove</td><td>solid</td><td>_and</td><td>N, A-dimethyl</td>

formamide and excess dichloropyridine were distilled off at atmospheric pressure. Distillation of the product under reduced pressure (bp 139-141 ° C, 7 mm) afforded 113.4 g of the desired intermediate as a clear yellow oil.⁴1H NMR (CDCl3): δ 8.45 (d, 1H), 8.15 (s, 1H), 7.93 (d, 1H), 7.36 (t, 1H), 6.78 (s, 1H) ).

Step C: Preparation of 1- (3-Chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazolo-5-carboxylic acid

To a solution of 3-chloro-2- [3- (trifluoromethyl) β-pyrazol-1-yl] pyridine (ie the pyrazole product from step B) (105.0 g, 425 mmol) in dry tetrahydrofuran (700 At -75 ° C a solution of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (100 ml) was added via cannula at -30 ° C. The dark red solution was stirred for 15 minutes, after which carbon dioxide was bubbled at -63 ° C until the solution turned pale yellow and exothermicity ceased. The reaction was stirred for a further 20 minutes and then quenched with water (20 mL). The solvent was removed under reduced pressure, and the reaction mixture was partitioned between ether and 0.5 N aqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3x), filtered through Celite® diatom filter to remove solids. residual, and then acidified to a

991599463 pH of approximately 4, which formed an orange oil. The aqueous mixture was stirred vigorously and additional acid was added to lower the pH to 2.5-3. The orange oil froze to a granular solid which was filtered, washed successively with water and 1N hydrochloric acid, and dried under vacuum at 50 ° C to yield 130 g of the title product as an off-white solid. The product of another assay following a similar procedure melted at 175-176 ° C.

²1 H NMR (DMSO-d 6): δ 7.61 (s, 1H), 7.76 (dd, 1H),

8.31 (d, 1H), 8.60 (d, 1H).

Step D: Preparation of 2- [1- (3-Chloro-2-pyridinyl) -3-trifluoromethyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl4A-3,1-benzoxazin-4 one

To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) in acetonitrile (50 mL) was added dropwise a mixture of 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) - 1α-pyrazolo-5-carboxylic acid (ie the carboxylic acid product of Step C) (10.0 g, 34.31 mmol) and triethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at -5 ° C. The reaction temperature was then maintained at 0 ° C by successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-iodobenzoic acid (ie, the product from Step A) (9.51 g, 34.31 mmol) was added and stirring was continued for a further 10 minutes. minutes A solution of triethylamine (9.56 mL, 68.62 mmol) in acetonitrile (15 mL)

1599463 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 silica gel chromatography to yield 8.53 g of the title compound as a yellow solid.

²1H NMR (CDCl3)₃): δ 8.59 (dd, 1H), 8.35 (d, 1H),

7.97 (dd, 1H), 7.86 (d, 1H), 7.49 (m, 2H), 1.79 (s, 3H).

Step E: Preparation of 2- [1- (3-Chloro-2-pyridinyl) -3- (trifluoromethyl) -1A-pyrazol-5-yl] -6-iodo-8-methyl4A-3,1-benzoxazin-2-one 4-one

To a solution of 2- [1- (3-chloro-2-pyridinyl) -3 (trifluoromethyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl-47α-3,1benzoxazin -4-one (ie the benzoxazinone product from Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper (I) iodide (180 mg, 0.094 mmol), tetrakis (triphenylphosphine) palladium (0) (5.4 mg, 0.047 mmol) and copper (I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture to reflux overnight, additional copper (I) cyanide (420 mg, 4.7 mmol), copper (I) iodide (107 mg, 0.56 mmol) and tetrakis (triphenylphosphine) were added. ) palladium (0) (325 mg, 0.28 mmol) and reflux was continued for hour. The reaction mixture turned black at

991599463 silica gel thin layer chromatography confirmed that the reaction had been completed. 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 dried (MgSO4).₄) and concentrated under reduced pressure to yield 410 mg of the title compound as a yellow solid.

³Η NMR (CDCl1)₃): δ 8.59 (dd, 1H), 8.33 (d, 1H),

8.03 (dd, 1H), 7.95 (d, 1H), 7.56 (m, 2H), 1.88 (s, 3H).

Step F: Preparation of 1- (3-Chloro-2-pyridinyl) -N [4-cyano-2-methyl-6- (aminocarbonyl) phenyl] -3 (trifluoromethyl) -1A-pyrazolo-5-carboxamide

To a solution of 2- [1- (3-chloro-2-pyridinyl) -3 (trifluoromethyl) -1H-pyrazol-5-yl] -6-cyano-8-methyl-4- A-3,1benzoxazin-4-one (i.e. the cyanobenzoxazinone product from Step E) (200 mg, 0.46 mmol) in tetrahydrofuran (5 mL9) 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 time silica gel thin layer chromatography confirmed that the reaction was complete. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by silica gel chromatography to yield 620 mg of the title compound, a compound of the present invention, as a solid melting at 200-202 ° C. ³Η NMR:

ΡΕ1599463

<td>(CDC1₃) δ</td><td> 10,65</td><td>(s, 1H),</td><td> 8,43</td><td>(dd,</td><td>1H),</td><td> 7,9</td><td>(dd,</td><td>1H),</td><td> 7,</td><td> 67</td>

<td>(s, 1H),</td><td> 7,63</td><td>(s, 1H),</td><td> 7, 45</td><td>(m,</td><td>1H),</td><td> 7,25</td><td>(s,</td><td>1H),</td><td> 6,</td><td> 21</td>

<td>(is, 1H),</td><td> 5, 75</td><td>(is, 1H),</td><td> 2,26</td><td>(s,</td><td>3H).</td><td></td><td></td><td></td><td></td><td></td>

EXAMPLE 2

Preparation of 1- (3-chloro-2-pyridinyl) -A- [4-cyano2-methyl-6 - [(methylamino) carbonyl] phenyl] -3- (trifluoromethyl) 1A-pyrazolo-5-carboxamide

Step A: Preparation of 1- (3-Chloro-2-pyridinyl) -A [4-iodo-2-methyl-6 - [(methylamino) carbonyl] phenyl] -3 (trifluoromethyl) -1A-pyrazolo-5-carboxamide

To a solution of 2- [1- (3-chloro-2-pyridinyl) -3 (trifluoromethyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl-4- A-3,1benzoxazin-2-one 4-One (ie the benzoxazinone product of Example 1, Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (15 mL) was added dropwise methylamine (2.0 M solution in THF, 1.4 (2.8 mmol) and the reaction mixture was stirred for 3 hours at which time silica gel thin layer chromatography confirmed that the reaction was complete. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by silica gel chromatography to yield 400 mg of the title compound as a yellow solid.

⁴1H NMR (CDCl3): δ 10.25 (s, 1H), 8.45 (dd, 1H),

7.85 (dd, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m, 1H), 6.15 (d 1H), 2.93 (d, 3H), 2.12 (s, 3H).

ΡΕ1599463

Step B: Preparation of 1- (3-Chloro-2-pyridinyl) -N [4-cyano-2-methyl-6 - [(methylamino) carbonyl] phenyl] -3 (trifluoromethyl) -1A-pyrazolo-5 -carboxamide

To a solution of 1- (3-chloro-2-pyridinyl) -N- [4iodo-2-methyl-6 - [(methylamino) carbonyl] phenyl] -3 (trifluoromethyl) -1,2-pyrazolo-5-one carboxamide (ie the diamide product from Step A) (410 mg, 0.72 mmol) in tetrahydrofuran (8 mL) was added copper (I) iodide (24 mg, 0.126 mmol), tetrakis (triphenylphosphine) palladium (0) ( 70 mg, 0.060 mmol) and copper (I) cyanide (640 mg, 7.2 mmol) sequentially at room temperature. The reaction mixture was heated at reflux for 4.5 hours. Silica gel thin layer chromatography confirmed that the reaction was complete. 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 dried (MgSO4).₄) and concentrated under reduced pressure and the residual solid was purified by silica gel chromatography to afford 114 mg of the title compound, a compound of the present invention, as a white solid, melting at 214-216 ° C.

⁴1 H NMR (CDCl3): δ 10.70 (s, 1H), 8.46 (dd, 1H), 7.87 (dd, 1H), 7.57 (s, 1H), 7.45 (m, 1H) ), 7.31 (s, 1H),

6.35 (d, 1H), 2.98 (d, 3H), 2.24 (s, 3H).

ΡΕ1599463

EXAMPLE 3

Preparation of 3-Chloro-1- (3-chloro-1- (3-chloro-2-pyridinyl) -N- [4-cyano-2-methyl-6 [(methylamino) carbonyl] phenyl] -1A-pyrazolo-5 -carboxamide

Step A: Preparation of 3-Chloro-N, N-Dimethyl-1-Pyrazolo-1-sulfonamide

To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at 78 ° C was added dropwise a solution of 2.5 M 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 kept at -78 ° C for a further 45 minutes, after which time a solution of hexachloroethane (279 g, 1.138 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was kept for one hour at -78 ° C, warmed to -20 ° C and then blocked with water (IL). The reaction mixture was extracted with methylene chloride (4x500 mL); The organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by silica gel chromatography using

<td>chloride</td><td>in</td><td>methylene as</td><td>eluent to</td><td>to produce</td><td> 160</td><td>g of</td>

<td>compound</td><td>of</td><td>title as one</td><td>yellow oil.</td><td></td><td></td><td></td>

<td></td><td>⁴H</td><td>NMR (CDCl1)₃): δ</td><td>7.61 (s, 1H),</td><td>6.33 (s,</td><td>1H),</td><td> 3,07</td>

(d, 6H).

ΡΕ1599463

Step B: Preparation of 3-Chloropyrazole

To trifluoroacetic acid (290 mL) was added dropwise 3-chloro-N, N-dimethyl-1B-pyrazolo-1-sulfonamide (ie the chloropyrazole product from Step A) (160 g), and the reaction mixture was stirred. at room temperature for 1.5 hrs and then concentrated under reduced pressure. The residue was taken up in hexane, insoluble solids were filtered off, and hexane was concentrated to yield crude product as an oil. The crude product was further purified by silica gel chromatography using ether / hexane (40:60) as eluent to yield 64.44 g of the title product as a yellow oil.

⁴1H NMR (CDCl3): δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 ds, 1H)

Step C: Preparation of 3-Chloro-2- (3-Chloro-1-Pyrazol-1-yl) pyridine

To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (ie the product of Step B) (64.44 g, 0.629 mol) in N, N-dimethylformamide (400 mL Potassium carbonate (147.78 g, 1.06 mol) was added, and the reaction mixture was then heated at 100 ° C for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. Precipitated solids were filtered and washed with water. The filtered solid block was taken up in ethyl acetate, dried over

991599463 Magnesium sulfate and concentrate. The crude solid was chromatographed on silica gel using 20% ​​ethyl acetate / hexane as eluant to afford 39.75 g of the title compound as a white solid.⁴1H NMR (CDCl3): δ 6.43 (s,

1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.41 (d,

1H).

Step D: Preparation of 3-Chloro-1- (3-chloro2-pyridinyl) -1A-pyrazolo-5-carboxylic acid

To a solution of 3-chloro-2- (3-chloro-1 H -pyrazol-1 H -pyrazol) pyridine (ie pyrazole product from Step C) (39.75 g, 186 mmol) in dry tetrahydrofuran (400 mL ) at -78 ° C a solution of 2.0 M lithium diisopropylamide (93 mL, 186 mmol) in tetrahydrofuran was added dropwise. Carbon dioxide was bubbled through an amber solution for 14 minutes, after which the solution became pale yellowish brown. The reaction was made basic with 1 N aqueous sodium hydroxide solution and extracted with ether (2 x 500 mL). The aqueous extracts were acidified with 6N hydrochloric acid followed by extraction with ethyl acetate (3x500 mL). The ethyl acetate extracts were dried over magnesium sulfate and concentrated to yield 42.96 g of the title compound as an off-white solid. The product of another assay following the same procedure melted at 198-199 ° C.

⁴1H NMR (DMSO-d₆): δ 6.99 (s, 1H), 7.45 (m, 1H),

7.93 (d, 1H), 8.51 (d, 1H).

ΡΕ1599463

Step E: Preparation of 2- [3-Chloro-1- (3-chloro-2-pyridinyl) -1A-pyrazol-5-yl] -6-iodo-8-methyl-1-4-3,1benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.63 mL, 8.13 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole -5-carboxylic acid (ie the carboxylic 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 reaction mixture was then stirred for 15 minutes at 0 ° C. 2-Amino-3-methyl-5-iodobenzoic acid (ie the product of Example 1, Step A) (2.14 g, 7.75 mmol) was then added, and stirring was continued for a further 5 minutes. A solution of triethylamine (2.17 mL, 15.15 mmol) in acetonitrile (5 mL) was then added dropwise while maintaining 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 successively washed with 10% aqueous sodium bicarbonate (1x20 mL) and brine (1x20 mL), dried (MgSO4).₄) and concentrated to yield 3.18 g of the title product as a yellow solid. ²Η NMR (CDCl3): δ 8.55 (dd, 1H),

ΡΕ1599463

8.33 (d, 1H), 7.95 (dd, 1H), 7.82 (s, 1H), 7.45 (m, 1H), 7.16 (s, 1H), 1.77 (s, 3H)

Step F: Preparation of 2- [3-Chloro-1- (3-chloro-2-pyridinyl) -1A-pyrazol-5-yl] -6-cyano-8-methyl-4- A-3,1benzoxazin-4-one

To a solution of 2- [3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl-4H-3,1-benzoxazin-4-one ( ie the benzoxazinone product from Step E) (600 mg, 1.2 mmol) in tetrahydrofuran (15 mL) was added copper (I) iodide (137 mg, 0.72 mmol), tetrakis (triphenylphosphine) palladium (0) ( 416 mg, 0.36 mmol) and copper (I) cyanide (860 mg, 9.6 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black, at which point thin layer chromatography on silica gel confirmed that the reaction was complete. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by three washes with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO 4) and concentrated under reduced pressure to yield 397 mg of the title compound as a crude yellow solid.

(dd, 1H), ²1H NMR (CDCl3): δ 8.50 (q, 1H), 8.22 (d, 1H), 7.90

7.67 (d, 1H), 7.45 (m, 1H), 7.15 (s, 1H), 1.79 (s, 3H).

ΡΕ1599463

Step G: Preparation of 3-Chloro-1- (3-chloro-2-pyridinyl) -N- [4-cyano-2-methyl-6- (methylamino) carbonyl] phenyl] 1A-pyrazole-5-carboxamide

To a solution of 2- [3-chloro-1- (3-chloro-2-pridinyl) -1H-prazol-5-1] -6-cyano-8-methyl-4- A-3,1-benzoxazin-4-one one (eg the cyanobenzoxazinone product from 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 silica thin layer chromatography. The gel confirmed that the reaction was complete. The tetrahydrofuran solvent was evaporated under reduced pressure; and the residual solid was purified by silica gel chromatography 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.

²1H NMR (CDCl3)₃): δ 10.55 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.55 (d, 2H), 7.40 (m, 1H), 6, 97 (d, 1H), 6.30 (d, 1H), 2.98 (d, 3H), 2.24 (d, 3H).

EXAMPLE 5

Preparation of 3-Bromo-1- (3-chloro-2-pyridinyl) -N [4-cyano-2-methyl-6 - [(methylamino) carbonyl] phenyl] 17'-pyrazolo5-carboxamide

ΡΕ1599463

Step A: Preparation of 3-Bromo-N, N-Dimethyl-1-Pyrazolo-1-sulfonamide

To a solution of N, N-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. During the addition a thick solid formed. After complete addition the reaction mixture was kept for a further 15 minutes, after which a solution of 1,2dibromotetrachloroethane (90g, 0.276 mol) in tetrahydrofuran (150 mL) was added dropwise while maintaining the temperature below -70 ° C. ° C. the reaction mixture turned clear orange; stirring was continued for a further 15 minutes. The bath at -78 ° C 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 silica gel chromatography using methylene chloride hexane (50:50) as eluent to yield 57.04 g of the title product as a clear colorless oil.

^l1H NMR (CDCl3): δ 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H)

Step B: Preparation of 3-Bromopyrazole

To trifluoroacetic acid (70 mL) was added

1599463 slowly 3-bromo-N, N-dimethyl-1 H -pyrazolo-1-sulfonamide (ie the bromopyrazole product from Step A) (57.04 g). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was taken up in hexane, insoluble solids were filtered off, and hexane was evaporated to yield crude product as an oil. The crude product was further purified by silica gel chromatography 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 yield 25.9 g of the title product as a white solid, mp 61-30 ° C. 64 ° C.⁴1 H NMR (CDCl 3): δ 6.37 (d, 1H), 7.59 (s, 1H), 12.4 (1 s, 1H).

Step C: Preparation of 2- (3-Bromo-1A-pyrazol-1yl) -3-chloropyridine

To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (ie the product of Step B) (25.4 g, 176 mmol) in dry N, N-dimethylformamide (88 potassium carbonate (48.6 g, 352 mmol) was added, and the reaction mixture was heated at 125 ° C for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 h, filtered and washed with water (2x100 mL). The filtered solid block was taken up in methylene chloride and washed

159 9463 sequentially with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water and salt. The organic extracts were dried over magnesium sulfate and concentrated to yield 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1h. The solids were filtered, washed with hexane and dried to yield 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. ²1 H NMR (CDCl 3): δ 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05 (s, 1H), 8.43 (d, 1H) ).

Step D: Preparation of 3-Bromo-1- (3-chloro2-pyridinyl) -1H-pyrazolo-5-carboxylic acid

To a solution of 2- (3-bromo-1 H -pyrazol-1-yl) -3-chloropyridine (ie the pyrazole product from Step C) (30.4 g, 118 mmol) in dry tetrahydrofuran (250 mL) At -76 ° C a solution of lithium diisopropylamide (118 mmol) in tetrahydrofuran was added dropwise at a rate of mold keeping the temperature below -71 ° C. The reaction mixture was stirred for 15 minutes at -76 ° C, and then carbon dioxide was bubbled through the solution for 10 minutes, causing warming to -57 ° C. The reaction mixture was heated to -20 ° C and quenched with water. The reaction mixture was concentrated and taken up in water (IL) and ether (500 mL), and then aqueous sodium hydroxide solution (1 N, 20 mL).

ΡΕ1599463 washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered off, washed with water and dried to yield 27.7 g of the title product as a brown solid. The product of another synthesis following similar procedure melted at 200-201 ° C.

²1H NMR (DMSO-d₆): δ 7.25 (s, 1H), 7.68 (dd, 1H),

8.56 (d, 1H).

Step E: Preparation of 2- [3-Bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl-4-4-3,1benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.54 mL, 6.94 mmol) in acetonitrile (15 mL) was added dropwise a mixture of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-acid. -pyrazolo-5-carboxylic acid (ie the carboxylic acid product from Step D) (2.0 g, 6.6 mmol) and 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. 2-Amino-3-methyl-5-iodobenzoic acid (ie the product of Example 1, Step A) (1.8 g, 6.6 mmol) was then added, and stirring was continued for a further 5 minutes. A solution of triethylamine (1.85 mL, 13.2 mmol) in acetonitrile (5 mL) was then added dropwise while maintaining the temperature below 5 ° C. The reaction 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

ΡΕ1599463

<td>agitated</td><td>during the night.</td><td>The mix</td><td>from r</td><td>action</td><td>was</td><td>So</td>

<td>diluted</td><td>with water (50 mL)</td><td>and extracted</td><td>with</td><td colspan="2">acetate</td><td>ethyl</td>

<td colspan="2">(3x50 mL). The extracts</td><td>of acetate</td><td>in</td><td>ethyl</td><td colspan="2">combined</td>

<td>were</td><td colspan="2">successively washed with</td><td colspan="2">bicarbonate</td><td>in</td><td>sodium</td>

<td>aqueous</td><td>10% (1x20 mL)</td><td>and water and</td><td>salt</td><td>(1x20</td><td>mL),</td><td>dry</td>

<td>(MgSO₄)</td><td colspan="2">and concentrates to produce</td><td> 2,24</td><td>g of</td><td colspan="2">product of</td>

<td>title</td><td>as a solid</td><td>yellow. ⁴H</td><td>NMR</td><td>(CDC1</td><td>3): δ</td><td> 8,55</td>

<td>(dd, 1H)</td><td>, 8.33 (d, 1H),</td><td colspan="2">7.95 (dd, 1H),</td><td> 7, 85</td><td>(s, 1H)</td><td> , 7, 45</td>

<td>(m, 1H),</td><td>7.25 (s, 1H), 1.77</td><td>(s, 3H)</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">Step F: Preparation of 2-</td><td colspan="2">[3-bromo-1-</td><td colspan="2">(3-chloro-2-</td>

pyridinyl) -1H-pyrazol-5-yl] -6-cyano-8-methyl-4.H-3,1benzoxazin-4-one

To a solution of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (ie the benzoxazinone product from Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper (I) iodide (126 mg, 0.86 mmol), tetrakis (triphenylphosphine) palladium (0 ) (382 mg, 0.33 mmol) and copper (I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black, at which point thin layer chromatography on silica gel confirmed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by three washes with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated to

991599463 reduced pressure to yield 440 mg of the title compound as a yellow solid.

⁴1H NMR (CDCl3)₃): δ 8.55 (m, 1H), 8.31 (d, 1H), 7.96 (dd, 1H), 7.73 (s, 1H), 7.51 (m, 1H), 7.31 ( s, 1H), 1.86 (s, 3H).

Step G: Preparation of 3-Bromo-1- (3-chloro-2-pyridinyl) -N- [4-cyano-2-methyl-6- (methylamino) carbonyl] phenyl] -1A-pyrazole-5-carboxamide

To a solution of 2- [3-bromo-1- (3-chloro-2-pridinyl) -1H-prazol-5-1] -6-cano-8-methyl-4- A-3,1-benzoxazin-2-one 4-one (eg the cyanobenzoxazinone product from Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1 mL). 0.1 mmol) and the reaction mixture was stirred for 5 minutes at which point silica gel thin layer chromatography confirmed that the reaction was complete. The tetrahydrofuran solvent was evaporated under reduced pressure; and the residual solid was purified by silica gel chromatography to afford the title compound, a compound of the present invention, as a white solid (41 mg), which decomposed in the melting apparatus above 180 ° C.

⁴1 H NMR (CDCl 3): δ 10.55 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.57 (s, 2H), 7.37 (m, 1H) ), 7.05 (s, 1H), 6.30 (d, 1H), 2.98 (d, 3H), 2.24 (d, 3H).

ΡΕ1599463

7

EXAMPLE 7

Preparation of 3-Chloro-1- (3-chloro-2-pyridinyl) -N [2-chloro-4-cyano-6 - [(methylamino) carbonyl] phenyl] -1H-pyrazolo-5-carboxamide

Step A: Preparation of 2-Amino-3-Chloro-5iodobenzoic Acid

To a solution of 2-amino-3-chlorobenzoic acid (Aldrich, 5g, 29.1 mmol) in N, N-dimethylformamide (30 mL) was added N-iodosuccinimide (5.8 g, 26 mmol) and the mixture of The reaction 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 light 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 light brown solid (7.2 g). ²1 H NMR (DMSO-d): δ 7.96 (d, 1H), 7.76 (t, 1H).

Step B: Preparation of 8-Chloro-2- [3-chloro-1- (3-chloro-2-pyridinyl) -1A-pyrazol-5-yl] -6-iodo-4.H-3,1benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.31 mL, 4.07 mmol) in acetonitrile was added dropwise a mixture of pyridinyl) -1H-pyrazolo-5-carboxylic acid (10 mL) was added.

3-chloro-1- (3-chloro-2 (ie the acid product

1599463 carboxylic acid 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. 2-Amino-3-chloro5-iodobenzoic acid (ie the product of Step A) (1.15 g, 3.87 mmol) was then added, and stirring continued for a further 5 minutes. A solution of triethylamine (1.08 mL, 7.74 mmol) in acetonitrile (5 mL) was then added dropwise while maintaining 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 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 successively washed with 10% aqueous sodium bicarbonate (1x20 mL) and brine (1x20 mL), dried (MgSO4) and concentrated under reduced pressure. The residual solid was purified by silica gel chromatography to yield 575 mg of the title compound as a yellow solid. W NMR (CDCl3)₃): δ 8.55 (q, 1H), 8.39 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.45 (m, 1H), 7, 19 (s, 1H).

Step C: Preparation of 8-Chloro-2- [3-chloro-1- (3-chloro-2-pyridinyl) -1A-pyrazol-5-yl] -6-cyano-8-methyl-4A-3,1benzoxazin-4 -one

To a solution of 8-chloro-2- [3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-iodo-4H-3,1-benzoxazin-4-one

991599463 (ie the benzoxazinone product from Step B) (575 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper (I) iodide (840 mg, 0.44 mmol), tetrakis (triphenylphosphine) palladium (O) ( 255 mg, 0.22 mmol) and copper (I) cyanide (500 mg, 5.5 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black, at which point thin layer chromatography on silica gel confirmed that the reaction was complete. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by three washes with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4).₄) and concentrated under reduced pressure to yield 375 mg of the title compound as a yellow solid.

⁴1 H NMR (CDCl 3): δ 8.55 (q, 1H), 8.36 (d, 1H), 7.95 (m, 2H), 7.5 (m, 1H).

Step D: Preparation of 3-Chloro-1- (3-chloro-2-pyridinyl) -N- [4-cyano-6- (methylamino) carbonyl] phenyl] -1H-pyrazole-5-carboxamide

To a solution of 8-chloro-2- [3-chloro-1- (3-chloro-2-pridinyl) -1,2-plazol-5-1] -6-cyano-47,1,1-benzoxazin-4-one One (ie the cyanobenzoxazinone product from Step C) (187 mg, 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 added. stirred for 5 minutes at which point silica gel thin layer chromatography confirmed

991599463 that the reaction was complete. The tetrahydrofuran solvent was evaporated under reduced pressure; and the residual solid was purified by silica gel chromatography to afford 49 mg of the title compound, a compound of the present invention, as a white solid that melted at 197-200 ° C.

⁴1 H NMR (CDCl3): δ 10.05 (bs, 1H), 8.45 (q, 1H), 7.85 (dd, 1H), 7.70 (d, 1H), 7.59 (d, 1H) ), 7.38 (m, 1H), 7.02 (s, 1H), 6.35 (d, 1H), 2.94 (d, 3H).

By the procedures described herein together with methods known in the art, the following compounds of Table 1 may be prepared. The following abbreviations are used in the following Tables: i means this, Me means methyl, Et means ethyla and i-Pr means isopropyl.

Table 1

R2

<img file="PT1599463E_D0029.tif" />

Λ ₅

R⁴ R⁵

ΡΕ1599463

<td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td>

<td>Me</td><td>Cl</td><td>Cl</td><td>Me</td><td>H</td>

<td>Me</td><td>Cl</td><td>Cl</td><td>Et</td><td>H</td>

<td>Me</td><td>Cl</td><td>Cl</td><td>i-Pr</td><td>H</td>

<td>Me</td><td>Br</td><td>Cl</td><td>Me</td><td>H</td>

<td>Me</td><td>Br</td><td>Cl</td><td>Et</td><td>H</td>

<td>Me</td><td>Br</td><td>Cl</td><td>i -Pr</td><td>H</td>

<td>Me</td><td>cf₃</td><td>Cl</td><td>Me</td><td>H</td>

<td>Me</td><td>cf₃</td><td>Cl</td><td>Et</td><td>H</td>

<td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td>

<td>Cl</td><td>Cl</td><td>Cl</td><td>Me</td><td>H</td>

<td>Cl</td><td>Cl</td><td>Cl</td><td>Et</td><td>H</td>

<td>Cl</td><td>Cl</td><td>Cl</td><td>i-Pr</td><td>H</td>

<td>Cl</td><td>Br</td><td>Cl</td><td>Me</td><td>H</td>

<td>Cl</td><td>Br</td><td>Cl</td><td>Et</td><td>H</td>

<td>Cl</td><td>Br</td><td>Cl</td><td>i -Pr</td><td>H</td>

<td>Cl</td><td>cf₃</td><td>Cl</td><td>Me</td><td>H</td>

<td>Cl</td><td>cf₃</td><td>Cl</td><td>Et</td><td>H</td>

<td>Cl</td><td>cf₃</td><td>Cl</td><td>i -Pr</td><td>H</td>

Formulation / Utility

Compounds of this invention will generally be used as a formulation or composition with a carrier suitable for agronomic and non-agronomic use comprising at least one liquid diluent, solid diluent or surfactant. The ingredients of the formulation or composition are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, humidity and temperature. Useful formulations include liquids such as solutions (including emulsion concentrates), suspensions, emulsions (including microemulsions and / or suspoemulsions) and the like which may optionally be thickened to gels. Useful formulations further include solids such as dust, powders, granules, pellets, tablets, films and the like which may be dispersed in water (wettable) or solubilized in

991599463 water. The active ingredient may be (micro) encapsulated and further formed into a suspension or solid formulation; alternatively the entire active ingredient formulation may be encapsulated (or coated). Encapsulation may control or delay the release of the active ingredient. Spray formulations may be extended in suitable media and used in spray volumes from about one to several hundred liters per hectare. High strength compositions may primarily be used as intermediates for further formulation.

<td></td><td>At</td><td>formulations</td><td>will typically contain</td><td>quantities</td>

<td>effective</td><td>of</td><td>ingredient</td><td>active, diluent and</td><td>surfactant</td>

<td>inside</td><td>From</td><td>breaks</td><td colspan="2">following approximate</td>

add up to 100 percent by mass.

Mass Percentage

Active Diluent Ingredient

Surfactant

Water-dispersible Granules and Water-Soluble Granules 5-90 0-94 Water, Tablets and Powders.

1-15

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

<td>emulsion products)</td><td></td><td></td><td></td><td></td><td></td>

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

<td>Granules and Tablets</td><td></td><td></td><td> 0,01-99</td><td> 5-99,99</td><td> 0-5</td>

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

<td>Thinners</td><td>solid</td><td>typical</td><td>They are</td><td colspan="2">described</td>

Watkins, et al.

Handbook of Insecticide Dust Diluents and

ΡΕ1599463

Carriers, 2^The ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2^The ed, Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations may contain minimal amounts of additives to reduce foam, agglutination, corrosion, microbiological growth and the like, or thickeners to increase viscosity.

Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfnates, N, A-dialkyltaurates, lignin sulfonate formaldehyde condensate sulfonates , 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, N, A-dimethylformamide, dimethyl sulfoxide, A-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, olive oil, castor oils, flaxseed, fungus, sesame, corn, peanut, cottonseed soy and coconut esters

991599463 of fatty acids, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofuryl alcohol.

Solutions including emulsion concentrates can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by mixing and usually milling in a hammer mill or air-gas jet mill. Suspensions are generally prepared by wet milling; see, for example, U.S. 3,060,084. Granules and pellets may be prepared by spraying the active material on preformed granular carriers or by agglomeration techniques. See Browning, Agglomeration, Chemical Engineering, December 4, 1967, pp 147-48, Perry's

Chemical Engineer's Handbook, 4^The Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and PCT Publication WO 91/13546. Tablets may be prepared as described in US 4,172,714. Water-dispersible and water-soluble granules may be prepared as taught in US 4,144,050, US 3,920,442 and DE 3,246,493. Tablets may be prepared as taught in US 5 180 587, US 5 232 701 and US 5 208 030. Films may be prepared as taught in GB 2 095 558 and US 3,299,566.

For additional information regarding the art of formulation, see The Formulator's Toolbox - Product

Forms for Modem Agriculture in Pesticide Chemistry and

ΡΕ1599463

Bioscience, The Food-Environment Challenge, T. Brooks and T.

R. Roberts, Eds., Proceedings of the 9th International

Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, p. 120-133. See also USA

3,235,361, Col. 6, line 16 to Col. 7, line 19 and Examples

10-41; US 3,309,192, Col. 5, line 43 to Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140,

162-164, 166, 167 and 169-182; USA 2,891,855, Col. 3, line to Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control.

Handbook 8^The Ed., Blackwell Scientific Publications,

Oxford, 1989.

In the following examples, all percentages are by weight and all formulations are prepared in conventional manner. Compound numbers refer to compounds in the index in Table A.

Example A

Wettable Powder

Compound 1 65.0%

Polyethylene glycol dodecylphenolic ether 2.0% Sodium lignosulfonate 4.0%

Sodium silicoaluminate 6.0%

Montmorillonite (calcined) 23.0%

ΡΕ1599463

Example B

Granule

Compound 1 10.0%

Attapulgite granules (low volatility matter,

0.71 / 0.30 mm; USS No. 25-50) 90.0%

Example C

Expanded Tablet

Compound 1 25.0%

Anhydrous sodium sulfate 10.0%

Crude calcium lignin sulfonate 5.0%

Sodium alkylnaphthalenesulfonate 1.0%

Calcium / Magnesium Bentonite 59.0%

Example D

Emulsion Concentrate

Compound 1 20.0%

Mixture of soluble oil sulfonates and 10.0% polyoxyethylene ethers

Isophorone 70.0%

Example E

Granule

Compound 1

Cellulose

Lactose

Cornflour

0,5%

2,5%

4, 0%

93,0%

ΡΕ1599463

Compounds of this invention are characterized by favorable soil metabolic patterns and / or residues and exhibit activity controlling a spectrum of agronomic and non-agronomic invertebrate pests. Compounds of this invention are also characterized by foliar systemicity and / or favorable soil application in plants showing translocation to protect foliage and other parts of the plant not directly in contact with insecticide compositions comprising the present compounds. (In the context of this disclosure invertebrate pest control means inhibition of invertebrate pest development (including mortality) which causes significant reduction in food or other injury or damage caused by the pest; related expressions are defined analogously. Invertebrate pest term includes arthropods, gastropods and nematodes of economic importance as pests. 0 The term arthropod includes insects, mites, spiders, scorpions, centipedes, milfpedes, bugs and symphiles. The term gastropod includes snails, slugs and other helicopters. The term nematode includes all worms such as roundworms, heartworms and phytophagous nematodes (Nematoda), fasciola (Trematoda), Acanthocephala, and tapeworms (Cestoda). Those skilled in the art will recognize that not all compounds are equally effective against all pests. 0 agronomic term refers to the production of crops such as for food and fiber and includes the growth of

ΡΕ1599463 cereals (eg, wheat, oats, barley, rye, rice, corn), soybeans, vegetable crops (eg, lettuce, kale, tomatoes, beans), potatoes, sweet potatoes, grapes, cotton, and fruit trees (eg, fruits of pevides, stone fruits, citrus fruit). 0 non-agronomic term refers to other horticultural (eg, forest, greenhouse, nursery or ornamental plants not cultivated in the field), grass (commercial, golf, residential, recreational, etc.), wood products, public health (human) and animal, domestic and commercial structures, family homes, and applications or pests of stored products. For reasons of spectrum control of invertebrate pests and economic importance, the protection (from damage or injury caused by invertebrate pests) of cotton, maize, soybean, rice, vegetable crops, potatoes, sweet potatoes, grapes and fruit trees by invertebrate pest control is the preferred embodiment of the invention. Agronomic or non-agronomic pests include larvae of the order Lepidoptera such as maize caterpillars, screw caterpillars, caterpillars, and heliothines in the Noctuidae family (eg, corn cartridge caterpillar (Spodoptera fugiperda JE Smith), Knots (Spodoptera exigua Hubner), Blackthorn caterpillar (Agrotis ipsilon Hufnagel), Cabbage caterpillar (Trichoplusia ni Hubner), Tobacco caterpillar (Heliothis virescens Fabricius); borers, casebearers, pirales, pine cone caterpillars, cabbage caterpillars and skeletonizers of the Pyralidae family (eg, corn borer (Ostrinia nubilalis Hubner), orangeworm (Amyelois transitella Walker), corn pirale (Crambus caliginosellus Clemens), pirale da

ΡΕ1599463 grass (Herpetogramma licarsisalis Walker); leaf curlers, budworms, seed worms, and weevils of the fruit of the Tortricidae family (eg, pome worms (Cydia pomonella Linnaeus), grape moths (Endopiza viteana Clemens), eastern moth (Grapholita molesta Busck)); and many other economically important lepidopterans (eg, cruciferous moth (Plutella xylostella Linnaeus), pink caterpillar (Pectinophora gossypiella Saunders), Gypsy moth (Lymantria dispara Linnaeus)); Blattodea nymphs and adults including family cockroaches

Blattellidae and Blattidae (eg, Eastern cockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatella asahinai Mizukubo), German cockroach (Blattella germanica Linnaeus), Brown-striped cockroach (Supella longipalpa Fabricius), American cockroach (Periplaneta americana Linnaeus), Brown cockroach (Periplaneta brunnea Burmeister), cockroach from Madeira (Leucophaea maderae Fabricius); leaf-feeding larvae and adults including weevils of the families Anthribidae, Bruchidae, and Curculionidae (eg, Blackcucker (Anthonomus grandis Boheman), North American Rootworm (Lissorhoptrus oryzophilus Kuschel), granary weevil (Sitophilus granarius gum, Linnaeus) rice (Sitophilus oryzae Linnaeus); aphids, cucumber beetle, rootworms, red beetles, potato beetles, and mining caterpillars of the family Chrysomelidae (eg, potato beetle (Leptinotarsa ​​decemlineata Say), corn root system chrysomelid (Diabrotica virgifera virgifera LeConte and other beetles); of the Scaribaeidae family (eg, beetle

ΡΕ1599463 Japanese (Popillia japónica Newman) and European Beetle (Rhizotrogus majalis Razoumowsky)); carpet beetles of the family Dermestidae; yellow worms of the family Elateridae; Scolitidae scolitid and flour beetle of the Tenebrionidae family. In addition, agronomic and non-agronomic pests include: adults and larvae of the order Dermaptera including female bitches of the Forficulidae family (eg, European female bitch (Forficula auricularia Linnaeus), black bitch (Chelisoches morio Fabricius)); adults and nymphs of the orders Hemiptera and Homoptera such as bed bugs of the family Miridae, cicadas of the family Cicadidae, green leafhopper (eg Empoasca spp.) Of the family Cicadellidae, planthoppers of the families Fulgoroidae and Delphacidae, treehoppers of the family Membracidae, psyllids of the family Psyllidae, whiteflies of the family Aleyrodidae, aphids of the family Phylloxeridae, mealybugs of the family Pseudococcidae, Cochonidae , Diaspididae and Margarodidae, bed bugs in the Tingidae family, bed bugs in the Pentatomidae family, grass bug (eg, Blissus spp.) And other seed bugs from the Lygaeidae family, spittlebugs from the Cercopidae squash bugs from the Coreidae family, and red bed bugs and cotton spotting bugs from the Pyrrhocoridae family. Also included as agronomic and non-agronomic pests are adults and larvae of the order Acari (mites) such as pink mites and red mites of the Tetranychidae family (eg, European red mite (Panonychus ulmi Koch), red spider mite (Tetranychus urticae Koch), mite.

ΡΕ1599463

McDaniel (Tetranychus mcdanieli McGregor)), Tenuipalpidae mites (eg, citrus mites (Brevipalpus lewisi McGregor)), Eriophyidae fake rust mite and other important leaf-eating mites and mites ie. dust mites of the family Epidermoptidae, follicle mites of the family Demodicidae, dust mites of the family Glycyphagidae, ticks of the order Ixodidae (eg, deer tick (Ixodes scapularis Say), paralyzing tick of Australia (Ixodes holocyclus Neumann) (Dermacentor variabilis Say), lone star tick (Amblyomma americanum Linnaeus) and mange mites from the families Psoroptidae, Pyemotidae, and Sarcoptidae; adult and immature Orthoptera including locusts, acridios and crickets (eg, migratory locusts (eg, Melanoplus sanguinipes Fabricius, M. Thomas differentialis), American grasshoppers (eg, Schistocerca americana Drury), Desert acrids (Schistocercagregaria Forskal), Migratory acridsbush (Locusta migrativa Linnaeus), Bush acridios (Zonocerus spp.), Drake (Acheta domesticus Linnaeus), Grills (Gryllotal) spp.))); adult and immature animals of the order Diptera including leaf mints, mosquitoes, fruit flies (Tephritidae), wheat fly (eg, Oscinella frit Linnaeus), blowfly larvae, houseflies (eg, Musca domestica Linnaeus), houseflies ( eg, Fannia canicularis Linnaeus, F. femoralis Stein), stable flies (eg, Stomoxys calcitrans Linnaeus), face flies, horn flies, meat flies (eg, Chrysomya spp., Phormia spp.), and other fly pests ,

ΡΕ1599463 Horse flies (eg, Tabanus spp.), Estrus larvae (eg, Gastrophilus spp., Oestrus spp.), Cattle fly larvae (eg, Hypoderma spp.), Deer flies (eg, Chrysops spp.) , keds (eg, Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (eg, Aedes spp., Anopheles spp., Culex spp.), blackflies (eg, Prosimulium spp., Simulium spp.), biting mosquitoes, sand, cyiarids, and other Nematocera; immature adults of the order Thysanoptera including onion tripods (Thrips tabaci Lindeman), flower tripods (Frankliniella spp.), and other leaf-feeding tripod insect pests; insect pests of the order Hymenoptera including ants (eg, red carpenter ant (Camponotus ferrugineus Fabricius), black carpenter ant (Camponotus pennsylvanicus De Geer), pharaoh ant (Monomorium pharaonis Linnaeus), small fire ant (Wasmannia auropunctata Roger), fire (Solenopsis geminata Fabricius), imported red fire ant (Solenopsis invicta Buren), Argentine ant (Iridomyrmex humilis Mayr), crazy ant (Paratrechina longicornis Latreille), floor ant (Tetramorium caespitum Linnaeus), black ant (Lasius alienus Forster), odorous domestic ant (Tapinoma sessile Say)), bees (including carpenter bees), moscardos, drunfs, wasps, and flies defoliators (Neodiprion spp .; Cephus spp.); insect pests of the order Isoptera including the eastern underground termite (Reticulitermes flavipes Kollar), western underground termite (Reticulitermes hesperus Banks), Taiwan underground termite (Coptotermes formosanus Shiraki),

ΡΕ1599463 West Indians drywood termite (Incisitermes immigrans Snyder) and other termites of economic importance; insect pests of the order Thysanura such as lepisma (Lepisma saccharina Linnaeus) and firebrat (Thermobia domestica Packard); insect pests of the order Mallophaga and including head louse (Pediculus humanus capitis De Geer), body louse (Pediculus humanus humanus Linnaeus), chicken louse (Menacanthus stramineus Nitszch), dog louse (Trichodectes canis De Geer), hairy louse ( Goniocotes gallinae DeGeer), sheep louse (Bovicola ovis Schrank), short-nosed cattle louse (Haernatopinus eurystermus Nitzsch), long-nosed cattle louse (Linognathus vituli Linnaeus) and other sucking and chewing parasitic lice that attack men and animals; insect pests of the order Siphonoptera including eastern rat flea (Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felis Bouche), dog flea (Ctenocephalides canis Curtis), flea flea other gallinaceous fleas (Ceratophyllus gallinat stick), Schrank) (Echidnophaga gallinacea Westwood), human (Pulex irritans Linnaeus) and afflict mammals and birds. Additional invertebrate pests include: spiders of the order Araneae such as brown recluse spider (Loxosceles reclusa Gertsch &amp; Mulaik) and black widow spider (Latrodectus mactans Fabricius), and Scutigeromorpha centipedes such as domestic centipede (Scutigera coleoptrata Linnaeus). Compounds of the present invention also have activity in members of the Nematode, Cestoda, Trematoda, and Acanthocefala Classes.

ΡΕ1599463 including economically important members of the orders Strongylida, Ascaridida, Oxyurida, Rhabditida, Spirurida, and Enoplida as but not limited to agriculturally damaging genus lesion root hook (ie genus Meloidogyne, Pratylenchus nematodes, genus stubby root nematodes) Trichodorus, etc.) and animal and human health pests (ie all economically important fascicles, tapeworms, and roundworms, such as Strongylus vulgaris in horses, Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilaria immitis Leidy in dogs, Anoplocephala perfoliata in horses, Fasciola hepatica Linnaeus in ruminants, etc.).

Compounds of the invention show particularly high activity against pests of the order Lepidoptera (eg, Alabama argillacea Hubner (cotton leafworm), Archips argyrospila Walker (fruit tree winder), A. rosana Linnaeus (European leaf winder) and other Archips species, Chilo suppressalis Walker (rice shoot borer), Cnaphalocrosis medinalis Guenee (rice leaf winder) Crambus caliginosellus Clemens (Western corn root system chrysomelid), Crambus teterrellus Zincken (dog hair pyrale), Cydia pomonella Linnaeus (walnut caterpillar), Earias insulana Boisduval (prickly caterpillar), Earias vittella Fabricius (spotted caterpillar), Helicoverpa armigera Hubner (ear caterpillar), Helicoverpa zea Boddie (corn ear caterpillar), Heli othis virescens

ΡΕ1599463

Fabricius (tabacosod caterpillar), Herpetogramma licarsisalis Walker (grass pyrale), Lobesia botrana Denis &amp; Schiffermuller (grape moth), Pectinophora gossypiella Saunders (pink caterpillar), Phyllocnistis citrella Stainton (Citrus minerum caterpillar) great white), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (cruciferous moth), Spodoptera exigua Hubner (beet caterpillar), Spodoptera litura Fabricius (tobacco thread), Spodoptera frugiperda JE Smith (cartridge caterpillar), Trichoplusia ni Hubner (cabbage larvae) and Tuta Absolute Meyrick (tomato mining larva)). Compounds of the invention also have commercially significant activity in members of 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), Chaetosiphon fragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov / Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (pink apple aphid), Eriosoma lanigerum Hausmann (apple aphid), Hyalopterus pruni Geoffroy (plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophium dirrhodum Walker (cereal aphid), Macbiaipum ehor Thomas (potato aphid), Myzus persicae Sulzer (potato aphid, peach green aphid), Nasonovia ribisnigri Mosley (aphid)

Lettuce (1599463), Pemphigus spp. (root affdeos and gall affdeo), Rhopalosiphum maidis Fitch (corn leaf affdeo), Rhopalosiphum padi Linnaeus (bird cherryoat), Schizaphis graminum Rondani (green aphid), Sitobion avenae Fabricius (English grain affdeo), Therioaphis maculis Buckton (alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (citrus black aphid), and Toxoptera citricide Kirkaldy (citrus brown aphid); Adelges spp. (adelgids); Phylloxera devastatrix Pergande (Pecan Phylloxera); Bemisia tabaci Gennadius (white tobacco fly, sweet potato whitefly), Bemisia argentifolii Bellows &amp; Perring (whitefly), Dialeurodes citri Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (whitefly); Empoasca fabae Harris (green potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (green leafhopper marigold), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stâl (rice leafhopper) planthopper), Peregrinus maidis Ashmead (Corn planthopper cicada), Sogatella furei beast Horvath (whitebacked planthopper), Sogatodes orizicola Muir (rice delfacfdeo), Typhlocyba pomaria McAtee apple leafhopper, Erythroneoura spp. (vine leafhopper); Magicidada septendecim Linnaeus (periodic cicada); Icerya purchasi Maskell (Australian mealybug), Quadraspidiotus perniciosus Comstock (San Jose mealybug); Planococcus citri Risso (citrus mealybug); Pseudococcus spp.

ΡΕ1599463

- 67 (other scale insects); Cacopsylla pyricola Foerster (Pear Psila), Trioza diospyri Ashmead (Dispirator Psila). These compounds also have activity on members of the order Hemiptera including: Acrosternum hilare Say (Green Stinkbug), Anasa tristis De Geer (Pumpkin Bedbug), Blissus leucopterus leucopterus Say (Cereal Bedbug), Corythuca gossypii Fabricius (Cotton Yarn Bedbug), Dysdercus Herrich-Scháffer suturellus (cotton stains), Euchistus servus Say (brown stink bug), Beauvois palisot Euchistus variolarius, Graptosthetus spp. (seed bug complex), Leptoglossus corculus Say (leaffooted pine seed bug), Beauvois palisot Lygus lineolaris (tarnished plant bug), Nezara viridula Linnaeus (southern green smelly bedbug), Oebalus pugnax Fabricius (stinky rice bug), Oncopeltus fasciatus Dallas (milkworm aphid), Pseudatomoscelis seriatus Reuter (cotton flea). Other orders of insects controlled by compounds of the invention include Thysanoptera (eg, Frankliniella occidentalis Pergande (western flower tripe), Scirthothrips citri Moulton (citrus tripe), Sericothrips variabilis Beach (soybean tripe), and Thrips tabaci Lindeman (onion tripe). ); and the order Coleoptera (eg, Leptinotarsa ​​decemlineata Say (potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and yellow worms of the genus Agriotes, Athous or Limonius).

ΡΕ1599463

The compounds of this invention may 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, chemostilizers, semiochemicals, repellents, attractants, pheromones, growth stimulants. other biologically active compounds or entomopathogenic bacteria, viruses or fungi to form a multi-component pesticide giving an even broader spectrum of agronomic and non-agronomic utility. Thus the present invention also relates 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 active agent and may further comprise at least one surfactant, solid diluent or liquid diluent. Examples of such biologically active compounds or agents with which the compounds of this invention may be formulated are: insecticides such as abamectin, acefate, acetamiprid, acetoprole, amidoflumet (S-1955), avermectin, azadiractin, azinfos-methyl, bifenthrin, bifenazate, bistrifluron, buprofezin, carbofuran, chlorfenapyr, chlorfluuthurid, chlorpyridine, chlorpyridine, chlorofluoromethane betacycluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafentiuron, diazinon, diflubenzuron, dimethoate, dinotefuran, diofenolane, emamectin, endosulfan, sphenvalerate, etiprole, fenoticarb, phenoxycarb, fenpropatrin, fenvalerate, fipronil, flonicaΡΕ1599463 mid, fluctrinate, taufluvalinate, flufenerim (UR-50701), flufenoxuron, gamma-calotrin, halofenozuron, isoflurenofuranofuranulfonuronate metamidophos, methidionion, methomyl, metoprene, methoxychlor, methoxyphenozide, metofluthrin, monocrotophos, methoxyphenazide, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion methyl, permethrin, fosalone, fosmet, phosphamidon, pirimicarb, profenofos, profluthrin, protrifenbute, pimetrozine, pyridalyl, pyriproxyfen, rotenone, S1812 (Valent) spinosadene, spiromesifen (BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthridine, tefluthidine thiodicarb, thiosultap-sodium, tolfenpirad, tralometrine, trichlorphon and triflumuron; fungicides such as acibenzolar, Smethyl, azoxystrobin, benalazi-M, bentiavalicarb, benomyl, blasticidin-S, broth (tribasic copper sulfate), boscalid, bromuconazole, butiobate, carpropamid, captafol, captan, carbendazri, chloroneb, clone, copper oxychloride, copper salts, cimoxanil, ciazofamid, ciflufenamid, cyproconazole, cyprodinil, diclocimet, diclomezine, dichlorane, diphenoconazole, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dodine, eden fosetyl aluminum, furalaxil, furametapyr, guazatin, hexaconazole, himexazole, imazalil, imiΡΕ1599463 benconazole, iminoctadine, ipconazole, iprobenfos, iprodione, iprovalicarb, isoconazole, isoprothiolane, casugamicin, cresoximmethyl, mancozeb, maneb, mefenoxam, mepanapyrim, mepronil, metalaxyl, metconazole, metominostrobin / phenommostrobin, metrafenone, miconazole, miclobutanil, ferric metanoarsonate, nuarimazole, oxarobazole, piconazole, oxarazole picoxystrobin, probenazole, prochloraz, propamocarb, propiconazole, proquinazid, protioconazole, piraclostrobin, pyrimetanil, pyrifenox, pyroalkyl, quinoxyfen, siltiofam, simeconazole, sipconazole, spiroxamine, sulfur, tebuconazole, tetraconazole, tiadinil, tiabendazole, tifluzamide, thiophanate-methyl, tiram, tolylfluanid, triadimephon, triadimenol, triarimol, tricyclazole, trifloxistrole, triflazyzine, trifloxizinazole, triflazole nematocides such as aldicarb, oxamyl and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, quinomethionate, chlorobenzylate, cyhexatin, dicofol, dienochlor, ethoxazole, phenazaquine, fenbutatin oxide, fenpropathrin, fenpyroximate, hexithiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis including ssp. aizawai and kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, viruses and fungi. Compounds of this invention and compositions thereof may be applied to genetically transformed plants to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis toxin). The effect of compounds

No. 1599463 of this invention for exogenously applied invertebrate pest control may be synergistic with the expressed toxin proteins.

A general reference for these agricultural protectors is The Pesticide Manual, 12^The Edition, Tomlin CDS, Ed., British Crop Protection Council, Farnham, Surrey, UK, 2000.

Preferred insecticides and acaricides for mixing with compounds of this invention include pyrethroids such as acetamiprid, cypermethrin, cyhalothrin, cyfluthrin, beta-cyfluthrin, sphenvalerate, fenvalerate and tralometrine;

carbamates such as phenothicarb, methomyl, oxamyl and thiodicarb; neonicotinoids such as clotianidine, imidacloprid and thiacloprid; neuronal sodium channel blockers such as indoxacarb; insecticidal macrocyclic lactones such as spinosad, abamectin, avermectin and emamectin; γ-aminobutyric acid (GABA) antagonists such as endosulfan, etiprole and fipronil; insecticidal ureas such as flufenoxuron and triflumuron; juvenile hormone simulators such as diofenolane and pyriproxyfen; pymetrozine; and amitraz. Preferred biological agents for mixing with compounds of this invention include Bacillus thuringiensis and Bacillus thuringiensis delta endotoxin as well as naturally occurring and genetically modified viral insecticides including members of the Baculoviridae family as well as entomophagous fungi.

ΡΕ1599463

More preferred mixtures include a mixture of a compound of this invention with cyhalotrin; a mixture of a compound of this invention with beta-ciflutrin; a mixture of a compound of this invention with esfenvalerate; a mixture of a compound of this invention with methomyl; a mixture of one

<td>compound</td><td>of this</td><td>invention</td><td>with imidacloprid; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with thiacloprid; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with indoxacarb; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with abamectin; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with endosulfan; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with etiprole; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with fipronil; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with flufenoxuron; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention &lt;</td><td colspan="2">pyriproxyfen; a mix</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with pimetrozine; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td>with amitraz; an</td><td>mixture</td><td>in</td><td>one</td>

<td>compound</td><td>of this</td><td>invention</td><td colspan="4">with Bacillus thuringiensis aizawai</td>

<td colspan="4">or Bacillus thuringiensis kurstaki, and a</td><td>mixture</td><td>in</td><td>one</td>

compound of this invention with Bacillus thuringiensis delta endotoxin.

In certain cases, combinations with other invertebrate pest control compounds or agents having a similar control spectrum but a different mode of action will be particularly advantageous for resistance management. Thus, compositions of the present invention may further comprise a biologically effective amount of at least one additional invertebrate pest control compound or agent having a similar control spectrum but a

ΡΕ1599463 different mode of action. Contacting a genetically modified plant to express a plant protection compound (eg protein) or the site of a plant with a biologically effective amount of a compound of the invention may also provide a broader spectrum of plant protection and be advantageous for resistance management.

Invertebrate pests are controlled in agronomic and non-agronomic applications by applying one or more compounds of this invention, in an effective amount, to the pest environment including the agronomic and / or non-agronomic infestation site, the area to be protected, or directly to pests. be controlled. Thus, the present invention further comprises a method for controlling invertebrates in agronomic and non-agronomic applications, comprising contacting invertebrates or their environment with a biologically effective amount of one or more of the compounds of the invention, or a composition comprising at least one such compound or composition comprising at least one such compound and an effective amount of at least one additional biologically effective compound or agent. Examples of suitable compositions comprising a compound of the invention and an effective amount of at least one additional biologically effective compound or agent include granular compositions wherein the additional biologically effective compound is present in the same granule as the compound of the invention or in granules separate from those of the compound. of the invention.

ΡΕ1599463

A preferred method of contact is by spraying. Alternatively, a granular composition comprising a compound of the invention may be applied to plant foliage or soil. Compounds of this invention are also effectively distributed by plant uptake by contacting the plant with a composition comprising a compound of this invention applied as a soil remedy of a liquid formulation, a granular soil formulation, a treatment for a nursery in box or a sprinkler of transplants. The compounds are also effective for topical application of a composition comprising a compound of this invention at the infestation site. Other contact methods include applying a compound or composition of the invention by direct and residual spraying, aerial spraying, gels, seed coatings, microencapsulations, systemic absorption, baits, ear tags, bolus, nebulizers, fumigants, aerosols, powders and many others. The compounds of this invention may also be impregnated with materials for making invertebrate control devices (eg insect nests).

A compound of this invention may be incorporated into the composition of a bait that is consumed by an invertebrate pest or used with devices such as traps, bait stations, and the like. Such a bait composition may be in the form of granules comprising (a) an active ingredient, namely a compound of Formula

ΡΕ1599463

1, an N-oxide, or salt thereof, (b) one or more foods, (c) optionally an attractant, and (d) optionally one or more humectants. Of note are granules or bait compositions comprising from about 0.001-5% of the active ingredient; about 40-99% food and / or attractive; and optionally about 0.05-10% humectants; They are effective in controlling soil invertebrate pests at very low application rates, particularly at active ingredient dosages that are lethal by ingestion rather than by direct contact. Of note some foods will work as a source of food and attractive. Foods include carbohydrates, proteins and lipids. Examples of foods are flour, sugar, starches, animal fat, vegetable oil, yeast extracts and milk solids. Examples of attractants are odorants and flavors such as fruit and plant extracts, perfume, or other animal or plant component, pheromones or other agents known to attract an invertebrate pest. Example of humectants, ie moisture retaining agents, are glycols and other polyols, glycerin and sorbitol. Of note is a bait composition (and a method using such a bait composition) used to control invertebrate pests including individually or in combination with ants, termites, and cockroaches. An apparatus for controlling an invertebrate pest may comprise the present bait composition and a box adapted to receive the bait composition, wherein the box has at least one aperture of adequate size to allow the invertebrate pest to pass through the bait opening. so that

ΡΕ1599463

76 invertebrate pest can gain access to the bait composition from an off-box location, and wherein the box is further adapted to be placed on or near the site of the known potential activity of the invertebrate pest.

The compounds of this invention may be applied in their pure state, but most often the application will be a formulation comprising one or more compounds with suitable carriers, diluents and surfactants and possibly in combination with a foodstuff depending on the intended end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil concentrations, spray tubes, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance the effectiveness of the compound. For non-agronomic uses such sprays may be applied from sprays such as a can, a bottle or other container, either by pump or by releasing pressurized container, eg a pressurized aerosol spray package. Such spray compositions may take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions may still further comprise propellants, foaming agents, etc., as the case may be. Of note is a spray composition comprising a compound or composition of the present invention and a propellant. Representative propellants include, but

ΡΕ1599463 are not limited to methane, ethane, propane, iospropane, butane, isobutane, butene, pentane, iospentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Of note is a spray composition (and a method of using such a spray composition dispensed by a spray pack) used to control an invertebrate pest including individually or in combination mosquitoes, black flies, stable flies, deer flies, flies of horse, wasps, wasp (yellow jacktets), moscardos, ticks, spiders, ants, mosquito, (gnat), and the like.

The application rate required for effective control (ie biologically effective amount) will depend on such factors as the invertebrate species to be controlled, the pest life cycle, life stage, size, location, time of year, crop or host animal, feeding behavior, mating behavior, environmental humidity, temperature, and the like. Under normal circumstances application rates of about 0.01 to 2 kg active ingredient per hectare are sufficient for pest control in agronomic ecosystems, but as little as 0.0001 kg / hectare may be sufficient or as high as 8 kg / hectare may be required. For non-agronomic applications, effective use rates will range from about 1.0 to 50 mg / square meter but as little as 0.1 mg / square meter may be sufficient or as high as 150 mg / square meter may be required. . a

The skilled artisan can readily determine the biologically effective amount required for the desired level of invertebrate pest control.

The following TESTS demonstrate the effectiveness of controlling compounds of this invention in specific pests. Control efficacy represents inhibition of invertebrate pest development (including mortality) which causes significant reduction in feeding. The pest control protection produced by the compounds is not, however, limited to these species. See index Table A, B, and C for compound descriptions. The following abbreviations are used in the indices of the following Tables: i is iso, Me is methyl, Et is ethyl, and i-Pr is isopropyl. The abbreviation Ex represents Example and is followed by a number indicating which example the compound is prepared.

Table A index

R2

<img file="PT1599463E_D0030.tif" />

ΡΕ1599463

<td>Compound</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>mp (° C)</td>

<td>1 (Ex. 1)</td><td>Me</td><td>cf₃</td><td>Cl</td><td>H</td><td>H</td><td> 200-202</td>

<td>(Reference)</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>2 (Ex. 2)</td><td>Me</td><td>cf₃</td><td>Cl</td><td>Me</td><td>H</td><td> 214-216</td>

<td>3 (Ex. 3)</td><td>Me</td><td>Cl</td><td>Cl</td><td>Me</td><td>H</td><td> *</td>

<td>5 (Ex. 5)</td><td>Me</td><td>Br</td><td>Cl</td><td>Me</td><td>H</td><td>THE·</td>

<td>7 (Ex. 7)</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Me</td><td>H</td><td> 197-200</td>

<td> 9</td><td>Cl</td><td>Cl</td><td>Cl</td><td>i-Pr</td><td>H</td><td> 213-215</td>

<td> 10</td><td>Cl</td><td>Br</td><td>Cl</td><td>i-Pr</td><td>H</td><td> 222-225</td>

<td> 12</td><td>Cl</td><td>Br</td><td>Cl</td><td>Me</td><td>H</td><td> 198-201</td>

<td> 21</td><td>Cl</td><td>cf₃</td><td>Cl</td><td>i-Pr</td><td>H</td><td> 247-249</td>

<td> 22</td><td>Cl</td><td>cf₃</td><td>Cl</td><td>Me</td><td>H</td><td> 215-217</td>

<td> 24</td><td>Me</td><td>Cl</td><td>Cl</td><td>i-Pr</td><td>H</td><td> *</td>

<td> 25</td><td>Me</td><td>Br</td><td>Cl</td><td>i-Pr</td><td>H</td><td> *</td>

<td> 32</td><td>Me</td><td>cf₃</td><td>Cl</td><td>Et</td><td>H</td><td> 150-151</td>

<td> 33</td><td>Me</td><td>Cl</td><td>Cl</td><td>Et</td><td>H</td><td>THE·</td>

<td> 35</td><td>Me</td><td>Br</td><td>Cl</td><td>Et</td><td>H</td><td>THE·</td>

* See Table C index for data on ⁴H NMR Table C index

<td>Comp. No.</td><td>Data from ⁴H NMR (CDCl1 solution₃ unless otherwise indicated otherwise)</td>

<td> 3</td><td>(CDC1₃) 10.55 (s, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.55 (s, 2H), 7.40 (dd, 1H), 6.97 (s, 1H), 6.30 (1 q, 1H), 2.98 (d, 3H), 2.24 (s, 3H)</td>

<td> 5</td><td>(CDC1₃) 10.55 (s, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.57 (m, 2H), 7.37 (dd, 1H), 7.05 (s, 1H), 6.30 (1 q, 1H) 2.98 (d, 3H), 2.24 (s, 3H)</td>

ΡΕ1599463 (continued)

<td>Comp. No.</td><td>Data from ²Η NMR (solution of otherwise)</td><td>CDCI3 unless otherwise indicated</td>

<td> 24</td><td>(CDC1₃) 10.12 (s, 1H), 8.56</td><td>(d, 1H), 7.85 (d, 1H),</td>

<td></td><td>7.58 (m, 2H), 7.40 (dd, 1H),</td><td>6.97 (s, 1H), 6.00 (1</td>

<td></td><td>d, 1H) 4.22 (m, 1H), 2.25 (s,</td><td>3H), 1.26 (d, 6H)</td>

<td> 25</td><td>(CDCl3) 10.60 (s, 1H), 8.47</td><td>(d, 1H), 7.85 (dd, 1H),</td>

<td></td><td>7.56 (s, 2H), 7.39 (dd, 1H),</td><td>7.06 (s, 1H), 6.04 (b</td>

<td></td><td>d, 1H), 4.20 (m, 1H), 2.24 (s</td><td>, 3H), 1.26 (s, 6H)</td>

<td>Comp No.</td><td>Data from ²Η NMR (solution of otherwise)</td><td>CDCI3 unless otherwise indicated</td>

<td> 33</td><td>(CDCl3) 10.60 (s, 1H), 8.45</td><td>(d, 1H), 7.85 (d, 1H),</td>

<td></td><td>7.58 (s, 2H), 7.39 (m, 1H), 6</td><td>, 97 (s, 1H), 6.20 (1</td>

<td></td><td>t, 1H), 3.46 (m, 2H), 2.25 (s</td><td>, 3H), 1.25 (t, 3H)</td>

<td> 35</td><td>(CDCl3) 10.60 (s, 1H), 8.46</td><td>(d, 1H), 7.85 (d, 1H),</td>

<td></td><td>7.57 (s, 2H), 7.38 (m, 1H),</td><td>7.05 (s, 1H), 6.25 (1</td>

<td></td><td>t, 1H), 3.46 (m, 2H), 2.24 (s</td><td>, 3H), 1.25 (t, 3H)</td>

Biological Examples of the Invention

TEST THE

To assess control of cruciferous moth (Plutella xylostella) the test unit consisted of a small open package containing a 12-14 day radish plant. This was pre-infested with 10-15 newborn larvae on a piece of insect food using a cylindrical section collector to remove a block from a hardened insect food sheet having many larvae.

991599463 to grow and transfer the block containing the larvae and food to the test unit. Larvae moved to the test plant as the food block dried.

Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm alkylaryl polyoxyethylene X-77® Spreader Lo-Foam Formula non-ionic surfactant, free fatty acids, glycols and isopropanol (Loveland Industries, Inc. Greeley, Colorado USA). The formulated compounds were applied to 1 mL of liquid through a 1/8 JJ SUJ2 liquid sprayer (Spraying Systems Co. Wheaton, Illinois, USA) positioned 1.27 cm (0.5 swells) above the top of each test unit. All experimental compounds in these tests were sprayed at 50 ppm replicating three times. After spraying the formulated test compound, each test unit was allowed to dry for 1 hour and then a black shielded cap was placed on top. The test units were kept for 6 days in a growth chamber at 25 ° C and 70% relative humidity. Damage to the food plant was then visually assessed based on foliage consumption.

Of the compounds tested the following provided plant protection levels from very good to excellent (20% or less food damage): 2, 3, 5, 7,

9, 10, 12, 21, 22, 24, 25, 32, 33 and 35.

ΡΕ1599463

TEST B

To evaluate control of the cartridge caterpillar (or military caterpillar) (Spodoptera frugiperda) the test unit consisted of a small open package containing a 4-5 day corn plant. It was pre-infused (using a cylindrical collector) with 10-15 1 day old larvae in a piece of insect food.

Test compounds were formulated and sprayed as described for Test A. Applications were replicated three times. After spraying, the test units were kept in a growth chamber and then visually evaluated as described in test A.

Of the compounds tested the following proportions

<td>swam</td><td>levels of</td><td>protection of</td><td>plant of</td><td>much</td><td>good at</td>

<td colspan="2">excellent (20% or</td><td>less damage</td><td>in food)</td><td> : 2, 3,</td><td> 5, 7,</td>

<td> 9, 10,</td><td> 12, 21, 22,</td><td> 24, 25, 32, 33</td><td>and 35.</td><td></td><td></td>

TEST C

To assess control of peach green aphid (Myzus persicae) by contact and / or systemic means, the test unit consisted of a small open package containing a 12-15 day radish plant. This was pre-infested by placing a 30-40 aphid aphid on a leaf of the excised test plant

991599463 crop plant (leaf cut method). The larvae moved to the test plant as the leaf piece dried out. After pre-infestation, the soil of the test unit was covered with a layer of sand.

Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm alkylaryl polyoxyethylene X-77® Spreader Lo-Foam Formula containing free fatty acids, glycols and isopropanol (LOveland Industries, Inc. Greeley, Colorado USA). The formulated compounds were applied to 1 mL of liquid through a 1/8 JJ SUJ2 body spray (Spraying Systems Co. Wheaton, Illinois, USA) positioned 1.27 cm (0.5 swells) above the top of each test unit. All experimental compounds in these tests were sprayed at 250 ppm replicating three times. After spraying the formulated test compound, each test unit was allowed to dry for 1 hour and then a black shielded cap was placed on top. The test units were maintained 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: 2, 3, 5, 7, 9, 10, 12,

21, 22, 24, 25, 32, 33 and 35.

ΡΕ1599463

TEST D

To assess potato leafhopper (Empoasca fabae Harris) control by contact and / or systemic means, the test unit consisted of a small open package containing a 5-6 day green bean plant (primary leaves to emerge). White sand was added above the ground and one of the primary leaves was excised before application. Test compounds were formulated and sprayed at 250 ppm replicating three times as described in Test C. After spraying, the test units were allowed to dry for 1 hour before being post-infested with 5 potato stems (adults 18 to 21 days old). A black shielded cap was placed on top of the cylinder. The test units were kept for 6 days in a growth chamber at 1921 ° 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: 3, 5, 10, 12, 21, 22, 24, 25, 32, 33 and 35.

TEST AND

To assess control of the melon aphid (Aphis gossypii) through contact and / or systemic means, the test unit consisted of a small open package containing a 6-7 day old cotton plant. This was pre-1599463 infested with 30-40 insects on a piece of leaf according to the leaf cut 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 in Test D. Applications were replicated three times. After spraying, the test units were kept in a growth chamber and then visually evaluated as described in

Test D.

Of the compounds tested, the following resulted in at least 80% mortality: 2, 3, 5, 7, 9, 10, 12,

21, 22, 24, 25, 32, 33 and 35.

TEST F

To evaluate control of the corn planthopper (Peregrinus maidis) by contact and / or systemic means, the test unit consisted of a small open package containing a 3-4 day corn plant. White sand was added above the ground before application. Test compounds were formulated and sprayed at 250 ppm and replicated three times as described in Test C. After spraying, the test units were allowed to dry for 1 hour before being post-infested with 10-20 corn planthoppers (18-20 day nymphs) by spreading them on the sand with a salt shaker. A black shielded lid was placed

ΡΕ1599463 at the top of each cylinder. The test units were kept for 6 days in a growth chamber at 19-21 ° C and 5070% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 2, 3, 5, 7, 10, 12, 24, 25, 32, 33 and 35.

TEST G

To assess whitefly control (Bemisia tabaci), the test unit consisted of a 14-21 day old cotton plant grown in Redi-earth® (Scotts Co.) with at least two genuine nymph-infested leaves in the 2^Theand 3^The stages at the bottom of the leaves.

Test compounds were formulated in no more than 2 mL of acetone and then diluted with water to 2530 mL. The formulated compounds were applied using a 10 psi (69 kPa) air-induction flat sprayer (Spraying Systems 122440). Plants were sprayed for flow in a rotary sprayer. All experimental compounds in this assay were sprayed at 250 ppm and replicated three times. After spraying the test compound, the test units were kept for 6 days in a growth chamber at 50-70% relative humidity and temperatures of 28 ° C during the day and 24 ° C overnight. The leaves were then removed and the

ΡΕ1599463 live nymphs were counted to calculate percent mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 2, 3, 5, 7, 9, 10, 24, 25, 32, 33 and 35.

TEST H

To evaluate compound movement in plants and control of green peach aphid (Myzus persicae) and potato leafhopper (Empoasca fabae) after leaf movement of the compound across the plant, the test unit consisted of a small open package containing a 12-15 day radish plant (for the peach green aphid test) and a green bean plant (for the potato leafhopper test).

Test compounds were formulated using a solution containing 10% acetone, 90% water and 600 ppm alkylaryl polyoxyethylene X-77® Spreader Lo-Foam Formula non-ionic surfactant, free fatty acids, glycols and isopropanol (Loveland Industries, Inc. Greeley, Colorado USA). The formulated compounds were applied in 20 microliters per pipette to the two largest photosynthetically active leaves. All experimental compounds in this assay 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

991599463 a layer of sand and each test unit was allowed to dry for 1 hour and then a black shielded lid was placed on top. The test units were kept 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 peduncle 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 cicadas (beans) and kept in the growth chamber for an additional 8 days. Each test unit was then visually assessed for mortality of insects, which had been in contact and fed on untreated plant tissues.

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

Table A

Insect Mortality Percentage

Compound% PLH M% GPA M

96 81

ΡΕ1599463

TESTED

To evaluate the movement of compounds in plants and control of green peach aphid (Myzus persicae) and potato leafhopper (Empoasca fabae) after movement of the compost applied to the soil through the wood from roots to foliage, The test unit consisted of a small open package containing a 12-15 day radish plant (for the peach green aphid test) and a green bean plant (for the potato leafhopper test).

Test compounds were formulated using a solution containing 10% acetone, 90% water and 600 ppm alkylaryl polyoxyethylene X-77® Spreader Lo-Foam Formula non-ionic surfactant, free fatty acids, glycols and isopropanol (Loveland Industries, Inc. Greeley, Colorado USA). The formulated compounds were applied in 1 mL of pipette solution to the soil of the base of the plant. All experimental compounds in this assay were applied at 1000 ppm and the tests were replicated three times. After applying the formulated compounds, each test unit was allowed to dry for 1 hour. The soil of each test unit was covered with a layer of sand and then a black shielded cover was placed on top. The test units were kept in a growth chamber at about

20 ° C and 50-70% relative humidity.

ΡΕ1599463

After 2 days, the plants were then infested with 20-30 aphids (radish) or 20 cicadas (beans) and kept in the growth chamber for a further 5 days. Each test unit was then visually assessed for mortality of insects, which had been in contact and fed on untreated plant tissues.

The results of peach green aphid mortality (% GPA M) and potato leafhopper mortality (% PLH M) are listed in Table B.

Table B

Percentage of

Insect Mortality

Compound% PLH M% GPA M

Lisbon, August 28, 2013

ΡΕ1599463