RU2283840C2 - Anthranylamide derivative, composition for pest controlling composition for invertebrate insect controlling, method for pest controlling, and intermediates - Google Patents

Abstract

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I

or N-oxides thereof, wherein R¹ represents methyl, F, Cl, Br; R² represents F, Cl, Br, I, CF₃; R³ represents CF₃, Cl, Br, OCH₂CF₃; R^4a represents C₁-C₄-alkyl; R^4b represents H, CH₃; and R⁵ represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

Description

BACKGROUND OF THE INVENTION

This invention relates to certain anthranilamides, their N-oxides, agriculturally acceptable salts and compositions and methods for their use in controlling invertebrate pests such as arthropods (Arthropoda), both in agriculture and in non-agricultural conditions.

The control of invertebrate pests, such as arthropods, is extremely important for achieving high crop efficiency. Damage by invertebrate pests to growing and stored crops can cause a significant decrease in productivity and thereby increase the cost to the consumer. Also important is the control of invertebrate pests in forestry, the cultivation of greenhouse crops, ornamental crops, the cultivation of seedlings, the storage of food and fiber products, as well as pests of livestock, households and for public health and animal health. Many products are commercially available for these purposes, but there remains a need for new compounds that are more effective, less expensive, less toxic, more environmentally friendly, or have different mechanisms of action.

NL 9202078 describes derivatives of N-acylanthranilic acid of formula i as insecticides

Where

X is a direct bond;

Y is H or C ₁ -C ₆ alkyl;

Z is NH ₂ , NH (C ₁ -C ₃ alkyl) or N (C ₁ -C ₃ alkyl) ₂ ; and

R ¹ -R ⁹ independently represent H, halogen, C ₁ -C ₆ alkyl, phenyl, hydroxy, C ₁ -C ₆ alkoxy or C ₁ -C ₇ acyloxy.

SUMMARY OF THE INVENTION

This invention relates to a compound of formula 1, its N-oxide or an agriculturally acceptable salt of this compound

Where

R ¹ is CH ₃ , F, Cl or Br;

R ² is F, Cl, Br, I or CF ₃ ;

R ³ is CF ₃ , Cl, Br or OCH ₂ CF ₃ ;

R ^4a is C ₁ -C ₄ alkyl;

R ^4b represents H or CH ₃ and

R ⁵ is Cl or Br.

The present invention also relates to a composition for controlling invertebrate pests comprising a biologically effective amount of a compound of formula 1 and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. 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 component or agent.

The present invention also relates to a method of controlling invertebrate pests, comprising contacting an invertebrate pest or its environment with a biologically effective amount of a compound of formula 1 (for example, as a composition described herein). The present invention also relates to such a method in which an invertebrate pest or its environment is contacted with a biologically effective amount of a compound of formula 1 or a composition containing a compound of formula 1 and a biologically effective amount of at least one additional compound or agent for killing invertebrate pests.

The invention also relates to a benzoxazinone compound of formula 2

Where

R ¹ is CH ₃ , F, Cl or Br;

R ² is F, Cl, Br, I or CF ₃ ;

R ³ is CF ₃ , Cl, Br or OCH ₂ CF ₃ ;

R ⁵ is Cl or Br;

which is applicable as an intermediate in the synthesis to obtain the compounds of formula 1.

The invention also relates to a pyrazolecarboxylic acid compound of formula 4

Where

R ³ is CF ₃ , Cl, Br or OCH ₂ CF ₃ ; and

R ⁵ is Cl or Br;

which is applicable as an intermediate in the synthesis to obtain the compounds of formula 1.

DETAILED DESCRIPTION OF THE INVENTION

In the above enumerations, the term “alkyl”, used alone or in compound words, such as “alkylthio” or “haloalkyl”, means straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl or various butyl isomers. One skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides, since an unshared pair of electrons must be available on nitrogen for oxidation to oxide; one skilled in the art will understand which nitrogen-containing heterocycles can form N-oxides. One skilled in the art will also understand that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are very well known to one skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert- butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for producing N-oxides have been described in detail and discussed in the literature, see, for example: T.L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S.V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A.J. Boulton and A. McKillop, Eds., Pergamon Press; M.R. Grimmett and B.R.T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A.R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W.H. Cheeseman and E.S.G. Werstiuk in Advances in Heterocyclic Cheniistly, vol. 22, pp 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

The compounds of this invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will recognize that one stereoomer may be more active and / or may exhibit better effect when it enriches a mixture relative to another stereoisomer (other stereoisomers) or when separated from another stereoisomer (other stereoisomers). In addition, the person skilled in the art knows how to separate, enrich and / or selectively obtain these stereoisomers. Thus, this invention includes compounds selected from compounds of formula 1, their N-oxides and agriculturally acceptable salts. The compounds of this invention may be in the form of a mixture of stereoisomers, in the form of individual stereoisomers or in the form of an optically active form.

Salts of the compounds of this invention include acid addition salts (addition salts) with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic , tartaric, 4-toluenesulfonic or valerianic acid.

Preferred compounds for cost, ease of synthesis and / or biological effectiveness are:

Preferred compounds 1: compounds of formula 1, wherein R ^4a is C ₁ -C ₄ alkyl and R ^4b is H; or R ^4a is CH ₃ and R ^4b is CH ₃ .

Preferred compounds 2: preferred compounds 1, wherein R ⁵ is Cl.

Preferred compounds 3: preferred compounds 2, wherein R ^4b is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or C (CH ₃ ) ₃ .

Preferred compounds 4: preferred compounds 3, wherein R ² is Cl or Br.

Preferred compounds 5: preferred compounds 4, wherein R ¹ is CH ₃ .

Preferred compounds 6: preferred compounds 4, wherein R ¹ is Cl.

Preferred compounds 7: compounds of formula 1, where R ¹ is CH ₃ , Cl or Br; R ² is F, Cl, Br, I or CF ₃ ; R ³ is CH ₃ , Cl or Br; R ^4a is C ₁ -C ₄ alkyl; R ^4b is H and R ⁵ is Cl or Br.

Particularly preferred is a compound of formula 1 selected from the group consisting of:

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is CF ₃ , R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is CF ₃ , R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is Br, R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is Br, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is Cl, R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Br, R ³ is Cl, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is CH _3, R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is CH _3, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is Br _, R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is Br _, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is Cl _, R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is Cl _, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is OCH ₂ CF ₃ , R ^4a is CH (CH ₃ ) ₂ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is OCH ₂ CF ₃ , R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is Cl, R ² is Cl, R ³ is Br _, R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl;

compounds of formula 1, where R ¹ is CH ₃ , R ² is Cl, R ³ is OCH ₂ CF ₃ , R ^4a is CH ₃ , R ^4b is H and R ⁵ is Cl.

Preferred compositions of this invention are compositions that contain the above preferred compounds. Preferred methods of use are methods using the above preferred compounds.

Preferred are compounds of formulas 1, 2 and 4, in which R ¹ is CH ₃ , Cl or Br; R ² is F, Cl, Br, I or CH ₃ ; R ³ is CH ₃ , Cl or Br; R ^4a is C ₁ -C ₄ alkyl; R ^4b is H and R ⁵ is Cl or Br.

Compounds of formula 1 can be prepared using one or more of the following methods and options shown in Schemes 1-11. The definitions of R ¹ , R ² , R ³ , R ^4a , R ^4b and R ⁵ in the compounds of formulas 1-24 below are the same as defined above in the Summary of the Invention, unless otherwise indicated.

Compounds of formula 1 can be prepared by reacting benzoxazinones of formula 2 with C ₁ -C ₄ alkylamines, as shown in general form in Scheme 1.

Scheme 1

This reaction can proceed undiluted or in various suitable solvents, including tetrahydrofuran, diethyl ether, dichloromethane or chloroform, with optimum temperatures ranging from room temperature to the reflux temperature (boiling under reflux) of the solvent. The general reaction of benzoxazinones with amines to produce anthranilamides is well described in the chemical literature. For a review, see Jakobsen et al., Bioorganic and Medicinal Chemistry 2000, 8, 2095-2103 and the references cited in this review. See also G.M. Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

Benzoxazinones of formula 2 can be obtained in various ways. Two methods that are particularly applicable are described in detail in schemes 2-3. In Scheme 2, a benzoxazinone of formula 2 is prepared directly by coupling pyrazolecarboxylic acid of formula 4 with anthranilic acid of formula 3.

Scheme 2

It involves the sequential addition of methanesulfonyl chloride in the presence of a tertiary amine, such as triethylamine or pyridine, to the pyrazolecarboxylic acid of formula 4, followed by the addition of anthranilic acid of formula 3, followed by a second addition of tertiary amine and methanesulfonyl chloride. This method usually gives good yields of benzoxazinone and is illustrated in more detail in Example 1.

Scheme 3 depicts an alternative preparation of benzoxazinones of formula 2 using the coupling of an acid chloride of formula 6 with isatinic anhydride of formula 5 to directly produce benzoxazinone of formula 2.

Scheme 3

Suitable solvents for this reaction are pyridine or a pyridine / acetonitrile mixture. The acid chlorides of formula 6 can be prepared from the corresponding acids of formula 4 by known methods, such as chlorination with thionyl chloride or oxalyl chloride.

Anthranilic acids of the formula 3 can be obtained by various known methods. Many of these compounds are known. As shown in Scheme 4, anthranilic acids containing R ² as the substituent chlorine, bromine or iodine can be obtained by direct halogenation of unsubstituted anthranilic acid of formula 7 with N-chlorosuccinimide (NBS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS ), respectively, in solvents such as N, N-dimethylformamide (DMF), to give the corresponding substituted acid of formula 3.

Scheme 4

Obtaining isatinic anhydrides of formula 5 can be performed from isatins of formula 9, as shown in General form in scheme 5.

Scheme 5

Isatin of formula 9 can be obtained from derivatives of aniline of formula 8 according to methods described in the literature, such as F.D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and J.F.M. Da Silva et al., Journal of the Brazilian Society 2001, 12 (3), 273-324. Oxidation of isatin 9 with hydrogen peroxide usually gives good yields of the corresponding isatinic anhydride 5 (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223). isatinic anhydrides can also be prepared from anthranilic acids 3 through numerous known techniques, including reaction 3 with phosgene or phosgene equivalent.

Pyrazolecarboxylic acids of formula 4 can be obtained by the method presented in General form in scheme 6.

Scheme 6

Реакция пиразола 10 с 2,3-дигалогенпиридином формулы 11 дает хорошие выходы 1-пиридилпиразола 12 с хорошей специфичностью в отношении желаемой региохимии. Металлирование 12 диизопропиламидом лития (LDA) с последующим гашением соли лития диоксидом углерода дает пиразолкарбоновую кислоту формулы 4. Дополнительные детали методик для этого способа приведены в примерах 1, 3 и 5.

The reaction of pyrazole 10 with 2,3-dihalo-pyridine of formula 11 gives good yields of 1-pyridylpyrazole 12 with good specificity for the desired regiochemistry. Metallation of 12 with lithium diisopropylamide (LDA) followed by quenching of the lithium salt with carbon dioxide gives the pyrazolecarboxylic acid of formula 4. Additional details of the procedures for this method are given in examples 1, 3 and 5.

The starting pyrazoles 10, where R ³ is CH ₃ , Cl or Br, are known compounds. Pyrazole 10, in which R ³ is CH ₃ , is commercially available. Pyrazoles 10, in which R ³ is Cl or Br, can be obtained in accordance with methods described in the literature (H. Reimlinger and A. Van Overstraeten, Chem. Ber. 1966, 99 (10), 3350-7). A suitable alternative preparation method 10 in which R ³ is Cl or Br is depicted in Scheme 7.

Scheme 7

The metallation of sulfamoylpyrazole with 13 n-butyl lithium followed by direct halogenation of this anion with either hexachloroethane (if R ³ is Cl) or 1,2-dibromotetrachloroethane (if R ³ is Br) gives halogenated derivatives 14. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room the temperature proceeds without difficulty and with a good yield with the formation of pyrazoles 10, where R ³ represents Cl or Br, respectively. Additional experimental details for this method are described in examples 3 and 5.

As an alternative to the method illustrated in Scheme 6, pyrazolecarboxylic acids of formula 4, where R ³ is CF ₃ , can also be obtained by the method shown in general terms in Scheme 8.

Scheme 8

The reaction of a compound of formula 15, wherein R ⁶ is C ₁ -C ₄ alkyl, with a suitable base in a suitable organic solvent, gives a cyclized product of formula 16 after neutralization with an acid, such as acetic acid. A suitable base may be, for example, but not limited to, sodium hydride, sodium tert-butoxide, sodium dimsil (sodium dimethyl sulfoxide) (CH ₃ S (O) CH ₂ ^- Na ⁺ ), alkali metal carbonates or hydroxides (such as lithium, sodium or potassium), tetraalkyl fluorides or hydroxides (e.g. methyl, ethyl or butyl) of ammonium or 2-tert-butylamino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphonin. A suitable organic solvent may be, for example, but without limitation, acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide or N, N-dimethylformamide. The cyclization reaction is usually carried out in a temperature range from about 0 to 120 ° C. The effects of solvent, base, temperature and addition time are interdependent, and the choice of reaction conditions is important to minimize the formation of by-products. A preferred base is tetrabutylammonium fluoride.

Dehydration of a compound of formula 16 to give a compound of formula 17, followed by conversion of a functional group of a carboxylic acid ester to a functional group of a carboxylic acid, gives a compound of formula 4. Dehydration is performed by treating with a catalytic amount of a suitable acid. This catalytic acid may be, for example, but without limitation, sulfuric acid. The reaction is usually carried out using an organic solvent. As should be understood by a person skilled in the art, dehydration reactions can be carried out in a wide variety of solvents in a temperature range typically between about 0 and 200 ° C, more preferably between about 0 and 100 ° C. For dehydration in the method of Scheme 8, a solvent containing acetic acid and temperatures of about 65 ° C are preferred. Carboxylic acid ester compounds can be converted to carboxylic acid compounds in a variety of ways, including nucleophilic cleavage under anhydrous conditions or hydrolytic methods involving the use of either acids or bases (see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2 ^nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a review of the methods). For the process of Scheme 8, base-catalyzed hydrolytic processes are preferred. Suitable bases include alkali metal hydroxides (such as lithium, sodium or potassium). For example, ether can be dissolved in a mixture of water and an alcohol, such as ethanol. After treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to form the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, gives the carboxylic acid of formula 4. This carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

The compounds of formula 15 can be obtained by the method presented in General form in scheme 9.

Scheme 9

where R ³ is CF ₃ and R ⁶ is C ₁ -C ₄ alkyl.

Treatment of a hydrazine compound of formula 18 with a ketone of formula 19 in a solvent such as water, methanol or acetic acid gives a hydrazone of formula 20. It will be apparent to one skilled in the art that this reaction may require catalysis with the selected acid and may also require elevated temperatures depending on the molecular substitution of a hydrazone of formula 20. The reaction of a hydrazone of formula 20 with a compound of formula 21 in a suitable organic solvent, such as, for example, but not limited to, dichloromethane or tetrahydrofuran, the presence of an acid acceptor such as triethylamine gives a compound of formula 15. This reaction is usually carried out at a temperature between about 0 and 100 ° C. Additional experimental details for the method of Scheme 9 are illustrated in Example 7. Hydrazine compounds of formula 18 can be prepared by standard methods, such as contacting the corresponding halogen-containing compound of formula 11 with hydrazine.

As an alternative to the method illustrated in Scheme 6, pyrazolecarboxylic acids of formula 4, in which R ³ is Cl or Br, can also be obtained by the method presented in General form in scheme 10.

Pattern 10

where R ⁶ represents C ₁ -C ₄ alkyl.

The oxidation of a compound of formula 22, optionally in the presence of an acid, to give a compound of formula 17 followed by conversion of the carboxylic acid ester functional group to a carboxylic acid group, provides a compound of formula 4. The oxidizing agent may be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate potassium monopersulfate (e.g., Oxone®) or potassium permanganate. In order to obtain a complete conversion, at least one equivalent of an oxidizing agent relative to the compound of formula 22 should be used, preferably between about one and two equivalents. This oxidation is usually carried out in the presence of a solvent. The solvent may be an ether such as tetrahydrofuran, p-dioxane and the like, an organic ether such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic solvent such as N, N-dimethylformamide, acetonitrile, etc. P. Acids suitable for use in the oxidation step include inorganic acids such as sulfuric acid, phosphoric acid and the like, and organic acids such as acetic acid, benzoic acid and the like. The acid, when used, should be used in an amount greater than 0.1 equivalent with respect to the compound of formula 22. One to five equivalents of acid may be used to obtain complete conversion. Potassium persulfate is the preferred oxidizing agent, and the oxidation is preferably carried out in the presence of sulfuric acid. The reaction can be carried out by mixing a compound of formula 22 in a desired solvent and, if an acid is used, in acid. An oxidizing agent may then be added at a suitable rate. The reaction temperature usually ranges from a low temperature, such as about 0 ° C., to the boiling point of the solvent to obtain an acceptable reaction rate to complete the reaction within, preferably, less than 8 hours. The desired product, a compound of formula 17, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Methods suitable for converting an ester of formula 17 to a carboxylic acid of formula 4 are already described for Scheme 8. Additional experimental details for the method of Scheme 10 are illustrated in Examples 8 and 9.

Compounds of formula 22 can be prepared from the corresponding compounds of formula 23, as shown in Scheme 11.

Scheme 11

where R ⁶ represents C ₁ -C ₄ alkyl.

Treatment of a compound of formula 23 with a halogenating reagent, usually in the presence of a solvent, gives the corresponding halogen-containing compound of formula 22. Halogenating reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalo trialkylphosphoranes, dihalogenofenyl diphenyl phenyl. Phosphorus oxyhalides and phosphorus pentahalides are preferred. To obtain complete conversion, at least 0.33 equivalents of phosphorus oxyhalide relative to the compound of formula 23 should be used, preferably between about 0.33 and 1.2 equivalents. At least 0.20 equivalents of phosphorus pentahalide relative to the compound of formula 23 should be used to obtain complete conversion, preferably between about 0.20 and 1.0 equivalent. Compounds of formula 23 in which R ⁶ is C ₁ -C ₄ alkyl are preferred for this reaction. Typical solvents for this halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane and the like, aromatic solvents such as benzene, xylene, chlorobenzene and the like, ethers such as tetrahydrofuran, p-dioxane, diethyl ether and the like, and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. Optionally, an organic base such as triethylamine, pyridine, N, N-dimethylaniline or the like can be added. Optionally, a catalyst such as N, N-dimethylformamide may also be added. A process is preferred in which the solvent is acetonitrile and the base is absent. Typically, neither a base nor a catalyst is required when acetonitrile is used as a solvent. A preferred reaction is carried out by mixing the compound of formula 23 in acetonitrile. A halogenating reagent is then added at a convenient time, and then this mixture is kept at the desired temperature until the reaction is complete. The reaction temperature is usually between 20 ° C and the boiling point of acetonitrile, and the reaction time is usually less than 2 hours. Then the reaction mass is neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide, etc., or an organic base, such as sodium acetate. The desired product, a compound of formula 22, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

Alternatively, compounds of formula 22, where R ³ is Br or Cl, can be prepared by treating the corresponding compounds of formula 22, where R ³ is a different halogen (eg, Cl to obtain formula 22, where R ³ is Br) or a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate, hydrogen bromide or hydrogen chloride, respectively. Using this method, a halogen or sulfonate substituent R ³ in the starting compound of formula 22 is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. This reaction is carried out in a suitable solvent, such as dibromomethane, dichloromethane or acetonitrile. The reaction can be carried out at approximately atmospheric pressure or at a higher pressure than atmospheric pressure in an autoclave. When R ³ in the starting compound of formula 22 is a halogen, such as Cl, the reaction is preferably carried out in such a way that the hydrogen halide generated from this reaction is removed using a bubbler or other suitable means. The reaction can be conducted at a temperature between about 0 and 100 ° C, most preferably at about ambient temperature (e.g., at about 10-40 ° ^C), and more preferably between about 20 and 30 ° C. The addition of a Lewis acid (such as aluminum tribromide, to obtain a compound of formula 22, where R ³ is Br) as a catalyst can facilitate this reaction. The product of formula 22 is isolated by conventional methods known to those skilled in the art, including by extraction, distillation and crystallization. Additional details for this method are illustrated in Example 10.

The starting compounds of formula 22, where R ³ is Cl or Br, can be prepared by treating the corresponding compounds of formula 23 as already described. The starting compounds of formula 22, where R ³ is a sulfonate group, can also be prepared from the corresponding compounds of formula 23 by standard methods, such as treatment with a sulfonyl chloride (e.g. p-toluenesulfonyl chloride) and a base such as a tertiary amine (e.g. triethylamine) in a suitable solvent such as dichloromethane; further details for this method are illustrated in example 11.

As an alternative to the method illustrated in Scheme 6, pyrazolecarboxylic acids of formula 4, where R ³ is OCH ₂ CF ₃ , can also be obtained by the method presented in general form in Scheme 12.

Pattern 12

where R ⁶ is C ₁ -C ₄ alkyl and X is a leaving (cleavable) group.

In this method, instead of the halogenation shown in Scheme 11, the compound of formula 23 is oxidized to the compound of formula 17a. The reaction conditions for this oxidation have already been described to convert a compound of formula 22 to a compound of formula 17 in Scheme 10.

The compound of formula 17a is then alkylated to form a compound of formula 17b by contacting with an alkylating agent CH ₃ CH ₂ X (24) in the presence of a base. In an alkylating agent, 24 X denotes a leaving group of a nucleophilic reaction such as halogen (e.g. Br, I), OS (O) ₂ CH ₃ (methanesulfonate), OS (O) ₂ CF ₃ , OS (O) ₂ Ph-p- CH ₃ (p-toluenesulfonate) and the like; methanesulfonate works well. This reaction is carried out in the presence of at least one equivalent of base. Suitable bases include inorganic bases such as alkali metal carbonates and hydroxides (such as lithium, sodium or potassium), and organic bases such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene . The reaction is usually carried out in a solvent, which may contain alcohols, such as methanol and ethanol, halogenated alkanes, such as dichloromethane, aromatic solvents such as benzene, toluene and chlorobenzene, ethers such as tetrahydrofuran, and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as the base and acetonitrile as the solvent are preferred. The reaction is usually carried out at a temperature between approximately 0 and 150 ° C, most often between ambient temperature and 100 ° C. The product of formula 17b can be isolated by conventional methods, such as extraction. The ester of formula 17b is then converted to the carboxylic acid of formula 4 by the methods already described for converting the compound of formula 17 to the compound of formula 4 in Scheme 8. Additional details for the method of Scheme 12 are illustrated in Example 12.

Compounds of formula 23 can be prepared from compounds of formula 18, as shown in general form in Scheme 13.

Pattern 13

where R ⁶ denotes C ₁ -C ₄ alkyl.

In this method, a hydrazine compound of formula 18 is contacted with a compound of formula 25 (fumarate ether or maleate ether, or a mixture thereof can be used) in the presence of a base and a solvent. The base is usually a metal alkoxide salt such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide and the like. Greater than 0.5 equivalents of base should be used relative to the compound of formula 18, preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalent of a compound of formula 25 should be used, preferably between 1.0 and 1.3 equivalents. Polar protic and polar aprotic organic solvents such as alcohols, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like can be used. Preferred solvents are alcohols, such as methanol and ethanol. It is particularly preferred that the alcohol be the same alcohol with which the fumarate or maleate ester and alkoxide base are diluted. The reaction is usually carried out by mixing a compound of formula 18 and a base in a solvent. This mixture can be heated or cooled to the desired temperature, and the compound of formula 25 is added over a period of time. Typically, reaction temperatures are between 0 ° C. and the boiling point of the solvent used. The reaction can be carried out at a pressure higher than atmospheric pressure to increase the boiling point of the solvent. Generally preferred are temperatures between about 30 and 90 ° C. The addition time can be as fast as the heat transfer allows. Typical addition periods are between 1 minute and 2 hours. The optimum reaction temperature and the time of addition vary depending on the particular compounds of formula 18 and formula 25. After addition, the reaction mixture can be maintained for some time at the reaction temperature. Depending on the reaction temperature, the required holding time can be from 0 to 2 hours. Typical aging periods are 10-60 minutes. The reaction mass can then be acidified by the addition of an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid, and the like. Depending on the reaction conditions and isolation methods, the —CO ₂ R ⁶ group on the compound of formula 23 may be hydrolyzed to —CO ₂ H; for example, the presence of water in the reaction mixture may contribute to such hydrolysis. If a carboxylic acid (—CO ₂ H) is formed, it can be converted back to —CO ₂ R ⁶ , where R ⁶ is C ₁ -C ₄ alkyl using esterification methods well known in the art. The desired product, a compound of formula 23, can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.

It is understood that certain reagents and reaction conditions described above for the preparation of compounds of formula 1 may not be compatible with certain functional groups in the intermediates. In these cases, the inclusion of sequences of reactions of introduction / deprotection or interconversion of the functional group in this synthesis will help to obtain the desired products. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2 ^nd ed., John Wiley: New York, 1991). The specialist in this field should be clear that, in some cases, after the introduction of a specific reagent, as shown in any separate scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of formula 1. The specialist in this It will also be understood in the art that it may be necessary to perform the combination of steps illustrated in the above schemes in a different order than the order implied by the particular reaction sequence presented for the preparation of compounds of formula 1.

The authors of this invention believe that a specialist in this field, using the preceding description, will be able to use this invention to its greatest extent. Thus, the following examples should be considered only as illustrative, but not as limiting in any way this description. The steps in the following examples illustrate the procedure for each step in the overall synthetic conversion, and the starting material for each step may not necessarily be obtained in a particular preparative experiment, the procedure of which is described in other examples or steps. Percentages by weight are given (wt.%), With the exception of percentages for chromatographic mixtures of solvents or in special cases. Parts and percentages for chromatographic solvent mixtures are given by volume, unless otherwise indicated. ¹ H-NMR spectra are given in ppm. in the direction of the weak field from tetramethylsilane; “c” means a singlet, “d” means a doublet, “t” means a triplet, “k” means a quartet, “m” means a doublet, “dd” means a doublet of doublets, “dt” means a doublet of triplets and “shir. wide singlet.

EXAMPLE 1

Preparation of N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole- 5-carboxamide

Stage A: Obtaining 2-amino-3-methyl-5-chlorobenzoic acid

To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N, N-dimethylformamide (50 ml) was added N-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction the mixture was heated to 100 ° C for 30 minutes. Heating was stopped, the reaction mixture was cooled to room temperature and left overnight. The reaction mixture was then slowly poured into a mixture of ice water (250 ml) to precipitate a white solid. The solid was filtered and washed four times with water and then dissolved in ethyl acetate (900 ml). The ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure, and the remaining solid was washed with ether to give the desired intermediate as a white solid (13.9 g).

¹ H NMR (DMSO-d ₆ ) δ 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).

Stage B: Obtaining 3-chloro-2- [3- (trifluoromethyl) -1H-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 potassium carbonate (166 , 0 g, 1.2 mol) and then the reaction mixture was heated to 110-125 ° C for 48 hours. The reaction mixture was cooled to 100 ° C. and filtered through a Celite® diatom filter layer to remove solids. N, N-dimethylformamide and excess dichloropyridine were removed by distillation at atmospheric pressure. Distillation of the product under reduced pressure (mp. 139-141 ° C, 7 mm) gave the desired intermediate as a clear yellow oil (113.4 g).

¹ H NMR (CDCl ₃ ) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).

Stage C: Obtaining 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid

To a solution of 3-chloro-2- [3- (trifluoromethyl) -1H-pyrazol-1-yl] pyridine (i.e., the pyrazole product from step B) (105.0 g, 425 mmol) in dry tetrahydrofuran (700 ml ) at -75 ° C, a solution (-30 ° C) of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 ml) was added via cannula. The dark red solution was stirred for 15 minutes, after which carbon dioxide was bubbled through the solution at -63 ° C until the solution turned pale yellow and the heat evolution ceased. The reaction mixture was stirred for an additional 20 minutes and then quenched with water (20 ml). The solvent was removed under reduced pressure and the reaction mixture was partitioned between ether and 0.5N. sodium hydroxide solution. The aqueous extracts were washed with ether (3x), filtered through a Celite® diatom filter layer to remove any remaining solids, and then acidified to a pH of approximately 4, whereby an orange oil formed. The aqueous mixture was stirred vigorously and additional acid was added to lower the pH to 2.5-3. Orange oil solidified in a granular solid, which was filtered, washed successively with water and 1 N. hydrochloric acid and dried in vacuo at 50 ° C to give the title product as an off-white solid (130 g). (The product from another experiment was melted at 175-176 ° C by the same procedure).

¹ 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 6-chloro-2- [1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -8-methyl-4H-3,1-benzoxazine- 4-she

To a solution of methanesulfonyl chloride (2.2 ml, 28.3 mmol) in acetonitrile (75 ml) was added dropwise a mixture of 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (i.e., stage C carboxylic acid product) (7.5 g, 27.0 mmol) and triethylamine (3.75 ml, 27.0 mmol) in acetonitrile (75 ml) at 0-5 ° C. Then the reaction temperature was maintained at 0 ° C during the sequential addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-chlorobenzoic acid (i.e., the product from step A) (5.1 g, 27.0 mmol) was added and stirring was continued for an additional 5 minutes. Then, a solution of triethylamine (7.5 ml, 54.0 mmol) in acetonitrile (15 ml) was added dropwise and the reaction mixture was stirred for 45 minutes, followed by the addition of methanesulfonyl chloride (2.2 ml, 28.3 mmol). Then the reaction mixture was warmed to room temperature and stirred overnight. Then, about 75 ml of water was added to the precipitate of 5.8 g of a yellow solid. An additional amount of 1 g of product was isolated by extraction from the filtrate to give a total of 6.8 g of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ) δ 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m, 2H), 7.99 (m, 2H), 8.58 (d, 1H).

Step E: Preparation of N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H pyrazole-5-carboxyamide

To a solution of 6-chloro-2- [1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -8-methyl-4H-3,1-benzoxazin-4- it (i.e., the product of benzoxazinone stage D) (5.0 g, 11.3 mmol) in tetrahydrofuran (35 ml) was added dropwise isopropylamine (2.9 ml, 34.0 mmol) in tetrahydrofuran (10 ml) at room temperature. Then the reaction mixture was heated to dissolve all solids and was stirred for an additional five minutes, at which point thin-layer chromatography confirmed the completion of the reaction. The solvent tetrahydrofuran was evaporated under reduced pressure and the remaining solid was purified by silica gel chromatography, followed by trituration with an ether / hexane mixture, to give the title compound, a compound of this invention, as a solid (4.6 g), melting at 195-196 ° FROM.

¹ H NMR (CDCl ₃ ) δ 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95 (br.s.d, 1H), 7.1- 7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H), 8.50 (d, 1H), 10.24 (br .s, 1H).

EXAMPLE 2

Preparation of N- [4-chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide

To a solution of 6-chloro-2- [1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] -8-methyl-4H-3,1-benzoxazin-4- she (i.e., the product of benzoxazinone of Example 1, step D) (4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 ml) was added methylamine (2.0 M solution in THF, 15 ml, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the remaining solid was purified by silica gel chromatography to give 4.09 g of the title compound, a compound of the invention, as a white solid, melting at 185-186 ° C.

¹ H NMR (DMSO-d ₆ ) δ 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46 (dd, 1H), 7.65 ( dd, 1H), 7.74 (s, 1H), 8.21 (d, 1H), 8.35 (br s, 1H), 8.74 (d, 1H), 10.39 (s, 1H )

EXAMPLE 3

Preparation of 3-chloro-N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5- carboxamide

Stage A: Obtaining 3-chloro-N, N-dimethyl-1H-pyrazole-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. After complete addition, the reaction mixture was maintained at -78 ° C for an additional 45 minutes, after which a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 ml) was added dropwise. The reaction mixture was maintained at −78 ° C. for one hour, heated to −20 ° C., and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4x500 ml); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by silica gel chromatography using methylene chloride as an eluent to give the title compound as a yellow oil (160 g).

¹ H NMR (CDCl ₃ ) δ 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, 1H).

Stage B: Obtaining 3-chloropyrazole

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

¹ H NMR (CDCl ₃ ) δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H).

Stage C: Obtaining 3-chloro-2- (3-chloro-1H-pyrazol-1-yl) pyridine

To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of step B) (64.44 g, 0.629 mol) in N, N-dimethylformamide (400 ml) was added potassium (147.78 g, 1.06 mol) and then the reaction mixture was heated to 100 ° C for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were filtered off and washed with water. The solid filtered precipitate was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate / hexane as the eluent to afford the title product as a white solid (39.75 g).

¹ H NMR (CDCl ₃ ) 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-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid

To a solution of 3-chloro-2- (3-chloro-1H-pyrazol-1-yl) pyridine (i.e. the product of the pyrazole of 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 the amber-colored solution for 14 minutes, after which the solution turned pale brownish yellow. The reaction mixture was alkalinized with 1 N. sodium hydroxide solution and was extracted with ether (2 x 500 ml). The aqueous extracts were acidified with 6 N hydrochloric acid and was extracted with ethyl acetate (3 x 500 ml). The ethyl acetate extracts were dried over magnesium sulfate and concentrated to give the title compound as an off-white solid (42.96 g). (The product from another experiment was melted at 198-199 ° C by the same procedure).

¹ H NMR (DMSO-d ₆ ) δ 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51 (d, 1H).

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

To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 ml) was added dropwise a mixture of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (t ie the product of the carboxylic acid of stage D) (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 ml) at -5 ° C. Then the reaction mixture was stirred for 30 minutes at 0 ° C. Then 2-amino-3-methyl-5-chlorobenzoic acid (i.e., the product from Example 1, Step A) (10.79 g, 58.16 mmol) was added and stirring was continued for an additional 10 minutes. Then, a solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was added dropwise while maintaining the temperature below 10 ° C. The reaction mixture was stirred for 60 minutes at 0 ° C and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. Then the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated and the crude product was chromatographed on silica gel using methylene chloride as the eluent to give the title compound as a yellow solid (9.1 g).

¹ H NMR (CDCl ₃ ) δ 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98 (d, 2H), 8.56 (d, 1H).

Stage F: Preparation of 3-chloro-N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole -5-carboxamide

To a solution of 6-chloro-2- [3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -8-methyl-4H-3,1-benzoxazin-4-one ( for example, benzoxazinone product of step E) (6.21 g, 15.21 mmol) in tetrahydrofuran (100 ml) was added isopropylamine (4.23 g, 72.74 mmol) and then the reaction mixture was heated to 60 ° C, stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the remaining solid was purified by silica gel chromatography to obtain the title compound, a compound of this invention, as a white solid (5.05 g), melting at 173-175 ° C.

¹ H NMR (CDCl ₃ ) δ 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97 (d, 1H), 7.01 (m, 1H) 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83 (d, 1H), 8.43 (d, 1H), 10.15 (br.s, 1H).

EXAMPLE 4

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

To a solution of 6-chloro-2- [3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -8-methyl-4H-3,1-benzoxazin-4-one ( i.e., the benzoxazinone product of Example 3, step E) (6.32 g, 15.47 mmol) in tetrahydrofuran (50 ml) was added methylamine (2.0 M solution in THF, 38 ml, 77.38 mmol) and the reaction the mixture was heated to 60 ° C, stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the remaining solid was purified by silica gel chromatography to obtain the title compound, a compound of this invention, as a white solid (4.57 g), melting at 225-226 ° C.

¹ H NMR (CDCl ₃ ) δ 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, 1H), 7.06 (s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m, 1H), 7.83 (d, 1H), 8.42 (d, 1H), 10.08 (br s, 1H).

EXAMPLE 5

Preparation of 3-bromo-N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5- carboxamide

Stage A: Obtaining 3-bromo-N, N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of 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) at keeping the temperature below -60 ° C. A thick solid formed during the addition. After complete addition, the reaction mixture was kept for an additional 15 minutes, after which a solution of 1,2-dibromotetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150 ml) was added dropwise while maintaining the temperature below -70 ° C. The reaction mixture turned orange and became transparent; stirring was continued for an additional 15 minutes. A -78 ° C bath was removed and the reaction was quenched with water (600 ml). The reaction mixture was extracted with methylene chloride (4x) and the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by silica gel chromatography using methylene chloride-hexane (50:50) as an eluent to give the title compound as a clear colorless oil (57.04 g).

¹ H NMR (CDCl ₃ ) δ 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

Stage B: Obtaining 3-bromopyrazole

To trifluoroacetic acid (70 ml) 3-bromo-N, N-dimethyl-1H-pyrazole-1-sulfonamide (i.e., the product of bromopyrazole of step A) (57.04 g) was slowly added. 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 the hexane was evaporated to give the crude product as an oil. The crude product was further purified by silica gel chromatography using ethyl acetate / dichloromethane (10:90) as an eluent to give an oil. This oil was placed in dichloromethane, neutralized with an aqueous solution of sodium bicarbonate, extracted with methylene chloride (3x), dried over magnesium sulfate and concentrated to obtain the title compound as a white solid (25.9 g), mp 61-64 ° C.

¹ H NMR (CDCl ₃ ) δ 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H).

Stage C: Obtaining 2- (3-bromo-1H-pyrazol-1-yl) -3-chloropyridine

To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e., the product of step B) (25.4 g, 176 mmol) in dry N, N-dimethylformamide (88 ml) was added potassium carbonate (48.6 g, 352 mmol) and the reaction mixture was heated to 125 ° C for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 ml). A precipitate formed. The precipitated solids were stirred for 1.5 hours, filtered and washed with water (2 x 100 ml). A solid filter cake was placed in methylene chloride and washed successively with water, 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and saline. Then, the organic extracts were dried over magnesium sulfate and concentrated to obtain 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 hour. The solids were filtered, washed with hexane and dried to give the title compound as an off-white powder (30.4 g), which had a purity> 94% according to NMR. This material was used without further purification in step D.

¹ 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).

Stage D: Obtaining 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid

To a solution of 2- (3-bromo-1H-pyrazol-1-yl) -3-chloropyridine (i.e., the pyrazole product of 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 such a rate that the temperature was maintained below -71 ° C. The reaction mixture was stirred for 15 minutes at -76 ° C and then carbon dioxide was bubbled through it for 10 minutes, which caused heating to -57 ° C. The reaction mixture was heated to −20 ° C. and the reaction was quenched with water. The reaction mixture was concentrated and then placed in water (1 L) and ether (500 ml), and then an aqueous solution of sodium hydroxide (1 N, 20 ml) was added. The aqueous extracts were washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered, washed with water and dried to obtain the title compound as a tan solid (27.7 g). (A product from another experiment, according to the same procedure, melted at 200-201 ° C).

¹ H NMR (DMSO-d ₆ ) δ 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d, 1H).

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

A procedure similar to that of Example 1, step E, was used to convert 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (i.e., the pyrazolecarboxylic acid product of Example 5, step D ) (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of example 1, step A) (0.92 g, 4.96 mmol) to the specified in the title compound as a solid (1.21 g).

¹ H NMR (CDCl ₃ ) δ 2.01, (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d, 1H), 8.04 (m , 1H), 8.25 (s, 1H), 8.26 (d, 1H).

Step F: Preparation of 3-Bromo-N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole -5-carboxamide

To a solution of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H-3,1-benzoxazin-4-one ( i.e., the product of benzoxazinone stage E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 ml, 1.42 mmol) and the reaction mixture was heated to 60 ° C for 90 minutes and then cooled to room temperature temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the remaining solid was triturated with ether, filtered and dried to give the title compound, the compound of the present invention, as a solid (150 mg), mp. 159-161 ° C.

¹ H NMR (CDCl ₃ ) δ 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99 (m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41 (d, 1H).

EXAMPLE 6

Preparation of 3-bromo-N- [4-chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide

To a solution of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H-3,1-benzoxazin-4-one ( i.e., the product of benzoxazinone of Example 5, step E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 0.514 ml, 1.02 mmol) and the reaction mixture was heated to 60 ° C for 90 minutes and then cooled to room temperature. The solvent tetrahydrofuran was evaporated under reduced pressure and the remaining substance was triturated with ether, filtered and dried to obtain the title compound, the compound of the present invention, as a solid (40 mg), mp 162-164 ° C.

¹ H NMR (CDCl ₃ ) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).

The following Example 7 illustrates an alternative preparation of 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid, which can be used to produce, for example, N- [4-chloro-2 -methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide and N- [4- chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide using the additional steps illustrated in the examples 1 and 2.

EXAMPLE 7

Preparation of 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid

Step A: Preparation of (2,2,2-trifluoro-1-methylethylidene) hydrazone 3-chloro-2 (1H) -pyridinone

1,1,1-trifluoroacetone (7.80 g, 69.6 mmol) was added to hydrazone 3-chloro-2 (1H) pyridinone (alternatively called (3-chloropyridin-2-yl) hydrazine) (10 g, 69, 7 mmol) at 20-25 ° C. After complete addition, the mixture was stirred for approximately 10 minutes. The solvent was removed under reduced pressure and the mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was dried and evaporated. Silica gel chromatography (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), mp 64-64.5 ° C (after crystallization from ethyl acetate / hexanes).

IR (nujol) ν 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196, 1158, 1100, 1032, 992, 800 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ 2.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-8.32 (m, 2H).

MS m / z 237 (M ⁺ ).

Step B: Preparation of (3-chloro-2-pyridinyl) (2,2,2-trifluoro-1-methylethylidene) ethylhydroethanedioate hydrazide (alternatively called (3-chloro-2-pyridinyl) (2,2,2-trifluoro-1 methyl ethylidene) hydrazine ethylhydroethanedioate)

Triethylamine (20.81 g, 0.206 mol) was added to the (2,2,2-trifluoro-1-methylethylidene) hydrazone of 3-chloro-2 (1H) -pyridinone (i.e., the product of step A) (32.63 g , 0.137 mol) in dichloromethane (68 ml) at 0 ° C. Ethyl chloroxoacetate (18.75 g, 0.137 mol) in dichloromethane (69 ml) was added dropwise to this mixture at 0 ° C. The mixture was allowed to warm to 25 ° C for approximately 2 hours. The mixture was cooled to 0 ° C. and an additional portion of ethyl chloroxoacetate (3.75 g, 27.47 mmol) in dichloromethane (14 ml) was added dropwise. After approximately another hour, the mixture was diluted with dichloromethane (approximately 450 ml) and the mixture was washed with water (2 x 150 ml). The organic layer was dried and evaporated. Silica gel chromatography (eluted with 1: 1 ethyl acetate-hexanes) gave the product as a solid (42.06 g, 90% yield), mp. 73.0-73.5 ° C (after crystallization from ethyl acetate / hexanes).

IR (nujol) ν 1751, 1720, 1664, 1572, 1417, 1361, 1330, 1202, 1214, 1184, 1137, 1110, 1004, 1043, 1013, 942, 807, 836 cm ^-1 .

¹ H NMR (DMSO-d ₆ 115 ° C) 1.19 (t, 3H), 1.72 (br s, 3H), 4.25 (q, 2H), 7.65 (dd, J = 8 , 3, 4.7 Hz, 1H), 8.20 (dd, J = 7.6, 1.5 Hz, 1H), 8.55 (d, J = 3.6 Hz, 1H).

MS m / z 337 (M ⁺ ).

Stage C: Obtaining ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-5-hydroxy-3- (trifluoromethyl) -1H-pyrazole-5-carboxylate

(3-chloro-2-pyridinyl) (2,2,2-trifluoro-1-methylethylidene) ethylhydroethanedioate hydrazide (i.e., product of step B) (5 g, 14.8 mmol) in dimethyl sulfoxide (25 ml) was added to tetrabutylammonium fluoride hydrate (10 g) in dimethyl sulfoxide (25 ml) for 8 hours. After complete addition, the mixture was poured into acetic acid (3.25 g) in water (25 ml). Then, after stirring at 25 ° C. overnight, the mixture was extracted with toluene (4 x 25 ml) and the combined extracts in toluene were washed with water (50 ml), dried and evaporated to give a solid. Silica gel chromatography (eluted with 1: 2 ethyl acetate-hexanes) gave the product as a solid (2.91 g, 50% yield, containing approximately 5% (2,2,2-trifluoro-1-methylethylidene) hydrazone 3- chloro-2 (1H) -pyridinone), mp. 78-78.5 ° C (after recrystallization from ethyl acetate / hexanes).

IR (nujol) ν 3403, 1726, 1618, 1582, 1407, 1320, 1293, 1260, 1217, 1187, 1150, 1122, 1100, 1067, 1013, 873, 829 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ 1.19 (s, 3H), 3.20 (1/2 ABZ pattern, J = 18 Hz, 1H), 3.42 (1/2 ABZ pattern, J = 18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, J = 7.9, 4.9 Hz, 1H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H ), 8.03 (dd, 7 = 4.7, 1.5 Hz, 1H).

MS m / z 319 (M ⁺ ).

Stage D: Obtaining ethyl 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylate

Sulfuric acid (concentrated, 2 drops) was added to ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-5-hydroxy-3- (trifluoromethyl) -1H-pyrazole-5-carboxylate (i.e. The product of step C) (1 g, 2.96 mmol) in acetic acid (10 ml) and the mixture was heated to 65 ° C for approximately 1 hour. The mixture was allowed to cool to 25 ° C and most of the acetic acid was removed under reduced pressure. The mixture was partitioned between saturated aqueous sodium carbonate (100 ml) and ethyl acetate (100 ml). The aqueous layer was further extracted with ethyl acetate (100 ml). The combined organic extracts were dried and evaporated to give the product as an oil (0.66 g, 77% yield).

IR (neat) ν 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277, 1236, 1135, 1082, 1031, 973, 842, 802 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ 1.23 (t, 3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd, J = 8.1, 4.7 Hz, 1H), 7.94 (dd, J = 6.6, 2 Hz, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H).

MS m / z 319 (M ⁺ ).

Step E: Preparation of 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid

Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 ml) was added to ethyl 1- (3-chloro-2-pyridinyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylate (i.e., the product of step D) (0.66 g, 2.07 mmol) in ethanol (3 ml). After approximately 30 minutes, the solvent was removed under reduced pressure, and this mixture was dissolved in water (40 ml). The solution was washed with ethyl acetate (20 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). The combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), mp. 178-179 ° C (after crystallization from hexanes-ethyl acetate).

IR (nujol) ν 1711, 1586, 1565, 1550, 1440, 1425, 1292, 1247, 1219, 1170, 1135, 1087, 1059, 1031, 972, 843, 816 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H).

The following example 8 illustrates an alternative preparation of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid, which can be used to obtain, for example, 3-chloro-N- [4-chlorine -2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide and 3-chloro-N- [4- chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide, using the additional steps illustrated in examples 3 and 4.

EXAMPLE 8

Preparation of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid

Stage A: Obtaining ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (alternatively called ethyl 1- (3-chloro-2-pyridinyl) -3-pyrazolidinone-5-carboxylate)

A two-necked four-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel, a condenser for reflux and a nitrogen inlet was charged with absolute ethanol (250 ml) and ethanol solution of sodium ethoxide (21%, 190 ml, 0.504 mol). This mixture was heated under reflux for reflux at approximately 83 ° C. Then it was treated with 3-chloro-2 (1H) -pyridinone hydrazone (68.0 g, 0.474 mol). The mixture was reheated under reflux for reflux (boiling under reflux) for 5 minutes. Then the yellow suspension was treated dropwise with diethyl maleate (88.0 ml, 0.544 mol) for 5 minutes. The rate of reflux increased markedly during this addition. At the end of the addition, all of the starting material was dissolved. The resulting orange-red solution was maintained at reflux (boiling under reflux) for 10 minutes. After cooling to 65 ° C., the reaction mixture was treated with glacial acetic acid (50.0 ml, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 ml), which caused the dissolution of the precipitate. The orange solution was cooled in an ice bath. The product began to precipitate at 28 ° C. The suspension was kept at approximately 2 ° C for 2 hours. The product was isolated by filtration, washed with aqueous ethanol (40%, 3 x 50 ml) and then dried in air on the filter for approximately 1 hour. The title compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed according to ¹ H-NMR.

¹ H NMR (DMSO-d ₆ ) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q, 2H), 4.84 ( d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18 (s, 1H).

Stage B: Obtaining ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively called ethyl 1- (3-chloro-2-pyridinyl) - 3-chloro-3-pyrazoline-5-carboxylate)

A 2-liter four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet was charged with acetonitrile (1000 ml), ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate ( i.e., the product of step A) (91.0 g, 0.377 mol) and phosphorus oxychloride (35.0 ml, 0.375 mol). After adding phosphorus oxychloride, the mixture self-heated from 22 to 25 ° C and a precipitate formed. The light yellow suspension was heated under reflux for reflux at 83 ° C for 35 minutes, after which the precipitate was dissolved. The resulting orange solution was kept under reflux for 45 minutes, after which it became black and gray. The condenser used for reflux was replaced with a distillation head and 650 ml of solvent was removed by distillation. A second four-necked 2 L flask equipped with a mechanical stirrer was charged with sodium bicarbonate (130 g, 1.55 mol) and water (400 ml). The concentrated reaction mixture was added to the sodium bicarbonate suspension over 15 minutes. The resulting two-phase mixture was stirred vigorously for 20 minutes, after which the evolution of gas ceased. This mixture was diluted with dichloromethane (250 ml) and then stirred for 50 minutes. The mixture was treated with a filter substance from Celite® 545 diatomaceous earth (11 g) and then filtered to remove a black, resinous substance that suppressed phase separation. Since this filtrate was slowly separated into noticeable different phases, it was diluted with dichloromethane (200 ml) and water (200 ml) and treated with additional Celite® 545 (15 g). The mixture was filtered and the filtrate was transferred to a separatory funnel. The heavier dark green organic layer was separated. The layered phase (uneven layer) (50 ml) was re-filtered and then added to the organic layer. This organic solution (800 ml) was treated with magnesium sulfate (30 g) and silica gel (12 g), and the suspension was stirred with a magnetic stirrer for 30 minutes. The suspension was filtered to remove magnesium sulfate and silica gel, which became dark blue-green. The filter cake was washed with dichloromethane (100 ml). The filtrate was concentrated on a rotary evaporator. The product consisted of dark amber oil (92.0 g, 93% yield). The only detectable impurities observed using ¹ H-NMR were 1% starting material and 0.7% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H), 4.11 (q, 2H), 5.25 ( dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Stage C: Obtaining ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (alternatively called ethyl 1- (3-chloro-2-pyridinyl) -3-chloropyrazole-5- carboxylate)

Ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5 was charged with a 4-neck 2-liter flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet -carboxylate (i.e., product of step B) (with a purity of 95%, 99.5 g, 0.328 mol), acetonitrile (1000 ml) and sulfuric acid (98%, 35.0 ml, 0.661 mol). This mixture was self-heated from 22 to 35 ° C with the addition of sulfuric acid. After stirring for several minutes, this mixture was treated with potassium persulfate (140 g, 0.518 mol). The suspension was heated under reflux for reflux at 84 ° C for 4.5 hours. The resulting orange suspension, while it was still warm (50-65 ° C), was filtered to remove a fine white precipitate. The filter cake was washed with acetonitrile (50 ml). The filtrate was concentrated to approximately 500 ml on a rotary evaporator. A second 2 L four-necked flask equipped with a mechanical stirrer was charged with water (1250 ml). The concentrated reaction mass was added to water over about 5 minutes. The product was isolated by filtration, washed with aqueous acetonitrile (25%, 3 x 125 ml), washed once with water (100 ml) and then dried overnight in vacuo at room temperature. The product consisted of crystalline orange powder (79.3 g, 82% yield). The only measurable impurities observed using ¹ H-NMR were 1.9% water and 0.6% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71 (dd, 1H), 8.38 ( d, 1H); 8.59 (d, 1H).

Stage D: Preparation of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (alternatively called 1- (3-chloro-2-pyridinyl) -3-chloropyrazole-5-carboxylic acid)

A four-necked 1 L flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (i.e., product of stage C ) (with a purity of 97.5%, 79.3 g, 0.270 mol), methanol (260 ml), water (140 ml) and granules of sodium hydroxide (13.0 g, 0.325 mol). After adding sodium hydroxide, this mixture self-heated from 22 to 35 ° C and the starting material began to dissolve. After stirring for 45 minutes at ambient conditions, all of the starting material was dissolved. The resulting dark orange-brown solution was concentrated to approximately 250 ml on a rotary evaporator. Then, the concentrated reaction mixture was diluted with water (400 ml). The aqueous solution was extracted with ether (200 ml). Then, the aqueous layer was transferred to a 1 L Erlenmeyer flask with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol) for approximately 10 minutes. The product was isolated by filtration, resuspended in water (2 x 200 ml), washed on the surface once with water (100 ml) and then air-dried on the filter for 1.5 hours. The product consisted of a crystalline light brown powder (58.1 g, 83% yield). The only detectable impurity observed using ¹ H-NMR was 0.7% ether.

¹ H NMR (DMSO-d ₆ ) δ 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56 (d, 1H), 13.95 ( broad s, 1H).

The following Example 9 illustrates an alternative preparation of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid, which can be used to produce, for example, 3-bromo-N- [4-chloro -2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide and 3-bromo-N- [4- chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide, using the additional steps illustrated in examples 5 and 6.

EXAMPLE 9

Preparation of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid

Stage A1: Obtaining ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively called ethyl 1- (3-chloro-2-pyridinyl) - 3-bromo-2-pyrazoline-5-carboxylate) using phosphorus oxybromide

A four-necked 1-liter flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet was charged with acetonitrile (400 ml), ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (t ie, the product of example 8, step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange suspension was heated under reflux for reflux at 83 ° C for 20 minutes. The resulting cloudy orange solution was maintained at reflux for 75 minutes, at which time a dense tan crystalline precipitate formed. The reflux condenser was replaced with a distillation head and a cloudy, colorless distillate (300 ml) was collected. A second 1 L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 ml). The concentrated reaction mixture was added to the suspension in sodium bicarbonate over 5 minutes. The resulting two-phase mixture was vigorously stirred for 5 minutes, after which the evolution of gas ceased. The mixture was diluted with dichloromethane (200 ml) and then stirred for 75 minutes. The mixture was treated with a filter substance from Celite® 545 diatomaceous earth (5 g) and then filtered to remove the brown gum. The filtrate was transferred to a separatory funnel. The brown organic layer (400 ml) was separated and then treated with magnesium sulfate (15 g) and Darco® G60 activated carbon (2.0 g). The resulting suspension was stirred with a magnetic stirrer for 15 minutes and then filtered to remove magnesium sulfate and coal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. Dark blue-green silica gel was removed by filtration and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only detectable ¹ H NMR impurity was 0.3% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 ( dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Stage A2: Obtaining ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate using phosphorus pentabromide

A four-necked 1 L flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet was charged with acetonitrile (330 ml), ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (t ie, the product of example 8, step A) (52.0 g, 0.193 mol) and phosphorus pentabromide (41.0 g, 0.0952 mol). The orange suspension was heated under reflux for reflux at 84 ° C for 20 minutes. The resulting brick-red mixture was maintained at reflux for 90 minutes, at which time a dense tan crystalline precipitate formed. The condenser for reflux was replaced with a distillation head and a cloudy, colorless distillate (220 ml) was collected. A second 1 L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (40 g, 0.48 mol) and water (200 ml). The concentrated reaction mixture was added to the suspension in sodium bicarbonate over 5 minutes. The resulting two-phase mixture was vigorously stirred for 10 minutes, after which the evolution of gas ceased. The mixture was diluted with dichloromethane (200 ml) and then stirred for 10 minutes. The mixture was treated with a filter substance from Celite® 545 diatomaceous earth (5 g) and then filtered to remove the purple gum. The filter cake was washed with dichloromethane (50 ml). The filtrate was transferred to a separatory funnel. The purple-red organic layer (400 ml) was separated and then treated with magnesium sulfate (15 g) and Darco® G60 activated carbon (2.2 g). This suspension was stirred with a magnetic stirrer for 40 minutes. The suspension was filtered to remove magnesium sulfate and coal. The filtrate was concentrated on a rotary evaporator. The product consisted of dark amber oil (61.2 g, 95% yield), which crystallized upon standing. The only detectable ¹ H NMR impurity was 0.7% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 ( dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Stage B: Obtaining ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (alternatively called ethyl 1- (3-chloro-2-pyridinyl) -3-bromopyrazole-5- carboxylate)

Ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5 was charged with a four-necked 1-liter flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet -carboxylate (i.e., product of steps A1 and A2) (40.2 g, 0.121 mol), acetonitrile (300 ml) and sulfuric acid (98%, 13.0 ml, 0.245 mol). The mixture was self-heated from 22 to 36 ° C after addition of sulfuric acid. After stirring for several minutes, the mixture was treated with potassium persulfate (48.0 g, 0.178 mol). The suspension was heated under reflux for reflux at 84 ° C for 2 hours. The resulting orange suspension, while it was still warm (50-65 ° C), was filtered to remove a white precipitate. The filter cake was washed with acetonitrile (2 x 50 ml). The filtrate was concentrated to approximately 200 ml on a rotary evaporator. A second 1-neck four-necked flask equipped with a mechanical stirrer was charged with water (400 ml). The concentrated reaction mass was added to water over about 5 minutes. The product was isolated by filtration, washed successively with aqueous acetonitrile (20%, 100 ml) and water (75 ml) and then dried in air on the filter for 1 hour. The product consisted of crystalline orange powder (36.7 g, 90% yield). The only detectable impurities observed using ¹ H-NMR were 1% unknown substance and 0.5% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72 (dd, 1H), 8.39 ( d, 1H); 8.59 (d, 1H).

Stage C: Obtaining 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (alternatively called 1- (3-chloro-2-pyridinyl) -3-bromopyrazole-5-carboxylic acid acid)

A 300 ml four-necked flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was charged with ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (i.e., product of step B) ) (with a purity of 98.5%, 25.0 g, 0.0756 mol), methanol (75 ml), water (50 ml) and granules of sodium hydroxide (3.30 g, 0.0825 mol). After adding sodium hydroxide, this mixture self-heated from 29 to 34 ° C and the starting material began to dissolve. After stirring for 90 minutes at ambient conditions, all of the starting material was dissolved. The resulting dark orange solution was concentrated to approximately 90 ml on a rotary evaporator. Then, the concentrated reaction mixture was diluted with water (160 ml). The aqueous solution was extracted with ether (100 ml). The aqueous layer was then transferred to a 500 ml Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839 mol) for approximately 10 minutes. The product was isolated by filtration, resuspended in water (2 x 200 ml), washed on the surface once with water (25 ml) and then dried in air on the filter for 2 hours. The product consisted of a crystalline tan powder (20.9 g, 91% yield). The only detectable impurities observed using ¹ H-NMR were 0.8% unknown substance and 0.7% ether.

¹ H NMR (DMSO-d ₆ ) δ 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7, 68 (dd, 1H).

The following example 10 illustrates an alternative preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate, which can be used to obtain, for example, ethyl 3-bromo -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (i.e., the product of example 9, step B).

EXAMPLE 10

Obtaining ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate from ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4 , 5-dihydro-1H-pyrazole-5-carboxylate using hydrogen bromide

Hydrogen bromide was passed through a solution of ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (i.e., the product of example 8, stage B) (8, 45 g, 29.3 mmol) in dibromomethane (85 ml). After 90 minutes, the gas flow was stopped and the reaction mixture was washed with an aqueous solution of sodium bicarbonate (100 ml). The organic phase was dried and evaporated under reduced pressure to obtain the title product as an oil (9.7 g, 99% yield), which crystallized upon standing.

¹ H NMR (CDCl ₃ ) δ 1.19 (t, 3H), 3.24 (1/2 AB in ABX pattern, J = 9.3, 17.3 Hz, 1H), 3.44 (1/2 AB in ABX pattern, J = 11.7, 17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (X ABX, 1H, J = 9.3, 11.9 Hz), 6 85 (dd, J = 4.7, 7.7 Hz, 1H), 7.65 (dd, J = 1.6, 7.8 Hz, 1H), 8.07 (dd, J = 1.6 4.8 Hz, 1H).

The following Example 11 illustrates the preparation of ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-3 - [[(4-methylphenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate, which can be used to obtain ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate using procedures similar to those described in example 10.

EXAMPLE 11

Preparation of ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-3 - [[(4-methylphenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate

Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (i.e., the product of example 8, step A) ( 10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 ml) at 0 ° C. Additional portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. Then the reaction mixture was allowed to warm to room temperature and was stirred overnight. Then this mixture was diluted with dichloromethane (200 ml) and washed with water (3 x 70 ml). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. The product was recrystallized from ethyl acetate / hexanes, melting at 99.5-100 ° C.

IR (nujol) ν: 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 868, 845 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (1/2 AB in ABX pattern, J = 17.3, 9 Hz, 1H), 3.33 (1/2 AB in ABX pattern, J = 17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (X ABX, J = 9, 11.8 Hz , 1H), 6.79 (dd, J = 4.6, 7.7 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 1, 6, 7.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.01 (dd, J = 1.4, 4.6 Hz, 1H).

EXAMPLE 12

Preparation of N- [4-chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazole -5-carboxamide

Stage A: Obtaining ethyl 1- (3-chloro-2-pyridinyl) -2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate

To a suspension of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidine carboxylate (i.e. the product of example 8, step A) (27 g, 100 mmol), stirred in dry acetonitrile (200 ml) sulfuric acid (20 g, 200 ml) was added in one portion. The reaction mixture was liquefied to form a pale green, almost clear solution before thickening again to form a pale yellow suspension. Potassium persulfate (33 g, 120 mmol) was added in one portion and then the reaction mixture was heated under reflux to calmly reflux for 3.5 hours. After cooling with an ice bath, a white solid precipitate was removed by filtration and discarded. The filtrate was diluted with water (400 ml) and then extracted three times with ethyl ether (700 ml total). Concentration of the combined ether extracts to a reduced volume (75 ml) caused the precipitation of an off-white solid (3.75 g), which was collected by filtration. The ethereal mother liquor was further concentrated to give a second batch of off-white precipitate (4.2 g), which was also collected by filtration. A solid off-white solid also precipitated from the aqueous phase; this solid (4.5 g) was collected by filtration to give a total of 12.45 g of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t, 1H), 8.19 ( d, 1H), 8.5 (d, 1H), 10.6 (s, 1H).

Stage B: Obtaining ethyl 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazole-5-carboxylate

To a suspension of ethyl 1- (3-chloro-2-pyridinyl) -2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e., the product of stage A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 ml) at -5 ° C, potassium carbonate (0.85 g, 6.15 mmol) was added. The suspension was stirred for 15 minutes at 20 ° C. The stirred suspension was then cooled to 5 ^° C and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then refluxed for reflux, after which thin-layer chromatography showed completion of the reaction. Water (25 ml) was added to the reaction mixture, and then the mixture was extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated to give the title product compound (1.05 g) as a pale yellow oil.

¹ H NMR (CDCl ₃ ) δ 1.21 (t, 3H), 4.20 (q, 2H), 4.63 (q, 2H), 6.53 (s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H).

Stage C: Obtaining 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid

To a stirred solution of ethyl 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazole-5-carboxylate (i.e., the product of step B) (0.92 g, 2.8 mmol) in methanol (15 ml) was added water (5 ml), which caused a turbidity of the reaction mixture. An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 30 minutes, during which time the reaction mixture became transparent again. Water (20 ml) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and then extracted with ethyl acetate (50 ml). An ethyl acetate extract, which was washed with water (20 ml) and brine (20 ml), was dried over magnesium sulfate and concentrated to obtain the title compound isolated as a white solid (0.8 g).

¹ H NMR (DMSO-d ₆ ) δ 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d, 1H), 8.55 ( d, 1H), 13.7 (br s, 1H).

Stage D: Obtaining 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione

Trichloromethylchloroformate was added dropwise to a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e., the product of Example 1, step A) (97 g, 520 mmol) stirred in dry dioxane (750 ml) at room temperature. (63 g, 320 mmol). The reaction mixture was exothermically slowly heated to 42 ° C, and the solid was almost completely dissolved before again forming a thick suspension. After stirring this suspension at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether and dried to obtain the title product compound obtained as a white solid (98 g).

¹ H NMR (DMSO-d ₆ ) δ 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H), 11.2 (s, 1H).

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

To a suspension of 1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid (i.e., the product of stage C) (7.9 g, 24 mmol) stirred in dichloromethane (100 ml), N, N-dimethylformamide (4 drops) was added. Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated in vacuo. The isolated acid chloride was dissolved in dry acetonitrile (10 ml) and added to a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione (i.e., the product of stage D) (4 9 g, 23 mmol), stirred in dry acetonitrile (14 ml). Pyridine (10 ml) was added and this solution was heated under reflux for reflux for 6 hours. After cooling in an ice bath, a white solid precipitate (9.15 g) was collected. ^{The 1} H-NMR spectrum of the collected precipitate showed peaks consistent with the presence of the title compound and residual starting material of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4 (1H) dione. A small portion of the collected precipitate was recrystallized from acetonitrile to give the pure title product melting at 178-180 ° C.

¹ H NMR (DMSO-d ₆ ) δ 1.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7 (t, 1H), 7.75 ( s, 1H), 7.9 (s, 1H), 8.3 (d, 1H), 8.6 (d, 1H).

Step F: Preparation of N- [4-chloro-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) - 1H-pyrazole-5-carboxamide

To a suspension of 6-chloro-2- [1- (3-chloro-2-pyridinyl) -3- (2,2,2-trifluoroethoxy) -1H-pyrazol-5-yl] -8-methyl-4H-3, 1-benzoxazin-4-one (i.e., the product as a precipitate of step E) (3.53 g, 7.5 mmol) in tetrahydrofuran (15 ml) was added dropwise methylamine (2.0 M solution in THF, 11 ml, 22 mmol), and the resulting solution was stirred at room temperature for 45 minutes. After this, thin layer chromatography showed completion of the reaction. Ethyl ether (100 ml) was added and the reaction mixture was stirred for 2 hours to precipitate. The precipitate was collected by filtration and then recrystallized from acetonitrile to give a white solid (0.82 g). A second batch of white solid (0.35 g) was precipitated from the mother liquor in acetonitrile and collected by filtration. The stock ether / tetrahydrofuran stock solution was concentrated to dryness and the remaining solid was recrystallized from acetonitrile to give a third batch of white solid (0.95 g). These three batches were combined to give a total of 2.12 g (after drying) of the title compound isolated as a white solid, melting at 207-208 ° C.

¹ H NMR (CDCl ₃ ) δ 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.8 (d, 1H), 8.45 (d, 1H), 10, 0 (s, 1H).

Examples 13 and 14 illustrate alternatives to the reaction conditions described in example 5, step E, and in example 3, step E, respectively.

EXAMPLE 13

Preparation of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

Methanesulfonyl chloride (1.0 ml, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 ml) and this mixture was cooled to -5 ° C. A solution of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (i.e., the pyrazolecarboxylic acid product of Example 5, step D) was added dropwise (3.02 g, 10 mmol ) and pyridine (1.4 ml, 1.4 g, 17 mmol) in acetonitrile (10 ml) for 5 minutes at -5 ° C - 0 ° C. During this addition, a suspension formed. The mixture was stirred for 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e., the product of Example 1, step A) (1.86 g, 10 mmol) and pyridine (2) was added. , 8 ml, 2.7 g, 35 mmol) in acetonitrile (10 ml), with washing with additional acetonitrile (5 ml). This mixture was stirred for 15 minutes at -5 ° C to 0 ° C and then methanesulfonyl chloride (1.0 ml, 1.5 ml, 13 mmol) in acetonitrile (5 ml) was added dropwise over 5 minutes at a temperature of -5 ° С - 0 ° С. The reaction mixture was stirred for another 15 minutes at this temperature, then the mixture was allowed to warm slowly to room temperature and stirred for 4 hours. Water (20 ml) was added dropwise and the mixture was stirred for 15 minutes. This mixture was then filtered, and the solids were washed with a 2: 1 mixture of acetonitrile-water (3 x 3 ml), then with acetonitrile (2 x 3 ml) and dried under a nitrogen atmosphere to obtain the title product as a light yellow powder, 4 , 07 g (yield of crude product 90.2%), melting at 203-205 ° C. The HPLC of this product using a Zorbax® RX-C8 chromatography column (4.6 mm x 25 cm, eluent 25-95% acetonitrile / water pH 3) showed the main peak corresponding to the title compound and having 95.7% of the total peak area chromatograms.

¹ H NMR (DMSO-d ₆ ) δ 1.72 (s, 3H), 7.52 (s, 1H), 7.72-7.78 (m, 2H), 7.88 (m, 1H), 8.37 (dd, 1H); 8.62 (dd, 1H).

EXAMPLE 14

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

Methanesulfonyl chloride (1.0 ml, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 ml) and this mixture was cooled to -5 ° C. A solution of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (i.e., the carboxylic acid product of Example 3, step D) was added dropwise (2.58 g, 10 mmol ) and pyridine (1.4 ml, 1.4 g, 17 mmol) in acetonitrile (10 ml) for 5 minutes at -5 ° C - 0 ° C. During this addition, a suspension formed. The mixture was stirred for 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e., the product from Example 1, Step A) (1.86 g, 10 mmol) was added, all at once . Then, a solution of pyridine (2.8 ml, 2.7 g, 35 mmol) in acetonitrile (10 ml) was added dropwise over 5 minutes at -5 ° C to 0 ° C. This mixture was stirred for 15 minutes at -5 ° C to 0 ° C and then methanesulfonyl chloride (1.0 ml, 1.5 ml, 13 mmol) in acetonitrile (5 ml) was added dropwise over 5 minutes at -5 ° С - 0 ° С. The reaction mixture was stirred for 15 minutes at this temperature, then allowed to warm slowly to room temperature and stirred for 4 hours. Water (15 ml) was added dropwise and the mixture was stirred for 15 minutes. The mixture was then filtered and the solids washed with a 2: 1 mixture of acetonitrile-water (3 x 3 ml), then with acetonitrile (2 x 3 ml) and dried under nitrogen to give the title product as a pale yellow powder, 3, 83 g (crude product yield 94.0%), melting at 199-201 ° C. The HPLC of this product using a Zorbax® RX-C8 chromatography column (4.6 mm x 25 cm, eluent 25-95% acetonitrile / water pH 3) showed the main peak corresponding to the title compound and having 97.8% of the total peak area chromatograms.

¹ H NMR (DMSO-d ₆ ) δ 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H), 7.87 (m, 1H), 8.37 (dd, 1H); 8.62 (dd, 1H).

EXAMPLE 15

Preparation of 3-bromo-1- (3-chloro-1-oxide-2-pyridinyl) -N- [2,4-dichloro-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1H-pyrazole- 5-carboxamide

3-bromo-1- (3-chloro-2-pyridinyl) -N- [2,4-dichloro-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1H-pyrazole-5-carboxamide (compound 25, obtained by a method similar to that of Example 5, 487 mg, 0.916 mmol) was added to a mixture of methanol (1 ml) and methylene chloride (9 ml) followed by a 30% aqueous solution of H ₂ O ₂ (1 ml) and methyltrioxorenia (VII) (0.100 g, 0.401 mmol). The reaction mixture was stirred vigorously for 88 hours, and after this time the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The combined organic extracts were dried (MgSO ₄ ), concentrated and purified by column chromatography to obtain the title product, a compound of the present invention, as a solid phase (54.8 mg), melting point 224-226 ° C.

¹ H NMR (DMSO) δ 1.02 (dd, 6H), 3.88 (dd, 1H), 7.44, (s, 1 H) 7.50-7.57 (m, 2H), 7, 66 (d, 1H), 8.17 (d, NH), 7.83 (s, 1H), 10.51 (s, NH) 8.36 (d, 1H).

Using the techniques described here and using methods known in the art, the following compounds of Table 1 can be obtained. In the tables that follow, the following abbreviations were used: t means tertiary, s means secondary, n means normal, i means iso. Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl and Bu means butyl.

TABLE 1

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ CH ₃ F CF ₃ Me H Cl Cl F CF ₃ Me H Cl CH ₃ F CF ₃ Et H Cl Cl F CF ₃ Et H Cl CH ₃ F CF ₃ i-pr H Cl Cl F CF ₃ i-pr H Cl CH ₃ F CF ₃ t-bu H Cl Cl F CF ₃ t-bu H Cl CH ₃ F CF ₃ Me Me Cl Cl F CF ₃ Me Me Cl CH ₃ F CF ₃ Me H Br Cl F CF ₃ Me H Br CH ₃ F CF ₃ Et H Br Cl F CF ₃ Et H Br CH ₃ F CF ₃ i-pr H Br Cl F CF ₃ i-pr H Br CH ₃ F CF ₃ t-bu H Br Cl F CF ₃ t-bu H Br CH ₃ F CF ₃ Me Me Br Cl F CF ₃ Me Me Br CH ₃ F Cl Me H Cl Cl F Cl Me H Cl CH ₃ F Cl Et H Cl Cl F Cl Et H Cl CH ₃ F Cl i-pr H Cl Cl F Cl i-pr H Cl CH ₃ F Cl t-bu H Cl Cl F Cl t-bu H Cl CH ₃ F Cl Me Me Cl Cl F Cl Me Me Cl CH ₃ F Cl Me H Br Cl F Cl Me H Br CH ₃ F Cl Et H Br Cl F Cl Et H Br CH ₃ F Cl i-pr H Br Cl F Cl i-pr H Br CH ₃ F Cl t-bu H Br Cl F Cl t-bu H Br CH ₃ F Cl Me Me Br Cl F Cl Me Me Br CH ₃ F Br Me H Cl Cl F Br Me H Cl CH ₃ F Br Et H Cl Cl F Br Et H Cl CH ₃ F Br i-pr H Cl Cl F Br i-pr H Cl CH ₃ F Br t-bu H Cl Cl F Br t-bu H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ CH ₃ F Br Me Me Cl Cl F Br Me Me Cl CH ₃ F Br Me H Br Cl F Br Me H Br CH ₃ F Br Et H Br Cl F Br Et H Br CH ₃ F Br i-pr H Br Cl F Br i-pr H Br CH ₃ F Br t-bu H Br Cl F Br t-bu H Br CH ₃ F Br Me Me Br Cl F Br Me Me Br CH ₃ F OCH ₂ CF ₃ Me H Cl Cl F OCH ₂ CF ₃ Me H Cl CH ₃ F OCH ₂ CF ₃ Et H Cl Cl F OCH ₂ CF ₃ Et H Cl CH ₃ F OCH ₂ CF ₃ i-pr H Cl Cl F OCH ₂ CF ₃ i-pr H Cl CH ₃ F OCH ₂ CF ₃ t-bu H Cl Cl F OCH ₂ CF ₃ t-bu H Cl CH ₃ F OCH ₂ CF ₃ Me Me Cl Cl F OCH ₂ CF ₃ Me Me Cl CH ₃ F OCH ₂ CF ₃ Me H Br Cl F OCH ₂ CF ₃ Me H Br CH ₃ F OCH ₂ CF ₃ Et H Br Cl F OCH ₂ CF ₃ Et H Br CH ₃ F OCH ₂ CF ₃ i-pr H Br Cl F OCH ₂ CF ₃ i-pr H Br CH ₃ F OCH ₂ CF ₃ t-bu H Br Cl F OCH ₂ CF ₃ t-bu H Br CH ₃ F OCH ₂ CF ₃ Me Me Br Cl F OCH ₂ CF ₃ Me Me Br CH ₃ Cl CF ₃ Me H Cl Cl Cl CF ₃ Me H Cl CH ₃ Cl CF ₃ Et H Cl Cl Cl CF ₃ Et H Cl CH ₃ Cl CF ₃ i-pr H Cl Cl Cl CF ₃ i-pr H Cl CH ₃ Cl CF ₃ t-bu H Cl Cl Cl CF ₃ t-bu H Cl CH ₃ Cl CF ₃ Me Me Cl Cl Cl CF ₃ Me Me Cl CH ₃ Cl CF ₃ Me H Br Cl Cl CF ₃ Me H Br CH ₃ Cl CF ₃ Et H Br Cl Cl CF ₃ Et H Br CH ₃ Cl CF ₃ i-pr H Br Cl Cl CF ₃ i-pr H Br CH ₃ Cl CF ₃ t-bu H Br Cl Cl CF ₃ t-bu H Br CH ₃ Cl CF ₃ Me Me Br Cl Cl CF ₃ Me Me Br CH ₃ Cl Cl Me H Cl Cl Cl Cl Me H Cl CH ₃ Cl Cl Et H Cl Cl Cl Cl Et H Cl CH ₃ Cl Cl i-pr H Cl Cl Cl Cl i-pr H Cl CH ₃ Cl Cl t-bu H Cl Cl Cl Cl t-bu H Cl CH ₃ Cl Cl Me Me Cl Cl Cl Cl Me Me Cl CH ₃ Cl Cl Me H Br Cl Cl Cl Me H Br CH ₃ Cl Cl Et H Br Cl Cl Cl Et H Br CH ₃ Cl Cl i-pr H Br Cl Cl Cl i-pr H Br CH ₃ Cl Cl t-bu H Br Cl Cl Cl t-bu H Br CH ₃ Cl Cl Me Me Br Cl Cl Cl Me Me Br CH ₃ Cl Br Me H Cl Cl Cl Br Me H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ CH ₃ Cl Br Et H Cl Cl Cl Br Et H Cl CH ₃ Cl Br i-pr H Ci Cl Cl Br i-pr H Cl CH ₃ Cl Br t-bu H Cl Cl Cl Br t-bu H Cl CH ₃ Cl Br Me Me Cl Cl Cl Br Me Me Cl CH ₃ Cl Br Me H Br Cl Cl Br Me H Br CH ₃ Cl Br Et H Br Cl Cl Br Et H Br CH ₃ Cl Br i-pr H Br Cl Cl Br i-pr H Br CH ₃ Cl Br t-bu H Br Cl Cl Br t-bu H Br CH ₃ Cl Br Me Me Br Cl Cl Br Me Me Br CH ₃ Cl OCH ₂ CF ₃ Me H Cl Cl Cl OCH ₂ CF ₃ Me H Cl CH ₃ Cl OCH ₂ CF ₃ Et H Cl Cl Cl OCH ₂ CF ₃ Et H Cl CH ₃ Cl OCH ₂ CF ₃ i-pr H Cl Cl Cl OCH ₂ CF ₃ i-pr H Cl CH ₃ Cl OCH ₂ CF ₃ t-bu H Cl Cl Cl OCH ₂ CF ₃ t-bu H Cl CH ₃ Cl OCH ₂ CF ₃ Me Me Cl Cl Cl OCH ₂ CF ₃ Me Me Cl CH ₃ Cl OCH ₂ CF ₃ Me H Br Cl Cl OCH ₂ CF ₃ Me H Br CH ₃ Cl OCH ₂ CF ₃ Et H Br Cl Cl OCH ₂ CF ₃ Et H Br CH ₃ Cl OCH ₂ CF ₃ i-pr H Br Cl Cl OCH ₂ CF ₃ i-pr H Br CH ₃ Cl OCH ₂ CF ₃ t-bu H Br Cl Cl OCH ₂ CF ₃ t-bu H Br CH ₃ Cl OCH ₂ CF ₃ Me Me Br Cl Cl OCH ₂ CF ₃ Me Me Br CH ₃ Br CF ₃ Me H Cl Cl Br CF ₃ Me H Cl CH ₃ Br CF ₃ Et H Cl Cl Br CF ₃ Et H Cl CH ₃ Br CF ₃ i-pr H Cl Cl Br CF ₃ i-pr H Cl CH ₃ Br CF ₃ t-bu H Cl Cl Br CF ₃ t-bu H Cl CH ₃ Br CF ₃ Me Me Cl Cl Br CF ₃ Me Me Cl CH ₃ Br CF ₃ Me H Br Cl Br CF ₃ Me H Br CH ₃ Br CF ₃ Et H Br Cl Br CF ₃ Et H Br CH ₃ Br CF ₃ i-pr H Br Cl Br CF ₃ i-pr H Br CH ₃ Br CF ₃ t-bu H Br Cl Br CF ₃ t-bu H Br CH ₃ Br CF ₃ Me Me Br Cl Br CF ₃ Me Me Br CH ₃ Br Cl Me H Cl Cl Br Cl Me H Cl CH ₃ Br Cl Et H Cl Cl Br Cl Et H Cl CH ₃ Br Cl i-pr H Cl Cl Br Cl i-pr H Cl CH ₃ Br Cl t-bn H Cl Cl Br Cl t-bu H Cl CH ₃ Br Cl Me Me Cl Cl Br Cl Me Me Cl CH ₃ Br Cl Me H Br Cl Br Cl Me H Br CH ₃ Br Cl Et H Br Cl Br Cl Et H Br CH ₃ Br Cl i-pr H Br Cl Br Cl i-pr H Br

R ¹ R ² R ³ R ^4a R ^4b R ⁵ Rl R ² R ³ R ^4a R ^4b R ⁵ CH ₃ Br Cl t-bu H Br Cl Br Cl t-bu H Br CH ₃ Br Cl Me Me Br Cl Br Cl Me Me Br CH ₃ Br Br Me H Cl Cl Br Br Me H Cl CH ₃ Br Br Et H Cl Cl Br Br Et H Cl CH ₃ Br Br i-pr H Cl Cl Br Br i-pr H Cl CH ₃ Br Br t-bu H Cl Cl Br Br t-bu H Cl CH ₃ Br Br Me Me Cl Cl Br Br Me Me Cl CH ₃ Br Br Me H Br Cl Br Br Me H Br CH ₃ Br Br Et H Br Cl Br Br Et H Br CH ₃ Br Br i-pr H Br Cl Br Br i-pr H Br CH ₃ Br Br t-bu H Br Cl Br Br t-bu H Br CH ₃ Br Br Me Me Br Cl Br Br Me Me Br CH ₃ Br OCH ₂ CF ₃ Me H Cl Cl Br OCH ₂ CF ₃ Me H Cl CH ₃ Br OCH ₂ CF ₃ Et H Cl Cl Br OCH ₂ CF ₃ Et H Cl CH ₃ Br OCH ₂ CF ₃ i-pr H Cl Cl Br OCH ₂ CF ₃ i-pr H Cl CH ₃ Br OCH ₂ CF ₃ t-bu H Cl Cl Br OCH ₂ CF ₃ t-bu H Cl CH ₃ Br OCH ₂ CF ₃ Me Me Cl Cl Br OCH ₂ CF ₃ Me Me Cl CH ₃ Br OCH ₂ CF ₃ Me H Br Cl Br OCH ₂ CF ₃ Me H Br CH ₃ Br OCH ₂ CF ₃ Et H Br Cl Br OCH ₂ CF ₃ Et H Br CH ₃ Br OCH ₂ CF ₃ i-pr H Br Cl Br OCH ₂ CF ₃ i-pr H Br CH ₃ Br OCH ₂ CF ₃ t-bu H Br Cl Br OCH ₂ CF ₃ t-bu H Br CH ₃ Br OCH ₂ CF ₃ Me Me Br Cl Br OCH ₂ CF ₃ Me Me Br CH ₃ I CF ₃ Me H Cl Cl I CF ₃ Me H Cl CH ₃ I CF ₃ Et H Cl Cl I CF ₃ Et H Cl CH ₃ I CF ₃ i-pr H Cl Cl I CF ₃ i-pr H Cl CH ₃ I CF ₃ t-bu H Cl Cl I CF ₃ t-bu H Cl CH ₃ I CF ₃ Me Me Cl Cl I CF ₃ Me Me Cl CH ₃ I CF ₃ Me H Br Cl I CF ₃ Me H Br CH ₃ I CF ₃ Et H Br Cl I CF ₃ Et H Br CH ₃ I CF ₃ i-pr H Br Cl I CF ₃ i-pr H Br CH ₃ I CF ₃ t-bu H Br Cl I CF ₃ t-bu H Br CH ₃ I CF ₃ Me Me Br Cl I CF ₃ Me Me Br CH ₃ I Cl Me H Cl Cl I Cl Me H Cl CH ₃ I Cl Et H Cl Cl I Cl Et H Cl CH ₃ I Cl i-pr H Cl Cl I Cl i-pr H Cl CH ₃ I Cl t-bu H Cl Cl I Cl t-bu H Cl CH ₃ I Cl Me Me Cl Cl I Cl Me Me Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ CH ₃ I Cl Me H Br Cl I Cl Me H Br CH ₃ I Cl Et H Br Cl I Cl Et H Br CH ₃ I Cl i-pr H Br Cl I Cl i-pr H Br CH ₃ I Cl t-bu H Br Cl I Cl t-bu H Br CH ₃ I Cl Me Me Br Cl I Cl Me Me Br CH ₃ I Br Me H Cl Cl I Br Me H Cl CH ₃ I Br Et H Cl Cl I Br Et H Cl CH ₃ I Br i-pr H Cl Cl I Br i-pr H Cl CH ₃ I Br t-bu H Cl Cl I Br t-bu H Cl CH ₃ I Br Me Me Cl Cl I Br Me Me Cl CH ₃ I Br Me H Br Cl I Br Me H Br CH ₃ I Br Et H Br Cl I Br Et H Br CH ₃ I Br i-pr H Br Cl I Br i-pr H Br CH ₃ I Br t-bu H Br Cl I Br t-bu H Br CH ₃ I Br Me Me Br Cl I Br Me Me Br CH ₃ I OCH ₂ CF ₃ Me H Cl Cl I OCH ₂ CF ₃ Me H Cl CH ₃ I OCH ₂ CF ₃ Et H Cl Cl I OCH ₂ CF ₃ Et H Cl CH ₃ I OCH ₂ CF ₃ i-pr H Cl Cl I OCH ₂ CF ₃ i-pr H Cl CH ₃ I OCH ₂ CF ₃ t-bu H Cl Cl I OCH ₂ CF ₃ t-bu H Cl CH ₃ I OCH ₂ CF ₃ Me Me Cl Cl I OCH ₂ CF ₃ Me Me Cl CH ₃ I OCH ₂ CF ₃ Me H Br Cl I OCH ₂ CF ₃ Me H Br CH ₃ I OCH ₂ CF ₃ Et H Br Cl I OCH ₂ CF ₃ Et H Br CH ₃ I OCH ₂ CF ₃ i-pr H Br Cl I OCH ₂ CF ₃ i-pr H Br CH ₃ I OCH ₂ CF ₃ t-bu H Br Cl I OCH ₂ CF ₃ t-bu H Br CH ₃ I OCH ₂ CF ₃ Me Me Br Cl I OCH ₂ CF ₃ Me Me Br CH ₃ CF ₃ CF ₃ Me H Cl Cl CF ₃ CF ₃ Me H Cl CH ₃ CF ₃ CF ₃ Et H Cl Cl CF ₃ CF ₃ Et H Cl CH ₃ CF ₃ CF ₃ i-pr H Cl Cl CF ₃ CF ₃ i-pr H Cl CH ₃ CF ₃ CF ₃ t-bu H Cl Cl CF ₃ CF ₃ t-bu H Cl CH ₃ CF ₃ CF ₃ Me Me Cl Cl CF ₃ CF ₃ Me Me Cl CH ₃ CF ₃ CF ₃ Me H Br Cl CF ₃ CF ₃ Me H Br CH ₃ CF ₃ CF ₃ Et H Br Cl CF ₃ CF ₃ Et H Br CH ₃ CF ₃ CF ₃ i-pr H Br Cl CF ₃ CF ₃ i-pr H Br CH ₃ CF ₃ CF ₃ t-bu H Br Cl CF ₃ CF ₃ t-bu H Br CH ₃ CF ₃ CF ₃ Me Me Br Cl CF ₃ CF ₃ Me Me Br CH ₃ CF ₃ Cl Me H Cl Cl CF ₃ Cl Me H Cl CH ₃ CF ₃ Cl Et H Cl Cl CF ₃ Cl Et H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁴ R ¹ R ² R ³ R ^4a R ^4b R ⁵ CH ₃ CF ₃ Cl i-pr H Cl Cl CF ₃ Cl i-pr H Cl CH ₃ CF ₃ Cl t-bu H Cl Cl CF ₃ Cl t-bu H Cl CH ₃ CF ₃ Cl Me Me Cl Cl CF ₃ Cl Me Me Cl CH ₃ CF ₃ Cl Me H Br Cl CF ₃ Cl Me H Br CH ₃ CF ₃ Cl Et H Br Cl CF ₃ Cl Et H Br CH ₃ CF ₃ Cl i-pr H Br Cl CF ₃ Cl i-pr H Br CH ₃ CF ₃ Cl t-bu H Br Cl CF ₃ Cl t-bu H Br CH ₃ CF ₃ Cl Me Me Br Cl CF ₃ Cl Me Me Br CH ₃ CF ₃ Br Me H Cl Cl CF ₃ Br Me H Cl CH ₃ CF ₃ Br Et H Cl Cl CF ₃ Br Et H Cl CH ₃ CF ₃ Br i-pr H Cl Cl CF ₃ Br i-pr H Cl CH ₃ CF ₃ Br t-bu H Cl Cl CF ₃ Br t-bu H Cl CH ₃ CF ₃ Br Me Me Cl Cl CF ₃ Br Me Me Cl CH ₃ CF ₃ Br Me H Br Cl CF ₃ Br Me H Br CH ₃ CF ₃ Br Et H Br Cl CF ₃ Br Et H Br CH ₃ CF ₃ Br i-pr H Br Cl CF ₃ Br i-pr H Br CH ₃ CF ₃ Br t-bu H Br Cl CF ₃ Br t-bu H Br CH ₃ CF ₃ Br Me Me Br Cl CF ₃ Br Me Me Br CH ₃ CF ₃ OCH ₂ CF ₃ Me H Cl Cl CF ₃ OCH ₂ CF ₃ Me H Cl CH ₃ CF ₃ OCH ₂ CF ₃ Et H Cl Cl CF ₃ OCH ₂ CF ₃ Et H Cl CH ₃ CF ₃ OCH ₂ CF ₃ i-pr H Cl Cl CF ₃ OCH ₂ CF ₃ i-pr H Cl CH ₃ CF ₃ OCH ₂ CF ₃ t-bu H Cl Cl CF ₃ OCH ₂ CF ₃ t-bu H Cl CH ₃ CF ₃ OCH ₂ CF ₃ Me Me Cl Cl CF ₃ OCH ₂ CF ₃ Me Me Cl CH ₃ CF ₃ OCH ₂ CF ₃ Me H Br Cl CF ₃ OCH ₂ CF ₃ Me H Br CH ₃ CF ₃ OCH ₂ CF ₃ Et H Br Cl CF ₃ OCH ₂ CF ₃ Et H Br CH ₃ CF ₃ OCH ₂ CF ₃ i-pr H Br Cl CF ₃ OCH ₂ CF ₃ i-pr H Br CH ₃ CF ₃ OCH ₂ CF ₃ t-bu H Br Cl CF ₃ OCH ₂ CF ₃ t-bu H Br CH ₃ CF ₃ OCH ₂ CF ₃ Me Me Br Cl CF ₃ OCH ₂ CF ₃ Me Me Br CH ₃ Cl Cl n-Pr H Cl Cl Cl Cl n-Pr H Cl CH ₃ Cl Cl n-bu H Cl Cl Cl Cl n-bu H Cl CH ₃ Cl Cl s-bu H Cl Cl Cl Cl s-bu H Cl CH ₃ Cl Cl i-bu H Cl Cl Cl Cl i-bu H Cl CH ₃ Cl Cl Et Me Cl Cl Cl Cl Et Me Cl F F CF ₃ Me H Cl Br F CF ₃ Me H Cl F F CF ₃ Et H Cl Br F CF ₃ Et H Cl F F CF ₃ i-pr H Cl Br F CF ₃ i-pr H Cl F F CF ₃ t-bu H Cl Br F CF ₃ t-bu H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F F CF ₃ Me Me Cl Br F CF ₃ Me Me Cl F F CF ₃ Me H Br Br F CF ₃ Me H Br F F CF ₃ Et H Br Br F CF ₃ Et H Br F F CF ₃ i-pr H Br Br F CF ₃ i-pr H Br F F CF ₃ t-bu H Br Br F CF ₃ t-bu H Br F F CF ₃ Me Me Br Br F CF ₃ Me Me Br F F Cl Me H Cl Br F Cl Me H Cl F F Cl Et H Cl Br F Cl Et H Cl F F Cl i-pr H Cl Br F Cl i-pr H Cl F F Cl t-bu H Cl Br F Cl t-bu H Cl F F Cl Me Me Cl Br F Cl Me Me Cl F F Cl Me H Br Br F Cl Me H Br F F Cl Et H Br Br F Cl Et H Br F F Cl i-pr H Br Br F Cl i-pr H Br F F Cl t-bu H Br Br F Cl t-bu H Br F F Cl Me Me Br Br F Cl Me Me Br F F Br Me H Cl Br F Br Me H Cl F F Br Et H Cl Br F Br Et H Cl F F Br i-pr H Cl Br F Br i-pr H Cl F F Br t-bu H Cl Br F Br t-bu H Cl F F Br Me Me Cl Br F Br Me Me Cl F F Br Me H Br Br F Br Me H Br F F Br Et H Br Br F Br Et H Br F F Br i-pr H Br Br F Br i-pr H Br F F Br t-bu H Br Br F Br t-bu H Br F F Br Me Me Br Br F Br Me Me Br F F OCH ₂ CF ₃ Me H Cl Br F OCH ₂ CF ₃ Me H Cl F F OCH ₂ CF ₃ Et H Cl Br F OCH ₂ CF ₃ Et H Cl F F OCH ₂ CF ₃ i-pr H Cl Br F OCH ₂ CF ₃ i-pr H Cl F F OCH ₂ CF ₃ t-bu H Cl Br F OCH ₂ CF ₃ t-bu H Cl F F OCH ₂ CF ₃ Me Me Cl Br F OCH ₂ CF ₃ Me Me Cl F F OCH ₂ CF ₃ Me H Br Br F OCH ₂ CF ₃ Me H Br F F OCH ₂ CF ₃ Et H Br Br F OCH ₂ CF ₃ Et H Br F F OCH ₂ CF ₃ i-pr H Br Br F OCH ₂ CF ₃ i-pr H Br F F OCH ₂ CF ₃ t-bu H Br Br F OCH ₂ CF ₃ t-bu H Br F F OCH ₂ CF ₃ Me Me Br Br F OCH ₂ CF ₃ Me Me Br F Cl CF ₃ Me H Cl Br Cl CF ₃ Me H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F Cl CF ₃ Et H Cl Br Cl CF ₃ Et H Cl F Cl CF ₃ i-pr H Cl Br Cl CF ₃ i-pr H Cl F Ci CF ₃ t-bu H Cl Br Cl CF ₃ t-bu H Cl F Cl CF ₃ Me Me Cl Br Cl CF ₃ Me Me Cl F Cl CF ₃ Me H Br Br Cl CF ₃ Me H Br F Cl CF ₃ Et H Br Br Cl CF ₃ Et H Br F Cl CF ₃ i-pr H Br Br Cl CF ₃ i-pr H Br F Cl CF ₃ t-bu H Br Br Cl CF ₃ t-bu H Br F Cl CF ₃ Me Me Br Br Cl CF ₃ Me Me Br F Cl Cl Me H Cl Br Cl Cl Me H Cl F Ci Cl Et H Cl Br Cl Cl Et H Cl F Cl Cl i-pr H Cl Br Cl Cl i-pr H Cl F Cl Cl t-bu H Cl Br Cl Cl t-bu H Cl F Cl Cl Me Me Cl Br Cl Cl Me Me Cl F Cl Cl Me H Br Br Cl Cl Me H Br F Cl Cl Et H Br Br Cl Cl Et H Br F Cl Cl i-pr H Br Br Cl Cl i-pr H Br F Cl Cl t-bu H Br Br Cl Cl t-bu H Br F Cl Cl Me Me Br Br Cl Cl Me Me Br F Cl Br Me H Cl Br Cl Br Me H Cl F Cl Br Et H Cl Br Cl Br Et H Cl F Cl Br i-pr H Cl Br Cl Br i-pr H Cl F Cl Br t-bu H Cl Br Cl Br t-bu H Cl F Cl Br Me Me Cl Br Cl Br Me Me Cl F Cl Br Me H Br Br Cl Br Me H Br F Cl Br Et H Br Br Cl Br Et H Br F Cl Br i-pr H Br Br Cl Br i-pr H Br F Cl Br t-bu H Br Br Cl Br t-bu H Br F Cl Br Me Me Br Br Cl Br Me Me Br F Cl OCH ₂ CF ₃ Me H Cl Br Cl OCH ₂ CF ₃ Me H Cl F Cl OCH ₂ CF ₃ Et H Cl Br Cl OCH ₂ CF ₃ Et H Cl F Cl OCH ₂ CF ₃ i-pr H Cl Br Cl OCH ₂ CF ₃ i-pr H Cl F Cl OCH ₂ CF ₃ t-bu H Cl Br Cl OCH ₂ CF ₃ t-bu H Cl F Cl OCH ₂ CF ₃ Me Me Cl Br Cl OCH ₂ CF ₃ Me Me Cl F Cl OCH ₂ CF ₃ Me H Br Br Cl OCH ₂ CF ₃ Me H Br F Cl OCH ₂ CF ₃ Et H Br Br Cl OCH ₂ CF ₃ Et H Br F Cl OCH ₂ CF ₃ i-pt H Br Br Cl OCH ₂ CF ₃ i-pr H Br

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F Cl OCH ₂ CF ₃ t-bu H Br Br Cl OCH ₂ CF ₃ t-bu H Br F Cl OCH ₂ CF ₃ Me Me Br Br Cl OCH ₂ CF ₃ Me Me Br F Br CF ₃ Me H Cl Br Br CF ₃ Me H Cl F Br CF ₃ Et H Cl Br Br CF ₃ Et H Cl F Br CF ₃ i-pr H Cl Br Br CF ₃ i-pr H Cl F Br CF ₃ t-bu H Cl Br Br CF ₃ t-bu H Cl F Br CF ₃ Me Me Cl Br Br CF ₃ Me Me Cl F Br CF ₃ Me H Br Br Br CF ₃ Me H Br F Br CF ₃ Et H Br Br Br CF ₃ Et H Br F Br CF ₃ i-pr H Br Br Br CF ₃ i-pr H Br F Br CF ₃ t-bu H Br Br Br CF ₃ t-bu H Br F Br CF ₃ Me Me Br Br Br CF ₃ Me Me Br F Br Cl Me H Cl Br Br Cl Me H Cl F Br Cl Et H Cl Br Br Cl Et H Cl F Br Cl i-pr H Cl Br Br Cl i-pr H Cl F Br Cl t-bu H Cl Br Br Cl t-bu H Cl F Br Cl Me Me Cl Br Br Cl Me Me Cl F Br Cl Me H Br Br Br Cl Me H Br F Br Cl Et H Br Br Br Cl Et H Br F Br Cl i-pr H Br Br Br Cl i-pr H Br F Br Cl t-bu H Br Br Br Cl t-bu H Br F Br Cl Me Me Br Br Br Cl Me Me Br F Br Br Me H Cl Br Br Br Me H Cl F Br Br Et H Cl Br Br Br Et H Cl F Br Br i-pr H Cl Br Br Br i-pr H Cl F Br Br t-bu H Cl Br Br Br t-bu H Cl F Br Br Me Me Cl Br Br Br Me Me Cl F Br Br Me H Br Br Br Br Me H Br F Br Br Et H Br Br Br Br Et H Br F Br Br i-pr H Br Br Br Br i-pr H Br F Br Br t-bu H Br Br Br Br t-bu H Br F Br Br Me Me Br Br Br Br Me Me Br F Br OCH ₂ CF ₃ Me H Cl Br Br OCH ₂ CF ₃ Me H Cl F Br OCH ₂ CF ₃ Et H Cl Br Br OCH ₂ CF ₃ Et H Cl F Br OCH ₂ CF ₃ i-pr H Cl Br Br OCH ₂ CF ₃ i-pr H Cl F Br OCH ₂ CF ₃ t-bu H Cl Br Br OCH ₂ CF ₃ t-bu H Cl F Br OCH ₂ CF ₃ Me Me Cl Br Br OCH ₂ CF ₃ Me Me Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F Br OCH ₂ CF ₃ Me H Br Br Br OCH ₂ CF ₃ Me H Br F Br OCH ₂ CF ₃ Et H Br Br Br OCH ₂ CF ₃ Et H Br F Br OCH ₂ CF ₃ i-pr H Br Br Br OCH ₂ CF ₃ i-pr H Br F Br OCH ₂ CF ₃ t-bu H Br Br Br OCH ₂ CF ₃ t-bu H Br F Br OCH ₂ CF ₃ Me Me Br Br Br OCH ₂ CF ₃ Me Me Br F I CF ₃ Me H Cl Br I CF ₃ Me H Cl F I CF ₃ Et H Cl Br I CF ₃ Et H Cl F I CF ₃ i-pr H Cl Br I CF ₃ i-pr H Cl F I CF ₃ t-bu H Cl Br I CF ₃ t-bu H Cl F I CF ₃ Me Me Cl Br I CF ₃ Me Me Cl F I CF ₃ Me H Br Br I CF ₃ Me H Br F I CF ₃ Et H Br Br I CF ₃ Et H Br F I CF ₃ i-pr H Br Br I CF ₃ i-pr H Br F I CF ₃ t-bu H Br Br I CF ₃ t-bu H Br F I CF ₃ Me Me Br Br I CF ₃ Me Me Br F I Cl Me H Cl Br I Cl Me H Cl F I Cl Et H Cl Br I Cl Et H Cl F I Cl i-pr H Cl Br I Cl i-pr H Cl F I Cl t-bu H Cl Br I Cl t-bu H Cl F I Cl Me Me Cl Br I Cl Me Me Cl F I Cl Me H Br Br I Cl Me H Br F I Cl Et H Br Br I Cl Et H Br F I Cl i-pr H Br Br I Cl i-pr H Br F I Cl t-bu H Br Br I Cl t-bu H Br F I Cl Me Me Br Br I Cl Me Me Br F I Br Me H Cl Br I Br Me H Cl F I Br Et H Cl Br I Br Et H Cl F I Br i-pr H Cl Br I Br i-pr H Cl F I Br t-bu H Cl Br I Br t-bu H Cl F I Br Me Me Cl Br I Br Me Me Cl F I Br Me H Br Br I Br Me H Br F I Br Et H Br Br I Br Et H Br F I Br i-pr H Br Br I Br i-pr H Br F I Br t-bu H Br Br I Br t-bu H Br F I Br Me Me Br Br I Br Me Me Br F I OCH ₂ CF ₃ Me H Cl Br I OCH ₂ CF ₃ Me H Cl F I OCH ₂ CF ₃ Et H Cl Br I OCH ₂ CF ₃ Et H Cl

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F I OCH ₂ CF ₃ i-pr H Cl Br I OCH ₂ CF ₃ i-pr H Cl F I OCH ₂ CF ₃ t-bu H Cl Br I OCH ₂ CF ₃ t-bu H Cl F I OCH ₂ CF ₃ Me Me Cl Br I OCH ₂ CF ₃ Me Me Cl F I OCH ₂ CF ₃ Me H Br Br I OCH ₂ CF ₃ Me H Br F I OCH ₂ CF ₃ Et H Br Br I OCH ₂ CF ₃ Et H Br F I OCH ₂ CF ₃ i-pr H Br Br I OCH ₂ CF ₃ i-pr H Br F I OCH ₂ CF ₃ t-bu H Br Br I OCH ₂ CF ₃ t-bu H Br F I OCH ₂ CF ₃ Me Me Br Br I OCH ₂ CF ₃ Me Me Br F CF ₃ CF ₃ Me H Cl Br CF ₃ CF ₃ Me H Cl F CF ₃ CF ₃ Et H Cl Br CF ₃ CF ₃ Et H Cl F CF ₃ CF ₃ i-pr H Cl Br CF ₃ CF ₃ i-pr H Cl F CF ₃ CF ₃ t-bu H Cl Br CF ₃ CF ₃ t-bu H Cl F CF ₃ CF ₃ Me Me Cl Br CF ₃ CF ₃ Me Me Cl F CF ₃ CF ₃ Me H Br Br CF ₃ CF ₃ Me H Br F CF ₃ CF ₃ Et H Br Br CF ₃ CF ₃ Et H Br F CF ₃ CF ₃ i-pr H Br Br CF ₃ CF ₃ i-pr H Br F CF ₃ CF ₃ t-bu H Br Br CF ₃ CF ₃ t-bu H Br F CF ₃ CF ₃ Me Me Br Br CF ₃ CF ₃ Me Me Br F CF ₃ Cl Me H Cl Br CF ₃ Cl Me H Cl F CF ₃ Cl Et H Cl Br CF ₃ Cl Et H Cl F CF ₃ Cl i-pr H Cl Br CF ₃ Cl i-pr H Cl F CF ₃ Cl t-bu H Cl Br CF ₃ Cl t-bu H Cl F CF ₃ Cl Me Me Cl Br CF ₃ Cl Me Me Cl F CF ₃ Cl Me H Br Br CF ₃ Cl Me H Br F CF ₃ Cl Et H Br Br CF ₃ Cl Et H Br F CF ₃ Cl i-pr H Br Br CF ₃ Cl i-pr H Br F CF ₃ Cl t-bu H Br Br CF ₃ Cl t-bu H Br F CF ₃ Cl Me Me Br Br CF ₃ Cl Me Me Br F CF ₃ Br Me H Cl Br CF ₃ Br Me H Cl F CF ₃ Br Et H Cl Br CF ₃ Br Et H Cl F CF ₃ Br i-pr H Cl Br CF ₃ Br i-pr H Cl F CF ₃ Br t-bu H Cl Br CF ₃ Br t-bu H Cl F CF ₃ Br Me Me Cl Br CF ₃ Br Me Me Cl F CF ₃ Br Me H Br Br CF ₃ Br Me H Br F CF ₃ Br Et H Br Br CF ₃ Br Et H Br F CF ₃ Br i-pr H Br Br CF ₃ Br i-pr H Br F CF ₃ Br t-bu H Br Br CF ₃ Br t-bu H Br

R ¹ R ² R ³ R ^4a R ^4b R ⁵ R ¹ R ² R ³ R ^4a R ^4b R ⁵ F CF ₃ Br Me Me Br Br CF ₃ Br Me Me Br F CF ₃ OCH ₂ CF ₃ Me H Cl Br CF ₃ OCH ₂ CF ₃ Me H Cl F CF ₃ OCH ₂ CF ₃ Et H Cl Br CF ₃ OCH ₂ CF ₃ Et H Cl F CF ₃ OCH ₂ CF ₃ i-pr H Cl Br CF ₃ OCH ₂ CF ₃ i-pr H Cl F CF ₃ OCH ₂ CF ₃ t-bu H Cl Br CF ₃ OCH ₂ CF ₃ t-bu H Cl F CF ₃ OCH ₂ CF ₃ Me Me Cl Br CF ₃ OCH ₂ CF ₃ Me Me Cl F CF ₃ OCH ₂ CF ₃ Me H Br Br CF ₃ OCH ₂ CF ₃ Me H Br F CF ₃ OCH ₂ CF ₃ Et H Br Br CF ₃ OCH ₂ CF ₃ Et H Br F CF ₃ OCH ₂ CF ₃ i-pr H Br Br CF ₃ OCH ₂ CF ₃ i-pr H Br F CF ₃ OCH ₂ CF ₃ t-bu H Br Br CF ₃ OCH ₂ CF ₃ t-bu H Br F CF ₃ OCH ₂ CF ₃ Me Me Br Br CF ₃ OCH ₂ CF ₃ Me Me Br

As shown in Scheme 1 and further illustrated in Examples 1-10, benzoxazines of formula 2, such as those listed in table 2, are useful for preparing compounds of formula 1, including compounds listed in table 1.

TABLE 2

R ¹ R ² R ³ R ⁵ R ¹ R ² R ³ R ⁵ CH ₃ F CF ₃ Cl Cl F CF ₃ Cl CH ₃ F CF ₃ Br Cl F CF ₃ Br CH ₃ F Cl Cl Cl F Cl Cl CH ₃ F Cl Br Cl F Cl Br CH ₃ F Br Cl Cl F Br Cl CH ₃ F Br Br Cl F Br Br CH ₃ F OCH ₂ CF ₃ Cl Cl F OCH ₂ CF ₃ Cl CH ₃ F OCH ₂ CF ₃ Br Cl F OCH ₂ CF ₃ Br CH ₃ Cl CF ₃ Cl Cl Cl CF ₃ Cl CH ₃ Cl CF ₃ Br Cl Cl CF ₃ Br CH ₃ Cl Cl Cl Cl Cl Cl Cl

R ¹ R ² R ³ R ⁵ R ¹ R ² R ³ R ⁵ CH ₃ Cl Cl Br Cl Cl Cl Br CH ₃ Cl Br Cl Cl Cl Br Cl CH ₃ Cl Br Br Cl Cl Br Br CH ₃ Cl OCH ₂ CF ₃ Cl Cl Cl OCH ₂ CF ₃ Cl CH ₃ Cl OCH ₂ CF ₃ Br Cl Cl OCH ₂ CF ₃ Br CH ₃ Br CF ₃ Cl Cl Br CF ₃ Cl CH ₃ Br CF ₃ Br Cl Br CF ₃ Br CH ₃ Br Cl Cl Cl Br Cl Cl CH ₃ Br Cl Br Cl Br Cl Br CH ₃ Br Br Cl Cl Br Br Cl CH ₃ Br Br Br Cl Br Br Br CH ₃ Br OCH ₂ CF ₃ Cl Cl Br OCH ₂ CF ₃ Cl CH ₃ Br OCH ₂ CF ₃ Br Cl Br OCH ₂ CF ₃ Br CH ₃ I CF ₃ Cl Cl I CF ₃ Cl CH ₃ I CF ₃ Br Cl I CF ₃ Br CH ₃ I Cl Cl Cl I Cl Cl CH ₃ I Cl Br Cl I Cl Br CH ₃ I Br Cl Cl I Br Cl CH ₃ I Br Br Cl I Br Br CH ₃ I OCH ₂ CF ₃ Cl Cl I OCH ₂ CF ₃ Cl CH ₃ I OCH ₂ CF ₃ Br Cl I OCH ₂ CF ₃ Br CH ₃ CF ₃ CF ₃ Cl Cl CF ₃ CF ₃ Cl CH ₃ CF ₃ CF ₃ Br Cl CF ₃ CF ₃ Br CH ₃ CF ₃ Cl Cl Cl CF ₃ Cl Cl CH ₃ CF ₃ Cl Br Cl CF ₃ Cl Br CH ₃ CF ₃ Br Cl Cl CF ₃ Br Cl CH ₃ CF ₃ Br Br Cl CF ₃ Br Br CH ₃ CF ₃ OCH ₂ CF ₃ Cl Cl CF ₃ OCH ₂ CF ₃ Cl CH ₃ CF ₃ OCH ₂ CF ₃ Br Cl CF ₃ OCH ₂ CF ₃ Br F F CF ₃ Cl Br F CF ₃ Cl F F CF ₃ Br Br F CF ₃ Br F F Cl Cl Br F Cl Cl F F Cl Br Br F Cl Br F F Br Cl Br F Br Cl F F Br Br Br F Br Br F F OCH ₂ CF ₃ Cl Br F OCH ₂ CF ₃ Cl F F OCH ₂ CF ₃ Br Br F OCH ₂ CF ₃ Br

R ¹ R ² R ³ R ⁵ R ¹ R ² R ³ R ⁵ F Cl CF ₃ Cl Br Cl CF ₃ Cl F Cl CF ₃ Br Br Cl CF ₃ Br F Cl Cl Cl Br Cl Cl Cl F Cl Cl Br Br Cl Cl Br F Cl Br Cl Br Cl Br Cl F Cl Br Br Br Cl Br Br F Cl OCH ₂ CF ₃ Cl Br Cl OCH ₂ CF ₃ Cl F Cl OCH ₂ CF ₃ Br Br Cl OCH ₂ CF ₃ Br F Br CF ₃ Cl Br Br CF ₃ Cl F Br CF ₃ Br Br Br CF ₃ Br F Br Cl Cl Br Br Cl Cl F Br Cl Br Br Br Cl Br F Br Br Cl Br Br Br Cl F Br Br Br Br Br Br Br F Br OCH ₂ CF ₃ Cl Br Br OCH ₂ CF ₃ Cl F Br OCH ₂ CF ₃ Br Br Br OCH ₂ CF ₃ Br F I CF ₃ Cl Br I CF ₃ Cl F I CF ₃ Br Br I CF ₃ Br F I Cl Cl Br I Cl Cl F I Cl Br Br I Cl Br F I Br Cl Br I Br Cl F I Br Br Br I Br Br F I OCH ₂ CF ₃ Cl Br I OCH ₂ CF ₃ Cl F I OCH ₂ CF ₃ Br Br I OCH ₂ CF ₃ Br F CF ₃ CF ₃ Cl Br CF ₃ CF ₃ Cl F CF ₃ CF ₃ Br Br CF ₃ CF ₃ Br F CF ₃ Cl Cl Br CF ₃ Cl Cl F CF ₃ Cl Br Br CF ₃ Cl Br F CF ₃ Br Cl Br CF ₃ Br Cl F CF ₃ Br Br Br CF ₃ Br Br F CF ₃ OCH ₂ CF ₃ Cl Br CF ₃ OCH ₂ CF ₃ Cl F CF ₃ OCH ₂ CF ₃ Br Br CF ₃ OCH ₂ CF ₃ Br

As shown in Scheme 2 and further illustrated in Examples 1-10, pyrazolecarboxylic acids of formula 4, such as those listed in table 3, are useful in the preparation of compounds of formula 1, including compounds listed in table 1.

TABLE 3

R ³ R ⁵ R ³ R ⁵ & ³ R ⁵ CF ₃ Cl OCH ₂ CF ₃ Cl Br Br Cl Cl CF ₃ Br OCH ₂ CF ₃ Br Br Cl Cl Br

Formulation / Applicability

The compounds of this invention will usually be used in the form of a formulation or composition with an agriculturally acceptable carrier containing at least one liquid diluent, solid diluent or surfactant. The ingredients of the formulation or composition are selected so that they are compatible with the physical properties of the active ingredient, route of administration, and environmental factors such as soil type, moisture, and temperature. Suitable formulations include liquids, such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and / or suspension emulsions) or the like, which may optionally be gelled. In addition, suitable formulations include solids, such as dusts, powders, granules, spheres, tablets, films, and the like, which may be water dispersible ("wettable") or water soluble. The active ingredient may be (micro) encapsulated and further formulated in suspension or solid form; alternatively, the entire formulation of the active ingredient may be encapsulated (or "encased in a protective coating"). Encapsulation may control or delay the release of the active ingredient. Suitable for spraying compositions can be distributed in suitable environments and used in aerosol volumes from about one to several hundred liters per hectare. Compositions with a high concentration are primarily used as intermediates for the further preparation of finished forms.

Formulations typically contain effective amounts of the active ingredient, diluent and surfactant in the following exemplary ranges, which are added up to 100 percent by weight.

Percentage by Weight (wt.%) Active ingredient Diluent Surface-active substance Water-dispersible and water-soluble granules, tablets and powders 5-90 0-94 1-15 Suspensions, emulsions, solutions (including emulsifiable concentrates) 5-50 40-95 0-15 Dusty 1-25 70-99 0-5 Granules and balls 0.01-99 5-99.99 0-15 High Concentration Compositions 90-99 0-10 0-2

Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2 ^nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2 ^nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, and Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, lists of surfactants and recommended uses. All formulations may contain minor amounts of additives to reduce foaming, caking, corrosion, microbiological growth, etc., or thickeners to increase viscosity.

Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkyl phenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkyl benzenesulfonates, organosilicones, N, N-dialkyl sulfonates, sulfonates, sulfonates, sulfonates, sulfonates, polyoxypropylene. 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 sodium bicarbonate and sodium sulfate. Liquid diluents include e.g. peanut, cottonseed, soybean, stock and coconut oils, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol, benzyl and tetrahydrofurfur silt alcohol.

Solutions including emulsifiable concentrates can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by mixing and usually grinding, for example, in a hammer mill or a jet mill. Suspensions are usually prepared by wet grinding (in a wet grinding mill); see, for example, US Pat. No. 3,060,084. Granules and pellets can be prepared by spraying the active material onto preformed granular carriers or by agglomeration. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp. 147-48, Perry's Chemical Engineer's Handbook, 4 ^th Ed., McGraw-Hill, New York, 1963, pages 8-57 and the following pages, and PCT Publication WO 91/13546. Balls can be prepared as described in US Pat. No. 4,172,714. Water-dispersible and water-soluble granules can be prepared as described in US Pat. Nos. 4,144,050, 3,920,442 and German Patent 3,264,493. Tablets can be prepared as described in US Pat. Nos. 5,180,587, 5,232,701. and 5208030. Films can be prepared as described in UK patent 2095558 and US patent 3299566.

For additional information regarding the cooking area, see TSWoods, "The Formulator's Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and TRRoberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also U.S. 3235361, Column 6, line 16 to Column 7, line 1-9 and examples 10-41; U.S. 3309192, Column 5, line 43 to Column 7, line 62 and examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2891855, Column 3, line 66 to Column 5, line 17 and examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.

In the following examples, all percentages are percentages by weight (wt.%) And all formulations are prepared by conventional methods. Compound numbers refer to compounds in Index Table A.

Example A Wettable powder Compound 2 65.0% dodecylphenol ether and polyethylene glycol 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0% Example B Granule Compound 10 10.0% attapulgite granules (low volatility material, 90.0% 0.71 / 0.30 mm; Sieve U.S.S. No. 25-50) Example C Extruded ball Compound 20 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1,0% calcium / magnesium bentonite 59.0% Example D Emulsifiable Concentrate Compound 33 20.0% a mixture of oil soluble sulfonates and polyoxyethylene ethers 10.0% Isophorone 70.0%

The compounds of this invention are characterized by the favorable nature of the metabolic and / or soil residual distribution and exhibit activity of suppressing the spectrum of agricultural and non-agricultural invertebrate pests. (In this context, the term “invertebrate pest control” means inhibiting the development of invertebrate pests (including killing them), which causes a significant reduction in eating or other damage or damage caused by these pests; related expressions are defined similarly). The term "invertebrate pest" as used in this invention includes arthropods, gastropods, mollusks, and nematodes (roundworms) of economic importance as pests. The term "arthropods" (Arthropoda) includes insects, ticks, spiders, scorpions, leg-footed (centipedes), two-legged, woodlice and symphyllos. The term "gastropods" (Gastropoda) includes snails, slugs and other Stylommatophora. The term "nematode" (roundworms) includes helminths, such as roundworms, parasitic helminths in the heart, and herbivorous nematodes (Nematoda), trematodes (Trematoda), scrapers (Acanthocephala) and tapeworms (Cestoda). Specialists in this field should be clear that not all compounds are equally effective against all pests. The compounds of this invention are active against economically important agricultural and non-agricultural pests. The term "agricultural" refers to the production of field crops, for example, for food products and fibers, and includes the cultivation of cereals (for example, wheat, oats, barley, rye, rice, corn), soybeans, vegetables (for example, lettuce , cabbage, tomatoes, beans), potatoes, sweet potatoes (sweet potato), grapes, cotton, and the production of fruit trees (for example, fleshy (pome) fruits, stone fruits (drupes) and fruits of citrus or orange crops). The term "non-agricultural" refers to other horticultural plants (for example, forest, greenhouse plants, plants grown in nurseries or ornamental plants not growing in the field), public (human) and animal health, animal domestication structures and commercial structures, households and to applications for stored products or pests. Due to the wide range of invertebrate pest control and economic importance, protecting (from damage or damage caused by invertebrate pests) crops of cotton, corn, soybeans, rice, vegetables, potatoes, sweet potatoes (sweet potatoes), grapes and fruit trees by destroying invertebrate pests are preferred embodiments of the present invention. Agricultural or non-agricultural pests include the larvae (caterpillars) of the order Lepidoptera (Lepidoptera (butterflies)), such as “marching (military) worms”, i.e. caterpillars of some insects, forming large, mobile clusters), insects, biting plants, moths and scoops in the Noctuidae family (for example, grass scoop (Spodoptera fugiperda JE Smith), small scoop (Spodoptera exigua Hübner), ipsilon scrub (Agrotisagips) cabbage moth (scoop ni) (Trichoplusia ni Hübner), tobacco scoop (Heliothis virescens Fabricius)); drills (grinders), covers, caterpillars building a spider nest, cone-shaped worms, mermetids (Mermithidae) and pests, skeleton leaves (leaving only veins), from the family Pyralidae (for example, a corn moth (Ostrinia nubilalis Hübner), a caterpillar, (umbilical orange) (Amyelois transitella Walker), fire scoop (Crambus caliginosellus Clemens), meadow moth (Herpetogramma licarsisalis Walker)); leafworms, caterpillar leafworm and caterpillar tracks - seed and caterpillar pests - fruit pests (codling moths) in the Tortricidae family (e.g. apple moth (Cydia pomonella Linnaeus), grape leafwort (Endopiza viteana Clemens), Oriental busleckle peach) ; and many other economically important Lepidoptera (for example, cabbage moth (Plutella xylostella Linnaeus), pink cotton boxworm (Pectinophora gossypiella Saunders), unpaired silkworm (Lymantria dispar Linnaeus)); nymphs and adults of the order Blattodea (Cockroaches), including cockroaches from the families Blattellidae and Blattidae (for example, a black cockroach (Blatta orientalis Linnaeus), an Asian cockroach (Blatella asahinai Mizukubo), a red cockroach (Prusac) (Blattella germanica Linna brown-striped (Supella longipalpa Fabricius), American cockroach (Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeira cockroach (Leucophaea madera Fabricius)); foliage-feeding caterpillars and adult individuals of the Coleoptera order (coleoptera), including weevils (elephants) from the Anthribidae, Bruchidae and Curculionidae families (for example, cotton weevil (Anthonomus grandis Boheman), weevil rice weevil (Lissorhoptus amicophonus orchezophis grain) (Sitophilus granarius Linnaeus), rice weevil (Sitophillus oryzae Linnaeus)); earthen (garden) midges, cucumber flea beetles, root beetles, leaf beetles, potato and mining flies (fly-miners) in the Chrysomelidae family (for example, the Colorado beetle (Leptinotarsa decemlineata Say), corn flea (viferateraferateraferateraferateraferaferata) ; Scaribaeidae and other beetles from the Scaribaeidae family (for example, Japanese hrushchik (Popillia Japonica Newman) and European hrushchik (Rhizotrogus majalis Razoumowsky)); skin experts from the family Dermestidae; nutcracker beetles from the Elateridae family; bark beetles from the Scolytidae family and large flour beetles from the Tenebrionidae family. In addition, agricultural and non-agricultural pests include: adults and larvae (caterpillars) of the Dermaptera order (earwigs), including earwigs from the Forficulidae family (for example, an ordinary earwig (Forficula auricularia Linnaeus), black earwig (Chelisoches morio Fabricius) ; adults and nymphs of the orders Hemiptera (half-winged (bugs)) and Homoptera (homoptera), such as horsefly bugs from the family Miridae, cicadas from the Cicadidae family, cicadas (e.g. Empoasca spp.) from their family Cicadellidae, mare and dolphidae and Delphacidae, humpbacks from the Membracidae family, leaf flies from the Psyllidae family, whiteflies from the Aleyrodidae family, aphids from the Aphididae family, phylloxera from the Phylloxeridae family, mealybugs (feltfelds) from the Pseudococcidae family, insects, red worms, - Tingidae family lace mites, cabbage bugs Pentatomidae family, white-winged bugs (e.g. Blissus spp.) and other seed pests from the Lygaeidae family, pennies from the Cercopidae family, pumpkin bugs from the Coreidae family and cotton red bugs and red bugs from the Pyrrhocoridae family. The pest list also includes adults and larvae of the Acari order (acarid mites), such as spider mites and red mites in the Tetranychidae family (for example, European red mite (Panonychus ulmi Koch), two-spotted mite spider (Tetranychus urticae Kochani), Tetranychus mcdanieli McGregor)), squamous beetles in the Tenuipalpidae family (for example, citrus beetle (Brevipalpus lewisi McGregor)), gall-forming and bud mites in the Eriophydae family and other leaf-eating ticks and ticks that affect human health, i.e., animals house dust mites in the Epidermoptidae family, iron mites (cinnamon) in the Demodicidae family, grain mites in the Glycyphagidae family, ixodid mites in the Ixodidae family (for example, deer mite (Ixodes scapularis Say), Australian paralytic mite (Australian tick) Dermacentor variabilis Say), an amblyoma mite (Amblyomma americanum Linnaeus) and horse and itch mites in the families Psoroptidae, Pyemotidae and Sarcotidae; adult and not fully developed individuals of the order Orthoptera (orthoptera), including grasshoppers, grasshoppers, grasshoppers, Mexican (e.g. Melanoplus sanguinip es Fabricius, M. differentialis Thomas), locust (e.g. Schistocerca americana Drury), desert locust (Schistocerca gregaria Forskal), locust migratory (Locusta migratoria Linnaeus), brown cricket (Acheta domesticus Linnaeus), common bear (earth cancer) ( Gryllotalpa spp.)); Adult individuals and not fully developed individuals of the Diptera order (dipterous), including mining flies, gall midges, fruit flies (Tephritidae), Swedish flies (for example, Oscinella frit Linnaeus), soil larvae of flies, house flies ( for example, Musca domestica Linnaeus), small house flies (for example, Fannia canicularis Linnaeus, F. femoralis Stein), ordinary lighters (igra autumn ki) (for example, Stomoxis calcitrans Linnaeus), autumn flies, small cow lighters, blue meat flies (for example, Chrysomya spp., Phormia spp.), and other real pest flies, horse flies (for example, Tabanus spp.), horse nasopharyngeal gadflies (e.g. Gastrophilus spp., Oestrus spp.), bovine striped gadfly larvae (e.g. Hypoderma spp.), deer flies (e.g. Chrysops spp.), bloodsuckers (e.g. Melophagus ovinus Linnaeus) and other Brachycera (Short-billed ), mosquitoes (mosquitoes) (for example, Aedes spp., Anopheles spp., Culex spp.), black midges (for example, Prosimulium spp., Simulium spp.), biting midges, midges, mosquitoes, and other Nematocera; adults and not fully developed individuals of the Thysanoptera order (thrips), including onion (tobacco) thrips (Thrips tabaci Lindeman) and other leafy thrips; Hymenoptera pest insects (hymenoptera), including ants (e.g. red wood carp ant (Camponotus ferruginous Fabricius), black wood carp ant (Camponotus pennsylvanicus De Geer), pharaoh ant (Monomorium pharaonis Linnaepunata manor, you ), Richter's ant (Solenopsis geminata Fabricius), red forest ant (Solenopsis invicta Buren), Argentinean ant (Iridomyrmex humilis Mayr), paratrachin (Paratrechina longicornis Latreille), turfy ant (Tetramorium lasernesusesis), house odorous ant (Tapinoma sessile Say)), bees (including carpenter bees), hornets, golden Caranxes and wasps; insect pests of the order Isoptera (termites), including Mediterranean yellow-footed termite (Reticulitermes flavipes Kollar), Western Mediterranean termite (Reticulitermes hesperus Banks), Mediterranean Taiwanese termite (Coptotermes formosanus Shiraki), and ancient European-terrestrial insects other termites of economic importance; pests of the Thysanura order (bristle tails), such as common silverfish (Lepisma saccharina Linnaeus) and domestic silverfish (Thermobia domestica Packard); insect pests of the order Mallophaga (lice) and, including, head louse (Pediculus humanus capitis De Geer), louse (Pediculus humanus humanus Linnaeus), lice (Menacanthus stramineus Nitszsch), dog louse (Trichodectes canis De Geoed) chicken bellied (Goniocotes gallinae De Geer), sheep's lamb (Bovicola ovis Schrank), cattle louse, short-nosed blood-sucking (Haematopinus eurysternus Nitzsch), cattle louse, long-nosed blood-sucking (Linognathus vitriolidae, other attack people and animals; insect pests of the order Siphonoptera (fleas), including rat flea (Xenopsylla cheopis Rotschild), cat flea (Ctenocephalides felis Bouche), canine flea (Ctenocephalides canis Curtis), chicken flea (Gallus erythophyllus schaeophyllosa bacilliophyllus) ), human flea (Pulex irritans Linnaeus), and other fleas that bother mammals and birds. Additional covered arthropod pests include: Agapeae spiders (spiders), such as the brown hermit spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow weaver (Latrodectus mactans Fabricius), and the leg-footed in the Scutigeromorph (Scooters), such as the common flycatcher (Scutigera coleoptrata Linnaeus). The compounds of this invention are also active against members of the classes Nematoda (Nematodes, Roundworms), Cestoda (cestodes, tapeworms), Trematoda (trematodes) and Acanthocephala (scratches), including economically important members of the orders Strongylida, Ascaridida, Oxyurida, Rhabditida , Spirurida and Enoplida, such as, but not limited to, economically important agricultural pests (i.e., forming root growths, gall nematodes in the genus Meloidogyne, damaging nematodes in the genus Pratylenchus, causing root damage to the nematodes in the genus Trichodoris, etc. ) and affecting animal health x and human pests (i.e. all economically important trematodes, tapeworms and roundworms such as Strongylus vulgaris in horses, Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilaria immitis Leidy in dogs, Haemonchus contortus in sheep, Dirofilaria Leidy in dogs, Anoplocephala perfoliata in horses, Fasciola hepatica Linnaeus in ruminants, etc.)

The compounds of this invention exhibit particularly high activity against pests of the order Lepidoptera (Lepidoptera) (e.g. Alabama agrillacea Hübner (caterpillars of the American cotton scoop), Archips argyrospila Walker (fruit tree leaflets), A. rosana Linnaeus (ermine moth caterpillars) and other Archips species, Chilo suppressalis Walker (rice stem drill), Cnaphalocrosis medinalis Guenee (rice leaflet), Crambus caliginosellus Clemens (butterflies, corn roots), Crambus teterrellus Zincken (bluegrass fireworms, Cydia pomonas boomata Linomulus ), Earias vit ella Fabricius (spotted scoops), Helicoverpa armigera Hübner (American scoops), Helicoverpa zea Boddie (cotton scoops), Heliothis virescens Fabricius (tobacco scoops), Herpetogramma licarsisalis Walker (meadow moth), Lobesia botrana Denis & Schiffermulidae , Pectinophora gossypiella Saunders (pink boxed cotton worm), Phyllocnistis citrella Stainton (citrus juice beetle), Pieris brassicae Linnaeus (cabbage white), Pieris rapae Linnaeus (white boletus (Repubnica)), Plutella xeunbeteidaeusbünegella bunny beetroot camping worm), Spodoptera litura Fabricius (tobacco scoops, cocoonworms, whose caterpillars build about Suitable web nests), Spodoptera frugiperda J.E. Smith (scoops of grass), Trichoplusia ni Hübner (scoops of cabbage, scoops of neither) and Tuta absoluta Meyrick (flies of tomato mining)). The compounds of this invention also exhibit commercially significant activity on members of the order Homoptera (homoptera), including: Acyrthisiphon pisum Harris (aphid pea), Aphis craccivora Koch (aphid alfalfa), Aphis fabae Scopoli (aphid bean), Aphis gossa (aphid goboss) cotton, aphid gourd), Aphis pomi De Geer (aphid apple), Aphis spiraecola Patch (aphid meadowsweet), Aulacorthum solani Kaltenbach (aphid bindweed), Chaetosiphon fragaefolii Cockerell (aphid strawberry), Diuraphus russia) Dysaphis plantaginea Paaserini (aphid apple pink), Eriosoma lanigerum Hausmann (aphid apple blood), Hyalopterus pruni Geoffroy (aphid plum dust ), Lipaphis erysimi Kaltenbach (aphid cabbage), Metopolophium dirrhodum Walker (aphid cereal), Macrosipum euphorbiae Thomas (leaf aphid potato), Myzus persicae Sulzer (aphid peach-potato, aphid peach green), Nigian salad. Pemphigus spp. (root aphid and gall aphid), Rhopalosiphum maidis Fitch (leaf aphid aphids), Rhopalosiphum padi Linnaeus (bird aphid oats), Schizaphis graminum Rondani (common aphid aphids), Sitobion avenae Fabricius (aphyllous populus), spotted), Toxoptera aurantii Boyer de Fonscolombe (black aphid aphids) and Toxoptera citricida Kirkaldy (brown aphid aphids); Adelges spp. (hermes, adelges); Phylloxera devastatrix Pergande (phylloxera hickory), Bemisia tabaci Gennadius (tobacco whitefly, sweet potato whitefly), Bemisia argentifolii Bellows & Perring (magnolia whitefly), Dialeurodes citri Ashmead (whiteflies and whiteflies) Empoasca fabae Harris (potato cicadas), Laodelphax striatellus Fallen (small brown cicadas), Macrolestes quadrilineatus Forbes (aster cicadas), Nephotettix cinticeps Uhler (green cicadas), Nephotettix nigropictus Staleres brown cucumbers (Nigropictus stalgens), Pomegraniformes cereal maidis Ashmead (corn cicadas), Sogatella furcifera Horvath (white-backed cicadas), Sogatodes orizicola Muir (rice delphacide), Typhlocyba pomaria McAtee (apple cicadas), Erythroneoura spp. (grape cicadas); Magicidada septendecim Linnaeus (17-year-old cicadas); Icerya purchasi Maskell (Australian Scalyworm), Quadraspidiotus perniciosus Comstock (California Scorpion), Planococcus citri Risso (Citrus Worm) Pseudococcus spp. (a complex of other worms); Cacopsylla pyricola Foerster (pear throat), Trioza diospyri Ashmead (persimmon leaflet). These compounds also exhibit activity on members of the order Hemiptera (semi-rigid-winged (bugs)), including: Acrosternum hilare Say (green shield), Anasa tristis De Geer (sad diamond-bed bug), Blissus leucopterus leucopterus Say (white-winged bug) gossypii Fabricius (cotton bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-Schäffer (cotton red bug), Euchistus servus Say (brown bugs), Euchistus variolarius Palisot de Beauvous, with one henna grape (to spp. (a complex of bugs-pests of seeds), Leptoglossus corculus Say (bugs-bumps of pine seeds), Lygus lineolaris Palisot de Beauvois (meadow bugs), Nezara viridula Linnaeus (bugs of cotton-garden), Oebalus pugnax Fabricius (Onus of Dicus rice) (euphorbiaceae bug), Pseudatomoscelis seriatus Reuter (jumping cotton bug). Other insect orders suppressed by the compounds of this invention include the order Thysanoptera (thrips) (e.g., Frankliniella occidentalis Pergande (western thrips), Scirthothrips citri Moulton (citrus thrips), Sericothrips variabilis Beach (soybean thrips) and Thriman lapis linus , tobacco thrips); and the order Coleoptera (coleoptera) (for example, Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican beetle beetle) and nutcracker larvae of the genera Agriotes, Athous or Limonius).

The compounds of this invention can also be mixed with one or more other biologically active compounds or agents, including insecticides, fungicides, nematicides, bactericides, acaricides, growth regulators, such as rooting stimulants, chemostimulants, semi-chemicals, repellents, attractants, pheromones, stimulants nutrition, other biologically active compounds or entomopathogenic bacteria, virus or fungi, for the formation of a multicomponent pesticide, providing an even wider range of CTD agricultural applicability. Thus, this 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 agent, and this composition may further comprise at least one surfactant, at least one solid diluent or liquid diluent. Examples of such biologically active compounds or agents with which the compounds of this invention can be prepared are: insecticides such as abamectin, acefate, acetamipride, amidoflumet (S-1955), avermectin, azadirachtin, azinofos-methyl, bifentrin, binphenazate, buprofesin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenoside, clothianidin, cyfluthrin, beta-cyfluthrin, cygalotrin, lambda-cygalotrin, cypermethrin, ciromazin, deltamethrin, diafentiuron, diazinone, diazinone, diazinone, diazinone , Emamectin, endosulfan, esfenvalerate, ethiprole, fenotikarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonofos, halofenozide, hexaflumuron, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaldehyde, metamidophos, methidation, methomyl, methoprene, methoxychlor, monocrotophos, methoxyphenoside, nithiazine, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion methyl, permethrin, foratos, phosphonofon, phosphonofon, phosphonofon, phosphonofon, phosphonofon, phosphonofon, phosphonofon pymetrosine, pyridals , Pyriproxyfen, rotenone, spinosad, spiromezifin (BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon and triflumuron; fungicides such as acibenzolar, azoxystrobin, benomyl, blasticidin-3, Bordeaux liquid (tribasic copper sulfate), bromukonazole, carpropamide, captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cyclofenofenamide, cyclofenophenide (S) -3,5-dichloro-N- (3-chloro-1-ethyl 1-methyl-2-oxopropyl) -4-methylbenzamide (RH 7281), diclocimet (S-2900), diclomesine, dicloran, diphenoconazole, (S) -3,5-dihydro-5-methyl-2- (methylthio) -5-phenyl-3- (phenylamino) -4H-imidazol-4-one (RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole- M, dodin, edif nfos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenkaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorf, fentinacetate, fentinhydroxide, fluazinam, fludioxonil, flumethoformum fluoroformum (LFF97), RF25, RF25, RF25, RF25, RF33 ), fluquinconazole, fluzilazole, flutolanil, flutriafol, folpet, fosetil-aluminum, furalaxil, furametapir (S-82658), hexaconazole, ipconazole, iprobenfos, iprodione, isoprotiolan, kazugimeksimefilmekmecocimecimecmecophenolmec mimez, mromecoke, mrezocenec mimezocenec mrezocenec mrezocrebmecref , metconazole, metominostrobin / phenominostrob n (SSF-126), metraphenone (AC375839), miklobutanil, neo-azocin (iron (III) methanarsonate), nikobifen (BAS 510), oryzastrobin, oxadixyl, penconazole, penicuron, probenazole, prochlorase, propamocarb, proxinazole -KQ926), prothioconazole (JAU 6476), pyrifenox, pyraclostrobin, pyrimethanil, pyrochilone, quinoxifene, spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole, tifluzamide, triadistolimetholazole, triadiolazole, thiadialefin triazole, triadiol azide, triadiol azide, triadiol azide validamycin and vinclozolin; nematicides, such as aldicarb, oxamyl and phenamiphos; bactericides such as sterptomycin; acaricides such as amitraz, quinomethionate, chlorobenzylate, cyhexatin, dicofol, dienochlor, ethoxazole, phenazachine, phenbutatin oxide, fenpropatrin, fenpiroksimat, hexithiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis, including aizawai and kurstaki subspecies, Bacillus thuringiensis delta-endotoxin, baculovirus, and entomopathogenic bacteria, virus, and fungi. The compounds of this invention and their compositions can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as the toxin Bacillus thuringiensis). The action of exogenously applied compounds of this invention, inhibiting invertebrate pests, can be synergistic with expressed toxin proteins.

General reference regarding these agricultural protective agents is The Pesticide Manual, 12 ^{th Edition, CDS Tomlin, Ed.} , British Crop Protection Council, Farnham, Surrey, UK, 2000.

Preferred insecticides and acaricides for mixing with the compounds of this invention include pyrethroids such as cypermethrin, cygalotrin, tsiflutrin, beta-tsiflutrin, esfenvalerate, fenvalerate and tralamometrin; carbamates such as phenothicarb, methomyl, oxamyl and thiodicarb; neonicotinoids such as clothianidin, imidacloprid and thiacloprid; sodium neural channel blockers such as indoxacarb; insecticidal macrocyclic lactones such as spinosad, abamectin, avermectin and emamectin; γ-aminobutyric acid antagonists (GABA) such as endosulfan, etiprol and fipronil; insecticidal ureas such as flufenoxuron and tirflumuron; juvenile hormone mimetics such as diophenolan and pyriproxifen; pimetrosine; and amitraz. Preferred biological agents for mixing with the 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 insectivorous fungi.

Most preferred mixtures include a mixture of a compound of the invention with cygalotrin; a mixture of a compound of the present invention with beta-cyfluthrin; a mixture of a compound of this invention with esfenvalerate; a mixture of a compound of this invention with methomyl; a mixture of a compound of the invention with imidacloprid; a mixture of a compound of this invention with thiacloprid; a mixture of a compound of this invention with indoxacarb; a mixture of a compound of this invention with abamectin; a mixture of a compound of the present invention with endosulfan; a mixture of a compound of the present invention with etiprol; a mixture of a compound of the present invention with fipronil; a mixture of a compound of the present invention with flufenoxuron; a mixture of a compound of the present invention with pyriproxyphene; a mixture of a compound of the present invention with pimetrosine; a mixture of a compound of the present invention with amitraz; a mixture of a compound of the present invention with Bacillus thuringiensis and a mixture of a compound of the present invention with Bacillus thuringiensis delta-endotoxin.

In some cases, in order to overcome pest resistance, combinations with other compounds for controlling invertebrate pests will be particularly preferred. Thus, the composition according to the invention may further comprise a biologically effective amount of at least one additional invertebrate pest control compound or agent having a similar pest kill spectrum but a different mechanism of action. Contacting a plant genetically modified to express a plant protecting compound (eg, a protein) or a locus of the plant with a biologically effective amount of a compound of this invention can also provide a wider range of plant protection and be useful in overcoming pest resistance.

The quantitative proportions when using such compounds or agents together with the compound described by formula 1 are determined by the norms of application of the latter, well known to specialists from publicly available sources of information, in particular the above-mentioned reference source (1) "The Pesticide Manual", as well as other general reference manuals (The detailed output from the cited reference guides is given below after table 4).

The following Table 4 includes data on the norms of use of known biologically active compounds or agents in accordance with the indicated publicly available information sources and calculated mass ratios for the use of such compounds or agents together with the compound described by formula 1. Table 4 presents the name of the known biologically active compound or agent (column 1), the class to which it belongs by the type of its pesticidal action (column 2), the application rate in grams per hectare (g / ha) for a known biologically active compound or agent (column 3), a link to a known reference source from which the spread rate (column 4) and the mathematically obtained mass ratio between the compound described by formula 1 and the known biologically active compound or agent are obtained (column 5).

For example, the second row in table 4 shows that abamectin - a macrocyclic lactone - is characterized by a spread rate of 5-28 g / ha. This information is available in reference 1, The Pesticide Manual. The mass ratio between the compound described by formula 1 and abamectin is given as a range in the range from 400: 1 to 1: 2.8. The first 400: 1 ratio is obtained by dividing the highest norm for the compound described by formula 1 (2000 g / ha) by the lowest norm for abamectin (5 g / ha). Similarly, dividing the highest norm for abamectin (28 g / ha) by the lowest norm for the compound described by formula 1 (10 g / ha) results in a ratio of 1: 2.8. The mass ratios listed in table 4 for other known biologically active compounds or agents are calculated in a similar way.

TABLE 4

Additional biologically active component Class of biologically active component Application rate (g / ha) Reference source Possible mass ratio The compound described by formula 1 (main biologically active component) 10-2000 The present invention Abamectin Macrocyclic lactones 5-28 one 400: 1 to 1: 2.8 Acephate Organophosphorus compound 500-1000 one 4: 1 to 1: 100 Acetamipride Neonicotinoids 20-100 one 100: 1 to 1:10 Avermectin Macrocyclic lactones 5-40 one 400: 1 to 1: 4 Azadirahtin 10-20 2 200: 1 to 1: 2 Amitraz 300-1000 2 7: 1 to 1: 100 Bifentrin Pyrethroids 5-45 one 400: 1 to 1: 4.5 Binfenazate 250-750 one 8: 1 to 1:75 Buprofesin 50-500 one 40: 1 to 1:50 Carbofuran Carbamates 300-3400 2 7: 1 to 1: 340 Chlorfenapyr 50-100 2 40: 1 to 1:10 Chlorofluazuron 12-100 2 167: 1 to 1:10 Chlorpyrifos Organophosphorus compound 110-5700 2 18: 1 to 1: 570 Chlorpyrifosmethyl Organophosphorus compound 1500-5000 2 1: 1 to 1: 500 Chromafenoside 25-50 2 80: 1 to 1: 5 Clothianidin Neonicotinoids fifty 2 40: 1 to 1: 5 Tsiflutrin Pyrethroids 15-40 one 133: 1 to 1: 4 Beta-cyfluthrin Pyrethroids 7.5-20 one 267: 1 to 1: 2 Cigalotrin Pyrethroids 5-30 2 400: 1 to 1: 3 Lambda cygalothrin Pyrethroids 5-30 2 400: 1 to 1: 3 Cypermethrin Pyrethroids 23-85 2 87: 1 to 1: 8.5

Additional biologically active component Class of biologically active component Application rate (g / ha) Reference source Possible mass ratio Cyromazine 75-450 one 27: 1 to 1:45 Deltamethrin Pyrethroids 2,5-21 one 800: 1 to 1: 2.1 Diafentyuron 300-500 one 7: 1 to 1:50 Diazinon Organophosphorus compound 300-600 one 7: 1 to 1:60 Diflubenzuron 25-150 one 80: 1 to 1:15 Dimethoate Organophosphorus compound 300-700 2 7: 1 to 1:70 Diophenolan 10-15 2 200: 1 to 1: 1.5 Emamectin (benzoate) 5-25 one 400: 1 to 1: 2.5 Endosulfan 30-60 2 67: 1 to 1: 6 Etiprol 300-450 2 7: 1 to 1:45 Esfenvalerate Pyrethroids 5-25 one 400: 1 to 1: 2.5 Fenotikarb Carbamates 1200-1800 one 2: 1 to 1: 180 Phenoxycarb Juvenile hormone imitators 1130-1700 2 2: 1 to 1: 170 Fenpropatrine Pyrethroids 114 2 18: 1 to 1: 11.4 Fenvalerate Pyrethroids 55-227 2 36: 1 to 1: 22.7 Fipronil GABA antagonist 10-200 one 200: 1 to 1:20 Flonicamide 50-100 2 40: 1 to 1:10 Flucytrinate Pyrethroids 25-50 2 80: 1 to 1: 5 Tau flucytrinate Pyrethroids 28-114 2 71: 1 to 1: 11.4 Flufenerim 10-55 2 200: 1 to 1: 5.5 Flufenoxuron 5-100 2 400: 1 to 1:10 Phonophos 1000-1500 2 2: 1 to 1: 150 Halofenoside 1120-2240 one 2: 1 to 1: 224 Hexaflumuron Urea 70-280 2 From 29: 1

Additional biologically active component Class of biologically active component Application rate (g / ha) Reference source Possible mass ratio insecticidal action until 1:28 Imidacloprid Neonicotinoids 35-490 2 57: 1 to 1:49 Indoxacarb Neuronal Sodium Channel Blockers 12.5-125 one 160: 1 to 1: 12.5 Isofenfos Organophosphorus compound 1120-2240 3 2: 1 to 1: 224 Lufenuron Urea insecticidal action 10-50 one 200: 1 to 1: 5 Malathion 600-3400 2 3: 1 to 1: 340 Metamidophos Organophosphorus compound 350-1200 one 6: 1 to 1: 120 Methidation Organophosphorus compound 300-2300 2 7: 1 to 1: 230 Metomil Carbamates 110-1700 2 18: 1 to 1: 170 Metoprene Juvenile hormone imitators 57-114 2 35: 1 to 1: 11.4 Methoxychlor 280-560 2 7: 1 to 1:56 Monocrotophos Organophosphorus compound 250-500 2 8: 1 to 1:50 Methoxyphenoside 20-300 one 100: 1 to 1:30 Novaluron Urea insecticidal action 75-250 2 27: 1 to 1:25 Oxamil Carbamates 300 2 7: 1 to 1:30 Parathion Organophosphorus compound 113-1130 2 18: 1 to 1: 113 Parathionomethyl Organophosphorus compound 113-1130 2 18: 1 to 1: 113 Permethrin Pyrethroids 25-200 one 80: 1 to 1:20 Forat Organophosphorus compound 750-3400 one 3: 1 to 1: 340 Fozalon Organophosphorus compound 500-1500 2 4: 1 to 1: 150 Fosmet Organophosphorus compound 500-1000 one 4: 1 to 1: 100 Fosfamidone 300-1700 2 7: 1 to 1: 170

Additional biologically active component Class of biologically active component Application rate (g / ha) Reference source Possible mass ratio Pyrimicarb Carbamates 50-750 one 40: 1 to 1:75 Profenofos Organophosphorus compound 600-1200 one 3: 1 to 1: 120 Pymetrosine 150-300 one 13: 1 to 1:30 Pyridaben 100-300 one From 20: 1 to 1:30 Pyridyl 84-224 2 24: 1 to 1: 22.4 Pyriproxyphene Juvenile hormone simulator 25-125 2 80: 1 to 1: 12.5 Rotenone 600-2300 2 3: 1 to 1: 230 Spin garden Macrocyclic lactones 25-150 2 80: 1 to 1:15 Spiromesifen 400-750 one 5: 1 to 1:75 Sulphrophos Organophosphorus compound 600-1700 2 3: 1 to 1: 170 Tebufenoside 66-335 one 30: 1 to 1: 33.5 Teflubenzuron Urea insecticidal action 20-200 2 100: 1 to 1:20 Teflutrin Pyrethroids 12-150 2 167: 1 to 1:15 Terbufos Organophosphorus compound 250-2000 one 8: 1 to 1: 200 Tetrachlorvinphos Organophosphorus compound 110-1700 2 18: 1 to 1: 170 Thiacloprid Neonicotinoids 48-216 2 42: 1 to 1: 21.6 Thiamethoxam Neonicotinoids 10-200 one 200: 1 to 1:20 Thiodicarb Carbamates 200-1000 one 10: 1 to 1: 100 Tralomethrin Pyrethroids 7.5-20 one 267: 1 to 1: 2 Trichlorfon Organophosphorus compound 300-1200 one 7: 1 to 1: 120 Triflumuron 57-567 2 35: 1 to 1:57 Aldicarb Carbamates 600-11400 2 3: 1 to 1: 1140 Quinomethionate 415-1122 2 5: 1 to 1: 112

Additional biologically active component Class of biologically active component Application rate (g / ha) Reference source Possible mass ratio Cyhexatin 20-30 2 100: 1 to 1: 3 Dicofol 500-2000 one 4: 1 to 1: 200 Dienochlor 110-220 3 18: 1 to 1:22 Ethoxazole 50-100 one 40: 1 to 1:10 Phenazachine 56-560 2 36: 1 to 1:56 Fenbutatin oxide 600-2300 2 3: 1 to 1: 230 Fenpiroximate 25-50 2 80: 1 to 1: 5 Hexithiazox 150-300 one 13: 1 to 1:30 Propargite 750-1800 one 3: 1 to 1: 180 Tebufenpirad 50-200 one 40: 1 to 1:20 Delta-endotoxin Bacillus thuringiensis 560-2240 2 4: 1 to 1: 224 Bacillus thuringiensis, subspecies kurstaki 90-500 2 22: 1 to 1:50

(1) The Pesticide Manual, 12 ^{th Edition, CDS Tomlin, Ed.} , British Crop Protection Council, Farnham, Surrey, UK., 2000.

(2) Global Insecticide Directory, 2nd Edition, R. Bryant, M. G. Bite and W. L. Hopkins, Ed., Agranova, Orpington, Kent, UK., 1999.

(3) Insect and Disease Control Guide, Vol. 1, R. T. Meister Ed., Meister Publishing Company, Willoughby, OH, USA, 1999.

EXAMPLE E

Table E lists the specific compositions containing the compound described by formula 1, together with other biologically active components, intended to inhibit the development of invertebrate agricultural pests in accordance with the methods of the present invention. The compound numbers listed in the first column of Table E correspond to the compound numbers given in TABLE OF INDICES A.

The second column of Table E lists specific additional biologically active components (for example, “abamectin” in the first row). The third column of Table E gives the class to which the particular compound belongs. The fourth column of Table E gives a typical range of weight ratios for amounts in which an additional component is used with respect to the compound described by Formula 1 (for example, “From 50: 1 to 1:10” abamectin with respect to Compound 1 on a weight basis ) Thus, the first row of Table E, for example, specifically describes the combination of the compound described by formula 1, compound 1, and abamectin, and indicates that abamectin is a representative of macrocyclic lactones, and it is reported that abamectin and compound 1 are usually used in bulk ratio in the range from 50: 1 to 1:10. The information in the remaining rows in table E should be interpreted in the same way.

Table E

A composition comprising a compound described by formula 1, and at least one additional biologically active compound or agent.

Connection number Additional biologically active component Class The usual mass ratio one Abamectin Macrocyclic lactone 50: 1 to 1:10 2 Acephate Organophosphate 100: 1 to 1: 100 3 Acetamipride Neonicotinoid 150: 1 to 1: 200 four Aldicarb Carbamate 200: 1 to 1: 100 5 Amidoflumet 200: 1 to 1: 100 7 Amitraz Formamidine 200: 1 to 1: 100 8 Avermectin Macrocyclic lactone 50: 1 to 1:10 9 Azadirahtin Plant extracts 100: 1 to 1: 100 eleven Azinfosmetil Organophosphate 100: 1 to 1: 100 12 Delta-endotoxin Bacillus thuringiensis Biological agent 50: 1 to 1:10 13 Bacillus thuringiensis, subspecies Aizawai Biological agent 50: 1 to 1:10 fourteen Bacillus thuringiensis, a subspecies of Kurstaki Biological agent 50: 1 to 1:10 fifteen Baculovirus Biological agent 50: 1 to 1:10 16 Beta-cyfluthrin Pyrethroid 50: 1 to 1:20 17 Biphenazate 200: 1 to 1: 100 eighteen Bifentrin Pyrethroid 50: 1 to 1:10 19 Buprofesin Chitin Synthesis Inhibitor 10: 1 to 1: 150 21 Carbofuran Carbofuran 200: 1 to 1: 100 22 Quinomethionate Quinoxaline 200: 1 to 1: 100

Connection number Additional biologically active component Class The usual mass ratio 23 Chlorfenapyr Arylpyrrole 1200: 1 to 1: 200 24 Chlorofluazuron Chitin Synthesis Inhibitor 10: 1 to 1: 150 25 Chlorobenzylate Bridge Diphenyl 50: 1 to 1:50 26 Chlorpyrifos Organophosphate 100: 1 to 1: 100 27 Chlorpyrifosmethyl Organophosphate 100: 1 to 1: 100 28 Chromafenoside Moult hormone agonist 50: 1 to 1: 250 29th Clothianidin Neonicotinoid 100: 1 to 1: 400 31 Tsiflutrin Pyrethroid 50: 1 to 1:10 32 Cigalotrin Pyrethroid 50: 1 to 1:10 33 Cyhexatin Tin Organics 100: 1 to 1: 100 34 Cypermethrin Pyrethroid 50: 1 to 1:10 35 Cyromazine Chitin Synthesis Inhibitor 10: 1 to 1: 150 36 Deltamethrin Pyrethroid 50: 1 to 1:10 37 Diafentyuron Thiourea 150: 1 to 1: 200 38 Diazinon Organophosphate 100: 1 to 1: 100 39 Dicofol Bridge Diphenyl 200: 1 to 1: 100 41 Dienochlor Organochlorine 100: 1 to 1: 100 42 Diflubenzuron Chitin Synthesis Inhibitor 10: 1 to 1: 150 43 Dimethoate Organophosphate 100: 1 to 1: 100 44 Diophenolan Molt inhibitor From 100: 1

Connection number Additional biologically active component Class The usual mass ratio up to 1: 100 45 Emamectin Macrocyclic lactone 50: 1 to 1:10 46 Endosulfan GABA antagonist 50: 1 to 1: 100 47 Entomopathogenic bacterium Biological agent 50: 1 to 1:50 48 Entomopathogenic virus Biological agent 50: 1 to 1:50 49 Insectivorous fungus Biological agent 50: 1 to 1:50 51 Esfenvalerate Pyrethroid 100: 1 to 1:10 52 Etiprol GABA antagonist 50: 1 to 1: 100 . 53 Ethoxazole Tick development inhibitor 50: 1 to 1:50 54 Fenamiphos Organophosphate 100: 1 to 1: 100 55 Phenazachine Mitochondrial Electron Transport Inhibitor 200: 1 to 1: 100 56 Fenbutatin oxide Tin Organics 100: 1 to 1: 100 57 Fenotikarb Carbamate 200: 1 to 1: 100 58 Phenoxycarb Juvenile hormone simulator 200: 1 to 1: 100 59 Fenpropatrine Pyrethroid 100: 1 to 1:10 61 Fenpiroximate Mitochondrial Electron Transport Inhibitor 200: 1 to 1: 100 62 Fenvalerate Pyrethroid 100: 1 to 1:10 63 Fipronil GABA antagonist 50: 1 to 1: 100 64 Flonicamide Neonicotinoid 200: 1 to 1: 100

Connection number Additional biologically active component Class The usual mass ratio 65 Flucytrinate Pyrethroid 50: 1 to 1:10 66 Flufenerim Pyrimidinamine 200: 1 to 1: 100 67 Flufenoxuron Urea insecticidal action 10: 1 to 1: 150 68 Phonophos Organophosphate 100: 1 to 1: 100 69 Halofenoside Moult hormone agonist 50: 1 to 1: 250 71 Hexaflumuron Urea insecticidal action 10: 1 to 1: 150 72 Hexithiazox Tick development inhibitor 50: 1 to 1:50 73 Imidacloprid Neonicotinoid 100: 1 to 1: 200 74 Indoxacarb Neuronal Sodium Channel Blocker 100: 1 to 1: 200 75 Isofenfos Organophosphate 100: 1 to 1: 100 76 Lambda cygalothrin Pyrethroid 50: 1 to 1:10 77 Lufenuron Urea insecticidal action 10: 1 to 1: 150 78 Malathion Organophosphate 100: 1 to 1: 100 79 Metaldehyde 200: 1 to 1: 100 81 Metamidophos Organophosphate 100: 1 to 1: 100 82 Methidation Organophosphate 100: 1 to 1: 100 83 Metomil Carbamate 200: 1 to 1: 100 84 Metoprene Juvenile hormone simulator 200: 1 to 1: 100

Connection number Additional biologically active component Class The usual mass ratio 85 Methoxychlor Organochlorine 100: 1 to 1: 100 86 Methoxyphenoside Moult hormone agonist 50: 1 to 1: 250 87 Monocrotophos Organophosphate 100: 1 to 1: 100 88 Nithiazine Neonicotinoid 150: 1 to 1: 200 89 Novaluron Urea insecticidal action 10: 1 to 1: 150 91 Noviflumuron Chitin Synthesis Inhibitor 10: 1 to 1: 150 92 Oxamil Carbamate 100: 1 to 1:50 93 Parathion Organophosphate 100: 1 to 1: 100 94 Parathionomethyl Organophosphate 100: 1 to 1: 100 95 Permethrin Pyrethroid 100: 1 to 1:10 96 Forat Organophosphate 100: 1 to 1: 100 97 Fozalon Organophosphate 100: 1 to 1: 100 98 Fosmet Organophosphate 100: 1 to 1: 100 99 Fosfamidone Organophosphate 100: 1 to 1: 100 101 Pyrimicarb Carbamate 200: 1 to 1: 100 102 Profenofos Organophosphate 100: 1 to 1: 100 103 Propargite Sulfuric ester 100: 1 to 1: 200 104 Pymetrosine Antifidding 200: 1 to 1: 100 105 Pyridaben Mitochondrial inhibitor 200: 1 to 1: 100

Connection number Additional biologically active component Class The usual mass ratio electron transport 106 Pyridyl 200: 1 to 1: 100 107 Pyriproxyphene Juvenile hormone simulator 200: 1 to 1: 100 108 Rotenone Mitochondrial Electron Transport Inhibitor 200: 1 to 1: 100 109 Spin garden Macrocyclic lactone 50: 1 to 1:10 111 Spiromesifen Teronic Acid 100: 1 to 1: 200 112 Sulphrophos Organophosphate 100: 1 to 1: 100 113 Tau fluvalinate Pyrethroid 100: 1 to 1:10 114 Tebufenoside Moult hormone agonist 50: 1 to 1: 250 115 Tebufenpirad Mitochondrial Electron Transport Inhibitor 200: 1 to 1: 100 116 Teflubenzuron Chitin Synthesis Inhibitor 10: 1 to 1: 150 117 Teflutrin Pyrethroid 100: 1 to 1:10 119 Terbufos Organophosphate 100: 1 to 1: 100 121 Tetrachlorvinphos Organophosphate 100: 1 to 1: 100 122 Thiacloprid Neonicotinoid 100: 1 to 1: 200 123 Thiamethoxam Neonicotinoid 100: 1 to 1: 200 124 Thiodicarb Carbamates 200: 1 to 1: 100 125 Thiosultap Sodium Oksimkarbamat 200: 1 to 1: 100 126 Tralomethrin Pyrethroids 100: 1 to 1:10

Connection number Additional biologically active component Class The usual mass ratio 127 Trichlorfon Organophosphate 100: 1 to 1: 100 128 Triflumuron Urea insecticidal action 10: 1 to 1: 150

Mixtures containing combinations of the active components listed in Table E with 1: 1 weight ratios were prepared using a solution containing 10% acetone, 90% water and 300 ppm non-ionic surfactant X-77® Spreader Lo- Foam Formula containing alkylaryl polyoxyethylene, free fatty acids, glycols and isopropanol (from Loveland Industries, Inc.) and tested according to the protocol described for TEST A, in which the concentration of each active component was 50 ppm Each mixtures provided excellent plant protection levels (10% or less damage due to eating).

Invertebrate pests are destroyed in agricultural and non-agricultural applications by applying one or more compounds of this invention in an effective amount to the environment of these pests, including an agricultural and / or non-agricultural pest infection center, a zone to be protected, or directly to the pests to be destroyed. Thus, this invention further relates to a method of controlling invertebrate pests, comprising contacting invertebrate pests or their environment with a biologically effective amount of one or more compounds of the present invention or with a composition containing at least one such compound, or with a composition containing at least one such compound and an effective amount of at least one additional biologically active compound or agent. Examples of suitable compositions containing a compound of the present invention and an effective amount of at least one additional biologically active compound or agent include granular compositions in which the additional biologically active compound or agent is present on the same granule as the compound of the present invention, or on granules present separately from the granules of the compounds of this invention.

A preferred contact method is spraying. Alternatively, a granular composition containing a compound of the invention may be applied to the foliage of a plant or to the soil. The compounds of the present invention are also efficiently delivered through absorption by the plant by contacting the plant with a composition containing the compound of the present invention, applied in the form of impregnating the soil with a liquid finished form, applying a granular finished form to the soil, processing the seedling box or immersing seedlings. The compounds are also effective in topical application of a composition containing a compound of the present invention to a pest infection site. Other contacting methods include applying a compound or composition of the present invention using direct-acting contact spray solutions or aftereffect solutions, air spraying solutions, gels, seed pelleting (seed coating), microencapsulation, systemic absorption, baits, clips, boluses , fogging agents, fumigaites, aerosols, dusts and many other means. Compounds of this invention may also be impregnated with materials for the manufacture of invertebrate pest control devices (e.g., insect nets).

The compounds of this invention can be included in baits that are eaten by invertebrates, or can be found in devices such as traps and the like. Granules or baits containing 0.01-5% of the active ingredient, 0.05-10% of a moisture-retaining agent (s) and 40-99% of vegetable flour, are effective in killing soil insects at very low application rates, in particular when doses of the active ingredient that are lethal if swallowed rather than in direct contact.

The compounds of this invention can be used in pure form, but the most commonly used is a formulation containing one or more compounds with suitable carriers, diluents and surfactants and, optionally, in combination with food, depending on the intended end use. A preferred method of use includes spraying an aqueous dispersion or solution in the refined oil of these compounds. Combinations with spray oils, concentrations of spray oils, tackifiers, spreaders, adjuvants, other solvents and synergists such as piperonyl butoxide often increase the effectiveness of the compounds.

The application rate required for effective suppression (ie, a “biologically effective amount”) will depend on factors such as the type of invertebrate to be destroyed, the life cycle of the pest, stage of life, size, location, season, culture host animal, "feeding" behavior, mating behavior, humidity, ambient temperature, and the like. Under normal circumstances, application rates of approximately 0.01–2 kg of active ingredient per hectare are sufficient to kill pests in agricultural ecological systems, but as small as 0.0001 kg / hectare may be sufficient, or as large as may be required. 8 kg / hectare. For non-agricultural applications, effective application rates will be in the range of about 0.1 to 50 mg / square meter, but as small as 0.1 mg / square meter may be sufficient, or as large as 150 mg / may be required. square meter. One of skill in the art can easily determine the biologically effective amount necessary for the desired level of invertebrate pest control.

The following Tests in the Biological Examples section of the present invention demonstrate the effectiveness of suppressing the compounds of this invention on specific pests. "Suppression effectiveness" is an inhibition of arthropod development (including their mortality), which causes significantly reduced eating. However, the pest protection provided by these compounds is not limited to these species. See Index Table A for compound descriptions. The following abbreviations are used in this index table: t means tertiary, n means normal, i means iso, s means secondary. Me means methyl, Et means ethyl, Pr means propyl and Bu means butyl; accordingly, i-Pr means isopropyl, sBu means secondary butyl, etc. The abbreviation "Ex" means "Example" and is accompanied by a number indicating in which example this compound is obtained.

TABLE OF INDICES A

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Mp (° C) one Me Br CF ₃ i-pr H Cl 197-198 2 (Ex. 1) Me Cl CF ₃ i-pr H Cl 195-196 3 Me Cl CF ₃ t-bu H Cl 223-225 4 (Ex. 2) Me Cl CF ₃ Me H Cl 185-186 5 Br Br CF ₃ i-pr H Cl 192-193 6 Br Br CF ₃ t-bu H Cl 246-247 7 Br Br CF ₃ Me H Cl 162-163 8 Br Br CF ₃ Et H Cl 188-189 9 Cl Cl CF ₃ i-pr H Cl 200-201 10 Cl Cl CF ₃ t-bu H Cl 170-172 eleven Cl Cl CF ₃ Me H Cl 155-157 12 Cl Cl CF ₃ Et H Cl 201-202 13 Me Br CF ₃ t-bu H Cl 247-248 fourteen Me Br CF ₃ Et H Cl 192-193 fifteen Me F CF ₃ i-pr H Cl 179-180 16 Me Br Br i-pr H Cl 185-187 17 Me CF ₃ CF ₃ i-pr H Cl 235-236 eighteen Me CF ₃ CF ₃ Et H Cl 216-217 19 Me I CF ₃ i-pr H Cl 188-189 20 (Ex. 6) Me Cl Br Me H Cl 162-164 21 Me Cl Br t-bu H Cl 159-161 22 Br Br Br i-pr H Cl 162-163 23 Br Br Br Me H Cl 166-168 24 Br Br Br t-bu H Cl 210-212 25 Cl Cl Br i-pr H Cl 188-190

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Mp (° C) 26 Cl Cl Br t-bu H Cl 179-180 27 (Ex. 5) Me Cl Br i-pr H Cl 159-161 28 Cl Cl CF ₃ i-pr H Cl 200-202 29th Cl Br CF ₃ t-bu H Cl 143-145 thirty Cl Br CF ₃ Me H Cl 171-173 31 Me Br Br Me H Cl 147-149 32 Me Br CF ₃ Me H Cl 222-223 33 (Ex 3) Me Cl Cl i-pr H Cl 173-175 34 (Ex. 4) Me Cl Cl Me H Cl 225-226 35 Me Cl Cl t-bu H Cl 163-165 36 Me Br Cl i-pr H Cl 152-153 37 Me Br Cl Me H Cl 140-141 38 Me Br Br t-bu H Cl 215-221 39 Me I CF ₃ Me H Cl 199-200 40 Me CF ₃ CF ₃ t-bu H Cl 148-149 41 Me Cl Cl Et H Cl 199-200 42 Br Br Cl i-pr H Cl 197-199 43 Br Br Cl Me H Cl 188-190 44 Br Br Cl t-bu H Cl 194-196 45 Br Br Cl Et H Cl 192-194 46 Cl Cl Cl i-pr H Cl 197-199 47 Cl Cl Cl Me H Cl 205-206 48 Cl Cl Cl t-bu H Cl 172-173 49 Cl Cl Cl Et H Cl 206-208 fifty Me F Br t-bu H Cl 124-125 51 Br Br Br Et H Cl 196-197 52 Cl Cl Br Me H Cl 245-246 53 Cl Cl Br Et H Cl 214-215 54 Me Br Br Et H Cl 194-196 55 Me I Br Me H Cl 229-230 56 Me I Br i-pr H Cl 191-192 57 Me CF ₃ CF ₃ Me H Cl 249-250 58 Me Cl CF ₃ Et H Cl 163-164 59 Me I CF ₃ Et H Cl 199-200 60 Me I CF ₃ t-bu H Cl 242-243 61 Me Cl Br Et H Cl 194-195

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Mp (° C) 62 Me F CF ₃ Me H Cl 213-214 63 Me F CF ₃ Et H Cl 212-213 64 Me F CF ₃ t-bu H Cl 142-143 65 Me F Br Me H Cl 214-215 66 Me F Br Et H Cl 205-205 67 Me F Br i-pr H Cl 206-208 68 Me F Cl i-pr H Cl 184-185 69 Me F Cl Me H Cl 180-182 70 Me F Cl Et H Cl 163-165 71 Me Br Cl Et H Cl 192-194 72 Me I Cl Me H Cl 233-234 73 Me I Cl Et H Cl 196-197 74 Me I Cl i-pr H Cl 189-190 75 Me I Cl t-bu H Cl 228-229 76 Me Br Cl t-bu H Cl 224-225 77 Br Br Cl Me Me Cl 153-155 78 Me Br CF ₃ Me Me Cl 207-208 79 Cl Cl Cl Me Me Cl 231-232 80 Br Br Br Me Me Cl 189-190 81 Cl Cl Br Me Me Cl 216-218 82 Cl Cl CF ₃ Me Me Cl 225-227 83 Me Br OCH ₂ CF ₃ i-pr H Cl 213-215 84 Me Br OCH ₂ CF ₃ Me H Cl 206-208 85 Me Cl OCH ₂ CF ₃ i-pr H Cl 217-218 86 Me Cl OCH ₂ CF ₃ Et H Cl 205-207 87 (Project 10) Me Cl OCH ₂ CF ₃ Me H Cl 207-208 88 Me Br OCH ₂ CF ₃ Et H Cl 208-211 89 Me Br OCH ₂ CF ₃ t-bu H Cl 213-216 90 Br Br CF ₃ Me Me Cl 228-229 91 Cl Br CF ₃ Me Me Cl 238-239 92 Cl FROM OCH ₂ CF ₃ i-pr H Cl 232-235 93 Cl Cl OCH ₂ CF ₃ Me H Cl 192-195 94 Cl Cl OCH ₂ CF ₃ Me Me Cl 132-135 95 Br Br OCH ₂ CF ₃ i-pr H Cl 225-227 96 Br Br OCH ₂ CF ₃ Me H Cl 206-208 97 Br Br OCH ₂ CF ₃ Me Me Cl 175-177

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Mp (° C) 98 Cl Br Br Me Me Cl 237-238 99 Cl Br Cl Me H Cl 228-229 one hundred Cl Br Cl Me Me Cl 236-237 101 Cl Br Br Me H Cl 226-227 102 Cl F CF ₃ Me Me Cl 215-216 103 Cl F CF ₃ Me H Cl 219-220 104 Br F Br Me Me Cl 235-236 105 Br F Br Me H Cl 238-239 106 Br F Br i-pr H Cl 236-237 107 Br F Cl Me Me Cl 246-247 108 Br F Cl Me H Cl 233-234 109 Br F Cl i-pr H Cl 153-154 110 Me F Cl Me Me Cl 242-243 111 Cl F Br Me Me Cl 245-246 112 Cl F Br Me H Cl 217-218 113 Cl F Br i-pr H Cl 168-169 114 Cl F Cl Me Me Cl 239-240 115 Cl F Cl Me H Cl 248-249 116 Cl F Cl i-pr H Cl 169-170 117 Br F CF ₃ Me Me Cl 191-192 118 Br F CF ₃ Me H Cl 228-229 119 Br F CF ₃ i-pr H Cl 224-226 120 Br Cl Br Me Me Cl 188-189 121 Br Cl Br Me H Cl 248-249 122 Br Cl Br i-pr H Cl 252-253 123 Br Cl Cl Me Me Cl 147-148 124 Br Cl Cl Me H Cl 249-250 125 Br Cl Cl i-pr H Cl 239-240 126 Br Cl CF ₃ Me Me Cl 200-201 127 Br Cl CF ₃ Me H Cl 158-159 128 Br Cl CF ₃ i-pr H Cl 250-250 129 Me Cl Cl Me Me Cl 232-233 130 Me Cl Br Me Me Cl 210-211 131 F F Br Me H Cl 197-198 132 F F Br Me Me Cl 218-222 133 F Cl Br Me H Cl 203-204

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Mp (° C) 134 F Cl Br Me Me Cl 226-227 135 F Cl Br i-pr H Cl 207-208 136 F Cl Cl Me H Cl 211-212 137 F Cl Cl Me Me Cl 237-238 138 F F Cl Me H Cl 159-160 139 F F Cl Me Me Cl 225-226 140 F F Cl i-pr H Cl 201-202 141 F Br Br Me H Cl 209-210 142 F Br Br Me Me Cl 225-226 143 F Br Br i-pr H Cl 208-209 144 F Br Cl Me H Cl 209-210 145 F Br Cl Me Me Cl 244-245 146 F Br Cl i-pr H Cl 207-208 147 F Br OCH ₂ CF ₃ Me H Cl 210-211 148 F Br OCH ₂ CF ₃ Me Me Cl 204-206 TABLE OF INDICES IN

Compound R ¹ R ² R ³ R ^4a R ^4b R ⁵ Melting point (° C) 149 Cl Cl Br iso-Pr H Cl 224-226

TABLE OF INDEXES WITH

Compound R ¹ R ² R ³ R ⁵ Melting point (° C) 150 Me Br CF ₃ Cl * 151 Me Cl CF ₃ Cl * 152 Me Cl CF ₃ Cl * 153 Me Cl Br Cl * 154 Me Cl Cl Cl * 155 Me Cl OCH ₂ CF ₃ Cl * 156 Br Br Br Cl * 157 Cl Cl Cl Cl * 158 Me Br Br Cl 207-210 159 Me CF3 CF ₃ Cl * 160 F Cl Br Cl * * Data on ¹ H NMR are presented in the table of indices D.

BIOLOGICAL EXAMPLES OF THE INVENTION

TEST A

To assess the destruction of cabbage moths (Plutella xylostella), the test device consisted of a small open container, inside of which were 12-14-day-old radish plants. It was previously infected with 10-15 newborn caterpillars on a piece of the insect diet using a sampler with an internal cavity (rod) to collect the “cork” from the layer of the hardened insect diet, on which numerous caterpillars grow, and transfer this “cork” sample containing caterpillars and ration, in a device for testing.

Test compounds (test compounds) were prepared using a solution containing 10% acetone, 90% water and 300 ppm of a mixture of non-ionic surfactant X-77® Spreader Lo-Foam containing alkylaryl polyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), unless otherwise indicated. The prepared compounds were applied in 1 ml of liquid through a SUJ2 spray tip with a custom 1/8 JJ body (Spraying Systems Co.) placed 1.27 cm (0.5 inches) above the top of each test device. All experimental compounds in this screening were sprayed at a rate of 50 ppm and tested in triplicate. After spraying with the prepared test compound, each test device was allowed to dry for 1 hour, and then a black mesh cover was placed on top of it. These test devices were kept for 6 days in a growth chamber at 25 ° C. and 70% relative humidity. Then, damage caused by eating the plant was visually evaluated.

Of the tested compounds, the following compounds provided superior levels of plant protection (10% or less damage due to eating): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 , 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137.

TEST IN

To assess the destruction of a grassy scoop (Spodoptera frugiperda), the test device consisted of a small open container with 4-5-day-old corn plants inside it, pre-infected with 10-15 one-day caterpillars on a piece of insect diet using a sampler with an internal stem, as described in the test BUT.

Test compounds (test compounds) were prepared and sprayed at a rate of 50 ppm as described for Test A. Spraying was performed three times (in triplicate). After spraying, the test devices were kept in the growth chamber and then visually evaluated as described for test A.

Of the tested compounds, the following compounds provided superior levels of plant protection (10% or less damage due to eating): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137.

TEST WITH

To evaluate the destruction of the tobacco scoop (Heliothis virescens), the test device consisted of a small open container with 6-7-day-old cotton plants inside it, previously infected with 8 two-day caterpillars on a piece of insect diet using an internal stem sampler as described for Test A.

Test compounds (test compounds) were prepared and sprayed at a rate of 50 ppm as described for Test A. Spraying was performed three times (in triplicate). After spraying, the test devices were kept in the growth chamber and then visually evaluated as described for test A.

Of the tested compounds, the following compounds provided superior levels of plant protection (10% or less damage due to eating): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129.

TEST D

To evaluate the destruction of a small scoop (Spodoptera exigua), the test device consisted of a small open container with 4-5-day-old corn plants inside it, previously infected with 10-15 one-day caterpillars on a piece of insect ration using a sampler with an internal stem, as described for testing BUT.

Test compounds (test compounds) were prepared and sprayed at a rate of 50 ppm as described for Test A. Spraying was performed three times (in triplicate). After spraying, the test devices were kept in the growth chamber and then visually evaluated as described for test A.

Of the tested compounds, the following compounds provided superior levels of plant protection (10% or less damage due to eating): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 100 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129.

TEST E

To assess the destruction of peach green aphids (Myzus persicae) by contacting and / or in a systematic manner, the test device consisted of a small open container with 12-15-day-old radish plants inside it, previously infected by placing 30-40 insects on a leaf of the test plant on a piece of leaf cut from a cultivated plant (cut leaf method). Caterpillars moved to test plants as this piece of leaf dehydrated. After preliminary infection, the soil of the test device was covered with a layer of sand.

Test compounds (test compounds) were prepared using a solution containing 10% acetone, 90% water and 300 ppm of a mixture of non-ionic surfactant X-77® Spreader Lo-Foam containing alkylaryl polyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), unless otherwise indicated. The prepared compounds were applied in 1 ml of liquid through a SUJ2 spray tip with a custom 1/8 JJ body (Spraying Systems Co.) placed 1.27 cm (0.5 inches) above the top of each test device. All experimental compounds in this screening were sprayed at 250 ppm and tested in triplicate. After spraying with the prepared test compound, each test device was allowed to dry for 1 hour, and then a black mesh cover was placed on top of it. These test devices were kept for 6 days in a growth chamber at 19-21 ° C and 50-70% relative humidity. Each test device was then visually evaluated for insect mortality.

Of the tested compounds, the following compounds resulted in at least 80% mortality: 1, 2, 3.4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 20, 21, 22, 23, 25, 26, 27, 28, 29, 31, 32, 33, 36, 38, 39, 41, 42, 43, 45, 46, 47, 49, 51, 52, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 72, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 93, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 111, 112, 113, 114, 115, 116, 126, 127, 128, 131, 135.

TEST F

To assess the destruction of cotton aphid (Aphis gossypii) aphids by contacting and / or in a systematic way, the test device consisted of a small open container with 6-7-day-old cotton plants inside it, previously infected with 30-40 insects on a piece of leaf according to with the cut sheet method described for Test E, and the soil of the test device was covered with a layer of sand.

Test compounds (test compounds) were prepared and sprayed at a rate of 250 ppm as described for Test A. Spraying was tested in triplicate. After spraying, the test devices were kept in the growth chamber and then visually evaluated as described for test E.

Of the tested compounds, the following compounds resulted in at least 80% mortality: 1, 2, 4, 5, 7, 8, 10, 11, 12, 13, 14, 16, 20, 21, 22, 23, 25, 26, 27, 28, 29, 31, 32, 33, 34, 36, 38, 39, 42, 43, 45, 46, 47, 49, 51, 52, 53, 54, 55, 56, 58, 59, 62, 63, 65, 66, 67, 77, 78, 79, 80, 81, 82, 87, 88, 90, 91, 93, 94, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 131, 133, 135, 136.

TEST G

To assess the destruction of the Magnolia Whitefly (Bemisia tabaci), the test device consisted of 14-21-day-old cotton plants grown in Redi-earth® medium (Scotts Co.), with at least two true leaves infected with nymphs 2 and 3 its age stages on the underside of these leaves.

Test compounds (test compounds) were prepared in acetone (in an amount of not more than 2 ml) and then diluted with water to 25-30 ml. The prepared compounds were applied using a spray tip with a flat spray nozzle (Spraying Systems 122440) at a flow rate of 10 psi (69 kPa). Plants were sprayed to drip using a turntable sprayer (patent application EP-1110617-A1). All experimental compounds in this screening were sprayed at 250 ppm and tested in triplicate. After spraying with the test compound, the test devices were kept for 6 days in a growth chamber at 50-60% relative humidity and at a temperature of 28 ° C during the day and 24 ° C at night. Then the leaves were removed and dead and living nymphs were counted to calculate the percentage of mortality.

Of the compounds tested, the following compounds resulted in at least 80% mortality: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 33, 34, 39, 42, 43, 45, 46, 47, 49, 51, 52, 53, 54, 55, 56, 59, 77, 78, 79, 80, 81, 82, 87, 90, 93.

TEST N

To assess the soil systemic suppression of tobacco scoops (Heliothis virescens), cotton plants were grown in sassafras soil in vessels with a diameter of 15 cm in aluminum pallets. When the plants reached the stage of three sub-flowerbeds (sepals) of the cotton flower (the formation of buds on the plant), these plants were treated with the test compounds.

Test compounds were prepared in 0.25 ml of acetone and then diluted with water to obtain solutions of 1, 5, 10 and 50 ppm. 10 ml of treatment solutions was added to the vessels weekly for four weeks, with four repetitions for each treatment rate. One day after the second, third and fourth treatments, 35-50 larvae of Heliothis virescens of the first age stage were brushed off with a brush on each plant and placed on the apical zone, three flower beds (sepals) of cotton flowers or seed boxes. Five days after the last infection with the larvae, these plants were evaluated for damage. Of the compounds tested, the following compounds provided excellent plant protection levels at a rate of 10 ppm (10% or less damage by eating): 16.

Of the compounds tested, the following compounds also provided excellent protection for three flower beds and seed bolls at a rate of 10 ppm, without damage by eating or with minimal damage to the sepals: 16.

TEST I

Test I was carried out according to an alternative protocol for assessing soil systemic suppression of tobacco moths (Heliothis virescens). Cotton plants were grown in sassafras soil in vessels with a diameter of 15 cm in greenhouse conditions. When the plants reached the stage of three sub-flower of the cotton flower (the stage of bud formation on the plant), the soil surface was treated with test compounds.

Test compounds (test compounds) were prepared in 0.25 ml of acetone and then diluted with water. Ten ml of treatment solution containing 3 mg of the compound was added to the soil surface of each vessel. Plants were watered the next day and every day thereafter as needed. On days 1, 2 and 4 after treatment, the leaves were cut for evaluation. Two groups of leaves were selected from each plant: upper leaves at approximately the second node from the apical and with an area greater than 25 cm ² , and lower leaves at approximately the third node from the lower part and with an area greater than 25 cm ² . Cut leaves were cut into sections of 3 cm × 2 cm and placed in test trays made of high-strength styrene, consisting of sixteen adjacent holes, each 6 cm wide, 4 cm long and 3 cm deep, with a transparent plastic lid cast in this way that it blocks the entrance to each well through friction. Cured agar was placed at the bottom of each well to maintain moisture for the plant material. One tobacco scoop of the second age stage was placed in each well with plant material; the wells were sealed and kept at 25 ° C, providing 16 hours of illumination per day. For leaves cut on days 1, 2, and 4, mortality was observed 4 days after processing one scoop of tobacco of the second age stage.

Of the tested compounds, the following compounds provided excellent mortality rates (greater than 70% mortality) on upper leaves cut 4 days after treatment at the test norm: 2, 27, 33.

TEST J

To evaluate the soil systemic suppression of the grass scoop (Spodoptera frugiperda), maize (maize) plants (Pioneer # 3394) were grown in small vessels for 5 days until they reached a height of at least 4 cm and the first leaf unfolded.

Test compounds (test compounds) were dissolved in 0.25 ml of acetone and diluted with water to obtain solutions of 1, 10, 50 and 200 ppm 1 ml of the test solution was pipetted onto the soil surface in each vessel using eight plants for each compound / of each norm. The vessels were closed and kept at 25 ° C, providing 16 hours of illumination per day. Plants were watered the next day and every day thereafter as needed. After 6 days, the crop was cut above the first sheet and cut into 3 cm segments. Each test device was a high strength styrene tray (Supplier: Clearpack Company, 11610 Copengagen Court, Franklin Park, IL 60131), consisting of sixteen adjacent wells, each wide 6 cm, 4 cm long and 3 cm deep, with a transparent plastic cover molded so that it blocks the entrance to the hole by friction. Cured agar (2-4 ml) was placed at the bottom of each well to maintain moisture during the test. Each segment of a 3 cm corn plant was placed in a tray so that this plant material was contained in two wells. One grass scoop (Spodoptera frugiperda) of the second age stage was placed in each well, the tray was closed, and then these test devices were kept at 25 ° C with 16 hours of light per day. Mortality was observed after four days.

Concentrations of LC ₉₀ (concentrations of test compounds providing 90% killing of larvae (caterpillars)) were calculated on the basis of probit analysis (logarithmic linear regression) using the general linearized model (GLIM) of the SAS package of statistical computer analysis of the SAS Institute (Cary, NC, USA ) Of the compounds tested, the following compounds provided excellent mortality rates with LC ₉₀ values of 10 ppm or less: 1, 2, 4, 9, 11, 12, 14, 16, 20, 22, 24, 31, 32, 33, 34.

TEST TO

To evaluate the suppression of the Colorado potato beetle (Leptinotarsa decemlineate), 5 mg of the test compound (test compound) was dissolved in 1 ml of acetone. Then this solution was diluted to 100 ml of the total volume using an aqueous solution of 500 ppm, the surfactant Ortho X-77 ™. Serial dilutions were prepared to obtain a 50 ml concentration of 10 ppm.

Diluted solutions of the test compounds were sprayed before dripping onto three-week-old potato or tomato plants. These plants were placed on a rotary sprayer on a turntable (10 rpm). Test compounds were applied using a spray tip with a flat spray nozzle (Spraying Systems 122440) at a rate of 10 psi (69 kPa). After drying of each treated plant, the leaves of this treated plant were cut. The leaves were cut into pieces, which were placed one at a time in 5.5 cm × 3.5 cm cells of a sixteen-cell plastic tray. Each cell contained a 2.5 cm square of wet chromatographic paper to prevent drying. One larva of the second age stage was placed in each cell. Three days after infection, the total number of dead Colorado beetles was recorded.

Of the compounds tested, the following compounds resulted in at least 90% mortality at a rate of 10 ppm: 2, 4, 27, 33, 34, 41, 61, 85.

TEST L

To assess the destruction of cotton weevil (Anthonomus g. Grandis), samples of the test compounds were dissolved in 1 ml of acetone. Then this solution was diluted to 100 ml of the total volume using an aqueous solution of 500 ppm, the surfactant Ortho X-77 ™. Serial dilutions were prepared to obtain a 50 ml concentration of 50 ppm.

Diluted solutions of the test compounds were sprayed before draining onto three-week-old cotton plants. These plants were placed on a rotary sprayer on a turntable (10 rpm). Test compounds were applied using a flat tip spray tip (Spraying Systems 122440) at a rate of 10 psi (69 kPa). Sprayed and dried plants were placed in a plastic cylinder. Twenty weevils were placed in each cylinder containing a whole cotton plant. Three days after infection, damage from eating was assessed.

Of the compounds tested, the following compounds provided excellent plant protection levels at 50 ppm (10% or less damage by eating): 20, 27.

TEST M

To assess the destruction of thrips (Frankliniella sp.), Samples of the test compounds were dissolved in 1 ml of acetone. Then, this solution was diluted to 100 ml of the total volume using an aqueous solution of 500 ppm of the surfactant Ortho X-77 ™. Serial dilutions were prepared to obtain a 50 ml concentration of 10 ppm.

Diluted solutions of the test compounds were sprayed before dripping onto three-week-old cotton or soybean plants infected with thrips. These plants were placed on a rotary sprayer on a turntable (10 rpm). Test compounds were applied using a spray tip with a flat spray nozzle (Spraying Systems 122440) at a rate of 10 psi (69 kPa). Sprayed and dried plants were enclosed in a plastic cylinder. Three days after application, the total number of dead thrips was estimated.

Of the compounds tested, the following compounds resulted in at least 90% mortality at a rate of 10 ppm: 32.

TEST N

To assess the inhibition of the development of root nematode nematodes (Meloidogyne incognita) using contact and / or systemic action, a test device was used consisting of a small open container with tomato seedlings placed inside, 7-9 days old. Compositions of test compounds were prepared and sprayed at a content of 250 ppm, repeating the operation three times as described for Test A. After spraying, the test devices were left alone to dry for 1 hour, and then about 250 larvae were pipetted into the soil young stage 2 (J2) and then a black screen cover was placed on top. Testing devices were kept for 6 days at 25 ° C and 65-70% relative humidity. After that, a visual assessment of root damage was performed for each test device.

Among the tested compounds, excellent levels of plant protection (70% or more reduction in root gall formation) showed the following: 20.

TEST P

To evaluate the control of potato cicadas (Empoasca fabae Harris) by contact and / or systemic methods, each test unit consisted of a small open container containing a 5-6-day Longio bean plant (with the first leaves appearing). White sand was added over the soil and one of the first leaves was cut off before application. The test compounds were formulated as described above and sprayed in triplicate as described for Test A. After spraying, the test units were allowed to dry for 1 hour, and then they were infected with 5 potato cicadas (adults 18-21 days). A black blocking lid was placed on top of each container. The test units were kept for 6 days in a growth chamber at 19-21 ° C and 50-70% relative humidity. Each test unit was then visually evaluated for insect mortality.

TEST Q

To evaluate the control of corn cicadas (Peregrinus maidis) by contact and / or systemic methods, each test unit consisted of a small open cylindrical container containing 3-4 days old corn plant (maize) inside. White sand was added over the soil, and one of the first leaves was cut off before application. The test compounds were formulated as described above and sprayed in triplicate as described for Test A. After spraying, the test units were allowed to dry for 1 hour and then they were infected with 10-20 corn cicads (nymphs 18-21 days), spraying them on the sand with a shaker. A black blocking lid was placed on top of each container. The test units were kept for 6 days in a growth chamber at 19-21 ° C and 50-70% relative humidity. Each test unit was then visually evaluated for insect mortality.

TEST R

To evaluate the suppression of potato cicadas (Empoasca fabae Harris) using contact and / or systemic action, each test device consisted of a small open container placed inside the seedlings of Longjo beans from 5 to 6 days old (with primary leaves appearing). Pure quartz sand was applied over the soil, and one of the primary leaves was cut off before application. The test compositions were formulated as described above, and sprayed, repeating the operation 3 times, as described for test A. After spraying, the test devices were left alone to dry for 1 hour before they were infected using 5 potato cicadas (adults 18 to 21 days old). A black shielding lid was placed on top of each container. Testing devices were kept for 6 days in a growth chamber at 19-21 ° C and 50-70% relative humidity. After that, a visual assessment of insect mortality was performed for each test device.

The following are data illustrating additional effects observed upon incorporation of a known active compound or agent into a composition containing a compound of formula 1 (Tables G, H and J1-J6).

The active ingredients listed in Table G were tested according to the protocol described for TEST A, TEST E, TEST F, and TEST G, as described above; TEST P and TEST Q protocols are described above. Compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm non-ionic surfactant X-77® Spreader Lo-Foam Formula containing alkylaryl polyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), to obtain the concentration of test solutions of 1, 10, 100 and 250 ppm. Then the compositions of the test solutions were sprayed and evaluated in accordance with the protocols.

Compound numbers (other than compound names) listed in the first column of Table G indicate the compound number shown in Index Table A. Insecticidal activity is shown in Table G for categories A, B, C, D, and E. “A” means that the lowest concentration of the active ingredient required to suppress a particular pest by more than 90% is 1 ppm or less; “B” means 10 ppm or less; “C” means 100 ppm or less; “D” means 250 ppm or less; and “E” means more than 250 ppm. In other words, a category “A” compound is at least 100 times more active than a category “C” compound.

TABLE G The insecticidal activity of the compounds according to claim 1 in combination with known biologically active compounds Mode of action Compound Use A DBM * Use E GPA * Use F AGR * Use G WF * Use R PLH * Isp-Q NRC * Neonicotinoids acetamipride FROM AT BUT FROM AT BUT Neonicotinoids clothianidin AT AT AT AT Neonicotinoids imidacloprid BUT BUT BUT Neonicotinoids thiacloprid FROM AT AT BUT AT amitraz E E E E E thiamethoxam FROM BUT AT FROM BUT BUT chlorfenapyr AT FROM E E AT pyridaben AT AT AT pyridyl AT flonicamide E AT AT E D pymethrosine D AT AT E E AT chlorpyrifos E E E E carbamates metormil FROM FROM FROM E AT AT carbamates oxamyl E E FROM FROM D carbamates thiodicarb FROM E FROM E AT AT Pyrethroids deltamethrin BUT E Pyrethroids esfenvalerate BUT E BUT E

Na channel blockers indoxacarb BUT E E Pyrethroids Lambda cygalothrin BUT AT D BUT BUT buprofesin E E E E E AT cyromazine FROM E E E E E Insecticidal urea hexaflumuron E E E E E Insecticidal urea lufenuron AT AT Insecticidal urea Novaluron BUT E E E E E methoxyphenoside BUT E E tebufenoside D E E Macrocyclic lactones abamectin BUT BUT AT FROM AT Macrocyclic lactones spinosad AT E E E E E GABA antagonists fipronil BUT FROM FROM E AT AT Facial expressions of juvenile hormone phenoxycarb AT E E E E Facial expressions of juvenile hormone metoprene AT E E E E Facial expressions of juvenile hormone pyriproxyphene FROM E E AT E E Compound 1 BUT BUT D AT FROM E Compound 2 BUT FROM AT AT FROM E Compound 4 BUT FROM FROM AT FROM E Compound 7 BUT BUT AT BUT AT E Compound 8 BUT BUT FROM AT AT E Compound 11 BUT AT AT AT AT FROM Compound 12 BUT AT FROM AT AT E Compound 16 BUT AT FROM AT FROM E Compound 20 BUT FROM FROM AT AT E

Compound 26 BUT AT FROM AT AT FROM Compound 27 BUT FROM D AT FROM E Compound 33 BUT AT D AT FROM E Compound 34 BUT D E AT FROM FROM Compound 43 BUT AT AT AT AT E Compound 47 BUT AT AT AT AT FROM Compound 53 BUT AT FROM AT FROM E Compound 55 BUT AT AT AT FROM E Compound 79 BUT AT AT AT FROM FROM Compound 87 BUT AT FROM AT FROM E Compound 93 BUT FROM FROM AT AT E Compound 101 BUT AT AT AT FROM D Compound 120 BUT AT AT FROM FROM SS * Isp. - Test; DBM means cabbage moth, GPA means aphid peach, SMA means aphid cotton / melon; WF stands for silverlief whitefly, PLH stands for Potato Cicadas, and RNC stands for Corn Cicadas. TABLE N Corn cicada Concentration (ppm) % mortality Concentration (ppm) The ratio (A: B) % mortality AT Compound 20 500 28 A1 abamectin 40 one hundred A1 + B 40 + 500 1: 12.5 one hundred A2 clothianidin 10 one hundred A2 + B 10 + 500 1:50 one hundred A3 thiamethoxam 0.6 one hundred A3 + B 0.6 + 500 1: 833 one hundred A4 thiacloprid 3 one hundred A4 + B 3 + 500 1: 167 one hundred A5 spinosad 5 one hundred A5 + B 5 + 500 1: 100 one hundred Potato cicadas Concentration (ppm) % mortality Concentration (ppm) The ratio (A: B) % mortality AT Compound 20 fifty 54 A1 Abamectin one hundred one hundred A1 + B 100 + 50 2: 1 one hundred A2 Clothianidin 10 93 A2 + B 10 + 50 1: 5 one hundred A6 chlorfenapyr 5 one hundred A6 + B 5 + 50 1:10 one hundred

Aphid peach Concentration (ppm) % mortality Concentration (ppm) The ratio (A: B) % mortality AT Compound 20 10 24 A1 Abamectin 0.4 one hundred A1 + B 0.4 + 10 1:25 one hundred A2 clothianidin 0.08 one hundred A2 + B 0.08 + 10 1: 125 one hundred

The data presented in tables J to J6 below demonstrate that treating a pest using a mixture or composition of a known biologically active compound or agent and a new compound described by formula 1 (i.e., compound 20) obviously leads to an increased% pest mortality in comparison with the processing results using each ingredient taken separately. In addition, these mixtures or compositions also illustrate the mass ratios between the compound described by formula 1 and the additional biologically active compound or agent in the range from 250: 1 to 1: 500.

Table J1 Western flower trip (test method described in test M) Western flower trip Norm (ppm) Ratio % mortality (observed) Compound 20 one hundred 46 Thiacloprid one hundred thirty Compound 20 + thiacloprid 100 + 100 1: 1 60 Nitenpiram 500 80 Compound 20 + nitenpyram 100 + 500 1: 5 90 Dinotefuron twenty 60 Compound 20 + dinotefuron 100 + 20 5: 1 80 Chlorfenapyr 150 90 Compound 20 + chlorfenapyr 100 + 150 1: 1,5 90

Phenoxycarb 10 40 Compound 20 + phenoxycarb 100 + 10 10: 1 70 Phenoxycarb 1000 60 Compound 20 + phenoxycarb 100 + 1000 1:10 80 Metoprene one hundred 60 Compound 20 + Metoprene 100 + 100 1: 1 80 Indoxacarb 3000 fifty Compound 20 + indoxacarb 100 + 3000 1:30 80 Triazamate 10 70 Compound 20 + triazamate 100 + 10 10: 1 90 Tebufenoside one hundred 70 Compound 20 + tebufenoside 100 + 100 1: 1 90 Oxamil one thirty Compound 20 + oxamyl 100 + 1 100: 1 70 Thiacloprid 3000 40 Compound 20 + thiacloprid 100 + 3000 1:30 70 Table J2 Peach green aphid (test method described in test E) Aphid peach green Norm (ppm) Ratio % mortality (observed) Compound 20 twenty 35 Thiamethoxam 0.4 94 Compound 20 + Thiamethoxam 20 + 0.4 50: 1 98 Nitenpiram 150 17 Compound 20 + nitenpyram 20 + 150 1: 7.5 47 Novaluron 1000 25 Compound 20 + Novaluron 20 + 1000 1:50 49 Thiacloprid 0.2 13 Compound 20 + thiacloprid 20 + 0.2 100: 1 42 Compound 20 10 24 Me tomil fifty twenty Compound 20 + metomil 10 + 50 1: 5 40 Chlorfenapyr 7 36 Compound 20 + chlorfenapyr 10 + 7 1.4: 1 59

Spin garden 1000 59 Compound 20 + spinosad 10 + 1000 1: 100 72 Lufenuron 250 fifteen Compound 20 + Lufenuron 10 + 250 1:25 35 Lufenuron 1000 28 Compound 20 + Lufenuron 10 + 1000 1: 100 49 Table J3 Cotton / Melon Aphid (Test Method described in Test F) Cotton / Melon Aphid Norm (ppm) Ratio % mortality (observed) Compound 20 twenty 41 Metomil fifteen 64 Compound 20 + metomil 20 + 15 1.3: 1 81 Acetamipride 0.08 67 Compound 20 + acetamipride 20 + 0.08 250: 1 85 Lufenuron 0.4 39 Compound 20 + Lufenuron 20 + 0.4 50: 1 66 Pyridyl 2 32 Compound 20 + pyridinyl 20 + 2 10: 1 59 Spin garden one hundred 35 Compound 20 + spinosad 20 + 100 1: 5 62 Pyriproxyphene 1000 33 Compound 20 + pyriproxyphene 20 + 1000 1:50 59 Cyromazine 10 23 Compound 20 + Cyromazine 20 + 10 2: 1 60 Indoxacarb 10 16 Compound 20 + indoxacarb 20 + 10 2: 1 51 Clothianidin 0.08 75 Compound 20 + clothianidin 20 + 0.08 250: 1 84 Dinotefuron one 31 Compound 20 + dinotefuron 20 + 0.08 20: 1 62 Hexaflumuron 1000 thirty Compound 20 + hexaflumuron 20 + 1000 1:50 65 Hydramethylnon 1500 39 Compound 20 + hydramethylnon 20 + 1500 1:75 66

Table j4 Cabbage moth (test method described in test A) Cabbage Moth Norm (ppm) Ratio % mortality (observed) Compound 20 0.04 75 Dinotefuron 2,5 60 Compound 20 + dinotefuron 0.04 + 2.5 1: 125 90 Cryazine twenty 60 Compound 20 + cryomazine 0,04 + 20 1: 500 90 Chlorfenapyr 7 70 Compound 20 + chlorfenapyr 0.04 + 7 1: 175 90 Table J5 Magnolia Whitefly (test method described in Test G) Whitefly Magnolia Norm (ppm) Ratio % mortality (observed) Compound 20 6 3 Acetamipride twenty 83 Compound 20 + acetamipride 6 + 20 1: 3.3 91 Compound 20 10 5 Acetamipride twenty 83 Compound 20 + acetamipride 10 + 20 1: 2 87 Table J6 Potato cicadas (test method is described in test R) Potato cicadas Norm (ppm) Ratio % mortality (observed) Compound 20 fifty 54 Fipronil 0.5 7 Compound 20 + fipronil 50 + 0.5 100: 1 60

Claims (23)

1. Anthranilamide compound selected from compounds of formula 1 or their N-oxides

where R ¹ means CH ₃ , F, Cl or Br; R ² means F, Cl, Br, I or CF ₃ ; R ³ is CF ₃ , Cl, Br or OCH ₂ CF ₃ ; R ^4a means C ₁ -C ₄ alkyl; R ^4b means H or CH ₃ ; and R ⁵ means Cl or Br, or salt acceptable for use in agriculture. 2. The anthranilamide compound according to claim 1, selected from compounds of formula 1a or their N-oxides

where R ¹ means CH ₃ , Cl or Br; R ² means F, Cl, Br, I or CF ₃ ; R ³ is CF ₃ , Cl or Br; R ⁴ means C ₁ -C ₄ alkyl; and R ⁵ means Cl or Br, or salt acceptable for use in agriculture. 3. The compound according to claim 1, where R ^4a means C ₁ -C ₄ alkyl, a R ^4b means H; or R ^4a means CH ₃ and R ^4b means CH ₃ . 4. The compound according to claim 3, where R ⁵ means Cl. 5. The compound according to claim 4, where R ^4a means CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or C (CH ₃ ) ₃ . 6. The compound according to claim 5, where R ² means Cl or Br. 7. The compound according to claim 6, where R ¹ means CH ₃ . 8. The compound according to claim 7, where R ¹ means Cl. 9. The compound according to claim 1, which is selected from the group consisting of compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means CF ₃ , R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means CF ₃ , R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means Br, R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means Br, R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means Cl, R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Br, R ³ means Cl, R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means CF ₃ , R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means CF ₃ , R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means Br, R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means Br, R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means Cl, R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means Cl, R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means OCH ₂ CF ₃ , R ^4a means CH (CH ₃ ) ₂ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means OCH ₂ CF ₃ , R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means Cl, R ² means Cl, R ³ means Br, R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl; compounds of formula 1, where R ¹ means CH ₃ , R ² means Cl, R ³ means OCH ₂ CF ₃ , R ^4a means CH ₃ , R ^4b means H and R ⁵ means Cl. 10. An insect control composition comprising a biologically effective amount of a compound according to claim 1 and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. 11. An invertebrate pest control composition comprising a biologically effective amount of a compound according to claim 1 and an effective amount of at least one additional biologically active compound or agent. 12. The composition according to claim 11, where at least one additional biologically active compound or additional agent selected from arthropocides of the group consisting of pyrethroids, carbamates, neonicotinoids, sodium channel blockers of neurons, insecticidal macrocyclic lactones, γ-aminobutyric acid antagonists (GABA) , insecticidal ureas and mimetics of juvenile hormones. 13. The composition according to claim 11, where at least one additional biologically active compound or agent is selected from insecticides, nematicides, acaricides or biological agents of the group consisting of abamectin, acephate, acetamipride, amidoflumet, avermectin, azadirachtin, azinofosmethyl, bifentrin, binfenazate , buprofesin, carbofuran, chlorfenapyr, chlorofluazuron, chlorpyrifos, chlorpyrifosmethyl, chromaphenoside, clothianidin, cyfluthrin, beta-cyfluthrin, cygalotrin, lambda-cygalotrin, cypermethrin, cyromazine, deltamethrin, di afentiurona, diazinon, diflubenzuron, dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenotikarba, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerima, flufenoxuron, fonofos, halofenozide, hexaflumuron, imidacloprid, indoxacarb, isofenfos, lufenuron, malathion, metaldehyde, metamidophos, methidathione, methomil, metoprene, methoxychlor, monocrotophos, methoxyphenoside, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone, spinosad, spiromezifina, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon, triflumuron, aldicarb, oxamyl, fenamiphos, amitraz, quinomethionate, chlorobenzylate, cyhexatin, dicofol, dienochlor, ethoxazole, phenazachine, phenbutatin oxide, fenpiroximate, hexithiazox, proparbenite, pirite and tebufenpirada; and biological agents such as Bacillus thuringiensis, including the aizawai and kurstaki subspecies, Bacillus thuringiensis delta-endotoxin, baculoviruses and entomopathogenic bacteria, viruses and fungi. 14. The composition according to claim 11, where at least one additional biologically active compound or additional agent selected from insecticidal, nematicidal, acaricidal or biological agents of the group consisting of cypermethrin, cygalotrin, cyfluthrin and beta-cyfluthrin, esfenvalerate, fenvalerate, tralometrin, phenothicarb, metomil, oxamyl, thiodicarb, clothianidin, imidacloprid, thiacloprid, indoxacarb, spinosad, abamectin, avermectin, emamectin, endosulfan, etiprol, fipronil, flufenoxuron, triflumuron, diophenol on, pyriproxifene, pymetrosine, amitrase, Bacillus thuringiensis, delta-endotoxin Bacillus thuringiensis and entomophage fungi. 15. A method of controlling insects, comprising contacting the insects or their environment with a biologically effective amount of the compound according to claim 1. 16. A method of controlling insects, comprising contacting insects or their environment with a biologically effective amount of a composition according to claim 11. 17. The compound of formula 2

where R ¹ means CH ₃ , F, Cl or Br; R ² means F, Cl, Br, I or CF ₃ ; R ³ is CF ₃ , Cl, Br or OCH ₂ CF ₃ ; and R ⁵ means Cl or Br. 18. The compound of formula 4

where R ³ means CF ₃ , Cl, Br or OCH ₂ CF ₃ ; and R ⁵ means Cl or Br. 19. The method according to clause 15, comprising contacting the plants with a compound of formula I, its N-oxide or its salt acceptable for use in agriculture, by irrigating the soil with a liquid composition containing the compound. 20. The composition of claim 10 in the form of a liquid composition for irrigation of the soil. Priority on points and signs: 08/13/2001 - according to claim 1, in addition to R ¹ = F, R ³ = OCH ₂ CF ₃ , R ^4b = CH ₃ , clause 2, clause 3 except R ^4b = CH ₃ , 4, 5, 6, 7, 8, where R ¹ = Cl, item 9 (compounds 1-12), item 10 except R ¹ = F, R ³ = OCH ₂ CF ₃ , R ^4b = CH, item 15, p. 18 except R ³ = OCH ₂ CF ₃ ; 09/21/2001 - according to claims 11-14, 16, 17 except R ³ = OCH ₂ CF ₃ , claim 19, claim 20; 04/02/2002 - according to claim 1 (R ¹ = F, R ³ = OCH ₂ CF ₃ , R ^4b = CH ₃ ), p. 3 (R ^4b = CH ₃ ), p. 9 (compounds 13-16), p. 10 (R ¹ = F, R ³ = OCH ₂ CF ₃ , R ^4b = CH ₃ ), p. 17 (R ³ = OCH ₂ CF ₃ ), p. 18 (R ³ = OCH ₂ CF ₃ ).