EA022487B1 - Pteridines useful as agrochemicals and animal health products - Google Patents

Abstract

The present disclosure relates to 1- or 2-(4-(aryloxy)phenyl)ethylamino-, oxy- or sulfanyl)pteridines of general formula I-A and 1- or 2-(4-(heteroaryloxy)phenyl)ethylamino-, oxy- or sulfanyl)pteridines of general formula I-B and their use as agrochemicals and animal health products.

Description

FIELD OF THE INVENTION The present disclosure relates to 1- or 2- (4- (aryloxy) phenyl) ethylamino, hydroxy or sulfanyl) pteridines and 1- or 2- (4- (heteroaryloxy) phenyl) ethylamino, hydroxy or sulfanyl) pteridinam and their use as agrochemicals and for veterinary medicine.

BACKGROUND AND SUMMARY OF THE INVENTION The present invention provides novel organic compounds that can exhibit activity as pesticides, which means that they can control fungi, insects, ticks and / or parasites of animals. The invention also provides novel pesticidal methods and compositions using new compounds.

More specifically, the invention provides new compounds of the formula Ι-Α

where K is phenyl or a heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-thiadisole, thiazole, benzothiazole or quinolone, optionally substituted with H, halogen, C ₁ -C ₆ -alkyl, C ₁ -C _6- alkoxy, benzyloxy, C ₁ -C ₆ haloalkyl;

Ζ represents H, a single bond CC, O, OCH ₂ or OCH ₂ CH ₂ ; t has a value of 1-4;

K ¹ represents independently H, halogen, _C1-C6 alkyl, hydroxy, C1-C ₆ -alkoxy, halo-C ₁ -C ₆ alkyl, _halo-C1-C6 alkoxy, SR, C1-C ₆ - alkylcarbonyl, _C1-C6 alkoxycarbonyl;

Υ represents a simple bond CC, C (K ⁵ P) O or C (K ⁵ P); η has a value of 2;

K ² is independently H or C ₁ -C ₆ alkyl;

K ⁴ represents H, halogen or C ₁ -C ₆ alkyl;

K ⁵ represents H;

X ¹ represents ΝΚ ³ , O and 3. where K ^{3 is} selected from H or C ₁ -C ₆ alkyl;

X ² represents C ₁ -C ₆ alkyl;

X ³ represents H or C ₁ -C ₆ alkyl.

The present invention also provides novel compounds of the formula Ι-Β

where K is phenyl or a heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-thiadisole, thiazole, benzothiazole or quinolone, optionally substituted with H, halogen, C ₁ -C ₆ -alkyl, C ₁ -C _6- alkoxy, benzyloxy, C ₁ -C ₆ haloalkyl;

Ζ represents a simple bond CC, O, OCH2 or OCH2CH2; t has a value of 1-4;

K ¹ independently represents H, halogen, C ₁ -C ₆ -alkyl, hydroxy, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ alkyl, halogen-C ₁ -C ₆ -alkoxy, SI, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl;

Υ represents a simple bond CC, C (K ⁵ P) O or C (K ⁵ P); η has a value of 2;

K ² is independently H or C ₁ -C ₆ alkyl;

K ⁴ represents H, halogen or C ₁ -C ₆ alkyl;

K ⁵ represents H;

X ¹ represents IR ³ , O and 3, where K ^{3 is} selected from H or C ₁ -C ₆ alkyl;

X ² represents C ₁ -C ₆ alkyl;

X ³ represents H or C ₁ -C ₆ alkyl.

The present invention also provides novel pesticidal methods and compositions using compounds of formula Ι-Α and compounds of formula Ι-Β.

The invention includes fungicidal, insecticidal, acaricidal and antiparasitic compositions comprising an effective amount of a compound of the present invention in admixture with an agriculturally acceptable or pharmaceutically acceptable adjuvant or carrier.

The invention also includes methods for controlling fungi, insects, ticks or parasites,

- 1 022487 comprising applying an effective amount of a compound of the present invention to fungi, insects or mites, soil, plants, roots, leaves, seeds, locus or animals (for this purpose they can be administered orally, parenterally, subcutaneously or locally), where it is to be prevented or treat an infection.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are directed to compounds of the formula Ι-A and Ι-Β

Ι-A Ι-Β where K may be an optionally substituted phenyl or heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-thiadisole, thiazole, benzothiazole or quinolone, optionally substituted with H, halogen, C ₁ - With _6- alkyl, C ₁ -C ₆ -alkoxy, benzyloxy, haloalkyl.

In this document, all temperatures are indicated in degrees Celsius and all percentages are weight percent, unless otherwise indicated.

The terms alkyl, alkenyl and alkynyl, as well as derivative terms such as alkoxy and alkylthio, as used herein, encompass straight chain, branched chain and cyclic groups. The terms alkenyl and alkynyl include one or more unsaturated bonds.

The term halogen refers to atoms P, C1, Br and I.

The term C ₁ -C ₆ alkyl refers to C ₁ -C ₆ linear hydrocarbon chains and C ₃ -C ₆ branched and cyclic hydrocarbon groups.

The terms C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl refer to C ₂ -C ₆ linear hydrocarbon chains, and C ₃ (or C ₄ in the case of C ₄ -C ₆ alkynyl) -C ₆ branched hydrocarbon groups containing at least one unsaturated bond.

The term C ₁ -C ₆ alkoxy refers to the group O-lower alkyl.

The term haloalkyl refers to C ₁ -C ₆ alkyl groups substituted with one or more halogen atoms.

The term haloalkoxy refers to lower alkoxy groups substituted with one or more halogen atoms.

The term substituted phenyl refers to phenyl substituted with a C1-C6 alkyl, C1-C6 alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, halogen, hydroxy, ΝΟ ₂ , haloalkyl, haloalkoxy, haloalkylthio, ΟΝ, phenyl, substituted phenyl, O-phenyl, O-substituted phenyl, C ₁ -C ₄ alkanoyloxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, benzyloxy or and C ₁ -C ₆ -alkyl-8O _h , and c is an integer having a value from 0 to 2.

The term fused ring system refers to two rings connected as defined in Mo55, C.P. Riga apb Arriesb S11spY51gu. 1998, 70, 143: As for ring systems ... two rings that contain two atoms and one bond, common to them, can be considered as formed from two rings as separate objects. The ring connection method is thus called condensation.

In the present invention, when several substituents are independently selected, it should be understood that they are selected so as to be spatially compatible with each other. Spatial compatibility refers to the absence of steric hindrances, as the term is defined in Thys Sopysp5sb Systyu1 Oyyopagu, 71P sbyyup, Rstyoi Riyy5ypd So., Ν.Υ. R. 893 (1966), where the definition is given as follows: steric obstruction. A characteristic feature of the molecular structure in which molecules have such a spatial arrangement of their atoms that this reaction with another molecule is prevented or its speed slows down.

Spatial compatibility is characterized by substituents whose physical volume does not require a limitation in volumes insufficient to realize their normal behavior, as described in Ό.Τ Sgat and S. Nattopb, Ogdashs Sst15yu 2pb sbyup, MsGa \\ - HH1 Vook Sotrapu, Ν.Υ. , R. 215 (1964).

The compounds of the present invention are prepared using well-known chemical procedures. The necessary starting materials are commercially available or can be easily synthesized using standard procedures.

The synthesis of compounds of formula Ι-A, where X ¹ represents O.

- 2 022487

The compounds of formula Ι-A, where X ¹ represents O, can be obtained by condensation of the compounds of formula II

where K ⁴ , X ² and X ³ have the meanings defined for compounds of formula Ι-A; and b represents a group such as P, C1, Br, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or arylsulfinyl; with a compound of the formula ΙΙΙ-A

where K, K ¹ , K ² , Υ, Ζ, t, and η have the meanings defined for compounds of formula Ι-A, and X ¹ represents O, as in step e of scheme схемы. The reaction is preferably carried out in the presence of a base, in a non-reactive solvent, such as dichloromethane (CH ₂ Cl ₂ ), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or Ν, Ν-dimethylformamide (DMF), at a temperature in the range of 0 ° C to reflux.

Alternatively, compounds of formula Ι-A can be prepared by reacting a dicarbonyl or equivalent compound with a compound of formula ΙΝΤ -B

ΙΝΤ-Β where K, K ¹ , K ² , X ³ , Υ, Ζ, t and η have the meanings defined for compounds of formula Ι-A, and X ¹ represents O, as in step c of scheme схемы. Typical dicarbonyl compounds include glyoxal, 2,3-butanedione and 1,4-dioxane-2,3-diol. The reaction is preferably carried out in an alcohol solvent, alternatively containing toluene, at a temperature in the range from 0 ° C to a boiling point under reflux.

- 3 022487

Compounds of the formula ΙΝΤ-Β diaminopyrimidine compounds can be obtained by reacting 5,6-

where X ³ and b have the meanings defined for the compounds of formula II; with a compound of formula IIIA, where K, K ¹ , K ² , Υ, Ζ, t and η have the meanings defined for compounds of formula RA, and X ¹ represents O, as in step b of Scheme I. The reaction is preferably carried out in the presence of a base in a non-reactive solvent, such as CH ₂ Cl ₂ , THF, DMSO or DMF, at a temperature in the range of 0 ° C. to a reflux temperature.

Alternatively, compounds of formula ΓΝΤ-Β can be synthesized by reduction of a 6-amino5-nitropyrimidine compound of formula ΕΝΤ-A

where K, K ¹ , K ² , X ³ , Υ, Ζ, t, and η have the meanings determined for compounds of the formula PA, as in step b of Scheme I. The reduction can be carried out by hydrogenation in the presence of a palladium catalyst in an alcohol solvent.

Compounds of the formula UT-A can be synthesized by reacting a 5-nitro-6aminopyrimidine compound

where X ³ and b have the meanings defined for the compounds of formula II; with a compound of formula IIIA, where K, K ¹ , K ² , Υ, Ζ, t and η have the meanings defined for compounds of formula RA, as in step a of Scheme I. The reaction is preferably carried out in the presence of a base in a non-reactive solvent, such as CH ₂ Cl ₂ , THF, DMSO or DMF, at a temperature in the range from 0 ° C to a boiling point under reflux.

Compounds of formula SH-A, where K is phenyl or heteroaryl, can be synthesized by reacting compounds of formula SH-A, where K is H, with a compound of formula M-He !, where M is a group such as P, C1 , Br, I, 1,2,3-triazol-1-yl, 1,2,4triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or arylsulfinyl; and where not! represents phenyl or a heterocycle, as in the stage of Scheme I. Not! optionally substituted with one or more groups selected from H, halogen, lower alkyl, lower alkoxy, benzyloxy, lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, ΝΟ ₂ , ΟΝ, lower alkoxycarbonyl, lower alkylcarbonyl and lower alkyl-8O _h . The reaction is preferably carried out in the presence of a base in a non-reactive solvent, such as CH ₂ Cl ₂ , THF, DMSO or DMF, at a temperature in the range of 0 ° C. to the reflux temperature.

The synthesis of compounds of formula RA, where X ¹ represents ΝΉ or Ν-lower alkyl.

Compounds of the formula PA, wherein X ¹ is ΝΉ or Ν-lower alkyl and K, K ¹ , K ² , K ⁴ , X ² , X ³ , Υ, Ζ, t and η have the meanings defined for compounds of the formula PA, can get in the same way as described for scheme I, from compounds of formulas II, SH-A, ΕΝΤ-A, ΕΝΤ-Β, where K, K ¹ , K ² , K ⁴ , X ² , X ³ , Υ, Ζ , t, η and p have the meanings defined for the formula PA, and X ¹ represents ΝΉ or Ν-lower alkyl.

- 4 022487

Preferably the compounds of formula Ι-A, where X ¹ represents ΝΗ or Ν-lower alkyl and Ζ has the meaning defined for compounds of formula PA, can be obtained by condensation of the compounds of formula II

where K ⁴ , X ² and X ³ have the meanings defined for compounds of formula Ι-A; and b represents a group such as P, C1, Br, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or arylsulfinyl; with a compound of the formula ΙΙΙ-A

where K, K ¹ , K ² , Υ, Ζ, t, and η are as defined for compounds of formula формулы-A, and X ¹ is представляет or Ν-lower alkyl, optionally in the form of a salt (e.g., HC1), as on the circuit ΙΙ. The reaction is preferably carried out in the presence of a base, such as triethylamine, in an unreacted solvent, such as CH ₂ Cl ₂ , THF or DMF. Alternatively, the reaction can be carried out in hexamethyldisilazane in the presence of ammonium sulfate.

The compounds of formula Ι-A, where X ¹ represents ΝΗ or Ν-lower alkyl and K, K ¹ , K ² , K ³ , K ⁴

X ² , X ³ and Ζ have the meanings defined for compounds of formula Ι-A, where K is phenyl or heterocycle optionally substituted with one or more groups selected from halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, haloalkyl , haloalkoxy, ΝΟ ₂ , C ^ lower alkoxycarbonyl, lower alkylcarbonyl and lower alkyl-8O _hours , where c | represents an integer having a value from 0 to 2;

- 5 022487 alternatively, these compounds can be obtained by treating a compound of formula IV

where K ¹ , K ² , K ⁴ , X ² , X ³ , Υ, Ζ, t and η have the meanings defined for compounds of the formula Ι-A, and X ¹ represents ΝΗ or Ν-lower alkyl; the compound of the formula M-He1, where M represents a group such as P, C1, Br, I, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or arylsulfinyl; and where not! represents phenyl or a heterocycle, as in step c of Scheme III. Not! optionally substituted with one or more groups selected from H, halogen, lower alkyl, lower alkoxy, benzyloxy, lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, ΝΟ ₂ , ΟΝ, lower alkoxycarbonyl, lower alkylcarbonyl and lower alkyl-8O _h . The reaction is preferably carried out in the presence of a base in a non-reactive solvent, such as CH ₂ Cl ₂ , THF, DMSO or DMF, at a temperature in the range of 0 ° C. to the reflux temperature.

Some compounds of formula HA are prepared by modifications of other compounds of formula IA using the methods described in the experimental procedures of the Production and Examples sections.

Compounds of formula IV, where Ζ is oxygen, can be prepared by treating compounds of formula V

where K ¹ , K ² , K ³ , K ⁴ , Υ, t, and η are as defined for compounds of formula HA, X ¹ represents NΗ or Ν-lower alkyl, Ζ represents oxygen and K ⁶ represents lower alkyl; a reagent such as BBg ₃ in an inert organic solvent such as CH ₂ Cl ₂ .

Alternatively, compounds of formula IV can be prepared by treating compounds of formula VI, wherein K ⁴ , X ^2, and X ³ are as defined for a compound of formula HA

a compound of formula VII, optionally in the form of a salt (e.g., HC1)

where K ¹ , K ² , Υ, t and η have the meanings defined for compounds of the formula HA, and K ³ represents H; in the presence of acetic acid, optionally in the form of a solution in a suitable solvent, such as ethanol; when heated at a temperature of 25 ° C to a boiling point under reflux.

- 6 022487

Alternatively, compounds of formula IV can be prepared by treating compounds of formula II

where K ⁴ , X ² and X ³ have the meanings defined for compounds of formula Ι-A; and b represents a leaving group such as P, C1, Br, I, ΝΟ ₂ , 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, O81Me ₃ , arylthio, alkylthio alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or arylsulfinyl; a compound of formula VII, optionally in the form of a salt (e.g., HC1)

OH νπ

G where K ¹ , K ² , K ³ , Υ, t and η have the meanings defined for compounds of the formula RA; optionally in the presence of a base, in a solvent such as acetonitrile, THF or DMF.

Compounds of formula V are prepared by treating compounds of formula VI, wherein K ⁴ , X ² and X ³ are as defined for a compound of formula RA; a compound of the formula USh-A, optionally in the form of a salt (e.g., HC1)

where K ¹ , K ² , Υ, t and η have the meanings defined for compounds of formula RA, K ³ represents H and K ⁶ represents lower alkyl, as defined for compounds of formula RA; in the presence of acetic acid, optionally in the form of a solution, in a suitable solvent such as ethanol; when heated at a temperature of 25 ° C to a boiling point under reflux.

Amines of the formula USh-A, wherein K ¹ , K ² , K ³ , Υ, t and η are as defined for compounds of the formula PA, and K ⁶ is lower alkyl as defined for compounds of the formula PA; are commercially available or can be obtained using well-known methods. For example, compounds of formula SHN-A, where K ¹ , K ² , t and η have the meanings defined for compounds of formula RA, K ⁶ represents lower alkyl, K ³ represents H and Υ represents K ⁵ p, receive in the form their hydrochlorides by treatment with hydrogen of suitably substituted (4-alkoxyphenyl) acetonitriles in the presence of hydrochloric acid, a catalyst such as palladium on carbon, and a suitable solvent such as ethanol.

Alternatively, compounds of formula SHN-A, where K ¹ , K ² , t, and η have the meanings defined for compounds of formula PA, K ⁶ is lower alkyl, K ³ is H, Υ is K ⁵ p, obtained by processing borane-dimethyl sulfide complex or lithium aluminum hydride of suitably substituted (4-alkoxyphenyl) acetonitriles in a suitable solvent, such as tetrahydrofuran, at a temperature of from 20 ° C to a boiling temperature under reflux.

Alternatively, compounds of formula SHN-A, wherein K ¹ , K ² , t, and η are as defined for compounds of formula PA, K ⁶ is lower alkyl, K ³ is H, and Υ is K ⁵ p, are obtained as their hydrochlorides by treating with hydrogen suitably substituted 1-alkoxy-4 - ((E) -2-nitrovinyl) benzenes in the presence of hydrochloric acid, a catalyst such as palladium on carbon, and a suitable solvent such as ethanol.

Alternatively, compounds of formula SHN-A, wherein K ¹ , K ² , t, and η are as defined for compounds of formula PA, K ⁶ is alkyl or benzyl, K ³ is H, and Υ is K ⁵ p, are prepared by treating lithium aluminum hydride with suitably substituted 1-alkoxy-4 - ((E) -2-nitrovinyl) benzenes in a suitable solvent such as tetrahydrofuran.

RALCOXY-4 - ((E) -2-nitrovinyl) benzenes are prepared by treating with nitromethane a suitably substituted benzaldehyde in the presence of ammonium acetate.

Alternatively, the compounds of formula RA, where X represents ΝΗ obtained by processing

- 7 022487 compounds of the formula VI indicated above by a compound of the formula ΙΙΙ-Α, optionally in the form of a salt (for example, HC1), where K, K ¹ , K ² , Υ, Ζ, t, η and p have the meanings defined for the compounds formulas Ι-Α, and X represents ΝΗ; in the presence of acetic acid, optionally in the form of a solution in a suitable solvent, such as ethanol; when heated at a temperature of 25 ° C to a boiling point under reflux.

Similarly, compounds of formula Ι-B, where X ¹ is ΝΗ, can be obtained by treating a compound of formula νΙ, as defined above, with a compound of formula ΙΙΙ-B

optionally in the form if (for example, HC1), where K, K ¹ , K ² , Υ, Ζ, t and η have the meanings defined for compounds of formula Ι-B, and X represents ΝΗ; in the presence of acetic acid, optionally in the form of a solution in a suitable solvent, such as ethanol; when heated at a temperature of 25 ° C to a boiling point under reflux. Compounds of formula BB can be prepared using the methods described in the Production and Examples sections.

Compounds of formula νΙ

IN*

VI g

where K ⁴ , X ² and X ³ have the meanings defined for the compounds of formula Ι-Α, obtained by processing the compounds of formula K

Ν ΝΗ,

IX where K ⁴ and X ² have the meanings defined for the compound of the formula Ι-Α, Ν, Ν dimethylformamide dimethyl acetal in a suitable solvent, such as toluene, when heated at a temperature of from 25 ° C to a boiling temperature under reflux.

Compounds of formula K

where K ⁴ and X ² have the meanings defined for compounds of formula Ι-Α, are commercially available or obtained using well-known synthetic procedures.

The synthesis of compounds of formula Ι-Α, where X ¹ represents 8.

Ιν scheme

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Compounds of formula Ι-A, where K, K ¹ , K ² , K ⁴ , X ² , X ³ , Υ, Ζ, t and η have the meanings defined for compounds of formula Ι-A, and X ¹ represents 8, you can get as in scheme Ιν by condensation of the compounds of formula X

where K ⁴ , X ² and X ³ have the meanings defined for compounds of formula Ι-A; and X ¹ represents 8; with a compound of formula XI

XI g

where K, K ¹ , K ² , Υ, Ζ, t and η have the meanings defined for the formula Ι-A; and M has a value defined for the reacting partner M-Hc1 in Scheme ΙΙΙ, step c. In the compounds of formula XI, M is preferably chloro or bromo. The reaction is preferably carried out in the presence of a base, such as triethylamine, in an unreacted solvent, such as CH2C12, THF or DMF.

The compounds of the present invention can be pesticides that have fungicidal activity against harmful fungi, including, but not limited to, fungi that are pathogenic to plants, animals and humans. They are active against fungi of various classes, including oomycetes, deuteromycetes (Ripd1! TrsgGss11). basidiomycetes and ascomycetes. More specifically, one embodiment of the method of the present invention provides activity against phytopathogenic organisms, including, but not limited to, Rupsulapidae, species Co11cu1r1cnit, species Eglutidae, species Rhyspus, species Cocnuloproteus, species Aegnapapa, species Cepnopus, Cactus rhizens. Segsozrozog and Segsozroge11a and view of Rugepor Leg. Additional controlled diseases include powdery mildew caused by the pathogen 8pNaego1Nesa GiPdpea (powdery mildew of melons and gourds) and Ipsti1 pesuyug (powdery mildew of grapes), soybean rust caused by the causative agent of Rhinocephalus rosacea (powdery mildew such as , downy powdery mildew of grapes (P1azorata yuhso1a), scab of apples caused by the causative agent Vеηΐи ^^ а и тасшашпз, late blight caused by the causative agent Rnuyrnknog nigra nigella, and smut corn (IzN1ad about taub1z).

The compounds of the present invention may have insecticidal activity against harmful insects and ticks, including, but not limited to, insects that are pests or parasites of plants, animals and humans.

In other embodiments, the invention disclosed herein can be used to control pests, including nematode type, arthropod type, chelicera subtype, arachnid class, myriapod subtype, Simphilus class, six-legged subtype, insect class. In the class of insects, the invention disclosed in this document can be used to control beetles (bugs). A list of these pests, which is not exhaustive, includes, but is not limited to, AsapcNosseNesr. (weevils), AsaShnozseb without Oyesuyuz (bean kernels), Adgbiz p1ashrepshz (emerald ash grinder), AdpoUz spr. (wireworms), Aporhornidae dalactis (Asiatic long-horned beetle), Apkopotiz spr. (weevils), Apbyupopshz dgapb1z (cotton weevil), ArYbshz spr., Aryup spr. (weevils), Arodot spr. (larvae), Akayetz zrgekiZyz (B1ask TigGdgazz Akayetiz), Ayutapa Pepez (beet crumbs), Au1asorNoge spr., WokNupobeges ripsPuye Shpz (beet weevil), VgisNiz spr. (weevils), Prigonidae bacillus (Pea caryopsis), Sasoezulia tspi., Caenozoicumis tasiakakis (southern four-spotted caryopus), Sagornbiz Nepyrgaz (semi-winged cinquefoil), Cazorida cep. (leaf beetles), Soyuyusha 1GBigsa1e (bean leaf beetle), SeiYugNupsNiz spr. (weevils), SeiYugNupsNiz azzpshPz (rapeseed seed crypto-hunter), SeiYugNupsNiz par1 (cryptochnik reptile), S’NaYuspeta spr. (leaf beetles), Co1azr1z spr. (ground beetles), Sopobegiz zsa1apz, Sopobegiz zbdtoziz, SopoktasNe1 pepirNag (plum weevil), Soppiz nib1z (green June beetle), Sposepz azragad1 (leafy beetle asparagus), Gingerbread gingerbread, gingerbread Turkish Grain Beetle), Skheshega zrr. (wireworms), SigsyNo spr. (weevils), Sus1oserNa1a spr. (larvae), SuNpgoskirigiz abdisgrisis (weevil stem weevil), Oerogaiz nigella (mango weevil - 9 022487 leaf cutter), Begtecidae arteridae (ham skinned beetle), Begtecoecus arvensis, (leaf beetles), Epaspida nippea (Mexican bean caryopsis), Raikypik sibae, Huloba rake (weevil pale), Nurega crr. (weevils), Nureg rocissa (alfalfa weevil), Nureg Doer krr. (weevil NuregoDec), NuroIepetik Lattre1 (coffee beetle), 1 pk cr. (bark beetles), yak1oDegta ketsote (tobacco beetle), spruce Desca1sheaa (Colorado beetle), judepuk Giksik, b1depuk kiyyaPk, ykkogor Noryik ogu / orshik (weevil rice weed), b. (tree beetles / wood rodent beetles), Maecoe acreidae, Macaqueus c. date palm), Ogu / aerShik tegsa Yug (peanut beetle), Ogu / aerShik kshtpatepyk (sawtooth grain beetle), Oognups nik kr. krr. (May / June beetle), RNu11orNada sihuaapa, RNu11o1ge1a krr. (leaf beetles), Riups yek krr., Roryya) arosha (Japanese beetle), Rgok (erNapik (gypsum (ek (barbel, large flowering cereal large)), RY / oreyna DotShsa (grain grinder), RY / o1god krr. (European May beetle), RNupsNorNogik kog. weevils), 8so1u1ik krr. (tree beetles), 5> NeporNogik krr. (weevil), §йопе ИпеЫЫк (striped pea weevil), §йорЫ1ик кр. (grain weevils), §йорЫ1к дгапапек (weevil / barn) ae (rice weevil), §1dooshshsh rashseish (bread grinder), Tnoyit krr. (flour hrushchak), TpOpshp sak! apeish (chestnut hrushchak), TpjoPit soiGikish (small flour hrushchak), Tgododegta uapaPe (barn beetle) and 2a btik pepuyu Dek.

In yet another embodiment, the invention disclosed herein can be used to control winged bugs (earwigs).

In yet another embodiment, the invention disclosed herein can be used to control cockroaches (cockroaches). A list of these pests, which is not exhaustive, includes, but is not limited to, B1aye11a deptashsa (red cockroach (Prussacus)), Vaiae opeshaPk (black cockroach), Ratsoiia repus cucus, Repropeus aeptapa (American cockroach, American cockroach) Repr1ape1a hippea (red cockroach), repr1ape1a yydk so far (smoky brown cockroach), Ruspoke1ik kippatepkk (Surinamese cockroach) and §ire11a 1opd1ra1ra (brown striped cockroach).

In yet another embodiment, the invention disclosed herein can be used to control dipterans (true flies). A list of these pests, which is not exhaustive, includes, but is not limited to, AeDec krr. (mosquitoes), Ldgotu / a Ggop1e11a (moths alfalfa), Ldgotu / a cr. (mining flies), Lpakier (fruit flies), Lpakier for stalk (Caribbean Drosophila), Lpor Nelek cr. (mosquitoes), Wyosega crr. (fruit flies), Vasyosega sisyaye (melon fly), Vasyosega Dogkaik (oriental fruit fly), Setayyk crr. (fruit flies), Setayik sarya! a (Mediterranean fruit fly), SNGukork krr. (deer horsefly), SosNPotuta krr. (larvae of meat flies), Chapsha krr. (gall midges), Si1ekh krr. (mosquitoes), Baksheita krr. (gall midges), Baksheita Ltakkuaye (cabbage gall midge), BePa crr., BePa p1a! ita (larva of the fly sprout), Bgokorsha krr. (fruit flies), Raita krr. (house flies), Raita satsi1ayk (housefly small), Rapta ksa1apk (ladder fly), Sak1egorshik Shekaypayk (gastric gadfly), SgasPI regkeae, Nayatuya ygPapk (small cow lighter), NurPeta. (root fly larvae), NuroDegta Ppeaitg (bovine striped gadfly larva), yotu / a crr. (mining flies), yotu / a Lakkuya (cruciferous miner), Me1orNadik oushik (sheep’s runet), Mix crr. (real flies), Miksa aiitgpaPk (common field fly), Miksa Dotekisa (housefly), Oekyik ou1k (sheep’s nasopharyngeal gadfly), Oxse11aGn1 (Swedish front fly), Reduuaa bie (ae (beetroot fly), carrot fly), Ryado1eik setai (cherry fly), Rnado1Ok rotope11a (apple variegated larva), 8yoD1p1ok1 toka11apa (gall midge orange grass), Epohousk sa1syagapk (autumn lance) koar, tal.

In yet another embodiment, the invention disclosed herein can be used to control Unarrow (bugs). A list of these pests, which is not exhaustive, includes, but is not limited to, Lsgok1epsht Shage (green shield), Vykkik 1isor1etik (earthen bug), Ca1osopk potuyedik (potato bug-horsefly), Sateh NenirYugik (tropical bedclit, 1 bed bug) bedbug), Badiik Gaktyak, Bunyurk Gigsaygk, BukDetsik kishenik (red cotton bucket), Dedeka tedyapipa, Eatudak taiga (grain bug), Eksykyk Negok, Eksykyuk nepokyokyopnik (Brown tea), (brown tea), (brown tea), (brown), brown tea, (brown), Yadupo Yutik krr. (shields), yerusopka otaiyyk, yeryusopka oupsogshk, yudik krr. (horseflies), yudik Nekregik (western bedbug-bug), Masope ssossik ygkiik, no. RNUYUSOPK SAYGOTSHSIK, RNUYUSOPK TELAYUIK, Р1е / о Dogik DiyDshch Roesyosarkik IpeaYk (four-lane horsefly), Rka11ik uass1p1so1a, Rkeysasosky regkaye, 8sarososyekosykos kap.

In yet another embodiment, the invention disclosed herein can be used to control Notor South (plant aphids, scale insects, whiteflies, circadian). A list of these pests, which is not exhaustive, includes, but is not limited to, LsguYuyurNop

- 10 022487 rit (pea aphid), Lys1ds5 5ρρ. (hermes), A1eigoye5 rgo1s1s11a (cabbage whitefly), L1sigoShsi5 Sh5rsg5S5. L1eigo1Ng1 \ u5 yosso5I5 (white-winged whitefly), L1iasa 5p15 5ρρ., Atga5sa д 1 1 1 П П П П П а,, Λρгιгорорга 5ρρ. (cicadas), AotFe11a aigail (scutellaria red orange), Λρ1ιί5 5ρρ. (plant aphid), Λρ1ιί5 do55 \ '| eN (cotton aphid), Λρ1ιί5 1ео1ш (apple aphid), А11асойНит 5о1аш (digitala aphid), Vet151a 5ρρ. (whiteflies), Vet151a agdepnGoosh, Vet151a 1aaaa (batata whitefly), ВсасНусоНъ пппъ (Russian plant aphid), ВсасНусогупепа5 | (scale insects), ^ ιυρ ^^ гиЬп5 (wax red scale), CH ^ oia5ρ ^ 5 5ρρ. (scale insects), СН ^ у5otρНа1и5 5ρρ. (scale insects), Sossi5 5ρρ. (scale insects), Ό \ · 5; · ιρ1ιί5 ρ1; πιΙ; · ι§πκ; · ι (aphid pink apple), Εтроа5са 5ρρ. (cicadas), Epo5ota 1 ashdegit (aphid fluffy apple tree), 1 segua ριιπ: 1ι; · ΐ5ί (fluffy cushion), 1So5co1ei5 πίΙίάπ1π5 (mango cicadas), Laoyeff Nah 51pa1e11i5 (small, brown) 05 ^ ρNit 5ρρ., Mas ^ 05 ^ ρNit αιρΙκ ^ 'Νικ (potato aphid), Mas ^ 05 ^ ρNit dgapagtt (English grain aphid), Mas ^ o5 ^ ρNit go5ae (pink aphid), Masgo51e1e5 s. cicadas), MaNapagua Gggtu1a1a, Msoruo1oRH ^ it FgNoyit (pink grain aphid), Mgsi5 1opd1cogsh5, Mu / u5 ρα5Κ; κ (green peach aphid), NcρNoΐsi ^ x 5ρρ. (cicadas), NсρNoΐsi ^ x с ^ isΐ ^ ρc5 (green cicadas), N ^ 1араа ^ νаΐа 1idep5 (brown cicadas), PaPaYupa ρ ^; πιάίί (citrus flies), PaPaYupa ζίζίρΗί (blackfields) ), РЫ1аепи5 5ρρ. (pennies), RNu11okhega ugyGonaye (phylloxera grape leaf), RNu5okegte5 [ecoei (small spruce shield spruce small), P1aposossi5 5ρρ. (mealybugs), P5eysossi5 5ρρ. (mealybugs), Р5ейососси5 ^ ^ сν ^ ρс5 (apple mealybug), ^ аά ^ а5ρ ^ ά ^ оΐи5 ραπΚ ^ v. ^ (San Jose shield), КНаρа1о5 ^ ρНит 5ρρ. (plant aphid), КНаρа1о5 ^ ρNit taka (aphid corn aphid), КНаρа1о5 ^ ρNit ρπΗί (oat cherry aphid), §ag55eya 5ρρ. (scale insects), §ag55eya o1eae (black scale insect), §cH ^ ζаρН ^ 5 dgshitshit (green bug), Zhyoopop auepae (English grain aphid), 5> ode1e11a GigaGega (white-backed delphacid), THc ^ 5 5ρρρ. (plant aphid), Toiteue 11a 5ρρ. (scale insects), Toxoρΐs ^ a 5ρρ. (plant aphid), Tpa1eigske5 5ρρ. (whiteflies), Tpa1eigoye5 νаρо ^ а ^^ о ^ it (greenhouse whitefly), Tg1eigoye5 абий1opei5 (white-winged whitefly), ipa5 | E15 5ρρ. (scale insects), ipa5 | E15 uapopep815 (eastern scutellaria citrus) and Ζιι1ί; · ι epyepapa.

In yet another embodiment, the invention disclosed herein can be used to combat scouts (ants, wasps, and bees). A list of these pests, which is not exhaustive, includes, but is not limited to, Asgotugggteh 5ρρ., AShANa go5ai, Ayia 5ρρ. (leaf-cutting ants), Satruoоΐi5 5ρρ. (wood-boring ants), 01 | er1op 5ρρ. (sawflies), Notis 5ρρ. (ants), 1gkotugtekh NitgN5 (Argentinean ant), Mopotogtt 5ρρ., Moyotogst ttitit (small ant), Mopotogtt ρНа ^ ао ^ 5 (Pharaohs ant), №О | Epop 5ρρ. (sawfly), Rodopotugtekh 5ρρ. (reaper ants), Ро1 | 51е5 5ρρ. (paper wasps), §o1sioρ5 ^ 5 5ρρ. (fire ants), Ta | eotota 5е5511е (odorous house ant), Teiapotogt 5ρρ. (sod ants), ^ 5ρυΠ 5ρρ. (уеНота) аске15) and Xу1осоρа 5ρρ. (carpenter bees).

In yet another embodiment, the invention disclosed herein can be used to combat I5оρΐс ^ а (termites). A list of these pests, which is not exhaustive, includes, but is not limited to, Sapuΐs ^ mc5 5ρρ., Sopΐoΐs ^ mc5 sipadpa Pi, Sórΐoΐs ^ mc5 Ghepspv, Sórΐoΐs ^ mc5 Gogto5api5 (Taiwan) 5 nosed. (nosed termites), Spryt ^ 5ρρ. (dry termites), He1eg1egte5 5ρρ. (desert rhinothermites), He1eg1egte5 aigei5, Ka1o1egte5 5ρρ. (dry termites), 1ps151Pegte5 5ρρ. (dry termites), Masgo1egte5 5ρρ. (mushroom termites), MagdtPegte5 5ρρ. (dry termites), M | with only 1 term 5 5ρρ. (reaper termites), M | cg1egt. (Rinotermity) Keysi1yegte5 aiui1si8 ^ 5 Keysi1yegte5 dga55eg, Keysi1yegte5 ί1aν ^ ρs5 (termite Zheltonogov) Keysi1yegte5 wear Keysi1yegte5 ^ 5ρα gi5 (Western Mediterranean termite) Keysi1yegte5 5aiΐoisi5 ^ 5 Keysi1yegte5 5ραπΐυ5, Keysi1yegte5 yYaN5, Keysi1yegte5 uggdgtssh, 8sNeyogN | only 5 5ρρ. and Ζ∞ΐс ^ then ρ5 ^ 5 5ρρ. (woody termites).

In yet another embodiment, the invention disclosed herein can be used to combat ^ Γ ^ ρΙα; ·! (moths and butterflies). A list of these pests, which is not exhaustive, includes, but is not limited to, AcNoea 1apa1a, Aoxoxorus nos5 5ρρ., Anoxoxus nos5 ogapa, AdgoJ5 5ρρ. (scoops), Adgoi5 ^ ρ5 ^ 1oi (black scoop), A1aAbata agdShasea (cotton caterpillar feeding on leaves), Apogia sipepaa, Atue1o515 1gap5Pe11a (orange caterpillar), Apiaceidae apesa ), Apysagega detta1a1 | 5 (caterpillar-pest of velvet beans), Λ ^ cH ^ ρ5 a ^ du ^ 05ρ ^ 1a (leaflets affecting fruit trees), Λ ^ сН ^ ρ5 гсапа (leaflets affecting roses), Agdugoeta 5ρρ. (leaflets), Agdugoeta sygapa (citrus leafworms), Aiodod arpa na datta, Vopado Shpapoye5, Bogo stpaga (rice mulberry), Wissiuyt Pshrjepepa (cotton leaf perforator), Cauloo. (molar miners), Saraia geysiapa, Sagro5ta and ^ oisi8 ^ 5 (peach mole), SNPO 5ρρ., Syiteya yaguyesha (mango drill), gsaseapa (striped leafworm), SNu5oyeghg5 5pnaya, grasses. CoNa5 5ρρ., Co ^ ot ^ ka sagegeia, Co55i5 co55I5 (woodworm), Crgu5 5ρρ. (meadow moths), SUSHA Hypebapa (plum fruit moth), SuFa tol1e51a (oriental peach leaflet), S'uFa tdshsapa (pea leaflet), S'uFa rotois11a (apple codling moth), Eagpa Fjis1a ri; . (stem grinders), 0 | a1gaea 5ρρ. (stem grinders), 0 | a1gaea 5assNagaN5 (sugarcane moth), 0 | a1gaea dgasho5e11a (southwest cornflake), Eagga5 5ρρ. (cotton scoop)

- 11 022487

Eapa8 Sh8i1a (a (prickly worm), Eapa8 νίΐοΐΐα (northern bollworm), EsyuYurorNa aigapyapit, E1a8tora1ri8 Pdpo8e11i8 (small grinder cornstalks) Er1ru81a8 roPgiyapa (light-brown apple moth), Erekya 8rr. (Moth mill) Erekya san1e11a (moth suhofruktovaya ), Ephekia e1n1e11a (chocolate moth), Ephekia kieše11a (Mediterranean mill refractory), Yershesek 8 pp., Yershoya arogeta, Epopoda 1a \ (banana pest), Eropea sapiensa (fruit) , HerSha 8 pp. (Scoops), Ooyup 8 pp. (Dot stem foliage), Otaryo sha to1e8 (a (oriental peach leaf), Neu1er1a 1pShsa1a (pest of legumes), He11co \ 'erea 8 pp. (scoops), Neiso \' eryga atidega (cotton scoop), He1 ^ sowera e / cotton / boxed worm), He1yu11Y8 8 pp. (scoops), He1yu11Y8 \ lg8sep8 (caterpillar of the leaf bud-tobacco beetle), He11i1a cpbaPk (cabbage fire), 1batre1a kr. eggplant fruit), Leisorpega tarasophila, Lebeso11es8 8p. R. (scoops), boo \ addo8 a1yso81a (western scoop bean), baupita sh8rat (silkworm unpaired), baupeya s1egke11a (leaf apple moth), maanacea bogeo (oil palm sackcloth), maropot 8. (cocoa nest caterpillars, common common spider webs), Mathera bia881cae (cabbage marching worms), Matisa 1e81n1a8 (leguminous grinder), Mei8a p1aa (burlap), Muyeta syrypidae (true) yernps1aY8 (nymph pest rice), OretorSheta tita (a (looper winter) O81psha iiY1a118 (European corn borer), O \ 1Sha \ 'e8iPa, Rap0epY8 sega8apa (common currant tortrix), Rap0epY8 Neragapa (brown codling moth), Papilla yetoyosi8, Resipor Note up to 88 ur1e11a (pink boxed worm of cotton), RetShtota 8 pp. (scoops), RetShtota 8ais1a (variegated pest), Reyesorhera sogGee11a (white deciduous coffee worm miner), miners), P1eg18 garae (cabbage caterpillar), P1aShurepa 8caLga, P1oSha1 Shegripps1e11a (barn fire), P1н1е11а \ u1о81е11а (moth cabbage), Ploens grapefruits, olives, parsley, 8 pp. (scoops), P8eiba1eya ishripsya (worms), P8eyor1i81a FsShyeg (larva of the soybean moth), KasYr1i81a pi, §siror Nada 1pseg1i1a8, 5> e8apya 8rr. (stem grinders), 5> е8апя ФГегегъ (pink stalk grinder of rice), 5> е8апяя пппо Ше8, §е (ота пЦегъ, §йо! тодаееа1е11а (moth barley), §rattado11Y8 rShepapa, робrobr ( ), §Royor (eta ejudia (small scoop), §royor (eta Hygid reggae (autumn worms), §boron (eta oyyasha (southern worms), §uyiophera p. , Thyorea L88eSe11a (membranous clothes moth), Thyuophorum nu81 (scoop w), Tn1a ab8o1n1a, Uropothe sarr., 2en / eGoGeae (red branch grinder) and 2ey / ega rupa (spotted e).

In yet another embodiment, the invention disclosed herein can be used to control Ma11orNada (biting lice). A list of these pests, which is not exhaustive, includes, but is not limited to, Bo \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ with sheep (lice), Me ^ saiN ^ 81gatF1i8 (lice of chickens) and Meporop da Shpea (ordinary chicken louse).

In yet another embodiment, the invention disclosed herein can be used to control Oghoridae (grasshoppers, migratory locusts and crickets). A list of these pests, which is not exhaustive, includes, but is not limited to, Ashbt ^ 81tr1e \ (cricket Mogtop), Sku11o1a1pShae (marshes), bosi8 (and pidgyupa, Meiapor1i8 8rr. (Grasshoppers), Myegosekite (hengekeite) , P (EgorNu11a 8 pp. (Grasshoppers), §СЫ81Осесса дГедапа, 8сиййй Гнгса1а (grasshopper, fork-tailed bush) and Уа1апда 1псопЫ8 (short-grassed grasshopper).

In yet another embodiment, the invention disclosed herein can be used to control Piggyar (lice). A list of these pests, which is not exhaustive, includes, but is not limited to, Nayeta (Orshi 8 pp. (Cow and pork lice), Efodpuschii l11i8 (sheep louse), Rechsi1i8 Nitai8 sarSh8 (head louse), Reshitsi8 N8ash cephalic) and P (Ig8 ri18 (pubic louse).

In yet another embodiment, the invention disclosed herein can be used to control ShpNoparIuga (fleas). A list of these pests, which is not exhaustive, includes, but is not limited to, Closoconulosum cu8 (dog fleas), Clarosericon8 Ge118 (cat fleas), and P1lc1gr1 (ap8 (human flea).

In yet another embodiment, the invention disclosed herein can be used to control THi8apor1ega (thrips). A list of these pests, which is not exhaustive, includes, but is not limited to, Erythromycidae (Western flower thrips), Erythromycinidae (Iciforidae) ), P1p1yrNogoShpr8 sgieiay, 5> sShoShpr8 8pr., 5> sShoShpr8 syy (citrus thrips), §сShoShpr8 yog8aY8 (thrips of brewed tea), TaeyoShpr8 g1yur1ayeppr8 and 8.

In yet another embodiment, the invention disclosed herein can be used to control TNu8apigi (bristles). A list of these pests, which is not exhaustive, includes, but is not limited to, Ep18ta 8 pp. (silverfish) and Netto 8a pp. (Th-12 022487 home brew).

In yet another embodiment, the invention disclosed herein can be used to control Asagsha (ticks). A list of these pests, which is not exhaustive, includes, but is not limited to, Asagar818 \ νοοάί (tracheal tick of a honey bee), Asagi8 8 pp. (barn ticks), Asagis 8io (scab mite), Asepa tadghegae (mango bud mite), Asiopor8 sp., Asiopor8 1 aporeg81a (tick-destroyer), Asioporpidae8181, Asiis apisidae (gumiidae ), ВорЫЫ1и8 8рр. (ticks), Vgueu1ra1ri8 oYoua1i8 (ash mite), Vgeu1ra1ri8 pHoets18 (red and black flat mites), Etoyeh 8rr. (scabies mites), OegtaseShog 8 pp. (hard ticks), Oegtasepug yapaRUSh8 (American dog tick), Oegta1orkado10e8 p1opop88sh8 (home dust mite), Ео1е1гапусн8 8рр., Ео1е1гапусн8 сапр1 (mite spider yellow, Ep 8 exp. (ticks), Me1a1e1gapusi8 8 pp., No. 1 oyge8 sa, O11dopusNi8 8rr., ONdopusNi8 sogGee. Ondopus nuuidae Schi8 (southern red mite), Rapopus nu8 spp., Rapopus niu8 syp (citrus red mite), Rapopus nu8 u1t1 (European red mite), ryuuuuuuuuu mite (brown mite, mite1, mite) , K1y / od1ur1sh8 8 pp. (root mite), §agsor1e8 8caY1e1 (scabies mite), Tedo1or1sh8 reg8eaG1ogae, TegapusNi8 8 pp., Tegapus ni8 igisae (two-spotted spider mite) and honey-bee gum (bee gum).

In yet another embodiment, the invention disclosed herein can be used to combat HMT (nematodes). A list of these pests, which is not exhaustive, includes, but is not limited to, ArNe1epsNo1e8 8 pp. (root and deciduous & coniferous nematodes), Be1opo1a1ti8 8 pp. (stinging nematodes), Sspete 11a 8 pp. (round nematodes), OpoGlapa ηιηιηίΐί8 (iodine Neapitus), Pyuepsiu8 8 pp. (stem and tuberous nematodes), Ne1egoyega 8 pp. (vesiculate nematodes), He1egoyega / eae (maize vesiculate nematode), Br8cnapte11a 8 pp. (root nematodes), Нор1о1а1ти8 8рр. (lanceolate nematodes), Ме1о1йодупе 8рр. (root nodular nematodes), Ме1о1йодупе шсодпя (root nodular nematode), Opsnosegs uo1ui1i8 (sickle-tailed worm), Рга1у1епс1ш8 8рр. (affecting nematodes), CayorNo1i8 8 pp. (nematode-causing fistula) and Ko1u1epsNi8 geshGogtk (kidney-shaped nematode).

In yet another embodiment, the invention disclosed herein can be used to combat 8utrHu1a (symphyla). A list of these pests, which is not exhaustive, includes, but is not limited to, §iidege11a jptasi1a1a.

In yet another embodiment, the invention disclosed herein can be used to control animal and human parasites. A non-exhaustive list of these pests includes, but is not limited to, arthropods such as ticks (e.g. mesostigmatides, itching, scabies, thrombiculins), ticks (e.g. soft and hard), lice (e.g. sucking, biting) ), fleas (for example, dog flea, cat flea, eastern rat flea, human flea), bedbugs (for example, bed bugs, TpaJupy bugs), blood-sucking adults of flying insects (for example, small cow bug, horseflies, autumn louse, midge, deer fly, cr vososka, tsetse fly, mosquitoes), and parasitic flying insects (e.g., oestrinae, flower fly, screwworm, botfly bovine, sheep wool worm); helminths, such as nematodes (e.g. pinworm, pulmonary worm, worm, parasitic worm living in the pig’s intestines, nodular worm, gastric worm, roundworm, pinworm, Neo-Egt), cestodes (e.g. tapeworms) and trematodes (e.g. hepatic fluke, schistosome); protozoa, such as coccids, trypanosomes, trichomonads, amoeba and plasmodium; scrapers, such as key-headed worms (for example, 1shdi1aGiIIya); and pentameter, such as pentastomids.

Detailed information about the pests can be found in Napyook oG Re81 Sop1go1 - Tne VeNauyug, OGe H18yuu apy Sop1go1 oG Noi8eNo1y Re818 Agpo1y Mash8, 91k EiShop, sropps 2004 Yu ΟΙΕ Mefa directly in this application.

The present invention provides all carriers by which the composition of the present invention can be formulated for delivery and use as a pesticidal composition, including solutions, suspensions, emulsions, wettable powders and water-dispersible granules, emulsifiable concentrates, granules, powders, bait, etc. .P. Compositions suitable for administration to vertebrates or humans include preparations suitable for oral, parenteral, transdermal administration, for example, by application, or topical administration.

Compositions for oral administration include one or more compounds of the general formula Ι-A or Ι-B in combination with pharmaceutically acceptable carriers or coatings, and include, for example, tablets, pills, capsules, pastes, gels, impregnations, medicament feeds; potable water containing a drug; medicinal food additives, prolonged-action boluses, or other sustained-release drugs intended to delay the gastrointestinal tract. Any of these may include the active ingredient contained in microcapsules or having a decomposition in an acidic or alkaline medium or other pharmaceutically acceptable enteric coating. Nutrient additives and concentrates containing the compounds of the present invention may also be used for use in the preparation of drug-containing products, drinking water or other materials for animal consumption.

Compositions for parenteral administration include solutions, emulsions or suspensions in any suitable pharmaceutically acceptable carrier and solid or semi-solid subcutaneous implants or granules intended to release the active substance over an extended period, and they can be prepared and made sterile by any suitable method known in the art. area.

Compositions for transdermal and topical administration include sprays, powders, baths, wetting solutions, showers, injections, lubricants, shampoos, creams, waxes or topical preparations and devices (e.g. ear stickers) that are attached externally to the animals so that provide local or systemic control of arthropods.

Typically, compositions for application to plants, seeds or soil are used after diluting the concentrated composition with water in the form of aqueous solutions, suspensions or emulsions, or combinations thereof. Such solutions, suspensions or emulsions are obtained from water-soluble, suspended in water or water-suspended, emulsified in water or water-emulsifiable compositions or combinations thereof, which are solids, including and commonly known as wettable powders or water-dispersible granules: or liquids, including and commonly known as emulsifiable concentrates, aqueous suspensions or suspension concentrates, and aqueous emulsions or emulsions in water, or mixtures thereof, such as suspension emulsions. It should be understood that any materials to which this composition can be added can be used, provided that they provide the desired benefit without substantially interfering with the desired activity of the pesticidal active ingredients as pesticidal agents.

Wettable powders that can be compressed to form water-dispersible granules include a homogeneous mixture of one or more pesticidal active ingredients, an inert carrier, and surfactants.

The concentration of the pesticidal active ingredient in a wettable powder is typically from about 10 to about 90% by weight based on the total weight of the wettable powder, more preferably from about 25 to 75% by weight. In the preparation of wettable powder compositions, the pesticidally active ingredients can be mixed with any finely divided solid, such as profilite, talc, chalk, gypsum, fuller’s clay, bentonite, attapulgite, starch, casein, gluten, montmorillonite clay, diatomaceous earth, silicate earth, diatomaceous earth. Such procedures typically include mixing the finely divided carrier and surfactants with the compound (s) and grinding.

Emulsifiable concentrates of the pesticidal active ingredient include a convenient concentration, for example, from about 10 to about 50% by weight of the pesticidal active ingredient, in a suitable liquid, based on the total weight of the concentrate. The pesticidal active ingredients are dissolved in an inert carrier, which is either a water-miscible solvent or a mixture of water-immiscible organic solvents and emulsifiers. Concentrates can be diluted with water and oil to form sprayable mixtures in the form of an oil-in-water emulsion. Useful organic solvents include aromatic solvents, in particular high boiling naphthalene and olefin fractions of oil, such as heavy aromatic naphtha. Other organic solvents may also be used, such as, for example, terpene solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2ethoxyethanol.

Emulsifiers that can advantageously be used in the present invention can easily be determined by a person skilled in the art, and they include various nonionic, anionic, cationic and amphoteric emulsifiers or a mixture of two or more emulsifiers. Examples of non-ionic emulsifiers useful in the preparation of emulsifiable concentrates include polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as ethoxylated alkyl phenols and polyethylene ether polyethylene ethers. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include oil soluble salts (e.g. calcium) of alkylarylsulfonic acids, oil soluble salts of sulfated polyglycol ethers and suitable salts of phosphated polyglycol ether.

Representative organic liquids that can be used to prepare emulsifiable concentrates are aromatic liquids such as xylene, propylbenzene fractions; or mixed naphthalene fractions, mineral oils, liquids representing substituted aromatic organic compounds, such as dioctyl phthalate; kerosene; dialkylamides of various fatty acids, in particular dimethylamides; and glycol ethers such as nbutyl ether, ethyl ether or diethylene glycol methyl ether and triethylene glycol methyl ether and the like. Mixtures of two or more organic liquids can also be used to prepare an emulsifiable concentrate. Surfactant emulsifiers are typically used in liquid compositions in an amount of about 0.1 to 20% by weight, based on the total weight of emulsifiers. The compositions may also contain other compatible additives, for example plant growth regulators and other biologically active compounds used in agriculture.

Aqueous suspensions include suspensions of one or more water-insoluble pesticidally active ingredients dispersed in an aqueous carrier at a concentration in the range of about 5 to about 70% by weight based on the total weight of the aqueous suspension. Suspensions are obtained by finely grinding one or more pesticidal active ingredients and intensively mixing the ground substance in a carrier consisting of water and surfactants selected from the substances discussed above. Other components, such as inorganic salts and synthetic or natural resins, can also be added to increase the density and viscosity of the aqueous carrier. Often the most effective is the simultaneous grinding and mixing to obtain an aqueous mixture and homogenizing the mixture, for example, using a sand mill, ball mill or piston type homogenizer.

Aqueous emulsions include emulsions of one or more water-insoluble pesticidally active ingredients emulsified in an aqueous carrier at a concentration typically ranging from about 5 to about 70% by weight based on the total weight of the aqueous emulsion. When the pesticidal active ingredient is solid, it should be dissolved in a suitable water-immiscible solvent to form an aqueous emulsion. Emulsions are prepared by emulsifying a liquid pesticidal ingredient or a solution of the ingredient which is not miscible with water in an aqueous medium, typically with the inclusion of surfactants that contribute to the formation and stabilization of the emulsion, as described above. This is often accomplished by intensive mixing using mixers or homogenizers with a high shear rate.

The compositions of the present invention are also in the form of granules that are especially useful for application to the soil. Granular compositions typically contain from about 0.5 to about 10 wt.% Based on the total weight of the granular composition of the pesticidal active ingredient (s) dispersed in an inert carrier, which consists exclusively or mostly of a coarsely ground inert substance such as attapulgite, bentonite , diatomaceous earth, clay or the like, an inexpensive substance. Such compositions are usually prepared by dissolving the pesticidal active ingredients in a suitable solvent and applying to a granular carrier that has been prepared with a suitable particle size in the range of about 0.5 to about 3 mm. A suitable solvent is one in which the compound is substantially or completely soluble. Such compositions can also be obtained by preparing a thick mass or paste from a carrier and a compound and a solvent and grinding and drying to obtain the desired granular particles.

Powders can be obtained by closely mixing one or more pesticidally active ingredients in powder form with a suitable finely divided agricultural carrier, such as, for example, kaolin clay, crushed volcanic rock and the like. The powders may suitably contain from about 1 to about 10% by weight of the compounds, based on the total weight of the powder.

The compositions may further comprise adjuvants, such as surfactants, to enhance the deposition, wetting and penetration of pesticidal active ingredients into a target site, such as a crop or organism. These surfactants as adjuvants can optionally be used as a component of the composition or as a mixture for mixing in a tank. The amount of surfactant as adjuvant typically ranges from 0.01 to 1.0 vol.% Based on the sprayed volume of water, preferably from 0.05 to 0.5 vol.%. Suitable surfactants used as adjuvants include, but are not limited to, ethoxylated nonylphenols, ethoxylated synthetic or natural alcohols, salts of sulfosuccinic acid esters, ethoxylated organosilicones, ethoxylated fatty amines, and mixtures of surfactants with mineral or vegetable oils.

Compositions may optionally include combinations that contain one or more other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, nematicides, acaricides, arthropodicides, bactericides, plant growth stimulants or regulators, nitrification inhibitors, nutrients, or combinations thereof that are compatible with the compounds of the present invention in an environment selected for application and not antagonistic to the activity of the compounds of the present invention. The compounds of the present invention and the pesticidal compound in combination are typically present in a weight ratio of from about 1: 100 to 100: 1.

The compounds disclosed in the present invention may be in the form of pesticidally acceptable acid addition salts.

By way of non-limiting example, the amine functional group can form hydrogen chloride, hydrogen bromide, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, dairy, gluconic , ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic and hydroxyethanesulfonic acids.

Additionally, by way of non-limiting example, an acid functional group can form salts, including salts formed from alkali or alkaline earth metals, and salts formed from ammonia and amines. Examples of preferred cations include sodium, potassium, magnesium and aminium cations.

Salts are prepared by contacting the free base form with a sufficient amount of the desired acid to form a salt. Free base forms can be restored by treating the salt with a suitable dilute aqueous base solution, such as a dilute aqueous solution of ΝαΝ, potassium carbonate, ammonia and sodium bicarbonate. As an example, in many cases, the pesticide is modified to a more water-soluble form, for example, a salt of dimethylamine and 2,4-dichlorophenoxyacetic acid is a more water-soluble form of 2,4-dichlorophenoxyacetic acid, a well-known herbicide.

The compounds disclosed in the present invention can also form stable complexes with solvent molecules that remain intact after non-complexed solvent molecules are removed from the compounds. These complexes are often called solvates.

Certain compounds disclosed herein may exist as one or more stereoisomers. Various stereoisomers include geometric isomers, diastereomers and enantiomers. Thus, the compounds disclosed in the present invention include racemic mixtures, individual stereoisomers and optically active mixtures. Specialists in this field should be clear that one stereoisomer may be more active than others. Individual stereoisomers and optically active mixtures can be obtained by selective synthetic procedures, by traditional synthetic procedures using reduced starting materials, or by traditional reduction procedures.

The compounds of the present invention can also be combined with other agricultural fungicides to obtain fungicidal mixtures and synergistic mixtures. The fungicidal compounds of the present invention are often used in combination with one or more other fungicides to combat various undesirable diseases. When used in combination with another fungicide (s), the compounds of the present invention can be formulated with another fungicide (s), mixed in a tank with another fungicide (s), or applied sequentially with another fungicide (s). Such other fungicides include, but are not limited to, 2- (thiocyanatomethylthio) benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, amethoctradine, amisulbrom, antimycin, Ltrs1tuss5 sc. azaconazole, azoxystrobin, Vasyl Chick, Benalaxyl, Benomyl, bentiavalikarb-isopropyl, benzylaminobenzene-sulfonate (VLV8) salt, bicarbonates, biphenyl, bismerthiazole, bitertanol, bixafen, blastidin-borosulfon boroside, boron borazole, borazole, borazole, borazole, borazole, borazole, borazole, borazole, bazoral, borax, borazole, bazoral, borax, borazole, bazoral, borax, borax, boron bazole, borax, boron bazole, borax bosulfonamide, boron-boron-boron-boron-boron-boron-boron-boron-boron-boron-boron-boron-boron-donoxamide boron oxohydroxene , calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamide, carvone, chloren, chlorothalonil, chlozolinate, Sochoshugst t1t1ai8, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate, trisomide, cyanide, oxide cymoxani , ciproconazole, cyprodinil, coumarin, dazomet, debacarb, diammonium ethylene bis (dithiocarbamate), dichlorofluanide, dichlorofen, diclocimet, diclomezine, dichloran, dietofenocarbene, diphenocinoconimonofenone, diphenzinokinomonazole, difenocinokinomonazole, diphenocinformonazonazole, diphenocinformonazonazole, diphenocinformonazonazole, diphenocinformonazone , diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodinovoe free base, edifenphos, enestrobin, epoxiconazole, ethaboxam, ztoksikvin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, f enpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopikolid, fluopiram, ftorimid, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, folpet, formaldehyde, fosetyl, fosetil- aluminum, fuberidazole, furalaxyl, furametpir, guazatin, guazatin acetates, SU-81, hexachlorobenzene, hexaconazole, hemexazole, imazalil, imazalyl sulfate, imibenconazole, iminoktadin, iminoktadin triacetodipinodazene, imine, imine he, iprivalicarb, isoprothiolan, isopirazam, isothianyl, casugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, mandipropamide, maneb, mepanipyrim, mepronil, mercuric chloride, olefin oxide, mercuric oxide , metalaxyl-M, metam, metam ammonium, metam potassium, metam sodium, metconazole, metasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, miklobutanyl, nabam, nitrothalisopropyl, nuarimonuotio, okamit, okriminotura, okarimot greasy acids), oryzastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxyne, pefurazoate, penconazole, pencicuron, pentachlorophenol, pentachlorophenyl laurate, pentiopyrad, phenylrrutin oxyhydroxyinone polyoxybenoxycarboxylic acid, phthalynoxycarboxylic acid, phosphonic acid polyoxybenoxycarboxylic acid potassium, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole,

- 16 022487 propineb, proquinazide, prothioconazole, pyraclostrobin, pyramethostrobin, pyraxystrobin, pyrazofos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyroquilone, quinoxenophenol, quinone benzene, quinone benzene, 8 , sodium pentachlorophenoxide, spiroxamine, sulfur, 3ΥΡ-Ζ071, 3ΥΡ-Ζ048, tar, tebuconazole, tebufloquin, teknazen, tetraconazole, thiabendazole, tifluzamide, thiofanate methyl, thiram, thiadinyl, tolclofos-methyl, triadimel triadimel triadimel triadimel , Triazoksid, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, valifenalat, valifenal, vinclozolin, zineb, ziram, zoxamide, SapFya o1eorY1a, Fusarium oh18rogit, 01yus1aysht spp., RYeYor818 schdatea, 31ger1otuse8 dgkeoutyk, TpsNoyegta 8rr., ( K3) -I- (3,5-dichlorophenyl) -2 (methoxymethyl) succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2- (2-heptadecyl-2-imidazolin-1-yl) ethanol, 2,3-dihydro-5phenyl-1,4-dithiin 1,1,4,4-tetraoxide, 2-methoxyethyl mercury acetate, 2-methoxyethyl chloride uti, 2-methoxyethyl mercury silicate, 3- (4-chlorophenyl) -5-methylrodanine, 4- (2-nitroprop-1-enyl) phenylthiocyanate, ampropylphos, anilazine, azithiram, barium polysulfide, Waueg 32394, benodanil, benquinox, bentaluron benzamacryl; benzamacryl-isobutyl, benzamorph, binapacryl, bis (methylmercury) sulfate, bis (tributyltin) oxide, butiobate, cadmium calcium calcium copper sulfate chromate, carbamorph, CECA, chlobentiazone, chloroanifolmethane, chlorphenazole, chloroquinox, climbazyl-bis ) copper, zinc copper chromate, kufraneb, copper hydrazine sulfate, cuprobam, cyclafuramide, cipendazole, ciprofuram, decafentin, dichlon, dichlozolin, diclobutrazole, dimethyrimol, dinton, dinosulfone, dinoteron, ditholone, diodolone, diodolone, ditholone, ditholone, ditholone, ditholone, ditholone, ditholone, ditholone, diodolon etem, etirim, phenaminos ulf, phenapanil, phenytropan, fluotrimazole, furcarbanyl, furconazole, furconazole-cis, furmecyclox, furofanate, gliodin, griseofulvin, galacrinate, Negcy1e8 3944, hexylthiofos, 1C1A085fsodisulfonamide isopropylmethylene milneb, mucochloric acid anhydride, myclozoline, I-3,5-dichlorophenyl-succinimide, Ν-3-nitrophenyl-taconimide, natamycin, I-ethyl mercurio-4-toluenesulfonanilide, nickel bis (dimethyldithiocarbamate) nickel, OSH, phenyl dimethyldithiamide , prothiocarb; prothiocarb hydrochloride, pyracarbolide, pyridinitrile, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quikazamide, quinconazole, rabenzazole, salicylanilide, 33P-109, sultropen, tecoram, thiadifluor, thiophene, thiochlorphenfim, thiofanate, thioquinox, thioximide, triamiphos, triarimol, triazbutyl, tri-Clam, and any combination thereof.

Additionally, the compounds of the present invention can be combined with other pesticides, including insecticides, nematicides, acaricides, arthropodicides, bactericides or combinations thereof, which are compatible with the compounds of the present invention, in an environment selected for application and not antagonistic to the activity of the compounds of the present invention, to obtain pesticidal mixtures and their synergistic mixtures. The pesticidal compounds of the present invention are often used in combination with one or more other insecticides, acaricides or other pesticides to control various undesirable pests. When used in combination with other pesticides, the compounds of the present invention can be formulated with another pesticide (s), mixed in a tank with another pesticide (s), or they can be applied sequentially with another pesticide (s). Typical insecticides include, but are not limited to: antibiotic insecticides such as allosamidine and turringensin; macrocyclic lactone insecticides such as spinosad and spinetorams; avermectin-based insecticides such as abamectin, doramectin, emamectin, eprinomectin, ivermectin and selamectin; milbemycin-based insecticides such as lepimectin, milbemectin, milbemycin oxime and moxidectin; arsenic-based insecticides such as calcium arsenate, copper acetoarsenite, copper arsenate, lead arsenate, potassium arsenite and sodium arsenite; plant-based insecticides such as anabasin, azadiractin, ά-limonene, nicotine, pyrethrins, cinerins, cinerin I, cinerin ΙΙ, jasmoline Ι, jasmolin ΙΙ, pyrethrin Ι, pyrethrin ΙΙ, cassia, rotenone, riania and sabadilla; carbamate insecticides such as bendiocarb and carbaryl; benzofuranyl methyl carbamate insecticides such as benfuracarb, carbofuran, carbosulfan, decarbofuran and furatiocarb; dimethylcarbamate insecticides dimitan, dimethylan, gikvinkarb and pyrimikarb; hydroxycarbamate-based insecticides such as alanicarb, aldicarb, aldoxycarb, butocarboxime, butoxycarboxim, methomil, nitrile carb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenylmethylcarbamate-based insecticides such as allixicarb, aminocarb, bufencarb, butacarb, carbanolate, cloethocarb, ethiochencarb, phenethacarb, phenobucarb, proparcarb, methicarcarbecarb, methicarcarbecarb, methicarbarb, methacarbcarb, methacarb carbam, ; diamide insecticides such as chlorantraniliprol, cyanthraniliprol and flubendiamide; dinitrophenol insecticides such as dinex, dicoprop, dinos and EIOS; fluorine-containing insecticides such as barium hexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicate and sulfluramide; formamidine-based insecticides such as amitraz, chlordimeform, formanate and formpartate; respiratory insecticides such as acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform, chloropicrin, paradichlorobenzene, 1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene dichloride, ethylene oxide, hydrocyanic acid, iodomethane, methyl bromide, methylchloride, methylchloride, methyl chloride phosphine, sulfuryl fluoride and tetrachloroethane; inorganic insecticides such as borax, calcium polysulfide, copper oleate, mercury chloride, potassium thiocyanate and sodium thiocyanate; chitin synthesis inhibitors such as bistrifluuron, buprofesin, chlorofluazuron, cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, penfluuron, teflubenuron and three; juvenile hormone mimetics such as epofenonan, phenoxycarb, hydroprene, kinoprene, metoprene, pyriproxifen and triprene; juvenile hormones such as juvenile hormone I, juvenile hormone II and juvenile hormone III; molting hormone agonists such as chromaphenoside, halogenphenoside, methoxyphenoside and tebufenoside; molting hormones such as α-ecdysone and ecdysterone; molt inhibitors such as diophenolan; precocene, such as precocene I, precocene II and precocene III; unclassified insect growth regulators, such as dicyclanil; Nereistoxin analog insecticides such as bensultap, cartap, thiocyclam and thiosultap; nicotinoid insecticides such as flonicamide; nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethylene insecticides such as nitenpyram and nithiazine; pyridylmethylamine-based insecticides such as acetamipride, imidacloprid, nitenpyram and thiacloprid; organochlorine insecticides such as bromo-ΌΌΤ, camfechlor, ΌΌΤ, ρρ'-ΌΌΤ, ethyl-ΌΌΌ, HCH, gamma-HCH, lindane, methoxychlor, pentachlorophenol and ΤΌΕ; cyclodiene insecticides such as aldrin, bromocyclin, chlorobicyclene, chlordane, chlordecone, dieldrin, dealers, endosulfan, endrin, NEOE. heptachlor, NNEC isobenzene, isodrine, kelevan and mirex; organophosphate insecticides such as bromfenvinphos, chlorfenvinphos, crotoxifos, dichlorvos, dicrotophos, dimethylvinphos, phosphirate, heptenophos, metocrotophos, mevinphos, monocrotophos, frost, naphthalophos, tetramidone, phosphamidone, tetramidone; organothiophosphate insecticides such as dioxabenzophos, phosphomethylan and fentoate; aliphatic organothiophosphate insecticides such as acetone, amiton, cadusafos, chloroethoxyphos, chlormefos, demefion, demefion-O, demefion-δ, demeton, demeton-O, demeton-δ, demeton-methyl, demeton-O-methyl, demeton-8- methyl, demethone-8-methylsulfone, disulfotone, ethion, etoprofos, GR8P, isothioate, malathion, methacryphos, oxydemetone-methyl, oxydeprofos, oxide disulfoton, forat, sulfotep, terbufos and thiometon; aliphatic amide organothiophosphate insecticides such as amidithion, cyantoate, dimethoate, ztoate methyl, formotion, mekarbam, methomeate, protoate, sofamide and vamidothion; oxyorganorganothiophosphate insecticides such as chlorfoxime, foxime and foxime methyl; heterocyclic organothiophosphate insecticides such as azamethiphos, coumaphos, kumitoate, dioxathion, endotion, menazone, morfotion, fosalon, pyraclofos, pyridafetion and quinothion; benzothiopyranorganothiophosphate insecticides such as dithicrophos and ticrophos; benzotriazinorganothiophosphate insecticides such as azinphos-ethyl and azinphos-methyl; isoindolorganothiophosphate insecticides such as dialiphos and phosphate; isoxazole-organothiophosphate insecticides such as isoxathion and zolaprofos; pyrazolopyrimidine-organothiophosphate insecticides such as chlorprazophos and pyrazophos; pyridine-organothiophosphate insecticides such as chlorpyrifos and chlorpyrifos-methyl; pyrimidine-organothiophosphate insecticides such as butathiophos, diazinon, etrimphos, lyrimphos, pyrimifos-ethyl, pyrimifos-methyl, pyrimidophos, pyrimitate and tebupirimfos; quinoxaline-organothiophosphate insecticides such as quinalphos and quinalphos-methyl; thiadiazolorganothiophosphate insecticides such as atidation, lithidation, methidation and protidation; triazole-organothiophosphate insecticides such as isazophos and triazophos; phenyl-organotiofosfatnye insecticides such as azotoat, bromfos, bromfos-ethyl, karbofenotion, hlortiofos, cyanophos, tsitioat, dikapton, dihlofention, etafos, famfur, fenhlorfos, fenitrothion fensulfothion, fenthion, fenthion-ethyl, geterofos, yodfenfos, mesulfenfos, parathion, parathion-methyl, fencapton, fosnichlor, profenofos, prothiophos, sulprofos, temefos, trichloromethaphos-3 and triphenophos; phosphonate insecticides such as butonate and trichlorfon; phosphonothioate insecticides such as mecarphone; phenylethylphosphonothioate insecticides such as phonophos and trichlorate; phenyl-phenylphosphonothioate insecticides such as cyanophenphos, ΕΡΝ and leptophos; phosphoramidate insecticides such as krufomat, fenamiphos, fostetane, mefospholan, phospholan and pyrimethaphos; phosphoramidothioate insecticides such as acephate, isocarbophos, isofenphos, metamidophos and propetamphos; phosphorodiamide insecticides such as dimefox, mazidox, mipafox and shradan; oxadiazine insecticides such as indoxacarb; oxadiazolone insecticides such as methoxadiazone; phthalimide insecticides such as dialiphos, phosphate and tetramethrin; pyrazole insecticides such as acetoprol, cienopirafen, etiprol, fipronil, pyrafluprol, pyriprol, tebufenpyrad, tolfenpyrad and vanilliprol; pyrethroid ester insecticides such as acrinatrin, allethrin, bioallethrin, bartrin, bifentrin, bioethanometrin, cyclletrin, cycloprotrin, cyfluthrin, beta-cyfluthrin, cygalotrin, gammacygalotrin, lambda-cygalotrin, cypermetrin, alpha-cypermetrin, alpha-cypermethrin, alpha-cypermetrin, alpha-cypermetrin, alpha , zeta-cypermethrin, cifenotrin, deltamethrin, dimeflutrin, dimethrin, empentrine, fenflutrin, fenpyritrin, fenpropatrin, fenvalerate, esfenvalerate, flucytrinate, fluvalinate, taufluvalinate, fururerin, imiprotrin, perimetrin, permetrin Ranspermetrin, Phenotrin, Pralletrin, Proflutrin, Piresmetrin, Resmetrin, Bioresmetrin, Cismetrin, Teflutrin, Teralocrin, Tetramethrin, Tralometrin and Transfluthrin; pyrethroid ether insecticides,

- 18 022487 such as etofenprox, flufenprox, galfenprox, protrifenbut and silafluofen; pyrimidinamine insecticides such as flufenerim and pyrimidiphene; pyrrole insecticides such as chlorfenapyr; tetraamic acid insecticides such as spiro tetramate; tetron acid insecticides such as spiromesifen; thiourea based insecticides such as diafentyuroon; urea-based insecticides such as flucofuron and sulcofuron; and unclassified insecticides, such as closantel, copper naphthenate, crotamiton, ΕΧΌ, phenazaflor, phenoxacrim, hydramethylnon, isoprothiolane, malonoben, metaflumizone, nifluridine, plifenate, pyridaben, pyridylyl, pyridifriloxane triphrylafrylphanitriphanitriphanitriphanitriphanitriphanitriphanitriphanphrylphanitriphanphrylphanitriphanitriphanphrylphanitriphanitriphanphrylphanitriphanitriphanphrylphanitriphanitriphanitriphanitriphanifrilofanitriphanifrilafanifrinafrinafrinafrinafrinafrinafrinafrinafrinafinafinafirafinafinafirafinafridina

Additionally, the compounds of the present invention can be combined with herbicides that are compatible with the compounds of the present invention in an environment selected for application and not antagonistic to the activity of the compounds of the present invention, to obtain pesticidal mixtures and their synergistic mixtures. The pesticidal compounds of the present invention can be applied in combination with one or more herbicides to control various undesirable plants, diseases and pests. When used in combination with herbicides, the compounds of the present invention can be formulated with a herbicide (s), mixed in a reservoir with a herbicide (s), or applied sequentially with a herbicide (s). Typical herbicides include, but are not limited to: amide herbicides such as allidochlor, beflubutamide, benzadox, benzipram, bromobutide, safenstrol, ί'.ΌΕΛ. ciprazole, dimethenamide, dimethenamide-R, diphenamide, epronase, ethnpromide, fentrazamide, flupoxam, fomesafen, halosafen, isocarbamide, isoxaben, napropamide, napthalam, petoxamide, propisamide, quinonamide and tebutam; anilide herbicides such as chloranocryl, cisanilide, clomeprop, cypromide, diflufenican, etobenzanide, phenasulam, flufenacet, flufenican, mefenacet, mefluidide, metamifop, monalide, naproanilide, pentanochlor, and picolina; arylalanine herbicides such as benzoylprop, flamprop and flamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor, butachlor, butenachlor, delachlor, diethyl, dimethachlor, metazachlor, metolachlor, δ-metolachlor, pretilachlor, propachlor, propisochlor, prichachlor, terbuchlor, tenylchlor and xylachlor; sulfonanilide herbicides such as benzofluor, perfluidone, pyrimisulfan and profluazole; sulfonamide herbicides such as asulam, carbasulam, fenasulam and oryzaline; thioamide herbicides such as chlorothiamide; antibiotic herbicides such as bilanafos; benzoic acid herbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba; pyrimidinyloxybenzoic acid herbicides such as bispiribac and pyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac; phthalic acid herbicides such as chlortal; picolinic acid herbicides such as aminopyralid, clopyralid and picloram; quinoline carboxylic acid herbicides such as quinclorac and quinmerac; arsenic-based herbicides such as cacodilic acid, CMA, ΌδΜΑ, hexaflurate, MAA, MAMA, M8MA, potassium arsenite and sodium arsenite; benzoylcyclohexanedione herbicides such as mesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranylalkyl sulfonate herbicides such as benfuresate and etofumesate; benzothiazole herbicides such as benzazoline; carbamate herbicides such as asulam, carboxazole chloroprocarb, dichlormat, phenasulam, carbutylate and terbucarb; carbanilate herbicides such as barbane, HRBC, carbasulam, carbetamide, CEPC, chlorofuf, chlorpropram, CPPC, desmedifam, phenizofam, phenmedifam, phenmedifam ethyl, profam and swap, cyclohexenoxime herbicides such as butroxydimecimer, alcimedimoximed, , cycloxydim, profoxydim, sethoxydim, heatraloxydim and thralkoxydim; cyclopropylisoxazole herbicides such as isoxachlortol and isoxaflutol; dicarboximide herbicides such as cinidone-ethyl, flumezin, flumiklorak, flumioxazine and flumipropine; dinitroaniline herbicides such as benfluralin, butralin, dinitramine, etalfluralin, fluchloralin, isopropalin, metalpropalin, nitralin, oryzalin, pendimethalin, prodiamine, profluralin and trifluralin; dinitrophenol herbicides such as dinophenate, dinoprop, dinosam, dinoseb, dinoterb, PyOS, ethinophen and medinerb; diphenyl ether herbicides such as ethoxyphene; nitrophenyl ether-based herbicides such as acifluorfen, aclonifen, biphenox, chlomethoxifen, chloronitrophene, ethnipromide, fluorodiphene, fluoroglycophene, fluoronitrofen, fomesafen, furyloxifen, halogenfenfen, nitrofenorfenorfenfenrofenorfenrofenorfenrofenorfitrofen, nitrofenorfenrofenorfitrofenorfenorfitrofenorfenrofenorfenrofenorfenrofenorfenrofenorfenorfit dithiocarbamate herbicides such as dazomet and metam; halogenated aliphatic herbicides such as alorak, chlorpon, dalapon, flupropanate, hexachloroacetone, iodomethane, methyl bromide, monochloracetic acid, §MA and TCA; imidazolinone herbicides such as imazametabenz, imazamox, imazapik, imazapir, imazakvin and imazetapir; inorganic herbicides such as ammonium sulfamate, borax, calcium chlorate, copper sulfate, iron sulfate, potassium azide, potassium cyanate, sodium azide, sodium chlorate and sulfuric acid; nitrile herbicides such as brombonyl, bromoxynil, chloroxinyl, dichlobenyl, iodbonyl, yoxinyl and pyraclonyl; organophosphorus herbicides such as amiprofos-methyl, anilophos, bensulide, bilanafos, butamifos, 2,4-EER, EMRA, EVEP, fosamine, glufosinate, glufosinate-R, glyphosate and piperophos; phenoxy herbicides such as bromphenoxime, clomeprop, 2,4-EEV, 2,4-EER, diphenopentene, disul, erbon, ethnipromide, phentoracol and trifopsime; oxadiazoline herbicides such as metazole, oxadiargil, oxadiazone; oxazole herbicides such as phenoxasulfone; phenoxyacetic herbicides - 19 022487 slots, such as 4-CPA, 2,4-Ό, 3,4-EA, MCPA, MCPA-thioethyl and 2,4,5-Τ; phenoxybutyric acid-based herbicides such as 4-CPB, 2,4-ΌΒ, 3,4-МС, MCPB and 2,4,5-ΤΒ; phenoxypropionic acid herbicides such as cloprop, 4-CPP, dichloroprop, dichloroprop-P, 3,4-OP, phenoprop, mecoprop and mecoprop-P; aryloxyphenoxypropionic acid herbicides such as chlorazifop, clodinafop, clofop, cygalofop, diclofop, fenoxaprop, fenoxaprop-R, fentyaprop, fluazifop, fluazifop-R, haloxifopop, haloxifop-R, isoxisophiophytophisophytophisophytophisophytophisophytophisophyphiopisophytophyll trifop; phenylenediamine herbicides such as dinitramine and prodiamine; pyrazole herbicides such as pyroxasulfone; benzoylpyrazole herbicides such as benzofenap, pyrasulfotol, pyrazolinate, pyrazoxifene and topramezon; phenylpyrazole herbicides such as fluazolate, nipiraclofen, pyoxaden and piraflufen; pyridazine herbicides such as credazine, pyridafol and pyridate; pyridazinone herbicides such as bromopyrazone, chloridazone, dimidazone, flufenpir, metflurazone, norflurazone, oxapirazone and pidanone; pyridine herbicides such as aminopyralid, cliodinate, clopyralid, dithiopyr, fluroxypyr, haloxidine, picloram, picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine herbicides such as iprimidam and thioclorim; quaternary ammonium-based herbicides such as cyperquat, diethquat, diphenzoquat, diquat, morphamquat and paraquat; thiocarbamate herbicides such as butylate, cycloate, diallate, EPTS, esprocarb, etiolate, isopolinate, methiobencarb, molinate, orbencarb, pebulate, prosulfocarb, pyributicarb, sulfallate, thiobencarb, thiocarbazyl; thiocarbonate herbicides such as dimexano, EUE and proxane; thiourea-based herbicides such as methiuron; triazine herbicides such as dipropetrin, indaziflam, triaziflam and trihydroxytriazine; chlortriazine herbicides such as atrazine, chlorazine, cyachazine, ciprazine, eglinazine, ipazine, mesoprazine, procyazine, proglazine, propazine, sebutylazine, simazine, terbutylazine and trietazine; methoxytriazine herbicides such as atratone, methometon, prometon, secbumeton, simeton and terbumeton; methylthiotriazine herbicides such as ametrine, aziprotrin, cyanatrin, desmetrine, dimetamethrin, metoprotrin, promethrin, simethrin and terbutrin; triazinone herbicides such as ametridion, amibuzin, hexazinone, isomethiosine, metamitron and metribuzin; triazole herbicides such as amitrol, kafenstrol, epronase and flupoxam; triazolone herbicides such as amicarbazone, bencarbazone, carfentrazone, flucarbazone, ipfencarbazone, propoxycarbazone, sulfentrazone and thiencarbazone methyl; triazolopyrimidine herbicides, such as cloransulam, diclosulam, florarasulam, flumetsulam, metosulam, penocssulam and pyroxulam; uracil-based herbicides such as benzfendizone, bromacil, butafenacil, flupropacil, isocyl, lenacil, saflufenacil and terbacil; urea-based herbicides such as benzthiazuron, cumiluron, cycluron, dichloralurea, diflufenzopyr, isonoruron, isouron, metabenzthiazuron, monisouron and noruron; phenylurea-based herbicides such as Anisuron, Buturon, Chlorobromuron, Chloreturon, Chlortoluron, Chloroxuron, Daimuron, Diphenoxuron, Dimefuron, Diuron, Phenuron, Fluometuron, Fluotiuronuron, Methonuronuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methononuronuron, Methonuronuron, Methonuronuron, Methononuron, Meth , neburon, parafluron, phenobenzuron, siduron, tetrafluron and thidiazuron; herbicides pirimidinilsulfonilmocheviny such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flutsetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, metazosulfuron, nicosulfuron, ortosulfamuron, oxasulfuron, primisulfuron, propirisulfuron, pyrazosulfuron, rimsulfuron, sulfometuron sulfosulfuron and trifloxysulfuron; triazinylsulfonylureas based herbicides such as chlorosulfuron, cinosulfuron, etametsulfuron, iodosulfuron, metsulfuron, prosulfuron, tifensulfuron, triasulfuron, tribenuron, triflusulfuron and tritosulfuron; thiadiazolylurea-based herbicides such as butyuron, ethidimuron, tebutiuron, thiazafluron and thidiazuron; and unclassified herbicides, such as acrolein, allyl alcohol, aminocyclopirachlor, azafenidine, bentazone, benzobicyclone, bicyclopiron, butidazole, calcium cyanamide, cambendichlor, chlorfenac, chlorfenprop, chloroflurenolene-cinol-azolemnolazole-cinol-azole-cinol-azole-rinol-azole-cinol-azole-rinol-azole-cinolamine-cinol-azole-azole dimepiperate, endotal, fluormidine, fluridone, flurochloride, flurtamone, flutiacet, indanophan, methyl isothiocyanate, OCH, oxaziclomephone, pentachlorophenol, pentoxazone, phenylmercury acetate, prosulfalin, pyrilin benzenoxime , sulglycapine, thidiazimine, tridifan, trimethuron, tripropindane and tritak.

The compounds of the present invention can have a wide range of efficacy as pesticides. The exact amount of active substance to use depends not only on the particular active substance used, but also on the specific desired action, pathogen or pest that the composition is intended to control, and the stage of its growth, as well as part of the plant, animal or other medium with which contacts the connection. Thus, all compounds and compositions containing them may not be equally effective at the same concentrations or against the same type of pathogen and pest.

The compounds are effective when applied to plants in a phytologically acceptable amount. The term phytologically acceptable amount refers to the amount of a compound that kills or inhibits the pest or disease of the plant for which it is intended to be controlled, but is not substantially toxic to the plant. This amount is usually from about

- 20 022487

0.1 to about 1000 ppm, with an amount of 1-500 ppm being preferred.

The exact concentration of the compound that is needed varies depending on the pest or disease being controlled, the type of composition used, the method of application, the particular type of plant or animal, climatic conditions, etc. For fungicides, the dilution and application rate depend on the equipment used, the desired method and frequency of use and the diseases to be controlled, but the effective amount is usually from about 0.01 to about 20 kg of active ingredient (ai) per hectare (ha ) As a leaf fungicide, the compound of the present invention is usually applied to growing plants at a rate of from about 0.1 to about 5 and preferably from about 0.125 to about 0.5 kg per 1 ha.

For a fungicide applied to the seeds, the amount of poisonous substance that is applied to the seeds is usually from about 0.1 to about 250 g, and preferably from about 1 to about 60 g, per 100 kg of seeds. As for soil fungicide, the chemical can be applied to the soil or applied to the soil surface or to a rice nursery, usually at a rate of about 0.1 to about 5 kg per 1 ha.

The actual amount of insecticide or acaricide to be applied to areas where there are pests is usually not critical, and it can easily be determined by a person skilled in the art. As a rule, it is expected that concentrations from about 10 g of pesticide per 1 ha to about 5000 g of pesticide per 1 ha will provide good control.

The locus to which the pesticide is applied can be any locus populated by pests, such as garden crops, fruit and nut trees, vines, ornamental plants, domestic animals, the internal or external surfaces of buildings, and the soil around the buildings. Pest control usually means that pest populations, their activity, or both, decrease at a given locus. This occurs when pest populations are reflected from the locus; when pests are neutralized and incapacitated, partially or completely, temporarily or permanently, in or around the locus; or pest populations are eliminated, in whole or in part, in or around the locus. Of course, there may be a combination of these results. As a rule, it is desirable when the pest populations, their activity, or both are reduced by more than 50%, preferably more than 90%, even more preferably 99%.

As for baits, baits are mainly placed in the soil, for example termites can come into contact with baits. Bait can also be applied to the surface of the building (horizontal, vertical or inclined surface), where, for example, ants, termites, cockroaches and flies can come into contact with the bait.

Due to the unique ability of some pest eggs to resist pesticides, repeated applications may be required to combat newly emerged larvae.

The systemic movement of pesticides in plants can be used to control pests on a plant site by applying pesticides to another plant site or to a site where the plant's root system can absorb pesticides. For example, to combat insects affecting foliage, drip irrigation can be used, either by irrigation with furrows or seed treatment before planting. Seed treatment can be applied to all types of seeds, including those from which plants genetically transformed to display special properties will grow. Representative examples include those that express proteins that are toxic to invertebrate pests, such as Vaschik Ιΐιιιππβίοηκίδ or other insecticidal toxins, those that express herbicidal resistance, such as Coipyr RsaPu seeds. or those that include embedded foreign genes expressing insecticidal toxins, herbicidal resistance, improved nutrition, or any other beneficial properties. In addition, such seed treatments using the invention disclosed herein can further enhance the ability of a plant to better withstand stressful growth conditions. This results in a healthier, stronger plant, which can lead to higher yields.

It should be understood that the invention can be applied to plants genetically transformed to express special characteristics, for example, VasShik PshppDsgMk or other insecticidal toxins, or those that express herbicidal resistance, or those that include built-in foreign genes expressing insecticidal toxins, herbicidal resistance, improved nutrition or any other beneficial properties. An example of such an application is to spray such a plant with the compound of the invention disclosed herein.

The invention disclosed herein may be suitable for controlling endoparasites and ectoparasites in veterinary medicine or in the field of animal welfare. Here, the compounds in accordance with the present invention are applied in a known manner, such as oral administration in the form of, for example, tablets, capsules, drinks, granules, by application to the skin in the form of, for example, dipping, spraying, watering, staining and spraying, and by parenteral administration in the form of, for example, injection.

The invention disclosed herein can also be advantageously used for livestock, for example cows, sheep, pigs, chickens and geese. Suitable compositions may be administered to animals

- 21 022487 orally with drinking water or food. Dosages and compositions that are suitable depend on the type of animal.

Specialists in this field should be clear that the effectiveness of the compounds in relation to the above fungi and insects determines the overall usefulness of the compounds as fungicides and insecticides.

Definitions for chromatography.

Preparative RP-HPLC (preparative reverse phase high performance liquid chromatography):

column 20x250 mm §5 μm 120A UMS-AC or 50x250 mm §10 μm 120A UMS-AC, using mixtures of 0.1% vol./about. H ₃ PO ₄ with MeCN (acetonitrile) as eluent;

HPLC (high performance liquid chromatography): C8-C18 acetonitrile / water solvent system on a silica gel substrate) TLC (thin layer chromatography): §YU ₂ / glass plates, eluted with hexane, Εΐ ₂ Ο (diethyl ether), CH ₂ Cl ₂ ( dichloromethane), EuAc (ethyl acetate), MeOH (methanol) or any mixture of these solvents that can be used;

OS (gas chromatography);

OS-Mg (gas chromatography - mass spectrometry);

L-Mg (liquid chromatography - mass spectrometry).

Preparation 1. 2- (4-Benzyloxyphenyl) ethylamine.

To a suspension of potassium carbonate (K ₂ CO ₃ ; 1.4 g, 10.11 mmol) in acetone (40 ml) was added bromomethylbenzene (1.73 g, 10.11 mmol) and tert-butyl 2- (4-hydroxyphenyl) ethyl carbamate (2 g, 8.4 mmol). The reaction mixture was heated at reflux for 15 hours and then concentrated in vacuo. The residue was partitioned between diethyl ether (Εΐ ₂ Ο) and water (H ₂ O), and the organic fraction was washed with brine, dried over sodium sulfate (Ν α ₂ Ο ₄ ), filtered using a suction filter and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (§ίΟ ₂ ) using 25% Εΐ ₂ Ο in hexane to give [2- (4-benzyloxyphenyl) ethyl] carbamic acid tert-butyl ester as a white solid (2.4 d). This compound was dissolved in CH2C12 (50 ml) and trifluoroacetic acid (5 ml) was added. After stirring for 16 hours, the solvent was removed in vacuo and the residue was redissolved in CH ₂ Cl ₂ , washed with 1 M sodium hydroxide solution (NO. NO). dried (Να ₂ §Ο ₄ ) and filtered. The solvent was removed in vacuo to give 2- (4-benzyloxyphenyl) ethylamine (1.5 g). This compound was used in the next step without purification.

Example 1. [2- (4-Benzyloxyphenyl) ethyl] pteridin-4-yl-amine.

To a mixture of pteridin-4-ol (282 mg, 1.9 mmol) and 2- (4-benzyloxyphenyl) ethylamine (47 6 mg, 2.1 mmol) and hexamethyldisilazane (5 ml) in a 25 ml round bottom flask equipped with a reverse ammonium sulfate (100 mg, 0.76 mmol) was added with a refrigerator, a drying tube and a magnetic stirrer. The mixture was heated to 114 ° C. overnight and then the solvent was removed in vacuo. The residue was suspended in NJ and filtered. The filter cake was dissolved in CH ₂ Cl ₂ , dried with Να ₂ §Ο ₄ , filtered and concentrated in vacuo to give [2- (4-benzyloxyphenyl) ethyl] pteridin-4-yl-amine as a white solid (501 mg ): ¹ H NMR (300 MHz) δ 9.01 (d, 1 = 1.9 Hz, 1 H), 8.81 (s, 1 H), 8.61 (d, 7 = 1.9 Hz, 1 H) 7.49-7.29 (m, 6H), 7.25-7.15 (m, 3H), 6.96 (dd, 1 = 6.8, 4.8 Hz, 2H), 5.06 (s, 2H), 3.93 (dd, 1 = 13.2, 6.9 Hz, 2H), 3.00 (t, 1 = 7.0 Hz, 2H); E8BM8 t / ζ 358.1 ([M + H] +).

Example 2. 4- [2- (Pteridin-4-ylamino) ethyl] phenol.

To a solution of No.- (3-cyanopyrazin-2-yl) TOU-dimethylformamidine (prepared as described in A1bе1 αηύ ΟΙιΙα, ί. Сет. §Ос., С 1971, 3727-3730, which is directly incorporated by reference into the present application; 2.0 g, 11.4 mmol) in ethyl alcohol (EUN; 50 ml) was added 4- (2-aminoethyl) phenol (4.7 g, 34 mmol) and acetic acid (3.9 ml, 4.1 g , 68 mmol). The solution was heated to the boiling temperature under reflux for 19 h, concentrated in vacuo, the residue was suspended with NU and filtered using an suction filter. The filter cake was washed with ND and dried in a vacuum oven (80 ° C, 0.5 mm Hg) to give 4- [2- (pteridin-4ylamino) ethyl] phenol (2.7 g) as a white solid substances: melting point> 210 ° C; ¹ H NMR

- 22 022487 (DMSO-b ₆ ) δ 9.20 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.95 (t, 1 = 6.0 Hz, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 7.06 (d,

1 = 8.5 Hz, 2H), 6.69 (d, 1 = 8.2 Hz, 2H), 3.75 (t, 1 = 6.2 Hz, 2H), 2.85 (t, 1 = 7.6 Hz, 2H); Ε8ΙΜ8 t / ζ 268 (M +).

Example 3. Pteridin-4-yl- {2- [4- (5-trifluoromethylpyridin-2-yloxy) phenyl] ethyl) amine.

To a solution of 4- [2- (pteridin-4-ylamino) ethyl] phenol (270 mg, 1.0 mmol) and anhydrous DMSO (5 ml) was added 2-chloro-5-trifluoromethylpyridine (155 mg, 0.85 mmol) and K ₂ CO ₃ (280 mg, 2.0 mmol). This mixture was heated to 80 ° C for 3 hours, cooled to ambient temperature, poured into H ₂ O (20 ml) and extracted with CH ₂ Cl ₂ (20 ml). The solution of CH ₂ Cl _{2 was} washed with H ₂ O (2x10 ml), dried with No-s8O ₄ and the solution was filtered. The solution was concentrated in vacuo, redissolved in a minimal volume of CH2C12, and triturated with hexane until a solid precipitated. The solid was collected by filtration and dried in vacuo to give pteridin-4-yl- {2- [4 (5-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} amine (310 mg) as an off-white solid: temperature melting point 147-150 ° C; Ή NMR (300 MHz, SES1 ₃ ) δ 9.04 (d, 1 = 1.9 Hz, 1H), 8.85 (s, 1H), 8.64 (d, 1 = 1.9 Hz, 1H) 8.35 (d, 1 = 5.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.22 (dd, 1 = 5.2, 0.8 Hz, 1H), 7.19-7.05 (m, 3H), 4.01 (dd, 1 = 13.3, 7.0 Hz, 2H), 3.10 (t, 1 = 7.1 Hz, 2H); ΕδΙΜδ t / ζ 413 ([M + H] +).

Example 3 (alternative). Pteridin-4-yl- {2- [4- (4-trifluoromethylpyridin-2yloxy) phenyl] ethyl} amine.

To a solution of 4- [2- (pteridin-4-ylamino) ethyl] phenol (2.5 g, 9.3 mmol) and DMSO (20 ml) in a 100 ml round-bottom flask equipped with a reflux condenser, a drying tube and a magnetic stirrer 2-fluoro-4- (trifluoromethyl) pyridine was added (obtained as described in US Pat. No. 4,775,762, which is incorporated by reference in its entirety in the present application; 1.7 g, 10 mmol) and cesium carbonate (C5 ₂ CO ₃ ; 3.7 g, 11.5 mmol). This mixture was heated to 57 ° C for 16 hours, then cooled to ambient temperature and poured into ice-cold H ₂ O (150 ml) to precipitate an off-white solid. This material was collected by filtration using a suction filter and the filter cake was washed with H ₂ O and then with pentane. The filter cake was then dissolved in CH ₂ Cl ₂ , dried using No. ₂ 8O _4, and the solution was filtered. The solution was concentrated in vacuo to give pteridin-4-yl- {2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} amine (3.0 g) as an off-white solid: melting point 147- 149 ° C; ¹ H NMR (300 MHz, SES1 ₃ ) δ 9.04 (d, 1 = 1.9 Hz, 1H), 8.85 (s, 1H), 8.64 (d, 1 = 1.9 Hz, 1H ), 8.35 (d, 1 = 5.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.22 (dd, 1 = 5.2, 0.8 Hz, 1H) , 7.19-7.05 (m, 3H), 4.01 (dd, 1 = 13.3, 7.0 Hz, 2H), 3.10 (t, 1 = 7.1 Hz, 2H); Е8ВМ8 t / ζ 413 ([M + H] +).

Example 4. Pteridin-4-yl- {2- [4- (pyrazin-2-yloxy) phenyl] ethyl} amine.

To a solution of 4- [2- (pteridin-4-ylamino) ethyl] phenol (0.267 g, 1.0 mmol) and 2-chloropyrazine (0.114 g, 1.0 mmol) in anhydrous DMF (7 ml) was added portionwise 60% sodium hydride (No.-1H) in mineral oil (0.060 g, 1.5 mmol). The mixture was stirred at 55 ° C. overnight and then at 70 ° C. for a total of 32 hours. The solvent was removed in vacuo and the residue suspended in H ₂ O. The solid was collected by filtration using an suction filter, washed with H ₂ O and EO, dried in a vacuum oven at 55 ° C overnight to give pteridin-4-yl- {2 [4- (pyrazin-2-yl-xy) phenyl] ethyl} amine (0.291 g, 84%) as light brown solid: ¹ H NMR (300 MHz, SES _{1 3} ) δ 9.02 (d, 1 = 1.9 Hz, 1H), 8.82 (s, 1H), 8.63 (d, 1 = 1.9 Hz, 1H), 8.43 (d, 1 = 1.5 Hz, 1H), 8.26 (d, 1 = 2.4 Hz, 1H), 8.10 (dd, 1 = 2, 4, 1.5 g , 1H), 7.33 (d, 1 = 8.4 Hz, 2H), 7.13 (d, 1 = 8.4 Hz, 2H), 3.99 (dd, 1 = 13.6, 6, 9 Hz, 2H), 3.08 (t, 1 = 6.9 Hz, 2H); E8PM8 t / ζ 346.24 ([M + H] +).

Example 5. {2- [4- (6-Methoxypyridin-2-yloxy) phenyl] ethyl} pteridin-4-yl-amine.

{2- [4- (6-Fluoropyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine (200 mg, 0.55 mmol) was dissolved in ml of anhydrous DMSO, treated with sodium methoxide (300 mg, 5.5 mmol , 10 equiv.) And mixed in

- 23 022487 for 20 hours at 25 ° C. The mixture was poured into H ₂ O (15 ml) and extracted with CH ₂ Cl ₂ (2x25 ml). The combined extracts of CH ₂ Cl ₂ were washed with H ₂ O and brine, dried (Na ₂ 8 O ₄ ), filtered and evaporated. The gummy residue was dissolved in a minimal amount of CH2C12 and treated with hexane to precipitate the product as a solid, which was collected by filtration using an suction filter, washed with hexane and dried in vacuo to give {2- [4- (6-methoxypyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine (139 mg) as a tan solid: melting point 152-153 ° C; ¹ H NMR (DMSO-D ₆ ) δ 9.09 (s, 1H), 9.00 (t, 1 = 5.9 Hz, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.70 (t, 1 = 8.0 Hz, 1H), 7.30 (d, 1 = 8.3 Hz, 2H), 7.05 (d, 1 = 8.4 Hz, 2H) 6.51 (d, 1 = 8.0 Hz, 2H), 6.36 (d, 1 = 7.7 Hz, 2H), 3.83 (m, 2H), 3.65 (s, 3H) 3.00 (m, 2H); Ε8ΙΜ8 t / ζ 375 ([M + H] +).

Also obtained by the method of example 5.

Pteridin-4-yl- (2- {4- [6- (2,2,2-trifluoroethoxy) pyridin-2-yloxy] phenyl} ethyl) amine from 2,2,2 sodium trifluoroethoxide obtained by processing 2,2, 2-trifluoroethanol with sodium hydride.

{2- [4- (6-Ethoxypyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine from sodium ethoxide obtained by treating ethanol with sodium hydride.

Preparation 2. 6-Chloro-4,5-diamino-2-methylpyrimidine.

5-amino-4,6-dichloro-2-methylpyrimidine (7.2 g, 40 mmol) and a 2 M solution of ammonia in isopropanol (100 ml) were loaded into a 200 ml stainless steel Parra vessel and then closed and heated at 150 ° C within 16 hours. HPLC analysis indicated completion of conversion. The mixture was concentrated in vacuo and the residue suspended in a mixture of H ₂ O (10 ml) and isopropanol (35 ml). This mixture was stirred at 50 ° C for 1 h and then cooled to room temperature. The precipitate was collected by filtration using a suction filter, carefully washed with isopropanol, then dried in air on a filter to obtain 6-chloro-4,5-diamino-2-methylpyrimidine (5.8 g, 91%) as a brown powder, which was used without further purification in the next step.

Example 6. [1- (4-Methoxyphenyl) ethyl] -2-methylpteridin-4-yl-amine.

A mixture of 6-chloro-4,5-diamino-2-methylpyrimidine (317 mg, 2.0 mmol) and 1,4-dioxane-2,3-diol (240 mg, 2.0 mmol) in UNN (15 ml) was stirred at 25 ° C for 1 h, TLC analysis (1: 1 mixture of hexane / EYuLs occupies 8 to _2). pointed out that starting material is completely consumed. 1- (4 methoxyphenyl) ethylamine (332 mg, 2.2 mmol) and triethylamine (Εΐ ₃ Ν; 0.3 ml, 2.2 mmol) were added and the reaction mixture was stirred overnight. Most of the solvent was removed in vacuo and the residue was partitioned between EULS and H ₂ O. The organic layer was concentrated in vacuo to obtain a brown residue, which was purified by column chromatography on 8 S ₂ , eluting with a 2: 1 mixture of SULS / hexane, then 100% SULS. to obtain [1- (4-methoxyphenyl) ethyl] -2-methylpteridin-4-ylamine (126 mg) as a brown oil.

Obtaining 3. 1. 2-Methylthio-4- (2,2,2) -trifluoroethoxypyrimidine.

To a suspension of 60% N-) H (524 mg, 130.1 mmol) in DMSO (30 ml) was added 2,2,2-trifluoroethanol (1.31 g, 130.1 mmol). The reaction mixture was stirred for 0.5 h at 25 ° C., then 4-chloro-2 (methylthio) pyrimidine (2.0 g, 12.5 mmol) was added and stirred for 16 hours. The reaction mixture was diluted with H ₂ O and extracted with ₂ O. E1 E1 layer ₂ O was washed with saturated brine, concentrated in vacuo and filtered through a ₂ occupies 8 to give 2.16 g of a yellow oil which proved 60% pure on HPLC and was used without further cleaning in the next step.

2. 2-Methylsulfonyl-4- (2,2,2) -trifluoroethoxypyrimidine.

To a solution of 1.0 g (4.46 mmol) of the product from Preparation 3, step 1, in CH ₂ Cl ₂ (5 ml) was added methachloroperoxybenzoic acid (MCPBA; 1.6 g, 6.7 mmol) in CH ₂ Cl ₂ (6 ml). After 3 hours, the reaction mixture was diluted with CH ₂ Cl ₂ (20 ml) and washed with saturated aqueous sodium bicarbonate (No.-1 HCO ₃ ). The organic layer was dried (№ ₂ 8o _4), filtered and concentrated in vacuo to afford 2-methylsulfonyl-4- (2,2,2) -triftoretoksipirimidina (1.3 g, 70% purity by LC). it

- 24 022487 the compound was used without further purification.

Getting 4. 2-Chloro-4- (1,1-difluoroethyl) pyridine.

To a solution of 2-chloro-4-acetylpyridine (2.6 g, 17.2 mmol) in CH ₂ Cl ₂ (50 ml) was added diethylamino sulfur trifluoride (8 ml, 60 mmol) at 25 ° C and the mixture was stirred for 16 hours The reaction mixture was quenched by adding dropwise a saturated aqueous solution of NaHCO ₃ at 0 ° C. After separation of the two phases, the organic phase was dried over Na _{2 3} O ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on SC ₂ with 10% EJAc in hexane to give 2-chloro-4 (1,1-difluoroethyl) pyridine (1.72 g) as a light brown oil: E1MZ t / ζ 177 ([ M] +).

Also using this method received:

2-bromo-6- (1,1-difluoroethyl) pyridine, from 1- (6-bromo-pyridin-2-yl) ethanone. E1MZ t / ζ 222 ([M] +);

2-chloro-4-difluoromethylpyridine, from 2-chloropyridin-4-carbaldehyde. E1MZ t / ζ 163 ([M] +).

Getting 5.

1. 2-Fluoro-4-methoxy-1 - ((E) -2-nitrovinyl) benzene.

A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 33 mmol) and ammonium acetate (1.0 g, 13 mmol) in nitromethane (40 ml) was heated in a water bath for 2.5 hours. The reaction mixture was concentrated at reduced pressure and a viscous residue were partitioned between CH2C12 and H2O. The organic layer was washed with semi-saturated saline, dried (MgSO ₄ ), filtered and concentrated. The residue was triturated in hexane, the solid was filtered, washed with hexane and dried to give 2-fluoro-4-methoxy-1 - ((E) -2-nitrovinyl) benzene (5.57 g) as an orange solid: temperature melting point 80-82 ° C; ^! H NMR (SPS1 ₃ ): δ 8.02 (d, 1 = 13.5 Hz, 1H), 7.66 (d, 1 = 13.5 Hz, 1H), 7.43 (m, 1H), 6 68-6.80 (m, 2H); 3.87 (s, 3H); E1MZ t / ζ 197 ([M] +).

This material was used in the next step without further purification.

2. 2- (2-Fluoro-4-methoxyphenyl) ethylamine hydrochloride.

In a nitrogen atmosphere, 2-fluoro-4-methoxy-1 - ((E) -2-nitrovinyl) benzene (26.5 g, 134.5 mmol) was added in portions to a suspension of HAAH ₄ (16 g, 195 mmol) in THF ( 1 l) at 0 ° C. The mixture was then heated at the boiling temperature under reflux, after 3.5 hours the reaction mixture was cooled to 0 ° C and quenched carefully with H ₂ O (34.6 ml) and 10% aqueous NaOH solution (28 ml). After removing green sediment by filtration using a suction filter, the filtrate was dried over MgSO ₄ , filtered and evaporated under reduced pressure. The oily residue was dissolved in EJAc (150 ml) and then a concentrated HCl solution was added until the pH reached about 1. EbO (1 L) was added with stirring, the solid was collected by filtration using an suction filter and washed with a small amount of acetone, then dried under vacuum to obtain 12.3 g of 2- (2-fluoro-4-methoxyphenyl) ethylamine hydrochloride as a white solid, melting point 162-165 ° C. The filtrate was concentrated under reduced pressure, the residue was dried azeotropically by suspension in toluene and concentration in vacuo. The residue was dissolved in methanol and the solution was diluted with EAAc until additional product precipitated. A second batch was collected by filtration using a suction filter and washed with ethyl acetate to give another 7.3 g of product. Total yield 19.6 g (72%). 'H NMR (SECE): δ 8.29 (br, 3H), 7.24 (t, 1 = 8.7 Hz, 1H), 6.73-6.84 (m, 2H), 3.74 (s, 3H), 2.83-2.99 (m, 4H); E31MZ t / ζ 169.9 ([M] + HC1).

Preparation 6. 2-Chloro-4-methoxyiminoacetylpyridine.

To a solution of methoxylamine hydrochloride (0.37 g, 4.5 mmol) and sodium acetate (NaOAc; 0.37 g, 4.5 mmol) in H ₂ O (0.6 ml) and MeOH (5 ml) was added 2-chlorine -4-acetylpyridine (0.47 g, 3 mmol) and the reaction mixture was stirred overnight. MeOH was evaporated, H ₂ O was added and the solution was extracted with CH ₂ Cl ₂ . The organic layer was dried (Na ₂ ZO ₄ ), filtered and concentrated in vacuo to give 0.50 g of a crude product. E1MZ t / ζ 184 ([M] +).

- 25 022487

Getting 7.

1.4- [1 - (6-amino-5-nitropyrimidin-4-ylamino) ethyl] phenol.

4-amino-5-nitro-6-chloropyrimidine (5.0 g, 29 mmol), 4- (1-aminoethyl) phenol (4.3 g, 32 mmol) and Εΐ ₃ Ν (4.5 ml, 3, 2 g, 32 mmol) were combined in anhydrous DMF (30 ml). After stirring for 2 hours at 25 ° C., the mixture was poured into diluted citric acid (150 ml; pH approximately 3) and the precipitated product was collected by filtration using an suction filter and washed with H ₂ O. The solid was recrystallized from refluxing. a mixture of H ₂ O (100 ml) and EUN (50 ml) to obtain 6.6 g (84%).

2. 4- [1- (5,6-Diaminopyrimidin-4-ylamino) ethyl phenol.

The product from Preparation 7, stage 1, was dissolved in hot EHL (200 ml), the solution was cooled and sparged with nitrogen for 15 min, treated with Raney nickel (10 g) and hydrogenated for 2 hours in a Parr shaker. The catalyst was removed by filtration using a suction filter and the solvent was removed in vacuo to give 3.8 g (98%).

Example 7. 4- [1- (Pteridin-4-ylamino) ethyl] phenol.

The product from Preparation 7, step 2 (1.1 g, 4.5 mmol) was dissolved in UNN (5 ml) and treated with a 40 wt.% Aqueous solution of glyoxal (1.3 g, 9.0 mmol) and H ₂ O ( 10 ml) and heated at 75 ° C for 40 min. After cooling, the mixture was diluted with H ₂ O (20 ml) and the precipitated product was collected by filtration using a suction filter, washed with H ₂ O and dried in vacuum at 80 ° C to obtain 4- [1- (pteridin-4- ilamino) ethyl] phenol (900 mg, 75%). ¹ H NMR (300 MHz, SOST) δ 9.33 (s, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.63 ( s, 1H), 7.32 (d, 1 = 9 Hz, 2H), 6.73 (d, 1 = 9 Hz, 2H), 5.52 (t, 1 = 9 Hz, 1H), 1.60 (d, 1 = 9 Hz, 3H).

Getting 8. 4- (2-aminoethoxy) phenol.

1. (4-Benzyloxyphenoxy) acetonitrile.

A mixture of 4-benzyloxyphenol (9.4 g, 47 mmol), bromoacetonitrile (6.8 g, 56.7 mmol) in acetone (50 ml) with K ₂ CO ₃ (2 g, 14. 5 mmol) was heated to boiling point under reflux for 1 min, then at 40 ° C for 1 h with stirring. The reaction mixture was filtered, the solids were washed with acetone, and the filtrate was concentrated in vacuo to give a tan oil, which crystallized upon standing to give 10.70 g of (4-benzyloxyphenoxy) acetonitrile.

2. 4- (2-Aminoethyloxy) phenol.

The product from Preparation 8, Step 1 (10.7 g, 44.7 mmol) was dissolved in absolute UNN (100 ml) in a Parr vessel. The solution was treated with 37% HC1 solution (9 g) and 10% Pb / C (1.8 g). The reaction mixture was deaerated, then filled with hydrogen (initial pressure: 3.5 kg / cm ² H ₂ ) and shaken for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 4- (2 aminoethoxy) phenol hydrochloride, salt (7.22 g , 85%) as a beige solid. This substance was used without further purification.

As in Preparation 8, 3- (2-amino-ethyloxy) phenol hydrochloride salt, from 3-benzyloxyphenol, was obtained.

As in preparation 8, step 2, the following was obtained:

2- (4-methoxy-2,5-dimethylphenyl) ethylamine hydrochloride, from (4-methoxy-2,5dimethylphenyl) acetonitrile,

2- (4-methoxy-2-methylphenyl) ethylamine hydrochloride, from (4-methoxy-2-methylphenyl) acetonitrile,

2- (4-methoxy-2,3-dimethylphenyl) ethylamine hydrochloride, from (4-methoxy-2,3-dimethylphenyl) acetonitrile.

Example 8. (2- {4- [6- (2-Methoxyethoxy) -4-trifluoromethylpyridin-2-yloxy] phenyl} ethyl) pteridin-4ylamine.

To a solution of {2- [4- (6-chloro-4-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine (320 mg, 0.7 mmol) in anhydrous methoxyethanol (5 ml) was added No.-) N (50 mg, 60% dispersion in oil). This mixture was heated at 100 ° C. until TLC analysis indicated completion of the reaction. The reaction mixture was evaporated in a Ν2 atmosphere, the residue was taken up in Н2О (125 ml) and treated with a dilute НС1 solution until pH 7 was reached. The aqueous mixture was washed with ЕУАс, the layers were separated and the organic layer was concentrated in vacuo to obtain 0.22 g of resin. This resin was dissolved in E1 ₂ O, hexane was added and E1 ₂ O was evaporated until a solid precipitated. The product was collected by filtration using a suction filter to obtain (2- {4- [6- (2-methoxyethoxy) -4-26 022487 trifluoromethylpyridin-2-yloxy] phenyl} ethyl) pteridin-4-ylamine (97 mg) as beige powder:

melting point 101-104 ° C. ^! H NMR (СОС1 ₃ ) δ 9.03 (d, 1 = 2.0 Hz, 1Н), 8.84 (s, 1Н), 8.63 (d, 1 = 1.8 Hz,

1H), 7.31-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.13-7.09 (m, 2H), 6.73 (s, 1H) 6.55 (s, 1H), 4.30-4.28 (m, 2H), 4.013.96 (m, 2H), 3.63-3.61 (m, 2H), 3.38 (s , 3H); 3.10-3.07 (m, 2H); EPM8 t / ζ 487.3 ([M] +).

Example 9. Pteridin-4-yl- (2- {4- [4- (2,2,2-trifluoroethoxy) pyridin-2-yloxy] phenyl} ethyl) amine.

To the solution No. (2- {4 - [(4-iodopyridin-2-yl) oxy] phenyl} ethyl) pteridin-4-amine (300 mg, 0.64 mmol) and

2,2,2-trifluoroethanol (5 ml, 1.27 mmol) in a 45 ml Parr test vessel was added C8 ₂ CΟ ₃ (412 mg, 1.27 mmol), 1,10-phenanthroline (22 mg, 0.127 mmol) and CU (12 mg, 0.064 mmol). The reaction mixture was kept at 110 ° C for 72 hours, diluted with CH ₂ Cl ₂ and washed with ND. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give pteridin-4-yl- (2- {4- [4- (2,2,2-trifluoroethoxy) pyridin-2-yloxy] phenyl} ethyl) amine (74 mg, 26%) as a yellow solid: melting point 166 ° C; E! M8 t / ζ 442 ([M] +).

Example 10. {2- [4- (6-Fluoropyridin-3-yl) phenyl] ethyl} pteridin-4-yl-amine.

[2- (4-Bromophenyl) ethyl] pteridin-4-ylamine (200 mg, 0.61 mmol), 2-fluoro-5-pyridinboronic acid (102 mg, 0.73 mmol), Να ^ Ο were added to the round-bottom flask. ₃ (102 mg, 1.21 mmol), RyS1 ₂ (RR _{3) 2} (213 mg) and 50% aqueous solution of ethylene glycol dimethyl ether (DME, 3.0 ml). The reaction mixture was heated to reflux for 4.5 hours, after which the reaction mixture was cooled and the resulting orange precipitate was filtered. The filtered material was washed with EJAc and the filtrate was washed with NJ. The organic fractions were combined and concentrated in vacuo. The residue (229 mg) was purified using preparative reverse phase HPLC to give {2- [4- (6-fluoropyridin-3-yl) phenyl] ethyl} pteridin-4-ylamine (20 mg) as an orange solid: temperature melting point 184-186 ° C; E! M8 t / ζ 346 ([M] +).

Preparation 9.2- [6- (4-Trifluoromethylphenoxy) pyridin-3-yl] ethylamine.

1. Methyl ester of 6-chloronicotinic acid.

To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH ₂ Cl ₂ (250 ml) was added oxalyl chloride (123.3 ml, 0.15 mol) with 1-5 drops of DMF. The solution was stirred for 18 hours and concentrated in vacuo. The residue was dissolved in CH2C12 (100 ml) and cooled in an ice bath. MeΟH (20 ml) was added to the mixture, and the solution was stirred for 15 min, keeping the temperature below 40 ° С. The solvent was removed in vacuo and the residue dissolved in E1YU, washed NUDE and saturated brine, dried with Ν;. · Ϊ́2§Ο · ι and filtered through a ₂ occupies 8. The solvent was removed in vacuo to give 6-chloronicotinic acid methyl ester (21 g) as an off-white solid: ¹ NMR (300 MHz, COCE) δ 9.02 (d, 1 = 13.8 Hz, 1H), 8 51-8.06 (m, 1H); 7.76-7.30 (m, 1H); 4.01 (s, 3H); EPM8 t / ζ 171 ([M] +), which was used in step 2 without further purification.

2. 6- (4-Trifluoromethylphenoxy) nicotinic acid methyl ester.

To a suspension of EaH (60% dispersion in oil; 1.2 g, 30 mmol) in 30 ml of DMSO was added a solution of 4 (trifluoromethyl) phenol (1.86 g, 30 mmol) in 20 ml of DMSO and the mixture was stirred for 30 minutes. To this mixture was added methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution was heated overnight at 70 ° C. The reaction mixture was cooled to room temperature and then diluted with Ξΐ ^ Ο. The solution was washed with NJ and brine, dried with Να ₂ 8Ο ₄ , filtered using a suction filter, and the solvent was removed in vacuo. The residue was purified by normal-phase column chromatography on 8x10 ₂ using a mixture of 15% E1U / pentane to give 6- (4-trifluoromethylphenoxy) nicotinic acid methyl ester (4.5 g) as a colorless solid. ^! H NMR (300 MHz, COCE) δ 8.81 (dd, 1 = 2.5, 0.6 Hz, 1H), 8.33 (dd, 1 = 8.6, 2.4 Hz, 1H), 7 69 (d, 1 = 8.5 Hz, 2H), 7.31-7.24 (m, 2H), 7.02 (dd, 1 = 8.5, 0.6 Hz, 1H), 3, 93 (s, 3H); ETM8 t / ζ 297 ([M] +).

3. 5-Chloromethyl-2- (4-trifluoromethylphenoxy) pyridine.

- 27 022487

To a suspension of IAAH ₄ (0.051 g, 13.5 mmol) in THF (20 ml) was added dropwise a solution of 6- (4-trifluoromethylphenoxy) nicotinic acid methyl ester (4.0 g, 13.5 mmol) in THF (10 ml) ) Then the mixture was stirred for 1 h, the reaction mixture was quenched by the addition of 4 M solution No. OH (3 ml), followed by the addition of H ₂ O (3 ml). The resulting precipitate and THF were decanted. The precipitate was washed with hot THF 2 times. The organic fractions were combined and the solvent was removed in vacuo to give 3.5 g of a yellow oil, which was dissolved in toluene (15 ml) and cooled in an ice bath. To this solution was added 8OCl ₂ (3.9 ml) dropwise. The solution was allowed to warm to room temperature and stirred for 2 hours, after which the reaction mixture was concentrated in vacuo. The residue was dissolved in E! ₂ O and washed with 1 M solution of No. OH. Phase E! ₂ O was dried using No. ₂ 8 O ₄ and filtered using a suction filter through _{8 10} . The solvent was removed in vacuo to give 5-chloromethyl2- (4-trifluoromethylphenoxy) pyridine (1.8 g) as a yellow solid. ¹ H NMR (300 MHz, SIS) δ 8.17 (d, 1 = 2.5 Hz, 1H), 7.80 (dd, 1 = 8.5, 2.5 Hz, 1H), 7.66 ( dd, 1 = 5.5, 3.5 Hz, 2H), 7.30-7.17 (m, 2H), 7.00 (d, 1 = 8.4 Hz, 1H), 4.57 (s , 2H); EAB t / ζ 287 ([M] +).

4. [6- (4-Trifluoromethylphenoxy) pyridin-3-yl] acetonitrile.

To a solution of 5-chloromethyl-2- (4-trifluoromethylphenoxy) pyridine (1.8 g, 6.27 mmol) in E! OH (12 ml) was added NaCN (1.23 g, 25 mmol). The reaction mixture was heated to 50 ° C. for 16 hours. Additional ethanol (6 ml) was added and the reaction mixture was purified. After another 3 hours, the solvent was removed in vacuo, the residue was taken up in E! ₂ O and washed with H ₂ O. The organic layer was dried with No. ₂ 8 O ₄ , filtered using a suction filter and concentrated in vacuo. The residue was purified by flash chromatography (50% E! ₂ O in petroleum ether occupies 8 to ₂₎ to give [6- (4-trifluoromethylphenoxy) pyridin-3-yl] acetonitrile (1.3 g) as a pink solid. Ή NMR (300 MHz, SIS) δ 8.17-8.09 (m, 1H), 7.81-7.71 (m, 1H), 7.70-7.61 (m, 2H), 7, 29-7.19 (m, 2H), 7.04 (d, 1 = 8.4 Hz, 1H), 3.73 (s, 2H); ES8 t / ζ 278 ([M] +).

5. 2- {6- [4- (Trifluoromethyl) phenoxy1pyridin-3-yl} ethylamine.

To a solution of A1C1 ₃ (268 mg, 1.8 mmol) in E! ₂ О, cooled to 0 ° С in an ice bath, LА1Н ₄ (66 mg, 1.8 mmol) was added in one portion under Ν ₂ atmosphere. After stirring for 15 minutes, a solution of [6- (4-trifluoromethylphenoxy) pyridin-3-yl] acetonitrile (500 mg, 1.8 mmol) in E was added dropwise. ₂ O (2 ml) and THF (1 ml), which led to an exothermic reaction. The reaction mixture was cooled to room temperature and after 2 hours the reaction was quenched by the careful addition of 5 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was made alkaline by adding a 2 M solution of No. OH. The precipitate that formed was removed by filtration through celite. The phases of the filtrate were separated and the aqueous phase was extracted 3 times with E! ₂ O. The combined organic fractions were dried using No. ZO.- | and filtered using a suction filter. The solvent was removed in vacuo to give 2- [6- (4-trifluoromethylphenoxy) pyridin-3-yl] ethylamine (200 mg) as a brown oil.

As in Preparation 9, steps 4 and 5, 2- (4-methoxy-3-trifluoromethylphenyl) ethylamine hydrochloride was prepared from (4-methoxy-3-trifluoromethylphenyl) methanol.

As in Preparation 9, Step 5, 2- (3-fluoro-4-methoxyphenyl) ethylamine hydrochloride was prepared from (3-fluoro-4-methoxyphenyl) acetonitrile.

2- (4-Methoxy-3-methylphenyl) ethylamine hydrochloride, from (4-methoxy-3-methylphenyl) acetonitrile.

Getting 10. 6,7-Dimethylpteridin-4-ol.

A mixture of 6-chloropyrimidin-4,5-diamine (1.4 g, 10 mmol) and 2,3-butanedione (2.0 g, 23 mmol) in toluene (35 ml) and methanol (10 ml) was stirred at the boiling point under reflux for 1 h. Upon cooling, the product was precipitated and collected by filtration using a suction filter and washed with MeOH / E! ₂ O (approximately 1: 2), then dried in air to obtain 6,7-dimethylpteridin-4-ol (1.4 g, 72%) as a golden powder.

Example 11. {2- [4- (4-Isopropylphenoxy) phenyl] ethyl} pteridin-4-ylamine.

4- [2- (Pteridin-4-ylamino) ethyl] phenol (500 mg, 1.9 mmol), 4-isopropylphenylboronic acid (400 mg, 2.4 mmol), anhydrous Cu (OAc) ₂ (360 mg, 2 , 0 mmol) and powdered freshly activated 4A molecular sieves (approximately 1 g) were combined in CH ₂ Cl ₂ (15 ml), triturated with pyridine (920 μl, 900 mg, 11.4 mmol), sealed and stirred for 20 h with a moisture trap. The reaction mixture was filtered using a suction filter and the filtrate was shaken with a dilute aqueous solution of ΝΠ-OH. The organic phase was washed with H ₂ O and brine and concentrated in vacuo. The residue was purified using preparative reverse phase 28 022487 HPLC using a mixture of 80% MeCNH ₂ O to give {2- [4- (4isopropylphenoxy) phenyl] ethyl} pteridin-4-ylamine (78 mg, 11%) as reddish-brown solid: melting point 105-106.5 ° C.

Example 12. {2- [4- (tert-Butyldimethylsilanyloxy) phenyl] ethyl} pteridin-4-ylamine.

4- [2- (Pteridin-4-ylamino) ethyl] phenol (1.0 g, 3.7 mmol) was partially dissolved in dry DMF (75 ml), treated with imidazole (630 mg, 9.3 mmol), cooled to 0-5 ° C and treated dropwise with a solution of tert-butyldimethylsilyl chloride (680 mg, 4.5 mmol) in DMF (15 ml). After heating to 25 ° С, the mixture was stirred for 20 h, diluted with Н ₂ О (75 ml) and extracted with Е! ОАс. The extracts were washed with H ₂ O, brine, dried (No. ₂ 8 O ₄ ), filtered and concentrated in vacuo to give {2- [4- (tert-butyldimethylsilanyloxy) phenyl] ethyl} pteridin-4-ylamine (1.3 g ) as a white solid: melting point 164-165 ° C. Ή NMR (300 MHz, SIS) δ 8.99 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.26 (d, 1 = 5.9 Hz, 1H ), 6.8-7.2 (m, 5H), 3.98 (t, 1 = 6.2 Hz, 2H), 2.99 (t, 6.3 Hz, 2H), 1.02 (s 6H), 0.18 (s, 9H).

Example 13. {2- [4- (tert-butyldimethylsilanyloxy) phenyl] ethyl} pteridine-4yl-carbamic acid tert-butyl ester.

{2- [4- (tert-Butyldimethylsilanyloxy) phenyl] ethyl} pteridin-4-ylamine (10.15 g, 3.0 mmol) was dissolved in anhydrous DMF (50 ml), treated with di-tert-butyl dicarbonate (730 mg, 3.3 mmol) and OMAP (C ^ dimethyl-4-aminopyridine; 25 mg) and stirred at 25 ° C for 22 hours. The mixture was diluted with H ₂ O and extracted with E! OAc. E! OAc extracts were washed with H ₂ O, dried (No. ₂ 8 O ₄ ), filtered with a suction filter and concentrated in vacuo to give tert-butyl ether {2- [4- (tert-butyldimethylsilanyloxy) phenyl] ethyl} pteridine -4-ylcarbamic acid (1.2 g; 83%) as a yellow gum; EMMB t / ζ 482 ([M + H] +.

Example 14. [2- (4-Hydroxyphenyl) ethyl] pteridin-4-yl-carbamic acid tert-butyl ester. {2- [4 - (tert-butyldimethylsilanyloxy) phenyl] ethyl} pteridin-4-carbamic acid tert-butyl ester (68 0 mg, 1.4 mmol) was dissolved in 5 ml of CH ₂ Cl ₂ and treated with tetrabutylammonium fluoride-3H ₂ O in 10 ml of THF. After stirring for 18 hours, the solution was washed with H ₂ O, dried (No. ₂ 8 O ₄ ), filtered with a suction filter and concentrated in vacuo to give tert-butyl ether [2- (4-hydroxyphenyl) ethyl] pteridin-4 -yl-carbamic acid in the form of a tan solid, melting point 132-134 ° C (decomp.); E8GM8 t / ζ ([M + H] +) 368.

Example 15. 5- [2- (Pteridin-4-ylamino) ethyl] 2- (4-trifluoromethylpyridin-2yloxy) benzoic acid methyl ester.

To a solution of {2- [3-bromo-4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine (243 mg, 0.5 mmol) in methanol in a 45 ml Parr test vessel, Rb was added (OAc) ₂ (5.6 mg, 0.25 mmol), ΌΓΓΒ (21 mg, 0.5 mmol) and K ₂ CO ₃ (138 mg, 1 mmol). The reactor was sealed and filled with CO at a pressure of 21 kg / cm ² . The reaction mixture was heated to 110 ° C for 15 hours, cooled to ambient temperature, filtered through celite, and concentrated in vacuo. The residue was dissolved in CH2C12, washed with H2O, brine, dried over No. 28O4, filtered with a suction filter and concentrated in vacuo. The residue was suspended in E! 2O and pentane. The solvent was decanted to give 5- [2- (pteridin-4-ylamino) ethyl] 2- (4-trifluoromethylpyridin-2-yloxy) benzoic acid methyl ester (55 mg; 23% yield) as a light yellow solid: temperature melting point 171-172 ° C. ¹ H NMR (300 MHz, SES13) δ 9.04 (d, 1 = 2.0 Hz, 1H), 8.84 (s, 1H), 8.64 (d, 1 = 1.9 Hz, 1H) 8.23 (d, 1 = 5.0 Hz, 1H), 7.94 (d, 1 = 2.3 Hz, 1H), 7.52 (dd, 1 = 8.2, 2.2 Hz, 1H), 7.26-7.12 (m, 4H), 4.02 (dd, 1 = 13.7, 6.9 Hz, 2H), 3.67 (s, 3H), 3.13 (t , 1 = 7.3 Hz, 2H); E8BM8 t / ζ 471.

Example 16. Pteridin-4-yl- {2- [4- (3,5,6-trifluoro-4-trifluoromethylpyridin-2 yloxy) phenyl] ethyl} amine.

4- [2- (Pteridin-4-ylamino) ethyl] phenol (0.27 g, 1.0 mmol), 2,3,5,6-tetrafluoro-4- 29 022487 trifluoromethylpyridine (0.24 g, 1, 0 mmol) and DMF (5 ml) were added to a 25 ml round bottom flask equipped with a magnetic stirrer and a dry nitrogen conduit. Εΐ ₃ Ν (0.12 g, 1.2 mmol) was added to the reaction mixture. After stirring for 24 hours at room temperature, the reaction mixture was concentrated in vacuo and the residue was partitioned between H ₂ O and EUAc. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (mixture EYuAs / hexane on SiO ₂₎ to give the pteridine-4-yl- {2- [4- (3,5,6-trifluoro-4-trifluoromethyl-pyridin-2-yloxy) phenyl] ethyl} amine (110 mg) as a beige solid: melting point 103108 ° C.

Example 17. (2- {4- [2- (4-Benzyloxyphenyl) ethoxy] phenyl} ethyl) pteridin-4-ylamine. 4- [2- (Pteridin-4-ylamino) ethyl] phenol (300 mg, 10.1 mmol), triphenylphosphine (790 mg, 3.0 mmol) and

2- (4-benzyloxyphenyl) ethanol (700 mg, 3.0 mmol) was combined in 10 ml of anhydrous dioxane, treated with diisopropylazodicarboxylate (590 μl, 610 mg, 3.0 mmol) and stirred for 18 hours. Volatiles were removed in vacuo and the residue was chromatographed on ZO ₂ with EJAc (10 to 40%) in CH ₂ Cl ₂ to give (2- {4- [2- (4-benzyloxyphenyl) ethoxy] phenyl} ethyl) pteridin-4-ylamine (105 mg ; 20%) as a white solid: melting point 120-122 ° C. ¹ H NMR (300 MHz, SES1 ₃ ) δ 9.23 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 6.8-7.5 (m, 13H) 4.1 (m, 2H); 3.90 (m, 2H); 3.01 (m, 4H).

Example 18. 2- [4- (1,1-Difluoroethyl) pyridin-2-yloxy] -5- [2- (pteridin-4-ylamino) ethyl] phenol.

To a solution of (2- {4- [4- (1,1-difluoroethyl) pyridin-2-yloxy] -3-methoxyphenyl} ethyl) pteridin-4-ylamine (1.37 g, 3.13 mmol) in CH ₂ C1 ₂ (15 ml), cooled to 0 ° C, a mixture of 1 M BBg ₃ / hexane (9.4 ml, 9.4 mmol) was added. The solution was warmed to room temperature and stirred overnight. The reaction was quenched with methanol and concentrated in vacuo. The residue was dissolved in a small amount of methanol and poured into an aqueous NaHC- ₃ solution. The hydroxyaryl product was precipitated, collected by filtration using a suction filter and washed with H ₂ O. The filter cake was air dried on the filter to give 2- [4- (1,1-difluoroethyl) pyridin-2-yloxy] -5- [ 2 (pteridin-4-ylamino) ethyl] phenol (0.76 g) as a light brown solid. ¹ H NMR (300 MHz, b _6- DMSO) δ 9.53 (br s, 1H), 9.45 (s, 1H), 9.12 (s, 1H), 8.91 (d, 1 = 1.5 Hz, 1H), 8.78 (br, 1H), 8.20 (d, 1 = 5.3 Hz, 1H), 7.22 (d, 1 = 5.3 Hz, 1H), 7.08 (s, 1H), 6.98 (d, 1 = 8.1 Hz, 1H), 6.85 (d, 1 = 1.8 Hz, 1H), 6.72 (dd, 1 = 8 , 1, 1.8 Hz, 1H), 3.84 (dd, 1 = 14.7, 7.4 Hz, 2H), 2.93 (t, 1 = 7.4 Hz, 2H), 1.98 (t, 1 = 19.2 Hz, 3H); EZBMZ t / ζ 425 ([M + H] +).

Preparation 11. 2-Methoxy-6-chloro-4-trifluoromethylpyridine.

To a solution of 2,6-dichloro-4-trifluoromethylpyridine (10 g, 46.3 mmol) in methanol (200 ml) was added a mixture of 25% NO / MOH (12.5 g, 13.2 ml, 231 mmol), which then stirred at 50 ° C. for 2 hours and then at room temperature overnight. The reaction mixture was extracted with pentane and the extract was concentrated in vacuo to give 2-methoxy-6-chloro-4-trifluoromethylpyridine (9.79 g), which was used without further purification.

Preparation 12. 2-Chloro-4-tert-butylpyridine-H-oxide.

2-Chloro-4-tert-butylpyridine (5.0 g, 30 mmol) was dissolved in chloroform (75 ml), treated with MCPBA, approximately 75% (8.3 g, 36 mmol, 1.2 eq.), and heated to reflux for 19 hours. The mixture was stirred with sodium bisulfite solution until testing with iodine starch reactive paper indicated that the oxidizing agent was used up. The pH level was adjusted to 7 using a saturated aqueous NaHC- ₃ solution, the phases were separated, and the aqueous phase was extracted once with CH2C12. The organic phases were combined and washed twice with H ₂ O, once with brine, dried (No. ₂ 8O ₄ ) and concentrated in vacuo to give 2-chloro-4-tert-butylpyridine - ^ oxide (5 , 0 g, 90%), which upon standing crystallized with the formation of long white needle crystals.

Example 19. {2- [3- (Isopropoxy) -4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} pteridin-4ylamine.

To a solution of 5- [2- (pteridin-4-ylamino) ethyl] -2- (4-trifluoromethylpyridin-2-yloxy) phenol (200 mg, 0.47 mmol) in 2 ml of DMSO was added 2-iodopropane (62 mg, 0.5 mmol) and K ₂ CO ₃ (97 mg, 0.7 mmol). The solution was heated for 2 h at 50 ° C, after which the analysis of ΤCX indicated the absence of the starting material. The mixture was poured onto ice. The product was precipitated and collected by filtration using a suction filter, washed with H ₂ O and dried in air to give {2- [3- (isopropoxy) 4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethyl} pteridin-4 -ylamine (180 mg; 81% yield) as a light brown solid: Ε8ΙΜ8 t / ζ: 471 ([M + H] +).

Getting 13. 2,2-Dimethylpropyl ether of 2-chloroisonicotinic acid. 2-Chlorizonicotinic acid (2.0 g, 13 mmol) was suspended in 50 ml of anhydrous CH ₂ Cl ₂ and treated with oxalyl chloride (3.5 ml, 5.0 g, 39 mmol) plus 3 drops of DMF. The mixture was stirred for 4 hours, volatiles were removed in vacuo and the residue was taken up in 50 ml of CH2C12. After cooling to 0 ° C and treatment with neopentyl alcohol (1.7 ml, 1.4 g, 16 mmol), Εΐ ₃ Ν (2.5 ml, 1.8 g, 18 mmol) was added in portions. The mixture was heated to 25 ° C, stirred for 15 h, washed sequentially with 15 ml of H ₂ O, 15 ml of saturated aqueous solution No. 1NS.O ₃ and 15 ml of saturated saline, then dried (Tsa ₂ 8O ₄ ) , filtered and concentrated in vacuo to give 2.4 g (80%) of 2-chloroisonicotinic acid 2,2-dimethylpropyl ester as an oil, which was used without further purification. ^! H NMR (300 MHz, COSB) δ 8.56 (d, 1 = 5.6 Hz, 1H), 7.88 (s, 1H), 7.78 (d, 1 = 5.0 Hz, 1H), 4.06 (s, 2H); 1.05 (s, 9H).

Also obtained using the production method 13.

2-Chloroisonicotinic acid tert-butyl ester from tert-butanol.

Preparation 14. 2-Chloro-4- (1,1-difluoro) ethylpyridine - ^ oxide.

To a solution of 1.27 g (7 mmol) of 2-chloro-4- (1,1-difluoro) ethylpyridine (preparation 4) in TFA was added 30% hydrogen peroxide (6 ml) and the solution was heated at reflux for 2.5 hours. TFA was removed in vacuo and the residue was poured into ice-cold H ₂ O. The mixture was neutralized with No. ₂ CO ₃ and extracted with ΕΐOΑc and CH ₂ Cl ₂ . The combined organic layers were dried (№ ₂ 8o _4), filtered and concentrated in vacuo to give 2-chloro-4- (1,1diftoretil) pyridine 1-oxide (1.00 g) as a brown oil. ¹ H NMR (SES1 ₃ ): δ 8.39 (d, 1 = 6.6 Hz, 1H), 7.63 (d, 1 = 2.4 Hz, 1H), 7.33 (dd, 1 = 6 6, 2.4 Hz, 1H); 1.94 (t, 1 = 18 Hz, 3H); ΕΙΜ8 t / ζ 193 ([M] +).

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Example 20. 5- [2- (Pteridin-4-ylamino) ethyl-2- (4-trifluoromethylpyridin-2-yloxy) phenyl ester of acetic acid.

5- [2- (pteridin-4-ylamino) ethyl] -2- (4trifluoromethylpyridin-2-yloxy) phenol (330 mg, 0.7 mmol), pyridine (0.5 ml) and 5 were added to 4 ml of acetic anhydride. mg OMAR. The solution was stirred at ambient temperature for 15 hours, then diluted with CH ₂ Cl ₂ and washed successively with H ₂ O and a saturated aqueous NaHCO ₃ solution. The organic fraction was dried with Na _{2 3} O ₄ , filtered using a suction filter and concentrated in vacuo. The residue was diluted with 1: 1 EO / pentane. The product was precipitated, collected by filtration, and the filter cake was washed with a cold 1: 1EO / pentane mixture. This resulted in 184 mg (56% yield) of 5- [2- (pteridin-4-ylamino) ethyl] -2- (4-trifluoromethylpyridin-2yloxy) phenyl ester of acetic acid as an off-white solid: E31M8 t / ζ: 471 ([M] +).

Example 21. (2- {4- [4- (1,1-Difluoroethyl) -6-methoxypyridin-2-yloxy] phenyl} ethyl) pteridin-4-ylamine.

The (2- {4- [4- (1,1-difluoroethyl) -1-hydroxypyridin-2yloxy] phenyl} ethyl) pteridin-4-ylamine (0.52 g, 1.13 mmol), ethyl chloroformate ( 0.43 ml, 4.5 mmol), E1 ₃ S (0.95 ml, 6.81 mmol) and MeOH (10 ml) and were heated at reflux for 2 days. The solvent was removed and the residue was dissolved in CH ₂ Cl ₂ . The solution was washed with brine, dried over Na _{2 3} O ₄ , filtered, concentrated in vacuo and purified by preparative reverse phase HPLC to give (2- {4- [4- (1,1-difluoroethyl) -6 methoxypyridin-2- yloxy] phenyl} ethyl) pteridin-4-ylamine (0.130 g, 24% yield) as a pale yellow solid: Ή NMR (300 MHz, SES1 ₃ ) δ 9.02 (d, 1 = 1.9 Hz, 1H), 8.83 (s, 1H), 8.62 (d, 1 = 1.9 Hz, 1H), 7.29 (d, 1 = 8.1 Hz, 2H), 7.12 (d, 1 = 8.1 Hz, 2H), 6.54 (s, 1H), 6.44 (s, 1H), 3.98 (dd, 1 = 13.2, 6.9 Hz, 2H), 3, 79 (s, 3H), 3.08 (t, 1 = 6.9 Hz, 2H), 1.86 (t, 1 = 18.3 Hz, 3H); EZTMZ t / ζ 439.2 ([M + H] +).

Preparation 15. 4- (1,1-Difluoroethyl) -2-fluoropyridine.

1.2-fluoroisonicotinonitrile.

Cesium fluoride (30 g, 0.22 mmol) was suspended in anhydrous sulfolane (150 ml) and concentrated by vacuum distillation at a pressure of 0.5 mm RT. Art. After removing 20% solvent, the suspension was cooled and 2-chloroisonicotinonitrile (15 g, 0.11 mmol) was added, then it was stirred and heated at 100 ° C for 20 hours. This mixture was cooled to 25 ° C, poured into H ₂ O (200 ml) and extracted with E1 ₂ O. The E1 ₂ O phase was washed with H ₂ O, then with brine, dried over Na _{2 3} O ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on SC ₂ with CH ₂ Cl ₂ to give 2-fluoroisonicotinonitrile (12.0 g) as a low melting colorless solid: E1M3 t / ζ: 122 ([M] +). 'H NMR (SES1 ₃ ): δ 8.45 (dd, 1H), 7.47 (dd, 1H), 7.24 (m, 1H).

2.1- (2-Fluoropyridin-4-yl) ethanone.

To a solution of 2-fluoroisonicotinonitrile (10 g, 82 mmol) in anhydrous E1 ₂ O (250 ml), cooled in an ice-cold H2O bath, a 3 M solution of methylmagnesium bromide in hexane (40 ml, 120 mmol) was slowly added. The mixture was stirred at 25 ° C. overnight. The reaction mixture was slowly quenched with 1N. an aqueous solution of citric acid at 0 ° C until all solids are dissolved. Saturated brine was added and the two phases were separated. The organic phase was dried over Na ₂ ZO ₄ , filtered and concentrated in vacuo to give 1- (2-fluoropyridin-4-yl) ethanone (6.2 g) as a brown oil. The aqueous phase was stirred at 25 ° C. for 3 hours, then extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer was dried over Na ₂ ZO ₄ , filtered and concentrated in vacuo to give an additional 1.1 g of product, 7.3 g in total, and was used in the next step without further purification: E1MZ t / ζ 139 ([M] +). 'H NMR (SES1 ₃ ): δ 8.25 (dd, 1H), 7.47 (d, 1H), 7.21 (m, 1H).

3. 2-Fluoro-4- (1,1-difluoroethyl) pyridine.

1- (2-Fluoropyridin-4-yl) ethanone (6.2 g, 44.6 mmol) from the previous reaction was treated with diethylamino sulfur trifluoride (17 ml, 130 mmol), as in Preparation 4, to give 3.5 g of 2- fluoro-4- (1,1-difluoroethyl) pyridine (yield 45%) as a light yellow oil: ЕГМЗ t / ζ 161 ([М] +).

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Preparation 16. 4- (2-Aminoethoxy) -3-methylphenol hydrochloride.

1. 4-Benzyloxy-2-methylphenol.

2-Methylbenzene-1,4-diol (12.4 g, 0.1 mol) was dissolved in acetone (200 ml) in a 500 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and dry nitrogen piping. K ₂ CO ₃ (20.5 g) was added to the solution, followed by benzyl bromide (12.2 ml, 0.1 mol) with vigorous stirring. After stirring at room temperature for 72 hours, the reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between weakly acidic H ₂ O (the pH was adjusted to 5 with a 0.1N HCl solution) and a 1: 1 mixture of EO and pentane. The organic layer was filtered and concentrated in vacuo to give a black oil (20.66 g). The oil was extracted with isopentane (3x150 ml) and the combined isopentane fractions were concentrated in vacuo to give an orange oil (10 g); a dark insoluble residue was set aside. Orange oil was passed through a column of 3U ₂ with a mixture of E1 ₂ O / pentane (1: 1) as an eluent. The appropriate fractions were combined and concentrated in vacuo to give 7.0 g of 1,4-bisbenzyloxy-2methylbenzene as a pale yellow oil, which solidified upon standing.

The dark insoluble residue from the previous step was passed through a column with a mixture of ₂ 3YU EO / pentane (1: 2) as eluent. The appropriate fractions were combined and concentrated in vacuo to give 7.2 g of 4-benzyloxy-2-methylphenol and 4-benzyloxy-3-methylphenol (a mixture of approximately 1: 1 monobenzylated isomers) as an orange solid, which was used in the next step without further cleaning up.

2. (4-Benzyloxy-2-methylphenoxy) acetonitrile.

The 4-benzyloxy-2-methylphenol and 4-benzyloxy-3-methylphenol product from step 1 (5.76 g, 27 mmol) and bromoacetonitrile (3.24 g, 27 mmol) were dissolved in tetrahydrofuran (100 ml) in 500 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and dry nitrogen piping. The solution was treated with IA (60% dispersion in oil; 1.4 g, 35 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with dimethylformamide (20 ml) and then stirred for another 2 hours at room temperature. The reaction mixture was concentrated in vacuo, then transferred to H2O (200 ml). After adjusting the pH to 4 with 2n. HC1 solution, the aqueous solution was washed with an equal volume of EO / pentane (1: 1). The organic layer was concentrated in vacuo to give a tan oil (6.45 g). The oil was subjected to preparative HPLC to give a slightly purified product after combining the appropriate fractions. This product was extracted with boiling isopentane (3x100 ml) and the combined isopentane fractions were concentrated in vacuo to give 2.25 g of (4-benzyloxy-2-methylphenoxy) acetonitrile (isomer A) and (4-benzyloxy-3-methylphenoxy) acetonitrile (isomer B ), a mixture of approximately 2: 1 A: B (determined by ¹ H NMR integration), as a pale yellow oil. The insoluble residue was transferred to boiling pentane, decanted and cooled to room temperature. After 24 hours, crystals were formed. The supernatant was decanted and concentrated in vacuo to give 750 mg of isomers A and B in a ratio of 1: 3 (1 H NMR analysis). The crystals found turned out to be the desired isomer A. Subsequent treatment with pentane of the crude residues and crystallization eventually led to the recovery of 1.95 g of highly enriched (4-benzyloxy-2-methylphenoxy) acetonitrile (isomer A).

3. 4- (2-aminoethoxy) -3-methylphenol hydrochloride.

(4-Benzyloxy-2-methylphenoxy) acetonitrile (isomer A from step 2; 1.95 g, 7.7 mmol) was dissolved in absolute ethanol (100 ml) in a Parr vessel. The solution was treated with a concentrated solution of HCl (1.55 g) and 10% Pb-C (0.3 g), degassed, filled with hydrogen (3.85 kg / cm ² ) and shaken for 72

h. The suspension was filtered and concentrated in vacuo to give 1.92 g of 4- (2-aminoethoxy) -3 methylphenol hydrochloride as a beige solid, which was used without further purification: ΕΙΜ3 t / ζ 167 ([M] +).

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Example 22. 4- {2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pteridine.

1. 2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethanol.

2- (4-Hydroxyphenyl) ethanol (4.0 g, 29 mmol), K ₂ CO ₃ (8.0 g, 58 mmol) and 2-fluoro-4 trifluoromethylpyridine (3.6 g, 22 mmol) were combined in DMSO ( 30 ml) and stirred at 25 ° C for 20 hours. The mixture was poured into H ₂ O and extracted twice with EO. The combined EO extracts were washed with a 1 M solution of No. OH. H ₂ O, brine, and concentrated in vacuo to give 2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethanol (4.7 g; 57%), melting point 78-79 ° C; Е1М8 t / ζ 283. Ή NMR (300 MHz, DMSO-D ₆ ) δ 8.38 (d, 1 = 5.3 Hz, 1Н), 7.0-7.5 (m, 8Н), 4.67 (t, 1 = 5.0 Hz, 2H); 2.74 (t, 1 = 5.2 Hz, 2H).

2. 4-Nitro-6- {2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pyrimidin-5-ylamine.

2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethanol (product from step 1; 400 mg, 1.4 mmol) was dissolved in DMSO (10 ml), triturated with 95% N-) N (36 mg 1.5 mmol) and the mixture was heated to 50-60 ° C to obtain a clear solution. Upon cooling, the mixture was triturated with 4-amino-5-nitro-6-chloropyrimidine (260 mg, 1.5 mmol) and heated at 45 ° C for 6 hours. After cooling, the mixture was poured into H ₂ O (60 ml) and the precipitate collected by filtration using a suction filter, washed with H ₂ O and air dried on the filter. Ή NMR (300 MHz, SES1 ₃ ) δ 8.39 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.38 (m, 2H), 7.15 ( m, 4H), 4.69 (1, 1 = 6.8 Hz, 2H), 3.15 (t, 6.6 Hz, 2H).

This material was used in the next step without further purification.

3. 6- {2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pyrimidin-4,5-diamine.

4-Nitro-6- {2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pyrimidin-5-ylamine was transferred to 75 ml of absolute ethanol, treated with 100 mg of 5% RD / C and shaken under a hydrogen pressure of 3.5 kg / cm ² for 20 hours. After removal of the catalyst by filtration, crude diamine ether (6- {2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pyrimidine-4,5diamine) was obtained by removing the solvent in vacuo to give 6- {2- [4- (4-trifluoromethylpyridin-2yloxy) phenyl] ethoxy} pyrimidine-4,5-diamine, which was used in the next step without additional purity stki.

4. 4- {2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pteridine.

6- {2- [4- (4-Trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pyrimidin-4,5-diamine (75 mg, 0.19 mmol) was combined with a 50% aqueous solution of glyoxal (1 ml) in UNN (5 ml) and stirred overnight at 25 ° C. The solution was evaporated and the residue was extracted with CH2C12. The CH2C12 layer was washed with H ₂ O and concentrated in vacuo. The residue was recrystallized from hot HeCN to give 4- {2- [4- (4-trifluoromethylpyridin-2-yloxy) phenyl] ethoxy} pteridine (16 mg, 20%): melting point 172-173 ° C; Е1М8 t / ζ 413. Ή NMR (300 MHz, δ 9.24 (s, 1H), 9.07 (s, 1H), 9.02 (s,

1H), 8.30 (s, 1H), 7.43 (d, 1 = 9.5 Hz, 2H), 7.28 (d, 1 = 9.0 Hz, 2H), 4.63 (t, 6.8 Hz, 2H), 3.17 (t, 1 = 7.0 Hz, 2H).

Example 23. {2- [4- (4-tert-Butylpyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine. {2- [4- (4-tert-Butyl-1-hydroxypyridin-2-yloxy) phenyl] ethyl} pteridin-4-ylamine (500 mg, 1.2 mmol) and triphenylphosphine (310 mg, 1.2 mmol) dissolved in dry THF (15 ml) and rhenium was treated with a bistiolate catalyst (5 mg; obtained in accordance with ^. ^ APD APD 1.N. Ekreizoi, Ogd. LeD., 2000, 2 (22), 3525-26; specially included by reference to this application). The mixture was stirred for 1.5 hours, evaporated, and the residue was purified by preparative reverse phase HPLC using 85% HeCN to give {2- [4- (4-tert-butylpyridin-2-yloxy) phenyl] ethyl} pteridin- 4ilamine in the form of a tan solid (155 mg, 32%): melting point: 156-157 ° C; E81M8 t / ζ 400 ([M + H] +). Ή NMR (300 MHz, δ 9.02 (s, 1H), 8.82 (s, 1H), 8.62 (s, 1H),

8.08 (d, 1 = 5.9 Hz, 1H), 6.9-7.3 (m, 7H), 3.99 (t, 1 = 7.0 Hz, 2H), 3.055 (t, 7 , 0 Hz, 2H).

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Example 24. [2- (4-Methoxyphenyl) ethyl] - (2,6,7-trimethylpteridin-4-yl) amine.

1.2,6,7-Trimethylpteridin-4 (1H) -one.

A mixture of 6-chloro-2-methylpyrimidin-4,5-diamine (3.2 g, 20 mmol) and 2,3-butanedione (3.6 g, 42 mmol) in n-butanol (40 ml) was stirred at 75 80 ° C. for 1 h. After cooling, the reaction mixture was diluted with E1 ₂ O (50 ml) and the solid was collected by filtration using a suction filter. This material was dried in vacuo to give 2,6,7-trimethylpteridin-4 (1H) it (3.9 g) as a golden powder, which was used in the next step without further purification.

2. [2- (4-Methoxyphenyl) ethyl] - (2,6,7-trimethylpteridin-4-yl) amine.

A mixture of 2,6,7-trimethylpteridin-4 (1H) -one (1.1 g, 6.0 mmol), 4-methoxyphenethylamine (1.6 g, 11 mmol) and ammonium sulfate (0.56 g, 4, 2 mmol) in hexamethyldisilazane (16 ml) was heated at 115 ° C for 6 hours. After cooling, most of the solids were dissolved by adding CH ₂ Cl ₂ and H ₂ O and the solvents were removed in vacuo. The residue was suspended in a mixture of MeOH (5 ml) and H ₂ O (50 ml) and stirred for 45 minutes. The bronze solid was collected by filtration using a suction filter and dried in vacuum at 50 ° C. The residue was dissolved in MeOH / CH ₂ Cl ₂ mixture and diluted with EO, causing crystallization. All solvent was evaporated and the remaining solid was dried in vacuo to give [2- (4-methoxyphenyl) ethyl] - (2,6,7-trimethylpteridin-4yl) amine as a brown powder (1.3 g; 67%). 'H NMR (300 MHz, SES1 ₃ ) δ 7.22-7.14 (m, 2H), 6.95 (t, 1 = 6.3 Hz, 1H), 6.90-6.83 (m, 2H), 3.87 (dd, 1 = 13.5, 6.8 Hz, 2H), 3.80 (s, 3H), 2.97 (t, 1 = 7.2 Hz, 2H), 2, 69 (s, 3H), 2.66 (s, 3H), 2.61 (s, 3H).

- 35 022487

Table 1 „1, 2

Connection Examples yurmul Ι-A and Ι-B, including synthesis parameters ¹ ' ² 10 Structure Electrophile or other reactive substance (name of compounds, structure or number) Amine or other reactant (compound name, structure or number) Ways receiving (numbers examples) one Ρ'θΠ ^υ Getting 1 one 2 d Kpoh, 1. b; Ko £ ex5, K. W and 8. Pb (ep 14,775,762, 1988. 4 3 Alternative * 3 o> ΟΙ ^ Ν ^ ΟΡ, Ν ^ Ι 4 3 4 ^to | »» Gu A1LeL, A .; 01ia, K. ί. Sket. 5 on. C1971, 3727-3730. ,, F 2 5 SF Eh 4 3

- 36 022487

6 from" Mx | ^ xSR ₃ 4 3 7 Ό 4 3 8 W h N 4 3 nine FROM# (At 4 * 4 * γ A1bcp, A .; O (a, K. L C / get. Yaos C 1971, 3727-3730. 2 10 „~ Xg ° p (" 7 methanol 5 eleven ^ Xr ° p (»- < 7 trifgoethanol how in Example 5 12 CHAGT 7 ethanol how in Example 5 thirteen „„ -ΧΧΓ’ν f ’ ^α ν> СЫ 4 3

- 37 022487

and otote ,. from 'FROM 4 3 fifteen dl 4 3 sixteen ΟγΝ ^ Ο ^ 4 3 17 dbl ^sn> (At Chow L1eP, L .; Oh! Oi, K. 7. SAET, Zoe. FROM 1971, 3727-3730. 2 eighteen . „~ C £ 0 Oh> CH ει ^ Ν 4 3 nineteen G 'dDD> о Ч ^ Лсн, ^έΗ ' ^Ν \> 6 twenty ιΓχ ΗΝ ^ζ * ⁴ ^ ^4νζ4 ΟΗ OT CHA / ν ' one A1bе “, A.; O1ka, K. 7, Sket. Zoe. FROM 1971, 3727-3730 η η, ν ’^^^ Οη 2

- 38 022487

21 ί " Bip ^ -Toip®, K. ει a! .. Schaog% Me <1 Sket. 2003.7 /, 5529-5537. 4 4 22 aa Leip ^ -Typev, K, e (a)., >οο> · £. Me <1. Oh. 2003, 77.5529-5537, 4 4 23 „AP? σ> b 4 4 24 (Ά ° Ν Ν CK ^ C ^ C! 4 3 25 IG ^ ¹⁴ ) _{Η ()} Α ^ «у ¹ (А У γ Υ ^Ρ 5 Μ O Getting 2 4 3 26 .ΑΧΆ α> < SDZ® 4 4 27 ί »ъ = LI) Wow, b. β. 5. e (a! .. Rep. 5c1. 1989, 25, 219-225. 4 4

- 39 022487

- 40 022487

36 , ^ σχτ ¹ Ύγ ^! 4 3 37 „.CH, „~ Xg ί " 0 £, A1bey, A .; Oh. C.W. Sket. Hos. FROM 1971, 3727-3730. 2 38 “.UOg” ^Ηί τ £ φ Tau1og, Ε. FROM.; LAMAI | pa 1. Ε. 7. 0g§. Sket. 1977.42, 1523-1527. 2 39 γ, ο, ΝΝ XX 4 4 4F ω- XX 4 4 41 „„ Χπχ, % " XX 38 3 42 ^ ΧΓ ° ν ' ί >> BUT 4 4 43 „-Hl $ Ν Ν x> 4 4

- 41 022487

44 _ΗΝ ^ ΧΧ V ^e · SF BUT Getting 4 4 4 45 FROM" (At H ^ gSu A1b1, A .; OYa, K. L Svet. Nose. FROM 1971, 3727-3730. ^ choo-ΟίΛβ Η ₁ Ν '^ ⁴ ^ 2 46 - £ Χ-Ογ ha ^g &, twenty 4 47 „, -EX £ 0 ζά ^with chx twenty 4 48 XSA> (Th 4 3 49 . Liege (" / g 37 3 fifty , ^ άχς, Th? ^α Υ 1 ^Ν Ά; _Ν 37 3 51 ., - ^ ΐΧ ' σ> 37 3

- 42 022487

52 'ΎΦ F 38 3 53 hg 38 3 54 ^ aXC _; U '' χτ 4 3 55 TO 38 3 56 „Tot "L Hg ' 4 4 57 U ΰ.γ ^ ΟΝ 37 3 58 . ^ Crt? (" % 4 4 59 „~ O® £ SF 4 4

- 43 022487

60 „~ Oo5 ^! (Λ- <χ 4 4 61 ώ · ά: 4 3 62 / hg- ¢ / - ί & γ A1bep, A .; Oi, K. Λ Eat. $ ps. FROM 1971, 3727-3730. -HC1 Getting 5 2 63 „-ΧΤΐ / £ SF £ H C | RgeragaCop 6 4 4 64 , -ΧΤΎ / ν (" ”XL AUapv, Χ.Ί. e1 a!., Og% Lea. 2005.7.593-5595. 4 4 65 ί- ^, 4 | Α _Ν ΉΉ · _0Η Oh Getting 7 and an example 66 σ> l / 4 4 67 Lil / / ^Ps have ΟΙ ^ Ν 65 3

- 44 022487

68 "ΓΝγΟΡ, 65 3 69 Oh> ^s ' hrg ^{cp <} 4 4 70 SF ’ CH ek ' twenty 4 71 ^ 0¾ SF hk ZsousN, E C .; Ш15оп, C. 1. EP 63872 A1, 1982. twenty 4 72 05 cs. δεονβΙΙ, E. C ,; λνβιεοη, ϋ. one EP 63872 A1. 1982. 4 4 73 „„ ~ Lg l " L'l kl-lu Sga®oe, E. 3., 1g .; NOEM-N. and 5. Ra1ep1 3,299,063, 1967. X-SG 2 74 „~ Chi6 from" (to twenty 4 75 ™ ~ ogl ^α · γ ^Ν γ4 g ί ι = & srtg 73 3

- 45 022487

76 Κηοχ, I. b ,; Escape K.V. i. 8. Ρβιβηι 4,775,762,1988. 38 3 77 Sat ⁴ ' ά twenty 4 78 (/BUT- .-ABOUT- ¢ 6 Wtt, E.O. Zos. 1954, 3832-3839. 3 79 ιχΆ N N 'b-g ¢ 5 Vttt, E.O. er a!., / SN. Zos. 1954, 3832-3839. 3 80 _{is he} CC? one A1eP, A, O1Ia. K. 7. No. Zos. FROM 1971, 3727-3730. Getting 8 2 81 ΗΝ '° Υ ^<4 1 ψ 44? ^it (At ⁴ '• Λιτγ A1bcr (, A .; AB (a, K. 1. SN. Zoe. Since 1971, 3727-3730. ^N a ^| 'kx—' ₀ 4 ^ '' sc Obtain 8 2 82 ί ¹ Υ ^γ Ι. <ν Κηοχ, I. b .; Escape K.V. i. 8. Ρβιοηΐ 4,775,762, 1988. 65 3

- 46 022487

83 ^ίΛ -νά Ρ Κποχ, I. Κοβοκ, K. Β. υ.5. Wright 4,775,762, 1988. 80 3 84 Η „· 'Χ ^ ³ γ'4, ίύ / G ’ ΟΙ ^ Ν 80 3 85 ΗΝ '^' ° 'τ <Υ <»5, Ο1γγ € Ν Ν. ^ 80 3 86 Cha? ^ - ⁴ Κποχ, [Ε; ΚοβίΓϊ, K.V. υ.5. Ra 4,775,762, 1988. 81 3 87 ην ^λ ^ ° Ύ% "Α / U ^R ' 81 3 88 οΟ ϊ ^α γγ ^εΝ 81 3 89 ,, ^ σχΑ ' Ο> Ace 9 / efeg1, Ρ. 7. 11.5. Ra1ep (4,910,351, 1990. 4 3 90 . „~ Σν ^: σ> Λ Ριιηβ, A. 1. 11.8. Raksha 4,590.279, 1986. 4 3

- 47 022487

91 dao 4 ^ oo-sn. 90 2-methoxyethanol 8 92 BUT ZR 58206563 A, 1983. 4 3 93 „A ° A Οό & 177 4 94 yeah SL N N BUT 4 3 95 <Τ ^ΰ ΊΓΎ ° '^ (Y? \ A> T 36 methanol nine 96 ^ ΧτΧιΉ ' Yes 36 2,2,2-tris-toroethanol nine 97 „AA Yes g BUT 37 3 98 yy /? _α A and * ¹ (Y; ^x m * ^ lg BUT 4 4

- 48 022487

99 "Hee * ¹ $> Ί ^ Γ 4 4 one hundred ζϊ> Ρ, Γ '^' ΈΗΟ 4 3 101 ϊ gGg'tU ⁴ ' _ΗΗ -4χΜ G ^g W ^ ^! * m ° χΛ Ca1 # 1 £ M, 0. Βτίι. C1B Ra1. ΑρρΙ. 2002368 4 4 south _t- hHU Hd _a ύο Sh Ν gt cr ^^ sleep Woweg Α, -C. ΟΕ 4429465 Α1.1994. 4 3 103 ,, ΖΧτΧ ^ SF Λ 220 3 104 ^ ΧτΧ <„ Ο> ^MF G ⁵ 1 ^ν Ά = ν 220 3 105 „, -ΟΤΟγ. (Ά ' Do ' 220 3 106 .. ~ χνά / 4 3

- 49 022487

107 „-Χτά, ςό 4 3 108 Οό Α 4 3 109 with &, 174 4 110 (Λ CH 4 3 111 1 \ bP _Η ^ σ ° ύ OT 4 3 112 "~ 4ΧΧΧ; FROM" ' ' 4 3 113 4 3 114 , 4№ \. ΰύ · ΎΤ ’ Ρ --- Ν 220 3

- 50 022487

115 „„ TOCHF (f ^l ' CP ₅ 4 4 116 „„ ХХЦ Η, γγφ SC Bfgh Taukn, E. S .; LaMapsha, 1. b. 7. 0t§. C1it. 1971.42, 1523-1527. Η ^ ΟΟχ, Μ. 2 117 ef Φς 5co <e11, E, O.; ZAa (zop, 0.1. ΕΡ63872ΛΙ, 1982. 73 3 118 ..- HOF Eph ¹ F 73 3 119 -HA ef fs 73 3 120 ^: F (g 38 3 121 Gf ^ R ' f 222 6-fluoropyridine 3-boronic acid 10 122 F 222 3-trifluoromethyl- benzene boron acid 10

- 51 022487

123 „Heeo VGCD / Ρ ^G Getting 4 4 4 124 ,, ^ ΊΧ, rm 73 3 125 _ ~ σ ° SY 222 benzene boronic acid 10 126 ,., - ΧΧ Όγ- ¢ £, - A1bP, A .; OMa, K.}. Sket. 5 on. FROM 1971, 3727-3730. Getting 9 2 127 ^ ΧΤΧΟ Οό ” C “X ν / Γ ^ ΐη, T. and 484540786 A, 1985. 4 3 128 ω 4 3 129 οδ ¹ & 224 4 130 DD with ’ : χχ 37 3

- 52 022487

131 Ύ'Άϊ IT from Getting 10 GOTH one 132 Aeu 4 eleven (33 4 12 134 ·. <£ · ^ »Ί · Л ^ ХГЖ 133 thirteen 135 OTOT 36 methanol fifteen 136 FROM ° FROM from N N (At CHALU A1b ", A .; Oh, K. 7. Sket. Zoe. FROM 1971, 3727-3730. OTOT 2 137 and - Χ7 Όγ ⁰ - ^ SF ' FROM 4 3 138 Ο> ' 4 sixteen

- 53 022487

139 - 4-ethylphenylboronic acid 217 Example 11 140 (»Σ (At 4 17 141 Ά ’’ 174 4 142 Υύ ” Α ΟΝ 174 4 143 ..Αη \, (Λ ^Γ * Ά 174 4 144 h ”hell * Ά ^ρ σ> DG 175 4 145 Yes 175 4 146 ΑΧΦ ΓΤι ΐ ¹ Υ & ME, b .; Ρκνίάοΐΐ, R. ΕΡ37039Ι A2, 1990. 4 4

- 54 022487

147 , ρδ-Ά (" 175 4 148 > R 175 4 149 ek .. 5soe11, Ε. 0 .; \ ¥ amop, 0.1. EP 63872 ΑΙ, 1982. 175 4 150 (• ^ Άν ^Ρ ЧА / > χ 4 4 151 ί ⁴ .youh · 'ού ·' L1bet (, Λ .; OH1a, K. 7. &> pp. C 1971.3727-3730. As in Getting 8, Stage 2 2 152 (Υϊ ^h aT ^h LH 229 3 153 _Οτ · χ · $> 219 3 154 ^^ ΛΟ, ((ΒυΙ 4 4

- 55 022487

155 Λ 174 4 156 / G Ρ ^ Ι < 229 3 157 ", Ο ^ ο ..- ΟΧφ (Χ> / U ^R 'Ρ Ν 220 3 158 .L ’' Ο> <x / AGGEC A; THEY, K.}. Sb. Zoe. FROM 1971, 3727-3730. 2 159 γ £ αχλ Λλ 80 4 160 os 80 4 161 Η, ΑΑν * ¹ 131 eighteen 162 whether * m /5 Kpoh, I. b .; Κο ^ εΐΐ. K.V. and 5, Rais 4,775,762, 1988 161 3

- 56 022487

163 ^ρ χτ 161 3 164 „—ΏΟΧν * 'ίΑ °“ C1 co * Fr sll 4 3 165 (Ά N N HU “ hcg 4 3 166 $> δοονοΙΙ, E. S .; \ # A1bop, ϋ. one. EP 63872 A1, 1982. 174 3 167 U-X-u-'CH-O'sk. GT TU σ> * L SGUAomv Getting 11 174 3 168 ζ & L SG * H "G * OMV Getting 11 80 3 169 "~ Ό * Ο <Α BUT Getting 4 174 3

- 57 022487

170 „ΑΆ BUT Getting 4 37 3 171 H ^l > g g Sg'gt ^ OM Getting 11 4 3 172 _ ~ oh yeah ^¥ ' about Getting 12 4 3 173 AO / Of 36 2-propanol fifteen 174 Ay BUT 22) eighteen 175 n, e.on η ,, Ά BUT 228 eighteen 176 Aw ” BUT A1b (, A .; OH, K.L. Saet. Zoe. C 1971, 3727-3730. „,, Ag As in Getting Θ, Stage 5 2

- 58 022487

177 .G from 176 ,8 178 FROM" L ’ SG ^ gAy ^ Ly Getting 11 37 3 179 ΓΆ '#>“' ^ν '° G ’ oa / zh Getting 11 229 3 180 A _x 2-bromopropane 218 nineteen 181 Rut nn''echach (L ίΛν * SS I A1b1, A .; Oh, K. 7. Sket. 5 on. FROM 1971, 3727-3730. 2 182 , λΧΧ yes l ° ° ό \ Getting 13 4 4 183 „„ ~ Ode ί "° At cssol) 4 4

- 59 022487

184 ,, - ΑΧ, ν ' SA? χΑ Getting 14 4 4 185 SF * L 0 <-ΚΛ> Μθ Getting 11 Ι77 4 186 -Aso (X / * ' I 181 4 187 „.ААсА ' Sf & 230 3 188 g from 1-bromlrolane 218 nineteen 189 from BUT Getting 4 2) 9 4 190 .Agot <" acetic anhydride 218 twenty 191 _G % A »^ · ^ά 184 21

- 60 022487

192 (Y? -Λ, o at from tert-butanol as in Preparation 13 4 4 193 Affairs ¢¢,! H , ζ Getting 4 177 4 194 DNU (U ” Th Getting 15 229 4 195 bottom ·· οά 197 nineteen 196 <Y 197 twenty 197 (ΛυΫ ^. ΗΝ-νζ-ChE U (At 170 eighteen 198 „DuhG * t Η ^ Ο ^ ΐΓ ^ ίΓ BUT Getting 11 161 3

- 61 022487

199 n - ^ - ^cm = r her 1-bromopropane 197 nineteen 200 acl X> 161 3 201 .5 Κηοχ, I. C; Co. & EGs, K.V. i. 8. Raip 1 4,775,762, 1988 225 4 202 OF ° 4 4 203 / Αν η, οΆη, 4 4 204 ^about . ., Α ° Φ 37 4 205 ^l of en, "A £ ί) φ '-' 219 4 206 „-HGO ss>' ^l 3 Κηοχ, I. K; Ko @ eg5, K.V. i. 8. Ra (ep (4,775,762, 1988 22

- 62 022487

207 moss ί> 5 ^a ' ^Ln · 172 23 208 .zh ^Η '° Ύ ^Ν τ5ί F 24 209 yes _and 208 eighteen 210 /from·' ¢ 5 θ £ γ A1bel, A .; 0K1a, Κ, 7. Rally, Zoe. FROM 1971, E727-E730. 2 211 C0 210 eighteen 212 .. LJ ' (Th Κηοχ, I. b; Kovege K.V. i. 8. Ra (Yesh 4,775,762, 1988 211 3 213 ., F (X 212 methanol fifteen 214 _ ~ .Χτ ° Α ,. Same ' Hg 209 3

- 63 022487

215 ρ Τ ^ρ κ, ς ^ Ν ^ κΑοΗ! y5 Κηοχ, I. b .; Κοβοΐΐ, K. W, 11.8. Raksha 4,775,762,1988 209 3 216 ρψρ .4X ° tU from and. 4 4 217 α> 134 14 218 from 51 eighteen 219 .U? Yes SS one A1bHe, A.; OYa, C.W. Zos. FROM 1971, 3727-3730. 2 220 , UU Sat 62 eighteen 221 (U? (Y * 'ίΛν ^ ν- one A1bsp, A .; OH (a, C.W. SN.Z. Z. C 1971, 3727-3730. .,,,-4 As in Getting 9 Stage 5 2

- 64 022487

222 FROM* FROM FROM _T - L1Le!, L .; O1IA, K. 3. Sket. Zoe. From 1971.3727-3730. ,FROM' 2 223 FROM FROM Chow A1EeP, A .; Oh, K. 3. Sket. Zoe. FROM 1971, 3727-3730. , FROM ° ' As in Getting 8, Stage 2 2 224 n, g. - .on X ϋ nh ^h '· h X ίί XX Ν' Ν ' 223 eighteen 225 9 ^N = θό Ν Ν A | bcr1, A .: O1pa, K. 3. Sket. Zoe. FROM 1971, 3727-3730. ♦ HC1 Getting 16 2 226 depart C \ Χ 209 3 227 ¢ 0 '' > HC1 4' 228 FROM go Ν Ν FROM' A1bP, A .; Oh, K. 3. Sket. Zoe. FROM 1971, 3727-3730. ύ5γ ° ^χ As in Get 8, Stage 2 2 229 note Honeycomb 151 eighteen 230 From ί " 158 eighteen 231 OTU (Λ 4 (by-product in Preparation of Compound 59) 232 FROM* FROM γύ ° Α ^ρ EgePsot, V.A. e1 a!., 9 / O 9404527 A1, 1994. one

Notes to the table. one.

¹ All references to compounds used in the preparations and examples listed in table. 1 are expressly incorporated by reference into the present application.

² All compounds used for chemical synthesis, which are illustrated in table. 1 and are given without reference to references or receipt, purchased from commercial sources.

- 65 022487 ^{3 The} synthesis of compound 227 began with the conversion of (4-methoxy-3-trifluoromethylphenyl) methanol to 2 (4-methoxy-3-trifluoromethylphenyl) ethylamine hydrochloride in the same manner as described in Preparation 9, Steps 4 and 5. 2- ( 4-Methoxy-3-trifluoromethylphenyl) ethylamine hydrochloride was then subsequently treated by the same chemical transformations as in Examples 2, 18 and 4 (the other reactant was 2-chloro-4-trifluoromethylpyridine) to give compound 227.

Biological tests.

The following table 2 shows mass spectrometry and biological activity data of typical compounds of the formulas Ι-Α and Ι-B.

table 2

Examples of compounds of the formulas Ι-A and Ι-B, including mass spectrometry and biological activity against typical fungal diseases and insects

w M5 [M + H] + SOSN5A SOYEIA Γ, ΕΡΤΝΟ R8 RESI rssst ΡΥΚΙΟΚ > 80% Mortality any species insects @ 4000 suits / million one 358 ** * "* ** ♦ * "* - 2 413 y * *** *** *** * "* + 3 414 well ** ** *** *** *** 4 268 well " * " * to* 5 413 " ** ♦ *** ** " + b 413 * * "* + * "* ** " + 7 363 * * * *** *** * + * + 8 370 * ** " * * x * *** *** + nine 252 * * well *** F ** *** - 10 375 * * ** *** *** ** ♦ + eleven 443 * * ** ** *** ** ♦ 12 389 * * ** ♦ *** *** + thirteen 370 * * * »** * ★ * * "* + 14 370 * * * *** "4* I* + fifteen 346 * * *** ** ♦ ♦ "* + sixteen 376 * * * *** ** ♦ *** 17 282 well ** ** *** ** " *** - eighteen 371 * * * *** * "* *** - one" 296 * * * * * *** 2 " 268 * * * l ** 21 382 * "* * + ** ** ♦ *** 22 428 * ** ** ** *** *** - 23 429 * * * * *** ** 24 380 one" "* * I** 25 444 * * ** + + ** »** *** + 26 408 ♦ * * *** *** *** 27 458 + * * * ♦ ** *** 28 346 * * * *** *** * + * + 29th 362 * * 4g ** " * + thirty 413 * * ** *** *** + 31 385 N3 ' ΝΤ 'but ΝΤ ** b *** b ΝΤ 32 470 ΝΤ ΝΤ *but ΝΤ ** b ** b ΝΤ 33 430 * * ** * *** ** 34 414 * * ** + ** *** *** + 35 404 * * * ** " ***

- 66 022487

80 284 * * * * to to 81 284 * * " to** to to 82 413 * * ** to * to kkk * "* + 83 429 to kkk *** kkk kkk kkk 84 429 * kkk *** kkk kkk kkk + 83 386 • * * kkk kkk kkk - 86 429 * * ·. to#* kk " kk * 87 429 * * + * kkk kkk kkk - 88 386 * * ** kk * kk * *to - 89 467 * * *to * kk * ♦ * kkk 90 447 * * kk * kkk kkk kkk + 91 487 * * ** kkk kkk kkk + 92 447 * * ** kkk kkk to * to + 93 431 ** *** kk * kkk kkk kkk + 94 417 * kk kk ♦ to kk * kkk - 95 375 * kkk to** kkk kkk kkk 4 96 443 * * ♦ to * kkk kk * kkk + 97 444 + * to* kkk kkk to * to + 98 393 ΝΤ ΝΤ 'but ΝΤ ** b ** b ΝΤ 99 377 ΝΤ ΝΤ ** _a ΝΤ * to * _b kkk 5 ΝΤ one hundred 440 * * to* *** kk * kkk 101 395 * *** ♦ kk kkk kkk kkk + 102 407 * * * kk * *to* kkk 103 431 * * to** kk * *"to kk * + 104 389 * * kkk *to* kkk kkk + 105 431 ΝΤ ΝΤ ** ♦ _a ΝΤ *** b *** b ΝΤ 106 449 * * ** kkk kkk kkk + 107 381 * * kkk kkk kkk + 108 381 * * ** "to* kkk kkk + 109 427 to to* to* kkk kk * kkk + BY 423 * * *** kkk kkk kkk + 111 413 ♦ to* *** kkk *** kk * + 112 484 * * *** »Kk kkk kkk + 113 430 + * *** kkk kkk kkk •to 114 449 * * "to* kk * kkk kkk + 115 481 * * * kkk kkk kkk - 116 308 ΝΤ ΝΤ ♦ a ΝΤ * B ♦ * b + 117 483 ΝΤ ΝΤ ** but ΝΤ ** b *** b + 118 465 * * kk to kkk kk + 119 439 * * kk to kk kk 120 418 * * kk to kkk kk + 121 347 * * kkk *to* to "to to** ΝΤ 122 396 * * to* kk kkk kk * + 123 409 ΝΤ ΝΤ N3 ' ΝΤ ΝΤ ΝΤ ΝΤ

124 447 * to kkk »Kk *to* "* N1 125 328 * kk kk * "to" kkk kkk + 126 413 * kkk kkk kk * kkk kk * + 127 420 * to kk to* kkk * to to • 128 453 * to to* kkk kkk kk * 4· 129 427 to" kkk kkk kk * to * to + 130 461 to kk kkk kkk kkk + 131 310 * to to kkk kkk kkk + 132 386 to to to* kk * kkk to + 133 382 * to to kkk kkk to - 134 482 to to " to kk * to - 135 403 to to kk *to* kkk kk 136 358 to kk kk to"* kkk kkk 137 417 to to *to to kkk kkk + 138 467 to kkk to" kkk kkk *** + 139 472 to to * to kkk to - 140 478 to kk * kkk kkk kkk + 141 427 to kk kkk kk * kkk to »to + 142 418 to to kk kk * kkk kkk + 143 445 to to to + * kk * kkk to * to + 144 441 to to kk * kkk kkk kkk + 145 441 * to* kk * to * to *** to** 4- 146 408 to kk to* kkk kkk kkk + 147 432 to to kk "to* kk * *** - 148 459 * to kk to** kk * kkk + 149 477 to to kk kk * kkk kk * - 150 399 to to kkk kkk to"* kkk + 151 310 to to to kkk kk * kkk 152 441 BUT to kkk kk * *** to** + 153 457 * to kkk kk * kk * kk * + 154 444 ΝΤ ΝΤ k ** _a ΝΤ *** b *** b ΝΤ 155 384 ♦ to to kk kkk kkk kk * 4" 156 441 " to kk k kkk kkk kk * + 157 457 " to kk kkk kkk to »to + 158 316 * to to* to kkk *** - 159 379 to to to kkk kkk kkk 160 429 * to kk kk * kk * *** - 161 296 * to to to to* to* 162 441 to to * ^ to kk * kkk kkk + 163 459 to kk » kkk *to* kk * kkk + 164 465 to to kk to kkk kkk + 165 445 to to kkk kkk kkk kkk + sixteen" 463 to "to "Kk kkk kk * kkk + 167 457 to to kk kkk kkk kkk •

168 459 * 4 * ♦ well LJ * *** 169 423 * F * zhzhzh LJ * zhzhzh zhzhzh 4· 170 439 * * * " zhzhzh zhzhzh LJ * + 171 443 * F LJ zhzhzh zhzhzh zhzhzh - 172 417 * * ♦ ♦ LJ zhzhzh zhzhzh 173 431 * * * LJ * zhzhzh zhzhzh - 174 282 * * Well well LJ zhzhzh - 175 296 * * * well LJ * f * f 176 300 ♦ * well well zhzhzh "W * - 177 286 * * well well well LJ 178 473 * * "Well well zhzhzh LJ * - 179 * * * well zhzhzh f * - 180 ) * F * LJ zhzhzh *** zhzhzh - 181 328 * * well well LJ LJ * - 182 459 well * well zhzhzh LJ * * 183 417 * * f * "LJ "LJ "W * - 184 425 * F * ** zhzhzh "LJ zhzhzh 185 461 * * well "LJ zhzhzh zhzhzh - 186 473 * * f * zhzhzh LJ * LJ * 187 * F ** * w * zhzhzh zhzhzh ** ♦ + 188 * "** well zhzhzh LJ * "LJ + 189 451 ♦ LJ LJ zhzhzh LJ * Well "* - 190 471 well * well well LJ * LJ * + 191 439 * LJ f * zhzhzh *** LJ * - 192 445 * LJ * LJ Well LJ f ** *** + 193 427 * * f * Zhzhzh zhzhzh zhzhzh 194 437 * LJ * * w "LJ zhzhzh LJ * + 195 467 F * well "W * »** ** w - 196 467 * * well zhzhzh LJ * f * - 197 425 * well zhzhzh "W * zhzhzh - 198 471 * ** well f ** * ♦ * "F 199 467 * LJ "LJ LJ * zhzhzh + 200 441 BUT * LJ well LJ * *** + 201 443 * * LJ "LJ * w * zhzhzh 202 471 * * LJ * zhzhzh ** " zhzhzh + 203 387 Ί F * f * zhzhzh *** "W * + 204 417 * well "W * zhzhzh LJ + 205 431 * LJ zhzhzh zhzhzh f * 206 414 ΝΤ ΝΤ ♦ a ΝΤ * b mt ΝΤ 207 401 well * zhzhzh zhzhzh "W * - 208 324 * * well f * * F * zhzhzh 209 310 * * LJ well f * well 210 362 * LJ * *** * LJ - 211 348 * * well well f * LJ 212 493 LJ LJ * "Well ** " + 213 471 * * well "W * "LJ * w " + 214 473 * F zhzhzh well LJ * w 215 455 • * LJ LJ * LJ * * + 216 430 * * zhzhzh zhzhzh Well, Well LJ * + 217 368 LJ * ΝΤ LJ well well - 218 ΝΤ ΝΤ ΝΤ ΝΤ N1 ' ΝΤ ΝΤ 219 312 ΝΤ ΝΤ ΝΤ ΝΤ mt mt ΝΤ 220 286 MT MT ΝΤ MT ΝΤ mt ΝΤ 221 ΝΤ ΝΤ MT MT ΝΤ mt ΝΤ 222 ΝΤ ΝΤ ΝΤ ΝΤ ΝΤ mt ΝΤ 223 .. ΝΤ ΝΤ ΝΤ MT ΝΤ mt ΝΤ 224 - ΝΤ ΝΤ ΝΤ ΝΤ ΝΤ mt ΝΤ 225 - ΝΤ ΝΤ ΝΤ MT MT mt ΝΤ 226 at ΝΤ ΝΤ * but ΝΤ * b * b + 227 481 ΝΤ ΝΤ *** but ΝΤ *** b mt ΝΤ 228 - ΝΤ ΝΤ ΝΤ ΝΤ mt mt ΝΤ 229 297 ΝΤ ΝΤ ΝΤ ΝΤ ΝΤ kg ΝΤ 230 303 ΝΤ ΝΤ ΝΤ MT mt mt ΝΤ 231 338 * F * LJ F Learn LJ + 232 352 * f * well zhzhzh zhzhzh zhzhzh +

* = 0-49 percent control;

** = 50-79 percent control;

*** = 80-100 percent control;

+ = 80% activity against at least one insect species;

- = not 80% active against tested species of insects; a shows that the compound was tested at 75 ppm;

S shows that the compound was tested at 8.3 ppm;

ΝΤ indicates that the compound has not been tested.

Additional notes to the table. 2. For compounds 37, 57, 62, 179, 180, 187, 188, 218 and 226, the following descriptive data are provided.

¹ Compound 37: melting point 131-132 ° C; ¹ H NMR (300 MHz, DMSO _6th ) δ 9.06 (d, 1 = 2.0 Hz, 1H), 8.88 (d, 1 = 5.9 Hz, 1H), 8.80 (d , 1 = 1.9 Hz, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 7.31 (s, 0H), 6.79 (d, 1 = 1.6 Hz , 1H), 3.75 (dd, 1 = 14.6, 6.4 Hz, 2H), 3.70 (s, 3H), 2.91-2.80 (m, 2H).

² Compound 57: melting point 215 ° C; 'H NMR (300 MHz) δ 9.03 (d, 1 = 1.9 Hz, 1H), 8.84 (s, 1H), 8.63 (d, 1 = 1.9 Hz, 1H), 8 29 (dd, 1 = 5.0, 0.9 Hz, 1H), 7.17 (dd, 1 = 6.0, 1.0 Hz, 2H), 7.13-7.06 (m, 1H ), 6.92 (dt, 1 = 4.0, 2.0 Hz, 3H), 4.01 (dd, 1 = 13.3, 6.9 Hz, 3H), 3.08 (t, 1 = 7.1 Hz, 3H).

³ Connection 62 ^:! H NMR (300 MHz, COC1 _; ) δ 9.02 (d, 1 = 2.0 Hz, 1H), 8.80 (s, 1H), 8.63 (d, 1 = 1.9 Hz,

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1H), 7.24 (s, 0H), 7.13 (t, 1 = 8.8 Hz, 1H), 6.63 (ddd, 1 = 8.5, 6.7, 2.6 Hz, 2H ), 3.92 (dd, 1 = 13.1, 6.8 Hz, 2H), 3.79 (s, 3H), 3.03 (t, 1 = 6.9 Hz, 2H).

⁴ Compound ^179: H NMR (300 MHz, SIS1 ₃ ) δ 9.04 (d, 1 = 2.0 Hz, 1H), 8.84 (s, 1H), 8.63 (d, 1 = 1.9 Hz, 1H) 7.10 (s, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 3.94 (dd, 1 = 14.6, 6 , 3 Hz, 2H), 3.81 (s, 3H), 3.11-2.92 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H).

⁵ Compound 180 ^:! H NMR (300 MHz, SIS1 ₃ ) δ 9.04 (d, 1 = 2.0 Hz, 1H), 8.84 (s, 1H), 8.63 (d, 1 = 1.9 Hz, 1H) , 7.10 (s, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 3.94 (dd, 1 = 14.6, Hz) , 3H), 3.81 (s, 3H), 3.11-2.92 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H).

⁶ Compound 187: Ή NMR (300 MHz, DMSO) δ 9.17 (s, 1H), 9.10 (d, 1 = 1.9 Hz, 1H), 8.86 (d, 1 = 2.0 Hz , 1H), 8.67 (s, 1H), 8.36 (d, 1 = 5.1 Hz, 1H), 7.57-7.44 (m, 3H), 7.36-7.21 ( m, 2H), 3.88 (dd, 1 = 13.4, 6.9 Hz, 2H), 3.05 (t, 1 = 7.2 Hz, 2H).

⁷ Compound 188: Ή NMR (300 MHz, SIS1 ₃ ) δ 9.02 (dd, 1 = 4.8, 1.9 Hz, 1H), 8.82 (d, 1 = 6.4 Hz, 1H), 8.61 (dd, 1 = 6.5, 1.9 Hz, 1H), 8.28 (d, 1 = 5.4 Hz, 1H), 8.28 (d, 1 = 5.4 Hz, 1H ), 7.13 (dd, 1 = 12.9, 5.7 Hz, 4H), 6.996.82 (m, 2H), 4.07-3.91 (m, 2H), 3.84 (dd, 1 = 12.0, 5.7 Hz, 2H), 3.05 (dd, 1 = 11.8, 4.7 Hz, 2H), 1.52 (dd, 1 = 13.8, 6.4 Hz , 2H), 1.52 (dd, 1 = 13.8, 6.4 Hz, 2H), 0.68 (td, 1 = 7.4, 1.8 Hz, 3H).

⁸ Compound 218: Ή NMR (300 MHz, DMSO) δ 9.21 (d, 1 = 2.2 Hz, 1H), 9.11 (d, 1 = 2.1 Hz, 1H), 9.03 (s , 1H), 8.35 (d, 1 = 5.2 Hz, 1H), 7.42 (d, 1 = 5.3 Hz, 1H), 7.33 (s, 1H), 7.02 (d , 1 = 8.1 Hz, 1H), 6.91 (d, 1 = 2.0 Hz, 1H), 6.75 (dd, 1 = 8.1, 2.0 Hz, 1H), 4.13 -3.84 (m, 2H), 2.97 (t, 1 = 7.4 Hz, 2H).

⁹ Compound ^226: H NMR (300 MHz, SIS1 ₃ ) δ 8.30 (dd, 1 = 4.7, 1.5 Hz, 1H), 7.99 (dd, 1 = 7.6, 1.8 Hz, 1H), 7.37-7.29 (m, 2H), 7.17-7.11 (m, 2H), 7.09 (dd, 1 = 7.5, 4.9 Hz, 1H), 7.01 ( t, 1 = 5.9 Hz, 1H), 3.93 (dd, 1 = 13.4, 6.9 Hz, 2H), 3.05 (t, 1 = 7.1 Hz, 2H), 2, 69 (s, 3H), 2.68 (s, 3H), 2.62 (s, 3H).

Fungicidal activity.

It was found that the compounds of the present invention have a significant fungicidal effect, in particular for use in agriculture. Many compounds are especially effective for crops and horticultural plants. In particular, the compounds effectively control many unwanted fungi that infect beneficial crop plants. Activity was demonstrated for various fungi, including, for example, the following typical types of mushrooms: Anthracnose cucumbers (Co11a1o1ps1pcs 1adema ^^ it - --'ίΛ); Blight roots of wheat (SosShoo1i8 8ayui8 Gojan), Downy Mildew Cucumber (Rheiyoregogyuhroga sieschr - R8RESI), rice blast (MadmaroPNe dpvea RUKYUK), wheat leaf rust (Rissiia gesogLPa ΐηΐία -RISSKT) and Septoria Leaf Spot Koloskova wheat scales (erYuhrNaepa poyogish - Ε-ΗΠΤΗΟ )

One skilled in the art will understand that the effectiveness of the compounds against the fungi described above determines the overall usefulness of the compounds as fungicides. The activity of the compounds as effective fungicides was determined by applying the compounds to plants and monitoring the control of fungal diseases. Compounds were formulated at 200 ppm in 10 vol.% Acetone plus 90 vol.% Tgjop X water (deionized water 99.99 wt.% + 0.01 wt.% Tgjop X100) to obtain the formulated test compound. In some cases, the compounds were formulated at 75 or 8.3 ppm, rather than 200 ppm, in 10 vol.% Acetone plus 90 vol.% Tiop X water (deionized water 99.99 wt.% + 0 , 01 wt.% Tgjop X100), with obtaining the formulated test compound. The formulated test compounds were applied to plants using a sprayer with a swivel hose equipped with two opposing air spray nozzles that delivers approximately 1,500 l / ha of spray solution volume.

All plants were inoculated with fungal spores the day after treatment, then incubated in an environment conducive to the development of the disease. The severity of the disease was evaluated 4-15 days later, depending on the disease and the rate of development of the disease. The following experiments were performed in the laboratory to determine the fungicidal efficacy of the compounds of the present invention.

Wheat leaf rust (the causative agent of Risschus hesoglia 1pys1 = Rissia ssspga; Waueg code RISSKT). Wheat sprouts (cultivar ¥ ita) were grown from seeds in a potted mixture of peat with a small content of land (Mayoshkh), until the seedlings had a fully opened first leaf. Each pot contained 3-8 seedlings. These plants were sprayed before wetting with their formulated test compounds. The next day, the leaves were inoculated with an aqueous suspension of spores of Rissia hesoyu ΐηΐία and the plants were kept in high humidity overnight to allow spores to germinate and infect the leaves. The plants were then transferred to the greenhouse while the disease developed on untreated control plants.

Anthracnose of cucumbers (pathogen Co11e1o1psit Ideagipp; Vaueg code C код ^^^ A). Cucumber plants (cultivar VI5L SATRYUY) were grown from seeds in a pot mix based on peat with a small content of land (Mayoshkh), until the first leaf was opened at 20-80%. Each pot contained 1 seedling. These plants were sprayed prior to wetting with their formulated test compound. The next day, the leaves were inoculated with an aqueous suspension of Co11e1oysit Udepit spores and the plants were kept in high humidity overnight to allow spores to germinate and infect the leaves. The plants were then transferred to the greenhouse while the disease developed on untreated control plants.

False powdery mildew of cucumber (causative agent of Rhea doregopokrogrog siei518 Waueg code P8 RESI). Cucumber plants (cultivar VikN Sjatryup) were grown from seeds in a potted mixture of peat with a small content of land (Meggotk), until the first leaf was opened at 20-80%. Each pot contained 1 seedling. These plants were sprayed prior to wetting with their formulated test compound. The next day, the leaves were inoculated with an aqueous suspension of downy mildew sporangia and the plants were kept in high humidity for one day to allow sporangia to germinate and infect the leaves. Plants were then incubated in a seed germination chamber while the disease developed on untreated control plants.

Septoria of spikelet scales of wheat (pathogen Lepulophyta podogit = 81adapokrog pogodit; Vaueg code ^ ΕРТНО). Wheat sprouts (cultivar Kita) were grown from seeds in a mixture of 50% pasteurized soil / 50% soilless mixture, until the seedlings had a completely open first leaf. Each pot contained 3-20 seedlings. These plants were sprayed prior to wetting with their formulated test compound. The next day, the leaves were inoculated with an aqueous suspension of bp spores (okrNepa Pohogit and the plants were kept in high humidity (one day in a dark irrigated chamber, the next four days in a lighted irrigated chamber) to allow spores to germinate and infect the leaves. The plants were then transferred to a greenhouse while the disease developed on untreated control plants.

Rice pyriculariosis (the causative agent of MadparoPNe dpkea = Rupsiapa oguuae; Vaueg code PΥΚIОΚ). Rice plants (cultivar M202) were grown from seeds in a potted mixture of peat with a small content of land (Me1got1 \), until the second leaf of the seedlings was fully revealed. Each pot contained 5-20 seedlings. These plants were sprayed prior to wetting with their formulated test compound. The next day, the leaves were inoculated with an aqueous suspension of Rupsiapa oguoye spores and the plants were kept in high humidity overnight to allow spores to germinate and infect the leaves. The plants were then transferred to a seed germination chamber while the disease developed on untreated control plants.

In the table. 2 shows the activity of representative compounds of the present invention evaluated in these experiments. The effectiveness of the test compounds for controlling the disease when spraying leaves was determined by assessing the severity of the disease on the treated plants, then converting the severity assessment into a percentage of control based on the disease level on the untreated inoculated plants. Data represent the level (percent) of control of a given disease when the compound was applied to foliage at 200 ppm. In some cases (as indicated in the table), the compound was applied to plants at 75 ppm or 8.3 ppm.

Insecticidal activity.

It was found that the compounds of the present invention have insecticidal activity. Activity can be demonstrated for a number of insects, including, for example, the following representative species of insects: Small scoop (8roDor (ega ejudia - BARNES) or Caterpillar of tobacco leaf bud-leaves (NePodshk unexepk - NEYU1); Komar (Aedek aedurD - AEIroisela (AEIroisela) Igokory1a te1apodac (er - ICO8ME). It will be understood by those skilled in the art that the effectiveness of the compounds against the insects described above determines the overall usefulness of the compounds as insecticides.

The activity of the compounds as effective insecticides was determined by applying the compounds to food or water, placing insects in water or food and observing mortality after an appropriate incubation period. Compounds were formulated at 4000 or 400 ppm in dimethyl sulfoxide (DMSO) to give the formulated test compound. The formulated test compounds were diluted in 96-well plates with acetone: water solutions and applied to species-specific food or water. Plates were invaded and evaluated as described below. The results were average values from 2-6 repetitions.

ICO8ME: formulated test compounds were applied to a microtiter plate containing Drosophila agar (10% sugar-water solution) to give a dose of 80 μg of test compound per well. Plates were invaded by placing at least three flies in each well and sealing the plate. Mortality was evaluated after incubation for two days at room temperature.

AEI8AE: tablets containing formulated test compounds at a concentration of 6 μg / well were diluted with water containing mosquito larvae. Each well contained at least two larvae. Mortality was evaluated after incubation for three days at room temperature.

LARNES or NEUT formulated test compounds were applied onto 96-well plates containing butterfly food at 12 μg / well (one tenth of the norm used for

NEYU1). The plates were invaded by placing at least four fresh caterpillar or leaflet eggs in each well and hermetically closing the plate with a cotton pad and plastic.

Mortality was evaluated after incubation for seven days at a temperature of 28 ° C.

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In the table. 2 shows the activity of representative compounds of the present invention evaluated in these experiments. The effectiveness of the test compounds for insect control was determined by evaluating the mortality rates in the treated test tablets, then converting the average mortality to the percentage of control. Each compound was tested in at least two species. If any of the OKO8ME, AEE8AE, LARNES, or HEL1U1 species was controlled at 80% or more, the compound was considered active (shown as + in Table 2). If none of the species was controlled at 80% or more, the compound was considered inactive (shown as in Table 2).

Activity aimed at protecting animal health.

The compounds of the present invention have been found to have significant potential as antiparasitic agents in veterinary medicine. Tab. 3, presented below, represents the activity of representative compounds of the present invention evaluated in these experiments. Activity was demonstrated in four of the five compounds tested against Sayogia bibcidae, a free-living nematode, which is an indicator species for animal parasites. It will be understood by those skilled in the art that the efficacy of the four compounds against Salmonidae spp. 8, which at 10 μg / ml is equivalent to the commercial anti-parasitic product ivermectin, determines the potential usefulness of these compounds for controlling parasites that infect animals.

The activity of the compounds against Saeobacterium edema was determined by dissolving the compounds in DMSO, then applying them to Petri dishes containing agar with nematode growth medium to a final concentration of 10 μg of compound per 1 ml of agar. The Exxeponix soybean bacterium was grown on the tablets to obtain a food source for the larvae of Sapiomyosidae. Bacteria were killed by heating at 65 ° C. before adding the compound to the plates.

Compound plates and heat-killed bacteria invaded 10 μl of droplets containing eggs of wild-type Salmonidae worms. Adult worms were dissolved in KOH, decolorized and washed in Ringer's solution until an egg suspension was obtained. Each compound was screened with approximately 400 eggs divided between two Petri dishes. Hatching from eggs was evaluated after 24 hours at 20 ° C. Mortality rates were averaged for two tablets.

Table 3

The activity of compounds of the formula Ι-A against Sayeogia bibc e1edaic.

Application rate 10 μg per 1 ml of agar

Structure Percent mortality F ‘ one hundred .-Xt · © - ¹ ' one hundred one hundred .HhHu ... one 97 Ivermectin 95

Claims (7)

CLAIM 1. A compound of formula AD where K represents a phenyl or a heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-tiadizola, thiazole, benzothiazole or quinolone optionally substituted with H, halogen, _C1-C6 alkyl, C1-C ₆ -alkoxy, benzyloxy or _C1-C6 haloalkyl; Ζ represents a simple bond CC, O, OCH2 or OCH2CH2; t is an integer having a value from 1 to 4; K ¹ independently represents H, halogen, C ₃ -C ₆ -alkyl, hydroxy, C ₃ -C ₆ -alkoxy, halogen-C ₃ -C ₆ alkyl, halogen-C ₁ -C ₆ -alkoxy, ΟΝ, С1- C ₆ -alkylcarbonyl, C ₃ -C ₆ -alkoxycarbonyl; Υ represents a simple bond CC, C (K ⁵ P) O or C (K ⁵ P); η has a value of 2; K ² represents H or C ₃ -C ₆ alkyl; K ⁴ represents H, halogen or _C1-C6 alkyl; K ⁵ represents H; X ¹ represents ΝΚ ³ , O and 8, where K ^{3 is} selected from H or L-C ₆ -alkyl; X ² represents a _C1-C6 alkyl; X ³ represents H or _C1-C6 alkyl. 2. The compound of formula BA, where K represents a phenyl or a heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-tiadizola, thiazole, benzothiazole or quinolone optionally substituted with H, halogen, _C1-C6 alkyl, C ₃ -C ₆ alkoxy, benzyloxy or C 1 -C ₆ haloalkyl; Ζ represents a simple bond CC, O, OCH2 or OCH2CH2; t is an integer having a value from 1 to 4; K ¹ is independently H, halogen, C ₃ -C ₆ alkyl, hydroxy, C ₃ -C ₆ alkoxy, halogen-C ₃ -C ₆ alkyl, halogen-C ₃ -C ₆ alkoxy, ΟΝ, C1- C ₆ -alkylcarbonyl, C ₃ -C ₆ -alkoxycarbonyl; Υ represents a simple bond CC, C (K ⁵ p) O or C (K ⁵ p); η has a value of 2; K ² represents H or _C1-C6 alkyl; K ⁴ represents H, halogen or _C1-C6 alkyl; K ⁵ represents H; X ¹ represents ΝΡ ³ , O and 8, where K ^{3 is} selected from H or L-C ₆ -alkyl; X ² represents a _C1-C6 alkyl; X ³ represents H or _C1-C6 alkyl. 3. The compound according to claim 1, where Ζ represents O, OCH ₂ or OCH ₂ CH ₂ . 4. The compound according to claim 1, where Ζ represents O. 5. A compound according to claim 1, wherein K represents a heterocycle selected from pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-tiadizola, thiazole, benzothiazole or quinolone optionally substituted with H, halogen, _C1-C6 alkyl , _C1-C6 alkoxy, benzyloxy or _C1-C6 haloalkyl. 6. The compound according to claim 1, where the compound of formula BA is a 7. The compound according to claim 1, where the compound of formula BV is