TW201326124A - Plant growth regulating compounds - Google Patents

Abstract

The present invention relates to novel non-steroidal brassinosteroid mimetic derivatives, to processes and intermediates for preparing them, to plant growth regulator compositions comprising them and to methods of using them for controlling the growth of plants and/or promoting the germination of seeds.

Description

Plant growth regulating compound

The present invention relates to novel non-steroidal brassinosteroid mimetic derivatives, processes for their preparation and intermediates, plant growth regulator compositions comprising same, and their use for controlling plant growth and/or Or a method that promotes seed germination.

Various chemical derivatives acting on the Brassinolide signaling pathway have been described, for example, in Bioorganic Chemistry and Medicinal Chemistry (Bioorg. Med. Chem., 1998) , 6, p. 1975; Bioorganic Chemistry and Medicinal Chemistry Newsletter (Bioorg. Med. Chem. Lett., 1999 ), 9, p. 425; Agro-Food Chemistry (J. Agric. Food Chem., 2002 ), 50; p. 3486; Botany (Planta, 2001 ), 213, P.716; WO 2008/049729, WO 2009/109570 and Chemistry & Biology, 2009 , 16, p. 594-604. Brassinolide and its analogs have been described to have growth-regulating properties of useful plants.

Surprisingly, it has now been discovered that certain novel non-steroidal brassinolide mimetic derivatives have useful properties for controlling plant growth and/or promoting seed germination. Preferably, such novel compounds can result in improved plant growth characteristics such as faster growth, faster germination, earlier germination, and/or reduced toxicity. These compounds can provide other advantages Point, for example, enhanced solubility, or more formulation, provides for more efficient delivery to plants, provides improved plant intake, or is more biodegradable.

According to the invention, there is provided a compound of formula (I)

Wherein each W is independently O or S; R ₁ , R ₂ , and R _{9 are} independently H, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, cyano, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more hydroxyl or amine; X-based halogen, C ₁ -C ₆ haloalkyl, cyano, thiocyanate, nitro, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ - C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, amine , NC ₁ -C ₆ alkylamine, N,N-di-C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkane Oxycarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₃ -C ₈ cycloalkyl, indolyl, fluorenyl; or X-based heteroaryl or consisting of one or more halogens, cyano, C ₁ -C ₃ An alkyl group, a C ₁ -C ₃ haloalkyl substituted heteroaryl group; and the condition is that when X is a halogen, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, two Each of W is oxygen, and R ₈ is hydrogen, methyl, ethyl, propyl or hydroxy by one or two a C ₂ -C ₃ alkyl group substituted with a halogen or an amine, further R ₁ is not hydrogen, C ₁ -C ₂ alkyl, or a C ₂ alkyl group substituted by one or two halogen, hydroxy or amine; R ₃ Hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl; or R ₃ consists of one or more cyano Amine, carbonylamine substituted C ₁ -C ₆ alkyl; R ₄ , R ₅ , R ₆ and R _{7 are} independently hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ alkoxy, hydroxy, -OC(O)R ₁₀ , amine, NC ₁ -C ₆ alkylamine or N,N-di-C ₁ -C ₆ alkylamine R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ alkylcycloalkyl, benzyl or benzyl substituted by one to five substituents R ₁₁ , aryl or from one to five substituent group R ₁₁ substituted aryl, heteroaryl or by one to five substituents R ₁₁ substituted aryl, heteroaryl, or heterocyclyl group by one to five substituents R ₁₁ substituted heterocyclic group; or R ₈ by a line one or more of the following are substituted with the C ₁ -C ₆ Group: cyano, nitro, amine, NC ₁ -C ₆ alkylamine, N, N- two -C ₁ -C ₆ alkylamine, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C _1- C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, benzyl or benzyl substituted by one to five substituents R ₁₁ , aryl or substituted by one to five substituents R ₁₁ Aryl, heteroaryl or heteroaryl substituted by one to five substituents R ₁₁ , heterocyclyl or heterocyclyl substituted by one to five substituents R ₁₁ ; R ₁₀ is hydrogen, C ₁ -C ₆ An alkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkyl group; and each R _{11 is} independently a cyano group, a nitro group, an amine group, a hydroxyl group, a halogen group, a C ₁ -C ₆ alkyl group, C _1- C ₆ haloalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ halocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ - C ₄ alkoxy-C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ Alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, N -C ₁ -C ₆ Alkylamino, N , N -di-(C ₁ -C ₆ alkyl)-amino, N , N -di-(C ₁ -C ₆ alkyl)-aminocarbonyl, N , N -di-( C ₁ -C ₆ alkyl)-aminosulfonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ An alkylcarbonylamino group; or a salt or N-oxide thereof; and does not include the following compounds, wherein X is a trifluoromethyl group, R ₁ is a chlorine group, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, and both W are oxygen; X is chlorine or bromine, and R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, R ₄ is an amine, and both W are oxygen; X is iodine or bromine, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, and R ₂ and R ₈ are methyl. And both W are oxygen; X is bromine, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, R ₃ is ethyl, R ₈ is methyl, and two Each of W is oxygen; and X is a nitro group, an NC ₁ -C ₆ alkylamine or an N,N-di-C ₁ -C ₆ alkylamine, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are hydrogen, and both W are oxygen.

The compound according to formula (I') can be used in a plant growth regulator or seed germination promoter composition or as a plant growth regulator or a seed germination promoter, wherein formula (I) is the same as formula (I), However, when X is halogen under the following conditions, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₉ are hydrogen, both W are oxygen, and R ₈ is hydrogen, A a C ₂ -C ₃ alkyl group substituted by one or two hydroxyl groups, halogens or amines, in addition R ₁ is not hydrogen, C ₁ -C ₂ alkyl or one or two halogens a hydroxyl or amine substituted C ₂ alkyl group; and does not include the following compounds, wherein X is a nitro group, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are Hydrogen, and both W are oxygen.

The following compounds are therefore included in formula (I'): X-based trifluoromethyl, R ₁ is chlorine, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, And both W are oxygen; X is chlorine or bromine, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, R ₄ is amine, and both W are Is oxygen; X is iodine or bromine, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, R ₂ and R ₈ are methyl, and both W are oxygen; Is bromine, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, R ₃ is ethyl, R ₈ is methyl, and both W are oxygen; and X-based NC _1- C ₆ alkylamine or N,N-di-C ₁ -C ₆ alkylamine, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ Hydrogen, and both W are oxygen.

In a further embodiment of formula (I) and formula (I'), when X is halogen, R ₁ is not hydrogen, C ₁ -C ₂ alkyl or substituted by one or more halogen, hydroxy or amine C ₂ alkyl.

The compounds of formula (I) or (I') can exist in different geometric or optical isomers (diastereomers and enantiomers) or tautomeric forms. The present invention encompasses all such isomers as well as tautomers and mixtures thereof in all ratios, along with isotopic forms, such as deuterated compounds. The invention also encompasses all salts, N-oxidation of compounds of formula (I) or (I') And metal-like compounds.

Each alkyl moiety is linear or as part of a larger group (eg, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl) or Branched and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or new Amyl. The alkyl groups are preferably a C ₁ to C ₆ alkyl group, more preferably C ₁ - C ₄ and most preferably a C ₁ - C ₃ alkyl group.

Each alkenyl moiety has at least one carbon-carbon double bond, either alone or as part of a larger group (eg, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl). Also, for example, a vinyl group or an allyl group. The alkenyl group is preferably a C ₂ to C ₆ alkenyl group, more preferably a C ₂ -C ₄ alkenyl group.

Each alkynyl moiety has at least one carbon-carbon triple bond, either alone or as part of a larger group (eg, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl). And is, for example, an ethynyl group or a propargyl group. The alkynyl groups are preferably a C ₂ to C ₆ alkynyl group, more preferably a C ₂ -C ₄ alkynyl group. As used herein, the term "alkynyl", unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond, wherein alkyl is as defined above.

Halogen is fluorine, chlorine, bromine, or iodine.

Haloalkyl (either alone or as a larger group, such as haloalkoxy or haloalkylthio portion) is based one or more identical or different halogen atoms, substituted alkyl group, and is, for example -CF _3, -CF ₂ Cl, -CH ₂ CF ₃ or -CH ₂ CHF ₂ .

The hydroxyalkyl group is an alkyl group substituted by one or more hydroxy groups, and is, for example, -CH ₂ OH, -CH ₂ CH ₂ OH or -CH(OH)CH ₃ .

The term "aryl" in the context of the present specification refers to a ring which may be monocyclic, bicyclic or tricyclic system. Examples of such rings include phenyl, naphthyl, anthracenyl, fluorenyl or phenanthryl. Preferred aryl groups are phenyl groups.

Unless otherwise indicated, alkenyl and alkynyl, either by themselves or as part of another substituent, may be straight or branched, and preferably contain from 2 to 6 carbon atoms, preferably 2 to 4, more preferably 2 to 3, and if appropriate, can be in ( E )- or ( Z )-configuration. Examples include vinyl, allyl, and propargyl.

Unless otherwise specified, a cycloalkyl group may be monocyclic or bicyclic, and may be optionally substituted by one or more C ₁ -C ₆ alkyl groups, and preferably contains 3 to 7 carbon atoms, more preferably It is 3 to 6 carbon atoms. Examples of the cycloalkyl group include a cyclopropyl group, a 1-methylcyclopropyl group, a 2-methylcyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

Each W is independently O or S. Preferably, the two W systems are identical. More preferably, both W are O.

The term "heteroaryl" refers to an aromatic ring system comprising at least one heteroatom and consisting of a single ring or two or more fused rings. Preferably, the monocyclic ring comprises up to three heteroatoms and the bicyclic system comprises up to four heteroatoms, preferably selected from the group consisting of nitrogen, oxygen and sulfur. Examples of such groups include pyridyl, anthracene Base, pyrimidinyl, pyridyl Base, furanyl, phenylthio, Azolyl, different Azolyl, A oxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, and a tetrazolyl group. Preferred heteroaryl pyridines.

The term "heterocyclyl" is defined to include heteroaryl and, in addition, their unsaturated or partially unsaturated analogs, such as 4,5,6,7-tetrahydrobenzophenylthio, 9H-fluorenyl. , 3,4-dihydro-2H-benzo-1,4-dioxanthyl, 2,3-dihydro-benzofuranyl, piperidinyl, 1,3-dioxolanyl , 1,3-dioxanyl, 4,5-dihydroiso Azolyl, tetrahydrofuranyl and Alkyl group.

Preferred values for W, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and X in the compounds of formula I are in any combination, as set forth below : Both W are O; R ₁ is H, trifluoromethyl, cyano, halogen or methyl; R ₂ is H, trifluoromethyl, cyano, methoxy, halogen or methyl; Is a C ₁ -C ₆ haloalkyl or cyano group; R ₃ is H or C ₁ -C ₆ alkyl; R ₄ , R ₅ , R ₆ and R ₇ are each independently hydrogen or methyl; R ₈ is hydrogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or R _{8 is} derived from one or more C ₁ -C ₆ alkoxy a C ₁ -C ₆ alkylthio substituted C ₁ -C ₆ alkyl group; and R ₉ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen.

More preferably, R ₁ is H or methyl. In particular, R ₁ is H.

More preferably, R ₂ is H.

More preferably, X is a trifluoromethyl group or a cyano group. In particular, X is a trifluoromethyl group. In particular, X-based cyano group.

More preferably, R ₃ is H.

Preferably, R ₈ is hydrogen, methyl, ethyl, n-propyl or isopropyl. More preferably, R ₈ is hydrogen, methyl or ethyl. In particular, R ₈ is hydrogen or methyl.

More preferably, R ₉ is H.

In particular, R ₄ , R ₅ , R ₆ and R ₇ are H.

Table 1 below contains examples of compounds of formula (I) wherein W is oxygen and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and X As defined.

The compounds of formula I according to the invention may themselves be used as plant growth regulators or seed germination promoters, but they are usually formulated with plant adjuvants using formulation adjuvants such as carriers, solvents and surfactants (SFA). Or seed germination promotes the composition. Accordingly, the present invention further provides plant growth regulator compositions comprising the plant growth regulating compounds described herein and an agriculturally acceptable formulation adjuvant or carrier. The invention further provides a seed germination promoter composition comprising the seed germination promoter compound described herein and an agriculturally acceptable formulation adjuvant or carrier. Preferably, the composition consists essentially of a compound of formula I and an agriculturally acceptable formulation adjuvant or carrier. In the alternative, the composition consists of a compound of formula I and at least one agriculturally acceptable formulation adjuvant or carrier. In one embodiment, the invention provides a composition comprising a compound of formula I and an agriculturally acceptable carrier, wherein in formula I, W is O; R ₁ is H, trifluoromethyl, cyano, halogen Or methyl; R ₂ is H, methoxy, trifluoromethyl, cyano, halogen or methyl; X-based C ₁ -C ₆ haloalkyl or cyano; R ₃ H or C ₁ -C ₆ Alkyl; R ₄ , R ₅ , R ₆ , and R ₇ are each independently hydrogen or methyl; R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl group, or R ₈ lines by at least one C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio-substituted C ₁ -C ₆ alkyl; and R ₉ lines hydrogen.

In another embodiment, the present invention provides a composition comprising a compound and an agriculturally acceptable carrier comprising a formula I, wherein in formula I, W-based O; R ₁ Department H or methyl; R ₂ lines H X-based trifluoromethyl or cyano; R ₃ H; R ₄ , R ₅ , R ₆ , and R ₇ are each independently hydrogen or methyl; R ₈ is hydrogen or methyl; and R ₉ is hydrogen.

The composition may be in the form of a concentrate that is diluted prior to use, although it may also be formulated as a ready-to-use composition. The final dilution is usually carried out with water, but water may be substituted, or in addition to water, for example, liquid fertilizers, micronutrients, biological organisms, oils or solvents may be used.

The composition typically comprises from 0.1% to 99% by weight, especially from 0.1% by weight. To 95% of the compound of formula I and from 1% to 99.9% by weight of the formulation adjuvant, the formulation adjuvant preferably comprises from 0 to 25% by weight of surface active material.

The compositions may be selected from a variety of formulation types, many of which are from Manual on Development and Use of FAO Specifications for Plant Protection Products, 5th Edition, 1999 Learned. These include spreadable powder (DP), soluble powder (SP), water soluble particles (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release) ), soluble concentrate (SL), oil-miscible liquid (OL), ultra-low volume liquid (UL), emulsifiable concentrate (EC), dispersible concentrate (DC), emulsion (water) Formulations of both oil-in-oil (EW) and water-in-oil (EO), microemulsion (ME), suspension concentrate (SC), aerosol, capsule suspension (CS), and seed treatment. In any event, the type of formulation selected will depend on the particular purpose intended and the physical, chemical and biological properties of the compound of formula (I) or (I').

A sprinkable powder (DP) can be obtained by combining a compound of formula (I) or (I') with one or more solid diluents (for example, natural clay, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, Mixing kieselguhr, chalk soil, diatomaceous earths, calcium phosphate, calcium carbonate and magnesium carbonate, sulfur, lime, flour, talc and other organic and inorganic solid carriers and mechanically mixing the mixture It is prepared by milling into a fine powder.

The soluble powder (SP) may be obtained by reacting a compound of formula (I) or (I') with one or more water-soluble inorganic salts (such as sodium hydrogencarbonate, sodium carbonate or magnesium sulfate) or one or more water-soluble organic solids (such as Polysaccharides) and, optionally, one or more wetting agents, one or more dispersing agents, or a mixture of such agents are prepared to improve water dispersibility/water solubility. The mixture was then ground to a fine powder. Similar compositions can also be granulated to form water soluble particles (SG).

Wettable powder (WP) may be obtained by combining a compound of formula (I) or (I') with one or more solid diluents or carriers, one or more wetting agents, and, preferably, one or more dispersing agents, And, optionally, one or more suspending agents are mixed to prepare to promote dispersion in the liquid. The mixture was then ground to a fine powder. Similar compositions can also be granulated to form water dispersible granules (WG).

Granules (GR) may be formed by granulating a mixture of a compound of formula (I) or (I') with one or more powdered solid diluents or carriers, or by formula (I) or The compound of I') (or its solution in a suitable reagent) is absorbed into a porous particulate material (eg, pumice, attapulgite clay, fuller's earth, kieselguhr, diatomaceous earths, or corncob powder) Or by adsorbing a compound of formula (I) (or a solution thereof in a suitable reagent) onto a hard core material (such as sand, citrate, mineral carbonate, sulfate or phosphate) and if necessary Drying is formed from preformed blank particles. Agents commonly used to aid absorption or adsorption include solvents (eg, aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones, and esters) as well as adhesives (eg, polyvinyl acetate, polyvinyl alcohol, dextrin, sugar, and Vegetable oil). It is also possible to include one or more other additives (such as emulsifiers, wetting agents or dispersing agents) in the granules.

Dispersible concentrates (DC) can be prepared by dissolving a compound of formula (I) or (I') in water or an organic solvent such as a ketone, alcohol or glycol ether. The solvents may comprise a surfactant (for example to improve water dilution or prevent crystallization in a spray tank).

An emulsifiable concentrate (EC) or an oil-in-water emulsion (EW) may be dissolved in an organic solvent (optionally comprising one or more wetting agents, one or more emulsifiers) by dissolving a compound of formula (I) or (I) Or prepared by mixing the reagents). Suitable organic solvents for use in the EC include aromatic hydrocarbons such as alkylbenzenes or alkylnaphthalenes such as SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; registered trademarks of SOLVESSO, ketones such as cyclohexanone or methylcyclohexane. Ketones and alcohols (such as benzyl alcohol, mercapto or butanol), N-alkylpyrrolidone (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl decylamine of fatty acids (e.g., C ₈ -C ₁₀ fatty acid dimethyl decylamine) and chlorinated hydrocarbons. The EC product can be emulsified spontaneously upon addition to water, resulting in an emulsion that is sufficiently stable to allow for application by spraying with a suitable device.

The preparation of EW involves obtaining as a liquid (if it is not a liquid at room temperature, it can be melted at a reasonable temperature typically below 70 ° C) or in solution (by dissolving it in a suitable solvent) A compound of formula (I) or (I'), and then the resulting liquid or solution is emulsified under high shear into water containing one or more SEA to produce an emulsion. Suitable solvents for use in EW include vegetable oils, chlorinated hydrocarbons (e.g., chlorobenzene), aromatic solvents (e.g., alkylbenzenes or alkylnaphthalenes), and other suitable organic solvents having low solubility in water.

Microemulsions (ME) can be prepared by mixing water with a blend of one or more solvents and one or more SFAs to spontaneously produce a thermodynamically stable isotropic liquid formulation. The compound of formula (I) or (I') is initially present in water or in a solvent/SFA blend. Solvents suitable for use in ME include those described above for use in EC or EW. The ME can be an oil-in-water system or a water-in-oil system (which system can be determined by conductivity testing) and can be adapted to mix water-soluble and oil-soluble pesticides in the same formulation. The ME is suitable for dilution into water, remaining as a microemulsion or forming a conventional oil-in-water emulsion.

The suspension concentrate (SC) may comprise an aqueous or non-aqueous suspension of finely divided insoluble solid particles of the compound of formula (I) or (I'). SC may optionally be prepared by ball milling or bead milling of a solid compound of formula (I) or (I') using one or more dispersing agents to produce a fine particle suspension of the compound. One or more humectants may be included in the composition and may include suspension A floater to reduce the settling velocity of the particles. Alternatively, the compound of formula (I) or (I') can be dry milled and added to water containing the reagents described above to produce the desired end product.

The aerosol formulation comprises a compound of formula (I) or (I') and a suitable propellant (e.g., n-butane). The compound of formula (I) or (I') may also be dissolved or dispersed in a suitable medium such as water or a water-miscible liquid such as n-propanol to provide a manual spray pump which is not pressurized. The composition used in the process.

The capsule suspension (CS) can be prepared in a similar manner to the preparation of the EW formulation, except that in addition to the additional polymerization step, an aqueous dispersion of oil droplets is obtained, wherein each oil droplet is encapsulated by a polymer shell and Compounds containing formula (I) or (I') and, optionally, carriers or diluents for this purpose. The polymeric outer shell can be prepared by an interfacial polycondensation reaction or by a coacervation procedure. Such compositions can provide controlled release of the compounds of formula (I) or (I') and they can be used in seed treatment. Compounds of formula (I) or (I') may also be formulated in a biodegradable polymer matrix to provide a slow controlled release of the compound.

The composition may include one or more additives to improve the biological properties of the composition (e.g., by improving wettability, retention or distribution on the surface; rain resistance on the treated surface; formula (I) or ( Absorption or migration of the compound of I'). Such additives include surfactants (SFA), oil-based spray additives, such as certain mineral oils or natural vegetable oils (such as soybean and rapeseed oil), and these and other bio-enhancing adjuvants (which can help or change ( A blend of components of the action of I) or (I').

The humectants, dispersants and emulsifiers can be cationic, anionic, amphoteric or nonionic types of SFA.

Suitable cationic SFAs include quaternary ammonium compounds such as cetyltrimethyl bromide Ammonium), imidazoline and amine salts.

Suitable anionic SFAs include alkali metal salts of fatty acids, salts of fatty acid monoesters (eg, sodium lauryl sulfate), salts of sulfonated aliphatic compounds (eg, sodium dodecylbenzene sulfonate, twelve Calcium alkyl benzene sulfonate, butyl naphthalene sulfonate and sodium sulfonate mixture of diisopropyl and triisopropyl naphthalene), ether sulfate, alcohol ether sulfate (eg, laureth-3) - sodium sulfate), an ether carboxylate (such as sodium laureth-3-carboxylate), a phosphate ester (a product of one or more fatty alcohols reacted with phosphoric acid (mainly monoester) or phosphorus pentoxide The product of the reaction (mainly a diester), such as the reaction between lauryl alcohol and tetraphosphoric acid; in addition, the products may be ethoxylated), sulfosuccinamide, paraffin or olefin sulfonate , aminoethanesulfonate and lignosulfonate.

Suitable SFAs of the amphoteric type include betaine, propionate and glycinate.

Suitable nonionic types of SFA include alkylene oxides (such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof) with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkyl phenols (such as xin a condensation product of a phenol, a nonyl phenol or an octyl cresol; a partial ester derived from a long-chain fatty acid or a hexitol anhydride; a condensation product of the partial ester with ethylene oxide; a block polymer (containing a ring) Oxyethane and propylene oxide; alkanolamine; monoester (such as fatty acid polyethylene glycol ester); amine oxide (such as lauryl dimethyl amine oxide); and lecithin.

Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and expanded clays (such as bentonite or attapulgite).

The invention still further provides a method for modulating plant growth at a locus, wherein the method comprises applying a plant growth regulating amount of the composition according to the invention to the locus. Preferably, the composition is applied to the foliage of the plant by spray application.

The invention also provides methods for promoting seed germination, including to such seeds, or packages The seed-containing locus is applied to a composition according to the invention which promotes the amount of seed germination.

Application is usually carried out by spraying the composition, typically by means of a sprayer for large areas mounted on a tractor, but other methods such as dusting (for powder), dropping or wetting may also be used. Alternatively, the composition can be applied in the furrow or applied directly to the seed prior to planting or at the time of planting.

The compound or composition of the formula (I) or (I') of the present invention can be applied to a plant, a part of a plant, a plant organ, a plant propagation material or a surrounding area thereof.

In one embodiment, the invention relates to a method of treating a plant propagation material comprising applying a composition of the invention to a plant propagation material in an amount effective to promote germination and/or modulate plant growth. The invention further relates to plant propagation material treated with a compound or composition of formula (I) or (I') of the invention. Preferably, the plant propagation material is a seed.

The term "plant propagation material" refers to the reproductive parts of all plants, such as seeds, which can be used for the propagation of the latter as well as vegetative plant materials such as cuttings and tubers. In particular, seeds, roots, fruits, tubers, bulbs and root stems can be mentioned here.

Methods of applying active ingredients to plant propagation materials, particularly seeds, are known in the art and include dressing, coating, granulating, and dipping application methods of the propagation material. This treatment can be applied to the seed at any time between seed harvesting and seed sowing or during sowing. The seed can also be applied before or after the treatment. The compound of formula (I) or (I') can be optionally administered in combination with a controlled release coating or process to facilitate release of the compound over time.

The composition of the present invention can be applied before or after emergence. Suitably, when the composition is used to adjust the growth of a crop plant, it may be applied before or after emergence, but preferably Post-emergence application of crops. When the composition is used to promote seed germination, it can be applied before emergence.

The application rate of the compound of formula (I) can vary widely and depends on the nature of the soil, the method of application (pre-emergence or post-emergence; seed soaking; application to seed furrows; no-till applications, etc.), crop plants, The main climatic conditions, as well as other factors governed by the method of application, the time of application, and the target crop. For application to foliar or moist application, the compounds of formula I according to the invention are generally applied at a rate of from 0.001 to 2000 g/ha, in particular from 0.001 to 400 g/ha. For seed treatment, the application rate is usually between 0.0005 and 150 g per 100 kg of seed.

Plants in which the composition according to the invention may be used include crops such as cereals (for example wheat, barley, rye or oats); beets (for example beets or beets); fruits (for example pears, stone fruits or berries, for example Apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries or blackberries); legumes (eg broad beans, lentils, peas or soybeans); oil plants (eg canola, mustard, poppy, olives, sunflowers, coconuts) , castor oil plant, cocoa or groundnut); melons (such as tender gourd, cucumber or melon); fiber plants (such as cotton, flax, hemp or jute); citrus fruits (such as orange, lemon, grapefruit) Or orange); vegetables (such as spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, gourds or red peppers); medlar (such as avocado, Cinnamon or camphor); corn; rice; tobacco; Nuts; coffee; sugar cane; tea; vines; hops; durian; bananas; natural rubber plants; turf or ornamental plants (eg flowers, shrubs, broadleaf or evergreens such as conifers) ). This list does not represent any restrictions.

The invention can also be used to regulate growth, or to promote seed germination of non-crop plants, for example, to help control weeds by simultaneous germination.

Crops that should be understood also include those that have been modified by conventional breeding methods or by genetic engineering. For example, the present invention can be used in combination with crops that have been rendered tolerant to herbicides or multiple classes of herbicides such as ALS-, GS-, EPSPS-, PPO-, ACC enzymes, and HPPD inhibitors. . An example of a crop that has been rendered tolerant to imidazolinones (e.g., imazamox) by conventional breeding methods is Clearfield® Summer Canola (Corolla). Examples of crops that have been rendered tolerant to a variety of herbicides due to genetic engineering methods include glyphosate and glufosinate resistant corn varieties, which are commercially available under the RoundupReady® and LibertyLink® brand names. of. Methods for conferring tolerance to crop plants to HPPD inhibitors are known, for example, from WO 0246387; for example, crop plant lines are transgenic with respect to polynucleotides, the polynucleotide comprising the coding derived from bacteria (more specifically, from Pseudomonas fluorescens or Shewanella colwelliana ) or from plants (more specifically, derived from monocots or still more specifically from barley, corn, wheat, rice, genus DNA sequence of HPPD inhibitor-resistant HPPD enzymes, Chenchrus , ryegrass, fescue, foxtail, valerian , sorghum or oats species.

Crops are also understood to be those that have been rendered resistant to harmful insects by genetic engineering methods, such as Bt corn (anti-European corn borer) Bt cotton (anti-cotton boll weevil) and Bt potato (anti-Colorado beetle) ). An example of Bt corn is the NK® Bt 176 corn hybrid (Syngenta Seeds). The Bt toxin is a protein naturally formed by Bacillus thuringiensis soil bacteria. Examples of toxins or transgenic plants capable of synthesizing such toxins are described in, for example, EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073, and EP-A-427 529. in. Examples of transgenic plants comprising one or more genes encoding insecticide resistance and expression of one or more toxins are KnockOut® (corn), Yield Gard® (corn), NuCOTIN 33B® (cotton), Bollgard® (cotton), NewLeaf® (potato), NatureGard® and Protexcta®. Both plant crops or seeds can be herbicide resistant and at the same time resistant to insect feeding ("superimposed" transgenic results). For example, the seed material can have the ability to express insecticidal Cry3 protein while being glyphosate resistant.

Crops are also understood to include those obtained by conventional breeding or genetic engineering methods and including so-called output traits (e.g., improved storage capacity, higher nutritional value, and improved aroma).

The compounds of the invention may be in the form of an ester or acid, any of which may have plant growth regulating properties. As suggested in WO 2009/109570, the ester form of the compound of formula (I) is considered to be hydrolyzable to the acid form in plants. This can be a particular advantage when the esterified compound is more readily absorbed by plants (e.g., by leaf tissue).

In another aspect of the invention, the compounds or compositions of the invention may be administered in combination with one or more compounds having a pesticidal action. Such compounds include those having fungicidal, herbicidal, safe, plant growth regulating, insecticidal, nematicidal or acaricidal activity.

In another aspect of the invention, the compounds or compositions of the invention may be administered in combination with one or more other compounds having crop enhancing effects. Such compounds include micronutrients, sugars, amino acids, flavonoids, quinine, and plant activators/growth stimulators. For example, such compounds include natural or synthetic hormones, auxin, brassinosteroid, gibberellin, abscisic acid, cytokines, jasmonic acid, strigolactones, salicylic acid, ethylene , 1-methylcyclopropene, trinexaethyl ester or a derivative thereof. Such compounds also include pesticidal agents having crop enhancing effects, for example, strobilurins (including azoxystrobin, pyraclostrobin), and neonicotinoids (including thiamethoxam, and imidacloprid).

The compounds of the present invention can be prepared by the following methods.

The compound of the formula (I) or (I') can be produced by reacting a compound of the formula (III) with a compound of the formula (II) via deuteration, wherein a Z-based halogen such as chlorine and an R8-based C1-C6 alkyl group, C1-C6 haloalkyl, C1-C6 alkyl (protected or unprotected) substituted by hydroxy or amine, such reaction is usually carried out in the presence of a base and preferably in the presence of a nucleophilic catalyst. Alternatively, it is possible to carry out the reaction in a two-phase system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably sodium bicarbonate solution.

The compound of formula (II) is commercially available, for example, methyl succinate chloride or can be prepared by methods known to those skilled in the art.

Process 2

The compound of the formula (Ia) can be treated in a solvent such as ethanol or tetrahydrofuran in the presence of water, for example, by treating the formula (I) or (I') with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. a compound (wherein R ₈ is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkyl group (protected or unprotected) substituted by a hydroxyl group or an amine) is hydrolyzed under standard conditions. To prepare. Another alternative is to treat the ester of formula (Ia) with an acid such as trifluoroacetic acid in a solvent such as dichloromethane followed by the addition of water. The reaction is preferably carried out at a temperature of from -20 ° C to +100 ° C, more preferably from 20 ° C to 80 ° C, especially at 50 ° C.

Process 3

The compound of formula (I) or (I') can be passed from a compound of formula (Ia) via a deuteration reaction by a coupling agent, for example, DCC ( N,N' -dicyclohexyl-carbodiimide), EDC ( 1-ethyl-3-[3-dimethylamino-propyl]carbodiimide hydrochloride) or BOP-Cl (bis(2-oxo-3-) In the presence of an oxazolidinylphosphine), in the presence of a base such as pyridine, triethylamine, 4-(dimethylamino)pyridine or diisopropylethylamine, and optionally in a nucleophilic catalyst such as It is prepared by reacting an alcohol derivative in the presence of hydroxybenzotriazole.

Alternatively, a compound of formula (I) or (I') can be prepared from a compound of formula (Ib) via a oximation reaction. The deuteration reaction can be carried out under basic conditions (for example, in the presence of pyridine, triethylamine, 4-(dimethylamino)pyridine or diisopropylethylamine) in a suitable solvent such as tetrahydrofuran. It is carried out in the presence of a nucleophilic catalyst. The reaction is carried out at a temperature of from -120 ° C to +130 ° C, preferably from -100 ° C to 100 ° C. Alternatively, the reaction can be carried out in a two-phase system (including an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably sodium bicarbonate In a saturated solution).

Compounds of formula (Ib) can be prepared from compounds of formula (Ia) in a solvent such as dichloromethane under standard conditions, for example with sulfoxide dichloride or chloroform. The reaction is preferably carried out at a temperature of from -20 ° C to +100 ° C, more preferably from 0 ° C to 50 ° C, especially at ambient temperature.

Compounds of formula (Ia) can be prepared by treating a compound of formula (III) by treatment with an anhydride derivative of formula (IV), such as succinic anhydride, in a solvent such as tetrahydrofuran. The reaction is preferably carried out at a temperature of from -20 ° C to +120 ° C, more preferably from 20 ° C to 120 ° C.

a compound of the formula (I) or (I') wherein the X-based aryl, heteroaryl or C ₃ -C ₈ cycloalkyl derivative such as thiophene, vinyl, allyl or cyclopropyl may be borrowed Compounds of formula (Ic) wherein LG is present in the presence of a suitable catalyst/coordination system (typically a palladium (0) conjugate) and in the presence or absence of a base (eg, potassium carbonate) a suitable leaving group such as, for example, a halogen or a triflate salt, and a derivative of the formula ZX (wherein a Z-based boron or tin derivative and X is as defined for formula (I) or (I') The reaction described by the compound) is prepared. These reactions may or may not be carried out under microwave irradiation. Such reactions are known to those skilled in the art under the names of Stille and Suzuki coupling, see, for example, the strategic application of named reactions in organic synthesis (Strategic Applications of Named Reactions in Organic Synthesis); Kurti. Kurti (Laszlo); Cao Ke. Barbara (Czako, Barbara); Editor. USA. (2005), Publisher: Elsevier Academic Press, Burlington, Massachusetts. p.448 (Succhi coupling) and p.438 ( Stiller coupling) and cited references.

Compounds of formula (I) or (I') wherein X-CCR, wherein R-C ₁ -C ₆ alkyl, hydrogen or trialkylsulfonyl, may be employed in a suitable catalyst/coordination system (usually a palladium (0) conjugate with or without a copper source such as cuprous iodide) in the presence and absence of an organic base (eg, diisopropylethylamine), The compound of Ic), wherein LG is a suitable leaving group such as, for example, a halogen or a triflate, is prepared by reacting a derivative of the formula HCCR. The reaction is known to those skilled in the art under the name Sonogashira coupling, see, for example, the strategic application of named reactions in organic synthesis; Curti. Kurti (Laszlo); Cao Ke. Barbara (Czako, Barbara); Editor. USA. (2005), Publisher: Elsevier Academic Press, Burlington, Massachusetts. p. 424 (cococouple) and citations literature.

The compound of the formula (I) or (I') (wherein the X-based CCH) may be a compound of the formula (I) or (I') (wherein the X-based CCSiR ₃ wherein the R-based C1-C6 alkyl group) The reaction is prepared by reaction with a base, such as potassium carbonate or a fluoride source such as potassium fluoride.

A compound of formula (I) or (I') wherein W is sulfur may be derived from a compound of formula (I) or (I') (wherein W is oxygen) by a thiotransfer reagent (eg, lovi) Prepared by treatment with Lawesson's reagent or phosphorus pentasulfide.

Example

The following HPLC-MS method was used to analyze the compounds:

Method A:

The spectra were recorded on a ZQ mass spectrometer (single-phase quadrupole mass spectrometer) from Waters equipped with an electrospray source (polarity: positive or negative, capillary: 3.00 kV, taper: 30.00 V, Extractor: 2.00 V, source temperature: 100 ° C, desolvation temperature: 250 ° C, cone gas flow: 50 L/Hr, desolvated gas flow: 400 L/Hr; mass range: 100 Da to 900 Da) and Agilent (Agilent) 1100 LC (solvent degasser, binary pump, heated column chamber, and diode array detector). Column: Phenomenex Gemini C18, 3 μm, 30 × 3 mm, temperature: 60 ° C; DAD wavelength range (nm): 210 to 500, solvent gradient: A = water + 0.05% formic acid, B = acetonitrile / methanol (4: 1, v: v) + 0.04% formic acid; gradient: 0 min 5% B; -2.8 min 100% B; 2.9-3 min 5%. Flow rate (ml/min) 1.7

Method B:

The spectra were recorded on a ZQ mass spectrometer (single-phase quadrupole mass spectrometer) from Waters equipped with an electrospray source (polarity: positive or negative, capillary: 3.00 kV, taper: 30.00 V, Extractor: 2.00 V, source temperature: 100 ° C, desolvation temperature: 250 ° C, cone gas flow: 50 L/Hr, desolvated gas flow: 400 L/Hr; mass range: 100 Da to 900 Da) and Agilent (Agilent) 1100 LC (solvent degasser, binary pump, heated column chamber, and diode array detector). Column: Phenomenex Gemini C18, 3 μm, 30 × 3 mm, temperature: 60 ° C; DAD wavelength range (nm): 210 to 500, solvent gradient: A = water + 5% methanol + 0.05% formic acid, B = acetonitrile + 0.05% Formic acid; Gradient: 0 min 0% B; 2-2.8 min 100% B; 2.9-3 min 0%. Flow rate (ml/min) 1.7

Method C:

Spectra were recorded on a ZQ mass spectrometer (single-phase quadrupole mass spectrometer) from Waters equipped with an electric sprinkler (polarity: positive or negative, capillary: 3.00 kV, cone range: 30 V) Up to 60 V, extractor: 2.00 V, source temperature: 150 ° C, desolvation temperature: 350 ° C, cone gas flow: 50 L/Hr, desolvated gas flow: 40 0 L/Hr; mass range: 100 Da to 900 Da) and Acquity UPLC from Waters: Binary Pump, Heating Column Chamber, and Diode Array Detector. Solvent degasser, binary pump, heated column chamber and diode array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 × 2.1 mm, temperature: 60 ° C; DAD wavelength range (nm): 210 to 500, solvent gradient: A = water + 5% methanol + 0.05% formic acid, B = Acetonitrile + 0.05% formic acid; Gradient: 0 min 10% B, 90% A; 1.2-1.5 min 100% B; flow rate (ml/min) 0.85

Method D:

Spectra were recorded on an SQD mass spectrometer (single-phase quadrupole mass spectrometer) from Waters equipped with an electric sprinkler (polarity: positive or negative, capillary: 3.00 kV, cone range: 30 V) Up to 60 V, extractor: 2.00 V, source temperature: 150 ° C, desolvation temperature: 250 ° C, cone gas flow: 0 L/Hr, desolvated gas flow: 650 L/Hr; mass range: 100 Da to 900 Da) and Acquity UPLC from Waters: Binary Pump, Heating Column Chamber, and Diode Array Detector. Solvent degasser, binary pump, heated column chamber and diode array detector. Column: Phenomenex Gemini C18, 3 μm, 30 × 2 mm, temperature: 60 ° C; DAD wavelength range (nm): 210 to 500, solvent gradient: A = water + 5% methanol + 0.05% formic acid, B = acetonitrile + 0.05% Formic acid; Gradient: Gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; flow rate (ml/min) 0.85

Method E:

The same conditions used for Method C except that the spectrometer is: SDQ mass spectrometer (single phase quadrupole mass spectrometer) from Waters

Method F:

Spectra were recorded on a Waters (SDQ or ZQ single-phase quadrupole mass spectrometer) mass spectrometer equipped with an electrospray source (polarity: positive or negative, capillary: 3.00 kV, cone: 30 -60 V, extractor: 2.00 V, source temperature: 150 ° C, desolvation temperature: 350 ° C, cone gas flow: 0 L/Hr, desolvated gas flow: 650 L/Hr; mass range: 100 Da to 900 Da) and Acquity UPLC from Waters: Binary pump, heated column chamber and two poles Body array detector). Solvent degasser, binary pump, heated column chamber and diode array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 × 2.1 mm, temperature: 60 ° C; DAD wavelength range (nm): 210 to 500, solvent gradient: A = water + 5% methanol + 0.05% formic acid, B = acetonitrile + 0.05% formic acid; Gradient: Gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; flow rate (ml/min) 0.85

The following abbreviations are used throughout this section: s = single peak; bs = broad peak; d = doublet; dd = doublet; dt = double triplet; t = triplet; tt = triplet; = quartet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; Mp = melting point; RT = residence time; [M + H] ⁺ = molecular cation (eg , measured molecular weight).

Synthesis of intermediates:

Example I: Preparation of 6-Amino-5-methoxy-pyridine-3-carbonitrile

Add cyanide to a solution of 5-bromo-3-methoxy-pyridin-2-amine (3.00 g, 14.8 mmol) in N,N -dimethylformamide (55 mL) under nitrogen. Zinc (II) (2.78 g, 23.6 mmol) and tetrakis(triphenylphosphine)palladium (0) (2.06 g, 1.77 mmol). The reaction mixture was stirred at 100 ° C for 4 h. The reaction mixture was diluted with ethyl acetate and washed successively with aq. Separate the phases. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / cyclohexane: 1:5) to give 6-amino-5-methoxy-pyridine-3-carbonitrile (1.2 g, 54%) Yield). ¹ H NMR (400 MHz, CDCl ₃ ): 7.99 (s, 1H), 6.99 (s, 1H), 3.88 (s, 3H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ): 152.83, 144.58, 141.27, 118.32, 115.52, 97.66, 55.65. LC-MS (Method B): RT 0.69, 150 (M+H ⁺ )

The following compounds were prepared by the same procedure using the commercial or illustrated starting aminopyridine: 6-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (also commercially available): Starting material for A42

Example II: 4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A1

6-Amino-3-cyanopyridine (commercially available, 0.470 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), then N,N -dimethylaniline (0.5 mL, 1.0 eq. And methyl 4-chloro-4-oxo-butyrate (0.54 mL, 1.1 eq.). The mixture was refluxed for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butyric acid Ester A1 (71%). Mp = 161 ° C - 164 ° C. ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19,234 (M+H ⁺ )

The following compounds from Table A or B were prepared by the same procedure using the commercial or illustrated starting aminopyridine: 4-[(3-cyano-5-iodo-2-pyridyl)amino]- 4-sided oxygen-butyric acid methyl ester A3

4-[(3-Bromo-5-chloro-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A5

4-[(5-bromo-3-methoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A6

4-[(5-Cyano-3-methoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A7

4-[(5-bromo-3-chloro-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester A8

4-[(5-Cyano-4,6-dimethyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A9

4-[(3-chloro-5-cyano-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A10

4-[(3,5-Dichloro-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A11

4-oxo-4-[(3,5,6-trichloro-2-pyridyl)amino]butyric acid methyl ester A12

4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid ethyl ester A22 , 4-chloro-4-oxo-butyric acid ethyl ester by the same method Replacement of methyl-4-chloro-4-oxo-butyrate synthesis

4-sided oxo-4-[[5-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-pyridyl]amino]butyric acid methyl ester A24

4-[(5-Bromo-6-methoxy-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester A26

4-[(5-Methylsulfanyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A29

4-[(5-methoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A30

4-[(5-chloro-4-ethoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A31

4-[(5-Ethyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A33

4-[(5-Cyano-6-methyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A35

4-[(5-Cyano-2-pyridyl)amino]-2,2-dimethyl-4-oxo-butyric acid methyl ester B1, using acid chloride and a drop of DMF to produce acid chloride After the analog, commercial 2,2'-dimethylsuccinate methyl ester was used as a reactant

6-[(4-Methoxy-4-oxo-butenyl)amino]pyridine-3-carboxylic acid methyl ester A37

4-[(5-Bromo-4-ethoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A38

4-[[5-Cyano-3-(trifluoromethyl)-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester A42

4-[[5-bromo-3-(trifluoromethyl)-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester A44

4-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester A46

4-[(5-Cyano-3-methyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A48

4-[(5-Bromo-6-chloro-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester A49

4-[(5-nitro-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A55

4-[(5-Methanesulfonyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A56

4-[(5-chloro-4-methoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A57

4-[(5-chloro-6-methoxy-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester A58

4-[(5-Bromo-4-methoxy-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A59

4-sided oxo-4-[[5-(1,1,2,2,2-pentafluoroethyl)-2-pyridyl]amino]butyric acid methyl ester A60 , used as a starting material 5-- 1,1,2,2,2-pentafluoroethyl)pyridin-2-amine (Example X)

4-[(5-Mexyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A76

Example III: 4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid A2

6-Amino-3-cyanopyridine (commercially available, 1.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL) then succinic acid anhydride (1.04 g, 10.5 mmol). Stir at °C for 12 h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridinyl) Butyric acid A2 (0.325 g, 18%). ^{Mp = 220 ℃ -221 ℃, 1} H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 11.04 (s, 1H), 8.78 (s, 1H), 8.21 (m, 2H), 2.69 ( t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (MH ⁺ )

The following compounds from Table A were prepared by the same procedure: 4-[(5-bromo-3-chloro-2-pyridyl)amino]-4-oxo-butyric acid A13

4-[(5-Cyano-4,6-dimethyl-2-pyridyl)amino]-4-oxo-butyric acid A14

4-[(5-Cyano-3-methoxy-2-pyridyl)amino]-4-oxo-butyric acid A15

4-sided oxy-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butyric acid A19

4-[(5-bromo-6-methyl-2-pyridyl)amino]-4-oxo-butyric acid A21

4-[(5-bromo-3-methoxy-2-pyridyl)amino]-4-oxo-butyric acid A43

4-[[5-bromo-3-(trifluoromethyl)-2-pyridinyl]amino]-4-oxo-butyric acid A45

4-[[3-chloro-5-(trifluoromethyl)-2-pyridyl]amino]-4-oxo-butyric acid A47

Example IV: 4-[(3-Cyano-5-iodo-2-pyridyl)amino]-4-oxo-butyric acid A4

Add lithium hydroxide (0.058 g, 1.0 eq.) to 4-[(3-cyano-5-iodo-2-pyridyl)amino]-4-oxo-butyric acid methyl ester at ambient temperature (implementation) Example I, A3 , 0.500 g, 1.0 eq.) in a mixture of tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room temperature for 3 h. The residue was diluted with a saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (concentrated) and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated in vacuo over magnesium sulfate to give the desired compound A4 (23.4%). ^{Mp = 215 ℃ -218 ℃, 1} H NMR (400 MHz, DMSO-d6) δ 12.22 (bs, 1H), 10.98 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 2.72 ( t, 2H), 2.55 (m, 2H) ppm. LC-MS (Method A): RT 1.08, 344 (MH ⁺ )

The following compounds from Table A or B were prepared by the same procedure: 4-oxo-4-[(3,5,6-trichloro-2-pyridyl)amino]butyric acid A16

4-[(3,5-Dichloro-2-pyridyl)amino]-4-oxo-butyric acid A17

4-[(3-bromo-5-chloro-2-pyridyl)amino]-4-oxo-butyric acid A18

4-sided oxo-4-[[5-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-pyridyl]amino]butyric acid A25

4-[(5-bromo-6-methoxy-2-pyridyl)amino]-4-oxo-butyric acid A27

4-[(5-methylsulfanyl-2-pyridyl)amino]-4-oxo-butyric acid A28

4-[(5-chloro-4-ethoxy-2-pyridyl)amino]-4-oxo-butyric acid A32

4-[(5-Cyano-6-methyl-2-pyridyl)amino]-4-oxo-butyric acid A36

4-[(5-Cyano-2-pyridyl)amino]-2,2-dimethyl-4-oxo-butyric acid B2

4-[(5-bromo-4-ethoxy-2-pyridyl)amino]-4-oxo-butyric acid A39

4-[(5-bromo-6-chloro-2-pyridyl)amino]-4-oxo-butyric acid A50

4-[(5-chloro-4-methoxy-2-pyridyl)amino]-4-oxo-butyric acid A61

4-[(5-chloro-6-methoxy-2-pyridyl)amino]-4-oxo-butyric acid A62

4-[(5-bromo-4-methoxy-2-pyridinyl)amino]-4-oxo-butyric acid A63

4-sided oxo-4-[[5-(1,1,2,2,2-pentafluoroethyl)-2-pyridyl]amino]butyric acid A64

Example V: 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butyric acid methyl ester A20

4-Phenoxy-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butyric acid (Example II, A19 , 50 mg, 0.19 mmol) and trimethyl orthoformate (60.7) Mg, 3 eq.) was dissolved in methanol (4 mL) and sulphur sulphur dichloride (68.1 mg, 3 eq.) was added dropwise. The reaction was stirred at room temperature for 3 h. The solvent was evaporated and the crude extract Dowex 1 × 8 OH treatment, to obtain side 4- oxo-4 - [[5- (trifluoromethyl) -2-pyridinyl] amino] butanoate A20 (36 mg, 69%). ¹ H NMR (400 MHz, CDCl ₃ ): 2.77 (s, 4H), 3.73 (s, 3H), 7.91 (dd, 1H), 8.33 (d, 1H), 8.54 (s, 1H), 8.59 (s, 1H).

Example VI: 4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid benzyl ester A23

4-Benzyloxy-4-oxo-butyric acid (commercially available, 2.097 g, 10.1 mmol, 1.2 eq.) was dissolved in dichloromethane then EtOAc (2.sub.3 g, 1.4 mL, 16.8 mmol) , 2.0 equivalents) and one drop of N,N -dimethylformamide. The solution was stirred at room temperature for 1 h and then refluxed for 1 h. The solvent was removed and dried by vacuum. The residue was dissolved in 30 mL of THF (hexanes) (yield: THF (30 mL) and pyridine (1.99 g, 2.03 mL, 25.2 mmol, 3.0 eq.) of 6-aminopyridine-3-carbonitrile ( Commercially available, 1.00 g, 8.39 mmol, 1.0 eq.). The solution was refluxed for 4 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give 4-[(5-cyano-2-pyridyl)amino]-4- Benzyl oxy-butyrate A23 (2.49 g, 96%). LC-MS (Method A): RT 1.58, 310 (MH ⁺ ), 308 (MH ⁺ ).

Example VII: 4-Phenoxy-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butyric acid benzyl ester (Compound A34)

Thionylene dichloride (3 equivalents, 2.29 mmol, 0.169 mL) was added dropwise to a solution of benzyl alcohol (3 mL). After 5 min, 4-sided oxy-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butyric acid A19 (prepared as previously described, 201 mg, 0.766) was added to the solution. Mm). The reaction mixture was stirred at room temperature overnight. The reaction was stopped and the solution was partitioned between a saturated solution of ethyl acetate and sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with water (x2) and brine. Water was added until the above ester precipitated to remove benzyl alcohol. The ester was filtered and washed with water and hexanes (20 mL). The residue was first dissolved in ethyl acetate and then precipitated with cyclohexane and the obtained solid was filtered to give 4-y. Amino]benzyl butyrate A34 (32%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.7 (s, 1H), 8.31 (m, 1H), 8.22 (bs, 1H), 7.90 (m, 1H), 7.35 (m, 5H), 5.15 (s, 2H) ), 2.78 (m, 4H) ppm.

Compounds A51, A52, A53, A54, A73, A74, A78, A79, A80 and A81 from Table A were prepared by the same method using the corresponding alcohol.

Example VIII: Methyl 4-oxo-4-[(5-vinyl-2-pyridyl)amino]butanoate (Compound A40)

Add to a solution of 4-[(5-bromo-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester (commercially available, 0.25 g, 0.871 mmol) in toluene (10 mL) Palladium, triphenylphosphine (0.101 g, 0.0871 mmol) and tributyl(vinyl)stannane (0.33 g, 0.30 mL, 1.04 mmol). The reaction mixture was refluxed overnight. Then, 0.05 eq of palladium triphenylphosphine and 0.6 eq of tutyl vinylstannane were added. The volatile components were removed in vacuo and the residue taken up in acetonitrile. The acetonitrile phase was washed twice with hexanes and concentrated in vacuo. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give 4-oxo-4-[(5-vinyl-2-pyridyl)amine. Methyl butyrate (Compound A40 ) (0.20 g, 15%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.26 (s, 1H), 8.19 (sb, 1H), 8.15 (m, 2H), 7.76 (m, 1H), 6.65 (m, 1H), 5.34 (d, 1H) ), 5.30 (d, 1H), 3.72 (s, 3H), 2.75 (m, 4H) ppm.

Example IX: 4-[(5-ethynyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester (Compound A41) Step 1: 4-oxo-4-[[5-(2-trimethyldecylethynyl)-2-pyridyl]amino]butyrate methyl ester

To a solution of 4-[(5-bromo-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester (commercially available, 0.25 g, 0.871 mmol) in tetrahydrofuran, bis(triphenylbenzene) Palladium (II) (61.7536 mg, 0.087 mmol), copper (I) iodide (16.6 mg, 0.087 mmol), triethylamine (889 mg, 1.23 mL, 8.70 mmol) and ethynyl Methyl decane (130 mg, 0.19 mL, 1.30 mmol). The reaction mixture was stirred at 65 ° C overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to afford 4-y. Methyl-2-pyridyl]amino]butyrate (26 mg, 10% yield). ¹ H NMR (400 MHz, CDCl ₃ ) 8.39 (s, 1H), 8.14 (m, 2H), 7.74 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H), 0.24 (s, 9H) )ppm.

Step 2: 4-[(5-ethynyl-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A41

To a solution of methyl 4-oxo-4-[[5-(2-trimethyldecylethynyl)-2-pyridyl]amino]butanoate (26 mg, 0.085 mmol) in methanol Potassium carbonate (5.90 mg, 0.042 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 4 - [(5-ethynyl-2-pyridyl) amino] -4-oxo-side - butyric acid methyl ester A41 (12 mg , 60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) 8.39 (d, 1 H), 8.16 (m, 2H), 7.77 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H) ppm.

Example X: 5-(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine

To a solution of a mixture of 2-aminopyridine (25.0 g, 263 mmol) in water (250 ml) and tris-butylmethyl ether (25 ml), EtOAc (80 g, 315 mmol), sodium bisulfite (64.6 g, 26 ml, 315 mmol), sodium bicarbonate (26.5 g, 315.6 mmol) and tetrabutylammonium hydrogen sulfate ("TBAHS") (0.11 equivalent, 9.92 g, 28.9 mmol) ). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was filtered and the filtrate was extracted twice with tri-n-butyl methyl ether. The combined organic phases were washed sequentially with water, aq. The residue was purified by flash chromatography (ethyl acetate /hexane) to give 5-(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine 7%. ¹ H NMR (400 MHz, CDCl ₃ ) 8.23 (d, 1H), 7.61 (d, 1H), 6.72 (m, 1H), 5.04 (sb, 2H, NH ₂ ) ppm. The main by-product is 3,5-di(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine.

Example XI: 4-Phenoxy-4-[[5-(1H-tetrazol-5-yl)-2-pyridyl]amino]butyric acid methyl ester A65

4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid methyl ester A1 (0.200 g, 0.857 mmol), sodium azide (0.169 g, 0.09 mL, 2.57 mmol) A mixture of triethylammonium chloride (0.187 g, 0.17 ml, 1.33 mmol) was stirred in 1-methyl-2-pyrrolidone (10 mL) at 150 ° C for 4 h.

The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1 N), the filtrate was extracted twice with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to give 4-yt-oxy-4-[[5-(1H-tetraazol-5-yl)-2-pyridinyl]amino]butyric acid methyl ester A65 (0.06 g, 25% yield). Mp: 246 ° C - 248 ° C, LC-MS (Method F): RT 0.53, 277 (M+H ⁺ ).

Example XII: 4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid butyl ester A66

Thionylene dichloride (2.73 mmol, 0.200 mL, 3 eq) was added dropwise to a solution of butan-1-ol (3 mL). After 5 min, 4-[(5-cyano-2-pyridinyl)amino]-4-oxo-butyric acid A2 (prepared as above, 200 mg, 0.912 mmol) was added to this solution. The reaction mixture was stirred at room temperature overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate. The residue was first washed with cyclohexane, and the obtained solid was purified by flash chromatography eluting with hexane-ethyl acetate to afford 4-[(5- cyano-2-pyridyl) Amino]-4-oxo-butyl butyrate A66 (10%) and by-product 6-[(4-butoxy-4-oxo-butanyl)amino]pyridine-3-carboxylic acid butyl ester A67 (9%).

4-[(5-Cyano-2-pyridinyl)amino]-4-oxo-butyric acid butyl ester A66 ; LC-MS (Method F) RT 0.89, 276 (M+H ⁺ ).

6-[(4-Butoxy-4-oxo-butanyl)amino]pyridine-3-carboxylic acid butyl ester A67 ; LC-MS (Method F) RT: 0.11, 351 (M+H ⁺ ).

Example XIII: 4-[(5-Cyano-2-pyridyl)-methyl-amino]-4-oxo-butyric acid methyl ester A68

To 4-[(5-Cyano-2-pyridyl)amino]-4-oxo-butyric acid A2 (prepared as above, 200 mg, 0.857 mmol, 1 eq.) in acetonitrile (5 mL) Methyl iodide (10 equivalents, 8.57 mmol, 0.534 mL) and sodium hydride (1 eq, 0.857 mmol, 0.037 mL) were added to the solution. The reaction mixture was stirred at room temperature overnight. The next day, 1 equivalent of sodium hydride (34.3 mg) was added to increase the amount of product and the mixture was stirred at room temperature for 1 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo. The obtained solid was purified by flash chromatography eluting with cyclohexane-ethyl acetate, and then dissolved in ethyl acetate and precipitated with cyclohexane. After cooling with ice/water, the precipitated solid was filtered to give 4-[(5-cyano-2-pyridyl)-methyl-amino]-4-oxo-butyric acid methyl ester A68 (45%) ). ¹ H NMR (400 MHz, CDCl ₃ ) 8.69 (s, 1H), 7.90 (m, 2H), 3.71 (s, 3H), 3.52 (s, 3H), 2.92 (m, 2H), 2.71 (m, 2H) )ppm.

Compound A69 from Table A was prepared by the same method using the corresponding alkylating agent.

Example XIV: 4-[[5-(Difluoromethyl)-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester A77

A suspension of methyl 4-[(5-methylamido-2-pyridinyl)amino]-4-oxo-butyric acid A76 (0.09 g, 0.381 mmol, 1 eq.) in toluene (6 mL) It was heated at 80 ° C overnight in the presence of deoxy-fluorine (50% by mass). The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo. The obtained solid was purified by flash chromatography (FC) eluting with gradient cyclohexane-ethyl acetate to give 4-[[5-(difluoromethyl)-2-pyridinyl]amino] -4- Side Oxygen-butyric acid methyl ester A77 (52%). LC-MS (Method F): RT 0.71, 259 (M+H ⁺ ).

Example XV: 4-sided oxo-4-[[5-(2-thienyl)-2-pyridyl]amino]butyric acid methyl ester A71 and 4-sided oxy-4-[[5-(2- Thienyl)-2-pyridyl]amino]butyric acid A72

The microwave tube is charged with 4-[(5-bromo-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester (commercially available or as described in Example II) The starting material was commercially available 5-bromo 2-aminopyridine: 200 mg, 0.696 mmol, 1 equivalent of prepared, 2-thienylboronic acid (3 equivalents, 2.09 mmol, 3 equivalents), two (three-three grades) Butyl phosphine) palladium (0) (22 mg, 0.043 mmol, 0.06 eq.), potassium carbonate (179 mg, 1.28 mmol, 1.8 eq.) and dissolved in dimethyl ether (5 ml) / water (2 ml) . The reaction mixture was heated at 130 ° C for 20 minutes under microwave. The reaction was stopped and the solution was partitioned between ethyl acetate and basic water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo. The obtained solid was purified by flash chromatography eluting with gradient cyclohexane-ethyl acetate to give 4-oxo-4-[[5-(2-thienyl)-2-pyridinyl]amine Methyl]-butyric acid A71 (8%). %). LC-MS (Method F): RT 0.85, 291 (M+H ⁺ ).

The aqueous layer was acidified with hydrogen chloride to pH 1-2 and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo. The solid was washed with ethyl acetate, filtered and dried to give 4-t-[upta][sup.sup.sup.sup.[[5-(2-thienyl)-2-pyridinyl]amino]butyric acid A72 (31% yield) . %). LC-MS (Method F): RT 0.74, 277 (M+H ⁺ ).

Example XVI: 4-[[5-(5-methyl-1,2,4- Azoxa-3-yl)-2-pyridyl]amino]-4-oxo-butyric acid methyl ester A75 Step 1: 4-[[5-[(Z)-N'-hydroxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butyric acid methyl ester

Add 4-[(5-cyanide) to a solution of sodium bicarbonate (1.81 g, 21.4 mmol, 5 eq.) and hydroxylamine hydrochloride (1.50 g, 21.4 mmol, 5 eq.) in water (12 mL). A solution of benzyl-2-pyridyl)amino]-4-oxo-butyric acid A2 (1.00 g, 4.29 mmol, 1 eq.) in methanol (120 mL). The solution was heated to 80 ° C overnight before concentration under vacuum. The residue was partitioned between EtOAc (50 mL)EtOAc. The aqueous layer was separated and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo to afford 760 mg of crude. The crude product was adsorbed onto the isolute by flash chromatography eluting with gradient methanol and dichloromethane (0 to 10% in methanol) to give 4-[[5-[(Z)- Methyl N'-hydroxymethylindenyl]-2-pyridinyl]amino]-4-oxo-butyrate (0.46 g, 1.73 mmol, 40% yield).

Step 2: 4-[[5-[(Z)-N'-Ethyloxymethylindenyl]-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester

To 4-[[5-[(Z)-N'-hydroxymethylindenyl]-2-pyridyl]amino]-4-oxo-butyric acid methyl ester (as obtained in step 1, Acetic anhydride (1.98 mL, 20.3 mmol, 36 eq.) was added to a suspension of dichloromethane (30 mL). The mixture was stirred for 5 days before concentration under vacuum to give 4-[[5-[(Z)-N'-acetoxymethoxymethyl]-2-pyridyl]amino]-4- The side oxy-butyric acid methyl ester was used in the next step without additional purification.

Step 3: 4-[[5-(5-Methyl-1,2,4- Azoxa-3-yl)-2-pyridyl]amino]-4-oxo-butyric acid methyl ester A75

4-[[5-[(Z)-N'-Ethyloxymethylindenyl]-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester (at the step) To a solution of tetrabutylammonium fluoride (0.13 g, 0.058 mL, 0.058 mmol, 0.1 eq. Mol/L). The mixture was stirred at room temperature for 4 h. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography eluting with gradient ethyl acetate and cyclohexane to afford 4-[[5-(5-methyl-1,2,4- Moxazol-3-yl)-2-pyridinyl]amino]-4-oxo-butyric acid methyl ester A75 (0.062 g, 37% yield). LC-MS (Method F): RT 0.72, 291 (M+H ⁺ ).

Example XVII: 4-oxo-4-[[5-(3-pyridyl)-2-pyridyl]amino]butyric acid methyl ester A82

4-[(5-Bromo-2-pyridinyl)amino]-4-oxo-butyric acid methyl ester (commercially available or as described in Example II) in a microwave vial The material was dissolved in toluene with commercially available 5-bromo-2-aminopyridine: 200 mg, 0.697 mmol), and 3-pyridyltributylstannane (0.836 mmol, 0.290 mL) and tetrakis(triphenyl) were added. Phosphine) palladium (0) (0.069 mmol). Argon was bubbled through the mixture for about 5 min and the vial was heated under microwave irradiation for 10 min at 150 °C. The solvent was evaporated and the residue was diluted with EtOAc EtOAc (EtOAc) The product was purified by flash chromatography (RF-EtOAc, EtOAc/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc Methyl-2-pyridyl]amino]butyrate (Compound A82 ) (0.051 g, 26% yield). LC-MS (Method F): RT 0.50, 286 (M+H ⁺ ).

Compounds A83 , A84 and A85 from Table A were prepared by the same method using the corresponding coupling agents.

Biological example

Two biological assays were performed to facilitate determination of the activity of the compounds of the invention. In the first assay, the activity of the compound is quantified in the bean based on its effect on the elongation of the petiole of the second leaf. In the second assay, the effect of the compound on root growth of wheat was determined.

Example B1: Bean Determination

Fulvio, a French bean (Nut. bean) variety, is sown in sandy loam in a 0.5 liter pot without the need for additional fertilizer. Plants were grown under greenhouse conditions at 22 ° C / 18 ° C (day / night) and 80% relative humidity; light compensation exceeded 25 kLux.

After eleven days of sowing, when the second internode length was 2-5 mm, the plants were treated with the test compound. Prior to application, the compounds were each dissolved in dimethyl hydrazine and diluted in a mixture of lanolin oil and acetone (by volume, ratio 1:2). Pipette five microliters of test compound to the wound formed after the base of the second internode to remove the bract leaf. Fourteen days of application Thereafter, the length of the petiole of the second leaf (measured from the base of the petiole to the base of the first leaflet) was determined to quantify the activity of the compound.

The following compounds give an increase in the length of the petiole of at least 10% of the second leaf: A19, A2, A1, A4, A23, A31, A32, A38, A39, A52, A54, B2.

Example B2: Determination of wheat

The test compound was dissolved in a small volume of dimethyl hydrazine and diluted with water to the appropriate concentration. The seeds of the wheat (common wheat) variety Arina were sown in a mini pouch (10.5 x 9.0 cm) containing 5 mL of the appropriate compound solution. The mini pouch was stored at 17 ° C for 3 days to enable the seeds to germinate. The plants were then stored at 5 °C. After 12 days of sowing/administration, the plants were removed from the micro pouch and scanned. The action of this compound was quantified by determining the area of the plants (roots and shoots) and the curl of the roots (an indicator of the activity of the coiled brassinolide type).

The following compounds reduced the area of plants (roots and shoots) by at least 15% and showed the phenotype of the curled roots: A19, A2, A1, A22, A31, A32, A38, A39, A52, A54.

Claims (10)

a compound of formula (I), Wherein each W is independently O or S; R ₁ , R ₂ , and R _{9 are} independently H, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, cyano, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more hydroxyl or amine; X-based halogen, C ₁ -C ₆ haloalkyl, cyano, thiocyanate, nitro, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ - C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, amine , NC ₁ -C ₆ alkylamine, N,N-di-C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkane Oxycarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₃ -C ₈ cycloalkyl, indolyl, fluorenyl; or X-based heteroaryl or consisting of one or more halogens, cyano, C ₁ -C ₃ An alkyl group, a C ₁ -C ₃ haloalkyl substituted heteroaryl group; and the condition is that when X is a halogen, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, two Each of W is oxygen, and R ₈ is hydrogen, methyl, ethyl, propyl or hydroxy by one or two a C ₂ -C ₃ alkyl group substituted by a halogen or an amine, further R ₁ is not hydrogen, C ₁ -C ₂ alkyl or a C ₂ alkyl group substituted by one or two halogen, hydroxy or amine; R ₃ Hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl; or R ₃ consists of one or more cyano groups, Amine, carbonylamine substituted C ₁ -C ₆ alkyl; R ₄ , R ₅ , R ₆ and R _{7 are} independently hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, hydroxy, -OC(O)R ₁₀ , amine, NC ₁ -C ₆ alkylamine or N,N-di-C ₁ -C ₆ alkylamine; R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ - C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ alkylcycloalkyl, aryl or aryl substituted by one to five substituents R ₁₁ , heteroaryl or from one to five a heteroaryl group substituted with a substituent R ₁₁ , a heterocyclic group or a heterocyclic group substituted with one to five substituents R ₁₁ ; or R ₈ is a C ₁ -C ₆ alkyl group substituted by one or more of the following: cyanide Base, nitro, amine, NC ₁ -C ₆ alkylamine, N,N-di- C ₁ -C ₆ alkylamine, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C _1- C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, aryl or An aryl group substituted with one to five substituents R ₁₁ , a heteroaryl group or a heteroaryl group substituted with one to five substituents R ₁₁ , a heterocyclic group or a heterocyclic group substituted with one to five substituents R ₁₁ ; ₁₀ series hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl; and each R _{11 is} independently cyano, nitro, amine, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl , C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ halocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkyl Sulfosyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, N -C ₁ -C ₆ alkylamino, N , N -di-(C ₁ -C ₆ alkyl)-amino, N , N -di-(C ₁ -C ₆ alkyl)-aminocarbonyl, N , N -di- (C ₁ -C ₆ alkyl)-aminosulfonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C _{a 6} alkylcarbonylamino group; or a salt or N-oxide thereof; excluding the following compounds, wherein X is a trifluoromethyl group, R ₁ is a chlorine group, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, and both W are oxygen; X is chlorine or bromine, R1, R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, R _{a 4-} line amine, and both W are oxygen; X is iodine or bromine, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, and R ₂ and R ₈ are methyl, And both W are oxygen; X is bromine, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, R ₃ is ethyl, R ₈ is methyl, and two W is oxygen; and X is a nitro group, an NC ₁ -C ₆ alkylamine or an N,N-di-C ₁ -C ₆ alkylamine, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are hydrogen, and both W are oxygen. The compound of claim 1, wherein W is O; R ₁ is H, trifluoromethyl, cyano, halogen or methyl; R ₂ is H, trifluoromethyl, cyano, halogen or Methyl; X-based C ₁ -C ₆ haloalkyl or cyano; R ₃ H or C ₁ -C ₆ alkyl; R ₄ , R ₅ , R ₆ and R ₇ are each independently hydrogen or methyl; R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; or R _{8 is} derived from one or more C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylthio substituted C ₁ -C ₆ alkyl; and R ₉ is hydrogen. The compound of claim 2, wherein X is a trifluoromethyl group or a cyano group. The compound of any one of claims 1 to 3 wherein R ₈ is hydrogen, methyl, ethyl, n-propyl or isopropyl. The compound of claim 4, wherein R ₈ is hydrogen. A plant growth regulator or composition for promoting seed germination, comprising a compound according to formula (I'), and an agriculturally acceptable formulation adjuvant, formula (I') Wherein each W is independently O or S; R ₁ , R ₂ , and R _{9 are} independently H, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, cyano, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more hydroxyl or amine; X-based halogen, C ₁ -C ₆ haloalkyl, cyano, thiocyanate, nitro, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ - C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, amine , NC ₁ -C ₆ alkylamine, N,N-di-C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkane Oxycarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₃ -C ₈ cycloalkyl, indolyl, fluorenyl; or X-based heteroaryl or consisting of one or more halogens, cyano, C ₁ -C ₃ An alkyl group, a C ₁ -C ₃ haloalkyl substituted heteroaryl group; and the condition is that when X is a halogen, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ are hydrogen, two Each of W is oxygen, and R ₈ is hydrogen, methyl, ethyl, propyl or hydroxy by one or two a C ₂ -C ₃ alkyl group substituted by a halogen or an amine, further R ₁ is not hydrogen, C ₁ -C ₂ alkyl or a C ₂ alkyl group substituted by one or two halogen, hydroxy or amine; R ₃ Hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl; or R ₃ consists of one or more cyano groups, Amine, carbonylamine substituted C ₁ -C ₆ alkyl; R ₄ , R ₅ , R ₆ and R _{7 are} independently hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, hydroxy, -OC(O)R ₁₀ , amine, NC ₁ -C ₆ alkylamine or N,N-di-C ₁ -C ₆ alkylamine; R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ - C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ alkylcycloalkyl, aryl or aryl substituted by one to five substituents R ₁₁ , heteroaryl or from one to five a heteroaryl group substituted with a substituent R ₁₁ , a heterocyclic group or a heterocyclic group substituted with one to five substituents R ₁₁ ; or R ₈ is a C ₁ -C ₆ alkyl group substituted by one or more of the following: cyanide Base, nitro, amine, NC ₁ -C ₆ alkylamine, N,N-di- C ₁ -C ₆ alkylamine, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C _1- C ₆ alkylsulfinyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, aryl or An aryl group substituted with one to five substituents R ₁₁ , a heteroaryl group or a heteroaryl group substituted with one to five substituents R ₁₁ , a heterocyclic group or a heterocyclic group substituted with one to five substituents R ₁₁ ; ₁₀ series hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl; and each R _{11 is} independently cyano, nitro, amine, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl , C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ halocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, C ₁ -C ₆ alkyl Sulfosyl, C ₁ -C ₆ haloalkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, N -C ₁ -C ₆ alkylamino, N , N -di-(C ₁ -C ₆ alkyl)-amino, N , N -di-(C ₁ -C ₆ alkyl)-aminocarbonyl, N , N -di- (C ₁ -C ₆ alkyl)-aminosulfonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonylamino; or a salt or N-oxide thereof; excluding the following compounds, wherein X is a nitro group, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ R ₉ is hydrogen, and both W are oxygen. A method for regulating plant growth at a site, wherein the method comprises applying a plant growth regulating amount to a compound according to formula (I') as defined in claim 6 of the patent application, or as claimed The composition of claim 6. A method for promoting seed germination, comprising applying a compound according to formula (I') as defined in claim 6 to the seed, or a locus containing the seed, or as applying The composition of claim 6 of the patent scope. A method for controlling weeds comprising applying a compound according to formula (I') as defined in claim 6 of the scope of application for promoting seed germination to a site containing seeds, or as in claim 6 The composition described allows seed germination and then the post-emergence herbicide is applied to the locus. A use of a compound of the formula (I') as defined in claim 6 of the patent application, which is used as a plant growth regulator or a seed germination promoter.