Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms

Definitions

• the present invention relates to a process for the preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles (compounds I), which can be obtained through reaction of hydroxyamidine type compounds of formula II with trifluoroacetyl halides.
• Certain 3-substituted 5-trifluoromethyl-1,2,4-oxadiazoles are known as fungicides i.a. from EP 276432 A2, EP 3165093 A1, EP 3165094 A1, EP 3167716 A1, WO 2015/185485, WO 2017/055469, WO 2017/055473, WO 2017/076739, WO 2017/076740, WO 2017/076742, WO 2017/076757, WO 2017/076935, WO 2017/081309, WO 2017/081310, WO 2017081311, WO 2017081312, WO 2017/085098, WO 2017/085100, WO2017/093019, WO2017/093348, WO 2017/085100, WO2017/093348, WO2017/102006, WO2017/103219, WO2017/103223, WO2017/109044 and WO2017/118689.
• TFA trifluoroacetic acid
• TFA has a tendency to form cocrystals or clathrates with other solid reaction components.
• the removal of TFA is oftentimes cumbersome and requires elaborate additional purification steps (e. g. chromatography, distillation, crystallization, etc.).
• TFA is very corrosive and there is an interest to reduce the excess amounts of TFA furnished during or after the ring closing reaction, for example during workup.
• the reaction of compound II with TFAA produces one equivalent TFA. In the course of the oxadiazole ring closing/aromatisation reaction one equivalent of water is formed per equivalent of compound II.
• 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles can be obtained by the use of trifluoroacetyl halides, in particular trifluoroacetyl chloride (TFAC) or trifluoroacetyl fluoride (TFAF).
• TFAC trifluoroacetyl chloride
• TFAF trifluoroacetyl fluoride
• the process of this invention does not require a large excess of trifluoroacetyl halides in order to achieve high yields of the desired oxadiazoles, which is desirable from both, an economical and an ecological point of view.
• the total organic carbon content in the production waste water is reduced compared to the prior art processes, which makes the process eco-friendly.
• the use of trifluoroacetic halides results in the formation of a much smaller amount of TFA, which makes such process more production plant friendly and simplifies the workup procedure. As a result the production costs are significantly lower.
• the process of this invention provides the desired oxadiazoles in high yields and with reduced amounts of undesired side products.
• the in-situ preparation of compounds of type II enables a process, which proceeds in a smooth and controlled manner, which is very safe, simple, economical, user-friendly and commercially viable.
• the present invention relates to a process for preparing compounds of formula I,
• Hal is chlorine or fluorine
• the amidoxime compounds II can be obtained from cyano compounds V by treatment with hydroxylamine or a salt thereof, for example the hydrochloride salt, in the presence of a base, preferably triethylamine, in a suitable solvent, such as methanol, at a temperature between 0° C. and 100° C.
• a base preferably triethylamine
• suitable solvent such as methanol
• the formation of the amidoxime II and its transformation to compounds I takes place in a two-step one-pot reaction without any workup of the amidoxime II.
• compound IIa is trifluoacetyl chloride (TFAC).
• the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
• said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein.
• said process is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein.
• said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and in the absence of an inert solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
• said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or a solvent as defined herein; and in the presence of an inert solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
• inorganic solvent an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reactants or the products.
• the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles and any combination thereof.
• non-halogenated aliphatic hydrocarbons examples include pentane, hexane, heptane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
• non-halogenated cycloaliphatic hydrocarbons examples include cyclopentane, cyclohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cycloaliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
• Suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1,3,5-trimethylbenzene (mesitylene), and the like.
• toluene Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene), and any combination thereof.
• Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
• Suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1,2-dichloroethane and any combination thereof.
• halogenated aromatic hydrocarbons examples include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, ⁇ , ⁇ , ⁇ -trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
• Suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methyl-pyrrolidone, and the like and any combination thereof.
• Suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, and the like and any combination thereof.
• cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, and the like and any combination thereof.
• esters examples include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof.
• ketones examples include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof.
• suitable nitriles include acetonitrile, benzonitrile, and the like and any combination thereof.
• the inert organic solvent is selected from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons and any combination thereof.
• the inert organic solvent is selected from heptane, cyclohexane, cycloheptane, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene), chlorobenzene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, dioxane, ethyl acetate, methyl ethyl ketone and benzotrifluoride and any combination thereof.
• the inert organic solvent is selected from heptane, cyclohexane, toluene, dichloromethane and any combination thereof.
• the inert organic solvent is selected from heptane, cyclohexane, toluene and any combination thereof.
• inert organic solvents are non-halogenated aromatic hydrocarbons, especially non-halogenated alkylbenzenes which are mono-, di-, or tri-alkylsubstituted with each alkyl group containing 1 to 3 carbon atoms, and in particular those selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene and any combination thereof.
• the inert organic solvent is toluene.
• the volume ratio of the inert organic solvent to the hydroxyamidine II is generally from 0.01:1 to 20:1, preferably from 0.1:1 to 15:1, more preferably from 0.5:1 to 10:1, and most preferably from 1:1 to 5:1.
• the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an organic base.
• the base is selected from organic bases such as, for example: tertiary amines, pyridine, substituted pyridines, bicyclic amines and any mixture thereof. Preference is given to tertiary amines, pyridine, substituted pyridines and any mixture thereof. Particular preference is given to pyridine, substituted pyridines and any mixture thereof. Pyridine is especially preferred.
• tertiary amines examples include tri-(C 1 -C 6 )-alkylamines such as trimethylamine, triethylamine, tributylamine and diisopropylethylamine; di-(C 1 -C 6 )-alkyl-phenylamines such as N,N-dimethylaniline and N,N-diethylaniline; N-methyl imidazole, N,N-dimethylaminopyridine and the like.
• tri-(C 1 -C 6 )-alkylamines such as trimethylamine, triethylamine, tributylamine and diisopropylethylamine
• di-(C 1 -C 6 )-alkyl-phenylamines such as N,N-dimethylaniline and N,N-diethylaniline
• N-methyl imidazole N,N-dimethylaminopyridine and the like.
• Suitable substituted pyridines are collidine, lutidines, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine and the like.
• bicyclic amines examples include 1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and the like.
• the base is an organic base, which is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl imidazole, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine,1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and mixtures thereof.
• organic base which is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl
• the base is an organic base, which is selected from trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, N,N-dimethylaminopyridine and mixtures thereof.
• the base is an organic base, which is selected from trimethylamine, triethylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine and mixtures thereof.
• the base is selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates; alkali metal and alkaline earth metal sulfates and any combination thereof, even more preferably selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates and any combination thereof, in particular selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal acetates; particularly sodium acetate, potassium acetate; alkali metal and alkaline earth metal carbonates and any combination thereof, most preferably selected from alkali metal and alkaline earth metal phosphates
• the base is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof.
• the molar ratio of the base to hydroxyamidine II is generally from 3:1 to 0.4:1 or from 1:1 to 0.2:1, preferably from 0.02:1 to 0.3:1, more preferably from 0.02:1 to 0.25:1, most preferably from 0.02:1 to 0.2:1.
• the process of the present invention can be carried out under atmospheric pressure or under elevated or reduced pressure. Typically, the atmospheric and elevated pressure is employed. In a preferred embodiment the process of the present invention can be carried out at pressure ranges typically from 0.8 atmospheres (atm) to 80 atm, preferably form 1.0 atm to 20 atm, in particular from 1.0 to 7 atm.
• the temperature used in the process of the present invention can vary widely and is preferably from ⁇ 30 to 150° C., more preferably from ⁇ 10 to 120° C. and even more preferably from 0 to 100° C., 20 to 80° C. or 40 to 70° C.
• Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours.
• the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and at a pressure from 1 to 20 atm; and at a temperature from 0 to 100° C.
• an inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,
• said reaction is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and at a pressure from 1 to 7 atm; and at a temperature from 20 to 80° C.
• an inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-pic
• the process of the present invention may optionally be carried out in the presence of at least one phase-transfer catalyst.
• Phase transfer catalysts suitable for use in the process of this invention are those well known in the art such as, for example, quaternary ammonium salts.
• suitable phase-transfer catalysts are trimethyl(phenyl) ammonium chloride, bromide, iodide or hydroxide and tetra-n-C 1 -C 12 -alkyl-ammonium chlorides, bromides, iodides or hydroxides, preferably tetra-n-C 1 -C 8 -alkyl-ammonium chlorides, bromides, iodides or hydroxides, e.g.
• tetramethylammonium chloride bromide, iodide or hydroxide, tetraethylammonium chloride, bromide, iodide or hydroxide, tetra-n-propylammonium chloride, bromide, iodide or hydroxide, tetra-n-butylammonium chloride, bromide, iodide or hydroxide, tetra-n-pentylammonium chloride, bromide, iodide or hydroxide, tetra-n-hexylammonium chloride, bromide, iodide or hydroxide, tetra-n-heptylammonium chloride, bromide, iodide or hydroxide, tetra-n-octylammonium chloride, bromide, iodide or hydroxide, methyl-tri-n-butylammonium chloride, bro
• tetra-n-C 1 -C 4 -alkyl-ammonium chlorides bromides, iodides or hydroxides is preferred, in particular tetra-n-butylammonium chloride, bromide, iodide or hydroxide and methyl-tri-n-butylammonium chloride, bromide, iodide or hydroxide.
• phase-transfer catalysts which are usually solid in pure form, can be used as such or, preferably, in dissolved form.
• An effective amount of the phase-transfer catalyst may range from 0.001 to 0.5 molar equivalents, preferably 0.001 to 0.2 molar equivalents relative to compound II.
• a mixture of the E/Z-isomers of compounds of formula II is used, more preferably said mixture comprises an E/Z-isomer ratio of from 0.1:1 to 10:1, even more preferably of from 0.5:1 to 2:1.
• the E-isomer of compounds of formula II is used.
• the Z-isomer of compounds of formula II is used.
• the reaction mixture obtained is worked up and the compound I can be isolated in a customary manner, e. g. by an aqueous, extractive workup, in particular extraction with a basic or neutral aqueous medium, and by removing the solvent, e. g. under reduced pressure, or by a combination of these measures. Further purification can be effected, for example, by crystallization, thin-film-evaporation, rectification, sublimation, distillation or by chromatography.
• a compound of formula I, in which R is methyl is converted into valuable chemical products or intermediates. Accordingly, compounds of formula I, wherein R is methyl, can be further chlorinated to obtain a compound of formula Ib
• variables A 1 , A 2 and R A in compounds I and Ib are as defined or preferably defined herein.
• the chlorination of the methyl group R of compounds of formula I can be achieved using suitable chlorinating agents, for example molecular chlorine, N-chlorosuccinimide, trichloroisocyanuric acid, sulfuryl chloride or phosphorus pentachloride.
• suitable chlorinating agents for example molecular chlorine, N-chlorosuccinimide, trichloroisocyanuric acid, sulfuryl chloride or phosphorus pentachloride.
• the chlorination is conducted at temperatures between 0° C. and 200° C., preferably between 60° C. and 150° C., under irradiation or in the presence of radical starters, for example azobis(isobutyronitril) or dibenzoyl peroxide.
• radical starters for example azobis(isobutyronitril) or dibenzoyl peroxide.
• the chlorination is carried out in the presence of at least one inert organic solvent, or mixtures of such solvents.
• inert organic solvent means an organic solvent, which does not enter into any appreciable reaction with either the reactants or the products under the reaction conditions of the process of this invention.
• the inert organic solvent used in the process is preferably selected from halogenated aliphatic hydrocarbons and halogenated aromatic hydrocarbons, such as dichloromethane, tetrachloromethane, dichloroethane, chlorobenzene, homologues of dichlorobenzenes or 1,2,4-trichlorobenzene.
• the chlorination step is conducted in substance, for example with the liquid reaction product, which is directly obtained after the reaction of compounds II and IIa and in the absence of a further solvent, as described above.
• the chlorination can be performed in the presence or absence of TFA impurities originating from the previous reaction.
• TFA can be removed during the chlorination process via distillation or separately by distillation before carrying out the chlorination step. After completion of the reaction the reaction mixture is worked up in the usual manner or it can be used directly in the next step.
• the compound of formula Ib is hydrolyzed to obtain a compound of formula III
• variables A 1 , A 2 and R A in compounds Ib and III are as defined or preferably defined herein.
• this transformation is carried out in the presence of catalytic amounts of a lewis acid and water to obtain a compound of formula III, as described in WO 2007/063028 A2 on pages 42-43.
• the lewis acid is a metal salt, for example aluminum(III) chloride or iron(III) chloride, particularly iron(III) chloride.
• the lewis acid is used in sub-stoichiometric or catalytic amounts, for example 0.001 to 0.5 molar equivalents, preferably 0.002 to 0.2 molar equivalents, more preferably 0.005 to 0.1 molar equivalents, based on the amount of the compound of formula Ib.
• the hydrolysis step is carried out in the presence of at least one inert organic solvent, or mixtures of such solvents.
• the inert organic solvent used in the process of this invention is preferably selected from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles.
• the hydrolysis step is carried out in the absence of a solvent, i.e. in substance. Under these conditions the trichloromethyl compound Ib or the crude material comprising Ib, which was obtained from the previous reaction step, is heated to a temperature, where such material is a molten mass.
• the amount of water in the hydrolysis step is between 0.8 to 1.5 molar equivalents, preferably between 0.95 to 1.05 molar equivalents, based on the amount of the compound Ib.
• the reaction is carried out at temperatures between 20° C. and 200° C., preferably between 80° C. and 130° C. After completion of the reaction the reaction mixture is worked up in the usual manner or it can be used directly in the next step.
• the compound of formula III is reacted with an amine of formula IV to obtain a compound of formula Ic,
• variables A 1 , A 2 , R A , R 1 and R 2 in compounds of formulae III and IV are as defined or preferably defined herein.
• oxadiazole compounds of type Ic can be accessed by treating benzoic acid chloride of formula III with an amine of formula IV.
• the reaction is preferably carried out in a suitable inert organic solvent, such as non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles; for example, N,N-dimethylformamide, dichloromethane or tetrahydrofuran; preferably at a temperature between ⁇ 20° C. and 200° C., preferably between 0° C.
• the compound of formula Ic is used to obtain a compound of formula Id
• variables A 1 , A 2 , R A , R 1 and R 2 in compounds of formulae Ic and Id are as defined or preferably defined herein.
• Compounds of formula Ib can be prepared from compounds of formula Ic through treatment with Lawesson's reagent or phosphorus pentasulfide in an inert organic solvent, such as non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles; for example toluene, tetrahydrofuran, dioxane or ethyl acetate; at a temperature between 0° C. and 130° C., preferentially between 60° C. and 80° C.
• an inert organic solvent such as non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, n
• C n -C m indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.
• halogen refers to fluorine, chlorine, bromine and iodine.
• oxo refers to an oxygen atom ⁇ O, which is bound to a carbon atom or sulfur atom, thus forming, for example, a ketonyl —C( ⁇ O)— or sulfinyl —S( ⁇ O)— group.
• C 1 -C 6 -alkyl refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl.
• C 2 -C 6 -alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
• C 2 -C 6 -alkynyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.
• C 1 -C 6 -haloalkyl refers to a straight-chained or branched alkyl group having 1 to 6 carbon atoms (as defined above), wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloro
• C 1 -C 6 -alkoxy refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above) which is bonded via an oxygen, at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
• C 1 -C 6 -haloalkoxy refers to a C 1 -C 6 -alkoxy group as defined above, wherein some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example, OCH 2 F, OCHF 2 , OCF 3 , OCH 2 Cl, OCHCl 2 , OCCl 3 , chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC 2 F 5 , 2-fluoropropoxy, 3-fluoro
• phenyl-C 1 -C 4 -alkyl or heteroaryl-C 1 -C 4 -alkyl refer to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl or hetereoaryl radical respectively.
• C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C 1 -C 4 -alkoxy group (as defined above).
• C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C 1 -C 4 -alkylthio group.
• C 1 -C 6 -alkylthio refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as defined above) bonded via a sulfur atom.
• C 1 -C 6 -haloalkylthio refers to straight-chain or branched haloalkyl group having 1 to 6 carbon atoms (as defined above) bonded through a sulfur atom, at any position in the haloalkyl group.
• C 1 -C 4 -alkoxyimino refers to a divalent imino radical (C 1 -C 4 -alkyl-O—N ⁇ ) carrying one C 1 -C 4 -alkoxy group as substituent, e.g. methylimino, ethylimino, propylimino, 1-methylethyl-imino, butylimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino and the like.
• C 1 -C 6 -alkoxyimino-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C 1 -C 6 -alkoxyimino radical (C 1 -C 6 -alkyl-O—N ⁇ ) as defined above.
• C 2 -C 6 -alkenyloxyimino-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C 2 -C 6 -alkenyloxyimino radical (C 2 -C 6 -alkenyl-O—N ⁇ ).
• C 2 -C 6 -alkynyloxyimino-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C 2 -C 6 -alkynyloxyimino radical (C 2 -C 6 -alkynyl-O—N ⁇ ).
• hydroxyC 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a OH group.
• aminoC 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a NH 2 group.
• C 1 -C 6 -alkylamino refers to an amino group, which is substituted with one residue independently selected from the group that is defined by the term C 1 -C 6 -alkyl.
• diC 1 -C 6 -alkylamino refers to an amino group, which is substituted with two residues independently selected from the group that is defined by the term C 1 -C 6 -alkyl.
• C 1 -C 4 -alkylamino-C 1 -C 4 -alkyl refers to refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C 1 -C 4 -alkyl-NH-group which is bound through the nitrogen.
• diC 1 -C 4 -alkylamino-C 1 -C 4 -alkyl refers to refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a (C 1 -C 4 -alkyl) 2 N-group which is bound through the nitrogen.
• aminocarbonyl-C 1 -C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a —(C ⁇ O)—NH 2 group.
• C 2 -C 6 -alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
• C 2 -C 6 -alkynyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.
• C 3 -C 11 -cycloalkyl refers to a monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon radical having 3 to 11 carbon ring members that is connected through one of the ring carbon atoms by substitution of one hydrogen atom, such as cyclopropyl (C 3 H 5 ), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl (bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).
• bicyclic or tricyclic cycloalkyl radicals are found herein as examples R 1 0.1 to R 1 0.57.
• C 3 -C 11 -cycloalkyl refers to a monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon radical having 3 to 11 carbon ring members that is connected through one of the ring carbon atoms by substitution of one hydrogen atom, such as cyclopropyl (C 3 H 5 ), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl (bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).
• C 3 -C 11 -cycloalkyl-C 1 -C 6 -alkyl refers to alkyl having 1 to 11 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a C 3 -C 11 -cycloalkyl group as defined above.
• C 3 -C 11 -cycloalkoxy refers to a cyclic univalent hydrocarbon radical having 3 to 11 carbon ring members (as defined above) that is bonded via an oxygen, at any position in the cycloalkyl group, for example cyclopropyloxy.
• —C( ⁇ O)—C 1 -C 4 -alkyl refers to radicals which are attached through the carbon atom of the —C( ⁇ O)— group.
• aliphatic refers to compounds or radicals composed of carbon and hydrogen and which are non-aromatic compounds.
• An “alicyclic” compound or radical is an organic compound that is both aliphatic and cyclic. They contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character.
• cyclic moiety or “cyclic group” refer to a radical which is an alicyclic ring or an aromatic ring, such as, for example, phenyl or heteroaryl.
• any of the aliphatic or cyclic groups are unsubstituted or substituted with . . . ” refers to aliphatic groups, cyclic groups and groups, which contain an aliphatic and a cyclic moiety in one group, such as in, for example, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl; therefore a group which contains an aliphatic and a cyclic moiety both of these moieties may be substituted or unsubstituted independently of each other.
• phenyl refers to an aromatic ring systems including six carbon atoms (commonly referred to as benzene ring.
• heteroaryl refers to aromatic monocyclic or polycyclic ring systems including besides carbon atoms, 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S.
• saturated 3- to 7-membered carbocycle is to be understood as meaning monocyclic saturated carbocycles having 3, 4 or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms
• a 3- or 4-membered saturated heterocycle which contains 1 or 2 heteroatoms from the group consisting of N, O and S as ring members such as oxirane, aziridine, thiirane, oxetane, azetidine, thiethane, [1,2]dioxetane, [1,2]dithietane, [1,2]diazetidine;
• a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1, 2 or 3 heteroatoms from the group consisting of N, O and S as ring members such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,
• a 7-membered saturated or partially unsaturated heterocycle such as tetra- and hexahydroazepinyl, such as 2,3,4,5-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, hexahydroazepin-1-,-2-,-3- or- 4-yl, tetra- and hexahydrooxepinyl such as 2,3,4,5-tetrahydro[1H]o
• 5- or 6-membered heteroaryl or the term “5- or 6-membered aromatic heterocycle” refer to aromatic ring systems including besides carbon atoms, 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, for example, a 5-membered heteroaryl such as pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,
• the embodiments of the intermediates correspond to the embodiments of the compounds I.
• R is methyl, ethyl, iso-propyl, CH 2 F, CHF 2 , 2,2,2-trifluoroethyl or cyclopropyl.
• R is CR 3 R 4 NR 1 R 2 , wherein R 3 , R 4 and R 1 are as defined or preferably defined herein and R 2 is hydrogen.
• R is C( ⁇ O)NR 1 R 2 , CR 3 R 4 C( ⁇ O)NR 1 R 2 or CR 3 R 4 NR 2 C( ⁇ O)R 1 , wherein R 3 , R 4 and R 1 are as defined or preferably defined herein and R 2 is hydrogen.
• Embodiment R.1 R is COOH, —C( ⁇ W)NR 1 R 2 , CR 3 R 4 COOH, CR 3 R 4 C( ⁇ W)NR 1 R 2 or CR 3 R 4 NR 2 C( ⁇ W)R 1 .
• Embodiment R.2 R is COOH, —C( ⁇ O)NR 1 R 2 , CR 3 R 4 COOH, CR 3 R 4 C( ⁇ O)NR 1 R 2 or CR 3 R 4 NR 2 C( ⁇ O)R 1 .
• Embodiment R.3 R is COOH or CR 3 R 4 COOH.
• Embodiment R.4 R is —C( ⁇ W)NR 1 R 2 , CR 3 R 4 C( ⁇ W)NR 1 R 2 or CR 3 R 4 NR 2 C( ⁇ W)R 1 .
• Embodiment R.5 R is —C( ⁇ O)NR 1 R 2 , CR 3 R 4 C( ⁇ O)NR 1 R 2 or CR 3 R 4 NR 2 C( ⁇ O)R 1 .
• Embodiment R.6 R is CR 3 R 4 NR 2 R 1 .
• Embodiment R.7 R is CR 3 R 4 NR 2 C( ⁇ O)R 1 .
• Embodiment R.8 R is CF 2 COOH or CF 2 C( ⁇ O)NR 1 R 2 .
• Embodiment R.9 R is CH 2 COOH or CH 2 C( ⁇ O)NR 1 R 2 .
• Embodiment R.10 R is —C(CH 2 —CH 2 )COOH or —C(CH 2 —CH 2 )C( ⁇ O)NR 1 R 2 .
• W in compounds of formulae I, II and III is O.
• R 1 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, phenyl-C 1 -C 4 -alkyl, heteroaryl-C 1 -C 4 -alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals
• Embodiment 1.2 R 1 is phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R 1a as defined or preferably defined herein.
• Embodiment 1.3 R 1 is C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkenyl; and wherein the cyclic group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R 1a as defined or preferably defined herein.
• Embodiment 1.4 R 1 is C 1 -C 6 -alkyl; and wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R 1a as defined or preferably defined herein.
• Embodiment 1.5 R 1 is difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, 3,3,3-trifluoropropyl, CH 2 CF 2 CF 3 or CF 2 CF 2 CF 5 , CH(CH 3 )CF 3 , CH 2 CF 2 CH 3 , CH 2 C(CH 3 ) 2 F, CH 2 CH(CH 3 )CF 3 or CH 2 C(CH 3 ) 2 CF 3 .
• Embodiment 1.6 R 1 is C 1 -C 6 -alkoxyimino-C 1 -C 4 -alkyl, C 2 -C 6 -alkenyloxyimino-C 1 -C 4 -alkyl or C 2 -C 6 -alkynyloxyimino-C 1 -C 4 -alkyl.
• R 1 is a bicyclic or tricyclic C 4 -C 11 -cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 radicals selected from the group consisting of oxo, hydroxy, halogen and C 1 -C 3 -alkyl.
• Embodiment 1.8 R 1 is a bicyclic or tricyclic carbocycle selected from the group consisting of radicals R 1 0.1 to R 1 0.31 below; wherein each radical may be connected to the remainder of the compounds of formula I through one of the ring carbon atoms by substitution of one hydrogen atom; and wherein R 1 is unsubstituted or substituted with 1, 2 or 3 radicals selected from the group consisting of oxo, hydroxy, halogen and C 1 -C 3 -alkyl.
• R 1 is selected from the group consisting of R 1 0.32 to R 1 0.57 below, particularly from R 1 0.32 to R 1 0.49, which are further unsubstituted, and wherein “# C” indicates the carbon atom, which is attached to the remainder of the compounds of formula I.
• R 1a is defined as follows: In one embodiment R 1a is selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy and C 3 -C 8 -cycloalkyl.
• R 1a is selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy or cyclopropyl.
• R 1a is selected from the group consisting of halogen, C 1 -C 6 -alkyl and C 3 -C 8 -cycloalkyl; particularly from methyl, ethyl, fluorine and chlorine; more particularly from fluorine and chlorine.
• R 1 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R 1 are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R 1a ; wherein R 1a is halogen, oxo, cyano, NO 2 , OH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy or C 3 -C 8 -cycloalkyl.
• R 2 in formulae of compounds I, II and III is hydrogen, formyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, propargyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl, pyridinyl or —N(R 2a ) 2 ; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy; more preferably from halogen, in particular the radical is fluorine; and wherein R 2a is independently selected from the group consisting of
• Embodiment 2.1 R 2 independently of each other are hydrogen, formyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, propargyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy.
• Embodiment 2.2 R 2 independently of each other are hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH 2 —, allyl, phenyl, 4-F-phenyl, 2-F-phenyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino.
• Embodiment 2.3 R 2 independently of each other are hydrogen, formyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, propargyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino.
• Embodiment 2.4 R 2 independently of each other are hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH 2 —, allyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino.
• Embodiment 2.5 R 2 independently of each other are hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl or propargyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino.
• Embodiment 2.6 R 2 independently of each other are hydrogen, methy, ethyl, methoxy, ethyoxy, propyloxy, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino.
• Embodiment 2.7 R 2 is hydrogen.
• R 2 is C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy or C 3 -C 8 -cycloalkyl, and wherein any of the aliphatic or cyclic groups in R 2 are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from halogen.
• R 2 in formulae of compounds I, II and III is hydrogen, formyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, propargyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl, pyridinyl or —N(R 2a ) 2 ; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy; more preferably from halogen, in particular the radical is fluorine; and wherein R 2a is independently selected from the group consisting of
• R 2 in formulae of compounds I, II and III is hydrogen, formyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, propargyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino; and R 1 in formulae of compounds I, II and III is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, phenyl-C 1 -C 4 -alkyl, heteroaryl-C 1 -
• R 2 in formulae of compounds I, II and III is hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH 2 —, allyl, C 1 -C 6 -alkylamino or diC 1 -C 6 -alkylamino; and R 1 in formulae of compounds I, II and III is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; and wherein any of the aliphatic or cyclic groups in R 1 are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen or C 1 -
• Embodiment 3.1 R 3 and R 4 independently of each other are hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R 3 and R 4 together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
• Embodiment 3.2 R 3 and R 4 independently of each other are hydrogen or C 1 -C 4 -alkyl; Embodiment 3.3: R 3 and R 4 independently of each other are hydrogen, methyl or ethyl.
• Embodiment 3.4 R 3 and R 4 are independently of each other hydrogen, fluorine, chlorine, methyl or trifluoromethyl; or R 3 and R 4 together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
• Embodiment 3.5 R 3 and R 4 are both hydrogen.
• Embodiment 3.6 R 3 is hydrogen and R 4 is methyl.
• Embodiment 3.7 R 3 and R 4 are both methyl.
• Embodiment 3.8 R 3 and R 4 are both fluorine.
• Embodiment 3.9 R 3 and R 4 are both trifluoromethyl.
• Embodiment 3.10 R 3 and R 4 together with the carbon atom to which they are bound a saturated monocyclic 3- to 5-membered saturated heterocycle or saturated carbocycle; and wherein the saturated heterocycle includes beside one or more carbon atoms no heteroatoms or 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms; and wherein the heterocycle or the carbocycle is unsubstituted or substituted 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano and C 1 -C 2 -alkyl.
• Embodiment 3.11 R 3 and R 4 together with the carbon atom to which they are bound form a 3- or 4-membered carbocylic ring; and wherein the carbocylic ring is unsubstituted.
• Embodiment 3.12 R 3 and R 4 together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
• Embodiment 3.13 R 3 and R 4 together with the carbon atom to which they are bound form a saturated 3-membered heterocycle; wherein the heterocycle includes beside two carbon atoms one heteroatom selected from N, O and S as ring member atoms; and wherein the heterocycle is unsubstituted or substituted 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano and C 1 -C 2 -alkyl.
• Embodiment 3.14 R 3 is methyl and R 4 is fluorine.
• Embodiment 3.15 R 3 is hydrogen and R 4 is fluorine.
• R is CR 3 R 4 NR 2 C( ⁇ O)R 1 , wherein R 3 and R 4 are independently selected from hydrogen and C 1 -C 4 -alkyl, in particular both are hydrogen; and wherein R 1 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R 1 are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R 1a ; wherein R 1a is halogen, oxo, cyano, NO 2 , OH, C 1 -C 6 -alkyl, C
• R is CR 3 R 4 NR 2 C( ⁇ O)R 1 , wherein R 3 and R 4 are both hydrogen; and wherein R 1 is C 3 -C 6 -cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R 1 are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R 1a ; wherein R 1a is halogen, oxo, cyano, NO 2 , OH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy or C 3 -C
• Embodiment E1 A 1 and A 2 are CH and R A is hydrogen.
• Embodiment E2 A 1 and A 2 are CH and R A is fluorine.
• Embodiment E3 A 1 is N, A 2 is CH and R A is hydrogen.
• Embodiment E4 A 1 and A 2 are CH, R A is hydrogen, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
• Embodiment E5 A 1 and A 2 are CH, R A is fluorine, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
• Embodiment E6 A 1 is N, A 2 is CH, R A is hydrogen, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
• Embodiment E7 A 1 and A 2 are CH, R A is hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
• Embodiment E8 A 1 and A 2 are CH, R A is fluorine, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
• Embodiment E9 A 1 is N, A 2 is CH, R A is hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
• Embodiment E10 the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above, and R is methyl.
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A 1 , A 2 , R A corresponds to any one of the Embodiments E1, E2 or E3 defined above; and
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• the present invention relates to a process for preparing compounds of formula I, wherein
• embodiments E.1 to E.210 listed in Table E represent preferred combinations of the embodiments, which are defined above for each of the variables R, R 1 , R 2 , R 3 and R 4 .
• the present invention relates to compounds of the formula II, namely compounds II.A-1 to II.A-315, wherein A 1 and A 2 are CH, R A is hydrogen, and R in each of the compounds II.A-1 to II.A-315 is defined as in one corresponding line A-1 to A-315 in Table A below, and wherein # denotes the position, which is bound to the phenyl moiety.
• R is CO 2 H
• II.A-43 in correspondence to the definition in line A-43 in Table A.
• the present invention relates to the transformation of a compound of formula II with compounds of formula IIa to give compounds of formula I as described herein; and wherein the specific combination of reaction conditions is as defined in embodiments B-1 to B-32 in Table B below. All reactions defined by embodiments B1 to B-32 are carried out with 2 equivalents of trifluoroacetic acid chloride, based on the amount of compound II, with a molar ratio of the base to compound II of 1:1, at atmospheric pressure and whereas the other expressions in embodiments B-1 to B-32 have the following meaning:
• Acylating agent IIa 2 equivalents of trifluoroacetic acid chloride, based on the amount of compound II (ac1), 2 equivalents of trifluoroacetic acid fluoride, based on the amount of compound II (ac2).
• Base pyridine (b1), 2,4,6-collidine (b2), 2,6-lutidine (b3), trimethylamine (b4), triethylamin (b5), diisopropylethylamine (b6), sodium acetate (b7), potassium actetate (b8), tributylamine (b9), 2-picoline (b10), 3-picoline (b11), 4-picoline (b12), 5-ethyl-2-methyl-pyridine (b13), sodium carbonate (b14), potassium carbonate (b15).
• Solvents heptane (s1), cyclohexane (s2), toluene (s3), xylene (s4), dichloromethane (s5), 1,2-dichlorobenzene (s6), chlorobenzene (s7), 1,3,5-trimethylbenzene (s8), ethylbenzene (s9), tetrahydrofurane (s10), dioxane (s11), ethyl acetate (s12), methyl ethylketone (s13), benzotrifluoride (s14).
• volume ratio of solvent to compound II 1:2 (sa1), 1:1 (sa2), 5:1 (sa2).
• B-1 b1, s3, t2; B-2: b1, s3, t3; B-3: b1, s5, t2; B-4: b1, s5, t3; B-5: b1, s10, t2; B-6: b1, s10, t3; B-7: b1, s12, t2; B-8: b1, s12, t3; B-9: b4, s3, t2; B-10: b4, s3, t3; B-11: b4, s5, t2; B-12: b4, s5, t3; B-13: b4, s10, t2; B-14: b4, s10, t3; B-15: b4, s12, t2; B-16: b4, s12, t3; B-17: b5, s3, t2; B-18: b5, s3, t3; B-19: b5, s5, s5,
• the present invention relates to the transformation of a compound selected from the group of compounds II.A-1 to II.A-315 with TFAC to give compounds of formula I; and wherein the specific combination of the reaction conditions in each case is as defined in embodiments B-1 to B-32 of Table B.
• D-1 B-1 & II.A-1 to II-A-315; D-2: B-2 & II.A-1 to II-A-315; D-3: B-3 & II.A-1 to II-A-315; D-4: B-4 & II.A-1 to II-A-315; D-5: B-5 & II.A-1 to II-A-315; D-6: B-6 & II.A-1 to II-A-315; D-7: B-7 & II.A-1 to II-A-315; D-8: B-8 & II.A-1 to II-A-315; D-9: B-9 & II.A-1 to II-A-315; D-10: B-10 & II.A-1 to II- A-315; D-11: B-11 & II.A-1 to II-A-315; D-12: B-12 & II.A-1 to II-A-315; D-13: B-13 & II.A-1 to II- A-315; D-14: B-14 & II.A-1 to II-A-315;
• N′-hydroxy-4-methyl-benzamidine 5 g (0.026 mol) N′-hydroxy-4-methyl-benzamidine were suspended in 20 g (0.232 mol) in Me-THF. 62 g (0.0566 mol) ca. 12% solution of trifluoroacetyl chloride in Me-THF were added at room temperature and stirred for 102 hours. After addition of 140 g of a 4% sodium bicarbonate-solution, phases were separated. The organic phase was washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield 6.6 g (>98% HPLC purity, 93% yield) N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide.
• N-(2-fluorophenyl)-4-[(Z)-N′-hydroxycarbamimidoyl]benzamide 1000 mg, 3.65 mmol was suspended in Me-THF (10 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 1.9 g, 14.63 mmol) was added dropwise at room temperature and stirred for 10 hours at 60° C. The reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution. The organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield 955 mg of the title product.
• N′-hydroxy-4-[[methyl(methylsulfonyl)amino]methyl]benzamidine 500 mg, 2 mmol was suspended Me-THF (2 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 16.2 g, 14.63 mmol) was added dropwise at room temperature and stirred for 10 hours at 60° C.
• the reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution.
• the organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield the title product.

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