Compounds

Abstract

Compounds of the formula in which the substituents are as defined in claim 1, are suitable for use as nematicides. ##STR00001##

Claims

1. A compound of the formula I: ##STR00109## wherein: Y represents O or CH.sub.2; A is phenyl, wherein the phenyl is optionally substituted by one or more R.sub.2; B is pyrid-2-yl, thien-2-yl, pyrid-3-yl, pyrazol-3-yl, benzothiophen-2-yl, thiazol-5-yl, pyrimidin-5-yl, benzofuran-2-yl, quinol-3-yl, benzothiophen-2-yl, indazol-5-yl, benzothiazol-5-yl, indol-5-yl, 1,2,3,4-tetrahydroquinolin-8-yl, benzodioxol-5-yl, benzodioxol-4-yl, quinol-5-yl, thien-3-yl, or indol-4-yl, quinol-8-yl; each optionally substituted by one or more R.sub.4; R.sub.1 is hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4-cyanoalkyl or C.sub.3-C.sub.6-cycloalkylcarbonyl, C.sub.3-C.sub.6-cycloalkoxycarbonyl or benzyl; each R.sub.2 independently of one another represent halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or C.sub.1-C.sub.4-haloalkylthio; each R.sub.4 independently of one another represent halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6 haloalkynyl or C.sub.3-C.sub.6-cycloalkyl optionally substituted by one or more substituents R.sub.5; each R.sub.5 independently of one another represent halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl or C.sub.1-C.sub.4-alkyloxycarbonyl; or an enantiomer, a salt or an N-oxide of the compound.

2. A compound according to claim 1, wherein R.sub.1 is hydrogen.

3. A compound of formula (I) according to claim 1 wherein: Y represents O or CH.sub.2; R.sub.1 is hydrogen; each R.sub.2 independently of one another represent halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy or C.sub.1-C.sub.4-haloalkylthio; each R.sub.4 independently of one another represent halogen, cyano, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy or C.sub.3-C.sub.6-cycloalkyl optionally substituted by one or more substituents R.sub.5; each R.sub.5 independently of one another represent selected from halogen, C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-haloalkyl.

4. A compound of formula (I) according to claim 1 wherein: Y is CH.sub.2; A represents phenyl wherein the phenyl is optionally substituted by one or more R.sub.2; R.sub.1 is hydrogen; each R.sub.2 independently of one another represent halogen, difluoromethyl or trifluoromethyl; each R.sub.4 independently of one another represent halogen or trifluoromethyl.

5. A compound of formula (I) according to claim 1 wherein: Y represents CH.sub.2; A represents phenyl optionally substituted by one or more R.sub.2; R.sub.1 represents hydrogen; each R.sub.2 independently of one another represent halogen, difluoromethyl or trifluoromethyl; each R.sub.4 independently of one another represent halogen or trifluoromethyl.

6. A compound of formula (Iab): ##STR00110## wherein Y, A, B, and R.sub.1 are as defined in claim 1.

7. A pesticidal composition, which, in addition to comprising formulation adjuvants, comprises a nematicidal effective amount of a compound of the formula (I) according to claim 1.

8. A composition according to claim 7, which further comprises one or more insecticidally, acaricidally, nematicidally and/or fungicidally active agents.

Description

PREPARATION EXAMPLES

Example P1: Preparation of Racemic Cis N-[(2-(5-fluoro-2-pyridyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide

(1) ##STR00091##

(2) A solution of 5-fluoropyridine-2-carbaldehyde (1.163 g, 9.29 mmol) and 2-(trifluoromethyl)-N-vinyl-benzamide (2.0 g, 9.29 mmol) in acetonitrile (20 ml) was irradiated in a Rayonet reactor with 300 nm light. After 16 hours irradiation the solvent was evaporated to obtain 3.05 g of crude product, which was chromatographed on silica gel with a gradient of ethyl acetate/hexane to yield 970 mg of crude product, which was chromatographed again with a gradient of ethyl acetate/hexane to yield racemic cis N-[2-(5-fluoro-2-pyridyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide as a gum.

(3) .sup.1H NMR (CDCl3, 400 MHz) 4.78 (dd, J=7 & 7); 5.16 (dd, J=7 & 7) (together CH2O); 5.67 (dddd, 7 & 7 & 7 & 7, CHN); 5.97 (d, J=7, HC-pyridine); 7.03 (br d, J=7, NH) 7.2-7.7 (6H, aromatic), 8.50 (1H, s)

Example P2: Racemic cis N-[(2-(3-methyl-2-thienyl)cyclobutyl]-2-(trifluoromethyl)benzamide

(4) ##STR00092##

Step a. Preparation of 2-(cyclopropylidenemethyl)-3-methyl-thiophene

(5) To a suspension of (3-bromopropyl)triphenylphosphonium bromide (20.8 g, 44.0 mmol) in anhydrous THF (140 mL) was added potassium t-butoxide (10.1 g, 88.0 mmol) in 4 separate portions 15 minutes apart. The mixture was then heated to reflux for 10 minutes, and 3-methylthiophene-2-carbaldehyde (4.79 mL, 40.0 mmol) in anhydrous THF (10 mL) was added dropwise, then continued at reflux for 4 hours. The reaction mixture was cooled down to room temperature, diluted with hexanes and filtered through a Celite pad. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (hexanes), affording 2-(cyclopropylidenemethyl)-3-methylthiophene as a light yellow oil.

(6) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.06 (d, 1H), 6.98-6.93 (m, 1H), 6.81 (d, 1H), 2.28 (s, 3H), 1.35-1.23 (m, 4H) ppm.

Step b. Preparation of racemic 2-(3-methyl-2-thienyl)cyclobutanone

(7) To a solution of 2-(cyclopropylidenemethyl)-3-methyl-thiophene (3.71 g, 24.7 mmol) in CH.sub.2Cl.sub.2 (125 mL) was added m-chloroperbenzoic acid (ca. 75%, 5.69 g, 24.7 mmol) at 0 C. After stirring at 0 C. for 3 hours, the reaction mixture was washed with saturated NaHCO.sub.3 aqueous solution and brine, dried over Na.sub.2SO.sub.4 and concentrated.

(8) To the crude product in CH.sub.2Cl.sub.2 (85 mL) was added a 10% HBF.sub.4 aqueous solution (49 mL). After stirring at room temperature for 16 hours, the mixture was extracted with CH.sub.2Cl.sub.2, washed with saturated NaHCO.sub.3 aqueous solution and brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (hexanes:EtOAc 9:1), affording 2-(3-methyl-2-thienyl)cyclobutanone as a yellow oil.

(9) .sup.1H NMR (300 MHz, CDCl3) 7.09 (d, 1H), 6.83 (d, 1H), 4.72 (ddt, 1H), 3.24 (dddd, 1H), 3.08 (dddd, 1H), 2.69-2.52 (m, 1H), 2.25-2.09 (m, 4H) ppm.

Step c. Preparation of racemic (E/Z) mixture of 2-(3-methyl-2-thienyl)cyclobutanone oximes

(10) To a solution of 2-(3-methyl-2-thienyl)cyclobutanone (3.05 g, 18.4 mmol) in methanol (36 mL), sodium acetate (1.71 g, 20.2 mmol) and hydroxylamine hydrochloride (1.42 g, 20.2 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated. To the crude material was added water (100 mL) and the oximes were isolated by extraction with dichloromethane (2100 mL). The organic layer was finally washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (hexanes:Et.sub.2O 1:1), affording a racemic mixture of (E)- and (Z)-2-(3-methyl-2-thienyl)cyclobutanone oximes as a white solid.

(11) .sup.1H NMR (300 MHz, CDCl.sub.3) Major isomer 7.08 (d, 1H), 6.93 (s, 1H), 6.80 (d, 1H), 4.63 (m, 1H), 3.08 (m, 1H), 2.93 (dd, 1H), 2.57 (m, 1H), 2.19 (s, 3H), 2.17 (m, 1H).

Step d. Preparation of Racemic Cis 2-(3-methyl-2-thienyl)cyclobutanamine hydrochloride

(12) To a solution of racemic (E/Z) mixture of 2-(3-methyl-2-thienyl)cyclobutanone oximes (1.80 g, 9.93 mmol) in methanol (40 mL) was added nickel chloride hexahydrate (118 mg, 0.50 mmol) and the mixture was cooled to 10 C. Sodium borohydride (0.77 g, 19.9 mmol) was added in small portions during 1 hour. After stirring for 30 minutes at 10 C. the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was concentrated. To the crude material was added water (100 mL), then it was basified with 1M NaOH aqueous solution (ca. 14 mL) and the amine was isolated by extraction with dichloromethane (2100 mL). The organic layer was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (Et.sub.2O:hexanes:Et.sub.3N 9:3:0.1), affording the free cyclobutanamine as a light brown oil.

(13) To a solution of this free cyclobutanamine in CH.sub.2Cl.sub.2 (18 mL) was added dropwise 4M HCl in dioxane (12.2 mL, 48.7 mmol) at 0 C. under inert atmosphere. The reaction mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and the residue was triturated with Et.sub.2O:CH.sub.2Cl.sub.2 (10:1 mL) overnight at room temperature, then the suspension was cooled down in an ice bath and a precipitate was filtered off, washed with small amount of Et.sub.2O and dried under vacuum to give racemic cis 2-(3-methyl-2-thienyl)cyclobutanamine hydrochloride as an off-white solid.

(14) m.p. 181 C. (with dec.)

Step e. Preparation of Racemic Cis N-[(2-(3-methyl-2-thienyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(15) To the racemic cis 2-(3-methyl-2-thienyl)cyclobutanamine hydrochloride (129 mg, 0.60 mmol) and triethylamine (0.21 mL, 1.50 mmol) in anhydrous THF (5 mL) was added dropwise 2-(trifluoromethyl)benzoyl chloride (0.10 mL, 0.66 mmol) in anhydrous THF (2 mL) at 0 C. under inert atmosphere. The reaction mixture was stirred at room temperature overnight. Triethylamine hydrochloride was filtered off, washed with small amount of Et.sub.2O. The filtrate was concentrated and purified by column chromatography on silica gel (hexanes:Et.sub.2O 1:1), followed by purification on preparative TLC (hexanes:EtOAc 7:1), affording racemic cis N-[(2-(3-methyl-2-thienyl)cyclobutyl]-2-(trifluoromethyl) benzamide as a white solid.

(16) m.p. 111-112 C.

Example P3: N-[2-(benzothiophen-2-yl)cyclobutyl]-2-(trifluoromethyl)benzamide

(17) ##STR00093##

Step a. Preparation of N-(1-cyanocyclobutyl)-2-(trifluoromethyl)benzamide

(18) 1-cyanocyclobutanamine chloride (1 g, 7.54 mmol) was suspended in 10 mL of water. Sodium carbonate (1.60 g, 15.1 mmol) was added with stirring followed by 2-(trifluoromethyl)benzoyl chloride (1.57 g, 7.54 mmol). The reaction mixture was stirred for one hour and then shaken between ethyl acetate and 2M HCl, then washed with 2M sodium carbonate, and then with saturated brine. The resulting organic layer was dried over MgSO4 and concentrated. The resulting solid was triturated with cold diethylether to afford pure N-(1-cyanocyclobutyl)-2-(trifluoromethyl)benzamide. Melting point: 148-154 C.

(19) .sup.1H NMR (CDCl3, 400 MHz) 7.75 (d, J=10 Hz, 1H), 7.60 (m, 3H), 6.15 (br s, 1H), 2.9 (m, 2H), 2.5 (m, 1H), 2.2 (m, 2H) ppm

Step b. Preparation of N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(20) N-(1-cyanocyclobutyl)-2-(trifluoromethyl)benzamide (268 mg, 1 mmol) was dissolved in 1 ml of dry THF in dried flask under argon. tBuONa (2M in THF) (0.75 ml, 0.5 mmol) was then added and stirred at room temperature for four days. The reaction was diluted with tBuOMe and then quenched with 1M solution of NaHCO3, followed by a solution of saturated brine. The resulting organic layer was dried over MgSO4, filtered and concentrated to afford 245 mg of crude material, which was chromatographed on silica to obtain pure N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide. Melting point: 129-133 C.

(21) .sup.1H NMR (CDCl3, 400 MHz) 7.75 (d, J=10 Hz, 1H), 7.6 (m, 3H), 7.15 (br s, 1H), 5.6 (s, 1H), 2.8 (m, 2H), 2.45 (m, 2H) ppm

Step c. Preparation of N-(2-iodocyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(22) N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide (15 mg, 0.0622 mmol) was dissolved in 0.200 ml dichloromethane. Triethylamine (0.0105 mL, 0.0746 mmol, 7.63 mg) was added. Under stirring N-iodosuccinimide (14.4 mg, 0.0622 mmol) was added. It dissolved quickly. TLC (50% EtOAc/cyclohexane) after 10 minutes at RT showed complete reaction. The reaction mixture was shaken between tBuOMe and 1M NaHCO3, dried with MgSO4, and evaporated. Chromatography on silica with a 0 to 50% EtOAc/cyclohexane gradient gave pure N-(2-iodocyclobuten-1-yl)-2-(trifluoromethyl)benzamide.

(23) 1H-NMR (CDCl3) 2,78 (2H, t); 3.42 (2H, t); 7.20 (br s, NH); 7.61 (3H, m); 7.73 (1H, s).

Step d. Preparation of N-(2-bromocyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(24) N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide (3.86 g, 16 mmol) was stirred in dichloromethane (ca 30 ml) at ca 10 C. Na2CO3 (2M aq., ca 20 ml) was added and iPr2NEt (2.09 g, 16 mmol, 2.82 ml) was added, followed by N-bromosuccinimide (2.85 g). The organic phase was then dried with MgSO4, and evaporated to give the crude product, which was chromatographed on 120 g silica with a gradient of 0 to 50% EtOAc in cyclohexane to yield N-(2-bromocyclobuten-1-yl)-2-(trifluoromethyl)benzamide. M.p. 112-113-5 C.

(25) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.74 (d, 1H), 7.60 (m, 3H), 7.28 (br s, 1H), 3.21 (t, 2H), 2.78 (t, 2H) ppm

Step e. N-[2-(benzothiophen-2-yl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide (89-1)

(26) To a solution of N-(2-bromocyclobuten-1-yl)-2-(trifluoromethyl)benzamide (60 mol) in THF (0.7 ml) was added successively benzothiophen-2-ylboronic acid (120 mol), a solution of potassium phosphate (25.5 mg) in water (0.3 ml) and a solution of chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (4.7 mg; 6 mol) in THF (0.2 ml). The reaction mixture was flushed with argon and stirred at 110 C. for 30 minutes in a microwave oven. Then the THF was evaporated. The crude mixture was diluted with ethyl acetate (2 ml), washed 3 times with water (2 ml) and the organic phase was concentrated. The crude material was purified via chromatography to give N-[2-(benzothiophen-2-yl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide.

(27) This method was used to prepare all compounds from Table 115, except compounds 115-30 to 115-34.

Step f. N-[2-(benzothiophen-2-yl)cyclobutyl]-2-(trifluoromethyl)benzamide (90-24)

(28) To a solution of N-[2-(benzothiophen-2-yl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide. (22.3 mg) in methanol (2 ml) was added (1,1-bis(di-i-propylphosphino)ferrocene(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (4.3 mg) under inert atmosphere. The reaction mixture was placed in a stainless steel autoclave and was hydrogenated at 50 bar and ambient temperature for 22 hours. The crude mixture was concentrated. The crude material was purified via chromatography to give N-[2-(benzothiophen-2-yl)cyclobutyl]-2-(trifluoromethyl)benzamide

(29) 1H-NMR (CDCl3, 400 MHz): 7.80-7.05 (m, 9H), 5.75 (d, 1H), 5.04 (m, 1H), 4.25 (m, 1H), 2.65 (m, 1H), 2.45 (m, 1H), 2.25 (m, 2H) ppm.

(30) This method was used to prepare Compound Nos. 116-24 to 116-35 and 116-44 to 116-48 of Table 116.

Example P4: Preparation of N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(31) ##STR00094##

Step a. Preparation of 1-isocyano-1-(4-methylphenyl)sulfonyl-cyclobutane

(32) Sodium hydride (3.1 g, 57% in oil, 74 mmol) was washed with hexane under argon. A 3:1 mixture of DMSO and diethyl ether (50 ml) was added. This was stirred well and a solution of 1,3-dibromopropane (3.1 ml, 6.1 g, 31 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (5.0 g, 26 mmol) in a 3:1 mixture of DMSO and diethyl ether (30 ml) was added dropwise, causing an exotherm to 43 C. The addition took about 30 minutes. After one hour stirring a precipitate of NaBr came out, and the temperature sank to RT. Water (60 ml) was slowly added, and the crude mixture extracted with diethylether, which was then dried with Na2SO4 and evaporated down to give the crude material. This was stirred with ether, cooled in an ice bath, and the crystals filtered off to yield 1-isocyano-1-(4-methylphenyl)sulfonyl-cyclobutane as light coloured crystals.

(33) M.p. 94-97 C.

Step b. Preparation of N-(1-(4-methylphenyl)sulfonylcyclobutyl)formamide

(34) Hydrochloric acid (19 ml, 2M, 36 mmol) as added to a solution of 1-(1-isocyanocyclobutyl)sulfonyl-4-methyl-benzene (8.5 g, 36 mmol) in THF (50 ml) at 0-5 C. which was cooled in an ice-water bath. After TLC in 50% EtOAc in hexane showed complete reaction, NaHCO3 (1M) was added to make the mixture lightly basic. The mixture was extracted with tBuOMe, dried with Na2SO4, and evaporated to give the crude product, which was stirred in ether and left in the refrigerator at ca 0 to 5 C. The resulting solid was filtered off to yield N-(1-(4-methylphenyl)-sulfonyl-cyclobutyl)formamide as beige crystals.

(35) M.p. 83-88 C.

Step c. Preparation of N-(cyclobuten-1-yl)formamide

(36) A solution of N-[1-(p-tolylsulfonyl)cyclobutyl]formamide (500 mg, 1.97 mmol) in THF (3 ml) was cooled to 0 C. under argon. A solution of NaOtBu in THF (2.96 ml, 2M, 5.92 mmol, 3 equiv.) was added slowly. After 30 minutes at 0 C. the mixture was extracted between diethylether and NaHCO3 (aq). And the ether phase evaporated to yield N-(cyclobuten-1-yl)formamide as an oil. 1H-NMR showed a mixture of rotamers.

(37) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.33 (d, 1H), 8.19 (s, 1H), 5.45 (s, 1H), 5.05 (s, 1H), 2.73 (m, 2H), 2.38 (m, 2H).

Step d. Preparation of N-(cyclobuten-1-yl)-N-formyl-2-(trifluoromethyl)benzamide

(38) A solution of N-(cyclobuten-1-yl)formamide (190 mg, 1.956 mmol) in ether and THF as a solution obtained as above before evaporation was cooled to 0 C. Et3N (300 mg, 2.935 mmol) and DMAP (23.9 mg, 0.1956 mmol) were added then 2-(trifluoromethyl)benzoyl chloride (449 mg, 2.152 mmol) was added dropwise. There was an exotherm to 7 C. and a precipitate came out of solution. The cool bath was removed and the mixture stirred for 2 hours then shaken between EtOAc and NaHCO3 (aq.), washed with brine, dried with Na2SO4, and evaporated to give N-(cyclobuten-1-yl)-N-formyl-2-(trifluoromethyl)benzamide as a crude product

(39) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.88 (s, 1H), 5.82 (s, 1H), 2.83 (t, 2H), 2.38 (t, 2H)

Step e. Preparation of N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(40) N-(cyclobuten-1-yl)-N-formyl-2-(trifluoromethyl)benzamide (63 mg, 0.26 mmol) was dissolved in THF (1 ml) and cooled to 0 C. NaOH (2M, 1.2 equiv.) was added and stirred for 30 min at 0 C., then shaken between EtOAc and water, dried with Na2SO4, and evaporated to yield crude N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide .sup.1H NMR (CDCl3, 400 MHz) 7.75 (d, J=10 Hz, 1H), 7.6 (m, 3H), 7.15 (br s, 1H), 5.6 (s, 1H), 2.8 (m, 2H), 2.45 (m, 2H) ppm

Example P5: Preparation of N-(2-iodocyclobuten-1-yl)formamide

(41) ##STR00095##

(42) A solution of N-(cyclobuten-1-yl)formamide (82 mg, 0.8443 mmol) in ether and THF prepared as described above in example P3 was cooled to 0 C. A solution of K2CO3 (0.844 ml, 1.689 mmol, 2M, aq.) was added and iPr2NEt (109 mg, 0.8443 mmol) was added. Under stirring iodine (214 mg, 0.8443 mmol) was added. After performing a TLC examination with 50% EtOAc/cyclohexane the mixture was shaken between EtOAc and water, washed with NaS2O3 (aq.), then HCl (aq), then NaHCO3 (aq), then brine. It was dried with Na2SO4, and evaporated to give crude product, which was chromatographed on silica with EtOAc/cyclohexane to yield N-(2-iodocyclobuten-1-yl)formamide

(43) .sup.1H NMR (CDCl3, 400 MHz, mixture of two rotamers) 8.43 (d, 1H), 8.18 (s, 1H), 3.30 (t, 2H), 3.00 (t, 2H), 2.74 (m, 2H).

Example P6: Preparation N-(cyclobuten-1-yl)-4-methoxy-benzamide

(44) ##STR00096##

Step a. Preparation of N-(1-cyanocyclobutyl)-4-methoxy-benzamide

(45) 1-cyanocyclobutanamine hydrochloride (200 mg, 1.5084 mmol) was dissolved in THF, the solution was then cooled down to 0 C. Et3N (305 mg, 3.0168 mmol) was then added and stirred for 15 min. 4-methoxybenzoyl chloride (257 mg., 1.5084 mmol) was then added and the reaction mixture warmed up to room temperature. After 17 hours the mixture is a suspension. It was shaken between EtOAc and water, washed with NaHCO3 (1M, aq) and brine, dried over MgSO4 and evaporated to yield 255 mg of crude product, which was chromatographed on silica with EtOAc/cyclohexane to afford N-(1-cyanocyclobutyl)-4-methoxy-benzamide as a white solid. 1H NMR (CDCl3, 400 MHz) 7.75 (d, J=10 Hz, 2H), 6.95 (d, J=10 Hz, 2H), 6.38 (br s, 1H), 2.9 (m, 2H), 2.5 (m, 1H), 2.3 (m, 1H), 2.15 (m, 1H)

Step b. Preparation of N-(cyclobuten-1-yl)-4-methoxy-benzamide

(46) A solution of NaOtBu in THF (0.938 ml, 2M, 1.876 mmol) was added to a solution of N-(1-cyanocyclobutyl)-4-methoxy-benzamide (144 mg, 0.6253 mmol) in THF (3 ml). After 24 hours at RT the mixture was shaken between tBuOMe and NaHCO3 (1M, aq.), dried with MgSO4 and the solvent evaporated to afford crude product, which was chromatographed on silica to afford N-(cyclobuten-1-yl)-4-methoxy-benzamide as a white solid.

(47) M.p. 79-85 C.

(48) .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.75 (d, J=10 Hz, 2H), 7.5 (br s, 1H), 6.95 (d, J=10 Hz, 2H), 3.85 (s, 3H), 2.8 (m, 2H), 2.45 (m, 2H).

Example P7: Preparation N-(cyclobuten-1-yl)acetamide

(49) ##STR00097##

Step a. Preparation of N-(1-cyanocyclobutyl)acetamide

(50) Prepared according to example P3 step a to afford N-(1-cyanocyclobutyl)acetamide as a brown solid. Melting point: 70-72 C.

(51) 1H NMR (CDCl3, 400 MHz) 5.85 (br s, 1H), 2.7 (m, 2H), 2.3 (m, 2H), 2.15 (m, 1H), 2.05 (m, 1H), 1.95 (s, 3H)

Step b. Preparation of N-(cyclobuten-1-yl)acetamide

(52) Prepared according to example P3 step b to afford N-(cyclobuten-1-yl)acetamide as a pale yellow solid.

(53) 1H NMR (CDCl3, 400 MHz) 6.98 (br s, 1H), 5.40 (s, 1H), 2.68 (t, 2H), 2.48 (m, 2H), 2.01 (s 3H)

Example P8: Preparation of Racemic Cis N-[2-(2-pyridyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(54) ##STR00098##

Step a. Preparation of N-[2-(2-pyridyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(55) N-(2-iodocyclobuten-1-yl)-2-(trifluoromethyl)benzamide (0.272 mmol, 0.100 g) was introduced in a 25 ml three-neck round-bottom flask and dissolved in anhydrous tetrahydrofuran (5 ml). The reaction mixture was flushed three times with vacuum/argon cycles and submitted to an argon atmosphere. Palladium(II) acetate (0.00535 mmol, 0.00120 g) and XPhos (2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 0.0108 mmol, 0.00520 g) were added in one share, then freshly opened 2-pyridylzinc bromide in THF (0.5M; 0.409 mmol, 0.8 g, 0.8 ml) was added drop-wise. The reaction mixture was stirred at room temperature overnight (21 hours), then at 50 C. during 5 hours. Additional 2-pyridylzinc bromide in THF (0.5M; 0.136 mmol, 0.27 ml) was added and the reaction mixture was stirred at 50 C. overnight (18 hours). At this state the conversion of the starting material was total. The reaction mixture was cooled down to room temperature, quenched by pouring it on water and extracted twice with ethyl acetate. Organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give a dark oil. The crude mixture was purified by chromatography to afford a brownish sticky oil.

(56) 1H NMR (CDCl3, 400 MHz) 9.94 (1H, br. s.), 8.31-8.45 (1H, m), 7.53-7.81 (5H, m), 6.91-7.03 (2H, m), 3.34 (2H, t), 2.73, (2H, t).

Step b. Preparation of Racemic Cis N-[2-(2-pyridyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(57) Prepared according to example P3 step f to afford a pale yellow gum.

(58) LCMS characterization in table 116 (compound 116-49).

Example P9: Preparation of Racemic Cis N-[2-(3-chloro-2-pyridyl)cyclobutyl]-2-(trifluoromethyl)benzamide

(59) ##STR00099##

Step a. Preparation of N-[2-(3-chloro-2-pyridyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(60) N-(2-iodocyclobuten-1-yl)-2-(trifluoromethyl)benzamide (0.817 mmol, 0.300 g) and tributyl-(3-chloro-2-pyridyl)stannane (1.02 mmol, 0.411 g) were introduced in a 25 ml round-bottom flask and dissolved in anhydrous and degassed N,N-dimethylformamide (2 ml). In a separate 10 ml round bottom flask was introduced anhydrous and degassed N,N-dimethylformamide (3 ml). Palladium(II) chloride diacetonitrile complex (0.204 mmol, 0.0539 g), copper (I) iodide (0.817 mmol, 0.156 g, 0.0277 ml) and triphenylarsine (0.817 mmol, 0.250 g) were added subsequently in one share and the mixture was stirred under an argon atmosphere for 2 minutes. The mixture turned dark just after the addition of copper (I) iodide. The catalyst solution was then added drop-wise to the reaction mixture flask under an argon atmosphere. The reaction mixture was stirred at room temperature under an argon atmosphere overnight (18 hours). The reaction mixture was diluted in ethyl acetate, filtered through Celite and a small layer of silica. This organic solution was washed with water to remove a part of DMF, then washed with an aqueous potassium fluoride solution. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give a dark solid. The crude mixture was purified by chromatography to give an orange solid which was triturated with a small volume of cyclohexane. An orange solid was obtained.

(61) 1H NMR (CDCl3, 400 MHz) 10.35 (br. s., 1H) 8.25 (d, 1H) 7.77 (d, 1H) 7.55-7.73 (m, 4H) 6.91 (dd, 1H), 3.33 (m, 2H) 3.11 (t, 2H).

(62) This method was used to prepare Compound Nos. 115-31 to 115-33 of Table 115.

Step b. Preparation of Racemic Cis N-[2-(3-chloro-2-pyridyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(63) Prepared according to example P3 step f except the fact that the reaction time was extended to 51 hours. A colourless viscous oil was obtained.

(64) 1H NMR (CDCl3, 400 MHz) 8.38 (dd, 1H) 7.78 (d, 1H) 7.69 (dd, 1H) 7.61-7.67 (m, 1H) 7.45-7.55 (m, 2H) 7.29-7.36 (m, 1H) 7.12 (dd, 1H) 5.06-5.28 (m, 1H) 4.35-4.52 (m, 1H) 2.48-2.63 (m, 1H) 2.28-2.44 (m, 2H) 2.13-2.24 (m, 1H)

(65) This method was used to prepare Compound Nos. 116-50 and 116-51.

Example P10: Preparation of N-[(1S,2R)-2-(3-chloro-2-pyridyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(66) ##STR00100##

(67) (R)-1-[(S)-2-(Di-tert.-butylphosphino)ferrocenyl]ethyl-di-2-methylphenylphosphine (SL-J505-1, 0.0427 mmol, 0.0251 g) and bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.0388 mmol, 0.0182 g) were weighted and transferred to a vial in an inert atmosphere. Methanol was degassed by flushing it several times with vacuum/argon cycles. Degassed methanol (7 ml) was then introduced in a 25 ml round-bottom flask containing N-[2-(3-chloro-2-pyridyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide (0.388 mmol, 0.137 g), followed by the addition of both catalyst and ligand, and the reaction mixture was stirred at room temperature under an argon atmosphere until the reaction mixture becomes homogeneous (15 minutes). The solution was then canulated into a 100 ml autoclave previously inerted with argon. The autoclave was tightly closed and submitted to hydrogen pressure (50 bar) at 50 C. overnight (17 hours). The autoclave was cooled down, inerted with argon, and opened. The reaction mixture was filtered through Celite and a small layer of silica, washed with methanol and concentrated to give a brownish solid. The crude mixture was purified by chromatography to afford an orange viscous oil: It was analysed via chiral HPLC (method F) which showed an ee of 33% in favour of the desired enantiomer eluting at 4.66 min (minor enantiomer eluting at 6.38 min).

(68) 1H NMR (CDCl3, 400 MHz) 8.38 (dd, 1H) 7.78 (d, 1H) 7.69 (dd, 1H) 7.61-7.67 (m, 1H) 7.45-7.55 (m, 2H) 7.29-7.36 (m, 1H) 7.12 (dd, 1H) 5.06-5.28 (m, 1H) 4.35-4.52 (m, 1H) 2.48-2.63 (m, 1H) 2.28-2.44 (m, 2H) 2.13-2.24 (m, 1H)

Example P11: Preparation of Racemic Cis N-[2-(3,5-dichloro-2-pyridyl)cyclobutyl]-2-(trifluoromethyl)benzamide

(69) ##STR00101##

Step a. Preparation of tributyl-(3,5-dichloro-2-pyridyl)stannane

(70) 2-bromo-3,5-dichloro-pyridine (2.20 mmol, 0.500 g) was introduced in a 50 ml three-neck round-bottom flask and dissolved in anhydrous tetrahydrofuran (10 ml). The reaction mixture was flushed three times with vacuum/argon cycles, submitted to an argon atmosphere and cooled down to 78 C. with an acetone/dry ice slurry. At 78 C., n-butyllithium in hexane (1.6M; 2.42 mmol, 1.5 ml) was then added drop-wise within 5 minutes. The reaction mixture was stirred at 78 C. during 1 hour. Then tributyl(chloro)stannane (2.64 mmol, 0.861 g, 0.717 ml) was added and the cold bath was removed. The reaction mixture was stirred during 1 hour whereupon it slowly went back to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. Organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give a dark liquid. The crude mixture was purified by chromatography to afford a pale yellow liquid which was characterized as the desired product.

(71) 1H NMR (CDCl3, 400 MHz) 8.34-8.37 (m, 2H) 1.50-1.60 (m, 6H) 1.32-1.40 (m, 6H) 1.28-1.32 (m, 6H) 0.90 (t, 9H).

Step b. Preparation of N-[2-(3,5-dichloro-2-pyridyl)cyclobuten-1-yl]-2-(trifluoromethyl) benzamide

(72) Prepared according to example P9 step a except the fact that the reaction time was shortened to 3 hours to afford an amber viscous oil.

(73) 1H NMR (CDCl3, 400 MHz) 8.41 (s, 2H) 7.74 (d, 1H) 7.56-7.67 (m, 3H) 7.47 (br. s., 1H) 3.25 (t, 2H) 2.99 (t, 2H).

Step c. Preparation of Racemic Cis N-[2-(3,5-dichloro-2-pyridyl)cyclobutyl]-2-(trifluoromethyl) benzamide

(74) To (R)-1-[(S.sub.P)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (SL-J002-1, 2.4 mg, 0.03 eq.) and (S)-1-[(R.sub.P)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine Josiphos (SL-J002-2, 2.4 mg, 0.03 eq.) was added carefully degassed MeOH (1.5 ml). The suspension was stirred for 10 min at r.t. under argon and then Ru(COD)(OOCCF.sub.3).sub.2 dimer hydrate (3.2 mg, 0.05 eq.) was added. The suspension was stirred for 15 more minutes under argon. The reaction mixture became homogeneous. This yellow solution was added to N-[2-(3,5-dichloro-2-pyridyl)cyclobuten-1-yl]-2-(trifluoromethyl) benzamide (28 mg, 1 eq.). The reaction mixture was stirred 20 minutes under argon. It was then transferred to a 100 ml autoclave under argon atmosphere. The autoclave was tightly closed, purged with hydrogen and put under 50 bars of hydrogen. It was then heated to 50 C. with stirring (1000 rpm) for 3 days. The autoclave was cooled down to r.t. purged with argon, the reaction mixture was concentrated under vacuum (40 C., 30 mbar). The crude material was purified via chromatography.

(75) LCMS characterization in table 116 (compound 116-61).

Example P11: Preparation of N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(76) ##STR00102##

Step a. Preparation of 3-chloro-2-iodo-5-(trifluoromethyl)pyridine

(77) 2,3-dichloro-5-(trifluoromethyl)pyridine (11.8 g, 54.6 mmol) was dissolved in acetonitrile (80 ml), then sodium iodide (12.4 g, 81.9 mmol) was added in one portion. Acetyl chloride (5.89 ml, 81.9 mmol) was added slowly. The white suspension turned to intensive yellow and the reaction mixture was stirred at reflux for 4 hours. It turned into a dark brown suspension. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to give a colourless oil.

(78) 1H NMR (CDCl3, 400 MHz) 8.52 (d, 1H), 7.87 (d, 1H).

Step b. Preparation of tributyl-[3-chloro-5-(trifluoromethyl)-2-pyridyl]stannane

(79) 3-chloro-2-iodo-5-(trifluoromethyl)pyridine (1.7 g, 5.5 mmol) was dissolved in dry toluene (8 ml) and cooled down to 75 C. Butyl lithium in hexanes (1.6M; 5.5 mmol, 3.5 ml) were added slowly via a syringe to give a slightly yellow solution. The reaction mixture was stirred at 75 C. for 1 hour. The solution became dark green. Tributyltin chloride (6.1 mmol, 1.6 ml) was added slowly at 75 C. and the mixture was slowly warmed up to room temperature. The reaction mixture was poured into saturated aqueous NH4Cl solution (50 ml) and extracted with tBuOMe, dried with Na2SO4 and evaporated to give a dark mixture which was purified by silica gel chromatography to give the desired product as a colourless oil.

(80) 1H NMR (CDCl3, 400 MHz) 8.87 (dd, 1H) 7.73 (d, 1H) 1.53-1.62 (m, 6H) 1.28-1.39 (m, 6H) 1.21-1.28 (m, 6H) 0.90 (t, 9H)

Step c. Preparation of N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(81) Prepared according to example P9 step a except the fact that the reaction time was extended to 2 days to afford the desired product as a colourless oil.

(82) LCMS characterization in table 115 (compound 115-34).

(83) TABLE-US-00002 TABLE 113 Compounds of formula (II) (II) 03 [M + H] RT (meas- Meth- MP Entry B Y R1 (min) ured) od ( C.) 113-1 3-methyl-thien-2-yl CH2 H 181* 113-2 5-chloro-thien-2-yl CH2 H 218* 113-3 6-chloro-pyridin-3-yl CH2 H 0.25 183 A 113-4 4-chloro-1-methyl-1H- CH2 H 158* pyrazol-3-yl 113-5 6-trifluoromethyl- CH2 H 4.79 217 C pyridin-3-yl 113-6 2-(2,2-difluoro-1,3- CH2 H 0.36 228 A benzodioxol-4-yl) 113-7 2-(6-bromo-1,3- CH2 H 0.55 270 A benzodioxol-5-yl) 113-8 5-chloro-2-furyl CH2 H 0.39 172 A 113-9 5-bromo-2-furyl CH2 H 206- 208* *HCl Salt

(84) Table 113 shows selected melting point, selected HPLC-MS, selected GC-MS and selected NMR data for compounds (II) or their hydrochloride salt of the present invention. CDCl.sub.3 was used as the solvent for NMR measurements, unless otherwise stated. No attempt is made to list all characterising data in all cases.

(85) In Table 113 and throughout the description that follows, temperatures are given in degrees Celsius; NMR means nuclear magnetic resonance spectrum; HPLC is high pressure liquid chromatography; GC stands for gas chromatography, MS stands for mass spectrum; % is percent by weight, unless corresponding concentrations are indicated in other units. The following abbreviations are used throughout this description: m.p.=melting point [ C.] b.p.=boiling point. s=singlet br=broad d=doublet dd=doublet of doublets t=triplet q=quartet m=multiplet ppm=parts per million

(86) TABLE-US-00003 TABLE 114 Trans isomers of compounds (II) 04 RT [M + H] Entry B Y R1 (min) (measured) Method 114-1 2-(6-bromo-1,3- CH2 H 0.61 270 A benzodioxol-5-yl)

(87) TABLE-US-00004 TABLE 115 Compounds of formula (IX) (IX) 05 [M + H] RT (meas- Entry A B (min) ured) 115-1 2-trifluoromethylphenyl benzothiophen-2-yl 1.08* 374 115-2 2-trifluoromethylphenyl pyrimidin-5-yl 0.62* 320 115-3 2-trifluoromethylphenyl benzofuran-2-yl 1.06* 358 115-4 2-trifluoromethylphenyl 2-chloroquinol-3-yl 1.01* 403 115-5 2-trifluoromethylphenyl 3-quinolyl 0.75* 369 115-6 2-trifluoromethylphenyl 5-methylbenzo- 1.14* 388 thiophen-2-yl 115-7 2-trifluoromethylphenyl 2-methylindazol-5- 0.77* 372 yl 115-8 2-trifluoromethylphenyl 1-methylindazol-5- 0.84* 372 yl 115-9 2-trifluoromethylphenyl 1,3-benzothiazol-5- 0.88* 375 yl 115-10 2-trifluoromethylphenyl 2-pyrido[2,3- 0.66* 371 b]pyrazin-7-yl 115-11 2-trifluoromethylphenyl 2-methyl-1,3- 0.87* 373 benzoxazol-5-yl 115-12 2-trifluoromethylphenyl thiazol-5-yl 0.71* 325 115-13 2-trifluoromethylphenyl 4-(trifluoromethyl)- 0.88* 387 pyrid-3-yl 115-14 2-trifluoromethylphenyl 8-quinolyl 1.1* 369 115-15 2-trifluoromethylphenyl 1-methylindol-5-yl 0.96* 371 115-16 2-trifluoromethylphenyl benzothiophen-3-yl 1.05* 374 115-17 2-trifluoromethylphenyl 5-quinolyl 0.61* 369 115-18 2-trifluoromethylphenyl 5-isoquinolyl 0.53* 369 115-19 2-trifluoromethylphenyl 2,4-dimethoxy- 0.88* 380 pyrimidin-5-yl 115-20 2-trifluoromethylphenyl 1-methylindazol-6- 0.85* 372 yl 115-21 2-trifluoromethylphenyl 2,5-dichloro-3- 1.16* 392 thienyl 115-22 2-trifluoromethylphenyl 4-isoquinolyl 0.55* 369 115-23 2-trifluoromethylphenyl 1H-indol-4-yl 0.86* 357 115-24 2-trifluoromethylphenyl 5-(trifluoromethyl)- 0.92* 387 3-pyridyl 115-25 2-trifluoromethylphenyl 2-cyano-5-methyl- 0.93* 347 3-furyl 115-26 2-trifluoromethylphenyl pyrido[2,3- 0.67* 371 b]pyrazin-7-yl 115-27 2-trifluoromethylphenyl 4-pyridyl 0.36* 319 115-28 2-trifluoromethylphenyl 3-methylimidazol- 0.26* 322 4-yl 115-29 2-trifluoromethylphenyl 8-quinolyl 1.11* 369 115-30 2-trifluoromethylphenyl 2-pyridyl 0.92** 319 115-31 2-trifluoromethylphenyl 3-chloro-2-pyridyl 1.17** 353 115-32 2-trifluoromethylphenyl 5-(trifluoromethyl)- 1.18** 387 2-pyridyl 115-33 2-trifluoromethylphenyl 3,5-dichloro-2- 1.04** 387 pyridyl 115-34 2-trifluoromethylphenyl 3-chloro-5- 1.26** 421 trifluoromethyl-2- pyridyl *Method E used **FFMethod A used

(88) Table 115 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds (IX) of the present invention. CDCl.sub.3 was used as the solvent for NMR measurements, unless otherwise stated. No attempt is made to list all characterising data in all cases.

(89) TABLE-US-00005 TABLE 116 Compounds of formula (I) (I) 06 RT [M + H] Entry A B Y R1 (min) (measured) Method MP ( C.) 116-1 2-trifluoromethylphenyl 5-fluoro-pyrid-2-yl O H 0.77 341 A 116-2 3-trifluoromethylpyrid-2-yl 3-methyl-thien-2-yl CH2 H 1.06 341 A 116-3 3-trifluoromethylpyrid-2-yl 5-chloro-thien-2-yl CH2 H 1.07 361 A 116-4 2-trifluoromethylphenyl 3-methyl-thien-2-yl CH2 H 111-112 116-5 2-trifluoromethylphenyl 5-chloro-thien-2-yl CH2 H 137-138 116-6 2-trifluoromethylpyrid-3-yl 3-methyl-thien-2-yl CH2 H 0.96 341 A 148-149 116-7 2-trifluoromethylpyrid-3-yl 5-chloro-thien-2-yl CH2 H 0.99 361 A 150-151 116-8 3-trifluoromethylpyrazin-2-yl 5-chloro-thien-2-yl CH2 H 1.03 362 A 116-9 3-trifluoromethylpyrazin-2-yl 3-methyl-thien-2-yl CH2 H 1.02 342 A 123-124 116-10 2-trifluoromethylphenyl 6-chloro-pyridin-3-yl CH2 H 0.91 355 A 152-153 116-11 2-trifluoromethylpyrid-3-yl 6-chloro-pyridin-3-yl CH2 H 0.83 356 A 166-169 116-12 3-trifluoromethylpyrazin-2-yl 6-chloro-pyridin-3-yl CH2 H 0.85 357 A 159-162 116-13 3-chloropyrazin-2-yl 6-chloro-pyridin-3-yl CH2 H 141-143 116-14 3-trifluoromethylpyrid-2-yl 6-chloro-pyridin-3-yl CH2 H 0.87 356 A 134-135 116-15 2-trifluoromethylphenyl 4-chloro-1-methyl-1H-pyrazol-3-yl CH2 H 0.94 358 A 116-16 2-trifluoromethylpyrid-3-yl 4-chloro-1-methyl-1H-pyrazol-3-yl CH2 H 0.85 359 A 121-122 116-17 3-trifluoromethylpyrid-2-yl 4-chloro-1-methyl-1H-pyrazol-3-yl CH2 H 0.93 359 A 116-18 3-trifluoromethylpyrazin-2-yl 4-chloro-1-methyl-1H-pyrazol-3-yl CH2 H 0.9 360 A 116-19 2-trifluoromethylphenyl 6-trifluoromethyl-pyridin-3-yl CH2 H 0.96 389 164-165 116-20 2-trifluoromethylpyrid-3-yl 6-trifluoromethyl-pyridin-3-yl CH2 H 0.88 390 147-148 116-21 3-trifluoromethylpyrazin-2-yl 6-trifluoromethyl-pyridin-3-yl CH2 H 0.9 391 151-153 116-22 3-trifluoromethylpyrid-2-yl 6-trifluoromethyl-pyridin-3-yl CH2 H 0.93 390 155-157 116-23 3-chloropyrazin-2-yl 6-trifluoromethyl-pyridin-3-yl CH2 H 0.84 357 145-146 116-24 2-trifluoromethylphenyl benzothiophen-2-yl CH2 H 1.74 376 D 116-25 2-trifluoromethylphenyl thiazol-5-yl CH2 H 1.12 327 D 116-26 2-trifluoromethylphenyl 4-(trifluoromethyl)-pyridin-3-yl CH2 H 1.39 389 D 116-27 2-trifluoromethylphenyl pyrimidin-5-yl CH2 H 0.96 322 D 116-28 2-trifluoromethylphenyl benzofuran-2-yl CH2 H 1.65 360 D 116-29 2-trifluoromethylphenyl 3-quinolyl CH2 H 1.05 371 D 116-30 2-trifluoromethylphenyl 5-methylbenzothiophen-2-yl CH2 H 1.85 390 D 116-31 2-trifluoromethylphenyl 2-methylindazol-5-yl CH2 H 1.27 374 D 116-32 2-trifluoromethylphenyl 1-methylindazol-5-yl CH2 H 1.39 374 D 116-33 2-trifluoromethylphenyl 1,3-benzothiazol-5-yl CH2 H 1.39 377 D 116-34 2-trifluoromethylphenyl 1-methylindol-5-yl CH2 H 1.64 373 D 116-35 2-trifluoromethylphenyl 1,2,3,4-tetrahydroquinolin-8-yl CH2 H 0.7 375 D 116-36 2-trifluoromethylpyrid-3-yl 2-(6-bromo-1,3-benzodioxol-5-yl) CH2 H 0.97 443 A 138-140 116-37 2-trifluoromethylphenyl 2-(6-bromo-1,3-benzodioxol-5-yl) CH2 H 1.04 442 A 120-121 116-38 3-chloropyrazin-2-yl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 0.99 366 A 92-93 116-39 3-trifluoromethylpyrazin-2-yl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 1.03 402 A 103-104 116-40 3-trifluoromethylpyrid-2-yl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 1.07 401 A 116-41 2-chloropyrid-3-yl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 0.96 367 A 120-121 116-42 2-trifluoromethylpyrid-3-yl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 1.00 401 A 120-122 116-43 2-trifluoromethylphenyl 2-(2,2-difluoro-1,3-benzodioxol-4-yl) CH2 H 1.07 400 A 93-94 116-44 2-trifluoromethylphenyl 5-quinolyl CH2 H 1.11 371 D 116-45 2-trifluoromethylphenyl 2,5-dichloro-3-thienyl CH2 H 1.9 394 D 116-46 2-trifluoromethylphenyl 1H-indol-4-yl CH2 H 1.59 359 D 116-47 2-trifluoromethylphenyl 5-(trifluoromethyl)-3-pyridyl CH2 H 1.54 389 D 116-48 2-trifluoromethylphenyl 8-quinolyl CH2 H 1.3 371 D 116-49 2-trifluoromethylphenyl 2-pyridyl CH2 H 1 321 D 116-50 2-trifluoromethylphenyl 3-chloro-2-pyridyl CH2 H 0.97 355 A 116-51 2-trifluoromethylphenyl 5-(trifluoromethyl)-2-pyridyl CH2 H 1 389 A 116-52 2-trifluoromethylphenyl 5-chloro-2-furyl CH2 H 117-118 116-53 2-trifluoromethylphenyl 5-bromo-2-furyl CH2 H 90-92 116-54 2-trifluoromethylpyrid-3-yl 5-bromo-2-furyl CH2 H 87-89 116-55 3-trifluoromethylpyrid-2-yl 5-bromo-2-furyl CH2 H 0.99 389 A 116-56 3-trifluoromethylpyrazin-2-yl 5-bromo-2-furyl CH2 H 0.96 390 A 116-57 2-chloropyrid-3-yl 5-bromo-2-furyl CH2 H 81-82 116-58 3-chloropyrazin-2-yl 5-bromo-2-furyl CH2 H 0.9 356 A 116-59 2,6-difluoro-phenyl 5-bromo-2-furyl CH2 H 89-91 116-60 3-chloropyrid-2-yl 5-bromo-2-furyl CH2 H 0.94 355 A 116-61 2-trifluoromethylphenyl 3,5-dichloro-2-pyridyl CH2 H 0.96 389 A

(90) Table 116 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds(I) of the present invention. CDCl.sub.3 was used as tl solvent for NMR measurements, unless otherwise stated. No attempt is made to list all characterising data in all cases.

(91) TABLE-US-00006 TABLE 117 Trans isomers of (I) 07 [M + H] RT (meas- MP Entry A B Y R1 (min) ured) ( C.) 117-1 2- 2-(6-bromo-1,3- CH2 H 1.07* 442 145- trifluoro- benzodioxol- 146 methyl 5-yl) phenyl *Method A

(92) Table 117 shows selected melting point, selected HPLC-MS for trans isomers of compounds (I) of the present invention. No attempt is made to list all characterising data in all cases.

(93) RT refers to the retention time of the HPLC-MS method and RT refers to the retention time of the desired enantiomer in the chiral HPLC method

(94) TABLE-US-00007 TABLE 118 Compounds of formula (Iab) 08 [M + H] Chiral RT (meas- RT Meth- Entry A B Y R1 (min) ured) (min) od 118-1 2-trifluoro- 5-chloro- CH2 H 0.99* 361 3.90 B methyl- thien-2-yl pyrid-3-yl 118-2 2-trifluoro- 3-chloro-2- CH2 H 0.97* 355 4.66 F methylphenyl pyridyl 2-trifluoro- 5-fluoro-2- 118-3 methylphenyl pyridyl O H 0.77* 341 5.52 G *Method A

(95) Table 118 shows selected melting point, selected HPLC-MS for compounds of the present invention. No attempt is made to list all characterising data in all cases.

(96) RT refers to the retention time of the HPLC-MS method and RT refers to the retention time of the desired enantiomer in the chiral HPLC method. Compounds 118-1 and 118-3 were obtained through the resolution of racemates via preparative chiral HPLC.

(97) Method A

(98) Spectra were recorded on a Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 350 C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85

(99) Method B (Chiral)

(100) Waters UPLCHClass from Waters: solvent degasser, quaternary pump and PDA detector Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (p) 3, wavelength (nm): 240 nm, solvent: Isocratic Heptane:EtOH 80:20, injection volume 2 l, flow (ml/min) 1.0

(101) Method C (GC-MS)

(102) GC-MS was conducted on a Thermo, MS: ISQ and GC: TRACE GC ULTRA with a column from Zebron phenomenex: Phase ZB-5 ms 15 m, diam: 0.25 mm, 0.25 m, H.sub.2 flow 1.7 ml/min, temp injector: 250 C., temp detector: 220 C., method: start at 70 C., 25 C./min until 320 C., hold 2 min at 320 C., total time 12 min.

(103) Cl reagent gas: Methane, flow 1 ml/min

(104) Method D

(105) ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer)

(106) Ionisation method: Electrospray

(107) Polarity: positive ions

(108) Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature ( C.) 150, Desolvation Temperature ( C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700

(109) Mass range: 100 to 800 Da

(110) DAD Wavelength range (nm): 210 to 400

(111) Method Waters ACQUITY UPLC with the following HPLC gradient conditions

(112) (Solvent A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid)

(113) TABLE-US-00008 Time (minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75

(114) Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60 C.

(115) Method E

(116) ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer)

(117) Ionisation method: Electrospray

(118) Polarity: positive ions

(119) Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature ( C.) 150, Desolvation Temperature ( C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700

(120) Mass range: 100 to 800 Da

(121) DAD Wavelength range (nm): 210 to 400

(122) Method Waters ACQUITY UPLC with the following HPLC gradient conditions

(123) (Solvent A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid)

(124) TABLE-US-00009 Time (minutes) A (%) B (%) Flow rate (ml/min) Time (minutes) A (%) B (%) Flow rate (ml/min) 0 80 20 1 0.1 75 25 1 0.2 70 30 0.75 1.2 0 100 0.75 1.40 0 100 0.75 1.45 80 20 1

(125) Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60 C.

(126) Method F (Chiral)

(127) Waters UPLCHClass from Waters: solvent degasser, quaternary pump and PDA detector Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (p) 3, wavelength (nm): 272 nm, solvent: Isocratic Heptane:iPrOH 80:20, injection volume 2 l, flow (ml/min) 1.0

(128) Method G (Chiral)

(129) Waters UPLCHClass from Waters: solvent degasser, quaternary pump and PDA detector Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (p) 3, wavelength (nm): 265 nm, solvent: Isocratic Heptane:iPrOH 70:30, injection volume 2 l, flow (ml/min) 1.0

BIOLOGICAL EXAMPLES

Meloidogyne Spp. (Root-Knot Nematode)

(130) Nematicide, Contact Activity, Preventive.

(131) Filter papers (9 cm4.5 cm) with a small pocket were placed into plastic pouches (12 cm6 cm). One cucumber cv. Toshka seed was placed in the centre of the filter paper pocket of all the pouches needed for a test. The cucumber seeds in the pouches were treated with test solutions at 200 ppm by pipetting the solution directly over the cucumber seed in the filter paper pocket in the pouch. Prior to application, the compound solution was prepared at twice the concentration required and the egg suspension is prepared with FORL nutrient solution with 3000 eggs/0.5 ml. After applying all the treatments, 3000 eggs (in 0.5 ml of FORL nutrient solution) were pipetted into the pouches. The pouches were incubated in a moist chamber for twelve days and watered regularly to maintain good filter paper moisture essential for the growing cucumber root system. After this period, the filter paper containing the germinated cucumber seedling was removed from the plastic pouch to assess the number of galls caused by Meloidogyne spp. per root system.

(132) The following compounds showed a greater than 80% reduction of galling compared to the untreated control: 116-2, 116-3, 116-5, 116-6, 116-7, 116-8, 116-9, 116-10, 116-11, 116-12, 116-13, 116-14, 116-20, 116-21, 116-22, 116-23.

(133) Heterodera schachtii (Sugar beet cyst nematode), Nematicide, contact activity

(134) The tested application rate of each compound was 20 ppm. All solutions were brought to a concentration of 40 ppm, respectively, as they were subsequently diluted by adding the equivalent amount of water containing juvenile nematodes. After preparation of the suspensions, 1 ml of each suspension and concentration was transferred to 16-well assay plates with a total of three replicates per treatment. Approximately 500 juveniles of Heterodera schachtii were added in 1 ml of water to each well. Nematodes in water served as controls. The plates were placed in a dark box and stored at room temperature. Nematode paralysis was determined after 24 hours incubation at 25 C. in darkness. Nematodes that showed no movement were considered immotile.

(135) The following compounds showed a greater than 75% nematode immobilization compared to the untreated control: 116-2, 116-3, 116-4, 116-6, 116-7, 116-8, 116-9, 116-10, 116-11, 116-12, 116-13, 116-14, 116-17, 116-19, 116-21, 116-22, 116-26, 116-35, 116-48, 116-50, 116-51, 118-1, 118-2.

(136) Meloidogyne Spp. (Root-Knot Nematode)

(137) Nematicide, contact activity, preventive

(138) Cucumber cv. Toshka seeds were sown directly into pots filled with a sandy substrate. Six days later pots were each treated with 5 ml of a WP10 suspension of the test compound. Hereafter, pots were inoculated with 3000 eggs of M. incognita. The trial was harvested fourteen days after trial application and inoculation. Root galling was assessed according to Zeck's gall index (Zeck W. M. (1971) Ein Bonitierungsschema zur Feldauswertung von Wurzelgallenbefall. Pflanzenschutznachrichten Bayer 24, 1: 144-147.). The following compounds showed a greater than 80% reduction of galling compared to the untreated control: 116-3, 116-4, 116-5, 116-6, 116-7, 116-8, 116-10, 116-11, 116-12, 116-13, 116-14, 116-15, 116-16, 116-19, 116-21, 116-22, 116-23, 116-40, 116-42.

(139) C. elegans In-Vivo Assay:

(140) C. elegans were cultured using standard conditions as described in The nematode Caenorhabditis elegans (W. B. Wood, Cold Spring Harbor Laboratory Press 1988). Eggs from a drug hypersensitive C. elegans mutant strain were isolated. Eggs were placed on solutions of test compounds at a concentration of 50 ppm. Tests were conducted in duplicate. Eggs were incubated at 25 C. for 72 hours. Development of eggs was assessed visually after 72 hours and recorded photographically.

(141) The following compounds showed a total inhibition of egg development: 118-3.