4-membered ring carboxamides used as nematicides

Abstract

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

Claims

1. A compound selected from ##STR00163##

2. A composition comprising a compound of formula (I) selected from ##STR00164## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

3. A compound according to claim 1 which is ##STR00165##

4. A compound according to claim 1 which is ##STR00166##

5. A compound according to claim 1 which is ##STR00167##

6. A compound according to claim 1 which is ##STR00168##

7. A composition according to claim 2 comprising a compound of formula ##STR00169## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

8. A composition according to claim 2 comprising a compound of formula ##STR00170## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

9. A composition according to claim 2 comprising a compound of formula ##STR00171## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

10. A composition according to claim 2 comprising a compound of formula ##STR00172## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

11. A composition according to claim 2 comprising a compound of formula ##STR00173## wherein the ratio of the compound of formula (I) to its enantiomer is greater than 1.5:1, greater than 2.5:1, greater than 4:1, greater than 9:1, or greater than 20:1.

12. The composition according to claim 2, wherein the ratio of the compound of formula (I) to its enantiomer is greater than 9:1.

13. A method of controlling pests in soil, the method comprising: applying to the soil a composition according to claim 12.

14. The method of claim 13, wherein the application to the soil is through a solid carrier treated with the composition.

15. The method of claim 14, wherein the solid carrier is a seed.

16. The method of claim 13, wherein the pest is a nematode.

17. The composition of claim 2, wherein the ratio of the compound of formula (I) to its enantiomer is greater than 20:1.

Description

FIGURES

(1) FIG. 1. Structure of Example P17 with non-hydrogen atoms shown as thermal ellipsoids at the 50% probability level.

(2) FIG. 2. Numbering scheme for Example P17.

EXAMPLES

Preparation Examples

Example P1

Preparation of racemic N-[cis-2-(4-chlorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide

(3) ##STR00138##

(4) A solution of 4-fluorobenzaldehyde (288 mg, 2.32 mmol) and 2-trifluoromethyl-N-vinyl-benzamide (1 g, 4.65 mmol) in acetonitrile (15 ml) was irradiated with a sodium vapour lamp through a quartz filter for 7 days. The cloudy reaction mixture was evaporated down and the crude half-solid (1.6 g) was chromatographed on silica with EtOAc/cyclohexane, then again with MeOH/dichloromethane and again with EtOAc/cyclohexane to yield N-[cis-2-(4-chlorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide.

(5) 1H-NMR (CDCl3) 4.51 (1H, t); 5.17 (1H, t); 5.48 (1H, M); 5.71 (1H, br d); 6.08 (1H, d); 6.93 (1H, d); 7.12 (2H, t); 7.38 (2H, m); 7.47 (2H, m); 7.63 (1H, d).

Example P1 b

Preparation of 2-trifluoromethyl-N-vinyl-benzamide

(6) n-Propylamine (4.8 g, 82 mmol) was added to a solution of 10 g of the mixture of 2-trifluoromethyl-N-vinyl-N-formyl-benzamide (example P1c) and 2-trifluoromethyl-N-vinyl-benzamide (10 g, 41 mmol) in dichloromethane (50 ml). There was an exotherm, which was controlled by the use of a cold water bath. After one hour tlc (70% EtOAc/hexane) showed complete reaction so the mixture was separated between water and EtOAc, dried (MgSO.sub.4) and evaporated to yield 11 g of a brown oil which contained nPrNH2 according to NMR. This was dissolved in ethanol (ca 30 ml), warmed to 50? C., treated with water and allowed to cool. The crystals were then filtered off and dried to yield 2-trifluoromethyl-N-vinyl-benzamide as beige crystals. m.p. 92-95? C.

(7) 1H-NMR (CDCl.sub.3) 4.57 (1H, d); 4.72 (1H, d), 7.10 (1H, ddd); 7.44 (1H, br s); 7.60 (3H, m); 7.73 (1H, d).

Example P1c

Preparation of 2-trifluoromethyl-N-vinyl-N-formyl-benzamide

(8) 2-Trifluoromethyl-benzoyl chloride (32 g, 154 mmol) was added in portions to a stirred solution of N-vinylformamide (10 ml, 10 g, 140 mmol), 4-dimethylaminopyridine (1.7 g, 14 mmol), and triethylamine (29.2 ml, 21.2 g, 210 mmol) in dichloromethane in an ice/water bath at such a rate that the temperature stayed below 25? C. After complete addition the mixture was allowed to warm to room temperature. After two hours the mixture was separated between water and EtOAc, the organic phase dried and evaporated to give a brown oil. NMR showed a ca 1:1 mixture of 2-trifluoromethyl-N-vinyl-N-formyl-benzamide and 2-trifluoromethyl-N-vinyl-benzamide.

(9) 1H-NMR (CDCl3, signals given for 2-trifluoromethyl-N-vinyl-N-formyl-benzamide) 5.26 (1H, d); 5.72 (1H, d); 6.69 (1H, dd); 7.43 1H, d); 7.58 (1H, m); 7.68 (1H, m); 7.80 (1H, d); 8.87 (1H, s).

Example P2

Preparation of racemic cis N-[2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide

(10) ##STR00139##

a. Preparation of 2-(4-chlorophenyl)cyclobutanone

(11) To a stirred solution of 4-chloro-benzaldehyde (142 mg, 1 mmol) and cyclopropyldiphenylsulfonium tetrafluoroborate (317 mg, 1 mmol) in 10 ml dry THF, cooled to 0? C., was added dropwise, with stirring, a slurry of potassium tert. butoxide (1.4 ml; 1M). After addition was complete the reaction was stirred 30 min. and 1M tetrafluoroboric acid (10% in THF) (10 ml) was added. The mixture was allowed to warm to room temperature and was taken up into ether and the ether solution was washed with saturated NaHCO.sub.3, brine and water and was dried. Filtration and concentration by rotary evaporation gave an oil. Chromatography over silica gel and elution with hexanes:ether 5:1 gave 2-(4-chlorophenyl)cyclobutanone as an oil

(12) 1H-NMR (CDCl.sub.3) 2.20 (1H, m); 2.57 (1H, m); 3.06 (1H, m); 3.23 (1H, m); 4.51 (1H, m); 7.20 (2H, m); 7.29 (3H, m);

b. Preparation of 2-(4-chlorophenyl)cyclobutanone oxime

(13) A solution of 2-(4-chlorophenyl)cyclobutanone (1.122 g, 6.09 mmol), hydroxylamine hydrochloride (3.541 g. 8.2 eq.) and 36 ml of 5% NaOH in 30 ml EtOH was heated at reflux for 2 h. The solution was cooled, adjusted to pH 6, and extracted with CHCl.sub.3. The organic extract was washed with brine and dried. Filtration and concentration yielded 2-(4-chlorophenyl)cyclobutanone oxime as an oil. 1H-NMR (CDCl.sub.3) 2.13 (1H, m); 2.53 (1H, m); 3.01 (2H, m); 4.40 (1H, m); 7.27 (5H, m);

c. Preparation of 2-(4-chlorophenyl)cyclobutanamine

(14) To a solution of 2-(4-chlorophenyl)cyclobutanone oxime (200 mg, 1 mmol) in methanol (5 ml) was added MoO.sub.3 (205 mg, 1.4 eq.) and sodium borohydride (394 mg, 10 eq) at 0? C. After stirring at rt for 2 h the solvent was evaporated. A mixture of H.sub.2O and CH.sub.2Cl.sub.2 was added. Organic phase was separated, washed with brine, dried and concentrated in vacuo. 120 mg of product-amine was isolated as a mixture of cis and trans isomers 2:1. The crude product was used without purification in the next reaction.

d. Preparation of N-[2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide

(15) To a solution of 2-(4-chlorophenyl)cyclobutanamine (105 mg, 0.55 mmol) and triethylamine (140 mg 2.5 eq.) in THF was added 2-trifluoromethyl-benzoylchloride (127.46 mg, 1.1 eq.) at 0? C. The reaction mixture was stirred at rt for 2 h. Et.sub.3N.HCl was filtered off and the THF was evaporated. The residue-mixture of two isomers cis and trans (2:1) was purified and separated with chromatography on silica gel, eluent hexanes:diethylether 1:1, N-[cis-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide (cis) (m.p. 147-9? C.) and its trans isomer (m.p. 117-9? C.) were isolated as crystalline products.

Example P3

Preparation of 2-(4-chlorophenyl)cyclobutanone (alternative)

(16) ##STR00140##

a. Preparation of 1-chloro-4-(cyclopropylidenemethyl)benzene

(17) To a suspension of (3-bromopropyl)triphenylphosphonium bromide (29.3 g) in anhydrous THF (200 ml) was added in 5 separate portions 15 mins apart potassium tert. butoxide (14.19 g, 2.2 eq.) to give a yellow suspension. The mixture was heated to reflux for 10 min and 4-chlorobenzaldehyde (8.08 g, 56.9 mmol) was added to give an orange suspension. The reaction mixture was stirred and then heated at reflux for 4 h. The reaction mixture was then cooled to room temperature, and filtered through a Celite pad. The solvent was removed in vacuo, and the resulting crude material was subjected to flash chromatography with i-hexane as an eluent, affording 1-chloro-4-(cyclopropylidenemethyl)benzene.

(18) 1H-NMR (CDCl.sub.3) 1.19 (2H, m); 1.41 (2H, m); 6.70 (1H, m); 7.27 (2H, m); 7.46 (2H, m)

b. Preparation of 2-(4-chlorophenyl)cyclobutanone

(19) To a solution of 1-chloro-4-(cyclopropylidenemethyl)benzene (5 g, 30 mmol) in CH.sub.2Cl.sub.2 (80 ml) was added in 5 separate portions m-chloroperbenzoic acid (5.3 g, 30 mmol) at 0? C. After stirring at 0? C. for 3 h, the reaction mixture was washed with saturated NaHCO.sub.3 aqueous solution and brine, dried over Na.sub.2SO.sub.4 and concentrated. To the crude product in CH.sub.2Cl.sub.2 (40 ml) was added a 10% HBF.sub.4 (11.6 ml 48% HBF.sub.4 and 46 ml H.sub.2O). After stirring at rt for 17 h, the mixture was extracted with CH.sub.2Cl.sub.2, washed with saturated NaHCO.sub.3 aq. solution and brine. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent i-hexane) to give 2-(4-chlorophenyl)cyclobutanone.

Example P4

Preparation of N-[2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(20) ##STR00141##

(21) 2-(4-chlorophenyl)cyclobutanone (10 g) was dissolved in 50 ml toluene. The solution was cooled to 0? C. and ammonia in methanol (11.863 ml; 7M) and titanium isopropoxide (34.6 ml, 32.442 g) were added. The mixture was warmed to rt and stirred for 18 h, then cooled to 0? C. and triethylamine (31.2 ml, 22.6343 g) and 2-trifluoromethyl-benzoyl chloride (16.47 ml, 23.3259 g) were added subsequently. During the addition of the acid chloride a thick suspension was formed, so that toluene (ca. 50 ml) were added to get the reaction mixture more stirrable. After 2 hours stirring at RT, a solution of ethylene diamine-N,N,N,N-tetra-2-ethanol (33.3 ml, 34.3390 g) in a little toluene was added to the reaction mixture. The mixture was stirred at 60? C. (oil bath) for 15 min, cooled to rt and shaken between water (300 ml), ammonia solution (50 ml) and ethyl acetate. The organic phase was washed with water then brine, dried with Na2SO4, evaporated and the crude material stirred with 100 ml diethyl ether. The solid was filtered off and dried to yield 9.2 g of impure product. The mother liquors were chromatographed with EtOAc/hexane to yield 1.4 g of impure product. The two crude fractions were combined and chromatographed again to yield pure N-[2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide m.p. 165-8? C., 1H-NMR (CDCl3) 2.62 (2H, m); 3.16 (2H, m); 7.08 (2H, d), 7.27 (2H, d); 7.51 (1H, br s, NH); 7.61 (1H, m); 7.64 (2H, m), 7.76 (1H, d).

Example P5

Preparation of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide

(22) ##STR00142##

a. Preparation of N-[2-(4-chlorophenyl)cyclobuten-1-yl]-acetamide

(23) 2-(2,4-dichlorophenyl)cyclobutanone (100 g) was dissolved in toluene (280 ml) under argon at 0? C., and ammonia in methanol (99.6 ml; 7M) in methanol was added dropwise. No exotherm was observed. Titanium isopropoxide (291 ml, 272 g) was added dropwise (ca. over 1.5 h). An exotherm was observed, and so the internal temperature was held between 0 and 5? C. with an ice bath. The mixture was warmed to rt and stirred for 17 h. The mixture was cooled to 0? C. and triethylamine (262 ml, 190 g) was added over ca. 20 min followed by acetic anhydride (88.70 ml, 95.9 g). An exotherm was observed. The internal temperature was held between 0 and 5? C. then warmed to rt and stirred for 3 h. Ethylene diamine-N,N,N,N-tetra-2-ethanol (206 ml, 233 g) was added to the reaction mixture. The mixture was heated to 55? C. internal for 15 min, then cooled to rt. The mixture was shaken between water, ammonia solution and EtOAc. The aqueous phase was washed with tBuOMe, and the organic phases combined, dried over MgSO4 and the solvent was evaporated to give a oily brown solid. This crude was triturated with ethyl acetate (ca. 1 h), then isolated via suction, washed with TBME and dried via suction. The mother liquor was placed in the fridge over the weekend and a precipitation was observed. The solid was isolated via suction, washed with cyclohexane and dried in air. To give combined solids of good purity. The mother liquor was concentrated and chromatographed with EtOAc/hexane to yield nearly pure material, which was triturated with cyclohexane and the solids filtered off and washed with cyclohexane to yield pure product

(24) 1H-NMR (CDCl3) 2.06 (3H, s, Me); 2.65 (2H, m); 3.06 (2H, m); 7.12 (1H, d); 7.19 (1H, d); 7.32 (1H, s); 7.58 (1H, br, s, NH).

b. Preparation of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide

(25) N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (25 g) and dimethylammonium dichlorotri(mu-chloro)bis[(s)-(+2,2-bis(diphenylphosphino)-1,1-binaphthyl]diruthenate(II) (0.4078 g) were placed in an autoclave (vertex hpm) and methanol (250 ml) was added. The methanol was previously purged for 30 min with argon. It was purged with argon 3 times, then with hydrogen 3 times and an internal pressure of hydrogen of 50 bar was built up. The reaction mixture was stirred over 18 h at 45? C. After 18 h the autoclave was opened and the solvent was evaporated to give the crude (26.17 g) as a grey oil. This was chromatographed with ethyl acetate and cyclohexane to yield almost pure product. It was analyzed by chiral HPLC (method X) and showed an ee of 87% in favour of the desired enantiomer eluting at 9.59 min (minor enantiomer eluting at 8.11 min). This was combined with material from an analogous hydrogenation batch of N-[2-(4-chlorophenyl)cyclobuten-1-yl]acetamide, and recrystallized from ethyl acetate and cyclohexane to yield pure product with 98% ee.

(26) 1H-NMR (CDCl3) 1.76 (s, 3H, Me); 1.94 (1H, m); 2.26 (2H, m); 2.49 (1H, m); 4.14 (1H, m); 4.92 (1H, m), 4.99 (1H, br s, NH); 7.32 (m, 2H); 7.42 (1H, s).

c. Preparation of N-(1S,2S)-2-(2,4-dichlorophenyl)cyclobutylamine hydrochloride

(27) N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide (15.7 mmol, 4.04 g, ee=91%) was diluted in methanol (15 ml). hydrochloric acid 36% (157 mmol, 18.6 g, 15.7 ml) was then added drop-wise. The reaction mixture was stirred at reflux overnight (20 hours). Methanol was evaporated, then some TBME and water were added to the mixture. Both phases were separated and the aqueous phase was washed twice with TBME. The aqueous phase was mixed with TBME cooled down to 0? C. whereupon sodium hydroxide 30% solution (16 ml) was slowly added until the pH became basic. Both phases were separated again and the aqueous phase was extracted twice with TBME. Organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give an orange oil.

(28) The amine was diluted in diethyl ether and cooled down to 0? C. whereupon aqueous HCl (1M) in diethyl ether was added drop-wise. A solid precipitated. This solid was isolated by filtration, washing with diethyl ether and drying on high vacuum pump to afford a white powder. It was analysed via chiral HPLC (method Y) which showed an ee of 88% in favour of the desired enantiomer eluting at 7.85 min (minor enantiomer eluting at 5.08 min).

(29) 1H-NMR (CDCl3) 1.50 (1H, m); 2.26 (1H, m); 2.45 (1H, m); 2.91 (1H, m); 3.99 (2H, m); 7.22 (1H, d); 7.38 (2H, m); 8.03 (3H, br s, NH3+)

d. Preparation of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide

(30) N-(1S,2S)-2-(2,4-dichlorophenyl)cyclobutylamine hydrochloride (9.6 g, 38 mmol) was dissolved in 100 ml DMF, N-hydroxy-benztriazole. hydrate (11 g, 76 mmol), EDCl hydrochloride (15 g, 76 mmol), and 2-trifluoromethylnicotinic acid (8.7 g, 46 mmol) were added. Triethylamine (12 g, 110 mmol) was added to give a weak exotherm, and a slight suspension. It was stirred overnight at RT. The mixture was shaken between ether and water, washed with brine, dried with Na2SO4, and evaporated. The crude was stirred with hexane and the crystals filtered off, washed with hexane, and dried in vacuo to yield pure product. It was analyzed via chiral HPLC (method C) which showed an ee of 99.7% in favour of the desired enantiomer eluting at 4.81 min (minor enantiomer eluting at 9.32 min).

(31) m.p. 122-124? C.

(32) 1H-NMR (CDCl3) 2.07 (1H, m); 2.38 (2H, m); 2.12 (1H, m); 2.62 (1H, m); 4.26 (m, 1H); 5.05 (1H, m); 5.45 (1H, br d, NH); 7.28 (3H, m); 7.48 (1H, dd); 7.63 (1H, d); 8.68 (1H, d).

Example P6

Preparation of N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]formamide

(33) ##STR00143##

a. Preparation of N-[1-(2,4-difluorobenzoyl)cyclopropyl]formamide

(34) 2-Bromo-4-chloro-1-(2,4-difluorophenyl)butan-1-one (5 g) was dissolved in acetonitrile (16 ml) and dimethylformamide (0.84 ml). To this solution was added, at room temperature, (diformylamino)sodium (4 g), and the resulting beige suspension was heated under stirring at 60? C. for 6.5 hours. The reaction mixture was allowed to cool down to room temperature, and aqueous sodium hydroxide solution (16.8 ml; 2N) was then added. The biphasic mixture was then stirred for 15 minutes, before being poured into a separatory funnel containing aqueous hydrochloric acid solution (50 ml; 1N). The aqueous phase was separated and extracted twice with ethyl acetate (100 ml then 50 ml). The organic phase was extracted four times with water and once with brine, before the organic phases were combined and dried with solid sodium sulfate, filtered and concentrated under vacuum. N-[1-(2,4-difluorobenzoyl)-cyclopropyl]formamide was obtained as a brownish solid.

(35) .sup.1H NMR (400 MHz, CDCl3) ? ppm Minor rotamer: 8.13 (dd, J=11.74, 2.20 Hz, 1H), 7.53-7.49 (m, 1H), 6.99 (td, J=8.44, 2.20 Hz, 1H), 6.93-6.85 (m, 1H), 6.46 (bs, 1H), 1.90-1.83 (m, 2H), 1.42-1.38 (m, 2H).

(36) Major rotamer: 7.96 (s, 1H), 7.59-7.51 (m, 1H), 6.95 (td, J=8.44, 2.20 Hz, 1H), 6.86-6.80 (m, 1H), 6.52 (bs, 1H), 1.90-1.84 (m, 2 H), 1.31-1.27 (m, 2 H).

b. Preparation of N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]formamide

(37) N-[1-(2,4-Difluorobenzoyl)-cyclopropyl]formamide (1.79 g) was dissolved in ethanol (40 ml) and the solution was cooled down to 0? C. Sodium borohydride (150 mg) was added to the resulting solution in one portion. After 15 min stirring at 0? C., the reaction mixture was allowed to warm to room temperature and stirred for half an hour more. It was then cooled down to 0? C. and aqueous saturated ammonium chloride solution (12 ml) was added slowly. The mixture was then diluted with ethyl acetate and poured onto water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water, then brine, before being dried on solid sodium sulfate, filtered and concentrated under vacuum. The desired product N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]formamide was obtained as a pale yellow oil.

(38) .sup.1H NMR (400 MHz, CDCL3) ? ppm

(39) Minor rotamer: 7.86 (d, J=11.7 Hz, 1H), 7.52-7.44 (m, 1H), 6.94-6.85 (m, 1H), 6.83-6.77 (m, 1H), 6.18 (bs, 1H), 4.59 (d, J=2.6 Hz, 1H), 3.41 (d, J=3.3 Hz, 1H), 1.1-0.7 (m, 4H)

(40) Major rotamer: 7.97 (s, 1H), 7.54-7.46 (m, 1H), 6.94-6.85 (m, 1H), 6.80-6.74 (m, 1H), 6.21 (bs, 1H), 5.36 (d, J=5.5 Hz, 1H), 4.55 (d, J=5.5 Hz, 1H), 1.1-0.7 (m, 4H)

c. Preparation of N-[(2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide

(41) To a solution of N-[1-[(2,4-difluorophenyl)-hydroxymethyl]cyclopropyl]formamide (498 mg) in toluene (8.7 ml) was added sulfur trioxide pyridine complex (Py.SO3) (523 mg; 45% SO3). The resulting suspension was heated at 80? C. for 4 hours, before being diluted with ethyl acetate and added onto a saturated aqueous solution of sodium bicarbonate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide was obtained as a solid. .sup.1H NMR (400 MHz, CDCl3) ? ppm

(42) Major isomer: 8.39 (dd, J=11.37, 4.40 Hz, 1H), 7.88 (bs, 1H), 7.13-7.07 (m, 1H), 6.90-6.79 (m, 2H), 2.83-2.79 (m, 2H), 2.67-2.63 (m, 2H). Minor isomer: 8.22 (s, 1H), 7.73 (bs, 1H), 7.15-7.09 (m, 1H), 6.90-6.79 (m, 2H), 3.13-3.10 (m, 2H), 2.63-2.59 (m, 2H).

d. Preparation of N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]formamide

(43) Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (4.5 mg) and (R)-1-[(S.sub.P)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (5.4 mg) were dissolved in degassed 2,2,2-trifluoroethanol (4 mL) and the resulting catalyst solution was stirred for 30 min at room temperature under argon. Then, 2 mL of the catalysts solution and 3 mL degassed 2,2,2-trifluoroethanol were transferred via syringe into a 100 ml stainless steel reactor containing N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide (100 mg) set under an atmosphere of argon. The reactor was purged 3 times with hydrogen (10 bar) and finally pressurized to 50 bar. The reaction mixture was stirred under 50 bars of hydrogen at 50? C. After 18 h the autoclave was vented. The crude reaction mixture was filtrated over a pad of celite and evaporated giving N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]formamide as an oil.

(44) Chiral GC analysis (method AA), retention time 11.91 minutes (major enantiomer 93.7%) and 12.19 minutes (minor enantiomer 6.3%))

(45) Major rotamer: .sup.1H NMR (400 MHz, CDCl.sub.3): ?=2.00-2.08 (m, 1H), 2.27-2.35 (m, 2H), 2.48-2.65 (m, 1H), 4.03-4.14 (m, 1H), 4.88-4.96 (q, 1H), 5.29 (bs, 1H), 6.80-6.95 (m, 2H), 7.21-7.32 (m, 1H), 7.94 (s, 1H).

(46) Minor rotamer: .sup.1H NMR (400 MHz, CDCl.sub.3): ?=2.00-2.08 (m, 1H), 2.27-2.35 (m, 2H), 2.48-2.65 (m, 1H), 4.03-4.14 (m, 1H), 4.40-4.49 (q, 1H), 5.40 (bs, 1H), 6.80-6.95 (m, 2H), 7.21-7.32 (m, 1H), 7.95-7.98 (d, 1H).

Example P7

Preparation of N-[(2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide

(47) ##STR00144##

a. Preparation of N-[1-(2,4-difluorobenzoyl)cyclopropyl]-N-formyl-acetamide

(48) N-[1-(2,4-Difluorobenzoyl)cyclopropyl]formamide (2 g) was suspended acetonitrile (10.2 ml). To this was added acetic anhydride (4.2 ml) and triethylamine (2.47 ml). The resulting solution was heated under stirring at 75? C. overnight. After 28 h total time, the mixture was cooled down to room temperature, diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[(1-(2,4-difluorobenzoyl)cyclopropyl]-N-formyl-acetamide was obtained as an oil. .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.43-1.54 (m, 2 H), 1.91-1.99 (m, 2 H), 2.35 (s, 3 H), 6.76-6.99 (m, 2 H), 7.28-7.42 (m, 1 H), 9.14 (s, 1 H)

b. Preparation of N-[1-(2,4-difluorobenzoyl)cyclopropyl]acetamide

(49) N-[(1-(2,4-Difluorobenzoyl)cyclopropyl]-N-formyl-acetamide (2.7 g) was dissolved in methanol (10 ml). To this solution was added potassium carbonate (0.7 g). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with water, and then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. The crude material was purified over a 80 g silica gel chromatography column. N-[1-(2,4-difluorobenzoyl)cyclopropyl]acetamide was obtained as a solid. .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.21-1.27 (m, 2 H), 1.76 (s, 3 H), 1.78-1.84 (m, 2 H), 6.39 (br. s., 1 H), 6.82 (t, J=9.48 Hz, 1 H), 6.95 (td, J=8.25, 2.20 Hz, 1 H), 7.51-7.59 (m, 1 H)

c. Preparation of N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]acetamide

(50) N-[1-(2,4-Difluorobenzoyl)cyclopropyl]acetamide (1.525 g) was dissolved in ethanol (19 ml) and the solution was cooled down to 0? C. Sodium borohydride (72 mg) was added to the resulting solution in one portion. After 15 min stirring at 0? C., the reaction mixture was allowed to warm at room temperature and stirred for half an hour more. After that time and every half an hour for 90 minutes, sodium borohydride (12 mg) was added to the mixture. It was then cooled down to 0? C. and aqueous saturated ammonium chloride solution (12 ml) was added slowly. The mixture was then diluted with ethyl acetate and poured onto an aqueous saturated solution of ammonium chloride. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with an aqueous saturated solution of ammonium chloride, then brine, before being dried over solid sodium sulfate, filtered and concentrated under vacuum. The desired product N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]acetamide was obtained as a sticky oil. .sup.1H NMR (400 MHz, CDCl3) ? ppm 0.69-0.80 (m, 1 H), 0.90-1.07 (m, 1 H), 1.07-1.19 (m, 2 H), 1.88 (s, 3 H), 4.52 (d, J=5.50 Hz, 1 H), 5.85 (d, J=5.87 Hz, 1 H), 5.97 (br. s., 1 H), 6.76 (ddd, J=10.55, 8.53, 2.57 Hz, 1 H), 6.89 (td, J=8.25, 1.83 Hz, 1 H), 7.46-7.57 (m, 1 H)

d. Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide

(51) (d1)

(52) To a solution of N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]acetamide (216 mg) in toluene (2.7 ml) was added sulfur trioxide pyridine complex (Py.SO.sub.3; 214 mg; 45% SO.sub.3). The resulting suspension is heated at 80? C. for 90 minutes, before being diluted with ethyl acetate and added to a saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide was obtained as a solid.

(53) (d2)

(54) N-[2-(2,4-Difluorophenyl)cyclobuten-1-yl]-N-formyl-acetamide (123 mg) was dissolved in isopropanol (0.53 ml), and to this solution was added potassium carbonate (0.036 g). The reaction mixture was heated to 60? C. for 3 hours, before being allowed to cool down to room temperature, diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide was obtained as a solid. .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.08 (s, 3 H), 2.56 (t, J=3.30 Hz, 2 H), 3.09 (br. s., 2 H), 6.76-6.92 (m, 2 H), 7.03-7.15 (m, 1 H), 7.72 (d, J=9.90 Hz, 1 H)

e. Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-N-formyl-acetamide

(55) N-[2-(2,4-Difluorophenyl)cyclobuten-1-yl]formamide (0.5 g) was suspended in acetonitrile (2.8 ml). To this was added acetic anhydride (0.7 ml) and triethylamine (0.66 ml). The resulting solution was heated under stirring at 75? C. After 5 h, the mixture was cooled down to room temperature, diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]N-formyl-acetamide was obtained as an oil. .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.27 (s, 3 H), 2.73-2.77 (m, 2 H), 2.85-2.88 (m, 2 H), 6.80 (ddd, J=10.82, 8.62, 2.57 Hz, 1 H), 6.88 (td, J=8.25, 2.57 Hz, 1 H), 7.21-7.28 (m, 1 H), 9.31 (s, 1 H)

Example P8

Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide

(56) ##STR00145##

a. Preparation of 4-(2,4-dichlorophenyl)-5-oxa-7-azaspiro[2.4]hept-6-ene

(57) To a suspension of cyclopropylisonitrile (0.7 ml) in tetrahydrofurane (25 ml) was added, at ?78? C., nBuLi (6.05 mL; 1.6M hexane solution). After stirring at ?78? C. for 15 minutes, a solution of 2,4-dichlorobenzaldehyde (1.6 g) in THF (7 ml) was added dropwise. The reaction mixture was stirred 2 hours at ?78? C., before being quenched by the addition of methanol (4.5 ml). It was then allowed to warm to room temperature, before being diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous ammonium chloride solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed once more with saturated ammonium chloride aqueous solution, then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. The crude material was purified over a 80 g silica gel chromatography column. 4-(2,4-Dichlorophenyl)-5-oxa-7-azaspiro[2.4]hept-6-ene was obtained as an oil. .sup.1H NMR (400 MHz, CDCl3) ? ppm 0.43 (ddd, J=9.81, 6.88, 5.69 Hz, 1 H), 0.90-1.05 (m, 2 H), 1.24 (ddd, J=10.36, 7.06, 4.95 Hz, 1 H), 5.80 (s, 1 H), 7.03 (s, 1 H), 7.27-7.41 (m, 2 H)

b. Preparation of 2-bromo-4-chloro-1-(2,4-dichlorophenyl)butan-1-one

(58) To a solution of 4-chloro-1-(2,4-dichlorophenyl)butan-1-one (2.4 g) in dichloromethane (24 ml) was added, at room temperature, bromine (0.513 ml). After 30 minutes stirring, 9.5 mL of a 1N aqueous sodium hydroxide solution (9.5 ml; 1 N) was added slowly. The mixture was then diluted with dichloromethane and poured onto an aqueous solution of NaHSO3 (10%). The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phase was washed with an aqueous solution of NaHSO3 (10%), then with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. 2-bromo-4-chloro-1-(2,4-dichlorophenyl)butan-1-one was obtained as an oil. .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.47-2.67 (m, 2 H), 3.79 (dd, J=6.79, 4.95 Hz, 2 H), 5.43 (dd, J=8.80, 5.14 Hz, 1 H), 7.35 (dd, J=8.44, 1.83 Hz, 1 H), 7.47 (d, J=1.83 Hz, 1 H), 7.52 (d, J=8.44 Hz, 1 H)

c. Preparation of N-[1-(2,4-dichlorobenzoyl)cyclopropyl]formamide

(59) N-[1-(2,4-Dichlorobenzoyl)cyclopropyl]formamide was prepared according the procedure described above for N-[1-(2,4-difluorobenzoyl)cyclopropyl]formamide (Example P6 a). .sup.1H NMR (400 MHz, CDCl3) ? ppm (Major rotamer) 1.36-1.40 (m, 2 H), 1.87-1.92 (m, 2 H), 6.38 (br. s., 1 H), 7.26-7.38 (m, 3 H), 7.91 (s, 1 H)

d. Preparation of N-[1-[(2,4-dichlorophenyl)-hydroxy-methyl]cyclopropyl]formamide

(60) N-[1-[(2,4-Dichlorophenyl)-hydroxy-methyl]cyclopropyl]formamide was prepared according the procedure described above for N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]formamide (Example P6 b) .sup.1H NMR (400 MHz, CDCl3) ? ppm (Major rotamer) 0.80-1.00 (m, 3H), 1.27-1.33 (m, 1 H), 4.91 (d, J=4.40 Hz, 1H), 5.34 (d, J=4.77 Hz, 1H), 6.01 (br. s., 1H), 7.27 (dd, J=8.44, 1.83 Hz, 1H), 7.35 (d, J=2.20 Hz, 1H), 7.53 (d, J=8.44 Hz, 1H), 8.07 (s, 1 H)

e. Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide

(61) (e1)

(62) N-[2-(2,4-Dichlorophenyl)cyclobuten-1-yl]formamide was prepared according the procedure described above for N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide (Example P6 c)

(63) (e2)

(64) N-[2-(2,4-Dichlorophenyl)cyclobuten-1-yl]formamide was prepared from 4-(2,4-dichlorophenyl)-5-oxa-7-azaspiro[2.4]hept-6-ene. To a solution of 4-(2,4-dichlorophenyl)-5-oxa-7-azaspiro[2.4]hept-6-ene (40 mg) in dichloroethane (1 ml) was added, at room temperature, BF.sub.3.Et.sub.2O (0.011 ml). The reaction mixture was heated at 60? C. for 2 hours, before being allowed to cool down to room temperature, diluted with ethyl acetate and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with brine, the combined organic phases were then dried over solid sodium sulfate, filtered and concentrated under vacuum. N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide was obtained as a solid. .sup.1H NMR (400 MHz, CDCL3) ? ppm Major rotamer 2.75 (t, J=3.30 Hz, 1H), 2.80 (t, J=3.30 Hz, 1H), 7.14 (d, J=8.44 Hz, 1H), 7.22 (dd, J=8.44, 2.20 Hz, 1H), 7.37 (d, J=2.20 Hz, 1H), 7.87-8.12 (br.d., J=8.1 Hz, 1H), 8.39 (d, J=11.4 Hz, 1H) Minor rotamer 2.71 (t, J=3.48 Hz, 1 H), 3.08 (t, J=3.48 Hz, 1 H), 7.15 (d, J=8.44 Hz, 1H), 7.22 (dd, J=8.44, 2.20 Hz, 1H), 7.36 (d, J=2.20 Hz, 1H), 7.66 (br. s., 1 H), 8.23 (s, 1 H)

Example P9

Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide

(65) ##STR00146##

a. Preparation of N-[1-(2,4-dichlorobenzoyl)cyclopropyl]-N-formyl-acetamide

(66) N-[(1-(2,4-Dichlorobenzoyl)cyclopropyl]-N-formyl-acetamide was prepared according the procedure described above for N-[(1-(2,4-difluorobenzoyl)cyclopropyl]-N-formyl-acetamide (example P7 a). .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.82-2.00 (m, 2 H), 2.22 (s, 2 H), 2.40 (s, 3 H), 7.24 (d, J=8.44 Hz, 1H), 7.29 (dd, J=8.44, 2.20 Hz, 1H), 7.42 (d, J=1.83 Hz, 1 H), 9.19 (s, 1 H)

b. Preparation of N-[1-(2,4-dichlorobenzoyl)cyclopropyl]acetamide

(67) N-[1-(2,4-Dichlorobenzoyl)cyclopropyl]acetamide was prepared according the procedure described above for N-[1-(2,4-difluorobenzoyl)cyclopropyl]acetamide (Example P7 b). .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.30-1.35 (m, 2 H), 1.72 (s, 3 H), 1.83-1.88 (m, 2 H), 6.30 (br. s., 1 H), 7.29 (dd, J=8.07, 1.83 Hz, 1H), 7.33 (d, J=8.07 Hz, 1H), 7.36 (d, J=1.83 Hz, 1 H)

c. Preparation of N-[1-[(2,4-dichlorophenyl)-hydroxy-methyl]cyclopropyl]acetamide

(68) N-[1-[(2,4-Dichlorophenyl)-hydroxy-methyl]cyclopropyl]acetamide was prepared according to the procedure described above for N-[1-[(2,4-difluorophenyl)-hydroxy-methyl]cyclopropyl]acetamide (example P7 c). .sup.1H NMR (400 MHz, CDCl3) ? ppm 0.73-1.02 (m, 3H), 1.16-1.34 (m, 1H), 1.93 (s, 3H), 4.86 (s, 1 H), 5.86 (br. s., 1 H), 5.92 (br. s., 1 H), 7.25 (d, J=8.44 Hz, 1 H), 7.35 (s, 1 H), 7.52 (d, J=8.44 Hz, 1 H).

d. Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide

(69) N-[2-(2,4-Dichlorophenyl)cyclobuten-1-yl]acetamide was prepared according to the procedure described above for N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide (Example P7 d1). .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.06 (3H, s); 2.65 (2H, m); 3.06 (2H, m); 7.12 (1H, d); 7.19 (1H, d); 7.32 (1H, s); 7.58 (1H, br, s, NH).

Example P10

Preparation of (1S,2S)-2-(2,4-difluorophenyl)cyclobutanamine hydrochloride

(70) ##STR00147##

a. Preparation of 3-chloro-1-(2,4-difluorophenyl)propanone

(71) To a stirred suspension of aluminium chloride (15.7 g, 118.1 mmol) in 1,3-difluorobenzene (11 ml, 118.1 mmol) heated to 50? C. was added 3-chloropropanoyl chloride (10 g, 78.7 mmol) by syringe over 10 min. The mixture was stirred at 50? C. for 1 h. The reaction mixture was poured onto ice water (200 ml) and stirred for 3 min. The mixture was next extracted with AcOEt (3?100 ml), and the combined organic layers were washed with NaHCO.sub.3 (100 ml) and brine (100 ml). The organic layer was dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give 3-chloro-1-(2,4-difluorophenyl)propanone as an oil

(72) .sup.1H NMR (CDCl3) ? (ppm) 3.46 (d, 2H) 3.87-3.97 (m, 2H) 6.92 (ddd, 1H) 6.86-6.96 (m, 1H); 6.97-7.06 (m, 1H) 7.94-8.08 (m, 1H)

b. Preparation of 3-chloro-1-(2,4-difluorophenyl)propanol

(73) To a solution of 3-chloro-1-(2,4-difluorophenyl)propanone (5 g, 24.4 mmol) in methanol (83 mL) was added sodium borohydride (1.70 g, 44.0 mmol) portionwise at 0? C. The mixture was diluted with saturated aqueous NH.sub.4Cl (100 ml) and stirred for 10 min. It was extracted with AcOEt (3?100 ml), the combined organic layers were dried over Na.sub.2SO.sub.4 and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Cyclohexane:AcOEt, 0-30% AcOEt) to yield 3-chloro-1-(2,4-difluorophenyl)propanol as a slightly yellow oil.

(74) .sup.1H NMR (CDCl.sub.3) ? (ppm) 2.20-2.50 (m, 3H); 3.59-3.70 (m, 1H); 3.74-3.85 (m, 1H); 5.23 (m, 1H); 6.60-6.80 (m, 1H); 6.90-6.98 (m, 1H); 7.48 (d, 1H)

c. Preparation of 1-(1,3-dichloropropyl)-2,4-difluoro-benzene

(75) To 3-chloro-1-(2,4-difluorophenyl)propanol (1 g, 4.65 mmol) was added concentrated hydrogen chloride (4.23 ml) and the resulting emulsion was stirred at room temperature for 30 min then at 60? C. for another 30 min. Water (20 ml) was then carefully added to the reaction mixture and it was extracted with cyclohexane (3?20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo to give 1-(1,3-dichloropropyl)-2,4-difluoro-benzene as an oil.

(76) .sup.1H NMR (CDCl.sub.3) ? (ppm) 2.31-2.44 (m, 1H); 2.48-2.59 (m, 1H); 3.55-3.65 (m, 1H); 3.68-3.79 (m, 1H); 5.34-5.43 (m, 1H); 6.73-6.94 (m, 2H); 7.35-7.49 (m, 1H)

d. Preparation of N-[(2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide

(77) To a suspension of sodium hydroxide (0.43 g, 10.7 mmol) in DMSO (5.4 ml) was added a solution of toluenesulfonylmethyl isocyanide (0.47 g, 2.36 mmol) and 1-(1,3-dichloropropyl)-2,4-difluoro-benzene (0.51 g, 2.14 mmol) at room temperature for 4 h. Sodium hydroxide 5M (0.43 ml, 2.14 mmol) was then added and the resulting mixture was heated at 60? C. for 2 h then cooled down to r.t. Water (20 ml) was added to the reaction mixture and it was extracted with AcOEt (3?20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica (Cyclohexane:AcOEt, 0-40% AcOEt) to yield N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide as a brownish solid.

(78) Major rotamer: .sup.1H-NMR (400 MHz, CDCl.sub.3): ? I 2.65-2.70 (m, 2 H), 2.85-2.89 (m, 2 H), 6.87-6.93 (m, 2 H), 7.10-7.15 (m, 1 H), 7.95 (bs, 1 H), 8.38-8.52 (m, 2 H).

(79) Minor rotamer: .sup.1H-NMR (400 MHz, CDCl.sub.3): ? I 2.63-2.67 (m, 2 H), 3.14-3.20 (m, 2 H), 6.80-6.85 (m, 1 H), 7.10-7.16 (m, 2 H), 7.75 (bs, 1 H), 8.21-8.30 (m, 1 H).

e. Preparation of N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]formamide

(80) As performed in Example P6 step d.

f. Preparation of (1S,2S)-2-(2,4-difluorophenyl)cyclobutanamine hydrochloride

(81) N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]formamide (0.497 mmol, 0.105 g) was introduced in a 10 ml round-bottom flask and diluted in methanol (5 ml). Hydrochloric acid 36% (4.97 mmol, 0.592 g, 0.497 ml) was added in one portion, then the reaction mixture was stirred at reflux for 2 hours. Methanol was evaporated, then some diethyl ether and water were added to the mixture. The phases were separated and the aqueous phase was washed with a small volume of diethyl ether. The aqueous phase was mixed with diethyl ether and cooled down to 0? C. whereupon sodium hydroxide (30% solution; 0.5 ml) was slowly added. The phases were separated again and the aqueous phase was extracted twice with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give an orange oil. The oil was diluted in diethyl ether and cooled down to 0? C. whereupon HCl (2M in diethyl ether) was added drop-wise. A solid precipitated. This solid was isolated by filtration, washed with diethyl ether and dried on high vacuum pump to afford a white powder corresponding to the desired product. This solid was analyzed via chiral HPLC (method Z) which showed an ee of 81.8% in favour of the desired enantiomer eluting at 4.99 min (minor enantiomer eluting at 5.68 min).

(82) 1H NMR (400 MHz, DMSO-d6) d ppm 8.04 (3 H, br. s.), 7.45-7.60 (1 H, m), 7.18-7.28 (1 H, m), 7.13 (1 H, td), 4.07 (1 H, q), 3.81-3.97 (1 H, m), 2.69-2.85 (1 H, m), 2.39-2.48 (1 H, m), 2.12-2.25 (1 H, m), 1.80-1.95 (1 H, m).

Example P11

Preparation of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine

(83) ##STR00148##

a. Preparation of 3-chloro-1-(2,4-dichlorophenyl)propanone

(84) To a stirred suspension of aluminum chloride (12.6 g, 94.5 mmol) in 1,3-dichlorobenzene (13.5 ml, 118 mmol) was added 3-chloropropanoyl chloride (7.55 ml, 78.8 mmol) dropwise at 50? C. The resulting mixture was stirred at 50? C. for 2.5 h, then at 60? C. for 1.5 h. The reaction mixture was poured on ice and water (1:1, 500 ml) and it was stirred for 5 min. The mixture was then extracted with AcOEt (3?100 ml). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo. The crude product was further purified by distilling off remaining dichlorobenzene in vacuo (70? C., 10 mbar) to give 3-chloro-1-(2,4-dichlorophenyl)propanone.

(85) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=3.34 (t, 2 H) 3.79 (t, 2 H), 7.21-7.26 (m, 1 H), 7.33-7.39 (m, 1 H) 7.40-7.50 (m, 1 H).

b. Preparation of 3-chloro-1-(2,4-dichlorophenyl)propanol

(86) To a solution of 3-chloro-1-(2,4-dichlorophenyl)propanone (10 g, 35.8 mmol) in methanol (122 ml) was added sodium borohydride (1.37 g, 35.8 mmol) portionwise at 0? C. The resulting mixture was stirred at 0? C. for 2 h. An NH.sub.4Cl aqueous solution (half-saturated, 200 ml) was added to the reaction mixture and it was extracted with AcOEt (3?100 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (cyclohexane:AcOEt 0-20%) to give 3-chloro-1-(2,4-dichlorophenyl)propanol as an oil.

(87) .sup.1H-NMR (400 MHz, CDCl.sub.3): ? 2.05-2.25 (m, 3 H), 3.69-3.88 (m, 2 H), 5.31-5.38 (m, 1 H), 5.31-5.35 (m, 1 H), 5.40-5.43 (m, 1 H), 5.55-5.58 (m, 1 H).

c. Preparation of 1-(1,3-dichloropropyl)-2,4-dichloro-benzene

(88) To a solution of lithium chloride (0.087 g, 2.05 mmol) in DMF (1.0 ml) was added 3-chloro-1-(2,4-dichlorophenyl)propanol (129 mg, 0.51 mmol) and thionyl chloride (0.112 ml, 1.54 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. Water (10 ml) was added to the reaction mixture and it was extracted with tBuOMe (1?10 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo to give 1-(1,3-dichloropropyl)-2,4-dichloro-benzene as an oil.

(89) .sup.1H-NMR (400 MHz, CDCl.sub.3): ? 2.25-2.38 (m, 2 H), 3.51-3.71 (m, 2 H), 5.49-5.52 (m, 1 H), 7.17-7.22 (m, 1 H), 7.30-7.33 (m, 1 H), 7.40-7.44 (m, 1 H).

d. Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide

(90) To a suspension of potassium hydroxide (0.22 g, 3.89 mmol) in DMSO (2.0 ml) was added dropwise at RT a solution of 2,4-dichloro-1-(1,3-dichloropropyl)benzene (211 mg, 0.78 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (168 mg, 0.86 mmol) in DMSO (1.0 ml). The resulting mixture was stirred for 3 h at room temperature and 5M aqueous potassium hydroxide (0.78 mL, 3.89 mmol) was added. The mixture was then stirred overnight. Water (20 ml) and aqueous NH.sub.4Cl-solution (5 ml) was added to the reaction mixture and it was extracted with AcOEt (3?20 ml). The combined organic layers were washed with brine (10 ml), dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (Cyclohexane:AcOEt, 0-30% AcOEt) to yield the desired compound as a colourless solid.

(91) Major rotamer: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.64-2.73 (m, 2 H), 7.09-7.16 (m, 1 H), 7.10-7.16 (m, 1 H), 7.23-7.31 (m, 1 H), 7.88-8.06 (m, 1 H), 8.25-8.34 (m, 1 H) ppm.

(92) Minor rotamer: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.59-2.64 (m, 1 H), 2.96.3.03 (m, 1 H), 7.09-7.16 (m, 1 H), 7.10-7.16 (m, 1 H), 7.23-7.31 (m, 1 H), 7.51-7.62 (bs, 1 H), 8.09-8.13 (m, 1 H) ppm.

e. Preparation of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]formamide

(93) To an inert and degassed 2,2,2-trifluoroethanol (4 ml) was added (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]-ethyl-di-2-methylphenylphosphine (0.041 mmol, 24 mg) and bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.038 mmol, 18 mg) at room temperature under an argon atmosphere over 10 minutes. The reaction mixture was then transferred into a 100 ml autoclave previously filled with argon and N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide (0.38 mmol, 91 mg). The autoclave was tightly closed and submitted to hydrogen under 50 bar at 50? C. for 22 hours. The autoclave was opened then the reaction mixture was filtered through Celite and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica (dichloromethane:Methanol, 0-10% Methanol) to yield N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]formamide as an orange amorphous solid.

(94) Major rotamer: .sup.1H NMR (400 MHz, CDCl.sub.3): d=1.95-2.04 (m, 1H), 2.26-2.40 (m, 2H), 2.50-2.66 (m, 1H), 4.12-4.21 (m, 1H), 4.95-5.02 (q, 1H), 5.13 (bs, 1H), 7.43-7.45 (d, 1H), 7.94 (s, 1H).

(95) Minor rotamer: .sup.1H NMR (400 MHz, CDCl.sub.3): d=1.95-2.04 (m, 1H), 2.26-2.40 (m, 2H), 2.50-2.66 (m, 1H), 4.12-4.21 (m, 1H), 4.51-4.57 (q, 1H), 5.30 (bs, 1H), 7.40-7.43 (d, 1H), 7.96-7.99 (d, 1H).

f. Preparation of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine

(96) To a solution of N-[2-(2,4-dichlorophenyl)cyclobutyl]formamide (66 mg, 0.24 mmol) in methanol (2.4 mL) was added 36% HCl (0.21 mL, 2.43 mmol) and the mixture was heated to 65? C. The mixture was heated for 2 h and then cooled to room temperature. The solvent was removed under reduced pressure. The residue was taken up in water (30 ml) and washed with MTBE (20 ml). The aqueous layer was basified with 5M NaOH (ca.1 ml) and extracted with MTBE (2?20 ml). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated to yield a red oil. It was analysed via chiral HPLC (method Y) which showed an ee of 82% in favour of the desired enantiomer.

(97) .sup.1H-NMR (400 MHz, CDCl.sub.3) ppm 0.95-1.28 (m, 2 H), 1.63-1.75 (m, 1 H), 2.14-2.28 (m, 1 H), 2.29-2.98 (m, 2 H), 3.89-4.03 (m, 2 H), 7.27-7.32 (m, 2 H), 7.41-7.43 (m, 1H) ppm.

Example P12

Preparation of 2,4-difluoro-1-(2-isocyanocyclobuten-1-yl)benzene

(98) ##STR00149##

(99) To a suspension of sodium hydride (0.056 g, 1.40 mmol) in DMSO (0.88 ml) and diethyl ether (0.32 ml) was added a solution of 1-(1,3-dichloropropyl)-2,4-difluoro-benzene (100 mg, 0.40 mmol) and toluenesulfonylmethyl isocyanide (0.097 g, 0.48 mmol) in DMSO (0.32 ml) and diethyl ether (0.12 ml) at room temperature over 1 min. The mixture was stirred for 5 h at room temperature and water (20 ml) was then added. The reaction mixture was extracted with pentane (3?20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was carefully evaporated in light vacuo. .sup.1H-NMR (400 MHz, CDCl.sub.3): ? 2.64-2.74 (m, 2 H); 2.79-2.90 (m, 2 H); 6.73-7.00 (m, 2 H); 7.59-7.63 (m, 1 H) ppm

Example P13

Preparation of 2,4-difluoro-1-(2-isocyanocyclobuten-1-yl)benzene

(100) ##STR00150##

(101) To a suspension of sodium hydride (108 mg, 2.71 mmol) in DMSO (2 ml) was added dropwise at room temperature a solution of 1-(isocyanomethylsulfonyl)-4-methyl-benzene (187 mg, 0.93 mmol) and 2,4-dichloro-1-(1,3-dichloropropyl)benzene (200 mg, 0.78 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 2 h. Water (20 ml) was added to the reaction mixture and it was extracted with AcOEt (3?20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (Cyclohexane:AcOEt, 0-50% AcOEt) to yield the desired compound as a brown solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.70-2.78 (m, 2 H); 2.80-2.87 (m, 2 H); 7.15-7.23 (m, 1 H); 7.29-7.32 (m, 1 H); 7.60-7.65 (m, 1 H).

Example P14

Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(102) ##STR00151##

(103) To a suspension of sodium hydroxide (0.42 g, 10.5 mmol) in DMSO (5 ml) was added a solution of toluenesulfonylmethyl isocyanide (0.46 g, 2.32 mmol) and 1-(1,3-dichloropropyl)-2,4-difluoro-benzene (500 mg, 2.11 mmol) in DMSO (3.4 mL) at room temperature. The mixture was then stirred at room temperature for 1.5 h. Water (20 ml) was added to the reaction mixture and it was extracted with hexane (2?20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and filtered. The yellow solution was used in the next step without further purification.

(104) The above solution was cooled to 0? C. and DMSO (0.16 ml, 2.32 mmol) was added, followed by trifluoroacetic anhydride (0.15 ml, 1.06 mmol). The mixture was stirred at 0? C. for 20 min.

(105) A freshly prepared solution of 2-(trifluoromethyl)phenyl]magnesium bromide (from 1-bromo-2-(trifluoromethyl)benzene (500 mg, 2.22 mmol) in THF (6.7 ml) and (isopropyl)magnesium chloride (1.7 ml, 2.22 mmol) at 0? C. for 15 min then room temperature for 5 H) was then added and the reaction mixture was stirred at room temperature or 72 h. Water (50 ml) and NaHCO.sub.3 aqueous solution (10 ml) were added to the reaction mixture and it was extracted with AcOEt (3?20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was evaporated in vacuo. The resulting crude product was purified by flash chromatography (Cyclohexane:AcOEt, 0-10% AcOEt) to yield N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide as a colorless solid.

(106) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.63-2.69 (m, 2H); 3.21-3.28 (m, 2H); 6.71-6.81 (m, 1H); 6.84-6.92 (m, 1 H); 7.10-7.18 (m, 1H); 7.54-7.70 (m, 3H); 7.73-7.79 (m, 1H); 8.03-8.18 (m, 1H).

Example P15

Preparation of N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide

(107) ##STR00152##

a. Preparation of 3-chloro-1-(2,4-dichlorophenyl)propyl]methanesulfonate

(108) A solution of 3-chloro-1-(2,4-dichlorophenyl)propanol (2 g, 8.35 mmol) and triethylamine (1.76 ml, 1.28 g, 12.52 mmol) in dichloromethane (5 ml) was cooled to 0? C. and methanesulfonylchloride (0.714 ml, 1.05 g, 9.18 mmol) was added dropwise causing an exotherm. After the addition, the reaction mixture was stirred for 2 hours then poured onto ice and water. The mixture was extracted with tBuOMe, and the organic phase washed with HCl (1M), NaHCO3 (1M), and brine, then dried with Na2SO4 and evaporated to give [3-chloro-1-(2,4-dichlorophenyl)propyl]methanesulfonate as an oil.

(109) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.23-2.44 (m, 2H); 2.94 (s, 3H); 3.62-3.77 (m, 2H); 6.17 (dd, 1H); 7.35 (dd, 1H); 7.44 (d, 1H); 7.50 (d, 1H)

b. Preparation of 2,4-dichloro-1-[2-isocyano-2-(p-tolylsulfonyl)cyclobutyl]benzene

(110) A mixture of [3-chloro-1-(2,4-dichlorophenyl)propyl]methanesulfonate (1.3 g, 4.1 mmol), toluenesulfonylmethyl isocyanide (820 mg, 4.1 mmol) and tetrabutylammonium iodide (760 mg, 2.0 mmol) in dichloromethane (ca 6 ml) was stirred with NaOH (ca 6 ml; 30% aq.) under argon at room temperature overnight. The mixture was shaken between EtOAc and water, dried with Na2SO4 and evaporated to yield the crude product as an oil, which was chromatographed on silica with EtOAc and cyclohexane to yield pure 2,4-dichloro-1-[2-isocyano-2-(p-tolylsulfonyl)cyclobutyl]benzene as white crystals m.p. 130-137.

(111) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.30 (m, 1H); 2.40 (m, 1H); 2.46 (s, 3H); 2.59 (m, 1H); 4.97 (t, 1H); 7.32-7.48 (m, 5H); 7.88 (d, 2H).

c. Preparation of N-[(2-(2,4-dichlorophenyl)-1-(p-tolylsulfonyl)cyclobutyl]formamide

(112) To a solution of 2,4-dichloro-1-[2-isocyano-2-(p-tolylsulfonyl)cyclobutyl]benzene (100 mg, 0.26 mmol) in THF (0.5 ml) at room temperature was added HCl (2M, 0.26 mmol). The resulting mixture was stirred at room temperature for 5 h. Water and EtOAc were added. Layers were separated and the organic phase was further washed with aqueous NaHCO.sub.3, brine, dried and concentrated in vacuo to afford N-[2-(2,4-dichlorophenyl)-1-(p-tolylsulfonyl)cyclobutyl]formamide. .sup.1H-NMR showed the compound to exist in CDCl3 solution as a mixture of two (major and minor) amide rotamers.

(113) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.25-2.44 (m); 2.45 (2s, Me); 2.60-2.76 (m), 2.95 (m, minor); 3.08 (m, major); 3.20 (m, minor); 4.92 (dd, 1H, major); 5.04 (dd, 1H, minor); 5.31 (s, 1H, major); 5.33 (s, 1H, minor); 7.26-7.77 (m, 5H).

d. Preparation of N-[(2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide

(114) N-[2-(2,4-Dichlorophenyl)-1-(p-tolylsulfonyl)cyclobutyl]formamide (46.0 mg, 0.115 mmol) was dissolved in THF (0.5 ml) and sodium tert-butoxide (2M in THF; 0.35 mmol) was added dropwise. The mixture became cloudy and brown. After the addition TLC (50% EtOAc in cyclohexane) showed complete reaction. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with HCl (1M), aqueous NaHCO.sub.3, brine, dried with Na2SO4, and concentrated in vacuo. The crude product was triturated with diethyl ether to afford N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]formamide as white solid. M.p. 132-137? C. .sup.1H-NMR showed the compound to exist in CDCl3 solution as a mixture of two (major and minor) amide rotamers.

(115) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=2.70 (t, 2H, minor); 2.75 (t, 2H, major); 2.79 (t, 2H, major); 3.08 (t, 2H, minor); 7.12-7.38 (m, 3H major+minor); 7.57 (br s, 1H, minor); 7.86 (br s, 1H, major); 8.22 (s, 1H, minor); 8.40 (d, 1H, major).

Example P16

Preparation of N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide

(116) ##STR00153##

a. Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)pyridine-3-carboxamide

(117) 2-(Trifluoromethyl)pyridine-3-carbonyl chloride solution: To a stirred solution of 2-(trifluoromethyl)pyridine-3-carboxylic acid (1.7 g, 8.9 mmol) and a catalytic amount of dimethylformamide in dichloromethane (10 ml), was added dropwise oxalylchloride (0.83 ml). The reaction mixture was stirred at room temperature for 18 hours, evaporated in vacuo and dissolved again in dichloromethane (10 ml).

(118) 2-(Trifluoromethyl)pyridine-3-carbonyl chloride solution (5.6 mmol, 2.2 equivalents) was added dropwise to a stirred suspension of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]formamide (537 mg) in toluene (8 ml) at 0? C. followed by addition of triethyl amine (0.79 ml). The reaction mixture was stirred at 0? C. for 90 minutes and at 40? C. for 1 hour. Another portion of 2-(trifluoromethyl)pyridine-3-carbonyl chloride solution (2.6 mmol, 1 equivalent), triethyl amine (0.4 ml) and a catalytic amount of 4-dimethylaminopyridine were added and the reaction mixture was stirred at room temperature for additional 16 hours.

(119) LC/MS analysis reveals the presence of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-N-formyl-2-(trifluoromethyl)pyridine-3-carboxamide intermediate:

(120) LC-MS (ES+): m/z=383 (M+H) RT=1.69 (method G).

(121) The mixture was taken up into ethyl acetate and the ethyl acetate solution was washed with saturated NaHCO.sub.3, NH.sub.4Cl, brine and it was dried (Na.sub.2SO.sub.4). Filtration and concentration by rotary evaporation gave a brown oil. It was dissolved in methanol (6 ml). Potassium carbonate (289 mmol) was added and the mixture was stirred for 75 minutes at room temperature, filtered and evaporated. The mixture was taken up into ethyl acetate and the ethyl acetate solution was washed with saturated NH.sub.4Cl, brine and it was dried (Na.sub.2SO.sub.4). Filtration and concentration by rotary evaporation gave a brown solid.

(122) N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)pyridine-3-carboxamide was isolated by column chromatography over silica gel (hexanes:ethyl acetate gradient) as an off-white solid.

(123) m.p. 171-178? C.

(124) .sup.1H-NMR (CDCl.sub.3, 400 Mhz): ?=8.82 (d, 1H, J=4.4 Hz), 8.07 (bd, 1H, J=12.8 Hz), 7.99 (d, 1H, J=7.7 Hz), 7.59-7.64 (m, 1H), 7.11-7.18 (m, 1H), 6.85-6.92 (m, 1H), 6.73-6.81 (m, 1H), 3.20-3.25 (m, 2H), 2.64-2.69 (m, 2H).

b. Preparation of N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide

(125) Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (3.3 mg) and (R)-1-[(S.sub.P)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis(2-methyl phenyl)phosphine (4.0 mg) were dissolved in degassed methanol (5 ml) and the resulting catalyst solution was stirred for 30 min at room temperature under argon. Then, the catalysts solution (1 ml) and degassed methanol (4 ml) were transferred via syringe into a 100 ml stainless steel reactor containing N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)pyridine-3-carboxamide (50 mg) set under an atmosphere of argon. The reactor was purged 3 times with hydrogen (10 bar) and finally pressurized to 50 bar. The reaction mixture was stirred over 18 h at 50? C. After 18 h the autoclave was vented and the solvent was evaporated. N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide was isolated by column chromatography over silica gel (hexanes:ethyl acetate gradient) as a gum.

(126) Chiral HPLC analysis (method C) showed a ee=50% in favour of the desired enantiomer eluting at 5.48 min (minor enantiomer eluting at 8.28 min).

(127) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6=8.7 (d, 1H, J=4.4 Hz), 7.55-7.59 (m, 1H), 7.44-7.49 (m, 1H), 7.28-7.34 (m, 1H), 6.87-6.93 (m, 1H), 6.79-6.86 (m, 1H), 5.61 (bd, 1H, J=7.3 Hz), 4.95-5.04 (m, 1H), 4.11-4.19 (m, 1H), 2.58-2.69 (m, 1H), 2.29-2.43 (m, 2H), 2.07-2.18 (m, 1H).

Example P17

Preparation of (1R,4S)N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1,7,7-trimethyl-2-oxo-3-oxabicyclo[2.2.1]heptane-4-carboxamide

(128) ##STR00154##

a. Preparation of N-[2-(4-chlorophenyl)cyclobuten-1-yl]acetamide

(129) Dried acetamide (27.7 mmol, 1.67 g) and toluene-4-sulfonic acid monohydrate (0.0554 mmol, 0.0105 g) were introduced in a well dried 25 ml three-neck round-bottom flask equipped with a Dean Stark apparatus. Then 2-(4-chlorophenyl)cyclobutanone (5.54 mmol, 1.00 g; prepared as described in Example P3) was added as a solution in anhydrous toluene (11.1 ml), and the reaction mixture was submitted to an argon atmosphere and stirred at reflux. After overnight stirring at reflux (22 hours) with water collecting in the Dean Stark trap, the conversion of the starting material was almost complete. Water and ethyl acetate were added to the reaction mixture. A solid remained insoluble and was filtered off and discarded. The organic filtrate was washed with saturated sodium bicarbonate, dried with sodium sulfate and concentrated under vacuum to give a crude white solid. The crude was purified via recrystallization from AcOEt/cyclohexane to give the pure product.

(130) 1H-NMR (CDCl.sub.3): 7.30 (2H, d), 7.11 (2H, d), 3.04 (2H, m), 2.56 (2H, m), 2.21 (1H, br s), 2.11 (3H, s).

b. Preparation of N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]acetamide

(131) (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]-ethyl-di-2-methylphenylphosphine (0.0124 mmol, 0.00730 g) and bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.0113 mmol, 0.00529 g) were weighted and transferred to a vial in an inert atmosphere. Methanol (5 ml) was introduced in a 25 ml round-bottom flask and degassed by flushing the flask several times with vacuum/argon cycles. Both catalyst and ligand were added, and the reaction mixture was stirred at room temperature under an argon atmosphere until everything was dissolved (15-20 minutes). In a 100 ml autoclave previously inerted with argon was introduced N-[2-(4-chlorophenyl)cyclobuten-1-yl]acetamide (2.26 mmol, 0.500 g). The catalyst/ligand solution was then introduced into the autoclave. The autoclave was tightly closed and submitted to hydrogen pressure (50 bar) at 50? C. during 4 hours. The reaction mixture was filtrated through Celite and a small layer of silica and concentrated to give an amber sticky oil which crystallized over time. This was the desired product, whose ee was determined with chiral HPLC (method V), ee=86% in favour of the desired enantiomer eluting at 4.20 min (minor enantiomer eluting at 3.72 min).

(132) 1H-NMR (CDCl3): 7.35 (2 H, d), 7.16 (2 H, d), 5.04 (1 H, br. s.), 4.79 (1 H, quin), 3.86 (1 H, m), 2.50 (1 H, m), 2.32-2.14 (2 H, m), 2.00 (1 H, m), 1.75 (3 H, s)

c. Preparation of (1S,2S)-2-(4-chlorophenyl)cyclobutanamine hydrochloride

(133) N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]acetamide (0.867 mmol, 0.194 g, ee=66%) was introduced in a 25 ml round-bottom flask and dissolved in methanol (5 ml). Hydrochloric acid 36% (43.4 mmol, 5.16 g, 4.34 ml) was added drop-wise. The reaction mixture was stirred at reflux overnight (16 hours). Methanol and hydrochloric acid were evaporated to give a dark solid. Some toluene was added and evaporated to distill off the remaining water. The solid was triturated in diethyl ether, filtrated and dried on high vacuum pump to afford a grey powder. This solid was analyzed via chiral HPLC (method W) which showed an ee=64% in favour of the desired enantiomer eluting at 4.00 min (minor enantiomer eluting at 4.56 min).

(134) 1H-NMR (DMSO d6): 8.04 (3H, br s) 7.45-7.24 (4H, m), 3.92 (2H, m), 2.64 (1H, m), 2.38 (1H, m), 2.23 (1H, m), 1.96 (1H, m).

d. Preparation of (1R,4S)N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1,7,7-trimethyl-2-oxo-3-oxabicyclo[2.2.1]heptane-4-carboxamide

(135) (1S,2S)-2-(4-chlorophenyl)cyclobutanamine hydrochloride (1.83 mmol, 0.400 g, ee=64%) was introduced in a 25 ml round-bottom flask and dissolved in dichloromethane (15 ml).

(136) water (5 ml) and sodium bicarbonate (5.50 mmol, 0.462 g, 0.312 ml) were added subsequently, then the reaction mixture was cooled down to 0? C. (1S)-(?)-camphanic acid chloride (2.02 mmol, 0.437 g) was added drop-wise as a solution in dichloromethane (5 ml).

(137) The ice bath was removed and the reaction mixture was stirred at room temperature during 3 hours. The organic phase was separated from the aqueous one, dried with anhydrous sodium sulfate, filtered and concentrated to give a pale yellow solid which was purified on silica gel chromatography. The major diastereoisomer was isolated pure and was crystallized from AcOEt/cyclohexane.

(138) M.P: 148-149? C.

(139) The stereochemistry of this compound was confirmed by X-ray crystallography under the conditions set out below and in Table 57. Bond lengths and angles for Example P17 are set out in Table 58 and the X-ray crystal structure is shown in FIGS. 1 and 2.

(140) Sample Quality and Data Collection

(141) Example P17 was crystallized from ethyl acetate/cyclohexane. The sample consisted of dry colorless rhombic prisms of up to several mm in length. A block of approx. 0.3?0.3?0.3 mm3 was broken off of a larger one and mounted in NVH oil for data collection. Diffraction data were collected at 100K to a resolution of 0.9 ?. The quality of the x-ray data was excellent, with an Rmerge value of 1.8 (see Appendix A). Structure solution and refinement were straightforward, resulting in a model with very good quality indices (R1=3.5%).

(142) Structure

(143) The Example P17 crystals belonged to the non-centrosymmetric space group P212121 with one molecule per asymmetric unit (FIG. 1, see FIG. 2 for the numbering scheme). The crystals were enantiopure as expected. All atoms were crystallographically well defined, with no sign of disorder or anisotropic movement. For technical reasons, the numbering scheme used in these structures does not correspond to systematic nomenclature.

(144) Stereochemistry

(145) The absolute configuration of Example P17 could be determined with a high degree of accuracy (Flack parameter 0.00+/?0.02). The absolute structure of Example P17 is given in below. The systematic name of the compound is (1R,4S)N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1,7,7-trimethyl-2-oxo-3-oxabicyclo[2.2.1]heptane-4-carboxamide.

(146) ##STR00155##

(147) TABLE-US-00002 TABLE 57 X-ray data collection and refinement statistics for Example P17 Crystal parameters Space group P212121 Unit cell a = 6.5229(2) ? b = 10.1198(8)? c = 28.4586(12) ? Data collection statistics Resolution 0.90 ? # unique reflections 2664 Rmerge 1.8% Structure refinement R1/wR2 3.5%/8.5% GooF 0.997 Refinement target/cutoff F2/?3.0 L Observable/parameter ratio 11.6 Min/max difference density ?0.23/+0.21 e?/?3 Max. shift/esd 0.0001 Flack parameter 0.00 +/? 0.02 Scatterers C20H24Cl1N1O3

(148) TABLE-US-00003 TABLE 58 Bond lengths and angles for Example P17 Atoms Distance (?) Atoms Bond angle (?) Cl (1) C (2) 1.742 (3) Cl (1) C (2) C (3) 119.5 (2) C (2) C (3) 1.379 (4) Cl (1) C (2) C (7) 119.6 (2) C (2) C (7) 1.375 (4) C (3) C (2) C (7) 120.9 (2) C (3) C (4) 1.384 (4) C (2) C (3) C (4) 119.0 (3) C (4) C (5) 1.385 (3) C (3) C (4) C (5) 121.6 (3) C (5) C (6) 1.398 (3) C (4) C (5) C (6) 117.9 (2) C (5) C (8) 1.494 (3) C (4) C (5) C (8) 119.3 (2) C (6) C (7) 1.381 (4) C (6) C (5) C (8) 122.8 (2) C (8) C (9) 1.570 (3) C (5) C (6) C (7) 121.0 (2) C (8) C (25) 1.550 (3) C (2) C (7) C (6) 119.6 (3) C (9) N (10) 1.443 (3) C (5) C (8) C (9) 114.53 (17) C (9) C (24) 1.530 (3) C (5) C (8) C (25) 118.7 (2) N (10) C (11) 1.337 (3) C (9) C (8) C (25) 86.82 (17) C (11) O (12) 1.228 (3) C (8) C (9) N (10) 120.16 (18) C (11) C (13) 1.510 (3) C (8) C (9) C (24) 89.93 (17) C (13) O (14) 1.469 (3) N (10) C (9) C (24) 116.96 (19) C (13) C (18) 1.548 (3) C (9) N (10) C (11) 120.51 (19) C (13) C (22) 1.522 (3) N (10) C (11) O (12) 123.1 (2) O (14) C (15) 1.373 (3) N (10) C (11) C (13) 117.75 (19) C (15) O (16) 1.201 (3) O (12) C (11) C (13) 118.99 (19) C (15) C (17) 1.517 (3) C (11) C (13) O (14) 110.39 (17) C (17) C (18) 1.560 (3) C (11) C (13) C (18) 114.37 (18) C (17) C (21) 1.555 (3) O (14) C (13) C (18) 102.03 (16) C (17) C (23) 1.509 (3) C (11) C (13) C (22) 118.14 (18) C (18) C (19) 1.528 (3) O (14) C (13) C (22) 105.69 (17) C (18) C (20) 1.527 (3) C (18) C (13) C (22) 104.69 (17) C (21) C (22) 1.552 (3) C (13) O (14) C (15) 106.31 (16) C (24) C (25) 1.545 (3) O (14) C (15) O (16) 121.8 (2) O (14) C (15) C (17) 106.98 (19) O (16) C (15) C (17) 131.2 (2) C (15) C (17) C (18) 99.02 (17) C (15) C (17) C (21) 102.86 (18) C (18) C (17) C (21) 102.15 (18) C (15) C (17) C (23) 114.7 (2) C (18) C (17) C (23) 119.54 (19) C (21) C (17) C (23) 115.89 (19) C (13) C (18) C (17) 91.66 (16) C (13) C (18) C (19) 112.95 (17) C (17) C (18) C (19) 114.02 (19) C (13) C (18) C (20) 114.35 (19) C (17) C (18) C (20) 113.83 (18) C (19) C (18) C (20) 109.26 (19) C (17) C (21) C (22) 104.28 (18) C (13) C (22) C (21) 101.11 (18) C (9) C (24) C (25) 88.40 (18) C (8) C (25) C (24) 90.15 (17)

Example P18

N-[(1,2 cis)-2-(2,3-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide (racemic)

(149) ##STR00156##

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

(150) 1-Cyanocyclobutanamine hydrochloride (1 g, 7.54 mmol) was suspended in water (10 ml). 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.

(151) .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

(152) N-(1-cyanocyclobutyl)-2-(trifluoromethyl)benzamide (268 mg, 1 mmol) was dissolved in dry THF (1 ml) in a dried flask under argon. Sodium tert-butoxide (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 TBME 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 the crude material (245 mg), which was chromatographed on silica to obtain pure N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide.

(153) Melting point: 129-133? C.

(154) .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

(155) N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide (15 mg, 0.0622 mmol) was dissolved in dichloromethane (0.200 ml). 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 TBME and 1M NaHCO3, dried over MgSO4, and evaporated. Chromatography on silica with a 0 to 50% EtOAc/cyclohexane gradient gave pure N-(2-iodocyclobuten-1-yl)-2-(trifluoromethyl)benzamide.

(156) 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

(157) 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 H?nigs's base (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 silica (120 g) 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.

(158) .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-(2,3-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(159) To a solution of N-(2-bromocyclobuten-1-yl)-2-(trifluoromethyl)benzamide (50 mg, 150 ?mol) in THF (2.25 ml) were added successively 2,3-difluoro-phenylboronic acid (300 ?mol), a solution of potassium phosphate (65.6 mg) in water (0.75 ml) and chloro(2-dicyclohexylphosphino-2,4,6-thisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (12 mg; 15 ?mol). 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 water (10 ml) and extracted with ethyl acetate (3?10 ml). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and evaporated. The crude material was purified via column chromatography using cyclohexane and AcOEt as eluants. The desired product was isolated as white crystals.

(160) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.12 (br. d, 1H), 7.77 (d, 1H), 7.68-7.59 (m, 3H), 7.09-6.96 (m, 2H), 6.92 (t, 1H), 3.28 (t, 2H), 2.68 (t, 2H).

Step f. N-[(1,2 cis)-2-(2,3-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide (racemic)

(161) To a solution of N-[2-(2,3-difluorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide. (33 mg, 0.0915 mmol) in methanol (2 ml) was added (1,1-bis(di-1-propylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (4 mg, 5.5 ?mol) 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 and purified via column chromatography using cyclohexane and AcOEt as eluants. The desired product was isolated as white crystals.

(162) 1H-NMR (CDCl3, 400 MHz): 7.61 (m, 1H), 7.52-7.45 (m, 2H), 7.21 (d, 1H), 7.13-7.06 (m, 3H), 5.55 (br. d, 1H), 5.07 (quintet, 1H), 4.24 (q, 1H), 2.64 (m, 1H), 2.44-2.29 (m, 2H), 2.16 (m, 1H).

(163) This method was used to prepare Compound No. 60-247 and 60-248.

Example P19

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

(164) ##STR00157##

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

(165) Sodium hydride (3.1 g, 57% in oil, 74 mmol) was washed with hexane under argon. A mixture of DMSO and diethyl ether (3:1, 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 mixture of DMSO and diethyl ether (3:1, 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 room temperature. Water (60 ml) was slowly added, and the crude mixture extracted with diethylether, which was then dried over 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.

(166) M.p. 94-97? C.

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

(167) 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 TBME, dried over 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.

(168) M.p. 83-88? C.

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

(169) 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 sodium butoxide 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). The ether phase was evaporated to yield N-(cyclobuten-1-yl)formamide as an oil. 1H-NMR showed a mixture of rotamers.

(170) .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

(171) 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. Triethylamine (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 over Na2SO4, and evaporated to give N-(cyclobuten-1-yl)-N-formyl-2-(trifluoromethyl)benzamide as a crude product

(172) .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

(173) 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 over Na2SO4, and evaporated to yield crude N-(cyclobuten-1-yl)-2-(trifluoromethyl)benzamide

(174) .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 P20

Preparation of N-(2-iodocyclobuten-1-yl)formamide

(175) ##STR00158##

(176) 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 H?nig's base (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 over Na2SO4, and evaporated to give crude product, which was chromatographed on silica with EtOAc/cyclohexane to yield N-(2-iodocyclobuten-1-yl)formamide

(177) .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 P21

Preparation N-(cyclobuten-1-yl)-4-methoxy-benzamide

(178) ##STR00159##

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

(179) 1-Cyanocyclobutanamine chloride (200 mg, 1.5084 mmol) was dissolved in THF, the solution was then cooled down to 0? C. Triethylamine (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 (1 M, aq) and brine, dried over MgSO4 and evaporated to yield 255 mg of crude product, which was chromatographed on silica with EtOAc/cyclohexane to afforded N-(1-cyanocyclobutyl)-4-methoxy-benzamide as a white solid.

(180) 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

(181) A solution of sodium tert-butoxide 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 TBME and NaHCO3 (1 M, aq.), dried over 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.

(182) M.p. 79-85? C.

(183) .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 P22

Preparation N-(cyclobuten-1-yl)acetamide

(184) ##STR00160##

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

(185) Prepared according to example P21 step a to afford N-(1-cyanocyclobutyl)acetamide as a brown solid. Melting point: 70-72? C.

(186) 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

(187) Prepared according to example P21 step b to afford N-(cyclobuten-1-yl)acetamide as a pale yellow solid.

(188) 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 P23

Preparation of N-[(2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(189) ##STR00161##

Step a. Preparation of N-[(2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(190) A solution of racemic N-[(1,2 cis)-2-(4-chlorophenyl)-1-cyano-cyclobutyl]-2-(trifluoromethyl)benzamide (8 mg, 0.021 mmol) in THF was treated with a solution of sodium tert-butoxide (2M in THF; 0.211 ml, 0.422 mmol), and heated to 40? C. After 23 hours at 40? C., the reaction mixture was shaken between TBME and 1M NaHCO3 (aq), washed with brine, dried over MgSO4 and concentrated to give N-[2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide, the NMR signals of which are identical to those described in example P4.

Step a. Preparation of N-[(2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide

(191) From racemic N-[(1,2 trans)-2-(4-chlorophenyl)-1-cyano-cyclobutyl]-2-(trifluoromethyl)benzamide,

(192) N-[2-(4-chlorophenyl)cyclobuten-1-yl]-2-(trifluoromethyl)benzamide was prepared according to the procedure described above for step a.

Example P24

Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide

(193) ##STR00162##

Step a. Preparation of racemic (1,2 cis)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile and racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile

(194) A solution of 2-(2,4-difluorophenyl)cyclobutanone (1.2 g, 6.59 mmol) in methanol (20 ml) was treated under stirring under argon with ammonium acetate (762 mg, 9.88 mmol), then acetic acid (1.19 g, 19.76 mmol), then sodium cyanide (484 mg, 9.88 mmol), causing an exotherm to 28? C. After stirring overnight at 60? C., the mixture was shaken between TBME and 1M NaHCO3 (aq), then brine, then dried with Na2SO4, and the solvent evaporated to give 1.3 g of the crude mixture of products as a dark oil, which was chromatographed on silica with EtOAc/cyclohexane to yield racemic (1,2 cis)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile and racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile as oils.

(195) racemic (1,2 cis)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile: .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.43 (br s, 2H), 2,05 (m, 1H), 2.31 (m, 1H), 2.67 (m, 2H), 4.12 (t, 1H), 6.84 (m, 1H), 6.92 (m, 1H), 7.26 (m, 1H)

(196) racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile: .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.09 (br s, 2H), 2.13 (m, 2H), 2.23 (m, 1H), 2.57 (m, 1H), 3.73 (t, 1H), 6.85 (m, 1H), 6.92 (m, 1H), 7.24 (m, 1H).

Step b. Preparation of racemic N-[(1,2 cis)-1-cyano-2-(2,4-difluorophenyl)cyclobutyl]acetamide

(197) A solution of racemic (1,2 cis)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile (60 mg, 0.288 mmol) in 0.5 ml EtOAc was stirred with K2CO3 (79.7 mg, 0.576 mmol) and acetic anhydride (58.8 mg, 0.576 mmol) was added. The mixture was stirred for 3 days at room temperature then shaken between MTBE and water, dried and evaporated to yield racemic N-[(1,2 cis)-1-cyano-2-(2,4-difluorophenyl)cyclobutyl]acetamide as an oil.

(198) .sup.1H NMR (400 MHz, CDCl3) ? ppm 1.88 (s, 3H), 2.38 (m, 1H), 2.54 (m, 2H), 2.80 (m, 1H), 4.38 (t, 1H), 5.26 (br s, 1H), 6.92 (m, 1H), 6.98 (m, 1H), 7.26 (m, 1H).

Step c. Preparation of N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide

(199) A solution of racemic N-[(1,2 cis)-1-cyano-2-(2,4-difluorophenyl)cyclobutyl]acetamide (42 mg, 0.168 mmol) in THF (1 ml) was treated with a solution of sodium butoxide (2M in THF; 0.282 ml, 0.503 mmol) and the mixture heated overnight at 60? C. The mixture was then shaken between MTBE and brine, dried over Na2SO4, and the solvent evaporated to yield N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide as beige crystals. M.p. 137-140? C.; NMR signals identical to those described in example P7, step d2.

Step b. Preparation of racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile

(200) From racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile, racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile was prepared according to the procedure described in step b. M.p. 170-173? C.

(201) .sup.1H NMR (400 MHz, CDCl3) ? ppm 2.03 (s, 3H), 2.31 (m, 1H), 2.43 (m, 1H), 2.52 (m, 1H), 2.90 (m, 1H), 3.96 (t, 1H), 6.18 (br s, 1H), 6.88 (m, 1H), 6.98 (m, 1H), 7.33 (m, 1H).

Step c. Preparation of N-[(2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide

(202) From racemic (1,2 trans)-1-amino-2-(2,4-difluorophenyl)cyclobutanecarbonitrile, N-[2-(2,4-difluorophenyl)cyclobuten-1-yl]acetamide was prepared according to the procedure described in step c. The NMR signals were identical to those described in example P7, step d2.

(203) Table 59: Compounds of Formula (XIIa)

(204) Table 59 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds of formula (XIIa) (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.

(205) In Table 59 and throughout the description, temperatures are given in degrees Celsius; NMR means nuclear magnetic resonance spectrum; HPLC is high pressure liquid 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

(206) Table 60: Compounds of Formula (II)

(207) Table 60 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds of formula (II) 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.

(208) Table 61: Compounds of Formula (I)

(209) Table 61 shows selected melting point, selected HPLC-MS for compounds of formula (I) of the present invention. No attempt is made to list all characterising data in all cases.

(210) 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.

(211) All the compounds from Table 61 were obtained through the enantioselective reduction of an enamide intermediate as described in the previous example protocols except compounds 100, 101, 102, 155, 156, 175 and 176 which were obtained through the resolution of racemates via preparative chiral HPLC.

(212) Table 62: Compounds of Formula (XXXIII)

(213) Table 62 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds of formula (XXXIII) of the present invention. No attempt is made to list all characterising data in all cases.

(214) NMR 59.27

(215) ? (in ppm, 400 MHz, CDCl.sub.3): 7.59 (1H, d); 7.35 (2H, m); 7.12 (1H, m); 3.98 (2H, m); 2.39 (2H, m), 2.20 (1H, m); 1.68 (1H, m); 1.42 (2H, br s)

(216) NMR 60.13:

(217) ? (in ppm, 400 MHz, CDCl.sub.3): 2.11 (IH, m); 2.30 (2H, m); 2.61 (IH, m); 4.15 (IH, m); 5.02 (IH, m); 5.53 (1H, br d); 4.10 (1H, d); 7.10 (IH, m); 7.17 (2H, m); 7.27 (1H, m); 7.47 (2H, m); 7.61 (IH, d).

(218) NMR 60.234:

(219) ? (in ppm, 400 MHz, CDCl.sub.3): 4.51 (1H, dd); 5.18 (1H, dd); 5.50 (1H, ddd); 5.69 (1H, br d); 6.08 (1H, d); 6.90 (1H, d); 7.35-7.77 (7H, m).

(220) TABLE-US-00004 TABLE 59 RT [M + H] Entry Name (min) (measured) Method MP (? C.) 59.1 (1,2 cis)-2-(2,4-dichlorophenyl)cyclobutanamine hydrochloride 227-231 59.2 (1,2 cis)-2-(2,4-dichloro-6-isopropoxy-phenyl)cyclobutanamine hydrochloride 70-73 59.3 (1,2 cis)-2-(2,4-difluorophenyl)cyclobutanamine hydrochloride 242 59.4 (1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutanamine hydrochloride 239 59.5 (1,2 cis)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutanamine hydrochloride 256 59.6 (1,2 cis)-2-(3-chlorophenyl)cyclobutanamine hydrochloride 206-208 59.7 (1,2 cis)-2-(3-bromophenyl)cyclobutanamine hydrochloride 217 59.8 (1,2 cis)-2-(2,5-dichlorophenyl)cyclobutanamine hydrochloride 209 59.9 (1,2 cis)-2-(3,4-dichlorophenyl)cyclobutanamine hydrochloride 239 59.10 (1,2 cis)-2-(2-chlorophenyl)cyclobutanamine hydrochloride 240 59.11 (1,2 cis)-2-(3,5-dichlorophenyl)cyclobutanamine hydrochloride 260-262 59.12 (1,2 cis)-2-(2,6-dichlorophenyl)cyclobutanamine hydrochloride 217 59.13 (1,2 cis)-2-(4-isopropoxyphenyl)cyclobutanamine hydrochloride 259-262 59.14 (1,2 cis)-2-(2,3-dichlorophenyl)cyclobutanamine hydrochloride 249-252 59.15 (1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutanamine hydrochloride 251 59.16 (1,2 cis)-2-(2,4-dichloro-6-methoxy-phenyl)cyclobutanamine hydrochloride 237-239 59.17 (1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutanamine hydrochloride 262 59.18 (1,2 cis)-2-(4-fluorophenyl)cyclobutanamine hydrochloride 0.38 166 G 59.19 (1,2 cis)-2-(4-chlorophenyl)cyclobutanamine hydrochloride 0.52 182 B 59.20 (1,2 cis)-2-(4-bromophenyl)cyclobutanamine hydrochloride 0.53 226 B 59.21 (1,2 cis)-2-(2-bromo-4-fluoro-phenyl)cyclobutanamine 0.52 244 B 59.22 (1,2 cis)-2-(4-bromo-2-fluoro-phenyl)cyclobutanamine 0.54 244 B 59.23 (1,2 cis)-2-(2-fluorophenyl)cyclobutanamine 0.36 166 B 59.24 (1,2 cis)-2-(4-bromo-2-chloro-phenyl)cyclobutanamine 0.84 260 G 59.25 (1,2 cis)-2-[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclobutanamine hydrochloride 0.97 282 G 59.26 (1,2 cis)-2-(2,4,6-trifluorophenyl)cyclobutanamine 0.53 202 B 59.27 (1,2 cis)-2-(2-bromophenyl)cyclobutanamine

(221) TABLE-US-00005 TABLE 60 RT [M + H] MP Entry Name (min) (measured) Method (? C.) 60.1 2,6-difluoro-N-[(1,2 cis)-2-[4-(trifluoromethoxy)phenyl]cyclobutyl]benzamide 110-112 60.2 3-(difluoromethyl)-1-methyl-N-[(1,2 cis)-2-[4-(trifluoromethoxy)phenyl]cyclobutyl]pyrazole-4- 120-123 carboxamide 60.3 N-[(1,2 cis)-2-[4-(trifluoromethoxy)phenyl]cyclobutyl]-2-(trifluoromethyl)benzamide 128-131 60.4 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2,6-difluorobenzamide 138-140 60.5 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 147-149 60.6 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 120-123 60.7 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 124-126 60.8 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 126-128 60.9 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 157-159 60.10 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyrimidine-2-carboxamide 148-149 60.11 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]pyrimidine-2-carboxamide 1.29 288 A 60.12 N-[(1,2 cis)-2-(4-chloro-2-fluorophenyl)cyclobutyl]-2,6-difluorobenzamide 126-129 60.13 N-[(1,2 cis)-2-(4-chloro-2-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 60.14 N-[(1,2 cis)-2-[4-(difluoromethoxy)phenyl]cyclobutyl]-2,6-difluorobenzamide 1.71 354 A 60.15 N-[(1,2 cis)-2-[4-(difluoromethoxy)phenyl]cyclobutyl]-2-(trifluoromethyl)benzamide 1.78 386 A 60.16 2-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]pyridine-3-carboxamide 98-101 60.17 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-fluoropyridine-3-carboxamide 86-89 60.18 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 115-116 60.19 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-3-fluoropyridine-2-carboxamide 80-82 60.20 3-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]pyrazine-2-carboxamide 138-141 60.21 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 156-158 60.22 3-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]pyridine-2-carboxamide 122-124 60.23 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 109-111 60.24 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoropyridine-3-carboxamide 96-102 60.25 2-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 124-128 60.26 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-3-fluoropyridine-2-carboxamide 119-121 60.27 3-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 92-94 60.28 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 141-143 60.29 3-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 82-84 60.30 2,6-difluoro-N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]benzamide 134-135 60.31 N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 143-144 60.32 N-[(1,2 cis)-2-(4-bromophenyl)cyclobutyl]-2,6-difluorobenzamide 137-138 60.33 N-[(1,2 cis)-2-(4-bromophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 144-145 60.34 N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 156-157 60.35 N-[(1,2 cis)-2-(4-bromophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 139-140 60.36 N-[(1,2 cis)-2-(4-cyclopropylphenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 157-158 60.37 N-[(1,2 cis)-2-(4-cyanophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 170-174 60.38 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 72-77 60.39 N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 111-114 60.40 3-chloro-N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]pyridine-2-carboxamide 95-98 60.41 3-fluoro-N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]pyridine-2-carboxamide 75-80 60.42 3-chloro-N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]pyrazine-2-carboxamide 131-132 60.43 N-[(1,2 cis)-2-(4-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 122-124 60.44 N-[(1,2 cis)-2-(4-bromophenyl)cyclobutyl]-3-chloropyrazine-2-carboxamide 167-169 60.45 N-[(1,2 cis)-2-(4-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 166-170 60.46 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 106-108 60.47 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 124-126 60.48 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 146-147 60.49 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 108-110 60.50 N-[(1,2 cis)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-2-(trifluoromethyl)benzamide 131-133 60.51 N-[(1,2 cis)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-3-(trifluoromethyl)pyridine-2- 95-97 carboxamide 60.52 N-[(1,2 cis)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-2-(trifluoromethyl)pyridine-3- 137-139 carboxamide 60.53 N-[(1,2 cis)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 112-114 carboxamide 60.54 N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-2-(trifluoromethyl)benzamide 110-112 60.55 N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-3-(trifluoromethyl)pyridine-2- 109-111 carboxamide 60.56 N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-2-(trifluoromethyl)pyridine-3- 151-153 carboxamide 60.57 N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 152-154 carboxamide 60.58 2-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.74 354 A 60.59 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylbenzamide 1.74 334 A 60.60 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2,4,6-trifluorobenzamide 1.73 374 A 60.61 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylfuran-3-carboxamide 1.66 324 A 60.62 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluorobenzamide 1.76 338 A 60.63 2-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-6-fluorobenzamide 1.74 372 A 60.64 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methylpyridine-2-carboxamide 1.79 335 A 60.65 2-cyano-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.58 345 A 60.66 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoro-6-methylbenzamide 1.74 352 A 60.67 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methylpyrazine-2-carboxamide 1.62 336 A 60.68 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-iodobenzamide 1.79 446 A 60.69 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethoxy)benzamide 1.89 404 A 60.70 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoro-6-(trifluoromethyl)benzamide 1.81 406 A 60.71 2-bromo-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.75 397 A 60.72 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylpyridine-3-carboxamide 1.17 335 A 60.73 N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethylsulfanyl)benzamide 1.92 420 A 60.74 5-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyrimidine-4-carboxamide 1.58 356 A 60.75 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-methylbenzamide 1.63 300 A 60.76 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2,4,6-trifluorobenzamide 1.62 340 A 60.77 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-methylfuran-3-carboxamide 1.55 290 A 60.78 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-fluorobenzamide 1.64 304 A 60.79 2-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-6-fluorobenzamide 1.63 338 A 60.80 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-3-methylpyridine-2-carboxamide 1.65 301 A 60.81 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-cyanobenzamide 1.45 310 A 60.82 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-methoxybenzamide 1.56 334 A 60.83 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-methylbenzamide 1.63 318 A 60.84 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-3-methylpyrazine-2-carboxamide 1.49 301 A 60.85 2,6-dichloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]benzamide 1.69 354 A 60.86 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-iodobenzamide 1.68 411 A 60.87 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethoxy)benzamide 1.78 370 A 60.88 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-(trifluoromethyl)benzamide 1.71 372 A 60.89 2-bromo-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]benzamide 1.64 364 A 60.90 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-methylpyridine-3-carboxamide 1.03 301 A 60.91 N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethylsulfanyl)benzamide 1.83 386 A 60.92 5-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]pyrimidine-4-carboxamide 1.45 322 A 60.93 3-chloro-N-[(1,2 cis)-2-(2,4-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.66 355 A 60.94 2-chloro-N-[(1,2 cis)-2-(4-chlorophenyl)cyclobutyl]benzamide 1.62 320 A 60.95 N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 129-130 60.96 N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 124-125 60.97 N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 1.06 355 B 60.98 N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 110-111 60.99 2-chloro-N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]pyridine-3-carboxamide 131-132 60.100 3-chloro-N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]pyrazine-2-carboxamide 107-108 60.101 N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]-2,6-difluorobenzamide 97-99 60.102 3-chloro-N-[(1,2 cis)-2-(3-chlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.01 321 B 60.103 N-[(1,2 cis)-2-(4-bromo-2-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 109.2-118.1 60.104 N-[(1,2 cis)-2-(4-bromo-2-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 133.9-138 60.105 N-[(1,2 cis)-2-(4-bromo-2-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 144.3-149.1 60.106 N-[(1,2 cis)-2-(4-bromo-2-fluorophenyl)cyclobutyl]-3-chloropyrazine-2-carboxamide 125.6-132.9 60.107 N-[(1,2 cis)-2-(2-bromo-4-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 96.5-105.6 60.108 N-[(1,2 cis)-2-(2-bromo-4-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 140.2-148.3 60.109 N-[(1,2 cis)-2-(2-bromo-4-fluorophenyl)cyclobutyl]-3-chloropyrazine-2-carboxamide 0.98 384 B 60.110 N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 123-124 60.111 N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 177-178 60.112 N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 1.11 389 B 60.113 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 121-121 60.114 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 75-75 60.115 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 129-129 60.116 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 115-115 60.117 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-2-chloropyridine-3-carboxamide 140-140 60.118 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-3-chloropyrazine-2-carboxamide 105-105 60.119 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-2,6-difluorobenzamide 103-103 60.120 N-[(1,2 cis)-2-(3-bromophenyl)cyclobutyl]-3-chloropyridine-2-carboxamide 1.02 365 B 60.121 N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 153-154 60.122 2-chloro-N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 130-131 60.123 3-chloro-N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 1.03 356 B 60.124 N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 150-151 60.125 3-chloro-N-[(1,2 cis)-2-(2,5-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 110-111 60.126 N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.06 354 B 60.127 N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 1.05 355 B 60.128 N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 167-167 60.129 N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 133-133 60.130 2-chloro-N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]pyridine-3-carboxamide 148-148 60.131 3-chloro-N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]pyrazine-2-carboxamide 133-133 60.132 N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]-2,6-difluorobenzamide 164-164 60.133 3-chloro-N-[(1,2 cis)-2-(2-chlorophenyl)cyclobutyl]pyridine-2-carboxamide 82-82 60.134 3-chloro-N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]pyrazine-2-carboxamide 125-127 60.135 2-chloro-N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]pyridine-3-carboxamide 109-111 60.136 N-[(1,2 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-2-methylpyridine-3-carboxamide 135-138 60.137 N-[(1,2 cis)-2-(2-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 170-170 60.138 N-[(1,2 cis)-2-(2-bromophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 169-169 60.139 N-[(1,2 cis)-2-(2-bromophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 172-172 60.140 N-[(1,2 cis)-2-(2-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 171-171 60.141 N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 167-169 60.142 N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 124-126 60.143 N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 107-108 60.144 N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 104-105 60.145 2-chloro-N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 102-104 60.146 3-chloro-N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 117-118 60.147 N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 138-140 60.148 3-chloro-N-[(1,2 cis)-2-(3,4-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.07 355 B 60.149 N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 122-122 60.150 N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 139-139 60.151 N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 191-191 60.152 N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 177-177 60.153 2-chloro-N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 187-187 60.154 3-chloro-N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 173-173 60.155 N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 137-137 60.156 3-chloro-N-[(1,2 cis)-2-(2,6-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 116-116 60.157 N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 172-174 60.158 N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 156-157 60.159 N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 1.14 389 B 60.160 2-chloro-N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 136-137 60.161 3-chloro-N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 141-142 60.162 N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 120-121 60.163 N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 120-121 60.164 3-chloro-N-[(1,2 cis)-2-(3,5-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 129-130 60.165 N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 124-125 60.166 2-chloro-N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]pyridine-3-carboxamide 121-122 60.167 2,6-difluoro-N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]benzamide 119-120 60.168 N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 174-174 60.169 N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 169-169 60.170 N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 197-197 60.171 N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 178-178 60.172 2-chloro-N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]pyridine-3-carboxamide 169-169 60.173 3-chloro-N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]pyrazine-2-carboxamide 173-173 60.174 2,6-difluoro-N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]benzamide 177-177 60.175 3-chloro-N-[(1,2 cis)-2-(4-methylsulfonylphenyl)cyclobutyl]pyridine-2-carboxamide 152-152 60.176 N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 102-102 60.177 N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 117-117 60.178 N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 109-110 60.179 N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 152-153 60.180 N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 149-150 60.181 N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 105-106 60.182 N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 82-83 60.183 N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 128-129 60.184 N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 113-114 60.185 2-chloro-N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]pyridine-3-carboxamide 150-151 60.186 3-chloro-N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]pyrazine-2-carboxamide 108-109 60.187 3-chloro-N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 109-110 60.188 N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 162-163 60.189 3-chloro-N-[(1,2 cis)-2-(4-propan-2-yloxyphenyl)cyclobutyl]pyridine-2-carboxamide 101-102 60.190 3-chloro-N-[(1,2 cis)-2-(2,3-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 117-118 60.191 N-[(1,2 cis)-2-(4-bromo-2-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 146-150 60.192 N-[(1,2 cis)-2-(4-bromo-2-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 130-133 60.193 N-[(1,2 cis)-2-(4-bromo-2-chlorophenyl)cyclobutyl]-3-chloropyrazine-2-carboxamide 1.67 400 G 60.194 N-[(1,2 cis)-2-(4-bromo-2-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 1.86 433 G 60.195 N-[(1,2 cis)-2-(4-bromo-2-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.88 432 G 60.196 N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 120-121 60.197 N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 162-164 carboxamide 60.198 N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 177-179 carboxamide 60.199 N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 161-161 60.200 N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 138-138 60.201 2-chloro-N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]pyridine-3-carboxamide 143-143 60.202 3-chloro-N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 125-125 60.203 2,6-difluoro-N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]benzamide 113-113 60.204 3-chloro-N-[(1,2 cis)-2-(2,4,6-trichlorophenyl)cyclobutyl]pyridine-2-carboxamide 133-133 60.205 2-(trifluoromethyl)-N-[(1,2 cis)-2-[4-[3-(trifluoromethyl)pyrazol-1- 1.11 454 B yl]phenyl]cyclobutyl]benzamide 60.206 N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 147-148 carboxamide 60.207 2-chloro-N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]pyridine-3-carboxamide 135-136 60.208 3-chloro-N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]pyrazine-2-carboxamide 130-132 60.209 N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]-2,6-difluorobenzamide 132-135 60.210 3-chloro-N-[(1,2 cis)-2-(2,4-dichloro-6-methoxyphenyl)cyclobutyl]pyridine-2-carboxamide 165-167 60.211 2-(trifluoromethyl)-N-[(1,2 cis)-2-[4-[3-(trifluoromethyl)pyrazol-1- 191-192 yl]phenyl]cyclobutyl]pyridine-3-carboxamide 60.212 2-chloro-N-[(1,2 cis)-2-[4-[3-(trifluoromethyl)pyrazol-1- 146-147 yl]phenyl]cyclobutyl]pyridine-3-carboxamide 60.213 3-(trifluoromethyl)-N-[(1,2 cis)-2-[4-[3-(trifluoromethyl)pyrazol-1- 132-133 yl]phenyl]cyclobutyl]pyridine-2-carboxamide 60.214 3-chloro-N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]pyrazine-2-carboxamide 98-99.5 60.215 N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 124-125 60.216 N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 113-115 carboxamide 60.217 N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 170-172 carboxamide 60.218 N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 156-158 carboxamide 60.219 N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 136-138 60.220 2-chloro-N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]pyridine-3- 1.17 413 B carboxamide 60.221 3-chloro-N-[(1,2 cis)-2-(2,4-dichloro-6-propan-2-yloxyphenyl)cyclobutyl]pyrazine-2- 122-123 carboxamide 60.222 3-chloro-N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]pyridazine-4-carboxamide 135-136 60.223 3-chloro-N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]pyridazine-4-carboxamide 125-126 60.224 4-chloro-N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 157-158 carboxamide 60.225 N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 123-124 60.226 2-chloro-N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]pyridine-3-carboxamide 155-156 60.227 N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2-carboxamide 124-125 60.228 N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 133-134 60.229 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-4-(trifluoromethyl)pyridazine-3-carboxamide 123-126 60.230 N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridazine-4-carboxamide 152-155 60.231 N-[(1,2 cis)-2-(2-fluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridazine-4-carboxamide 133-136 60.232 4-chloro-N-[(1,2 cis)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 101-103 carboxamide 60.233 N-[(2,3 cis)-2-phenyloxetan-3-yl]-2-(trifluoromethyl)benzamide 158-167 60.234 N-[(2,3 cis)-2-(4-chlorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide 60.235 N-[(2,3 cis)-2-(4-fluorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide 0.88 340 A 60.236 2-(trifluoromethyl)-N-[(2,3 cis)-2-(2,4,6-trifluorophenyl)oxetan-3-yl]benzamide 0.89 376 A 60.237 N-[(2,3 cis)-2-[4-(difluoromethoxy)phenyl]oxetan-3-yl]-2-(trifluoromethyl)benzamide 115-120 60.238 2-(trifluoromethyl)-N-[(2,3 cis)-2[4-(trifluoromethyl)phenyl]oxetan-3-yl]benzamide 123-125 60.239 N-[(2,3 cis)-2-[2-fluoro-4-(trifluoromethyl)phenyl]oxetan-3-yl]-2-(trifluoromethyl)benzamide 99-108 60.240 N-[(2,3 cis)-2-(2,4-difluorophenyl)oxetan-3-yl]-2,6-difluorobenzamide 125-130 60.241 2,6-difluoro-N-[(2,3 cis)-2-(2,4,6-trifluorophenyl)oxetan-3-yl]benzamide 130-136 60.242 2,6-difluoro-N-[(2,3 cis)-2-(4-fluorophenyl)oxetan-3-yl]benzamide 95-101 60.243 N-[(2,3 cis)-2-(4-fluorophenyl)oxetan-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide 107-127 60.244 N-[(2,3 cis)-2-(2,4-difluorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide 129-132 60.245 N-[(2,3 cis)-2-(2,4-difluorophenyl)oxetan-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide 131-134 60.246 2-(trifluoromethyl)-N-[(2,3 cis)-2-(2,4,6-trifluorophenyl)oxetan-3-yl]pyridine-3-carboxamide 143-146 60.247 N-[(1,2 cis)-2-(2,3-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.01 356 60.248 N-[(1,2 cis)-2-(3,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.03 356

(222) TABLE-US-00006 TABLE 61 RT [M + H] RT Chiral MP Entry Name (min) (measured) Method (min) Method (? C.) 61.1 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 4.81 C 12-124 carboxamide 61.2 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 91-93 carboxamide 61.3 3-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 1.03 356 B 6.46 D 61.4 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 1.11 389 B 7.27 K carboxamide 61.5 3-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 85-87 61.6 2-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]benzamide 115-117 61.7 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylpyridine-3-carboxamide 0.86 335 B 61.8 2-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.11 398 B 61.9 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-iodobenzamide 119-121 61.10 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 5.48 C 108-110 carboxamide 61.11 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-methoxypyridine-2-carboxamide 1.32 317.06 R 61.12 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-5-cyclopropyl-1,2-oxazole-4- 1.89 317.07 R carboxamide 61.13 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-methoxybenzamide 1.67 316.07 R 61.14 3-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.77 369.92 R 61.15 3-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.54 364.94 R 132-134 61.16 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethylsulfanyl)benzamide 1.80 386.02 R 61.17 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-methylbenzamide 1.60 300.06 R 61.18 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-cyclopropylthiadiazole-5- 1.62 334.02 R carboxamide 61.19 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-methylfuran-3-carboxamide 1.52 290.05 R 61.20 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-fluorobenzamide 1.62 304.04 R 61.21 2-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]benzamide 1.61 363.96 R 127-132 61.22 2-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-6-fluorobenzamide 1.61 338.02 R 61.23 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-methylpyridine-3-carboxamide 1.02 301.06 R 61.24 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-methoxybenzamide 1.54 334.07 R 61.25 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-methylbenzamide 1.61 318.05 R 61.26 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-methylpyrazine-2-carboxamide 1.47 302.06 R 123-128 61.27 2,6-dichloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]benzamide 1.67 353.98 R 61.28 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1H-pyrrole-2-carboxamide 1.39 275.07 R 61.29 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-methyl-1,3-oxazole-5-carboxamide 1.33 291.02 R 61.30 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-methyl-1,2-thiazole-4-carboxamide 1.40 307.04 R 61.31 6-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1-oxidopyridin-1-ium-2- 1.49 337.02 R carboxamide 61.32 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-iodobenzamide 1.66 411.94 R 61.33 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1-methylpyrrole-2-carboxamide 1.54 289.06 R 61.34 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-(difluoromethyl)-1-methylpyrazole-4- 1.41 340.07 R carboxamide 61.35 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-methylthiadiazole-5-carboxamide 1.44 308.03 R 61.36 3-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.75 325.96 R 61.37 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiadiazole-4-carboxamide 1.44 293.99 R 61.38 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethoxy)benzamide 1.76 370.03 R 61.39 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-methoxythiophene-3-carboxamide 1.64 322.02 R 61.40 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-5-methyl-1,2-oxazole-4-carboxamide 1.66 291.02 R 61.41 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-fluoro-6-(trifluoromethyl)benzamide 1.69 372.04 R 114-125 61.42 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-6-(trifluoromethyl)-2,3-dihydro-1,4- 1.60 378 R oxathiine-5-carboxamide 61.43 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-6-methyl-2,3-dihydro-1,4-oxathiine-5- 1.56 324.04 R carboxamide 61.44 2-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiophene-3-carboxamide 1.68 369.94 R 61.45 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1,3-thiazole-4-carboxamide 1.43 293 R 61.46 3-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.52 321.01 R 61.47 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]pyrimidine-2-carboxamide 1.27 288.05 R 61.48 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-cyanobenzamide 1.43 311.06 R 61.49 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-methylpyridine-2-carboxamide 1.63 301.06 R 61.50 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-methyl-4-(trifluoromethyl)-1,3- 1.61 375.01 R thiazole-5-carboxamide 61.51 5-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.71 325.97 R 61.52 2-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]thiophene-3-carboxamide 1.68 325.96 R 61.53 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-iodothiophene-3-carboxamide 1.67 417.88 R 130-132 61.54 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)thiophene-3- 1.68 360 R carboxamide 61.55 5-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-1,3-thiazole-4-carboxamide 1.60 370.92 R 61.56 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methoxypyridine-2-carboxamide 1.43 351.01 R 61.57 5-cyclopropyl-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1,2-oxazole-4- 1.42 351.04 R carboxamide 61.58 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methoxybenzamide 1.76 350.03 R 61.59 3-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.87 403.89 R 61.60 3-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyridine-2-carboxamide 1.66 398.9 R 61.61 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2- 1.89 419.96 R (trifluoromethylsulfanyl)benzamide 61.62 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylbenzamide 1.71 334.03 R 61.63 4-cyclopropyl-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiadiazole-5- 1.74 368.02 R carboxamide 61.64 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methylfuran-3-carboxamide 1.63 324.01 R 120-120 61.65 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluorobenzamide 1.73 338.02 R 61.66 2-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-6-fluorobenzamide 1.71 371.98 R 84-85 61.67 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.61 325.96 R 61.68 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoro-6-methoxybenzamide 1.64 368.03 R 61.69 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoro-6-methylbenzamide 1.72 352.02 R 61.70 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methylpyrazine-2-carboxamide 1.60 336.03 R 61.71 2,6-dichloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.76 387.94 R 61.72 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1H-pyrrole-2-carboxamide 1.50 309.01 R 61.73 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-4-methyl-1,3-oxazole-5- 1.47 325.03 R carboxamide 61.74 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methyl-1,2-thiazole-4- 1.52 340.99 R 98-99 carboxamide 61.75 6-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1-oxidopyridin-1-ium-2- 1.63 370.99 R carboxamide 61.76 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1-methylpyrrole-2-carboxamide 1.65 323.03 R 61.77 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(difluoromethyl)-1- 1.54 374.02 R methylpyrazole-4-carboxamide 61.78 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-4-methylthiadiazole-5-carboxamide 1.57 341.98 R 61.79 3-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.86 359.92 R 61.80 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiadiazole-4-carboxamide 1.57 327.98 R 61.81 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethoxy)benzamide 1.86 403.98 R 61.82 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-4-methoxythiophene-3- 1.73 355.99 R carboxamide 61.83 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-5-methyl-1,2-oxazole-4- 1.52 325.02 R carboxamide 61.84 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-fluoro-6- 1.78 406.01 R (trifluoromethyl)benzamide 61.85 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-6-(trifluoromethyl)-2,3-dihydro-1,4- 1.70 411.97 R oxathiine-5-carboxamide 61.86 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-6-methyl-2,3-dihydro-1,4-oxathiine- 1.67 358 R 79-84 5-carboxamide 61.87 2-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-3-carboxamide 1.79 403.89 R 61.88 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1,3-thiazole-4-carboxamide 1.55 326.97 R 61.89 2-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.71 353.98 R 61.90 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyrimidine-2-carboxamide 1.39 322 R 61.91 2-cyano-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]benzamide 1.55 345.01 R 61.92 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methylpyridine-2-carboxamide 1.76 335.02 R 61.93 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-methyl-4-(trifluoromethyl)-1,3- 1.72 408.97 R thiazole-5-carboxamide 61.94 5-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-2-carboxamide 1.81 359.97 R 61.95 2-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]thiophene-3-carboxamide 1.79 359.93 R 61.96 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-iodothiophene-3-carboxamide 1.77 451.84 R 61.97 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)thiophene-3- 1.78 393.94 R carboxamide 61.98 5-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-1,3-thiazole-4- 1.73 404.88 R carboxamide 61.99 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 6.29 J 128-129 carboxamide 61.100 N-[(1S,2S)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-3- 5.46 I 74-75 (trifluoromethyl)pyridine-2-carboxamide 61.101 N-[(1S,2S)-2-[2-chloro-4-(trifluoromethyl)phenyl]cyclobutyl]-2- 4.66 H (trifluoromethyl)pyridine-3-carboxamide 61.102 N-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclobutyl]-2- 5.45 L 120-121 (trifluoromethyl)pyridine-3-carboxamide 61.103 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2,6-difluorobenzamide 3.00 M 102-104 61.104 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 2.89 N 89-91 61.105 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-methylfuran-3-carboxamide 65-67 61.106 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-4-methylfuran-3-carboxamide 93-94 61.107 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2,4-dimethylfuran-3-carboxamide 94-96 61.108 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-methylpyridine-2-carboxamide 1.58 303.02 A 61.109 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-methylbenzamide 1.55 302.02 A 61.110 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyrimidine-2-carboxamide 1.23 289.98 A 61.111 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)furan-3-carboxamide 128-130 61.112 5-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyrimidine-4-carboxamide 1.38 323.99 A 61.113 2-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]benzamide 1.55 321.99 A 61.114 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-4-(trifluoromethyl)pyridine-3- 1.43 357.15 A carboxamide 61.115 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]thiophene-2-carboxamide 1.43 293.95 A 61.116 2-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]benzamide 1.57 365.94 A 61.117 2-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-6-fluorobenzamide 1.55 339.99 A 61.118 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-fluoro-6-methylbenzamide 1.57 320.03 A 61.119 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-methylpyrazine-2-carboxamide 1.41 304.02 A 61.120 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridazine-3-carboxamide 1.28 290 A 61.121 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-fluorobenzamide 1.57 306 A 61.122 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-4-(trifluoromethyl)pyrimidine-5- 1.46 358.01 A carboxamide 61.123 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-4-methyl-1,3-oxazole-5- 1.29 293.03 A carboxamide 61.124 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-fluoropyridine-2-carboxamide 1.43 307.08 A 61.125 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-iodobenzamide 1.60 413.94 A 61.126 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-1-methylpyrrole-2-carboxamide 1.49 291.02 A 61.127 3-(difluoromethyl)-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-1- 1.38 342.05 A methylpyrazole-4-carboxamide 61.128 2-acetyl-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-3-carboxamide 1.33 331.05 A 61.129 3-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]thiophene-2-carboxamide 1.69 327.96 A 61.130 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-5-methyl-1,2-oxazole-4- 1.62 293.03 A carboxamide 61.131 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-fluoro-6- 1.64 374 A 100-101 (trifluoromethyl)benzamide 61.132 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-6-methyl-2,3-dihydro-1,4-oxathiine- 1.51 326.02 A 5-carboxamide 61.133 2-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-3-carboxamide 1.33 323 A 130-133 61.134 2-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]thiophene-3-carboxamide 1.62 371.91 A 61.135 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2,6-difluorobenzamide 1.49 324.09 A 61.136 5-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-1,3-thiazole-4- 1.55 372.9 A carboxamide 61.137 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)thiophene-3- 1.64 362.06 A carboxamide 61.138 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-1,3-thiazole-4-carboxamide 1.38 294.97 A 61.139 2-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]thiophene-3-carboxamide 1.62 327.96 A 61.140 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-methylpyridine-3-carboxamide 0.98 303.22 A 147-149 61.141 3-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-2-carboxamide 1.46 322.99 A 102-103 61.142 2-cyano-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]benzamide 1.38 313.03 A 61.143 3-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]thiophene-2-carboxamide 1.71 371.9 A 61.144 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-methylfuran-3-carboxamide 1.47 292.15 A 61.145 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-methyl-1,2-thiazole-4- 1.34 309.01 A carboxamide 61.146 3-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-2-carboxamide 1.49 366.94 A 61.147 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-iodothiophene-3-carboxamide 1.62 419.99 A 61.148 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-4-methylfuran-3-carboxamide 1.55 292.09 A 61.149 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.01 356 B 6.02 S 83-85 61.150 3-chloro-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyrazine-2-carboxamide 0.91 324 B 6.43 T 123-124 61.151 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 1.57 357.2 A 106-108 carboxamide 61.152 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-methylpyridazine-4-carboxamide 0.90 336 B 61.153 4-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2,5-dimethylpyrazole-3- 1.08 372 B carboxamide 61.154 N-[(1S,2S)-2-(4-fluorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 3.70 H 132-133 carboxamide 61.155 N-[(1S,2S)-2-(4-bromophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 3.87 H 151-152 carboxamide 61.156 N-[(1S,2S)-2-(4-bromophenyl)cyclobutyl]-3-(trifluoromethyl)pyrazine-2- 24.23 O 189-190 carboxamide 61.157 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2,3,6-trifluorobenzamide 138-140 61.158 2-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3,6-difluorobenzamide 86-88 61.159 2-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3,6-difluorobenzamide 109-111 61.160 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-5-methyl-1,3-oxazole-4- 1.04 325 B carboxamide 61.161 4-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-5-ethyl-2-methylpyrazole- 107-109 3-carboxamide 61.162 3-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyrazine-2-carboxamide 1.01 400 B 61.163 3-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]pyridazine-4-carboxamide 1.43 354 B 128-129 61.164 3-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]pyridazine-4-carboxamide 1.29 322 B 152-153 61.165 4-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine- 1.77 423 B 148-150 3-carboxamide 61.166 4-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3- 1.67 389 B 171-172 carboxamide 61.167 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-4-(trifluoromethyl)pyridazine-3- 1.65 390 B 143-144 carboxamide 61.168 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-4-(trifluoromethyl)pyridazine-3- 1.53 356 B 174-172 carboxamide 61.169 4-chloro-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine- 1.81 423 B 122-123 2-carboxamide 61.170 N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridazine-4- 1.46 356 B 166-167 carboxamide 61.171 4-chloro-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2- 1.69 389 B 129-130 carboxamide 61.172 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3,6-difluoro-2- (trifluoromethyl)benzamide 61.173 2-bromo-N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]furan-3-carboxamide 1.10 388 B 10.65 U 61.174 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)furan-3- 1.11 378 B carboxamide 61.175 N-[(2S,3S)-2-(2,4-difluorophenyl)oxetan-3-yl]-2-(trifluoromethyl)benzamide 2.27 P 78-80 61.176 N-[(2S,3S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]oxetan-3-yl]-2- 2.39 Q (trifluoromethyl)benzamide 61.177 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridazine-4- 1.59 390 B 195-196 carboxamide 61.178 N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(difluoromethyl)pyridine-3- 1.00 371 B carboxamide 61.179 2-(difluoromethyl)-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-3- 0.89 339 B carboxamide 61.180 2-bromo-N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]furan-3-carboxamide 109-111 61.181 N-[(1S,2S)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)furan-3- 91-92 carboxamide 61.182 2-bromo-N-[(1S,2S)-2-(4-chlorophenyl)cyclobutyl]furan-3-carboxamide 150-152

(223) TABLE-US-00007 TABLE 62 [M + h] Entry Name RT (min) (measured) Method MP (? C.) 62.1 N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 1.03 356 B 116-120 62.2 3-chloro-N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]pyrazine-2-carboxamide 0.93 324 B 150-152 62.3 N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]-1-methyl-3-(trifluoromethyl)pyrazole- 0.96 360 B 133-135 4-carboxamide 62.4 3-bromo-N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-2-carboxamide 0.98 367 B 134-137 62.5 3-chloro-N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-2-carboxamide 0.97 323 B 122-123 62.6 2-chloro-N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]pyridine-3-carboxamide 0.9 323 B 128-130 62.7 N-[(1,2 trans)-2-(2,4-difluorophenyl)cyclobutyl]-3-(trifluoromethyl)pyridine-2-carboxamide 0.99 357 B 82-86 62.8 N-[(1,2 trans)-2-[4-(difluoromethoxy)phenyl]cyclobutyl]-2-(trifluoromethyl)benzamide 1.8 386 B 62.9 N-[(1,2 trans)-2-[4-(difluoromethoxy)phenyl]cyclobutyl]-2,6-difluoro-benzamide 1.74 354 B 62.10 N-[(1,2 trans)-2-(4-chloro-2-fluoro-phenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 128-130 62.11 N-[(1,2 trans)-2-(4-chloro-2-fluoro-phenyl)cyclobutyl]-2,6-difluoro-benzamide 117-119 62.12 N-[(1,2 trans)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 147-148 62.13 N-[(1,2 trans)-2-phenylcyclobutyl]-2-(trifluoromethyl)benzamide 95-98 62.14 N-[(1,2 trans)-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide 117-119 62.15 N-[(1,2 trans)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide 112-115

(224) Analytical Methods

(225) Method A

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

(227) Ionisation method: Electrospray

(228) Polarity: positive ions

(229) 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

(230) Mass range: 100 to 800 Da

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

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

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

(234) 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

(235) 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.

(236) Method B

(237) 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, 30?2.1 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

(238) Method C (Chiral)

(239) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(240) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 240 nm, solvent: Isocratic Heptane:EtOH 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(241) Method D (Chiral)

(242) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(243) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 277 nm, solvent: Isocratic Heptane:EtOH 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(244) Method E (Chiral)

(245) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(246) Column: Chiralpak IE, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 220 nm, solvent: Isocratic Heptane:iPrOH 70:30, injection volume 2 ?l, flow (ml/min) 1.0

(247) Method F (Chiral)

(248) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(249) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane:EtOH:Et.sub.2NH 70:30:0.1, injection volume 2 ?l, flow (ml/min) 1.0

(250) Method G

(251) 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, 30?2.1 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; 2.7-3.0 min 100% B; Flow (ml/min) 0.85

(252) Method H (Chiral)

(253) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(254) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane:EtOH 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(255) Method I (Chiral)

(256) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(257) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane:iPrOH 90:10, injection volume 2 ?l, flow (ml/min) 1.0

(258) Method J (Chiral)

(259) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(260) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 250 nm, solvent: Isocratic Heptane:iPrOH 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(261) Method K (Chiral)

(262) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(263) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 270 nm, solvent: Isocratic Heptane:iPrOH 90:10, injection volume 2 ?l, flow (ml/min) 1.0

(264) Method L (Chiral)

(265) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(266) Column: Chiralpak IA, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane:iPrOH 90:10, injection volume 2 ?l, flow (ml/min) 1.0

(267) Method M (Chiral)

(268) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(269) Column: Chiralpak ID, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 265 nm, solvent: Isocratic TBME: EtOH 99:01, injection volume 2 ?l, flow (ml/min) 1.0

(270) Method N (Chiral)

(271) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(272) Column: Chiralpak IA, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 270 nm, solvent: Isocratic TBME: EtOH 99.5:0.5, injection volume 2 ?l, flow (ml/min) 1.0

(273) Method O (Chiral)

(274) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(275) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane:iPrOH 95:05, injection volume 2 ?l, flow (ml/min) 1.0

(276) Method P (Chiral)

(277) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(278) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane: AcOEt 70:30, injection volume 2 ?l, flow (ml/min) 1.0

(279) Method Q (Chiral)

(280) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(281) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane: AcOEt 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(282) Method R

(283) ZQ2000 Mass Spectrometer from Waters (Single quadrupole mass spectrometer)

(284) Ionisation method: Electrospray

(285) Polarity: positive ions

(286) Capillary (kV) 3.5, Cone (V) 60.00, Extractor (V) 3.00, Source Temperature (? C.) 150, Desolvation Temperature (? C.) 350, Cone Gas Flow (L/Hr) 50, Desolvation Gas Flow (L/Hr) 800

(287) Mass range: 140 to 800 Da

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

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

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

(291) TABLE-US-00009 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

(292) 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.

(293) Method S (Chiral)

(294) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(295) Column: Chiralpak ID, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 260 nm, solvent: Isocratic Heptane: AcOEt 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(296) Method T (Chiral)

(297) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(298) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 270 nm, solvent: Isocratic Heptane:EtOH 80:20, injection volume 2 ?l, flow (ml/min) 1.0

(299) Method U (Chiral)

(300) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(301) Column: Chiralpak IC, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 265 nm, solvent: Isocratic Heptane: AcOEt 90:10, injection volume 2 ?l, flow (ml/min) 1.0

(302) Method V (Chiral)

(303) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(304) Column: Chiralpak ID, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 225 nm, solvent: Isocratic Heptane:iPrOH 90:10, injection volume 2 ?l, flow (ml/min) 1.0

(305) Method W (Chiral)

(306) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(307) Column: Chiralpak ID, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 270 nm, solvent: Isocratic Heptane:EtOH: Et2NH 95:5:0.1, injection volume 2 ?l, flow (ml/min) 1.0

(308) Method X (Chiral)

(309) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(310) Column: Chiralpak IA, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 230 nm, solvent: Isocratic TBME: EtOH 98:2, injection volume 2 ?l, flow (ml/min) 1.0

(311) Method Y (Chiral)

(312) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(313) Column: Chiralpak IA, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 227 nm, solvent: Isocratic EtOH.MeOH 50:50, injection volume 2 ?l, flow (ml/min) 1.0

(314) Method Z (Chiral) Waters UPLC-HClass from Waters: solvent degasser, quaternary pump and PDA detector

(315) Column: Chiralpak IA, length (mm) 100, internal diameter (mm) 4.6, particle size (?) 3, wavelength (nm): 265 nm, solvent: Isocratic Heptane:iPrOH: Et.sub.2NH 95:5:0.1, injection volume 2 ?l, flow (ml/min) 1.0

(316) Method AA (Chiral GC)

(317) Chiral GC was conducted on a Thermo Focus GC Ultra, with a column from Astec Chiraldex BDM fused silica Capillary Column: 30 m, diam: 0.25 mm, 0.25 ?m, H2 flow 1. ml/min, temp injector:

(318) 220? C., FID Detector: temp detector: 220? C., method: start at 150? C., hold 5 min 5? C./min until 200? C., hold 3 min, total time 18 min.

(319) Biological Examples

(320) Meloidogyne spp. (Root-Knot Nematode)

(321) Nematicide, Contact Activity, Preventive.

(322) Filter papers (9 cm?4.5 cm) with a small pocket were placed into plastic pouches (12 cm?6 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. Phytotoxicity was measured as a reduction of growth of the emerged cucumber seedling in comparison to the control.

(323) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(324) 60.5, 60.6, 60.8, 60.9, 60.10, 60.12, 60.13, 60.14, 60.15, 60.16, 60.18, 60.19, 60.20, 60.21, 60.22, 60.23, 60.26, 60.27, 60.28, 60.29, 60.31, 60.33, 60.34, 60.35, 60.37, 60.39, 60.44, 60.45, 60.46, 60.47, 60.48, 60.49, 60.50, 60.51, 60.52, 60.53, 60.54, 60.55, 60.56, 60.57, 60.103, 60.104, 60.105, 60.106, 60.107, 60.108, 60.109, 60.110, 60.112, 60.122, 60.123, 60.126, 60.127, 60.128, 60.129, 60.130, 60.131, 60.132, 60.133, 60.134, 60.137, 60.138, 60.139, 60.140, 60.143, 60.144, 60.146, 60.163, 60.165, 60.166, 60.168, 60.171, 60.172, 60.176, 60.177, 60.178, 60.179, 60.180, 60.181, 60.182, 60.183, 60.184, 60.185, 60.187, 60.188, 60.190, 60.191, 60.192, 60.193, 60.194, 60.195, 60.214, 60.233, 60.235, 60.236, 60.237, 60.238, 60.239, 60.240, 60.241, 60.242, 60.243, 60.244, 60.245, 60.246, 61.1, 61.5, 61.7, 61.8, 61.9, 61.10, 61.41, 61.60, 61.64, 61.66, 61.68, 61.69, 61.76, 61.77, 61.95, 61.99

(325) Heterodera schachtii (Sugar Beet Cyst Nematode), Nematicide, Contact Activity

(326) The tested application rate of each compound was 200 ppm. All solutions were brought to a concentration of 400 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.

(327) The following compounds showed a greater than 75% nematode immobilization compared to the untreated control:

(328) 60.6, 60.7, 60.8, 60.9, 60.10, 60.11, 60.15, 60.16, 60.18, 60.20, 60.21, 60.22, 60.23, 60.24, 60.26, 60.27, 60.28, 60.29, 60.31, 60.33, 60.34, 60.35, 60.37, 60.39, 60.40, 60.42, 60.43, 60.44, 60.45, 60.46, 60.47, 60.48, 60.49, 60.50, 60.51, 60.52, 60.53, 60.54, 60.55, 60.56, 60.57, 60.58, 60.59, 60.60, 60.61, 60.62, 60.63, 60.64, 60.65, 60.66, 60.67, 60.68, 60.69, 60.70, 60.71, 60.72, 60.73, 60.74, 60.75, 60.78, 60.79, 60.86, 60.88, 60.89, 60.90, 60.93, 60.94, 60.95, 60.96, 60.97, 60.98, 60.103, 60.104, 60.105, 60.106, 60.107, 60.108, 60.109, 60.110, 60.111, 60.112, 60.113, 60.114, 60.116, 60.134, 60.135, 60.136, 60.137, 60.138, 60.139, 60.140, 60.142, 60.143, 60.144, 60.146, 60.149, 60.165, 60.166, 60.167, 60.168, 60.169, 60.176, 60.178, 60.179, 60.180, 60.182, 60.183, 60.184, 60.185, 60.186, 60.187, 60.190, 60.191, 60.192, 60.193, 60.194, 60.195, 60.199, 60.203, 60.204, 60.219, 60.229, 60.235, 60.236, 60.237, 60.238, 60.239, 60.241, 60.244, 60.245, 60.246, 61.1, 61.2, 61.3, 61.4, 61.5, 61.6, 61.7, 61.8, 61.9, 61.10, 61.11, 61.14, 61.15, 61.21, 61.22, 61.23, 61.24, 61.25, 61.26, 61.36, 61.41, 61.46, 61.47, 61.52, 61.53, 61.54, 61.56, 61.58, 61.59, 61.60, 61.62, 61.64, 61.65, 61.66, 61.68, 61.69, 61.70, 61.72, 61.73, 61.74, 61.76, 61.77, 61.79, 61.81, 61.83, 61.84, 61.85, 61.86, 61.87, 61.88, 61.89, 61.90, 61.91, 61.92, 61.93, 61.95, 61.96, 61.97, 61.98, 61.99, 61.100, 61.101, 61.102, 61.103, 61.104, 61.106, 61.108, 61.109, 61.110, 61.113, 61.114, 61.116, 61.117, 61.118, 61.119, 61.121, 61.122, 61.124, 61.125, 61.126, 61.127, 61.129, 61.131, 61.133, 61.136, 61.137, 61.140, 61.141, 61.143, 61.144, 61.146, 61.151, 61.154, 61.155, 61.156, 61.158, 61.159, 61.162, 61.167, 61.172, 61.173, 61.174, 61.175, 61.176

(329) Meloidogyne spp. (Root-Knot Nematode)

(330) Nematicide, Contact Activity, Preventive

(331) 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). Phytotoxicity was measured as a reduction of growth of the emerged cucumber seedling in comparison to the control.

(332) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(333) 60.1, 60.2, 60.3, 60.4, 60.5, 60.6, 60.7, 60.9, 60.10, 60.12, 60.13, 60.14, 60.15, 60.16, 60.18, 60.19, 60.20, 60.21, 60.22, 60.23, 60.24, 60.26, 60.27, 60.28, 60.29, 60.30, 60.31, 60.32, 60.33, 60.34, 60.35, 60.37, 60.39, 60.40, 60.41, 60.44, 60.45, 60.46, 60.47, 60.48, 60.49, 60.50, 60.51, 60.52, 60.53, 60.54, 60.55, 60.56, 60.57, 60.103, 60.104, 60.105, 60.106, 60.107, 60.108, 60.109, 60.110, 60.111, 60.112, 60.113, 60.115, 60.116, 60.122, 60.125, 60.126, 60.127, 60.128, 60.129, 60.130, 60.131, 60.132, 60.133, 60.134, 60.135, 60.136, 60.137, 60.138, 60.139, 60.140, 60.142, 60.143, 60.144, 60.146, 60.148, 60.149, 60.151, 60.155, 60.163, 60.165, 60.166, 60.168, 60.171, 60.172, 60.176, 60.177, 60.178, 60.179, 60.180, 60.181, 60.182, 60.183, 60.184, 60.185, 60.187, 60.188, 60.190, 60.191, 60.192, 60.193, 60.194, 60.195, 60.214, 60.233, 60.234, 60.235, 60.236, 60.237, 60.238, 60.239, 60.240, 60.241, 60.242, 60.243, 60.244, 60.245, 60.246, 61.1, 61.5, 61.6, 61.7, 61.8, 61.9, 61.10, 61.14, 61.15, 61.16, 61.17, 61.18, 61.20, 61.21, 61.22, 61.23, 61.24, 61.25, 61.26, 61.32, 61.38, 61.41, 61.44, 61.48, 61.49, 61.53, 61.54, 61.55, 61.58, 61.59, 61.60, 61.62, 61.64, 61.65, 61.66, 61.67, 61.68, 61.69, 61.70, 61.73, 61.74, 61.77, 61.79, 61.81, 61.84, 61.85, 61.86, 61.87, 61.88, 61.89, 61.90, 61.92, 61.95, 61.96, 61.97, 61.98, 61.99, 61.104, 61.106

(334) Meloidogyne spp. (Root-Knot Nematode)

(335) Nematicide, Contact Activity, Preventive

(336) Coated tomato cv. Roter Gnom seeds were sown 0.5 to 1 cm deep in 45 ml pots filled with field soil. Then pots were infested with nematodes by pipetting 2000 eggs of Meloidogyne spp. within a 2 ml suspension on top of the seed. The seed hole was filled with soil hereafter. Assessment of phytotoxicity (in %) and root galling occurred 28 days after inoculation. The roots were washed free of soil debris and the gall index was assessed according to Zeck 1971 on a scale from 0 to 7.

(337) Seed treatment rate: 1 mg AI/seed

(338) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(339) 60.6, 60.7, 60.8, 60.9, 60.48, 60.49, 60.51, 60.56, 60.107, 60.108, 60.126, 60.129, 60.134, 60.214, 60.236, 60.241, 60.245, 61.1, 61.3, 61.5, 61.7, 61.10

(340) Pratylenchus zeae (Corn Lesion Nematode)

(341) Nematicide, Contact Activity, Preventive

(342) Coated corn cv. LG4620 seeds were sown 1 cm deep into 45 ml pots with soil (7:3 w/wa mixture of 70% field soil and 30% quartz Sand). Two days after sowing the pots were infested with 1500 nematodes (all stages) of Pratylenchus zeae within a 2 ml suspension in two holes to the left and right of the seed hole. Assessment of phytotoxicity (in %) and nematode numbers within the root system occurred 7 days after inoculation. The upper plant part was cut off and the roots were washed free of soil debris. Nematodes within the roots were stained with acid fuchsin stain solution. Nematodes within the roots were quantified under a dissecting scope at 40?.

(343) Seed treatment rate: 1 mg AI/seed

(344) The following compounds showed a greater than 80% reduction of nematode population compared to the untreated control:

(345) 60.9, 60.38, 60.46, 60.49, 60.52, 60.214, 60.236, 61.1, 61.10

(346) Heterodera schachtii (Sugar Beet Cyst Nematode)

(347) Nematicide, Contact Activity, Preventive

(348) Coated sugar beat cv. Impulse seeds were planted in 45 ml pots filled with field soil. Seven days after sowing pots were infested with 500 J2 of Heterodera schachtii within a 2 ml suspension in two holes to the left and right of the seedling. Assessment of nematode numbers per g of root occurred 10 days after inoculation. The upper plant part was cut off and the roots were washed free of soil debris. Nematodes within the roots were stained with acid fuchsin stain solution. Nematodes within the roots were quantified under a dissecting scope at 40?.

(349) Seed treatment rate: 0.6 mg AI/seed

(350) The following compounds showed a greater than 80% reduction of nematode population compared to the untreated control:

(351) 60.6, 60.46, 60.48, 60.49, 60.51, 60.52, 60.53, 60.54, 60.55, 60.56, 60.57, 60.139, 60.244, 61.3, 61.4, 61.10, 61.64, 61.92.