Insecticidal compounds based on isoxazoline derivatives

Abstract

Compounds of formula III ##STR00001##
wherein R.sup.1, R.sup.2, L, Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are defined in claim 1.

Claims

1. A compound of formula III ##STR00235## wherein L is a C.sub.1-C.sub.8alkylene; R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkylcarbonyl-, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkoxy-C.sub.1-C.sub.8alkyl or C.sub.1-C.sub.8alkoxycarbonyl-; R.sup.2 is hydrogen, C.sub.1-C.sub.8haloalkyl or C.sub.1-C.sub.8alkyl; Y.sup.1 is CR.sup.7R.sup.8 or C═O; and Y.sup.2, Y.sup.3 and Y.sup.4 are independently CR.sup.7R.sup.8, C═O, N—R.sup.9, O, S, SO or SO.sub.2; wherein at least two adjacent ring atoms in the ring formed by Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are heteroatoms; each R.sup.7 and R.sup.8 is independently hydrogen, halogen, C.sub.1-C.sub.8alkyl, or C.sub.1-C.sub.8haloalkyl; each R.sup.9 is independently hydrogen, cyano, cyano-C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl where one carbon atom is replaced by O, S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl where one carbon atom in the cycloalkyl group is replaced by O, S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8hydroxyalkyl, C.sub.1-C.sub.8alkoxy-C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl, C.sub.2-C.sub.8haloalkynyl, phenyl, phenyl substituted by one to three R.sup.10, phenyl-C.sub.1-C.sub.4alkyl, phenyl-C.sub.1-C.sub.4alkyl wherein the phenyl moiety is substituted by one to three R.sup.10, 5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl or 5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl wherein the heteroaryl moiety is substituted by one to three R.sup.10, or C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkyl-O—N═)C—CH.sub.2—; and each R.sup.10 is independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkoxy, or C.sub.1-C.sub.8haloalkoxy; or a salt or N-oxide thereof; wherein the compound is not ##STR00236##

2. The compound according to claim 1, wherein L is C.sub.1-C.sub.4alkylene.

3. The compound according to claim 1, wherein L is methylene.

4. The compound according to claim 3, wherein Y.sup.3 is N—R.sup.9 and R.sup.9 is cyano, cyano-C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl where one carbon atom is replaced by S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl where one carbon atom in the cycloalkyl group is replaced by S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl, C.sub.2-C.sub.8haloalkynyl, phenyl, phenyl substituted by one to three R.sup.10, phenyl-C.sub.1-C.sub.4alkyl, phenyl-C.sub.1-C.sub.4alkyl wherein the phenyl moiety is substituted by one to three R.sup.10, 5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl or 5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl wherein the heteroaryl moiety is substituted by one to three R.sup.10, C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkyl-O—N═)C—CH.sub.2—, and wherein heteroaryl refers to pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl or thiazolyl.

5. The compound according to claim 4, wherein Y.sup.3 is N—R.sup.9 and R.sup.9 is cyclopropyl, cyclobutyl, oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl, propargyl, cyanomethyl, benzyl, benzyl substituted by one to three R.sup.10.

6. The compound according to claim 5, wherein each R.sup.10 and R.sup.8 is independently hydrogen, halogen, C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4haloalkyl.

7. The compound according to claim 6, wherein each R.sup.10 is independently halogen, cyano, nitro, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, or C.sub.1-C.sub.4haloalkoxy.

8. The compound according to claim 7, wherein R.sup.2 is hydrogen, C.sub.1-C.sub.4haloalkyl or C.sub.1-C.sub.4alkyl.

9. The compound according to claim 8, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylcarbonyl-, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.4alkyl or C.sub.1-C.sub.4alkoxycarbonyl-.

10. The compound according to claim 9, wherein Y.sup.4 is C═O.

11. The compound according to claim 10, wherein Y.sup.2 is O.

12. The compound according to claim 1, wherein Y.sup.3 is N—R.sup.9 and R.sup.9 is cyano, cyano-C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyl where one carbon atom is replaced by S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8alkyl where one carbon atom in the cycloalkyl group is replaced by S, S(O) or SO.sub.2, or C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl, C.sub.2-C.sub.8haloalkynyl, phenyl, phenyl substituted by one to three R.sup.10, phenyl-C.sub.1-C.sub.4alkyl, phenyl-C.sub.1-C.sub.4alkyl wherein the phenyl moiety is substituted by one to three R.sup.10, 5-6 membered heteroaryl-C.sub.1-C.sub.8alkyl or 5-6 membered heteroaryl-C.sub.1-C.sub.4alkyl wherein the heteroaryl moiety is substituted by one to three R.sup.10, C.sub.1-C.sub.4alkyl-(C.sub.1-C.sub.4alkyl-O—N═)C—CH.sub.2—, and wherein heteroaryl refers to pyridazinyl, pyrimidinyl, pyrazinyl, pyrazoyl, furanyl, thiophenyl, oxazolyl, isoxazolyl or thiazolyl.

13. The compound according to claim 12, wherein Y.sup.3 is N—R.sup.9 and R.sup.9 is cyclopropyl, cyclobutyl, oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl, propargyl, cyanomethyl, benzyl, benzyl substituted by one to three R.sup.10.

Description

EXAMPLE 1: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-N-[1,2]DITHIOLAN-4-YL-2-METHYL-BENZAMIDE (COMPOUND A1)

(1) ##STR00015##

Step A: Thioacetic Acid S-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester

(2) ##STR00016##

(3) Methanesulfonic acid 2-tert-butoxycarbonylamino-3-methanesulfonyloxy-propyl ester (Synthesis (1998), (8), 1113-1118) in dimethylformamide (5 ml) and potassium thioacetate (685 mg) in dimethylformamide (5 ml) were added dropwise. The reaction was stirred overnight at room temperature then poured into water. A yellow-brown solid precipitated which was filtered and washed with water to give 220 mg of the title product. The aqueous phase was extracted with diethyl ether, the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give another 110 mg of the title product. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.80 (m, 1H), 3.90 (m, 1H), 3.10 (m, 4H), 2.40 (s, 6H), 1.40 (s, 9H).

Step B: [1,2]Dithiolan-4-yl-carbamic Acid Tert-Butyl Ester

(4) ##STR00017##

(5) A solution of thioacetic acid S-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester (330 mg) in ethanol (5 ml) was treated with 2.5 ml of 1N sodium hydroxide for 1 hour at room temperature. The yellow solid turned green-brown. The reaction mixture was diluted with dichloromethane (25 ml) and then an aqueous solution of 0.1M iodine (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and quenched by addition of 1M sodium bisulfite solution. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent evaporated in vacuo to afford the tide product (170 mg). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.00 (br s, 1H), 4.90 (m, 1H), 3.15 (d, 2H), 3.05 (d, 2H), 1.40 (s, 9H).

Step C: [1,2]Dithiolan-4-ylamine

(6) ##STR00018##

(7) The BOC protecting group was removed as described in Example 3, Step B to afford the title compound (trifluoroacetic acid salt), which was used directly in the next step.

Step D: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[1,2]dithiolan-4-yl-2-methyl-benzamide

(8) ##STR00019##

(9) Amide coupling was performed as described in Example 3, Step C to afford the title compound as a solid (40 mg). M.p. 73° C.; LCMS (Method F) 2.20 min, M−H 519/521. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.50-7.30 (m, 6H), 6.20 (m, 1H), 5.35 (m, 1H), 4.00 (d, 1H), 3.60 (d, 1H), 3.30 (m, 2H), 3.20 (m, 2H), 2.40 (s, 3H).

EXAMPLE 2: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND B1)

(10) ##STR00020##

(11) Oxalyl chloride (0.122 ml) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.5 g) (prepared according to WO 2009/080250) in dichloromethane (3 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to give the acid chloride as a yellow solid, which was used in the next step without further purification.

(12) D-cycloserine (21 mg) was added to a solution of the acid chloride (45 mg) and triethylamine (0.1 ml) in toluene (2 ml). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and ethyl acetate and the phases were separated. The organic phase was washed twice with water, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 5%) to give the title compound (28 mg) as a colorless solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.60 (s, br., 1H), 7.60-7.45 (m, 6H), 6.40 (s, 1H), 5.05 (m, 1H), 4.85 (m, 1H), 4.20 (t, 1H), 4.05 (d, 1H), 3.70 (d, 1H), 2.50 (s, 3H) ppm.

EXAMPLE 3: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-2-METHYL-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND B2)

Step A: ((R)-2-Methyl-3-oxo-isoxazolidin-4-yl)-carbamic Acid Tert-Butyl Ester

(13) ##STR00021##

(14) (3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (1.01 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in dimethylformamide (5 ml), the solution was cooled to 0° C. and 616 mg of potassium t-butoxide was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour then 710 mg methylene iodide was added and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was then washed several times with water, dried over sodium sulphate and the solvent removed in vacuo. Crude ((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (140 mg) was obtained as a white solid. LCMS (method A) 1.11 min, MH.sup.+ 217; .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.20 (m, 1H), 4.70 (m, 1H), 4.55 (m, 1H), 4.00 (dd, 1H), 3.20 (s, 3H), 1.40 (s, 9H).

Step B: (R)-4-Amino-2-methyl-isoxazolidin-3-one

(15) ##STR00022##

(16) ((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester of Step A (108 mg) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (0.2 ml). The reaction mixture was stirred at room temperature for 1 hour and the solvent removed in vacuo to afford (R)-4-Amino-2-methyl-isoxazolidin-3-one (trifluoroacetic acid salt), which was used directly in the next step.

Step C: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-benzamide

(17) ##STR00023##

(18) To a suspension of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid (175 mg, prepared as described in WO2009/080250) in dichloromethane (5 ml) was added oxalyl chloride (0.05 ml) and then one drop of dimethylformamide. The reaction mixture stirred at room temperature for 2 hours 30 minutes, and the solvent was evaporated in vacuo to give a pink solid (acid chloride, 170 mg). The acid chloride thus obtained was dissolved in dichloromethane (2 ml) and the resulting solution was added dropwise to a solution of triethylamine (0.35 ml) and (R)-4-Amino-2-methyl-isoxazolidin-3-one (obtained in Step B) in dichloromethane (3 ml) at room temperature, under argon. The reaction was stirred overnight at room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed two times with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (eluent cyclohexane/ethyl acetate) afforded the title compound as a solid (70 mg). M.p. 87° C.; LCMS (Method A) 1.99 min. MH.sup.+ 516/518. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.60-7.40 (m, 6H), 6.45 (m, 1H), 5.00 (t, 1H), 4.87 (m, 1H), 4.10 (m, 2H), 3.70 (d, 1H), 3.25 (s, 3H), 2.50 (s, 3H).

(19) The following compounds were prepared following a similar method to that described in Example 3: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-propargyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound B3) (using propargyl bromide as an alkylating agent in Step A); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-benzyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound B4) (using benzyl bromide as an alkylating agent in Step A); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(2,2,2-trifluoroethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound B5) (using 2,2,2-trifluoroethyl trifluoromethanesulfonate as alkylating agent in Step A); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-methyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound E1) (starting from (S)-cycloserine)

EXAMPLE 4: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-2-ETHYL-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND B6)

Step A: ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamic Acid Tert-Butyl Ester

(20) ##STR00024##

(21) (3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002. 50(4) 554-557) was dissolved in acetonitrile (20 ml) then potassium carbonate (0.69 g), potassium iodide (0.175 g) and bromoethane (0.13 g) were added. The reaction was heated under microwave irradiation for 1 hour at 140° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.29 min, MH.sup.+(−BOC) 131; .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.10 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 3.95 (m, 1H), 3.60 (m, 2H), 1.50 (s, 9H), 1.20 (m, 3H).

Step B: (R)-4-Amino-2-ethyl-isoxazolidin-3-one

(22) ##STR00025##

(23) The BOC protecting group was removed as described in Example 3, Step B to afford (R)-4-amino-2-ethyl-isoxazolidin-3-one (trifluoroacetic acid salt), which was used directly in the next step.

Step C: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide

(24) ##STR00026##

(25) Amide coupling was performed as described in Example 3, Step C to afford the title compound as a solid (160 mg). M.p. 140° C.; LCMS (Method A) 2.05 min, M−H 528/530. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.60-7.40 (m, 6H), 6.45 (br s, 1H), 5.00 (t, 1H), 4.85 (dt, 1H), 4.10 (d, 1H), 4.00 (dd, 1H), 3.70 (d, 1H), 3.60 (m, 2H), 2.50 (s, 3H), 1.25 (m, 3H).

(26) The following compounds were prepared following a similar method to that described in Example 1: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(2-methoxyethyl)-3-oxo-isoxazolidin-4-yl)-benzamide (compound B7) (using 2-bromo-1-methoxy-ethane as alkylating agent in Step A); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-butyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound B8) (using butyl bromide as alkylating agent in Step A); 4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C1), 4-[5-(3,5-Dichloro-4-bromo-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C2); 4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C3); 4-[5-(3,5-trifluoromethyl-4-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C4); 4-[5-(3-chloro-5-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C5); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound E2) (starting from (S)-cycloserine).

(27) When this reaction was carried out to obtain 4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C1), it was possible to separate the two diastereoisomers by precipitation after the work up. The crude mixture was stirred with diethyl ether and a solid precipitated out of the solution. The solid (enriched in 1 diastereomer) was analysed by chiral HPLC (method K): 9.72 min (93.8%), 16.6 min (06.17%). The filtrate (enriched in the other diastereomer) was also analysed by chiral HPLC (method K): 9.99 min (11.53%), 16.6 min (85.16%).

(28) Similarly when this reaction was carried out to obtain 4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (compound C3), it was possible to separate the two diastereoisomers by precipitation after the work up. The crude mixture was stirred with diethyl ether and a solid precipitated out of the solution. The solid (enriched in 1 diastereomer) was analysed by chiral HPLC (method K): 8.88 min (88.87%), 15.98 min (05.95%). The filtrate (enriched in the other diastereomer) was also analysed by chiral HPLC (method K): 8.61 min (24.10%). 12.25 min (74.49%).

EXAMPLE 5: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-2-(2-HYDROXY-ETHYL)-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND B9)

Step A: ((R)-2-(hydroxy-ethyl)-3-oxo-isoxazolidin-4-yl)-carbamic Acid Tert-Butyl Ester

(29) ##STR00027##

(30) (3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in acetonitrile (20 ml), then potassium carbonate (0.69 g), potassium iodide (0.175 g) and 2-bromoethanol (0.137 g) were added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.05 min, MH.sup.+ 259; .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.55 (br s, 1H), 4.65 (m, 2H), 4.10 (t, 1H), 3.80 (m, 1H), 3.20 (br s, 1H), 1.50 (s, 9H), 1.20 (m, 3H).

Step B: (R)-4-Amino-2-(2-hydroxyethyl)-isoxazolidin-3-one

(31) ##STR00028##

(32) The BOC protecting group was removed as described in Example 3, Step B to afford (R)-4-amino-2-(2-hydroxyethyl)-isoxazolidin-3-one (trifluoroacetic acid salt), which was used directly in the next step.

Step C: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-benzamide

(33) ##STR00029##

(34) Amide coupling was performed as described in Example 3, Step C to afford the title compound as a solid (24 mg). M.p. 78° C.; LCMS (Method A) 1.94 min, M−H 544/550.

EXAMPLE 6: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-2-(THIETAN-3-YL)-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND B10)

Step A: ((R)-2-(thietan-3yl)-3-oxo-isoxazolidin-4-yl)-carbamic Acid Tert-Butyl Ester

(35) ##STR00030##

(36) A solution of triphenylphosphine (0.79 g) in THF (22 ml) was cooled under argon to −10° C. Diethylazodicarboxylate (DEAD, 1.57 g) was added dropwise then thietan-3-ol (0.4 g) and (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.27 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557). The reaction mixture was stirred at room temperature for 24 hours then the solvent was removed in vacuo. The crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford the title product as a white solid (51 mg). H-NMR (CDCl.sub.3, 400 MHz): 5.45 (q, 1H), 5.05 (m, 1H), 4.90 (m, 1H), 4.50 (t, 1H), 4.10 (dd, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 1.50 (s, 9H).

Step B: (R)-4-Amino-2-(thietan-3-yl)-isoxazolidin-3-one

(37) ##STR00031##

(38) Using the product obtained in Step A (43 mg), the BOC protecting group was removed as described in Example 3, Step B to afford the title product, which was used directly in the next step. LCMS (Method A) 0.17 min, M−H 175.

Step C: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(thietan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide

(39) ##STR00032##

(40) Amide coupling was performed as described in Example 3, Step C to afford the tide compound as a yellow resin (10 mg); LCMS (Method A) 2.13 min, M−H 573/574.

(41) The following compounds were prepared following a similar method to that described in Example 6: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(cyclobutyl)-3-oxo-isoxazolidin-4-yl)-benzamide (compound B11); 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(oxetan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide (compound B12)

EXAMPLE 7: GENERAL METHOD FOR PREPARING THE COMPOUNDS OF THE INVENTION IN PARALLEL

(42) ##STR00033##

(43) To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-3-oxo-isoxazolidin-4-yl)-benzamide (30 μmol) in N,N-dimethylformamide (“DMF”) (0.5 ml) was added a solution of an alkylhalogenide of formula R—X (32 μmol) in N,N-dimethylformamide (“DMF”) (0.3 ml) followed by addition of potassium carbonate (80 μmol). The reaction mixture was stirred at ambient temperature for 16 hours. Then the reaction mixture was separated by HPLC. This method was used to prepare a number of compounds (Compound Nos. B13 to B29 of Table B) in parallel.

EXAMPLE 8: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-(2-OXO-2LAMBDA*4*-[1,2]OXATHIOLAN-4-YL)-BENZAMIDE (COMPOUND A2)

Step A: (R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylamine Trifluoroacetic Acid Salt

(44) ##STR00034##

(45) (2-Oxo-2lambda*4*-[1,2]oxathiolan-4-yl)-carbamic acid tert-butyl ester (prepared in 3 steps from L-cystine according to J. Org. Chem. 1981, 46, 5408-5413) (345 mg) was dissolved in dichloromethane (7.8 ml) and treated with trifluoroacetic acid (0.36 ml). The reaction mixture was stirred at room temperature overnight and the solvent removed in vacuo to afford (R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylamine (trifluoroacetic acid salt), which was used directly in the next step. LCMS (Method E) 0.20 min, M+H 122.

Step B: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-2lambda*4*-[1,2]oxathiolan-4-yl)-benzamide

(46) ##STR00035##

(47) Oxalyl chloride (0.027 ml) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (100 mg) (prepared according to WO 2009/080250) in dichloromethane (1.2 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to give the acid chloride as a yellow solid, which was used in the next step without further purification.

(48) To a solution of the acid chloride in dichloromethane were added triethylamine (0.074 mL) followed by (R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylamine (trifluoroacetic acid salt) (59 mg). The reaction mixture was then stirred at room temperature for 24 hours. The reaction was quenched by adding water and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Purification using reverse phase chromatography afforded 16 mg of a first mixture of 2 diastereomers as an oil, followed by 21 mg of a second mixture of 2 other diastereomers as an oil. Fraction 1: LCMS (Method F) 2.04 min, M−H 519/521. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.56-7.47 (m. 4H), 7.46-7.42 (m, 1H), 7.41-7.34 (m, 1H), 6.24-6.04 (m, 1H), 5.23-5.12 (m, 1H), 4.99 (dd, 1H), 4.75 (dd, 1H), 4.08 (d, 1H), 3.70 (d, 1H), 3.34 (d, 1H), 3.09 (d, 1H, J=6.6 Hz), 2.50 (s, 3H). Fraction 2: LCMS (Method) min, M−H 519/521. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.58-7.39 (m, 6H), 5.48-5.37 (m, 1H), 4.88 (d, 1H), 4.62 (d, 1H), 4.08 (d, 1H), 3.70 (d, 1H), 3.63-3.54 (m, 1H), 3.31 (d, 1H), 2.46 (s, 3H).

EXAMPLE 9: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-N-(2-ETHYL-1,1-DIOXO-1LAMBDA*6*-ISOTHIAZOLIDIN-4-YLMETHYL)-2-METHYL-BENZAMIDE (COMPOUND D1)

Step A: N-(3-Benzyloxy-2-hydroxy-propyl)-N-ethyl-methanesulfonamide

(49) ##STR00036##

(50) Triethylamine (0.043 ml, 0.1 equiv) was added to a mixture of N-ethylmethanesulfonamide (413 mg, 1.1 equiv) and 2-benzyloxymethyloxirane (500 mg, 3.04 mmol) prepared according to (J. Am. Chem. Soc., 1996, 118, 7094-7100) in anhydrous dioxane (1 ml). The reaction mixture was then heated to 50° C. overnight. As the reaction was not complete, it was heated to 100° C. for another 5 hours (reaction complete according to TLC). The volatiles were then removed in vacuo. Flash chromatography eluting with cyclohexane/Ethyl acetate (6/4 then 1/1) afforded 836 mg (2.91 mmol, 96%). LCMS (Method E) 1.44 min, M+H 288. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.43-7.27 (m, 5H), 4.57 (s, 2H), 4.11-3.90 (m, 1H), 3.62-3.44 (m, 2H), 3.43-3.20 (m, 4H), 2.90 (s, 3H), 1.14-1.33 (m, 3H).

Step B: 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide

(51) ##STR00037##

(52) Benzenesulfonyl chloride (0.41 ml, 1.1 equiv) was added to a solution of N-(3-Benzyloxy-2-hydroxy-propyl)-N-ethyl-methanesulfonamide (836 mg, 2.91 mmol) in pyridine (5.8 ml). The reaction mixture was then heated to 50° C. for 24 hours. Ethyl acetate was added and a precipitate (pyridinium hydrochloride salt) formed. It was filtered and the residue was diluted in ethyl acetate. The organic phase was then washed with 1M aqueous HC, water, CuSO.sub.4 aqueous solution and NaHCO.sub.3 saturated aqueous solution. The organic phase was then dried (Na.sub.2SO.sub.4) and evaporated.

(53) To a solution of the aforementioned residue (2.61 mmol) in anhydrous tetrahydrofuran at −78° C. was added n-BuLi (5.4 mL, 2.5 equiv). The reaction mixture was then allowed to warm up to 0° C. and stirred at this temperature for 2 hours. It was quenched by addition of saturated aqueous NH.sub.4Cl. The reaction mixture was then extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Flash chromatography eluting with cyclohexane/Ethyl acetate (7/3) afforded 274 mg (1.017 mmol, 40%). LCMS (Method E) 1.59 min, M+H 270. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.40-7.27 (m. 5H), 4.60-4.45 (m, 2H), 3.54 (dd, 2H), 3.37-3.20 (m, 2H), 3.17-2.85 (m, 5H), 1.22 (t, 3H).

Step C: (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol

(54) ##STR00038##

(55) A mixture of 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide (254 mg) and Pd/C (108 mg, 0.1 equiv) in methanol was purged with H.sub.2 and left to stir under an H.sub.2 atmosphere for 24 h. As LCMS indicated completion, the reaction mixture was filtered through a pad of silica (rinsing with MeOH). The filtrate was evaporated and 162 mg of the expected alcohol were obtained. It was pure enough to be used as such in the next step. LCMS (Method E) 0.25 min, M+H 170. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 3.8-3.70 (m, 2H), 3.39-3.25 (m, 2H), 3.20-3.01 (m, 4H), 2.94-2.78 (m, 1H), 1.24 (t, 3H).

Step D: 2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-Ylmethyl)-isoindole-1,3-dione

(56) ##STR00039##

(57) To a stirred solution of phthalimide (133 mg, 1 equiv) in tetrahydrofuran (4.5 ml) was added triphenylphosphine (237 mg, 1 equiv) and (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol (0.905 mmol). This solution was cooled down to 0° C. for the dropwise addition of diisopropylazodicarboxylate (0.18 ml, 1 equiv). The reaction mixture was stirred at room temperature over the weekend. It was then concentrated, and stirred in diethyl ether for 5 hours. Volatiles were removed in vacuo. Flash chromatography eluting with cyclohexane/ethyl acetate (7/3) afforded 261 mg (0.85 mmol, 94%). LCMS (Method E) 1.40 min, M+H 309. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.93-7.84 (m, 2H), 7.83-7.72 (m, 2H), 3.89 (dd, 2H), 3.41-3.23 (m, 2H), 3.17-2.98 (m, 5H), 1.22 (t, 3H).

Step E: C-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methylamine

(58) ##STR00040##

(59) To a solution of 2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3-dione (261 mg, 0.85 mmol) in EtOH (4 ml) was added hydrazine monohydrate (0.165 ml, 4 equiv). The reaction mixture was then refluxed overnight and a white gum formed. The reaction mixture was filtered (rinsing several times with EtOH) and the filtrate was evaporated to afford 81 mg of the expected amine contaminated by 10% of 2,3-Dihydro-phthalazine-1,4-dione. It was used as such in the next step.

(60) .sup.1H-NMR (MeOD, 400 MHz): 3.52-3.36 (m, 2H), 3.20-2.97 (m, 4H), 2.92-2.83 (m, 2H), 2.83-2.69 (m, 1H), 1.26 (t, 3H).

Step F: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-(2-ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-2-methyl-benzamide

(61) ##STR00041##

(62) Oxalyl chloride (0.027 ml) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (100 mg) (prepared according to WO 2009/080250) in dichloromethane (1.2 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to give the acid chloride as a yellow solid, which was used in the next step without further purification.

(63) To a solution of the acid chloride in dichloromethane were added triethylamine (0.037 ml) followed by (C-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methylamine (45 mg).

(64) The reaction mixture was then stirred at room temperature for 24 hours. The reaction was quenched by adding water and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Purification using reverse phase chromatography afforded 18 mg of a mixture of two diastereomers as an oil. LCMS (Method D) 2.21 min, M+H 578/580. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.56-7.49 (m, 4H), 7.47-7.40 (m, 2H), 6.23-6.32 (m, 1H), 4.09 (d, 1H), 3.74-3.53 (m, 3H), 3.46-3.27 (m, 2H), 3.17-3.00 (m, 5H), 2.47 (s, 3H), 1.23 (t, 3H).

EXAMPLE 10: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDROISOXAZOL-3-YL]-N-(2-ETHYL-ISOXAZOLIDIN-4-YL)-2-METHYL-BENZAMIDE (COMPOUND A3)

Step A: 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoic Acid Methyl ester

(65) ##STR00042##

(66) Triethylamine (0.11 ml, 0.1 equiv) was added to a mixture of N-hydroxyphthalimide (1.13 g, 6.9 mmol) and 2-Bromomethyl-1-(2-nitro-benzenesulfonyl)-aziridine (7.6 mmol, 1.1 equiv) (prepared according to Org. Biomol. Chem. 2008, 6, 1902-1904) in anhydrous dioxane (4.5 ml). The reaction mixture was then heated to 50° C. over the weekend. Then methanol (2.5 ml) and triethylamine (1.1 ml, 1 equiv) were added and the reaction mixture was heated at 50° C. for another 4 hours. Volatiles were then removed in vacuo. Flash chromatography eluting with cyclohexane/ethyl acetate (1/1 then 3/7) afforded 2.46 g of the title compound (5.67 mmol, 74%). LCMS (Method E) 1.55 min, M+H 435. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.21-8.11 (m, 1H), 8.00 (d, 1H), 7.90-7.67 (m, 3H), 7.63-7.56 (m, 1H), 7.55-7.46 (m, 1H). 7.41 (d. 1H), 6.87-6.73 (m, 1H), 4.77-4.67 (m, 1H), 4.22-3.95 (m, 5H), 3.93-3.75 (m, 2H).

Step B: 2-(4-Amino-isoxazolidine-2-carbonyl)-benzoic Acid Methyl Ester

(67) ##STR00043##

(68) A solution of 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoic acid methyl ester (200 mg, 0.46 mmol) and PhSH (0.035 ml, 1.1 equiv) in acetonitrile (2.3 ml) under argon at rt was treated with K.sub.2CO.sub.3 (95 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (9/1) afforded 85 mg of the expected amine (0.34 mmol, 74%). LCMS (Method E) 0.55 and 1.41 min, M+H 251. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.95 (d, 1H), 7.63-7.52 (m, 1H), 7.51-7.36 (m, 2H), 4.17-3.92 (m, 3H), 3.87 (s, 3H), 3.80-3.55 (m, 2H), 2.04-1.75 (m, 2H).

Step C: 2-(4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazolidine-2-carbonyl)-benzoic Acid Methyl Ester

(69) ##STR00044##

(70) Oxalyl chloride (0.037 ml) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (135 mg) (prepared according to WO 2009/080250) in dichloromethane (1.6 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to give the acid chloride as a yellow solid, which was used in the next step without further purification.

(71) To a solution of the acid chloride in dichloromethane (3.2 ml) were added triethylamine (0.090 ml) followed by 2-(4-Amino-isoxazolidine-2-carbonyl)-benzoic acid methyl ester (85 mg). The reaction mixture was then stirred at room temperature for 24 hours. The reaction was quenched by adding water and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Flash column chromatography eluting with cyclohexane/EtOAc (1/1) afforded 187 mg the expected amine as a mixture of (separable) diastereomers (0.29 mmol, 90%). LCMS (Method F) 2.11 and 2.15 min, M−H 648/650. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.96 (d, 1H), 7.81-7.68 (m, 1H), 7.68-7.60 (m, 1H), 7.60-7.42 (m, 8H), 5.39-5.42 (m, 1H), 4.57-4.43 (m, 1H), 4.31-4.24 (m, 1H), 4.08 (d, 1H), 4.01-3.88 (m, 1H), 3.87-3.78 (m, 1H), 3.72 (d, 1H), 3.62 (s, 3H), 2.52 (s, 3H).

Step D: 4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic Acid Tert-Butyl Ester

(72) ##STR00045##

(73) 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoic acid methyl ester (2.67 g, 6.14 mmol) was suspended in 20 ml 2M aqueous HCl and the mixture was refluxed for 48 hours. It was then filtered and the solids were washed with water. The filtrate was then evaporated and dried under vacuum. The residue was triturated in i-PrOH. The solid was filtered and the filtrate evaporated. This filtrate (177 mg) was used as such without further purification. LCMS (Method E) 0.87 and 0.95 min, M+H 274.

(74) A suspension of the aforementioned residue in MeCN (30 ml) was treated with Et.sub.3N (3.62 ml, 4.2 equiv) and the reaction mixture turned clear. Then Boc.sub.2O (2.01 g, 1.5 equiv) was added and the reaction mixture was left to stir under argon at rt for 36 hours. It was quenched by addition of water and extracted with EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated. Flash chromatography eluting with cyclohexane/ethyl acetate (6/4) afforded 1.69 g (4.52 mmol, 74%). LCMS (Method D) 1.66 min, M+Na 396. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.18-8.13 (m, 1H), 7.95-7.88 (m, 1H), 8.85-7.74 (m, 2H), 5.78 (d, 1H). 4.54-4.42 (m, 1H), 3.95 (dd, 1H), 3.91-3.80 (m, 2H), 3.49 (dd, 1H), 1.49 (s, 9H).

Step E: 4-Amino-isoxazolidine-2-carboxylic Acid Tert-Butyl Ester

(75) ##STR00046##

(76) A solution of 4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic acid tert-butyl ester (694 mg. 1.86 mmol) and PhSH (0.142 ml, 1.1 equiv) in MeCN (10 ml) under argon at room temperature was treated with K.sub.2CO.sub.3 (386 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (10/0 then 9/1) afforded 336 mg of the title amine (1.8 mmol, 96%). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.03-3.92 (m, 3H), 3.89-3.76 (m, 1H), 3.70 (dd, 1H), 3.37 (dd, 1H), 1.51 (s, 9H).

Step F: 4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazolidine-2-carboxylic Acid Tert-Buty Ester

(77) ##STR00047##

(78) Oxalyl chloride (0.20 ml) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (749 mg) (prepared according to WO 2009/080250) in dichloromethane (9 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to give the acid chloride as a yellow solid, which was used in the next step without further purification.

(79) To a solution of the acid chloride in dichloromethane (18 ml) were added triethylamine (0.30 ml) followed by 4-Amino-isoxazolidine-2-carboxylic acid tert-butyl ester (336 mg). The reaction mixture was then stirred at room temperature for 24 hours. The reaction was quenched by adding water and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Flash column chromatography eluting with cyclohexane/EtOAc (1/1) afforded 197 mg the expected amine as a mixture of diastereomers.

(80) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.60-7.48 (m, 4H), 7.47-7.36 (m, 2H), 6.23.6.15 (m, 1H), 5.08-4.98 (m, 1H), 4.20-3.94 (m, 4H), 3.70 (d, 1H), 3.66-3.58 (m, 1H), 2.48 (s, 3H), 1.50 (s, 9H).

Step G: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamide Trifluoroacetic Acid Salt

(81) ##STR00048##

(82) To a solution of 4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazolidine-2-carboxylic acid tert-butyl ester (198 mg, 0.34 mmol) in dichloromethane (1.7 ml) was added trifluoroacetic acid (0.15 ml, 5 equiv). The reaction mixture immediately turned black. The reaction mixture was left to stir for 6 hours. Volatiles were then removed in vacuo. Flash column chromatography eluting with ethyl acetate/methanol (10/0 to 9/1) afforded 92 mg of the expected compound as a mixture of diastereomers. LCMS (Method E) 1.93 min, M+H 488/490.

Step H: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-(2-ethyl-isoxazolidin-4-yl)-2-methyl-benzamide

(83) ##STR00049##

(84) Crude 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamide trifluoroacetic acid salt (0.16 mmol) was dissolved in MeOH (0.8 ml). Then acetaldehyde (0.090 ml, 10 equiv) was added at 0° C. under an argon atmosphere. After stirring for 1 hour at 0° C., NaBH.sub.3CN (20 mg, 2 equiv) was added. The reaction mixture was left to stir over the weekend. It was then evaporated. Flash column chromatography eluting with ethyl acetate/methanol (10/0 to 9/1) afforded 7.5 mg of the expected compound as a mixture of diastereomers. LCMS (Method E) 2.02 min, M+H 516/518. .sup.1H-NMR (MeOD, 400 MHz): 7.70-7.53 (m, 5H), 7.52-7.37 (m, 1H), 4.92-4.85 (m, 1H), 4.40-4.22 (m, 2H), 4.00 (d, 1H), 3.83-3.62 (m, 1H), 3.29-2.52 (m, 4H), 2.43 (s, 3H), 1.16 (t, 3H).

EXAMPLE 11: 4-[5-(3,5-DICHLOROPHENYL)-5-(TRIFLUOROMETHYL)-4H-ISOXAZOL-3-YL]-2-METHYL-N-[(2-OXIDO-1,3,2-DIOXATHIOLAN-2-IUM-4-YL)METHYL]BENZAMIDE (COMPOUND F5)

Step A: Preparation of 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,3-dihydroxy-propyl)-2-methylbenzamide

(85) ##STR00050##

(86) A solution of 10% Sulfuric acid (0.1 ml) and 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-2-methylbenzamide (1 g, 1.9 mmol) in methanol (50 ml) was stirred at 70° C. for 4 hours. The solvent was evaporated and the crude mixture was diluted with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml×2) and then with water (50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the title compound as a solid (0.7 g). M.p. 98-98° C. LCMS (Method G) 3.65 min, MH.sup.+ 491. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.37-7.49 (m, 6H), 6.59 (t, 1H), 4.12 (d, 1H), 3.88 (m, 1H), 3.67 (d, 1H), 3.60 (m, 4H), 2.41 (s, 3H).

Step B: Preparation of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[(2-oxido-1,3,2-dioxathiolan-2-ium-4-yl)methyl]benzamide

(87) ##STR00051##

(88) A solution of 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,3-dihydroxy-propyl)-2-methylbenzamide (100 mg, 0.2 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with Pyridine (0.08 ml, 1.0 mmol) and thionyl chloride (0.03, 0.4 mmol), and stirred for 6 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound (65 mg) as a mixture of diastereoisomers. Purification by preparative HPLC gave the diastereoisomer 1 (28 mg) and the diastereoisomer 2 (18 mg);

(89) Diastereoisomer 1: LCMS (Method G) 4.07 min, MH.sup.+ 536. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.37-7.50 (m, 6H), 6.26 (m, 1H), 5.16 (m, 1H), 4.79 (m, 1H), 4.32 (m, 1H), 4.10 (m, 2H), 3.71 (m, 2H), 2.45 (s, 3H).

(90) Diastereoisomer 2: LCMS (Method G) 4.17 min, MH.sup.+ 536. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.47-7.52 (m, 5H), 7.42 (s, 1H), 6.58 (m, 1H), 4.88 (m, 1H), 4.59 (m, 1H), 4.47 (m, 1H), 4.10 (m, 2H), 3.75 (m, 2H), 2.45 (s, 3H).

EXAMPLE 12: N-(2-BENZYL-ISOXAZOLIDIN-5-YLMETHYL)-4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-BENZAMIDE (COMPOUND F1)

Step A: (2-Benzyl-isoxazolidin-5-ylmethyl)-carbamic Acid Tert-Butyl Ester

(91) ##STR00052##

(92) Following the procedure described in Tetrahedron 55, 1999, 4685-4698, N-BOC-allylamine (2 g) was dissolved in toluene (130 ml) and ethanol (45 ml) then benzylhydroxylamine hydrochloride (3.05 g), paraformaldehyde (3.16 g) and triethylamine (1.93 g) were added. The reaction mixture was allowed to stir at room temperature for 24 hours, then the solvent was evaporated in vacuo. The resulting residue was diluted in ethyl acetate and the hydrochloride salt of triethylamine was filtered off. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a colorless oil (4.37 g). LCMS (Method F) 1.53 min, M+H 293.

Step B: C-(2-Benzyl-isoxazolidin-5-yl)-methylamine

(93) ##STR00053##

(94) A solution of (2-benzyl-isoxazolidin-5-ylmethyl)-carbamic acid tert-butyl ester (Step A, 0.5 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1.95 g). The solution was stirred at room temperature for 4 hours then concentrated in vacuo to afford the crude title product, which was used directly for the next step. LCMS (Method F) 0.20 min, M+H 194.

Step C: N-(2-Benzyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide

(95) ##STR00054##

(96) To a stirred solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.75 g) (prepared according to WO 2009/080250) in acetonitrile (35 ml) and triethylamine (2.04 ml) were added under nitrogen atmosphere TBTU (1.61 g), AZA.HOBT (0.68 g) and C-(2-Benzyl-isoxazolidin-5-yl)-methylamine (Step B, 1.61 g) were added. The resulting solution was stirred at room temperature for 4 hours, then quenched by addition of aqueous saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate, dried over sodium sulfate, filtered then concentrated in vacuo. The residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a white solid (60 mg, (mixture of diastereoisomers). LCMS (Method F) 2.20 min, M+H 636/638.

(97) The following compound was prepared following a similar method to that described in Example 12: N-(2-methyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (compound F2).

EXAMPLE 13: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-[3-OXO-2-ETHYL-ISOXAZOLIDIN-5-YLMETHYL]-BENZAMIDE (COMPOUND F3)

Step A: (3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamic Acid Tert-Butyl Ester

(98) ##STR00055##

(99) Following the procedure described in Tetrahedron 46.1990, 1975-1986, N-BOC-allylamine (1.8 g) was dissolved in ethyl acetate and treated with sodium hydrogenocarbonate (4.38 g) and dibromoformaldoxime (2.55 g). The reaction mixture was stirred at room temperature for 4 hours, then poured into water, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and the solvent removed in vacuo. The title crude product was thus obtained as a colorless oil (3.16 g). LCMS (Method F) 1.48 min, M+H 179/181 (M-BOC).

Step B: (3-Oxo-isoxazolidin-5-ylmethyl)-carbamic Acid Tert-Butyl Ester

(100) ##STR00056##

(101) Following the procedure described in Tetrahedron 46, 1990, 1975-1986, the crude product obtained in Step A (1.5 g) was dissolved in THF and treated with 1N aqueous sodium hydroxide (150 ml) in the presence of tetrabutyl ammonium sulfate (0.54 g). After 24 hours stirring at room temperature, aqueous sodium hydroxide (1N, 50 ml) was added again and the reaction mixture stirred for another 48 hours at 60° C. The reaction mixture was then cooled to room temperature, extracted with diethyl ether and the pH of the aqueous layer adjusted to 1 by addition of 2N HCL. The aqueous layer was then extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate and the solvents removed in vacuo. Column chromatography (ethyl acetate/cyclohexane 1:1) afforded the title product as a white solid (220 mg). LCMS (Method F) 1.06 min, M+H 217. .sup.1HNMR (CDCl.sub.3, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H), 3.40 (m, 2H), 2.75 (dd, 1H), 2.60 (dd, 1H), 1.50 (s, 9H).

Step C: (2-Ethyl-3-oxo-isoxazolidin-5-ylmethyl)-carbamic Acid Tert-Butyl Ester

(102) ##STR00057##

(103) The product obtained in Step B (0.1 g) was alkylated with bromoethane as described in Example 4, step A to afford the O-alkylated product (18 mg), .sup.1HNMR (CDCl.sub.3, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H), 4.2 (q, 2H), 3.35 (m, 2H), 3.00 (dd, 1H), 2.75 (dd, 1H), 1.50 (s, 9H), 1.35 (t, 3H); and the title N-alkylated product (63 mg). .sup.1HNMR (CDCl.sub.3, 400 MHz): 4.85 (m, 1H), 4.55 (m, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 2.80 (dd, 1H), 2.60 (dd, 1H), 1.50 (s, 9H), 1.20 (t, 3H).

Step D: 5-Aminomethyl-2-ethyl-isoxazolidin-3-one

(104) ##STR00058##

(105) A solution of the product obtained in Step C in dichloromethane (2 ml) was treated with trifluoroacetic acid (0.15 g). The solution was stirred at room temperature for 4 hours then concentrated in vacuo to afford the crude title product, which was used directly for the next step. LCMS (Method F) 0.18 min, M+H 145.

Step E: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[3-oxo-2-ethyl-isoxazolidin-5-ylmethyl]-benzamide

(106) ##STR00059##

(107) 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.3 g) (prepared according to WO 2009/080250) was coupled with the amine obtained in Step D (0.12 g) as described in Example 12, Step C to afford the title product as a beige solid (62 mg, mixture of diastereoisomers). LCMS (Method F) 2.02 min, M+H 542/544.

(108) The following compound was prepared following a similar method to that described in Example 13: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[3-oxo-2-(1,1,1-trifluoroethyl)-isoxazolidin-5-ylmethyl]-benzamide (compound F4).

EXAMPLE 14: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-N-[2-(4-METHOXY-PHENYL)-1,1-DIOXO-1LAMBDA*6*-ISOTHIAZOLIDIN-5-YLMETHYL]-2-METHYL-BENZAMIDE (COMPOUND F6)

Step A: 2-Nitrilo-ethanesulfonic Acid (4-methoxy-phenyl)-amid

(109) ##STR00060##

(110) To a solution of para-anisidine (1.95 g) in acetonitrile (25 ml) at 15° C. under argon atmosphere was added pyridine (1.25 g), then cyanomethanesulfonyl chloride (2 g) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml water and the pH was made basic by addition of 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, then concentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane 1:1) afforded the title product as an orange solid (590 mg). .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.30 (d, 2H), 6.95 (d, 2H), 6.70 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H).

Step B: 2-(4-Methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidine-5-carbonitrile

(111) ##STR00061##

(112) To a solution of the compound obtained in Step A (0.59 g) in dimethylformamide (40 ml) was added potassium carbonate (1.1 g). Then, a solution of 1,2-dibromoethane (0.59 g) in dimethylformamide (25 ml) was added dropwise at 55° C. The reaction mixture was then stirred at 55° C. for 2 hours, cooled to room temperature, poured into 15 ml water, and aqueous 2N hydrochloric acid was added to acidic pH. The aqueous layer was then extracted with dichloromethane, the combined organic layers washed two times with 2% aqueous hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane 7:3) afforded the title product as a beige solid (310 mg). .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.30 (d, 2H), 6.90 (d, 2H), 4.25 (m, 1H), (m, 1H), 3.70-3.90 (m, 5H), 2.95 (m, 1H), 2.80 (m, 1H).

Step C: [2-(4-Methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-carbamic Acid Tert-Butyl Ester

(113) ##STR00062##

(114) To a solution at 0° C. of the product obtained in Step B (500 mg) in methanol (15 ml) were added di-tert-butyldicarbonate (807 mg) and nickel(II) chloride hexahydrate (90 mg). Sodium borohydride (490 mg) was added portionwise. The reaction mixture was allowed to stir at room temperature for 24 hours. Diethylenetriamine (190 mg) was added, the reaction mixture was stirred for 30 min at room temperature then the solvent was removed in vacuo. The purple solid residue was diluted in ethyl acetate then washed with aqueous saturated hydrogen bicarbonate. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification using the Combi Flash200 afforded the title product as an impure brown oil (80 mg), which was used directly in the next step.

Step D: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[2-(4-methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-2-methyl-benzamide

(115) ##STR00063##

(116) The compound obtained in Step C (94 mg) was deprotected and coupled with 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.125 g) (prepared according to WO 2009/080250) as described in Example 4, Steps B and C to afford the title compound as a brown solid (65 mg). LCMS (Method F) 2.02 min, M−H 654/655.

(117) The following compounds were prepared following a similar method to that described in Example 14: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[2-(2,2,2-trifluoroethyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-2-methyl-benzamide (Compound F7).

EXAMPLE 15: PREPARATION OF ENANTIOMERICALLY PURE ISOMERS OF 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-(2-ETHYL-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE

(118) 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (prepared as described in WO 2009/080250) was separated through chiral phase preparative HPLC (Column: CHIRALPAK® AD-H 5 μm; Mobile Phase: 80/20 Carbon Dioxide/Ethanol+1% Diethylamine; Flow Rate: 120 ml/min; Detection: 270 nm; Temperature: 25° C.: Outlet Pressure: 150 bars) to afford 4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (α.sub.D+51.43°) and 4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (α.sub.D −51.90°).

(119) Amide coupling with (R)-4-Amino-2-ethyl-isoxazolidin-3-one and (S)-4-Amino-2-ethyl-isoxazolidin-3-one using the procedure described in Example 12, Step C afforded the 4 isomers of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide:

(120) 4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound G1) Chiral HPLC (method H) RT 21.30 min, purity 97%.

(121) 4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound G2): Chiral HPLC (method H) RT 19.79, purity 82%.

(122) 4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound G3): Chiral HPLC (method H) RT 21.11, purity 91%.

(123) 4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide (Compound G4): Chiral HPLC (method H) RT 17.07, purity 95%.

EXAMPLE 16: 4-[(S)-5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-N—[(R)-2-(2,2-DIFLUORO-ETHYL)-3-OXO-ISOXAZOLIDIN-4-YL]-2-METHYL-BENZAMIDE (COMPOUND G6)

(124) ##STR00064##

Step A: [(R)-2-(2,2-Difluoro-ethyl)-3-oxo-isoxazolidin-4-yl]-carbamic Acid Tert-Butyl Ester

(125) ##STR00065##

(126) As described in Example 4, Step A, (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.30 g) was alkylated with 2,2-difluoroethyl trifluoromethanesulfonate (0.35 g), to afford the title product as a white solid (138 mg); .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6.05 (tt, 1H), 5.10 (m, 1H), 4.90 (m, 1H), 4.35 (dt, 2H), 4.20 (dd, 1H), 1.50 (s, 9H); along with the O-alkylated product (179 mg): .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.95 (tt, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 3.80-4.10 (m, 3H), 1.50 (s, 9H).

Step B: (R)-4-Amino-2-(2,2-difluoroethyl)-isoxazolidin-3-one

(127) ##STR00066##

(128) The BOC protecting group was removed as described in Example 4, Step B to afford (R)-4-amino-2-(2,2-difluoroethyl)-isoxazolidin-3-one (trifluoroacetic acid salt), which was used directly in the next step.

Step C: 4-[5-(3,5-Dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(2,2-difluoroethyl)-3-oxo-isoxazolidin-4-yl)-benzamide

(129) ##STR00067##

(130) Amide coupling was performed using 4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.27 g, prepared according to Example 15) as described in Example 12, step C. The title compound was obtained as a white solid (158 mg). M.p. 77-78° C.; LCMS (Method F) 2.09 min, M+H 564/566.

(131) The following compound was prepared following a similar method to that described in Example 16: 4-[5-(3,5-Dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-((R)-2-(2,2-difluoroethyl)-3-oxo-isoxazolidin-4-yl)-benzamide (compound G5).

EXAMPLE 17: 6-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-4-METHYL-N—[(R)-3-OXO-2-(2,2,2-TRIFLUORO-ETHYL)-ISOXAZOLIDIN-4-YL]-NICOTINAMIDE (COMPOUND C6)

Step A: 5-Bromo-2-iodo-4-methyl-pyridine

(132) ##STR00068##

(133) To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile (40 ml) at room temperature under argon were added sodium iodide (4.8 g) then acetyl chloride (0.94 g). After 3 hours stirring at room temperature the white solid formed was filtered off and the filtrate was neutralized with aqueous saturated solution of sodium hydrogenocarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/cyclohexane) to afford the title product as a brown solid (2.04 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s, 3H),

Step B: 5-Bromo-4-methyl-pyridine-2-carbaldehyde

(134) ##STR00069##

(135) In an oven-dried flask the compound obtained in Step A (4.67 g) was dissolved in tetrahydrofuran (22 ml). The solution was cooled to −15° C., then isopropyl magnesium bromide (17.2 ml, 15% solution in THF) was added dropwise at a rate to keep the internal temperature between −15° C. to −10° C. The reaction was stirred at this temperature for 1 hour, then anhydrous dimethylformamide (1.8 ml) was added at a rate to keep the internal temperature below 0° C. The reaction was stirred at this temperature for 1 hour, then poured into water and extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude title aldehyde product (2.4 g, brown solid) was used as such in the next step.

Step C: 5-Bromo-4-methyl-pyridine-2-carbaldehyde Oxime

(136) ##STR00070##

(137) To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at room temperature. The white solid was filtered off and the solution concentrated in vacuo to afford the crude title product (2.2 g, white solid), which was used directly for the next step. LCMS (Method F) 2.09 min, M+H 564/566.

Step D: 5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-pyridine

(138) ##STR00071##

(139) To a solution of the compound obtained in Step C (2.2 g) in dimethylformamide (24 ml) was added N-chlorosuccinimide (1.4 g) in three portions at room temperature under argon. The reaction mixture was allowed to stir overnight at room temperature then a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g, prepared as described in WO 2009/080250) in DMF (6 ml) was added followed by triethylamine (1.43 ml) in DMF (14 ml). The reaction stirred at room temperature for 1 hour then poured into ice water. A white solid precipitated, which was filtered, washed with water and dried under vacuum to give the title product (4.1 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.60 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.40 (s, 1H), 4.20 (d, 1H), 3.85 (d, 1H), 2.45 (s, 3H),

Step E: 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-nicotinic Acid

(140) ##STR00072##

(141) In a 300 ml flask were charged n-butanol (90 ml), palladium acetate (38 mg) and n-butyl-diadamantylphosphine (184 mg). Then, tetramethylendiamine (1.93 ml) and 5-bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-pyridine (7.5 g, obtained as described in Step D) were added.

(142) The reaction was performed under carbon monoxide at 15 bar at room temperature for 20 min. The reaction mixture was then diluted in toluene and the suspension was filtered on Celite and washed with toluene. The solvent was removed under reduced pressure to obtain a red oil. The residue was purified by column chromatography (ethyl acetate, cyclohexane) to yield the butyl ester of the title product as a liquid (3.45 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.03 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.40 (s, 1H), 4.35 (t, 2H), 4.25 (d, 1H), 3.90 (d. 1H), 2.55 (s, 3H), 1.80 (q, 2H), 1.50 (q, 2H), 1.00 (t, 3H). This ester was dissolved in tetrahydrofuran (8 ml), and sodium hydroxide (0.58 g) in methanol (8 ml) and water (16 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate and acidified with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate then concentrated in vacuo. The residue was triturated in heptane and filtered to obtain the title product as a beige solid (2 g). LCMS (Method F) 2.22 min, M+H 419/421.

Step F: 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotinamide

(143) ##STR00073##

(144) The title compound was obtained by coupling the carboxylic acid obtained in Step E (0.15 g) with (R)-4-Amino-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-3-one (0.10 g, obtained as described in Example 3 for the preparation of compound B5) as described in Example 12, Step C. The title product was obtained as a white solid (48 mg). M.p. 53-55° C. LCMS (Method F) 2.13 min, M+H 583/585.

(145) The following compound was prepared following a similar method to that described in Example 17: 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotinamide (compound C7).

(146) Similarly, when this reaction was carried out to obtain 2-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzamide (compound C8), it was possible to separate the two diastereoisomers by precipitation after the purification by column chromatography. The product obtained after column chromatography was thus stirred with diethyl ether and a solid precipitated out of the solution. The solid (enriched in one diastereomer) was analysed by chiral HPLC (method K): 8.90 min (91.02%), 11.97 min (08.98%). The filtrate (enriched in the other diastereomer) was also analysed by chiral HPLC (method K): 8.66 min (17.50%). 11.02 min (69.38%).

(147) Similarly, when this reaction was carried out to obtain 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-benzamide (compound C9), it was possible to separate the two diastereoisomers by precipitation after the purification by column chromatography. The residue was stirred with diethyl ether and a solid precipitated out of the solution. The solid (enriched in one diastereomer) was analysed by chiral HPLC (method K): 8.31 min (87.79%). The filtrate (enriched in the other diastereomer) was also analysed by chiral HPLC (method K): 8.28 min (18.15%), 10.75 min (81.85%).

EXAMPLE 18: GENERAL METHOD FOR PREPARING THE COMPOUNDS OF THE INVENTION IN PARALLEL

(148) ##STR00074##

(149) To a solution of a benzoic acid of the formula (Uh) (20 μmol) in N,N-dimethylacetamide (“DMA”) (0.4 ml) was added successively a solution of an amine of the formula (IIIh) (26 μmol) in N,N-dimethylacetamide (“DMA”) (0.4 ml), diisopropylethylamine (Hunig's Base) (0.03 ml), and a solution of bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (10.2 mg) in N,N-dimethylacetamide (“DMA”) (0.2 ml). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was concentrated and the crude mixture was redissolved in acetonitrile/N,N-dimethylacetamide (4:1) (0.8 ml) and purified by HPLC. This method was used to prepare a number of compounds (Compound Nos. H1 to H26 of Table H) in parallel. The starting carboxylic acids used for the preparation of compounds of Table H were obtained as described in Examples 19 to 31.

EXAMPLE 19: 2-METHYL-4-[5-(3-TRIFLUOROMETHOXY-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(150) ##STR00075##

(151) This compound was prepared following a similar mute to that described in Example 24.

EXAMPLE 20: 6-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-NICOTINIC ACID

(152) ##STR00076##

(153) This compound was prepared from 2,5-dibromo-6-methyl-pyridine following a similar mute to that described in Example 17, Steps A-E.

EXAMPLE 21: 8-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-QUINOLINE-5-CARBOXYLIC ACID

(154) ##STR00077##

(155) The title product was prepared from 5-bromo-quinoline-8-carbaldehyde using the same synthetic route described in Example 17, Steps C-E.

(156) 5-Bromo-quinoline-8-carbaldehyde was prepared as follows:

Step A: 5-Bromo-8-methyl-quinoline

(157) ##STR00078##

(158) A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150° C. for 3 hrs. The solution was cooled to 0° C. then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (dichloromethane) to afford the title compound as a solid (6 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).

Step B: 5-Bromo-8-dibromomethyl-quinoline

(159) ##STR00079##

(160) Radical dibromination was performed using standard method from the compound obtained in Step A (4.4 g), N-bromo-succinimide (8.9 g) in tetrachloromethane (200 ml) at reflux for 12 hours in the presence of dibenzoyl peroxide (245 mg). At the end of the reaction, the succinimide was filtered off, the solvent was removed in vacuo, and the crude product used as such for the next step. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 8.90 (m, 1H), 8.45 (dd, 1H), 8.15 (d, 1H), 8.10 (s, 1H), 7.80 (d, 1H), 7.45 (m, 1H).

Step C: 5-Bromo-quinoline-8-carbaldehyde

(161) ##STR00080##

(162) Hydrolysis of the dibromo compound obtained using the method described in Step B (9 g) was carried out in acetone (138 ml) and water (23 ml) in the presence of silver nitrate (9.7 g) in the dark at room temperature for 5 hours. The silver salts were filtered off through a pad of Celite. The filtrate was diluted with ethyl acetate (150 ml), transferred to a separatory funnel, then washed successively with saturated aqueous sodium bicarbonate (100 ml), water (3×50 ml), and brine (50 ml). The organic layer was dried over sodium sulphate filtered, and evaporated under reduced pressure to afford the title product (4.70 g) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 11.4 (s, 1H, CHO) 9.05 (m, 1H), 8.61 (dd, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.60 (m, 1H)

EXAMPLE 22: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-PYRIDINE-2-CARBOXYLIC ACID

(163) ##STR00081##

(164) This compound was prepared from 5-formyl-pyridine-2-carboxylic acid methyl ester using the standard synthesis described in WO 2009/080250. 5-Formyl-pyridine-2-carboxylic acid methyl ester was synthesized by reductive formylation of 5-bromo-pyridine-2-carboxylic acid methyl ester using the conditions described in Angewandte Chemie, International Edition (2006), 45(1), 154-158.

EXAMPLE 23: 2-CYCLOPROPYL-4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(165) ##STR00082##

(166) This acid was prepared from the methyl ester of 2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid (Example 27) as follows:

(167) A solution of cyclopropyl boronic acid (0.67 g), 2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (3 g) and Bis(triphenylphosphine)palladium(II) chloride (210 mg) were sequentially added to degassed toluene (38 ml). The reaction mixture was stirred for 30 min at room temperature then a degassed aqueous 2N solution of potassium phosphate (7 ml) was added and the resulting mixture was heated at 110° C. overnight. The reaction mixture was filtered over Hyflo and the resulting solution was concentrated in vacuo to give a yellow oil, which was poured into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and the solvents were evaporated in vacuo. The product was used as such for the saponification step, as described in Example 17, Step E to afford the title acid compound (2.5 g) as a yellow solid. LCMS (Method F) 2.15 min M−H 442/444.

EXAMPLE 24: 2-METHYL-4-[5-(4-CYANO-3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(168) ##STR00083##

Steps A-C: Preparation of 2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile

(169) ##STR00084##
Step A

(170) To a solution of Bis(1,5-cyclooctadiene)dimethoxydiiridium (35 mg) in hexane (10 ml) under argon was added 4,4′-Di-tert-butyl-2,2′-bipyridine (110 mg). To this dark brown suspension was added pinacol diborane (2.23 g) and the solution was stirred at room temperature for 5 min. To this solution was added 2,6-Dichloro-benzonitrile (1 g) and the mixture was heated at 50° C. for 22 hours. The solution was then filtered on a Celite pad and the filtrate was concentrated. The residue was then dissolved with ethyl acetate and extracted with saturated ammonium chloride. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was used as such in the next reaction.

(171) Step B

(172) To a solution of crude 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (2.32 g) in a 4:1 mixture THF/H.sub.2O (63 ml) was added sodium periodate (5.01 g). The solution was stirred for 30 min. At room temperature aqueous hydrochloric acid (1N, 5.5 ml) was added to the suspension. The solution was further stirred at room temperature for 6 hours then water and diethyl ether were added and the phases were separated. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was used as such in the next reaction.

(173) Step C

(174) To a solution of crude 2,6-dichloro-4-(boronic acid)-benzonitrile (1.2 g) in a 2:1 mixture THF/H.sub.2O (27 ml) was added 2-Bromo-3,3,3-trifluoro-propene (1.2 ml), potassium carbonate (1.54 g), and then 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene(1,4-naphthoquinone)palladium (438 mg). The reaction mixture was stirred at 60° C. for 3 hours. The solution was allowed to cool to room temperature and then filtered on a Celite pad. The filtrate was concentrated undervacuo and the residue was then dissolved with diethyl ether, extracted with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g). .sup.19F-NMR (CDCl.sub.3, 75 MHz): −64.65 ppm.

(175) Similarly, 1-Chloro-3-trifluoromethyl-5-(1-trifluoromethyl-vinyl)-benzene was obtained. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −63.00 and −65.04 ppm.

(176) Similarly, 1-Bromo-3-chloro-5-(1-trifluoromethyl-vinyl)-benzene was obtained. .sup.19F-NMR (CDCl.sub.3, 375 MHz): −64.95 ppm.

Step D: Preparation of 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene

(177) ##STR00085##

(178) To a solution of 3-Trifluoromethoxy-benzeneboronic acid (2.5 g) in a 2:1 mixture THF/H.sub.2O (36 ml) was added 2-Bromo-3,3,3-trifluoro-propene (3.1 ml), potassium carbonate (3.35 g), then Bis(triphenylphosphine)paladium(II) dichloride (169 mg). The reaction mixture was stirred at 60° C. for 7 hours. The solution was allowed to cool to room temperature then filtered on a Celite pad. The filtrate was concentrated in vacuo and the residue was then dissolved with ethyl acetate, extracted with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene (1.23 g). .sup.19F-NMR (CDCl.sub.3, 75 MHz): −57.87 ppm and −64.94 ppm.

Step E: Preparation of 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic Acid Tert-Butyl Ester

(179) ##STR00086##

(180) To a solution of 4-(hydroxyimino-methyl)-2-methyl-benzoic acid tert-butyl ester (1.47 g) in N,N-dimethylformamide (13 ml) was added N-chlorosuccinimide (“NCS”) (832 mg). The reaction mixture was stirred at ambient temperature for 2 hours. More N-chlorosuccinimide (“NCS”)(850 mg) was added and the reaction mixture was stirred at ambient temperature for 1 hour. A solution of 2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g) and triethylamine (0.72 ml) in N,N-dimethylformamide (13 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 17 hours. Water and ethyl acetate were added and the phases were separated. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (0.902 g). .sup.19F-NMR (CDCl.sub.3, 75 MHz): −78.93 ppm.

(181) Similarly. 4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester was obtained when 1-Bromo-3-chloro-5-(1-trifluoromethyl-vinyl)-benzene was used as reagent. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −79.49 ppm.

(182) Similarly, 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester was obtained when 1-Chloro-3-trifluoromethyl-5-(1-trifluoromethyl-vinyl)-benzene was used as reagent. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −62.83 and −79.59 ppm.

(183) Similarly, 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoic acid tert-butyl ester was obtained when 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene was used as reagent. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −57.87 ppm and −79.85 ppm.

Step F: Preparation of 4-[5-(3,5-dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic Acid

(184) ##STR00087##

(185) To a solution of 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (763 mg) in dichloromethane (9 ml) was added trifluoromethyl acetic acid (“TFA”) (0.9 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Ethyl acetate was added and the mixture was washed with water, dried over sodium sulfate and concentrated to give 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −78.91 ppm.

(186) Similarly, 4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid was obtained when 4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester was used as starting material. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −79.46 ppm.

(187) Similarly, 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid was obtained when 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester was used as starting material. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −62.84 and −79.56 ppm.

(188) Similarly, 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoic acid was obtained when 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoic acid tert-butyl ester was used as starting material. .sup.19F-NMR (CDCl.sub.3, 75 MHz): −57.87 ppm and −79.83 ppm.

EXAMPLE 25: 1-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-ISOQUINOLINE-4-CARBOXYLIC ACID

(189) ##STR00088##

(190) The title product was prepared from 4-bromo-1-methyl-isoquinoline following a similar route to that described in described in Example 21.

EXAMPLE 26: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(191) ##STR00089##

(192) This compound was prepared as described in WO 2005/085216.

EXAMPLE 27: 2-BROMO-4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(193) ##STR00090##

(194) This compound was prepared as described in WO 2009/080250.

EXAMPLE 28: 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-NAPHTHALENE-1-CARBOXYLIC ACID

(195) ##STR00091##

(196) This compound was prepared as described in WO 2010/025998.

EXAMPLE 29: 2-METHYL-4-[5-(3-CHLORO-5-TRIFLUOROMETHYL-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(197) ##STR00092##

(198) This compound was prepared following a similar route to that described in Example 24.

EXAMPLE 30: 2-METHYL-4-[5-(3-CHLORO-5-BROMO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(199) ##STR00093##

(200) This compound was prepared following a similar route to that described in Example 24.

EXAMPLE 31: 2-METHYL-4-[5-(3,5-DICHLORO-PHENYL)-5-CHLORODIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-BENZOIC ACID

(201) ##STR00094##

Step A: Preparation of 4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic Acid Tert-Butyl Ester

(202) ##STR00095##

(203) To a solution of benzoic acid 4-[chloro(hydroxyimino)methyl]-2-(trifluoromethyl) tert-butyl ester (prepared according to WO 2009/080250) (1.25 g) and 1,3-dichloro-5-[1-(chloro-difluoro-methyl)-vinyl]-benzene (1.19 g) (prepared according to WO 2005/085216) in dichloromethane (30 ml) triethylamine (1.9 ml) was added. The reaction mixture was filtered over a plug of silica and concentrated to give (1.95 g) 4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.69 g) which was used in the following step without any further purification.

Step B: 4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic Acid

(204) ##STR00096##

(205) To a solution of 4-[5-(chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.95 g) in dichloromethane (20 ml) was added trifluoromethyl acetic acid (“TFA”) (3 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The dichloromethane was removed by distillation. The residue was purified over silica gel (eluent: ethyl acetate/heptane gradient from 1:1 to 1:0) to give 4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.37 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.10 (d, 1H), 7.65-7.45 (m, 5H), 4.15 (m, 11H), 3.75 (d, 1H), 2.70 (s, 3H).

EXAMPLE 32: PREPARATION OF (5{4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-BENZOYLAMINO}-METHYL-2-OXO-[1,2,3]OXATHIAZOLIDINE-3-CARBOXYLIC ACID CARBAMIC ACID TER-BUTYL ESTER (COMPOUND F8)

Step A: Preparation of (3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamic Acid Tert-butyl Ester

(206) ##STR00097##

(207) Oxalyl chloride (0.9 ml) was added dropwise to a solution of 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid (0.9 g) in dichloromethane (20 ml) and 1 drop of N,N-dimethylformamide and stirred at room temperature under nitrogen for 6 hours. The mixture was concentrated and the residue was dissolved in acetonitrile (50 ml), treated with a solution of (3-amino-2-hydroxy-propyl)-carbamic acid ter-butyl ester (0.8 g) (J. Med. Chem. 1998, 41, 236-246), and a solution of triethylamine (0.9 ml) in acetonitrile (50 ml) and stirred for 16 hours under nitrogen atmosphere. The reaction mixture was concentrated and purified by chromatography on silica gel (eluent hexane/ethyl acetate 50:50) to give the title compound (0.51 g). LCMS (Method G) 4.00 min, MH.sup.+ 590. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.42-7.51 (m, 6H), 6.77 (m, 1H), 5.11 (t, 1H), 4.09 (d, 1H), 3.86 (m, 1H), 3.80 (m, 1H), 3.72 (d, 1H), 3.67 (m, 1H), 3.48 (m, 1H), 3.26 (m, 2H), 2.47 (s, 3H), 1.42 (s, 9H).

Step B: Preparation of (5{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-methyl-2-oxo-[1,2,3]oxathiazolidine-3-carboxylic Acid Carbamic Acid Tert-Butyl Ester

(208) ##STR00098##

(209) A solution of (3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamic acid tert-butyl ester (150 mg) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.16 ml) and thionyl chloride (0.04 ml) and stirred for 2 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (50 mg). LCMS (Method G) 4.29 min, MH.sup.+ 636. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.13-7.59 (m, 6H), 5.15 (m, 1H), 5.45 (m, 1H), 3.94-4.23 (m, 3H), 3.72 (m, 2H), 3.40 (m, 1H), 2.45 (s, 3H), 1.51 (s, 9H).

EXAMPLE 33: PREPARATION OF 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-(2-OXO-[1,2,3]OXATHIAZOLIDIN-5-YLMETHYL)-BENZAMIDE (COMPOUND F9)

Step A: Preparation of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide

(210) ##STR00099##

(211) A solution of (3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with trifluoroacetic acid (0.5 ml) and stirred for 10 h. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (50 ml), washed with saturated aqueous solution of sodium bicarbonate (20 ml) and finally with water (2×20 ml). The organic layer was separated, dried over sodium sulfate and concentrated to give the tide compound (0.13 g). LCMS (Method G) 2.84 min, MH.sup.+ 490. .sup.1HNMR (CDCl.sub.3, 400 MHz): 8.05 (t, 1H), 7.81 (m, 1H), 7.80 (brs, 2H), 7.59 (m, 4H), 7.48 (d, 1H), 4.36 (dd, 2H), 3.85 (m, 2H), 3.28 (m, 2H), 2.50 (m, 1H), 2.37 (s, 3H).

Step B: Preparation of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-[1,2,3]oxathiazolidin-5-ylmethyl)-benzamide

(212) ##STR00100##

(213) A solution of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid, and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88 min, (M−H).sup.− 534. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m, 1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m, 3H), 2.46 (s, 3H).

EXAMPLE 34: PREPARATION OF 4-[5-(3,5-DICHLORO-PHENYL)-5-METHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-N-(1-METHYL-3-OXO-PYRAZOLIDIN-4-YL)-BENZAMIDE (COMPOUND A4)

Step A: Preparation of 4-amino-1-methyl-pyrazolidin-3-one

(214) ##STR00101##

(215) A solution of 4-benzyloxycarbonylamino-1-methyl-pyrazolidin-3-one (240 mg, 1 mmol) (Tetrahedron 1998, 44(1). 3231-3240) in methanol (50 ml) was treated with 10% Pd/C (24 mg) and hydrogenated at 3 bar pressure for 3 hours. The suspension was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (110 mg). LCMS (Method G) 0.42 min, (M−H).sup.+ 116. .sup.1HNMR (MeOD, 400 MHz): 2.96 (t, 1H), 3.00 (s, 3H), 3.55 (m, 1H), 3.72 (t, 1H), 3.85 (bs, 2H).

Step B: Preparation of 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(1-methyl-3-oxo-pyrazolidin-4-yl)-benzamide

(216) ##STR00102##

(217) Oxalyl chloride (0.18 ml) was added dropwise to a solution of 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid (0.398 g) in dichloromethane (10 ml) and 1 drop of N,N-dimethylformamide and stirred at room temperature under nitrogen for 6 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (30 ml), treated with a solution of 4-amino-1-methyl-pyrazolidin-3-one (0.11 g), a solution of triethylamine (0.5 ml) in tetrahydrofuran (20 ml), and stirred for 16 hours under nitrogen. The reaction mixture was concentrated and purified by chromatography on silica gel (eluent hexane/ethyl acetate 60:40) to give 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(1-methyl-3-oxo-pyrazolidin-4-yl)-benzamide as a solid compound which is a mixture of diasteromers (5 mg). .sup.1HNMR (CDCl.sub.3): 2.42 (s, 3H), 3.01 (s, 3H), 3.55 (t, 1H), 3.71 (dd, 2H), 3.86 (m, 1H), 4.08 (dd, 1H), 5.13 (m, 1H), 6.29 (br. d, 1H), 7.4-7.6 (m, 6H).

EXAMPLE 35: PREPARATION OF COMPOUNDS OF THE INVENTION IN PARALLEL

(218) ##STR00103##

(219) Following the general procedure described in Example 18, several compounds of formula (Ij) were prepared in parallel (compounds J1-J32 in Table J). Two diastereoisomers were separated in each case, named A and B in Table J.

EXAMPLE 36: PREPARATION OF 4-[3-(3,5-DICHLORO-PHENYL)-4,4,4-TRIFLUORO-BUT-2-ENOYL]-N-((R)-2-ETHYL-3-OXO-ISOXAZOLIDIN-4-YL)-2-METHYL-BENZAMIDE

Step A: 4-Acetyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide

(220) ##STR00104##

(221) To a suspension of 4-acetyl-2-methyl-benzoic acid (1 g, prepared as described in WO2009001942) in dichloromethane (200 ml) and dimethylformamide (0.2 ml) under argon atmosphere at room temperature, was added dropwise oxalyl chloride (0.53 ml) then the resulting mixture was stirred 1 hour at room temperature until the solid was dissolved. The solvent was removed in vacuo to afford crude 4-acetyl-2-methyl-benzoic acid chloride. To a solution of (R)-4-amino-2-ethyl-isoxazolidin-3-one (1.64 g, Example 4, Step B) in dry dichloromethane (10 ml) was added dropwise at room temperature triethylamine (5 ml). The solution of acid chloride in dichloromethane (5 ml) was added dropwise at room temperature. The resulting mixture was allowed to stir 4 hours at room temperature, then quenched with water. The organic phase was washed with 1N aqueous hydrochloric acid solution. The organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure to afford a residue, which was purified by crystallization from diethyl ether to give a beige solid (1 g). LCMS (Method A) 1.23 min, (M+H)+ 291. Chiral HPLC (method H) 30.18 min (98.99%), 33.62 min (1.01%). 1HNMR (CDCl3, 400 MHz): 1.20 (t, 3H), 2.50 (s, 3H), 2.60 (s, 3H), 3.65 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t, 1H), 6.45 (bs, 1H), 7.50 (d, 1H), 7.70-7.90 (m, 2H).

Step B: 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide

(222) ##STR00105##

(223) To a solution of 4-Acetyl-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (1 g) in 1,2-dichloroethane (5 ml) were added 3.5 dichloro 2,2,2 trifuloroacetophenon (0.92 g), potassium carbonate (0.48 g), and triethylamine (35 mg). The mixture was heated at 100° C. overnight, cooled to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulphate and the solvents removed in vacuo. The residue was purified by column chromatography (ethyl acetate/cyclohexane) to obtain the title compound as a yellow solid (1 g). LCMS (Method A) 2.02 min, (M+H).sup.+ 515/517. .sup.1HNMR (CDCl.sub.3, 400 MHz): 83:17 mixture of diastereoisomers ((E) and (Z)). Major isomer: 1.25 (t, 3H), 2.50 (s, 3H), 3.70 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t, 1H), 6.35 (bd, 1H), 7.15-7.65 (m, 6H), Minor isomer: 1.25 (t, 3H), 2.55 (s, 3H), 3.70 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t, 1H), 6.40 (bd, 1H), 7.15-7.65 (m, 6H).

EXAMPLE 37: ASYMMETRIC PREPARATION OF 4-[5-(3,5-DICHLORO-PHENYL)-5-TRIFLUOROMETHYL-4,5-DIHYDRO-ISOXAZOL-3-YL]-2-METHYL-N-((R)-2-ETHYL-3-OXO-ISOXAZOLIDIN-4-YL)-BENZAMIDE

Step A: Catalyst Preparation: 2,3,4,5,6-pentafluorophenyl-methyl Quininium Bromide

(224) ##STR00106##

(225) A solution of 1-bromomethyl-2,3,4,5,6-pentafluorobenzene (0.52 g) and quinine (0.5 g) in toluene (9 ml) was heated at 80° C. for 18 hours. The reaction mixture was poured in diethyl ether and then filtrate to afford the tide product as a white solid (0.90 g). M.p. 162-165° C. (decomposed). LCMS (method G) 1.08 min, M+505; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.78 (d, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.39 (dd, 1H), 7.18 (d, 1H), 6.73 (m, 1H), 6.41 (d, 1H), 6.09 (d, 1H), 5.50 (m, 1H), 5.04 (d, 1H), 4.98 (d, 1H), 4.70 (m, 1H), 4.63 (d, 1H), 3.98 (s, 3H), 3.97 (m, 1H), 3.74 (m, 2H), 3.10 (m, 1H), 2.81 (m, 1H), 2.30 (m, 2H), 2.05 (m, 2H), 1.41 (m, 1H). .sup.19F NMR (376 MHz, CDCl.sub.3) −132.67 (s, 1F), −146.60 (s, 2F), −158.28 (s, 2F).

(226) Similarly were prepared the two catalysts 3,4,5-trimethoxybenzyl quininium bromide and anthracenyl-methyl dihydroquininium bromide.

Step B: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide

(227) ##STR00107##

(228) A pre-cooled solution of 5M sodium hydroxide (0.09 ml) was added to a solution of hydroxylamine (50% in water. 0.024 ml) at 5° C. (ice bath). The solution was stirred for 15 min at 5° C. then added to a vigorously stirred solution of 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (100 mg) and anthracenyl-methyl quininium bromide (20 mg) (Step A) in dichloroethane (1 ml) cooled in an ice-acetone bath. The mixture was stirred rapidly at 0° C. for 4 hours. The reaction mixture was diluted with dichloromethane, passed through an isolute phase separating cartridge and concentrated in vacuo to leave yellow oil. This residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 5%) to give the title compound (9 mg). The product was analysed by chiral HPLC (method H): 18.7 min (42.5%), 19.6 min (24.2%), 21.4 min (8.5%), 22.8 min (24.8%).

(229) Similarly, using 3,4,5-trimethoxybenzyl quininium bromide as a catalyst, the following ratio of isomers was obtained (38 mg): 18.5 min (14.9%), 19.5 min (35.9%), 21.2 min (12.5%), 22.7 min (36.7%).

(230) Similarly, using 2,3,4,5,6-pentafluorophenyl-methyl quininium bromide as a catalyst, the following ratio of isomers was obtained (23 mg): 18.6 min (16.8%), 19.6 min (38.0%), 21.3 min (9.2%), 22.7 min (36.0%).

(231) TABLE-US-00013 TABLE A Compounds of formula (Ia): (Ia) 08 Comp LCMS mass No. R.sup.5 Y.sup.1 Y.sup.2 Y.sup.3 Y.sup.4 R.sup.2 Method RT (min) spectrum A1 Me CH.sub.2 S S CH.sub.2 H F 2.20 519/521 A2 Me CH.sub.2 S(O) O CH.sub.2 H F 2.04 519/521 A3 Me CH.sub.2 O N—Et CH.sub.2 H E 2.02 516/518 A4 Me CH.sub.2 N—Me N—H C(O) H NMR see Example 34

(232) TABLE-US-00014 TABLE B Compounds of formula (Ib): (Ib) 09 Comp LCMS mass No. R.sup.5 G.sup.1 R.sup.9 Method RT (min) spectrum B1 Me O H F 1.99 500/502 B2 Me O CH3 A 1.99 516/518 B3 Me O propargyl A 2.06 538/540 B4 Me O benzyl F 2.17 590/592 B5 Me O 2,2,2-trifluoroethyl F 2.11 582/584 B6 Me O CH2CH3 F 2.05 528/530 B7 Me O 2-methoxyethyl F 2.02 558/560 B8 Me O n-butyl F 2.14 556/558 B9 Me O 2-hydroxyethyl F 1.94 544/546 B10 Me O thietan-3yl F 2.13 572/574 B11 Me O cyclobutyl F 2.16 554/556 B12 Me O oxetan-3yl F 2.06 556/558 B13 Me O 3-methyl-but-2- J 2.04 570.29 enyl B14 Me O 4-nitro-benzyl J 1.90 637.28 B15 Me O 1,1,1- J 1.96 598.24 trifluoropropan-3-yl B16 Me O 4-fluoro-benzyl J 2.04 610.27 B17 Me O 1,1,1- J 2.01 612.27 trifluorobutan-4-yl B18 Me O 2-cyanoethyl J 1.80 555.24 B19 Me O 2,6-difluoro-benzyl J 2.04 628.29 B20 Me O cyclopropylmethyl J 1.95 556.3 B21 Me O 2-[1,3]dioxan-2-yl- J 1.88 616.3 ethyl B22 Me O 5-trifluoromethyl- J 2.07 650.24 furan-2- ylmethyl B23 Me O 2,5-dimethyl-2H- J 1.85 611.32 [1,2,3]triazol-4- ylmethyl B24 Me O cyclobutylmethyl J 2.05 570.29 B25 Me O 3-cyanopropyl J 1.82 569.27 B26 Me O tetrahydro-pyran-2- J 1.96 600.33 ylmethyl B27 Me O 3-phenyl-propyl J 2.14 620.33 B28 Me O but-2-ynyl J 1.92 554.25 B29 Me O cyclohexylmethyl J 2.18 598.34 B30 Me O (propan-2-one J 1.93 587.26 O-methyl-oxime)- 1-yl

(233) TABLE-US-00015 TABLE C Compounds of formula (Ic): (Ic) 0 Comp LCMS mass No. R.sup.4 A.sup.3 R.sup.9 Method RT (min) spectrum C1 3,4,5-trichloro-phenyl CH ethyl F 2.09 562/564/566 C2 3,5-dichloro-4- CH ethyl F 2.09 605/607/609 bromo-phenyl C3 3,5-dichloro-4- CH ethyl F 2.04 546/548 fluoro-phenyl C4 3,5-trifluoromethyl- CH ethyl F 2.15 630/63.2 4-chloro-phenyl C5 3-chloro-5-fluoro- CH ethyl F 1.99 512/514 phenyl C6 3,5-dichlorophenyl N 2,2,2- F 2.13 583/585 tritium- oethyl C7 3,5-dichlorophenyl N ethyl F 2.03 529/531 C8 3,4,5-trichloro-phenyl CH 2,2,2- F 2.18 616/618/620 trifluoro- ethyl C9 3,5-dichloro-4- CH 2,2,2- F 2.13 600/602 fluoro-phenyl trifluoro- ethyl

(234) TABLE-US-00016 TABLE D Compounds of formula (Id): (Id) Comp LCMS RT mass No. R.sup.4 R.sup.9 Method (min) spectrum D1 3,5-trichloro-phenyl ethyl D 2.21 578/580

(235) TABLE-US-00017 TABLE E Compounds of formula (Ie): (Ie) Comp LCMS mass No. R.sup.5 G.sup.1 R.sup.9 Method RT (min) spectrum E1 Me O CH.sub.3 F 1.98 514/516 E2 Me O CH.sub.2CH.sub.3 F 2.06 528/530

(236) TABLE-US-00018 TABLE F Compounds of formula (If): (If) Comp LCMS mass No. R.sup.5 Y.sup.1 Y.sup.2 Y.sup.3 Y.sup.4 Method RT (min) spectrum F1 Me CH.sub.2 CH.sub.2 N— O F 2.20 590/591 CH.sub.2Ph F2 Me CH.sub.2 CH.sub.2 N—CH.sub.3 O F 1.80 514/516 F3 Me CH.sub.2 C(O) N— O F 2.02 542/544 CH.sub.2CH.sub.3 F4 Me CH.sub.2 C(O) N— O F 2.11 596/598 CH.sub.2CF.sub.3 F5 Me CH.sub.2 O S(O) O G 4.07 536 F6 Me CH.sub.2 CH.sub.2 N-(4- SO.sub.2 F 2.02 654/655 methoxy- phenyl) F7 Me CH.sub.2 CH.sub.2 N-(2,2,2- SO.sub.2 F 2.41 630/632 trifluoro- ethyl) F8 Me CH.sub.2 N— S(O) O G 4.29 636 COOtBu F9 Me CH.sub.2 NH S(O) O G 3.88 534

(237) TABLE-US-00019 TABLE G Compounds of formula (Ig): (Ig) Comp Stereochemistry Stereochemistry HPLC RT mass No. at C-5 at C-4′ R.sup.9 Method (min) spectrum G1 (S) (R) ethyl H 21.3 — G2 (R) (R) ethyl H 19.8 — G3 (S) (S) ethyl H 21.1 — G4 (R) (S) ethyl H 17.1 — G5 (S) (R) 2,2,2- F 2.25 582/584 trifluoro- ethyl G6 (S) (R) 2,2- F 2.09 564/566 difluoro- ethyl

(238) TABLE-US-00020 TABLE H Compounds of formula (Ih): (Ih) Comp No. R.sup.4 R.sup.3 R.sup.9 LCMS Method RT (min) MH.sup.+ H1 CF.sub.3 CH.sub.2CH.sub.3 J 1.78 546.31 H2 0 CF.sub.3 CH.sub.2CH.sub.3 J 1.85 530.64 H3 CF.sub.3 CH.sub.2CH.sub.3 J 1.92 567.25 H4 CF.sub.3 CH.sub.2CH.sub.3 J 1.85 517.24 H5 CF.sub.3 CH.sub.2CH.sub.3 J 1.94 556.27 H6 CF.sub.3 CH.sub.2CH.sub.3 J 1.75 555.26 H7 0 CF.sub.3 CH.sub.2CH.sub.3 J 2 567.25 H8 CF.sub.3 CH.sub.2CH.sub.3 J 1.82 516.26 H9 CF.sub.3 CH.sub.2CH.sub.3 J 1.9 594.14 H10 CF.sub.3 CH.sub.2CH.sub.3 J 1.97 566.27 H11 CF.sub.3 CH.sub.2CH.sub.3 J 1.89 564.28 H12 0 CF.sub.3 CH.sub.2CH.sub.3 J 1.89 574.19 H13 CClF.sub.2 CH.sub.2CH.sub.3 J 1.9 546.23 H14 CF.sub.3 CH.sub.2CF.sub.3 J 1.95 677.26 H15 CF.sub.3 CH.sub.2CF.sub.3 J 1.88 600.28 H16 CF.sub.3 CH.sub.2CF.sub.3 J 1.95 585.24 H17 0 CF.sub.3 CH.sub.2CF.sub.3 J 2.02 621.25 H18 CF.sub.3 CH.sub.2CF.sub.3 J 1.95 571.22 H19 CF.sub.3 CH.sub.2CF.sub.3 J 2.03 610.25 H20 CF.sub.3 CH.sub.2CF.sub.3 J 1.85 609.21 H21 CF.sub.3 CH.sub.2CF.sub.3 J 1.93 569.83 H22 0 CF.sub.3 CH.sub.2CF.sub.3 J 1.99 648.15 H23 CF.sub.3 CH.sub.2CF.sub.3 J 2.05 620.25 H24 CF.sub.3 CH.sub.2CF.sub.3 J 1.98 618.26 H25 CF.sub.3 CH.sub.2CF.sub.3 J 1.98 628.2  H26 CClF.sub.2 CH.sub.2CF.sub.3 J 2 600.22

(239) TABLE-US-00021 TABLE J Compounds of formula (Ij): (Ij) Comp No. 0 R.sup.4 R.sup.3 Diatereo- isomer LCMS Method RT (min) MH.sup.+ J1 CClF.sub.2 A J 1.82 537.23 J2 CClF.sub.2 B J 1.88 537.14 J3 CF.sub.3 A J 1.9 555.13 J4 CF.sub.3 B J 1.95 555.15 J5 0 CF.sub.3 A J 1.82 555.22 J6 CF.sub.3 B J 1.86 555.22 J7 CF.sub.3 A J 1.91 599.13 J8 CF.sub.3 B J 1.95 599.17 J9 CF.sub.3 A J 1.9 647.07 J10 0 CF.sub.3 B J 1.95 647.09 J11 CF.sub.3 A J 1.82 565.14 J12 CF.sub.3 B J 1.86 565.14 J13 CF.sub.3 A J 1.82 539.19 J14 CF.sub.3 B J 1.86 539.16 J15 00 CF.sub.3 A J 1.75 522.19 J16 01 02 CF.sub.3 B J 1.78 522.19 J17 03 04 CF.sub.3 A J 1.82 585.12 J18 05 06 CF.sub.3 B J 1.87 585.09 J19 07 08 CF.sub.3 A J 1.9 557.15 J20 09 0 CF.sub.3 B J 1.94 557.2 J21 CF.sub.3 A J 1.86 547.21 J22 CF.sub.3 B J 1.92 547.2 J23 CF.sub.3 A J 1.68 546.18 J24 CF.sub.3 B J 1.72 546.18 J25 0 CF.sub.3 A J 1.77 507.16 J26 CF.sub.3 B J 1.81 507.15 J27 CF.sub.3 A J 1.66 521.26 J28 CF.sub.3 B J 1.71 520.72 J29 CF.sub.3 A J 1.85 589.24 J30 0 CF.sub.3 B J 1.89 589.23 J31 CF.sub.3 A J 1.86 575.16 J32 CF.sub.3 B J 1.91 575.15

BIOLOGICAL EXAMPLES

(240) This Example illustrates the pesticidal/insecticidal properties of compounds of formula (I). Tests were performed as follows:

(241) Spodoptera littoralis (Egyptian Cotton Leafworm):

(242) Cotton leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with 5 L1 larvae. The samples were checked for mortality, feeding behavior, and growth regulation 3 days after treatment (DAT).

(243) The following compounds gave at least 80% control of Spodoptera littoralis:

(244) A1, A3, B1. B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, B6, H1, H2, H3, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18, H19, H20, H21, H22, H23, H24, H25, and H26.

(245) Heliothis virescens (Tobacco Budworm):

(246) Eggs (0-24 h old) were placed in 24-well microtiter plate on artificial diet and treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After an incubation period of 4 days, samples were checked for egg mortality, larval mortality, and growth regulation.

(247) The following compounds gave at least 80% control of Heliothis virescens:

(248) A1, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H2, H3, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H5, H16, H18, H19, H20, H21, H22, H23, H24, H25, H26, J10, and J16.

(249) Plutella xylostella (Diamond Back Moth):

(250) 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTP's were infested with L2 larvae (7-12 per well). After an incubation period of 6 days, samples were checked for larval mortality and growth regulation.

(251) The following compounds gave at least 80% control of Plutella xylostella:

(252) A1. A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18, H19, H20, H21, H22, H23, H24, H25, H26, J1, J10, and J13.

(253) Diabrotica balteata (Corn Root Worm):

(254) A 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTP's were infested with L2 larvae (6-10 per well). After an incubation period of 5 days, samples were checked for larval mortality and growth regulation.

(255) The following compounds gave at least 80% control of Diabrotica balteata:

(256) A1, A3, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18, H19, H20, H21, H22, H23, H24, H25, H26, J4, and J20.

(257) Myzus persicae (Green peach aphid), systemic test: Roots of pea seedlings, infested with an aphid population of mixed ages, are placed directly in the test solutions at an application rate of 12.5 ppm. 6 days after introduction, samples are checked for mortality and special effects on the plant. The following compounds gave at least 80% control of Myzus persicae:

(258) A3, B2, B3, B5, B6, B7, B8, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, G1, G3, G5, G6, H1, H5, H6, H9, H10, H1, H12, H13, H14, H18, H19, H20, H24, H25, and H26.

(259) Thrips tabaci (Onion Thrips):

(260) Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an aphid population of mixed ages. After an incubation period of 7 days, samples were checked for mortality.

(261) The following compounds gave at least 80% control of Thrips tabaci:

(262) A1, A3, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, G1, G3, G5, G6, H, H2, H3, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H18, H19, H20, H21, H22, H23, H24, H25, H26, J3, J6, J8, J10, J19, and J20.

(263) Tetranychus urticae (Two-Spotted Spider Mite):

(264) Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality.

(265) The following compounds gave at least 80% control of Tetranychus urticae:

(266) A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H2, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H18, H19, H20, H21, H22, H23, H24, H25, and H26.