Spiroindolinone derivatives

Preparation of intermediate E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one

M. W. 249.74 C 14 H 16 ClNO

To the mixture of 6-chlorooxindole (0.26 g, 1.49 mmol) (Crescent) and 3,3-dimethyl-butyraldehyde (0.21 g, 2.09 mmol) (Aldrich) in methanol (20 mL) was added pyrrolidine (0.15 g, 2.09 mmol) (Aldrich) dropwise. The mixture was then heated at 100° C. for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and dried in vacuo to give the crude E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one as a white solid (Yield 0.37 g, 100%).

Preparation of intermediate 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 253.81 C 12 H 16 ClNOSi

To 1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 mL) was added, followed by the addition of 3-chloro-benzaldehyde (1.19 mL, 10.5 mmol) (Aldrich). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 mL, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (1.9 mL, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 mL, 13.6 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(3-chlorophenyl)-3-trimethylsilyloxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Similar transformation has been reported by Ghosez, L., Bayard, Ph., Nshimyumukiza, P., Gouverneur, V., Sainte, F., Beaudegnies, R., Rivers, M., Frique-Hesbain, A.-M. and Wynants, C. in Tetrahedron 1995, 11021-11042.

Preparation of racemic (2′S,3S,4′S)-6-chloro-2′-(3-chlorophenyl)-4′-(2,2-dimethylpropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 431.36 C 23 H 24 Cl 2 N 2 O 2

To a mixture of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.25 g, 1 mmol) prepared in example 1b, and toluene (4 mL) was added E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.25 g, 1 mmol) prepared in example 1a. The reaction mixture was heated in a sealed tube under nitrogen at 110° C. for 18 h. The mixture was cooled to room temperature, and methanol (10 mL) was added. The mixture was concentrated and the residue was purified by chromatography (EtOAc/hexanes=2:1) to give racemic (2′S,3S,4′S)-6-chloro-2′-(3-chlorophenyl)-4′-(2,2-dimethylpropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a brown solid (Yield 0.15 g, 35%).

HRMS (ES + ) m/z Calcd for C 23 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 431.1288. Found: 431.1285

Similar transformation has been reported by Ghosez, L. and Jnoff, E. in J. Am. Chem. Soc 1999, 2617-2618.

Preparation of intermediate E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one

M. W. 235.72 C 13 H 14 ClNO

In a manner similar to the method described in example 1a, 6-chlorooxindole (0.88 g, 5 mmol) was reacted with 2,2-dimethyl-propionaldehyde (0.43 g, 5 mmol) (Aldrich), pyrrolidine (0.36 g, 5 mmol) in methanol to give a mixture of E- and Z-6-Chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one. Purification by chromatography (EtOAc:hexanes=1:2) led to E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one as an off-white foam (Yield 0.82 g, 70%).

Preparation of racemic (2′SR,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 417.34 C 22 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 1c, E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one (0.23 g, 1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.63 g, 2.5 mmol) prepared in example 1b, in toluene to give racemic (2′SR,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a mixture of two sets of diastereomers (Yield 0.21 g, 50%).

HRMS (ES + ) m/z Calcd for C 22 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 417.1131. Found: 417.1129

Preparation of intermediate E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one

M. W. 221.69 C 12 H 12 ClNO

In a manner similar to the method described in example 1a, 6-chlorooxindole (0.85 g, 4.8 mmol) was reacted with 2-methyl-propionaldehyde (0.42 g, 5.8 mmol) (Aldrich), pyrrolidine (0.41 g, 5.8 mmol) in methanol (40 mL) to give a mixture of E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one as a brown foam (Yield 1.0 g, 100%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 403.31 C 21 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 1c, E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one (0.25 g, 1.1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.2 g, 4.7 mmol) prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 56%).

HRMS (ES + ) m/z Calcd for C 21 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 403.0975. Found: 403.0975.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 290.15 C 15 H 9 Cl 2 NO

To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 25.2 g, 95%).

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 362.22 C 18 H 13 Cl 2 NO 3

To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 4a (1.33 g, 4.6 mmol) in dichloromethane (50 mL) at 0° C. was added ethyl chloroformate (0.66 mL, 6.9 mmol) (Aldrich), followed by the addition of triethylamine (0.93 g, 9.2 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na 2 SO 4 , and concentrated to give E/Z-6-chloro-3-(3-chloro-benzyl indene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid and used for the next step without further purification (Yield 1.7 g, 100%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 543.84 C 27 H 21 Cl 3 N 2 O 4

To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (20 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in example 6b (0.3 g, 0.83 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.45 g, 100%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester prepared in example 4c (0.45 g, 0.92 mmol) in methanol (30 mL) was added NaOH (66 mg, 1.65 mmol). The mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous HCl solution (1 N). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and then concentrated. The residue was purified with chromatography (EtOAc:CH 2 Cl 2 =1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione as a white solid (Yield 0.2 g, 51%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0431.0.

Preparation of chiral (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (84 mg) prepared in example 4d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 10 mg, 12%). HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0431 and chiral (2′S,3S,4′R)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 17 mg, 20%). HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0428.

Preparation of intermediate E/Z-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one

M. W. 247.73 C 14 H 14 ClNO

In a manner similar to the method described in example 1a, 6-chlorooxindole (1.16 g, 6.59 mmol) was reacted with cyclopentanecarbaldehyde (0.77 g, 7.85 mmol) (Wiley) and piperidine (0.67 g, 7.85 mmol) in methanol to give a mixture of E- and Z-6-Chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one as a brown oil (Yield 0.8 g, 49%).

Preparation of intermediate E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 319.79 C 17 H 18 ClNO 3

In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one (0.8 g, 3.2 mmol) was reacted with ethyl chloroformate (0.46 mL, 4.9 mmol) and triethylamine (0.9 mL, 6.4 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as brown oil (Yield 0.6 g, 58%).

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 501.41 C 26 H 26 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.32 g, 1.00 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as an off-white foam (Yield 0.26 g, 52%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.26 g, 0.52 mmol) was reacted with NaOH (37 mg, 0.93 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.13 g, 59%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1121.

Preparation of intermediate E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one

M. W. 261.75 C 15 H 16 ClNO

In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with cyclohexanecarbaldehyde (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.35 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one as a brown solid (Yield 2.71 g, 91%).

Preparation of intermediate E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 333.82 C 18 H 20 ClNO 3

In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one (2.71 g, 10.4 mmol) was reacted with ethyl chloroformate (1.47 mL, 15.6 mmol) and triethylamine (2.89 mL, 20.7 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a brown solid (Yield 3.3 g, 95%).

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 515.44 C 27 H 28 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic ((2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.2 g, 32%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.2 g, 0.39 mmol) was reacted with NaOH (28 mg, 0.70 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.05 g, 29%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1288.

Preparation of intermediate 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 253.81 C 12 H 16 ClNOSi

In a manner similar to the method described in example 1b, 4-chloro-benzaldehyde (1.48 g, 10.5 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 515.44 C 27 H 28 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) prepared in example 6b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a white solid (Yield 0.45 g, 72%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.4 g, 0.78 mmol) was reacted with NaOH (56 mg, 1.4 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 44%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1287.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 543.84 C 27 H 21 Cl 3 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.3 g, 0.83 mmol) prepared in example 4b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.45 g, 72%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 0.83 mmol) was reacted with NaOH (60 mg, 1.49 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.2 g, 51%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0427.

Preparation of intermediate E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 290.15 C 15 H 9 Cl 2 NO

In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with 4-chloro-benzaldehyde (1.91 g, 13.6 mmol) (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.34 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield: 3.3 g, 100%).

Preparation of intermediate E/Z 6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 362.22 C 18 H 13 Cl 2 NO 3

In a manner similar to the method described in example 4b, E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (3.3 g, 11.3 mmol) was reacted with ethyl chloroformate (1.62 mL, 17.0 mmol) and triethylamine (3.16 mL, 22.6 mmol) in dichloromethane to give E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 3.0 g, 73%).

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 543.84 C 27 H 21 Cl 3 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.35 g, 0.97 mmol) prepared in example 9b was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.5 g, 95%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.5 g, 0.92 mmol) was reacted with NaOH (67 mg, 1.67 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 18%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0427.

Preparation of intermediate 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 233.39 C 13 H 19 NOSi

In a manner similar to the method described in example 1b, 3-methyl-benzaldehyde (1.30 g, 10.5 mmol) (Matrix) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 523.42 C 28 H 24 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.10 mmol) prepared in example 4b was reacted with 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 10a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.5 g, 86%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.35 C 25 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.5 g, 0.96 mmol) was reacted with NaOH (69 mg, 1.72 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 35%).

HRMS (ES + ) m/z Calcd for C 25 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 451.0975. Found: 451.0976.

Preparation of intermediate 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 237.35 C 12 H 16 FNOSi

In a manner similar to the method described in example 1b, 3-fluoro-benzaldehyde (1.11 mL, 10.5 mmol) (Fluka) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 527.38 C 27 H 21 Cl 2 FN 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.25 g, 0.69 mmol) prepared in example 4b was reacted with 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 11a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.35 g, 97%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 455.314 C 24 H 17 Cl 2 FN 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.35 g, 0.66 mmol) was reacted with NaOH (48 mg, 1.19 mmol) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 50%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 2 FN 2 O 2 +H [(M+H) + ]: 451.0975. Found: 451.0976.

Preparation of intermediate E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one

M. W. 255.71 C 15 H 10 ClNO

In a manner similar to the method described in example 1a, 6-chlorooxindole (1.0 g, 5.7 mmol) was reacted with benzaldehyde (0.6 g, 5.7 mmol) (Aldrich) and pyrrolidine (0.4 g, 5.7 mmol) in methanol to give a mixture of E- and Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 100%).

Preparation of intermediate E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 327.77 C 18 H 14 ClNO 3

In a manner similar to the method described in example 4b, E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 5.87 mmol) was reacted with ethyl chloroformate (0.83 mL, 8.8 mmol) and triethylamine (1.64 mL, 12 mmol) in dichloromethane to give E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 2.0 g, 100%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 437.33 C 24 H 18 Cl 2 N 2 O 2

To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1c in toluene (30 mL) was added E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in Example 12b (0.4 g, 1.22 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature, methanol (40 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in methanol (30 mL) and 1N of NaOH solution (5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h, then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow oil (Yield 0.5 g, 100%).

HRMS (ES + ) m/z Calcd for C 24 H 18 Cl 2 N 2 O 2 +H [(M+H) + ]: 437.0818. Found: 437.0817.

Preparation of intermediate 1-(3-chlorophenyl)-4-methyl-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 267.83 C 13 H 18 ClNOSi

In a manner similar to the method described in example 1b, propionyl chloride (1.2 g, 13.mmol) (Aldrich) was used as the starting material in place of acetyl chloride to react with 1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), 3-chloro-benzaldehyde (1.4 g, 10 mmol) (Aldrich), trimethylsilyl chloride (1.1 g, 10 mmol) and triethylamine (1.36 g, 13 mmol) to give 1-(3-chlorophenyl)-4-methyl-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′S,3S,4′R,5′R)-6-chloro-2′-(3-chlorophenyl)-5′-methyl-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.36 C 25 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 12c, E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.32 g, 0.98 mmol) prepared in example 12b was reacted with 1-(3-chlorophenyl)-4-methyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.5 g, 5.6 mmol) prepared in example 13a in toluene and then 2 N of NaOH solution (4 mL, 8 mmol) in methanol to give racemic (2′S,3S,4′R,5′R)-6-chloro-2′-(3-chlorophenyl)-5′-methyl-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white foam (Yield 0.21 g, 48%).

HRMS (ES + ) m/z Calcd for C 25 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 451.0975. Found: 451.0972.

Preparation of intermediate 1-phenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 219.36 C 12 H 17 NOSi

In a manner similar to the method described in example 1b, benzaldehyde (1.06 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chlorobenzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.6 mL, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.08 mL, 10 mmol), triethylamine (1.31 mL, 13 mmol) and acetyl chloride (1.02 g, 13 mmol) to give 1-phenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 437.33 C 24 H 18 Cl 2 N 2 O 2

To a solution of 1-phenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.5 g, 6.8 mmol) prepared in example 14a in toluene (30 mL) was added E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.22 g, 0.61 mmol) prepared in example 4b. The reaction mixture was stirred under nitrogen in a sealed tube at 150° C. for 1.5 h. After the solution was cooled to room temperature, methanol (40 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in ethanol (20 mL) and NaOH (0.2 g, 5 mmol) was added, followed by the addition of a couple drops of H 2 O. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between ethyl acetate and 1N of HCl solution. The organic layer was separated and concentrated. The residue was purified by chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.14 g, 52%).

HRMS (ES + ) m/z Calcd for C 24 H 18 Cl 2 N 2 O 2 +H [(M+H) + ]: 437.0818. Found: 437.0816.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 437.33 C 24 H 18 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 14b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (25 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (27 mg).

Preparation of intermediate 1-(3-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 249.39 C 13 H 19 NO 2 Si

In a manner similar to the method described in example 1b, 3-methoxy-benzaldehyde (1.3 g, 9.5 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.53 g, 9.5 mmol), n-butyllithium (2.5 M, 3.8 mL, 9.5 mmol), trimethylsilyl chloride (1.2 mL, 9.5 mmol), triethylamine (1.72 mL, 12.4 mmol) and acetyl chloride (0.88 mL, 12.4 mmol) to give 1-(3-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 467.36 C 25 H 20 Cl 2 N 2 O 3

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.23 g, 0.63 mmol) prepared in example 4b was reacted with 1-(3-methoxyphenyl)-3-trimethylsilyoxy-4-methyl-2-aza-1,3-butadiene (2 g, 8.0 mmol) prepared in example 15a in toluene and then 2 N of NaOH solution (4 mL, 8 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.2 g, 69%).

HRMS (ES + ) m/z Calcd for C 25 H 20 Cl 2 N 2 O 3 +H [(M+H) + ]: 467.0924. Found: 467.0925.

Preparation of intermediate 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 253.81 C 12 H 16 ClNOSi

In a manner similar to the method described in example 1b, 2-chloro-benzaldehyde (1.3 g, 9.25 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.49 g, 9.25 mmol), n-butyllithium (2.5 M, 3.7 mL, 9.25 mmol), trimethylsilyl chloride (1.2 mL, 9.25 mmol), triethylamine (1.7 mL, 12.0 mmol) and acetyl chloride (0.85 mL, 12.0 mmol) to give 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 543.84 C 27 H 21 Cl 3 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.31 g, 0.85 mmol) prepared in example 4b was reacted with 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.27 mmol) prepared in example 16a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow gum (Yield 0.31 g, 67%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.3 g, 0.55 mmol) was reacted with NaOH (2N, 5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.21 g, 81%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 3 N 2 O 2 +H [(M+H) + ]: 471.0429. Found: 471.0430.

Preparation of chiral (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 471.77 C 24 H 17 Cl 3 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 16c was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (53 mg) and (2′S,3S,4′R)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (51 mg).

Preparation of intermediate 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 233.39 C 13 H 19 NOSi

In a manner similar to the method described in example 1b, 2-methyl-benzaldehyde (1.2 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.62 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.3 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 523.42 C 28 H 24 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.32 g, 0.88 mmol) prepared in example 4b was reacted with 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.4 g, 1.71 mmol) prepared in example 17a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.4 g, 87%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.36 C 25 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.4 g, 0.76 mmol) was reacted with 2 N of NaOH solution (10 mL, 20 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.24 g, 70%).

HRMS (ES + ) m/z Calcd for C 25 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 451.0975. Found: 451.0972.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.36 C 25 H 20 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 23c was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (52 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (52 mg).

Preparation of intermediate 1-(2-ethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 247.42 C 14 H 21 NOSi

In a manner similar to the method described in example 1b, 2-ethyl-benzaldehyde (1.6 g, 11.8 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.96 g, 11.8 mmol), n-butyllithium (2.5 M, 4.7 mL, 11.8 mmol), trimethylsilyl chloride (1.50 mL, 11.8 mmol), triethylamine (2.13 mL, 15.3 mmol) and acetyl chloride (1.09 mL, 15.3 mmol) to give 1-(2-ethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.1 mmol) prepared in example 4b was reacted with 1-(2-ethylphenyl)-3-trimethylsilyoxy-4-methyl-2-aza-1,3-butadiene (3.2 g, 12.9 mmol) prepared in example 18a in toluene and then 2 N of NaOH solution (5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.085 g, 17%).

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131. Found: 465.1132.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 17b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (25 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (27 mg).

Preparation of intermediate 4-methyl-1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 247.42 C 14 H 21 NOSi

In a manner similar to the method described in example 13a, 2-methyl-benzaldehyde (1.2 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and propionyl chloride (1.2 g, 13 mmol) to give 4-methyl-1-(2-methyl phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification

Preparation of racemic (2′R,3R,4′S,5′S)-6-chloro-4′-(3-chlorophenyl)-5′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.36 g, 0.99 mmol) prepared in example 4b was reacted with 4-methyl-1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene) prepared in example 19a in toluene and then 2 N of NaOH solution (4 mL, 8 mmol) in methanol to give racemic (2′R,3R,4′S,5′S)-6-chloro-4′-(3-chlorophenyl)-5′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.26 g, 56%).

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131. Found: 465.1132.

Preparation of racemic (2′R,3R,4′S,5′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-5′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 485.80 C 25 H 19 Cl 3 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.36 g, 0.99 mmol) prepared in example 4b was reacted with 1-(3-chlorophenyl)-4-methyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.2 g, 8.9 mmol) prepared in example 13a in toluene and then 2 N of NaOH solution (4 mL, 8 mmol) in methanol to give racemic (2′R,3R,4′S,5′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-5′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.26 g, 57%).

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 3 N 2 O 2 +H [(M+H) + ]: 485.0585. Found: 485.0583

Preparation of intermediate 1-(2-isopropylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 261.44 C 15 H 23 NOSi

In a manner similar to the method described in example 1b, 2-isopropyl-benzaldehyde (1.5 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.3 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2-isopropylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.41 C 27 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.38 g, 1.05 mmol) prepared in example 4b was reacted with 1-(2-isopropylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.7 g, 10.3 mmol) prepared in example 21a in toluene and then 2 N of NaOH solution (5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.26 g, 52%).

HRMS (ES + ) m/z Calcd for C 27 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 479.1288. Found: 479.1289.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.41 C 27 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 21b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (61 mg) and (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (66 mg).

Preparation of intermediate 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 298.26 C 12 H 16 BrNOSi

In a manner similar to the method described in example 1b, 2-bromo-benzaldehyde (1.85 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.62 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.3 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 588.29 C 27 H 21 BrCl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.1 mmol) prepared in example 4b was reacted with 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.0 g, 10 mmol) prepared in example 22a, in toluene to give racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 69%).

Preparation of racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 516.23 C 24 H 17 BrCl 2 N 2 O 2

In a manner similar to the method described in example 4d, racemic (2′S,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 0.76 mmol) was reacted with NaOH in methanol (2N, 5 mL, 10 mmol) to give racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 64%).

HRMS (ES + ) m/z Calcd for C 24 H 17 BrCl 2 N 2 O 2 +H [(M+H) + ]: 514.9923. Found: 514.9926.

Preparation of chiral (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 516.23 C 24 H 17 BrCl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 22c was conducted by chiral SFC to provide chiral (2′S,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(2-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (86 mg) and chiral (2′R,3S,4′R)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (76 mg).

Preparation of intermediate 1-(3-cyanophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 244.37 C 13 H 16 N 2 OSi

In a manner similar to the method described in example 1b, 3-cyano-benzaldehyde (1.2 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.62 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.3 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(3-cyanophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-cyanophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 462.34 C 25 H 17 Cl 2 N 3 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.42 g, 1.2 mmol) prepared in example 4b was reacted with 1-(3-cyanophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.0 g, 8.18 mmol) prepared in example 23a in toluene and then 2 N of NaOH solution (5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-cyanophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white foam (Yield 0.11 g, 20%).

HRMS (ES + ) m/z Calcd for C 25 H 17 Cl 2 N 3 O 2 +H [(M+H) + ]: 462.0771 Found: 462.0771.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 390.27 C 20 H 17 Cl 2 NO 3

To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 4a (1 g, 3.4 mmol) in dichloromethane (50 mL) at room temperature was added Di-tert-butyl-dicarbonate (1.5 g, 6.9 mmol) (Aldrich), followed by the addition of 4-dimethylaminopyridine (1 g, 8.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was purified by chromatography to give E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as an orange solid (Yield 1.3 g, 96%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 551.47 C 30 H 28 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2.6 mmol) prepared in example 24a was reacted with 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.3 g, 14.1 mmol) prepared in example 17a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.92 g, 65%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 565.50 C 31 H 30 Cl 2 N 2 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.25 g, 0.45 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added LiH (90 mg, 11.2 mmol) (Aldrich), followed by the addition of iodomethane (0.39 g, 2.74 mmol). The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate, and then washed with saturated NH 4 Cl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over MgSO 4 . The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (Yield 0.20 g, 77%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

Trifluoroacetic acid (5 mL) was added to a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.20 g, 0.35 mmol) prepared in example 24c in dichloromethane (10 mL). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. To this residue was added saturated NaHCO 3 solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over MgSO 4 . The solvent was removed and the residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:4) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.075 g, 46%).

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131. Found: 465.1132.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 24d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (24 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (23 mg).

Preparation of intermediate 1-(3-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 251.38 C 13 H 18 FNOSi

In a manner similar to the method described in example 1b, 3-fluoro-2-methyl-benzaldehyde (1.4 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.62 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(3-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 541.41 C 28 H 23 Cl 2 FN 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.39 g, 1.08 mmol) prepared in example 4b was reacted with 1-(3-fluoro-phenyl-2-methyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.6 g, 10.3 mmol) prepared in example 31a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.35 g, 60%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 469.35 C 25 H 19 Cl 2 FN 2 O 2

In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.35 g, 0.65 mmol) was reacted with NaOH (2N, 5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 83%).

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 2 FN 2 O 2 +H [(M+H) + ]: 469.0881. Found: 469.0885.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 469.35 C 25 H 19 Cl 2 FN 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 25c was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (71 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (74 mg).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 579.53 C 32 H 32 Cl 2 N 2 O 4

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.3 g, 0.54 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and iodoethane (2 mL, 25 mmol) in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.2 g, 63%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.41 C 27 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 24d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.2 g, 0.34 mmol) prepared in example 26a was reacted with trifluoroacetic acid in dichlormethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white foam (Yield: 0.11 g, 69%).

HRMS (ES + ) m/z Calcd for C 27 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 479.1288. Found: 479.1284.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.41 C 27 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in 26b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (29 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (27 mg).

Preparation of intermediate 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 247.42 C 14 H 21 NOSi

In a manner similar to the method described in example 1b, 2,6-dimethyl-benzaldehyde (1.3 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as an orange oil and used for the next step without further purification.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 537.45 C 29 H 26 Cl 2 N 2 O 4

In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.08 mmol) prepared in example 4b was reacted with 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.9 g, 11.7 mmol) prepared in example 27a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.41 g, 71%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 4d, (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.41 g, 0.76 mmol) was reacted with NaOH (0.4 g, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.25 g, 71%).

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131. Found: 465.1131.

Preparation of intermediate 1-(2,3-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 247.42 C 14 H 21 NOSi

In a manner similar to the method described in example 1b, 2,3-dimethyl-benzaldehyde (1.34 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,3-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-dimethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.3 g, 0.83 mmol) prepared in example 4b was reacted with 1-(2,3-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.4 g, 9.72 mmol) prepared in example 28a in toluene and then NaOH (0.2 g, 5 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-dimethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.20 g, 53%).

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131. Found: 465.1131.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 623.54 C 33 H 32 Cl 2 N 2 O 6

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (1.02 g, 1.86 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and methyl bromoacetate (0.57 g, 3.72 mmol) (Aldrich) to give racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white solid (Yield: 0.37 g, 32%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 523.42 C 28 H 24 Cl 2 N 2 O 4

In a manner similar to the method described in example 24d, racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.37 g, 0.59 mmol) prepared in example 29a was reacted with trifluoroacetic acid (20 mL) in dichlormethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.21 g, 67%).

HRMS (ES + ) m/z Calcd for C 28 H 24 Cl 2 N 2 O 4 +H [(M+H) + ]: 523.1186. Found: 523.1183.

Preparation of racemic (2′S,3R,4R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 419.38 C 21 H 20 Cl 2 N 2 OS

The mixture of racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′,4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.15 mmol) prepared in example 3b and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (100 mg, 0.25 mmol) (Aldrich) in toluene (20 mL) was heated at 120° C. for 0.5 h. The mixture was cooled to room temperature and then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 60 mg, 92%).

HRMS (ES + ) m/z Calcd for C 21 H 20 Cl 2 N 2 OS+H [(M+H) + ]: 419.0746. Found: 419.0744.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 509.39 C 27 H 22 Cl 2 N 2 O 4

To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.21 g, 0.4 mmol) prepared in 29b in the mixture of methanol (10 mL) and tetrahydrofuran (20 mL) was added aqueous NaOH solution (1N, 10 mL, 10 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. The residue was neutralized to “pH” ˜7, then extracted with ethyl acetate. The organic layer was separated, washed with H 2 O, brine, dried over MgSO 4 and concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white foam.

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 N 2 O 4 +H [(M+H) + ]: 509.1030. Found: 509.1028.

Preparation of intermediate 1-[2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 287.36 C 13 H 16 F 3 NOSi

In a manner similar to the method described in example 1b, 2-(trifluoromethyl)-benzaldehyde (1.75 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-[2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 505.33 C 25 H 17 Cl 2 F 3 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.5 g, 1.38 mmol) prepared in example 4b was reacted with 1-[2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.2 g, 11.1 mmol) prepared in example 32a in toluene and then NaOH (0.2 g, 5 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.45 g, 64%).

HRMS (ES + ) m/z Calcd for C 25 H 17 Cl 2 F 3 N 2 O 2 +H [(M+H) + ]: 505.0692. Found: 505.0688.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-6′-thioxo-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 521.39 C 25 H 17 Cl 2 F 3 N 2 OS

In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 0.79 mmol) prepared in example 32b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.4 g, 0.99 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-6′-thioxo-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.15 g, 36%).

HRMS (ES + ) m/z Calcd for C 25 H 17 Cl 2 F 3 N 2 OS+H [(M+H) + ]: 521.0464. Found: 521.0458.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 511.38 C 27 H 21 Cl 2 FN 2 O 3

To the solution of (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 31 in dichloromethane (40 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H 2 O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO 4 , concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.12 g, 98%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-carbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 578.50 C 31 H 29 Cl 2 N 3 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in 34a in tetrahydrofuran (10 mL) in a sealed tube was added morpholine (41 mg, 0.47 mmol), N-methylmorpholine (47 mg, 0.47 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol). After the mixture was heated under microwave irradiation at 100° C. for 10 min, the mixture was diluted with ethyl acetate, washed with 1N of HCl aqueous solution and H 2 O. The organic layer was separated, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (MeOH:EtOAc=1:19) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-carbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.11 g, 85%).

HRMS (ES + ) m/z Calcd for C 31 H 29 Cl 2 N 3 O 4 +H [(M+H) + ]: 578.1608. Found: 578.1600.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-carbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 578.50 C 31 H 29 Cl 2 N 3 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-2-oxoethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (51 mg) prepared in example 34b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-2-oxoethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 15 mg, 29%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)-1′-[2-(4-morpholinyl)-carbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 14 mg, 27%).

Preparation of intermediate 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 305.35 C 13 H 15 F 4 NOSi

In a manner similar to the method described in example 1b, 5-fluoro-2-(trifluoromethyl)-benzaldehyde (1.9 g, 10 mmol) (Matrix) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 523.32 C 25 H 16 Cl 2 F 4 N 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.41 g, 1.13 mmol) prepared in example 4b was reacted 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.9 g, 9.5 mmol) prepared in example 35a in toluene and then NaOH (0.2 g, 5 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.31 g, 52%).

HRMS (ES + ) m/z Calcd for C 25 H 16 Cl 2 F 4 N 2 O 2 +H [(M+H) + ]: 523.0598. Found: 523.0593.

Preparation of intermediate 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 251.38 C 13 H 18 FNOSi

In a manner similar to the method described in example 1b, 5-fluoro-2-methyl-benzaldehyde (1.38 g, 10 mmol) (Platte) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 469.35 C 25 H 19 Cl 2 FN 2 O 2

In a manner similar to the method described in example 14b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.25 g, 0.69 mmol) prepared in example 4b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.5 g, 9.9 mmol) prepared in example 36a in toluene and then NaOH (1N, 5 mL, 5 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.13 g, 41%).

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 2 FN 2 O 2 +H [(M+H) + ]: 469.0881. Found: 469.0881.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 469.35 C 25 H 19 Cl 2 FN 2 O 2

Separation of the two enantiomers (35 mg) from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 36b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 10.7 mg, 30%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 11 mg, 31%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(cyclopropylamino)-carbonyl-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 548.47 C 30 H 27 Cl 2 N 3 O 3

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in example 34a was reacted with cyclopropylamine (0.1 g, 1.8 mmol) (Aldrich), N-methylmorpholine (48 mg, 0.47 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(cyclopropylamino)-carbonyl-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.039 g, 30%).

HRMS (ES + ) m/z Calcd for C 30 H 27 Cl 2 N 3 O 3 [(M+H) + ]: 548.1502. Found: 548.1501.

Preparation of racemic (2′R,3R,4′S)-6-chloro-[[2-[6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6-dioxospiro[3H-indole-3,3′-piperidin]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester

M. W. 691.66 C 37 H 40 Cl 2 N 4 O 5

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in example 34a was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.5 mmol) (Aldrich), N-methylmorpholine (48 mg, 0.47 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-[[2-[6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6-dioxospiro[3H-indole-3,3′-piperidin]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester as an off-white solid (Yield 0.036 g, 22%).

HRMS (ES + ) m/z Calcd for C 37 H 40 Cl 2 N 4 O 5 [(M+H) + ]: 691.2449. Found: 691.2441.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 485.41 C 25 H 19 Cl 2 FN 2 OS

In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 36b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.2 g, 0.49 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 0.095 g, 92%).

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 2 FN 2 OS+H [(M+H) + ]: 485.0652. Found: 485.0648.

Preparation of racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-[2-(trifluoromethyl)phenyl)]-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]-hydrazine carboxylic acid ethyl ester

M. W. 591.42 C 28 H 23 Cl 2 F 3 N 4 O 3

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-6′-thioxo-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2(1H)-one (0.035 g, 0.067 mmol) prepared in example 33 in tetrahydrofuran (30 mL) was added ethyl carbazate (0.019 g, 0.134 mmol) (Aldrich) and mercuric acetate (0.042 g, 0.134 mmol). After the reaction mixture was stirred at room temperature for 2 h, the reaction mixture was filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-[2-(trifluoromethyl)-phenyl)]-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]-hydrazinecarboxylic acid ethyl ester as a white solid (Yield: 0.036 g, 91%).

HRMS (ES + ) m/z Calcd for C 28 H 23 Cl 2 F 3 N 4 O 3 +H [(M+H) + ]: 591.1172. Found: 591.1168

Preparation of intermediate 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 255.34 C 12 H 15 F 2 NOSi

In a manner similar to the method described in example 1b, 2,4-difluoro-benzaldehyde (1.4 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloroben-zaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 473.31 C 24 H 16 Cl 2 F 2 N 2 O 2

To a solution of 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 41a (2.4 g, 9.40 mmol) in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.3 g, 0.77 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 0.5 h. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO 3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.23 g, 63.9%).

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 F 2 N 2 O 2 +H [(M+H) + ]: 473.0630. Found: 473.0630.

Preparation of intermediate 1-(5-fluoro-2-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 267.38 C 13 H 18 FNO 2 Si

In a manner similar to the method described in example 1b, 5-fluoro-2-methoxy-benzaldehyde (1.5 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(5-fluoro-2-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 485.36 C 25 H 19 Cl 2 FN 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(5-fluoro-2-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.4 g, 9.0 mmol) prepared in example 42a in toluene and then trifluoroacetic acid (15 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.18 g, 49%).

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 2 FN 2 O 3 +H [(M+H) + ]: 485.0830. Found: 485.0827.

Preparation of intermediate 1-(1-naphthalenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 269.42 C 16 H 19 NOSi

In a manner similar to the method described in example 1b, naphthalene-1-carbaldehyde (1.6 g, 10 mmol) (Lancaster) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1-naphthalenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-naphthalenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 487.39 C 28 H 10 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(1-naphthalenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.7 g, 10.0 mmol) prepared in example 43a in toluene and then trifluoroacetic acid (15 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-naphthalenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.21 g, 57%).

HRMS (ES + ) m/z Calcd for C 28 H 10 Cl 2 N 2 O 2 +H [(M+H) + ]: 487.0975. Found: 487.0975.

Preparation of intermediate 1-(3-pyridinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 220.35 C 11 H 16 N 2 OSi

In a manner similar to the method described in example 1b, pyridine-3-carbaldehyde (1.1 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(3-pyridinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-pyridinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 438.32 C 23 H 17 Cl 2 N 3 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(3-pyridinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 9.5 mmol) prepared in example 44a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-pyridinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.21 g, 62%).

HRMS (ES + ) m/z Calcd for C 23 H 17 Cl 2 N 3 O 2 +H [(M+H) + ]: 438.0771. Found: 438.0771.

Preparation of intermediate 1-(2,3-difluoro-6-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 285.37 C 13 H 17 F 2 NO 2 Si

In a manner similar to the method described in example 1b, 2,3-difluoro-6-methoxy-benzaldehyde (1.8 g, 10 mmol) (Apollo) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,3-difluoro-6-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as an orange gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 503.34 C 25 H 18 Cl 2 F 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(2,3-difluoro-6-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.5 g, 8.8 mmol) prepared in example 45a in toluene and then trifluoroacetic acid (15 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.22 g, 56%).

HRMS (ES + ) m/z Calcd for C 25 H 18 Cl 2 F 2 N 2 O 3 +H [(M+H) + ]: 503.0736. Found: 503.0735.

Preparation of intermediate 1-(3,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 255.34 C 12 H 15 F 2 NOSi

In a manner similar to the method described in example 1b, 3,4-difluoro-benzaldehyde (1.4 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(3,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as an orange gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 473.31 C 24 H 16 Cl 2 F 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(3,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.2 mmol) prepared in example 46a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 100%).

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 F 2 N 2 O 2 +H [(M+H) + ]: 473.0630. Found: 473.0631.

Preparation of intermediate 1-(1-cyclohexenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 223.39 C 12 H 21 NOSi

In a manner similar to the method described in example 1b, 1-cyclohexene-1-carboxaldehyde (1.1 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1-cyclohexenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as an off-white gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclohexenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 441.36 C 24 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.26 g, 0.67 mmol) was reacted with 1-(1-cyclohexenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 9.42 mmol) prepared in example 47a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclohexenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (0.14 g, 48%).

HRMS (ES + ) m/z Calcd for C 24 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 441.1131. Found: 441.1131.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 489.37 C 24 H 16 Cl 2 F 2 N 2 OS

In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.63 mmol) prepared in example 46b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.32 g, 0.77 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.29 g, 94%).

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 F 2 N 2 OS+H [(M+H) + ]: 489.0401. Found: 489.0402.

Preparation of racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester

M. W. 559.40 C 27 H 22 Cl 2 F 2 N 4 O 3

In a manner similar to the method described in example 40, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (0.24 g, 0.49 mmol) prepared in example 48 was reacted with ethyl carbazate (0.1 g, 0.99 mmol), mercuric acetate (0.24 g, 0.76 mmol) and triethylamine (0.1 g, 0.99 mmol) in tetrahydrofuran (20 mL) to give racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester as a white solid (Yield 0.21 g, 77.8%).

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 F 2 N 4 O 3 +H [(M+H) + ]: 559.1110. Found: 559.1109.

Preparation of intermediate 1-(1,3-benzodioxol-4-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 263.37 C 13 H 17 NO 3 Si

In a manner similar to the method described in example 1b, 2,3-(methylenedioxy)-benzaldehyde (1.5 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1,3-benzodioxol-4-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-(1,3-benzodioxol-4-yl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 481.34 C 25 H 18 Cl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.25 g, 0.67 mmol) was reacted with 1-(1,3-benzodioxol-4-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 7.98 mmol) prepared in example 50a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-2′-(1,3-benzodioxol-4-yl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (0.20 g, 62%).

HRMS (ES + ) m/z Calcd for C 25 H 18 Cl 2 N 2 O 4 +H [(M+H) + ]: 481.0717. Found: 481.0717.

Preparation of racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester

M. W. 555.44 C 28 H 25 Cl 2 FN 4 O 3

In a manner similar to the method described in example 40, (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (0.17 g, 0.35 mmol) prepared in example 39 was reacted with ethyl carbazate (0.15 g, 1.49 mmol), mercuric acetate (0.26 g, 0.82 mmol) and triethylamine (0.17 g, 1.69 mmol) in tetrahydrofuran (20 mL) to give racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester as a white solid (Yield 0.14 g, 73.7%).

Preparation of intermediate 2,3-difluoro-6-methyl-benzaldehyde

M. W. 156.13 C 8 H 6 F 2 O

To a solution of 1,2-difluoro-4-methyl-benzene (5.0 g, 39 mmol) in tetrahydrofuran (200 mL) at −78° C. was added lithium diisopropyl amine (24 mL, 1.8 M in THF, 43 mmol) dropwise during a period of 15 mins. The mixture was stirred at −78° C. for another 20 min. Then N,N-dimethyl-formamide (3.6 mL, 47 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (9.4 g, 1.56 mmol) and followed by the addition of water (37.6 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give 2,3-difluoro-6-methyl-benzaldehyde as colorless oil (Yield: 3.5 g, 57.5%).

Preparation of intermediate 1-(2,3-difluoro-6-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 269.37 C 13 H 17 F 2 NOSi

In a manner similar to the method described in example 1b, 2,3-difluoro-6-methyl-benzaldehyde (1.56 g, 10 mmol) prepared in example 52a was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,3-difluoro-6-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as an orange gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 487.34 C 25 H 18 Cl 2 F 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.03 mmol) was reacted with 1-(2,3-difluoro-6-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.7 g, 10.0 mmol) prepared in example 52b in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

(Yield: 0.41 g, 83.7%).

HRMS (ES + ) m/z Calcd for C 25 H 18 Cl 2 F 2 N 2 O 2 +H [(M+H) + ]: 487.0786 Found: 487.0780.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one

M. W. 308.14 C 15 H 8 Cl 2 FNO

In a manner similar to the method described in example 1a, 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (0.25 g, 1.35 mmol, prepared in procedure described in EP153818) was reacted with 3-chloro-benzaldehyde (0.34 g, 2.44 mmol) and pyrrolidine (0.19 g, 2.68 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 408.26 C 20 H 16 Cl 2 FNO 3

In a manner similar to the method described in example 24a, E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one (0.45 g, 1.46 mmol) was reacted with di-tert-butyl-dicarbonate (0.4 g, 1.83 mmol) (Aldrich), triethyl amine (0.5 g, 4.95 mmol) and 4-dimethylaminopyridine (5 mg) in dichloromethane (30 mL) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 0.6 g, 100%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 487.34 C 25 H 18 Cl 2 F 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 53b (0.4 g, 0.98 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.37 mmol) prepared in example 36a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 0.35 g, 72.9%).

HRMS (ES + ) m/z Calcd for C 25 H 18 Cl 2 F 2 N 2 O 2 +H [(M+H) + ]: 487.0786. Found: 487.0779.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 503.40 C 25 H 18 Cl 2 F 2 N 2 OS

In a manner similar to the method described in example 30, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.37 mmol) prepared in example 52c was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.32 g, 0.96 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.13 g, 69.8%).

HRMS (ES + ) m/z Calcd for C 25 H 18 Cl 2 F 2 N 2 OS+H [(M+H) + ]: 503.0558. Found: 503.0554.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one

M. W. 420.41 C 21 H 23 Cl 2 NO 2 Si

To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 4a (2.3 g, 7.9 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added NaH (60% in mineral oil) (0.32 g, 7.9 mmol) (Aldrich), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.32 g, 7.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na 2 SO 4 . The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:5) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 3.0 g, 90%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 599.61 C 31 H 33 Cl 2 FN 2 O 3 Si

To a solution of 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a in toluene (50 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in example 55a (3.0 g, 7.14 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 148° C. for 40 min. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:Hexane=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as an off-white solid (Yield 2.1 g, 49%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 713.76 C 37 H 43 Cl 2 FN 2 O 5 Si

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.0 g, 1.67 mmol) prepared in example 55b in N,N-dimethyl-formamide (20 mL) at room temperature was added bromo-acetic acid tert-butyl ester (0.8 g, 4.1 mmol) and cesium carbonate (3.0 g, 9.20 mmol). The reaction mixture was stirred under nitrogen for 4 h, then poured into saturated aqueous NH 4 Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:4) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 0.58 g, 48.7%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 527.38 C 27 H 21 Cl 2 FN 2 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.54 g, 0.76 mmol) prepared in example 55c in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1 mL, 5.53 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO 4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 75%).

HRMS (ES + ) m/z Calcd for C 27 H 21 Cl 2 FN 2 O 4 +H [(M+H) + ]: 527.0935 Found: 527.0926.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 613.64 C 32 H 35 Cl 2 FN 2 O 3 Si

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.3 g, 0.5 mmol) prepared in example 55b was reacted with LiH (0.17 g, 21.4 mmol) (Aldrich) and iodomethane (4 g, 28.2 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white solid (Yield: 0.16 g, 51.6%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol

M. W. 513.40 C 27 H 23 Cl 2 FN 2 O 3

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.16 g, 0.26 mmol) prepared in example 56a in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated. The residue was neutralized with saturated NaHCO 3 aqueous solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO 4 and concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (Yield 90 mg, 67.7%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 483.37 C 26 H 21 Cl 2 FN 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (0.09 g, 0.175 mmol) prepared in example 56b in methanol (10 mL) was added N,N′-diisopropylethylamine (2 mL, 11.1 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.06 g, 70.6%).

HRMS (ES + ) m/z Calcd for C 26 H 21 Cl 2 FN 2 O 2 +H [(M+H) + ]: 483.1037. Found: 483.1042.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 483.37 C 26 H 21 Cl 2 FN 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg) prepared in example 56c was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 20 mg, 40%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 20 mg, 40%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 529.37 C 27 H 20 Cl 2 F 2 N 2 O 3

In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(hydroxycarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione g, 0.19 mmol) prepared in example 55d was reacted with cyanuric fluoride (51 mg, 0.38 mmol) (Alfa) and pyridine (45 mg, 0.57 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.1 g, 100%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 623.56 C 33 H 33 Cl 2 FN 4 O 3

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 1-methyl-piperidin-4-ylamine (0.1 g, 0.88 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.041 g, 36.7%).

HRMS (ES + ) m/z Calcd for C 33 H 33 Cl 2 FN 4 O 3 +H [(M+H) + ]: 623.1987. Found: 623.1989.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 623.56 C 33 H 33 Cl 2 FN 4 O 3

Separation of the two enantiomers from (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg) prepared in example 57b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 10 mg, 17%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 10 mg, 17%).

Preparation of racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonyl-methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 709.65 C 37 H 39 Cl 2 FN 4 O 5

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.50 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonyl-methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.075 g, 58.6%).

HRMS (ES + ) m/z Calcd for C 37 H 39 Cl 2 FN 4 O 5 +H [(M+H) + ]: 709.2355. Found: 709.2354.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 609.53 C 32 H 31 Cl 2 FN 4 O 3

To a solution of racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonyl-methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.07 g, 0.099 mmol) prepared in 58 in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was neutralized with saturated NaHCO 3 solution, extracted with ethyl acetate. The organic layer was separated, dried over MgSO 4 , concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.06 g, 99%).

HRMS (ES + ) m/z Calcd for C 32 H 31 Cl 2 FN 4 O 3 +H [(M+H) + ]: 609.1830 Found: 609.1820.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 609.53 C 32 H 31 Cl 2 FN 4 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg) prepared in example 59a was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 12 mg, 30%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 12 mg, 30%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 676.14 C 34 H 38 Cl 3 FN 2 O 5 Si

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.8 g, 1.33 mmol) prepared in example 55b was reacted with LiH (0.5 g, 62.5 mmol) and 1-chloro-3-iodo-propane (3.9 g, 19.1 mmol) in N,N-dimethyl-formamide (20 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.43 g, 47.8%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 596.53 C 32 H 32 Cl 2 FN 3 O 3

The mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-(3-chloro-propyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.24 g, 0.36 mmol) prepared in example 60a and morpholine (10 mL) was heated at 120° C. for 1 h. The mixture was concentrated to dryness. The resulting residue was added dichloromethane (20 mL) and then trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was separated and concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (2 mL, 11.0 mmol) and the crude was heated at 100° C. for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (MeOH:EtOAc=1:9) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 37.9%).

HRMS (ES + ) m/z Calcd for C 32 H 32 Cl 2 FN 3 O 3 +H [(M+H) + ]: 596.1878 Found: 596.1877.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 596.53 C 32 H 32 Cl 2 FN 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg) prepared in example 60b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 34 mg, 34%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 35 mg, 35%).

Preparation of intermediate 1-(1-isopropyl-4-methyl-1-pentenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 267.49 C 15 H 29 NOSi

In a manner similar to the method described in example 1b, 2-isopropyl-5-methyl-2-hexenal (1.54 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1-isopropyl-4-methyl-1-pentenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-4-methyl-pent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 485.46 C 27 H 30 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.3 g, 0.77 mmol) was reacted with 1-(1-isopropyl-4-methyl-1-pentenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.2 mmol) prepared in example 61a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-4-methyl-pent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (0.18 g, 48.7%).

HRMS (ES + ) m/z Calcd for C 27 H 30 Cl 2 N 2 O 2 +H [(M+H) + ]: 485.1757. Found: 485.1755.

Preparation of intermediate 1,2-difluoro-4-isopropoxy-benzene

M. W. 172.18 C 9 H 10 F 2 O

To a solution of 3,4-difluoro-phenol (5 g, 38.4 mmol) in acetone (50 mL) was added potassium carbonate (54 g, 38.4 mmol) and 2-iodo-propane. The reaction mixture was heated at refluxing for 24 h. The crude was cooled down and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:9) to give 1,2-difluoro-4-isopropoxy-benzene as colorless oil (Yield 6.12 g, 92.3%).

Preparation of intermediate 2,3-difluoro-6-isopropoxy-benzaldehyde

M. W. 200.19 C 10 H 10 F 2 O 2

In a manner similar to the method described in example 52a, 1,2-difluoro-4-isopropoxy-benzene (5.77 g, 33.5 mmol) prepared in example 62a was reacted with lithium diisopropyl amine (20.5 mL, 1.8 M in THF, 36.9 mmol), N,N-dimethyl-formamide (3.11 mL, 40.2 mmol) and quenched with acetic acid (8.0 g, 134 mmol) in tetrahydrofuran to give 2,3-difluoro-6-isopropoxy-benzaldehyde as a white crystal (Yield: 6.02 g, 89.9%).

Preparation of intermediate 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 313.42 C 15 H 21 F 2 NO 2 Si

In a manner similar to the method described in example 1b, 2,3-difluoro-6-isopropoxy-benzaldehyde (2.0 g, 10 mmol) prepared in example 62b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 531.39 C 27 H 22 Cl 2 F 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.5 g, 7.98 mmol) prepared in example 62c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.41 g, 75.9%).

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 F 2 N 2 O 3 +H [(M+H) + ]: 531.1049. Found: 531.1049.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 531.39 C 27 H 22 Cl 2 F 2 N 2 O 3

Separation of the two enantiomers from (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 62d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (RO5131636-000-001) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-(3-pyrrolidin-1-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 580.54 C 32 H 32 Cl 2 FN 3 O 2

In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 60a (91 mg, 0.134 mmol) was reacted with pyrrolidine (2 mL), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-pyrrolidin-1-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (21 mg, 26.9%).

HRMS (ES + ) m/z Calcd for C 32 H 32 Cl 2 FN 3 O 2 +H [(M+H) + ]: 580.1929. Found: 580.1926.

Preparation of intermediate 1-(3-methoxycarboxyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 277.40 C 14 H 19 NO 3 Si

In a manner similar to the method described in example 1b, 3-formyl-benzoic acid methyl ester (1.5 g, 10 mmol) (Acros) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(3-methoxycarboxyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxycarbonyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 495.37 C 26 H 20 Cl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(3-methoxycarbonyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.4 g, 8.65 mmol) prepared in example 64a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxycarbonyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.28 g, 56%).

HRMS (ES + ) m/z Calcd for C 26 H 20 Cl 2 N 2 O 4 +H [(M+H) + ]: 495.0873 Found: 495.0872.

Preparation of racemic (2′R,3R,4′S)-1′-[3-(4-acetyl-piperazin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 637.59 C 34 H 35 Cl 2 FN 4 O 3

In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 60a (88 mg, 0.134 mmol) was reacted with pyrrolidine (0.4 g, 3.1 mmol), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-1′-[3-(4-acetylpiperazin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (33 mg, 38.8%).

HRMS (ES + ) m/z Calcd for C 34 H 35 Cl 2 FN 4 O 3 +H [(M+H) + ]: 637.2143 Found: 637.2139.

Preparation of intermediate 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 211.38 C 11 H 21 NOSi

In a manner similar to the method described in example 1b, 2-ethyl-but-2-enal (1.54 g, 10 mmol) (TCI-US) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 9.93 mmol) prepared in example 66a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.24 g, 54.5%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1129.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 66b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 644.60 C 32 H 32 Cl 2 FN 3 O 4 S

In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 60a (0.21 mg, 0.31 mmol) was reacted with thiomorpholin 1,1-dioxide (0.47 g, 3.48 mmol), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (72 mg, 36.2%).

HRMS (ES + ) m/z Calcd for C 32 H 32 Cl 2 FN 3 O 4 S+H [(M+H) + ]: 644.1548. Found: 644.1542.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 644.60 C 32 H 32 Cl 2 FN 3 O 4 S

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 67a was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-[3-(1,1-dioxo-thiomorpholin-4-yl)-propyl]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid.

Preparation of intermediate 1-(2,5-dimethyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 247.42 C 14 H 21 NOSi

In a manner similar to the method described in example 1b, 2,5-dimethyl-benzaldehyde (1.34 g, 10 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,5-dimethyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(2,5-dimethyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.3 g, 9.31 mmol) prepared in example 68a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid.

HRMS (ES + ) m/z Calcd for C 26 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 465.1131 Found: 465.1128.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 465.38 C 26 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 68b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid and chiral ((2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid.

Preparation of intermediate 1-(2,5-dimethyl-2H-pyrazole-3-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 237.38 C 11 H 19 N 3 OSi

In a manner similar to the method described in example 1b, 2,5-dimethyl-2H-pyrazole-3-carbaldehyde (1.24 g, 10 mmol) (ASDI-INTER) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,5-dimethyl-2H-pyrazole-3-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-2H-pyrazole-3-yl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 455.35 C 23 H 20 Cl 2 N 4 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(2,5-dimethyl-2H-pyrazole-3-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.5 g, 10.5 mmol) prepared in example 69a in toluene and then trifluoroacetic acid (15 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,5-dimethyl-2H-pyrazole-3-yl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.14 g, 30.4%).

HRMS (ES + ) m/z Calcd for C 23 H 20 Cl 2 N 4 O 2 +H [(M+H) + ]: 455.1036 Found: 455.1035.

Preparation of intermediate 1-(1-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 197.36 C 10 H 19 NOSi

In a manner similar to the method described in example 1b, 2-methyl-but-2-enal (0.84 g, 10 mmol) (EASTMAN) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(1-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 415.32 C 22 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.35 g, 0.89 mmol) was reacted with 1-(1-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 9.93 mmol) prepared in example 70a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.19 g, 51.4%).

HRMS (ES + ) m/z Calcd for C 22 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 415.0975. Found: 415.0975.

Preparation of intermediate 1-(1-methyl-but-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 211.38 C 11 H 21 NOSi

In a manner similar to the method described in example 1b, 2-methyl-pent-2-enal (2.0 g, 20 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 8 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.7 g, 26 mmol) and acetyl chloride (2.0 g, 26 mmol) to give 1-(1-methyl-but-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl-but-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(1-methyl-but-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.2 g, 15.2 mmol) prepared in example 71a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl-but-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.24 g, 54.5%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1127.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 431.37 C 23 H 24 Cl 2 N 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.70 mmol) prepared in example 66b in ethyl acetate (30 mL) was added platinum oxide (0.35 g, 1.54 mmol). The resulting suspension was vigorously shaken under hydrogen (50 psi) for 6 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.11 g, 37.7%).

HRMS (ES + ) m/z Calcd for C 23 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 431.1288 Found: 431.1285.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 431.37 C 23 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 24 mg, 40%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

(Yield: 24 mg, 40%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 661.65 C 33 H 36 Cl 2 F 2 N 2 O 4 Si

In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in example 55a (3.4 g, 8.10 mmol) was reacted with 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (16 g, 51.1 mmol) prepared in example 62c in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as an off-white solid.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 738.18 C 36 H 41 Cl 3 F 2 N 2 O 4 Si

In a manner similar to the method described in example 24c, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.8 g, 2.72 mmol) prepared in example 73a was reacted with LiH (1.0 g, 125 mmol) and 1-chloro-3-iodo-propane (5.0 g, 24.5 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.67 g, 33.5%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 658.58 C 34 H 35 Cl 2 F 2 N 3 O 4

In a manner similar to the method described in example 60b, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 73b (0.3 g, 0.41 mmol) was reacted with morpholine (10 mL), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (1 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.15 g, 55.6%).

HRMS (ES + ) m/z Calcd for C 34 H 35 Cl 2 F 2 N 3 O 4 +H [(M+H) + ]: 658.2046. Found: 658.2038.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 658.58 C 34 H 35 Cl 2 F 2 N 3 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg) prepared in example 73c was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 55 mg, 46%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 54 mg, 45%).

Preparation of intermediate 1-(1-ethylidene-pentyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 239.44 C 13 H 25 NOSi

In a manner similar to the method described in example 1b, 2-ethyllidene-hexanal (1.1 g, 8.68 mmol) (Aldrich) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (2.7 g, 13 mmol) and acetyl chloride (1.0 g, 26 mmol) to give 1-(1-ethylidene-pentyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethylidene-pentyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 457.40 C 25 H 26 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(1-ethylidene-pentyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.77 mmol) prepared in example 74a in toluene and then trifluoroacetic acid (15 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethylidene-pentyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (0.13 g, 27.7%).

HRMS (ES + ) m/z Calcd for C 25 H 26 Cl 2 N 2 O 2 +H [(M+H) + ]: 457.1444 Found: 457.1443.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 547.46 C 27 H 22 Cl 2 F 2 N 2 O 2 S

In a manner similar to the method described in example 30, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 0.85 mmol) prepared in example 62d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.6 g, 1.8 mmol) in toluene to give racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.36 g, 78.3%).

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 F 2 N 2 O 2 S+H [(M+H) + ]: 547.0820. Found: 547.0821.

Preparation of racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester

M. W. 617.48 C 30 H 28 Cl 2 F 2 N 4 O 4

In a manner similar to the method described in example 40, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (0.30 g, 0.55 mmol) prepared in example 75 was reacted with ethyl carbazate (0.3 g, 2.97 mmol), mercuric acetate (0.30 g, 0.95 mmol) and triethylamine (0.1 g, 0.99 mmol) in tetrahydrofuran (40 mL) to give racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester as a white solid (Yield 0.25 g, 73.5%).

HRMS (ES + ) m/z Calcd for C 30 H 28 Cl 2 F 2 N 4 O 4 +H [(M+H) + ]: 617.1529. Found: 617.1523.

Preparation of intermediate cyclopent-1-enecarbaldehyde

M. W. 96.13 C 6 H 8 O

To an acidic solution of sodium periodate (28.3 g, 0.13 mol) (Aldrich) in water (250 mL) was added the solution of 1,2-cyclohexanediol (12 g, 0.10 mol) (Acros) in ethyl ether (150 mL). The mixture was stirred vigorously for 0.5 h at room temperature. After addition of KOH aqueous solution (20%, 38.4 mL), the reaction mixture was stirred for an additional 1 h. The mixture was extracted with ethyl ether. The organic layers were combined and dried. The solvent was removed to give cyclopent-1-enecarbaldehyde as yellow oil (Yield: 7.2 g, 75%)

Preparation of intermediate 1-(cyclopent-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 209.37 C 11 H 19 NOSi

In a manner similar to the method described in example 1b, 2 cyclopent-1-enecarbaldehyde (1.4 g, 14.6 mmol) prepared in example 77a was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (2.7 g, 13 mmol) and acetyl chloride (1.0 g, 26 mmol) to give 1-(cyclopent-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(cyclopent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 427.33 C 23 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(cyclopent-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.0 g, 9.55 mmol) prepared in example 77b in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(cyclopent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.12 g, 27.3%).

HRMS (ES + ) m/z Calcd for C 23 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 427.0975 Found: 427.0972.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 72, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(cyclopent-1-enyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.23 mmol) prepared in example 77c was treated with platinum oxide in ethyl acetate under hydrogen (50 psi) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.031 g, 31%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131 Found: 429.1131.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg) prepared in example 78a was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6 mg, 20%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6 mg, 20%).

Preparation of intermediate E-2-Isopropyl-but-2-en-1-ol

M. W. 114.19 C 7 H 14 O

To a solution of 2-butyn-1-ol (14 g, 0.2 mol) (Aldrich) and CuI (32 g, 0.2 mol) (Aldrich) in ether at 0° C. was added isopropylmagnesium chloride (2 M, 300 mL, 0.6 mol) solution in tetrahydrofuran dropwise. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with aqueous saturated NH 4 Cl solution, extracted with ether twice. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (EtOAc:Hexane=1:8) to give E-2-isopropyl-but-2-en-1-ol as pale yellow oil (Yield 5.3 g, 23%).

The same transformation has been reported by Duboudin, J. G.; Jousseaume, B. in J. Organometallic Chem . (1979), 168(1), 1-11 and J. Organometallic Chem . (1975), 91(1), C1-C3.

Preparation of intermediate E-2-Isopropyl-but-2-enal

M. W. 112.17 C 7 H 12 O

To a solution of oxalyl chloride (6.49 g, 51 mmol) (Aldrich) in dichloromethane (50 mL) at −78° C. was added a solution of dimethyl sulfoxide (7.25 mL, 102 mmol) in dichloromethane (40 mL) dropwise. After 5 mins, the solution of E-2-isopropyl-but-2-en-1-ol (5.3 g, 46 mmol) prepared in example 79a in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (22 mL, 0.19 mol) was added and the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 45 mins. Water was added, and organic layer was separated. The aqueous layer was extracted with ether. The organic layers were combined, washed with 10% of HCl, saturated NaHCO 3 , brine, dried over MgSO 4 , and concentrated to give crude E-2-Isopropyl-but-2-enal as a yellow oil (Yield 5.3 g, 98%).

Preparation of intermediate 1-(1-isopropyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 225.41 C 12 H 23 NOSi

In a manner similar to the method described in example 1b, E-2-isopropyl-but-2-enal prepared in example 79b (2.2 g, 20 mmol) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 4 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.72 g, 26 mmol) and acetyl chloride (2 g, 26 mmol) to give 1-(1-isopropyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.3 mmol) was reacted with 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.7 g, 16.4 mmol) prepared in example 79c in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.28 g, 50%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1284

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg) prepared in example 79d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (12 mg, 30%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-isopropyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (12 mg, 30%).

Preparation of intermediate 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 197.36 C 10 H 19 NOSi

In a manner similar to the method described in example 1b, ethylacrolein (2.1 g, 22 mmol) (TCI-US) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 8 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.9 g, 27 mmol) and acetyl chloride (2 g, 27 mmol) to give 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 415.32 C 22 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.42 g, 1.1 mmol) was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.2 g, 16.2 mmol) prepared in example 80a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.31 g, 67%).

HRMS (ES + ) m/z Calcd for C 22 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 415.0975. Found: 415.0975

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 415.32 C 22 H 20 Cl 2 N 2 O 2

Separation of the two enantiomers of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg) prepared in example 80b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (63 mg, 42%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (60 mg, 40%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 559.61 C 29 H 36 Cl 2 N 2 O 3 Si

In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (5.4 g, 12.8 mmol) prepared in example 55a was reacted with 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 g, 95 mmol) prepared in example 66a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white gum (Yield 6.1 g, 85%).

Preparation of intermediate racemic (2′R,3R,4′S)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 673.76 C 35 H 46 Cl 2 N 2 O 5 Si

In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.6 g, 2.8 mmol) prepared in example 81a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethylformamide to give racemic (2′R,3R,4′S)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 0.7 g, 37%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 487.39 C 25 H 24 Cl 2 N 2 O 4

In a manner similar to the method described in example 55d, racemic (2′R,3R,4′S)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.6 g, 0.89 mmol) prepared in example 81b was reacted to form racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.35 g, 80%).

HRMS (ES + ) m/z Calcd for C 25 H 24 Cl 2 N 2 O 4 +H [(M+H) + ]: 487.1186, Found: 487.1186

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 489.38 C 25 H 23 Cl 2 FN 2 O 3

In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1-hydroxycarbonyl-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.33 mmol) prepared in example 81c was reacted with cyanuric fluoride (0.044 mL, 1.64 mmol) (Alfa) and pyridine (0.13 g, 1.64 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.12 g, 75%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 558.51 C 29 H 33 Cl 2 N 3 O 4

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 82a was reacted with 2-amino-2-methyl-propan-1-ol (73 mg, 0.82 mmol), N-methylmorpholine (0.2 g, 1.98 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonylmethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 92 mg, 67%).

HRMS (ES + ) m/z Calcd for C 29 H 33 Cl 2 N 3 O 4 +H [(M+H) + ]: 558.1921. Found: 558.1921

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 558.51 C 29 H 33 Cl 2 N 3 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethyl ethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg) prepared in example 82b was conducted by chiral SFC to provide chiral (2′R,3R,4′S-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 21 mg, 42%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethyl ethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 19 mg, 38%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 636.14 C 32 H 41 Cl 3 N 2 O 3 Si

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.4 g, 4.3 mmol) prepared in example 81a was reacted with LiH (1 g, 125 mmol) and 1-chloro-3-iodo-propane (8 g, 39 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.61 g, 22%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 556.54 C 30 H 35 Cl 2 N 3 O 3

In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 83a (0.3 g, 0.47 mmol) was reacted with morpholine (12 mL), trifluoroacetic acid (5 mL) and then N,N-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.15 g, 57%).

HRMS (ES + ) m/z Calcd for C 30 H 35 Cl 2 N 3 O 3 +H [(M+H) + ]: 556.2128. Found: 556.2123.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 556.54 C 30 H 35 Cl 2 N 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg) prepared in example 83b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 61 mg, 41%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 63 mg, 42%).

Preparation of intermediate 3-Methyl-2-methylene-butan-1-ol

M. W. 100.16 C 6 H 12 O

In a manner similar to the method described in example 79a, isopropyl magnesium chloride (2M in ether, 300 mL, 0.6 mol) was reacted with propargyl alcohol (11.2 g, 0.2 mol, Aldrich) and CuI (32 g, 0.2 mol) to give 3-methyl-2-methylene-butan-1-ol as a colorless oil (Yield, 2.4 g, 12%)

Preparation of intermediate 3-Methyl-2-methylene-butyraldehyde

M. W. 98.15 C 6 H 10 O

In a manner similar to the method described in example 79b, 3-methyl-2-methylene-butan-1-ol (2.4 g, 24 mmol) prepared in example 84a was oxidized to give 3-methyl-2-methylene-butyraldehyde as a yellow oil (Yield: 1.6 g, 68%)

Preparation of intermediate 1-(2-methyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 211.38 C 11 H 21 NOSi

In a manner similar to the method described in example 1b, 3-methyl-2-methylene-butyraldehyde prepared in example 84b (1.3 g, 13 mmol) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13 mmol) and acetyl chloride (1.02 g, 13 mmol) to give 1-(2-methyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methyl-1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.41 g, 1.1 mmol) was reacted with 1-(2-methyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 10 mmol) prepared in example 84c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methyl-1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (0.13 g, 28%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1133

Preparation of intermediate 3,3-Dimethyl-2-methylene-butan-1-ol

M. W. 114.19 C 7 H 14 O

In a manner similar to the method described in example 79a, tert-butyl magnesium chloride (2 M in ether, 300 mL, 0.6 mol) was reacted with propargyl alcohol (11.2 g, 0.2 mol, Aldrich) and CuI (32 g, 0.2 mol) to give 3,3-dimethyl-2-methylene-butan-1-ol as a pale yellow oil (Yield, 12.3 g, 54%)

Preparation of intermediate 3,3-Dimethyl-2-methylene-butyraldehyde

M. W. 112.17 C 7 H 12 O

In a manner similar to the method described in example 79b, 3,3-dimethyl-2-methylene-butan-1-ol (12.3 g, 0.11 mol) prepared in example 85a was oxidized to give 3,3-dimethyl-2-methylene-butyraldehyde as a yellow oil (Yield: 8.3 g, 67%)

Preparation of intermediate 1-(2,2-dimethyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 225.41 C 12 H 23 NOSi

In a manner similar to the method described in example 1b, 3,3-dimethyl-2-methylene-butyraldehyde prepared in example 85b (2.2 g, 20 mmol) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 8 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.7 g, 27 mmol) and acetyl chloride (2 g, 27 mmol) to give 1-(2,2-dimethyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,2-dimethyl-1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.41 g, 1.1 mmol) was reacted with 1-(2,2-dimethyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.4 g, 15 mmol) prepared in example 85c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,2-dimethyl-1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (0.27 g, 55%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1288

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-morpholin-4-yl-ethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 599.56 C 31 H 36 Cl 2 N 4 O 4

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-ethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 83a was reacted with 4-(2-aminoethyl)morpoline (85 mg, 0.66 mmol) (Aldrich), N-methylmorpholine (0.1 g, 0.98 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-morpholin-4-yl-ethyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 31 mg, 22%).

HRMS (ES + ) m/z Calcd for C 31 H 36 Cl 2 N 4 O 4 +H [(M+H) + ]: 599.2187. Found: 599.2185

Preparation of intermediate 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 183.33 C 9 H 17 NOSi

In a manner similar to the method described in example 1b, 2-methacrolein (2 g, 20 mmol) (Acros) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 8 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.7 g, 27 mmol) and acetyl chloride (2.0 g, 27 mmol) to give 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 401.30 C 21 H 18 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.41 g, 1.1 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.4 g, 18 mmol) prepared in example 87a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.27 g, 61%).

HRMS (ES + ) m/z Calcd for C 21 H 18 Cl 2 N 2 O 2 +H [(M+H) + ]: 401.0818. Found: 401.0818

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 401.30 C 21 H 18 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (80 mg) prepared in example 87b was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (28 mg, 35%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (26 mg, 33%).

Preparation of intermediate 2-Methylene-pentan-1-ol

M. W. 100.16 C 6 H 12 O

In a manner similar to the method described in example 79a, propylmagnesium chloride (2 M in ether, 375 mL, 0.75 mol) was reacted with propargyl alcohol (14 g, 0.25 mol) and CuI (40 g, 0.25 mol) to give 2-methylene-pentan-1-ol as a colorless oil (Yield, 16.9 g, 67%)

Preparation of intermediate 2-Methylene-pentanal

M. W. 98.15 C 6 H 10 O

In a manner similar to the method described in example 79b, 2-methylene-pentan-1-ol (16.5 g, 0.165 mol) prepared in example 88a was oxidized to give 2-methylene-pentanal as a yellow oil (Yield: 6.7 g, 41%)

Preparation of intermediate 1-(1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 211.38 C 11 H 21 NOSi

In a manner similar to the method described in example 1b, 2-methylene-pentanal prepared in example 88b (2.1 g, 21 mmol) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (3.2 g, 20 mmol), n-butyllithium (2.5 M, 8 mL, 20 mmol), trimethylsilyl chloride (2.2 g, 20 mmol), triethylamine (2.7 g, 27 mmol) and acetyl chloride (2 g, 27 mmol) to give 1-(1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.45 g, xx mmol) was reacted with 1-(1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.45 g, 1.1 mmol) prepared in example 88c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (0.34 g, 72%).

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1131

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (90 mg) prepared in example 88d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (32 mg, 36%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (30 mg, 33%).

Preparation of intermediate 4-Methyl-2-methylene-pentan-1-ol

M. W. 114.19 C 7 H 14 O

In a manner similar to the method described in example 79a, isobutyl magnesium chloride (2 M in ether, 375 mL, 0.75 mol) was reacted with propargyl alcohol (14 g, 0.25 mol) and CuI (40 g, 0.25 mol) to give 4-methyl-2-methylene-pentan-1-ol as a colorless oil (Yield, 27 g, 95%)

Preparation of intermediate 4-Methyl-2-methylene-pentanal

M. W. 112.17 C 7 H 12 O

In a manner similar to the method described in example 79b, 4-methyl-2-methylene-pentan-1-ol prepared in example 89a was oxidized to give 4-methyl-2-methylene-pentanal as a yellow oil (Yield: 21 g, 77%)

Preparation of intermediate 1-(3-Methyl-1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 225.41 C 12 H 23 NOSi

In a manner similar to the method described in example 1b, 4-methyl-2-methylene-pentanal prepared in example 89b (11 g, 100 mmol) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (16 g, 100 mmol), n-butyllithium (2.5 M, 40 mL, 100 mmol), trimethylsilyl chloride (11 g, 100 mmol), triethylamine (13.6 g, 14 mmol) and acetyl chloride (10.2 g, 14 mmol) to give 1-(3-methyl-1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methyl-1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2 g, 5 mmol) was reacted with 1-(3-methyl-1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (21 g, 93 mmol) prepared in example 89c in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methyl-1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (1.3 g, 59%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1285

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methyl-1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methyl-1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg) prepared in example 89d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methyl-1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (130 mg, 43%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (130 mg, 43%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one

M. W. 459.44 C 24 H 24 Cl 2 N 2 OS

In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.4 g, 3.1 mmol) prepared in example 89d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (1.7 g, 4.25 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a off white solid (Yield 1.2 g, 84%).

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 OS+H [(M+H) + ]: 459.1059. Found: 459.1055.

Preparation of intermediate 4-Ethoxy-1,2-difluoro-benzene

M. W. 158.15 C 8 H 8 F 2 O

To a solution of 3,4-difluoro-phenol (10 g, 77 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (20 g, 145 mmol) and iodoethane (50 g, 320 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 4-ethoxy-1,2-difluoro-benzene as colorless oil (Yield 11 g, 90%).

Preparation of intermediate 6-Ethoxy-2,3-difluoro-benzaldehyde

M. W. 186.16 C 9 H 8 F 2 O 2

In a manner similar to the method described in example 52a, 4-ethoxy-1,2-difluoro-benzene (10 g, 63 mmol) prepared in example 91a was reacted with lithium diisopropylamine (39 mL, 1.8 M in THF, 70 mmol), N,N-dimethylformamide (5.88 mL, 76 mmol) and quenched with acetic acid (15.2 g, 253 mmol) in tetrahydrofuran to give 6-ethoxy-2,3-difluoro-benzaldehyde as a off white solid (Yield: 8.9 g, 76%).

Preparation of intermediate 1-(4-ethoxy-1,2-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 299.40 C 14 H 19 F 2 NO 2 Si

In a manner similar to the method described in example 1b, 6-ethoxy-2,3-difluoro-benzaldehyde (1.9 g, 11 mmol) prepared in example 91b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(4-ethoxy-1,2-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 517.36 C 26 H 20 Cl 2 F 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.6 g, 1.5 mmol) was reacted with 1-(4-ethoxy-1,2-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.3 g, 7.6 mmol) prepared in example 91c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.39 g, 50%).

HRMS (ES + ) m/z Calcd for C 26 H 20 Cl 2 F 2 N 2 O 3 +H [(M+H) + ]: 517.0892. Found: 517.0889.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 517.36 C 26 H 20 Cl 2 F 2 N 2 O 3

Separation of the two enantiomers from (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (98 mg) prepared in example 91d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (36 mg, 36%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (33 mg, 33%).

Preparation of intermediate E/Z-3-Chloro-5-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzoic acid methyl ester

M. W. 348.19 C 17 H 11 Cl 2 NO 3

In a manner similar to the method described in example 1a, 6-chlorooxindole (3.2 g, 18 mmol) was reacted with 3-chloro-5-formyl-benzoic acid methyl ester (3.92 g, 18 mmol) and pyrrolidine (1.3 g, 18 mmol) in methanol to give a mixture of E- and Z-3-Chloro-5-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzoic acid methyl ester as a yellow solid (Yield: 6.1 g, 97%).

3-chloro-5-formyl-benzoic acid methyl ester was prepared using dimethyl 5-chloroisophthalate (Matrix.) as the starting material according to the procedure described by Mitchelotti et al. in U.S. Pat. No. 5,254,584

Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-5-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 448.31 C 22 H 19 Cl 2 NO 5

In a manner similar to the method described in example 24a, E/Z-3-Chloro-5-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzoic acid methyl ester (3 g, 8.6 mmol) was reacted with di-tert-butyl-dicarbonate (1.9 g, 8.6 mmol) (Aldrich), triethylamine (0.87 g, 8.6 mmol) and 4-dimethylaminopyridine (5 mg) in dichloromethane (100 mL) to give E/Z-6-Chloro-3-(3-chloro-5-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 3.7 g, 96%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-methoxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 473.36 C 24 H 22 Cl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-Chloro-3-(3-chloro-5-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 92b (2.4 g, 5.3 mmol) was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 g, 66 mmol) prepared in example 80a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-methoxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (1.6 g, 64%).

HRMS (ES + ) m/z Calcd for C 24 H 22 Cl 2 N 2 O 4 +H [(M+H) + ]: 473.1030. Found: 473.1031.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.33 C 23 H 20 Cl 2 N 2 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-methoxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.6 g, 33 mmol) prepared in example 92c in the mixture of tetrahydrofuran (60 mL) and methanol (30 mL) was added the solution of sodium hydroxide (1N, 30 mL). After the reaction mixture was stirred at room temperature for 2 h, the crude was concentrated. The residue was neutralized to “pH”-4 with the dilute hydrochloride solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO 4 , concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 1.5 g, 99%).

HRMS (ES + ) m/z Calcd for C 23 H 20 Cl 2 N 2 O 4 +H [(M+H) + ]: 459.0873. Found: 459.0873.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 461.32 C 23 H 19 Cl 2 FN 2 O 3

To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.43 mmol) prepared in example 93 in dichloromethane (20 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H 2 O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO 4 , concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.2 g, 100%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[3-chloro-5-(4-methanesulfonyl-piperazine-1-carbonyl)-phenyl]-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 605.55 C 28 H 30 Cl 2 N 4 O 5 S

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 36 mmol) prepared in example 94a was reacted with N-methylsulfonylpiperazine (59 mg, 36 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-[3-chloro-5-(4-methanesulfonyl-piperazine-1-carbonyl)-phenyl]-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.2 g, 92%).

HRMS (ES + ) m/z Calcd for C 28 H 30 Cl 2 N 4 O 5 S+H [(M+H) + ]: 619.1543. Found: 619.1544.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the methods described in example 56a, 56b, 56c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1 g, 1.8 mmol) prepared in example 81a was reacted to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield, 0.50 g, 65%)

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288. Found: 443.1288.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (85 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 33 mg, 39%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 26 mg, 31%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 403.31 C 21 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 72a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl ene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.25 mmol) prepared in example 87b was hydrogenated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 61 mg, 60%).

HRMS (ES + ) m/z Calcd for C 21 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 403.0975 Found: 403.0976.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 403.31 C 21 H 20 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 15 mg, 30%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 14 mg, 28%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 545.59 C 28 H 34 Cl 2 N 2 O 3 Si

In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (3 g, 7.1 mmol) prepared in example 55a was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (19 g, 96 mmol) prepared in example 80a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 3.5 g, 90%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the methods described in example 56a, 56b, 56c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.6 g, 1.1 mmol) prepared in example 97a was reacted to form racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methyl ene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield, 0.16 g, 35%)

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131. Found: 429.1131.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (160 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 80 mg, 50%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 80 mg, 50%).

Preparation of racemic (2′R,3R,4′S)-2′-sec-Butyl-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 417.34 C 22 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 72a, (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.38 g, 0.91 mmol) prepared in example 80b was hydrogenated to give racemic (2′R,3R,4′S)-2′-sec-butyl-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 66%).

HRMS (ES + ) m/z Calcd for C 22 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 417.1131 Found: 417.1134

Preparation of intermediate 2-(tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol

M. W. 202.37 C 10 H 22 O 2 Si

To a solution of 2-methylene-propane-1,3-diol (5.3 g, 60.15 mmol) (Aldrich) in tetrahydrofuran (100 mL) was added sodium hydride (3.61 g, 90.3 mmol). After the reaction mixture was stirred at room temperature for 20 min, tert-butyldimethylchlorosilane (10.89 g, 72.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then poured into water and extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over dried over MgSO 4 , filtered and concentrated to give 2-(tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol as colorless oil (Yield 12.0 g, 99%).

Preparation of intermediate 2-(tert-butyl-dimethyl-silanyloxymethyl)-propenal

M. W. 200.36 C 10 H 20 O 2 Si

2-(Tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol (6 g, 29.7 mmol) prepared in example 99a was dissolved in dichloromethane (296 mL) containing both the molecular sieves (4 A) (Aldrich) and N-methyl morpholine oxide (5.2 g, 44.47 mmol). After stirring the mixture for 1 h, (Tetra-n-butyl ammonium perruthenate) (0.47 g, 1.48 mmol) (Aldrich) was added and the reaction mixture was stirred at room temperature for 1 h. Then another batch of (Tetra-n-butyl ammonium per-ruthenate) (0.23 g, 0.74 mmol) was added and the mixture was stirred at room temperature for another 1 h. The reaction mixture was diluted with dichloromethane. The organic layer was washed with Na 2 S 2 O 3 solution, brine and saturated copper (II) sulfate solution, then dried over dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography to give 2-(tert-butyl-dimethyl-silanyloxymethyl)-propenal to as colorless oil (Yield 1.3 g, 22%).

Preparation of intermediate 1-[1-(tert-butyl-dimethyl-silanyloxymethyl)-vinyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 313.59 C 15 H 31 NO 2 Si 2

In a manner similar to the method described in example 1b, 2-(tert-butyl-dimethyl-silanyloxymethyl)-propenal (1.05 g, 5.25 mmol) prepared in example 99b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.09 mL, 5.25 mmol), n-butyllithium (2.5 M, 2.1 mL, 5.25 mmol), trimethylsilyl chloride (0.67 mL, 5.25 mmol), triethylamine (0.95 mL, 6.8 mmol) and acetyl chloride (0.48 mL, 6.8 mmol) to give 1-[1-(tert-butyl-dimethyl-silanyloxymethyl)-vinyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-hydroxymethyl-vinyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 417.34 C 21 H 18 Cl 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.2 g, 0.51 mmol) was reacted with 1-[1-(tert-butyl-dimethyl-silanyloxymethyl)-vinyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 99c in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-hydroxymethyl-vinyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid.

HRMS (ES + ) m/z Calcd for C 21 H 18 Cl 2 N 2 O 3 +H [(M+H) + ]: 417.0767 Found: 417.0767.

Preparation of intermediate 2-methoxymethyl-propenal

M. W. 100.12 C 5 H 8 O 2

A stirred mixture of acrolein (22.4 g, 0.4 mol) (Aldrich), methanol (62 g, 1.82 mol), triethanolamine (1.5 g, 0.01 mol) and 85% phosphoric acid (1.14 g, 0.0098 mol) in water was heated at refluxing temperature for overnight, then cooled to room temperature and filtered. The filtrate is diluted with water and then treated with a 37% formaldehyde solution (32.4 g, 0.4 mol) (Aldrich), concentrated sulfuric acid (2.32 g, 0.02 mol) and dibutylamine (5.4 g, 0.04 mol) (Aldrich). The crude mixture was heated at refluxing temperature for 4 h, cooled to room temperature and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (hexanes) to give 2-methoxymethyl-propenal as colorless oil (Yield 2.8 g, 7.0%).

Preparation of intermediate 1-(1-methoxymethyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 213.75 C 10 H 19 NO 2 Si

In a manner similar to the method described in example 1b, 2-methoxymethyl-propenal (1.35 mL, 10.5 mmol) prepared in example 100a was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(1-methoxymethyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methoxymethyl-vinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 431.32 C 22 H 20 Cl 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(1-methoxymethyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 158b in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methoxymethyl-vinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.12 g, 27.2%).

HRMS (ES + ) m/z Calcd for C 22 H 20 Cl 2 N 2 O 3 +H [(M+H) + ]: 431.0924 Found: 431.0928.

Preparation of intermediate 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene

M. W. 188.18 C 9 H 10 F 2 O 2

To a solution of 3,4-difluoro-phenol (10 g, 76.9 mmol) (Aldrich) in N,N-dimethylformamide (100 mL) was added sodium hydride (4.6 g, 115 mmol) and 1-bromo-2-methoxy-ethane (12.8 g, 92.2 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 2 h, then heated at 80 ° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (EtOAc:Hexane=1:10) to give 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene as colorless oil (Yield 6.3 g, 44%).

Preparation of intermediate 2,3-difluoro-6-(2-methoxy-ethoxy)-benzaldehyde

M. W. 216.19 C 10 H 10 F 2 O 3

In a manner similar to the method described in example 52a, 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene (6.3 g, 33.4 mmol) prepared in example 101a was reacted with lithium diisopropylamine (20.1 mL, 2.0 M in THF, 40.1 mmol), N,N-dimethyl-formamide (3.11 mL, 40.1 mmol) and quenched with acetic acid (8.1 g, 134 mmol) and water (41.2 mL) in tetrahydrofuran to give 2,3-difluoro-6-(2-methoxy-ethoxy)-benzaldehyde as yellow oil (Yield: 5.8 g, 80.6%).

Preparation of intermediate 1-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 329.42 C 15 H 21 F 2 NO 3 Si

In a manner similar to the method described in example 1b, 2,3-difluoro-6-(2-methoxy-ethoxy)-benzaldehyde (2.23 g, 10.5 mmol) prepared in example 101b was reacted with 1,1,1,3,3,3-hexamethyldisilazane (1.7 g, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 g, 10.5 mmol), triethylamine (1.9 mL, 13 mmol) and acetyl chloride (0.97, 13 mmol) to give 1-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 547.39 C 27 H 22 Cl 2 F 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 101c in toluene and then trifluoroacetic acid (8 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.12 g, 21.4%).

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 F 2 N 2 O 4 +H [(M+H) + ]: 547.0998 Found: 547.0997.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 483.37 C 26 H 21 Cl 2 FN 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (80 mg) prepared in example 101d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 35 mg, 43.7%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 33 mg, 41.2%).

Preparation of intermediate 2,3-dimethyl-but-2-enoic acid ethyl ester

M. W. 142.20 C 8 H 14 O 2

Triethyl phosphonopropionate (23.8 g, 0.1 mol) (Aldrich) was added dropwise to a stirred solution of sodium hydride (2.64 g, 0.11 mol) in dimethoxyethane (100 mL) at 0° C. After stirring at room temperature for 20 mins, acetone (5.8 g, 0.1 mol) was added and the reaction mixture was refluxed for overnight. The two phase mixture was cooled, diluted with water and extracted with ether. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (Hexane) to give 2,3-dimethyl-but-2-enoic acid ethyl ester as colorless oil (Yield 9.6 g, 67.7%).

Preparation of intermediate 2,3-dimethyl-but-2-en-1-ol

M. W. 100.16 C 6 H 12 O

The solution of 2,3-dimethyl-but-2-enoic acid ethyl ester (9.6 g, 67.7 mmol) in ether (100 mL) was added to a stirred solution of LAH (1M in ether, 67 mL, 67.7 mmol) dropwisely. After stirring at room temperature for 30 mins, the reaction mixture was quenched with saturate NH 4 Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO 4 and filtered. The solvent was removed to give 2,3-dimethyl-but-2-en-1-ol as colorless oil (Yield 4.4 g, 66%).

Preparation of intermediate 2,3-dimethyl-but-2-enal

M. W. 98.15 C 6 H 10 O

To a solution of oxalyl chloride (6.13 g, 48.3 mmol) (Aldrich) in dichloromethane (50 mL) at −78° C. was added the solution of dimethyl sulfoxide (6.85 mL, 96.6 mmol) in dichloromethane dropwise. After 5 mins, the solution of 2,3-dimethyl-but-2-en-1-ol (4.4 g, 43.9 mmol) prepared in example 160b in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 mins. Triethyl amine (22 mL, 0.19 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 mins. The water was added. The organic layers were separated, combined, washed with 10% of HCl, saturated NaHCO 3 , brine, dried over MgSO 4 , filtered and concentrated to give 2,3-dimethyl-but-2-enal as yellow liquid (Yield 4.0 g, 93%).

Preparation of intermediate 1-(1,2-dimethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 211.38 C 11 H 21 NOSi

In a manner similar to the method described in example 1b, 2,3-dimethyl-but-2-enal (1.03 g, 10.5 mmol) prepared in example 102c was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(1,2-dimethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1,2-dimethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 429.35 C 23 H 22 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(1,2-dimethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 102d in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1,2-dimethyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid.

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 2 +H [(M+H) + ]: 429.1131 Found: 429.1132.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 417.30 C 21 H 18 Cl 2 N 2 O 3

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.72 mmol) prepared in example 80b in methanol and dichloromethane (1:1, 50 mL) at −78° C. was passed a stream of ozone until the color of the solution turned blue. The reaction mixture was degassed with nitrogen, then methyl disulfide (5 mL) was added. The reaction was slowly warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:1) to give the racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 160 mg, 50%)

HRMS (ES + ) m/z Calcd for C 21 H 18 Cl 2 N 2 O 3 +H [(M+H) + ]: 417.0767. Found: 417.0770.

Preparation of intermediate 1,2-difluoro-4-propoxy-benzene

M. W. 172.18 C 9 H 10 F 2 O

To a solution of 3,4-difluoro-phenol (20 g, 154 mmol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (30 g, 217 mmol) and iodopropane (50 g, 293 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 1,2-difluoro-4-propoxy-benzene as a colorless oil (Yield 17 g, 100%).

Preparation of intermediate 2,3-difluoro-6-propoxy-benzaldehyde

M. W. 200.19 C 10 H 10 F 2 O 2

In a manner similar to the method described in example 52a, 1,2-difluoro-4-propoxy-benzene (17 g, 98.8 mmol) prepared in example 104a was reacted with lithium diisopropyl amine (59.2 mL, 2.0 M in THF, 0.118 mmol), N,N-dimethyl-formamide (9.17 mL, 0.118 mol) and quenched with acetic acid (23.7 g, 0.395 mol) and water (41.2 mL) in tetrahydrofuran to give 2,3-difluoro-6-propoxy-benzaldehyde as a yellow solid (Yield: 8.2 g, 42%).

Preparation of intermediate 1-(2,3-difluoro-6-propoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 313.42 C 15 H 21 F 2 NO 2 Si

In a manner similar to the method described in example 1b, 2,3-difluoro-6-propoxy-benzaldehyde (2.1 g, 10.5 mmol) prepared in example 104b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (1.7 g, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 g, 10.5 mmol), triethylamine (1.9 mL, 13 mmol) and acetyl chloride (0.97, 13 mmol) to give 1-(2,3-difluoro-6-propoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 531.39 C 27 H 22 Cl 2 F 2 N 2 O 3

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.4 g, 1.02 mmol) was reacted with 1-(2,3-difluoro-6-propoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 104c in toluene and then trifluoroacetic acid (8 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as yellow oil.

HRMS (ES + ) m/z Calcd for C 27 H 22 Cl 2 F 2 N 2 O 3 +H [(M+H) + ]: 531.1049 Found: 531.1049.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 531.39 C 27 H 22 Cl 2 F 2 N 2 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.67 g) prepared in example 104d was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 135 mg, 20.1%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-propoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 150 mg, 22.3%).

Preparation of intermediate 2-cyclopropyl-prop-2-en-1-ol

M. W. 98.15 C 6 H 10 O

To a solution of propargyl alcohol (4.2 g, 74.9 mmol) (Aldrich) and CuI (14.28 g, 74.9 mmol) (Aldrich) in ether at 0° C. was added cyclopropylmagnesium chloride (0.5 M, 0.45 L, 0.225 mol) solution in tetrahydrofuran dropwise. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was quenched with saturate NH 4 Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (EtOAc:Hexane=1:8) to give 2-cyclopropyl-prop-2-en-1-ol as yellow oil (Yield 5.9 g, 80.9%).

Preparation of intermediate 2-cyclopropyl-propenal

M. W. 96.13 C 6 H 8 O

In a manner similar to the method described in example 102c, 2-cyclopropyl-prop-2-en-1-ol (5.95 g, 60.7 mmol) prepared in example 105a was reacted with oxalyl chloride (8.48 g, 60.7 mmol), dimethyl sulfoxide (9.47 mL, 133.5 mmol) and triethylamine (30.4 mL, 218 mmol) in dichloromethane to give 2-cyclopropyl-propenal as yellow oil (Yield: 4.8 g, 34.5%).

Preparation of intermediate 1-(1-cyclopropyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 209.37 C 11 H 19 NOSi

In a manner similar to the method described in example 1b, 2-cyclopropyl-propenal (1.0 g, 10.5 mmol) prepared in example 105b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(1-cyclopropyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclopropyl-vinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 427.33 C 23 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.35 g, 0.90 mmol) was reacted with 1-(1-cyclopropyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 105c in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclopropyl-vinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid.

HRMS (ES + ) m/z Calcd for C 23 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 427.0975 Found: 427.0973.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-hydroxycarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 473.36 C 24 H 22 Cl 2 N 2 O 4

In a manner similar to the methods described in example 81b, 81c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (7 g, 12.8 mmol) prepared in example 97a was reacted to form racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-hydroxycarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (3.6 g, 59%).

HRMS (ES + ) m/z Calcd for C 24 H 22 Cl 2 N 2 O 4 +H [(M+H) + ]: 473.1030 Found: 473.1032.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 475.35 C 24 H 21 Cl 2 FN 2 O 3

In a manner similar to the method described in example 82a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-hydroxycarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.2 g, 2.5 mmol) prepared in example 166 was reacted to form racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 1.1 g, 92%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 633.60 C 30 H 34 Cl 2 N 4 O 5 S

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was reacted with 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetic acid salt (0.2 g, 0.34 mmol), N-methylmorpholine (0.2 g, 2 mmol) and 4-dimethylaminopyridine (1 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 58 mg, 44%).

HRMS (ES + ) m/z Calcd for C 30 H 34 Cl 2 N 4 O 5 S+H [(M+H) + ]: 633.1700. Found: 633.1701.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-(aminocarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 472.38 C 24 H 23 Cl 2 N 3 O 3

Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was stirred in a methanolic ammonia solution (7N, 10 mL) at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 41 mg, 40%).

HRMS (ES + ) m/z Calcd for C 24 H 23 Cl 2 N 3 O 3 +Na [(M+Na) + ]: 494.1008 Found: 494.1008

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-(aminocarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 472.38 C 24 H 23 Cl 2 N 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (32 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-(aminocarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 9 mg, 28%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-(aminocarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 9 mg, 28%).

Preparation of intermediate 2-ethyl-3-methyl-but-2-enoic acid ethyl ester

M. W. 156.23 C 9 H 16 O 2

In a manner similar to the method described in example 102a, triethyl 2-phosphonobutyrate (25.2 g, 0.1 mol) was reacted with NaH (2.64 g, 0.11 mol), and then acetone (5.8 g, 0.1 mol) in dimethoxyethane to give 2-ethyl-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 11.4 g, 73%).

Preparation of intermediate 2-ethyl-3-methyl-but-2-en-1-ol

M. W. 114.19 C 7 H 14 O

In a manner similar to the method described in example 102b, 2-ethyl-3-methyl-but-2-enoic acid ethyl ester (11.4 g, 73 mmol) prepared in example 109a was reacted with LAH (1M in ether, 73 mL, 73 mmol) in diethyl ether to give 2-ethyl-3-methyl-but-2-en-1-ol as colorless oil (Yield: 7.62 g, 91.5%).

Preparation of intermediate 2-ethyl-3-methyl-but-2-enal

M. W. 112.17 C 7 H 12 O

In a manner similar to the method described in example 102c, 2-ethyl-3-methyl-but-2-en-1-ol (7.62 g, 66.8 mmol) prepared in example 109b was reacted with oxalyl chloride (9.3 g, 73.5 mmol), dimethyl sulfoxide (10.44 mL, 146.9 mmol) and triethylamine (33.4 mL, 240 mmol) in dichloromethane to give 2-ethyl-3-methyl-but-2-enal as yellow oil (Yield: 7.5 g, 99%).

Preparation of intermediate 1-(1-ethyl-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 225.41 C 12 H 23 NOSi

In a manner similar to the method described in example 1b, 2-ethyl-3-methyl-but-2-enal (1.18 g, 10.5 mmol) prepared in example 109c was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-(1-ethyl-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-2-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 443.38 C 24 H 24 Cl 2 N 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.35 g, 0.89 mmol) was reacted with 1-(1-ethyl-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 109d in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-2-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid.

HRMS (ES + ) m/z Calcd for C 24 H 24 Cl 2 N 2 O 2 +H [(M+H) + ]: 443.1288 Found: 443.1287.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 533.36 C 26 H 20 Cl 2 F 2 N 2 O 4

To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.22 mmol) prepared in example 101d in dichloromethane (5 mL) at −78° C. was added boron tribromide (1M, 2.19 ml, 2.19 mmol) dropwise. The reaction was gradually warmed up to room temperature and stirred at room temperature for 2 h. Then the crude was diluted with dichloromethane. The organic layer was washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as white solid (Yield: 46 mg, 39.3%).

HRMS (ES + ) m/z Calcd for C 26 H 20 Cl 2 F 2 N 2 O 4 +H [(M+H) + ]: 533.0841. Found: 533.0842.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 533.36 C 26 H 20 Cl 2 F 2 N 2 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 30 mg, 42.8%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 20 mg, 28.5%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-hydroxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 489.31 C 24 H 16 Cl 2 F 2 N 2 O 4

In preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione in example 110a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-hydroxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was obtained as a side product.

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 F 2 N 2 O 4 +H [(M+H) + ]: 489.0579. Found: 489.0580.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-1-hydroxy-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 447.37 C 23 H 24 Cl 2 N 2 O 3

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.24 mmol) prepared in example 103 in tetrahydrofuran (3 mL) at −78° C. was added a tetrahydrofuran solution of ethylmagnesium chloride (2M, 6 mL, 12 mmol). The reaction mixture was stirred at −78° C. for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The mixture was poured into saturated aqueous NH 4 Cl solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO 4 , concentrated. The residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-1-hydroxy-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 93%)

HRMS (ES + ) m/z Calcd for C 23 H 24 Cl 2 N 2 O 3 +H [(M+H) + ]: 447.1237. Found: 447.1237.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-3-methyl-oxiranyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 575.61 C 29 H 36 Cl 2 N 2 O 4 Si

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.2 g, 2.1 mmol) prepared in example 81a in dichloromethane (50 mL) was added m-chloroperoxybenzoic acid (77%, 8.9 g,) and NaHCO 3 (2 g). The reaction mixture was stirred at room temperature for 18 h, the poured into an aqueous solution of Na 2 SO 3 , then extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 , concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-3-methyl-oxiranyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield, 1.0 g, 82%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-3-methyl-oxiranyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 445.35 C 23 H 22 Cl 2 N 2 O 3

In a manner similar to the methods described in example 56b and 56c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-3-methyl-oxiranyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.19 g, 0.33 mmol) prepared in example 113a was reacted to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-3-methyl-oxiranyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield, 0.42 g, 29%)

HRMS (ES + ) m/z Calcd for C 23 H 22 Cl 2 N 2 O 3 +H [(M+H) + ]: 445.1080. Found: 445.1081.

Preparation of intermediate 2-fluoro-3-methyl-but-2-enoic acid ethyl ester

M. W. 146.16 C 7 H 11 FO 2

Triethyl 2-fluoro-2-phosphonoacetate (20 g, 82.6 mmol) (Aldrich) was added dropwise to a stirred solution of sodium hydride (3.6 g, 90.8 mmol) in dimethoxyethane (100 mL) at 0° C. After stirring at room temperature for 20 min, acetone (4.78 g, 82.6 mmol) was added and the reaction mixture was refluxed for overnight. The two phase mixture was cooled, diluted with water and extracted with ether. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography (Hexanes) to give 2-fluoro-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 9.0 g, 61.6%).

Preparation of intermediate 2-fluoro-3-methyl-but-2-en-1-ol

M. W. 104.14 C 5 H 9 FO

The solution of 2-fluoro-3-methyl-but-2-enoic acid ethyl ester (9.0 g, 61.6 mmol) in ether (100 mL) was added to a stirred solution of LAH (1M in ether, 61.6 mL, 67.7 mmol) dropwise. After stirring at room temperature for 30 mins, the reaction mixture was quenched with saturate NH 4 Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO 4 and filtered. The solvent was removed to give 2-fluoro-3-methyl-but-2-en-1-ol as colorless oil (Yield: 5.21 g, 81.3%).

Preparation of intermediate 2-fluoro-3-methyl-but-2-enal

M. W. 102.11 C 5 H 7 FO

To a solution of oxalyl chloride (6.98 g, 50 mmol) (Aldrich) in dichloromethane (50 mL) at −78° C. was added the solution of dimethyl sulfoxide (7.80 mL, 110 mmol) in dichloromethane dropwise. After 5 mins, the solution of 2-fluoro-3-methyl-but-2-en-1-ol (5.21 g, 50 mmol) prepared in example 114b in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (25 mL, 0.18 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, combined, washed with 10% of HCl, saturated NaHCO 3 , brine, dried over MgSO 4 , filtered and concentrated to give 2-fluoro-3-methyl-but-2-enal as yellow liquid (Yield: 4.02 g, 82.4%).

Preparation of intermediate 1-(1-fluoro-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 215.35 C 10 H 18 FNOSi

In a manner similar to the method described in example 1b, 2-fluoro-3-methyl-but-2-enal (2.14 g, 21 mmol) prepared in example 114c was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol), n-butyllithium (2.5 M, 8.4 mL, 21 mmol), trimethylsilyl chloride (2.66 mL, 21 mmol), triethylamine (3.8 mL, 27.2 mmol) and acetyl chloride (1.94 mL, 27.2 mmol) to give 1-(1-fluoro-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-fluoro-2-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 433.31 C 22 H 19 Cl 2 FN 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (1.0 g, 2.56 mmol) was reacted with 1-(1-fluoro-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 114e in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-fluoro-2-methyl-propenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid.

HRMS (ES + ) m/z Calcd for C 22 H 19 Cl 2 FN 2 O 2 +H [(M+H) + ]: 433.0881 Found: 433.0879.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isobutyrylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 431.32 C 22 H 20 Cl 2 N 2 O 3

In a manner similar to the methods described in example 103, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methyl-1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.47 mmol) prepared in example 139d was reacted to form racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isobutyrylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield, 0.13 g, 66%).

HRMS (ES + ) m/z Calcd for C 22 H 20 Cl 2 N 2 O 3 +H [(M+H) + ]: 431.0924. Found: 431.0925.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 531.56 C 27 H 32 Cl 2 N 2 O 3 Si

In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chlorobenzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (8 g, 20 mmol) prepared in example 55a was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (21 g, 99 mmol) prepared in example 87a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white gum (3.5 g, 33%)

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 645.71 C 33 H 42 Cl 2 N 2 O 5 Si

In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (3 g, 5.64 mmol) prepared in example 116a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield: 2.98 g, 79%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.33 C 23 H 22 Cl 2 N 2 O 4

In a manner similar to the method described in example 55d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.88 g, 4.46 mmol) prepared in example 116b was reacted with trifluoroacetic acid, then ethyl-diisopropyl-amine to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as yellow oil (Yield 1.7 g, 85.8%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 461.32 C 23 H 19 Cl 2 FN 2 O 3

In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1-[hydroxycarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.42 g, 0.91 mmol) prepared in example 116c was reacted with cyanuric fluoride (0.31 mL, 2.01 mmol) (Alfa) and pyridine (0.14 g, 1.82 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield: 0.38 g, 90%).

Preparation of racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 458.35 C 23 H 21 Cl 2 N 3 O 3

To a solution of ammonia (2 M, 10 mL) in methanol was added racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d. The reaction mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was separated, combined and concentrated. The residue was purified with chromatography (MeOH:EtOAc=5:95) to give racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 70 mg, 38.9%).

HRMS (ES + ) m/z Calcd for C 23 H 21 Cl 2 N 3 O 3 +H [(M+H) + ]: 458.1033. Found: 458.1033.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 498.41 C 26 H 25 Cl 2 N 3 O 3

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (49 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 38%).

HRMS (ES + ) m/z Calcd for C 26 H 25 Cl 2 N 3 O 3 +H [(M+H) + ]: 498.1346 Found: 498.1345.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione

M. W. 555.51 C 29 H 32 Cl 2 N 4 O 3

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methyl-piperidin-4-ylamine (0.134 mg, 0.95 mmol), N-methylmorpholine (99 mg, 0.95 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 75 mg, 31.2%).

HRMS (ES + ) m/z Calcd for C 29 H 32 Cl 2 N 4 O 3 +H [(M+H) + ]: 555.1924 Found: 555.1925.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methylsulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione

M. W. 619.57 C 29 H 32 Cl 2 N 4 O 5 S

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methylsulfonyl-piperidin-4-yl-amine (0.15 g, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methylsulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 92 mg, 38.3%).

HRMS (ES + ) m/z Calcd for C 29 H 32 Cl 2 N 4 O 5 S+H [(M+H) + ]: 619.1543 Found: 619.1541.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 502.40 C 25 H 25 Cl 2 N 3 O 4

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-ethanol (61 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 36.8%).

HRMS (ES + ) m/z Calcd for C 25 H 25 Cl 2 N 3 O 4 +H [(M+H) + ]: 502.1295 Found: 502.1296.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 530.46 C 27 H 29 Cl 2 N 3 O 4

In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (69 mg, 0.78 mmol), N-methylmorpholine (81 mg, 0.78 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 74 mg, 35.9%).

HRMS (ES + ) m/z Calcd for C 27 H 29 Cl 2 N 3 O 4 +H [(M+H) + ]: 502.1295 Found: 502.1296.

Preparation of intermediate Z-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-(3-chloro-phenyl)-acetonitrile

M. W. 315.16 C 16 H 8 Cl 2 N 2 O

To the mixture of 3-chlorobenzyl cyanide (1.8 g, 12 mmol) (Aldrich) and 6-chloroisotin (1.81 g, 10 mmol) (TCI-US) in ethanol (40 mL) was added DBU (1.9 g, 12.5 mmol) (Aldrich). The reaction mixture was heated at 100° C. for 1 h. TCL analysis indicated the formation of mixture of E- and Z-isomers of the desired product and almost complete consumption of starting materials. The mixture was cooled to room temperature, concentrated to a small volume, then diluted with ethyl ether, washed with dilute HCl aqueous solution. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by chromatography (EtOAc:hexanes=1:2) to give the desire Z-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-(3-chloro-phenyl)-acetonitrile as an orange solid (0.9 g, 29%). The other isomer E-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-(3-chloro-phenyl)-acetonitrile was also obtained as an orange solid (0.9 g, 29%).

Preparation of intermediate Z-6-Chloro-3-[(3-chloro-phenyl)-cyano-methylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 415.28 C 21 H 16 Cl 2 N 2 O 3

In a manner similar to the method described in example 24a, Z-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-(3-chloro-phenyl)-acetonitrile (0.4 g, 1.3 mmol) was reacted with di-tert-butyl-dicarbonate (1.9 g, 8.6 mmol) (Aldrich), triethylamine (0.87 g, 8.6 mmol) and 4-dimethylaminopyridine (5 mg) in dichloromethane (100 mL) to give Z-6-Chloro-3-[(3-chloro-phenyl)-cyano-methylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 0.3 g, 56%).

Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-(3-chloro-phenyl)-4′-cyano-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 440.33 C 23 H 19 Cl 2 N 3 O 2

In a manner similar to the method described in example 41b, Z-6-Chloro-3-[(3-chloro-phenyl)-cyano-methylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 122b (0.3 g, 0.72 mmol) was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2 g, 10 mmol) prepared in example 80a in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3S,4′R)-6-chloro-4′-(3-chloro-phenyl)-4′-cyano-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (0.1 g, 31%).

HRMS (ES + ) m/z Calcd for C 23 H 19 Cl 2 N 3 O 2 +H [(M+H) + ]: 440.0927. Found: 440.0927.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 608.09 C 30 H 37 Cl 3 N 2 O 3 Si

In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.57 g, 2.95 mmol) prepared in example 116a was reacted with LiH (2.3 g, 29.5 mmol) and 1-chloro-3-iodo-propane (6.04 g, 29.5 mmol) in N,N-dimethyl-formamide (100 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.6 g, 33.5%).

Preparation of racemic (2′R,3R,4′S)-1′-[3-(4-acetylamino-piperidin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione

M. W. 583.56 C 31 H 36 Cl 2 N 4 O 3

In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.12 g, 0.20 mmol) was reacted with N-piperidin-4-yl-acetamide (0.56 g, 4 mmol), trifluoroacetic acid (2 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-1′-[3-(4-acetylamino-piperidin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a brown solid (Yield: 47 mg, 40.8%).

HRMS (ES + ) m/z Calcd for C 31 H 36 Cl 2 N 4 O 3 +H [(M+H) + ]: 583.2237 Found: 583.2239.

Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 280.72 C 16 H 9 ClN 2 O

In a manner similar to the method described in example 1a, 6-cyanooxindole (1 g, 6.44 mmol) (Combi-blocks) was reacted with 3-chloro-benzaldehyde (0.73 mL, 6.44 mmol) (Aldrich) and piperidine (0.635 mL, 6.44 mmol) in methanol to give a mixture of E- and Z-6-cyano-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a brown solid (Yield: 1.34 g, 74.4%).

Preparation of intermediate E/Z-6-cyano-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 380.83 C 21 H 17 ClN 2 O 3

In a manner similar to the method described in example 24a, E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1.34 g, 4.77 mmol) was reacted with di-tert-butyl-dicarbonate (1.91 g, 8.73 mmol) (Aldrich), triethylamine (3.29 mL, 23.6 mmol) and 4-dimethylaminopyridine (25 mg) in dichloromethane (100 mL) to give E/Z-6-cyano-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 1.7 g, 93.4%).

Preparation of racemic (2′R,3R,4′S)-4′-(3-chloro-phenyl)-6′-cyano-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 405.89 C 23 H 20 ClFN 3 O 2

In a manner similar to the method described in example 41b, E/Z-6-cyano-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 124b (0.4 g, 1.05 mmol) was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 80a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-4′-(3-chloro-phenyl)-6′-cyano-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 90 mg, 21.1%).

HRMS (ES + ) m/z Calcd for C 23 H 20 ClFN 3 O 2 +H [(M+H) + ]: 406.1317 Found: 406.1316.

Preparation of racemic (2′R,3R,4′S)-4′-(3-chloro-phenyl)-6-cyano-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.91 C 26 H 19 ClFN 3 O 2

In a manner similar to the method described in example 41b, E/Z-6-cyano-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 124b (0.4 g, 1.05 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-4′-(3-chloro-phenyl)-6′-cyano-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 0.12 g, 16.9%).

HRMS (ES + ) m/z Calcd for C 26 H 19 ClFN 3 O 2 +H [(M+H) + ]: 460.1223. Found: 460.1223.

Preparation of racemic (2′R,3R,4′S)-1′-[3-(4-acetyl-piperazin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 569.54 C 30 H 34 Cl 2 N 4 O 3

In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.2 g, 0.20 mmol) was reacted with 1-piperazin-1-yl-ethanone (0.51 g, 4 mmol), trifluoroacetic acid (2 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-1′-[3-(4-acetyl-piperazin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 95 mg, 50.8%).

HRMS (ES + ) m/z Calcd for C 30 H 34 Cl 2 N 4 O 3 +H [(M+H) + ]: 569.2081 Found: 569.2079.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-(3-piperidin-1-yl-propyl)spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione

M. W. 526.51 C 29 H 33 Cl 2 N 3 O 2

In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.12 g, 0.20 mmol) was reacted with piperidine (2 mL), trifluoroacetic acid (1 mL) and then N,N′-diisopropylethylamine (1.5 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-(3-piperidin-1-yl-propyl)spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 40 mg, 23.1%).

HRMS (ES + ) m/z Calcd for C 29 H 33 Cl 2 N 3 O 2 +H [(M+H) + ]: 526.2023 Found: 526.2020.

Preparation of intermediate Acetic acid 2-(2-formyl-4-methyl-phenoxy)-ethyl ester

M. W. 222.24 C 12 H 14 O 4

To a solution of 2-hydroxy-5-methyl-benzaldehyde (2.4 g, 18 mmol) (Aldrich) in N,N-dimethylformamide (30 mL) was added cesium carbonate (6 g, 18 mmol), potassium iodide (3 g, 18 mmol) and 2-bromoethyl acetate (7 g, 42 mmol), Aldrich). The reaction mixture was heated at 100° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl ether, washed with water, brine, separated, and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:6) to give acetic acid 2-(2-formyl-4-methyl-phenoxy)-ethyl ester as a yellow oil (Yield 4 g, 100%).

Preparation of intermediate 1-[2-(2-Acetoxy-ethoxy)-5-methyl-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 335.48 C 17 H 25 NO 4 Si

In a manner similar to the method described in example 1b, acetic acid 2-(2-formyl-4-methyl-phenoxy)-ethyl ester (2.5 g, 11 mmol) prepared in example 128a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 553.45 C 29 H 26 Cl 2 N 2 O 5

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol) was reacted with 1-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (2 g, 6 mmol) prepared in example 128b in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-2′-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.2 g, 28%).

HRMS (ES + ) m/z Calcd for C 29 H 26 Cl 2 N 2 O 5 +H [(M+H) + ]: 553.1292. Found: 553.1291.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[6-(2-hydroxy-ethoxy)-3-methyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 511.41 C 27 H 24 Cl 2 N 2 O 4

To a solution of racemic (2′R,3R,4′S)-2′-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.29 mmol) prepared in example 128c in tetrahydrofuran (30 mL) and methanol (10 mL) was added sodium hydroxide aqueous solution (1N, 10 mL). the reaction mixture was stirred at room temperature for 3 h, then neutralized to “pH” 7 by aqueous HCl. The mixture was then extracted with ethyl acetate. The organic layer was separated, concentrated, and purified by chromatography (EtOAc:MeOH=19:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-methyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (70 mg, 47%)

HRMS (ES + ) m/z Calcd for C 27 H 24 Cl 2 N 2 O 4 +H [(M+H) + ]: 511.1186. Found: 511.1185.

Preparation of intermediate 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde

M. W. 359.34 C 15 H 23 BrO 2 Si

To a solution of 5-bromo-2-hydroxy-benzaldehyde (14 g, 69.6 mmol) (Aldrich) in N,N-dimethylformamide (300 mL) was added K 2 CO 3 (29 g, 208.9 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (20 g, 83.5 mmol) (Aldrich). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated to give 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde as brown oil (Yield: 25 g, 100%).

Preparation of intermediate 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde

M. W. 320.51 C 18 H 28 O 3 Si

To a solution of 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (5 g, 13.9 mmol) prepared in example 130a in toluene (75 mL) and water (7.5 mL) was added cyclopropylboronic acid (1.7 g, 19.8 mmol) (Aldrich) and potassium phosphate (14.6 g, 68.9 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(tricyclohexyl-phosphine) (1.03 g, 1.39 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 4 h. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde as yellow oil (Yield: 3.2 g, 76.2%).

Preparation of intermediate 1-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 433.74 C 23 H 39 NO 3 Si 2

In a manner similar to the method described in example 1b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde (3.36 g, 10.5 mmol) prepared in example 130b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give 1-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-cyclopropyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 537.45 C 29 H 26 Cl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol) was reacted with 1-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 130c in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-cyclopropyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.14 g, 20.3%).

HRMS (ES + ) m/z Calcd for C 29 H 26 Cl 2 N 2 O 4 +H [(M+H) + ]: 537.1343 Found: 537.1343.

Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde

M. W. 314.89 C 15 H 23 ClO 3 Si

To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added potassium carbonate (20 g, 145 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10 g, 42 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (EtOAc:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a white solid (Yield 10 g, 99%).

Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 428.12 C 20 H 34 ClNO 3 Si 2

In a manner similar to the method described in example 1b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (5.2 g, 17 mmol) prepared in example 131a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (1.6 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 531.83 C 26 H 21 Cl 3 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.6 g, 1.5 mmol) was reacted with 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (5.2 g, 12 mmol) prepared in example 131b in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-2′-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.25 g, 31%).

HRMS (ES + ) m/z Calcd for C 26 H 21 Cl 3 N 2 O 4 +H [(M+H) + ]: 531.0640. Found: 531.0640.

Preparation of intermediate tert-Butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane

M. W. 304.87 C 14 H 22 ClFO 2 Si

To a solution of 4-chloro-3-fluoro-phenol (10 g, 68 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (19 g, 136 mmol), potassium iodide (11 g, 68 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18 g, 75 mmol, Aldrich). The reaction mixture was heated at 100° C. for 24 h. The crude was cooled, diluted with ethyl ether, washed with water, NaHCO 3 solution, and brine. The organic layer was separated, dried over Na 2 SO 4 , and concentrated. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:20) to give tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane as colorless oil (Yield 14 g, 69%).

Preparation of intermediate 6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde

M. W. 332.88 C 15 H 22 ClFO 2 Si

In a manner similar to the method described in example 52a, tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane (14.3 g, 47 mmol) prepared in example 132a was reacted with lithium diisopropylamine (34 mL, 1.8 M in THF, 61 mmol), N,N-dimethyl-formamide (4.7 mL, 61 mmol) and quenched with acetic acid (14 g, 234 mmol) in tetrahydrofuran to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde as a white solid (Yield: 6.4 g, 41%).

Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy-3-chloro-2-fluoro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 446.11 C 20 H 33 C l FNO 3 Si 2

In a manner similar to the method described in example 1b, 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde (3.3 g, 10 mmol) prepared in example 132b was reacted with 1,1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy-3-chloro-2-fluoro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as an orange oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-[3-chloro-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 549.82 C 26 H 20 Cl 3 FN 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol) was reacted with 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (3 g, 6.7 mmol) prepared in example 132c in toluene and then trifluoroacetic acid (10 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-2′-[3-chloro-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.28 g, 40%).

HRMS (ES + ) m/z Calcd for C 26 H 20 Cl 3 FN 2 O 4 +H [(M+H) + ]: 549.0546 Found: 549.0545.

Preparation of intermediate E/Z-6-Chloro-3-(3,5-difluoro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one

M. W. 421.95 C 21 H 22 ClF 2 NO 2 Si

In a manner similar to the methods described in example 4a, 55a, 3,5-difluoro-benzaldehyde (0.89 g, 6.27 mmol) in place of 3-chlorobenzaldehyde was reacted in two steps to give E/Z-6-Chloro-3-(3,5-difluoro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one as a yellow oil (1.25 g, 50% for two steps).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3,5-difluoro-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 416.86 C 22 H 19 ClF 2 N 2 O 2

In a manner similar to the method described in example 97a, 55d, E/Z-6-Chloro-3-(3,5-difluoro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (0.21 g, 0.5 mmol) prepared in example 133a was reacted with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (1 g, 5.25 mmol) prepared in example 80a in toluene, then treated with trifluoroacetic acid (5 ml) in dichloromethane, followed by treatment with diisopropylethylamine (1 mL) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (35 mg, 18% for two steps).

HRMS (ES + ) m/z Calcd for C 22 H 19 ClN 2 O 2 F 2 +H[(M+H)]: 417.1176; Found: 417.1177

Preparation of intermediate E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile

M. W. 280.72 C 16 H 9 ClN 2 O

In a manner similar to the method described in example 1a, 3-formyl-benzonitrile was used in place of 3-chlorobenzaldehyde to form E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile as a yellow solid.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-cyano-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 405.89 C 23 H 20 ClN 3 O 2

E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (280 mg, 1 mmol) prepared in example 134a was heated with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene freshly prepared in example 80a (2.06 g, 10.5 mmol) in toluene (20 mL) in a sealed tube at 135° C. for 1 h, then cooled to room temperature. Methanol (80 mL) was added, and the mixture was filtered through a short pad of celite. The filtrate was concentrated, the residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-cyano-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (180 mg, 35%).

HRMS (ES + ) m/z Calcd for C 23 H 20 ClN 3 O 2 +H [(M+H)]: 406.1317; Found: 406.1315

Preparation of racemic (2′R,3R,4′S)-4′-(3-Bromo-phenyl)-6-chloro-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.77 C 22 H 20 BrClN 2 O 2

In a manner similar to the methods described in example 134a, 134b, 3-bromo-benzaldehyde was used in place of 3-formyl-benzonitrile in two steps to give racemic (2′R,3R,4′S)-4′-(3-bromo-phenyl)-6-chloro-2′-(1-methyl ene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (142 mg).

HRMS (ES + ) m/z Calcd for C 22 H 20 BrClN 2 O 2 +H [(M+H)]: 459.0470; Found: 459.0469

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-methoxy-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 410.90 C 23 H 23 ClN 2 O 3

In a manner similar to the methods described in example 134a, 134b, 3-methoxy-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-methoxy-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (20 mg).

HRMS (ES + ) m/z Calcd for C 23 H 23 ClN 2 O 3 +H[(M+H)]: 433.1289; Found; 433.1288

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-fluoro-2-methyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 412.90 C 23 H 22 ClFN 2 O 2

In a manner similar to the methods described in example 134a, 134b, 5-fluoro-2-methyl-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-4′-(5-fluoro-2-methyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 15%).

HRMS (ES + ) m/z Calcd for C 23 H 22 ClFN 2 O 2 +Na [(M+Na)]: 435.1246; Found: 435.1243

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-fluoro-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 398.87 C 22 H 20 ClFN 2 O 2

In a manner similar to the methods described in example 134a, 134b, 3-fluoro-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-fluoro-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 17%).

HRMS (ES + ) m/z Calcd for C 22 H 20 ClFN 2 O 2 +H [(M+H)]: 399.1270; Found: 399.1267

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-m-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 394.90 C 23 H 23 ClFN 2 O 2

In a manner similar to the methods described in example 134a, 134b, 3-methyl-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-m-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 130 mg, 33%).

HRMS (ES + ) m/z Calcd for C 23 H 23 ClFN 2 O 2 +H [(M+H)]: 395.1521; Found: 395.1521

Preparation of racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-o-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 394.90 C 23 H 23 ClFN 2 O 2

In a manner similar to the methods described in example 134a, 134b, 2-methyl-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-o-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 55 mg, 14%).

HRMS (ES + ) m/z Calcd for C 23 H 23 ClFN 2 O 2 +H[(M+H)]: 395.1521; Found: 395.1521

Preparation of racemic (2′R,3R,4′R)-6-chloro-2′-(1-methylene-propyl)-4′-thiophen-3-ylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 386.90 C 20 H 19 ClN 2 O 2 S

In a manner similar to the methods described in example 134a, 134b, thiophene-3-carbaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-thiophen-3-ylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 74 mg, 19%).

HRMS (ES + ) m/z Calcd for C 20 H 19 ClN 2 O 2 S+H[(M+H)]: 387.0929; Found: 387.0929

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3,5-dichloro-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 449.77 C 22 H 19 Cl 3 N 2 O 2

In a manner similar to the methods described in example 134a, 134b, 3,5-dichloro-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-4′-(3,5-dichloro-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 50 mg, 11%).

HRMS (ES + ) m/z Calcd for C 22 H 19 Cl 3 N 2 O 2 +H [(M+H)]: 449.0585; Found: 449.0585

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-trifluoromethyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 483.32 C 23 H 19 Cl 2 F 3 N 2 O 2

In a manner similar to the methods described in example 134a, 134b, 5-chloro-2-trifluoromethyl-benzaldehyde was used in place of 3-formyl-benzonitrile to give racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-trifluoromethyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 50 mg, 10%).

HRMS (ES + ) m/z Calcd for C 23 H 19 Cl 2 F 3 N 2 O 2 +H[(M+H)]: 483.0849; Found: 483.0848

Preparation of racemic (2′R,3R,4′S)-4′-(3-Bromo-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 445.75 C 21 H 18 BrClN 2 O 2

In a manner similar to the method described in example 197, 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene freshly prepared in example 142a was used in place of 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 135a to give racemic (2′R,3R,4′S)-4′-(3-bromo-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 21 mg).

HRMS (ES + ) m/z Calcd for C 21 H 18 BrClN 2 O 2 +H [(M+H)]: 445.0313; Found: 445.0313

Preparation of intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one

M. W. 287.72 C 16 H 11 ClFNO

To the mixture of 6-chlorooxindole (3.6 g, 21.6 mmol) and 5-Fluoro-2-methyl-benzaldehyde (3.0 g, 21.6 mmol) in methanol (25 mL) was added pyrrolidine (1.53 g, 21.6 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 5.3 g, 85%).

Preparation of intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester

M. W. 359.79 C 19 H 15 ClFNO 3

To a solution of E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (0.20 g, 0.71 mmol) in dichloromethane (3 mL) at 0° C. was added ethyl chloroformate (0.10 mL, 1.1 mmol), followed by the addition of triethylamine (0.14 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na 2 SO 4 , and concentrated to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid. The crude product was purified by chromatography to obtain 75 mg yellow solid (Yield 1.7 g, 30%).

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester

M. W. 541.41 C 28 H 23 Cl 2 FN 2 O 4

To a toluene (15 ml) solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (30 ml) was added E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.16 g, 0.45 mmol) prepared in example 145b. The reaction tube was sealed and heated by microwave irradiation at 135° C. for 35 min. After the solution was cooled to room temperature, methanol (25 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:3) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 200 mg, 82%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 469.35 C 25 H 19 Cl 2 FN 2 O 2

To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester prepared in example 145c (0.20 g, 0.31 mmol) in methanol (12 mL) was added NaOH (22 mg, 0.56 mmol). The mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous HCl solution (1 N). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and then concentrated. The residue was purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (9 mg).

MS m/z (M+H) + : 469

Preparation of intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one

M. W. 417.99 C 22 H 25 ClFNO 2 Si

To a solution E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (5.0 g, 17.4 mmol) in N,N-dimethyl-formamide (40 mL) at 0° C. was added NaH (60% in mineral oil) (0.70 g, 17.4 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.9 g, 17.4 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na 2 SO 4 . The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 5.7 g, 78%).

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 599.61 C 31 H 33 Cl 2 FN 2 O 3 Si

To a toluene (12 ml) solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (50 mL) was added E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (0.30 g, 0.72 mmol) prepared in example 146a. The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 35 min at 135° C. After the solution was cooled to room temperature, methanol (25 mL) was added. The reaction solutions were concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:3) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (0.45 g)

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 713.76 C 37 H 43 Cl 2 FN 2 O 5 Si

To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.5 g, 4.18 mmol) prepared in example 146b in N,N-dimethyl-formamide (20 mL) at room temperature was added bromo-acetic acid tert-butyl ester (2.0 g, 10.4 mmol) and cesium carbonate (7.5 g, 23.0 mmol). The reaction mixture was stirred under nitrogen for 4 h, then was poured into saturated aqueous NH 4 Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (Yield 0.85 g).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 527.38 C 27 H 21 Cl 2 FN 2 O 4

To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.85 g, 1.19 mmol) prepared in example 146d in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1.57 mL, 8.70 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO 4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 440 mg, 70%).

MS m/z (M+H) + : 527

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 540.43 C 28 H 24 Cl 2 FN 3 O 3

The mixture of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.13 mmol) prepared in example 146d, Methylamine hydrochloride (11 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (69 mg, 0.533 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (29 mg as a white solid.

MS m/z [M+H] + : 540.

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-1′-(dimethylamino-carbonyl-methyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 554.45 C 29 H 26 Cl 2 FN 3 O 3

In a similar manner to the method described in example 147, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-1′-(dimethylamino-carbonyl-methyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was prepared.

MS m/z (M+H) + : 554

Preparation of racemic (2′S,3S,4′R)-1′-[(4-aminocarbonyl-piperidin-1-yl)carbonyl-methyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 637.54 C 33 H 31 Cl 2 FN 4 O 4

In a similar manner described in example 147, racemic (2′S,3S,4′R)-1′-[(4-aminocarbonyl-piperidin-1-yl)carbonyl-methyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was prepared.

MS m/z (M+H) + : 637

Preparation of racemic (2′S,3S,4′R)-1′-[(3-aminocarbonyl-piperidin-1-yl)carbonyl-methyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 637.54 C 33 H 31 Cl 2 FN 4 O 4

In a similar manner described in example 147, racemic (2′S,3S,4′R)-1′-[(3-aminocarbonyl-piperidin-1-yl)carbonyl-methyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was prepared.

MS m/z (M+H) + : 637

Preparation of racemic (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 526.40 C 27 H 22 Cl 2 FN 3 O 3

In a manner similar to the method described in example 146d and 146e racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (50 mg g, 0.08 mmol) was reacted with 2-bromo-acetamide (35 mg, 0.25 mmol) and cesium carbonate (163 mg, 0.50 mmol) in DMF (2 ml). The resulting residue was dissolved in a mixture solution of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO 4 and concentrated. The residue was triturated purified by Prep-HPLC to give racemic (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).

MS m/z (M+H) + : 526

Preparation of intermediate racemic (2′S,3S,4′R)-6-chloro-1′-(3-chloro-propyl)-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 676.14 C 34 H 38 Cl 3 FN 2 O 5 Si

Racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.40 g, 0.67 mmol) prepared in example 146a was reacted with LiH (0.13 g, 16.70 mmol) and 1-chloro-3-bromo-propane (0.63 g, 4.01 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI. After the solution was stirred overnight, the solution was poured into water. The water layer was extracted with ethyl acetate and the combined organic layers were dried, concentrated to obtain the crude product. The crude product was purified by chromatography to give racemic (2′S,3S,4′R)-6-chloro-1′-(3-chloro-propyl)-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (Yield: 0.11 g, 24%).

Preparation of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-1′-(dimethylamino-propyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 554.50 C 30 H 30 Cl 2 FN 3 O 2

To a solution of racemic (2′S,3S,4′R)-6-chloro-1′-(3-chloro-propyl)-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.11 g, 0.16 mmol) prepared in example 152a in N,N-dimethyl-formamide (3 mL) at room temperature was added dimethylamine hydrochloride (0.53 g, 6.53 mmol) and cesium carbonate (2.66 g, 8.16 mmol), and a catalytic amount of KI. The reaction mixture was stirred overnight, then the solution was poured into saturated aqueous NH 4 Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na 2 SO 4 and concentrated to obtain 110 mg yellow solid. To the yellow solid was added dichloromethane (10 mL) and trifluoracetic acid (10 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was separated and concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (2 mL) and the crude was heated at 100° C. for 1 h. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-1′-(dimethylamino-propyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (10 mg).

MS m/z (M+H) + : 554

Preparation of intermediate racemic (2′S,3S,4′R)-1′-[(tert-butoxycarbonylamino)ethyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 742.80 C 38 H 46 Cl 2 FN 3 O 5 Si

In a manner similar to the method described in example 152a, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.45 g, 0.75 mmol) was reacted with LiH (0.15 g, 18.8 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 4.52 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI to give racemic (2′S,3S,4′R)-1′-[(tert-butoxycarbonylamino)ethyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (80 mg).

Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methanesulfonyl-piperidine-4-yl)carbonylamino-ethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 701.6 C 34 H 35 Cl 2 FN 4 O 5 S

Racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbamoy)ethyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 153a (80 mg) was added dichloromethane (5 mL) and then trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was separated and concentrated. The residue was redissolved in methanol (5 mL). To the resulting solution was added N,N′-diisopropylethylamine (2 mL) and the crude was heated at 100° C. for 1 h. The reaction mixture was concentrated. The mixture of the residue, 1-methanesulfonyl-piperidine-4-carboxylic acid (60 mg, 0.29 mmol), EDC.HCl (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and DIPEA (101 mg, 0.78 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methanesulfonyl-piperidine-4-yl)carbonylamino-ethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (14 mg).

MS m/z (M+H) + : 701

Preparation of intermediate E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one

M. W. 296.18 C 13 H 7 Cl 2 NOS

In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 4-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.3 g, 62%)

Preparation of racemic (2′R,3R,4′R)-6-chloro-4′-[2-(4-chloro-2-thiophenyl)]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 475.37 C 23 H 17 Cl 2 FN 2 O 2 S

In a manner similar to the method described in example 1c, E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one (0.2 g, 0.68 mmol) prepared in example 154a was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a to give racemic (2′R,3R,4′R)-6-chloro-4′-[2-(4-chloro-2-thiophenyl)]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an white solid (7 mg).

MS m/z (M+H) + : 475

Preparation of intermediate E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one

M. W. 296.18 C 13 H 7 Cl 2 NOS

In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 5-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 71%)

Preparation of racemic (2′R,3R,4′R)-6-chloro-4′-[2-(5-chloro-2-thiophenyl)]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine ]-2,6′(1H)-dione

M. W. 475.37 C 23 H 17 Cl 2 FN 2 O 2 S

In a manner similar to the method described in example 1c, E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one (0.2 g, 0.68 mmol) prepared in example 155a was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 6b to give racemic (2′R,3R,4′R)-6-chloro-4′-[2-(5-chloro-2-thiophenyl)]-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an white solid (6 mg).

MS m/z (M+H) + : 475

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(2,2-dimethylpropyl)-2′-(5-fluoro-2-methylphenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 428.94 C 24 H 26 ClFN 2 O 2

In a manner similar to the method described in example 1c, E/Z-6-Chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.2 g, 0.80 mmol) prepared in example 1a was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a to give racemic (2′R,3R,4′S)-6-chloro-4′-(2,2-dimethylpropyl)-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an white solid (7 mg).

MS m/z (M+H) + : 429

Preparation of intermediate E/Z-6-bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 334.60 C 15 H 9 BrClNO

To the mixture of 6-bromooxindole (16.2 g, 92 mmol) (Combi-block) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 16.2 g, 63%).

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 495.81 C 25 H 20 BrClN 2 O 2

To a solution of 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 17a in toluene (20 mL) was added E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole prepared in example 157a (0.3 g, 0.83 mmol). The reaction mixture was stirred and heated under microwave irradiation in a sealed tube at 135° C. for 0.5 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:3) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield 0.22 g, 53%).

MS m/z [(M+H) + ]: 495

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 513.80 C 25 H 19 BrClFN 2 O 2

In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 54%).

MS m/z [(M+H) + ]: 513

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 513.80 C 25 H 19 BrClFN 2 O 2

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg) prepared in example 158a was conducted by chiral column chromatography to provide chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 11 mg, 31%) and chiral (2′S,3S,4′R)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 11 mg, 31%).

MS m/z [(M+H) + ]: 513

Preparation of intermediate 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 288.25 C 12 H 15 Cl 2 NOSi

In a manner similar to the method described in example 1b, 2,5-dichloro-benzaldehyde (1.75 g, 10 mmol) was used as the starting material in place of 3-chlorobenzaldehyde to react with Lithium bis(trimethylsilyl)amide (1M solution in THF, 10 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 550.67 C 24 H 16 BrCl 3 N 2 O 2

In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 159a, in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2,5-dichlorophenyl)-2,6′-dioxospiro[indole-3,3′-piperidine as a white solid. (Yield 0.4 g, 67%).

MS m/z [(M+H) + ]: 549

Preparation of intermediate 1-(5-chloro-2-methyl phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 267.83 C 13 H 18 ClNOSi

In a manner similar to the method described in example 1b, 5-chloro-2-methyl-benzaldehyde (1.54 g, 10 mmol) was used as the starting material in place of 2-methylbenzaldehyde to react with react with Lithium bis(trimethylsilyl)amide (1M solution in THF, 10 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-chloro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 530.25 C 25 H 19 BrCl 2 N 2 O 2

In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(5-chloro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 160a, in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2,3-dihydro-2′-(5-chloro-2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine] as a white solid. (Yield 0.3 g, 51%).

MS m/z [(M+H) + ]: 529

Preparation of intermediate E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one

M. W. 464.87

C 21 H 23 BrClNO 2 Si

To a solution of E/Z 6-Bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 16 mmol) prepared in example 157a in N,N-dimethyl-formamide (50 mL) at 0° C. was added NaH (60% in mineral oil) (0.64 g, 16 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 16 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na 2 SO 4 . The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as a yellow oil (Yield 4.5 g, 60%).

Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 590.04 C 28 H 34 BrClN 2 O 3 Si

To a solution of 1-(1-ethyl-ethenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (42 mmol) prepared in example 80a in toluene (50 mL) was added E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (2 g, 4.3 mmol) prepared in example 161a. The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After cooling to room temperature, methanol (100 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:Hexane=2:1) gave racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a solid (Yield 350 mg).

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.77 C 22 H 20 BrClN 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (50 mg, 0.08 mmol) prepared in example 161b in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 0.5 h. After removing the solvent, the residue was dissolved in methanol (2 mL). To the resulting solution was added N,N′-diisopropylethylamine (1 mL). The reaction tube was then heated at 135 ° C. for 20 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to obtain racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as solid (30 mg).

Preparation of chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.77

C 22 H 20 BrClN 2 O 2

Racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg) was separated by chiral column chromatography to give chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (7 mg white solid) and chiral (2′S,3S,4′R)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (7 mg).

MS m/z [(M+H) + ]: 459

Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 604.06 C 29 H 36 BrClN 2 O 3 Si

CH 2 I 2 (1.2 g, 4.6 mmol) was dissolved in dry toluene (5 mL) at 0° C. After stirred for 10 min under Argon, Et 2 Zn (1 M in THF, 3.3 mL, 3.67 mmol) was added. After stirred for 15 min, a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (270 mg, 0.46 mmol) prepared in example 161b in dry toluene (10 mL) was added. After stirred at room temperature for 3 h, the reaction was quenched with saturated NH 4 Cl (20 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na 2 SO 4 , concentrated, the residue, was used for next step without further purification.

Preparation of chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 473.80 C 23 H 22 BrClN 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (48 mg, 0.079 mmol) prepared in example 162a in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 5 h. Then the solvent was removed in vacuo. The residue was dissolved in methanol (2 mL). To the resulting solution was added N,N′-diisopropylethylamine (1 mL). The mixture was heated at 135 ° C. for 20 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to obtain racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione. The racemic compound was separated by chiral column chromatography to obtain chiral (2R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (4.5 mg) and chiral (2S,3S,4′R)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (4.5 mg).

MS m/z [(M+H) + ]: 473

Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 573.92 C 28 H 30 BrClN 2 O 4

Racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (220 mg, 0.47 mmol) prepared in example 162b, (Boc) 2 O (121.9 mg, 0.56 mmol) and DMAP (73.9 mg, 0.61 mmol) were mixed in tetrahydrofuran (10 mL). After stirred for 0.5 h, the solution was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with 0.5N HCl aqueous solution for several times. Then the organic layer was dried and concentrated to obtain yellow solid (240 mg).

Preparation of intermediate racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-cyclopropyl-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 535.09 C 31 H 35 ClN 2 O 4

Under Argon atmosphere, racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (28 mg, 0.049 mmol), cyclopropylboronic acid (4.5 mg, 0.0524 mmol), Pd(PPh 3 ) 4 (5 mg), K 3 PO 4 (50 mg) and a few drops of water were mixed in toluene (3 mL). The mixture was heated under microwave irradiation at 130° C. for 20 min. Then the solution was poured into water and the aqueous layer was extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by Prep-TLC to obtain racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (10 mg).

Preparation of racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 434.97 C 26 H 27 ClN 2 O 2

Racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (10 mg, 0.019 mmol) was dissolved in a methanolic solution of HCl (6 M, 10 mL). After 10 min, the solution was concentrated to obtain racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield, 5.9 mg, 72%)

MS m/z [(M+H) + ]: 435

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 569.47 C 30 H 27 Cl 2 FN 2 O 4

To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.64 mmol) prepared in example 36c in dichloromethane (30 mL) was added 4-dimethylaminopyridine (94 mg, 0.77 mmol) and di-tert-butyl-dicarbonate (153 mg, 0.71 mmol). The mixture was stirred at room temperature for 30 min, and then purified by column chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as solid (350 mg, 96%).

Preparation of intermediate racemic (2′R,3R,4′S)-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2′-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 648.36 C 30 H 26 BrCl 2 FN 2 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (900 mg, 1.58 mmol) in carbon tetrachloride (20 mL) was added benzoyl peroxide (380 mg, 1.58 mmol) and NBS (280 mg, 1.58 mmol). The mixture was heated under microwave irradiation at 100 ° C. for 30 min, then purified by column chromatography to give racemic (2′R,3R,4′S)-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2′-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as solid (170 mg, 16%). The starting material racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (550 mg, 0.96 mmol) was recovered.

Preparation of racemic (2′R,3R,4′S)-2′-[2-(4-aminocarbonyl-piperidin-1-yl)methyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 595.51 C 31 H 29 Cl 2 FN 4 O 3

To a solution of racemic (2′R,3R,4′S)-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2′-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) prepared inex ample 164b in acetonitrile (5 mL) was added K 2 CO 3 (13 mg, 0.094 mmol) and piperidine-4-carboxylic acid amide (12 mg, 0.094 mmol). The mixture was refluxed for 2 h, then concentrated. The residue was purified by prep-HPLC to give racemic (2′R,3R,4′S) 2′-[2-(4-aminocarbonyl-piperidin-1-yl)methyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as solid (2.6 mg,).

MS m/z [(M+H) + ]: 595

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(4-methanesulfonyl-piperazin-1-yl)methyl-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 631.56 C 30 H 29 Cl 2 FN 4 O 4 S

To a solution of racemic (2′R,3R,4′S)-2′-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) prepared in example 164b in acetonitrile (5 mL) was added K 2 CO 3 (13 mg, 0.094 mmol) and 1-methanesulfonyl-piperazine (15 mg, 0.094 mmol). The mixture was refluxed for 2 h, concentrated. The residue was dissolved in trifluoroacetic acid and stirred at room temperature for 30 min, then concentrated and purified by prep-HPLC to give (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(4-methanesulfonyl-piperazin-1-yl)methyl-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as solid (5 mg, 17%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{5-fluoro-2-[(1-methanesulfonyl-piperidin-4-yl)carbonylamino-methyl]-phenyl}-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 673.6 C 32 H 31 Cl 2 FN 4 O 5 S

To aqueous ammonia solution (17%, 2 mL, ˜20 mmol) was added a solution of racemic (2′R,3R,4′S)-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2′-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) prepared in example 164b in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 2 h, followed by addition of EtOAc (20 mL). The organic phase was separated and washed by water, dried over Na 2 SO 4 . The solvent was removed in vacuo, and the residue was dissolved in dichloromethane. Then 1-methanesulfonyl-piperidine-4-carboxylic acid (20 mg) dimethylaminepiperidine (25 mg) and EDCI (40 mg) were added to the solution. The mixture was stirred at room temperature for 2 h, then diluted with dichloromethane, washed by aqueous HCl solution (1N, 10 mL), water (10 mL), dried over Na 2 SO 4 . The organic layer was separated, concentrated and the residue was purified by preparative HPLC to give the titled compound as solid (12 mg).

MS m/z [(M+H) + ]: 673

Preparation of intermediate 6-fluoro-1,3-dihydro-indol-2-one

M. W. 151.14 C 8 H 6 FNO

To a mixture of NaH (60%, 7 g, 0.16 mol) in dimethyl sulfoxide (150 mL) was added dropwise dimethyl malonate (20 mL, 0.16 mol). The mixture was heated to 100° C. for 10 min then cooled to room temperature, followed by the addition of 2,5-difluoronitrobenzene (14 g, 0.08 mol). After stirred at 90° C. for 2 h, the mixture was cooled and poured into 5% aq.HCl with ice cooling. EtOAc (50 mL) was added and the organic phase was separated, washed by water and dried with Na 2 SO 4 . The solvent was removed in vacuo to give 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (19.4 g). 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (6 g, 22 mmol) was dissolved in glacial acetic acid (30 mL), the aqueous HCl (6N, 30 mL) was added and the reaction mixture were heated ar refluxing for 4 h, Iron power (5 g, 88 mmol) was added portionwise to the mixture and the refluxing was allowed to continue for another 2 h. The solvent was removed in vacuo and the remaining residue was extracted by EtOAc. The organic phase washed with aqueous HCl (1N), brine and dried over Na 2 SO 4 . concentrated to give the titled compound as a yellow solid (3 g, 89%).

MS m/z (M+H) + : 152

Preparation of intermediate E/Z-6-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 273.70 C 15 H 9 ClFNO

To the mixture of 6-fluorooxindole (13.9 g, 92 mmol) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 17.5 g, 64%).

MS m/z (M+H) + : 274

Preparation of chiral (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 452.89 C 25 H 19 ClF 2 N 2 O 2

In a manner similar to the method described in example 1c, E/Z-6-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 167b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.1 g). The racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was separated by chiral column chromatography to give the titled compounds as a white solid.

MS m/z (M+H) + : 453

Preparation of intermediate 6-methoxy-1,3-dihydro-indol-2-one

M. W. 163.18 C 9 H 9 NO 2

In a manner similar to the method described in example 167a, 1-chloro-4-methoxy-2-nitro-benzene (19 g, 0.1 mol) was reacted with dimethyl malonate (16 g, 0.2 mol), NaH and iron power to give 6-methoxy-1,3-dihydro-indol-2-one (3 g, 18%).

MS m/z (M+H) + : 164

Preparation of intermediate E/Z-6-methoxy-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 285.73 C 16 H 12 ClNO 2

To the mixture of 6-methoxyoxindole (1.60 g, 10 mmol) and 3-chloro-benzaldehyde (1.4 g, 10 mmol) in methanol (10 mL) was added pyrrolidine (0.82 mL, 10 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-methoxy-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 1.7 g, 60%).

MS m/z (M+H) + : 286

Preparation of racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxy spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 464.93 C 26 H 22 ClFN 2 O 3

In a manner similar to the method described in example 1c, E/Z-6-methoxy-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 168b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxy spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.05 g, 10%).

MS m/z (M+H) + : 465

Preparation of intermediate E/Z-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 255.71 C 15 H 10 ClNO

To the mixture of oxindole (2.66 g, 20 mmol) and 3-chloro-benzaldehyde (2.81 g, 20 mmol) in methanol (20 mL) was added pyrrolidine (1.65 mL, 20 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 4 g, 78%).

MS m/z (M+H) + : 256

Preparation of racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 434.90 C 25 H 20 ClFN 2 O 2

In a manner similar to the method described in example 1c, E/Z-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 169a was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 15%).

MS m/z (M+H) + : 435

Preparation of intermediate 5-fluoro-1,3-dihydro-indol-2-one

M. W. 151.14 C 8 H 6 FNO

To the solution of 3-fluorophenylacetic acid (1.23 g, 8 mmol) in concentrated H 2 SO 4 (2.0 mL, 40 mmol) at 0° C. was added HNO 3 (0.374 mL, 8 mmol) slowly. The resulting reaction mixture was stirred under argon for 2 h at 0° C., and poured into ice-water. The white solid was precipitated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na 2 SO 4 , and concentrated. The crude (5-fluoro-2-nitro-phenyl)-acetic acid was dissolved in acetic acid. To the solution was added iron power (1.79 g, 32 mmol). The reaction mixture was stirred and heated at reflux for 2 h. Then the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, and The organic layer was separated, washed by aqueous HCl (1N), brine, dried over Na 2 SO 4 , concentrated in vacuo to give the desired product (1 g, 82%).

MS m/z (M+H) + : 152

Preparation of intermediate E/Z-5-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one

M. W. 273.70 C 15 H 9 ClFNO

To the mixture of 5-fluorooxindole (3.00 g, 20 mmol) and 3-chloro-benzaldehyde (2.8 g, 20 mmol) in methanol (20 mL) was added pyrrolidine (1.72 mL, 10 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-5-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 1.7 g, 30%).

MS m/z (M+H) + : 274

Preparation of racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 452.89 C 25 H 19 ClF 2 N 2 O 2

In a manner similar to the method described in example 1c, E/Z-5-fluoro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 170b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-5-fluoro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 2 g, 41%).

MS m/z (M+H) + : 453

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 501.41 C 26 H 26 Cl 2 N 2 O 2

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 1 mmol) prepared in example 87c in dichloromethane (10 mL) at 0° C. was added di-tert-butyl-dicarbonate (0.47 g, 2 mmol), followed by the addition of 4-dimethylaminopyridine (0.29 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 1 h, then poured into ice-water. The organic layer was separated, washed by aqueous HCl (0.5 N), dried over Na 2 SO 4 , concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white solid. (Yield 0.47 g, 95%).

MS m/z (M+H) + : 501

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 415.32 C 22 H 20 Cl 2 N 2 O 2

To a solution of CH 2 I 2 (1.2 g, 4.6 mmol) in anhydrous toluene (5 mL) under Argon at 0° C. was added a toluene solution of Et 2 Zn (1.1M, 3.3 ml, 3.67 mmol). The mixture was stirred for 15 min, then a toluene solution (10 mL) of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (230 mg, 0.46 mmol) prepared in example 171a was added. The reaction mixture was stirred at room temperature for 3 h, then quenched with aqueous saturated NH 4 Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na 2 SO 4 and concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (162 mg). Then racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione by chiral SFC to give chiral (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (50 mg).

HRMS (ES + ) m/z Calcd for C 22 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 415.0975 Found: 415.0975.

Preparation of intermediate E/Z-6-Bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 434.72 C 20 H 17 BrClNO 3

In a manner similar to the method described in example 24a, E/Z-6-bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (2.4 g, 7.2 mmol) prepared in example 157a was reacted with di-tert-butyl-dicarbonate (1.86 g, 10 mmol) and 4-dimethylaminopyridine (1.46 g, 12 mmol) to give E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield 1.5 g, 48%).

MS m/z (M+H) + : 434

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 445.75 C 21 H 18 BrClN 2 O 2

In a manner similar to the method described in example 41b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 12.8 mmol) prepared in example 172a was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 87b in toluene, then treated with trifluoroacetic acid to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 2.2 g, 40%).

MS m/z (M+H) + : 445

Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester

M. W. 545.87 C 26 H 26 BrClN 2 O 4

In a manner similar to the method described in example 171a, racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 1 mmol) prepared in example 172b was reacted with ditert-butyl-dicarbonate (0.24 g, 1 mmol) and 4-dimethylaminopyridine (0.15 g, 1.2 mmol) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester as a white solid (Yield 0.49 g, 90%).

MS m/z (M+H) + : 545

Preparation of chiral (2′R,3R,4′S)-6-bromo-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.77 C 22 H 20 BrClN 2 O 2

In a manner similar to the method described in example 171b, racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester (250 mg, 0.46 mmol) prepared in example 173a was reacted with CH 2 I 2 (1.2 g, 4.6 mmol) and Et 2 Zn (3.3 ml, 3.67 mmol) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 183 mg, 87%). The racemic (2′R,3R,4′S)-6-bromo-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was separated by chiral column chromatography to give chiral (2′R,3R,4′S)-6-bromo-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as white solid (15 mg).

MS m/z (M+H) + : 459

Preparation of racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 390.87 C 23 H 17 ClN 2 O 2

A mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester-1,3-dihydro-indole-2-one (54 mg, 0.1 mmol) prepared in example 173a, Pd(PPh 3 ) 4 (20 mg, 0.02 mmol), K 3 PO 4 (110 mg, 0.5 mmol), dimethyl trimethylsilylethynylborate (1 mL, 0.5 M, 0.5 mmol) in toluene (3 mL) was heated under microwave irradiation at 130° C. for 1 hour. The solvent was removed in vacuo. To the residue was added methanol (3 mL) and aqueous NaOH (2 N, 3 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was diluted with ethyl acetate (20 mL), washed with brine, saturated NH 4 Cl, brine, then organic layer was separated, and concentrated. The residue was purified by preparative HPLC to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2 mg).

Dimethyl trimethylsilylethynylborate solution was prepared according to literature procedure in Lutzen, L. et al Synthesis, 2006, No 3, 519-527

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methylsulphonyl-4-piperidinyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 687.62 C 33 H 33 Cl 2 FN 4 O 5 S

The 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetic acid salt (111 mg, 0.38 mmol) was stirred with N-methyl morpholine (208 uL, 1.9 mmol) and DMAP (3 mg) in DMF (2 ml) for 5 min to obtain a clear solution. A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a in DMF (1 mL) was added and the mixture was heated in a microwave oven for 15 min at 100° C. The mixture was poured into water and was extracted with EtOAc (4×). The organic layer was washed with water, brine, dried and concentrated to give a yellow residue which was purified by a 12 g silica gel column eluted with 0-5% MeOH in methylene chloride. A white powder (74.3 mg, 60% yield) was obtained as desired racemic mixture. This was separated into two optically pure enantiomeric compounds (24 mg each) by chiral SFC using 30% methanol.

MS m/z (M+H) + : 687

Preparation of intermediate 4-[2-(1,1-Dioxo-isothiazolidin-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester

M. W. 333.45 C 14 H 27 N 3 O 4 S

To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol) and triethylamine (1 mL) in THF (10 ML), 3-chloro-propylsulfonyl chloride (Aldrich, 0.68 mL, 6.94 mmol) was added slowly at room temperature. The mixture was stirred for 30 minutes at and the reaction was quenched with water. The new mixture was extracted with ethyl acetate and the extracts were combined and dried (Na 2 SO 4 ). The solution was concentrated and the residue was dissolved in THF (20 mL) and Cs 2 CO 3 (500 mg), NaI (80 mg) were added and the mixture was stirred at reflux overnight. The mixture was cooled to room temperature and poured into water. The new mixture was extracted with ethyl acetate (3×15 mL) and the extracts were combined and dried (Na 2 SO 4 ). Removal of the solvent on a rotary evaporator gave a solid. 2.01 g.

MS m/z (M+H) + : 334

Preparation of intermediate 1-[2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl]-piperazine di-trifluoroacetic acid

M. W. 233.33 C 9 H 19 N 3 O 2 S

4-[2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.01 g) was treated with 30% TFA/CH 2 Cl 2 (10 mL) and the mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to give a solid. 2.46 g.

MS m/z (M+H) + : 234

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-{[4-(1,1-dioxido-2-isothiazolidinyl)ethyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 742.70 C 36 H 38 Cl 2 FN 5 O 5 S

In a manner similar to the method described in example 175, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 1-[2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl]-piperazine di-trifluoroacetic acid prepared in example 176b and chiral SFC separation to give chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methyl phenyl)-1′-{[4-(1,1-dioxido-2-isothiazolidinyl)ethyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′91H)-dione.

MS m/z (M+H) + : 742

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-{[3-(methylsulphonyl)propyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 715.68 C 35 H 37 Cl 2 FN 4 O 5 S

In a manner similar to the method described in example 176, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 1-[(3-methylsulfonyl)propyl]piperazine dihydrochloride (US23289) and chiral separation to give chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-{[3-(methylsulphonyl)propyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

MS m/z (M+H) + : 715

Preparation of intermediate 1-(2-Bromo-2-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 316.25 C 12 H 15 BrFNOSi

In a manner similar to the method described in example 1b, 2-bromo-2-fluoro-benzaldehyde (8.1 g, 40 mmol) (Alfa) was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (6.4 g, 40 mmol), n-butyllithium (2.5 M, 16 mL, 40 mmol), trimethylsilyl chloride (4.4 g, 40 mmol), triethylamine (5.6 g, 52 mmol) and acetyl chloride (4.1 g, 52 mmol) to give 1-(2-bromo-2-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-(2-bromo-5-fluorophenyl) 6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 534.22 C 24 H 16 BrCl 2 FN 2 O 2

To a stirred solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (3.76 g, 8.13 mmol) prepared in example 55a in toluene (40 mL), 1-(2-bromo-2-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.25 g, 32 mmol) prepared in example 178a was added and the mixture was stirred at reflux for 2.5 h. The reaction mixture was cooled to room temperature and methanol (20 mL) was added. The new mixture was stirred for 1 hr at room temperature and then passed through a short silica gel pad. The column was rinsed with 30% (EtOAc/Hexanes). The solvent was removed and the residue was purified by chromatography on an ISCO machine (0-44% EtOAc/Hexanes, 30 min.) to give a pale yellow solid. 4.22 g.

This solid (1.5 g, 2.12 mmol) was treated with TFA/CH 2 Cl 2 (30%) and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in methanol (20 mL). DIPEA (Aldrich, 2 mL) was then added and the mixture was stirred at reflux for 2 h. The solvent was removed and the residue was purified by chromatography on an ISCO machine (25-48% EtOAc/Hexanes, 30 min.) to give an off-white solid. 520 mg.

MS m/z (M+H) + : 534

Preparation of racemic (2′R,3R,4′S)-2′-6-chloro-4′-(3-chlorophenyl)-(2-ethynyl-5-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.34 C 26 H 17 Cl 2 FN 2 O 2

To a stirred solution of racemic (2′R,3R,4′S)-2′-(2-bromo-5-fluorophenyl) 6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.23 mmol) prepared in example 178b in DMF (2 mL), trimethylsilanyl-acetylene (Aldrich, 88 mg, 0.92 mmol), PdCl 2 (PPh 3 ) 2 (Aldrich, 10 mg) and Et 3 N (Aldrich, 0.35 mL) were added and the mixture was purged with nitrogen and then heated at 100° C. for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the stirred solution, KF (210 mg) was added and the new mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by chromatography on an ISCO machine (30-40 EtOAc/Hexanes, 30 min.) to give a pale yellow solid. 32 mg.

MS m/z (M+H) + : 479

Preparation of racemic (2′R,3R,4′S)-2′-6-chloro-4′-(3-chlorophenyl)-{5-fluoro-2-[3-(methanesulfonyl-methyl-amino)-prop-1-ynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 600.50 C 29 H 24 Cl 2 FN 3 O 4 S

To a stirred solution of racemic (2′R,3R,4′S)-2′-(2-bromo-5-fluorophenyl) 6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (63 mg, 0.12 mmol) prepared in example 178b in DMF (2 mL), N-methyl-N-prop-2-ynyl-methanesulfonamide (prepared by treatment of the amine chloride with triethylamine, methanesulfonyl chloride, 70 mg, 0.48 mmol), PdCl 2 (PPh 3 ) 2 (20 mg) and Et 3 N (0.5 mL) were added and the mixture was purged with nitrogen and then heated at 100° C. for 4 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on an ISCO machine (50% EtOAc/hexanes, 30 min.) to give a white solid. 20 mg.

MS m/z (M+H) + : 479

Preparation of intermediate 1-[5-bromo-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 472.57 C 20 H 34 BrNO 3 Si 2

In a manner similar to the method described in example 1b, 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (17.25 g, 48 mmol) prepared in example 130a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (8.28 g, 48 mmol), n-butyllithium (2.5 M, 19.2 mL, 48 mmol), trimethylsilyl chloride (6.07 mL, 48 mmol), triethylamine (8.7 mL, 62.5 mmol) and acetyl chloride (4.53 mL, 62 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxyethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 576.28 C 26 H 21 BrCl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2.5 g, 6.4 mmol) was reacted with 1-[5-bromo-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 181a in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (1.52 g, 41%).

MS m/z (M+H) + : 576

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 521.40 C 28 H 22 Cl 2 N 2 O 4

To a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.11 mmol) prepared in example 181b in DMF (2 mL), Et 3 N (0.3 mL), PdCl 2 (Ph 3 P) 2 (Aldrich, 15 mg) were added and the mixture was purged with nitrogen and sealed. The vessel was heated on a microwave reactor for 25 min. and the mixture was poured into water. The mixture was extracted with EtOAc. The extracts were combined and dried with sodium sulfate and dried to give a brown oil, which was purified by chromatography on an ISCO machine (30-100% EtOAc/Hexanes) to give a foam. 45 mg. The foam was then dissolved in methanol (4 mL) and KF (Aldrich, 53 mg) was added. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partioned between EtOAc/water. The organic layer was dried and concentrated and the residue was purified by chromatography on ISCO machine (30-100% EtOAc/Hexane) to give an off-white solid. 25 mg.

MS m/z (M+H) + : 521

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 521.40 C 28 H 22 Cl 2 N 2 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (65 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 26.3 mg, 40%) (RO5195715-000) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 25 mg, 38%).

Preparation of intermediate [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane

M. W. 349.32 C 14 H 22 BrFO 2 Si

In a manner similar to the method described in example 132a, 4-bromo-3-fluoro-phenol (12 g, 62.3 mmol) was reacted with K 2 CO 3 (26 g, 188 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18.0 g, 75.3 mmol) to give [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane as yellow oil (17.2 g, 77%).

Preparation of intermediate 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde

M. W. 377.33 C 15 H 22 BrFO 3 Si

In a manner similar to the method described in example 52a, 1 [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (17.2 g, 49.3 mmol) prepared in example 183a was reacted with lithium diisopropyl amide (32.8 mL, 2.0 M in THF, 59.1 mmol), N,N-dimethyl-formamide (4.57 mL, 59.1 mmol) and quenched with acetic acid (12.1 g, 197.2 mmol) and water (61.8 mL) in tetrahydrofuran to give 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde as white solid (Yield: 12 g, 67%).

Preparation of intermediate 1-{3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 490.57 C 20 H 33 BrFNO 3 Si 2

In a manner similar to the method described in example 1b, 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde (3.96 g, 10.5 mmol) prepared in example 183b was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13 mmol) and acetyl chloride (0.97 mL, 13 mmol) to give 1-{3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 594.27 C 26 H 20 BrCl 2 FN 2 O 4

To a solution of 1-{3-bromo-2-fluoro-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 183c in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO 3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride solution (1M in THF, 10 mL) was added. The reaction mixture was stirred at room temperature for 10 min, then poured into water and extracted with ethyl acetate. The combined organic layer was dried over MgSO 4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.4 g, 65.6%).

HRMS (ES + ) m/z Calcd for C 26 H 20 BrCl 2 FN 2 O 4 +H [(M+H) + ]: 593.0041. Found: 593.0039.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 611.58 C 31 H 29 Cl 2 FN 2 O 4 Si

To a solution of racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.202 mmol) prepared in example 183d in N,N-dimethyl formamide (1 mL) was added ethynyl-trimethyl-silane (0.28 mL, 2.0 mmol) (Aldrich) and triethylamine (0.127 g, 2.0 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(triphenyl-phosphine) (14 mg, 0.02 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for overnight. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as brown solid (Yield: 50 mg, 40.6%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 539.39 C 28 H 21 Cl 2 FN 2 O 4

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol) prepared in example 184a in methanol (2 mL) was added KF (9.5 mg, 0.16 mmol) (Aldrich). The reaction mixture was stirred at room temperature for overnight. The solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as brown solid.

HRMS (ES + ) m/z Calcd for C 28 H 21 Cl 2 FN 2 O 4 +H [(M+H) + ]: 539.0935. Found: 539.0935.

Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde

M. W. 308.50 C 17 H 28 O 3 Si

In a manner similar to the method described in example 130a, 5-ethyl-2-hydroxy-benzaldehyde (4.75 g, 31.7 mmol) was reacted with K 2 CO 3 (13.1 g, 95.1 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (9.09 g, 38.0 mmol) to give 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde as dark brown oil (9.0 g, 92.7%).

Preparation of intermediate 1-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 421.73 C 22 H 39 NO 3 Si 2

In a manner similar to the method described in example 1b, 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde (3.24 g, 10.5 mmol) prepared in example 185a was used as the starting material in place of 3-chloro-benzaldehyde to react with 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol), n-butyllithium (2.5 M, 4 mL, 10.5 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.4 g, 13 mmol) and acetyl chloride (1.0 g, 13 mmol) to give 1-{2-[2-(tert-butyl-dimethylsilanyloxy)-ethoxy]-5-ethyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 525.44 C 28 H 26 Cl 2 N 2 O 4

In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol) was reacted with 1-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 185b in toluene and then trifluoroacetic acid (20 mL) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethyl-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.20 g, 29.8%).

HRMS (ES + ) m/z Calcd for C 28 H 26 Cl 2 N 2 O 4 +H [(M+H) + ]: 525.1343 Found: 525.1343.

Preparation of Chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 502.40 C 25 H 25 Cl 2 N 3 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Example 120, 50 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (24 mg, 48%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (16 mg, 32%).

Preparation of Chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 458.35 C 23 H 21 Cl 2 N 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Example 116e, 37 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (11 mg, 30%) and chiral (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (9 mg, 24%).

Preparation of Chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 498.41 C 26 H 25 Cl 2 N 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Example 117, 50 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (12 mg, 24%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-(cyclopropylaminocarbonyl-methyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (14 mg, 28%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 530.46 C 27 H 29 Cl 2 N 3 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Example 121, 60 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (14 mg, 23%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (18 mg, 30%).

Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde

M. W. 406.34 C 15 H 23 IO 3 Si

To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K 2 CO 3 (11.17 g, 80.7 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.74 g, 32.3 mmol, Aldrich). The reaction mixture was heated at 65° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO 4 , concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde as a yellow oil (Yield 10 g, 100%).

Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 519.58 C 20 H 34 INO 3 Si 2

To 1,1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 8.4 mL, 21 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (60 mL) was added, followed by the addition of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde (8.53 g, 21 mmol) prepared in Example 190c. After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (2.66 mL, 21 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (3.8 mL, 27.2 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (1.94 mL, 27.2 mmol) in diethyl ether (100 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow oil and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 623.28 C 26 H 21 Cl 2 IN 2 O 4

To a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 190b (21 mmol) in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (1.2 g, 3.1 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, the reaction mixture was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (20 mL) was added. After the reaction mixture was stirred at room temperature for 4 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO 3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1;3) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light yellow solid (Yield 0.46 g, 25%).

HRMS (ES + ) m/z Calcd for C 26 H 21 Cl 2 IN 2 O 4 +H [(M+H) + ]: 622.9996. Found: 622.9995.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-cyano-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 521.09 C 27 H 21 Cl 2 N 2 O 4

To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.16 mmol) prepared in Example 190c in triethylamine (0.8 mL) was added trimethylsilyl cyanide (23.8 mg, 0.24 mmol) (Aldrich), Tetrakis(triphenylphosphine)palladium (3.7 mg, Aldrich) sequentially. The reaction mixture was refluxed under nitrogen for 2 h. After cooled to room temperature, the reaction mixture was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-cyano-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 38 mg, 46%).

HRMS (ES + ) m/z Calcd for C 27 H 21 Cl 2 N 2 O 4 +H [(M+H) + ]: 522.0982. Found: 522.0984.

Preparation of intermediate 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 345.25 C 12 H 16 INOSi

In a manner similar to the method described in example 190b, 3-iodo-benzaldehyde (0.9 g, 3.88 mmol) (Aldrich) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (0.62 g, 3.88 mmol), n-butyllithium (2.5 M, 1.6 mL, 3.88 mmol), trimethylsilyl chloride (0.42 g, 3.88 mmol), triethylamine (0.53 g, 5.28 mmol) and acetyl chloride (0.41 g, 5.28 mmol) to give 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 563.23 C 24 H 17 Cl 2 IN 2 O 2

To a solution of 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 192a (1.2 g, 3.5 mmol) in toluene (40 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (10 mL) was added. After the reaction mixture was stirred at room temperature for 0.5 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO 3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (EtOAc:CH 2 Cl 2 =1:3 then 1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.56 g, 77%).

HRMS (ES + ) m/z Calcd for C 24 H 17 Cl 2 IN 2 O 2 +H [(M+H) + ]: 562.9785. Found: 562.9786.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 461.35 C 26 H 18 Cl 2 N 2 O 2

A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.56 g, 1 mmol) prepared in example 192b in anhydrous tetrahydrofuran (30 mL) was added trimethylsilyl acetylene (0.1 g, 2.0 mmol) (Aldrich), CuI (0.38 g, 2.0 mmol) (Aldrich) and triethylamine (0.2 g, 2.0 mmol) was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium(0) (140 mg, 0.2 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added methanol (10 mL) and aqueous NaOH solution (1 N, 2 mL). The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated. The residue was purified with chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.24 g, 52%).

HRMS (ES + ) m/z Calcd for C 26 H 18 Cl 2 N 2 O 2 +H [(M+H) + ]: 461.0818. Found: 461.0818.

Preparation of intermediate 1-(2-fluoro-5-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 363.25 C 12 H 15 FINOSi

In a manner similar to the method described in example 190b, 2-fluoro-5-iodobenzaldehyde (2.62 g, 10.5 mmol) (Aldrich) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.14 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give crude 1-(2-fluoro-5-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-fluoro-5-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 581.22 C 24 H 16 Cl 2 FIN 2 O 2

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (1 g, 2.56 mmol) was reacted with crude 1-(2-fluoro-5-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 194a (10.5 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-fluoro-5-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.61 g, 41%)

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 FIN 2 O 2 +H [(M+H) + ]: 580.9691. Found: 580.9691.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.34 C 26 H 17 Cl 2 FN 2 O 2

In a manner similar to the method described in example 193, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-fluoro-5-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 194b (0.45 g, 0.77 mmol) was reacted with trimethylsilyl acetylene (1.1 mL, 7.7 mmol), CuI (10 mg), triethylamine (3.22 mL, 23 mmol), and dichlorobis(triphenylphosphine)palladium (54 mg, 0.077 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light brown solid (Yield 57 mg)

HRMS (ES + ) m/z Calcd for C 26 H 17 Cl 2 FN 2 O 2 +H [(M+H) + ]: 479.0724. Found: 479.0725.

Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde

M. W. 406.34 C 15 H 23 IO 3 Si

To a solution of 5-iodovanillin (10 g, 35.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K 2 CO 3 (14.9 g, 108 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10.3 g, 43 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO 4 , concentrated, and purified by chromatography to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde as a yellow oil (Yield 15 g, 96%).

Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 549.60 C 21 H 36 INO 4 Si 2

In a manner similar to the method described in example 190b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde (4.58 g, 11 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.18 mL, 11 mmol), n-butyllithium (2.5 M, 4.2 mL, 11 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give crude 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-iodo-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 653.31 C 27 H 23 Cl 2 IN 2 O 5

In a manner similar to the method described in example 190c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (1 g, 2.56 mmol) was reacted with 1-[2-(tert-butyldimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 196b (11 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-iodo-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.62 g, 42%).

HRMS (ES + ) m/z Calcd for C 27 H 23 Cl 2 IN 2 O+H [(M+H) + ]: 653.0102. Found: 653.0102.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 551.43 C 29 H 24 Cl 2 N 2 O 5

In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-iodo-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 196c (0.3 g, 0.46 mmol) was reacted with trimethylsilyl acetylene (0.65 mL, 4.6 mmol), CuI (10 mg), triethylamine (1.9 mL, 13.8 mmol), and dichlorobis(triphenylphosphine)palladium (32 mg, 0.046 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light brown solid (Yield 28 mg).

HRMS (ES + ) m/z Calcd for C 29 H 24 Cl 2 N 2 O 5 +H [(M+H) + ]: 551.1135. Found: 551.1136.

Preparation of intermediate 5-Iodo-2-methyl-benzaldehyde

M. W. 246.05 C 8 H 7 IO

To a solution of 5-iodo-2-methyl benzoic acid (24 g, 91 mmol) (AKSCI) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 250 mL, 250 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated to give an off-white solid. The solid was dissolved into dichloromethane (300 mL), and activated MnO 2 (20 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-Iodo-2-methyl-benzaldehyde as an off-white solid (Yield 5.5 g, 25%).

Preparation of intermediate 1-(5-iodo-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 359.28 C 13 H 18 INOSi

In a manner similar to the method described in example 190b, 5-iodo-2-methylbenzaldehyde prepared in example 198a (5.4 g, 22 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (3.53 g, 22 mmol), n-butyllithium (2.5 M, 8.8 mL, 22 mmol), trimethylsilyl chloride (2.22 g, 22 mmol), triethylamine (3 mL, 30 mmol) and acetyl chloride (2.34 g, 30 mmol) to give crude 1-(5-iodo-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 577.25 C 25 H 19 Cl 2 IN 2 O 2

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2.2 g, 5.6 mmol) was reacted with 1-(5-Iodo-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 198b (6.8 g, 19 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 2.5 g, 77%)

HRMS (ES + ) m/z Calcd for C 25 H 19 Cl 2 IN 2 O 2 +H [(M+H) + ]: 576.9941. Found: 576.9942.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 475.38 C 27 H 20 Cl 2 N 2 O 2

In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 198c (0.27 g, 0.47 mmol) was reacted with trimethylsilyl acetylene (92 mg, 0.94 mmol), CuI (0.18 g, 0.94 mmol), triethylamine (95 mg, 0.94 mmol), and dichlorobis(triphenylphosphine)palladium (66 mg, 0.094 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.12 g, 54%)

HRMS (ES + ) m/z Calcd for C 27 H 20 Cl 2 N 2 O 2 +H [(M+H) + ]: 475.0975. Found: 475.0977.

Preparation of Chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 539.39 C 28 H 21 Cl 2 FN 2 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Example 184b, 70 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (32 mg, 47%) and chiral (2′R,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (31 mg, 44%).

Preparation of intermediate 5-Iodo-2-nitro-benzaldehyde

M. W. 277.02 C 7 H 41 NO 3

To a solution of 5-iodo-2-nitrobenzoic acid (37 g, 126 mmol) (APIN) in anhydrous tetrahydrofuran (200 mL) at 0° C. was added borane tetrahydrofuran (1 M, 360 mL, 360 mmol) dropwise. The reaction mixture was then stirred at room temperature for 24 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO 4 , concentrated, and triturated. The precipitate 5-Iodo-2-nitro-phenyl)-methanol was collected as a yellow solid (20 g, 57%). The solid (5.5 g) was dissolved into dichloromethane (100 mL), and activated MnO 2 (15 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated to give 5-Iodo-2-nitro-benzaldehyde as a yellow solid (Yield 4.2 g, 76%).

Preparation of intermediate 1-(5-iodo-2-nitrophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 390.26 C 12 H 15 IN 2 OSi

In a manner similar to the method described in example 190b, 5-iodo-2-nitrobenzaldehyde prepared in Example 201a (4.2 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (2.1 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1-(5-Iodo-2-nitrophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 608.22 C 24 H 16 Cl 2 IN 3 O 4

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2 g, 5 mmol) was reacted with 1-(5-iodo-2-nitrophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 201b (15 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 1.8 g, 59%)

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 2 IN 3 O 4 +H [(M+H) + ]: 607.9636. Found: 607.9638.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 506.35 C 26 H 17 Cl 2 N 3 O 4

In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 201c (0.36 g, 0.59 mmol) was reacted with trimethylsilyl acetylene (120 mg, 1.18 mmol), CuI (0.23 g, 1.18 mmol), triethylamine (120 mg, 1.18 mmol), and dichlorobis(triphenylphosphine)palladium(0) (83 mg, 0.118 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 84%)

HRMS (ES + ) m/z Calcd for C 26 H 17 Cl 2 N 3 O 4 +H [(M+H) + ]: 506.0669. Found: 506.0671.

Preparation of racemic (2′R,3R,4′S)-2′-(2-amino-5-iodophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 578.24 C 24 H 18 Cl 2 IN 3 O 2

To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 201c (0.7 g, 1.15 mmol) in methanol (50 ml) was added aqueous NH 4 Cl solution (0.61 g, 11.5 mmol, 20 mL), followed by addition of Zn powder (0.75 g, 11.5 mmol). The reaction mixture was stirred at room temperature for 1 h, then filtered throught a short pad of celite. The filtrate was concentrated, extracted with ethyl acetate and dichloromethane. The organic layers were combined, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (EtOAc, then EtOAc:MeOH=19;1) to give racemic (2′R,3R,4′S)-2′-(2-amino-5-iodophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.41 g, 61%)

HRMS (ES + ) m/z Calcd for C 24 H 18 Cl 2 IN 3 O 2 +H [(M+H) + ]: 577.9894. Found: 577.9894.

Preparation of racemic (2′R,3R,4′S)-2′-(2-amino-5-ethynylphenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 476.37 C 26 H 19 Cl 2 N 3 O 2

In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-2′-(2-amino-5-iodophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 203 (0.2 g, 0.35 mmol) was reacted with trimethylsilyl acetylene (68 mg, 0.69 mmol), CuI (0.13 g, 0.69 mmol), triethylamine (70 mg, 0.69 mmol), and dichlorobis(triphenylphosphine)palladium (49 mg, 0.069 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-2′-(2-amino-5-ethynylphenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 84%)

HRMS (ES + ) m/z Calcd for C 26 H 19 Cl 2 N 3 O 2 +H [(M+H) + ]: 476.0927. Found: 476.0929.

Preparation of intermediate 1-(3-bromo-4-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 316.25 C 12 H 15 BrFNOSi

In a manner similar to the method described in example 190b, 3-bromo-4-fluorobenzaldehyde (4.6 g, 21 mmol) (Lancaster) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol), n-butyllithium (2.5 M, 8.4 mL, 21 mmol), trimethylsilyl chloride (2.66 mL, 21 mmol), triethylamine (3.8 mL, 27.2 mmol) and acetyl chloride (1.94 mL, 27.2 mmol) to give crude 1-(3-bromo-4-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-(3-bromo-4-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 534.22 C 24 H 16 BrCl 2 FN 2 O 2

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2 g, 5.6 mmol) was reacted with crude 1-(3-bromo-4-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 20a (10.5 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-2′-(3-bromo-4-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 2 g, 67%)

HRMS (ES + ) m/z Calcd for C 24 H 16 BrCl 2 FN 2 O 2 +H [(M+H) + ]: 532.9829. Found: 532.9832.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-4-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 479.34 C 26 H 17 Cl 2 FN 2 O 2

In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-2′-(3-bromo-2-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 205b (0.3 g, 0.56 mmol) was reacted with trimethylsilyl acetylene (0.8 mL, 5.6 mmol), CuI (10 mg), triethylamine (2.34 mL, 16.8 mmol), and dichlorobis(triphenylphosphine)palladium(0) (39 mg, 0.056 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-4-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a grey solid (Yield 56 mg)

HRMS (ES + ) m/z Calcd for C 26 H 17 Cl 2 FN 2 O 2 +H [(M+H) + ]: 479.0724. Found: 479.0724.

Preparation of intermediate 1-(1-benzofuran-5-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 259.38 C 14 H 17 NO 2 Si

In a manner similar to the method described in example 190b, 1-benzofuran-5-carbaldehyde (1.2 g, 10 mmol) (Maybr-INT) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 mL, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1 g, 13.6 mmol) to give crude 1-(1-benzofuran-5-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-(1-benzofuran-5-yl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 477.35 C 26 H 18 Cl 2 N 2 O 3

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (0.4 g, 1.4 mmol) was reacted with crude 1-(1-benzofuran-5-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 207a (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-2′-(1-benzofuran-5-yl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 45%)

HRMS (ES + ) m/z Calcd for C 26 H 18 Cl 2 N 2 O 3 +H [(M+H) + ]: 477.0767. Found: 477.0767.

Preparation of intermediate 5-chloro-2-Iodo-benzaldehyde

M. W. 266.47 C 7 H 4 ClIO

To a solution of 5-chloro-2-iodo benzoic acid (4.92 g, 17 mmol) (TRANS) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 34 mL, 34 mmol) dropwise. The reaction mixture was then stirred at room temperature for 18 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated to give a colorless oil. The oil was dissolved into 1,2-dichloroethane (50 mL), and activated MnO 2 (15 g) was added. The mixture was then heated at reflux for 2 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-chloro-2-Iodo-benzaldehyde as a white solid (Yield 5.5 g, 25%).

Preparation of intermediate 1-(5-chloro-2-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 379.70 C 12 H 15 ClINOSi

In a manner similar to the method described in example 190b, 5-chloro-2-iodobenzaldehyde prepared in example 208a (3.97 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (2 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1-(5-chloro-2-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-chloro-2-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 597.67 C 24 H 16 Cl 3 IN 2 O 2

In a manner similar to the method described in example 192b, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (2 g, 5.6 mmol) was reacted with crude 1-(5-chloro-2-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 208b (5.6 g, 15 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-chloro-2-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 2.1 g, 63%)

HRMS (ES + ) m/z Calcd for C 24 H 16 Cl 3 IN 2 O 2 +H [(M+H) + ]: 596.9395. Found: 596.9393.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 535.43 C 29 H 24 Cl 2 N 2 O 4

To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c in dioxane (10 mL) was added CuI (5 mg, 0.026 mmol) (Aldrich). The mixture was degassed under nitrogen for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.026 mmol, Strem), tri-phenylphosphine (6.7 mg, 0.026 mmol), and tributyl(1-propynyl)tin (1.1 g, 3.2 mmol, Aldrich) were added sequentially. The reaction mixture was heated at 80° C. under nitrogen for 1 h. After cooled to room temperature, the reaction mixture was filtered through a short pad of celite. The filtrate was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.17 g, 99%).

HRMS (ES + ) m/z Calcd for C 29 H 24 Cl 2 N 2 O 4 +H [(M+H) + ]: 535.1186. Found: 535.1187.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 535.43 C 29 H 24 Cl 2 N 2 O 4

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 209a (200 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (50 mg, 25%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (49 mg, 25%).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3,3-dimethyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 577.51 C 32 H 30 Cl 2 N 2 O 4

A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.15 g, 0.24 mmol) prepared in Example 190c in anhydrous N,N-dimethylformamide (10 mL) was added CuI (3 mg), 3,3-dimethyl-1-butyne (19.7 mg, 2.4 mmol) (Aldrich), and triethylamine (1 mL, 7.2 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium (8.4 mg, 0.012 mmol) (Strem) was added and the reaction mixture was heated at 80° C. under nitrogen for 0.5 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3,3-dimethyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 41 mg, 30%).

HRMS (ES + ) m/z Calcd for C 32 H 30 Cl 2 N 2 O 4 +H [(M+H) + ]: 577.1656. Found: 577.1655.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-cyclopropyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 561.47 C 31 H 26 Cl 2 N 2 O 4

In a manner similar to the method described in example 209, ethynylcyclopropane (0.16 g, 2.4 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.15 g, 0.24 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (1 mL, 7.2 mmol), and dichlorobis(triphenylphosphine)palladium(0) (8.4 mg, 0.012 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-cyclopropyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 84 mg, 62%)

HRMS (ES + ) m/z Calcd for C 31 H 26 Cl 2 N 2 O 4 +H [(M+H) + ]: 561.1343. Found: 561.1344.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 563.49 C 31 H 28 Cl 2 N 2 O 4

In a manner similar to the method described in example 209a, 3-methyl-1-butyne (0.22 g, 3.2 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (0.97 g, 9.6 mmol), and dichlorobis(triphenylphosphine)palladium (11.2 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 50 mg, 28%)

HRMS (ES + ) m/z Calcd for C 31 H 28 Cl 2 N 2 O 4 +H [(M+H) + ]: 563.1499. Found: 561.1501.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-vinyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 523.41 C 28 H 24 Cl 2 N 2 O 4

To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.16 mmol) prepared in Example 190c in dioxane (10 mL) was added CuI (5 mg, 0.026 mmol) (Aldrich). The mixture was degassed under nitrogen for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (11.7 mg, 0.013 mmol, Strem), tri-phenylphosphine (3.35 mg, 0.013 mmol), and tributyl(vinyl)tin (46 uL, 1.0 mmol, Aldrich) were added sequentially. The reaction mixture was heated at 60° C. under nitrogen for 2 h. After cooled to room temperature, the reaction mixture was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-vinyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 80 mg, 96%).

HRMS (ES + ) m/z Calcd for C 28 H 24 Cl 2 N 2 O 4 +H [(M+H) + ]: 523.1186. Found: 523.1187.

Preparation of intermediate 4-iodo-2-tert-butyl-dimethylsilanyloxy-benzaldehyde

M. W. 362.29 C 13 H 19 IO 2 Si

To a stirred solution of 5-iodo-2hydroxy-benzaldehyde (Aldrich, 15.5 g, 62.5 mmol) in methylene chloride (100 mL) were added imidazole (Aldrich, 4.28 g, 63 mmol) and tert-butyl-dimethyl-chloro-silane (Aldrich, 9.45 g, 63 mmol). The mixture was stirred at room temperature for 5.5 hrs and then poured into 1 N sodium hydroxide solution (150 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×50 mL). The combined extracts were washed with water, brine and dried over magnesium sulfate. Removal of the solvent gave an oil, which was chromatographed (hexane as eluent) to give a colorless oil. 16.6 g.

Preparation of intermediate 1-[5-bromo-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3-trimethylsilanyloxy-2-aza-1,3-butadiene

M. W. 475.52 C 18 H 30 INO 2 Si 2

To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (6.4 g, 40 mmol) at 0° C., n-Buli (2.5 M, 16 mL) was added slowly and the mixture was stirred for 15 min. Then THF (80 mL) was added followed by 4-iodo-2-tert-butyl-dimethylsilanyloxy-benzaldehyde (14.48 g, 40 mmol). The mixture was stirred at rt for 30 min. Then, trimethylsilanyl chloride (40 mmol), acetyl chloride (40 mmol) and trimethylamine (40 mmol) were added and the mixture was stirred at rt for 1 hr. The mixture was quickly passed through a short pad of silica gel and the pad was washed with 30 EtOAc/Hexanes to make sure the azadiene has completely passed through. The filtrate was concentrated at rt and directly used for the next step.

Preparation of intermediate racemic (2′R,3R,4′S)-2′-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 793.61 C 35 H 39 Cl 21 N 2 O 5 Si

E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (3.85 g, 13 mmol) and 1-[5-bromo-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3-trimethylsilanyloxy-2-aza-1,3-butadiene (40 mmol) were combined into toluene (110 mL). The mixture was stirred at 110° C. for 2 hrs. The solvent was removed and the residue was chromatographed (15%-35% EtOAc/Hexanes) to give a foam. 4.65 g. MS (H + ), 693.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 579.23 C 24 H 17 Cl 2 IN 2 O 3

Racemic (2′R,3R,4′S)-2′-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (200 mg, 0.25 mmol) was dissolved in 30% TFA/CH 2 Cl 2 (5 mL) and the solution was stirred at rt for 2 h. The solvent was removed and the residue was partioned between water and methylene chloride. The organic layer was separated and dried with sodium sulfate and concentrated. The residue was chromatographed to give a white solid which was directly used for next step. MS (H + ), 579.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 549.53 C 29 H 26 Cl 2 N 2 O 3 Si

To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (100 mg) in DMF (2 mL) were added PdCl 2 (PPh 3 ) 2 (18 mg), CuI (4 mg), trimethylsilyl acetylene (Aldrich, 0.40 mL) and Et 3 N (Aldrich, 0.62 mL) and the mixture was purged with nitrogen and then heated at 83° C. for 3 hrs. The solvent was removed and the crude was directly used for next step. MS (H + ), 549.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-hydroxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 477.35 C 26 H 18 Cl 2 N 2 O 3

Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione was dissolved in methanol (10 mL). To the stirred solution, KF (Aldrich, 270 mg) was added and the mixture was stirred at rt overnight. The solvent was removed under reduced and the residue was treated with 6 mL of 5% MeOH in methylene chloride. The solid was filtered out and the filtrate was concentrated to about 2 mL and loaded on to an ISCO column. Chromatography (eluent with 5% MeOH in methylene chloride) gave a white solid. 30 mg. MS (H + ), 477.

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-hydroxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 477.35 C 26 H 18 Cl 2 N 2 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-hydroxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (50 mg) was conducted by chiral SFC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-hydroxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione as a white solid (8 mg, 16%) and chiral (2′S,3S,4′R)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-hydroxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione as a white solid (6 mg, 12%).

Preparation of intermediate racemic (2′R,3R,4′S)-2′-[2-(2-allyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 719.41 C 32 H 29 Cl 2 IN 2 O 5

To a stirred solution of racemic (2′R,3R,4′S)-2′-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (500 mg, 0.63 mmol) in THF (3 mL) was added Tetrabutylammonium fluoride (Aldrich, 0.56 mL, 1 M in THF) at room temperature and the mixture was stirred for 20 min. To the resulting mixture, sodium bicarbonate (300 mg) and allyl iodide (0.075 mL, 0.82 mmol) were added and the mixture was stirred at 40° C. for overnight. The solvent was removed and the residue was chromatographed (5% MeOH/CH 2 Cl 2 ) to give a yellow foam, 340 mg. MS (H + ), 719.

Preparation of racemic (2′R,3R,4′S)-2′-[2-(2-allyloxy)-5-iodo-phenyl)]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 619.29 C 27 H 21 Cl 2 IN 2 O 3

Racemic (2′R,3R,4′S)-2′-[2-(2-allyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (335 mg) was dissolved in 30% TFA/CH 2 Cl 2 (5 mL) and the solution was stirred at rt for 30 min. The solvent was removed under reduced pressure and the residue was treated with aqueous saturated NaHCO 3 solution, extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated to give an off white foam. 225 mg. MS (H + ), 619

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 653.31 C 27 H 23 Cl 2 IN 2 O 5

To a stirred solution of racemic (2′R,3R,4′S)-2′-[2-(2-allyloxy)-5-iodo-phenyl)]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.194 mmol) in CH 2 Cl 2 (3 ml) was added acetone (2 ml) and water (2 ml), followed by a solution of OsO 4 (50 mg, 0.194 mmol) in water. N-methyl morpholine oxide (24 uL, 0.214 mmol) was added and the reaction was stirred at r.t. for 20 minutes, and then quenched by a solution of Na 2 SO 3 . The reaction was diluted with CH 2 Cl 2 and water. Organic layer was separated, the aqueous layer was extracted CH 2 Cl 2 . The combined organic solution was concentrated and purified by flash chromatography eluting with EtOAc to 5% MeOH in EtOAc. Yield 68 mg (54%) white foam. MS (H + ), 653

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 623.61 C 32 H 32 Cl 2 N 2 O 5 Si

To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.183 mmol) in DMF (2 mL) were added PdCl 2 (PPh 3 ) 2 (15 mg), CuI (2 mg), trimethylsilyl acetylene (Aldrich, 2 mL) and Et 3 N (Aldrich, 2 mL) and the mixture was purged with nitrogen and then heated at 75° C. for 3 hrs. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by chromatography (0-4% MeOH in EtOAc). Yield 8 mg. MS (H + ), 623

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2,3-dihydroxy-propoxy)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 551.43 C 29 H 24 Cl 2 N 2 O 5

To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (7.8 mg, 0.013 mmol) in MeOH (3 ml) was added 2N NaOH (1 mL) dropwise. The reaction mixture was stirred at room temperature for 30 min and then extracted with ethyl acetate several times. The combined organic extract was dried over MgSO 4 and concentrated to give the title compound as a white solid (6.2 mg). MS (H + ), 551

Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-methylsulfanyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 562.32 C 25 H 19 BrCl 2 N 2 O 2 S

In a manner similar to the method described in examples 214b, 214c, 214d, the title compound was prepared in 3 steps starting from 5-bromo-2-methylsulfanyl-benzaldehyde (Aldrich). MS (H + ), 561.

Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-methylsulfonyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 594.32 C 25 H 19 BrCl 2 N 2 O 4 S

To a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-methylsulfanyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione (360 mg, 0.64 mmol) in dichloromethane (5 ml) at 0° C. was added MCPBA (442 mg, 2.56 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 0.5 h, then at room temperature for 1.5 h. The reaction was quenched by addition of aqueous Na 2 SO 3 solution. The mixture was extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO 4 and concentrated to give the title compound as an off white solid (360 mg). MS (M+H + ), 595

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methylsulfonyl-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 611.62 C 30 H 28 Cl 2 N 2 O 4 SSi

In a manner similar to the method described in example 214e, racemic (2′S,3R,4′S)-2′-[5-bromo-2-methylsulfonyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl 2 (PPh 3 ) 2 , CuI, trimethylsilyl acetylene and Et 3 N (Aldrich, 0.62 mL) in DMF to give the title compound.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-methylsulfonyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 539.44 C 27 H 20 Cl 2 N 2 O 4 S

In a manner similar to the method described in example 214f, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methylsulfonyl-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with KF in methanol to give the title compound. MS (M+H + ) 539

Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-methoxy-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 524.25 C 25 H 19 BrCl 2 N 2 O 3

In a manner similar to the method described in examples 214b, 214c, 214d, the title compound was prepared in 3 steps starting from 5-bromo-2-methoxy-benzaldehyde (Aldrich). MS (H + ), 545.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methoxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 563.56 C 30 H 28 Cl 2 N 2 O 3 Si

In a manner similar to the method described in example 214e, racemic (2′R,3′R,4′S)-2′-[5-bromo-2-methoxy-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl 2 (PPh 3 ) 2 , CuI, trimethylsilyl acetylene and Et 3 N (Aldrich, 0.62 mL) in DMF to give the title compound. MS (H + ),

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-methoxy-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 491.38 C 27 H 20 Cl 2 N 2 O 3

To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methoxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (50 mg, 0.088 mmol) in MeOH (2 ml) was added 2N NaOH dropwise. The reaction was stirred for 30 min and extracted with EtOAc. The combined organic extract was dried and concentrated and was purified by flash chromatography, eluting with CH 2 Cl 2 , then EtOAc. Recrystallization gave the title compound as a white solid (13 mg, 13% yield). MS (H + ), 491

Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(3-trifluoroprop-1-ynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 589.40 C 29 H 21 Cl 2 F 3 N 2 O 4

To a stirred solution of THF (10 mL) at −78° C., 3,3,3-trifluoropropyne (Aldrich) was bubbled in until 1.34 g (14 mmol) was condensed. To the stirred solution, n-BuLi (Aldrich, 2.5 M in hexanes, 5.5 mL, 14 mmol) was added slowly and the mixture was stirred for 1 hr. Bu 3 SnCl (Aldrich, 3.25 g, 10 mmol) was added and the reaction was gradually warmed to rt in 1 hr. The solvent was removed and the crude was directly used for next step.

Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-iodo-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.19 mmol), triphenylphosphine (Aldrich, 33 mg) and tris(dibenzylideneacetone)dipalladium (Strem, 17 mg) were combined into 1.4-dioxane (4 mL) and the mixture was stirred at 86° C. for 3 h. The solvent was removed and the residue was dissolved in 2 mL of 5% methanol/methylene chloride and chromatographed on an ISCO machine to give an off-white solid. 37 mg. The product was then resolved on a SFC machine at 2 mL/min., 30% methanol, 100 bar and 30° C. to give chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(3-trifluoroprop-1-ynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione. MW (H + ), 589.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(2-trimethylsilanyl-ethynyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 593.59 C 31 H 30 Cl 2 N 2 O 4 Si

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (6.05 g, 9.71 mmol) prepared in example 190c in DMF (80 mL) were added trimethylsilylacetylene (10 mL), CuI (40 mg), Et 3 N (50 mL), PdCl 2 (Ph 3 P) 2 (Aldrich, 205 mg, 0.29 mmol) were added. The mixture was purged with nitrogen and heated at 76° C. for 1.5 h, then cooled to room temperature. The mixture was poured into water, extracted with EtOAc several times. The extracts were combined and dried with sodium sulfate and dried to give a foam. The foam was purified by chromatography to give the title compound as a light yellow solid. Yield 3.28 g, 57%.

Preparation of intermediate racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(2-trimethylsilanyl-ethynyl)-2-(2-methanesulfonoxy)-ethoxy-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 671.68 C 32 H 32 Cl 2 N 2 O 6 SSi

To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(2-trimethylsilanyl-ethynyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione (1.68 g) in methylene chloride (20 mL) at 0° C., methanesulfonyl chloride (0.24 ml, 3.12 mmol) and triethylamine (0.44 mL, 3.12 mmol) were added successively and the mixture was stirred at room temperature for 15 min. The mixture was poured into water and the new mixture was extracted with methylene chloride (2×20 mL). The extracts were dried over sodium sulfate and concentrated to give a solid. 1.70 g. MS (H + ), 671.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{5-ethynyl-2-[2-(1-piperidinyl)-ethoxy]-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 588.54 C 33 H 31 Cl 2 N 3 O 3

Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(2-trimethylsilanyl-ethynyl)-2-(2-methanesulfonoxy)-ethoxy-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione (100 mg, 0.15 mmol) was dissolved in DMF (3 mL). To the stirred solution, piperidine (Aldrich, 240 mg) was added and the mixture was stirred at 80° C. overnight. The reaction was cooled to rt and tetrabutyl ammonium fluoride (0.15 mL, 1 M in THF) was added and the mixture was stirred for 30 min. The solvent was removed and the residue was chromatographed (ISCO machine, 4% MeOH/CH 2 Cl 2 ) to give a white solid. 34 mg. MS (H + ), 588.

Preparation of racemic (2′R,3R,4′S)-2′-[2-(2-azido-ethoxy)-5-ethynyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 546.42 C 28 H 21 Cl 2 N 5 O 3

In a manner similar to the method described in example 222c, The title compound was prepared starting from racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(2-trimethylsilanyl-ethynyl)-2-(2-methanesulfonoxy)-ethoxy-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione using sodium azide as the reagent in place of piperidine. MS (H + ), 546.

Preparation of racemic (2′R,3R,4′S)-2′-[2-(2-aminoethyl)-5-ethynyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione

M. W. 520.42 C 28 H 21 Cl 2 N 5 O 3

To a solution of racemic (2′R,3R,4′S)-2′-[2-(2-azido-ethoxy)-5-ethynyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione (40 mg, 0.064 mmol) in THF (2 ml) was add a 1M solution of trimethyl phosphine in THF (77 uL, 0.77 mmol) and water (14 uL, 0.077 mmol). The reaction was stirred at room temperature for 4 h, after which more reagents (50 uL PMe 3 and 5 uL water) was added. The mixture was stirred overnight and concentrated on rotary evaporator.

The residue was dissolved in MeOH (2 mL) and 2N NaOH (1 mL) was added dropwise. After 2 h the reaction was concentrated and residue was dissolved in acetonitrile and water and the mixture was freeze dried to give a powder. To the powder was added absolute EtOH. The liquid was removed and concentrated and was purified on HPLC. The title compound was obtained as a white powder (20 mg, 60% yield, two steps) after freeze drying. MS (H + ), 520

Preparation of intermediate racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane

M. W. 647.09 C 30 H 37 BrClN 3 O 4 Si

Racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2 g, 3.4 mmol) prepared in Example 161b, 2-bromo-acetamide (1.4 g, 10.2 mmol) and cesium carbonate (6.6 g, 20.4 mmol) were mixed in DMF (10 mL). The mixture was stirred overnight. Then the solution was concentrated and the residue was purified by Prep-TLC to give product (800 mg).

Preparation of racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 516.83 C 24 H 23 BrClN 3 O 3

Racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (350 mg) was dissolved in a solution of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated. The residue was redissolved in a mixture of methanol (3 ml) and DIPEA. The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 30 min at 120° C. The reaction mixture was concentrated and the residue was concentrated and the residue was purified by Prep-HPLC to obtain 70 mg product.

Preparation of chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 516.83 C 24 H 23 BrClN 3 O 3

Separation of the two enantiomers from racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg) was conducted by chiral HPLC to provide chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (29 mg) and chiral (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (24 mg).

m/z (M+H) + : 516

Preparation of intermediate racemic (2′R,3R,4′S)-1′-(tert-butoxycarbonyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester

M. W. 601.53 C 31 H 34 Cl 2 N 2 O 6

To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.5 g, 1.25 mmol) prepared in Example 87c in dichloromethane (10 mL) at 0° C. was added ditert-butyl-dicarbonate (1.64 g, 7.5 mmol), followed by the addition of 4-dimethylaminopyridine (0.29 g, 2.4 mmol). The reaction mixture was stirred at r.t. overnight, the organic layer was washed by 0.5N HCl, dried over Na 2 SO 4 . The solvent was removed to give title compound as a solid (0.7 g).

m/z (M+H) + : 601

Preparation of intermediate trimethylsilyl fluorosulfonyldifluoroacetate

M. W. 250.27 C 5 H 9 F 3 O 4 SSi

Under argon protection and at 0° C., trimethylsilyl chloride (11.5 g, 106 mmol) was added dropwise slowly into 2-(fluorosulphonyl)difluoroacetic acid (5 g, 28 mmol). Then the mixture was stirred over weekend at r.t. Then the solvent was removed to give 5.3 g crude product as a liquid.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-((R)-2,2-difluoro-1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.30 C 22 H 18 Cl 2 F 2 N 2 O 2

Racemic (2′R,3R,4′S)-1′-(tert-butoxycarbonyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (100 mg, 1.6 mmol) prepared in Example 226a, catalytic amount of KF and a large amount of trimethylsilyl fluorosulfonyldifluoroacetate was dissolved in toluene (1 mL). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 115° C. for 30 min. The solution was concentrated and the residue was purified by Prep-TLC (CH 2 Cl 2 :CH 3 OH=30:1) to obtain title compound (2.6 mg) of Example 226d and (4.1 mg) of the title compound.

m/z (M+H) + : 451.

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-((S)-2,2-difluoro-1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 451.30 C 22 H 18 Cl 2 F 2 N 2 O 2

The title compound was obtained as the other product in Example 226c.

m/z (M+H) + : 451.

Preparation of intermediate 5-chloro-2-isopropoxy-benzaldehyde

M. W. 198.65 C 10 H 11 ClO 2

5-Chloro-2-hydroxy-benzaldehyde (3 g, 19.16 mmol),2-Iodo-propane (4.88 g, 28.74 mmol) and K 2 CO 3 (4 g, 28.74 mmol) was mixed in anhydrous DMF. The reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 30 min at 100° C. Then the solution was filtered and the filtration was concentrated to obtain the crude product (3 g). The crude product was used into next step reaction without further purification.

Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one

M. W. 348.23 C 18 H 15 Cl 2 NO 2

5-Chloro-2-isopropoxy-benzaldehyde (3 g, 15.1 mmol) and 6-chlorooxindole (2 g, 12.6 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.07 g, 15.1 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (3.4 g).

Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 448.35 C 23 H 23 Cl 2 NO 4

To a solution E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one (3.4 g, 9.8 mmol) in dichloromethane (50 mL) at r.t was added ditert-butyl-dicarbonate (2.56 g, 11.7 mmol), followed by the addition of 4-dimethylaminopyridine (0.12 g, 1 mmol). The reaction mixture was stirred at r.t. for 0.5 h, then the mixture was washed with 0.5N HCl aqueous solution. The organic layer was separated, dried and concentrated to give E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow oil. (4.2 g).

Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-isopropoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 459.38 C 24 H 24 Cl 2 N 2 O 3

In a manner similar to the method described in Example 41b, E/Z-6-Chloro-3-(5-chloro-2-isopropoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2 g, 4.47 mmol) was reacted with 1-(1-methyl-ethenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (22.37 mmol) in toluene to give title compound as a white solid (1.3 g).

m/z (M+H) + : 459

Preparation of intermediate acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester

M. W. 242.66 C 11 H 11 CO 4

5-Chloro-2-hydroxy-benzaldehyde (2 g, 12.8 mmol), acetic acid 2-bromo-ethyl ester (2.57 g, 15.4 mmol), K 2 CO 3 (5.3 g, 38.5 mmol) and KI (0.26 g, 1.54 mmol) were mixed in DMF (20 mL). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH 2 Cl 2 and the organic layer was washed with water for several times. Then the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to obtain a yellow solid. (2.7 g)

Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(2-hydroxy-ethoxy)-benzylidene]-1,3-dihydro-indol-2-one

M. W. 350.20 C 17 H 13 Cl 2 NO 3

Acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester (1.5 g, 9.3 mmol) and 6-chlorooxindole (2.7 g, 11.2 mmol) were mixed in anhydrous methanol (20 mL) at room temperature. Then Pyrrolidine (0.8 g, 11.2 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h, then cooled to r.t and the precipitation was collected by filtration to obtain title compound as a yellow solid (1.4 g).

Preparation of intermediate E/Z-3-[2-(2-tert-Butoxycarbonyloxy-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M. W. 550.44 C 27 H 29 Cl 2 NO 7

To a solution of E/Z-6-Chloro-3-[5-chloro-2-(2-hydroxy-ethoxy)-benzylidene]-1,3-dihydro-indol-2-one (1.4 g, 4.01 mmol) in dichloromethane (10 mL) at r.t was added ditert-butyl-dicarbonate (1.9 g, 8.8 mmol), followed by the addition of 4-dimethylaminopyridine (0.049 g, 0.4 mmol). The reaction mixture was stirred at r.t. for 2 h and then washed by 0.1N HCl. The organic layer was separated, dried, and concentrated to give title compound as a yellow oil (1 g)

Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-[5-fluoro-2-methyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 529.40 C 27 H 23 Cl 2 FN 2 O 4

To a toluene solution (10 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.93 mmol) was added E/Z-3-[2-(2-tert-Butoxycarbonyloxy-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 1.82 mmol). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 40 min. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid and dichloromethane was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (11 mg).

m/z (M+H) + : 529

Preparation of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M.W 529.40 C 27 H 23 Cl 2 FN 2 O 4

Separation of the two enantiomers from racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (4 mg) and chiral (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (3 mg).

m/z (M+H) + : 529

Preparation of intermediate 2-(4-Chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester

M. W. 270.72 C 13 H 15 ClO 4

5-Chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (11.4 g, 58 mmol), K 2 CO 3 (18.6 g, 135 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (20 mL). Then the reaction mixture was heated at 110° C. for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na 2 SO 4 and concentrated to give title compound (7 g)

Preparation of intermediate E/Z-2-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester

M. W. 420.30 C 21 H 19 Cl 2 NO 4

In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) was reacted with 6-chlorooxindole (3.6 g, 22 mmol) and pyrrolidine (1.85 g, 26 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).

Preparation of intermediate E/Z 6-Chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

M.W 520.41 C 26 H 27 Cl 2 NO 6

In a manner similar to the method described in Example 227c, E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (7.2 g, 17.2 mmol) was reacted with ditert-butyl-dicarbonate (4.5 g, 20.6 mmol) and DMAP (0.2 g, 1.72 mmol) in dichloromethane to give title compound as a yellow solid (8 g).

Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M.W 599.49 C 31 H 29 Cl 2 FN 2 O 5

In a manner similar to the method described in Example 228d, E/Z 6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (8 g, 15.44 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (77 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (2.7 g).

m/z (M+H) + : 599

Preparation of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M. W. 599.49 C 31 H 29 Cl 2 FN 2 O 5

Separation of the two enantiomers from racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg) was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (14 mg) and chiral (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (14 mg).

m/z (M+H) + : 599

Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M.W 571.44 C 29 H 25 Cl 2 FN 2 O 5

Racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2.7 g, 4.5 mmol) was dissolved in THF (20 mL). Then aqueous solution (10 mL) of KOH (0.5 g) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl solution. The white solid was collected by filtration to give title compound (1.6 g).

m/z (M+H) + : 571

Preparation of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M.W 571.44 C 29 H 25 Cl 2 FN 2 O 5

Separation of the two enantiomers from racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg) and chiral (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).

m/z (M+H) + : 571

Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione

M.W 557.45 C 29 H 27 Cl 2 FN 2 O 4

With cooling of an ice bath, LiAlH 4 (19 mg, 0.5 mmol) was suspended in THF, then a solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.167 mmol) in THF was added. The reaction mixture was stirred at 0° C. for 10 min, the water (1 mL) was added to the mixture. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give title compound as white solid (9 mg).

m/z (M+H) + : 557

Preparation of intermediate 5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde

M.W 283.05 C 9 H 6 BrF 3 O 2

5-Bromo-2-hydroxy-benzaldehyde (1.5 g, 7.5 mmol), 1,1,1-trifluoro-2-iodo-ethane (1.57 g, 7.5 mmol) and K 2 CO 3 (2.07 g, 15 mmol) was mixed in anhydrous DMF (20 mL). The reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 180° C. for 50 min. Then the solution was filtered and the filtrate was concentrated to obtain the crude product (3 g). The crude product was purified by chromatography to give a yellow oil (1.5 g).

Preparation of intermediate 1-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene

M. W. 396.28 C 14 H 17 BrF 3 NO 2 Si

To anhydrous tetrahydrofuran (15 mL) was added 1M THF solution of LiHMDS (5.3 mmol, 5.3 mL) under Ar at room temperature, followed by the addition of 5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (1.5 g, 5.3 mmol). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (0.67 mL, 5.3 mmol) was added dropwise. Then the temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (1 mL, 6.8 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.5 mL, 6.8 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)phenyl]-6-chloro-4′-(3-chlorophenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione