# Patent

## Title
Spiroindolinone derivatives

## Abstract

The present invention relates to spiroindolinone derivatives of the formula




and their enantiomers and pharmaceutically acceptable salts and esters thereof wherein R1, R2, R3, R4, R5, R6, R7 and R8, are as herein described.

The compounds have utility as antiproliferative agents, especially, as anticancer agents.

## Background
PRIORITY TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No. 11/712,883, filed Mar. 1, 2007, now pending which claims the benefit of U.S. Provisional Application No. 60/881,756, filed Jan. 22, 2007 and U.S. Provisional Application No. 60/781,958, filed Mar. 13, 2006, which is hereby incorporated by reference in its entirety.


SUMMARY OF THE INVENTION
The present invention relates to spiroindolinone derivatives of the formula




and pharmaceutically acceptable salts and esters thereof wherein R1, R2, R3, R4, R5, R6, R7 and R8, are as herein described.

The compounds have utility as antiproliferative agents, especially, as anticancer agents.
BACKGROUND OF THE INVENTION
p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
A series of spiroindolinone as antagonists of MDM2 has previously been disclosed in J. Am. Chem. Soc., 2005, 127, 10130.
The present invention provides spiroindolinone derivatives which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in G1 and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to 3,3′-spiroindolinones of the formula




wherein

    X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,
    Y is hydrogen or fluorine,
    R4 and R5 are hydrogen or lower alkyl,
    one of R1 and R8 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
    one of R6 and R7 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, cyano or lower alkyl,
    R2 is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,
    R3 is selected from the group consisting of oxygen, sulfur and NNH(C═O)OR9,
    R9 is lower alkyl or substituted lower alkyl,

and the pharmaceutically acceptable salts and esters thereof.



Preferred are compounds of formula I having a stereochemical structure as shown as formula II




wherein

    X is hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy, and vinyl,
    Y is hydrogen or fluorine,
    R1 is hydrogen,
    R2 is hydrogen, lower alkyl or substituted lower alkyl,
    R4 and R5 are hydrogen or lower alkyl,
    R6 is hydrogen, cyano, or lower alkyl,
    R3 is O, S or NNH(C═O)OR9,
    R7/R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
    R9 is lower alkyl or substituted lower alkyl.


Further preferred are compounds of formula II wherein

    X is chlorine or bromine,
    Y is hydrogen,
    R1 is hydrogen,
    R4 and R5 are both hydrogen,
    R6 is hydrogen,
    R3 is O,
    R7 is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:






    R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and
    R2 is hydrogen, lower alkyl or substituted lower alkyl,
    with the proviso that when R2 is lower alkyl or substituted lower alkyl, R8 is selected from lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl.


Also further preferred are compounds of formula II wherein

    X is Cl or Br,
    Y is hydrogen,
    R1 is hydrogen,
    R4 and R5 are both hydrogen,
    R6 is hydrogen,
    R3 is O,
    R7 is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:






and

    R8 is selected from the group consisting of:






wherein

    R1′ is hydrogen, methyl, ethyl, propyl, isopropyl, CF3, F, CHF2, or CH2F,
    R2′ is hydrogen, methyl, ethyl, propyl, isopropyl, CF3, F, CHF2, or CH2F,
    R3′ is hydrogen, F, CF3, CH2F, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl or sec-butyl,
    R4′ is hydrogen, F, Cl, Br, I, methyl, ethyl, cyclopropyl, cyano, methoxy, or ethynyl,
    R5′ is hydrogen, F or methyl,
    R6′ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, lower alkynyl, substituted lower alkynyl
    R7′ is hydrogen, F or methyl,
    R8′ is hydrogen, F, methyl, ethyl, propyl, isopropyl, tert-butyl or sec-butyl,
    R9′ is hydrogen, hydroxyl, or F,
    R10′ is hydrogen or F,
    R11′ is hydrogen or methyl,
    R12′ is hydrogen or methyl,
    R2 is hydrogen, lower alkyl or substituted lower alkyl
    with the proviso that when R2 is lower alkyl or substituted lower alkyl, R8 is selected from:






Also preferred are compounds of formula I having a stereochemical structure as shown in structure III




wherein

    X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy, and vinyl,
    Y is hydrogen or fluorine,
    R1 is hydrogen,
    R2 is hydrogen, lower alkyl or substituted lower alkyl,
    R4 and R5 are hydrogen or lower alkyl,
    R6 is hydrogen, cyano or lower alkyl,
    R3 is O, S or NNH(C═O)OR9,
    R7/R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and
    R9 is lower alkyl or substituted lower alkyl.


Further preferred are compounds of formula III wherein

    X is Cl or Br,
    Y is hydrogen,
    R1 is hydrogen,
    R2 is hydrogen, lower alkyl or substituted lower alkyl,
    R4 and R5 are both hydrogen,
    R6 is hydrogen,
    R3 is O,
    R8 is a substituted phenyl with the substituted phenyl selected from group consisting of






    R7 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.


In particular, preferred compounds are those of the formula

    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,
    racemic (2′S/R,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-cyanophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′S,3R,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-naphthalenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-pyridinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclohexenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonylmethyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one,
    racemic (2′R,3R,4′S)-[6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxyphenyl)-2,3-dihydro-2-oxospiro[3H-indole-3,3′-piperidin]-6-ylene]hydrazine carboxylic acid ethyl ester,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(4-ethoxy-1,2-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    racemic (2′R,3R,4′S)-2′-sec-Butyl-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isobutyrylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-fluoro-phenyl)-2′-(1-methyl ene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-m-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-o-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-4′-(3-Bromo-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxyspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methylsulphonyl-4-piperidinyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-{[4-(1,1-dioxido-2-isothiazolidinyl)ethyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    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,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro 2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2,2-dimethyl-3-hydroxy propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S) 4′-[2-(2-amino-ethoxy)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-cyclopropyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-nitro-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-4′-(2-acetylamino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methanesulfonylamino-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-iodophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-(5-chloro-2-(2,2,2-trifluoro-ethoxy)hydroxy-phenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(3-hydroxypropoxyl)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxy ethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-bromo-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-hydroxymethyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-hydroxyethoxy)-phenyl]-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(hydroxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2-chloro-5-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
    chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
    racemic (2′R,3R,4′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.


In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, aminocarbonyl, carboxy, NO2, lower-alkoxy, thio-lower-alkoxy, lower-alkylsulfonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl)2-lower-alkoxy, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, NH2, N(H, lower-alkyl) or N(lower-alkyl)2. Preferred substituents for the aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl and amino.
If alkyl, alkenyl, alkynyl or similar groups are linked with both ends to the same moiety, cyclic structures may result, where two hydrogens of said moiety are being replaced by the two ends of the alkyl, alkenyl, alkynyl or similar group, thus creating cyclic structures, such as, tetralin, macrocycles or spiro compounds.
The term “alkyl” refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term “lower alkyl” refers to alkyl groups having from 1 to 8 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, “cycloalkyl” is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term “cycloalkenyl” is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term “alkenyl” as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 8, preferably 2 to 6 carbon atoms. Examples of such “alkenyl group” are vinyl (ethenyl), allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term “alkynyl” as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such “alkynyl group” are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The term “halogen” as used in the definitions means fluorine, chlorine, iodine or bromine, preferably fluorine and chlorine.
“Aryl” means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
“Heteroaryl” means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
“Heterocycle” means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, aromatic or non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like.
“Hetero atom” means an atom selected from N, O and S.
“Alkoxy, alkoxyl or lower alkoxy” refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
“Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
The compounds of formulas I or II or III as well as their salts have at least one asymmetric carbon atom and therefore may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography. The invention includes all stereoisomers.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I or II or III compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
“Effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
“IC50” refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
“Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formulas I or II or III having a carboxyl group or hydroxy group, which esters retain the biological effectiveness and properties of the compounds of formulas I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid or alcohol respectively.
Synthesis
Compounds of this invention in formula I or II or III can be synthesized according to the following general schemes. It will be readily apparent to those of ordinary skill in the art that compounds in formula I-III can be prepared by substitution of the reagents or agents in the general synthesis routes. The starting materials are either commercially available or can be synthesized by well-established literature methods known to those of ordinary skill in the art. The key step of the transformation is a convergent [4+2] cycloaddition utilizing aza Diels-Alder reaction to generate a racemic mixture of spiroindolinone compounds in formula I in a stereoselective and efficient manner. By using purification of chiral chromatography, compounds in formula II or formula III can be obtained as an optically pure or enriched enantiomers.




In general an appropriately selected aldehyde I can be reacted with lithium hexamethyldisilamide, chlorotrialkylsilane and a selectively substituted acyl chloride in a one-pot, multi-steps manner to generate 2-aza-1,3-butadiene II (Scheme I) and can be used as a crude product. Ghosez, L. and others have reported the preparation of 2-aza-1,3-butadienes and their use in aza Diels-Alder reaction to form heterocycle (Ref: Tetrahedron 1995, 11021; J. Am. Chem. Soc. 1999, 2617; and literatures cited therein). The appropriately selected aldehyde I are either commercially available or can be synthesized by well-established multiple literature methods.




Oxindole III can be reacted with an appropriately substituted aldehyde or ketone in the presence of base under heated condition in either a protic like methanol, ethanol or an aprotic solvent like toluene, o-xylene to give intermediate IV. The commonly used base is either pyrrolidine or piperidine. Intermediate IV can then be reacted with 2-aza-1,3-butadiene II in toluene or o-xylene under heating from about 110° C. to 160° C. and anhydrous condition to afford a racemic mixture of spiroindolinone V and V′ as the major products shown together with other minor stereoisomers. 6-substituted or 5,6-disubstituted oxindole III starting materials are either commercially available or prepared according to literature methods, for examples, Kraynack, E. A.; Dalgard, J. E.; Gaeta, F. C. A. Tetrahedron Letters, 1998, 39, 7679-7682, EP153818 for 5-fluoro-6-chlorooxindole, etc




When R6 is a strong electron withdrawing group in reagent VII, intermediate IV can be prepared alternatively from Isatin VI and reagent VII. For example, when R6 is cyano and R7 is a substituted aryl, hetereoaryl, Isatin VI can react with various R7 substituted cyanide VII in the presence of a base like DBU in methanol under heated condition to form IV (Scheme 3). 6-substituted or 5,6-disubstituted isatin VI starting materials are either commercially available or prepared according to literature methods




Intermediate IV can be protected to give intermediate VIII. The protective group can be attached by using ethyl chloroformate, di-tert-butyl dicarbonate, SEM-Cl, benzyl bromide, and a base like 4-(dimethylamine)pyridine (DMAP), triethylamine, NaH, or LiH according to well established literature procedures. Examples of protective group formation and their deprotection have been described and reviewed comprehensively by Greene, T. W. et al in “Protective Groups in Organic Synthesis, 2nd Edition. John Wiley & Sons Inc. In a similar manner intermediate VIII can be reacted with a selected 2-aza-butadiene II prepared in Scheme 1 in toluene or o-xylene under heating from 110° C. to 160° C. and anhydrous condition to form intermediate IX and IX′ as the major products shown as a racemic mixture of two enantiomers together with other minor stereoisomers (Scheme 4). Intermediate IX can be converted into V by a deprotection reaction (Scheme 5). A useful Pg can be ethyl carbamate, tert-butyl carbamate (BOC), or trimethylsilylethoxymethyl (SEM). Ethyl carbamate can be removed easily by treatment of IX with a base like NaOH in methanol or ethanol at room temperature. tert-butyl carbamate (BOC) can be readily removed by treatment of IX with trifluoroacetic acid at room temperature. Deprotection of trimethylsilylethoxymethyl (SEM) can be achieved by treatment with trifluoroacetic acid in dichloromethane at room temperature first, followed by heating with diisopropylethylamine in methanol.




When R8 is selected from a certain group such as lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, alternative synthetic methods can be used to gain access to compounds V or intermediate IX. Typically, the compounds of V or intermediate IX with R8 selected from a related lower alkenyl, or substituted alkenyl, or cycloalkenyl, or substituted cycloalkenyl, would be prepared first according to the methods in scheme 2 or scheme 4, followed by a catalytic hydrogenation reaction to give those V or IX with a R8 as the corresponding lower alkyl, or substituted lower alkyl, or cycloalkyl, or substituted cycloalkyl. Treatment of the compounds of V or intermediate IX with R8 selected from a related lower alkenyl, or substituted alkenyl with Simmons-Smith reagent (CH2I2-Et2Zn) will lead to those V or IX with a R8 as the corresponding substituted cyclopropyl group.
V can be selectively protected to give IX under controlled conditions. In this case, a useful protective group Pg here can be ethyl carbamate, or tert-butyl carbamate (BOC) (Scheme 6). The protective group can be attached by using ethyl chloroformate, or di-tert-butyl dicarbonate, and a base like 4-(dimethylamine)pyridine (DMAP) in dichloromethane at room or lowered temperature similar to the transformation from IV to VIII in Scheme 4.




By using either an organic base diisopropylethyl amine or an inorganic base like Cs2CO3, LiH or NaH, and an appropriately selected alkylation reagent, N-alkylate intermediate X can be prepared from IX. A subsequent reaction to remove protective group (Pg) leads to various R2 derivatized compound XI (Scheme 7).
When Pg is trimethylsiloxyethoxymethyl (SEM) group and R2 is —(CH2)nCl, R2 can be functionalized with other substituting group. For example, intermediate X with —(CH2)nCl can be reacted with HNR10R11 in neat or a solvent like isopropanol under heated condition, followed by treatment of trifluoroacetic acid and diisopropylamine to give compounds XI with R2 as —(CH2)nNR10R11 
When R2 group is —(CH2)mC(═O)OR′, in which R′ is hydrogen or a lower alkyl group, compound XI can be converted to give compounds XI with R2 as (CH2)mC(═O)NR10R11 by using well-known methods for carboxamide formation.
R10 or R11 is independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, or R10 and R11 may be linked to form a heterocycle, substituted heterocycle, heteroaryl, or substituted heteroaryl.

    n=2, 3, 4
    m=1, 2, 3






In one step compound XI can be selectively converted into thioamide analogue XII by using Lawesson reagent or other similarly related reagents (Scheme 8)




When R2 is hydrogen, thioamide compound XIII can also be a useful intermediate to prepare various R3 derivatized analogues. For example, compound XIII can be reacted with active nucleophilic, appropriately substituted hydrazide R9—O(O═C)NHNH2, and a mercuric reagent like HgCl2 or Hg(OAc)2 to form analogues XIV (Scheme 9). R9 is lower alkyl or substituted lower alkyl.




Compound V and V′ can be readily resolved into two optically pure or enriched chiral enantiomers by separation using chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral column chromatography (Scheme 10). In a similar manner to the methods in the reaction schemes above, the chiral enantiomer of intermediate X and compounds XI, XII, XIII, XIV can be prepared by substitution of V with its enantiomer V′, or substitution of IX with IX′. The compounds V and V′, intermediates IX and IX′ were generated initially as a racemic mixture and subsequently reacted without chiral separation to give the corresponding racemic mixture of X, XI, XII, XIII, or XIV together with their enantiomers. All these racemic mixture of IX, X, XI, XII, XIII, XIV and their enantiomers in the reaction schemes above can also be readily separated into optically pure or enriched chiral enantiomeric pairs in a similar manner as scheme 10.




The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
EXAMPLE 1a
Preparation of intermediate E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one




M. W. 249.74 C14H16ClNO
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 Na2SO4, 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%).
EXAMPLE 1b
Preparation of intermediate 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 253.81 C12H16ClNOSi
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.
EXAMPLE 1c
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 C23H24Cl2N2O2 
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 C23H24Cl2N2O2+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.
EXAMPLE 2a
Preparation of intermediate E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one




M. W. 235.72 C13H14ClNO
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%).
EXAMPLE 2b
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 C22H22Cl2N2O2 
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 C22H22Cl2N2O2+H [(M+H)+]: 417.1131. Found: 417.1129
EXAMPLE 3a
Preparation of intermediate E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one




M. W. 221.69 C12H12ClNO
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%).
EXAMPLE 3b
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 C21H20Cl2N2O2 
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 C21H20Cl2N2O2+H [(M+H)+]: 403.0975. Found: 403.0975.
EXAMPLE 4a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 290.15 C15H9Cl2NO
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%).
EXAMPLE 4b
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 C18H13Cl2NO3 
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 Na2SO4, 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%).
EXAMPLE 4c
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 C27H21Cl3N2O4 
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:CH2Cl2=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%).
EXAMPLE 4d
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 C24H17Cl3N2O2 
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:CH2Cl2=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 C24H17Cl3N2O2+H [(M+H)+]: 471.0429. Found: 471.0431.0.
EXAMPLE 4e
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 C24H17Cl3N2O2 
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 C24H17Cl3N2O2+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 C24H17Cl3N2O2+H [(M+H)+]: 471.0429. Found: 471.0428.
EXAMPLE 5a
Preparation of intermediate E/Z-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one




M. W. 247.73 C14H14ClNO
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%).
EXAMPLE 5b
Preparation of intermediate E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester




M. W. 319.79 C17H18ClNO3 
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%).
EXAMPLE 5c
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 C26H26Cl2N2O4 
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%).
EXAMPLE 5d
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1121.
EXAMPLE 6a
Preparation of intermediate E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one




M. W. 261.75 C15H16ClNO
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%).
EXAMPLE 6b
Preparation of intermediate E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester




M. W. 333.82 C18H20ClNO3 
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%).
EXAMPLE 6c
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 C27H28Cl2N2O4 
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%).
EXAMPLE 6d
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1288.
EXAMPLE 7a
Preparation of intermediate 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 253.81 C12H16ClNOSi
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.
EXAMPLE 7b
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 C27H28Cl2N2O4 
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%).
EXAMPLE 7c
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1287.
EXAMPLE 8a
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 C27H21Cl3N2O4 
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%).
EXAMPLE 8b
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 C24H17Cl3N2O2 
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 C24H17Cl3N2O2+H [(M+H)+]: 471.0429. Found: 471.0427.
EXAMPLE 9a
Preparation of intermediate E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 290.15 C15H9Cl2NO
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%).
EXAMPLE 9b
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 C18H13Cl2NO3 
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%).
EXAMPLE 9c
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 C27H21Cl3N2O4 
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%).
EXAMPLE 9d
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 C24H17Cl3N2O2 
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 C24H17Cl3N2O2+H [(M+H)+]: 471.0429. Found: 471.0427.
EXAMPLE 10a
Preparation of intermediate 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 233.39 C13H19NOSi
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.
EXAMPLE 10b
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 C28H24Cl2N2O4 
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%).
EXAMPLE 10c
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 C25H20Cl2N2O2 
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 C25H20Cl2N2O2+H [(M+H)+]: 451.0975. Found: 451.0976.
EXAMPLE 11a
Preparation of intermediate 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 237.35 C12H16FNOSi
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.
EXAMPLE 11b
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 C27H21Cl2FN2O4 
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%).
EXAMPLE 11c
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 C24H17Cl2FN2O2 
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 C24H17Cl2FN2O2+H [(M+H)+]: 451.0975. Found: 451.0976.
EXAMPLE 12a
Preparation of intermediate E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one




M. W. 255.71 C15H10ClNO
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%).
EXAMPLE 12b
Preparation of intermediate E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester




M. W. 327.77 C18H14ClNO3 
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%).
EXAMPLE 12c
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 C24H18Cl2N2O2 
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:CH2Cl2=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 C24H18Cl2N2O2+H [(M+H)+]: 437.0818. Found: 437.0817.
EXAMPLE 13a
Preparation of intermediate 1-(3-chlorophenyl)-4-methyl-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 267.83 C13H18ClNOSi
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.
EXAMPLE 13b
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 C25H20Cl2N2O2 
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 C25H20Cl2N2O2+H [(M+H)+]: 451.0975. Found: 451.0972.
EXAMPLE 14a
Preparation of intermediate 1-phenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 219.36 C12H17NOSi
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.
EXAMPLE 14b
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 C24H18Cl2N2O2 
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 H2O. 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 C24H18Cl2N2O2+H [(M+H)+]: 437.0818. Found: 437.0816.
EXAMPLE 14c
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 C24H18Cl2N2O2 
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).
EXAMPLE 15a
Preparation of intermediate 1-(3-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 249.39 C13H19NO2Si
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.
EXAMPLE 15b
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 C25H20Cl2N2O3 
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 C25H20Cl2N2O3+H [(M+H)+]: 467.0924. Found: 467.0925.
EXAMPLE 16a
Preparation of intermediate 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 253.81 C12H16ClNOSi
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.
EXAMPLE 16b
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 C27H21Cl3N2O4 
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%).
EXAMPLE 16c
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 C24H17Cl3N2O2 
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 C24H17Cl3N2O2+H [(M+H)+]: 471.0429. Found: 471.0430.
EXAMPLE 16d
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 C24H17Cl3N2O2 
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).
EXAMPLE 17a
Preparation of intermediate 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 233.39 C13H19NOSi
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.
EXAMPLE 17b
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 C28H24Cl2N2O4 
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%).
EXAMPLE 17c
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 C25H20Cl2N2O2 
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 C25H20Cl2N2O2+H [(M+H)+]: 451.0975. Found: 451.0972.
EXAMPLE 17d
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 C25H20Cl2N2O2 
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).
EXAMPLE 18a
Preparation of intermediate 1-(2-ethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 247.42 C14H21NOSi
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.
EXAMPLE 18b
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 C26H22Cl2N2O2 
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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1132.
EXAMPLE 18c
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 C26H22Cl2N2O2 
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).
EXAMPLE 19a
Preparation of intermediate 4-methyl-1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 247.42 C14H21NOSi
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
EXAMPLE 19b
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 C26H22Cl2N2O2 
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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1132.
EXAMPLE 20
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 C25H19Cl3N2O2 
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 C25H19Cl3N2O2+H [(M+H)+]: 485.0585. Found: 485.0583
EXAMPLE 21a
Preparation of intermediate 1-(2-isopropylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 261.44 C15H23NOSi
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.
EXAMPLE 21b
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 C27H24Cl2N2O2 
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 C27H24Cl2N2O2+H [(M+H)+]: 479.1288. Found: 479.1289.
EXAMPLE 21c
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 C27H24Cl2N2O2 
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).
EXAMPLE 22a
Preparation of intermediate 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 298.26 C12H16BrNOSi
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.
EXAMPLE 22b
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 C27H21BrCl2N2O4 
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%).
EXAMPLE 22c
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 C24H17BrCl2N2O2 
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 C24H17BrCl2N2O2+H [(M+H)+]: 514.9923. Found: 514.9926.
EXAMPLE 22d
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 C24H17BrCl2N2O2 
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).
EXAMPLE 23a
Preparation of intermediate 1-(3-cyanophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 244.37 C13H16N2OSi
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.
EXAMPLE 23b
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 C25H17Cl2N3O2 
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 C25H17Cl2N3O2+H [(M+H)+]: 462.0771 Found: 462.0771.
EXAMPLE 24a
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 C20H17Cl2NO3 
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%).
EXAMPLE 24b
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 C30H28Cl2N2O4 
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%).
EXAMPLE 24c
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 C31H30Cl2N2O4 
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 NH4Cl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over MgSO4. 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%).
EXAMPLE 24d
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 C26H22Cl2N2O2 
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 NaHCO3 solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over MgSO4. The solvent was removed and the residue was purified by chromatography (EtOAc:CH2Cl2=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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1132.
EXAMPLE 24e
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 C26H22Cl2N2O2 
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).
EXAMPLE 25a
Preparation of intermediate 1-(3-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 251.38 C13H18FNOSi
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.
EXAMPLE 25b
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 C28H23Cl2FN2O4 
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%).
EXAMPLE 25c
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 C25H19Cl2FN2O2 
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 C25H19Cl2FN2O2+H [(M+H)+]: 469.0881. Found: 469.0885.
EXAMPLE 25d
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 C25H19Cl2FN2O2 
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).
EXAMPLE 26a
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 C32H32Cl2N2O4 
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%).
EXAMPLE 26b
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 C27H24Cl2N2O2 
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 C27H24Cl2N2O2+H [(M+H)+]: 479.1288. Found: 479.1284.
EXAMPLE 26c
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 C27H24Cl2N2O2 
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).
EXAMPLE 27a
Preparation of intermediate 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 247.42 C14H21NOSi
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.
EXAMPLE 27b
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 C29H26Cl2N2O4 
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%).
EXAMPLE 27c
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 C26H22Cl2N2O2 
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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1131.
EXAMPLE 28a
Preparation of intermediate 1-(2,3-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 247.42 C14H21NOSi
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.
EXAMPLE 28b
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 C26H22Cl2N2O2 
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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1131.
EXAMPLE 29a
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 C33H32Cl2N2O6 
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%).
EXAMPLE 29b
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 C28H24Cl2N2O4 
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 C28H24Cl2N2O4+H [(M+H)+]: 523.1186. Found: 523.1183.
EXAMPLE 30
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 C21H20Cl2N2OS
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 C21H20Cl2N2OS+H [(M+H)+]: 419.0746. Found: 419.0744.
EXAMPLE 31
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 C27H22Cl2N2O4 
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 H2O, brine, dried over MgSO4 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 C27H22Cl2N2O4+H [(M+H)+]: 509.1030. Found: 509.1028.
EXAMPLE 32a
Preparation of intermediate 1-[2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 287.36 C13H16F3NOSi
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.
EXAMPLE 32b
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 C25H17Cl2F3N2O2 
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 C25H17Cl2F3N2O2+H [(M+H)+]: 505.0692. Found: 505.0688.
EXAMPLE 33
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 C25H17Cl2F3N2OS
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 C25H17Cl2F3N2OS+H [(M+H)+]: 521.0464. Found: 521.0458.
EXAMPLE 34a
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 C27H21Cl2FN2O3 
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 H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, 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%).
EXAMPLE 34b
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 C31H29Cl2N3O4 
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 H2O. The organic layer was separated, dried over Na2SO4 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 C31H29Cl2N3O4+H [(M+H)+]: 578.1608. Found: 578.1600.
EXAMPLE 34c
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 C31H29Cl2N3O4 
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%).
EXAMPLE 35a
Preparation of intermediate 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 305.35 C13H15F4NOSi
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.
EXAMPLE 35b
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 C25H16Cl2F4N2O2 
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 C25H16Cl2F4N2O2+H [(M+H)+]: 523.0598. Found: 523.0593.
EXAMPLE 36a
Preparation of intermediate 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 251.38 C13H18FNOSi
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.
EXAMPLE 36b
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 C25H19Cl2FN2O2 
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 C25H19Cl2FN2O2+H [(M+H)+]: 469.0881. Found: 469.0881.
EXAMPLE 36c
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 C25H19Cl2FN2O2 
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%).
EXAMPLE 37
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 C30H27Cl2N3O3 
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 C30H27Cl2N3O3 [(M+H)+]: 548.1502. Found: 548.1501.
EXAMPLE 38
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 C37H40Cl2N4O5 
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 C37H40Cl2N4O5 [(M+H)+]: 691.2449. Found: 691.2441.
EXAMPLE 39
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 C25H19Cl2FN2OS
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 C25H19Cl2FN2OS+H [(M+H)+]: 485.0652. Found: 485.0648.
EXAMPLE 40
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 C28H23Cl2F3N4O3 
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 C28H23Cl2F3N4O3+H [(M+H)+]: 591.1172. Found: 591.1168
EXAMPLE 41a
Preparation of intermediate 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 255.34 C12H15F2NOSi
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.
EXAMPLE 41b
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 C24H16Cl2F2N2O2 
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 NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 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 C24H16Cl2F2N2O2+H [(M+H)+]: 473.0630. Found: 473.0630.
EXAMPLE 42a
Preparation of intermediate 1-(5-fluoro-2-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 267.38 C13H18FNO2Si
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.
EXAMPLE 42b
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 C25H19Cl2FN2O3 
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 C25H19Cl2FN2O3+H [(M+H)+]: 485.0830. Found: 485.0827.
EXAMPLE 43a
Preparation of intermediate 1-(1-naphthalenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 269.42 C16H19NOSi
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.
EXAMPLE 43b
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 C28H10Cl2N2O2 
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 C28H10Cl2N2O2+H [(M+H)+]: 487.0975. Found: 487.0975.
EXAMPLE 44a
Preparation of intermediate 1-(3-pyridinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 220.35 C11H16N2OSi
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.
EXAMPLE 44b
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 C23H17Cl2N3O2 
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 C23H17Cl2N3O2+H [(M+H)+]: 438.0771. Found: 438.0771.
EXAMPLE 45a
Preparation of intermediate 1-(2,3-difluoro-6-methoxyphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 285.37 C13H17F2NO2Si
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.
EXAMPLE 45b
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 C25H18Cl2F2N2O3 
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 C25H18Cl2F2N2O3+H [(M+H)+]: 503.0736. Found: 503.0735.
EXAMPLE 46a
Preparation of intermediate 1-(3,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 255.34 C12H15F2NOSi
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.
EXAMPLE 46b
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 C24H16Cl2F2N2O2 
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 C24H16Cl2F2N2O2+H [(M+H)+]: 473.0630. Found: 473.0631.
EXAMPLE 47a
Preparation of intermediate 1-(1-cyclohexenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 223.39 C12H21NOSi
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.
EXAMPLE 47b
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 C24H22Cl2N2O2 
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 C24H22Cl2N2O2+H [(M+H)+]: 441.1131. Found: 441.1131.
EXAMPLE 48
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 C24H16Cl2F2N2OS
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 C24H16Cl2F2N2OS+H [(M+H)+]: 489.0401. Found: 489.0402.
EXAMPLE 49
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 C27H22Cl2F2N4O3 
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 C27H22Cl2F2N4O3+H [(M+H)+]: 559.1110. Found: 559.1109.
EXAMPLE 50a
Preparation of intermediate 1-(1,3-benzodioxol-4-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 263.37 C13H17NO3Si
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.
EXAMPLE 50b
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 C25H18Cl2N2O4 
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 C25H18Cl2N2O4+H [(M+H)+]: 481.0717. Found: 481.0717.
EXAMPLE 51
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 C28H25Cl2FN4O3 
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%).
EXAMPLE 52a
Preparation of intermediate 2,3-difluoro-6-methyl-benzaldehyde




M. W. 156.13 C8H6F2O
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%).
EXAMPLE 52b
Preparation of intermediate 1-(2,3-difluoro-6-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 269.37 C13H17F2NOSi
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.
EXAMPLE 52c
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 C25H18Cl2F2N2O2 
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 C25H18Cl2F2N2O2+H [(M+H)+]: 487.0786 Found: 487.0780.
EXAMPLE 53a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one




M. W. 308.14 C15H8Cl2FNO
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.
EXAMPLE 53b
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 C20H16Cl2FNO3 
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%).
EXAMPLE 53c
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 C25H18Cl2F2N2O2 
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 C25H18Cl2F2N2O2+H [(M+H)+]: 487.0786. Found: 487.0779.
EXAMPLE 54
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 C25H18Cl2F2N2OS
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 C25H18Cl2F2N2OS+H [(M+H)+]: 503.0558. Found: 503.0554.
EXAMPLE 55a
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 C21H23Cl2NO2Si
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 Na2SO4. 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%).
EXAMPLE 55b
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 C31H33Cl2FN2O3Si
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%).
EXAMPLE 55c
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 C37H43Cl2FN2O5Si
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 NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 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%).
EXAMPLE 55d
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 C27H21Cl2FN2O4 
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 MgSO4 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 C27H21Cl2FN2O4+H [(M+H)+]: 527.0935 Found: 527.0926.
EXAMPLE 56a
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 C32H35Cl2FN2O3Si
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%).
EXAMPLE 56b
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 C27H23Cl2FN2O3 
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 NaHCO3 aqueous solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=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%).
EXAMPLE 56c
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 C26H21Cl2FN2O2 
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:CH2Cl2=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 C26H21Cl2FN2O2+H [(M+H)+]: 483.1037. Found: 483.1042.
EXAMPLE 56d
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 C26H21Cl2FN2O2 
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%).
EXAMPLE 57a
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 C27H20Cl2F2N2O3 
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%).
EXAMPLE 57b
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 C33H33Cl2FN4O3 
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 C33H33Cl2FN4O3+H [(M+H)+]: 623.1987. Found: 623.1989.
EXAMPLE 57c
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 C33H33Cl2FN4O3 
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%).
EXAMPLE 58
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 C37H39Cl2FN4O5 
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 C37H39Cl2FN4O5+H [(M+H)+]: 709.2355. Found: 709.2354.
EXAMPLE 59a
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 C32H31Cl2FN4O3 
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 NaHCO3 solution, extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, 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 C32H31Cl2FN4O3+H [(M+H)+]: 609.1830 Found: 609.1820.
EXAMPLE 59b
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 C32H31Cl2FN4O3 
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%).
EXAMPLE 60a
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 C34H38Cl3FN2O5Si
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%).
EXAMPLE 60b
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 C32H32Cl2FN3O3 
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 NaHCO3 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 C32H32Cl2FN3O3+H [(M+H)+]: 596.1878 Found: 596.1877.
EXAMPLE 60c
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 C32H32Cl2FN3O3 
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%).
EXAMPLE 61a
Preparation of intermediate 1-(1-isopropyl-4-methyl-1-pentenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 267.49 C15H29NOSi
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.
EXAMPLE 61b
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 C27H30Cl2N2O2 
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 C27H30Cl2N2O2+H [(M+H)+]: 485.1757. Found: 485.1755.
EXAMPLE 62a
Preparation of intermediate 1,2-difluoro-4-isopropoxy-benzene




M. W. 172.18 C9H10F2O
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%).
EXAMPLE 62b
Preparation of intermediate 2,3-difluoro-6-isopropoxy-benzaldehyde




M. W. 200.19 C10H10F2O2 
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%).
EXAMPLE 62c
Preparation of intermediate 1-(2,3-difluoro-6-isopropoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 313.42 C15H21F2NO2Si
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.
EXAMPLE 62d
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 C27H22Cl2F2N2O3 
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 C27H22Cl2F2N2O3+H [(M+H)+]: 531.1049. Found: 531.1049.
EXAMPLE 62e
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 C27H22Cl2F2N2O3 
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.
EXAMPLE 63
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 C32H32Cl2FN3O2 
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 C32H32Cl2FN3O2+H [(M+H)+]: 580.1929. Found: 580.1926.
EXAMPLE 64a
Preparation of intermediate 1-(3-methoxycarboxyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 277.40 C14H19NO3Si
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.
EXAMPLE 64b
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 C26H20Cl2N2O4 
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 C26H20Cl2N2O4+H [(M+H)+]: 495.0873 Found: 495.0872.
EXAMPLE 65
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 C34H35Cl2FN4O3 
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 C34H35Cl2FN4O3+H [(M+H)+]: 637.2143 Found: 637.2139.
EXAMPLE 66a
Preparation of intermediate 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 211.38 C11H21NOSi
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.
EXAMPLE 66b
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1129.
EXAMPLE 66c
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 C23H22Cl2N2O2 
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.
EXAMPLE 67a
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 C32H32Cl2FN3O4S
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 C32H32Cl2FN3O4S+H [(M+H)+]: 644.1548. Found: 644.1542.
EXAMPLE 67b
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 C32H32Cl2FN3O4S
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.
EXAMPLE 68a
Preparation of intermediate 1-(2,5-dimethyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 247.42 C14H21NOSi
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.
EXAMPLE 68b
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 C26H22Cl2N2O2 
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 C26H22Cl2N2O2+H [(M+H)+]: 465.1131 Found: 465.1128.
EXAMPLE 68c
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 C26H22Cl2N2O2 
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.
EXAMPLE 69a
Preparation of intermediate 1-(2,5-dimethyl-2H-pyrazole-3-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 237.38 C11H19N3OSi
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.
EXAMPLE 69b
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 C23H20Cl2N4O2 
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 C23H20Cl2N4O2+H [(M+H)+]: 455.1036 Found: 455.1035.
EXAMPLE 70a
Preparation of intermediate 1-(1-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 197.36 C10H19NOSi
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.
EXAMPLE 70b
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 C22H20Cl2N2O2 
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 C22H20Cl2N2O2+H [(M+H)+]: 415.0975. Found: 415.0975.
EXAMPLE 71a
Preparation of intermediate 1-(1-methyl-but-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 211.38 C11H21NOSi
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.
EXAMPLE 71b
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1127.
EXAMPLE 72a
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 C23H24Cl2N2O2 
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:CH2Cl2=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 C23H24Cl2N2O2+H [(M+H)+]: 431.1288 Found: 431.1285.
EXAMPLE 72b
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 C23H24Cl2N2O2 
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%).
EXAMPLE 73a
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 C33H36Cl2F2N2O4Si
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.
EXAMPLE 73b
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 C36H41Cl3F2N2O4Si
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%).
EXAMPLE 73c
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 C34H35Cl2F2N3O4 
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 C34H35Cl2F2N3O4+H [(M+H)+]: 658.2046. Found: 658.2038.
EXAMPLE 73d
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 C34H35Cl2F2N3O4 
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%).
EXAMPLE 74a
Preparation of intermediate 1-(1-ethylidene-pentyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 239.44 C13H25NOSi
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.
EXAMPLE 74b
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 C25H26Cl2N2O2 
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 C25H26Cl2N2O2+H [(M+H)+]: 457.1444 Found: 457.1443.
EXAMPLE 75
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 C27H22Cl2F2N2O2S
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 C27H22Cl2F2N2O2S+H [(M+H)+]: 547.0820. Found: 547.0821.
EXAMPLE 76
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 C30H28Cl2F2N4O4 
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 C30H28Cl2F2N4O4+H [(M+H)+]: 617.1529. Found: 617.1523.
EXAMPLE 77a
Preparation of intermediate cyclopent-1-enecarbaldehyde




M. W. 96.13 C6H8O
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%)
EXAMPLE 77b
Preparation of intermediate 1-(cyclopent-1-enyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 209.37 C11H19NOSi
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.
EXAMPLE 77c
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 C23H20Cl2N2O2 
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 C23H20Cl2N2O2+H [(M+H)+]: 427.0975 Found: 427.0972.
EXAMPLE 78a
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131 Found: 429.1131.
EXAMPLE 78b
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 C23H22Cl2N2O2 
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%).
EXAMPLE 79a
Preparation of intermediate E-2-Isopropyl-but-2-en-1-ol




M. W. 114.19 C7H14O
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 NH4Cl solution, extracted with ether twice. The organic layers were combined, washed with water, brine, dried over MgSO4, 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.
EXAMPLE 79b
Preparation of intermediate E-2-Isopropyl-but-2-enal




M. W. 112.17 C7H12O
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 NaHCO3, brine, dried over MgSO4, and concentrated to give crude E-2-Isopropyl-but-2-enal as a yellow oil (Yield 5.3 g, 98%).
EXAMPLE 79c
Preparation of intermediate 1-(1-isopropyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 225.41 C12H23NOSi
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.
EXAMPLE 79d
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1284
EXAMPLE 79e
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 C24H24Cl2N2O2 
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%).
EXAMPLE 80a
Preparation of intermediate 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 197.36 C10H19NOSi
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.
EXAMPLE 80b
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 C22H20Cl2N2O2 
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 C22H20Cl2N2O2+H [(M+H)+]: 415.0975. Found: 415.0975
EXAMPLE 80c
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 C22H20Cl2N2O2 
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%).
EXAMPLE 81a
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 C29H36Cl2N2O3Si
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%).
EXAMPLE 81b
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 C35H46Cl2N2O5Si
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%).
EXAMPLE 81c
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 C25H24Cl2N2O4 
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 C25H24Cl2N2O4+H [(M+H)+]: 487.1186, Found: 487.1186
EXAMPLE 82a
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 C25H23Cl2FN2O3 
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%).
EXAMPLE 82b
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 C29H33Cl2N3O4 
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 C29H33Cl2N3O4+H [(M+H)+]: 558.1921. Found: 558.1921
EXAMPLE 82c
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 C29H33Cl2N3O4 
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%).
EXAMPLE 83a
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 C32H41Cl3N2O3Si
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%).
EXAMPLE 83b
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 C30H35Cl2N3O3 
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 C30H35Cl2N3O3+H [(M+H)+]: 556.2128. Found: 556.2123.
EXAMPLE 83c
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 C30H35Cl2N3O3 
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%).
EXAMPLE 84a
Preparation of intermediate 3-Methyl-2-methylene-butan-1-ol




M. W. 100.16 C6H12O
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%)
EXAMPLE 84b
Preparation of intermediate 3-Methyl-2-methylene-butyraldehyde




M. W. 98.15 C6H10O
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%)
EXAMPLE 84c
Preparation of intermediate 1-(2-methyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 211.38 C11H21NOSi
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.
EXAMPLE 84d
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1133
EXAMPLE 85a
Preparation of intermediate 3,3-Dimethyl-2-methylene-butan-1-ol




M. W. 114.19 C7H14O
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%)
EXAMPLE 85b
Preparation of intermediate 3,3-Dimethyl-2-methylene-butyraldehyde




M. W. 112.17 C7H12O
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%)
EXAMPLE 85c
Preparation of intermediate 1-(2,2-dimethyl-1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 225.41 C12H23NOSi
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.
EXAMPLE 85d
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1288
EXAMPLE 86
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 C31H36Cl2N4O4 
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 C31H36Cl2N4O4+H [(M+H)+]: 599.2187. Found: 599.2185
EXAMPLE 87a
Preparation of intermediate 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 183.33 C9H17NOSi
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.
EXAMPLE 87b
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 C21H18Cl2N2O2 
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 C21H18Cl2N2O2+H [(M+H)+]: 401.0818. Found: 401.0818
EXAMPLE 87c
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 C21H18Cl2N2O2 
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%).
EXAMPLE 88a
Preparation of intermediate 2-Methylene-pentan-1-ol




M. W. 100.16 C6H12O
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%)
EXAMPLE 88b
Preparation of intermediate 2-Methylene-pentanal




M. W. 98.15 C6H10O
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%)
EXAMPLE 88c
Preparation of intermediate 1-(1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 211.38 C11H21NOSi
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.
EXAMPLE 88d
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131
EXAMPLE 88e
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 C23H22Cl2N2O2 
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%).
EXAMPLE 89a
Preparation of intermediate 4-Methyl-2-methylene-pentan-1-ol




M. W. 114.19 C7H14O
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%)
EXAMPLE 89b
Preparation of intermediate 4-Methyl-2-methylene-pentanal




M. W. 112.17 C7H12O
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%)
EXAMPLE 89c
Preparation of intermediate 1-(3-Methyl-1-methylene-butyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 225.41 C12H23NOSi
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.
EXAMPLE 89d
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1285
EXAMPLE 89e
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 C24H24Cl2N2O2 
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%).
EXAMPLE 90
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 C24H24Cl2N2OS
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 C24H24Cl2N2OS+H [(M+H)+]: 459.1059. Found: 459.1055.
EXAMPLE 91a
Preparation of intermediate 4-Ethoxy-1,2-difluoro-benzene




M. W. 158.15 C8H8F2O
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%).
EXAMPLE 91b
Preparation of intermediate 6-Ethoxy-2,3-difluoro-benzaldehyde




M. W. 186.16 C9H8F2O2 
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%).
EXAMPLE 91c
Preparation of intermediate 1-(4-ethoxy-1,2-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 299.40 C14H19F2NO2Si
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.
EXAMPLE 91d
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 C26H20Cl2F2N2O3 
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 C26H20Cl2F2N2O3+H [(M+H)+]: 517.0892. Found: 517.0889.
EXAMPLE 91e
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 C26H20Cl2F2N2O3 
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%).
EXAMPLE 92a
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 C17H11Cl2NO3 
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
EXAMPLE 92b
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 C22H19Cl2NO5 
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%).
EXAMPLE 92c
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 C24H22Cl2N2O4 
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 C24H22Cl2N2O4+H [(M+H)+]: 473.1030. Found: 473.1031.
EXAMPLE 93
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 C23H20Cl2N2O4 
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 MgSO4, 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 C23H20Cl2N2O4+H [(M+H)+]: 459.0873. Found: 459.0873.
EXAMPLE 94a
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 C23H19Cl2 FN2O3 
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 H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, 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%).
EXAMPLE 94b
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 C28H30Cl2N4O5S
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 C28H30Cl2N4O5S+H [(M+H)+]: 619.1543. Found: 619.1544.
EXAMPLE 95a
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288. Found: 443.1288.
EXAMPLE 95b
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 C24H24Cl2N2O2 
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%).
EXAMPLE 96a
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 C21H20Cl2N2O2 
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 C21H20Cl2N2O2+H [(M+H)+]: 403.0975 Found: 403.0976.
EXAMPLE 96b
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 C21H20Cl2N2O2 
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%).
EXAMPLE 97a
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 C28H34Cl2N2O3Si
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%).
EXAMPLE 97b
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131. Found: 429.1131.
EXAMPLE 97c
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 C23H22Cl2N2O2 
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%).
EXAMPLE 98
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 C22H22Cl2N2O2 
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 C22H22Cl2N2O2+H [(M+H)+]: 417.1131 Found: 417.1134
EXAMPLE 99a
Preparation of intermediate 2-(tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol




M. W. 202.37 C10H22O2Si
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 MgSO4, filtered and concentrated to give 2-(tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol as colorless oil (Yield 12.0 g, 99%).
EXAMPLE 99b
Preparation of intermediate 2-(tert-butyl-dimethyl-silanyloxymethyl)-propenal




M. W. 200.36 C10H20O2Si
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 Na2S2O3 solution, brine and saturated copper (II) sulfate solution, then dried over dried over MgSO4, 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%).
EXAMPLE 99c
Preparation of intermediate 1-[1-(tert-butyl-dimethyl-silanyloxymethyl)-vinyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 313.59 C15H31NO2Si2 
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.
EXAMPLE 99d
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 C21H18Cl2N2O3 
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 C21H18Cl2N2O3+H [(M+H)+]: 417.0767 Found: 417.0767.
EXAMPLE 100a
Preparation of intermediate 2-methoxymethyl-propenal




M. W. 100.12 C5H8O2 
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 MgSO4, filtered and concentrated. The residue was purified with chromatography (hexanes) to give 2-methoxymethyl-propenal as colorless oil (Yield 2.8 g, 7.0%).
EXAMPLE 100b
Preparation of intermediate 1-(1-methoxymethyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 213.75 C10H19NO2Si
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.
EXAMPLE 100c
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 C22H20Cl2N2O3 
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 C22H20Cl2N2O3+H [(M+H)+]: 431.0924 Found: 431.0928.
EXAMPLE 101a
Preparation of intermediate 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene




M. W. 188.18 C9H10F2O2 
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 MgSO4, 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%).
EXAMPLE 101b
Preparation of intermediate 2,3-difluoro-6-(2-methoxy-ethoxy)-benzaldehyde




M. W. 216.19 C10H10F2O3 
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%).
EXAMPLE 101c
Preparation of intermediate 1-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 329.42 C15H21F2NO3Si
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.
EXAMPLE 101d
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 C27H22Cl2F2N2O4 
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 C27H22Cl2F2N2O4+H [(M+H)+]: 547.0998 Found: 547.0997.
EXAMPLE 101e
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 C26H21Cl2FN2O2 
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%).
EXAMPLE 102a
Preparation of intermediate 2,3-dimethyl-but-2-enoic acid ethyl ester




M. W. 142.20 C8H14O2 
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 MgSO4, 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%).
EXAMPLE 102b
Preparation of intermediate 2,3-dimethyl-but-2-en-1-ol




M. W. 100.16 C6H12O
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 NH4Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO4 and filtered. The solvent was removed to give 2,3-dimethyl-but-2-en-1-ol as colorless oil (Yield 4.4 g, 66%).
EXAMPLE 102c
Preparation of intermediate 2,3-dimethyl-but-2-enal




M. W. 98.15 C6H10O
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 NaHCO3, brine, dried over MgSO4, filtered and concentrated to give 2,3-dimethyl-but-2-enal as yellow liquid (Yield 4.0 g, 93%).
EXAMPLE 102d
Preparation of intermediate 1-(1,2-dimethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 211.38 C11H21NOSi
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.
EXAMPLE 102e
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 C23H22Cl2N2O2 
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 C23H22Cl2N2O2+H [(M+H)+]: 429.1131 Found: 429.1132.
EXAMPLE 103
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 C21H18Cl2N2O3 
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:CH2Cl2=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 C21H18Cl2N2O3+H [(M+H)+]: 417.0767. Found: 417.0770.
EXAMPLE 104a
Preparation of intermediate 1,2-difluoro-4-propoxy-benzene




M. W. 172.18 C9H10F2O
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%).
EXAMPLE 104b
Preparation of intermediate 2,3-difluoro-6-propoxy-benzaldehyde




M. W. 200.19 C10H10F2O2 
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%).
EXAMPLE 104c
Preparation of intermediate 1-(2,3-difluoro-6-propoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 313.42 C15H21F2NO2Si
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.
EXAMPLE 104d
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 C27H22Cl2F2N2O3 
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 C27H22Cl2F2N2O3+H [(M+H)+]: 531.1049 Found: 531.1049.
EXAMPLE 104e
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 C27H22Cl2F2N2O3 
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%).
EXAMPLE 105a
Preparation of intermediate 2-cyclopropyl-prop-2-en-1-ol




M. W. 98.15 C6H10O
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 NH4Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO4, 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%).
EXAMPLE 105b
Preparation of intermediate 2-cyclopropyl-propenal




M. W. 96.13 C6H8O
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%).
EXAMPLE 105c
Preparation of intermediate 1-(1-cyclopropyl-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 209.37 C11H19NOSi
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.
EXAMPLE 105d
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 C23H20Cl2N2O2 
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 C23H20Cl2N2O2+H [(M+H)+]: 427.0975 Found: 427.0973.
EXAMPLE 106
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 C24H22Cl2N2O4 
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 C24H22Cl2N2O4+H [(M+H)+]: 473.1030 Found: 473.1032.
EXAMPLE 107a
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 C24H21Cl2FN2O3 
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%).
EXAMPLE 107b
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 C30H34Cl2N4O5S
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 C30H34Cl2N4O5S+H [(M+H)+]: 633.1700. Found: 633.1701.
EXAMPLE 108a
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 C24H23Cl2N3O3 
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 C24H23Cl2N3O3+Na [(M+Na)+]: 494.1008 Found: 494.1008
EXAMPLE 108b
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 C24H23Cl2N3O3 
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%).
EXAMPLE 109a
Preparation of intermediate 2-ethyl-3-methyl-but-2-enoic acid ethyl ester




M. W. 156.23 C9H16O2 
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%).
EXAMPLE 109b
Preparation of intermediate 2-ethyl-3-methyl-but-2-en-1-ol




M. W. 114.19 C7H14O
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%).
EXAMPLE 109c
Preparation of intermediate 2-ethyl-3-methyl-but-2-enal




M. W. 112.17 C7H12O
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%).
EXAMPLE 109d
Preparation of intermediate 1-(1-ethyl-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 225.41 C12H23NOSi
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.
EXAMPLE 109e
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 C24H24Cl2N2O2 
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 C24H24Cl2N2O2+H [(M+H)+]: 443.1288 Found: 443.1287.
EXAMPLE 110a
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 C26H20Cl2F2N2O4 
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 MgSO4, 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 C26H20Cl2F2N2O4+H [(M+H)+]: 533.0841. Found: 533.0842.
EXAMPLE 110b
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 C26H20Cl2F2N2O4 
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%).
EXAMPLE 111
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 C24H16Cl2F2N2O4 
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 C24H16Cl2F2N2O4+H [(M+H)+]: 489.0579. Found: 489.0580.
EXAMPLE 112
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 C23H24Cl2N2O3 
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 NH4Cl solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, 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 C23H24Cl2N2O3+H [(M+H)+]: 447.1237. Found: 447.1237.
EXAMPLE 113a
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 C29H36Cl2N2O4Si
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 NaHCO3 (2 g). The reaction mixture was stirred at room temperature for 18 h, the poured into an aqueous solution of Na2SO3, then extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, 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%).
EXAMPLE 113b
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 C23H22Cl2N2O3 
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 C23H22Cl2N2O3+H [(M+H)+]: 445.1080. Found: 445.1081.
EXAMPLE 114a
Preparation of intermediate 2-fluoro-3-methyl-but-2-enoic acid ethyl ester




M. W. 146.16 C7H11FO2 
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 MgSO4, 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%).
EXAMPLE 114b
Preparation of intermediate 2-fluoro-3-methyl-but-2-en-1-ol




M. W. 104.14 C5H9FO
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 NH4Cl solution, extracted with ether. The organic layers were combined, washed with water, brine, dried over MgSO4 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%).
EXAMPLE 114c
Preparation of intermediate 2-fluoro-3-methyl-but-2-enal




M. W. 102.11 C5H7FO
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 NaHCO3, brine, dried over MgSO4, filtered and concentrated to give 2-fluoro-3-methyl-but-2-enal as yellow liquid (Yield: 4.02 g, 82.4%).
EXAMPLE 114d
Preparation of intermediate 1-(1-fluoro-2-methyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 215.35 C10H18FNOSi
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.
EXAMPLE 114e
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 C22H19Cl2FN2O2 
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 C22H19Cl2FN2O2+H [(M+H)+]: 433.0881 Found: 433.0879.
EXAMPLE 115
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 C22H20Cl2N2O3 
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 C22H20Cl2N2O3+H [(M+H)+]: 431.0924. Found: 431.0925.
EXAMPLE 116a
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 C27H32Cl2N2O3Si
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%)
EXAMPLE 116b
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 C33H42Cl2N2O5Si
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%).
EXAMPLE 116c
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 C23H22Cl2N2O4 
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%).
EXAMPLE 116d
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 C23H19Cl2FN2O3 
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%).
EXAMPLE 116e
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 C23H21Cl2N3O3 
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 C23H21Cl2N3O3+H [(M+H)+]: 458.1033. Found: 458.1033.
EXAMPLE 117
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 C26H25Cl2N3O3 
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 C26H25Cl2N3O3+H [(M+H)+]: 498.1346 Found: 498.1345.
EXAMPLE 118
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 C29H32Cl2N4O3 
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 C29H32Cl2N4O3+H [(M+H)+]: 555.1924 Found: 555.1925.
EXAMPLE 119
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 C29H32Cl2N4O5S
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 C29H32Cl2N4O5S+H [(M+H)+]: 619.1543 Found: 619.1541.
EXAMPLE 120
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 C25H25Cl2N3O4 
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 C25H25Cl2N3O4+H [(M+H)+]: 502.1295 Found: 502.1296.
EXAMPLE 121
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 C27H29Cl2N3O4 
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 C27H29Cl2N3O4+H [(M+H)+]: 502.1295 Found: 502.1296.
EXAMPLE 122a
Preparation of intermediate Z-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-(3-chloro-phenyl)-acetonitrile




M. W. 315.16 C16H8Cl2N2O
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 Na2SO4, 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%).
EXAMPLE 122b
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 C21H16Cl2N2O3 
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%).
EXAMPLE 122c
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 C23H19Cl2N3O2 
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 C23H19Cl2N3O2+H [(M+H)+]: 440.0927. Found: 440.0927.
EXAMPLE 123a
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 C30H37Cl3N2O3Si
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%).
EXAMPLE 123b
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 C31H36Cl2N4O3 
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 C31H36Cl2N4O3+H [(M+H)+]: 583.2237 Found: 583.2239.
EXAMPLE 124a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 280.72 C16H9ClN2O
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%).
EXAMPLE 124b
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 C21H17ClN2O3 
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%).
EXAMPLE 124c
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 C23H20ClFN3O2 
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 C23H20ClFN3O2+H [(M+H)+]: 406.1317 Found: 406.1316.
EXAMPLE 125
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 C26H19ClFN3O2 
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 C26H19ClFN3O2+H [(M+H)+]: 460.1223. Found: 460.1223.
EXAMPLE 126
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 C30H34Cl2N4O3 
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 C30H34Cl2N4O3+H [(M+H)+]: 569.2081 Found: 569.2079.
EXAMPLE 127
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 C29H33Cl2N3O2 
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 C29H33Cl2N3O2+H [(M+H)+]: 526.2023 Found: 526.2020.
EXAMPLE 128a
Preparation of intermediate Acetic acid 2-(2-formyl-4-methyl-phenoxy)-ethyl ester




M. W. 222.24 C12H14O4 
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%).
EXAMPLE 128b
Preparation of intermediate 1-[2-(2-Acetoxy-ethoxy)-5-methyl-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 335.48 C17H25NO4Si
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.
EXAMPLE 128c
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 C29H26Cl2N2O5 
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 C29H26Cl2N2O5+H [(M+H)+]: 553.1292. Found: 553.1291.
EXAMPLE 129
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 C27H24Cl2N2O4 
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 C27H24Cl2N2O4+H [(M+H)+]: 511.1186. Found: 511.1185.
EXAMPLE 130a
Preparation of intermediate 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde




M. W. 359.34 C15H23BrO2Si
To a solution of 5-bromo-2-hydroxy-benzaldehyde (14 g, 69.6 mmol) (Aldrich) in N,N-dimethylformamide (300 mL) was added K2CO3 (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 MgSO4, filtered and concentrated to give 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde as brown oil (Yield: 25 g, 100%).
EXAMPLE 130b
Preparation of intermediate 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde




M. W. 320.51 C18H28O3Si
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 MgSO4, 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%).
EXAMPLE 130c
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 C23H39NO3Si2 
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.
EXAMPLE 130d
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 C29H26Cl2N2O4 
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 C29H26Cl2N2O4+H [(M+H)+]: 537.1343 Found: 537.1343.
EXAMPLE 131a
Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde




M. W. 314.89 C15H23ClO3Si
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%).
EXAMPLE 131b
Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 428.12 C20H34ClNO3Si2 
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.
EXAMPLE 131c
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 C26H21Cl3N2O4 
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 C26H21Cl3N2O4+H [(M+H)+]: 531.0640. Found: 531.0640.
EXAMPLE 132a
Preparation of intermediate tert-Butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane




M. W. 304.87 C14H22ClFO2Si
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, NaHCO3 solution, and brine. The organic layer was separated, dried over Na2SO4, 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%).
EXAMPLE 132b
Preparation of intermediate 6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde




M. W. 332.88 C15H22ClFO2Si
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%).
EXAMPLE 132c
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 C20H33ClFNO3Si2 
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.
EXAMPLE 132d
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 C26H20Cl3FN2O4 
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 C26H20Cl3FN2O4+H [(M+H)+]: 549.0546 Found: 549.0545.
EXAMPLE 133a
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 C21H22ClF2NO2Si
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).
EXAMPLE 133b
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 C22H19ClF2N2O2 
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 C22H19ClN2O2F2+H[(M+H)]: 417.1176; Found: 417.1177
EXAMPLE 134a
Preparation of intermediate E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile




M. W. 280.72 C16H9ClN2O
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.
EXAMPLE 134b
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 C23H20ClN3O2 
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 C23H20ClN3O2+H [(M+H)]: 406.1317; Found: 406.1315
EXAMPLE 135
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 C22H20BrClN2O2 
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 C22H20BrClN2O2+H [(M+H)]: 459.0470; Found: 459.0469
EXAMPLE 136
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 C23H23ClN2O3 
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 C23H23ClN2O3+H[(M+H)]: 433.1289; Found; 433.1288
EXAMPLE 137
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 C23H22ClFN2O2 
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 C23H22ClFN2O2+Na [(M+Na)]: 435.1246; Found: 435.1243
EXAMPLE 138
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 C22H20ClFN2O2 
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 C22H20ClFN2O2+H [(M+H)]: 399.1270; Found: 399.1267
EXAMPLE 139
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 C23H23ClFN2O2 
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 C23H23ClFN2O2+H [(M+H)]: 395.1521; Found: 395.1521
EXAMPLE 140
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 C23H23ClFN2O2 
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 C23H23ClFN2O2+H[(M+H)]: 395.1521; Found: 395.1521
EXAMPLE 141
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 C20H19ClN2O2S
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 C20H19ClN2O2S+H[(M+H)]: 387.0929; Found: 387.0929
EXAMPLE 142
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 C22H19Cl3N2O2 
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 C22H19Cl3N2O2+H [(M+H)]: 449.0585; Found: 449.0585
EXAMPLE 143
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 C23H19Cl2F3N2O2 
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 C23H19Cl2F3N2O2+H[(M+H)]: 483.0849; Found: 483.0848
EXAMPLE 144
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 C21H18BrClN2O2 
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 C21H18BrClN2O2+H [(M+H)]: 445.0313; Found: 445.0313
EXAMPLE 145a
Preparation of intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one




M. W. 287.72 C16H11ClFNO
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%).
EXAMPLE 145b
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 C19H15ClFNO3 
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 Na2SO4, 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%).
EXAMPLE 145c
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 C28H23Cl2FN2O4 
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:CH2Cl2=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%).
EXAMPLE 145d
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 C25H19Cl2FN2O2 
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
EXAMPLE 146a
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 C22H25ClFNO2Si
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 Na2SO4. 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%).
EXAMPLE 146b
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 C31H33Cl2FN2O3Si
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:CH2Cl2=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)
EXAMPLE 146c
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 C37H43Cl2FN2O5Si
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 NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 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).
EXAMPLE 146d
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 C27H21Cl2FN2O4 
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 MgSO4 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
EXAMPLE 147
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 C28H24Cl2FN3O3 
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.
EXAMPLE 148
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 C29H26Cl2FN3O3 
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
EXAMPLE 149
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 C33H31Cl2FN4O4 
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
EXAMPLE 150
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 C33H31Cl2FN4O4 
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
EXAMPLE 151
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 C27H22Cl2FN3O3 
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 MgSO4 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
EXAMPLE 152a
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 C34H38Cl3FN2O5Si
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%).
EXAMPLE 152b
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 C30H30Cl2FN3O2 
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 NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 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 NaHCO3 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
EXAMPLE 153a
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 C38H46Cl2FN3O5Si
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).
EXAMPLE 153b
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 C34H35Cl2FN4O5S
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 NaHCO3 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
EXAMPLE 154a
Preparation of intermediate E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one




M. W. 296.18 C13H7Cl2NOS
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%)
EXAMPLE 154b
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 C23H17Cl2FN2O2S
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
EXAMPLE 155a
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one




M. W. 296.18 C13H7Cl2NOS
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%)
EXAMPLE 155b
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 C23H17Cl2FN2O2S
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
EXAMPLE 156
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 C24H26ClFN2O2 
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
EXAMPLE 157a
Preparation of intermediate E/Z-6-bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 334.60 C15H9BrClNO
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%).
EXAMPLE 157b
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 C25H20BrClN2O2 
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:CH2Cl2=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
EXAMPLE 158a
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 C25H19BrClFN2O2 
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
EXAMPLE 158b
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 C25H19BrClFN2O2 
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
EXAMPLE 159a
Preparation of intermediate 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 288.25 C12H15Cl2NOSi
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.
EXAMPLE 159b
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 C24H16BrCl3N2O2 
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
EXAMPLE 160a
Preparation of intermediate 1-(5-chloro-2-methyl phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 267.83 C13H18ClNOSi
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.
EXAMPLE 160b
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 C25H19BrCl2N2O2 
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
EXAMPLE 161a
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
C21H23BrClNO2Si
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 Na2SO4. 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%).
EXAMPLE 161b
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 C28H34BrClN2O3Si
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).
EXAMPLE 161c
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 C22H20BrClN2O2 
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).
EXAMPLE 161d
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
C22H20BrClN2O2 
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
EXAMPLE 162a
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 C29H36BrClN2O3Si
CH2I2 (1.2 g, 4.6 mmol) was dissolved in dry toluene (5 mL) at 0° C. After stirred for 10 min under Argon, Et2Zn (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 NH4Cl (20 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated, the residue, was used for next step without further purification.
EXAMPLE 162b
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 C23H22BrClN2O2 
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
EXAMPLE 163a
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 C28H30BrClN2O4 
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)2O (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).
EXAMPLE 163b
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 C31H35ClN2O4 
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(PPh3)4 (5 mg), K3PO4 (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).
EXAMPLE 163c
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 C26H27ClN2O2 
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
EXAMPLE 164a
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 C30H27Cl2FN2O4 
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%).
EXAMPLE 164b
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 C30H26BrCl2FN2O4 
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.
EXAMPLE 164c
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 C31H29Cl2FN4O3 
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 K2CO3 (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
EXAMPLE 165
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 C30H29Cl2FN4O4S
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 K2CO3 (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%).
EXAMPLE 166
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 C32H31Cl2FN4O5S
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 Na2SO4. 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 Na2SO4. 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
EXAMPLE 167a
Preparation of intermediate 6-fluoro-1,3-dihydro-indol-2-one




M. W. 151.14 C8H6FNO
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 Na2SO4. 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 Na2SO4. concentrated to give the titled compound as a yellow solid (3 g, 89%).
MS m/z (M+H)+: 152
EXAMPLE 167b
Preparation of intermediate E/Z-6-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 273.70 C15H9ClFNO
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
EXAMPLE 167c
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 C25H19ClF2N2O2 
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
EXAMPLE 168a
Preparation of intermediate 6-methoxy-1,3-dihydro-indol-2-one
M. W. 163.18 C9H9NO2 
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
EXAMPLE 168b
Preparation of intermediate E/Z-6-methoxy-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 285.73 C16H12ClNO2 
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
EXAMPLE 168c
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 C26H22ClFN2O3 
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
EXAMPLE 169a
Preparation of intermediate E/Z-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 255.71 C15H10ClNO
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
EXAMPLE 169b
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 C25H20ClFN2O2 
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
EXAMPLE 170a
Preparation of intermediate 5-fluoro-1,3-dihydro-indol-2-one




M. W. 151.14 C8H6FNO
To the solution of 3-fluorophenylacetic acid (1.23 g, 8 mmol) in concentrated H2SO4 (2.0 mL, 40 mmol) at 0° C. was added HNO3 (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 Na2SO4, 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 Na2SO4, concentrated in vacuo to give the desired product (1 g, 82%).
MS m/z (M+H)+: 152
EXAMPLE 170b
Preparation of intermediate E/Z-5-fluoro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 273.70 C15H9ClFNO
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
EXAMPLE 170c
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 C25H19ClF2N2O2 
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
EXAMPLE 171a
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 C26H26Cl2N2O2 
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 Na2SO4, 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
EXAMPLE 171b
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 C22H20Cl2N2O2 
To a solution of CH2I2 (1.2 g, 4.6 mmol) in anhydrous toluene (5 mL) under Argon at 0° C. was added a toluene solution of Et2Zn (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 NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 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 C22H20Cl2N2O2+H [(M+H)+]: 415.0975 Found: 415.0975.
EXAMPLE 172a
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 C20H17BrClNO3 
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
EXAMPLE 172b
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 C21H18BrClN2O2 
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
EXAMPLE 173a
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 C26H26BrClN2O4 
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
EXAMPLE 173b
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 C22H20BrClN2O2 
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 CH2I2 (1.2 g, 4.6 mmol) and Et2Zn (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
EXAMPLE 174
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 C23H17ClN2O2 
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(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (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 NH4Cl, 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
EXAMPLE 175
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 C33H33Cl2FN4O5S
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
EXAMPLE 176a
Preparation of intermediate 4-[2-(1,1-Dioxo-isothiazolidin-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester




M. W. 333.45 C14H27N3O4S
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 (Na2SO4). The solution was concentrated and the residue was dissolved in THF (20 mL) and Cs2CO3 (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 (Na2SO4). Removal of the solvent on a rotary evaporator gave a solid. 2.01 g.
MS m/z (M+H)+: 334
EXAMPLE 176b
Preparation of intermediate 1-[2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl]-piperazine di-trifluoroacetic acid




M. W. 233.33 C9H19N3O2S
4-[2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.01 g) was treated with 30% TFA/CH2Cl2 (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
EXAMPLE 176c
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 C36H38Cl2FN5O5S
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
EXAMPLE 177
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 C35H37Cl2FN4O5S
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
EXAMPLE 178a
Preparation of intermediate 1-(2-Bromo-2-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 316.25 C12H15BrFNOSi
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.
EXAMPLE 178b
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 C24H16BrCl2FN2O2 
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/CH2Cl2 (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
EXAMPLE 179
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 C26H17Cl2FN2O2 
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), PdCl2(PPh3)2 (Aldrich, 10 mg) and Et3N (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
EXAMPLE 180
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 C29H24Cl2FN3O4S
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), PdCl2(PPh3)2 (20 mg) and Et3N (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
EXAMPLE 181a
Preparation of intermediate 1-[5-bromo-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 472.57 C20H34BrNO3Si2 
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.
EXAMPLE 181b
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 C26H21BrCl2N2O4 
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
EXAMPLE 182a
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 C28H22Cl2N2O4 
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), Et3N (0.3 mL), PdCl2(Ph3P)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
EXAMPLE 182b
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 C28H22Cl2N2O4 
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%).
EXAMPLE 183a
Preparation of intermediate [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane




M. W. 349.32 C14H22BrFO2Si
In a manner similar to the method described in example 132a, 4-bromo-3-fluoro-phenol (12 g, 62.3 mmol) was reacted with K2CO3 (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%).
EXAMPLE 183b
Preparation of intermediate 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde




M. W. 377.33 C15H22BrFO3Si
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%).
EXAMPLE 183c
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 C20H33BrFNO3Si2 
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.
EXAMPLE 183d
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 C26H20BrCl2FN2O4 
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 NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 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 MgSO4 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 C26H20BrCl2FN2O4+H [(M+H)+]: 593.0041. Found: 593.0039.
EXAMPLE 184a
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 C31H29Cl2FN2O4Si
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 MgSO4, 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%).
EXAMPLE 184b
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 C28H21Cl2FN2O4 
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 MgSO4, 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 C28H21Cl2FN2O4+H [(M+H)+]: 539.0935. Found: 539.0935.
EXAMPLE 185a
Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde




M. W. 308.50 C17H28O3Si
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 K2CO3 (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%).
EXAMPLE 185b
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 C22H39NO3Si2 
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.
EXAMPLE 185c
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 C28H26Cl2N2O4 
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 C28H26Cl2N2O4+H [(M+H)+]: 525.1343 Found: 525.1343.
EXAMPLE 186
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 C25H25Cl2N3O4 
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%).
EXAMPLE 187
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 C23H21Cl2N3O3 
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%).
EXAMPLE 188
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 C26H25Cl2N3O3 
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%).
EXAMPLE 189
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 C27H29Cl2N3O4 
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%).
EXAMPLE 190a
Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde




M. W. 406.34 C15H23IO3Si
To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (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 MgSO4, concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde as a yellow oil (Yield 10 g, 100%).
EXAMPLE 190b
Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 519.58 C20H34INO3Si2 
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.
EXAMPLE 190c
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 C26H21Cl2IN2O4 
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 NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=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 C26H21Cl2IN2O4+H [(M+H)+]: 622.9996. Found: 622.9995.
EXAMPLE 191
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 C27H21Cl2N2O4 
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 Na2SO4 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 C27H21Cl2N2O4+H [(M+H)+]: 522.0982. Found: 522.0984.
EXAMPLE 192a
Preparation of intermediate 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 345.25 C12H16INOSi
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.
EXAMPLE 192b
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 C24H17Cl2IN2O2 
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 NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=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 C24H17Cl2IN2O2+H [(M+H)+]: 562.9785. Found: 562.9786.
EXAMPLE 193
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 C26H18Cl2N2O2 
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 MgSO4 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 C26H18Cl2N2O2+H [(M+H)+]: 461.0818. Found: 461.0818.
EXAMPLE 194a
Preparation of intermediate 1-(2-fluoro-5-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 363.25 C12H15FINOSi
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.
EXAMPLE 194b
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 C24H16Cl2FIN2O2 
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 C24H16Cl2FIN2O2+H [(M+H)+]: 580.9691. Found: 580.9691.
EXAMPLE 195
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 C26H17Cl2FN2O2 
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 C26H17Cl2FN2O2+H [(M+H)+]: 479.0724. Found: 479.0725.
EXAMPLE 196a
Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-3-methoxy-benzaldehyde




M. W. 406.34 C15H23IO3Si
To a solution of 5-iodovanillin (10 g, 35.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (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 MgSO4, 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%).
EXAMPLE 196b
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 C21H36INO4Si2 
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.
EXAMPLE 196c
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 C27H23Cl2IN2O5 
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 C27H23Cl2IN2O+H [(M+H)+]: 653.0102. Found: 653.0102.
EXAMPLE 197
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 C29H24Cl2N2O5 
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 C29H24Cl2N2O5+H [(M+H)+]: 551.1135. Found: 551.1136.
EXAMPLE 198a
Preparation of intermediate 5-Iodo-2-methyl-benzaldehyde




M. W. 246.05 C8H7IO
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 MgSO4, and concentrated to give an off-white solid. The solid was dissolved into dichloromethane (300 mL), and activated MnO2 (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%).
EXAMPLE 198b
Preparation of intermediate 1-(5-iodo-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 359.28 C13H18INOSi
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.
EXAMPLE 198c
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 C25H19Cl2IN2O2 
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 C25H19Cl2IN2O2+H [(M+H)+]: 576.9941. Found: 576.9942.
EXAMPLE 199
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 C27H20Cl2N2O2 
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 C27H20Cl2N2O2+H [(M+H)+]: 475.0975. Found: 475.0977.
EXAMPLE 200
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 C28H21Cl2FN2O4 
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%).
EXAMPLE 201a
Preparation of intermediate 5-Iodo-2-nitro-benzaldehyde




M. W. 277.02 C7H41NO3 
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 MgSO4, 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 MnO2 (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%).
EXAMPLE 201b
Preparation of intermediate 1-(5-iodo-2-nitrophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 390.26 C12H15IN2OSi
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.
EXAMPLE 201c
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 C24H16Cl2IN3O4 
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 C24H16Cl2IN3O4+H [(M+H)+]: 607.9636. Found: 607.9638.
EXAMPLE 202
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 C26H17Cl2N3O4 
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 C26H17Cl2N3O4+H [(M+H)+]: 506.0669. Found: 506.0671.
EXAMPLE 203
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 C24H18Cl2IN3O2 
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 NH4Cl 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 MgSO4, 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 C24H18Cl2IN3O2+H [(M+H)+]: 577.9894. Found: 577.9894.
EXAMPLE 204
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 C26H19Cl2N3O2 
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 C26H19Cl2N3O2+H [(M+H)+]: 476.0927. Found: 476.0929.
EXAMPLE 205a
Preparation of intermediate 1-(3-bromo-4-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 316.25 C12H15BrFNOSi
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.
EXAMPLE 205b
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 C24H16BrCl2FN2O2 
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 C24H16BrCl2FN2O2+H [(M+H)+]: 532.9829. Found: 532.9832.
EXAMPLE 206
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 C26H17Cl2FN2O2 
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 C26H17Cl2FN2O2+H [(M+H)+]: 479.0724. Found: 479.0724.
EXAMPLE 207a
Preparation of intermediate 1-(1-benzofuran-5-yl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 259.38 C14H17NO2Si
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.
EXAMPLE 207b
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 C26H18Cl2N2O3 
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 C26H18Cl2N2O3+H [(M+H)+]: 477.0767. Found: 477.0767.
EXAMPLE 208a
Preparation of intermediate 5-chloro-2-Iodo-benzaldehyde




M. W. 266.47 C7H4ClIO
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 MgSO4, and concentrated to give a colorless oil. The oil was dissolved into 1,2-dichloroethane (50 mL), and activated MnO2 (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%).
EXAMPLE 208b
Preparation of intermediate 1-(5-chloro-2-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 379.70 C12H15ClINOSi
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.
EXAMPLE 208c
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 C24H16Cl3IN2O2 
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 C24H16Cl3IN2O2+H [(M+H)+]: 596.9395. Found: 596.9393.
EXAMPLE 209a
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 C29H24Cl2N2O4 
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 Na2SO4 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 C29H24Cl2N2O4+H [(M+H)+]: 535.1186. Found: 535.1187.
EXAMPLE 209b
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 C29H24Cl2N2O4 
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%).
EXAMPLE 210
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 C32H30Cl2N2O4 
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 MgSO4 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 C32H30Cl2N2O4+H [(M+H)+]: 577.1656. Found: 577.1655.
EXAMPLE 211
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 C31H26Cl2N2O4 
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 C31H26Cl2N2O4+H [(M+H)+]: 561.1343. Found: 561.1344.
EXAMPLE 212
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 C31H28Cl2N2O4 
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 C31H28Cl2N2O4+H [(M+H)+]: 563.1499. Found: 561.1501.
EXAMPLE 213
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 C28H24Cl2N2O4 
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 Na2SO4 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 C28H24Cl2N2O4+H [(M+H)+]: 523.1186. Found: 523.1187.
EXAMPLE 214a
Preparation of intermediate 4-iodo-2-tert-butyl-dimethylsilanyloxy-benzaldehyde




M. W. 362.29 C13H19IO2Si
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.
EXAMPLE 214b
Preparation of intermediate 1-[5-bromo-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3-trimethylsilanyloxy-2-aza-1,3-butadiene




M. W. 475.52 C18H30INO2Si2 
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.
EXAMPLE 214c
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 C35H39Cl21N2O5Si
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.
EXAMPLE 214d
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 C24H17Cl2IN2O3 
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/CH2Cl2 (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.
EXAMPLE 214e
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 C29H26Cl2N2O3Si
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 PdCl2(PPh3)2 (18 mg), CuI (4 mg), trimethylsilyl acetylene (Aldrich, 0.40 mL) and Et3N (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.
EXAMPLE 214f
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 C26H18Cl2N2O3 
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.
EXAMPLE 214g
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 C26H18Cl2N2O3 
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%).
EXAMPLE 215a
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 C32H29Cl2IN2O5 
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/CH2Cl2) to give a yellow foam, 340 mg. MS (H+), 719.
EXAMPLE 215b
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 C27H21Cl2IN2O3 
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/CH2Cl2 (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 NaHCO3 solution, extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to give an off white foam. 225 mg. MS (H+), 619
EXAMPLE 215c
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 C27H23Cl2IN2O5 
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 CH2Cl2 (3 ml) was added acetone (2 ml) and water (2 ml), followed by a solution of OsO4 (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 Na2SO3. The reaction was diluted with CH2Cl2 and water. Organic layer was separated, the aqueous layer was extracted CH2Cl2. 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
EXAMPLE 215d
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 C32H32Cl2N2O5Si
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 PdCl2(PPh3)2 (15 mg), CuI (2 mg), trimethylsilyl acetylene (Aldrich, 2 mL) and Et3N (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
EXAMPLE 215e
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 C29H24Cl2N2O5 
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 MgSO4 and concentrated to give the title compound as a white solid (6.2 mg). MS (H+), 551
EXAMPLE 216
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 C25H19BrCl2N2O2S
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.
EXAMPLE 217
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 C25H19BrCl2N2O4S
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 Na2SO3 solution. The mixture was extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO4 and concentrated to give the title compound as an off white solid (360 mg). MS (M+H+), 595
EXAMPLE 218a
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 C30H28Cl2N2O4SSi
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 PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound.
EXAMPLE 218b
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 C27H20Cl2N2O4S
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
EXAMPLE 219
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 C25H19BrCl2N2O3 
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.
EXAMPLE 220a
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 C30H28Cl2N2O3Si
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 PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound. MS (H+),
EXAMPLE 220b
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 C27H20Cl2N2O3 
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 CH2Cl2, then EtOAc. Recrystallization gave the title compound as a white solid (13 mg, 13% yield). MS (H+), 491
EXAMPLE 221
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 C29H21Cl2F3N2O4 
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. Bu3SnCl (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.
EXAMPLE 222a
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 C31H30Cl2N2O4Si
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), Et3N (50 mL), PdCl2(Ph3P)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%.
EXAMPLE 222b
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 C32H32Cl2N2O6SSi
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.
EXAMPLE 222c
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 C33H31Cl2N3O3 
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/CH2Cl2) to give a white solid. 34 mg. MS (H+), 588.
EXAMPLE 223
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 C28H21Cl2N5O3 
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.
EXAMPLE 224
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 C28H21Cl2N5O3 
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 PMe3 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
EXAMPLE 225a
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 C30H37BrClN3O4Si
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).
EXAMPLE 225b
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 C24H23BrClN3O3 
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.
EXAMPLE 225c
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 C24H23BrClN3O3 
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
EXAMPLE 226a
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 C31H34Cl2N2O6 
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 Na2SO4. The solvent was removed to give title compound as a solid (0.7 g).
m/z (M+H)+: 601
EXAMPLE 226b
Preparation of intermediate trimethylsilyl fluorosulfonyldifluoroacetate




M. W. 250.27 C5H9F3O4SSi
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.
EXAMPLE 226c
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 C22H18Cl2F2N2O2 
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 (CH2Cl2:CH3OH=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.
EXAMPLE 226d
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 C22H18Cl2F2N2O2 
The title compound was obtained as the other product in Example 226c.
m/z (M+H)+: 451.
EXAMPLE 227a
Preparation of intermediate 5-chloro-2-isopropoxy-benzaldehyde




M. W. 198.65 C10H11ClO2 
5-Chloro-2-hydroxy-benzaldehyde (3 g, 19.16 mmol),2-Iodo-propane (4.88 g, 28.74 mmol) and K2CO3 (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.
EXAMPLE 227b
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one




M. W. 348.23 C18H15Cl2NO2 
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).
EXAMPLE 227c
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 C23H23Cl2NO4 
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).
EXAMPLE 227d
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 C24H24Cl2N2O3 
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
EXAMPLE 228a
Preparation of intermediate acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester




M. W. 242.66 C11H11CO4 
5-Chloro-2-hydroxy-benzaldehyde (2 g, 12.8 mmol), acetic acid 2-bromo-ethyl ester (2.57 g, 15.4 mmol), K2CO3 (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 CH2Cl2 and the organic layer was washed with water for several times. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain a yellow solid. (2.7 g)
EXAMPLE 228b
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 C17H13Cl2NO3 
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).
EXAMPLE 228c
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 C27H29Cl2NO7 
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)
EXAMPLE 228d
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 C27H23Cl2FN2O4 
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
EXAMPLE 228e
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 C27H23Cl2FN2O4 
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
EXAMPLE 229a
Preparation of intermediate 2-(4-Chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester




M. W. 270.72 C13H15ClO4 
5-Chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (11.4 g, 58 mmol), K2CO3 (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 Na2SO4 and concentrated to give title compound (7 g)
EXAMPLE 229b
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 C21H19Cl2NO4 
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).
EXAMPLE 229c
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 C26H27Cl2NO6 
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).
EXAMPLE 229d
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 C31H29Cl2FN2O5 
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
EXAMPLE 229e
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 C31H29Cl2FN2O5 
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
EXAMPLE 230a
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 C29H25Cl2FN2O5 
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
EXAMPLE 230b
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 C29H25Cl2FN2O5 
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
EXAMPLE 231
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 C29H27Cl2FN2O4 
With cooling of an ice bath, LiAlH4 (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
EXAMPLE 232a
Preparation of intermediate 5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde




M.W 283.05 C9H6BrF3O2 
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 K2CO3 (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).
EXAMPLE 232b
Preparation of intermediate 1-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 396.28 C14H17BrF3NO2Si
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.
EXAMPLE 232c
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




M.W 614.25 C26H18BrCl2F3N2O3 
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 (200 mg, 0.5 mmol) prepared in Example 24a was reacted with 1-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.57 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (13 mg).
m/z (M+H)+: 613
EXAMPLE 233
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxyethoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M.W 461.35 C23H22Cl2N2O4 
In a manner similar to the method described in Example 41b, 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 (350 mg, 0.637 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.82 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (10 mg).
m/z (M+H)+: 461
EXAMPLE 234a
Preparation of intermediate (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester




M. W. 228.63 C10H9ClO4 
5-Chloro-2-hydroxy-benzaldehyde (30 g, 192 mmol), bromo-acetic acid methyl ester (29.4 g, 192 mmol), K2CO3 (53 g, 384 mmol) and KI (9.6 g, 57 mmol) were mixed in acetone (100 mL). Then the mixture was heated at 80° C. for 30 min. The mixture was filtered and the filterate was concentrated. The residue was dissolve in ethyl acetate and washed with base aqueous solution (1N NaOH). The organic layer was separated, dried and concentrated to give (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester yellow solid. (44 g)
EXAMPLE 234b
Preparation of intermediate E/Z-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-acetic acid methyl ester




M. W. 378.21 C18H13Cl2NO4 
In a manner similar to the method described in Example 227b, (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester (34 g, 149 mmol) was reacted with 6-chlorooxindole (20.7 g, 124 mmol) and pyrrolidine (10.58 g, 149 mmol) in methanol to give title compound as a yellow solid (35 g).
EXAMPLE 234c
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-methoxycarbonyl methoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 478.33 C23H21Cl2NO6 
In a manner similar to the method described in Example 227c, E/Z-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-acetic acid methyl ester (35 g, 92.8 mmol) was reacted with ditert-butyl-dicarbonate (22.3 g, 102 mmol) and DMAP (2.3 g, 18.6 mmol) in CH2Cl2 to give title compound as yellow oil (30 g).
EXAMPLE 234d
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 478.33 C23H21Cl2NO6 
E/Z-6-Chloro-3-(5-chloro-2-methoxycarbonyl methoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6 g, 12.6 mmol),1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (63 mmol) were dissolved in toluene (50 mL). After the sealed tube was heated to 140° C. for 2 h, the solution was concentrated. The residue was diluted with ethyl acetate, washed with water. The organic layer was separated, dried and concentrated. The residue was purified by chromatography to obtain a crude product (600 mg). The crude product (50 mg) was purified further by Prep-HPLC to give title compound as a white solid (11 mg).
m/z (M+H)+: 478
EXAMPLE 235
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 475.33 C23H20Cl2N2O5 
Racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (80 mg, 0.164 mmol) was dissolved in THF (10 mL). Then aqueous solution (1 mL) of NaOH (20 mg) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and acidified to “pH” 2-3. The mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The crude product (50 mg) was purified by Prep-HPLC to give the title compound as a white solid (14 mg).
m/z (M+H)+: 475
EXAMPLE 236a
Preparation of intermediate 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 255.34 C12H15F2NOSi
To dry tetrahydrofuran (100 mL) was added 1M THF solution of LiHMDS (105 mmol, 105 mL) under nitrogen at room temperature, followed by the addition of 2,5-difluorobenzaldehyde (14.9 g, 105 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (13.3 mL, 105 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 (19 mL, 136 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (3.88 mL, 54.4 mmol) in diethyl ether (300 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 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
EXAMPLE 236b
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 603.45 C30H26Cl2F2N2O5 
Under argon protection, 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 prepared in Example 229c (8 g, 15.4 mmol) and 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30.8 mmol) were dissolved in toluene. The solution was heated at 80° C. for 5 h. Then the solution was concentrated and the residue was purified by chromatography (CH2Cl2:CH3OH=50:1) to obtain 1.7 g crude product. The crude product (50 mg) was purified again by Prep-HPLC to obtain give title compound as a white solid (12 mg).
m/z (M+H)+: 603
EXAMPLE 237
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 575.40 C28H22Cl2F2N2O5 

    racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg, 0.66 mmol) was dissolved in THF (10 mL). Then aqueous solution (1 mL) of NaOH (111 mg, 1.99 mmol) was added. The mixture was refluxed for 1 h. The solution was cooled to room temperature, concentrated and acidified to “pH” 2-3. The precipitate was collected by filtration to give title compound as a white solid (300 mg).


m/z (M+H)+: 575
EXAMPLE 238
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 561.42 C28H24Cl2F2N2O4 
In a manner similar to the method described in Example 231, racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) was reacted with LiAlH4 (63 mg, 1.66 mmol) in THF and the crude product was purified by Prep-HPLC to give title compound as a white solid (6 mg).
EXAMPLE 239a
Preparation of intermediate 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester




M. W. 286.35 C13H18O5S
A mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 100 mmol), 4-methyl-benzenesulfonyl chloride (18.1 g, 90 mmol), 4-dimethylamino pyridine (15.9 g, 130 mmol) in dichloromethane was stirred at room temperature for 1 h. Then the mixture was washed by aqueous HCl solution (1 N), brine and dried over Na2SO4. The solvent was removed in vacuum to give title compound (23 g).
EXAMPLE 239b
Preparation of intermediate 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester




M. W. 315.17 C13H15BrO4 
5-Bromo-2-hydroxy-benzaldehyde (4 g, 2 mmol), 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 150° C. for 1 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 Na2SO4 and concentrated to give title compound 5.7 g.
EXAMPLE 239c
Preparation of intermediate E/Z-3-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester




M. W. 464.75 C21H19BrClNO4 
In a manner similar to the method described in Example 227b, 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (3.4 g, 10.8 mmol) was reacted with 6-chlorooxindole (1.8 g, 10.8 mmol) and pyrrolidine (0.84 g, 11.8 mmol) in methanol to give E/Z-3-[4-Bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester as a yellow solid (2.7 g).
EXAMPLE 239d
Preparation of intermediate E/Z-3-[1-[5-Bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-methylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 564.87 C26H27BrClNO6 
In a manner similar to the method described in Example 227c, E/Z-3-[4-Bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester (2.7 g, 5.81 mmol) was reacted with ditert-butyl-dicarbonate (1.5 g, 6.98 mmol) and DMAP (0.07 g, 0.58 mmol) in CH2Cl2 to give title compound as a yellow oil (2.7 g).
EXAMPLE 239e
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro 2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 680.82 C30H26BrCl3N2O5 
In a manner similar to the method described in Example 228d, E/Z-3-[1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-methylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1-(2,5-dichloro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 159a (6.9 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as white solid (14 mg).
m/z (M+H)+: 679
EXAMPLE 240
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 652.80 C29H26BrCl3N2O4 
In a manner similar to the method described in Example 231, racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (220 mg, 0.32 mmol) was reacted with LiAlH4 (61 mg, 1.62 mmol) in THF and the crude product was purified by Prep-HPLC to give title compound as a white solid (13 mg).
m/z (M+H)+: 651
EXAMPLE 241
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 643.94 C31H29BrClFN2O5 
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.4 g, 2.48 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.44 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (260 mg).
m/z (M+H)+: 643
EXAMPLE 242
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 615.93 C30H29BrClFN2O4 
In a manner similar to the method described in Example 231, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.187 mmol) was reacted with LiAlH4 (35 mg, 0.934 mmol) in THF and the crude product was purified by Prep-HPLC to give title compound as a white solid (13 mg).
m/z (M+H)+: 615
EXAMPLE 243a
Preparation of intermediate E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester




M. W. 315.17 C13H15BrO4 
5-Bromo-2-hydroxy-benzaldehyde (20 g, 100 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (29 g, 150 mmol), K2CO3 (27.6 g, 200 mmol) and KI (3.2 g, 19 mmol) were mixed in DMF (100 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 Na2SO4 and concentrated to give title compound (21 g)
EXAMPLE 243b
Preparation of intermediate E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester




M. W. 464.75 C21H19BrClNO4 
To the mixture of 6-chlorooxindole (10.6 g, 63 mmol) and 2-(4-bromo-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (20 g, 63 mmol) in methanol (150 mL) was added pyrrolidine (4.5 g, 6 3 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (18.5 g, 63%).
EXAMPLE 243c
Preparation of intermediate E/Z 3-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 564.87 C26H27BrClNO6 
To a solution of E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (5 g, 11 mmol) in dichloromethane (50 mL) at r.t was added di-tert-butyl-dicarbonate (2.4 g, 11 mmol), followed by the addition of 4-dimethylaminopyridine (1 g, 8.2 mmol). The reaction mixture was stirred at r.t. for 2 h, washed with aqueous HCl solution (0.5M) and water. The organic layer was separated, dried over Na2SO4, concentrated to give E/Z 3-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow oil (5.5 g, 88%).
EXAMPLE 243d
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 680.82 C30H26BrCl3N2O5 
In a manner similar to the method described in Example 228d, E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (2.2 g, 3.9 mmol) was reacted with 1-(2,5-dichloro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.8 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (240 mg).
m/z (M+H)+: 679
EXAMPLE 244
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 652.76 C28H22BrCl3N2O5 
Racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.22 mmol) was dissolved in THF (5 mL). Then aqueous solution (1 mL) of KOH (50 mg, 0.88 mmol) was added. The mixed solution was refluxed for 1 h. The mixture was cooled, concentrated and acidified to “pH” 2-3. The solution was concentrated and the residue was purified by Prep-HPLC to obtain a white solid (13 mg).
m/z (M+H)+: 651
EXAMPLE 245a
Preparation of intermediate 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 428.40 C18H26BrNO4Si
To anhydrous tetrahydrofuran (40 mL) was added 1M THF solution of LiHMDS (25.9 mmol, 25.9 mL) under nitrogen at room temperature, followed by the addition of 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (8 g, 25.9 mmol). The mixture was stirred at room temperature for 1 h, then trimethylsilyl chloride (3.3 mL, 25.9 mmol) was added dropwise. The temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (4.6 mL, 33.2 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (2.35 mL, 33.2 mmol) in diethyl ether (100 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 title compound as a yellow gum and used for the next step without further purification.
EXAMPLE 245b
Preparation of intermediate E/Z-6-Chloro-3-(2,5-dichloro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 324.60 C15H8Cl3NO
In a manner similar to the method described in Example 227b, 2,5-dichloro-benzaldehyde (5 g, 28.57 mmol) was reacted with 6-chlorooxindole (4.77 g, 28.57 mmol) and pyrrolidine (2.43 g, 34.3 mmol) in methanol to give title compound as yellow solid (10 g).
EXAMPLE 245c
Preparation of intermediate E/Z-6-chloro-3-(2,5-dichloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 424.71 C20H16Cl3NO3 
In a manner similar to the method described in Example 227c, E/Z-6-Chloro-3-(2,5-dichloro-benzylidene)-1,3-dihydro-indol-2-one (10 g, 30.9 mmol) was reacted with ditert-butyl-dicarbonate (8.1 g, 37.1 mmol) and DMAP (0.38 g, 3.09 mmol) in CH2Cl2 to give title compound as a yellow oil (7.5 g).
EXAMPLE 245d
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 680.82 C30H26BrCl3N2O5 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-(2,5-dichloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.8 g, 4.3 mmol) was reacted with 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (220 mg).
m/z (M+H)+: 679
EXAMPLE 246
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2,2-dimethyl-3-hydroxy propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 652.80 C29H26BrCl3N2O4 
In a manner similar to the method described in Example 231, racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.177 mmol) was reacted with LiAlH4 (34 mg, 0.885 mmol) in THF to give title compound as a white solid (21 mg).
m/z (M+H)+: 651
EXAMPLE 247a
Preparation of intermediate (2-bromo-ethyl)-carbamic acid tert-butyl ester




M. W. 224.10 C7H14BrNO2 
Di-tert-butyl-dicarbonate (17.8 g, 0.081 mol) and DIPEA (11.6 g, 0.090 mol) were dissolved in ethanol (200 mL) at room temperature. Then 2-aminoethylbromide hydrobromide (20 g, 0.098 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was dissolved in ethyl acetate and washed with water for three times. The organic layer was separated, dried over Na2SO4 and concentrated to give (2-bromo-ethyl)-carbamic acid tert-butyl ester as light yellow oil. (15 g)
EXAMPLE 247b
Preparation of intermediate [2-(4-chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester




M. W. 299.76 C14H18ClNO4 
In a manner similar to the method described in Example 227a, (2-bromo-ethyl)-carbamic acid tert-butyl ester (10 g, 44.8 mmol) was reacted with 5-chloro-2-hydroxy-benzaldehyde (7 g, 44.8 mmol), K2CO3 (18.6 g, 134 mmol) and KI (1.48 g, 8.96 mmol) to give title compound as oil (9.56 g)
EXAMPLE 247c
Preparation of intermediate E/Z-{2-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester




M. W. 449.34 C22H22Cl2N2O4 
In a manner similar to the method described in Example 227b, [2-(4-chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-Chlorooxindole (4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol to give title compound as a yellow solid (16 g).
EXAMPLE 247d
Preparation of intermediate E/Z-3-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 549.46 C27H30Cl2N2O6 
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]-ethyl}-carbamic acid tert-butyl ester (12 g, 30.27 mmol) was reacted with di-tert-butyl-dicarbonate (5.8 g, 27 mmol) and DMAP (0.66 g, 5.4 mmol) in CH2Cl2 to give E/Z-3-[2-(2-tert-Butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (12.4 g)
EXAMPLE 247e
Preparation of racemic (2′R,3R,4′S) 4′-[2-(2-amino-ethoxy)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 528.42 C27H24Cl2FN3O3 
In a manner similar to the method described in Example 228d, E/Z-3-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4 g, 7.3 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (29 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (130 mg).
m/z (M+H)+: 528
EXAMPLE 248
Preparation of racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-cyclopropyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 406.92 C24H23ClN2O2 
Under nitrogen atmosphere, to a solution 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 (0.050 g) prepared in Example 172b in toluene (5 mL) was added water (0.1 mL), cyclopropyl boronic acid (0.020 g, 0.23 mmol), K3PO4 (0.098 g, 0.46 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol). The mixture was irradiated at 130° C. by microwave for 0.5 h. Then 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 trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 0.5 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with NaHCO3 aqueous solution, dried over MgSO4 and concentrated. The residue was purified with Prep.LC to give title compound as a white solid (Yield: 8 mg).
m/z (M+H)+: 407
EXAMPLE 249a
Preparation of intermediate 3-chloro-2H-pyridine-1-carboxylic acid phenyl ester




M. W. 235.67 C12H10ClNO2 
To a solution of 3-chloro-pyridine (6.0 g, 53 mmol) in methanol (50 mL) was added NaBH4 (2.6 g, 69 mmol) at −78° C., following addition of phenyl chloroformate (8.3 g, 53 mmol) at same temperature. The mixture was stirred at r.t. for 0.5 h. Then water (200 mL) was added slowly into the solution. The precipitate was collected by filtration to give crude product (Yield: 8.2 g, 67%).
m/z (M+H)+: 236
EXAMPLE 249b
Preparation of intermediate 3-chloro-5-formyl-2H-pyridine-1-carboxylic acid phenyl ester




M. W. 263.68 C13H10ClNO3 
Phosphorus oxychloride (5.4 g, 57.9 mmol) was added slowly to a stirred solution of DMF (8.9 mL, 116 mmol) in dichloromethane (10 mL) at 0° C. After addition, the solution was stirred at same temperature for 25 min., then transferred a solution of 3-chloro-2H-pyridine-1-carboxylic acid phenyl ester (5.67 g, 26.3 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The ice bath was removed and stirring was continued at r.t. for 2 h, then the mixture was refluxed for 40 min. After the mixture was cooled to 0° C., an aqueous solution of KOAc (15 g, 153 mmol) in water (50 mL) was added slowly. The mixture was refluxed for 20 min., organic layer was separated, and aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, washed with saturated NaHCO3, water and brine then dried over MgSO4, concentrated to give the crude product (Yield: 6.7 g).
m/z (M+H)+: 264
EXAMPLE 249c
Preparation of intermediate 5-chloro-pyridine-3-carbaldehyde




M. W. 141.56 C6H4ClNO
The mixture of 3-chloro-5-formyl-2H-pyridine-1-carboxylic acid phenyl ester (2.3 g, 8.8 mmol), sublimed sulfur (0.29 g, 9 mmol) and naphthalene (6 g) was refluxed under an argon atmosphere for 2 h. After the reaction was complete, the mixture was cooled to r.t., dissolved in ethyl ether (30 mL), and extracted with aqueous 10% HCl. The combined acid extracts were washed with ethyl ether (20 mL) and cooled to 0° C. Dichloromethane (30 mL) was added and “pH” of the mixture was adjusted to be basic with 25% aqueous NaOH, and the mixture was extracted with dichloromethane (20 mL). The combined organic phase was washed with brine, dried over K2CO3, filtered, and concentrated to give a brown solid. (0.8 g, 76%).
m/z (M+H)+: 142
EXAMPLE 249d
Preparation of intermediate 6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-1,3-dihydro-indol-2-one




M. W. 291.14 C14H8ClN2O
To the mixture of 6-chlorooxindole (0.93 g, 5.6 mmol) and 5-chloro-pyridine-3-carbaldehyde (0.8 g, 5.6 mmol) in methanol (10 mL) was added pyrrolidine (0.6 g, 5.6 mmol) dropwise. The mixture was then heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 1.0 g, 63%).
m/z (M+H)+: 291
EXAMPLE 249e
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 391.26 C19H16Cl2N2O3 
To a solution of E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-1,3-dihydro-indol-2-one (1 g, 3.4 mmol) in dichloromethane (50 mL) was added di-tert-butyl-dicarbonate (1.5 g, 6.9 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (1 g, 8.2 mmol). The reaction mixture was stirred at same 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 (Yield: 1.3 g, 96%).
m/z (M+H)+: 391
EXAMPLE 249f
Preparation of chiral (2′R,3R,4′S)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 402.28 C20H17Cl2N3O2 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.4 g, 1 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.5 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 31 mg). Separation of the two enantiomers from racemic compound (21 mg) was conducted by chiral HPLC to provide chiral (2′R,3R,4′S)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (6 mg) and chiral (2′S,3S,4′R)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).
m/z (M+H)+: 402
EXAMPLE 250a
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-nitro-benzylidene)-1,3-dihydro-indol-2-one




M. W. 335.15 C15H8Cl2N2O3 
To the mixture of 6-Chlorooxindole (3.3 g, 20 mmol) and 5-chloro-2-nitro-benzaldehyde (3.75 g, 20 mmol) in methanol (30 mL) was added pyrrolidine (1.63 mL, 20 mmol) dropwise. The mixture was then heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-2-nitro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 6 g, 91%).
m/z (M+H)+: 335
EXAMPLE 250b
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-nitro-benzylidene-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 435.27 C20H16Cl2N2O5 
To a solution of E/Z-6-chloro-3-(5-chloro-2-nitro-benzylidene)-1,3-dihydro-indol-2-one (6.68 g, 20 mmol) in dichloromethane (50 mL) at room temperature was added di-tert-butyl-dicarbonate (5.2 g, 24 mmol), followed by the addition of 4-dimethylaminopyridine (0.24 g, 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-(5-chloro-2-nitro-benzylidene-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (Yield 2.7 g).
m/z (M+H)+: 435
EXAMPLE 250c
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-nitro-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 446.29 C21H17Cl2N3O4 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-(5-chloro-2-nitro-benzylidene-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.7 g, 6.2 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (31 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give the title compound as a solid (Yield: 0.44 g).
m/z (M+H)+: 446
EXAMPLE 251
Preparation of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 416.31 C21H19Cl2N3O2 
The reaction mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-nitro-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (290 mg, 0.65 mmol), Raney Ni (39 mg) and NH2NH2.H2O (320 mg) in methanol was stirred at 80° C. for 0.5 h. The mixture was cooled to 4° C., and concentrated. To the residue were added ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography to give the title compound as a solid (Yield: 260 mg).
m/z (M+H)+: 416
EXAMPLE 252
Preparation of racemic (2′R,3R,4′S)-4′-(2-acetylamino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 458.35 C23H21Cl2N3O3 
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), acetic acid (9 mg, 0.15 mmol), EDCI.HCl (29 mg, 0.15 mmol), and HOBt (20 mg, 0.15 mmol) in acetonitrile (5 mL) was added DIPEA (0.052 mL, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated 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 dried over MgSO4 and concentrated. The residue was purified with Prep HPLC to give the title compound as a white solid (Yield: 9 mg).
m/z (M+H)+: 458
EXAMPLE 253
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methanesulfonylamino-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 494.40 C22H21Cl2N3O4S
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), methanesulfonyl chloride (0.0092 mL, 0.15 mmol), in acetonitrile (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep. HPLC to give the title compound as a white solid (Yield: 8 mg).
m/z (M+H)+: 494
EXAMPLE 254a
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-iodo-benzylidene)-1,3-dihydro-indol-2-one




M. W. 416.05 C15H8Cl2INO
To the mixture of 6-chlorooxindole (3.3 g, 20 mmol) and 5-chloro-2-iodo-benzaldehyde prepared in Example 208a (5 g, 20 mmol) in methanol (30 mL) was added pyrrolidine (1.63 mL, 20 mmol) dropwise. The mixture was then heated at 70° C. for 3 h and cooled to room temperature. Then the precipitate was collected by filtration to give a mixture of E/Z-6-chloro-3-(5-chloro-2-iodo-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 5.3 g).
m/z (M+H)+: 416
EXAMPLE 254b
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-iodo-benzylidene-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 516.17 C20H16Cl21NO3
To a solution of E/Z-6-chloro-3-(5-chloro-2-iodo-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 12.8 mmol) in dichloromethane (50 mL) at room temperature was added di-tert-butyl-dicarbonate (3.4 g, 15.3 mmol), followed by the addition of 4-dimethylaminopyridine (0.16 g, 1.3 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-(5-chloro-2-iodo-benzylidene-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (Yield 5.5 g).
m/z (M+H)+: 516
EXAMPLE 254c
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-iodophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 595.24 C25H18Cl2FIN2O2 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-(5-chloro-2-iodo-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2 g, 4 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 0.8 g).
m/z (M+H)+: 595
EXAMPLE 255a
Preparation of intermediate 5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzaldehyde




M. W. 242.70 C12H15CIO3 
5-Chloro-benzaldehyde (3.1 g, 20 mmol), 3-bromo-2,2-dimethyl-propan-1-ol (3 mL, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.5 g) were mixed in DMF (20 mL). Then mixture was irradiated under microwave at 200° C. for 1 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 anhydrous Na2SO4 and concentrated to give title compound as yellow solid (Yield: 1.6 g).
m/z (M+H)+: 243
EXAMPLE 255b
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzylidene]-1,3-dihydro-indol-2-one




M. W. 392.29 C20H19Cl2NO3 
5-Chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzaldehyde (2.4 g, 10 mmol) and 6-chloro-1,3-dihydro-indol-2-one (1.7 g, 10 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (0.8 g, 11.2 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. Then the precipitate was collected by filtration to give title compound as yellow solid (Yield: 3.8 g).
m/z (M+H)+: 392
EXAMPLE 255c
Preparation of intermediate E/Z-3-[2-(3-tert-butoxycarbonyloxy-2,2-dimethyl-propoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 592.52 C30H35Cl2NO7 
To a solution of E/Z-6-chloro-3-[5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzylidene]-1,3-dihydro-indol-2-one (4 g, 10 mmol) in dichloromethane (10 mL) was added di-tert-butyl-dicarbonate (5.6 g, 25 mmol) at r.t., followed by the addition of 4-dimethylaminopyridine (0.1 g, 1 mmol). The reaction mixture was stirred for 2 h and washed with 0.1N hydrochloride, then the solvent was removed to give title compound (Yield: 5 g).
m/z (M+H)+: 592
EXAMPLE 255d
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 571.48 C30H29Cl2FN2O4 
In a manner similar to the method described in Example 228d, E/Z-3-[2-(3-tert-butoxycarbonyloxy-2,2-dimethyl-propoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (60 mg, 0.1 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (1 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 10 mg).
m/z (M+H)+: 571
EXAMPLE 256a
Preparation of intermediate 5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde




M. W. 238.60 C9H6ClF3O2 
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 1,1,1-trifluoro-2-iodo-ethane (2.4 mL, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 180° C. for 1 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 anhydrous Na2SO4 and concentrated to give title compound as a yellow solid (Yield: 4 g).
m/z (M+H)+: 239
EXAMPLE 256b
Preparation of intermediate E/Z 6-Chloro-3-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-1,3-dihydro-indol-2-one




M. W. 388.18 C17H10Cl2F3NO2 
5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.8 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 4.45 g, 72%).
m/z (M+H)+: 338
EXAMPLE 256c
Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 488.29 C22H18Cl2F3NO4 
To a solution of E/Z-6-chloro-3-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-1,3-dihydro-indol-2-one (4.45 g, 11.5 mmol) in dichloromethane (10 mL) at r.t was added di-tert-butyl-dicarbonate (3.7 g, 17.2 mmol), followed by the addition of 4-dimethylaminopyridine (0.14 g, 1.7 mmol). The reaction mixture was stirred for 2 h and washed with 0.1N hydrochloride, then the solvent was removed to give title compound (Yield: 5 g, 89%).
m/z (M+H)+: 488
EXAMPLE 256d
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-(5-chloro-2-(2,2,2-trifluoro-ethoxy)hydroxy-phenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 567.37 C27H20Cl2F4N2O3 
In a manner similar to the method described in Example 228d, E/Z-6-Chloro-3-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was reacted with 1-(5-Fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 50 mg).
m/z (M+H)+: 567
EXAMPLE 257a
Preparation of intermediate 3-(4-chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester




M. W. 270.72 C13H15ClO4 
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 150° C. for 1 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 Na2SO4 and concentrated to give title compound (Yield: 5 g, 92.5%).
m/z (M+H)+: 271
EXAMPLE 257b
Preparation of intermediate E/Z-3-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester




M. W. 420.30 C21H19Cl2NO4 
3-(4-Chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (6.7 g, 25 mmol) and 6-Chlorooxindole (4.35 g, 25 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (2 mL, 25 mmol) was added slowly at r.t. The mixture was heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 7 g, 67%).
m/z (M+H)+: 420
EXAMPLE 257c
Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 520.41 C26H27Cl2NO6 
To a solution of E/Z-3-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester (7 g, 16.7 mmol) in dichloromethane (20 mL) at r.t. was added di-tert-butyl-dicarbonate (5.4 g, 25 mmol), followed by the addition of 4-dimethylaminopyridine (0.2 g, 1.7 mmol). The reaction mixture was stirred for 2 h and washed with 0.1N hydrochloride, then the solvent was removed to give title compound (Yield: 8 g).
m/z (M+H)+: 420
EXAMPLE 257d
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 599.49 C31H29Cl2FN2O5 
In a manner similar to the method described in Example 228d, E/Z-6-chloro-3-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl esteras ester (4.5 g, 9 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (63 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 300 mg, 5.5%).
m/z (M+H)+: 599
EXAMPLE 258a
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 585.46 C30H27Cl2FN2O5 
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg), NaOH (80 mg), H2O (10 mL) and methanol (10 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl. The white precipitate was collected by filtration to give title compound (Yield: 250 mg).
m/z (M+H)+: 585
EXAMPLE 258b
Preparation of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 585.46 C30H27Cl2FN2O5 
Separation of the two enantiomers from racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (RO5219363-000), (20 mg) was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6.5 mg) and chiral (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6.5 mg).
m/z (M+H)+: 585
EXAMPLE 259a
Preparation of intermediate 5-chloro-2-(3-hydroxy-propoxy)-benzaldehyde




M. W. 214.65 C10H11ClO3 
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 20 mmol), 3-bromo-propan-1-ol (4.1 mL, 24 mmol), K2CO3 (5.5 g, 4 mmol) and KI (0.5 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 200° C. for 1 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 Na2SO4 and concentrated to give title compound (Yield: 1.7 g, 59%).
m/z (M+H)+: 215
EXAMPLE 259b
Preparation of intermediate of E/Z-6-chloro-3-[5-chloro-2-(3-hydroxy-propoxy)-benzylidene]-1,3-dihydro-indol-2-one




M. W. 364.23 C18H15Cl2NO3 
5-Chloro-2-(3-hydroxy-1-propoxy)-benzaldehyde (8 g, 37 mmol) and 6-chlorooxindole (6.2 g, 37 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (3 mL, 37 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 11.8 g).
m/z (M+H)+: 364
EXAMPLE 259c
Preparation of intermediate E/Z-3-[2-(3-tert-butoxycarbonyloxy-propoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 564.47 C28H31Cl2NO7 
To a solution of E/Z-6-chloro-3-[5-chloro-2-(3-hydroxy-propoxy)-benzylidene]-1,3-dihydro-indol-2-one (11.8 g, 31.6 mmol) in dichloromethane (100 mL) at r.t was added di-tert-butyl-dicarbonate (15 g, 69 mmol), followed by the addition of 4-dimethylaminopyridine (0.4 g, 3 mmol). The reaction mixture was stirred for 2 h and washed with 0.1N hydrochloride, then the solvent was removed to give title compound. (Yield: 12 g)
m/z (M+H)+: 564
EXAMPLE 259d
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(3-hydroxypropoxyl)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 543.43 C28H25Cl2FN2O4 
In a manner similar to the method described in Example 228d, E/Z-3-[2-(3-tert-butoxycarbonyloxy-propoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4 g, 7.1 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (35 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 6 mg).
m/z (M+H)+: 543
EXAMPLE 260
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 561.37 C27H20Cl2F2N2O5 
In a manner similar to the method described in Example 228d, E/Z-6-chloro-3-(5-chloro-2-methoxycarbonylmethyoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (9.5 g, 20 mmol) was reacted with 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (60 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 1.5 g).
m/z (M+)+: 561
EXAMPLE 261
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 547.35 C26H18Cl2F2N2O5 
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (600 mg), NaOH (120 mg), H2O (5 mL) and methanol (5 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated to half of its volume. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl (1.5 mL). The white precipitate was collected by filtration to give title (Yield: 500 mg).
m/z (M+H)+: 547
EXAMPLE 262a
Preparation of intermediate 5-chloro-2-methyl-benzaldehyde




M. W. 154.60 C8H7ClO
A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 mL) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 min to give a 10% solution of formaldoxime.
In a separate flask, a mixture of 2-chloro-4-methylaniline (35.5 g, 0.25 mol) and water (50 mL) was stirred at room temperature, and aqueous concentrated HCl (57 mL) was added slowly. The mixture was cooled to room temperature, ice (100 g) was added, and the temperature of the mixture was maintained at −5° C. to +5° C. by an ice-salt bath. To the stirred mixture was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water (25 mL). After the addition, the stirring was continued for 15 min. The stirred solution of the diazonium salt was neutralized by the addition of a solution of hydrated sodium acetate in water (35 mL).
To the aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mol), and a solution of hydrated sodium acetate (160 g) in water (180 mL). The temperature of the solution was maintained at 10-15° C. by a cold-water bath and stirring vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition was complete, the stirring was continued for additional 1 h and then the mixture was treated with concentrated aqueous HCl (230 mL). The reaction mixture was gently heated at reflux for 2 h. The mixture was cooled to room temperature, extracted with ethyl ether (3×150 mL), and the ethereal extracts were washed with brine. The organic layer was separated, dried over Na2SO4 and concentrated to obtain a yellow solid (Yield: 21 g, 6%).
m/z (M+H)+: 155
EXAMPLE 262b
Preparation of intermediate E/Z-6-Chloro-3-(5-chloro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one




M. W. 304.18 C16H11Cl2NO
5-Chloro-2-methyl-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.5 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as yellow solid (Yield: 4.5 g).
m/z (M+H)+: 304
EXAMPLE 262c
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 404.30 C21H19Cl2NO3 
To a solution of E/Z-6-chloro-3-(5-chloro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one (4.7 g, 15.5 mmol) in dichloromethane (10 mL) at r.t was added di-tert-butyl-dicarbonate (5.0 g, 15.5 mmol), followed by the addition of 4-dimethylaminopyridine (0.2 g, 1.6 mmol). The reaction mixture was stirred for 2 h and washed with 0.1N hydrochloride, then the solvent was removed to give title compound. (Yield: 5 g).
m/z (M+H)+: 404
EXAMPLE 262d
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 660.40 C31H29BrCl2N2O5 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-[5-chloro-2-methyl-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.4 g, 6 mmol) was reacted with 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (Yield: 180 mg).
m/z (M+H)+: 659
EXAMPLE 263
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 646.37 C30H27BrCl2N2O5 
A mixture of (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg), NaOH (40 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 20 mg).
m/z (M+H)+: 645
EXAMPLE 264
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 660.40 C31H29BrCl2N2O5 
In a manner similar to the method described in Example 228d, 3-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.9 g, 8 mmol) was reacted with 1-(5-chloro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 160a (21 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give the title compound as a white solid (Yield: 600 mg).
m/z (M+H)+: 659
EXAMPLE 265
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 632.34 C29H25BrCl2N2O5 
A mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg), NaOH (80 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg).
m/z (M+H)+: 631
EXAMPLE 266
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 632.39 C30H29BrCl2N2O4 
LiAlH4 (11.4 mg, 0.3 mmol) was suspended in THF in ice bath, then a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 262d (63 mg, 0.1 mmol) in THF (2 mL) was added slowly. The reaction mixture was stirred at room temperature for 10 min, water (1 mL) was added and the resulting mixture was filtered. The filtration was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (Yield: 31 mg).
m/z (M+H)+: 631
EXAMPLE 267a
Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




To a solution of 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) prepared in Example 87a in toluene was added E/Z-6-bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in Example 161a (1.0 g, 2.16 mmol). The reaction mixture was refluxed under Argon for overnight. The mixture was cooled to room temperature, methanol (30 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (CH2Cl2:CH3OH=50:1) to give crude product (0.42 g).
EXAMPLE 267b
Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 620.06 C29H36BrClN2O4Si
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (150 mg, 0.26 mmol) and acetic acid 2-bromo-ethyl ester (867 mg, 5.22 mmol) was added LiH (63 mg, 7.9 mmol). The mixture was stirred at room temperature for 20 h, then diluted with ethyl acetate (10 mL), quenched with water (10 mL). The organic layer was separated, washed with water for 5 times, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give product (57 mg).
EXAMPLE 267c
Preparation of intermediate chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 620.06 C29H36BrClN2O4Si
Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (57 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (27 mg) and chiral (2′S,3S,4′R)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (20 mg).
EXAMPLE 267d
Preparation of chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxy ethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 489.80 C23H22BrClN2O3 
The chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxyethyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (27 mg) was dissolved in a solution of trifluoroacetic acid (2 mL) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, then concentrated. The residue was dissolved in a solution of methanol (3 mL) and N,N′-Diisopropylethylamine (1 mL). The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give title compound (20 mg, 93%). m/z (M+H)+: 489
EXAMPLE 268a
Preparation of intermediate racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (100 mg, 0.17 mmol) and 2-bromo-acetamide (72 mg, 0.52 mmol) in DMF (1 mL) was added Cs2CO3 (332 mg, 1.01 mmol). The mixture was stirred at room temperature for overnight. Then additional 2-bromo-acetamide (72 mg, 0.52 mmol) and Cs2CO3 (332 mg, 1.01 mmol) were added to the reaction mixture. The resulting mixture was heated at 50° C. for 2 h, then poured into ethyl acetate (20 mL). The organic layer was washed with water 3 times, dried over Na2SO4, purified by column chromatography to give title compound 60 mg.
EXAMPLE 268b
Preparation of intermediate chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 633.06 C29H35BrClN3O4Si
Separation of the two enantiomers from racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (60 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (27 mg, 90%) and chiral (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (27 mg, 90%).
EXAMPLE 268c
Preparation of chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 502.80 C23H21BrClN3O3 
The chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (27 mg, 0.043 mmol) was dissolved in a solution of trifluoroacetic acid (2 mL) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, then concentrated. The residue was dissolved in a solution of methanol (3 mL) and N,N′-diisopropylethylamine (1 mL). The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give title compound (20 mg, 93%) m/z (M+H)+: 502
EXAMPLE 269a
Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 590.04 C28H34BrClN2O3Si
A solution of diiodomethane (3.7 g, 0.013 mmol) in toluene (10 mL) was cooled in ice-salt bath. Then diethylzinc (1.1M in toluene, 10 mL, 11 mmol) was added dropwise into the above solution slowly. After the addition, the mixture was stirred for 10 min. To the resulting mixture was added a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in Example 267a (800 mg, 1.4 mmol) in toluene (10 mL). The mixture was then allowed to warm to room temperature and stirred for 3 h, quenched with aqueous NH4Cl. The organic layer was separated, washed with water, dried over Na2SO4, purified by column chromatography to give title compound (800 mg).
EXAMPLE 269b
Preparation of intermediate racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 647.09 C30H37BrClN3O4Si
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (800 mg, 1.36 mmol) and 2-bromo-acetamide (938 mg, 6.8 mmol) in DMF (1 mL) was added Cs2CO3 (4.4 g, 13.4 mmol). The mixture was stirred at 50° C. for 1.5 h, then purified by column chromatography to give title compound (60 mg, 6.8%).
EXAMPLE 269c
Preparation of intermediate chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 647.09 C30H37BrClN3O4Si
Separation of the two enantiomers from racemic (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (60 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (25 mg) and chiral (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (25 mg).
EXAMPLE 269d
Preparation of chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 516.83 C24H23BrClN3O3 
The chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (25 mg, 0.039 mmol) was dissolved in a solution of trifluoroacetic acid (2 mL) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, then concentrated. The residue was dissolved in a solution of methanol (3 mL) and N,N′-diisopropylethylamine (1 mL). The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give title compound (10 mg, 50%) m/z (M+H)+: 516
EXAMPLE 270a
Preparation of intermediate racemic (2′R,3R,4′S)-1′-allyl-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 630.10 C31H38BrClN2O3Si
To a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (200 mg, 0.34 mmol) and allyl bromide (1.2 g, 10 mmol) in DMF (15 mL) was added Cs2CO3 (4 g, 12.1 mmol). The mixture was stirred at room temperature for 2 h, then poured into water (100 mL), extracted with ethyl acetate for 3 times. The organic layer was washed with water, dried over Na2SO4, concentrated to give crude product as a light yellow solid (210 mg).
EXAMPLE 271b
Preparation of intermediate racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane




M. W. 664.12 C31H40BrClN2O5Si
To a mixture of racemic (2′R,3R,4′S)-1′-allyl-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (100 mg, 0.16 mmol), N-methylmorpholine N-oxide (30 mg, 0.22 mmol) and 3 drops of water in acetone (3 mL) was added OsO4 (10 mg, 0.04 mmol). The mixture was stirred at room temperature for 1 h, then purified by Prep-HPLC to give the title compound as a white solid (40 mg, 37%).
EXAMPLE 271c
Preparation of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 533.85 C25H26BrClN2O4 
The compound racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (40 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL). The solution was stirred at room temperature for 1 h, then concentrated. The residue was dissolved in a solution of methanol (3 mL) and N,N′-diisopropylethylamine (1 mL). The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give title compound (20 mg, 63%) m/z (M+H)+: 533
EXAMPLE 271d
Preparation of chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 533.85 C25H26BrClN2O4 
Separation of the two enantiomers from racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (14 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (5.1 mg, 73%) and chiral (2′S,3S,4′R)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (5.1 mg, 73%). m/z (M+H)+: 533
EXAMPLE 272a
Preparation of intermediate 2-bromo-propenal




M. W. 134.96 C3H3BrO
A dichloromethane solution of propenal (0.6 M, 1.13 L, 0.68 mol) was cooled in ice-bath. To this solution was added aqueous HBr (2 M, 750 mL, 1.5 mol) and OXONE® (450 g, 0.72 mol) slowly. After the addition, the mixture was stirred at room temperature for 1.5 h. Then triethylamine (250 mL) was added slowly. The resulting mixture was stirred at room temperature for additional 1.5 h. The organic layer was separated and washed with aqueous HCl (0.8 N) (3×) and water (2×), then concentrated in vacuo. The residue was distilled to give product 2-bromo-propenal as oil (15 g, 16%).
EXAMPLE 272b
Preparation of intermediate 1-(1-bromo-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 248.20 C8H14BrNOSi
In a manner similar to the method described in Example 87a, 2-bromo-propenal (5 g, 37 mmol) was used as the starting material in place of 2-methacrolein to react with LiHMDS (1M solution in THF, 37 mL, 37 mmol), trimethylsilyl chloride (4.65 mL, 37 mmol), triethylamine (6.8 mL, 48 mmol) and acetyl chloride (3.43 mL, 48 mmol) to give 1-(1-bromo-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene and used for the next step without further purification.
EXAMPLE 272c
Preparation of racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 466.16 C20H15BrCl2N2O2 
To a toluene solution of 1-(1-bromo-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in toluene (1 M, 37 mL, 37 mmol) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (2.8 g, 7.2 mmol). The reaction mixture was refluxed overnight under argon protection and purified by Prep-HPLC to give product as a white solid (120 mg, 7%).
m/z (M+H)+: 465
EXAMPLE 273a
Preparation of intermediate racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester




M. W. 566.28 C25H23BrCl2N2O4 
To a mixture of racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.26 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in dichloromethane (10 mL) was added Di-t-butyldicarbonate (74 mg, 0.34 mmol). The mixture was stirred at room temperature for 2 h, then washed with aqueous HCl (0.5 M) and water. The organic layer was separated, dried over Na2SO4, concentrated to give the title compound (130 mg, 88%).
EXAMPLE 273b
Preparation of intermediate chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester




M. W. 566.28 C25H23BrCl2N2O4 
Separation of the two enantiomers from racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (20 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white solid (9 mg, 90%) and chiral (2′R,3S,4′R)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (9 mg, 90%).
EXAMPLE 273c
Preparation of chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 466.16 C20H15BrCl2N2O2 
A solution of chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (9 mg, 0.016 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 10 min, then concentrated in vacuo. The residue was purified by Prep-HPLC to give title compound (5.7 mg, 76%). m/z (M+H)+: 465
EXAMPLE 274a
Preparation of intermediate 2-(4-chloro-phenyl)-4,4-dimethyl-oxazolidine




To a solution of 2-amino-2-methyl-propan-1-ol (59 g, 0.66 mol) in dichloromethane (120 mL) at 0° C. was added dropwise a solution of 4-chloro-benzoyl chloride (53 g, 0.3 mol) in dichloromethane (75 mL). The resulting mixture was stirred at r.t. for 2.5 h, then filtered and the filtrate was concentrated. Then SOCl2 (120 g, 1 mol) was added dropwise. The mixture was stirred at room temperature for overnight, then diluted with ethyl ether (150 mL). The resulting mixture was cooled in an ice bath, neutralized with aqueous NaOH (20%). The organic layer was separated, and aqueous layer was extracted with ethyl ether for 3 times. The organic lays were combined and washed with water twice, dried over anhydrous Na2SO4 and concentrated. The residue was distilled in vacuo to give the title product (25 g) as oil.
EXAMPLE 274b
Preparation of intermediate 5-chloro-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-benzaldehyde




To a cold solution of 2-(4-chloro-phenyl)-4,4-dimethyl-oxazolidine (17.2 g, 82 mmol) in ethyl ether (100 mL) and hexane (100 mL) at −30° C. was added n-BuLi (1.6 M in hexane, 67 mL, 107 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h, then cooled to −20° C. To the mixture was added DMF (12.6 mL), and the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into water (200 mL), extracted with ethyl ether for 3 times. The organic layers were combined, washed with water, dried over anhydrous Na2SO4, concentrated in vacuo to give the title product (13 g).
EXAMPLE 274c
Preparation of intermediate 5-chloro-3-hydroxy-3H-isobenzofuran-1-one




The mixture of 5-chloro-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-benzaldehyde (10 g, 42 mmol) in aqueous HCl solution (4 M, 300 mL) was refluxed for 4 h, then cooled to room temperature, extracted with ethyl ether twice. The organic layers were combined, washed with water, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title product as light yellow solid (3.8 g).
EXAMPLE 274d
Preparation of intermediate 4-chloro-2-formyl-benzoic acid methyl ester




A solution of 5-chloro-3-hydroxy-3H-isobenzofuran-1-one (10 g, 54 mmol) and iodomethane (80 g, 560 mmol) in dichloromethane (200 mL) was heated at reflux, then the heating bath was removed. To the above solution was added triethylamine (60 g) at a rate that maintained a brisk reflux. After the addition was completed, the mixture was allowed to cool to room temperature and stirred for 72 h. The mixture was purified by column chromatography to give the title product (1.5 g).
EXAMPLE 274e
Preparation of intermediate E/Z 4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzoic acid methyl ester




M. W. 348.19 C17H11Cl2NO3 
To the mixture of 6-chlorooxindole (1.2 g, 7 mmol) and 4-chloro-2-formyl-benzoic acid methyl ester (1.4 g, 7 mmol) in methanol (10 mL) was added pyrrolidine (490 mg, 7 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (500 mg).
EXAMPLE 274f
Preparation of intermediate E/Z 6-Chloro-3-(5-chloro-2-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 448.31 C22H19Cl2NO5 
To a solution of E/Z 4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzoic acid methyl ester (500 mg, 1.4 mmol) in dichloromethane (10 mL) at r.t was added di-tert-butyl-dicarbonate (470 mg, 2.1 mmol), followed by the addition of 4-dimethylaminopyridine (100 mg, 0.82 mmol). The reaction mixture was stirred at r.t. for 2 h, then purified by column chromatography to give E/Z 6-Chloro-3-(5-chloro-2-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow oil (450 mg)
EXAMPLE 274g
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 459.33 C23H20Cl2N2O4 
In a manner similar to the method described in Example 41b, E/Z 6-Chloro-3-(5-chloro-2-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (450 mg, 1 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 87a, (1M solution in toluene, 4 mL, 4 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (60 mg). m/z (M+H)+: 459
EXAMPLE 275
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 445.31 C22H18Cl2N2O4 
To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.13 mmol) in methanol (3.5 mL) was added a solution of NaOH (26 mg, 0.6 mmol) in water (1.5 mL). The mixture was heated at 70° C. for 3 h, concentrated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give title compound as a white solid (33 mg). m/z (M+H)+: 445
EXAMPLE 276a
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 646.37 C30H27BrCl2N2O5 
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 (1.5 g, 3.8 mmol) was reacted with 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 245a (1 M solution in toluene, 12 mL, 12 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (300 mg).
EXAMPLE 276b
Preparation of chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 646.37 C30H27BrCl2N2O5 
Separation of the two enantiomers from racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (5 mg, 50%) and (2′S,3S,4′R)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6 mg, 60%) (RO5223164-000). m/z (M+H)+: 645
EXAMPLE 277a
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 632.34 C29H25BrCl2N2O5 
To a mixture of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (106 mg, 0.16 mmol) in methanol (6 mL) was added a solution of NaOH (30 mg, 0.75 mmol) in water (3 mL). The mixture was heated at 60° C. for 5 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give title product as a white solid (70 mg). m/z (M+H)+: 631
EXAMPLE 277b
Preparation of chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 632.34 C29H25BrCl2N2O5 
Separation of the two enantiomers from racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (10 mg) was conducted by chiral Prep-HPLC to provide chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (3.1 mg, 62%) and (2′S,3S,4′R)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (2.9 mg, 58%). m/z (M+H)+: 631
EXAMPLE 278a
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 618.36 C29H27BrCl2N2O4 
To a mixture of LiAlH4 (10 mg, 0.26 mmol) in diethyl ether (2 mL) was added racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 276b (40 mg, 0.062 mmol). The mixture was stirred at room temperature for 10 min, quenched with methanol, purified by Prep-HPLC to give title compound (16 mg, 42%). m/z (M+H)+: 617
EXAMPLE 278b
Preparation of chiral (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 618.36 C29H27BrCl2N2O4 
Separation of the two enantiomers from racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg) was conducted by chiral Prep-HPLC to provide chiral racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethylpropoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6 mg, 60%) and racemic (2′S,3S,4′R)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (6 mg, 60%).
EXAMPLE 279a
Preparation of intermediate 1-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 428.4 C18H26BrNO4Si
In a manner similar to the method described in Example 1b, 2-(4-bromo-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (g, 19 mmol) was used as the starting material in place of 3-chlorobenzaldehyde to react with LiHMDS (1M solution in THF, 19 mL, 19 mmol), trimethylsilyl chloride (2.4 mL, 19 mmol), triethylamine (3.44 mL, 24.6 mmol) and acetyl chloride (1.75 mL, 24.6 mmol) to give title compound and used for the next step without further purification.
EXAMPLE 279b
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 646.37 C30H27BrCl2N2O5 
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 (1.5 g, 3.8 mmol).) was reacted with 1-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (1M solution in toluene, 12 mL, 12 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (800 mg).
EXAMPLE 279c
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 618.32 C28H23BrCl2N2O5 
To a mixture of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (700 mg, 1.08 mmol) in methanol (20 mL) was added a solution of NaOH (120 mg, 3 mmol) in water (10 mL). The mixture was heated at 60° C. for 1.5 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (610 mg). m/z (M+H)+: 617
EXAMPLE 280
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-bromo-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 604.33 C28H25BrCl2N2O4 
To a mixture of LiAlH4 (2.5 mg, 0.066 mmol) in diethyl ether (1 mL) was added racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (10 mg, 0.016 mmol). The mixture was stirred at room temperature for 10 min, quenched with MeOH, purified by Prep-HPLC to give product (3.7 mg, 38%). (M+H)+: 603
EXAMPLE 281
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 643.94 C31H29BrClFN2O5 
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 243c (1.5 g, 2.6 mmol).) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2 M solution in toluene, 5 mL, 10 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (700 mg). m/z (M+H)+: 643
EXAMPLE 282
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 615.89 C29H25BrClFN2O5 
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (75 mg). m/z (M+H)+: 615
EXAMPLE 283
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 647.91 C30H26BrClF2N2O5
In a manner similar to the method described in Example 228d, product E/Z 3-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.6 mmol).) was reacted with 1-(2,5-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2 M solution in toluene, 5 mL, 10 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (500 mg). m/z (M+H)+: 647
EXAMPLE 284
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 619.85 C28H22BrClF2N2O5 
To a mixture of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (80 mg). m/z (M+H)+: 619
EXAMPLE 285a
Preparation of intermediate 1-(4-Chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester




M. W. 268.70 C13H13ClO4 
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol, prepared according to Bulletin of the Chemical Society of Japan, 36, 145-7; 1963). The mixture was heated at 140° C. for 1.5 h. Then additional 1-Bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min. The mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with water (4×), dried over Na2SO4, concentrated to afford crude product 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester as a dark oil (18 g).
EXAMPLE 285b
Preparation of intermediate E/Z-1-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-cyclobutanecarboxylic acid methyl ester




M. W. 418.28 C21H17Cl2NO4 
To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester (18 g, 64 mmol) in methanol (100 mL) was added pyrrolidine (4.5 g, 63 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z 1-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-cyclobutanecarboxylic acid methyl ester (6 g, 24%).
EXAMPLE 285c
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 518.40 C26H25Cl2NO6 
To a solution of E/Z-1-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-cyclobutanecarboxylic acid methyl ester (6 g, 14 mmol) in dichloromethane (50 mL) at r.t was added di-tert-butyl-dicarbonate (4.7 g, 21 mmol), followed by the addition of 4-dimethylaminopyridine (1 g, 8.2 mmol). The reaction mixture was stirred at r.t. for 2 h, washed with aqueous HCl solution (0.5 M) and water, dried over Na2SO4, concentrated to give E/Z 6-Chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow oil (5 g, 69%)
EXAMPLE 285d
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 597.48 C31H27Cl2FN2O5 
In a manner similar to the method described in Example 228d, E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol).) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2 M solution in toluene, 5 mL, 10 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (340 mg). m/z (M+H)+: 597
EXAMPLE 286
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 583.45 C30H25Cl2FN2O5 
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) in methanol (4 mL) was added a solution of NaOH (40 mg, 1 mmol) in water (2 mL). The mixture was heated at 70° C. for 2 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (175 mg). m/z (M+H)+: 583
EXAMPLE 287
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-hydroxymethyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 569.47 C30H27Cl2FN2O4 
To a mixture of LiAlH4 (15 mg, 0.4 mmol) in THF (2 mL) was added racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (RO5247453-000) (60 mg, 0.1 mmol). The mixture was stirred in a ice bath for 1.5 h, quenched with MeOH, purified by Prep-HPLC to give title compound (14 mg, 24%). m/z (M+H)+: 569
EXAMPLE 288a
Preparation of intermediate 2-(tert-butyl-dimethyl-silanyloxy)-5-chloro-benzaldehyde




M. W. 270.83 C13H19CIO2Si
To a solution of 5-chloro-2-hydroxy-benzaldehyde (9.3 g) in DMF (45 mL) was added DIPEA (20 mL) and tert-butyl-chloro-dimethyl-silane (19 g). The mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ice water (200 mL), extracted with ether (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4. The solvent was removed to give the title compound which was used directly for next step.
EXAMPLE 288b
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one




M. W. 306.15 C15H9Cl2NO2 
To the mixture of 6-chlorooxindole (3.34 g) and 2-(tert-butyl-dimethylsilanyloxy)-5-chloro-benzaldehyde (7.1 g) in methanol (40 mL) was added pyrrolidine (2 g) 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-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid.
EXAMPLE 288c
Preparation of intermediate E/Z 3-(2-tert-butoxycarbonyloxy-5-chloro-benzylidene)-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 506.39 C25H25Cl2NO6 
To a solution of E/Z-6-chloro-3-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one prepared above (3.05 g, 10 mmol) in dichloromethane (30 mL) at room temperature was added Di-tert-butyl-dicarbonate (5.2 g, 24 mmol), followed by the addition of 4-dimethylaminopyridine (0.5 g, 4.1 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 title compound as brown oil (4.8 g).
MS+: 506
EXAMPLE 288d
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 417.30 C21H18Cl2N2O3 
In a manner similar to the method described in Example 41b, E/Z-3-(2-tert-butoxycarbonyloxy-5-chloro-benzylidene)-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl (1.52 g, 3 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.2 g, 12 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxy-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (0.18 g).
m/z (M+H)+: 417
EXAMPLE 289
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 531.44 C27H28Cl2N2O5 
In a manner similar to the method described in Example 41b, E/Z-6-Chloro-3-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 229c (0.41 g, 0.8 mmol) was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.5 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.045 g).
m/z (M+H)+: 531
EXAMPLE 290
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 517.41 C26H26Cl2N2O5 
A mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg), NaOH (80 mg), H2O (5 mL) and MeOH (1 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give title compound (15 mg).
m/z (M+H)+: 517
EXAMPLE 291
Preparation of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 734.43 C33H31BrCl2N2O8 
In a manner similar to the method described in Example 41b, E/Z-6-chloro-3-(5-chloro-2-methoxycarbonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 234c (0.24 g, 0.5 mmol) was reacted with 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 245a (4 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.03 g).
m/z (M+H)+: 733
EXAMPLE 292
Preparation of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-hydroxyethoxy)-phenyl]-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 678.41 C31H31BrCl2N2O6 
To a cooled solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (22 mg) in THF (3 mL) was added LiAlH4 (3.7 mg). The mixture was stirred at 0° C. for 30 min, followed by addition of ethyl acetate (2 mL). Then the mixture was filtrated and the filtrate was concentrated. The residue was purified by preparative HPLC to give title compound as a white solid (6.7 mg).
m/z (M+H)+: 677
EXAMPLE 293
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 557.41 C28H23Cl2FN2O5 
In a manner similar to the method described in Example 228d, E/Z-6-chloro-3-(5-chloro-2-methoxycarbonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 234c (0.95 g, 2 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.06 g).
EXAMPLE 294
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(hydroxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 543.38 C27H21Cl2FN2O5 
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (12 mg), NaOH (20 mg), H2O (5 mL) and methanol (1 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give title compound (5 mg)
m/z (M+H)+: 543
EXAMPLE 295a
Preparation of intermediate E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one




M.W432.63 C17H10BrClF3NO2 
5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde prepared in Example 232a (11 g, 39 mmol) and 6-chlorooxindole (5.4 g, 32 mmol) were mixed in anhydrous methanol (50 mL) at room temperature. Then pyrrolidine (2.7 g, 39 mmol) was added 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-3-[5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one as yellow solid (9.6 g).
EXAMPLE 295b
Preparation of intermediate E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 532.75 C22H18BrClF3NO4 
To a solution of E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one (9.6 g, 22 mmol) in dichloromethane (100 mL) at r.t was added di-tert-butyl-dicarbonate (5.8 g, 27 mmol), followed by the addition of 4-dimethylaminopyridine (0.27 g, 2 mmol). The reaction mixture was stirred at r.t. for 0.5 h, then washed with 0.5N HCl aqueous solution, dried and concentrated to give E/Z-3-[5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow oil. (11 g)
EXAMPLE 295c
Preparation of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 611.82 C27H20BrClF4N2O3 
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.06 g, 2 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.06 g).
m/z MS−+: 609
EXAMPLE 296
Preparation of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 648.70 C26H17BrCl3F3N2O3 
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.53 g, 1 mmol) was reacted with 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 159a (6 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.06 g).
m/z MS−+: 645
EXAMPLE 297a
Preparation of intermediate 1-(5-chloro-2-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 271.80 C12H15ClFNOSi
In a manner similar to the method described in Example 1b, 2-fluoro-5-chloro benzaldehyde (3 g, 19 mmol) was used as the starting material in place of 3-chlorobenzaldehyde to react with LiHMDS (1M solution in THF, 19 mL, 19 mmol), trimethylsilyl chloride (2.4 mL, 19 mmol), triethylamine (3.44 mL, 24.6 mmol) and acetyl chloride (1.75 mL, 24.6 mmol) to give title compound and used for the next step without further purification.
EXAMPLE 297b
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 619.91 C30H26Cl3FN2O5
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 prepared in Example 229c (1.04 g, 2 mmol) was reacted with 1-(2-fluoro-5-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.48 g).
m/z (M+H)+: 619
EXAMPLE 298
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 591.86 C28H22Cl3FN2O5
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (185 mg), NaOH (120 mg), H2O (15 mL) and methanol (5 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 1 by concentrated aqueous HCl solution. The white precipitate was collected by filtration to give title compound as a white solid (150 mg).
m/z (M+H)+: 591
EXAMPLE 299
Preparation of chiral (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 632.34 C29H25BrCl2N2O5 
Separation of the two enantiomers from racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg) was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-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)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).
EXAMPLE 300a
Preparation of intermediate 1-(2-chloro-5-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene




M. W. 271.80 C12H15ClFNOSi
In a manner similar to the method described in Example 1b, 2-chloro-5-fluoro benzaldehyde (3 g, 19 mmol) was used as the starting material in place of 3-chlorobenzaldehyde to react with LiHMDS (1M solution in THF, 19 mL, 19 mmol), trimethylsilyl chloride (2.4 mL, 19 mmol), triethylamine (3.44 mL, 24.6 mmol) and acetyl chloride (1.75 mL, 24.6 mmol) to give title compound and used for the next step without further purification.
EXAMPLE 300b
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2-chloro-5-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 619.91 C30H26Cl3FN2O5
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 prepared in Example 229c (3 g, 5.8 mmol) was reacted with 1-(2-chloro-5-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (23 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.4 g).
m/z (M+H)+: 619
EXAMPLE 301a
Preparation of intermediate 2-(4-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester




M. W. 25426 C13H15FO4 
5-Fluoro-2-hydroxy-benzaldehyde (14 g, 100 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (19.5 g, 100 mmol), K2CO3 (27 g, 196 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (150 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 aqueous 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (9 g).
EXAMPLE 301b
Preparation of intermediate E/Z-2-[4-fluoro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester




M. W. 403.84 C21H19ClFNO4 
In a manner similar to the method described in Example 227b, 2-(4-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (8 g, 31.5 mmol) was reacted with 6-chlorooxindole (5.3 g, 33 mmol) and pyrrolidine (2.6 mL) in methanol to give E/Z 2-[4-chloro-2-(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (10 g).
EXAMPLE 301c
Preparation of intermediate E/Z-6-Chloro-3-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M.W 520.41 C26H27Cl2NO6 
In a manner similar to the method described in Example 227c, E/Z-2-[4-fluoro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (5 g, 12 mmol) was reacted with di-tert-butyl-dicarbonate (3.1 g, 14 mmol) and DMAP (0.2 g, 1.72 mmol) in dichloromethane to give title compound as a yellow oil (6.5 g).
EXAMPLE 301d
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-fluoro-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 583.04 C31H29ClF2N2O5 
In a manner similar to the method described in Example 228d, E/Z-6-chloro-3-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 9.6 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (40 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.8 g).
m/z (M+H)+: 583
EXAMPLE 302
Preparation of racemic (2′R,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-hydroxycarbonyl-1-methyl-ethyl)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M.W 554.98 C29H25Cl2FN2O5 
Racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol) was dissolved in THF (10 mL). Then aqueous solution (1 mL) of NaOH (0.2 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 (0.26 g).
m/z (M+H)+: 555
EXAMPLE 303a
Preparation of intermediate 2-(4-Chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester




M. W. 298.77 C15H19ClO4 
5-Chloro-2-hydroxy-benzaldehyde (15.6 g, 100 mmol), 2-bromo-2-methyl-propionic acid tert-butyl ester (33.4 g, 150 mmol), K2CO3 (27.6 g, 200 mmol) and KI (3 g, 19 mmol) were mixed in DMF (100 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 Na2SO4 and concentrated to give title compound (16 g)
EXAMPLE 303b
Preparation of intermediate E/Z-2-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester




M. W. 448.35 C23H23Cl2NO4 
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (9 g, 30 mmol) was reacted with 6-chlorooxindole (5.1 g, 30 mmol) and pyrrolidine (2.49 g, 35 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 tert-butyl ester as a yellow oil (6.2 g).
EXAMPLE 303c
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M.W 548.47 C28H31Cl2NO6 
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 tert-butyl ester (5.49 g, 10 mmol) was reacted with di-tert-butyl-dicarbonate (2.5 g, 11.5 mmol) and DMAP (0.12 g, 1 mmol) in dichloromethane to give title compound as a yellow solid (3.8 g).
EXAMPLE 303d
Preparation of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M.W 627.55 C33H33Cl2FN2O5 
In a manner similar to the method described in Example 228d, E/Z 6-chloro-3-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.47 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (22 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.7 g).
m/z (M+H)+: 627
EXAMPLE 303e
Preparation of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M.W 627.55 C33H33Cl2FN2O5 
Separation of the two enantiomers from racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (700 mg) was conducted by chiral HPLC to provide chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (200 mg).
m/z (M+H)+: 627
EXAMPLE 304a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester




M. W. 408.26 C20H16Cl2FNO3 
In a manner similar to the method describeds in Example 4a and Example 24a, 3-chloro-2-fluorobenzaldehyde (3.1 g, 20 mmol) was reacted with 6-chlorooxindole (3.3 g, 20 mmol) and pyrrolidine in methanol, then di-tert-butyl-dicarbonate (6.5 g, 30 mmol) (Aldrich), triethylamine and 4-dimethylaminopyridine in dichloromethane to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 6.1 g, 75%).
EXAMPLE 304b
Preparation of racemic (2′R,3R,4′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione




M. W. 487.33 C25H18Cl2F2N2O2 
In a manner similar to the method described in example 41b, E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.41 g, 1 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.2 g, 8.7 mmol) prepared in example 36a in toluene and then trifluoroacetic acid in dichloromethane to give racemic (2′R,3R,4′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.24 g, 49%).
HRMS (ES+) m/z Calcd for C25H18Cl2F2N2O2+H [(M+H)+]: 487.0786. Found: 487.0782
EXAMPLE 305
In Vitro Activity Assay
The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Lane et al.). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin-conjugated Allophycocyanin (APC).
Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing: 90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1:5 dilution in reaction buffer) to each well, mix by shaking. Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37° C. for 1 h. Add 20 uL streptavidin-APC and Eu-anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM streptavidin-APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF-capable plate reader at 665 and 615 nm (Victor 5, Perkin ElmerWallac). If not specified, the reagents were purchased from Sigma Chemical Co.
IC50's showing the biological activity of this invention exhibit activities less than about 10 μM.
Representative values are, for example:














Example
IC50 (μM, 0.02% BSA)









 5d
2.4315



14b
0.4403



20
1.8111



26b
0.4899



31
0.3721

## Claims

1. A compound of the formula




wherein
X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,
Y is hydrogen or fluorine,
R4 and R5 are hydrogen or lower alkyl,
one of R1 and R8 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
one of R6 and R7 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, cyano or lower alkyl,
R2 is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,
R3 is selected from the group consisting of oxygen, sulfur and NNH(C═O)OR9,
R9 is lower alkyl or substituted lower alkyl,

and the pharmaceutically acceptable salts carboxylic acid and esters thereof.

2. A compound of the formula




wherein
X is hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy, and vinyl,
Y is hydrogen or fluorine,
R1 is hydrogen,
R2 is hydrogen, lower alkyl or substituted lower alkyl,
R4 and R5 are hydrogen or lower alkyl,
R6 is hydrogen, cyano, or lower alkyl,
R3 is O, S or NNH(C═O)OR9,
R7/R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
R9 is lower alkyl or substituted lower alkyl,

and the pharmaceutically acceptable salts carboxylic acid and esters thereof.

3. The compound of claim 2 wherein
X is chlorine or bromine,
Y is hydrogen,
R1 is hydrogen,
R4 and R5 are both hydrogen,
R6 is hydrogen,
R3 is O,
R7 is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of




R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and
R2 is hydrogen, lower alkyl or substituted lower alkyl,
with the proviso that when R2 is lower alkyl or substituted lower alkyl, R8 is selected from lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl.

4. The compound of claim 3 wherein
X is Cl or Br,
Y is hydrogen,
R1 is hydrogen,
R4 and R5 are both hydrogen,
R6 is hydrogen,
R3 is O,
R7 is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of





and
R8 is selected from the group consisting of





wherein
R1′ is hydrogen, methyl, ethyl, propyl, isopropyl, CF3, F, CHF2, or CH2F,
R2′ is hydrogen, methyl, ethyl, propyl, isopropyl, CF3, F, CHF2, or CH2F,
R3′ is hydrogen, F, CF3, CH2F, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl or sec-butyl,
R4′ is hydrogen, F, Cl, Br, I, methyl, ethyl, cyclopropyl, cyano, methoxy, or ethynyl,
R5′ is hydrogen, F or methyl,
R6′ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, lower alkynyl, substituted lower alkynyl
R7′ is hydrogen, F or methyl,
R8′ is hydrogen, F, methyl, ethyl, propyl, isopropyl, tert-butyl or sec-butyl,
R9′ is hydrogen, hydroxyl, or F,
R10′ is hydrogen or F,
R11′ is hydrogen or methyl,
R12′ is hydrogen or methyl,
R2 is hydrogen, lower alkyl or substituted lower alkyl
with the proviso that when R2 is lower alkyl or substituted lower alkyl, R8 is selected from the group consisting of

5. A compound of the formula




wherein
X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy, and vinyl,
Y is hydrogen or fluorine,
R1 is hydrogen,
R2 is hydrogen, lower alkyl or substituted lower alkyl,
R4 and R5 are hydrogen or lower alkyl,
R6 is hydrogen, cyano or lower alkyl,
R3 is O, S or NNH(C═O)OR9,
R7/R8 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and
R9 is lower alkyl or substituted lower alkyl,
and the pharmaceutically acceptable salts carboxylic acid and esters thereof.

6. The compound of claim 5 wherein
X is Cl or Br,
Y is hydrogen,
R1 is hydrogen,
R2 is hydrogen, lower alkyl or substituted lower alkyl,
R4 and R5 are both hydrogen,
R6 is hydrogen,
R3 is O,
R8 is a substituted phenyl with the substituted phenyl selected from group consisting of




R7 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.

7. A compound of claim 1 selected from the group consisting 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,
Racemic (2′S/R,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
(2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

8. A compound of claim 1 selected from the group consisting 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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methoxyphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

9. A compound of claim 1 selected from the group consisting 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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-ethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-isopropylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-cyanophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

10. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
racemic (2′S,3R,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one.

11. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

12. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-naphthalenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-pyridinyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-cyclohexenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
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.

13. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

14. A compound of claim 1 selected from the group consisting of
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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

15. A compound of claim 1 selected from the group consisting of
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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

16. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

17. A compound of claim 1 selected from the group consisting of
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
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,
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,
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,
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,
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 and
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.

18. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
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 and
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.

19. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

20. A compound of claim 1 selected from the group consisting 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,
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,
racemic (2′R,3R,4′S)-2′-sec-Butyl-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
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.

21. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

22. A compound of claim 1 selected from the group consisting 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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isobutyrylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
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,
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 and
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.

23. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

24. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-m-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3R,4′S)-6-chloro-2′-(1-methylene-propyl)-4′-o-tolylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

25. A compound of claim 1 selected from the group consisting 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,
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,
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,
racemic (2′R,3R,4′S)-4′-(3-Bromo-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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,
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,
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,
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 and
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.

26. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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 and
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.

27. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxyspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

28. A compound of claim 1 selected from the group consisting 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,
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,
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,
racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methylsulphonyl-4-piperidinyl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-{[4-(1,1-dioxido-2-isothiazolidinyl)ethyl]piperazinyl-carbonyl-methyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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 and
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.

29. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxyethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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 and
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.

30. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
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,
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 and
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.

31. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

32. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

33. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

34. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
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,
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,
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,
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,
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 and
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.

35. A compound of claim 1 selected from the group consisting 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,
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,
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,
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,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro 2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

36. A compound of claim 1 selected from the group consisting of
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2,2-dimethyl-3-hydroxy propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S) 4′-[2-(2-amino-ethoxy)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-cyclopropyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
chiral (2′R,3R,4′S)-6-chloro-4′-(5-chloro-3-pyridinyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

37. A compound of claim 1 selected from the group consisting of
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-nitro-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-4′-(2-acetylamino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methanesulfonylamino-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-iodophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-(5-chloro-2-(2,2,2-trifluoro-ethoxy)hydroxy-phenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

38. A compound of claim 1 selected from the group consisting of
racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(3-hydroxypropoxyl)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-methoxy)-phenyl]-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2-hydroxy ethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

39. A compound of claim 1 selected from the group consisting of
chiral (2′R,3R,4′S)-1′-(aminocarbonyl-methyl)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-1′-(2,3-dihydroxy-propyl)-2′-(1-methylcyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-2′-(1-bromo-vinyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

40. A compound of claim 1 selected from the group consisting of
chiral (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′R,3R,4′S)-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-bromo-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

41. A compound of claim 1 selected from the group consisting of
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-hydroxymethyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-hydroxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-hydroxyethoxy)-phenyl]-2′-[5-bromo-2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(methoxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(hydroxycarbonyl-methoxy)-phenyl]-2-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

42. A compound of claim 1 selected from the group consisting of
racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2-chloro-5-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione,
chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione and
racemic (2′R,3R,4′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione.

43. A pharmaceutical formulation comprising a compound of the formula




wherein
X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,
Y is hydrogen or fluorine,
R4 and R5 are hydrogen or lower alkyl,
one of R1 and R8 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
one of R6 and R7 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, cyano or lower alkyl,
R2 is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,
R3 is selected from the group consisting of oxygen, sulfur and NNH(C═O)OR9,
R9 is lower alkyl or substituted lower alkyl,

and the pharmaceutically acceptable salts carboxylic acid and esters thereof together with a pharmaceutically acceptable carrier or excipient.

44. A process to produce a compound of the formula




wherein
X is selected from the group consisting of hydrogen, halogen, cyano, nitro, cyclopropyl, methyl, ethyl, and isopropyl
Y is hydrogen or fluorine,
R1 is hydrogen,
R4 and R5 are hydrogen or lower alkyl,
R8 is selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl, one of R6 and R7 are selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, cyano or lower alkyl

which comprises reacting a compound of the formula




with a compound of the formula




at about 110-160° C. and under anhydrous conditions to produce a compound of formula II or III.

45. A process to produce a compound of the formula




wherein
X is selected from the group consisting of hydrogen, halogen, cyano, nitro, cyclopropyl, methyl, ethyl, and isopropyl,
Y is hydrogen or fluorine,
R1 is hydrogen,
R4 and R5 are hydrogen or lower alkyl,
R8 is selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl, one of R6 and R7 are selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, cyano or lower alkyl

which comprises reacting a compound of the formula




with a suitable protecting group
to provide a compound of the formula




which is thereafter reacted with a compound of the formula




at about 110-160° C. under anhydrous conditions and thereafter deprotecting the resultant product to produce a compound of formula II and III.