CN101400680B - Spiroindolinone derivatives - Google Patents

Spiroindolinone derivatives Download PDF

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CN101400680B
CN101400680B CN2007800087501A CN200780008750A CN101400680B CN 101400680 B CN101400680 B CN 101400680B CN 2007800087501 A CN2007800087501 A CN 2007800087501A CN 200780008750 A CN200780008750 A CN 200780008750A CN 101400680 B CN101400680 B CN 101400680B
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chloro
phenyl
piperidines
indoles
diketone
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CN101400680A (en
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陈力
丁清杰
刘进军
杨颂
张筑明
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Abstract

The present invention relates to spiroindolinone derivatives of the formula (I) and enantiomers and pharmaceutically acceptable salts and esters thereof which have utility as antiproliferative agents, especially, as anticancer agents.

Description

Spiroindolinone derivatives
The present invention relates to the Spiroindolinone derivatives of formula I,
Figure G2007800087501D00011
And pharmaceutical salts and ester,
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7And R 8As described herein.
Described compound has as antiproliferative, particularly as the effect of carcinostatic agent.
P53 albumen is the tumor suppressor protein that in preventing cancer development, plays a crucial role.Its protection cell integrity and the propagation of preventing the clone of cell permanent lesion through induced growth inhibition or apoptosis.On molecular level, p53 can activate one group to relate to the gene transcription factor of regulating cell cycle and apoptosis.P53 is the effective cell cycle inhibitor that closely regulated by MDM2.MDM2 and p53 form feedback control loop.MDM2 can combine p53 and suppress the ability of its trans-activation p53-regulatory gene.In addition, the MDM2 mediation relies on the p53 degraded of ubiquitin.P53 can activate MDM2 genetic expression, increases the proteic cell levels of MDM2 thus.This feedback control loop guaranteed MDM2 and p53 in normal proliferative cell, all remain on low-level on.MDM2 also is the cofactor of E2F, and it plays a crucial role in Cycle Regulation.
The ratio of MDM2 and p53 (E2F) receives unusual adjusting in many cancers.For example, confirmed to take place usually on the p16INK4/p19ARF locus the damaged MDM2 proteolytic degradation that influenced of molecule.The interaction that in tumour cell, suppresses MDM2-p53 and wild type p53 should cause p53 accumulation, cell cycle to be suppressed and/or apoptosis.Therefore, the MDM2 antagonist as the single-activity agent can for cancer therapy provide new tool or with other antitumor therapy coupling widely.Be used to suppress the feasibility that the interactional different macromole instruments of MDM2-p53 (for example antibody, antisense oligonucleotide, peptide class) have confirmed this strategy through use.Like p53, MDM2 also combines the E2F-dependent transcription of E2F and activating cells cyclin A through conservative land, point out the MDM2 antagonist in the p53 mutant cells, to have effect thus.
At J.Am Chem.Soc., a series of Spiroindolinones as the MDM2 antagonist are disclosed in advance in 2005,127,10130.
The present invention provides Spiroindolinone derivatives, and they are the interactional micromolecular inhibitors of MDM2-p53.In acellular and test based on cell, compound exhibits of the present invention goes out to suppress the interaction of MDM2 albumen and p53-appearance peptide.In the test based on cell, these compounds have proved machine-processed activity (mechanistic activity).Cancer cells is incubated with wild type p53 causes p53 albumen accumulation, induce p21 gene that p53-regulates and cell cycle arrest, caused at external effective antiproliferative activity to the wild type p53 cell in G1 and G2 phase.On the contrary, under suitable compound concentration, in the cancer cells that has two mutants p53, do not observe these activity.Therefore, the activity of MDM2 antagonist is relevant with its mechanism of action probably.These compounds can be effectively with carcinostatic agent optionally.
The present invention relates to 3 of following formula I, 3 '-Spiroindolinone,
Figure G2007800087501D00021
Wherein
X is selected from hydrogen, halogen, cyanic acid, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group and vinyl;
Y is hydrogen or fluorine;
R 4And R 5Be hydrogen or low alkyl group;
R 1And R 8In one be selected from low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl, aryl; Substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle; Naphthenic base, substituted naphthenic base, cycloalkenyl group and substituted cycloalkenyl group, and another is a hydrogen; R 6And R 7In one be selected from low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl; Aryl, substituted aryl, heteroaryl, substituted heteroaryl; Heterocycle, substituted heterocycle, naphthenic base, substituted naphthenic base; Cycloalkenyl group and substituted cycloalkenyl group, and another is hydrogen, cyanic acid or low alkyl group;
R 2Be selected from hydrogen, low alkyl group and substituted low alkyl group;
R 3Be selected from oxygen, sulphur and NNH (C=O) OR 9
R 9Be low alkyl group or substituted low alkyl group;
And pharmaceutical salts and ester.
Preferably have formula I compound suc as formula the stereochemical structure shown in the II,
Figure G2007800087501D00031
Wherein
X is a hydrogen, halogen, cyanic acid, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group, and vinyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 2Be hydrogen, low alkyl group or substituted low alkyl group;
R 4And R 5Be hydrogen or low alkyl group;
R 6Be hydrogen, cyanic acid, or low alkyl group;
R 3Be O, S or NNH (C=O) OR 9
R 7/ R 8Be independently selected from: low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, naphthenic base, substituted naphthenic base, cycloalkenyl group and substituted cycloalkenyl group;
R 9Be low alkyl group or substituted low alkyl group;
Further formula II compound preferably, wherein
X is Cl or Br;
Y is a hydrogen;
R 1Be hydrogen;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 7Be substituted phenyl or substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl are selected from:
Figure G2007800087501D00041
R 8Be independently selected from: low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, naphthenic base, substituted naphthenic base, cycloalkenyl group and substituted cycloalkenyl group; And
R 2Be hydrogen, low alkyl group or substituted low alkyl group;
Condition is to work as R 2When being low alkyl group or substituted low alkyl group, R 8Be selected from: low-grade alkenyl, substituted low-grade alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, naphthenic base, substituted naphthenic base, cycloalkenyl group or substituted cycloalkenyl group.
Further formula II compound preferably also, wherein
X is-Cl or-Br;
Y is a hydrogen;
R 1Be hydrogen;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 7Be substituted phenyl or substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl are selected from:
Figure G2007800087501D00051
And
R 8Be selected from:
Figure G2007800087501D00052
and
Figure G2007800087501D00053
Wherein
R 1' be hydrogen, methyl, ethyl, propyl group, sec.-propyl ,-CF 3,-F ,-CHF 2, or-CH 2F; R 2' be hydrogen, methyl, ethyl, propyl group, sec.-propyl ,-CF 3,-F ,-CHF 2, or-CH 2F; R 3' be hydrogen ,-F ,-CF 3,-CH 2F, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, the tertiary butyl or sec.-butyl;
R 4' be hydrogen ,-F ,-Cl ,-Br ,-I, methyl, ethyl, cyclopropyl, cyanic acid, methoxyl group, or ethynyl;
R 5' be hydrogen ,-F or methyl;
R 6' be selected from hydrogen, halogen, hydroxyl, cyano-lower alkyl group, substituted low alkyl group, lower alkoxy, substituted lower alkoxy, low-grade alkynyl, substituted low-grade alkynyl;
R 7' be hydrogen ,-F or methyl;
R 8' be hydrogen ,-F, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl or sec.-butyl;
R 9' be hydrogen, hydroxyl, or-F;
R 10' be hydrogen or-F;
R 11' be hydrogen or methyl;
R 12' be hydrogen or methyl;
R 2Be hydrogen, low alkyl group or substituted low alkyl group;
Condition is to work as R 2When being low alkyl group or substituted low alkyl group, R 8Be selected from:
Figure G2007800087501D00061
The formula I compound that further preferably has the stereochemical structure shown in formula III,
Wherein
X is selected from hydrogen, halogen, cyanic acid, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group, and vinyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 2Be hydrogen, low alkyl group or substituted low alkyl group;
R 4And R 5Be hydrogen or low alkyl group;
R 6Be hydrogen, cyanic acid or low alkyl group;
R 3Be O, S or NNH (C=O) OR 9
R 7/ R 8Be independently selected from: low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, naphthenic base, substituted naphthenic base, cycloalkenyl group and substituted cycloalkenyl group, and
R 9Be low alkyl group or substituted low alkyl group.
Further preferred formula III is a compound, wherein
X is-Cl or-Br;
Y is a hydrogen;
R 1Be hydrogen;
R 2Be hydrogen, low alkyl group or substituted low alkyl group;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 8Be substituted phenyl, wherein said substituted phenyl is selected from
Figure G2007800087501D00071
and
Figure G2007800087501D00072
; And
R 7Be selected from low alkyl group, substituted low alkyl group, low-grade alkenyl, substituted low-grade alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, naphthenic base, substituted naphthenic base, cycloalkenyl group and substituted cycloalkenyl group.
Further formula I preferably also, the compound of II or III, wherein
X is-Cl;
Y; R 1R 2R 4R 5And R 6Be hydrogen;
R 3Be oxygen; And
R 7And R 8Be phenyl, they are unsubstituted or by following replacement 1,2 or 3 times independently of one another: low alkyl group, and rudimentary-thiazolinyl, rudimentary-alkynyl, dioxo-rudimentary-alkylidene group (forming for example benzo dioxy base), halogen, hydroxyl ,-CN ,-CF 3,-NH 2,-N (H, rudimentary-alkyl), N (rudimentary-alkyl) 2, aminocarboxyl, carboxyl ,-NO 2, rudimentary-alkoxyl group, sulfo--rudimentary-alkoxyl group, rudimentary-alkyl sulphonyl; Amino-sulfonyl, rudimentary-alkyl-carbonyl, rudimentary-the alkyl-carbonyl oxygen base, rudimentary-alkoxy carbonyl; Rudimentary-alkyl-carbonyl-NH, fluoro-is rudimentary-alkyl, and fluoro-is rudimentary-alkoxyl group, rudimentary-alkoxyl group-carbonyl-rudimentary-alkoxyl group; Carboxyl-rudimentary-alkoxyl group, formamyl-rudimentary-alkoxyl group, hydroxyl-rudimentary-alkoxyl group ,-NH 2-rudimentary-alkoxyl group ,-N (H, rudimentary-alkyl)-rudimentary-alkoxyl group ,-N (rudimentary-alkyl) 2-rudimentary-alkoxyl group, benzyloxy-rudimentary-alkoxyl group, single-or the substituted amino-alkylsulfonyl of two-low alkyl group with can be randomly by halogen, hydroxyl ,-NH 2,-N (H, rudimentary-alkyl) or-N (rudimentary-alkyl) 2Substituted rudimentary-alkyl.
Particularly preferably be formula I, the compound of II or III, wherein
X is-Cl;
Y; R 1R 2R 4R 5And R 6Be hydrogen;
R 3Be oxygen; And
R 7And R 8Be phenyl, they are unsubstituted or are substituted base and replace 1,2 or 3 time that described substituting group is independently selected from independently of one another:
Halogen, C 2-4-alkynyl or-O-(C 1-4Alkyl) and
Said C 2-4-alkynyl or-O-(C 1-4Alkyl) be unsubstituted or by hydroxyl or-N (C 1-4Alkyl)-S (O) 2-CH 3Replace 1 time.
Particularly, preferred compound is those compounds of following formula:
(2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
(2 ' SR, 3S, 4 ' R)-4 '-(tertiary butyl)-6-chloro-2 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
(2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-)-5 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(methoxycarbonyl) methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(hydroxycarbonyl group)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(cyclopropyl is amino)-carbonyl-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-[[2-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6-dioxo spiral shell [3H-indoles-3,3 '-piperidines]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-[2-(trifluoromethyl) phenyl)]-2-oxo spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit]-hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-p-methoxy-phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclohexenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(1,3-benzo dioxole-4-yl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-4-methyl-penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-tetramethyleneimine-1-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methoxycarbonyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-but-1-ene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethylidene-amyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(ring penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-methyl isophthalic acid-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,2-dimethyl--1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-morpholine-4-base-ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-methoxycarbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-hydroxycarbonyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[3-chloro-5-(4-methylsulfonyl-piperazine-1-carbonyl)-phenyl]-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-sec.-butyl-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-hydroxymethyl-vinyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methoxymethyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1,2-dimethyl--propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-propionyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclopropyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-hydroxycarbonyl group methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[(1-methylsulfonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-hydroxyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-1-hydroxyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-fluoro-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-isobutyryl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-(aminocarboxyl-methyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(cyclopropyl aminocarboxyl-methyl)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl sulphonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-1,1-dimethyl--ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl)-4 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-acetylamino-piperidines-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6-cyanic acid-2 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-(3-piperidines-1-base-propyl group) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[6-(2-hydroxyl-oxyethyl group)-3-methyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-cyclopropyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-cyanic acid-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-methoxyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-fluoro-2-methyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-o-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-thiene-3-yl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two chloro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-(methylamino-carbonyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-carbonyl-methyl)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(4-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(3-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-(aminocarboxyl-methyl)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-propyl group)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-ethyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(4-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(5-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(2, the 2-dimethyl propyl)-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2, the 5-dichlorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S) 2 '-[2-(4-aminocarboxyl-piperidines-1-yl) methyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(4-methylsulfonyl-piperazine-1-yl) methyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-fluoro-2-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-methyl]-phenyl }-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6-methoxyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-ethynyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl sulphonyl-4-piperidyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [4-(1,1-dioxy-2-isothiazole alkyl) ethyl] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [3-(methyl sulphonyl) propyl group] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromo-5-fluorophenyl) 6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-(2-ethynyl-5-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2-[3-(methylsulfonyl-methyl-amino)-third-1-alkynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[3-ethynyl-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
With
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
In this manual, when indication, various groups can be individual by 1-5, or preferred 1-3 substituting group replaces; Described substituting group is independently selected from: low alkyl group, and rudimentary-thiazolinyl, rudimentary-alkynyl, dioxo-rudimentary-alkylidene group (forming for example benzo dioxy base); Halogen, hydroxyl ,-CN ,-CF 3,-NH 2,-N (H, rudimentary-alkyl), N (rudimentary-alkyl) 2, aminocarboxyl, carboxyl ,-NO 2, rudimentary-alkoxyl group, sulfo--rudimentary-alkoxyl group, rudimentary-alkyl sulphonyl; Amino-sulfonyl, rudimentary-alkyl-carbonyl, rudimentary-the alkyl-carbonyl oxygen base, rudimentary-alkoxy carbonyl; Rudimentary-alkyl-carbonyl-NH, fluoro-is rudimentary-alkyl, and fluoro-is rudimentary-alkoxyl group, rudimentary-alkoxyl group-carbonyl-rudimentary-alkoxyl group; Carboxyl-rudimentary-alkoxyl group, formamyl-rudimentary-alkoxyl group, hydroxyl-rudimentary-alkoxyl group ,-NH 2-rudimentary-alkoxyl group ,-N (H, rudimentary-alkyl)-rudimentary-alkoxyl group ,-N (rudimentary-alkyl) 2-rudimentary-alkoxyl group, benzyloxy-rudimentary-alkoxyl group, single-or the substituted amino-alkylsulfonyl of two-low alkyl group with can choose by halogen hydroxyl ,-NH wantonly 2,-N (H, rudimentary-alkyl) or-N (rudimentary-alkyl) 2Substituted rudimentary-alkyl.
Be used for aryl, heteroaryl and heterocyclic preferred substituents are halogens, lower alkoxy, low alkyl group and amino.
If alkyl, thiazolinyl, two ends of alkynyl or similar group are connected on the identical part; Then can obtain ring texture, two hydrogen of wherein said part are by described alkyl, thiazolinyl; Two terminal replacements of alkynyl or similar group, thus ring texture produced, as 1; 2,3, the 4-tetraline, greatly the ring or spirocyclic compound.
Term " alkyl " is meant to have the 1 straight or branched saturated hydrocarbyl to about 20 carbon atoms.In certain embodiments, alkyl substituent can be a low-grade alkyl substituent.Term " low alkyl group " is meant the alkyl with 1 to 8 carbon atom, and in certain embodiments, is the alkyl with 1 to 4 carbon atom.Preferably, term " low alkyl group " is meant the C1-4 alkyl.The instance of alkyl includes but not limited to, methyl, and ethyl, just-and propyl group, different-propyl group, just-and butyl, the second month in a season-butyl, tert-butyl, just-amyl group, and uncle-amyl group.
As used herein; " naphthenic base " means any stable monocycle or the multi-loop system of only being made up of carbon atom; Its any ring all is saturated; And term " cycloalkenyl group " means any stable monocycle or the multi-loop system of only being made up of carbon atom, and wherein its at least one ring is that part is unsaturated.The instance of naphthenic base includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl; Cyclohexyl, suberyl, adamantyl; The ring octyl group, bicyclic alkyl comprises that double-octane is like [2.2.2] double-octane or [3.3.0] double-octane; Bicyclic nonane like [4.3.0] bicyclic nonane and dicyclo decane like [4.4.0] dicyclo decane (naphthane), or spirocyclic compound.The instance of cycloalkenyl group includes but not limited to, cyclopentenyl or cyclohexenyl.
Term as used herein " thiazolinyl " is meant and contains two keys and have 2 to 8, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 6 carbon atoms.The instance of like this " thiazolinyl " is vinyl (vinyl), allyl group, pseudoallyl, 1-propenyl, 2-methyl isophthalic acid-propenyl; The 1-butylene base, crotyl, 3-crotonyl, 2-ethyl-1-butylene base, 3-methyl-2-butene base; The 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl; 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
Term as used herein " alkynyl " is meant and contains one three key and have 2 to 6, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 4 carbon atoms.The instance of like this " alkynyl " is an ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexyn, 2-hexyn, 3-hexyn, 4-hexyn and 5-hexyn.
Be meant fluorine like employed term " halogen " in definition, chlorine, iodine or bromine, preferred fluorine and chlorine.
" aryl " is meant the aromatic carbocyclic alkyl of univalent monocycle or dicyclo, the first aromatic ring of preferred 6-10 system.Preferred aryl groups includes but not limited to, phenyl, naphthyl, tolyl, and xylyl.
" heteroaryl " is meant and contains the aromatic heterocycle system of two rings at the most.Preferred heteroaryl includes but not limited to thienyl, furyl, indyl, pyrryl, pyridyl, pyrazinyl ， oxazolyl, thiazolyl (thiaxolyl), quinolyl, pyrimidyl, imidazoles and tetrazyl.
Under the situation of the aryl of dicyclo or heteroaryl, should be understood that a ring can be an aryl, and another is a heteroaryl, and two all is to replace or unsubstituted.
" heterocycle " be meant and replace or unsubstituted 5 to 8 yuan of lists-or the aromatics or the non-aromatic hydrocarbon of dicyclo, and wherein the heteroatoms that is selected from nitrogen, oxygen or the sulphur atom of 1 to 3 carbon atom replaces.Instance comprises tetramethyleneimine-2-base; Tetramethyleneimine-3-base; Piperidyl; Morpholine-4-base etc.
" heteroatoms " is meant and is selected from N, the atom among O and the S.
" alcoxyl, alkoxyl group or lower alkoxy " is meant any above-mentioned low alkyl group that is connected on the Sauerstoffatom.Typical lower alkoxy comprises: methoxyl group, oxyethyl group, isopropoxy or propoxy-, butoxy etc.What in the implication of alkoxyl group, further comprise is a plurality of alkoxyl group side chains, ethoxy ethoxy for example, methoxy ethoxy, methoxy ethoxy oxyethyl group etc.; With substituted alkoxyl group side chain, dimethylamino ethoxy for example, diethyl amino base oxethyl, dimethoxy-phosphoryl methoxy base etc.
" medicinal " is meant as far as the experimenter who gives specific compound it is acceptable and have basically no toxic on the pharmacology like pharmaceutical carrier, vehicle etc.
" pharmaceutical salts " is meant the biological effectiveness that keeps The compounds of this invention and characteristic and the salt of the conventional acid addition that formed by the nontoxicity organic acid that suits or mineral acid or organic bases or mineral alkali or the salt of alkali addition.The instance of salt of acid addition comprise those derive from mineral acid, such as the salt of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid and those derive from organic acid, such as the salt of tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, Hydrocerol A, oxysuccinic acid, lactic acid, fumaric acid etc.The instance of the salt of alkali addition comprise those derive from the salt of ammonium, potassium, sodium and quaternary ammonium hydroxide, such as tetramethylammonium hydroxide.With medical compounds (being medicine) chemical modification salify is physics and chemicalstability, water absorbability, flowability and the deliquescent technology that the well-known acquisition compound of Pharmaceutical Chemist improves.For example, referring to " pharmaceutical dosage form and drug delivery systems " such as H.Ansel (Pharmaceutical Dosage Forms and Drug Delivery Systems) (the 6th edition 1995) 196 and 1456-1457 page or leaf.
Formula I or II or III compound and their salt have at least one unsymmetrical carbon, therefore can be used as racemic mixture or different steric isomer existence.Can separate various isomer by separation method such as chromatography that oneself knows.The present invention includes all steric isomers.
Compound of the present invention is used for treatment or control cell proliferation disorders, particularly tumor disease.These compounds can be used for treatment or controlled entity knurl with the preparation that contains these compounds, such as mammary gland, colon, lung and tumor of prostate.
The amount that is meant effective prevention, alleviation or improves disease symptoms or prolong the compound that the experimenter that treats of institute survives according to the treatment significant quantity of compound of the present invention.The mensuration of treatment significant quantity belongs in the scope of art technology.
The treatment significant quantity of The compounds of this invention or dosage can be measured according to mode well known in the art in the tolerance in change.Can comprise particular compound, route of administration, disease of being treated that is given and the patient who is treated according to this type of individual need adjustment dosage in every kind of particular case.In general, with regard to the adult oral or parenterai administration that body weight is about 70Kg, about 10mg is to about 10,000mg, and preferably about 200mg is to about 1, and dosage every day of 000mg should be suitable, but, when indicating, can surpass the upper limit.Can with every day dosage as single dose or divided dose administration, or with regard to parenterai administration, can be used as the continuous infusion administration.
Preparation of the present invention comprises and is suitable for following those: oral, nose, part (comprising cheek and hypogloeeis), rectum, vagina and/or parenteral admin.Said preparation can exist with unit dosage form easily, and can be by method preparation known in the pharmacopedics field.Can with solid support material combination will be with the amount of the activeconstituents that produces the single dose form according to the main body of treatment and the concrete mode of administration are changed.Can will be to produce the formula I of result of treatment or the amount of II or III compound usually with the amount of the activeconstituents that produces the single dose form with solid support material combination.Usually, in 100 per-cents, the scope of this amount is about 1 per-cent to about 99 per-cent activeconstituentss, and preferred about 5 per-cents are about 70 per-cents extremely, most preferably from about 10 per-cents to about 30 per-cents.
Preparing these preparations or method for compositions may further comprise the steps: with compound of the present invention and carrier, and one or more optional ancillary component combinations.Usually, through with compound of the present invention and liquid vehicle or solid carrier in small, broken bits, or they both, evenly and combination nearly, then, if desired, be shaped to product.
The preparation that the present invention is suitable for oral administration can be following form: capsule, cachet, sachet, pill, tablet, lozenge (use the matrix (flavored basis) of rectifying flavor; Normally sucrose and gum arabic or tragacanth gum), pulvis, granule or as solution or suspensoid in water-based or non-aqueous liquid; Or as oil-in-water or water-in-oil liquid emulsion; Or as elixir or syrup, or (use inert base (inert base), like gelatin and glycerine as pastille; Or sucrose and gum arabic) and/or mouth wash shua etc., the The compounds of this invention that contains predetermined amount separately is as activeconstituents.Can also be with compound of the present invention as bolus (bolus), electuary or paste administration.
" significant quantity " is meant effective prevention, alleviation or improves disease symptoms or prolong the consumption that the experimenter that treats of institute is survived.
" IC 50" be meant for the concentration that suppresses the active 50% needed particular compound of particular measurement.Wherein, IC 50Can be especially like the said measurement in back.
" medicinal ester " is meant the general formula I that has carboxyl or hydroxyl or the II or the III compound of conventional esterification, this ester class kept biological effectiveness and the characteristic of compound of Formula I and in vivo (in vivo) be cracked into corresponding active carboxylic acid or alcohol respectively.
The compounds of this invention among formula I or II or the III can be synthetic according to following general scheme.Be in general synthetic route, to prepare the compound among the formula I-III for what those of ordinary skill in the art understood easily through replacement reagent or reagent.Raw material is commercially available, or can be synthetic by the known literature method used for a long time of those of ordinary skill in the art.The committed step of this transformation be utilize azepine Diels-Alder reaction compile [4+2] cycloaddition, thereby with the racemic mixture of the Spiroindolinone compound among stereoselectivity and the efficient manner production I.Through using the purifying of chiral chromatography, can obtain the formula II of or enrichment enantiomer pure or the compound in the formula III as optically-active.
Figure G2007800087501D00271
Scheme 1
Usually, the suitable aldehyde I that selects can with hexamethl disilamine base lithium, the substituted acyl chlorides of chlorine trialkyl silane and selectivity reacts with the multistep mode in single jar, generating 2-azepine-1,3-butadiene II (scheme I), and can be used as the raw product use.Ghosez, people such as L. have reported that the preparation of 2-azepine-1,3-butadiene forms heterocyclic with them and uses (reference: Tetrahedron 1995,11021 in azepine Diels-Alder reaction; J.Am.Chem.Soc.1999,2617; The document of wherein quoting).The suitable aldehyde I that selects is commercially available, or can be synthetic by the known literature method used for a long time of those of ordinary skill in the art.
Figure G2007800087501D00281
Scheme 2
In the presence of alkali, under heating condition, at protonic solvent such as methyl alcohol, ethanol or aprotic solvent such as toluene, in the o-Xylol, oxindole III can react with suitable substituted aldehydes or ketones, to obtain intermediate compound IV.Normally used alkali is tetramethyleneimine or piperidines.Then in toluene or o-Xylol; Under about 110 ℃ to 160 ℃ heating and anhydrous condition; Intermediate compound IV can with 2-azepine-1,3-] diene II reaction, provide show with other minority steric isomer together, as the Spiroindolinone V of primary product and the racemic mixture of V '.6-is substituted or 5, and 6-disubstituted oxindoles III raw material is commercially available, or according to the literature method preparation, described literature method is Kraynack for example, E.A; Dalgard, J.E; Gaeta, F.C.A.Tetrahedron Letters, 1998,39,7679-7682, EP153818 is used for 5-fluoro-6-chlorine oxindole etc.
Figure G2007800087501D00291
Scheme 3
R in reagent VII 6When being strong electron-withdrawing group group, intermediate compound IV can be alternatively by isatin VI and reagent VII preparation.For example, at R 6Be cyanic acid, and R 7Be substituted aryl, during heteroaryl, in the presence of alkali such as DBU, in methyl alcohol, the heating condition under, isatin VI can with various R 7Substituted prussiate VII reaction is to form IV (scheme 3).6-is substituted or 5, and the dibasic isatin VI of 6-raw material is commercially available, or according to the literature method preparation.
Figure G2007800087501D00292
Scheme 4
Can intermediate compound IV be protected, to obtain midbody VIII.Through the use Vinyl chloroformate, tert-Butyl dicarbonate, SEM-Cl, bromotoluene and alkali such as 4-(n n dimetylaniline) pyridine (DMAP), triethylamine, NaH, or LiH according to document program used for a long time, can connect the protection base.Protection base form with their instance of deprotection by Greene, description such as T.W. and summarizing in " the protection base in the organic synthesis (Protective Groups in Organic Synthesis), the 2nd edition .JohnWiley & Sons Inc.In a similar fashion; In toluene or o-Xylol; Under 110 ℃ to 160 ℃ heating and anhydrous condition; Midbody VIII can with the 2-azepine-divinyl II reaction of the selection of preparation in scheme 1, form intermediate compound I X and IX ', it is shown as the racemic mixture (scheme 4) with other minority steric isomer two kinds of enantiomers together as primary product.Intermediate compound I X can change into V (scheme 5) through deprotection reaction.Useful Pg can be a urethanum, t-butyl carbamate (BOC), or trimethylsilyl ethoxyl methyl (SEM).Through in methyl alcohol or ethanol, in room temperature, handle IX with alkali such as NaOH, can remove urethanum.Through in room temperature, handle IX with trifluoroacetic acid, can easily remove t-butyl carbamate (BOC).Through at first in methylene dichloride, in room temperature, handle with trifluoroacetic acid, then in methyl alcohol, heat with diisopropylethylamine, can realize the deprotection of trimethylsilyl ethoxyl methyl (SEM).
Figure G2007800087501D00301
Scheme 5
At R 8Be selected from some group such as low alkyl group, substituted low alkyl group when naphthenic base, substituted naphthenic base, can use alternative compound method to obtain compound V or intermediate compound I X.Typically, have and be selected from relevant low-grade alkenyl, or substituted thiazolinyl, or cycloalkenyl group, or the R of substituted cycloalkenyl group 8Compound V or intermediate compound I X should then be catalytic hydrogenation, to obtain wherein R at first according to the preparation of the method in scheme 2 or the scheme 4 8Be corresponding low alkyl group, or substituted low alkyl group, or naphthenic base, or those V or the IX of substituted naphthenic base.With Simmons-Smith reagent (CH 2I 2-Et 2Zn) handle to have and be selected from relevant low-grade alkenyl, or the R of substituted thiazolinyl 8Compound V or intermediate compound I X will obtain R 8Be those V or the IX of corresponding substituted cyclopropyl.
Under controlled conditions, can carry out selective protection to V, to obtain IX.In the case, useful herein protection base Pg can be a urethanum, or t-butyl carbamate (BOC) (scheme 6).Be similar in the scheme 4 transformation from IV to VIII, in methylene dichloride, at room temperature or low temperature, through using Vinyl chloroformate, or tert-Butyl dicarbonate and alkali such as 4-(n n dimetylaniline) pyridine (DMAP), can connect the protection base.
Figure G2007800087501D00311
Scheme 6
Through using organic bases diisopropylethylamine or mineral alkali such as Cs 2CO 3, LiH or NaH and the suitable alkylating agent of selecting can prepare N-alkylation intermediate X by IX.The reaction of removing protection base (Pg) subsequently obtains various R 2The compounds X I of derivatize (scheme 7).
At Pg is trimethyl silyl oxygen ethoxyl methyl (SEM) group and R 2Be-(CH 2) nDuring Cl, can other the functionalized R of substituted radical 2For example, have-(CH 2) nThe intermediate X of Cl can with HNR 10R 11With pure form or in solvent such as Virahol, reaction under heating condition is then handled with trifluoroacetic acid and Diisopropylamine, obtains R 2For-(CH 2) nNR 10R 11Compounds X I.
Work as R 2Group is-(CH 2) m(=O) OR ' when wherein R ' is hydrogen or low alkyl group, is used for all perception methods that methane amide forms through use to C, can transform compounds X I, obtains R 2Be (CH 2) mC (=O) NR 10R 11Compounds X I.
R 10Or R 11Be independently selected from: hydrogen, low alkyl group, substituted low alkyl group, lower alkoxy, substituted lower alkoxy, naphthenic base, substituted naphthenic base, heterocycle, substituted heterocycle, or R 10And R 11Can be connected to form heterocycle, substituted heterocycle, heteroaryl, or substituted heteroaryl.
n＝2，3，4
m＝1，2，3
Figure G2007800087501D00321
Scheme 7
In a step,, can compound I X selective conversion be become the similar thing XII of thioamides (scheme 8) through using Lawesson reagent or other similar related reagent.
Figure G2007800087501D00322
Scheme 8
At R 2When being hydrogen, thioamide compound XIII can also be a useful as intermediates, to prepare various R 3The analogue of derivatize.For example, compounds X III can with active nucleophilic, suitable substituted hydrazides R 9-O (O=C) NHNH2 and mercury reagent such as HgCl 2Or Hg (OAc) 2Reaction is to form analogue XIV (scheme 9).R 9Be low alkyl group or substituted low alkyl group.
Figure G2007800087501D00331
Scheme 9
Through using the ultra liquid chromatography of chirality (SFC) or chirality HPLC or chiral column chromatographic separation, can be easily compound V and V ' be split into the enantiomer (scheme 10) of the pure or enrichment chirality of two kinds of optically-actives.With with the upper mattress scheme in the similar mode of method, replace through V being used for enantiomer V ', or IX use IX ' replacement, can prepare intermediate X and compounds X I, XII, XIII, the chirality enantiomer of XIV.Compound V and V ', intermediate compound I X and IX ' at first produce as racemic mixture, react under the situation of chiral separation not having subsequently, obtain X, XI, XII, XIII, or the corresponding racemic mixture of XIV and their enantiomer.With the similar mode of scheme 10, also can be easily with all these the IX for preparing in superincumbent each reaction scheme, X; XI; It is right that XII, XIII, the racemic mixture of XIV and their corresponding enantiomers separate into the pure or spissated chirality enantiomer of optically-active.
Figure G2007800087501D00332
Scheme 10
Provide the following example and reference to help understanding the present invention, true scope of the present invention is listed in the appended claim.
Embodiment
Embodiment 1a
Preparation intermediate E/Z-6-chloro-3-(3,3-dimethyl--butylidene)-1, the 3-dihydro-indol-2-one
M.W.249.74?C 14H 16ClNO
((0.21g 2.09mmol) in (Aldrich) mixture in methyl alcohol (20mL), drips tetramethyleneimine (0.15g, 2.09mmol) (Aldrich) to 3-dimethyl--butyraldehyde for 0.26g, 1.49mmol) (Crescent) and 3 to 6-chlorine oxindole.Then, mixture is heated 1h in 100 ℃.Mixture is concentrated, and residuum is distributed between ETHYLE ACETATE and water.Organic layer is separated, use Na 2SO 4Drying concentrates, and vacuum-drying, obtains rough E/Z-6-chloro-3-(3,3-dimethyl--butylidene)-1, and the 3-dihydro-indol-2-one is white solid (yield 0.37g, 100%).
Embodiment 1b
Preparation midbody 1-(3-chloro-phenyl-)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.253.81?C 12H 16ClNOSi
Under nitrogen, in room temperature, to 1,1,3,3, (2.18mL 10.5mmol) in (Aldrich), adds n-Butyl Lithium (2.5M, 4.2mL, 10.5mmol) (Aldrich) to the 3-hexamethyldisilazane.With reaction mixture in stirring at room 10 minutes.Add anhydrous tetrahydro furan (30mL) then, go into 3-chloro-phenyl aldehyde (1.19mL, 10.5mmol) (Aldrich) after then adding.With mixture behind stirring at room 0.5h, drip trimethylsilyl chloride (1.33mL, 10.5mmol) (Aldrich).Then, on the refrigerative ice bath, the temperature of mixture is reduced to 0 ℃.In this mixture, (1.9mL 13.6mmol), follows dripping acetyl chloride (0.97mL, 13.6mmol) solution in diethyl ether (50mL) to add triethylamine with portion.Remove cooling bath, and with mixture in stirring at room 1h.Under nitrogen, mixture is filtered on zeyssatite rapidly, and it is under reduced pressure concentrated to filtrate; Obtain rough 1-(3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Similarly change by Ghosez L., Bayard, Ph., Nshimyumukiza, P.; Gouverneur, V., Sainte, F., Beaudegnies, R.; Rivers, M., Frique-Hesbain, A.-M. and Wynants, C. are reported in Tetrahedron 1995, among the 11021-11042.
Embodiment 1c
Preparation racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.431.36?C 23H 24Cl 2N 2O 2
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; 3-divinyl (0.25g; 1mmol) and in the mixture of toluene (4mL), be added in preparation E/Z-6-chloro-3-(3,3-dimethyl--butylidene)-1 among the embodiment 1a; The 3-dihydro-indol-2-one (0.25g, 1mmol).Under nitrogen, reaction mixture is heated 18h in 110 ℃ in ST.Mixture is cooled to room temperature, and adds methyl alcohol (10mL).Mixture is concentrated and (purifying of EtOAc/ hexane=2:1) obtains racemize (2 ' S, 3S by chromatogram with residuum; 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2; The 2-dimethyl propyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be brown solid (yield 0.15g, 35%).
HRMS (ES +) m/z calculated value C 23H 24Cl 2N 2O 2+ H [(M+H) +]: 431.1288.Measured value: 431.1285
Similarly change by Ghosez, L. and Jnoff, E. is reported in J.Am.Chem.Soc1999, among the 2617-2618.
Embodiment 2a
Preparation intermediate E-6-chloro-3-(2,2-dimethyl--propylidene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00361
M.W.235.72?C 13H 14ClNO
With with the similar mode of method described in the embodiment 1a, (0.88g is 5mmol) with 2 with 6-chlorine oxindole; 2-dimethyl--propionic aldehyde (0.43g, 5mmol) (Aldrich), tetramethyleneimine (0.36g; 5mmol) in methyl alcohol, react; Obtain E-and Z-6-chloro-3-(2,2-dimethyl--propylidene)-1, the mixture of 3-dihydro-indol-2-one.(EtOAc: the purifying of hexane=1:2) obtains E-6-chloro-3-(2,2-dimethyl--propylidene)-1, and the 3-dihydro-indol-2-one is pearl foam (yield 0.82g, 70%) by chromatogram.
Embodiment 2b
Preparation racemize (2 ' SR, 3S, 4 ' R)-4 '-(tertiary butyl)-6-chloro-2 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.417.34?C 22H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 1c, with E-6-chloro-3-(2,2-dimethyl--propylidene)-1; The 3-dihydro-indol-2-one (0.23g, 1mmol) with 1-(3-chloro-phenyl-)-3-front three of in embodiment 1b, preparing for siloxy--2-azepine-1,3-butadiene (0.63g; 2.5mmol) in toluene, react, obtain racemize (2 ' SR, 3S; 4 ' R)-4 '-(tertiary butyl)-6-chloro-2 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; It is the mixture (yield 0.21g, 50%) of two groups of diastereomers.
HRMS (ES +) m/z calculated value C 22H 22Cl 2N 2O 2+ H [(M+H) +]: 417.1131.Measured value: 417.1129
Embodiment 3a
Preparation intermediate E/Z-6-chloro-3-isobutylene-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00371
M.W.221.69?C 12H 12ClNO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (0.85g, 4.8mmol) with 2-methyl-propionic aldehyde (0.42g; 5.8mmol) (Aldrich), tetramethyleneimine (0.41g, 5.8mmol) reaction in methyl alcohol (40mL); Obtain E/Z-6-chloro-3-isobutylene-1; The mixture of 3-dihydro-indol-2-one is brown foam (yield 1.0g, 100%).
Embodiment 3b
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00372
M.W.403.31?C 21H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 1c, with E/Z-6-chloro-3-isobutylene-1,3-dihydro-indol-2-one (0.25g; 1.1mmol) (1.2g 4.7mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-the chloro-phenyl-)-3-front three that in embodiment 1b, prepares; Obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.25g, 56%).
HRMS (ES +) m/z calculated value C 21H 20Cl 2N 2O 2+ H [(M+H) +]: 403.0975.Measured value: 403.0975.
Embodiment 4a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
M.W.290.15?C 15H 9Cl 2NO
(16.2g, 92mmol) (12.9g 92mmol) in (Aldrich) mixture in methyl alcohol (109mL), drips tetramethyleneimine (6.55g, 92mmol) (Aldrich) for (Crescent) and 3-chloro-phenyl aldehyde to 6-chlorine oxindole.Then mixture is heated 3h in 70 ℃.After being cooled to 4 ℃, mixture to be filtered, and will obtain the throw out collection, drying obtains E/Z-6-chloro-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 25.2g, 95%).
Embodiment 4b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
M.W.362.22?C 18H 13Cl 2NO 3
In 0 ℃; To preparation E/Z-6-chloro-3-(3-chloro-tolylene)-1 in embodiment 4a, (1.33g is 4.6mmol) in the solution in methylene dichloride (50mL) for the 3-dihydro-indol-2-one; Add Vinyl chloroformate (0.66mL; 6.9mmol) (Aldrich), then add triethylamine (0.93g, 9.2mmol).Reaction mixture was stirred 30 minutes in 0 ℃.Then mixture is poured in the HCl aqueous solution (1N).Organic layer is separated, and water layer is used ethyl acetate extraction.Organic layer is merged and uses Na 2SO 4Drying, and concentrate, obtaining E/Z-6-chloro-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid, and under situation about not being further purified, is used for next step (yield 1.7g, 100%).
Embodiment 4c
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-s)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
M.W.543.84?C 27H 21Cl 3N 2O 4
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; In the solution of 3-divinyl in toluene (20mL); Be added in E/Z-6-chloro-3-(3-chloro-the tolylene)-2-oxo-2 for preparing among the embodiment 6b; 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.3g, 0.83mmol).Reaction mixture under nitrogen, is stirred 1h in 135 ℃ in ST.After solution is cooled to room temperature, add methyl alcohol (50mL), then mixture is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-s)-2,3-dihydro-2, and 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester is yellow oil (yield 0.45g, 100%).
Embodiment 4d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.471.77?C 24H 17Cl 3N 2O 2
To the racemize that in embodiment 4c, prepares (2 ' R, 3R, 4 ' S)-6-chloro-2 '; 4 '-two (3-chloro-phenyl-s)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-carboxylic acid, ethyl ester (0.45g; 0.92mmol) in the solution in methyl alcohol (30mL), add NaOH (66mg, 1.65mmol).With mixture in stirring at room 0.5h.Except that desolvating and residuum being distributed between the ETHYLE ACETATE and the HCl aqueous solution (1N).Water layer is used ethyl acetate extraction.Organic layer is merged, concentrate then.With residuum with chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2, and 6 '-diketone is white solid (yield 0.2g, 51%).
HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0431.0.
Embodiment 4e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00402
M.W.471.77?C 24H 17Cl 3N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' the S)-6-chloro-2 ' that among embodiment 4d, prepares; The separation of two kinds of enantiomers in 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (84mg) is to provide chirality (2 ' R; 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 10mg, 12%).HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0431 and chirality (2 ' S, 3S, 4 ' R)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 17 mg, 20%).HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0428.
Embodiment 5a
Preparation intermediate E/Z-6-chloro-3-cyclopentyl methylene radical-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00411
M.W.247.73?C 14H 14ClNO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (1.16g, 6.59mmol) with pentamethylene formaldehyde (0.77g; 7.85mmol) (Wiley) and piperidines (0.67g; 7.85mmol) in methyl alcohol, react, obtain E-and Z-6-chloro-3-cyclopentyl methylene radical-1, the mixture of 3-dihydro-indol-2-one; Be brown oil (yield 0.8g, 49%).
Embodiment 5b
Preparation intermediate E/Z-6-chloro-3-cyclopentyl methylene radical-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure G2007800087501D00412
M.W.319.79?C 17H 18ClNO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-6-chloro-3-cyclopentyl methylene radical-1,3-dihydro-indol-2-one (0.8g; 3.2mmol) with Vinyl chloroformate (0.46mL, 4.9mmol) and triethylamine (0.9mL 6.4mmol) reacts in methylene dichloride; Obtain E/Z-6-chloro-3-cyclopentyl methylene radical-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid, ethyl ester is brown oil (yield 0.6g, 58%).
Embodiment 5c
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00421
M.W.501.41?C 26H 26Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, with E/Z-6-chloro-3-cyclopentyl methylene radical-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.32g; 1.00mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(3-the chloro-phenyl-)-3-front three that in embodiment 1b, prepares, obtain racemize (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be pearl foam (yield 0.26g, 52%).
Embodiment 5d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.26g; 0.52mmol) (37mg 0.93mmol) reacts in methyl alcohol, obtains racemize (2 ' S with NaOH; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.13g, 59%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1121.
Embodiment 6a
Preparation intermediate E/Z-6-chloro-3-cyclohexylmethylene-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00431
M.W.261.75?C 15H 16ClNO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (2g, 11.4mmol) with hexanaphthene formaldehyde (1.53g; 13.6mmol) (Aldrich) and piperidines (1.35mL; 13.6mmol) in methyl alcohol, react, obtain E-and Z-6-chloro-3-cyclohexylmethylene-1, the mixture of 3-dihydro-indol-2-one; Be brown solid (yield 2.71g, 91%).
Embodiment 6b
Preparation intermediate E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure G2007800087501D00432
M.W.333.82?C 18H 20ClNO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one (2.71g; 10.4mmol) with Vinyl chloroformate (1.47mL, 15.6mmol) and triethylamine (2.89mL 20.7mmol) reacts in methylene dichloride; Obtain E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid, ethyl ester is brown solid (yield 3.3g, 95%).
Embodiment 6c
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00441
M.W.515.44?C 27H 28Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, with E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.40g; 1.20mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(3-the chloro-phenyl-)-3-front three that in embodiment 1b, prepares, obtain racemize ((2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow oil (yield 0.2g, 32%).
Embodiment 6d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.2g; 0.39mmol) (28mg 0.70mmol) reacts in methyl alcohol, obtains racemize (2 ' S with NaOH; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.05g, 29%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1288.
Embodiment 7a
Preparation midbody 1-(4-chloro-phenyl-)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00451
M.W.253.81?C 12H 16ClNOSi
With with the similar mode of method described in the embodiment 1b, with 4-chloro-phenyl aldehyde (1.48g, 10.5mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction; Obtain 1-(4-chloro-phenyl-)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 7b
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00452
M.W.515.44?C 27H 28Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2 that will in embodiment 6b, prepare, 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.40g; 1.20mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(4-the chloro-phenyl-)-3-front three that in embodiment 7a, prepares, obtain racemize (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be white solid (yield 0.45g, 72%).
Embodiment 7c
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00461
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.4g; 0.78mmol) (56mg 1.4mmol) reacts in methyl alcohol, obtains racemize (2 ' S with NaOH; 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.15g, 44%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1287.
Embodiment 8a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00462
M.W.543.84?C 27H 21Cl 3N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.3g; 0.83mmol) with in embodiment 7a, prepare 1-(4-chloro-phenyl-)-3-front three and in toluene, react for siloxy--2-azepine-1,3-butadiene, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow solid (yield 0.45g, 72%).
Embodiment 8b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.471.77?C 24H 17Cl 3N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.45g; 0.83mmol) (60mg 1.49mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH; 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.2g, 51%).
HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0427.
Embodiment 9a
Preparation intermediate E/Z-6-chloro-3-(4-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00472
M.W.290.15?C 15H 9Cl 2NO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (2g, 11.4mmol) with 4-chloro-phenyl aldehyde (1.91g; 13.6mmol) (1.53g, 13.6mmol) (1.34mL 13.6mmol) reacts in methyl alcohol for (Aldrich) and piperidines; Obtain E-and Z-6-chloro-3-(4-chloro-tolylene)-1; The mixture of 3-dihydro-indol-2-one is yellow solid (yield: 3.3g, 100%).
Embodiment 9b
Preparation intermediate E/Z6-chloro-3-(4-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure G2007800087501D00481
M.W.362.22?C 18H 13Cl 2NO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-6-chloro-3-(4-chloro-tolylene)-1,3-dihydro-indol-2-one (3.3g; 11.3mmol) with Vinyl chloroformate (1.62mL, 17.0mmol) and triethylamine (3.16mL 22.6mmol) reacts in methylene dichloride; Obtain E/Z-6-chloro-3-(4-chloro-tolylene)-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid (yield 3.0g, 73%).
Embodiment 9c
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00482
M.W.543.84?C 27H 21Cl 3N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 9b, prepare (4-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.35g; 0.97mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(3-the chloro-phenyl-)-3-front three that in embodiment 1b, prepares, obtain racemize (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow solid (yield 0.5g, 95%).
Embodiment 9d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00491
M.W.471.77?C 24H 17Cl 3N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.5g; 0.92mmol) (67mg 1.67mmol) reacts in methyl alcohol, obtains racemize (2 ' S with NaOH; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.08g, 18%).HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0427.
Embodiment 10a
Preparation midbody 1-(3-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00492
M.W.233.39?C 13H 19NOSi
With with the similar mode of method described in the embodiment 1b, with 3-methyl-phenyl aldehyde (1.30g, 10.5mmol) (Matrix) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction; Obtain 1-(3-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 10b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(3-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00501
M.W.523.42?C 28H 24Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(3-the aminomethyl phenyl)-3-front three that in embodiment 10a, prepares, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(3-aminomethyl phenyl)-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow oil (yield 0.5g, 86%).
Embodiment 10c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00502
M.W.451.35?C 25H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(3-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.5g; 0.96mmol) (69mg 1.72mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.15g, 35%).
HRMS (ES +) m/z calculated value C 25H 20Cl 2N 2O 2+ H [(M+H) +]: 451.0975.Measured value: 451.0976.
Embodiment 11a
Preparation midbody 1-(3-fluorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00511
M.W.237.35?C 12H 16FNOSi
With with the similar mode of method described in the embodiment 1b, with 3-fluoro-phenyl aldehyde (1.11mL, 10.5mmol) (Fluka) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction; Obtain 1-(3-fluorophenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 11b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00512
M.W.527.38?C 27H 21Cl 2FN 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.25g; 0.69 mmol) react in toluene for siloxy--2-azepine-1,3-butadiene, obtain racemize (2 ' R with 1-(3-the fluorophenyl)-3-front three that in embodiment 11a, prepares; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow oil (yield 0.35g, 97%).
Embodiment 11c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00521
M.W.455.314?C 24H 17Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.35g; 0.66mmol) (48mg 1.19mmol) reacts, and obtains racemize (2 ' R with NaOH; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.15g, 50%).
HRMS (ES +) m/z calculated value C 24H 17Cl 2FN 2O 2+ H [(M+H) +]: 451.0975.Measured value: 451.0976.
Embodiment 12a
Preparation intermediate E/Z-3-tolylene-6-chloro-1, the 3-dihydro-indol-2-one
Figure G2007800087501D00522
M.W.255.71?C 15H 10ClNO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (1.0g, 5.7mmol) with phenyl aldehyde (0.6g; 5.7mmol) (Aldrich) and tetramethyleneimine (0.4g; 5.7mmol) in methyl alcohol, react, obtain E-and Z-3-tolylene-6-chloro-1, the mixture of 3-dihydro-indol-2-one; Be yellow solid (yield 1.5g, 100%).
Embodiment 12b
Preparation intermediate E/Z-3-tolylene-6-chloro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure G2007800087501D00531
M.W.327.77?C 18H 14ClNO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-3-tolylene-6-chloro-1,3-dihydro-indol-2-one (1.5g; 5.87mmol) with Vinyl chloroformate (0.83mL, 8.8mmol) and triethylamine (1.64mL 12mmol) reacts in methylene dichloride; Obtain E/Z-3-tolylene-6-chloro-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid (yield 2.0g, 100%).
Embodiment 12c
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.437.33?C 24H 18Cl 2N 2O 2
To the 1-that in embodiment 1c, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; In the solution of 3-divinyl in toluene (30mL); Be added in the E/Z-3-tolylene-6-chloro-2-oxo-2 for preparing among the embodiment 12b; 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g, 1.22mmol).Reaction mixture under nitrogen, is stirred 1h in 140 ℃ in ST.After solution is cooled to room temperature, add methyl alcohol (40mL).The short pad of reaction mixture through zeyssatite glue filtered, and wash with ETHYLE ACETATE.To filtrate and concentrate.Residuum is dissolved in the methyl alcohol (30mL), and the NaOH solution of adding 1N (5mL, 5mmol).Reaction mixture in stirring at room 0.5h, is concentrated mixture then.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:4) purifying obtains racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is yellow oil (yield 0.5g, 100%).
HRMS (ES +) m/z calculated value C 24H 18Cl 2N 2O 2+ H [(M+H) +]: 437.0818.Measured value: 437.0817.
Embodiment 13a
Preparation midbody 1-(3-chloro-phenyl-)-4-methyl-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00541
M.W.267.83?C 13H 18ClNOSi
With with the similar mode of method described in the embodiment 1b, with propionyl chloride (1.2g, 13.mmol) (Aldrich) as the raw material replacing acetyl chloride, with 1,1; 3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), 3-chloro-phenyl aldehyde (1.4g; 10mmol) (Aldrich), trimethylsilyl chloride (1.1g, 10mmol) and triethylamine (1.36g, 13mmol) reaction; Obtain 1-(3-chloro-phenyl-)-4-methyl-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 13b
Preparation racemize (2 ' S, 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.451.36?C 25H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 12c, the E/Z-3-tolylene that will in embodiment 12b, prepare-6-chloro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.32g; 0.98mmol) (1.5g 5.6mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-the chloro-phenyl-)-4-methyl-3-front three that in embodiment 13a, prepares; (4mL 8mmol) reacts in methyl alcohol, obtains racemize (2 ' S with 2NNaOH solution then; 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white foam (yield 0.21g, 48%).
HRMS (ES +) m/z calculated value C 25H 20Cl 2N 2O 2+ H [(M+H) +]: 451.0975.Measured value: 451.0972.
Embodiment 14a
Preparation midbody 1-phenyl-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00551
M.W.219.36?C 12H 17NOSi
With with the similar mode of method described in the embodiment 1b, with phenyl aldehyde (1.06g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 3,3, and the 3-hexamethyldisilazane (1.6mL, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.08mL; 10mmol), triethylamine (1.31mL, 13mmol) and Acetyl Chloride 98Min. (1.02g, 13mmol) reaction; Obtain 1-phenyl-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 14b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00552
M.W.437.33?C 24H 18Cl 2N 2O 2
To the 1-phenyl-3-front three that in embodiment 14a, prepares for siloxy--2-azepine-1; 3-divinyl (1.5g; 6.8mmol) in the solution in toluene (30mL); Be added in the E/Z-3-tolylene-6-chloro-2-oxo-2 for preparing among the embodiment 4b, and 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.22g, 0.61mmol).Reaction mixture under nitrogen, is stirred 1.5h in 150 ℃ in ST.After solution is cooled to room temperature, add methyl alcohol (40mL).The short pad of reaction mixture through zeyssatite glue filtered, and wash with ETHYLE ACETATE.To filtrate and concentrate.Residuum is dissolved in the ethanol (20mL), and (0.2g 5mmol), then adds two H to add NaOH 2O.With reaction mixture behind stirring at room 1h, mixture is concentrated.Residuum is distributed between ETHYLE ACETATE and 1NHCl solution.Organic layer is separated, and concentrate.With residuum by chromatogram (EtOAc: the purifying of hexane=2:1), obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (yield 0.14g, 52%).
HRMS (ES +) m/z calculated value C 24H 18Cl 2N 2O 2+ H [(M+H) +]: 437.0818.Measured value: 437.0816.
Embodiment 14c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00561
M.W.437.33?C 24H 18Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [the 3H-indoles-3 that among embodiment 14b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be yellow solid (25mg) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (27mg).
Embodiment 15a
Preparation midbody 1-(3-p-methoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.249.39?C 13H 19NO 2Si
With with the similar mode of method described in the embodiment 1b, with 3-methoxyl group-phenyl aldehyde (1.3g, 9.5mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.53g, 9.5mmol); Just-and butyllithium (2.5M, 3.8mL, 9.5mmol), trimethylsilyl chloride (1.2mL; 9.5mmol), triethylamine (1.72mL, 12.4mmol) and Acetyl Chloride 98Min. (0.88mL, 12.4mmol) reaction; Obtain 1-(3-p-methoxy-phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 15b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00572
M.W.467.36?C 25H 20Cl 2N 2O 3
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.23g; 0.63mmol) and in embodiment 15a, prepare 1-(3-p-methoxy-phenyl)-3-front three for siloxy--(2g 8.0mmol) reacts 4-methyl-2-azepine-1,3-butadiene in toluene; (4mL 8mmol) reacts in methyl alcohol, obtains racemize (2 ' R with 2NNaOH solution then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (yield 0.2g, 69%).
HRMS (ES +) m/z calculated value C 25H 20Cl 2N 2O 3+ H [(M+H) +]: 467.0924.Measured value: 467.0925.
Embodiment 16a
Preparation midbody 1-(2-chloro-phenyl-)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00581
M.w.253.81?C 12H 16ClNOSi
With with the similar mode of method described in the embodiment 1b, with 2-chloro-phenyl aldehyde (1.3g, 9.25mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.49g, 9.25mmol); Just-and butyllithium (2.5M, 3.7mL, 9.25mmol), trimethylsilyl chloride (1.2mL; 9.25mmol), triethylamine (1.7mL, 12.0mmol) and Acetyl Chloride 98Min. (0.85mL, 12.0mmol) reaction; Obtain 1-(2-chloro-phenyl-)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 16b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00582
M.W.543.84?C 27H 21Cl 3N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.31g; 0.85mmol) (2.1g 8.27mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-the chloro-phenyl-)-3-front three that in embodiment 16a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester; Be yellow glue (yield 0.31g, 67%).
Embodiment 16c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00591
M.W.471.77?C 24H 17Cl 3N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2, (0.3g is 0.55mmol) with NaOH (2N for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester; 5mL 10mmol) reacts in methyl alcohol, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 0.21g, 81%).
HRMS (ES +) m/z calculated value C 24H 17Cl 3N 2O 2+ H [(M+H) +]: 471.0429.Measured value: 471.0430.
Embodiment 16d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00592
M.W.471.77?C 24H 17Cl 3N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [the 3H-indoles-3 that among embodiment 16c, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (53mg) and (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (51mg).
Embodiment 17a
Preparation midbody 1-(2-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00601
M.W.233.39?C 13H 19NOSi
With with the similar mode of method described in the embodiment 1b, with 2-methyl-phenyl aldehyde (1.2g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.62g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.3g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 17b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00602
M.W.523.42?C 28H 24Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.32g; 0.88mmol) (2.4g 1.71mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-the aminomethyl phenyl)-3-front three that in embodiment 17a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(2-aminomethyl phenyl)-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (yield 0.4g, 87%).
Embodiment 17c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-33 '-piperidines]-26 ' (1H)-diketone
Figure G2007800087501D00611
M.W.451.36?C 25H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester (0.4g, 0.76mmol) (10mL 20mmol) reacts in methyl alcohol with 2NNaOH solution; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.24g, 70%).
HRMS (ES +) m/z calculated value C 25H 20Cl 2N 2O 2+ H [(M+H) +]: 451.0975.Measured value: 451.0972.
Embodiment 17d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00612
M.W.451.36?C 25H 20Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [the 3H-indoles-3 that among embodiment 23c, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (52mg) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (52mg).
Embodiment 18a
Preparation midbody 1-(2-ethylphenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00621
M.W.247.42?C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2-ethyl-phenyl aldehyde (1.6g, 11.8mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.96g, 11.8mmol); Just-and butyllithium (2.5M, 4.7mL, 11.8mmol), trimethylsilyl chloride (1.50mL; 11.8mmol), triethylamine (2.13mL, 15.3mmol) and Acetyl Chloride 98Min. (1.09mL, 15.3mmol) reaction; Obtain 1-(2-ethylphenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 18b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00622
M.W.465.38?C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g; 1.1 mmol) with 1-(2-ethylphenyl)-3-front three of in embodiment 18a, preparing for siloxy--(3.2g 12.9mmol) reacts in toluene 4-methyl-2-azepine-1,3-butadiene; (5mL 10mmol) reacts in methyl alcohol, obtains racemize (2 ' R with 2NNaOH solution then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (yield 0.085g, 17%).
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131.Measured value: 465.1132.
Embodiment 18c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00631
M.W.465.38?C 26H 22Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [the 3H-indoles-3 that among embodiment 17b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (25mg) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (27mg).
Embodiment 19a
Preparation midbody 4-methyl isophthalic acid-(2-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00632
M.W.247.42?C 14H 21NOSi
With with the similar mode of method described in the embodiment 13a, with 2-methyl-phenyl aldehyde (1.2g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and propionyl chloride (1.2g, 13mmol) reaction; Obtain 4-methyl isophthalic acid-(2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 19b
Preparation racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00641
M.W.465.38?C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.36g; 0.99mmol) with 4-methyl isophthalic acid-(2-aminomethyl phenyl)-3-front three of in embodiment 19a, preparing for siloxy--2-azepine-1,3-butadiene) in toluene, react, then with 2NNaOH solution (4mL; 8mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R; 4 ' S; 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 0.26g, 56%).
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131.Measured value: 465.1132.
Embodiment 20
Preparation racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-)-5 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00651
M.W.485.80?C 25H 19Cl 3N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.36g, 0.99mmol) with 1-(3-chloro-phenyl-)-4-methyl-3-front three of in embodiment 13a, preparing for siloxy--2-azepine-1; (2.2g 8.9mmol) reacts in toluene the 3-divinyl, then with 2NNaOH solution (4mL; 8mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R; 4 ' S, 5 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-)-5 '-methylspiro [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.26g, 57%).
HRMS (ES +) m/z calculated value C 25H 19Cl 3N 2O 2+ H [(M+H) +]: 485.0585.Measured value: 485.0583
Embodiment 21a
Preparation midbody 1-(2-isopropyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00652
M.W.261.44?C 15H 23NOSi
With with the similar mode of method described in the embodiment 1b, with 2-sec.-propyl-phenyl aldehyde (1.5g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.3g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(2-isopropyl phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 21b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00661
M.W.479.41?C 27H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.38g; 1.05mmol) (2.7g 10.3mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-the isopropyl phenyl)-3-front three that in embodiment 21a, prepares; (5mL 10mmol) reacts in methyl alcohol, obtains racemize (2 ' R with 2NNaOH solution then; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 0.26g, 52%).
HRMS (ES +) m/z calculated value C 27H 24Cl 2N 2O 2+ H [(M+H) +]: 479.1288.Measured value: 479.1289.
Embodiment 21c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00662
M.W.479.41?C 27H 24Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [the 3H-indoles-3 that among embodiment 21b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (61mg) and (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (66mg).
Embodiment 22a
Preparation midbody 1-(2-bromophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00671
M.W.298.26?C 12H 16BrNOSi
With with the similar mode of method described in the embodiment 1b, with 2-bromo-phenyl aldehyde (1.85g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.62g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.3g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(2-bromophenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 22b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00672
M.W.588.29?C 27H 21BrCl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g; 1.1mmol) (3.0g 10mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-the bromophenyl)-3-front three that in embodiment 22a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.45g, 69%).
Embodiment 22c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00681
M.W.516.23?C 24H 17BrCl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2, (0.45g is 0.76mmol) with NaOH (2N in methyl alcohol for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester; 5mL, 10mmol) reaction obtains racemize (2 ' R; 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.25g, 64%).
HRMS (ES +) m/z calculated value C 24H 17BrCl 2N 2O 2+ H [(M+H) +]: 514.9923.Measured value: 514.9926.
Embodiment 22d
Preparation chirality (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00682
M.W.516.23?C 24H 17BrCl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [the 3H-indoles-3 that among embodiment 22c, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(2-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (86mg) and chirality (2 ' S, 3S, 4 ' R)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (76mg).
Embodiment 23a
Preparation midbody 1-(3-cyano-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00691
M.W.244.37?C 13H 16N 2OSi
With with the similar mode of method described in the embodiment 1b, with 3-cyanic acid-phenyl aldehyde (1.2g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.62g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.3g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(3-cyano-phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 23b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.462.34?C 25H 17Cl 2N 3O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.42g; 1.2mmol) (2.0g 8.18mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-the cyano-phenyl)-3-front three that in embodiment 23a, prepares; (5 mL 10mmol) react in methyl alcohol, obtain racemize (2 ' R with 2NNaOH solution then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white foam (yield 0.11g, 20%).
HRMS (ES +) m/z calculated value C 25H 17Cl 2N 3O 2+ H [(M+H) +]: 462.0771 measured values: 462.0771.
Embodiment 24a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
Figure G2007800087501D00701
M.W.390.27?C 20H 17Cl 2NO 3
In room temperature; To the E/Z-6-chloro-3-that in embodiment 4a, prepares (3-chloro-tolylene)-1, (1g is 3.4mmol) in the solution in methylene dichloride (50mL) for the 3-dihydro-indol-2-one; Add tert-Butyl dicarbonate (1.5g; 6.9mmol) (Aldrich), then add 4-dimethylaminopyridine (1g, 8.2mmol).With reaction mixture in stirring at room 1h.Then mixture is concentrated and with residuum by chromatogram purification, obtain E/Z-6-chloro-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester is orange solids (yield 1.3g, 96%).
Embodiment 24b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
M.W.551.47?C 30H 28Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (1g; 2.6mmol) (3.3g 14.1mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-the aminomethyl phenyl)-3-front three that in embodiment 17a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester; Be white foam (yield: 0.92g, 65%).
Embodiment 24c
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-methyl-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
Figure G2007800087501D00711
M.W.565.50?C 31H 30Cl 2N 2O 4
In 0 ℃, to racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (0.25g; 0.45mmol) at N, in the solution in N-dimethyl--methane amide (20mL), add LiH (90mg; 11.2mmol) (Aldrich), then add methyl iodide (0.39g, 2.74mmol).Reaction mixture is warmed to room temperature, and in stirring at room 3h.Mixture is diluted with ETHYLE ACETATE, use saturated NH then 4The Cl solution washing.Water layer is used ethyl acetate extraction, and the organic layer that merges is used MgSO 4Dry.Remove and to desolvate, and (EtOAc: the purifying of hexane=1:2) obtains racemize (2 ' R by chromatogram with residuum; 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-methyl-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-carboxylic acid tert-butyl ester (yield 0.20g, 77%).
Embodiment 24d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00721
M.W.465.38?C 26H 22Cl 2N 2O 2
Trifluoroacetic acid (5mL) is joined the racemize (2 ' R that in embodiment 24c, prepares; 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-methyl-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(0.20g is 0.35mmol) in the solution in methylene dichloride (10mL) for the 1-carboxylic acid tert-butyl ester.With mixture in stirring at room 1h.Vacuum evaporating solvent.In this residuum, add saturated NaHCO 3Solution, and use ethyl acetate extraction.Organic layer is merged, and water and brine wash are used MgSO 4Dry.Remove desolvate and with residuum by chromatogram (EtOAc:CH 2Cl 2=1:4) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield: 0.075g, 46%).
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131.Measured value: 465.1132.
Embodiment 24e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00722
M.W.465.38?C 26H 22Cl 2N 2O 2
Through chirality SFC, carry out from the racemize (2 ' R, the 3R that among embodiment 24d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (24mg) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (23mg).
Embodiment 25a
Preparation midbody 1-(3-fluoro-2-methyl-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00731
M.W.251.38?C 13H 18FNOSi
With with the similar mode of method described in the embodiment 1b, with 3-fluoro-2-methyl-phenyl aldehyde (1.4g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 3,3, and the 3-hexamethyldisilazane (1.62g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(3-fluoro-2-methyl-phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 25b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00732
M.W.541.41?C 28H 23Cl 2FN 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.39g; 1.08mmol) (2.6g 10.3mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-fluoro-phenyl-2-the methyl)-3-front three that in embodiment 31a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl)-2; 3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (yield 0.35g, 60%).
Embodiment 25c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00741
M.W.469.35?C 25H 19Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 4d, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl)-2; 3-dihydro-2, (0.35g is 0.65mmol) with NaOH (2N for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester; 5mL 10mmol) reacts in methyl alcohol, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.25g, 83%).
HRMS (ES +) m/z calculated value C 25H 19Cl 2FN 2O 2+ H [(M+H) +]: 469.0881.Measured value: 469.0885.
Embodiment 25d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00742
M.W.469.35?C 25H 19Cl 2FN 2O 2
Through chirality SFC, carry out from the racemize (2 ' R, the 3R that among embodiment 25c, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (71mg) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (74mg).
Embodiment 26a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
M.W.579.53?C 32H 32Cl 2N 2O 4
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 24b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(2-aminomethyl phenyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (0.3g; 0.54mmol) and LiH (86mg, 10.9mmol) (2mL is 25mmol) at N for (Aldrich) and iodic ether; React in N-dimethyl--methane amide, obtain racemize (2 ' R, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester, be white foam (yield: 0.2g, 63%).
Embodiment 26b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00752
M.W.479.41?C 27H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 24d, racemize (2 ' R, the 3R that will in embodiment 26a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(0.2g 0.34mmol) reacts in methylene dichloride with trifluoroacetic acid the 1-carboxylic acid tert-butyl ester, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pearl foam (yield: 0.11g, 69%).
HRMS (ES +) m/z calculated value C 27H 24Cl 2N 2O 2+ H [(M+H) +]: 479.1288.Measured value: 479.1284.
Embodiment 26c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00761
M.W.479.41?C 27H 24Cl 2N 2O 2
Through chirality SFC, carry out from the racemize (2 ' R, the 3R that among 26b, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (29mg) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (27mg).
Embodiment 27a
Preparation midbody 1-(2, the 6-3,5-dimethylphenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.247.42?C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2,6-dimethyl--phenyl aldehyde (1.3g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol); Triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; The 6-3,5-dimethylphenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be orange, and under situation about not being further purified, be used for next step.
Embodiment 27b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D00771
M.W.537.45?C 29H 26Cl 2N 2O 4
With with the similar mode of method described in the embodiment 4c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g; 1.08mmol) with 1-(2, the 6-3,5-dimethylphenyl)-3-front three of in embodiment 27a, preparing for siloxy--2-azepine-1,3-butadiene (2.9g; 11.7mmol) in toluene, react, obtain racemize (2 ' R, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (yield 0.41g, 71%).
Embodiment 27c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00772
M.W.465.38?C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 4d, with (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; The 6-3,5-dimethylphenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (0.41g; 0.76mmol) (0.4g 10mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.25g, 71%).
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131.Measured value: 465.1131.
Embodiment 28a
Preparation midbody 1-(2, the 3-3,5-dimethylphenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.247.42C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2,3-dimethyl--phenyl aldehyde (1.34g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol); Triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; The 3-3,5-dimethylphenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 28b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00782
M.W.465.38?C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2, (0.3g is 0.83mmol) with the 1-(2 that in embodiment 28a, prepares for 3-dihydro-indoles-1-carboxylic acid, ethyl ester; The 3-3,5-dimethylphenyl)-(2.4g 9.72mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; (0.2g 5mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.20g, 53%).
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131.Measured value: 465.1131.
Embodiment 29a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-[(methoxycarbonyl)-methyl]-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
M.W.623.54?C 33H 32Cl 2N 2O 6
With with the similar mode of method described in the embodiment 24c, racemize (2 ' R, the 3R that will in embodiment 24b, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(1.02g is 1.86mmol) with LiH (86mg, 10.9mmol) (Aldrich) and methyl bromoacetate (0.57g for the 1-carboxylic acid tert-butyl ester; 3.72mmol) (Aldrich) reaction, obtain racemize 2 ' R, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-[(methoxycarbonyl)-methyl]-2 '-(2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester, be white solid (yield: 0.37g, 32%).
Embodiment 29b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(methoxycarbonyl) methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00801
M.W.523.42 C 28H 24Cl 2N 2O 4
With with the similar mode of method described in the embodiment 24d, the racemize 2 ' R that will in embodiment 29a, prepare, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-1 '-[(methoxycarbonyl)-methyl]-2 '-(2 monomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-carboxylic acid tert-butyl ester (0.37g, O.59 mmol) and trifluoroacetic acid (20 mL) react in methylene dichloride, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(methoxycarbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 0.21g, 67%).
HRMS (ES +) m/z calculated value C 28H 24Cl 2N 2O 4+ H [(M+H) +]: 523.1186.Measured value: 523.1183.
Embodiment 30
The preparation racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D00802
M.W.419.38 C 21H 20Cl 2N 2OS
The racemize that will in embodiment 3b, prepare (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 ', 4 '-sec.-propyl spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (60 mg, 0.15 mmol) and 2; 4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-diphosphine fourth ring (diphosphetane) 2; 4-disulfide (100mg, 0.25 mmol) (Aldrich) mixture in toluene (20 mL) heats 0.5h in 120 ℃.Mixture is cooled to room temperature, concentrates then.(EtOAc: the purifying of hexane=1:1), (2 ' S 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, is white solid (yield 60mg, 92%) to obtain racemize by chromatogram with residuum.
HRMS (ES +) m/z calculated value C 21H 20Cl 2N 2OS+H [(M+H) +]: 419.0746.Measured value: 419.0744.
Embodiment 31
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(hydroxycarbonyl group)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.509.39?C 27H 22Cl 2N 2O 4
To the racemize that in 29b, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(methoxycarbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; (0.21g 0.4mmol) in the solution in the mixture of methyl alcohol (10mL) and THF (20mL), adds the NaOH aqueous solution (1N to 6 ' (1H)-diketone; 10mL, 10mmol).Reaction mixture in stirred overnight at room temperature, is concentrated then.Residuum is neutralized to " pH "～7, uses ethyl acetate extraction then.Organic layer is separated, use H 2O, brine wash is used MgSO 4Drying, and concentrate, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(hydroxycarbonyl group)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white foam.
HRMS (ES +) m/z calculated value C 27H 22Cl 2N 2O 4+ H [(M+H) +]: 509.1030.Measured value: 509.1028.
Embodiment 32a
Preparation midbody 1-[2-(trifluoromethyl)-phenyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.287.36C 13H 16F 3NOSi
With with the similar mode of method described in the embodiment 1b, with 2-(trifluoromethyl)-phenyl aldehyde (1.75g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-[2-(trifluoromethyl)-phenyl]-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 32b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00821
M.W.505.33?C 25H 17Cl 2F 3N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.5g; 1.38mmol) (3.2g 11.1mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-[2-(trifluoromethyl)-the phenyl]-3-front three that in embodiment 32a, prepares; (0.2g 5mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH then; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield 0.45g, 64%).
HRMS (ES +) m/z calculated value C 25H 17Cl 2F 3N 2O 2+ H [(M+H) +]: 505.0692.Measured value: 505.0688.
Embodiment 33
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D00831
M.W.521.39?C 25H 17Cl 2F 3N 2OS
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 32b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines] and-2,6 ' (1H)-diketone (0.4g, 0.79mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1; 3-dithia-2,4-diphosphine fourth ring 2,4-disulfide (0.4g; 0.99mmol) in toluene, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.15g, 36%).
HRMS (ES +) m/z calculated value C 25H 17Cl 2F 3N 2OS+H [(M+H) +]: 521.0464.Measured value: 521.0458.
Embodiment 34a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00832
M.W.511.38?C 27H 21Cl 2FN 2O 3
In 0 ℃, to (2 ' R, the 3R of preparation in embodiment 31; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(hydroxycarbonyl group)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.12g; 0.24mmol) in the solution in methylene dichloride (40mL); Add cyanuric fluoride (48mg, 0.35mmol) (Alfa) and pyridine (37mg, 0.48mmol).With mixture in 0 ℃ stir 2h after, with mixture at H 2Distribute between O and the methylene dichloride.Organic layer is separated, and water layer is used dichloromethane extraction.Organic layer is merged, use MgSO 4Drying concentrates, and obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone; Be yellow glue, and under situation about not being further purified, be used for next step (yield: 0.12g, 98%).
Embodiment 34b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00841
M.W.578.50?C 31H 29Cl 2N 3O 4
To the racemize that in 34a, prepares in ST (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines] (0.12g is 0.23mmol) in the solution in THF (10mL) for-2,6 ' (1H)-diketone; The adding morpholine (41mg, 0.47mmol), N-methylmorpholine (47mg; 0.47mmol) and 4-dimethylaminopyridine (3mg, 0.025mmol).With mixture under the microwave exposure in 100 ℃ the heating 10min after, mixture is diluted with ETHYLE ACETATE, with the 1N HCl aqueous solution and H 2The O washing.Organic layer is separated, use Na 2SO 4Drying, and concentrate.With residuum by chromatogram (MeOH:EtOAc=1:19) purifying; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 0.11g, 85%).
HRMS (ES +) m/z calculated value C 31H 29Cl 2N 3O 4+ H [(M+H) +]: 578.1608.Measured value: 578.1600.
Embodiment 34c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00842
M.W.578.50?C 31H 29Cl 2N 3O 4
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-2-oxoethyl] spiral shell [the 3H-indoles-3 that among embodiment 34b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (51mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-2-oxoethyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 15mg, 29%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 14mg, 27%).
Embodiment 35a
Preparation midbody 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00851
M.W.305.35?C 13H 15F 4NOSi
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-(trifluoromethyl)-phenyl aldehyde (1.9g, 10mmol) (Matrix) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 35b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00861
M.W.523.32?C 25H 16Cl 2F 4N 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.41g; 1.13mmol) (2.9g 9.5mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-[5-fluoro-2-(trifluoromethyl)-the phenyl]-3-front three that in embodiment 35a, prepares; (0.2g 5mmol) reacts in methyl alcohol, obtains racemize (2 ' R with NaOH then; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield 0.31g, 52%).
HRMS (ES +) m/z calculated value C 25H 16Cl 2F 4N 2O 2+ H [(M+H) +]: 523.0598.Measured value: 523.0593.
Embodiment 36a
Preparation midbody 1-(5-fluoro-2-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00862
M.W.251.38?C 13H 18FNOSi
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-methyl-phenyl aldehyde (1.38g, 10mmol) (Platte) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(5-fluoro-2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 36b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00871
M.W.469.35?C 25H 19Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 14b, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.25g; 0.69mmol) with in embodiment 36a, prepare 1-(5-fluoro-2-aminomethyl phenyl)-(2.5g 9.9mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; (1N, 5mL 5mmol) react in methyl alcohol with NaOH then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.13g, 41%).
HRMS (ES +) m/z calculated value C 25H 19Cl 2FN 2O 2+ H [(M+H) +]: 469.0881.Measured value: 469.0881.
Embodiment 36c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.469.35?C 25H 19Cl 2FN 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [the 3H-indoles-3 that among embodiment 36b, prepares; 3 '-piperidines] separation of two kinds of enantiomers (35mg) in-2,6 ' (1H)-diketone, so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 10.7mg, 30%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 11mg, 31%). 1HNMR(300MHz，DMSO-d6)：δ＝2.33(s，3H)，2.72(dd，J＝6.6，18.2Hz，1H)，3.03(dd，J＝12.3，18.2Hz，1H)，4.02(dd，J＝6.6，12.3Hz，1H)，5.44(d，J＝1.5Hz，1H)，6.36(dd，J＝3，11.4Hz，1H)，6.47(d，J＝2Hz，1H)，6.81-6.89(m，2H)，7.11(dd，J＝8.1，15Hz，1H)，7.15(brt，J＝7Hz，1H)，7.20(dd，J＝2，8.1Hz，1H)，7.62(d，J＝8.1Hz，1H)，8.09(s，1H)，10.23(s，1H)ppm。
Embodiment 37
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(cyclopropyl is amino)-carbonyl-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00881
M.W.548.47?C 30H 27Cl 2N 3O 3
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 34a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.12g; 0.23mmol) and cyclopropylamine (0.1g, 1.8mmol) (Aldrich), N-methylmorpholine (48mg; 0.47mmol) and 4-dimethylaminopyridine (2mg 0.017mmol) reacts in THF, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(cyclopropyl is amino)-carbonyl-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.039g, 30%).
HRMS (ES +) m/z calculated value C 30H 27Cl 2N 3O 3[(M+H) +]: 548.1502.Measured value: 548.1501.
Embodiment 38
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-[[2-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6-dioxo spiral shell [3H-indoles-3,3 '-piperidines]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester
Figure G2007800087501D00891
Ro5099251-000
M.W.691.66?C 37H 40Cl 2N 4O 5
With with the similar mode of method described in the embodiment 34b, the racemize that will in embodiment 34a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines] (0.12g is O.23mmol) with 4-amino-piperadine-1-carboxylic acid tert-butyl ester (0.1g for-2,6 ' (1H)-diketone; 0.5mmol) (Aldrich), N-methylmorpholine (48mg, 0.47mmol) and 4-dimethylaminopyridine (2mg; 0.017mmol) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-[[2-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6-dioxo spiral shell [3H-indoles-3; 3 '-piperidines]-the 1-yl]-the 1-oxoethyl]-amino]-the piperidine carboxylic acid tert-butyl ester, be pale solid (yield 0.036g, 22%).
HRMS (ES +) m/z calculated value C 37H 40Cl 2N 4O 5[(M+H) +]: 691.2449.Measured value: 691.2441.
Embodiment 39
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D00892
M.W.485.41?C 25H 19Cl 2FN 2OS
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 36b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines] and-2,6 ' (1H)-diketone (0.1g, 0.21mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1; 3-dithia-2,4-diphosphine fourth ring 2, (0.2g 0.49mmol) reacts in toluene the 4-disulfide; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.095g, 92%).
HRMS (ES +) m/z calculated value C 25H 19Cl 2FN 2OS+H [(M+H) +]: 485.0652.Measured value: 485.0648.
Embodiment 40
Preparation racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-[2-(trifluoromethyl) phenyl)]-2-oxo spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit]-hydrazine carboxylic acid's ethyl ester
Figure G2007800087501D00901
M.W.591.42?C 28H 23Cl 2E 3N 4O 3
Racemize (2 ' R to preparation in embodiment 33; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.035g; 0.067mmol) in the solution in THF (30mL); Add the carbazic acid ethyl ester (0.019g, 0.134mmol) (Aldrich) and mercuric acetate (0.042g, 0.134mmol).With reaction mixture behind stirring at room 2h, reaction mixture is filtered through short Celite pad.To filtrate concentrate and with residuum by chromatogram (EtOAc) purifying; Obtain racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-[2-(trifluoromethyl)-phenyl)]-2-oxo spiral shell [3H-indoles-3; 3 '-piperidines]-the 6-subunit]-hydrazine carboxylic acid's ethyl ester, be white solid (yield: 0.036g, 91%).
HRMS (ES +) m/z calculated value C 28H 23Cl 2F 3N 4O 3+ H [(M+H) +]: 591.1172.Measured value: 591.1168
Embodiment 41a
Preparation midbody 1-(2,4 difluorobenzene base)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00911
M.W.255.34?C 12H 15F 2NOSi
With with the similar mode of method described in the embodiment 1b, with 2,4-two fluoro-phenyl aldehydes (1.4g, 10mmol) (Aldrich) replaces the 3-chlorobenzaldehyde as raw material, with 1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol); Triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; The 4-difluorophenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 41b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.473.31?C 24H 16Cl 2F 2N 2O 2
To the 1-that in embodiment 41a, prepares (2; The 4-difluorophenyl)-the 3-front three is for siloxy--2-azepine-1; (2.4g 9.40mmol) in the solution in toluene (30mL), is added in E/Z-6-chloro-3-(3-chlorine the tolylene)-2-oxo-2 for preparing among the embodiment 24a to the 3-divinyl; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol).Reaction mixture under nitrogen, is stirred 0.5h in 140 ℃ in ST.After solution is cooled to room temperature, add methyl alcohol (10mL).The short pad of reaction mixture through zeyssatite glue filtered, and wash with ETHYLE ACETATE.To filtrate and concentrate.Residuum is dissolved in the methylene dichloride (20mL), and adds trifluoroacetic acid (15mL).With reaction mixture behind stirring at room 1h, mixture is concentrated.With residuum at saturated NaHCO 3Distribute between solution and the ETHYLE ACETATE.Water layer is used ethyl acetate extraction.The organic layer that merges is used Na 2SO 4Drying, and concentrate.(EtOAc: the purifying of hexane=2:1) obtains racemize (2 ' R, 3R by chromatogram with residuum; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.23g, 63.9%).
HRMS (ES +) m/z calculated value C 24H 16Cl 2F 2N 2O 2+ H [(M+H) +]: 473.0630.Measured value: 473.0630.
Embodiment 42a
Preparation midbody 1-(5-fluoro-2-p-methoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00921
M.W.267.38?C 13H 18FNO 2Si
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-methoxyl group-phenyl aldehyde (1.5g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(5-fluoro-2-p-methoxy-phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 42b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.485.36?C 25H 19Cl 2FN 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) with in embodiment 42a, prepare 1-(5-fluoro-2-p-methoxy-phenyl)-(2.4g 9.0mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; React in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.18g, 49%).
HRMS (ES +) m/z calculated value C 25H 19Cl 2FN 2O 3+ H [(M+H) +]: 485.0830.Measured value: 485.0827.
Embodiment 43a
Preparation midbody 1-(1-naphthyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00931
M.W.269.42?C 16H 19NOSi
With with the similar mode of method described in the embodiment 1b, with naphthalene-1-formaldehyde (1.6g, 10mmol) (Lancaster) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(1-naphthyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 43b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00932
M.W.487.39?C 28H 10Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) (2.7g 10.0mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-the naphthyl)-3-front three that in embodiment 43a, prepares; React in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.21g, 57%).
HRMS (ES +) m/z calculated value C 28H 10Cl 2N 2O 2+ H [(M+H) +]: 487.0975.Measured value: 487.0975.
Embodiment 44a
Preparation midbody 1-(3-pyridyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00941
M.W.220.35?C 11H 16N 2OSi
With with the similar mode of method described in the embodiment 1b, with pyridine-3-formaldehyde (1.1g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(3-pyridyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 44b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00942
M.W.438.32?C 23H 17Cl 2N 3O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) (2.1g 9.5mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-the pyridyl)-3-front three that in embodiment 44a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (0.21g, 62%).
HRMS (ES +) m/z calculated value C 23H 17Cl 2N 3O 2+ H [(M+H) +]: 438.0771.Measured value: 438.0771.
Embodiment 45a
Preparation midbody 1-(2,3-two fluoro-6-p-methoxy-phenyls)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00951
M.W.285.37?C 13H 17F 2NO 2Si
With with the similar mode of method described in the embodiment 1b, with 2,3-two fluoro-6-methoxyl group-phenyl aldehydes (1.8g, 10mmol) (Apollo) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; 3-two fluoro-6-p-methoxy-phenyls)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be orange glue, and under situation about not being further purified, be used for next step.
Embodiment 45b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-p-methoxy-phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00961
M.W.503.34?C 25H 18Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) with 1-(2,3-two fluoro-6-p-methoxy-phenyls)-3-front three of in embodiment 45a, preparing for siloxy--2-azepine-1,3-butadiene (2.5g; 8.8mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-p-methoxy-phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (0.22g, 56%).
HRMS (ES +) m/z calculated value C 25H 18Cl 2F 2N 2O 3+ H [(M+H) +]: 503.0736.Measured value: 503.0735.
Embodiment 46a
Preparation midbody 1-(3, the 4-difluorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00962
M.W.255.34?C 12H 15F 2NOSi
With with the similar mode of method described in the embodiment 1b, with 3,4-two fluoro-phenyl aldehydes (1.4g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(3; The 4-difluorophenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be orange glue, and under situation about not being further purified, be used for next step.
Embodiment 46b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00971
M.W.473.31?C 24H 16Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) with 1-(3, the 4-difluorophenyl)-3-front three of in embodiment 46a, preparing for siloxy--2-azepine-1,3-butadiene (2.1g; 8.2mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (0.4g, 100%).
HRMS (ES +) m/z calculated value C 24H 16Cl 2F 2N 2O 2+ H [(M+H) +]: 473.0630.Measured value: 473.0631.
Embodiment 47a
Preparation midbody 1-(1-cyclohexenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D00972
M.W.223.39?C 12H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 1-tetrahydrobenzene-1-formaldehyde (1.1g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(1-cyclohexenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be greyish white coloring agent, and under situation about not being further purified, be used for next step.
Embodiment 47b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclohexenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D00981
M.W.441.36?C 24H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.26g; 0.67mmol) (2.1g 9.42mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-the cyclohexenyl)-3-front three that in embodiment 47a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclohexenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (0.14g, 48%).
HRMS (ES +) m/z calculated value C 24H 22Cl 2N 2O 2+ H [(M+H) +]: 441.1131.Measured value: 441.1131.
Embodiment 48
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D00982
M.W.489.37?C 24H 16Cl 2F 2N 2OS
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 46b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3; The 4-difluorophenyl) (0.3g is 0.63mmol) with 2 for spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; 4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-diphosphine fourth ring 2,4-disulfide (0.32g; 0.77mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3; The 4-difluorophenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.29g, 94%).
HRMS (ES +) m/z calculated value C 24H 16Cl 2F 2N 2OS+H [(M+H) +]: 489.0401.Measured value: 489.0402.
Embodiment 49
Preparation racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
Figure G2007800087501D00991
M.W.559.40?C 27H 22Cl 2F 2N 4O 3
With with the similar mode of method described in the embodiment 40, the racemize that will in embodiment 48, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3; The 4-difluorophenyl) (0.24g is 0.49mmol) with carbazic acid ethyl ester (0.1g for-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone; 0.99mmol), mercuric acetate (0.24g, 0.76mmol) and triethylamine (0.1g; 0.99mmol) reaction in THF (20mL), obtain racemize (2 ' R, 3R; 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3; 3 '-piperidines]-the 6-subunit] hydrazine carboxylic acid's ethyl ester, be white solid (yield 0.21g, 77.8%).
HRMS (ES +) m/z calculated value C 27H 22Cl 2F 2N 4O 3+ H [(M+H) +]: 559.1110.Measured value: 559.1109.
Embodiment 50a
Preparation midbody 1-(1,3-benzo dioxole-4-yl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01001
M.W.263.37?C 13H 17NO 3Si
With with the similar mode of method described in the embodiment 1b, with 2,3-(methylene-dioxy)-phenyl aldehyde (1.5g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol); Triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(1; 3-benzo dioxole-4-yl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow oil, and under situation about not being further purified, be used for next step.
Embodiment 50b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-(1,3-benzo dioxole-4-yl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01002
M.W.481.34?C 25H 18Cl 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.25g; 0.67mmol) with 1-(1,3-benzo dioxole-4-yl)-3-front three of in embodiment 50a, preparing for siloxy--2-azepine-1,3-butadiene (2.1g; 7.98mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-2 '-(1,3-benzo dioxole-4-yl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (0.20g, 62%).
HRMS (ES +) m/z calculated value C 25H 18Cl 2N 2O 4+ H [(M+H) +]: 481.0717.Measured value: 481.0717.
Embodiment 51
Preparation racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
Figure G2007800087501D01011
M.W.555.44?C 28H 25Cl 2FN 4O 3
With with the similar mode of method described in the embodiment 40, (2 ' R, the 3R that will in embodiment 39, prepare; 4 ' S)-(0.17g is 0.35mmol) with carbazic acid ethyl ester (0.15g for 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone; 1.49mmol), mercuric acetate (0.26g, 0.82mmol) and triethylamine (0.17g; 1.69mmol) reaction in THF (20mL), obtain racemize (2 ' R, 3R; 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester; Be white solid (yield 0.14g, 73.7%).
Embodiment 52a
Preparation midbody 2,3-two fluoro-6-methyl-phenyl aldehydes
Figure G2007800087501D01012
M.W.156.13?C 8H 6F 2O
In-78 ℃, to 1, (5.0g, 39mmol) in the solution in THF (200mL), (24mL, 1.8M is in THF, 43mmol) to drip lithium diisopropylamine in the time of 15min for 2-two fluoro-4-methyl-benzene.Mixture is stirred other 20min in-78 ℃.Add N with portion then, and N-dimethyl--methane amide (3.6mL, 47mmol).In-78 ℃ of stirring 10min, (9.4g, 1.56mmol) quencher then add entry (37.6mL) to use acetate then with mixture.Mixture is distributed between ETHYLE ACETATE and water.Organic layer is separated, concentrate.With residuum by chromatogram (EtOAc: the purifying of hexane=1:1), obtain 2,3-two fluoro-6-methyl-phenyl aldehydes are colorless oil (yield: 3.5g, 57.5%).
Embodiment 52b
Preparation midbody 1-(2,3-two fluoro-6-aminomethyl phenyls)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01021
M.W.269.37?C 13H 17F 2NOSi
With with the similar mode of method described in the embodiment 1b, will in embodiment 52a, prepare 2, (1.56g 10mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-two fluoro-6-methyl-phenyl aldehydes, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; 3-two fluoro-6-aminomethyl phenyls)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be orange glue, and under situation about not being further purified, be used for next step.
Embodiment 52c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.487.34?C 25H 18Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.03mmol) with 1-(2,3-two fluoro-6-aminomethyl phenyls)-3-front three of in embodiment 52b, preparing for siloxy--2-azepine-1,3-butadiene (2.7g; 10.0mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (yield: 0.41g, 83.7%).
HRMS (ES +) m/z calculated value C 25H 18Cl 2F 2N 2O 2+ H [(M+H) +]: 487.0786 measured values: 487.0780.
Embodiment 53a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-5-fluoro-1, the 3-dihydro-indol-2-one
M.W.308.14?C 15H 8Cl 2FNO
With with the similar mode of method described in the embodiment 1a, with 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (0.25g; 1.35mmol, according to the method described in EP153818 preparation) with 3-chloro-phenyl aldehyde (0.34g, 2.44mmol) and tetramethyleneimine (pyrolidine) (0.19g; 2.68mmol) in methyl alcohol, react; Obtain E-and Z-6-chloro-3-(3-chloro-tolylene)-5-fluoro-1, the mixture of 3-dihydro-indol-2-one is yellow solid.
Embodiment 53b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-5-fluoro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
M.W.408.26?C 20H 16Cl 2FNO 3
With with the similar mode of method described in the embodiment 24a, with E/Z-6-chloro-3-(3-chloro-tolylene)-5-fluoro-1,3-dihydro-indol-2-one (0.45g; 1.46mmol) and tert-Butyl dicarbonate (0.4g; 1.83mmol) (Aldrich), triethylamine (0.5g, 4.95mmol) and 4-dimethylaminopyridine (5mg) in methylene dichloride (30mL), react; Obtain E/Z-6-chloro-3-(3-chloro-tolylene)-5-fluoro-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester is yellow solid (yield: 0.6g, 100%).
Embodiment 53c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.487.34?C 25H 18Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 53b, prepare (3-chloro-tolylene)-5-fluoro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 0.98mmol) with 1-(5-fluoro-2-aminomethyl phenyl)-3-front three of in embodiment 36a, preparing for siloxy--2-azepine-1; (2.1g 8.37mmol) reacts in toluene the 3-divinyl, reacts in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (yield: 0.35g, 72.9%).
HRMS (ES +) m/z calculated value C 25H 18Cl 2F 2N 2O 2+ H [(M+H) +]: 487.0786.Measured value: 487.0779.
Embodiment 54
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D01051
M.W.503.40?C 25H 18Cl 2F 2N 2OS
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 52c, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-aminomethyl phenyls) (0.18g is 0.37mmol) with 2 for spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; 4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-diphosphine fourth ring 2,4-disulfide (0.32g; 0.96mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-aminomethyl phenyls)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.13g, 69.8%).HRMS (ES +) m/z calculated value C 25H 18Cl 2F 2N 2OS+H [(M+H) +]: 503.0558.Measured value: 503.0554.
Embodiment 55a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D01052
M.W.420.41?C 21H 23Cl 2NO 2Si
In 0 ℃, to the E/Z-6-chloro-3-that in embodiment 4a, prepares (3-chloro-tolylene)-1,3-dihydro-indol-2-one (2.3g; 7.9mmol) at N, in the solution in N-dimethyl--methane amide (20mL), add NaH (60%; In MO) (0.32g; 7.9mmol) (Aldrich), then drip 2-(trimethylsilyl) ethoxyl methyl chlorine in THF (20mL) (1.32g, 7.9mmol).Reaction mixture in 0 ℃ of stirring 0.5h, is poured in ice-water then.With rough thing with twice of ethyl acetate extraction.The organic layer that merges is used Na 2SO 4Dry.Remove desolvate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:5), obtain E/Z-6-chloro-3-(3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one is yellow oil (yield 3.0g, 90%).
Embodiment 55b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01061
M.W.599.61?C 31H 33Cl 2FN 2O 3Si
To the 1-that in embodiment 36a, prepares (5-fluoro-2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1; In the solution of 3-divinyl in toluene (50mL); Be added in E/Z-6-chloro-3-(3-chloro-the tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1 for preparing among the embodiment 55a; The 3-dihydro-indol-2-one (3.0g, 7.14mmol).Reaction mixture under nitrogen, is stirred 40min in 148 ℃ in ST.After solution is cooled to room temperature, add methyl alcohol (50mL), then mixture is concentrated.(EtOAc: the purifying of hexane=2:1) obtains racemize (2 ' R, 3R by chromatogram with residuum; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be pale solid (yield 2.1g, 49%).
Embodiment 55c
Preparation midbody racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01071
M.W.713.76?C 37H 43Cl 2FN 2O 5Si
In room temperature, to the racemize that in embodiment 55b, prepares (2 ' R, 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(1.0g is 1.67mmol) at N, in the solution in N-dimethyl--methane amide (20mL) for 1-methoxy ethyl trimethyl silane; Add the bromo-tert.-butyl acetate (0.8g, 4.1mmol) and cesium carbonate (3.0g, 9.20mmol).Reaction mixture is stirred 4h under nitrogen, pour into saturated NH then 4In the Cl aqueous solution.Mixture is used ethyl acetate extraction.Organic layer is merged, use Na 2SO 4Drying, and concentrate.(EtOAc: the purifying of hexane=1:4) obtains racemize (2 ' R, 3R by chromatogram with residuum; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be white foam (yield 0.58g, 48.7%).
Embodiment 55d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01072
M.W.527.38?C 27H 21Cl 2FN 2O 4
To the racemize that in embodiment 55c, prepares (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(0.54g 0.76mmol) in the solution in methylene dichloride (10mL), adds trifluoroacetic acid (20mL) to 1-methoxy ethyl trimethyl silane.With reaction mixture in stirring at room 18h.Reaction mixture is concentrated.Residuum is dissolved in the methyl alcohol (10mL).In the solution that obtains, add N, N '-diisopropylethylamine (1mL, 5.53mmol), and with rough thing backflow 1h.Reaction mixture is concentrated and residuum is distributed between the ETHYLE ACETATE and the HCl aqueous solution (1N).Organic layer is separated, use MgSO 4Drying, and concentrate.Residuum is ground with ETHYLE ACETATE and hexane; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.3g, 75%).
HRMS (ES +) m/z calculated value C 27H 21Cl 2FN 2O 4+ H [(M+H) +]: 527.0935 measured values: 527.0926.
Embodiment 56a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-methyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01081
M.W.613.64?C 32H 35Cl 2FN 2O 3Si
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 55b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.3g; 0.5mmol) and LiH (0.17g, 21.4mmol) (4g is 28.2mmol) at N for (Aldrich) and methyl iodide; Reaction obtains racemize (2 ' R, 3R in N-dimethyl--methane amide (40mL); 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-methyl-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white solid (yield: 0.16g, 51.6%).
Embodiment 56b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-methyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-ethanol
Figure G2007800087501D01091
M.W.513.40?C 27H 23Cl 2FN 2O 3
To the racemize that in embodiment 56a, prepares (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-methyl-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(0.16g 0.26mmol) in the solution in methylene dichloride (10mL), adds trifluoroacetic acid (20mL) to 1-methoxy ethyl trimethyl silane.With reaction mixture in stirring at room 3h.Reaction mixture is concentrated.Residuum is used saturated NaHCO 3Ethyl acetate extraction is used in aqueous solution neutralization then.Organic layer is separated, use MgSO 4Drying, and concentrate.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-methyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-ethanol (yield 90mg, 67.7%).
Embodiment 56c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01092
M.W.483.37?C 26H 21Cl 2FN 2O 2
To the racemize that in embodiment 56b, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-1 '-methyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-ethanol (0.09g; 0.175mmol) in the solution in methyl alcohol (10mL), add N, N '-diisopropylethylamine (2mL; 11.1mmol), and with rough thing backflow 1h.Reaction mixture is concentrated and residuum is distributed between ETHYLE ACETATE and water.Organic layer is separated, and concentrate.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:2) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 0.06g, 70.6%).
HRMS (ES +) m/z calculated value C 26H 21Cl 2FN 2O 2+ H [(M+H) +]: 483.1037.Measured value: 483.1042.
Embodiment 56d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01101
M.W.483.37?C 26H 21Cl 2FN 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [the 3H-indoles-3 that among embodiment 56c, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (50mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 20mg, 40%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 20mg, 40%).
Embodiment 57a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01111
M.W.529.37?C 27H 20Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 34a, racemize (2 ' R, the 3R that will in embodiment 55d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(hydroxycarbonyl group-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g; 0.19mmol) and cyanuric fluoride (51mg, 0.38mmol) (45mg 0.57mmol) reacts in methylene dichloride for (Alfa) and pyridine; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 0.1g, 100%).
Embodiment 57b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01112
M.W.623.56?C 33H 33Cl 2FN 4O 3
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 57a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g; 0.18mmol) and 1-methyl-piperidines-4-amine (0.1g, 0.88mmol), N-methylmorpholine (0.1g; 0.99mmol) and 4-dimethylaminopyridine (1mg 0.008mmol) reacts in THF, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.041 g, 36.7%).
HRMS (ES +) m/z calculated value C 33H 33Cl 2FN 4O 3+ H [(M+H) +]: 623.1987.Measured value: 623.1989.
Embodiment 57c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01121
M.W.623.56?C 33H 33Cl 2FN 4O 3
Through chirality SFC, carry out from (2 ' R, the 3R that among embodiment 57b, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (30mg) in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 10mg; 17%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 10mg, 17%).
Embodiment 58
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01131
M.W.709.65?C 37H 39Cl 2FN 4O 5
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 57a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g; 0.18mmol) and 4-amino-piperadine-1-carboxylic acid tert-butyl ester (0.1g, 0.50mmol), N-methylmorpholine (0.1g; 0.99mmol) and 4-dimethylaminopyridine (2mg 0.017mmol) reacts in THF, obtains racemize (2 ' R; 3R, 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.075g, 58.6%).
HRMS (ES +) m/z calculated value C 37H 39Cl 2FN 4O 5+ H [(M+H) +]: 709.2355.Measured value: 709.2354.
Embodiment 59a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.609.53?C 32H 31Cl 2FN 4O 3
Racemize (2 ' R to preparation in 58; 3R; 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.07g; 0.099mmol) in the solution in methylene dichloride (20mL), add trifluoroacetic acid (5mL).Reaction mixture in stirring at room 1h, is concentrated then.With residuum and saturated NaHCO 3Ethyl acetate extraction is used in the solution neutralization.Organic layer is separated, use MgSO 4Drying concentrates, and obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.06g, 99%).
HRMS (ES +) m/z calculated value C 32H 31Cl 2FN 4O 3+ H [(M+H) +]: 609.1830 measured values: 609.1820.
Embodiment 59b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01141
M.W.609.53?C 32H 31Cl 2FN 4O 3
Through chirality SFC, carry out from the racemize (2 ' R, the 3R that among embodiment 59a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (40mg) in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 12mg; 30%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 12mg, 30%).
Embodiment 60a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(3-chloro-propyl group)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01151
M.W.676.14?C 34H 38Cl 3FN 2O 5Si
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 55b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.8g; 1.33mmol) and LiH (0.5g, 62.5mmol) (3.9g is 19.1mmol) at N with 1-chloro-3-iodo-propane; Reaction obtains racemize (2 ' R, 3R in N-dimethyl--methane amide (20mL); 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-1 '-(3-chloro-propyl group)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white foam (yield: 0.43g, 47.8%).
Embodiment 60b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01152
M.W.596.53?C 32H 32Cl 2FN 3O 3
Racemize (2 ' the R that will in embodiment 60a, prepare; 3R; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-1 '-(3-chloro-propyl group)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.24g, 0.36mmol) and the mixture of morpholine (10mL) in 120 ℃ the heating 1h.Mixture is concentrated into drying.The residuum that obtains is added methylene dichloride (20mL), add trifluoroacetic acid (20mL) then.With reaction mixture in stirring at room 4h.With reaction mixture concentrate and with residuum at ETHYLE ACETATE and saturated NaHCO 3Distribute between the solution.Organic layer is separated, and concentrate.Residuum is dissolved in the methyl alcohol (10mL) again.In the solution that obtains, add N, N '-diisopropylethylamine (2mL, 11.0mmol), and with rough thing in 100 ℃ of heating 1h.With reaction mixture concentrate and with residuum by chromatogram (MeOH:EtOAc=1:9) purifying; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.08g, 37.9%).
HRMS (ES +) m/z calculated value C 32H 32Cl 2FN 3O 3+ H [(M+H) +]: 596.1878 measured values: 596.1877.
Embodiment 60c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01161
M.W.596.53?C 32H 32Cl 2FN 3O 3
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [the 3H-indoles-3 that among embodiment 60b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (100mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 34mg, 34%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 35mg, 35%).
Embodiment 61a
Preparation midbody 1-(1-sec.-propyl-4-methyl-1-pentene base)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D0117102810QIETU
M.W.267.49?C 15H 29NOSi
With with the similar mode of method described in the embodiment 1b, with 2-sec.-propyl-5-methyl-2-hexenoic aldehyde (1.54g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 13mmol) reaction obtains 1-(1-sec.-propyl-4-methyl-1-pentene base)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 61b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-4-methyl-penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.485.46?C 27H 30Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.77mmol) (2.1g 8.2mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-sec.-propyl-4-methyl-1-pentene the base)-3-front three that in embodiment 61a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2;-(1-sec.-propyl-4-methyl-penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (0.18g, 48.7%).
HRMS (ES +) m/z calculated value C 27H 30Cl 2N 2O 2+ H [(M+H) +]: 485.1757.Measured value: 485.1755.
Embodiment 62a
Preparation midbody 1,2-two fluoro-4-isopropoxy-benzene
Figure G2007800087501D01181
M.W.172.18?C 9H 10F 2O
To 3, (5g, 38.4mmol) in the solution in acetone (50mL), (54g is 38.4mmo) with 2-iodo-propane to add salt of wormwood for 4-two fluoro-phenol.With reaction mixture reflux 24h.With rough thing cooling, and through short Celite pad filtration.To filtrate concentrate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:9), obtain 1,2-two fluoro-4-isopropoxy-benzene are colorless oil (yield 6.12g, 92.3%).
Embodiment 62b
Preparation midbody 2,3-two fluoro-6-isopropoxy-phenyl aldehydes
Figure G2007800087501D01182
M.W.200.19?C 10H 10F 2O 2
With with the similar mode of method described in the embodiment 52a, will in embodiment 62a, prepare 1,2-two fluoro-4-isopropoxy-benzene (5.77g, 33.5mmol) with lithium diisopropylamine (20.5mL; 1.8M, in THF, 36.9mmol), N; N-dimethyl--methane amide (3.11mL, 40.2mmol) reaction, and be used in acetate (8.0g, 134mmol) quencher in the THF; Obtain 2,3-two fluoro-6-isopropoxy-phenyl aldehydes are white crystal (yield: 6.02g, 89.9%).
Embodiment 62c
Preparation midbody 1-(2,3-two fluoro-6-isopropoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01191
M.W.313.42?C 15H 21F 2NO 2Si
With with the similar mode of method described in the embodiment 1b, will in embodiment 62b, prepare 2, (2.0g 10mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-two fluoro-6-isopropoxy-phenyl aldehydes, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; 3-two fluoro-6-isopropoxy-phenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow oil, and under situation about not being further purified, be used for next step.
Embodiment 62d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01192
M.W.531.39?C 27H 22Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) with 1-(2,3-two fluoro-6-isopropoxy-phenyl)-3-front three of in embodiment 62c, preparing for siloxy--2-azepine-1,3-butadiene (2.5g; 7.98mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.41g, 75.9%).
HRMS (ES +) m/z calculated value C 27H 22Cl 2F 2N 2O 3+ H [(M+H) +]: 531.1049.Measured value: 531.1049.
Embodiment 62e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.531.39?C 27H 22Cl 2F 2N 2O 3
Through chirality SFC, carry out from (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-(2 that among embodiment 62d, prepares; 3-two fluoro-6-isopropoxy-phenyl) separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is to provide chirality (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid.
Embodiment 63
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-tetramethyleneimine-1-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01202
M.W.580.54?C 32H 32Cl 2FN 3O 2
With with the similar mode of method described in the embodiment 60b, racemize (2 ' R, the 3R that will in embodiment 60a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-1 '-(3-chloro-propyl group)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (91 mg, 0.134mmol) with tetramethyleneimine (pyrrolodine) (2mL), trifluoroacetic acid (10mL) reaction; With N, N '-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-tetramethyleneimine-1-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (21mg, 26.9%).
HRMS (ES +) m/z calculated value C 32H 32Cl 2FN 3O 2+ H [(M+H) +]: 580.1929.Measured value: 580.1926.
Embodiment 64a
Preparation midbody 1-(3-methoxyl group carboxyl-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01211
M.W.277.40?C 14H 19NO 3Si
With with the similar mode of method described in the embodiment 1b, with 3-formyl radical-oil of Niobe (1.5g, 10mmol) (Acros) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-(3-methoxyl group carboxyl-phenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 64b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methoxycarbonyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01212
M.W.495.37?C 26H 20Cl 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) (2.4g 8.65mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-methoxycarbonyl-phenyl)-3-front three that in embodiment 64a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methoxycarbonyl-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.28g, 56%).
HRMS (ES +) m/z calculated value C 26H 20Cl 2N 2O 4+ H [(M+H) +]: 495.0873 measured values: 495.0872.
Embodiment 65
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01221
M.W.637.59?C 34H 35Cl 2FN 4O 3
With with the similar mode of method described in the embodiment 60b, the racemize that will in embodiment 60a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(3-chloro-propyl group)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (88mg; 0.134mmol) and tetramethyleneimine (pyrrolodine) (0.4g, 3.1mmol), trifluoroacetic acid (10mL) reaction; With N, N '-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (33mg, 38.8%).HRMS (ES +) m/z calculated value C 34H 35Cl 2FN 4O 3+ H [(M+H) +]: 637.2143 measured values: 637.2139.
Embodiment 66a
Preparation midbody 1-(1-ethyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01231
M.W.211.38?C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2-ethyl-but-2-ene aldehyde (1.54g, 10mmol) (TCI-US) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 13mmol) reaction obtains 1-(1-ethyl-propenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 66b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) (2.1g 9.93mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-ethyl-propenyl)-3-front three that in embodiment 66a, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.24g, 54.5%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1129.
Embodiment 66c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01241
M.W.429.35?C 23H 22Cl 2N 2O 2
Through chirality SFC, carry out from (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [the 3H-indoles-3 that among embodiment 66b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone, so that chirality (2 ' R, 3R to be provided; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid.
Embodiment 67a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.644.60?C 32H 32Cl 2FN 3O 4S
With with the similar mode of method described in the embodiment 60b, the racemize that will in embodiment 60a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(3-chloro-propyl group)-2 '-(5-fluoro-2-aminomethyl phenyl)-2; 3-dihydro-2, (0.21mg is 0.31mmol) with thiomorpholine 1 for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; The 1-dioxide (0.47g, 3.48mmol), trifluoroacetic acid (10mL) reaction is then with N; N '-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (72mg, 36.2%).
HRMS (ES +) m/z calculated value C 32H 32Cl 2FN 3O 4S+H [(M+H) +]: 644.1548.Measured value: 644.1542.
Embodiment 67b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01251
M.W.644.60?C 32H 32Cl 2FN 3O 4S
Through chirality SFC, carry out from the racemize (2 ' R, the 3R that among embodiment 67a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; The separation of two kinds of enantiomers in 6 ' (1H)-diketone is to provide chirality (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid.
Embodiment 68a
Preparation midbody 1-(2,5-dimethyl--phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01261
M.W.247.42?C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2,5-dimethyl--phenyl aldehyde (1.34g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; 5-dimethyl--phenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 68b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01262
M.W.465.38?C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) with 1-(2,5-dimethyl--phenyl)-3-front three of in embodiment 68a, preparing for siloxy--2-azepine-1,3-butadiene (2.3g; 9.31mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid.
HRMS (ES +) m/z calculated value C 26H 22Cl 2N 2O 2+ H [(M+H) +]: 465.1131 measured values: 465.1128.
Embodiment 68c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01271
M.W.465.38?C 26H 22Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-(2 that among embodiment 68b, prepares; 5-dimethyl--phenyl) separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is to provide chirality (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid and chirality ((2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 5-dimethyl--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid.
Embodiment 69a
Preparation midbody 1-(2,5-dimethyl--2H-pyrazole-3-yl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.237.38?C 11H 19N 3OSi
With with the similar mode of method described in the embodiment 1b, with 2,5-dimethyl--2H-pyrazoles-3-formaldehyde (1.24g, 10mmol) (ASDI-INTER) replaces 3-chloro-phenyl aldehyde as raw material, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2; 5-dimethyl--2H-pyrazole-3-yl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 69b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01281
M.W.455.35?C 23H 20Cl 2N 4O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) with 1-(2,5-dimethyl--2H-pyrazole-3-yl)-3-front three of in embodiment 69a, preparing for siloxy--2-azepine-1,3-butadiene (2.5g; 10.5mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--2H-pyrazole-3-yl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.14g, 30.4%).
HRMS (ES +) m/z calculated value C 23H 20Cl 2N 4O 2+ H [(M+H) +]: 455.1036 measured values: 455.1035.
Embodiment 70a
Preparation midbody 1-(1-methyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01282
M.W.197.36?C 10H 19NOSi
With with the similar mode of method described in the embodiment 1b, with 2-methyl-but-2-ene aldehyde (0.84g, 10mmol) (EASTMAN) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 13mmol) reaction obtains 1-(1-methyl-propenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 70b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01291
M.W.415.32?C 22H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.35g; 0.89mmol) (2.1g 9.93mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methyl-propenyl)-3-front three that in embodiment 70a, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.19g, 51.4%).
HRMS (ES +) m/z calculated value C 22H 20Cl 2N 2O 2+ H [(M+H) +]: 415.0975.Measured value: 415.0975.
Embodiment 71a
Preparation midbody 1-(1-methyl-but-1-ene base)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01292
M.W.211.38?C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2-methyl-penta-2-olefine aldehydr (2.0g, 20mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 8mL, 20mmol); Trimethylsilyl chloride (2.2g, 20mmol), triethylamine (2.7g, 26mmol) and Acetyl Chloride 98Min. (2.0g; 26mmol) reaction obtains 1-(1-methyl-but-1-ene base)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 71b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-but-1-ene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01301
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) (3.2g 15.2mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methyl-but-1-ene the base)-3-front three that in embodiment 71a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-but-1-ene base) spiral shell [3H-pyrrole diindyl-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.24g, 54.5%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1127.
Embodiment 72a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01311
M.W.431.37?C 23H 24Cl 2N 2O 2
To the racemize that in embodiment 66b, prepares (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (0.3g; 0.70mmol) in the solution in ETHYLE ACETATE (30mL), add platinum oxide (0.35g, 1.54mmol).The suspension-s that obtains brute force under hydrogen (50psi) is shaken 6h.Mixture is filtered through short Celite pad.To filtrate and concentrate.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 0.11g, 37.7%).
HRMS (ES +) m/z calculated value C 23H 24Cl 2N 2O 2+ H [(M+H) +]: 431.1288 measured values: 431.1285.
Embodiment 72b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01312
M.W.431.37?C 23H 24Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (60mg), so that chirality (2 ' R, 3R to be provided; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 24mg; 40%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 24mg, 40%).
Embodiment 73a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01321
M.W.661.65?C 33H 36Cl 2F 2N 2O 4Si
With with the similar mode of method described in the embodiment 55b, the E/Z-6-chloro-3-that will in embodiment 55a, prepare (3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1,3-dihydro-indol-2-one (3.4g; 8.10mmol) with 1-(2,3-two fluoro-6-isopropoxy-phenyl)-3-front three of in embodiment 62c, preparing for siloxy--2-azepine-1,3-butadiene (16g; 51.1mmol) in toluene, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be pale solid.
Embodiment 73b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01322
M.W.738.18?C 36H 41Cl 3F 2N 2O 4Si
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 73a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (1.8g; 2.72mmol) and LiH (1.0g, 125mmol) (5.0g 24.5mmol) at N, reacts in N-dimethyl--methane amide (40mL) with 1-chloro-3-iodo-propane; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white foam (yield: 0.67g, 33.5%).
Embodiment 73c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01331
M.W.658.58?C 34H 35Cl 2F 2N 3O 4
With with the similar mode of method described in the embodiment 60b, the racemize that will in embodiment 73b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.3g; 0.41mmol) and morpholine (10mL), trifluoroacetic acid (10mL) reaction is then with N; N '-diisopropylethylamine (1mL) reaction obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.15g, 55.6%).
HRMS (ES +) m/z calculated value C 34H 35Cl 2F 2N 3O 4+ H [(M+H) +]: 658.2046.Measured value: 658.2038.
Embodiment 73d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.658.58?C 34H 35Cl 2F 2N 3O 4
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-(2 that among embodiment 73c, prepares; 3-two fluoro-6-isopropoxy-phenyl) separation of two kinds of enantiomers in-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (120mg); So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2 to be provided; 3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield: 55mg, 46%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 54mg, 45%).
Embodiment 74a
Preparation midbody 1-(1-ethylidene-amyl group)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01342
M.W.239.44?C 13H 25NOSi
With with the similar mode of method described in the embodiment 1b, with 2-ethylidene-hexanal (1.1g, 8.68mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (2.7g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 26mmol) reaction obtains 1-(1-ethylidene-amyl group)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 74b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethylidene-amyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01351
M.W.457.40?C 25H 26Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) (2.1g 8.77mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-ethylidene-amyl group)-3-front three that in embodiment 74a, prepares; React in methylene dichloride with trifluoroacetic acid (15mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethylidene-amyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (0.13g, 27.7%).
HRMS (ES+) m/z calculated value C 25H 26Cl 2N 2O 2+ H [(M+H) +]: 457.1444 measured values: 457.1443.
Embodiment 75
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure G2007800087501D01352
M.W.547.46?C 27H 22Cl 2F 2N 2O 2S
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 62d, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.45g; 0.85mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2; 4-diphosphine fourth ring 2, (0.6g 1.8mmol) reacts in toluene the 4-disulfide; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.36g, 78.3%).
HRMS (ES +) m/z calculated value C 27H 22Cl 2F 2N 2O 2S+H [(M+H) +]: 547.0820.Measured value: 547.0821.
Embodiment 76
Preparation racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
M.W.617.48?C 30H 28Cl 2F 2N 4O 4
With with the similar mode of method described in the embodiment 40, the racemize that will in embodiment 75, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2; 3-two fluoro-6-isopropoxy-phenyl) (0.30g is 0.55mmol) with carbazic acid ethyl ester (0.3g for-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone; 2.97mmol), mercuric acetate (0.30g, 0.95mmol) and triethylamine (0.1g; 0.99mmol) reaction in THF (40mL), obtain racemize (2 ' R, 3R; 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3; 3 '-piperidines]-the 6-subunit] hydrazine carboxylic acid's ethyl ester, be white solid (yield 0.25g, 73.5%).
HRMS (ES +) m/z calculated value C 30H 28Cl 2F 2N 4O 4+ H [(M+H) +]: 617.1529.Measured value: 617.1523.
Embodiment 77a
Preparation midbody ring penta-1-cyclohexene carboxaldehyde
Figure G2007800087501D01371
M.W.96.13?C 6H 8O
(28.3g 0.13mol) in (Aldrich) acidic solution in water (250mL), adds 1,2-cyclohexane diol (12g, 0.10mol) (Acros) solution in ether (150mL) to sodium periodate.In room temperature, with the powerful 0.5h that stirs of mixture.Add the KOH aqueous solution (20%, 38.4mL) after, reaction mixture is stirred other 1h.Mixture is used extracted with diethyl ether.Organic layer is merged and drying.Remove and desolvate, obtain encircling penta-1-cyclohexene carboxaldehyde, be yellow oil (yield: 7.2g, 75%)
Embodiment 77b
Preparation midbody 1-(ring penta-1-thiazolinyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01372
M.W.209.37?C 11H 19NOSi
With with the similar mode of method described in the embodiment 1b, (1.4g 14.6mmol) replaces 3-chloro-phenyl aldehyde as raw material to 2 ring penta-1-cyclohexene carboxaldehydes that will in embodiment 77a, prepare, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (2.7g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 26mmol) reaction obtains 1-(ring penta-1-thiazolinyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 77c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(ring penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.427.33?C 23H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) (ring penta-1-thiazolinyl)-(2.0g 9.55mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene with the 1-that in embodiment 77b, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(ring penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.12g, 27.3%).
HRMS (ES +) m/z calculated value C 23H 20Cl 2N 2O 2+ H [(M+H) +]: 427.0975 measured values: 427.0972.
Embodiment 78a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 72, under hydrogen (50psi), the racemize (2 ' R that will in embodiment 77c, prepare; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(ring penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; (0.1g 0.23mmol) reacts in ETHYLE ACETATE with platinum oxide 6 ' (1H)-diketone, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.031g, 31%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131 measured values: 429.1131.
Embodiment 78b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01391
M.W.429.35?C 23H 22Cl 2N 2O 2
Through chirality SFC, carry out from (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [the 3H-indoles-3 that among embodiment 78a, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (30mg), so that chirality (2 ' R, 3R to be provided; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (6mg; 20%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (6mg, 20%).
Embodiment 79a
Preparation intermediate E-2-sec.-propyl-but-2-ene-1-alcohol
Figure G2007800087501D01392
M.W.114.19?C 7H 14O
In 0 ℃, (14g, 0.2mol) (32g 0.2mol) in (Aldrich) solution in ether, drips isopropyl-magnesium chlorine (2M, 300mL, 0.6mol) solution in THF for (Aldrich) and CuI to 2-butyne-1-alcohol.With reaction mixture in stirring at room 24h.Reaction mixture is used saturated NH 4The quencher of the Cl aqueous solution is with twice of extracted with diethyl ether.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates.With residuum by chromatogram (EtOAc: the purifying of hexane=1:8), obtain E-2-sec.-propyl-but-2-ene-1-alcohol, be faint yellow oily thing (yield 5.3g, 23%).Identical transformation is by Duboudin, J.G.; Jousseaume, B. are reported in J.OrganometallicChem. (1979), and 168 (1), 1-11 and J.Organometallic Chem. (1975), 91 (1), among the C1-C3.
Embodiment 79b
Preparation intermediate E-2-sec.-propyl-but-2-ene aldehyde
Figure G2007800087501D01401
M.W.112.17?C 7H 12O
In-78 ℃, (6.49g 51mmol) in (Aldrich) solution in methylene dichloride (50mL), drips methyl-sulphoxide (7.25mL, 102mmol) solution in methylene dichloride (40mL) to oxalyl chloride.Behind 5min, drip E-2-sec.-propyl-but-2-ene-1-alcohol (5.3g, 46mmol) solution in methylene dichloride (10mL) that in embodiment 79a, prepares.Reaction mixture is stirred 15min in-78 ℃.(22mL 0.19mol), and is warmed to room temperature with reaction mixture at leisure, and in stirring at room 45min to add triethylamine.Add entry, and organic layer is separated.Water layer is used extracted with diethyl ether.Organic layer is merged, use 10%HCl, saturated NaHCO 3, brine wash is used MgSO 4Drying, and concentrate, obtain rough E-2-sec.-propyl-but-2-ene aldehyde, be yellow oil (yield 5.3g, 98%).
Embodiment 79c
Preparation midbody 1-(1-sec.-propyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01402
M.W.225.41?C 12H 23NOSi
With with the similar mode of method described in the embodiment 1b, (2.2g 20mmol) replaces 3-chloro-phenyl aldehyde as raw material to the E-2-sec.-propyl-but-2-ene aldehyde that will in embodiment 79b, prepare, with 1,1; 1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 4mL, 20mmol); Trimethylsilyl chloride (2.2g, 20mmol), triethylamine (2.72g, 26mmol) and Acetyl Chloride 98Min. (2g; 26mmol) reaction obtains 1-(1-sec.-propyl-propenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 79d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01411
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g; 1.3mmol) (3.7g 16.4mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-ethyl-propenyl)-3-front three that in embodiment 79c, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.28g, 50%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1284
Embodiment 79e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01412
M.W.443.38?C 24H 24Cl 2N 2O 2
Through chirality SFC, carry out from (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [the 3H-indoles-3 that among embodiment 79d, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (40mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (12mg, 30%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (12mg, 30%).
Embodiment 80a
Preparation midbody 1-(1-methylene radical-propyl group)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01421
M.W.197.36?C 10H 19NOSi
With with the similar mode of method described in the embodiment 1b, with ethyl acrylic aldehyde (2.1g, 22mmol) (TCI-US) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 8mL, 20mmol); Trimethylsilyl chloride (2.2g, 20mmol), triethylamine (2.9g, 27mmol) and Acetyl Chloride 98Min. (2g; 27mmol) reaction obtains 1-(1-methylene radical-propyl group)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 80b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01422
M.W.415.32?C 22H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.42g; 1.1mmol) (3.2g 16.2mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-propyl group)-3-front three that in embodiment 80a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.31g, 67%).
HRMS (ES +) m/z calculated value C 22H 20Cl 2N 2O 2+ H [(M+H) +]: 415.0975.Measured value: 415.0975
Embodiment 80c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.415.32?C 22H 20Cl 2N 2O 2
Through chirality SFC, carry out racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [the 3H-indoles-3 that in embodiment 80b, prepares; 3 '-piperidines] separation of two kinds of enantiomers of-2,6 ' (1H)-diketone (150mg), so that chirality (2 ' R, 3R to be provided; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 ,-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (63mg, 42%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (60mg, 40%). 1H?NMR(300MHz，DMSO-d6)：δ＝0.68(t，J＝7.5Hz，3H)，1.35-1.51(m，1H)，1.72-1.85(m，1H)，2.56(dd，J＝6.0，18.3Hz，1H)，2.90(dd，J＝12.3，18.3Hz，1H)，3.77(dd，J＝6.0，12.3Hz，1H)，4.53(s，1H)，4.70(s，1H)，4.78(s，1H)，6.61(d，J＝1.8Hz，1H)，6.62(d，J＝6Hz，1H)，6.74(s，1H)，7.04-7.13(m，2H)，7.18(brd，J＝8.6Hz，1H)，7.35(d，J＝8.6Hz，1H)，7.93(s，1H)，10.45(s，1H)ppm。
Embodiment 81a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01441
M.W.559.61?C 29H 36Cl 2N 2O 3Si
With with the similar mode of method described in the embodiment 55b, the E/Z-6-chloro-3-that will in embodiment 55a, prepare (3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1,3-dihydro-indol-2-one (5.4g; 12.8mmol) (20g 95mmol) reacts in toluene (200mL) for siloxy--2-azepine-1,3-butadiene with 1-(1-ethyl-propenyl)-3-front three that in embodiment 66a, prepares; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white size (yield 6.1g, 85%).
Embodiment 81b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
M.W.673.76?C 35H 46Cl 2N 2O 5Si
With with the similar mode of method described in the embodiment 55c, racemize (2 ' R, the 3R that will in embodiment 81a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (1.6g, 2.8mmol) with bromo-tert.-butyl acetate and cesium carbonate at N, react in the dinethylformamide; Obtain racemize (2 ' R, 3R, 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be white foam (yield 0.7g, 37%).
Embodiment 81c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.487.39?C 25H 24Cl 2N 2O 4
With with the similar mode of method described in the embodiment 55d, racemize (2 ' R, the 3R that will in embodiment 81b, prepare; 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.6g, 0.89mmol) reaction is to form racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.35g, 80%).
HRMS (ES+) m/z calculated value C 25H 24Cl 2N 2O 4+ H [(M+H) +]: 487.1186, measured value: 487.1186.
Embodiment 82a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-fluorine carbonyl methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01452
M.W.489.38?C 25H 23Cl 2FN 2O 3
With with the similar mode of method described in the embodiment 34a, racemize (2 ' R, the 3R that will in embodiment 81c, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1-hydroxycarbonyl group-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.16g; 0.33mmol) and cyanuric fluoride (0.044mL, 1.64mmol) (0.13g 1.64mmol) reacts in methylene dichloride for (Alfa) and pyridine; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-fluorine carbonyl methyl-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 0.12g, 75%).
Embodiment 82b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.558.51?C 29H 33Cl 2N 3O 4
With with the similar mode of method described in the embodiment 34b, the racemize that will in embodiment 82a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-fluorine carbonyl methyl-spiral shell [3H-indoles-3; 3 '-piperidines] (0.12g is 0.24mmol) with 2-amino-2-methyl-third-1-alcohol (73mg for-2,6 ' (1H)-diketone; 0.82mmol), N-methylmorpholine (0.2g, 1.98mmol) and 4-dimethylaminopyridine (2mg; 0.016mmol) in THF, react, obtain racemize racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 92mg, 67%).
HRMS (ES+) m/z calculated value C 29H 33Cl 2N 3O 4+ H [(M+H) +]: 558.1921.Measured value: 558.1921
Embodiment 82c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01471
M.W.558.51?C 29H 33Cl 2N 3O 4
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(the 2-hydroxyl-1 that among embodiment 82b, prepares; The 1-dimethyl ethyl) aminocarboxyl-methyl] separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (50mg); So that chirality (2 ' R, 3R, 4 ' S-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1 to be provided; The 1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield: 21mg, 42%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 19mg, 38%).
Embodiment 83a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01472
M.W.636.14?C 32H 41Cl 3N 2O 3Si
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 81a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-ethyl-propenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (2.4g; 4.3mmol) and LiH (1g, 125mmol) (8g is 39mmol) at N with 1-chloro-3-iodo-propane; Reaction obtains racemize (2 ' R, 3R in N-dimethyl--methane amide (40mL); 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white foam (yield: 0.61g, 22%).
Embodiment 83b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01481
M.W.556.54?C 30H 35Cl 2N 3O 3
With with the similar mode of method described in the embodiment 60b, racemize (2 ' R, the 3R that will in embodiment 83a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.3g, 0.47mmol) with morpholine (12mL), trifluoroacetic acid (5mL) reaction; With N, N-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.15g, 57%).
HRMS (ES +) m/z calculated value C 30H 35Cl 2N 3O 3+ H [(M+H) +]: 556.2128.Measured value: 556.2123.
Embodiment 83c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01491
M.W.556.54?C 30H 35Cl 2N 3O 3
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [the 3H-indoles-3 that among embodiment 83b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (150mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 61mg, 41%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 63mg, 42%).
Embodiment 84a
Preparation midbody 3-methyl-2-methylene radical-Ding-1-alcohol
Figure G2007800087501D01492
M.W.100.16?C 6H 12O
With with the similar mode of method described in the embodiment 79a, (2M is in ether with isopropyl-magnesium chlorine; 300mL is 0.6mol) with propynol (11.2g, 0.2mol; Aldrich) and CuI (32g, 0.2mol) reaction obtain 3-methyl-2-methylene radical-Ding-1-alcohol; Be colorless oil (yield, 2.4g, 12%)
Embodiment 84b
Preparation midbody 3-methyl-2-methylene radical-butyraldehyde
Figure G2007800087501D01493
M.W.98.15?C 6H 10O
With with the similar mode of method described in the embodiment 79b, (2.4g, 24mmol) oxidation obtain 3-methyl-2-methylene radical-butyraldehyde to the 3-methyl-2-methylene radical-Ding that will in embodiment 84a, prepare-1-alcohol, are yellow oil (yield: 1.6g, 68%)
Embodiment 84c
Preparation midbody 1-(2-methyl isophthalic acid-methylene radical-propyl group)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01501
M.W.211.38?C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, (1.3g 13mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 3-methyl-2-methylene radical-butyraldehyde that will in embodiment 84b, prepare, with 1,1; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.36g, 13mmol) and Acetyl Chloride 98Min. (1.02g; 13mmol) reaction obtains 1-(2-methyl isophthalic acid-methylene radical-propyl group)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 84d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-methyl isophthalic acid-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01502
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.41g; 1.1mmol) (2.1g 10mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(2-methyl isophthalic acid-methylene radical-the propyl group)-3-front three that in embodiment 84c, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-methyl isophthalic acid-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (0.13g, 28%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1133
Embodiment 85a
Preparation midbody 33-dimethyl--2-methylene radical-Ding-1-alcohol
M.W.114.19?C 7H 14O
With with the similar mode of method described in the embodiment 79a, with tertiary butyl magnesium chlorine (2M, in ether, 300mL; 0.6mol) with propynol (11.2g, 0.2mol, Aldrich) and CuI (32g; 0.2mol) reaction, obtain 3,3-dimethyl--2-methylene radical-Ding-1-alcohol; Be faint yellow oily thing (yield, 12.3g, 54%)
Embodiment 85b
Preparation midbody 3,3-dimethyl--2-methylene radical-butyraldehyde
Figure G2007800087501D01512
M.W.112.17?C 7H 12O
With with the similar mode of method described in the embodiment 79b, will in embodiment 85a, prepare 3,3-dimethyl--2-methylene radical-Ding-1-alcohol (12.3g; 0.11mol) oxidation, obtain 3,3-dimethyl--2-methylene radical-butyraldehyde; Be yellow oil (yield: 8.3g, 67%)
Embodiment 85c
Preparation midbody 1-(2,2-dimethyl--1-methylene radical-propyl group)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01521
M.W.225.41?C 12H 23NOSi
With with the similar mode of method described in the embodiment 1b, will in embodiment 85b, prepare 3, (2.2g 20mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-dimethyl--2-methylene radical-butyraldehyde, with 1; 1,1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 8mL, 20mmol), trimethylsilyl chloride (2.2g; 20mmol), triethylamine (2.7g, 27mmol) and Acetyl Chloride 98Min. (2g, 27mmol) reaction; Obtain 1-(2,2-dimethyl--1-methylene radical-propyl group)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, be used for next step.
Embodiment 85d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,2-dimethyl--1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01522
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.41g; 1.1mmol) with 1-(2,2-dimethyl--1-methylene radical-propyl group)-3-front three of in embodiment 85c, preparing for siloxy--2-azepine-1,3-butadiene (3.4g; 15mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,2-dimethyl--1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (0.27g, 55%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1288
Embodiment 86
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-morpholine-4-base-ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01531
M.W.599.56?C 31H 36Cl 2N 4O 4
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 83a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.12g; 0.24mmol) and 4-(2-amino-ethyl) morpholine (85mg, 0.66mmol) (Aldrich), N-methylmorpholine (0.1g; 0.98mmol) and 4-dimethylaminopyridine (2mg 0.015mmol) reacts in THF, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-morpholine-4-base-ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 31mg, 22%).
HRMS (ES +) m/z calculated value C 31H 36Cl 2N 4O 4+ H [(M+H) +]: 599.2187.Measured value: 599.2185
Embodiment 87a
Preparation midbody 1-pseudoallyl-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01532
M.W.183.33?C 9H 17NOSi
With with the similar mode of method described in the embodiment 1b, with methacrolein (2g, 20mmol) (Acros) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 8mL, 20mmol); Trimethylsilyl chloride (2.2g, 20mmol), triethylamine (2.7g, 27mmol) and Acetyl Chloride 98Min. (2.0g; 27mmol) reaction obtains 1-pseudoallyl-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 87b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01541
M.W.401.30?C 21H 18Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.41g; 1.1mmol) (3.4g 18mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with the 1-pseudoallyl-3-front three that in embodiment 87a, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.27g, 61%).HRMS (ES +) m/z calculated value C 21H 18Cl 2N 2O 2+ H [(M+H) +]: 401.0818.Measured value: 401.0818
Embodiment 87c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01542
M.W.401.30?C 21H 18Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [the 3H-indoles-3 that among embodiment 87b, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (80mg), so that chirality (2 ' R, 3R to be provided; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (28mg; 35%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (26mg, 33%).
1H?NMR(300MHz，DMSO-d6)：δ＝1.24(s，3H)，2.55(dd，J＝6.0，18.0Hz，1H)，2.89(dd，J＝13.2，18.0Hz，1H)，3.75(dd，J＝6.0，13.2Hz，1H)，4.49(s，1H)，4.71(s，1H)，4.77(s，1H)，6.60-6.63(m，2H)，6.74(t，J＝1.8Hz，1H)，7.04-7.12(m，2H)，7.17(brd，J＝8.1Hz，1H)，7.34(d，J＝8.1Hz，1H)，8.00(s，1H)，10.44(s，1H)ppm。
Embodiment 88a
Preparation midbody 2-methylene radical-penta-1-alcohol
Figure G2007800087501D01551
M.W.100.16?C 6H 12O
With with the similar mode of method described in the embodiment 79a, with propyl group magnesium chlorine (2M, in ether, 375mL; 0.75mol) with propynol (14g, 0.25mol) (it is pure to obtain 2-methylene radical-penta-1-for 40g, 0.25mol) reaction with CuI; Be colorless oil (yield, 16.9g, 67%)
Embodiment 88b
Preparation midbody 2-methylene radical-valeral
Figure G2007800087501D01552
M.W.98.15?C 6H 10O
With with the similar mode of method described in the embodiment 79b, (16.5g, 0.165mol) oxidation obtain 2-methylene radical-valeral to the 2-methylene radical that will in embodiment 88a, prepare-penta-1-alcohol, are yellow oil (yield: 6.7g, 41%)
Embodiment 88c
Preparation midbody 1-(1-methylene radical-butyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.211.38?C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, (2.1g 21mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-methylene radical-valeral that will in embodiment 88b, prepare, with 1,1; 1,3,3,3-hexamethyldisilazane (3.2g; 20mmol), just-butyllithium (2.5M, 8mL, 20mmol); Trimethylsilyl chloride (2.2g, 20mmol), triethylamine (2.7g, 27mmol) and Acetyl Chloride 98Min. (2g; 27mmol) reaction obtains 1-(1-methylene radical-butyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 88d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01562
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.45g; Xxmmol) (0.45g 1.1mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-butyl)-3-front three that in embodiment 88c, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (0.34g, 72%).
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1131
Embodiment 88e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01571
M.W.429.35?C 23H 22Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [the 3H-indoles-3 that among embodiment 88d, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (90mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (32mg, 36%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (30mg, 33%).
Embodiment 89a
Preparation midbody 4-methyl-2-methylene radical-penta-1-alcohol
Figure G2007800087501D01572
M.W.114.19?C 7H 14O
With with the similar mode of method described in the embodiment 79a, with isobutyl-magnesium chlorine (2M, in ether, 375mL; 0.75mol) with propynol (14g, 0.25mol) (it is pure to obtain 4-methyl-2-methylene radical-penta-1-for 40g, 0.25mol) reaction with CuI; Be colorless oil (yield, 27g, 95%)
Embodiment 89b
Preparation midbody 4-methyl-2-methylene radical-valeral
Figure G2007800087501D01573
M.W.112.17?C 7H 12O
With with the similar mode of method described in the embodiment 79b, the oxidation of the 4-methyl-2-methylene radical that will in embodiment 89a, prepare-penta-1-alcohol obtains 4-methyl-2-methylene radical-valeral, is yellow oil (yield: 21g, 77%)
Embodiment 89c
Preparation midbody 1-(3-methyl isophthalic acid-methylene radical-butyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01581
M.W.225.41?C 12H 23NOSi
With with the similar mode of method described in the embodiment 1b, (11g 100mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 4-methyl-2-methylene radical-valeral that will in embodiment 89b, prepare, with 1,1; 1,3,3,3-hexamethyldisilazane (16g; 100mmol), just-butyllithium (2.5M, 40mL, 100mmol); Trimethylsilyl chloride (11g, 100mmol), triethylamine (13.6g, 14mmol) and Acetyl Chloride 98Min. (10.2g; 14mmol) reaction obtains 1-(3-methyl isophthalic acid-methylene radical-butyl)-3-front three for siloxy--2-azepine-1,3-butadiene, and under situation about not being further purified, is used for next step.
Embodiment 89d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (2g; 5mmol) (21g 93mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(3-methyl isophthalic acid-methylene radical-the butyl)-3-front three that in embodiment 89c, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chlorine 4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (1.3g, 59%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1285
Embodiment 89e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01591
M.W.443.38?C 24H 24Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [the 3H-indoles-3 that among embodiment 89d, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (300mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (130mg, 43%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (130mg, 43%).
Embodiment 90
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.459.44?C 24H 24Cl 2N 2OS
With with the similar mode of method described in the embodiment 30, the racemize that will in embodiment 89d, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3; 3 '-piperidines] and-2,6 ' (1H)-diketone (1.4g, 3.1mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1; 3-dithia-2,4-diphosphine fourth ring 2, (1.7g 4.25mmol) reacts in toluene the 4-disulfide; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone, be pale solid (yield 1.2g, 84%).
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2OS+H [(M+H) +]: 459.1059.Measured value: 459.1055.
Embodiment 91a
Preparation midbody 4-oxyethyl group-1,2-two fluoro-benzene
Figure G2007800087501D01602
M.W.158.15?C 8H 8F 2O
To 3,4-two fluoro-phenol (10g, 77mmol) at N, in the solution in the dinethylformamide (50mL), add salt of wormwood (20g, 145mmo) and iodic ether (50g, 320mmol, Aldrich).With reaction mixture reflux 48h.Rough thing is cooled to room temperature, and filters through short Celite pad.To filtrate concentrate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:8), obtain 4-oxyethyl group-1,2-two fluoro-benzene are colorless oil (yield 11g, 90%).
Embodiment 91b
Preparation midbody 6-oxyethyl group-2,3-two fluoro-phenyl aldehydes
Figure G2007800087501D01611
M.W.186.16?C 9H 8F 2O 2
With with the similar mode of method described in the embodiment 52a, the 4-oxyethyl group-1 that will in embodiment 91a, prepare, 2-two fluoro-benzene (10g, 63mmol) with lithium diisopropylamine (39mL; 1.8M, in THF, 70mmol), N; Dinethylformamide (5.88mL, 76mmol) reaction, and be used in acetate (15.2g, 253mmol) quencher in the THF; Obtain 6-oxyethyl group-2,3-two fluoro-phenyl aldehydes are pale solid (yield: 8.9g, 76%).
Embodiment 91c
Preparation midbody 1-(4-oxyethyl group-1,2-two fluoro-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01612
M.W.299.40?C 14H 19F 2NO 2Si
With with the similar mode of method described in the embodiment 1b, the 6-oxyethyl group-2 that will in embodiment 91b, prepare, (1.9g 11mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-two fluoro-phenyl aldehydes, with 1; 1,1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(4-oxyethyl group-1; 2-two fluoro-phenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow oil, and under situation about not being further purified, be used for next step.
Embodiment 91d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01621
M.W.517.36?C 26H 20Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.6g; 1.5mmol) with 1-(4-oxyethyl group-1,2-two fluoro-phenyl)-3-front three of in embodiment 91c, preparing for siloxy--2-azepine-1,3-butadiene (2.3g; 7.6mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.39g, 50%).
HRMS (ES +) m/z calculated value C 26H 20Cl 2F 2N 2O 3+ H [(M+H) +]: 517.0892.Measured value: 517.0889.
Embodiment 91e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01622
M.W.517.36?C 26H 20Cl 2F 2N 2O 3
Through chirality SFC, carry out from (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(the 4-oxyethyl group-1 that among embodiment 91d, prepares; 2-two fluoro-phenyl) separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (98mg) is to provide chirality (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (36mg, 36%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (33mg, 33%).
Embodiment 92a
Preparation intermediate E/Z-3-chloro-5-(6-chloro-2-oxo-1,2-dihydro-indoles-3-ylidenylmethyl)-oil of Niobe
Figure G2007800087501D01631
M.W.348.19?C 17H 11Cl 2NO 3
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (3.2g, 18mmol) with 3-chloro-5-formyl radical-oil of Niobe (3.92g; 18mmol) and tetramethyleneimine (1.3g; 18mmol) in methyl alcohol, react, obtain the mixture of E-and Z-3-chloro-5-(6-chloro-2-oxo-1,2-dihydro-indoles-3-ylidenylmethyl)-oil of Niobe; Be yellow solid (yield: 6.1g, 97%).
3-chloro-5-formyl radical-oil of Niobe is to use 5-chlorine dimethyl isophthalate (Matrix.) as raw material, according to by Mitchelotti etc. in the preparation of the method described in the US5254584.
Embodiment 92b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-5-methoxycarbonyl-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
Figure G2007800087501D01632
M.W.448.31?C 22H 19Cl 2NO 5
With with the similar mode of method described in the embodiment 24a, with E/Z-3-chloro-5-(6-chloro-2-oxo-1,2-dihydro-indoles-3-ylidenylmethyl)-oil of Niobe (3g; 8.6mmoll) and tert-Butyl dicarbonate (1.9g; 8.6mmol) (Aldrich), triethylamine (0.87g, 8.6mmol) and 4-dimethylaminopyridine (5mg) in methylene dichloride (100mL), react; Obtain E/Z-6-chloro-3-(3-chloro-5-methoxycarbonyl-tolylene)-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester is yellow solid (yield: 3.7g, 96%).
Embodiment 92c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-methoxycarbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01641
M.W.473.36?C 24H 22Cl 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 92b, prepare (3-chloro-5-methoxycarbonyl-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (2.4g; 5.3mmol) (13g 66mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-propyl group)-3-front three that in embodiment 80a, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-methoxycarbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (1.6g, 64%).
HRMS (ES +) m/z calculated value C 24H 22Cl 2N 2O 4+ H [(M+H) +]: 473.1030.Measured value: 473.1031.
Embodiment 93
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-hydroxycarbonyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01651
M.W.459.33?C 23H 20Cl 2N 2O 4
Execute the racemize (2 ' R for preparing among the routine 92c; 3R, 4 ' S)-6-chloro-4 '-(3-chloro--5-methoxycarbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (1.6g; 33mmol) in the mixture of THF (60mL) and methyl alcohol (30mL), and the solution of adding sodium hydroxide (1N, 30mL).With reaction mixture behind stirring at room 2h, rough thing is concentrated.Residuum is neutralized to " pH "～4 with dilute hydrochloric acid solution, uses ethyl acetate extraction then.Organic layer is separated, use MgSO 4Drying concentrates, and obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-hydroxycarbonyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 1.5g, 99%).
HRMS (ES +) m/z calculated value C 23H 20Cl 2N 2O 4+ H [(M+H) +]: 459.0873.Measured value: 459.0873.
Embodiment 94a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.461.32?C 23H 19Cl 2FN 2O 3
In 0 ℃, to racemize (2 ' R, the 3R of preparation in embodiment 93; 4 ' S)-6-chloro-4 '-(3-chloro-5-hydroxycarbonyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.2g; 0.43mmol) in the solution in methylene dichloride (20mL); Add cyanuric fluoride (48mg, 0.35mmol) (Alfa) and pyridine (37mg, 0.48mmol).With mixture in 0 ℃ stir 2h after, with mixture at H 2Distribute between O and the methylene dichloride.Organic layer is separated, and water layer is used dichloromethane extraction.Organic layer is merged, use MgSO 4Drying concentrates, and obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone; Be yellow glue, and under situation about not being further purified, be used for next step (yield: 0.2g, 100%).
Embodiment 94b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[3-chloro-5-(4-methylsulfonyl-piperazine-1-carbonyl)-phenyl]-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01661
M.W.605.55?C 28H 30Cl 2N 4O 5S
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 94a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.16g; 36mmol) with N-methyl sulphonyl piperazine (59mg, 36mmol), N-methylmorpholine (0.1g; 0.99mmol) and 4-dimethylaminopyridine (1mg 0.008mmol) reacts in THF, obtains racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-[3-chloro-5-(4-methylsulfonyl-piperazine-1-carbonyl)-phenyl]-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield 0.2g, 92%).
HRMS (ES +) m/z calculated value C 28H 30Cl 2N 4O 5S+H [(M+H) +]: 619.1543.Measured value: 619.1544.
Embodiment 95a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01671
M.W.443.38?C 24H 24Cl 2N 2O 2
With with EXAMPLE Example 56a, 56b, the similar mode of the method described in the 56c, the racemize (2 ' R that will in embodiment 81a, prepare; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-ethyl-propenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (1g, 1.8mmol) reaction obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield, 0.50g, 65%)
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288.Measured value: 443.1288.
Embodiment 95b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.443.38?C 24H 24Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (85mg) in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 33mg; 39%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 26mg, 31%).
Embodiment 96a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01681
M.W.403.31?C 21H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 72a, the racemize that will in embodiment 87b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines] (0.1g, 0.25mmol) hydrogenation obtain racemize (2 ' R to-2,6 ' (1H)-diketone; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 61mg, 60%).
HRMS (ES +) m/z calculated value C 21H 20Cl 2N 2O 2+ H [(M+H) +]: 403.0975 measured values: 403.0976.
Embodiment 96b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01682
M.W.403.31?C 21H 20Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (50g), so that chirality (2 ' R, 3R to be provided; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 15mg; 30%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 14mg, 28%).
Embodiment 97a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01691
M.W.545.59?C 28H 34Cl 2N 2O 3Si
With with the similar mode of method described in the embodiment 55b, the E/Z-6-chloro-3-that will in embodiment 55a, prepare (3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1,3-dihydro-indol-2-one (3g; 7.1mmol) (19g 96ml) reacts in toluene (200mL) for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-propyl group)-3-front three that in embodiment 80a, prepares; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white foam (yield 3.5g, 90%).
Embodiment 97b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01692
M.W.429.35?C 23H 22Cl 2N 2O 2
With with EXAMPLE Example 56a, 56b, the similar mode of the method described in the 56c, the racemize (2 ' R that will in embodiment 97a, prepare; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.6g, 1.1mmol) reaction is to form racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield, 0.16g, 35%)
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131.Measured value: 429.1131.
Embodiment 97c
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01701
M.W.429.35?C 23H 22Cl 2N 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (160mg) in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 80mg; 50%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 80mg, 50%).
Embodiment 98
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-sec.-butyl-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01702
M.W.417.34?C 22H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 72a, (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 ' that will in embodiment 80b, prepare-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines] (0.38g, 0.91mmol) hydrogenation obtain racemize (2 ' R to-2,6 ' (1H)-diketone; 3R, 4 ' S)-2 '-sec.-butyl-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 0.25g, 66%).
HRMS (ES +) m/z calculated value C 22H 22Cl 2N 2O 2+ H [(M+H) +]: 417.1131 measured values: 417.1134
Embodiment 99a
Preparation midbody 2-(tertiary butyl-dimethyl--silanyloxy base (silanyloxy) methyl)-third-2-alkene-1-alcohol
Figure G2007800087501D01711
M.W.202.37?C 10H 22O 2Si
To 2-methylene radical-propane-1, and the 3-glycol (5.3g, 60.15mmol) in (Aldrich) solution in THF (100mL), the adding sodium hydride (3.61g, 90.3mmo).With reaction mixture behind stirring at room 20min, add TERT-BUTYL DIMETHYL CHLORO SILANE (10.89g, 72.2mmol).Reaction mixture in stirring at room 3h, is toppled in the entry then, and use ethyl acetate extraction.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates, and obtains 2-(tertiary butyl-dimethyl--siloxy methyl)-third-2-alkene-1-alcohol, is colorless oil (yield 12.0g, 99%).
Embodiment 99b
Preparation midbody 2-(tertiary butyl-dimethyl--siloxy methyl)-propenal
Figure G2007800087501D01712
M.W.200.36?C 10H 20O 2Si
The 2-that will in embodiment 99a, prepare (tertiary butyl-dimethyl--siloxy methyl)-third-2-alkene-1-alcohol (6g; 29.7mmol) be dissolved in and contain molecular sieve (4A) simultaneously (Aldrich) (5.2g is in methylene dichloride 44.47mmol) (296mL) with the N-methylmorpholine oxide compound.Behind the 1h that stirs the mixture, add (crossing ruthenic acid tetra-n-butyl ammonium) (0.47g, 1.48mmol) (Aldrich), and with reaction mixture in stirring at room 1h.Add then another batch (cross ruthenic acid tetra-n-butyl ammonium) (0.23g, 0.74mmol), and with mixture in the other 1h of stirring at room.Reaction mixture is diluted with methylene dichloride.Organic layer is used Na 2S 2O 3Solution, salt solution and copper/saturated copper sulphate (II) solution washing is used MgSO then 4Drying is filtered, and concentrates.Residuum is used chromatogram purification, obtain 2-(tertiary butyl-dimethyl--siloxy methyl)-propenal, be colorless oil (yield 1.3g, 22%).
Embodiment 99c
Preparation midbody 1-[1-(tertiary butyl-dimethyl--siloxy methyl)-vinyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.313.59?C 15H 31NO 2Si 2
With with the similar mode of method described in the embodiment 1b, (1.05g 5.25mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-that will in embodiment 99b, prepare (tertiary butyl-dimethyl--siloxy methyl)-propenal, with 1; 1,1,3,3; The 3-hexamethyldisilazane (1.09mL, 5.25mmol), just-butyllithium (2.5M, 2.1mL; 5.25mmol), trimethylsilyl chloride (0.67mL, 5.25mmol), triethylamine (0.95mL; 6.8mmol) and Acetyl Chloride 98Min. (0.48mL, 6.8mmol) reaction obtains 1-[1-(tertiary butyl-dimethyl--siloxy methyl)-vinyl]-3-front three for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 99d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-hydroxymethyl-vinyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01722
M.W.417.34?C 21H 18Cl 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.2g; 0.51mmol) react in toluene for siloxy--2-azepine-1,3-butadiene, react in methylene dichloride with trifluoroacetic acid (20mL) then with 1-[1-(tertiary butyl-dimethyl--siloxy methyl)-the vinyl]-3-front three that in embodiment 99c, prepares; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-hydroxymethyl-vinyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid.
HRMS (ES +) m/z calculated value C 21H 18Cl 2N 2O 3+ H [(M+H) +]: 417.0767 measured values: 417.0767.
Embodiment 100a
Preparation midbody 2-methoxymethyl-propenal
M.W.100.12?C 5H 8O 2
((62g, 1.82mol), (1.5g, 0.01mol) (1.14g, 0.0098mol) stirred solution in water is cooled to room temperature and filtration in the reflux temperature heated overnight to trolamine to methyl alcohol then with 85% phosphoric acid for 22.4g, 0.4mol) (Aldrich) with propenal.With filtrate water dilution, ((2.32g is 0.02mol) with dibutylamine (5.4g, 0.04mol) (Aldrich) processing for the vitriol oil for 32.4g, 0.4mol) (Aldrich) to use 37% formaldehyde solution then.Rough mixture heats 4h at reflux temperature, is cooled to room temperature, and uses dichloromethane extraction.Organic layer is merged, use brine wash, use MgSO 4Drying is filtered, and concentrates.Residuum with chromatogram (hexane) purifying, is obtained 2-methoxymethyl-propenal, be colorless oil (yield 2.8g, 7.0%).
Embodiment 100b
Preparation midbody 1-(1-methoxymethyl-vinyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01741
M.W.213.75?C 10H 19NO 2Si
With with the similar mode of method described in the embodiment 1b, (1.35mL 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-methoxymethyl-propenal that will in embodiment 100a, prepare, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction; Obtain 1-(1-methoxymethyl-vinyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 100c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methoxymethyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01742
M.W.431.32?C 22H 20Cl 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) with 1-(1-methoxymethyl-vinyl)-3-front three of in embodiment 158b, preparing for siloxy--2-azepine-1; The 3-divinyl reacts in toluene, reacts in methylene dichloride with trifluoroacetic acid (20mL) then, obtains racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methoxymethyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield: 0.12g, 27.2%).
HRMS (ES +) m/z calculated value C 22H 20Cl 2N 2O 3+ H [(M+H) +]: 431.0924 measured values: 431.0928.
Embodiment 101a
Preparation midbody 1,2-two fluoro-4-(2-methoxyl group-oxyethyl group)-benzene
Figure G2007800087501D01751
M.W.188.18?C 9H 10F 2O 2
To 3, and 4-two fluoro-phenol (10g, 76.9mmol) (Aldrich) at N, and in the solution in the dinethylformamide (100mL), (4.6g is 115mmo) with 1-bromo-2-methoxyl group-ethane (12.8g, 92.2mmol) (Aldrich) to add sodium hydride.Reaction mixture in stirring at room 2h, is heated 16h at 80 ℃ then.Reaction mixture is cooled to room temperature, and topples in the entry, use ethyl acetate extraction.Organic layer is merged, and water, brine wash are used MgSO 4Drying is filtered, and concentrates.With residuum with chromatogram (EtOAc: the purifying of hexane=1:10), obtain 1,2-two fluoro-4-(2-methoxyl group-oxyethyl group)-benzene are colorless oil (yield 6.3g, 44%).
Embodiment 101b
Preparation midbody 2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl aldehyde
Figure G2007800087501D01752
M.W.216.19?C 10H 10F 2O 3
With with the similar mode of method described in the embodiment 52a, will in embodiment 101a, prepare 1,2-two fluoro-4-(2-methoxyl group-oxyethyl group)-benzene (6.3g, 33.4mmol) with lithium diisopropylamine (20.1mL; 2.0M, in THF, 40.1mmol); N, N-dimethyl--methane amide (3.11mL, 40.1mmol) reaction; And (8.1g 134mmol) and water (41.2mL) quencher, obtains 2 to be used in acetate in the THF; 3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl aldehyde are yellow oil (yield: 5.8g, 80.6%).
Embodiment 101c
Preparation midbody 1-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01761
M.W.329.42?C 15H 21F 2NO 3Si
With with the similar mode of method described in the embodiment 1b, will in embodiment 101b, prepare 2, (2.23g is 10.5mmol) with 1,1 for 3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl aldehyde; 1,3,3, and the 3-hexamethyldisilazane (1.7g, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33g, 10.5mmol); Triethylamine (1.9mL, 13mmol) and Acetyl Chloride 98Min. (0.97,13mmol) reaction, obtain 1-[2; 3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 101d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01762
M.W.547.39?C 27H 22Cl 2F 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-the phenyl]-3-front three that in embodiment 101c, prepares; React in methylene dichloride with trifluoroacetic acid (8mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2; 3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.12g, 21.4%).
HRMS (ES +) m/z calculated value C 27H 22Cl 2F 2N 2O 4+ H [(M+H) +]: 547.0998 measured values: 547.0997.
Embodiment 101e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01771
M.W.483.37?C 26H 21Cl 2FN 2O 2
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-[2 that among embodiment 101d, prepares; 3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (80mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 35mg, 43.7%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 33mg, 41.2%).
Embodiment 102a
Preparation midbody 2,3-dimethyl--but-2-ene acetoacetic ester
Figure G2007800087501D01772
M.W.142.20?C 8H 14O 2
In 0 ℃, (23.8g, 0.1mol) (Aldrich) drops to sodium hydride (2.64g is 0.11mol) in the stirred solution in glycol dimethyl ether (100mL) with phosphono propionic acid triethyl.Behind stirring at room 20min, (5.8g 0.1mol), and spends the night reaction mixture refluxed to add acetone.With this two-phase mixture cooling, dilute with water, and use extracted with diethyl ether.The organic layer that merges is used MgSO 4Drying is filtered, and concentrates.Residuum with chromatogram (hexane) purifying, is obtained 2, and 3-dimethyl--but-2-ene acetoacetic ester is colorless oil (yield 9.6g, 67.7%).
Embodiment 102b
Preparation midbody 2,3-dimethyl--but-2-ene-1-alcohol
M.W.100.16?C 6H 12O
With 2,3-dimethyl--but-2-ene acetoacetic ester (9.6g, 67.7mmol) drips of solution in ether (100mL) be added to LAH stirred solution (1M, in ether, 67mL, 67.7mmol) in.Behind stirring at room 30min, reaction mixture is used saturated NH 4Extracted with diethyl ether is used in the quencher of Cl solution.Organic layer is merged, water, brine wash is used MgSO 4Drying and filtration.Remove and desolvate, obtain 2,3-dimethyl--but-2-ene-1-alcohol is colorless oil (yield 4.4g, 66%).
Embodiment 102c
Preparation midbody 2,3-dimethyl--but-2-ene aldehyde
Figure G2007800087501D01782
M.W.98.15?C 6H 10O
In-78 ℃, (6.13g 48.3mmol) in (Aldrich) solution in methylene dichloride (50mL), drips methyl-sulphoxide (6.85mL, 96.6mmol) solution in methylene dichloride to oxalyl chloride.Behind the 5min, drip in embodiment 160b, prepare 2,3-dimethyl--but-2-ene-1-alcohol (4.4g, 43.9mmol) solution in methylene dichloride (10mL).Reaction mixture is stirred 15min in-78 ℃.(22mL 0.19mol), and is warmed to room temperature with reaction mixture at leisure, and in stirring at room 45min to add triethylamine.Add entry.Organic layer is separated, merge, use 10%HCl, saturated NaHCO 3, brine wash is used MgSO 4Drying is filtered, and concentrates, and obtains 2, and 3-dimethyl--but-2-ene aldehyde is yellow liquid (yield 4.0g, 93%).
Embodiment 102d
Preparation midbody 1-(1,2-dimethyl--propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.211.38?C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, will in embodiment 102c, prepare 2, (1.03g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-dimethyl--but-2-ene aldehyde, with 1; 1,1,3,3,3-hexamethyldisilazane (2.18mL; 10.5mmol), just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction, obtain 1-(1; 2-dimethyl--propenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 102e
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1,2-dimethyl--propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01792
M.W.429.35?C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(1,2-dimethyl--propenyl)-3-front three that in embodiment 102d, prepares; React in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1,2-dimethyl--propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid.
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 2+ H [(M+H) +]: 429.1131 measured values: 429.1132.
Embodiment 103
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-propionyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.417.30?C 21H 18Cl 2N 2O 3
In-78 ℃, to the racemize that in embodiment 80b, prepares (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (300mg; 0.72mmol) at methyl alcohol and methylene dichloride (1:1; In the solution 50mL),, become blueness up to the color of solution through flow of ozone.Reaction mixture is outgased with nitrogen, add methyl disulfide (5mL) then.Reactant is warmed to room temperature at leisure, and stirred overnight.Mixture is concentrated, and with residuum by chromatogram (EtOAc:CH2Cl2=1:1) purifying, obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-propionyl group spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 160mg, 50%)
HRMS (ES+) m/z calculated value C 21H 18Cl 2N 2O 3+ H [(M+H) +]: 417.0767.Measured value: 417.0770.
Embodiment 104a
Preparation midbody 1,2-two fluoro-4-propoxy--benzene
Figure G2007800087501D01802
M.W.172.18?C 9H 10F 2O
To 3,4-two fluoro-phenol (20g, 154mmol) at N, in the solution in the dinethylformamide (70mL), add salt of wormwood (30g, 217mmo) with iodo propane (50g, 293mmol, Aldrich).With reaction mixture reflux 48h.Rough thing is cooled to room temperature and passes through short Celite pad filtration.To filtrate concentrate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:8), obtain 1,2-two fluoro-4-propoxy--benzene are colorless oil (yield 17g, 100%).
Embodiment 104b
Preparation midbody 2,3-two fluoro-6-propoxy--phenyl aldehydes
Figure G2007800087501D01811
M.W.200.19?C 10H 10F 2O 2
With with the similar mode of method described in the embodiment 52a, will in embodiment 104a, prepare 1,2-two fluoro-4-propoxy--benzene (17g, 98.8mmol) with lithium diisopropylamine (59.2mL; 2.0M, in THF, 0.118mmol), N; N-dimethyl--methane amide (9.17mL, 0.118mol) reaction, and be used in acetate in the THF (23.7g, 0.395mol) and water (41.2mL) quencher; Obtain 2,3-two fluoro-6-propoxy--phenyl aldehydes are yellow solid (yield: 8.2g, 42%).
Embodiment 104c
Preparation midbody 1-(2,3-two fluoro-6-propoxy--phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01812
M.W.313.42?C 15H 21F 2NO 2Si
With with the similar mode of method described in the embodiment 1b, will in embodiment 104b, prepare 2, (2.1g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to 3-two fluoro-6-propoxy--phenyl aldehydes, with 1; 1,1,3,3,3-hexamethyldisilazane (1.7g; 10.5mmol), just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33g; 10.5mmol), triethylamine (1.9mL, 13mmol) and Acetyl Chloride 98Min. (0.97,13mmol) reaction, obtain 1-(2; 3-two fluoro-6-propoxy--phenyl)-and the 3-front three is for siloxy--2-azepine-1,3-butadiene, and be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 104d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01821
M.W.531.39?C 27H 22Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.02mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(2,3-two fluoro-6-propoxy--phenyl)-3-front three that in embodiment 104c, prepares; React in methylene dichloride with trifluoroacetic acid (8mL) then, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow oil.
HRMS (ES +) m/z calculated value C 27H 22Cl 2F 2N 2O 3+ H [(M+H) +]: 531.1049 measured values: 531.1049.
Embodiment 104e
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01822
M.W.531.39?C 27H 22Cl 2F 2N 2O 3
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-(2 that among embodiment 104d, prepares; 3-two fluoro-6-propoxy--phenyl) separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.67g) is to provide chirality (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 135mg, 20.1%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 150mg, 22.3%).
Embodiment 105a
Preparation midbody 2-cyclopropyl-third-2-alkene-1-alcohol
Figure G2007800087501D01831
M.W.98.15?C 6H 10O
In 0 ℃, (4.2g, 74.9mmol) (14.28g 74.9mmol) in (Aldrich) solution in ether, drips cyclopropyl magnesium chlorine (0.5M, 0.45L, 0.225mol) solution in THF for (Aldrich) and CuI to propynol.With reaction mixture in stirring at room 48h.Reaction mixture is used saturated NH 4Extracted with diethyl ether is used in the quencher of Cl solution.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates.With residuum with chromatogram (EtOAc: the purifying of hexane=1:8), obtain 2-cyclopropyl-third-2-alkene-1-alcohol, be yellow oil (yield 5.9g, 80.9%).
Embodiment 105b
Preparation midbody 2-cyclopropyl-propenal
Figure G2007800087501D01832
M.W.96.13?C 6H 8O
With with the similar mode of method described in the embodiment 102c, (5.95g is 60.7mmol) with oxalyl chloride (8.48g for the 2-cyclopropyl that will in embodiment 105a, prepare-third-2-alkene-1-alcohol; 60.7mmol), methyl-sulphoxide (9.47mL, 133.5mmol) and triethylamine (30.4mL; 218mmol) in methylene dichloride, react; Obtain 2-cyclopropyl-propenal, be yellow oil (yield: 4.8g, 345%).
Embodiment 105c
Preparation midbody 1-(1-cyclopropyl-vinyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01841
M.W.209.37?C 11H 19NOSi
With with the similar mode of method described in the embodiment 1b, (1.0g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-cyclopropyl-propenal that will in embodiment 105b, prepare, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol); Just-and butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL; 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction; Obtain 1-(1-cyclopropyl-vinyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 105d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclopropyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.427.33?C 23H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.35g; 0.90mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(1-cyclopropyl-vinyl)-3-front three that in embodiment 105c, prepares, react in methylene dichloride with trifluoroacetic acid (20mL) then; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclopropyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid.
HRMS (ES +) m/z calculated value C 23H 20Cl 2N 2O 2+ H [(M+H) +]: 427.0975 measured values: 427.0973.
Embodiment 106
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-hydroxycarbonyl group methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01851
M.W.473.36?C 24H 22Cl 2N 2O 4
With with embodiment 81b, the similar mode of the method described in the 81c, racemize (2 ' R, the 3R that will in embodiment 97a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (7g, 12.8mmol) reaction forms racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-hydroxycarbonyl group methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (3.6g, 59%).
HRMS (ES +) m/z calculated value C 24H 22Cl 2N 2O 4+ H [(M+H) +]: 473.1030 measured values: 473.1032.
Embodiment 107a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01852
M.W.475.35?C 24H 21Cl 2FN 2O 3
With with the similar mode of method described in the embodiment 82a, racemize (2 ' R, the 3R that will in embodiment 166, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-hydroxycarbonyl group methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (1.2g; 2.5mmol) reaction, to form racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 1.1g, 92%).
Embodiment 107b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[(1-methylsulfonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.633.60?C 30H 34Cl 2N 4O 5S
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 107a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g; 0.21mmol) and 1-methylsulfonyl-piperidines-4-amine trifluoroacetate (0.2g, 0.34mmol), N-methylmorpholine (0.2g; 2mmol) and 4-dimethylaminopyridine (1mg) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[(1-methylsulfonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield 58mg, 44%).
HRMS (ES +) m/z calculated value C 30H 34Cl 2N 4O 5S+H [(M+H) +]: 633.1700.Measured value: 633.1701.
Embodiment 108a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01862
M.W.472.38?C 24H 23Cl 2N 3O 3
In room temperature; The racemize that will in embodiment 107a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; (0.1g, 0.21mmol) (7N stirs 18h in 10mL) to 6 ' (1H)-diketone at the methanol solution of ammonia.Reaction mixture is concentrated, and with residuum by chromatogram (EtOAc:MeOH=10:1) purifying, obtain racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be yellow solid (yield 41mg, 40%).
HRMS (ES +) m/z calculated value C 24H 23Cl 2N 3O 3+ Na [(M+Na) +]: 494.1008 measured values: 494.1008
Embodiment 108b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01871
M.W.472.38?C 24H 23Cl 2N 3O 3
Through chirality SFC, carry out from racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (32mg) in the separation of two kinds of enantiomers; So that chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3 to be provided; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield: 9mg; 28%) and chirality (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 9mg, 28%).
Embodiment 109a
Preparation midbody 2-ethyl-3-methyl-but-2-ene acetoacetic ester
Figure G2007800087501D01872
M.W.156.23?C 9H 16O 2
With with the similar mode of method described in the embodiment 102a, with 2-HPBA triethyl (25.2g, 0.1mol) with NaH (2.64g; 0.11mol) reaction; (5.8g 0.1mol) reacts in glycol dimethyl ether, obtains 2-ethyl-3-methyl-but-2-ene acetoacetic ester with acetone then; Be colorless oil (yield: 11.4g, 73%).
Embodiment 109b
Preparation midbody 2-ethyl-3-methyl-but-2-ene-1-alcohol
Figure G2007800087501D01881
M.W.114.19?C 7H 14O
With with the similar mode of method described in the embodiment 102b, the 2-ethyl that will in embodiment 109a, prepare-3-methyl-but-2-ene acetoacetic ester (11.4g, 73mmol) with LAH (1M; In ether; 73mL 73mmol) reacts in diethyl ether, obtains 2-ethyl-3-methyl-but-2-ene-1-alcohol; Be colorless oil (yield: 7.62g, 91.5%).
Embodiment 109c
Preparation midbody 2-ethyl-3-methyl-but-2-ene aldehyde
M.W.112.17?C 7H 12O
With with the similar mode of method described in the embodiment 102c, (7.62g is 66.8mmol) with oxalyl chloride (9.3g for the 2-ethyl-3-methyl-but-2-ene that will in embodiment 109b, prepare-1-alcohol; 73.5mmol), methyl-sulphoxide (10.44mL, 146.9mmol) and triethylamine (33.4mL; 240mmol) in methylene dichloride, react; Obtain 2-ethyl-3-methyl-but-2-ene aldehyde, be yellow oil (yield: 7.5g, 99%).
Embodiment 109d
Preparation midbody 1-(1-ethyl-2-methyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01891
M.W.225.41?C 12H 23NOSi
With with the similar mode of method described in the embodiment 1b, (1.18g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-ethyl that will in embodiment 109c, prepare-3-methyl-but-2-ene aldehyde, with 1; 1,1,3,3; The 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL; 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL; 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction obtains 1-(1-ethyl-2-methyl-propenyl)-3-front three for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 109e
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01892
M.W.443.38?C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.35g; 0.89mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(1-ethyl-2-methyl-propenyl)-3-front three that in embodiment 109d, prepares, react in methylene dichloride with trifluoroacetic acid (20mL) then; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid.
HRMS (ES +) m/z calculated value C 24H 24Cl 2N 2O 2+ H [(M+H) +]: 443.1288 measured values: 443.1287.
Embodiment 110a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01901
M.W.533.36?C 26H 20Cl 2F 2N 2O 4
In-78 ℃, to the racemize that in embodiment 101d, prepares (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; (0.12g 0.22mmol) in the suspension-s in methylene dichloride (5mL), drips boron tribromide (1M to 6 ' (1H)-diketone; 2.19ml, 2.19mmol).Reactant little by little is warmed to room temperature, and in stirring at room 2h.Then rough thing is diluted with methylene dichloride.With the organic layer water, brine wash is used MgSO 4Drying is filtered, and concentrates.Residuum with chromatogram (EtOAc) purifying, is obtained racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 46mg, 39.3%).
HRMS (ES +) m/z calculated value C 26H 20Cl 2F 2N 2O 4+ H [(M+H) +]: 533.0841.Measured value: 533.0842.
Embodiment 110b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01902
M.W.533.36?C 26H 20Cl 2F 2N 2O 4
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2; 3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] separation of two kinds of enantiomers in spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (70mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 30mg, 42.8%) and chirality (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 20mg, 28.5%).
Embodiment 111
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-hydroxyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01911
M.W.489.31?C 24H 16Cl 2F 2N 2O 4
Racemize in embodiment 110a (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2; 3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2, in the preparation of 6 ' (1H)-diketone; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2 as by product; 3-two fluoro-6-hydroxyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
HRMS (ES +) m/z calculated value C 24H 16Cl 2F 2N 2O 4+ H [(M+H) +]: 489.0579.Measured value: 489.0580.
Embodiment 112
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-1-hydroxyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01912
M.W.447.37?C 23H 24Cl 2N 2O 3
In-78 ℃, to racemize (2 ' R, the 3R of preparation in embodiment 103; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-propionyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H) diketone (100mg; 0.24mmol) in the solution in THF (3mL); The tetrahydrofuran solution of adding magnesium ethide chlorine (2M, 6mL, 12mmol).Reaction mixture in-78 ℃ of stirring 0.5h, is warmed to room temperature then at leisure, and stirs 2h.Mixture is poured into saturated NH 4In the Cl aqueous solution, and mixture used ethyl acetate extraction.Organic layer is separated, use MgSO 4Drying concentrates.Residuum by chromatogram (EtOAc:MeOH=10:1) purifying, is obtained racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-1-hydroxyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 100mg, 93%)
HRMS (ES +) m/z calculated value C 23H 24Cl 2N 2O 3+ H [(M+H) +]: 447.1237.Measured value: 447.1237.
Embodiment 113a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle)-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
M.W.575.61?C 29H 36Cl 2N 2O 4Si
To the racemize that in embodiment 81a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-ethyl-propenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (1.2g; 2.1mmol) in the solution in methylene dichloride (50mL); Between adding-chloroperoxybenzoic acid (77%, 8.9g) and NaHCO 3(2g).Reaction mixture in stirring at room 18h, is poured into Na 2SO 3In the aqueous solution, use ethyl acetate extraction then.Organic layer is separated, use Na 2SO 4Drying concentrates.(EtOAc: the purifying of hexane=1:1) obtains racemize (2 ' R, 3R by chromatogram with residuum; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be white foam (yield, 1.0g, 82%).
Embodiment 113b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01931
M.W.445.35?C 23H 22Cl 2N 2O 3
With with the similar mode of method described in embodiment 56b and the 56c, the racemize that will in embodiment 113a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.19g; 0.33mmol) reaction, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield, 0.42g, 29%)
HRMS (ES +) m/z calculated value C 23H 22Cl 2N 2O 3+ H [(M+H) +]: 445.1080.Measured value: 445.1081.
Embodiment 114a
Preparation midbody 2-fluoro-3-methyl-but-2-ene acetoacetic ester
Figure G2007800087501D01932
M.W.146.16?C 7H 11FO 2
In 0 ℃, (20g, 82.6mmol) (Aldrich) is added drop-wise to sodium hydride (3.6g is 90.8mmol) in the stirred solution in glycol dimethyl ether (100mL) with 2-fluoro-2-phosphine acyl acetic acid three ethyl.Behind stirring at room 20min, (4.78g 82.6mmol), spends the night reaction mixture refluxed to add acetone.With the two-phase mixture cooling, dilute with water, and use extracted with diethyl ether.The organic layer that merges is used MgSO 4Drying is filtered, and concentrates.Residuum by chromatogram (hexane) purifying, is obtained 2-fluoro-3-methyl-but-2-ene acetoacetic ester, be colorless oil (yield: 9.0g, 61.6%).
Embodiment 114b
Preparation midbody 2-fluoro-3-methyl-but-2-ene-1-alcohol
M.W.104.14?C 5H 9FO
With 2-fluoro-3-methyl-but-2-ene acetoacetic ester (9.0g, 61.6mmol) drips of solution in ether (100mL) be added to LAH stirred solution (1M, in ether, 61.6mL, 67.7mmol) in.Behind stirring at room 30min, will react to mix and use saturated NH 4Extracted with diethyl ether is used in the quencher of Cl solution.Organic layer is merged, water, brine wash is used MgSO 4Drying and filtration.Remove and desolvate, obtain 2-fluoro-3-methyl-but-2-ene-1-alcohol, be colorless oil (yield: 5.21g, 81.3%).
Embodiment 114c
Preparation midbody 2-fluoro-3-methyl-but-2-ene aldehyde
Figure G2007800087501D01942
M.W.102.11?C 5H 7FO
In-78 ℃, (6.98g 50mmol) in (Aldrich) solution in methylene dichloride (50mL), drips methyl-sulphoxide (7.80mL, 110mmol) solution in methylene dichloride to oxalyl chloride.Behind the 5min, drip 2-fluoro-3-methyl-but-2-ene-1-alcohol (5.21g, 50mmol) solution in methylene dichloride (10mL) that in embodiment 114b, prepares.Reaction mixture is stirred 15min in-78 ℃.(25mL 0.18mol), and is warmed to room temperature with reaction mixture at leisure, and in stirring at room 45min to add triethylamine.Add entry.Organic layer is separated, merge, use 10%HCl, saturated NaHCO 3, brine wash is used MgSO 4Drying is filtered, and concentrates, and obtains 2-fluoro-3-methyl-but-2-ene aldehyde, is yellow liquid (yield: 4.02g, 82.4%).
Embodiment 114d
Preparation midbody 1-(1-fluoro-2-methyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D01951
M.W.215.35?C 10H 18FNOSi
With with the similar mode of method described in the embodiment 1b, (2.14g 21mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-fluoro-3-methyl-but-2-ene aldehyde that will in embodiment 114c, prepare, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (4.36mL, 21mmol); Just-and butyllithium (2.5M, 8.4mL, 21mmol), trimethylsilyl chloride (2.66mL; 21mmol), triethylamine (3.8mL, 27.2mmol) and Acetyl Chloride 98Min. (1.94mL, 27.2mmol) reaction; Obtain 1-(1-fluoro-2-methyl-propenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 114e
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-fluoro-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.433.31?C 22H 19Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (1.0g; 2.56mmol) react in toluene for siloxy--2-azepine-1,3-butadiene, react in methylene dichloride with trifluoroacetic acid (20mL) then with 1-(1-fluoro-2-methyl-propenyl)-3-front three that in embodiment 114e, prepares; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-fluoro-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid.
HRMS (ES +) m/z calculated value C 22H 19Cl 2FN 2O 2+ H [(M+H) +]: 433.0881 measured values: 433.0879.
Embodiment 115
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-isobutyryl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01961
M.W.431.32?C 22H 20Cl 2N 2O 3
With with the similar mode of method described in the embodiment 103, racemize (2 ' R, the 3R that will in embodiment 139d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-methyl isophthalic acid-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.2g; 0.47mmol) reaction, to form racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-isobutyryl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield, 0.13g, 66%).
HRMS (ES +) m/z calculated value C 22H 20Cl 2N 2O 3+ H [(M+H) +]: 431.0924.Measured value: 431.0925.
Embodiment 116a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01962
M.W.531.56?C 27H 32Cl 2N 2O 3Si
With with the similar mode of method described in the embodiment 55b, the E/Z-6-chloro-3-that will in embodiment 55a, prepare (3-chlorine tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1,3-dihydro-indol-2-one (8g; 20mmol) (21g 99mmol) reacts in toluene (200mL) for siloxy--2-azepine-1,3-butadiene with the 1-pseudoallyl-3-front three that in embodiment 87a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be white size (3.5g, 33%)
Embodiment 116b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D01971
M.W.645.71?C 33H 42Cl 2N 2O 5Si
With with the similar mode of method described in the embodiment 55c, racemize (2 ' R, the 3R that will in embodiment 116a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (3g, 5.64mmol) with bromo-tert.-butyl acetate and cesium carbonate at N, react in N-dimethyl--methane amide; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be white foam (yield: 2.98g, 79%).
Embodiment 116c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01981
M.W.459.33?C 23H 22Cl 2N 2O 4
With with the similar mode of method described in the embodiment 55d, the racemize that will in embodiment 116b, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (2.88g; 4.46mmol) react with trifluoroacetic acid, with ethyl-di-isopropyl-amine reaction, obtain racemize (2 ' R then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is yellow oil (yield 1.7g, 85.8%).
Embodiment 116d
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01982
M.W.461.32?C 23H 19Cl 2FN 2O 3
With with the similar mode of method described in the embodiment 34a, racemize (2 ' R, the 3R that will in embodiment 116c, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1-[hydroxycarbonyl group-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.42g; 0.91mmol) and cyanuric fluoride (0.31mL, 2.01mmol) (0.14g 1.82mmol) reacts in methylene dichloride for (Alfa) and pyridine; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (yield: 0.38g, 90%).
Embodiment 116e
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-(aminocarboxyl-methyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.458.35?C 23H 21Cl 2N 3O 3
(2M 10mL) in the solution in methyl alcohol, is added in the racemize (2 ' R for preparing among the embodiment 116d to ammonia; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (0.18g, 0.39mmol).With reaction mixture in stirred overnight at room temperature.Except that desolvating and residuum being distributed between ETHYLE ACETATE and water.Organic layer is separated merging and concentrated.With residuum with chromatogram (MeOH:EtOAc=5:95) purifying; Obtain racemize (2 ' R, 3R, 4 ' S)-1 '-(aminocarboxyl-methyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 70mg, 38.9%).
HRMS (ES +) m/z calculated value C 23H 21Cl 2N 3O 3+ H [(M+H) +]: 458.1033.Measured value: 458.1033.
Embodiment 117
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(cyclopropyl aminocarboxyl-methyl)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D01992
M.W.498.41?C 26H 25Cl 2N 3O 3
With with the similar mode of method described in the embodiment 34b, the racemize that will in embodiment 116d, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3; 3 '-piperidines] (0.2g is 0.433mmol) with 2-amino-2-methyl-third-1-alcohol (49mg for-2,6 ' (1H)-diketone; 0.86mmol), N-methylmorpholine (90mg, 0.86mmol) and 4-dimethylaminopyridine (5mg) in THF, react; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4;-(3-chloro-phenyl-)-1 ,-(cyclopropyl aminocarboxyl-methyl)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield: 80mg, 38%).
HRMS (ES +) m/z calculated value C 26H 25Cl 2N 3O 3+ H [(M+H) +]: 498.1346 measured values: 498.1345.
Embodiment 118
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02001
M.W.555.51?C 29H 32Cl 2N 4O 3
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 116d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.2g; 0.433mmol) and 1-methyl-piperidin-4-yl amine (0.134mg, 0.95mmol), N-methylmorpholine (99mg; 0.95mmol) and 4-dimethylaminopyridine (5mg) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield: 75mg, 31.2%).
HRMS (ES +) m/z calculated value C 29H 32Cl 2N 4O 3+ H [(M+H) +]: 555.1924 measured values: 555.1925.
Embodiment 119
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl sulphonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02002
M.W.619.57?C 29H 32Cl 2N 4O 5S
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 116d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.2g; 0.433mmol) and 1-methyl sulphonyl-piperidin-4-yl-amine (0.15g, 0.86mmol), N-methylmorpholine (90mg; 0.86mmol) and 4-dimethylaminopyridine (5mg) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl sulphonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield: 92mg, 38.3%).
HRMS (ES +) m/z calculated value C 29H 32Cl 2N 4O 5S+H [(M+H) +]: 619.1543 measured values: 619.1541.
Embodiment 120
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02011
M.W.502.40?C 25H 25Cl 2N 3O 4
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 116d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.2g; 0.433mmol) and 2-amino-ethanol (61mg, 0.86mmol), N-methylmorpholine (90mg; 0.86mmol) and 4-dimethylaminopyridine (5mg) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be pale solid (yield: 80mg, 36.8%).
HRMS (ES +) m/z calculated value C 25H 25Cl 2N 3O 4+ H [(M+H) +]: 502.1295 measured values: 502.1296.
Embodiment 121
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-1,1-dimethyl--ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.530.46?C 27H 29Cl 2N 3O 4
With with the similar mode of method described in the embodiment 34b, racemize (2 ' R, the 3R that will in embodiment 116d, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.18g; 0.39mmol) and 2-amino-2-methyl-third-1-alcohol (69mg, 0.78mmol), N-methylmorpholine (81mg; 0.78mmol) and 4-dimethylaminopyridine (5mg) in THF, react, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-1,1-dimethyl--ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (yield: 74mg, 35.9%).
HRMS (ES +) m/z calculated value C 27H 29Cl 2N 3O 4+ H [(M+H) +]: 502.1295 measured values: 502.1296.
Embodiment 122a
Preparation midbody Z-(6-chloro-2-oxo-1,2-dihydro-indoles-3-subunit)-(3-chloro-phenyl)-acetonitrile
Figure G2007800087501D02022
M.W.315.16?C 16H 8Cl 2N 2O
(1.8g, 12mmol) (1.81g, 10mmol) (TCI-US) mixture in ethanol (40mL) add DBU (1.9g, 12.5mmol) (Aldrich) for (Aldrich) and 6-chlorine isotin to 3-chlorine Bian Jiqing.Reaction mixture is heated 1h in 100 ℃.The TCL analysis revealed: the E-of required product and Z-mixture of isomers form and raw material almost completely consumes.Mixture is cooled to room temperature, is concentrated into small volume, then with the ether dilution, with rare HCl solution washing.Organic layer is separated, use Na 2SO 4Drying concentrates, and by chromatogram (EtOAc: the purifying of hexane=1:2), obtain Z-(6-chloro-2-oxo-1,2-dihydro-indoles-3-subunit)-(3-chloro-phenyl)-acetonitrile of needing, be orange solids (0.9g, 29%).Also obtain another isomer E-(6-chloro-2-oxo-1,2-dihydro-indoles-3-subunit)-(3-chloro-phenyl)-acetonitrile, be orange solids (0.9g, 29%).
Embodiment 122b
Preparation midbody Z-6-chloro-3-[(3-chloro-phenyl)-cyanic acid-methylene radical]-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02031
M.W.415.28?C 21H 16Cl 2N 2O 3
With with the similar mode of method described in the embodiment 24a, with Z-(6-chloro-2-oxo-1,2-dihydro-indoles-3-subunit)-(3-chloro-phenyl)-acetonitrile (0.4g; 1.3mmol) and tert-Butyl dicarbonate (1.9g; 8.6mmol) (Aldrich), triethylamine (0.87g, 8.6mmol) and 4-dimethylaminopyridine (5mg) in methylene dichloride (100mL), react; Obtain Z-6-chloro-3-[(3-chloro-phenyl)-cyanic acid-methylene radical]-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester is yellow solid (yield: 0.3g, 56%).
Embodiment 122c
Preparation racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl)-4 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.440.33?C 23H 19Cl 2N 3O 2
With with the similar mode of method described in the embodiment 41b, the Z-6-chloro-3-that will in embodiment 122b, prepare [(3-chloro-phenyl)-cyanic acid-methylene radical]-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g; 0.72mmol) (2g 10mmol) reacts in toluene for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-propyl group)-3-front three that in embodiment 80a, prepares; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl)-4 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is pale solid (0.1g, 31%).
HRMS (ES +) m/z calculated value C 23H 19Cl 2N 3O 2+ H [(M+H) +]: 440.0927.Measured value: 440.0927.
Embodiment 123a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-pseudoallyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02041
M.W.608.09?C 30H 37Cl 3N 2O 3Si
With with the similar mode of method described in the embodiment 24c, the racemize that will in embodiment 116a, prepare (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-pseudoallyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (1.57g; 2.95mmol) and LiH (2.3g, 29.5mmol) (6.04g is 29.5mmol) at N with 1-chloro-3-iodo-propane; Reaction obtains racemize (2 ' R, 3R in N-dimethyl--methane amide (100mL); 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-pseudoallyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane, be white foam (yield: 0.6g, 33.5%).
Embodiment 123b
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-acetylamino-piperidines-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone
M.W.583.56?C 31H 36Cl 2N 4O 3
With with the similar mode of method described in the embodiment 60b, (2 ' R, 3R, 4 ' the S)-6-chloro-4 ' that will in embodiment 123a, prepare-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-pseudoallyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.12g; 0.20mmol) and N-piperidin-4-yl-ethanamide (0.56g, 4mmol), trifluoroacetic acid (2mL) reaction; With N, N '-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-1 '-[3-(4-acetylamino-piperidines-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2; 6 ' (1H)-diketone is brown solid (yield: 47mg, 40.8%).
HRMS (ES +) m/z calculated value C 31H 36Cl 2N 4O 3+ H [(M+H) +]: 583.2237 measured values: 583.2239.
Embodiment 124a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02052
M.W.280.72?C 16H 9ClN 2O
With with the similar mode of method described in the embodiment 1a, with 6-cyanic acid oxindole (1g, 6.44mmol) (Combi-blocks) and 3-chloro-phenyl aldehyde (0.73mL; 6.44mmol) (Aldrich) and piperidines (0.635mL; 6.44mmol) in methyl alcohol, react, obtain E-and Z-6-cyanic acid-3-(3-chloro-tolylene)-1, the mixture of 3-dihydro-indol-2-one; Be brown solid (yield: 1.34g, 74.4%).
Embodiment 124b
Preparation intermediate E/Z-6-cyanic acid-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02061
M.W.380.83?C 21H 17ClN 2O 3
With with the similar mode of method described in the embodiment 24a, with E/Z-6-chloro-3-(3-chloro-tolylene)-1,3-dihydro-indol-2-one (1.34g; 4.77mmol) and tert-Butyl dicarbonate (1.91g; 8.73mmol) (Aldrich), triethylamine (3.29mL, 23.6mmol) and 4-dimethylaminopyridine (25mg) in methylene dichloride (100mL), react; Obtain E/Z-6-cyanic acid-3-(3-chloro-tolylene)-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester is yellow solid (yield: 1.7g, 93.4%).
Embodiment 124c
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02062
M.W.405.89?C 23H 20ClFN 3O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-cyanic acid-3-that will in embodiment 124b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.05mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(1-methylene radical-propyl group)-3-front three that in embodiment 80a, prepares, react in methylene dichloride with trifluoroacetic acid (20mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield: 90mg, 21.1%).
HRMS (ES +) m/z calculated value C 23H 20ClFN 3O 2+ H [(M+H) +]: 406.1317 measured values: 406.1316.
Embodiment 125
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6-cyanic acid-2 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02071
M.W.459.91?C 26H 19ClFN 3O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-cyanic acid-3-that will in embodiment 124b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g; 1.05mmol) with 1-(5-fluoro-2-methyl-phenyl)-3-front three of in embodiment 36a, preparing for siloxy--2-azepine-1; The 3-divinyl reacts in toluene, reacts in methylene dichloride with trifluoroacetic acid (20mL) then, obtains racemize (2 ' R; 3R; 4 ' S)-4 '-(3-chloro-phenyl)-6 '-cyanic acid-2 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be yellow solid (yield: 0.12g, 16.9%).
HRMS (ES +) m/z calculated value C 26H 19ClFN 3O 2+ H [(M+H) +]: 460.1223.Measured value: 460.1223.
Embodiment 126
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.569.54?C 30H 34Cl 2N 4O 3
With with the similar mode of method described in the embodiment 60b, (2 ' R, 3R, 4 ' the S)-6-chloro-4 ' that will in embodiment 123a, prepare-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-pseudoallyl-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.2g; 0.20mmol) and 1-piperazine-1-base-ethyl ketone (0.51g, 4mmol), trifluoroacetic acid (2mL) reaction; With N, N '-diisopropylethylamine (2mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield: 95mg, 50.8%).
HRMS (ES +) m/z calculated value C 30H 34Cl 2N 4O 3+ H [(M+H) +]: 569.2081 measured values: 569.2079.
Embodiment 127
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-(3-piperidines-1-base-propyl group) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02081
M.W.526.51?C 29H 33Cl 2N 3O 2
With with the similar mode of method described in the embodiment 60b, (2 ' R, the 3R that will in embodiment 123a, prepare; 4 ' S)-and 6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-chloro-propyl group)-2 '-pseudoallyl-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.12g, 0.20mmol) with piperidines (2mL), trifluoroacetic acid (1mL) reaction; With N, N '-diisopropylethylamine (1.5mL) reaction obtains racemize (2 ' R then; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-(3-piperidines-1-base-propyl group) spiral shell [3H-indoles-3,3 ' piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield: 40mg, 23.1%).
HRMS (ES +) m/z calculated value C 29H 33Cl 2N 3O 2+ H [(M+H) +]: 526.2023 measured values: 526.2020.
Embodiment 128a
Preparation midbody acetate 2-(2-formyl radical-4-methyl-phenoxy)-ethyl ester
Figure G2007800087501D02091
M.W.222.24?C 12H 14O 4
To 2-hydroxy-5-methyl base-phenyl aldehyde (2.4g, 18mmol) (Aldrich) at N, in the solution in the dinethylformamide (30mL), add cesium carbonate (6g, 18mmol), potassiumiodide (3g, 18mmol) with acetate 2-bromine ethyl ester (7g, 42mmol), Aldrich).Reaction mixture is heated 3h in 100 ℃.Mixture is cooled to room temperature, and with the ether dilution, water, brine wash is separated, and concentrates.With residuum by chromatogram (EtOAc: purifying hexane=1: 6), obtain acetate 2-(2-formyl radical-4-methyl-phenoxy)-ethyl ester, be yellow oil (yield 4g, 100%).
Embodiment 128b
Preparation midbody 1-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02092
M.W.335.48?C 17H 25NO 4Si
With with the similar mode of method described in the embodiment 1b, (2.5g is 11mmol) with 1,1,1 for the acetate 2-that will in embodiment 128a, prepare (2-formyl radical-4-methyl-phenoxy)-ethyl ester; 3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol); Just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction; Obtain 1-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow oil, and under situation about not being further purified, be used for next step.
Embodiment 128c
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02101
M.W.553.45?C 29H 26Cl 2N 2O 5
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g; 1.28mmol) with in embodiment 128b, prepare 1-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-(2g 6mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.2g, 28%).
HRMS (ES +) m/z calculated value C 29H 26Cl 2N 2O 5+ H [(M+H) +]: 553.1292.Measured value: 553.1291.
Embodiment 129
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[6-(2-hydroxyl-oxyethyl group)-3-methyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02102
M.W.511.41?C 27H 24Cl 2N 2O 4
To the racemize that in embodiment 128c, prepares (2 ' R; 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (0.16g; 0.29mmol) in the solution in THF (30mL) and methyl alcohol (10mL), add aqueous sodium hydroxide solution (1N, 10mL).Reaction mixture in stirring at room 3h, is neutralized to " pH " 7 with the HCl aqueous solution then.Then mixture is used ethyl acetate extraction.Organic layer is separated, concentrate, and by chromatogram (EtOAc:MeOH=19:1) purifying; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(2-hydroxyl-oxyethyl group)-5-methyl-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (70mg, 47%)
HRMS (ES +) m/z calculated value C 27H 24Cl 2N 2O 4+ H [(M+H) +]: 511.1186.Measured value: 511.1185.
Embodiment 130a
Preparation midbody 5-bromo-2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl aldehyde
Figure G2007800087501D02111
M.W.359.34?C 15H 23BrO 2Si
(14g, 69.6mmol) (Aldrich) in the solution in the dinethylformamide (300mL), adds K at N to 5-bromo-2-hydroxyl-phenyl aldehyde 2CO 3(29g is 208.9mmo) with (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl--silane (20g, 83.5mmol) (Aldrich).Reaction mixture is stirred 16h in 60 ℃.Reaction mixture is cooled to room temperature, and topples in the entry, use ethyl acetate extraction.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates, and obtains 5-bromo-2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl aldehyde, is brown oil (yield: 25g, 100%).
Embodiment 130b
Preparation midbody 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl aldehyde
M.W.320.51?C 18H 28CO 3Si
To the 5-bromo-2-that in embodiment 130a, prepares [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl aldehyde (5g; 13.9mmol) in the solution in toluene (75mL) and water (7.5mL); Add cyclopropylboronic acid (1.7g; 19.8mmol) (Aldrich) and potassiumphosphate (14.6g, 68.9mmol).Behind 5min that reaction mixture is outgased, add two chloro-two-(thricyclohexyl-phosphine) (1.03g, 1.39mmol) (Strem), and under nitrogen, with reaction mixture in 100 ℃ of heating 4h.Reaction mixture is cooled to room temperature, and dilute with water, ethyl acetate extraction used.Organic layer is merged, water, brine wash, dry with MgSO4, filter, and concentrate.Residuum is used chromatogram purification, obtain 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl aldehyde, be yellow oil (yield: 3.2g, 76.2%).
Embodiment 130c
Preparation midbody 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl }-the 3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.433.74?C 23H 39NO 3Si 2
With with the similar mode of method described in the embodiment 1b, (3.36g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-that will in embodiment 130b, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl aldehyde, with 1; 1,1,3,3; The 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL; 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL; 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction obtains 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl }-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 130d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-cyclopropyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02131
M.W.537.45?C 29H 26Cl 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g; 1.28mmol) with 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-cyclopropyl-phenyl of in embodiment 130c, preparing-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl reacts in toluene, reacts in methylene dichloride with trifluoroacetic acid (20mL) then, obtains racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-cyclopropyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.14g, 20.3%).
HRMS (ES +) m/z calculated value C 29H 26Cl 2N 2O 4+ H [(M+H) +]: 537.1343 measured values: 537.1343.
Embodiment 131a
Preparation midbody 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl aldehyde
Figure G2007800087501D02132
M.W.314.89?C 15H 23ClO 3Si
To the 5-chloro-salicylic aldehyde (5g, 32mmol) (Aldrich) at N, in the solution in the dinethylformamide (40mL), add salt of wormwood (20g, 145mmo) with (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl--silane (10g, 42mmol, Aldrich).With 60 ℃ of heating of reaction mixture eyeball 18h.Rough thing is cooled to room temperature, with ETHYLE ACETATE dilution, water, brine wash.Organic layer is separated, concentrates, and with residuum by chromatogram (EtOAc: hexane=1:8,1:4 then) purifying, obtain 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl aldehyde, be white solid (yield 10g, 99%).
Embodiment 131b
Preparation midbody 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02141
M.W.428.12?C 20H 34ClNO 3Si 2
With with the similar mode of method described in the embodiment 1b, (5.2g is 17mmol) with 1,1 for the 2-that will in embodiment 131a, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl aldehyde; 1,3,3,3-hexamethyldisilazane (2.4g; 15mmol), just-butyllithium (2.5M, 6mL, 15mmol); Trimethylsilyl chloride (1.6g, 15mmol), triethylamine (1.6g; 20mmol) and Acetyl Chloride 98Min. (1.5g, 20mmol) reaction obtains 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl]-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl is yellow oil, and under situation about not being further purified, is used for next step.
Embodiment 131c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02142
M.W.531.83?C 26H 21Cl 3N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.6g; 1.5mmol) with 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl of in embodiment 131b, preparing]-(5.2g 12mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.25g, 31%).
HRMS (ES +) m/z calculated value C 26H 21Cl 3N 2O 4+ H [(M+H) +]: 531.0640.Measured value: 531.0640.
Embodiment 132a
The preparation midbody tertiary butyl-[2-(4-chloro-3-fluoro-phenoxy)-oxyethyl group]-dimethyl--silane
Figure G2007800087501D02151
M.W.304.87?C 14H 22ClFO 2Si
(10g is 68mmol) at N, in the solution in the dinethylformamide (50mL) to 4-chloro-3-fluoro-phenol; Adding salt of wormwood (19g, 136mmol), potassiumiodide (11g; 68mmol) with (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl--silane (18g, 75mmol, Aldrich).Reaction mixture is heated 24h in 100 ℃.With rough thing cooling, with ether dilution, water, NaHCO 3Solution, and brine wash.Organic layer is separated, use Na 2SO 4Drying, and concentrate.To filtrate concentrate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:20), obtain the tertiary butyl-[2-(4-chloro-3-fluoro-phenoxy)-oxyethyl group]-dimethyl--silane, be colorless oil (yield 14g, 69%).
Embodiment 132b
Preparation midbody 6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-3-chloro-2-fluoro-phenyl aldehyde
Figure G2007800087501D02152
M.W.332.88?C 15H 22ClFO 2Si
With with the similar mode of method described in the embodiment 52a, the tertiary butyl that will in embodiment 132a, prepare-[2-(4-chloro-3-fluoro-phenoxy)-oxyethyl group]-dimethyl--silane (14.3g, 47mmol) with lithium diisopropylamine (34mL; 1.8M, in THF, 61mmol); N, N-dimethyl--methane amide (4.7mL, 61mmol) reaction; And (14g, 234mmol) quencher obtain 6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-3-chloro-2-fluoro-phenyl aldehyde to be used in acetate in the THF; Be white solid (yield: 6.4g, 41%).
Embodiment 132c
Preparation midbody 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group-3-chloro-2-fluoro-phenyl]-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02161
M.W.446.11?C 20H 33C 1FNO 3Si 2
With with the similar mode of method described in the embodiment 1b, (3.3g is 10mmol) with 1,1 for the 6-that will in embodiment 132b, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-3-chloro-2-fluoro-phenyl aldehyde; 1,3,3,3-hexamethyldisilazane (1.6g; 10mmol), just-butyllithium (2.5M, 4mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g; 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group-3-chloro-2-fluoro-phenyl]-3-front three for siloxy--2-azepine-1; The 3-divinyl is orange, and under situation about not being further purified, is used for next step.
Embodiment 132d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02162
M.W.549.82?C 26H 20Cl 3FN 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g; 1.28mmol) with in embodiment 132c, prepare 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group-phenyl]-(3g 6.7mmol) reacts in toluene the 3-front three for siloxy--2-azepine-1,3-butadiene; React in methylene dichloride with trifluoroacetic acid (10mL) then; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (0.28g, 40%).
HRMS (ES +) m/z calculated value C 26H 20Cl 3FN 2O 4+ H [(M+H) +]: 549.0546 measured values: 549.0545.
Embodiment 133a
Preparation intermediate E/Z-6-chloro-3-(3,5-two fluoro-tolylenes)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02171
M.W.421.95?C 21H 22ClF 2NO 2Si
With with embodiment 4a, the similar mode of the method described in the 55a is with replacing 3 of 3-chlorobenzaldehyde; (0.89g 6.27mmol) with two-step reaction, obtains E/Z-6-chloro-3-(3 to 5-two fluoro-phenyl aldehydes; 5-two fluoro-tolylenes)-1-(2-trimethyl silyl-ethoxyl methyl)-1; The 3-dihydro-indol-2-one is yellow oil (1.25g is 50% for two steps).
Embodiment 133b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02181
M.W.416.86?C 22H 19ClF 2N 2O 2
With with embodiment 97a, the similar mode of the method described in the 55d, the E/Z-6-chloro-3-(3 that will in embodiment 133a, prepare; 5-two fluoro-tolylenes)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one (0.21g, 0.5mmol) with 1-(1-methylene radical-propyl group)-3-front three of in embodiment 80a, preparing for siloxy--2-azepine-1; (1g 5.25mmol) reacts in toluene the 3-divinyl, and the trifluoroacetic acid (5ml) that is used in then in the methylene dichloride is handled; The diisopropylethylamine (1mL) that then is used in the methyl alcohol is handled, and obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (35mg is 18% for two steps).
HRMS (ES+) m/z calculated value C 22H 19ClN 2O 2F 2+ H [(M+H) +]: 417.1176; Measured value: 417.1177
Embodiment 134a
Preparation intermediate E/Z-3-(6-chloro-2-oxo-1,2-dihydro-indoles-3-ylidenylmethyl)-benzonitrile
M.W.280.72?C 16H 9ClN 2O
With with the similar mode of method described in the embodiment 1a, use 3-formyl radical-benzonitrile to replace the 3-chlorobenzaldehyde, to form E/Z-3-(6-chloro-2-oxo-1,2-dihydro-indoles-3-ylidenylmethyl)-benzonitrile, be yellow solid.
Embodiment 134b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-cyanic acid-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02191
M.W.405.89?C 23H 20ClN 3O 2
In ST; The E/Z-3-that will in embodiment 134a, prepare (6-chloro-2-oxo-1; 2-dihydro-indoles-3-ylidenylmethyl)-benzonitrile (280mg, 1mmol) with 1-(1-methylene radical-propyl group)-3-front three of prepared fresh in embodiment 80a for siloxy--2-azepine-1,3-butadiene (2.06g; 10.5mmol) in toluene (20mL), in 135 ℃ of heating 1h, be cooled to room temperature then.Add methyl alcohol (80mL), and mixture is filtered through short Celite pad.To filtrate concentrates, and residuum by chromatogram (EtOAc) purifying, is obtained racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-cyanic acid-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is solid (180mg, 35%).
HRMS (ES+) m/z calculated value C 23H 20ClN 3O 2+ H [(M+H)]: 406.1317; Measured value: 406.1315
Embodiment 135
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02192
M.W.459.77?C 22H 20BrClN 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b is in two steps; Use 3-bromo-phenyl aldehyde to replace 3-formyl radical-benzonitrile, obtain racemize (2 ' R, 3R; 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be solid (142mg).
HRMS (ES+) m/z calculated value C 22H 20BrClN 2O 2+ H [(M+H)]: 459.0470; Measured value: 459.0469
Embodiment 136
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-methoxyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02201
M.W.410.90?C 23H 23ClN 2O 3
With with embodiment 134a, the similar mode of the method described in the 134b uses 3-methoxyl group-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-methoxyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is solid (20mg).
HRMS (ES+) m/z calculated value C 23H 23ClN 2O 3+ H [(M+H)]: 433.1289; Measured value; 433.1288
Embodiment 137
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-fluoro-2-methyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02202
M.W.412.90?C 23H 22ClFN 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 5-fluoro-2-methyl-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-fluoro-2-methyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 100mg, 15%).
HRMS (ES+) m/z calculated value C 23H 22ClFN 2O 2+ Na [(M+Na)]: 435.1246; Measured value: 435.1243
Embodiment 138
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02211
M.W.398.87?C 22H 20ClFN 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 3-fluoro-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 100mg, 17%).
HRMS (ES+) m/z calculated value C 22H 20ClFN 2O 2+ H [(M+H)]: 399.1270; Measured value: 399.1267
Embodiment 139
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02212
M.W.394.90?C 23H 23ClFN 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 3-methyl-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-tolyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 130mg, 33%).
HRMS (ES+) m/z calculated value C 23H 23ClFN 2O 2+ H [(M+H)]: 395.1521; Measured value: 395.1521
Embodiment 140
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-o-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02221
M.W.394.90?C 23H 23ClFN 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 2-methyl-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-o-tolyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 55mg, 14%).
HRMS (ES+) m/z calculated value C 23H 23ClFN 2O 2+ H [(M+H)]: 395.1521; Measured value: 395.1521
Embodiment 141
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-thiene-3-yl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02222
M.W.386.90?C 20H 19ClN 2O 2S
With with embodiment 134a, the similar mode of the method described in the 134b uses thiophene-3-formaldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-thiene-3-yl-spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 74mg, 19%).
HRMS (ES+) m/z calculated value C 20H 19ClN 2O 2S+H [(M+H)]: 387.0929; Measured value: 387.0929
Embodiment 142
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two chloro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02231
M.W.449.77?C 22H 19Cl 3N 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 3; 5-two chloro-phenyl aldehydes replace 3-formyl radical-benzonitrile, obtain racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3,5-two chloro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 50mg, 11%).
HRMS (ES+) m/z calculated value C 22H 19Cl 3N 2O 2+ H [(M+H)]: 449.0585; Measured value: 449.0585
Embodiment 143
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chlorine 4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02232
M.W.483.32?C 23H 19Cl 2F 3N 2O 2
With with embodiment 134a, the similar mode of the method described in the 134b uses 5-chloro-2-trifluoromethyl-phenyl aldehyde to replace 3-formyl radical-benzonitrile; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 50mg, 10%).
HRMS (ES+) m/z calculated value C 23H 19Cl 2F 3N 2O 2+ H [(M+H)]: 483.0849; Measured value: 483.0848
Embodiment 144
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02241
M.W.445.75?C 21H 18BrClN 2O 2
With with the similar mode of method described in the embodiment 197; 1-(1-methylene radical-propyl group)-3-front three that the 1-pseudoallyl-3-front three of use prepared fresh in embodiment 142a replaces in embodiment 135a, preparing for siloxy--2-azepine-1,3-butadiene is for siloxy--2-azepine-1,3-butadiene; Obtain racemize (2 ' R; 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield 21mg).
HRMS (ES+) m/z calculated value C 21H 18BrClN 2O 2+ H [(M+H)]: 445.0313; Measured value: 445.0313
Embodiment 145a
Preparation intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-1, the 3-dihydro-indol-2-one
M.W.287.72?C 16H 11ClFNO
To 6-chlorine oxindole (3.6g, 21.6mmol) with 5-fluoro-2-methyl-phenyl aldehyde (3.0g, 21.6mmol) in the mixture in methyl alcohol (25mL), drip tetramethyleneimine (1.53g, 21.6mmol).Then mixture is heated 3h in 70 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-6-chloro-3-(3-chloro-tolylene)-1, and the 3-dihydro-indol-2-one is faint yellow solid (yield 5.3g, 85%).
Embodiment 145b
Preparation intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure G2007800087501D02251
M.W.359.79?C 19H 15ClFNO 3
In 0 ℃; To the E/Z-6-chloro-3-that in embodiment 145a, prepares (5-fluoro-2-methyl-tolylene)-1, (0.20g is 0.71mmol) in the solution in methylene dichloride (3mL) for the 3-dihydro-indol-2-one; Add Vinyl chloroformate (0.10mL; 1.1mmol), then add triethylamine (0.14g, 1.4mmol).Reaction mixture was stirred 30 minutes in 0 ℃.Then mixture is poured in the HCl aqueous solution (1N).Organic layer is separated, and water layer is used ethyl acetate extraction.Organic layer is merged and uses Na 2SO 4Drying, and concentrate, obtaining E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid.Raw product obtains 75mg yellow solid (yield 1.7g, 30%) by chromatogram purification.
Embodiment 145c
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure G2007800087501D02252
M.W.541.41?C 28H 23Cl 2FN 2O 4
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; In toluene (15ml) solution of 3-divinyl in toluene (30ml); Be added in E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-2-oxo-2 for preparing among the embodiment 145b; 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.16g, 0.45mmol).With the reaction tubes sealing, and pass through microwave exposure in 135 ℃ of heating 35 min.After solution is cooled to room temperature, add methyl alcohol (25mL), then mixture is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' S, 3S; 4 ' R)-and 6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid, ethyl ester, be yellow oil (yield 200mg, 82%).
Embodiment 145d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02261
M.W.469.35?C 25H 19Cl 2FN 2O 2
To the racemize that in embodiment 145c, prepares (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2; (0.20g is 0.31mmol) in the solution in methyl alcohol (12mL) for 6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester; Adding NaOH (22mg, 0.56mmol).With mixture in stirring at room 0.5h.Except that desolvating and residuum being distributed between the ETHYLE ACETATE and the HCl aqueous solution (1N).Water layer is used ethyl acetate extraction.Organic layer is merged, concentrate then.Residuum by preparation-HPLC purifying, is obtained racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (9mg).
MSm/z(M+H) +：469
Embodiment 146a
Preparation intermediate E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02271
M.W.417.99?C 22H 25ClFNO 2Si
In 0 ℃, to the E/Z-6-chloro-3-that in embodiment 145a, prepares (3-chloro-tolylene)-1,3-dihydro-indol-2-one (5.0g; 17.4mmol) at N, in the solution in N-dimethyl--methane amide (40mL), add NaH (60%; In the MO) (0.70g; 17.4mmol), then drip 2-(trimethylsilyl) ethoxyl methyl chlorine in THF (40mL) (2.9g, 17.4mmol).Reaction mixture in 0 ℃ of stirring 0.5h, is poured in ice-water then.With rough thing with twice of ethyl acetate extraction.The organic layer that merges is used Na 2SO 4Dry.Remove desolvate and with residuum by chromatogram (hexane) purifying, obtain E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one is yellow oil (yield 5.7g, 78%).
Embodiment 146b
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02272
M.W.599.61?C 31H 33Cl 2FN 2O 3Si
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1; In toluene (12ml) solution of 3-divinyl in toluene (50mL); Be added in E/Z-6-chloro-3-(5-fluoro-2-methyl-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1 for preparing among the embodiment 146a; The 3-dihydro-indol-2-one (0.30g, 0.72mmol).Then reaction tubes is placed in the chamber of focusing single mold microwave reactor drum, and with the content in the flask in 135 ℃ of irradiation 35min.After solution is cooled to room temperature, add methyl alcohol (25mL).Reaction soln is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' S, 3S; 4 ' R)-and 6-chloro-2 '-(3-chloro-phenyl-)-4 ,-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane is yellow solid (0.45g)
Embodiment 146c
Preparation midbody racemize (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02281
M.W.713.76?C 37H 43Cl 2FN 2O 5Si
In room temperature, to the racemize that in embodiment 146b, prepares (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4;-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(2.5g is 4.18mmol) at N, in the solution in N-dimethyl--methane amide (20mL) for 1-methoxy ethyl trimethyl silane; Add the bromo-tert.-butyl acetate (2.0g, 10.4mmol) and cesium carbonate (7.5g, 23.0mmol).Under nitrogen, reaction mixture is stirred 4h, pour into saturated NH then 4In the Cl aqueous solution.Mixture is used ethyl acetate extraction.Organic layer is merged, use Na 2SO 4Drying, and concentrate.With residuum by chromatogram (EtOAc: the purifying of hexane=1:4); Obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane is yellow solid (yield 0.85g).
Embodiment 146d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02291
M.W.527.38?C 27H 21Cl 2FN 2O 4
To the racemize that in embodiment 146d, prepares (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1 '-[(tertbutyloxycarbonyl) methyl]-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(0.85g 1.19mmol) in the solution in methylene dichloride (10mL), adds trifluoroacetic acid (20mL) to 1-methoxy ethyl trimethyl silane.With reaction mixture in stirring at room 18h.Reaction mixture is concentrated.Residuum is dissolved in the methyl alcohol (10mL) again.In the solution that obtains, add N, N '-diisopropylethylamine (1.57mL, 8.70mmol), and with rough thing backflow 1h.Reaction mixture is concentrated and residuum is distributed between the ETHYLE ACETATE and the HCl aqueous solution (1N).Organic layer is separated, use MgSO 4Drying, and concentrate.Residuum is ground with ETHYLE ACETATE and hexane; Obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 440mg, 70%).
MSm/z(M+H) +：527
Embodiment 147
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-(methylamino-carbonyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02292
M.W.540.43?C 28H 24Cl 2FN 3O 3
The racemize that will in embodiment 146d, prepare (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (70mg, 0.13mmol), methylamine hydrochloride (11mg; 0.16mmol), EDC.HCl (31mg, 0.16mmol); HOBt (22mg, 0.16mmol) and DIPEA (69mg, 0.533mmol) mixture in DMF (2mL) is in stirred overnight at room temperature.Then rough thing is used preparation-HPLC purifying, obtain racemize (2 ' S, 3S; 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-(methylamino-carbonyl-methyl) spiral shell [3H-indoles-3; 3 '-piperidines] (29mg is white solid to-2,6 ' (1H)-diketone.
MSm/z[M+H] +：540.
Embodiment 148
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-carbonyl-methyl)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02301
M.W.554.45?C 29H 26Cl 2FN 3O 3
With with the similar mode of method described in the embodiment 147; Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-carbonyl-methyl)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone.
MSm/z(M+H) +：554
Embodiment 149
Preparation racemize (2 ' S, 3S, 4 ' R)-1 '-[(4-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02311
M.W.637.54?C 33H 31Cl 2FN 4O 4
With with the similar mode of method described in the embodiment 147; Preparation racemize (2 ' S; 3S; 4 ' R)-1 '-[(4-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
MSm/z(M+H) +：637
Embodiment 150
Preparation racemize (2 ' S, 3S, 4 ' R)-1 '-[(3-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02312
M.W.637.54?C 33H 31Cl 2FN 4O 4
With with the similar mode of method described in the embodiment 147; Preparation racemize (2 ' S; 3S; 4 ' R)-1 '-[(3-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
MSm/z(M+H) +：637
Embodiment 151
Preparation racemize (2 ' S, 3S, 4 ' R)-1 '-(aminocarboxyl-methyl)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.526.40?C 27H 22Cl 2FN 3O 3
With with the similar mode of method described in embodiment 146d and the 146e, with racemize (2 ' S, 3S; 4 ' R)-and 6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (50mgg; 0.08mmol) (35mg, 0.25mmol) (163mg 0.50mmol) reacts in DMF (2ml) with cesium carbonate with 2-bromo-ethanamide.The residuum that obtains is dissolved in the mixing solutions of trifluoroacetic acid (5mL) and methylene dichloride (5mL).With reaction mixture in stirring at room 18h.Reaction mixture is concentrated.Residuum is dissolved in the methyl alcohol (10mL) again.In the solution that obtains, add N, N '-diisopropylethylamine, and with rough thing backflow 1h.Reaction mixture is concentrated and residuum is distributed between the ETHYLE ACETATE and the HCl aqueous solution (1N).Organic layer is separated, use MgSO 4Drying, and concentrate.Residuum is ground,, obtain racemize (2 ' S by preparation-HPLC purifying; 3S, 4 ' R)-1 '-(aminocarboxyl-methyl)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (8mg).
MSm/z(M+H) +：526
Embodiment 152a
Preparation midbody racemize (2 ' S, 3S, 4 ' R)-6-chloro-1 '-(3-chloro-propyl group)-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02331
M.W.676.14?C 34H 38Cl 3FN 2O 5Si
The racemize that will in embodiment 146a, prepare (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.40g; 0.67mmol) and at N, (0.13g is 16.70mmol) with 1-chloro-3-bromo-propane (0.63g for the LiH in N-dimethyl--methane amide (3mL); 4.01mmol), the KI reaction of catalytic amount.After solution stirring is spent the night, solution is toppled in the entry.Water layer is used ethyl acetate extraction, and the organic layer that merges is dry, concentrate, obtain raw product.Raw product by chromatogram purification, is obtained racemize (2 ' S, 3S; 4 ' R)-6-chloro-1 '-(3-chloro-propyl group)-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane; Be yellow solid (yield: 0.11g, 24%).
Embodiment 152b
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-propyl group)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02332
M.W.554.50?C 30H 30Cl 2FN 3O 2
In room temperature, to the racemize that in embodiment 152a, prepares (2 ' S, 3S, 4 ' R)-6-chloro-1 '-(3-chloro-propyl group)-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.11g; 0.16mmol) at N, in the solution in N-dimethyl--methane amide (3mL), add dimethylamine hydrochloride 0.53g; 6.53mmol) and cesium carbonate (2.66g, 8.16mmol) and the KI of catalytic amount.With the reaction mixture stirred overnight, then solution is poured into saturated NH 4In the Cl aqueous solution.Mixture is used ethyl acetate extraction.Organic layer is merged, use Na 2SO 4Drying, and concentrate, the 110mg yellow solid obtained.In yellow solid, add methylene dichloride (10mL) and trifluoroacetic acid (10mL).With reaction mixture in stirring at room 4h.With reaction mixture concentrate and with residuum at ETHYLE ACETATE and saturated NaHCO 3Distribute between the solution.Organic layer is separated, and concentrate.Residuum is dissolved in the methyl alcohol (10mL) again.In the solution that obtains, add N, N '-diisopropylethylamine (2mL), and with rough thing in 100 ℃ of heating 1h.With reaction mixture concentrate and with residuum by preparation-HPLC purifying; Obtain racemize (2 ' S; 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-propyl group)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (10mg).
MSm/z(M+H) +：554
Embodiment 153a
Preparation midbody racemize (2 ' S; 3S, 4 ' R)-1 '-[(t-butoxycarbonyl amino) ethyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02341
M.W.742.80?C 38H 46Cl 2FN 3O 5Si
With with the similar mode of method described in the embodiment 152a, with racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (0.45g; 0.75mmol) and at N, (0.15g is 18.8mmol) with (2-bromo-ethyl)-t-butyl carbamate (1.0g for the LiH in N-dimethyl--methane amide (3mL); 4.52mmol), the KI reaction of catalytic amount obtains racemize (2 ' S; 3S, 4 ' R)-1 '-[(t-butoxycarbonyl amino) ethyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane is yellow solid (80mg).
Embodiment 153b
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-ethyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02351
M.W.701.6?C 34H 35Cl 2FN 4O 5S
The racemize that in embodiment 153a, prepares (2 ' S; 3S; 4 ' R)-and 6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1 '-[(tert.-butoxy formamyl) ethyl]-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-1-methoxy ethyl trimethyl silane (80mg) adding methylene dichloride (5mL), add trifluoroacetic acid (5mL) then.With reaction mixture in stirring at room 4h.With reaction mixture concentrate and with residuum at ETHYLE ACETATE and saturated NaHCO 3Distribute between the solution.Organic layer is separated, and concentrate.Residuum is dissolved in the methyl alcohol (5mL) again.In the solution that obtains, add N, N '-diisopropylethylamine (2mL), and with rough thing in 100 ℃ of heating 1h.Reaction mixture is concentrated.With residuum, 1-methylsulfonyl-piperidines-4-carboxylic acid (60mg, 0.29mmol), EDC.HCl (56mg, 0.29mmol), HOBt (39mg, 0.29mmol) and DIPEA (101mg, 0.78mmol) mixture in DMF (2mL) is in stirred overnight at room temperature.Then; Rough thing with preparation-HPLC purifying, is obtained racemize (2 ' S, 3S; 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-ethyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be yellow solid (14mg).
MSm/z(M+H) +：701
Embodiment 154a
Preparation intermediate E/Z-6-chloro-3-(4-chloro-thiophene-2-methylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02361
M.W.296.18?C 13H 7Cl 2NOS
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (1.2g, 7.2mmol) with 4-chloro-thiophene-2-formaldehyde (1.05g; 7.2mmol) and tetramethyleneimine (0.7g; 9.9mmol) reaction, obtain E/Z-6-chloro-3-(4-chloro-thiophene-2-methylene)-1, the 3-dihydro-indol-2-one; Be yellow solid (yield 1.3g, 62%)
Embodiment 154b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(4-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02362
M.W.475.37?C 23H 17Cl 2FN 2O 2S
With with the similar mode of method described in the embodiment 1c, the E/Z-6-chloro-3-that will in embodiment 154a, prepare (4-chloro-thiophene-2-methylene)-1,3-dihydro-indol-2-one (0.2g; 0.68mmol) with 1-(5-fluoro-2-methyl-phenyl)-3-front three of in embodiment 36a, preparing for siloxy--2-azepine-1; The reaction of 3-divinyl obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-[2-(4-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (7mg).
MSm/z(M+H) +：475
Embodiment 155a
Preparation intermediate E/Z-6-chloro-3-(5-chloro-thiophene-2-methylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02371
M.W.296.18?C 13H 7Cl 2NOS
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (1.2g, 7.2mmol) with 5-chloro-thiophene-2-formaldehyde (1.05g; 7.2mmol) and tetramethyleneimine (0.7g; 9.9mmol) reaction, obtain E/Z-6-chloro-3-(5-chloro-thiophene-2-methylene)-1, the 3-dihydro-indol-2-one; Be yellow solid (yield 1.5g, 71%)
Embodiment 155b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(5-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.475.37?C 23H 17Cl 2FN 2O 2S
With with the similar mode of method described in the embodiment 1c, the E/Z-6-chloro-3-that will in embodiment 155a, prepare (5-chloro-thiophene-2-methylene)-1,3-dihydro-indol-2-one (0.2g; 0.68mmol) with 1-(5-fluoro-2-methyl-phenyl)-3-front three of in embodiment 6b, preparing for siloxy--2-azepine-1; The reaction of 3-divinyl obtains racemize (2 ' R, 3R; 4 ' S)-6-chloro-4 '-[2-(5-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (6mg).
MSm/z(M+H) +：475
Embodiment 156
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(2, the 2-dimethyl propyl)-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02381
M.W.428.94?C 24H 26ClFN 2O 2
With with the similar mode of method described in the embodiment 1c, the E/Z-6-chloro-3-that will in embodiment 1a, prepare (3,3-dimethyl--butylidene)-1; (0.2g 0.80mmol) reacts for siloxy--2-azepine-1,3-butadiene with 1-(5-fluoro-2-methyl-phenyl)-3-front three that in embodiment 36a, prepares the 3-dihydro-indol-2-one; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(2; The 2-dimethyl propyl)-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (7mg).
MSm/z(M+H) +：429
Embodiment 157a
Preparation intermediate E/Z-6-bromo-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02382
M.W.334.60?C 15H 9BrClNO
To 6-bromine oxindole (16.2g, 92mmol) (Combi-block) and 3-chloro-phenyl aldehyde (12.9g, 92mmol) in the mixture in methyl alcohol (109mL), drip tetramethyleneimine (6.55g, 92mmol).Then mixture is heated 3h in 65 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-6-chloro-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 16.2g, 63%).
Embodiment 157b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02391
M.W.495.81?C 25H 20BrClN 2O 2
To the 1-that in embodiment 17a, prepares (2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1; In the solution of 3-divinyl in toluene (20mL); Be added in E/Z-6-bromo-3-(3-chloro-the tolylene)-2-oxo-2 for preparing among the embodiment 157a; 3-dihydro-indoles (0.3g, 0.83mmol).Under microwave exposure, in ST,, reaction mixture is stirred and heating 0.5h in 135 ℃.After solution is cooled to room temperature, add methyl alcohol (50mL), then mixture is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid.(yield 0.22g, 53%).
MSm/z[(M+H) +]：495
Embodiment 158a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02392
M.W.513.80?C 25H 19BrClFN 2O 2
With with the similar mode of method described in the embodiment 157b, the E/Z-6-bromo-3-that will in embodiment 157a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(5-fluoro-2-the aminomethyl phenyl)-3-front three that in embodiment 36a, prepares, obtain racemize (2 ' R; 3R; 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 0.3g, 54%).
MSm/z[(M+H) +]：513
Embodiment 158b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02401
M.W.513.80?C 25H 19BrClFN 2O 2
By the chiral column chromatogram, carry out from racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [the 3H-indoles-3 that among embodiment 158a, prepares; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (35mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 11mg, 31%) and chirality (2 ' S; 3S, 4 ' R)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 11mg, 31%).
MSm/z[(M+H) +]：513
Embodiment 159a
Preparation midbody 1-(2, the 5-dichlorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.288.25?C 12H 15Cl 2NOSi
With with the similar mode of method described in the embodiment 1b, with 2, (1.75g 10mmol) replaces the 3-chlorobenzaldehyde as raw material to 5-two chloro-phenyl aldehydes; With two (trimethylsilyl) Lithamide (the 1M solution among the THF, 10mL, 10mmol), trimethylsilyl chloride (1.1g; 10mmol), and triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g; 13mmol) reaction obtains 1-(2, the 5-dichlorophenyl)-3-front three for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 159b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2, the 5-dichlorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02411
M.W.550.67?C 24H 16BrCl 3N 2O 2
With with the similar mode of method described in the embodiment 157b, the E/Z-6-bromo-3-that will in embodiment 157a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(2, the 5-the dichlorophenyl)-3-front three that in embodiment 159a, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2; 3-dihydro-2 '-(2, the 5-dichlorophenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines is white solid.(yield 0.4g, 67%).
MSm/z[(M+H) +]：549
Embodiment 160a
Preparation midbody 1-(5-chloro-2-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.267.83?C 13H 18ClNOSi
With with the similar mode of method described in the embodiment 1b, (1.54g 10mmol) replaces the 2-tolyl aldehyde as raw material with 5-chloro-2-methyl-phenyl aldehyde; With with two (trimethylsilyl) Lithamide (the 1M solution among the THF, 10mL, 10mmol); Trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g; 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(5-fluoro-2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 160b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02421
M.W.530.25?C 25H 19BrCl 2N 2O 2
With with the similar mode of method described in the embodiment 157b, the E/Z-6-bromo-3-that will in embodiment 157a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(5-chloro-2-the aminomethyl phenyl)-3-front three that in embodiment 160a, prepares, obtain racemize (2 ' R; 3R; 4 ' S)-and 6-bromo-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(5-chloro-2-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines], be white solid.(yield 0.3g, 51%).
MSm/z[(M+H) +]：529
Embodiment 161a
Preparation intermediate E/Z-6-bromo-3-(3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02422
M.W.464.87?C 21H 23BrClNO 2Si
In 0 ℃, to the E/Z6-bromo-3-that in embodiment 157a, prepares (3-chloro-tolylene)-1,3-dihydro-indol-2-one (5.3g; 16mmol) at N, in the solution in N-dimethyl--methane amide (50mL), add NaH (60%; In the MO) (0.64g; 16mmol), then drip 2-(trimethylsilyl) ethoxyl methyl chlorine in THF (40mL) (2.65g, 16mmol).Reaction mixture in 0 ℃ of stirring 0.5h, is poured in ice-water then.With rough thing with twice of ethyl acetate extraction.The organic layer that merges is used Na 2SO 4Dry.Remove desolvate and with residuum by chromatogram (hexane) purifying, obtain E/Z-6-bromo-3-(3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one is yellow oil (yield 4.5g, 60%).
Embodiment 161b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02431
M.W.590.04?C 28H 34BrClN 2O 3Si
To the 1-that in embodiment 80a, prepares (1-ethyl-vinyl)-3-front three for siloxy--2-azepine-1; In the solution of 3-divinyl (42mmol) in toluene (50mL); Be added in E/Z-6-bromo-3-(3-chloro-the tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1 for preparing among the embodiment 161a; The 3-dihydro-indol-2-one (2g, 4.3mmol).Under nitrogen, in ST, reaction mixture is stirred 1h in 135 ℃.After being cooled to room temperature, add methyl alcohol (100mL), then mixture is concentrated.With residuum by chromatogram (EtOAc: the purifying of hexane=2:1); Obtain racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-2; 3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane is solid (yield 350mg).
Embodiment 161c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02441
M.W.459.77?C 22H 20BrClN 2O 2
To the racemize that in embodiment 161b, prepares (2 ' R; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(50mg 0.08mmol) in the solution in methylene dichloride (5mL), adds trifluoroacetic acid (5mL) to 1-methoxy ethyl trimethyl silane.With reaction mixture in stirring at room 0.5h.Except that after desolvating, residuum is dissolved in the methyl alcohol (2mL).In the solution that obtains, add N, N '-diisopropylethylamine (1mL).Then, reaction tubes is heated 20min in 135 ℃.With reaction mixture concentrate and with residuum by preparation-HPLC purifying, obtain racemize (2 ' R, 3R; 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be solid (30mg).
Embodiment 161d
Preparation chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.459.77?C 22H 20BrClN 2O 2
By chiral column chromatographic separation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone (30mg), obtain chirality (2 ' R; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (7mg white solid) and chirality (2 ' S, 3S, 4 ' R)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (7mg).
MSm/z[(M+H) +]：459
Embodiment 162a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure G2007800087501D02451
M.W.604.06?C 29H 36BrClN 2O 3Si
In 0 ℃, with CH 2I 2(1.2g 4.6mmol) is dissolved in the dry toluene (5mL).After under argon gas, stirring 10min, add Et 2Zn (1M, in THF, 3.3mL, 3.67mmol).After stirring 15min; Be added in racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(the 1-methylene radical-propyl group)-2 for preparing among the embodiment 161b; 3-dihydro-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (270mg, 0.46mmol) solution in dry toluene (10mL).Behind stirring at room 3h, will react and use saturated NH 4Cl (20mL) quencher.Water layer is extracted with EtOAc.The organic layer that merges is used Na 2SO 4Drying concentrates, and residuum is used for next step under situation about not being further purified.
Embodiment 162b
Preparation chirality (2R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02452
M.W.473.80?C 23H 22BrClN 2O 2
To the racemize that in embodiment 162a, prepares (2 ' R; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2; 6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-(48mg 0.079mmol) in the solution in methylene dichloride (5mL), adds trifluoroacetic acid (5mL) to 1-methoxy ethyl trimethyl silane.With mixture in stirring at room 5h.Remove in the vacuum then and desolvate.Residuum is dissolved in the methyl alcohol (2mL).In the solution that obtains, add N, N '-diisopropylethylamine (1mL).Mixture is heated 20min in 135 ℃.With reaction mixture concentrate and with residuum by preparation-HPLC purifying, obtain racemize (2R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.Racemic compound by the chiral column chromatographic separation, is obtained chirality (2R, 3R; 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (4.5mg) and chirality (2S; 3S; 4 ' R)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (4.5mg).
MSm/z[(M+H) +]：473
Embodiment 163a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02461
M.W.573.92?C 28H 30BrClN 2O 4
The racemize that will in embodiment 162b, prepare (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (220mg, 0.47mmol), (Boc) 2O (121.9mg, 0.56mmol) and DMAP (73.9mg 0.61mmol) is mixed in the THF (10mL).After stirring 0.5h, be dissolved among the EtOAc with solution concentration and with residuum.With organic layer for several times with the 0.5NHCl solution washing.Then that organic layer is dry, and concentrate, yellow solid (240mg) obtained.
Embodiment 163b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-cyclopropyl-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02471
M.W.535.09?C 31H 35ClN 2O 4
Under argon gas atmosphere, with racemize (2 ' R, 3R; 4 ' S)-and 6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester (28mg, 0.049mmol), cyclopropylboronic acid (4.5mg; 0.0524mmol), Pd (PPh 3) 4(5mg), K 3PO 4(50mg) be mixed in the toluene (3mL) with several dripping.Mixture is heated 20min in 130 ℃ under microwave exposure.Then solution is toppled in the entry, and water layer is extracted with EtOAc.Organic layer is dry, and concentrate.Residuum by preparation-TLC purifying, is obtained racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (10mg).
Embodiment 163c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02472
M.W.434.97?C 26H 27ClN 2O 2
With racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-2; 3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (10mg; 0.019mmol) be dissolved in HCl methanol solution (6M, 10mL) in.Behind the 10min,, obtain racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid solution concentration.(yield, 5.9mg, 72%)
MSm/z[(M+H) +]：435
Embodiment 164a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02481
M.W.569.47?C 30H 27Cl 2FN 2O 4
To the racemize that in embodiment 36c, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3; 3 '-piperidines]-2; (300mg 0.64mmol) in the mixture in methylene dichloride (30mL), adds 4-dimethylaminopyridine (94mg to 6 ' (1H)-diketone; 0.77mmol) and tert-Butyl dicarbonate (153mg, 0.71mmol).Mixture in stirring at room 30min, then by purified, is obtained racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2; 6 '-dioxo-spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester, be solid (350mg, 96%).
Embodiment 164b
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-(2-brooethyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02482
M.W.648.36?C 30H 26BrCl 2FN 2O 4
To racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-2; 3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (900mg; 1.58mmol) in the solution in tetracol phenixin (20mL); Add Lucidol (380mg, 1.58mmol) and NBS (280mg, 1.58mmol).With mixture under microwave exposure in 100 ℃ the heating 30min, then by purified, obtain racemize (2 ' R; 3R, 4 ' S)-(2-brooethyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2,3-dihydro-2; 6 '-dioxo-spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester, be solid (170mg, 16%).Reclaim raw material racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (550mg, 0.96mmol).
Embodiment 164c
Preparation racemize (2 ' R, 3R, 4 ' S) 2 '-[2-(4-aminocarboxyl-piperidines-1-yl) methyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02491
M.W.595.51?C 31H 29Cl 2FN 4O 3
To the racemize that in embodiment 164b, prepares (2 ' R; 3R, 4 ' S)-(2-brooethyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-2,3-dihydro-2; 6 '-dioxo-spiral shell [indoles-3; 3 '-piperidines]-(30mg 0.046mmol) in the solution in acetonitrile (5mL), adds K to the 1-carboxylic acid tert-butyl ester 2CO 3(13mg, 0.094mmol) and piperidines-4-carboxylic acid amide (12mg, 0.094mmol).With the mixture 2h that refluxes, concentrate then.Residuum by preparation-HPLC purifying, is obtained racemize (2 ' R, 3R; 4 ' S) 2 '-[2-(4-aminocarboxyl-piperidines-1-yl) methyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be solid (2.6mg).
MSm/z[(M+H) +]：595
Embodiment 165
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(4-methylsulfonyl-piperazine-1-yl) methyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02501
M.W.631.56?C 30H 29Cl 2FN 4O 4S
To the racemize that in embodiment 164b, prepares (2 ' R; 3R, 4 ' S)-2 '-(2-brooethyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2; 6 '-dioxo-spiral shell [indoles-3; 3 '-piperidines]-(30mg 0.046mmol) in the solution in acetonitrile (5mL), adds K to the 1-carboxylic acid tert-butyl ester 2CO 3(13mg, 0.094mmol) with 1-methylsulfonyl-piperazine (15mg, 0.094mmol).With the mixture 2h that refluxes, concentrate.Residuum is dissolved in the trifluoroacetic acid, and, concentrates then in stirring at room 30min; And, obtain (2 ' R, 3R by preparation-HPLC purifying; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(4-methylsulfonyl-piperazine-1-yl) methyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be solid (5mg, 17%).
Embodiment 166
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-fluoro-2-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-methyl]-phenyl }-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02502
M.W.673.6?C 32H 31Cl 2FN 4O 5S
To ammonia soln (17%, 2mL ,～20mmol) in; Be added in racemize (2 ' R, 3R, 4 ' S)-(2-brooethyl-5-fluoro-phenyl)-6-chloro-4 '-(the 3-chloro-phenyl-)-2 '-2 for preparing among the embodiment 164b; 3-dihydro-2,6 '-dioxo-spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (40mg; 0.06mmol) at N, the solution in the dinethylformamide (2mL).Mixture in stirring at room 2h, is then added EtOAc (20mL).Organic phase is separated, and use water washing, use Na 2SO 4Dry.Remove in the vacuum and desolvate, and residuum is dissolved in methylene dichloride.Then 1-methylsulfonyl-piperidines-4-carboxylic acid (20mg) n n dimetylaniline piperidines (25mg) and EDCI (40mg) are joined in the solution.In stirring at room 2h, then with the methylene dichloride dilution, (1N, 10mL), Na is used in water (10mL) washing with the HCl aqueous solution with mixture 2SO 4Dry.Organic layer is separated, concentrate and with residuum by preparation HPLC purifying, obtain title compound, be solid (12mg).
MSm/z[(m+H) +]：673
Embodiment 167a
Preparation midbody 6-fluoro-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02511
M.W.151.14?C 8H 6FNO
To NaH (60%, 7g, 0.16mol) in the mixture in methyl-sulphoxide (150mL), drip methyl-malonate (20mL, 0.16mol).With mixture heating up to 100 ℃ 10min, be cooled to room temperature then, then add 2, the 5-difluoro nitrobenzene (14g, 0.08mol).Behind 90 ℃ of stirring 2h,, and pour into in the ice-cooled 5%HCl aqueous solution with the mixture cooling.Add EtOAc (50mL), and organic phase is separated, use water washing, and use Na 2SO 4Dry.Remove in the vacuum and desolvate, obtain 2-(4-fluoro-2-nitro-phenyl)-methyl-malonate (19.4g).(6g 22mmol) is dissolved in the Glacial acetic acid min. 99.5 (30mL), adds the HCl aqueous solution (6N with 2-(4-fluoro-2-nitro-phenyl)-methyl-malonate; 30mL), and with reaction mixture reflux 4h, with iron powder (5g; 88mmol) join in the mixture with pursuing part, and make the other 2h of continuation that refluxes.Remove in the vacuum and desolvate, and residual residuum is extracted by EtOAc.With organic phase with the HCl aqueous solution (1N), brine wash, and use Na 2SO 4Drying concentrates, and obtains title compound, is yellow solid (3g, 89%).
MSm/z(M+H) +：152
Embodiment 167b
Preparation intermediate E/Z-6-fluoro-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02521
M.W.273.70?C 15H 9ClFNO
To 6-fluorine oxindole (13.9g, 92mmol) with 3-chloro-phenyl aldehyde (12.9g, 92mmol) in the mixture in methyl alcohol (109mL), drip tetramethyleneimine (6.55g, 92mmol).Then mixture is heated 3h in 65 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-6-fluoro-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 17.5g, 64%).
MSm/z(M+H) +：274
Embodiment 167c
Preparation chirality (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02522
M.W.452.89?C 25H 19ClF 2N 2O 2
With with the similar mode of method described in the embodiment 1c, the E/Z-6-fluoro-3-that will in embodiment 167b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) 1-(5-fluoro-2-aminomethyl phenyl)-3-front three of in embodiment 36a, preparing is for siloxy--2-azepine-1; The 3-divinyl reacts in toluene, obtains racemize (2 ' R, 3R; 4 ' S)-4 '-(3-chloro-phenyl-)-6-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.1g).Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone by the chiral column chromatographic separation, is obtained title compound, be white solid.
MSm/z(M+H) +：453
Embodiment 168a
Preparation midbody 6-methoxyl group-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02531
M.W.163.18?C 9H 9NO 2
With with the similar mode of method described in the embodiment 167a, (19g, 0.1mol) (16g, 0.2mol), NaH and iron powder react, and obtain 6-methoxyl group-1,3-dihydro-indol-2-one (3g, 18%) with methyl-malonate with 1-chloro-4-methoxyl group-2-nitro-benzene.
MSm/z(M+H) +：164
Embodiment 168b
Preparation intermediate E/Z-6-methoxyl group-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02532
M.W.285.73?C 16H 12ClNO 2
To 6-methoxyl group oxindole (1.60g, 10mmol) with 3-chloro-phenyl aldehyde (1.4g, in the mixture of 10mmol in methyl alcohol (10mL), drip tetramethyleneimine (0.82mL, 10mmol).Then mixture is heated 3h in 65 ℃.After being cooled to 4 ℃, mixture to be filtered, and will obtain the throw out collection, drying obtains E/Z-6-methoxyl group-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 1.7g, 60%).
MSm/z(M+H) +：286
Embodiment 168c
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6-methoxyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02541
M.W.464.93?C 26H 22ClFN 2O 3
With with the similar mode of method described in the embodiment 1c, the E/Z-6-methoxyl group-3-that will in embodiment 168b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(5-fluoro-2-the aminomethyl phenyl)-3-front three that in embodiment 36a, prepares, obtain racemize (2 ' R; 3R; 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6-methoxyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 0.05g, 10%).
MSm/z(M+H) +：465
Embodiment 169a
Preparation intermediate E/Z-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
M.W.255.71?C 15H 10ClNO
To oxindole (2.66g, 20mmol) with 3-chloro-phenyl aldehyde (2.81g, 20mmol) in the mixture in methyl alcohol (20mL), drip tetramethyleneimine (1.65mL, 20mmol).Then mixture is heated 3h in 65 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 4g, 78%).
MSm/z(M+H) +：256
Embodiment 169b
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02551
M.W.434.90?C 25H 20ClFN 2O 2
With with the similar mode of method described in the embodiment 1c, the E/Z-3-that will in embodiment 169a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(5-fluoro-2-the aminomethyl phenyl)-3-front three that in embodiment 36a, prepares, obtain racemize (2 ' R; 3R; 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 0.08g, 15%).
MSm/z(M+H) +：435
Embodiment 170a
Preparation midbody 5-fluoro-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02552
M.W.151.14?C 8H 6FNO
In 0 ℃, (1.23g is 8mmol) at dense H to 3-fluorophenyl acetate 2SO 4(2.0mL in the solution in 40mmol), adds HNO at leisure 3(0.374mL, 8mmol).Under argon gas,, the reaction mixture that obtains is stirred 2h, and pour in ice-water in 0 ℃.Collect white solid, and water is used ethyl acetate extraction.Organic phase is used brine wash, use Na 2SO 4Drying, and concentrate.Rough (5-fluoro-2-nitro-phenyl)-acetate is dissolved in the acetate.In solution, and the adding iron powder (1.79g, 32mmol).Reaction mixture is stirred and reflux 2h.Then with concentrating in the mixture vacuum.Residuum is used ethyl acetate extraction, and organic layer is separated, by HCl (1N), brine wash is used Na 2SO 4Drying concentrates in the vacuum, obtains the product (1g, 82%) that needs.
MSm/z(M+H) +：152
Embodiment 170b
Preparation intermediate E/Z-5-fluoro-3-(3-chloro-tolylene)-1, the 3-dihydro-indol-2-one
Figure G2007800087501D02561
M.W.273.70?C 15H 9ClFNO
To 5-fluorine oxindole (3.00g, 20mmol) with 3-chloro-phenyl aldehyde (2.8g, 20mmol) in the mixture in methyl alcohol (20mL), drip tetramethyleneimine (1.72mL, 10mmol).Then mixture is heated 3h in 65 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-5-fluoro-3-(3-chloro-tolylene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 1.7g, 30%).
MSm/z(M+H) +：274
Embodiment 170c
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02562
M.W.452.89?C 25H 19ClF 2N 2O 2
With with the similar mode of method described in the embodiment 1c, the E/Z-5-fluoro-3-that will in embodiment 170b, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles (0.4g; 1.10mmol) in toluene, react for siloxy--2-azepine-1,3-butadiene with 1-(5-fluoro-2-the aminomethyl phenyl)-3-front three that in embodiment 36a, prepares, obtain racemize (2 ' R; 3R; 4 ' S)-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (yield 2g, 41%).
MSm/z(M+H) +：453
Embodiment 171a
Preparation midbody racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester
M.W.501.41?C 26H 26Cl 2N 2O 2
In 0 ℃, to the racemize that in embodiment 87c, prepares (2 ' R, 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.4g; 1mmol) in the solution in methylene dichloride (10mL), and the adding tert-Butyl dicarbonate (0.47g, 2mmol); Then add 4-dimethylaminopyridine (0.29g, 2.4mmol).Reaction mixture in stirring at room 1h, is poured in ice-water then.Organic layer is separated,, use Na with the HCl aqueous solution (0.5N) washing 2SO 4Drying concentrates, and obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2, and 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester is white solid. and (yield 0.47g, 95%).
MSm/z(M+H) +：501
Embodiment 171b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02572
M.W.415.32?C 22H 20Cl 2N 2O 2
Under argon gas, in 0 ℃, to CH 2I 2(1.2g 4.6mmol) in the solution in dry toluene (5mL), adds Et 2The toluene solution of Zn (1.1M, 3.3ml, 3.67mmol).Mixture is stirred 15min, be added in the racemize (2 ' R, the 3R that prepare among the embodiment 171a then; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (230mg, toluene solution 0.46mmol) (10mL).Reaction mixture in stirring at room 3h, is used saturated NH then 4The Cl aqueous solution (20mL) quencher.Organic layer is separated, and water layer is used ethyl acetate extraction.Organic layer is merged, use Na 2SO 4Drying, and concentrate, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (162mg).Then with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone separates through chirality SFC, obtains chirality (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (50mg).
HRMS (ES +) m/z calculated value C 22H 20Cl 2N 2O 2+ H [(M+H) +]: 415.0975 measured values: 415.0975.
1H?NMR(400MHz，DMSO-d6)：δ＝0.10(m，2H)，0.23(s，3H)，0.36(m，1H)，0.55(m，1H)，2.60(dd，J＝6.4，18.4Hz，1H)，2.85(dd，J＝12.8，18.4Hz，1H)，3.14(s，1H)，3.66(dd，J＝6.4Hz，13.2Hz，1H)，6.62(d，J＝8Hz，1H)，6.71(d，J＝2Hz，1H)，6.74(d，J＝1.6Hz，1H)，7.08-7.14(m，2H)，7.18～7.20(m，1H)，7.36(d，J＝8Hz，1H)，8.05(s，1H)，10.56(s，1H)ppm。
Embodiment 172a
Preparation intermediate E/Z-6-bromo-3-(3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
M.W.434.72?C 20H 17BrClNO 3
With with the similar mode of method described in the embodiment 24a, the E/Z-6-bromo-3-that will in embodiment 157a, prepare (3-chloro-tolylene)-1,3-dihydro-indol-2-one (2.4g; 7.2mmol) with tert-Butyl dicarbonate (1.86g, 10mmol) (1.46g 12mmol) reacts with 4-dimethylaminopyridine; Obtain E/Z-6-bromo-3-(3-chloro-tolylene)-2-oxo-2; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester is yellow solid (yield 1.5g, 48%).
MSm/z(M+H) +：434
Embodiment 172b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02591
M.W.445.75?C 21H 18BrClN 2O 2
With with the similar mode of method described in the embodiment 41b, the E/Z-6-bromo-3-that will in embodiment 172a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (5g; 12.8mmol) in toluene, react, handle with trifluoroacetic acid then for siloxy--2-azepine-1,3-butadiene with the 1-pseudoallyl-3-front three that in embodiment 87b, prepares; Obtain racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is yellow solid (yield 2.2g, 40%).
MSm/z(M+H) +：445
Embodiment 173a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxyl 1acid tert-butyl ester
Figure G2007800087501D02592
M.W.545.87?C 26H 26BrClN 2O 4
With with the similar mode of method described in the embodiment 171a, the racemize that will in embodiment 172b, prepare (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3; 3 '-piperidines] (0.45g is 1mmol) with tert-Butyl dicarbonate (0.24g for-2,6 ' (1H)-diketone; 1mmol) and 4-dimethylaminopyridine (0.15g, 1.2mmol) reaction, obtain racemize (2 ' R; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2,6 '-dioxo spiral shell [indoles-3; 3 '-piperidines]-the 1-carboxylic acid tert-butyl ester, be white solid (yield 0.49g, 90%).
MSm/z(M+H) +：545
Embodiment 173b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02601
M.W.459.77?C 22H 20BrClN 2O 2
With with the similar mode of method described in the embodiment 171b, racemize (2 ' R, the 3R that will in embodiment 173a, prepare; 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester (250mg, 0.46mmol) and CH 2I 2(1.2g, 4.6mmol) and Et 2(3.3ml, 3.67mmol) reaction obtains racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone to Zn, is white solid (yield 183mg, 87%).By chiral column chromatographic separation racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone, obtain chirality (2 ' R; 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (15mg).
MSm/z(M+H) +：459
1H?NMR(400MHz，DMSO-d6)：δ＝0.10(m，2H)，0.25(s，3H)，0.34(m，1H)，0.54(m，1H)，2.59(dd，J＝6.4，18.4Hz，1H)，2.85(dd，J＝12.8，18.4Hz，1H)，3.13(s，1H)，3.62-3.67(dd，J＝6.4，12.8Hz，1H)，6.62(d，J＝8Hz，1H)，6.74(s，1H)，6.83(s，1H)，7.10(t，J＝7.8?Hz，1H)，7.19(d，J＝8.4Hz，1H)，7.25-7.32(m，2H)，8.06(s，1H)，10.56(s，1H)ppm。
Embodiment 174
Preparation racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-ethynyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02611
M.W.390.87?C 23H 17ClN 2O 2
The racemize that will in embodiment 173a, prepare (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-2; 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid tert-butyl ester-1,3-dihydro-indol-2-one (54mg; 0.1mmol), Pd (PPh 3) 4(20mg, 0.02mmol), K 3PO 4(110mg, 0.5mmol), (0.5mmol) mixture in toluene (3mL) is under microwave exposure, in 130 ℃ of heating 1 hour for 1mL, 0.5M for trimethylsilyl ethynyl trimethyl borate.Remove in the vacuum and desolvate.In residuum, and the adding methyl alcohol (3mL) and the NaOH aqueous solution (2N, 3mL).With mixture in stirring at room 2h.Remove in the vacuum and desolvate, residuum with ETHYLE ACETATE (20mL) dilution, is used salt solution, saturated NH 4Cl, brine wash is separated organic layer then, and concentrates.Residuum by preparation HPLC purifying, is obtained racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-ethynyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (2mg).
Trimethylsilyl ethynyl trimethyl borate solution is according at Lutzen, L. etc., Synthesis, 2006, No3, the literature method preparation among the 519-527.
Embodiment 175
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl sulphonyl-4-piperidyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02621
M.W.687.62?C 33H 33Cl 2FN 4O 5S
With 1-methylsulfonyl-piperidines-4-amine trifluoroacetate (111mg, 0.38mmol) with N-methylmorpholine (208uL, 1.9mmol) and DMAP (3mg) in DMF (2ml), stir 5min together, obtain clear solution.Be added in the racemize (2 ' R for preparing among the embodiment 57a; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (0.1g; 0.18mmol) solution in DMF (1mL), and with mixture in microwave oven, in 100 ℃ of heating 15min.Mixture is toppled in the entry, and extract with EtOAc (4x).With the organic layer water, brine wash, drying, and concentrate, obtaining yellow residuum, it is used in the 0-5%MeOH wash-out in the methylene dichloride through 12g silicagel column purifying.Obtain white powder (74.3mg, 60% yield), be the racemic mixture of needs.It separates into two kinds of optically pure enantiomer compounds (each 24mg) by the chirality SFC that uses 30% methyl alcohol.
MSm/z(M+H) +：687
Embodiment 176a
Preparation midbody 4-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester
Figure G2007800087501D02622
M.W.333.45?C 14H 27N 3O 4S
To 1-Boc-4-(2-amino-ethyl)-piperazine (1.26g, 6.8mmol) and in the stirred solution of triethylamine (1mL) in THF (10ML), in room temperature add at leisure 3-chloro-sulfonyl propyl chlorine (Aldrich, 0.68mL, 6.94mmol).Mixture was stirred 30 minutes, and will react the water quencher.New blend is used ethyl acetate extraction, and extract is merged and dry (Na 2SO 4).Be dissolved among the THF (20mL) with solution concentration and with residuum, add Cs 2CO 3(500mg), NaI (80mg), and with mixture stirred overnight under refluxing.Mixture is cooled to room temperature, and topples in the entry.New blend with ethyl acetate extraction (3x15mL), and is merged extract and dry (Na 2SO 4).Remove to desolvate on the rotatory evaporator and obtain solid.2.01g。
MSm/z(M+H) +：334
Embodiment 176b
Preparation midbody 1-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine two-trifluoroacetic acid
Figure G2007800087501D02631
M.W.233.33?C 9H 19N 3O 2S
4-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.01g) is used 30%TFA/CH 2Cl 2(10mL) handle, and with mixture in stirring at room 30min.Decompression removes down and desolvates, and obtains solid.2.46g。
MSm/z(M+H) +：234
Embodiment 176c
Preparation chirality (2 ' R; 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [4-(1,1-dioxy (dioxo)-2-isothiazole alkyl) ethyl] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone
M.W.742.70?C 36H 38Cl 2FN 5O 5S
With with the similar mode of method described in the embodiment 175, racemize (2 ' R, the 3R that will in embodiment 57a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g; 0.18mmol) react with the 1-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl] that in embodiment 176b, prepares-piperazine two-trifluoroacetic acid, and carry out chirality SFC and separate; Obtain chirality (2 ' R; 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [4-(1,1-dioxy-2-isothiazole alkyl) ethyl] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' 91H)-diketone.
MSm/z(M+H) +：742
Embodiment 177
Preparation chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [3-(methyl sulphonyl) propyl group] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02641
M.W.715.68?C 35H 37Cl 2FN 4O 5S
With with the similar mode of method described in the embodiment 176, racemize (2 ' R, the 3R that will in embodiment 57a, prepare; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(fluorine carbonyl)-methyl]-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3; 3 '-piperidines] (0.1g is 0.18mmol) with the reaction of 1-[(3-methyl sulphonyl) propyl group] piperazine dihydrochloride (US23289) for-2,6 ' (1H)-diketone; And carry out chiral separation; Obtain chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [3-(methyl sulphonyl) propyl group] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3; 3 '-piperidines]-2,6 ' (1H)-diketone.
MSm/z(M+H) +：715
Embodiment 178a
Preparation midbody 1-(2-bromo-2-fluorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02651
M.W.316.25?C 12H 15BrFNOSi
With with the similar mode of method described in the embodiment 1b, with 2-bromo-2-fluoro-phenyl aldehyde (8.1g, 40mmol) (Alfa) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1; 1,3,3, and the 3-hexamethyldisilazane (6.4g, 40mmol); Just-and butyllithium (2.5M, 16mL, 40mmol), trimethylsilyl chloride (4.4g; 40mmol), triethylamine (5.6g, 52mmol) and Acetyl Chloride 98Min. (4.1g, 52mmol) reaction; Obtain 1-(2-bromo-2-fluorophenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 178b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromo-5-fluorophenyl) 6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.534.22?C 24H 16BrCl 2FN 2O 2
To the E/Z-6-chloro-3-that in embodiment 55a, prepares (3-chloro-tolylene)-1-(2-trimethyl silyl-ethoxyl methyl)-1; 3-dihydro-indol-2-one (3.76g; 8.13mmol) in the stirred solution in toluene (40mL), be added in 1-(2-bromo-2-fluorophenyl)-3-front three of preparing among the embodiment 178a for siloxy--2-azepine-1,3-butadiene (10.25g; 32mmol), and with mixture under refluxing, stir 2.5h.Reaction mixture is cooled to room temperature, and adds methyl alcohol (20mL).In room temperature, new blend is stirred 1h, then through short silicagel pad.With post with 30% (EtOAc/ hexane) rinsing.Remove and desolvate, and (the 0-44%EtOAc/ hexane, 30min.) purifying obtains faint yellow solid by the chromatogram on the ISCO machine with residuum.4.22g。
(1.5g 2.12mmol) uses TFA/CH with this solid 2Cl 2(30%) handle, and with mixture in stirred overnight at room temperature.Except that desolvating and residuum being dissolved in the methyl alcohol (20mL).Then, adding DIPEA (Aldrich, 2mL), and with mixture stirring 2h under refluxing.Remove and desolvate, and (the 25-48%EtOAc/ hexane, 30min.) purifying obtains pale solid by the chromatogram on the ISCO machine with residuum.520mg。
MSm/z(M+H) +：534
Embodiment 179
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-(2-ethynyl-5-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02661
M.W.479.34?C 26H 17Cl 2FN 2O 2
To the racemize that in embodiment 178b, prepares (2 ' R, 3R, 4 ' S)-2 '-(2-bromo-5-fluorophenyl) 6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines] (120mg is 0.23mmol) in the stirred solution in DMF (2mL) for-2,6 ' (1H)-diketone; Add TMS-acetylene (Aldrich; 88mg, 0.92mmol), PdCl 2(PPh 3) 2(Aldrich, 10mg) and Et 3(Aldrich 0.35mL), and uses nitrogen purging with mixture to N, then in 100 ℃ of heating 2h.Decompression removes down and desolvates, and residuum is dissolved in the methyl alcohol (5mL).In stirred solution, add KF (210mg), and with new blend in stirred overnight at room temperature.Remove and desolvate, and (the 30-40EtOAc/ hexane, 30min.) purifying obtains faint yellow solid by the chromatogram on the ISCO machine with residuum.32mg。
MSm/z(M+H) +：479
Embodiment 180
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-{ 5-fluoro-2-[3-(methylsulfonyl-methyl-amino)-third-1-alkynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02662
M.W.600.50?C 29H 24Cl 2FN 3O 4S
To the racemize that in embodiment 178b, prepares (2 ' R, 3R, 4 ' S)-2 '-(2-bromo-5-fluorophenyl) 6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines] (63mg is 0.12mmol) in the stirred solution in DMF (2mL) for-2,6 ' (1H)-diketone; (through using triethylamine, methylsulfonyl chloride is handled said ammonia chloride preparation, 70mg to add N-methyl-N-third-2-alkynes-Toluidrin; 0.48mmol), PdCl 2(PPh 3) 2(20mg) and Et 3N (0.5mL), and mixture used nitrogen purging, then in 100 ℃ of heating 4h.Decompression removes down and desolvates, and (50%EtOAc/ hexane, 30min.) purifying obtain white solid by the chromatogram on the ISCO machine with residuum.20mg。
MSm/z(M+H) +：479
Embodiment 181a
Preparation midbody 1-[5-bromo-2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02671
M.W.472.57?C 20H 34BrNO 3Si 2
With with the similar mode of method described in the embodiment 1b, (17.25g is 48mmol) with 1,1 for the 5-bromo-2-that will in embodiment 130a, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl aldehyde; 1,3,3,3-hexamethyldisilazane (8.28g; 48mmol), just-butyllithium (2.5M, 19.2mL, 48mmol); Trimethylsilyl chloride (6.07mL, 48mmol), triethylamine (8.7mL; 62.5mmol) and Acetyl Chloride 98Min. (4.53mL, 62mmol) reaction obtains 1-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-chloro-phenyl]-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl is yellow oil, and under situation about not being further purified, is used for next step.
Embodiment 181b
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02681
M.W.576.28?C 26H 21BrCl 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (2.5g; 6.4mmol) with 1-[5-bromo-2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-phenyl of in embodiment 181a, preparing]-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl reacts in toluene, reacts in methylene dichloride with trifluoroacetic acid then, obtains racemize (2 ' R; 3R; 4 ' S)-2 '-[5-bromo-2-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be solid (1.52g, 41%).
MSm/z(M+H) +：576
Embodiment 182a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02682
M.W.521.40?C 28H 22Cl 2N 2O 4
To the racemize that in embodiment 181b, prepares (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines]-2; (60mg 0.11mmol) in the solution in DMF (2mL), adds Et to 6 ' (1H)-diketone 3N (0.3mL), PdCl 2(Ph 3P) 2(Aldrich, 15mg), and with mixture with nitrogen purging and sealing.Container is heated 25min on microwave reactor, and mixture is toppled in the entry.Mixture is extracted with EtOAc.Extract is merged, and use dried over sodium sulfate, and dry, obtaining brown oil, it obtains foam through chromatogram (30-100%EtOAc/ hexane) purifying on the ISCO machine.45mg。Then, foam is dissolved in the methyl alcohol (4mL), and adding KF (Aldrich, 53mg).With mixture in stirred overnight at room temperature.Except that desolvating and residuum being distributed between EtOAc/ water.Organic layer is dry, and concentrate and with residuum by the chromatogram on the ISCO machine (30-100%EtOAc/ hexane) purifying, obtain pale solid.25mg。
MSm/z(M+H) +：521
Embodiment 182b
Preparation chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02691
M.W.521.40?C 28H 22Cl 2N 2O 4
Through chirality SFC, carry out from racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines] separation of two kinds of enantiomers in-2,6 ' (1H)-diketone (65mg), so that chirality (2 ' R to be provided; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 26.3mg, 40%) and chirality (2 ' S; 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone is white solid (yield: 25mg, 38%).
1H?NMR(300MHz，DMSO-d6)：δ＝2.51(m，1H)，2.98(dd，J＝13.9，15.6Hz，1H)，3.75-3.96(m，6H)，4.65(brs，1H)，5.58(s，1H)，6.40(d，J＝1.8Hz，1H)，6.68(d，J＝9Hz，1H)，6.78(d，J＝8.5Hz，1H)，6.81(dd，J＝9.3Hz，2.4，2H)，7.04-7.1(m，2H)，7.13(dd，J＝9.5Hz，2.1Hz，2H)，7.50(d，J＝8.2Hz，1H)，8.06(br，1H)，10.27(br，s，1H)ppm。
Embodiment 183a
Preparation midbody [2-(4-bromo-3-fluoro-phenoxy)-the oxyethyl group]-tertiary butyl-dimethyl--silane
M.W.349.32?C 14H 22BrFO 2Si
With with the similar mode of method described in the embodiment 132a, with 4-bromo-3-fluoro-phenol (12g, 62.3mmol) and K 2CO 3(26g, 188mmo) (18.0g, 75.3mmol) reaction obtains [2-(4-bromo-3-fluoro-phenoxy)-the oxyethyl group]-tertiary butyl-dimethyl--silane, is yellow oil (17.2g, 77%) with (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl--silane.
Embodiment 183b
Preparation midbody 3-bromo-6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-2-fluoro-phenyl aldehyde
Figure G2007800087501D02702
M.W.377.33?C 15H 22BrFO 3Si
With with the similar mode of method described in the embodiment 52a, 1 [2-(4-bromo-3-fluoro-the phenoxy)-the oxyethyl group]-tertiary butyl-dimethyl--silane that will in embodiment 183a, prepare (17.2g, 49.3mmol) with lithium diisopropylamine (32.8mL; 2.0M, in THF, 59.1mmol); N, N-dimethyl--methane amide (4.57mL, 59.1mmol) reaction; And (12.1g 197.2mmol) and water (61.8mL) quencher, obtains 3-bromo-6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-2-fluoro-phenyl aldehyde to be used in acetate in the THF; Be white solid (yield: 12g, 67%).
Embodiment 183c
Preparation midbody 1-{3-bromo-6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-2-fluoro-phenyl }-the 3-front three is for siloxy--2-azepine-1,3-butadiene
Figure G2007800087501D02711
M.W.490.57?C 20H 33BrFNO 3Si 2
With with the similar mode of method described in the embodiment 1b, (3.96g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 3-bromo-6-that will in embodiment 183b, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-2-fluoro-phenyl aldehyde, with 1; 1,1,3,3; The 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL; 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL; 13mmol) and Acetyl Chloride 98Min. (0.97mL, 13mmol) reaction obtains 1-{3-bromo-6-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-2-fluoro-phenyl }-the 3-front three is for siloxy--2-azepine-1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 183d
Preparation racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02712
M.W.594.27?C 26H 20BrCl 2FN 2O 4
To 1-{3-bromo-2-fluoro-6-[2-(tertiary butyl-dimethyl--siloxy)-the oxyethyl group]-phenyl that in embodiment 183c, prepares }-the 3-front three is for siloxy--2-azepine-1; In the solution of 3-divinyl in toluene (30mL); Be added in E/Z-6-chloro-3-(3-chlorine the tolylene)-2-oxo-2 for preparing among the embodiment 24a; 3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g, 1.28mmol).Under nitrogen, in ST, reaction mixture is stirred 45min in 140 ℃.After solution is cooled to room temperature, add methyl alcohol (10mL).The short pad of reaction mixture through zeyssatite glue filtered, and wash with ETHYLE ACETATE.To filtrate and concentrate.Residuum is dissolved in methylene dichloride (20mL), and adds trifluoroacetic acid (15mL).With reaction mixture behind stirring at room 1h, mixture is concentrated.With residuum at saturated NaHCO 3Distribute between solution and the ETHYLE ACETATE.Water layer is used ethyl acetate extraction.The organic layer that merges is used Na 2SO 4Drying, and concentrate.Residuum is dissolved in the THF (10mL), and (1M is in THF, 10mL) to add tetrabutylammonium fluoride solution.Reaction mixture in stirring at room 10min, is toppled in the entry then, and use ethyl acetate extraction.The organic layer that merges is used MgSO 4Drying, and concentrate.Residuum by chromatogram purification, is obtained racemize (2 ' R, 3R; 4 ' S)-2 '-[3-bromo-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be yellow solid (yield 0.4g, 65.6%).
HRMS (ES +) m/z calculated value C 26H 20BrCl 2FN 2O 4+ H [(M+H) +]: 593.0041.Measured value: 593.0039.
Embodiment 184a
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02721
M.W.611.58?C 31H 29Cl 2FN 2O 4Si
To the racemize that in embodiment 183d, prepares (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3; 3 '-piperidines] (0.12g is 0.202mmol) at N for-2,6 ' (1H)-diketone; In the solution in the dinethylformamide (1mL); Add ethynyl-trimethylammonium-silane (0.28mL, 2.0mmol) (Aldrich) and triethylamine (0.127g, 2.0mmol).Behind 5min that reaction mixture is outgased, add two chloro-two-(triphenyl-phosphine) (14mg, 0.02mmol) (Strem), and under nitrogen, with reaction mixture in 100 ℃ of heated overnight.Reaction mixture is cooled to room temperature, and dilute with water, ethyl acetate extraction used.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates.Residuum is used chromatogram purification; Obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3; 3 '-piperidines]-2; 6 ' (1H)-diketone is brown solid (yield: 50mg, 40.6%).
Embodiment 184b
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[3-ethynyl-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.539.39?C 28H 21Cl 2FN 2O 4
To the racemize that in embodiment 184a, prepares (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2; 6 ' (1H)-diketone (50mg; 0.08mmol) in the solution in methyl alcohol (2mL), add KF (9.5mg, 0.16mmol) (Aldrich).With reaction mixture in stirred overnight at room temperature.Remove and desolvate, and, use ethyl acetate extraction the residuum dilute with water.Organic layer is merged, water, brine wash is used MgSO 4Drying is filtered, and concentrates.Residuum is used chromatogram purification, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[3-ethynyl-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be brown solid.
HRMS (ES +) m/z calculated value C 28H 21Cl 2FN 2O 4+ H [(M+H) +]: 539.0935.Measured value: 539.0935.
1H?NMR(400MHz，DMSO-d6)：δ＝2.51(dd，J＝4.9，17.6Hz，1H)，3.18(dd，J＝14.2，17.6Hz，1H)，3.75-3.96(m，5H)，4.23(s，1H)，4.79(brs，1H)，5.67(s，1H)，6.40(d，J＝2Hz，1H)，6.67(d，J＝9Hz，1H)，6.71(d，J＝7.9Hz，1H)，6.82(s，1H)，6.99(d，J＝7.9Hz，1H)，7.09(t，J＝7.8Hz，1H)，7.17(d，J＝9Hz，1H)，7.26(t，J＝8.1Hz，1H)，7.66(m，1H)，8.25(s，1H)，10.43(s，1H)ppm。
Embodiment 185a
Preparation midbody 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl aldehyde
M.W.308.50?C 17H 28O 3Si
With with the similar mode of method described in the embodiment 130a, with 5-ethyl-2-hydroxyl-phenyl aldehyde (4.75g, 31.7mmol) and K 2CO 3(13.1g, 95.1mmo) (9.09g, 38.0mmol) reaction obtains 2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl aldehyde, is Vandyke brown oily matter (9.0g, 92.7%) with (2-bromo-the oxyethyl group)-tertiary butyl-dimethyl--silane.
Embodiment 185b
Preparation midbody 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl }-the 3-front three is for siloxy--2-azepine 1,3-butadiene
Figure G2007800087501D02742
M.W.421.73?C 22H 39NO 3Si 2
With with the similar mode of method described in the embodiment 1b, (3.24g 10.5mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 2-that will in embodiment 185a, prepare [2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl aldehyde, with 1; 1,1,3,3; The 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4mL; 10.5mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g; 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction obtains 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl }-the 3-front three is for siloxy--2-azepine 1; The 3-divinyl is yellow glue, and under situation about not being further purified, is used for next step.
Embodiment 185c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure G2007800087501D02751
M.W.525.44?C 28H 26Cl 2N 2O 4
With with the similar mode of method described in the embodiment 41b, the E/Z-6-chloro-3-that will in embodiment 24a, prepare (3-chloro-tolylene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.5g; 1.28mmol) with 1-{2-[2-(tertiary butyl-dimethyl--siloxy)-oxyethyl group]-5-ethyl-phenyl of in embodiment 185b, preparing-the 3-front three is for siloxy--2-azepine 1; The 3-divinyl reacts in toluene, reacts in methylene dichloride with trifluoroacetic acid (20mL) then, obtains racemize (2 ' R; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone; Be white solid (0.20g, 29.8%).
HRMS (ES +) m/z calculated value C 28H 26Cl 2N 2O 4+ H [(M+H) +]: 525.1343 measured values: 525.1343.
Embodiment 186
Activity test in vitro
Test by HTRF (homogeneous phase time discrimination fluorescence); Measure compound and suppress interactional ability between p53 and the MDM2 albumen; In HTRF (homogeneous phase time discrimination fluorescence) test, the MDM2 of reorganization GST-mark is attached on the peptide, and described peptide is similar to the MDM2-interaction area (Lane etc.) of p53.The combination of GST-MDM2 albumen and p53-peptide (at biotinylation on its N-end) is to write down through the FRET (fluorescence resonance energy transmission) between the allophycocyanin (APC) of anti--GST antibody of europium (Eu)-mark and chain enzyme antibiotin-put together.
At TV is 40uL; Accommodate: 90nM biotinylation peptide; 160ng/mlGST-MDM2; 20nM chain enzyme antibiotin-APC (PerkinElmerWallac), the anti--GST-antibody (PerkinElmerWallac) of 2nMEu-mark, 0.2% bovine serum albumin(BSA) (BSA); In the flat 384-orifice plate of black (Costar) of 1mM WR 34678 (DTT) and 20mM Tris-borate salt solution (TBS) damping fluid, test as follows: the GST-MDM2 (640ng/ml working solution) of 10uL in reaction buffer joined in each hole.The compound (in reaction buffer, diluting with 1:5) of 10uL dilution is joined in each hole, mix through vibration.The biotinylation p53 peptide (180nM working solution) of 20uL in reaction buffer joined in each hole, and on vibrator, mix.In 37 ℃ of incubation 1h.Add the chain enzyme antibiotin-APC of 20uL in containing the TBS damping fluid of 0.2%BSA anti-with Eu--GST mixtures of antibodies (6nM Eu-resists-GST and 60nM chain enzyme antibiotin-APC make solution); In room temperature vibration 30 minutes; And use can TRF plate reader in 665 and 615nm (Victor5, PerkinElmerWallac) reading.If do not specify, reagent is available from Sigma chemistry ltd (SigmaChemical Co.).
Show said bioactive IC of the present invention 50Show the activity that is lower than about 10 μ M.
Representative value for example has:
Embodiment IC 50 (μ M, 0.02%BSA)
5d 2.4315
14b 0.4403
20 1.8111
26b 0.4899
31 0.3721

Claims (37)

1. formula I compound
Figure FSB00000676414000011
Wherein
X is selected from hydrogen, halogen, cyanic acid, cyclopropyl, methyl, ethyl, sec.-propyl, and methoxyl group;
Y is hydrogen or fluorine;
R 4And R 5Be hydrogen or C 1-8-alkyl;
R 1And R 8In one be selected from C 1-8-alkyl is by C 1-8-alkyl, halogen, C 1-8The substituted C of-alkyl-carbonyl or hydroxyl 1-8-alkyl, C 2-8-thiazolinyl is by C 1-8The substituted C of-alkyl, halogen, naphthenic base or hydroxyl 2-8-thiazolinyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, naphthenic base, C 2-6-alkynyl, CF 3Or the substituted aryl of hydroxyl, heteroaryl is by C 1-8The substituted heteroaryl of-alkyl or halogen, naphthenic base, and cycloalkenyl group, and another is a hydrogen;
R 6And R 7In one be selected from C 1-8-alkyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, hydroxyl, CF 3, C 1-8-alkyl-carbonyl or C 1-8The substituted aryl of-alkoxy carbonyl, heteroaryl and by the substituted heteroaryl of halogen, and another is hydrogen, cyanic acid or C 1-8-alkyl;
R 2Be selected from hydrogen, C 1-8-alkyl and by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl;
R 3Be selected from oxygen, sulphur and NNH (C=O) OR 9
R 9Be C 1-8-alkyl;
Wherein, Said naphthenic base is meant any stable monocycle or the multi-loop system of only being made up of carbon atom; Its any ring all is saturated, and said cycloalkenyl group is meant any stable monocycle or the multi-loop system of only being made up of carbon atom, and wherein its at least one ring is that part is unsaturated;
Said aryl is meant phenyl or naphthyl;
Said heteroaryl is meant thienyl or pyridyl; Perhaps
Following compound:
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(cyclopropyl is amino)-carbonyl-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-[[2-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6-dioxo spiral shell [3H-indoles-3,3 '-piperidines]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-tetramethyleneimine-1-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-morpholine-4-base-ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[3-chloro-5-(4-methylsulfonyl-piperazine-1-carbonyl)-phenyl]-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclopropyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[(1-methylsulfonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(cyclopropyl aminocarboxyl-methyl)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl sulphonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-1,1-dimethyl--ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-acetylamino-piperidines-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-(3-piperidines-1-base-propyl group) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-cyclopropyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-(methylamino-carbonyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-carbonyl-methyl)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(4-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(3-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-ethyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S) 2 '-[2-(4-aminocarboxyl-piperidines-1-yl) methyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(4-methylsulfonyl-piperazine-1-yl) methyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-fluoro-2-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-methyl]-phenyl }-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl sulphonyl-4-piperidyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [4-(1,1-dioxo-2-isothiazole alkyl) ethyl] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [3-(methyl sulphonyl) propyl group] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2-[3-(methylsulfonyl-methyl-amino)-third-1-alkynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(1,3-benzo dioxole-4-yl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
And pharmaceutical salts.
2. the described compound of claim 1, it is a formula II compound,
Wherein
X is a hydrogen, halogen, cyanic acid, cyclopropyl, methyl, ethyl, sec.-propyl, and methoxyl group;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 2Be hydrogen, C 1-8-alkyl or by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl;
R 4And R 5Be hydrogen or C 1-8-alkyl;
R 6Be hydrogen, cyanic acid, or C 1-8-alkyl;
R 3Be O, S or NNH (C=O) OR 9
R 7Be selected from C 1-8-alkyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, hydroxyl ,-CF 3, C 1-8-alkyl-carbonyl or C 1-8The substituted aryl of-alkoxy carbonyl, heteroaryl and by the substituted heteroaryl of halogen;
R 8Be selected from C 1-8-alkyl is by C 1-8-alkyl, halogen, C 1-8The substituted C of-alkyl-carbonyl or hydroxyl 1-8-alkyl, C 2-8-thiazolinyl is by C 1-8The substituted C of-alkyl, halogen, naphthenic base or hydroxyl 2-8-thiazolinyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, naphthenic base, C 2-6-alkynyl ,-CF 3Or the substituted aryl of hydroxyl, heteroaryl is by C 1-8The substituted heteroaryl of-alkyl or halogen, naphthenic base, and cycloalkenyl group;
R 9Be C 1-8-alkyl;
Wherein, Said naphthenic base is meant any stable monocycle or the multi-loop system of only being made up of carbon atom; Its any ring all is saturated, and said cycloalkenyl group is meant any stable monocycle or the multi-loop system of only being made up of carbon atom, and wherein its at least one ring is that part is unsaturated;
Said aryl is meant phenyl or naphthyl;
Said heteroaryl is meant thienyl or pyridyl;
And pharmaceutical salts.
3. the described compound of claim 2, wherein
X is a chlorine or bromine;
Y is a hydrogen;
R 1Be hydrogen;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 7Be substituted phenyl or substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl are selected from
Figure FSB00000676414000061
R 8Be independently selected from: C 1-8-alkyl is by C 1-8-alkyl, halogen, C 1-8The substituted C of-alkyl-carbonyl or hydroxyl 1-8-alkyl, C 2-8-thiazolinyl is by C 1-8The substituted C of-alkyl, halogen, naphthenic base or hydroxyl 2-8-thiazolinyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, naphthenic base, C 2-6-alkynyl ,-CF 3Or the substituted aryl of hydroxyl, heteroaryl is by C 1-8The substituted heteroaryl of-alkyl or halogen, naphthenic base, and cycloalkenyl group; And
R 2Be hydrogen, C 1-8-alkyl or by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl; Condition is to work as R 2Be C 1-8-alkyl or substituted C 1-8During-alkyl, R 8Be selected from: C 2-8-thiazolinyl is by C 1-8The substituted C of-alkyl, halogen, naphthenic base or hydroxyl 2-8-thiazolinyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, naphthenic base, C 2-6-alkynyl, CF 3Or the substituted aryl of hydroxyl, heteroaryl is by C 1-8The substituted heteroaryl of-alkyl or halogen, naphthenic base, and cycloalkenyl group.
4. the described compound of claim 3, wherein
X is-Cl or-Br;
Y is a hydrogen;
R 1Be hydrogen;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 7Be substituted phenyl or substituted heteroaryl, wherein said substituted phenyl or substituted heteroaryl are selected from
Figure FSB00000676414000071
And
R 8Be selected from
Figure FSB00000676414000072
Wherein
R 1' be hydrogen, methyl, ethyl, propyl group, or sec.-propyl;
R 2' be hydrogen, methyl, ethyl, propyl group, or sec.-propyl;
R 3' be hydrogen ,-F, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, the tertiary butyl or sec.-butyl;
R 4' be hydrogen ,-F ,-Cl ,-Br ,-I, methyl, ethyl, cyclopropyl, cyanic acid, methoxyl group, or ethynyl;
R 5' be hydrogen ,-F or methyl;
R 6' be selected from hydrogen, halogen, hydroxyl, cyanic acid, C 1-8-alkyl is by the substituted C of halogen 1-8-alkyl, C 1-8-alkoxyl group is by C 1-8-alkyl, C 1-8-alkoxyl group, hydroxyl or C 1-8The substituted C of-alkyl-carbonyl 1-8-alkoxyl group, C 2-6-alkynyl, or by N (C 1-4-alkyl)-S (O) 2-CH 3Substituted C 2-6-alkynyl;
R 7' be hydrogen ,-F or methyl;
R 8' be hydrogen ,-F, methyl, ethyl;
R 9' be hydrogen, hydroxyl, or-F;
R 10' be hydrogen or-F;
R 11' be hydrogen or methyl;
R 12' be hydrogen or methyl;
R 2Be hydrogen, C 1-8-alkyl or by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl; Condition is to work as R 2Be C 1-8-alkyl or substituted C 1-8During-alkyl, R 8Be selected from:
Figure FSB00000676414000081
5. the described compound of claim 1, it is the formula III compound
Figure FSB00000676414000082
Wherein
X is selected from hydrogen, halogen, cyanic acid, cyclopropyl, methyl, ethyl, sec.-propyl, and methoxyl group;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 2Be hydrogen, C 1-8-alkyl or by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl;
R 4And R 5Be hydrogen or C 1-8-alkyl;
R 6Be hydrogen, cyanic acid or C 1-8-alkyl;
R 3Be O, S or NNH (C=O) OR 9
R 7Be selected from C 1-8-alkyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, hydroxyl ,-CF 3, C 1-8-alkyl-carbonyl or C 1-8The substituted aryl of-alkoxy carbonyl, heteroaryl and by the substituted heteroaryl of halogen;
R 8Be selected from C 1-8-alkyl is by C 1-8-alkyl, halogen, C 1-8The substituted C of-alkyl-carbonyl or hydroxyl 1-8-alkyl, C 2-8-thiazolinyl is by C 1-8The substituted C of-alkyl, halogen, naphthenic base or hydroxyl 2-8-thiazolinyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, naphthenic base, C 2-6-alkynyl ,-CF 3Or the substituted aryl of hydroxyl, heteroaryl is by C 1-8The substituted heteroaryl of-alkyl or halogen, naphthenic base, and cycloalkenyl group; And
R 9Be C 1-8-alkyl;
Wherein, Said naphthenic base is meant any stable monocycle or the multi-loop system of only being made up of carbon atom; Its any ring all is saturated, and said cycloalkenyl group is meant any stable monocycle or the multi-loop system of only being made up of carbon atom, and wherein its at least one ring is that part is unsaturated;
Said aryl is meant phenyl or naphthyl;
Said heteroaryl is meant thienyl or pyridyl;
And pharmaceutical salts.
6. the described compound of claim 5, wherein
X is-Cl or-Br;
Y is a hydrogen;
R 1Be hydrogen;
R 2Be hydrogen, C 1-8-alkyl or by C 1-8-alkyl ,-NH-C 1-8-alkyl, N (C 1-8-alkyl) 2, aminocarboxyl, carboxyl, C 1-8-alkoxyl group, C 1-8-alkyl-carbonyl or C 1-8The substituted C of-alkoxy carbonyl 1-8-alkyl;
R 4And R 5All be hydrogen;
R 6Be hydrogen;
R 3Be O;
R 8Be substituted phenyl, wherein said substituted phenyl is selected from
Figure FSB00000676414000101
and
R 7Be selected from C 1-8-alkyl, aryl is by C 1-8-alkyl, C 1-8-alkoxyl group, halogen, cyanic acid, hydroxyl ,-CF 3, C 1-8-alkyl-carbonyl or C 1-8The substituted aryl of-alkoxy carbonyl, heteroaryl and by the substituted heteroaryl of halogen.
7. according to claim 1,2 or 5 formula I, II or III compound, wherein
X is-Cl;
Y; R 1R 2R 4R 5And R 6Be hydrogen;
R 3Be oxygen; And
R 7And R 8Be phenyl, they are unsubstituted independently of one another or are replaced 1,2 or 3 time by following group:
C 1-8-alkyl, C 2-6-alkynyl, dioxo-C 1-8-alkylidene group, halogen, hydroxyl ,-CN ,-CF 3,
C 1-8-alkoxyl group, hydroxyl-C 1-8-alkoxyl group and can choosing wantonly by halogen or the substituted C of hydroxyl 1-8-alkyl.
8. according to claim 1,2 or 5 formula I, II or III compound, wherein
X is-Cl;
Y; R 1R 2R 4R 5And R 6Be hydrogen;
R 3Be oxygen; And
R 7And R 8Be phenyl, they are unsubstituted or are substituted base and replace 1,2 or 3 time that described substituting group is independently selected from independently of one another:
Halogen, C 2-4-alkynyl or-O-(C 1-4Alkyl), and
Said C 2-4-alkynyl or-O-(C 1-4Alkyl) be unsubstituted or by hydroxyl or-N (C 1-4Alkyl)-S (O) 2-CH 3Replace 1 time.
9. the compound of claim 1, it is selected from:
(2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
(2 ' SR, 3S, 4 ' R)-4 '-(tertiary butyl)-6-chloro-2 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
(2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-cyclohexyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(4-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(4-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
10. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(2-chloro-phenyl-)-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone.
11. the compound of claim 1, it is selected from:
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-ethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-2 ', 4 '-two (3-chloro-phenyl-)-5 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-isopropyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-2 '-(2-bromophenyl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
12. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-ethyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 6-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(methoxycarbonyl) methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone.
13. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(hydroxycarbonyl group)-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl)-1 '-[2-(4-morpholinyl)-carbonyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(cyclopropyl amino)-carbonyl-methyl]-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-[[2-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(2-aminomethyl phenyl)-2,6-dioxo spiral shell [3H-indoles-3,3 '-piperidines]-1-yl]-1-oxoethyl]-amino]-piperidine carboxylic acid tert-butyl ester.
14. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-[2-(trifluoromethyl) phenyl)]-2-oxo spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit]-hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-p-methoxy-phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclohexenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone.
15. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-2 '-(1,3-benzo dioxole-4-yl)-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-fluorine carbonyl methyl-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
16. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl)-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[1-tertbutyloxycarbonyl-piperidin-4-yl) aminocarboxyl-methyl] 6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-4-methyl-penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
17. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-(3-tetramethyleneimine-1-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methoxycarbonyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[3-(1,1-dioxo-thiomorpholine-4-yl)-propyl group]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl--2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
18. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methyl-but-1-ene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethylidene-amyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(ring penta-1-thiazolinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
19. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-cyclopentyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-sec.-propyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-hydroxyl-1,1-dimethyl ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
20. the compound of claim 1, it is selected from:
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-(3-morpholine-4-base-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2-methyl isophthalic acid-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,2-dimethyl--1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-[(2-morpholine-4-base-ethyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
21. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(4-oxyethyl group-1,2-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-methoxycarbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-hydroxycarbonyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-5-fluorine carbonyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[3-chloro-5-(4-methylsulfonyl-piperazine-1-carbonyl)-phenyl]-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
22. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-sec.-butyl-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-hydroxymethyl-vinyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methoxymethyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-methoxyl group-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1,2-dimethyl--propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-propionyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
23. the compound of claim 1, it is selected from:
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-propoxy--phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-cyclopropyl-vinyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-hydroxycarbonyl group methyl-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-[(1-methylsulfonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-1 '-(aminocarboxyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2,3-two fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-hydroxyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
24. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-1-hydroxyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-3-methyl-Oxyranyle) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-fluoro-2-methyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-isobutyryl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-hydroxycarbonyl group methylspiro [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-(aminocarboxyl-methyl)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(cyclopropyl aminocarboxyl-methyl)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-[(1-methyl sulphonyl-piperidin-4-yl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
25. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-[(2-hydroxyl-1,1-dimethyl--ethyl) aminocarboxyl-methyl]-2 '-pseudoallyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl)-4 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-acetylamino-piperidines-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6 '-cyanic acid-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl)-6-cyanic acid-2 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl-1 '-(3-piperidines-1-base-propyl group) spiral shell [3H-indoles-3,3 ' piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[2-(2-acetoxyl group-oxyethyl group)-5-methyl-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[6-(2-hydroxyl-oxyethyl group)-3-methyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-cyclopropyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
26. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[5-chloro-2-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-[3-chloro-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-cyanic acid-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-methoxyl group-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-fluoro-2-methyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-fluoro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-o-tolyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
27. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-2 '-(1-methylene radical-propyl group)-4 '-thiene-3-yl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3,5-two chloro-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(5-chloro-2-trifluoromethyl-phenyl)-2 '-(1-methylene radical-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-bromo-phenyl)-6-chloro-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-hydroxycarbonyl group methyl-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-1 '-(methylamino-carbonyl-methyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-carbonyl-methyl)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(4-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' S, 3S, 4 ' R)-1 '-[(3-aminocarboxyl-piperidines-1-yl) carbonyl-methyl]-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
28. the compound of claim 1, it is selected from:
Racemize (2 ' S, 3S, 4 ' R)-1 '-(aminocarboxyl-methyl)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(5-fluoro-2-methyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-1 '-(dimethylamino-propyl group)-4 '-(5-fluoro-2-methyl-phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-ethyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(4-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-[2-(5-chloro-thienyl)]-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(2, the 2-dimethyl propyl)-2 '-(5-fluoro-2-aminomethyl phenyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(2, the 5-dichlorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
29. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(5-chloro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-propyl group)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-cyclopropyl-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-cyclopropyl base)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S) 2 '-[2-(4-aminocarboxyl-piperidines-1-yl) methyl-5-fluoro-phenyl)-6-chloro-4 '-(3-chloro-phenyl-)-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(4-methylsulfonyl-piperazine-1-yl) methyl-phenyl]-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-{ 5-fluoro-2-[(1-methylsulfonyl-piperidin-4-yl) carbonylamino-methyl]-phenyl }-spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6-methoxyl group spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
30. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl-)-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-bromo-4 '-(3-chloro-phenyl)-2 '-(1-methyl-cyclopropyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-4 '-(3-chloro-phenyl-)-6-ethynyl-2 '-pseudoallyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-[(1-methyl sulphonyl-4-piperidyl) aminocarboxyl-methyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [4-(1,1-dioxy-2-isothiazole alkyl) ethyl] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-1 '-{ [3-(methyl sulphonyl) propyl group] piperazinyl-carbonyl-methyl } spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone and
Racemize (2 ' R, 3R, 4 ' S)-2 '-(2-bromo-5-fluorophenyl) 6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
31. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-(2-ethynyl-5-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2-[3-(methylsulfonyl-methyl-amino)-third-1-alkynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[5-bromo-2-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Chirality (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethynyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-2 '-[3-bromo-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl]-6-chloro-4 '-(3-chloro-phenyl-) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-fluoro-6-(2-hydroxyl-oxyethyl group)-3-trimethyl silyl ethynyl-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[3-ethynyl-2-fluoro-6-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone,
With
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-ethyl-2-(2-hydroxyl-oxyethyl group)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone.
32. a pharmaceutical prepn, it comprises formula I compound according to claim 1,
Figure FSB00000676414000271
Wherein, X, Y and R 1-R 8Such as in claim 1 definition,
And pharmaceutical salts, and pharmaceutical carrier or vehicle.
33. be used for treating the application of the medicine of cancer in preparation according to the compound of claim 1 to 31.
34. be used for treating the application of the medicine of solid tumor in preparation according to the compound of claim 1 to 31.
35. be used for treating the application of the medicine of mammary gland, colon, lung and tumor of prostate in preparation according to the compound of claim 1 to 31.
36. one kind prepares according to the compound of the formula II of claim 2 or according to the method for the compound of the formula III of claim 5,
Figure FSB00000676414000272
Wherein, X, Y and R 1-R 8Such as in claim 2 or 5 definition,
This method comprises: at about 110-160 ℃ and under anhydrous condition, make the compound of following formula,
Figure FSB00000676414000281
With the compound reaction of following formula,
Figure FSB00000676414000282
Compound with preparation formula II or III.
37. one kind prepares according to the compound of the formula II of claim 2 or according to the method for the compound of the formula III of claim 5,
Figure FSB00000676414000283
Wherein, X, Y and R 1-R 8Such as in claim 2 or 5 definition,
This method comprises: the compound that makes following formula
With suitable protection radical reaction, so that the compound of following formula to be provided,
Figure FSB00000676414000285
Then, at about 110-160 ℃ and under anhydrous condition, the reaction of the compound of itself and following formula,
Figure FSB00000676414000291
Then with the product deprotection that obtains, with the compound of preparation formula II and III.
CN2007800087501A 2006-03-13 2007-03-05 Spiroindolinone derivatives Expired - Fee Related CN101400680B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US78195806P 2006-03-13 2006-03-13
US60/781,958 2006-03-13
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