WO2009077357A1 - Spiroindolinone derivatives - Google Patents

Spiroindolinone derivatives Download PDF

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Publication number
WO2009077357A1
WO2009077357A1 PCT/EP2008/066874 EP2008066874W WO2009077357A1 WO 2009077357 A1 WO2009077357 A1 WO 2009077357A1 EP 2008066874 W EP2008066874 W EP 2008066874W WO 2009077357 A1 WO2009077357 A1 WO 2009077357A1
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WIPO (PCT)
Prior art keywords
chloro
phenyl
indole
spiro
dione
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PCT/EP2008/066874
Other languages
French (fr)
Inventor
Qingjie Ding
Nan Jiang
Song Yang
Jing Zhang
Zhuming Zhang
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F. Hoffmann-La Roche Ag
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Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to MX2010006107A priority Critical patent/MX2010006107A/en
Priority to BRPI0821255-4A priority patent/BRPI0821255A2/en
Priority to JP2010537394A priority patent/JP2011506380A/en
Priority to EP08861848A priority patent/EP2229396B1/en
Priority to CA2707456A priority patent/CA2707456A1/en
Priority to AT08861848T priority patent/ATE519764T1/en
Priority to CN2008801198987A priority patent/CN101896486A/en
Priority to AU2008337651A priority patent/AU2008337651A1/en
Publication of WO2009077357A1 publication Critical patent/WO2009077357A1/en
Priority to IL205354A priority patent/IL205354A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis.
  • p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis.
  • p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53- regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53.
  • MDM2 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein.
  • This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
  • MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
  • MDM2 The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
  • spiroindolinone as antagonists of MDM2 has previously been disclosed in J. Am Chem. So ⁇ , 2005, 127, 10130.
  • the present invention provides spiroindolinone derivatives which are small molecule inhibitors of the MDM2-p53 interaction.
  • compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53- like peptide. In cell-based assays, these compounds demonstrate mechanistic activity.
  • the present invention relates to spiroindolinones of the formula (I)
  • X is -Cl, -F or -Br
  • R is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:
  • W is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, cyclopropyl, cyano, methoxy, hydroxy methyl, -COOMe, ethynyl, -CF 3 , vinyl, isopropenyl, 1 -propynyl, 3-methyl-1 -butynyl, 3,3-dimethyl-1-butynyl, 3-thfluoroethynyl, phenyl, 2- furany, 2-thiophenyl and 4-thiazolyl;
  • Y is hydrogen, -F, -Cl or methyl
  • V is hydrogen, -F, -Cl or methyl;
  • Ri , R 2 are hydrogen or lower alkyl, or may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; and R 3, R 4 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, lower alkenyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl with the proviso that R 3, R 4 are not both hydrogen, or R3/R 4 may independently link to form a cyclic structure selected from a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocycle; and
  • R' is piperidinyl, tetrahydro-pyranyl, cyclohexyl, pyrrol id inyl, phenyl, pyrazinyl and pyrazolyl, all of which may be unsubstituted or substituted by 1 -5 substituents; and all remaining substituents have the meanings given herein before.
  • Most preferred compounds are those of the formula: racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4
  • a benzodioxyl group halogen, hydroxy, -CN, -CF 3 , -NH 2 , -N(H, lower-alkyl), -N(lower-alkyl) 2 , aminocarbonyl, carboxy, -NO 2 , lower-alkoxy, thio- lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fl uoro-lower-al koxy, lower-al koxy-carbonyl-lower-al koxy, carboxy-lower-al koxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, -NH 2 -lower-alkoxy, -N(H, lower-alkyl)-
  • alkyl, alkenyl, alkynyl or similar groups are linked with both ends to the same moiety, cyclic structures may result, where two hydrogens of said moiety are being replaced by the two ends of the alkyl, alkenyl, alkynyl or similar group, thus creating cyclic structures, such as, tetralin, macrocycles or spiro compounds.
  • alkyl refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents.
  • lower alkyl refers to alkyl groups having from 1 to 8 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s- butyl, t-butyl, n-pentyl, and s-pentyl.
  • cycloalkyl is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated
  • cycloalkenyl is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. In both cases mono- or bicyclic systems consisting of 5 to 12 carbon atoms are especially preferred.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds.
  • cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
  • alkenyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 8, preferably 2 to 6 carbon atoms.
  • alkenyl group examples include vinyl (ethenyl), allyl, isopropenyl, 1 -propenyl, 2-methyl-1-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1- butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
  • alkynyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms.
  • alkynyl group examples include ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • halogen as used in the definitions means fluorine, chlorine, iodine or bromine, preferably fluorine and chlorine.
  • Aryl means a monovalent, monocyclic or bicyclic, aromatic hydrocarbon radical, preferably a 6-10 member aromatic ring system.
  • Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • Heteroaryl means a mono- or bicyclic, preferably 5-10 member, aromatic hydrocarbon, wherein 1-4 carbon atoms are replaced by hetero atoms.
  • Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, pyrazolyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
  • aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
  • Heterocycle means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, aromatic or non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin- 2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like. - o -
  • Hetero atom means an atom selected from N, O and S.
  • Alkoxy, alkoxyl or lower alkoxy refers to any of the above lower alkyl groups attached to an oxygen atom.
  • Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like.
  • Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, thfluoro acetic acid and the like.
  • Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
  • Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
  • the compounds of formula (I) as well as their salts have at least one asymmetric carbon atom and therefore may be present as racemic mixtures or different stereoisomers.
  • the various isomers can be isolated by known separation methods, e.g., chromatography.
  • the invention includes all stereoisomers.
  • the compounds of the present invention are useful as medicaments, in particular in the treatment or control of cell proliferative disorders, more particularly oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
  • a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I or Il or III compound which produces a therapeutic effect.
  • compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • Effective amount means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • IC 5 o refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
  • “Pharmaceutically acceptable ester” refers to a conventionally estehfied compound of formula (I) having a carboxyl group or hydroxy group, which esters retain the biological effectiveness and properties of the compounds of formulas I and are cleaved in vivo (in the organism) to the corresponding active carboxyl ic acid or alcohol respectively.
  • an appropriately selected aldehyde I can be reacted with lithium hexamethyldisilamide, chlorotrialkylsilane and acteyl chloride in a one-pot, multi-steps manner to generate 2-aza-1 ,3-butadiene Il (Scheme I) and can be used as a crude product.
  • Scheme I 2-aza-1 ,3-butadiene Il
  • Ghosez, L. and others have reported the preparation of 2-aza-1 ,3-butadienes and their use in aza Diels-Alder reaction to form heterocycle (Ref: Tetrahedron 1995, 11021 ; J. Am. Chem. Soc. 1999, 2617; and literatures cited therein).
  • the appropriately selected aldehyde I are either commercially available or can be synthesized by well- established multiple literature methods.
  • Oxindole III can be reacted with an appropriately substituted aldehyde or ketone in the presence of base under heated condition in either a protic like methanol, ethanol or an aprotic solvent like toluene, o-xylene to give intermediate IV.
  • the commonly used base is either pyrrolidine or pipehdine.
  • Intermediate IV can be protected to give intermediate V.
  • the protective group can be attached by using ethyl chloroformate, di-tert-butyl dicarbonate, SEM-CI, benzyl bromide, and a base like 4-(dimethylamine)pyhdine (DMAP), triethylamine, NaH, or LiH according to well established literature procedures. Examples of protective group formation and their deprotection have been described and reviewed comprehensively by Greene, T.W. et al in "Protective Groups in Organic Synthesis, 2 nd Edition. John Wiley & Sons Inc. - -
  • Intermediate V can be reacted with a selected 2-aza-butadiene Il prepared in Scheme 1 in toluene or o-xylene under heating from 110 0 C to 160 0 C and anhydrous condition to form intermediate Vl and Vl' as the major products shown as a racemic mixture of two enantiomers.
  • a subsequent reaction to remove protective group (Pg) leads to various R2 derivatized compound VII and VM'.
  • Pg is Boc group
  • Boc group can be removed by either thfluoroacetic acid or prolonged heating at a temperarure between 110 to 116 0 C.
  • Racemic mixture of Vl and Vl' or VII and VM' can be readily resolved into two chiral enantiomers by chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral column chromatography.
  • SFC Super Fluid Chromatography
  • compound I can be prepared by reaction of reagent VIII, and compound R'-L, a base like K2CO3 or CS2CO3 in anhydrous N 1 N- dimethylformamide or N,N-dimethylacetamide under heating conditions.
  • L is a good leaving group like Cl, Br, I, OMs or OTs.
  • Compound VIII is either commercially available or readily prepared according to well eastablished literature procedure (Scheme 4).
  • starting material IX can be reacted R'-OH under Mltsunobu reaction cindtion to give intermediate X, which can be reduced by LiAIH 4 or DIBAL to alcohol, then oxidized by MnO2 or under Swern oxidation condtions to give intermediate I (Scheme 5).
  • intermediate I can be prepared by a coupling reaction of compound Xl and R'- OH under heated conditions (Scheme 6).
  • R 2 H: CuI, NEt 3 , trimethylsilyl acetylene, PdCI 2 (PPh 3 ) 2 (cat.),100 0 C; then NaOH/MeOH, rt,
  • Analogues Xlll-a are prepared first according to the methods in Scheme 1- 3, followed by reduction of nitro group to amine group in Xlll-b, then a reductive amination reaction to give Xlll-c (Scheme 8).
  • Analogue XIV-b can be prepared according to the procedure in Scheme 9.
  • thmethylsilyl chloride (0.55 g, 5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 0 C on a cooling ice bath. To this mixture was added thethylamine (0.7 g, 6.8 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.5 g, 6.8 mmol) in diethyl ether (40 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h.
  • Trifluoroacetic acid (30 ml_) was added to a solution of racemic (2'R, 3R, 4'S)-2'-[2-(1- (tert-butoxycarbonyl)-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (2 g, 2.62 mmol) prepared in example 4c in dichloromethane (30 ml_). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo, then aqueous saturated NaHCO 3 solution was added.
  • the mixture was diluted with ethyl acetate, washed with water.
  • the organic layer was separated, and aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over MgSO 4 , concentrated.
  • the sloid was dissolved into methanol (10 ml_), and aqueous NaOH solution (1 N, 1.2 ml_) was added. The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO 4 and concentrated.
  • the reaction mixture was stirred at room temperature for 1 h, then concentrated.
  • the residue was partitioned between ethyl acetate and water.
  • the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over MgSO 4 , and concentrated.
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methyl-4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione prepared in example 7 (0.35 g, 0.51 mmol) was reacted with trimethylsilyl acetylene (0.51 ml_, 5.1 mmol), CuI (10 mg), thethylamine (1.56 g, 15.3 mmol), and dichlorobis(thphenylphosphine) palladium (0) (36 mg, 0.051 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4
  • the reaction mixture was heated at reflux (180 0 C) for 8 h, then cooled to room temperature and concentrated.
  • methanol (10 ml_) methanol
  • acetic acid 1 ml_
  • NaCNBH 3 0.1 g, 1.6 mmol
  • the reaction mixture was stirred at room temperature for 1 h, then concentrated.
  • the residue was partitioned between ethyl acetate and water. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO 4 , and concentrated.
  • propionyl chloride (15.4 mg, 0.17 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a and triethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(1-propionyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehd
  • the reaction mixture was heated at 68 0 C for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • Example 13a Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1-ethyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (80 mg, 0.116 mmol) was reacted with trimethylsilyl acetylene (0.114 g, 1.16 mmol), CuI (5 mg), thethylamine (0.35 g, 3.46 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8 mg, 0.012 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4
  • racemic (2'R, 3R, 4'S)-2'- [3-bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (42 mg, 0.066 mmol) prepared in Example 18a was reacted with dimethylcarbamyl chloride (8.54 mg, 0.079 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-dimethylcarbamoyl-4- pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isopropyl-4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (80 mg, 0.11 mmol) was reacted with thmethylsilyl acetylene (0.11 g, 1.1 mmol), CuI (5 mg), triethylamine (0.34 g, 3.3 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8 mg, 0.012 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-
  • racemic (2'R, 3R, 4'S)-6- chloro-2'-[3-chloro-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (87.7 mg, 0.149 mmol) prepared in Example 26a was reacted with dimethylcarbamyl chloride (19.2 mg, 0.178 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1- dimethylcarbamoyl-4-pipehdinyloxy)-2-fluoro-phenyl] -4'-(3-chlorophenyl) spiro[3H- indole-3,3'-pipe
  • racemic (2'R, 3R, 4'S)-2'- [3-bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (40 mg, 0.063 mmol) prepared in Example 18a was reacted with triethylamine and methy isocyanate (4.3 mg, 0.076 mmol) to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-methylcarbamoyl-4-pipehdinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a was reacted with dimethylcarbamyl chloride (19.5 mg, 0.18 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl- 4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.15 g, 0.23 mmol) prepared in Example 5a was reacted with 4-methylpiperazine-1-carbonyl chloride (44.5 mg, 0.27 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'- ⁇ 5-iodo-2- [1 -(4-methylpiperazine-1 -carbonyl)-4-pipehdinyloxy]-phenyl ⁇ spiro[3H-indole-3,3'
  • E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester prepared in example 5b (1.2 g, 3 mmol) was added to the solution of 1 -[5- lodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) in toluene (30 ml_).
  • the reaction mixture was heated under nitrogen at 140 0 C for 2 h.
  • the mixture was cooled to room temperature, concentrated.
  • racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.11 g, 0.179 mmol) prepared in Example 16a was reacted with ethyl chloroformate (23.3 mg, 0.214 mmol) and triethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -ethoxycarbonyl-4-pipehdinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'
  • racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (50 mg, 0.081 mmol) prepared in Example 16a was reacted with isobutyryl chloride (10 mg, 0.097 mmol) and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isobutyryl-4-piperidinyloxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-di
  • racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.1 g, 0.16 mmol) prepared in Example 16a was reacted with isopropyl chloroformate (0.19 ml_, 0.196 mmol) and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -isopropoxycarbonyl-4-piperidinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (0.32 g, 0.48 mmol) prepared in example 5a was reacted with tert-butyl bromoacetate (0.14 g, 0.72 mmol) and thethylamine in ethanol to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(
  • the reaction mixture was heated at 80 0 C for 1 h, then cooled to room temperature.
  • the mixture was partitioned between ethyl acetate and water.
  • the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over MgSO 4 , and concentrated.
  • the reaction mixture was heated under nitrogen at 100 0 C for 1 h, then cooled to room temperature.
  • the mixture was diluted with ethyl acetate, washed with 1 N HCI aqueous solution and H 2 O.
  • the organic layer was separated, dried over Na 2 SO 4 and concentrated.
  • racemic (2'R, 3R, 4'S)-2'- [5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.18 g, 0.28 mmol) was reacted with N-(2- aminoethyl)pyrrolidine (0.4 g, 3.5 mmol), N-methylmorpholine and 4- dimethylaminopyhdine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'- ⁇ 5-bromo-2- [4-(2-pyrrolidin-1 -yl-ethyl carbamoyl )-phenoxy]-phenyl ⁇ -6-chloro-4'-(3-chlorophenyl)
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'- ⁇ 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl ⁇ spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.9 g, 1.26 mmol) was reacted with trimethylsilyl acetylene (0.25 g, 2.5 mmol), CuI (0.48 g, 2.5 mmol), triethylamine (0.25 g, 2.5 mmol) and dichlorobis(thphenylphosphine) palladium(O) (0.18 g, 0.025 mmol) in tetrahydrofuran, then treated with aqueous NaOH solution in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-
  • the mixture was heated under nitrogen at 170 0 C for 0.5 h.
  • the mixture was cooled to room temperature, partitioned between ethyl acetate and water.
  • the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over MgSO 4 , and concentrated.
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.65 g, 0.96 mmol) was reacted with trimethylsilyl acetylene (0.94 g, 9.6 mmol), CuI (10 mg), triethylamine (2.89 g, 28.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (53.6 mg, 0.077 mmol) in anhydrous N 1 N- dimethylformannide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophen
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (0.29 g, 0.42 mmol) was reacted with trimethylsilyl acetylene (0.41 g, 4.2 mmol), CuI (5 mg), triethylamine (1.76 ml_, 12.7 mmol), and dichlorobis(thphenylphosphine) palladium (0) (23.4 mg, 0.034 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.45 g, 0.63 mmol) was reacted with thmethylsilyl acetylene (0.45 g, 6.3 mmol), CuI (3 mg), triethylamine (2.63 ml_, 18.9 mmol), and dichlorobis(thphenylphosphine) palladium (0) (35.3 mg, 0.05 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.68 g, 0.95 mmol) was reacted with an aqueous solution of LiOH (0.41 g, 9.5 mmol) in tetrahydrofuran and methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)- 5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)-5-iodo-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.4 g, 0.57 mmol) was reacted with EDCI (0.22 g, 1.14 mmol), HOBT (0.154 g, 1.14 mmol), diisopropylethylamine (0.29 g, 2.28 mmol), NH 4 CI (60 mg, 1.14 mmol) in N,N-dimethylformamide to give racemic (2'R, 3R, 4'S)-2'- [2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4'-(3-chloroph
  • racemic (2'R, 3R, 4'S)-2'-[2- (4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (0.35 g, 0.5 mmol) was reacted with trimethylsilyl acetylene (0.49 g, 5 mmol), CuI (3 mg), triethylamine (1.52 ml_, 15 mmol), and dichlorobis(triphenylphosphine) palladium (0) (28 mg, 0.04 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-
  • racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyhdinyloxy)-5-iodo-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.62 g, 0.9 mmol) was reacted with thmethylsilyl acetylene (0.89 g, 9 mmol), CuI (5 mg), thethylamine (2.74 g, 27 mmol), and dichlorobis(thphenylphosphine) palladium (0) (50.7 mg, 0.07 mmol) in anhydrous N 1 N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlor

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Abstract

There are provided compounds of the formula (I), and pharmaceutically acceptable salts and esters thereof, wherein W, V, X, Y, A, R and R' are as described herein, processes for making said compounds and methods for using them, in particular as anticancer agents.

Description

SPIROINDOLINONE DERIVATIVES
p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53- regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
A series of spiroindolinone as antagonists of MDM2 has previously been disclosed in J. Am Chem. Soα, 2005, 127, 10130. The present invention provides spiroindolinone derivatives which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53- like peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in G1 and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.
The present invention relates to spiroindolinones of the formula (I)
Figure imgf000003_0001
wherein
X is -Cl, -F or -Br;
R is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:
Figure imgf000003_0002
W is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, cyclopropyl, cyano, methoxy, hydroxy methyl, -COOMe, ethynyl, -CF3, vinyl, isopropenyl, 1 -propynyl, 3-methyl-1 -butynyl, 3,3-dimethyl-1-butynyl, 3-thfluoroethynyl, phenyl, 2- furany, 2-thiophenyl and 4-thiazolyl;
Y is hydrogen, -F, -Cl or methyl;
V is hydrogen, -F, -Cl or methyl; A is selected from the group consisting of a bond, O, NH, CH2, C(=O), C(=O)NH, NHC(=O), NHC(=O)NH, S, S(=O)2 and O(CH2)n; n = 1 , 2 or 3;
R' is selected from the group consisting of heterocycle, substituted heterocyle, heteroaryl, substitluted heteroaryl, aryl, substituted aryl, substituted cycloalkyl, and -CRiR2C(=O)NR3R4 wherein
Ri, R2 are hydrogen or lower alkyl, or may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; and R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, lower alkenyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl with the proviso that R3, R4 are not both hydrogen, or R3/R4 may independently link to form a cyclic structure selected from a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocycle; and
the pharmaceutically acceptable salts and esters thereof.
Preferred are compounds of formula (I) wherein W, X, Y, A, R and R' are as described above and V is hydrogen or F.
Further preferred are compounds of formula (I) wherein W, X, A, R and R' are as described above, V is hydrogen or F and Y is hydrogen or F.
Yet further preferred are compounds of formula (I) wherein X, A, R and R' are as described above, W is F, Cl, Br, I or ethynyl, Y is hydrogen or F and V is hydrogen or F.
Still further preferred are compounds of formula (I) wherein X, R and R' are as described above, W is F, Cl, Br, I or ethynyl, Y is hydrogen or F, V is hydrogen or F and A is O or NH with the proviso that V and Y are not both F.
Still further preferred are the compounds of formula (I), wherein R is 3-chlorophenyl; A is -O- or -NH-;
R' is piperidinyl, tetrahydro-pyranyl, cyclohexyl, pyrrol id inyl, phenyl, pyrazinyl and pyrazolyl, all of which may be unsubstituted or substituted by 1 -5 substituents; and all remaining substituents have the meanings given herein before.
Most preferred compounds are those of the formula: racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylmethoxy)-5-ethynyl-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-pipehdinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-methyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -methyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylamino)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylamino)-5-ethynyl-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-propionyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(3- nnethanesulfonyl-propyl)-4-pipendinyloxy]-phenyl} spiro[3H-indole-3,3'-pipendine]- 2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-methanesulfonyl- 4-piperidinyloxy)phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -methanesulfonyl-4- piperidinyloxy)phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl-4- piperidinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-(tert-butoxycarbonyl)-4-piperidinyloxy)- phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-(tert-butoxycarbonyl)-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-piperidinyloxy)-3-bromo-2-fluoro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethyl-4-piperidinyloxy)-5- ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-piperidinyloxy)-phenyl]-6-chloro-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-dimethylcarbamoyl-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -dimethylcarbamoyl-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -diethylcarbamoyl-4- piperidinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(pyrrolidine-1 - carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, - - racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(pyrrolidine-1 - carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-isopropyl-4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(2-oxo- imidazolidine-1 -carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[6-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-3-chloro-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-piperidinyloxy)-3-chloro-2-fluoro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -dimethylcarbamoyl-4-piperidinyloxy)-2- fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -methylcarbamoyl-4-piperidinyloxy)-2- fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-methylcarbamoyl-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(4- methylpiperazine-1 -carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-lodo-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[1-(1 -pyrrolidine-carbonyl)-4-piperidinyloxy]- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 -pyrrolidine-carbonyl)-4-pipendinyloxy]-phenyl}- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-dimethylcarbamoyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethoxycarbonyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-ethoxycarbonyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isobutyryl-4-piperidinyloxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isopropoxycarbonyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isobutyryl-4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isopropoxycarbonyl- 4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[1 -(2-hydroxy-ethyl)-4- piperidinyloxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methoxycarbonylmethyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonylmethyl-4-piperidinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -hydroxycarbonylmethyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -carbamoylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -carbamoylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, - o - chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxy-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,5-dimethyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxy-4-methoxycarbonyl-phenoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-Bromo-2-[4-(2-hydroxy-1 ,1 -dimethyl-ethylcarbamoyl)- phenoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-carbamoyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methoxycarbonyl-phenoxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)- phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]- 5-iodo-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy- ethoxy)-phenoxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,6-dimethyl-4-pyridinyloxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-(5-chloro-2-imidazol-1-yl-phenyl)-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxy-phenoxy)- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy- phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy-phenoxy)- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxycarbonyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxycarbonyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)-
5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyridinyloxy)-5- iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyridinyloxy)-5- ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluoro-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-trifluoromethyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(4-trifluoromethyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-cyano-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-phenyl}-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfanyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfonyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfinyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-nitro-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(4-acetylamino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 ,3,5-trimethyl-i H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-i H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-1 H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 ,3,5-trimethyl-i H-pyrazol-4-yloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-oxo-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3R, 4'S)-6-chloro-2'-[2-chloro-6-(4-methoxy-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy-cyclohexyloxy)-phenyl]- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy-cyclohexyloxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro- pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dion, racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-4-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro- pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[2-(4-acetyl-piperazin-1-yl)-1 ,1 -dimethyl-2-oxo- ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2-[ 2-(4,4-difluoro-piperidin-1 -yl)-1 ,1-dimethyl-2-oxo- ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2- [1 -methyl-1-(2,2,2-trifluoro-ethylcarbamoyl)- ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2- (1 -dimethylcarbamoyl-1-methyl-ethoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2-dimethylcarbamoyl-2-methyl-propoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2,2-dimethyl-3-oxo-3-pyrrolidin-1-yl-propoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-bromo- 2-(3-methyl-oxetan-3- ylmethoxy) phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2-(4-fluoro-benzyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonyl-piperidin-4-yloxy)]-5-trifluoromethyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-methyl-piperidin-4-ylamino)-phenyl]-6-chloro-4'- (5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-(2- thiophenyl)-phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-(2-furanyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-phenyl- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2-pyrazinyloxy)- phenyl]-spiro-[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-(2-furanyl)-2-hydroxy-phenyl]- spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiofuranyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-phenyl]-phenyl- spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiazolyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiazolyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R,4'S)-2'-{2-[3-(tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro-phenyl}-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3-pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-methanesulfonyl-pyrolidinyloxy)-phenyl]-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-ethylcarbamoyl-pyrolidinyloxy)-phenyl}-4'-
(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-3-pyrolidinyloxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[trans-4-(3-hydroxy-1 - methanesulfonyl-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'- dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(tetrahydro-thiopyran- 4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(1 ,1-dioxo-tetrahydro- thiopyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(cyclohexyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(cyclopentyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'-(3-chloro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro2'-[5-chlororo-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-4'- (3-fluoro-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(1 ,1 -dioxo-tetrahydro-thiopyran-4-yloxy)- phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro -4'-(3-fluoro -phenyl)-2'-[5-fluoro-2-(4-fuloro-phenoxy- phenyl)] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[ 2-(2,4-difluoro-phenyloxy)-5- fluoro-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl]-4'-
(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-
6-fluoro spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)-phenyl]-4'-(3- fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[5-fluoro-2-(4-methoxy- phenyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2-(4-methoxy-phenyloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-[5-fluoro-2-(4-methoxy- phenyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-{ 5-fluoro-2-[4-(2-hydroxy-ethoxy)-phenoxy] phenyl}-
4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-{ 5-fluoro-2-[4-(2- hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro -phenyl )-6-fluoro-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-4'-(5- chloro-2-trifluoromethyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, S'R^'SJ-e-chloro^'^δ-chloro^-tπfluoromethyl-phenyl^'-tδ-iodo^-
(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, (2'R, 3'R,4'S)-6-chloro-4'-(5-chloro-2-trifluoromethyl-phenyl)-2'-[2-(cyclohexyloxy)-5- fluoro-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl] -4'-(3- fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-iodo)-phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-fluoro)-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-ethynyl)-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2-(cyclohexyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2-(cyclohexyloxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-4'-
(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-2'-[2-cyclohexyloxy-5-fluoro-phenyl] -4'-(2,5-difluoro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-2'-[5-chloro-2-(cyclohexyloxy)-phenyl]-4'-(3-chloro-phenyl)-6- fluoro spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[5-chloro-2-(tetrahedro-thiopyran-4-yloxy- phenyl)]-6-fluoro spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'-(3-fluoro - phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione and chiral (2'R, 3'R,4'R)-6-chloro-4'-(2,5-difluoro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione. - in the specification and claims, where indicated the various groups, in particular the groups in R', may be substituted by 1-5, or preferably 1-3, substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo- lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, -CN, -CF3, -NH2, -N(H, lower-alkyl), -N(lower-alkyl)2, aminocarbonyl, carboxy, -NO2, lower-alkoxy, thio- lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fl uoro-lower-al koxy, lower-al koxy-carbonyl-lower-al koxy, carboxy-lower-al koxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, -NH2-lower-alkoxy, -N(H, lower-alkyl)- lower-alkoxy, -N(lower-alkyl)2-lower-alkoxy, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, -NH2, -N(H, lower-alkyl) or -N(lower-alkyl)2. Preferred substituents for the aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl and amino.
If alkyl, alkenyl, alkynyl or similar groups are linked with both ends to the same moiety, cyclic structures may result, where two hydrogens of said moiety are being replaced by the two ends of the alkyl, alkenyl, alkynyl or similar group, thus creating cyclic structures, such as, tetralin, macrocycles or spiro compounds.
The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 8 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s- butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, "cycloalkyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. In both cases mono- or bicyclic systems consisting of 5 to 12 carbon atoms are especially preferred. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 8, preferably 2 to 6 carbon atoms. Examples of such "alkenyl group" are vinyl (ethenyl), allyl, isopropenyl, 1 -propenyl, 2-methyl-1-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1- butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such "alkynyl group" are ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The term "halogen" as used in the definitions means fluorine, chlorine, iodine or bromine, preferably fluorine and chlorine.
"Aryl" means a monovalent, monocyclic or bicyclic, aromatic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
"Heteroaryl" means a mono- or bicyclic, preferably 5-10 member, aromatic hydrocarbon, wherein 1-4 carbon atoms are replaced by hetero atoms. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, pyrazolyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl. In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
"Heterocycle" means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, aromatic or non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin- 2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like. - o -
"Hetero atom" means an atom selected from N, O and S.
"Alkoxy, alkoxyl or lower alkoxy" refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, thfluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
The compounds of formula (I) as well as their salts have at least one asymmetric carbon atom and therefore may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography. The invention includes all stereoisomers. The compounds of the present invention are useful as medicaments, in particular in the treatment or control of cell proliferative disorders, more particularly oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I or Il or III compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
" IC5o" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
"Pharmaceutically acceptable ester" refers to a conventionally estehfied compound of formula (I) having a carboxyl group or hydroxy group, which esters retain the biological effectiveness and properties of the compounds of formulas I and are cleaved in vivo (in the organism) to the corresponding active carboxyl ic acid or alcohol respectively.
Compounds of formula (I) according to this invention can be synthesized according to the following general schemes. It will be readily apparent to those of ordinary skill in the art that compounds in formula (I) can be prepared by substitution of the reagents or agents in the general synthesis routes. Using purification by chiral chromatography, compounds in formula (I) can be obtained as an optically pure or enriched enantiomers. - -
1 ) LiHMDS
Figure imgf000022_0002
Figure imgf000022_0001
Scheme 1
In general an appropriately selected aldehyde I can be reacted with lithium hexamethyldisilamide, chlorotrialkylsilane and acteyl chloride in a one-pot, multi-steps manner to generate 2-aza-1 ,3-butadiene Il (Scheme I) and can be used as a crude product. Ghosez, L. and others have reported the preparation of 2-aza-1 ,3-butadienes and their use in aza Diels-Alder reaction to form heterocycle (Ref: Tetrahedron 1995, 11021 ; J. Am. Chem. Soc. 1999, 2617; and literatures cited therein). The appropriately selected aldehyde I are either commercially available or can be synthesized by well- established multiple literature methods.
Protection
Figure imgf000022_0003
Figure imgf000022_0004
Scheme 2
Oxindole III can be reacted with an appropriately substituted aldehyde or ketone in the presence of base under heated condition in either a protic like methanol, ethanol or an aprotic solvent like toluene, o-xylene to give intermediate IV. The commonly used base is either pyrrolidine or pipehdine. Intermediate IV can be protected to give intermediate V. The protective group can be attached by using ethyl chloroformate, di-tert-butyl dicarbonate, SEM-CI, benzyl bromide, and a base like 4-(dimethylamine)pyhdine (DMAP), triethylamine, NaH, or LiH according to well established literature procedures. Examples of protective group formation and their deprotection have been described and reviewed comprehensively by Greene, T.W. et al in "Protective Groups in Organic Synthesis, 2nd Edition. John Wiley & Sons Inc. - -
Figure imgf000023_0001
VII VII, racemic mixture
Scheme 3
Intermediate V can be reacted with a selected 2-aza-butadiene Il prepared in Scheme 1 in toluene or o-xylene under heating from 110 0C to 160 0C and anhydrous condition to form intermediate Vl and Vl' as the major products shown as a racemic mixture of two enantiomers. A subsequent reaction to remove protective group (Pg) leads to various R2 derivatized compound VII and VM'. (Scheme 3). In the case Pg is Boc group, Boc group can be removed by either thfluoroacetic acid or prolonged heating at a temperarure between 110 to 116 0C. Racemic mixture of Vl and Vl' or VII and VM' can be readily resolved into two chiral enantiomers by chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral column chromatography.
Figure imgf000023_0002
VIII
Scheme 4 - -
When R' is a heterocycle or substituted group, compound I can be prepared by reaction of reagent VIII, and compound R'-L, a base like K2CO3 or CS2CO3 in anhydrous N1N- dimethylformamide or N,N-dimethylacetamide under heating conditions. L is a good leaving group like Cl, Br, I, OMs or OTs. Compound VIII is either commercially available or readily prepared according to well eastablished literature procedure (Scheme 4). Alternatively, starting material IX can be reacted R'-OH under Mltsunobu reaction cindtion to give intermediate X, which can be reduced by LiAIH4 or DIBAL to alcohol, then oxidized by MnO2 or under Swern oxidation condtions to give intermediate I (Scheme 5).
Figure imgf000024_0001
IX X
Scheme 5
Figure imgf000024_0002
,OH
X = F or Cl R'-OH =
R1
Xl
Scheme 6
When R' is selected from aryl, substituted aryl, hetereoaryl, or substituted heteroaryl group, intermediate I can be prepared by a coupling reaction of compound Xl and R'- OH under heated conditions (Scheme 6).
When W is ethynyl, 1-propynyl, isopropenyl, 1-propynyl, 3-methyl-1-butynyl, 3,3- dimethyl-1-butynyl, 3-trifluoroethynyl, alternative synthetic methods can be used to gain access to compounds or Xll-a or Xll-b. Typically, the analogues Xll-a with corresponding lodo- or bromo-substituted phenyl are preparaed first according to the - - methods in Scheme 1- 3, followed by a catalytic palladium mediated Sonogashira reaction to give those Xll-b (Scheme 7).
Figure imgf000025_0001
W = I or Br R2 = H, Me, CF3, ethyl, isopropyl, cyclopropv tert-butyl
Xll-a Xll-b
Reagents and conditions: 1) If R2 = Me, Et, iPr, cyleopropyl, tBu, CF3, CuI, NEt3, PdCI2(PPh 3)2 (cat.), 100 0C -R2
2) If R2 = H: CuI, NEt3, trimethylsilyl acetylene, PdCI2(PPh3)2 (cat.),100 0C; then NaOH/MeOH, rt,
Scheme 7
Analogues Xlll-a are prepared first according to the methods in Scheme 1- 3, followed by reduction of nitro group to amine group in Xlll-b, then a reductive amination reaction to give Xlll-c (Scheme 8). Analogue XIV-b can be prepared according to the procedure in Scheme 9.
Figure imgf000025_0002
Xlll-c
Xlll-a Xlll-b
Reagents and conditions:
1) Zn, NH4CI, or Raney Ni, NH2NH2;
2) R'C(=O)R", cat p-toluensufonic acid, o-xylene, heating;
3) NaCNBH3, MeOH
Scheme 8 - -
Figure imgf000026_0001
A = Br or I XIV-a XIV-b
Reagents and conditions:
CuI, Cs2CO3, NHR1R", N.N.N'.N'-tetramethyletheylenediamine, heating, DMF
Scheme 9
The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example 1a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1 ,3-dihydro-indol-2- one
Figure imgf000026_0002
M. W. 290.15 Ci5H9CI2NO
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chloro- benzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 ml_) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwise. The mixture was then heated at 70 0C for 3 h. After cooled to 4 0C, the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1 ,3-dihydro-indol-2-one as a bright yellow solid (Yield 25.2 g, 95 %). - Z -
Example 1b
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro- indole-1 -carboxylic acid te/f-butyl ester
Figure imgf000027_0001
M.W. 390.27 C20Hi7CI2NO3
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1 ,3-dihydro-indol-2-one prepared in example 5a (1 g, 3.4 mmol) in dichloromethane (50 ml_) at room temperature was added Di-te/t-butyl-dicarbonate (1.5 g, 6.9 mmol) (Aldrich), followed by the addition of 4-dimethylaminopyhdine (1 g, 8.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was purified by chromatography to give E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro- indole-1 -carboxylic acid te/f-butyl ester as an orange solid (Yield 1.3 g, 96%).
Example 1c
Preparation of intermediate 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000027_0002
M.W. 445.30 Ci8H24INO4 To a solution of 5-iodosalicylaldehyde (2 g, 8.2 mmol) (Aldrich) in N1N- dimethylformamide (20 ml_) was added anhydrous K2CO3 (1.15 g, 8.2 mmol), and 4- bromomethyl-pipehdine-1-carboxylic acid tert-butyl ester (2.3 g, 8.2 mmol, Pharmacore). The reaction mixture was heated at 60 0C for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 4-(2-formyl-4-iodo-phenoxymethyl)- pipehdine-1 -carboxylic acid tert-butyl ester (Yield 2.3 g, 63%). Example 1d
Preparation of intermediate 1-[2-(1 -(tert-butoxycarbonyl)-4-pipehdinylmethoxy)-5-iodo- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000028_0001
M. W. 558.54 C23H35IN2O4Si
To 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (0.8 g, 5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 2 ml_, 5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (20 ml_) was added, followed by the addition of 4-(2-formyl-4-iodo-phenoxymethyl)- pipehdine-1 -carboxylic acid tert-butyl ester (2.3 g, 5 mmol) prepared in Example 1 c. After the mixture was stirred at room temperature for 0.5 h, thmethylsilyl chloride (0.55 g, 5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (0.7 g, 6.8 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.5 g, 6.8 mmol) in diethyl ether (40 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -[2-(1 -(tert-butoxycarbonyl)-4-pipehdinylmethoxy)-5-iodo-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow oil and used for the next step without further purification.
Example 1e
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-(tert-butoxycarbonyl)-4- pipehdinylmethoxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000028_0002
M.W. 776.49 C35H36CI2IN3O5 To a solution of 1-[2-(1 -(tert-butoxycarbonyl)-4-pipendinylnnethoxy)-5-iodo-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene prepared in example 1d (5 mmol) in toluene (20 ml_) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1 - carboxylic acid te/t-butyl ester prepared in Example 1 b (0.7 g, 1.8 mmol). The reaction mixture was heated under nitrogen at 150 0C for 5 h. After the solution was cooled to room temperature, methanol (10 ml_) was added and the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2 =1 ;1 then EtOAc) to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 0.89 g, 64%).
HRMS(ES+) m/z Calcd for C35H36CI2IN3O5+ H [(IVRH)+]: 776.1150. Found: 776.1154.
Example 2
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-(tert-butoxycarbonyl)-4- pipehdinylmethoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000029_0001
M.W. 674.62 C37H37CI2N3O5 A solution of racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-pipehdinylmethoxy)- 5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (0.89 g, 1.15 mmol) prepared in example 1 e in anhydrous tetrahydrofuran (30 ml_) was added trimethylsilyl acetylene (0.23 g, 2.3 mmol) (Aldrich), CuI (0.44 g, 2.3 mmol) (Aldrich) and thethylamine (0.13 g, 2.3 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(thphenylphosphine) palladium(O) (160 mg, 0.23 mmol) (Strem) was added and the reaction mixture was heated at 80 0C under nitrogen for 2 h. The reaction mixture was cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added methanol (20 ml_) and aqueous NaOH solution (1 N, 10 ml_). The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The reidue was purified with chromatography (EtOAc: hexanes=2:1 ) to give racemic (2'R, 3R, 4'S)-2'-[2-(1-tert-butoxycarbonyl)-4- pipehdinylmethoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.24 g, 31 %).
HRMS(ES+) m/z Calcd TOr C37H37CI2N3O5+ H [(M+H)+]: 674.2183. Found: 674.2185.
Example 3a
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- ethynyl-2-(4-pipehdinylmethoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000030_0001
M.W. 574.51 C32H29CI2N3O3
Racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.22 g, 0.32 mmol) prepared in Example 2 was dissolved in formic acid (88%, Alfa). The reaction mixture was stirred at room temperature for 1 h, then poured into aqueous saturated NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated to give crude racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4- pipehdinylmethoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield: 0.19 g, 100%).
Example 3b
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinylmethoxy)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000030_0002
M.W. 616.54 C34H3ICI2N3O4 To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4- piperidinylmethoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.19 g, 0.32 mmol) prepared in Example 3a in dichloromethane (10 ml_) was added anhydrous K2CO3 (0.2 g, 1.5 mmol), and acetic anhydride (50 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:MeOH = 92:8) to give racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-piperidinylmethoxy)-5-ethynyl-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.12 g, 61 %).
HRMS(ES+) m/z Calcd for C34H3ICI2N3O4+ H [(M+H)+]: 616.1765. Found: 616.1764.
Example 4a
Preparation of intermediate 4-(2-formyl-4-iodo-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000031_0001
M.W. 431.21 Ci7H22INO4
To a solution of 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) in N1N- dimethylformamide (20 ml_) was added anhydrous K2CO3 (5 g, 36.3 mmol), and A- (toluene-4-sulfonyloxy)-pipehdine-1-carboxylic acid tert-butyl ester (5.4 g, 18.1 mmol, ASTATECH). The reaction mixture was heated at 60 0C for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give crude 4-(2-formyl-4-iodo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (Yield 4.38 g, 84%).
Example 4b
Preparation of intermediate 1-[2-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-5-iodo- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000032_0001
M.W. 544.51 C22H33IN2O4Si
In a manner similar to the method described in example 1d, 4-(2-formyl-4-iodo- phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (22 g, 51 mmol) prepared in Example 4a was used as the starting material in place of 4-(2-formyl-4-iodo- phenoxymethyl)-pipehdine-1-carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3- hexamethyldisilazane (13.4 ml_, 51 mmol), n-butyllithium (2.5 M, 25.7 ml_, 51 mmol), trimethylsilyl chloride (8.09 ml_, 51 mmol), thethylamine (11.7 ml_, 66 mmol) and acetyl chloride (5.88 ml_, 66 mmol) to give crude 1 -[2-(1 -(tert-butoxycarbonyl)-4- pipehdinyloxy)-5-iodo-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 4c
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-(tert-butoxycarbonyl)-4-pipehdinyloxy)-5- iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000032_0002
M.W. 762.47 C34H34CI2IN3O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (14 g, 36 mmol) was reacted with 1 -[2-(1 -(tert-butoxycarbonyl)-4- pipehdinyloxy)-5-iodo-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene prepared in example 4b (66 mmol) in toluene (200 ml_) at 140 0C for 6 h to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 4.1 g, 15%) HRMS(ES+) m/z Calcd for C34H34CI2IN3O5+ H [(IVKH)+]: 762.0993. Found: 762.0993
Example 5a
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- iodo-2-(4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000033_0001
M.W. 662.36 C29H26CI2IN3O3
Trifluoroacetic acid (30 ml_) was added to a solution of racemic (2'R, 3R, 4'S)-2'-[2-(1- (tert-butoxycarbonyl)-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (2 g, 2.62 mmol) prepared in example 4c in dichloromethane (30 ml_). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo, then aqueous saturated NaHCO3 solution was added. The mixture was extracted with ethyl acetate. The organic layers wwas separated, washed with water and brine, dried over MgSO4, and concentrated to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield: 1.7 g, 98%).
Example 5b
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000033_0002
M.W. 704.39 C3IH28CI2IN3O4
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg, 0.076 mmol) prepared in Example 5a in anhydrous tetrahydrofuran (2 ml_) was added triethylamine (11.4 mg, 0.114 mmol), and acetyl chloride (6.5 mg, 0.083 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was diluted with ethyl acetate, washed with water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, concentrated. The residue was triturated with dichloromethane and hexanes to give racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-piperidinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 43 mg, 81 %). HRMS(ES+) m/z Calcd for C3IH28CI2IN3O4+ H [(M+H)+]: 704.0575. Found: 704.0573.
Example 5c
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000034_0001
M.W. 704.39 C3IH28CI2IN3O4 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4- pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (64 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (20 mg, 31 %) (RO5219461 -000) and chiral (2'S, 3S, 4'R)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (17 mg, 27%) (RO5219462-000).
Example 6a Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-ethynyl-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000035_0001
M.W. 602.52 C33H29CI2N3O4
A solution of racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.14 mmol) prepared in example 5b in anhydrous N,N-dimethylformamide (1 ml_) was added trimethylsilyl acetylene (0.2 ml_, 1.4 mmol) (Aldrich), CuI (2 mg) (Aldrich) and triethylamine (0.59 ml_, 4.2 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(thphenylphosphine) palladium(O) (10 mg, 0.014 mmol) (Strem) was added and the reaction mixture was heated under nitrogen at 90 0C for 2 h. The mixture was cooled to room temperature, partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The rsidue was purified by chromatography to give a yellow solid (50 mg). The sloid was dissolved into methanol (10 ml_), and aqueous NaOH solution (1 N, 1.2 ml_) was added. The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated. The reidue was purified with chromatography to give racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 17 mg, 20%). HRMS(ES+) m/z Calcd for C33H29CI2N3O4+ H [(M+H)+]: 602.1608. Found: 602.1610.
Example 6b
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-pipehdinyloxy)-5-ethynyl-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000035_0002
M.W. 602.52 C33H29CI2N3O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4- piperidinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione prepared in Example 6a (70 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-piperidinyloxy)-5-ethynyl-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (15 mg, 22%) (RO5208434-000) and chiral (2'S, 3S, 4'R)-2'-[2-(1-acetyl-4- piperidinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (30 mg, 44%) (RO5208432-000).
Example 7
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000036_0001
M.W. 676.38 C30H28CI2IN3O3
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.2 g, 0.3 mmol) prepared in example 5a in methanol (10 ml_) was added an aqueous solution (37 wt%, Aldrich) of formaldehyde (0.045 ml_, 0.6 mmol) and NaCNBH3 (28 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The rsidue was purified by chromatography (EtOAc:thethylamine = 10: 3.5) to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 70 mg, 35%). HRMS(ES+) m/z Calcd for C30H28CI2IN4O4+ H [(M+H)+]: 676.0625. Found: 676.0628. - JD -
Example 8a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - methyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000037_0001
M.W. 574.51 C32H29CI2N3O3
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methyl-4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione prepared in example 7 (0.35 g, 0.51 mmol) was reacted with trimethylsilyl acetylene (0.51 ml_, 5.1 mmol), CuI (10 mg), thethylamine (1.56 g, 15.3 mmol), and dichlorobis(thphenylphosphine) palladium (0) (36 mg, 0.051 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(3-ethynyl-4- fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (Yield 0.1 15 g, 39%)
Example 8b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - methyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000037_0002
M.W. 574.51 C32H29CI2N3O3
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(1-methyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione prepared in Example 8a (100 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - methyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (35 mg, 35%) (RO5212439-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(1-methyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione as a yellow solid (40 mg, 40%) (RO5212440-000). HRMS(ES+) m/z Calcd for C32H29CI2N3O3+ H [(IVKH)+]: 574.1659. Found: 574.1656.
Example 9a Preparation of intermediate 5-lodo-2-nitro-benzaldehyde
Figure imgf000038_0001
M.W. 277.02 C7H4INO3 To a solution of 5-iodo-2-nitrobenzoic acid (37 g, 126 mmol) (APIN) in anhydrous tetrahydrofuran (200 ml_) at 0 0C was added borane tetrahydrofuran (1 M, 360 ml_, 360 mmol) dropwise. The reaction mixture was then stirred at room temperature for 24 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, concentrated, and triturated. The precipitate 5-lodo-2-nitro-phenyl)-methanol was collected as a yellow solid (20 g, 57%).
The solid (5.5 g) was dissolved into dichloromethane (100 ml_), and activated MnO2 (15 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated to give 5-lodo-2-nitro-benzaldehyde as a yellow solid (Yield 4.2 g, 76%).
Example 9b
Preparation of intermediate 1-(5-lodo-2-nitrophenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000038_0002
M.W. 390.26 Ci2Hi5IN2OSi
In a manner similar to the method described in example 1d, 5-iodo-2-nitrobenzaldehyde prepared in Example 9a (4.2 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1 ,1 ,3,3,3- hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 ml_, 15 mmol), - Jo - trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (2.1 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1-(5-lodo-2-nitrophenyl)-3-trimethylsilyoxy-2- aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 9c
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(5- iodo-2-nitrophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000039_0001
M.W. 608.22 C24Hi6CI2IN3O4
To a solution of 1-(5-lodo-2-nitrophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene prepared in example 9b (15 mmol) in toluene (40 ml_) was added E/Z-6-chloro-3-(3- chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid te/t-butyl ester prepared in Example 1 b (2 g, 5 mmol). The reaction mixture was stirred under nitrogen at 150 0C for 3 h. After the solution was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 ml_) and thfluoroactic acid (10 ml_) was added. After the reaction mixture was stirred at room temperature for 0.5 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetae. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2CI2 =1 :4 ) to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-(5-iodo-2-nitrophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 1.8 g, 59%) HRMS(ES+) m/z Calcd for C24Hi6CI2IN3O4+ H [(IVRH)+]: 607.9636. Found: 607.9638. Example 9d
Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-(2-amino-5-iodophenyl)-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000039_0002
M.W. 578.24 C24Hi8CI2IN3O2
To a suspension of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(5-iodo-2- nitrophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in Example 9c (0.7 g, 1.15 mmol) in methanol (50 ml_) was added aqueous NH4CI solution (0.61 g, 11.5 mmol, 20 ml_), followed by addition of Zn powder (0.75 g, 11.5 mmol). The reaction mixture was stirred at room temperature for 1 h, then filtered throught a short pad of celite. The filtrate was concentrated, extracted with ethyl acetate and dichloromethane. The organic layers were combined, dried over MgSO4, and concentrated. The residue was purifed by chromatography (EtOAc, then EtOAc:MeOH=19;1 ) to give racemic (2'R, 3R, 4'S)-2'-(2-amino-5-iodophenyl)-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.41 g, 61 %) HRMS(ES+) m/z Calcd for C24Hi8CI2IN3O2+ H [(M+H)+]: 577.9894. Found: 577.9894.
Example 9e Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinylamino)-5-iodo-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000040_0001
M.W. 703.40 C3IH29CI2IN4O3 To a suspension of racemic (2'R, 3R, 4'S)-2'-(2-amino-5-iodophenyl)-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in Example 9d (0.16 g, 0.28 mmol) in o-xylene (50 ml_) was added 1 -acetyl-4-piperidinone (0.14 g, 1 mmol, Lancaster) and p-toluenesulfonic acid monohydrate (15 mg). The reaction mixture was heated at reflux (180 0C) for 8 h, then cooled to room temperature and concentrated. To the residue was added methanol (10 ml_), acetic acid (1 ml_), and NaCNBH3 (0.1 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purifed by chromatography (EtOAc:MeOH = 9;1 ) to give racemic(2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipeπdinylannino)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 0.15 g, 76%) HRMS(ES+) m/z Calcd for C3IH29CI2IN4O3+ H [(IVKH)+]: 703.0734. Found: 703.0730.
Example 10
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinylamino)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000041_0001
M.W. 601.53 C33H30CI2N4O3
In a manner similar to the method described in example 2, racemic(2'R, 3R, 4'S)-2'-[2- (1 -acetyl-4-pipehdinylamino)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione prepared in example 9e (0.14 g, 0.2 mmol) was reacted with thmethylsilyl acetylene (39 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), triethylamine (40 mg, 0.4 mmol), and dichlorobis(thphenylphosphine) palladium (0) (30 mg, 0.04 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylamino)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (Yield 0.25 g, 84%) HRMS(ES+) m/z Calcd for C33H30CI2N4O3+ H [(M+H)+]: 601.1768. Found: 601.1767.
Example 11a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - propionyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000041_0002
M.W. 718.42 C32H30CI2IN3O4
In a manner similar to the method described in example 5b, propionyl chloride (15.4 mg, 0.17 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a and triethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(1-propionyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 0.11 g, 100%).
Example 11b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - propionyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000042_0001
M.W. 616.54 C34H3ICI2N3O4 In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -propionyl-4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione prepared in example 11 a (0.1 g, 0.14 mmol) was reacted with trimethylsilyl acetylene (0.14 g, 1.4 mmol), CuI (2 mg), triethylamine (0.42 g, 4.17 mmol), and ichlorobis(triphenylphosphine) palladium (0) (9.8 mg, 0.014 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1- propionyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (Yield 10 mg)
HRMS(ES+) m/z Calcd for C34H3iCI2N3O4+ H [(M+H)+]: 616.1765. Found: 616.1760.
Example 12a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(3- methanesulfonyl-propyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000043_0001
M.W. 782.53 C33H34CI2IN3O5S
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 ml_) was methanesulfonic acid 3-methanesulfonyl- propyl ester (54 mg, 0.25 mmol) (WO2001062668) and triethylamine (0.031 ml_, 0.225 mmol). The reaction mixture was heated at 68 0C for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give crude racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5- iodo-2-[1 -(3-methanesulfonyl-propyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.1 g)
Example 12b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(3- methanesulfonyl-propyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000043_0002
M.W. 680.65 C35H35CI2N3O5S
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(3-methanesulfonyl-propyl)-4-pipehdinyloxy]- phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in example 12a (0.1 g, 0.13 mmol) was reacted with trimethylsilyl acetylene (0.13 ml_, 1.3 mmol), CuI (3 mg), triethylamine (0.39 g, 3.84 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8.9 mg, 0.013 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)- 2'-{5-ethynyl-2-[1 -(3-methanesulfonyl-propyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a brown solid (Yield 39 mg, 45%) HRMS(ES+) m/z Calcd for C35H35CI2N3O5S+ H [(IVRH)+]: 680.1747. Found: 680.1746.
Example 13a Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000044_0001
M.W. 740.45 C30H28CI2IN3O5S To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a in dichloromethane (2 ml_) was added triethylamine (18.3 mg, 0.18 mmol), and methanesulfonyl chloride (19.1 mg, 0.165 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was diluted with dichloromethane, washed with water. The organic layer was separated, washed with brine, dried over MgSO4, concentrated to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(1-methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield 0.11 g, 99%).
Example 13b Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000045_0001
M.W. 638.57 C32H29CI2N3O5S
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in example 13a (0.11 g, 0.15 mmol) was reacted with trimethylsilyl acetylene (0.15 ml_, 1.49 mmol), CuI (3 mg), triethylamine (0.45 g, 4.46 mmol), and dichlorobis(thphenylphosphine) palladium (0) (10 mg, 0.015 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- ethynyl-2-(1 -methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a light yellow solid (Yield 51 mg, 54%) HRMS(ES+) m/z Calcd for C32H29CI2N3O5S+ H [(IVRH)+]: 638.1278. Found: 638.1274.
Example 13c Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000045_0002
M.W. 638.57 C32H29CI2N3O5S Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(1 -methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione prepared in Example 13b (100 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'- [5-ethynyl-2-(1 -methanesulfonyl-4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (31 mg, 31 %) (RO5246414-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -methanesulfonyl-4- piperidinyloxy)phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (34 mg, 34%) (RO5216413-000).
Example 14a Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - dimethylcarbamoyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000046_0001
M.W. 733.44 C32H3ICI2IN4O4 In a manner similar to the method described in example 5b, dimethylcarbamyl chloride (17.9 mg, 0.17 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1-dimethylcarbamoyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 0.1 g, 91 %).
Example 14b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - dimethylcarbamoyl-4-pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000046_0002
M.W. 631.56 C34H32CI2N4O4 - -
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1-dimethylcarbamoyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in example 14a (0.1 g, 0.14 mmol) was reacted with trimethylsilyl acetylene (0.13 g, 1.4 mmol), CuI (3 mg), triethylamine (0.41 g, 4.08 mmol), and dichlorobis(thphenylphosphine) palladium (0) (9.5 mg, 0.014 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)- 2'-[2-(1 -dimethylcarbamoyl-4-pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 35 mg, 41 %) HRMS(ES+) m/z Calcd for C34H32CI2N4O4+ H [(IVRH)+]: 631.1874. Found: 631.1873.
Example 15a
Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000047_0001
M.W. 384.27 Ci7H22BrNO4
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (5.65 g, 28 mmol) (Aldrich) reacted with 4-(toluene-4-sulfonyloxy)-pipehdine-1 - carboxylic acid tert-butyl ester (5 g, 14 mmol, ASTATECH) and K2CO3 in N1N- dimethylformamide to give 4-(4-bromo-2-formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester as a yellow gum (Yield 5.15 g, 51 %).
Example 15b
Preparation of intermediate 1-[5-bromo-2-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000047_0002
M.W. 497.51 C22H33BrN2O4Si In a manner similar to the method described in example 1d, 4-(4-bromo-2-formyl- phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (5.5 g, 14.3 mmol) prepared in Example 15a was used as the starting material in place of 4-(2-formyl-4-iodo- phenoxymethyl)-pipehdine-1-carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3- hexamethyldisilazane (3.97 ml_, 14.3 mmol), n-butyllithium (2.5 M, 5.7 ml_, 14.3 mmol), trimethylsilyl chloride (1.81 ml_, 14.3 mmol), triethylamine (2.59 ml_, 18.6 mmol) and acetyl chloride (1.31 ml_, 18.6 mmol) to give crude 1-[5-bromo-2-(1 -(tert- butoxycarbonyl)-4-pipehdinyloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 15c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -(tert-butoxycarbonyl)-4- pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000048_0001
M.W. 715.47 C34H34CI2BrN3O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.8 g, 4.62 mmol) was reacted with 1 -[5-bromo-2-(1-(tert-butoxycarbonyl)- 4-pipehdinyloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene prepared in example 15b (14.3 mmol) in toluene (50 ml_) at 140 0C for 6 h to give racemic (2'R, 3R, 4'S)-2'- [5-bromo-2-(1-(tert-butoxycarbonyl)-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 4.1 g, 15%) HRMS(ES+) m/z Calcd for C34H34CI2BrN3O5+ H [(IVRH)+]: 714.1132. Found: 714.1134
Example 16a
Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000049_0001
M.W. 615.36 C29H26CI2BrN3O3
In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.13 g, 0.18 mmol) reacted with trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4- pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (Yield: 90 mg, 82%).
Example 16b
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-piperidinyloxy)-5-bromo-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000049_0002
M.W. 657.39 C3IH28CI2BrN3O4 In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (90 mg, 0.146 mmol) reacted with acetyl chloride (13.8 mg, 0.175 mmol) and thethylamine in anhydrous tetrahydrofuran to give (2'R, 3R, 4'S)-2'-[2- (1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 50 mg, 52%).
HRMS(ES+) m/z Calcd for C3i H28CI2BrN3O4+ H [(M+H)+]: 656.0713. Found: 656.0713.
Example 16c
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000050_0001
M.W. 657.39 C3IH28CI2BrN3O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4- piperidinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (140 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (49 mg, 35%) (RO5219468-000) and chiral (2'S, 3S, 4'R)-2'-[2-(1-acetyl-4-pipehdinyloxy)-5-bromo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (54 mg, 39%) (RO5219469-000).
Example 17a
Preparation of intermediate 3-bromo-2-fluoro-6-methoxy-benzaldehyde
Figure imgf000050_0002
M.W. 233.04 C8H6BrO2
To a solution of 4-bromo-3-fluoroanisole (10 g, 48.7 mmol, Matrix) in tetrahydrofuran (100 ml_) at -78 0C was added lithium diisopropyl amine (32.5 ml_, 1.8 M in THF, 58.4 mmol) dropwise during a period of 15 min. The mixture was stirred at -78 0C for another 20 mins. Then N,N-dimethyl-formamide (4.53 ml_, 58.4 mmol) was added in one portion. The mixture was stirred at -78 0C for 10 min, then quenched with acetic acid (12 g, 194 mmol) and followed by the addition of water (61 ml_). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography ( EtOAc :hexanes =1 :4) to give 3-bromo-2- fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 89%)
Example 17b Preparation of intermediate 3-bromo-2-fluoro-6-hydroxy-benzaldehyde
Figure imgf000051_0001
M.W. 219.01 C7H4BrFO2
To a solution of 3-bronno-2-fluoro-6-nnethoxy-benzaldehyde (9.8 g, 42.06 mmol,) in dichloromethane (200 ml_) at -50 0C was added a dichloromethane solution (1 M) of BBr3 (126 ml_, 126 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give 3-bromo-2-fluoro-6-hydroxy-benzaldehyde as a off white solid (Yield: 9 g, 98%)
Example 17c
Preparation of intermediate 4-(4-bromo-3-fluoro-2-formyl-phenoxy)-pipehdine-1 - carboxylic acid tert-butyl ester
Figure imgf000051_0002
M.W. 402.26 Ci7H2iBrFNO4
In a manner similar to the method described in example 4a, 3-bromo-2-fluoro-6- hydroxy-benzaldehyde (3.69 g, 16.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)- pipehdine-1 -carboxylic acid tert-butyl ester (4 g, 11.2 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-bromo-3-fluoro-2-formyl-phenoxy)-piperidine-1- carboxylic acid tert-butyl ester as a brown oil (Yield 4.23 g, 94%).
Example 17d
Preparation of intermediate 1-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-2- fluoro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000051_0003
M.W. 515.50 C22H32BrFN2O4Si
In a manner similar to the method described in example 1d, 4-(4-bromo-3-fluoro-2- formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester (4.22 g, 10.5 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-piperidine-1 - carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (2.18 ml_, 10.5 mmol), n-butyllithium (2.5 M, 4.2 ml_, 10.5 mmol), trimethylsilyl chloride (1.33 ml_, 10.5 mmol), thethylamine (1.9 ml_, 13.6 mmol) and acetyl chloride (0.97 ml_, 13.6 mmol) to give crude 1 -[3-bromo-6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 17e
Preparation of racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4- pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000052_0001
M.W. 733.46 C34H33BrCI2FN3O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.36 g, 3.5 mmol) was reacted with 1 -[3-bromo-6-(1-(tert-butoxycarbonyl)- 4-pipehdinyloxy)-2-fluoro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10.5 mmol) in toluene (30 ml_) at 140 0C for 6 h to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert- butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.7 g, 28%) HRMS(ES+) m/z Calcd for C34H33BrCI2FN3O5+ H [(M+H)+]: 732.1038. Found: 732.1035 Example 17f
Preparation of chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4- piperidinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000053_0001
M.W. 733.46 C34H33BrCI2FN3O5
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert- butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (87 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (37 mg, 43%) (RO5219470-000) and chiral (2'S, 3S, 4'R)-2'-[3-bromo- 6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (28 mg, 32%) (RO5219473-000).
Example 18a
Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(4- pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000053_0002
M.W. 633.35 C29H25BrCI2FN3O3
In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-2'-[3- bromo-6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.6 g, 0.818 mmol) reacted with trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[3- bromo-2-fluoro-6-(4-piperidinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield: 0.5 g, 98%).
Example 18b
Preparation of racemic (2'R, 3R, 4'S)-2'-[6-(1-acetyl-4-piperidinyloxy)-3-bromo-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000054_0001
M.W. 675.38 C3IH27BrCI2FN3O4
In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-2'-[3- bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.158 mmol) reacted with acetyl chloride (14.9 mg, 0.189 mmol) and thethylamine in anhydrous tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-piperidinyloxy)-3-bromo-2-fluoro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield
48 mg, 45%).
HRMS(ES+) m/z Calcd for C3i H27BrCI2FN3O4+ H [(IVRH)+]: 674.0619. Found: 674.0617.
Example 19a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethyl-4- pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000054_0002
M.W. 690.41 C3IH30CI2IN3O3 In a manner similar to the method described in example 7, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.17 g, 0.257 mmol) prepared in example 5a was reacted with acetaldehyde (22 mg, 0.514 mmol) and NaCNBH3 (22.5 mg, 0.39 mmol) in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethyl-4- pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 80 mg, 45%).
Example 19b Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethyl-4- pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000055_0001
M.W. 588.53 C33H31CI2N3O3 In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1-ethyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (80 mg, 0.116 mmol) was reacted with trimethylsilyl acetylene (0.114 g, 1.16 mmol), CuI (5 mg), thethylamine (0.35 g, 3.46 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8 mg, 0.012 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(3-ethynyl-4-fluoro-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a off white solid (Yield 54 mg, 79%) HRMS(ES+) m/z Calcd for C33H31CI2N3O3+ H [(IVRH)+]: 588.1815. Found: 588.1818.
Example 20a Preparation of racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000056_0001
M.W. 647.37 C30H27BrCI2FN3O3
In a manner similar to the method described in example 7, racemic (2'R, 3R, 4'S)-2'-[3- bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (0.12 g, 0.189 mmol) prepared in Example 18a was reacted with formaldehyde (37 wt%, Aldrich, 0.028 ml_, 0.38 mmol) and NaCNBH3 (18 mg, 0.28 mmol) in methanol to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 - methyl-4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 25 mg, 20%). HRMS(ES+) m/z Calcd for C30H27BrCI2FN3O3+ H [(IVRH)+]: 646.0670. Found: 646.0674.
Example 20b
Preparation of chiral (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1-methyl-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000056_0002
M.W. 647.37 C30H27BrCI2FN3O3
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6- (1 -methyl-4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (105 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off whitesolid (39 mg, 37%) (RO5221404-000) and chiral (2'S, 3S, 4'R)-2'-[3-bromo-2-fluoro-6-(1-methyl-4- pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a light yellow solid (41 mg, 39%) (RO5221405-000). - J -
Example 21a
Preparation of racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -dimethylcarbamoyl-4- piperidinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000057_0001
M.W. 704.42 C32H30BrCI2FN4O4
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-2'- [3-bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (42 mg, 0.066 mmol) prepared in Example 18a was reacted with dimethylcarbamyl chloride (8.54 mg, 0.079 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-dimethylcarbamoyl-4- pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 27 mg, 58%). HRMS(ES+) m/z Calcd for C32H30BrCI2FN4O4+ H [(IVRH)+]: 703.0885. Found: 703.0882.
Example 21b
Preparation of chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -dimethylcarbamoyl-4- pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000057_0002
M.W. 704.42 C32H30BrCI2FN4O4 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 - dimethylcarbamoyl^-piperidinyloxy^-fluoro-phenyll-G-chloro^'^S-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (100 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -dimethylcarbamoyl-4-piperidinyloxy)-2- fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as an off white solid (28 mg, 28%) (RO5219463-000) and chiral (2'S, 3S, 4'R)-2'- [3-bromo-6-(1-dimethylcarbamoyl-4-pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (23 mg, 23%) (RO5219466-000).
Example 22a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - diethylcarbamoyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000058_0001
M.W. 761.49 C34H35CI2IN4O4
In a manner similar to the method described in example 5b, diethylcarbamyl chloride (24.6 mg, 0.18 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-pipehdinyloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1 -diethyl carbamoyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 50 mg, 36%).
Example 22b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - diethylcarbamoyl-4-pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione - J O -
Figure imgf000059_0001
M.W. 659.61 C36H36CI2N4O4
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(1 -diethyl carbamoyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg, 0.066 mmol) was reacted with trimethylsilyl acetylene (64.7 mg, 0.66 mmol), CuI (5 mg), triethylamine (0.2 g, 1.97 mmol), and dichlorobis(thphenylphosphine) palladium (0) (4.56 mg, 0.0066 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -diethylcarbamoyl-4- pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 36 mg, 83%) HRMS(ES+) m/z Calcd for C36H36CI2N4O4+ H [(IVRH)+]: 659.2187. Found: 659.2192.
Example 23a Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -
(pyrrolidine-1-carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000059_0002
M.W. 759.48 C34H33CI2IN4O4 In a manner similar to the method described in example 5b, 1-pyrrolidinecarbonyl chloride (24.2 mg, 0.18 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-pipehdinyloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a and triethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(pyrrolidine-1 -carbonyl)-4-piperidinyloxy]- phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 90 mg,
82%).
HRMS(ES+) m/z Calcd for C34H33CI2IN4O4+ H [(IVKH)+]: 759.0997. Found: 759.1002.
Example 23b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 - (pyrrolidine-1-carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000060_0001
M.W. 657.60 C36H34CI2N4O4
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(pyrrolidine-1 -carbonyl)-4-pipehdinyloxy]- phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (90 mg, 0.118 mmol) was reacted with trimethylsilyl acetylene (0.117 g, 1.18 mmol), CuI (5 mg), thethylamine (0.36 g, 3.55 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8.3 mg, 0.012 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 - (pyrrolidine-1-carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white white solid (Yield 8 mg, 10%)
HRMS(ES+) m/z Calcd for C36H34CI2N4O4+ H [(M+H)+]: 657.2030. Found: 657.2034.
Example 24a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - isopropyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione - O -
Figure imgf000061_0001
M.W. 704.44 C32H32CI2IN3O3
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in N,N-dimethyformannide (2 ml_) was added thethylamine (30.5 mg, 0.3 mmol) and 2-iodopropane (77 mg, 0.45 mmol). The reaction mixture was heated at 75 0C for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, concentrated to give crude racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(1-isopropyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 80 mg, 73%).
Example 24b Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 - isopropyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000061_0002
M.W. 602.56 C34H33CI2N3O3 In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isopropyl-4-pipehdinyloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (80 mg, 0.11 mmol) was reacted with thmethylsilyl acetylene (0.11 g, 1.1 mmol), CuI (5 mg), triethylamine (0.34 g, 3.3 mmol), and dichlorobis(thphenylphosphine) palladium (0) (8 mg, 0.012 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -isopropyl-4-pipehdinyloxy)- - - phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 10 mg,
15%)
HRMS(ES+) m/z Calcd for C34H33CI2N3O3+ H [(IVKH)+]: 602.1972. Found: 602.1977.
Example 25a Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(2- oxo-imidazolidine-1-carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-
2,6'(1 H)-dione
Figure imgf000062_0001
M.W. 774.45 C33H30CI2IN5O5 In a manner similar to the method described in example 5b, 1-chlorocarbonyl-2- imidazolidinone (40.4 mg, 0.27 mmol) (Aldrich) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.15 g, 0.23 mmol) prepared in Example 5a and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1-(2-oxo-imidazolidine-1 - carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.12 g, 71 %).
Example 25b Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(2- oxo-imidazolidine-1-carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-
2,6'(1 H)-dione
Figure imgf000062_0002
M.W. 672.57 C35H3ICI2N5O5 - Z -
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(2-oxo-imidazolidine-1 -carbonyl)-4- pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.12 g, 0.15 mmol) was reacted with trimethylsilyl acetylene (0.15 g, 1.55 mmol), CuI (5 mg), triethylamine (0.47 g, 4.65 mmol), and dichlorobis(thphenylphosphine) palladium (0) (11 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)- 2'-{5-ethynyl-2-[1 -(2-oxo-imidazolidine-1 -carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 25 mg, 25%) HRMS(ES+) m/z Calcd for C35H31CI2N5O5+ H [(IVRH)+]: 672.1775. Found: 672.1774.
Example 26a
Preparation of intermediate 3-chloro-2-fluoro-6-methoxy-benzaldehyde
Figure imgf000063_0001
M.W. 188.59 C8H6CIO2
To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 ml_) at -78 0C was added lithium diisopropyl amine (42.3 ml_, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at -78 0C for another 20 mins. Then N,N-dimethyl-formamide (5.9 ml_, 76.2 mmol) was added in one portion. The mixture was stirred at -78 0C for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 ml_). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%)
Example 25b Preparation of intermediate 3-chloro-2-fluoro-6-hydroxy-benzaldehyde
Figure imgf000063_0002
M.W. 174.56 C7H4CIFO2
To a solution of 3-chloro-2-fluoro-6-methoxy-benzaldehyde (10 g, 53.2 mmol,) in dichloromethane (200 ml_) at -78 0C was added a dichloromethane solution (1 M) of - DJ -
BBr3 (159 ml_, 159 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give a residue. The residu was triturated with dichloromethane and hexanes to afford 3-chloro-2-fluoro-6-hydroxy-benzaldehyde as a brown solid (Yield: 2.07 g, 22%)
Example 25c
Preparation of intermediate 4-(4-chloro-3-fluoro-2-formyl-phenoxy)-pipehdine-1 - carboxylic acid tert-butyl ester
Figure imgf000064_0001
M.W. 357.81 Ci7H2iCIFNO4
In a manner similar to the method described in example 4a, 3-chloro-2-fluoro-6-hydroxy- benzaldehyde (2.07 g, 11.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1- carboxylic acid tert-butyl ester (3.51 g, 9.88 mmol, ASTATECH) and K2CO3 in N1N- dimethylformamide to give 4-(4-chloro-3-fluoro-2-formyl-phenoxy)-pipehdine-1 - carboxylic acid tert-butyl ester as a brown oil (Yield 3.75 g, 84%).
Example 25d Preparation of intermediate 1-[6-(1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-3-chloro-2- fluoro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000064_0002
M.W. 471.05 C22H32CIFN2O4Si
In a manner similar to the method described in example 1d, 4-(4-chloro-3-fluoro-2- formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester (3.75 g, 10.5 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 - carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (2.18 ml_, - -
10.5 mmol), n-butyllithium (2.5 M, 4.2 ml_, 10.5 mmol), trimethylsilyl chloride (1.33 ml_, 10.5 mmol), triethylamine (1.9 ml_, 13.6 mmol) and acetyl chloride (0.97 ml_, 13.6 mmol) to give crude ^^-(i -^ert-butoxycarbonylJ^-piperidinyloxyJ-S-chloro^-fluoro-phenyll-S- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 25e
Preparation of racemic (2'R, 3R, 4'S)-2'-[6-(1-(tert-butoxycarbonyl)-4-piperidinyloxy)-3- chloro-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000065_0001
M.W. 689.01 C34H33CI3FN3O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.63 g, 4.2 mmol) was reacted with 1 -[6-(1-(tert-butoxycarbonyl)-4- pipehdinyloxy)-3-chloro-2-fluoro-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (10.5 mmol) in toluene (50 ml_) at 140 0C for 6 h to give racemic (2'R, 3R, 4'S)-2'-[6-(1-(tert- butoxycarbonyl)-4-pipehdinyloxy)-3-chloro-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 1.13 g, 39%) HRMS(ES+) m/z Calcd for C34H33CI3FN3O5+ H [(IVRH)+]: 688.1543. Found: 688.1541.
Example 26a
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-2-fluoro-6-(4- pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione - J -
Figure imgf000066_0001
M.W. 588.90 C29H25CI3FN3O3
In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-2'-[6- (1 -(tert-butoxycarbonyl)-4-pipehdinyloxy)-3-chloro-2-fluoro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (1.0 g, 1.45 mmol) reacted with trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[3- chloro-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield: 0.85 g, 100%).
Example 26b
Preparation of racemic (2'R, 3R, 4'S)-2'-[6-(1-acetyl-4-piperidinyloxy)-3-chloro-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000066_0002
M.W. 630.93 C3IH27CI3FN3O4 In a manner similar to the method described in example 5a, racemic (2'R, 3R, 4'S)-6- chloro-2'-[3-chloro-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (72.5 mg, 0.123 mmol) reacted with acetyl chloride (11.6 mg, 0.148 mmol) and thethylamine in anhydrous tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-pipehdinyloxy)-3-chloro-2-fluoro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 30 mg, 39%). HRMS(ES+) m/z Calcd for C31 H27CI3FN3O4+ H [(M+H)+]: 630.1124. Found: 630.1128. - -
Example 27
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -dimethylcarbamoyl-4- piperidinyloxy)-2-fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000067_0001
M.W. 659.97 C32H30CI3FN4O4
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-2'-[3-chloro-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (87.7 mg, 0.149 mmol) prepared in Example 26a was reacted with dimethylcarbamyl chloride (19.2 mg, 0.178 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1- dimethylcarbamoyl-4-pipehdinyloxy)-2-fluoro-phenyl] -4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 51 mg, 52%). HRMS(ES+) m/z Calcd for C32H30CI3FN4O4+ H [(IVRH)+]: 659.1390. Found: 659.1392.
Example 28
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -methylcarbamoyl-4- pipehdinyloxy)-2-fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000067_0002
M.W. 645.94 C32H28CI3FN4O4
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-2-fluoro-6-(4- pipehdinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- - - dione (0.1 g, 0.17 mmol) prepared in Example 26a in dichloromethane (2 ml_) was added triethylamine (34.3 mg, 0.34 mmol) and methy isocyanate (11.6 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was diluted with dichloromethane, washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was thtruated with dichloromethane and hexanes to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -methylcarbamoyl-4-pipehdinyloxy)-2- fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 23 mg, 21 %).
HRMS(ES+) m/z Calcd for C32H28CI3FN4O4+ H [(M+H)+]: 645.1233. Found: 645.1232.
Example 29
Preparation of racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -methylcarbamoyl-4- pipehdinyloxy)-2-fluoro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000068_0001
M.W. 690.39 C32H28BrCI2FN4O4
In a manner similar to the method described in Example 28, , racemic (2'R, 3R, 4'S)-2'- [3-bromo-2-fluoro-6-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (40 mg, 0.063 mmol) prepared in Example 18a was reacted with triethylamine and methy isocyanate (4.3 mg, 0.076 mmol) to give racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-methylcarbamoyl-4-pipehdinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 37 mg, 85%).
HRMS(ES+) m/z Calcd for C32H28BrCI2FN4O4+ H [(M+H)+]: 689.0728. Found: 689.0732.
Example 30
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - dimethylcarbamoyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione - Do -
Figure imgf000069_0001
M.W. 733.43 C32H3ICI2IN4O4
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a was reacted with dimethylcarbamyl chloride (19.5 mg, 0.18 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl- 4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 75 mg, 68%). HRMS(ES+) m/z Calcd for C32H3iCI2IN4O4+ H [(IVRH)+]: 733.0840. Found: 733.0841.
Example 31a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(4- methylpiperazine-1 -carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000069_0002
M.W. 788.52 C35H36CI2IN5O4
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.15 g, 0.23 mmol) prepared in Example 5a was reacted with 4-methylpiperazine-1-carbonyl chloride (44.5 mg, 0.27 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2- [1 -(4-methylpiperazine-1 -carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a yellow gum (Yield 0.19 g, 99%). - -
Example 31b
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(4- methylpiperazine-1 -carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000070_0001
M.W. 686.64 C37H37CI2N5O4
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(4-methylpiperazine-1-carbonyl)-4- pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.18 g 0.23 mmol) was reacted with trimethylsilyl acetylene (0.23 g, 2.28 mmol), CuI (5 mg), triethylamine (0.69 g, 6.8 mmol), and dichlorobis(thphenylphosphine) palladium (0) (16 mg, 0.023 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5- ethynyl-2-[1 -(4-methylpiperazine-1 -carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a brown solid (Yield 0.12 g, 71 %) HRMS(ES+) m/z Calcd for C37H37CI2N5O4+ H [(IVRH)+]: 686.2296. Found: 686.2295.
Example 32a Preparation of intermediate methanesulfonic acid tetrahydropyran-4-yl ester
O JO O
M.W. 180.22 C6Hi2O4S
To a solution of 4-hydroxytetrahydropyran (4.5 g, 44 mmol) (Aldrich) in dichloromethane (90 ml_) at 0 0C was added triethylamine (5.4 g, 53 mmol), and methanesulfonyl chloride (3.73 ml_, 48 mmol, Aldrich). The reaction mixture was stirred at 0 0C for 1 h, then at room temperature for 1.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid tetrahydropyran-4-yl ester as a white solid (Yield 8 g, 100%).
Similar transformation has been described by Suto, M.J. et al in J. Med. Chem, 1991 , 2484.
Example 32b Preparation of intermediate 5-lodo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde
Figure imgf000071_0001
M.W. 332.14 Ci2Hi3IO3 In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) and K2CO3 in N,N-dimethylformamide to give 5-lodo-2-(tetrahydro-pyran-4- yloxy)-benzaldehyde as a yellow solid (Yield 3.4 g, 85%).
Example 32c
Preparation of intermediate 1-[5-lodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000071_0002
M.W. 445.38 Ci7H24INO3Si In a manner similar to the method described in example 1d, 5-lodo-2-(tetrahydro-pyran- 4-yloxy)-benzaldehyde (3.3 g, 10 mmol) was used as the starting material in place of 4- (2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), thmethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1 g, 13.6 mmol) to give crude 1 -[5-lodo-2-(tetrahydro-pyran-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 32d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-lodo-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000072_0001
M.W. 663.33 C29H25CI2IN2O4
E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester prepared in example 5b (1.2 g, 3 mmol) was added to the solution of 1 -[5- lodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) in toluene (30 ml_). The reaction mixture was heated under nitrogen at 140 0C for 2 h. The mixture was cooled to room temperature, concentrated. The residue was diluted with dichloromethane (10 ml_), followed by the addition of thfuloroacetic acid (5 ml_). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was neutralized to "pH" 7 by aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:CH2CI2 = 1 :1 ) to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- lodo-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 1.5 g, 75%)
HRMS(ES+) m/z Calcd for C29H25CI2IN2O4+ H [(M+H)+]: 663.0309. Found: 663.0309 .
Example 33a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000072_0002
M.W. 561.46 C31 H26CI2N2O4
In a manner similar to the method described in Example 2, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-lodo-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (1.3 g, 1.97 mmol) was reacted with trimethylsilyl acetylene (0.4 g, 3.94 mmol), CuI (0.75 g, 3.94 mmol), triethylamine (0.4 ml_, 3.94 mmol) and dichlorobis(thphenylphosphine) palladium(O) (0.28 g, 0.39 mmol), then treated with aqueous NaOH solution in methanol to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 0.62 g, 56%). HRMS(ES+) m/z Calcd for C3IH26CI2N2O4+ H [(IVRH)+]: 561.1343. Found: 561.1342.
Example 33b Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-
(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000073_0001
M.W. 561.46 C3IH26CI2N2O4 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.6 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (0.177 g, 30%) (RO5236850-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (0.176 g, 29%) (RO5236849-000).
Example 34a
Preparation of intermediate 5-bromo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde
Figure imgf000073_0002
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (3 g, 15 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformannide to give 5- bromo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2.86 g, 67%).
Example 34b
Preparation of intermediate 1-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000074_0001
M.W. 398.38 Ci7H24BrNO3Si In a manner similar to the method described in example 1d, 5-bromo-2-(tetrahydro- pyran-4-yloxy)-benzaldehyde (2.86 g, 10 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1 g, 13.6 mmol) to give crude 1 -[5-lodo-2-(tetrahydro-pyran-4- yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 34c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000074_0002
M.W. 616.34 C29H25BrCI2N2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.0 g, 2.5 mmol) was reacted with 1 -[5-bromo-2-(tetrahydro-pyran-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (4 g, 10 mmol) in toluene at 140 0C , then treated with thfuloroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'S)-2'- [5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield 0.76 g, 49%) HRMS(ES+) m/z Calcd for C29H25BrCI2N2O4+ H [(IVKH)+]: 615.0448. Found: 615.0444.
Example 34d
Preparation of chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000075_0001
M.W. 616.34 C29H25BrCI2N2O4 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-
(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.7 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (0.208 g, 30%) (RO5249032-000) and chiral (2'S, 3S, 4'R)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (0.21 g, 30%) (RO5249031-000).
Example 35a Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 -pyrrolidine-carbonyl)-4- pipehdinyloxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000075_0002
M.W. 712.47 C34H33BrCI2N4O4 In a manner similar to the method described in example 5b, 1-pyrrolidinecarbonyl chloride (26 mg, 0.195mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.1 g, 0.16 mmol) prepared in Example 16a and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[1-(1 -pyrrol idine-carbonyl)-4-piperidinyloxy]-phenyl}-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 54 mg, 82%). HRMS(ES+) m/z Calcd for C34H33BrCI2N4O4+ H [(IVRH)+]: 711.1135. Found: 711.1133.
Example 35b Preparation of chiral (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 -pyrrolidine-carbonyl)-4- pipehdinyloxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000076_0001
M.W. 712.47 C34H33BrCI2N4O4 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 - pyrrolidine-carbonyl)-4-pipehdinyloxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (140 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 -pyrrolidine-carbonyl)-4-pipehdinyloxy]-phenyl}- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (38 mg, 27%) (RO5221431 -000) and chiral (2'S, 3S, 4'R)-2'-{5-bromo-2-[1 - (1 -pyrrolidine-carbonyl)-4-pipehdinyloxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (37 mg, 26%) (RO5221430- 000).
Example 36
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -dimethylcarbamoyl-4- pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione - -
Figure imgf000077_0001
M.W. 686.43 C32H3IBrCI2N4O4
In a manner similar to the method described in example 5b, dimethylcarbamyl chloride (25 mg, 0.234 mmol) as the starting material in place of acetyl chloride to react with racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.12 g, 0.195 mmol) prepared in Example 16a and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-dimethylcarbamoyl-4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 87 mg, 65%).
HRMS(ES+) m/z Calcd for C32H3I BrCI2N4O4+ H [(IVRH)+]: 685.0979. Found: 685.0975.
Example 37
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - ethoxycarbonyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000077_0002
M.W. 734.41 C32H30CI2IN3O5
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.15 g, 0.23 mmol) prepared in Example 5a was reacted with ethyl chloroformate (29.4 mg, 0.27 mmol) and trimethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethoxycarbonyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.11 g, 65%).
HRMS(ES+) m/z Calcd for C32H30CI2IN3O5+ H [(IVKH)+]: 734.0680. Found: 734.0682.
Example 38
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -ethoxycarbonyl-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000078_0001
M.W. 687.42 C32H30BrCI2N3O5
In a manner similar to the method described in example 5b, racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.11 g, 0.179 mmol) prepared in Example 16a was reacted with ethyl chloroformate (23.3 mg, 0.214 mmol) and triethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -ethoxycarbonyl-4-pipehdinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 17 mg, 14%). HRMS(ES+) m/z Calcd for C32H30BrCI2N3O5+ H [(M+H)+]: 686.0819. Found: 686.0814.
Example 39
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -isobutyryl-4-pipehdinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000078_0002
M.W. 685.44 C33H32BrCI2N3O4 - o -
In a manner similar to the method described in example 5b, racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (50 mg, 0.081 mmol) prepared in Example 16a was reacted with isobutyryl chloride (10 mg, 0.097 mmol) and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isobutyryl-4-piperidinyloxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (Yield 42 mg, 76%). HRMS(ES+) m/z Calcd for C33H32BrCI2N3O4+ H [(IVRH)+]: 684.1026. Found: 684.1025.
Example 40
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -isopropoxycarbonyl-4- pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000079_0001
M.W. 701.44 C33H32BrCI2N3O5
In a manner similar to the method described in example 5b, racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.1 g, 0.16 mmol) prepared in Example 16a was reacted with isopropyl chloroformate (0.19 ml_, 0.196 mmol) and thethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -isopropoxycarbonyl-4-piperidinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 27 mg, 24%). HRMS(ES+) m/z Calcd for C33H32BrCI2N3O5+ H [(M+H)+]: 700.0975. Found: 700.0972.
Example 41
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - isobutyryl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000080_0001
M.W. 732.44 C33H32CI2IN3O4
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.15 g, 0.23 mmol) prepared in Example 5a was reacted with isobutyryl chloride (29 mg, 0.27 mmol) and thmethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isobutyryl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 91 mg, 54%). HRMS(ES+) m/z Calcd for C33H32CI2IN3O4+ H [(IVRH)+]: 732.0888. Found: 732.0892.
Example 42
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - isopropoxycarbonyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000080_0002
M.W. 748.44 C33H32CI2IN3O5
In a manner similar to the method described in Example 5b, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in Example 5a was reacted with isopropyl chloroformate (0.15 ml_, 0.15 mmol) and thmethylamine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - isopropoxycarbonyl-4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a light yellow solid (Yield 54 mg, 48%). - o -
HRMS(ES+) m/z Calcd for C33H32CI2IN3O5+ H [(IVKH)+]: 748.0837. Found: 748.0835.
Example 43
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[1 -(2-hydroxy- ethyl)-4-pipehdinyloxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000081_0001
M.W. 706.40 C3IH30CI2IN3O4
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 ml_) was added thethylamine (45.7 mg, 0.46 mmol) and 2-bromoethanol (42.4 mg, 0.345 mmol) (Aldrich). The reaction mixture was heated at 80 0C for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH: EtOAc: N Et3= 12:88:5) to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[1-(2-hydroxy-ethyl)-4-piperidinyloxy]-5-iodo- phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 36 mg, 34%) HRMS(ES+) m/z Calcd for C3i H30CI2IN3O4+ H [(M+H)+]: 706.0731. Found: 706.0729.
Example 44
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methoxycarbonylmethyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione - o -
Figure imgf000082_0001
M.W. 734.41 C32H30CI2IN3O5
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (0.36 g, 0.54 mmol) prepared in example 5a in ethanol (2 ml_) was added thethylamine (0.15 ml_, 1.08 mmol) and methyl bromoacetate (0.124 g, 0.81 mmol) (Aldrich). The reaction mixture was heated at 80 0C for 2 h, then cooled to room temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc = 7:93) to give racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methoxycarbonylmethyl-4-pipehdinyloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.21 g, 53%) HRMS(ES+) m/z Calcd for C32H30CI2IN3O5+ H [(M+H)+]: 734.0680. Found: 734.0683.
Example 45
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-tert-butoxycarbonylmethyl-4- pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000082_0002
M.W. 776.49 C35H36CI2IN3O5
In a manner similar to the method described in Example 44, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (0.32 g, 0.48 mmol) prepared in example 5a was reacted with tert-butyl bromoacetate (0.14 g, 0.72 mmol) and thethylamine in ethanol to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.25 g, 67%)
HRMS(ES+) m/z Calcd TOr C35H36CI2IN3O5+ H [(IVRH)+]: 776.1150. Found: 776.1147.
Example 46
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - hydroxycarbonylmethyl-4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000083_0001
M.W. 720.38 C3IH28CI2IN3O5 To a solution of racemic (2'R, 3R, 4'S)-2'-[2-(1-tert-butoxycarbonylmethyl-4- pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.22 g, 0.28 mmol) in dichloromethane (2 ml_) was added trifluoroacetic acid (2 ml_). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was triturated with dichlormethane and hexanes to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -hydroxycarbonylmethyl- 4-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as trifluoroacetic acid salt: yellow solid (Yield 0.18 g) HRMS(ES+) m/z Calcd for C3i H28CI2IN3O5+ H [(M+H)+]: 720.0524. Found: 720.0525.
Example 47a Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-carbamoylmethyl-4-pipehdinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000084_0001
M.W. 719.40 C3IH29CI2IN4O4
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 - hydroxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (50 mg, 0.069 mmol) in anhydrous N,N-dimethylfornnannide (2 ml_) was added EDCI (26.5 mg, 0.139 mmol), HOBT (18.8 mg, 0.139 mmol), diisopropylethylamine (35.9 mg, 0.278 mmol), NH4CI (7.4 mg, 0.278 mmol). The reaction mixture was heated at 80 0C for 1 h, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc = 8:92) to give racemic (2'R, 3R, 4'S)- 2'-[2-(1 -carbamoyl methyl^-pipehdinyloxyJ-δ-iodo-phenyll-e-chloro^'^S-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 25.6 mg, 51 %) HRMS(ES+) m/z Calcd for C3i H29CI2IN4O4+ H [(M+H)+]: 719.0684. Found: 719.0690.
Example 47b
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(1 -carbamoyl methyl-4-pipehdinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000084_0002
M.W. 719.40 C3IH29CI2IN4O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(1- carbamoylmethyl-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.3 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[2-(1 -carbannoylnnethyl-4-pipeπdinyloxy)-5-iodo-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (83 mg, 28%) (RO5236850-000) and chiral (2'S, 3S, 4'R)-2'-[2-(1 -carbamoyl methyl-4- piperidinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione as a light yellow solid (88 mg, 29%) (RO5249057-000).
Example 48a
Preparation of intermediate (S)-3-methanesulfonyloxy-pyrrolidine-1 -carboxylic acid tert- butyl ester
Figure imgf000085_0001
To a solution of (S)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (7.7 g, 41 mmol) (Aldrich) in dichloromethane (130 ml_) at 0 0C was added thethylamine (10.4 g, 103 mmol), and methanesulfonyl chloride (8 g, 70 mmol, Aldrich). The reaction mixture was stirred at 0 0C for 1 h, then at room temperature for 0.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude (S)-3- methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (Yield 11 g, 100%).
Example 48b
Preparation of intermediate (R/S)-3-(4-bromo-2-formyl-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester
Figure imgf000085_0002
M.W. 370.25 Ci6H20BrNO4
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (3.6 g, 18 mmol) (Aldrich) reacted with (S)-3-methanesulfonyloxy-pyrrolidine-1- carboxylic acid tert-butyl ester (5.3 g, 20 mmol) and K2CO3 in N,N-dimethylformamide to give (R/S)-3-(4-bronno-2-fornnyl-phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester as an orange oil (Yield 3.6 g, 54%).
Example 48c
Preparation of intermediate (R/S)-1 -[5-bromo-2-(1 -tert-butoxycarbonyl-3- pyrrolidinyloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000086_0001
M.W. 483.48 C2IH3IBrN2O3Si In a manner similar to the method described in example 1d, (R/S)-3-(4-bromo-2-formyl- phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (2.7 g, 7.4 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (1.2 g, 7.4 mmol), n- butyllithium (2.5 M, 3 ml_, 7.5 mmol), trimethylsilyl chloride (0.8 g, 7.4 mmol), triethylamine (1 g, 10 mmol) and acetyl chloride (0.79 g, 10 mmol) to give crude (R/S)-1- [5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-3-thmethylsilyoxy-2-aza- 1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 48d
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -tert-butoxycarbonyl-3- pyrrolidinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000086_0002
M.W. 687.42 C33H32BrCI2N3O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (0.6 g, 1.5 mmol) was reacted with (R/S)-1-[5-bromo-2-(1 -tert- - oD - butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (7.4 mmol) in toluene (30 ml_) at 140 0C for 6 h to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (1 -tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 0.5 g, 48%) HRMS(ES+) m/z Calcd for C33H32BrCI2N3O5+ H [(IVRH)+]: 700.0975. Found: 700.0973.
Example 49a
Preparation of intermediate (R/S)-3-(2-formyl-4-iodo-phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester
Figure imgf000087_0001
M.W. 417.25 Ci6H20INO4
In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (5 g, 20 mmol) (Aldrich) reacted with (S)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (7 g, 26 mmol) prepared in Example 48a and K2CO3 in N1N- dimethylformamide to give (R/S)- 3-(2-formyl-4-iodo-phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester as a white foam (Yield 5 g, 60%).
Example 49b
Preparation of intermediate (R/S)-1 -[2-(1 -tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000087_0002
h
M.W. 530.48 C2iH3ilN2O3Si
In a manner similar to the method described in example 1d, (R/S)- 3-(2-formyl-4-iodo- phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (4.2 g, 10 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n- butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1 g, 13.6 mmol) to give crude (R/S)-1 -[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-3-thmethylsilyoxy-2- - o - aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 49c Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5- iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000088_0001
M.W. 748.44 C33H32CI2IN3O5 In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.1 g, 2.8 mmol) was reacted with (R/S)-1-[2-(1 -tert-butoxycarbonyl-3- pyrrolidinyloxy)-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (5.3 g, 10 mmol) in toluene (30 ml_) at 140 0C for 4 h to give racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert- butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield 0.5 g, 48%)
HRMS(ES+) m/z Calcd for C33H32CI2IN3O5+ H [(IVRH)+]: 748.0837. Found: 748.0837
Example 50a
Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester
Figure imgf000088_0002
M.W. 335.16 Ci5HnBrO4
To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N1N- dimethylacetamide (30 ml_) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170 0C for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was - oo - extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc: hexanes = 1 :8 then 1 :4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%).
Similar transformations have been described by Marsh, G. et al in Eur. J. Org. Chem. 2003, 2566-2576. The procedures were used with little modification.
Example 50b Preparation of intermediate 1-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000089_0001
M.W. 448.39 C20H22BrNO4Si In a manner similar to the method described in example 1d, 4-(4-bromo-2-formyl- phenoxy)-benzoic acid methyl ester (5 g, 15 mmol) was reacted with 1 ,1 ,3,3,3- hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 ml_, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), thethylamine (2 g, 20 mmol) and acetyl chloride (1.5 g, 15 mmol) to give crude 1-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 50c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000089_0002
M.W. 666.35 C32H23BrCI2N2O5 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.1 g, 2.8 mmol) was reacted with 1 -[5-bromo-2-(4-methoxycarbonyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (6.6 g, 15 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 1.2 g, 64%) HRMS(ES+) m/z Calcd for C32H23BrCI2N2O5+ H [(IVRH)+]: 665.0240. Found: 665.0238.
Example 5Od
Preparation of chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000090_0001
M.W. 666.35 C32H23BrCI2N2O5 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4- methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (79 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (26 mg, 33%) (RO5224517-000) and chiral (2'S, 3S, 4'R)-2'-[5-bromo-2-(4-methoxycarbonyl- phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (27 mg, 34%) (RO5224528-000).
Example 51a Preparation of intermediate 5-bromo-2-(4-methoxy-phenoxy)-benzaldehyde
Figure imgf000090_0002
M.W. 335.16 Ci5HnBrO3
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (2.1 g, 10 mmol) (Alfa) was reacted with 4-methoxyphenol (1.24 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-methoxy- phenoxy)-benzaldehyde as a white solid (Yield 3.1 g, 92%).
Example 51b
Preparation of intermediate 1-[5-bromo-2-(4-methoxy-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000091_0001
M.W. 420.38 Ci9H22BrNO3Si
In a manner similar to the method described in example 1d, 5-bromo-2-(4-methoxy- phenoxy)-benzaldehyde (3.1 g, 10 mmol) was reacted with 1 ,1 ,3,3,3- hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 13.6 mmol) to give crude 1 -[5-bromo-2-(4-methoxy-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 51c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxy-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000091_0002
M.W. 638.34 C3IH23BrCI2N2O4 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.6 g, 1.5 mmol) was reacted with 1 -[5-bromo-2-(4-methoxy-phenoxy)- phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (4.2 g, 10 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4- methoxy-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as an off white solid (Yield 0.61 g, 64%) HRMS(ES+) m/z Calcd for C3IH23BrCI2N2O4+ H [(IVRH)+]: 637.0291. Found: 637.0289.
Example 52a
Preparation of intermediate 5-bromo-2-(2,5-dimethyl-phenoxy)-benzaldehyde
Figure imgf000092_0001
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (2.1 g, 10 mmol) (Alfa) was reacted with 2,5-dimethylphenol (1.4 g, 11 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(2,5-dimethyl- phenoxy)-benzaldehyde as an orange oil (Yield 3 g, 98%).
Example 52b
Preparation of intermediate 1-[5-bromo-2-(2,5-dimethyl-phenoxy)-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000092_0002
M.W. 418.41 C20H24BrNO2Si
In a manner similar to the method described in example 1d, 5-bromo-2-(2,5-dimethyl- phenoxy)-benzaldehyde (1.6 g, 5 mmol) was reacted with 1 ,1 ,3,3,3- hexamethyldisilazane (0.8 g, 5 mmol), n-butyllithium (2.5 M, 2 ml_, 5 mmol), trimethylsilyl chloride (0.55 g, 10 mmol), thethylamine (0.7 g, 7 mmol) and acetyl chloride (0.5 g, 7 mmol) to give crude 1 -[5-bromo-2-(2,5-dimethyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 52c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,5-dimethyl-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000093_0001
M.W. 636.37 C32H25BrCI2N2O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.3 g, 0.77 mmol) was reacted with 1 -[5-bromo-2-(2,5-dimethyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (2.2 g, 5 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,5- dimethyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as an off white solid (Yield 0.38 g, 78%). HRMS(ES+) m/z Calcd for C32H25BrCI2N2O3+ H [(IVRH)+]: 635.0499. Found: 635.0498.
Example 53a
Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-3-methoxy-benzoic acid methyl ester
Figure imgf000093_0002
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl vanillate (3.64 g, 20 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl- phenoxy)-3-methoxy-benzoic acid methyl ester as a white solid (Yield 3.1 g, 92%).
Example 53b
Preparation of intermediate 1-[5-bromo-2-(2-methoxy-4-methoxycarbonyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000094_0001
M.W. 478.42 C2IH24BrNO5Si
In a manner similar to the method described in example 1d, 4-(4-bromo-2-formyl- phenoxy)-3-methoxy-benzoic acid methyl ester (3.7 g, 10 mmol) was reacted with 1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 10 mmol) to give crude 1-[5-bromo-2-(2-methoxy-4-methoxycarbonyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 53c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxy-4-methoxycarbonyl- phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000094_0002
M.W. 696.38 C33H25BrCI2N2O6
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.0 g, 2.56 mmol) was reacted with 1 -[5-bromo-2-(2-methoxy-4- methoxycarbonyl-phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (4.8 g, 10 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxy-4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 0.65 g, 36%) HRMS(ES+) m/z Calcd for C33H25BrCI2N2O6+ H [(M+H)+]: 695.0346. Found: 695.0346. Example 54
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000095_0001
M.W. 652.33 C3IH2IBrCI2N2O5
To a solution of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione prepared in Example 50c (0.8 g, 1.2 mmol) in tetrahydrofuran (20 ml_) was added an aqueous solution (1 M) of NaOH (10 ml_, 10 mmol) and methanol (10 ml_). The reaction mixture was stirred at room temperature for 18 h, then acidified to "pH" 2 with concentrated aqueous HCI solution. The mixture was concentrated, partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4- hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.6 g, 74%).
HRMS(ES+) m/z Calcd for C3iH2i BrCI2N2O5+ H [(M+H)+]: 651.0084. Found: 651.0083.
Example 55a
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000095_0002
M.W. 654.32 C3IH20BrCI2FN2O4
To the solution of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.18 g, 0.28 mmol) in dichloromethane (50 ml_) at 0 0C was added cyanuhc fluoride (120 mg, 0.88 mmol) (Alfa) and pyridine (100 mg, 1.3 mmol). After the mixture was stirred at O 0C for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow foam and used for the next step without further purification (Yield: 0.18 g, 98%).
Example 55b Preparation of racemic (2'R, 3R, 4'S)-2'-{5-Bromo-2-[4-(2-hydroxy-1 ,1 -dimethyl- ethylcarbamoyO-phenoxyl-phenylJ-θ-chloro^'^S-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000096_0001
M.W. 723.46 C35H30BrCI2N3O5 To a solution of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluorocarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.18 g, 0.28 mmol) in tetrahydrofuran (20 ml_) was added 2-amino-2-methyl-propan-1-ol (0.2 g, 2.24 mmol) , N-methylmorpholine (0.2 g, 2 mmol) and 4-dimethylaminopyhdine (3 mg, 0.025 mmol). The reaction mixture was heated under nitrogen at 100 0C for 1 h, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with 1 N HCI aqueous solution and H2O. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by chromatography (MeOH:EtOAc = 1 :19) to give racemic (2'R, 3R, 4'S)-2'-{5-Bromo-2-[4-(2-hydroxy-1 ,1 -dimethyl- ethylcarbamoyO-phenoxyl-phenylJ-e-chloro^'-β-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield: 84 mg, 42%).
HRMS(ES+) m/z Calcd for C35H30BrCI2N3O5+ H [(M+H)+]: 722.0819. Found: 722.0815. - -
Example 56
Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(2-pyrrolidin-1 -yl- ethylcarbamoyO-phenoxyl-phenylJ-θ-chloro^'^S-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000097_0001
M.W. 748.50 C37H33BrCI2N4O4
In a manner similar to the method described in example 55b, racemic (2'R, 3R, 4'S)-2'- [5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.18 g, 0.28 mmol) was reacted with N-(2- aminoethyl)pyrrolidine (0.4 g, 3.5 mmol), N-methylmorpholine and 4- dimethylaminopyhdine in tetrahydrofuran to give racemic (2'R, 3R, 4'S)-2'-{5-bromo-2- [4-(2-pyrrolidin-1 -yl-ethyl carbamoyl )-phenoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.17 g, 83%). HRMS(ES+) m/z Calcd for C37H33BrCI2N4O4+ H [(IVRH)+]: 747.1135. Found: 747.1133.
Example 57
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-carbamoyl-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000097_0002
M.W. 651.34 C3IH22BrCI2N3O4
Racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.14 g, 0.21 mmol) prepared in example 55a was stirred in a methanolic ammonia solution (7 N, 10 ml_) at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by chromatography (EtOAc: MeOH=I 9:1 ) to give racemic (2'R, 3R, 4'S)-2'-[5- bromo-2-(4-carbamoyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (Yield 0.11 g, 80%).
HRMS(ES+) m/z Calcd for C3IH22BrCI2N3O4 +H [(M+H)+]: 650.0244, Found: 650.0246.
Example 58a
Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-3-chloro-benzoic acid methyl ester
Figure imgf000098_0001
M.W. 369.60 Ci5Hi0BrCIO4
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl 3-chloro-4- hydroxybenzoate (4 g, 21 mmol)(l_ancaster) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl-phenoxy)-3-chloro-benzoic acid methyl ester as an off white solid (Yield 3.7 g, 50%).
Example 58b Preparation of intermediate 1-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000098_0002
M.W. 482.84 C20H2IBrCINO4Si
In a manner similar to the method described in example 1d, 4-(4-bromo-2-formyl- phenoxy)-3-chloro-benzoic acid methyl ester (3.7 g, 10 mmol) was reacted with 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 13.6 mmol) to give crude 1 -[5-bromo-2-(2-chloro-4-methoxycarbonyl- phenoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 58c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-chloro-4-methoxycarbonyl- phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000099_0001
M.W. 700.80 C32H22BrCI3N2O5
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.6 g, 1.53 mmol) was reacted with 1 -[5-bromo-2-(2-methoxy-4- methoxycarbonyl-phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (4.6 g, 9.5 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 0.6 g, 56%) HRMS(ES+) m/z Calcd for C32H22BrCI3N2O5+ H [(IVRH)+]: 698.9851. Found: 698.9845.
Example 59a Preparation of intermediate 4-(4-chloro-2-formyl-phenoxy)-benzoic acid methyl ester
Figure imgf000099_0002
M.W. 290.71 Ci5HiiCIO4 In a manner similar to the method described in Example 50a, 5-chloro-2- fluorobenzaldehyde (4.2 g, 26 mmol) (Alfa) was reacted with methyl 4-hydroxybenzoate (4 g, 28 mnnol)(Aldrich) and K2CO3 in N,N-dimethylacetannide to give 4-(4-chloro-2- formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.1 g, 80%).
Example 59b Preparation of intermediate 1-[5-chloro-2-(4-methoxycarbonyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000100_0001
M.W. 403.94 C20H22CINO4Si In a manner similar to the method described in example 1d, 4-(4-chloro-2-formyl- phenoxy)-benzoic acid methyl ester (2.9 g, 10 mmol) was reacted with 1 ,1 ,3,3,3- hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 10 mmol) to give crude 1-[5-chloro-2-(4-methoxycarbonyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 59c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methoxycarbonyl- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000100_0002
M.W. 621.90 C32H23CI3N2O5
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.0 g, 2.56 mmol) was reacted with 1 -[5-chloro-2-(4-methoxycarbonyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (4 g, 9.9 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5- chloro-2-(4-methoxycarbonyl-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione as an off white solid (Yield 1.2 g, 75%)
HRMS(ES+) m/z Calcd for C32H23CI3N2O5+ H [(IVKH)+]: 621.0746. Found: 621.0744.
Example 60a
Preparation of intermediate 4-(2-hydroxy-ethoxy)-phenol
Figure imgf000101_0001
M.W. 154.17 C8Hi0O3
To a solution of 4-hydroxyphenoxyacetic acid (4.9 g, 29 mmol) (Aldrich) in anhydrous tetrahydrofuran (30 ml_) at 0 0C was added borane tetrahydrofuran (1 M, 90 ml_, 90 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give title compound as a yellow oil (4.2 g, 94%)
Example 60b Preparation of intermediate 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol
Figure imgf000101_0002
M.W. 268.43 Ci4H24O3Si To a solution of 4-(2-hydroxy-ethoxy)-phenol (4.2 g, 27 mmol) in anhydrous N1N- dimethylformamide (30 ml_) at 0 0C was added imidazole (2.1 g, 31 mmol) and tert- butyldimethylchlorosilane (4 g, 27 mmol). The reaction mixture was then stirred at 0 0C for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography ( EtOAc :hexanes = 1 ;4) to give 4-[2-(tert-butyl- dimethyl-silanyloxy)-ethoxy]-phenol as a colorless oil (5.1 g, 70%)
Example 60c Preparation of intermediate 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde
Figure imgf000102_0001
M.W. 384.17 Ci5Hi3IO4
In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (2.5 g, 10 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-phenol (2.7 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide at 170 0C for 0.5 h to give 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde as a yellow solid (Yield 3.8 g, 98%).
Example 6Od Preparation of intermediate 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5- iodo-benzaldehyde
Figure imgf000102_0002
M.W. 498.44 C2IH27IO4Si
In a manner similar to the method described in Example 60b, 2-[4-(2-hydroxy-ethoxy)- phenoxy]-5-iodo-benzaldehyde (3.8 g, 9.8 mmol) was reacted with tert- butyldimethylchlorosilane (1.8 g, 12 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-iodo-benzaldehyde as a white solid (Yield 4.7 g, 95%).
Example 6Oe
Preparation of intermediate 1-{2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}- 5-iodo-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000102_0003
M.W. 611.67 C26H38INO4Si2
In a manner similar to the method described in example 1d, 2-{4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-phenoxy}-5-iodo-benzaldehyde (4.7 g, 9.4 mmol) was reacted with 1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyl lithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 10 mmol) to give crude 1-{2-{4-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-phenoxy}-5-iodo-phenyl}-3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 6Of
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy- ethoxy)-phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000103_0001
M.W. 715.37 C32H25CI2IN2O5 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.0 g, 2.56 mmol) was reacted with 1 -{2-{4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-phenoxy}-5-iodo-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (5 g, 8.2 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo- phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.9 g,
49%)
HRMS(ES+) m/z Calcd for C32H25CI2IN2O5+ H [(M+H)+]: 715.0258. Found: 715.0258.
Example 6Og
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy- ethoxy)-phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000104_0001
M.W. 715.37 C32H25CI2IN2O5
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (220 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo- phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (93 mg, 42%) (RO5250875-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2- hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (87 mg, 40%) (RO5250874-000).
Example 61a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2- hydroxy-ethoxy)-phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000104_0002
M.W. 613.49 C34H26CI2N2O5
In a manner similar to the method described in Example 2, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.9 g, 1.26 mmol) was reacted with trimethylsilyl acetylene (0.25 g, 2.5 mmol), CuI (0.48 g, 2.5 mmol), triethylamine (0.25 g, 2.5 mmol) and dichlorobis(thphenylphosphine) palladium(O) (0.18 g, 0.025 mmol) in tetrahydrofuran, then treated with aqueous NaOH solution in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (Yield 0.58 g, 75%).
HRMS(ES+) m/z Calcd for C34H26CI2N2O5+ H [(IVKH)+]: 613.1292. Found: 613.1289.
Example 61b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2- hydroxy-ethoxy)-phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000105_0001
M.W. 613.49 C34H26CI2N2O5
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl} spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (550 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as na off white solid (195 mg, 36%) (RO5246718-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)- 2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione as na off white solid (183 mg, 30%) (RO5246719-000).
Example 62a
Preparation of intermediate 5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-benzaldehyde
Figure imgf000105_0002
M.W. 292.72 Ci5Hi3CIO4
In a manner similar to the method described in Example 50a, 5-chloro-2- fluorobenzaldehyde (1.2 g, 7.6 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl- dimethyl-silanyloxy)-ethoxy]-phenol (2.1 g, 7.8 mmol) prepared in Example 60b and K2CO3 in N,N-dimethylacetamide at 170 0C for 0.5 h to give 5-chloro-2-[4-(2-hydroxy- ethoxy)-phenoxy]-benzaldehyde as a colorless oil (Yield 1.68 g, 75%).
Example 62b Preparation of intermediate 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5- chloro-benzaldehyde
Figure imgf000106_0001
M.W. 406.99 C2IH27CIO4Si
In a manner similar to the method described in Example 60b, 5-chloro-2-[4-(2-hydroxy- ethoxy)-phenoxy]-benzaldehyde (1.68 g, 5.7 mmol) was reacted with tert- butyldimethylchlorosilane (1.3 g, 8.6 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-chloro-benzaldehyde as a white solid (Yield 2.1 g, 90%).
Example 62c
Preparation of intermediate 1-{2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}- 5-chloro-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000106_0002
M.W. 520.22 C26H38CINO4Si2 In a manner similar to the method described in example 1d, 2-{4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-phenoxy}-5-chloro-benzaldehyde (2.1 g, 5.1 mmol) was reacted with 1 ,1 ,3,3,3-hexamethyldisilazane (0.8 g, 5 mmol), n-butyl lithium (2.5 M, 2 ml_, 5 mmol), trimethylsilyl chloride (0.55 g, 5 mmol), thethylamine (0.68 g, 6.8 mmol) and acetyl chloride (0.5 g, 6.8 mmol) to give crude 1-{2-{4-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-phenoxy}-5-chloro-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. - o -
Example 62d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl}-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000107_0001
M.W. 623.92 C32H25CI3N2O5
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.4 g, 1.03 mmol) was reacted with 1 -{2-{4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-phenoxy}-5-chloro-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (2.5 g, 4.8 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.36 g, 57%)
HRMS(ES+) m/z Calcd for C32H25CI3N2O5+ H [(IVRH)+]: 623.0902. Found: 623.0900.
Example 62e
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl}-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000107_0002
M.W. 623.92 C32H25CI3N2O5
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2- [4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (200 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a yellow solid (84 mg, 42%) (RO5249565-000) and chiral (2'S, 3S, 4'R)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy- ethoxy)-phenoxy]-phenyl}-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a yellow solid (77 mg, 39%) (RO5249599-000).
Example 63a
Preparation of intermediate 5-bromo-2-(2,6-dimethyl-pyhdin-4-yloxy)-benzaldehyde
Figure imgf000108_0001
M.W. 306.16 Ci4Hi2BrNO2 In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 2,6-dimethyl-4- hydroxypyridine (2.5 g, 20 mmol) and K2CO3 in N,N-dimethylacetamide to give 5- bromo-2-(2,6-dimethyl-pyhdin-4-yloxy)-benzaldehyde as an off white solid (Yield 6 g, 98%). Example 63b
Preparation of intermediate 1-[5-bromo-2-(2,6-dimethyl-pyridin-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000108_0002
M.W. 419.40 Ci9H23BrN2O2Si In a manner similar to the method described in example 1d, 5-bromo-2-(2,6-dimethyl- pyridin-4-yloxy)-benzaldehyde (3.1 g, 10 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13.6 mmol) and acetyl chloride (1.0 g, 13.6 mmol) to give crude 1 -[5-bromo-2-(2,6-dimethyl-pyridin-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. - o -
Example 63c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,6-dimethyl-4-pyridinyloxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000109_0001
M.W. 637.36 C3IH24BrCI2N3O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.0 g, 2.56 mmol) was reacted with 1 -[5-bromo-2-(2,6-dimethyl-pyhdin-4- yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (4.2 g, 10 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,6- dimethyl-4-pyhdinyloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.99 g, 61 %) HRMS(ES+) m/z Calcd for C3i H24BrCI2N3O3+ H [(IVRH)+]: 636.0451. Found: 636.0454.
Example 64a
Preparation of intermediate 5-chloro-2-lodo-benzaldehyde
Figure imgf000109_0002
M.W. 266.47 C7H4CIIO To a solution of 5-chloro-2-iodo benzoic acid (4.92 g, 17 mmol) (TRANS) in anhydrous tetrahydrofuran (100 ml_) at 0 0C was added borane tetrahydrofuran (1 M, 34 ml_, 34 mmol) dropwise. The reaction mixture was then stirred at room temperature for 18 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give a colorless oil. The oil was dissolved into 1 ,2-dichloroethane (50 ml_), and activated MnO2 (15 g) was added. The mixture was then heated at reflux for 2 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1 ;8) to give 5- chloro-2-lodo-benzaldehyde as a white solid (Yield 5.5 g, 25%). Example 64b
Preparation of intermediate 1-(5-chloro-2-iodophenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000110_0001
M.W. 379.70 Ci2Hi5CIINOSi
In a manner similar to the method described in example 5d, 5-chloro-2- iodobenzaldehyde prepared in example 23a (3.97 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1 ,1 ,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 ml_, 15 mmol), thmethylsilyl chloride (1.6 g, 15 mmol), thethylamine (2 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1 -(5-chloro-2-iodophenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 64c
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(5- chloro-2-iodophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000110_0002
M.W. 597.67 C24Hi6CI3IN2O2 In a manner similar to the method described in example 7b, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (2 g, 5.6 mmol) was reacted with crude 1-(5-chloro-2-iodophenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene prepared in example 23b (5.6 g, 15 mmol) in toluene and then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)- 6-chloro-4'-(3-chlorophenyl)-2'-(5-chloro-2-iodophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a yellow solid (Yield 2.1 g, 63%) HRMS(ES+) m/z Calcd for C24Hi6CI3IN2O2+ H [(M+H)+]: 596.9395. Found: 596.9393. Example 64d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-(5-chloro-2-imidazol-1 -yl-phenyl)-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000111_0001
M.W. 537.83 C27Hi9CI3N4O2
A solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(5-chloro-2- iodophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.3 g, 0.5 mmol) in anhydrous N,N-dimethylformamide (10 ml_) was added Cs2COs (1.2 g, 4 mmol) (Aldrich), CuI (95 mg, 0.5 mmol) (Aldrich), N,N,N',N'-tetramethylethylenediamine (0.2 ml_, 2 mmol), and imidazole (80 mg, 1 mmol). The mixture was heated under nitrogen at 170 0C for 0.5 h. The mixture was cooled to room temperature, partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:MeOH=9:1 ) to give a crude product 997 mg), which was further purified by RP- HPLC to give racemic (2'R, 3R, 4'S)-6-chloro-2'-(5-chloro-2-imidazol-1 -yl-phenyl)-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 16 mg). HRMS(ES+) m/z Calcd for C27Hi9CI3N4O2+ H [(M+H)+]: 537.0647. Found: 537.0646.
Example 65a Preparation of intermediate 4-(2-formyl-4-iodo-phenoxy)-benzonithle
Figure imgf000111_0002
M.W. 349.13 Ci4H8INO2 In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (2 g, 8 mmol) (Aldrich) was reacted with 4-cyanophenol (1.43 g, 12 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(2-formyl-4-iodo-phenoxy)- benzonithle as a light yellow solid (Yield 1.9 g, 70.4%). - -
Example 65b
Preparation of intermediate 1-[2-(4-cyano-phenoxy)-5-iodo-phenyl]-3-thmethylsilyoxy-2- aza-1 ,3-butadiene
Figure imgf000112_0001
M.W. 462.37 Ci9Hi9IN2O2Si
In a manner similar to the method described in example 1d, 4-(2-formyl-4-iodo- phenoxy)-benzonithle (1.9 g, 5.44 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.13 ml_, 5.44 mmol), n-butyllithium (2.5 M, 2.18 ml_, 5.45 mmol), trimethylsilyl chloride (0.69 ml_, 5.44 mmol), triethylamine (0.98 ml_, 7.07 mmol) and acetyl chloride (0.66 ml_, 7.07 mmol) to give crude 1-[2-(4-cyano-phenoxy)-5-iodo- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 65c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano- phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000112_0002
M.W. 680.32 C3IH20CI2IN3O3 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.85 g, 2.18 mmol) was reacted with 1 -[2-(4-cyano-phenoxy)-5-iodo- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (5.44 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (Yield 0.8 g, 54%) HRMS(ES+) m/z Calcd for C3IH20CI2IN3O3+ H [(IVKH)+]: 679.9999. Found: 679.9999.
Example 65d
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano- phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000113_0001
M.W. 680.32 C3IH20CI2IN3O3
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (500 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (0.23 g, 46%) (RO5249341 -000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (0.21 g, 42%) (RO5249340-000).
Example 66a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano- phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000113_0002
M.W. 578.45 C33H2ICI2N3O3
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.65 g, 0.96 mmol) was reacted with trimethylsilyl acetylene (0.94 g, 9.6 mmol), CuI (10 mg), triethylamine (2.89 g, 28.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (53.6 mg, 0.077 mmol) in anhydrous N1N- dimethylformannide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 0.285 g, 51 %) HRMS(ES+) m/z Calcd for C33H2ICI2N3O3+ H [(IVRH)+]: 578.1033. Found: 578.1030.
Example 66b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano- phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000114_0001
M.W. 578.45 C33H2ICI2N3O3
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (260 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (98 mg, 38%) (RO5249051 -000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano- phenoxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (102 mg, 39%) (RO5249050-000).
Example 67a Preparation of intermediate 5-iodo-2-(4-methoxy-phenoxy)-benzaldehyde
M.W. 354.15 Ci4HiolO3 In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (1.2 g, 4.8 mmol) (Aldrich) was reacted with 4-methoxyphenol (0.71 g, 5.76mnnol) and K2CO3 in N,N-dinnethylacetannide to give 5-iodo-2-(4-methoxy- phenoxy)-benzaldehyde as a yellow oil (Yield 1.12 g, 66%).
Example 67b
Preparation of intermediate 1-[5-iodo-2-(4-methoxy-phenoxy)-phenyl]-3-thmethylsilyoxy-
2-aza-1 ,3-butadiene
Figure imgf000115_0001
M.W. 467.38 Ci9H22INO3Si In a manner similar to the method described in example 1d, 5-iodo-2-(4-methoxy- phenoxy)-benzaldehyde (1.12 g, 3.16 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (0.66 ml_, 3.16 mmol), n-butyllithium (2.5 M, 1.26 ml_, 3.16 mmol), trimethylsilyl chloride (0.4 ml_, 3.16 mmol), thethylamine (0.57 ml_, 4.1 mmol) and acetyl chloride (0.39 ml_, 4.1 mmol) to give crude 1 -[5-iodo-2-(4-methoxy-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 67c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000115_0002
M.W. 685.34 C3IH23CI2IN2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.49 g, 1.26 mmol) was reacted with 1 -[5-iodo-2-(4-methoxy-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (3.16 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione as a white solid (Yield 0.35 g, 41 %)
HRMS(ES+) m/z Calcd TOr C3IH23CI2IN2O4+ H [(IVKH)+]: 685.0153. Found: 685.0155.
Example 68a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4- methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000116_0001
M.W. 583.47 C33H24CI2N2O4 In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (0.29 g, 0.42 mmol) was reacted with trimethylsilyl acetylene (0.41 g, 4.2 mmol), CuI (5 mg), triethylamine (1.76 ml_, 12.7 mmol), and dichlorobis(thphenylphosphine) palladium (0) (23.4 mg, 0.034 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.15 g, 61 %) HRMS(ES+) m/z Calcd for C33H24CI2N2O4+ H [(M+H)+]: 583.1186. Found: 583.1187.
Example 68b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4- methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000116_0002
M.W. 583.47 C33H24CI2N2O4 - o -
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (500 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (0.24 g, 48%) (RO5249052-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2- (4-methoxy-phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a light yellow solid (0.24 g, 48%) (RO5249053-000).
Example 69a
Preparation of intermediate 4-(2-formyl-4-iodo-phenoxy)-benzoic acid methyl ester
Figure imgf000117_0001
M.W. 382.16 CI5HH IO4
In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (3.6 g, 14.4 mmol) (Aldrich) was reacted with methyl A- hydroxybenzoate (2.62 g, 17.3 mmol) and K2CO3 in N,N-dimethylacetamide to give A- (2-formyl-4-iodo-phenoxy)-benzoic acid methyl ester as a yellow oil (Yield 3.8 g, 69%).
Example 69b Preparation of intermediate 1-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000117_0002
M.W. 495.39 C20H22INO4Si
In a manner similar to the method described in example 1d, 4-(2-formyl-4-iodo- phenoxy)-benzoic acid methyl ester (3.8 g, 9.94 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (2.06 ml_, 9.94 mmol), n-butyllithium (2.5 M, 3.97 ml_, 9.94 mmol), trimethylsilyl chloride (1.26 ml_, 9.94 mmol), triethylamine (1.79 ml_, 12.9 mmol) and acetyl chloride (1.22 ml_, 12.9 mmol) to give crude 1-[5-iodo-2-(4-methoxycarbonyl- phenoxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 69c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4- methoxycarbonyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000118_0001
M.W. 713.35 C32H23CI2IN2O5 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.55 g, 3.98 mmol) was reacted with 1 -[5-iodo-2-(4-methoxycarbonyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (9.94 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 1.5 g, 53%) HRMS(ES+) m/z Calcd for C32H23CI2IN2O5+ H [(IVRH)+]: 713.0102. Found: 713.0102.
Example 70 Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4- methoxycarbonyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000118_0002
M.W. 611.48 C34H24CI2N2O5 - o -
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.45 g, 0.63 mmol) was reacted with thmethylsilyl acetylene (0.45 g, 6.3 mmol), CuI (3 mg), triethylamine (2.63 ml_, 18.9 mmol), and dichlorobis(thphenylphosphine) palladium (0) (35.3 mg, 0.05 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxycarbonyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.28 g, 73%) HRMS(ES+) m/z Calcd for C34H24CI2N2O5+ H [(IVRH)+]: 611.1135. Found: 611.1134.
Example 71
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4- hydroxycarbonyl-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000119_0001
M.W. 699.32 C31 H2ICI2IN2O5
In a manner similar to the method described in Example 54, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.68 g, 0.95 mmol) was reacted with an aqueous solution of LiOH (0.41 g, 9.5 mmol) in tetrahydrofuran and methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)- 5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.5 g, 75%).
HRMS(ES+) m/z Calcd for C3iH2iCI2IN2O5+ H [(M+H)+]: 698.9945. Found: 698.9941.
Example 72a
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000120_0001
M.W. 698.35 C3IH22CI2IN3O4
In a manner similar to the method described in Example 47a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)-5-iodo-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.4 g, 0.57 mmol) was reacted with EDCI (0.22 g, 1.14 mmol), HOBT (0.154 g, 1.14 mmol), diisopropylethylamine (0.29 g, 2.28 mmol), NH4CI (60 mg, 1.14 mmol) in N,N-dimethylformamide to give racemic (2'R, 3R, 4'S)-2'- [2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 0.35 g, 88%)
Example 72b
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000120_0002
M.W. 596.47 C33H23CI2N3O4
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-2'-[2- (4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (0.35 g, 0.5 mmol) was reacted with trimethylsilyl acetylene (0.49 g, 5 mmol), CuI (3 mg), triethylamine (1.52 ml_, 15 mmol), and dichlorobis(triphenylphosphine) palladium (0) (28 mg, 0.04 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (Yield 0.25 g, 84%) HRMS(ES+) m/z Calcd for C33H23CI2N3O4+ H [(M+H)+]: 596.1139. Found: 596.1135. Example 72c
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000121_0001
M.W. 596.47 C33H23CI2N3O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl- phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (300 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)- 2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as an off white solid (111 mg, 37%) (RO5247924- 000) and chiral (2'S, 3S, 4'R)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as an off white solid (112 mg, 37%) (RO5247926-000).
Example 73a Preparation of intermediate 2-(2,6-dimethyl-pyridin-4-yloxy)-5-iodo-benzaldehyde
Figure imgf000121_0002
M.W. 353.16 Ci4Hi2INO2 In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (2 g, 8 mmol) (Aldrich) was reacted with 2,6-dimethyl-4- hydroxypyridine (1.08 g, 8.8 mmol) and K2CO3 in N,N-dimethylacetamide to give 2- (2,6-dimethyl-pyhdin-4-yloxy)-5-iodo-benzaldehyde as a yellow solid (Yield 2.63 g, 92%). Example 73b
Preparation of intermediate 1-[2-(2,6-dimethyl-pyridin-4-yloxy)-5-iodo-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000122_0001
M.W. 466.40 Ci9H23IN2O2Si
In a manner similar to the method described in example 1d, 2-(2,6-dimethyl-pyridin-4- yloxy)-5-iodo-benzaldehyde (2.63 g, 7.4 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.55 ml_, 7.4 mmol), n-butyllithium (2.5 M, 2.98 ml_, 7.4 mmol), trimethylsilyl chloride (0.945 ml_, 7.4 mmol), triethylamine (1.34 ml_, 9.7 mmol) and acetyl chloride (0.68 ml_, 9.7 mmol) to give crude 1 -[2-(2,6-dimethyl-pyhdin-4-yloxy)-5- iodo-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 73c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4- pyridinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000122_0002
M.W. 684.49 C3IH24CI2IN3O3 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.15 g, 2.96 mmol) was reacted with1 -[2-(2,6-dimethyl-pyhdin-4-yloxy)-5- iodo-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (7.4 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyhdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.8 g, 39%) HRMS(ES+) m/z Calcd for C3i H24CI2IN3O3+ H [(M+H)+]: 684.0312. Found: 684.0315. Example 74
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4- pyridinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000123_0001
M.W. 582.49 C33H25CI2N3O3
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyhdinyloxy)-5-iodo-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.62 g, 0.9 mmol) was reacted with thmethylsilyl acetylene (0.89 g, 9 mmol), CuI (5 mg), thethylamine (2.74 g, 27 mmol), and dichlorobis(thphenylphosphine) palladium (0) (50.7 mg, 0.07 mmol) in anhydrous N1N- dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyhdinyloxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a pale yellow solid (Yield 0.28 g, 53%) HRMS(ES+) m/z Calcd for C33H25CI2N3O3+ H [(IVRH)+]: 582.1346. Found: 582.1346.
Example 75a
Preparation of intermediate 5-bromo-2-(4-fluoro-phenoxy)-benzaldehyde
Figure imgf000123_0002
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 4-fluorophenol (2.5 g, 22 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-fluoro- phenoxy)-benzaldehyde as a yellow solid (Yield 5.8 g, 97%). Example 75b
Preparation of intermediate 1-[5-bromo-2-(4-fluoro-phenoxy)-phenyl]-3-thmethylsilyoxy-
2-aza-1 ,3-butadiene
Figure imgf000124_0001
M.W. 408.35 Ci8Hi9BrFNO2Si
In a manner similar to the method described in example 1d, 5-bromo-2-(4-fluoro- phenoxy)-benzaldehyde (5.8 g, 20 mmol) was reacted with 1 ,1 ,1 , 3,3,3- hexamethyldisilazane (4.1 ml_, 20 mmol), n-butyllithium (2.5 M, 8 ml_, 20 mmol), trimethylsilyl chloride (2.5 ml_, 20 mmol), thethylamine (3.55 ml_, 25 mmol) and acetyl chloride (1.8 ml_, 25.5 mmol) to give crude 1 -[5-bromo-2-(4-fluoro-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 75c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluoro-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000124_0002
M.W. 626.31 C30H20BrCI2FN2O3 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (3.1 g, 7.8 mmol) was reacted with 1 -[5-bromo-2-(4-fluoro-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (20 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluoro- phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (Yield 0.67 g, 14%) HRMS(ES+) m/z Calcd for C30H20BrCI2FN2O3+ H [(M+H)+]: 625.0091. Found: 625.0094. Example 76a
Preparation of intermediate 5-bromo-2-(4-trifluoromethyl-phenoxy)-benzaldehyde
Figure imgf000125_0001
M.W. 345.12 Ci4H8BrF3O2
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (2.1 g, 11 mmol) (Alfa) was reacted with 4-thfluoromethyl phenol (1.9 g, 12 mmol)(Aldhch) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4- trifluoromethyl-phenoxy)-benzaldehyde as a yellow solid (Yield 2.47 g, 68%).
Example 76b
Preparation of intermediate 1-[5-bromo-2-(4-thfluoromethyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000125_0002
M.W. 458.35 Ci9Hi9BrF3NO2Si
In a manner similar to the method described in example 1d, 5-bromo-2-(4- trifluoromethyl-phenoxy)-benzaldehyde (2.47 g, 7 mmol) was reacted with 1 ,1 ,1 , 3,3,3- hexamethyldisilazane (1.5 ml_, 7 mmol), n-butyllithium (2.5 M, 2.9 ml_, 7 mmol), trimethylsilyl chloride (0.9 ml_, 7 mmol), thethylamine (1.3 ml_, 9 mmol) and acetyl chloride (0.5 ml_, 9 mmol) to give crude 1-[5-bromo-2-(4-thfluoromethyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 76c Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-thfluoromethyl-phenoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000126_0001
M.W. 676.31 C3IH20BrCI2F3N2O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.1 g, 2.8 mmol) was reacted with 1 -[5-bromo-2-(4-thfluoromethyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (7 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4- trifluoromethyl-phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.3 g, 16%) HRMS(ES+) m/z Calcd for C3i H20BrCI2F3N2O3+ H [(IVRH)+]: 675.0059. Found: 675.0060.
Example 77a
Preparation of intermediate 5-chloro-2-(4-thfluoromethyl-phenoxy)-benzaldehyde
Figure imgf000126_0002
M.W. 300.67 Ci4H8CIF3O2
In a manner similar to the method described in Example 50a, 5-chloro-2- fluorobenzaldehyde (0.88 g, 5.6 mmol) (Beta Pharma) was reacted with 4- thfluoromethylphenol (1 g, 6.6 mmol)(Aldhch) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-thfluoromethyl-phenoxy)-benzaldehyde as a yellow solid (Yield 0.98 g, 58%).
Example 77b
Preparation of intermediate 1-[5-chloro-2-(4-thfluoromethyl-phenoxy)-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000127_0001
M.W. 413.90 Ci9Hi9CIF3NO2Si
In a manner similar to the method described in example 1d, 5-chloro-2-(4- trifluoromethyl-phenoxy)-benzaldehyde (0.98 g, 3.3 mmol) was reacted with 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (0.67 ml_, 3.3 mmol), n-butyllithium (2.5 M, 1.3 ml_, 3.3 mmol), thmethylsilyl chloride (0.41 mL, 3.3 mmol), triethylamine (0.59 ml_, 4.2 mmol) and acetyl chloride (0.3 mL, 4.2 mmol) to give crude 1-[5-chloro-2-(4-thfluoromethyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 77c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(4- trifluoromethyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000127_0002
M.W. 631.86 C3IH20CI3F3N2O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.5 g, 1.3 mmol) was reacted with 1 -[5-chloro-2-(4-thfluoromethyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (3.3 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-chloro-2-(4-thfluoromethyl-phenoxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.22 g, 27%) HRMS(ES+) m/z Calcd for C3i H20CI3F3N2O3+ H [(M+H)+]: 631.0565. Found: 631.0568.
Example 78a
Preparation of intermediate 3-(4-bromo-2-formyl-phenoxy)-benzonithle
Figure imgf000128_0001
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (2.2 g, 11 mmol) (Alfa) was reacted with 3-cyanophenol (1.4 g, 12 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 3-(4-bromo-2-formyl- phenoxy)-benzonithle as a brown solid (Yield 3 g, 100%).
Example 78b
Preparation of intermediate 1-[5-bromo-2-(3-cyano-phenoxy)-phenyl]-3-thmethylsilyoxy- 2-aza-1 ,3-butadiene
Figure imgf000128_0002
M.W. 415.37 Ci9Hi9BrN2O2Si
In a manner similar to the method described in example 1d, 3-(4-bromo-2-formyl- phenoxy)-benzonithle (3 g, 10 mmol) was reacted with 1 ,1 ,1 , 3,3,3- hexamethyldisilazane (2.1 ml_, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.3 ml_, 10 mmol), thethylamine (1.8 ml_, 13 mmol) and acetyl chloride (0.92 ml_, 13 mmol) to give crude 1 -[5-bromo-2-(3-cyano-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 78c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-cyano-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000128_0003
- o -
M.W. 633.33 C3IH20BrCI2N3O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.55 g, 4 mmol) was reacted with 1 -[5-bromo-2-(3-cyano-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-cyano- phenoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (Yield 0.4 g, 16%)
HRMS(ES+) m/z Calcd for C3i H20BrCI2N3O3+ H [(IVRH)+]: 632.0138. Found: 632.0140.
Example 79a Preparation of intermediate 5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde
Figure imgf000129_0001
In a manner similar to the method described in Example 50a, 5-bromo-2- fluorobenzaldehyde (5.5 g, 27 mmol) (Alfa) was reacted with 3-(4-hydroxyphenyl)-1 - propanol (4.5 g, 30 mmol)(Aldhch) and K2CO3 in N,N-dimethylacetamide to give 5- bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde as a brown oil (Yield 9 g, 99%).
Example 79b
Preparation of intermediate 5-bromo-2-{4-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]- phenoxy}-benzaldehyde
Figure imgf000129_0002
M.W. 449.46 C22H29BrO3Si In a manner similar to the method described in Example 60b, 5-bromo-2-[4-(3-hydroxy- propyl)-phenoxy]-benzaldehyde (9 g, 27 mmol) was reacted with tert- butyldimethylchlorosilane (4.45 g, 30 mmol) and imidazole in N,N-dimethylformamide to give 5-bronno-2-{4-[3-(tert-butyl-dinnethyl-silanyloxy)-propyl]-phenoxy}-benzaldehyde as a brown oil (Yield 12 g, 100%).
Example 79c
Preparation of intermediate 1-{5-bromo-2-{4-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]- phenoxy}-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000130_0001
M.W. 562.70 C27H40BrNO3Si2 In a manner similar to the method described in example 1d, 5-bromo-2-{4-[3-(tert-butyl- dimethyl-silanyloxy)-propyl]-phenoxy}-benzaldehyde (4.72 g, 10.5 mmol) was reacted with 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (2.18 ml_, 10.5 mmol), n-butyllithium (2.5 M, 4.2 ml_, 10.5 mmol), trimethylsilyl chloride (1.33 ml_, 10.5 mmol), thethylamine (1.89 ml_, 13.6 mmol) and acetyl chloride (0.97ml_, 13.6 mmol) to give crude 1-{5-bromo-2-{4-[3- (tert-butyl-dimethyl-silanyloxy)-propyl]-phenoxy}-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3- butadiene as a yellow gum and used for the next step without further purification.
Example 79d
Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000130_0002
M.W. 666.40 C33H27BrCI2N2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.64 g, 4.2 mmol) was reacted with 1 -{5-bromo-2-{4-[3-(tert-butyl-dimethyl- silanyloxy)-propyl]-phenoxy}-phenyl}-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10.5mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'- {5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.4 g, 14%) HRMS(ES+) m/z Calcd for C33H27BrCI2N2O4+ H [(IVRH)+]: 665.0604. Found: 665.0600.
Example 80a
Preparation of intermediate 4-(4-chloro-2-formyl-phenoxy)-benzonithle
Figure imgf000131_0001
M.W. 257.68 Ci4H8CINO2 In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro- benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-cyanophenol (1.67 g, 14 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(4-chloro-2-formyl-phenoxy)- benzonitrile as a light yellow solid (Yield 2.81 g, 85%).
Example 80b
Preparation of intermediate 1-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-3-thmethylsilyoxy-
2-aza-1 ,3-butadiene
Figure imgf000131_0002
M.W. 370.91 Ci9Hi9CIN2O2Si In a manner similar to the method described in example 1d, 4-(4-chloro-2-formyl- phenoxy)-benzonithle (2.8 g, 11 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (2.3 ml_, 11 mmol), n-butyllithium (2.5 M, 4.4 ml_, 11 mmol), trimethylsilyl chloride (1.4 ml_, 11 mmol), thethylamine (2 ml_, 14 mmol) and acetyl chloride (1 ml_, 14 mmol) to give crude 1-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 80c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000132_0001
M.W. 588.88 C31H20CI3N3O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.7 g, 4.4 mmol) was reacted with 1 -[5-chloro-2-(4-cyano-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (11 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.6 g, 23%)
HRMS(ES+) m/z Calcd for C31 H20CI3N3O3+ H [(IVRH)+]: 588.0643. Found: 588.0643.
Example 8Od
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000132_0002
M.W. 588.88 C3iH20CI3N3O3
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2- (4-cyano-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (500 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro- 2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (0.19 g, 38%) (RO5254876-000) and chiral (2'S, 3S, 4'R)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (0.19 g, 38%) (RO5254875-000).
Example 81a
Preparation of intermediate 5-chloro-2-(4-methylsulfanyl-phenoxy)-benzaldehyde
Figure imgf000133_0001
M.W. 278.76 Ci4H8CINO2
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro- benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-(methylthio)phenol (1.97 g, 14 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4- methylsulfanyl-phenoxy)-benzaldehyde as a brown oil (Yield 3.5 g, 98%).
Example 81b Preparation of intermediate 1-[5-chloro-2-(4-methylsulfanyl-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000133_0002
M.W. 392.00 Ci9H22CINO2SSi In a manner similar to the method described in example 1d, 5-chloro-2-(4- methylsulfanyl-phenoxy)-benzaldehyde (3.5 g, 12.6 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (2.6 ml_, 12.6 mmol), n-butyllithium (2.5 M, 5 ml_, 12.6 mmol), trimethylsilyl chloride (1.6 ml_, 12.6 mmol), thethylamine (2.3 ml_, 16 mmol) and acetyl chloride (1.2 ml_, 16 mmol) to give crude 1 -[5-chloro-2-(4-methylsulfanyl-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 81c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfanyl- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000134_0001
M.W. 609.96 C31 H23CI3N2O3S
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.96 g, 5 mmol) was reacted with 1 -[5-chloro-2-(4-methylsulfanyl- phenoxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (12.6 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5- chloro-2-(4-methylsulfanyl-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.6 g, 20%)
HRMS(ES+) m/z Calcd for C3i H23CI3N2O3S + H [(IVRH)+]: 609.0568. Found: 609.0568.
Example 82
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfonyl- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000134_0002
M.W. 641.96 C31 H23CI3N2O5S
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfanyl- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.36 g, 0.59 mmol) was added MCPBA (67%, 0.145 g, 0.87 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then washed with saturated aqueous solution of Na2S2O3, and aqueous solution of NaHCO3 sequentially. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:CH2CI2=1 :1 ) to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4- methylsulfonyl-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a light yellow solid (Yield 0.16 g, 42%). HRMS(ES+) m/z Calcd TOr C3IH23CI3N2O5S + H [(IVRH)+]: 641.0466. Found: 641.0464.
Example 83
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfinyl-phenoxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000135_0001
M.W. 625.96 C3IH23CI3N2O4S
Purifcation by chromatography (MeOH :EtOAc=6:94) in Example 82 led to the other minor product racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfinyl-phenoxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.07 g, 19%).
HRMS(ES+) m/z Calcd for C3i H23CI3N2O4S + H [(M+H)+]: 625.0517. Found: 625.0515.
Example 84a
Preparation of intermediate 5-chloro-2-(4-nitro-phenoxy)-benzaldehyde
Figure imgf000135_0002
M.W. 277.67 Ci3H8CINO4
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro- benzaldehyde (1.71 g, 10.9 mmol) (Beta Pharma) was reacted with 4-nitrophenol (1.67 g, 12 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-nitro- phenoxy)-benzaldehyde as a brown oil (Yield 2.23 g, 73%). Example 84b
Preparation of intermediate 1-[5-chloro-2-(4-nitro-phenoxy)-phenyl]-3-thmethylsilyoxy-2- aza-1 ,3-butadiene
Figure imgf000136_0001
M.W. 390.90 Ci8Hi9CIN2O4Si
In a manner similar to the method described in example 1d, 5-chloro-2-(4-nitro- phenoxy)-benzaldehyde (2.23 g, 8 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.67 ml_, 8 mmol), n-butyllithium (2.5 M, 3.2 ml_, 8 mmol), trimethylsilyl chloride (1.0 ml_, 8 mmol), thethylamine (1.45 mL, 10 mmol) and acetyl chloride (0.74 mL, 10 mmol) to give crude 1 -[5-chloro-2-(4-nitro-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 85c Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-nitro-phenoxy)-phenyl]- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000136_0002
M.W. 608.86 C30H20CI3N3O5 In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.25 g, 3.2 mmol) was reacted with 1 -[5-chloro-2-(4-nitro-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (8 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-nitro- phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.4 g, 21 %)
HRMS(ES+) m/z Calcd for C30H20CI3N3O5+ H [(M+H)+]: 608.0542. Found: 608.0543. - e -
Example 86a
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000137_0001
M.W. 578.88 C30H22CI3N3O3
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-nitro-phenoxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.31 g, 0.51 mmol) in anhydrous ethanol (20 ml_) was added Raney-Ni (0.6 g) and anhydrous hydrazine (0.118 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then filtered through a short pad of celite. The filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with water, brine, and dried over MgSO4, and concentrated to give racemic (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.28 g, 95%). HRMS(ES+) m/z Calcd for C30H22CI3N3O3 + H [(M+H)+]: 578.0800. Found: 578.0797.
Example 86b
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000137_0002
M.W. 578.88 C30H22CI3N3O3 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)- 5-chloro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (60 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-2'-[2-(4- amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione as a off white solid (24 mg, 40%) (RO5259489-000) and chiral (2'S, 3S, 4'R)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (24 mg, 40%) (RO5259490-000).
Example 87
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(4-acetylamino-phenoxy)-5-chloro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000138_0001
M.W. 620.92 C32H24CI3N3O4
In a manner similar to the method described in example 5b, racemic (2'S, 3S, 4'R)-2'-[2- (4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.18 g, 0.32 mmol) prepared in Example 86a was reacted with acetyl chloride (28 mg, 0.352 mmol) and triethylamine in tetrahydrofuran to give racemic (2'S, 3S, 4'R)-2'-[2-(4-acetylamino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a yellow solid (Yield 0.13 g, 65%). HRMS(ES+) m/z Calcd for C32H24CI3N3O4+ H [(IVRH)+]: 620.0905. Found: 620.0905.
Example 88a
Preparation of intermediate 5-iodo-2-(1 ,3,5-thmethyl-1 H-pyrazol-4-yloxy)-benzaldehyde
Figure imgf000138_0002
M.W. 356.17 Ci3Hi3IN2O2 - JO -
In a manner similar to the method described in Example 50a, 2-fluoro-5- iodobenzaldehyde (5.84 g, 23.4 mmol) (Aldrich) was reacted with 1 ,3,5-trimethyl-i H- pyrazol-4-ol (3.24 g, 25.7 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-iodo-2- (1 ,3,5-thmethyl-1 H-pyrazol-4-yloxy)-benzaldehyde as a yellow solid (Yield 8.1 g, 97%). 1 ,3,5-Thmethyl-1 H-pyrazol-4-ol was prepared according to the procedures described by Fagan, P. J., et al in Can. J. Chem. 1979, vol 57, 904-912
Example 88b
Preparation of intermediate 1-[5-iodo-2-(1 ,3,5-trimethyl-i H-pyrazol-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000139_0001
M.W. 469.40 Ci8H24IN3O2Si
In a manner similar to the method described in example 1d, 5-iodo-2-(1 ,3,5-trimethyl- 1 H-pyrazol-4-yloxy)-benzaldehyde (8.1 g, 23 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (4.7 ml_, 23 mmol), n-butyllithium (2.5 M, 9.1 ml_, 23 mmol), trimethylsilyl chloride (2.9 mL, 23 mmol), triethylamine (4.1 ml_, 30 mmol) and acetyl chloride (2.1 mL, 30 mmol) to give crude 1 -[5-iodo-2-(1 ,3,5-trimethyl-1 H-pyrazol-4- yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 88c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 ,3,5- trimethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000139_0002
M.W. 687.36 C30H25CI2IN4O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (3.5 g, 9 mmol) was reacted with1-[5-iodo-2-(1 ,3,5-trimethyl-1 H-pyrazol-4- yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (23 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-iodo-2-(1 ,3,5-thmethyl-i H-pyrazol-4-yloxy)-phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a pale yellow solid (Yield 0.64 g, 10%) HRMS(ES+) m/z Calcd for C30H25CI2IN4O3+ H [(IVRH)+]: 687.0421. Found: 687.0425.
Example 89a
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5- trimethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000140_0001
M.W. 585.49 C32H26CI2N4O3
In a manner similar to the method described in example 6a, racemic (2'R, 3R, 4'S)-6- chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.62 g, 0.9 mmol) was reacted with trimethylsilyl acetylene (0.88 g, 9 mmol), CuI (10 mg), triethylamine (2.71 g, 27 mmol), and dichlorobis(triphenylphosphine) palladium (0) (50.5 mg, 0.07 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-1 H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.47 g, 90%)
HRMS(ES+) m/z Calcd for C32H26CI2N4O3+ H [(M+H)+]: 584.1455. Found: 584.1457.
Example 89b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5- trimethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000140_0002
M.W. 585.49 C32H26CI2N4O3 Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (0.4 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-thmethyl-1 H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (0.18 g, 45%) (RO5260375-000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3- chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-thmethyl-1 H-pyrazol-4-yloxy)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a off white solid (0.17 g, 44%) (RO5260376- 000).
Example 90a
Preparation of intermediate 5-bromo-2-(1 ,3,5-trimethyl-i H-pyrazol-4-yloxy)- benzaldehyde
Figure imgf000141_0001
M.W. 309.16 Ci3Hi3BrN2O2
In a manner similar to the method described in Example 50a, 5-bromo-2-fluoro- benzaldehyde (2 g, 10 mmol) (Acros) was reacted with 1 ,3,5-thmethyl-1 H-pyrazol-4-ol (1.3 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(1 ,3,5- trimethyl-1 H-pyrazol-4-yloxy)-benzaldehyde as a white solid (Yield 3.1 g, 100%).
Example 90b
Preparation of intermediate 1-[5-bromo-2-(1 ,3,5-thmethyl-1 H-pyrazol-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000141_0002
M.W. 422.40 Ci8H24BrN3O2Si
In a manner similar to the method described in example 1d, 5-bromo-2-(1 ,3,5-thmethyl- 1 H-pyrazol-4-yloxy)-benzaldehyde (3.1 g, 10 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13 mmol) and acetyl chloride (1 g, 13 mmol) to give crude 1 -[5-bromo-2-(1 ,3,5-trimethyl-1 H-pyrazol-4-yloxy)- phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 90c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 ,3,5-trimethyl-i H-pyrazol-4- yloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000142_0001
M.W. 640.36 C30H25BrCI2N4O3
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.2 g, 3 mmol) was reacted with1-[5-bromo-2-(1 ,3,5-trimethyl-1 H-pyrazol- 4-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (4.2 g, 10 mmol) in toluene then trifluoroacetic acid in dichloromethane to give racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (1 ,3,5-thmethyl-1 H-pyrazol-4-yloxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a pale yellow solid (Yield 0.2 g, 10%) HRMS(ES+) m/z Calcd for C30H25BrCI2N4O3+ H [(IVRH)+]: 639.0560. Found: 639.0561. Example 91a
Preparation of intermediate methanesulfonic acid 1 ,4-dioxa-spiro[4.5]dec-8-yl ester
Figure imgf000142_0002
M.W. 236.29 C9Hi6O5S
In a manner similar to the method described in example 32a, 1 ,4-dioxa-spiro[4.5]decan- 8-ol (5.1 g, 32 mmol) (Alfa) was reacted with methanesulfonyl chloride (3.7 g, 32 mmol, Aldrich) and triethylamine in dichloromethane to give methanesulfonic acid 1 ,4-dioxa- spiro[4.5]dec-8-yl ester as a light yellow oil (Yield 6.8 g, 90%). Example 91b
Preparation of intermediate 5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-benzaldehyde
Figure imgf000143_0001
M.W. 296.75 Ci5Hi7CIO4 In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (2.32 g, 14.8 mmol) (Aldrich) reacted with methanesulfonic acid 1 ,4-dioxa-spiro[4.5]dec- 8-yl ester (3.5 g, 14.8 mmol) and K2CO3 in N,N-dimethylformamide to give 5-chloro-2- (1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-benzaldehyde as a colorless oil (Yield 1.5 g, 34%).
Example 91c
Preparation of intermediate 1-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000143_0002
M.W. 409.99 C20H28CINO4Si In a manner similar to the method described in example 1d, 5-chloro-2-(1 ,4-dioxa- spiro[4.5]dec-8-yloxy)-benzaldehyde (1.5 g, 5 mmol) was used as the starting material in place of 4-(2-formyl-4-iodo-phenoxymethyl)-pipehdine-1 -carboxylic acid tert-butyl ester to react with 1 ,1 ,3,3,3-hexamethyldisilazane (0.8 g, 5 mmol), n-butyllithium (2.5 M, 2 ml_, 5 mmol), thmethylsilyl chloride (.0.55 g, 5 mmol), thethylamine (0.7 g, 6.8 mmol) and acetyl chloride (0.5 g, 6.8 mmol) to give crude 1-[5-chloro-2-(1 ,4-dioxa- spiro[4.5]dec-8-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 91 d Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8- yloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000144_0001
M.W. 627.95 C32H29CI3N2O5
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.4 g, 1 mmol) was reacted 1-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (1.5 g, 5 mmol) in toluene to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a off white solid (Yield 0.23 g, 37%) HRMS(ES+) m/z Calcd for C32H29CI3N2O5+ H [(IVRH)+]: 627.1215. Found: 627.1217.
Example 92
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-oxo-cyclohexyloxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000144_0002
M.W. 583.90 C30H25CI3N2O4
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec- 8-yloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.2 g, 0.32 mmol) in tetrahydrofuran (15 ml_) and water (1 ml_) was added aqueous HCI (2 N, 1 ml_). The reaction mixture was stirred at room temperature for 1 h, then neutralized to "pH" 7 by aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:CH2CI2 = 1 : 1 ) to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-oxo-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 0.1 g, 54%)
HRMS(ES+) m/z Calcd for C30H25CI3N2O4+ H [(IVKH)+]: 583.0953. Found: 583.0953.
Example 93a
Preparation of intermediate 2-chloro-6-(4-methoxy-phenoxy)-benzaldehyde
Figure imgf000145_0001
M.W. 262.69 Ci4HiiCIO3
In a manner similar to the method described in Example 50a, 2,6-dichlorobenzaldehyde (2.7 g, 15 mmol) (Aldrich) was reacted with 4-methoxyphenol (1.8 g, 15 mmol) and K2CO3 in N,N-dimethylacetamide to give 2-chloro-6-(4-methoxy-phenoxy)- benzaldehyde as a yellow oil (Yield 3.2 g, 80%).
Example 93b Preparation of intermediate 1-[2-chloro-6-(4-methoxy-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000145_0002
M.W. 375.93 Ci9H22CINO3Si In a manner similar to the method described in example 1d, 2-chloro-6-(4-methoxy- phenoxy)benzaldehyde (2.8 g, 10 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), trimethylsilyl chloride (1.1 g, 10 mmol), thethylamine (1.36 g, 13 mmol) and acetyl chloride (1 g, 10 mmol) to give crude 1 -[2-chloro-6-(4-methoxy-phenoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 93c
Preparation of racemic (2'S, 3R, 4'S)-6-chloro-2'-[2-chloro-6-(4-methoxy-phenoxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000146_0001
M.W. 593.89 C3IH23CI3N2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.56 g, 1.4 mmol) was reacted with 1 -[2-chloro-6-(4-methoxy-phenoxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) in toluene then thfluoroacetic acid in dichloromethane to give racemic (2'S, 3R, 4'S)-6-chloro-2'-[2-chloro-6-(4- methoxy-phenoxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a light yellow solid (Yield 0.52 g, 60%)
HRMS(ES+) m/z Calcd for C3i H23CI3N2O4+ H [(IVRH)+]: 593.0796. Found: 593.0797.
Example 94a Preparation of intermediate trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol
Figure imgf000146_0002
M.W. 230.43 Ci2H26O2Si To a solution of trans-1 ,4-cyclohexanediol (3 g, 26 mmol) in anhydrous N1N- dimethylformamide (30 ml_) at 0 0C was added imidazole (1.7 g, 26 mmol) and tert- butyldimethylchlorosilane (3.87 g, 26 mmol). The reaction mixture was then stirred at 0 0C for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography ( EtOAc :hexanes = 1 ;2) to give trans-4-(tert- buyl-dimethyl-silanyloxy)-cyclohexanol as a white solid (3.9 g, 65%). - -
The starting material trans-1 ,4-cyclohexanediol was prepared by crystallization from 1 :1 mixture of cis-Arans-i ^-cyclohexanediol according to procedures described by Doyle, MP. et al in Org. Lett. 2005, VoI 7, No. 22, 5035-5038 supplimental materials without modification.
Example 94b
Preparation of intermediate cis^-^-^ert-butyl-dimethyl-silanyloxyJ-cyclohexyloxyl-δ- chloro-benzoic acid methyl ester
Figure imgf000147_0001
M.W. 399.01 C20H3ICIO4Si
To a solution of methyl 5-chloro-2-hydroxybenzoate (2.07 g, 11 mmol) and diisopropyl azodicarboxylate (2.98 g, 14 mmol) (Aldrich) in anhydrous tetrahydrofuran (10 ml_) at 0 0C was added a mixture of trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (3.2 g, 14 mmol) and thphenylphosphine (3.64 g, 14 mmol) in tetrahydrofuran (40 ml_). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water, extracted with ethyl acetate (3x). The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (5% EtOAc;hexanes) to give cis-2-[4-(tert-butyl-dimethyl-silanyloxy)- cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 4.0 g, 90%).
Example 94c
Preparation of intermediate cis-2-[ 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5- chloro-benzaldehyde
Figure imgf000147_0002
M.W. 368.98 Ci9H29CIO3Si
To a solution of cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester (4 g, 10 mmol) in anhydrous ethyl ether (30 ml_) at 0 0C was added an ethyl ether (1 M) solution of LiAIH4 (10 ml_, 10 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 0.5 h. The mixture was quenched by sequential dropwise addition of water (0.38 ml_), aqueous NaOH solution (15%, 0.38 ml_), and water (1.14 ml_). The mixture was filtered, the granular precipitate was wahed with ethyl acetate (3x). The filtrate were combined, washed with water, brine, separated, dried over MgSO4, and concentrated to give a colorless oil (3.6 g). The oil was dissolved into 1 ,2-dichloroethane, and activated MnO2 (8.34 g, 97 mmol) was added. The reaction mixture was heated at 80 0C for 1 h. The mixture was cooled to room temperature, filtered through a short pad of celite. The filtrate was concentrated to give cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzaldehyde as a yellow solid (Yield 3.6 g, 97%).
Example 94d
Preparation of intermediate i-^-tcis^-^ert-butyl-dimethyl-silanyloxyJ-cyclohexyloxyl-δ- chloro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000148_0001
M.W. 482.22 C24H40CINO3Si2
In a manner similar to the method described in example 1d, cis-2-[4-(tert-butyl-dimethyl- silanyloxy)-cyclohexyloxy]-5-chloro-benzaldehyde (3.6 g, 9.8 mmol) was reacted with 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (1.6 g, 10 mmol), n-butyllithium (2.5 M, 4 ml_, 10 mmol), thmethylsilyl chloride (1.1 g, 10 mmol), triethylamine (1.36 g, 13 mmol) and acetyl chloride (1 g, 13 mmol) to give crude 1-[2-[cis-4-(tert-butyl-dimethyl-silanyloxy)- cyclohexyloxy]-5-chloro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 94d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000149_0001
M.W. 585.91 C30H27CI3N2O4
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (1.52 g, 3.8 mmol) was reacted 1 -[2-[cis-4-(tert-butyl-dimethyl-silanyloxy)- cyclohexyloxyl-δ-chloro-phenyll-S-thmethylsilyoxy^-aza-I .S-butadiene (9.8 mmol) in toluene to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a white solid (Yield 0.4 g, 18%) HRMS(ES+) m/z Calcd for C30H27CI3N2O4+ H [(IVRH)+]: 585.1109. Found: 585.1111.
Example 94e
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000149_0002
M.W. 585.91 C30H27CI3N2O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2- (cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (350 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (0.15 g, 43%) (RO5256716-000) and chiral (2'S, 3S, 4'R)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (0.15 g, 43%) (RO5256713-000). Example 95a
Preparation of intermediate cis-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol
Figure imgf000150_0001
M.W. 230.43 Ci2H26O2Si In a manner similar to the method described in example 94a, cis-1 ,4-cyclohexanediol (3.8 g, 33 mmol) was reacted with tert-butyldimethylchlorosilane (5 g, 34 mmol) and imidazole in N,N-dimethylformamide to give cis-4-(tert-buyl-dimethyl-silanyloxy)- cyclohexanol as a colorless oil (2.4 g, 31 %).
The starting material cis-1 ,4-cyclohexanediol was prepared from 1 :1 mixture of cis- /trans-1 ,4-cyclohexanediol according to the procedures described in EP218433 without modification.
Example 95b Preparation of intermediate trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5- chloro-benzoic acid methyl ester
Figure imgf000150_0002
M.W. 399.01 C20H3ICIO4Si
In a manner similar to the method described in example 94b, cis-4-(tert-buyl-dimethyl- silanyloxy)-cyclohexanol (2.7 g, 12 mmol) was reacted with methyl 5-chloro-2- hydroxybenzoate (1.77 g, 9.5 mmol) and diisopropyl azodicarboxylate, triphenylphosphine in tetrahydrofuran to give trans-2-[4-(tert-butyl-dimethyl-silanyloxy)- cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 2.7 g, 71 %).
Example 95c
Preparation of intermediate trans-2-[ 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5- chloro-benzaldehyde
Figure imgf000151_0001
M.W. 368.98 Ci9H29CIO3Si
In a manner similar to the method described in example 94c, trans-2-[4-(tert-butyl- dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester (2.7 g, 6.76 mmol) was reacted with LiAIH4 (1 M, 6.76 ml_, 6.76 mmol) in ethyl ether, then oxidized with activated MnO2 (4.64 g, 54 mmol) in dichloromethane to give trans-2-[4-(tert-butyl- dimethyl-silanyloxyj-cyclohexyloxyl-δ-chloro-benzaldehyde as a white solid (Yield 1.12 g, 44%).
Example 95d
Preparation of intermediate 1-[2-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]- 5-chloro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000151_0002
M.W. 482.22 C24H40CINO3Si2 In a manner similar to the method described in example 1d, trans-2-[4-(tert-butyl- dimethyl-silanyloxyj-cyclohexyloxyl-δ-chloro-benzaldehyde (1.12 g, 3 mmol) was reacted with 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (0.63 ml_, 3 mmol), n-butyl lithium (2.5 M, 1.2 ml_, 3 mmol), trimethylsilyl chloride (0.39 mL, 3 mmol), thethylamine (0.55 mL, 4 mmol) and acetyl chloride (0.28 mL, 4 mmol) to give crude 1 -[2-[trans-4-(tert-butyl- dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3- butadiene as a yellow gum and used for the next step without further purification.
Example 95d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000152_0001
M.W. 585.91 C30H27CI3N2O4
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.47 g, 1.2 mmol) was reacted 1 -[2-[trans-4-(tert-butyl-dimethyl-silanyloxy)- cyclohexyloxyl-δ-chloro-phenyll-S-thmethylsilyoxy^-aza-I .S-butadiene (3 mmol) in toluene to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a pale yellow solid (Yield 0.3 g, 42%) HRMS(ES+) m/z Calcd for C30H27CI3N2O4+ H [(IVRH)+]: 585.1109. Found: 585.1111.
Example 95e
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy- cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000152_0002
M.W. 585.91 C30H27CI3N2O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2- (trans-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (250 mg) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (88 mg, 35%) .
Example 96a
Preparation of intermediate 5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde
Figure imgf000153_0001
M.W. 258.68 Ci2Hi2CIFO3
In a manner similar to the method described in example 4a, 5-chloro-4-fluoro-2- benzaldehyde (2 g, 11.5 mmol) was reacted with methanesulfonic acid tetrahydropyran- 4-yl ester (3.72 g, 17 mmol) prepared in Example 32a and K2CO3 in N1N- dimethylformamide to give 5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 1.32 g, 44%).
The starting material 5-chloro-4-fluoro-2-benzaldehyde was prepared according to the procedures described by Carter, J. S., et al in US6077850 without modification.
Example 96b
Preparation of intermediate 1-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000153_0002
M.W. 371.92 Ci7H23CIFNO3Si
In a manner similar to the method described in example 1d, 5-chloro-4-fluoro-2- (tetrahydro-pyran-4-yloxy)-benzaldehyde (1.32 g, 5 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (0.8 g, 10 mmol), n-butyllithium (2.5 M, 2 ml_, 5 mmol), trimethylsilyl chloride (0.55 g, 5 mmol), thethylamine (0.7 g, 7 mmol) and acetyl chloride (0.5 g, 7 mmol) to give crude 1 -[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]- 3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 96c Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran- 4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000154_0001
M.W. 589.88 C29H24CI3FN2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (0.79 g, 2 mmol) was reacted with 1 -[5-chloro-4-fluoro-2-(tetrahydro-pyran- 4-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (5 mmol) in toluene, then treated with thfluoroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'S)-6- chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.59 g, 50%) HRMS(ES+) m/z Calcd for C29H24CI3FN2O4+ H [(IVRH)+]: 589.0859. Found: 589.0858.
Example 96c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran- 4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000154_0002
M.W. 589.88 C29H24CI3FN2O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4- fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (0.3 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (0.099 g, 33%) (RO5259545-000) and chiral (2'S, 3S, 4'R)-6-chloro-2'-[5-chloro-4-fluoro-2- (tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (0.128 g, 43%) (RO5259544-000). Example 97a
Preparation of intermediate 5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)- benzaldehyde
Figure imgf000155_0001
M.W. 254.72 Ci3Hi5CIO3
In a manner similar to the method described in example 4a, 5-chloro-4-methyl-2- benzaldehyde (2 g, 11.7 mmol) (Asta tech) was reacted with methanesulfonic acid tetrahydropyran-4-yl ester (3.8 g, 17.6 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)- benzaldehyde as a yellow solid (Yield 2 g, 67%).
Example 97b
Preparation of intermediate 1-[5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000155_0002
M.W. 367.95 Ci8H26CINO3Si
In a manner similar to the method described in example 1d, 5-chloro-4-methyl-2- (tetrahydro-pyran-4-yloxy)-benzaldehyde (2 g, 7.9 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.6 ml_, 7.9 mmol), n-butyllithium (2.5 M, 3.1 ml_, 7.9 mmol), trimethylsilyl chloride (0.99 ml_, 7.9 mmol), thethylamine (1.42 ml_, 10 mmol) and acetyl chloride (0.73 ml_, 10 mmol) to give crude 1 -[5-chloro-4-methyl-2-(tetrahydro-pyran-4- yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 97c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-methyl-2-(tetrahydro- pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000156_0001
M.W. 585.91 C30H27CI3N2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.22 g, 3.14 mmol) was reacted with 1 -[5-chloro-4-methy-2-(tetrahydro- pyran-4-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (7.8 mmol) in toluene, then treated with thfluoroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'S)-6- chloro-2'-[5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (Yield 0.59 g, 33%) HRMS(ES+) m/z Calcd for C30H27CI3N2O4+ H [(IVRH)+]: 585.1109. Found: 585.1109.
Example 98a
Preparation of intermediate methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-
4-yl ester
Figure imgf000156_0002
M.W. 236.33 Ci0H20O4S
In a manner similar to the method described in example 32a, 2,2,6,6-Tetramethyl- tetrahydro-pyran-4-ol (5.5 g, 35 mmol) was reacted with methanesulfonyl chloride (6 g, 52 mmol, Aldrich) and thethylamine in dichloromethane to give methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester as a yellow oil (Yield 8.5 g, 100%).
The starting material 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol was prepared according to the procedures described by Nemeroff, N. et al in J. Org. Chem. 1978, 43(2), 331 - 334 with slight modification. - j -
Example 98b
Preparation of intermediate 5-chloro-2-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)- benzaldehyde
Figure imgf000157_0001
M.W. 296.80 Ci6H2iCIO3
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (4.6 g, 30 mmol) (Aldrich) reacted with methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro- pyran-4-yl ester (8 g, 34 mmol) and K2CO3 in N,N-dimethylformamide to give 5-chloro-2- (2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-benzaldehyde as a off white solid (Yield 0.94 g, 10%).
Example 98c
Preparation of intermediate 1-[5-chloro-2-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000157_0002
M.W. 410.03 C2IH32CINO3Si
In a manner similar to the method described in example 1d, 5-chloro-2-(2, 2,6,6- tetramethyl-tetrahydro-pyran-4-yloxy)-benzaldehyde (0.94 g, 3 mmol) was reacted with 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (0.66 ml_, 3 mmol), n-butyllithium (2.5 M, 1.3 ml_, 3 mmol), thmethylsilyl chloride (.0.4 ml_, 3 mmol), thethylamine (0.57 ml_, 4 mmol) and acetyl chloride (0.29 ml_, 4 mmol) to give crude 1 -[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 98d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2- (2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000158_0001
M.W. 627.99 C33H33CI3N2O4
In a manner similar to the method described in example 1 e, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 1 b (0.49 g, 1.3 mmol) was reacted 1 -[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (3 mmol) in toluene to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2- (2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (Yield 0.3 g, 37%) HRMS(ES+) m/z Calcd for C33H33CI3N2O4+ H [(IVRH)+]: 627.1579. Found: 627.1576.
Example 98e
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6- tetramethyl-tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000158_0002
M.W. 627.99 C33H33CI3N2O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.1 g) was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6- tetramethyl-tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a white solid (33 mg, 33%) (RO5260373-000) and chiral (2'S, 3S, 4'R)-6- chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetrannethyl-tetrahydro-pyran-4-yloxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (33 mg, 33%) (RO5260374-000).
Example 99a
Preparation of intermediate 5-chloro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde
M.W. 240.69 Ci2Hi3CIO3
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (6 g, 39 mmol) (Aldrich) was reacted with methanesulfonic acid tetrahydropyran-4-yl ester (10 g, 46 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2 g, 64%).
Example 99b
Preparation of intermediate 1-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000159_0002
M.W. 353.92 Ci7H24CINO3Si
In a manner similar to the method described in example 1d, 5-chloro-2-(tetrahydro- pyran-4-yloxy)-benzaldehyde (2 g, 8.3 mmol) was reacted with 1 ,1 ,1 ,3,3,3- hexamethyldisilazane (1.7 ml_, 8.3 mmol), n-butyllithium (2.5 M, 3.3 ml_, 8.3 mmol), trimethylsilyl chloride (1.06 ml_, 8.3 mmol), thethylamine (1.5 ml_, 11 mmol) and acetyl chloride (0.77 ml_, 11 mmol) to give crude 1 -[5-chloro-4- 2-(tetrahydro-pyran-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 99c
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000160_0001
M.W. 571.89 C29H25CI3N2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid te/t-butyl ester prepared in example 5b (1.3 g, 3.3 mmol) was reacted with 1 -[5-chloro-2-(tetrahydro-pyran-4-yloxy)- phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (8.3 mmol) in toluene, then treated with trifluoroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'S)-6-chloro-2'-[5- chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 1.2 g, 64%) HRMS(ES+) m/z Calcd for C29H25CI3N2O4+ H [(IVRH)+]: 571.0953. Found: 571.0951.
Example 100a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000160_0002
M.W. 408.26 C20Hi6CI2FNO3 In a manner similar to the method deschbeds in Example 1 a and Example 1 b, 3-chloro- 2-fluorobenzaldehyde (3.1 g, 20 mmol) was reacted with 6-chlorooxindole (3.3 g, 20 mmol) and pyrrolidine in methanol, then di-te/t-butyl-dicarbonate (6.5 g, 30 mmol) (Aldrich), triethylamine and 4-dimethylaminopyridine in dichloromethane to give E/Z-6- chloro-3-(3-chloro-2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester as a yellow solid (Yield: 6.1 g, 75% ). - -
Example 100b
Preparation of racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-[5-chloro- 2-(tetrahydro-pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000161_0001
M.W. 589.88 C29H24CI3FN2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- 2-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (0.68 g, 1.66 mmol) was reacted with 1 -[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (4 mmol) in toluene, then treated with trifluoroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'R)-6-chloro-4'-(3- chloro-2-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 0.12 g, 12%) HRMS(ES+) m/z Calcd for C29H24CI3FN2O4+ H [(IVRH)+]: 589.0859. Found: 589.0856.
Example 101a
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000161_0002
M.W. 408.26 C20Hi6CI2FNO3
In a manner similar to the method deschbeds in Example 1 a and Example 1 b, 3-chloro- 4-fluorobenzaldehyde (3.5 g, 23 mmol) was reacted with 6-chlorooxindole (4.7 g, 28 mmol) and pyrrolidine in methanol, then di-te/t-butyl-dicarbonate (5 g, 23 mmol) (Aldrich), triethylamine and 4-dimethylaminopyridine in dichloromethane to give E/Z-6- chloro-3-(3-chloro-4-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester as a yellow solid (Yield: 4.5 g, 48% ). - -
Example 101b
Preparation of racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-4-fluoro-phenyl)-2'-[5-chloro- 2-(tetrahydro-pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000162_0001
M.W. 589.88 C29H24CI3FN2O4
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro- 4-fluoro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (0.68 g, 1.66 mmol) was reacted with 1 -[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (4 mmol) in toluene, then treated with trifluoroacetic acid in dicloromethane to give racemic (2'R, 3R, 4'R)-6-chloro-4'-(3- chloro-4-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (Yield 0.14 g, 14%) HRMS(ES+) m/z Calcd for C29H24CI3FN2O4+ H [(IVRH)+]: 589.0859. Found: 589.0856.
Example 102a
Preparation of intermediate 2-(4-bromo-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester
Figure imgf000162_0002
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), Kl (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 ml_) was added 2-bromo-2-methyl-propionic acid ethyl ester (17.6 g, 90 mmol). The mixture was heated at 14O0C for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (15 g). - z -
Example 102b
Preparation of intermediatel -[5-bromo-2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000163_0001
M.W. 428.40 Ci8H26BrNO4Si
To a mixture of 2-(4-bromo-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (6 g, 19 mmol) in THF (80 ml_) at O 0C was added a solution of lithium bis(thmethylsilyl)amide in THF (1 M, 19 ml_, 19 mmol). The mixture was stirred under argon at O 0C for 1 h. Then trimethylsilyl chloride (2.4 ml_, 19 mmol) was added dropwise, followed by addition of triethylamine (3.44 ml_, 24.6 mmol) in one portion and a solution of acetyl chloride (1.75 ml_, 24.6 mmol) in diethyl ether (80 ml_) dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under argon, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (19 ml_) to give a solution (1 M) of the title compound.
Example 102c
Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -ethoxycarbonyl-1 - methyl-ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000163_0002
M.W. 646.37 C30H27BrCI2N2O5
To a solution of 1-[5-bromo-2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene in toluene (1 M, 12 ml_, 12 mmol) was added E/Z- 6-chloro-3-(3-chloro-benzylidene)-1-(carboxylic acid tert-butyl ester)- 1 ,3-dihydro-indole- 2-one(1.5 g, 3.8 mmol). The reaction mixture was irradiated by microwave at 1350C for - -
40 min, then purified by column chromatography to give the title compound as a white solid (800 mg).
Example 102d Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-hydroxycarbonyl-1- methyl-ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000164_0001
M.W. 618.32 C28H23BrCI2N2O5 To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -ethoxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)- dione (700 mg, 1.08 mmol) in methanol (20 ml_) was added a solution of NaOH (120 mg, 3 mmol) in water (10 ml_). The mixture was heated at 6O 0C for 1.5 h, evaporated to remove methanol, cooled to room temperature, and acidified to "pH" 2 with HCI aq.. The precipitate was collected, washed with water and dried to give the title compound as a white solid (610 mg).
Example 102e
Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[2-(4-acetyl-piperazin-1-yl)-1 ,1 - dimethyl-2-oxo-ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000164_0002
M.W. 728.468 C34H33BrCI2N4O5 To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)- dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (25 mg, 0.2 mmol) in THF (2 ml_) was added 1 -piperazin-1 -yl-ethanone (25 - - mg, 0.195 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (11 mg). m/z (IvRH)+: 727
Example 103
Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2-[ 2-(4,4-difluoro-piperidin-1 -yl)-1 ,1- dimethyl-2-oxo-ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000165_0001
M.W. 721.423 C33H30BrCI2F2N3O4
To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)- dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 ml_) was added 4,4- difluoropipehdine hydrochloride (30 mg, 0.195 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19mg). m/z (M+H)+: 720
Example 104 Preparation of racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2- [1 -methyl-1 -(2,2,2-trifluoro- ethylcarbamoyl)-ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000165_0002
M.W. 699.349 C30H2BrCI2F3N3O4
To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)- dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 ml_) was added 2,2,2-thfluoroethylamine hydrochloride (25 mg, 0.185 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19 mg). m/z (IvRH)+: 698
Example 105
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2- (1 -dimethylcarbamoyl-i -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000166_0001
M.W. 645.378 C30H28BrCI2N3O4
To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)- dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 ml_) was added dimethylamine hydrochloride (20 mg, 0.25 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (26 mg). m/z (M+H)+: 644
Example 106a Preparation of intermediate 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester
Figure imgf000166_0002
M.W. 286.35 Ci3Hi8O5S
To a mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 0.1 mol), K2CO3 (20 g, 0.14 mol) and DMAP (6.2 g, 0.05 mol) in DCM (100 ml_) was added p- toluenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature overnight, then filtered. The filtrate was washed with HCI aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (15 g). - oo -
Example 106b
Preparation of intermediate 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester
Figure imgf000167_0001
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (4 g, 20 mmol), Kl (1 g) and K2CO3 (4 g, 29 mmol) in DMF (10 ml_) was added 2,2-dimethyl-3-(toluene-4-sulfonyloxy)- propionic acid methyl ester (6.9 g, 24 mmol). The mixture was heated at 14O0C for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water (3x), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (5.4 g).
Example 106c
Preparation of intermediate 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy) phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000167_0002
M.W. 428.4 Ci8H26BrNO4Si To a mixture of 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (5 g, 16mmol) in THF (80 ml_) at O 0C was added a solution of lithium bis(trimethylsilyl) amide in THF (1 M, 16ml_, 16mmol). The mixture was stirred at same temperature for 1.5 h under argon. Then thmethylsilyl chloride (2 ml_, 16 mmol) was added dropwise, followed by addition of thethylamine (2.87 ml_, 20.8 mmol) in one portion and a solution of acetyl chloride (1.46 ml_, 20.8 mmol) in diethyl ether (80 ml_) dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under - - reduced pressure. The residue was dissolved in toluene (16 ml_) to give a solution (1 M) of the title compound.
Example 106d Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxycarbonyl-2- methyl-propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000168_0001
M.W. 646.37 C30H27BrCI2N2O5 To a solution of 1-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy) phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene in toluene (1 M, 12 ml_, 12 mmol) was added E/Z- 6-chloro-3-(3-chloro-benzylidene)-1-(carboxylic acid tert-butyl ester)-1 ,3-dihydro-indole- 2-one(1.5 g, 3.8 mmol). The reaction mixture was irradiated by microwave at 1350C for 40 min, then purified by column chromatography to give the title compound as a white solid (300 mg).
Example 106e
Preparation of intermediate racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-hydroxycarbonyl-2- methyl-propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000168_0002
M.W. 632.34 C29H25BrCI2N2O5
To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxycarbonyl-2-methyl- propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (106 mg, 0.16 mmol) in methanol (6 ml_) was added a solution of NaOH (30 mg, 0.75 mmol) in water (3 ml_). The mixture was heated at 6O 0C for 5h, evaporated to remove methanol, cooled to room temperature, and acidified to "pH" 2 with HCI aq.. - oo -
The precipitate was collected and dried to give the title compound as a white solid (70 mg). m/z (M+H)+: 617
Example 106f Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2-dimethylcarbamoyl-2-methyl- propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000169_0001
M .W. 659.405 C3IH30BrCI2N3O4 To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-hydroxycarbonyl-2-methyl- propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (50 mg, 0.08 mmol), EDCI (23 mg, 0.12 mmol), HOBt (18.4 mg, 0.12 mmol) and DIPEA (62 mg, 0.48 mmol) in THF (2ml_) was added dimethylamine hydrochloride (20 mg, 0.25 mmol). The mixtue was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (20mg). m/z (M+H)+: 658
Example 107 Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2,2-dimethyl-3-oxo-3-pyrrolidin-1 - yl-propoxy)-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000169_0002
M.W. 685.443 C33H32BrCI2N3O4
To a mixture of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-hydroxycarbonyl-2-methyl- propoxyJ-phenyll-θ-chloro^'^S-chlorophenylJ spiroISH-indole-S.S'-piperidinel^.θXI H)- dione (50 mg, 0.08 mmol), EDCI (23 mg, 0.12 mmol), HOBt (18.4 mg, 0.12 mmol) and DIPEA (62 mg, 0.48 mmol) in THF (2 ml_) was added pyrrolidine (17 mg, 0.24 mmol). The mixtue was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (33 mg). - - m/z (M+H)+: 684
Example 108a
Preparation of intermediate toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester
Figure imgf000170_0001
M.W. 256.32 Ci2Hi6O4S
To a mixture of (3-methyl-oxetan-3-yl)-methanol (10.2 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 ml_) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCI aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (18 g).
Example 108b
Preparation of intermediate 5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde
Figure imgf000170_0002
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), Kl (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 ml_) was added toluene-4-sulfonic acid 3-methyl-oxetan- 3-ylmethyl ester (18 g, 70 mmol). The mixture was heated at 14O0C for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (10 g).
Example 108c
Preparation of intermediate1-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000171_0001
M.W. 398.38 Ci7H24BrNO3Si
To a mixture of 5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-benzalclehycle (4.5 g, 16mmol) in THF (80 ml_) at O 0C was added a solution of lithium bis(thmethylsilyl)amide in THF (1 M, 16ml_, 16mmol). The mixture was stirred at same temperature for 1 h under argon. Then trimethylsilyl chloride (2 ml_, 16 mmol) (Aldrich) was added dropwise, followed by addition of thethylamine (2.87 ml_, 20.9 mmol) in one portion and a solution of acetyl chloride (1.46 ml_, 20.9 mmol) in diethyl ether (80 ml_) dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (16 ml_) to give a solution (1 M) of the title compound.
Example 108d Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000171_0002
M.W. 616.337 C29H25BrCI2N2O4
To a solution of 1-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) phenyl]-3-trimethylsilyoxy- 2-aza-1 ,3-butadiene in toluene (1 M, 12 ml_, 12 mmol) was added E/Z-6-chloro-3-(3- chloro-benzylidene)-1-(carboxylic acid tert-butyl ester)-1 ,3-dihydro-indole-2-one(1.5 g, 3.8 mmol). The reaction mixture was irradiated by microwave at 1350C for 40 min, then purified by column chromatography to give the title compound as a white solid (300 mg). m/z (M+H)+: 616
Example 108e
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-bromo- 2-(3- methyl-oxetan-3-ylmethoxy) phenyl] spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000172_0001
M.W. 616.337 C29H25BrCI2N2O4
Separation of the two enantiomers from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3- chlorophenyl)-2'-[5-bromo- 2-(3-methyl-oxetan-3-ylmethoxy) phenyl] spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (RO5220487-000) (40 mg) was conducted by chiral Prep- HPLC to provide chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-bromo- 2-(3- methyl-oxetan-3-ylmethoxy) phenyl] spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione (15 mg) (RO5247601 -000) and chiral (2'S, 3S, 4'R)-6-chloro-4'-(3-chlorophenyl)-2'-[5- bromo- 2-(3-methyl-oxetan-3-ylmethoxy) phenyl] spiro[3H-indole- 3,3'-piperidine]- 2,6'(1 H)-dione (15 mg) (RO5247602-000).
Example 109a
Preparation of intermediate 5-bromo-2-(4-fluoro-benzyloxy)-benzaldehyde
Figure imgf000172_0002
M.W. 309.14 Ci4Hi0BrFO2
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (5 g, 25 mmol), Kl (2 g) and K2CO3 (7 g, 50 mmol) in DMF (100 ml_) was added 1 -chloromethyl-4-fluoro-benzene (3.96 g, 28 mmol). The mixture was heated at 14O0C for 2h, then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (4.5 g).
Example 109b
Preparation of 1-[5-bromo-2-(4-fluoro-benzyloxy) phenyl]-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000172_0003
M.W. 422.37 C19H21 BrFNO2Si
To a mixture of 5-bromo-2-(4-fluoro-benzyloxy)-benzaldehyde (4.4 g, 14mmol) in THF (60 ml_) at O 0C was added a solution of lithium bis(thmethylsilyl)amide in THF (1 M, 14 ml_, 14 mmol). The mixture was stirred at same temperature for 1 h under argon. Then trimethylsilyl chloride (1.75 ml_, 14 mmol) was added dropwise, followed by addition of triethylamine (2.51 ml_, 18 mmol) in one portion and a solution of acetyl chloride (1.28 ml_, 18 mmol) in diethyl ether (60 ml_) dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (14 ml_) to give a solution (1 M) of the title compound.
Example 109c
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2-(4-fluoro-benzyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000173_0001
M.W. 640.334 C3IH22BrCI2FN2O3
To a solution of 1-[5-bromo-2-(4-fluoro-benzyloxy) phenyl]-3-thmethylsilyoxy- 2-aza-1 ,3- butadiene in toluene (1 M, 12 ml_, 12 mmol) was added E/Z-6-chloro-3-(3-chloro- benzylidene)-1 -(carboxylic acid tert-butyl ester)-1 ,3-dihydro-indole-2-one(1.5 g, 3.8 mmol). The reaction mixture was irradiated by microwave at 1350C for 40 min, then purified by column chromatography to give the title compound as a white solid (160 mg). m/z (M+H)+: 639
Example 110a Preparation of intermediate toluene-4-sulfonic acid 3-ethyl-oxetan-3-yl methyl ester
Figure imgf000173_0002
M.W. 270.35 Ci3Hi8O4S
To a mixture of (3-ethyl-oxetan-3-yl)-methanol (11.6 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 ml_) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCI aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (19 g).
Example 110b Preparation of intermediate 5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy)-benzaldehyde
Figure imgf000174_0001
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), Kl (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 ml_) was added toluene-4-sulfonic acid 3-ethyl-oxetan-3- ylmethyl ester (19 g, 70 mmol). The mixture was heated at 14O0C for 2h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (1 O g).
Example 110c
Preparation of intermediate 1-[5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy) phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000174_0002
M.W. 412.40 Ci8H26BrNO3Si
To a mixture of 5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy)-benzaldehyde (5.9 g, 20 mmol) in THF (80 ml_) at O 0C was added a solution of lithium bis(thmethylsilyl)amide in THF (1 M, 2OmL, 20mmol). The mixture was stirred at same temperature for 1 h under argon. Then trimethylsilyl chloride (2.5 ml_, 20 mmol) (Aldrich) was added dropwise, followed by addition of thethylamine (3.6 ml_, 26 mmol) in one portion and a solution of acetyl chloride (1.83 ml_, 26 mmol) in diethyl ether (80 ml_) dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (20 ml_) to give a solution (1 M) of the title compound.
Example 11Od
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000175_0001
M.W. 630.363 C30H27BrCI2N2O4 To a solution of 1-[5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy) phenyl]-3-thmethylsilyoxy-2- aza-1 ,3-butadiene in toluene (1 M, 12 ml_, 12 mmol) was added E/Z-6-chloro-3-(3- chloro-benzylidene)-1-(carboxylic acid tert-butyl ester)-1 ,3-dihydro-indole-2-one(1.5 g, 3.8 mmol). The reaction mixture was irradiated by microwave at 1350C for 40 min, then purified by column chromatography to give the title compound as a white solid (200 mg). m/z (M+H)+: 629.
Example 111a
Preparation of intermediate 4-methanesulfonyloxy-pipehdine-1-caboxylic acid tert-butyl ester
Figure imgf000175_0002
M.W. 279.36 CiiH2iNO5S
At 0 0C, to a solution of 4-hydroxy-pipehdine-1-carboxylic acid tert-butyl ester (4 g, 20.20 mmol) and DMAP (3 g, 24 mmol) in DCM (50 ml_) was added methanesulfonyl chloride (2.7 g, 24 mmol). After stirred for 2h, the mixture was filtrated. The filtrate was washed by 0.5/V HCI (50 ml_), Na2CO3 aqueous solution (1 M, 50 ml_) and brine (50 ml_), dried over anhydrous Na2SO4, and concentrated to give the title compound as a yellow solid (5 g). Example 111b
Preparation of intermediate 4-(2-formyl-4-trifluoromethyl-phenoxy)-pipehdine-1- carboxylic acid tert-butyl ester
Figure imgf000176_0001
M.W. 373.38 Ci8H22F3NO4
A mixture of 2-hydroxy-5-thfluoromethyl-benzaldehyde (1.36 g, 7.17 mmol), 4- methanesulfonyloxy-pipehdine-1-carboxylic acid tert-butyl ester (2.2 g, 7.88 mmol) and K2CO3 (2.96 g, 21.5 mmol) in anhydrous N,N-dimethylformamide (15 ml_) was heated at 100 0C for 1 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 ml_). The solution was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound (1.43 g).
Example 111c Preparation of intermediate 1-[2-(1 -tert-butoxycarbonyl-pipehdin-4-yloxy)]-5- trifluoromethyl-phenyl]-3-trimethylsilyoxy-2-aza- 1 ,3-butadiene
Figure imgf000176_0002
M.W. 486.61 C23H33F3N2O4Si To dry tetrahydrofuran (10 ml_) was added a solution of LiHMDS (3.8 mmol, 3.8 ml_) in THF (1 M) under argon at room temperature , followed by the addition of 4-(2-formyl-4- trifluoromethyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester (1.43 g, 3.83 mmol) . After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (0.48 ml_, 3.8 mmol) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (0.71 ml, 4.87 mmol) in one portion, followed by dropwise addition of a solution of acetyl - - chloride (0.36 ml, 4.87 mmol) in diethyl ether (20 ml). The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was quickly filtered on celite under nitrogen, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow gum and used for the next step without further purification.
Example 111d
Preparation of racemic (2'R, 3R, 4'S)-2'-[2-(1-tert-butoxycarbonyl-pipehdin-4-yloxy)]-5- trifluoromethyl-phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000177_0001
M.W. 704.58 C35H34CI2F3N3O5
To a solution of 1 -[2-( 1 -tert-butoxycarbonyl-pipehdin-4-yloxy)]-5- thfluoromethyl- phenyl]-3-thmethylsilyoxy-2-aza- 1 ,3-butadiene (2.6 g, 5.4 mmol) in toluene (5.4 ml_) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-1-carboxylic acid tert-butyl ester-1 ,3- dihydro-indole-2-one (300 mg, 0.77 mmol). The mixture was heated at 130 0C for 30 min by microwave irradiation under argon. After cooled to room temperature, the mixture was concentrated and the residue was purified by flash column to give title compound (10 mg). m/z (M+H)+: 704
Example 112a
Preparation of intermediate 5-bromo-2-iodo-benzaldehyde
Figure imgf000177_0002
M.W. 310.92 C7H4BrIO
To a solution of 5-bromo-2-iodo- benzomithle (1.54 g, 5 mmol) in DCM (15 ml_) was added a solution of DIBALH (6 ml_, 6 mmol) dropwise at O0C. After the addition, the reaction mixture was warmed to r.t. and stirred for 2 h. Then the mixture was poured into 20 g of ice and 20 ml_ of 1 N HCI, filtered and extracted by DCM (40 ml_), washed with aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give crude product (Yield: 1.2 g).
Example 112b
Preparation of intermediate 1-(2-iodo-5-bromo-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000178_0001
M.W. 424.15 Ci2Hi5BrIOSi
To dry tetrahydrofuran (120 ml_) was added a solution of LiHMDS (42 mmol, 42 ml) in THF under argon at room temperature, followed by the addition of 5-bromo-2-iodo- benzaldehyde (13 g, 42 mmol). After the mixture was stirred at room temperature for 0.5 h, thmethylsilyl chloride (5.32 ml_, 42 mmol) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (7.6 ml_, 54.4 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (3.9 ml_, 54.4 mmol) in diethyl ether (200 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give the title compound as a yellow gum and used for the next step without further purification.
Example 112c
Preparation of intermediate racemic (2'S, 3R, 4'S)-2'-(5-bromo-2-iodo-phenyl)-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000178_0002
- o -
M.W. 642.12 C24Hi6BrCI2N2O2
In a manner similar to the method described in 32d, E/Z-6-chloro-3-(3-chloro- benzylidene)-1 -carboxylic acid tert-butyl ester-1 ,3-dihydro-indole-2-one (3.9 g, 8 mmol) was reacted with 1 -(5-bromo-2-lodo)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (21 mmol) in toluene to give the title compound as a white solid (Yield: 600 mg).
Example 112d
Preparation of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 -methyl-pipehdi n-4-ylamino)-phenyl]-6-chloro-4'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000179_0001
To a solution of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-(5-bromo-2-iodo- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (32 mg, 0.05 mmol) in DMF (5 ml_) was added 1 -methyl-pipehdin-4-ylamine (8 mg g, 0.075 mmol), Cs2COs (33 mg, 0.01 mmol), 2-acetyl-cyclohexanone (1.4 mg) and CuI (1 mg) under argon. The mixture was stirred at r.t. for 5 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with NaHCO3 aqueous solution, dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give title compound as a white solid (Yield: 10 mg). m/z (M+H)+: 627
Example 113a Preparation of intermediate 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo- benzaldehyde
Figure imgf000179_0002
M.W. 406.34 Ci5H23IO3Si
To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N1N- dimethylfornnannide (150 ml_) was added anhydrous K2CO3 (11.17 g, 80.7 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.74 g, 32.3 mmol, Aldrich). The reaction mixture was heated at 65 0C for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5- iodo-benzaldehyde as a yellow oil (Yield 1 O g, 100%).
Example 113b
Preparation of intermediate 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-
3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000180_0001
M.W. 519.58 C20H34INO3Si2 To 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (4.36 ml_, 21 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 8.4 ml_, 21 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (60 ml_) was added, followed by the addition of 2-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-5-iodo-benzaldehyde (8.53 g, 21 mmol). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (2.66 ml_, 21 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added triethylamine (3.8 ml_, 27.2 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (1.94 ml_, 27.2 mmol) in diethyl ether (100 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -[2-(tert- butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow oil and used for the next step without further purification.
Example 113c
Preparation of intermediate racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- iodo-2-(2-hydroxy-ethoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000181_0001
M.W. 623.28 C26H2ICI2IN2O4
To a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (21 mmol) in toluene (30 ml_) was added E/Z-6- chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid te/f-butyl ester prepared in Example 1 b (1.2 g, 3.1 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140 0C for 45 min. After the solution was cooled to room temperature, the reaction mixture was concentrated. The residue was dissolved in dichloromethane (20 ml_) and trifluoroactic acid (20 ml_) was added. After the reaction mixture was stirred at room temperature for 4 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetae. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2CI2 =1 ;3) to give racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5- iodo-2-(2-hydroxy-ethoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a light yellow solid (Yield 0.46 g, 25%). HRMS(ES+) m/z Calcd for C26H2iCI2IN2O4+ H [(IVRH)+]: 622.9996. Found: 622.9995.
Example 113d
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy- ethoxy)-5-(2-thiophenyl)-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000181_0002
M.W. 579.51 C30H24CI2N2O4S Racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-iodo- phenyl]- spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (150 mg, 0.24 mmol), thphenyl phophine (Aldrich, 25 mg), ths(dibenzylideneacetone)dipalladium (Strem Chemicals, - o -
MA, 25 mg), copper iodide (2 mg, Aldrich), and 2-(tributylstannyl)thiophene (585 mg, 1.56 mmol, Aldrich) were combined into 1.4-dioxane (4 ml_). The mixture was purged with nitrogen and was stirred at 85 0C for 1.5 h. The reaction mixture was poured into water and was extracted with EtOAc. The combined organic was washed with H2O, brine, dried with MgSO4 and concentrated to give a yellow residue. It was chromatographied on an ISCO machine eluting with EtOAc to 5% MeOH/EtOAc followed by recrystalization from CH2CI2/Hexane to give an off-white solid. 20 mg. HRMS(ES+) m/z Calcd for C30H24CI2N2O4S+ H [(M+H)+]: observed, 579.0905; calculated, 579.0907.
Example 114
Preparation of chiral (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy- ethoxy)-5-(2-furanyl)-phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000182_0001
M. W. 563.44 C30H24CI2N2O5
Racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-iodo- phenyl]- spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (120 mg, 0.19 mmol), thphenyl phophine (Aldrich, 30 mg), ths(dibenzylideneacetone)dipalladium (Strem Chemicals, MA, 20 mg), CuI (2 mg, Aldrich), and 2-(tributylstannyl)furan (200 mg, 0.56 mmol, Aldrich) were combined into 1 , 4-dioxane (4 ml_). The mixture was purged with nitrogen and was stirred at 8O0C for 1.5 hrs. The reaction mixture was poured into water and was extracted with EtOAc. The combined organic was washed with H2O, brine, dried with MgSO4 and concentrated to give a yellow residue. It was chromatographied on an ISCO machine eluting with EtOAc to 5% MeOH/EtOAc to give a yellow film. 32 mg. The product was then resolved on a SFC machine at 2mL/min., 35% methanol, 100 bar and 3O0C to give two enantiomers.
HRMS(ES+) m/z Calcd for C30H24CI2N2O5+ H [(M+H)+]: observed, 563.1133; calculated, 563.1135. Example 115
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy- ethoxy)-5-phenyl-phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000183_0001
M. W. 573.48 C32H26CI2N2O4
Racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-iodo- phenyl]- spiro[3H-indole-3,3'-piperidine]-2,6'-dione (200 mg, 0.32 mmol), triphenyl phophine (Aldrich, 30 mg), tris(dibenzylideneacetone)dipalladium (Strem Chemicals, MA, 32 mg), CuI (3 mg, Aldrich), and tributylphenyltin (587 mg, 1.60 mmol, Aldrich) were combined into 1.4-dioxane (4 ml_). The mixture was purged with nitrogen and was stirred at 80 0C for 2 h. The reaction mixture was diluted with THF, filtered through celite. The filtrate was concentrated to give a brown residue, which was chromatographied on an ISCO machine eluting with 50%EtOAc/Hexane to EtOAc followed by HPLC purification with 25-65% CH3CN/H2O to give a white solid. 7.8 mg. HRMS(ES+) m/z Calcd for C32H26CI2N2O4+ H [(M+H)+]: observed, 573.1340; calculated, 573.1343.
Example 116a Preparation of intermediate 4-chloro-2-tert-butyl-dimethylsilanyloxy-benzaldehyde
Figure imgf000183_0002
M.W. 270.83 Ci3Hi9CIO2Si
To a stirred solution of 5-chloro-2-hydroxy-benzaldehyde (Aldrich, 7.83 g, 50 mmol) in methylene chloride (150 ml_) were added imidazole (Aldrich, 3.72 g, 54.6 mmol) and tert-butyl-dimethyl-chloro-silane (Aldrich, 7.84 g, 52 mmol). The mixture was stirred at room temperature for 5 hrs. A second portion of imidazole (1.2 g) was added and mixture was stirred for 1 hr. The mixture was then poured into saturated sodium bicarbonate solution (150 ml_). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2x50 ml_). The combined extracts were washed with water, brine and dried over magnesium sulfate. Removal of the solvent gave an off white solid. 13.62 g.
Example 116b
Preparation of intermediatel -[2-(tert-butyl-dimethylsilanyloxy)-5-chloro-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000184_0001
M.W. 384.07 Ci8H30CINO2Si2
To a stirred solution of 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (3.34 g, 20 mmol) at O0C, n- BuIi (2.5 M, 8 ml_) was added slowly and the mixture was stirred for 15 min.. Then THF (40 ml_) was added followed by 4-chloro-2-tert-butyl-dimethylsilanyloxy-benzaldehyde (5.42 g, 20 mmol). The mixture was stirred at rt for 30 min.. Then, thmethylsilanyl chloride (26 mmol), acetyl chloride (26 mmol) and thmethylamine (26 mmol) were added and the mixture was stirred at rt for 1 hr. The mixture was quickly passed through a short pad of silica gel and the pad was washed with 30% EtOAc/Hexanes to make sure the azadiene has completely passed through. The filtrate was concentrated at rt and directly used for the next step.
Example 116c
Preparation of intermediate racemic (2'R, 3R,4'S)-2'-[2-(tert-butyl-dimethylsilanyloxy)-5- chloro-phenyl]-6-chloro-4'-(3-chlorophenyl)-2,6'-dioxo-spiro[3H-indole-3,3'-piperidine]-1 - carboxylic acid tert-butyl ester
Figure imgf000185_0001
M.W. 700.17 C35H39CI3N2O5Si
E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester (3.89 g, 10 mmol) and 1 -[5-chloro-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene (20 mmol) were combined into toluene (110 ml_). The mixture was stirred at 11O0C for 2 hrs. The solvent was removed and the residue was chromatographied (15% -35% EtOAc/Hexanes) to give a foam. 1.66 g. MS (H+), 701.
Example 116d
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2- pyrazinyloxy)-phenyl]-spiro-[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000185_0002
M.W. 565.85, C28Hi9CI3N4O3 To a stirred solution of racemic (2'R, 3R,4'S)-2'-[2-(tert-butyl-dimethylsilanyloxy)-5- chloro-phenyl]-6-chloro-4'-(3-chlorophenyl)-2,6'-dioxo-spiro[3H-indole-3,3'-pipehdine]-1 - carboxylic acid tert-butyl ester (140 mg, 0.2 mmol) in 1 ,4-dioxane ( 4 ml_), tetra- butylammonium fluoride (Aldrich, 0.4 mmol, 0.4 ml_ of 1 M solution in THF) was added and the mixture was stirred for 30 min. at rt. Then 2-chloro-pyrazine (Aldrich, 0.40 mmol) was added and the resulting mixture was stirred at reflux for 8 hrs. The solvent was removed and the residue was chromatographied on an ISCO machine (5% MeOH in methylene chloride) to give a brown solid. 24 mg. MS (H+), 565 Example 117a
Preparation of intermediate 4-iodo-2-tert-butyl-dimethylsilanyloxy-benzaldehyde
Figure imgf000186_0001
M.W. 362.29 Ci3Hi9IO2Si
To a stirred solution of 5-iodo-2hydroxy-benzaldehyde (Aldrich, 15.5 g, 62.5 mmol) in methylene chloride (100 ml_) were added imidazole (Aldrich, 4.28 g, 63 mmol) and tert- butyl-dimethyl-chloro-silane (Aldrich, 9.45 g, 63 mmol). The mixture was stirred at room temperature for 5.5 hrs and then poured into 1 N sodium hydroxide solution (150 ml_). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2x50 ml_). The combined extracts were washed with water, brine and dried over magnesium sulfate. Removal of the solvent gave an oil, which was chromatographied (hexane as eluent) to give a colorless oil. 16.6 g.
Example 117b
Preparation of intermediatel -[5-bromo-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000186_0002
M.W. 475.52 Ci8H30INO2Si2 To a stirred solution of 1 ,1 ,1 , 3,3,3-hexamethyldisilazane (6.4 g, 40 mmol) at O0C, n-Buli (2.5 M, 16 ml_) was added slowly and the mixture was stirred for 15 min.. Then THF (80 ml_) was added followed by 4-iodo-2-tert-butyl-dimethylsilanyloxy-benzaldehyde (14.48 g, 40 mmol). The mixture was stirred at rt for 30 min.. Then, trimethylsilanyl chloride (40 mmol), acetyl chloride (40 mmol) and trimethylamine (40 mmol) were added and the mixture was stirred at rt for 1 hr. The mixture was quickly passed through a short pad of - oυ - silica gel and the pad was washed with30 EtOAc/Hexanes to make sure the azadiene has completely passed through. The filtrate was concentrated at rt and directly used for the next step.
Example 117c
Preparation of intermediate racemic (2'R, 3R,4'S)-2'-[2-(tert-butyl-dimethylsilanyloxy)-5- iodo-phenyll-e-chloro^'^S-chlorophenyl^.G'-dioxo-spirotSH-indole-S.S'-piperidinel-i - carboxylic acid tert-butyl ester
Figure imgf000187_0001
M.W. 793.61 C35H39CI2IN2O5Si
E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester (3.85 g, 13 mmol) and 1 -[5-bromo-2-(tert-butyl-dimethylsilanyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene (40 mmol) were combined into toluene (110 ml_). The mixture was stirred at 110 0C for 2 hrs. The solvent was removed and the residue was chromatographied (15% -35% EtOAc/Hexanes) to give a foam. 4.65 g. MS (H+), 693.
Example 117d
Preparation of racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000187_0002
M.W. 579.23 C24Hi7CI2IN2O3
Racemic (2'R, 3R,4'S)-2'-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl)-2,6'-dioxo-spiro[3H-indole-3,3'-pipehdine]-1 -carboxylic acid tert-butyl ester (200 mg, 0.25 mmol) was dissolved in 30% TFA/CH2CI2 (5 ml_) and the solution was stirred at rt for 2 h. The solvent was removed and the residue was partioned - o - between water and methylene chloride. The organic layer was separated and dried with sodium sulfate and concentrated. The residue was chromatographied to give a white solid which was directly used for next step. MS (H+), 579.
Example 117e
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-(2-furanyl)-2- hydroxy-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000188_0001
M.W. 519.39, C28H20CI2N2O4
In a manner similar to the method described in Example 114, the title compound was prepared from racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione.
HRMS(ES+) m/z Calcd for C28H20CI2N2O4+ H [(M+H)+]: observed, 519.0873; calculated, 519.0873
Example 118
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2- thiofuranyl)-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000188_0002
M.W. 535.45, C28H20CI2N2O3S
In a manner similar to the method described in Example 113d, the title compound was prepared from racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione. MS(ES+) m/z Calcd for C28H20CI2N2O3S + H [(M+H)+]: observed, 535; calculated, 534. - oo -
Example 119
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5- phenyl]-phenyl-spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000189_0001
M.W. 529.43, C30H22CI2N2O3
In a manner similar to the method described in Example 115, the title compound was prepared from racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione . HRMS(ES+) m/z Calcd for C30H22CI2N2O3 + H [(IVKH)+]: observed, 529.1080; calculated, 529.1080.
Example 120
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2- thiazolyl)-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000189_0002
M.W. 536.44, C27Hi9CI2N3O3S
In a manner similar to the method described in Example 113d, the title compound was prepared from racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (214d) and 4-(thbutylstannyl) thiazole (Synthonix).
HRMS(ES+) m/z Calcd for C27Hi9CI2N3O3S + H [(M+H)+]: observed, 536.0598; calculated, 536.0597.
Example 121
Preparation of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2- thiazolyl)-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000190_0001
M.W. 536.44, C27Hi9CI2N3O3S
In a manner similar to the method described in Example 113d, the title compound was prepared from racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione and 2-(thbutylstannyl) thiazole (Synthonix).
HRMS(ES+) m/z Calcd for C27H19CI2N3O3S+H [(IVKH)+]: observed, 536.0598; calculated, 536.0597.
Example 122a
Preparation of intermediate (S)-3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester
Figure imgf000190_0002
M.W. 325.79, Ci6H20CINO4
To a solution of (R)-1-N-boc-3-hydroxy pyrrolidine (4.89 g, 26.12 mmol, Aldrich) in CH2CI2 (100 ml_) at 0 0C was added methanesulfonyl chloride, followed by Et3N (4.4 ml_, 31.35 mmol). The reaction was stirred at room temperature for 2 h, washed with 0.5 N HCI, Water and brine, dried over MgSO4, filtered and concentrated to give a light yellow oil.
The yellow oil was combined with 5-chlorosalicylaldehyde (4.07 g, 26 mmol, Aldrich) and Cs2CO3 (21.2 g, 65 mmol) in DMF (100 ml), heated at 750C overnight, poured into water and was extracted with EtOAc (3x). The combined organic was washed with 0.5 N NaOH, water, brine, dried over MgSO4, filtered and concentrated to give a thick yellow oil (6.82 g, 80% yield), which was used directly for the next step. Example 122b
Preparation of chiral (2'R, 3R,4'S)-2'-{2-[3-(tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000191_0001
MW 656.9991 C33H32CI3N3O5
In a manner similar to the method described in examples 48C, 48d, the title diastereomeric compound (RO5254307-000) was prepared in 2 steps starting from intermediate (R)-3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester MS (H+), 656. Further purification with Chiral SFC gave chiral (2'R, 3R,4'S)-2'-{2- [3-(tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (RO5254767-000)
HRMS(ES+) m/z Calcd for C33H32CI3N3O5+H [(M+H)+]: observed, 656.1481 ; calculated, 656.1481.
Example 123
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3- pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000191_0002
MW 556.8808 C28H24CI3N3O3
Racemic (2'R, 3R,4'S)-2'-{2-[3-(tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro-phenyl}-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (800 mg, 1.22 mmol) was dissolved in 30% TFA/CH2CI2 (15 ml_) and the solution was stirred at rt for 30 min. The solvent was removed and the residue was partioned between EtOAc and - -
10% Na2CO3. The organic layer was separated, washed with water, brine and dried with sodium sulfate and concentrated. A yellow solid was obtained which was directly used for next step. MS (H+), 556.
In a manner similar, the title compound was prepared from chiral (2'R, 3R,4'S)-2'-{2-[3- (tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione. MS (H+), 556.
Example 124
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-methanesulfonyl- pyrolidinyloxy)-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000192_0001
MW 634.97 C29H26CI3N3O5S
In a manner similar to the method described in example 13a, the title compound was prepared from chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3- pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (RO5256628-000) .HRMS(ES+) m/z Calcd for C29H26CI3N3O5S+H [(M+H)+]: observed, 634.0729; calculated, 634.0732.
Example 125
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-ethylcarbamoyl- pyrolidinyloxy)-phenyl}-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000192_0002
627.96 C3iH2gCI3N4O4 In a manner similar to the method described in example 29, the title compound was prepared from racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3- pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione. Subsequent chiral SFC separation gave the title compound. HRMS(ES+) m/z Calcd for C31H29CI3N4O4+H [(M+H)+]: observed, 627.1324; calculated, 627.1327.
Example 126
Preparation of chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-3-pyrolidinyloxy)-5-chloro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000193_0001
M.W. 570.91 , C29H26CI3N3O3
In a manner similar to the method described in example 6a, the title compound was prepared from chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3- pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione. HRMS(ES+) m/z C29H26CI3N3O3+H [(M+H)+]: observed, 570 calculated, 570.
Example 127a Preparation of intermediate 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert- butyl ester
Figure imgf000193_0002
M.W. 199.25, Ci0Hi7NO3
To a stirred solution of 3,6-dihydro-2H-pyhdine-1 -carboxylic acid tert-butyl ester (Aldrich, 15.99 g, 87.28 mmol) in methylene chloride (600 ml_) at O0C, mCPBA (Aldrich, 29.4 g, 77%, 131 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% Na2S2θ3 and the organic layer was separated and washed with 5% sodium carbonate, brine and water and dried over sodium sulfate and concentrated to give a light yellow oil, which was chromatographied (10% EtOAc/Hexane) to yield a colorless oil. 14.93 g. The compound was used directly for the next step.
Example 127b
Preparation of intermediate racemic 4-(2-formyl-4-iodo-phenoxy)-3-hydroxy-pipehdine-
1 -carboxylic acid tert-butyl ester
Figure imgf000194_0001
M.W. 447, Ci7H22INO5
To a stirred solution of 2-hydroxy-5-iodo-benzaldehyde (Aldrich, 4.96 g, 20 mmol) in DMF (80 ml_), potassium carbobate (10 g, 60 mmol) and 7-oxa-3-aza- bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (8 g, 40 mmol) were added and the mixture was stirred at 7O0C for three days and 800C for two days.
The mixture was poured into 1 N HCI and the mixture was extracted with EtOAc (3x50 ml_). The extracts were combined and dried over sodium sulfate and concentrated to give an oil, which was chromatographied on an ISCO machine (10-30% EtOAc/Hexanes) to yield an oil, 3.4 g. MS (H+), 348.
Example 127c
Preparation of intermediate 3-(tert-butyl-dimethyl-silanyloxy)-4-(2-formyl-4-iodo- phenoxy)-piperidine1 -carboxylic acid tert-butyl ester
Figure imgf000194_0002
M.W.561.54, C23H36INO5Si
To a stirred solution of 4-(2-formyl-4-iodo-phenoxy)-3-hydroxy-pipehdine-1 -carboxylic acid tert-butyl ester (1.12 g, 2.50 mmol) in DMF (7ml_), at 0 0C, 2,6-lutidine (Aldrich, 1.16 ml_, 10 mmol) was added followed by TBDSOTf (Aldrich, 10 mmol) and the mixture was stirred for 40 min.. The reaction mixture was poured into water and extracted with EtOAc (3x25 ml_). The extracts were combined and dried and concentrated to give a yellow oil. 1.6 g. Which was purified by chromatorgraphy. MS (H+), 562.
Example 127d
Preparation of intermediate 3-(tert-butyl-dimethyl-silanyloxy)-4-[4-iodo-2-(2-aza-3- trimethylsilanyloxy-buta-1 ,3-dienyl)-phenoxy]-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000195_0001
M.W.674.77, C28H47IN2O5Si2
To a stirred solution of bistrimetylsilanyl amine (Aldrich, 0.50 ml_, 2.4 mmol) at -2O0C, n- BuIi (Aldrich, 2.5 M in hexanes, 0.96 ml_, 2.4 mmol) was added slowly and the mixture was stirred for 5 min.. The THF (10 ml_) was added followed by the addition of 3-(tert- butyl-dimethyl-silanyloxy^^-formyl^-iodo-phenoxyj-piperidinei -carboxylic acid tert- butyl ester ( 2.4 mmol, made above) in 10 mL of THF. The mixture was gradually warmed to rt and stirred for 1 hr. The reaction was cooled to O 0C and TMSCI (Aldrich, 2.4 mmol), Et3N (Aldrich, 2.4 mmol) and acetyl chloride (Aldrich, 2.4 mmol) were added and the mixture was stirred for 2 hrs. The mixture was then filtered through a short pad of celite and the filtrate was concentrated under redeuced pressure to give a thick yellow paste, which was directly used for the next step.
Example 127e
Preparation of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[trans-4-(3- hydroxy-1 -methanesulfonyl-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'-dione
Figure imgf000196_0001
M.W.757, C30H28CI2IN3O6S
3-(Tert-butyl-dimethyl-silanyloxy)-4-[4-iodo-2-(2-aza-3-trinnethylsilanyloxy-buta-1 ,3- dienyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (2.4 mmol) and E/Z-6- chloro-3-[1 -(3-chloro-phenyl)-meth-ylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester in example 1 b (375 mg, 0.96 mmol) were combined into 10 ml_ of toluene and the mixture was stirred at 125 0C for 14 h. The solvent was removed under reduced pressure and the residue was chromatographed on an ISCO machne ( EtOAc/Hexanes, 0% to 40%) to yield a yellow foam. 324 mg.
The solid (250 mg, 0.28 mmol) was dissolved in 5 ml_ of THF. To the stirred solution, tetrabutylammonium fluoride (Aldrich, 1 M in THF, 0.6 ml_) was added and the mixture was stirred at rt overnight. The solvent was removed and the residue was dissolved in 4 ml_ of methylene chloride and thfluoro acetic acid (1 :1 ). The mixture was stirred at rt for 30 min. and the solvent was removed to yield a foam, which was directly used for the next step.
The solid was dissolved in THF (3 ml_). To the stirred solution, saturated sodium bicarbonate (1.5 ml_) was added followed by methane sulfonyl chloride ( Aldrich, 2 eq, 0.56 mmol). The reaction mixture was stirred at rt for 1 h and extracted with EtOAc (3x5 ml_). The erxtracts were combined and dried. The residue was purified on a reversed phase HPLC (30-70 acetonitrile/Water) to give an white powder. 9 mg . MS (H+), 756.
Example 128a Preparation of intermediate 5-fluoro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde
Figure imgf000196_0002
MW 224.23, Ci2Hi3FO3 - -
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-pyran-4-yl ester (Example 32a) and potassium carbonate in dimethylformamide to give a solid. MS (H+), 225.
Example 128b
Preparation of intermediatel -[5-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000197_0001
MW 337.47, Ci7H24FNO3Si
In a manner similar to the method described in Example 112b, 5-fluoro-2-(tetrahydro- pyran-4-yloxy)-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro-thethyl-silane to give the desired compound, which was directly used for the next step.
Example 128c
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000197_0002
MW 555, C29H25CI2FN2O4
In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[5-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene gave the desired product. MS(M+H+), 555. Example 129a
Preparation of intermediate 6-chloro-3-[1 -(3-fluoro-phenyl)-methylidene]-1 ,3-dihydro- indol-2-one
Figure imgf000198_0001
M.W 237.7, Ci5H9CIFNO
6-Chloro-1 ,3-dihydro-indol-2-one (Aldrich, 7.5 g, 44.92 mmol) was treated with 3-fluoro- benzaldehyde (Aldrich, 5.57 g, 44.92 mmol) in methanol ( 50 ml_) and piperdine (0.2 ml_). The mixture was heated at 750C overnight and then cooled to room temperature. The solid was filtered and dried to give a yellow solid. 8.8 g.
Example 129b
Preparation of intermediate 6-chloro-3-[1 -(3-fluoro-phenyl)-methylidene]-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000198_0002
M.W 373.8, C20H17CIFNO3
6-chloro-3-[1 -(3-fluoro-phenyl)-methylidene]-1 ,3-dihydro-indol-2-one (3.8 g, 13.1 mmol) was treated with (t-BuOCO)2O (Aldrich, 3.05 g, 14 mmol) in methylen chloride ( 50 ml_) and a catalytic amount of DMAP (Aldrich, 25 mg). The mixture was stirred at rt for 5 h and washed quickly with 0.05 N HCI and dried over sodium sulfate. Removed of solvent gave a yellow solid. 4.1 g. - -
Example 129c
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-[5-fluoro-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000199_0001
MW 538.98, C29H25CIF2N2O4
In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3-fluoro- phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-fluoro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 128b gave the desired product. MS(IvRH+), 539.
Chiral SFC separation (30% MeOH, 100 Par, 3O0C) gave the desired enantiomer. MS(M+H+), 539.
Example 130a
Preparation of intermediate methanesulfonic acid tetrahydro-thiopyran-4-yl ester
Figure imgf000199_0002
MW 196.29, C6H12O3S2
To a stirred solution of 4-hydroxy-tetrahedro-thiopyran (Aldrich, 2.0 g, 17 mmol) in methylene chloride at O0C, Methane sulfonyl chloride (18 mmol) and thethyl amine (18 mmol) were added slowly and the mixture was stirred 1 h. The reaction was quenched with water and the mixture was extracted with methylene chloride. The extracts were combined and dried with sodium sulfate. Removal of solvent gave an off white solid. 2.15 g. Example 130b
Preparation of intermediate 5-fluoro-2-(tetrahydro-thiopyran-4-yloxy) benzaldehyde
Figure imgf000200_0001
MW 240, Ci2Hi3FO2S
In a manner similar to the method described in Example 128a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 241.
Example 130c
Preparation of intermediatel -[5-fluoro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000200_0002
In a manner similar to the method described in Example 112b, 5-fluoro-2-(tetrahydro- thiopyran-4-yloxy)-benzaldehyde was treated with LHMDS, acetyl chloride, triethylamine and thmethyl silane to give the desired compound, which was directly used for the next step.
Example 13Od
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2- (tetrahydro-thiopyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione - -
Figure imgf000201_0001
MW, 571.5, C29H25CI2FN2O3S
In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[5-fluoro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 130c gave the desired product. MS(IvRH+), 571.
Example 131
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(1 ,1-dioxo- tetrahydro-thiopyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000201_0002
MW 603.5, C29H25CI2FN2O5S To a stirred solution of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2- (tetrahydro-thiopyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (300 mg) in methylene chloride (15 ml_), MCPBA (Aldrich, 77%, 180 mg, 0.79 mmol) was added and the mixture was stirred overnight. The reaction was quenched with saturated solution of sodium thiosulfate and the organic layer was separated and washed with sodium bicarbonate solution and dried (MgSO4). Removal of solvent gave the crude, which was chromatographied on a ISCO machine (EtOAc/CH2CI2) to the desired product as a white solid. 72 mg. MS(M+H+), 603.
The racemate was further separated on SFC at condition of 30% MeOH, I OOPar and 30 0C to give the enantiomer. 26 mg. MS(M+H+), 603.
Example 132a
Preparation of intermediate methanesulfonic acid cyclohexyl ester
Figure imgf000202_0001
MW 178, C7Hi4O3S
To a stirred solution of cyclohexanol (Aldrich, 10.2 g, 100 mmol) in methylene chloride (250 ml_) at 0 0C, Methane sulfonyl chloride (8.52 ml_, 110 mmol) and triethyl amine (17.5 ml_, 125 mmol) were added slowly and the mixture was stirred for 2 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCI and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a yellow oil. 18.05 g.
Example 132b Preparation of intermediate 5-fluoro-2-cyclohexyl-benzaldehyde
Figure imgf000202_0002
MW, 222.26, Ci3Hi5FO2
In a manner similar to the method described in Example 4a, 5-fuloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclohexyl ester and potassium carbonate in dimethylformamide to give a solid. MS (H+), 223.
Example 132c
Preparation of intermediatel -[5-fluoro-2-(cyclohexyloxy)-phenyl]-3-trimethylsilanyloxy-
2-aza-1 ,3-butadiene - -
Figure imgf000203_0001
MW 335.5, Ci8H26FNO2Si
In a manner similar to the method described in Example 112b, 5-fluoro-2- (cyclohexyloxy)-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 132d
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2- (cyclohexyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000203_0002
MW 552.14, C30H27CI2FN2O3
In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[5-fluoro-2-(cyclohexyloxy)-phenyl]-3-thmethylsilyoxy-2- aza-1 ,3-butadiene prepared in Example 132c gave the desired product. MS(M+H+), 553.
The racemate was further separated on SFC at condition of 30% MeOH, I OOPar and 30 0C to give the enantiomer. MS(M+H+), 553. Example 133a
Preparation of intermediate methanesulfonic acid cyclopentyl ester
Figure imgf000204_0001
M.W, 164, C6Hi2O3S
To a stirred solution of cyclopentanol (Aldrich, 2.58 g, 30 mmol) in methylene chloride (150 ml_) at O0C, Methane sulfonyl chloride (2.55 ml_, 33 mmol) and thethyl amine (5.23 ml_, 37.5 mmol) were added slowly and the mixture was stirred for 1.5 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCI and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a colorless oil. 5.1 g.
Example 133b Preparation of intermediate 2-cyclopentyloxy-5-fluoro-benzaldehyde
Figure imgf000204_0002
MW, 220.26, Ci2Hi3FO2
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclopentyl ester prepared in Example 133a and potassium carbonate in dimethylformamide to give a pale yellow oil. MS (H+), 221.
Example 133c
Preparation of intermediatel -[5-fluoro-2-(cyclopentyloxy)-phenyl]-3-thmethylsilanyloxy-
2-aza-1 ,3-butadiene
Figure imgf000205_0001
MW, 321.5, Ci7H24FNO2Si
In a manner similar to the method described in Example 112b, 5-fluoro-2- (cyclopentyloxy)-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 133d
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2- (cyclopentyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000205_0002
MW, 539.44, C29H25CI2FN2O3 In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[5-fluoro-2-(cyclopentyloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 133c gave the desired product. MS(M+H+), 539. The racemate was separated by chiral SFC (30% MeOH, 100 Par, 30 0C) to give the desired enantiomer. Example 134a
Preparation of intermediate 5-chloro-2-cyclohexyloxy-benzaldehyde
Figure imgf000206_0001
MW, 238.72, Ci3Hi5CIO2
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclohexyl ester prepared in Example 132a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 239.
Example 134b
Preparation of intermediatel -[5-chloro-2-(cyclohexyloxy)-phenyl]-3-trimethylsilanyloxy-
2-aza-1 ,3-butadiene
Figure imgf000206_0002
MW 351.14, Ci8H26CINO2Si In a manner similar to the method described in Example 112b, 5-chloro-2- cyclohexyloxy-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 134c
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'- (3-chloro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione - -
Figure imgf000207_0001
MW, 569.91 , C30H27CI3N2O3
In a manner similar to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (3-chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester with i-β-chloro^^cyclohexyloxyJ-phenyll-S- thmethylsilanyloxy -2-aza-1 ,3- butadiene gave a white solid. MS(IvRH+), 569.
Example 135a
Preparation of intermediate 5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-benzaldehyde
Figure imgf000207_0002
MW, 256.75, Ci2Hi3CIO2S
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 257.
Example 135b Preparation of intermediate1-[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-3- trimethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000207_0003
- -
In a manner similar to the method described in Example 112b, 5-chloro-2-(tetrahydro- thiopyran-4-yloxy)-benzaldehyde was treated with LHMDS, acetyl chloride, triethylamine and thmethyl silane to give the desired compound, which was directly used for the next step.
Example 135c
Preparation of racemic (2'R, 3'R,4'S)-6-chloro2'-[5-chlororo-2-(tetrahydro-thiopyran-4- yloxy)-phenyl]-4'-(3-fluoro-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000208_0001
MW, 571.50, C29H25CI2FN2O3 S
In a similar manner to the preparation of Example 1 e, reaction of 6-chloro-3-[1 -(3-fluoro- phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadienegave the desired product. MS(M+H+), 571.
Example 136
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(1 ,1 -dioxo-tetrahydro- thiopyran-4-yloxy)-phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000208_0002
MW, 603.50, C29H25CI2FN2O3 S
In a similar manner to the preparation of Example 131 , reaction of (2'R, 3'R,4'S)-6- chloro-4'-(3-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl] - - spiro[3H-indole-3,3'-piperidine]-2,6'-dione with MCPBA gave the desired product. MS(M+ H+), 603.
Example 137a
Preparation of intermediatel -[5-fluoro-2-(4-fluoro-phenoxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000209_0001
MW, 347.44, Ci8Hi9F2NO2Si In a manner similar to the method described in Example 112b, 5-fluoro-2-(4-fluoro- phenyloxy)-benzaldehyde(VWR) was treated with LHMDS, acetyl chloride, triethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 137b
Preparation of racemic (2'R, 3'R,4'S)-6-chloro -4'-(3-fluoro -phenyl )-2'-[5-fluoro-2-(4- fuloro-phenoxy-phenyl)] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000209_0002
MW, 548.95, C30H20CIF3N2O3
In a manner similar to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-fluoro-2-(4-fluoro-phenoxy)-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene gave a white solid. MS(M+H+), 549. - -
Example 138a
Preparation of intermediatel -[5-fluoro-2-(2,4-difluoro-phenyloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000210_0001
MW, 365.43, Ci8Hi8F3NO2Si
In a manner similar to the method described in Example 112b, 5-fluoro-2-(2,4-fluoro- phenyloxy)-benzaldehyde (VWR) was treated with LHMDS, acetyl chloride, triethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 138b
Preparation of intermediateb 3-[1 -(3-chloro-phenyl)-methylidene]-6-fluoro-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000210_0002
M.W 373.81 , C20HI7CIFNO3
In a manner similar to the methods described in Examples 1 a and 1 b, 6-fluoro-1 ,3- dihydro-indol-2-one (Aldrich) reacted with 3-chloro-benzaldehyde to give 6-fluoro-3-[1- (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with (t-BuOCO)2O and DMAP and used directly for next step. - -
Example 138c
Preparation of racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[ 2-(2,4-difluoro- phenyloxy)-5-fluoro-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000211_0001
MW, 566.94, C30Hi9CIF4N2O3
In a similar manner to the preparation of Example 1 e, reaction of 6-fluoro-3-[1 -(3-chloro- phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester with 1- [2-(2,4-difluoro-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene gave the desired product. MS(IvRH+), 567.
Example 139a
Preparation of intermediate 5-chloro-2-[(2-chloro-6-fluoro-benzyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000211_0002
MW, 411 , Ci9H20CI2FNO2Si
In a manner similar to the method described in Example 112b, 5-chloro-2-(2-chloro-6- fluoro-benzyloxy)-benzaldehyde (Chembrdg-BB) was treated with LHMDS, acetyl chloride, thethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step. - - Example 139b
Preparation of intermediate 6-chloro-3-[1 -(2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000212_0001
M-W SgLSI 1 C2OHi6CIF2NO3
In a manner similar to the methods decribed in Examplea 1 a and 1 b, 6-chloro-1 ,3- dihydro-indol-2-one (Aldrich) reacted with 2,5-difluoro-benzaldehyde to give 6-chloro-3- [1 -(2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with (t-BuOCO)2O and DMAP.
Example 139c
Preparation of racemic (2'R, S'R^'RJ-e-chloro^'-β-chloro^-^-chloro-e-fluoro- benzyloxy)-phenyl]-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000212_0002
MW, 631.86, C3IH20CI3F3N2O3 In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester with 5-chloro-2-[(2-chloro-6-fluoro-benzyloxy)-phenyl]-3-thmethylsilanyloxy-2-aza- 1 ,3-butadiene gave the desired product. MS(M+H+), 631. Example 140a
Preparation of intermediate 2-(4-cyanophenyloxy)-5-fluoro-benzaldehyde
Figure imgf000213_0001
MW, 241 , Ci4Hi8FNO2
To stirred solution of 4-cyanophenol(Aldhch, 5.00 g, 42 mmol) in DMF (100 ml_), potassium carbonate (63 mmol) and 2-4, difluoro-benzaldehyde (Aldrich, 5.97 g, 42 mmol) were added and the mixture was stirred at 9O0C overnight. The mixture was cooled to room temperature and poured into water. The solid was filtered and dried to give a pale yellow solid. 5.2 g MS (H+), 242.
Example 140b
Preparation of intermediate 1-[2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-3- thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000213_0002
MW, 359, Ci9Hi9FN2O2Si
In a manner similar to the method described in Example 112b, 2-(4-cyano-phenyloxy)-5- fluoro-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro- trimethyl-silane to give the desired compound, which was directly used for the next step.
Example 140c
Preparation of racemic (2'R, 3'R,4'R)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro- phenyl]-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione - -
Figure imgf000214_0001
MW, 573.96, C31H19CIF3N3O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene gave the desired product. MS(M+H+), 573.
Example 141
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro- phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000214_0002
MW, 555.96, C31 H20CI F2N3O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 140b gave the desired product. MS(M+H+), 556.
Example 142
Preparation of racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[ 2-(4-cyano-phenyloxy)-5- fluoro-phenyl]-6-fluoro spiro[3H-indole-3,3'-piperidine]-2,6'-dione - -
Figure imgf000215_0001
MW, 555.96, C3i H20CI F2N3O3
In a similar manner to the method described in Example 1 e, reaction of 6-fluoro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 138b with 1 -[2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 140b gave the desired product. MS(IvRH+), 556.
Example 143a
Preparation of intermediate 2-(4-methoxy-phenyloxy)-5-fluoro-benzaldehyde
Figure imgf000215_0002
MW, 246J Ci4HiiFO3
In a similar manner to the method described in Example 140a, 2,4-difluoro- benzaldehyde (Aldrich) was reacted with 4-methoxy-phenol and potassium carbonate to give a solid. MS (H+), 247.
Example 143b
Preparation of intermediatel -[5-fluoro-2-(4-methoxy-phenyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene - -
Figure imgf000216_0001
MW, 359, Ci9H22FNO3Si
In a manner similar to the method described in Example 112b, 2-(4-methoxy- phenyloxy)-5-fluoro-benzaldehyde was treated with LHMDS, acetyl chloride, triethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step.
Example 143c
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)- phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000216_0002
MW, 560.98, C3IH23CIF2N2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[2-(4-methoxy-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene gave the desired product. MS(M+H+), 561.
Example 144
Preparation of racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[5-fluoro-2-(4- methoxy-phenyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione - -
Figure imgf000217_0001
MW, 560.98, C3IH23CIF2N2O4
In a similar manner to the method described in Example 1 e, reaction of 6-fluoro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 138b with 1 -[2-(4-methoxy-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 143b gave the desired product. MS(IvRH+), 561.
Example 145
Preparation of racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)- phenyl]-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000217_0002
MW, 578.97, C3IH22CIF3N2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 5-fluoro-1 -[2-(4-methoxy-phenyloxy)-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 143b gave the desired product. MS(M+H+), 579.
Example 146
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2-(4- methoxy-phenyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione - -
Figure imgf000218_0001
MW, 577.43, C3IH23CI2FN2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[2-(4-methoxy-phenyloxy)-5-fluoro-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 143b gave the desired product. SFC separation (30% MeOH, 100 par, 3O0C) gave the desired enantiomer. . MS(M+H+), 577.
Example 147a
Preparation of intermediate 6-chloro-3-(5-chloro-2-fluoro-benzylidene)-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000218_0002
M.W 408.26, C20Hi6CI2FNO3 In a manner similar to the methods dechbed in Examples 1 a and 1 b, 6-chloro-1 ,3- dihydro-indol-2-one (Aldrich) reacted with 5-chloro-2-fluoro-benzaldehyde to give 6- chloro-3-[1 -(5-chloro-2-fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently protected with (t-BuOCO)2O and DMAP. - -
Example 147b
Preparation of chiral (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-[5-fluoro-2- (4-methoxy-phenyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione
MW, 595.43, C3IH22CI2F2N2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-5-chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester with 1 -[2-(4-methoxy-phenyloxy)-5-fluoro-phenyl]-3-thmethylsilanyloxy-2-aza- 1 ,3-butadiene prepared in Example 143b gave the desired product SFC separation (30% MeOH, 100 par, 3O0C) gave the desired enantiomer. . MS(M+H+), 595.
Example 148a
Preparation of intermediate 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol
Figure imgf000219_0002
MW, 268.43, Ci4H24O3Si
To a stirred solution of hydroquinone (Aldrich, 11.01 g, 100 mmol) in DMF (300 ml_), (2- bromo-ethoxy)-tert-butyl-dimethyl-silane (Aldrich, 12.0 g, 50 mmol), cesium carbonate (40.7 g, 125 mol) were added and the mixture was stirred at 6O0C overnight. The mixture was poured into water (300 ml_) and 6N HCI was added to adjust the "pH" to 6. The mixture was extracted with EtOAc ( 3x 60 ml_) and the extracts were combined and dried. Removal of solvent gave the crude, which was chromatographied on a ISCO machine eluting with EtOAc/hexane (0-30%) to give a light brown solid. 5.71 g. - -
Example 148b
Preparation of intermediate 5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)ethoxy]- phenoxyj-benzaldehyde
Figure imgf000220_0001
MW1 SgCSS1 C2IH27FO4Si
In a similar manner to the method described in Example 140a, 2,4-difluoro- benzaldehyde (Aldrich) reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol and potassium carbonate to give a light brown oil which solidifies on standing. MS (H+), 391.
Example 148c
Preparation of intermediatel -[5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)ethoxy]- phenoxy}-phenyl]-3-thmethylsilanyloxy-2-aza-1 ,3-butadiene
Figure imgf000220_0002
MW, 503.77, C26H38FNO4Si2
In a manner similar to the method described in example 112b, 5-fluoro-2-{4-[2-(tert- butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-benzaldehyde was treated with LHMDS, acetyl chloride, thethylamine and chloro-thmethyl-silane to give the desired compound, which was directly used for the next step. - -
Example 148d
Preparation of racemic (2'R, 3'R,4'R)-6-chloro-2'-{ 5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl}-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000221_0001
MW, 609, C32H24CIF3N2O5
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[ 5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-phenoxy}phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene followed by deprotection reaction with tetrabutylammonium fluoride gave the desired product as white solid. MS(IvRH+), 609.
Example 149
Preparation of racemic (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-{ 5-fluoro- 2-[4-(2-hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000221_0002
MW, 625.45, C32H24CI2F2N2O5
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(2- fluoro-5-chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester prepared in Example 147a with 1 -[5-fluoro-2-{4-[2-(tert-butyl-dimethyl- - - silanyloxy)-ethoxy]-phenoxy}phenyl]-3-trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 148c followed by deprotection reaction with tetrabutylammonium fluoride gave the desired product as white solid. MS(IvRH+), 625.
Example 150
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-{5-fluoro-2-[4-(2- hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000222_0001
MW, 591.01 , C32H25CIF2N2O5
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-phenoxy}phenyl]-3-thmethylsilyoxy-2-aza-1 ,3-butadiene prepared in Example 148c followed by deprotection reaction with tetrabutylammonium fluoride gave the desired product as white solid. MS(M+H+), 591.
Example 151
Preparation of racemic (2'R, 3'R,4'S)-4'-(3-chloro -phenyl )-6-fluoro-2'-{5-fluoro-2-[4-(2- hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione - -
Figure imgf000223_0001
MW 591.01 , C32H25CIF2N2O5
In a similar manner to the method described in Example 1 e, reaction of 6-fluoro -3-[1 -(3- chloro -phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 138b with 1 -[ 5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-phenoxy}phenyl]-3- thmethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 148c followed by deprotwction reaction with tetrabutylammonium fluoride gave the desired product as white solid. MS(M+ H+), 591.
Example 152
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-{5-fluoro-2-[4-(2- hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000223_0002
MW, 607.46, C3IH23CI2FN2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[5-fluoro-2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]- phenoxy}phenyl]-3-thmethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 148c , followed by deprotection reaction with tetrabutylammonium fluoride gave the desired product as white solid. MS(M+H+), 607. Example 153a
Preparation of intermediate 6-chloro-3-[1 -(2-chloro-5-thfluoromethyl-phenyl)- methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000224_0001
M.W. 458.27, C2IHi6CI2F3NO3
In a manner similar to the methods described in Examples 1 a and 1 b, 6-chloro-1 ,3- dihydro-indol-2-one (Aldrich) reacted with 2-chloro-5-thfluoromethyl- benzaldehyde(Aldhch) to give 6-chloro-3-[1 -(2-chloro-5-trifluoromethyl-phenyl)- methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with di-te/t- butyl-dicarbonate and DMAP and directly used for the next step.
Example 153b
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)- phenyl]-4'-(5-chloro-2-thfluoromethyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000224_0002
MW, 639.89, C30H24CI3FN2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-2-thfluoromethyl -phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester with 1-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 99b gave the desired product. MS(IVkH+), 639.
Example 154a
Preparation of intermediatel -[5-iodo-2-(cyclohexyloxy)-phenyl]-3-trimethylsilanyloxy-2- aza-1 ,3-butadiene
Figure imgf000225_0001
MW, 443.4, Ci8H26INO2Si
In a manner similar to the methods described in Example 128a and112b, 5-iodo-2- hydroxy-benzaldehyde was reacted with methanesulfonic acid cyclohexyl ester and potassium carbonate to give 5-lodo-2-(cyclohexyloxy)-benzaldehyde, which was subsequentyly reacted with LHMDS, acetyl chloride, thethylamine and chloro-tri methyl - silane to give the title compound and directly used for the next step.
Example 154b Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(5-chloro-2-thfluoromethyl-phenyl)-2'- [5-iodo-2-(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000225_0002
MW, 731.34, C30H24CI2F3IN2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-2-thfluoromethyl -phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 153a with 1 -[5-iodo-2-(tetrahydro-pyran-4- yloxy)-phenyl]-3-thmethylsilanyloxy-2-aza-1 ,3-butadiene gave the desired product. MS(M+H+), 731. - -
Example 155
Preparation of (2'R, 3'R,4'S)-6-chloro-4'-(5-chloro-2-trifluoromethyl-phenyl)-2'-[2- (cyclohexyloxy)-5-fluoro-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000226_0001
MW, 621.46, C3IH26CI2F4N2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-2-thfluoromethyl -phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 153a with 1 -[2-(cyclohexyloxy)-5-fluoro- phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 132c gave the desired product. MS(IvRH+), 621.
Example 156
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)- phenyl] -4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000226_0002
MW, 555.44, C29H25CI2FN2O4
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in example 99b gave the desired product. MS(M+H+), 555.
Chiral SFC separation (30% MeOH, 100 Par, 3O0C) gave the desired enantiomer. MS(M+H+), 555. - -
Example 157
Preparation of chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4'-(3- fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000227_0001
MW, 522.98, C29H25CIF2N2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fuloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-fluoro-2-(cyclopentyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 133c gave the desired product. MS(IvRH+), 523.
The racemate was further separated on SFC at a condition of 30% MeOH, 100 Par and 30 0C to give the enantiomer. MS(M+H+), 523.
Example 158
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-iodo)-phenyl]-4'- (3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000227_0002
MW, 644.91 , C30H27CIFIN2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[2-(cyclohexyloxy-5-iodo)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 154a gave the desired product. - -
MS(M+H+), 645.
Example 159
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-fluoro)-phenyl]-4'- (3-fluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione
Figure imgf000228_0001
MW, 537.00, C30H27CIF2N2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[2-(cyclohexyloxy-5-fluoro)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 132c gave the desired product. MS(M+H+), 537.
Example 160
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-ethynyl)-phenyl]- 4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000228_0002
MW, 543.03, C32H28CIFN2O3
To a stirred solution of racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-iodo)- phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione (100 mg, 0.16 mmol) prepared in Example 158 in DMF (3 ml_), thmethylsilyl acetylene (Aldrich, 220 uL, 1.55 mmol), PdCI2(PPh3)2 (Aldrich, 5 mg, 0.07 mmol), CuI (Aldrich, 1 mg) and Et3N (1 ml_) were added and the mixture was stirred under nitrogen at 65 0C for 3 h. The - - mixture was poured into water and the new mixture was extracted with EtOAc ( 3x10 ml_), dried with sodium sulfate. The solvent was removed and the residue was purified on a ISCO machine ( 2% EtOAc/methylene chloride) to give an off-white solid. The off- white solid was stirred in a mixture of aqueous NaOH (2N, 3 ml_) and methanol (3 ml_) at rt for 2 h. The mixture was acidified to "pH" 5 and the solid was filtered and dried. 50.8 mg. MS(IvRH+), 543.
Example 161
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2- (cyclohexyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000229_0001
MvV1 GeLSe1 C3OH27CI2IN2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Example 1 b with 1 -[2-(cyclohexyloxy-5-iodo)-phenyl]-3-thmethylsilanyloxy- 2-aza-1 ,3-butadiene prepared in Example 132c gave the desired product. MS(M+H+), 661.
Example 162
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2- (cyclohexyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000229_0002
MW, 543.03, C32H28CI2N2O3 - -
In manner similar to the method described in Example 160, reaction of racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2-(cyclohexyloxy-5-iodo)-phenyl] spiro[3H- indole-3,3'-piperidine]-2,6'-dione with trimethylsilyl acetylene, PdCl2(PPh3)2 , CuI and Et3N, followed by reaction with NaOH in methanol gave a white solid. MS(IvRH+), 543.
Example 163
Preparation of racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-thiopyran-4- yloxy)-phenyl]-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000230_0001
MW, 589.49, C29H24CI2F2N2O3 S
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)- phenyl]-3- thmethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 135b gave the desired product. MS(M+H+), 589.
Example 164 Preparation of chiral (2'R, 3'R,4'R)-6-chloro-2'-[2-cyclohexyloxy-5-fluoro-phenyl] -4'- (2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000230_0002
MW, 554.99, C29H24CIF3N2O3 S - -
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[5-fluoro-2-(cyclohexyloxy)-phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 132c gave the desired product. Chiral SFC separation (30% MeOH, 100 Par, 3O0C) gave the desired enantiomer. MS(IvRH+), 555.
Example 165 Preparation of racemic (2'R, 3'R,4'S)-2'-[5-chloro-2-(cyclohexyloxy)-phenyl]-4'-(3-chloro- phenyl)-6-fluoro spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000231_0001
MW, 553.46, C30H27CI2N2O3
In manner similar to the method described in Example 1 e, reaction of 6-fluoro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Examplei 38b with i -β-chloro^cyclohexyloxyJ-phenylJ-S- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 134b gave a white solid. MS(M+H+), 553.
Example 166
Preparation of racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[5-chloro-2-(tetrahedro- thiopyran-4-yloxy-phenyl)]-6-fluoro spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000231_0002
MW, 571 .50, C29H25FCI2N2O3S - -
In manner similar to the method described in Example 1 e, reaction of 6-fluoro-3-[1 -(3- chloro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester prepared in Examplei 38b with 1 -[5-chloro-2-(tetrahedro-thiopyran-4-yloxy - phenyl]-3- trimethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 135b gave a white solid. MS(IvRH+), 571.
Example 167
Preparation of racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'- (3-fluoro -phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
MW, 553.46, C30H27CI2N2O3
In manner similar to the method described in Example 1 e, reaction of 6-chloro-3-[1 -(3- fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 129b with 1 -[5-chloro-2-(cyclohexyloxy)-phenyl]-3- thmethylsilanyloxy-2-aza-1 ,3-butadiene prepared in Example 134b gave a white solid. MS(M+H+), 553.
Example 168
Preparation of chiral (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)- phenyl]-4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000232_0002
MW, 573.42, C29H24CI2F2N2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[5-chloro-2-( tetrahedro-pyran-4-yloxy)-phenyl]- 3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 99b gave the desired product. Chiral SFC separation (30% MeOH, 100 Par, 3O0C) gave the desired enantiomer. MS(IvRH+), 573
Example 169
Preparation of chiral (2'R, 3'R,4'R)-6-chloro-4'-(2,5-difluoro-phenyl)-2'-[5-fluoro-2- (tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione
Figure imgf000233_0001
MW, 573.42, C29H24CIF3N2O3
In a similar manner to the method described in Example 1 e, reaction of 6-chloro-3-[1 - (2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 139b with 1 -[5-fluoro-2-( tetrahydro-pyran-4-yloxy)-phenyl]-3- trimethylsilanyloxy -2-aza-1 ,3-butadiene prepared in Example 128b gave the desired product. Chiral SFC separation (30% MeOH, 100 Par, 3O0C) gave the desired enantiomer. MS(M+H+), 557.
Example 170
In Vitro Activity Assay The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2- interacting region of p53 (Lane et al.). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin- conjugated Allophycocyanin (APC).
Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1 :5 dilution in reaction buffer) to each well, mix by shaking. Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37°C for 1 h. Add 20 uL streptavidin-APC and Eu-anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM streptavidin-APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF-capable plate reader at 665 and 615 nm (Victor 5, Perkin ElmerWallac). If not specified, the reagents were purchased from Sigma Chemical Co.
IC5O 1S showing the biological activity of this invention exhibit activities less than about 1 OnM.
Representative values are, for example:
Example 1C™ (uM. 0.2%BSA)
2 0.205
5c 0.034
22b 0.042
56 0.131
87 0.048

Claims

- - Claims
1. A compound of the formula
wherein
X is -Cl, -F or -Br;
R is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:
Figure imgf000235_0002
W is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, cyclopropyl, cyano, methoxy, hydroxy methyl, -COOMe, ethynyl, -CF3, vinyl, isopropenyl, 1 -propynyl, 3-methyl-1 -butynyl, 3,3-dimethyl-1-butynyl, 3-thfluoroethynyl, phenyl, 2- furany, 2-thiophenyl and 4-thiazolyl;
Y is hydrogen, -F, -Cl or methyl;
V is hydrogen, -F, -Cl or methyl;
A is selected from the group consisting of a bond, O, NH, CH2, C(=O), C(=O)NH, NHC(=O), NHC(=O)NH, S, S(=O)2 and O(CH2)n; n = 1 , 2 or 3;
R' is selected from the group consisting of heterocycle, substituted heterocyle, heteroaryl, substitluted heteroaryl, aryl, substituted aryl, substituted cycloalkyl, and -CRiR2C(=O)NR3R4 wherein
Ri, R2 are hydrogen or lower alkyl, or may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; and
R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, lower alkenyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl with the proviso that R3, R4 are not both hydrogen, or R3/R4 may independently link to form a cyclic structure selected from a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocycle; and
the pharmaceutically acceptable salts and esters thereof.
2. The compound of claim 1 wherein W , X, Y, A, R and R' are as described in claim 1 and V is hydrogen or F.
3. The compound of claim 1 wherein W, X, A, R and R' are as described in claim 1 , V is hydrogen or F and Y is hydrogen or F.
4. The compound of claim 1 wherein X, A, R and R' are as described in claim 1 , W is F, Cl, Br, I or ethynyl, Y is hydrogen or F and V is hydrogen or F.
5. The compound of claim 1 wherein X, R and R' are as described in claim 1 , W is F, Cl, Br, I or ethynyl, Y is hydrogen or F, V is hydrogen or F and A is O or NH with the proviso that Y and V are not both F.
6. The compound of claim 1 , wherein R is 3-chlorophenyl;
A is -O- or -NH-;
R' is piperidinyl, tetrahydro-pyranyl, cyclohexyl, pyrrolidinyl, phenyl, pyrazinyl and pyrazolyl, all of which may be unsubstituted or substituted by 1 -5 substituents; and all remaining substituents have the meanings given in claim 1.
7. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, - - racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinylmethoxy)-5-ethynyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylnnethoxy)-5-ethynyl-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -methyl-4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-methyl-4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -methyl-4- piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylamino)-5-iodo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinylamino)-5-ethynyl-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
8. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-propionyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(3- methanesulfonyl-propyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-methanesulfonyl- 4-pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 -methanesulfonyl-4- pipehdinyloxy)phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl-4- piperidinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-(tert-butoxycarbonyl)-4-piperidinyloxy)- phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-(tert-butoxycarbonyl)-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-piperidinyloxy)-3-bromo-2-fluoro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethyl-4-piperidinyloxy)-5- ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and chiral (2'R, 3R, 4'S)-2'-[3-bromo-2-fluoro-6-(1 -methyl-4-piperidinyloxy)-phenyl]-6-chloro- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
9. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-dimethylcarbamoyl-4-pipehdinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[3-bromo-6-(1 -dimethylcarbamoyl-4-pipehdinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -diethylcarbamoyl-4- pipehdinyloxy)-5-ethynyl-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-iodo-2-[1 -(pyrrolidine-1 - carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(pyrrolidine-1 - carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1-isopropyl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(2-oxo- imidazolidine-1 -carbonyl)-4-piperidinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione> racemic (2'R, 3R, 4'S)-2'-[6-(1 -(tert-butoxycarbonyl)-4-piperidinyloxy)-3-chloro-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[6-(1 -acetyl-4-piperidinyloxy)-3-chloro-2-fluoro-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -dimethylcarbamoyl-4-piperidinyloxy)-2- fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[3-chloro-6-(1 -methylcarbamoyl-4-piperidinyloxy)-2- fluoro-phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[3-bromo-6-(1-methylcarbamoyl-4-piperidinyloxy)-2-fluoro- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -dimethylcarbamoyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
10. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[1 -(4- methylpiperazine-1 -carbonyl)-4-pipehdinyloxy]-phenyl} spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-lodo-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[1-(1 -pyrrolidine-carbonyl)-4-pipehdinyloxy]- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-{5-bromo-2-[1 -(1 -pyrrolidine-carbonyl)-4-pipehdinyloxy]-phenyl}- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-dimethylcarbamoyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -ethoxycarbonyl-4- piperidinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-ethoxycarbonyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isobutyryl-4-piperidinyloxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-isopropoxycarbonyl-4-piperidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
11. A compound of calim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isobutyryl-4- pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 -isopropoxycarbonyl- 4-pipehdinyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[1 -(2-hydroxy-ethyl)-4- pipehdinyloxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 - methoxycarbonylmethyl-4-piperidinyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonylmethyl-4-pipehdinyloxy)-5-iodo- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(1 -hydroxycarbonylmethyl-4- pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -carbamoylmethyl-4-pipehdinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -carbamoylmethyl-4-pipehdinyloxy)-5-iodo-phenyl]-6-chloro-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-methoxy-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
12. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,5-dimethyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-methoxy-4-methoxycarbonyl-phenoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-Bromo-2-[4-(2-hydroxy-1 ,1 -dimethyl-ethylcarbamoyl)- phenoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]- phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-carbamoyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2-chloro-4-methoxycarbonyl-phenoxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methoxycarbonyl-phenoxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)- phenoxy]-5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{2-[4-(2-hydroxy-ethoxy)-phenoxy]- 5-iodo-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy- ethoxy)-phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-{5-ethynyl-2-[4-(2-hydroxy-ethoxy)- phenoxy]-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione and chiral (2'R, 3R, 4'S)-6-chloro-2'-{5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-phenyl}-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
13. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(2,6-dimethyl-4-pyhdinyloxy)-phenyl]-6-chloro-4'-
(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-(5-chloro-2-imidazol-1-yl-phenyl)-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-cyano-phenoxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxy-phenoxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy- phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxy-phenoxy)- phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(4-methoxycarbonyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(4-methoxycarbonyl- phenoxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(4-hydroxycarbonyl-phenoxy)-
5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione and chiral (2'R, 3R, 4'S)-2'-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione.
14. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyhdinyloxy)-5- iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2,6-dimethyl-4-pyridinyloxy)-5- ethynyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-fluoro-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(4-trifluoromethyl-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(4- trifluoromethyl-phenoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-cyano-phenoxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-phenyl}-6-chloro-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-cyano-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfanyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfonyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-methylsulfinyl-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-nitro-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione.
15. A compound of claim 1 selected from the group consisting of chiral (2'R, 3R, 4'S)-2'-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(4-acetylamino-phenoxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-iodo-2-(1 ,3,5-trimethyl-i H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-i H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-ethynyl-2-(1 ,3,5-trimethyl-1 H- pyrazol-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1 ,3,5-trimethyl-i H-pyrazol-4-yloxy)-phenyl]-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)- phenyl]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(4-oxo-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3R, 4'S)-6-chloro-2'-[2-chloro-6-(4-methoxy-phenoxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy-cyclohexyloxy)-phenyl]- 4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(trans-4-hydroxy-cyclohexyloxy)-phenyl]-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
16. A compound of claim 1 selected from the group consisting of racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-fluoro-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-4-methyl-2-(tetrahydro-pyran-4-yloxy)- phenyl]]-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]]-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro- pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'R)-6-chloro-4'-(3-chloro-4-fluoro-phenyl)-2'-[5-chloro-2-(tetrahydro- pyran-4-yloxy)-phenyl]] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo-2-[2-(4-acetyl-piperazin-1 -yl)-1 ,1 -dimethyl -2-oxo- ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2-[ 2-(4,4-difluoro-piperidin-1 -yl)-1 ,1- dimethyl-2-oxo-ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-{5-bromo- 2- [1 -methyl-1-(2,2,2-trifluoro-ethylcarbamoyl)- ethoxy]-phenyl}-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2- (1 -dimethylcarbamoyl-1-methyl-ethoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2-dimethylcarbamoyl-2-methyl-propoxy)-phenyl]- 6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2- (2,2-dimethyl-3-oxo-3-pyrrolidin-1-yl-propoxy)- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione.
17. A compound of claim 1 selected from the group consisting of chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-bromo- 2-(3-methyl-oxetan-3- ylmethoxy) phenyl] spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo- 2-(4-fluoro-benzyloxy)-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(3-ethyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-4'- (3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[2-(1 -tert-butoxycarbonyl-pipehdin-4-yloxy)]-5-thfluoromethyl- phenyl]-6-chloro-4'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3R, 4'S)-2'-[5-bromo-2-(1-methyl-pipehdin-4-ylamino)-phenyl]-6-chloro-4'- (5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-(2- thiophenyl)-phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-(2-furanyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-(2-hydroxy-ethoxy)-5-phenyl- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-2-(2-pyrazinyloxy)- phenyl]-spiro-[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-(2-furanyl)-2-hydroxy-phenyl]- spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiofuranyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-phenyl]-phenyl- spiro[3H-indole-3,3'-piperidine]-2,6'-dione and racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiazolyl)- phenyl]-spiro[3H-indole-3,3'-piperidine]-2,6'-dione.
18. A compound of claim 1 selected from the group consisting of racemic (2'R, 3'R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[2-hydroxy-5-(2-thiazolyl)- phenyl]-spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3R,4'S)-2'-{2-[3-(tert-butoxycarbonyl)-pyrolidinyloxy]-5-chloro-phenyl}-6- chloro-4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-chloro-(3-pyrolidinyloxy)-phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-methanesulfonyl-pyrolidinyloxy)-phenyl]-
4'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3R, 4'S)-6-chloro-2'-[5-chloro-2-(3-ethylcarbamoyl-pyrolidinyloxy)-phenyl}-4'-
(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3R, 4'S)-2'-[2-(1 -acetyl-3-pyrolidinyloxy)-5-chloro-phenyl]-6-chloro-4'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3R, 4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[trans-4-(3-hydroxy-1 - methanesulfonyl-pipehdinyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'- dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, - - chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(tetrahydro-thiopyran- 4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(1 ,1-dioxo-tetrahydro- thiopyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(cyclohexyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chlorophenyl)-2'-[5-fluoro-2-(cyclopentyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione and racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'-(3-chloro- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione.
19. A compound of claim 1 selected from the group consisting of racemic (2'R, 3'R,4'S)-6-chloro2'-[5-chlororo-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-4'-
(3-fluoro-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(1 ,1 -dioxo-tetrahydro-thiopyran-4-yloxy)- phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro -4'-(3-fluoro -phenyl)-2'-[5-fluoro-2-(4-fuloro-phenoxy- phenyl)] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[ 2-(2,4-difluoro-phenyloxy)-5- fluoro-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(2-chloro-6-fluoro-benzyloxy)-phenyl]-4'-
(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[ 2-(4-cyano-phenyloxy)-5-fluoro-phenyl]- 6-fluoro spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)-phenyl]-4'-(3- fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-6-fluoro-2'-[5-fluoro-2-(4-methoxy- phenyloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-fluoro-2-(4-methoxy-phenyloxy)-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[5-fluoro-2-(4-methoxy-phenyloxy)- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-[5-fluoro-2-(4-methoxy- phenyloxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione and racemic (2'R, 3'R,4'R)-6-chloro-2'-{ 5-fluoro-2-[4-(2-hydroxy-ethoxy)-phenoxy] phenyl}- 4'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'-dione.
20. A compound of claim 1 selected from the group consisting of racemic (2'R, 3'R,4'R)-6-chloro-4'-(5-chloro-2-fluoro-phenyl)-2'-{ 5-fluoro-2-[4-(2- hydroxy-ethoxy)-phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-fluoro-phenyl)-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro -phenyl )-6-fluoro-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-{5-fluoro-2-[4-(2-hydroxy-ethoxy)- phenoxy] phenyl} spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-4'-(5- chloro-2-thfluoromethyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, S'R^'SJ-e-chloro^'-^-chloro^-trifluoromethyl-phenyl^'-β-iodo^-
(tetrahydro-pyran-4-yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione,
(2'R, 3'R,4'S)-6-chloro-4'-(5-chloro-2-thfluoromethyl-phenyl)-2'-[2-(cyclohexyloxy)-5- fluoro-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl] -4'-(3- fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'S)-6-chloro-2'-[5-fluoro-2-(cyclopentyloxy)-phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-iodo)-phenyl]-4'-(3-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-fluoro)-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[2-(cyclohexyloxy-5-ethynyl)-phenyl]-4'-(3-fluoro- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2-(cyclohexyloxy)-5-iodo-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione and racemic (2'R, 3'R,4'S)-6-chloro-4'-(3-chloro-phenyl)-2'-[2-(cyclohexyloxy)-5-ethynyl- phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'-dione.
21. A compound of claim 1 selected from the group consisting of racemic (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-thiopyran-4-yloxy)-phenyl]-4'-
(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-2'-[2-cyclohexyloxy-5-fluoro-phenyl] -4'-(2,5-difluoro- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-2'-[5-chloro-2-(cyclohexyloxy)-phenyl]-4'-(3-chloro-phenyl)-6- fluoro spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-4'-(3-chloro-phenyl)-2'-[5-chloro-2-(tetrahedro-thiopyran-4-yloxy- phenyl)]-6-fluoro spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, racemic (2'R, 3'R,4'S)-6-chloro-2'-[5-chloro-2-(cyclohexyloxy-phenyl)]-4'-(3-fluoro - phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione, chiral (2'R, 3'R,4'R)-6-chloro-2'-[5-chloro-2-(tetrahydro-pyran-4-yloxy)-phenyl]-4'-(2,5- difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'-dione and chiral (2'R, 3'R,4'R)-6-chloro-4'-(2,5-difluoro-phenyl)-2'-[5-fluoro-2-(tetrahydro-pyran-4- yloxy)-phenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'-dione.
22. A pharmaceutical composition comprising a compound according any one of claims 1 to 21 , together with a pharmaceutically acceptable carrier or excipient.
23. A compound according to any one of claims 1 to 21 for use as a medicament.
24. A compound according to any one of claims 1 to 21 for use as a medicament for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
25. The use of a compound according to any one of claims 1 to 21 for the manufacture of medicaments for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
26. The novel compounds, methods, processes and uses substantially as described herein before.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011506524A (en) * 2007-12-19 2011-03-03 エフ．ホフマン−ラ ロシュ アーゲー Spiroindolinone derivatives
WO2012121361A1 (en) 2011-03-10 2012-09-13 第一三共株式会社 Dispiropyrrolidine derivative
JP2013518921A (en) * 2010-02-09 2013-05-23 エフ．ホフマン−ラ ロシュ アーゲー Substituted pyrrolidine-2-carboxamide
WO2014038606A1 (en) 2012-09-06 2014-03-13 第一三共株式会社 Crystal of dispiropyrrolidine derivative
WO2015027067A3 (en) * 2013-08-23 2015-05-07 Virginia Commonwealth University Ester nitrates derivatives of aromatic aldehydes with multiple pharmalogic properties to treat sickle cell disease
WO2016001376A1 (en) 2014-07-03 2016-01-07 Boehringer Ingelheim International Gmbh New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
WO2017060431A1 (en) 2015-10-09 2017-04-13 Boehringer Ingelheim International Gmbh Spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
WO2017201449A1 (en) 2016-05-20 2017-11-23 Genentech, Inc. Protac antibody conjugates and methods of use
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US10485794B2 (en) 2015-04-13 2019-11-26 Daiichi Sankyo Company, Limited Treatment method by combined use of MDM2 inhibitor and BTK inhibitor
US10716790B2 (en) 2015-02-20 2020-07-21 Daiichi Sankyo Company, Limited Method for treating cancer by combined use
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Families Citing this family (10)

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Publication number Priority date Publication date Assignee Title
JP2013510860A (en) 2009-11-12 2013-03-28 ザ、リージェンツ、オブ、ザ、ユニバーシティ、オブ、ミシガン Spiro-oxindole MDM2 antagonist
US8288431B2 (en) * 2010-02-17 2012-10-16 Hoffmann-La Roche Inc. Substituted spiroindolinones
NZ611866A (en) 2010-11-12 2015-04-24 Univ Michigan Spiro-oxindole mdm2 antagonists
CN102584835B (en) * 2011-01-17 2014-08-27 苏州大学 Spiral heterocyclic compound containing indole structure and method for preparing same
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CN102321095B (en) * 2011-05-26 2014-09-10 兰州大学 Chiral spiro indole-pyran pyridine alkaline compound and preparation and application thereof
WO2013049250A1 (en) * 2011-09-27 2013-04-04 Amgen Inc. Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer
CN102627650B (en) * 2012-03-08 2015-07-08 徐州师范大学 Chiral spiro(pyrrolidine-3, 2'-oxindole)compound and synthesis method thereof
EP3936192A4 (en) 2019-03-06 2022-11-16 Daiichi Sankyo Company, Limited Pyrrolopyrazole derivative
CN116253736A (en) * 2023-01-06 2023-06-13 中山大学 Pyrazole beta-lactam derivative and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007104714A1 (en) * 2006-03-13 2007-09-20 F. Hoffmann-La Roche Ag Spiroindolinone derivatives
WO2007104664A1 (en) * 2006-03-13 2007-09-20 F. Hoffmann-La Roche Ag Spiroindolinone derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7495007B2 (en) 2006-03-13 2009-02-24 Hoffmann-La Roche Inc. Spiroindolinone derivatives
US7638548B2 (en) 2006-11-09 2009-12-29 Hoffmann-La Roche Inc. Spiroindolinone derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007104714A1 (en) * 2006-03-13 2007-09-20 F. Hoffmann-La Roche Ag Spiroindolinone derivatives
WO2007104664A1 (en) * 2006-03-13 2007-09-20 F. Hoffmann-La Roche Ag Spiroindolinone derivatives

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JP2013518921A (en) * 2010-02-09 2013-05-23 エフ．ホフマン−ラ ロシュ アーゲー Substituted pyrrolidine-2-carboxamide
WO2012121361A1 (en) 2011-03-10 2012-09-13 第一三共株式会社 Dispiropyrrolidine derivative
US8629133B2 (en) 2011-03-10 2014-01-14 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
US9884871B2 (en) 2012-09-06 2018-02-06 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
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US10030030B2 (en) 2012-09-06 2018-07-24 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
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US9718830B2 (en) 2012-09-06 2017-08-01 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
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US10716790B2 (en) 2015-02-20 2020-07-21 Daiichi Sankyo Company, Limited Method for treating cancer by combined use
US10485794B2 (en) 2015-04-13 2019-11-26 Daiichi Sankyo Company, Limited Treatment method by combined use of MDM2 inhibitor and BTK inhibitor
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