WO2009080488A1 - Spiroindolinone derivatives as anticancer agents - Google Patents

Spiroindolinone derivatives as anticancer agents Download PDF

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Publication number
WO2009080488A1
WO2009080488A1 PCT/EP2008/067061 EP2008067061W WO2009080488A1 WO 2009080488 A1 WO2009080488 A1 WO 2009080488A1 EP 2008067061 W EP2008067061 W EP 2008067061W WO 2009080488 A1 WO2009080488 A1 WO 2009080488A1
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WIPO (PCT)
Prior art keywords
chloro
phenyl
methyl
indole
spiro
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PCT/EP2008/067061
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French (fr)
Inventor
Li Chen
Xingchun Han
Yun He
Song Yang
Zhuming Zhang
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F. Hoffmann-La Roche Ag
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Priority to AT08863724T priority Critical patent/ATE524470T1/en
Priority to CN2008801217831A priority patent/CN101903388A/en
Priority to EP08863724A priority patent/EP2235017B1/en
Priority to AU2008340473A priority patent/AU2008340473A1/en
Priority to JP2010538565A priority patent/JP2011506524A/en
Priority to MX2010006332A priority patent/MX2010006332A/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to DK08863724.4T priority patent/DK2235017T3/en
Priority to PL08863724T priority patent/PL2235017T3/en
Priority to CA2708312A priority patent/CA2708312A1/en
Priority to BRPI0820699A priority patent/BRPI0820699A2/en
Publication of WO2009080488A1 publication Critical patent/WO2009080488A1/en
Priority to IL205506A priority patent/IL205506A0/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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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 and also in US-2007-0213341 -A1 published September 13, 2007.
  • 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.
  • these compounds demonstrate mechanistic activity.
  • the present invention relates to spiroindolinones of the formula
  • X is -Cl, -F or -Br
  • X' is hydrogen or -F
  • V is -F, -Cl or -Br
  • V is hydrogen or -F
  • Y is hydrogen, methyl, methoxy, -F or -Cl
  • W is -F, -Cl, -Br, -I, ethynyl or isopropenyl;
  • Ri , R 2 are hydrogen or lower alkyl, and in the case of Ri and R 2 they may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; provided that if B is a bond, then
  • R is selected from heterocycle, substituted heterocyle, heteroaryl, substituted heteroaryl, aryl, substituted aryl or substituted cycloalkyl; and if
  • R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and
  • X is -Cl
  • X' is hydrogen or -F
  • A is O
  • V is -F or -Cl
  • V is hydrogen or -F
  • Y is methyl, methoxyl, -Cl or -F
  • W is -Cl, -F or -Br
  • A is O
  • R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and the remaining substituents have any of the meanings given herein before.
  • Most preferred compounds are those of the formula: racemic (2'S, 3S, 4'R)-6-chloro-4'- ⁇ 5-chloro-2-[1 -methyl-1 - (1 -methyl-pipehdin-4- ylcarbamoyl)-ethoxy]-phenyl ⁇ -2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -cyclobutylcarbamoyl-i -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6
  • 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, fluoro-lower-alkoxy, lower- alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy- lower-alkoxy, -NH 2 -lower-alkoxy, -N(H, lower-alkyl )-lower-alkoxy, -
  • 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, preferably 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, preferably mono- or bicyclic system which consists of carbon atoms only, preferably of 3-14 carbon atoms, more preferably of 6-12 carbon atoms, any ring of which being saturated.
  • cycloalkenyl is intended to refer to any stable monocyclic or polycyclic, preferably mono- or bicyclic system which consists of carbon atoms only, preferably of 4-14 carbon atoms, more preferably of 6-12 carbon atoms, with at least one ring thereof being at least partially unsaturated.
  • 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 an aromatic hydrocarbon containing up to two rings, preferably consisting of 6-12 atoms, wherein up to 4 carbon atoms are replaced by hetero atoms.
  • Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, 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 4 to 12 membered, preferably 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 4, preferably 1 to 3 carbon atoms are replaced by a hetero atom.
  • Examples include oxetanyl; pyrrolidinyl (in particular pyrrolidin-2-yl and pyrrolidin-3-yl); piperidinyl; piperazinyl; morpholinyl (in particular morpholin-4-yl); tetrahydropyranyl and the like.
  • Hetero atom means an atom selected from N, O and S.
  • Alkoxy, alkoxyl or lower alkoxy refers to any of the above lower alkyl groups attached to an oxygen atom.
  • Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like.
  • Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, 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 in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
  • the present invention therefore provides the compounds of formula (I) for use as medicaments, more particularly as anti cancer medicaments, specifically for the treatment of solid tumors such as 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.
  • 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 compound of formula 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 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
  • intermediate I can be prepared by reaction of reagent VIII, and compound R-B-L, a base like K 2 CO 3 or CS2CO3 in anhydrous N,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).
  • intermediate I can be prepared by Ullman reaction of compound Xl and R-OH under heated conditions (Scheme 5).
  • B is selected from lower alkyl or lower cycloalkyl in formula I
  • the analogues X-a are preparaed first according to the methods in Scheme 1- 3, followed by a hydrolysis reaction to give the corresponding acid, which is converted into analogues X-b by using well-known methods for carboxamide formation (Scheme 6).
  • R1 is lower alkyl X-a X-b
  • the mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at -5 0 C to +5 0 C by means of an ice-salt bath.
  • a solution of sodium nitrite (17.5 g, 0.25 mol) in water(25 ml_) was added to the stirred mixture.
  • the stirring was continued for a period of 15 minutes.
  • the stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 ml_).
  • the aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (16O g ) in water(180 ml_).
  • the solution was maintained at 10-15 0 C by means of a cold-water bath and stirred vigorously.
  • the neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 ml_). The mixture was gently heated under reflux for 2 hours.
  • racemic (2'S, 3S, 4'R)-6- chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-ethoxy)- phenyl]-2'- (5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione (150 mg, 0.263 mmol) was reacted with 4,4-difluoropiperidine hydrochloride (83 mg, 0.526 mmol), EDCHCI (100 mg, 0.526 mmol), HOBt (71 mg, 0.526 mmol) and DIPEA (204 mg, 1.579 mmol) in anhydrous THF (3 ml_) to give title compound as a white solid (40 mg).
  • Example 22d To a solution of 1-(2,5-difluoro-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene in Example 22d (30.8 mmol) in anhydrous toluene (30 ml_) was added E/Z 6-Chloro-3- [5- chloro-2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester in Example 1 c (8 g,15.4 mmol). The solution was heated to 80 0 C for 5 h under Ar.
  • Example 50a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert- butoxycarbonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
  • Example 65b Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'- ⁇ 5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl ⁇ -2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
  • Example 68a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'- ⁇ 5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl ⁇ -2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-

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Abstract

There are provided compounds of the formula (I) and pharmaceutically acceptable salts, esters and enantiomers thereof, wherein W, X, X', Y, V, V', A, B and R are as described herein; processes for making such compounds and methods for using them. The compounds have utility as antiproliferative agents, especially, as anticancer agents.

Description

SPIROINDOLINONE DERATIVES AS ANTICANCER AGENTS
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 and also in US-2007-0213341 -A1 published September 13, 2007. 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
Figure imgf000003_0001
wherein
X is -Cl, -F or -Br;
X' is hydrogen or -F;
V is -F, -Cl or -Br;
V is hydrogen or -F; Y is hydrogen, methyl, methoxy, -F or -Cl;
W is -F, -Cl, -Br, -I, ethynyl or isopropenyl;
A is -O-, -NH-, -CH2-, -C(=O)-, -C(=O)NH-, -NHC(=O)- or -NHS(=O)2-;
B is a bond or -(CH2)mCRiR2(CH2)n-; m=0 or 1 ; n=0 or 1 ;
Ri, R2 are hydrogen or lower alkyl, and in the case of Ri and R2 they may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; provided that if B is a bond, then
R is selected from heterocycle, substituted heterocyle, heteroaryl, substituted heteroaryl, aryl, substituted aryl or substituted cycloalkyl; and if
B is not a bond, then
R is selected from -OR", -NR1R", -C(=O)NR'R", -NHC(=O)R", -NHS(=O)2R", -NHC(=O)NR'R" or -C(=O)NR'S(=O)2R", and
R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and
the pharmaceutically acceptable salts, esters and enantiomers thereof.
In one preferred embodiment according to the present invention, there are provided the compounds of formula (I) as described above, wherein A is O.
In another preferred embodiment according to the present invention, there are provided the compounds of formula (I) as described above, wherein B is a bond.
In another preferred embodiment according to the present invention, there are provided the compounds of formula (I) as described above, wherein B is -(CH2)mCRiR2(CH2)n--
In still another preferred embodiment there are provided the compounds of formula (I), wherein
X is -Cl;
X' is hydrogen or -F;
A is O;
V is -F or -Cl; V is hydrogen or -F; Y is methyl, methoxyl, -Cl or -F; W is -Cl, -F or -Br; and
the remaining substituents have the meaning given above.
In still another preferred embodiment there are provided the compounds of formula (I), wherein
A is O;
B is -(CH2)mCRi R2(CH2)n-; m=0 or 1 ; n=O or 1 ;
Ri, R2 are hydrogen or lower alkyl; R is -C(=O)NR'R" or -C(=O)NR'S(=O)2R"; and
R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and the remaining substituents have any of the meanings given herein before.
In this last embodiment, the compounds wherein R is -C(=O)NR'R" are especially preferred.
Most preferred compounds are those of the formula: racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1 - (1 -methyl-pipehdin-4- ylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -cyclobutylcarbamoyl-i -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(2-hydroxy- ethylcarbamoyl)-1-methyl- ethoxy] -phenyl}-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-{2- [1-(2-acetylamino-ethylcarbamoyl)-1 -methyl-ethoxy]-5- chloro-phenyl}-6-chloro-2'-(5- fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione,
(2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -(S-2,3-dihydroxy-propyl carbamoyl)-1 -methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(2-methoxy-ethylcarbamoyl)-1-methyl- ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(3-dimethylamino-propylcarbamoyl)-1- methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-nnethyl- phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -methyl-1 -(2-piperidin-1 -yl- ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)- 4'-[5-bromo-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5- fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonylaminocarbonyl- cyclobutoxy)-phenyl]-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(4-fluoro- benzenesulfonylaminocarbonyl)-cyclobutoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)- spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) -phenyl]-6-chloro-
2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-isopropenyl- 2-(3-methyl-oxetan-3-ylmethoxy)- phenyl]-2'-(5-chloro-2-methyl- phenyl )-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-2'-(5-chloro-2-methyl-phenyl)- 4'-[5-ethynyl-2-(3-methyl- oxetan-3-ylmethoxy)-phenyl]-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 - tert-butoxycarbonyl-piperidin-4-yloxy)-5-chloro-phenyl]- 6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-piperidinyloxy)-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-piperidinyloxy)-5-chloro-phenyl]- 6-chloro-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonyl-4- piperidinyloxy)- phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (pyrimidin-2-yloxy)-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H- indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2,2-dimethyl-3-oxo-3-pyrrolidin-1 -yl- propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-dimethylcarbamoyl- 2-methyl-propoxy)- phenyl]-2'-(5-fluoro-2-methylphenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-{[(2-hydroxy- ethyl)-methyl-carbamoyl]- methoxy}- phenyl]-2'-[2,5-difluorophenyl] spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- dimethylcarbamoylmethoxy-phenyl]-2'- (2,5-difluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-oxo- 2-pyrrolidin-1 -yl-ethoxy) -phenyl]- 2'-(2,5-difluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-bromo-2-(1 - dimethylcarbamoyl-1 -methyl -ethoxy)- phenyl]-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-{2-[2- (4-acetyl-piperazin-1 -yl)-1 ,1-dimethyl-2-oxo-ethoxy]-5- chloro-phenyl}-6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1 - (2,2,2-thfluoro- ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1 -yl)-1 ,1- dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1-yl)-1 ,1 -dimethyl-
2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (3-methyl-oxetan-3-ylmethoxy) -phenyl]- 2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-i -methyl-ethoxy) - phenyl]-2'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5-chloro-phenyl]-6-chloro-2'-(5-fluoro-2- methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- methanesulfonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-[2- (3,3-dimethyl-ureido)-ethoxy]-phenyl]-
2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy) - phenyl]-2'-(2-fluoro-5chloro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-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'S, 3S, 4'R)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-
(3-fluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-pipehdin-4-yloxy)-phenyl]-
6-chloro-2'-(3-fluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-2'-(5- fluorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3- fluorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-pipehdinyloxy)-phenyl]- 6-chloro-2'-(3- fluorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-pipehdin-4-yloxy)-phenyl]-
6-chloro-2'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro-2'-(5- chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3- chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-pipehdinyloxy)-phenyl]- 6-chloro-2'-(3- chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-ethoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-2'-(2-chloro-5-fluoro-phenyl)-4'-[5-chloro-2-(2- methanesulfonylannino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methoxylcarbannoyl-1 -nnethyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyanocarbamoyl-1-methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro- 4'-[5-fluoro-2-(2-methanesulfonylamino-1 ,1 -dimethyl -2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-methoxy-phenoxy)-phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[(2-cyclobutanecarbonyl-amino)-ethoxy]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyano-2-cyclopropyl-methoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyano-cyclopentyl-methoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-phenyl]-6- chloro -2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(piperazin-1 -yl)-phenyl]-2'-(5-fluoro-2- methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(4-acetyl-piperazin-1 -yl)-5-chloro-phenyl]-6-chloro-2'-(5- fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyclopropanesulfonylamino-1 ,1 -dinnethyl- 2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-trifluoro-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-2-oxo-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)- 4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methoxy-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -hydroxycarbonyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -dimethylcarbamoyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -dimethylcarbamoyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(2-hydroxy- ethylcarbamoyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3-pipehdine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1-carbonyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 -carbonyl)-propoxy]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylanninocarbonyl- propoxyJ-phenyll^'^δ-chloro^-nnethyl-phenylJ-spirotSH-inclole-S.S'-pipeπclinel^.GXI H)- dione, chiral (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-ethanesulfonylamino-1 ,1-dimethyl-2-oxo-ethoxy)- phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylannino-1 ,1 -dinnethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5-methyl-2-nnethoxy-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(3-methanesulfonylamino-2,2-dimethyl-3- oxo-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(2-methoxy-ethanesulfonylamino)-1 ,1 - dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylaminocarbonyl-1-propyl- butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylaminocarbonyl-1- propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylanninocarbonyl-1-propyl- butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-(5-chloro-2-methanesulfinylmethoxy-phenyl)-2'-(5- fluoro-2-methyl -phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-[2-(tert-butylsulfamoyl-methoxy)-5-chloro-phenyl]-6-chloro-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -diethyl-2- oxo-ethoxy)-phenyl]-5-fluoro-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
In the specification where indicated the various groups may be "optionally 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, fluoro-lower-alkoxy, lower- alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy- lower-alkoxy, -NH2-lower-alkoxy, -N(H, lower-alkyl )-lower-alkoxy, -N(lower-alkyl)2-lower- alkoxy, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, -NH2, -N(H, lower-alkyl) or -N(lower-alkyl)2. Preferred substituents for the aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl and amino.
If alkyl, alkenyl, alkynyl or similar groups are linked with both ends to the same moiety, cyclic structures may result, where two hydrogens of said moiety are being replaced by the two ends of the alkyl, alkenyl, alkynyl or similar group, thus creating cyclic structures, such as, tetralin, macrocycles or spiro compounds.
The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 8, preferably 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, preferably mono- or bicyclic system which consists of carbon atoms only, preferably of 3-14 carbon atoms, more preferably of 6-12 carbon atoms, any ring of which being saturated. The term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic, preferably mono- or bicyclic system which consists of carbon atoms only, preferably of 4-14 carbon atoms, more preferably of 6-12 carbon atoms, with at least one ring thereof being at least partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 8, preferably 2 to 6 carbon atoms. Examples of such "alkenyl group" are vinyl (ethenyl), allyl, isopropenyl, 1 -propenyl, 2-methyl-1-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1- butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such "alkynyl group" are ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The term "halogen" as used in the definitions means fluorine, chlorine, iodine or bromine, preferably fluorine and chlorine. "Aryl" means a monovalent, monocyclic or bicyclic, aromatic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
"Heteroaryl" means an aromatic hydrocarbon containing up to two rings, preferably consisting of 6-12 atoms, wherein up to 4 carbon atoms are replaced by hetero atoms. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
"Heterocycle" means a substituted or unsubstituted 4 to 12 membered, preferably 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 4, preferably 1 to 3 carbon atoms are replaced by a hetero atom. Examples include oxetanyl; pyrrolidinyl (in particular pyrrolidin-2-yl and pyrrolidin-3-yl); piperidinyl; piperazinyl; morpholinyl (in particular morpholin-4-yl); tetrahydropyranyl and the like.
"Hetero atom" means an atom selected from N, O and S.
"Alkoxy, alkoxyl or lower alkoxy" refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, 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 in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
In a preferred embodiment the present invention therefore provides the compounds of formula (I) for use as medicaments, more particularly as anti cancer medicaments, specifically for the treatment of solid tumors such as 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 compound of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxyl ic acid or alcohol respectively.
Compounds of this invention in formula (I) can be synthesized according to the following general schemes, wherein unless explicitly otherwise stated all substituents have the meanings given above. 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. C
1 ) LiHMDS
Figure imgf000018_0002
Figure imgf000018_0001
Il
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.
Figure imgf000019_0001
Scheme 2
Oxindole III can be reacted with an appropriately substituted aldehyde 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 imgf000020_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 imgf000021_0001
VIII
Scheme 4
When A is O, B is selected from lower alkyl or lower cycloalkyl, intermediate I can be prepared by reaction of reagent VIII, and compound R-B-L, a base like K2CO3 or CS2CO3 in anhydrous N,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).
Figure imgf000021_0002
Scheme 5
When A is O, B is a bond, and R is selected from aryl, substituted aryl, hetereoaryl, or substituted heteroaryl group informular I, intermediate I can be prepared by Ullman reaction of compound Xl and R-OH under heated conditions (Scheme 5). When B is selected from lower alkyl or lower cycloalkyl in formula I, the analogues X-a are preparaed first according to the methods in Scheme 1- 3, followed by a hydrolysis reaction to give the corresponding acid, which is converted into analogues X-b by using well-known methods for carboxamide formation (Scheme 6).
Figure imgf000022_0001
R1 is lower alkyl X-a X-b
Reagents and conditions:
1 ) NaOH, MeOH/THF/H2O;
2) NHR1R", EDCI, HOBt, JPr2NEt in THF at room temperature.
Scheme 6
Analogues Xl-a are prepared first according to the methods in Scheme 1- 3, Xl-a can be then converted into Xl-b, Xl-c, Xl-d (Scheme 7).
Figure imgf000023_0001
Xl-d
Reagents and conditions:
1) R'R"C(=O)CI, pyridine, DCM, room temperarure
2) R"S(=O)2CI, NEt3 in DMF, room temperature;
3) R'R"NC(=O)CI, NEt3 Or R11NCO, room temperature;
Scheme 7
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 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester
Figure imgf000024_0001
M.W. 270.72 Ci3Hi5CIO4
5-Chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (11.4 g, 58 mmol), K2CO3 (18.6 g, 135 mmol) and Kl (0.97 g, 5.8 mmol) were mixed in DMF (20 ml_). Then the reaction mixture was heated at 110 0C for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1 N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (7 g).
Example 1b Preparation of intermediate E/Z-2-{4-Chloro-2-[6-chloro-2-oxo-1 ,2-dihydro-indol- ylidenemethyl]-phenoxy}-2-methyl-propionic acid ethyl ester
Figure imgf000024_0002
M.W. 420.30 C2iHi9CI2NO4 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester(7 g, 26 mmol) and 6- chlorooxindole (3.6 g, 22 mmol) were mixed in anhydrous methanol (30 ml_) at room temperature.Then pyrrolidine (1.85 g, 26 mmol) was added slowly. The reaction mixture was heated at 70 0C for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2- oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g). Example 1c
Preparation of intermediate E/Z 6-Chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1 -methyl- ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000025_0001
M.W 520.41 C26H27CI2NO6
To a solution of E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl) -phenoxy]-2-methyl-propionic acid ethyl ester (7.2 g, 17.2 mmol) in dichloromethane (50 ml_) at r.t was added di-tert-butyl-dicarbonate (4.5 g, 20.6 mmol) , followed by the addition of 4-dimethylaminopyhdine (0.2 g, 1.72 mmol). The reaction mixture was stirred at r.t. for 0.5 h, then the mixture was washed with 0.5/V HCI aqueous solution. The organic layer was separated, dried and concentrated to give give title compound as a yellow solid (8 g).
Example 1d Preparation of intermediate 1-(5-fluoro-2-methylphenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000025_0002
M.W. 251.38 Ci3Hi8FNOSi To 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (2.18 ml_, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 ml_, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 ml_) was added, followed by the addition of 5-fluoro-2-methyl- benzaldehyde (1.38 g, 10 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 ml_, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (1.9 ml_, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 ml_, 13.6 mmol) in diethyl ether (50 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -(5-fluoro-2- methylphenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 1e
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000026_0001
M.W 599.49 C31 H29CI2FN2O5
To a toluene solution (50 ml_) of 1 -(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza- 1 ,3-butadiene (77 mmol) was added E/Z 6-chloro-3-[5-chloro-2-(1 -ethoxycarbonyl-1- methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (8 g, 15.44 mmol). Then the reaction mixture were heated at 130 0C for 2. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of thfluoroacetic acid (10 ml_) and dichloromethane (30 ml_) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give give title compound as a white solid (2.7 g). m/z (M+H)+: 599 Example 1f
Preparation of intermediate racemic (2'S,3S,4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000027_0001
M.W 571.44 C29H25CI2FN2O5
Racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethoxycarbonyl-1 -methyl-ethoxy) - phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (2.7 g, 4.5 mmol) was dissolved in THF (20 ml_). Then aqueous solution (10 ml_) of KOH (0.5 g) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to "pH" 2-3 by addition of concentrated aqueous HCI solution. The white solid was collected by filtration to give title compound (1.6 g). m/z (IvRH)+: 571
Example 1g
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1- (1-methyl- pipehdin-4-ylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-
3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000027_0002
M.W. 667.605 C35H37CI2FN4O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)- phenyl]- 2'-[5-fluoro-2-methylphenyl]- spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 ml_) was added 1 -methyl- piperidin-4-ylamine (21 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg). m/z (M+H)+: 667
Example 2
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1-cyclobutylcarbamoyl-i - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000028_0001
M.W. 624.537 C33H32CI2FN3O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- hyd roxy- 1 ,1 -dimethyl - ethoxy)- phenyl]- 2'-[5-fluoro-2-methylphenyl]- spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 ml_) was added cyclobutylamine (13 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (16 mg). m/z (M+H)+: 624
Example 3
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1-(2-hydroxy- ethylcarbamoyl)-1 -methyl-ethoxy] -phenyl}-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H- indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000028_0002
M.W. 614.498 C31 H30CI2FN3O5
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)phenyl]- 2'-[5-fluoro-2-methylphenyl] spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 ml_) was added 2-amino- ethanol (11 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (9 mg). m/z (M+H)+: 614
Example 4
Preparation of racemic (2'S, 3S, 4'R)-4'-{2- [1-(2-acetylamino-ethylcarbamoyl)-1-methyl- ethoxy]-5-chloro-phenyl}-6-chloro-2'-(5- fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000029_0001
M.W. 655.551 C33H33CI2FN4O5 To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)-phenyl]- 2'-[5-fluoro-2-methylphenyl]- spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2ml_) was added N-(2-amino- ethyl)-acetamide (19 mg, 0.18 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 (M+H)+: 655
Example 5
Preparation of (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -(S-2,3-dihydroxy-propyl carbamoyl )-1-methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000029_0002
M.W. 644.524 C32H32CI2FN3O6 To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- hyd roxy- 1 ,1 -dimethyl - ethoxy)- phenyl]- 2'-[5-fluoro-2-methylphenyl]-spiro [3H-indole-3,3'-piperidine]- 2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2ml_) was added S-3-amino- 1 ,2-propanediol (17 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep- HPLC to give the title compound as a white solid (7 mg). m/z (IvRH)+: 644
Example 6 Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1-(2-methoxy- ethylcarbamoyl)-1 -methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000030_0001
M.W. 628.525 C32H32CI2FN3O5 To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)- phenyl]-2'-[5-fluoro-2-methylphenyl]-spiro [3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2ml_) was added 2-methoxy-ethylamine (14 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (10 mg). m/z (M+H)+: 628.
Example 7
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1-(3-dimethylamino- propylcarbamoyl)-1 -methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000030_0002
M.W. 655.594 C34H37CI2FN4O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)-phenyl]-2'-[5-fluoro-2-methyl phenyl] spiro [3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2ml_) was added N,N-dimethyl-propane-1 ,3-diamine (19 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg). m/z (IvRH)+: 655
Example 8
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -methyl-1 -(2-piperidin-1 - yl-ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000031_0001
M.W. 681.632 C36H39CI2FN4O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)- phenyl]-2'-[5-fluoro-2-methylphenyl]-spiro [3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (35 mg, 0.06 mmol), EDCI (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2ml_) was added 2-pipehdin-1 -yl-ethylamine (24 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep- HPLC to give the title compound as a white solid (7 mg). m/z (IvRH)+: 681
Example 9a Preparation of intermediate 2-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester
Figure imgf000031_0002
Figure imgf000032_0001
5-Bromo-2-hydroxy-benzaldehyde (20 g, 100 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (29 g, 150 mmol), K2CO3 (27.6 g, 200 mmol) and Kl (3.2 g, 19 mmol) were mixed in DMF (100 ml_). Then the reaction mixture was heated at 110 0C for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1 N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (21 g)
Example 9b Preparation of intermediate E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester
Figure imgf000032_0002
M.W. 464.75 C2IHi9BrCINO4
To the mixture of 6-chlorooxindole (10.6 g, 63 mmol) and 2-(4-bromo-2-formyl- phenoxy)-2-methyl-propionic acid ethyl ester (20 g, 63 mmol) in methanol (150 ml_) was added pyrrolidine (4.5 g, 6 3mmol) dropwise. The mixture was then heated at 70 0C for 1 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (18.5g, 63%).
Example 9c
Preparation of intermediate E/Z 3-[5-bromo-2-(1 -ethoxycarbonyl-1-methyl-ethoxy)- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000033_0001
M.W. 564.87 C26H27BrCINO6
To a solution of E/Z-2-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl) - phenoxy]-2-methyl-propionic acid ethyl ester (5 g, 11 mmol) in dichloromethane (50 ml_) at r.t was added di-tert-butyl-dicarbonate (2.4 g, 11 mmol) , followed by the addition of 4-dimethylaminopyhdine (1 g, 8.2 mmol). The reaction mixture was stirred at r.t. for 2 h, washed with aqueous HCI solution (0.5M) and water. The organic layer was separated, dried over Na2SO4, concentrated to give E/Z 3-[5-bromo-2-(1 -ethoxycarbonyl-1-methyl- ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester as a yellow oil (5.5 g, 88%).
Example 9d
Preparation of intermediate racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -ethoxycarbonyl-1- methyl-ethoxy)-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000033_0002
M.W. 643.94 C3iH29BrCIFN2O5
In a manner similar to the method described in Example 1 e, E/Z- 3-[5-bromo-2-(1 - ethoxycarbonyl-i-methyl-ethoxyJ-benzylidenel-e-chloro^-oxo^.S-dihydro-indole-i - carboxylic acid tert-butyl ester (1.5 g, 2.6 mmol).) was reacted with 1 -(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (2 M solution in toluene, 5 ml_, 10 mmol) and then trifluoroacetic acid in dichloromethane to give the title compound (RO5233645- 000) (700 mg). m/z (M +H)+: 643
Example 9e Preparation of intermediate racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -hydroxycarbonyl-1- methyl-ethoxy)-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000034_0001
M.W. 615.89 C29H25BrCIFN2O5
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -ethoxycarbonyl-1 -methyl- ethoxy)-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (120 mg, 0.19 mmol) in methanol (4 ml_) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 ml_). The mixture was heated at 7O 0C for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to "pH" 1 with aqueous HCI solution. The precipitate was collected and dried to give product as a white solid (75 mg). m/z (M+H)+: 615
Example 9f Preparation of racemic (2'S, 3S, 4'R)- 4'-[5-bromo-2- (2-methanesulfonylamino-1 ,1 - dimethyl^-oxo-ethoxyJ-phenyll-θ-chloro^'^S- fluoro^-methyl-phenylJ-spiroISH-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000034_0002
M.W. 692.987 C30H28BrCIFN3O6S A solution of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -hydroxycarbonyl-1 -methyl-ethoxy)- phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (20 mg, 0.032 mmol) and CDI (11 mg, 0.064 mmol) in DMF (0.2 ml_) was heated at 60 0C for 30 min, then cooled to room temperature. To this solution was added a mixture of methanesulfonamide (19 mg, 0.2 mmol) and NaH (8 mg, 60%, 0.2 mmol) in DMF (0.2 ml_). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (10 mg).
Example 10a
Preparation of intermediate1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester
Figure imgf000035_0001
M.W. 268.70 Ci3Hi3CIO4
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol), Kl (3 g) and K2CO3 (13 g, 94 mmol) in DMF (100 ml_) was added 1 -bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol). The mixture was heated at 14O 0C for 1.5 h. Then additional 1-bromo- cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 14O 0C for additional 10 min, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated to give the title compound as dark oil (18g).
Example 10b
Preparation of intermediate E/Z-1 -[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro- indol-3- ylidenemethyl)- phenoxy]-cyclobutanecarboxylic acid methyl ester
Figure imgf000035_0002
M.W. 418.28 C2iHi7CI2NO4 To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1 -(4-chloro-2-formyl-phenoxy)- cyclobutanecarboxylic acid methyl este (18 g, 67 mmol) in methanol (100 ml_) was added pyrrolidine (4.5 mg, 63 mmol) dropwise. The mixture was then heated at 80 0C for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound (6 g).
Example 10c Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl- cyclobutoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000036_0001
M.W. 518.40 C26H25CI2NO6
To a solution of E/Z-1 -[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)- phenoxy]-cyclobutanecarboxylic acid methyl ester (6 g, 14mmol) in DCM (50 ml_) at r.t was added diteret-butyl-dicarbonate (4.7 g, 21 mmol) , followed by the addition of 4- dimethylaminopyhdine (1 g, 8.2 mmol). The reaction mixture was stirred at r.t. for 2 h, washed with HCI aq. (0.5 M) and water, dried over anhydrous Na2SO4, concentrated to give the title compound as a yellow solid (5 g )
Example 1Od
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1- methoxycarbonyl-cyclobutoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-
3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000036_0002
M.W. 597.48 C3IH27CI2FN2O5
To a toluene solution of 1 -(5-fluoro-2-methylphenyl)-3-thmethylsilyoxy- 2-aza-1 ,3- butadiene in toluene (2 M, 5 ml_, 10 mmol) was added E/Z 6-chloro-3-[5-chloro-2- (1- methoxycarbonyl-cyclobutoxy)-benzylidene]- 2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol). The reaction mixture was heated at 8O0C overnight under argon protection, then TFA (5 ml_) was added, and the resulting mixture was stirred at room temperature for 20 min, evaporated in vacuo. The residue was partitioned between ethyl acetate and NaOH aq. (1 M). The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give the title compound as a white solid (340 mg).
Example 1Oe
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-cyclobutoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000037_0001
M .W. 583.45 C30H25CI2FN2O5
To a mixture of racemic (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 -methoxycarbonyl- cyclobutoxy)-phenyl]-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione (200 mg, 0.33 mmol) in methanol (4 ml_) was added a solution of NaOH (40 mg, 1 mmol) in water (2 ml_). The mixture was heated at 7O 0C for 2h, evaporated to remove methanol, cooled to room temperature, and acidified to "pH" 1 with HCI aq.. The precipitate was collected, washed with water and dried to give the title compound as a white solid (175 mg).
Example 1Of Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1- methanesulfonylaminocarbonyl-cyclobutoxy)-phenyl]-2'-(5- fluoro-2-methyl- phenyl)- spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000037_0002
M.W. 660.547 C3IH28CI2FN3O6S A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl- cyclobutoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (50 mg, 0.086 mmol) and CDI (28 mg, 0.17 mmol) in DMF (0.5 ml_) was heated at 6O0C for 30 min, and then cooled to root temperature. To this solution was added a mixture of methanesulfonamide (95 mg, 1 mmol) and NaH (40 mg, 60%, 1 mmol) in DMF (1 ml_). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound t as a white solid (20 mg).
Example 11
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1-(4-fluoro- benzenesulfonylaminocarbonyl)-cyclobutoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)- spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000038_0001
M.W. 740.608 C36H29CI2F2N3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl- cyclobutoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (50 mg, 0.086 mmol) and CDI (28 mg, 0.17 mmol) in DMF (0.5 ml_) was heated at 60 0C for 30 min, and then cooled to root temperature. To this solution was added a mixture of 4-fluoro-benzenesulfonamide (175 mg, 1 mmol) and NaH (40 mg, 60%, 1 mmol) in DMF (1 ml_). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (20 mg).
Example 12a
Preparation of intermediate chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000038_0002
M.W 571.44 C29H25CI2FN2O5 Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione was conducted by chiral HPLC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (8 mg) (RO5221490-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (8 mg) (RO5221491 -000). m/z (IvRH)+: 571 Example 12b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000039_0001
M .W. 648.536 C30H28CI2FN3O6S
A solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxy-1 ,1 -dimethyl- ethoxy)-phenyl]-2'-[5-fluoro-2-methylphenyl] spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)- dione (20 mg, 0.035 mmol) and CDI (11 mg, 0.068 mmol) in DMF (0.2 ml_) was heated at 6O0C for 30 min, and then cooled to root temperature. To this solution was added a mixture of methanesulfonamide (19 mg, 0.2 mmol) and NaH (8 mg, 60%, 0.2 mmol) in DMF (0.2 ml_). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Example 13a Preparation of intermediate of 5-chloro-2-methyl-benzaldehyde
Figure imgf000039_0002
M.W.154.60 C8H7CIO
A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 ml_) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 minutes to give a 10% solution of formaldoxime. A mixture of 2-choro-4-methylaniline (35.5 g, 0.25 mol) and water (50 ml_) was stirred , and concentrated hydrochloric acid (57 ml_) was added slowly. The mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at -50C to +50C by means of an ice-salt bath. To the stirred mixture there was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water(25 ml_). After completion of the addition, the stirring was continued for a period of 15 minutes. The stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 ml_). The aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (16O g ) in water(180 ml_). The solution was maintained at 10-150C by means of a cold-water bath and stirred vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 ml_). The mixture was gently heated under reflux for 2 hours. The mixture was extracted with three portions of ether (150 ml_), and the ethereal extracts were washed with a saturated NaCI solution, Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain yellow solid (Yield: 21 g, 36%). m/z (M+H)+: 155
Example 13b Preparation of intermediate 1-(5-chloro-2-methylphenyl)-3- trimethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000040_0001
M.W. 267.83 Ci3Hi8CINOSi
In a manner similar to the method described in example 1 c, 5-chloro-2- methylbenzaldehyde (15 g, 97 mmol) was used as the starting to react with 1 M THF solution of LiHMDS (97 mmol, 97 ml_), trimethylsilyl chloride (10.3 g, 97 mmol), triethylamine (13.2 g, 126 mmol) and acetyl chloride (9.5 g, 126 mmol) to give crude 1- (5-chloro-2- methylphenyl)- 3-trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used without further purification.
Example 13c Preparation of intermediate toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester
Figure imgf000041_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 13d Preparation of intermediate 5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde
Figure imgf000041_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 13e
Preparation of intermediate E/Z 3-[5-bromo-2-(3-methyl-oxetan-3-ylm ethoxy)-benzylidene]-6-chloro-1 ,3-dihydro-indol-2-one
Figure imgf000042_0001
M.W. 434.72 C20Hi7BrCINO3
To the mixture of 6-chlorooxindole (1.2 g, 7 mmol) and 4-Chloro-2-formyl- benzoic acid methyl ester (1.4 g, 7 mmol) in methanol (10 ml_) was added pyrrolidine (490 mg, 7 mmol) dropwise. The mixture was then heated at 70 0C for 3 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (500 mg).
Example 13f Preparation of intermediate E/Z-3-[5-Bromo-2-(3-methyl-oxetan-3-ylmethoxy)- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000042_0002
M.W. 448.31 C22Hi9CI2NO5
To a solution E/Z -4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol -3- ylidenemethyl) - benzoic acid methyl ester (500 mg, 1.4 mmol) in DCM (10 ml_) at rt was added diteret- butyl-dicarbonate (470 mg, 2.1 mmol) , followed by the addition of 4- dimethylaminopyridine (100 mg, 0.82 mmol). The reaction mixture was stirred at r.t. for 2 h, then purified by column chromatography to give the title compound as a yellow solid (450 mg).
Example 13g
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) - phenyll-e-chloro^'^δ-chloro^-methyl-phenyO-spirotSH-indole-S.S'- pipehdinel^.eXI H)- dione
Figure imgf000043_0001
M.W. 630.37 C30H27BrCI2N2O4
In a manner similar to the method described in example 1 e, E/Z -6-chloro-3-(5-chloro- 2-methoxycarbonyl-benzylidene)-2-oxo-2,3-dihydro- indole-1 -carboxylic acid tert-butyl ester (450 mg, 1 mmol) was reacted with intermediate 1 -(5-chloro-2-methylphenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (1 M solution in toluene, 4 ml_, 4 mmol) to give the title compound (60 mg). m/z (IvRH)+: 459
Example 14
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-isopropenyl- 2-(3-methyl-oxetan-3- ylmethoxy)-phenyl]-2'-(5-chloro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000043_0002
M.W. 591.532 C33H32CI2N2O4
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) - phenyll-e-chloro^'^δ-chloro^-methyl-phenyO-spirotSH-indole-S.S'- pipehdinel^.eXI H)- dione (50 mg, 0.08 mmol), isopropenylboronic acid pinacol ester (40 mg, 0.24 mmol) and K3PO4 (50 mg, 0.24 mmol) in THF was added Pd(PPh3)4 (15 mg). The mixture was heated at 80 0C for 8 h under an argon atmosphere, purified by prep-HPLC to give the title compound as a white solid (6 mg).
Example 15a
Preparation of intermediate trimethylsilylacetylene boronic acid dimethyl ester
Figure imgf000043_0003
M.W. 155.06 C6Hi2BO2Si A solution of trimethylsilylacetylene (0.51 mL) in THF (4 ml_) was cooled to -780C under argon, and then a solution of n-BuLi in n-hexane (1.6 M, 2.25 mL, 3.6 mmol) was added via syringe. The resulting mixture was stirred at the same temperature for 15 min, then trimethylborate (0.4 mL, 3.6 mmol) was added. The cooling bath was removed, and the mixture was stirred at room temperature for 15 min to give a solution of the title compound.
Example 15b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-2'-(5-chloro-2-methyl- phenyl)-4'-[2-(3-methyl-oxetan-3-ylmethoxy)-5-thmethylsilanylethynyl-phenyl] spiro[3H- indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000044_0001
M.W. 647.68 C35H36CI2N2O4Si
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(3-methyl-oxetan-3- ylmethoxy)- phenyl]-6-chloro-2'-(5-chloro-2-methyl- phenyl)-spiro[3H- indole-3,3'- piperidine]-
2,6'(1 H)-dione (50 mg, 0.08 mmol), trimethylsilylacetylene boronic acid dimethyl ester (0.7 M, 0.7 mL, 0.49mmol) and K3PO4 (100 mg, 0.48 mmol) in THF was added Pd(PPh3)4 (15 mg) under argon. The reaction mixture was heated at 8O0C for 20 h, purified by prep-HPLC to give the title compound as a white solid.
Example 15c
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-2'-(5-chloro-2-methyl-phenyl)- 4'-[5- ethynyl-2-(3-methyl- oxetan-3-ylmethoxy)-phenyl]-spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000044_0002
M.W. 575.489 C32H28CI2N2O4
To a solution of racemic (2'S, 3S, 4'R)-6-chloro-2'-(5-chloro-2-methyl- phenyl)-4'-[2-(3- methyl-oxetan-3-ylmethoxy)-5-trimethylsilanylethynyl-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione in methanol (5 ml_) was added K2CO3 (100 mg). The mixture was stirred at room temperature for 2 h, purified by prep-HPLC to give the title compound as a white solid (2.5 mg).
Example 16a
Preparation of intermediate 4-methanesulfonyloxy-pipehdine-1-caboxylic acid tert-butyl ester
Figure imgf000045_0001
To a solution of 4-hydroxy-pipehdine-1 -carboxylic acid tert-butyl ester (2 g, 20 mmol) and DMAP (3 g, 24 mmol) in DCM (50 ml_) was dropped methanesulfonyl chlohde(2.7 g, 24 mmol) in ice bath. The reaction mixture was stirred for 2 h at room temperature. Then the mixture was filtered and washed by 0.5N HCI (50ml_),1 N Na2CO3 (50 ml_) and brine (50 ml_), dried over anhydrous Na2SO4, concentrated to give title compound as a white solid (Yield: 5 g, 90%).
Example 16b
Preparation of intermediate 4-(4-chloro-2-formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000045_0002
M.W. 339.82 Ci7H22CINO4
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (3.15 g, 20 mmol), Kl (0.1 g) and K2CO3 (8.28 g, 60 mmol) in DMF (100 ml_) was added 4-methanesulfonyloxy- pipehdine-1 -caboxylic acid tert-butyl ester (7.26 g, 26 mmol). The mixture was heated at 1000C for 2 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1 N NaOH (3OmL), water, and dried over anhydrous Na2SO4, concentrated to give the title compound as white solid (Yield:5.3g, 78%).
Example 16c Preparation of intermediate E/Z-4-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-pipehdine-1-carboxylic acid tert-butyl ester
Figure imgf000046_0001
M.W. 489.40 C25H26CI2N2O4
To a mixture of 6-chlorooxindole (0.84 g, 5 mmol) and 4-(4-chloro-2-formyl-phenoxy)- piperidine-1 -carboxylic acid tert-butyl ester (1.7 g, 5 mmol) in methanol (10 ml_) was added pyrrolidine (0.4 ml_, 5 mmol) dropwise. The mixture was then heated at 70 0C for 3 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1 g).
Example 16d
Preparation of intermediate E/Z-3-[2-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-5-chloro- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000046_0002
M.W. 589.52 C30H34CI2N2O6 To a solution of E/Z- 4-[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)- phenoxy]-pipehdine-1-carboxylic acid tert-butyl ester (2.44 g, 5 mmol) in DCM (10 ml_) at r.t. was added diteret-butyl-dicarbonate (1.6 g, 7.5 mmol) , followed by the addition of 4-dimethylaminopyridine (0.06 g, 0.5 mmol). The reaction mixture was stirred for 2 h and washed with 0.5N hydrochloric acid, dried over anhydrous Na2SO4, then the solvent was removed to give title compound (Yield: 2.7 g, 92%).
Example 16e
Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(1 - tert-butoxycarbonyl-pipehdin-4-yloxy)-5- chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000047_0001
M.W. 668.60 C35H36CI2FN3O5
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-thmethylsilyoxy- 2-aza- 1 ,3-butadiene (15 ml_, 30 mmol) in toluene (50 ml_) was added E/Z-3-[2-(1 -tert-Butoxycarbonyl- pipehdin-4-yloxy)- 5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (3.6 g, 6 mmol) . The reaction mixture was stirred under argon at 65 0C for 3 h and then heated at 130 0C for 4 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to give the title compound as a white solid (Yield: 1 g ). m/z (IvRH)+: 669
Example 17a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-piperidinyloxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000047_0002
M.W. 568.48 C30H28CI2FN3O3
A solution of racemic (2'S, 3S, 4'R)-4'-[2-(1 - tert-butoxycarbonyl-piperidin-4-yloxy)-5- chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (0.7 g, 1 mmol) in TFA (10 ml_) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1 N Na2CO3 aq. (50 ml_) and brine (50 ml_), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.6 g).
Example 17b Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-piperidinyloxy)-5-chloro-phenyl]- 6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000048_0001
M.W. 610.52 C32H30CI2FN3O4 To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-pipehdinyloxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (110 mg, 0.2 mmol), acetyl chloride (0.017 ml_, 0.24 mmol) in DCM (5 ml_) was added pyhdine(23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg). m/z (M+H)+: 611
Example 18 Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonyl-4- pipehdinyloxy)-phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000049_0001
M.W. 646.57 C31 H30CI2FN3O5S
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-piperidinyloxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (110 mg, 0.2 mmol) , methanesulonyl chloride (0.0185 ml_, 0.24 mmol) in DCM (5 ml_) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg). m/z (M+H)+: 494
Example 19a
Preparation of intermediate 5-chloro-2-(pyhmidin-2-yloxy)-benzaldehyde
Figure imgf000049_0002
M.W. 234.64 CnH7CIN2O2
5-Chloro-2-hydroxy-benzaldehyde (4 g, 25.6 mmol), 2-chloro-pyhmidine (5.4 g , 48 mmol), f-BuOK (3.5 g, 29 mmol) were mixed in DMF (20 ml_). Then the mixture was heated for 2 hour at 120 0C. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1 N NaOH. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to give title compound as a white solid (Yield :1.5 g, 25%). Example 19b
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(pyhmidin-2-yloxy)- benzylidene]-1 ,3-dihydro-indol-2-one
Figure imgf000050_0001
M.W. 384.22 CI9HHCI2N3O2
To a mixture of 6-chlorooxindole (1.1 g, 6.4 mmol) and 5-chloro-2-(pyhmidin- 2-yloxy)- benzaldehyde (1.5 g, 6.4 mmol) in methanol (10 ml_) was added pyrrolidine (0.5 ml_, 6.4 mmol) dropwise. The mixture was then heated at 70 0C for 3 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1.3 g).
Example 19c
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(pyhmidin-2-yloxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester
Figure imgf000050_0002
M.W. 484.34 C24Hi9CI2N3O4
To a solution of E/Z-6-Chloro-3-[5-chloro-2-(pyrimidin-2-yloxy)-benzylidene]- 1 ,3- dihydro- indol-2-one (1.33 g, 3.5 mmol) in DCM (10 ml_) was added diteret-butyl- dicarbonate (0.9 g, 4.2 mmol) at r.t., followed by the addition of 4-dimethylaminopyhdine (0.04 g, 0.35 mmol). The reaction mixture was stirred for 2 h and washed with 0.5N hydrochloric acid, dried over anhydrous Na2SO4, then the solvent was removed to give title compound. (Yield: 1.4 g) Example 19d
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (pyrimidin-2-yloxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000051_0001
M.W. 563.42 C29H2ICI2FN4O3
In a manner similar to the method described in example 1 e, 6-chloro- 3-[5-chloro-2- (pyhmidin-2-yloxy)-benzylidene]-2-oxo-2,3-dihydro- indole- 1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was reacted with 1 -(5-fluoro- 2-methyl phenyl )-3- trimethylsilyoxy- 2- aza-1 ,3-butadiene (10 mL, 20 mmol) in toluene to give title compound as a white solid (Yield: 40 mg). m/z (IvRH)+: 563
Example 20a
Preparation of intermediate 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester
Figure imgf000051_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).
Example 20b Preparation of intermediate 3-(4-chloro-2-formyl-phenoxy)-2,2-d imethyl-propionic acid methyl ester
Figure imgf000052_0001
M.W.270.72 Ci3Hi5CIO4 δ-chloro^-hydroxy-benzaldehyde (3.1 g, 2 mmol), 2,2-dimethyl-3-(toluene- 4- sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and Kl (0.1 g) were mixed in DMF (20 ml_). Then the mixture was irradiated by microwave for an hour at 150 0C. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1 N NaOH. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to give title compound (Yield: 5 g, 92.5%).
Example 20c
Preparation of intermediate E/Z -3-[4-Chloro-2-(6-chloro-2-oxo- 1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester
Figure imgf000052_0002
M.W. 420.30 C2iHi9CI2NO4
3-(4-chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (6.7 g, 25 mmol) and 6-Chloro-1 ,3-dihydro-indol-2-one(4.35 g, 25 mmol) were mixed in 20 ml_ of anhydrous methanol. Then pyrrolidine (2 ml_, 25 mmol) was added dropwise at r.t. The mixture was heated to 70 0C for 3 h and cooled to room temperature. The precipitate was collected by filtration and dried to give title compound as yellow solid (Yield: 7 g, 67%). m/z (M+H)+: 420
Example 2Od Preparation of intermediate E/Z- 6-Chloro-3-[5-chloro-2- (2-methoxycarbonyl- 2-methyl- propoxy)-benzylidene]-2-oxo- 2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000053_0001
M.W. 520.41 C26H27CI2NO6
To a solution of E/Z -3-[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro- indol-3-ylidenemethyl)- phenoxy]-2,2-dimethyl-propionic acid methyl ester (7 g, 16.7 mmol) in DCM (20 ml_) at r.t. was added di-teret-butyl-dicarbonate (5.4 g, 25 mmol), followed by the addition of 4- dimethylaminopyhdine (0.2 g, 1.7 mmol). The reaction mixture was stirred for 2h and washed with 0.5 N hydrochloric acid, then the solvent was removed to give title compound (Yield: 8 g).
Example 2Oe
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2- methoxycarbonyl-2-methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000053_0002
M.W.599.49 C3IH29CI2FN2O5
In a manner similar to the method described in Example 1 e, E/Z -6-chloro-3-[5-chloro-2- (2-methoxycarbonyl-2-methyl-propoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (4.5 g, 9 mmol) was reacted with 1 -(5-Fluoro-2- methylphenyl)- 3-thmethylsilyoxy- 2-aza-1 ,3-butadiene (63 mmol) in toluene to give title compound as a white solid (Yield: 300 mg, 5.5%). m/z (M+H)+: 599 Example 2Of
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2- hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000054_0001
M.W.585.46 C30H27CI2FN2O5
A mixture of 330 mg racemic (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2-methoxycarbonyl- 2-methyl-propoxy)-phenyl]-2'-(5-fluoro-2- methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (330 mg, 0.55 mmol), NaOH (80 mg, 2 mmol), H2O (5 ml_) and methanol (10 ml_) was heated at 6O 0C for 2 h. Then the methanol was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid to "pH" 2. The white precipitate was collected by filtration to give title compound (Yield: 250 mg) .
Example 2Og
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2,2-dimethyl-3-oxo-3- pyrrolidin-1 -yl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000054_0002
M.W. 638.57 C34H34CI2FN3O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2- methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (40 mg, 0.07 mmol ), pyrrolidine (0.0083 ml_, 0.1 mmol), EDCHCI (20 mg, 0.1 mmol),and HOBt (14 mg, 0.1 mmol) in THF (5 ml_) was added DIPEA (0.018 ml_, 0.2 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg). m/z (M+H)+: 638
Example 21
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-dimethylcarbamoyl- 2- methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl)- spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000055_0001
M.W. 612.53 C32H32CI2FN3O4
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl- 2- methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (40 mg, 0.07 mmol ), dimethylamine hydrochloric salt (8.2 mg, 0.1 mmol), EDCHCI (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 ml_) was added DIPEA (0.018 ml_, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg). m/z (M+H)+: 612
Example 22a Preparation of intermediate (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester
Figure imgf000055_0002
M.W. 228.63 Ci0H9CIO4
5-Chloro-2-hydroxy-benzaldehyde (30 g, 192 mmol), bromo-acetic acid methyl ester (29.4 g, 192 mmol), K2CO3 (53 g, 384 mmol) and Kl (9.6 g, 57 mmol) were mixed in acetone (100 ml_). Then the mixture was heated at 80 0C for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolve in ethyl acetate and washed with base aqueous solution(1 N NaOH). The organic layer was separated, dried and concentrated to give (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester yellow solid. (44 g)
Example 22b
Preparation of intermediate E/Z-[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-acetic acid methyl ester
Figure imgf000056_0001
M.W. 378.21 Ci8Hi3CI2NO4 In a manner similar to the method described in Example 227b, (4-chloro-2-formyl- phenoxy)-acetic acid methyl ester (34 g, 149 mmol) was reacted with 6-chlorooxindole (20.7 g, 124 mmol) and pyrrolidine (10.58 g, 149 mmol) in methanol to give title compound as a yellow solid (35 g).
Example 22c
Preparation of intermediate E/Z -6-chloro-3-(5-chloro-2-methoxycarbonylmethoxy- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000056_0002
M.W. 478.33 C23H2ICI2NO6 In a manner similar to the method described in Example 227c, E/Z-[4-Chloro-2-(6- chloro^-oxo-i ^-dihydro-indol-S-ylidenemethylJ-phenoxyl-acetic acid methyl ester (35 g, 92.8 mmol) was reacted with diteret-butyl-dicarbonate (22.3 g, 102 mmol) and DMAP (2.3 g, 18.6 mmol) in CH2Cb to give title compound as yellow oil (30 g).
Example 22d
Preparation of intermediate 1-(2,5-difluoro-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000057_0001
M.W. 255.34 Ci2Hi5F2NOSi
To dry tetrahydrofuran (100 ml_) was added 1 M THF solution of LiHMDS (105 mmol, 105 ml_) under nitrogen at room temperature, followed by the addition of 2,5- difluorobenzaldehyde (14.9 g, 105 mmol) . After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (13.3 ml_, 105 mmol) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (19 ml_, 136 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (3.88 ml_, 54.4 mmol) in diethyl ether (300 ml). The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give 1 -(2,5-difluoro-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 22e Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2- methoxycarbonyl-methoxy)-phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000058_0001
M.W.561.37 C27H20CI2F2N2O5
In a manner similar to the method described in Example 1 e, E/Z-6-Chloro- 3-(5-chloro- 2- methoxycarbonylmethoxy-benzylidene)-2-oxo-2,3-dihydro- indole-1 -carboxylic acid tert-butyl ester (9.5 g, 20 mmol) was reacted with 1 -(2,5-difluoro-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (60 mmol) in toluene to give title compound as a white solid (Yield: 1.5 g). m/z (M+H)+: 561
Example 22f
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- hydroxycarbonyl- methoxy) -phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000058_0002
M.W.547.35 C26Hi8CI2F2N2O5
A mixture of (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methoxycarbonyl- methoxy) - phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione (600 mg,1.07 mmol), NaOH(120 mg, 3 mmol), H2O (5 ml_) and methanol (5 ml_) was heated at 6O 0C for 2 h. Then the methanol was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid (1.5 ml_) to "pH" 2. The white precipitate was collected by filtration to give title (Yield: 500 mg). m/z (IvRH)+: 547 Example 22g
Preparation of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-{[(2-hydroxy- ethyl )-methyl- carbamoyl]-methoxy}- phenyl]-2'-[2,5-difluorophenyl] spiro[3H- indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000059_0001
M.W. 604.44 C29H25CI2FN3O5
To a mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-hydroxycarbonyl- methoxy)-phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (76 mg, 0.14 mmol ), 2-methylamino-ethanol (0.018 ml_, 0.21 mmol), EDCHCI (40 mg, 0.21 mmol), and HOBt (28 mg, 0.21 mmol) in THF (5 ml_) was added DIPEA (0.036 ml_, 0.4 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 36mg). m/z (M+H)+: 604
Example 23 Preparation of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- dimethylcarbamoylmethoxy-phenyl]-2'-(2,5-difluorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000059_0002
M.W. 574.42 C28H23CI2FN3O4 To a mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-hydroxycarbonyl- methoxy) -phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (76 mg, 0.14 mmol ), dimethylamine hydrochloric salt (17 mg, 0.21 mmol), EDCHCI (40 mg, 0.21 mmol), and HOBt (28 mg, 0.21 mmol) in THF (5 ml_) was added DIPEA(0.036 ml_, 0.4 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg). m/z (IvRH)+: 574
Example 24
Preparation of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-oxo- 2-pyrrolidin-1-yl- ethoxy) -phenyl]-2'-(2,5-difluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000060_0001
M.W. 600.45 C30H25CI2F2N3O4
To a mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl- methoxy) -phenyl]-2'-[2,5-difluorophenyl] spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (76 mg, 0.14 mmol ), pyrrolidine (0.017 ml_, 0.21 mmol), EDCHCI (40 mg, 0.21 mmol),and HOBt (28 mg, 0.21 mmol) in THF (5 ml_) was added DIPEA (0.036 ml_, 0.4 mmol) at rt. The reaction mixture was stirred for 4h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 33 mg). m/z (M+H)+: 600 Example 25a
Preparation of intermediate racemic (2'S, 3S, 4'R)- 4'-[5-bromo-2- (2-ethoxycarbonyl-2- methyl-ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000061_0001
M.W.660.40 C3IH29BrCI2N2O5
In a manner similar to the method described in Example 1 e, 3-[5-bromo-2- (1 - ethoxycarbonyl-i-methyl-ethoxyJ-benzylidenel-θ-chloro^-oxo^.S-dihydro-indole-i - carboxylic acid tert-butyl ester (3.9 g, 8 mmol) was reacted with 1 -(5-chloro-2- methylphenyl)-3- thmethylsilyoxy-2- aza- 1 ,3- butadiene (21 mmol) in toluene to give the title compound as a white solid (Yield: 600 mg ).
Example 25b Preparation of intermediate racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(2- hydroxycarbonyl-2- methyl-ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000061_0002
M.W.632.34 C29H25BrCI2N2O5 A mixture of racemic (2'S, 3S, 4'R)- 4'-[5-bromo-2- (2-ethoxycarbonyl-2-methyl-ethoxy)- phenyl]-6-chloro-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (200 mg, 0.3 mmol), NaOH (40 mg, 1 mmol), H2O (5 ml_) and THF (5 ml_) was heated at 8O 0C for 2 h. Then THF was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid (1.5 ml_) to "pH" 2. The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg). m/z (IvRH)+: 631 Example 25c
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-bromo-2-(1- dimethylcarbamoyl-1- methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000062_0001
M.W. 659.41 C3IH30BrCI2N3O4
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(2- hydroxycarbonyl-2-methyl- ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (44 mg, 0.07 mmol ), dimethylamine hydrochloric salt (17 mg, 0.21 mmol), EDCHCI (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 ml_) was added DIPEA (0.018 ml_, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 14 mg). m/z (IvRH)+: 659
Example 26a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000062_0002
M.W. 598.51 C3IH30CI2FN3O4 A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2- methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione in Example 1f (150 mg, 0.263 mmol), dimethylamine hydrochloride (43 mg, 0.526 mmol), EDCHCI (100 mg, 0.526 mmol), HOBt (71 mg, 0.526 mmol) and DIPEA (204 mg, 1.579 mmol) in anhydrous THF (3 ml_) was stirred at room temperature overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give title compound as a white solid (50 mg). m/z (M+H)+: 598
Example 26b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- dimethylcarbamoyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000063_0001
M .W. 598.51 C3IH30CI2FN3O4 Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'- [5-chloro- 2- (1 -dimethylcarbamoyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (RO5215923-000, 10 mg) was conducted by chiral column to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -dimethylcarbamoyl- 1- methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (1.4 mg) (RO5217765-000) and chiral (2'R, 3R, 4'S)-6- chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl- 1-methyl-ethoxy)-phenyl]- 2'-(5-fluoro-2- methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (2 mg) (RO5217766-000). m/z (M+H)+: 598
Example 27
Preparation of racemic (2'S, 3S, 4'R)-4'-{2-[2- (4-acetyl-piperazin-1-yl)-1 ,1 -dimethyl-2- oxo-ethoxy]-5-chloro-phenyl}-6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000064_0001
M.W. 681.60 C35H35CI2FN4O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-hydroxycarbonyl- 2- methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-nnethyl- phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione (150 mg, 0.263 mmol) , /V-acetylpiperazine (67 mg, 0.526 mmol),
EDCHCI (100 mg, 0.526 mmol), HOBt (71 mg, 0.526 mmol) and DIPEA (204 mg, 1.579 mmol) in anhydrous THF (3 ml_) was stirred at room temperature overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep- HPLC to give title compound as a white solid (40 mg). m/z (M+H)+: 681
Example 28
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1- (2,2,2- trifluoro-ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000064_0002
M .W. 652.48 C3IH27CI2F4N3O4
In a manner similar to the method described inExample 27, racemic (2'S, 3S, 4'R)-6- chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2-methyl- ethoxy)- phenyl]-2'- (5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione (150 mg, 0.263 mmol) was reacted with 2,2,2- trifluoroethylamine hydrochloride (71 mg, 0.526 mmol), EDCHCI (100 mg, 0.526 mmol), HOBt (71 mg, 0.526 mmol) and DIPEA (204 mg, 1.579 mmol) in anhydrous THF (3 ml_) to give title compound as a white solid (50 mg). m/z (M+H)+: 652 Example 29a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1- yl)-1 ,1 -dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000065_0001
M.W. 674.55 C34H32CI2F3N3O4
In a manner similar to the method described in Example 27, racemic (2'S, 3S, 4'R)-6- chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-ethoxy)- phenyl]-2'- (5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione (150 mg, 0.263 mmol) was reacted with 4,4-difluoropiperidine hydrochloride (83 mg, 0.526 mmol), EDCHCI (100 mg, 0.526 mmol), HOBt (71 mg, 0.526 mmol) and DIPEA (204 mg, 1.579 mmol) in anhydrous THF (3 ml_) to give title compound as a white solid (40 mg). m/z (IvRH)+: 674
Example 29b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1 - yl)-1 ,1 -dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000065_0002
M.W. 674.55 C34H32CI2F3N3O4
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'- {5-chloro-2- [ 2-(4,4-difluoro-piperidin-1-yl)-1 ,1 -dimethyl-2-oxo-ethoxy]- phenyl}-2'- (5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione (RO5215926-000, 30 mg) was conducted by chiral column to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-{5- chloro-2-[ 2-(4,4- difluoro- piperidin-1-yl)-1 ,1 - di methyl -2-oxo- ethoxy]-phenyl}-2'-(5- fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione as a white solid (9 mg) (RO5217767-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'- {5-chloro-2-[ 2-(4,4- difluoro-piperidin-1 -yl)-1 ,1-dinnethyl-2-oxo-ethoxy]- phenyl}-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (8 mg) (RO5217769- 000). m/z (M+H)+: 674
Example 30a Preparation of intermediate 5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde
Figure imgf000066_0001
M.W. 240.69 Ci2Hi3CIO3
A mixture of 5-chloro-2-hydroxy-benzaldehyde (4.5 g, 29 mmol), toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester in Example 13c (6.4 g, 25 mmol) and K2CO3 (8 g, 58 mmol) in anhydrous N,N-dimethylformamide (40 ml_) was heated at 100 0C for 1 h. Then the mixture was filtered and the filtrate was concentrated. The residue was dissolve in EtOAc (50 ml_). The solution was washed with water, dried and concentrated to give title compound as a yellow oil (5.2 g).
Example 30b
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(3-methyl-oxetan- 3-ylmethoxy)- benzylidene]-1 ,3-dihydro-indol-2-one
Figure imgf000066_0002
M.W. 390.27 C20Hi7CI2NO3 To the mixture of 5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde (2 g, 8.3 mmol) and 6-Chloro-1 ,3-dihydro-indol-2-one(1.27 g, 7.6 mmol) in methanol (20 ml_) was added pyrrolidine (0.6 g, 9.1 mmol) dropwise. The mixture was then heated at 70 0C for 2 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give title compound as a yellow solid (2.3 g).
Example 30c Preparation of intermediate E/Z- 6-Chloro-3-[5-chloro-2-(3-methyl-oxetan- 3-ylmethoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester
Figure imgf000067_0001
M.W. 490.39 C25H25CI2NO5
At room temperature, to a solution of E/Z- 6-Chloro-3-[5-chloro-2- (3-methyl- oxetan-3- ylmethoxy)-benzylidene]-1 ,3-dihydro-indol-2-one (2.3 g) in DCM (30 ml_) was added Di- te/t-butyl-dicarbonate (1.5 g), followed by the addition of 4-dimethylaminopyhdine (0.072 g). After stirring for 0.5 h at room temperature, the solution was washed with 0.5/V HCI aqueous solution twice, dried over anhydrous Na2SO4 and concentrated to give title compound as a yellow oil (2.5 g).
Example 3Od
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (3-methyl-oxetan-3- ylmethoxy) -phenyl]-2'-(5-fluoro-2-methyl- phenyl )-spiro[3H-indole-3, 3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000067_0002
M.W. 569.47 C30H27CI2FN2O4
To a solution of 1-(5-fluoro -2-methyl-phenyl)-3-thmethylsilyoxy- 2-aza-1 ,3-butadiene (7.1 mmol) in anhydrous toluene (7 ml_) was added E/Z- θ-Chloro-S-β-chloro- 2-(3- methyl-oxetan-3-ylmethoxy)-benzylidene]- 2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (0.7 g, 1.4 mmol). The solution was stirred under Ar in a sealed tube at 140 0C for 3 h. After the solution was cooled to room temperature and concentrated, the residue was purified by chromatography (DCM:CH3OH =50:1 ) to give crude product. The crude product was purified again by Prep-HPLC to give title compound as a white solid (12 mg). m/z (M+H)+: 569
Example 31a
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-2'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000068_0001
M.W. 603.45 C30H26CI2F2N2O5
To a solution of 1-(2,5-difluoro-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene in Example 22d (30.8 mmol) in anhydrous toluene (30 ml_) was added E/Z 6-Chloro-3- [5- chloro-2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester in Example 1 c (8 g,15.4 mmol). The solution was heated to 80 0C for 5 h under Ar. After the solution was cooled to room temperature and concentrated, the residue was purified by chromatography (DCM:CH3OH =50:1 ) to give title compound as a white solid (1.7 g). m/z (IvRH)+: 603
Example 31b
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2- hydroxycarbonyl-2-methyl-ethoxy) -phenyl]-2'-(2,5-difluoro phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000068_0002
M.W. 575.40 C28H22CI2F2N2O5 A mixture of racemic (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2-ethoxycarbonyl-2-methyl- ethoxy) -phenyl]-2'-(2,5-difluoro phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (400 mg), NaOH (111 mg), H2O (5 ml_) and THF (10 ml_) was heated at 800C for 1 h. Then THF was removed by vacuum. The water solution was acidified by concentrated hydrochloric acid to "pH" 1. The white precipitate was collected by filtration to give title compound as a white solid (300 mg). m/z (IvRH)+: 575
Example 31c Preparation of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 - methyl-ethoxy) -phenyl]-2'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000069_0001
M.W. 602.47 C30H27CI2F2N3O4 A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- hydroxycarbonyl-2- methyl-ethoxy) -phenyl]-2'-(2,5-difluoro phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (100 mg, 0.174 mmol), dimethylamine hydrochloride (28 mg, 0.348 mmol), EDCHCI (66 mg, 0.348 mmol), HOBt (47 mg, 0.348 mmol) and DIPEA (135 mg, 1.044 mmol) in anhydrous DMF (3 ml_) was stirred at room temperature overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (50 mg). m/z (IvRH)+: 602
Example 32a Preparation of intermediate (2-Bromo-ethyl)-carbamic acid tert-butyl ester
Figure imgf000069_0002
At room temperature, to a mixture of Di-te/t-butyl-dicarbonate(17.8 g) and DIPEA(11.6 g) in EtOH (200 ml_) was added 2-aminoethylbromide hydrobromide (20 g). After stirring for 3h, the solution was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with water for 3 times, dried over anhydrous 82SO4 and concentrated to give title compound as a light yellow oil (15 g).
Example 32b
Preparation of intermediate [2-(4-chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert- butyl ester
Figure imgf000070_0001
M.W. 299.76 Ci4Hi8CINO4 In a manner similar to the method described in Example 1 a, (2-bromo-ethyl)-carbamic acid tert-butyl ester (10 g, 44.8 mmol) was reacted with 5-chloro-2-hydroxy- benzaldehyde (7 g, 44.8 mmol), K2CO3 (18.6 g, 134 mmol) and Kl (1.48 g, 8.96 mmol) to give title compound as a oil (9.56 g)
Example 32c
Preparation of intermediate E/Z -{2-[4-Chloro-2-(6-chloro-2-oxo-1 ,2- dihydro-indol-3-ylidenemethyl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester
Figure imgf000070_0002
M.W. 449.34 C22H22CI2N2O4 In a manner similar to the method described in Example 1 b, [2-(4-Chloro-2-formyl- phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-chloro- 1 ,3-dihydro-indol-2-one(4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol (70 ml_) to give title compound as a yellow solid (16 g).
Example 32d
Preparation of intermediate E/Z- 3-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-chloro- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester
Figure imgf000071_0001
M.W. 549.46 C27H30CI2N2O6
In a manner similar to the method described in Example 1 c, E/Z- {2-[4-chloro-2- (6- chloro-2-oxo- 1 ,2-dihydro-indol-3-ylidenemethyl)- phenoxy]-ethyl}-carbamic acid tert- butyl ester (12 g,30, 27 mmol) was reacted with di-tert-butyl-dicarbonate (5.8 g, 27 mmol) and DMAP (0.66 g, 5.4 mmol) in CH2CI2 (150 ml_) to give title compound as a yellow solid (12.4 g)
Example 32e Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5-chloro-phenyl]-6-chloro- 2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000071_0002
M.W. 528.42 C27H24CI2FN3O3 In a manner similar to the method described in Example 1 e, E/Z-3-[2-(2-tert- butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole- 1 -carboxylic acid tert-butyl ester (4 g, 7.3 mmol) was reacted with 1 -(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy- 2-aza- 1 ,3-butadiene (29 mmol) in toluene and then trifluoroacetic acid (20 ml_) in dichloromethane (30 ml_) to give title compound as a white solid (130 mg) (RO5246764-000). m/z (M+H)+: 528
Example 32f
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- methanesulfonylamino- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000072_0001
M.W. 606.50 C28H26CI2FN3O5S
At 0 0C, to a mixture of racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5-chloro-phenyl]-6- chloro-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (40 mg, 0.076 mmol) and methanesulfonyl chloride (85 mg, 0.76 mmol) in DMF (1 ml_) was added triethylamine slowly (75 mg, 0.76 mmol). After stirring for 0.5 h, the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (20 mg). m/z (IvRH)+: 606 Example 32g
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000072_0002
M.W. 606.50 C28H26CI2FN3O5S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (5 mg) (RO5253420-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2- methanesulfonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (5 mg) (RO5253422-000). m/z (IvRH)+: 606 Example 33
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-[2- (3,3-dimethyl-ureido)- ethoxy]-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000073_0001
M.W. 599.49 C30H29CI2FN4O4
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5- chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (40 mg, 0.076 mmol), dimethylcarbamoyl chloride (41 mg, 0.379 mmol) and thethylamine (38 mg, 0.379 mmol) was stirred 0.5 h. Then the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (10 mg). m/z (M+H)+: 599
Example 34a
Preparation of intermediate 1-(5-chloro-2-fluoro-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000073_0002
M.W. 271.80 Ci2Hi5CIFNOSi
In a manner similar to the method described in Example 1d, 2-fluoro-5-chloro benzaldehyde (3 g, 19 mmol) was reacted with LiHMDS (1 M solution in THF, 19 ml_, 19 mmol), trimethylsilyl chloride (2.4 ml_, 19 mmol), thethylamine (3.44 ml_, 24.6 mmol) and acetyl chloride (1.75 ml_, 24.6 mmol) to give title compound and used for the next step without further purification. Example 34b
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2'-(5-chloro-2-fluoro-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000074_0001
M.W. 619.91 C30H26CI3FN2O5
In a manner similar to the method described in Examplel e, E/Z-6-chloro-3- [5-chloro-2- (i -ethoxycarbonyl-i-methyl-ethoxyJ-benzylidenel^-oxo^.S-dihydro-indole-i -carboxylic acid tert-butyl ester prepared in Example 1 c (1.04 g, 2 mmol) was reacted with 1 -(2- fluoro-5-chlorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.48 g)- m/z (M+H)+: 619
Example 34c
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-chloro-2-fluoro-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000074_0002
M.W. 591.86 C28H22CI3FN2O5
A mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethoxycarbonyl- 1 -methyl- ethoxy) -phenyl]-2'-(5-chloro-2-fluoro-phenyl) spiro [3H-indole-3,3'-pipehdine] -2,6'(1 H)- dione (185 mg), NaOH (120 mg), H2O (15 ml_) and methanol (5 ml_) was heated at 80 for 2h. Then the mixture was concentrated. The remaining aqueous solution was acidified to "pH" 1 by concentrated aqueous HCI solution. The white precipitate was collected by filtration to give title compound as a white solid (150 mg ). m/z (M+H)+: 591
Example 34d
Preparation of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 - methyl-ethoxy) -phenyl]-2'-(2-fluoro-5chloro-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000075_0001
M.W. 618.92 C30H27CI3FN3O4
A mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl -1- methyl-ethoxy) -phenyl]-2'-(5-chloro-2-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine] - 2,6'(1 H)-dione (30mg), dimethylamine hydrochloride (8.5mg), 4-dimethylamino pyridine (18mg), EDCI (21 mg) and DIPEA (129mg) in THF (4ml_) was stirred at room temperature overnight. Then the solvent was removed and the residue was separated by preparative HPLC to give title compound as white solid (7mg). m/z (M+H)+: 618.
Example 35a Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester
Figure imgf000075_0002
M.W. 335.16 Ci5HnBrO4 To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N1N- dimethylacetannide (30 ml_) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldhch). 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 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 35b Preparation of intermediate E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-benzoic acid methyl ester
Figure imgf000076_0001
M. W. 484.74 C23Hi5BrCINO4
In a manner similar to the method described in Examplel a, 6-chlorooxindole (1.6 g, 9.2 mmol) (Crescent) was reacted with 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester (2.8 g, 8.4 mmol) and pyrrolidine in methanol at 90 0C for 2 h to give EIZ-A-[A- bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-benzoic acid methyl ester as a bright yellow solid (Yield 3 g, 81 %).
Example 35c
Preparation of intermediate E/Z-3-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- benzylidene]-6-chloro-2-oxo-2,3 -dihydro-indole-1 -carboxylic acidtert-butyl ester
Figure imgf000077_0001
M.W. 584.86 C28H23BrCINO6
In a manner similar to the method described in Examplei b, E/Z-4-[4-bromo-2-(6-chloro- 2-0X0-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-benzoic acid methyl ester (3 g, 6.1 mmol) was reacted with di-te/t-butyl-dicarbonate (1.9 g, 8.7 mmol) (Aldrich) and 4- dimethylaminopyridine to give E/Z-3-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acidtert-butyl ester as an orange solid (Yield 3.2 g, 88%).
Example 35d
Preparation of intermediate 1-(3-chlorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000077_0002
M.W. 253.81 Ci2Hi6CINOSi To 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (2.18 ml_, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 ml_, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 ml_) was added, followed by the addition of 3-chloro-benzaldehyde (1.19 ml_, 10.5 mmol) (Aldrich). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 ml_, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added thethylamine (1.9 ml_, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 ml_, 13.6 mmol) in diethyl ether (50 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -(3-chlorophenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 35e
Preparation of racemic (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
Figure imgf000078_0001
M.W. 666.35 C32H23BrCI2N2O5
In a manner similar to the method described in Examplel e, E/Z-6-chloro-3-[5-bromo-2-
(4-methoxycarbonyl-phenoxy)-benzylidene]-2-oxo-
2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.2 g, 2 mmol) was reacted with 1 -
(3-chlorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (15 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a off white solid (0.6 g,
45%).
HRMS(ES+) m/z Calcd for C32H23BrCI2N2O5+ H [(IVRH)+]: 665.0240. Found: 665.0235
Example 36a Preparation of intermediate 1-(3-fluorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene
Figure imgf000078_0002
M.W. 237.35 Ci2Hi6FNOSi In a manner similar to the method described in example 35d, 3-fluoro-benzaldehyde (1.11 ml_, 10.5 mmol) (Fluka) was used as the starting material in place of 3-chloro- benzaldehyde to react with 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (2.18 ml_, 10.5 mmol), n- butyllithium (2.5 M, 4.2 ml_, 10.5 mmol), thmethylsilyl chloride (1.33 ml_, 10.5 mmol), triethylamine (1.9 ml_, 13.6 mmol) and acetyl chloride (0.97 ml_, 13.6 mmol) to give 1 -(3- fluorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 36b Preparation of racemic (2'S, 3S, 4'R)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)- phenyl]-6-chloro-4'-(3-fluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000079_0001
M.W. 649.90 C32H23BrCIFN2O5 In a manner similar to the method described in Examplel e, E/Z-6-chloro-3-[5-bromo-2- (4-methoxycarbonyl-phenoxy)-benzylidene]-2-oxo-
2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 1.7 mmol) was reacted with 1 - (3-fluorophenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10.5 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a off white solid (0.68 g, 58%). HRMS(ES+) m/z Calcd for C32H23BrCIFN2O5+ H [(IVRH)+]: 649.0536. Found: 649.0538.
Example 37a
Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000080_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)-piperidine-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 37a Preparation of intermediate E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-pipehdine-1 -carboxylic acid tert-butyl ester
Figure imgf000080_0002
M.W. 533.85 C25H26BrCIN2O4
To a mixture of 6-chlorooxindole (4. 58 g, 20 mmol) and 4-(4-bromo-2-formyl-phenoxy)- pipehdine-1 -carboxylic acid tert-butyl ester (10 g, 26mmol) in methanol (50 ml_) was added pipehdine (2.56 ml_, 26 mmol) dropwise. The mixture was then heated at 100 0C for 3 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (12.4 g, 90%).
Example 37c
Preparation of intermediate E/Z-3-[5-bromo-2-(1 -tert-butoxycarbonyl-pipehdin-4-yloxy)- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000081_0001
M.W. 633.97 C30H34BrCIN2O6
To a solution of E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)- phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (12.4 g, 23 mmol) in DCM (200 ml_) at r.t. was added di-tert-butyl-dicarbonate (9.27 g, 42.4 mmol) , followed by the addition of 4-dimethylaminopyhdine (0.13 g) and thethylamine (16 ml_, 114 mmol). The reaction mixture was stirred at 0 0C for 0.5 h and washed with 0.5N hydrochloric acid, dried over anhydrous Na2SO4, then the solvent was removed. The residue was purified by chromatography (20%EtOAc:hexanes) to give title compound as a yellow solid (Yield: 10.8 g, 74%).
Example 37d
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-piperidin-4- yloxy)-phenyl]-6-chloro-2'-(3-fluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000081_0002
M.W. 699.01 C34H34BrCIFN3O5
To a solution of 1-(3-fluoro-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene in example 36a (24 mmol) in toluene (100 ml_) was added E/Z-3-[5-bromo-2-(1 -tert-butoxycarbonyl- pipehdin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester (3.85 g, 6 mmol) . The reaction mixture was stirred under argon at 140 0C for 5 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography (20%-30%EtOAc:DCM) to give the title compound as a off white solid (Yield: 0.38 g ).
HRMS(ES+) m/z Calcd for C34H34BrCIFN3O5+ H [(IVRH)+]: 698.1427. Found: 698.1423.
Example 38a
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro- 2'-(5-fluorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000082_0001
M.W. 598.90 C29H26BrCIFN3O3
A solution of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-piperidin-4- yloxy)-phenyl]-6-chloro-2'-(3-fluorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (0.35 g, 0.5 mmol) in TFA (2 ml_) and dichloromethane (2 ml_) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1 N Na2CO3 aq. (50 ml_) and brine (50 ml_), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.21 g, 70%).
Example 38b
Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3-fluorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000082_0002
M.W. 640.93 C3IH28BrCIFN3O4
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-pipehdinyloxy)-phenyl]-6-chloro- 2'-(3-fluorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (60 mg, 0.1 mmol), acetyl chloride (9.4 mg, 0.12 mmol) in tetrahydrofuran (2 ml_) was added thethylamine (0.027 ml_, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated in dichloromethane and hexanes to give the title compound as a off white solid (Yield: 43 mg).
HRMS(ES+) m/z Calcd for C3IH28BrCIFN3O4+ H [(M+H)+]: 640.1009. Found: 640.1007
Example 39
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-piperidinyloxy)-phenyl]- 6-chloro-2'-(3-fluorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000083_0001
M.W. 612.92 C30H28BrCIFN3O3
To a mixture of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro- 2'-(3-fluorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (150 mg, 0.25 mmol) in methanol (10 ml_) was added an aqueous solution (37 wt%, Aldrich) of formaldehyde (0.03 ml_, 0.38 mmol) and NaCNBH3 (25 mg, 0.38 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 (MeOH:EtOAc:triethylamine = 12:88:5) to give racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1- methyl-4-pipehdinyloxy)-phenyl]- 6-chloro-2'-(3-fluorophenyl) spiro[3H-indole- 3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (Yield 100 mg, 65%).
HRMS(ES+) m/z Calcd for C30H28BrCIFN3O3+ H [(M+H)+]: 612.1060. Found: 612.1059.
Example 40
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-piperidin-4- yloxy)-phenyl]-6-chloro-2'-(3-chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000084_0001
M.W. 715.47 C34H34BrCI2N3O5
In a manner similar to the method described in Example 37d, 1 -(3-chloro-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene in example 35d (43 mmol) in was reacted with EIZ- 3-[5-bromo-2-(1 -tert-butoxycarbonyl-pipehdin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester in example 37c (10.8 g, 17 mmol) in toluene at 140 0C for 5 h to give the title compound as a yellow solid (Yield: 1.5 g ).
HRMS(ES+) m/z Calcd for C34H34BrCI2N3O5+ H [(IVRH)+]: 714.1132. Found: 714.1128
Example 41a
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro- 2'-(5-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000084_0002
M.W. 615.36 C29H26BrCI2N3O3
In a manner similar to the method described in Example 38a, racemic (2'S, 3S, 4'R)-4'- [5-bromo-2-(1- tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-6-chloro-2'-(3- chlorophenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (0.75 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane to give title compound as a yellow solid (Yield: 0.6 g, 93%).
Example 41b
Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-pipehdinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000085_0001
M.W. 657.39 C3IH28BrCI2N3O4
In a manner similar to the method described in Example 38b, racemic (2'S, 3S, 4'R)-4'- [5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2'-(3-chlorophenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (85 mg, 0.14 mmol) was reacted with acetyl chloride (13 mg, 0.17 mmol), thethylamine in tetrahydrofuran to give the title compound as a white solid (Yield: 43 mg).
HRMS(ES+) m/z Calcd for C3i H28BrCI2N3O4+ H [(IVRH)+]: 656.0713. Found: 656.0708
Example 42
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-piperidinyloxy)-phenyl]- 6-chloro-2'-(3-chlorophenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000085_0002
M.W. 629.38 C30H28BrCI2N3O3
In a manner similar to the method described in Example 39, racemic (2'S, 3S, 4'R)-4'- [5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2'-(chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (100mg, 0.16 mmol) in methanol (10 mL) was reacted with aqueous solution (37 wt%, Aldrich) of formaldehyde (0.02 mL, 0.24 mmol) and NaCNBH3 (15 mg, 0.24 mmol) in methanol to give the title compound as a white solid (Yield 57 mg, 57%).
HRMS(ES+) m/z Calcd for C30H28BrCI2N3O3+ H [(M+H)+]: 628.0764. Found: 628.0765. Example 43a
Preparation of intermediatel -(2-chloro-5-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000086_0001
M.W. 271.80 Ci2Hi5CIFNOSi
To dry tetrahydrofuran (200 ml_) was added 1 M THF solution of LiHMDS (210 ml_, 210 mmol) under Ar protection at room temperature, followed by the addition of 2-chloro-5- fluoro-benzaldehyde (33 g, 210 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (26.6 ml_, 210 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 (38 ml_, 273 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (20 ml_, 273 mmol) in diethyl ether (500 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 4 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(2-chloro-5-fluoro-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 43b
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2'-(2-chloro-5-fluoro-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000086_0002
M.W. 619.91 C30H26CI3FN2O5 In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2- (i -ethoxycarbonyl-i-methyl-ethoxyJ-benzylidenel^-oxo^.S-dihydro-indole-i -carboxylic acid tert-butyl ester (3 g, 5.76 mmol) was reacted with 1 -(2-chloro-5-fluoro-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (23 mmol) in toluene to give the title compound as a white solid (400 mg). m/z (M+H)+: 619
Example 43c
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-2'-(2-chloro-5-fluoro- phenyl)-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl-ethoxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000087_0001
M.W 591.86 C28H22CI3FN2O5 A mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethoxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(2-chloro-5-fluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (150 mg, 0.24 mmol), NaOH (70 mg, 1.75 mmol), H2O (2 ml_) and THF (6 ml_) was heated at 70 0C for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to "pH" 2-3 by addition of concentrated aqueous HCI. The white solid was collected by filtration to give the title compound which was used for next step reaction without further purification. m/z (M+H)+: 591
Example 43d
Preparation of racemic (2'R, 3S, 4'R)-6-chloro-2'-(2-chloro-5-fluoro-phenyl)-4'-[5-chloro- 2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000088_0001
M.W 668.96 C29H25CI3FN3O6S
A solution of racemic (2'R, 3S, 4'R)-6-chloro-2'-(2-chloro-5-fluoro-phenyl)-4'-[5-chloro-2- (1 -hydroxycarbonyl-1 -methyl-ethoxy)-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (143 mg, 0.24 mmol) and CDI (78 mg, 0.48 mmol) in DMF (5 ml_) was stirred at room temperature for 30 min. Then to this solution was added a mixture of methanesulfonamide (475 mg, 5 mmol) and NaH (200 mg, 60%, 5 mmol) in DMF (5 ml_), which had been stirred for 1 h at room temperature. After the resulting mixture was heated at 60 0C for 1 h, it was poured into water (5 ml_) and the mixture was acidified by concentrated aqueous HCI, extracted with EtOAc twice. The combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg). m/z (M+H)+: 668
Example 44 Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1- dimethyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000088_0002
M.W. 634.56 C30H30CI2FN3O5S At 0 0C, to a solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2- methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (20 mg, 0.03 mmol) prepared in Example 12b in THF (1 ml_) was added a toluene solution (1 M) of DIBALH (0.18 ml_, 0.18 mmol) in one portion. After stirred for 0.5 h, the mixture was quenched with water. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (9 mg). m/z (M+H)+: 634
Example 45
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methoxylcarbamoyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000089_0001
M.W. 600.48 C30H28CI2FN3O5
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (30 mg, 0.05 mmol) prepared in Example 1f, EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 ml_) was added o- methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (11 mg). m/z (M+H)+: 600
Example 46
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyanocarbamoyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000089_0002
M.W. 595.46 C30H25CI2FN4O4 To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (30 mg, 0.05 mmol) prepared in Example 1f, EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (20 mg, 0.15 mmol) in THF (1 ml_) was added cyanamide (50% in H2O) (20 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (14 mg). m/z (IvRH)+: 595
Example 47
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbamoyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione
Figure imgf000090_0001
M.W. 586.45 C29H26CI2FN3O5
To a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (30 mg, 0.053 mmol) prepared in Example 1f, EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 ml_) was added hydroxylamine hydrochlohde( (18 mg, 0.26 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (14 mg). m/z (IvRH)+: 586
Example 48a
Preparation of intermediate E/Z-2-[2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)- 4-fluoro-phenoxy]-2-methyl-propionic acid ethyl ester
Figure imgf000091_0001
M.W 403.84 C2iHi9CIFNO4
To the mixture of 6-chlorooxindole (5.3 g, 31.7 mmol) and 2-(4-fluoro-2-formyl- phenoxy)-2-methyl-propionic acid ethyl ester (8 g, 31.7 mmol) in methanol (30 ml_) was added pyrrolidine (2.6 ml_, 31.7 mmol) dropwise. Then the mixture was heated at 70 0C for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (10 g).
Example 48b Preparation of intermediate E/Z-6-chloro-3-[2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-5- fluoro-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000091_0002
M.W. 503.96 C26H27CIFNO6 To a solution of E/Z-2-[2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-4-fluoro- phenoxy]-2-methyl-propionic acid ethyl ester (5 g, 12 mmol) in dichloromethane (50 ml_) at room temperature was added di-tert-butyl-dicarbonate (3.1 g, 14 mmol), followed by the addition of 4-dimethylaminopyhdine (0.15 g, 1.2 mmol). After the reaction mixture was stirred at room temperature for 2 h, the solution was washed with HCI aq. (1 M) and brine twice, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow solid (6.5 g ).
Example 48c
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-fluoro-2-(1 - ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000092_0001
M.W. 583.04 C31 H29CI F2N2O5
In a manner similar to the method described in Example 1e, E/Z-6-Chloro-3-[2-(1- ethoxycarbonyl-1-methyl-ethoxy)-5-fluoro-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1 -(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (40 mmol) in toluene to give the title compound as a white solid (800 mg). m/z (IvRH)+: 583
Example 48d
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-fluoro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000092_0002
M.W 554.98 C29H25CIF2N2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-fluoro-2-(1-ethoxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (300 mg, 0.52 mmol), NaOH (41 mg, 1.03 mmol), H2O (1 ml_) and THF (10 ml_) was heated at 65 0C for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to "pH" 2-3 by addition of concentrated aqueous HCI. The white solid was collected by filtration, dried to give the title compound
(200 mg). m/z (M+H)+: 555 Example 48e
Preparation of racemic (2'S, 3S, 4'R)-6-chloro- 4'-[5-fluoro-2-(2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000093_0001
M.W 632.09 C30H28CIF2N3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-fluoro-2-(1-hydroxycarbonyl-1-methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (100 mg, 0.18 mmol) and CDI (58 mg, 0.36 mmol) in DMF (5 ml_) was heated at 60 0C for 0.5 h. Then to this solution was added a mixture of methanesulfonamide (475 mg, 5 mmol) and NaH (200 mg, 60%, 5 mmol) in DMF (5 ml_),which had been stirred for 1 h at room temperature. After the resulting mixture was stirred at room temperature for 0.5 h, it was poured into water (5 ml_) and the aqueous solution was acidified to "pH" 2- 3 by concentrated aqueous hydrochloride. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (80 mg). m/z (M+H)+: 632
Example 49a Preparation of intermediate 5-chloro-2-(4-methoxy-phenoxy)-benzaldehyde
Figure imgf000093_0002
M.W 262.69 Ci4HiiCIO3 At the room temperature, anhydrous Na2CO3 (16 g, 0.15 mol) was added into a mixuter of 4-methoxy-phenol (14.8 g, 0.12 mol) and 5-chloro-2-fluoro-benzaldehyde (16 g, 0.10 mol) in N,N-Dimethylacetamide (100 ml_). After the mixture was refluxed for 3 h, it was cooled to room temperatue. Then DCM and water were added. The organic phase was separated, washed with aqueous NaOH (1 N) and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (16 g).
Example 49b
Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(4-methoxy-phenoxy)- benzylidene]-1 ,3-dihydro-indol-2-one
Figure imgf000094_0001
M.W 412.28 C22Hi5CI2NO3
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 5-chloro-2-(4-methoxy- phenoxy)-benzaldehyde (13 g, 49.7 mmol) in methanol (100 ml_) was added pyrrolidine (4.1 ml_, 49.5 mmol) dropwise. The mixture was then heated at 70 0C for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Example 49c
Preparation of intermediate E/Z-6-Chloro-3-[5-chloro-2-(4-methoxy-phenoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester
Figure imgf000094_0002
M.W. 512.39 C27H23CI2NO5 To a solution of E/Z-6-chloro-3-[5-chloro-2-(4-methoxy-phenoxy)-benzylidene]-1 ,3- dihydro-indol-2-one (15.5 g, 38 mmol) in dichloromethane (100 ml_) at room temperature was added di-tert-butyl-dicarbonate (12.3 g, 56 mmol), followed by the addition of 4-dimethylaminopyridine (0.46 g, 3.8 mmol). After the reaction mixture was stirred at room temperature for 2 h, the solution was washed with 1 M HCI solution and brine twice, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow solid (16.5 g).
Example 49d
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-methoxy-phenoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000095_0001
M.W. 591.47 C32H25CI2FN2O4
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2- (4-methoxy-phenoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3-thmethylsilyoxy-2- aza-1 ,3-butadiene (50 mmol) in toluene to give the title compound as a white solid (160 mg). m/z (IvRH)+: 591
Example 50a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert- butoxycarbonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000095_0002
M.W. 628.53 C32H32CI2FN3O5 In a manner similar to the method described in Examplele, E/Z-3-[2-(2-tert- butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole- 1 -carboxylic acid tert-butyl ester (8 g, 14.6 mmol) prepared in Example 32d was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (43.8 mmol) in toluene (22 ml_) to give the title compound as a white solid (830 mg). m/z (M+H)+: 628
Example 50b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000096_0001
M.W. 628.53 C32H32CI2FN3O5
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-tert-butoxycarbonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (40 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (RO5252565-000,13 mg) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2- tert-butoxycarbonylamino-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (RO5252566-000,10 mg). m/z (M+H)+: 628
Example 51 Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[(2-cyclobutanecarbonyl- amino)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000097_0001
M.W. 610.52 C32H30CI2FN3O4
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5- chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (100 mg, 0.189 mmol) prepared in Example 32e, cyclobutanecarboxylic acid (98 mg, 0.948 mmol), EDCHCI (181 mg, 0.948 mmol), HOBt (128 mg, 0.948 mmol) and DIPEA (245 mg, 1.897 mmol) in anhydrous DMF (4 ml_) was stirred overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (19 mg). m/z (M+H)+: 610
Example 52a Preparation of intermediate toluene-4-sulfonic acid 1 -cyano-cyclopropyl methyl ester
Figure imgf000097_0002
M.W 251.31 Ci2Hi3NO3S
At 0 0C, to a solution of 1 -hydroxymethyl-cyclopropanecarbonithle (3.7 g, 38 mmol) in CH2CI2 (40 ml_) was added pyridine (3.62 g, 45.8 mmol) and p-toluenesulfonyl chloride (7.27 g, 38 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification.
Example 52b Preparation of intermediate 1-(4-chloro-2-formyl-phenoxymethyl)- cyclopropanecarbonithle
Figure imgf000098_0001
To a solution of the crude toluene-4-sulfonic acid i-cyano-cyclopropyl methyl ester in DMF (30 ml_) was added 5-chloro-2-hydroxy-benzaldehyde (5.9 g, 38 mmol) and K2CO3 (10.5 g, 76 mmol) slowly. The reaction mixture was placed in a sealed tube and irradiated by microwave reactor at 75 0C for 30 min. After cooled to room temperature, the mixture was poured into water. The solution was diluted with EtOAc (200 ml_), washed with water, dried and concentrated to give the title compound as a black oil (4.76 g). The oil was used for next step reaction directly without further purification.
Example 52c
Preparation of intermediate E/Z-1 -[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethylj-phenoxymethylj-cyclopropanecarbonithle
Figure imgf000098_0002
M.W. 385.25 C20Hi4CI2N2O2
In a manner similar to the method described in Example 1b, 1 -(4-chloro-2-formyl- phenoxymethyl)-cyclopentanecarbonithle (4.7 g, 20 mmol) was reacted with 6- chlorooxindole (2.78 g, 16.67 mmol) and pyrrolidine (1.54 g, 21.67 mmol) in methanol to give the title compound as a yellow solid (3.43 g).
Example 52d
Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(1-cyano-cyclopropylmethoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester
Figure imgf000099_0001
M.W. 485.37 C25H22CI2N2O4
In a manner similar to the method described in Example 1c, E/Z-1-[4-chloro-2-(6- chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxymethyl]- cyclopropanecarbonitrile (3.43 g, 8.93 mmol) was reacted with di-te/t-butyl-dicarbonate (4.68 g, 21.44 mmol) and 4-dimethylaminopyhdine (0.109 g, 0.893 mmol) in CH2CI2 to give the title compound as a red oil (4 g).
Example 52e Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyano-2- cyclopropyl-methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000099_0002
M.W. 564.45 C30H24CI2FN3O3
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro- 2-(1 -cyano-cyclopropylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (4 g, 8.25 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3- thmethylsilyoxy-2-aza-1 ,3-butadiene (40 mmol) in toluene (40 ml_) and then trifluoroacetic acid (10 ml_) in dichloromethane (30 ml_) to give the title compound as a white solid (60 mg). m/z (M+H)+: 564 Example 52f
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyano-2-cyclopropyl- methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000100_0001
M.W. 564.45 C30H24CI2FN3O3
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-cyano-2- cyclopropyl-methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (40 mg) was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyano-2- cyclopropyl-methoxy)-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (9 mg) (RO5259160-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2-cyano-2- cyclopropyl-methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (5 mg) (RO5259161 -000). m/z (IvRH)+: 564
Example 53a
Preparation of intermediate toluene-4-sulfonic acid 1 -cyano-cyclopentyl methyl ester
Figure imgf000100_0002
M.W 279.36 Ci4Hi7NO3S
At 0 0C, to a solution of 1 -hydroxymethyl-cyclopentanecarbonithle (10 g, 79.9 mmol) in CH2CI2 (100 ml_) was added pyridine (6.3 g, 79.9 mmol) and p-toluenesulfonyl chloride (12.18 g, 63.9 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification. Example 53b
Preparation of intermediate 1-(4-chloro-2-formyl-phenoxymethyl)- cyclopentanecarbonitrile
Figure imgf000101_0001
M.W 263.73 Ci4Hi4CINO2
To a solution of the crude toluene-4-sulfonic acid 1-cyano-cyclopentyl methyl ester in DMF (70 ml_) was added 5-chloro-2-hydroxy-benzaldehyde (12.48 g, 80 mmol) and K2CO3 (13.25 g, 96 mmol). After heated at 100 0C for 3 h, the reaction mixture was poured into water. The solution was diluted with EtOAc (200 ml_), washed with water, dried and concentrated to give the title compound as a yellow oil (17.4 g). The oil was used for next step reaction directly without further purification.
Example 53c Preparation of E/Z-1 -[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)- phenoxymethyl]-cyclopentanecarbonithle
Figure imgf000101_0002
M.W. 413.31 C22Hi8CI2N2O2
In a manner similar to the method described in Example 1b, 1 -(4-chloro-2-formyl- phenoxymethyl)-cyclopentanecarbonithle (17.4 g, 66 mmol) was reacted with 6- chlorooxindole (8.5 g, 51 mmol) and pyrrolidine (4.69 g, 66 mmol) in methanol to give the title compound as a yellow solid (19 g).
Example 53d Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(1-cyano-cyclopentylmethoxy)- benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester
Figure imgf000102_0001
M.W. 513.43 C27H26CI2N2O4
In a manner similar to the method described in Example 1c, E/Z-1-[4-chloro-2-(6- chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxymethyl]- cyclopentanecarbonitrile (19 g, 46 mmol) was reacted with di-te/t-butyl-dicarbonate (15 g, 69 mmol) and 4-dimethylaminopyhdine (0.56 g, 4.6 mmol) in CH2CI2 to give the title compound as a yellow oil (14 g).
Example 53e Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyano- cyclopentyl-methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6'-dioxo spiro[indole-3,3'-pipehdine]-1-carboxylic acid te/t-butyl ester
Figure imgf000102_0002
M.W. 692.62 C37H36CI2FN3O5 To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (30 mmol) in toluene (30 ml_) was added E/Z-6-Chloro-3-[5-chloro-2-(1 -cyano- cyclopentylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6 g, 11.7 mmol). Then the reaction mixture were heated at 70 0C overnight. After the solution was cooled to room temperature, methanol was added. The solution was concentrated and the residue was purified by flash column to give the title compound as a white solid (500 mg). m/z (IvRH)+: 692 Example 53f
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyano-cyclopentyl- methoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione
Figure imgf000103_0001
M.W. 592.50 C32H28CI2FN3O3 racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyano- cyclopentyl-methoxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6'-dioxo spiro[indole-3,3'-piperidine]-1 - carboxylic acid te/t-butyl ester (100 mg) was dissolved in trifluoroacetic acid (5 ml_).
After stirred at room temperature for 0.5 h, the reaction mixture was concentrated and the residue was purified by recrystallization to give the title compound as a yellow solid
(38 mg). m/z (M+H)+: 592
Example 54a
Preparation of intermediate 4-Chloro-2-[1 ,3]dioxolan-2-yl-phenol
Figure imgf000103_0002
M.W. 200.62 C9H9CIO3
A mixture of 5-chloro-2-hydroxybenzaldehyde (20.0 g, 0.128 mol), ethane-1 ,2-diol (40.0 g, 0.644 mol) and p-toluenesulfonic acid monohydrate (0.44 g, 2.56 mmol) dissolved in toluene (200 ml_) was refluxed for 40 h with a dean-stark to remove water. After the reaction mixture was cooled to room temperature, EtOAc (200 ml_) was added. Then the organic phase was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light-yellow solid (24.6 g). Example 54b
Preparation of intermediate (4-Chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-acetonithle
Figure imgf000104_0001
M.W. 239.66 C11H10CINO3
At room temperature, 2-chloroacetonithle (12 g, 0.16 mol) was added into a mixture of 4-chloro-2-[1 ,3]dioxolan-2-yl-phenol (24.6 g, 0.123mol) and K2CO3 (34 g, 0.246 mol) in DMF (150 ml_). After the reaction mixture was heated at 100 0C for 3 h and cooled to room temperature, water was added. The aqueous phase was extracted with EtOAc twice, washed with saturated K2CO3 solution, water, and dried over anhydrous Na2SO4 to give crude (4-Chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-acetonitrile. The crude product was used for next step without further purification.
Example 54c
Preparation of intermediate (4-chloro-2-formyl-phenoxy)-acetonithle
Figure imgf000104_0002
M.W. 195.61 C9H6CINO2
At room temperature, a mixture of (4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-acetonitrile (28.68 g, 0.12 mol) and thfluoroacetic acid (41.04 g, 0.36 mol) in EtOAc (500 ml_) was stirred overnight. Then the solution was washed with water, saturated NaHCO3 solution twice, dried over anhydrous Na2SO4, and concentrated to give crude product (22 g). The crude product was directly used for next step without further purification.
Example 54d
Preparation of intermediate E/Z-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-acetonithle
Figure imgf000105_0001
M.W. 345.19 CI7HI0CI2N2O2
To the mixture of 6-chlorooxindole (18.4 g, 0.110 mol) and (4-chloro-2-formyl-phenoxy)- acetonitrile (21.5 g, 0.110 mol) in methanol (200 ml_) was added pyrrolidine (8.60 g, 0.121 mol) dropwise. Then the mixture was heated at 70 0C for 2 h. After cooled to room temperature, the mixture was filtered. The precipitate was collected and dried to give the title compound as a yellow solid (8.5 g).
Example 54e Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-cyanomethoxy-benzylidene)-2- oxo-2, 3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000105_0002
M.W. 445.31 C22Hi8CI2N2O4 To a solution of E/Z-[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)- phenoxy]-acetonithle (8.10 g, 23.46 mmol) in dichloromethane (100 ml_) at room temperature was added di-tert-butyl-dicarbonate (6.15 g, 28.16 mmol), followed by the addition of 4-dimethylaminopyhdine (0.86 g, 7.037 mmol). After the reaction mixture was stirred at room temperature for 2 h, the solution was washed with HCI aq. (0.5 M) and brine twice, dried over anhydrous Na2SO4 and concentrated to give the title compound as a red solid (8.70 g).
Example 54f
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
M.W. 524.38 C27H20CI2FN3O3
In a manner similar to the method described in Example 1Od, E/Z-6-chloro-3-(5-chloro- 2-cyanomethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 11 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza- 1 ,3-butadiene (44 mmol) in toluene to give the title compound as a white solid (100 mg). m/z (IvRH)+: 524
Example 54g Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000106_0002
M.W. 524.38 C27H20CI2FN3O3 Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- cyanomethoxy-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (70 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6- chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (18 mg) (RO5259573-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (30 mg) (RO5259574-000) m/z (M+H)+: 524 Example 55a
Preparation of intermediate 4-(4-chloro-2-formyl-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester
Figure imgf000107_0001
M.W. 324.81 Ci6H2ICIN2O3
A mixture of 5-chloro-2-fluoro-benzaldehyde (10 g, 63 mmol), Piperazine-1 -carboxylic acid tert-butyl ester (12g, 63 mmol), K2CO3 (17 g, 123 mmol) in DMF (60 ml_) was heated at 150 0C for 2 h. After cooled to room temperature, the mixture was poured into water (300 ml_) and partitioned between diethyl ether and water. The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a yellow solid (9 g).
Example 55b Preparation of intermediate E/Z-4-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenyl]-piperazine-1 -carboxylic acid tert-butyl ester
Figure imgf000107_0002
M.W. 474.39 C24H25CI2N3O3
In a manner similar to the method described in Example 1b, 4-(4-chloro-2-formyl- phenyl)-piperazine-1-carboxylic acid tert-butyl ester (8 g, 25 mmol) was reacted with 6- chlorooxindole (4.1 g, 25 mmol) and pyrrolidine (1.8 g, 25 mmol) in methanol (50 ml_) to give the title compound as a yellow solid (11 g).
Example 55c Preparation of intermediate E/Z-3-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000108_0001
M.W. 574.51 C29H33CI2N3O5
At room temperature, to a solution of E/Z-4-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro- indol-3-ylidenemethyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (11 g, 23 mmol) in dichloromethane (100 ml_) added di-te/t-butyl-dicarbonate (5.6 g, 25 mmol), followed by the addition of 4-dimethylaminopyridine (2 g, 16 mmol). After stirred for 1 h, the mixture was washed by 1 N HCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a yellow solid (8 g).
Example 55d
Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(4-tert-butoxycarbonyl-piperazin-1 -yl)-5- chloro-phenyl]-6-chloro -2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione
Figure imgf000108_0002
M.W. 653.59 C34H35CI2FN4O4
In a manner similar to the method described in Examplele, E/Z-3-[2-(4-tert- butoxycarbonyl-piperazin-1 -yl)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole- 1 -carboxylic acid tert-butyl ester (3 g, 5.2 mmol) was reacted with 1 -(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (14 mmol) in toluene to give the title compound as a white solid (600 mg). m/z (M+H)+: 653
Example 55e
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(piperazin-1-yl)-phenyl]-2'- (5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000109_0001
M.W. 553.47 C29H27CI2FN4O2
At room temperature, trifluoroacetic acid (2 ml_) was added into a solution of racemic (2'S, 3S, 4'R)-4'-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-phenyl]-6-chloro -2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (280 mg, 0.43 mmol) in DCM (10 ml_). After stirred for 2 h, the mixture was concentrated. The residue was dissolved in EtOAc, washed with 1 N NaOH and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (230 mg).
Example 55f
Preparation of racemic (2'S, 3S, 4'R)-4'-[2-(4-acetyl-piperazin-1-yl)-5-chloro-phenyl]-6- chloro-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000109_0002
M.W. 595.51 C3IH29CI2FN4O3 At room temperature, to a solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (piperazin-1 -yl)-phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (30 mg, 0.054 mmol) in THF was added acetic anhydride (6 mg, 0.06 mmol). After stirred for 1 h, the mixture was concentrated and the residue was purified by Prep-HPLC to give the tiltle compound as a white solid (10 mg). m/z (M+H)+: 595 Example 56
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[4-(2-hydroxy-ethyl)- piperazin-1 -yl]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000110_0001
M.W. 597.52 C3IH3ICI2FN4O3
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(piperazin-1 -yl)-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (50 mg, 0.09 mmol), 2-lodo-ethanol (155 mg, 0.9 mmol) and Et3N (18 mg, 0.18 mmol) in acetone (1 ml_) was heated at 80 0C for 1 h. Then the mixture was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (26 mg). m/z (IvRH)+: 597
Example 57
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- cyclopropanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000110_0002
M.W 674.58 C32H30CI2FN3O6S
A solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (45 mg, 0.079 mmol) prepared in Example 12a and CDI (26 mg, 0.16 mmol) in DMF (0.5 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of cyclopropanesulfonamide (48 mg, 0.4 mmol) and NaH (13 mg, 60%, 0.3 mmol) in DMF (1 ml_),which had been stirred for 1 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water (5 ml_) and the aqueous solution was acidified to "PH" 2-3 by addition of concentrated hydrochloride solution. After the aqueous phase was extracted with EtOAc twice, the combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (38 mg). m/z (M+H)+: 674
Example 58
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-thfluoro- methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000111_0001
M.W 702.51 C30H25CI2F4N3O6S
A solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (120 mg, 0.21 mmol) prepared in Example 12a and CDI (68 mg, 0.42 mmol) in DMF (5 ml_) was heated at 65 0C for 2 h. Then to this solution was added a mixture of trifluoro-methanesulfonamide (314 mg, 2.10 mmol) and NaH (84 mg, 60%, 2.10 mmol) in DMF (5 ml_), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 2 h, it was poured into water and the aqueous phase was acidified to "PH" 2-3 by addition of concentrated hydrochloric acid. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by Prep- HPLC to give the title compound as a yellow solid (14 mg). m/z (M+H)+: 702 - I l l -
Example 59a
Preparation of intermediate 1-(2,3-difluoro-6-methyl-phenyl)-3-trimethylsilyoxy-2-aza-
1 ,3-butadiene
Figure imgf000112_0001
M.W. 269.37 Ci3Hi7F2NOSi
To dry tetrahydrofuran (15 ml_) was added 1 M THF solution of LiHMDS (24.7mmol, 24.7 ml_) under Ar protection at room temperature, followed by the addition of 5,6-Difluoro-2- methyl-benzaldehyde (3.86 g, 24.7 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (3.1 ml_, 24.7 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 (4.47 ml_, 32 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (2.35 ml_, 32 mmol) in diethyl ether (30 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 4 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(2,3-difluoro-6-methyl-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification.
Example 59b
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methoxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000112_0002
M.W. 603.45 C30H26CI2F2N2O5 In a manner similar to the method described in Examplele, E/Z-6-chloro-3-[5-chloro-2- (1 -methoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (3 g, 5.94 mmol) was reacted with 1-(2,3-difluoro-6- methyl-phenyl)-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (18 mmol) in toluene to give the title compound as a white solid (510 mg). m/z (M+H)+: 603
Example 59c
Preparation of intermediate racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000113_0001
M.W 589.43 C29H24CI2F2N2O5 A mixture of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methoxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (110 mg, 0.18 mmol), NaOH (15 mg, 0.375 mmol), H2O (2 ml_) and methanol (5 ml_) was heated at 80 0C for 2 h. After cooled to room temperature, the solution was acidified to "pH" 1-2 by addition of concentrated aqueous HCI solution. The aqueous phase was extracted with EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with ether twice to give the title compound as a white solid (10 mg). m/z (IvRH)+: 589
Example 59d
Preparation of racemic (2'R, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000114_0001
M.W 666.53 C30H27CI2F2N3O6S
A solution of racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(2,3-difluoro-6-nnethyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (30 mg, 0.05 mmol) and CDI (16.2 mg, 0.1 mmol) in DMF (1 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (28.5 mg, 0.3 mmol) and NaH (10 mg, 60%, 0.25 mmol) in DMF (0.5 ml_), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 2 h, it was poured into water and the aqueous solution was acidified to "PH" 1 -2 by addition of concentrated hydrochloric acid. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by Prep- HPLC to give the title compound (25 mg). m/z (M+H)+: 666
Example 60a
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- methoxycarbonyl-methoxy)-phenyl]-2'-[5-difluoro-2-methyl-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000114_0002
M.W. 557.41 C28H23CI2FN2O5
In a manner similar to the method described in ExampleiOd, E/Z-6-chloro-3-(5-chloro- 2-methoxycarbonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester (3 g, 6.2 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (18 mmol) in toluene to give the title compound as a white solid (700 mg). m/z (M+H)+: 557
Example 60b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- hydroxycarbonyl-methoxy)-phenyl]-2'-[5-fluoro-2-methyl-phenyl] spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000115_0001
M.W 543.38 C27H2ICI2FN2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methoxycarbonyl- methoxy)-phenyl]-2'-[5-difluoro-2-methyl-phenyl] spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (300 mg, 0.54 mmol), NaOH (43 mg, 1.07 mmol), H2O (5 ml_) and methanol (10 ml_) was heated at 80 0C for 2 h. After cooled to room temperature, the solution was acidified to "pH" 1-2 by addition of concentrated HCI solution. The water phase was extrated with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid (280 mg). m/z (M+H)+: 543
Example 60c
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino- 2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione
Figure imgf000115_0002
M.W 620.49 C28H24CI2FN3O6S A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl- methoxy)-phenyl]-2'-[5-fluoro-2-methyl-phenyl] spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (300 mg, 0.55 mmol) and CDI (178 mg, 1.1 mmol) in DMF (5 ml_) was heated at 70 0C for 1 h. Then to this solution was added a mixture of methanesulfonamide (313 mg, 3.3 mmol) and NaH (110 mg, 60%, 2.75 mmol) in DMF (3 ml_), which had been stirred for 1 h at room temperature. After the resulting mixture was stirred at room temperature for 10 min, it was poured into water and the aqueous solution was acidified to "PH" 2 by addition of concentrated hydrochloric acid. After the aqueous phase was extracted with EtOAc twice, the combined organic extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid(50 mg). m/z (M+H)+: 620
Example 61a Preparation of intermediate 1-(5-chloro-2-methoxy-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000116_0001
M.W. 283.83 Ci3Hi8CINO2Si To dry tetrahydrofuran (50 ml_) was added 1 M THF solution of LiHMDS (45 mmol, 45 ml_) under Ar protection at room temperature, followed by the addition of 5-chloro-2- methoxy-benzaldehyde (7.65 g, 45 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (5.6 ml_, 45 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 (8.1 ml_, 58.5 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (4.17 ml_, 58.5 mmol) in diethyl ether (200 ml_). The cooling bath was removed, and the mixture was stirred at room temperature for 4 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -(5-chloro-2-methoxy-phenyl)- 3-thmethylsilyoxy-2-aza-1 ,3-butadiene as a yellow gum and used for the next step without further purification. Example 61b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methoxy-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000117_0001
M.W. 631.95 C31 H29CI3N2O6
In a manner similar to the method described in Example 1Od, E/Z-6-chloro-3-[5-chloro- 2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (7 g, 13.5 mmol) was reacted with 1-(5-chloro-2-methoxy- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (45 mmol) in toluene to give title compound as a white solid (850 mg). m/z (IvRH)+: 631
Example 61c
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methoxy-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000117_0002
M.W 603.89 C29H25CI3N2O6
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethoxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-chloro-2-methoxy-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (150 mg, 0.24 mmol), NaOH (20 mg, 0.48 mmol), H2O (3 ml_) and THF (10 ml_) was heated at 65 for 2 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to "pH" 2-3 by addition of concentrated HCI solution. The precipitate was collected and dried to give the title compound as a white solid (100 mg). m/z (M+H)+: 603
Example 61 d
Preparation of racemic (2'S, 3S, 4'R)- 4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methoxy-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000118_0001
M.W 680.99 C30H28CI3N3O7S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methoxy-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (122 mg, 0.2 mmol) and CDI (65 mg, 0.4 mmol) in DMF (5 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (144 mg, 1.2 mmol) and NaH (48 mg, 60%, 1.2 mmol) in DMF (5 ml_), which had been stirred for 3 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water (5 ml_) and the aqueous solution was acidified to "PH" 2-3 by addition of concentrated hydrochloride acid. After the aqueous phase was extracted with EtOAc twice, the combined organic extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (11 mg). m/z (M+H)+: 680 Example 62a
Preparation of intermediate 2-(4-chloro-2-formyl-phenoxy)-butyhc acid methyl ester
Figure imgf000119_0001
M.W 256.69 Ci2Hi3CIO4
A mixture of 5-chloro-2-hydroxy-benzaldehyde (156 g, 1 mol), 2-bromo-butyhc acid methyl ester (271 g, 1.5 mol), Kl (2 g, 0.012 mol) and K2CO3 (276 g, 2 mol) in DMF (500 ml_) was heated at 130 0C for 2 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (240 g).
Example 62b Preparation of intermediate of 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-butyhc acid methyl ester
Figure imgf000119_0002
M.W 300.74 Ci4Hi7CIO5 A mixture of 2-(4-chloro-2-formyl-phenoxy)-butyric acid methyl ester (50 g, 0.195 mol), ethylene glycol (89 ml_, 1.56 mol) and p-toluenesulfonic acid (2.8 g, 16.5 mmol) in toluene (400 ml_) was refluxed with a Dean-Stark trap attacehd to remove the water. After 3 h, the reaction was cooled and washed with water,saturated NaHCO3 and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (40 g).
Example 62c
Preparation of intermediate of 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-2-ethyl-butyhc acid methyl ester
Figure imgf000120_0001
M.W 328.80 Ci6H2iCIO5 Lithium bis(tπmethylsilyl)amide (60 ml_, 60 mmol, 1 M in THF) was slowly added to a solution of 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-butyhc acid methyl ester (15 g, 50 mmol) in anhydrous THF (150 ml_) at -78 0C. After the mixture was stirred for 15 min, iodoethane (9.3 g, 60 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4CI, dried over anhydrous Na2SO4 and concentrated to give the crude product as a oil (16 g).
Example 62d
Preparation of intermediate of 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyhc acid methyl ester
Figure imgf000120_0002
M.W 284.74 Ci4Hi7CIO4
A solution of 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-2-ethyl-butyhc acid methyl ester
(16 g, 48.8 mmol) in thfluoroacetic acid (20 ml_) was stirred at room temperature for 3 h. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with 1N NaOH solution, water, dried over anhydrous Na2SO4 and concentrated to give the title compound (13 g).
Example 62e
Preparation of intermediate of E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-ethyl-butyhc acid methyl ester
Figure imgf000121_0001
M.W 434.32 C22H2ICI2NO4
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 2-(4-chloro-2-formyl- phenoxy)-2-ethyl-butyric acid methyl ester (13 g, 45.8 mmol) in methanol (200 ml_) was added pyrrolidine (4.1 ml_, 49.7 mmol) dropwise. The mixture was then heated at 70 0C for 2 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Example 62f Preparation of intermediate E/Z-3-[5-chloro-2-(1 -ethyl-1 -methoxycarbonyl-propoxy)- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000121_0002
M.W. 534.44 C27H29CI2NO6 To a solution of E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)- phenoxy]-2-ethyl-butyhc acid methyl ester (15.5 g, 36 mmol) in dichloromethane (200 ml_) at room temperature was added di-tert-butyl-dicarbonate (8.6 g, 39 mmol), followed by the addition of 4-dimethylaminopyhdine (0.4 g, 3.3 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solution was washed with 1 M HCI and brine twice, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow solid (15 g ). Example 62g
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methoxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000122_0001
M.W. 613.52 C32H3ICI2FN2O5
In a manner similar to the method described in ExampleiOd, E/Z-3-[5-chloro-2-(1 - methoxycarbonyl-1 -ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (7.6 g, 15 mmol) was reacted with 1-(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (60 mmol) in toluene to give the title compound as a white solid (2.2 g). m/z (IvRH)+: 613
Example 62 h
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -hydroxycarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000122_0002
M.W. 599.49 C3IH29CI2FN2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethyl-1 -methoxycarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (200 mg, 0.33 mmol), LiOH-H2O (69 mg, 1.16 mmol), H2O (2 ml_) and methanol (20 ml_) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to "pH" 2-3 by addition of concentrated HCI solution. The precipitate was collected by filtration to give the title compound as a white solid (57 mg). m/z (M+H)+: 599
Example 62 i
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000123_0001
M.W 676.60 C32H32CI2FN3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (30 mg, 0.05 mmol) and CDI (20 mg, 0.12 mmol) in DMF (1 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (28 mg, 0.3 mmol) and NaH (12 mg, 60%, 0.3 mmol) in DMF (1 ml_), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to "PH" 1 -2 by addition of concentrated HCI solution. The aqueous phase was extracted with EtOAc twice, The combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg). m/z (M+H)+: 676
Example 62j Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000124_0001
M.W 676.60 C32H32CI2FN3O6S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -ethyl-1 -methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (400 mg) was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (130 mg) (RO5306899-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (110 mg) (RO5306900-000). m/z (IvRH)+: 676
Example 63a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - dimethylcarbamoyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000124_0002
M.W 626.56 C33H34CI2FN3O4 At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (50 mg, 0.084 mmol) prepared in Example 62h, dimethylamine hydrochloride (13.5 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 ml_) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (40 mg). m/z (M+H)+: 626
Example 63b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethyl-1 -dimethylcarbamoyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione
Figure imgf000125_0001
M.W 626.56 C33H34CI2FN3O4
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -ethyl-1 -dimethylcarbamoyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione (30 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -dimethylcarbamoyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (11 mg) (RO5314967-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2- (1 -ethyl-1 -dimethylcarbamoyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (10 mg) (RO5314968-000). m/z (M+H)+: 626
Example 64
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(2-hydroxy- ethylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3- piperidine]-2,6'(1 H)-dione
Figure imgf000126_0001
M.W 642.56 C33H34CI2FN3O5
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (50 mg, 0.084 mmol), ethanol amine (10 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 ml_) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic layers were washed with saturated brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (10 mg). m/z (M+H)+: 642
Example 65a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3- dihydroxy-propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000126_0002
M.W. 672.59 C34H36CI2FN3O6
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[1 -ethyl-5-chloro-2- (1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (50 mg, 0.084 mmol), (S)-3-amino-1 ,2-propanediol (27 mg, 0.3 mmol), HATU (114 mg, 0.30 mmol) and DMAP (72 mg, 0.59 mmol) in DMF (2 ml_) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (40 mg). m/z (M+H)+: 672
Example 65b Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000127_0001
M.W. 672.59 C34H36CI2FN3O6 Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -ethyl-1 -((S)-2,3-dihydroxy-propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione (30 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3- dihydroxy-propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H- indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (10 mg) (RO5314969-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (13 mg) (RO5314970-000).
Example 66a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000128_0001
M.W 652.60 C35H36CI2FN3O4
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (50 mg, 0.084 mmol), pyrrolidine (12 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 ml_) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic layers were washed with saturated NaCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (30 mg). m/z (M+H)+: 652
Example 66b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000128_0002
M.W 652.60 C35H36CI2FN3O4
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -ethyl-1 -(pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (30 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 -carbonyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (10 mg) (RO5315526-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'- {5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (10 mg) (RO5315527-000). m/z (M+H)+: 652
Example 67a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000129_0001
M.W 668.60 C35H36CI2FN3O5
At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (120 mg, 0.2 mmol), (S)-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 ml_) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with saturated NaCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg). m/z (M+H)+: 668
Example 67b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000130_0001
M.W 668.60 C35H36CI2FN3O5
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)- 6-chloro-4'-{5-chloro-2- [1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (30 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)- 6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (10 mg) (RO5317810-000) and chiral (2'R, 3R, 4'S)- 6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1-carbonyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (10 mg) (RO5317813-000). m/z (IvRH)+: 668
Example 68a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000130_0002
M.W 668.60 C35H36CI2FN3O5 At room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (120 mg, 0.2 mmol), R-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 ml_) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCI aqueous solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg). m/z (M+H)+: 668
Example 68b
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000131_0001
M.W 668.60 C35H36CI2FN3O5
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (30 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy- pyrrolidine-1 -carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione as a white solid (10 mg) (RO5317816-000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 -carbonyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione as a white solid (10 mg) (RO5317818-000). m/z (M+H)+: 668
Example 69a Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)- dione
Figure imgf000132_0001
M.W. 598.51 C3IH30CI2FN3O4
At the room temperature, a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- ethyl-1 -hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione (100 mg, 0.167 mmol), NH3 in THF (8.5 mg, 0.5 mmol), HATU (100 mg, 0.25 mmol) and DMAP (60 mg, 0.50 mmol) in DMF (3 ml_) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (70 mg). m/z (M+H)+: 598
Example 69b Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)- dione
Figure imgf000132_0002
M.W. 598.51 C3IH30CI2FN3O4 Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'- pipehdine]-2,6'(1 H)-dione (50 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (15 mg) (RO5324251 -000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 - ethyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione as a white solid (15 mg) (RO5324253-000). m/z (M+H)+: 598
Example 70a
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methoxycarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000133_0001
M.W 629.97 C32H3ICI3N2O5
In a manner similar to the method described in Example 1Od, E/Z-3-[5-chloro-2-(1 - methoxycarbonyl-1 -ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (2.63 g, 4.9 mmol) prepared in Example 62f was reacted with 1 -(5-chloro-2-methyl-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (20 mmol) prepared in Example 13b in toluene (20 ml_) to give the title compound as a white solid (600 mg). m/z (IvRH)+: 629
Example 70b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - hydroxycarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000133_0002
M.W. 615.95 C3iH29CI3N2O5 A mixture of racemic (2'S, 3S, 4'R)-4'-[5-chloro-2-(1 -ethyl-1 -methoxycarbonyl-propoxy)- phenyll-e-chloro^'^δ-chloro^-rnethyl-phenyO spirotSH-indole-S.S'-pipeπdinel^.eXI H)- dione (100 mg, 0.159 mmol), LiOH (19.87 mg, 0.8 mmol), H2O (2 ml_) and methanol (3 ml_) was heated at 40 0C for 4 h. Then methanol was removed by vacuum. The aqueous solution was acidified to "PH" 1 -2 by addition of concentrated hydrochloride acid. The precipitate was collected by filtration and purified by Prep-HPLC to give the title compound as a white solid (50 mg). m/z (IvRH)+: 615
Example 7Od
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000134_0001
M.W 693.05 C32H32CI3N3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl- propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (150 mg, 0.244 mmol) and CDI (80 mg, 0.49 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h, then cooled to room temperature. In a separate flask a mixture of methanesulfonamide (231 mg, 2.44 mmol) and NaH (78 mg, 60%, 1.95 mmol) was stirred in DMF (3 ml_) at room temperature for 2 h, then the resulting mixture was added into the above solution. The reaction mixture was stirred at room temperature for 1 h, then poured into water and "pH" was acidified to 2-3 by addition of concentrated HCI solution. The mixture was extracted with EtOAc twice, the combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg). m/z (M+H)+: 692 Example 71a
Preparation of intermediate racemic (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 - ethyl-i -methanesulfonylaminocarbonyl-propoxyj-phenyll^'^δ-chloro^-nriethyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000135_0001
M.W. 735.09 C34H34CI3N3O7S
At room temperature, to a mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethyl-i -methanesulfonylaminocarbonyl-propoxyj-phenyll^'^δ-chloro^-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (400 mg, 0.58 mmol) and acetic anhydride (71 mg, 0.69 mmol) in DCM (20 ml_) was added DMAP (7 mg, 0.06 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5/V HCI solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (100 mg).
Example 71b
Preparation of intermediate chiral (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 -ethyl- i -methanesulfonylaminocarbonyl-propoxyj-phenyll^'^δ-chloro^-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000135_0002
M.W. 735.09 C34H34CI3N3O7S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5- chloro-2-(1-ethyl-1 -methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2- methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-1-acetyl-6-chloro-4'-[5-chloro-2-(1-ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione as a white solid (15 mg) (RO5319795- 000). m/z (M+H)+: 734
Example 71c
Preparation of chiral (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000136_0001
M.W 693.05 C32H32CI3N3O6S
At room temperature, a mixture of chiral (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2- (1 -ethyl-1 -methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl- phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (20 mg, 0.027 mmol)
(RO5319795-000), NaOH (2 mg, 0.05 mmol), H2O (0.5 ml_) and methanol (2 ml_) was stirred overnight. Then methanol was removed by vacuum. The aqueous solution was acidified by addition of concentrated HCI to "pH" 1 -2 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid (10 mg). m/z (M+H)+: 692
Example 72a
Preparation of intermediate chiral (2'R, 3R, 4'S)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 - ethyl-i -methanesulfonylaminocarbonyl-propoxyj-phenyll^'^δ-chloro^-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000137_0001
M.W. 735.09 C34H34CI3N3O7S
In the separation of the two enantiomers from racemic (2'S, 3S, 4'R)-1-acetyl-6-chloro- 4'-[5-chloro-2-(1-ethyl-1 -methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2- methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg) by chiral SFC in Example 70b, chiral (2'R, 3R, 4'S)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione was obtained as the second product: a white solid (15 mg) (RO5319796-000). m/z (M+H)+: 734
Example 72b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1-ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000137_0002
M.W 693.05 C32H32CI3N3O6S
At room temperature, a mixture of chiral (2'R, 3R, 4'S)-1 -acetyl-6-chloro-4'-[5-chloro-2- (1 -ethyl-1 -methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl- phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (20 mg, 0.027 mmol) ( RO5319796-000), NaOH (2 mg, 0.05 mmol), H2O (0.5 ml_) and methanol (2 ml_) was stirred overnight. Then methanol was removed by vacuum. The aqueous solution was acidified by addition of concentrated HCI to "pH"1 -2 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound as a white solid (10 mg). m/z (M+H)+: 692
Example 73
Preparation of chiral (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-ethanesulfonylamino-1 ,1-dimethyl- 2-oxo-ethoxy)-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000138_0001
M.W 662.57 C3IH30CI2FN3O6S
A solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (57 mg, 0.1 mmol) prepared in Example 12a and CDI (32 mg, 0.2 mmol) in DMF (1 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of ethanesulfonamide (66 mg, 0.6 mmol) and NaH (24 mg, 60%, 0.6 mmol) in DMF (1 ml_), which had been stirred for 2 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to "pH" 1-2 by addition of concentrated HCI. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg). m/z (M+H)+: 662
Example 74a Preparation of intermediate 1-(5-methyl-2-methoxy-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene
Figure imgf000139_0001
M.W. 277.44 Ci5H23NO2Si
To dry tetrahydrofuran (60 ml_) was added 1 M THF solution of LiHMDS (51 mmol, 51 ml_) under Ar at room temperature, followed by the addition of 2-Methoxy-5-methyl- benzaldehyde (7.65 g, 51 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (6.3 ml_, 51 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 triethylamine (9.3 ml_, 66 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (4.71 ml_, 66 mmol) in diethyl ether (300 ml_). The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1 -(5-methyl-2-methoxy-phenyl)-3-thmethylsilyoxy-2-aza- 1 ,3-butadiene as a yellow gum and used for the next step without further purification
Example 74b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methoxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-methyl-2-methoxy-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000139_0002
M.W 597.50 C3IH30CI2N2O6
In a manner similar to the method described in Example 1Od, E/Z-6-chloro-3-[5-chloro- 2-(1 -methoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (5 g, 10.31 mmol) prepared in Example 1c was reacted with 1 -(5-methyl-2-methoxy-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (51 mmol) in toluene to give the title compound as a white solid (143 mg). m/z (M+H)+: 597 Example 74c
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-methyl-2-methoxy-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000140_0001
M.W 583.47 C30H28CI2N2O6
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-methoxycarbonyl-1- methyl-ethoxy)-phenyl]-2'-(5-methyl-2-methoxy-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (100 mg, 0.167 mmol), NaOH (33.5 mg, 0.837 mmol), H2O (2 ml_) and methanol (3 ml_) was heated at 7O 0C for 1 h. Then methanol was removed by vacuum and the aqueous solution was acidified to "pH" 1 -2 by addition of concentrated HCI aqueous solution. The precipitate was collected by filtration and washed with CH2CI2 twice to give the title compound as a white solid (21 mg). m/z (IvRH)+: 583
Example 74d
Preparation of racemic (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2'-(5-methyl-2-methoxy-phenyl)-spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000140_0002
M.W 660.58 C3IH3ICI2N3O7S
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1-methyl- ethoxy)-phenyl]-2'-(5-methyl-2-methoxy-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (70 mg, 0.12 mmol) and CDI (39 mg, 0.24 mmol) in dry DMF (2 ml_) was heated at 65 0C for 2 h. In a separate flask a mixture of methanesulfonamide (91 mg, 0.962 mmol) and NaH (60% in mineral oil) (38 mg, 0.95 mmol) (Aldrich) in DMF (3 ml_), was stirred at room temperature for 2 h, then was added slowly to the above solution. The reaction mixture was stirred at room temperature for 2 h, then poured into water (3 ml_) and the aqueous phase was acidified to "pH" 1 -2 by addition of concentrated HCI. The mixture was extracted with EtOAc (20 ml_) twice. The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and the residue was purified by Prep-HPLC to give the title compound as a white solid (8.5 mg).
Example 75
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(3-methanesulfonylamino- 2,2-dimethyl-3-oxo-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000141_0001
M.W 662.57 C3IH30CI2FN3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-hydroxycarbonyl-2- methyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (300 mg, 0.5 mmol) prepared in Example 2Of and CDI (160 mg, 1 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (285 mg, 3 mmol) and NaH (120 mg, 60%, 3 mmol) in DMF (1 ml_), which had been mixed and stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to "pH" 1 -2 by addition of concentrated HCI. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (70 mg). m/z (M+H)+: 662 Example 76a
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione
Figure imgf000142_0001
M.W 648.54 C30H28CI2FN3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (16 g, 0.028 mol) prepared in Example 1f and CDI (9 g, 0.056 mol) in DMF (70 ml_) was heated at 65 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (16 g, 0.168 mol) and NaH (5.6 g, 60%, 0.14 mol) in DMF (100 ml_), which had been mixed and stirred at room temperature for 2h. After the resulting mixture was stirred at room temperature for 2 h, it was poured into water and the aqueous solution was acidified to "pH" 1 -2 by addition of concentrated HCI. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by recrystallized to give the title compound (11.4 g). m/z (M+H)+: 648
Example 76b
Preparation of chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000142_0002
M.W 648.54 C30H28CI2FN3O6S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione (50 mg), was conducted by chiral SFC to provide chiral (2'R, 3R, 4'S)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 - dimethyl^-oxo-ethoxyJ-phenyll-G-chloro^'-tδ-chloro^- (2-methanesulfonylamino-i ,1 - dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (RO5302327-000,15 mg) and chiral (2'S, 3S, 4'R)- 6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-i ,1 -di methyl -2-oxo-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (RO5248115-000,10 mg). m/z (M+H)+: 648
Example 77a Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methoxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000143_0001
M.W. 601.92 C30H27CI3N2O5 In a manner similar to the method described in Example 1Od, E/Z-6-chloro-3-[5-chloro- 2-(1 -methoxycarbonyl-1 -methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (7 g, 14 mmol) prepared in Example 1c was reacted with 1 -(5-chloro-2-methyl-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (42 mmol) prepared in Example 13b in toluene and then trifluoroacetic acid in dichloromethane to give the title compound (1.8 g). m/z (M+H)+: 601 Example 77b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H- indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000144_0001
M.W 587.89 C29H25CI3N2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-methoxycarbonyl-1- methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (600 mg, 1 mmol), NaOH (80 mg, 2 mmol), H2O (3 ml_) and methanol (10 ml_) was heated at 70 0C for 2 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to "pH" 2-3 by addition of concentrated HCI. The white solid was collected by filtration to give the title compound as a white solid (50 mg). m/z (IvRH)+: 587
Example 77c
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000144_0002
M.W 665.00 C30H28CI3N3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 - methyl-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (300 mg, 0.5 mmol) and CDI (160 mg, 1 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (285 mg, 3 mmol) and NaH (120 mg, 60%, 3 mmol) in DMF (5 ml_), which had been stirred at room temperature for 3 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to "pH" 1-2 by addition of concentrated HCI. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg). m/z (IvRH)+: 664
Example 77d
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000145_0001
M.W 665.00 C30H28CI3N3O6S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl- phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino- 1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione as a white solid (RO5305963-000,13 mg) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)- phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (RO5305964-000,11 mg). m/z (IvRH)+: 664 Example 78
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(2-methoxy- ethanesulfonylamino)-1 ,1 -dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000146_0001
M.W 692.60 C32H32CI2FN3O7S
A solution of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbonyl-1 -methyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (50 mg, 0.09 mmol) prepared in Example 12a and CDI (32 mg, 0.2 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of 2- methoxy-ethanesulfonic acid amide (139 mg, 1 mmol) and NaH (35 mg, 60%, 0.9 mmol) in DMF (2 ml_), which had been stirred at room temperature for 3 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to "pH" 1 -2 by addition of concentrated HCI. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg). m/z (M+H)+: 692
Example 79a
Preparation of intermediate 2-(4-chloro-2-formyl-phenoxy)-penta noic acid ethyl ester
Figure imgf000146_0002
M.W 284.74 Ci4Hi7CIO4 A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 ml_) was heated at 140 0C for 1 h. After cooled to room temperature, the mixture was poured into water and the water phase was extrated with EtOAc thrice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Example 79b
Preparation of intermediate 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester
Figure imgf000147_0001
M.W 328.80 Ci6H2iCIO5 A mixture of 2-(4-chloro-2-formyl-phenoxy)-pentanoic acid ethyl ester (15 g, 53 mmol), ethylene glycol (25 ml_, 440 mmol) and p-toluenesulfonic acid (0.8 g, 4.65 mmol) in toluene (150 ml_) was refluxed with a Dean-Stark trap attacehd. After 3 h, the reaction was cooled and washed with water,saturated NaHCO3 solution and water, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (16 g).
Example 79c
Preparation of intermediate 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-2-propyl pentanoic acid ethyl ester
Figure imgf000147_0002
M.W 370.88 Ci9H27CIO5 Lithium bis(thmethylsilyl)amide (26 ml_, 26 mmol, 1 M in THF) was slowly added to a solution of 2-(4-Chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester (6.6 g, 20 mmol) in anhydrous THF (60 ml_) at -78 0C. After the mixture was stirred for 30 min at -78 0C, 1 -iodopropane (4 ml_, 40 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4CI, and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (5 g).
Example 79d
Preparation of intermediate 2-(4-chloro-2-formyl-phenoxy)-2-propyl-pentanoic acid ethyl ester
Figure imgf000148_0001
M.W 326.82 Ci7H23CIO4 A solution of 2-(4-chloro-2-[1 ,3]dioxolan-2-yl-phenoxy)-2-propyl-pentanoic acid ethyl ester (15 g, 42 mmol) in TFA (30 ml_) was stirred at room temperature overnight. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with NaOH solution (1 N), water, dried over anhydrous Na2SO4 and concentrated to give the title compound (14 g).
Example 79e Preparation of intermediate E/Z-2-[4-Chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-propyl-pentanoic acid ethyl ester
Figure imgf000148_0002
M.W 476.40 C25H27CI2NO4 To the mixture of 6-chlorooxindole (9.3 g, 55.7 mmol) and 2-(4-chloro-2-formyl- phenoxy)-2-propyl-pentanoic acid ethyl ester (14 g, 42.9 mmol) in methanol (100 ml_) was added pyrrolidine (3.3 g, 47.2 mmol) dropwise. The mixture was then heated at 80 0C for 2 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by flash column to give the title compound (4.2 g).
Example 79f
Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1 -propyl- butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000149_0001
M.W. 576.52 C30H35CI2NO6
To a solution of E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3-ylidenemethyl)- phenoxy]-2-propyl-pentanoic acid ethyl ester (4.2 g, 8.8 mmol) in dichloromethane (100 ml_) at room temperature was added di-tert-butyl-dicarbonate (2.2 g, 9.68 mmol), followed by the addition of 4-dimethylaminopyridine (0.5 g, 4.1 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solution was concentrated. The residue was purified by flash column to give the title compound as a yellow solid (2.6 g).
Example 79g Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000150_0001
M.W. 672.05 C35H37CI3N2O5
In a manner similar to the method described in ExampleiOd, E/Z-6-chloro-3-[5-chloro- 2-(1 -ethoxycarbonyl-1 -propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1 -(5-chloro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) prepared in Example 13b in toluene to give the title compound as a white solid (310 mg). m/z (M+H)+: 671
Example 79h
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -propyl-butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000150_0002
M.W. 644.00 C33H33CI3N2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethoxycarbonyl-1 -propyl- butoxy)-phenyl]- 2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (280 mg, 0.41 mmol), LiOH-H2O (1 g, 24.6 mmol), H2O (12 ml_) and methanol (38 ml_) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the mixture was acidified to "pH" 1 -2 by addition of concentrated HCI solution and then extrated with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (220 mg). m/z (IvRH)+: 643 Example 79 i
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methanesulfonylaminocarbonyl-i-propyl-butoxyj-phenyll^'^δ-chloro^-nriethyl-pheriyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000151_0001
M.W 721.11 C34H36CI3N3O6S
A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 -propyl- butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (140 mg, 0.22 mmol) and CDI (70 mg, 0.44 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (207 mg, 2.2 mmol) and NaH (78 mg, 60%, 2 mmol) in DMF (2 ml_),which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the mixture was acidified to "pH" 1-2 by addition of concentrated HCI solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg). m/z (M+H)+: 720
Example 79j
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- methanesulfonylaminocarbonyl-i-propyl-butoxyj-phenyll^'^δ-chloro^-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000151_0002
M.W 721.11 C34H36CI3N3O6S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-chloro-2-methyl- phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione (50 mg), was conducted by chiral SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-chloro-2-nnethyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (25 mg) (RO5315392- 000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1-methanesulfonylaminocarbonyl- 1 -propyl-butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione as a white solid (11 mg) (RO5315394-000). m/z (M+H)+: 720
Example 80a Preparation of intermediate racemic (2'S, 3S, 4'R)-4'-[5-chloro-2-(1 -ethoxycarbonyl-1 - propyl-butoxy)-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000152_0001
M.W. 655.60 C35H37CI2FN2O5 In a manner similar to the method described in ExampleiOd, E/Z-6-chloro-3-[5-chloro- 2-(1 -ethoxycarbonyl-1 -propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1 -(5-fluoro-2-methyl- phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (10 mmol) prepard in Example 1d in toluene to give the title compound as a white solid (150 mg). m/z (IvRH)+: 655 Example 80b
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000153_0001
M.W. 627.55 C33H33CI2FN2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-ethoxycarbonyl-1 -propyl- butoxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (130 mg, 0.198 mmol), LiOH-H2O (1 g, 24.6 mmol), H2O (5 ml_) and methanol (15 ml_) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the water phase was acidified to "pH" 1 2 by addition of concentrated HCI solution and then extrated with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (115 mg). m/z (M+H)+: 627
Example 80c
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000153_0002
M.W 704.65 C34H36CI2FN3O6S A solution of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1 -propyl- butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (80 mg, 0.13 mmol) and CDI (40 mg, 0.25 mmol) in DMF (2 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (123 mg, 1.3 mmol) and NaH (52 mg, 60%, 1.3 mmol) in DMF (2 ml_), which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified by concentrated HCI solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (60 mg). m/z (M+H)+: 704
Example 8Od
Preparation of chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000154_0001
M.W 704.65 C34H36CI2FN3O6S
Separation of the two enantiomers from racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonylaminocarbonyl-1 -propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione (50 mg), was conducted by chiral
SFC to provide chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1- methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (13 mg) (RO5315395- 000) and chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1- methanesulfonylaminocarbonyl-1-propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione as a white solid (11 mg) (RO5315396-
000). m/z (M+H)+: 704 Example 81a
Preparation of intermediate E/Z-2-{2-[6-bromo-2-oxo-1 ,2-dihydro-indol-(3E)- ylidenemethyl]-4-chloro-phenoxy}-2-ethyl-butyric acid methyl ester
Figure imgf000155_0001
M.W 478.77 C22H2IBrCINO4
To the mixture of 6-bromooxindole (10.5 g, 49.7 mmol) and 2-(4-chloro-2-formyl- phenoxy)-2-ethyl-butyhc acid methyl ester (13 g, 45.8 mmol) prepared in Example 62d in methanol (200 ml_) was added pyrrolidine (4.1 ml_, 49.7 mmol) dropwise. The mixture was then heated at 70 0C for 2 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (16 g).
Example 81b Preparation of intermediate E/Z-6-bromo-3-[1 -[5-chloro-2-(1 -ethyl-1 -methoxycarbonyl- propoxy)-phenyl]-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butylester
Figure imgf000155_0002
M.W. 578.89 C27H29BrCINO6 To a solution of E/Z-2-{2-[6-bromo-2-oxo-1 ,2-dihydro-indol-(3E)-ylidenemethyl]-4-chloro- phenoxy}-2-ethyl-butyhc acid methyl ester (16 g, 33.5 mmol) in dichloromethane (200 ml_) at room temperature was added di-tert-butyl-dicarbonate (8.6 g, 39 mmol), followed by the addition of 4-dimethylaminopyridine (0.4 g, 3.3 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solution was washed with 1 M HC and brine twice, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow solid (16 g ).
Example 81c
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1-ethyl-1 - methoxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000156_0001
M.W. 657.97 C32H3IBrCIFN2O5
In a manner similar to the method described in ExampleiOd, E/Z-6-bromo-3-[1 -[5- chloro-2-(1-ethyl-1 -methoxycarbonyl-propoxy)-phenyl]-meth-(E)-ylidene]-2-oxo-2,3- dihydro-indole-1 -carboxylic acid tert-butyl ester (6 g, 10 mmol) was reacted with 1 -(5- fluoro-2-methyl-phenyl)-3-thmethylsilyoxy-2-aza-1 ,3-butadiene (40 mmol) in toluene to give the title compound as a white solid (1.2 g). m/z (M+H)+: 657
Example 81 d Preparation of intermediate racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1 -ethyl-1 - hydroxycarbonyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000156_0002
M.W. 643.94 C3IH29BrCIFN2O5 A mixture of racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1-ethyl-1-methoxycarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione (1.2 g, 1.8 mmol), LiOH-H2O (1.5 g, 36 mmol), H2O (3 ml_) and methanol (10 ml_) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated. The water pahse was acidified to "pH" 2-3 by addition of concentrated HCI solution and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was washed with methanol to give the title compound (660 mg). m/z (IvRH)+: 643
Example 81 e
Preparation of racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000157_0001
M.W 721.05 C32H32BrCIFN3O6S
A solution of racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione (480 mg, 0.75 mmol) and CDI (242 mg, 1.5 mmol) in DMF (5 ml_) was heated at 60 0C for 2 h. Then to this solution was added a mixture of methanesulfonamide (712 mg, 7.5 mmol) and NaH (300 mg, 60%, 7.5 mmol) in DMF (5 ml_), which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified by concentrated HCI solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (300 mg). m/z (M+H)+: 720 Example 82a
Preparation of intermediate 5-chloro-2-methylsulfanylmethoxy-benzaldehyde
Figure imgf000158_0001
M.W. 216.69 C9H9CIO2S A mixture of 5-chloro-2-hydroxy-benzaldehyde (15.6 g, 0.1 mol), chloro-methylsulfanyl- methane (9.6 g, 0.1 mol), K2CO3 (14 g, 0.1 mol) and Kl (1 g, 0.006 mol) in DMF (70 ml_) was heated at 70 0C for 2 h. After cooled to the room temperature, the mixture was poured into ice water. The aqueous phase was extracted with diethyl ether. The combined organic layers were washed with NaOH solution (1 N), dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (14.2 g).
Example 82b
Preparation of intermediate 5-chloro-2-methanesulfonylmethoxy-benzaldehyde
Figure imgf000158_0002
M.W. 248.69 C9H9CIO4S
At 0 0C, to a solution of 5-Chloro-2-methylsulfanylmethoxy-benzaldehyde (4.32 g, 20 mmol) in DCM (100 ml_) was added m-CPBA (1 O g, 77%, 40 mmol) slowly. The solution was stirred at room temperature for 1 h. Then the solution was washed with saturated K2CO3 solution, 1N NaOH solution, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give 5-chloro-2-methanesulfonylmethoxy- benzaldehyde as a white solid (2.78 g).
Example 82c
Preparation of intermediate E/Z- 6-chloro-3-(5-chloro-2-methanesulfo nylmethoxy-benzylidene)-1 ,3-dihydro-indol-2-one
Figure imgf000159_0001
M.W. 398.27 Ci7Hi3CI2NO4S
In a manner similar to the method described in Example 9b, 5-chloro-2- methanesulfinylmethoxy-benzaldehyde (1.25 g, 5 mmol) was reacted with 6- chlorooxindole (0.9 g, 5.4 mmol) and pyrrolidine (0.5 ml_, 6.1 mmol) in methanol (50 ml_) to give the title compound as a yellow solid (1.8 g).
Example 82d
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-methanesulfonylmethoxy- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000159_0002
M.W. 498.39 C22H2ICI2NO6S
In a manner similar to the method described in Example 9c, E/Z- 6-chloro-3-(5-chloro- 2-methanesulfonylmethoxy-benzylidene)-1 ,3-dihydro-indol-2-one (1.0 g, 2.5 mmol) was reacted with Di-te/t-butyl-dicarbonate (0.6 g, 2.8 mmol) and 4-dimethylaminopyhdine (0.1 g, 0.8 mmol) in CH2CI2 to give the title compound as a yellow solid (1.2 g).
Example 82e
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-(5-chloro-2 methanesulfonylmethoxy-phenyl)-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000160_0001
M.W. 577.46 C27H23CI2FN2O5S
In a manner similar to the method described in Example 1Od, E/Z-6-chloro-3-(5-chloro- 2-methanesulfonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester (600 mg, 1.2 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (40 mg). m/z (IvRH)+: 577
Example 83a
Preparation of intermediate 5-chloro-2-methanesulfinylmethoxy-benzaldehyde
Figure imgf000160_0002
M.W. 232.69 C9H9CIO3S
In the preparation of 5-chloro-2-methanesulfonylmethoxy-benzaldehyde as described in Example 81b, a second product δ-chloro^-methanesulfinylmethoxy-benzaldehyde was obtained as a light yellow solid (0.62 g).
Example 83b
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-methanesulfinylmethoxy- benzylidene)-1 ,3-dihydro-indol-2-one
Figure imgf000160_0003
In a manner similar to the method described in Example 9b, 5-chloro-2- methanesulfinylmethoxy-benzaldehyde (0.4 g, 1.72 mmol) was reacted with 6- chlorooxindole (0.31 g, 1.86 mmol) and pyrrolidine (0.13 g, 1.86 mmol) in methanol (10 ml_) to give the title compound as a yellow solid (0.6 g).
Example 83c
Preparation of intermediate E/Z-6-chloro-3-(5-chloro-2-methanesulfinylmethoxy- benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000161_0001
M.W. 482.39 C22H2ICI2NO5S
In a manner similar to the method described in Example 9c, E/Z-6-chloro-3-(5-chloro-2- methanesulfinylmethoxy-benzylidene)-1 ,3-dihydro-indol-2-one (400 mg, 1.05 mmol) was reacted with di-te/t-butyl-dicarbonate (300 mg, 1.39 mmol) and 4-dimethylaminopyhdine (50 mg, 0.41 mmol) in CH2CI2 to give the title compound as a yellow solid (500 mg).
Example 83d
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-(5-chloro-2-methanesulfinylmethoxy- phenyl)-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000161_0002
M.W. 561.46 C27H23CI2FN2O4S
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro- 2-methanesulfinylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert- butyl ester (400 mg, 0.83 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3- trimethylsilyoxy-2-aza-1 ,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (45 mg). m/z (M+H)+: 561
Example 84a
Preparation of intermediate N-tert-butyl-C-chloro-methanesulfonamide
Figure imgf000162_0001
M.W. 185.67 C5Hi2CINO2S
At 0 0C, to a mixture of tert-butylamine (10.3 g, 141 mmol) and N-methylmorpholine (14.9 g, 147 mmol) in diethyl ether (200 ml_) was added dropwise a solution of chloromethanesulfonyl chloride (20 g, 134 mmol) in diethyl ether (400 ml_). After stirred for 5 h, the solution was diluted with ethyl acetate (200 ml_). The organic phase was washed with HCI solution (1 N), water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a colorless oil (16 g).
Example 84b
Preparation of intermediate N-tert-butyl-C-(4-chloro-2-formyl-phenoxy)- methanesulfonamide
Figure imgf000162_0002
M.W. 305.78 Ci2Hi6CINO4S
A mixture of 5-chloro-2-hydroxy-benzaldehyde (13.9 g, 89.2 mmol), K2CO3 (24.6 g, 178.3 mmol) and N-tert-butyl-C-chloro-methanesulfonamide (16.5 g, 89.2 mmol) in DMF (20 ml_) was heated at 60 0C overnight. After cooled to room temperature, the mixture was neutralized by addition of aqueous HCI solution and extracted with ethyl acetate. The organic phase was washed with wate, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with diethyl ether to give the title compound (13.5 g). Example 84c
Preparation of intermediate E/Z-N-tert-butyl-C-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro- indol-3-ylidenemethyl)-phenoxy]-methanesulfonamide
Figure imgf000163_0001
M.W. 455.36 C20H20CI2N2O4S
To the mixture of 6-chlorooxindole (3.05 g, 10 mmol) and N-tert-butyl-C-(4-chloro-2- formyl-phenoxy)-methanesulfonamide (1.65 g, 10 mmol)) in methanol (20 ml_) was added pyrrolidine (1.41 g, 20 mmol) dropwise. The mixture was then heated at 70 0C for 1 h. After cooled to 4 0C, the mixture was filtered and the precipitate was collected, dried to give the title compound (4 g).
Example 84d
Preparation of intermediate E/Z-3-[2-(tert-butylsulfamoyl-methoxy)-5-chloro- benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000163_0002
M.W. 555.48 C25H28CI2N2O6S
To a solution of N-tert-butyl-C-[4-chloro-2-(6-chloro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-methanesulfonamide (4 g, 8.79 mmol) in dichloromethane (50 ml_) at r.t was added di-tert-butyl-dicarbonate (6.54 g, 30 mmol), followed by the addition of 4-dimethylaminopyridine (3.66 g, 30 mmol). After stirred at room temperature overnight, the mixture was concentrated. The residue was purified by column chromatography to give the title compound as a yellow solid (3.8 g). Example 84e
Preparation of intermediate racemic (2'S, 3S, 4'R)-[2-(tert-butylsulfamoyl-methoxy)-5- chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-4'-2,6'-dioxo spiro[indole-3,3'-pipehdine]-1-carboxylic acid tert-butyl ester
Figure imgf000164_0001
M.W. 734.68 C35H38CI2FN3O7S
To a toluene solution of 1 -(5-fluoro-2-methylphenyl)-3-thmethylsilyoxy-2-aza-1 ,3- butadiene (10.8 mmol) prepared in Example 1d was added E/Z-3-[2-(tert- butylsulfamoyl-methoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1 - carboxylic acid tert-butyl ester (2 g, 3.61 mmol). After stirred at room temperature for 4 h, methanol was added. The stirring was continued for 1 h and the white solid was precipitated from the solvent. The precipitate was filtered and washed with diethyl ether to give the title compound (1.3 g).
Example 84f
Preparation of racemic (2'S, 3S, 4'R)-[2-(tert-butylsulfamoyl-methoxy)-5-chloro-phenyl]- 6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000164_0002
M.W. 634.56 i C30H30CI2FN3O5S At room temperature, TFA (114 mg, 1 mmol) was added a solution of racemic (2'S, 3S, 4'R)-[2-(tert-butylsulfamoyl-methoxy)-5-chloro-phenyl]-6-chloro-2'-(5-fluoro-2-methyl- phenyl)-2,6'-dioxo spiro[indole-3,3'-piperidine]-1 -carboxylic acid tert-butyl ester in DCM (2 ml_). Then the mixture was heated at 40 0C for 3 h. After cooled to room temperature, the mixture was concentrated and EtOAc was added. The precipitate was collected and dried to give the title compound (65 mg).
Example 85a
Preparation of intermediate (tetrahydro-pyran-4-yl)-methanol
Figure imgf000165_0001
M.W. 116.16 C6Hi2O2
At 0 0C, to a solution of 4-tetrahydropyran carboxylic acid methyl ester (28.83 g, 0.2 mol) in THF (200 ml_) was added LiAIH4 (7.6 g, 0.2 mol) in several portions. After stirred for 2 h, the reaction was quenched with water slowly. Then diethyl ether (300 ml_) was added and the mixture was filtered. The filtrate was washed with 2 N HCI and brine, dried and concentrated to give the title compound as a yellow oil (12.8 g).
Example 85b
Preparation of intermediate toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester
Figure imgf000165_0002
M.W. 270.35 Ci3Hi8O4S
At room temperature, a mixture of (tetrahydro-pyran-4-yl)-methanol (2.4 g, 20.7 mmol), p-toluenesulfonyl chloride (6.73 g, 35.4 mmol), thethylamine (6.6 ml_, 47.6 mmol) and DMAP (0.288 g, 2.36 mmol) in DCM (50 ml_) was stirred overnight. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as an oil (4.2 g)- Example 85c
Preparation of intermediate 5-chloro-2-(tetrahydro-pyran-4-yl-methoxy)-benzaldehyde
Figure imgf000166_0001
Figure imgf000166_0002
A mixture of 5-chlorosalicylaldehyde (5.0 g, 32 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-yl methyl ester (8.6 g, 32 mmol) and K2CO3 (9.5 g, 68.8 mmol) in DMF (50 ml_) was heated at 75 0C overnight. After cooled to room temperature, the mixture was poured into water. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (7.0 g).
Example 85d Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(tetrahydro-pyran-4-ylmethoxy) benzyl idene]-1 ,3-dihydro-indol-2-one
Figure imgf000166_0003
M.W. 404.30 C2iHi9CI2NO3
To the mixture of 6-xhlorooxindole (0.96 g, 5.7 mmol) and 5-chloro-2-(tetrahydro-pyran- 4-yl-methoxy)-benzaldehyde (2.03 g, 8.0 mmol) in methanol (90 ml_) was added pyrrolidine (0.67 ml_, 8.0 mmol) dropwise. Then the mixture was heated at 100 0C for 2 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (1.81 g). Example 85e
Preparation of intermediate E/Z-1 -(1 -tert-butoxy-vinyl)-6-chloro-3-[5-chloro-2- (tetrahydro-pyran-4-ylmethoxy)-benzylidene]-1 ,3-dihydro-indol-2-one
Figure imgf000167_0001
M.W. 504.41 C26H27CI2NO5
To a solution of E/Z-6-chloro-3-[5-chloro-2-(tetrahydro-pyran-4-ylmethoxy)-benzylidene]- 1 ,3-dihydro-indol-2-one (1.69 g, 4.2 mmol) in dichloromethane (25 ml_) at room temperature was added di-tert-butyl-dicarbonate (1.83 g, 8.4 mmol), followed by the addition of 4-dimethylaminopyhdine (1.23 g, 10.1 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solution concentrated. The residue was purified by column chromatography to give the title compound as a brown solid (2.02 g ).
Example 85f Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(tetrahydro- pyran-4-ylmethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione
Figure imgf000167_0002
M.W. 583.49 C3IH29CI2FN2O4 In a manner similar to the method described in ExampleiOd, E/Z-1 -(1-tert-butoxy-vinyl)- 6-chloro-3-[5-chloro-2-(tetrahydro-pyran-4-ylmethoxy)-benzylidene]-1 ,3-dihydro-indol-2- one (2 g, 3.97 mmol) was reacted with 1 -(5-fluoro-2-methyl-phenyl)-3-thmethylsilyoxy-2- aza-1 ,3-butadiene (20 mmol) in toluene to give the title compound as a white solid (770 mg). m/z (M+H)+: 583
Example 86a
Preparation of intermediate of E/Z-2-[4-chloro-2-(6-chloro-5-fluoro-2- oxo-1 ,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-ethyl-butyhc acid methyl ester
Figure imgf000168_0001
M.W 452.31 C22H20CI2FNO4 To the mixture of 6-chloro-5-fluoro-1 ,3-dihydro-indol-2-one (500 mg, 2.7 mmol) and 2- (4-chloro-2-formyl-phenoxy)-2-ethyl-butyhc acid methyl ester (844 mg, 2.97 mmol) in methanol (5 ml_) was added pyrrolidine (95 mg, 1.35 mmol) dropwise. The mixture was then heated at 70 0C for 1 h. After cooled to room temperature, the mixture was partitioned between EtOAc and diluted HCI solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product as a red-yellow solid, which was used for the next step reaction without further purification.
Example 86b Preparation of intermediate E/Z-6-chloro-3-[5-chloro-2-(1 -ethyl-1 - methoxycarbonylpropoxy)-benzylidene]-5-fluoro-2-oxo-2,3-dihydro-indole-1 -carboxylic acid tert-butyl ester
Figure imgf000169_0001
M.W. 552.43 C27H28CI2FNO6
To a solution of E/Z-2-[4-dhloro-2-(6-chloro-5-fluoro-2-oxo-1 ,2-dihydro-indol-3- ylidenemethyl)-phenoxy]-2-ethyl-butyric acid methyl ester (1.22 g, 2.7 mmol) in dichloromethane (10 ml_) at room temperature was added di-tert-butyl-dicarbonate (0.7 g, 3.24 mmol), followed by the addition of 4-dimethylaminopyhdine (0.05 g, 0.41 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solution was concentrated. The residue was purified by flash column to give the title compound as a yellow solid (1.4 g).
Example 86c
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - methoxycarbonyl-1 -ethyl-propoxy)-phenyl]-5-fluoro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione
Figure imgf000169_0002
M.W. 631.51 C32H30CI2F2N2O5
In a manner similar to the method described in ExampleiOd, E/Z-6-chloro-3-[5-chloro- 2-(1 -ethyl-1-methoxycarbonyl-propoxy)-benzylidene]-5-fluoro-2-oxo-2,3-dihydro-indole- 1 -carboxylic acid tert-butyl ester (1.4 g, 2.5 mmol) was reacted with 1 -(5-fluoro-2- methyl-phenyl)-3-trimethylsilyoxy-2-aza-1 ,3-butadiene (8 mmol) in toluene (8 ml_) to give the title compound (300 mg). m/z (M+H)+: 631 Example 86d
Preparation of intermediate racemic (2'S, 3S, 4'R)-6-chloro-5-fluoro-4'-[5-chloro-2-(1 - hydroxycarbonyl-1 -ethyl-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000170_0001
M.W. 617.48 C3IH28CI2F2N2O5
A mixture of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1-methoxycarbonyl-1-ethyl- propoxy)-phenyl]-5-fluoro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (120 mg, 0.19 mmol), LiOH. H2O (140 mg, 3.3 mmol), H2O (1.25 mL) and methanol (3.75 mL) was heated at 80 0C for 1 h. After cooled to room temperature, the mixture was acidified by addition of 0.5 N HCI and partitioned between EtOAc and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used for the next step reaction without further purification. m/z (IvRH)+: 617
Example 86e
Preparation of racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino- 1 ,1 -diethyl-2-oxo-ethoxy)-phenyl]-5-fluoro-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-
3,3'-piperidine]-2,6'(1 H)-dione
Figure imgf000170_0002
M.W 694.59 C32H3ICI2F2N3O6S A solution of racemic (2'S, 3S, 4'R)-6-chloro-5-fluoro-4'-[5-chloro-2-(1 -hydroxycarbonyl- 1 -ethyl-propoxy)-phenyl]-2'-(5-fluoro-2-nnethyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione (100 mg, 0.16 mmol) and CDI (123 mg, 0.64 mmol) in DMF (3 ml_) was heated at 75 0C for 3 h. Then to this solution was added a mixture of methanesulfonamide (144 mg, 1.5 mmol) and NaH (53 mg, 60%, 1.3 mmol) in DMF (1.5 ml_),which had been previously stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 20 mins, it was poured into water and the aqueous solution was acidified by diluted HCI solution. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound (50 mg). m/z (M+H)+: 694
Example 87 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 ICsn (uM, 0.02%BSA)
1g 0.278
8 0.327 1 1 0.065
29b 0.054
34d 0.155

Claims

Claims
1. A compound of the formula
Figure imgf000173_0001
wherein
X is -Cl, -F or -Br;
X' is hydrogen or -F; V is -F, -Cl or -Br;
V is hydrogen or -F;
Y is hydrogen, methyl, methoxy, -F or -Cl; W is -F, -Cl, -Br, -I, ethynyl or isopropenyl;
A is -O-, -NH-, -CH2-, -C(=O)-, -C(=O)NH-, -NHC(=O)- or -NHS(=O)2-; B is a bond or -(CH2)mCRiR2(CH2)n-; m=0 or 1 ; n=0 or 1 ;
Ri, R2 are hydrogen or lower alkyl, and in the case of Ri and R2 they may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl; provided that if
B is a bond, then
R is selected from heterocycle, substituted heterocyle, heteroaryl, substitluted heteroaryl, aryl, substituted aryl or substituted cycloalkyl; and if
B is not a bond, then
R is selected from -OR", -NR1R", -C(=O)NR'R", -NHC(=O)R", -NHS(=O)2R", -NHC(=O)NR'R" or -C(=O)NR'S(=O)2R", and R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and
the pharmaceutically acceptable salts, esters and enantiomers thereof.
2. The compounds according to claim 1 , wherein B is a bond.
3. The compounds according to claim 1 , wherein B is -(CH2)mCRiR2(CH2)n-.
4. The compound according to any one of claims 1 to 3, wherein X is -Cl;
X' is hydrogen or -F;
A is O; V is -F or -Cl;
V is hydrogen or -F;
Y is methyl, methoxyl, -Cl or -F; W is -Cl, -F or -Br; and
the remaining substituents have the meaning given in claim 1.
5. The compounds according to claim 1 or 4, wherein A is O;
B is -(CH2)mCRi R2(CH2)n-; m=0 or 1 ; n=O or 1 ;
Ri, R2 are hydrogen or lower alkyl; R is -C(=O)NR'R" or -C(=O)NR'S(=O)2R"; and
R', R" is 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" is not a hydrogen, and in the case of R and R they may independently link to form a cyclic structure selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle; and
the remaining substituents have the meanings given in claim 1.
6. A compound of claim 1 selected from the group consisting of racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1 - (1 -methyl-pipehdin-4- ylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -cyclobutylcarbamoyl-i -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(2-hydroxy- ethylcarbamoyl)-1-methyl- ethoxy] -phenyl}-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-{2- [1-(2-acetylamino-ethylcarbamoyl)-1 -methyl-ethoxy]-5- chloro-phenyl}-6-chloro-2'-(5- fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione,
(2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -(S-2,3-dihydroxy-propyl carbamoyl )-1-methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(2-methoxy-ethylcarbamoyl)-1 -methyl- ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(3-dimethylamino-propylcarbamoyl)-1- methyl-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -methyl-1 -(2-piperidin-1 -yl- ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)- 4'-[5-bromo-2- (2-nnethanesulfonylannino-1 ,1 -dinnethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5- fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipendine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonylaminocarbonyl- cyclobutoxy)-phenyl]-2'-(5- fluoro-2-methyl- phenyl)-spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2- [1 -(4-fluoro- benzenesulfonylaminocarbonyl)-cyclobutoxy]-phenyl}-2'-(5-fluoro-2-nnethyl- phenyl)- spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'- piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy) -phenyl]-6-chloro- 2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-isopropenyl- 2-(3-methyl-oxetan-3-ylmethoxy)- phenyl]-2'-(5-chloro-2-methyl- phenyl )-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-2'-(5-chloro-2-methyl-phenyl)- 4'-[5-ethynyl-2-(3-methyl- oxetan-3-ylmethoxy)-phenyl]-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 - tert-butoxycarbonyl-piperidin-4-yloxy)-5-chloro-phenyl]- 6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-pipehdinyloxy)-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-pipehdinyloxy)-5-chloro-phenyl]- 6-chloro-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole- 3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (1 -methanesulfonyl-4- pipehdinyloxy)- phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (pyhmidin-2-yloxy)-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H- indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2,2-dimethyl-3-oxo-3-pyrrolidin-1 -yl- propoxy)-phenyl]-2'-(5-fluoro-2-methylphenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-dimethylcarbamoyl- 2-methyl-propoxy)- phenyl]-2'-(5-fluoro-2-methylphenyl)- spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-{[(2-hydroxy- ethyl)-methyl-carbamoyl]- methoxy}- phenyl]-2'-[2,5-difluorophenyl] spiro[3H- indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2- dimethylcarbamoylmethoxy-phenyl]-2'- (2,5-difluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-oxo- 2-pyrrolidin-1 -yl-ethoxy) -phenyl]- 2'-(2,5-difluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-bromo-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-chloro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-{2-[2- (4-acetyl-piperazin-1 -yl)-1 ,1-dimethyl-2-oxo-ethoxy]-5- chloro-phenyl}-6-chloro-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -methyl-1 - (2,2,2-thfluoro- ethylcarbamoyl)-ethoxy]-phenyl}-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1 -yl)-1 ,1 - dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(4,4- difluoro-piperidin-1 -yl)-1 ,1 -dimethyl- 2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (3-methyl-oxetan-3-ylmethoxy) -phenyl]- 2'-(5-fluoro-2-methyl- phenyl )-spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy) - phenyl]-2'-(2,5-difluoro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(2-amino-ethoxy) 5-chloro-phenyl]-6-chloro-2'-(5-fluoro-2- methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2- methanesulfonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-[2- (3,3-dimethyl-ureido)-ethoxy]-phenyl]- 2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 - dimethylcarbamoyl-1 -methyl-ethoxy) - phenyl]-2'-(2-fluoro-5chloro-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-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'S, 3S, 4'R)-2'-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4'-
(3-fluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-
6-chloro-2'-(3-fluorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2'-(5- fluorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3- fluorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-piperidinyloxy)-phenyl]- 6-chloro-2'-(3- fluorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 - tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-
6-chloro-2'-(3-chlorophenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2'-(5- chlorophenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(1 -acetyl-4-piperidinyloxy)-5-bromo-phenyl]- 6-chloro-2'-(3- chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[5-bromo-2-(1 -methyl-4-piperidinyloxy)-phenyl]- 6-chloro-2'-(3- chlorophenyl) spiro[3H-indole- 3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-ethoxy)-phenyl]-2'-
(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-6-chloro-2'-(2-chloro-5-fluoro-phenyl)-4'-[5-chloro-2-(2- methanesulfonylamino-1 ,1 -dimethyl-2-oxo-ethoxy)-phenyl] spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl- ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methoxylcarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyanocarbamoyl-1-methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -hydroxycarbamoyl-1 -methyl-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro- 4'-[5-fluoro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]- 2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(4-methoxy-phenoxy)-phenyl]-2'-(5-fluoro- 2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-tert-butoxycarbonylamino-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[(2-cyclobutanecarbonyl-amino)-ethoxy]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyano-2-cyclopropyl-methoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -cyano-cyclopentyl-methoxy)-phenyl]-2'- (5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2- methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-cyanomethoxy-phenyl]-2'-(5-fluoro-2-methyl- phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-phenyl]-6- chloro -2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(piperazin-1 -yl)-phenyl]-2'-(5-fluoro-2- methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-4'-[2-(4-acetyl-piperazin-1 -yl)-5-chloro-phenyl]-6-chloro-2'-(5- fluoro-2-methyl phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-cyclopropanesulfonylamino-1 ,1 -dimethyl- 2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-pipehdine]- 2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-trifluoro-methanesulfonylamino-1 ,1- dimethyl-2-oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'R, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(2,3-difluoro-6-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-2-oxo-ethoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)- 4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5-chloro-2-methoxy-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -hydroxycarbonyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -dimethylcarbamoyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -dimethylcarbamoyl-propoxy)- phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(2-hydroxy- ethylcarbamoyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-2,3-dihydroxy- propylcarbamoyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 -carbonyl)- propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -(pyrrolidine-1 -carbonyl)-propoxy]- phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-pipehdine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((S)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[1 -ethyl-1 -((R)-3-hydroxy-pyrrolidine-1 - carbonyl)-propoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'-
(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -carbamoyl-1 -ethyl-propoxy)-phenyl]-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-1 -acetyl-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2-(1 -ethyl-1 -methanesulfonylaminocarbonyl- propoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, chiral (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-ethanesulfonylamino-1 ,1-dimethyl-2-oxo-ethoxy)- phenyl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2-oxo- ethoxy)-phenyl]-6-chloro-2'-(5-methyl-2-methoxy-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(3-methanesulfonylamino-2,2-dimethyl-3- oxo-propoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione, chiral (2'R, 3R, 4'S)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'- piperidine]-
2,6'(1 H)-dione> racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl-2- oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(2-methanesulfonylamino-1 ,1 -dimethyl -2- oxo-ethoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-{5-chloro-2-[2-(2-methoxy-ethanesulfonylamino)-1 ,1 - dimethyl-2-oxo-ethoxy]-phenyl}-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylaminocarbonyl-1-propyl- butoxy)-phenyl]-2'-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylaminocarbonyl-1- propyl-butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-
2,6'(1 H)-dione, chiral (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2-(1 -methanesulfonylaminocarbonyl-1-propyl- butoxy)-phenyl]-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)- dione, racemic (2'S, 3S, 4'R)-6-bromo-4'-[5-chloro-2-(1 -ethyl-1 - methanesulfonylaminocarbonyl-propoxy)-phenyl]- 2'-(5-fluoro-2-methyl-phenyl)- spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-6-chloro-4'-(5-chloro-2-methanesulfinylmethoxy-phenyl)-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione, racemic (2'S, 3S, 4'R)-[2-(tert-butylsulfamoyl-methoxy)-5-chloro-phenyl]-6-chloro-2'-(5- fluoro-2-methyl-phenyl) spiro[3H-indole-3,3'-piperidine]-2,6'(1 H)-dione and racemic (2'S, 3S, 4'R)-6-chloro-4'-[5-chloro-2- (2-methanesulfonylamino-1 ,1 -diethyl-2- oxo-ethoxy)-phenyl]-5-fluoro-2'-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3'- piperidine]-2,6'(1 H)-dione.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, together with a pharmaceutically acceptable carrier or excipient.
8. A compound according to any one of claims 1 to 6 for the use as a medicament.
9. A compound according to any one of claims 1 to 6 for the use as a medicament for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
10. The use of a compound according to any one of claims 1 to 6 for the manufacture of medicaments for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
11. The novel compounds, methods, processes and uses substantially as described herein before.
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