Patent Grant
8058269
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.
The present invention relates to oxindole derivatives which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents. The present compounds are of the general formula
wherein R6, W, X, Y, V, Q and n are as hereinafter described.
The present invention relates to compounds of the formula
R11 is selected from the group consisting of hydrogen, lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, lower-alkoxy, thio-lower-alkoxy, lower-alkylsulfonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, 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, N(H, lower-alkyl)-carbonyl, N(lower-alkyl)2-carbonyl,
R12 is selected from the group consisting of hydrogen, lower alkyl, aminocarbonyl, lower-alkylsulfonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkoxycarbonyl, fluoro-lower-alkyl, N(H, lower-alkyl)-carbonyl, N(lower-alkyl)2-carbonyl, 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,
R13 is selected from the group consisting of hydrogen, lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), hydroxy, CN, NH2, heterocycloalkyl, N(H, lower-alkyl), N(lower-alkyl)2, lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyloxy, 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, lower-alkyl which can optionally be substituted with halogen, hydroxy, NH2, N(H, lower-alkyl) or N(lower-alkyl)2, N(H, lower-alkyl)-carbonyl, N(lower-alkyl)2-carbonyl,
Preferred are compounds wherein Y is
Also preferred are compounds wherein Y is
Further preferred of the compounds immediately above are those wherein
Especially preferred are compounds of the formula
rac-6-chloro-3-(3-chloro-benzyl)-3-{cyclohexyl-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amino}-1,3-dihydro-indol-2-one,
rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2′,3′-dihydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester,
rac-2-{(R)-Bicyclo[2.2.1]hept-2-yl-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-amino}-N-cyclobutyl-acetamide,
In the specification, where indicated, the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, aminocarbonyl, carboxy, NO2, lower-alkoxy, thio-lower-alkoxy, lower-alkylsulfonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, carbamoyl-lower cycloalkyl, 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 alkyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl and amino.
The term “alkyl” refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term “lower alkyl” refers to alkyl groups having from 1 to 6 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, “cycloalkyl” is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term “cycloalkenyl” is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term “alkenyl” as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 6, preferably 2 to 4 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, bromine, or iodine, preferably fluorine and chlorine.
“Aryl” means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
“Heteroaryl” means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
“Heterocycle” or “heterocycloalkyl” means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like.
“Hetero atom” means an atom selected from N, O and S.
“Alkoxy, alkoxyl or lower alkoxy” refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
“Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
The compounds of formula I as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography.
Compounds disclosed herein and covered by formula I above may exhibit tautomerism or structural isomerism. It is intended that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural isomeric form depicted in formula I above.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
“Effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
“IC50” refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
Compounds of this invention can be synthesized according to the following general schemes. It will be readily apparent to those of ordinary skill in the art that compounds in formula I can be prepared by substitution of the reagents or agents in the general synthesis routes. The starting materials are either commercially available or can be synthesized by well-established literature methods known to those of ordinary skill in the art. For example, the 6-substituted oxindole I starting materials were either commercially available or prepared from the corresponding 4-substituted 2-nitro-fluoro or chlorobenzene according to Kraynack, E. A.; Dalgard, J. E.; Gaeta, F. C. A. Tetrahedron Letters, 1998, 39, 7679-7682. 4, 6-disubstituted oxindole I can be synthesized similar to the procedures exemplified in EP0869122A1, or Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y. et al, J. Med. Chem. 2003, 46, 1116-1119, or Crestini, C.; Saladino, R. Synthetic Communications, 1994, 24, 2835-2841. 3-Mono-substituted 1,3-dihydro-indol-2-one II can be synthesized by multiple methods. These include, among others, the methods of Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45, 1487-1499 or Elliott, I. W.; Rivers, P. J. Org. Chem. 1964, 29, 2438-2440 and Andreani, A.; Rambaldi, M.; Locatelli, A.; Bossa, R.; Galatulas, I.; Ninci, M. Eur. J. Med. Chem. 1990, 25, 187-190 (Scheme 1). Oxindole I can be reacted with an appropriately substituted aldehyde in the presence of base under heated condition in either a protic like methanol, ethanol to give intermediate II. The commonly used base is either pyrrolidine or piperidine. Intermediate II can then be readily reduced by NaBH4 in methanol or ethanol to afford intermediate IV. Bromination of 3-position by pyridinium tribromide can be achieved in tert-butanol at room temperature. Subsequent nucleophilic displacement of bromide by R2R9NH or R2OH leads to the desired product V or VI.
Modified glycine intermediate VIII can be prepared by reductive amination of glycine starting material VII with varied aldehyde or ketone using NaCNBH3. Nucleophilic substitution of bromide in V by intermediate VIII generate IX. Hydrolysis of IX lead to the formation of carboxylic acid intermediate X. Derivatized compound XI can be prepared starting from acid X by using well-known coupling methods for carboxamide formation.
In a similar manner to the method described in Scheme 1, anthranilic acid XIII can be prepared from intermediate V and anthranilic acid XII. XII is either commercially available or readily prepared according to the well-established literature procedure. Various compounds XIV can be prepared from acid XIII and amine R1R6NH by using well-known coupling methods for carboxamide formation.
Sulfone analogue XVII can be formed from intermediates XVI and XVIII in a similar fashion as V in Scheme 1 (Scheme 4). Intermediate XVI is synthesized from commercially available, α,β-unsaturated XV and varied amine R2NH2 in one step by a Michael addition type reaction.
Diverse derivatives XXIV and XXV can be achieved according to the general Scheme 5. Intermediate XXI is prepared in two steps starting from commercially available compound XIX. Similar to the method in Scheme 1, compound XXII is formed by the nucleophilic displacement of Br by XXI. Deprotection of Boc group by trifluoroacid acid leads to amine intermediate XXIII. Subsequently compound XXIV or XXV can be prepared by selectively attaching a derivatized acyl or sulfonyl group on the R2NH. R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heterocycle or substituted heterocycle.
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.
To the mixture of 6-chlorooxindole (16.7 g, 0.1 mol) (Crescent) and 3-chlorobenzaldehyde (14.1 g, 0.1 mol) (Aldrich) in methanol (100 mL) was added pyrrolidine (7.1 g, 0.1 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 20 g of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 1a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 hr-1 hr. After adding to water (200 mL), the resulting precipitate was collected and dried to give 18 g of rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
Pyridinium bromide perbromide (21.7 g, 68 mmol) (Aldrich) was added in one portion to a solution of rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (18 g, 62 mmol) (from example 1b supra) in t-BuOH (400 mL) and water (2 mL) at room temperature with stirring. After stirring at room temperature for 4 h, the mixture was diluted with water (500 mL) and stirred for 1 h. The resulting precipitate was collected and dried to give 22 g of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a pale yellow solid. MS: 371 (M+H)+.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 4-propoxy-phenylamine (61 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in propan-2-ol (10 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the desired product was precipitated out, then filtrated and dried to give 98 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one as a white solid. MS: 441 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 452 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 443 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 443 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 441 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 419 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 427 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 401 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 419 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 435 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 480 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 411 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 441 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.22 (m, 1H), 7.15 (m, 2H), 7.02 (dd, 1H), 6.86 (t, 1H), 6.76 (d, 1H), 6.64 (d, 1H), 6.54 (m, 2H), 6.18 (m, 3H), 4.28 (m, 1H), 3.24 (dd, 2H), 1.13 (d, 6H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 452 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 419 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.22 (m, 3H), 7.05 (m, 2H), 6.84 (m, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 6.15 (m, 1H), 5.96 (m, 1H), 3.31 (d, 1H), 3.14 (d, 1H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 467 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.22 (m, 3H), 7.05 (m, 3H), 6.86 (t, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.46 (m, 1H), 6.19 (dd, 1H), 6.12 (d, 1H), 3.29 (d, 1H), 3.15 (d, 1H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 413 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 449 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.20 (m, 3H), 7.03 (dd, 1H), 6.85 (t, 1H), 6.80 (d, 2H), 6.76 (d, 1H), 6.70 (d, 1H), 6.66 (d, 1H), 6.22 (m, 2H), 3.29 (d, 1H), 3.15 (d, 1H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 449 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 451 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 455 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 425 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 383 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 413 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 451 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.22 (m, 5H), 7.03 (d, 1H), 6.86 (t, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.70 (d, 1H), 6.57 (s, 1H), 6.35 (dd, 1H), 3.31 (d, 1H), 3.17 (d, 1H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 408 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 427 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 417 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 476 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 476 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 415 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 419 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 451 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 401 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 415 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 431 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 437 (M+H)+.
H1-NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.22 (m, 4H), 7.07 (dd, 2H), 6.84 (t, 1H), 6.76 (d, 1H), 6.71 (d, 1H), 5.96 (m, 2H), 3.31 (d, 1H), 3.14 (d, 1H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 417 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 431 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 399 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 413 (M+H)+.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), cyclohexylamine (40 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in dimethyl formide (2 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated and the residue was purified by preparative HPLC to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one as a white solid. MS: 389 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 375 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 403 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 347 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 421 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 407 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 405 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 361 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 418 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 391 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 377 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 363 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 407 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 418 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 390 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 470 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 521 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 395 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 393 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 347 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 391 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 390 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.40 (d, 1H), 7.13 (m, 3H), 6.89 (s, 1H), 6.80 (d, 1H), 6.59 (s, 1H), 3.37 (dd, 2H), 2.88 (s, 4H), 2.33 (s, 4H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 405 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 393 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.20 (m, 1H), 7.18 (t, 1H), 7.00 (m, 3H), 6.80 (m, 1H), 6.66 (t, 1H), 4.21 (t, 1H), 3.29 (m, 1H), 3.19 (m, 1H), 3.31 (d, 1H), 2.83 (d, 1H), 2.47 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H), 0.70 (dd, 6H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 417 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 395 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 406 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.30 (d, 1H), 7.13 (m, 3H), 6.96 (t, 1H), 6.87 (t, 1H), 6.78 (m, 2H), 6.57 (s, 1H), 3.33 (m, 1H), 3.17 (dd, 2H), 2.84 (d, 1H), 1.72 (m, 1H), 0.80 (dd, 6H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 421 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 404 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.82 (d, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 7.08 (m, 3H), 6.79 (s, 1H), 6.70 (d, 1H), 6.55 (s, 1H), 4.40 (d, 1H), 3.19 (dd, 2H), 2.75 (m, 1H), 2.21 (m, 1H), 1.90 (m, 2H), 1.60 (m, 2H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 381 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 477 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 403 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 365 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 441 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ12.45 (s, 1H), 10.42 (s, 1H), 7.44 (d, 1H), 7.16 (m, 4H), 6.96 (m, 1H), 6.93 (m, 3H), 6.76 (m, 1H), 6.67 (d, 1H), 6.64 (d, 1H), 4.00 (dd, 2H), 3.31 (dd, 2H).
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 4-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (100 mL) was added pyrrolidine (6.55 g, 92 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 21 g of E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of 6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 76a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 h-1 h. After water (200 mL) was added, the resulting precipitate was collected and dried to give 18.3 g of rac-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
The title compound was prepared by the same procedure for rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 371 (M+H)+.
The solution of bromine (2.2 g, 14.4 mmol) in dichloromethane (10 mL) was added dropwisely to the solution of rac-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one (2.0 g, 6.85 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 1 h and then washed with water (3×50 mL), dried over Na2SO4 and concentrated in vacuo to give 2.2 g of rac-3,5-dibromo-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one as a solid. MS: 451 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 389 (M+H)+. H1-NMR (400 MHz, Acetone-d6) δ 7.30 (d, 1H), 7.10 (d, 2H), 7.05 (dd, 1H), 6.80 (d, 2H), 6.72 (d, 1H), 3.00 (dd, 2H), 2.20 (m, 1H), 1.15 (m, 5H), 1.00 (m, 5H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 469 (M+H)+.
To the mixture of 2-chloro-1-piperidin-1-yl-ethanone (41 mg, 31 mmol) and KI (43 mg, 0.26 mmol) in dimethylformide (5 mL) was added rac-3-bromo-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.26 mmol) prepared in example 76c. After stirring at room temperature for 2 h, water (10 mL) was added and the crude was extracted with ethyl acetate (3×20 mL). The combined organic solution was concentrated in vacuo. The residue was purified with preparative HPLC to give rac-6-chloro-3-(4-chloro-benzyl)-3-cyclohexylamino-1-(2-oxo-2-piperidin-1-yl-ethyl)-1,3-dihydro-indol-2-one as a white solid. MS: 514 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(4-chloro-benzyl)-3-cyclohexylamino-1-(2-oxo-2-piperidin-1-yl-ethyl)-1,3-dihydro-indol-2-one
MS: 594 (M+H)+; H1-NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.19 (m, 2H), 7.09 (s, 1H), 6.84 (d, 2H), 4.33 (dd, 2H), 3.40 (m, 4H), 3.00 (dd, 2H), 2.62 (d, 1H), 2.20 (m, 1H), 1.57 (m, 10H), 0.90 (m, 6H).
To a solution of cyclohexylamine (45 g, 0.45 mol) in dichloromethane (100 mL) was slowly added bromo-acetic acid ethyl ester (15 g, 0.09 mol) in dichloromethane (150 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 1 h and then washed with water (3×200 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography (DCM: MeOH=30:1) to give cyclohexylamino-acetic acid ethyl ester as an oil. MS: 186 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-1H-indol-2-one. MS: 476 (M+H)+; H1-NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.50 (d, 1H), 7.11 (dd, 1H), 7.04 (m, 1H), 6.93 (t, 1H), 1H), 6.78 (t, 1H), 6.66 (d, 2H), 4.35 (d, 1H), 4.18 (q, 2H), 3.59 (d, 1H), 3.31 (d, 1H), 3.17 (d, 1H), 2.66 (m, 1H), 1.66 (m, 6H), 1.30 (t, 3H), 1.00 (m, 4H).
To the mixture of methanol (120 mL) and water (30 mL) were added rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-yl]-cyclohexyl-amino}-acetic acid ethyl ester.
(5 g, 105 mmol) and KOH (0.8 g, 210 mmol). After the reaction mixture was heated at reflux for overnight, the crude was concentrated. Then water (100 mL) was added. The mixture was acidified with HCl to PH=4 and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give 4.7 g of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid as a light yellow solid. MS: 447 (M+H)+.
To the mixture of DIPEA (43 mg, 0.33 mmol), HATU (64 mg, 0.17 mmol) and 1-piperazin-1-yl-ethanone (22 mg, 0.17 mmol) in dichloromethane (3 mL) was added rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-yl]-cyclohexyl-amino}-acetic acid (50 mg, 0.11 mmol). After the mixture was stirred at room temperature for 3 h, the crude was washed with water (3×10 mL). The organic solution was concentrated in vacuo and the residue was puritificated by preparative HPLC to give 24 mg of rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. MS: 557 (M+H)+.
To a solution of DIC (21 mg, 0.17 mmol) in dichloromethane (3 mL) was added rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-yl]-cyclohexyl-amino}-acetic acid (50 mg, 0.11 mmol). After the mixture was stirred at room temperature for 3 h, the crude was washed with water (3×10 mL). The organic solution was concentrated in vacuo and the residue was purified by preparative HPLC to give 21 mg of rac-1-(2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetyl)-1,3-diisopropyl-urea as a white solid. MS: 573 (M+H)+
H1-NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.26 (s, 2H), 7.00 (dd, 1H), 6.96 (t, 1H), 6.83 (t, 1H), 6.67 (s, 1H), 6.55 (d, 1H), 6.47 (d, 1H), 4.42 (d, 1H), 4.28 (m, 1H), 3.92 (m, 1H), 3.59 (d, 1H), 3.17 (dd, 2H), 2.64 (m, 1H), 1.57 (m, 6H), 1.35 (dd, 6H), 1.15 (dd, 6H), 0.90 (m, 4H).
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 616 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 529 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 557 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 574 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 559 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 540 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.12 (d, 1H), 7.78 (d, 1H), 7.12 (m, 3H), 6.70 (s, 1H), 6.66 (d, 1H), 6.50 (s, 1H), 4.32 (m, 1H), 3.91 (d, 1H), 3.48 (d, 1H), 3.21 (dd, 2H), 2.47 (m, 1H), 2.12 (m, 4H), 1.38 (m, 12H).
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 516 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 531 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 558 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 556 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 529 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 526 (M+H)+. H1-NMR (400 MHz, DMSO-d6) δ10.30 (s, 1H), 8.40 (t, 1H), 7.80 (d, 1H), 7.52 (q, 1H), 7.13 (m, 2H), 7.03 (t, 1H), 6.67 (t, 1H), 6.58 (d, 1H), 6.52 (d, 1H), 6.38 (m, 2H), 4.44 (m, 2H), 4.13 (d, 1H), 3.50 (d, 1H), 3.17 (dd, 2H), 2.42 (m, 1H), 1.12 (m, 10H).
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 518 (M+H)+.
To trifluoroacetic acid (1 mL) was added rac-4-(2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro!-indol-3-yl]-cyclohexyl-amino}-acetyl)-piperazine-1-carboxylic acid-butyl ester (100 mg, 0.163 mmol). After the mixture was stirred at room temperature for 1 h, the crude was concentrated in vacuo to give 68 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-oxo-2-piperazin-1-yl-ethyl)-amino]-1,3-dihydro-indol-2-one as a solid.
MS: 515 (M+H)+; H1-NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.82 (s, 1H), 7.52 (d, 1H), 7.09 (d, 1H), 6.96 (d, 1H), 6.87 (t, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.51 (d, 1H), 3.99 (m, 6H), 3.30 (m, 6H), 2.82 (m, 1H), 1.22 (m, 10H).
To the aqueous solution K2CO3 (1.6 μL, 1N) was added (2S)-amino-4-methyl-pentanoic (106 mg, 0.81 mmol), then followed by the addition of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.54 mmol) in dioxane (5 mL). After the mixture was stirred at room temperature for 4 h, the reaction mixture was concentrated in vacuo. Water (10 mL) was added and the crude was acidified with HCl to PH=4. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated in vacuo. The residue was purified by chromatography (DCM: MeOH=80:1) to give 184 mg of rac-(2S)-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-4-methyl-pentanoic acid as a white solid. MS: 421 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.12 (m, 5H), 6.93 (t, 1H), 6.76 (m, 2H), 3.32 (m, 1H), 3.16 (dd, 2H), 1.89 (m, 1H), 1.50 (m, 2H), 0.90 (dd, 6H).
The title compound was prepared by the same procedure for rac-(2S)-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-ylamino]-4-methyl-pentanoic acid. MS: 407 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 551 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 524 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 538 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 553 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 510 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 484 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 531 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 490 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 532 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 464 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 504 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 528 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 522 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 488 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 502 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 486 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one. MS: 435 (M+H)+
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.270 mmol), 1-(4-trifluoromethyl-phenyl)-piperazine (75 mg, 0.324 mmol) and DIPEA (42 mg, 0.324 mmol) In acetonitrile (3 mL) was stirred at room temperature for overnight. The crude was concentrated and the residue was purified with preparative HPLC to give 76 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one as a white solid. MS: 520 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 7.584 (s, 1H), 7.493 (d, 2H), 7.240 (d, 1H), 7.081 (t, 2H), 7.011 (t, 1H), 6.908 (d, 3H), 6.766 (d, 1H), 6.684 (d, 1H), 3.431 (d, 1H), 3.329-3.206 (m, 5H), 2.947 (t, 4H).
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one. MS m/z 486 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one. MS m/z 452 (M+H)+.
The mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetic acid (70 mg, 0.159 mmol), cyclohexylamine (19 mg, 0.191 mmol) EDC.HCl (36 mg, 0.191 mmol), HOBt (26 mmg, 0.191 mmol) and DIPEA (25 mg, 0.191 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and the residue was purified with chromatography to give 45 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide as a yellow solid. MS m/z 522 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 482 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 508 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 480 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 516 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 567 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 494 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 535 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 609 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 523 (M+H)+.
To an aqueous solution of NaOH (1N, 10 mL) at 0° C. was added L-2-amino-3-phenyl-propionic acid (1.47 g, 8.92 mmol), followed by the addition of solution of 3,6-dichloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (3 g, 8.1 mmol) in 1,4-dioxane (3 mL). After the reaction mixture was stirred at 0° C. for 4 h, the solution was concentrated and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated.
The residue was purified with preparative HPLC to give rac-(2S)-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-lamino]-3-phenyl-propionic acid. ???? MS m/z 455 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 552 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 538 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 498 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 567 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide MS m/z 565 (M+H)+.
The mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetic acid (70 mg, 0.159 mmol), piperazine-1-carboxylic acid tert-butyl ester (36 mg, 0.191 mmol), EDC.HCl (36 mg, 0.191 mmol), HOBt (26 mmg, 0.191 mmol) and DIPEA (42 mg, 0.191 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated.
The residue was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 0.5 h. Then the solution was concentrated and the residue was purified by preparative HPLC to give 5.8 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[(2-oxo-2-piperazin-1-yl-ethyl)-phenyl-amino]-1,3-dihydro-indol-2-one as a yellow solid. MS m/z 509 (M+H)+
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1 g, 2.703 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.604 g, 3.24 mmol) and DIPEA (0.419 g, 3.24 mmol) in acetonitrile (20 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated to give 1.1 g of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS m/z 476 (M+H)+.
The mixture of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (900 mg, 1.89 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 0.5 h. Then the solution was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated to give 0.6 g of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one as a yellow solid. MS m/z 376 (M+H)+.
The mixture of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one (100 mg, 0.266 mmol), benzoyl chloride (37 mg, 0.266 mmol) and DIPEA (34 mg, 0.266 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. Then the mixture was concentrated and the residue was purified with preparative HPLC to give 29 mg of rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light orange solid. MS m/z 480 (M+H)+.
The title compound was prepared following the same procedure for rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS m/z 516 (M+H)+
The title compound was prepared following the same procedure for rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS m/z 522 (M+H)+.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (740 mg, 2 mmol), 3-amino-benzoic acid (301 mg, 2.2 mmol) and K2CO3 (552 mg, 4 mmol) in DMF (5 mL) was stirred for 0.5 h and then poured into water (100 mL). The resulting solution was acidified by acetic acid and filtered. The filter cake was washed by water and dried to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid as a pale yellow solid. MS m/z 425 (M−H)−.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS m/z 425 (M−H)−.
To the mixture of piperidine-3-carboxylic acid (600 mg, 4.5 mmol) and NaOH (360 mg, 9 mmol) in water (5 mL) and dioxane (5 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.1 g, 3 mmol). The mixture was stirred at room temperature for 1 h and then diluted by water (30 mL). The resulting solution was neutralized to pH=7 with hydrochloride acid and extracted by dichloromethane. The organic phase was dried over Na2SO4, filtered and concentrated to give rac-1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-3-carboxylic acid yield: (0.9 g, 71%). MS: [M−H]−=417.
The mixture of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (60 mg, 0.14 mmol), 1-methyl-piperazine (56 mg, 0.56 mmol) and EDCl (54 mg, 0.28 mmol) in dichlorometahne (2 mL) was stirred at room temperature for overnight. The reaction mixture was purified by preparative HPLC to give rac-6-chloro-3-(3-chloro-benzyl)-3-[3-(4-methyl-piperazine-1-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a powder. 1H NMR (CDCl3, 400 MHz): δ 7.21-6.74 (m, 9H), 6.49 (d, 1H), 6.17 (s, 1H), 4.70 (s, 1H), 3.80-3.45 (br, 8H), 3.28-3.15 (q, 2H), 2.66 (s, 3H). MS: [M+H]+=509
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=537
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=553
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=539
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=537
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=529
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=529
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=488
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=539
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=501
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=531
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=545.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=496.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=589.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=564
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=605.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=565.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=631.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=545.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=462.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=492.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=531.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=504.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=537.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=537.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=553.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=496.
To a solution of triphosgene (3 g, 10 mmol) in dichloromethane (150 mL) at −10° C. was added pyridine (1.6 mL, 20 mmol), followed by the addition of a solution of (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (4 g, 20 mmol) in dichloromethane (5 mL). The mixture was allowed to warm up to room temperature and stirred at room temperature for 4 h. Then the mixture was cooled to −10° C. again and HCl (1N, 20 mL) was added. After the mixture was stirred at −10° C. for 0.5 h, the mixture was partitioned. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography to give 2 g of (3S)-(chloro-carbonyl-amino)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil.
The mixture of (3S)-(chloro-carbonyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol), 1-methyl-piperazine (100 mg, 1 mmol) and Na2CO3 (1 g, 9.4 mmol) in dichloromethane (5 mL)) was stirred at room temperature for 4 h. Then the mixture was diluted with dichloromethane (10 mL), washed with water, dried over Na2SO4 and concentrated to give 300 mg of (3S)-[(4-methyl-piperazine-1-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil.
(3S)-[(4-methyl-piperazine-1-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.15 mmol) was dissolved in TFA (2 mL) and stirred for 0.5 h. The mixture was concentrated in vacuo and the residue was dissolved in dioxane (2 mL) and DMF (0.5 mL). To the above solution were added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (40 mg, 0.11 mmol) and DIPEA (220 mg, 1.7 mmol). The resulting mixture was stirred for 1 h, concentrated in vacuo. The residue was purified by preparative HPLC to give 29 mg of rac-(4-methyl-piperazine-1-carboxylic acid{1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-(3S)-yl}-amide. MS: [M+H]+=516
The title compound was prepared following the similar procedure as rac-4-methyl-piperazine-1-carboxylic acid{1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-(3S)-yl}-amide. MS: [M+H]+=546
The title compound was prepared following the similar procedure as rac-4-methyl-piperazine-1-carboxylic acid{1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-(3S)-yl}-amide. MS: [M+H]+=503.
The title compound was prepared following the similar procedure as rac-4-methyl-piperazine-1-carboxylic acid{1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-(3S)-yl}-amide. MS: [M+H]+=560.
The title compound was prepared following the similar procedure as rac-4-methyl-piperazine-1-carboxylic acid{1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-(3S)-yl}-amide. MS: [M+H]+=544.
To a solution of cyclopropanemethylamine (142 mg, 2.0 mmol) in dichloromethane (20 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.37 g, 0.99 mmol). After the mixture was stirred at room temperature for 1 h, another portion of dichloromethane (20 mL) was added. The mixture was washed with water (20 mL×2). The organic layer was separated, dried over Na2SO4 and concentrated to give 0.34 g of rac-6-chloro-3-(3-chloro-benzyl)-3-(cyclopropylmethyl-amino)-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=361
To the mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid (22 mg) and morpholine (6 mg) in dichloromethane (2 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg) and 4-dimethylaminopyrimidine (12 mg). After stirred for 3 h at room temperature, the mixture was purified with chromatograghy to give 20 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-2-oxo-ethyl)-amin-1,3-dihydro-indol-2-one as a white solid MS: [M+H]+=516.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: [M+H]+=529.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: [M+H]+=557.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: [M+H]+=559.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: [M+H]+=573.
The mixture of 2-amino-4-chloro benzoic acid (171 mg, 1 mmol) and K2CO3 (200 mg, 1.4 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The mixture was then poured into ice water, followed by the addition of HCl (1N) until pH ˜7. The mixture was extracted with dichloromethane (50 ml×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 320 mg of rac-4-chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid as a white solid. MS: [M+H]+=461.
The mixture of 4-chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (23 mg, 0.05 mmol), morpholine (26 mg, 0.3 mmol) and EDCl (15 mg, 0.08 mmol) in dichloromethane (1 mL) was stirred at room temperature for overnight. The crude was then purified with chromatography to give 22 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=530.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=570.9.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=542.9.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=573.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=587.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=571.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), N-phenylethanolamine (165 mg, 1.2 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (2 mL) was stirred at room temperature for 3 h. The mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[(2-hydroxy-ethyl)-phenyl-amino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=427.
The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), 2-phenylamino-acetamide (200 mg, 1.33 mmol) and K2CO3 (300 mg, 2.2 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was poured into water (30 ml), extracted with ethyl acetate (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 60 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=439.8.
The mixture of 3-methoxyaniline (3.7 g), ethyl bromoacetate (5 g) and triethylamine (4 g) in dichloromethane (30 mL) was stirred at room temperature for overnight. The mixture was washed with water (50 ml), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 1.7 g of (3-methoxy-phenylamino)-acetic acid ethyl ester. 1HNMR: δ 1.33 (3H), 3.796 (3H), 3.92 (2H), 4.26 (2H), 6.21 (1H), 6.29 (1H), 6.36 (1H), 7.13 (1H).
The title compound was prepared following the similar procedure as rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=499.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one. MS m/z 496 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS m/z 461 (M−H)−.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS m/z 487 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS m/z 457 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 532 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 556 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 526 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 490 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 476 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 575 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS m/z 589 (M+H)+.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=514.
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-{3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-1,3-dihydro-indol-2-one. MS: [M+H]+=529
Sodium borohydride (2.0 g, 53 mmol) (Aldrich) was added in small portions to a mixture of 6-Chloro-1H-indole (1.0 g, 6.6 mmol) (Aldrich) in TFA (10 mL), which was cooled in ice-water bath, at such a rate that gas evolution was not too vigorous. When the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with Na2CO3 solution, dried with Na2SO4, and concentrated to give 0.6 g crude 6-Chloro-2,3-dihydro-1H-indole. MS: [M+H]+=154
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 6-Chloro-2,3-dihydro-1H-indole (62 mg, 0.45 mmol) and K2CO3 (110 mg, 0.80 mmol) in DMF (1 mL) was stirred at room temperature overnight. Then water (10 mL) was added and the desired product was precipitated out. The crude product was purified by prep-HPLC to give 55 mg rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=443
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=443
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=409
Sodium cyanoborohydride (750 mg, 12 mmol) (Aldrich) was added in small portions to a mixture of 6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol) (Aldrich) in TFA (10 mL), which was cooled in ice-water bath, at such a rate that gas evolution was not too vigorous. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2.5 hr. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with Na2CO3 solution, dried with Na2SO4, and concentrated to give 400 mg rac-6-Methoxy-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester. MS: [M+H]+=222
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=511
A mixture of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester (250 mg, 0.5 mmol), NaOH (40 mg, 1.0 mmol) in methanol (4 mL) and water (2 mL) was heated to reflux for 3 hr. Then the mixture was concentrated in vacuo to remove methanol. Water (10 mL) was added to the residue. The resulting mixture was acidified with acetic acid, extracted with ethyl acetate. The organic layer was washed with water, dried with Na2SO4, concentrated in vacuo to give 250 mg rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid. MS: [M−H]−=481
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=536
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=564
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=595
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=566
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=556
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=542
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=597
The solution of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester (1.0 g, 1.9 mmol) and DDQ (0.73 g, 3.2 mmol) in toluene (50 mL) was heated to 90° C. for 4 h. Then the mixture was cooled to room temperature and washed with NaOH solution (10%) and water. The organic layer was dried with Na2SO4, concentrated in vacuo to give 0.9 g rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2′-oxo-2′,3′-dihydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester as yellow solid. MS: [M+H]+=513
The title compound was prepared following the similar procedure as rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid. MS: [M−H]−=483
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=538
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=595
The title compound was prepared following the similar procedure as rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: [M−H]−=449
The title compound was prepared following the similar procedure as rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: [M−H]−=503
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=574
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=520
From 2-hydroxyl-3-isopropyl benzoic acid and rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one, the title compound was prepared following the similar procedure as rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: [M−H]−=468
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=546
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=587
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=561
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=615
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=539
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=580
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=532
The mixture of 4-Chloro-2-nitro-phenylamine (2.0 g, 11.6 mmol) (Aldrich) in TFA (30 mL) and conc. hydrochloric acid (3 mL) was cooled to −5° C., then a solution of NaNO2 in water (5 mL) was dropped into at such a rate that the temperature did not above 5° C. When the addition was complete, the mixture was stirred at 0° C. for additional 5 min, then poured into a mixture of acetic acid (40 mL), sulfurous acid (40 mL), CuCl2 (824 mg, 6.1 mmol) and CuCl (50 mg, 0.5 mmol), which was cooled to 0° C. in advance. The whole was stirred at room temperature for 40 min, diluted with water (100 mL), filtered. The filter cake was washed with water, dried in vacuo to give 1.5 g 4-Chloro-2-nitro-benzenesulfonyl chloride. MS: [M+H]+=256
The mixture of 4-Chloro-2-nitro-benzenesulfonyl chloride (255 mg, 1 mmol), 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol) in DCM (3 mL) was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was dissolved in methanol, and then Ra—Ni (0.5 g) and hydrazine (1 mL, 17 mmol) was added. The resulting mixture was stirred at room temperature for 2 hr, filtered concentrated in vacuo. The residue was purified by column chromatography to give 380 mg 4-(2-Amino-4-chloro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester as pale white solid. MS: [M+H]+=390
The mixture of 4-(2-Amino-4-chloro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.051 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (30 mg, 0.081 mmol) and K2CO3 (30 mg, 0.22 mmol) in DCM (1 mL) was stirred at room temperature overnight. The mixture was purified by column chromatography to give 22 mg rac-4-{4-Chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzenesulfonylamino}-piperidine-1-carboxylic acid tert-butyl ester. MS: [M+H]+=679
The title compound was prepared following the similar procedure as rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: [M−H]−=460
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=687
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=531
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=572
To a solution of rac-4-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.044 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred for 3 h, concentrated. The residue was dissolved in DCM, the resulting solution was washed with Na2CO3 solution, dried with Na2SO4, concentrated to give 22 mg rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-piperidin-4-yl-benzamide. MS: [M+H]+=587
The title compound was prepared following the similar procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one. MS: [M+H]+=631
The title compound was prepared following the similar procedure as rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=406
To a mixture of Isopropylamine (7 mL, 75 mmol), K2CO3 (2.7 g, 20 mmol) in acetonitrile (20 mL) was added dropwise a solution of (2-Bromo-ethyl)-carbamic acid tert-butyl ester (3.4 g, 15 mmol) in acetonitrile (10 mL). The resulting mixture was heated to 60° C. for 1.5 hr, concentrated in vacuo. The residue was dissolved in DCM, filtered and concentrated to give 3 g 2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester as light yellow oil. MS: [M+H]+=203
A mixture of (2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.5 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (185 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) in DCM (1 mL) and acetonitrile (2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography to give 180 mg rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: [M+H]+=492
To the solution of rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.2 mmol) in DCM (10 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 2 hr, then washed with NaOH solution (5%) and water. The organic layer was dried over Na2SO4, concentrated in vacuo to give 60 mg rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=392
To a mixture of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) and K2CO3 (35 mg, 0.25 mmol) in DCM (2 mL) was added methylsulfonyl chloride (16 mg, 0.14 mmol). The resulting solution was stirred at room temperature for 2 hr, then purified by flash column chromatography to give 65 mg rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=470
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=434
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=463
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=546
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=505
The mixture of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (60 mg, 0.15 mmol), cyclobutanecarboxylic acid (18.4 mg, 0.18 mmol), EDCl (37 mg, 0.19 mmol), HOBt (30 mg, 0.19 mmol) and DIPEA (40 uL, 0.225) in DCM (2 mL) was stirred at root temperature for 2 hr. The mixture was purified by flash column chromatography to give 60 mg rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=474
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=545
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=541
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=541
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=526
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=579
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=579
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=564
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=542
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=514
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=573
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=538
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=510
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=569
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=567
The mixture of [[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid 100 mg, 0.211 mmol), Cyclohexylamine (25 mg, 0.253 mmol), EDC.HCl (48 mmg, 0.253 mmol), HOBt (34 mmg, 0.253 mmol) and DIPEA (82 mmg, 0.633 mmol) in acetonitrile (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 48 mg of rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide as a yellow solid. MS: [M+H]+=556.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 528 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 585 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 587 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 545 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 517 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 488 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 519 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 488 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 463 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 460 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 516 (M+H)+.
At room temperature, (3-Chloro-phenylamino)-acetic acid (1.25 g, 6.8 mmol) was dissolved in 10 ml 1N K2CO3 aqueous solution, then 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (2.5 g, 6.8 mmol) and 10 ml 1,4-dioxane were added slowly. After stirred for about 3 h, the solution was concentrated and the water layer was extracted with CH2Cl2. The organic layer was dried, concentrated to obtain the crude product and the crude product was purified by chromatography to obtain 1.2 g yellow solid rac-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid.
MS: 475 (M+H)+.
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (4.57 g, 12.3 mmol) and Isopropylamino-acetic acid ethyl ester (2.15 g, 14.8 mmol), DIPEA (2.14 ml) were mixed in about 40 ml dichloromethane. After stirred for about 3 h, the solution was concentrated and the crude product was purified by chromatography to obtain 4.7 g solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester. MS: 435 (M+H)+.
rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester (4.5 g, 10.4 mmol) was dissolved in a mixture of MeOH and KOH aqueous solution. This mixed solution was refluxed overnight and then the solution was concentrated. The PH of water layer was adjusted to 5-6 and then the water layer was extracted with dichloromethane. The organic layer was dried, concentrated and purified by chromatography to obtain 3.2 g solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid.
MS: 407 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid MS: 435 (M+H)+.
At room temperature, 6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one (60 mg, 0.115 mmol) and DDQ (47 mg, 0.207 mmol) were dissolved in 5 ml toluene. After stirred overnight, the solution was concentrated and then the residue was dissolved in EtOAc. The organic layer was washed with 10% NaOH aqueous solution and dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 20 mg yellow solid rac-6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-1′,3′-dihydro-[1,3′]biindolyl-2′-one. MS: 520 (M+H)+.
The title compound was prepared by the same procedure rac-6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-1′,3′-dihydro-[1,3′]biindolyl-2′-one
MS: 561 (M+H)+.
The title compound was prepared by the same procedure rac-6′-Chloro-3′-(3-chloro-benzyl)-2-(morpholine-4-carbonyl)-1′,3′-dihydro-[1,3′]biindolyl-2′-one
MS: 504 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 563 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 563 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 522 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 522 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 506 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 581 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 540 (M+H)+.
At room temperature, 2-Amino-3-ethoxy-benzoic acid (0.59 g, 3.26 mmol), 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.21 g, 3.26 mmol) and DIPEA (0.68 ml) were mixed in about 6 ml CH2Cl2. After stirred overnight, the solution was concentrated and the crude product was purified by chromatography to obtain 400 mg solid rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid. MS: 471 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid.
MS: 461 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid.
MS: 441 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid. MS: 455 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid.
MS: 453 (M+H)+.
At room temperature, 4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.17 mmol) was dissolved a mixture solution of CF3COOH and CH2Cl2. After stirred 0.5 h, the solution was concentrated and the organic layer was washed with NaOH aqueous solution. The organic layer was dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 200 mg rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide.
MS: 501 (M+H)+.
At room temperature, rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide (77 mg, 0.154 mmol) and dimethylcarbamyl chloride (14 mg, 0.185 mmol) and K2CO3 were mixed in about 2 ml CH2Cl2. After stirred for about 1 h, the solution was concentrated and the crude product was purified by chromatography to obtain 20 mg solid rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide.
MS: 572 (M+H)+.
The title compound was prepared by the same procedure for rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide MS: 543 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid.
MS: 601 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 579 (M+H)+.
The title compound was prepared by the same procedure for rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide
MS: 567 (M+H)+.
The title compound was prepared by the same procedure for rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide
MS: 531 (M+H)+.
The title compound was prepared by the same procedure for rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide MS: 489 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 589 (M+H)+.
The title compound was prepared by the same procedure for rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide
MS: 615 (M+H)+.
At room temperature, 3-(5-Bromo-2-hydroxymethyl-phenylamino)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.137 mmol) was dissolved in 2 ml dried CH2Cl2. Then SOCl2 (49 mg, 0.333 mmol) was added slowly. After stirred for about half an hour, K2CO3 (84 mg, 0.612 mmol) and 1-piperazin-1-yl-ethanone (32 mg, 0.245 mmol) were added. This solution was stirred for about 2 h, then the solution was concentrated and the crude product was purified by Prep-HPLC to obtain 7 mg white solid rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
MS: 601 (M+H)+.
The title compound was prepared by the same procedure for rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide
MS: 651 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one MS: 673 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one MS: 544 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one MS: 560 (M+H)+.
The title compound was prepared by the same procedure for solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester.
MS: 491 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 617 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 575 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
MS: 554 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
MS: 598 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
MS: 572 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 589 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 568 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 612 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 589 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 586 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one
MS: 617 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one MS: 603 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 679 (M+H)+.
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (800 mg, 2.16 mmol), 4-Chloro-2-methylamino-benzoic acid (400 mg, 2.16 mmol) and K2CO3 (298 mg, 2.16 mmol) were dissolved in about 8 ml DMSO. After stirred for about 2 h, the solution was poured into water to obtain the crude product. The crude product was purified by chromatography to obtain 600 mg solid rac-4-Chloro-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-benzoic acid
MS: 475 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 544 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 582 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 559 (M+H)+.
The title compound was prepared by the same procedure for rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide MS: 559 (M+H)+.
The title compound was prepared by the same procedure for rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid ethyl ester. MS: 461 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid ethyl ester. MS: 489 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid ethyl ester. MS: 447 (M+H)+.
The title compound was prepared by the same procedure rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 433 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 461 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 472 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 486 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 458 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 531 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 529 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 472 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 486 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 545 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 543 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 528 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 542 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 573 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 571 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 474 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 488 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 502 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 516 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 446 (M+H)+.
To the solution of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester (0.65 g, 1.31 mmol) in 10 mL toluene was added DDQ (0.51 g, 2.23 mmol). The reaction mixture was stirred at room temperature for 6 hour. And the mixture was washed with water (3×10 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography to give white solid. MS: 495 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 461 (M+H)+.
The title compound was prepared by the same procedure for rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 481 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 474 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one. MS: 460 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 534 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 562 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 591 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 593 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 550 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: 441 (M+H)+.
The title compound was prepared by the same procedure for rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: 445 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 494 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 510 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 498 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 555 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 542 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 545 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 530 (M+H)+.
The title compound was prepared by the same procedure rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 447 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 500 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 528 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 531 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 516(M+H)+.
The title compound was prepared by the same procedure for rac-1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-3-carboxylic acid.
MS: 433 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 514 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 486 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 543 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 472 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 556 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 512 (M+H)+.
The title compound was prepared by the same procedure E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one. MS: 262(M+H)+.
The title compound was prepared by the same procedure rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 264(M+H)+.
The title compound was prepared by the same procedure rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 342(M+H)+.
To a solution of cyclohexylamine (61 μL, 0.80 mmol) and DIPEA (300 μL, 1.59 mmol) in dichloromethane (2 mL) was slowly added 2-bromo-N-cyclobytyl-acetamide (156 mg, 0.80 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 4 h. Then rac-3-bromo6-chloro-3-cyclohexylmethyle-1,3-dihydro-indol-2-one was added in the reaction mixture. The reaction mixture was stirred for 2 hour at room temperature.
And the mixture was washed with water (3×5 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography to give white solid. MS: 472 (M+H)+.
Cyclohexanone (2.00 g, 20.4 mmol) and 2-morpholin-4-yl-ethylamine (2.98 mL, 20.4 mmol) were dissolved in 10 mL methanol. The solution was stirred at room temperature for an hour. NaBH3CN (1.62 g, 24.4 mmol) was slowly added portionwise in the solution. After the addition, the mixture was stirred at room temperature for 4 hour then concentrated under reduced pressure. To the residue was added 50 mL water and the mixture was adjusted to PH=10 with dilute aqueous KOH and extracted with ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo to give an oil. MS: 213(M+H)+.
The title compound was prepared by the same procedure rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-1H-indol-2-one. MS: 502 (M+H)+.
The title compound was prepared by the same procedure for of rac-6-Chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-ethyl)-amino]-1,3-dihydro-indol-2-one MS: 516 (M+H)+.
The title compound was prepared by the same procedure for of rac-6-Chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: 462 (M+H)+.
The title compound was prepared by the same procedure of rac-6-Chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-morpholin-4-yl-ethyl)-amino]-1,3-dihydro-indol-2-one. MS: 476 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 574(M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 545 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 474 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 581 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 595(M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 488 (M+H)+.
Methyl vinyl sulfone (5.7 mL, 64.8 mmol) was added to a solution of cyclohexylamine (6.2 mL, 54 mmol) in 50 mL DCM. The reaction mixture was stirred at room temperature for 4 hour and concentrated in vacuo, then purified by flash column chromatopgraphy to give oil. MS: 206 (M+H)+.
The title compound was prepared by the same procedure for rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-1H-indol-2-one. MS: 495(M+H)+.
The title compound was prepared by the same procedure for rac-6-Chloro-3-(3-chloro-benzyl)-3-[cyclohexyl-(2-methanesulfonyl-ethyl)-amino]-1,3-dihydro-indol-2-one MS: 455 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 553 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 474 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 567 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 488 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 609(M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 595 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 488 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 609 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 545 (M+H)+.
A mixture of 1.5 g 2,2-Dimethyl-propionaldehyde, 2.18 g 3-Amino-propionic acid methyl ester and 50 ml MeOH was stirred at room temperature for 30 min. 1.5 g NaCNBH3 was added in small portion. The mixture was stirred for another 3 hrs. The solvent was removed in vacuum. 50 mL Water was added to the residue and the mixture was basified to PH10 by 1N NaOH. The solution was extracted by EtOAc (30 mL×3). The organic phase was washed by 20 mL water, dried over Na2SO4. Removed the solvent gave 0.66 g target molecule as clear oil.
The title compound was prepared by the same procedure rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: 463 (M+H)+.
To a mixture of 720 mg rac-3-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H!-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-propionic acid methyl ester in 10 mL MeOH was added 10 mL 1N NaOH. The mixture was heated at 90° C. for 3 hours. Most of the MeOH was removed in vacuum. 20 mL water was added into the residue. Acidigied to PH3 by 2N HCl. The precipitate was collected by filtration and washed by water gave 680 mg target molecule as light yellow solid. MS: 449 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 559 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 518 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 462 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 476 (M+H)+.
The title compound was prepared by the same procedure rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: 559 (M+H)+.
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: 549 (M+H)+.
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: 462 (M+H)+.
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: 462 (M+H)+.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=616.
The title compound was prepared following the similar procedure as rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid. MS: [M−H]−=600.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=615.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=629.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=671.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=712.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=483.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=497.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=554.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=521.
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-acetamide. MS: [M+H]+=448.
The title compound was prepared following the similar procedure as rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=484.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=538.
The title compound was separated from rac-6-Chloro-3-(3-chloro-benzyl)-3-((2,2-dimethyl-propyl)-{2-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amino)-1,3-dihydro-indol-2-one by chiral prep-HPLC. MS: [M+H]+=609.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=643.
The title compound was prepared following the similar procedure as rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=553.
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.55 mmol) (from example 1c supra), 6-Chloro-3,4-dihydro-1H-quinoxalin-2-one (100 mg, 0.55 mmol) and K2CO3 (150 mg, 1.09 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hour. The mixture was concentrated in vacuo and purified by flash column chromatography to give 110 mg 6-Chloro-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-1H-quinoxalin-2-one. MS: [M+H]+=472.
The mixture 3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (120 mg, 0.286 mmol), 1-Acetyl-piperidine-4-carboxylic acid (59 mg, 0.344 mmol), EDC.HCl (66 mg, 0.344 mmol), HOBt (46 mg, 0.344 mmol) and DIPEA (111 mg, 0.860 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 54 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide of as a white solid. Then 18 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral preparative HPLC to obtain 7 mg 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide MS: [M+H]+=573.
The mixture 3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (75 mg, 0.179 mmol), 4-Acetyl-piperazine-1-carbonyl chloride (41 mg, 0.215 mmol) and K2CO3 (37 mg, 0.268 mmol) in dichloro-methane (2 mL) was stirred at room temperature for 2 h. Then the solution was concentrated and the crude product was purified by chromatography to give 42 mg rac-4-Acetyl-piperazine-1-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide of as a yellow solid. Then 15 mg rac-4-Acetyl-piperazine-1-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral column to obtain 4 mg 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide
MS: [M+H]+=574.
The mixture 4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (150 mg, 0.298 mmol), (S)-N-Piperidin-3-yl-acetamide (63 mg, 0.446 mmol), EDC.HCl (85 mg, 0.446 mmol), HOBt (60 mg, 0.446 mmol) and DIPEA (154 mg, 1.190 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 33 mg N-((S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide as yellow solid.
MS: [M+H]+=629.
The title compound was prepared by the same procedure for N-((S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide. MS: [M+H]+=658
The title compound was prepared by the same procedure for N-(S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide. MS: [M+H]+=700.
The title compound was prepared by the same procedure for N-(S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide. MS: [M+H]+=665.
The title compound was prepared by the same procedure for N-((S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide. MS: [M+H]+=601.
The mixture 4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (1.5 g, 0.003 mol), (S)-3-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 0.0036 mol), EDC.HCl (0.68 g, 0.0036 mol), HOBt (0.49 g, 0.0036 mol) and DIPEA (1.15 g, 0.0089 mol) in DMF (20 mL) was stirred at room temperature for overnight. Then the mixture was poured into water and the mixture solution was filtered to obtain the crude product. The crude product was purified by chromatography to obtain 1.2 g yellow solid 3-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-(S)-piperidine-1-carboxylic acid tert-butyl ester. Then 100 mg 3-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-(S)-piperidine-1-carboxylic acid tert-butyl ester was dissolved a mixture solution of CF3COOH and CH2Cl2. After stirred 0.5 h, the solution was concentrated and the organic layer was washed with NaOH aqueous solution. The organic layer was dried, concentrated to obtain crude product. The crude product was purified by Prep-HPLC to obtain 31 mg 4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-(S)-piperidin-3-yl-benzamide. MS: 587 (M+H)+.
Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N -(S)-piperidin-3-yl-benzamide (150 mg, 0.214 mmol), Acetic Anhydride (22 mg, 0.214 mmol) and DIPEA (111 mg, 0.859 mmol) were dissolved in 2 ml CH3CN. After stirred for 2 h at r.t, the solution was concentrated and the crude product was purified by Prep-HPLC to obtain 32 mg N-((S)-1-Acetyl-piperidin-3-yl)-4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzamide as a white solid. MS: [M+H]+=629.
The title compound was prepared by the same procedure for N-((S)-1-Acetyl-piperidin-3-yl)-4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzamide. MS: [M+H]+=700.
The title compound was prepared by the same procedure for N-((S)-1-Acetyl-piperidin-3-yl)-4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzamide. MS: [M+H]+=658
(2-Amino-ethyl)-carbamic acid tert-butyl ester (1.2 g, 7.5 mmol) and 2,2-Dimethyl-propionaldehyde (0.65 g, 7.5 mmol) were dissolved in 20 ml methanol. After the mixture was stirred for 1 h at r.t, NaBH3CN (0.6 g, 9 mmol) was added. Then the mixture was stirred overnight and concentrated under reduced pressure. To the residue was added 20 ml of water, and the mixture was adjusted to PH=10 with dilute aqueous NaOH and extracted with EtOAc. The combined organic layers were dried and concentrated to obtain 1.3 g oil. This oil, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (2.1 g, 5.65 mmol) and K2CO3 (0.94 g, 6.78 mmol) were dissolved in 10 ml DMF. After stirred for about 3 h, the mixture was poured into water and the mixture solution was filtered to obtain the crude product. The crude product was purified by chromatography to obtain 1.8 g {2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-carbamic acid tert-butyl ester as a yellow solid. Then this 1.8 g yellow solid was dissolved in a mixture solution of CF3COOH and CH2Cl2. After stirred for 1 h, the solution was concentrated and the organic layer was washed with NaOH aqueous solution. The organic layer was dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 566 mg rac-3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a yellow solid. MS: [M+H]+=420.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=498
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=533.
The title compound was prepared by the same procedure 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=573.
18 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral column to obtain 7 mg 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=573.
The title compound was prepared by the same procedure rac-3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one MS: [M+H]+=420.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=574.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=574.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=498.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=533.
The title compound was prepared by the same procedure 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=573.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=588.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=547.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=512
The title compound was prepared by the same procedure 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=587.
The title compound was prepared by the same procedure 4-Acetyl-piperazine-1-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide. MS: [M+H]+=519.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=590.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=632.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=590.
The title compound was prepared by the same procedure as rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclohexyl-amino}-acetic acid. MS: 562 (M+H)+.
The title compound was prepared following the similar procedure as rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-methylcarbamoylmethyl-benzamide MS: [M+H]+=575.
The title compound was prepared following the similar procedure as rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-methylcarbamoylmethyl-benzamide MS: [M+H]+=589.
The title compound was prepared following the similar procedure as rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-methylcarbamoylmethyl-benzamide MS: [M+H]+=631.
The title compound was prepared following the similar procedure as rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-methylcarbamoylmethyl-benzamide MS: [M+H]+=741.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=804
The rac-(S)-6-Amino-2-(2-{4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-acetylamino)-6-tert-butoxycarbonylamino-hexanoic acid methyl ester (200 mg, 0.25 mmol) in 5 mL of TFA was stirred at room temperature for 0.5 hour, and concentrated in vacuo. The residue was added by 10 mL of DCM, then rinsed with 20 mL of water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 146 mg white solid. MS: 704 (M+H)+.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=588.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=633.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=659.
The title compound was prepared by the same procedure as rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-1H-indol-2-one. MS: 535 (M+H)+.
The title compound was prepared by the same procedure as rac-(S)-6-Amino-2-(2-{4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-acetylamino)-hexanoic acid methyl ester. MS: 436 (M+H)+.
To a solution of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-bromo-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (270 mg, 0.48 mmol) and DIPEA (167 uL, 0.96 mmol) in 5 mL of DCM was added 4-acetyl-piperazine-1-carbonyl chloride (137 mg, 0.72 mmol) at room temperature, and stirred at same temperature overnight. The reaction mixture was rinsed with 20 mL water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 180 mg white solid. MS: [M+H]+=590.
The title compound was prepared following the similar procedure as rac-4-Acetyl-piperazine-1-carboxylic acid (2-{[6-bromo-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide MS: [M+H]+=539.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=649.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=581.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=525.
The title compound was prepared following the similar procedure as rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=623.
In a cell based assay, the ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured. 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).
The 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.
This application claims the benefit of U.S. Provisional Application No. 60/846,201, filed Sep. 21, 2006, which is hereby incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3441570 | Meyer | Apr 1969 | A |
| Number | Date | Country |
|---|---|---|
| 0947511 | Oct 1999 | EP |
| WO 0015657 | Mar 2000 | WO |
| WO 2006136606 | Dec 2006 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20080081810 A1 | Apr 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60846201 | Sep 2006 | US |
