Patent Grant
7579368
The present invention provides chiral cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide with a potency that is approximately 100 fold greater than a p53-derived peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in G1 and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.
This invention relates to at least one compound of the formula I
or pharmaceutically acceptable salts thereof,
wherein Y1, Y2, X1, X2, X3 and R are as described in this application. These compounds are believed to inhibit MDM2-p53 interaction and as such the compounds will have anti-hyperproliferative cellular activity.
The present invention provides at least one compound of formula I
and the pharmaceutically acceptable salts and esters thereof, wherein
with the proviso that X2 and X3 are both not hydrogen, lower alkyl, or lower alkoxy,
with the proviso that when X2 or X3 is hydrogen, the other is not lower alkyl, lower alkoxy, or halogen,
Preferred compounds are compounds of formula I wherein Y1 and Y2 are each independently selected from —Cl and —Br.
Further preferred compounds are compounds of formula I wherein R is piperazinyl substituted by oxo or lower alkyl substituted by R2.
Also preferred compounds are compounds in which the two hydrogen atoms of the imidazoline ring are in a cis configuration to each other. The compounds may be in a racemic form and may be optically active. The preferred absolute stereochemistry at the 4 and 5 position of the imidazoline ring are S and R, respectively.
Especially preferred compounds are:
“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.
“Halogen” means fluorine, chlorine, bromine or iodine.
“Hetero atom” means an atom selected from N, O and S.
“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.
“Alkyl” denotes a straight-chained or branched saturated aliphatic hydrocarbon.
“Lower alkyl” groups denote C1-C6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. Generally, lower alkyl is preferably C1-C4 alkyl, and more preferably C1-C3 alkyl.
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.
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.
“Alkoxy” denotes —O-alkyl. “Lower alkoxy” denotes —O-lower alkyl.
“Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid.
Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
“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, 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., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
“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.
“Substituted” means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
“Therapeutically effective amount” means an amount of at least one designated compound, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
Compounds of the present invention as exemplified advantageously show IC50s from about 0.005 uM to about 1 uM.
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.
The present invention also provides pharmaceutical compositions comprising at least one compound of formula I, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or excipient.
The compounds of the present invention can be prepared according to the following scheme 1.
The synthesis commences with the coupling reaction of the benzoic acid ester 2 (Z=methyl, ethyl, etc.) with meso-1,2-bis-(4-chlorophenyl)-ethane-1,2-diamine 1 (prepared according to the procedure described by Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) using trimethylaluminum as a catalyst in a solvent such as toluene with heating at reflux (Moormann, A. E. et al J. Med. Chem. 1990, 33, 614-626). Benzoic acid esters 2 are prepared using the procedures known in the art. Treatment of the imidazoline 3 with phosgene in the presence of a base such as triethylamine gives the racemic carbamoyl chloride 4. Coupling of the racemic carbamoyl chloride 4 with appropriate R amine groups provides the compounds of the formula I as racemic mixtures. Many R amine groups are commercially available. If it is desired, R amine groups can be prepared using synthetic methods known in the art. Suitable processes for making these R amine groups are provided in the examples.
If it is desired to prepare the optically active compounds of formula I, the enantiomers of the carbamoyl chloride rac-4 can be separated using chiral chromatography. The chiral stationary phase R,R-Whelk-O1, available through Regis Technologies, can be used. Coupling of the desired enantiomer 5A with appropriate R amine groups provides the compounds of the formula I.
Also the optically active compounds of formula I can be obtained by chiral separation of the racemic mixtures of I. The chiral stationary phase Diacel ChiralPak OD or AD can be used.
The absolute stereochemistry of the preferred enantiomer of I is determined based on the crystal structure of its complex with the human MDM2 (Vassilev et al. Science, 2004, 303, 844-848.
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.
Iron (16.19 g, 290 mmol) was added to a slurry mixture of 2-ethoxy-4-nitrobenzoic acid (24.00 g, 114 mmol) in ethanol (200 mL) and saturated aqueous solution of ammonium chloride (120 mL). The mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. It was rinsed with methylene chloride and the combined filtrate diluted with water and extracted with methylene chloride and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography of the brown residue over silica gel using 1-5% methanol in methylene chloride produced 4-amino-2-ethoxybenzoic acid as a yellow solid (14.94 g, 73%).
To a cooled solution of 4-amino-2-ethoxybenzoic acid (500 mg, 2.76 mmol) in 2 M hydrochloric acid (1.0 mL) was added a solution of sodium nitrite (192 mg, 2.8 mmol) in water (0.55 mL). The mixture was stirred for 15 min and neutralized by adding small amounts of solid sodium bicarbonate. This solution was then added to a freshly prepared solution of copper(I) cyanide at 0° C. (prepared from sodium cyanide and copper(I) chloride according to Org. Syn. Coll. Vol VI, p. 514) in water (7.5 mL) and benzene (2.5 mL). The reaction was allowed to warm up to room temperature and stirred for 2 h. The mixture was filtered through Celite and the filtrate extracted with ethyl acetate. The aqueous phase was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4-cyano-2-ethoxybenzoic acid as a light brown solid (280 mg, 53%), which was used in the next step without further purification.
(Trimethylsilyl)diazomethane (2 M in hexanes, 1.47 mL, 2.93 mmol) was added to a solution of 4-cyano-2-ethoxybenzoic acid (280 mg, 1.47 mmol) in benzene (8.0 mL) and methanol (1.6 mL). The reaction was stirred for 1 h and then degassed with air for 30 min. Evaporation of the solvent and purification of the crude residue by flash column chromatography (silica gel, eluting with 0-20% ethyl acetate in hexanes) gave methyl 4-cyano-2-ethoxybenzoate as a yellow solid (218 mg, 71%).
To a cooled solution of chlorosulfonic acid (12.0 mL) and thionyl chloride (3.4 mL) was added ethyl 2-ethoxybenzoate (10.7 g, 59.0 mmol) dropwise over 30 min. The reaction was stirred overnight at room temperature and carefully added to ice (300 g). The resulting white solid was filtered, washed with water and dried in vacuo overnight to give ethyl 2-ethoxy-5-(chlorosulfonyl) benzoate as a white solid (9.5 g, 59%).
To a cooled solution of ethyl 2-ethoxy-5-(chlorosulfonyl)benzoate (480 mg, 1.6 mmol) in methylene chloride (5.0 mL) was added triethylamine (0.35 mL, 2.5 mmol) and dimethylamine (2 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The reaction was stirred at room temperature for 2 h and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-50% ethyl acetate in hexanes) gave ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate as a off-white solid (210 mg, 43%
In an analogous manner, there were obtained:
To a cooled solution of ethyl 4-fluoro-2-ethoxy-5-(chlorosulfonyl)benzoate (1.0 g, 3.2 mmol, example 2) in methylene chloride (25 mL) was added 2-(methylamine)ethanol (0.75 mL, 10.6 mmol). The reaction was stirred at room temperature for 1 h and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 30-70% ethyl acetate in hexanes) gave ethyl 4-fluoro-2-ethoxy-5-(N-methyl-N-(2-hydroxyethyl)sulfonamide)benzoate (0.76 g, 64%).
Sodium hydride (89 mg, 2.2 mmol, 60% in mineral oil) was added to a solution of 4-fluoro-2-ethoxy-5-(N-methyl-N-(2-hydroxyethyl)sulfonamide)benzoate (520 mg, 1.5 mmol) in dimethylformamide (8.0 mL) at 0° C. The reaction was stirred at 0° C. for 1 h. The reaction mixture was quenched with a dilute aqueous solution of ammonium chloride and extracted with diethyl ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 25-50% ethyl acetate in hexanes) gave 8-carboethoxy-7-ethoxy-2-methyl-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,6-b][1,4,5]oxathiazepine as a white solid (430 mg, 88%).
To a stirring solution of 2-ethoxy-5-formyl-benzoic acid ethyl ester (1.0 g, 4.5 mmol) in 10 mL of dimethylformamide was added dropwise sulfamic acid (610.4 mg, 6.3 mmol) in 5 mL of water. After addition of sulfamic acid, sodium chlorite (737.2 mg, 8.2 mmol) in 5 mL of water was added dropwise. Reaction was allowed to stir for 2 h at room temperature. Reaction was diluted with brine and extracted with ethyl acetate. Organic extract was dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4-ethoxy isopthalic acid 3-ethyl ester as a white solid (900 mg, 84%). LC-MS: 239.2 [(M+H)+].
To a solution of 4-ethoxy isopthalic acid 3-ethyl ester (600 mg, 2.5 mmol) in 10 mL of acetonitrile was added piperidine (429 mg, 5.0 mmol). The resulting mixture was cooled to 0° C. To this solution was added HBTU (1.4 g, 3.78 mmol, in 5 mL of acetonitrile) followed by N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with 10% potassium carbonate and extracted with methylene chloride. The organic extract was concentrated and purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 632 mg (2.07 mmol, 82%) of pure 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester. LC-MS: 306.3 [(M+H)+].
In an analogous manner, there were obtained:
To a solution of 4-chloro-2-ethoxy-benzoic acid ethyl ester (1.46 g, 6.4 mmol) in 13 mL of water and methylene chloride (1:1 mixture) was added bromine (360 uL, 7 mmol). The reaction was stirred for three days. The organic layer was separated. It was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (1.26 g, 64%). LC-MS: 307.1 [(M+H)+].
To a solution of 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (940 mg, 3.0 mmol) in 20 mL of dimethylformamide was added copper(I) cyanide (327 mg, 3.65 mmol). The reaction was stirred at reflux overnight. The reaction was diluted with methylene chloride. It was washed twice with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (359 mg, 47%). LC-MS: 254.1 [(M+H)+].
To a solution of 5-bromo-4-ethoxy-2-fluoro-benzonitrile (2 g, 8.2 mmol) in 16.5 mL of dioxane was added dimethylamine (16.5 mL, 33 mmol, 2.0 M in tetrahydrofuran). The reaction was stirred at 80° C. overnight. The reaction mixture was concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-2-dimethylamino-4-ethoxy-benzonitrile (1.95 g, 88%). LC-MS: 269.2 [(M+H)+].
To a solution of 5-bromo-2-dimethylamino-4-ethoxy-benzonitrile (1.95 g, 7.3 mmol) in 7.25 mL of dioxane was added sodium methoxide (581 mg, 10.77 mmol), methyl formate (1.85 mL, 30 mmol), and trans-dichlorobis(triphenylphosphine) palladium(II) (281 mg, 0.4 mmol). The mixture was agitated by bubbling nitrogen gas through the solution. To the opening of the vial is affixed a balloon. The reaction was cautiously warmed to 60° C. as gas evolution can cause a froth to enter the balloon. The reaction mixture was stirred for 20 h at 65° C. It was diluted with dioxane and stirred for an additional 5 min. The warm solution was filtered through Celite, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave cyano-4-dimethylamino-2-ethoxy-benzoic acid methyl ester (218 mg, 12%).
To a solution of 3-hydroxy-4-iodo-benzoic acid (4 g, 15.15 mmol) in 2-butanone (100 mL) were added potassium carbonate (20 g, finely ground) and ethyl iodide (4.85 mL). The mixture was stirred at reflux overnight. Upon cooling to room temperature, the solids were filtered off, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with 10% sodium carbonate solution, brine, and concentrated. The residue reconstituted in methanol. 1.0 M sodium hydroxide was added giving a cloudy solution. Tetrahydrofuran was added to clarity and the mixture stirred at room temperature for one hour. The volatiles were evaporated and the residue was dissolved in water. It was washed once with diethyl ether and then acidified with 37% hydrochloric acid to precipitate a white solid. The solid was filtered, washed with water and dried in a vacuum oven to give 3-ethoxy-4-iodo-benzoic acid (2.73 g, 62%). LC-MS: 293 [(M+H)+].
3-Ethoxy-4-iodo-benzoic acid (2.73 grams, 9.36 mmol) was suspended in methylene chloride (25 mL), and oxalyl chloride (5.15 mL, 2.0 M in methylene chloride, 10.3 mmol) was added by pipette. Three drops of dimethylformamide was added and this mixture was stirred overnight at room temperature. The volatiles from the now homogeneous reaction were removed under vacuum and the residue reconstituted in methylene chloride. One half of this was treated with piperidine (2.0 mL, 20 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride, washed with 1.0 M hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layers was dried (magnesium sulfate), filtered and concentrated to give (3-ethoxy-4-iodo-phenyl)-piperidin-1-yl-methanone (1.69 g, 100%).
(3-Ethoxy-4-iodo-phenyl)-piperidin-1-yl-methanone was methoxycarbonylated using the procedure described in example 6 to give 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester.
In an analogous manner, there was obtained:
To a stirring solution of 2-ethoxy-4-methoxy-benzoic acid ethyl ester (1.5 g, 6.7 mmol) in 1,2-dichloroethane (2 mL) was added chlorosulfonyl isocyanate (0.923 mL, 10.6 mmol, in 1 mL of 1,2-dichloroethane) in several portions. The reaction was stirred at 50° C. overnight. Reaction was diluted with methylene chloride (2 mL) and water (1 mL), and extracted. The organic layer was washed with brine and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 900 mg (54% yield) of 5-cyano-2-ethoxy-4-methoxy-benzoic acid ethyl ester. LC-MS: 236.2 [(M+H—CH3)+].
Potassium carbonate (14.0 g, 101 mmol) and iodoethane (3.3 mL, 40.4 mmol) were added to a stirred solution of 4-thiomethyl-2-ethoxy-benzoic acid (4.3 g, 20.2 mmol, prepared according to Robertson, D. et al. J. Med. Chem. 1985, 28, 717-727) in acetone (203 mL). The resulting mixture was heated in a 60° C. oil bath for 16 h and then allowed to cool. The reaction mixture was washed with sodium bicarbonate solution (2×), dried over anhydrous magnesium sulfate, and evaporated to give ethyl 4-methylthio-2-ethoxybenzoate as a yellow oil (4.3 g, 90%). It was used without further purification.
To a cooled solution of ethyl 4-methylthio-2-ethoxybenzoate (1.1 g, 4.6 mmol) in methylene chloride (40 mL) was added 3-chloroperoxybenzoic acid (1.1 g, 4.5 mmol, 77%) in several portions. The reaction mixture was stirred at 0° C. for 15 min, after which TLC (50% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was quenched with a solution of sodium thiosulfate and neutralize with a solution of sodium bicarbonate. The product was extracted three times with methylene chloride. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-methanesulfinylbenzoate as a yellow oil (0.70 g, 58%). LC-MS: 257.2 [(M+H)+].
To a cooled solution of ethyl 4-methylthio-2-ethoxybenzoate (1.6 g, 6.7 mmol) in methylene chloride (60 mL) was added 3-chloroperoxybenzoic acid (3.0 g, 13.3 mmol, 77%). The reaction mixture was stirred at 0° C. for 15 min, quenched with a saturated solution of sodium thiosulfate, and neutralized with a saturated solution of sodium bicarbonate. The solution was extracted with methylene chloride. The combined organic phases were washed with sodium bicarbonate, brine and dried over magnesium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50% ethyl acetate in hexanes) gave ethyl 4-(methylsulfonyl)-2-ethoxy-benzoate as a clear oil (1.45 g, 83%).
Potassium carbonate (22.0 g, 159 mmol) and iodoethane (9.0 mL, 112 mmol) were added to a stirred solution of 5-methylthio-2-hydroxy-benzoic acid (5.00 g, 27 mmol) in 2-butanone (125 mL). The resulting mixture was heated in an oil bath (80° C.) for 16 h and then allowed to cool. The solution was concentrated and redissolved in methylene chloride. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 5-15% ethyl acetate in hexanes) gave ethyl 5-methylthio-2-ethoxybenzoate as a yellow oil (5.5 g, 85%).
To a cooled solution of ethyl 5-methylthio-2-ethoxybenzoate (1.1 g, 4.6 mmol) in methylene chloride (40 mL) was added 3-chloroperoxybenzoic acid (2.0 g, 9.0 mmol, 77%). The reaction mixture was stirred at 0° C. for 2 h, quenched with a saturated solution of sodium thiosulfate, and neutralized with a saturated solution of sodium bicarbonate. The solution was extracted with methylene chloride. The combined organic phases were washed with sodium bicarbonate, brine and dried over sodium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 25-50% ethyl acetate in hexanes) gave ethyl 4-methylsulfonyl-2-ethoxybenzoate as a yellow oil (0.54 g, 43%).
2-Ethoxy-4-thiol-benzoic acid (1.6 g, 8.08 mmol, prepared according to Robertson, D. et al. J. Med. Chem. 1985, 28, 717-727) was taken up in methanol (80 mL) and cooled to 0° C. Thionyl chloride (1.2 mL, 16.2 mmol) was added slowly. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. Evaporation of the solvents afforded a mixture of sulfide and disulfide methyl ester (1.9 g, 100%) as a yellow oil, which was used without further purification. This crude sulfide/disulfide ester was taken up in acetic acid and cooled to 0° C. A small amount of toluene was added to the reaction mixture to prevent the reaction mixture from freezing. Chlorine gas (Cl2) was bubbled into the reaction mixture until TLC (50% ethyl acetate in hexanes) showed consumption of starting material. Argon gas (Ar) was bubbled into the reaction mixture to remove excess chlorine. The reaction mixture was concentrated to dryness in vacuo to give quantitative yield of the methyl 4-chlorosulfonyl-2-ethoxy-benzoate.
Methyl 4-chlorosulfonyl-2-ethoxy-benzoate (1.3 g, 4.55 mmol) was taken up in anhydrous methylene chloride (30 mL) and cooled to 0° C. Dimethylamine (9.1 mL, 18.2 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-50% ethyl acetate in hexanes) gave methyl 4-dimethylsulfamoyl-2-ethoxy-benzoate as a yellow solid (0.528 g, 41%). LC-MS: 288.1 [(M+H)+].
In an analogous manner, there was obtained:
Ethyl 5-chlorosulfonyl-2-ethoxy-4-fluorobenzoate (1.5 g, 4.84 mmol; prepared as described in example 2) was taken up in 36 mL of anhydrous methylene chloride and cooled to 0° C. Dimethylamine (7.3 mL, 14.5 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-40% ethyl acetate in hexanes) gave ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate as a white solid (1.02 g, 68%). LC-MS: 320.2 [(M+H)+].
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (1.02 g, 3.20 mmol) was taken up in 5 mL of anhydrous dimethylformamide. Dimethylamine (8.0 mL, 15.9 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The reaction was allowed to cool to room temperature and diluted with water. The product was extracted three times with methylene chloride. The combined organics extracts were washed with brine, dried over magnesium sulfate and concentrated to give ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxy-benzoate as a tan solid (1.05 g, 95%). LC-MS: 345.3 [(M+H)+].
To a cooled solution of ethyl 4-fluoro-2-ethoxy-5-(chlorosulfonyl)benzoate (1.3 g, 4.2 mmol; prepared as described in example 2) in methylene chloride (25 mL) was added piperidine (1.5 mL, 18 mmol). The reaction was stirred at room temperature for 2 h and concentrated. Purification of the crude residue by chromatography over silica gel using 25-50% ethyl acetate in hexanes gave ethyl 4-piperidino-5-piperidinosulfamoyl-2-ethoxybenzoate (1.25 g, 70%).
Potassium carbonate (60.4 g, 437 mmol) and iodoethane (17.6 mL, 218.4 mmol) were added to a mechanically stirred solution of 2-hydroxy-4-nitro-benzoic acid (10.0 g, 54.6 mmol) in 2-butanone (165 mL). The resulting mixture was heated in an 80° C. oil bath for 16 h and then allowed to cool. TLC (20% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was concentrated to dryness, and the residue was taken up in ethyl acetate and washed three times with a saturated solution of sodium thiosulfate, dried over magnesium sulfate and concentrated to give ethyl 2-ethoxy-4-nitro-benzoate as a yellow solid (12.7 g, 97%). LC-MS: 240.1 [(M+H)+].
To a solution of ethyl 2-ethoxy-4-nitro-benzoate (12.7 g, 53.1 mmol) in ethanol (94 mL) was added a solution of ammonium chloride (56 mL). The formation of a precipitate was observed. Iron (15.2 g, 271 mmol) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled and filtered through Celite, and the Celite was rinsed with methylene chloride. Water was added and the product was extracted three times with methylene chloride. The organic layers were dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 0-3% methanol in chloroform) gave ethyl 4-amino-2-ethoxy-benzoate as a tan solid (10.3 g, 99%).
4-Amino-2-ethoxy-benzoic acid ethyl ester (1.0 g, 5.13 mmol) was taken up in pyridine (40 mL) and cooled to 0° C. Methanesulfonyl chloride (1.5 mL, 15.3 mmol) was added and the reaction temperature was allowed to warm slowly to room temperature and stirred for 16 h. The reaction mixture was diluted with methylene chloride and washed with 1N hydrochloric acid until aqueous phase remained acidic. The organic layers were dried over magnesium sulfate and concentrated to give ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate as an orange solid (1.3 g, 87%). It was used without further purification.
In an analogous manner, there were obtained:
Potassium carbonate (100 g, 724 mmol) and iodoethane (29.1 mL, 364 mmol) were added to a mechanically stirred solution of 2-hydroxy-4-iodobenzoic acid (16.0 g, 60.6 mmol, prepared according to Singh, S.; et al. J. Med. Chem. 1997, 40, 2472-2481) in 2-butanone (250 mL). The resulting mixture was heated at 80° C. for 16 h and then allowed to cool. Diethyl ether (250 mL) was added to the reaction vessel and the supernatant was transferred to a separatory funnel. Diethyl ether (250 mL) was again added to the reaction vessel to wash the remaining solid and the supernatant was again transferred to the separatory funnel. Water (400 mL) was added and the phases were separated. The aqueous phase was washed twice with diethyl ether (500 mL, 200 mL) and then the combined organic phases were washed with water (400 mL), brine (400 mL), dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 10% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-iodobenzoate as an off-white solid (9.50 g, 49%).
Chlorosulfonic acid (2.3 mL) and thionyl chloride (0.6 mL) were combined and stirred in and ice-salt bath. Ethyl 2-ethoxy-4-iodobenzoate (0.800 g, 2.50 mmol) was added in portions over approximately 2 m. The cooling bath was removed and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then warmed to 60° C. for 1.75 h then allowed to cool and poured carefully into a vigorously stirred mixture of ice and water (˜50 mL). The resulting mixture was washed with ethyl acetate (2×30 mL) and the combined organic phases were dried over magnesium sulfate and evaporated to yield the sulfonyl chloride which was used without further purification. This crude sulfonyl chloride was dissolved in methylene chloride (12 mL) and cooled in an ice-salt bath. Triethylamine (1.74 mL, 12.5 mmol) and dimethylamine (12.5 mL, 25.0 mmol, 2.0 M in tetrahydrofuran) were added. The cooling bath was removed and the reaction mixture was stirred for 1.5 h and then concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 25% ethyl acetate in hexanes) gave ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate as a white solid (0.599 g, 56%). LC-MS: 427.9 [(M+H)+].
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate (1.01 g, 2.36 mmol), zinc cyanide (0.167 g, 1.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.191 g, 0.165 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (9 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate as an off-white solid (0.708 g, 92%). LC-MS: 327.1 [(M+H)+].
A solution of bromine (0.338 mL, 6.60 mmol) in acetic acid (6 mL) was added dropwise to a mixture of ethyl 2,5-diethoxybenzoate (1.36 mL, 6.02 mmol) and acetic acid (24 mL) cooled in a water bath. After stirring 1 h, more bromine (0.102 mL, 1.99 mmol) was added dropwise to the reaction mixture. After stirring an additional 4 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with 10% diethyl ether in hexanes) to give ethyl 4-bromo-2,5-diethoxybenzoate as an off-white solid (0.610 g, 32%).
Ethyl 4-bromo-2,5-diethoxybenzoate (0.615 g, 1.94 mmol), zinc cyanide (0.137 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (7 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-2,5-diethoxy-benzoate as an off-white solid (0.416 g, 81%).
3,3,3-Trifluoro-1-propyne (approx. 0.6 mL, approx. 6 mmol) was condensed in a flame-dried Schlenk tube immersed in a dry ice/acetone bath. Tetrahydrofuran (3 mL) was added followed by a solution of butyllithium in hexanes (2.15 mL, 3.44 mmol, 1.6 M). After stirring 2.5 h at −78° C., zinc chloride (6.87 mL, 3.44 mmol, 0.5 M solution in tetrahydrofuran) was added to the reaction mixture and the reaction vessel was transferred to an ice-water bath and maintained at 0° C. for 30 min. Ethyl 2-ethoxy-4-iodobenzoate (1.00 g, 3.12 mmol, prepared as described in example 14) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) were then added. The reaction vessel was allowed to warm to room temperature and then after 1 h warmed to 50° C. for 18 h. After cooling, the reaction mixture was partitioned between brine (70 mL) and methylene chloride (2×100 mL), dried over magnesium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 1/1 mixture of methylene chloride and hexanes) gave ethyl 4-trifluoroprop-1-ynylbenzoate as an off-white solid (0.474 g, 53%).
Ethyl 2-ethoxy-4-iodobenzoate (0.763 g, 2.38 mmol, example 14), copper(I) iodide (0.0227 g, 0.119 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.167 g, 0.238 mmol) and (trimethylsilyl)acetylene (0.404 mL, 2.86 mmol) were dissolved under nitrogen in a flame-dried flask in a mixture of triethylamine (3.5 mL) and dimethylformamide (3.5 mL). The reaction mixture was heated at 50° C. for 2 h and then allowed to cool. Water (100 mL) was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over Sodium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 10% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-trimethylsilanylethynyl-benzoate as a yellow oil (0.624 g, 90%).
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate (0.142 g, 0.332 mmol; prepared as described in example 14), dichlorobis(triphenylphosphine)palladium(II) (0.023 g, 0.032 mmol), copper(II) iodide (3.2 mg, 0.017 mmol) dimethylformamide (0.5 mL), triethylamine (0.5 mL) and (trimethylsilyl)acetylene (0.066 mL, 0.47 mmol) were added sequentially to a flame-dried Schienk tube. The reaction mixture was heated at 50° C. oil bath for 2 h, allowed to cool to room temperature overnight and then partitioned between water (20 mL) and diethyl ether (3×20 mL), dried over magnesium sulfate and evaporated. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in hexanes) to give ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynylbenzoate as an off-white glass (0.111 g, 84%). LC-MS: 398.3 [(M+H)+].
A solution of 1-tert-butyloxycarbonyl-piperazine (4.581 mmol) and diisopropylethylamine (5.09 mmol) in methylene chloride (5 mL) was added to a 40 mL vial. 3,5-Dimethyl-isoxazole-4-carbonyl chloride (5.09 mmol) was added to the vial and the reaction was shaken overnight at room temperature. When the reaction was complete, it was diluted with methylene chloride (5 mL) and washed with 4 mL of 1 N hydrochloric acid followed by 4 mL of 10% potassium carbonate. The organic layer was concentrated in vacuo. The crude residue was dissolved in 5 mL of dioxane and 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was shaken overnight at room temperature then centrifuged. The supernatant was removed and the remaining solid was shaken with hexanes then centrifuged. The supernatant was removed, and the solids were collected and dried in vacuo to give (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone. LR-MS: 210.2 [(M+H)+].
In an analogous manner, there were obtained:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and ethylsulfonyl chloride using the procedure described in example 12.
In an analogous manner, there was obtained:
2-Methoxy-1-methyl-ethylamine (15 mmol) and diisopropylethylamine (17 mmol) were diluted with methylene chloride to give a total volume of 8 mL. The amine solution was added in a portion-wise fashion via a syringe to a solution of chloroacetylchloride (13 mmol) in methylene chloride (10 mL) cooled to approximately 40° C. in a sealed 40 mL vial. The reaction mixture was stirred for 1 h at reduced temperature. The solution was then made acidic with 1N hydrochloric acid and then diluted with 10 mL of methylene chloride. The vial was agitated and centrifuged. The organic layer was transferred to 40 mL vials and concentrated in vacuo. The residue (1.69 g, 10.21 mmol) was diluted with 10 mL of dimethylformamide. Piperazine-1-carboxylic acid tert-butyl ester (8.67 mmol) and diisopropylethylamine (13.27 mmol) were added. The reaction mixture was shaken at 65° C. overnight and concentrated in vacuo. The crude residue was dissolved in 10 mL of dioxane and 10 mL of 4 M hydrochloric acid in dioxane. The solution was shaken overnight at room temperature then centrifuged. The supernatant was removed, and the remaining solids were shaken with hexanes then centrifuged. The supernatant was removed, and the solids was collected and dried in vacuo to give N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide. LR-MS: 216.4 [(M+H)+].
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N,N-bis-(2-methoxy-ethyl)amine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-methoxy-N-methylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-isopropyl-N-methylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-(2-cyanoethyl)-N-methylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and methanesulfonic acid 3-methanesulfonyl-propyl ester (prepared according to Baerlocher, F. J. et al. Aust. J. Chem. 1999, 52, 167-172) in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and 3-bromopropionitrile in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl-chloride and N-tert-butylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-cyanomethyl-N-methylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and piperidine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl-chloride and cyclopropylamine in an analogous manner as described in example 21.
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and 2-methoxyethylamine in an analogous manner as described in example 21.
Methyl vinyl sulfone (1.8 mL, 20.1 mmol) was added to a solution of 1-(tert-butyloxycarbonyl)piperazine (1.50 g, 8 mmol) in methanol (84 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated to a white solid. Purification of the solid by flash column chromatography (silica gel, eluting with 1-5% methanol in methylene chloride) gave 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine as a white solid (2.29 g, 95%).
Hydrochloric acid (42 mL, 168 mmol, 4 M in 1,4-dioxane) was added to a cooled solution of 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine (2.29 g, 7.8 mmol) in 1,4-dioxane (42 mL). The mixture was stirred at room temperature overnight then concentrated to give 1-(2-methanesulfonylethyl)piperazine bishydrochloride as a white solid (2.05 g).
Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1 M hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%).
To a cooled solution of 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 0.2 mmol) in dioxane (20 mL) was added hydrochloric acid (4M in dioxane, 10 mL) and the reaction was stirred at room temperature for 12 h and concentrated to give N-(2-methanosulfonylethyl)-piperazine hydrochloride as a white solid (0.55 g, 95%).
To a solution of meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (1.7 g, 6.04 mmol) in toluene (60 mL) was added dropwise trimethylaluminum (2.62 mL, 2.0 M solution in toluene, diluted with 2.2 mL of toluene). At the end of addition, the mixture was stirred at 80° C. until the gas evolution was completed. The reaction was cooled to room temperature and methyl 4-cyano-2-ethoxybenzoate (1.2 g, 5.75 mmol, example 1) in toluene (6 mL) was added. The reaction was at 100° C. for 7 h and cooled back to room temperature. Water (1.9 mL) was added dropwise, followed by methylene chloride (5 mL) and methanol (5 mL). This mixture was refluxed for 20 min, cooled to room temperature and filtered through a small pad of sodium sulfate. The solids were washed with toluene, methylene chloride, and methanol. The filtrate was concentrated, and the residue was reconstituted in ethyl acetate. It was refluxed for 30 min, and the hot solution was filtered through sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (1.25 g, 48%).
A solution of meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (3.60 g, 12.8 mmol) in toluene (41 mL) was added dropwise to a solution of trimethylaluminum (6.4 mL, 2 M in toluene) in toluene (36 mL) cooled in an ice-salt bath. After addition was complete, the cooling bath was removed and the reaction mixture was stirred for 45 min. A solution of ethyl 2-ethoxy-4-trimethylsilanylethynylbenzoate (2.48 g, 8.54 mmol, example 17) in toluene (37 mL) was added and the reaction mixture was heated to reflux for 6 h and then allowed to cool to room temperature and stirred for 10 h more. Water (4.31 mL), methanol (11.3 mL) and methylene chloride (11.3 mL) were added and the reaction mixture was heated at 100° C. for 15 min. After cooling to room temperature, the reaction mixture was dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate (100 mL) and heated at 100° C. for 15 min and then concentrated. The residue was purified by flash column chromatography (silica gel, eluting with 2% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-trimethylsilanylethynylphenyl)-4,5-dihydro-1H-imidazole as a faintly yellow glass (3.96 g, 91%). LC-MS: 507.3 [(M+H)+].
A solution of tetrabutylammonium fluoride in tetrahydrofuran (3.45 mL, 3.45 mmol) was added dropwise to a solution of methanol (1.33 mL) and 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-trimethylsilanylethynylphenyl)-4,5-dihydro-1H-imidazole (3.50 g, 6.90 mmol) in tetrahydrofuran (70 mL) cooled in an ice bath. After stirring for 30 min, the reaction mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with methylene chloride (300 mL, 2×100 mL). The combined organic phases were dried over magnesium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 2% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole as a yellow foam (2.66 g, 89%). LC-MS: 435.2 [(M+H)+].
A solution of meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (1.58 g, 5.62 mmol) in toluene (18 mL) was added dropwise to a solution of trimethylaluminum (2.81 mL, 5.62 mmol, 2 M in toluene) in toluene (12 mL) cooled in an ice-salt bath. After addition was complete, the cooling bath was removed and the reaction mixture was stirred for 45 min. A solution of ethyl 2-ethoxy-4-iodobenzoate (1.20 g, 3.75 mmol; example 14) in toluene (18 mL) was added and the reaction mixture was heated to reflux for 6 h and then allowed to cool to room temperature and stirred 12 h more. Water (1.9 mL), methanol (5.0 mL) and methylene chloride (5.0 mL) were added and the reaction mixture was heated at 100° C. for 15 min. After cooling to room temperature, the reaction mixture was dried over sodium sulfate and evaporated. The residue was dissolved in ethyl acetate (50 mL) and heated at 100° C. for 15 min, then dried over sodium sulfate, evaporated. The residue was purified by column chromatography (silica gel, eluting with 1% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole as a faintly yellow glass (1.80 g, 90%). LC-MS: 537.2 [(M+H)+].
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (0.900 g, 1.68 mmol), tributyl-(1-ethoxyvinyl)tin (0.679 mL, 2.01 mmol) and tetrakis(triphenyl-phosphine)-palladium(0) (0.194 g, 0.168 mmol) were combined in toluene (10 mL) in a flame-dried Schlenk tube then heat at 120° C. for 20 h. After evaporation of volatiles, the residue was purified by flash column chromatography (silica gel, eluting with a gradient of 2-5% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-ethoxyvinyl)phenyl]-4,5-dihydro-1H-imidazole as a faintly green foam (0.639 g, 79%). LC-MS: 481.4 [(M+H)+].
An aqueous solution of hydrochloric acid (2 M, 18 mL) was sparged for 10 min with nitrogen and then used to slurry 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-ethoxyvinyl)phenyl]-4,5-dihydro-1H-imidazole (0.638 g, 1.33 mmol). Tetrahydrofuran (18 mL) was added to create a homogeneous solution. After stirring 1 h, the reaction mixture was poured into a mixture of 2 M sodium hydroxide (16 mL) and 10% sodium carbonate solution (50 mL) and extracted with methylene chloride (2×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-3% methanol in chloroform) to give 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone as a faintly yellow foam (0.392 g, 65%). LC-MS: 453.3 [(M+H)+].
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (566 mg, 1.05 mmol, example 27), copper(I) iodide (9.5 mg, 0.11 mmol), dichlorobis(triphenylphosphine)-palladium(II) (148 mg, 0.211 mmol) and 3,3-dimethyl-1-butyne (0.182 mL, 1.48 mmol) were dissolved under nitrogen in a flame-dried Schlenk tube in a mixture of triethylamine (1.7 mL) and dimethylformamide (1.7 mL). The reaction mixture was warmed in a 50° C. oil bath for 20 h, allowed to cool to room temperature and then partitioned between 2% sodium carbonate solution (70 mL) and diethyl ether (2×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 1% methanol in methylene chloride) to give 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole as an off-white foam (0.432 g, 83%). LC-MS: 491.3 [(M+H)+].
4,5-Bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole (1.25 g, 2.88 mmol, example 25) was dissolved in methylene chloride and diisopropylethylamine (2.41 mL, 13.8 mmol) was added. The mixture was cooled in an ice bath and phosgene (6.09 mL, 11.52 mmol, 20% in toluene) was added. The reaction mixture was stirred for 30 mm at ice temperature and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (1.35 g, 94%).
The enantiomers of 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a R,R-Whelk-01 column (25 cm×2 in). Eluent: 35% methylene chloride in hexanes. Flow rate: 85 mL/min. The first peak coming off the column is the desired (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (retention time: ˜19 min).
The unwanted isomer, (4R,5S)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (retention time: ˜28 min), was isolated and reconstituted in methylene chloride. This was stirred biphasically with 5% sodium carbonate and 5% dimethylaminopyridine to yield the parent imidazoline, 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole, which could be treated again with phosgene to give the racemic 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride.
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).
The enantiomers of 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester were separated by chiral chromatography using a R,R-Whelk-01 column (25 cm×10 mm). eluting with 15% iso-propanol in hexanes. The first peak coming off the column is the desired (4S,5R)-2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester.
A solution of morpholin-4-yl-2-piperazin-1-yl-ethanone (17 mg, 0.081 mmol, Oakwood Products) and diisopropylethylamine (10 mg, 0.077 mmol) in 0.5 mL of methylene chloride was added to a solution of (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (35 mg, 0.070 mmol, example 29) in 0.5 mL of methylene in a 4-mL vial. The vial was then capped and shaken for 1 h at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to a 4-mL vial and concentrated in vacuo. The crude was dissolved in 0.5 mL of acetonitrile, and then 0.6 mL of water and 0.492 mL of 0.5 M hydrochloric acid (2.46 mmol) were added to the sample. The sample was frozen with liquid nitrogen and lyophilized to give 4-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-benzonitrile hydrochloride (47.6 mg, 91% yield). LC-MS: 675.3 [(M+H)+].
To a solution of (4S,5R)-2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester (9 mg, 0.0124 mmol) in 0.5 mL of dimethylformamide was added a solution of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (5.3 mg, 0.026 mmol) and diisopropylethylamine (4.53 uL). The resulting mixture was heated to 40° C. for 1 h. The solution was concentrated in vacuo then extracted from 1 mL of water with 1 mL of methylene chloride. The organic extract was applied to a 4 gram silica gel cartridge. The product was eluted using a gradient of methanol in methylene chloride to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide (9.69 mg, 97%). LC-MS: 777.3 [(M+H)+].
The racemic 5-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N,N-dimethyl-benzenesulfonamide was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-5-dimethylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31.
The enantiomers of 5-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N,N-dimethyl-benzenesulfonamide (105 mg) were separated by chiral chromatography using a Diacel Chiralpak AD column (21 mm×250 mm) eluting with i-propanol/ethanol (7:3) containing 0.05% trifluoroacetic acid at a flow rate of 30 mL/min. Injection volume: 3.0 mL (10-15 mg of the racemic compound). Retention time: 3.35 min and 5.50 min. After the volatiles were evaporate, the resulting trifluoroacetate salts were lyophilized with hydrochloric acid to give the two enantiomers as white solids (40 mg).
5-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxy-benzenesulfonamide was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31.
5-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxy-benzenesulfonamide (˜10 mg) was dissolved in 2 mL of trifluoroacetic acid and heated to 80° C. for 30 min. The reaction mixture was diluted with 2 mL of methylene chloride and 1.5 mL of 10% potassium carbonate solution then agitated. The organic layer was separated and concentrated in vacuo to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-benzenesulfonamide as trifluoroacetate salt. LC-MS: 763.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 29 and 31. LC-MS: 562.4 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 592.4 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 4-pyrrolidin-1-yl-piperidine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 616.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 644.3 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 674.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 4-pyrrolidin-1-yl-piperidine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 698.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-5-dimethylsulfamoyl-2-ethoxy-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 678.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-5-dimethylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 791.5 [(M+H)+].
Sodium hydride (0.35 g, 8.6 mmol, 60% in mineral oil) was added to a solution of 4-tert-butyloxycarbonyl-piperazin-2-one (0.86 g, 4.3 mmol) in dimethylformamide (20.0 mL) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To this mixture was added 2-bromoethoxy-tert-butyldimethylsilane (2.3 mL, 10.8 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20% ethyl acetate in hexanes) gave 4-tert-butyloxycarbonyl-1-[2-(tert-butyldimethylsilyloxy)ethyl]-piperazin-2-one (1.17 g, 76%).
To a solution of 4-tert-butyloxycarbonyl-1-[2-(tert-butyldimethylsilyloxy)ethyl]-piperazin-2-one (0.88 g, 2.5 mmol) in tetrahydrofuran (30 mL) was added tetrabutylammonium fluoride (3.6 mL, 3.6 mmol, 1.0 M in tetrahydrofuran) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by flash column chromatography (silica gel, eluting with 30% ethyl acetate in hexanes) gave 4-tert-butyloxycarbonyl-1-(2-hydroxyethyl)-piperazin-2-one (0.45 g, 75%).
Hydrochloric acid (1.8 mL, 7.4 mmol, 4 M in 1,4-dioxane) was added to a solution of 4-tert-butyloxycarbonyl-1-(2-hydroxyethyl)-piperazin-2-one (0.45 g, 1.8 mmol) in 1,4-dioxane (5.0 mL). The mixture was stirred overnight and concentrated to give 1-(2-hydroxyethyl)-piperazin-2-one hydrochloride as an off-white solid (0.30 g, 91%).
5-{4,5-Bis-(4-chloro-phenyl)-1-[4-(2-hydroxy-ethyl)-3-oxo-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N,N-dimethyl-benzenesulfonamide was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-5-dimethylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-(2-hydroxyethyl)-piperazin-2-one hydrochloride in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 722.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 674.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 704.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 745.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 766.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 29 and 31. LC-MS: 654.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-5-dimethylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) following successively the procedures described for examples 25, 29 and 31. The enantiomers were separated using the procedure described in example 33. LC-MS: 708.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfinyl-2-ethoxybenzoate (example 9a) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfonyl-2-ethoxybenzoate (example 9b) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfinyl-2-ethoxybenzoate (example 9a) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfonyl-2-ethoxybenzoate (example 9b) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfinyl-2-ethoxybenzoate (example 9a) and 1-(2-methanesulfonylethyl)-piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfonyl-2-ethoxybenzoate (example 9b) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfinyl-2-ethoxybenzoate (example 9a) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methylsulfonyl-2-ethoxybenzoate (example 9b) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and piperidine-4-carboxylic acid amide (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 590.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 29 and 31. LC-MS: 671.4 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and cyclopropyl-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 29 and 31. LC-MS: 616.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 3-methyl-1-piperazin-1-yl-but-2-en-1-one (example 19) following successively the procedures described for examples 29 and 31. LC-MS: 630.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperazine (example 20) following successively the procedures described for examples 29 and 31. LC-MS: 707.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 592.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 3-piperazin-1-yl-propionitrile (example 22f) following successively the procedures described for examples 29 and 31. LC-MS: 601.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 606.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 29 and 31. LC-MS: 688.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and piperidine-3-carboxylic acid amide (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 590.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-acetylpiperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 716.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 29 and 31. LC-MS: 677.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 4-piperidinemethanol (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 577.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 3-hydroxypiperidine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 563.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 29 and 31. LC-MS: 562.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 633.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 2-piperazin-1-yl-1-piperidin-1-yl-ethanone (example 22i) following successively the procedures described for examples 29 and 31. LC-MS: 673.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 29 and 31. LC-MS: 640.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and piperidine-4-carboxylic acid amide (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 672.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 753.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and cyclopropyl-piperazin-1-yl-methanone (example 19) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 698.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 3-methyl-1-piperazin-1-yl-but-2-en-1-one (example 19) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 712.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperazine (example 20) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 789.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 3-piperazin-1-yl-propionitrile (example 22f) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 683.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 688.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 770.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and N-methyl-2-piperazin-1-yl-acetamide (example 22h) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 701.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and piperidine-3-carboxylic acid amide (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 672.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-acetylpiperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 798.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 759.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 4-piperidinemethanol (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 659.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 3-hydroxypiperidine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 645.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 715.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 757.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 2-piperazin-1-yl-1-piperidin-1-yl-ethanone (example 22i) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 755.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(N,N-dimethylsulfonamide)benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 722.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 686.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)-piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 778.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 757.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 764.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 812.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 801.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 716.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and N-methyl-2-piperazin-1-yl-acetamide (example 22h) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 743.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 799.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and cyclopropyl-piperazin-1-yl-methanone (example 19) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 740.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(isobutyl-methyl-sulfamoyl)-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 730.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 732.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 824.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 803.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 858.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 847.4 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and N-methyl-2-piperazin-1-yl-acetamide (example 22h) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 789.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 845.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-[bis-(2-methoxy-ethyl)-sulfamoyl]-2-ethoxy-benzoate (example 2) and cyclopropyl-piperazin-1-yl-methanone (example 19) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 786.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 684.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonyl-ethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 776.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 755.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 762.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 810.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 799.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 714.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-methyl-2-piperazin-1-yl-acetamide (example 22h) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 741.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 797.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and cyclopropyl-piperazin-1-yl-methanonein an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 738.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 688.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 780.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 759.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 766.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 814.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 803.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 718.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(2-methoxy-1-methyl-ethylsulfamoyl)-benzoate (example 2) and N-methyl-2-piperazin-1-yl-acetamide (example 22h) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 745.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 670.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 762.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 741.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 796.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 785.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 700.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 662.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 692.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 733.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 1-(2-methanesulfonylethyl)-piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 754.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 8-carboethoxy-7-ethoxy-2-methyl-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,6-b][1,4,5]oxathiazepine (example 3) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 672.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 8-carboethoxy-7-ethoxy-2-methyl-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,6-b][1,4,5]oxathiazepine (example 3) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 764.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 8-carboethoxy-7-ethoxy-2-methyl-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,6-b][1,4,5]oxathiazepine (example 3) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 785.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 733.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 754.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 775.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 644.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 736.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 757.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 715.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-methylsulfonyl-2-ethoxybenzoate (example 10) and 2-piperazinone (Avocado Organics) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 615.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-methylsulfonyl-2-ethoxybenzoate (example 10) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 707.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-methylsulfonyl-2-ethoxybenzoate (example 10) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 728.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate (example 14) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 669.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate (example 14) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 740.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate (example 14) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 761.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate (example 14) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 782.8 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 5-cyano-2-ethoxy-4-methoxy-benzoic acid ethyl ester (example 8) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 705.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 5-cyano-2-ethoxy-4-methoxy-benzoic acid ethyl ester (example 8) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 592.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 5-cyano-2-ethoxy-4-methoxy-benzoic acid ethyl ester (example 8) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 684.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 745.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 787.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 6-ethoxy-N,N-dimethyl-isophthalamic acid ethyl ester (example 4) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 721.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 6-ethoxy-N,N-dimethyl-isophthalamic acid ethyl ester (example 4) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 700.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 6-ethoxy-N,N-dimethyl-isophthalamic acid ethyl ester (example 4) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 608.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(pyrrolidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 747.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(pyrrolidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 726.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 761.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 740.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 648.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-5-(morpholine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 763.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 662.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-methyl-5-(pyrrolidine-1-sulfonyl)-benzoic acid ethyl ester (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 797.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 796.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 831.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 810.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 718.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 833.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 812.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 720 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-methyl-5-(pyrrolidine-1-sulfonyl)-benzoic acid ethyl ester (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 776.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 811.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 790.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 698.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 813.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 792.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 700.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 817.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 644.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 736.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 754.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, methyl 4-dimethylsulfamoyl-2-ethoxybenzoate (example 11) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 715.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 29 and 31. LC-MS: 661.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 29 and 31. LC-MS: 605.2 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-cyanomethyl-N-methyl-2-piperazin-1-yl-acetamide (example 22h) following successively the procedures described for examples 29 and 31. LC-MS: 658.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-cyclopropyl-2-piperazin-1-yl-acetamide (example 22j) following successively the procedures described for examples 29 and 31. LC-MS: 645.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22k) following successively the procedures described for examples 29 and 31. LC-MS: 663.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 29 and 31. LC-MS: 721.4 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 29 and 31. LC-MS: 649.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 29 and 31. LC-MS: 661.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 29 and 31. LC-MS: 672.3 [(M+H)+].
The title compound was prepared from 4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (example 25) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 576.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-fluoro-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 704.3 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-fluoro-5-(morpholine-4-sulfonyl)-benzoate (example 2) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 718.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-fluoro-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 796.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-fluoro-5-(morpholine-4-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 817.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(morpholine-4-sulfonyl)-benzoic acid methyl ester (example 11) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 686.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(morpholine-4-sulfonyl)-benzoic acid methyl ester (example 11) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 778.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(morpholine-4-sulfonyl)-benzoic acid methyl ester (example 11) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 799.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(pyrrolidine-1-sulfonyl)-benzoic acid methyl ester (example 11) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 670.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(pyrrolidine-1-sulfonyl)-benzoic acid methyl ester (example 11) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 762.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(pyrrolidine-1-sulfonyl)-benzoic acid methyl ester (example 11) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 783.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 30 and 32. LC-MS: 787.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-2,5-diethoxy-benzoate (example 15) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 606.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-2,5-diethoxy-benzoate (example 15) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 620.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-2,5-diethoxy-benzoate (example 15) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 698.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-cyano-2,5-diethoxy-benzoate (example 15) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 719.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-piperidino-5-piperidinosulfamoyl-2-ethoxybenzoate (example 12b) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 767.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-piperidino-5-piperidinosulfamoyl-2-ethoxybenzoate (example 12b) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 781.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-piperidino-5-piperidinosulfamoyl-2-ethoxybenzoate (example 12b) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 859.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-piperidino-5-piperidinosulfamoyl-2-ethoxybenzoate (example 12b) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 879.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate (example 12a) and ethyl chloroformate (Aldrich) in an analogous manner using the procedures described for examples 25, 29 and 31 (except chiral purification). LC-MS: 633.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate (example 12a) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 687.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate (example 12a) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 779.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate (example 12a) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 701.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxybenzoate (example 12a) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 800.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (example 5) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 709.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-isopropylsulfamoyl-4-methyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 764.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-isopropylsulfamoyl-4-methyl-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 672.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-methylsulfamoyl-4-methyl-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 757.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-methylsulfamoyl-4-methyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 736.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-methylsulfamoyl-4-methyl-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 644.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (example 5) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 688.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (example 5) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 596.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 5-cyano-4-dimethylamino-2-ethoxy-benzoic acid methyl ester (example 6) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 718.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 5-cyano-4-dimethylamino-2-ethoxy-benzoic acid methyl ester (example 6) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 697.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-isopropylsulfamoyl-4-methyl-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 785.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 29 and 31. LC-MS: 561.3 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and [1,4]diazepan-5-one (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 575.3 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 29 and 31. LC-MS: 653.3 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 674.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 784.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2), and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 759.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 749.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 650.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 742.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 693.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 749.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-4-chloro-2-ethoxy-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29, 31 and 34. LC-MS: 728.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, N-tert-butyl-2-ethoxy-terephthalamic acid methyl ester (example 7) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 728.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, N-tert-butyl-2-ethoxy-terephthalamic acid methyl ester (example 7) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 679.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 757.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 761.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 747.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 648.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 740.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid ethyl ester (example 4) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 691.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 747.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-(piperidine-1-carbonyl)-benzoic acid methyl ester (example 7) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 726.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-methylsulfamoyl-4-methyl-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 30 and 32. LC-MS: 773.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 30 and 32. LC-MS: 784.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 30 and 32. LC-MS: 735.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 30 and 32. LC-MS: 791.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 30 and 32. LC-MS: 770.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 30 and 32. LC-MS: 763.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 30 and 32. LC-MS: 664 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 30 and 32. LC-MS: 756.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 30 and 32. LC-MS: 707.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 30 and 32. LC-MS: 763.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-methylsulfamoyl-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 30 and 32. LC-MS: 742.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 30 and 32. LC-MS: 805.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 30 and 32. LC-MS: 801.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 30 and 32. LC-MS: 791.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-chloro-2-ethoxy-5-isopropylsulfamoyl-benzoate (example 2) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 30 and 32. LC-MS: 692.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 2-ethoxy-4-[methanesulfonyl-(3-oxo-piperazine-1-carbonyl)-amino]-benzoic acid ethyl ester (example 13) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 756.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-methanesulfonylamino-2-ethoxybenzoate (example 13) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 940.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-(2,2-dimethyl-propionylamino)-2-ethoxy-benzoic acid ethyl ester (example 13) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 636.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynylbenzoate (example 18) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 668.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynylbenzoate (example 18) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 760.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynylbenzoate (example 18) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 781.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynyl-benzoate (example 18) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 767.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-(2,2-dimethyl-propionylamino)-2-ethoxy-benzoic acid ethyl ester (example 13) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 728.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-(2,2-dimethyl-propionylamino)-2-ethoxy-benzoic acid ethyl ester (example 13) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 707.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, 4-(2,2-dimethyl-propionylamino)-2-ethoxy-benzoic acid ethyl ester (example 13) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 749.5 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 29 and 31. LC-MS: 660.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 29 and 31. LC-MS: 648.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 29 and 31. LC-MS: 668.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 29 and 31. LC-MS: 639.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-(2-hydroxy-ethyl)-piperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 605.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-acetylpiperazine (Aldrich) following successively the procedures described for examples 29 and 31. LC-MS: 589.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 3-piperazin-1-yl-propionitrile (example 22f) following successively the procedures described for examples 29 and 31. LC-MS: 600.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 29 and 31. LC-MS: 667.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 29 and 31. LC-MS: 604.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 29 and 31. LC-MS: 660.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole (example 26) and 3-piperazinyl-propionic acid (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 619.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-trifluoroprop-1-ynylbenzoate (example 16) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 25, 29 and 31. LC-MS: 629.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-trifluoroprop-1-ynylbenzoate (example 16) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 721.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-trifluoroprop-1-ynylbenzoate (example 16) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 742.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-trifluoroprop-1-ynylbenzoate (example 16) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 728.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 797.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 741.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 857.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 785.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 797.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 808.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 813.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 807.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 776.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 805.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methyl-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 804.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 785.4 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 729.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 845.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 773.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 785.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 796.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 801.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 795.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 764.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 793.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 792.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 778.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methyl-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 799.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 773.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 717.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 833.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 761.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 773.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 789.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 783.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 752.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 780.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-4-methyl-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 766.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 813.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 757.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 873.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 801.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 813.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 824.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 829.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 823.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 792.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 821.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 820.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 806.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 827.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 789.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 733.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 849.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 777.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 789.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 800.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 805.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 799.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 768.1 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 797.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 796.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 782.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-4-methoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 803.2 [(M+H)+].
The title compound was prepared from 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone (example 27) and 2-piperazinone (Avocado Organics) following successively the procedures described for examples 29 and 31. LC-MS: 579.4 [(M+H)+].
The title compound was prepared from 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone (example 27) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 29 and 31. LC-MS: 671.4 [(M+H)+].
The title compound was prepared from 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone (example 27) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 692.4 [(M+H)+].
The title compound was prepared from 1-{4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}ethanone (example 27) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 29 and 31. LC-MS: 685.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 4-trifluoroprop-1-ynylbenzoate (example 16) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 735.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 771.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 715.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 831.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 759.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 771.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 782.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 787.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 781.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 750.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 779.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 778.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 764.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 785.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 783.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 727.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 843.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 771.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 783.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 794.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 799.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 793.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 762.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 791.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 790.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 776.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(piperidine-1-sulfonyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 797.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 759.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 703.2 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 22a) following successively the procedures described for examples 25, 29 and 31. LC-MS: 819.4 [(M+H)+]
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 747.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 759.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 22d) following successively the procedures described for examples 25, 29 and 31. LC-MS: 770.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide (example 21) following successively the procedures described for examples 25, 29 and 31. LC-MS: 775.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 19) following successively the procedures described for examples 25, 29 and 31. LC-MS: 769.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-ethanesulfonyl-piperazine (example 20) following successively the procedures described for examples 25, 29 and 31. LC-MS: 738.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and N-(2-methanosulfonylethyl)-piperazine hydrochloride (example 24) following successively the procedures described for examples 25, 29 and 31. LC-MS: 767.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 766.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 752.3 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 2-ethoxy-5-(methoxy-methyl-sulfamoyl)-benzoate (example 2) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 25, 29 and 31. LC-MS: 773.3 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole (example 28) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 29 and 31. LC-MS: 709.4 [(M+H)+].
The title compound was prepared from 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole (example 28) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) following successively the procedures described for examples 29 and 31. LC-MS: 730.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 2-piperazin-1-yl-acetamide (Matrix) following successively the procedures described for examples 25, 29 and 31. LC-MS: 745.1 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 22g) following successively the procedures described for examples 25, 29 and 31. LC-MS: 801.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 22b) following successively the procedures described for examples 25, 29 and 31. LC-MS: 789.4 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 22c) following successively the procedures described for examples 25, 29 and 31. LC-MS: 801.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 1-(3-methanesulfonyl-propyl)-piperazine (example 22e) following successively the procedures described for examples 25, 29 and 31. LC-MS: 808.5 [(M+H)+].
The title compound was prepared from meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine, ethyl 5-tert-butylsulfamoyl-2-ethoxy-4-methoxy-benzoate (example 2) and 1-(2-methanesulfonylethyl)piperazine bishydrochloride (example 23) following successively the procedures described for examples 25, 29 and 31. LC-MS: 794.5 [(M+H)+].
The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Lane et al.). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin-conjugated Allophycocyanin (APC).
Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing: 90 nM biotinylated 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.
IC50s showing biological activity that applies to compounds of the subject matter of this invention ranges from about 0.005 uM to about 1 uM. Specific data for some examples are as follows:
This application claims the benefit of U.S. Provisional Application No. 60/662,516, filed Mar. 16, 2005, which is hereby incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 6734302 | Kong et al. | May 2004 | B2 |
| 7425638 | Haley et al. | Sep 2008 | B2 |
| Number | Date | Country |
|---|---|---|
| WO 03051359 | Jun 2003 | WO |
| WO 03051359 | Jun 2003 | WO |
| WO 2005110996 | Nov 2005 | WO |
| WO 2005123691 | Dec 2005 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20060211693 A1 | Sep 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60662516 | Mar 2005 | US |
