N-ethyl-N',N'-dimethylethane-1,2-diamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (16.9 mg, 48 μmol) and N,N-dimethyl-N′-ethylethylenediamine (4.6 mg, 40 μmol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-[2-(dimethylamino)ethyl]-N-ethyl-4-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]benzamid (3 mg, 20%). 1H NMR (400 MHz, d6-DMSO): 8.21 (m, 3H), 7.97 (s, 1H), 7.87 (dd, 1H), 7.49 (m, 3H), 6.90 (d, 1H), 3.41 (m, 4H), 2.33 (m, 2H), 2.22 (m, 6H), 1.97 (s, 3H), 1.10 (m, 3H); MS (EI) for C24H28N4O3: 421 (MH+). The reaction mixture was concentrated in vacuo Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N′-ethyl-N,N-dimethyl-ethane-1,2-diamine gives “A91”; method 1: HPLC/MS: 1.08 min, [M+H]=433; gives “A91” 1.08 min, [M+H]=433

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N′-ethyl-N,N-dimethylethane-1,2-diamine (0.62 mL, 4.4 mmol) in methylene chloride (10 mL) was added 6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature followed by the extraction with aqueous HCl (5%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.7 gram (60% yield) of the title compound: MS (ES) m/z 292 (M++1). followed by the extraction with aqueous HCl (5%) extracted with methylene chloride The organic phase was dried (Na2SO4) evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N′-ethyl-N,N-dimethylethane-1,2-diamine (0.62 mL, 4.4 mmol) in methylene chloride (10 mL) was added 6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature followed by the extraction with aqueous HCl (5%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.7 gram (60% yield) of the title compound: MS (ES) m/z 292 (M++1). followed by the extraction with aqueous HCl (5%) extracted with methylene chloride The organic phase was dried (Na2SO4) evaporated in vacuo

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dilinoleyl methanol (1.0 g, 1.9 mmol) and pyridine (230 μL, 4.7 mmol) in anhydrous ether (10 mL) cooled to −15° C. under nitrogen was slowly added diphosgene (0.38 mL, 3.14 mmol). The reaction was stirred for 1 hour at −15° C., then N,N-dimethyl-N′-ethyl-ethylenediamine (2.2 mL, 14.2 mmol) was added. The solution was warmed to room temperature and stirred for 30 minutes. The solution was diluted with diethyl ether (50 mL) and filtered to remove the urea and ammonium salts. The ether filtrate was concentrated in vacuo to dryness and the residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (990 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 5.41-5.27 (m, 8H), 4.77-4.69 (m, 1H), 3.55-3.20 (m, 4H), 2.79-2.72 (m, 4H), 2.72-2.56 (m, 1H), 2.55-2.21 (m, 7H), 2.08-1.96 (m, 8H), 1.58-1.44 (m, 4H), 1.39-1.15 (m, 36H), 1.10 (t, J=7.0 Hz, 3H), 0.90-0.82 (m, 6H). The solution was warmed to room temperature stirred for 30 minutes filtered to remove the urea and ammonium salts The ether filtrate was concentrated in vacuo to dryness the residue was purified by column chromatography (100% ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (16.9 mg, 48 μmol) and N,N-dimethyl-N′-ethylethylenediamine (4.6 mg, 40 μmol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-[2-(dimethylamino)ethyl]-N-ethyl-4-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]benzamid (3 mg, 20%). 1H NMR (400 MHz, d6-DMSO): 8.21 (m, 3H), 7.97 (s, 1H), 7.87 (dd, 1H), 7.49 (m, 3H), 6.90 (d, 1H), 3.41 (m, 4H), 2.33 (m, 2H), 2.22 (m, 6H), 1.97 (s, 3H), 1.10 (m, 3H); MS (EI) for C24H28N4O3: 421 (MH+). The reaction mixture was concentrated in vacuo Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: are obtained analogously by reacting 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one with corresponding amounts (instead of with N-methylpiperazine) of morpholine, N-benzylpiperazine, N-ethylpiperazine, 1,3-dimethylpiperazine, N,N,N'-trimethylethylenediamine, N,N,N'-triethylethylenediamine, N'-ethyl-N,N-dimethylethylenediamine and hexahydro-1-methyl-1H-1,4-diazepine, respectively. are obtained analogously

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[2-(Dimethylamino)ethyl]-N-ethyl-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and commercially available N,N-dimethyl-N'-ethylethylenediamine as described for Example 17, Step 5. The compound is purified by reverse phase HPLC on C18 silica gel (gradient elution from 0.1% trifluoroacetic acid in 5% MeCN/H2O to 100% MeCN). Neutralization of the trifluroacetate salt after concentrating the fractions from the HPLC run afforded the title compound as an amorphous solid that was triturated in ether: mp 120°-123 ° C.; 1H NMR (Me2SO-d6, 400 MHz), 1:1 mixture of amide rotamers, a: b) δ 9.00 (s, 1Ha), 8.94 (s, 1Hb), 8.54 (s, 1Ha), 8.51 (s, 1Hb), 7.99 (d, J=7.9 Hz, 1Hb), 7.96 (d, J=8.1 Hz, 1Ha), 7.73 (d, J=8.5 Hz, 2Hb), 7.69 (m, 2Ha, 1 H), 7.49 (t, J=8.1 Hz, 1 H), 7.30 (m, 5 H), 7.26 (d, J=8.3 Hz, 1 H), 6.89 (d, J=8.7 Hz, 2Hb), 6.85 (d, J=8.5 Hz, 2Ha), 3.96 (s, 3 H), 3.74(m, 1 H), 3.46(s, 2H),3.11 (m, 4H),2.80(d,J=10.4Hz, 2H),2.18(t,J=5.6 Hz, 2Hb), 2.02 (m, 2 H), 1.99 (s, 6Hb), 1.83 (s, 6Ha), 1.70 (m, 2 H, 2Ha), 1.56 (qd, J=10.8, 3.6Hz, 2 H), 0.91 (t, J=6.9 Hz, 3Hb), 0.61 (t, J=6.9 Hz, 3Ha). N-[2-(Dimethylamino)ethyl]-N-ethyl-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared The compound is purified by reverse phase HPLC on C18 silica gel (gradient elution from 0.1% trifluoroacetic acid in 5% MeCN/H2O to 100% MeCN) Neutralization of the trifluroacetate salt after concentrating the fractions from the HPLC run