, 4-dihydroquinazolin-6-yl)-N 1 -(2,4-dichlorophenyl)thiourea (7f): According to the method B (r.t., 1 h), compound 7f was isolated as a colorless solid (446 mg, 89%), p.265
24 (s, 1H, DMSO-d 6 ) ? 10.28 (s, 1H, NH), 9.70 (s, 1H, NH), 8.32 (d, J = 2.4 Hz, 1H, H 5 ), vol.8, p.1 ,
, 188-190?C; 1 H-NMR (DMSO-d 6 ) ? 10.29 (s, 1H, NH), N-(3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N 1 -(pyridin-3-yl)thiourea (7g): According to the method A (40?C (µW), 1 h), compound 7g was isolated as a colorless solid (309 mg, 89%), mp, vol.10, p.707, 1257.
, 99 (s, 1H, NH), N-(3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N 1 -(p-tolyl)thiourea (7h): According to the method B (r.t., 2 h), compound 7h was obtained as a colorless solid (386 mg, 89%), vol.9, p.1, 1037.
, 81 (s, 1H, NH), 8.27 (d, J = 1.8 Hz, 1H, H 5 ), N-(3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)-N 1 -(4-methoxyphenyl)thiourea (7i): According to the method B (r.t., 2 h), compound 7i was isolated as a colorless solid (395 g, 87%), vol.9, p.1
, 4-dihydroquinazolin-6-yl)-N 1 -(4-methoxyphenyl)thiourea (7j): According to the method A (r.t., 10 min.), compound 7j was isolated as a grey solid (340 mg, 87%), mp, pp.210-212
0 Hz, 2H, ArH), 6.72 (d, J = 9.0 Hz, 2H, ArH), 2.89 (s, 6H, NCH 3 ), 3.33-3.21 (m, 1H, NCH), DMSO-d 6 ) ? 9.77 (s, 1H, NH), 9.70 (s, 1H, NH), 8.27 (d, J = 2.4 Hz, 1H, H 5 ), 8.20 (s, 1H, H 2 ), 7.93 (dd, J = 8.7, 2.4 Hz, 1H, H 7 ), 7.59 (d, J = 8.7 Hz, 1H, H 8 ), 7.22 (d, J = 9 ,
, 4-dihydroquinazolin-6-yl)-N 1 -(2,4-dimethoxyphenyl)thiourea (7k): According to the method A (r.t., 30 min.), product 7k was isolated as a black solid (396 mg, 97%), mp, pp.166-168
mmol) and bromine (19.0 µL, 0.37 mmol, 1.0 equiv.), 2 h at room temperature. After purification, 8g was isolated as a colorless solid (100 mg, 80%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 10, 7.95 (dd, J = 8.7, 2.4 Hz, 1H, H 7 ), 7.60 (d, J = 8.7 Hz, 1H, H 8 ), 7.47 (d, J = 8.4 Hz, 1H, H 6 1 ), 6.64 (d, J = 2.7 Hz, 1H, H 3 1 ), 6.53 (dd, J = 8.4, 2.7 Hz, 1H, H 5 1 ), vol.3 ,
, after 1 h at room temperature. After purification, 10a was isolated as a colorless solid (37 mg, 30%), mp. 258-260?C; 1 H-NMR (DMSO-d 6 ) ? 10.93 (s, 1H, NH), 8.72 (d, J = 2.3 Hz, 1H, H 5 ), mmol) in presence of bromine, vol.9, 1490.
, 35 (s, 1H, H 2 ), 8.07 (dd, J = 2.5, 8.8 Hz, 1H, mmol) and bromine (16.4 µL, 0.32 mmol, 1.0 equiv.), 30 min at room temperature. After purification, 10l was isolated as a colorless solid (113 mg, 90%), mp. 200?C; 1 H-NMR (DMSO-d 6 ) ? 10.73 (s, 1H, NH), 8.71 (d, J = 2.5 Hz, 1H, H 5 ), vol.8, p.625, 1219.
, 100 mg, 0.31 mmol, 1.0 equiv.) in DME (3 mL) was added the appropriate amine (0.33 mmol, 1.05 equiv.) at room temperature for 30 min. to 12 h. After completion, copper(I) iodide (5.7 mg, 0.03 mmol, 10 mol %) and cesium carbonate (208 mg, 0.64 mmol, 2.0 equiv.) were added and the resulting suspension was heated under microwave at 80?C for 1 h. The resulting mixture was adsorbed on Celite ® and purified by flash chromatography using ethyl acetate/methylene chloride (0/100 to 50/50, v/v) as eluent to furnish the expected fused 2-arylaminothiazoloquinazolinones 8a; c; h-n and 14a
, 204-206?C; 1 H-NMR (DMSO-d 6 ) ? 10.69 (s, 1H, NH), 8.30 (s, 1H, thiourea intermediate was obtained from 13 and aniline (30.7 mg) after 12 h at room temperature. After purification, 8a was isolated as a colorless solid (82.9 mg, 80%), mp, vol.696, p.1
, 8H)-one (8c): According to the general procedure, thiourea intermediate was obtained from 13 and 4-fluoroaniline (56.8 mg) after 2 h at room temperature. After purification
69 (s, 1H, NH), 8.29 (s, 1H, 8.05 (d, J = 8.7 Hz, 1H, H 4 ), 7.88-7.86 (m, 1H, Molecules, vol.10, p.27, 2016. ,
, 7.66 (d, J = 8.7 Hz, 1H, H 5 ), 7.24 (m, 2H, Ph)
URL : https://hal.archives-ouvertes.fr/in2p3-01112063
, According to the general procedure, thiourea intermediate was obtained from 13 and p-toluidine (35.4 mg,) after 2 h at room temperature. After purification, -Cyclopropyl-2-(p-tolylamino)thiazolo[5,4-f]quinazolin-9(8H)-one (8h)
, DMSO-d 6 ) ? 10.56 (s, 1H, NH), 8.28 (s, 1H, H 7 ), 8.02 (d, J = 8.7 Hz, 1H, H 4 ), 7.71 (d, J = 8.1 Hz, 2H, Ph), 7.63 (d, J = 8.7 Hz, 1H, H 5 ), 7.20 (d, J = 8.1 Hz, vol.2, 1140.
, 8H)-one (8i): According to the general procedure, thiourea intermediate was obtained from 13 and p-anisidine (40.6 mg) after 2 h at room temperature. After purification
, 7.78 (d, J = 8.7 Hz, 1H, H 4 ), 7.72 (d, J = 9.0 Hz, 2H, Ph), 7.62 (d, J = 8.7 Hz, 1H, H 5 ), 6.98 (d, J = 9.0 Hz, vol.2, p.826, 1029.
, mg) after 1 h at room temperature. After purification, 8j was isolated as a pale yellow solid (101.7 mg, 87%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 10.27 (s, 1H, NH), 8.24 (s, 1H, H 7 ), 7.94 (d, J = 8.7 Hz, 1H, H 4 ), 7.61-7.56 (m, 3H, Ph + H 5 ), 7.78 (d, J = 9.1 Hz, vol.1, 1244.
, 5 mg) after 30 min. at room temperature. After purification, 8k was isolated as a brown solid (105.1 mg, 86%), mp. 240-242?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.2, p.822, 1023.
, According to the general procedure, thiourea intermediate was obtained from 13 and 4-aminoveratrole (50.5 mg) after 30 min. at room temperature. After purification, 8l was isolated as a colorless solid (110 mg, 90%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 10.47 (s, 1H, NH), vol.8
, , vol.3201, p.1, 1025.
, 2-(Benzylamino)-8-cyclopropylthiazolo[5,4-f]quinazolin-9(8H)-one (14a): According to the general procedure, thiourea intermediate was obtained from 13 and benzylamine (35.4 mg) after 30 min, thiourea intermediate was obtained from 13 and 4-aminobenzenesulfonamide (56.8 mg) after 12 h at room temperature. After purification, 8l was isolated as a beige solid (128.1 mg, 77%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 11.10 (s, 1H, NH), 8.30 (s, 1H, H 7 ), 8.10 (d, J = 8.6 Hz, 1H, H 4 ), 8.00 (d, J = 8.8, 2H, Ph), 7.83 (d, J = 8.8 Hz, Ph), vol.3296, p.832, 1153.
1 mg) after 30 min. at room temperature. After purification, 14b was isolated as a colorless solid (98.0 mg, 96%), mp. 210-212?C; 1 H-NMR (DMSO-d 6 /CDCl 3 ) ? 8.12 (s, 1H, vol.29 ,
, According to the general procedure, thiourea intermediate was obtained from 13 and 2-piperiridinylethylamine (43.0 mg) after 30 min. at room temperature. After purification, 14c was isolated as a colorless solid (104 mg, 91%), mp. 218-220?C; 1 H-NMR (DMSO-d 6 ) ? 8
, , vol.833, p.1, 1297.
, According to the general procedure, thiourea intermediate was obtained from 13 and 2-morpholinoethylamine (43.0 mg) after 30 min. at room temperature. After purification, 14d was isolated as a colorless solid (102 mg, 89%), mp. 222-224?C; 1 H-NMR (DMSO-d 6 ) ? 8.27 (s, 1H, 8.25 (br, 1H, NH), 7.89 (d, J = 8.4 Hz, 1H, H 4 ), vol.7, p.61
, 8H)-one (14e): According to the general procedure, thiourea intermediate was obtained from 13 and piperidine (26.3 mg) after 30 min, pp.244-246
, CDCl 3 ) ? 8.05 (s, 1H, H 7 ), 7.88 (d, J = 8.4 Hz, 1H, H 4 ), vol.7, p.27
, 1280 found 327.1283. 8-Cyclopropyl-2-(piperidin-1-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (14f): According to the general procedure, thiourea intermediate was obtained from 13 and morpholine (28.7 mg) after 30 min. at room temperature. After purification, 14f was isolated as a colorless solid (93.6 mg, 92%), mp. 230-232?C; 1 H-NMR (DMSO-d 6 ) ? 8.26 (s, 1H, HRMS calcd for C 17 H 19 N 4 OS, vol.824, p.1, 1112.
, General Procedure for the Synthesis of N-Alkyl-8-cyclopropyl-9-oxo-8,9-dihydrothiazolo[5,4-f ] quinazoline-2-carboximidamides 17a-f from 16
, In a sealed tube, a solution of carbonitrile derivative 16 (75 mg, 0.28 mmol) and the appropriate amine (2.8 mmol, 10 equiv.) in THF (1 mL) was heated under microwaves at 100?C for 45 min under argon atmosphere. The solvent was removed under vacuum and the crude residue was adsorbed on Celite ®
, quinazoline-2-carboximidamide (17a): beige powder (105 mg, 93%), mp. 148-150?C; 1 H-NMR (DMSO-d 6 ) ? 8.48 (s, 1H, H 7 ), 8.43 (d, J = 9.0 Hz, 1H, H 4 ), 7.84 (d, J = 9.0 Hz, 1H, H 5 ), 7.49-7.23 (m, 5H, Ph), 6.99, vol.3328, p.826, 1091.
, quinazoline-2-carboximidamide (17b): colorless solid (99 mg, 99%), mp. 168-170?C; 1 H-NMR (DMSO-d 6 ) ? 8.46 (s, 1H, vol.8
, -morpholinoethyl)-9-oxo-8,9-dihydrothiazolo[5,4-f]quinazoline-2-carboximidamide (17c): colorless solid (63 mg, 57%), mp, pp.154-156
m, 4H, OCH 2 ), 3.48 (t, J = 6.0 Hz, H1 1 ), 3.37-3.32 (m, 1H, NCH), 2.76 (t, J = 6.0 Hz, H2 1 ), 2.63-2.60 (m, 4H, NCH 2 ), 1.30-1.23 (m, 2H, CH, vol.3374, p.1, 1110. ,
(m, 2H, H1 1 ), 3.37-3.33 (m, 1H, NCH), 2.70-2.66 (m, 1H, H2 1 ), 2.52-2.50 (m, 4H, NCH), 1.65-1.59 (m, 4H, CH), 1.49-1.30 (m, 4H, CH), 1.30-1, vol.3325, p.1, 1040. ,
, mg, 54%), mp. 184-186?C ; 1 H-NMR (DMSO-d 6 ) ? 8.48 (s, 1H, H 7 ), vol.8, p.1, 1109.
, HRMS calcd for C 17 H 25 N 5 O 2 S
, 204-206?C ; 1 H-NMR (DMSO-d 6 ) ? 8.50 (s, 1H, mg, 59%), mp, vol.8
N 1 -tetraacetic acid (EGTA), 1 mM dithiothreitol (DTT), 25 mM Tris-HCl pH 7.5, 50 µg heparin/mL. Buffer B: ?-Glycerophosphate (60 mM), 30 mM p-nitrophenylphosphate, Buffer A: MgCl 2 (10 mM), 1 mM ethylene glycol-bis, vol.25 ,
, Kinase Preparations and Assays Kinase activities were assayed in triplicates in buffer A or B, for 30 min. at 30?C, at a final adenosine triphosphate (ATP) concentration of 15 µM. Blank values were substracted and activities expressed in % of the maximal activity, i.e., in the absence of inhibitors. Controls were performed with appropriate dilutions of dimethylsulfoxide (DMSO). IC 50 values were calculated from dose-response curves established by Sigma-Plots. The GSK-3, CK1, DYRK1A and CLK1 peptide substrates were obtained from Proteogenix
, Its kinase activity was assayed in buffer A, with 1 mg of histone H1/mL, in the presence of 15 µM, CDK5/p25. (Human, recombinant) was prepared as previously described, vol.45
, Ci/mmol; 10 mCi/mL) in a final volume of 30 µL. After 30 min incubation at 30?C, 25 µL aliquots of supernatant were spotted onto sheets of Whatman P81 phosphocellulose paper, and 20 s later, the filters were washed eight times (for at least 5 min each time) in a solution of 10 mL phosphoric acid/L of water. The wet filters were counted in the presence of 1 mL ACS (Amersham) scintillation fluid. GSK-3?/?. (Porcine brain, native) was assayed, as described for CDK5/p25 but in buffer A and using a GSK-3 specific substrate, vol.46
Porcine brain, native) was assayed as described for CDK5/p25 but using the CK1-specific peptide substrate RRKHAAIGpSAYSITA, vol.47 ,
GST) fusion protein) was purified by affinity chromatography on glutathione-agarose and assayed, as described for CDK5/p25 using Woodtide (KKISGRLSPIMTEQ) (1.5 µg/assay) as a substrate. CLK1. (Human, recombinant, expressed in E. coli as GST fusion protein) was assayed in buffer A (+0.15 mg BSA/mL) with RS ,
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