Intermediate synthesis 3
To a stirred solution of 1-(2-aminophenyl)ethanone (5.0 g) in EtOH (50 mL) was added phenylhydrazine (5.5 g) and glacial acetic acid (5 mL). The reaction mixture was stirred at reflux for 6 hours and then allowed to warm to room temperature, the solvent was concentrated under reduced pressure. The yellow solid obtained is filtered off, washed with ethanol and dried over this; giving the corresponding phenylhydrazone (5.8 mg, 70%) which was used directly in the next step without further purification.
Intermediate synthesis 4
do (mi)-2-(1-(2-phenylhydrazono)ethyl)anilin (1,50 g, 6,60 mmol), Eatonov-reagens (P2O5and methanesulfonic acid) (10.0 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 30 minutes and cooled to room temperature. After completion of the reaction, ice water and NaOH solution were added to adjust pH = 7. The desired white solid was filtered off and dried by washing with petroleum ether and purified by flash chromatography.
Intermediate synthesis 6
For the mixture 2-(1H-indol-2-ilo)anilin(4)(0,50 g, 2,4 mmol) i aldehid(5)(2.65 mmol) in EtOH (30 mL), TFA (7.90 mmol) was added at 0 °C in free air and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, the solvent was evaporated and the desired product was purified by column chromatography.
Intermediate synthesis 8
In the solution replaced by 11H-indolo[3,2-c]quinoline or acetone(6)(0,01 mmol), Cs2CON3(0.012) was added and mixed under N2atmospheres 30 min. Then methyl 4-(bromomethyl)benzoate (7(0.01 mmol) and KI (0.1 mmol) and the reaction mixture was stirred at room temperature for 2 h. After the starting material was consumed, the reaction mixture was filtered through celite and purified by chromatography on a silica gel column.
Intermediate synthesis 9
In a MeOH (30 mL) solution of the intermediate8(2.0 mmol, 1.0 eq.), a solution of vodka LiOH (5 mmol, 2.5 eq., dissolved in 20 ml of H2O) was added at 0°C. The resulting mixture was stirred at room temperature. 2 hours. The solvent was removedin a vacuumand the residue was diluted with H20, then 4M hydrochloric acid was added until pH = 2. Finally, the mixture was filtered and the filtrate was dried to give the intermediate9(100,0%).
General Procedures for the Preparation of Compounds 10a-o
To a mixture of acid (1.00 mmol), EDCI (1.50 mmol), hydroxybenzotriazole (HOBT) (1.50 mmol) in dry DMF (10 mL), NH2OH.HCl (1,10 mmol) i Et3N (2.00 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, it is neutralized with 1N HCl and the compound is extracted with EtOAc. The organic layer was separated and washed with brine. The organic phase was dried over Na 2 SO 44and evaporated. The crude reaction mixture was purified by chromatography on a silica gel column. Clean connection preferred(10 a–o)it was produced with a good yield (11.2-28.4%).
4-((11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)-N-HYDROXYBENZAMID (10A)
White solid, yield: 24.8%.1H NMR (400 MHz,D6-DMSO)D11.12 (s, IH), 9.73 (s, IH), 9.04 (s, IH), 8.46 (d,J=7,6 Hz, 1H), 8,36 (t,J=9,2 Hz, 1H), 8,18 (d,J=8,4 Hz, 1H), 7,85 (d,J= 8.0 Hz, 2H), 7.70 (t,J=7,2 Hz, 1H), 7,65 (d,J=8,0 Hz, 4H), 7,58-7,50 (m, 2H), 7,45 (t,J=9,2 Hz, 1H), 7,19 (dd,J=8.0 Hz, 2H) and 6.30 (s, 2H).13C NMR (101 MHz,D6-DMSO)D169.4, 150.1, 142.6, 141.8, 140.8, 136.3, 134.3, 130.0, 129.6, 128.7, 127.4, 125.9, 117, 4, 116.5 and 116.5. melting point: 120.3-122.5 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H22N3O2: 444.1625, found: 444.1629. HPLC:TR13.216 min., purity 97.95%.
4-((6-(4-BROMPHENYL)-11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)-N-HYDROXYBENZAMID (10B)
White solid, yield: 19.6%.1H NMR (400 MHz,D6-DMSO)D11.13 (s, IH), 9.03 (s, IH), 8.41 (d,J=8,4 Hz, 1H), 8,17 (d,J=7,2 Hz, 1H), 7,88 (dd,J=6.4, 2.0 Hz, 3H), 7.80 (d,J= 8.4 Hz, 2H), 7.73 (t,J=7,2 Hz, 1H), 7,69 (d,J=8,4 Hz, 2H), 7,56-7,51 (m, 2H), 7,49-7,46 (m, 1H), 7,25 (t,J=7,6 Hz, 1H), 7,20 (d,J=8.0 Hz, 2H) and 6.33 (s, 2H).13C NMR (101 MHz,D6-DMSO)D155.6; 20.6, 117.5, 112.4 and 66.71. melting point: 129.7-131.1 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H21BrN3O2: 522.0781, found: 522.0788. HPLC:TR13.155 min., purity 96.19%.
4-((6-(4-FLUOROPENYL)-11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)-N-HYDROXYBENZAMID (10C)
White solid, yield: 21.1%.1H NMR (400 MHz,D6-DMSO)D11.10 (s, IH), 8.98 (s, IH), 8.40 (d,J=8,4 Hz, 1H), 8,16 (d,J=8,0 Hz, 1H), 7,86 (t,J=8,4 Hz, 3H), 7,72 (t,J=7,2 Hz, 1H), 7,68 (d,J=8,0 Hz, 2H), 7,56-7,43 (m, 5H), 7,23 (t,J=7,6 Hz, 1H), 7,19 (d,J=8.0 Hz, 2H) and 6.33 (s, 2H).13C NMR (101 MHz,D6-DMSO)D165.55. 121.40, 116.84, 116.62, 115.68, 113.71, 112.31 and 49.27. melting point: 126.4-128.0 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H21FN3O2: 462.1529, found: 462.1532. HPLC:TR14.607 min., purity 99.46%.
4-((6-(4-CHLOROPHENYL)-11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)-N-HYDROXYBENZAMID (10D)
White solid, yield: 23.1%.1H NMR (400 MHz,D6-DMSO)D11.13 (s, IH), 9.01 (s, IH), 8.40 (d,J=8,4 Hz, 1H), 8,17 (d,J=8,4 Hz, 1H), 7,86 (d,J= 8.0 Hz, 3H), 7.72 (d,J= 8.0 Hz, 3H), 7.68 (d,J=7,6 Hz, 2H), 7,56-7,45 (m, 3H), 7,25 (t,J=7,2 Hz, 1H), 7,19 (d,J=8.0 Hz, 2H) and 6.33 (s, 2H).13C NMR (101 MHz,D6-DMSO)D152.1, 142.3, 141.3, 141.0, 136.3, 134.3, 130.0, 129.6, 128.7, 127.6, 125.9, 119.4, 117, 5, 66.5. smeltepunkt: 133,1-134,8 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H21ClN3O2: 478.1269, found: 478.1265. HPLC:TR13.456 min., purity 98.55%.
N-HYDROXY-4-((6-(3,4,5-TRIMETHOXYPHENYL)-11H-INDOLO[3,2-C]KINOLIN-11-YL)METHYLO)BENZAMID (10E)
White solid, yield: 23.7%.1H NMR (400 MHz,D6-DMSO)D11.13 (s, IH), 9.00 (s, IH), 8.39 (d,J=8,0 Hz, 1H), 8,16 (d,J=8,0 Hz, 1H), 7,84 (d,J=8,4 Hz, 1H), 7,71 (dd,J=7,2, 2,4 Hz, 3H), 7,57-7,48 (m, 3H), 7,26 (t,J=6,8 Hz, 1H), 7,21 (d,J=7,6 Hz, 2H), 7,09 (s, 2H), 6,32 (s, 2H) i 3,83 (s, 9H).13C NMR (101 MHz,D6-DMSO)D167.2, 160.2, 153.9, 152.5, 143.1, 141.9, 140.0, 134.2, 131.8, 129.2, 128.1, 128.0, 127, 5, 127. 2 5.6, 116.2, 116.10, 115.7, 108.0, 63.9, 60.2 and 56.0. melting point: 125.1-127.0 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C32H28N3O5: 534.2088, found: 534.2085. HPLC:TR14.109 min., purity 98.81%.
N-HYDROXI-4-((6-(4-METHOXYPHENYL)-11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)BENZAMID (10F)
White solid, yield: 20.5%.1H NMR (400 MHz,D6-DMSO)D11.12 (s, IH), 9.01 (s, IH), 8.38 (d,J=8,4 Hz, 1H), 8,14 (d,J=8,4 Hz, 1H), 7,84 (d,J=8,4 Hz, 1H), 7,77 (d,J=8,8 Hz, 2H), 7,71 (d,J=7,6 Hz, 1H), 7,67 (d,J=8,0 Hz, 2H), 7,57 (d,J=8,4 Hz, 1H), 7,53-7,47 (m, 2H), 7,24-7,18 (m, 5H), 6,31 (s, 2H), 3,92 (s, 3H).13C NMR (101 MHz,D6-DMSO)D170.8; 2 2.1, 121.7, 121.3, 116.6, 113.9, 113.8, 109.4, 64.1 and 55.4. melting point: 133.1-135.4 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C30H24N3O3: 474.1770, found: 474.1773. HPLC:TR13.232 min., purity 98.19%.
N-HYDROXY-4-((6-(P-TOLYL)-11H-INDOLO[3,2-C]QINOLIN-11-YL)METHYLO)BENZAMIDE (10G)
White solid, yield: 16.3%.1H NMR (400 MHz,D6-DMSO)D11.11 (s, IH), 8.98 (s, IH), 8.39 (d,J=8,8 Hz, 1H), 8,14 (d,J=8,4 Hz, 1H), 7,83 (d,J=8,4 Hz, 1H), 7,72 (dt,J=7,6, 8,4 Hz, 5H), 7,54-7,45 (m, 5H), 7,22 (dd,J=8,0, 4,8 Hz, 3H), 6,31 (s, 2H) i 2,50 (s, 3H).13C NMR (101 MHz,D6-DMSO)D168.5, 156.4, 145.8, 140.9, 140.7, 140.5, 139.1, 137.1, 130.7, 129.3, 128.8, 128.4, 126, 0, 125. 16.6, 113.8, 109.4, 63.8 and 29.6. melting point: 136.8-139.8 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C30H24N3O2: 458.1844, found: 458.1847. HPLC:TR13.178 min., purity 99.41%.
4-((6-(4-CYANOPHENYL)-11H-INDOLO[3,2-C]QUINOLIN-11-YL)METHYL)-N-HYDROXYBENZAMID (10H)
White solid, yield: 17.4%.1H NMR (400 MHz,D6-DMSO)D11.14 (s, IH), 8.99 (s, IH), 8.39 (t,J=8,8 Hz, 1H), 8,17 (d,J=6.0 Hz, 3H), 7.90 (d,J=7,6 Hz, 3H), 7,73-7,68 (m, 2H), 7,54-7,50 (m, 3H), 7,42 (d,J=7,2 Hz, 1H), 7,26-7,22 (m, 3H) i 6,36 (s, 2H).13C NMR (101 MHz,D6-DMSO)D167.9, 150.4, 143.5, 142.1, 138.8, 138.7, 133.1, 132.4, 132.2, 131.2, 130.6, 129.7, 128, 9, 1224. 2 2.2, 121.7, 121.0, 117.8, 115.5, 113.4, 111.0 and 65.7. melting point: 141.4-142.9 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C30H21N4O2: 469.1677, found: 469.1672. HPLC:TR13.604 min., purity 98.03%.
4-((6-(3-CYANOPHENYL)-11H-INDOLO[3,2-C]QUINOLIN-11-YL)METHYL)-N-HYDROXYBENZAMID (10I)
White solid, yield: 11.2%.1H NMR (400 MHz,D6-DMSO)D11.13 (s, IH), 9.71 (s, IH), 9.01 (s, IH), 8.41 (d,J=8,0 Hz, 1H), 8,17 (t,J=8,4 Hz, 2H), 7,96 (d,J=7,2 Hz, 1H), 7,87 (dd,J= 8.0, 8.4 Hz, 2H), 7.75 (t,J=7,6 Hz, 1H), 7,69 (d,J=6,8 Hz, 2H), 7,57-7,41 (m, 3H), 7,23 (t,J=8,0 Hz, 3H) i 6,33 (s, 2H).13C NMR (101 MHz,D6-DMSO)D168.2, 168.1, 167.8, 151.6, 151.0, 143.1, 142.6, 141.9, 141.7, 139.5, 139.2, 133.3, 132, 5, 131. 3 1.0, 130.8, 130.5, 129.5, 128.8, 128.6, 128.4 and 65.5. melting point: 122.4-124.0 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C30H21N4O2: 469.1670, found: 469.1671. HPLC:TR14.244 min., purity 99.74%.
N-HYDROXY-4-((6-(4-NITROPHENYL)-11H-INDOLO[3,2-C]QUINOLIN-11-YL)METHYLO)BENZAMID (10J)
White solid, yield: 23.7%.1H NMR (400 MHz,D6-DMSO)D11.00 (s, IH), 9.06 (s, IH), 8.52 (d,J=8,4 Hz, 2H), 8,43 (d,J=8,4 Hz, 1H), 8,19 (d,J=8,4 Hz, 1H), 8,12 (d,J= 8.4 Hz, 2H), 7.87 (t,J=8,4 Hz, 1H), 7,75 (t,J=8,0 Hz, 1H), 7,68 (d,J= 8.0 Hz, 2H), 7.58 (t,J=8,0 Hz, 1H), 7,52 (t,J=8,0 Hz, 1H), 7,43 (t,J=8,0 Hz, 1H), 7,24 (td,J= 8,4, 8,0 Hz, 3H), 6,34 (s, 2H).13C NMR (101 MHz,D6-DMSO)D167.9, 165.0, 149.8, 143.5, 142.1, 137.7, 136.7, 132.8, 132.4, 130.9, 129.2, 129.0, 128, 9, 127. 2 4.4, 123.0, 121.8, 121.7, 121.1, 115.3, 113.4, 111.2 and 66.9. melting point: 126.8-128.1 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H21N4O4: 489.1558, found: 489.1556. HPLC:TR14.889 min., purity 95.47%.
4-((6-(2-chlor-6-fluorphenyl)-11H-indolo[3,2-C]quinolin-11-yl)methyl)-N-HYDROXYBENZAMID (10K)
White solid, yield: 26.7%.1H NMR (400 MHz,D6-DMSO)D11.02 (s, IH), 9.13 (s, IH), 8.45 (d,J=8,4 Hz, 1H), 8,21 (d,J=8,4 Hz, 1H), 7,89 (d,J=8,4 Hz, 1H), 7,79-7,74 (m, 2H), 7,69 (dd,J=7,6, 5,8 Hz, 3H), 7,64 (dd,J=17,2, 8,8 Hz, 2H), 7,58 (dd,J=14,2, 6,4 Hz, 2H), 7,24 (td,J=16,4, 8,0 Hz, 3H) i 6,34 (s, 2H).13C NMR (101 MHz,D6-DMSO)D167.8. 2 2.9, 122.3, 121.0, 120.9, 118.6, 115.6, 115.4, 115.0, 111.2 and 50.1. melting point: 134.5-136.2 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C29H20ClFN3O2: 496.1102, found: 496.1109. HPLC:TR13.159 min., purity 98.23%.
N-HIDROKSI-4-((6-(PYRIDINO-2-IL)-11H-INDOL[3,2-C]KINOLIN-11-IL)METHYL)BENZAMID (10L)
White solid, yield: 28.4%.1H NMR (400 MHz,D6-DMSO)D11.12 (s, IH), 8.99 (s, IH), 8.87 (d,J=4,0 Hz, 1H), 8,44 (d,J=8,4 Hz, 1H), 8,20 (d,J=8,0 Hz, 1H), 8,14 (td,J=7,6, 1,6 Hz, 1H), 8,04 (d,J=8,0 Hz, 1H), 7,87 (dd,J=17,2, 8,4 Hz, 1H), 7,75 (t,J=7,2 Hz, 1H), 7,68 (d,J=8,4 Hz, 2H), 7,62 (d,J=8,0 Hz, 1H), 7,58 (t,J=8,0 Hz, 1H), 7,50 (t,J=8,0 Hz, 1H), 7,24-7,18 (m, 3H) i 6,34 (s, 2H).13C NMR (101 MHz,D6-DMSO)D164.0, 150.6, 149.5, 148.6, 143.6, 142.4, 139.0, 138.8, 136.9, 132.7, 132.5, 129.1, 128, 9, 127. 24.2, 124.1, 122.2, 121.1, 115.8, 113.5, 112.4 and 49.4. melting point: 130.4-131.9 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C28H21N4O2: 454.1569, found: 454.1563. HPLC:TR13.824 min., purity 99.04%.
N-HYDROXY-4-((6-(PYRIDINO-3-YL)-11H-INDOLO[3,2-C]QUINOLIN-11-YL)METHYLO)BENZAMID (10M)
White solid, yield: 18.7%.1H NMR (400 MHz,D6-DMSO)D11.17 (s, IH), 9.02 (s, IH), 8.86 (d,J=4,0 Hz, 1H), 8,41 (t,J=8,0 Hz, 1H), 8,26 (d,J=8,0 Hz, 1H), 8,19 (d,J=8,4 Hz, 1H), 7,88 (t,J=7,2 Hz, 2H), 7,74-7,69 (m, 2H), 7,54 (dt,J=15,2, 7,6 Hz, 2H), 7,38 (d,J=8,0 Hz, 1H), 7,23 (dd,J=18,8, 8,0 Hz, 3H) i 6,34 (s, 2H).13C NMR (101 MHz,D6-DMSO)D164.0, 162.9, 146.6, 145.7, 145.3, 144.6, 143.3, 142.4, 139.0, 137.1, 132.6, 129.9, 129, 3, 128. 2 4.5, 124.2, 122.0, 121.6, 121.0, 115.8, 114.3, 112.6 and 49.3. melting point: 125.4-127.3 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C28H21N4O2: 454.1569, found: 454.1565. HPLC:TR14,202 min., purity 97.36%.
N-HYDROXY-4-((6-(PYRIDINO-4-YL)-11H-INDOLO[3,2-C]QUINOLIN-11-YL)METHYLO)BENZAMID (10N)
White solid, yield: 22.8%.1H NMR (400 MHz,D6-DMSO)D12.92 (s, IH), 8.89 (d,J=4,4 Hz, 2H), 8,41 (d,J=8,4 Hz, 1H), 8,20 (d,J=8,0 Hz, 1H), 7,87 (dd,J=22,8, 6,4 Hz, 5H), 7,76 (t,J=7,6 Hz, 1H), 7,59-7,51 (m, 2H), 7,43 (d,J=7,6 Hz, 1H), 7,25 (d,J=7,6 Hz, 3H) i 6,37 (s, 2H).13C NMR (101 MHz,D6-DMSO)D166.6, 162.6, 150.3, 148.7, 146.4, 141.3, 140.9, 130.9, 130.7, 129.9, 128.5, 126.4, 125, 9, 1219, 121. 2 1.4, 116.9, 109.6 and 52.3. melting point: 124.4-125.8 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C28H21N4O2: 454.1569, found: 454.1567. HPLC:TR14.774 min., purity 96.00%.
N-HYDROXI-4-((6-(1-METHYLO-1H-INDOL-3-IL)-11H-INDOLO[3,2-C]KINOLIN-11-IL)METHYLO)BENZAMID (10O)
White solid, yield: 23.9%.1H NMR (400 MHz,D6-DMSO)D11.15 (s, IH), 9.05 (s, IH), 8.38 (d,J=8,4 Hz, 1H), 8,12 (d,J=8,4 Hz, 1H), 8,00 (s, 1H), 7,82 (d,J=8,4 Hz, 1H), 7,70-7,63 (m, 5H), 7,57 (d,J=8,0 Hz, 1H), 7,47 (dd,J= 15.6, 8.0 Hz, 2H), 7.28 (t,J=7,6 Hz, 1H), 7,20 (d,J=8,0 Hz, 1H), 7,15-7,06 (m, 2H), 6,32 (s, 2H) i 4,02 (s, 3H).13C NMR (101 MHz,D6-DMSO)D167.9, 146.2, 143.0, 141.8, 139.1, 137.2, 136.9, 133.1, 131.8, 131.0, 130.9, 128.2, 127, 8, 125, 125. 2 3.4, 122.7, 121.5, 121.3, 120.6, 114.8, 113.6, 110.9, 110.4, 105.5, 49.8 and 33.5. melting point: 132.4-134.2 °C. HRMS (ESI-Q-TOF)m/z: [M + H]+intended for C32H25N4O2: 497.1933, found: 497.1935. HPLC:TR15.442 min., purity 99.12%.