2.1. Synthesis of Quinazolinamines
1H NMR and 13C NMR spectra were acquired with a Bruker 400 UltrashieldTM spectrophotometer (400 MHz). Infrared spectra (IR) were acquired with PerkinElmer Spectrum 100 FT-IR Spectrometers with the exclusive universal ATR accessory. High resolution mass spectra (HRMS) were obtained for all target compounds on a Waters Xevo G2-XS QToF mass spectrometer equipped with H-Class UPLC inlet and a LockSpray electrospray ionization (ESI) source. Reactions were monitored by thin layer chromatography (TLC) and visualized using UV light at 254 nm. TLC was performed using Analtech UniplateTM Silica Gel GF 250 Micron plates. The purification of the reaction mixtures was conducted using silica gel column chromatography or Reveleris® X2 flash chromatography system by BÜCHI Labortechnik AG. Melting points were determined on a Thomas-Hoover Capillary Melting Point Apparatus. The purity of all target compounds was determined by high-performance liquid chromatography (HPLC), (LC, Agilent 1200 Infinity; column, Agilent HC-C18(2), 170 Å, 4.6 × 250 mm, 5 µm; column temperature, 25 °C; mobile phase, solvent A, methanol, solvent B, water, gradient elution, 30–99% solvent A; flow rate, 1 mL/min; UV signals were recorded at 254 nm). All tested compounds were shown to have >95% purity according to HPLC. Chemicals were purchased from Acros Organics or Alfa Aesar Chemical Company and used without further purification.
2-(Pyridin-4-yl)quinazolin-4(3H)-one (1). A mixture of anthranilamide (681 mg, 5 mmol), 4-pyridinecarboxaldehyde (536 mg, 5 mmol), iodine (1.40 g, 5.5 mmol), and anhydrous potassium carbonate (690 mg, 5 mmol) in 10 mL of dimethylformamide (DMF) was stirred at reflux for 4 h. Completion of the reaction was monitored by TLC and the mixture was poured into crushed ice to obtain a precipitate. The pH of the mixture was adjusted to 7.0 with concentrated HCl to optimize the precipitation of the desired product. After filtering off the precipitate, it was thoroughly washed with a 20% sodium thiosulfate solution (50 mL) followed by 50 mL of hot distilled water (50 mL). Purification was performed by recrystallization from ethanol to yield 1 as a white solid in 65% yield. 1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.80 (dd, J = 4.6, 1.5 Hz, 2H), 8.19 (dd, J = 7.9, 1.1 Hz, 1H), 8.14–8.09 (m, 2H), 7.93–7.85 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.63–7.55 (m, 1H).
4-Chloro-2-(pyridin-4-yl)quinazolinamine (2). Compound 1 (446 mg, 2 mmol) was added to the DMF (5 mL) containing phosphorus oxychloride (0.47 mL, 5 mmol) and stirred for 10 min at room temperature. The mixture was then refluxed for 2 h and the reaction monitored by TLC. After the completion of the reaction, excess phosphorus oxychloride was removed under reduced pressure and the residue was poured into ice water (20 mL). Subsequently, the pH of the mixture was adjusted slowly to 7.0 with 25% NaOH solution and extracted three times with dichloromethane (3 × 20 mL). The organic phase was collected, washed with brine (50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain Compound 2 as a white solid, which was recrystallized from isopropanol in 96% yield. 1H NMR (400 MHz, DMSO) δ 8.84 (dd, J = 4.6, 1.5 Hz, 2H), 8.37 (dd, J = 4.5, 1.6 Hz, 3H), 8.28–8.16 (m, 2H), 7.95 (ddd, J = 8.2, 6.5, 1.6 Hz, 1H).
2.1.1. General Procedure for the Preparation of the Substituted 4-Anilinoquinazolinamines 3–5
4-Chloroquinazolinamine derivative 2 was added to a solution of a para substituted aniline derivative in isopropanol and the mixture was refluxed for a period of 2 h until the completion of the reaction as indicated by TLC. The precipitate that was formed was filtered off, washed with isopropanol (10 mL) and recrystallized from ethanol.
2-(Pyridin-4-yl)-N-(p-tolyl)quinazolin-4-amine (3). Compound 3 was synthesized from Compound 2 (42 mg, 0.17 mmol) reacted with para-methyl aniline (21 mg, 0.20 mmol) as described in the general procedure. It was obtained as a yellow solid (30 mg) in 56% yield, mp. 269–270 °C; IR: 3058, 1562, 1500, 1422, 815, 786 cm−1; 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 9.00 (dd, J = 5.3, 1.3 Hz, 2H), 8.72 (d, J = 8.3 Hz, 1H), 8.66 (d, J = 6.5 Hz, 2H), 8.04–7.95 (m, 2H), 7.82–7.71 (m, 3H), 7.31 (d, J = 8.2 Hz, 2H), 2.37 (s, 3H). 13C NMR (101 MHz, DMSO) δ 158.79, 155.65, 151.17, 149.24, 145.06, 136.26, 134.50, 134.15, 129.52, 128.34, 128.17, 124.34, 123.89, 123.39, 114.84, 21.09. HRMS (ESI) m/z calcd for [C20H16N4 + H]+ 313.1453, found 313.1463.
N-(4-Ethylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (4). Compound 4 was synthesized from Compound 2 (48 mg, 0.20 mmol) reacted with para-ethyl aniline (26 mg, 0.21 mmol), as described in the general procedure. It was obtained as a yellow solid (50 mg) in 77% yield, mp. 228–230 °C; IR: 2969, 1589, 1614, 1366, 798, 776 cm−1; 1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 8.76 (d, J = 5.8 Hz, 2H), 8.62 (d, J = 8.3 Hz, 1H), 8.28 (dd, J = 4.5, 1.5 Hz, 2H), 7.92 (d, J = 3.8 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.72–7.65 (m, 1H), 7.33 (d, J = 8.5 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 158.63, 157.11, 150.15, 148.96, 148.85, 147.75, 140.12, 136.85, 134.12, 128.59, 128.27, 127.65, 123.59, 123.01, 114.85, 28.15, 16.09. HRMS (ESI) m/z calcd for [C21H18N4 + H]+ 327.1610, found 327.1611
N-(4-Propylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (5). Compound 5 was synthesized from Compound 2 (241 mg, 1 mmol) reacted with para-propyl aniline (135 mg, 1 mmol), as described in the general procedure as a yellow solid (241 mg) in 71% yield, mp. 212–214 °C; IR: 2931, 1513, 1366, 797, 766 cm−1; 1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 8.75 (d, J = 5.9 Hz, 2H), 8.62 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 5.9 Hz, 2H), 7.92 (d, J = 3.9 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.69 (dt, J = 8.4, 4.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 2.65–2.57 (m, 2H), 1.65 (dd, J = 15.0, 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 158.61, 157.77, 150.65, 150.53, 146.10, 138.35, 137.06, 133.97, 128.85, 128.76, 127.33, 123.52, 122.84, 122.28, 114.87, 37.22, 24.58, 14.13. HRMS (ESI) m/z calcd for [C22H20N4 + H]+ 341.1766, found 341.1780.
2.1.2. General Procedure for the Preparation of the Quinazolinamine Derivatives 6–8
A mixture of anthranilamide (1.36 g, 10 mmol), the corresponding aldehyde (10 mmol) and iodine (6.3 g, 25 mmol) in ethanol (20 mL) was refluxed for 6 h. During the reaction, air was pushed into the mixture. Completion of the reaction was monitored by TLC and the mixture was poured into 20% sodium thiosulfate (50 mL) solution followed by hot distilled water (50 mL). Purification was performed by recrystallization from ethanol.
2-(
p-Tolyl)quinazolin-4(3
H)-one (
6). Compound
6 [
11] was synthesized as described in the general procedure. A mixture of anthranilamide (681 mg, 5 mmol), the para-methyl aldehyde (661 mg, 5.5 mmol), iodine (1.397 g, 5.5 mmol) in ethanol (20 mL) was refluxed for 5 h. Compound
6 was obtained as a white solid (980 mg) in 83% yield.
1H NMR (400 MHz, DMSO)
δ 12.49 (s, 1H), 8.15 (d,
J = 7.9 Hz, 1H), 8.11 (d,
J = 8.2 Hz, 2H), 7.83 (d,
J = 7.0 Hz, 1H), 7.74 (d,
J = 8.1 Hz, 1H), 7.52 (t,
J = 7.6 Hz, 1H), 7.37 (d,
J = 8.4 Hz, 2H), 2.40 (s, 3H).
2-(4-Ethylphenyl)quinazolin-4(3
H)-one (
7). Compound
7 [
11] was synthesized as described in the general procedure. A mixture of anthranilamide (680 mg, 5 mmol), the para-ethyl aldehyde (670 mg, 5 mmol), and iodine (1.397 g, 5.5 mmol) in ethanol (30 mL) was refluxed for 7 h. Compound
7 was obtained as a white solid (1.288 g) in 84% yield.
1H NMR (400 MHz, DMSO)
δ 12.50 (s, 1H), 8.15 (dd,
J = 14.0, 4.8 Hz, 3H), 7.87–7.81 (m, 1H), 7.74 (d,
J = 8.1 Hz, 1H), 7.55–7.48 (m, 1H), 7.40 (d,
J = 8.2 Hz, 2H), 2.70 (q,
J = 7.6 Hz, 2H), 1.23 (t,
J = 7.6 Hz, 3H).
2-(4-Propylphenyl)quinazolin-4(3H)-one (
8). Compound
8 [
12] was synthesized as described in the general procedure. A mixture of anthranilamide (680 mg, 5 mmol), the para-propyl aldehyde (740 mg, 5 mmol), and iodine (1.397 g, 5.5 mmol) in ethanol (30 mL) was refluxed for 7 h. Compound
8 was obtained as a white solid in 98% yield.
1H NMR (400 MHz, DMSO)
δ 12.49 (s, 1H), 8.18–8.09 (m, 3H), 7.84 (ddd,
J = 8.6, 7.1, 1.6 Hz, 1H), 7.73 (dd,
J = 8.2, 0.6 Hz, 1H), 7.55–7.49 (m, 1H), 7.38 (d,
J = 8.4 Hz, 2H), 2.69–2.62 (m, 2H), 1.72–1.57 (m, 2H), 0.92 (dd,
J = 8.5, 6.2 Hz, 3H).
2.1.3. General Procedure for the Preparation of the 4-Chloro-quinazolinamine Derivatives 9–11
Quinazolinamine derivative 6–8 (2 mmol) was added to the DMF (5 mL) containing phosphorus oxychloride (0.47 mL, 5 mmol) and stirred for 10 min at room temperature. The mixture was then refluxed for 2 h and the reaction monitored by TLC. After completion of the reaction, excess phosphorus oxychloride was removed under reduced pressure and the residue was poured into ice water (20 mL). Subsequently, the pH of the mixture was adjusted slowly to 7.0 with 25% NaOH solution and was extracted three times with dichloromethane (3 × 20 mL). With a separatory funnel, the organic phase was collected, washed with 50 mL brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain a white solid, which was recrystallized from isopropanol.
4-Chloro-2-(p-tolyl)quinazolinamine (9). Compound 9 was synthesized from Compound 6 as described in the general procedure. Compound 6 (590 mg, 2.5 mmol) reacted with phosphorus oxychloride (5 mL) to obtain a white solid (540 mg) in 85% yield. 1H NMR (400 MHz, DMO) δ 8.17 (dd, J = 7.9, 1.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.87 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.59–7.52 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H).
4-Chloro-2-(4-ethylphenyl)quinazolinamine (10). Compound 10 was synthesized with Compound 7, as described in the general procedure. Compound 7 (500 mg, 2.0 mmol) reacted with phosphorus oxychloride (2 mL) to obtain a white solid (520 mg) in 97% yield. 1H NMR (400 MHz, DMSO) δ 8.18 (dd, J = 7.9, 1.4 Hz, 1H), 8.14–8.08 (m, 2H), 7.92–7.83 (m, 2H), 7.58 (ddd, J = 8.1, 6.7, 1.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).
4-Chloro-2-(4-propylphenyl)quinazolinamine (11). Compound 11 was synthesized with Compound 8 as described in the general procedure. Compound 8 (792 mg, 3.0 mmol) reacted with phosphorus oxychloride (6 mL) to obtain a white solid (770 mg) in 91% yield. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J = 8.3 Hz, 2H), 8.31–8.27 (m, 1H), 8.16–8.09 (m, 2H), 7.84 (ddd, J = 8.2, 4.8, 3.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 2.71–2.63 (m, 2H), 1.73–1.60 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).
2.1.4. General Procedure for the Preparation of the Substituted 4-Anilinoquinazolinamines 12–14
4-Chloroquinazolinamine derivative 9–11 (1 equivalent), p-aminopyridine (94 mg, 1.1 equivalent) and triethylamine (1.1 equivalent) were taken into isopropanol (5 mL). The mixture was refluxed for a period of 3 h until the completion of the reaction as indicated by TLC. The solvent was removed under reduced pressure and the remaining solid was purified using flash column chromatography.
N-(Pyridin-4-yl)-2-(p-tolyl)quinazolin-4-amine (12). Compound 12 was synthesized as described in the general procedure. Compound 9 (25 mg, 0.1 mmol) was added to a solution of p-aminopyridine (10 mg, 0.11 mmol) and triethylamine (11 mg, 0.11 mmol) to obtain a white solid (17 mg) in 53% yield, mp. 278–279 °C; IR: 2997, 1642, 1542, 1370, 1321, 1160, 732 cm−1; 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.76 (d, J = 7.2 Hz, 2H), 8.47 (d, J = 8.2 Hz, 2H), 8.27 (d, J = 8.0 Hz, 1H), 8.19 (t, J = 7.0 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 7.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.1 Hz, 2H), 2.43 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.97, 159.50, 159.47, 153.81, 142.80, 142.24, 136.53, 133.79, 130.09, 129.71, 129.11, 128.75, 124.59, 116.78, 109.88, 21.56. HRMS (ESI) m/z calcd for [C20H16N4 + H]+ 313.1453, found 313.1455.
2-(4-Ethylphenyl)-N-(pyridin-4-yl)quinazolin-4-amine (13). Compound 13 was synthesized as described in the general procedure. Compound 10 (134 mg, 0.5 mmol) was added to a solution of p-aminopyridine (55 mg, 0.55 mmol) and triethyl-amine (11 mg, 0.11 mmol) to obtain a yellow solid (106 mg) in 65% yield, mp. 234–236 °C; IR: 3294, 2967, 1569, 1503, 826, 755 cm−1; 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.59 (dd, J = 14.2, 7.3 Hz, 3H), 8.41 (d, J = 8.3 Hz, 2H), 8.10 (dd, J = 4.9, 1.5 Hz, 2H), 7.93 (d, J = 3.8 Hz, 2H), 7.67 (dt, J = 8.3, 4.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 159.44, 158.27, 151.17, 150.52, 147.03, 146.98, 136.00, 134.19, 128.68, 128.53, 126.75, 123.55, 115.55, 114.53, 28.55, 15.84. HRMS (ESI) m/z calcd for [C21H18N4 + H]+ 327.1610, found 327.1619.
2-(4-Propylphenyl)-N-(pyridin-4-yl)quinazolin-4-amine (14). Compound 14 was synthesized as described in the general procedure. Compound 11 (177 mg, 0.63 mmol) was added to a solution of p-aminopyridine (65 mg, 0.66 mmol) and triethylamine (66 mg, 0.66 mmol) to obtain a yellow solid (134 mg) in 63% yield, mp. 218–220 °C; IR: 2962, 1569, 1504, 822, 754 cm−1; 1H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.60 (dd, J = 14.2, 7.3 Hz, 3H), 8.41 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 6.3 Hz, 2H), 7.93 (d, J = 4.3 Hz, 2H), 7.68 (dt, J = 8.2, 4.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 2.70–2.61 (m, 2H), 1.72–1.59 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 159.45, 158.28, 151.18, 150.53, 146.98, 145.42, 136.03, 134.20, 129.12, 128.68, 128.45, 126.75, 123.56, 115.55, 114.53, 37.58, 24.35, 14.11. HRMS (ESI) m/z calcd for [C22H20N4 + H]+ 341.1766, found 341.1773.
2.1.5. Preparation of Compounds 15–17
Methyl 3-benzamidopicolinate (
15) [
13]. To a mixture of methyl 3-aminopicolinate (2.09 g, 5 mmol) and triethylamine (0.7 mL, 5 mmol) in chloroform (10 mL), benzoyl chloride (428 mg, 5.5 mmol) was added dropwise at 5 °C. After stirring at room temperature for 2.5 h, the reaction mixture was diluted with chloroform and washed with saturated sodium bicarbonate (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate to obtain Compound 15 as a white solid in 86% yield.
1H NMR (400 MHz, DMSO)
δ 11.32 (s, 1H), 8.74 (dd,
J = 8.5, 1.5 Hz, 1H), 8.46 (dd,
J = 4.5, 1.5 Hz, 1H), 8.01–7.95 (m, 2H), 7.75–7.57 (m, 4H), 3.89 (s, 3H).
2-Phenylpyrido[3,2-d]pyrimidin-4(3
H)-one (
16) [
14]. To a solution of 15 (256 mg, 1 mmol) in methanol (20 mL) was added 28% aqueous ammonia (20 mL). After stirring at room temperature for 2 h, the reaction mixture was filtered to obtain a mixture of uncyclized benzamide. Isopropanol (5 mL) and 2 N sodium hydroxide (2 mL) were added and the crude mixture was heated at reflux for 3 h. The mixture was cooled, neutralized with 2 N HCl, and the solution was evaporated to obtain a precipitate, which was collected to obtain 23 as a white solid in 60% yield.
1H NMR (400 MHz, DMSO)
δ 12.83 (s, 1H), 8.79 (dd,
J = 4.3, 1.5 Hz, 1H), 8.23–8.13 (m, 3H), 7.84 (dd,
J = 8.3, 4.3 Hz, 1H), 7.66–7.54 (m, 3H).
4-Chloro-2-phenylpyrido[3,2-d]pyrimidine (17). Compound 16 (2 mmol) was added to DMF (5 mL) containing phosphorus oxychloride (0.47 mL, 5 mmol) and stirred for 10 min at room temperature. The mixture was then refluxed for 2 h and the reaction was monitored by TLC. After completion of the reaction, excess phosphorus oxychloride was removed under reduced pressure and the residue was poured into ice water (20 mL). Subsequently, the pH of the mixture was adjusted slowly to 7.0 with 25% NaOH solution and was extracted three times with dichloromethane (3 × 20 mL). The organic phase was collected, washed with brine (50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain a white solid, which was recrystallized from isopropanol in 94% yield. 1H NMR (400 MHz, DMSO) δ 9.17 (dd, J = 4.1, 1.5 Hz, 1H), 8.60–8.47 (m, 3H), 8.13 (dd, J = 8.6, 4.1 Hz, 1H), 7.67–7.57 (m, 3H).
2.1.6. General Procedure for the Preparation of the Substituted 4-Anilinoquinazolinamines 18–29
4-Chloroquinazolinamine derivative 2 (1 equivalent) or 17 (1 equivalent) was added to a solution of a para-substituted aniline derivative (1.1 equivalent) and triethylamine (1.1 equivalent) in isopropanol (3 mL) to synthesize 18–20, 22–25, 27–29. In the case of compounds 21 and 26, 4-dimethylaminopyridine was used in place of triethylamine. The mixture was refluxed for a period of 3 h until completion of the reaction as indicated by TLC. The solvent was removed under reduced pressure and the remaining solid was purified with flash column.
2-Phenyl-N-(p-tolyl)pyrido[3,2-d]pyrimidin-4-amine (18). Compound 18 was synthesized as described in the general procedure. Compound 17 (90 mg, 0.37 mmol) was added to a solution of 4-methylaniline (53 mg, 0.5 mmol) and triethylamine (55.6 mg, 0.55 mmol) to obtain a yellow solid (84 mg) in 73% yield, mp. 161–162 °C; IR: 3333, 1597, 1563, 1409, 802 cm−1; 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.59 (dd, J = 14.2, 7.3 Hz, 3H), 8.41 (d, J = 8.3 Hz, 2H), 8.10 (dd, J = 4.9, 1.5 Hz, 2H), 7.93 (d, J = 3.8 Hz, 2H), 7.67 (dt, J = 8.3, 4.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 160.29, 157.77, 149.06, 145.60, 138.40, 136.72, 136.41, 133.21, 131.19, 131.12, 129.49, 129.13, 129.00, 128.60, 122.02, 21.03. HRMS (ESI) m/z calcd for [C20H16N4 + H]+ 313.1453, found 313.1465.
N-(4-Ethylphenyl)-2-phenylpyrido[3,2-d]pyrimidin-4-amine (19). Compound 19 was synthesized as described in the general procedure. Compound 17 (90 mg, 0.37 mmol) was added to a solution of 4-ethylaniline (60 mg, 0.5 mmol) and triethylamine (50 mg, 0.5 mmol) to obtain as a yellow solid (121 mg) in 75% yield, mp. 137–138 °C; IR: 3330, 2962, 1595, 1564, 823, 707 cm−1; 1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.91 (dd, J = 4.2, 1.5 Hz, 1H), 8.55–8.45 (m, 2H), 8.28 (dd, J = 8.5, 1.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.93 (dd, J = 8.5, 4.2 Hz, 1H), 7.61–7.51 (m, 3H), 7.32 (d, J = 8.5 Hz, 2H), 2.65 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 160.35, 157.72, 149.11, 145.53, 139.69, 138.36, 136.87, 136.36, 131.15, 131.11, 129.14, 129.01, 128.60, 128.33, 121.92, 28.14, 16.16. HRMS (ESI) m/z calcd for [C21H18N4 + H]+ 327.1610, found 327.1620.
2-Phenyl-N-(4-propylphenyl)pyrido[3,2-d]pyrimidin-4-amine (20). Compound 20 was synthesized as described in the general procedure. Compound 17 (77 mg, 0.32 mmol) was added to a solution of 4-propylaniline (47 mg, 0.35 mmol) and triethylamine (39 mg, 0.39 mmol) to obtain a yellow solid (74 mg) in 68% yield, mp. 117–119 °C; IR:3342, 2929, 1594, 1565, 803, 707 cm−1; 1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.91 (dd, J = 4.2, 1.5 Hz, 1H), 8.49 (dd, J = 6.6, 3.2 Hz, 2H), 8.29 (dd, J = 8.5, 1.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.93 (dd, J = 8.5, 4.2 Hz, 1H), 7.56 (dd, J = 5.2, 1.8 Hz, 3H), 7.30 (d, J = 8.5 Hz, 2H), 2.64–2.56 (m, 2H), 1.70–1.58 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 160.33, 157.69, 149.06, 145.53, 138.37, 138.00, 136.93, 136.36, 131.12, 129.10, 128.99, 128.89, 128.61, 121.80, 37.22, 24.60, 14.13. HRMS (ESI) m/z calcd for [C22H20N4 + H]+ 341.1766, found 341.1775.
N-Phenyl-2-(pyridin-4-yl)quinazolin-4-amine (21). Compound 21 was synthesized, as described in the general procedure. Compound 2 (24 mg, 0.1 mmol) was added to a solution of phenylamine (10 mg, 0.11 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) to yield a white solid (25 mg) in 85% yield, mp. 282–284 °C; IR:3261, 3043, 1554, 1523, 1411, 745 cm−1; 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.75 (d, J = 6.0 Hz, 2H), 8.63 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 6.0 Hz, 2H), 7.95 (dd, J = 9.9, 5.9 Hz, 4H), 7.74–7.66 (m, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 158.67, 157.73, 150.72, 150.62, 145.99, 139.44, 134.01, 129.05, 128.82, 127.35, 124.48, 123.62, 122.98, 122.23, 114.91. HRMS (ESI) m/z calcd for [C19H14N4 + H]+ 299.1297, found 299.1303.
N-(4-Cyclopropylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (22). Compound 22 was synthesized as described in the general procedure. Compound 2 (50 mg, 0.21 mmol) was added to a solution of 4-cyclopropylaniline (42 mg, 0.25 mmol) and triethylamine (25 mg, 0.25 mmol) to obtain a yellow solid (35 mg) in 50% yield, mp. 231–232 °C; IR: 3003, 1515, 1409, 1363, 765 cm−1; 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.75 (d, J = 5.8 Hz, 2H), 8.60 (d, J = 8.4 Hz, 1H), 8.34–8.21 (m, 2H), 7.91 (d, J = 3.7 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.74–7.61 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 2.03–1.92 (m, 1H), 1.03–0.92 (m, 2H), 0.79–0.67 (m, 2H). 13C NMR (101 MHz, DMSO) δ 158.56, 157.79, 150.72, 150.58, 146.05, 139.78, 136.80, 133.90, 128.79, 127.24, 125.89, 123.58, 122.89, 122.23, 114.92, 15.26, 9.74. HRMS (ESI) m/z calcd for [C22H18N4 + H]+ 339.1610, found 339.1617.
N-(4-Isopropylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (23). Compound 23 was synthesized as described in the general procedure. Compound 2 (48 mg, 0.2 mmol) was added to a solution of 4-isopropylaniline (30 mg, 0.22 mmol) and triethylamine (22 mg, 0.22 mmol) to obtain a yellow solid (52 mg) in 76% yield, mp. 225–226 °C; IR: 2958, 1563, 1513, 1415, 764 cm−1; 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.84–8.70 (m, 2H), 8.63 (d, J = 8.3 Hz, 1H), 8.37–8.20 (m, 2H), 7.91 (t, J = 5.7 Hz, 4H), 7.69 (dt, J = 8.3, 4.2 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 2.95 (dt, J = 13.5, 6.7 Hz, 1H), 1.27 (s, 3H), 1.26 (s, 3H). 13C NMR (101 MHz, DMSO) δ 158.55, 157.81, 150.73, 150.57, 146.05, 144.48, 137.24, 133.91, 128.81, 127.25, 126.77, 123.60, 122.68, 122.24, 114.92, 33.46, 24.49. HRMS (ESI) m/z calcd for [C22H20N4 + H]+ 341.1766, found 341.1780.
N-(3-Ethylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (24). Compound 24 was synthesized as described in the general procedure. Compound 2 (84 mg, 0.35 mmol) was added to a solution of 3-ethylaniline (48 mg, 0.40 mmol) and triethylamine (40 mg, 0.40 mmol) to obtain a yellow solid (89 mg) in 78% yield, mp. 236–238 °C; IR: 2963, 2440, 1568, 1378, 767 cm−1; 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.94 (d, J = 4.8 Hz, 2H), 8.68 (d, J = 8.1 Hz, 1H), 8.58 (s, 2H), 7.99 (s, 2H), 7.81–7.69 (m, 3H), 7.40 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 2.71 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 158.95, 155.71, 145.11, 144.67, 138.93, 134.57, 128.99, 128.41, 124.62, 124.36, 124.00, 122.84, 120.86, 114.99, 40.63, 40.42, 40.21, 40.00, 39.80, 39.59, 39.38, 28.77, 16.10. HRMS (ESI) m/z calcd for [C21H18N4 + H]+ 327.1610, found 327.1620.
N-(3-Propylphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (25). Compound 25 was synthesized as described in the general procedure. Compound 2 (31 mg, 0.13 mmol) was added to a solution of 3-propylaniline (21 mg, 0.16 mmol) and triethylamine (39 mg, 0.39 mmol) to obtain a yellow solid (32 mg) in 72% yield, mp. 205–207 °C; IR: 2955, 1524, 1365, 787, 757 cm−1; 1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.74 (d, J = 6.0 Hz, 2H), 8.63 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 6.0 Hz, 2H), 7.92 (d, J = 3.6 Hz, 2H), 7.84 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.72–7.65 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 2.68–2.61 (m, 2H), 1.70 (dt, J = 14.5, 7.2 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 158.65, 157.69, 150.65, 146.05, 142.90, 139.36, 133.97, 128.84, 127.32, 124.65, 123.62, 123.00, 122.23, 120.36, 114.94, 37.94, 24.65, 14.19. HRMS (ESI) m/z calcd for [C22H20N4 + H]+ 341.1766, found 341.1779.
2-Nitro-4-((2-(pyridin-4-yl)quinazolin-4-yl)amino)phenol (26). Compound 26 was synthesized as described in the general procedure. Compound 2 (24 mg, 0.1 mmol) was added to a solution of 4-amino-2-nitrophenol (17 mg, 0.11 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) and triethylamine (39 mg, 0.39 mmol) to obtain a yellow solid (30 mg) in 83% yield, mp. 267–268 °C; IR: 3427, 3194, 1527, 1487, 1224, 769 cm−1; 1H NMR (400 MHz, DMSO) δ 8.83–8.69 (m, 2H), 8.43 (d, J = 8.3 Hz, 1H), 8.14 (s, 2H), 8.09–7.99 (m, 2H), 7.87 (s, 1H), 7.40 (d, J = 5.8 Hz, 2H), 7.06 (d, J = 8.9 Hz, 1H), 5.91 (s, 2H). 13C NMR (101 MHz, DMSO) δ 167.04, 157.17, 152.03, 150.95, 148.30, 144.29, 142.53, 135.93, 134.08, 129.37, 128.50, 126.09, 124.13, 121.88, 120.28, 115.02, 108.96. HRMS (ESI) m/z calcd for [C19H13N5O3 + H]+ 360.1097, found 360.1103.
N-(4-Methoxyphenyl)-2-(pyridin-4-yl)quinazolin-4-amine (27). Compound 27 was synthesized as described in the general procedure. Compound 2 (120 mg, 0.5 mmol) was added to a solution of 4-methoxyaniline (68 mg, 0.55 mmol) and triethylamine (55 mg, 0.55 mmol) to obtain a yellow solid (139 mg) in 85% yield. mp. 219–221 °C; IR: 3291, 1510, 1242, 823, 767 cm−1; 1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.74 (d, J = 5.4 Hz, 2H), 8.58 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 5.4 Hz, 2H), 7.90 (d, J = 3.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.67 (dt, J = 8.0, 4.1 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.79 (d, J = 22.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 158.64, 157.78, 156.38, 150.64, 150.51, 146.08, 133.75, 132.30, 128.74, 127.10, 124.69, 123.51, 122.21, 114.85, 114.18, 55.72. HRMS (ESI) m/z calcd for [C20H16N4O + H]+ 329.1402, found 329.1411.
N1-(2-(Pyridin-4-yl)quinazolin-4-yl)benzene-1,4-diamine (28). Compound 28 was synthesized as described in the general procedure. Compound 2 (58 mg, 0.24 mmol) was added to a solution of 4-aminoaniline (30 mg, 0.28 mmol) and triethylamine (28 mg, 0.28 mmol) to obtain a pale white solid (66 mg) in 88% yield. mp. 301–303 °C; IR: 3445, 3363, 1556, 1512, 1411, 761 cm−1; 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.73 (d, J = 5.0 Hz, 2H), 8.54 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 5.6 Hz, 2H), 7.86 (d, J = 3.8 Hz, 2H), 7.62 (dt, J = 8.1, 4.0 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 5.34 (s, 2H). 13C NMR (101 MHz, DMSO) δ 158.72, 157.86, 150.57, 150.47, 146.28, 145.79, 133.59, 128.64, 128.13, 126.94, 124.98, 123.45, 122.20, 114.91, 114.34, 40.64, 40.43, 40.22, 40.01, 39.80, 39.59, 39.38. HRMS (ESI) m/z calcd for [C19H15N5 + H]+ 314.1406, found 314.1417.
N,2-Di(pyridin-4-yl)quinazolin-4-amine (29). Compound 29 was synthesized as described in the general procedure. Compound 2 (20 mg, 0. 08 mmol) was added to a solu-tion of p-aminopyridine (10 mg, 0.09 mmol) and triethylamine (9.1 mg, 0.09 mmol) to obtain a yellow solid (20 mg) in 80% yield. mp. 277–279 °C; IR: 2941, 1645, 1544, 1384, 1171, 776, 745 cm−1; 1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.87 (d, J = 5.9 Hz, 2H), 8.77 (d, J = 7.4 Hz, 2H), 8.44 (d, J = 6.0 Hz, 2H), 8.36 (d, J = 8.4 Hz, 1H), 8.26 (t, J = 7.7 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 161.10, 159.91, 157.58, 153.59, 151.26, 143.73, 142.83, 136.86, 130.84, 129.49, 124.93, 122.36, 117.73, 109.92, 40.63, 40.42, 40.22, 40.01, 39.80, 39.59, 39.38. HRMS (ESI) m/z calcd for [C18H13N5 + H]+ 300.1249, found 300.1285.
2.1.7. Preparation of Compounds 30–33
N-(4-Isothiocyanatophenyl)-2-(pyridin-4-yl)quinazolin-4-amine (30). A solution of amine 28 (31 mg, 0.1 mmol) in dichloromethane (10 mL) was treated dropwise with a solution of di-2-pyridyl thionocarbonate (23 mg, 0.11 mmol) in dicholoromethane (1 mL) over a period of 1 min with vigorous stirring at room temperature. The precipitates were filtered and recrystallized from ethyl acetate to obtain a white solid in 73% yield, mp. 307–309 °C; IR: 3279, 3039, 2053, 1491, 1410, 749 cm−1; 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.77 (d, J = 5.0 Hz, 2H), 8.61 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 4.9 Hz, 2H), 8.15–8.02 (m, 2H), 7.95 (d, J = 3.4 Hz, 2H), 7.79–7.67 (m, 1H), 7.57 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 158.39, 157.61, 150.81, 150.71, 145.78, 139.21, 134.24, 133.50, 128.91, 127.56, 126.84, 125.29, 123.65, 123.56, 122.26, 114.94. HRMS (ESI) m/z calcd for [C20H13N5S + H]+ 356.0970, found 356.0985.
2-Bromo-N-(4-((2-(pyridin-4-yl)quinazolin-4-yl)amino)phenyl)acetamide (31). A solution of amine 28 (62 mg, 0.2 mmol) in dichloromethane (2 mL) was treated dropwise with a solution of bromoacetyl bromide (25 mg, 0.2 mmol) in dichloromethane (1 mL) over a period of 1 min with vigorous stirring at 0 °C. The reaction was stirred at room temperature for 24 h. Then, water (10 mL) was added into the mixture, and the precipitates were filtered and recrystallized from ethyl acetate to obtain a yellow solid in 72% yield, mp. 336–338 °C; IR: 3033, 1566, 1510, 763 cm−1; 1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 10.15 (s, 1H), 8.87 (d, J = 5.2 Hz, 2H), 8.63 (d, J = 8.2 Hz, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.95 (d, J = 3.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.7 Hz, 3H), 4.08 (s, 2H). 13C NMR (101 MHz, TFA) δ 169.70, 159.95, 151.90, 147.91, 142.88, 138.31, 138.12, 135.44, 132.91, 131.48, 126.93, 125.42, 123.09, 122.84, 120.14, 112.46, 25.86. HRMS (ESI) m/z calcd for [C21H16BrN5O + H]+ 434.0616, found 434.0627.
N-(4-((2-(Pyridin-4-yl)quinazolin-4-yl)amino)phenyl)acetamide (32). To a solution of amine 28 (62 mg, 0.2 mmol) and triethylamine (0.28 mL, 2 mmol) in dichloromethane (5 mL), acetic anhydride (0.02 mL, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The precipitates were filtered and recrystallized from ethyl acetate to obtain a white solid in 85% yield, mp. 367–369 °C; IR: 3341, 3038, 1670, 1560, 1510, 760 cm−1; 1H NMR (400 MHz, DMSO) δ 9.98 (d, J = 8.7 Hz, 2H), 8.75 (d, J = 5.1 Hz, 2H), 8.60 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 4.9 Hz, 2H), 7.91 (d, J = 3.8 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.8 Hz, 3H), 2.05 (d, J = 27.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 168.74, 158.61, 157.78, 150.68, 150.54, 146.06, 136.01, 134.43, 133.95, 128.76, 127.30, 123.56, 123.50, 122.24, 119.60, 114.84, 24.40. HRMS (ESI) m/z calcd for [C21H17N5O + H]+ 356.1511, found 356.1521.
N-(4-Azidophenyl)-2-(pyridin-4-yl)quinazolin-4-amine (33). A solution of amine 28 (62 mg, 0.2 mmol) in water (2 mL) was treated dropwise with conc. hydrochloric acid (0.2 mL) and stirred at 0 °C, followed by dropwise addition of sodium nitrite (14 mg, 0.2 mmol) dissolved in water (1 mL) at 0 °C. A solution of sodium azide (13 mg, 0.2 mmol) in water (1 mL) was then added to the reaction mixture at 0 °C and the reaction mixture was stirred for 2 h at room temperature. After the reaction was stirred at room temperature for 2 h, 5 mL of water was added, and the precipitates were filtered and recrystallized from ethyl acetate to obtain a yellow solid in 59% yield, mp. 304–305 °C; IR: 3324, 3033, 2114, 1505, 1410, 761 cm−1; 1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.77 (s, 2H), 8.61 (d, J = 8.4 Hz, 1H), 8.30 (s, 2H), 8.09–7.97 (m, 2H), 7.94 (d, J = 3.5 Hz, 2H), 7.76–7.65 (m, 1H), 7.27 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 158.55, 157.69, 150.67, 150.60, 145.99, 136.69, 135.02, 134.06, 128.84, 127.41, 124.41, 123.59, 119.76, 114.89. HRMS (ESI) m/z calcd for [C19H13N7 + H]+ 340.1311, found 340.1319.