Solvents and reagents were obtained from commercial suppliers and used as received. Melting points were determined on a Stuart SMP3 melting point apparatus. All final compounds had a percentage purity of at least 95%, as measured by HPLC. A SpectraSYSTEM (ThermoFisher Scientific, Waltham, MA, USA) or an Ultimate 3000 (ThermoFisher Scientific) LC system was used, either consisting of a pump, an autosampler, and a UV detector. Mass spectrometry was performed on an MSQ plus electrospray mass spectrometer (ThermoFisher, Dreieich, Germany). An RP C18 column was used as the stationary phase. Three different methods were used in which the solvent system consisted of water containing 0.1% TFA or FA (A) and 0.1% TFA or FA in acetonitrile (B). HPLC Method 1: flow rate 1 mL/min; the percentage of B started at an initial of 5%, was increased up to 100% during 15 min, kept at 100% for 5 min, and flushed to 5% in 4 min and maintained for 1 min. Method 2: flow rate 0.9 mL/min; the percentage of B started at an initial of 5%, was increased up to 100% during 10 min, kept at 100% for 1 min, and flushed to 5% in 1 min. Method 3: flow rate 0.7 mL/min; the percentage of B started at an initial of 5% for 2 min, was increased to 98% during 6 min, kept at 98% for 2 min, and flushed to 5% in 2 min. Chemical shifts were recorded as δ values in ppm units and referenced against the residual solvent peak (DMSO-d6, δ = 2.50). Splitting patterns describe apparent multiplicities and are designated as s (singlet), brs (broad singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet). Coupling constants (J) are given in hertz (Hz).
General Synthetic Procedures and Experimental Details
Procedure A, procedure for synthesis of compounds b2–c2.
2-Amino-5-nitrobenzonitrile (5 g, 30.6 mmol) was held at reflux in triethyl orthoformate (50 mL) for 16 h in the presence of acetic anhydride (10 drops). The reaction was then concentrated under vacuum, and the remaining residue was poured onto ice water, at which point a precipitate formed. The precipitate was filtered under vacuum and left to dry to provide compound a. Compound a (1.1 g, 5 mmol) was held at reflux for 1 h with the corresponding aniline derivative in 8 mL glacial acetic acid. A precipitate was formed during the reaction, which was filtered while hot, and the precipitate was then washed with Et2O to provide the corresponding nitroquinazoline derivatives (b1–c1). Consequently, the desired nitroquinazoline derivative (b1–c1) (5 mmol) was mixed with stannous chloride (5.625 gm, 25 mmol) in MeOH (20 mL), and then the mixture was stirred at reflux for 30 min under a nitrogen atmosphere. Excess MeOH was removed under reduced pressure; the remaining residue was dissolved in EtOAc (200 mL) and made alkaline with an aqueous solution of NaHCO3. The resulting mixture was filtrated under vacuum followed by separation of the organic phase from the aqueous phase. The aqueous phase was extracted with EtOAc (2 × 20 mL), the organic fractions were combined, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the corresponding aminoquinazoline derivative (b2–c2).
Procedure B, procedure for synthesis of compounds 1–11 and 17–20.
The selected aminoquizaoline derivative b2 (2 mmol) was added to water (20 mL), into which concentrated HCl (1 mL) was then added and stirred at 0 °C. Thiophosgene (0.253 gm, 2.2 mmol) was then added dropwise in a well-ventilated hood to the stirred solution; stirring continued for 3 h, after which the formed precipitate was filtered and washed with Et2O to provide compound b3. Afterwards, a mixture of the isothiocyanate derivative (1 mmol) and the corresponding amine derivative (1 mmol) was stirred at room temperature for 5 h in DMF (10 mL). The solution was then poured onto ice water, at which point a precipitate formed that was then filtered. The solid was then purified by column chromatography to provide the final compounds.
Procedure C, procedure for synthesis of compounds 12–16.
The desired aminoquinazoline derivative b2 or c2 (1 mmol) and the corresponding isocyanate or isothiocyanate derivative (1 mmol) were stirred at room temperature for 5 h in DMF (10 mL). The solution was then poured onto ice water, at which point a precipitate formed that was then filtered. The solid was then purified by column chromatography to provide the corresponding thiourea derivatives.
N4-(3-Chlorophenyl)quinazoline-4,6-diamine (b2)
The compound was synthesized according to procedure A using 3-chloroaniline. Yield 81%; 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.39 (s, 1H), 8.12 (t, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.2, 1.2 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.43– 7.33 (m, 2H), 7.27 (dd, J = 8.9, 2.3 Hz, 1H), 7.09 (dd, J = 7.6, 1.7 Hz, 1H), 5.62 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 156.17, 150.02, 147.87, 143.21, 142.09, 133.16, 130.41, 129.23, 124.33, 122.66, 121.06, 120.08, 117.20, 101.32; MS (+ESI): m/z = 270.89 (M + H)+
1-(4-(tert-Butyl)benzyl)-3-(4-((3-chlorophenyl)amino)quinazolin-6-yl)thiourea (1)
The compound was synthesized according to procedure B using b3 and (4-(tert-butyl)phenyl)methanamine. Yield 48%; m.p. 203–205 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.87 (d, J = 6.2 Hz, 2H), 8.64 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 8.12 (t, J = 1.9 Hz, 1H), 7.87 (dd, J = 8.2, 1.0 Hz, 1H), 7.82 (dd, J = 8.9, 2.1 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.30 (q, J = 8.5 Hz, 4H), 7.17 (ddd, J = 8.1, 2.1, 0.8 Hz, 1H), 4.72 (d, J = 4.9 Hz, 2H), 1.23 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 181.34, 157.15, 153.58, 149.31, 147.29, 140.92, 137.01, 135.83, 132.79, 131.70, 130.13, 128.16, 127.31, 124.95, 123.00, 121.02, 119.99, 117.67, 115.28, 47.40, 34.13, 31.12. MS (+ESI): m/z = 476.15 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(4-methoxybenzyl)thiourea (2)
The compound was synthesized according to procedure B using b3 and (4-methoxyphenyl)methanamine. Yield 52%; m.p. 165–167 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.83 (d, J = 8.4 Hz, 2H), 8.64 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.13 (t, J = 1.9 Hz, 1H), 7.85 (ddd, J = 11.0, 8.6, 1.6 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 7.9, 1.4 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 4.70 (d, J = 4.3 Hz, 2H), 3.71 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 181.28, 158.32, 157.15, 153.63, 147.41, 140.94, 137.05, 132.78, 131.78, 130.83, 130.14, 128.89, 128.18, 123.00, 121.07, 120.04, 117.67, 115.27, 113.63, 55.05, 47.05. MS (+ESI): m/z = 450.05 (M + H) +.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(4-(trifluoromethyl)benzyl)thiourea (3)
The compound was synthesized according to procedure B using b3 and (4-(trifluoromethyl)phenyl)methanamine. Yield 25%; m.p. 165–167 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.97 (s, 1H), 8.67 (s, 1H), 8.50 (s, 2H), 8.11 (s, 1H), 7.85 (dd, J = 8.8, 1.9 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.19 (ddd, J = 7.9, 1.9, 0.7 Hz, 1H), 4.87 (d, J = 5.0 Hz, 2H). MS (+ESI): m/z = 488.08 (M + H) +.
1-(4-Chlorobenzyl)-3-(4-((3-chlorophenyl)amino)quinazolin-6-yl)thiourea (4)
The compound was synthesized according to procedure B using b3 and (4-chlorophenyl)methanamine. Yield 58%; m.p. 166–168 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.85 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.86 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (dd, J = 8.9, 2.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.38 (s, 4H), 7.17 (dd, J = 7.9, 1.4 Hz, 1H), 4.77 (d, J = 5.2 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 181.54, 157.17, 153.70, 147.45, 140.89, 138.21, 136.83, 132.78, 131.83, 131.33, 130.15, 129.27, 128.28, 128.13, 123.05, 121.09, 120.06, 117.95, 115.29, 46.79. MS (+ESI): m/z = 454.03 (M + H) +.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(4-fluorobenzyl)thiourea (5)
The compound was synthesized according to procedure B using b3 and (4-fluorophenyl)methanamine. Yield 44%; m.p. 164–166 °C; 1H NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.13 (t, J = 1.9 Hz, 1H), 7.86 (dd, J = 8.2, 1.1 Hz, 1H), 7.83 (dd, J = 8.9, 1.9 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.43–7.38 (m, 3H), 7.19–7.12 (m, 3H), 4.76 (d, J = 4.6 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 181.48, 161.21 (d, J = 242.5 Hz), 157.15, 153.71, 147.54, 140.92, 136.87, 135.28, 132.77, 131.83, 130.14, 129.44 (d, J = 8.1 Hz), 128.30, 123.01, 121.07, 120.04, 117.91, 115.29, 114.91 (d, J = 21.2 Hz), 46.74; MS (+ESI): m/z = 438.01 (M + H) +.
1-(4-((3-chlorophenyl)amino)quinazolin-6-yl)-3-(2,4-difluorobenzyl)thiourea (6)
The compound was synthesized according to procedure B using b3 and (2,4-difluorophenyl)methanamine. Yield 33%; m.p. 178–180 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.85 (dd, J = 11.2, 4.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.45 (dt, J = 16.3, 8.4 Hz, 2H), 7.24–7.19 (m, 1H), 7.17 (dd, J = 7.9, 1.4 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 4.77 (d, J = 5.0 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 181.74, 161.36 (dd, J = 245.2, 12.1 Hz), 159.92 (dd, J = 247.1, 12.3 Hz), 157.16, 153.74, 147.55, 140.91, 136.88, 132.77, 131.84, 130.69, 130.15, 128.28, 123.03, 122.12 (dd, J = 14.7, 2.7 Hz), 121.09, 120.06, 117.92, 115.27, 111.18 (dd, J = 21.1, 3.2 Hz), 103.62 (t, J = 25.8 Hz), 40.87; MS (+ESI): m/z = 456.05 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(2,4-dimethoxybenzyl)thiourea (7)
The compound was synthesized according to procedure B using b3 and (2,4-dimethoxyphenyl)methanamine. Yield 43%; m.p. 204–206 °C. 1H NMR (500 MHz, DMSO) δ 9.82 (s, 2H), 8.63 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.18 (dd, J = 16.0, 8.1 Hz, 2H), 6.57 (s, 1H), 6.49 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H). 13C NMR (126 MHz, DMSO) δ 181.36, 159.91, 157.83, 157.11, 153.61, 147.42, 140.96, 137.28, 132.76, 131.73, 130.12, 129.30, 128.07, 122.98, 121.09, 120.06, 118.27, 117.32, 115.22, 104.26, 98.29, 55.46, 55.22, 42.73. MS (+ESI): m/z = 480.11 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(3-methoxybenzyl)thiourea (8)
The compound was synthesized according to procedure B using b3 and (3-methoxyphenyl)methanamine. Yield 54%; m.p. 183–185 °C; 1H NMR (500 MHz, DMSO) δ 9.87 (d, J = 14.5 Hz, 2H), 8.64 (s, 1 H), 8.46 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.88–7.81 (m, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.9, 1.8 Hz, 1H), 6.93 (d, J = 7.4 Hz, 2H), 6.84–6.78 (m, 1H), 4.75 (d, J = 4.4 Hz, 2H), 3.73 (s, 3H); 13C NMR (126 MHz, DMSO) δ 181.55, 159.27, 157.17, 153.66, 147.41, 140.90, 140.59, 137.01, 132.76, 131.87, 130.13, 129.30, 128.17, 123.04, 121.14, 120.11, 119.61, 117.85, 115.27, 113.23, 112.10, 54.99, 47.49. MS (+ESI): m/z = 450.04 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(thiophen-2-yl-methyl)thiourea (9)
The compound was synthesized according to procedure B using b3 and thiophen-2-ylmethanamine. Yield 60%; mp 178.8–180.7 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.83 (s, 1H), 8.64 (s, 1H), 8.43 (d, J = 2.0 Hz, 2H), 8.13 (t, J = 2.0 Hz, 1H), 7.86 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 7.82 (dd, J = 8.9, 2.1 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.39 (dd, J = 5.1, 1.2 Hz, 1H), 7.17 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 7.07 (dd, J = 3.4, 1.1 Hz, 1H), 6.96 (dd, J = 5.1, 3.4 Hz, 1H), 4.95 (d, J = 5.5 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 181.08, 157.13, 153.72, 147.59, 141.62, 140.91, 136.82, 132.76, 131.82, 130.11, 128.26, 126.47, 126.05, 125.19, 122.98, 121.07, 120.04, 117.88, 115.27, 42.56; MS (ESI) m/z = 425.65 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(furan-2-ylmethyl)thiourea (10)
The compound was synthesized according to procedure B using b3 and furan-2-ylmethanamine. Yield 14%; mp 195.6–198.2 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.83 (d, J = 5.0 Hz, 2H), 8.64 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.33 (s, 1H), 8.12 (t, J = 2.0 Hz, 1H), 7.88–7.82 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 0.9 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.25–7.10 (m, 1H), 6.42 (dd, J = 3.1, 1.9 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 181.48, 157.14, 153.70, 151.70, 147.56, 142.16, 140.92, 137.03, 132.75, 131.84, 130.11, 128.13, 122.99, 121.11, 120.08, 117.86, 115.21, 110.51, 107.40, 40.92; MS (ESI) m/z = 409.75 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(pyridin-3-ylmethyl)thiourea (11)
The compound was synthesized according to procedure B using b3 and pyridin-3-ylmethanamine. Yield 11%; mp 205.6–207.9 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.84 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.52–8.37 (m, 3H), 8.13 (t, J = 1.9 Hz, 1H), 7.86 (dd, J = 8.3, 1.1 Hz, 1H), 7.83–7.74 (m, 3H), 7.42 (t, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.7, 4.7 Hz, 1H), 7.17 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 4.80 (d, J = 5.4 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 181.60, 157.15, 153.76, 148.93, 148.05, 147.62, 140.89, 136.70, 135.22, 134.65, 132.76, 131.78, 130.12, 128.39, 123.33, 123.02, 121.11, 120.07, 117.98, 115.30, 45.12; MS (ESI) m/z = 420.74 (M + H)+.
1-(3-Chlorobenzyl)-3-(4-((3-chlorophenyl)amino)quinazolin-6-yl)urea (12)
The compound was synthesized according to procedure C using b2 and 1-chloro-3-(isocyanatomethyl)benzene. Yield 32%; mp 225.5–227 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.96 (s, 1H), 8.54 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.06 (t, J = 2.0 Hz, 1H), 7.86 (dd, J = 9.0, 2.3 Hz, 1H), 7.80 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.41–7.38 (m, 2H), 7.38–7.36 (m, 1H), 7.33–7.29 (m, 2H), 7.14 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 6.96 (t, J = 6.0 Hz, 1H), 4.37 (d, J = 6.0 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 156.97, 155.19, 152.21, 145.61, 143.09, 141.19, 138.46, 133.01, 132.66, 130.22, 129.97, 128.37, 126.85, 126.67, 126.44, 125.78, 122.75, 121.27, 120.27, 115.71, 109.30, 42.29; MS (ESI) m/z = 437.76 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(3-fluorobenzyl)urea (13)
The compound was synthesized according to procedure C using b2 and 1-fluoro-3-(isocyanatomethyl)benzene. Yield 39%; mp 210.8–212 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.95 (s, 1H), 8.54 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.06 (t, J = 2.0 Hz, 1H), 7.87 (dd, J = 9.0, 2.3 Hz, 1H), 7.80 (ddd, J = 8.3, 2.0, 0.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.42–7.35 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 7.16–7.12 (m, 2H), 7.07 (td, J = 8.6, 2.7 Hz, 1H), 6.95 (t, J = 6.0 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 162.28 (d, J = 243.3 Hz), 156.97, 155.21, 152.21, 145.60, 143.50 (d, J = 6.9 Hz), 141.19, 138.48, 132.66, 130.27 (d, J = 8.3 Hz), 129.97, 128.37, 126.44, 123.04 (d, J = 2.5 Hz), 122.76, 121.27, 120.28, 115.71, 113.68 (d, J = 21.5 Hz), 113.46 (d, J = 20.9 Hz), 109.29, 42.34; MS (ESI) m/z = 421.75 (M + H)+.
1-(3-Chlorobenzyl)-3-(4-((3-ethynylphenyl)amino)quinazolin-6-yl)urea (14)
The compound was synthesized according to procedure C using c2 and 1-chloro-3-(isocyanatomethyl)benzeneYield 22%; mp 222.4–228.8 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.95 (s, 1H), 8.51 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.94–7.82 (m, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.38 (td, J = 7.8, 2.6 Hz, 3H), 7.31 (dd, J = 8.3, 4.6 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 4.18 (s, 1H).13C NMR (126 MHz, DMSO-d6) δ 157.08, 155.21, 152.31, 145.58, 143.10, 139.85, 138.39, 133.01, 130.23, 128.82, 128.33, 126.86, 126.67, 126.43, 126.38, 125.79, 124.86, 122.72, 121.68, 115.69, 109.39, 83.59, 80.48, 42.30; MS (ESI) m/z = 427.58 (M + H)+.
N-((4-((3-Chlorophenyl)amino)quinazolin-6-yl)carbamoyl)benzamide (15)
The compound was synthesized according to procedure C using b2 and benzoyl isocyanate. Yield 45%; mp 252.4–254 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 11.24 (s, 1H), 9.88 (s, 1H), 8.62 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 9.0, 2.2 Hz, 1H), 8.11 (t, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.4, 1.2 Hz, 2H), 7.88–7.82 (m, 2H), 7.70–7.65 (m, 1H), 7.57 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 8.1 Hz, 1H), 7.17 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 169.09, 157.04, 153.24, 151.40, 146.65, 140.88, 135.88, 133.21, 132.75, 132.15, 130.06, 128.76, 128.63, 128.37, 126.95, 123.05, 121.32, 120.26, 115.43, 112.13; MS (ESI) m/z = 417.57 (M + H)+.
N-((4-((3-Chlorophenyl)amino)quinazolin-6-yl)carbamothioyl)benzamide (16)
The compound was synthesized according to procedure C using b2 and benzoyl isothiocyanate. Yield 74%; mp 186.1–188.5 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 11.83 (s, 1H), 9.95 (s, 1H), 8.69 (s, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 8.07–7.97 (m, 2H), 7.85 (d, J = 8.9 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.19 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 180.40, 168.60, 157.34, 154.24, 147.92, 140.68, 136.27, 133.29, 132.78, 132.04, 131.72, 130.13, 128.75, 128.52, 127.74, 123.28, 121.39, 120.30, 118.78, 115.06; MS (ESI) m/z = 433.70 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-cyclopropylthiourea (17)
The compound was synthesized according to procedure B using b3 and cyclopropanamine. Yield 42%; mp 219.1–220.2 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.64 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.13 (t, J = 2.0 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.17 (ddd, J = 8.0, 2.1, 0.8 Hz, 1H), 2.89 (s, 1H), 0.71 (d, J = 68.4 Hz, 4H); 13C NMR (126 MHz, DMSO-d6) δ 182.16, 157.17, 153.68, 147.61, 140.93, 137.50, 132.74, 131.69, 130.09, 127.71, 123.00, 121.20, 120.15, 116.17, 114.99, 30.69, 6.94; MS (ESI) m/z = 369.84 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-(cyclopropylmethyl)thiourea (18)
The compound was synthesized according to procedure B using b3 and cyclopropylmethanamine. Yield 27%; mp 226.3–228 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.72 (s, 1H), 8.63 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.13 (t, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.87–7.85 (m, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.16 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 3.39 (s, 2H), 1.21–1.07 (m, 1H), 0.45 (d, J = 6.9 Hz, 2H), 0.26 (dd, J = 4.7, 1.4 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 180.90, 157.10, 153.57, 147.37, 140.95, 137.25, 132.75, 131.64, 130.10, 128.11, 122.96, 121.09, 120.06, 117.24, 115.23, 48.75, 10.40, 3.31; MS (ESI) m/z = 383.83 (M + H)+.
1-(4-((3-Chlorophenyl)amino)quinazolin-6-yl)-3-cyclopentylthiourea (19)
The compound was synthesized according to procedure B using b3 and cyclopentanamine. Yield 32%; mp 229.1–231.6 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.55 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 4.58 (s, 1H), 1.96 (d, J = 5.4 Hz, 2H), 1.66 (s, 2H), 1.58–1.45 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ 180.60, 157.12, 153.40, 147.08, 140.94, 137.59, 132.75, 131.53, 130.10, 127.64, 122.99, 121.15, 120.11, 116.76, 115.15, 55.53, 31.93, 23.39; MS (ESI) m/z = 397.82 (M + H)+.
1-(tert-Butyl)-3-(4-((3-chlorophenyl)amino)quinazolin-6-yl)thiourea (20)
The compound was synthesized according to procedure B using b3 and tert-butylamine. Yield 54%; mp 177.5–179.4 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.47 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.12 (t, J = 2.0 Hz, 1H), 7.89 (dd, J = 8.9, 2.2 Hz, 1H), 7.84 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.63 (s, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.16 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 1.51 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 180.37, 157.06, 153.47, 147.27, 140.98, 137.65, 132.73, 132.36, 130.08, 127.59, 122.93, 121.14, 120.10, 117.11, 115.09, 52.86, 28.58; MS (ESI) m/z = 385.81 (M + H)+.