Supporting information for:
Ultrasound-promoted synthesis and immunosuppressive activity of
novel quinazoline derivatives
Lei Zhang a, Zhe Gao b, Chen Peng a, Zheng-Yang Bin a, Dan Zhao a, Jing Wu a,
Qiang Xu b, Jian-Xin Li a,*
a
State Key lab of Analytical Chemistry for Life Science, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China
b
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science,
Nanjing University, Nanjing 210093, China
*Corresponding author. Tel. & fax: +86-25-83686419; e-mail: lijxnju@nju.edu.cn
SI1
1. Synthesis…………………………………………………………….……...….3
2. Biological assays………………………………………………………………23
3. The 1H NMR spectrums of representative compounds………………..………25
SI2
1. Synthesis
1.1 General
All reagents and solvents were used as supplied without further purification.
Melting points were measured with an X-4 melting point apparatus (Bei Jing Taike
Co., Ltd.) and were uncorrected. 1H NMR and 13C NMR were determined in CDCl3 or
DMSO-d6 or TFA-d4 on a Brucker 300 spectrometer at room temperature, respectively,
and tetramethylsilane (TMS) served as an internal standard. Spin multiplicities are
given as s (singlet), d (doublet), t (triplet) and m (multiplet) as well as b (broad).
Coupling constants (J) are given in hertz. ESI-MS and high resolution MS (HRMS)
were carried out on a LTQ Orbitrap XL (The Thermo Scientific, USA). Sonication
was performed in KQ-300DE ultrasonic cleaner (Kunshan ultrasonic instrument Co.,
Ltd.) with the frequency of 40 kHz and an output power 120-300 W. All experiments
were monitored by thin layer chromatography (TLC). TLC was performed on
pre-coated silica gel plates (Qingdao Haiyang Chemical Co., Ltd). Amine 2b was
purchased from Accela ChemBio Co., Ltd.
1.2. 2-aminobenzaldehyde (2a)
To a 1 L round bottomed flask was charged with 2-nitrobenzaldehyde (1a, 15.1g,
100 mmol), ethanol (370 mL), water (80 mL), and iron powder (44.8g, 800 mmol),
and heated to 50 oC. While stirring concentrated hydrochloric acid (1 mL) was added
as catalyst. The progress of the reaction was monitored by TLC (hexane/ethyl acetate,
v/v, 5:1). Upon completion, the reaction mixture cooled to room temperature, filtered
with suction, and washed with ethanol. For the filtrate, remove solvent under reduced
pressure. To the residue, ethyl acetate (400 mL) was added, the resulting solution was
washed with brine, dried over Na2SO4. Remove ethyl acetate under reduced pressure
afford 2a as pale yellow oil, 11.3g, Yield: 93%. 1H NMR (300 MHz, CDCl3) δ 9.87 (s,
1H), 7.48 (dd, J = 7.8, 1.4 Hz, 1H), 7.36 – 7.27 (m, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.65
(d, J = 8.3 Hz, 1H), 6.12 (brs, 2H); MS (ESI): 122.10 [M+H]+.
SI3
1.3. General procedure for compounds 3
To a solution of 2 (70 mmol) and triethlyamine (11.7 mL, 84 mmol, 1.2 equiv) in
DCM (200 mL) was added 4-nitrobenzoic acid chloride (13.0g, 70 mmol, 1.0 equiv)
in portions, in ice-water bath. The progress of the reaction was monitored by TLC
(hexane/ethyl acetate, v/v, 5:1). Upon completion, solvent was removed under
reduced pressure. To the residue, water (500 mL) was added and the mixture exposed
to ultrasound irradiation for 15 min and filtered. The filter cake was washed with
water and dried under reduced pressure gave desired amide 3.
1.3.1. N-(2-Formylphenyl)-4-nitrobenzamide (3a). Pale yellow solid; Yield: 92.4%;
1
H NMR (300 MHz, CDCl3) δ = 12.26 (s, 1H), 10.02 (s, 1H), 8.93 (d, J= 8.4 Hz, 1H),
8.51 – 8.33 (m, 2H), 8.29 – 8.14 (m, 2H), 7.86 – 7.67 (m, 2H), 7.46 – 7.29 (m, 1H);
MS (ESI): 270.95 [M+H]+.
1.3.2. N-(2-Benzoylphenyl)-4-nitrobenzamide (3b). Pale yellow solid; Yield: 95.8%;
1
H NMR (300 MHz, CDCl3) δ = 12.21 (s, 1H), 8.87 (dd, J = 8.8, 1.0 Hz, 1H), 8.42 –
8.31 (m, 2H), 8.28 – 8.18 (m, 2H), 7.81 – 7.59 (m, 5H), 7.52 (t, J = 7.4 Hz, 2H), 7.24
– 7.11 (m, 1H); MS (ESI): 347.00 [M+H]+.
1.4. General procedure for quinazoline cores 4 and 37
To a 250 mL sealed tube was charged with amides 3 or 36 (18 mmol), 25%
ammonia water (24 mL, 360 mmol), and water (150 mL). The tube was located in the
maximum energy area in the ultrasonic generator at 80 oC and exposed for 3h. The
resulting mixture cooled to room temperature and filtered. The filter cake was washed
with water and dried under reduced pressure furnishing desired product 4 and 37.
1.4.1. 2-(4-Nitrophenyl)quinazoline (4a). Pale yellow solid; Yield: 89.5%; 1H NMR
(300 MHz, CDCl3): δ = 9.52 (s, 1H), 8.82 (d, J = 9.0 Hz, 2H), 8.38 (d, J = 9.0 Hz,
SI4
2H), 8.14 (d, J = 8.9 Hz, 1H), 7.98 (t, J = 7.7 Hz, 2H), 7.78 – 7.63 (m, 1H); 13C NMR
(75 MHz, TFA-d4): δ = 152.8, 150.7, 146.3, 142.30, 134.9, 132.5, 129.9, 129.8, 124.4,
124.3, 122.5; MS (ESI): 252.00 [M+H]+.
1.4.2. 2-(4-Nitrophenyl)-4-phenylquinazoline (4b). White solid; Yield: 93.3%; 1H
NMR (300 MHz, CDCl3): δ = 8.89 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 9.0 Hz, 2H), 8.19
(dd, J = 7.7, 6.3 Hz, 2H), 8.02 – 7.81 (m, 3H), 7.70 – 7.54 (m, 4H);
13
C NMR (75
MHz, CDCl3): δ = 173.2, 162.4, 156.4 153.7, 148.6, 141.8, 138.6, 134.8, 134.7,
134.0, 133.9, 133.3, 132.7, 131.7, 128.2, 126.5; MS (ESI): 327.95 [M+H]+.
1.4.2. 5,7-dimethoxy-2,4-dimethylquinazoline (37). White solid; Yield: 95.2%; Mp
= 106–108 oC; 1H NMR (300 MHz, DMSO-d6): δ = 6.79 (d, J = 2.3 Hz, 1H), 6.59 (d,
J = 2.3 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.82 (s, 3H), 2.56 (s, 3H); 13C NMR (75
MHz, CDCl3): δ = 165.9, 163.9, 163.4, 158.5, 154.0, 110.6, 99.1, 98.8, 56.3, 55.9,
27.3, 25.9; MS (ESI): 219.00 [M+H]+; HRMS (ESI): calcd for C12H14N2O2 [M+H]+
219.1134, found 219.1130.
1.5. General procedure for amino quinazoline cores 5
To a 250 mL round bottomed flask was charged with nitroquinazoline 4 (20
mmol), ethanol (150 mL), water (30 mL), and iron powder (9g, 160 mmol), and
heated to 50 oC. Followed, concentrated hydrochloric acid (0.5 mL) was added as
catalyst. The progress of the reaction was monitored by TLC (hexane/ethyl acetate,
v/v, 5:1). Upon completion, the reaction mixture cooled to room temperature, filtered
with suction, and washed with ethanol. For the filtrate, remove solvent under reduced
pressure. To the residue DCM (200 mL) was added, the resulting solution was washed
with brine, and dried over Na2SO4. Remove DCM under reduced pressure afford 5.
1.5.1. 4-(quinazolin-2-yl)aniline (5a) Pale yellow solid; Yield: 88.1%; 1H NMR (300
MHz, CDCl3) δ 9.39 (d, J = 0.6 Hz, 1H), 8.55 – 8.37 (m, 2H), 8.03 (d, J = 9.0 Hz, 1H),
SI5
7.91 – 7.80 (m, 2H), 7.54 (td, J = 7.3, 1.1 Hz, 1H), 6.90 – 6.69 (m, 2H), 3.91 (s, 2H);
MS (ESI): 222.10 [M+H]+.
1.5.2. 4-(4-phenylquinazolin-2-yl)aniline (5b) Pale yellow solid; Yield: 92.3%; 1H
NMR (300 MHz, CDCl3) δ 8.54 (d, J = 8.6 Hz, 2H), 8.08 (t, J = 7.8 Hz, 2H), 7.96 –
7.75 (m, 3H), 7.67 – 7.51 (m, 3H), 7.47 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H),
3.98 (s, 2H); MS (ESI): 298.00 [M+H]+.
1.6 General procedure for paralleled sulfonamide derivatives (6-25)
To a solution of 5b (1 mmol) in pyridine (8 mL) was added sulfonyl chloride (1.1
mmol, 1.1 equiv) in portions, at room temperature, followed, stired at 50 oC for 5h.
Remove pyridine under reduced pressure. To the residue, ethyl acetate (50 mL) was
added, the solution was washed with saturated NaHCO3, brine, and dried over
anhydrous Na2SO4. Remove ethyl acetate under reduced pressure. The residue was
washed with ethyl ether, and furnished target compounds (6-25).
1.6.1. N-(4-(quinazolin-2-yl)phenyl)methanesulfonamide (6a). Brown solid; Yield:
83.1%; Mp = 193–195 oC; 1H NMR (300 MHz, CDCl3) δ 9.47 (s, 1H), 8.64 (d, J =
8.6 Hz, 2H), 8.12 (d, J = 8.3 Hz, 1H), 8.02 – 7.88 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H),
7.37 (d, J = 8.7 Hz, 2H), 6.71 (s, 1H), 3.09 (s, 3H);
13
C NMR (75 MHz, CDCl3) δ
160.5, 150.6, 138.9, 134.7, 134.2, 130.1, 128.4, 127.3, 127.1, 123.5, 119.47, 39.50;
MS (ESI): 297.95 [M+H]+; HRMS (ESI): calcd for C15H14N3O2S [M+H]+ 300.0807,
found 300.0793.
1.6.2.
N-(4-(4-phenylquinazolin-2-yl)phenyl)methanesulfonamide
(6b).
Pale
yellow solid; Yield: 85.4%; Mp = 224–226 oC; 1H NMR (300 MHz, CDCl3) δ 8.69 (d,
J = 8.5 Hz, 2H), 8.14 (t, J = 7.5 Hz, 2H), 7.97 – 7.79 (m, 3H), 7.68 – 7.49 (m, 4H),
7.36 (d, J = 8.6 Hz, 2H), 6.81 (s, 1H), 3.08 (s, 3H);
13
C NMR (75 MHz, CDCl3) δ
168.4, 159.2, 151.8, 138.8, 137.4, 135.0, 133.6, 130.2, 130.1, 123.0, 128.9, 128.5,
127.0, 121.6, 119.5, 39.4; MS (ESI): 370.00 [M+H]+; HRMS (ESI): calcd for
C21H18N3O2S [M+H]+ 376.1120, found 376.1100.
SI6
1.6.3. N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (7a). Pale yellow solid;
Yield: 90.7%; Mp = 200–202 oC; 1H NMR (300 MHz, CDCl3) δ 9.43 (s, 1H), 8.50 (d,
J = 8.6 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.99 – 7.76 (m, 4H), 7.61 (t, J = 7.5 Hz, 1H),
7.53 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 8.2 Hz, 3H), 6.95 (s, 1H);
C NMR (75 MHz, CDCl3) δ 160.4, 160.2, 150.5, 144.8, 139.6, 139.4, 134.1, 133.9,
13
132.7, 129.6, 128.9, 128.3, 127.1, 126.1, 123.3, 120.1; MS (ESI): 361.95 [M+H]+;
HRMS (ESI): calcd for C20H16N3O2S [M+H]+ 362.0963, 362.0947.
1.6.4.
N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide
(7b).
Pale
yellow solid; Yield: 89.3%; Mp = 219–221 oC; 1H NMR (300 MHz, CDCl3) δ 8.58 (d,
J = 8.6 Hz, 2H), 8.19 – 8.03 (m, 2H), 7.95 – 7.73 (m, 5H), 7.67 – 7.47 (m, 5H), 7.43 (t,
J = 7.5 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.02 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
168.2, 159.4, 151.7, 139.4, 137.4, 134.2, 133.5, 132.6, 130.0, 129.9, 129.6, 128.8,
128.4, 127.1, 126.9, 126.8, 121.4, 120.2; MS (ESI): 437.95 [M+H]+; HRMS (ESI):
calcd for C26H20N3O2S [M+H]+ 438.1276, found 438.1258.
1.6.5.
4-methyl-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide
(8a).
Pale
yellow solid; Yield: 93.4%; Mp = 184–186 oC; 1H NMR (300 MHz, CDCl3) δ 9.44 (s,
1H), 8.50 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.91 (t, J = 7.6 Hz, 2H), 7.72
(d, J = 8.2 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.30 – 7.14 (m, 3H), 6.91 (s, 1H), 2.36 (s,
3H);
13
C NMR (75 MHz, CDCl3) δ 160.5, 159.8, 144.0, 139.0, 135.8, 134.5, 134.1,
129.9, 129.7, 128.2, 127.4, 127.22, 127.17, 123.3, 120.4; MS (ESI): 375.95 [M+H]+;
HRMS (ESI): calcd for C21H18N3O2S [M+H]+ 376.1120, found 376.1104.
1.6.6. 4-methyl-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (8b).
Pale yellow solid; Yield: 85.5%; Mp = 228–229 oC; 1H NMR (300 MHz, CDCl3) δ
8.57 (d, J = 8.5 Hz, 2H), 8.12 (t, J = 7.1 Hz, 2H), 7.94 – 7.79 (m, 3H), 7.72 (d, J = 8.2
Hz, 2H), 7.65 – 7.46 (m, 4H), 7.31 – 7.11 (m, 4H), 6.91 (s, 1H), 2.35 (s, 3H);
13
C
NMR (75 MHz, CDCl3) δ 168.1, 159.4, 151.7, 143.3, 139.9, 137.4, 136.6, 133.7,
133.5, 123.0, 129.8, 129.5, 129.4, 128.8, 128.4, 127.1, 126.7, 126.8, 121.3, 119.8,
21.3; MS (ESI): 452.00 [M+H]+; HRMS (ESI): calcd for C27H22N3O2S [M+H]+
452.1433, found 452.1403.
SI7
1.6.7.
3-methyl-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide
(9a).
Pale
yellow solid; Yield: 85.8%; Mp = 186–188 oC; 1H NMR (300 MHz, CDCl3) δ 9.43 (s,
1H), 8.51 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.91 (t, J = 7.7 Hz, 2H), 7.72 –
7.53 (m, 3H), 7.36 – 7.28 (m, 2H), 7.23 (s, 1H), 6.88 (s, 1H), 2.36 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 160.4 160.1, 150.6, 139.3, 138.7, 134.6, 134.2, 133.9, 129.7,
129.2, 128.9, 128.4, 127.5, 127.5, 127.1, 124.4, 123.4, 120.3, 21.2; MS (ESI): 376.00
[M+H]+; HRMS (ESI): calcd for C21H18N3O2S [M+H]+ 376.1120, found 376.1100.
1.6.8. 3-methyl-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (9b).
Pale yellow solid; Yield: 86.3%; Mp = 213–214 oC; 1H NMR (300 MHz, CDCl3) δ
8.58 (d, J = 8.5 Hz, 2H), 8.12 (t, J = 7.9 Hz, 2H), 7.97 – 7.76 (m, 3H), 7.74 – 7.46 (m,
6H), 7.40 – 7.13 (m, 4H), 6.92 (s, 1H), 2.35 (s, 3H);
13
C NMR (75 MHz, CDCl3) δ
168.4, 159.2, 151.6, 139.3, 138.7, 138.6, 137.4, 134.7, 133.9, 133.7, 130.0, 129.9,
129.8, 128.84, 128.79, 128.5, 127.5, 127.0, 124.4, 121.5, 120.4, 21.2; MS (ESI):
452.00 [M+H]+; HRMS (ESI): calcd for C27H22N3O2S [M+H]+ 452.1433, found
452.1410.
1.6.9.
4-fluoro-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide
(10a).
Pale
yellow solid; Yield: 88.5%; Mp = 207–209 oC; 1H NMR (300 MHz, CDCl3) δ 9.45 (s,
1H), 8.53 (d, J = 8.5 Hz, 2H), 8.09 (d, J = 8.6 Hz, 1H), 7.92 (t, J = 7.6 Hz, 2H), 7.88 –
7.77 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 8.5 Hz,
2H), 6.81 (s, 1H);
13
C NMR (75 MHz, CDCl3) δ 160.5, 160.0, 150.6, 138.3, 135.1,
134.8, 134.2, 130.0, 130.0, 129.8, 128.4, 127.2 (d, J = 15.9 Hz), 123.4, 120.8, 116.4
(d, J = 22.7 Hz); MS (ESI): 379.95 [M+H]+; HRMS (ESI): calcd for C20H15FN3O2S
[M+H]+ 380.0869, found 380.0852.
1.6.10. 4-fluoro-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (10b).
White solid; Yield: 82.8%; Mp = 171–173 oC; 1H NMR (300 MHz, CDCl3) δ 8.60 (d,
J = 8.5 Hz, 2H), 8.12 (dd, J = 8.0, 4.2 Hz, 2H), 7.97 – 7.72 (m, 5H), 7.68 – 7.43 (m,
4H), 7.33 – 7.16 (m, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.79 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 168.4, 166.9, 163.5, 159.1, 151.8, 138.1, 137.4, 135.3, 134.8, 133.6, 130.0,
129.90, 129.88, 128.9, 128.5, 127.0 (d, J = 4.4 Hz), 121.5, 120.8, 116.3 (d, J = 22.7
SI8
Hz); MS (ESI): 455.95 [M+H]+; HRMS (ESI): calcd for C26H19FN3O2S [M+H]+
456.1182, found 456.1169.
1.6.11. 4-chloro-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (11a). Pale
yellow solid; Yield: 83.0%; Mp = 218–219 oC; 1H NMR (300 MHz, CDCl3) δ 9.44 (s,
1H), 8.53 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.7 Hz, 2H), 7.76
(d, J = 8.6 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6
Hz, 2H), 6.92 (s, 1H);
13
C NMR (75 MHz, DMSO) δ 160.5, 160.0, 150.6, 139.7,
138.3, 137.2, 135.1, 134.2, 129.8, 129.4, 128.6, 128.4, 127.3, 127.1, 123.4, 120.8; MS
(ESI): 396.00 [M+H]+; HRMS (ESI): calcd for C20H15ClN3O2S [M+H]+ 396.0574,
found 396.0557.
1.6.12. 4-chloro-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (11b).
White solid; Yield: 90.2%; Mp = 220–222 oC; 1H NMR (300 MHz, CDCl3) δ 8.61 (d,
J = 8.6 Hz, 2H), 8.13 (t, J = 8.0 Hz, 2H), 7.96 – 7.79 (m, 3H), 7.75 (d, J = 8.5 Hz, 2H),
7.67 – 7.45 (m, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.31 – 7.13 (m, 2H), 6.88 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 168.3, 159.3, 151.7, 139.1, 137.9, 137.4, 134.5, 133.5,
130.0, 129.9, 129.7, 129.1, 128.8, 128.6, 128.4, 126.9, 121.4, 120.4; MS (ESI):
471.95 [M+H]+; HRMS (ESI): calcd for C26H19ClN3O2S [M+H]+ 472.0887, found
472.0867.
1.6.13. 4-bromo-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (12a). Pale
yellow solid; Yield: 92.3%; Mp = 221–223 oC; 1H NMR (300 MHz, CDCl3) δ 9.44 (s,
1H), 8.53 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.92 (t, J = 7.8 Hz, 2H), 7.73 –
7.48 (m, 5H), 7.24 (d, J = 8.9 Hz, 2H), 6.91 (s, 1H);
13
C NMR (75 MHz, CDCl3) δ
160.5, 160.0, 150.6, 138.2, 137.8, 135.1, 134.2, 132.4, 129.8, 128.7, 128.4, 128.3,
127.3, 127.1, 123.4, 120.8; MS (ESI): 439.85 [M+H]+; HRMS (ESI): calcd for
C20H15BrN3O2S [M+H]+ 442.0048, found 442.0030.
1.6.14. 4-bromo-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (12b).
White solid; Yield: 86.7%; Mp = 236–237 oC; 1H NMR (300 MHz, CDCl3) δ 8.60 (d,
J = 8.6 Hz, 2H), 8.18 – 8.04 (m, 2H), 7.94 – 7.77 (m, 3H), 7.67 (d, J = 8.6 Hz, 2H),
SI9
7.60 – 7.46 (m, 6H), 7.33 – 7.11 (m, 2H), 6.90 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
168.2, 159.4, 151.8, 139.2, 138.5, 137.4, 134.5, 133.5, 132.1, 130.0, 129.9, 129.7,
128.9, 128.6, 128.4, 127.6, 126.9, 126.9, 121.4, 120.4; MS (ESI): 515.90 [M+H]+;
HRMS (ESI): calcd for C26H19BrN3O2S [M+H]+ 516.0381, found 516.0361.
1.6.15. 4-nitro-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (13a). Yellow
solid; Yield: 86.0%; Mp = 255–257 oC; 1H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H),
8.57 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 8.7 Hz, 1H), 8.08 –
7.88 (m, 4H), 7.67 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H); 13C NMR (75 MHz,
DMSO) δ 161.6, 159.5, 150.3, 150.2, 145.1, 139.8, 135.2, 133.9, 129.8, 128.7, 128.1,
128.1, 128.0, 125.1, 123.5, 120.2; MS (ESI): 407.00 [M+H]+; HRMS (ESI): calcd for
C20H15N4O4S [M+H]+ 407.0814, found 407.0796.
1.6.16. 4-nitro-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide (13b).
Yellow solid; Yield: 78.6%; Mp = 213–214 oC; 1H NMR (300 MHz, CDCl3) δ 8.61 (d,
J = 8.3 Hz, 2H), 8.26 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 7.5 Hz, 2H), 7.98 (d, J = 8.5 Hz,
2H), 7.90 – 7.77 (m, 3H), 7.73 – 7.42 (m, 4H), 7.25 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H);
C NMR (75 MHz, CDCl3) δ 168.2, 159.2, 151.7, 149.8, 145.4, 138.8, 137.4, 134.9,
13
133.6, 130.0, 129.9, 129.7, 128.9, 128.41, 128.38, 126.9, 124.0, 121.4, 120.7; MS
(ESI): 482.95 [M+H]+; HRMS (ESI): calcd for C26H19N4O4S [M+H]+ 483.1127,
found 483.1109.
1.6.17.
N-(4-(quinazolin-2-yl)phenyl)-4-(trifluoromethyl)benzenesulfonamide
(14a). White solid; Yield: 79.9%; Mp = 226–228 oC; 1H NMR (300 MHz, CDCl3) δ
9.49 (s, 1H), 8.57 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 8.3 Hz, 1H), 8.03 – 7.89 (m, 4H),
7.78 – 7.61 (m, 3H), 7.28 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H).;
13
C NMR (75 MHz,
CDCl3) δ 160.5, 159.9, 150.6, 142.3, 137.9, 135.8, 134.3, 129.9, 128.4, 127.7, 127.4,
127.1, 126.3, 126.2, 123.4, 121.0; MS (ESI): 429.95 [M+H]+; HRMS (ESI): calcd for
C21H15F3N3O2S [M+H]+ 430.0837, found 430.0815.
1.6.18.
N-(4-(4-phenylquinazolin-2-yl)phenyl)-4-(trifluoromethyl)benzenesulfonamide
SI10
(14b). Pale yellow solid; Yield: 80.3%; Mp = 204–206 oC; 1H NMR (300 MHz,
CDCl3) δ 8.62 (d, J = 8.6 Hz, 2H), 8.27 – 8.03 (m, 2H), 8.01 – 7.78 (m, 5H), 7.70 (d,
J = 8.3 Hz, 2H), 7.65 – 7.47 (m, 4H), 7.32 – 7.16 (m, 2H), 6.93 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 168.4, 159.1, 151.7, 142.3, 137.8, 137.4, 135.6, 133.7, 130.0, 130.0,
128.9, 128.5, 127.7, 127.1, 127.0, 126.23, 126.18, 121.5, 121.0; MS (ESI): 506.00
[M+H]+; HRMS (ESI): calcd for C27H19F3N3O2S [M+H]+ 506.1150, found
506.1128.
1.6.19. 4-methoxy-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (15a). White
solid; Yield: 75.8%; Mp = 159–160 oC; 1H NMR (300 MHz, CDCl3) δ 9.43 (s, 1H),
8.50 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.90 (t, J = 7.7 Hz, 2H), 7.78 (d, J =
8.9 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 9.3 Hz, 2H), 6.96 (s, 1H), 6.88 (d, J
= 8.8 Hz, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 160.4, 160.1, 150.6,
138.9, 134.5, 134.2, 130.3, 129.7, 129.4, 128.4, 127.2, 127.1, 120.3, 114.2, 55.5; MS
(ESI): 391.95 [M+H]+; HRMS (ESI): calcd for C21H18N3O3S [M+H]+ 392.1069,
found 392.1051.
1.6.20.
4-methoxy-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide
(15b). Pale yellow solid; Yield: 70.8%; Mp = 263–265 oC; 1H NMR (300 MHz,
CDCl3) δ 8.59 (d, J = 8.6 Hz, 2H), 8.13 (t, J = 9.4 Hz, 2H), 7.95 – 7.81 (m, 3H), 7.76
(d, J = 8.9 Hz, 2H), 7.67 – 7.47 (m, 4H), 7.23 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.9 Hz,
2H), 6.81 (s, 1H), 3.80 (s, 3H);
C NMR (75 MHz, CDCl3) δ 168.3, 163.1, 159.3,
13
151.7, 138.8, 137.4, 134.7, 133.6, 130.3, 130.0, 129.9, 129.8, 129.4, 128.9, 128.5,
127.0, 121.5, 120.4, 114.2, 55.4; MS (ESI): 468.00 [M+H]+; HRMS (ESI): calcd for
C27H22N3O3S [M+H]+ 468.1382, found 468.1362.
1.6.21. N-(4-(quinazolin-2-yl)phenyl)quinoline-8-sulfonamide (16a). Tan solid;
Yield: 84.5%; Mp = 258–260 oC; 1H NMR (300 MHz, DMSO) δ 10.53 (s, 1H), 9.56
(s, 1H), 9.14 (d, J = 2.6 Hz, 1H), 8.47 (t, J = 8.3 Hz, 2H), 8.25 (d, J = 8.4 Hz, 3H),
8.07 (d, J = 8.0 Hz, 1H), 8.02 – 7.83 (m, 2H), 7.81 – 7.55 (m, 3H), 7.25 (d, J = 8.6 Hz,
2H);
13
C NMR (75 MHz, DMSO) δ 161.5, 159.6, 151.9, 150.1, 143.1, 140.7, 137.3,
135.5, 135.1, 134.8, 132.8, 132.7, 129.2, 128.8, 128.1, 128.0, 127.8, 126.0, 123.4,
SI11
123.0, 119.1; MS (ESI): 412.95 [M+H]+; HRMS (ESI): calcd for C23H17N4O2S
[M+H]+ 413.1072, found 413.1055.
1.6.22.
N-(4-(4-phenylquinazolin-2-yl)phenyl)quinoline-8-sulfonamide
(16b).
Brown solid; Yield: 85.3%; Mp = 264–266 oC; 1H NMR (300 MHz, DMSO) δ 10.51
(s, 1H), 9.14 (d, J = 2.5 Hz, 1H), 8.46 (t, J = 8.3 Hz, 2H), 8.26 (t, J = 8.7 Hz, 3H),
7.98 (t, J = 9.0 Hz, 3H), 7.86 – 7.49 (m, 9H), 7.25 (d, J = 8.5 Hz, 2H); 13C NMR (75
MHz, DMSO) δ 168.2, 158.9, 151.9, 151.5, 143.1, 140.7, 137.31, 137.25, 135.4,
134.8, 134.7, 132.9, 132.8, 130.4, 130.3, 129.3, 128.9, 128.80, 127.96, 127.1, 126.0,
123.0, 121.1, 119.2; MS (ESI): 489.00 [M+H]+; HRMS (ESI): calcd for
C29H21N4O2S [M+H]+ 489.1385, found 489.1371.
1.6.23. N-(4-(quinazolin-2-yl)phenyl)cyclopropanesulfonamide (17a). Yellow solid;
Yield: 65.3%; Mp = 203–205 oC; 1H NMR (300 MHz, CDCl3) δ 9.48 (s, 1H), 8.63 (d,
J = 8.6 Hz, 2H), 8.14 (d, J = 8.3 Hz, 1H), 7.94 (t, J = 7.7 Hz, 2H), 7.64 (t, J = 7.4 Hz,
1H), 7.41 (d, J = 8.6 Hz, 2H), 6.64 (s, 1H), 2.63 – 2.46 (m, 1H), 1.30 – 1.16 (m, 2H),
1.07 – 0.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.5, 160.1, 150.6, 139.1, 134.7,
134.7, 129.9, 128.4, 127.3, 127.1, 123.4, 120.5, 30.1, 5.6; MS (ESI): 325.95 [M+H]+;
HRMS (ESI): calcd for C17H16N3O2S [M+H]+ 326.0963, found 326.0946.
1.6.24.
N-(4-(4-phenylquinazolin-2-yl)phenyl)cyclopropanesulfonamide
(17b).
Brown solid; Yield: 66.7%; Mp = 195–197 oC; 1H NMR (300 MHz, CDCl3) δ 8.69 (d,
J = 8.4 Hz, 2H), 8.14 (t, J = 9.1 Hz, 2H), 7.98 – 7.80 (m, 3H), 7.69 – 7.46 (m, 4H),
7.40 (d, J = 8.7 Hz, 2H), 6.66 (s, 1H), 2.69 – 2.40 (m, 1H), 1.33 – 1.10 (m, 2H), 1.07
– 0.80 (m, 2H);
13
C NMR (75 MHz, CDCl3) δ 168.3, 159.3, 151.9, 138.9, 137.5,
135.0, 133.6, 130.0, 129.9, 129.0, 128.5, 127.0, 121.5, 120.5, 30.0, 5.6; MS (ESI):
402.00 [M+H]+; HRMS (ESI): calcd for C23H20N3O2S [M+H]+ 402.1276, found
402.1258.
1.6.25. N-(4-(quinazolin-2-yl)phenyl)thiophene-2-sulfonamide (18a). White solid;
Yield: 75.2%; Mp = 213–215 oC; 1H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H), 8.55 (d,
J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 7.92 (t, J = 7.8 Hz, 2H), 7.62 (t, J = 7.4 Hz,
SI12
1H), 7.56 (d, J = 3.6 Hz, 1H), 7.53 (d, J = 5.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.00
(t, J = 6.0 Hz, 1H), 6.90 (s, 1H);
13
C NMR (75 MHz, CDCl3) δ 160.3, 160.1, 150.4,
139.6, 134.0, 133.8, 132.1, 131.7, 129.3, 128.1, 127.0, 123.2, 120.0; MS (ESI):
367.95 [M+H]+; HRMS (ESI): calcd for C18H14N3O2S2 [M+H]+ 368.0527, found
368.0509.
1.6.26. N-(4-(4-phenylquinazolin-2-yl)phenyl)thiophene-2-sulfonamide (18b). Pale
yellow solid; Yield: 77.5%; Mp = 206–208 oC; 1H NMR (300 MHz, CDCl3) δ 8.64 (d,
J = 8.5 Hz, 2H), 8.25 – 8.06 (m, 2H), 7.99 – 7.78 (m, 3H), 7.69 – 7.44 (m, 6H), 7.29
(d, J = 8.6 Hz, 2H), 7.00 – 6.93 (m, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
168.4, 159.2, 151.7, 139.2, 138.3, 137.4, 135.2, 133.7, 133.0, 132.5, 130.05, 129.96,
129.9, 128.8, 128.5, 127.3, 127.04, 126.97, 121.5, 120.8; MS (ESI): 443.95 [M+H]+;
HRMS (ESI): calcd for C24H18N3O2S2 [M+H]+ 444.0840, found 444.0819.
1.6.27.
5-bromo-N-(4-(quinazolin-2-yl)phenyl)thiophene-2-sulfonamide
(19a).
White solid; Yield: 69.3%; Mp = 183–185 oC; 1H NMR (300 MHz, CDCl3) δ 9.48 (s,
1H), 8.60 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 8.9 Hz, 1H), 7.95 (t, J = 7.4 Hz, 2H), 7.65
(t, J = 7.3 Hz, 1H), 7.38 – 7.28 (m, 3H), 6.97 (d, J = 4.0 Hz, 1H), 6.90 (s, 1H);
13
C
NMR (75 MHz, CDCl3) δ 160.5, 1560.0, 150.7, 138.0, 135.4, 134.3, 133.1, 130.3,
129.9, 128.4, 127.4, 127.1, 123.5, 120.9, 120.7; MS (ESI): 445.85 [M+H]+; HRMS
(ESI): calcd for C18H13BrN3O2S2 [M+H]+ 445.9633, found 445.9613.
1.6.28. 5-bromo-N-(4-(4-phenylquinazolin-2-yl)phenyl)thiophene-2-sulfonamide
(19b). Pale yellow solid; Yield: 70.8%; Mp = 216–218 oC; 1H NMR (300 MHz,
CDCl3) δ 8.65 (d, J = 8.7 Hz, 2H), 8.14 (t, J = 9.0 Hz, 2H), 7.98 – 7.76 (m, 3H), 7.69
– 7.44 (m, 4H), 7.38 – 7.27 (m, 3H), 6.96 (d, J = 4.0 Hz, 1H), 6.90 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 168.4, 159.1, 151.7, 139.8, 137.8, 137.4, 135.6, 133.7, 133.1,
130.3, 130.1, 123.0, 128.9, 128.5, 127.1, 127.0, 121.5, 120.9, 120.6; MS (ESI):
521.85 [M+H]+; HRMS (ESI): calcd for C24H17BrN3O2S2 [M+H]+ 523.9925, found
523.9908.
1.6.29.
4-(tert-butyl)-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide
SI13
(20a).
Pale yellow solid; Yield: 77.6%; Mp = 210–212 oC; 1H NMR (300 MHz, CDCl3) δ
9.44 (s, 1H), 8.51 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.91 (t, J = 7.7 Hz,
2H), 7.78 (d, J = 8.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.27
(d, J = 7.7 Hz, 2H), 7.01 (s, 1H), 1.28 (s, 11H); 13C NMR (75 MHz, CDCl3) δ 160.4,
160.1, 156.9, 150.6, 138.9, 135.9, 134.4, 134.2, 129.7, 128.4, 127.9, 127.2, 127.1,
126.1, 123.4, 120.1, 35.1, 30.9; MS (ESI): 418.00 [M+H]+; HRMS (ESI): calcd for
C24H24N3O2S [M+H]+ 418.1589, found 418.1572.
1.6.30. 4-(tert-butyl)-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide
(20b).
Pale yellow solid; Yield: 79.5%; Mp = 208–210 oC; 1H NMR (300 MHz,
CDCl3) δ 8.58 (d, J = 8.7 Hz, 2H), 8.13 (t, J = 9.1 Hz, 2H), 7.94 – 7.81 (m, 3H), 7.76
(d, J = 8.3 Hz, 2H), 7.65 – 7.49 (m, 4H), 7.44 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 6.2 Hz,
2H), 1.28 (s, 9H);
13
C NMR (75 MHz, CDCl3) δ 168.3, 159.4, 156.9, 151.8, 138.8,
137.4, 135.9, 134.7, 133.6, 130.0, 129.9, 129.8, 128.9, 128.5, 127.1, 126.9, 126.1,
121.5, 120.7, 120.0, 35.0, 30.9; MS (ESI): 494.05 [M+H]+; HRMS (ESI): calcd for
C30H28N3O2S [M+H]+ 494.1902, found 494.1880.
1.6.31. 1-methyl-N-(4-(quinazolin-2-yl)phenyl)-1H-imidazole-4-sulfonamide (21a).
Brown solid; Yield: 58.3%; Mp = 284–286 oC; 1H NMR (300 MHz, DMSO) δ 10.60
(s, 1H), 9.62 (s, 1H), 8.39 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 7.9 Hz, 1H), 8.04 – 7.85 (m,
3H), 7.81 – 7.60 (m, 2H), 7.31 (d, J = 8.6 Hz, 2H), 3.64 (s, 3H); 13C NMR (75 MHz,
DMSO) δ 161.6, 159.8, 150.2, 143.2, 141.1, 140.3, 135.1, 132.3, 129.4, 128.2, 128.1,
127.8, 126.2, 123.5, 118.5, 33.9; MS (ESI): 365.95 [M+H]+; HRMS (ESI): calcd for
C18H16N5O2S [M+H]+ 366.1025, found 366.1010.
1.6.32.
1-methyl-N-(4-(4-phenylquinazolin-2-yl)phenyl)-1H-imidazole-4-sulfonamide
(21b). Brown solid; Yield: 60.4%; Mp = 313–315 oC; 1H NMR (300 MHz, DMSO) δ
10.59 (s, 1H), 8.42 (d, J = 8.6 Hz, 2H), 8.13 – 7.95 (m, 3H), 7.92 (s, 1H), 7.85 – 7.84
(m, 2H), 7.73 (s, 1H), 7.69 – 7.64 (m, 4H), 7.32 (d, J = 8.6 Hz, 2H), 3.64 (s, 3H); 13C
NMR (75 MHz, DMSO) δ 168.3, 159.1, 151.6, 141.1, 140.3, 135.7, 134.7, 132.3,
130.5, 130.3, 129.4, 129.0, 128.9, 128.0, 127.2, 126.2, 121.2, 120.9, 118.5, 33.9; MS
SI14
(ESI): 442.00 [M+H]+; HRMS (ESI): calcd for C24H20N5O2S [M+H]+ 442.1338,
found 442.1325.
1.6.33. 3,5-dimethyl-N-(4-(quinazolin-2-yl)phenyl)isoxazole-4-sulfonamide (22a).
Pale yellow solid; Yield: 83.8%; Mp = 177–179 oC; 1H NMR (300 MHz, CDCl3) δ
9.45 (s, 1H), 8.58 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 7.93 (t, J = 7.7 Hz,
2H), 7.63 (t, J = 7.1 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.03 (s, 1H), 2.53 (s, 3H), 2.35
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 160.4, 160.0, 157.6, 150.5, 138.7, 134.8,
134.2, 129.6, 128.4, 127.2, 127.1, 123.4, 120.8, 115.7, 12.6, 10.7; MS (ESI): 380.95
[M+H]+; HRMS (ESI): calcd for C19H17N4O3S [M+H]+ 381.1021, found 381.1004.
1.6.34.
3,5-dimethyl-N-(4-(4-phenylquinazolin-2-yl)phenyl)isoxazole-4-sulfonamide
(22b). Pale yellow solid; Yield: 86.4%; Mp = 207–209 oC; 1H NMR (300 MHz,
DMSO) δ 8.67 (d, J = 8.6 Hz, 2H), 8.21 – 8.12 (m, 2H), 7.99 – 7.77 (m, 3H), 7.69 –
7.50 (m, 4H), 7.25 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 2.52 (s, 3H), 2.35 (s, 3H);
13
C
NMR (75 MHz, CDCl3) δ 174.2, 168.4, 158.9, 157.4, 151.7, 137.44, 137.35, 135.9,
133.7, 130.1, 130.0, 128.9, 128.5, 127.2, 127.0, 121.5, 115.3, 12.6, 10.8; MS (ESI):
457.00 [M+H]+; HRMS (ESI): calcd for C25H21N4O3S [M+H]+ 457.1334, found
457.1314.
1.6.35. 3,4-dimethoxy-N-(4-(quinazolin-2-yl)phenyl)benzenesulfonamide (23a).
White solid; Yield: 90.1%; Mp = 202–205 oC; 1H NMR (300 MHz, CDCl3) δ 9.44 (s,
1H), 8.52 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 1H), 7.91 (t, J = 7.7 Hz, 2H), 7.62
(t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.34 – 7.18 (m, 2H), 6.97 (s, 1H), 6.84 (d,
J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.4, 160.0,
152.8, 150.6, 149.0, 139.0, 134.6, 134.1, 130.3, 129.7, 128.4, 127.2, 127.1, 123.4,
121.4, 120.5, 110.4, 109.5, 56.1, 56.0; MS (ESI): 422.00 [M+H]+; HRMS (ESI): calcd
for C22H20N3O4S [M+H]+ 422.1175, found 422.1159.
1.6.36. 3,4-dimethoxy-N-(4-(4-phenylquinazolin-2-yl)phenyl)benzenesulfonamide
(23b). Pale yellow solid; Mp = Yield: 90.3%; 156–158 oC; 1H NMR (300 MHz,
SI15
DMSO) δ 10.45 (s, 1H), 8.43 (d, J = 8.7 Hz, 2H), 8.08 – 7.99 (m, 3H), 7.92 – 7.74 (m,
2H), 7.68 – 7.60 (m, 4H), 7.39 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 – 7.28 (m, 3H), 7.05 (d,
J = 8.6 Hz, 1H), 3.75 (s, 6H);
13
C NMR (75 MHz, DMSO) δ 168.3, 158.9, 152.7,
151.5, 149.0, 140.9, 137.3, 134.7, 133.2, 131.2, 130.5, 130.3, 129.6, 129.0, 128.9,
128.0, 127.2, 121.2, 121.1, 119.6, 111.3, 109.7, 56.1; MS (ESI): 489.05 [M+H]+;
HRMS (ESI): calcd for C28H24N3O4S [M+H]+ 498.1488, found 498.1466.
1.6.37. N-(4-(quinazolin-2-yl)phenyl)pyridine-3-sulfonamide (24a). White solid;
Yield: 55.8%; Mp = 249–251 oC; 1H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 9.63
(s, 1H), 8.95 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 3.8 Hz, 1H), 8.43 (d, J = 8.6 Hz, 2H),
8.18 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 3.5 Hz, 2H), 7.76 –
7.64 (m, 1H), 7.60 (dd, J = 7.9, 4.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H); 13C NMR (75
MHz, DMSO) δ 161.6, 159.5, 154.1, 150.2, 147.5, 134.0, 136.1, 135.2, 135.1, 133.8,
129.7, 128.2, 128.1, 128.0, 124.8, 123.6, 120.1; MS (ESI): 363.05 [M+H]+; HRMS
(ESI): calcd for C19H15N4O2S [M+H]+ 363.0916, found 363.0910.
1.6.38. N-(4-(4-phenylquinazolin-2-yl)phenyl)pyridine-3-sulfonamide (24b). Pale
yellow solid; Yield: 55.3%; Mp = 271–273 oC; 1H NMR (300 MHz, DMSO) δ 10.84
(s, 1H), 8.95 (s, 1H), 8.77 (d, J = 4.1 Hz, 1H), 8.46 (d, J = 8.3 Hz, 2H), 8.18 (d, J =
7.9 Hz, 1H), 8.11 – 7.90 (m, 3H), 7.83 (s, 2H), 7.72 – 7.61 (m, 5H), 7.31 (d, J = 8.3
Hz, 2H);
13
C NMR (75 MHz, DMSO) δ 168.3, 158.8, 154.0, 151.5, 147.5, 139.9,
137.3, 136.1, 135.2, 134.7, 133.9, 130.4, 130.3, 129.8, 128.9, 128.1, 127.2, 124.8，
121.2, 120.1; MS (ESI): 438.95 [M+H]+; HRMS (ESI): calcd for C25H19N4O2S
[M+H]+ 439.1229, found 439.1215.
1.6.39.
N-(4-(N-(4-(quinazolin-2-yl)phenyl)sulfamoyl)phenyl)acetamide
(25a).
White solid; Yield: 63.1%; Mp = 261–262 oC; 1H NMR (300 MHz, DMSO) δ 10.55 (s,
1H), 10.28 (s, 1H), 9.61 (s, 1H), 8.39 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H),
7.97 (d, J = 3.4 Hz, 2H), 7.85 – 7.56 (m, 5H), 7.27 (d, J = 8.6 Hz, 2H), 2.01 (s, 3H);
C NMR (75 MHz, DMSO) δ 169.4, 161.5, 159.7, 150.2, 143.7, 140.7, 135.1, 133.2,
13
133.0, 129.6, 128.4, 128.1, 127.8, 123.5, 119.4, 119.0, 24.4; MS (ESI): 419.00
[M+H]+; HRMS (ESI): calcd for C22H19N4O3S [M+H]+ 419.1178, found 419.1159.
SI16
1.6.40. N-(4-(N-(4-(4-phenylquinazolin-2-yl)phenyl)sulfamoyl)phenyl)acetamide
(25b). Pale yellow solid; Yield: 64.2%; Mp = 287–288 oC; 1H NMR (300 MHz,
DMSO) δ 10.53 (s, 1H), 10.27 (s, 1H), 8.42 (d, J = 8.5 Hz, 2H), 8.15 – 7.92 (m, 3H),
7.83 (d, J = 3.5 Hz, 2H), 7.79 – 7.52 (m, 8H), 7.27 (d, J = 8.6 Hz, 2H), 2.01 (s, 3H);
C NMR (75 MHz, DMSO) δ 169.5, 168.1, 158.8, 151.5, 143.6, 140.7, 137.2, 134.5,
13
133.3, 133.1, 130.3, 130.2, 129.6, 128.8, 128.4, 127.8, 127.0, 121.1, 119.4, 119.0; MS
(ESI): 495.00 [M+H]+; HRMS (ESI): calcd for C28H23N4O3S [M+H]+ 495.1491,
found 495.1468.
1.7. General procedure for urea derivatives (26-34)
To a solution of 5b (1 mmol) in toluene (8 mL) was added isocyanate (1.1 mmol,
1.1 equiv) in portions, at room temperature, followed, stired at 70 oC for 7h. Remove
toluene under reduced pressure. To the residue, ethyl ether (15 mL) was added,
filtered and washed with ethyl ether, furnished target compounds (26-34).
1.7.1. 1-(3-acetylphenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (26). White
solid; Yield: 86.5%; Mp = 254–256 oC; 1H NMR (300 MHz, DMSO) δ 9.05 (s, 1H),
8.98 (s, 1H), 8.53 (d, J = 8.7 Hz, 2H), 8.18 – 7.93 (m, 4H), 7.93 – 7.81 (m, 2H), 7.74
– 7.55 (m, 8H), 7.45 (d, J = 7.9 Hz, 1H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO) δ
198.1, 168.3, 159.3, 152.7, 151.7, 142.5, 140.3, 137.8, 137.4, 134.7, 131.4, 130.4,
130.3, 129.6, 129.5, 129.0, 128.9, 127.8, 127.2, 123.3, 122.5, 121.2, 118.3, 117.9,
27.1; MS (ESI): 459.00 [M+H]+; HRMS (ESI): calcd for C29H23N4O2 [M+H]+
459.1821, found 459.1804.
1.7.2. 1-(4-(4-phenylquinazolin-2-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
(27). White solid; Yield: 82.7%; Mp = 262–264 oC; 1H NMR (300 MHz, DMSO) δ
9.07 (s, 1H), 8.97 (s, 1H), 8.53 (d, J = 8.2 Hz, 2H), 8.16 – 7.93 (m, 3H), 7.86 (s, 2H),
7.76 – 7.45 (m, 8H), 7.29 (d, J = 8.2 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 168.3,
159.3, 152.7, 151.6, 143.1, 142.5, 139.2, 137.4, 134.7, 131.4, 130.4, 130.3, 129.5,
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129.0, 128.8, 127.8, 127.2, 122.1, 121.2, 119.9, 118.3; MS (ESI): 459.00 [M+H]+;
HRMS (ESI): calcd for C28H20F3N4O2 [M+H]+ 501.1538, found 501.1520.
1.7.3.
1-(-4-methylcyclohexyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea
(28).
White solid; Yield: 47.9%; Mp = 268–269 oC; 1H NMR (300 MHz, DMSO) δ 8.61 (s,
1H), 8.45 (d, J = 8.7 Hz, 2H), 8.15 – 7.92 (m, 3H), 7.85 (s, 2H), 7.72 – 7.58 (m, 4H),
7.55 (d, J = 8.7 Hz, 2H), 6.08 (d, J = 7.5 Hz, 1H), 3.51 – 3.32 (m, 1H), 1.86 (d, J =
10.9 Hz, 2H), 1.66 (d, J = 11.8 Hz, 2H), 1.31 (s, 1H), 1.21 – 0.90 (m, 4H), 0.86 (d, J =
6.4 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 168.2, 159.4, 154.6, 151.7, 143.6, 137.5,
134.6, 130.4, 130.3, 129.4, 129.0, 128.8, 127.6, 127.2, 121.1, 117.5, 48.6, 34.0, 33.3,
31.8, 22.5; MS (ESI): 437.20 [M+H]+; HRMS (ESI): calcd for
C28H29N4O
[M+H]+ 437.2341, found 437.2319.
1.7.4. 1-(2-chlorophenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (29). White
solid; Yield: 76.0%; Mp = 258–260 oC; 1H NMR (300 MHz, DMSO) δ 9.72 (s, 1H),
8.55 (d, J = 8.6 Hz, 2H), 8.39 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.13 – 7.93 (m, 3H),
7.87 (s, 2H), 7.75 – 7.55 (m, 6H), 7.46 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H),
7.04 (t, J = 7.7 Hz, 1H);
13
C NMR (75 MHz, DMSO) δ 168.21 (s), 159.2, 152.3,
151.6, 142.4, 137.4, 136.1, 134.6, 131.5, 130.4, 130.3, 129.5, 129.0, 128.8, 128.0,
127.8, 127.1, 123.9, 122.4, 121.8, 121.2, 118.2; MS (ESI): 451.10 [M+H]+; HRMS
(ESI): calcd for C27H20ClN4O [M+H]+ 451.1326, found 451.1304.
1.7.5. 1-(4-chlorophenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (30). White
solid; Yield: 77.1%; Mp = 270–271 oC; 1H NMR (300 MHz, DMSO) δ 9.03 (s, 1H),
8.88 (s, 1H), 8.52 (d, J = 7.9 Hz, 2H), 8.10 – 7.97 (m, 3H), 7.87 (s, 2H), 7.65 (s, 6H),
7.50 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H);
13
C NMR (75 MHz, DMSO) δ
168.2, 159.3, 152.6, 151.7, 142.5, 138.9, 137.4, 134.7, 131.3, 130.4, 130.3, 129.5,
129.0, 128.9, 127.8, 127.2, 125.9, 121.2, 120.2, 118.2; MS (ESI): 451.05 [M+H]+;
HRMS (ESI): calcd for C27H20ClN4O [M+H]+ 451.1326, found 451.1303.
1.7.6.
1-(4-isopropylphenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea
(31).
White solid; Yield: 85.0%; Mp = 226–228 oC; 1H NMR (300 MHz, DMSO) δ 8.94 (s,
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1H), 8.63 (s, 1H), 8.52 (d, J = 8.6 Hz, 2H), 8.13 – 7.94 (m, 3H), 7.86 (s, 2H), 7.71 –
7.55 (m, 6H), 7.37 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 2.93 – 2.72 (m, 1H),
1.17 (d, J = 6.9 Hz, 6H);
C NMR (75 MHz, DMSO) δ 168.2, 159.3, 152.7, 151.7,
13
142.8, 142.5, 137.5, 137.4, 134.6, 131.1, 130.4, 130.3, 129.5, 129.0, 128.8, 127.7,
127.1, 126.9, 121.1, 118.9, 118.0, 33.1, 24.4; MS (ESI): 459.20 [M+H]+; HRMS (ESI):
calcd for C30H27N4O [M+H]+ 459.2185, found 459.2163.
1.7.7. 1-(3-chloro-4-fluorophenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (32).
White solid; Yield: 83.3%; Mp = 260–262 oC; 1H NMR (300 MHz, DMSO) δ 9.08 (s,
1H), 8.93 (s, 1H), 8.53 (d, J = 8.6 Hz, 2H), 8.16 – 7.93 (m, 3H), 7.93 – 7.76 (m, 3H),
7.73 – 7.55 (m, 6H), 7.33 (d, J = 7.0 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 168.2,
159.2, 154.4, 152.6, 151.6, 151.2, 142.4, 137.3 (d, J = 19.5 Hz), 134.6, 131.5, 130.4,
130.3, 129.4, 128.9, 128.8, 127.7, 127.1, 121.2, 120.1, 119.6 (d, J = 18.2 Hz), 119.0 (d,
J = 6.5 Hz), 118.3, 117.2 (d, J = 21.7 Hz); MS (ESI): 469.10 [M+H]+; HRMS (ESI):
calcd for C27H19ClFN4O [M+H]+ 469.1231, found 469.1208.
1.7.8. 1-(4-ethoxycarbonyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (33). White
solid; Yield: 59.1%; Mp = 252–253 oC; 1H NMR (300 MHz, DMSO) δ 9.15 (s, 1H),
9.11 (s, 1H), 8.53 (d, J = 8.6 Hz, 2H), 8.14 – 7.93 (m, 3H), 7.93-7.79 (m, 4H),
7.73-7.51 (m, 8H), 4.26 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, DMSO) δ 168.2, 165.8, 159.2, 152.3, 151.6, 144.5, 142.3, 137.4, 134.53 (s),
131.6, 130.7, 130.3, 129.5, 128.9, 128.8, 127.7, 127.1, 123.3, 121.1, 118.3, 117.7,
60.6, 14.6; MS (ESI): 489.20 [M+H]+; HRMS (ESI): calcd for
C30H25N4O3
[M+H]+ 489.1927, found 489.1906.
1.7.9. 1-(4-ethoxyphenyl)-3-(4-(4-phenylquinazolin-2-yl)phenyl)urea (34). White
solid; Yield: 81.1%; Mp = 289–291 oC; 1H NMR (300 MHz, DMSO) δ 8.91 (s, 1H),
8.59 – 8.42 (m,1H), 8.13 – 7.95 (m, 3H), 7.86 (s, 2H), 7.64 (brs, 5H), 7.35 (d, J = 8.5
Hz, 2H), 6.85 (d, J = 7.5 Hz, 2H), 3.96 (q, J = 6.7 Hz, 2H), 1.29 (t, J = 6.7 Hz, 3H);
C NMR (75 MHz, DMSO) δ 168.2, 159.3, 154.2, 152.8, 151.7, 142.9, 137.4, 134.6,
13
132.7, 131.0, 130.4, 130.3, 129.4, 129.0, 128.8, 127.7, 127.2, 121.1, 120.6, 118.0,
114.9, 63.5, 15.1; MS (ESI): 461.15 [M+H]+; HRMS (ESI): calcd for
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C29H25N4O2
[M+H]+ 461.1978, found 461.1960.
1.8. Synthesis of amide (35)
To a solution of 5b (1 mmol) and TEA (0.2 mL, 1.5 mmol) in DCM (8 mL) was
added furan-2-carbonyl chloride (1.1 mmol, 1.1 equiv) dropwise, at room temperature,
followed, stired at room temperature for 3h. Remove DCM under reduced pressure.
To the residue, ethyl acetate (50 mL) was added. The solution was washed with
saturated NaHCO3, brine, and dried over anhydrous Na2SO4. Remove ethyl acetate
under reduced pressure. The residue was subjected to silica gel column
chromatography (2.5% MeOH/DCM), and furnished target compounds (35). White
solid; Yield: 61.6%; Mp = 199–201 oC; 1H NMR (300 MHz, CDCl3) δ 8.74 (d, J = 7.7
Hz, 2H), 8.34 – 8.03 (m, 3H), 8.00 – 7.74 (m, 4H), 7.67 – 7.44 (m, 5H), 7.32 – 7.21
(m, 2H), 6.58 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 168.3, 159.5, 155.9, 151.8, 147.7,
144.2, 139.5, 137.6, 134.1, 133.5, 130.1, 129.9, 129.6, 128.9, 128.4, 127.0, 126.8,
121.5, 119.4, 115.4, 112.6; MS (ESI): 392.10 [M+H]+; HRMS (ESI): calcd for
C25H18N3O2 [M+H]+ 392.1399, found 392.1379.
1.9. Synthesis of 4-alkly-5,7-dimethoxylquinazoline derivatives (38-40)
1.9.1. (E)-5,7-dimethoxy-2-methyl-4-(2-nitrostyryl)quinazoline (38)
A mixture of 37 (2.28g, 10 mmol), 2-nitrobenzoadehyde (1.8g, 12 mmol, 1.2
equiv), and glacial acid (50 mL) was refluxed overnight. Remove solvent, the residue
was subjected to silica gel column chromatography (40% EA/PE) afforded 38 as
yellow solid, 2.8g, Yield: 79.8%. Mp = 231–233 oC; 1H NMR (300 MHz, CDCl3) δ
8.41 (d, J = 15.6 Hz, 1H), 8.33 (d, J = 15.6 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.82 (d,
J = 7.5 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 6.97 (s, 1H), 6.52 (d,
J = 2.0 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
175.1, 164.1, 160.2, 158.0, 155.3, 148.6, 132.9, 132.6, 132.5, 132.2, 129.0, 128.9,
SI20
124.6, 109.7, 99.5, 98.8, 55.9, 55.7, 25.9; MS (ESI): 352.10 [M+H]+; HRMS (ESI):
calcd for C19H18N3O4 [M+H]+ 352.1297, found 352.1277.
1.9.2. 2-(2-(5,7-dimethoxy-2-methylquinazolin-4-yl)ethyl)aniline (39)
Compound 38 (350 mg, 1mmol) was dissolved in methanol and 10% Pd/C (35
mg) was added. Followed remove the system’s air and flashed with hydrogen two
times, kept hydrogen at 1atm for 5 h at room temperature. The resulting mixture
filtered, removed solvent furnished 39 as pale yellow solid. 281 mg, Yield: 86.7%.
Mp = 153–155 oC; 1H NMR (300 MHz, CDCl3) δ 7.15 (dd, J = 7.4, 1.0 Hz, 1H), 7.06
(td, J = 7.7, 1.6 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.75 (dd, J = 7.4, 1.1 Hz, 1H), 6.71
(d, J = 7.6 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.64 (t, J = 9.0
Hz, 1H), 2.94 (t, J = 9.0 Hz, 1H), 2.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.3,
163.8, 158.1, 154.5, 144.5, 129.5, 127.0, 126.1, 118.3, 115.4, 110.5, 99.2, 99.1, 98.9,
55.8, 55.6, 38.6, 30.9, 26.0; MS (ESI): 324.10 [M+H]+; HRMS (ESI): calcd for
C19H22N3O2 [M+H]+ 324.1712, found 324.1693.
1.9.3.
N-(2-(2-(5,7-dimethoxy-2-methylquinazolin-4-yl)ethyl)phenyl)isonicotinamide
(40)
To a solution of 39 (160 mg, 0.5 mmol) and TEA (0.1 mL, 0.75 mmol, 1.5 equiv)
in DCM (8 mL) was added isonicotinoyl chloride (77 mg, 0.55 mmol, 1.1 equiv), at
room temperature, followed, stired at room temperature for 3h. Remove DCM under
reduced pressure. To the residue, ethyl acetate (50 mL) was added. The solution was
washed with saturated NaHCO3, brine, and dried over anhydrous Na2SO4. Remove
ethyl acetate under reduced pressure. The residue was subjected to silica gel column
chromatography (5% MeOH/DCM), and furnished 40 as white solid. 312 mg, Yield:
73.0%. Mp = 196–198 oC; 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 8.82 (d, J =
5.6 Hz, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 4.8 Hz, 2H), 7.32 (d, J = 7.8 Hz,
SI21
1H), 7.16 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 3.98
(s, 3H), 3.91 (s, 3H), 3.88 (t, J = 7.0 Hz, 2H), 3.22 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H);
C NMR (75 MHz, CDCl3) δ 168.3, 164.2, 164.0, 163.1, 158.3, 154.2, 150.5, 142.4,
13
134.8, 134.0, 129.4, 126.7, 125.8, 124.6, 121.4, 110.6, 99.2, 99.1, 55.9, 55.7, 39.61 (s),
28.4, 25.6; MS (ESI): 429.15 [M+H]+; HRMS (ESI): calcd for
C25H25N4O3
[M+H]+ 429.1927, found 429.1900.
2. Biological assays
2.1. Materials
Stock solutions of compounds were prepared with dimethylsulfoxide (DMSO,
Sigma) and diluted with RPMI-1640 medium containing 10% fetal bovine serum
(FBS). MTT (3-(4,5-dimethylthylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide),
Concanavalin A (ConA) was purchased from Sigma (St Louis, Mo). Cyclosporin A
(CsA) was obtained from Sandoz Ltd (Basel, Switzerland).
2.2. Animals
Female BALB/c mice (6–8 weeks old, 18–22g) were supplied by the Laboratory
Animal Center of Yangzhou University (Jiangsu, China). They were maintained with
free access to pellet food and water in plastic cages at 21±2 oC and kept on a 12h
light-dark cycle. Animal welfare and experimental procedures were carried out strictly
in accordance with the ‘Guide for the Care and Use of Laboratory Animals’ (National
Research Council, 1996) and the related ethical regulations of our university. All
efforts were made to minimize the animals’ suffering and to reduce the number of
animals used.
2.3. MTT assay [1]
Fresh spleen cells were obtained from BALB/c mice (male, 6–8 weeks old).
5×105 spleen cells were cultured in triplicate in 96-well flat plates with 200 μL
SI22
RPMI-1640 media containing 10% FBS, 100 U/mL penicillin, and 100 U/mL
streptomycin in a humidified, 37 oC, 5% CO2-containing incubator for 48 h in the
presence or absence of various concentrations of compounds. The cells with media
alone were used as control. 20 μL MTT (5 mg/mL) reagent was added 4 h before the
end of culture. Removed supernatant after centrifuge and DMSO (200 μL) was added.
Shaking to make a clear solution and the absorbance value at 570 nm was collected by
microplate reader. The percentage of cell growth inhibition was determined using the
following formula:
Cytotoxicity (%) = (1－[Compounds (OD570)－Background (OD570)] / [Control
(OD570)－Background (OD570)])×100
The compounds were dissolved in dimethylsulfoxide (DMSO) followed by
dilution with culture medium to desired concentrations, and DMSO final
concentration was 0.1%. DMSO at 0.1% was added into control group and showed no
effects on cells.
2.4. ConA-induced T cell and LPS-induced B cell proliferation assay [1]
Fresh spleen cells were obtained from BALB/c mice (male, 6–8 weeks). 5×105
Spleen cells were cultured at the same conditions as those mentioned above. The
cultures were unstimulated or stimulated with 5 mg/mL ConA or 10 mg/ml of
lipopolysaccharide (LPS) to induce T cell or B cell proliferative response,
respectively. The compounds were added to cultures with desired concentrations to
test their bio-activities. The cells stimulated with ConA or LPS were used as control
and CsA as positive control. Proliferation was assessed by MTT assay as above (2.3.).
2.5. Statistics
All experiments were repeated 3–5 times with the similar outcome. The p-values
SI23
between two experimental groups were tested by two-tailed Student’s t-test, and
p-values of 0.05 or less were considered to be statistically significant.
References
1. Liu, G.-B.; Xu, J.-L.; He, C.-C.; Chen, G.; Xu, Q.; Xu, H.-X.; Li, J.-X. Bioorg. Med. Chem.
2009, 17, 5433.
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The 1H NMR spectrums of compounds 2-8, 35, 38-40
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