3476 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9
Feng et al.
(m, 1H), 7.35-7.11 (m, 4H), 6.44-6.33 (m, 2H), 5.53 (s, 1H),
3.88-3.83 (dd, 2H), 2.86-2.78 (m, 2H), 2.25-2.11 (m, 2H).
3-Methoxy-7-(2-methoxyphenyl)-7,10-dihydro-5H-benzo[h]-
thiazolo[2,3-b]quinazolin-9(6H)-one (5i). In the same manner
as described in the preparation of 5a, 5i was prepared from
2-(2-methoxybenzylidene)-5-(benzyloxy)-1-tetralone (3i). Yield:
62.3%. 1H NMR (CDCl3): δ 7.63-7.60 (m, 1H), 7.32-7.21 (m,
2H), 7.01-6.97 (m, 2H), 6.78-6.75 (m, 2H), 5.32 (s, 1H), 3.81 (s,
3H), 3.75 (s, 3H), 3.74-3.69 (dd, 2H), 2.72-2.51 (m, 2H),
2.20-2.10 (m, 1H), 1.91-1.80 (m, 1H).
4-(Benzyloxy)-7-(2-methoxyphenyl)-7,10-dihydro-5H-benzo[h]-
thiazolo[2,3-b]quinazolin-9(6H)-one (5j). In the same manner
as described in the preparation of 5a, 5j was prepared from
2-(2-methoxybenzylidene)-5-(benzyloxy)-1-tetralone (3j). Yield:
65.3%. 1H NMR (CDCl3): δ 7.65-7.63 (m, 1H), 7.54-7.14 (m,
8H), 6.95-6.68 (m, 3H), 5.97 (s, 1H), 5.13 (s, 2H), 3.85 (s, 3H),
3.84-3.74 (dd, 2H), 2.82-2.75 (m, 2H), 2.36-1.98 (m, 2H).
7-(2-Methoxyphenyl)-9-oxo-6,7,9,10-tetrahydro-5H-benzo[h]-
thiazolo[2,3-b]quinazolin-4-ylbiphenyl-2-carboxylate (5k). In the
same manner as described in the preparation of 5a, 5k was prepared
from 2-(2-methoxybenzylidene)-5-(biphenyl-2-carboxylate)-1-tet-
ralone (3k). Yield: 62.3%. 1H NMR (CDCl3): δ 7.96 (d, 1H, J =
7.5 Hz), 7.82 (d, 1H, J = 7.5 Hz), 7.61-7.56 (m, 1H), 7.49-7.33
(m, 6H), 7.29-7.17 (m, 4H), 6.95-6.87 (m, 2H), 6.70 (d, 1H, J =
8.1 Hz), 5.54 (s, 1H), 3.99 (s, 3H), 3.97-3.68 (dd, 2H), 2.46-2.34
(m, 2H), 2.12-2.09 (m, 1H), 1.98-1.92 (m, 1H).
(E)-9-(3-Fluorobenzylidene)-5-(3-fluorophenyl)-6,7,8,9-tetra-
hydro-2H-thiazolo[2,3-b]quinazolin-3(5H)-one (5l). In the same
manner as described in the preparation of 5a, 5l was prepared
from 2,6-bis(3-fluorobenzylidene)cyclohexanone (3l). Yield:
67.3%. 1H NMR (CDCl3): δ 7.71 (d, 1H, J = 7.8 Hz), 7.63-
7.56 (m, 2H), 7.39-7.11 (m, 4H), 7.10 (d, 1H, J = 8.1 Hz), 5.17
(s, 1H), 3.04-3.00 (m, 2H), 2.68-2.64 (m, 2H), 2.20-2.13 (m,
2H).
5-(2-Methoxyphenyl)-7-phenyl-2H-thiazolo[3,2-a]pyrimidin-
3(5H)-one (5m). In the same manner as described in the prepara-
tion of 5a, 5m was prepared from 3-(2-methoxyphenyl)-1-phenyl-
prop-2-en-1-one (3m). Yield: 62.8%. 1H NMR (CDCl3): δ 7.92-
7.64 (m, 3H), 7.57-7.35 (m, 2H), 7.57-7.35 (m, 2H), 7.06 -6.96
(m, 2H), 6.01 (d, 1H, J = 4.2 Hz), 5.91 (d, 1H, J = 4.2 Hz), 3.74
(m, 3H), 3.87-3.73 (dd, 2H).
7-(3-Methoxyphenyl)-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-9(6H)-one (5n). In the same manner as described in
the preparation of 5a, 5n was prepared from 2-(3-methoxy-
benzylidene)-1-tetralone (3n). Yield: 73.3%. 1H NMR (CDCl3):
δ7.97 (d, 1H, J =8.4Hz), 7.36-7.10 (m,4H), 6.83-6.79 (m, 2H),
6.83-6.79 (m, 2H), 5.56 (s, 1H), 3.89-3.72 (dd, 2H), 3.83 (s, 3H),
2.780-2.67 (m, 2H), 2.21-2.03 (m, 2H).
7-(4-Methoxyphenyl)-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-9(6H)-one (5o). In the same manner as described in
the preparation of 5a, 5o was prepared from 2-(4-methoxy-
benzylidene)-1-tetralone (3o). Yield: 74.8%. 1H NMR (CDCl3):
δ7.95 (d, 1H, J =7.5Hz), 7.36-7.29 (m,3H), 7.23-7.17 (m, 1H),
7.11-7.09 (m, 1H), 6.89-6.84 (m, 2H), 5.54 (s, 1H), 3.86-3.68
(dd, 2H), 3.80 (s, 3H), 2.86-2.65 (m, 2H), 2.25-2.01 (m, 2H).
3-Methoxy-7-(3-fluorophenyl)-7,10-dihydro-5H-benzo[h]-
thiazolo[2,3-b]quinazolin-9(6H)-one (5p). In the same manner
as described in the preparation of 5a, 5p was prepared from
(3-fluorobenzylidene)-6-methoxy-1-tetralone (3p). Yield: 75.5%;
1H NMR (CDCl3): δ 7.86 (d, 1H, J = 8.4 Hz), 7.33-7.00 (m,
5H), 6.83-6.79 (m, 1H), 6.67 (d, 1H, J = 2.4 Hz), 5.55 (s, 1H),
3.88-3.71 (dd, 2H), 3.82 (s, 3H), 2.79-2.68 (m, 2H), 2.22-2.04
(m, 2H).
CH2Cl2/CH3OH (20:1 v/v) to afford the target compound 1 as
a yellow solid. Yield: 70.2%. HPLC: 98.35%, tR = 1.496 min. 1H
NMR (300 MHz, DMSO-d6): δ 7.78 (d, J = 7.8 Hz, 1H), 7.54 (s,
1H), 7.42-7.36 (m, 1H), 7.29-6.90 (m, 10H), 6.01 (s, 1H), 4.51 (s,
2H), 3.79 (s, 3H), 2.77-2.69 (m, 1H), 2.60-2.52 (m, 1H),
2.32-2.22 (m, 1H), 1.93-1.83 (m, 1H). ESI-MS m/z 523 [M -
H]-. HRMS (EI) m/z calcd for C30H24N2O5S (Mþ) 524.1406,
found 524.1411. Enantiomeric analysis: determined by HPLC
(Chiralpak AD-H, hexane/2-propanol/HOAc = 65/35/0.1 (v/v/
=
22
v), flow rate 0.5 mL/min), isomer 1-1(S), tR = 9.105 min, [R]D
-40 (c 0.14 g/1000 mL, in CH2Cl2); isomer 1-2 (R), tR = 13.123
min, [R]D22 = -11 (c 0.10 g/100 mL, in CH2Cl2).
(Z)-Ethyl-2-(3-((7-(2-methoxyphenyl)-9-oxo-5H-benzo[h]-
thiazolo[2,3-b]quinazolin-10(6H,7H,9H)-ylidene)methyl)phenoxy)-
acetate (6). In the same manner as described in the preparation of
1, compound 6 was prepared from 5a and ethyl 2-(3-formylphe-
noxy)acetate. Yield: 61.2%. HPLC: 95.22%, tR = 10.653 min. 1H
NMR (300 MHz, CDCl3): δ 7.95 (d, 1H, J = 7.8 Hz), 7.93 (s, 1H),
7.41-7.08 (m, 7H), 7.01-6.89 (m, 4H), 6.10 (s, 1H), 4.67 (s, 2H),
4.35-4.28 (q, 2H), 3.86 (s, 3H), 2.82-2.77 (m, 1H), 2.72-2.64 (m,
1H), 2.32-2.25 (m, 1H), 2.15-2.06 (m, 1H), 1.34 (t, 3H). EI-MS
m/z 552 (M). HRMS (EI) m/z calcd for C32H28N2O5S (Mþ)
552.1719, found 552.1723.
(Z)-2-(2-((7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo-
[2,3-b]quinazolin-10(6H,7H,9H)-ylidene)methyl)phenoxy)acetic
Acid (7). In the same manner as described in the preparation of 1,
compound 7 was prepared from 5a and 2-(2-formylphenoxy)ace-
tic acid. Yield: 54.8%. HPLC: 96.21%, tR = 1.876 min. 1H NMR
(300 MHz, DMSO-d6): δ 7.81 (d, 1H, J = 7.5 Hz), 7.60-7.55 (t,
3H), 7.31-6.93 (m, 9H), 6.06 (s, 1H), 4.80 (s, 2H), 3.76 (s, 3H),
2.79-2.72 (m, 1H), 2.63-2.52 (m, 1H), 2.36-2.23 (m, 1H),
2.19-1.85 (m, 1H). ESI-MS m/z 523 [M - H]-. HRMS (EI)
m/z calcd for C30H24N2O5S (Mþ) 524.1406, found 524.1413.
(Z)-2-(4-((7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-10(6H,7H,9H)-ylidene)methyl)phenoxy)acetic Acid (8).
In the same manner as described in the preparation of 1, compound
8was prepared from 5a and 2-(4-formylphenoxy)acetic acid. Yield:
1
73.3%. HPLC: 96.62%, tR = 1.747 min. H NMR (300 MHz,
DMSO-d6): δ 7.92 (s, 1H), 7.78 (d, 1H, J = 7.5 Hz), 7.44-7.41 (m,
1H), 7.38-6.85 (m, 10H), 56.06 (s, 1H), 4.26 (s, 2H), 3.76 (s, 3H),
2.78-2.73 (m, 1H), 2.71-2.54 (m, 1H), 2.35-2.18 (m, 1H),
1.96-1.76 (m, 1H). ESI-MS m/z 523 [M - H]-. HRMS (EI)
m/z calcd for C30H24N2O5S (Mþ) 524.1406, found 524.1411.
(Z)-3-(4-((E)-(7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo-
[2,3-b]quinazolin-10(6H,7H,9H)-ylidene)methyl)phenyl)acrylic
Acid (9). In the same manner as described in the preparation
of 1, compound 9 was prepared from 5a and (E)-3-(4-formyl-
phenyl)acrylic acid. Yield: 89.8%. HPLC: 100.00%, tR
=
4.246 min. 1H NMR (300 MHz, DMSO-d6): δ 7.91-7.67 (m,
3H), 7.62-7.57 (m, 4H), 7.29-6.90 (m, 7H), 6.72-6.59 (m,
1H), 6.04 (s, 1H), 6.03 (s, 1H), 3.70 (s, 3H), 2.78-2.69 (m, 1H),
2.60-2.47 (m, 1H), 2.33-2.22 (m, 1H), 1.97-1.82 (m, 1H).
ESI-MS m/z 519 [M - H]-. HRMS (EI) m/z calcd for C31H24
-
N2O4S [Mþ] 520.1457, found 520.1449.
(Z)-4-((7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-10(6H,7H,9H)-ylidene)methyl)benzoic Acid (10). In the
same manner as described in the preparation of 1, 10 was prepared
from 5a and 4-formylbenzoic acid. Yield: 92.5%. HPLC:
1
100.00%, tR = 3.076 min. H NMR (300 MHz, DMSO-d6): δ
8.05-8.03 (d, 2H, J = 8.4 Hz), 7.79-7.65 (m, 4H), 7.30-6.90 (m,
7H), 6.04 (s, 1H), 3.72 (s, 3H), 2.78-2.69 (m, 1H), 2.61-2.47 (m,
1H), 2.34-2.23 (m, 1H), 1.97-1.823 (m, 1H). ESI-MS m/z 493 [M
- H]-. HRMS (EI) m/z calcd for C29H22N2O4S [Mþ] 494.1300,
found 494.1308.
(Z)-30-((7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-10(6H,7H,9H)-ylidene)methyl)biphenyl-3-carboxylic
Acid (11). In the same manner as described in the preparation of
1, 13 was prepared from 5a and 30-formylbiphenyl-3-carboxylic
acid. Yield: 90.1%. HPLC: 100.00%, tR = 5.371 min. 1H NMR
(300 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.97-7.53 (m, 10H),
(Z)-2-(3-((7-(2-Methoxyphenyl)-9-oxo-5H-benzo[h]thiazolo[2,3-b]-
quinazolin-10(6H,7H,9H)-ylidene)methyl)phenoxy)acetic Acid (1).
Representative Procedure for 1, 1a-1i, 6-13, and 12a-12k. The
mixture of thiones 5a (1 mmol), 2-(3-formylphenoxy)acetic acid
(1 mmol), and piperidine was dissolved in EtOH. The mixture
was reflux for 3 h. The precipitate was collected by filtration,
washed with EtOH, and purified by chromatography with