Design, synthesis and biological activity evaluation of 2-mercapto-4(3H)-quinazolinone derivatives as novel inhibitors of protein tyrosine phosphatase 1B

Article abstract of DOI:10.3987/COM-12-12477

A series of novel 2-mercapto-4(3H)-quinazolinone derivatives have been synthesized and their inhibitory effects on PTP1B and TCPTP are evaluated for the first time. Most of these derivatives showed good inhibitory activity on PTP1B and reasonable selectivity for PTP1B over TCPTP, among them 32 was the most potent PTP1B inhibitor (IC₅₀ = 1.50 μ ;g/mL), and 27 possessed the best selectivity of 3.0-fold.

Full text of DOI:10.3987/COM-12-12477

HETEROCYCLES, Vol. 85, No. 8, 2012
1897
HETEROCYCLES, Vol. 85, No. 8, 2012, pp. 1897 - 1911. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2012, Accepted, 8th June, 2012, Published online, 18th June, 2012
DOI: 10.3987/COM-12-12477
DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY EVALUATION OF
2-MERCAPTO-4(3H)-QUINAZOLINONE DERIVATIVES AS NOVEL
INHIBITORS OF PROTEIN TYROSINE PHOSPHATASE 1B
Hui Li,a Jin-Ping Wang,a Fan Yang,a Ting Liu,a Wen-Wei Qiu,b Jing-Ya Li,c
Jia Li,*c and Jie Tang*a
a. Shanghai Engineering Research Center of Molecular Therapeutics and New
Drug Development, East China Normal University, Shanghai 200062, China
(phone: +86-21-62232764; fax: +86-21-62232100; e-mail: jtang@chem.
ecnu.edu.cn)
b. Department of Chemistry, East China Normal University, Shanghai 200062, P.
R. China
c. National Center for Drug Screening, Shanghai Institute of Materia Medica,
Shanghai Institute for Biological Science, Chinese Academy of Science, Shanghai
201203, China (phone: +86-21-50801313×132; fax: +86-21-50801552; e-mail:
jli@mail.shcnc.ac.cn)
Abstract – A series of novel 2-mercapto-4(3H)-quinazolinone derivatives have
been synthesized and their inhibitory effects on PTP1B and TCPTP are evaluated
for the first time. Most of these derivatives showed good inhibitory activity on
PTP1B and reasonable selectivity for PTP1B over TCPTP, among them 32 was
the most potent PTP1B inhibitor (IC50 = 1.50 g/mL), and 27 possessed the best
selectivity of 3.0-fold.
INTRODUCTION
Protein tyrosine phosphatases (PTPs) form a superfamily containing more than 100 members,1 which are
expressed in insulin sensitive tissues and play a regulatory role in insulin signaling pathway.2,3
Malfunctions in PTP activity lead to aberrant tyrosine phosphorylation which causes various diseases,
such as diabetes, obesity, cancer, inflammation and neurodegenerative diseases.4-7 Protein tyrosine
phosphatase 1B (PTP1B), one of the PTPs, has been implicated as a key negative regulator of the insulin
and the leptin signaling pathway respectively by dephosphorylating the phosphotyrosine (pTyr) residues
on the insulin receptor (IR), 8 insulin receptor substrates (IRS)9 and Janus kinase 2 (JAK2),10,11 which is

1898
HETEROCYCLES, Vol. 85, No. 8, 2012
downstream of leptin receptor. PTP1B deficient mice display more sensitive to insulin and resistant to
diet induced obesity.12,13 Thereby, inhibition of PTP1B enhances sensitivity to insulin and resistance to
obesity.14 PTP1B inhibitors represent potential and attractive therapeutic agents for treating type II
diabetes and obesity.15-17 Numerous PTP1B inhibitors have been developed recently as candidates for
anti-diabetes and anti-obesity.17-21 However, most of them have not been successfully applied in clinical
trials due to the poor bioavailability and low selectivity for PTP1B over the most homogeneous T-Cell
protein tyrosine phosphatase (TCPTP).22-24 Therefore it is quite worthwhile to find novel PTP1B
inhibitors for the development of antidiabetic drugs.
Quinazolinone derivatives have showed various pharmacological and biological properties, such as
antimicrobial, 25,26 anticonvulsant,27 sedative,28 antidepressant,29 anti-inflammatory,29,30 antimalarial31 and
diuretic,32 Histamine H3 Receptor Inverse Agonists33 as well as cholecystokinin inhibitor.34,35 Herein, we
disclosed for the first time the inhibitory activities on PTP1B of
a
series of
2-mercapto-4(3H)-quinazolinone derivatives.
RESULTS AND DISCUSSION
1. Chemistry. The synthetic method of compound 2 is based on classical procedure, which involves the
fusion of 2-aminobenzoic acid with formamide.36 2-Methoxyphenyl isothiocyanate reacted with
2-aminobenzoic acid in EtOH to give 3.37,38 2-Aminobenzoic acid was refluxed in the presence of SOCl2,
then reacted with NH4SCN to afford the intermediate 4. Compounds 5 and 6 were produced by reaction
of 4 with prenyl bromide or benzyl bromide respectively in EtOH. Compound 6 reacted with EtI to afford
2, 3-disubstituted-2-mercapto-4(3H)-quinazolinone derivative 7 39 as shown in Scheme 1.
O
O
O
CO2H
NH2
NH
NH
c
a
NH
d
R1
N
H
4
S
N
2
S
N
5 R1= -CH2CH=CMe2
1
6 R1= -CH2C6H5
b
e
O
O
N
N
OMe
N
H
S
N
7
S
3
Scheme 1
a) HCONH2, reflux, 3 h, 65%. b) 2-methoxyphenyl isothiocyanate, EtOH, reflux, 5 h, 66%. c) SOCl2,
reflux, 2 h, then NH4SCN, rt, 0.5 h. d) KOH, EtOH, prenyl bromide or benzyl bromide, rt, 2 h, 72% for 5,
78% for 6. e) KOH, DMF, EtI, rt, 2 h, 90% for 7.

HETEROCYCLES, Vol. 85, No. 8, 2012
1899
Compounds 8, 9, 10, 11, 16 and 17 were obtained by the reaction of phenyl isothiocyanate with
2-aminobenzoic acid or 4-substituted 2-aminobenzoic acid derivatives, respectively, in refluxing EtOH.
Prenyl bromide reacted with 8, 9, 10 and 11 respectively in the presence of KOH to produce 12, 13, 14
and 15. Compounds 18, 19, 20, 21 and 22 were generated by the reaction of benzyl bromide with
2,3-dihydro-3-phenyl-2-thioxoquinazolin-4(1H)-one derivatives respectively.39 Compound 23 was
afforded by demethylation of C-6 methyl ether of 21 with boron tribromide in DCM. Compound 24 was
prepared by reduction of C-6 nitro group of 22 with zinc powder, as shown in Scheme 2.
O
R1
CO2H
NH2
R1
N
a
N
S
H
O
N
35
8
9
R1 = -I
R1
N
R1 = -Br
b
O
10
11
16
R1 = -Cl
R1 = -H
S
R1
c
N
12 R1 = -I
R1 = -OMe
13 R1 = -Br
14 R1 = -Cl
15 R1 = -H
N
S
17 R1 = -NO2
R1 = -Br
R1 = -Cl
18
19
20
O
R1 = -H
HO
N
d
21
22
R1 = -OMe
R1 = -NO2
N
S
23
e
O
H2N
N
N
S
24
Scheme 2
a) phenyl isothiocyanate, EtOH, reflux, 5 h. b) KOH, EtOH, prenyl bromide, rt, 2 h, 76% for 12, 80% for
13, 68% for 14, 83% for 15. c) KOH, EtOH, benzyl bromide, rt, 2 h, 67% for 18, 62% for 19, 67% for 20,
65% for 21, 60% for 22. d) BBr3, DCM, -50 ℃-rt, 10 h, 96%. e) Zn, NH4Cl, MeOH/THF/H2O, reflux, 2 h,
80%.
Compound 23 reacted with Ac2O, MsCl or TsCl respectively in the presence of TEA to give 25, 26 and
27. Compound 28 was synthesized by the reaction of ethyl bromoacetate with 23 in the presence of
K2CO3 in DMF. Compound 29 was generated by hydrolysis of 28 with LiOH in MeOH as shown in
Scheme 3.

1900
HETEROCYCLES, Vol. 85, No. 8, 2012
O
N
O
RO
HO
N
N
a
S
N
S
23
25 R = -COMe
26 R = -SO2Me
b
R = -SO2C6H5Me
27
O
N
O
N
EtO2C
O
c
HO2C
O
N
S
N
S
28
29
Scheme 3
a) Ac2O, MsCl or TsCl, DCM, Et3N, rt, 10 h, 68% for 25, 57% for 26 and 56% for 27. b) K2CO3,
BrCH2CO2CH2CH3, DMF, rt, 1 h, 62% for 28. c) LiOH, MeOH, rt, 5 h, 73% for 29.
Acylation and sulfonylation of 24 with AcCl, BzCl or TsCl, respectively, afforded 30, 31 and 32.
Compound 33 was obtained by reaction of 24 with MsCl. Compound 34 was prepared by deprotonation
of 24 with NaH, then reacted with MeI in DMF, as shown in Scheme 4.
O
O
O
RHN
N
H2N
N
N
N
c
a
N
S
N
S
N
S
34
30 R = -COMe
24
31 R = -COC6H5
b
O
R = -SO2C6H5Me
32
CO2H
SO2Me
N
O
O
O
MeO2S
N
36
HO2C
N
S
33
O
Scheme 4
a) AcCl, BzCl or TsCl, pyridine, rt, 10 h, 76% for 30, 96% for 31, 72% for 32. b) MsCl, DCM, Et3N, rt,
10 h, 64% for 33. c) NaH, DMF, MeI, rt, 14 h, 78% for 34.
2. In vitro biological evaluation. In this paper, we designed and synthesized a series of
2-mercapto-4(3H)-quinazolinone derivatives. All these compounds were evaluated in the enzyme

HETEROCYCLES, Vol. 85, No. 8, 2012
1901
inhibition assay against PTP1B by the method of p-nitrophenyl phosphate using compound 36 as a
reference compound (Table 1).40 Homogeneous TCPTP inhibitory activities were investigated
simultaneously by the same method for further selectivity study (Table 2).
Table 1. Inhibitory activity of 2-mercapto-4(3H)-quinazolinone derivatives on PTP1B
IC50 (μM)
Compounds
2
IC50 (μM)
Compounds
>60
23
24
25
26
21.28
±
±
±
±
1.55
22.73
29.34
23.53
1.00
1.74
1.74
3
5
6
>60
>60
>60
7
27
28
29
30
31
32
9.64
±
±
1.05
3.16
51.86
24.45
±
±
21.49
5.22
12
26.65
>60
>60
13
>60
33.20
8.89
2.92
9.97
±
±
±
±
5.73
0.54
0.35
0.78
14
15
18
42.27
±
±
8.13
22.30
29.48
1.82
6.94
±
19
33
35.86
23.60
39.47
±
±
±
3.05
4.19
34
18.92
3.89
±
±
1.29
0.10
20
21
22
36a
16.36
a) Positive control.
The IC50 of these 2-mercapto-4(3H)-quinazolinone derivatives (2-34) were tested on PTP1B. The results
(Table 1) indicated that the quinazolinone (2) and the 2- or 3-substituted- 2-mercapto-4(3H)-
quinazolinone derivatives (3, 5 and 6) showing no inhibition on PTP1B. Whereas, to our delight, the
inhibition on PTP1B of all the 2,3-disubstituted-2-mercapto-4(3H)-quinazolinone derivatives (7, 15 and
20) and most of 2,3,6-trisubstituted-2-mercapto-4(3H)-quinazolinone derivatives (18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 30, 31, 32, 33 and 34) were increased significantly, and the IC50 value of the most
potent compound 32 was improved to 2.92 M. The benzyl substituent is a better group than prenyl
group at 2-position on PTP1B inhibition (15 vs. 20, 13 vs. 18 and 14 vs. 19). The inhibitory activity was
increased in some extent when the nitro group of 22 was reduced to amino group (22 vs. 24). The
inhibition of the derivatives (25, 26, 28 and 29) was decreased slightly by introducing small substituted
groups at 6-hydroxy group of 23, whereas the inhibition was improved significantly (27) when
p-tolysulfonyl group was introduced at the same position. To our delight, the inhibition of the

1902
HETEROCYCLES, Vol. 85, No. 8, 2012
derivatives (31, 32, 33 and 34), except compound 30, was increased while small substituents were linked
with 6-amino group of 24, especially for the p-tolysulfonyl substituted derivative 32, which inhibition
was 7-fold more potent than 24. Hence, the results indicated that p-tolysulfonyl group connecting with
6-hydroxy of 23 or 6-amino of 24 could ameliorate the PTP1B inhibitory potency dramatically.
Table 2. Inhibitory activity of selected 2-mercapto-4(3H)-quinazolinone derivatives on TCPTP and their
selectivity for PTP1B over TCPTP
IC50 (μM)
TCPTP/PTP1Ba
Compounds
TCPTP
>60
21
23
>2.5
1.4
29.33 ± 5.60
>2.6
>60
>60
>60
24
25
26
27
30
>2.0
>2.5
3.0
28.91 ± 5.36
42.87 ± 4.61
5.52 ± 0.71
4.38 ± 0.84
27.99 ± 4.71
40.62 ± 6.32
5.92 ± 0.18
1.3
0.6
1.5
2.8
31
32
33
2.1
1.6
34
35b
a) TCPTP/PTP1B, the ratio of IC50 of TCPTP and PTP1B. b) Positive control
Moreover, some derivatives which had good inhibition on PTP1B were also evaluated on the
homogenous enzymes TCPTP (Table 2). The results showed that these compounds, except compound 31,
had some selectivity, and the compound 27 had the best selectivity of 3-fold for PTP1B over TCPTP.
CONCLUSION
In summary, a series of 2-mercapto-4(3H)-quinazolinone derivatives were synthesized and evaluated on
PTP1B and TCPTP for the first time. Some potent PTP1B inhibitors with p-tolysulfonyl or benzoyl
substituted group at 6-position were discovered. Most of these derivatives had good inhibitory activity
on PTP1B and reasonable selectivity between PTP1B and TCPTP.
These novel
2-mercapto-4(3H)-quinazolinone derivatives could be promising lead compounds for the development of
a new class of PTP1B inhibitors.

HETEROCYCLES, Vol. 85, No. 8, 2012
1903
EXPERIMENTAL
General. 1H (400 and 500 MHz) and 13C (100 and 125 MHz) NMR spectra were recorded on a JEOL-400
or Bruker AM-500 Fourier transform spectrometer. The chemical shifts were reported (in ppm) using
the = 7.26, 2.5 signals of CDCl3, DMSO-d6 (1H NMR), and using the  = 77.23, 39.51 signals of CDCl3,
DMSO-d6 (13C NMR) as internal standards. High-resolution mass data were obtained on a Micromass Tof
II spectrometer.
General procedure for synthesis of compounds 5-6, 12-15, and 18-22. Compound 4 or its derivatives
(1.0 mmol) was dissolved in EtOH (10.0 mL). To this solution, KOH (56 mg, 1.0 mmol) and RBr (1.0
mmol) were added. After stirring for 0.5 h at rt, the reaction mixture was poured into 1 M HCl (40 mL)
and extracted with AcOEt (3×15 mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (CC).
General procedure for synthesis of compounds 3, 8-11, and 16-17. Compound 35 (2.75 mmoL) and
2-methoxyphenyl isothiocyanate or phenyl isothiocyanate (3.30 mmol) were dissolved in EtOH (5.0 mL).
The reaction mixture was heated under reflux for 5 h. After cooling, the mixture was concentrated. The
residue was purified by CC.
General procedure for synthesis of compounds 25-27. Compound 23 (0.12 g, 0.33 mmol) was
dissolved in pyridine (5.0 mL). To this solution, Ac2O, MsCl or TsCl (0.66 mmoL) was added. The
reaction mixture was stirred for 12 h at rt, then poured into 1 M HCl (40 mL) and extracted with AcOEt
(3×15 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by CC.
General procedure for synthesis of compounds 30-33. Compound 24 (0.36 g, 1.0 mmol) was dissolved
in pyridine (5.0 mL). To this solution, AcCl, PhCOCl, MsCl or TsCl (0.66 mmol) was added. The
reaction mixture was stirred for 12 h at rt, then poured into 1 M HCl (40 mL) and extracted with AcOEt
(3×15 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by CC.
Compound 2. Compound 1 (0.41 g, 3.00 mmol) was dissolved in formamide (5.0 mL). The reaction
mixture was heated under reflux for 3 h. After cooling, the mixture was poured into H2O (20 mL) and
extracted with AcOEt (3×15 mL). The combined organic phase was washed with brine, dried over
anhydrous Na2SO4 and concentrated. The residue was purified by CC (DCM/MeOH 100:1) to give 2 (284
o
o
1
mg, 65%) as a white solid. Mp 215-216 C (Lit.41 216 C). H NMR (400 MHz, DMSO-d6) δ 8.13-8.10
(m, 2 H), 7.81-7.79 (m, 1 H), 7.67-7.65 (m, 1 H), 7.53-7.52 (m, 1 H); ESI-HRMS (m/z): [M+H]+ calcd.
for C8H7N2O, 147.0553; found 147.0543.
o
Compound 3. CC (PE/EA 3:1), afforded 3 (516 mg, 66%) as a white powder solid. Mp 270-271 C
(Lit.42 266-268 oC). 1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1 H), 8.13 (d, 1 H, J = 7.8 Hz), 7.64-7.60 (m,

1904
HETEROCYCLES, Vol. 85, No. 8, 2012
13
1 H), 7.48-7.45 (m, 1 H), 7.31-7.28 (m, 1 H), 7.24-7.21 (m, 1 H), 7.17-7.06 (m, 3 H), 3.79 (s, 3 H); C
NMR (125 MHz, DMSO-d6) δ 175.9, 159.2, 154.3, 139.6, 135.7, 130.1, 129.8, 127.5, 127.4, 124.4, 120.5,
115.7, 115.7, 112.6, 55.7; ESI-HRMS (m/z): [M+Na]+ calcd. for C15H12N2NaO2S, 307.0512; found
307.0540.
Compound 4. Compound 1 (685 mg, 5.0 mmol) was dissolved in SOCl2 (15.0 mL). The reaction
mixture was heated under reflux for 2 h. After cooling, the mixture was concentrated. The residue was
dissolved in acetone (10.0 mL) and added to a solution of NH4SCN (380 mg, 5.00 mmol) in acetone
(10.0 mL). The reaction mixture was stirred at rt for 0.5 h, then was filtered, and the filter cake was
dissolved in a mixture of DCM and MeOH (10:1). The organic layer was dried over anhydrous Na2SO4
and concentrated to give 4 (739.2 mg, 83% yield) as a yellow solid, which was used without further
purification.
o
Compound 5. CC (PE/EA 10:1), afforded 5 (171.1 mg, 72%) as a white powder solid. Mp 157-158 C.
1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1 H, J = 8.0 Hz), 7.67 (d, 1 H, J = 8.3 Hz), 7.56 (d, 1 H, J = 8.3
Hz), 7.38-7.35 (m, 1 H), 5.36 (t, 1 H, J = 7.8 Hz), 3.92 (d, 2 H, J = 7.8 Hz), 1.77 (s, 3 H), 1.74 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 163.6, 155.1, 149.4, 137.9, 134.8, 126.8, 126.4, 125.7, 119.9, 118.1, 29.2,
25.7, 18.1; ESI-HRMS (m/z): [M+Na]+ calcd. for C13H14N2NaOS, 269.0719; found 269.0712.
o
Compound 6. CC (PE/EA 10:1), afforded 6 (209.0 mg, 78%) as a white powder solid. Mp 211-212 C
(Lit.43 212-213 oC). 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1 H), 8.15 (d, 1 H, J = 7.3 Hz), 7.68-7.65 (m,
1 H), 7.56 (d, 1 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 7.1 Hz), 7.35-7.31 (m, 1 H), 7.27-7.21 (m, 3 H), 4.49 (s,
2 H); ESI-HRMS (m/z): [M+Na]+ calcd. for C15H12N2NaOS, 291.0563; found 291.0560.
Compound 7. Compound 6 (268 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) were dissolved in dry
DMF (10.0 mL). MeI (284 mg, 2.0 mmol) was added to the reaction mixture, after stirring for 0.5 h at rt,
the reaction mixture was poured into 1 M HCl (40 mL). The mixture was extracted with AcOEt (3×15
mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated.
The residue was purified by CC (PE/EA 10:1) to give 7 (266.4 mg, 90%) as a white powder solid. Mp
88-89 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1 H, J = 8.1 Hz), 7.71-7.67 (m, 1 H), 7.58 (d, 1 H, J =
8.3 Hz), 7.46 (d, 2 H, J = 7.3 Hz), 5.27-7.39 (m, 4 H), 4.55 (s, 2 H), 4.15 (q, 2 H, J = 7.1 Hz), 1.33 (t, 3 H,
13
J = 7.1 Hz); C NMR (125 MHz, CDCl3) δ 161.3, 155.8, 147.3, 136.3, 134.0, 129.2 (×2), 128.5 (×2),
127.5, 126.8, 125.9, 125.5, 119.4, 39.5, 36.3, 13.1; ESI-HRMS (m/z): [M+Na]+ calcd. for C17H16N2NaOS,
319.0876; found 319.0825.
Compounds 8, 9, 10, 11, 16 and 17. The products were used without further purification.
Compound 12. CC (PE/EA 10:1), afforded 12 (340.5 mg, 76%) as a white powder solid. Mp 136-137 oC.
1H NMR (500 MHz, CDCl3) δ 8.54 (d, 1 H, J = 2.0 Hz), 7.97 (dd, 1 H, J = 8.6, 2.1 Hz), 7.54 (s, 1 H),
7.53 (d, 2 H, J = 2.2 Hz), 7.34 (d, 1 H, J = 8.6 Hz), 7.30-7.28 (m, 2 H), 5.24 (t, 1 H, J = 8.0 Hz), 3.79 (d,

HETEROCYCLES, Vol. 85, No. 8, 2012
1905
2 H, J = 7.9 Hz), 1.71 (s, 3 H), 1.70 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 160.4, 158.7, 147.2, 143.2,
138.0, 135.9, 135.7, 130.0, 129.7 (×2), 129.0 (×2), 128.1, 121.5, 117.4, 89.4, 31.3, 25.7, 18.0; ESI-HRMS
(m/z): [M+Na]+ calcd. for C19H17IN2NaOS, 470.9998; found 470.9971.
Compound 13. CC (PE/EA 10:1), afforded 13 (320.8 mg, 80%) as a white powder solid. Mp 143-144 oC.
1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1 H, J = 2.5 Hz), 7.80 (d, 1 H, J = 8.8 Hz), 7.54-7.56 (m, 3 H),
7.50 (d, 1 H, J = 9.0 Hz), 7.30-7.32 (m, 2 H), 5.28 (t, 1 H, J = 8.0 Hz), 3.81 (d, 2 H, J = 8.0 Hz), 1.73 (s, 3
13
H), 1.72 (s, 3 H); C NMR (100 MHz, CDCl3) δ 160.3, 158.5, 146.8, 137.9, 137.6, 135.8, 130.0, 129.7,
129.7 (×2), 129.1 (×2), 128.1, 121.3, 118.8, 117.6, 31.3, 25.7, 18.0; ESI-HRMS (m/z): [M+Na]+ calcd.
for C19H17BrN2NaOS, 423.0137; found 423.0188.
Compound 14. CC (PE/EA 10:1), afforded 14 (242.4 mg, 68%) as a white powder solid. Mp 139-140 oC.
1H NMR (500 MHz, CDCl3) δ 8.17 (d, 1 H, J = 2.4 Hz), 7.63 (dd, 1 H, J = 8.7, 2.5 Hz), 7.54-7.51 (m, 3
H), 7.29-7.28 (m, 3 H), 5.24 (t, 1 H, J = 7.9 Hz), 3.78 (d, 2 H, J = 7.9 Hz), 1.70 (s, 3 H), 1.69 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 160.8, 158.3, 146.4, 137.9, 135.7, 134.9, 131.2, 130.0, 129.7 (×2), 129.0 (×2),
127.8, 126.5, 120.8, 117.4, 31.3, 25.7, 18.0; ESI-HRMS (m/z): [M+Na]+ calcd. for C19H17ClN2NaOS,
379.0648; found 379.0705.
Compound 15. CC (PE/EA 10:1), afforded 15 (267.3 mg, 83%) as a white powder solid. Mp 130-132 oC.
1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1 H, J = 8.0 Hz), 7.69 (d, 1 H, J = 6.8 Hz), 7.59 (d, 1 H, J = 8.0
Hz), 7.71-7.50 (m, 3 H), 7.39-7.37 (m, 1 H), 7.31-7.29 (m, 2 H), 5.27 (t, 1 H, J = 7.8 Hz), 3.80 (d, 2 H, J
= 7.8 Hz), 1.70 (s, 3 H), 1.68 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.9, 157.7, 148.0, 137.6, 136.1,
134.6, 129.8, 129.6 (×2), 129.2(×2), 127.3, 126.2, 125.7, 119.9, 117.8, 31.3, 25.7, 18.0; ESI-HRMS
(m/z): [M+Na]+ calcd. for C19H18N2NaOS, 345.1032; found 345.1068.
Compound 18. CC (PE/EA 10:1), afforded 18 (283.4 mg, 67%) as a white powder solid. Mp 132-133 oC.
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.81 (d, 1 H, J = 8.7 Hz), 7.51-7.55 (m, 4 H), 7.35 (d, 2 H, J
13
= 7.3 Hz), 7.23-7.29 (m, 5 H), 4.39 (s, 2 H); C NMR (100 MHz, CDCl3) δ 160.6, 157.9, 146.6, 137.8,
136.1, 135.5, 130.1, 129.7 (×2), 129.3 (×2), 129.1 (×2), 128.7 (×2), 128.6, 128.1, 127.6, 121.4, 119.0,
37.2; ESI-HRMS (m/z): [M+H]+ calcd. for C21H16BrN2OS, 423.0161; found 423.0227.
Compound 19. CC (PE/EA 10:1), afforded 19 (234.7 mg, 62%) as a white powder solid. Mp 143-144 oC.
1H NMR (500 MHz, CDCl3) δ 8.18 (d, 1 H, J = 2.4 Hz), 7.66 (dd, 1 H, J =8.7, 2.5 Hz), 7.59 (d, 1 H, J =
8.7 Hz), 7.51-7.50 (m, 3 H), 7.35 (d, 2 H, J = 7.0 Hz), 7.29-7.25 (m, 5 H), 4.39 (s, 2 H); 13C NMR (100
MHz, CDCl3) δ 160.8, 157.7, 146.3, 136.2, 135.5, 135.0, 131.4, 130.1, 129.7 (×2), 129.3 (×2), 129.1 (×2),
128.6 (×2), 127.9, 127.6, 126.6, 121.0, 37.2; ESI-HRMS (m/z): [M+Na]+ calcd. for C21H15ClN2NaOS,
401.0491; found 401.0532.
o
Compound 20. CC (PE/EA 10:1), afforded 20 (220 mg, 67%) as a white powder solid. Mp 172-173 C
(Lit.44 176.5-177 oC). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1 H, J = 7.9 Hz), 7.78-7.75 (m, 1 H), 7.67 (d,

1906
HETEROCYCLES, Vol. 85, No. 8, 2012
1 H, J = 8.2 Hz), 7.53-7.51 (m, 3 H), 7.43-7.38 (m, 3 H), 7.32-7.22 (m, 5H), 4.40 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 161.8, 157.1, 147.8, 136.4, 135.8, 134.6, 129.9, 129.6 (×2), 129.4 (×2), 129.2 (×2), 128.5
(×2), 127.5, 127.3, 126.2, 125.8, 120.0, 37.1; ESI-HRMS (m/z): [M+Na]+ calcd. for C21H16N2NaOS,
367.0876; found 367.0901.
Compound 21. CC (PE/EA 10:1), afforded 21 (243.1 mg, 65%) as a white powder solid. Mp 177-178 oC.
1H NMR (500 MHz, CDCl3) δ 7.63-7.61 (m, 2 H), 7.53-7.51 (m, 3 H), 7.38-7.35 (m, 3 H), 7.30-7.28 (m,
4 H), 7.25-7.23 (m, 1 H), 4.39 (s, 2 H), 3.90 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.7, 157.6, 154.3,
142.6, 136.4, 135.9, 129.8, 129.5 (×2), 129.3 (×2), 129.1 (×2), 128.4 (×2), 127.7, 127.4, 124.6, 120.5,
106.7, 55.7, 36.0; ESI-HRMS (m/z): [M+Na]+ calcd. for C22H18N2NaO2S, 397.0981; found 397.1011.
Compound 22. CC (PE/EA 10:1), afforded 22 (233.4 mg, 60%) as a yellow powder solid. Mp 184-185
oC. 1H NMR (500 MHz, CDCl3) δ 9.08 (d, 1 H, J = 3.0 Hz), 8.52 (dd, 1 H, J = 9.0, 2.5 Hz), 7.74 (d, 1 H,
J = 9.0 Hz), 7.55-7.53 (m, 3 H), 7.35 (d, 1 H, J = 7.0 Hz), 7.30-7.25 (m, 5 H), 4.43 (s, 2 H); 13C NMR
(100 MHz, CDCl3) δ 164.2, 162.3, 160.4, 151.5, 144.8, 135.6, 135.0, 130.4, 130.0 (×2), 129.3 (×2), 128.9
(×2), 128.7 (×2), 127.7, 127.6, 124.1, 119.9, 37.5; ESI-HRMS (m/z): [M+Na]+ calcd. for C21H15N3NaO3S,
412.0726; found 412.0755.
Compound 23. Compound 21 (0.1 g, 0.27 mmol) was dissolved in DCM (10.0 mL). BBr3 in DCM (1 M,
0.04 mL) was added to the reaction mixture at -50 oC, and the reaction mixture was stirred at rt for 10 h.
The reaction mixture was poured into H2O (50 mL) and extracted with AcOEt (2×15 mL). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was
o
purified by CC (PE/EA 3:1) to give 23 (93 mg, 96%) as a white powder solid. It decomposes at 200 C.
1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1 H), 7.56 (d, 1 H, J = 8.8 Hz), 7.50-7.38 (m, 8 H), 7.32-7.20
(m, 4 H), 4.35 (s, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 160.6, 155.6, 152.9, 140.7, 136.8, 136.0, 129.7,
129.4 (×2), 129.4 (×2), 129.3 (×2), 128.4 (×2), 127.7, 127.2, 124.2, 120.4, 109.5, 35.8; ESI-HRMS (m/z):
[M+Na]+ calcd. for C21H16N2NaO2S, 383.0825; found 383.0843.
Compound 24. Compound 22 (0.1 g, 0.25 mmol) was dissolved in the mixture solution (9.0 mL, MeOH:
H2O: THF = 5:1:3). Zinc dust (0.05 g, 0.75 mmol) and NH4Cl (0.07 g, 1.25 mmol) were added to the
reaction mixture. The reaction mixture was heated under reflux for 2 h. After cooling, the reaction
mixture was poured into H2O (20 mL) and extracted with AcOEt (2×15 mL). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by CC
o
1
(PE/EA 3:1) to give 24 (72 mg, 80%) as a yellow powder solid. Mp 168-169 C. H NMR (500 MHz,
CDCl3) δ 7.52-7.49 (m, 4 H), 7.43 (d, 1 H, J = 2.1 Hz), 7.36 (d, 2 H, J = 7.5 Hz), 7.30-7.28 (m, 4 H),
13
7.23-7.22 (m, 1 H), 7.10 (dd, 1 H, J = 8.6, 2.4 Hz), 4.37 (s, 2 H), 3.29 (br, 2 H); C NMR (100 MHz,
CDCl3) δ 161.8, 152.7, 144.8, 141.0, 136.6, 136.1, 129.7, 129.5 (×2), 129.3 (×2), 129.2 (×2), 128.4 (×2),
127.4, 127.3, 123.3, 120.8, 109.6, 36.9; ESI-HRMS (m/z): [M+H]+ calcd. for C21H18N3OS, 360.1165;

HETEROCYCLES, Vol. 85, No. 8, 2012
1907
found 360.1156.
o
Compound 25. CC (PE/EA 3:1), afforded 25 (90.2 mg, 68%) as a white powder solid. Mp 180-181 C.
1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1 H), 7.67 (d, 1 H, J = 8.6 Hz), 7.49-7.47 (m, 6 H), 7.37-7.35 (m, 3
H), 7.28-7.22 (m, 2 H), 4.39 (s, 2 H), 2.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 169.30, 161.2, 157.0,
148.1, 145.7, 136.3, 135.6, 130.0, 129.7 (×2), 129.3 (×2), 129.1 (×2), 128.9, 128.5 (×2), 127.6, 127.5,
120.6, 119.2, 37.0, 21.0; ESI-HRMS (m/z): [M+Na]+ calcd. for C23H18N2NaO3S, 425.0930; found
425.0931.
o
Compound 26. CC (PE/EA 3:1), afforded 26 (82.4 mg, 57%) as a white powder solid. Mp 179-180 C.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1 H, J = 2.4 Hz), 8.05-7.66 (m, 2 H), 7.52-7.50 (m, 3 H), 7.35 (d,
2 H, J = 7.0 Hz), 7.29-7.22 (m, 5 H), 4.39 (s, 2 H), 3.17 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 160.8,
158.1, 146.6, 146.2, 136.0, 135.3, 130.1, 129.7 (×2), 129.3, 129.2 (×2), 128.9 (×2), 128.5 (×2), 128.4,
127.5, 120.7, 119.6, 37.4, 31.4; ESI-HRMS (m/z): [M+Na]+ calcd. for C22H18N2NaO4S2, 461.0600; found
461.0616.
o
Compound 27. CC (PE/EA 3:1), afforded 27 (95.0 mg, 56%) as a white powder solid. Mp 160-161 C.
1H NMR (500 MHz, CDCl3) δ 7.73 (d, 2 H, J = 8.2 Hz), 7.69 (d, 1 H, J = 2.6 Hz), 7.62 (d, 1 H, J = 8.9
Hz), 7.52-7.50 (m, 4 H), 7.36-7.35 (m, 2 H), 7.31 (d, 2 H, J = 8.1 Hz), 7.29-7.24 (m, 5 H), 4.37 (s, 2 H),
2.44 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 160.7, 157.9, 146.8, 146.4, 145.7, 136.1, 135.3, 132.0,
130.0, 129.9 (×2), 129.7, 129.5 (×2), 129.3 (×2), 128.9 (×2), 128.5 (×2), 128.4 (×2), 128.0, 127.5, 120.5,
119.9, 37.1, 21.7; ESI-HRMS (m/z): [M+H]+ calcd. for C28H23N2O4S2, 515.1094; found 515.1142.
Compound 28. Compound 23 (0.1 g, 0.28 mmol) and K2CO3 (0.08 g, 0.56 mmol) were dissolved in
DMF (5.0 mL). BrCH2CO2Et (0.06 mL, 0.56 mmol) was added to the reaction mixture. After stirring at rt
for 1 h, the reaction mixture was poured into 1 M HCl (50 mL) and extracted with AcOEt (2×15 mL).
The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The
residue was purified by CC (PE/EA 5:1) to give 28 (78 mg, 62%) as a white powder solid. Mp 151-152
1
oC. H NMR (500 MHz, CDCl3) δ 7.63 (d, 1 H, J = 9.0 Hz), 7.54-7.50 (m, 4 H), 7.44 (dd, 1 H, J = 8.9,
3.0 Hz), 7. 36 (d, 2 H, J =7.2 Hz), 7.29-7.28 (m, 4 H), 7.24-7.23 (m, 1 H), 4.72 (s, 2 H), 4.38 (s, 2 H),
13
4.26 (q, 2 H, J = 7.2 Hz), 1.30 (t, 3 H, J = 7.2 Hz); C NMR (100 MHz, CDCl3) δ 168.3, 161.5, 155.7,
155.0, 143.2, 136.4, 135.8, 129.9, 129.6 (×2), 129.3 (×2), 129.0 (×2), 128.4 (×2), 128.1, 127.4, 125.1,
120.4, 107.7, 65.5, 61.4, 37.0, 14.1; ESI-HRMS (m/z): [M+Na]+ calcd. for C25H22N2NaO4S, 469.1192;
found 469.1199.
Compound 29. Compound 28 (80 mg, 0.18 mmol) and LiOH (0.02 g, 0.36 mmol) were dissolved in
MeOH (5.0 mL). After stirring at rt for 5 h, the reaction mixture was poured into 1 M HCl (50 mL) and
extracted with AcOEt (2×15 mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated. The residue was purified by CC (DCM/MeOH 50:1) to give 29 (55

1908
HETEROCYCLES, Vol. 85, No. 8, 2012
mg, 73%) as a white powder solid. It decomposes at 185 oC. 1H NMR (500 MHz, DMSO-d6) δ 7.64 (d, 1
H, J = 8.9 Hz), 7.52-7.50 (m, 3 H), 7.45 (dd, 1 H, J = 8.9, 2.9 Hz), 7.40-7.38 (m, 4 H), 7.36 (d, 1 H, J =
2.8 Hz), 7.27-7.25 (m, 2 H), 7.22-7.20 (m, 1 H), 4.75 (s, 2 H), 4.36 (s, 2 H); 13C NMR (100 MHz,
DMSO-d6) δ 160.5, 155.6, 154.4, 142.1, 136.7, 135.8, 129.8, 129.4 (×2), 129.3 (×2), 129.2 (×2), 128.3
(×2), 127.8, 127.2, 124.4, 120.1, 107.7, 64.9, 35.8; ESI-HRMS (m/z): [M+H]+ calcd. for C23H19N2O4S,
419.1060; found 419.1065.
Compound 30. CC (PE/EA 3:1), afforded 30 (304.8 mg, 76%) as a white powder solid. It decomposes at
160 oC. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1 H), 8.39 (d, 1 H, J = 2.1 Hz), 8.03 (dd, 1 H, J = 8.8,
2.2 Hz), 7.65 (d, 1 H, J = 8.8 Hz), 7.53-7.52 (m, 3 H), 7.43-7.40 (m, 4 H), 7.28-7.26 (m, 2 H), 7.22-7.20
(m, 1 H), 4.38 (s, 2 H), 2.10 (s, 3 H); 13C NMR (125 MHz, DMSO-d6) δ 168.6, 160.7, 155.0, 143.1, 137.3,
136.7, 135.9, 129.8, 129.5 (×2), 129.4 (×2), 129.3 (×2), 128.4 (×2), 127.3, 126.7, 126.3, 119.8, 114.9,
36.0, 24.0; ESI-HRMS (m/z): [M+Na]+ calcd. for C23H19N3NaO2S, 424.1090; found 424.1157.
Compound 31. CC (PE/EA 5:1), afforded 31 (444.5 mg, 96%) as a yellow powder solid. Mp 214-215 oC.
1H NMR (500 MHz, CDCl3) δ 8.50 (dd, 1 H, J = 2.4, 8.9 Hz), 8.40 (s, 1 H), 8.10 (d, 1 H, J = 2.4 Hz),
7.86 (d, 2 H, J = 7.4 Hz), 7.70 (d, 1 H, J = 8.9 Hz), 7.56-7.53 (m, 1 H), 7.47-7.42 (m, 5 H), 7.37 (d, 2 H, J
13
= 7.3 Hz), 7.30-7.23 (m, 5 H), 4.40 (s, 2 H); C NMR (100 MHz, CDCl3) δ 165.9, 161.8, 155.8, 144.5,
136.5, 136.3, 135.6, 134.3, 131.7, 129.9, 129.6 (×2), 129.4 (×2), 129.0 (×2), 128.5 (×2), 128.4 (×2), 127.5,
127.3 (×2), 127.0, 119.8, 117.6, 37.1; ESI-HRMS (m/z): [M+Na]+ calcd. for C28H21N3NaO2S, 486.1247;
found 486.1257.
o
Compound 32. (CC) (PE/EA 5:1), afforded 32 (369.4 mg, 72%) as a white powder solid. Mp 98-99 C.
1H NMR (500 MHz, CDCl3) δ 7.73 (dd, 1 H, J = 2.5, 8.7 Hz), 7.68-7.57 (m, 5 H), 7.51-7.49 (m, 4 H),
13
7.38 (s, 1 H), 7.35 (d, 2 H, J = 8.4 Hz), 7.30-7.20 (m, 8 H), 4.37 (s, 2 H), 2.37 (s, 3 H); C NMR (100
MHz, CDCl3) δ 160.3, 155.1, 143.7, 142.5, 134.9, 134.6, 134.2, 133.8, 128.7, 128.4 (×2), 128.3 (×2),
128.0 (×2), 127.7 (×2), 127.3, 127.2 (×2), 126.8, 126.1, 125.9 (×2), 118.8, 116.8, 35.8, 20.2; ESI-HRMS
(m/z): [M+Na]+ calcd. for C28H23N3NaO3S2, 536.1073; found 536.1045.
Compound 33. CC (PE/EA 3:1), afforded 33 (329.6 mg, 64%) as a white powder solid. Mp 159-160 oC.
1H NMR (500 MHz, CDCl3) δ 8.22 (d, 1 H, J = 2.5 Hz), 7.73 (d, 1 H, J = 8.6 Hz), 7.65 (dd, 1 H, J = 8.6,
2.5 Hz), 7.54-7.53 (m, 3 H), 7.36 (d, 2 H, J = 6.9 Hz), 7.30-7.27 (m, 4 H), 7.26-7.24 (m, 1 H), 4.41 (s, 2
H), 3.45 (s, 6 H); 13C NMR (100 MHz, DMSO-d6) δ 160.7, 159.6, 148.7, 136.4, 136.0, 135.2, 130.4,
130.2, 129.8 (×2), 129.6, 129.2 (×2), 128.9 (×2), 128.5 (×2), 128.0, 127.5, 120.6, 42.8 (×2), 37.1;
ESI-HRMS (m/z): [M+H]+ calcd. for C23H22N3O5S3, 516.0716; found 516.0760.
Compound 34. Compound 24 (83 mg, 0.23 mmol) and NaH (60% suspended in mineral oil, 0.05 g, 1.15
mmol) were dissolved in DMF (5.0 mL). MeI (0.06 mL, 0.92 mmol) was added to the reaction mixture.
After stirring for 14 h at rt, the reaction mixture was poured into 1 M HCl (50 mL) and extracted with

HETEROCYCLES, Vol. 85, No. 8, 2012
1909
AcOEt (2×15 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4
and concentrated. The residue was purified by CC (PE/EA 5:1) to give 34 (69.4 mg, 78%) as a yellow
o
1
powder solid. Mp 175-176 C. H NMR (400 MHz, CDCl3) δ 7.57 (d, 1 H, J = 8.0 Hz), 7.50-7.49 (m, 3
13
H), 7.38-7.36 (m, 3 H), 7.29-7.26 (m, 6 H), 4.39(s, 2 H), 3.05 (s, 6 H); C NMR (100 MHz, CDCl3) δ
160.6, 150.2, 147.1, 137.8, 135.1, 134.6, 128.0, 127.9 (×2), 127.8 (×2), 127.6 (×2), 126.8 (×2), 125.7,
125.4, 119.1, 119.0, 105.2, 39.1 (×2), 35.3; ESI-HRMS (m/z): [M+Na]+ calcd. for C23H21N3NaOS,
410.1298; found 410.1298.
ACKNOWLEDGMENTS
This research was financially supported by Shanghai Science and Technology Council (No 09142200800,
10142200800), National Natural Science Foundation of China (No. 20802020) and Shanghai Key
Laboratory of Green Chemistry and Chemical Processes, We also thank the Laboratory of Organic
Functional Molecules, Sino-French Institute of ECNU for support.
REFERENCES AND NOTES
1. A. Alonso, J. Sasin, N. Bottini, I. Friedberg, A. Osterman, A. Godzik, T. Hunter, J. Dixon, and T.
Mustelin, Cell, 2004, 117, 699.
2. A. Cheng, N. Dubè, F. Gu, and M. L. Tremblay, Eur. J. Biochem., 2002, 269, 1050.
3. Z. Zhang, B. Zhou, and L. Xie, Pharmacol. Therap., 2002, 93, 307.
4. Z. Y. Zhang, Curr. Opin. Chem. Biol., 2001, 5, 416.
5. R. H. Van Huijsduijnen, A. Bombrun, and D. Swinnen, Drugs Discov. Today, 2002, 7, 1013.
6. W. J. Hendriks, A. Elson, S. Harroch, and A. W. Stoker, FEBS J., 2008, 275, 816.
7. S. G. Julien, N. Dubé, M. Read, J. Penney, M. Paquet, Y. X. Han, B. P. Kennedy, W. J. Muller, and
M. L. Tremblay, Nat. Genet., 2007, 39, 338.
8. S. Wälchli, M. L. Curchod, R. P. Gobert, S. Arkinstall, and R. H. Van Huijsduijnen, J. Biol. Chem.,
2000, 275, 9792.
9. B. J. Goldstein, A. Bittner-Kowalczyk, M. F. White, and M. Harbeck, J. Biol. Chem., 2000, 275,
4283.
10. A. Cheng, N. Uetani, P. D. Simoncic, V. P. Chaubey, A. Lee-Loy, C. J. McGlade, B. P. Kennedy,
and M. L. Tremblay, Dev. Cell, 2002, 2, 497.
11. J. M. Zabolotny, K. K. Bence-Hanulec, A. Stricker-Krongrad, F. Haj, Y. Wang, Y. Minokoshi, Y. B.
Kim, J. K. Elmquist, L. A. Tartaglia, B. B. Kahn, and B. G. Neel, Dev. Cell, 2002, 2, 489.
12. M. Elchebly, P. Payette, E. Michaliszyn, W. Cromlish, S. Collins, A. L. Loy, D. Normandin, A.
Cheng, J. Himms-Hagen, C. C. Chan, C. Ramachandran, M. J. Gresser, M. L. Tremblay, and B. P.

1910
HETEROCYCLES, Vol. 85, No. 8, 2012
Kennedy, Science, 1999, 283, 1544.
13. L. D. Klaman, O. Boss, O. D. Peroni, J. K. Kim, J. L. Martino, J. M. Zabolotny, N. Moghal, M.
Lubkin, Y. B. Kim, A. H. Sharpe, A. Stricker-Krongrad, G. I. Shulman, B. G. Neel, and B. B. Kahn,
Mol. Cell. Biol., 2000, 20, 5479.
14. D. Popov, Biochem. Biophys. Res. Commun., 2011, 410, 377.
15. B. P. Kennedy and C. Ramachandran, Biochem. Pharmacol., 2000, 60, 877.
16. T. O. Johnson, J. Ermolieff, and M. R. Jirousek, Nat. Rev. Drug Discov., 2002, 1, 696.
17. S. Zhang and Z. Y. Zhang, Drug Discov. Today, 2007, 12, 373.
18. S. Lee and Q. Wang, Med. Res. Rev., 2007, 27, 553.
19. L. Shi, H. P. Yu, Y. Y. Zhou, J. Q. Du, Q. Shen, J. Y. Li, and J. Li, Acta Pharmacol. Sin., 2008, 29,
278.
20. Y. Zhang, Y. Li, Y. W. Guo, H. L. Jiang, and X. Shen, Acta Pharmacol. Sin., 2009, 30, 333.
21. Z. Liu, Q. Chai, Y. Y. Li, Q. Shen, L. P. Ma, L. N. Zhang, X. Wang, L. Sheng, J. Y. Li, J. Li, and J.
K. Shen, Acta Pharmacol. Sin., 2010, 31, 1005.
22. M. J. Hartshorn, C. W. Murray, A. Cleasby, M. Frederickson, I. J. Tickle, and H. Jhoti, J. Med.
Chem., 2005, 48, 403.
23. D. P. Wilson, Z. K. Wan, W. X. Xu, S. J. Kirincich, B. C. Follows, D. Joseph-McCarthy, K.
Foreman, A. Moretto, J. J. Wu, M. Zhu, E. Binnun, Y. L. Zhang, M. Tam, D. V. Erbe, J. Tobin, X.
Xu, L. Leung, A. Shilling, S. Y. Tam, T. S. Mansour, and J. Lee, J. Med. Chem., 2007, 50, 4681.
24. M. Hussain, V. Ahmed, B. Hill, Z. Ahmed, and S. D. Taylor, Bioorg. Med. Chem., 2008, 16, 6764.
25. P. Kumar, K. N. Dhawan, S. Vrat, K. P. Bhargava, and K. Kishore, Arch. Pharm., 1983, 316, 759.
26. N. S. Habib and M. A. Khalils, J. Pharm. Sci., 1984, 73, 982.
27. V. Jatav, P. Mishra, S. Kashaw, and J. P. Stables, Eur. J. Med. Chem., 2008, 43, 1945.
28. S. Hayao, H. J. Havera, W. G. Strycker, T. J. Leipzig, R. A. Kulp, and H. E. Hartzler, J. Med. Chem.,
1965, 8, 807.
29. J. A. 3rd. Lowe, R. L. Archer, D. S. Chapin, J. B. Cheng, D. Helweg, J. L. Johnson, B. K. Koe, L. A.
Lebel, and P. F. Moore, J. Med. Chem., 1991, 34, 624.
30. C. Qi, L. Deng, H. Shih, L. M. Leoni, D. Genini, D. A. Carson, and H. B. Cottam, J. Med. Chem.,
1999, 42, 3860.
31. B. R. Baker, R. E. Schaub, J. P. Joseph, F. J. McEvoy, and J. H. Williams, J. Org. Chem., 1952, 17,
149.
32. A. R. Maarouf, E. R. El-Bendary, and F. E. Goda, Arch. Pharm. Pharm. Med. Chem., 2004, 337,
527.
33. T. Nagase, T. Mizutani, E. Sekino, S. Ishikawa, S. Ito, Y. Mitobe, Y. Miyamoto, R. Yoshimoto, T.

HETEROCYCLES, Vol. 85, No. 8, 2012
1911
Tanaka, A. Ishihara, N. Takenaga, S. Tokita, and N. Sato, J. Med. Chem., 2008, 51, 6889.
34. M. J. Yu, J. R. McCowan, N. R. Mason, J. B. Deeter, and L. G. Mendelsohn, J. Med. Chem., 1992,
35, 2534.
35. J. K. Padia, M. Field, J. Hinton, K. Meecham, J. Pablo, R. Pinnock, B. D. Roth, L. Singh, N.
Suman-Chauhan, B. K. Trivedi, and L. Webdale, J. Med. Chem., 1998, 41, 1042.
36. K. Smith, G. A. El-Hiti, M. F. Abdel-Megeed, and M. A. Abdo, J. Org. Chem., 1996, 61, 647.
37. V. Alagarsamy, D. Shankar, and S. Murugesan, Biomed. Pharmacother., 2008, 62, 173.
38. V. Alagarsamy, V. R. Solomon, and K. Dhanaba, Bioorg. Med. Chem., 2007, 15, 235.
39. L. M. Yun, S. Yangibaev, K. M. Shakhidoyatov, V. Ya. Alekseeva, and K. A. V'yunov, Chem.
Heterocycl. Comp., 1987, 23, 214.
40. Y. T. Chen and C. T. Seto, J. Med. Chem., 2002, 45, 3946.
41. F. R. Alexandre, A. Berecibara, and T. Besson, Tetrahedron Lett., 2002, 43, 3911.
42. R. M. Shafik, A. A. B. Hazzaa, and N. S. Habib, Pharmazie, 1979, 34, 148.
43. L. M. Yun, S. Yangibaev, Kh. M. Shakhidoyatov, V. Ya. Alekseeva, and K. A. V'yunov, Chem.
Heterocycl. Comp., 1987, 23, 214.
44. J. E. McCarty, E. L. Haines, and C. A. VanderWerf, J. Am. Chem. Soc., 1960, 82, 964.