Synthesis of novel thiazolyl-pyrimidines and their anticancer activity in vitro

Article abstract of DOI:10.1002/ardp.201000238

A series of novel compounds 7-43 were prepared via the condensation of enaminones 4a-h and the guanidines carbonate 6a-f. The structures of these newly synthesized compounds were confirmed by ¹H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9 and 30 exhibited more efficient activity against Ishikawa, A549. Thiazolyl-pyrimidines were synthesized by the general pyrimidine condensation of Bredereck and their in-vitro anticancer activities were evaluated. Copyright

Full text of DOI:10.1002/ardp.201000238

Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
675
Full Paper
Synthesis of Novel Thiazolyl-Pyrimidines and Their
Anticancer Activity in Vitro
Hai-Bo Shi1,2, Hai-Bo Li3, Kong-Qin Lu2, Xia-Re Zhu2, Wei-Xiao Hu1, and Wen Pei4
1 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P.R. China
2 Zhejiang Pharmaceutical College, Ningbo, P.R. China
3 Nantong Center for Disease Control and Prevention, Nantong, P.R. China
4 College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou,
P.R. China
A series of novel compounds 7–43 were prepared via the condensation of enaminones 4a–h and the
guanidines carbonate 6a–f. The structures of these newly synthesized compounds were confirmed by
1H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against
human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them
showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9
and 30 exhibited more efficient activity against Ishikawa, A549.
Keywords: Anticancer activity / Pyrimidine / Thiazole
Received: August 22, 2010; Revised: November 25, 2010; Accepted: November 30, 2010
DOI 10.1002/ardp.201000238
Introduction
a consequence of cellular inhibition of aurora A and B
kinases [9]. CYC116 is currently undergoing phase I clinical
evaluation in cancer patients [10, 11].
The cyclin-dependent kinases (CDKs) are key regulators of
progression through the various stages of the eukaryotic cell
cycle [1, 2]. It has been shown that overexpression and/or loss
of function of key proteins implicated in the chain of events
upstream and downstream of the CDKs leads to tumorigen-
esis and neoplastic transformation [3]. Campbell McInnes
firstly reported use of computational methods to elucidate
the characteristics of selectivity and derive the structural
basis for specific, high-affinity binding of inhibitors to the
CDK4 active site. The findings showed that 2-anilino-4-thiazol-
5-yl) pyrimidine pharmacophore are potent and highly
selective ATP antagonists of CDK4/cyclin D1 [4]. 2-Anilino-4-
(thiazol-5-yl) pyrimidine, also including a thiazole and a
pyrimidine structure, showed good biological activities
These facts prompted us to design a new series of thiazole
derivatives in order to find more potential antitumor com-
pounds, and to carry out a structure-activity relationship
study. The present work is an extension of our ongoing efforts
towards the development of new aminothiazole derivatives
and their biological activities [12, 13]. Accordingly, we
attempt to investigate whether introduction of arylamino
group into CYC116 with retaining the thiazole and pyrimi-
dine could enhance their anticancer activities or not. Here,
we describe the synthesis and the cytotoxic activity in vitro
against human cancer cell lines of this novel class of
compounds.
and a series of analogs by the modification of the structure Result and Discussion
were synthesized [5–8]. For example (Figure 1), the studies
of Wang et al. showed that the anticancer effects of lead
compound CYC116 (Ki values of 8.0 and 9.2 nM for aurora
A and B, respectively) were shown to emanate from cell
death following mitotic failure and increased polyploidy as
{4-[4-Methyl-2-(methyl-aryl amino)-thiazol-5-yl]-pyrimidine-2-
yl}-arylamines were synthesized (Scheme 1) by the general
pyrimidine condensation of Bredereck [14]. N-substituted
thioureas 1a–h were prepared by known methods in high
yields [15, 16]. Treatment of acetylacetone with NCS (N-chloro-
succinimide) in carbon tetrachloride under reflux for 5 h
resulted in 3-chloro-acetylacetone 2. The aminothiazole 3a–h
were prepared by thioureas 1a–h and 2 refluxing in methanol
via the method of Hantzsch [17] and were converted to the
Correspondence: Wei-Xiao Hu, College of Pharmaceutical Science,
Zhejiang University of Technology, Hangzhou 310032, P.R. China.
E-mail: huyang@mail.hz.zj.cn
Fax: þ86 571 88320557
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676
H.-B. Shi et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
cancer cell SPC-A-01 and human gastric cancer cell SGC-7901.
Cisplatin was employed as a positive control in the assay. The
results are summarized in Table 1.
N
N
As shown in Table 1, most of the tested compounds showed
moderate to potent cytotoxic activity against Ishikawa, A549,
BEL-7404, SPC-A-01 and SGC-7901. It was noteworthy that the
cytotoxic effects were more pronounced against Ishikawa cell
compared with the others, displayed higher activities (e.g. 9,
14, 22, 31 and 33 with IC50 1.42–3.87 mM) in comparison with
cisplatin (IC50 15.67 mM). Comparing the results of com-
pounds 7–11 with the same R1 substituent (R1 ¼ H) but
different R2, it could be found that compound 9 (R2 ¼ 3-Cl)
showed strong cytotoxic activity efficient against Ishikawa,
A549 and BEL-7404 cell with IC50 values of 1.99, 2.99 and
8.25 mM, respectively. Moreover, compound 14 (R2 ¼ 3-Cl)
has better activities among compounds 12–16 (R1 ¼ 4-CH3),
and 21 (R2 ¼ 4-F) has better activities among 17–21 (R1 ¼ 3-
CH3), and 22 (R2 ¼ H) have better activities among 22–24
(R1 ¼ 2-CH3). The result implied that the R1 groups such as
H, CH3 and the R2 group such as Cl may be positive to
enhance the inhibitory activities.
S
N
H2N
HN
N
O
Figure 1. The structure of CYC116.
enaminones 4a–h by heating in N,N-dimethyl formamide
dimethyl acetal (DMF-DMA) and N,N-dimethyl formamide
(DMF). The aniline guanidines carbonate 6a–f were derived
from the corresponding anilines 5a–f by treatment of hydro-
chloride with cyanamide [18]. Enaminones 4a–h were then
condensed to the desired thiazolyl-pyrimidines at elevated
temperature catalyzed by sodium hydroxide in 2-methoxy-
ethanol with guanidines carbonate 6a–f. It is interesting that
according to the approach methods of Wang et al. isolation of
the structure of thiazolyl-pyrimidine is aryl-methylamino
group at the thiazole C2 position and not arylamino group
that been reported[19]. The structures of synthesized com-
On the other hand, comparing the activities among 25–29,
33–36 and 34–48 with the same R1 such as Cl, 3,4-Cl, 3-Cl-4-F
but different R2, the results revealed that the compounds
such as 28 (R2 ¼ 3-OCH3), 30 (R2 ¼ H), 31 (R2 ¼ 3-CH3), 32
(R2 ¼ 3-Cl), 33 (R2 ¼ 3-OCH3), 35 (R2 ¼ 3-CH3) and 42
(R2 ¼ 3-Cl) were beneficial for the inhibitory activities. The
most potent compound 30 exhibited significant activity
against Ishikawa, A549 and SGC-7901 with IC50 values of
1
pounds 7–43 were determined by H-NMR, MS, EA and IR.
A preliminary evaluation of the cytotoxic activity of all the
target compounds was performed by MTT assays in vitro
against several human cancer cell lines including endo-
metrial adenocarcinoma cell Ishikawa, human lung cancer
cell A549, human liver cancer cell BEL-7404, human lung
N
O
O
O
O
S
S
NH2
S
DMF-DMA
b
2
Cl
a
NH
N
N
N
R1
NH
R1
R1
1a-h
3a-h
4a-h
R2
NH2
NH
R2
NH2
c
N
H
d
5a-f
6a-f
H
N
N
R
R
1 = H, 2-CH3, 3-CH3, 4-CH3, 2-Cl, 4-Cl, 3,4-Cl, 3-Cl-4-F;
2 = H, 2-CH3, 3-CH3, 3-OCH3, 4-Cl, 4-F
R2
Scheme 1. Synthesis route of compounds 7–
43. Reagents and conditions: (a): Methanol,
reflux; (b): DMF-DMA, DMF, N2, 908C; (c):
Conc. HCl, 50% aq. cyanamide, 27% aq.
sodium carbonate, r.t. to 858C; (d): 2-
Methoxyethanol, NaOH, N2, 1108C.
N
S
N
N
7-43
R1
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Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
Synthesis of Novel Thiazolyl-Pyrimidines
677
Table 1. In-vitro cytotoxic activity of compounds 7–43 against human cancer cell lines.
Compds.
Substituent
Cell lines (IC50, mM)a,b
R1
R2
Ishikawa
A549
BEL-7404
SPC-A-01
SGC-7901
7
8
9
H
H
H
H
H
3-CH3
3-Cl
3-OCH3
4-F
H
3-CH3
3-Cl
3-OCH3
4-F
H
3-CH3
3-Cl
3-OCH3
4-F
H
3-CH3
3-Cl
H
3-CH3
3-Cl
3-OCH3
4-F
H
3-CH3
3-Cl
>268
21.03
1.99
>248
>256
60.96
26.81
1.85
22.18
>247
26.95
15.29
29.28
43.07
10.54
1.81
>268
82.66
2.90
>268
13.75
8.25
>268
42.69
46.11
>248
104.25
>258
>249
34.38
>240
>247
99.53
>249
100.90
57.65
37.01
61.16
104.36
70.20
>245
>238
>266
36.55
130.58
6.26
26.33
33.78
21.62
76.90
135.96
>219
106.57
>212
>235
103.09
218.93
37.87
>220
3.73
>268
18.60
11.24
>248
>256
117.78
25.16
3.65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
Cisplatin
>248
>256
>258
>249
10.75
>240
>247
19.22
90.17
142.51
41.08
23.38
10.72
21.60
26.95
17.99
>238
>226
19.82
141.93
1.52
>248
>256
112.79
31.15
17.46
50.58
>247
29.20
133.94
110.70
81.77
42.86
13.13
43.87
75.28
79.93
>238
>226
17.87
120.73
5.06
22.16
13.42
16.43
36.04
90.20
>219
36.43
>212
>235
48.33
160.52
19.59
>220
8.07
H
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
2-CH3
2-CH3
2-CH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2-Cl
2-Cl
2-Cl
2-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
40.74
>247
67.60
128.93
89.42
124.44
21.14
24.86
39.98
36.04
11.95
>238
92.96
58.38
119.06
12.64
39.50
11.58
12.73
12.62
60.50
>219
30.51
>212
158
4.21
16.30
48.27
>238
>226
24.16
>235
7.98
3.87
4.95
1.42
146
11.48
7.44
4.73
3-OCH3
H
3-CH3
2-CH3
3-Cl
3-OCH3
H
3-CH3
2-CH3
3-Cl
>226
74.80
132.68
61.76
89.68
34.45
76.50
98.61
56.83
>220
34.83
9.85
81.84
111.44
88.52
19.65
30.15
122.18
5.10
38.52
130.22
8.51
49.37
30.1
3-OCH3
>220
15.67
a
IC50, compound concentration required to inhibit tumor cell proliferation by 50%.b Values are the mean of three experiments.
7.98, 1.52 and 12.64 mM, respectively, which is 2-, 23-, and 2.4-
fold more potent than that of cisplatin. Moreover, comparing
the activities of compounds 30–33 with the same R1 (R1 ¼ 2-
Cl) and different R2 (R2 ¼ H, 3-CH3, 3-Cl, 3-OCH3), these all
exhibited significant cytotoxic activity against all of the
tested cell lines. In addition, when the ortho-methyl group
of 22–24 was replaced by the ortho-chloro group of 30–32, it
could be found that the ortho-chloro group could obviously
increase the cytotoxic activity. So the better substituent R1
may be 2-Cl moiety and positive to enhance the activities.
Furthermore, in order to investigate the effects of the
position of substituents R1 on the anticancer activity, com-
paring the compounds with the same R2 and the different R1
such as R2 ¼ H (12, 17 and 22) or R2 ¼ 3-OCH3 (28, 38 and 43)
or R2 ¼ 3-CH3 (13, 18 and 23) or R2 ¼ 3-CH3 (26, 31 and 35), it
showed IC50 values decreased in the sequence of ortho-, meta-
and para-position. Therefore, it inferred that cytotoxic
activity correlate with the presence of position of electron-
adopting group on the benzene ring and whether further
studies of other electron-adopting groups such as CF3, NO2,
etc., could enhance their anticancer activities or not are
under way.
In conclusion, a series of novel compounds 7–43 were
prepared and some of them showed high or moderate cyto-
toxic against human cancer cell lines. Among them, the most
potent compound 9 and 30 exhibited significant activity
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678
H.-B. Shi et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
m/z (%): 315 (Mþ, 23), 298 (9), 271 (75), 245 (13), 217 (8), 195 (17),
151 (100), 144 (21), 136 (45), 121 (23), 105 (15), 98 (55), 91 (23), 82
(11), 69 (12), 55 (28).
against Ishikawa, A549. The preliminary structure-activity
relationships showed the position of electron-adopting
group R1 on the benzene ring was related to cytotoxic inhibi-
tory effect.
3-Dimethylamino-1-[4-methyl-2-(methyl-m-tolyl-amino)-
thiazol-5-yl]-propenone 4c
Yield 56.4%. M.p. 187–1908C. IR: nmax (KBr) cmꢀ1: 3357, 2965,
2931, 2804, 1634, 1571, 1513, 1488, 1459, 1414, 1366, 1313.
Experimental
1H-NMR (CDCl3, TMS, 400 MHz,
–
d ppm): 7.70 (d, 1H,
J ¼ 12.4 Hz, CH), 7.27–7.24 (m, 1H, Ar-H), 7.14 (t, J ¼ 9.4 Hz,
Melting points were taken on X-4 apparatus and are uncorrected
(Shanghai Optical instrument, China). IR spectra (KBr pellets)
were obtained on a Bruker TENSOR27 spectrometer (Bruker
Optics, Germany). 1H NMR spectra were recorded on a Bruker
ADVANCE spectrometer operating at 400 MHz or a Bruker
AVANCE III spectrometer at 500 MHz using TMS as the internal
standard in CDCl3 (Bruker). MS spectra were recorded on an
HP5989B instrument (Agilent, USA). Elemental analyses were
–
2H, Ar-H), 6.93 (d, 1H, J ¼ 7.6 Hz, Ar-H), 5.33 (d, 1H, J ¼ 12 Hz,
–
CH), 3.52 (s, 3H, CH ), 2.99 (brs, 6H, 2 CH ), 2.61 (s, 3H, CH ), 2.37
–
3
3
3
(s, 3H, CH3). EIMS m/z (%): 315 (Mþ, 31), 300 (10), 271 (20), 257 (59),
231 (11), 195 (11), 151 (100), 136 (36), 98 (56), 91 (18), 60 (12),
55 (37).
performed on
a Flash EA1112 Elemental analyzer (CE,
3-Dimethylamino-1-[4-methyl-2-(methyl-p-tolyl-amino)-
thiazol-5-yl]-propenone 4d
ThermoFingnigan). Reagents and solvents were purchased from
SinoPharm Chemical Reagent Co., Ltd and were used without
further purification. The process of the reaction was monitored
by thin layer chromatography (TLC).
Yield 68.6%. M.p. 48–518C. IR: nmax (KBr) cmꢀ1: 3359, 3236, 2930,
2804, 1624, 1520, 1435, 1415, 1363, 1316. H-NMR (CDCl3, TMS,
1
–
400 MHz, d ppm): 7.62 (d, 1H, J ¼ 12 Hz, CH), 7.27 (d, 2H,
–
J ¼ 5.6 Hz, Ar-H), 7.24 (d, 2H, J ¼ 5.6 Hz, Ar-H), 5.20 (d, 1H,
–
J ¼ 12 Hz, CH), 3.51 (s, 3H, CH ), 2.93 (brs, 6H, 2 CH ), 2.63
–
Chemistry
3
3
(s, 3H, CH3), 2.38 (s, 3H, CH3). EIMS m/z (%): 315 (Mþ, 45), 298 (10),
271 (83), 245 (15), 217 (8), 195 (20), 151 (100), 144 (19), 136 (48),
121 (20), 105 (11), 98 (51), 91 (20), 82 (10), 69 (10), 55 (26).
The compounds 1a–h and 2-chloro-acetylacetone 2 were synthe-
sized according to the known method [15, 16, 20]. The com-
pounds 3a–h were prepared by the Hantsch’s method [17]. The
aniline guanidines carbonates 6 were prepared according to [18].
3-Dimethylamino-1-{2-[(2-Chloro-phenyl)-methyl-amino]-
4-methyl-thiazol-5-yl}-propenone 4e
General method for synthesis of compounds 4a–h
A
solution of 2-phenylamino-4-methyl-5-acetyl-thiazole 3a
Yield 41%. M.p. 50–528C. IR: nmax (KBr) cmꢀ1: 3425, 2922, 2803,
(2.32 g, 10 mmol) and N,N-dimethylformamide dimethylacetal
(3.57 g, 30 mmol) in DMF (20 mL) was heated at 908C under N2
for 14 h (EtOAc/toluene, 1:2, monitored by TLC). The reaction
mixture was cooled and poured into ice-water with stirring, then
stood overnight in refrigerator. When crude product separated
out as a dark solid or oil, it was filtered and washed liberally
with H2O, then purified by preparative layer chromatography,
eluting with toluene/ethyl acetate (2:1) to afford the title com-
pound 4a as a light-yellow solid. Compounds 4b–h were also
prepared by the procedure described above.
1638, 1552, 1503, 1433, 1366, 1316. 1H-NMR (CDCl3, TMS,
–
400 MHz, d ppm): 7.62 (d, 1H, J ¼ 12.4 Hz, CH), 7.55–7.53
–
(m, 1H, Ar-H), 7.44–7.41 (m, 1H, Ar-H), 7.39–7.35 (m, 2H, Ar-H),
–
5.19 (d, 1H, J ¼ 12.4 Hz, CH), 3.47 (s, 3H, CH ), 2.94 (brs, 6H, 2
–
3
CH3), 2.63 (s, 3H, CH3). EIMS m/z (%): 335 (Mþ, 26), 318 (10), 300
(43), 291 (67), 265 (20), 255 (11), 203 (26), 165 (14), 151 (64), 136
(100), 113 (23), 98 (81), 82 (13), 70 (18), 55 (35).
3-Dimethylamino-1-{2-[(4-chloro-phenyl)-methyl-amino]-
4-methyl-thiazol-5-yl}-propenone 4f
Yield 60.9%. M.p. 111–1138C. IR: nmax (KBr) cmꢀ1: 3426, 2918,
2812, 1634, 1547, 1490, 1434, 1400, 1363, 1340, 1316. 1H-NMR
3-Dimethylamino-1-[4-methyl-2-(methyl-phenyl-amino)-
thiazol-5-yl]-propenone 4a
–
(CDCl3, TMS, 400 MHz, d ppm): 7.64 (d, 1H, J ¼ 12.4 Hz, CH),
–
Yield 38.5%. M.p. 53–558C. IR: nmax (KBr) cmꢀ1: 3442, 2919,
7.39 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.35 (d, J ¼ 8.8 Hz, 2H, Ar-H), 5.22
2804, 1638, 1551, 1496, 1433, 1366, 1322. 1H-NMR (CDCl3,
–
–
(d, 1H, J ¼ 12.4 Hz, CH), 3.51 (s, 3H, CH ), 2.95 (brs, 6H, 2 CH ),
3
3
–
2.62 (s, 3H, CH3). EIMS m/z (%): 335 (Mþ, 35), 318 (8), 291 (70), 265
(14), 195 (26), 166 (16), 151 (100), 136 (55), 125 (10), 111 (10), 98
(60), 82 (12), 70 (16), 55 (35).
TMS, 400 MHz, d ppm): 7.63 (d, 1H, J ¼ 12 Hz, CH), 7.46–
–
7.38 (m, 4H, Ar-H), 7.32–7.27 (m, 1H, Ar-H), 5.21 (d, 1H,
–
J ¼ 12 Hz, CH), 3.54 (s, 3H, CH ), 2.94 (brs, 6H, 2 CH ), 2.63
–
3
3
(s, 3 H, CH3). EIMS m/z (%): 301 (Mþ, 40), 284 (10), 257 (78), 231 (19),
203 (12), 195 (17), 151 (100), 136 (47), 106 (17), 98 (61), 91 (14), 82
(11), 77 (20), 70 (12), 55 (25).
3-Dimethylamino-1-{2-[(3,4-dichloro-phenyl)-methyl-
amino]-4-methyl-thiazol-5-yl}-propenone 4g
Yield 50%. M.p. 115–1178C. IR: nmax (KBr) cmꢀ1: 3435, 3270, 3069,
2903, 2802, 1635, 1545, 1486, 1438, 1410, 1353, 1324. 1H-NMR
3-Dimethylamino-1-[4-methyl-2-(methyl-o-tolyl-amino)-
thiazol-5-yl]-propenone 4b
–
(CDCl , TMS, 500 MHz, d ppm): 7.69 (d, 1H, J ¼ 12 Hz, CH), 7.53
–
3
Yield 61.7%. M.p. 73–758C. IR: nmax (KBr) cmꢀ1: 3424, 2920, 2804,
(d, J ¼ 3 Hz, 1H, Ar-H), 7.49 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.31
1632, 1503, 1433, 1367, 1319. 1H-NMR (CDCl3, TMS, 400 MHz,
(dd, J1 ¼ 3.0 Hz, J2 ¼ 2.5 Hz, 1H, Ar-H), 5.25 (d, J ¼ 11.5 Hz,
–
1H, CH), 3.53 (s, 3H, CH ), 2.97 (brs, 6H, 2 CH ), 2.63 (s, 3H,
–
3 3
–
d ppm): 7.61 (d, 1H, J ¼ 12 Hz, CH), 7.35–7.28 (m, 3H, Ar-H),
–
–
CH3). EIMS m/z (%): 369 ([M - H]þ, 9), 355 (6), 325 (44), 195 (16), 177
7.25–7.18 (m, 1H, Ar-H), 5.16 (d, 1H, J ¼ 12 Hz, CH), 3.45 (s, 3H,
–
CH3), 2.91 (brs, 6H, 2 CH3), 2.63 (s, 3H, CH3), 2.25 (s, 3H, CH3). EIMS
(13), 151 (100), 136 (45), 98 (8).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
Synthesis of Novel Thiazolyl-Pyrimidines
679
3-Dimethylamino-1-{2-[(3-dichloro-4-fluoro–phenyl)-
{4-[2-(Phenyl-methyl-amino)-4-methyl-thiazol-5-y}-
methyl-amino]-4-methyl-thiazol-5-yl}-propenone 4h
Yield 72.3%. M.p. 95–978C. IR: nmax (KBr) cmꢀ1: 3439, 3030, 2908,
2808, 1640, 1549, 1496, 1434, 1417, 1363, 1331, 1311. 1H-NMR
pyrimidin-2-yl}-(3-methoxy-phenyl)-amine 10
Yield 63.6%. M.p. 174–1778C. IR: nmax (KBr) cmꢀ1: 3274, 3204,
3005, 1596, 1582, 1537, 1494, 1463, 1428, 1340, 1368, 1335.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.28 (s, 1H, J ¼ 4.4 Hz,
Py-H), 7.51–7.35 (m, 5H, Ar-H), 7.14 (t, 1H, J ¼ 8.0 Hz, Ar-H), 7.06
(s, 1H, Ar-H), 6.88 (d, 1H, J ¼ 8.0 Hz, Ar-H), 6.84 (d, 1H, J ¼ 5.2 Hz,
Py-H), 6.54 (d, 1H, J ¼ 8.0 Hz, Ar-H), 3.64 (s, 3H, OCH3), 3.57 (s, 3H,
CH3), 2.60 (s, 3H, CH3). EIMS m/z (%): 403 (Mþ, 100), 388 (8), 311 (9),
256 (10), 238 (9), 129 (10), 105 (8), 97 (10), 83 (10), 73 (17), 57 (21).
Anal. calcd. for C22H21N5OS: C, 65.49; H, 5.25; N, 17.36; Found: C,
65.42; H, 5.34; N, 17.30.
–
(CDCl , TMS, 400 MHz, d ppm): 7.65 (d, 1H, J ¼ 12 Hz, CH), 7.46
–
3
(dd, J1 ¼ 2.8 Hz, J2 ¼ 2.4 Hz, 1H, Ar-H), 7.32–7.28 (m, 1H, Ar-H),
–
7.19 (t, J ¼ 8.8 Hz, 1H, Ar-H), 5.23 (d, 1H, J ¼ 12 Hz, CH), 3.49
–
(s, 3H, CH3), 2.97 (brs, 6H, 2 CH3), 2.61 (s, 3H, CH3). EIMS m/z (%):
355 (Mþ, 32), 336 (9), 309 (67), 283 (13), 195 (24), 184 (9), 162 (16),
151 (100), 136 (57), 129 (10), 98 (70), 82 (13), 70 (22), 55 (34).
General method for preparation of compounds 7–43
A
mixture of 3-dimethylamino-1-[4-methyl-2-(methyl-phenyl-
{4-[2-(Phenyl-methyl-amino)-4-methyl-thiazol-5-y}-
amino)-thiazol-5-yl]-propenone (1.51 g, 5 mmol) and NaOH
(0.2 g, 5 mmol) in 2-methoxylethanol (20 mL) was treated with
N-phenyl-guanidine carbonate (1.48 g, 7.5 mmol). The reaction
mixture was heated at 1108C under N2 for 21 h. After concen-
tration, the residue was filtered and washed liberally with
ethanol and water. Recrystallization from acetone afforded the
title compound 7 as light-yellow needle crystals. Compounds 8–43
were also prepared by the procedure described above.
pyrimidin-2-yl}-(4-fluoro-phenyl)-amine 11
Yield 45.2%. M.p. 211–2138C. IR: nmax (KBr) cmꢀ1: 3433, 3260,
3049, 2920, 1622, 1574, 1541, 1507, 1488, 1425, 1405, 1366,
1335. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.23 (brs, 1H,
Py-H), 7.48–6.95 (m, 9H, Ar-H), 6.81 (brs, 1H, Py-H), 3.58 (s, 3H,
CH3), 3.60 (s, 3H, CH3). EIMS m/z (%): 391 (Mþ, 100), 299 (16), 226
(13), 97 (9), 83 (13), 71 (16), 57 (25). Anal. calcd. for C21H18FN5S: C,
64.43; H, 4.63; N, 17.89; Found: C, 64.41; H, 4.79; N, 17.94.
{4-[2-(Phenyl-methyl-amino)-4-methyl-thiazol-5-yl}-
pyrimidin-2-yl}-phenylamine 7
{4-[2-(p-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
Yield 60.6%. M.p. 214–2178C. IR: nmax (KBr) cmꢀ1: 3425, 3257,
3189, 3042, 1618, 1598, 1580, 1486, 1448, 1402, 1340. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.28 (d, 1H, J ¼ 4.8 Hz, Py-H), 7.58
(d, 2H, J ¼ 7.6 Hz, Ar-H), 7.47–7.45 (m, 3H, Ar-H), 7.39–7.34
(m, 1H, Ar-H), 7.28–7.24 (m, 2H, Ar-H), 7.01–6.99 (m, 2H, Ar-H),
6.81 (d, 1H, J ¼ 5.2 Hz, Py-H), 3.58 (s, 3H, CH3), 2.61 (s, 3H, CH3).
EIMS m/z (%): 373 (Mþ, 100), 358 (8), 281 (13), 240 (12), 208 (14), 186
(14), 77 (12). Anal. calcd. for C21H19N5S: C, 67.53; H, 5.13; N, 18.75;
Found: C, 67.37; H, 5.22; N, 18.65.
pyrimidin-2-yl}-phenyl-amine 12
Yield 34.5%. M.p. 191–1948C. IR: nmax (KBr) cmꢀ1: 3425, 3261,
3040, 1618, 1580, 1540, 1513, 1488, 1447, 1340. 1H-NMR (CDCl3,
TMS, 500 MHz, d ppm): 8.26 (d, 1H, J ¼ 5.5 Hz, Py-H), 7.57 (d, 2H,
J ¼ 8 Hz, Ar-H), 7.31–7.24 (m, 5H, Ar-H), 7.06 (s, 1H, Ar-H), 6.99
(t, 1H, J ¼ 7.5 Hz, Ar-H), 6.79 (d, 1H, J ¼ 5.0 Hz, Py-H), 3.54 (s, 3H,
CH3), 2.60 (s, 3H, CH3), 2.41 (s, 3H, CH3). EIMS m/z (%): 387 (Mþ,
100), 372 (8), 281 (12), 240 (10), 208 (12), 193 (14), 105 (8), 91 (8), 77
(9). Anal. calcd. for C22H21N5S: C, 68.19; H, 5.46; N, 18.07. Found:
C, 68.32; H, 5.33; N, 18.15.
{4-[2-(Phenyl-methyl-amino)-4-methyl-thiazol-5-y}-
{4-[2-(p-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-m-tolyl-amine 8
Yield 4%. M.p. 160–1638C. IR: nmax (KBr) cmꢀ1: 3420, 3268, 3160,
3088, 2980, 1625, 1589, 1525, 1493, 1469, 1395, 1296. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.26 (d, 1H, J ¼ 5.6 Hz, Py-H), 7.64
(s, 1H, Ar-H), 7.48–7.42 (m, 3H, Ar-H), 7.38–7.31 (m, 1H, Ar-H),
7.17–7.11 (m, 3H, Ar-H), 6.82 (d, 1H, J ¼ 5.2 Hz, Py-H), 6.79
(mꢁ, 1H, Ar-H), 3.58 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.21 (s, 3H,
CH3) (ꢁ overlapped with Py-H). EIMS m/z (%): 387 (Mþ, 100), 372 (9),
295 (15), 254 (9), 222 (14). Anal. calcd. for C22H21N5S: C, 68.19;
H, 5.46; N, 18.07; Found: C, 68.26; H, 5.25; N, 18.11.
pyrimidin-2-yl}-m-tolyl-amine 13
Yield 22.8%. M.p. 183–1858C. IR: nmax (KBr) cmꢀ1: 3417, 3269,
3202, 3066, 3034, 1601, 1563, 1539, 1492, 1428, 1400, 1367,
1335. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.25 (d, 1H,
J ¼ 4.8 Hz, Py-H), 7.69 (s, 1H, Ar-H), 7.33–7.25 (m, 4H, Ar-H),
7.19–7.11 (m, 2H, Ar-H), 6.86 (mꢁ, 1H, Ar-H), 6.79 (brs, 1H,
Py-H), 3.53 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.19
(s, 3H, CH3) (ꢁ overlapped with Py-H). EIMS m/z (%): 401 (Mþ, 100),
386 (8), 295 (19), 254 (8), 222 (12). Anal. calcd. for C23H23N5S:
C, 68.80; H, 5.77; N, 17.44; Found: C, 68.94; H, 5.91; N, 17.21.
{4-[2-(Phenyl-methyl-amino)-4-methyl-thiazol-5-y}-
{4-[2-(p-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-(3-chloro-phenyl)-amine 9
Yield 19.7%. M.p. 204–2078C. IR: nmax (KBr) cmꢀ1: 3426, 3268,
3184, 3110, 1598, 1575, 1531, 1490, 1421, 1410, 1365, 1333.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.27 (d, 1H, J ¼ 5.6 Hz,
Py-H), 8.03 (s, 1H, NH), 7.49–7.39 (m, 4H, Ar-H), 7.35–7.29 (m, 2H,
Ar-H), 7.15–7.14 (m, 2H, Ar-H), 6.94 (d, 1H, J ¼ 4.0 Hz, Ar-H), 6.86
(d, 1H, J ¼ 5.2 Hz, Py-H), 3.58 (s, 3H, CH3), 2.61 (s, 3H, CH3).
EIMS m/z (%): 407 (Mþ, 100), 315 (29), 303 (15), 274 (8), 242
(10), 207 (20), 186 (9), 164 (11), 91 (7), 77 (7). Anal. calcd. for
C21H18ClN5S: C, 61.83; H, 4.45; N, 17.17; Found: C, 61.75; H, 4.33;
N, 17.03.
pyrimidin-2-yl}-(3-chloro-phenyl)-amine 14
Yield 36.9%. M.p. 206–2088C. IR: nmax (KBr) cmꢀ1: 3425, 3267,
2920, 1607, 1576, 1531, 1495, 1425, 1400, 1368, 1334. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.27 (d, 1H, J ¼ 5.2 Hz, Py-H), 8.06
(s, 1H, NH), 7.31–7.27 (m, 3H, Ar-H), 7.21–7.10 (m, 4H, Ar-H), 6.94
(d, 1H, J ¼ 7.2 Hz, Ar-H), 6.85 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.55
(s, 3H, CH3), 2.61 (s, 3H, CH3), 2.40 (s, 3H, CH3). EIMS m/z (%):
421 (Mþ, 100), 406 (8), 388 (5), 315 (27), 303 (12), 207 (10). Anal.
calcd. for C22H20ClN5S: C, 62.62; H, 4.78; N, 16.60; Found: C,
62.78; H, 4.57; N, 16.65.
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680
H.-B. Shi et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
{4-[2-(p-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
{4-[2-(m-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-(3-methoxy-phenyl)-amine 15
pyrimidin-2-yl}-(3-methoxy-phenyl)-amine 20
Yield 46.7%. M.p. 180–1838C. IR: nmax (KBr) cmꢀ1: 3460, 3280,
3207, 3132, 3076, 3013, 1620, 1584, 1553, 1529, 1501, 1464,
1445, 1422, 1407, 1376, 1361, 1318. 1H-NMR (CDCl3, TMS,
400 MHz, d ppm): 8.27 (s, 1H, J ¼ 4.8 Hz, Py-H), 7.53 (s, 1H,
Ar-H), 7.29–7.07 (m, 5H, Ar-H), 6.87 (d, 1H, J ¼ 8.0 Hz, Ar-H),
6.83 (d, 1H, J ¼ 5.2 Hz, Py-H), 6.54 (d, 1H, J ¼ 8.0 Hz, Ar-H),
3.64 (s, 3H, OCH3), 3.54 (s, 3H, CH3), 2.60 (s, 3H, CH3), 2.41
(s, 3H, CH3). EIMS m/z (%): 417 (Mþ, 100), 402 (7), 311 (12), 105
(9), 91 (10), 73 (12), 57 (17). Anal. calcd. for C23H23N5OS: C, 66.16;
H, 5.55; N, 16.77; Found: C, 66.23; H, 5.69; N, 16.96.
Yield 55.1%. M.p. 183–1848C. IR: nmax (KBr) cmꢀ1: 3272, 3208,
3191, 3119, 3047, 3005, 1953, 1582, 1566, 1538, 1503, 1457,
1428, 1399, 1371, 1333. 1H-NMR (CDCl3, TMS, 400 MHz,
d ppm): 8.27 (s, 1H, J ¼ 5.2 Hz, Py-H), 7.51 (s, 1H, NH), 7.35
(t, 1H, J ¼ 7.6 Hz, Ar-H), 7.21–7.12 (m, 4H, Ar-H), 7.06 (s, 1H,
Ar-H), 6.89 (d, 1H, J ¼ 8.0 Hz, Ar-H), 6.84 (d, 1H, J ¼ 5.2 Hz,
Py-H), 6.54 (d, 1H, J ¼ 8.4 Hz, Ar-H), 3.64 (s, 3H, OCH3), 3.55
(s, 3H, CH3), 2.60 (s, 3H, CH3), 2.40 (s, 3H, CH3). EIMS m/z (%):
417 (Mþ, 100), 402 (8), 311 (10), 270 (9), 238 (8), 208 (9), 91 (8). Anal.
calcd. for C23H23N5OS: C, 66.16; H, 5.55; N, 16.77; Found: C, 66.41;
H, 5.35; N, 16.65.
{4-[2-(p-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
{4-[2-(m-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-(4-fluoro-phenyl)-amine 16
Yield 67.6%. M.p. 215–2188C. IR: nmax (KBr) cmꢀ1: 3425, 3260,
3216, 3041, 1621, 1574, 1541, 1506, 1488, 1424, 1402, 1366,
1337. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.24 (s, 1H,
J ¼ 5.2 Hz, Py-H), 7.52–7.49 (m, 2H, Ar-H), 7.31–7.28 (m, 3H,
Ar-H), 6.96–6.93 (m, 3H, Ar-H), 6.79 (s, 1H, J ¼ 5.2 Hz, Py-H),
3.54 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.41 (s, 3H, CH3). EIMS
m/z (%): 405 (Mþ, 100), 391 (13), 299 (16), 226 (13), 105 (10),
91 (9). Anal. calcd. for C22H20FN5S: C, 65.16; H, 4.97; N, 17.27;
Found: C, 65.39; H, 4.83; N, 17.42
pyrimidin-2-yl}-(4-fluoro-phenyl)-amine 21
Yield 43.8%. M.p. 152–1538C. IR: nmax (KBr) cmꢀ1: 3454, 3280,
3219, 3124, 3056, 1619, 1588, 1557, 1536, 1505, 1463, 1417,
1365, 1340, 1317. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm):
8.25 (s, 1H, J ¼ 3.2 Hz, Py-H), 7.50 (mꢁ, 1H, Ar-H), 7.37–7.33
(m, 1H, Ar-H), 7.23–7.15 (m, 3H, Ar-H), 7.00–6.93 (m, 3H, Ar-H),
6.80 (s, 1H, J ¼ 3.6 Hz, Py-H), 3.56 (s, 3H, CH3), 2.59 (s, 3H, CH3),
2.41 (s, 3H, CH3) (ꢁ overlapped with NH). EIMS m/z (%): 405
(Mþ, 100), 390 (8), 299 (14), 226 (12). Anal. calcd. for
C22H20FN5S: C, 65.16; H, 4.97; N, 17.27; Found: C, 65.29;
H, 4.86; N, 17.23.
{4-[2-(m-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-phenyl-amine 17
Yield 8.2%. M.p. 170–1738C. IR: nmax (KBr) cmꢀ1: 3422, 3265, 3188,
3032, 1644, 1605, 1580, 1536, 1496, 1445, 1369, 1339. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.27 (d, 1H, J ¼ 5.2 Hz, Py-H), 7.58
(d, 2H, J ¼ 8.0 Hz, Ar-H), 7.35 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.28–7.22
(m, 4H, Ar-H), 7.15 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.00 (t, 1H, J ¼ 7.4 Hz,
Ar-H), 6.81 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.56 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 2.41 (s, 3H, CH3). EIMS m/z (%): 387 (Mþ, 100), 372 (6), 281
(17), 269 (7), 208 (13). Anal. calcd. for C22H21N5S: C, 68.19; H, 5.46;
N, 18.07; Found: C, 68.35; H, 5.31; N, 18.15.
{4-[2-(o-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-phenyl-amine 22
Yield 40%. M.p. 181–1838C. IR: nmax (KBr) cmꢀ1: 3425, 3266, 3193,
3110, 3047, 1612, 1583, 1539, 1497, 1447, 1370, 1340, 1323. 1H-
NMR (CDCl3, TMS, 400 MHz, d ppm): 8.25 (d, 1H, J ¼ 5.2 Hz, Py-H),
7.55 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.38–7.27 (m, 4H, Ar-H), 7.25–7.21
(m, 2H, Ar-H), 6.98 (t, 1H, J ¼ 7.4 Hz, Ar-H), 6.93 (s, 1H, NH), 6.78
(d, 1H, J ¼ 5.2 Hz, Py-H), 3.49 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.29
(s, 3H, CH3). EIMS m/z (%): 387 (Mþ, 100), 372 (35), 354 (16), 263
(50), 256 (8), 235 (8), 208 (14), 194 (8), 185 (13), 171 (8), 146 (13),
129 (11), 118 (23), 91 (17), 77 (33), 65 (17), 55 (22). Anal. calcd. for
C22H21N5S: C, 68.19; H, 5.46; N, 18.07; Found: C, 68.35; H, 5.63;
N, 18.28.
{4-[2-(m-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-m-tolyl-amine 18
Yield 14.6%. M.p. 165–1678C. IR: nmax (KBr) cmꢀ1: 3424, 3267,
3054, 1599, 1579, 1558, 1428, 1398, 1369, 1339. 1H-NMR (CDCl3,
TMS, 400 MHz, d ppm): 8.26 (d, 1H, J ¼ 5.6 Hz, Py-H), 7.63 (s, 1H,
Ar-H), 7.34 (t, 1H, J ¼ 8.0 Hz, Ar-H), 7.22 (d, 2H, J ¼ 6.4 Hz, Ar-H),
7.18–7.11 (m, 3H, Ar-H), 7.08 (s, 1H, Ar-H), 6.81 (d, 1H, J ¼ 5.6 Hz,
Py-H), 3.56 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.21
(s, 3H, CH3). EIMS m/z (%): 401 (Mþ, 100), 386 (9), 269 (11), 256 (14),
237 (12), 222 (10). Anal. calcd. for C23H23N5S: C, 68.80; H, 5.77;
N, 17.44; Found: C, 68.61; H, 5.65; N, 17.65.
{4-[2-(o-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-m-tolyl-amine 23
Yield 58.5%. M.p. 182–1858C. IR: nmax (KBr) cmꢀ1: 3424, 3268,
3201, 1601, 1581, 1561, 1542, 1509, 1423, 1368, 1337. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.24 (d, 1H, J ¼ 5.2 Hz, Py-H), 7.65
(s, 1H, Ar-H), 7.36–7.27 (m, 4H, Ar-H), 7.13–7.09 (m, 2H, Ar-H), 6.92
(s, 1H, Ar-H), 6.79 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.49 (s, 3H, CH3), 2.61
(s, 3H, CH3), 2.29 (s, 3H, CH3), 2.15 (s, 3H, CH3). EIMS m/z (%): 401
(Mþ, 100), 386 (28), 368 (17), 283 (9), 222 (8), 129 (10), 118 (8), 98
(11), 91 (15), 83 (12), 73 (21), 65 (10), 57 (28). Anal. calcd.
for C23H23N5S: C, 68.80; H, 5.77; N, 17.44; Found: C, 68.72;
H, 5.65; N, 17.58.
{4-[2-(m-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-(3-chloro-phenyl)-amine 19
Yield 41.2%. M.p. 173–1758C. IR: nmax (KBr) cmꢀ1: 3431, 3264, 3182,
3105, 1607, 1575, 1532, 1497, 1424, 1332. 1H-NMR (CDCl3, TMS,
400 MHz, d ppm): 8.28 (brs, 1H, Py-H), 8.01 (s, 1H, NH), 7.35 (s, 1H,
Ar-H), 7.26–7.12 (m, 6H, Ar-H), 6.94 (s, 1H, Ar-H), 6.86 (brs, 1H, Py-H),
3.56 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.40 (s, 3H, CH3). EIMS m/z (%): 421
(Mþ, 100), 406 (5), 315 (16), 274 (8), 242 (9), 209 (14), 193 (23), 178
(10), 164 (10), 120 (10), 105 (18), 91 (18). Anal. calcd. for C22H20ClN5S:
C, 62.62; H, 4.78; N, 16.60; Found: C, 62.85; H, 4.99; N, 16.55.
{4-[2-(o-Tolyl-methyl-amino)-4-methyl-thiazol-5-y}-
pyrimidin-2-yl}-(3-chloro-phenyl)-amine 24
Yield 38.7%. M.p. 195–1988C. IR: nmax (KBr) cmꢀ1: 3422, 3265,
3183, 3101, 3067, 3016, 1599, 1575, 1561, 1525, 1422, 1367,
1336. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.26 (d, 1H,
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Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
Synthesis of Novel Thiazolyl-Pyrimidines
681
J ¼ 5.2 Hz, Py-H), 8.01 (s, 1H, NH), 7.35–7.28 (m, 4H, Ar-H), 7.15–
7.07 (m, 3H, Ar-H), 6.91 (d, 1H, J ¼ 6.0 Hz, Ar-H), 6.83 (d, 1H,
J ¼ 5.6 Hz, Py-H), 3.50 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.29 (s, 3H,
CH3). EIMS m/z (%): 421 (Mþ, 100), 406 (32), 388 (15), 303 (13), 284
(18), 256 (14), 241 (10), 213 (10), 185 (14), 171 (11), 157 (8), 129 (28),
118 (10), 105 (15), 97 (18), 83 (21), 73 (60), 55 (53). Anal. calcd. for
C22H20ClN5S: C, 62.62; H, 4.78; N, 16.60; Found: C, 62.36; H, 4.62;
N, 16.51.
(4-{2-[(4-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-(4-fluoro-phenyl)-amine 29
Yield 69.3%. M.p. 216–2178C. IR: nmax (KBr) cmꢀ1: 3423, 3264, 3222,
3050, 1625, 1578, 1539, 1493, 1427, 1399, 1369, 1337. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.25 (s, 1H, J ¼ 5.2 Hz, Py-H), 7.53–
7.50 (m, 2H, Ar-H), 7.40 (dd, 4H, J1 ¼ 8.4 Hz, J2 ¼ 8.8 Hz, Ar-H),
7.16 (s, 1H, NH), 6.98 (t, 2H, J ¼ 8.4 Hz, Ar-H), 6.81 (s, 1H,
J ¼ 5.2 Hz, Py-H), 3.55 (s, 3H, CH3), 2.59 (s, 3H, CH3). EIMS m/z
(%): 425 (Mþ, 100), 299 (22), 258 (10), 226 (19), 212 (9), 111 (8), 95 (9),
83 (8), 57 (8). Anal. calcd. for C21H17ClFN5S: C, 59.22; H, 4.02;
N, 16.44; Found: C, 59.36; H, 4.13; N, 16.62.
(4-{2-[(4-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-phenyl-amine 25
Yield 23.2%. M.p. 203–2058C. IR: nmax (KBr) cmꢀ1: 3426, 3258,
3188, 3044, 1617, 1571, 1541, 1488, 1447, 1403, 1367, 1341.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.28 (d, 1H, J ¼ 5.2 Hz,
Py-H), 7.58 (d, 2H, J ¼ 7.6 Hz, Ar-H), 7.44–7.36 (m, 4H, Ar-H), 7.32–
7.29 (m, 2H, Ar-H), 7.03 (t, 1H, J ¼ 7.2 Hz, Ar-H), 6.83 (d, 1H,
J ¼ 5.6 Hz, Py-H), 3.55 (s, 3H, CH3), 2.60 (s, 3H, CH3). EIMS m/z
(%): 407 (Mþ, 100), 392 (9), 372 (5), 281 (35), 267 (7), 240 (14), 208
(27). Anal. calcd. for C21H18ClN5S: C, 61.83; H, 4.45; N, 17.17;
Found: C, 61.75; H, 4.35; N, 17.29.
(4-{2-[(2-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-phenyl-amine 30
Yield 40.8%. M.p. 168–1708C. IR: nmax (KBr) cmꢀ1: 3416, 3267,
3192, 3115, 3059, 3034, 2927, 2860, 1934, 1934, 1611, 1580,
1537, 1499, 1434, 1402, 1370, 1338. 1H-NMR (CDCl3, TMS,
400 MHz, d ppm): 8.27 (s, 1H, J ¼ 5.2 Hz, Py-H), 7.58–7.54
(m, 3H, Ar-H), 7.46–7.45 (m, 1H, Ar-H), 7.41–7.39 (m, 2H, Ar-H),
7.24–7.22 (m, 1H, Ar-H), 7.02–6.97 (m, 2H, Ar-H), 6.80 (d, 1H,
J ¼ 5.2 Hz, Py-H), 3.51 (s, 3H, CH3), 2.61 (s, 3H, CH3). EIMS m/z
(%): 407 (Mþ, 91), 372 (100), 240 (12), 238 (8), 208 (20), 186 (44), 77
(19). Anal. calcd. for C21H18ClN5S: C, 61.83; H, 4.45; N, 17.17;
Found: C, 61.79; H, 4.63; N, 17.11.
(4-{2-[(4-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-m-tolyl-amine 26
Yield 17.5%. M.p. 205–2088C. IR: nmax (KBr) cmꢀ1: 3425, 3280,
1601, 1580, 1561, 1539, 1490, 1425, 1401, 1368, 1336. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.27 (d, 1H, J ¼ 5.6 Hz, Py-H), 7.65
(s, 1H, Ar-H), 7.40 (dd, 4H, J1 ¼ 8.8 Hz, J2 ¼ 8.8 Hz, Ar-H), 7.15
(d, 3H, J ¼ 4.8 Hz, Ar-H), 6.83 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.55 (s, 3H,
CH3), 2.60 (s, 3H, CH3), 2.24 (s, 3H, CH3). EIMS m/z (%): 421
(Mþ, 100), 406 (10), 295 (23), 254 (11), 222 (17), 207 (10). Anal.
calcd. for C22H20ClN5S: C, 62.62; H, 4.78; N, 16.60; Found: C,
62.79; H, 4.67; N, 16.51.
(4-{2-[(2-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-m-tolyl-amine 31
Yield 56.7%. M.p. 189–1918C. IR: nmax (KBr) cmꢀ1: 3425, 3269,
3200, 3068, 1925, 1752, 1601, 1580, 1563, 1541, 1505, 1423,
1401, 1367, 1336. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.23
(brs, 1H, Py-H), 7.64 (s, 1H, NH), 7.58–7.56 (m, 1H, Ar-H), 7.45–7.39
(m, 3H, Ar-H), 7.22–7.12 (m, 3H, Ar-H), 6.81 (d, 1H, J ¼ 5.6 Hz,
Py-H), 6.79 (mꢁ, 1H, Ar-H), 3.52 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.17
(s, 3H, CH3) (ꢁ overlapped with Py-H). EIMS m/z (%): 421 (Mþ, 100),
406 (11), 386 (90), 254 (10), 222 (13), 207 (9), 193 (15), 186 (33), 129
(12), 111 (10), 91 (13), 73 (19), 57 (23). Anal. calcd. for C22H20ClN5S:
C, 62.62; H, 4.78; N, 16.60; Found: C, 62.71; H, 4.64; N, 16.37.
(4-{2-[(4-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-(3-chloro-phenyl)-amine 27
Yield 50.1%. M.p. 226–2298C. IR: nmax (KBr) cmꢀ1: 3424, 3266,
3184, 3109, 1614, 1595, 1575, 1532, 1486, 1424, 1365, 1338.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.18 (d, 1H, J ¼ 5.2 Hz,
Py-H), 8.06 (s, 1H, NH), 7.44–7.34 (m, 4H, Ar-H), 7.17–7.02 (m, 4H,
Ar-H), 6.89 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.58 (s, 3H, CH3), 2.63 (s, 3H,
CH3). EIMS m/z (%): 441 (Mþ, 100), 406 (8), 315 (66), 303 (15), 274
(13), 242 (16), 207 (28), 202 (11), 164 (11), 125 (11), 75 (8). Anal.
calcd. for C21H17Cl2N5S: C, 57.02; H, 3.87; N, 15.83; Found: C,
57.21; H, 3.73; N, 15.95.
(4-{2-[(2-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-(3-chloro-phenyl)-amine 32
Yield 53%. M.p. 195–1988C. IR: nmax (KBr) cmꢀ1: 3417, 3261, 3180,
3067, 3005, 1815, 1747, 1608, 1576, 1503, 1419, 1368, 1536.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.28 (s, 1H, J ¼ 5.2 Hz,
Py-H), 8.03 (s, 1H, NH), 7.57–7.55 (m, 1H, Ar-H), 7.47–7.45 (m, 1H,
Ar-H), 7.39–7.38 (m, 2H, Ar-H), 7.16–7.08 (m, 3H, Ar-H), 6.92 (d, 1H,
J ¼ 7.2 Hz, Ar-H), 6.86 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.52 (s, 3H, CH3),
2.62 (s, 3H, CH3). EIMS m/z (%): 441 (M þ, 67), 406 (100), 331 (10),
296 (13), 256 (11), 207 (13), 186 (35), 164 (9), 129 (15), 111 (16), 97
(14), 85 (15), 73 (32), 57 (35). Anal. calcd. for C21H17Cl2N5S:
C, 57.02; H, 3.87; N, 15.83; Found: C, 57.15; H, 3.95; N, 15.79.
(4-{2-[(4-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-(3-methoxy-phenyl)-amine 28
Yield 60%. M.p. 180–1838C. IR: nmax (KBr) cmꢀ1: 3419, 3280, 3197,
3121, 3067, 3053, 1598, 1583, 1561, 1537, 1491, 1456, 1429,
1401, 1369, 1338. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.28
(s, 1H, J ¼ 4.4 Hz, Py-H), 7.49 (s, 1H, NH), 7.40 (dd, 4H, J1 ¼ 8.0 Hz,
J2 ¼ 8.0 Hz, Ar-H), 7.16 (t, 2H, J ¼ 8.0 Hz, Ar-H), 6.92 (d, 1H,
J ¼ 7.6 Hz, Ar-H), 6.85 (d, 1H, J ¼ 4.8 Hz, Py-H), 6.57 (d, 1H,
J ¼ 8.0 Hz, Ar-H), 3.71 (s, 3H, OCH3), 3.54 (s, 3H, CH3), 2.59
(s, 3H, CH3). EIMS m/z (%): 437 (Mþ, 100), 422 (8), 403 (10),
311 (10), 284 (9), 270 (9), 256 (9), 238 (10), 185 (9), 129 (17),
111 (14), 97 (20), 83 (21), 73 (33), 55 (48). Anal. calcd. for
C22H20ClN5OS: C, 60.34; H, 4.60; N, 15.99; Found: C, 60.52;
H, 4.71; N, 15.87.
(4-{2-[(2-Chloro-phenyl)-methyl-amino]-4-methyl-thiazol-
5-yl}-pyrimidin-2-yl)-(3-methoxy-phenyl)-amine 33
Yield 43.6%. M.p. 165–1678C. IR: nmax (KBr) cmꢀ1: 3424, 3282, 3212,
3114, 3012, 1585, 1538, 1503, 1462, 1424, 1399, 1368, 1337.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.28 (brs, 1H, Py-H),
7.57–6.85 (m, 8H, Ar-H), 6.52 (brs,1H, Py-H), 3.64 (s, 3H, OCH3),
3.50 (s, 3H, CH3), 2.61 (s, 3H, CH3). EIMS m/z (%): 437 (Mþ, 100), 402
(72), 256 (11), 201 (12), 185 (16), 129 (13), 111 (12), 97 (18), 83 (17), 73
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

682
H.-B. Shi et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
(29), 57 (42). Anal. calcd. for C22H20ClN5OS: C, 60.34; H, 4.60; N,
15.99; Found: C, 60.39; H, 4.53; N, 15.83.
(4-{2-[(3,4-Dichloro-phenyl)-methyl-amino]-4-methyl-
thiazol-5-yl}-pyrimidin-2-yl)-(3-methoxy-phenyl)-amine 38
Yield 41.6%. M.p. 184–1868C. IR: nmax (KBr) cmꢀ1
: 3384,
(4-{2-[(3,4-Dichloro-phenyl)-methyl-amino]-4-methyl-
3261, 3054, 3016, 1699, 1627, 1574, 1543, 1503, 1460, 1430,
1407, 1370, 1338. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm):
8.32 (d, 1H, J ¼ 5.6 Hz, Py-H), 7.56 (d, 1H, J ¼ 2.4 Hz, Ar-H),
7.51 (d, 1H, J ¼ 8.4 Hz, Ar-H), 7.46 (t, 1H, J ¼ 2.2 Hz, Ar-H),
7.33 (dd, 1H, J1 ¼ 2.8 Hz, J2 ¼ 2.4 Hz, Ar-H), 7.19 (t, 1H,
J ¼ 8.4 Hz, Ar-H), 7.02 (brs, 1H, NH), 6.97 (dd, 1H, J1 ¼ 1.2 Hz,
J2 ¼ 1.6 Hz, Ar-H), 6.86 (d, 1H, J ¼ 5.6 Hz, Py-H), 6.58 (dd, 1H,
J1 ¼ 2.0 Hz, J2 ¼ 2.0 Hz, Ar-H), 3.75 (s, 3H, OCH3), 3.54 (s, 3H,
CH3), 2.59 (s, 3H, CH3). EIMS m/z (%): 471 (Mþ, 100), 456 (10), 440
(7), 311 (10), 270 (9), 256 (15), 238 (12), 213 (10), 185 (10), 171 (8),
129 (17), 111 (10), 97 (15), 83 (16), 73 (42), 55 (39). Anal. calcd. for
C22H19Cl2N5OS: C, 55.94; H, 4.05; N, 14.83; Found: C, 55.76;
H, 4.31; N, 14.75.
thiazol-5-yl}-pyrimidin-2-yl)-phenyl-amine 34
Yield 20.4%. M.p. 178–1798C. IR: nmax(KBr) cmꢀ1: 3425, 3276,
3116, 3067, 3047, 1613, 1580, 1553, 1496, 1427, 1402, 1365,
1344. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.29 (d, 1H,
J ¼ 5.2 Hz, Py-H), 7.61–7.59 (m, 3H, Ar-H), 7.51 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.34–7.29 (m, 3H, Ar-H), 7.04 (t, 1H,
J ¼ 7.4 Hz, Ar-H), 6.84 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.55 (s, 3H,
CH3), 2.60 (s, 3H, CH3). EIMS m/z (%): 441 (Mþ, 100), 426 (9),
281 (18), 256 (17), 240 (17), 221 (9), 208 (27), 185 (11), 171 (10),
129 (23), 111 (11), 97 (18), 83 (20), 73 (53), 55 (47). Anal. calcd. for
C21H17Cl2N5S: C, 57.02; H, 3.87; N, 15.83; Found: C, 57.21; H, 3.71;
N, 15.97.
(4-{2-[(3,4-Dichloro-phenyl)-methyl-amino]-4-methyl-
(4-{2-[(3-Chloro-4-fluoro-phenyl)-methyl-amino]-4-methyl-
thiazol-5-yl}-pyrimidin-2-yl)-m-tolyl-amine 35
thiazol-5-yl}-pyrimidin-2-yl)-phenyl-amine 39
Yield 15%. M.p. 199–2008C. IR: nmax (KBr) cmꢀ1: 3424, 3266, 3201,
3067, 1601, 1581, 1563, 1541, 1496, 1425, 1401, 1368, 1336.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.30 (d, 1H, J ¼ 5.2 Hz,
Py-H), 7.61 (s, 1H, Ar-H), 7.57 (d, 1H, J ¼ 2.8 Hz, Ar-H), 7.51 (d, 1H,
J ¼ 8.8 Hz, Ar-H), 7.33 (dd, 1H, J1 ¼ 2.4 Hz, J2 ¼ 2.4 Hz, Ar-H),
7.23–7.15 (m, 2H, Ar-H), 7.04 (s, 1H, Ar-H), 6.84 (d, 1H, J ¼ 5.6 Hz,
Py-H), 3.54 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.27 (s, 3H, CH3). EIMS m/z
(%): 455 (Mþ, 100), 440 (9), 295 (11), 256 (12), 222 (13), 213 (9), 185
(10), 171 (8), 129 (19), 111 (9), 97 (16), 85 (19), 73 (41), 65 (8), 57 (48).
Anal. calcd. for C22H19Cl2N5S: C, 57.90; H, 4.20; N, 15.35; Found:
C, 57.81; H, 4.22; N, 15.19.
Yield 14.9%. M.p. 176–1788C. IR: nmax (KBr) cmꢀ1: 3442, 3284,
2923, 1618, 1580, 1540, 1491, 1448, 1402, 1368, 1341. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.30 (d, 1H, J ¼ 5.6 Hz, Py-H),
7.59 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.52 (dd, 1H, J1 ¼ 2.8 Hz,
J2 ¼ 2.8 Hz, Ar-H), 7.35–7.20 (m, 3H, Ar-H), 7.08–7.01 (m, 2H,
Ar-H), 6.83 (d, 1H, J ¼ 5.6 Hz, Py-H), 3.53 (s, 3H, CH3), 2.59
(s, 3H, CH3). EIMS m/z (%): 425 (Mþ, 100), 410 (8), 281 (13), 240
(14), 208 (20), 170 (7), 143 (8), 129 (10), 77 (14), 60 (10). Anal. calcd.
for C21H17ClFN5S: C, 59.22; H, 4.02; N, 16.44; Found: C, 59.26;
H, 4.17; N, 16.64.
(4-{2-[(3-Chloro-4-fluoro-phenyl)-methyl-amino]-4-methyl-
(4-{2-[(3,4-Dichloro-phenyl)-methyl-amino]-4-methyl-
thiazol-5-yl}-pyrimidin-2-yl)-m-tolyl-amine 40
thiazol-5-yl}-pyrimidin-2-yl)-o-tolyl-amine 36
Yield 23%. M.p. 182–1848C. IR: nmax (KBr) cmꢀ1: 3424, 3474, 3201,
3069, 1601, 1581, 1563, 1540, 1493, 1423, 1401, 1367, 1336.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.29 (d, 1H, J ¼ 5.2 Hz,
Py-H), 7.61 (s, 1H, Ar-H), 7.50 (dd, 1H, J1 ¼ 2.4 Hz, J2 ¼ 2.0 Hz,
Ar-H), 7.35–7.32 (m, 1H, Ar-H), 7.24–7.14 (m, 3H, Ar-H), 7.01
(s, 1H, Ar-H), 6.83 (d, 1H, J ¼ 5.2 Hz, Py-H), 3.53 (s, 3H, CH3),
2.59 (s, 3H, CH3), 2.26 (s, 3H, CH3). EIMS m/z (%): 439 (Mþ, 100),
424 (10), 295 (10), 256 (11), 222 (12), 213 (10), 185 (8), 129 (17),
97 (12), 83 (13), 73 (34), 65 (8), 57 (31). Anal. calcd. for
C22H19ClFN5S: C, 60.06; H, 4.35; N, 15.92; Found: C, 59.92;
H, 4.23; N, 15.75.
Yield 13.6%. M.p. 159–1618C. IR: nmax(KBr) cmꢀ1: 3430, 3239,
3186, 3036, 1541, 1483, 1450, 1400, 1368, 1339. 1H-NMR
(CDCl3, TMS, 400 MHz, d ppm): 8.29 (d, 1H, J ¼ 5.6 Hz, Py-H),
7.98 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.57 (d, 1H, J ¼ 2.4 Hz, Ar-H), 7.50
(d, 1H, J ¼ 8.8 Hz, Ar-H), 7.32 (dd, 1H, J1 ¼ 2.4 Hz, J2 ¼ 3.2 Hz,
Ar-H), 7.22–7.18 (m, 2H, Ar-H), 7.02 (t, 1H, J ¼ 7.6 Hz, Ar-H), 6.81
(d, 1H, J ¼ 5.6 Hz, Py-H), 6.78 (brs, 1H, NH), 3.54 (s, 3H, CH3), 2.57
(s, 3H, CH3), 2.32 (s, 3H, CH3). EIMS m/z (%): 455 (Mþ, 73), 440 (9),
401 (15), 281 (12), 256 (25), 222 (24), 213 (19), 199 (8), 185 (17), 171
(18), 157 (15), 143 (10), 129 (39), 115 (15), 97 (27), 83 (30), 73 (89),
55 (81). Anal. calcd. for C22H19Cl2N5S: C, 57.90; H, 4.20; N, 15.35;
Found: C, 58.02; H, 4.37; N, 15.43.
(4-{2-[(3-Chloro-4-fluoro-phenyl)-methyl-amino]-4-methyl-
thiazol-5-yl}-pyrimidin-2-yl)-o-tolyl-amine 41
(4-{2-[(3,4-Dichloro-phenyl)-methyl-amino]-4-methyl-
Yield 16.3%. M.p. 159–1618C. IR: nmax (KBr) cmꢀ1
: 3442,
thiazol-5-yl}-pyrimidin-2-yl)-(3-chloro-phenyl)-amine 37
Yield 17.2%. M.p. 215–2178C. IR: nmax (KBr) cmꢀ1: 3425, 3265,
3184, 3106, 3007, 1620, 1574, 1531, 1487, 1460, 1364, 1338.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.30 (d, 1H, J ¼ 5.2 Hz,
Py-H), 8.05 (s, 1H, NH), 7.56 (d, 1H, J ¼ 2.4 Hz, Ar-H), 7.51 (d, 1H,
J ¼ 8.8 Hz, Ar-H), 7.34 (dd, 1H, J1 ¼ 2.4 Hz, J2 ¼ 2.4 Hz, Ar-H),
7.22–7.16 (m, 3H, Ar-H), 7.00–6.97 (m, 1H, Ar-H), 6.89 (d, 1H,
J ¼ 5.6 Hz, Py-H), 3.55 (s, 3H, CH3), 2.60 (s, 3H, CH3). EIMS m/z
(%): 475 (Mþ, 95), 455 (12), 315 (24), 284 (8), 274 (11), 242 (13), 220
(11), 207 (16), 185 (8), 171 (10), 157 (9), 129 (30), 111 (24), 97 (25),
83 (26), 73 (69), 55 (67). Anal. calcd. for C21H16Cl3N5S: C, 52.90;
H, 3.38; N, 14.69; Found: C, 52.77; H, 3.31; N, 14.73.
3238, 3185, 3037, 1601, 1562, 1542, 1500, 1484, 1453, 1428,
1401, 1367, 1338. 1H-NMR (CDCl3, TMS, 400 MHz, d ppm):
8.28 (d, 1H, J ¼ 5.6 Hz, Py-H), 7.98 (d, 1H, J ¼ 8.0 Hz, Ar-H),
7.50 (dd, 1H, J ¼ 2.80 Hz, Ar-H), 7.34–7.30 (m, 1H, Ar-H), 7.24–
7.16 (m, 3H, Ar-H), 7.01 (t, 1H, J ¼ 7.2 Hz, Ar-H), 6.80 (d, 1H,
J ¼ 5.2 Hz, Py-H), 6.75 (brs, 1H, NH), 3.52 (s, 3H, CH3), 2.57
(s, 3H, CH3), 2.31 (s, 3H, CH3). EIMS m/z (%): 439 (Mþ, 100), 424
(10), 284 (15), 256 (15), 222 (19), 207 (12), 185 (11), 171 (8), 157 (11),
143 (9), 129 (27), 111 (8), 97 (15), 83 (18), 73 (44), 60 (43). Anal.
calcd. for C22H19ClFN5S: C, 60.06; H, 4.35; N, 15.92; Found:
C, 60.13; H, 4.28; N, 15.99.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 675–683
Synthesis of Novel Thiazolyl-Pyrimidines
683
We are grateful for the Natural Science Foundation of Ningbo City (grant
No. 2009A610185) for financial support and Nantong Center for Disease
Control and Prevention, Jiangsu, PR China for drug screening.
(4-{2-[(3-Chloro-4-fluoro-phenyl)-methyl-amino]-4-methyl-
thiazol-5-yl}-pyrimidin-2-yl)-(3-chloro-phenyl)-amine 42
Yield 14.1%. M.p. 196–1988C. IR: nmax (KBr) cmꢀ1: 3422, 3268,
3186, 3112, 1617, 1576, 1532, 1490, 1460, 1421, 1364, 1338.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.31 (d, 1H, J ¼ 5.2 Hz,
Py-H), 8.04 (s, 1H, NH), 7.49 (d, 1H, J ¼ 5.6 Hz, Ar-H), 7.33 (brs, 1H,
Ar-H), 7.23–7.11 (m, 4H, Ar-H), 6.97 (d, 1H, J ¼ 6.8 Hz, Ar-H), 6.88
(d, 1H, J ¼ 5.2 Hz, Py-H), 3.54 (s, 3H, CH3), 2.60 (s, 3H, CH3). EIMS
m/z (%): 459 (Mþ, 100), 315 (20), 274 (9), 242 (10), 207 (12), 129 (12),
111 (13), 97 (10), 83 (11), 71 (16), 57 (22). Anal. calcd. for
C21H16ClFN5S: C, 54.79; H, 3.50; N, 15.21; Found: C, 54.62;
H, 3.41; N, 15.35.
The authors have declared no conflict of interest.
References
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thiazol-5-yl}-pyrimidin-2-yl)-(3-methoxy-phenyl)-amine 43
Yield 5.5%. M.p. 181–1838C. IR: nmax (KBr) cmꢀ1: 3425, 3279, 3213,
3119, 3066, 1584, 1538, 1498, 1459, 1427, 1398, 1368, 1338.
1H-NMR (CDCl3, TMS, 400 MHz, d ppm): 8.31 (brs, 1H, Py-H),
7.47 (d, 2H, J ¼ 14.4 Hz, Ar-H), 7.32–7.17 (m, 2H, Ar-H), 7.04
(s, 1H, Ar-H), 6.96 (d, 1H, J ¼ 5.6 Hz, Ar-H), 6.85 (s, 1H, Ar-H),
6.57 (d, 1H, J ¼ 5.2 Hz, Py-H), 3.74 (s, 3H, OCH3), 3.52 (s, 3H, CH3),
2.59 (s, 3H, CH3). EIMS m/z (%): 455 (Mþ, 100), 311 (8), 270 (8), 238
(9), 227 (8), 129 (10), 97 (8), 83 (8), 73 (13), 57 (18). Anal. calcd. for
C22H19ClFN5S: C, 57.95; H, 4.20; N, 15.36; Found: C, 57.92; H, 4.23;
N, 15.15.
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Biological Assays
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after cells were treated with drug for 72 h, and cells were incu-
bated for a further 3 h at 378C. The purple formazan crystals
were dissolved in 150 mL DMSO. After 5 min, the plates were read
on an automated microplate spectrophotometer (Bio-Tek
Instruments, Winooski, VT, USA) at 570 nm. Assays were per-
formed in triplicate in three independent experiments. The
concentration required for 50% inhibition of cell viability
(IC50) was calculated using the software, Dose-Effect Analysis
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