Synthesis of piperazine tethered 4-aminoquinoline-pyrimidine hybrids as potent antimalarial agents

Article abstract of DOI:10.1039/c4ra02276a

A series of 4-aminoquinoline-pyrimidine hybrids linked through piperazine were synthesized and evaluated for their in vitro antimalarial activity against chloroquine (CQ)-sensitive and chloroquine (CQ)-resistant strains of Plasmodium falciparum and cytoto

Full text of DOI:10.1039/c4ra02276a

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Synthesis of piperazine tethered 4-
aminoquinoline-pyrimidine hybrids as potent
Cite this: RSC Adv., 2014, 4, 20729
antimalarial agents†
a
b
a
*
Anuj Thakur, Shabana I. Khan and Diwan S. Rawat
A series of 4-aminoquinoline-pyrimidine hybrids linked through piperazine were synthesized and evaluated
for their in vitro antimalarial activity against chloroquine (CQ)-sensitive and chloroquine (CQ)-resistant
strains of Plasmodium falciparum and cytotoxicity against mammalian cell line (Vero). Nine compounds
(5e, 5f, 5g, 5h, 5i, 5j, 5k, 7a, 7d) displayed good antimalarial activity against both the strains out of which
compound 5j was the most potent with IC50 values in the range of 0.13–0.14 mM. The antimalarial
activity of 5j was 2.5 fold stronger than chloroquine in the CQ-resistant strain of P. falciparum. None of
the compounds were found to be cytotoxic against Vero cells. The X-ray crystal structure of one of the
compounds was also determined.
Received 15th March 2014
Accepted 28th April 2014
DOI: 10.1039/c4ra02276a
www.rsc.org/advances
P. falciparum.4 In spite of the problem of drug resistance, the
4-aminoquinoline class of therapeutics remains a frontline
Introduction
pharmacophore for the drug development purposes due to its
excellent clinical efficacy, ease of administration, low toxicity
and low cost of synthesis.5 Due to these features there is a con-
tinous interest in further development of this pharmacophore.
In order to solve the problem of drug resistance, numerous
strategies such as modication of existing leads, combination
therapy, reversal of drug-resistance by chemo-sensitizers and
exploring new chemotherapeutics6 have been used. More
recently, the concept of molecular hybrids7,8 has been introduced
inan anticipationthat these kind of moleculesmay overcome the
drug resistance problem to a considerable extent. In this strategy
two or more pharmacophore are covalently linked and it is
anticipated that these kinds of double sword molecules may act
by inhibiting simultaneously two or more conventional targets of
antimalarial therapy. This multiple target strategy led to the
discovery of various molecular hybrids such as 4-aminoquino-
Malaria is one of the most virulent devastating diseases caused
by ve species of Plasmodium viz. P. vivax, P. malariae, P. ovale, P.
knowlesi and P. falciparum. Among these, infection caused by P.
falciparum is the most fatal leading to 60% malaria related
deaths.1 Impact of this disease on the public health can be
judged by the fact that it affects 200–500 million people world-
wide and causes over 1.2 million deaths annually.2 Since the
development of quinine(I) as an antimalarial drug, quinoline
nucleus has been the mainstay of antimalarial therapy.3 Chlo-
roquine (CQ, II), an aminoquinoline based compound, has been
used most widely for the treatment of malaria (Fig. 1). CQ, once
hailed the status of wonder drugs for malarial chemotherapy,
lost its efficacy due to the wide spread of CQ-resistant strains of
line-cinnamic
acid,9
4-aminoquinoline-ferrocenophane,10
quinoline-rhodanine,11 4-aminoquinoline-clotrimazole,12 4-am-
inoquinoline-triazine,13 4-aminoquinoline-g-hydroxy-g-lactam,14
4-aminoquinoline-furoxan,15 and more recently 4-aminoquino-
line-pyrimidines.16,17 It is important to mention here that some of
these hybrid compounds have also entered into the clinical
trials.7 Encouraged by these reports and therapeutic advantages
of the molecular hybrids in medicinal chemistry, recently we
reported in vitro and in vivo antimalarial activity and cytotoxicity
of 4-aminoquinoline-pyrimidine based molecular hybrids.16
These hybrids exhibited promising antimalarial activity against
CQ-sensitive as well as CQ-resistant strain. In order to gain
further insight on the effect of the linker on antimalarial activity
and in continuation of our ongoing efforts in this area,18 we
decided to connect these two pharmacophores via more rigid
Fig. 1 Quinine(I) and chloroquine (CQ, II).
aDepartment of Chemistry, University of Delhi, Delhi-110007, India. E-mail: dsrawat@
chemistry.du.ac.in; Fax: +91-11-27667501; Tel: +91-11-27662683
bNational Center for Natural Products Research, School of Pharmacy, University of
Mississippi, MS 38677, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02276a
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Scheme 1 (a) Piperazine, DMF, 90–100 ꢀC, 4–5 h, 75–85%; (b) 2,4-dichloro-pyrimidine (3a) or 2,4-dichloro-6-methyl-pyrimidine (3b), N,N-
diisopropylethylamine, THF, 0–15 ꢀC, overnight, 80–90%; (c) R1 ¼ aliphatic amines, DMF, 110–120 ꢀC, 8–10 h, 62–90%.
linker and therefore used piperazine as a scaffold to covalently
link these two pharmacophores.
Results and discussion
Chemistry
Synthesis of piperazine linked quinoline-pyrimidine hybrids is
depicted in Schemes 1 and 2. To start with, aromatic nucleo-
philic substitution of commercially available 4,7-dichlor-
Fig. 2 Molecular structure of compound 4a. Thermal ellipsoidal is
drawn at the 30% level; hydrogen atoms have been omitted for clarity.
oquinoline (1) with excess of piperazine, afforded intermediate
2,19 which was coupled with 2,4-dichloro-pyrimidine (3a) or 2,4-
dichloro-6-methyl-pyrimidine (3b) at 0–15 ꢀC, yielding inter-
mediate (4a or 4b) (Scheme 1). Intermediate (4a or 4b) was then
reacted with various primary and secondary aliphatic amines at
an elevated temperature (110–120 ꢀC) in DMF leading to the
desired 4-aminoquinoline-pyrimidine hybrids (5a–k) in good to
excellent yields.
Antimalarial activity and cytotoxicity
The present work was designed to understand the role of linker
between aminoquinoline and pyrimidine scaffolds. Therefore,
we decided to introduce some rigidity yet maintaining the basic
nature of the linker. Piperazine met all the criteria and was used
as a linker between aminoquinoline and pyrimidine in the
present study. All the synthesized compounds 4a,b, 5a–k and
7a–i were evaluated for their in vitro antimalarial activity against
CQ-sensitive (D6) strain and CQ-resistant (W2) strain of P. fal-
ciparum (Table 1) using procedure as described earlier.20
Among 22 compounds, several compounds showed antima-
larial activity with IC50 values below 1 mM for both the strains.
However, compound 5j was the most potent with IC50 values of
0.13 mM and 0.14 mM for D6 and W2 strains, respectively with a
high selectivity index (>80). The activity of 5j was 2.5 times
higher than CQ against CQ-resistant strain (W2) as shown in
Table 1. Seven compounds (5e–i, 5k and 7d) have displayed
activity in the IC50 range of 0.27–0.44 mM for D6 strain and 0.30–
0.77 mM for W2 strain. Structure activity relationship indicates
that substitution of Cl at 4th position of pyrimidine ring of the
hybrids with different aliphatic amines increases activity.
Piperidine and morpholine substituted compounds (5a–d) have
shown a similar activity prole. On decreasing ring size from
piperidine to pyrrolidine (5c,d vs. 5e,f), three to four fold
improvement in activity was observed (IC50 1.21–1.50 mM vs.
0.38–0.60 mM). Substitution of secondary cyclic amines with
primary amines in the pyrimidine ring of the hybrids (5g–k) led
to the improvement of activity with IC50 values ranging between
0.13–0.39 mM against D6 strain while some of these compounds
The reaction of substituted anilines with 4a or 4b led to the
formation of the desired product in very poor yield. To
circumvent these problems, the second approach (Scheme 2)
was adopted. Initially dichloropyrimidines (3a or 3b) were
subjected to nucleophilic substitution with different
substituted anilines yielding intermediates 6a–i in 95% yield,
followed by reaction with intermediate (2) to yield nal products
(7a–i). All the compounds were puried by column chroma-
tography over silica gel and structures were established on the
basis of various spectroscopic techniques and elemental anal-
ysis. Crystal structure of compound 4a was also determined
(Fig. 2).
Scheme 2 (a) Substituted anilines, N,N-diisopropylethylamine, tert-
BuOH, 50–60 ꢀC, 7–9 h, 85–95%; (b) 2, K2CO3, DMF, 110–120 ꢀC, 8–
10 h, 80–90%.
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Table 1 In vitro antimalarial activity and cytotoxicity of the title and reference compounda
P. falciparum (D6 clone)
P. falciparum (W2 clone)
Entry
R
R1
IC50 (mM)
SI
IC50 (mM)
SI
Vero cell cytotoxicity
4a
4b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
7a
7b
7c
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
H
Me
H
Me
H
H
Me
H
Cl
Cl
2.65
2.45
1.45
1.26
1.33
1.21
0.44
0.38
0.29
0.27
0.39
0.13
0.30
0.48
1.35
1.2
0.44
2.35
2.83
3.98
1.19
1.10
0.03
>4.9
>5.1
>7.9
>8.8
>8.7
>8.7
>26.8
>30.2
>37.9
>38.9
>31.4
>88.4
>38.9
>20.5
>7.2
>8.7
>23.3
>4.8
>3.9
>2.7
>8.8
>8.7
>300
4.77
3.33
2.28
2.06
1.50
1.46
0.60
0.47
0.43
0.30
0.48
0.14
0.40
1.68
1.16
1.86
0.77
2.96
2.04
3.43
1.88
1.25
0.34
>2.7
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
>3.8
>5.07
>5.43
>7.72
>7.70
>19.9
>24.6
>25.9
>36.1
>25.6
>83.5
>31.3
>5.9
>8.3
>5.7
>13.4
>3.9
>5.4
>3.1
>5.6
>7.7
>26.5
Morpholine
Morpholine
Piperidine
Piperidine
Pyrrolidine
Pyrrolidine
Cyclohexylamine
Cyclohexylamine
Ethanolamine
Ethanolamine
Propanolamine
3,5-Dimethoxy
3,5-Dimethoxy
4-Methoxy
4-Methoxy
H
7d
7e
7f
7g
7h
7i
4-Fluro
4-Fluro
4-Chloro
4-Bromo
H
Chloroquine
a
NC: non cytotoxic; selectivity index (SI): IC50 for cytotoxicity towards VERO cells/IC50 for antimalarial activity.
were more active than CQ against resistant strains (IC50 ¼ 0.14– replaced primary and secondary amines with substituted
0.48 mM). In order to understand the role of amine functionality anilines which led to a decrease in activity with exception of
at 2nd position of the pyrimidine ring of the hybrids, we compounds 7a and 7d.
Cytotoxicity of all the synthesized hybrids (4a,b, 5a–k and 7a–
i) was determined against Vero cells. All the compounds were
Table 2 Predicted ADME properties of compound 5j
non-cytotoxic up to the highest tested concentration of 4.76 mg
mLꢁ1, demonstrating safety towards mammalian cells.
Compound
5j
ADME properties of the most potent hybrid (5j) were evalu-
ated using Quikprop (Schrodinger soware)21 as shown in Table
2. Compound 5j satises the Lipinski rule of ve (Mw < 500,
log Po/w < 5, donor HB # 5, accept HB # 10) which demon-
strates its drug-likeness. For a drug molecule to pass through
biological membranes and eventually enter the systemic circu-
lation, an optimal balance in its lipophilic and hydrophilic
properties is required.22 This, in turn, can be predicted by its
octanol/water partition coefficient (log Po/w) and aqueous
solubility (log S). Compound 5j shows an optimal log Po/w and
log S value of 3.90 and ꢁ5.98 respectively. From the predicted
cell permeability values (PCaco2, PMDCK), it is clear that aer
the absorption process, distribution, metabolism and excretion
parameters are within acceptable range. The predicted HERG
inhibition potential of compound 5j is slightly on the higher
side but comparable to CQ (predicted ¼ ꢁ6.29, experimental ¼
ꢁ5.60).23 Predicted solvent accessible surface area with its
hydrophobic and hydrophilic components of the compounds
determines that they have ‘transfer free energy’ to move from
the aqueous environment to non-polar environment. Almost all
the predicted properties were found to be within the acceptable
range.
Molecular weighta
log Po/wb
398.89
3.90
log Sc
ꢁ5.98
1052.75
1290.08
ꢁ5.908
3
701.84
311.51
102.66
100
PCaco2d
PMDCKe
log HERGf
No. of primary metabolitesg
SASAh
FOSAi
FISAj
Percent human-oral
absorption
Donor HBk
Acceptor HBl
2
6.7
a
b
Range 95% of drugs (130/725). Log of the octanol/water partition
c
coefficient, range 95% of drugs (ꢁ2/6.5). Log of aqueous solubility S
(mol Lꢁ1), range 95% of drugs (ꢁ6.5/0.5). Caco2 cell permeability in
d
nm sꢁ1, range 95% of drugs (<25 poor, >500 high). MDCK cell
e
permeability in nm sꢁ1, range 95% of drugs (<25 poor, >500 high).
f
Predicted IC50 value for the blockage of HERG K+ channels, range
g
95% of drugs (concern below ꢁ5). Range 95% of drugs (1/8).
h
Solvent-accessible surface area (SASA), range 95% of drugs (300.0/
i
1000.0). Hydrophobic SASA, range 95% of drugs (0.0/750.0).
j
k
Hydrophilic SASA, range 95% of drugs (7.0/330.0). Donor–hydrogen
l
bonds, range 95% of drugs (0.0/6.0). Acceptor–hydrogen bonds,
range 95% of drugs (2.0/20.0).
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completion of reaction (TLC), water (15 mL) was added to the
reaction mixture and it was extracted with EtOAc (3 ꢂ 30 mL).
The organic extract was dried over Na2SO4 and concentrated in
vacuo. The crude residue thus obtained was puried by column
chromatography using MeOH/CHCl3 as eluent to afford
respective compounds 5a–k in excellent yield.
Experimental section
All the starting materials were purchased from Sigma Aldrich
and were used without further purication. Progress of the
reaction was monitored by TLC (E. Merck Kieselgel 60 F254) and
visualization was accomplished using UV light. All the inter-
mediates and nal compounds were puried using silica gel
7-Chloro-4-[4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-
quinoline (5a). Yield: 85%; mp 166–168 ꢀC; IR (cmꢁ1, lm):
2966, 2859, 1576, 1474, 1446, 1380, 1236, 1112, 1070, 999, 944,
1
column chromatography. H NMR and 13C NMR spectra were
recorded on a Jeol Spectrospin spectrometer at 400 MHz and
100 MHz respectively, and the chemical shis are given in parts
per million (ppm) on the delta scale (d) and are referenced to
tetramethylsilane. Perkin-Elmer FT-IR spectrophotometer was
used for recording IR spectra and the values are expressed as
lmax per centimeter. Mass spectra were recorded on Jeol-Accu-
TOF JMS-T100LC and micromass LCT Mass Spectrometer/Data
system. Melting points were recorded on an ERS automated
melting point apparatus and are uncorrected.
1
865, 789, 712, 630; H NMR (400 MHz, CDCl3): 3.26–3.29 (m,
4H), 3.75–3.77 (m, 8H), 3.86–3.88 (m, 4H), 5.97 (d, 1H, J ¼ 6.10
Hz), 6.86 (d, 1H, J ¼ 4.88 Hz), 7.46 (dd, 1H, J ¼ 8.54 Hz, J ¼ 2.44
Hz), 7.99–8.05 (m, 2H), 8.07 (d, 1H, J ¼ 2.44 Hz), 8.75 (d, 1H, J ¼
5.49 Hz); 13C NMR (100 MHz, CDCl3): 43.75, 44.24, 51.84, 66.86,
93.25, 109.10, 121.79, 124.85, 126.41, 128.93, 135.05, 150.06,
151.90, 156.57, 156.89, 161.53, 162.45; ESI-MS (m/z): 411.19 (M +
H)+, 413.16 (M + 2)+; anal. calcd for C21H23ClN6O: C, 61.38; H,
5.64; N, 20.45%; found: C, 61.44; H, 5.70; N, 20.49%.
7-Chloro-4-[4-(6-methyl-2-morpholin-4-yl-pyrimidin-4-yl)-
piperazin-1-yl]-quinoline (5b). Yield: 83%; mp 188–190 ꢀC; IR
(cmꢁ1, lm): 2960, 2849, 1575, 1420, 1380, 1265, 1245, 1193,
General procedure for the synthesis of compound 4a and 4b
Compound 2 (5 g, 1 mmol) and N,N-diisopropylethylamine (4.5
mL, 1.3 mmol) were mixed in 50 mL of THF at 0 ꢀC for 20
minutes. To this, 2,4-dichloro-pyrimidine (3a) or 2,4-dichloro-6-
methyl-pyrimidine (3b) (3 g, 1 mmol) was added and the
resulting reaction mixture was allowed to stir overnight at 10–15
ꢀC. Aer complete consumption of starting material as evi-
denced by the TLC, THF was evaporated under reduced pres-
sure. The residue was treated with water and extracted with
EtOAc (3 ꢂ 50 mL). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated. The residue was
puried by column chromatography to afford 4a or 4b.
1
1116, 1013, 991, 870, 753; H NMR (400 MHz, CDCl3): 2.27 (s,
3H), 3.26–3.28 (m, 4H), 3.73–3.79 (m, 8H), 3.84–3.87 (m, 4H),
5.86 (s, 1H), 6.85 (d, 1H, J ¼ 5.13 Hz), 7.46 (dd, 1H, J ¼ 8.79 Hz, J
¼ 2.20 Hz), 8.00 (d, 1H, J ¼ 9.52 Hz), 8.06 (d, 1H, J ¼ 1.46 Hz),
8.74 (d, 1H, J ¼ 4.39 Hz); ESI-MS (m/z): 425.16 (M + H)+, 427.19
(M + 2)+; anal. calcd for C22H25ClN6O: C, 62.18; H, 5.93; N,
19.78%; found: C, 62.22; H, 5.95; N, 19.76%.
7-Chloro-4-[4-(2-piperidin-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-
quinoline (5c). Yield: 88%; mp 126–128 ꢀC; IR (cmꢁ1, lm):
2935, 2851, 1577, 1444, 1377, 1231, 1204, 1122, 991, 869, 788; 1H
NMR (400 MHz, CDCl3): 1.59–1.66 (m, 6H), 3.26–3.28 (m, 4H),
3.73–3.76 (m, 4H), 3.85–3.87 (m, 4H), 5.89 (d, 1H, J ¼ 6.59 Hz),
6.85 (d, 1H, J ¼ 5.13 Hz), 7.45 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz),
7.99 (s, 1H), 8.00–8.01 (m, 1H), 8.06 (d, 1H, J ¼ 2.20 Hz), 8.74 (d,
1H, J ¼ 5.13 Hz); ESI-MS (m/z): 409.17 (M + H)+, 411.21 (M + 2)+;
anal. calcd for C22H25ClN6: C, 64.62; H, 6.16; N, 20.55%; found:
C, 64.65; H, 6.19; N, 20.51%.
7-Chloro-4-[4-(2-chloro-pyrimidin-4-yl)-piperazin-1-yl]-quino-
line (4a). Yield: 86%; mp 184–186 ꢀC; IR (cmꢁ1, lm): 2980,
2895, 1578, 1534, 1495, 1449, 1424, 1356, 1249, 1173, 979, 870,
1
754; H NMR (400 MHz, CDCl3): 3.28–3.31 (m, 4H), 3.89–4.01
(m, 4H), 6.49 (d, 1H, J ¼ 5.95 Hz), 6.87 (d, 1H, J ¼ 5.04 Hz), 7.48
(dd, 1H, J ¼ 9.16 Hz, J ¼ 1.83 Hz), 7.98 (d, 1H, J ¼ 8.70 Hz), 8.08
(d, 1H, J ¼ 1.83 Hz), 8.12 (d, 1H, J ¼ 5.95 Hz), 8.76 (d, 1H, J ¼
5.04 Hz); 13C NMR (100 MHz, CDCl3): 43.96, 51.62, 101.31,
109.26, 121.72, 124.63, 126.64, 129.03, 135.18, 150.10, 151.92,
156.15, 157.65, 160.80, 162.76; ESI-MS (m/z): 360.09 (M + H)+,
362.07 (M + 2)+; anal. calcd for C17H15Cl2N5: C, 56.68; H, 4.20; N,
19.44%; found: C, 56.73; H, 4.29; N, 19.49%.
7-Chloro-4-[4-(6-methyl-2-piperidin-1-yl-pyrimidin-4-yl)-
piperazin-1-yl]-quinoline (5d). Yield: 83%; mp 158–160 ꢀC; IR
(cmꢁ1, lm): 2932, 2848, 1571, 1444, 1418, 1295, 1244, 1196,
1
101, 1011, 990, 869, 754; H NMR (400 MHz, CDCl3): 1.59–1.64
(m, 4H), 2.25 (s, 3H), 3.25–3.28 (m, 4H), 3.74–3.77 (m, 4H), 3.83–
3.86 (m, 4H), 5.79 (s, 1H), 6.85 (d, 1H, J ¼ 5.13 Hz), 7.45 (dd, 1H,
J ¼ 8.79 Hz, J ¼ 2.20 Hz), 8.00 (d, 1H, J ¼ 8.79 Hz), 8.06 (d, 1H, J
¼ 2.20 Hz), 8.74 (d, 1H, J ¼ 5.13 Hz); 13C NMR (100 MHz, CDCl3):
24.64, 24.96, 25.84, 43.91, 44.73, 51.95, 90.99, 109.06, 121.86,
124.97, 126.32, 128.94, 134.99, 150.13, 151.93, 156.75, 161.69,
163.29, 166.67; ESI-MS (m/z): 423.24 (M + H)+, 425.22 (M + 2)+;
anal. calcd for C23H27ClN6: C, 65.31; H, 6.43; N, 19.87%; found:
C, 65.34; H, 6.44; N, 19.85%.
7-Chloro-4-[4-(2-chloro-6-methyl-pyrimidin-4-yl)-piperazin-1-
yl]-quinoline (4b). Yield: 80%; mp 118–120 C; IR (cmꢁ1, lm):
ꢀ
2964, 2851, 1593, 1496, 1424, 1380, 1296, 1214, 1194, 1073, 985,
871, 755; 1H NMR (400 MHz, CDCl3): 2.31 (s, 3H), 3.21–3.23 (m,
4H), 3.82–3.91 (m, 4H), 6.29 (s, 1H), 6.80 (d, 1H, J ¼ 5.13 Hz),
7.41 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 7.92 (d, 1H, J ¼ 8.79 Hz),
8.00 (d, 1H, J ¼ 2.20 Hz), 8.69 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z):
374.06 (M + H)+, 376.09 (M + 2)+; anal. calcd for C18H17Cl2N5: C,
57.76; H, 4.58; N, 18.71%; found: C, 57.81; H, 4.60; N, 18.76%.
7-Chloro-4-[4-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-
quinoline (5e). Yield: 87%; mp 152–154 ꢀC; IR (cmꢁ1, lm):
2969, 2856, 1578, 1554, 1471, 1424, 1381, 1322, 1242, 1190,
General procedure for the synthesis of compounds (5a–k)
To a solution of 4a or 4b (0.2 g, 2 mmol) in DMF (7 mL), 1125, 1071, 1014, 972, 870, 752; 1H NMR (400 MHz, CDCl3):
respective amine (3 eq.) was added dropwise and the reaction 1.94–1.98 (m, 4H), 3.26–3.28 (m, 4H), 3.52–3.58 (m, 4H), 3.87–
mixture was allowed to stir at 110–120 ꢀC for 8–10 h. Upon the 3.91 (m, 4H), 5.90 (d, 1H, J ¼ 6.10 Hz), 6.86 (d, 1H, J ¼ 4.88 Hz),
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7.44–7.47 (m, 1H), 7.98–8.01 (m, 2H), 8.05–8.07 (m, 1H), 8.74 (d, 1071, 991, 928, 871, 722; 1H NMR (400 MHz, CDCl3): 2.24 (s,
1H, J ¼ 4.88 Hz); 13C NMR (100 MHz, CDCl3): 25.48, 43.69, 3H), 3.25–3.27 (m, 4H), 3.55–3.57 (m, 2H), 3.80–3.82 (m, 2H),
46.34, 51.89, 91.84, 109.07, 121.82, 124.93, 126.36, 128.88, 3.84–3.87 (m, 4H), 5.32 (br s, 1H), 5.88 (s, 1H), 6.85 (d, 1H, J ¼
135.00, 150.05, 151.89, 156.69, 156.89, 160.09, 162.37; ESI-MS 5.13 Hz), 7.47 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 7.99 (d, 1H, J ¼
(m/z): 395.18 (M + H)+, 397.19 (M + 2)+; anal. calcd for 8.79 Hz), 8.07 (d, 1H, J ¼ 2.20 Hz), 8.74 (d, 1H, J ¼ 5.13 Hz); ESI-
C
21H23ClN6: C, 63.87; H, 5.87; N, 21.28%; found: C, 63.91; H, MS (m/z): 399.18 (M + H)+, 401.15 (M + 2)+; anal. calcd for
5.93; N, 21.34%.
C20H23ClN6O: C, 60.22; H, 5.81; N, 21.07%; found: C, 60.21; H,
7-Chloro-4-[4-(6-methyl-2-pyrrolidin-1-yl-pyrimidin-4-yl)- 5.84; N, 21.10%.
piperazin-1-yl]-quinoline (5f). Yield: 85%; mp 120–122 ꢀC; IR
3-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-2-
(cmꢁ1, lm): 2966, 2852, 1573, 1514, 1455, 1417, 1380, 1343, ylamino}-propan-1-ol (5k). Yield: 87%; mp 190–192 ꢀC; IR
1
1273, 1246, 1187, 1071, 992, 963, 871, 752, 662; H NMR (400 (cmꢁ1, lm): 3247, 2922, 2850, 1580, 1520, 1423, 1380, 1244,
1
MHz, CDCl3): 1.92–1.95 (m, 4H), 2.27 (s, 3H), 3.25–3.28 (m, 4H), 1142, 1009, 972, 870, 753; H NMR (400 MHz, CDCl3): 1.73 (s,
3.55–3.58 (m, 4H), 3.85–3.88 (m, 4H), 5.80 (s, 1H), 6.85 (d, 1H, J 2H), 3.23–3.28 (m, 4H), 3.56–3.64 (m, 4H), 3.86 (s, 4H), 4.98 (br
¼ 5.13 Hz), 7.45 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 8.00 (d, 1H, J s, 1H), 5.97 (d, 1H, J ¼ 5.13 Hz), 6.86 (d, 1H, J ¼ 5.13 Hz), 7.46 (d,
¼ 8.79 Hz), 8.06 (d, 1H, J ¼ 2.20 Hz), 8.73 (d, 1H, J ¼ 5.13 Hz); 1H, J ¼ 8.79 Hz), 7.91 (d, 1H, J ¼ 5.86 Hz), 7.99 (d, 1H, J ¼ 8.79
ESI-MS (m/z): 409.22 (M + H)+, 411.17 (M + 2)+; anal. calcd for Hz), 8.06 (s, 1H), 8.74 (d, 1H, J ¼ 5.13 Hz); 13C NMR (100 MHz,
C
22H25ClN6: C, 64.62; H, 6.16; N, 20.55%; found: C, 64.66; H, DMSO-d6): 32.50, 37.88, 43.18, 51.45, 58.75, 92.23, 109.62,
6.18; N, 20.57%.
{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}- 56.67, 161.93, 162.18; ESI-MS (m/z): 399.18 (M + H)+, 401.16 (M +
cyclohexyl-amine (5g). Yield: 62%; mp 180–180 ꢀC; IR (cmꢁ1 2)+; anal. calcd for C20H23ClN6O: C, 60.22; H, 5.81; N, 21.07%;
121.33, 125.86, 126.07, 128.08, 133.64, 149.62, 152.19, 155.90,
,
lm): 3256, 2928, 2853, 1577, 1449, 1423, 1380, 1294, 1246, found: C, 60.24; H, 5.83; N, 21.06%.
1159, 1012, 1012, 977, 865, 791, 755; 1H NMR (400 MHz, CDCl3):
1.17–1.25 (m, 4H), 1.33–1.40 (m, 2H), 1.59–1.62 (m, 1H), 1.70–
1.74 (m, 2H), 2.00–2.04 (m, 2H), 3.23–3.26 (m, 4H), 3.83–3.85
General procedure for the synthesis of compounds 6a–i
(m, 4H), 4.91 (br s, 1H), 5.90 (d, 1H, J ¼ 6.10 Hz), 6.84 (d, 1H, J ¼ To a well stirred solution of substituted aniline (0.5 g, 1 mmol)
4.88 Hz), 7.45 (dd, 1H, J ¼ 9.16 Hz, J ¼ 2.44 Hz), 7.91 (d, 1H, J ¼ and N,N-diisopropylethylamine (1.3 mmol) in tert-BuOH (15
6.10 Hz), 7.97–7.99 (m, 1H), 8.05 (d, 1H, J ¼ 1.83 Hz), 8.72 (d, mL) at room temperature, compound 3a or 3b (1 mmol) was
1H, J ¼ 4.88 Hz); 13C NMR (100 MHz, CDCl3): 24.87, 25.73, added. The reaction mixture was allowed to stir at 50–60 ꢀC for
33.26, 43.66, 49.51, 51.84, 92.91, 109.07, 121.78, 124.88, 126.37, 8–10 h. Aer completion of reaction as monitored by TLC, tert-
128.90, 134.98, 150.07, 151.87, 156.57, 156.74, 161.22, 162.63; BuOH was evaporated under reduced pressure and the residue
ESI-MS (m/z): 423.22 (M + H)+, 425.17 (M + 2)+; anal. calcd for was treated with water. The mixture was extracted with EtOAc (3
C
23H27ClN6: C, 65.31; H, 6.43; N, 19.87%; found: C, 65.34; H, ꢂ 30 mL) and the combined organic phase was dried over
6.42; N, 19.89%. Na2SO4 and concentrated in vacuo. The crude product was
{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-6-methyl- puried by column chromatography to give the corresponding
pyrimidin-2-yl}-cyclohexyl-amine (5h). Yield: 66%; mp 106–108 intermediates (6a–6i).
ꢀC; IR (cmꢁ1, lm): 3393, 2924, 2852, 1577, 1420, 1379, 1294,
(2-Chloro-pyrimidin-4-yl)-(3,5-dimethoxy-phenyl)-amine (6a).
1248, 1199, 1072, 1011, 928, 872, 790; 1H NMR (400 MHz, Yield: 87%; mp 172–174 ꢀC; H NMR (400 MHz, CDCl3): 3.80
CDCl3): 1.22–1.27 (m, 4H), 1.33–1.42 (m, 2H), 1.59–1.62 (m, 1H), (s, 6H), 6.33–6.44 (m, 1H), 6.47 (d, 2H, J ¼ 2.20 Hz), 6.67 (d, 1H,
1.72–1.75 (m, 2H), 2.00–2.02 (m, 2H), 2.23 (s, 3H), 3.26–3.29 (m, J ¼ 6.59 Hz), 7.00 (br s, 1H), 8.13 (d, 1H, J ¼ 5.86 Hz); ESI-MS
4H), 3.84–3.91 (m, 4H), 5.81 (s, 1H), 6.86 (d, 1H, J ¼ 4.88 Hz), (m/z): 266.09 (M + H)+, 268.06 (M + 2)+; anal. calcd for
7.46 (dd, 1H, J ¼ 9.16 Hz, J ¼ 1.83 Hz), 8.00 (d, 1H, J ¼ 9.16 Hz), C12H12ClN3O2: C, 54.25; H, 4.55; N, 15.82%; found: C, 54.57; H,
8.06–8.07 (m, 1H), 8.73 (d, 1H, J ¼ 4.88 Hz); ESI-MS (m/z): 437.25 4.53; N, 15.81%.
1
(M + H)+, 439.22 (M + 2)+; anal. calcd for C24H29ClN6: C, 65.97;
H, 6.69; N, 19.23%; found: C, 65.95; H, 6.72; N, 19.22%.
(2-Chloro-6-methyl-pyrimidin-4-yl)-(3,5-dimethoxy-phenyl)-amine-
1
(6b). Yield: 91%; mp 186–188 ꢀC; H NMR (400 MHz, CDCl3):
2-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidinꢁ-21- 2.35 (s, 3H), 3.81 (s, 6H), 6.32–6.34 (m, 1H), 6.45 (d, 2H, J ¼ 2.20
ylamino}-ethanol (5i). Yield: 82%; mp 214–216 ꢀC; IR (cm
,
Hz), 6.52 (s, 1H), 6.89 (br s, 1H); ESI-MS (m/z): 280.09 (M + H)+,
lm): 3392, 2919, 2849, 1577, 1420, 1379, 1233, 1070, 1008, 973, 282.08 (M + 2)+; anal. calcd for C13H14ClN3O2: C, 55.82; H, 5.04;
1
869, 790; H NMR (400 MHz, CDCl3): 3.25–3.29 (m, 4H), 3.52– N, 15.02%; found: C, 55.84; H, 5.09; N, 15.06%.
3.58 (m, 2H), 3.81–3.83 (m, 2H), 3.85–3.88 (m, 4H), 5.28 (br s,
(2-Chloro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine
(6c).
1H), 5.89–6.00 (m, 1H), 6.85–6.87 (m, 1H), 7.45–7.48 (m, 1H), Yield: 85%; mp 176–178 ꢀC; 1H NMR (400 MHz, CDCl3): 3.83 (s,
7.91–7.98 (m, 1H), 8.00–8.02 (m, 1H), 8.07 (d, 1H, J ¼ 2.20 Hz), 3H), 6.40 (d, 1H, J ¼ 5.13 Hz), 6.93–6.95 (m, 2H), 7.19–7.21 (m,
8.74 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 385.16 (M + H)+, 387.14 3H), 8.05 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 236.07 (M + H)+,
(M + 2)+; anal. calcd for C19H21ClN6O: C, 59.29; H, 5.50; N, 238.05 (M + 2)+; anal. calcd for C11H10ClN3O: C, 56.06; H, 4.28;
21.84%; found: C, 59.34; H, 5.56; N, 21.88%.
N, 17.83%; found: C, 56.10; H, 4.32; N, 17.84%.
2-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-6-methyꢀl-pyri-
(2-Chloro-6-methyl-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine
1
ꢀ
midin-2-ylamino}-ethanol (5j). Yield: 85%; mp 210–212 C; IR (6d). Yield: 90%; mp 170–172 C; H NMR (400 MHz, CDCl3):
(cmꢁ1, lm): 3247, 2923, 2852, 2367, 1571, 1422, 1294, 1219, 2.29 (s, 3H), 3.83 (s, 3H), 6.22 (s, 1H), 6.94 (d, 2H, J ¼ 8.79 Hz),
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7.20 (d, 2H, J ¼ 8.79 Hz), 7.28 (br s, 1H); ESI-MS (m/z): 250.10 (M calcd for C25H25ClN6O2: C, 62.95; H, 5.28; N, 17.62%; found: C,
+ H)+, 252.09 (M + 2)+; anal. calcd for C12H12ClN3O: C, 57.72; H, 62.99; H, 5.33; N, 17.65%.
4.84; N, 16.83%; found: C, 57.71; H, 4.89; N, 16.84%.
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-6-methyl-pyri-
(2-Chloro-pyrimidin-4-yl)-phenyl-amine (6e). Yield: 92%; mp midin-4-yl}-(3,5-dimethoxy-phenyl)-amine (7b). Yield: 89%; mp
1
184–186 C; H NMR (400 MHz, CDCl3): 6.59 (d, 1H, J ¼ 5.86 212–214 ꢀC; IR (cmꢁ1, lm): 3401, 2958, 2840, 1574, 1479, 1423,
ꢀ
Hz), 7.23–7.27 (m, 2H), 7.30–7.32 (m, 2H), 7.40–7.44 (m, 2H), 1381, 1250, 1203, 1152, 1070, 927, 875, 754; 1H NMR (400 MHz,
8.12 (d, 1H, J ¼ 5.86 Hz); ESI-MS (m/z): 206.06 (M + H)+, 208.05 CDCl3): 2.26 (s, 3H), 3.25–3.27 (m, 4H), 3.78 (s, 6H), 4.08–4.11
(M + 2)+; anal. calcd for C10H8ClN3: C, 58.41; H, 3.92; N, 20.43%; (m, 4H), 5.98 (s, 1H), 6.21–6.24 (m, 1H), 6.52 (br s, 1H), 6.58 (d,
found: C, 58.44; H, 3.96; N, 20.49%.
2H, J ¼ 2.20 Hz), 6.86 (d, 1H, J ¼ 5.13 Hz), 7.46 (dd, 1H, J ¼ 8.79
(2-Chloro-pyrimidin-4-yl)-(4-uoro-phenyl)-amine (6f). Yield: Hz, J ¼ 2.20 Hz), 8.03 (d, 1H, J ¼ 8.79 Hz), 8.06 (d, 1H, J ¼ 2.20
86%; mp 178–180 ꢀC; 1H NMR (400 MHz, CDCl3): 6.46 (d, 1H, J Hz), 8.73 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 491.22 (M + H)+,
¼ 8.05 Hz), 7.08–7.14 (m, 2H), 7.25 (br s, 1H), 7.28–7.31 (m, 2H), 493.17 (M + 2)+; anal. calcd for C26H27ClN6O2: C, 63.60; H, 5.54;
8.11 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 224.05 (M + H)+; 226.07 N, 17.12%; found: C, 63.64; H, 5.56; N, 17.14%.
(M + 2)+; anal. calcd for C10H7ClFN3: C, 53.71; H, 3.15; N,
18.79%; found: C, 53.74; H, 3.21; N, 18.85%.
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-
ꢀ
(4-methoxy-phenyl)-amine (7c). Yield: 85%; mp 168–170 C; IR
(2-Chloro-6-methyl-pyrimidin-4-yl)-(4-uoro-phenyl)-amine (cmꢁ1, lm): 3292, 2935, 2835, 1574, 1509, 1463, 1381, 1245,
1
(6g). Yield: 90%; mp 148–150 ꢀC; H NMR (400 MHz, CDCl3): 1124, 1011, 933, 868, 824, 754; 1H NMR (400 MHz, CDCl3): 3.14–
2.32 (s, 3H), 6.29 (s, 1H), 7.09–7.14 (m, 2H), 7.17 (br s, 1H), 7.27– 3.21 (m, 4H), 3.73 (s, 3H), 3.94–4.00 (m, 4H), 5.84 (d, 1H, J ¼ 5.13
7.30 (m, 2H); ESI-MS (m/z): 238.06 (M + H)+, 240.05 (M + 2)+; Hz), 6.59 (br s, 1H), 6.77 (d, 1H, J ¼ 5.13 Hz), 6.82 (d, 2H, J ¼ 8.05
anal. calcd for C11H9ClFN3: C, 55.59; H, 3.82; N, 17.68%; found: Hz), 7.18 (d, 1H, J ¼ 8.05 Hz), 7.38 (d, 1H, J ¼ 7.32 Hz), 7.89–7.98
C, 55.64; H, 3.87; N, 17.74%.
(m, 4H), 8.64 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 447.16 (M + H)+,
(4-Chloro-phenyl)-(2-chloro-pyrimidin-4-yl)-amine
(6h). 449.18 (M + 2)+; anal. calcd for C24H23ClN6O: C, 64.50; H, 5.19;
Yield: 94%; mp 200–202 ꢀC; 1H NMR (400 MHz, CDCl3): 6.55 (d, N, 18.80%; found: C, 64.55; H, 5.23; H, 18.84%.
1H, J ¼ 5.13 Hz), 6.97 (br s, 1H), 7.28–7.30 (m, 2H), 7.37–7.39 (m,
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-6-methyl-pyri-
2H), 8.15 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 240.05 (M + H)+, midin-4-yl}-(4-methoxy-phenyl)-amine (7d). Yield: 82%; mp
242.01 (M + 2)+; anal. calcd for C10H7Cl2N3: C, 50.03; H, 2.94; N, 122–124 ꢀC; IR (cmꢁ1, lm): 3298, 2955, 2835, 1577, 1508, 1442,
17.50%; found: C, 50.10; H, 2.99; N, 17.54%.
1381, 1244, 1177, 1017, 998, 876, 754; 1H NMR (400 MHz,
(4-Bromo-phenyl)-(2-chloro-pyrimidin-4-yl)-amine (6i). Yield: CDCl3): 2.29 (s, 3H), 3.25–3.27 (m, 4H), 3.82 (s, 3H), 4.06–4.08
85%; mp 207–209 ꢀC; 1H NMR (400 MHz, CDCl3): 6.56 (d, 1H, J (m, 4H), 5.80 (s, 1H), 6.39 (br s, 1H), 6.86 (d, 1H, J ¼ 5.13 Hz),
¼ 5.13 Hz), 6.97 (br s, 1H), 7.23–7.25 (m, 2H), 7.51–7.54 (m, 2H), 6.91 (d, 2H, J ¼ 8.79 Hz), 7.23–7.26 (m, 2H), 7.46 (dd, 1H, J ¼
8.15 (d, 1H, J ¼ 5.13 Hz); ESI-MS (m/z): 283.99 (M + H)+, 258.97 8.79 Hz, J ¼ 2.20 Hz), 8.02–8.06 (m, 2H), 8.73 (d, 1H, J ¼ 5.13
(M + 2)+; anal. calcd for C10H7BrClN3: C, 42.21; H, 2.48; N, Hz); 13C NMR (100 MHz, CDCl3): 24.31, 43.82, 52.27, 55.47,
14.77%; found: C, 42.25; H, 2.59; N, 14.80%.
Typical proceudre for the synthesis of {2-[4-(7-chloro-quino- 131.60, 134.94, 150.10, 151.89, 156.73, 157.10, 161.79, 162.40,
lin-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-(3,5-dimethoxy-phenyl)-
166.83; ESI-MS (m/z): 461.19 (M + H)+, 463.18 (M + 2)+; anal.
92.92, 109.05, 114.41, 121.94, 124.83, 125.15, 126.24, 128.83,
amine (7a) and related compounds (7b–i). To a stirred solution calcd for C25H25ClN6O: C, 65.14; H, 5.47; N, 18.23%; found: C,
of compound 6a (300 mg, 1 mmol) and compound 2 (279 mg, 1 65.14; H, 5.48; N, 18.23%.
mmol) in DMF (7 mL), K2CO3 (311 mg, 2 mmol) was added.
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-
Reaction mixture was stirred at 110–120 ꢀC for 8–10 h. Aer phenyl-amine (7e). Yield: 89%; mp 230–232 ꢀC; IR (cmꢁ1, lm):
completion of reaction, water was added to the reaction mixture 3432, 2967, 2843, 1565, 1496, 1476, 1436, 1384, 1296, 1227,
1
and the product was extracted with EtOAc (3 ꢂ 30 mL). The 1011, 934, 866, 826, 750, 690; H NMR (400 MHz, DMSO-d6):
combined organic layer was dried over Na2SO4 and solvent was 3.21–3.24 (m, 4H), 3.96–3.97 (m, 4H), 6.08 (d, 1H, J ¼ 5.13 Hz),
evaporated under reduced pressure. The crude product was 6.92–6.98 (m, 1H), 7.04 (d, 1H, J ¼ 5.13 Hz), 7.27–7.31 (m, 2H),
puried by column chromatography using EtOAc/hexane as 7.56 (dd, 1H, J ¼ 9.52 Hz, J ¼ 2.20 Hz), 7.62 (d, 2H, J ¼ 8.79 Hz),
eluent to afford pure compound 7a.
7.96 (d, 1H, J ¼ 5.13 Hz), 7.98 (d, 1H, J ¼ 2.20 Hz), 8.13 (d, 1H, J
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}- ¼ 8.79 Hz), 8.70 (d, 1H, J ¼ 5.13 Hz), 9.29 (br s, 1H); ESI-MS (m/
(3,5-dimethoxy-phenyl)-amine (7a). Yield: 82%; mp 228–230 ꢀC; z): 417.18 (M + H)+, 419.15 (M + 2)+; anal. calcd for C23H21ClN6:
IR (cmꢁ1, lm): 3370, 2932, 2849, 1573, 1461, 1423, 1341, 1224, C, 66.26; H, 5.08; N, 20.16%; found: C, 66.30; H, 5.12; N, 20.18%.
1152, 1067, 1014, 994, 825, 753; 1H NMR (400 MHz, DMSO-d6):
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-
3.21–3.24 (m, 4H), 3.72 (s, 6H), 3.99–4.00 (m, 4H), 6.09 (d, 1H, J (4-uoro-phenyl)-amine (7f). Yield: 81%; mp 226–228 ꢀC; IR
¼ 5.86 Hz), 6.11–6.12 (m, 1H), 6.93 (d, 2H, J ¼ 2.20 Hz), 7.03– (cmꢁ1, lm): 3275, 2962, 2853, 1577, 1506, 1441, 1350, 1297,
7.05 (m, 1H), 7.57 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 7.96–8.00 1220, 1125, 1086, 1053, 1011, 979, 933, 870, 834, 731, 655, 517;
(m, 2H), 8.13 (d, 1H, J ¼ 8.79 Hz), 8.70 (d, 1H, J ¼ 5.13 Hz), 9.29 1H NMR (400 MHz, DMSO-d6): 3.20–3.23 (m, 4H), 3.95–3.98 (m,
(br s, 1H); 13C NMR (100 MHz, DMSO-d6): 43.48, 51.58, 55.00, 4H), 6.05 (d, 1H, J ¼ 5.86 Hz), 7.02 (d, 1H, J ¼ 5.13 Hz), 7.11–7.15
94.36, 96.79, 97.33, 97.41, 109.67, 121.42, 125.92, 126.07, (m, 2H), 7.57 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 7.61–7.64 (m,
128.03, 133.62, 141.96, 149.60, 152.21, 156.10, 156.31, 160.42, 2H), 7.96 (d, 1H, J ¼ 5.86 Hz), 7.98 (d, 1H, J ¼ 2.20 Hz), 8.12 (d,
161.01; ESI-MS (m/z): 477.19 (M + H)+, 479.17 (M + 2)+; anal. 1H, J ¼ 8.79 Hz), 8.70 (d, 1H, J ¼ 5.13 Hz), 9.31 (br s, 1H); ESI-MS
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(m/z): 435.17 (M + H)+, 437.14 (M + 2)+; anal. calcd for
Acknowledgements
C
23H20ClFN6: C, 63.52; H, 4.64; N, 19.32%; found: C, 63.58; H,
4.65; N, 19.34%.
DSR thanks University Grants Commission [F. no. 41-202/
2012(SR)], New Delhi, India and University of Delhi, Delhi, India
for nancial support. AT is thankful to CSIR for the award of
senior research fellowship. Thanks to USIC-CIF, University of
Delhi for analytical data. SIK is thankful to United States
Department of Agriculture (USDA), Agricultural Research
Service Specic Cooperative Agreement no. 58-6408-2-0009 for
partial support of this work. Mr Sumit Srivastava for X-ray
crystallography and John Trott for bioassay is also
acknowledged.
{2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-6-methyl-pyri-
midin-4-yl}-(4-uoro-phenyl)-amine (7g). Yield: 86%; mp 236–
238 ꢀC; IR (cmꢁ1, lm): 3308, 2918, 2848, 1577, 1506, 1446,
1361, 1233, 1214, 1176, 1073, 998, 876, 754; 1H NMR (400 MHz,
CDCl3): 2.25 (s, 3H), 3.25–3.27 (m, 4H), 4.06–4.08 (m, 4H), 5.84
(s, 1H), 6.48 (br s, 1H), 6.86 (d, 1H, J ¼ 5.13 Hz), 7.03–7.07 (m,
2H), 7.30–7.34 (m, 2H), 7.46 (dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz),
8.03 (d, 1H, J ¼ 8.79 Hz), 8.06 (d, 1H, J ¼ 2.20 Hz), 8.73 (d, 1H, J
¼ 5.13 Hz); ESI-MS (m/z): 449.18 (M + H)+, 451.17 (M + 2)+; anal.
calcd for C24H22ClNFN6: C, 64.21; H, 4.94; N, 18.72%; found: C,
64.26; H, 4.97; N, 18.75%.
(4-Chloro-phenyl)-{2-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-
pyrimidin-4-yl}-amine (7h). Yield: 88%; mp 198–200 ꢀC; IR
(cmꢁ1, lm): 3314, 3190, 2841, 1609, 1572, 1465, 1380, 1237,
1125, 1087, 1008, 933, 825, 793, 714; 1H NMR (400 MHz, CDCl3):
3.26–3.28 (m, 4H), 4.06–4.08 (m, 4H), 6.01 (d, 1H, J ¼ 5.13 Hz),
6.66 (br s, 1H), 6.86 (d, 1H, J ¼ 5.13 Hz), 7.30–7.38 (m, 4H), 7.46
(dd, 1H, J ¼ 8.79 Hz, J ¼ 2.20 Hz), 8.02–8.06 (m, 3H), 8.73 (d, 1H,
J ¼ 5.13 Hz); 13C NMR (100 MHz, CDCl3): 43.82, 52.18, 95.39,
109.12, 121.93, 122.60, 125.09, 126.38, 128.79, 128.83, 129.13,
135.03, 137.42, 150.09, 151.89, 157.00, 157.19, 160.72, 161.61;
ESI-MS (m/z): 451.13 (M + H)+, 453.11 (M + 2)+; anal. calcd for
Notes and references
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23H20Cl2N6: C, 61.20; H, 4.47; N, 18.62%; found: C, 61.26; H,
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4.51; N, 18.66%.
(4-Bromo-phenyl)-{2-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-
pyrimidin-4-yl}-amine (7i). Yield: 81%; mp 184–186 ꢀC; IR
(cmꢁ1, lm): 3314, 3098, 2841, 1609, 572, 1488, 1465, 1351,
1
1295, 1237, 1087, 1008, 933, 867, 825, 793; H NMR (400 MHz,
CDCl3): 3.26–3.31 (m, 4H), 4.05–4.13 (m, 4H), 6.01 (d, 1H, J ¼
5.13 Hz), 6.60 (brs, 1H), 6.86 (d, 1H, J ¼ 5.13 Hz), 7.29–7.33 (m,
2H), 7.44–7.49 (m, 3H), 8.02–8.07 (m, 3H), 8.73 (d, 1H, J ¼ 5.13
Hz); ESI-MS (m/z): 495.08 (M + H)+; 497.09 (M + 2)+; anal. calcd
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