Novel 5-anilinoquinazoline-8-nitro derivatives as inhibitors of VEGFR-2 tyrosine kinase: Synthesis, biological evaluation and molecular docking

Article abstract of DOI:10.1039/c3ob40368h

Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC ₅₀ values in the submicromolar range (compound 6f, IC₅₀ 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40368h

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Novel 5-anilinoquinazoline-8-nitro derivatives as
inhibitors of VEGFR-2 tyrosine kinase: synthesis,
Cite this: Org. Biomol. Chem., 2013, 11,
4367
biological evaluation and molecular docking†
Liang Xi,a Jian-Qiang Zhang,a Zhi-Cheng Liu,b Ji-Hong Zhang,b Ju-Fang Yan,c Yi Jin*a
and Jun Lin*a,d
Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to
promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoqui-
nazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds
described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various
cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibi-
tors with in vitro IC50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a
weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were
studied using molecular docking studies.
Received 20th February 2013,
Accepted 8th May 2013
DOI: 10.1039/c3ob40368h
www.rsc.org/obc
VEGFR-2 has lower affinity for VEGF than VEGFR-1, VEGFR-2
exhibits robust protein tyrosine kinase activity in response to
Introduction
Most signal transduction pathways are mediated by protein its ligands. VEGFR-2 is expressed at abnormally high levels in
kinases, and aberrant kinase signaling leads to proliferation of a large variety of human solid tumors.2a,4 There is much evi-
cancer cells as well as angiogenesis and growth of solid dence that direct inhibition of the kinase activity of VEGFR-2
tumors such as prostate, colon, breast, and gastric cancers.1 will result in a reduction in angiogenesis and the suppression
The VEGF family of receptors consists of three protein tyrosine of this signaling pathway has become an inhibiting method of
kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3) and two tumor growth. Therefore, inhibition of VEGFR-2 is an attractive
non-protein kinase co-receptors (neuropilin-1 and neuropilin- strategy in the treatment of cancers.5
2). These components are key intermediates in tumor angio-
This research has led to the development of an USAFDA
genesis and in the formation of new blood vessel networks approved anti-VEGF antibody, bevacizumab (Avastin),6 as well
required to supply nutrition and oxygen for tumor growth.2 as three small molecule inhibitors of VEGFR-2 kinase, i.e. sora-
Vascular endothelial growth factor receptor-2 (VEGFR-2, KDR) fenib (BAY-43-9006),7 sunitinib (Su-11248)8 and pazopanib9
is the main mediator that plays important roles in regulating (Fig. 1). Numerous other small molecule targeting agents and
vascular permeability, migration, endothelial cell proliferation monoclonal antibodies are currently in clinical development
and angiogenesis under physiological conditions mediated by
the vascular endothelial growth factor (VEGF).3 Although
aKey Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry of Education, School of Chemical Science and Technology, Yunnan
University, Kunming, 650091, P. R. China. E-mail: jinyi@ynu.edu.cn,
linjun@ynu.edu.cn; Fax: +86 871 5033215
bFaculty of Life Science and Technology, Kunming University of Science and
Technology, Kunming 650224, P. R. China
cChengdu DiAo Pharmaceut Grp Co Ltd, Drug Screening Ctr, Chengdu 610041,
P. R. China
dState Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin,
300071, P. R. China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40368h
Fig. 1 VEGFR-2 tyrosine kinase inhibitors.
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with the intention of inhibiting this critical pathway in angio-
genesis,10 for example, indolin-2-ones, quinolinones, imidazo-
Results and discussion
pyridines, benzimidazoles, quinazolines, quinolyl–thienyl All compounds of the series were subjected to in vitro VEGFR-2
chalcones, phthalazines and quinoline amides have been and EGFR kinase inhibitory assays followed by cell prolifer-
reported as potent inhibitors of VEGFR-2 and angiogenesis.11
ation assays using human umbilical vein endothelial cells
Quinazoline derivatives, specifically 4-anilinoquinazolines, (HUVEC) which overexpress VEGFR-2 glycoprotein,
have attracted interest over the years because of their multiple HepG2 hepatocellular carcinoma cells, MCF-7 breast cancer
biological activities, notably as selective epidermal growth cells and SK-OV-3 ovarian cancer cells (Table 1).
factor receptor (EGFR) inhibitors.12 However, to date, no inhi-
For the kinase inhibitory assay, all compounds showed
bition towards VEGFR tyrosine kinase activity has been weak to strong inhibitory activity for VEGFR-2 kinase, but
reported with 5-anilinoquinazolines. We previously discovered failed against EGFR kinase (>10 μM). This may have occurred
a series of 5-anilinoquiniazoline derivatives as potent EGFR because the aryl–aryl or alkyl–aryl urea substituent at the
inhibitors.13 In the current investigation, we discovered a novel 5-position in the quinazoline skeleton is too bulky, and does
series of 5-anilinoquinazolin-8-nitro compounds as a new not fit in the region of the EGFR kinase activity pocket. As in
class of small-molecule inhibitors of VEGFR-2.
previous work, small ordinary aniline fragments substituted at
the 5-position of quinazoline showed some inhibitory activity
against EGFR.13
The first SAR study focused on the quinazoline skeleton
substituted at the 5-position by 1,4-dianiline, 1,3-dianiline,
1,2-dianiline, 1,4-cyclohexanediamine, piperazine and 1,3-pro-
panediamine substituted with aryl urea. The 1,4-dianiline sub-
stitution at the 5-position of quinazoline afforded the best
inhibitors of VEGFR-2 kinase (6a–6f), and 1,2-dianiline and
1,3-dianiline substitution provided some inhibitory activity
(6g–6p), but piperazine, 1,4-cyclohexanediamine and 1,3-pro-
panediamine substitution resulted in no significant inhibition
of VEGFR-2 (IC50 > 5 μM). Among these compounds, those
with 1,4-diamine substituted aryl–aryl ureas were 50-fold more
active than their 1,3-diamine and 1,2-diamine analogs, and
1000-fold more potent than the compounds with diamine sub-
stituted aryl–alkyl ureas.
With respect to the substituent (R1) effect at the terminal
benzene ring of the aryl–aryl urea portion, electronic effects
and a substituted position were found to be important for the
activity of our 5-anilinoquinazoline series. Substitution in the
benzene ring with electron-withdrawing groups showed a
remarkable positive response, e.g. the 3-trifluoromethyl (6d),
2,5-dichloro (6e) and 2-chloro-5-trifluoromethyl (6f) substi-
tuted compounds demonstrated much more activity against
VEGFR-2 than with 3-methyl or 4-methyl substitution.
Additionally, electron-withdrawing groups at the 2,5-position
were more beneficial, e.g. the 2,5-dichloro and 2-chloro-5-tri-
fluoromethyl derivatives (6e, 6f) were the most potent inhibi-
tors of VEGFR-2 kinase, but were not better than the reference
compound sorafenib.
Chemistry
We developed an efficient and facile synthetic approach to
prepare a variety of 5-anilinoquinazoline-8-nitro derivatives
with various C-5 aryl urea substituents. The various key inter-
mediates and final compounds were synthesized according to
the general method described in Scheme 1. 5-Chloro-quinazo-
line-8-nitro (5) was prepared from our previously reported
method in five steps.13 The aliphatic diamines or aromatic di-
amines were reacted with Boc anhydride to afford single N-Boc
protected diamines (2). The synthesis of the N,N′-disubstituted
ureas (4a–4z) was performed by reacting the corresponding iso-
cyanates (3a–3f) in the presence of single N-Boc protected di-
amines or dianilines with high yields and short reaction
times. The preparation of 5-anilinoquiniazoline-8-nitro ana-
logues was performed using a two step procedure: deprotec-
tion of N-Boc in CH2Cl2 with TFA and nucleophilic
substitution of 5-chloro-quinazoline-8-nitro with a series of
1-amino-3-arylureas in moderate yields.
For the cell proliferation assays, all compounds showed low
(IC50 > 10 μM) to moderate (IC50 1–10 μM) antiproliferative
activity with no obvious correlation to VEGFR-2 inhibition,
perhaps as a result of poorer membrane permeability due to
the ionizable 4-hydroxy group of quinazoline, because of
4-hydroxy quinazolines having a lower log D (calculated at pH
= 7.4). Interestingly, only the 1,4-dianiline substituents (6a, 6e,
6f) were found to inhibit HUVEC cell proliferation; this result
was consistent with VEGFR-2 kinase inhibition. Specifically
the 2-chloro-5-trifluoromethyl substituent (6f, IC50 = 1.8 μM)
exhibited better inhibition results than the positive control
Scheme 1 Synthesis of intermediates. Reagents and conditions: (a) Boc anhy-
dride, DCM, 0 °C, 60–150 min (50–75%); (b) isocyanates, toluene, 10–20 min,
r.t. (90%); (c) (1) TFA, DCM, r.t. (95%) (2) EA–DMF, r.t. 8–72 h (40–70%).
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Table 1 Enzymatic inhibition (VEGFR-2/EGFR) and antiproliferative activity towards human umbilical vein endothelial cells (HUVEC), HepG2 hepatocellular carci-
noma cells, MCF-7 breast cancer cells and SK-OV-3 ovarian cancer cells
Enzymatic inhibition (IC50/μM)
Proliferative inhibition (% inhibition or IC50/μM)
Cpd
X
R1
VEGFR-2
0.045
EGFR
>10
HUVEC
6.4
HepG2
>10
MCF-7
40.07
SK-OV-3
38.9
6a
3-CH3
6b
6c
6d
6e
6f
4-CH3
0.108
0.079
0.167
0.026
0.012
>10
>10
>10
>10
>10
>10
>10
>10
5.7
>10
>10
>10
>10
>10
18.24
>50
35.39
>50
3-Cl
4-CH3
3-CF3
>50
40.2
41.9
36.4
2-Cl
5-Cl
>50
2-Cl
5-CF3
1.8
>50
6g
6h
6i
4-CH3
0.742
2.34
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>50
>50
>50
46.94
>50
>50
>50
3-Cl
4-CH3
>50
3-CF3
0.98
37.22
>50
6j
2-Cl
5-Cl
1.47
6k
6l
2-Cl
5-CF3
0.84
9.98
19.4
3-CH3
4-CH3
>10
6m
6n
6o
>10
>10
9.23
>10
>10
>10
>10
>10
>10
>10
>10
>10
22.4
10.5
21.5
>50
>50
>50
3-Cl
4-CH3
3-CF3
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Table 1 (Contd.)
Enzymatic inhibition (IC50/μM)
Proliferative inhibition (% inhibition or IC50/μM)
Cpd
X
R1
VEGFR-2
8.89
EGFR
>10
HUVEC
>10
HepG2
>10
MCF-7
7.41
SK-OV-3
37.9
6p
2-Cl
5-Cl
6q
6r
6s
6t
3-CH3
4-CH3
>10
>10
9.80
>10.
>10
>10
>10
>10
>10
>10
>10
>10
>10
9.42
>10
>10
>50
>50
>50
>50
>50
>50
>50
>50
2-Cl
5-Cl
2-Cl
5-CF3
6u
6v
4-CH3
3-CF3
3-CH3
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
2.36
>10
9.34
37.56
23.6
42.0
37.7
>50
6w
6x
6y
6z
4-CH3
3-CF3
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
4.78
>10
34.2
10.5
9.03
>50
>50
>50
2-Cl
5-CF3
Sorafenib
Taxol
DPP
0.002
N.D.
N.D.
>10
N.D.
N.D.
6.1
0.1
N.D.
6.69
0.01
N.D.
N.D.
N.D.
6.3
N.D.
N.D.
49.19
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Fig. 2 Putative binding modes of the optimized analog 6f (indicated in brown) in VEGFR-2 kinase, predicted by molecular modeling. The 3-D picture was prepared
with Accelrys Discovery Studio, while the 2-D picture was drawn with Molecular Operating Environment. The key residues within the binding pocket are indicated in
green, and the dashed lines illustrate atom pairs within hydrogen bonds.
sorafenib (IC50 = 6.1 μM). Additionally, almost all compounds
As shown previously, the active site in VEGFR-2 kinase is
showed no antiproliferative activity against hepatocellular car- formed by a channel in the protein between two large, solvent-
cinoma cells (HepG2), except the three alkyl–aryl urea substitu- accessible pockets, with the active site glutamic acid and
ents (piperazine linker 6v, 1,4-cyclohexanediamine linker 6r aspartic residues encircling the ligand. The costructure of 6f
and 1,3-propanediamine linker 6y), which were found to have (Fig. 2) revealed that the hydrophobic 2-chloro-5-(trifluoro-
moderate activity, similar to the result of sorafenib (IC50
=
methyl)-benzene moiety was buried in one end of the active
6.69 μM), but far worse than taxol (IC50 = 0.01 μM). These site of VEGFR-2, with the carbonyl oxygen of the urea directed
three compounds (6v, 6r, 6y) may inhibit HepG2 cell growth toward aspartic acid (Asp1044) and the urea N–H directed
through other biological mechanisms. In the breast cancer toward glutamic acid (Gly883) in the active site. Interestingly,
(MCF-7) and ovarian cancer (SK-OV-3) antiproliferation assays, the structure shows the phenyl ring of dianiline forming a π–
compounds 6p, 6u and 6v showed moderate or weak activity in cation interaction with the nitrogen atoms of the Lys866
MCF-7 cells (IC50: 6p, 7.41 μM; 6u, 9.34 μM; 6v, 37.56 μM) and residue, thus supporting the more favorable binding inter-
weak activity in SK-OV-3 cells (IC50: 6p, 37.9 μM; 6u, 42.0 μM; actions of aryl–aryl urea substituents with VEGFR-2 kinase
6v, 37.7 μM); this result is similar to using the positive control compared to aryl–alkyl urea substituents. Moreover, the
cisplatin (DPP, IC50: 6.3 μM for MCF-7, 49.19 μM for SK-OV-3).
2-chloro-5-(trifluoromethyl)benzene moiety matched the flat
shape of the hydrophobic pocket, which could have contribu-
ted to improved potency. Furthermore, the B ring of quinazo-
line and the benzene ring of the Phe916 residue have formed a
π–π stacking interaction, and the quinazoline hydroxyl is
directed toward the cysteine (Cys917) to form a hydrogen
bond, which may further stabilize the binding conformation.
Molecular modelling
To better understand the molecular basis for the improved
potency of the 5-anilinoquinazoline derivatives, the com-
pounds were docked into the structure of VEGFR-2 kinase, pre-
viously reported to be cocrystallized with 4-amino-3-(4-((2-
fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)-
phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (pdb code:
Conclusions
1YWN, Fig. 1).14 The most active compound (6f) was docked In summary, a series of 5-anilinoquinazolin-8-nitro derivatives
into the catalytic site using the program Autodock,15 assuming showed significant VEGR-2 kinase inhibition. Substitution of
the same binding mode and exhibiting the same hydrogen 5-quinazoline by the aromatic 1,4-dianilino group increased
bonding interaction pattern with the enzyme as observed for inhibition against VEGFR-2 in vitro. Varying groups on the
the 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino- 5-quinazoline scaffold by the aliphatic diamine or changing
carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimi- the substituted position of the aromatic dianiline led to a
dine. The lowest energy conformation was adopted as the weakening or loss of activity against VEGFR-2 kinase and
final binding conformation.
HUVEC cell proliferation. The aliphatic diamine substituents
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showed weak to moderate inhibitory activity on HepG2, MCF-7 mL−1 poly(Glu, Tyr)4:1 (Sigma) as a substrate. In each well,
and SK-OV-3 cancer cells. This study provides a new promising 85 μL of an 8 μM ATP solution and 10 μL of the compound
scaffold for further development of new anticancer drugs target- were added at varying concentrations. Sorafenib was used as a
ing VEGFR-2 kinase. Some compounds, particularly compound positive control for VEGFR-2 and EGFR kinase, and 0.1% (v/v)
6v, exhibited significant antiproliferative activity on cancer cells, DMSO was the negative control. Experiments at each concen-
supporting its use as a positive control compound. Conse- tration were performed in triplicate. The reaction was initiated
quently, further pharmacological studies are required to deter- by adding 5 μL of VEGFR-2 or EGFR kinase. After incubation
mine the exact mechanism of action, and chemical for 1 h at 37 °C, the plate was washed three times with PBS
modification via fragment modifications guided by structure containing 0.1% Tween 20 (T-PBS). Next, 100 μL of anti-phos-
and ligand-based computational methodologies may lead to the photyrosine (PY99; 1 : 500 dilution) antibody was added. After
discovery of better agents as potential clinical candidates.
1 h of incubation at room temperature, the plate was washed
three times. Goat anti-mouse IgG horseradish peroxidase
(100 μL; 1 : 2000 dilution) diluted in T-PBS containing 5 mg
mL−1 BSA was added. The plate was reincubated at room temp-
erature for 1 h, and washed as before. Finally, 100 μL of devel-
oping solution (0.03% H2O2, 2 mg mL−1 o-phenylenediamine
in citrate buffer 0.1 M, pH 5.5) was added and incubated at
room temperature until color emerged. The reaction was termi-
nated by the addition of 100 μL of 2 M H2SO4, and A492 was
measured using a multiwell spectrophotometer (VERSAmax™).
The inhibition rate (%) was calculated using the equation:
Experimental
Molecular modeling
The crystal structure of the kinase domain of EGFR in a complex
with its inhibitor LIF301 (PDB entry code 1WYN)14 was recovered
from Brookhaven Protein Database (PDB). The missing atoms
and residues were modeled in Sybyl 6.8.17. The kinds of
atomic charges were taken as Kollman-united-atom16 for the
macromolecule and Gasteiger–Marsili17 for the inhibitor.
To investigate the binding mode of compound 6f to the
kinase domain of VEGFR-2, the advanced docking program
Autodock 3.0.315 was used to automatically dock the inhibitor
to the enzyme. The Lamarckian genetic algorithm (LGA) was
applied to deal with the inhibitor–enzyme interaction. A Solis
and Wets local search performed the energy minimization on
a user-specified proportion of the population. The docked con-
formations of the inhibitor were generated after a reasonable
number of evaluations.
The whole docking operation in this study can be summar-
ised as follows. First, the kinase domain of VEGFR-2 was
checked for polar hydrogens and assigned for partial atomic
charges, then a PDBQ file was created, and the atomic sol-
vation parameters were assigned for the macromolecule.
Meanwhile, some of the torsion angles of the inhibitor that
would be explored during molecular docking stage were
defined, allowing the conformation search for the ligand
during the docking process. Second, the grid map with 60 × 60
× 60 points and a spacing of 0.375 Å was calculated using the
AutoGrid program in order to evaluate the binding energies
between the inhibitor and the macromolecule. Third, some
important parameters for LGA calculations were rationally set.
Not only the atom types, but also the generations and the
number of runs for the LGA algorithm were edited and properly
assigned according to the requirements of the Amber force
field. The maximum number of generations, energy evaluations
and docking runs was set to 3.0 × 105, 1.5 × 107, and 30, respecti-
vely. Finally, the docked complex of the inhibitor–enzyme for the
inhibitor was selected according to the criterion of interaction
energy combined with geometrical matching quality.
Inhibition rate ð%Þ ¼ ½1 ꢀ ðA492=A492 controlÞꢁ ꢂ 100%
Cell growth inhibition assay. Four human carcinoma cell
lines, i.e. human umbilical vein endothelial cells (HUVEC),
HepG2 hepatocellular carcinoma cells, MCF-7 breast cancer
cells and SK-OV-3 ovarian cancer cells, were used for the
cell proliferation assay. Cells were maintained in
RPMI-1640 medium supplemented with 10% (v/v) fetal bovine
serum, 2 mmol L−1 glutamine, 100 U mL−1 penicillin and
100 μg mL−1 streptomycin (Gibco, Grand Island, NY, USA) in a
highly humidified atmosphere of 95% air with 5% CO2 at
37 °C. Growth inhibition was analyzed by the sulforhodamine
B (SRB, Sigma) assay.18 Briefly, cells were seeded at 6000 cells
per well in 96-well plates (Falcon, CA, USA) and allowed to
attach overnight. The cells were treated in triplicate with
graded concentrations of the compounds at 37 °C for 72 h,
Taxol and DPP (cisplatin) were used as positive controls. Then,
they were fixed with 10% trichloroacetic acid and incubated
for 60 min at 4 °C. Next, the plates were washed and dried.
SRB solution (0.4% w/v in 1% acetic acid) was added and the
culture was incubated for an additional 15 min. After the
plates were washed and dried, bound stain was solubilized
with Tris buffer, and the optical densities were read on the
plate reader (model VERSA Max, Molecular Devices) at
515 nm. The growth inhibitory rate % of treated cells was cal-
culated by the following formula: [1 − (A515 treated/A515
control)] × 100%. The results were also expressed as IC50 (the
compound concentration required for 50% growth inhibition of
tumor cells), which was calculated by the Logit method. The mean
IC50 was determined from the results of three independent tests.
Biology
Chemistry
EGFR and VEGFR-2 kinase activity assays by ELISA. The
General information. All compounds were fully character-
assay was performed in 96-well plates pre-coated with 20 μg ized by spectroscopic data. The NMR spectra were recorded on
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a Bruker DRX500 (1H: 500 MHz, 13C: 125 MHz), chemical 9.40 (s, 1H, ArH), 9.60 (s, 1H, NH); 13C NMR (125 MHz, DMSO-
shifts (δ) are expressed in ppm, and J values are given in Hz, d6): δ = 28.5, 28.5, 28.5, 79.4, 108.4, 112.4, 112.8, 116.8, 119.4,
and deuterated CDCl3 and DMSO-d6 were used as the solvents. 125.5, 129.4, 130.7, 137.4, 139.7, 140.5, 152.3, 153.1.
IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360
tert-Butyl 4-(3-(2,5-dichlorophenyl)ureido)phenylcarbamate
1
using KBr pellets. The reactions were monitored by thin layer (4e). White solid; Mp 220–230 °C; H NMR (500 MHz, DMSO-
chromatography (TLC) using silica gel GF254. The melting d6): δ = 1.48 (s, 9H, CH3), 7.06–7.49 (m, 5H, ArH), 8.34–8.39
points were determined on an XT-4A melting point apparatus (m, 2H, ArH), 8.24 (s, 1H, NH), 9.40 (s, 1H, NH); 13C NMR
and are uncorrected. HRMs were performed on an Agilent LC/ (125 MHz, DMSO-d6): δ = 28.5, 28.5, 28.5, 79.2, 119.3, 119.3,
Msd TOF instrument. All chemicals and solvents were used as 120.2, 122.8, 130.8, 130.8, 132.3, 133.9, 134.8, 137.8, 152.3,
received without further purification unless otherwise stated. 153.2.
Column chromatography was performed on silica gel
tert-Butyl 4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)-
(200–300 mesh). Compounds 2 were prepared according to the phenylcarbamate (4f). White solid; Mp 221–245 °C; 1H NMR
literature. The materials 3a–c were purchased from Aldrich (500 MHz, DMSO-d6): δ = 1.48 (s, 9H, CH3), 2.90 (s, 2H, NCH2),
Corporation Limited.
7.05–7.06 (m, 1H, ArH), 7.33–7.41 (m, 6H, ArH), 7.68–7.70 (m,
General procedure. Single-Boc protected diamine com- 1H, ArH), 8.55 (s, 1H, NH), 8.66 (s, 1H, NH), 9.45 (s, 1H, NH);
pound 2 (0.50 mmol) was dissolved in 10 mL of toluene in a 13C NMR (125 MHz, DMSO-d6): δ = 28.5, 28.5, 28.5, 79.2, 117.0,
25 mL round-bottom flask, and substituted phenyl isocyanate 119.2, 119.2, 119.4, 119.4, 123.1, 125.5, 128.5, 128.7, 130.7,
(0.57 mmol) dissolved in 3 mL of toluene was added slowly 133.8, 134.9, 137.5, 152.4, 153.2.
with stirring at room temperature. A white or light yellow solid
tert-Butyl 3-(3-p-tolylureido)phenylcarbamate (4g). White
1
was generated, and the precipitate was collected by filtration to solid; Mp 260–255 °C; H NMR (500 MHz, DMSO-d6): δ = 1.49
get the intermediate compound 4 (yield > 90%). Compound 4 (s, 9H, CH3), 2.25 (s, 1H, ArCH3), 7.02–7.18 (m, 6H, ArH),
(0.23 mmol) and 15 mL of CH2Cl2 were added to the flask, 7.33–7.35 (m, 2H, ArH), 7.60 (s, 1H, ArH), 8.45 (s, 1H, NH),
then trifluoroacetic acid (32 mg, 0.28 mmol) was added drop- 8.64 (s, 1H, NH), 9.33 (s, 1H, NH); 13C NMR (125 MHz, DMSO-
wise with stirring. When TLC showed the completion of the d6): δ = 20.7, 28.5, 28.5, 28.5, 79.3, 108.4, 112.3, 118.6, 118.6,
deprotection reaction, the mixture was diluted with 15 mL of 128.6, 129.2, 129.3, 129.5, 129.5, 131.0, 137.5, 140.3, 140.5,
ethyl acetate. The organic phase was washed with saturated 152.8, 153.1.
aqueous sodium bicarbonate (20 mL), dried over Na2SO4, and
tert-Butyl 3-(3-(3-chloro-4-methylphenyl)ureido)phenylcarba-
concentrated to afford a solid. This solid (25 mg, 0.096 mmol), mate (4h). White solid; Mp 176–197 °C; 1H NMR (500 MHz,
without purification, and the quinazoline compound 5 (25 mg, DMSO-d6): δ = 1.48 (s, 9H, CH3), 2.27 (s, 1H, ArCH3), 7.02–7.25
0.1 mmol) were dissolved in 10 mL of ethyl acetate and 2 mL (m, 5H, ArH), 7.61 (s, 1H, ArH), 7.70 (s, 1H, ArH), 8.65 (s, 1H,
of DMF. The reaction mixture was stirred for ∼48–72 h at room NH), 8.72 (s, 1H, NH), 9.33 (s, 1H, NH); 13C NMR (125 MHz,
temperature. The reaction solution color gradually trans- DMSO-d6): δ = 19.2, 28.5, 28.5, 28.5, 79.6, 108.6, 112.5, 112.5,
formed from pale yellow to orange. The resulting mixture was 117.3, 118.4, 128.6, 129.2, 131.5, 133.5, 139.3, 140.2, 140.3,
washed with water (20 mL), dried over Na2SO4, concentrated 152.7, 153.1.
and purified by flash column chromatography to afford the
product 6 (yield 40 to 80%). The products were further charac- bamate (4i). White solid; Mp 146–150 °C; H NMR (500 MHz,
terised by FT-IR, NMR and HRMS, and the results were in DMSO-d6): δ = 1.48 (s, 9H, CH3), 7.05–7.06 (m, 1H, ArH),
tert-Butyl 3-(3-(3-(trifluoromethyl)phenyl)ureido)phenylcar-
1
good agreement with the assigned structures.
7.13–7.16 (m, 2H, ArH), 7.30–7.31 (m, 1H, ArH), 7.49–7.56 (m,
tert-Butyl 4-(3-m-tolylureido)phenylcarbamate (4a). White 2H, ArH), 7.64 (s, 1H, ArH), 8.03 (s, 1H, ArH), 8.80 (s, 1H, NH),
1
solid; Mp 231–245 °C; H NMR (500 MHz, DMSO-d6): δ = 1.48 8.92 (s, 1H, NH), 9.33 (s, 1H, NH); 13C NMR (125 MHz, DMSO-
(s, 9H, CH3), 2.28 (s, 1H, ArCH3), 6.77–6.79 (m, 1H, ArH), d6): δ = 29.0, 29.0, 29.0, 79.8, 109.3, 113.2, 113.2, 114.9, 118.9,
7.13–7.38 (m, 7H, ArH), 8.50 (s, 1H, NH), 8.51 (s, 1H, NH), 9.19 122.6, 126.2, 129.7, 130.6, 130.7, 140.5, 140.7, 141.5, 153.2,
(s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.6, 28.5, 153.6.
28.5, 28.5, 79.1, 115.7, 119.0, 119.0, 119.2, 119.2, 122.8, 128.6,
128.9, 129.3, 134.3, 134.6, 138.3, 140.1, 153.0, 153.3.
tert-Butyl 3-(3-(2,5-dichlorophenyl)ureido)phenylcarbamate
(4j). White solid; Mp 147–151 °C; H NMR (500 MHz, DMSO-
1
tert-Butyl 4-(3-p-tolylureido)phenylcarbamate (4b). White d6): δ = 1.49 (s, 9H, CH3), 7.03–7.25 (m, 4H, ArH), 7.49–7.50
1
solid; Mp 263–354 °C; H NMR (500 MHz, DMSO-d6): δ = 1.47 (m, 2H, ArH), 7.63 (s, 1H, ArH), 7.49–7.56 (m, 2H, ArH), 7.63
(s, 9H, CH3), 2.24 (s, 1H, CH3), 7.07–7.08 (m, 2H, ArH), (s, 1H, ArH), 8.35 (s, 1H, ArH), 8.41 (s, 1H, NH), 9.37 (s, 1H,
7.32–7.37 (m, 6H, ArH), 8.46 (s, 1H, NH), 8.47 (s, 1H, NH), 9.18 NH), 9.54 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 28.5,
(s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 20.7, 28.5, 28.5, 28.5, 79.4, 108.4, 112.3, 112.8, 120.1, 122.7, 129.4, 120.9,
28.5, 28.5, 79.1, 118.6, 118.6, 119.1, 119.1, 129.5, 129.5, 130.8, 132.3, 137.7, 139.8, 140.4, 152.1, 153.1.
134.2, 134.7, 137.6, 153.0, 153.3.
tert-Butyl 4-(3-(3-(trifluoromethyl)phenyl)ureido)phenylcar- solid; Mp 149–153 °C; H NMR (500 MHz, DMSO-d6): δ = 1.47
bamate (4d). White solid; Mp 145–150 °C; H NMR (500 MHz, (s, 9H, CH3), 2.90 (s, 3H, CH3), 6.79–6.80 (m, 1H, ArH),
tert-Butyl 2-(3-m-tolylureido)phenylcarbamate (4l). White
1
1
DMSO-d6): δ = 1.48 (s, 9H, CH3), 7.06–7.36 (m, 4H, ArH), 7.00–7.03 (m, 1H, ArH), 7.10–7.30 (m, 5H, ArH), 7.78–7.79 (m,
7.65–7.71 (m, 2H, ArH), 8.56 (s, 1H, ArH), 8.67 (s, 1H, NH), 1H, ArH), 8.03 (s, 1H, NH), 8.50 (s, 1H, NH), 9.10 (s, 1H, NH);
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13C NMR (125 MHz, DMSO-d6): δ = 21.6, 28.5, 28.5, 28.5, 79.6, 9H, CH3), 1.78–1.80 (m, 2H, CH2), 1.89–1.91 (m, 2H, CH2),
115.7, 119.0, 122.4, 122.9, 123.1, 125.4, 125.9, 129.0, 138.3, 2.30 (s, 1H, NCH), 3.25 (s, 1H, NCH), 7.23–7.27 (m, 2H, ArH),
140.1, 153.2, 154.1.
7.63–7.66 (m, 1H, ArH), 8.24 (s, 1H, NH), 8.66 (s, 1H, NH); 13C
tert-Butyl 2-(3-p-tolylureido)phenylcarbamate (4m). White NMR (125 MHz, DMSO-d6): δ = 28.6, 28.6, 28.6, 31.5, 31.5,
1
solid; Mp 143–150 °C; H NMR (500 MHz, DMSO-d6): δ = 1.46 31.8, 31.8, 48.2, 48.8, 77.7, 109.3, 116.3, 118.6, 124.6, 125.7,
(s, 9H, CH3), 2.25 (s, 1H, ArCH3), 6.99–7.35 (m, 5H, ArH), 7.77 128.4, 138.0, 154.2, 155.2.
(s, 1H, ArH), 8.01 (s, 1H, ArH), 8.52 (s, 1H, NH), 9.08 (s, 1H,
tert-Butyl 4-(p-tolylcarbamoyl)piperazine-1-carboxylate
1
NH); 13C NMR (125 MHz, DMSO-d6): δ = 20.7, 28.5, 28.5, 28.5, (4u). White solid; Mp 197–200 °C; H NMR (500 MHz, DMSO-
79.5, 118.6, 118.6, 122.5, 123.1, 125.4, 125.8, 129.2, 129.6, d6): δ = 1.42 (s, 9H, CH3), 2.23 (s, 3H, ArCH3), 3.05–3.06 (s, 2H,
129.6, 131.0, 133.5, 137.6, 153.3, 154.1.
NCH2), 3.35 (s, 5H, NCH2), 3.55 (s, 5H, NCH2), 7.02–7.04 (d,
tert-Butyl 2-(3-(3-chloro-4-methylphenyl)ureido)phenylcarba- 2H, J = 8.20 Hz, ArH), 7.34–7.36 (d, 2H, J = 8.25 Hz, ArH), 8.54
mate (4n). White solid; Mp 150–155 °C; 1H NMR (500 MHz, (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 20.7, 28.4,
DMSO-d6): δ = 1.46 (s, 9H, CH3), 2.27 (s, 1H, ArCH3), 7.03–7.25 28.4, 28.4, 42.7, 42.7, 43.9, 43.9, 79.4, 120.2, 120.2, 129.1,
(m, 4H, ArH), 7.32 (s, 1H, NH), 7.72 (s, 1H, ArH), 7.77 (s, 1H, 129.1, 131.0, 138.2, 154.3, 155.4.
ArH), 8.05 (s, 1H, ArH), 8.56 (s, 1H, NH), 9.29 (s, 1H, NH), 9.33
tert-Butyl 4-(3-(trifluoromethyl)phenylcarbamoyl)pipera-
1
(s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 19.2, 28.4, zine-1-carboxylate (4v). White solid; Mp 149–154 °C; H NMR
28.4, 28.4, 79.6, 117.2, 118.4, 122.8, 123.4, 125.4, 125.8, 128.5, (500 MHz, DMSO-d6): δ = 1.43 (s, 9H, CH3), 3.55–3.70 (m, 8H,
129.3, 131.6, 133.2, 133.5, 139.4, 153.1, 154.1.
NCH2), 7.27–7.28 (m, 1H, ArH), 7.46–7.49 (m, 1H, ArH),
tert-Butyl 4-(3-(2,5-dichlorophenyl)ureido)cyclohexylcarba- 7.73–7.75 (m, 1H, ArH), 7.92–7.95 (m, 1H, ArH), 8.91 (s, 1H,
mate (4p). White solid; Mp 149–157 °C; 1H NMR (300 MHz, NH); 13C NMR (125 MHz, DMSO-d6): δ = 28.4, 28.4, 28.4, 43.9,
DMSO-d6): δ = 1.48 (s, 9H, CH3), 7.02–7.14 (m, 3H, ArH), 43.9, 43.9, 43.9, 79.5, 115.8, 118.3, 123.2, 125.7, 129.4, 129.8,
7.35–7.37 (m, 1H, ArH), 7.46–7.49 (m, 1H, ArH), 7.68–7.70 (m, 141.7, 154.2, 155.0.
1H, ArH), 8.27–8.28 (m, 1H, ArH), 8.03 (s, 1H, NH), 8.83 (s, 1H,
tert-Butyl 3-(3-p-tolylureido)propylcarbamate (4x). White
1
NH), 8.87 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 28.0, solid; Mp 124–151 °C; H NMR (500 MHz, DMSO-d6): δ = 1.39
28.0, 28.0, 79.1, 120.3, 120.4, 122.6, 123.2, 123.5, 124.7, 125.0, (s, 9H, CH3), 1.50–1.53 (m, 2H, CH2), 2.21 (s, 3H, ArCH3),
129.8, 130.5, 131.8, 137.5, 152.5, 153.4.
tert-Butyl 4-(3-m-tolylureido)cyclohexylcarbamate
2.96–2.97 (m, 2H, NCH2), 3.05–3.07 (m, 2H, NCH2), 6.07 (s,
(4q). 1H, NH), 6.82 (s, 1H, NH), 7.01–7.02 (d, 2H, J = 8.05 Hz, ArH),
White solid; Mp 250–272 °C; 1H NMR (500 MHz, DMSO-d6): 7.26–7.27 (d, 2H, J = 8.15 Hz, ArH), 8.36 (s, 1H, NH); 13C NMR
δ = 1.15–1.24 (m, 4H, CH2), δ = 1.37 (s, 9H, CH3), 1.76–1.78 (m, (125 MHz, DMSO-d6): δ = 20.6, 28.6, 28.6, 28.6, 30.8, 37.0, 37.8,
2H, CH2), 1.84–1.86 (m, 2H, CH2), 2.22 (s, 3H, ArCH3), 3.21 (s, 77.8, 118.1, 118.1, 129.4, 129.4, 130.0, 138.4, 155.7, 156.1.
2H, NCH), 5.98–5.99 (m, 1H, NH), 6.68–6.69 (m, 1H, ArH),
tert-Butyl 3-(3-(3-(trifluoromethyl)phenyl)ureido)propylcar-
1
7.05–7.18 (m, 3H, ArH), 8.18 (s, 1H, NH), 8.30 (s, 1H, NH); 13C bamate (4y). White solid; Mp 147–151 °C; H NMR (300 MHz,
NMR (125 MHz, DMSO-d6): δ = 21.6, 28.6, 28.6, 28.6, 31.7, CDCl3): δ = 1.43 (s, 9H, CH3), 1.64 (s, 2H, CH2), 3.19 (t, 2H, J =
31.7, 32.1, 32.1, 48.0, 48.9, 79.5, 115.2, 118.5, 122.1, 128.8, 6.3 Hz, NCH2), 3.29 (t, 2H, J = 6.0 Hz, NCH2), 7.26–7.36 (m,
138.1, 140.8, 154.9, 155.3.
2H, ArH), 7.65 (m, 2H, ArH).
tert-Butyl 4-(3-p-tolylureido)cyclohexylcarbamate (4r). White
tert-Butyl 3-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)-
solid; Mp 145–151 °C; 1H NMR (500 MHz, DMSO-d6): δ = propylcarbamate (4z). White solid; Mp 148–155 °C; 1H NMR
1.16–1.25 (m, 4H, CH2), 1.39 (s, 9H, CH3), 1.77–1.87 (m, 4H, (500 MHz, DMSO-d6): δ = 1.38 (s, 9H, CH3), 1.55–1.57 (m, 2H,
CH2), 2.21 (s, 3H, ArCH3), 2.51 (s, 1H, NCH), 3.22 (s, 1H, CH2), 2.97–3.00 (m, 2H, NCH2), 3.10–3.13 (m, 2H, NCH2), 6.84
NCH), 5.94–5.95 (m, 1H, NH), 6.68 (s, 1H, NH), 7.00–7.02 (d, (s, 1H, NH), 7.20–7.28 (m, 2H, ArH), 7.63–7.65 (m, 1H, ArH),
2H, J = 7.35 Hz, ArH), 7.24–7.25 (d, 2H, J = 7.45 Hz, ArH), 8.15 8.36 (s, 1H, NH), 8.64 (s, 1H, NH); 13C NMR (125 MHz, DMSO-
(s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 20.6, 28.6, d6): δ = 28.6, 28.6, 28.6, 30.3, 37.1, 37.9, 77.9, 116.6, 118.6,
28.6, 28.6, 31.7, 31.7, 32.1, 32.1, 47.9, 48.9, 77.7, 118.1, 118.1, 123.2, 125.3, 128.6, 130.5, 138.1, 155.0, 156.0.
129.4, 129.4, 130.0, 138.3, 155.0, 155.2.
1-(4-(4-Bydroxy-8-nitroquinazolin-5-lamino)phenyl)-3-m-tolyl-
tert-Butyl 2-(3-(2,5-dichlorophenyl)ureido)phenylcarbamate urea (6a). Yellow solid; Mp 171–174 °C; IR (KBr): 3317, 3044,
1
(4s). White solid; Mp 146–151 °C; H NMR (500 MHz, DMSO- 2923, 1661, 1600, 1540, 1519, 704, 528 cm−1
;
1H NMR
d6): δ = 1.17–1.26 (m, 4H, CH2), δ = 1.38 (s, 9H, CH3), 1.78–1.80 (500 MHz, DMSO-d6): δ = 2.28 (s, 3H, CH3), 6.78 (s, 1H, ArH),
(m, 2H, CH2), 1.88–1.91 (m, 2H, CH2), 3.25 (s, 2H, NCH), 6.70 6.92 (s, 2H, ArH), 7.00–7.02 (d, J = 7.1 Hz, 1H, ArH), 7.07 (s,
(s, 1H, ArH), 6.98–6.99 (m, 1H, ArH), 7.10–7.11 (m, 1H, ArH), 1H, ArH), 7.23 (s, 1H, ArH), 7.30 (s, 1H, ArH), 7.38 (s, 2H,
7.41–7.43 (m, 1H, ArH), 8.06 (s, 1H, NH), 8.32 (s, 1H, NH); 13C ArH), 8.15–8.17 (d, J = 7.1 Hz, 1H, ArH), 8.27 (s, 1H, NCHvN),
NMR (125 MHz, DMSO-d6): δ = 28.6, 28.6, 28.6, 31.6, 31.6, 8.57 (s, 1H, NH), 8.66 (s, 1H, NH), 11.49 (s, 1H, NH), 12.90 (s,
31.8, 31.8, 48.2, 48.8, 77.8, 119.5, 121.9, 130.7, 132.2, 138.4, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 21.6, 111.3, 115.8,
154.1, 155.3.
112.9, 119.1, 119.3, 119.3, 120.0, 120.0, 122.9, 129.0, 130.8,
tert-Butyl 4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)- 132.3, 132.5, 134.8, 136.8, 138.3, 140.0, 141.8, 148.2, 152.9,
cyclohexylcarbamate (4t). White solid; Mp 140–145 °C; 1H 164.4; HRMS (TOF ES+): m/z calcd for C22H18N6O4 [(M + Na)+],
NMR (500 MHz, DMSO-d6): δ = 1.16–1.28 (m, 4H, CH2), 1.38 (s, 453.1287; found, 453.1293.
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1-(4-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-p- 8.55 Hz, 2H, ArH), 7.75–7.73 (d, J = 8.35 Hz, 1H, ArH),
tolylurea (6b). Yellow solid; Mp 165–170 °C; IR (KBr): 3303, 8.21–8.19 (d, J = 9.05 Hz, 1H, ArH), 7.96 (s, 1H, NH), 8.02 (s,
3046, 2924, 1664, 1600, 1303, 823, 708 cm−1
;
1H NMR 1H, ArH), 8.17–8.18 (d, J = 8.45 Hz, 1H, ArH), 8.26–8.31 (m,
(500 MHz, DMSO-d6): δ = 2.24 (s, 3H, CH3), 6.91–6.93 (d, J = 1H, NH), 8.65 (s, 1H, NCHvN), 9.59 (s, 1H, NH), 11.52 (s, 1H,
8.15 Hz, 2H, ArH), 6.91–7.00 (m, 2H, ArH), 7.08–7.09 (d, J = OH); 13C NMR (125 MHz, DMSO-d6): δ = 111.3, 117.2, 119.5,
7.75 Hz, 2H, ArH), 7.33–7.34 (d, J = 7.95 Hz, 2H, ArH), 119.6, 119.6, 120.0, 120.0, 123.1, 125.8, 128.2, 128.5, 128.8,
7.37–7.38 (d, J = 8.30 Hz, 2H, ArH), 7.96 (s, 1H, NH), 8.15–8.17 130.7, 132.5, 135.9, 137.3, 141.7, 148.2, 148.7, 152.4, 159.0,
(s, 1H, ArH), 8.27 (s, 1H, NCHvN), 8.55 (s, 1H, NH), 8.63 (s, 162.7; HRMS (TOF ES+): m/z calcd for C22H14ClF3N6O4
1H, NH), 11.49 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = [(M + Na)+], 541.0615; found, 541.0625.
20.7, 111.3, 115.7, 118.7, 118.7, 119.2, 119.2, 120.0, 120.0,
1-(3-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-p-
129.5, 129.5, 131.0, 132.5, 134.7, 136.8, 137.5, 141.8, 148.2, tolylurea (6g). Yellow-red solid; Mp 167–171 °C; IR (KBr):
152.9, 154.4, 162.7, 164.7; HRMS (TOF ES+): m/z calcd for 3328, 3175, 3050, 2926, 1660, 1601, 1541, 1459, 1251, 1099,
1
C22H18N6O4[(M + Na)+], 453.1287; found, 453.1291.
872, 823 cm−1; H NMR (500 MHz, DMSO-d6): δ = 2.24 (s, 3H,
1-(3-Chloro-4-methylphenyl)-3-(4-(4-hydroxy-8-nitro-quinazo- CH3), 6.56–6.57 (m, 1H, ArH), 7.07–7.09 (m, 4H, ArH),
lin-5-ylamino)phenyl)urea (6c). Yellow solid; Mp 169–171 °C; 7.16–7.20 (m, 1H, ArH), 7.23 (s, 1H, ArH), 7.31–7.33 (d, J = 8.15
IR (KBr): 3326, 3269, 3036, 1600, 1503, 1380, 1306, 827, Hz, 2H, ArH), 7.66–7.72 (m, 1H, NH), 8.19–8.22 (m, 1H, ArH),
703 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3), 8.28 (s, 1H, NCHvN), 8.54 (s, 1H, NH), 8.66 (s, 1H, NH), 11.49
6.91 (s, 2H, ArH), 7.00 (s, 2H, ArH), 7.20 (s, 2H, ArH), 7.37 (s, (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 20.6, 108.4,
2H, ArH), 7.67 (s, 1H, ArH), 8.14 (s, 1H, ArH), 8.24 (s, 1H, 111.6, 112.2, 114.4, 116.7, 118.7, 118.8, 118.8, 129.5, 129.5,
NCHvN), 8.73 (s, 1H, NH), 8.77 (s, 1H, NH), 11.52 (s, 1H, OH); 129.8, 131.2, 132.3, 132.9, 137.3, 141.1, 141.2, 148.2, 152.7,
13C NMR (125 MHz, DMSO-d6): δ = 19.1, 111.3, 115.7, 115.7, 154.3, 164.3; HRMS (TOF ES+): m/z calcd for C22H18N6O4
117.4, 118.6, 119.5, 119.5, 120.0, 120.0, 128.6, 131.5, 132.3, [(M + Na)+], 453.1287; found, 453.1293.
133.5, 135.0, 136.5, 138.3, 141.8, 148.4, 152.8, 154.3, 164.7;
1-(3-Chloro-4-methylphenyl)-3-(3-(4-hydroxy-8-nitroquina-
HRMS (TOF ES+): m/z calcd for C22H17ClN6O4[(M − H)+], zolin-5-ylamino)phenyl)urea (6h). Red solid; Mp 173–175 °C;
463.0922; found, 463.3003.
IR (KBr): 3386, 3297, 2925, 1664, 1599, 1541, 1254, 876 cm−1
;
1-(4-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-(3- 1H NMR (500 MHz, DMSO-d6): δ = 2.25 (s, 3H, CH3), 6.57–6.59
(trifluoromethyl)phenyl)urea (6d). Yellow-red solid; Mp (m, 1H, ArH), 7.07–7.24 (m, 5H, ArH), 7.67 (s, 1H, ArH),
170–175 °C; IR (KBr): 3287, 3056, 2928, 1658, 1603, 1455, 1332, 8.19–8.28 (m, 2H, ArH), 8.81 (s, 1H, NCHvN), 11.52 (s, 1H,
1264, 1168, 1121 cm−1 1H NMR (500 MHz, DMSO-d6): δ = NH); 13C NMR (125 MHz, DMSO-d6): δ = 19.1, 108.6, 111.6,
;
6.94–6.96 (d, J = 7.25 Hz, 2H, ArH), 7.03–7.04 (d, J = 8.15 Hz, 1H, 112.4, 114.5, 116.5, 117.4, 118.6, 128.7, 129.8, 131.5, 132.3,
ArH), 7.32 (s, 1H, ArH), 7.40–7.42 (d, J = 7.45 Hz, 2H, ArH), 7.52 132.9, 133.5, 139.1, 140.9, 141.1, 141.2, 148.3, 152.7, 154.3,
(s, 1H, ArH), 7.58 (s, 1H, ArH), 7.96 (s, 1H, NH), 8.02 (s, 1H, ArH), 164.6; HRMS (TOF ES+): m/z calcd for C22H17ClN6O4
8.17–8.18 (d, J = 8.45 Hz, 1H, ArH), 8.27 (s, 1H, NCHvN), 8.80 (s, [(M + Na)+], 487.0898; found, 487.0897.
1H, NH), 9.04 (s, 1H, NH), 11.50 (s, 1H, OH); 13C NMR (125 MHz,
1-(3-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-(3-
DMSO-d6): δ = 111.3, 114.6, 115.9, 118.4, 119.6, 119.7, 119.7, (trifluoromethyl)phenyl)urea (6i). Red solid; Mp 169–175 °C;
119.9, 122.2, 125.7, 130.2, 132.5, 135.2, 136.3, 140.9, 141.6, 141.7, IR (KBr): 3452, 3376, 3081, 1663, 1604, 1552, 1333, 700 cm−1
148.1, 152.8, 152.9, 162.8, 164.4; HRMS (TOF ES+): m/z calcd for 1H NMR (500 MHz, DMSO-d6): δ = 6.62–6.63 (d, J = 7.2 Hz, 1H,
C22H15F3N6O4 [(M + Na)+], 507.1005; found, 507.1000.
ArH), 7.12–7.25 (m, 3H, ArH), 7.27–7.60 (m, 4H, ArH), δ =
;
1-(2,5-Dichlorophenyl)-3-(4-(4-hydroxy-8-nitroquinazolin-5- 7.98–8.00 (d, J = 10.45 Hz, 1H, ArH), δ = 8.22–8.24 (d, J = 9.1
ylamino)phenyl)urea (6e). Red solid; Mp 175–179 °C; IR Hz, 1H, ArH), 8.30 (s, 1H, NCHvN), 8.88 (s, 1H, NH), 9.07
1
(KBr): 3310, 2927, 1661, 1589, 1519, 1100, 831 cm−1; H NMR (s, 1H, NH), 11.52 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6):
(500 MHz, DMSO-d6): δ = 6.96 (s, 2H, ArH), 7.03 (s, 1H, ArH), δ = 108.8, 111.6, 112.6, 114.6, 114.7, 118.6, 122.3, 129.9, 130.3,
7.40 (s, 2H, ArH), 7.47 (s, 1H, ArH), 7.96 (s, 1H, NH), 8.17 (s, 132.3, 132.9, 140.7, 141.0, 141.2, 148.2, 148.7, 152.7, 162.8;
1H, ArH), 8.26 (s, 1H, ArH), 8.32 (s, 1H, ArH), 8.41 (s, 1H, HRMS (TOF ES+): m/z calcd for C22H15F3N6O4 [(M + Na)+],
NCHvN), 9.51 (s, 1H, NH), 11.50 (s, 1H, NH), 12.89 (s, 1H, 507.1005; found, 507.1005.
OH); 13C NMR (125 MHz, DMSO-d6): δ = 111.3, 115.9, 119.5,
1-(2,5-Dichlorophenyl)-3-(3-(4-hydroxy-8-nitroquinazolin-
119.5, 120.0, 120.3, 120.0, 122.9, 130.8, 132.5, 132.5, 135.4, 5-ylamino)phenyl)urea (6j). Red solid; Mp 178–180 °C; IR
1
136.0, 137.6, 141.7, 148.2, 152.2, 154.3, 162.7, 164.5; HRMS (KBr): 3734, 3383, 2925, 1662, 1593, 1523, 1278, 718 cm−1; H
(TOF ES+): m/z calcd for C21H14Cl2N6O4[(M + Na)+], 507.0351; NMR (500 MHz, DMSO-d6): δ = 6.63 (s, 1H, ArH), 7.09–7.23 (m,
found, 507.0351.
1-(2-Chloro-5-(trifluoromethyl)phenyl)-3-(4-(4-hydroxy-8- NCHvN), 8.46 (s, 1H, NH), 9.56 (s, 1H, NH), 11.53 (s, 1H, NH),
nitroquinazolin-5-ylamino)phenyl)urea
(6f). Yellow-red 12.97 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 108.5,
5H, ArH), 7.48 (s, 1H, ArH), 8.21 (s, 1H, ArH), 8.28 (s, 1H,
solid; Mp 167–171 °C; IR (KBr): 3338, 3064, 2928, 1663, 1542, 111.6, 112.9, 114.5, 116.7, 120.4, 120.5, 123.1, 130.0, 130.8,
1428, 1262, 1111, 828 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 132.3, 132.9, 137.5, 140.5, 141.3, 148.3, 152.1, 154.3, 162.7,
6.98–6.99 (d, J = 8.55 Hz, 2H, ArH), 7.06–7.07 (d, J = 9.05 Hz, 164.5; HRMS (TOF ES+): m/z calcd for C21H14Cl2N6O4
1H, ArH), 7.41–7.39 (d, J = 8.5 Hz, 1H, ArH), 7.44–7.43 (d, J = [(M + Na)+], 507.0351; found, 507.0357.
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1-(2-Chloro-5-(trifluoromethyl)phenyl)-3-(3-(4-hydroxy-8- HRMS (TOF ES+): m/z calcd for C22H15F3N6O4[(M + Na)+],
nitroquinazolin-5-ylamino)phenyl)urea (6k). Red solid; Mp 507.1005; found, 507.0997.
162–165 °C; IR (KBr): 3346, 3383, 2925, 1662, 1593, 1523, 1278,
718 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 6.65–6.66 (m, 1H, ylamino)phenyl)urea (6p). Red solid; Mp 179–183 °C; IR
ArH), 6.99–7.37 (m, 4H, ArH), 7.37 (s, 1H, ArH), 8.21–8.29 (m, (KBr): 2942, 2356, 1678, 1584, 1521, 1262, 1103, 813, 719 cm−1
1-(2,5-Dichlorophenyl)-3-(2-(4-hydroxy-8-nitroquinazolin-5-
;
3H, ArH), 8.31–8.32 (m, 1H, NCHvN), 8.61 (s, 1H, NH), 9.65 1H NMR (500 MHz, DMSO-d6): δ = 6.88–6.89 (m, 1H, ArH),
(s, 1H, NH), 11.53 (s, 1H, NH), 12.73 (s, 1H, OH); 13C NMR 6.93–6.96 (m, 3H, ArH), 7.48–7.49 (m, 1H, ArH), 7.91 (s, 1H,
(125 MHz, DMSO-d6): δ = 108.7, 111.6, 112.9, 114.5, 117.2, ArH), 8.17–8.19 (m, 1H, ArH), 8.29 (s, 1H, ArH), 8.34 (s, 1H,
119.7, 120.6, 125.8, 128.1, 128.7, 129.9, 130.7, 132.2, 132.9, NCHvN), 8.97–8.98 (m, 1H, NH), 9.30–9.31 (m, 1H, NH),
147.8, 148.6, 152.2, 152.3, 154.2, 158.9, 162.7, 164.3; HRMS 11.23 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 111.1,
(TOF ES+): m/z calcd for C22H14ClF3N6O4 [(M + Na)+], 541.0615; 111.8, 116.5, 119.6, 120.7, 120.9, 123.1, 124.0, 125.8, 130.9,
found, 541.0620.
132.2, 132.4, 132.6, 137.7, 143.2, 148.3, 152.7, 154.3, 156.8,
1-(2-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-m- 164.4; HRMS (TOF ES + ): m/z calcd for C21H14Cl2N6O4 [(M +
tolylurea (6l). Red solid; Mp 171–173 °C; IR (KBr): 3440, 2926, Na)+], 507.0351; found, 507.0353.
1662, 1453, 1103, 1051, 831, 715 cm−1
;
1H NMR (500 MHz,
1-(4-(4-Hydroxy-8-nitroquinazolin-5-ylamino)cyclohexyl)-3-m-
DMSO-d6): δ = 2.29 (s, 3H, CH3), 6.79–6.81 (m, 1H, ArH), tolylurea (6q). Yellow solid; Mp 169–174 °C; IR (KBr): 3379,
6.86–6.89 (m, 2H, ArH), 7.08–7.33 (m, 4H, ArH), 7.95 (s, 1H, 3203, 2932, 1659, 1581, 1257, 1091, 710, 561 cm−1 1H NMR
;
ArH), 8.02–8.03 (m, 1H, ArH), 8.16–8.18 (m, 1H, ArH), 8.30 (s, (500 MHz, DMSO-d6): δ = 1.22–1.29 (m, 4H, CH2), 1.90 (s, 4H,
1H, NCHvN), 8.40 (s, 1H, NH), 9.13–9.14 (m, 1H, NH), 11.15 CH2), 2.51 (s, 3H, CH3), 3.12 (s, 2H, CH), 6.83 (s, 1H, ArH),
(s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 21.6, 111.7, 6.98 (s, 1H, NH), 7.14 (s, 2H, ArH), 7.40 (s, 2H, ArH), 7.77 (s,
115.5, 115.6, 116.5, 118.9, 120.0, 121.5, 130.0, 131.0, 133.4, 1H, NH), 8.07 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.30 (s, 1H,
132.6, 133.5, 138.4, 139.9, 143.5, 143.7, 148.3, 152.8, 154.1, NCHvN), 10.02 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ
162.7, 164.5; HRMS (TOF ES+): m/z calcd for C22H18N6O4 [(M + = 30.8, 30.8, 31.2, 31.2, 39.4, 47.6, 53.5, 110.9, 114.1, 119.5,
Na)+], 453.1287; found, 453.1300.
122.0, 130.7, 132.2, 132.2, 132.5, 138.3, 145.2, 148.0, 148.7,
1-(2-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-p- 154.1, 154.3, 164.2; HRMS (TOF ES+): m/z calcd for
tolylurea (6m). Yellow-red solid; Mp 163–168 °C; IR (KBr): C22H24N6O4[(M + Na)+], 459.1757; found, 459.1753.
3330, 3134, 2925, 1672, 1601, 1512, 1457, 1262, 747, 535 cm−1
;
1-(4-(4-Hydroxy-8-nitroquinazolin-5-ylamino)cyclohexyl)-3-p-
1H NMR (500 MHz, DMSO-d6): δ = 2.25 (s, 3H, CH3), 6.86 (s, 2H, tolylurea (6r). Yellow solid; Mp 164–166 °C; IR (KBr): 3409,
ArH), 7.10 (s, 3H, ArH), 7.36 (s, 2H, ArH), 8.02 (s, 1H, ArH), 8.16 3309, 3075, 2931, 1668, 1548, 1459, 820, 735 cm−1 1H NMR
;
(s, 1H, ArH), 8.29 (s, 1H, ArH), 8.36 (s, 1H, NCHvN), 9.09 (s, (500 MHz, DMSO-d6): δ = 1.22 (s, 4H, CH2), 1.88 (s, 4H, CH2),
1H, NH), 11.14 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 2.20 (s, 3H, CH3), 3.01 (s, 2H, CH), 6.01 (s, 1H, ArH), 6.83 (s,
20.7, 111.7, 116.5, 118.4, 118.5, 118.5, 120.0, 121.5, 122.9, 126.1, 1H, NH), 7.01 (s, 2H, ArH), 7.24 (s, 2H, ArH), 8.06 (s, 1H, ArH),
129.6, 129.6, 131.1, 132.4, 132.6, 133.6, 137.5, 143.7, 148.3, 8.22 (s, 1H, NCHvN), 8.22 (s, 1H, NH), 10.01 (s, 1H, NH),
152.9, 154.1, 164.6; HRMS (TOF ES+): m/z calcd for C22H18N6O4 12.76 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 20.6,
[(M + Na)+], 453.1287; found, 453.1289.
31.2, 31.5, 47.6, 53.5, 110.9, 114.3, 118.1, 118.1, 129.4, 129.4,
1-(3-Chloro-4-methylphenyl)-3-(2-(4-hydroxy-8-nitro-quinazo- 130.1, 132.2, 132.5, 138.3, 145.3, 132.3, 148.0, 155.0, 164.0;
lin-5-ylamino)phenyl)urea (6n). Red solid; Mp 174–180 °C; IR HRMS (TOF ES+): m/z calcd for C22H24N6O4 [(M + Na)+],
(KBr): 3354, 3179, 3105, 1683, 1588, 1512, 1204, 714, 604 cm−1
;
459.1757; found, 459.1753.
1-(2,5-Dichlorophenyl)-3-(4-(4-hydroxy-8-nitroquinazolin-5-
1H NMR (500 MHz, DMSO-d6): δ = 2.27 (s, 3H, CH3), 6.87–6.88
(m, 1H, ArH), 7.08–7.26 (m, 4H, ArH), 7.75 (s, 1H, ArH), ylamino)cyclohexyl)urea (6s). Yellow solid; Mp 185–189 °C;
7.98–8.00 (m, 1H, ArH), 8.15–8.17 (m, 1H, ArH), 8.31 (s, 1H, IR (KBr): 3371, 2921, 1655, 1557, 1467, 1327, 821, 727 cm−1; 1H
ArH), 8.49 (s, 1H, NCHvN), 9.35 (s, 1H, NH), 11.14 (s, 1H, NMR (500 MHz, DMSO-d6): δ = 1.71 (s, 4H, CH2), 2.06 (s, 4H,
NH), 12.97 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = CH2), 2.93 (s, 2H, CH), 5.86 (s, 1H, NH), 6.53 (s, 1H, NH),
19.2, 111.8, 116.7, 117.1, 118.3, 120.1, 121.7, 123.2, 126.1, 6.66–6.67 (d, J = 6.4 Hz, 2H, ArH), 6.91 (s, 2H, ArH), 6.96 (s,
128.8, 131.3, 131.6, 132.4, 132.6, 133.3, 133.6, 139.3, 143.7, 1H, ArH), 7.03 (s, 1H, ArH), 7.78 (s, 1H, NH), 7.89–7.90 (s, J =
148.3, 148.8, 152.8, 162.7; HRMS (TOF ES+): m/z calcd for 7.4 Hz, 1H, ArH), 8.03 (s, 1H, NCHvN), 8.06 (s, 1H, NH), 9.84
C22H17ClN6O4[(M + Na)+], 487.0898; found, 487.0899.
(s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 31.2, 31.2,
1-(2-(4-Hydroxy-8-nitroquinazolin-5-ylamino)phenyl)-3-(3-(tri- 31.5, 31.5, 47.6, 53.5, 110.9, 114.1, 115.2, 118.6, 122.1, 128.9,
fluoromethyl)phenyl)urea (6o). Red solid; Mp 162–173 °C; IR 128.8, 132.5, 138.1, 140.6, 145.3, 148.0, 154.5, 154.7, 164.1;
(KBr): 3444, 3230, 2925, 1653, 1521, 1398, 1304, 729, 524 cm−1
;
HRMS (TOF ES+): m/z calcd for C21H20Cl2N6O4 [(M + Na)+],
1H NMR (500 MHz, DMSO-d6): δ = 7.48–7.50 (m, 4H, ArH), 513.0821; found, 513.0833.
7.70–7.72 (m, 2H, ArH), 7.96 (s, 1H, ArH), 8.08–8.09 (m, 2H,
1-(2-Chloro-5-(trifluoromethyl)phenyl)-3-(4-(4-hydroxy-8-
ArH), 8.18 (s, 1H, ArH), 8.24 (s, 1H, NH), 8.53 (s, 1H, NCHvN), nitroquinazolin-5-ylamino)cyclohexyl)urea
(6t). Yellow
12.46 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 120.9, solid; Mp 169–172 °C; IR (KBr): 3441, 3342, 3113, 2929, 1665,
1
121.8, 121.8, 122.6, 124.6, 128.2, 129.4, 129.4, 130.8, 130.8, 1544, 1433, 824, 715 cm−1; H NMR (500 MHz, DMSO-d6): δ =
131.8, 138.2, 144.4, 146.1, 147.8, 148.8, 154.1, 155.1, 159.4; 1.17–1.31 (m, 4H, CH2), 1.92 (s, 4H, CH2), 3.14 (s, 1H, CH),
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3.49 (s, 1H, CH), 6.82–6.84 (m, 1H, ArH), 7.18–7.20 (m, 1H,
1-(3-(4-Hydroxy-8-nitroquinazolin-5-ylamino)propyl)-3-(3-(tri-
ArH), 7.62–7.64 (m, 1H, ArH), 7.95 (s, 1H, ArH), 8.06–8.08 (m, fluoromethyl)phenyl)urea (6y). Yellow solid; Mp 166–172 °C;
1H, ArH), 8.26 (s, 1H, NCHvN), 8.64 (s, 1H, NH), 10.03 (s, 2H, IR (KBr): 3414, 3060, 2923, 2855, 1678, 1584, 1453, 711,
1
ArH), 12.76 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 523 cm−1; H NMR (500 MHz, DMSO-d6): δ = 1.84 (t, J = 6.35
30.8, 30.8, 31.2, 31.2, 47.8, 53.4, 110.9, 114.3, 116.4, 118.6, Hz, 2H, CH2), 2.90 (s, 2H, NCH2), 3.21 (m, 2H, NCH2), 6.38 (m,
125.3, 128.9, 130.5, 132.2, 132.5, 138.0, 145.3, 148.1, 154.2, 1H, NH), 6.81–6.83 (d, J = 8.75 Hz, 1H, ArH), 7.24–7.25 (d, J =
154.6, 162.3, 164.1; HRMS (TOF ES+): m/z calcd for 6.25 Hz, 1H, ArH), 7.20–7.22 (d, J = 8.05 Hz, 2H, ArH),
C22H20ClF3N6O4[(M + Na)+], 547.1084; found, 547.1090.
7.44–7.47 (m, 2H, ArH), 7.93 (s, 1H, ArH), 8.09–8.11 (d, J = 9.05
4-(4-Hydroxy-8-nitroquinazolin-5-yl)-N-p-tolylpiperazine-1- Hz, 2H, ArH), 8.22 (s, 1H, NCHvN), 8.83 (s, 1H, NH) 10.00 (s,
carboxamide (6u). Red solid; Mp 171–173 °C; IR (KBr): 3454, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 30.3, 36.8, 44.5,
2912, 1640, 1512, 1237, 1005, 816 cm−1 1H NMR (500 MHz, 110.2, 113.4, 113.9, 117.6, 121.5, 123.6, 125.7, 129.9, 131.1,
;
DMSO-d6): δ = 2.22 (s, 3H, CH3), 3.06 (s, 4H, NCH2), 3.57 (s, 141.5, 141.6, 146.9, 147.0, 148.1, 154.2, 155.3, 162.7, 164.2;
4H, NCH2), 7.04 (s, 2H, ArH), 7.34 (s, 2H, ArH), 7.48 (s, 1H, HRMS (TOF ES+): m/z calcd for C19H17F3N6O4 [(M + Na)+],
ArH), 8.07 (s, 1H, NH), 8.17 (s, 1H, ArH), 8.48 (s, 1H, NCHvN), 473.1161; found, 473.1164.
12.44 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 20.7,
1-(2-Chloro-5-(trifluoromethyl)phenyl)-3-(3-(4-hydroxy-8-
44.7, 44.7, 50.6, 50.6, 120.1, 120.1, 120.9, 124.5, 129.1, 129.1, nitroquinazolin-5-ylamino)propyl)urea (6z). Yellow solid;
129.4, 130.9, 130.9, 144.5, 146.0, 147.7, 154.1, 155.5, 159.3; Mp 179–181 °C; IR (KBr): 3428, 3093, 2925, 1662, 1584, 1443,
1
HRMS (TOF ES+): m/z calcd for C20H20N6O4 [(M + H)+], 716, 536 cm−1; H NMR (500 MHz, DMSO-d6): δ = 1.82 (s, 2H,
409.1624; found, 409.1626.
CH2), 2.73 (s, 2H, NCH2), 3.21 (s, 2H, NCH2), 6.75 (s, 1H, ArH),
4-(4-Hydroxy-8-nitroquinazolin-5-yl)-N-(3-(trifluorometh-yl)- 7.25 (s, 1H, ArH), 7.61 (s, 1H, ArH), 7.95 (s, 1H, ArH), 7.25 (s,
phenyl)piperazine-1-carboxamide (6v). Yellow solid; Mp 1H, ArH), 8.04 (s, 1H, ArH), 8.26 (s, 1H, NCHvN), 8.53 (s, 1H,
167–171 °C; IR (KBr): 3426, 3089, 2925, 1678, 1547, 1448, 1240, NH), 9.97 (s, 1H, NH), 12.69 (s, 1H, OH); 13C NMR (125 MHz,
1
794, 577 cm−1; H NMR (500 MHz, DMSO-d6): δ = 3.10 (s, 4H, DMSO-d6): δ = 30.2, 36.8, 44.6, 110.2, 118.7, 124.8, 125.1,
NCH2), 3.61 (s, 4H, NCH2), 7.27–7.29 (d, J = 7.8 Hz, 1H, ArH), 128.2, 128.4, 128.8, 130.4, 132.7, 137.9, 146.8, 146.9, 147.9,
7.48–7.52 (m, 2H, ArH), 7.75–7.77 (m, 1H, ArH), 7.94–7.95 (d, 148.7, 154.8, 162.7; HRMS (TOF ES+): m/z calcd for
J = 4.3 Hz, 1H, ArH), 8.09–8.11 (d, J = 8.9 Hz, 1H, ArH), 8.24 (s, C19H16ClF3N6O4 [(M + Na)+], 507.0771; found, 507.0766.
1H, NCHvN); 13C NMR (125 MHz, DMSO-d6): δ = 21.3, 29.4,
29.4, 39.4, 39.4, 111.5, 115.8, 116.4, 119.4, 125.4, 129.4, 132.3,
132.3, 132.9, 139.0, 140.6, 141.1, 148.2, 154.3, 164.4; HRMS
Acknowledgements
(TOF ES+): m/z calcd for C20H17F3N6O4 [(M + Na)+], 485.1161;
found, 485.1148.
Financial support from the National Natural Science Foun-
1-(3-(4-Hydroxy-8-nitroquinazolin-5-ylamino)propyl)-3-m- dation of China (Nos. 20902079, 21262043, 81160384,
tolylurea (6w). Yellow solid; Mp 167–171 °C; IR (KBr): 3316, 21262042 and U1202221) is greatly appreciated. The authors
3146, 2925, 1654, 1565, 1462, 1103, 541 cm−1 1H NMR thank the High Performance Computing Center at Yunnan
;
(500 MHz, DMSO-d6): δ = 1.78–1.80 (m, 2H, CH2), 2.23 (s, 3H, University for use of the high performance computing
CH3), 2.87 (s, 2H, NCH2), 3.16–3.17 (m, 2H, NCH2), 6.68–6.70 platform.
(m, 1H, ArH), 6.79–6.81 (m, 1H, ArH), 7.05–7.17 (m, 2H, ArH),
8.07–8.09 (m, 1H, ArH), 8.20 (s, 1H, ArH), 8.30 (s, 1H,
NCHvN), 8.53 (s, 1H, NH), 9.99 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): δ = 21.6, 30.5, 36.9, 44.6, 110.2, 113.5,
References
115.3, 118.7, 122.1, 128.8, 131.1, 132.7, 138.0, 140.7, 147.0,
148.0, 155.5, 164.1, 169.4; HRMS (TOF ES+): m/z calcd for
C19H20N6O4 [(M + Na)+], 419.1444; found, 419.1440.
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3 (a) A. K. Olsson, A. Kimberg, J. Kreuger and L. Claesson-
Welsh, Nat. Rev. Mol. Cell Biol., 2006, 7, 359; (b) N. Ferrara,
H. Gerber and J. LeCouter, J. Nat. Med., 2003, 9, 669;
(c) P. Carmeliet, Nat. Med., 2003, 9, 653–660; (d) J. C. Yang,
L. Haworth, R. M. Sherry, P. Hwu, D. J. Schwartzentruber;,
1-(3-(4-Hydroxy-8-nitroquinazolin-5-ylamino)propyl)-3-p-tolyl-
urea (6x). Yellow solid; Mp 171–174 °C; IR (KBr): 3454, 3399,
3224, 2929, 1662, 1589, 1506, 1265, 825, 708 cm−1
;
1H NMR
(500 MHz, DMSO-d6): δ = 1.78 (t, J = 5.7 Hz, 2H, CH2), 2.20 (s,
3H, CH3), 2.86 (s, 2H, NCH2), 3.15 (m, 2H, NCH2), 6.12–6.13
(m, 1H, NH), 6.79–6.81 (d, 1H, ArH), 6.99–7.01 (d, J = 8.05 Hz,
2H, ArH), 7.20–7.22 (d, J = 8.05 Hz, 2H, ArH), 8.07–8.08 (d, J =
8.95 Hz, 1H, ArH), 8.20 (s, 1H, NCHvN), 8.24 (s, 1H, NH)
10.00 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ = 20.6,
30.5, 36.8, 44.5, 110.2, 113.5, 118.2, 118.3, 129.3, 129.3, 130.1,
131.1, 132.7, 138.1, 146.9, 148.1, 154.3, 155.6, 164.1; HRMS
(TOF ES+): m/z calcd for C19H20N6O4 [(M + Na)+], 419.1444;
found, 419.1442.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4367–4378 | 4377

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