Design and synthesis of novel quinazoline derivatives and their evaluation as PI3Ks inhibitors

Article abstract of DOI:10.1248/cpb.c14-00560

The aim of this work was to synthesize 4-acetamido-, 4-amino- and 4-oxo-6-substituted aminoquinazolines and to evaluate them as phosphoinositide 3-kinases (PI3Ks) inhibitors. The respective chemotype was designed based on combining the structural features

Full text of DOI:10.1248/cpb.c14-00560

1166
Communication to the Editor
Chem. Pharm. Bull. 62(12) 1166–1172 (2014)
Vol. 62, No. 12
Thus, it is believed that the design of new inhibitors of
PI3Kγ could present a novel strategy for the treatment of
inflammatory diseases. However, such inhibitors should be
selective to PI3Kγ in order to minimize the side effects associ-
ated with interfering with the function of other PI3K enzymes.
In the past few years, numerous selective PI3Kγ inhibitors
have been developed, many of which can be grouped into
three chemical classes: thiazolidinones, aminoheterocyclic de-
rivatives and quinazoline derivatives.6,7)
Herein, we report the design and synthesis of novel 6-sub-
stituted N4-acetyl aminoquinazoline derivatives (D) as a
hybrid structure obtained from two scaffolds that were pre-
viously reported to inhibit PI3Kγ, which are quinazolinone
derivatives and aminoheterocyclic derivatives (B and C)8,9)
(A)7) (Fig. 1). Moreover, two extra series of compounds were
synthesized, which are 6-substituted 4-aminoquinazolines (E)
and quinazoline-4-ones (F) to test the effect of removing the
N4-acetyl group on the PI3Kγ inhibitory effect.
Design and Synthesis of Novel
Quinazoline Derivatives and Their
Evaluation as PI3Ks Inhibitors
Omar Maged El-Said,a Mostafa Mohamed Hamed,a,b
,a
Stefan Laufer,c and Ashraf Hassan Abadi*
a Department of Pharmaceutical Chemistry, Faculty of
Pharmacy and Biotechnology, German University in Cairo; Cairo
11835, Egypt: b Helmholz Institute for Pharmaceutical Research,
Saarland University; Campus C2.3, D-66123 Saarbrücken,
Germany: and c Department of Pharmaceutical & Medicinal
Chemistry, Institute of Pharmacy, Eberhard-Karls-University
Tuebingen; Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Received August 3, 2014; accepted September 7, 2014
The aim of this work was to synthesize 4-acetamido-,
4-amino- and 4-oxo-6-substituted aminoquinazolines and
to evaluate them as phosphoinositide 3-kinases (PI3Ks) in-
hibitors. The respective chemotype was designed based on
combining the structural features of two previously reported
scaffolds acting as potent PI3Kγ inhibitors, which are quinaz-
oline derivatives and amino-heterocyclic derivatives. In vitro
enzymatic assay at 10µM against all the eight human PI3K
isoforms showed that an unsubstituted benzamide group at
position 6 and an acetyl group at N4 gave the best inhibitory
activity on PI3Kγ. Interestingly, compounds 5a and 5e showed
a significant, inhibitory effect on Class II PI3K-C2γ. This is of
high value since there are very few inhibitors for this isoform
reported in the literature.
Of the many interactions that have been reported between
the active site of PI3Kγ and previously discovered inhibitors,
hydrogen bonding with Val882 in the hinge region is con-
sidered the most frequently identified and reported in either
co-crystal structures or docking results for most PI3Kγ in-
hibitors.8–11) Since the design of our aminoquinazoline scaffold
was derived from such previous inhibitors, a docking experi-
ment was implemented to test if the Val882 H-bonding is still
conserved for our synthesized compounds. Gold software was
used for this docking experiment with the crystal structure of
PI3Kγ (PDB code: 3DBS).12) Results showed that most of our
synthesized compounds were involved in hydrogen bonding
between N1 of the quinazoline ring and Val882 as well as
other CH–π interactions with Ile881, Ile963 and Tyr867 (Fig.
2). These findings suggest a possible activity for our designed
compounds which still needs to be confirmed by biological
Key words kinase; phosphoinositide; inhibitor; aminoquin-
azoline
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid ki- testing.
nases that are considered to be key players in signal transduc-
Synthesis of the quinazoline nucleus was carried out
tion by generating certain phospholipids that are collectively through reflux of 2-amino-5-nitrobenzonitrile 1 with for-
involved in many homeostatic cell functions such as cell pro- mamide, as shown in Chart 1, to give the 6-nitro-iminoquin-
liferation and differentiation, metabolism and immune func- azoline derivative 2. The cyclization reaction was confirmed
tions.1–3) Different isoenzymes of this family can be grouped by the disappearance of the cyano group absorption peak at
1
into three classes; class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ), 2228.6cm−1 in the IR spectrum. Moreover, its H-NMR spec-
class II (PI3K-C2α, PI3K-C2β and PI3K-C2γ) and class III trum showed two broad singlet peaks at 8.52 and 8.20ppm
(Vps34).4)
corresponding to the protons of the two –NH groups which
Of these classes, class I PI3Ks is the most studied and it is would suggest the predominance of the 4-imino rather than
further subdivided into class IA, comprising three members the 4-amino quinazoline derivative. Following reduction of
(PI3Kα, PI3Kβ, PI3Kδ), and class IB with its sole member the nitro group, different carboxamide or urea derivatives
PI3Kγ,1) differing in their tissue expression levels and their were introduced in position 6 by reaction of quinazoline-4,6-
mechanism of activation, class IB PI3Kγ was found to be diamine 3 with the corresponding acyl chloride or isocyanate,
predominantly expressed in cells of the hematopoietic system,
specifically leukocytes, and is activated through G-protein
coupled receptors (GPCRs), unlike Class IA members, such
as PI3Kα and PI3Kβ which are ubiquitously expressed in the
body and are activated through receptor tyrosine kinases.5)
Moreover, PI3Kγ was found to be involved in many inflam-
matory signaling pathways leading to leukocytic migration
and chemotaxis, reactive oxygen species (ROS) production
and mast cell degranulation.5,6) On the other hand class II iso-
enzymes are the least understood and their functions are still
ambigious.4–6)
Fig. 1. Scaffolds of Previously Reported Inhibitors to PI3Kγ (A–C) and
Scaffolds of Synthesized Compounds in This Work (D, E)
The authors declare no conflict of interest.
© 2014 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: ashraf.abadi@guc.edu.eg

December 2014
1167
respectively. The regioselectivity of this reaction was con-
1
firmed by the H-NMR spectrum in which the singlet peak
corresponding to the 6-amino group (5.38ppm) disappeared,
while the singlet peak corresponding to the 4-amino group
(7.33ppm) remained. An acetyl moiety was then introduced on
the amino group in position 4 using acetic anhydride to give
the corresponding acetylated carboxamide or acetylated urea
derivatives.
An alternative, parallel scheme was followed for synthe-
sizing other 6-urea or thiourea derivatives of N4-acetyl ami-
noquinazolines (Chart 2), where the 4-imino intermediate 2
was acetylated by reflux in acetic anhydride to give N-(6-
nitroquinazolin-4-yl)acetamide 8 followed by reduction of the
nitro group using palladium on activated carbon in presence
of H2 gas giving the N-(6-aminoquinazolin-4-yl)acetamide
9. It should be noted that a trial was conducted in which the
acetylated derivative 8 was reduced using stannous chloride,
as in the first Chart, but breakage of the acetyl group oc-
curred. Such breakage was evident by the absence of the CH3
(a) Formamide, reflux, 10h; (b) SnCl2·2H2O/MeOH, reflux, 3h; (c) RCOCl,
NaHCO3, acetone or DMF, 0°C, 2–3h; (d) Ph-NCO, DMF, 0°C, 2h; (e) acetic anhy-
dride, reflux, 30min.
Chart 1
1
peak in the H-NMR spectrum of the reduction product.
Following the reduction step, different side chains were in-
troduced in position 6 of the quinazoline ring by the reaction
(a) Acetic anhydride, reflux, 30min; (b) H2, Pd/C, MeOH, 3h; (c) RNCX, DMF,
rt, 2–3h.
Chart 2
(a) Formic acid, reflux, 6h; (b) SnCl2·2H2O/MeOH, reflux, 3h; (c) PhCOCl,
NaHCO3, acetone, 0°C, 3h.
Chart 3
Fig. 2. 2D Ligand Interactions of One of Our Compounds (5a) with
PI3Kγ
Table 1. % Residual Activity of PI3Ks Following Inhibition by 6-Substituted N4-Acetyl Aminoquinazoline Derivatives
Compound
PI3Kγ
PI3Kα
PI3Kβ
PI3Kδ
PI3K-C2α
PI3K-C2β
PI3K-C2γ
Vps34
5a
5b
5c
5d
5e
5f
72
85
87
80
83
104
98
90
81
85
93
102
83
94
97
97
89
71
88
89
82
78
84
81
94
87
97
47
83
90
89
85
89
79
95
91
79
96
78
78
78
88
92
77
84
86
124
81
81
94
93
45
95
87
84
92
99
84
90
5g
5h
5i
78
70
82
96
94
91
89
87
81
83
91
91
83
96
73
69
81
81
96
74
93
5j
88
136
100
78
85
91
97
63
96
5k
5l
90
85
90
95
83
96
86
87
93
93
69
99
7
87
76
81
90
89
73
93
10a
10b
13
4a
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Residual activity as % of control. ND: Not determined.

1168
Vol. 62, No. 12
with the corresponding isocyanates or isothiocyanates to give
Finally, despite the fact that the tested compounds didn’t
thiourea or benzoyl urea derivatives 10a and b.
show appreciable inhibitory effect on PI3Kγ when compared
Aside from the 4-aminoquinazoline derivatives, the quin- to other isoforms, two compounds (5a, e) showed a significant,
azoline-4-one nucleus was synthesized by refluxing 2-amino- inhibitory effect on PI3K-C2γ, one of class II PI3Ks. This may
5-nitrobenzonitrile 2 with formic acid to give 6-nitroquinazo- be useful for further modification of these two compounds
lin-4-(3H)-one 11 (Chart 3). Cyclization was confirmed simi- to develop potent, selective inhibitors for this isoform whose
larly to the 4-imino-quinazoline nucleus by the disappearance function in the body is not yet determined and to which no
of the cyano absorption peak from the IR spectrum. The nitro inhibitors have been reported.
group of compound 11 was reduced using stannous chloride,
followed by acylation of the newly formed amine using the
corresponding acid chlorides to give final compounds 13a and
13b.
Experimental
Chemistry All reagents and solvents were of commer-
cial quality and used without further purification. Reactions
The synthesized compounds were biologically assayed, were carried out under argon whenever inert atmosphere was
using the enzymatic ADP-Glo™ assay, for their inhibitory needed. Flash chromatography was carried out using Inter-
effect on the eight different PI3K isoforms in order to test chim Puriflash with stationary phase DAVISIL LC60A 20–45
their activity as well as their selectivity. Testing was done at a Micron. NMR data were recorded at ambient temperature
single screening dose of 10µM where the inhibitory activities on a Bruker Avance 200 at 200MHz (1H) or 50MHz (13C), a
of the compounds are expressed based on the residual activity Bruker Ultra Shield 400 at 400MHz (1H) or 101MHz (13C) or
as % of control and are shown in Table 1.
a Bruker DRX-500 at 500MHz (1H) or 126MHz (13C) using
The major set of tested compounds contained an aryl or het- dimethylsulfoxide (DMSO)-d6 as the solvent. Chemical shifts
eroaryl group directly linked through an amide linker to posi- (δ) are reported in ppm relative to the solvent resonance and
tion 6 of the quinazoline ring. Based on the residual activity all coupling constants (J) are given in Hz. Low resolution
of PI3Kγ at a single dose of 10µM of our tested compounds.
mass spectral (LR-MS) analysis were performed on a Bruker
Compound 5a having an unsubstituted phenyl group Esquire 3000 plus (electrospray ionization (ESI)-ion trap)
showed appreciable inhibition to the isoform PI3K-C2γ when while for all final compounds, High-resolution mass spectral
compared to other monosubstituted phenyl derivatives with analyses (ESI-time-of-flight (TOF)-MS) were performed on a
either a para substituent, particularly as in compounds 5b, d, Bruker MAXIS 4G using ESI as the ionization method. The
and g, or a meta substitutent, as in compound 5c. Comparing purity of the final compounds were determined by HPLC on
the effect of different substituents on the phenyl ring, it was a HPLC Hewlett-Packard HP 1090 Series II liquid chromato-
found that a p-fluoro substituent led to a decrease in activity graph equipped with a UV diode array detector (DAD) (detec-
when compared to the unsubstituted phenyl which suggested tion at 230nm and 254nm) using a Thermo Betasil C8 column
that an electon withdrawing group in the para position may (150 mm×4.6mm, dp=5µm) or a ZORBAX Eclipse XDB-C8
lead to a decrease in activity. Moreover, the replacement of column (150mm×4.6mm, dp=5µm), employing a gradient of
the p-chloro substituent in 5b with a less bulky p-fluoro in 5d 0.01M KH2PO4 (pH=2.3) and methanol as the solvent system
increased the activity, while replacement with the more bulky with a flow rate of 1.5mL/min. The purity was determined
p-tert-butyl and p-nitro in 5f and g, respectively decreases the based on the area under the curve as calculated by Agilent
activity. This trend suggested that aside from the electronic ChemStation Rev. A.09.03. All final compounds were >95%
effect of the substituent, increasing the size of the para sub- pure except for compound 10a having a purity of 94%. Melt-
stituent would lower the activity as PI3Kγ inhibitors. In addi- ing points were determined on a Buchi Melting Point B-540
tion, moving the bulky chloro substituent from the para to the apparatus and are uncorrected. FT-IR spectra were recorded
meta position in compound 5c caused no significant change in on Nicolet Avatar 380 spectrometer.
activity.
6-Nitroquinazoline-4-(3H)-imine (2)13) To 5g (30mmol)
On the other hand, the bioisosteric replacement of the of 2-amino-5-nitrobenzonitrile, 55mL of formamide were
phenyl ring with a thiophene ring in compound 5k led to a added and the mixture was refluxed for 10h while stirring.
significant decrease in activity. This drop in activity was ob- The reaction mixture was then poured on ice water yielding a
served with other heteroaryl groups exemplified in either a 6 green precipitate which was separated by filtration and washed
membered heteroaromatic ring such as pyridine in compounds with acetone to give the pure product 2. Yield: 70%; mp:
1
5h and i or a 5 membered heteroaromatic ring such as furan 330°C; H-NMR (500MHz, DMSO-d6) δ: 9.33–9.30 (m, 1H),
in compound 5j. In addition, replacing the aromatic ring with 8.55 (s, 1H), 8.52 (s, 1H), 8.46 (dd, J=9.2, 2.5Hz, 1H), 8.20 (s,
an alicyclic ring such as cyclopentane in compound 5l led to 1H), 7.80 (d, J=9.2Hz, 1H); 13C-NMR (126MHz, DMSO-d6)
a significant decrease of activity which probably indicates the δ: 162.79, 158.59, 153.19, 143.82, 128.98, 126.41, 121.39, 113.31;
importance of a π-electron system in this position. Finally, re- IR (cm−1): 3274, 3084, 1952, 1682, 1618, 1587, 1510, 1482,
placing the amide linkage present between the aryl moiety and 1342, 1320, 1284, 1260, 1199, 1094; MS (ESI): m/z=190.8
the quinazoline ring with a more extended linkage, such as (M+H)+.
urea or thiourea, led to a decrease in activity. This was proven
by comparing the activity of the urea derivatives (7, 10b) and of 6-nitroquinazoline-4-(3H)-imine 2 and 6g (25mmol) of
.2H O in 25mL methanol was heated to reflux for 3h
Quinazoline-4,6-diamine (3)14) A mixture of 1g (5mmol)
the thiourea derivative (10a) to their carboxamide analogue SnCl2
2
while stirring under inert atmosphere. The solvent was evapo-
rated then 200mL saturated aqueous NaHCO3 solution were
acetyl analogue 5a, which suggested the added to the residue and left stirring for 10min. The suspen-
5a. It was also found that the 4-amino- and 4-oxo derivatives
(4a, 13, respectively) showed decreased activity when com-
pared to their N4
importance of the acetyl group in this position.
sion was then filtered and the aqueous filtrate was collected

December 2014
1169
and evaporated. The desired product was then extracted from 161.45, 154.40, 146.60, 141.78, 135.85, 131.58, 128.99, 128.17,
the residue with N,N-dimethylformamide (DMF) and purified 127.65, 127.61, 114.45, 114.26, 20.98 ; MS (ESI): m/z=278.9
using column chromatography (85% dichloromethane (DCM), (M+H)+; purity (HPLC): 97.1%.
15% 0.5M NH3 in methanol solution). Yield: 83%; mp:
N-(4-Aminoquinazolin-6-yl)-4-nitrobenzamide (4f) Yield:
1
1
280–283°C; H-NMR (400MHz, DMSO-d6) δ: 8.14 (s, 1H), 71%; mp: 328–330°C; H-NMR (400MHz, DMSO-d6) δ: 10.84
7.42 (d, J=8.8Hz, 1H), 7.33 (s, 2H), 7.16 (d, J=7.6Hz, 1H), (s, 1H), 8.56 (s, 1H), 8.40 (d, J=8.3Hz, 2H), 8.37 (s, 1H), 8.25
7.04 (s, 1H), 5.38 (s, 2H); 13C-NMR (101MHz, DMSO-d6) δ: (d, J=8.3Hz, 2H), 7.93 (d, J=8.6Hz, 1H), 7.76 (s, 2H), 7.71
160.24, 150.78, 146.54, 141.65, 127.71, 123.45, 115.56, 101.99; (d, J=8.8Hz, 1H); 13C-NMR (101MHz, DMSO-d6) δ: 163.87,
MS (ESI): m/z=160.8 (M+H)+.
161.56, 154.48, 149.28, 146.55, 140.14, 135.35, 129.17, 128.17,
General Synthesis of Compounds 4a to 4l To a mix- 127.56, 123.62, 114.81, 114.20; MS (ESI): m/z=309.9 (M+H)+;
ture of 1mmol of quinazoline-4,6-diamine 3 and 1.1mmol of purity (HPLC): 92.1%.
NaHCO3, 15mL acetone (or DMF for compounds 4h and i)
N-(4-Aminoquinazolin-6-yl)-4-(tert-butyl)benzamide (4g)
1
were added. Then, 1.1mmol of the corresponding acid chlo- Yield: 35%; mp: 324–325°C; H-NMR (400MHz, DMSO-d6)
ride was dissolved in 1.5mL acetone (or DMF for compounds δ: 10.42 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=8.1Hz,
4h and i) and was added drop wise to the previously prepared 2H), 7.90 (d, J=8.9Hz, 1H), 7.68 (d, J=8.9Hz, 1H), 7.64 (s,
mixture while stirring in an ice bath. The reaction was left for 2H), 7.58 (d, J=8.3Hz, 2H), 1.34 (s, 9H); 13C-NMR (101MHz,
2–3h. The mixture was then poured on a saturated solution of DMSO-d6) δ: 165.41, 161.46, 154.60, 154.37, 146.63, 135.92,
NaHCO3 to form a precipitate which was separated by filtra- 131.79, 128.05, 127.64, 127.50, 125.21, 114.29, 114.24, 34.66,
tion and purified using column chromatography to give the 30.89; MS (ESI): m/z=320.9 (M+H)+; purity (HPLC): 98.2%.
pure compounds 4a to 4l.
N-(4-Aminoquinazolin-6-yl)-2-chloroisonicotinamide (4h)
N-(4-Aminoquinazolin-6-yl)benzamide (4a) Yield: 35%; Yield: 70%; mp: 279–280°C; 1H-NMR (500MHz, DMSO-
mp: 322–323°C; 1H-NMR (400MHz, DMSO-d6) δ: 10.52 d6) δ: 10.83 (s, 1H), 8.66 (dd, J=5.1, 0.7Hz, 1H), 8.53 (d,
(s, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 8.02 (d, J=7.2Hz, 2H), J=2.2Hz, 1H), 8.36 (s, 1H), 8.05 (dd, J=1.4, 0.7Hz, 1H), 7.92
7.92 (d, J=8.9Hz, 1H), 7.78–7.60 (m, 4H), 7.56 (t, J=7.3Hz, (dd, J=5.1, 1.5Hz, 1H), 7.90 (dd, J=9.0, 2.3Hz, 1H), 7.72 (s,
2H); 13C-NMR (101MHz, DMSO-d6) δ: 165.47, 161.48, 2H), 7.70 (s, 1H); 13C-NMR (126MHz, DMSO-d6) δ: 162.46,
154.40, 146.64, 135.80, 134.51, 131.70, 128.44, 128.17, 127.61, 161.51, 154.73, 150.90, 150.84, 147.02, 145.09, 134.89, 127.94,
114.49, 114.27; high resolution (HR)-MS (ESI-TOF-HR): 127.89, 122.24, 121.22, 114.79, 114.24; MS (ESI): m/z=299.8
(M+H)+=265.10859 (Calcd for 265.10339); purity (HPLC): (M+H)+, 301.8 [(M+H)++2]; purity (HPLC): 100%.
99.7%.
N-(4-Aminoquinazolin-6-yl)-4-chlorobenzamide
N-(4-Aminoquinazolin-6-yl)nicotinamide (4i) Yield: 40%;
(4b) mp: 305–307°C; H-NMR (500MHz, DMSO-d6) δ: 10.70 (s,
1
1
Yield: 50%; mp: 343–345°C; H-NMR (400MHz, DMSO-d6) 1H), 9.17 (dd, J=2.3, 0.7Hz, 1H), 8.79 (dd, J=4.8, 1.6Hz, 1H),
δ: 10.59 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.05 (d, J=8.3Hz, 8.54 (d, J=2.2Hz, 1H), 8.37–8.33 (m, 2H), 7.91 (dd, J=8.9,
2H), 7.90 (d, J=8.9Hz, 1H), 7.68 (d, J=9.1Hz, 2H), 7.64 (d, 2.3Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.67 (s, 2H), 7.60 (ddd,
J=8.4Hz, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 164.38, J=7.9, 4.8, 0.8Hz, 1H); 13C-NMR (126MHz, DMSO-d6) δ:
161.47, 154.50, 146.77, 136.58, 135.55, 133.19, 129.58, 128.55, 164.02, 161.48, 154.59, 152.27, 148.68, 146.89, 135.42, 135.37,
128.15, 127.70, 114.65, 114.26; HR-MS (ESI-TOF-HR): 130.16, 128.02, 127.83, 123.58, 114.59, 114.28; MS (ESI):
(M+H)+=299.06950 (Calcd for 299.06942); purity (HPLC): m/z=265.8 (M+H)+; purity (HPLC): 99.2%.
100%.
N-(4-Aminoquinazolin-6-yl)-3-chlorobenzamide
N-(4-Aminoquinazolin-6-yl)furan-2-carboxamide
(4c) Yield: 25%; mp: 278–279°C; H-NMR (400MHz, DMSO-d6)
(4j)
1
1
Yield: 33%; mp: 299–300°C; H-NMR (400MHz, DMSO-d6) δ: 10.46 (s, 1H), 8.47 (d, J=1.2Hz, 1H), 8.35 (s, 1H), 7.97 (s,
δ: 10.63 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.98 1H), 7.92 (dd, J=8.9, 1.6Hz, 1H), 7.68 (d, J=9.0Hz, 3H), 7.39
(d, J=7.4Hz, 1H), 7.92 (d, J=8.8Hz, 1H), 7.70 (d, J=8.6Hz, (d, J=3.1Hz, 1H), 6.73 (d, J=1.5Hz, 1H); 13C-NMR (101MHz,
4H), 7.60 (t, J=7.7Hz, 1H); 13C-NMR (101MHz, DMSO- DMSO-d6) δ: 161.46, 156.28, 154.41, 147.36, 146.55, 145.85,
d6) δ: 164.03, 161.51, 154.46, 146.63, 136.47, 135.51, 133.29, 135.10, 128.12, 127.58, 114.86, 114.63, 114.24, 112.16; MS
131.54, 130.48, 128.14, 127.61, 127.38, 126.44, 114.64, 114.23; (ESI): m/z=254.8 (M+H)+; purity (HPLC): 100%.
MS (ESI): m/z=298.8 (M+H)+, 300.8 [(M+H)++2]; purity
(HPLC): 97%.
N-(4-Aminoquinazolin-6-yl)thiophene-2-carboxamide (4k)
Yield: 35%; mp: 292–293°C; H-NMR (400MHz, DMSO-d6)
1
N-(4-Aminoquinazolin-6-yl)-4-fluorobenzamide
(4d) δ: 10.53 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.08 (d, J=2.7Hz,
Yield: 38%; mp: 337–338°C; 1H-NMR (400MHz, DMSO- 1H), 7.93–7.84 (m, 2H), 7.69 (d, J=9.0Hz, 3H), 7.26 (t,
d6) δ: 10.54 (s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 8.19–8.02 (m, J=3.6Hz, 1H); 13C-NMR (101MHz, DMSO-d6) δ: 161.47,
2H), 7.90 (d, J=8.7Hz, 1H), 7.69 (d, J=9.0Hz, 3H), 7.40 (t, 159.95, 154.42, 146.53, 139.66, 135.32, 132.03, 129.22, 128.15,
J=8.6Hz, 2H); 13C-NMR (101MHz, DMSO-d6) δ: 164.38, 127.62, 114.67, 114.27; MS (ESI): m/z=270.8 (M+H)+; purity
1
164.16 (d, JC-F=249.4Hz), 161.47, 154.46, 146.74, 135.68, (HPLC): 98%.
4
3
130.93 (d, JC-F=2.8Hz), 130.36 (d, JC-F=9.1Hz), 128.17,
N-(4-Aminoquinazolin-6-yl)cyclopentanecarboxamide (4l)
2
1
127.68, 115.40 (d, JC-F=21.9Hz), 114.59, 114.27; MS (ESI): Yield: 39%; mp: 310–311°C; H-NMR (500MHz, DMSO-d6)
m/z=282.8 (M+H)+; purity (HPLC): 98%.
δ: 10.08 (s, 1H), 8.40 (d, J=2.1Hz, 1H), 8.30 (s, 1H), 7.74
(4e) (dd, J=8.9, 2.3Hz, 1H), 7.61 (d, J=8.9Hz, 1H), 7.56 (s, 2H),
N-(4-Aminoquinazolin-6-yl)-4-methylbenzamide
1
Yield: 30%; mp: 314–316°C; H-NMR (400MHz, DMSO-d6) 2.83 (p, J=8.0Hz, 1H), 1.91–1.82 (m, 2H), 1.81–1.64 (m, 4H),
δ: 10.43 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 7.94 (d, J=8.1Hz, 1.63–1.52 (m, 2H); 13C-NMR (126MHz, DMSO-d6) δ: 174.38,
2H), 7.90 (s, 1H), 7.68 (d, J=9.1Hz, 3H), 7.36 (d, J=7.8Hz, 161.35, 154.08, 146.23, 136.15, 127.75, 126.84, 114.36, 112.45,
2H), 2.40 (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 165.29, 45.01, 30.05, 25.68; MS (ESI): m/z=256.9 (M+H)+; purity

1170
Vol. 62, No. 12
(HPLC): 99.7%.
N-(4-Acetamidoquinazolin-6-yl)-4-methylbenzamide
(5e)
1
1-(4-Aminoquinazolin-6-yl)-3-phenylurea Derivatives (6) Yield: 74%; mp: 232–233°C; H-NMR (400MHz, DMSO-d6)
To 1.2mmol of phenyl isocyanate dissolved in 10mL DMF, δ: 10.86 (s, 1H), 10.60 (s, 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.28
1mmol of quinazoline-4,6-diamine 3 was added and the (d, J=8.9Hz, 1H), 7.98 (s, 1H), 7.94 (d, J=8.3Hz, 2H), 7.38 (d,
mixture was then left to stir in an ice bath for 2h. The reac- J=7.7Hz, 2H), 2.40 (s, 3H), 2.32 (s, 3H); 13C-NMR (101MHz,
tion mixture was then poured on ice water where a precipi- DMSO-d6) δ: 170.12, 165.68, 157.16, 152.90, 147.93, 142.00,
tate is formed, separated by filtration and then purified with 137.78, 131.52, 128.99, 128.83, 128.21, 127.77, 118.51, 113.80,
column chromatography to yield compound 6. Yield: 34%; 24.04, 21.00; HR-MS (ESI-TOF-HR): (M+Na)+=343.11665
1
mp: 318–319°C; H-NMR (400MHz, DMSO-d6) δ: 9.18 (d, (Calcd for 343.11655); purity (HPLC): 99.1%.
J=12.6Hz, 2H), 8.29 (s, 1H), 8.12 (s, 1H), 7.85 (d, J=7.7Hz,
N-(4-Acetamidoquinazolin-6-yl)-4-nitrobenzamide
(5f)
1
1H), 7.62 (d, J=8.7Hz, 3H), 7.50 (d, J=6.4Hz, 2H), 7.29 (s, Yield: 32%; mp: 249–251°C; H-NMR (400MHz, DMSO-d6)
2H), 6.97 (s, 1H); 13C-NMR (101MHz, DMSO-d6) δ: 161.16, δ: 10.99 (s, 1H), 10.89 (s, 1H), 8.97 (s, 1H), 8.65 (s, 1H), 8.41
153.65, 152.70, 145.56, 139.69, 136.87, 128.74, 127.86, 126.13, (d, J=7.9Hz, 2H), 8.29 (s, 1H), 8.25 (d, J=8.6Hz, 2H), 8.00
121.83, 118.17, 114.63, 110.63; MS (ESI): m/z=279.9 (M+H)+; (d, J=9.0Hz, 1H), 2.32 (s, 3H); 13C-NMR (101MHz, DMSO-
purity (HPLC): 99.5%.
d6) δ: 170.18, 164.26, 157.30, 153.19, 149.35, 148.20, 140.03,
General Synthesis of Compounds 5a to 5l and 7 To 137.17, 129.30, 128.74, 128.43, 123.62, 118.47, 114.38, 24.04;
0.3mmol of the corresponding compounds 4a to 4n and 6, 3 HR-MS (ESI-TOF-HR): (M+Na)+=374.08586 (Calcd for
to 4mL of acetic anhydride were added and the reaction mix- 374.08597); purity (HPLC): 97%.
ture was refluxed for 30min while stirring. The product was
then filtered, washed with diethyl ether (3×10mL) and then Yield: 68%; mp: 217–219°C; H-NMR (400MHz, DMSO-d6)
re-crystallized from methanol to yield the pure final com- δ: 10.86 (s, 1H), 10.61 (s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.27
N-(4-Acetamidoquinazolin-6-yl)-4-tert-butylbenzamide (5g)
1
pounds 5a to 5l and 7.
N-(4-Acetamidoquinazolin-6-yl)benzamide
(d, J=8.9Hz, 1H), 8.01–7.92 (m, 3H), 7.59 (d, J=8.0Hz, 2H),
(5a) Yield: 2.32 (s, 3H), 1.33 (s, 9H); 13C-NMR (101MHz, DMSO-d6) δ:
62%; mp: 228–229°C; 1H-NMR (400MHz, DMSO-d6) δ: 170.12, 165.82, 157.17, 154.80, 152.89, 147.94, 137.81, 131.73,
10.87 (s, 1H), 10.70 (s, 1H), 8.95 (s, 1H), 8.67 (s, 1H), 8.29 128.77, 128.23, 127.60, 125.23, 118.54, 113.69, 34.69, 30.89,
(d, J=9.0Hz, 1H), 8.02 (d, J=7.2Hz, 2H), 7.98 (d, J=9.1Hz, 24.04; HR-MS (ESI-TOF-HR): (M+Na)+=385.16366 (Calcd for
1H), 7.60 (dt, J=25.0, 7.1Hz, 3H), 2.32 (s, 3H); 13C-NMR 385.16350); purity (HPLC): 99.4%.
(101 MHz, DMSO-d6) δ: 170.14, 165.90, 157.20, 152.95, 147.99,
N-(4-Acetamidoquinazolin-6-yl)-2-chloroisonicotinamide
137.70, 134.44, 131.87, 128.81, 128.46, 128.25, 127.72, 118.52, (5h) Yield: 62%; mp: 266–267°C; 1H-NMR (400MHz,
113.90, 24.04; HR-MS (ESI-TOF-HR): (M+Na)+=329.10095 DMSO-d6) δ: 10.99 (s, 1H), 10.91 (s, 1H), 8.97 (s, 1H), 8.66
(Calcd for 329.10090); purity (HPLC): 98.1%.
N-(4-Acetamidoquinazolin-6-yl)-4-chlorobenzamide
(d, J=5.0Hz, 1H), 8.62 (s, 1H), 8.25 (d, J=9.0Hz, 1H), 8.06
(5b) (s, 1H), 8.00 (d, J=9.1Hz, 1H), 7.92 (d, J=4.1Hz, 1H), 2.32 (s,
Yield: 60%; mp: 240–242°C; H-NMR (400MHz, DMSO-d6) 3H); 13C-NMR (101MHz, DMSO-d6) δ: 170.18, 162.88, 157.35,
δ: 10.88 (s, 1H), 10.75 (s, 1H), 8.95 (s, 1H), 8.64 (s, 1H), 8.26 153.28, 150.89, 150.80, 148.29, 144.98, 136.81, 128.62, 128.50,
(d, J=8.9Hz, 1H), 8.05 (d, J=8.2Hz, 2H), 7.98 (d, J=9.0Hz, 122.29, 121.26, 118.46, 114.52, 24.03.; HR-MS (ESI-TOF-HR):
1H), 7.65 (d, J=8.2Hz, 2H), 2.32 (s, 3H); 13C-NMR (101MHz, (M+Na)+=364.05692 (Calcd for 364.05717); purity (HPLC):
DMSO-d6) δ: 170.14, 164.78, 157.22, 153.03, 148.05, 137.47, 99.5%.
1
136.76, 133.10, 129.69, 128.79, 128.56, 128.30, 118.48, 114.07,
N-(4-Acetamidoquinazolin-6-yl)nicotinamide (5i) Yield:
1
24.04; HR-MS (ESI-TOF-HR): (M+Na)+=363.06155 (Calcd for 59%; mp: 270–271°C; H-NMR (400MHz, DMSO-d6) δ: 10.88
363.06192); purity (HPLC): 99.4%.
(s, 2H), 9.17 (s, 1H), 8.96 (s, 1H), 8.80 (d, J=4.1Hz, 1H), 8.65
N-(4-Acetamidoquinazolin-6-yl)-3-chlorobenzamide
(5c) (s, 1H), 8.36 (d, J=7.8Hz, 1H), 8.27 (d, J=8.8Hz, 1H), 7.99
1
Yield: 61%; mp: 248–250°C; H-NMR (400MHz, DMSO-d6) (d, J=9.0Hz, 1H), 7.61 (dd, J=7.5, 5.0Hz, 1H), 2.32 (s, 3H);
δ: 10.88 (s, 1H), 10.78 (s, 1H), 8.96 (s, 1H), 8.63 (s, 1H), 8.27 13C-NMR (101MHz, DMSO-d6) δ: 170.16, 164.45, 157.26,
(d, J=8.9Hz, 1H), 8.07 (s, 1H), 7.98 (d, J=7.7Hz, 2H), 7.71 (d, 153.10, 152.39, 148.73, 148.10, 137.33, 135.54, 130.13, 128.68,
J=7.5Hz, 1H), 7.61 (t, J=7.7Hz, 1H), 2.32 (s, 3H); 13C-NMR 128.40, 123.56, 118.50, 114.08, 24.04; HR-MS (ESI-TOF-HR):
(101 MHz, DMSO-d6) δ: 170.16, 164.41, 157.24, 153.07, (M+Na)+=330.09632 (Calcd for 330.09615); purity (HPLC):
148.09, 137.38, 136.37, 133.29, 131.70, 130.49, 128.77, 128.33, 99.1%.
127.46, 126.56, 118.48, 114.14, 24.04; HR-MS (ESI-TOF-HR):
N-(4-Acetamidoquinazolin-6-yl)furan-2-carboxamide
(5j)
(M+Na)+=363.06146 (Calcd for 363.06192); purity (HPLC): Yield: 74%; mp: 253–255°C; 1H-NMR (400MHz, DMSO-
99.6%.
N-(4-Acetamidoquinazolin-6-yl)-4-fluorobenzamide
d6) δ: 10.85 (s, 1H), 10.63 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H),
(5d) 8.29 (dd, J=9.0, 1.4Hz, 1H), 7.99 (s, 1H), 7.96 (d, J=9.1Hz,
Yield: 51%; mp: 237–239°C; 1H-NMR (400MHz, DMSO- 1H), 7.43 (d, J=3.2Hz, 1H), 6.75 (d, J=1.5Hz, 1H), 2.32
d6) δ: 10.87 (s, 1H), 10.70 (s, 1H), 8.95 (s, 1H), 8.63 (s, (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 170.14, 157.18,
1H), 8.27 (d, J=9.1Hz, 1H), 8.11 (dd, J=8.4, 5.6Hz, 2H), 156.45, 152.99, 147.96, 147.13, 146.09, 137.08, 128.69, 128.29,
7.98 (d, J=9.1Hz, 1H), 7.41 (t, J=8.7Hz, 2H), 2.32 (s, 3H); 118.48, 115.34, 113.99, 112.28, 24.04; HR-MS (ESI-TOF-HR):
13C-NMR (101MHz, DMSO-d6) δ: 170.16, 164.78, 164.25 (M+Na)+=319.07979 (Calcd for 319.08016); purity (HPLC):
1
(d, JC-F=249.6Hz), 157.19, 152.99, 148.00, 137.58, 130.83 98.7%.
4
3
(d, JC-F=2.9Hz), 130.51 (d, JC-F=9.2Hz), 128.82, 128.28,
N-(4-Acetamidoquinazolin-6-yl)thiophene-2-carboxamide
118.49, 115.45 (d, JC-F=21.9Hz), 113.96, 24.04; HR-MS (ESI- (5k) Yield: 65%; mp: 209–210°C; 1H-NMR (400MHz,
2
TOF-HR): (M+Na)+=347.09136 (calcd for 347.09147); purity DMSO-d6) δ: 10.87 (s, 1H), 10.67 (s, 1H), 8.95 (s, 1H), 8.59
(HPLC): 98%.
(s, 1H), 8.25 (d, J=9.0Hz, 1H), 8.11 (d, J=3.1Hz, 1H), 7.98

December 2014
1171
(d, J=9.0Hz, 1H), 7.92 (d, J=4.8Hz, 1H), 7.27 (t, J=3.9Hz, DMSO-d6) δ: 180.05, 170.22, 156.86, 153.37, 148.46, 139.14,
1H), 2.32 (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 170.15, 138.18, 132.28, 128.53, 127.62, 124.80, 123.89, 117.81, 117.55,
160.23, 157.16, 153.00, 147.99, 139.41, 137.26, 132.40, 129.61, 24.29; HR-MS (ESI-TOF-HR): (M+H)+=338.10698 (Calcd for
128.72, 128.35, 128.16, 118.47, 113.95, 24.07; HR-MS (ESI- 338.10701); purity (HPLC): 94.3%.
TOF-HR): (M+Na)+=335.05737 (Calcd for 335.05732); purity
(HPLC): 99.1%.
1-(4-Acetamidoquinazolin-6-yl)-3-benzoylurea (10b) To
1mmol of benzoyl isocyanate, 10mL of DMF were added fol-
N-(4-Acetamidoquinazolin-6-yl)cyclopentanecarboxamide lowed by the addition of 0.8mmol of N-(6-aminoquinazolin-4-
(5l) Yield: 61%; mp: 246–248°C; 1H-NMR (400MHz, yl)acetamide 9. The reaction mixture was left stirring for 1h
DMSO-d6) δ: 10.81 (s, 1H), 10.32 (s, 1H), 8.91 (s, 1H), 8.50 at room temperature then was poured on ice water to give a
(s, 1H), 8.06 (d, J=9.1Hz, 1H), 7.91 (d, J=9.0Hz, 1H), 2.85 white precipitate. After filtration, the product obtained was
(p, J=7.7Hz, 1H), 2.29 (s, 3H), 1.94–1.81 (m, 2H), 1.81–1.65 washed with diethyl ether (3×10mL) and was re-crystallized
(m, 4H), 1.62–1.51 (m, 2H); 13C-NMR (101MHz, DMSO- from methanol to give the pure corresponding compounds
d6) δ: 174.87, 170.05, 157.03, 152.60, 147.64, 137.96, 128.33, 10b. Yield: 58%; mp: 262–265°C; 1H-NMR (400MHz,
127.79, 118.69, 112.18, 45.27, 30.02, 25.65, 23.99; HR-MS (ESI- DMSO-d6) δ: 11.20 (s, 2H), 10.82 (s, 1H), 8.92 (s, 1H), 8.40
TOF-HR): (M+Na)+=321.13216 (Calcd for 321.13220); purity (s, 1H), 8.34 (d, J=9.0Hz, 1H), 8.05 (d, J=7.5Hz, 2H), 7.97
(HPLC): 98.7%.
1-(4-Acetamidoquinazolin-6-yl)-3-phenylurea
(d, J=9.0Hz, 1H), 7.68 (t, J=7.3Hz, 1H), 7.57 (t, J=7.6Hz,
(7) Yield: 2H), 2.36 (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 170.36,
47%; mp: 228–229°C; 1H-NMR (400MHz, DMSO-d6) δ: 10.83 168.85, 156.80, 152.97, 151.29, 147.78, 136.35, 133.15, 132.17,
(s, 1H), 9.81 (s, 1H), 9.48 (s, 1H), 8.86 (s, 1H), 8.29 (s, 1H), 128.71, 128.60, 128.30, 128.09, 117.81, 113.09, 24.53; HR-MS
8.00 (s, 1H), 7.90 (s, 1H), 7.51 (s, 2H), 7.29 (s, 2H), 6.98 (s, (ESI-TOF-HR): (M+Na)+=372.10680 (Calcd for 372.10671);
1H), 2.31 (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 170.41, purity (HPLC): 99%.
156.59, 152.66, 152.04, 147.01, 139.59, 138.70, 128.75, 128.41,
6-Nitroquinazolin-4-(3H)-one (11)16) To 2g of 2-amino-
127.26, 121.94, 118.82, 118.22, 110.10, 24.13; HR-MS (ESI- 5-nitrobenzonitrile 1, 25mL of formic acid were added and
TOF-HR): (M+Na)+=344.11170 (Calcd for 344.11180); purity the mixture was refluxed for 6h while stirring. The reaction
(HPLC): 96%.
mixture was then poured on ice water resulting in the forma-
N-(6-Nitroquinazolin-4-yl)acetamide (8)15) A suspension tion of a yellow precipitate which was separated by filtration
of 1g of 6-nitroquinazoline-4-(3H)-imine 2 in 15mL acetic to give compound 11.
anhydride was refluxed for 30min. The product was filtered
6-Aminoquinazolin-4-(3H)-one (12)17)
A mixture of
and washed with diethyl ether (3×20mL) to give the pure 1g (5mmol) of 6-nitroquinazolin-4-(3H)-one 11 and 6g
1
product 8. Yield: 82%; mp: 271–273°C; H-NMR (200MHz, (25mmol) of SnCl2·2H2O in 25mL methanol was heated to
DMSO-d6) δ: 11.25 (s, 1H), 9.39 (d, J=2.0Hz, 1H), 9.09 (s, reflux for 3h while stirring under argon. The solvent was
1H), 8.62 (dd, J=9.3, 2.5Hz, 1H), 8.09 (d, J=9.1Hz, 1H), evaporated then 200mL saturated aqueous NaHCO3 solution
2.40 (s, 3H); 13C-NMR (50MHz, DMSO-d6) δ: 170.90, 159.18, were added to the residue and left stirring for 10min. The
157.50, 153.60, 145.36, 130.31, 127.66, 122.56, 116.18, 25.47; suspension was then filtered and the aqueous filtrate was col-
MS (ESI): m/z=254.8 (M+Na)+.
N-(6-Aminoquinazolin-4-yl)acetamide (9) To
lected and evaporated. The product was then extracted from
sus- the residue using DMF and purified using column chroma-
a
pension of 0.3g (1.3mmol) of N-(6-nitroquinazolin-4-yl)- tography (90% DCM, 10% 0.5M NH3 in methanol solution)
acetamide 8 in 25mL methanol, 30mg of palladium on to give the pure compound 12. Yield: 30%; mp: 310–312°C;
activated carbon were added slowly and the reaction mixture 1H-NMR (200MHz, DMSO-d6) δ: 11.80 (s, 1H), 7.74 (s, 1H),
was left stirring for 3h at room temperature in presence of 7.36 (d, J=8.6Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 7.05 (dd, J=8.7,
H2 gas. After completion of the reaction, the mixture was 2.4Hz, 1H), 5.59 (s, 2H); 13C-NMR (50MHz, DMSO-d6) δ:
filtered under vacuum and the product was retrieved from the 161.03, 148.20, 140.63, 139.97, 128.38, 123.99, 122.49, 106.48;
1
filtrate by evaporation. Yield: 90%; mp: 191–194°C; H-NMR MS (ESI): m/z=161.9 (M+H)+.
(400MHz, DMSO-d6) δ: 10.48 (s, 1H), 8.64 (s, 1H), 7.66 (d,
N-(4-Oxo-3,4-dihydroquinazolin-6-yl)benzamide (13) To
J=8.9Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 6.96 (s, 1H), 5.85 (s, a mixture of 1mmol of 6-aminoquinazolin-4-(3H)-one 12
2H), 2.24 (s, 3H); 13C-NMR (101MHz, DMSO-d6) δ: 169.82, and 1.1mmol of NaHCO3, 15mL acetone were added. Then,
154.79, 149.22, 147.84, 144.55, 128.58, 125.49, 120.18, 101.56, 1.1mmol of benzoyl chloride was dissolved in 1.5mL acetone
23.92; MS (ESI): m/z= 224.8 (M+Na)+.
and was added drop wise to the previously prepared mixture
1-(4-Acetamidoquinazolin-6-yl)-3-phenylthiourea (10a) while stirring in an ice bath. The reaction mixture was stirred
To 1.2mmol of phenyl isothiocyanate dissolved in 8mL DMF, for 3h at 0°C. The mixture was then poured on a saturated
1mmol of N-(6-aminoquinazolin-4-yl)acetamide 9 was added solution of NaHCO3 to form a precipitate which was sepa-
and the mixture was left stirring overnight at room tempera- rated by filtration and purified using column chromatography
1
ture. After completion of the reaction, the solution was poured to give compound 13. Yield: 47%; mp: 322–323°C; H-NMR
on ice water to form a precipitate which was separated by (400MHz, DMSO-d6) δ: 12.20 (s, 1H), 10.59 (s, 1H), 8.66
filtration. The obtained solid was washed with diethyl ether (s, 1H), 8.19 (d, J=8.8Hz, 1H), 8.02 (d, J=9.0Hz, 2H), 7.99
(3×10mL) and then re-crystallized from ethyl acetate to (s, 1H), 7.68 (d, J=8.8Hz, 1H), 7.58 (dt, J=25.3, 7.1Hz, 3H);
yield the pure compound 10a. Yield: 9%; mp: 140–143°C; 13C-NMR (101MHz, DMSO-d6) δ: 165.70, 160.60, 144.93,
1H-NMR (400MHz, DMSO-d6) δ: 10.81 (s, 1H), 10.16 (s, 1H), 144.07, 137.69, 134.56, 131.74, 128.41, 127.69, 127.65, 127.00,
10.05 (s, 1H), 8.94 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=8.4Hz, 122.83, 115.64; HR-MS (ESI-TOF-HR): (M+Na)+=288.07449
1H),7.91 (d, J=8.6Hz, 1H), 7.49 (d, J=6.5Hz, 2H), 7.36 (s, (Calcd for 288.07435); purity (HPLC): 99.9%.
2H), 7.17 (d, J=5.9Hz, 1H), 2.31 (s, 3H); 13C-NMR (101MHz,
Molecular Modeling GOLD software was used to per-

1172
Vol. 62, No. 12
6) Rückle T., Schwarz M. K., Rommel C., Nat. Rev. Drug Discov., 5,
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form the docking protocol using a co-crystal structure of a
PI3Kγ inhibitor with the enzyme (PDB code: 3DBS).12) The
binding site residues of PI3Kγ were defined by specifying the
crystal structure ligand coordinates and using a cutoff radius
of 10Å, with the ‘detect cavity’ option enabled. The docking
protocol was performed using Gold Score as the scoring func-
tion and the search efficiency of the genetic algorithm was in-
creased to 125%. Early termination of the docking experiment
was enabled when the top three solutions were within 1.5Å
RMSD. The two dimensional (2D) ligand–receptor interac-
tions of these poses were viewed using the “compute ligand
interaction” option of MOE.
Acknowledgments The authors are grateful to the staff
of Proqinase Company for carrying out the in vitro enzymatic
assay for our synthesized compounds.
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Inf. Model., 53, 1447–1462 (2013).
13) Loidreau Y., Besson T., Tetrahedron, 67, 4852–4857 (2011).
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Pharmacol., 50, 803–809 (1995).
15) Morley J. S., Simpson J. C. E., J. Chem. Soc., 360–366 (1948).
16) Domarkas J., Dudouit F., Williams C., Qiyu Q., Banerjee R., Bra-
himi F., Jean-Claude B. J., J. Med. Chem., 49, 3544–3552 (2006).
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