Uses of dimedone for the synthesis of new heterocyclic derivatives with anti-tumor, c-Met, tyrosine, and Pim-1 kinases inhibitions

Article abstract of DOI:10.1007/s00044-018-2208-7

The reaction of dimedone (1) with any of the diazonium salts 2a–c to give the arylhydrazone derivatives 3a–c. The Gewald’s reaction of any of compounds 3a–c using elemental sulfur and either of malononitrile or ethyl cyanoacetate gave the thiophene deriva

Full text of DOI:10.1007/s00044-018-2208-7

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2208-7
ORIGINAL RESEARCH
Uses of dimedone for the synthesis of new heterocyclic derivatives
with anti-tumor, c-Met, tyrosine, and Pim-1 kinases inhibitions
Rafat M. Mohareb1 Fatma O. Al Farouk1 Wagnat W. Wardakhan2
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Received: 13 March 2018 / Accepted: 14 June 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The reaction of dimedone (1) with any of the diazonium salts 2a–c to give the arylhydrazone derivatives 3a–c. The Gewald’s
reaction of any of compounds 3a–c using elemental sulfur and either of malononitrile or ethyl cyanoacetate gave the
thiophene derivatives 5a–f, respectively. Compounds 5a, 5c, and 5e underwent a series of heterocclization reactions to give
potentially anticancer agents. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against
c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). All target
compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line. The most
promising compounds were 5c, 6c, 6d, 8e, 8f, 12d, 14e, and 14f were further investigated against tyrosin kinase (c-Kit, Flt-3,
VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h, 12c, 12d, 12f, and 14f were selected to examine
their Pim-1 kinase inhibition activity where compounds 3c, 6c, 8g, 12c, and 14f showed high activities.
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Keywords Arylhydrazone Anti-proliferative Dimedone Thiophene Tryrosine kinase
Introduction
Knoevenagel condensation of cyclohexane-1,3-done or
dimedone with aldehydes have been conducted with numer-
ous methods including promotion via amines (Chassainga
et al. 2012), Lewis acids (Amoozadeh et al. 2015), surfactants
(Deb Bhuyan 2005), zeolites (Jiao et al. 2011), ionic liquids
(Khurana and Magoo 2009). The use of environmentally
benign methods like in aqueous medium or in the absence of
solvents (Nikoofar and Yielzoleh 2017) and the usage of
ultrasound or microwave heating (Neimi and Nazif, 2014)
have also been developed in recent years. The reactions
usually proceed further through Michael addition reaction of
the second molecule of dimedone to yield tetraketones as main
products (Silva et al. 2018). On the other hand, tetraketones
could be easily converted to 9-substituted 1,8-dioxo-xanthenes
by dehydration step (Jiao et al. 2011). 1,8-Dioxo-xanthenes
can also be directly prepared from the condensation of two
molecules of dimedone with aromatic aldehydes in the pre-
sence of different kinds of catalysts (Ilangovan et al. 2011;
Jiao et al. 2011) such as Amberlyst (Maripi et al. 2017),
triethylbenzylammonium chloride (Darvish et al. 2007), dia-
mmonium hydrogen phosphate (Jin et al. 2006), sulfonic acid
and ionic liquid under ultrasonic irradiation (Venkatesan et al.
2008; Rostamizadeh et al. 2010). In our continued interest in
the design of new multicomponent reactions and the appli-
cation in the synthesis of heterocyclic compounds (Mohareb
et al. 2017, 2018), we found some unprecedented reaction
As typical reactive 1,3-dicarbonyl compounds, cyclohexane-
1,3-dione, and its analogy 5,5-dimethyl cyclohexane-1,3-
dione(dimedone) have been widely used in versatile synthetic
reactions (Dutra et al. 2014; Yadav et al. 2009). Dimedone is
not only a typical reagent for Knoevenagel condensation, but
also adds easily to electron-deficient alkenes via Michael
addition. On the other hand, its one or two carbonyl groups
could take part in substitution and cyclization reactions
through the tautomerized enolate form. Thus the cascade
reactions of addition, elimination and substitution could be
achieved in many reactions involving dimedone. The reactions
of cyclohexane-1,3-dione or dimedone with aldehydes have
been extensively studied in the past years, from which several
types of compounds have been produced according to the
reaction conditions (Nadaraj et al. 2009). The normal
* Rafat M. Mohareb
raafat_mohareb@yahoo.com
1
Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
2
National Organization for Durg Control and Research, P.
O. 29, Cairo, Egypt

Medicinal Chemistry Research
Scheme 1 Synthesis of
compounds 3a–c, 5a–f, and 6a–f
patterns in the reaction of the ary hydrazodimedone deriva-
tives with elemental sulfur and cyanomethylene reagents to
produce thiophene derivatives these were capable for further
heterocyclization reactions to produce potential antitumor
agents.
derivatives are depicted in Schemes 1–3. Thus, the reaction
of dimedone (1) with the aryldiazonium salts 2a–c in ethanol
containing sodium acetate gave the arylhydrazone deriva-
tives 3a–c, respectively. Compounds 3a–c exist in the
arylhydrazone form as this structure is stabilized via the
intramolecular N-H–O=C- hydrogen bonding (Drew 1982).
We speculated that thiophene-fused derivatives can be
obtained via the use of the Gewald’s thiophene synthesis.
Initially, we have investigated the reaction of any of the
arylhydrazo compounds 3a–c with elemental sulfur and
either of malonitrile (4a) or ethyl cyanoacetate (4b) to give
the thiophene derivatives 5a–f, respectively. The structures
of compounds 5a–f were based on their respective analytical
Results and discussion
The synthetic route to prepare a new class of biologically
active heterocycles compounds linked dimedone moiety
starting with the 2-arylhydrazodimedone derivatives. The
synthetic pathways employed to prepare the new targeted

Medicinal Chemistry Research
Scheme 2 Synthesis of
compounds 8a–m and 10a–f
1
and spectral data. Thus, the H-NMR of 5a showed, beside
the expected signals, the presence of a singlet at δ 4.49 ppm
(D2O exchangeable) indicating the presence of the NH2
group and a singlet at δ 2.70 ppm equivalent to the CH2
group. In addition, the 13C-NMR specrum revealed the
presence of signals at 142.8, 140.4, 138.7, 136.5, 131.8,
126.4, 124.3, and 120.2 corresponding to the C6H5 and
tiophene carbons and a signal at 116.7 confirming the pre-
sence of the CN group. It is important to note that in such
series of dimedone derivatives, although the 5,5-dimethyl
groups as in the case of compounds 3a–c and the 7,7-
dimethyl moieties in compounds 5a–f showed a slight dif-
ference through the 1H-NMR like δ 1.08 and 1.09 ppm as in
case of 3a, however, the 13C-NMR both of the two CH3
groups gave one signal at 24.8. Such findings was in
agreement with some reported literature (Drew 1982)
although in other reports the 1H-NMR and 13C-NMR
showed two signals in each measurement (Gurumurthi
et al. 2009).
We then turn our attention to the preparation of cinnoline
derivatives through the reaction of any of compounds 5a,c,e
with either of malononitrile (4a) or ethyl cyanoacetate (4b)
to give the 2,3,5,6-tetrahydrothieno[2,3-h]cinnoline deriva-
tives 6a–f, respectively (Scheme 1).
The reaction of any of compounds 6a–f with either of
hydrazine hydrate (7a) or phenylhydrazine (7b) gave the
diarlhydrazone derivatives 8a–m, respectively. The ana-
lytical and spectral data of the latter compounds were
1
consistent with their respective products. Thus, the H-
NMR of compound 8a (as an example) revealed the
presence the two singlets at δ 4.47 and 5.03 ppm (D2O
exchangeable) corresponding to the two NH2 groups
beside the 13C-NMR spectrum that showed the presence
of two signals 179.8 and 176.5 corresponding to the two
C=N groups and signals at 179.8, 176.5 (C-4, C-5),
141.6, 140.8, 139.3, 135.9, 134.3, 128.6, 124.1, and
120.1 indicating the presence of C6H5 and thiophene
carbons.

Medicinal Chemistry Research
Scheme 3 Synthesis of
compounds 12a–f and 14a–m
Encouraged by the initial success, we applied the optimal
condition to the synthesis of a series of thienopyrimidino
derivatives. Interestingly, the reaction of any of compounds
5a–f with phenylisothiocyanate (9) gave the hexahy-
drobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)yttrium deriva-
tives 10a–f, respectively (Scheme 2). It is of an interest to
mention that compounds 5a–f and 10a–f exist in the aryl-
hydrazone form like compounds 3a–c due to the stability of
these tautomeric structures due to the intramolecular H-
bonding (Drew 1982).
give the corresponding oxime derivative followed by
dehydration. Finally, the reaction of any of compounds 5a–f
with the cinnamonitrile derivatives 13a and 13b gave the
thieno[2,3-g]chromene derivatives 14a–m, respectively.
Compounds 14a–m were structurally characterized by
1
various spectroscopic techniques including H, 13C-NMR,
EI-MS, and IR.
Biology
On the other hand, the reaction of any of compounds
10a–f with hydroxylamine hydrochloride afforded the tria-
zolo[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]thieno[2,3-d]pyrimidin-10-
yl)yttrium 12a–f. Formation of the latter products were
explained through the first reaction of the hydroxylamine to
Materials
Adenosine triphosphate (ATP), DMSO, MgCl2 were
obtained from Sigma (St. Louis, MO, USA) kinase buffer

Medicinal Chemistry Research
Table 1 c-Met enzymatic activity of the newly synthesized
compounds
Table 1 (continued)
Compound no
X
Y
R
IC50 (nM)
c-Met
IC50 (nM)
PC-3
Compound no
X
Y
R
IC50 (nM)
c-Met
IC50 (nM)
PC-3
14g
14h
14i
Cl
Cl
NH2 COOEt 2.28 1.63
OH COOEt 3.79 1.64
1.14 0.83
0.64 0.04
2.29 1.59
1.07 0.72
3a
H
–
–
8.25 2.69
1.02 0.63
2.14 0.92
10.52 2.84
2.48 1.20
3.84 1.27
3b
Cl
–
–
OCH3 NH2 CN
OCH3 OH CN
6.73 2.52
5.62 2.49
3c
OCH3
H
–
–
14k
14l
5a
–
CN
12.28 3.91 3.29 1.59
OCH3 NH2 COOEt 14.63 4.52 16.39 3.63
5b
H
–
COOEt 10.62 2.59 4.26 2.83
14m
OCH3 OH COOEt 4.82 1.29
6.73 2.80
5c
Cl
–
CN
COOEt 1.53 0.87
CN
COOEt 14.02 4.72 1.02 0.82
0.38 0.19
0.22 0.13
–
–
Foretinib
SGI-1776
4.86 0.16
5d
Cl
–
2.62 1.28
1.16 0.17
5e
OCH3
OCH3
H
–
12.49 3.53 5.73 1.69
5f
–
was prepared with 5 mmol L−1 MgCl2, 1 mmol L−1 DTT, or
5 mmol L−1 MgCl2, 1 mmol L−1 MnCl2 and 1 mmol L−1
DTT. Receptor tyrosine kinases c-Kit, Flt-3, VEGFR-2,
EGFR, and PDGFR were purchased from Carna Bios-
ciences (Kobe, Japan).
6a
NH
O
NH
O
–
18.52 6.93 10.72 2.83
6b
H
–
8.16 2.62
0.39 0.21
0.08 0.03
10.93 3.29
0.63 0.25
0.19 0.66
6c
Cl
–
6d
Cl
–
6e
OCH3 NH
–
12.59 2.73 10.91 3.62
8.28 2.59 7.39 1.42
12.46 4.63 6.28 2.25
6f
OCH3
H
O
–
HTRF kinase assay
8a
H
CN
CN
8b
H
Ph
H
8.28 2.53
9.16 2.72
2.03 0.83
The c-Met kinase activity of all compounds was evaluated
(Table 1) using homogeneous time-resolved fluorescence
(HTRF) assay as previously reported (Tang et al. 2016; Liu
et al. 2016). In addition the most active compounds 5c, 6c,
6d, 8e, 8f, 12d, 14e, and 14f were further evaluated against
other five tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR,
and PDGFR) using the same screening method (Table 3).
Briefly, 20 μg/mL poly (Glu, Tyr) 4:1 (Sigma) was pre-
coated as a substrate in 384-well plates. Then 50 μL of
10 mM ATP (Invitrogen) solution diluted in kinase reaction
buffer (50 μM HEPES, Ph 7.0, 1 M DTT, 1 M MgCl2, 1 M
MnCl2, and 0.1% NaN3) was added to each well. Various
concentrations of compounds diluted in 10 μL of 1% DMSO
(v/v) were used as the negative control. The kinase reaction
was initiated by the addition of purified tyrosine kinase
proteins diluted in 39 μL of kinase reaction buffer solution.
The incubation time for the reactions was 30 min at 25 °C
and stopped by the addition of 5 μL of Streptavidin-XL665
and 5 μL Tk Antibody Cryptate working solution to all of
wells. The plates were read using Envision (PerkinElmer) at
320 and 615 nM. The inhibition rate (%) was calculated
using the following equation: Percentage inhibition = 100 −
[(Activity of enzyme with tested compounds − Min)/(Max
− Min)] × 100 (Max: the observed enzyme activity mea-
sured in the presence of enzyme, substrates, and cofactors;
Min: the observed enzyme activity in the presence of sub-
strates, cofactors and in the absence of enzyme). IC50 values
were calculated from the inhibition curves.
8c
H
COOEt 8.62 2.59
8d
H
Ph
H
COOEt 12.52 4.90 18.39 4.68
8e
Cl
CN
CN
0.25 0.06
0.63 0.09
8f
Cl
Ph
H
0.08 0.006 4.15 1.80
8g
Cl
COOEt 20.69 4.80 10.63 2.80
8h
Cl
Ph
H
COOEt 1.14 0.79
2.38 0.70
0.74 0.23
1.60 0.69
8i
OCH3
CN
CN
6.37 1.72
8.39 2.63
8k
OCH3 Ph
OCH3
OCH3 Ph
8l
H
COOEt 14.27 4.72 18.08 5.27
8m
10a
10b
10c
10d
10e
10f
12a
12b
12c
12d
12e
12f
14a
14b
14c
14d
14e
14f
COOEt 8.06 2.72
6.73 1.52
1.81 0.94
H
NH2
–
–
–
–
–
–
–
–
–
–
–
–
7.46 2.79
H
OH
NH2
OH
10.28 2.63 8.72 3.92
Cl
Cl
4.73 2.18
1.05 0.83
8.42 2.93
0.62 0.25
OCH3 NH2
OCH3 OH
12.52 2.69 5.79 1.80
3.72 1.58 1.15 0.82
10.53 2.80 17.19 4.93
H
NH2
OH
H
8.69 2.32
2.39 1.60
0.83 0.26
9.53 3.86
3.93 1.72
0.87 0.15
Cl
Cl
NH2
OH
OCH3 NH2
OCH3 OH
14.73 4.74 8.82 0.62
15.26 4.93 12.39 3.49
H
NH2 CN
OH CN
6.18 1.59
8.63 3.53
10.53 2.90
8.60 3.32
H
H
NH2 COOEt 14.93 4.72 18.25 2.39
OH COOEt 10.17 3.80 8.63 2.70
H
Cl
Cl
NH2 CN
OH CN
0.06 0.05
0.54 0.32
It has been reported that the c-Met kinase activity cor-
related to the prostate cancer where the transformation of
prostate cancer from the primary androgen-sensitive to the
androgen-insensitive status along with the gain of
0.07 0.006 8.02 2.52

Medicinal Chemistry Research
radioresistance that signaling by the receptor tyrosine kinase
(RTK) c-Met played a key role in it. Firstly, an inverse
correlation between the expression of androgen receptor
(AR) and c-Met has been observed in prostate epithelium
and prostate cancer cells (Knudsen et al. 2002; Humphrey
et al. 1995). Secondly, AR signaling suppressed c-Met
transcription, while the removal of androgen increased c-
Met expression (Verras et al. 2007). Thirdly, it is observed
that c-Met expression is high in late stage and bone meta-
static prostate cancer (Knudsen et al. 2002). Furthermore, a
recent study has demonstrated that c-Met expression has a
close relationship with the cellular radiosensitivity (Bacco
et al. 2011). Based on these reported observations, we
studied the activity of the synthesized compounds toward
PC-3 prostate cancer cell line, results were demonstrated
through Table 1.
cell line with IC50’s 0.38 and 0.22 nM, respectively. It was
surprised that compound compound 5f (X = OCH3, R =
COOEt) showed low potency against c-Met enzyme but
high potency against PC-3 cell line. Compounds 5c and 5f
showed higher potency than foretinib against the c-Met
enzyme. Considering the 2,3,5,6-tetrahydrothieno[2,3-h]
cinnoline-4-carbonitrile derivatives 6a–f, it clear tha com-
pounds 6c and 6d showed the highest potency against the c-
Met enzyme and PC-cell line. Considering the bishydrazone
derivatives 8a–m which were produced from the reaction of
any of 5a–f with either of hydrazine hydrate or phenyhy-
drazine, it is clear that compounds 8a, 8b, 8c, 8d, 8g, 8l,
and 8m revealed low potencies toward c-Met enzyme and
PC-3 cell line. While compounds 8e, 8f, and 8h showed the
highest potency anainst c-Met enzyme. Compounds 8e, 8i,
and 8k showed high inhibition toward PC-3 cell line. On the
other hand for compounds tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidinone derivatives 10a–f, it is clear that compound
10d (X = Cl, Y = OH) showed the highest potency against
c-Met enzyme with IC50 1.05 nM while compounds 10a,
10d, and 10f showed the highest potencies against PC-3 cell
lines with IC’50 1.81. 0.62 and 1.15 nM, respectively.
Considering the nitrogen rich the triazolo[4ʺ,5ʺ:5′,6′]benzo
[1′,2′:4,5]thieno[2,3-d]pyrimidine derivatives 12a–f, it is
obvious that compounds 12c and 12d were the most potent
compounds through such series of compounds against the c-
Met while compound 12d was the only compound that
showed high cytotoxic compound toward the PC-3 cell line.
Finally for the thieno[2,3-g]chromene derivatives 14a–m
compounds 14e and 14f showed the highest potencies
among the new synthesized compounds toward c-Met
enzymatic activity. The potencies of compounds 14e and
14f were higher than that of the reference drug foretinib
with IC50’s 0.06 and 0.07 nM. On the other hand, com-
pounds 4e, 14g, 14h, 14i, and 14k were the most potent
compounds toward PC-cell line, in addition, thie potency
higher than the reference drug SGI-1776 with IC50’s 0.54,
1.14, 0.64, 2.29, and 1.07 nM, respectively.
In vitro enzymatic assays
All the newly synthesized the aryl hydrazone derivatives were
evaluated for their inhibitory activity toward c-Met enzyme
(Zhang et al. 2012) using a homogeneous time-resolved
fluorescence (HTRF) assay. Taking foretinib as the positive
control, the results expressed as IC50 were summarized in
Table 1. The IC50 values are the average of at least three
independent experiments.. The anti-proliferative activity of all
target compounds against the human prostatic cancer PC-3
cell line were measured using MTT assay (Tiedt et al. 2011;
Takayuki et al. 2010) using SGI-1776 as the reference drug.
The mean values of three independent experiments, expressed
as IC50 values, were presented in Table 1. Most of the syn-
thesized compounds exhibited potent anti-proliferative activity
with IC50 values less than 30 μM. Generally, the variations of
substituents within the thienopyridine moiety together with the
hetero cycle ring being attached have a notable influence
on the anti-proliferative activity. The most potent
compounds were the seven compounds 5c, 6c, 8e, 8f, 12d,
14e, and 14f.
As illustrated in Table 1, all the tested compounds dis-
played potent c-Met enzymatic activity with IC50 values
ranging from 0.08 to 25.28 nM and potent prostate PC-3
cell line with IC50 values ranging from 0.06 to 20.69 nM.
Compared with foretinib (IC50 = 1.16 nM), seven com-
pounds (5c, 6c, 8e, 8f, 12d, 14e, and 14f) exhibited
equivalent or higher potency with IC50 values less than
1.00 nM. It is clear from Table 1 that for compounds 3a–c,
compound 3b (X = Cl) showed IC50 1.02 nM against c-Met
enzyme while it showed moderate potency toward PC-3 cell
line. The reaction of any of compounds 3a–c with elemental
sulfur and either of malononitrile and ethyl cyanoacetate to
give the thiophene derivatives 5a–f, respectively. It is clear
that compound 5c (X = Cl, R = CN) showed the highes
potency among the six compounds against c-Met and PC-3
Inhibition of tyrosine kinases (Enzyme IC50 (nM)
Compounds 5c, 6c, 6d, 8e, 8f, 12d, 14e, and 14f were
selected for inhibition of the five tyrosine kinases c-Kit, Flt-
3, VEGFR-2, EGFR, and PDGFR. It clear from Table 2 that
compounds 5c (X = Cl, R = CN) and 14f (X = Cl, Y = OH,
R = CN) were the most potent compounds among the tested
compounds toward the five tyrosin kinases. Compound 8e
showed high potency toward the three kinases c-Kit,
VEGFR-2, and PDGFR with IC50’s 0.29, 0.19, and
0.93 nM, respectively. In addition compound 6c showed
activity against VEGFR-2 with IC50 0.96 nM. Compound 8f
showed the lowest potencies among the tested compounds
but compounds 6c and 12d showed moderate potencies.

Medicinal Chemistry Research
Table 2 Inhibition of tyrosine kinases (Enzyme IC50 (nM) by
compounds 5c, 6c, 6d, 8e, 8f, 12d, 14e, and 14f
least three independent experiments. The data listed in Table
3 revealed that the compounds possessed moderate to strong
cytotoxicity against the five tested cell lines in the single-digit
lM range, and high selectivity for inhibition A549, H460, and
MKN-45 cells. The promising compounds were 3b, 5d, 6c,
8f, 8e, 8f, 8g, 8h, 10c, 10d, 12c, 14f, and 14g were more
active than foretinib against U87MG cell line with IC50 values
of 0.59, 0.29, 0.38, 0.79, 0.35, 0.84, 0.80, 0.37, 0.25, 0.78,
and 0.78 μM, respectively. The study of structure–activity
relationships (SARs) indicated that these analogs showed
similar SARs as summarized in the c-Met kinase level. Where
compound 3b showed high potency against the tesed cell line
which was attributed to the presence of the 4-chkorophenyl
moiety. On the other hand, compound 5d was the most potent
compounds among the series 5a–f due to the presence of the
Cl and COOEt groups. For compounds 6a–f, it was obvious
from Table 3 that compounds 6c and 6d were the most potent
compounds. Considering compounds 10a–m, it was clear that
compounds 8e, 8f, 8g, 8h, and 8m were the most cytotoxic
compounds. Compounds 10c, 10f were the most active
compounds among the series of 10a–f. The same for com-
pounds 12a–f where comounds 12c and 12d were the most
active compounds. It is obvious that the presence of the
electronegative Cl group and the OH or NH2 groups were
responsible for the high potency of these compounds. Con-
sidering the thieno[2,3-g]chromene derivatives 14a–m it is
clear from Table 3 that compounds 14e, 14f, and 14g were the
most cytotoxic compounds among the twelve compounds.
The highcytotoxicity of the three compounds 14e, 14f and
14g was attributed to the presence of the Cl and/or NH2 or the
OH groups.
Compound
c-Kit
Flt-3
VEGFR-2
EGFR
PDGFR
5c
0.08
1.26
0.69
0.29
6.73
1.08
0.49
0.06
0.19
0.25
1.22
0.77
1.68
4.82
0.83
0.28
0.51
0.17
0.62
0.96
0.38
0.19
6.29
1.52
0.19
0.28
0.20
0.27
4.80
0.52
1.83
8.31
1.60
0.83
0.42
0.13
0.39
1.31
0.93
0.93
4.90
2.84
0.35
0.80
0.26
6c
6d
8e
8f
12d
14e
14f
Foretinib
Cell proliferation assay
The anti-proliferative activities of the newly synthesized
compounds (Table 3) were evaluated against the five c-Met-
dependent cancer cell lines (A549, HT-29, MKN-45,
U87MG, and SMMC-7721) and one c-Met-independent
cancer cell line (H460) using the standard MTT assay
in vitro, with foretinib as the positive control (Li et al. 2013;
Fathi et al. 2012). The cancer cell lines were cultured in
minimum essential medium (MEM) supplemented with
10% fetal bovine serum (FBS). Approximately 4 × 103 cells,
suspended in MEM medium, were plated onto each well of
a 96-well plate and incubated in 5% CO2 at 37 °C for 24 h.
The compounds tested at the indicated final concentrations
were added to the culture medium and the cell cultures were
continued for 72 h. Fresh MTT was added to each well at a
terminal concentration of 5 μg/mL, and incubated with cells
at 37 °C for 4 h. The formazan crystals were dissolved in
100 μL of DMSO each well, and the absorbency at 492 nM
(for absorbance of MTT formazan) and 630 nM (for the
reference wavelength) was measured with an ELISA reader.
All of the compounds were tested three times in each cell
line. The results expressed as IC50 (inhibitory concentration
50%) were the averages of three determinations and cal-
culated by using the Bacus Laboratories Incorporated Slide
Scanner (Bliss) software.
Inhibition of selected toward Pim-1 kinase
Furthermore, compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h, 12c,
12d, 12f, and 14f were selected to examine their Pim-1
kinase inhibition activity (Table 4) as these compounds
showed high inhibition toward the c-Met kinase and the
tested cancer cell lines at a range of 10 concentrations and
the IC50 values were calculated. Compounds 3c, 6c, 8g, 12c,
and 14f were the most potent to inhibit Pim-1 activity with
IC50 value of 0.18, 0.16, 0.36. 0.14, 0.17 μM, while 5, 6d,
8f, 8h, 12d, 12f, and 13b were less effective (IC50 > 10 μM).
SGI-1776 was used as positive control with IC50 0.048 μM
in the assay. These profiles in combination with cell growth
inhibition data of compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h,
12c, 12d, 12f, and 14f were listed in Table 4 which indi-
cated that Pim-1 was a potential target of these compounds.
In vitro cell assays
All the synthesized compounds were assessed the inhibitory
activities against A549 (non-small cell lung cancer), H460
(human lung cancer), HT-29 (human colon cancer), and
MKN-45 (human gastric cancer cancer) cancer cell lines
together with foretinib as the positive control by a MTT assay.
Furthermore, all compounds were further evaluated against
U87MG (human glioblastoma) and SMMC-7721 (human
liver cancer) cell lines. The results expressed as IC50 were
summarized in Table 3. The IC50 values are the average of at
Experimental
The solvents used through this work were dried prior to
their use. All melting points of the synthesized compounds

Medicinal Chemistry Research
Table 3 In vitro growth inhibitory effects IC50 SEM (μM) of the newly synthesized compounds against cancer cell lines
Compound no
IC50 SEM (μM)
A549
H460
HT29
MKN-45
U87MG
SMMC-7721
9.52 3.51
3a
8.38 0.80
0.26 0.73
1.47 0.83
8.55 2.37
8.32 2.57
9.28 2.49
0.26 0.19
1.20 0.82
9.53 2.63
8.57 2.40
8.59 2.27
0.34 0.29
0.42 0.37
6.26 1.39
8.42 3.58
9.53 3.57
8.59 2.52
5.42 2.58
6.42 2.57
1.27 0.53
0.26 0.15
0.67 0.36
0.25 0.08
6.42 1.38
2.27 0.95
4.61 1.65
0.93 0.32
8.42 2.57
2.34 0.95
1.72 0.69
0.63 0.42
5.25 0.53
1.06 0.78
4.27 1.58
7.29 1.42
0.98 0.63
2.16 1.35
4.52 1.39
6.48 2.53
8.36 2.58
3.22 1.79
4.58 1.37
3.69 1.52
0.38 0.15
0.32 0.31
1.80 0.73
9.32 2.08
0.63 0.25
0.69 0.32
9.29 2.63
8.72 2.68
8.36 2.59
0.42 0.22
1.94 0.82
8.81 2.92
8.59 2.41
7.59 1.63
0.67 0.53
0.25 0.16
8.49 2.23
7.26 2.59
9.72 3.89
8.42 2.49
5.94 2.39
2.58 1.82
0.82 0.57
0.36 0.14
0.47 0.25
0.15 0.07
7.28 2.59
2.50 0.81
3.72 1.42
1.59 0.95
9.28 3.52
3.59 0.93
1.38 0.28
0.82 0.49
7.31 2.69
1.52 0.73
3.94 1.80
8.92 2.69
1.08 0.76
1.28 0.63
3.70 1.53
6.70 1.93
6.29 1.47
7.39 1.25
3.53 1.52
4.62 1.39
0.83 0.52
0.94 0.25
0.89 0.30
9.26 2.39
1.08 0.53
0.84 0.59
8.37 3.72
9.29 2.72
10.17 3.63
0.19 0.03
2.73 0.95
9.68 2.48
7.62 1.39
8.74 2.64
0.72 0.35
0.84 0.53
8.58 2.49
9.27 2.57
8.42 2.63
6.73 1.69
6.25 2.59
3.39 1.51
0.83 0.82
0.39 0.15
1.69 0.26
0.68 0.15
6.24 2.80
1.25 0.69
2.50 0.82
1.66 0.94
8.80 3.63
2.38 0.84
1.69 0.36
0.49 0.83
8.92 2.73
1.85 0.59
6.81 2.39
6.49 2.73
1.38 0.69
2.39 0.83
4.63 2.59
6.42 1.59
6.50 1.62
8.63 2.44
4.92 1.62
6.52 2.59
1.03 0.95
1.07 0.88
0.67 0.42
6.16 1.42
0.42 0.23
1.65 0.39
8.69 2.48
8.83 2.60
8.39 2.68
0.82 0.39
1.62 0.89
8.63 3.77
8.72 3.80
6.52 2.63
0.39 0.17
0.42 0.28
7.39 2.38
5.16 1.42
8.38 1.83
6.73 1.73
6.39 2.16
4.27 1.72
1.72 0.94
0.15 0.06
0.92 0.36
0.49 0.15
6.25 1.64
3.62 1.27
2.63 0.98
1.37 0.72
6.70 2.83
4.53 1.51
0.69 0.25
0.08 0.01
6.27 2.39
0.93 0.32
5.62 1.73
8.28 2.37
0.89 0.26
1.92 0.83
3.22 1.80
4.84 1.96
6.49 1.39
6.39 2.58
5.63 1.87
8.32 2.39
0.54 0.27
0.63 0.29
0.93 0.42
8.59 2.59
0.59 0.25
0.84 0.42
9.30 3.27
9.38 3.80
9.49 2.29
0.29 0.17
1.59 0.93
8.53 3.56
9.59 2.53
8.93 2.73
0.38 0.24
1.29 0.39
8.59 2.49
6.69 2.54
8.90 2.85
6.74 1.52
5.62 2.37
6.29 1.85
0.79 0.26
0.35 0.15
0.84 0.29
0.80 0.32
7.90 2.35
2.49 0.57
3.16 1.80
2.58 0.96
7.93 1.27
3.26 1.42
0.37 0.15
0.25 0.03
7.62 2.49
0.74 0.29
6.29 2.32
6.37 1.62
0.93 0.69
3.58 1.62
4.52 1.63
4.39 1.73
7.39 2.92
4.70 2.09
6.42 2.74
4.72 1.49
1.09 0.82
0.78 0.36
0.78 0.39
3b
0.38 0.16
0.77 0.25
8.57 2.63
6.60 1.73
6.36 2.67
0.69 0.29
2.68 0.83
8.73 2.52
8.49 2.17
8.59 1.62
0.29 0.16
0.25 0.09
6.27 1.25
7.58 2.62
8.52 3.41
7.63 2.51
6.25 1.94
3.63 1.59
0.59 0.24
0.15 0.08
1.25 0.48
0.59 0.38
6.83 2.49
2.38 0.32
2.57 1.25
2.25 1.02
6.38 1.25
4.28 2.63
2.81 0.53
0.92 0.08
6.80 2.39
1.28 0.90
4.56 1.25
7.79 1.32
1.03 0.95
2.72 0.94
5.72 1.38
5.84 2.62
3.69 0.93
9.48 3.24
6.29 2.63
3.83 1.37
0.98 0.32
1.18 0.79
0.73 0.26
3c
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
8a
8b
8c
8d
8e
8f
8g
8h
8i
8k
8l
8m
10a
10b
10c
10d
10e
10f
12a
12b
12c
12d
12e
12f
14a
14b
14c
14d
14e
14f
14g

Medicinal Chemistry Research
Table 3 (continued)
Compound no
IC50 SEM (μM)
A549
H460
HT29
MKN-45
U87MG
SMMC-7721
2.28 0.69
14h
3.38 1.52
10.17 2.39
8.25 1.73
9.87 1.65
6.39 1.52
0.08 0.01
2.26 0.53
9.38 2.42
10.62 3.60
6.48 1.33
1.38 0.69
0.18 0.03
1.36 0.53
10.49 3.80
8.72 2.55
7.202 2.72
3.34 1.48
0.15 0.023
2.63 0.88
8.52 2.95
8.20 1.83
8.73 2.68
1.89 0.88
0.03 0.0055
1.29 0.25
8.53 2.27
6.39 1.72
6.49 2.42
2.84 1.52
0.90 0.13
14i
9.73 2.59
7.93 1.27
4.83 1.59
4.58 1.38
14k
14l
14m
Foretinib
0.44 0.062
Table 4 The inhibitor activity of compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g,
8h, 12c, 12d, 12f and 14f on Pim-1 Kinase
(0.92 g, 0.01 mol), 4-chloroaniline (1.27 g, 0.01 mol) or 4-
methoxyaniline (1.23 g, 0.01 mol) dissolved in concentrated
hydrochloric acid (9.0 mL, 18 mol) was added with con-
tinuous stirring] added. The reaction mixture was stirred at
room temperature for 2 h and the formed solid product, in
each case, was collected by filtration.
Compound
Inhibition
ratio
IC50
(μM)
At 10 μM
3c
94
32
96
92
21
18
98
31
97
28
26
95
–
0.18
>10
0.16
0.36
>10
>10
0.14
>10
0.12
>10
>10
0.17
0.048
5c
5,5-Dimethyl-2-(2-phenylhydrazono)cyclohexane-1,3-dione
(3a)
5d
6c
6d
Orange-red crystals (ethanol), yield 70% (1.71 g), m.p.
8f
149–152 °C; (IR (KBr) νmax 3486–3325, 3055, 2984,
8g
1
1689, 1687, 1635, 1580; H-NMR (DMSO-d6, 200 MHz):
8h
δ = 8.28 (s, 1H, D2O exchangeable, NH), 7.26–7.39 (m,
5H, C6H5), 2.73, 2.71 (2s, 4H, 2CH2), 1.08, 1.09 (2 s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 182.3 (C-2, C-
4), 133.5, 127.2, 124.8, 120.5 (C6H5), 50.3 (C-4, C-6), 24.8
(2CH3); EIMS: m/z 244 [M]+ (48%); Analysis Calcd for
C14H16N2O2 (244.29): C, 68.83; H, 6.60; N, 11.47%.
Found: C, 68.69; H, 6.49; N, 11.72%.
12c
12d
12f
14f
SGI-1776
were recorded on Buchi melting point apparatus D-545; IR
spectra (KBr discs) were recorded on Bruker Vector 22
2-(2-(4-Chlorophenyl)hydrazono)-5,5-dimethylcyclohexane-
1,3-dione (3b)
1
instrument. 13C-NMR and H-NMR spectra were recorded
on Bruker DPX200 instrument in DMSO-d6 with TMS as
internal standard. Chemical shifts are mentioned in δ (ppm).
Mass spectra were measured using EIMS (Shimadzu) and
ESI-esquire 3000 Bruker Daltonics instrument. Elemental
analyses were carried out using the Microanalytical Data
center at Cairo University. The completion of all reactions
was monitored by TLC on 2 × 5 cm pre-coated silica gel 60
F254 plates of thickness of 0.25 mm (Merck).
Orange crystals (ethanol), yield 78% (2.16 g), m.p.
168–170 °C; (IR (KBr) νmax 3493–3335, 3050, 2985,
1689, 1688, 1632, and 1583; 1H-NMR (DMSO-d6,
200 MHz): δ = 8.26 (s, 1H, D2O exchangeable, NH),
7.22–7.49 (m, 4H, C6H4), 2.71, 2.70 (2 s, 4H, 2CH2), 1.05,
1.07 (2 s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ =
182.3 (C-2, C-4), 135.8, 128.5, 126.7, 121.8 (C6H4), 50.1
(C-4, C-6), 24.5 (2CH3); EIMS: m/z 278 [M]+ (38%);
Analysis Calcd for C14H15ClN2O2 (278.73): C, 60.33; H,
5.42; N, 10.05%. Found: C, 60.42; H, 5.70; N, 9.85%.
General procedure for the synthesis of the arylhydrazone
derivatives 3a–c
To a solution of dimedone (1.40 g, 0.01 mol) in ethanol
(40 mL) containing sodium acetate (4.0 g) any of benzene-
diazonium chloride (0.01 mol), 4-chlorobenzenediazonium
chloride (0.01 mol) or 4-methoxybenzenediazonium chloride
(0.01 mol) [prepared through the addition of sodium nitrite
(0.70 g, 0.01 mol) to a cold solution 0–5 °C any of aniline
2-(2-(4-Methoxyphenyl)hydrazono)-5,5-
dimethylcyclohexane-1,3-dione (3c)
Orange crystals (ethanol), yield 69% (1.89 g), m.p.
144–147 °C; (IR (KBr) νmax 3482–3317, 3050, 2987, 1688,
1
1686, 1630, 1584; H-NMR (DMSO-d6, 200 MHz): δ =

Medicinal Chemistry Research
8.27 (s, 1H, D2O exchangeable, NH), 7.20–7.46 (m, 4H,
C6H4), 3.68 (s, 3 H, OCH3), 2.74, 2.71 (2 s, 4H, 2CH2), 1.06,
1.08 (2 s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ =
182.3 (C-2, C-4), 135.5, 127.8, 125.6, 120.3 (C6H4), 52.6
(OCH3), 50.2 (C-4, C-6), 24.6 (2CH3); EIMS: m/z 274 [M]+
(28%); Analysis Calcd for C15H18N2O3 (274.32): C, 65.68;
H, 6.61; N, 10.21%. Found: C, 65.73; H, 6.49; N, 10.08%.
2-Amino-4-(2-(4-chlorophenyl)hydrazono)-7,7-dimethyl-5-
oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile
(5c)
Yellow crystals (ethanol), yield 80% (2.86 g), m.p.
207–210 °C; (IR (KBr) νmax 3477–3321, 3056, 2980,
1
2220, 1689, 1630, 1560; H-NMR (DMSO-d6, 200 MHz):
δ = 8.25 (s, 1H, D2O exchangeable, NH), 7.47–7.22 (m,
4H, C6H4), 4.47 (s, 2H, D2O exchangeable, NH2), 2.75 (s,
2H, CH2), 1.07, 1.02 (2 s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 179.4 (C-4), 164.9 (C-5), 142.6, 141.8,
138.5, 136.9, 130.8, 125.6, 123.8, 120.3 (C6H5, C-2, C-3,
C-3a, C-7a), 116.8 (CN), 50.2 (C-4, C-6), 38.5 (C-7), 24.6
(2CH3),; EIMS: m/z 358 [M]+ (41%); Analysis Calcd for
C17H15ClN4OS (358.85): C, 56.90; H, 4.21; N, 15.61; S,
8.94%. Found: C, 56.76; H, 4.39; N, 15.80; S, 8.76%.
General procedure for the synthesis of the 6,7-
dihydrobenzo[b]thiophen-5(4H)-one derivatives 5a–f
To a solution of any of compound 3a (2.44 g, 0.01 mol), 3b
(2.78 g, 0.01 mol) or 3c (2.74 g, 0.01 mol) in 1,4-dioxan
(40 mL) containing triethylamine (0.50 g) each of elemental
sulfur (0.32 g, 0.01 mol) and either of malononitrile (0.66 g,
0.01 mol) or ethyl cyanoacetate (1.3 g, 0.01 mol) were
added. The reaction mixture was heated under reflux for 2 h
then left to cool and the formed solid product, in each case
was collected by filtration.
Ethyl 2-amino-4-(2-(4-chlorophenyl)hydrazono)-7,7-
dimethyl-5-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (5d)
2-Amino-7,7-dimethyl-5-oxo-4-(2-phenylhydrazono)-
4,5,6,7-tetrahydrobenzo-[b]thiophene-3-carbonitrile (5a)
Yellow crystals (ethanol), yield 73% (2.95 g), m.p.
205–208 °C; (IR (KBr) νmax 3496–3317, 3056, 2983,
1689, 1630, 1552; H-NMR (DMSO-d6, 200 MHz): δ =
1
Yellow crystals (ethanol), yield 78% (2.52 g), m.p.
213–216 °C; (IR (KBr) νmax 3474–3316, 3056, 2982,
2220, 1688, 1635, 1565; H-NMR (DMSO-d6, 200 MHz):
8.25 (s, 1H, D2O exchangeable, NH), 7.47–7.23 (m, 4H,
C6H4), 4.49 (s, 2H, D2O exchangeable, NH2), 4.24 (q, 2H, J
= 6.83 Hz, CH2), 2.72 (s, 2H, CH2), 1.13 (t, 3H, J =
6.83 Hz, CH3), 1.08, 1.04 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 179.7 (C-4), 168.2, 164.7 (C-5,
ester CO), 141.8, 140.6, 138.5, 137.3, 131.8, 127.9, 126.4,
120.4 (C6H5, C-2, C-3, C-3a, C-7a) 52.6 (OCH2CH3), 50.1
(C-4, C-6), 16.2 (OCH2CH3), 38.7 (C-7), 24.8 (2CH3);
EIMS: m/z 405 [M]+ (42%); Analysis Calcd for
C19H20ClN3O3S (405.90): C, 56.22; H, 4.97; N, 10.35; S,
7.90%. Found: C, 56.39; H, 5.16; N, 10.63; S, 8.03%.
1
δ = 8.26 (s, 1H, D2O exchangeable, NH), 7.28–7.38 (m,
5H, C6H5), 4.49 (s, 2H, D2O exchangeable, NH2), 2.70 (s,
2H, CH2), 1.06, 1.05 (2 s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 179.2 (C-5), 142.8, 140.4, 138.7, 136.5,
131.8, 126.4, 124.3, 120.2 (C6H5, C-2, C-3, C-3a, C-7a)
116.7 (CN), 50.3 (C-4, C-6), 24.6 (2CH3), 38.6 (C-7);
EIMS: m/z 324 [M]+ (32%); Analysis Calcd for
C17H16N4OS (324.40): C, 62.94; H, 4.97; N, 17.27; S,
9.88%. Found: C, 63.15; H, 5.21; N, 17.06; S, 10.02%.
Ethyl 2-amino-7,7-dimethyl-5-oxo-4-(2-phenylhydrazono)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5b)
2-Amino-4-(2-(4-methoxyphenyl)hydrazono)-7,7-dimethyl-
5-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile
(5e)
Yellow crystals (ethanol), yield 68% (2.52 g), m.p.
177–179 °C; (IR (KBr) νmax 3481–3324, 3054, 2980,
1687, 1632, 1560; H-NMR (DMSO-d6, 200 MHz): δ =
Yellow crystals (ethanol), yield 68% (2.40 g), m.p.
1
258–261 °C; (IR (KBr) νmax 3449–3349, 3054, 2983,
1
8.28 (s, 1H, D2O exchangeable, NH), 7.26–7.39 (m, 5H,
C6H5), 4.46 (s, 2H, D2O exchangeable, NH2), 4.22 (q, 2H, J
= 7.11 Hz, CH2), 2.72 (s, 2H, CH2), 1.13 (t, 3H, J =
7.11 Hz, CH3), 1.08, 1.04 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 179.4 (C-4), 164.6, 168.2 (C-5,
ester C=O), 141.8, 138.9, 137..5, 136.8, 132.2, 128.1,
126.7, 120.9 (C6H5, C-2, C-3, C-3a, C-7a), 50.3 (C-4, C-6),
38.5 (C-7), 24.6 (2CH3); EIMS: m/z 371 [M]+ (28%);
Analysis Calcd for C19H21N3O3S (371.45): C, 61.44; H,
5.70; N, 11.31; S, 8.63%. Found: C, 61.58; H, 5.39; N,
11.42; S, 8.82%.
2222, 1687, 1632, 1564; H-NMR (DMSO-d6, 200 MHz):
δ = 8.26 (s, 1H, D2O exchangeable, NH), 7.45–7.27 (m,
4H, C6H4), 4.49 (s, 2H, D2O exchangeable, NH2), 3.69 (s,
3H, OCH3), 2.79 (s, 2H, CH2), 1.08, 1.04 (2s, 6H, 2CH3);
13C-NMR (DMSO-d6, 75 MHz): δ = 179.6 (C-4), 165.2 (C-
5), 142.2, 141.8, 138.2, 134.5, 131.6, 128.3, 125.3, 120.8
(C6H4, C-2, C-3, C-3a, C-7a), 116.9 (CN), 52.6 (OCH3),
50.4 (C-4, C-6), 38.8 (C-7), 24.8 (2CH3),; EIMS: m/z 354
[M]+ (36%); Analysis Calcd for C18H18N4O2S (354.43): C,
61.00; H, 5.12; N, 15.81; S, 9.05%. Found: C, 60.85; H,
4.94; N, 15.69; S, 8.95%.

Medicinal Chemistry Research
Ethyl 2-amino-4-(2-(4-methoxyphenyl)hydrazono)-7,7-
dimethyl-5-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (5f)
2221, 2220, 1689, 1636, 1560; 1H-NMR (DMSO-d6,
200 MHz): δ = 7.41–7.25 (m, 5H, C6H5), 4.49 (s, 2H, D2O
exchangeable, NH2), 2.73 (s, 2H, CH2), 1.06, 1.02 (2s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 178.8, 168.2
(C-3, C-9b), 143.6, 142.2, 140.5, 138.6, 137.2, 136.2,
133.8, 129.9, 126.2, 120.8 (C6H5, C-2, C-3, C-6a, C-9a, C-
4, C-4a), 116.8, 117.2 (2CN), 50.1 (C-4, C-6), 38.7 (C-6),
24.5 (2CH3); EIMS: m/z 373 [M]+ (42%); Analysis Calcd
for C20H15N5OS (373.43): C, 64.33; H, 4.05; N, 18.75; S,
8.59%. Found: C, 64.58; H, 4.19; N, 18.93; S, 8.64%.
Yellow crystals (ethanol), yield 77% (3.08 g), m.p.
156–159 °C; (IR (KBr) νmax 3484–3326, 3056, 2982,
1
1688, 1630, 1553; H-NMR (DMSO-d6, 200 MHz): δ =
8.27 (s, 1H, D2O exchangeable, NH), 7.39–7.27 (m, 4H,
C6H4), 4.46 (s, 2H, D2O exchangeable, NH2), 4.21 (q, 2H, J
= 7.02 Hz, CH2), 2.76 (s, 2H, CH2), 1.12 (t, 3H, J =
7.02 Hz, CH3), 1.05, 1.03 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 179.5 (C-4), 165.2, 168.7 (C-5,
ester CO),), 142.6, 140.3, 136.8, 134.7, 132.6, 127.5, 125.3,
120.5 (C6H4, C-2, C-3, C-3a, C-7a), 52.8 (OCH3), 52.4
(OCH2CH3), 50.3 (C-4, C-6), 38.9 (C-7), 24.7 (2CH3), 16.8
(OCH2CH3),; EIMS: m/z 401 [M]+ (32%); Analysis Calcd
for C20H23N3O4S (401.48): C, 59.83; H, 5.77; N, 10.47; S,
7.99%. Found: C, 59.73; H, 5.80; N, 10.59; S, 8.15%.
8-Amino-2-(4-chlorophenyl)-3-imino-6,6-dimethyl-2,3,5,6-
tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile (6c)
Yellow crystals (ethanol), yield 72% (2.92 g), m.p.
177–179 °C; (IR (KBr) νmax 3480–3317, 3054, 2982,
1
2222, 2220, 1646, 1556; H-NMR (DMSO-d6, 200 MHz):
δ = 8.41 (s, 1H, D2O exchangeable, NH), 7.48–7.21 (m,
4H, C6H4), 4.43 (s, 2H, D2O exchangeable, NH2), 2.77 (s,
2H, CH2), 1.08, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 179.6, 175.6 (C-3, C-9b), 143.3, 141.8,
140.2, 139.4, 138.1, 136.8, 134.5, 129.4, 127.8, 122.1
(C6H5, C-2, C-3, C-6a, C-9a, C-4, C-4a), 116.7, 117.2
(2CN), 50.3 (C-4, C-6), 38.6 (C-6), 24.3 (2CH3); EIMS: m/z
406 [M]+ (38%); Analysis Calcd for C20H15ClN6S
(406.89): C, 59.04; H, 3.72; N, 20.65; S, 7.88%. Found: C,
59.25; H, 3.82; N, 20.73; S, 8.04%.
General procedure for the synthesis of the 2,3,5,6-
tetrahydrothieno[2,3-h]cinnoline derivatives 6a–f
To a solution of any of compounds 5a (3.24 g, 0.01 mol), 5c
(3.58 g, 0.01 mol), and 5e (3.54 g, 0.01 mol) in 1,4-dioxan
(40 mL) containing triethylamine (0.50 g, 0.01 mol) either
of malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate
(1.13 g, 0.01 mol) was added. The reaction mixture, in each
case, was heated under reflux for 3 h then poured onto ice/
water containing few drops of hydrochloric acid and the
formed solid product was collected by filtration.
8-Amino-2-(4-chlorophenyl)-6,6-dimethyl-3-oxo-2,3,5,6-
tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile (6d)
8-Amino-3-imino-6,6-dimethyl-2-phenyl-2,3,5,6-
tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile (6a)
Yellow crystals (ethanol), yield 58% (2.36 g), m.p.
177–179 °C; (IR (KBr) νmax 3458–3315, 3055, 2980,
2222, 2220, 1688, 1633, 1562; 1H-NMR (DMSO-d6,
200 MHz): δ = 7.46–7.23 (m, 4H, C6H4), 4.42 (s, 2H, D2O
exchangeable, NH2), 2.78 (s, 2H, CH2), 1.08, 1.03 (2s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 178.5, 167.9
(C-3, C-9b), 143.3, 142.7, 141.8, 139.2, 137.7, 136.1,
132.3, 127.3, 123.1, 120.5 (C6H4, C-2, C-3, C-6a, C-9a, C-
4, C-4a), 116.5, 117.1 (2CN), 50.5 (C-4, C-6), 38.3 (C-6),
24.6 (2CH3); EIMS: m/z 407 [M]+ (28%); Analysis Calcd
for C20H14ClN5OS (407.88): C, 58.89; H, 3.46; N, 17.17; S,
7.86%. Found: C, 58.66; H, 3.59; N, 16.93; S, 7.69%.
Yellow crystals (ethanol), yield 78% (2.90 g), m.p.
187–190 °C; (IR (KBr) νmax 3498–3326, 3054, 2983,
1
2224, 2220, 1632, 1564; H-NMR (DMSO-d6, 200 MHz):
δ = 8.28 (s, 1H, D2O exchangeable, NH), 7.38–7.25 (m,
5H, C6H5), 4.47 (s, 2H, D2O exchangeable, NH2), 2.79 (s,
2H, CH2), 1.08, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 178.5, 175.4 (C-3, C-9b), 143.8, 142.6,
140.9, 138.3, 137.0, 136.5, 135.3, 127.5, 124.6, 120.5
(C6H5, C-2, C-3, C-6a, C-9a, C-4, C-4a), 116.9, 117.3
(2CN), 50.3 (C-4, C-6), 38.4 (C-6), 24.1 (2CH3); EIMS: m/z
372 [M]+ (22%); Analysis Calcd for C20H16N6S (372.45):
C, 64.50; H, 4.33; N, 22.56; S, 8.61%. Found: C, 64.68; H,
4.51; N, 22.69; S, 8.79%.
8-Amino-3-imino-2-(4-methoxyphenyl)-6,6-dimethyl-
2,3,5,6-tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile
(6e)
8-Amino-3-oxo-6,6-dimethyl-2-phenyl-2,3,5,6-
Yellow crystals (ethanol), yield 78% (3.15 g), m.p.
tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile (6b)
231–233 °C; (IR (KBr) νmax 3458–3341, 3056, 2982, 2223,
2220, 1642, 1553; H-NMR (DMSO-d6, 200 MHz): δ =
1
Yellow crystals (ethanol), yield 83% (3.09 g), m.p.
8.45 (s, 1H, D2O exchangeable, NH), 7.43–7.27 (m, 4H,
233–236 °C; (IR (KBr) νmax 3474–3352, 3056, 2983,
C6H4), 4.41 (s, 2H, D2O exchangeable, NH2), 3.68 (s, 3H,

Medicinal Chemistry Research
OCH3), 2.79 (s, 2H, CH2), 1.07, 1.05 (2s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 179.9, 175.3 (C-3, C-9b),
142.3, 141.5, 140.9, 138.2, 137.8, 135.3, 134.2, 128.1,
127.3, 122.8 (C6H5, C-2, C-3, C-6a, C-9a, C-4, C-4a), 116.9,
117.2 (2CN), 52.6 (OCH3), 50.1 (C-4, C-6), 38.5 (C-6), 24.6
(2CH3); EIMS: m/z 402 [M]+ (58%); Analysis Calcd for
C21H18N6OS (402.47): C, 62.67; H, 4.51; N, 20.88; S,
7.97%. Found: C, 62.80; H, 4.92; N, 20.63; S, 8.7%.
2-Amino-7,7-dimethyl-4,5-bis(2-phenylhydrazono)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carbonitrile (8b)
Orange crystals (ethanol), yield 69% (2.85 g), m.p.
155–158 °C; (IR (KBr) νmax 3479–3317, 3055, 2980, 2220,
1653, 1563; 1H-NMR (DMSO-d6, 200 MHz): δ = 8.32, 8.26
(2s, 2H, D2O exchangeable, 2NH), 7.37–7.24 (m, 10H,
2C6H5), 4.49 (s, 2H, D2O exchangeable, NH2), 2.76 (s, 2H,
CH2), 1.07, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 179.7, 176.3 (C-4, C-5), 142.8, 140.6, 137.8,
135.4, 134.6, 127.3, 126.5, 125.2, 124.8, 123.5, 122.7,120.1
(2C6H5, C-2, C-3, C-3a, C-7a) 116.5 (CN), 50.2 (C-4), 38.3
(C-7), 24.2 (2CH3); EIMS: m/z 414 [M]+ (65%); Analysis
Calcd for C23H22N6S (414.53): C, 66.64; H, 5.35; N, 20.27;
S, 7.74%. Found: C, 66.86; H, 5.53; N, 20.38; S, 7.93%.
8-Amino-2-(4-methoxyphenyl)-6,6-dimethyl-3-oxo-2,3,5,6-
tetrahydrothieno[2,3-h]cinnoline-4,9-dicarbonitrile (6f)
Yellow crystals (ethanol), yield 88% (3.54 g), m.p.
244–246 °C; (IR (KBr) νmax 3473–3328, 3054, 2983,
1
2220, 1688, 1642, 1550; H-NMR (DMSO-d6, 200 MHz):
δ = 8.45 (s, 1H, D2O exchangeable, NH), 7.46–7.23 (m,
4H, C6H4), 4.41 (s, 2H, D2O exchangeable, NH2), 3.69 (s,
3H, OCH3), 2.79 (s, 2H, CH2), 1.07, 1.04 (2s, 6H, 2CH3);
13C-NMR (DMSO-d6, 75 MHz): δ = 179.9, 175.3 (C-3, C-
9b), 142.8, 141.6, 140.8, 138.3, 136.4, 135.1, 132.8, 129.6,
126.3, 121.8 (C6H5, C-2, C-3, C-6a, C-9a, C-4, C-4a),
116.9, 117.4 (2CN), 50.1 (C-4, C-6), 38.3 (C-6), 24.6
(2CH3); EIMS: m/z 403 [M]+ (46%); Analysis Calcd for
C21H17N5O2S (403.46): C, 62.52; H, 4.25; N, 17.36; S,
7.95%. Found: C, 562.80; H, 4.73; N, 17.46; S, 8.26%.
Ethyl 2-amino-5-hydrazono-7,7-dimethyl-4-(2-
phenylhydrazono)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8c)
Orange crystals (ethanol), yield 69% (2.85 g), m.p.
155–158 °C; (IR (KBr) νmax 3479–3332, 3053, 2980,
1
1689, 1653, 1563; H-NMR (DMSO-d6, 200 MHz): δ =
8.27 (s, 1H, D2O exchangeable, NH), 7.39–7.27 (m, 5H,
C6H5), 4.47, 5.13 (2s, 4H, D2O exchangeable, 2NH2), 4.22
(q, 2H, J = 6.38 Hz, OCH2CH3), 2.73 (s, 2H, CH2), 1.16 (t,
3H, J = 6.38 Hz, OCH2CH3), 1.08, 1.04 (2s, 6H, 2CH3);
13C-NMR (DMSO-d6, 75 MHz): δ = 179.9, 176.5 (C-4, C-
5), 164.8 (ester CO), 142.8, 140.6, 137.8, 134.6, 126.5,
124.8, 122.7, 120.1 (C6H5, C-2, C-3, C-3a, C-7a), 52.6
(OCH2CH3), 50.5 (C-4), 38.2 (C-7), 24.5 (2CH3), 19.2
(OCH2CH3); EIMS: m/z 385 [M]+ (78%); Analysis Calcd
for C19H23N5O2S (385.48): C, 59.20; H, 6.01; N, 18.17; S,
8.32%. Found: C, 59.30; H, 5.88; N, 18.27; S, 8.60%.
General procedure for the synthesis of the tetrahydrobenzo
[b]thiophene derivatives 8a-m
To a solution of any of 5a (3.24 g, 0.01 mol), 5b (3.71 g,
0.01 mol), 5c (3.58 g, 0.01 mol), 5d (4.05 g, 0.01 mol), 5e
(3.54 g, 0.01 mol) or 5f (4.01 g, 0.01 mol) in ethanol (40 mL)
either of hydrazinehydrate (0.50 mL, 0.01 mol) or phe-
nylhydrazine (1.08 g, 0.01 mol) was added. The reaction
mixture, in each case, was heated under reflux for 3 h then
poured onto ice/water containing few drops of hydrochloric
acid and the formed solid product was collected by filtration.
Ethyl 2-amino-7,7-dimethyl-4,5-bis(2-phenylhydrazono)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (8d)
2-Amino-5-hydrazono-7,7-dimethyl-4-(2-phenylhydrazono)-
Reddish brown crystals (ethanol), yield 73% (3.36 g), m.p.
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (8a)
207–210 °C; (IR (KBr) νmax 3459–3341, 3055, 2980,
1688, 1653, 1563; H-NMR (DMSO-d6, 200 MHz): δ =
1
Yellow crystals (ethanol), yield 74% (2.50 g), m.p.
8.27 (s, 1H, D2O exchangeable, NH), 7.41–7.29 (m, 10H,
2C6H5), 4.43, 5.11 (2s, 4H, D2O exchangeable, 2NH2), 4.22
(q, 2H, J = 7.11 Hz, OCH2CH3), 2.78 (s, 2H, CH2), 1.13 (t,
3 H, J = 7.11 Hz, OCH2CH3), 1.06, 1.02 (2s, 6H, 2CH3);
13C-NMR (DMSO-d6, 75 MHz): δ = 179.5, 176.1 (C-4, C-
5), 164.9 (ester CO), 142.9, 141.2, 138.6, 137.4, 134.6,
126.5, 125.8, 124.2, 123.1, 122.3, 121.2, 120.0 (2C6H5, C-
2, C-3, C-3a, C-7a), 52.8 (OCH2CH3), 50.3 (C-4), 38.5 (C-
7), 24.2 (2CH3), 19.6 (OCH2CH3); EIMS: m/z 461 [M]+
(36%); Analysis Calcd for C25H27N5O2S (461.58): C,
65.05; H, 5.90; N, 15.17; S, 6.95%. Found: C, 64.87; H,
5.79; N, 15.35; S, 7.17%.
196–198 °C; (IR (KBr) νmax 3496–3335, 3054, 2980,
1
2223, 1655, 1561; H-NMR (DMSO-d6, 200 MHz): δ =
8.29, (s, 1H, D2O exchangeable, NH), 7.39–7.29 (m, 5H,
C6H5), 4.47, 5.03 (2s, 4H, D2O exchangeable, 2NH2), 2.73
(s, 2H, CH2), 1.09, 1.02 (2s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 179.8, 176.5 (C-4, C-5), 141.6, 140.8,
139.3, 135.9, 134.3, 128.6, 124.1, 120.1 (C6H5, C-2, C-3,
C-3a, C-7a) 116.9 (CN), 50.3 (C-4), 38.8 (C-7), 24.6
(2CH3); EIMS: m/z 338 [M]+ (18%); Analysis Calcd for
C17H18N6S (338.43): C, 60.33; H, 5.36; N, 24.83; S, 9.47%.
Found: C, 60.54; H, 5.48; N, 24.65; S, 9.61%.

Medicinal Chemistry Research
2-Amino-4-(2-(4-chlorophenyl)hydrazono)-5-hydrazono-7,7-
dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carbonitrile (8e)
Ethyl 2-amino-4-(2-(4-chlorophenyl)hydrazono)-7,7-
dimethyl-5-(2-phenylhydrazono)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (8h)
Yellow crystals (ethanol), yield 83% (3.08 g), m.p.
211–214 °C; (IR (KBr) νmax 3477–3321, 3055, 2980,
2220, 1655, 1563; 1H-NMR (DMSO-d6, 200 MHz): δ = 8.3
(s, 1H, D2O exchangeable, NH), 7.48–7.23 (m, 4H, C6H4),
4.45, 5.06 (2s, 4H, D2O exchangeable, 2NH2), 2.76 (s, 2H,
CH2), 1.07, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 179.6, 176.3 (C-4, C-5), 143.3, 141.6, 137.1,
135.2, 134.0, 127.3, 122.8, 120.6 (C6H4, C-2, C-3, C-3a, C-
7a) 116.6 (CN), 50.6 (C-4), 38.4 (C-7), 24.9 (2CH3); EIMS:
m/z 372 [M]+ (42%); Analysis Calcd for C17H17ClN6S
(372.88): C, 54.76; H, 4.60; N, 22.54; S, 8.60%. Found: C,
54.49; H, 4.82; N, 22.80; S, 8.74%.
Reddish brown crystals (ethanol), yield 65% (3.22 g), m.p.
168–170 °C; (IR (KBr) νmax 3473–3326, 3055, 2980, 1650,
1557; 1H-NMR (DMSO-d6, 200 MHz): δ = 8.29 (s, 1H, D2O
exchangeable, NH), 7.49–7.23 (m, 10H, 2C6H5), 4.48 (s, 2H,
D2O exchangeable, NH2), 4.23 (q, 2H, J = 5.80 Hz,
OCH2CH3), 2.73 (s, 2H, CH2), 1.12 (t, 3H, J = 5.80 Hz,
OCH2CH3), 1.09, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 179.5, 176.7 (C-4, C-5), 165.3 (ester CO),
143.4, 142.0, 138.8, 137.3, 134.1, 126.8, 124.1, 123.0, 122.9,
122.6, 121.4, 120.3 (C6H5, C6H4, C-2, C-3, C-3a, C-7a), 52.6
(OCH2CH3), 50.8 (C-4), 38.1 (C-7), 24.0 (2CH3), 19.2
(OCH2CH3); EIMS: m/z 496 [M]+ (44%); Analysis Calcd for
C25H26ClN5O2S (496.02): C, 60.53; H, 5.28; N, 14.12; S,
6.46%. Found: C, 60.74; H, 5.41; N, 14.27; S, 6.80%.
2-amino-4-(2-(4-chlorophenyl)hydrazono)-7,7-dimethyl-5-
(2-phenylhydrazono)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carbonitrile (8f)
2-Amino-5-hydrazono-4-(2-(4-methoxyphenyl)hydrazono)-
7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carbonitrile (8i)
Red crystals (ethanol), yield 72% (3.22 g), m.p. 148–151 °
C; (IR (KBr) νmax 3469–3326, 3056, 2982, 2220, 1657,
1
1561; H-NMR (DMSO-d6, 200 MHz): δ = 8.36, 8.29 (2s,
Yellow crystals (ethanol), yield 70% (2.57 g), m.p.
2H, D2O exchangeable, 2NH), 7.47–7.21 (m, 9H, C6H5,
C6H4), 4.49 (s, 2H, D2O exchangeable, NH2), 2.76 (s, 2H,
CH2), 1.07, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 179.5, 176.1 (C-4, C-5), 142.5, 140.3, 136.9,
135.1, 134.8, 126.7, 126.2, 125.0, 124.9, 123.8,
122.3,120.8 (C6H5, C6H4, C-2, C-3, C-3a, C-7a) 116.9
(CN), 50.5 (C-4), 38.6 (C-7), 24.3 (2CH3); EIMS: m/z 448
[M]+ (26%); Analysis Calcd for C23H21ClN6S (448.97): C,
61.53; H, 4.71; N, 18.72; S, 7.14%. Found: C, 61.70; H,
4.58; N, 18.90; S, 7.35%.
166–168 °C; (IR (KBr) νmax 3493–3331, 3054, 2982,
2220, 1650, 1553; H-NMR (DMSO-d6, 200 MHz): δ =
1
8.32 (s, 1H, D2O exchangeable, NH), 7.45–7.25 (m, 4H,
C6H4), 4.43, 5.02 (2 s, 4H, D2O exchangeable, 2NH2), 3.66
(s, 3H, OCH3), 2.79 (s, 2H, CH2), 1.06, 1.01 (2s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 179.3, 176.1
(C-4, C-5), 143.6, 141.1, 138.5, 136.8, 134.3, 128.8, 123.7,
120.2 (C6H4, C-2, C-3, C-3a, C-7a), 117.3 (CN), 50.8 (C-4),
38.2 (C-7), 24.3 (2CH3); EIMS: m/z 368 [M]+ (31%);
Analysis Calcd for C18H20N6OS (368.46): C, 58.68; H,
5.47; N, 22.81; S, 8.70%. Found: C, 58.72; H, 5.29; N,
22.69; S, 8.83%.
Ethyl 2-amino-4-(2-(4-chlorophenyl)hydrazono)-5-
hydrazono-7,7-dimethyl-4,5,6,7-tetra-hydrobenzo[b]
thiophene-3-carboxylate (8g)
2-Amino-4-(2-(4-methoxyphenyl)hydrazono)-7,7-dimethyl-
5-(2-phenylhydrazono)-4,5,6,7-tetrahydrobenzo[b]
thiophene-3-carbonitrile (8k)
Orange crystals (ethanol), yield 77% (3.22 g), m.p.
236–239 °C; (IR (KBr) νmax 3458–3341, 3055, 2987,
1650, 1560; H-NMR (DMSO-d6, 200 MHz): δ = 8.29 (s,
1
Red crystals (ethanol), yield 64% (2.84 g), m.p. 244–247 °
C; (IR (KBr) νmax 3482–3340, 3054, 2980, 2220, 1653,
1560; H-NMR (DMSO-d6, 200 MHz): δ = 8.39, 8.25 (2s,
1H, D2O exchangeable, NH), 7.48–7.24 (m, 4H, C6H4),
4.49, 5.15 (2s, 4H, D2O exchangeable, 2NH2), 4.21 (q, 2H,
J = 7.39 Hz, OCH2CH3), 2.70 (s, 2H, CH2), 1.12 (t, 3H, J
= 7.39 Hz, OCH2CH3), 1.07, 1.02 (2s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 179.3, 176.1 (C-4, C-5),
165.2 (ester CO), 141.9, 141.2, 136.3, 134.8, 128.9, 125.8,
123.5, 120.3 (C6H5, C6H4, C-2, C-3, C-3a, C-7a), 52.3
(OCH2CH3), 50.2 (C-4), 38.0 (C-7), 24.3 (2CH3), 19.0
(OCH2CH3); EIMS: m/z 419 [M]+ (42%); Analysis Calcd
for C19H22ClN5O2S (419.93): C, 54.34; H, 5.28; N, 16.68;
S, 7.64%. Found: C, 54.62; H, 5.39; N, 16.88; S, 7.80%.
1
2H, D2O exchangeable, 2NH), 7.49–7.20 (m, 9H, C6H5,
C6H4), 4.44 (s, 2H, D2O exchangeable, NH2), 3.72 (s, 3H,
OCH3), 2.73 (s, 2H, CH2), 1.08, 1.02 (2s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 179.8, 176.2 (C-4, C-5),
142.8, 140.6, 136.2, 133.5, 132.6, 128.3, 126.4, 125.2,
124.5, 123.2, 122.6, 120.3 (C6H5, C6H4, C-2, C-3, C-3a, C-
7a) 116.9 (CN), 52.4 (OCH3), 50.2 (C-4), 38.3 (C-7), 24.5
(2CH3); EIMS: m/z 444 [M]+ (28%); Analysis Calcd for

Medicinal Chemistry Research
C24H24N6OS (444.55): C, 64.84; H, 5.44; N, 18.90; S,
7.21%. Found: C, 64.62; H, 5.60; N, 18.83; S, 7.29%.
ice/water containing few drops of hydrochloric acid and the
formed solid product was collected by filtration.
Ethyl 2-amino-5-hydrazono-4-(2-(4-methoxyphenyl)
hydrazono)-7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]
thiophene-3-carboxylate (8l)
4-Amino-8,8-dimethyl-3-phenyl-5-(2-phenylhydrazono)-2-
thioxo-2,3,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-
6(5H)-one (10a)
Orange crystals (ethanol), yield 78% (3.23 g), m.p.
Orange crystals (ethanol), yield 83% (3.80 g), m.p.
190–194 °C; (IR (KBr) νmax 3492–3348, 3055, 2987,
1688, 1560; H-NMR (DMSO-d6, 200 MHz): δ = 8.27 (s,
180–184 °C; (IR (KBr) νmax 3468–3315, 3056, 2980,
1653, 1552, 1205; H-NMR (DMSO-d6, 200 MHz): δ =
1
1
1H, D2O exchangeable, NH), 7.46–7.23 (m, 4H, C6H4),
4.45, 5.18 (2s, 4H, D2O exchangeable, 2NH2), 4.22 (q, 2H,
J = 5.95 Hz, OCH2CH3), 3.76 (s, 3H, OCH3), 2.68 (s, 2H,
CH2), 1.13 (t, 3H, J = 5.95 Hz, OCH2CH3), 1.09, 1.03 (2s,
6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 179.6,
176.3 (C-4, C-5), 164.8 (ester CO), 142.8, 141.8, 136.6,
134.2, 128.7, 125.6, 124.2, 120.6 (C6H5, C-2, C-3, C-3a, C-
7a), 52.1 (OCH2CH3), 52.6 (OCH3), 50.0 (C-4), 38.3 (C-7),
24.3 (2CH3), 19.3 (OCH2CH3); EIMS: m/z 415 [M]+
(28%); Analysis Calcd for C20H25N5O3S (415.51): C,
57.81; H, 6.06; N, 16.85; S, 7.72%. Found: C, 57.68; H,
5.82; N, 16.93; S, 7.83%.
8.36 (s, 1H, D2O exchangeable, NH), 7.42–7.29 (m, 10H,
2C6H5), 4.78 (s, 2H, D2O exchangeable, NH2), 2.79 (s, 2H,
CH2), 1.08, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 180.1 (C-2), 179.3, 176.1, 165.3 (C-5, C-9a,
C-6), 142.8, 141.3, 139.1, 137.1, 134.8, 126.3, 125.2,
124.8, 122.6, 121.8, 121.6, 120.2 (2C6H5, C-4, C-4a, C-4b,
C-8a), 50.6 (C-7), 38.7 (C-8), 24.3 (2CH3); EIMS: m/z 459
[M]+ (18%); Analysis Calcd for C24H29N5OS2 (459.59): C,
62.72; H, 4.61; N, 15.24; S, 13.95%. Found: C, 62.59; H,
4.85; N, 15.41; S, 14.22%.
4-Hydroxy-8,8-dimethyl-3-phenyl-5-(2-phenylhydrazono)-2-
thioxo-2,3,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-
6(5H)-one (10b)
Ethyl 2-amino-4-(2-(4-methoxyphenyl)hydrazono)-7,7-
dimethyl-5-(2-phenylhydrazono)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (8m)
Yellow crystals (acetic acid), yield 79% (3.63 g), m.p.
211–213 °C; (IR (KBr) νmax 3459–3338, 3054, 2980,
1652, 1550, 1207; H-NMR (DMSO-d6, 200 MHz): δ =
1
Orange crystals (ethanol), yield 78% (3.82 g), m.p.
203–206 °C; (IR (KBr) νmax 3483–3342, 3055, 2980,
1689, 1650, 1550; H-NMR (DMSO-d6, 200 MHz): δ =
10.28 (s, 1H, D2O exchageable, OH), 8.37 (s, 1H, D2O
exchangeable, NH), 7.40–7.26 (m, 10H, 2C6H5), 2.74 (s,
2H, CH2), 1.06, 1.02 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 180.4 (C-2), 179.6, 176.5, 165.7 (C-5, C-9a,
C-6), 143.2, 142.6, 138.7, 137.5, 134.1, 128.6, 125.1,
124.5, 123.3, 120.8, 119.8, 119.4 (2C6H5, C-4, C-4a, C-4b,
C-8a), 50.8 (C-7), 38.3 (C-8), 24.2 (2CH3); EIMS: m/z 460
[M]+ (38%); Analysis Calcd for C24H20N4O2S2 (460.57): C,
62.59; H, 4.38; N, 12.16; S, 13.92%. Found: C, 62.42; H,
4.57; N, 12.49; S, 14.16%.
1
8.32, 8.26 (2s, 2H, D2O exchangeable, 2NH), 7.49–7.23 (m,
9 H, C6H5, C6H4), 4.52 (s, 2H, D2O exchangeable, NH2),
4.20 (q, 2H, J = 6.22 Hz, OCH2CH3), 3.70 (s, 3H, OCH3),
2.75 (s, 2H, CH2), 1.13 (t, 3H, J = 6.22 Hz, OCH2CH3),
1.07, 1.02 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz):
δ = 179.3, 176.1 (C-4, C-5), 165.2 (ester CO), 143.2, 141.8,
138.3, 136.1, 134.1, 126.84, 125.8, 123.2, 122.3, 121.9,
121.2, 120.6 (C6H5, C6H4, C-2, C-3, C-3a, C-7a), 116.9
(CN), 53.6 (OCH3), 52.3 (OCH2CH3), 50.8 (C-4), 38.3 (C-
7), 24.1 (2CH3), 18.5 (OCH2CH3); EIMS: m/z 491 [M]+
(24%); Analysis Calcd for C26H29N5O3S (491.61): C,
63.52; H, 5.95; N, 14.25; S, 6.52%. Found: C, 63.80; H,
5.72; N, 14.39; S, 6.76%.
4-Amino-5-(2-(4-chlorophenyl)hydrazono)-8,8-dimethyl-3-
phenyl-2-thioxo-2,3,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]
pyrimidin-6(5H)-one (10c)
Yellow crystals (acetic acid), yield 68% (3.35 g), m.p.
General procedure for the synthesis benzo[4,5]thieno[2,3-d]
pyrimidine derivatives 10a–f
177–179 °C; (IR (KBr) νmax 3484–3358, 3054, 2980,
1650, 1555, 1205; H-NMR (DMSO-d6, 200 MHz): δ =
1
8.39 (s, 1H, D2O exchangeable, NH), 7.52–7.23 (m, 9H,
C6H5, C6H4), 4.79 (s, 2H, D2O exchangeable, NH2), 2.72 (s,
2H, CH2), 1.07, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 180.6 (C-2), 179.9, 176.2, 165.4 (C-5, C-9a,
C-6), 142.9, 141.4, 139.8, 138.3, 135.6, 130.8, 127.5,
125.2, 123.6, 121.8, 120.5, 120.0 (2C6H5, C-4, C-4a, C-4b,
C-8a), 50.5 (C-7), 38.3 (C-8), 24.6 (2CH3); EIMS: m/z 494
To a solution of any of compounds 5a (3.24 g, 0.01 mol),
5b (3.71 g, 0.01 mol), 5c (3.58 g, 0.01 mol), 5d (4.05 g,
0.01 mol), 5e (3.54 g, 0.01 mol), or 5f (4.01 g, 0.01 mol) in
1,4-dioxan (40 mL) containing triethylamine (0.50 mL)
phenylisothiocyanate was added. The reaction mixture, in
each case, was heated under reflux for 6 h then poured onto

Medicinal Chemistry Research
[M]+ (42%); Analysis Calcd for C24H20ClN5OS2 (494.03):
C, 58.35; H, 4.08; N, 14.18; S, 12.98%. Found: C, 58.59; H,
4.29; N, 13.87; S, 13.14%.
132.2, 128.9, 125.6, 124.8, 122.8, 120.9, 120.3 (2C6H5, C-
4, C-4a, C-4b, C-8a), 52.6 (OCH3), 50.3 (C-7), 38.3 (C-8),
24.1 (2CH3); EIMS: m/z 490 [M]+ (18%); Analysis Calcd
for C25H22N4O3S2 (490.60): C, 61.20; H, 4.52; N, 11.42; S,
13.07%. Found: C, 61.38; H, 4.71; N, 11.62; S, 13.19%.
5-(2-(4-Chlorophenyl)hydrazono)-4-hydroxy-8,8-dimethyl-3-
phenyl-2-thioxo-2,3,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]
pyrimidin-6(5H)-one (10d)
General procedure for the synthesis of the triazolo
[4ʺ,5ʺ:5′,6′]benzo [1′,2′:4,5]thieno[2,3-d]pyrimidine
derivatives 12a–f
Pale yellow crystals (1,4-dioxan), yield 80% (3.95 g), m.p.
215–218 °C; (IR (KBr) νmax 3463–3342, 3056, 2983,
1654, 1550, 1206; H-NMR (DMSO-d6, 200 MHz): δ =
1
To a solution of any of 10a (4.59 g, 0.01 mol), 10b (4.60 g,
0.01 mol), 10c (4.94 g, 0.01 mol), 10d (4.54 g, 0.01 mol),
10e (4.89 g, 0.01 mol), or 10f (4.90 g, 0.01 mol) in 1,-
dioxan (50 mL) containing sodium acetate (2.0 g) hydro-
xylamine hydrochloride (1.40 g, 0.02 mol) was added. The
reaction mixture, in each case, was heated under reflux for
3 h then poured onto ice/water and the formed solid product
was collected by filtration.
10.22 (s, 1H, D2O exchangeable, OH), 8.35 (s, 1H, D2O
exchangeable, NH), 7.49–7.21 (m, 9H, C6H5, C6H4), 2.73
(s, 2H, CH2), 1.08, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 180.3 (C-2), 179.5, 176.8, 165.8 (C-5, C-
9a, C-6), 142.7, 142.1, 138.4, 136.8, 135.9, 132.5, 127.8,
126.8, 123.3, 121.5, 120.2, 119.3 (2C6H5, C-4, C-4a, C-4b,
C-8a), 50.8 (C-7), 38.1 (C-8), 24.3 (2CH3); EIMS: m/z 495
[M]+ (28%); Analysis Calcd for C24H19ClN4O2S2 (495.02):
C, 58.23; H, 3.87; N, 11.32; S, 12.96%. Found: C, 58.41; H,
3.69; N, 11.50; S, 13.25%.
10-Amino-5,5-dimethyl-2,9-diphenyl-4,5-dihydro-2H-[1,2,3]
triazolo[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]thieno[2,3-d]pyrimidin-8
(9 H)-one oxime (12a)
4-Amino-5-(2-(4-methoxyphenyl)hydrazono)-8,8-dimethyl-
3-phenyl-2-thioxo-2,3,7,8-tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidin-6(5H)-one (10e)
Pale yellow crystals (1,4-dioxan), yield 55% (2.50 g), m.p.
173–176 °C; (IR (KBr) νmax 3570–3329, 3057, 2981,
1
1656, 1553; H-NMR (DMSO-d6, 200 MHz): δ = 10.42 (s,
Yellow crystals (ethanol), yield 80% (3.91 g), m.p.
1H, D2O exchangeable, OH), 7.46–7.28 (m, 10 H, 2C6H5),
4.57 (s, 2H, D2O exchageable, NH2), 2.78 (s, 2H, CH2),
1.09, 1.02 (2 s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz):
δ = 176.5, 175.2, 173.6, 170.2 (C-8, C-6a, C-3a, C-10c),
145.2, 144.6, 141.7, 138.2, 135.1, 130.8, 127.3, 125.2,
124.5, 123.5, 122.6, 120.4 (2C6H5, C-10, C-10a, C-5a, C-
10b), 50.6 (C-4), 38.6 (C-7), 24.3 (2CH3); EIMS: m/z 455
[M]+ (20%); Analysis Calcd for C24H21N7OS (455.53): C,
63.28; H, 4.65; N, 21.52; S, 7.04%. Found: C, 63.52; H,
4.82; N, 21.73; S, 7.27%.
155–157 °C; (IR (KBr) νmax 3491–3339, 3054, 2985,
1
1688, 1656, 1551, 1203; H-NMR (DMSO-d6, 200 MHz):
δ = 8.36 (s, 1H, D2O exchangeable, NH), 7.43–7.27 (m,
9 H, C6H5, C6H4), 4.76 (s, 2H, D2O exchangeable, NH2),
3.72 (s, 3H, OCH3), 2.72 (s, 2H, CH2), 1.09, 1.02 (2s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 180.3(C-2),
179.5, 176.5, 165.8 (C-5, C-9a, C-6), 142.8, 142.6, 139.2,
137.6, 136.4, 132.3, 127.3, 125.7, 123.2, 121.6, 120.3,
119.6 (2C6H5, C-4, C-4a, C-4b, C-8a), 52.6 (OCH3), 50.2
(C-7), 38.1 (C-8), 24.7 (2CH3); EIMS: m/z 489 [M]+ (32%);
Analysis Calcd for C25H23N5O2S2 (489.61): C, 61.33; H,
4.73; N, 14.30; S, 13.10%. Found: C, 61.26; H, 4.53; N,
14.25; S, 13.28%.
10-Hydroxy-5,5-dimethyl-2,9-diphenyl-4,5-dihydro-2H-
[1,2,3]triazolo[4ʺ,5ʺ:5′,6′]-benzo[1′,2′:4,5]thieno[2,3-d]
pyrimidin-8(9 H)-one oxime (12b)
4-Hydroxy-5-(2-(4-methoxyphenyl)hydrazono)-8,8-
dimethyl-3-phenyl-2-thioxo-2,3,7,8-tetrahydrobenzo[4,5]
thieno[2,3-d]pyrimidin-6(5H)-one (10f)
Pale yellow crystals (1,4-dioxan), yield 55% (2.50 g), m.p.
203–206 °C; (IR (KBr) νmax 3587–3338, 3054, 2986,
1
1652, 1553; H-NMR (DMSO-d6, 200 MHz): δ = 10.28,
10.47 (2 s, 2H, D2O exchangeable, 2OH), 7.48–7.25 (m,
10 H, 2C6H5), 2.73 (s, 2H, CH2), 1.08, 1.04 (2 s, 6H, 2CH3);
13C-NMR (DMSO-d6, 75 MHz): δ = 176.8, 175.6, 173.2,
170.8 (C-8, C-6a, C-3a, C-10c), 144.8, 143.3, 140.9, 137.8,
135.1, 132.5, 127.8, 125.5, 123.2, 122.8, 122.3, 120.8
(2C6H5, C-10, C-10a, C-5a, C-10b), 50.3 (C-4), 38.2 (C-7),
24.1 (2CH3); EIMS: m/z 456 [M]+ (28%); Analysis Calcd
for C24H20N6O2S (456.52): C, 63.14; H, 4.42; N, 18.41; S,
7.02%. Found: C, 63.35; H, 4.36; N, 18.60; S, 7.29%.
Pale yellow crystals (1,4-dioxan), yield 69% (3.38 g), m.p.
150–153 °C; (IR (KBr) νmax 3480–3319, 3054, 2981,
1
1652, 1550; H-NMR (DMSO-d6, 200 MHz): δ = 10.29 (s,
1H, D2O exchangeable, OH), 8.33 (s, 1H, D2O exchange-
able, NH), 7.46–7.28 (m, 9H, C6H5, C6H4), 3.77 (s, 3H,
OCH3), 2.71 (s, 2H, CH2), 1.06, 1.03 (2s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 180.1 (C-2), 179.9, 176.5,
165.4 (C-5, C-9a, C-6), 142.8, 142.3, 138.2, 136.5, 135.3,

Medicinal Chemistry Research
10-Amino-2-(4-chlorophenyl)-5,5-dimethyl-9-phenyl-4,5-
dihydro-2H-[1,2,3]triazolo-[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]thieno
[2,3-d]pyrimidin-8(9 H)-one oxime (12c)
4.77; N, 20.19; S, 6.60%. Found: C, 62.08; H, 4.85; N,
20.38; S, 6.84%.
10-Hydroxy-2-(4-methoxyphenyl)-5,5-dimethyl-9-phenyl-
4,5-dihydro-2H-[1,2,3]triazolo-[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]
thieno[2,3-d]pyrimidin-8(9 H)-one oxime (12f)
Yellow crystals (1,4-dioxan), yield 82% (4.40 g), m.p.
233–237 °C; (IR (KBr) νmax 3593–3352, 3057, 2986,
1
1653, 1547; H-NMR (DMSO-d6, 200 MHz): δ = 10.45 (s,
1H, D2O exchangeable, OH), 7.53–7.25 (m, 9 H, C6H5,
C6H4), 4.54 (s, 2H, D2O exchageable, NH2), 2.76 (s, 2H,
CH2), 1.07, 1.03 (2 s, 6H, 2CH3); 13C-NMR (DMSO-d6,
75 MHz): δ = 176.8, 175.5, 173.2, 170.5 (C-8, C-6a, C-3a,
C-10c), 146.3, 143.3, 140.9, 138.6, 133.5, 130.5, 127.0,
125.8, 124.1, 123.7, 123.2, 120.8 (C6H5, C6H4, C-10, C-
10a, C-5a, C-10b), 50.8 (C-4), 38.9 (C-7), 24.2 (2CH3);
EIMS: m/z 489 [M]+ (35%); Analysis Calcd for
C24H20ClN7OS (489.98): C, 58.83; H, 4.11; N, 20.01; S,
6.54%. Found: C, 58.93; H, 4.29; N, 20.26; S, 6.80%.
Orange crystals (1,4-dioxan), yield 69% (3.35 g), m.p.
211–214 °C; (IR (KBr) νmax 3595–3334, 3055, 2983,
1
1652, 1550; H-NMR (DMSO-d6, 200 MHz): δ = 10.28,
10.43 (2 s, 2H, D2O exchangeable, 2OH), 7.56–7.22 (m,
9 H, C6H5, C6H4), 2.73 (s, 2H, CH2), 1.08, 1.04 (2 s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 176.8, 174.3,
173.4, 171.6 (C-8, C-6a, C-3a, C-10c), 143.9, 141.7, 140.6,
137.3, 134.2, 133.7, 128.0, 125.6, 124.8, 122.2, 121.5,
120.4 (C6H5, C6H4, C-10, C-10a, C-5a, C-10b), 52.8
(OCH3), 50.9 (C-4), 38.3 (C-7), 24.2 (2CH3); EIMS: m/z
486 [M]+ (24%); Analysis Calcd for C25H22N6O3S
(486.55): C, 61.71; H, 4.56; N, 17.27; S, 6.59%. Found: C,
61.93; H, 4.80; N, 17.41; S, 6.83%.
2-(4-Chlorophenyl)-10-hydroxy-5,5-dimethyl-9-phenyl-4,5-
dihydro-2H-[1,2,3]triazolo-[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]thieno
[2,3-d]pyrimidin-8(9 H)-one oxime (12d)
General procedure for the synthesis of the thieno[2,3-g]
Orange crystals (1,4-dioxan), yield 76% (3.72 g), m.p.
chromene derivatives 14a-m
155–158 °C; (IR (KBr) νmax 3565–3314, 3055, 2983,
1650, 1555; H-NMR (DMSO-d6, 200 MHz): δ = 10.25,
1
To a solution of any of compounds 5a (3.24 g, 0.01 mol), 5b
(3.71 g, 0.01 mol), 5c (3.58 g, 0.01 mol), 5d (4.05 g,
0.01 mol), 5e (3.54 g, 0.01 mol), or 5f (4.01 g, 0.01 mol) in
1,4-dioxan (40 mL) containing triethylamine (0.50 mL)
either of α-cyanocinnamate (1.54 g, 0.01 mol) or ethyl α-
cyanocinnamate (2.01 g, 0.01 mol) was added. The reaction
mixture, in each case, was heated under reflux for 6 h then
poured onto ice/water containing few drops of hydrochloric
acid and the formed solid product was collected by filtration.
10.49 (2 s, 2H, D2O exchangeable, 2OH), 7.53–7.25 (m,
9 H, C6H5, C6H4), 2.76 (s, 2H, CH2), 1.07, 1.02 (2 s, 6H,
2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 176.7, 174.9,
173.6, 170.3 (C-8, C-6a, C-3a, C-10c), 144.5, 142.7, 140.3,
137.5, 134.8, 132.1, 128.2, 125.9, 124.2, 123.3, 121.8,
120.2 (2C6H5, C-10, C-10a, C-5a, C-10b), 50.6 (C-4), 38.5
(C-7), 24.4 (2CH3); EIMS: m/z 490 [M]+ (17%); Analysis
Calcd for C24H19ClN6O2S (490.96): C, 58.71; H, 3.90; N,
17.12; S, 6.53%. Found: C, 58.48; H, 4.15; N, 17.37; S,
6.72%.
2,6-Diamino-9,9-dimethyl-8-phenyl-4-(2-phenylhydrazono)-
8,9-dihydro-4H-thieno[2,3-g]chromene-3,7-dicarbonitrile
(14a)
10-Amino-2-(4-methoxyphenyl)-5,5-dimethyl-9-phenyl-4,5-
dihydro-2H-[1,2,3]triazolo-[4ʺ,5ʺ:5′,6′]benzo[1′,2′:4,5]thieno
[2,3-d]pyrimidin-8(9 H)-one oxime (12e)
Yellow crystals (1,4-dioxan), yield 67% (3.20 g), m.p.
120–123 °C; IR (KBr) νmax 3468–3339, 3054, 2985, 2223,
2220, 1654, 1553; H-NMR (DMSO-d6, 200 MHz): δ =
1
Pale brown crystals (1,4-dioxan), yield 80% (3.88 g), m.p.
266–269 °C; (IR (KBr) νmax 3574–3341, 3053, 2982,
1650, 1552; H-NMR (DMSO-d6, 200 MHz): δ = 10.47 (s,
8.39 (s, 1H, D2O exchangeable, NH), 6.13 (s, 1H, H-8),
7.41–7.26 (m, 10H, 2C6H5), 4.59, 5.39 (2s, 4H, D2O
exchangeable, 2NH2), 1.11, 1.05 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 179.3 (C-4), 144.2, 143.1, 138.6,
137.8, 134.8, 132.1, 128.6, 125.8, 124.7, 123.2, 122.4,
122.9, 121.6, 120.4, 120.3, 119.6 (2C6H5, C-2, C-3, C-6, C-
7, C-3a, C-4a, C-8a, C-9a), 38.6 (C-9), 26.9 (C-8), 117.8,
166.7 (2CN), 24.4 (2CH3); EIMS: m/z 478 [M]+ (48%);
Analysis Calcd for C27H22N6OS (478.57): C, 67.76; H,
4.63; N, 17.56; S, 6.70%. Found: C, 67.84; H, 4.75; N,
17.80; S, 6.93%.
1
1H, D2O exchangeable, OH), 7.56–7.22 (m, 9 H, C6H5,
C6H4), 4.57 (s, 2H, D2O exchageable, NH2), 3.72 (s, 3 H,
OCH3), 2.73 (s, 2H, CH2), 1.07, 1.05 (2 s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 176.3, 173.4, 172.8, 170.6
(C-8, C-6a, C-3a, C-10c), 145.8, 142.7, 141.3, 138.3, 133.2,
130.9, 126.7, 125.2, 124.8, 123.3, 122.6, 121.4 (C6H5,
C6H5, C-10, C-10a, C-5a, C-10b), 52.8 (OCH3), 50.4 (C-4),
38.3 (C-7), 24.5 (2CH3); EIMS: m/z 485 [M]+ (42%);
Analysis Calcd for C25H23N7O2S (485.56): C, 61.84; H,

Medicinal Chemistry Research
2-Amino-6-hydroxy-9,9-dimethyl-8-phenyl-4-(2-
phenylhydrazono)-8,9-dihydro-4H-thieno[2,3-g]chromene-
3,7-dicarbonitrile (14b)
128.3, 126.7, 125.2, 123.3, 122.4, 121.8, 121.3, 121.0,
120.4, 119.6 (2C6H5, C-2, C-3, C-6, C-7, C-3a, C-4a, C-8a,
C-9a), 116.6 (CN), 52.9 (OCH2CH3), 38.7 (C-9), 26.4 (C-
8), 24.5 (2CH3), 19.6 (OCH2CH3); EIMS: m/z 526 [M]+
(22%); Analysis Calcd for C29H26N4O4S (526.61): C,
66.14; H, 4.98; N, 10.64; S, 6.09%. Found: C, 66.26; H,
5.18; N, 10.19; S, 6.18%.
Yellow crystals (1,4-dioxan), yield 78% (3.73 g), m.p.
187–190 °C; IR (KBr) νmax 3583–3369, 3056, 2985, 2224,
1
2220, 1651, 1557; H-NMR (DMSO-d6, 200 MHz): δ =
10.29 (s, 1H, D2O exchangeable, OH), 8.37 (s, 1H, D2O
exchangeable, NH), 6.11 (s, 1H, H-8), 7.44–7.23 (m, 10H,
2C6H5), 4.68 (s, 2H, D2O exchangeable, NH2), 1.14, 1.04
(2s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 179.6
(C-4), 144.6, 142.9, 138.3, 137.5, 135.6, 132.4, 128.8,
127.6, 124.2, 123.6, 122.8, 122.1, 121.6, 121.3, 120.8,
120.4 (2C6H5, C-2, C-3, C-6, C-7, C-3a, C-4a, C-8a, C-9a),
117.5, 116.9 (2CN), 38.9 (C-9), 26.9 (C-8), 24.6 (2CH3);
EIMS: m/z 479 [M]+ (35%); Analysis Calcd for
C27H21N5O2S (479.55): C, 67.62; H, 4.41; N, 14.60; S,
6.69%. Found: C, 67.74; H, 4.63; N, 14.79; S, 6.82%.
2,6-Diamino-4-(2-(4-chlorophenyl)hydrazono)-9,9-dimethyl-
8-phenyl-8,9-dihydro-4H-thieno[2,3-g]chromene-3,7-
dicarbonitrile (14e)
Pale orange crystals (1,4-dioxan), yield 65% (3.34 g), m.p.
186–189 °C; (IR (KBr) νmax 3439–3314, 3057, 2982,
1
2222, 2220, 1654, 1550; H-NMR (DMSO-d6, 200 MHz):
δ = 8.36 (s, 1H, D2O exchangeable, NH), 6.12 (s, 1H, H-8),
7.49–7.22 (m, 9H, C6H5, C6H4), 4.62, 5.35 (2s, 4H, D2O
exchangeable, 2NH2), 1.10, 1.04 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 179.6 (C-4), 143.8, 143.1, 139.2,
135.2, 133.9, 132.0, 128.8, 127.3, 126.8, 125.7, 123.4,
122.1, 122.5, 121.3, 120.1, 119.5 (C6H5, C6H4, C-2, C-3, C-
6, C-7, C-3a, C-4a, C-8a, C-9a), 117.4, 116.5 (2CN), 38.7
(C-9), 26.3 (C-8), 24.4 (2CH3); EIMS: m/z 513 [M]+ (34%);
Analysis Calcd for C27H21ClN6OS (513.01): C, 63.21; H,
4.13; N, 16.38; S, 6.25%. Found: C, 63.47; H, 4.29; N,
16.52; S, 6.41%.
Ethyl 2,6-diamino-7-cyano-9,9-dimethyl-8-phenyl-4-(2-
phenylhydrazono)-8,9-dihydro-4H-thieno[2,3-g]chromene-
3-carboxylate (14c)
Pale brown crystals (1,4-dioxan), yield 72% (3.78 g), m.p.
233–236 °C; IR (KBr) νmax 3469–3369, 3050, 2982, 2220,
1
1653, 1550; H-NMR (DMSO-d6, 200 MHz): δ = 8.35 (s,
1H, D2O exchangeable, NH), 6.13 (s, 1H, H-8), 7.41–7.26
(m, 10H, 2C6H5), 4.65, 5.28 (2s, 4H, D2O exchangeable,
2NH2), 4.22 (q, 2H, J = 6.93 Hz, OCH2CH3), 1.15 (t, 3H, J
= 6.93 Hz, OCH2CH3), 1.13, 1.02 (2s, 6H, 2CH3); 13C-
NMR (DMSO-d6, 75 MHz): δ = 179.6 (C-4), 144.6, 142.9,
138.3, 137.5, 135.6, 132.4, 128.8, 126.4, 124.2, 122.8,
122.3, 122.1, 121.6, 121.3, 120.8, 120.4 (2C6H5, C-2, C-3,
C-6, C-7, C-3a, C-4a, C-8a, C-9a), 117.0 (CN), 52.8
(OCH2CH3), 38.9 (C-9), 26.9 (C-8), 24.6 (2CH3), 19.2
(OCH2CH3); EIMS: m/z 525 [M]+ (48%); Analysis Calcd
for C29H27N5O3S (525.62): C, 66.27; H, 5.18; N, 13.32; S,
6.10%. Found: C, 66.48; H, 5.25; N, 13.57; S, 6.26%.
2-Amino-4-(2-(4-chlorophenyl)hydrazono)-6-hydroxy-9,9-
dimethyl-8-phenyl-8,9-dihydro-4H-thieno[2,3-g]chromene-
3,7-dicarbonitrile (14f)
Yellow crystals (1,4-dioxan), yield 80% (4.10 g), m.p.
266–270 °C; (IR (KBr) νmax 3563–3349, 3055, 2983,
1
2223, 2220, 1654, 1553; H-NMR (DMSO-d6, 200 MHz):
δ = 10.32 (s, 1H, D2O exchangeable, OH), 8.39 (s, 1H, D2O
exchangeable, NH), 6.13 (s, 1H, H-8), 7.48–7.21 (m, 9H,
C6H5, C6H4), 4.63 (s, 2H, D2O exchangeable, NH2), 1.12,
1.05 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ =
179.8 (C-4), 143.3, 142.2, 138.6, 136.9, 133.4, 132.8,
129.0, 127.5, 125.6, 123.1, 122.9, 122.3, 121.4, 121.0,
120.6, 120.1 (C6H5, C6H4, C-2, C-3, C-6, C-7, C-3a, C-4a,
C-8a, C-9a), 117.1, 116.7 (2CN), 38.9 (C-9), 26.7 (C-8),
24.3 (2CH3); EIMS: m/z 514 [M]+ (42%); Analysis Calcd
for C27H20ClN5O2S (514.00): C, 63.09; H, 3.92; N, 13.63S,
6.24%. Found: C, 62.95; H, 4.19; N, 13.58; S, 6.57%.
Ethyl 2-amino-7-cyano-6-hydroxy-9,9-dimethyl-8-phenyl-4-
(2-phenylhydrazono)-8,9-dihydro-4H-thieno[2,3-g]
chromene-3-carboxylate (14d)
Pale brown crystals (1,4-dioxan), yield 78% (4.10 g), m.p.
195–197 °C; IR (KBr) νmax 3573–3324, 3050, 2982, 2221,
1
1650, 1554; H-NMR (DMSO-d6, 200 MHz): δ = 10.42 (s,
1H, D2O exchangeable, OH), 8.32 (s, 1H, D2O exchange-
able, NH), 6.16 (s, 1H, H-8), 7.44–7.25 (m, 10H, 2C6H5),
4.68 (s, 2H, D2O exchangeable, NH2), 4.21 (q, 2H, J =
5.79 Hz, OCH2CH3), 1.15 (t, 3H, J = 5.79 Hz, OCH2CH3),
1.15, 1.04 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz):
δ = 179.2 (C-4), 143.8, 142.2, 138.6, 136.3, 135.2, 133.9,
Ethyl 2,6-diamino-4-(2-(4-chlorophenyl)hydrazono)-7-
cyano-9,9-dimethyl-8-phenyl-8,9-dihydro-4H-thieno[2,3-g]
chromene-3-carboxylate (14g)
Pale brown crystals (1,4-dioxan), yield 80% (4.48 g), m.p.
189–192 °C; (IR (KBr) νmax 3448–3329, 3050, 2982,

Medicinal Chemistry Research
1
2222, 1650, 1554; H-NMR (DMSO-d6, 200 MHz): δ =
16.52; S, 6.30%. Found: C, 66.03; H, 4.68; N, 16.75; S,
6.52%.
8.38 (s, 1H, D2O exchangeable, NH), 6.15 (s, 1H, H-8),
7.49–7.23 (m, 9H, C6H5, C6H4), 4.63, 5.25 (2s, 4H, D2O
exchangeable, 2NH2), 4.24 (q, 2H, J = 7.19 Hz,
OCH2CH3), 1.14 (t, 3H, J = 7.19 Hz, OCH2CH3), 1.13,
1.02 (2s, 6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ =
179.3 (C-4), 143.3, 142.6, 138.8, 136.1, 135.8, 132.2,
128.8, 126.4, 125.3, 124.3, 123.4, 122.8, 121.1, 121.6,
120.3, 119.4 (C6H5, C6H4, C-2, C-3, C-6, C-7, C-3a, C-4a,
C-8a, C-9a), 117.0 (CN), 52.4 (OCH2CH3), 38.5 (C-9), 26.3
(C-8), 24.3 (2CH3), 19.4 (OCH2CH3); EIMS: m/z 560 [M]+
(48%); Analysis Calcd for C29H26ClN5O3S (560.07): C,
62.19; H, 4.68; N, 12.50; S, 5.73%. Found: C, 62.30; H,
4.72; N, 12.69; S, 5.82%.
2-Amino-6-hydroxy-4-(2-(4-methoxyphenyl)hydrazono)-9,9-
dimethyl-8-phenyl-8,9-dihydro-4H-thieno[2,3-g]chromene-
3,7-dicarbonitrile (14k)
Yellow crystals (1,4-dioxan), yield 77% (3.91 g), m.p.
230–234 °C; (IR (KBr) νmax 3579–3318, 3055, 2982,
1
2224, 2220, 1653, 1556; H-NMR (DMSO-d6, 200 MHz):
δ = 10.36 (s, 1H, D2O exchangeable, OH), 8.33 (s, 1H, D2O
exchangeable, NH), 6.11 (s, 1H, H-8), 7.52–7.24 (m, 9H,
C6H5, C6H4), 4.60 (s, 2H, D2O exchangeable, NH2), 3.69 (s,
3H OCH3), 1.15, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 179.4 (C-4), 145.1, 143.6, 137.9, 134.8,
133.5, 132.1, 127.5, 126.1, 125.9, 123.4, 122.7, 122.1,
121.7, 120.3, 120.1, 119.7 (C6H5, C6H4, C-2, C-3, C-6, C-7,
C-3a, C-4a, C-8a, C-9a), 117.3, 116.9 (2CN), 52.6 (OCH3),
38.6 (C-9), 26.3 (C-8), 24.4 (2CH3); EIMS: m/z 509 [M]+
(28%); Analysis Calcd for C28H23N5O3S (509.58): C,
66.00; H, 4.55; N, 13.74, S, 6.29%. Found: C, 65.80; H,
4.39; N, 13.83; S, 6.41%.
Ethyl 2-amino-4-(2-(4-chlorophenyl)hydrazono)-7-cyano-6-
hydroxy-9,9-dimethyl-8-phenyl-8,9-dihydro-4H-thieno[2,3-
g]chromene-3-carboxylate (14h)
Brown crystals (1,4-dioxan), yield 58% (3.25 g), m.p.
210–213 °C; (IR (KBr) νmax 3559–3346, 3050, 2980,
1
2220, 1650, 1550; H-NMR (DMSO-d6, 200 MHz): δ =
10.44 (s, 1H, D2O exchangeable, OH), 8.32 (s, 1H, D2O
exchangeable, NH), 6.16 (s, 1H, H-8), 7.44–7.25 (m, 9 H,
C6H5, C6H4), 4.69 (s, 2H, D2O exchangeable, NH2), 4.26
(q, 2H, J = 5.79 Hz, OCH2CH3), 1.13 (t, 3H, J = 5.79 Hz,
OCH2CH3), 1.17, 1.03 (2s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 178.8 (C-4), 145.2, 142.7, 138.9, 137.4,
135.8, 133.2, 126.8, 125.4, 124.7, 123.1, 123.0, 122.8,
121.6, 121.2, 120.4, 119.9 (C6H5, C6H4, C-2, C-3, C-6, C-7,
C-3a, C-4a, C-8a, C-9a), 116.8 (CN), 52.4 (OCH2CH3),
38.9 (C-9), 26.2 (C-8), 24.5 (2CH3), 19.5 (OCH2CH3);
EIMS: m/z 561 [M]+ (38%); Analysis Calcd for
C29H25ClN4O4S (561.05): C, 62.08; H, 4.49; N, 9.99; S,
5.72%. Found: C, 61.93; H, 4.73; N, 10.07; S, 5.95%.
Ethyl 2,6-diamino-7-cyano-4-(2-(4-methoxyphenyl)
hydrazono)-9,9-dimethyl-8-phenyl-8,9-dihydro-4H-thieno
[2,3-g]chromene-3-carboxylate (14l)
Pale brown crystals (1,4-dioxan), yield 77% (4.27 g), m.p.
240–243 °C; (IR (KBr) νmax 3443–3329, 3055, 2982,
1
2222, 1653, 1550; H-NMR (DMSO-d6, 200 MHz): δ =
8.36 (s, 1H, D2O exchangeable, NH), 6.12 (s, 1H, H-8),
7.47–7.25 (m, 9H, C6H5, C6H4), 4.68, 5.28 (2s, 4H, D2O
exchangeable, 2NH2), 4.21 (q, 2H, J = 7.36 Hz,
OCH2CH3), 3.70 (s, 3H, OCH3), 1.12 (t, 3H, J = 7.36 Hz,
OCH2CH3), 1.09, 1.02 (2s, 6H, 2CH3); 13C-NMR (DMSO-
d6, 75 MHz): δ = 179.2 (C-4), 145.6, 143.2, 138.6, 136.6,
135.2, 133.8, 128.5, 127.3, 126.9, 124.6, 123.2, 122.7,
121.4, 121.2, 120.2, 120.0 (2C6H5, C-2, C-3, C-6, C-7, C-
3a, C-4a, C-8a, C-9a), 116.8 (CN), 52.9 (OCH2CH3), 52.6
(OCH3), 38.3 (C-9), 26.4 (C-8), 24.5 (2CH3), 19.6
(OCH2CH3); EIMS: m/z 555 [M]+ (28%); Analysis Calcd
for C30H29N5O4S (555.65): C, 64.85; H, 5.26; N, 12.60; S,
5.77%. Found: C, 64.94; H, 5.07; N, 12.48; S, 5.79%.
2,6-Diamino-4-(2-(4-methoxyphenyl)hydrazono)-9,9-
dimethyl-8-phenyl-8,9-dihydro-4H-thieno[2,3-g]chromene-
3,7-dicarbonitrile (14i)
Pale orange crystals (1,4-dioxan), yield 83% (4.21 g), m.p.
244–248 °C; (IR (KBr) νmax 3459–3316, 3053, 2982,
1
2225, 2220, 1652, 1550; H-NMR (DMSO-d6, 200 MHz):
δ = 8.39 (s, 1H, D2O exchangeable, NH), 6.14 (s, 1H, H-8),
7.46–7.25 (m, 9H, C6H5, C6H4), 4.64, 5.32 (2s, 4H, D2O
exchangeable, 2NH2), 3.71 (s, 3H, OCH3), 1.08, 1.03 (2s,
6H, 2CH3); 13C-NMR (DMSO-d6, 75 MHz): δ = 179.9 (C-
4), 145.2, 143.6, 139.6, 135.4, 134.3, 132.6, 127.3, 126.3,
125.9, 124.7, 123.6, 122.9, 122.2, 121.8, 120.7, 120.3
(C6H5, C6H4, C-2, C-3, C-6, C-7, C-3a, C-4a, C-8a, C-9a),
117.2, 116.9 (2CN), 52.6 (OCH3), 38.5 (C-9), 26.5 (C-8),
24.6 (2CH3); EIMS: m/z 508 [M]+ (46%); Analysis
Calcd for C28H24N6O2S (508.59): C, 66.12; H, 4.76; N,
Ethyl 2-amino-7-cyano-6-hydroxy-4-(2-(4-methoxyphenyl)
hydrazono)-9,9-dimethyl-8-phenyl-8,9-dihydro-4H-thieno
[2,3-g]chromene-3-carboxylate (14m)
Brown crystals (1,4-dioxan), yield 78% (4.33 g), m.p.
188–191 °C; (IR (KBr) νmax 3574–3325, 3050, 2980, 2221,
1
1653, 1551; H-NMR (DMSO-d6, 200 MHz): δ = 10.48 (s,
1H, D2O exchangeable, OH), 8.31 (s, 1H, D2O exchange-
able, NH), 6.19 (s, 1H, H-8), 7.48–7.25 (m, 9H, C6H5,

Medicinal Chemistry Research
C6H4), 4.71 (s, 2H, D2O exchangeable, NH2), 4.23 (q, 2H, J
= 6.02 Hz, OCH2CH3), 3.68 (s, 3H, OCH3), 1.12 (t, 3H, J =
6.02 Hz, OCH2CH3), 1.19, 1.01 (2s, 6H, 2CH3); 13C-NMR
(DMSO-d6, 75 MHz): δ = 178.5 (C-4), 144.8, 143.3, 138.6,
136.1, 135.4, 133.8, 127.4, 126.5, 125.2, 123.6, 123.0,
122.5, 121.8, 121.7, 120.4, 119.4 (C6H5, C6H4, C-2, C-3, C-
6, C-7, C-3a, C-4a, C-8a, C-9a), 116.6 (CN), 52.3
(OCH2CH3), 38.6 (C-9), 26.5 (C-8), 24.2 (2CH3), 19.3
(OCH2CH3); EIMS: m/z 556 [M]+ (40%); Analysis Calcd
for C30H28N4O5S (556.63): C, 64.73; H, 5.07; N, 10.07; S,
5.76%. Found: C, 64.69; H, 4.95; N, 10.26; S, 5.83%.
Darvish F, Balalaei S, Chadegani F, Salehi P (2007) Diammonium
hydrogen. phosphate as a neutral and efficient catalyst for
synthesis of 1,8-dioxo-. octahydroxanthene derivatives in aqu-
eous media. Synth Commun 37:1059–1066
Deb ML, Bhuyan PJ (2005) Uncatalysed Knoevenagel condensation in
aqueous mediumat room temperature. Tetrahedron Lett
46:6453–6456
Drew MGB (1982) Phenylhydrazone derivatives of dimedone:
hydrogen bonding, spectral (I3C and H nuclear magnetic reso-
nance) and conformational considerations. Crystal and molecular
structures of 5,5-dimethylcyclohexane-1, 2,3-trione 2-(4-methyl-
phenylhydrazone) (1) and 5, 5-dimethylcyclohexane-1,2,3-trione
2-(4-nitrophenylhydrazone) (2).
J Chem Soc Perkin Trans
II:1297–1303
Dutra LG, Saibert C, Vicentini DS, Sa MM (2014) Diazo transfer
reaction to 1,3-dicarbonyl compounds with sulfonyl azides cata-
lyzed by molecular sieves. J Mol Catal A: Chem 386:35–41
Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D,
Marmsater F, Robinson JE, Gross SD, Martinson M, Alle S,
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Conclusion
In conclusion, an efficient and practical synthesis of new
series of thiophene derivatives were synthesized and char-
acterized. The c-Met kinase activity and the anti-
proliferative activities of compounds were evaluated
against five c-Met-dependent cancer cell lines (A549, HT-
29, MKN-45, U87MG, and SMMC-7721) and one c-Met-
independent cancer cell line (H460) the results showed that
compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h, 12c, 12d, 12f, and
14f were the most active compounds. The Pim-1 kinase
inhibition activity of some selected compounds showed that
compounds 3c, 6c, 8g, 12c, and 14f were high potencies
toward Pim-1 kinases.
Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer
RT, Day ML (1995) Hepatocyte growth factor and its receptor (c-
MET) in prostatic carcinoma. Am J Pathol 147:386–396
Ilangovan A, Malayappasamy S, Muralidharan S, Maruthamuthu S
(2011)
A highly efficient green synthesis of 1, 8-dioxo-
octahydroxanthenes. Chem Cent 5:81
Jiao C, Jian Sm Chao-guo Y (2011) Synthesis of spiro dihydrofurans
and 1,8-dioxo-xanthenes via DABCO catalyzed tandem reaction
of aldehyde with cyclohexane-1,3-dione and dimedone. Chem
Res Chin Univ 27:49–53
Compliance with ethical standards
Jin TS, Zhang JS, Wang AQ, Li TS (2006) Ultrasound-assisted
synthesis of 1,8-dioxo-octahydroxanthene derivatives catalyzed
by p-dodecylbenzenesulfonic acid in aqueous media. Ultrason
Sonochem 13:220–224
Conflict of interest The authors declare that they have no competing
interests.
Khurana JM, Magoo D (2009) Efficient one-pot syntheses of 2H-
indazolo[2,1-b] phthalazine-triones by catalytic H2SO4 in
water–ethanol or ionic liquid. Tetrahedron Lett 52:7300–7303
Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus
DM, Kattan MW, Gerald WL, Woude GF (2002) High expres-
sion of the Met receptor in prostate cancer metastasis to bone.
Urology 60:1113–1117
Li S, Huang Q, Liu Y, Zhang X, Liu S, He C, Gong P (2013) Design,
synthesis and antitumour activity of bisquinoline derivatives
connected by 4-oxy-3-fluoroaniline moiety. Eur J Med Chem
64:62–73
Liu J, Nie M, Wang Y, Hu J, Zhang F, Gao Y, Liu Y, Gong P (2016)
Design, synthesis and structure-activity relationships of novel 4-
phenoxyquinoline derivatives containing 1,2,4-triazolone moiety
as c-Met kinase inhibitors. Eur J Med Chem 123:431–446
Maripi S, Korupolu RB, Madasu SB (2017) Nano nickel-cobalt ferrite
catalysed one-pot multi-component synthesis of xanthenediones
and acridinediones GSC 7:70–84
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