Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors

Article abstract of DOI:10.1007/s11030-019-10008-x

Abstract: A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibitors by Ellman’s method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over acetylcholines

Full text of DOI:10.1007/s11030-019-10008-x

Molecular Diversity
https://doi.org/10.1007/s11030-019-10008-x
ORIGINAL ARTICLE
Design and synthesis of benzodiazepine‑1,2,3‑triazole hybrid
derivatives as selective butyrylcholinesterase inhibitors
1
2
3
1
1
4
Mehrdad Mehrazar · Mahdi Hassankalhori · Mahsa Toolabi · Fereshteh Goli · Setareh Moghimi · Hamid Nadri ·
5
1
3,6
Syed Nasir Abbas Bukhari · Loghman Firoozpour · Alireza Foroumadi
Received: 20 June 2019 / Accepted: 18 October 2019
©
Springer Nature Switzerland AG 2019
Abstract
A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibi-
tors by Ellman’s method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over ace-
tylcholinesterase. The most potent compound was 3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one, identiꢀed as a submicromolar inhibitor of BuChE
with IC value of 0.2 µM. In addition, the amyloid-β self-aggregation evaluation studies for selected compounds showed
5
0
potent inhibitory eꢁects compared to donepezil. The docking and cell viability studies supported the potential of compound
b-6 as signiꢀcant BuChE inhibitor.
9
Graphic abstract
Keywords Alzheimer’s disease · Benzodiazepine · 1,2,3-Triazole · Butyrylcholinesterase inhibitor · Click chemistry
Electronic supplementary material The online version of this
Introduction
article (https://doi.org/10.1007/s11030-019-10008-x) contains
supplementary material, which is available to authorized users.
Dementia is one of the most widespread illnesses, aꢁect-
*
*
Loghman Firoozpour
roozpour@gmail.com
ing the lives of millions of people around the world [1–3].
Alzheimer’s disease (AD) is a neurodegenerative, chronic,
and progressive disease, associated with losses of mental
capabilities in terms of memory and learning. These dis-
abilities gradually lead to the tragic isolation of an individual
ꢀ
Alireza Foroumadi
aforoumadi@yahoo.com
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Molecular Diversity
due to the inability of communication with other people and
the world. AD accounts for nearly 70% of dementia cases in
people 65 years of age or older and classiꢀed as the apparent
consequence of brain cells death especially pyramidal cells
eꢁects of those molecules containing this heterocyclic core
[16]. This special chemical structure has introduced unique
derivatives from which a wide range of bioactivities such
as anticonvulsant, antifungal, antibacterial and anti-inꢂam-
matory activities are observed [17]. On the basis of recent
reports, some compounds containing benzodiazepine core
exhibited anticholinesterase eꢁects including: diazepam and
cyclopenin [18, 19]. Therefore, the structure of benzodiaz-
epine can be proposed as the scaꢁold for the production of
bioactive compounds with anticholinesterase eꢁects [20].
1,2,3-Triazoles are key structural motif in diꢁerent areas
of science from bioactive compounds to material sciences
[21–23]. The presence of two H-bond acceptors, capable
of forming signiꢀcant interactions with the biomolecular
targets through H-bonding, π–π stacking, and dipole inter-
actions and the unique chemical stability of this core in
biological environments, results in improved pharmacoki-
netic and toxicity properties of compounds with this core.
Moreover, the highly eꢃcient preparation method, click
reaction, has conꢀrmed the interest of organic and medici-
nal chemists towards the development of highly desirable
and green approaches for the construction of triazole-con-
taining molecules [24–28]. The presence of triazole ring in
diꢁerent systems enhanced the anti-AChE activity in vari-
ous synthesized compounds [29–32]. Our look in the design
strategy was focused on the structure of donepezil and our
tries devoted to mimic the aromatic moiety of the donepezil
with another aromatic group. Donepezil is a synthetic and
reversible acetylcholinesterase inhibitor, exhibiting improve-
ments in cognition and memory in AD patients. Based on
the abovementioned points and our previous expertise in
the synthesis of cholinesterase inhibitors [33–37], in this
paper, we designed and synthesized some new anticholinest-
erase agents by hybridization of small molecules, benzodi-
azepine and triazole, to target pathological routes with AD
[38] (Fig. 1).
[
4]. The tremendous impact on abilities of people with this
disease has urged the needs for persistent care by family
members and (un)paid caregivers along with expensive ther-
apies. Accordingly, to both reduce economic consequences
of the disease on society and increase the life expectancy in
an old population, a growing budget should be applied to
develop novel treatment approaches [5, 6].
There are diꢁerent hypotheses about the causes of this
destruction process including: protein aggregation, ROS pro-
duction, oxidative stress, mitochondrial dysfunction, neuro-
inꢂammation, and cholinergic depletion. Protein aggrega-
tion is the biochemical process which led to the formation
of abnormal protein within and outside of the brain cells
including senile plaques and neuroꢀbrillary tangles. The
plaques come to existence because of the breakdown of the
amyloid precursor protein (APP) to an insoluble β-amyloid
peptide (Aβ) [7–9]. These pathological characters lead to the
loss of neuronal synapses and pyramidal neurons by which
the devastating eꢁects of the disease occur [10, 11]. Oxida-
tive stress and mitochondrial dysfunction are also increased
by protein aggregation, resulting in the generation of ample
reactive oxygen and nitrogen species and consequently neu-
ronal damage.
The ꢀrst proposed theory to explain AD, the cholinergic
hypothesis, deals with the decline in cholinergic activity of
some areas of brain which are vital in memory and cognitive
activities. The main idea of this theory is based on utilizing
cholinergic agonists [12] and acetylcholinesterase inhibitors
(
AChEIs), eꢃciently providing the promising improvement
in cognitive functions by increasing acetylcholine level
ACh). Acetylcholine hydrolysis occurs by two cholinester-
(
ase forms, acetyl- (AChE, EC 3.1.1.7) and butyrylcholinest-
erase (BuChE, EC3.1.1.8). The level of AChE declines as
AD progresses, so BuChE handles its function and becomes
important in advanced levels of the disease [13, 14]. In
recent years, the speciꢀc inhibition of BuChE, expressed
in those parts of brain which are involved in cognition, has
opened new horizons in the treatment of neurodegenera-
tive disease. By considering all these facts and similarities
between these enzymes in terms of amino acid sequence,
overall structure, and mechanism, we can conclude that a
promising approach for AD treatment could be the inhibi-
tion of ChE and thus keeping the synaptic level of ACh at its
proper quantity [15]. As a result, the development of drugs
capable of preventing the acetylcholine hydrolysis is a chal-
lenge which should be approached by developing new bioac-
tive compounds as cholinesterase inhibitors.
Results and discussion
Chemistry
As outlined in Scheme 1, the reaction between benzene
1,2-diamine and 5,5-dimethylcyclohexane-1,3-dione (dime-
done) in reꢂuxing toluene aꢁorded compound 3 [39, 40],
which was cyclized upon the reaction with propargylated
aromatic aldehydes 6a–c. The propargylated derivatives
were obtained from the reaction of diꢁerently substituted
hydroxyl benzaldehydes 4a–c and propargyl bromide in the
presence of K CO in DMF at 90 °C [41–43]. In the last
2
3
step, the target compounds were prepared from the click
Benzodiazepines have become widespread in the drug
market, related to their eꢁectiveness, safety, and low side
reaction of 7a–c, benzyl halide derivatives and sodium azide
in H O/t-BuOH (Scheme 1). By utilizing diꢁerent ortho-,
2
1
3

Molecular Diversity
Fig. 1 Design strategy
Donepezil
ChE inhibitor
Target compounds, 9a-c
9
a: ortho substituted derivatives
9
b: meta substituted derivatives
c: para substituted derivatives
The core structure
9
of classical Benzodiazepines
meta- and para-substituted aromatic aldehydes, three series
of compounds were synthesized and evaluated as cholinest-
erase inhibitors.
at para-position. In para-substituted ꢂuorine-, chlorine- and
bromine-containing derivatives, those compounds that con-
taining the most electronegative atom, ꢂuorine, possessed
the worst inhibitory activities. Conversely, the presence of
ꢂuorine at meta-position led to the better or same activi-
ties compared to chlorine-containing derivatives. Therefore,
moving the ꢂuorine atom from ortho-position to meta-posi-
tion increased the activity, while the reduced activity was
observed in para-ꢂuorine-containing derivatives compared
to meta-ꢂuorine-containing analogues. The same pattern
was observed by moving nitro group from meta to para-
position (Table 1).
Cholinesterase activity evaluation
The activity of three series of compounds against AChE and
BuChE was evaluated by modiꢀed Ellman’s method, and the
following results are obtained [44]. The results are shown
as IC and the percent of inhibition in Table 1. None of
5
0s
the target compounds is active against AChE, while most
of them are potent and selective BuChE inhibitors at micro-
molar and sub-micro molar ranges. Among the synthesized
compounds, 9a-4 and 9b-6 showed IC values of 0.4 μM
Docking studies
5
0
and 0.2 μM, respectively, which are 17–34 times more potent
than donepezil with IC value of 6.9 μM. Generally, among
Docking studies were conducted to predict the binding sites
and interactions of compounds 9b-3 and 9b-6 as the most
potent compounds into the active site of acetylcholinester-
ase and butyrylcholinesterase enzymes, respectively [45,
46]. Docking studies were validated by re-docking tacrine
and donepezil into the binding site. The root-mean-square
distance (RMSD) of co-crystallized and re-docked ligands
for tacrine and donepezil was obtained 0.62 Å and 1.12 Å,
respectively, which showed high reliability of docking pro-
tocol (Fig. 2).
50
three series of compounds, 9a and 9b series showed better
AChE and BuChE inhibitory eꢁects compared to 9c. In other
words, meta-substituted derivatives were better butyrylcho-
linesterase inhibitors compared to ortho-substituted deriva-
tives, except 9b-1 and 9b-3. In all series, those derivatives
containing chlorine at ortho-position showed better or same
activities compared to ꢂuorine-containing ones. Among dif-
ferent groups at meta-position, the presence of nitro group
led to the weak or the same activities compared to ꢂuorine-/
chlorine-containing counterparts. Comparing the R groups
at para-position revealed that the compound containing
methyl group showed almost better inhibitory activity com-
pared to other derivatives in all series. A decrease in the
inhibitory activity was observed for electron-withdrawing
containing compounds meaning nitro and ꢂuorine groups
Considering the obtained docking results, we can con-
clude that these structures can be ideal inhibitors of this
enzyme due to the establishment of multiple interactions
with diꢁerent sites of the active site of the enzyme, including
the peripheral anionic site (PAS). As shown in Fig. 3, the
dimethyl group of compound 9b-3 involved in the π-alkyl
1
3

Molecular Diversity
Scheme 1 a Toluene, reꢂux, 7 h; b K CO , DMF, 90 °C, 3–4 h; c EtOH, acetic acid, r.t., 24 h; d NaN , H O/t-BuOH, Et N, r.t., 1 h;
2
3
3
2
3
CuSO ·5H O, sodium ascorbate, 7a–c, r.t., 18 h
4
2
interaction with Trp286, which is an aromatic residue of the
peripheral anionic site. The π-anion interaction between Asp
phenyl ring established another π–π stacking interaction with
Phe329 and Tyr332.
7
4 and phenyl ring of this core stabilized this compound in
the active site of AChE. 3-Fluoro-substituted benzyl ring
displayed π–π stacking with the indole ring of the Trp86
and hydrogen bonds with Trp 133 and Ala 127. The nitro-
gen of triazole ring also made a hydrogen bond with both
Ser203 and His447. The binding interaction energy of com-
pound 9b-3 was −6.6 kcal/mol, which stated that 9b-3 is
less potent than donepezil (-8.4 kcal/mol) towards AChE
inhibition.
Inhibitory efects on the amyloid‑β(1–42) selꢀ‑aggre‑
gation
The potent compounds of each series were selected and
evaluated for the determination of self-induced amyloid-β
self-aggregation by thioꢂavin T (ThT) ꢂuorescence assay
(Table 2) [47]. Interestingly, all these compounds have sig-
niꢀcant eꢁects on amyloid-β self-aggregation in comparison
with donepezil as the reference compound. Compounds 9c-
7 and 9c-9 exhibited 4–5 times superior anti-aggregation
activity compared with donepezil.
The molecular docking of compound 9b-6 (Fig. 4) repre-
sented that the ligand was well inserted into the active site
of enzyme with the best score energy (−8.6 kcal/mol) and
the oxygen atom of the OCH linker in this compound estab-
Toxicity of some synthesized compounds on PC12 cells
was measured according to the previous reports (Fig. 5) [48].
The PC12 cells were incubated with varying concentrations
(0.01–100 μM) of the test compounds for 24 h. The results
are displayed in Fig. 5, and the average of cell viability
2
lished a hydrogen bonding with Ser198 and His438. The
phenyl group attached to this linker involved in π–π inter-
action with Trp82 and π-anion interaction with negatively
charged oxygen of Glu197. Moreover, 4-methyl-substituted
1
3

Molecular Diversity
Table 1 Cholinesterase inhibitory activities of target compounds 9a–
results revealed the useful interactions of ligands with the
active site of enzymes conꢀrming the anticholinesterase
activities of target compounds. Our studies led to the iden-
tiꢀcation of the selective butyrylcholinesterase inhibitors
with a potential application in the treatment of age-related
neurodegenerative disorder, AD.
9
c series
Compound
R
AChE
IC (μM)
50
a
Inhibition (%)
BuChE
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
a-1
a-2
a-3
a-4
a-5
a-6
a-7
a-8
a-9
a-10
a-11
b-1
b-2
b-3
b-4
b-5
b-6
b-7
b-8
b-9
b-10
c-1
2-F
30.3
30.9
30.5
28.2
25.3
25.3
26.5
24.5
24.6
20.8
23.6
26.2
22.2
31.7
18.3
31.4
12.9
29.3
16.7
10.7
16.7
7.1
14.3
13.7
8.1
12.3
16.2
4.7
12.6
4.3
2.1
1.3± 0.01
1.3± 0.02
2.9± 0.06
0.4± 0.008
1.7± 0.07
5.3± 0.09
2.3± 0.07
8.5± 0.2
2.7± 0.06
2.2± 0.08
12.9± 0.4
1.7± 0.02
0.6± 0.007
0.8± 0.003
0.7± 0.008
0.7± 0.002
0.2± 0.002
1.1± 0.03
0.6± 0.05
0.6± 0.08
0.9± 0.06
7.5± 0.1
1.5± 0.02
2.8± 0.03
5.1± 0.09
6.1± 0.07
9.6± 0.08
1.2± 0.02
17.3± 0.2
0.9± 0.07
10.8± 0.1
N/A
2-Cl
3-CH3
3-F
3-Cl
3-NO2
4-CH3
4-F
4-Cl
4-Br
4-NO2
2-F
2-Cl
3-F
3-Cl
3-NO2
4-CH3
4-F
4-Cl
4-Br
4-NO2
2-F
2-Cl
3-CH3
3-F
3-Cl
3-NO2
4-CH3
4-F
Materials and methods
Chemistry
All the materials were prepared from Fluka, Sigma and
Merck companies or in the laboratory. The melting points
of the products were measured with a Koꢂer hot-stage
apparatus. The nuclear magnetic resonance spectra were
1
taken with the Bruker 500 MHz device. To record the H
1
3
NMR spectra and C NMR, deuterated dimethyl sulfox-
ide (DMSO-d ) and chloroform (CDCl ) solvents were
6
3
used and the chemical shift was measured relative to the
tetramethyl silane (TMS) as standard. The IR spectra were
recorded with the Nicolet FT-IR Magna 550 spectrometer.
Also, the percentage of carbon, hydrogen and nitrogen ele-
ments was obtained using the LECO 600 CHN Elemental
Analyzer. Agilent LC–MS6410 QQQHPLC Series 1200
(
Santa Clara, USA) was used for LC-MS analysis. Positive
c-2
ESI–MS mass spectra were recorded on an Agilent 6410
triple quadrupole mass spectrometer.
c-3
c-4
c-5
c-6
General procedure ꢀor the preparation oꢀ 3‑((2‑ami‑
nophenyl) amino)‑5,5‑dimethylcyclohex‑2‑enone
c-7
c-8
c-9
4-Cl
4-Br
4-NO2
–
A mixture of benzene-1,2-diamine (1 mmol) and
c-10
c-11
5
,5-dimethylcyclohexane-1,3-dione (1 mmol) in toluene
10.9
99.2
(
15 mL) was reꢂuxed for 7 h. After this time, the mix-
Donepezil
6.9± 0.1
ture was allowed to come to the room temperature and
the precipitate was collected and recrystallized from ethyl
acetate/petroleum ether (2/8).
The most potent compound was written in bold
a
IC (µM) or inhibition % at 30 µM concentration. Values were the
50
means of three replicates± standard deviation (SD)
percentage for compounds 9b-2, 9c-9 and donepezil was
General procedure ꢀor the preparation
oꢀ (prop‑2‑yn‑1‑yloxy) benzaldehydes; ortho‑, meta‑
and para‑substituted derivatives
8
7.2± 2.9, 88.5± 2.6, and 99.5± 4.7, respectively.
Conclusion
A mixture of ortho-, meta- and para-substituted hydroxy-
substituted benzaldehydes (1 mmol), propargyl bromide
(1 mmol) and K CO (1 mmol) in DMF (10 mL) was
The present study described the synthesis and evaluation
of benzodiazepine-triazole hybrid systems as cholinester-
ase inhibitors. The target compounds showed signiꢀcant
inhibitory activity against both BuChE and self-induced
Aβ1–42 aggregation compared to donepezil. The docking
2
3
heated at 90 °C for 3–4 h. After completion, the mixture
was poured into ice water (approx. 200 mL) and the result-
ant solid was ꢀltered and used without further puriꢀcation.
1
3

Molecular Diversity
Fig. 2 Validation of the docking methodology. a Superimposition
of the docking best pose for tacrine (grey) with the crystallographic
structure of 4BDS complexed with tacrine (green), b Superimposi-
tion of the docking best pose for donepezil (grey) with the crystallo-
graphic structure of 4EY7 complexed with donepezil (green). (Color
ꢀgure online)
Fig. 3 interactions of the best
pose of 9b-3 in the active site
of AChE
Fig. 4 interactions of the best
pose of 9b-6 in the active site
of BuChE
1
3

Molecular Diversity
Table 2 Inhibitory eꢁects on Aβ(1–42) self-aggregation
General procedure ꢀor the preparation oꢀ target
compounds 9a–c
Samples
% Aggregation inhibitiona
9
9
9
9
9
9
9
a-1
a-4
b-2
b-6
c-2
c-7
c-9
55.6± 2.4
52.9± 2.2
47.4± 1.7
49.6± 2.5
63.9± 1.8
72.4± 1.9
68.4± 2.9
14.9± 2.5 (10 µM)
A mixture of benzyl chloride/bromide derivatives 8
(
0.5 mmol), Et N (0.5 mmol) and NaN (0.5 mmol) in
3 3
H O/t-BuOH (4 mL, 1:1) was stirred at room temperature for
2
1
h. Then, 7a–c (0.5 mmol), sodium ascorbate (0.05 mmol)
were added, followed by CuSO ·5H O (0.005 mmol). The
4
2
reaction was continued at room temperature for 18 h. After
this time, the mixture was poured into ice water and stirred.
The precipitate was collected and crystallized from ethyl
acetate and petroleum ether (diꢁerent ratios) to yield target
compounds.
Donepezil
a
Inhibition of self-induced Aβ
aggregation (10 µM) produced by
1–42)
(
the tested compound at 100 µM concentration. Values are expressed
as mean± SEM of three experiments
1
1‑(2‑((1‑(2‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
General procedure ꢀor the preparation oꢀ 7a–c
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑1)
To a mixture of 3 (0.7 mmol) and 6a–c (0.7 mmol) in etha-
nol (10 mL), 3–4 drops of glacial acetic acid was added
and the mixture was stirred at room temperature for 24 h.
Afterwards, the mixture was added to ice water (approx.
White solid; Yield: 0.175 g (67%); mp 201–202 °C; IR
−
1
1
(KBr, cm ): 3299, 3239, 1596, 1535. H NMR (500 MHz,
DMSO-d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2.07 (d, J = 15.9 Hz, 1H, H-4), 2.16 (d, J = 15.9 Hz, 1H,
H-4), 2.61–2.66 (m, 2H, H-2), 5.20 (d, J = 11.9 Hz, 1H,
OCH ), 5.32–5.36 (m, 2H, H-11 and OCH ), 5.77 (s, 2H,
2
00 mL) and the precipitated solid was ꢀltered and used
without further puriꢀcation.
2
2
Fig. 5 Cytotoxicity in PC12 cells, MTT Assay
1
3

Molecular Diversity
NCH ), 5.89 (d, J=5.1 Hz, 1H, NHCH), 6.46 (d, J=7.4 Hz,
(m, 2H, H-5′ and H-6′), 7.14–7.16 (m, 3H, H-2″, H-4″ and
H-6″), 7.69 (t, J=7.9 Hz, 1H, H-5″), 8.42 (s, 1H, H-4, tria-
2
1
1
H, H-9), 6.51 (t, J=7.0 Hz, 1H, H-8), 6.56 (t, J=7.0 Hz,
1
3
H, H-7), 6.59–6.61 (m, 2H, H-6 and H-4′), 6.91 (d,
zole), 8.84 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
J = 7.6 Hz, 1H, H-3′), 7.00–7.03 (m, 1H, H-5′), 7.07 (d,
J=7.9 Hz, 1H, H-6′), 7.21–7.29 (m, 2H, H-5″ and H-6″),
21.0, 27.7, 28.3, 31.9, 44.1, 49.5, 52.4, 52.9, 61.5, 108.7,
111.9, 119.9, 120.1, 120.3, 122.7, 124.5, 125.1, 126.5,
127.8, 128.5, 128.7, 128.8, 129.7, 131.0, 131.6, 135.9,
138.1, 138.4, 143.4, 155.6, 155.8, 192.1. Anal. Calcd. For
C H N O : C, 73.96; H, 6.40; N, 13.48%. Found: C, 74.25;
7
.37–7.43 (m, 2H, H-3″ and H-4″), 8.44 (s, 1H, H-4, tria-
1
3
zole), 8.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
3
1
1
1
J
2.8, 33.4, 36.9, 49.2, 52.1, 54.6, 57.5, 66.6, 113.8, 117.0,
3
2
33
5
2
+
20.8 (d, J =20.0 Hz), 125.0, 125.2, 125.4, 127.8, 127.9,
H, 6.16; N, 13.23%. ESI–MS m/z: 520 [M+H] .
C-F
28.0, 129.8, 130.0, 131.7, 132.9, 135.9 (d, J =3.8 Hz),
C-F
36.0, 136.2, 136.7, 143.5, 148.4, 160.6, 161.0, 165.3 (d,
=245.2 Hz), 197.2. Anal. Calcd. For C H FN O : C,
11‑(2‑((1‑(3‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑4)
C-F
7
31 30
5
2
1.11; H, 5.78; N, 13.38%. Found: C, 71.47; H, 5.55; N,
+
1
3.05%. ESI–MS m/z: 524 [M+H] .
1
1‑(2‑((1‑(2‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
White solid; Yield: 0.178 g (68%); mp 173–174 °C; IR (KBr,
−1
1
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑2)
cm ): 3299, 3242, 1596, 1534. H NMR (500 MHz, DMSO-
d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.07
6
3 2
3 2
(
d, J = 15.8 Hz, 1H, H-4), 2.16 (d, J= 15.8 Hz, 1H, H-4),
White solid; Yield: 0.175 g (65%); mp 208–209 °C; IR
2.58–2.66 (m, 2H, H-2), 5.21 (d, J=11.9 Hz, 1H, OCH ),
2
−
1
1
(
KBr, cm ): 3287, 3236, 1599, 1517. H NMR (500 MHz,
5.33–5.36 (m, 2H, H-11 and OCH ), 5.69 (s, 2H, NCH ),
2
2
DMSO-d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
5.88 (d, J = 5.5 Hz, 1H, NHCH), 6.44 (d, J = 7.4 Hz, 1H,
H-9), 6.50 (t, J=7.2 Hz, 1H, H-8), 6.56 (t, J=7.2 Hz, 1H,
H-7), 6.59–6.61 (m, 2H, H-6 and H-4′), 6.91 (d, J=7.7 Hz,
1H, H-3′), 7.01–7.03 (m, 1H, H-5′), 7.07 (d, J=8.0 Hz, 1H,
H-6′), 7.16–7.22 (m, 3H, H-2″, H-4″ and H-6″), 7.42–7.43
(m, 1H, H-5″), 8.47 (s, 1H, H-4, triazole), 8.83 (s, 1H, NH).
6
3 2
3 2
2
.07 (d, J = 15.9 Hz, 1H, H-4), 2.16 (d, J = 15.9 Hz, 1H,
H-4), 2.61–2.63 (m, 2H, H-2), 5.19 (d, J = 11.95 Hz, 1H,
OCH ), 5.33–5.35 (m, 2H, H-11 and OCH ), 5.73 (s, 2H,
2
2
NCH ), 5.89 (d, J=5 Hz, 1H, NHCH), 6.45 (d, J=7.5 Hz,
2
1
1
H, H-9), 6.50 (t, J=7.0 Hz, 1H, H-8), 6.56 (t, J=7.0 Hz,
1
3
H, H-7), 6.59–6.61 (m, 2H, H-6 and H-4′), 6.91 (d,
C NMR (125 MHz, DMSO-d ): 27.7, 28.3, 31.8, 44.2,
6
J = 7.8 Hz, 1H, H-3′), 7.00–7.03 (m, 1H, H-5′), 7.07 (d,
J=7.9 Hz, 1H, H-6′), 7.21–7.29 (m, 2H, H-5″ and H-6″),
49.5, 52.3, 52.4, 61.5, 108.7, 111.9, 114.8, 115.0, 115.2,
119.9, 120.1, 120.3, 122.7, 124.1, 124.6, 126.6, 127.8, 131.0
(2C), 131.1, 131.6, 138.4, 138.7, 143.5, 155.6, 155.8, 165.5
(d, J =248.9 Hz), 192.1. Anal. Calcd. For C H FN O :
7
.37–7.43 (m, 2H, H-3″ and H-4″), 8.44 (s, 1H, H-4, tria-
1
3
zole), 8.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
C-F
31 30
5
2
2
1
1
1
7.7, 28.4, 31.8, 49.5, 50.8, 52.4, 57.3, 61.5, 108.7, 112.0,
19.9, 120.1, 121.3, 122.7 (2C), 125.0, 126.6, 127.8, 128.4,
29.7, 130.3, 130.6, 131.1, 131.5, 132.7, 133.3, 138.4,
43.2, 155.6, 155.9, 192.1. Anal. Calcd. For C H ClN O :
C, 71.11; H, 5.78; N, 13.38%. Found: C, 71.35; H, 5.54; N,
+
13.05%. ESI–MS m/z: 524 [M+H] .
31
30
5
2
C, 68.94; H, 5.60; N, 12.97%. Found: C, 68.65; H, 5.43; N,
11‑(2‑((1‑(3‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑5)
+
1
3.23%. ESI–MS m/z: 541 [M+H] .
3,3‑Dimethyl‑11‑(2‑((1‑(3‑methylbenzyl)‑1H‑1,2,3
‑
triazol‑4‑yl)methoxy)phenyl)‑2,3,4,5,10,11‑hexahy‑
White solid; Yield: 0.172 g (64%); mp 207–208 °C; IR
−
1
1
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑3)
(KBr, cm ): 3296, 3240, 1597, 1533. H NMR (500 MHz,
DMSO-d ): 1.07 (s, 6H, C(CH ) ), 2.08 (d, J = 15.9 Hz,
6
3 2
White solid; Yield: 0.158 g (61%); mp 184–185 °C; IR
1H, H-4), 2.17 (d, J = 15.9 Hz, 1H, H-4), 2.58–2.63 (m,
−
1
1
(
KBr, cm ): 3294, 3239, 1597, 1535. H NMR (500 MHz,
2H, H-2), 5.20 (d, J=11.9 Hz, 1H, OCH ), 5.34–5.37 (m,
2
DMSO-d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
2H, H-11 and OCH ), 5.70 (s, 2H, NCH ), 5.89 (brs, 1H,
6
3 2
3 2
2
2
2
.07 (d, J = 15.3 Hz, 1H, H-4), 2.16 (d, J = 15.3 Hz, 1H,
NHCH), 6.45 (d, J=7.5 Hz, 1H, H-9), 6.51–6.61 (m, 4H,
H-6, H-7, H-8 and H-4′), 6.92 (d, J = 7.75 Hz, 1H, H-3′),
7.03–7.07 (m, 2H, H-5′ and H-6′), 7.31 (m, 1H, H-6″),
7.42–7.46 (m, 3H, H-2″, H-4″ and H-5″), 8.47 (s, 1H, H-4,
triazole), 8.84 (s, 1H, NH). Anal. Calcd. For C H ClN O :
H-4), 2.18 (s, 3H, CH ), 2.58–2.66 (m, 2H, H-2), 5.20
3
(
d, J = 11.9 Hz, 1H, OCH ), 5.33–5.35 (m, 2H, H-11
2
and OCH ), 5.61 (s, 2H, NCH ), 5.87 (d, J = 5.5 Hz, 1H,
2
2
NHCH), 6.45 (d, J=7.5 Hz, 1H, H-9), 6.49 (t, J=7.1 Hz,
H, H-8), 6.56 (t, J=7.1 Hz, 1H, H-7), 6.57–6.60 (m, 2H,
H-6 and H-4′), 6.91 (d, J = 7.7 Hz, 1H, H-3′), 7.02–7.06
31
30
5
2
1
C, 68.94; H, 5.60; N, 12.97%. Found: C, 68.67; H, 5.32; N,
+
13.32%. ESI–MS m/z: 541 [M+H] .
1
3

Molecular Diversity
3
,3‑Dimethyl‑11‑(2‑((1‑(3‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
1,4]diazepin‑1‑one (9a‑6)
11‑(2‑((1‑(4‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑9)
[
Yellow solid; Yield: 0.187 g (68%); mp 184–185 °C; IR
White solid; Yield: 0.178 g (66%); mp 188–189 °C; IR (KBr,
−
1
1
−1
1
(
KBr, cm ): 3291, 3237, 1581, 1530. H NMR (500 MHz,
cm ): 3297, 3240, 1599, 1536. H NMR (500 MHz, DMSO-
DMSO-d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.08
6
3 2
3 2
6
3 2
3 2
2
.07 (d, J = 15.9 Hz, 1H, H-4), 2.16 (d, J = 15.9 Hz, 1H,
(d, J = 16.0 Hz, 1H, H-4), 2.16 (d, J= 16.0 Hz, 1H, H-4),
H-4), 2.58–2.66 (m, 2H, H-2), 5.21 (d, J = 12.1 Hz, 1H,
2.58–2.66 (m, 2H, H-2), 5.20 (d, J = 12 Hz, 1H, OCH ),
2
OCH ), 5.32–5.37 (m, 2H, H-11 and OCH ), 5.85 (s, 2H,
5.33–5.35 (m, 2H, H-11 and OCH ), 5.67 (s, 2H, NCH ),
2
2
2
2
NCH ), 5.87 (d, J=5.5 Hz, 1H, NHCH), 6.44 (d, J=7.5 Hz,
5.88 (d, J = 4.9 Hz, 1H, NHCH), 6.44 (d, J = 7.5 Hz, 1H,
H-9), 6.49 (t, J=7.2 Hz, 1H, H-8), 6.56 (t, J=7.2 Hz, 1H,
H-7), 6.59–6.61 (m, 2H, H-6 and H-4′), 6.91 (d, J=7.7 Hz,
1H, H-3′), 7.02–7.03 (m, 1H, H-5′), 7.07 (d, J = 7.9 Hz,
1H, H-6′), 7.37 (d, J=7.8 Hz, 2H, H-3″ and H-5″), 7.45 (d,
2
1
1
H, H-9), 6.50 (t, J=7.2 Hz, 1H, H-8), 6.56 (t, J=7.2 Hz,
H, H-7), 6.59- 6.61 (m, 2H, H-6 and H-4′), 6.91 (d,
J = 7.7 Hz, 1H, H-3′), 7.01–7.03 (m, 1H, H-5′), 7.07 (d,
J=8.0 Hz, 1H, H-6′), 7.69 (t, J=7.9 Hz, 1H, H-5″), 7.80 (d,
J=7.9 Hz, 1H, H-6″), 8.21 (d, J=7.9 Hz, 1H, H-4″), 8.29 (s,
J=7.8 Hz, 2H, H-2″ and H-6″), 8.44 (s, 1H, H-4, triazole),
1
3
13
1
H, H-2″), 8.53 (s, 1H, H-4, triazole), 8.85 (s, 1H, NH).
C
8.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): 27.7,
6
NMR (125 MHz, DMSO-d ): 27.7, 28.3, 31.9, 44.3, 49.5,
28.3, 31.8, 44.9, 49.5, 52.1, 52.4, 61.5, 108.8, 111.9, 119.9,
120.1, 120.3, 122.7, 124.6, 126.2, 127.8, 128.8, 130.0,
131.1, 131.6, 132.9, 134.1, 135.0, 138.4, 143.4, 155.6,
155.8, 192.1. Anal. Calcd. For C H ClN O : C, 68.94;
6
5
1
1
1
1
5
1.9, 52.4, 61.5, 108.7, 111.9, 119.9, 120.1, 120.3, 122.8,
23.0, 123.2, 124.8, 126.6, 127.8, 130.5, 131.0, 131.5,
34.9, 135.5, 138.1, 138.4, 143.6, 147.9, 155.6, 155.8,
92.1. Anal. Calcd. For C H N O : C, 67.62; H, 5.49; N,
3
1
30
5
2
H, 5.60; N, 12.97%. Found: C, 68.71; H, 5.37; N, 12.63%.
3
1
30
6
4
+
5.26%. Found: C, 67.38; H, 5.13; N, 15.54%. ESI–MS m/z:
ESI–MS m/z: 541 [M+H] .
+
51 [M+H] .
1
1‑(2‑((1‑(4‑Bromobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
11‑(2‑((1‑(4‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑10)
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9a‑8)
White solid; Yield: 0.187 g (64%); mp 218–219 °C; IR (KBr,
−1
1
White solid; Yield: 0.170 g (65%); mp 201–202 °C; IR
cm ): 3308, 3241, 1628, 1525. H NMR (500 MHz, DMSO-
−
1
1
(
KBr, cm ): 3309, 3240, 1603, 1529. H NMR (500 MHz,
d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.07
6
3 2
3 2
DMSO-d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
(d, J = 15.9 Hz, 1H, H-4), 2.17 (d, J= 15.9 Hz, 1H, H-4),
6
3 2
3 2
2
.07 (d, J = 15.9 Hz, 1H, H-4), 2.17 (d, J = 15.9 Hz, 1H,
2.58–2.66 (m, 2H, H-2), 5.20 (d, J = 12 Hz, 1H, OCH ),
2
H-4), 2.58–2.65 (m, 2H, H-2), 5.20 (d, J = 12.0 Hz, 1H,
5.32–5.35 (m, 2H, H-11 and OCH ), 5.65 (s, 2H, NCH ),
2
2
OCH ), 5.32–5.35 (m, 2H, H-11 and OCH ), 5.65 (s, 2H,
5.88 (d, J = 5.5 Hz, 1H, NHCH), 6.43 (d, J = 7.6 Hz, 1H,
H-9), 6.49 (t, J=7.5 Hz, 1H, H-8), 6.56 (t, J=7.5 Hz, 1H,
H-7), 6.57–6.60 (m, 2H, H-6 and H-4′), 6.91 (d, J=7.8 Hz,
1H, H-3′), 7.00–7.03 (m, 1H, H-5′), 7.07 (d, J = 8.0 Hz,
1H, H-6′), 7.30 (d, J=8.1 Hz, 2H, H-3″ and H-5″), 7.58 (d,
2
2
NCH ), 5.88 (d, J=5.5 Hz, 1H, NHCH), 6.45 (d, J=7.6 Hz,
2
1
H, H-9), 6.50 (t, J=7.5 Hz, 1H, H-8), 6.57–6.61 (m, 3H,
H-7, H-6 and H-4′), 6.91 (d, J=7.8 Hz, 1H, H-3′), 7.03–7.06
m, 2H, H-5′ and H-6′), 7.31–7.34 (m, 2H, H-3″ and H-5″),
(
7
8
3
1
1
1
.58 (m, 2H, H-2″ and H-6″), 8.43 (s, 1H, H-4, triazole),
J=8.1 Hz, 2H, H-2″ and H-6″), 8.44 (s, 1H, H-4, triazole),
1
3
13
.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): 32.8,
8.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): 27.2,
6
6
3.4, 36.9, 48.8, 54.6, 57.2, 57.5, 66.6, 113.8, 117.0, 117.1,
20.7, 120.9, 125.0, 125.2, 125.4, 127.8, 129.5, 130.9,
31.7, 132.9, 135.4, 135.5, 136.2, 136.7, 137.4, 143.5,
48.5, 160.7, 160.9, 197.2. Anal. Calcd. For C H FN O :
27.7, 31.3, 43.6, 49.0, 51.6, 51.8, 61.0, 108.2, 111.4, 119.3
(2C), 119.5, 119.7, 120.9, 122.1, 124.0, 126.0, 127.2, 129.7
(2C), 130.5, 131.1, 131.2 (2C), 134.8, 137.8, 142.9, 154.9,
155.3, 191.5. Anal. Calcd. For C H BrN O : C, 63.70;
3
1
30
5
2
31 30
5
2
C, 71.11; H, 5.78; N, 13.38%. Found: C, 71.44; H, 5.96; N,
H, 5.17; N, 11.98%. Found: C, 63.56; H, 5.32; N, 11.77%.
+
+
1
3.13%. ESI–MS m/z: 524 [M+H] .
ESI–MS m/z: 585 [M+H] .
1
3

Molecular Diversity
3
,3‑Dimethyl‑11‑(2‑((1‑(4‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
1,4]diazepin‑1‑one (9a‑11)
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2.08 (d, J = 15.8 Hz, 1H, H-4), 2.17 (d, J = 15.8 Hz, 1H,
[
H-4), 2.57–2.60 (m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.65
2
(
d, J=5 Hz, 1H, H-11), 5.70 (s, 2H, NCH ), 6.16 (brs, 1H,
2
Yellow solid; Yield: 0.18 g (69%); mp 180–181 °C; IR (KBr,
NHCH), 6.52–6.60 (m, 3H, H-7, H-8 and H-9), 6.67–6.68
(m, 2H, H-4′ and H-6′), 6.75 (s, 1H, H-2′), 6.90 (d,
J=7.4 Hz, 1H, H-6), 7.01 (t, J=7.7 Hz, 1H, H-5′), 7.21 (d,
J=7.1 Hz, 1H, H-6″), 7.35–7.42 (m, 2H, H-4″ and H-5″),
7.52 (d, J=7.6 Hz, 1H, H-3″), 8.18 (s, 1H, H-4, triazole),
−1
1
cm ): 3341, 3292, 1631, 1527. H NMR (500 MHz, DMSO-
d ): 1.06 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.07
6
3 2
3 2
(
d, J = 15.0 Hz, 1H, H-4), 2.16 (d, J= 15.0 Hz, 1H, H-4),
2
5
5
.58–2.66 (m, 2H, H-2), 5.20 (d, J=12.1 Hz, 1H, OCH ),
2
1
3
.23–5.35 (m, 2H, H-11 and OCH ), 5.65 (s, 2H, NCH ),
8.76 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): 27.0,
2
2
6
.87 (d, J = 5.5 Hz, 1H, NHCH), 6.43 (d, J = 7.7 Hz, 1H,
27.8, 31.2, 43.5, 48.9, 50.0, 55.2, 60.2, 111.2, 113.5, 118.9,
119.4, 119.9, 122.1, 124.3, 127.2, 128.0, 129.0, 129.7 (2C),
129.9, 130.4 (2C), 132.0, 132.6, 137.9, 142.2, 145.8, 154.2,
157.1, 191.5. Anal. Calcd. For C H ClN O : C, 68.94;
H-9), 6.49 (t, J=7.5 Hz, 1H, H-8), 6.56 (t, J=7.5 Hz, 1H,
H-7), 6.59–6.62 (m, 2H, H-6 and H-4′), 6.91 (d, J=7.85 Hz,
1
1
H, H-3′), 7.00–7.03 (m, 1H, H-5′), 7.07 (d, J = 8.2 Hz,
H, H-6′), 7.30 (d, J = 7.9 Hz, 2H, H-3″ and H-5″), 7.58
3
1
30
5
2
H, 5.60; N, 12.97%. Found: C, 68.63; H, 5.37; N, 13.11%.
+
(
d, J=7.9 Hz, 2H, H-2″ and H-6″), 8.44 (s, 1H, H-4, tria-
ESI–MS m/z: 541 [M+H] .
1
3
zole), 8.83 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
2
7.6, 28.6, 31.9, 44.2, 49.6, 51.9, 55.4, 61.0, 110.6, 113.8
11‑(3‑((1‑(3‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑3)
(
2C), 119.5, 120.0, 120.6, 122.7, 122.9, 123.2, 124.9, 128.4
2C), 130.5, 131.2, 134.8, 137.3, 138.1, 138.7, 143.4, 148.0,
(
1
54.8, 156.2, 192.2. Anal. Calcd. For C H N O : C, 67.62;
31 30 6 4
H, 5.49; N, 15.26%. Found: C, 67.45; H, 5.23; N, 15.39%.
White solid; Yield: 0.175 g (67%); mp 99–100 °C; IR
+
−1
1
ESI–MS m/z: 551 [M+H] .
(KBr, cm ): 3323, 3277, 1661, 1550. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
1
1‑(3‑((1‑(2‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
2.09 (d, J = 15.7 Hz, 1H, H-4), 2.18 (d, J = 15.7 Hz, 1H,
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑1)
H-4), 2.57–2.60 (m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.62
2
(s, 2H, NCH ), 5.66 (d, J = 5.8 Hz, 1H, H-11), 6.17 (brs,
2
1
H, NHCH), 6.54–6.60 (m, 3H, H-7, H-8 and H-9),
White solid; Yield: 0.183 g (70%); mp 113–114 °C; IR
6.67–6.68 (m, 2H, H-4′ and H-6′), 6.75 (s, 1H, H-2′), 6.90
(d, J = 7.3 Hz, 1H, H-6), 7.02 (t, J = 7.3 Hz, 1H, H-5′),
7.13–7.18 (m, 3H, H-2″, H-4″ and H-6″), 7.42–7.43 (m,
1H, H-5″), 8.24 (s, 1H, H-4, triazole), 8.75 (s, 1H, NH).
−
1
1
(
KBr, cm ): 3332, 3281, 1642, 1531. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2
.08 (d, J = 15.9 Hz, 1H, H-4), 2.18 (d, J = 15.9 Hz, 1H,
1
3
H-4), 2.57–2.60 (m, 2H, H-2), 4.95 (s, 2H, OCH ),
C NMR (125 MHz, DMSO-d ): 27.5, 28.4, 31.8, 44.0,
6
2
5
.65–5.72 (m, 3H, NCH and H-11), 6.15 (brs, 1H, NHCH),
49.4, 52.1, 55.8, 60.7, 109.9, 111.7, 114.0, 114.8, 114.9,
115.1, 119.5, 120.0, 120.5, 122.6, 124.1 (2C), 124.7, 128.6,
130.8, 130.9, 131.0, 138.6, 143.0, 154.8, 157.7, 163.1 (d,
J = 209 Hz), 192.1. Anal. Calcd. For C H FN O : C,
2
6
.52–6.60 (m, 3H, H-7, H-8 and H-9), 6.67–6.68 (m, 2H,
H-4′ and H-6′), 6.74 (s, 1H, H-2′), 6.90 (d, J=7.4 Hz, 1H,
H-6), 7.01 (t, J=7.8 Hz, 1H, H-5′), 7.21–7.28 (m, 2H, H-5″
and H-6″), 7.34 (t, J = 7.15 Hz, 1H, H-3″), 7.42–7.43 (m,
3
1
30
5
2
71.11; H, 5.78; N, 13.38%. Found: C, 71.47; H, 5.51; N,
1
3
+
1
H, H-4″), 8.19 (s, 1H, H-4, triazole), 8.75 (s, 1H, NH).
C
13.69%. ESI–MS m/z: 524 [M+H] .
NMR (125 MHz, DMSO-d ): 27.0, 27.8, 31.2, 43.5, 46.3,
6
4
1
1
8.9, 55.2, 60.2, 109.4, 111.2, 113.4, 115.0 (d, J=20.0 Hz),
18.9, 119.4, 119.9, 122.1, 122.2, 124.1, 124.3, 128.0, 130.2,
30.2, 130.2, 130.4, 137.9, 142.3, 145.8, 154.2, 157.1, 159.5
11‑(3‑((1‑(3‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑4)
(
d, J = 245.0 Hz), 191.5. Anal. Calcd. For C H FN O :
31 30 5 2
C, 71.11; H, 5.78; N, 13.38%. Found: C, 71.47; H, 5.51; N,
White solid; Yield: 0.170 g (63%); mp 118–119 °C; IR
+
−1
1
1
3.09%. ESI–MS m/z: 524 [M+H] .
(KBr, cm ): 3340, 3198, 1656, 1548. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
11‑(3‑((1‑(2‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
2.08 (d, J=16 Hz, 1H, H-4), 2.17 (d, J=16 Hz, 1H, H-4),
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑2)
2.57–2.60 (m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.62 (s, 2H,
2
NCH ), 5.65 (d, J=5.6 Hz, 1H, H-11), 6.16 (d, J=4.3 Hz,
2
1
H, NH), 6.54–6.60 (m, 3H, H-7, H-8 and H-9), 6.67–6.68
White solid; Yield: 0.175 g (65%); mp 117–118 °C; IR
(m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′), 6.90 (d,
J = 7.0 Hz, 1H, H-6), 7.02 (t, J = 7.0 Hz, 1H, H-5′), 7.27
−
1
1
(
KBr, cm ): 3324, 3292, 1654, 1542. H NMR (500 MHz,
1
3

Molecular Diversity
(
s, 1H, H-6″), 7.41 (m, 3H, H-2″, H-4″ and H-5″), 8.25 (s,
123.0, 123.8, 128.2 (2C), 128.8 (2C), 129.8, 134.3, 134.4,
136.9, 138.2, 143.8, 146.2, 153.0, 157.9, 197.2. Anal. Calcd.
For C H N O : C, 73.96; H, 6.40; N, 13.48%. Found: C,
1
3
1
H, H-4, triazole), 8.75 (s, 1H, NH). C NMR (125 MHz,
DMSO-d ): 27.5, 28.4, 31.8, 42.5, 49.4, 52.0, 55.8, 60.7,
6
32 33
5
2
+
1
1
1
09.9, 111.7, 113.9, 119.3, 119.5, 119.7, 119.9, 121.4,
22.6, 124.5, 128.6, 130.2, 130.8, 131.0, 131.7, 132.4,
35.4, 138.9, 143.0, 147.7, 154.8, 157.7, 192.1. Anal. Calcd.
73.87; H, 6.49; N, 13.41%. ESI–MS m/z: 520 [M+H] .
11‑(3‑((1‑(4‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑7)
For C H ClN O : C, 68.94; H, 5.60; N, 12.97%. Found:
3
1
30
5
2
+
C, 68.69; H, 5.45; N, 13.20%. ESI–MS m/z: 541 [M+H] .
White solid; Yield: 0.180 g (69%); mp 117–118 °C; IR
3
,3‑Dimethyl‑11‑(3‑((1‑(3‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
1,4]diazepin‑1‑one (9b‑5)
−1
1
(
KBr, cm ): 3309, 3275, 1660, 1556. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
[
2
.08 (d, J=15.9 Hz, 1H, H-4), 2.18 (d, J=15.9 Hz, 1H, H-4),
2
.57–2.60 (m, 2H, H-2), 4.94 (s, 2H, OCH ), 5.58 (s, 2H,
2
Yellow solid; Yield: 0.190 g (69%); mp 98–99 °C; IR
NCH ), 5.65 (d, J=5.3 Hz, 1H, H-11), 6.15 (d, J=5.5 Hz,
−
1
1
2
(
KBr, cm ): 3337, 3258, 1674, 1533. H NMR (500 MHz,
1
H, NHCH), 6.52–6.60 (m, 3H, H-7, H-8 and H-9), 6.66–6.68
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
(
m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′), 6.90 (d, J=7.3 Hz,
2
.08 (d, J = 15.9 Hz, 1H, H-4), 2.17 (d, J = 15.9 Hz, 1H,
1
H, H-6), 7.01 (t, J=7.7 Hz, 1H, H-5′), 7.21 (m, 2H, H-3″
H-4), 2.57–2.60 (m, 2H, H-2), 4.97 (s, 2H, OCH ), 5.65
2
and H-5″), 7.37–7.39 (m, 2H, H-2″ and H-6″), 8.20 (s,
(
d, J = 5.8 Hz, 1H, H-11), 5.78 (s, 2H, NCH ), 6.15 (d,
2
13
1
H, H-4, triazole), 8.73 (s, 1H, NH). C NMR (125 MHz,
J = 4.3 Hz, 1H, NHCH), 6.52–6.61 (m, 3H, H-7, H-8 and
H-9), 6.67–6.68 (m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′),
DMSO-d ): 26.0, 27.8, 32.5, 40.1, 42.4, 49.9, 52.2, 52.2, 58.0,
6
1
1
1
10.7, 113.0, 115.2 (d, J=20.0 Hz, 2C), 115.6, 117.9, 120.0,
20.2, 122.5, 123.0, 123.8, 129.8, 130.2 (d, J=7.5 Hz, 2C),
33.0, 134.3, 138.2, 143.8, 146.2, 153.0, 157.9, 162.1 (d,
6
7
8
1
.90 (d, J=7.6 Hz, 1H, H-6), 7.02 (t, J=7.8 Hz, 1H, H-5′),
.69 (t, J=7.7 Hz, 1H, H-5″), 7.77 (d, J=7.7 Hz, 1H, H-6″),
.21 (d, J=7.7 Hz, 1H, H-4″), 8.24 (s, 1H, H-2″), 8.30 (s,
J=252.5 Hz), 197.2. Anal. Calcd. For C H FN O : C, 71.11;
1
3
31 30
5 2
H, H-4, triazole), 8.75 (s, 1H, NH). C NMR (125 MHz,
H, 5.78; N, 13.38%. Found: C, 71.35; H, 5.91; N, 13.66%.
DMSO-d ): 27.0, 27.8, 31.2, 43.5, 48.9, 51.2, 55.3, 60.2,
6
+
ESI–MS m/z: 524 [M+H] .
1
1
1
09.4, 111.2, 113.4, 119.0, 119.4, 119.5, 120.0, 122.1,
22.3, 122.6, 124.2, 128.1, 129.8, 130.5, 134.2, 137.4,
37.8, 142.6, 145.8, 147.3, 154.2, 157.1, 191.5. Anal. Calcd.
1
1‑(3‑((1‑(4‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑8)
For C H N O : C, 67.62; H, 5.49; N, 15.26%. Found: C,
3
1
30
6
4
+
6
7.94; H, 5.57; N, 15.14%. ESI–MS m/z: 551 [M+H] .
White solid; Yield: 0.173 g (64%); mp 123–124 °C; IR (KBr,
−1
1
3
,3‑Dimethyl‑11‑(3‑((1‑(4‑methylbenzyl)‑1H‑1,2,3
cm ): 3319, 3266, 1654, 1537. H NMR (500 MHz, DMSO-
‑triazol‑4‑yl)methoxy)phenyl)‑2,3,4,5,10,11‑hexahy‑
d ): 1.03 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.11 (d,
6
3 2
3 2
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑6)
J=15.5 Hz, 1H, H-4), 2.18 (d, J=15.5 Hz, 1H, H-4), 2.54 (d,
J=16.2 Hz, 1H, H-2), 2.59 (d, J=16.2 Hz, 1H, H-2), 4.95 (s,
2H, OCH ), 5.60 (s, 2H, NCH ), 5.73 (s, 1H, H-11), 6.60–6.63
White solid; Yield: 0.158 (61%); mp 111–112 °C; IR (KBr,
2
2
−1
1
cm ): 3318, 3266, 1660, 1541. H NMR (500 MHz, DMSO-
(m, 4H, NHCH, H-7, H-8 and H-9), 6.67–6.69 (m, 2H, H-4′
and H-6′), 6.76 (s, 1H, H-2′), 6.94–6.96 (m, 1H, H-6), 7.02 (t,
J=7.7 Hz, 1H, H-5′), 7.33 (d, J=8.1 Hz, 2H, H-2″ and H-6″),
7.44 (d, J=8.1 Hz, 2H, H-3″ and H-5″), 8.23 (s, 1H, H-4,
d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.09 (d,
6
3 2
3 2
J=15.8 Hz, 1H, H-4), 2.17 (d, J=15.8 Hz, 1H, H-4), 2.27
(
s, 3H, CH ), 2.56–2.58 (m, 2H, H-2), 4.93 (s, 2H, OCH ),
3
2
13
5
.53 (s, 2H, NCH ), 5.65 (d, J=5.2 Hz, 1H, H-11), 6.16 (d,
triazole), 8.88 (brs, 1H, NH). C NMR (125 MHz, DMSO-
2
J=5.1 Hz, 1H, NHCH), 6.52–6.59 (m, 3H, H-7, H-8 and H-9),
d ): 27.6, 28.3, 31.3, 31.8, 44.0, 49.3, 52.0, 60.7, 112.1, 114.0,
6
6
.66–6.67 (m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′), 6.90 (d,
120.0, 120.1, 121.5, 122.7, 124.7, 125.4, 126.2, 128.8, 129.9,
130.4, 132.9, 134.9, 135.1, 136.6, 143.0, 154.9 (2C), 157.7,
192.1. Anal. Calcd. For C H ClN O : C, 68.94; H, 5.60; N,
J=7.3 Hz, 1H, H-6), 7.01 (t, J=7.7 Hz, 1H, H-5′), 7.17 (d,
J=7.1, 2H, H-3″ and H-5″), 7.22 (d, J=7.1, 2H, H-2″ and
31
30
5
2
13
H-6″), 8.17 (s, 1H, H-4, triazole), 8.74 (s, 1H, NH). C NMR
12.97%. Found: C, 68.67; H, 5.83; N, 12.69%. ESI–MS m/z:
+
(
125 MHz, DMSO-d ): 24.2, 25.3, 26.1, 29.5, 41.8, 47.2, 49.7,
541 [M+H] .
6
5
3.6, 58.6, 110.6, 113.0, 115.6, 117.9, 120.0, 120.2, 122.5,
1
3

Molecular Diversity
1
1‑(3‑((1‑(4‑Bromobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
2.07 (d, J = 15.9 Hz, 1H, H-4), 2.17 (d, J = 15.9 Hz, 1H,
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9b‑9)
H-4), 2.55–2.59 (m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.64 (s,
2
2H, NCH ), 5.65 (d, J=5.7 Hz, 1H, H-11), 6.13 (brs, 1H,
2
NHCH), 6.51 (d, J=7.3 Hz, 1H, H-9), 6.54–6.59 (m, 2H,
H-7 and H-8), 6.74 (d, J=8.1 Hz, 2H, H-3′ and H-5′), 6.90
(d, J=7.5 Hz, 1H, H-6), 6.99 (d, J=8.1 Hz, 2H, H-2′ and
H-6′), 7.19–7.26 (m, 2H, H-5″ and H-6″), 7.31 (t, J=7.4 Hz,
1H, H-3″), 7.40–7.41 (m, 1H, H-4″), 8.19 (s, 1H, H-4, tria-
White solid; Yield: 0.184 g (63%); mp 118–119 °C; IR
−
1
1
(
KBr, cm ): 3328, 3273, 1645, 1587. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2
.08 (d, J = 15.9 Hz, 1H, H-4), 2.18 (d, J = 15.9 Hz, 1H,
1
3
H-4), 2.57–2.60 (m, 2H, H-2), 4.95 (s, 2H, OCH ), 5.58
zole), 8.74 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
2
6
(
s, 2H, NCH ), 5.66 (d, J = 5.0 Hz, 1H, H-11), 6.15 (d,
28.2, 29.2, 32.5, 44.8, 50.2, 52.7, 55.9, 61.6, 110.6, 115.2
(d, J = 20.0 Hz), 115.8 (2C), 117.9, 120.3, 122.5, 123.0,
123.4 (d, J = 20.0 Hz), 123.8, 124.7, 126.8 (2C), 128.9,
130.6, 134.3, 136.4, 138.2, 146.2, 153.0, 157.0, 160.7 (d,
J = 251.1 Hz), 197.2. Anal. Calcd. For C H FN O : C,
2
J = 4.3 Hz, 1H, NHCH), 6.52–6.60 (m, 3H, H-7, H-8 and
H-9), 6.67–6.68 (m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′),
6
7
2
.90 (d, J=7.5 Hz, 1H, H-6), 7.01 (t, J=7.5 Hz, 1H, H-5′),
.27 (d, J=7.9 Hz, 2H, H-2″ and H-6″), 7.57 (d, J=7.9 Hz,
H, H-3″ and H-5″), 8.21 (s, 1H, H-4, triazole), 8.74 (s, 1H,
3
1
30
5
2
71.11; H, 5.78; N, 13.38%. Found: C, 71.47; H, 5.44; N,
1
3
+
NH). C NMR (125 MHz, DMSO-d ): 27.5, 28.4, 31.8,
13.62%. ESI–MS m/z: 524 [M+H] .
6
4
1
9.5, 52.0, 55.8, 58.9, 62.2, 109.9, 111.7, 113.9, 119.5,
19.9, 120.5, 121.4, 122.6, 128.6, 130.2 (2C), 131.0, 131.7
11‑(4‑((1‑(2‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑2)
(
2C), 135.4, 138.5, 143.0, 146.4, 154.8, 157.7, 192.1. Anal.
Calcd. For C H BrN O : C, 63.70; H, 5.17; N, 11.98%.
3
1
30
5
2
Found: C, 63.46; H, 5.43; N, 11.64%. ESI–MS m/z: 585
+
−1
[
M+H] .
White solid; Yield: 0.181 g (67%); IR (KBr, cm ): 3342,
1
3
227, 1641, 1555. H NMR (500 MHz, DMSO-d ): 1.02 (s,
6
3
,3‑Dimethyl‑11‑(3‑((1‑(4‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
1,4]diazepin‑1‑one (9b‑10)
3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.07 (d, J=15.8 Hz,
3 3 2
2
1H, H-4), 2.17 (d, J=15.8 Hz, 1H, H-4), 2.55–2.59 (m, 2H,
[
H-2), 4.98 (s, 2H, OCH ), 5.63 (d, J = 5.7 Hz, 1H, H-11),
2
5
.68 (s, 2H, NCH ), 6.12 (d, J=5.6 Hz, 1H, NHCH), 6.51
2
Yellow solid; Yield: 0.187 g (68%); mp 118–119 °C; IR
(d, J=7.4 Hz, 1H, H-9), 6.54–6.59 (m, 2H, H-7 and H-8),
6.75 (d, J=8.4 Hz, 2H, H-3′ and H-5′), 6.90 (d, J=7.4 Hz,
1H, H-6), 6.99 (d, J=8.4 Hz, 2H, H-2′ and H-6′), 7.18 (d,
J=7.2 Hz, 1H, H-6″), 7.33–7.40 (m, 2H, H-5″ and H-3″),
7.51 (m, 1H, H-4″), 8.18 (s, 1H, H-4, triazole), 8.73 (s, 1H,
−
1
1
(
KBr, cm ): 3325, 3271, 1671, 1542. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2
.85 (d, J = 14.6, 1H, H-4), 2.18 (d, J = 14.6 Hz, 1H,
H-4), 2.55–2.59 (m, 2H, H-2), 4.98 (s, 2H, OCH ), 5.65
2
1
3
(
d, J = 5.6 Hz, 1H, H-11), 5.78 (s, 2H, NCH ), 6.16 (d,
NH). C NMR (125 MHz, DMSO-d ): 26.9, 27.9, 31.2,
2
6
J = 5.7 Hz, 1H, NHCH), 6.25–6.46 (m, 3H, H-7, H-8 and
H-9), 6.67–6.68 (m, 2H, H-4′ and H-6′), 6.74 (s, 1H, H-2′),
43.5, 48.9, 50.0, 54.7, 60.2, 109.9, 113.2, 118.9, 119.4,
120.0, 122.0, 124.3, 127.1, 127.7 (2C), 129.0 (2C), 129.7,
129.9, 130.5, 132.0, 132.6, 136.6, 138.1, 142.4, 154.1,
155.5, 191.5. Anal. Calcd. For C H ClN O : C, 68.94;
6
7
2
.9 (d, J=7.5 Hz, 1H, H-6), 7.02 (t, J=7.8 Hz, 1H, H-5′),
.52 (d, J=8.4 Hz, 2H, H-2″ and H-6″), 8.24 (d, J=8.4 Hz,
H, H-3″ and H-5″), 8.27 (s, 1H, H-4, triazole), 8.74 (s, 1H,
3
1
30
5
2
H, 5.60; N, 12.97%. Found: C, 68.63; H, 5.77; N, 12.74%.
1
3
+
NH). C NMR (125 MHz, DMSO-d ): 27.0, 27.8, 31.2,
ESI–MS m/z: 541 [M+H] .
6
4
1
1
1
5
3.5, 48.9, 51.4, 55.2, 60.3, 109.5, 111.2, 113.5, 118.9,
19.4, 119.9, 122.0, 123.3 (2C), 124.4, 128.0, 128.5 (2C),
30.4, 137.9, 142.6, 142.7, 145.8, 146.6, 151.4, 154.2,
57.1, 191.5. Anal. Calcd. For C H N O : C, 67.62; H,
3,3‑Dimethyl‑11‑(4‑((1‑(3‑methylbenzyl)‑1H‑1,2,3
‑triazol‑4‑yl)methoxy)phenyl)‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑3)
3
1
30
6
4
.49; N, 15.26%. Found: C, 67.48; H, 5.11; N, 15.09%.
+
ESI–MS m/z: 551 [M+H] .
White solid; Yield: 0.166 g (64%); mp 122–123 °C; IR
−
1
1
(
KBr, cm ): 3351, 3243, 1650, 1572. H NMR (500 MHz,
11‑(4‑((1‑(2‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
DMSO-d ): 1.03 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
3 2 3 2
6
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑1)
2.07 (d, J = 15.8 Hz, 1H, H-4), 2.19 (d, J = 15.8 Hz, 1H,
H-4), 2.27 (s, 3H, CH ), 2.55–2.58 (m, 2H, H-2), 4.96 (s,
3
2
H, OCH ), 5.52 (s, 2H, NCH ), 5.65 (d, J = 5.5 Hz, 1H,
2
2
White solid; Yield: 0.186 g (71%); mp 133–134 °C; IR
H-11), 6.11 (brs, 1H, NHCH), 6.51 (d, J = 7.5 Hz, 1H,
H-9), 6.55–6.60 (m, 2H, H-7 and H-8), 6.75 (d, J=8.5 Hz,
2H, H-3′ and H-5′), 6.90 (d, J=7.4 Hz, 1H, H-6), 7.00 (d,
−
1
1
(
KBr, cm ): 3333, 3240, 1653, 1571. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
1
3

Molecular Diversity
J = 8.5 Hz, 2H, H-2′ and H-6′), 7.07–7.13 (m, 3H, H-2″,
H-4″ and H-5″), 7.22–7.24 (m, 1H, H-6″), 8.18 (s, 1H, H-4,
149.7, 157.0, 193.1. Anal. Calcd. For C H ClN O : C,
31 30 5 2
68.94; H, 5.60; N, 12.97%. Found: C, 68.62; H, 5.87; N,
1
3
+
triazole), 8.72 (s, 1H, NH). C NMR (125 MHz, DMSO-
12.74%. ESI–MS m/z: 541 [M + H] .
d ): 20.3, 26.9, 27.9, 31.2, 43.5, 48.9, 52.2, 54.6, 60.3, 110.0,
6
1
1
1
13.1, 118.8, 119.3, 119.9, 122.0, 123.9, 124.5, 127.7 (2C),
27.9, 128.1, 128.2 (2C), 130.5, 135.3, 136.6, 137.4, 138.1,
42.5, 154.0, 155.5, 191.4. Anal. Calcd. For C H N O :
3,3‑Dimethyl‑11‑(4‑((1‑(3‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
[1,4]diazepin‑1‑one (9c‑6)
3
2
33
5
2
C, 73.96; H, 6.40; N, 13.48%. Found: C, 73.64; H, 6.77; N,
+
1
3.16%. ESI–MS m/z: 520 [M+H] .
Yellow solid; Yield: 0.192 g (70%); mp 132–133 °C; IR
−
1
1
11‑(4‑((1‑(3‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
(KBr, cm ): 3347, 3223, 1647, 1569. H NMR (500 MHz,
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑4)
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2.07 (d, J = 15.8 Hz, 1H, H-4), 2.17 (d, J = 15.8 Hz, 1H,
H-4), 2.55–2.58 (m, 2H, H-2), 4.98 (s, 2H, OCH ), 5.63
2
White solid; Yield: 0.178 g (68%); mp 125–127 °C; IR
(d, J = 5.5 Hz, 1H, H-11), 5.76 (s, 2H, NCH ), 6.17 (brs,
2
−
1
1
(
KBr, cm ): 3325, 3219, 1667, 1581. H NMR (500 MHz,
1H, NHCH), 6.51 (d, J = 7.2 Hz, 1H, H-9), 6.55–6.59 (m,
2H, H-7 and H-8), 6.75 (d, J = 8.3 Hz, 2H, H-3′ and H-5′),
6.90 (d, J = 7.5 Hz, 1H, H-6), 6.99 (d, J = 8.3 Hz, 2H,
H-2′ and H-6′), 7.67 (t, J = 7.8 Hz, 1H, H-5″), 7.74 (d,
J = 7.4 Hz, 1H, H-6″), 8.19 (d, J = 8.2 Hz, 1H, H-4″), 8.22
(s, 1H H-2″), 8.28 (s, 1H, H-4, triazole), 8.73 (s, 1H, NH).
DMSO-d ): 1.03 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
2
.07 (d, J = 15.8 Hz, 1H, H-4), 2.18 (d, J = 15.8 Hz, 1H,
H-4), 2.55–2.60 (m, 2H, H-2), 4.97 (s, 2H, OCH ), 5.60
2
(
s, 2H, NCH ), 5.63 (d, J = 5.7 Hz, 1H, H-11), 6.11 (d,
2
J = 5.2 Hz, 1H, NHCH), 6.51 (d, J = 7.4 Hz, 1H, H-9),
1
3
6
.54–6.61 (m, 2H, H-7 and H-8), 6.75 (d, J= 8.4 Hz, 2H,
C NMR (125 MHz, DMSO-d ): 26.9, 27.9, 31.2, 43.5,
6
H-3′ and H-5′), 6.90 (d, J = 7.4 Hz, 1H, H-6), 6.99 (d,
J = 8.4 Hz, 2H, H-2′ and H-6′), 7.11 (d, J = 7.7 Hz, 1H,
H-6″), 7.15–7.16 (m, 2H, H-2″ and H-4″), 7.39–7.43 (m,
48.9, 51.2, 54.7, 60.3, 109.9, 113.2, 118.9, 119.4, 120.0,
122.0, 122.2, 122.5, 124.2, 127.8 (2C), 129.8 (2C), 130.5,
134.1, 136.6, 137.4, 138.1, 142.7, 147.3, 154.1, 155.5,
191.5. Anal. Calcd. For C H N O : C, 67.62; H, 5.49;
1
3
1
H, H-5″), 8.23 (s, 1H, H-4, triazole), 8.71 (s, 1H, NH). C
3
1
30
6
4
NMR (125 MHz, DMSO-d ): 27.6, 28.7, 31.9, 44.3, 49.6,
N, 15.26%. Found: C, 67.79; H, 5.63; N, 15.51%. ESI–MS
6
+
5
0.8, 55.4, 60.9, 110.6, 114.6 (d, J = 20.0 Hz), 115.3 (d,
m/z: 551 [M + H] .
J=20.0 Hz), 115.8 (2C), 117.9, 120.2, 122.5, 123.0, 123.8,
1
1
24.3, 126.8 (2C), 130.1, 134.3, 136.4, 137.9, 138.2, 146.2,
53.0, 157.0, 162.8 (d, J=252.5 Hz), 197.2. Anal. Calcd.
3,3‑Dimethyl‑11‑(4‑((1‑(4‑methylbenzyl)‑1H‑1,2,3
‑triazol‑4‑yl)methoxy)phenyl)‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑7)
For C H FN O : C, 71.11; H, 5.78; N, 13.38%. Found:
3
1
30
5
2
+
C, 71.38; H, 5.51; N, 13.07%. ESI–MS m/z: 524 [M+H] .
1
1‑(4‑((1‑(3‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
White solid; Yield: 0.163 g (63%); mp 124–125 °C;
−
1
1
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑5)
IR (KBr, cm ): 3341, 3225, 1668, 1565. H NMR
(500 MHz, DMSO-d ): 1.03 (s, 3H, C(CH ) ), 1.07 (s,
6
3 2
3
H, C(CH ) ), 2.07 (d, J = 15.9 Hz, 1H, H-4), 2.19 (d,
3
2
White solid; Yield: 0.181 g (67%); mp 119–120 °C; IR
J = 15.9 Hz, 1H, H-4), 2.26 (s, 3H, CH ), 2.54–2.58
3
−
1
1
(
KBr, cm ): 3342, 3264, 1665, 1556. H NMR (500 MHz,
(m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.51 (s, 2H, NCH ),
2
2
DMSO-d ): 1.03 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
5.65 (d, J = 5.7 Hz, 1H, H-11), 6.13 (d, J = 5.7 Hz, 1H,
NHCH), 6.52 (d, J = 7.5 Hz, 1H, H-9), 6.52–6.60 (m, 2H,
H-7 and H-8), 6.74 (d, J = 8.4 Hz, 2H, H-3′ and H-5′),
6.91 (d, J = 7.5 Hz, 1H, H-6), 7.00 (d, J = 8.4 Hz, 2H,
H-2′ and H-6′), 7.16–7.20 (m, 4H, H-2″, H-3″, H-5″ and
6
3 2
3 2
2
.07 (d, J = 15.9 Hz, 1H, H-4), 2.17 (d, J = 15.9 Hz, 1H,
H-4), 2.55–2.68 (m, 2H, H-2), 4.98 (s, 2H, OCH ), 5.59
2
(
s, 2H, NCH ), 5.64 (d, J = 5.6 Hz, 1H, H-11), 6.10 (brs,
2
1
2
6
H, NHCH), 6.51 (d, J = 7.5 Hz, 1H, H-9), 6.54–6.59 (m,
H, H-7 and H-8), 6.75 (d, J = 8.4 Hz, 2H, H-3′ and H-5′),
.90 (d, J =7.5 Hz, 1H, H-6), 7.00 (d, J =8.4 Hz, 2H, H-2′
1
3
H-6″), 8.16 (s, 1H, H-4, triazole), 8.74 (s, 1H). C NMR
(125 MHz, DMSO-d ): 20.7, 27.5, 28.5, 31.8, 44.1, 49.5,
6
and H-6′), 7.23–7.25 (m, 1H, H-4″), 7.37–7.39 (m, 3H,
H-2″, H-5″ and H-6″), 8.23 (s, 1H, H-4, triazole), 8.71
52.6, 55.2, 60.3, 110.4, 113.7, 119.4, 119.9, 120.5, 122.6,
124.4, 128.0 (2C), 128.3, 129.3 (2C), 131.0, 133.0, 137.1,
137.5, 138.7, 143.0, 154.6, 156.1, 192.0. Anal. Calcd. For
C H N O : C, 73.96; H, 6.40; N, 13.48%. Found: C,
1
3
(
s, 1H, NH). C NMR (125 MHz, DMSO-d ): 25.8, 26.8,
6
3
1
1
0.1, 42.4, 47.8, 50.3, 53.5, 59.1, 110.0, 115.8 (2C), 117.9,
20.2, 122.5, 123.0, 123.8, 126.8 (2C), 127.2, 127.4,
28.4, 129.7, 134.0, 134.2, 136.4, 137.2, 138.2, 146.2,
3
2
33
5
2
+
73.79; H, 6.17; N, 13.24%. ESI–MS m/z: 520 [M + H] .
1
3

Molecular Diversity
1
1‑(4‑((1‑(4‑Fluorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
2.07 (d, J = 15.8 Hz, 1H, H-4), 2.19 (d, J = 15.8 Hz, 1H,
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑8)
H-4), 2.55–2.58 (m, 2H, H-2), 4.97 (s, 2H, OCH ), 5.56
2
(s, 2H, NCH ), 5.63 (d, J = 5.5 Hz, 1H, H-11), 6.13 (brs,
2
1
H, NHCH), 6.52 (d, J=7.5 Hz, 1H, H-9), 6.54–6.61 (m,
White solid; Yield: 0.177 g (68%); mp 120–121 °C; IR (KBr,
2H, H-7 and H-8), 6.74 (d, J=8.4 Hz, 2H, H-3′ and H-5′),
6.90 (d, J=7.5 Hz, 1H, H-6), 6.99 (d, J=8.4 Hz, 2H, H-2′
and H-6′), 7.24 (d, J=8.5 Hz, 2H, H-2″ and H-6″), 7.56 (d,
J=8.5 Hz, 2H, H-3″ and H-5″), 8.20 (s, 1H, H-4, triazole),
−1
1
cm ): 3345, 3223, 1624, 1542. H NMR (500 MHz, DMSO-
d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ), 2.07
6
3 2
3 2
(
d, J = 15.9 Hz, 1H, H-4), 2.19 (d, J= 15.9 Hz, 1H, H-4),
1
3
2
.55–2.58 (m, 2H, H-2), 4.96 (s, 2H, OCH ), 5.56 (s, 2H,
8.73 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): 28.2,
2
6
NCH ), 5.64 (d, J=5.5 Hz, 1H, H-11), 6.13 (d, J=5.4 Hz,
29.1, 32.5, 44.8, 50.1, 51.3, 56.5, 61.5, 110.0, 115.8 (2C),
118.0, 120.2, 121.8, 122.5, 123.0, 123.8, 126.8 (2C), 130.2
(2C), 131.5 (2C), 134.0, 135.3, 136.4, 138.2, 146.2, 149.67,
157.0, 193.1. Anal. Calcd. For C H BrN O : C, 63.70;
2
1
2
6
H, NHCH), 6.51 (d, J=7.4 Hz, 1H, H-9), 6.54–6.61 (m,
H, H-7 and H-8), 6.74 (d, J=8.3 Hz, 2H, H-3′ and H-5′),
.90 (d, J=7.5 Hz, 1H, H-6), 6.99 (d, J=8.3 Hz, 2H, H-2′
3
1
30
5
2
and H-6′), 7.19–7.21 (m, 2H, H-2″ and H-6″), 7.37–7.40 (m,
H, 5.17; N, 11.98%. Found: C, 63.47; H, 5.34; N, 11.74%.
+
2
H, H-3″ and H-5″), 8.20 (s, 1H, H-4, triazole), 8.73 (s, 1H,
ESI–MS m/z: 585 [M+H] .
1
3
NH). C NMR (125 MHz, DMSO-d ): 26.9, 27.9, 31.2, 43.
6
6
, 48.9, 51.4, 54.7, 60.3, 110.0, 113.2 (2C), 115.1 (d, 2C,
3,3‑Dimethyl‑11‑(4‑((1‑(4‑nitrobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]
[1,4]diazepin‑1‑one (9c‑11)
J=21.2 Hz), 118.9, 119.4, 120.0, 122.4, 123.8, 127.7 (2C),
1
1
29.7 (d, 2C, J=8.7 Hz), 130.5, 131.6, 136.6, 138.2, 142.6,
54.0, 155.5, 161.3 (d, J=257.5 Hz), 191.4. Anal. Calcd.
For C H FN O : C, 71.11; H, 5.78; N, 13.38%. Found:
Yellow solid; Yield: 0.190 g (69%); mp 142–143 °C; IR
3
1
30
5
2
+
−1
1
C, 71.21; H, 5.63; N, 13.15%. ESI–MS m/z: 524 [M+H] .
(KBr, cm ): 3344, 3215, 1667, 1524. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
1
1‑(4‑((1‑(4‑Chlorobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
2.07 (d, J = 15.9 Hz, 1H, H-4), 2.19 (d, J = 15.9 Hz, 1H,
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑9)
H-4), 2.55–2.58 (m, 2H, H-2), 4.99 (s, 2H, OCH ), 5.63
2
(d, J = 5.6 Hz, 1H, H-11), 5.76 (s, 2H, NCH ), 6.12 (d,
2
J = 5.6 Hz, 1H, NHCH), 6.51 (d, J = 7.5 Hz, 1H, H-9),
6.55–6.59 (m, 2H, H-7 and H-8), 6.75 (d, J= 8.4 Hz, 2H,
H-3′ and H-5′), 6.90 (d, J = 7.5 Hz, 1H, H-6), 7.00 (d,
J=8.4 Hz, 2H, H-2′ and H-6′), 7.51 (d, J=8.5 Hz, 2H, H-2″
and H-6″), 8.23 (d, J=8.5 Hz, 2H, H-3″ and H-5″), 8.27 (s,
White solid; Yield: 0.175 g (65%); mp 121–122 °C; IR
−
1
1
(
KBr, cm ): 3358, 3222, 1649, 1537. H NMR (500 MHz,
DMSO-d ): 1.03 (s, 3H, C(CH ) ), 1.08 (s, 3H, C(CH ) ),
6
3 2
3 2
2
.09 (d, J = 15.9 Hz, 1H, H-4), 2.20 (d, J = 15.9 Hz, 1H,
1
3
H-4), 2.55–2.63 (m, 2H, H-2), 4.97 (s, 2H, OCH ), 5.61
1H, H-4, triazole), 8.73 (s, 1H, NH). C NMR (125 MHz,
2
(
s, 2H, NCH ), 5.67 (d, J = 5.5 Hz, 1H, H-11), 6.19 (d,
DMSO-d ): 27.4, 28.5, 31.8, 44.6, 49.6, 51.9, 55.4, 60.3,
2
6
J = 5.7 Hz, 1H, NHCH), 6.54–6.63 (m, 3H, H-7, H-8 and
H-9), 6.69 (d, J = 8.4 Hz, 2H, H-3′ and H-5′), 6.76 (d,
J=7.5 Hz, 1H, H-6), 6.92 (d, J=8.4 Hz, 2H, H-2′ and H-6′),
109.4, 110.4, 113.7, 119.8, 120.3, 121.7, 123.9, 125.5,
128.3, 129.0, 131.0, 136.4, 137.1, 138.8, 143.4, 147.2,
154.7, 156.0, 192.1. Anal. Calcd. For C H N O : C, 67.62;
31
30
6
4
7
2
.34 (d, J=8.5 Hz, 2H, H-2″ and H-6″), 7.45 (d, J=8.5 Hz,
H, H-3″ and H-5″), 8.23 (s, 1H H-4, triazole), 8.77 (s, 1H,
H, 5.49; N, 15.26%. Found: C, 67.29; H, 5.27; N, 15.07%.
+
ESI–MS m/z: 551 [M+H] .
1
3
NH). C NMR (125 MHz, DMSO-d ): 27.0, 27.8, 31.2,
6
4
1
3.5, 48.9, 51.4, 55.2, 60.2, 109.4, 111.2, 113.4, 118.9,
Molecular modelling
19.4 (2C), 119.9, 122.1, 124.0 (2C), 128.2 (2C), 129.3
(
2C), 130.4, 132.3, 134.3, 137.9, 142.5, 145.8, 154.2, 157.1,
Docking studies were performed with Autodock (ver. 4.2.6.)
The 3D structure of acetylcholinesterase (PDB entry code
(4EY7) in complex with donepezil) and butyrylcholinester-
ase (PDB entry code (4BDS) in complex with tacrine) was
obtained from protein data bank. After editing the crystallo-
graphic structure which contains removing ligand and water
molecules and adding hydrogen atoms, the prepared ligands
(the ligands were sketched and optimized in MarvinSketch
1
91.5. Anal. Calcd. For C H ClN O : C, 68.94; H, 5.60;
31 30 5 2
N, 12.97%. Found: C, 68.79; H, 5.37; N, 13.19%. ESI–MS
+
m/z: 541 [M+H] .
11‑(4‑((1‑(4‑Bromobenzyl)‑1H‑1,2,3‑triazol‑4‑yl)
methoxy)phenyl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑
dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one (9c‑10)
1
5.8.1, 2015) were docked into the active site of protein.
White solid; Yield: 0.181 g (62%); mp 132–133 °C; IR
Upon completion of docking simulations, the superior dock-
ing poses were selected and their interactions with the recep-
tor were drafted and viewed by Discovery Studio visualizer
−
1
1
(
KBr, cm ): 3347, 3268, 1685, 1563. H NMR (500 MHz,
DMSO-d ): 1.02 (s, 3H, C(CH ) ), 1.07 (s, 3H, C(CH ) ),
6
3 2
3 2
1
3

Molecular Diversity
4
.5. To visualize the 3D and 2D diagram interactions, we
Compliance with ethical standards
open the ligand and receptor complex ꢀle created by Auto-
dock with this programme.
Conflict of interest The authors declare that they have no conꢂict of
interest.
Anticholinesterase assay
Biological tests were performed to determine the amount
of inhibition of acetylcholinesterase enzyme by Ellman
method. In this method, hydrolysis of acetylthiocholine
and butyrylthiocholine by AChE and BuChE yields to the
production of acetate or butyrate and thiocholine. Butyryl-
cholinesterase and acetylcholinesterase are obtained from
equine serum and electrophorus electricus (AChE, eel),
respectively. Each compound was tested in ꢀve diꢁerent
concentrations against the enzyme to achieve a range of
inhibition between 20 and 80%. After 5-min incubation of
a mixture containing phosphate buꢁer (0.1 M, pH= 8.0,
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2
min using a Synergy BioTech multiplate reader. The stock
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1
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Determination oꢀ the inhibitory potency on Aβ1–42
selꢀ‑aggregation
In order to determinate the inhibitory properties of com-
pounds on the Aβ
self-aggregation, a Thioꢂavin T (ThT)-
1
–42
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1
–42
peptide with ꢀnal Aβ concentration of 50 μM, Aβ
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◦
buꢁer (pH 7.4) and incubated at 37 C for 72 h. To perform-
ing the experiment, 10 μL Aβ
was added to phosphate
–42
1
1
buꢁer (pH 7.4) with and without inhibitor (100 μM) and
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5
0 μL of thioꢂavin-T with 200 µM concentration in 50 mM
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where IF and IF are the ꢂuorescence intensities obtained
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Aꢀliations
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1
1
4
Mehrdad Mehrazar · Mahdi Hassankalhori · Mahsa Toolabi · Fereshteh Goli · Setareh Moghimi · Hamid Nadri ·
5
1
3,6
Syed Nasir Abbas Bukhari · Loghman Firoozpour · Alireza Foroumadi
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4
Drug Design and Development Research Center, The
Institute of Pharmaceutical Sciences (TIPS), Tehran
University of Medical Sciences, Tehran, Iran
Department of Medicinal Chemistry, Faculty of Pharmacy,
Shahid Sadoughi University of Medical Sciences, Yazd, Iran
5
Department of Pharmaceutical Chemistry, College
of Pharmacy, Jouf University, Aljouf, Sakaka 2014,
Saudi Arabia
Department of Medicinal Chemistry, Faculty of Pharmacy,
Tehran Medical Sciences, Islamic Azad University, Tehran,
Iran
6
Neuroscience Research Center, Institute
of Neuropharmacology, Kerman University of Medical
Sciences, Kerman, Iran
Department of Medicinal Chemistry, Faculty of Pharmacy,
Tehran University of Medical Sciences, Tehran, Iran
1
3