Synthesis and evaluation of antitumor activity of dibenzodiazepine derivatives

Article abstract of DOI:10.1007/s11030-020-10051-z

Abstract: A series of dibenzodiazepine 2-position derivatives, bearing N-methylpiperazine at the C-11 position, were prepared by using a concise approach. Their inhibitory activities of tumor cell proliferation in vitro were tested in five cell lines, including breast cancer cell BCAP37, gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell HeLa and acute promyelocytic leukemia cell HL-60. Several compounds showed efficient tumor activity with IC₅₀ values down to 0.30?μM. These compounds are expected to be a new class of potential anticancer lead compounds. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11030-020-10051-z

Molecular Diversity
https://doi.org/10.1007/s11030-020-10051-z
SHORT COMMUNICATION
Synthesis and evaluation of antitumor activity of dibenzodiazepine
derivatives
Ke Cao1 · Jianwei Yan1 · Fulin Yan1,2 · Tiantian Yin2
Received: 21 October 2019 / Accepted: 7 February 2020
© Springer Nature Switzerland AG 2020
Abstract
A series of dibenzodiazepine 2-position derivatives, bearing N-methylpiperazine at the C-11 position, were prepared by
using a concise approach. Their inhibitory activities of tumor cell proliferation in vitro were tested in fve cell lines, includ-
ing breast cancer cell BCAP37, gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell HeLa and acute
promyelocytic leukemia cell HL-60. Several compounds showed efcient tumor activity with IC50 values down to 0.30 μM.
These compounds are expected to be a new class of potential anticancer lead compounds.
Graphic abstract
Keywords Dibenzodiazepine · Halogenation · Suzuki reaction · N-methylpiperazine · Antitumor activity
Introduction
drugs were used in clinical patients, the emergence of drug
resistance, adverse side efects and high costs of the produc-
tion have limited their utilization [4, 5]. It is still urgent for
researchers to design and synthesize novel antitumor drugs
with new skeletons.
Malignant tumors are serious diseases that threaten human
health [1, 2]. As one of the three main treatments for cancer,
chemotherapy is a systemic treatment in which chemothera-
peutic drugs interfere with the cell cycle, leading to cell divi-
sion and induction of tumor cell apoptosis through a variety
of pathways [3]. Although a large number of antineoplastic
Dibenzodiazepines are an important class of heterocyclic
compounds displaying diverse biological activities (Fig. 1).
Diazepinomicin 1, a secondary metabolite extracted from
the marine actinomycete spores [6], could induce apopto-
sis in hepatoma cells [7] and inhibit tumor invasion and
angiogenesis in vitro [8]. Triazole derivative 2 could inhibit
tumor cell proliferation through apoptosis induction [9].
Compound 3 was a highly selective p21-activated kinase
1 (PAK1) inhibitors [10]. 5,10-Dihydro-dibenzo[b,e] [1,
4] diazepin-11-ones 4 were a selective checkpoint kinase 1
(Chk1) inhibitors and exhibited a strong ability to abrogate
G2 arrest and increased the cytotoxicity of camptothecin
[11]. Dibenzodiazepinone 5 represents an inhibitor of the
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-020-10051-z) contains
supplementary material, which is available to authorized users.
* Fulin Yan
yannz2009@163.com
1
Pharmacy College, Xinxiang Medical University,
Xinxiang 453003, China
2
Sanquan College of Xinxiang Medical University,
Xinxiang 453003, China
Vol.:(0123456789)
1 3

Molecular Diversity
Fig. 1 Structures of representative dibenzodiazepinone compounds
EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S)
mutants [12]. Amide derivative 6 exhibits high muscarinic
receptor afnity [13]. As potential atypical antipsychotic,
sulfonyloxypiperazinyldibenzazepine 7 acts on a variety of
CNS receptors [14]. Clozapine 8, a dibenzodiazepine deriva-
tive with a piperazinyl side chain, is one of the representa-
tives of atypical antipsychotic drugs [15]. The Lee and Kim
group reported that clozapine could modulate the PI3K/Akt/
GSK-3β pathway, resulting in the inhibition of cell cycle
progression [16]. Jesien-Lewandowicz group reported a
female schizophrenia, 39 months after diagnosis of meta-
static small-cell carcinoma, is disease free associated with
long-term use of clozapine [17]. Massari group reported
clozapine exhibits an antitumoral efect in vitro and in vivo
on human melanoma [18]. These reports suggested that
dibenzodiazepine derivatives containing N-methylpiperazine
side chains may have antitumor efect. However, the reports
about antitumor active of dibenzodiazepine compounds with
N-methylpiperazine side chain are rare. In order to further
explore the antitumor activity of dibenzodiazepine deriva-
tives and to fnd precursor compounds with better activity,
we synthesized a series of dibenzodiazepine 2-position
derivatives, bearing N-methylpiperazine at the C-11 posi-
tion, and estimated their antitumor activities [19].
Results and discussion
The dibenzodiazepine compounds were synthesized as
depicted in scheme 1. Initially, esterifcation of o-iodoben-
zoic acid gives ethyl iodobenzoate, following reaction with
o-phenylenediamine in the presence of 5 mol % CuI full of
nitrogen in microwave irradiation at 180 °C to give 5a in
50% yield [20, 21]. The compound 5a was refuxed with
POCl3 and N,N-dimethylaniline under nitrogen protec-
tion at 130 °C for 12 h, removed excess POCl3 and added
N-methylpiperazine to continue reaction for 12 h to form
compound 6a [22]. Alternatively, o-phenylenediamine was
replaced with 4,5-dimethyl-1,2-phenylenediamine under the
same conditions to react with ethyl iodobenzoate to yield
compound 6b fnally.
Compound 5a was treated with N-bromosuccinimide
(NBS) in N,N-dimethylformamide (DMF) at 0 °C to aford
monobrominated compound 7a and dibrominated compound
7b. The structure of monobrominated product 7a was con-
frmed by single-crystal X-ray difraction analysis (Fig. 2).
The replace site 2-position and the 8-position of 7b was
determined by spectral analysis. Similarly, compound 5a
was treated with 1,3-dichloro-5,5-dimethylhydantoin in tet-
rahydrofuran at 0 °C to aford chlorinated intermediates 7c
Scheme 1 Reagents and conditions: a absolute ethanol, H2SO4,
90 °C refux 10 h, 96%; b benzene-1,2-diamine or 4,5-dimethylb-
enzene-1,2-diamine, CuI, K3PO4, ethylene glycol, N2, MW 180 °C,
1 h, 51–65%; c N,N-dimethylaniline, POCl3, N2, 130 °C refux 12 h;
1-methylpiperazine, 130 °C, 12 h, 4.6–75%
1 3

Molecular Diversity
In order to construct the derivatives with structural diver-
sity more efciently and conveniently, we synthesized the
2-substituted dibenzoxazinium compounds by using Suzuki
reaction in Scheme 3. Compound 7a reacted with various
boric acid derivatives and Pd(PPh3)4 or Pd(PPh3)2Cl2 as a
catalyst in mixed solvent at 80 °C or 130 °C for 4–12 h to
yield compounds 9a–9u [23]. These compound interme-
diates were refuxed, respectively, with POCl3 and N,N-
dimethylaniline under nitrogen protection at 130 °C for
12 h, removed excess POCl3 and added N-methylpiperazine
to continue reaction for 12 h to form compounds 10a–10u
(Scheme 2).
The inhibitory activity of synthesized dibenzoazepine
derivatives against fve diferent human tumor cell lines
including breast (BCAP37), gastric (SGC7901), liver
(HepG2), cervical (HeLa) and acute promyelocytic leu-
kemia (HL-60) was screened by using SRB assay, and
the results are illustrated in Table 1. The results indicated
that the inhibition rates of compounds 8b, 10f, 10j, 10k,
10m, 10p, 10r, 10s against these fve tumor cells ranged
Fig. 2 X-ray crystallographic structures of 7a
and 7d. The intermediates were refuxed with POCl3 in N,N-
dimethylaniline under nitrogen protection at 130 °C for 12 h,
removing excess POCl3 and adding N-methylpiperazine to
continue reaction for 12 h to form compounds 8a, 8b, 8c
[22] and 8d, respectively (Scheme 2).
Scheme 2 Reagents and condi-
tions: c N,N-dimethylaniline,
POCl3, N2, 130 °C refux 12 h;
1-methylpiperazine, 130 °C
12 h 4.6–75%; d for 7a, 7b:
NBS, DMF, 0 °C, 2 h, 10–60%;
e for 7c, 7d: 1,3-dichloro-5,5-di-
methylhydantoin, tetrahydro-
furan, 0 °C, 2 h, 10–60%
Scheme 3 Reagents and conditions: c N,N-dimethylaniline, POCl3,
N2, 130 °C refux 12 h; 1-methylpiperazine, 130 °C 12 h 4.6–75%;
water=4:2:1, 80 °C, 6-12 h, 43%-89%; g for 9p, 9q: R5-B(OH)2,
Pd(PPh3)2Cl2, K2CO3, N,N-dimethylformamide/water=2:1, 130 °C,
4 h, 78–90%
f
for 9a-9o: R5-B(OH)2, Pd(PPh3)4, K2CO3, toluene/alcohol/
1 3

Molecular Diversity
Table 2 In vitro antitumor activities of synthesized compoundsa
Table 1 In vitro antitumor activities of synthesized compounds with
inhibition rate % at 5 μM
Compound
IC50 (μmol/L)
Compound
Inhibition rate (%)
BCAP37
SGC7901
HepG2
HeLa
HL-60
BCAP37
SGC7901
HepG2
HeLa
HL-60
8b
0.9
3.8
1.5
1.0
1.2
1.1
1.4
2.9
2.2
0.26
0.8
0.7
0.57
2.0
2.8
2.0
1.5
0.8
1.2
2.0
1.8
1.1
0.3
0.9
0.8
0.3
5.1
NTb
NT
NT
5.1
3.0
2.5
4.8
3.1
1.5
2.6
1.5
1.2
2.8
NT
NT
NT
2.3
2.7
5.1
5.7
5.4
1.6
3.2
1.4
2.5
1.5
2.5
1.3
1.0
2.1
1.6
0.9
6.2
5.4
0.5
0.8
0.9
0.3
6a
0
4
0
91
3
8
5
0
7
5
89
10
7
5
5
0
64
14
10
4
1
4
7
70
3
5
4
6
17
5
69
11
10
7
10f
6b
10j
10k
10l
8a
8b
8c
10m
10n
10o
10p
10q
10r
10s
5-FU
8d
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
6
14
21
11
6
73
10
10
4
85
90
NT
85
NT
NT
84
NT
93
90
18
13
8
6
9
12
7
10
8
1
9
2
7
NT
59
NT
NT
76
NT
70
73
8
7
8
6
7
3
8
6
12
11
2
NT
61
NT
NT
68
NT
75
72
12
8
4
1
28
13
66
17
4
17
13
6
73
7
3
4
91
84
NT
91
NT
NT
86
NT
88
93
21
8
2
and 4-Cl phenyl derivative 10j and 10k on BCAP37,
SGC7901 and HL-60 cells increased obviously. However,
compounds 10g and 10i substituted, respectively, by 4-F
phenyl and 2-Cl phenyl at the 2-position showed almost
no inhibition rates on these fve cells. 3-CF3, 4-CF3, 2-CH3
3-CH3, 4-CH3 phenyl group-substituted dibenzodiazepine
derivatives 10l–10p showed remarkable cytotoxic activity
on these fve tumor cells, and the IC50 ranged between
0.8 and 5.7 μmol/L. When dibenzodiazepine substituted
in 2-position with 4-ethylphenyl, the activity of the com-
pound 10q on fve tumor cells increased signifcantly, with
IC50 down to 0.26–1.6 μmol/L. Compound 10q exhibited
more stronger activities than 5-FU in the breast cancer
cell BCAP37 and cervical cancer cell HeLa. When larger
groups 1-naphthyl and 2-naphthyl were introduced into
2-position, compounds 10r and 10s also displayed strong
anticancer activities in fve cell lines.
82
82
NT
80
NT
NT
91
NT
80
82
11
15
9
from 59% to 93% at a single concentration (5 μM). Subse-
quently, we tested the IC50 of compounds 8b, 10l–10s on
fve tumor cells and the IC50 of compounds 10f, 10j and
10k on BCAP37, SGC7901 and HL-60 cells to further
evaluate the antitumor activity of these active compounds.
As illustrated in Table 2, the IC50 values ranged from 0.2 to
5.7 μmol·L−1. As shown by data, unsubstituted compound
6a and the 2-position phenyl group-substituted compound
10a did not exhibit inhibitory activity on fve tumor cells.
2-Position and 8-position dibromo dibenzodiazepine
derivative 8b displayed moderate-to-potent growth inhi-
bition against the tested cancer cells and selective potency
against BCAP37 cells with IC50 value down to 0.9 μmol/L.
The 2-position 3-F phenyl group compound 10f exhib-
ited moderate growth inhibition potency against BCAP37,
SGC7901 and HL-60. The inhibition rates of 3-Cl phenyl
Conclusion
In conclusion, some dibenzodiazepine compounds, intro-
duced by N-methylpiperazine side chain, showed remark-
able antitumor activity. Among them, compounds 10q, 10r
and 10s have the similar or better activity as 5-FU on fve
diferent cells. These compounds are expected to become a
potential new type of anticancer drugs and laid the founda-
tion for further derivatization and pharmacological studies
of the class of dibenzodiazepine compounds.
1 3

Molecular Diversity
Experimental section
General
in suitable DMF was added a solution of NBS (979 mg,
5.5 mmol) in DMF (2 mL), dropwise over 5 min. The reac-
tion was stirred at 0 °C for 2 h. TLC analysis indicated the
starting material had been consumed. The reaction mixture
was diluted with EtOAc and washed with H2O and brine.
The organic layer was dried over Na2SO4, and concentrated
in vacuo. The residue was purifed by column chromatog-
raphy on silica gel (eluting with 5:1 petroleum ether/ethyl
acetate) to yield compound 7a (864 mg, 60%) as a yellow
solid. 1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.04 (s,
1H), 7.74 (d, J=2.4 Hz, 1H), 7.49 (dd, J=8.6, 2.5 Hz, 1H),
6.99–6.89 (m, 5H).
Chemistry
1
All H NMR and 13C NMR spectra were measured in
DMSO-d6 or CDCl3 using a Bruker ASCEND 400 spec-
trometer. Chemical shifts were expressed in ppm, and J val-
ues were given in Hz. High-resolution mass spectra were
recorded on Bruker micrOTOF-QIII MS (ESI and APCI).
Column chromatography was performed with 200–300 mesh
silica gel using fash column techniques. Melting points
(uncorrected) were determined on a yalixien X-4 melting
point apparatus. All the solvents and reagents were used
directly as obtained commercially unless otherwise noted.
2,8‑dibromo‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑
one (7b) The title compound was prepared in the same
manner as described for 7a; in addition to compound 7a,
compound 7b (183 mg, 10%) as a brown solid was also
obtained. 1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.18
(s, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.51 (dd, J=8.6, 2.5 Hz,
1H), 7.17–7.09 (m, 2H), 6.92 (dd, J=8.4, 4.3 Hz, 2H).
Preparation of Compound 5a–b, 7a–d 5H-dibenzo[b,e] [1,
4] diazepin-11(10H)-one (5a) A mixture of o-iodobenzoic
acid (4.96 g, 20 mmol) and suitable H2SO4 in absolute etha-
nol solvent (10 mL) was refuxed at 90 °C for 10 h. TLC
analysis indicated the starting material had been consumed.
The reaction mixture was diluted with EtOAc and washed
with H2O and brine. The organic layer was dried over
Na2SO4, fltered and concentrated under reduced pressure
to yield ethyl iodobenzoate (5.30 g, 96%) as a yellow oil.
A microwave tube was charged with ethyl iodobenzoate
(5.52 g, 20 mmol), o-phenylenediamine (1.08 g, 10 mmol),
CuI (190 mg, 1 mmol) and K3PO4 (6.36 g, 30 mmol). The
tube was evacuated and backflled with nitrogen before suit-
able ethylene glycol was added. The reaction mixture was
stirred in microwave irradiation at 180 °C for 1 h. After the
reaction mixture was diluted with EtOAc and washed with
water and brine, the solution was dried over Na2SO4 and
concentrated in vacuo. The residue was purifed by column
chromatography on silica gel (eluting with 100:1 dichlo-
romethane/methanol) to provide compound 5a (1.37 g, 65%)
2‑chloro‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑one
(7c) To a 0 °C solution of compound 5a (1.05 g, 5 mmol)
in suitable THF was added a solution of 1,3-dichloro-
5,5-dimethylhydantoin (591 mg, 3 mmol) in THF (2 mL),
dropwise over 5 min. The reaction was stirred at 0 °C for
2 h. TLC analysis indicated the starting material had been
consumed. The reaction mixture was diluted with EtOAc
and washed with H2O and brine. The organic layer was dried
over Na2SO4 and concentrated in vacuo. The residue was
purifed by column chromatography on silica gel (eluting
with 5:1 petroleum ether/ethyl acetate) to yield compound
1
7c (732 mg, 60%) as a yellow solid. H NMR (400 MHz,
DMSO) δ 9.98 (s, 1H), 8.03 (s, 1H), 7.61 (d, J=2.6 Hz, 1H),
7.38 (dd, J=8.6, 2.6 Hz, 1H), 7.02–6.89 (m, 5H).
2,8‑dichloro‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑
one (7d) The title compound was prepared in the same
manner as described for 7c; in addition to compound 7c,
compound 7d (139 mg, 10%) as a brown solid was also
obtained. 1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.16
(s, 1H), 7.61 (d, J=2.6 Hz, 1H), 7.39 (dd, J=8.6, 2.7 Hz,
1H), 7.03–6.96 (m, 4H).
1
as a bright yellow solid. H NMR (400 MHz, DMSO) δ
9.85(s, 1H), 7.85 (s, 1H), 7.67 (d, J =7.5 Hz, 1H), 7.33 (t,
J=7.2 Hz, 1H), 7.02–6.86(m, 6H).
7,8‑dimethyl‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)
‑one (5b) The title compound was prepared in the same
manner as described for 5a using 4,5-dimethyl-1,2-phe-
nylenediamine instead of o-phenylenediamine, with a yield
Preparation of Compound 6a–b, 8a–d General Procedure
for Compounds 6a–b, 8a–d A mixture of compound 5 (or 7)
(0.5 mmol), N,N-dimethylaniline(36.3 mg, 0.3 mmol) and
suitable POCl3 was refuxed under a nitrogen atmosphere
at 130 °C for 12 h, removed excess POCl3, and added suit-
able N-methylpiperazine to continue reaction for 12 h. The
reaction mixture was diluted with EtOAc and washed with
H2O and brine. The organic layer was dried over Na2SO4
and concentrated in vacuo. The residue was purifed by col-
1
of 51% as a yellow solid. H NMR (400 MHz, DMSO) δ
9.69 (s, 1H), 7.67–7.60 (m, 2H), 7.34–7.26 (m, 1H), 6.95 (d,
J=7.9 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 6.76 (s, 1H), 6.71
(s, 1H), 2.08 (d, J=5.6 Hz, 6H).
2‑bromo‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑one
(7a) To a 0 °C solution of compound 5a (1.05 g, 5 mmol)
1 3

Molecular Diversity
umn chromatography on silica gel (eluting with 25:1 dichlo-
2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.2, 151.7,
141.5, 140.2, 131.7, 130.0, 128.3, 127.5, 125.2, 124.7,
124.2, 121.4, 119.5, 55.1, 47.5, 46.3. HRMS (ESI) calcd
for C18H20ClN4 (M+H)+ 327.1371, found 327.1374.
romethane/methanol) to yield compound 6 (or 8).
11‑(4‑methylpiperazin‑1‑yl)‑5H‑dibenzo[b,e] [1, 4]
diazepine (6a) Yield 75%. Yellow solid, m.p. 173-174 °C.
1H NMR (400 MHz, CDCl3) δ 7.31–7.25 (m, 2H), 7.09 (dd,
J = 7.8, 1.0 Hz, 1H), 6.98 (dd, J = 15.5, 7.8 Hz, 2H), 6.88
(td, J=7.6, 1.3 Hz, 1H), 6.82 (d, J =8.0 Hz, 1H), 6.70 (d,
J = 7.7 Hz, 1H), 4.93 (s, 1H), 3.47 (s, 4H), 2.52 (s, 4H),
2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 153.4,
142.0, 140.6, 131.9, 130.5, 127.4, 124.5, 124.0, 123.8,
123.0, 120.2, 119.5, 55.2, 47.5, 46.3. HRMS (ESI) calcd
for C18H21N4 (M+H)+ 293.1761, found 293.1759.
2,8‑dichloro‑11‑(4‑methylpiperazin‑1‑yl)‑5H‑
dibenzo[b,e] [1, 4] diazepine (8d) Yield 54%. Yellow
solid, m.p. 111–112 °C. 1H NMR (400 MHz, CDCl3) δ 7.27–
7.23 (m, 2H), 7.06 (d, J = 2.3 Hz, 1H), 6.83 (dd, J = 8.3,
2.3 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.60 (d, J= 8.4 Hz,
1H), 4.88 (s, 1H), 3.46 (s, 4H), 2.52 (s, 4H), 2.35 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 161.6, 151.3, 141.6, 140.1,
131.9, 130.0, 129.6, 128.6, 127.1, 125.1, 123.6, 121.6,
120.3, 55.1, 47.5, 46.3. HRMS (ESI) calcd for C18H19Cl2N4
(M+H)+ 361.0981, found 361.0982.
7,8‑dimethyl‑11‑(4‑methylpiperazin‑1‑yl)‑5H‑
dibenzo[b,e] [1, 4] diazepine (6b) Yield 51%. Yellow
solid, m.p. 169–171 °C. 1H NMR (400 MHz, CDCl3) δ 7.28–
7.21 (m, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.89 (s, 1H), 6.79 (d,
J=7.9 Hz, 1H), 6.48 (s, 1H), 4.85 (s, 1H), 3.43 (s, 4H), 2.50
(s, 4H), 2.34 (s, 3H), 2.12 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 162.5, 153.6, 139.4, 138.0, 132.3, 132.1, 131.7,
130.5, 128.3, 123.7, 122.8, 120.7, 119.9, 55.2, 47.5, 46.3,
19.1, 19.0. HRMS (ESI) calcd for C20H25N4 (M + H)+
321.2074, found 321.2074.
Preparation of Compound 9a–u General Procedure for
Compounds 9a–u A mixture of compound 7 (1 mmol),
phenylboronic acid (1.5 mmol), K2CO3 (2 mmol) and
Pd(PPh3)4 (0.05 mmol) in mixed solvent (toluene/ethanol/
water=4/2/1) was stirred under a nitrogen atmosphere at
80 °C for 10 h. TLC analysis indicated the starting mate-
rial had been consumed. The reaction mixture was diluted
with EtOAc and washed with H2O and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purifed by column chromatography on silica
gel (eluting with 5:1 petroleum ether/ethyl acetate) to yield
compound 9.
2‑bromo‑11‑(4‑methylpiperazin‑1‑yl)‑5H‑dibenzo[b,e]
[1, 4] diazepine (8a) Yield 43%. Yellow solid, m.p. 185–
187 °C. 1H NMR (400 MHz, CDCl3) δ 7.37–7.32 (m, 2H),
7.05 (dd, J = 7.8, 1.4 Hz, 1H), 6.96 (td, J = 7.6, 1.4 Hz,
1H), 6.86 (td, J=7.5, 1.5 Hz, 1H), 6.70–6.63 (m, 2H), 4.93
(s, 1H), 3.42 (s, 4H), 2.50 (s, 4H), 2.33 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 161.1, 152.3, 141.4, 140.2, 134.6,
132.9, 127.5, 125.6, 124.7, 124.2, 121.8, 119.6, 115.5, 55.0,
47.5, 46.3. HRMS (ESI) calcd for C18H20BrN4 (M + H)+
371.0866, found 371.0868.
2‑phenyl‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑one
1
(9a) Yield 79%. H NMR (400 MHz, DMSO) δ 9.94 (s,
1H), 7.99 (d, J = 27.4 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H),
7.58 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.31 (t,
J=7.0 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 7.03–6.89 (m, 4H).
2‑(2‑methoxyphenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9b) Yield 64%. 1H NMR (400 MHz,
DMSO) δ 9.87 (s, 1H), 7.95 (s, 1H), 7.78 (d, J = 2.2 Hz,
1H), 7.46 (dd, J=8.3, 2.2 Hz, 1H), 7.33–7.28 (m, 1H), 7.24
(dd, J=7.5, 1.6 Hz, 1H), 7.09–6.96 (m, 6H), 6.95–6.89 (m,
1H), 3.74 (s, 3H).
2,8‑dibromo‑11‑(4‑methylpiperazin‑1‑yl)‑5H‑
dibenzo[b,e] [1, 4] diazepine (8b) Yield 44%. Yellow
solid, m.p. 195–196 °C. 1H NMR (400 MHz, CDCl3) δ 7.39-
7.31 (m, 2H), 7.18 (d, J= 2.2 Hz, 1H), 6.93 (dd, J = 8.3,
2.3 Hz, 1H), 6.66 (d, J= 8.2 Hz, 1H), 6.51 (d, J= 8.3 Hz,
1H), 4.93 (s, 1H), 3.42 (s, 4H), 2.48 (s, 4H), 2.31 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 161.5, 151.8, 141.9, 140.6,
134.8, 132.9, 129.9, 126.5, 125.4, 121.9, 120.7, 117.0,
115.8, 55.0, 47.5, 46.2. HRMS (ESI) calcd for C18H19Br2N4
(M+H)+ 448.9971, found 448.9976.
2‑(3‑methoxyphenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9c) Yield 83%. 1H NMR (400 MHz,
DMSO) δ 9.93 (s, 1H), 8.02 (s, 1H), 7.94 (d, J = 2.3 Hz,
1H), 7.67 (dd, J=8.4, 2.3 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H),
7.15 (d, J=7.9 Hz, 1H), 7.11–7.06(m, 2H), 7.03–6.87 (m,
5H), 3.80 (s, 3H).
2‑chloro‑11‑(4‑methylpiperazin‑1‑yl)‑5H‑dibenzo[b,e] [1, 4]
diazepine (8c) Yield 33%. Yellow solid, m.p. 196–197 °C.
1H NMR (400 MHz, CDCl3) δ 7.26–7.21 (m, 2H), 7.08 (dd,
J = 7.8, 1.2 Hz, 1H), 6.98 (td, J = 7.6, 1.2 Hz, 1H), 6.89
(td, J=7.5, 1.4 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.68 (dd,
J=7.7, 1.1 Hz, 1H), 4.93 (s, 1H), 3.45 (s, 4H), 2.53 (s, 4H),
2‑(4‑methoxyphenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9d) Yield 86%. 1H NMR (400 MHz,
DMSO) δ 9.91 (s, 1H), 7.94 (s, 1H), 7.88 (d, J=2.3 Hz, 1H),
1 3

Molecular Diversity
7.61 (dd, J=8.4, 2.3 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.06
(d, J=8.4 Hz, 1H), 7.02–6.88 (m, 6H), 3.77 (s, 3H).
J=2.3 Hz, 1H), 7.93–7.87 (m, 2H), 7.76 (dd, J=8.4, 2.4 Hz,
1H), 7.66 (d, J=4.9 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 7.04–
6.96 (m, 3H), 6.95–6.90 (m, 1H).
2‑(2‑fluorophenyl)‑5H‑dibenzo[b,e] [1, 4] diazepin‑
11(10H)‑one (9e) Yield 70%. 1H NMR (400 MHz, DMSO)
δ 9.92 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=8.4 Hz,
1H), 7.48 (td, J=7.9, 1.5 Hz, 1H), 7.40–7.34 (m, 1H), 7.31–
7.24 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 7.04–6.89 (m, 4H).
2‑(4‑(trifluoromethyl)phenyl)‑5H‑dibenzo[b,e] [1,
1
4] diazepin‑11(10H)‑one (9m) Yield 62%. H NMR
(400 MHz, DMSO) δ 9.98 (s, 1H), 8.15 (s, 1H), 8.04 (s,
1H), 7.86–7.70 (m, 5H), 7.12 (d, J=8.4 Hz, 1H), 7.04–6.89
(m, 4H).
2‑(3‑fluorophenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
1
epin‑11(10H)‑one (9f) Yield 68%. H NMR (400 MHz,
2‑(o‑tolyl)‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑one
1
DMSO) δ 9.94 (s, 1H), 8.07 (s, 1H), 7.97 (d, J=2.1 Hz, 1H),
7.70 (dd, J=8.4, 2.2 Hz, 1H), 7.51–7.39 (m, 3H), 7.17–7.06
(m, 2H), 7.04–6.89 (m, 4H).
(9n) Yield 66%. H NMR (400 MHz, DMSO) δ 9.90 (s,
1H), 7.98 (s, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.34 (dd, J=8.2,
2.2 Hz, 1H), 7.28–7.20 (m, 3H), 7.18–7.13 (m, 1H), 7.06
(d, J=8.3 Hz, 1H), 7.05–7.01 (m, 1H), 7.00–6.89 (m, 3H),
2.21 (s, 3H); 13C NMR (101 MHz, DMSO) δ 167.8, 149.3,
140.2, 139.8, 134.7, 133.5, 132.4, 130.4, 129.8, 129.3,
127.2, 126.0, 124.6, 123.0, 122.4, 121.4, 119.8, 119.0, 20.2.
2‑(4‑fluorophenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9g) Yield 70%. 1H NMR (400 MHz,
DMSO) δ 9.94 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 2.3 Hz,
1H), 7.68–7.55 (m, 3H), 7.24 (t, J = 8.8 Hz, 2H), 7.08 (d,
J = 8.4 Hz, 1H), 7.02 (dd, J = 7.6, 1.1 Hz, 1H), 7.00–6.94
(m, 2H), 6.94–6.88 (m, 1H).
2‑(m‑tolyl)‑5H‑dibenzo[b,e] [1, 4] diazepin‑
11(10H)‑one (9o) Yield 70%. 1H NMR (400 MHz, DMSO)
δ 9.93 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.65
(dd, J = 8.4, 2.3 Hz, 1H), 7.41–7.35 (m, 2H), 7.30 (t,
J=7.6 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.08 (d, J=8.4 Hz,
1H), 7.03–6.89 (m, 4H), 2.35 (s, 3H).
3‑(11‑oxo‑10,11‑dihydro‑5H‑dibenzo[b,e] [1, 4]
1
diazepin‑2‑yl)benzonitrile (9h) Yield 71%. H NMR
(400 MHz, DMSO) δ 9.95 (s, 1H), 8.10 (d, J=10.1 Hz, 2H),
8.00 (d, J=2.2 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.82–7.72
(m, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H),
7.06–6.88 (m, 4H).
2‑(p‑tolyl)‑5H‑dibenzo[b,e] [1, 4] diazepin‑11(10H)‑one
1
(9p) Yield 75%. H NMR (400 MHz, DMSO) δ 9.92 (s,
1H), 7.98 (s, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.4,
2.1 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.23 (d, J= 8.0 Hz,
2H), 7.07 (d, J=8.4 Hz, 1H), 7.03–6.89 (m, 4H), 2.31 (s,
3H).
2‑(2‑chlorophenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9i) Yield 80%. H NMR (400 MHz,
1
DMSO) δ 9.92 (s, 1H), 8.06 (s, 1H), 7.73 (d, J = 2.2 Hz,
1H), 7.53 (d, J=7.3 Hz, 1H), 7.43 (dd, J=8.3, 2.3 Hz, 1H),
7.41–7.33 (m, 3H), 7.08 (d, J=8.3 Hz, 1H), 7.04–6.90 (m,
4H).
2‑(4‑ethylphenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9q) Yield 59%. 1H NMR (400 MHz,
DMSO) δ 9.92 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 2.1 Hz,
1H), 7.64 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H),
7.26 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.03–6.95
(m, 3H), 6.95–6.89 (m, 1H), 2.61 (q, J=7.6 Hz, 2H), 1.18
(t, J=7.6 Hz, 3H).
2‑(3‑chlorophenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
1
epin‑11(10H)‑one (9j) Yield 71%. H NMR (400 MHz,
DMSO) δ 9.95 (s, 1H), 8.08 (s, 1H), 7.96 (d, J=2.3 Hz, 1H),
7.70 (dd, J=8.4, 2.4 Hz, 1H), 7.63 (t, J=1.6 Hz, 1H), 7.56
(d, J=8.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.36 (dd, J=8.0,
0.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.03–6.89 (m, 4H).
2‑(naphthalen‑1‑yl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
1
epin‑11(10H)‑one (9r) Yield 89%. H NMR (400 MHz,
2‑(4‑chlorophenyl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9k) Yield 63%. 1H NMR (400 MHz,
DMSO) δ 9.94 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 2.3 Hz,
1H), 7.67 (dd, J=8.4, 2.3 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H),
7.46 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 7.03–6.89
(m, 4H).
DMSO) δ 9.94 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 7.6 Hz,
1H), 7.92 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.77
(d, J = 2.2 Hz, 1H), 7.58–7.46 (m, 4H), 7.40 (dd, J= 7.0,
0.9 Hz, 1H), 7.16 (d, J= 8.3 Hz, 1H), 7.07 (d, J= 7.9 Hz,
1H), 7.02–6.91 (m, 3H).
2‑(naphthalen‑2‑yl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9s) Yield 43%. 1H NMR (400 MHz,
DMSO) δ 9.95 (s, 1H), 8.15 (s, 1H), 8.12 (d, J = 2.3 Hz,
1H), 8.06 (s, 1H), 8.01–7.95 (m, 2H), 7.92 (d, J=7.5 Hz,
2‑(3‑(trifluoromethyl)phenyl)‑5H‑dibenzo[b,e] [1,
1
4] diazepin‑11(10H)‑one (9l) Yield 74%. H NMR
(400 MHz, DMSO) δ 9.97 (s, 1H), 8.11 (s, 1H), 8.01 (d,
1 3

Molecular Diversity
1H), 7.84 (dd, J=8.4, 2.4 Hz, 1H), 7.79 (dd, J=8.6, 1.8 Hz,
1H), 7.55–7.47 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.03 (dd,
J=7.6, 1.4 Hz, 1H), 7.01–6.95 (m, 2H), 6.95–6.90 (m, 1H).
47.5, 46.3. HRMS (ESI) calcd for C25H27N4O (M + H)+
399.2179, found 399.2178.
2‑(3‑methoxyphenyl)‑11‑(4‑methylpiperazin‑1‑yl)
2‑(pyridin‑3‑yl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9t) Yield 90%. H NMR (400 MHz,
‑5H‑dibenzo[b,e] [1, 4] diazepine (10c) Yield 34%. Yel-
1
1
low solid, m.p. 90–91 °C. H NMR (400 MHz, CDCl3) δ
DMSO) δ 9.98 (s, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.51 (dd,
J=4.7, 1.5 Hz, 1H), 8.10 (s, 1H), 8.02–7.95 (m, 2H), 7.73
(dd, J=8.4, 2.4 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.12
(d, J=8.4 Hz, 1H), 7.04–6.89 (m, 4H).
7.52–7.43 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.10 (dd, J=7.8,
0.9 Hz, 1H), 7.05 (d, J= 7.7 Hz, 1H), 7.01–6.93 (m, 2H),
6.91–6.83 (m, 3H), 6.70 (dd, J=7.6, 0.6 Hz, 1H), 4.99 (s,
1H), 3.83 (s, 3H), 3.49 (s, 4H), 2.51 (s, 4H), 2.33 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 162.5, 160.2, 152.8, 141.8,
141.7, 140.6, 135.9, 130.5, 130.1, 129.0, 127.5, 124.5,
124.0, 124.0, 120.5, 119.5, 119.3, 112.7, 112.6, 55.5, 55.2,
47.6, 46.3. HRMS (ESI) calcd for C25H27N4O (M + H)+
399.2179, found 399.2179.
2‑(pyridin‑4‑yl)‑5H‑dibenzo[b,e] [1, 4] diaz‑
epin‑11(10H)‑one (9u) Yield 78%. 1H NMR (400 MHz,
DMSO) δ 9.98 (s, 1H), 8.57 (d, J = 5.9 Hz, 2H), 8.21 (s,
1H), 8.09 (d, J=2.2 Hz, 1H), 7.83–7.79 (m, 1H), 7.63 (d,
J=6.0 Hz, 2H), 7.12 (d, J=8.5 Hz, 1H), 7.03–6.90 (m, 4H).
2‑(4‑methoxyphenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
5H‑dibenzo[b,e] [1, 4] diazepine (10d) Yield 23%. Yel-
low jelly. 1H NMR (400 MHz, CDCl3) δ 7.47–7.34 (m, 4H),
7.09 (dd, J=7.8, 1.4 Hz, 1H), 6.97 (dd, J=7.4, 1.4 Hz, 1H),
6.95–6.92 (m, 2H), 6.87 (dd, J=7.6, 1.5 Hz, 1H), 6.85–6.82
(m, 1H), 6.69 (dd, J =7.7, 1.3 Hz, 1H), 5.01 (s, 1H), 3.81
(s, 3H), 3.49 (s, 4H), 2.51 (s, 4H), 2.32 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 162.5, 159.2, 152.1, 142.0, 140.5,
135.7, 132.6, 130.0, 128.4, 127.8, 127.4, 124.4, 124.0,
123.9, 120.5, 119.5, 114.4, 55.5, 55.1, 47.5, 46.2. HRMS
(ESI) calcd for C25H27N4O (M + H)+ 399.2179, found
399.2180.
Preparation of Compound 10a–u General Procedure for
Compounds 10a–u A mixture of compound 9 (0.5 mmol),
N,N-dimethylaniline(0.3 mmol) and suitable POCl3 was
refuxed under a nitrogen atmosphere at 130 °C for 12 h,
removed excess POCl3 and added suitable N-methylpipera-
zine to continue reaction for 12 h. The reaction mixture was
diluted with EtOAc and washed with H2O and brine. The
organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was purifed by column chromatography
on silica gel (eluting with 25:1 dichloromethane/methanol)
to yield compound 10.
11‑(4‑methylpiperazin‑1‑yl)‑2‑phenyl‑5H‑dibenzo[b,e] [1, 4]
diazepine (10a) Yield 29%. Yellow solid, m.p. 95–96 °C.
1H NMR (400 MHz, CDCl3) δ 7.54–7.44 (m, 4H), 7.41 (t,
J=7.5 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 7.11 (d, J=7.7 Hz,
1H), 6.98 (t, J = 7.5 Hz, 1H), 6.91–6.81 (m, 2H), 6.70 (d,
J = 7.7 Hz, 1H), 5.01 (s, 1H), 3.50 (s, 4H), 2.51 (s, 4H),
2.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.5, 152.7,
141.8, 140.5, 140.1, 136.0, 130.4, 129.0, 128.9, 127.4,
127.4, 126.7, 124.5, 124.0, 124.0, 120.6, 119.5, 55.2, 47.5,
46.3. HRMS (ESI) calcd for C24H25N4 (M+H)+ 369.2074,
found 369.2078 .
2‑(2‑fluorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
5H‑dibenzo[b,e] [1, 4] diazepine (10e) Yield 35%. Yel-
1
low solid, m.p. 204–205 °C. H NMR (400 MHz, CDCl3)
δ 7.49 (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.33–7.24 (m, 2H),
7.19–7.08 (m, 3H), 6.97 (td, J=7.6, 1.2 Hz, 1H), 6.94–6.82
(m, 2H), 6.70 (dd, J =7.7, 0.9 Hz, 1H), 5.00 (s, 1H), 3.50
(s, 4H), 2.52 (s, 4H), 2.33 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.4, 159.9 (d, J=247.3 Hz), 152.9, 141.7, 140.6,
132.3 (d, J=2.4 Hz), 131.2 (d, J=3.5 Hz), 130.5, 130.4 (d,
J = 4.6 Hz), 129.2 (d, J = 8.3 Hz), 128.1 (d, J = 13.2 Hz),,
127.5, 124.7 (d, J = 3.7 Hz), 124.6, 124.0, 123.6, 120.3,
119.5, 116.3 (d, J=22.7 Hz), 55.2, 47.6, 46.3. HRMS (ESI)
calcd for C24H24FN4 (M+H)+ 387.1980, found 387.1984.
2‑(2‑methoxyphenyl)‑11‑(4‑methylpiperazin‑1‑yl)
‑5H‑dibenzo[b,e] [1, 4] diazepine (10b) Yield 30%. Yel-
1
low solid, m.p. 143–145 °C. H NMR (400 MHz, CDCl3)
2‑(3‑fluorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
δ 7.45–7.38 (m, 2H), 7.29 (td, J = 8.2, 1.7 Hz, 1H), 7.18
(dd, J = 7.5, 1.7 Hz, 1H), 7.08 (dd, J = 7.8, 1.4 Hz, 1H),
7.01–6.93 (m, 3H), 6.87 (dd, J = 7.6, 1.5 Hz, 1H), 6.83
(d, J=8.0 Hz, 1H), 6.70 (dd, J=7.7, 1.2 Hz, 1H), 4.97 (s,
1H), 3.77 (s, 3H), 3.54 (s, 4H), 2.51 (s, 4H), 2.33 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 162.5, 156.5, 152.1, 142.0,
140.7, 133.3, 132.9, 131.7, 130.7, 129.7, 128.8, 127.4,
124.4, 123.9, 123.1, 121.1, 119.8, 119.5, 111.3, 55.7, 55.3,
5H‑dibenzo[b,e] [1, 4] diazepine (10f) Yield 14%. Yel-
1
low solid, 175–176 °C. H NMR (400 MHz, CDCl3) δ
7.49–7.44 (m, 2H), 7.39–7.32 (m, 1H), 7.23 (d, J=7.5 Hz,
1H), 7.18–7.12 (m, 1H), 7.09 (dd, J = 7.8, 1.1 Hz, 1H),
7.03–6.94 (m, 2H), 6.91–6.84 (m, 2H), 6.70 (dd, J = 7.7,
0.9 Hz, 1H), 4.99 (s, 1H), 3.47 (s, 4H), 2.51 (s, 4H), 2.33 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 163.4 (d, J=245.8 Hz),
162.3, 153.2, 142.4 (d, J=7.7 Hz), 141.7, 140.5, 134.8 (d,
J=2.2 Hz), 130.6 (d, J=8.5 Hz), 130.4, 129.0, 127.5, 124.6,
1 3

Molecular Diversity
124.2, 124.1, 122.4 (d, J = 2.7 Hz), 120.7, 119.6, 114.2
(d, J = 21.2 Hz), 113.7 (d, J = 22.1 Hz), 55.2, 47.7, 46.3.
HRMS (ESI) calcd for C24H24FN4 (M+H)+ 387.1980, found
387.1981.
126.9, 124.9, 124.6, 124.1, 124.1, 120.7, 119.6, 55.1,
47.6, 46.2. HRMS (ESI) calcd for C24H24ClN4 (M + H)+
403.1684, found 403.1687.
2‑(4‑chlorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
5H‑dibenzo[b,e] [1, 4] diazepine (10k) Yield 40%,
hazel solid, m.p. 194–195 °C. 1H NMR (400 MHz, CDCl3)
δ 7.47–7.39 (m, 2H), 7.39–7.30 (m, 4H), 7.09 (dd, J=7.8,
1.4 Hz, 1H), 6.97 (td, J= 7.6, 1.4 Hz, 1H), 6.91–6.82 (m,
2H), 6.69 (dd, J = 7.7, 1.3 Hz, 1H), 4.99 (s, 1H), 3.47 (s,
4H), 2.50 (s, 4H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 162.3, 153.0, 141.7, 140.5, 138.6, 134.8, 133.5, 130.2,
129.2, 128.8, 128.0, 127.5, 124.6, 124.1, 124.1, 120.7,
119.6, 55.2, 47.6 46.3. HRMS (ESI) calcd for C24H24ClN4
(M+H)+ 403.1684, found 403.1686.
2‑(4‑fluorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
5H‑dibenzo[b,e] [1, 4] diazepine (10g) Brown solid, m.p.
216–217 °C. 1H NMR (400 MHz, CDCl3) δ 7.45–7.37 (m,
4H), 7.12–7.05 (m, 3H), 6.97 (td, J=7.6, 1.4 Hz, 1H), 6.90–
6.83 (m, 2H), 6.70 (dd, J =7.7, 1.3 Hz, 1H), 5.00 (s, 1H),
3.48 (s, 4H), 2.50 (s, 4H), 2.32 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.5 (d, J = 246.2 Hz), 162.4, 152.7, 141.8,
140.5, 136.3 (d, J=3.2 Hz), 135.1, 130.3, 128.8, 128.3 (d,
J=8.0 Hz), 127.4, 124.6, 124.1, 124.0, 120.6, 119.5, 115.9
(d, J = 21.5 Hz), 55.2, 47.6, 46.3. HRMS (ESI) calcd for
C24H24FN4 (M+H)+ 387.1980, found 387.1977.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(3‑(trifluoromethyl)
phenyl)‑5H‑dibenzo[b,e] [1, 4] diazepine (10l) Yield
75%. Yellow solid: m.p. 163–164 °C. 1H NMR (400 MHz,
CDCl3) δ 7.69 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.58–7.46
(m, 4H), 7.09 (dd, J = 7.8, 1.4 Hz, 1H), 6.97 (td, J = 7.6,
1.4 Hz, 1H), 6.93–6.82 (m, 2H), 6.71 (dd, J=7.7, 1.3 Hz,
1H), 5.01 (s, 1H), 3.48 (s, 4H), 2.51 (s, 4H), 2.33 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 162.3, 153.5, 141.6,
140.9, 140.5, 134.6, 131.5 (d, J = 32.3 Hz), 130.5, 130.0,
129.6, 129.1, 127.5, 127.4, 124.3, 124.3 (d, J=272.1 Hz),
124.2, 124.1 (d, J = 3.8 Hz), 123.6(q, J = 3.9 Hz), 120.8,
119.6, 55.2, 47.1, 46.3. HRMS (ESI) calcd for C25H24F3N4
(M+H)+ 437.1948, found 437.1946.
3‑(11‑(4‑methylpiperazin‑1‑yl)‑5H‑dibenzo[b,e] [1,
4] diazepin‑2‑yl)benzonitrile (10h) Yield 4.6%. Yel-
1
low solid, m.p. 98–100 °C. H NMR (400 MHz, CDCl3)
δ 7.86–7.64 (m, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.52 (d,
J=7.8 Hz, 1H), 7.49–7.42 (m, 2H), 7.09 (dd, J=7.8, 1.2 Hz,
1H), 6.98 (td, J=7.6, 1.2 Hz, 1H), 6.94–6.82 (m, 2H), 6.70
(dd, J=7.7, 1.0 Hz, 1H), 5.01 (s, 1H), 3.47 (s, 4H), 2.53 (s,
4H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.1,
153.8, 141.5, 141.4, 140.4, 133.7, 131.1, 130.8, 130.4,
130.3, 130.0, 129.0, 127.6, 124.8, 124.5, 124.3, 121.0,
119.6, 118.9, 113.3, 55.1, 47.7, 46.3. HRMS (ESI) calcd
for C25H24N5 (M+H)+ 394.2026, found 394.2029.
2‑(2‑chlorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
11‑(4‑methylpiperazin‑1‑yl)‑2‑(4‑(trifluoromethyl)
phenyl)‑5H‑dibenzo[b,e] [1, 4] diazepine (10m) Yield
26%. Yellow solid, m.p. 210–211 °C. 1H NMR (400 MHz,
CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H),
7.52–7.47 (m, 2H), 7.10 (dd, J=7.8, 1.2 Hz, 1H), 6.98 (td,
J=7.6, 1.2 Hz, 1H), 6.91–6.86 (m, 2H), 6.71 (dd, J=7.7,
1.0 Hz, 1H), 5.03 (s, 1H), 3.48 (s, 4H), 2.51 (s, 4H), 2.33
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.3, 153.6,
143.6, 141.6, 140.5, 134.5, 130.6, 129.5 (d, J = 32.5 Hz),
129.2, 127.5, 127.0, 126.1 (q, J=3.7 Hz), 124.7, 124.4 (d,
J=271.8 Hz), 124.3, 124.2, 120.8, 119.6, 55.2, 47.6, 46.3.
HRMS (ESI) calcd for C25H24F3N4 (M + H)+ 437.1948,
found 437.1950.
5H‑dibenzo[b,e] [1, 4] diazepine (10i) Yield 25%. Yel-
1
low solid, m.p. 171–172 °C. H NMR (400 MHz, CDCl3)
δ 7.48–7.43 (m, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.31 (dd,
J = 8.1, 2.1 Hz, 1H), 7.29–7.25 (m, 2H), 7.22–7.18 (m,
1H), 7.11 (dd, J=7.8, 1.4 Hz, 1H), 6.99 (td, J=7.6, 1.4 Hz,
1H), 6.91 (dd, J=7.6, 1.5 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H),
6.72 (dd, J = 7.7, 1.3 Hz, 1H), 5.03 (s, 1H), 3.52 (s, 4H),
2.52 (s, 4H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 162.3, 152.7, 141.8, 140.6, 139.6, 134.2, 132.8, 132.6,
131.6, 131.4, 130.1, 128.9, 127.5, 127.2, 124.5, 124.0,
123.4, 120.0, 119.5, 55.2, 47.6, 46.3. HRMS (ESI) calcd
for C24H24ClN4 (M+H)+ 403.1684, found 403.1684.
2‑(3‑chlorophenyl)‑11‑(4‑methylpiperazin‑1‑yl)‑
11‑(4‑methylpiperazin‑1‑yl)‑2‑(o‑tolyl)‑5H‑dibenzo‑
[b,e] [1, 4] diazepine (10n) Yield 40%..Yellow solid: m.p.
122–123 °C. 1H NMR (400 MHz, CDCl3) δ 7.29–7.18 (m,
5H), 7.15–7.06 (m, 2H), 6.99 (td, J=7.6, 1.1 Hz, 1H), 6.91
(td, J=7.6, 1.3 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.75 (dd,
J=7.7, 0.9 Hz, 1H), 5.08 (s, 1H), 3.55 (s, 4H), 2.57 (s, 4H),
2.36 (s, 3H), 2.24 (s, 3H); 13C NMR (101 MHz, DMSO)
δ 162.4, 152.1, 142.0, 140.8, 140.5, 136.8, 135.4, 132.8,
130.9, 130.5, 129.9, 127.6, 127.5, 126.1, 124.4, 124.1,
5H‑dibenzo[b,e] [1, 4] diazepine (10j) Yield 29%. Yel-
1
low solid, m.p. 102–103 °C. H NMR (400 MHz, CDCl3)
δ 7.47–7.40 (m, 3H), 7.33–7.25 (m, 3H), 7.10 (dd, J=7.8,
1.4 Hz, 1H), 6.97 (td, J=7.6, 1.4 Hz, 1H), 6.88 (dd, J=7.6,
1.5 Hz, 1H), 6.86–6.83 (m, 1H), 6.69 (dd, J=7.7, 1.3 Hz,
1H), 5.04 (s, 1H), 3.47 (s, 4H), 2.50 (s, 4H), 2.32 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 162.3, 153.3, 141.9, 141.7,
140.5, 134.9, 134.5, 130.4, 130.3, 128.9, 127.5, 127.3,
1 3

Molecular Diversity
123.3, 120.0, 119.6, 54.9, 47.3, 46.0, 20.7. HRMS (ESI)
calcd for C25H26N4Na (M+Na)+ 405.2050, found 405.2051.
46.2. HRMS (ESI) calcd for C28H27N4 (M+H)+ 419.2230,
found 419.2238.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(m‑tolyl)‑5H‑dibenzo‑
[b,e] [1, 4] diazepine (10o) Yield 41%. Yellow solid:
m.p. 115–116 °C. 1H NMR (400 MHz, CDCl3) δ 7.50–7.46
(m, 2H), 7.32–7.25 (m, 3H), 7.13 (d, J=7.0 Hz, 1H), 7.09
(dd, J = 7.8, 1.3 Hz, 1H), 6.96 (td, J = 7.6, 1.4 Hz, 1H),
6.90–6.84 (m, 2H), 6.70 (dd, J=7.7, 1.2 Hz, 1H), 4.96 (s,
1H), 3.50 (s, 4H), 2.51 (s, 4H), 2.39 (s, 3H), 2.33 (s, 3H);
13C NMR (101 MHz, DMSO) δ 162.5, 152.6, 141.9, 140.2,
138.7, 136.3, 130.5, 129.0, 128.2, 127.7, 127.5, 124.6,
124.0, 124.0, 123.9, 120.5, 119.5, 55.2, 47.6, 46.3, 21.8.
HRMS (ESI) calcd for C25H27N4 (M+H)+ 383.2230, found
383.2234.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(naphthalen‑2‑yl)‑5
H‑dibenzo[b,e] [1, 4] diazepine (10s) Yield 24%. Yel-
low solid, m.p. 110–111 °C. 1H NMR (400 MHz, CDCl3) δ
7.91–7.82 (m, 4H), 7.64–7.58 (m, 3H), 7.51–7.44 (m, 2H),
7.14 (dd, J=7.8, 1.1 Hz, 1H), 6.99 (td, J=7.7, 1.1 Hz, 1H),
6.93–6.86 (m, 2H), 6.72 (d, J=7.6 Hz, 1H), 5.04 (s, 1H),
3.53 (s, 4H), 2.52 (s, 4H), 2.33 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.5, 152.8, 141.8, 140.6, 137.4, 135.9, 133.8,
132.6, 130.7, 129.2, 128.7, 128.2, 127.8, 127.5, 126.6,
126.2, 125.3, 125.2, 124.5, 124.1, 124.0, 120.6, 119.6,
55.2, 47.6, 46.3. HRMS (ESI) calcd for C28H27N4 (M+H)+
419.2230, found 419.2234.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(p‑tolyl)‑5H‑dibenz
o[b,e] [1, 4] diazepine (10p) Yield 33%. Yellow solid,
m.p. 109-110 °C. 1H NMR (400 MHz, CDCl3) δ 7.55–7.42
(m, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.25–7.21 (m, 2H), 7.11
(dd, J = 7.8, 1.3 Hz, 1H), 6.98 (td, J = 7.6, 1.3 Hz, 1H),
6.92–6.84 (m, 2H), 6.71 (dd, J=7.7, 1.2 Hz, 1H), 4.97 (s,
1H), 3.50 (s, 4H), 2.51 (s, 4H), 2.38 (s, 3H), 2.34 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 162.5, 152.4, 141.9, 140.6,
137.3, 137.2, 136.0, 130.3, 129.8, 128.7, 127.4, 126.6,
124.5, 124.0, 124.0, 120.5, 119.5, 55.3, 47.6, 46.3, 21.3.
HRMS (ESI) calcd for C25H27N4 (M+H)+ 383.2230, found
383.2231.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(pyridin‑3‑yl)‑5H‑dibe
nzo[b,e] [1, 4] diazepine (10t) Yield 32%. Yellow solid,
1
m.p. 111–112 °C. H NMR (400 MHz, CDCl3) δ 8.71 (d,
J=2.2 Hz, 1H), 8.53 (dd, J=4.8, 1.4 Hz, 1H), 7.74–7.69 (m,
1H), 7.47–7.42 (m, 2H), 7.30 (dd, J=7.9, 4.8 Hz, 1H), 7.07
(dd, J=7.8, 1.2 Hz, 1H), 6.94 (td, J=7.6, 1.2 Hz, 1H), 6.90
(d, J=8.9 Hz, 1H), 6.85 (td, J=7.5, 1.4 Hz, 1H), 6.70 (dd,
J=7.7, 1.0 Hz, 1H), 5.21 (s, 1H), 3.46 (s, 4H), 2.51 (s, 4H),
2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.1, 153.6,
148.5, 147.9, 141.6, 140.3, 135.6, 134.0, 132.4, 130.4,
128.9, 127.5, 124.6, 124.3, 124.1, 123.8, 120.9, 119.6,
55.0, 47.5, 46.1. HRMS (ESI) calcd for C23H24N5 (M+H)+
370.2026, found 370.2020.
2‑(4‑ethylphenyl)‑11‑(4‑methylpiperazin‑1‑yl)
‑5H‑dibenzo[b,e] [1, 4] diazepine (10q) Yield 50%. Yel-
low solid: m.p. 144–145 °C. 1H NMR (400 MHz, CDCl3) δ
7.47 (s, 2H), 7.39 (d, J=7.7 Hz, 2H), 7.24 (s, 2H), 7.09 (d,
J=7.5 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 6.87 (t, J=7.7 Hz,
2H), 6.70 (d, J=7.4 Hz, 1H), 4.95 (s, 1H), 3.49 (s, 4H), 2.66
(dd, J=14.9, 7.4 Hz, 2H), 2.51 (s, 4H), 2.33 (s, 3H), 1.25
(t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6,
152.4, 143.6, 141.9, 140.6, 137.6, 136.1, 134.6, 133.0,
130.4, 128.8, 128.6, 127.5, 126.7, 124.6, 124.0, 124.0,
120.6, 119.5, 55.3, 47.7, 46.4, 28.7, 15.8. HRMS (ESI) calcd
for C26H29N4 (M+H)+ 397.2387, found 397.2388.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(pyridin‑4‑yl)‑5H‑dibe
nzo[b,e] [1, 4] diazepine (10u) Yield 30%. Yellow solid,
1
m.p. 107-108 °C. H NMR (400 MHz, CDCl3) δ 8.60 (d,
J=6.0 Hz, 2H), 7.55–7.51 (m, 2H), 7.36 (dd, J=4.6, 1.5 Hz,
2H), 7.08 (dd, J=7.8, 1.4 Hz, 1H), 6.96 (td, J=7.6, 1.3 Hz,
1H), 6.92 (d, J=8.2 Hz, 1H), 6.88 (td, J=7.5, 1.5 Hz, 1H),
6.71 (dd, J=7.7, 1.2 Hz, 1H), 5.20 (s, 1H), 3.52 (s, 4H), 2.60
(s, 4H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.9,
154.6, 150.5, 147.1, 141.4, 140.2, 132.7, 130.4, 129.0,
127.6, 124.7, 124.4, 124.2, 121.1, 121.0, 119.7, 54.7, 47.1,
45.9. HRMS (ESI) calcd for C23H24N5 (M+H)+ 370.2026,
found 370.2024.
11‑(4‑methylpiperazin‑1‑yl)‑2‑(naphthalen‑1‑yl)‑5H‑
dibenzo[b,e] [1, 4] diazepine (10r) Yield 22%. Yellow
solid, m.p. 160–162 °C. 1H NMR (400 MHz, CDCl3) δ 7.90
(d, J=8.1 Hz, 1H), 7.88–7.76 (m, 2H), 7.49 (t, J=7.6 Hz,
2H), 7.46–7.35 (m, 3H), 7.31 (d, J=6.8 Hz, 1H), 7.15 (dd,
J=7.7, 0.8 Hz, 1H), 7.02 (td, J=7.7, 0.9 Hz, 1H), 6.97–6.85
(m, 2H), 6.75 (d, J=7.6 Hz, 1H), 5.05 (s, 1H), 3.53 (s, 4H),
2.48 (s, 4H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 162.5, 152.5, 142.0, 140.6, 139.1, 135.5, 134.0, 133.5,
131.9, 131.7, 128.6, 127.9, 127.5, 127.0, 126.3, 126.1,
125.8, 125.6, 124.5, 124.1, 123.7, 120.1, 119.6, 55.1, 47.7,
Pharmacology
The cell proliferation of adherent cells was determined by
sulforhodamine B assay (SRB) [24]. Cells were seeded in
96-well plates and then treated with diferent concentra-
tions of drugs. After 72 h of incubation, cells were fxed
with 10% trichloroacetic acid for 1 h at 4 °C and washed 5
times with tap water and air-dried. Cells that survived were
stained with 0.4% (w/v) sulforhodamine B (SRB) for 20 min
1 3

Molecular Diversity
7. Rambabu V, Vijayakumar SJB, Pathology A (2014) in vitro
cytotoxicity perspective of diazepinomicin (eco-4601) on
human hepatoma cell line (hepg2). Biomed Aging Pathol
4(1):65–70. https://doi.org/10.1016/j.biomag.2013.10.004
8. Miyanaga S, Sakurai H, Saiki I, Onaka H, Igarashi y (2010)
Anti-invasive and anti-angiogenic activities of naturally occur-
ring dibenzodiazepine bu-4664l and its derivatives. Bioorg
Med Chem Lett 20(3):963–965. https://doi.org/10.1016/j.
bmcl.2009.12.055
at room temperature and washed 5 times with 1% acetic acid.
Bound SRB was solubilized with 10 mM Tris, and absorb-
ance was measured at 540 nm using a SPECTRA MAX 190
spectrophotometer.
X‑ray crystallographic analysis
of compounds 7a
9. Praveen Kumar C, Reddy TS, Mainkar PS, Praveen KC, Reddy
TS, Mainkar PS, Bansal V, Shukla R, Chandrasekhar S, Hügel
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Single crystals of C11H10NOBr were studied. A suitable
crystal was selected and examined on a SuperNova, single
source at ofset, EosS2 difractometer. The crystal was kept
at 288.9(3) K during data collection. Using Olex2, the struc-
ture was solved with the ShelXT structure solution program
using intrinsic phasing and refned with the ShelXL refne-
ment package using least squares minimization.
Crystal data for C11H10NOBr (M = 172.20 g/mol): tri-
clinic, space group P-1 (no. 2), a=6.9797(4) Å, b=8.873
9(5) Å, c=10.4430(7) Å, α=100.128(5)°, β=99.779(5)°,
γ = 111.392(5)°, V = 573.22(6) Å3, Z = 3, T = 288.9(3) K,
μ(MoKα) = 0.097 mm−1, Dcalc = 1.497 g/cm3, 6120
refections measured (6.73° ≤ 2θ ≤ 50.976°), 2098 unique
(Rint =0.0357, Rsigma =0.0399) which were used in all cal-
culations. The fnal R1 was 0.0361 (I>2σ(I)) and wR2 was
0.0792 (all data).
11. Wang L, Sullivan GM, Hexamer LA, Hasvold LA, Thalji R, Przy-
tulinska M, Tao Z-F, Li G, Chen Z, Xiao Z, Gu W-Z, Xue J, Bui
M-H, Merta P, Kovar P, Bouska JJ, Zhang H, Park C, Stewart
KD, Sham HL, Sowin TJ, Rosenberg SH, Lin N-H (2007) Design,
synthesis, and biological activity of 5,10-dihydro-dibenzo[b, e]
[1,4]diazepin-11-one-based potent and selective chk-1 inhibitors.
J Med Chem 50(17):4162–4176. https://doi.org/10.1021/jm070
105d
12. De Clercq DJH, Heppner DE, To C, Jang J, Park E, Yun C-H,
Mushajiang M, Shin BH, Gero TW, Scott DA, Jänne PA, Eck
MJ, Gray NS (2019) Discovery and optimization of dibenzodi-
azepinones as allosteric mutant-selective EGFR inhibitors. ACS
Med Chem Lett 10(11):1549–1553. https://doi.org/10.1021/acsme
dchemlett.9b00381
Funding The funding was provided by Natural Science Foundation of
Henan Province (182300410356).
13. Kassiou M, Roger RW, Shi XQ (1997) synthesis and evaluation
of halogenated dibenzodiazepines as muscarinic receptor ligands.
Bioorg Med Chem Lett 7(7):799–804. https://doi.org/10.1016/
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