Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety

Article abstract of DOI:10.1016/j.bmc.2015.11.027

In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.

Full text of DOI:10.1016/j.bmc.2015.11.027

Accepted Manuscript
Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-
substituted quinazolin-4(3H)-one moiety
Hao Zhang, Min-Hang Xin, Xiao-Xiao Xie, Shuai Mao, Sai-Jie Zuo, She-Min Lu, San-Qi
Zhang
PII:
S0968-0896(15)30150-4
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.11.027
BMC 12675
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 October 2015
17 November 2015
20 November 2015
Please cite this article as: Zhang, H., Xin, M-H., Xie, X-X., Mao, S., Zuo, S-J., Lu, S-M., Zhang, S-Q., Synthesis
and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety,
Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.11.027
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Synthesis and antitumor activity evaluation of PI3K inhibitors
containing 3-substituted quinazolin-4(3H)-one moiety
a
a
a
a
Hao Zhang , Min-Hang Xin a, Xiao-Xiao Xie , Shuai Mao , Sai-Jie Zuo, She-Min
Lu b, San-Qi Zhang a *
a Department of Medicinal Chemistry, School of Pharmacy, Xian Jiaotong University,
Xian, Shaanxi, 710061, PR China
b Department of Genetics and Molecular Biology, School of Basic Medical Science,
Xian Jiaotong University, Xian, Shaanxi, 710061, PR China
*Corresponding author: San-Qi Zhang, Ph. D., Professor, E-mail address:
sqzhang@xjtu.edu.cn (S. Q. Zhang).
Abstract
In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-
6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative
activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer
cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and
(S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially
against PI3K. In addition, compound (S)-C5 can efficaciously inhibit tumor growth
in a mice S-180 model. These findings suggest that our designed compounds can
serve as potent PI3K inhibitors and effective anticancer agents.
Key Words quinazolin-4(3H)-ones  synthesis  PI3K inhibitor  antitumor activity
1

1. Introduction
PI3K/AKT/mTOR signal transduction pathway is an important signaling
pathway, playing key regulatory roles in many cellular processes, including cell
growth, proliferation, differentiation, motility and survival.1 Dysregulated expression
of PI3K/AKT/mTOR signal transduction pathway is linked to development of many
cancers.2 Therefore, the compounds that inhibit the PI3K/AKT/mTOR signal
transduction pathway has been regarded to have great potential for treatment of
malignant tumors. PI3K and mTOR are the key nodes of the PI3K/AKT/mTOR
pathway, which have been identified as promising druggable targets in this pathway
for cancer therapy.3,4 Recently, several PI3K inhibitors and PI3K/mTOR dual
inhibitors have been in clinical development.5,6 Among the reported PI3K/mTOR dual
inhibitors, N-(5-(quinilin-6-yl)-pyridin-3-yl)phenylsulfonamide derivatives are a class
of PI3K/mTOR dual inhibitors with potent anticancer activity in vitro and in vivo. The
two ring nitrogen atoms in pyridine and quinoline ring are the main components of
pharmacophore. GlaxoSmithKline discovered GSK2126458 (Figure 1) as a potent,
orally bioavailable PI3Kα and mTOR dual inhibitor.7 Amgen designed, synthesized
and
evaluated
several
classes
of
N-(2,5-disubstituted-pyridin-3-yl)
phenylsulfonamides, and discovered that compound A (Figure 1) is potent
PI3K/mTOR dual inhibitor.8 According to the X-ray co-crystal structure of PI3Kγ
with GSK2126458, we proposed that the structure of an amide group may take the
place of the water molecule bridge. Thereupon, we synthesized a series of
2-substituted-3- phenylsulfonylamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides
as novel PI3K/mTOR inhibitors.9 Later, we discovered another novel PI3K/mTOR
inhibitors as potent anticancer agents by combining of the benzamide moiety with
2-aminobenzothiazole.10 However, the emerging clinical data show limited
single-agent activity of the inhibitors targeting PI3K, AKT or mTOR at tolerated
doses.11 Some candidates displayed off-target effects or dose-limiting toxicities.12
Recently, we disclosed the structures of PI3K/mTOR dual inhibitors with low
toxicity.13,14 It has been reported that PI3K/mTOR dual inhibitor VS-5584 can
2

preferentially targets cancer stem cells.15 This discovery may potentially bring a
breakthrough to the treatment of cancer with PI3K/mTOR dual inhibitor. Therefore,
The development of new PI3K/mTOR dual inhibitors with reduced toxicity and
increased efficacy is still needed.
Figure 1. The structures of PI3K and mTOR dual inhibitors
Quinazoline and quinazolin-4(3H)-one have been regarded as two important drug
scaffolds in drug discovery. Many launched drugs or clinical drug candidates contain
quinazoline and quinazolin-4(3H)-one framework, such as gefitinib, erlotinib,
lapatinib, and several other clinical EGFR-TKIs.16,17 Furthermore, the
quinazolin-4(3H)-one derivatives are reported to exhibit a broad spectrum of
biological activities, such as antitumor, antimicrobial, antifungal, anti-inflammatory,
anticonvulsant, antidiabetic and antihypertensive activities.18-22 Recently, Several
PI3K inhibitors bearing a quinazolin-4(3H)-one moiety were mentioned.23 In an
attempt to develop novel anticancer agents, we intend to replace the quinoline moiety
in compound A with 3-substituted quinazolin-4(3H)-one to search for the novel
PI3K/mTOR dual inhibitors containing 3-substituted quinazolin-4(3H)-one moiety
and probe their structure-activity relationship (Figure 2). In this paper, we describe the
synthesis, biological activities evaluation of N-(2-methoxy-5-(3-substituted
quinazolin-4(3H)- one-6-yl)-pyridin-3-yl)phenylsulfonamide in vitro and in vivo.
Figure 2. The design of title compounds
3

2. Results and discussion
2.1. Synthesis of designed compounds
The synthetic route of compounds A, B, C and D is outlined in Scheme 1.
Scheme 1. Reagents and conditions: (a) EtOH, I2, reflux, 4–6 h, 45.2%–83.4%; (b) TFA/DCM, r.t.,
2 h; (c) cyclopropylformaldehyde, NaBH(OAc)3, AcOH, DCE, r.t., overnight, 37.7%–90.6% (two
steps); (d) AcOH or c-PrCO2H, HATU, DIPEA, DCM, reflux, 2 h, 75.0%–86.0% (two steps); (e)
bis(pinacolato)diboron, PdCl2(dppf), KOAc, 1,4-dioxane, reflux, 2 h; (f) 1a–(R)-1u, PdCl2(dppf),
Na2CO3 or K2CO3, DME/H2O, reflux, 4–6 h, 42.5%–83.1% (two steps).
Commercially available 2-amino-5-bromobenzoic acid, triethyl orthoformate and
amine were refluxed in ethanol for 4-6 h to produce the intermediates 1a–1m, (S)-1n,
1o, (R)-1p.22 The intermediates (S)-1q, (R)-1r, and 1s was prepared, respectively,
from intermediates (S)-1n, 1o and (R)-1p by the remove of N-Boc with TFA and
reductive amination with cyclopropylformaldehyde in the presence of sodium
triacetoxyborohydride. Similarly, intermediates (R)-1t and (R)-1u was synthesized by
the remove of N-Boc in intermediate (R)-1p with TFA and acylation with acetic acid
or cyclopropyl formic acid in the presence of HAUT and DIPEA, respectively. The
phenylsulfonamides 2 were prepared from 2-amino-5-bromopyridine according to the
steps reported in our previous work.24 Catalyzed by PdCl2(dppf), intermediate 2
reacted with bis(pinacolato)diboron to yield corresponding arylboronic esters 3.
4

Without isolation of the 3, intermediate 1, PdCl2(dppf), water and potassium
carbonate as well were added to the above reaction mixture. The resulted mixture was
refluxed to produce the designed compounds A, B, C or D. The preparation of
arylboronic esters and Suzuki coupling were completed in one pot.
Compound (S)-C1 and D1 were synthesized according to the scheme 1. The
remove of N-Boc in (S)-C1 and D1 with TFA produced, respectively, (S)-C2 and D2,
which were acylated with acetic acid, cyclopropyl formic acid or
tetrahydro-2H-pyran-4-carboxylic acid to produce title compounds (S)-C3, (S)-C5,
(S)-C7 and D3–D5 (Scheme 2).
Scheme 2. Reagents and conditions: (a) TFA/DCM, r.t., 2 h, 46.0%–61.7%.; (b) RCO2H, HATU,
DIPEA, DCM, reflux, 2 h, 45.8%–94.9%.
1
13
The newly synthesized compounds were characterized by H NMR, C NMR,
and HRMS.
2.2. Biological evaluations
2.2.1. Antiproliferative assays in vitro
We first evaluated the antiproliferative activities of synthesized compounds
against human colon carcinoma cell line (HCT-116, PI3CA mutant: H1047R), human
breast adenocarcinoma carcinoma cell line (MCF-7, PI3CA mutant: E545K) by
applying the MTT colorimetric assay. The PI3K/mTOR dual inhibitors BEZ235 was
used as the positive controls. The results are summarized in Table 1.
5

Table 1 Antiproliferative activities of compounds A, B, C and D (
, n = 3)
x  s
IC50 (µM)
Compds
R1
R2
HCT-116
4.06±0.72
2.69±0.16
1.20±0.25
1.82±0.24
1.45±0.28
2.64±0.27
2.75±0.15
2.02±0.16
1.35±0.17
1.03±0.18
4.74±0.36
2.80±0.41
2.95±0.52
1.29±0.23
1.42±0.32
1.25±0.06
0.66±0.10
1.46±0.16
1.25±0.21
4.72±0.71
0.71±0.03
6.09±1.04
0.60±0.14
0.67±0.07
4.88±0.34
1.53±0.13
1.15±0.12
1.30±0.25
1.35±0.09
0.96±0.06
1.22±0.06
MCF-7
4-F
4-F
4-F
4-F
CH2CH2CH3
CH2N(CH3)2
CH2N(CH2CH3)2
CH2N(CH2CH2)2O
CH2N(CH2CH2)2NCH3
CH2N(CH2)4
CH2N(CH2)5
CH2N(CH2CH2)2O
CH2N(CH2CH2)2O
CH2N(CH2CH3)2
Ph
3.93±0.20
3.72±0.32
2.34±0.20
3.20±0.13
3.00±0.25
3.82±0.26
2.95±0.18
4.14±0.61
3.48±0.24
2.59±0.21
5.90±0.78
3.34±0.28
1.84±0.33
1.78±0.20
3.49±0.57
4.60±0.95
2.73±0.50
2.77±0.24
2.52±0.17
2.45±0.11
2.36±0.25
2.26±0.20
1.62±0.30
1.03±0.21
2.03±0.03
4.36±0.44
1.67±0.17
2.63±0.30
2.73±0.41
2.90±0.23
2.26±0.20
A1
A2
A3
A4
4-F
4-F
4-F
4-Cl
A5
A6
A7
A8
4-CH3
A9
2,4-di-F
A10
A11
A12
A13
A14
B1
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
Ph-4-OCH3
Py-4
Py-3
CH2N(CH2CH2)2O
CH2N(CH2CH2)2NCH3
Boc
B2
(S)-C1
(S)-C2
(S)-C3
(R)-C4
(S)-C5
(R)-C6
(S)-C7
(S)-C8
(R)-C9
D1
H
Ac
Ac
COPr-c
COPr-c
COCH(CH2CH2)2O
CH2Pr-c
CH2Pr-c
Boc
H
D2
Ac
D3
COPr-c
D4
COCH(CH2CH2)2O
CH2Pr-c
D5
D6
0.56±0.06
1.09±0.15
BEZ235
As expected, all compounds exhibited significant antiproliferative activities
6

against HCT-116 and MCF-7 with an IC50 of 0.41–6.09 μM and 1.62–5.90 μM,
respectively. Compared with compound A1 (IC50 = 4.06 μM against HCT-116, 3.93
μM against MCF-7), compounds A2–A7 (IC50 = 1.20–2.75 μM against HCT-116,
2.34–3.82 μM against MCF-7) with tertiary amines at the 3-position of
quinazolin-4(3H)-one displayed a slight increase in cell-based activity against both
HCT-116 and MCF-7. This data indicate that polar group were preferred in this region.
As the lipophilicity of the substituent R2 increased in going from dimethylaminoethyl
(A2, IC50 = 2.69 μM against HCT-116, 3.72 μM against MCF-7) to phenyl (A11, IC50
= 4.74 μM against HCT-116, 5.90 μM against MCF-7), the drops of cellular activity
was observed. However, substituted phenyl (A12, B1 and B2) or pyridinyl (A13 and
A14) at the 3-position of quinazolin-4(3H)-one were well tolerated. This results
suggest that the reducing lipophilicity of the substitutes at the 3-position of
quinazolin-4(3H)-one may improve the antiproliferative activity. When the R1 in
compounds A changed from 4-F (A3, A4) to 4-Cl (A8), 4-CH3 (A9) and 2,4-di-F
(A10), the compounds displayed the similar potency. These results are consistent with
the observation in our previous work.30 Compounds C with different 1-substituted
pyrrolidin-3-yl attached to the 3-position of quinazolin-4(3H)-one moiety displayed
significantly different antiproliferative activity. The compounds ((S)-C3, (S)-C5 and
(S)-C8) with a (S)-1-substituted pyrrolidin-3-yl exhibit higher activity than the
compounds ((R)-C4, (R)-C6 and (R)-C9) with a (R)-1-substituted pyrrolidin-3-yl. We
also noticed that the activity of compound (S)-C8 displayed 8-fold to compound
(R)-C9 against HCT-116 cell. The replacement of cyclopropylcarbonyl in (S)-C5
with cyclopropylmethyl produced compounds (S)-C8, which showed an improved
antiproliferative activity against HCF-7 cells. Furthermore, the replacement of
pyrrolid-3-yl in compounds C with piperid-4-yl gave compounds D, which displayed
a drop in cell-based activity. Building on the discussions above, we consider that
(S)-1-substituted pyrrolidin-3-yl moiety is the suitable substituent at the 3-position of
quinazolin-4(3H)-one moiety. To be worth mention, the potency of compounds
(S)-C5, and (S)-C8 are comparable to that of positive drug BEZ235 against HCT-116.
Therefore, we investigated these compounds in next study.
7

2.2.2. PI3K and mTOR enzymatic activity assay
Next, to elucidate the mechanism of antiproliferative activities of title
compounds, compounds (S)-C5 and (S)-C8 were selected to evaluate their inhibitory
activity against PI3Ks and mTOR by performing an ATP depletion assay.25,26
BEZ235 was used as the positive drug. The data are listed in Table 2.
Table 2 Inhibitory activity of (S)-C5 and (S)-C8 against PI3Ks and mTOR (n = 2)
IC50 (nM)
Compds
mTOR
208
PI3K
7.3
PI3K
209
PI3K
116
PI3K
106
21
(S)-C5
(S)-C8
BEZ235
6.7
24
181
114
89
421
169
204
97
The data in Table 2 indicated compounds (S)-C5 and (S)-C8 displayed
remarkable potency against PI3Ks and mTOR, especially against PI3K. The
inhibitory activities of compounds (S)-C5 and (S)-C8 against PI3Kα were 7.3 nM and
6.7 nM respectively, which are approximately 10-fold more potent than that of
BEZ235. The replacement of cyclopropylcarbonyl in (S)-C5 with cyclopropylmethyl
produced compounds (S)-C8, which displayed an improved inhibitory activity against
PI3K, PI3K and mTOR. These results suggest that compounds (S)-C5 and (S)-C8
are potent selective PI3Kα inhibitors.
Considering PIK3CA mutations in both HCT-116 and MCF-7, the excellent
potency of compounds (S)-C5 and (S)-C8 on PI3K further supported the significant
antiproliferative activities of compounds (S)-C5 and (S)-C8 against HCT-116 and
MCF-7. Compounds (S)-C5 and (S)-C8 exhibited more potent activities than
BEZ235 in enzyme-based activities, but similar activities in cell based-activity. These
differences may relate to other property of compounds (S)-C5 and (S)-C8, such as
their undesirable cell permeability.
2.2.3. Anticancer effect in the mice S-180 homograft models in vivo
8

Compound (S)-C5 displayed potent antiproliferative activity and inhibitory
activity against PI3K. Thus, we evaluated whether compound (S)-C5 could inhibit
tumor growth in vivo. A study using mice bearing sarcoma S-180 was performed.
Compound (S)-C5 was dissolved in DMSO : PEG400 : 5% glucose injection (1 : 7 : 2,
V/V/V) and dosed orally at 20 mg/kg or 40 mg/kg once a day for 8 days. Considering
that it is difficult to measure the volumes of S-180 tumor, tumor weights were used as
evaluating indicators. The tumor weights and daily body weights were depicted in
Figure 3. The inhibitory ratios of compound (S)-C5 at 20 mg/kg and 40 mg/kg were
34.5% and 58.0%, respectively. In addition, the body weight of two dose groups
dropped a little in the first few days. These results suggested that compound (S)-C5 is
an effective anticancer agent in vivo.
Figure 3. (A) The anticancer effect of compound (S)-C5 in establishing mice S-180 homograft
*
model. P < 0.05 vs vehicle; **P < 0.01 vs vehicle. (B) The change of tested mice body weights.
Mice bearing subcutaneous cancers were orally administered solvent, compound (S)-C5 (20
mg/kg or 40 mg/kg) once daily for 8 days (mpk: mg/kg).
2.3. Docking studies
To further explain the potent activities of compounds (S)-C5 and (S)-C8, we
performed a docking analysis utilizing the C-DOCKER program within Discovery
Studio 2.5 software package. Docking simulations were carried out on human PI3Kγ
(PDB code 3S2A)8 with compound (S)-C5 or (S)-C8, and the results were depicted in
Figure 4. From the docking results, we observed that: (1) the nitrogen atom of
pyridine ring formed hydrogen bonds via an ordered water molecule with Tyr867 and
9

Asp841; (2) the two oxygen atoms at 2-position and 3-sulfonamido of pyridine ring
simultaneously formed hydrogen bonds with Lys833; (3) the hydrogen atom at the
3-amino of pyridine ring formed a hydrogen bond with Asp964; (4) the 1-nitrogen
atom of quinazolin-4(3H)-one moiety formed a hydrogen bond with Val882; (5) the
oxygen atom from cyclopropylcarbonyl in (S)-C5 formed a hydrogen bond with
Lys890 (Figure 4a). These formation of hydrogen bonds suggest that both (S)-C5 and
(S)-C8 can exactly interact with the catalytic domain of PI3K.
Figure 4. (a) Compound (S)-C5 docked into the ATP-binding site of PI3Kγ (PDB code: 3S2A). (b)
Compound (S)-C8 docked into the ATP-binding site of PI3Kγ. (S)-C5 and (S)-C8 is shown as
sticks. Hydrogen bonds within 2.5 Å are shown as yellow dashed lines.
3. Conclusion
In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-
6-yl)-pyridin-3-yl)-phenyl sulfonamides were synthesized and characterized. All
compounds exhibited significant antiproliferative activities against HCT-116 and
MCF-7. The discussion of SAR revealed that the antiproliferative activity is closely
related to the substituted group at the 3-position of quinazolin-4(3H)-one moiety. The
compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and
mTOR, especially against PI3K. In addition, compound (S)-C5 can efficaciously
inhibit tumor growth in a mice S-180 model. These results suggest that our designed
compounds can serve as potent PI3K inhibitors and effective anticancer agents.
10

4. Experimental
4.1. Chemistry and chemical methods
Unless specified otherwise, all starting materials, reagents and solvents were
commercially available. All reactions were monitored by thin-layer chromatography
on silica gel plates (GF-254) and visualized with UV light. All the melting points
were determined on a Shanghai micro melting-point apparatus (model: SGW® X-4B)
and thermometer was uncorrected. NMR spectra were recorded on a 400 Bruker
NMR spectrometer with tetramethylsilane (TMS) as an internal reference. All
chemical shifts are reported in parts per million (ppm). High-resolution mass
measurements were performed using electrospray ionization (positive mode) on a
quadrupole time-of-flight (QTOF) mass spectrometer (Maxis Q-TOF, Bruker Inc.).
4.1.1. General procedures for the synthesis of intermediates 1a-1p
The mixture of 2-amino-5-bromobenzoic acid (1.00 g, 4.63 mmol), triethyl
orthoformate (1.00 mL, 6.02 mmol), amine (6.02 mmol), iodine (0.12 g, 0.046 mmol)
and anhydrous ethanol (20 mL) was refluxed under nitrogen atmosphere for 4–6 h,
then concentrated under vacuum to give a residue which was dissolved in ethyl
acetate (90 mL). The ethyl acetate solution was washed with 1 N aqueous sodium
hydroxide (20 mL×3) and brine (30 mL×3), dried over anhydrous sodium sulfate and
concentrated to give a white or light yellow solid.
4.1.1.1. 6-Bromo-3-butylquinazolin-4(3H)-one (1a)
1
White solid; Yield 56.2%; mp: 112.0–113.5 C. H NMR (CDCl3) δ 8.44 (d, J =
2.3 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.59 (d, J
= 8.7 Hz, 1H, Ar-H), 4.00 (t, J = 7.4 Hz, 2H, CH2), 1.81–1.73 (m, 2H, CH2),
1.47–1.35 (m, 2H, CH2), 0.97 (t, J = 7.3 Hz, 3H, CH3). ESI-MS m/z: 280.9 [M + H] +.
4.1.1.2. 6-Bromo-3-(2-(dimethylamino)ethyl)quinazolin-4(3H)-one (1b)
Light yellow solid; Yield 83.9%; mp: 58.9–60.5 C. 1H NMR (CDCl3) δ 8.43 (d,
J = 2.3 Hz, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57
(d, J = 8.7 Hz, 1H, Ar-H), 4.07 (t, J = 6.0 Hz, 2H, CH2), 2.65 (t, J = 6.0 Hz, 2H, CH2),
2.29 (s, 6H, NCH3×2). ESI-MS m/z: 295.9 [M + H] +.
11

4.1.1.3. 6-Bromo-3-(2-(diethylamino)ethyl)quinazolin-4(3H)-one (1c)
1
White solid; Yield 78.0%; mp: 57.9–59.8 C. H NMR (CDCl3) δ: 8.44 (d, J =
2.3 Hz, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 7.81 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57 (d, J
= 8.7 Hz, 1H, Ar-H), 4.00 (t, J = 5.8 Hz, 2H, CH2), 2.74 (t, J = 5.8 Hz, 2H, CH2), 2.52
(q, J = 7.1 Hz, 4H, CH2CH3), 0.91 (t, J = 7.1 Hz, 6H, CH2CH3). ESI-MS m/z: 324.0
[M + H] +.
4.1.1.4. 6-Bromo-3-(2-(4-morpholino)ethyl)quinazolin-4(3H)-one (1d)
1
Light yellow solid; Yield 81.4%; mp: 109.0–111.0 C. H NMR (CDCl3) δ: 8.43
(d, J = 2.3 Hz, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 7.83 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),
7.58 (d, J = 8.7 Hz, 1H, Ar-H), 4.10 (t, 2H, NCH2), 3.78–3.56 (m, 4H, OCH2×2),
2.72 (t, 2H, NCH2), 2.52 (s, 4H, NCH2×2). ESI-MS m/z: 338.0 [M + H] +.
4.1.1.5. 6-Bromo-3-(2-(4-methylpiperazin-1-yl)ethyl)quinazolin-4(3H)-one (1e)
Light yellow solid; Yield 28.7%; mp: 103.2–105.4 C. 1H NMR (CDCl3) δ: 8.43
(d, J = 2.1 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H),
7.58 (d, J = 8.7 Hz, 1H, Ar-H), 4.07 (t, J = 5.8 Hz, 2H, CH2), 2.70 (t, J = 5.8 Hz, 2H,
CH2), 2.65–2.31 (m, 8H, NCH2), 2.28 (s, 3H, NCH3). ESI-MS m/z: 351.1 [M + H] +.
4.1.1.6. 6-Bromo-3-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one (1f)
White solid; Yield 80.5%; mp: 82.3–84.4 C. 1H NMR (CDCl3) δ 8.43 (d, J = 2.3
Hz, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57 (d, J =
8.7 Hz, 1H, Ar-H), 4.11 (t, J = 6.2 Hz, 2H, CH2), 2.84 (t, J = 6.2 Hz, 2H, CH2), 2.58 (t,
4H, NCH2), 1.83–1.72 (m, 4H, CH2). ESI-MS m/z: 322.0 [M + H] +.
4.1.1.7. 6-Bromo-3-(2-(piperidin-1-yl)ethyl)quinazolin-4(3H)-one (1g)
White solid; Yield 80.1%; mp: 62.6–64.8 C. 1H NMR (CDCl3) δ 8.43 (d, J = 2.3
Hz, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57 (d, J =
8.7 Hz, 1H, Ar-H), 4.07 (t, J = 5.9 Hz, 2H, CH2), 2.64 (t, J = 5.9 Hz, 2H, CH2), 2.43 (t,
4H, NCH2), 1.58–1.50 (m, 4H, CCH2), 1.46–1.37 (m, 2H, CH2). ESI-MS m/z: 336.1
[M + H] +.
4.1.1.8. 3-Benzyl-6-bromoquinazolin-4(3H)-one (1h)
White solid; Yield 48.63%; mp: 126.0–128.0 C. 1H NMR (CDCl3) δ 8.37 (d, J =
2.3 Hz, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 7.74 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.50 (d, J
12

= 8.7 Hz, 1H, Ar-H), 7.33–7.14 (m, 5H, Ar-H), 5.11 (s, 2H, CH2). ESI-MS m/z: 314.9
[M + H] +.
4.1.1.9. 6-Bromo-3-(4-methoxybenzyl)quinazolin-4(3H)-one (1i)
White solid; Yield 75.0%; mp: 129.6–131.7 C. 1H NMR (CDCl3) δ 8.45 (d, J =
2.3 Hz, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57 (d, J
= 8.7 Hz, 1H, Ar-H), 7.31 (d, J = 8.6 Hz, 2H, Ar-H), 6.91–6.85 (m, 2H, Ar-H), 5.12 (s,
2H, CH2), 3.79 (s, 3H, OCH3). ESI-MS m/z: 345.0 [M + H] +.
4.1.1.10. 6-Bromo-3-(pyridin-4-ylmethyl)quinazolin-4(3H)-one (1j)
1
White solid; Yield 71.43%; mp: 116.5–118.6 C. H NMR (DMSO-d6) δ 8.61 (s,
1H, Ar-H), 8.53 (dd, J = 4.6, 1.4 Hz, 1H, Ar-H), 8.24 (d, J = 2.4 Hz, 2H, Ar-H), 8.02
(dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 7.69 (d, J = 8.7 Hz, 1H, Ar-H), 7.30 (d, J = 6.0 Hz,
2H, Ar-H), 5.25 (s, 2H, CH2). ESI-MS m/z: 315.9 [M + H] +.
4.1.1.11. 6-Bromo-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one (1k)
White solid; Yield 76.1%; mp: 158.0–159.8 C. 1H NMR (CDCl3) δ 8.69 (s, 1H,
Ar-H), 8.60 (d, J = 4.1 Hz, 1H, Ar-H), 8.44 (d, J = 2.3 Hz, 1H, Ar-H), 8.14 (s, 1H,
Ar-H), 7.84 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.74 (d, J = 7.9 Hz, 1H, Ar-H), 7.59 (d, J
= 8.7 Hz, 1H, Ar-H), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, Ar-H), 5.20 (s, 2H, CH2). ESI-MS
m/z: 315.9 [M + H] +.
4.1.1.12. 6-Bromo-3-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one (1l)
White solid; Yield 16.22%; mp: 152.1–153.9 C. 1H NMR (CDCl3) δ: 8.49 (d, J
= 2.3 Hz, 1H, Ar-H), 8.12 (s, 1H, Ar-H), 7.88 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.64 (d,
J = 8.7 Hz, 1H, Ar-H), 7.55 (d, J = 7.9 Hz, 2H, Ar-H), 7.37 (d, J = 8.3 Hz, 2H, Ar-H),
3.76 (s, 4H, OCH2), 3.60 (s, 2H, NCH2), 2.52 (s, 4H, , NCH2). ESI-MS m/z: 400.1
[M+H]+. ESI-MS m/z: 400.0 [M + H] +.
4.1.1.13.
6-Bromo-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-
4(3H)-one (1m)
Light yellow solid; Yield 66.5%; mp: 119.8–122.5 C. 1H NMR (CDCl3) δ: 8.48
(d, J = 2.3 Hz, 1H, Ar-H), 8.12 (s, 1H, Ar-H), 7.88 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),
7.64 (d, J = 8.7 Hz, 1H, Ar-H), 7.52 (d, J = 8.3 Hz, 2H, Ar-H), 7.35 (d, J = 8.3 Hz, 2H,
Ar-H), 3.58 (s, 2H, CH2), 2.52–2.43 (m, 8H, NCH2), 2.31 (s, 3H, NCH3). ESI-MS m/z:
13

413.0 [M + H] +.
4.1.1.14.
t-Butyl
(S)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1-
carboxylate ((S)-1n)
White solid; Yield 46.15%; mp: 115.0–117.0 C. 1H NMR (CDCl3) δ 8.44 (d, J =
2.3 Hz, 1H, Ar-H), 8.12–8.06 (m, 1H, Ar-H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),
7.61 (d, J = 8.7 Hz, 1H, Ar-H), 5.50–5.32 (m, 1H, CH2), 3.87 (dd, J = 12.3, 7.1 Hz,
1H, CH2), 3.74–3.68 (m, 1H, CH), 3.59 (s, 2H, CH2), 2.46–2.36 (m, 1H, CH2), 2.22 (s,
1H, CH2), 1.48 (s, 9H, CH3×3). ESI-MS m/z: 394.0 [M + H] +.
4.1.1.15. t-Butyl 4-(6-bromo-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate
(1o)
White solid; Yield 42.54%; mp: 166.8–169.4 C. 1H NMR (CDCl3) δ 8.44 (d, J =
2.2 Hz, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.84 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.59 (d, J
= 8.7 Hz, 1H, Ar-H), 5.04–4.89 (m, 1H, CH), 4.35 (s, 2H, CH2), 2.91 (s, 2H, CH2),
2.01–1.91 (m, 2H, CH2), 1.91–1.73 (m, 2H, CH2), 1.49 (s, 9H, CH3  3). ESI-MS m/z:
408.0 [M + H] +.
4.1.1.16.
t-Butyl
(R)-3-(6-bromo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1-
carboxylate ((R)-1p)
1
White solid; Yield 36.6%; H NMR (CDCl3) δ 8.44 (d, J = 2.3 Hz, 1H, Ar-H),
8.04–8.12 (m, 1H, Ar-H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.61 (d, J = 8.7 Hz, 1H,
Ar-H), 5.03–4.87 (m, 1H, CH), 3.87 (dd, J = 12.3, 7.1 Hz, 1H, CH2), 3.75–3.65 (m,
1H, CH2), 3.59 (s, 2H, CH2), 2.51–2.33 (m, 1H, CH2), 2.20 (s, 1H), 1.47 (s, 9H, CH3
×3). ESI-MS m/z: 394.1 [M + H] +.
4.1.17. (S)-6-Bromo-3-(1-(cyclopropylmethyl)pyrrolidin-3-yl)quinazolin-4(3H)-
one ((S)-1q)
To a solution of (S)-1n (250 mg, 0.63 mmol) in dichloromethane (DCM, 10 mL),
trifluoroacetic acid (TFA, 2 mL) was added. The resulting mixture was stirred at room
temperature for 2 h, concentrated under vacuum to give a yellow product, which was
dissolved in 1, 2-dichloroethane (DCE, 10 mL), and then cyclopropylformaldehyde
(44 mg, 0.63 mmol), NaBH(OAc)3 (200 mg, 0.95 mmol) and AcOH (38 mg, 0.63
mmol) were added. The resulted suspension was stirred overnight, quenched with
14

aqueous sodium hydrogen carbonate and extracted with DCM twice (30 mL×2). The
combined organic phase was washed with brine, and dried over Na2SO4, filtered,
concentrated in vacuum. The residue was purified by column chromatography on
silica gel to produce (S)-1q as light yellow oil. Yield 90.6%; 1H NMR (CDCl3) δ 8.43
(d, J = 2.2 Hz, 1H, Ar-H), 8.21 (s, 1H, Ar-H), 7.84 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),
7.59 (d, J = 8.6 Hz, 1H, Ar-H), 5.06–4.96 (m, 1H, CH), 3.40–3.30 (m, 2H), 2.44–2.34
(m, 2H, CH2), 2.12–2.01 (m, 2H), 1.25–1.18 (m, 2H), 0.95–0.83 (m, 1H, cPr-CH),
0.70–0.60 (m, 2H, cPr-CH2), 0.14–0.12 (m, 2H, cPr-CH2). ESI-MS m/z: 348.0 [M +
H]+.
Intermediates (R)-1r and 1s were prepared according to the process described in
(S)-1q.
4.1.18. (R)-6-Bromo-3-(1-(cyclopropylmethyl)pyrrolidin-3-yl)quinazolin-4(3H)-
one ((R)-1r)
1
Light yellow oil; Yield 37.7%; H NMR (CDCl3) δ 8.43 (d, J = 2.2 Hz, 1H,
Ar-H), 8.21 (s, 1H, Ar-H), 7.84 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.59 (d, J = 8.6 Hz,
1H, Ar-H), 4.98-4.88 (m, 1H, CH), 3.38–3.30 (m, 2H), 2.34–2.30 (m, 2H, CH2),
2.03–1.97 (m, 2H), 1.25–1.20 (m, 2H), 0.91–0.88 (m, 1H, c-Pr-CH), 0.62–0.57 (m,
2H, cPr-CH2), 0.14–0.12 (m, 2H, cPr-CH2). ESI-MS m/z: 348.0 [M + H] +.
4.1.19.
(1s)
6-Bromo-3-(1-(cyclopropylmethyl)piperidin-4-yl)quinazolin-4(3H)-one
White solid; Yield 82.0%; mp: 176.8–178.6 C. 1H NMR (CDCl3) δ 8.44 (d, J =
2.3 Hz, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 7.83 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 7.57 (d, J
= 8.7 Hz, 1H, Ar-H), 4.90-4.84 (m, 1H, CH), 3.28 (d, J = 11.9 Hz, 2H, CH2), 2.34 (d,
J = 6.5 Hz, 2H, CH2), 2.23–2.19 (m, 2H, CH2), 2.02–1.98 (m, 4H, CH2), 0.92–0.88 (m,
1H, CH), 0.58–0.53 (m, 2H, CH2), 0.14–0.12 (m, 2H, CH2). ESI-MS m/z: 362.0 [M +
H] +.
4.1.20. (R)-3-(1-Acetylpyrrolidin-3-yl)-6-bromoquinazolin-4(3H)-one ((R)-1t)
To a solution of (R)-1p (150 mg, 0.38 mmol) in DCM (8 mL), trifluoroacetic acid
(2 mL) was added. The resulting solution was stirred at room temperature for 2 h,
concentrated under vacuum to produce crude product, which was dissolved in DCM
15

(15 mL). Then, acetic acid (30 mg, 0.50 mmol), HATU (570 mg, 1.5 mmol), and
DIPEA (1.2 mL) was added. The resulted mixture was refluxed for 2 h. The solvent
were removed under vacuum and the residue was purified through a column
chromatography on silica gel to produce (R)-1t as a light yellow solid. Yield 86.0%;
mp: 89.0–91.5 C. 1H NMR (CDCl3) δ 8.43 (d, J = 2.2 Hz, 1H, Ar-H), 8.03 (d, J =
27.5 Hz, 1H, Ar-H), 7.86 (ddd, J = 8.6, 5.0, 2.3 Hz, 1H, Ar-H), 7.59 (dd, J = 8.7, 5.5
Hz, 1H, Ar-H), 5.38–5.30 (m, 1H, CH), 4.05–3.99 (m, 1H, CH2), 3.87–3.82 (m, 1H,
CH2), 3.71–3.66 (m, 2H, CH2), 2.46–2.41 (m, 2H, CH2), 2.11 (d, J = 18.7 Hz, 3H,
COCH3). ESI-MS m/z: 335.9 [M + H] +.
Intermediates (R)-1u was synthesized according to the process described in
(S)-1t.
4.1.20. (R)-6-Bromo-3-(1-(cyclopropanecarbonyl)pyrrolidin-3-yl)quinazolin-
4(3H)-one ((R)-1u)
Light yellow oil; Yield 75.0%; 1H NMR (CDCl3) δ 8.43 (s, 1H, Ar-H), 8.06 (d, J
= 27.7 Hz, 1H, Ar-H), 7.84 (d, J = 5.8 Hz, 1H, Ar-H), 7.59 (dd, J = 8.2, 5.3 Hz, 1H,
Ar-H), 5.42 (s, 1H, CH), 3.99–3.93 (m, 4H, CH2), 2.48–2.43 (m, 2H, CH2), 1.63–1.58
(m, 1H, cPr-CH), 1.04–1.02 (m, 2H, c-Pr-CH2), 0.91–0.87 (m, 2H, c-Pr-CH2).
ESI-MS m/z: 361.9 [M + H] +.
4.2.1. N-(5-(3-Butyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)-
4-fluorophenylsulfonamide (A1)
N-(5-Bromo-2-methoxypyridin-3-yl)-4-arylsulfonamide was prepared as our
reported steps.24 The mixture of N-(5-Bromo-2-methoxypyridin-3-yl)-4-fluoro
phenylsulfonamide (100 mg, 0.28 mmol), bis(pinacolato)diboron (78 mg, 0.31
mmol), potassium acetate (82 mg, 0.84 mmol), PdCl2(dppf) (16 mg, 0.021 mmol)
and 1,4-dioxane (10 mL) was reflux under nitrogen atmosphere for 2 h, then
concentrated in vacuum. To the resulted residue was added 1a (63 mg, 0.25 mmol),
K2CO3 (116 mg, 0.84 mmol), PdCl2(dppf) (16 mg, 0.021 mmol),
1,2-dimethoxyethane (DME, 10 mL) and water (4 mL). The obtained mixture was
refluxed under nitrogen atmosphere for 4 h. The volatile was removed under vacuum
and the residue was purified through a column chromatography on silica gel with
16

dichloromethane /methanol (V:V = 40:1) as eluent to produce A1 as white solid.
1
yield 61.1%; mp: 176.0–178.0 C. H NMR (DMSO-d6): δ 10.13 (s, 1H, SO2NH),
8.45 (s, 1H, Ar-H), 8.39 (d, J = 2.2 Hz, 1H, Ar-H), 8.27 (d, J = 2.1 Hz, 1H, Ar-H),
8.09 (dd, J = 8.5, 2.0 Hz, 1H, Ar-H), 7.93 (d, J = 2.3 Hz, 1H, Ar-H), 7.85-7.80 (m,
2H, Ar-H), 7.78 (d, J = 8.5 Hz, 1H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H, Ar-H), 4.01 (t, J =
7.2 Hz, 2H, CH2), 3.68 (s, 3H, OCH3), 1.78–1.64 (m, 2H, CH2), 1.41-1.26 (m, 2H,
CH2), 0.93 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz),
160.5, 157.2, 148.7, 147.8, 142.0, 137.0, 135.4, 132.8, 132.1, 130.3, 130.2, 128.9,
128.6, 123.5, 122.4, 121.0, 116.8, 116.6, 54.0, 46.2, 31.2, 19.8, 14.0. ESI-HRMS m/z:
calc’d for C24H23FN4O4S [M+H]+: 483.1497; found 483.1497.
Compounds A2–A14, B1, B2, (S)-C1, (R)-C4, (R)-C6, (S)-C8, (R)-C9, D1 and
D6 were synthesized according to the process described in A1.
4.2.2.
N-(5-(3-(2-(Dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-
methoxypyridin-3-yl)-4-fluorophenylsulfonamide (A2)
Yield 61.18%; mp: 172.0–174.0 C. 1H NMR (DMSO-d6) δ 10.09 (s, 1H, SO2NH),
8.39–8.33 (m, 2H, Ar-H), 8.26 (d, J = 2.1 Hz, 1H, Ar-H), 8.08 (dd, J = 8.5, 2.2 Hz, 1H,
Ar-H), 7.92 (d, J = 2.3 Hz, 1H, Ar-H), 7.86–7.79 (m, 2H, Ar-H), 7.77 (d, J = 8.5 Hz,
1H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 4.12 (t, J = 5.9 Hz, 2H, CH2), 3.69 (s, 3H,
OCH3), 2.61 (t, J = 5.9 Hz, 2H, CH2), 2.23 (s, 6H, CH3×2). 13C NMR (DMSO-d6) δ
164.73 (d, JC-F = 250 Hz), 160.6, 157.1, 148.9, 147.7, 141.4, 137.3, 137.2, 135.4,
132.8, 131.5, 130.3, 130.2, 128.8, 128.5, 123.5, 122.4, 121.7, 116.7, 116.5, 57.6, 54.0,
45.6(CH3×2), 43.87. ESI-HRMS m/z: calc’d for C24H25FN5O4S [M+H]+: 498.1606;
found 498.1606.
4.2.3.
N-(5-(3-(2-(Diethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-
methoxypyridin-3-yl)-4-fluorophenylsulfonamide (A3)
Yield 74.43%; mp: 157.0–159.0 C. 1H NMR (DMSO-d6) δ 10.04 (s, 1H, SO2NH),
8.37 (d, J = 1.6 Hz, 1H, Ar-H), 8.31 (s, 1H, Ar-H), 8.27 (d, 1H, Ar-H), 8.08 (dd, J =
8.4 Hz, 1H, Ar-H), 7.92 (d, J = 1.6 Hz, 1H, Ar-H), 7.82 (dd, J = 8.3, 5.3 Hz, 2H,
Ar-H), 7.77 (d, J = 8.5 Hz, 1H, Ar-H), 7.42 (t, J = 8.7 Hz, 2H, Ar-H), 4.05 (t, J = 5.4
Hz, 2H, CH2), 3.68 (s, 3H, OCH3), 2.71 (t, J = 5.3 Hz, 2H, CH2), 0.86 (t, J = 7.0 Hz,
17

6H, CH3×2). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.7, 157.1, 149.1,
147.7, 141.4, 137.1, 135.3, 132.8, 131.5, 130.3, 130.2, 128.7, 128.5, 123.3, 122.3,
121.6, 116.7, 116.5, 54.0, 50.7, 49.1, 47.2, 44.7, 12.1(CH3×2). ESI-HRMS m/z: calc’d
for C26H29FN5O4S [M + H]+: 526.1919; found 526.1919.
4.2.4.
4-Fluoro-N-(2-methoxy-5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A4)
1
Yield 44.35%; mp: 202.0–204.0 C. H NMR (DMSO-d6): δ 10.06 (s, 1H,
SO2NH), 8.34 (d, J = 2.3 Hz, 1H, Ar-H), 8.31 (s, 1H, Ar-H), 8.22 (d, J = 2.1 Hz, 1H,
Ar-H), 8.04 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.88 (d, J = 2.3 Hz, 1H, Ar-H), 7.81-7.75
(m, 2H, Ar-H), 7.73 (d, J = 8.5 Hz, 1H, Ar-H), 7.37 (t, J = 8.8 Hz, 2H, Ar-H), 4.08 (t,
J = 5.8 Hz, 2H, CH2), 3.63 (s, 3H, OCH3), 3.53–3.44 (m, 4H, OCH2×2), 2.59 (t, J =
5.8 Hz, 2H, CH2), 2.41 (s, 4H, NCH2×2). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250
Hz), 160.5, 157.2, 149.0, 147.8, 142.0, 137.1, 135.3, 132.8, 132.1, 130.3, 130.2, 128.9,
128.6, 123.6, 122.4, 121.0, 116.8, 116.6, 66.7 (CH2×2), 56.8, 54.0, 53.7 (CH2×2),
43.2. ESI-HRMS m/z: calc’d for C26H27FN5O5S [M+H]+: 540.1705; found 540.1711.
4.2.5.
4-Fluoro-N-(2-methoxy-5-(3-(2-(4-methylpiperazin-1-yl)ethyl)-4-oxo-
3,4-dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A5)
Yield 58.75%; mp: 151.0–153.0 C. 1H NMR (DMSO-d6) δ 8.37-8.31 (m, J = 2.4
Hz, 2H, Ar-H), 8.26 (d, J = 2.1 Hz, 1H, Ar-H), 8.08 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H),
7.90 (d, J = 2.3 Hz, 1H, Ar-H), 7.82 (dd, J = 8.8, 5.2 Hz, 2H, Ar-H), 7.77 (d, J = 8.5
Hz, 1H, Ar-H), 7.41 (t, J = 8.8 Hz, 2H, Ar-H), 4.11 (t, J = 5.8 Hz, 2H, CH2), 3.69 (s,
3H, OCH3), 2.64 (t, J = 5.8 Hz, 2H, CH2), 2.42 (s, 4H, CH2×2), 2.24 (s, 3H, NCH3).
13C NMR (DMSO-d6) δ 172.5, 164.7 (d, JC-F = 250 Hz), 160.5, 157.2, 149.0, 147.8,
141.0, 137.5, 135.5, 132.8, 131.3, 130.2, 130.1, 128.8, 128.6, 123.5, 122.4, 122.2,
116.7, 116.5, 56.1, 54.9 (CH2×2), 53.9, 52.5 (CH2×2), 45.5, 43.4. ESI-HRMS m/z:
calc’d for C27H30FN6O4S [M+H]+: 553.2028; found 553.2028.
4.2.6.
4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-
dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A6)
Yield 67.04%; mp: 187.0–189.0 C. 1H NMR (DMSO-d6) δ 10.08 (s, 1H, SO2NH),
8.41-8.33 (m, 2H, Ar-H), 8.26 (d, J = 2.1 Hz, 1H, Ar-H), 8.08 (dd, J = 8.5, 2.2 Hz, 1H,
18

Ar-H), 7.91 (d, J = 2.3 Hz, 1H, Ar-H), 7.82 (dd, J = 8.8, 5.2 Hz, 2H, Ar-H), 7.77 (d, J
= 8.5 Hz, 1H, Ar-H), 7.41 (t, J = 8.8 Hz, 2H, Ar-H), 4.14 (t, J = 6.0 Hz, 2H, CH2),
3.69 (s, 3H, OCH3), 2.82 (t, J = 5.9 Hz, 2H, CH2), 2.58 (t, 4H, CH2×2), 1.75–1.63 (m,
13
4H, CH2×2). C NMR (DMSO-d6) δ 164.7 (d, JC-F = 250 Hz), 160.6, 157.2, 148.8,
147.7, 141.2, 137.4, 135.5, 132.8, 131.4, 130.2, 130.1, 128.8, 128.6, 123.5, 122.4,
121.9, 116.7, 116.5, 54.2 (CH2×2), 54.1, 53.9, 45.1, 23.6 (CH2×2). ESI-HRMS m/z:
calc’d for C26H27FN5O4S [M+H]+: 524.1763; found 524.1762.
4.2.7.
4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A7)
Yield 62.64%; mp: 195.0–197.0 C. 1H NMR (DMSO-d6) δ 10.06 (s, 1H, SO2NH),
8.36 (d, J = 2.2 Hz, 1H, Ar-H), 8.33 (s, 1H, Ar-H), 8.26 (d, J = 2.0 Hz, 1H, Ar-H),
8.08 (dd, J = 8.5, 2.1 Hz, 1H, Ar-H), 7.92 (d, J = 2.2 Hz, 1H, Ar-H), 7.83 (dd, J = 8.8,
5.2 Hz, 2H, Ar-H), 7.77 (d, J = 8.5 Hz, 1H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 4.12
(t, J = 5.9 Hz, 2H, CH2), 3.69 (s, 3H, OCH3), 2.61 (t, J = 5.9 Hz, 2H, CH2), 2.44 (s,
4H, CH2×2), 1.50–1.41 (m, J = 4.7 Hz, 4H, CH2×2), 1.40–1.31 (m, J = 4.5 Hz, 2H,
13
CH2). C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.5, 157.1, 149.0, 147.8,
141.8, 137.2, 135.4, 132.8, 131.7, 130.3, 130.2, 128.8, 128.6, 123.5, 122.4, 121.5,
116.8, 116.5, 56.9, 54.4 (CH2×2), 54.0, 43.5, 26.0 (CH2×2), 24.3. ESI-HRMS m/z:
calc’d for C27H29FN5O4S [M+H]+: 538.1919; found 538.1919.
4.2.8.
4-Chloro-N-(2-methoxy-5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A8)
Yield 44.1%; mp: 214.0–216.0 C. 1H NMR (DMSO-d6) δ 10.20 (s, 1H, SO2NH),
8.40 (d, J = 2.3 Hz, 1H, Ar-H), 8.37 (s, 1H, Ar-H), 8.28 (d, J = 2.1 Hz, 1H, Ar-H),
8.09 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.94 (d, J = 2.3 Hz, 1H, Ar-H), 7.77 (dd, J = 11.8,
5.1 Hz, 3H, Ar-H), 7.66 (d, J = 8.7 Hz, 2H, Ar-H), 4.13 (t, J = 5.9 Hz, 2H, CH2), 3.67
(s, 3H, OCH3), 3.54 (t, 4H, OCH2×2), 2.64 (t, J = 5.8 Hz, 2H, CH2), 2.46 (s, 4H,
NCH2×2). 13C NMR (DMSO-d6) δ 160.5, 157.2, 149.0, 147.8, 142.1, 139.5, 138.3,
135.3, 132.8, 132.3, 129.7 (Ar-C×2), 129.1 (Ar-C×2), 128.9, 128.6, 123.6, 122.4,
120.9, 66.7 (CH2×2), 56.8, 54.0, 53.7 (CH2×2), 43.1. ESI-HRMS m/z: calc’d for
C26H27ClN5O5S [M+H]+: 556.1416; found 556.1416.
19

4.2.9.
N-(2-methoxy-5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)-4-methylphenylsulfonamide (A9)
Yield 71.3%; mp: 212.0–214.0 C. 1H NMR (DMSO-d6) δ 9.99 (s, 1H, SO2NH),
8.37 (s, 1H, Ar-H), 8.34 (d, J = 2.3 Hz, 1H, Ar-H), 8.23 (d, J = 2.1 Hz, 1H, Ar-H),
8.06 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.87 (d, J = 2.3 Hz, 1H, Ar-H), 7.77 (d, J = 8.5
Hz, 1H, Ar-H), 7.67 (d, J = 8.3 Hz, 2H, Ar-H), 7.38 (d, J = 8.2 Hz, 2H, Ar-H), 4.13 (t,
J = 5.9 Hz, 2H, CH2), 3.71 (s, 3H, OCH3), 3.54 (t, 4H, OCH2×2), 2.63 (t, J = 5.9 Hz,
2H, CH2), 2.46 (s, 4H, NCH2×2), 2.36 (s, 3H, Ar-CH3). 13C NMR (DMSO-d6) δ 160.5,
156.8, 149.0, 147.8, 143.9, 141.3, 137.6, 135.4, 132.8, 130.7 (Ar-C×2), 130.0, 128.7,
128.6, 127.2 (Ar-C×2), 123.4, 122.4, 121.5, 66.7 (CH2×2), 56.8, 54.0, 53.7 (CH2×2),
43.1, 21.4. ESI-HRMS m/z: calc’d for C27H30N5O5S [M+H]+: 536.1963; found
536.1962.
4.2.10.
N-(5-(3-(2-(diethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-
methoxypyridin-3-yl)-2,4-difluorophenylsulfonamide (A10)
Yield 63.9%; mp: 177.5–179.5 C. 1H NMR (DMSO-d6) δ 10.26 (s, 1H, SO2NH),
8.38 (d, J = 2.3 Hz, 1H, Ar-H), 8.31 (s, 1H, Ar-H), 8.28 (d, J = 2.2 Hz, 1H, Ar-H),
8.09 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.93 (d, J = 2.3 Hz, 1H, Ar-H), 7.82–7.73 (m, 2H,
Ar-H), 7.60–7.51 (m, 1H, Ar-H), 7.25–7.16 (m, J = 8.5, 2.3 Hz, 1H, Ar-H), 4.07 (t, J
= 5.9 Hz, 2H, CH2), 3.68 (s, 3H, OCH3), 2.75 (t, J = 5.9 Hz, 2H, CH2), 2.59–2.52 (m,
13
4H, NCH2×2), 0.88 (t, J = 7.1 Hz, 6H, CH3×2). C NMR (DMSO-d6) δ 165.40 (d,
JC-F = 252 Hz), 160.7, 159.9 (d, JC-F = 255 Hz), 158.0, 149.1, 147.8, 141.8, 135.3,
133.2, 132.8, 132.3, 128.8, 128.5, 123.4, 122.4, 121.6, 112.3, 112.1, 106.2, 53.9, 50.8,
47.2 (CH2×2), 44.6, 12.1 (CH3×2). ESI-HRMS m/z: calc’d for C26H27F2N5NaO4S
[M+Na]+: 632.1950; found 632.1950.
4.2.11.
N-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-
yl)-4-fluorophenylsulfonamide (A11)
Yield 61.1%; mp: 211.5–213.5 C. 1H NMR (DMSO-d6) δ 10.13 (s, 1H, SO2NH),
8.64 (s, 1H, Ar-H), 8.39 (d, J = 2.3 Hz, 1H, Ar-H), 8.27 (d, J = 2.1 Hz, 1H, Ar-H),
8.10 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.94 (d, J = 2.3 Hz, 1H, Ar-H), 7.84–7.78 (m, 3H,
13
Ar-H), 7.45–7.27 (m, 7H, Ar-H), 5.24 (s, 2H, CH2), 3.67 (s, 3H, OCH3). C NMR
20

(DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.5, 157.2, 148.7, 147.8, 142.1, 137.2, 137.0,
135.6, 133.0, 132.2, 130.3, 130.2, 129.1 (Ar-C×2), 128.8, 128.7, 128.2 (Ar-C×3),
123.6, 122.6, 120.9, 116.8, 116.6, 54.0, 49.5. ESI-HRMS m/z: calc’d for
C27H22FN4O4S [M+H]+: 517.1341; found 517.1340.
4.2.12.
4-Fluoro-N-(2-methoxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A12)
Yield 83.1%; mp: 219.0–221.5 C. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H,
SO2NH), 8.63 (s, 1H, Ar-H), 8.39 (d, J = 2.3 Hz, 1H, Ar-H), 8.27 (d, J = 2.1 Hz, 1H,
Ar-H), 8.09 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.94 (d, J = 2.3 Hz, 1H, Ar-H), 7.85–7.76
(m, 3H, Ar-H), 7.46–7.33 (m, 4H, Ar-H), 6.92 (d, J = 8.7 Hz, 2H, Ar-H), 5.16 (s, 2H,
CH2), 3.72 (s, 3H, OCH3), 3.67 (s, 3H, OCH3). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F
= 250 Hz), 160.5, 159.3, 157.2, 148.5, 147.7, 142.1, 137.0, 136.9, 135.5, 132.9, 132.2,
130.3, 129.9 (Ar-C×2), 129.2, 128.8, 128.7, 123.6, 122.6, 121.0, 116.8, 116.6, 114.5
(Ar-C×2), 55.5, 54.0, 48.9. ESI-HRMS m/z: calc’d for C28H23FN4NaO5S [M+Na]+:
569.1266; found 569.1265.
4.2.13.
4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A13)
Yield 43.8%; mp: 215.0–217.0 C. 1H NMR (DMSO-d6) δ 10.13 (s, 1H, SO2NH),
8.62 (s, 1H, Ar-H), 8.54 (d, J = 4.6 Hz, 2H Ar-H), 8.40 (d, J = 2.1 Hz, 1H Ar-H), 8.27
(d, J = 1.8 Hz, 1H Ar-H), 8.13 (dd, J = 8.5, 1.9 Hz, 1H Ar-H), 7.94 (d, J = 2.1 Hz, 1H
Ar-H), 7.86–7.78 (m, 3H Ar-H), 7.42 (t, J = 8.8 Hz, 2H Ar-H), 7.32 (d, J = 5.1 Hz, 2H
Ar-H), 5.28 (s, 2H, CH2), 3.67 (s, 3H, OCH3). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F
=
250 Hz), 160.6, 157.2, 150.3 (Ar-C×2), 148.7, 147.8, 146.0, 142.1, 137.0, 136.9,
135.7, 133.1, 132.2, 130.3, 130.2, 128.8, 128.7, 123.6, 122.8, 122.5, 121.0, 116.8,
116.6, 54.0, 48.8. ESI-HRMS m/z: calc’d for C26H21FN5O4S [M+H]+: 518.1293;
found 518.1293.
4.2.14.
4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (A14)
Yield 54.31%; mp: 215.0–217.0 C. 1H NMR (DMSO-d6) δ 10.13 (s, 1H, SO2NH),
8.71 (s, 1H, Ar-H), 8.69 (s, 1H, Ar-H), 8.53 (d, J = 4.2 Hz, 1H, Ar-H), 8.39 (d, J = 2.2
21

Hz, 1H, Ar-H), 8.26 (d, J = 2.0 Hz, 1H, Ar-H), 8.11 (dd, J = 8.5, 2.1 Hz, 1H, Ar-H),
7.93 (d, J = 2.2 Hz, 1H, Ar-H), 7.87–7.78 (m, 4H, Ar-H), 7.42 (dd, J = 11.8, 5.7 Hz,
13
3H, Ar-H), 5.27 (s, 2H, CH2), 3.67 (s, 3H, OCH3). C NMR (DMSO-d6) δ 164.8 (d,
JC-F = 250 Hz), 160.6, 157.2, 149.3, 148.9, 148.5, 147.7, 142.1, 137.0, 136.9, 136.7,
135.6, 133.0, 132.2, 130.3, 130.2, 128.7, 128.7, 124.5, 123.6, 122.5, 120.9, 116.8,
116.6, 54.0, 47.5. ESI-HRMS m/z: calc’d for C26H21FN5O4S [M+H]+: 518.1293;
found 518.1293.
4.2.15.
4-Fluoro-N-(2-methoxy-5-(3-(4-(morpholinomethyl)phenyl)-4-oxo-3,4-
dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (B1)
Yield 61.1%; mp: 217.0–219.0 C. 1H NMR (DMSO-d6) δ 10.14 (s, 1H, SO2NH),
8.40 (d, J = 2.0 Hz, 1H, Ar-H), 8.39 (s, 1H, Ar-H), 8.29 (d, J = 1.8 Hz, 1H, Ar-H),
8.14 (dd, J = 8.5, 1.9 Hz, 1H, Ar-H), 7.93 (d, J = 2.0 Hz, 1H, Ar-H), 7.86–7.79 (m, 3H,
Ar-H), 7.51 (s, J = 9.5 Hz, 4H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 3.68 (s, 3H,
OCH3), 3.61 (t, J = 3.9 Hz, 4H, OCH2×2), 3.56 (s, 2H, CH2), 2.41 (s, 4H, NCH2×2).
13C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.4, 157.2, 147.9, 147.6, 142.0,
139.1, 137.0, 136.8, 135.8, 133.2, 131.9, 130.3, 130.2, 130.0 (Ar-C×2), 128.8, 127.7
(Ar-C×2), 123.9, 122.8, 121.1, 116.8, 116.6, 66.7 (CH2×2), 62.2, 54.0, 53.6 (CH2×2).
ESI-HRMS m/z: calc’d for C31H29FN5O5S [M+H]+: 602.1868; found 602.1868.
4.2.16. 4-Fluoro-N-(2-methoxy-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-
4-oxo-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (B2)
Yield 16.82%; mp: 218.5–220.5 C. 1H NMR (DMSO-d6) δ 10.12 (s, 1H, SO2NH),
8.38 (s, 1H, Ar-H), 8.32 (d, 1H), 8.28 (s, 1H), 8.13 (dd, J = 7.9 Hz, 1H), 7.89 (s, 1H),
7.82 (dd, J = 11.1, 6.2 Hz, 3H), 7.55–7.46 (m, 4H, Ar-H), 7.40 (t, J = 8.7 Hz, 2H,
Ar-H), 3.69 (s, 3H, OCH3), 3.56 (s, 2H, CH2), 2.49–2.30 (m, 8H, CH2×4), 2.23 (s, 3H,
13
NCH3). C NMR (DMSO-d6) δ 164.6 (d, JC-F = 250 Hz), 160.4, 157.2, 147.8, 147.5,
140.8, 139.6, 137.7, 136.7, 136.1, 133.2, 131.0, 130.2, 130.1, 129.9, 128.7, 128.7,
127.7, 123.8, 122.8, 122.5, 116.7, 116.5, 61.8, 55.0 (CH2×2), 53.9, 52.7 (CH2×2), 45.8.
ESI-HRMS m/z: calc’d for C32H32FN6O4S [M+H]+: 615.2185; found 615.2184.
4.2.17. t-Butyl (S)-3-(6-(5-((4-fluorophenyl)sulfonamido)-6-methoxypyridin-
3-yl)-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1-carboxylate ((S)-C1)
22

Yield 42.54%; mp: 137.0–139.0 C. 1H NMR (DMSO-d6) δ 10.13 (s, 1H, SO2NH),
8.39 (d, J = 2.3 Hz, 1H, Ar-H), 8.35 (s, 1H, Ar-H), 8.27 (d, J = 2.1 Hz, 1H, Ar-H),
8.10 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.93 (d, J = 2.3 Hz, 1H, Ar-H), 7.86–7.80 (m, 2H,
Ar-H), 7.78 (d, J = 8.5 Hz, 1H, Ar-H), 7.47–7.39 (m, 2H, Ar-H), 5.29–5.15 (m, 1H,
CH), 3.82–3.73 (m, J = 8.8 Hz, 1H, CH2), 3.68 (s, 3H, OCH3), 3.60–3.50 (m, 2H,
CH2), 3.45–3.38 (m, 1H, CH2), 2.46–2.26 (m, 2H, CH2), 1.43 (d, J = 7.3 Hz, 9H,
CH3×3). 13C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.7, 157.2, 153.9, 147.2,
145.9, 142.0, 137.0, 137.0, 135.5, 133.0, 132.1, 130.3, 128.8, 128.5, 123.7, 122.3,
121.0, 116.8, 116.6, 79.2, 54.8, 54.0, 49.6, 44.5, 28.9, 28.6 (CH3×3). ESI-HRMS m/z:
calc’d for C29H31FN5O6S [M+H]+: 596.1974; found 596.1974.
4.2.18. (R)-N-(5-(3-(1-acetylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-
2-methoxypyridin-3-yl)-4-fluorophenylnesulfonamide ((R)-C4)
Yield 75.1%; mp: 118.0–120.0 C. 1H NMR (DMSO-d6) δ 10.12 (s, 1H, SO2NH),
8.41–8.34 (m, 2H, Ar-H), 8.28 (t, J = 2.6 Hz, 1H, Ar-H), 8.11 (dt, J = 8.5, 2.3 Hz, 1H,
Ar-H), 7.98–7.92 (m, J = 2.1, 1.0 Hz, 1H, Ar-H), 7.87–7.81 (m, 3H, Ar-H), 7.43 (t, J
= 8.8 Hz, 2H, Ar-H), 5.33–5.20 (m, 1H, CH), 3.90–3.80 (m, 2H, CH2), 3.69 (s, 3H,
OCH3), 3.55–3.42 (m, 2H, CH2), 2.45–2.32 (m, 2H, CH2), 2.00 (d, J = 14.9 Hz, 3H,
COCH3). 13C NMR (DMSO-d6) δ 164.9 (d, JC-F = 250 Hz), 160.7, 157.2, 147.2, 145.9,
141.9, 135.5, 133.0, 132.0, 130.3, 130.2, 128.8, 128.5, 123.7, 122.3, 121.1, 116.8,
116.6, 54.9, 54.0, 53.9, 50.5, 49.1, 45.6, 44.1, 30.4, 28.8, 22.8, 22.4. ESI-HRMS m/z:
calc’d for C26H25FN5O5S [M+H]+: 538.1555; found 538.1555.
4.2.19. (R)-N-(5-(3-(1-(cyclopropanecarbonyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide ((R)-C6)
Yield 63.0%; mp: 236.0–238.0 C.1H NMR (DMSO-d6) δ 10.12 (s, 1H, SO2NH),
8.40–8.35 (m, J = 17.4, 15.6 Hz, 2H, Ar-H), 8.30–8.22 (m, 1H, Ar-H), 8.15–8.05 (m,
1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.83–7.74 (m, 3H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H,
Ar-H), 5.30–5.20 (m, 1H, CH), 3.82–3.72 (m, 7H, OCH3+CH2×2), 2.45–2.35 (m, 2H,
CH2), 1.82–1.75 (m, 1H, cPr-CH), 0.79–0.74 (m, 4H, cPr-CH2×2). 13C NMR
(DMSO-d6) δ 164.9 (d, JC-F = 250 Hz), 160.7, 157.2, 147.2, 146.0, 145.9, 142.0, 137.0,
135.5, 133.0, 132.0, 130.3, 130.2, 128.8, 128.5, 123.7, 122.3, 121.0, 116.8, 116.6,
23

74.0, 54.9, 54.0, 53.7, 49.8, 49.5, 45.0, 44.5, 30.3, 28.4, 25.4, 12.5, 12.13, 7.6
(CH2×2). ESI-HRMS m/z: calc’d for C28H27FN5O5S [M+H]+: 586.1531; found
586.1540.
4.2.20.
(S)-N-(5-(3-(1-(cyclopropylmethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide ((S)-C8)
Yield 38.7%; mp: 203.0–205.0 C.1H NMR (DMSO-d6) δ 10.10 (s, 1H,
SO2NH), 8.65 (s, 1H, Ar-H), 8.35 (d, J = 2.3 Hz, 1H, Ar-H), 8.25 (d, J = 2.1 Hz, 1H,
Ar-H), 8.08 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.90 (d, J = 2.3 Hz, 1H, Ar-H), 7.85–7.79
(m, 3H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 5.34 (s, 1H, CH), 3.69 (s, 3H, OCH3),
3.21–3.10 (m, 2H, CH2), 2.71 (dd, J = 10.5, 7.3 Hz, 1H, CH2), 2.44–2.34 (m, 4H,
CH2), 1.99–1.88 (m, 1H, CH2), 0.90–0.85 (m, 1H, cPr-CH), 0.49–0.43 (m, 2H,
13
cPr-CH2), 0.15–0.12 (m, 2H, cPr-CH2). C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250
Hz), 160.3, 157.1, 147.2, 146.3, 141.3, 137.4, 135.6, 132.8, 131.4, 130.3, 130.2, 128.8,
128.5, 123.7, 122.1, 121.8, 116.8, 116.5, 59.9, 59.4, 53.9, 53.4, 53.0, 32.0, 10.0, 4.1
(CH2×2). ESI-HRMS m/z: calc’d for C28H29FN5O4S [M+H]+: 550.1919; found
550.1928.
4.2.21.
(R)-N-(5-(3-(1-(cyclopropylmethyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide ((R)-C9)
Yield 38.0%; mp: 195.0–197.0 C.1H NMR (DMSO-d6) δ 10.10 (s, 1H, SO2NH),
8.66 (s, 1H, Ar-H), 8.33 (s, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 8.08 (d, J = 7.5 Hz, 1H,
Ar-H), 7.85–7.77 (m, 4H, Ar-H), 7.41 (t, J = 8.7 Hz, 2H, Ar-H), 5.38–5.27 (m, 1H,
CH), 3.70 (s, 3H, OCH3), 3.22–3.11 (m, 2H, CH2), 2.71–2.65 (m, 1H, CH2),
2.42–2.36 (m, 4H, CH2), 1.94–1.88 (m, J = 8.2 Hz, 1H, CH2), 0.95–0.90 (m, 1H,
13
cPr-CH), 0.49 (d, J = 7.4 Hz, 2H, cPr-CH2), 0.15 (d, J = 4.4 Hz, 2H, cPr-CH2). C
NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.3, 157.1, 147.2, 146.3, 141.3, 137.4,
135.6, 132.8, 131.4, 130.3, 130.2, 128.8, 128.5, 123.7, 122.1, 121.8, 116.8, 116.5,
59.9, 59.4, 53.9, 53.4, 53.0, 32.0, 10.0, 4.1 (CH2×2).ESI-HRMS m/z: calc’d for
C28H29FN5O4S [M+H]+: 550.1919; found 550.1935.
4.2.22. t-Butyl4-(6-(5-((4-fluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-
4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (D1)
24

Yield 71.3%; mp: 219.5–221.5 C. 1H NMR (DMSO-d6) δ 10.13 (s, 1H, SO2NH),
8.52 (s, 1H, Ar-H), 8.38 (s, 1H, Ar-H), 8.26 (s, 1H, Ar-H), 8.10 (m, 1H, Ar-H), 7.92 (s,
1H, Ar-H), 7.83 (dd, J = 8.2, 5.4 Hz, 2H, Ar-H), 7.78 (d, J = 8.4 Hz, 1H, Ar-H), 7.43
(t, J = 8.7 Hz, 2H, Ar-H), 4.87–4.76 (m, 1H, CH), 4.15 (s, 2H, CH2), 3.68 (s, 3H,
OCH3), 2.92 (s, 2H, CH2), 1.99–1.90 (m, 2H, CH2), 1.86–1.79 (m, 2H, CH2), 1.44 (s,
13
9H, CH3×3). C NMR (DMSO-d6) δ 164.8 (d, JC-F = 250 Hz), 160.2, 157.1, 154.2,
147.1, 146.2, 141.7, 137.1, 135.5, 132.9, 131.8, 130.3, 130.2, 128.8, 128.5, 123.7,
122.2, 121.3, 116.8, 116.6, 79.4 (CH2×2), 63.5, 54.0 (CH2×2), 52.8, 30.7, 28.6
(CH3×3). ESI-HRMS m/z: calc’d for C30H32FN5NaO6S [M + Na]+: 632.1950; found
632.1950.
4.2.23.
N-(5-(3-(1-(cyclopropylmethyl)piperidin-4-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide (D6)
Yield 84.4%; mp: 217.0–219.0 C.1H NMR (DMSO-d6) δ 10.06 (s, 1H, SO2NH),
8.51 (s, 1H, Ar-H), 8.33 (d, J = 2.1 Hz, 1H, Ar-H), 8.25 (d, J = 1.6 Hz, 1H, Ar-H),
8.08 (dd, J = 8.5, 1.8 Hz, 1H, Ar-H), 7.89 (d, J = 2.1 Hz, 1H, Ar-H), 7.83 (dd, J = 8.7,
5.2 Hz, 2H, Ar-H), 7.77 (d, J = 8.5 Hz, 1H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H),
4.69–4.60 (m, 1H, CH), 3.69 (s, J = 7.9 Hz, 3H, OCH3), 3.20–3.10 (m, 2H, CH2), 2.32
(d, J = 6.6 Hz, 2H, CH2), 2.19–2.11 (m, 4H, CH2), 1.90–1.80 (m, 2H, CH2), 0.90–0.80
13
(m, 1H, CH), 0.51–0.42 (m, 2H, cPr-CH2), 0.16–0.13 (m, 2H, cPr-CH2). C NMR
(DMSO-d6) δ 164.7 (d, JC-F = 250 Hz), 160.3, 157.1, 147.1, 146.0, 141.1, 137.5, 135.6,
132.9, 131.2, 130.2, 130.1, 128.8, 128.5, 123.7, 122.2, 116.7, 116.5, 62.7, 53.9, 52.9
(CH2×2), 52.8, 30.5 (CH2×2), 8.7, 4.3 (CH2×2). ESI-HRMS m/z: calc’d for
C28H29FN5O4S [M+H]+: 564.2075; found 564.2080.
4.2.24.
(S)-4-fluoro-N-(2-methoxy-5-(4-oxo-3-(pyrrolidin-3-yl)-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide ((S)-C2)
To a solution of (S)-C1 (480 mg, 8.63 mmol) in DCM (5 mL), trifluoroacetic
acid (2 mL) was added. The resulting solution was stirred at room temperature for 2 h,
concentrated under vacuum and neutralized by slow addition of a saturated aqueous
sodium carbonate solution at 0°C, and then extracted with DCM (30 mL×2). The
organic phase was dried over anhydrous sodium sulfate, followed by filtration,
25

concentration, and drying to produce (S)-C2 as off-white solid. Yield 46.0%; mp:
130.0-133.0 C. 1H NMR (DMSO-d6) δ 13.58 (s, 1H, SO2NH), 8.44 (s, 1H, Ar-H),
8.20 (d, J = 2.1 Hz, 1H, Ar-H), 8.01 (dd, J = 8.6, 2.1 Hz, 2H, Ar-H), 7.83–7.79 (m, 2H,
Ar-H), 7.75 (d, J = 8.5 Hz, 1H, Ar-H), 7.73 (d, J = 2.2 Hz, 1H, Ar-H), 7.34–7.29 (m,
2H, Ar-H), 5.27–5.16 (m, 1H, CH), 3.76 (s, 3H, OCH3), 3.44–3.42 (m, 1H, CH2),
3.38–3.35 (m, 1H, CH2), 3.19–3.06 (m, 2H, CH2), 2.45–2.37 (m, 1H, CH2), 2.25–2.13
(m, 1H, CH2). 13C NMR (DMSO-d6) δ 164.0 (d, JC-F = 247 Hz), 160.9, 157.2, 147.1,
146.9, 140.1, 136.7, 136.4, 132.8, 129.9, 129.8, 128.5, 128.4, 126.9, 123.2, 122.3,
116.2, 116.0, 56.3, 53.7, 50.0, 46.0, 30.7. ESI-HRMS m/z: calc’d for C24H23FN5O4S
[M+H]+: 496.1450; found 496.1449.
Compounds D2 were synthesized according to the procedure described in (S)-C2.
4.2.25.
4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(piperidin-4-yl)-3,4-dihydro
quinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (D2)
1
Yield 61.7%; mp: 146.0–148.0 C. H NMR (DMSO-d6) δ 8.36 (s, 1H, Ar-H),
8.19 (s, 1H, Ar-H), 8.01 (d, J = 9.0 Hz, 2H, Ar-H), 7.91–7.70 (m, 4H, Ar-H), 7.33 (t,
J = 8.6 Hz, 2H, Ar-H), 4.92–4.75 (m, 1H, CH), 3.75 (s, 3H, OCH3), 3.34–3.24 (m, 2H,
13
CH2), 2.95–2.85 (m, 2H, CH2), 2.19–2.09 (m, 2H, CH2), 2.02–1.92(m, 2H, CH2). C
NMR (DMSO-d6) δ 163.8 (d, JC-F = 247 Hz), 160.3, 157.1, 146.8, 145.7, 140.5, 140.4,
136.9, 135.5, 132.8, 130.0, 129.8, 128.5, 128.4, 126.1, 123.4, 122.3, 116.1, 115.9,
53.7, 51.9, 44.5 (CH2×2), 29.1 (CH2×2). ESI-HRMS m/z: calc’d for C25H24FN5O4S
[M+H]+: 510.1606; found 510.1606.
4.2.26.
(S)-N-(5-(3-(1-acetylpyrrolidin-3-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-
2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide ((S)-C3)
The mixture of (S)-C2 (60 mg, 0.12 mmol), acetic acid (36 mg, o.6 mmol),
HATU (90 mg, 0.24 mmol), DIPEA (0.5 mL) and DCM (15 mL) was refluxed for 2 h.
The volatile were removed under vacuum and the residue was purified through a
column chromatography on silica gel with dichloromethane /methanol (V:V = 30:1) as
eluent to produce (S)-C3 as light yellow solid. Yield 32.87%; mp: 116.0–118.0 C. 1H
NMR (DMSO-d6) δ 10.01 (s, 1H, SO2NH), 8.43–8.30 (m, 2H, Ar-H), 8.27 (s, 1H,
Ar-H), 8.13–8.07 (m, 1H, Ar-H), 7.92 (d, J = 1.7 Hz, 1H, Ar-H), 7.88–7.73 (m, 3H,
26

Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 5.37–5.20 (m, 1H, CH), 3.95–3.73 (m, 2H,
CH2), 3.69 (s, 3H, OCH3), 3.65–3.61 (m, 1H, CH2), 3.48–3.39 (m, 1H, CH2),
2.48–2.30 (m, 2H, CH2), 2.00 (s, 3H, COCH3). 13C NMR (DMSO-d6) δ 169.0, 168.8,
164.8 (d, JC-F = 250 Hz), 160.7, 157.2, 147.1, 145.9, 141.7, 137.2, 135.6, 133.0, 131.8,
130.3, 130.2, 128.8, 128.5, 123.7, 122.3, 116.8, 116.6, 54.9, 54.0, 53.9, 50.5, 49.1,
45.6, 44.1, 30.38, 28.8, 22.8. ESI-HRMS m/z: calc’d for C26H24FN5NaO5S [M+Na]+:
560.1375; found 560.1374.
Compounds (S)-C5, (S)-C7 and D3-D5 were synthesized according to the
process described in (S)-C2.
4.2.27. (S)-N-(5-(3-(1-(cyclopropanecarbonyl)pyrrolidin-3-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide ((S)-C5)
Yield 93.42%; mp: 82.0–84.0 C. 1H NMR (DMSO-d6) δ 9.53 (s, 1H, SO2NH),
8.43–8.32 (m, 2H, Ar-H), 8.28 (s, 1H, Ar-H), 8.13–8.08 (m, 1H, Ar-H), 7.92 (s, 1H,
Ar-H), 7.85–.76 (m, 3H, Ar-H), 7.42 (t, J = 8.8 Hz, 2H, Ar-H), 5.40–5.20 (m, 1H, CH),
4.01–3.92 (m, 1H, CH2), 3.90–3.77 (m, 1H, CH2), 3.72–3.68 (s, 3H, OCH3),
3.68–3.61 (m, 1H, CH2), 3.50–3.39 (m, 1H, CH2), 2.49–2.28 (m, 2H, CH2), 1.89–1.73
13
(m, 1H, COCH), 0.81–0.70 (m, J = 8.2 Hz, 4H, c-Pr-H). C NMR (DMSO-d6) δ
171.65, 164.72 (d, JC-F = 250 Hz), 160.7, 157.2, 147.1, 146.0, 145.9, 141.4, 137.4,
135.7, 133.0, 131.6, 130.3, 130.2, 128.8, 128.5, 123.6, 122.3, 117.1, 116.6, 54.0, 53.7,
53.4, 45.0, 41.9, 30.3, 18.1, 13.1, 12.5, 12.1, 7.6. ESI-HRMS m/z: calc’d for
C28H26FN5NaO5S [M+Na]+: 586.1533; found 586.1531.
4.2.28.
(S)-4-fluoro-N-(2-methoxy-5-(4-oxo-3-(1-(tetrahydro-2H-pyran-4-
carbonyl)pyrrolidin-3-yl)-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfona
mide ((S)-C7)
Yield 94.3%; mp: 113.0–116.0 C. 1H NMR (DMSO-d6) δ 9.90 (s, 1H, SO2NH),
8.39–8.30 (m, 2H, Ar-H), 8.29–8.25 (m, 1H, Ar-H), 8.12–8.08 (m, 1H, Ar-H), 7.92 (s,
1H, Ar-H), 7.85–7.77 (m, 3H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H, , Ar-H), 5.36–5.21 (m,
1H, CH), 3.93–3.90 (m, 1H, CH2), 3.90–3.82 (m, 4H, OCH2×2), 3.71 (s, 1H),
3.48–3.38 (m, 1H), 2.81–2.68 (m, 1H), 2.47–2.41 (m, 1H, CH2), 2.39–2.33 (m, 1H,
13
CH), 1.64–1.58 (m, 4H, CH2×2). C NMR (DMSO) δ 174.6, 172.9, 164.7 (d, JC-F
=
27

250 Hz), 160.7, 157.2, 147.2, 146.0, 141.9, 140.0, 137.1, 135.6, 133.0, 132.0, 130.3,
130.2, 130.2, 128.8, 128.5, 123.7, 122.2, 121.3, 121.2, 116.8, 116.6, 66.8, 54.9, 54.0,
53.7, 49.4, 44.7, 42.1, 38.6, 30.4, 28.8. ESI-HRMS m/z: calc’d for C30H30FN5NaO6S
[M+Na]+: 630.1794; found 630.1793.
4.2.29.
N-(5-(3-(1-acetylpiperidin-4-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-
methoxypyridin-3-yl)-4-fluorophenylsulfonamide (D3)
Yield 55.1%; mp: 143.0–146.0 C. 1H NMR (DMSO-d6) δ 10.14 (s, 1H, SO2NH),
8.51 (s, 1H, Ar-H), 8.38 (d, J = 2.3 Hz, 1H, Ar-H), 8.26 (d, J = 2.2 Hz, 1H, Ar-H),
8.10 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.92 (d, J = 2.3 Hz, 1H, Ar-H), 7.86–7.80 (m, 2H,
Ar-H), 7.78 (d, J = 8.5 Hz, 1H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H, Ar-H), 4.99–4.84 (m,
1H, CH), 4.65–4.55 (m, 1H, CH2), 4.05–3.95 (m, 1H, CH2), 3.68 (s, 3H, OCH3),
3.51–3.38 (m, 1H, CH2), 2.74–2.63 (m, 1H, CH2), 2.07 (s, 3H, OCH3), 1.96–1.83 (m,
4H,CH2). 13C NMR (DMSO-d6) δ 168.6, 164.8 (d, JC-F = 250 Hz), 160.2, 157.1, 147.1,
146.2, 142.0, 137.0, 135.5, 132.9, 132.0, 130.3, 130.2, 128.8, 128.5, 123.8, 122.2,
121.0, 116.8, 116.6, 56.5, 54.0, 52.6, 43.4, 45.8, 40.9, 30.9, 31.2, 30.6, 21.8, 19.0.
ESI-HRMS m/z: calc’d for C27H26FN5NaO5S [M+Na]+: 574.1531; found 574.1531.
4.2.30.
N-(5-(3-(1-(cyclopropanecarbonyl)piperidin-4-yl)-4-oxo-3,4-dihydro
quinazolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorophenylsulfonamide (D4)
Yield 48.9%; mp: 165.0–167.0 C. 1H NMR (DMSO-d6) δ 10.14 (s, 1H, SO2NH),
8.53 (s, 1H, Ar-H), 8.39 (d, J = 2.2 Hz, 1H, Ar-H), 8.27 (d, J = 2.1 Hz, 1H, Ar-H),
8.10 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 7.92 (d, J = 2.3 Hz, 1H, Ar-H), 7.83 (dd, J = 8.8,
5.2 Hz, 2H, Ar-H), 7.78 (d, J = 8.5 Hz, 1H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H, Ar-H),
5.03–4.87 (m, 1H, CH), 4.67–4.41 (m, 2H, CH2), 3.68 (s, 3H, OCH3), 3.32–3.22 (m,
1H, CH2), 2.78–2.70 (m, 1H, CH2), 2.14–2.01 (m, 2H, CH2), 2.01–1.93 (m, 2H, CH2),
1.89 (s, 1H, COCH), 0.83–0.74 (m, 4H, coPr-H). 13C NMR (DMSO-d6) δ 171.3,
164.8 (d, JC-F = 250 Hz), 160.2, 157.1, 147.1, 146.2, 141.9, 137.0, 135.4, 132.9, 132.0,
130.3, 130.2, 128.8, 128.5, 123.8, 122.2, 121.0, 116.8, 116.6, 54.0 (CH2×2), 52.9,
43.3, 31.0, 10.9 (CH2×2), 7.5, 7.4. ESI-HRMS m/z: calc’d for C29H29FN5O5S [M+H]+:
578.1868; found 578.1868.
4.2.31. 4-Fluoro-N-(2-methoxy-5-(4-oxo-3-(1-(tetrahydro-2H-pyran-4-carbonyl)
28

piperidin-4-yl)-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)phenylsulfonamide (D5)
Yield 78.5%; mp: 237.0–239.0 C. 1H NMR (DMSO-d6) δ 10.14 (s, 1H, SO2NH),
8.51 (s, 1H, Ar-H), 8.38 (d, J = 2.2 Hz, 1H, Ar-H), 8.26 (d, J = 2.0 Hz, 1H, Ar-H),
8.10 (dd, J = 8.5, 2.1 Hz, 1H, Ar-H), 7.92 (d, J = 2.2 Hz, 1H, Ar-H), 7.83 (dd, J = 8.8,
5.2 Hz, 2H, Ar-H), 7.78 (d, J = 8.5 Hz, 1H, Ar-H), 7.43 (t, J = 8.8 Hz, 2H, Ar-H),
4.99–4.85 (m, 1H, CH), 4.63–4.53 (m, 1H, CH2), 4.25–4.15 (m, 1H, CH2),
3.87–3.77(m, 2H, CH2), 3.68 (s, 3H, OCH3), 3.42–3.32(m, 2H, CH2), 3.22 (t, J = 12.0
Hz, 1H, CH2), 3.00–2.90 (m, 1H, CH2), 2.70 (t, J = 11.1 Hz, 1H, CH2), 2.10–1.85 (m,
4H, CH2×2), 1.74–1.52 (m, 4H, CH2×2). 13C NMR (DMSO-d6) δ 172.6, 164.8 (d, JC-F
= 250 Hz), 160.2, 157.1, 147.1, 146.2, 141.9, 137.0, 135.5, 132.9, 132.0, 130.3, 130.2,
128.8, 128.5, 123.8, 122.2, 121.1, 116.8, 116.6, 66.8 (CH2×2), 54.0 (CH2×2), 52.9,
43.0, 44.7, 41.2, 36.8 (CH2×2), 31.1, 31.6, 30.6, 29.5 (CH2×2). ESI-HRMS m/z:
calc’d for C31H33FN5O6S [M+H]+: 622.2131; found 622.2130.
4.3. Biology assay methods
4.3.1. Cell Culture
The human cell lines HCT-116 and MCF-7 were maintained as a monolayer
culture in DMEM, supplemented with 10% FBS in a humidified atmosphere (5% CO2)
at 37 C.
4.3.2. Antiproliferative assays
BEZ235 was purchased from Shanghai Biochempartner Company (Purity: 99%,
HPLC). 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-2H-tetrazolium bromide (MTT)
was purchased from Sigma (St. Louis, MO, USA). Cellular chemosensitivity was
determined by using a modified MTT method assay in vitro. In brief, HCT-116,
MCF-7 cells in 200 μL culture medium were seeded into 96-well microplates at
3000-5000 cells per well respectively and cultured in DMEM with 10% FBS or
RPMI-1640 with 10% calf serum, incubated at 37 °C for 24 h prior to drug exposure.
Cell numbers were titrated to keep control cells growing in the exponential phase
throughout the 72 h incubation period. Cells were treated with final concentrations of
10.0, 5.0, 1.0 and 0.5 M of tested compounds simultaneously and incubated for 72 h
29