Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-benzylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters reuptake

Article abstract of DOI:10.1016/j.bmc.2018.09.033

Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.

Full text of DOI:10.1016/j.bmc.2018.09.033

Accepted Manuscript
Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-ben-
zylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters re-
uptake
Suresh Paudel, Xiao Min, Srijan Acharya, Daulat Bikram Khadka, Goon Yoon,
Kyeong-Man Kim, Seung Hoon Cheon
PII:
S0968-0896(18)31322-1
https://doi.org/10.1016/j.bmc.2018.09.033
BMC 14558
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 July 2018
22 September 2018
25 September 2018
Please cite this article as: Paudel, S., Min, X., Acharya, S., Khadka, D.B., Yoon, G., Kim, K-M., Cheon, S.H.,
Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-benzylpiperidine napthyl ethers as inhibitors
of monoamine neurotransmitters reuptake, Bioorganic & Medicinal Chemistry (2018), doi: https://doi.org/10.1016/
j.bmc.2018.09.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-
benzylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters
reuptake
Suresh Paudela, Xiao Mina, Srijan Acharyaa, Daulat Bikram Khadkaa, Goon Yoonb, Kyeong-Man
Kima*, Seung Hoon Cheona*
aCollege of Pharmacy and Research Institute of Drug Development, Chonnam National
University, Gwangju 61186, Republic of Korea
bCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University,
Jeonnam 58554, Republic of Korea
 Corresponding author. Tel.: +82625302929; fax: +82625302911; e-mail: shcheon@jnu.ac.kr
(S.H. Cheon); Tel.: +82625302936; fax: +82625302949; e-mail: kmkim@jnu.ac.kr (K. M. Kim).

Abstract:
Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on
structure-activity relationship (SAR) and docking model of reported monoamine
neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and
their biological activities were evaluated. Several compounds were proven to be potent inhibitors
of serotonin and norepinephrine reuptake. Computer docking was performed to study the
interaction of the most potent compound 35 with human serotonin transporter. The results of the
analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be
promising antidepressants worthy of further studies.
Keywords: Depression, 4-arylpiperazine, 4-benzylpiperidine, naphthyl ether, serotonin reuptake
inhibitor, norepinephrine reuptake inhibitor, docking

1. Introduction:
The global incidence of central nervous system (CNS) disorders, including depression, is
showing an increasing trend, therefore, extensive research on monoamine transporters has been
conducted.1-12 Monoamine transporters regulates monoamine neurotransmitters: serotonin (5-
HT), norepinephrine (NE), and dopamine (DA) and are the key regulators of depression.13
Consequently, monoamine transporters are potential therapeutic targets for several (CNS)
diseases, such as depression, generalized anxiety disorder (GAD), social phobia, Parkinson’s
disease, attention deficit hyperactivity disorder (ADHD), restless legs syndrome (RLS).14-19
In the 1950s, the first-generation of agents for the treatment of depression was introduced,
comprising tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)
However, the limitations of TCAs and MAOIs like poor tolerances, off target pharmacology and
drug-drug interactions, encouraged to the discovery of second-generation agents, selective
serotonin reuptake inhibitors (SSRIs), and dual serotonin and norepinephrine reuptake inhibitors
(SNRIs). Despite the improved safety and tolerability profiles of these agents, they also induce
side effects such as sexual dysfunction, weight gain, and insomnia.20-21 New therapeutic agents
with improved efficacy, safety, and time to onset, which do not induce side effects, are desired.
Thus, there is an urgent need for the development of next generation of antidepressants.22-24
The design of molecule with scaffold different from established drug is a common strategy to
avoid drug–related side effects and was used by our group to develop 4-benzylpiperidine–
arylamides.25 The essential features of the neurotransmitter reuptake inhibitors include a variable
aromatic region (Ar1), piperazine/piperidine-aromatic region (Ar2), a linker (aliphatic chain with
2–4 carbons) and a functional group (FG, Figure 1A). Further modifications of these basic
components of the neurotransmitter reuptake inhibitors provided arylpiperazine–
benzylpiperidines,26 arylpiperazine–tetrazoles,27 1,4-disubstituted piperazines/piperidines,28 4-
benzylpiperidine-tetrazoles29 and arylpiperazine–arylamides.30 Most of these derivatives
possessed inhibitory effects on monoamine reuptake.

Fig. 1. (A) Structural outline of monoamine neurotransmitter reuptake inhibitor. (B)
Hypothetical binding mode of human serotonin transporter (hSERT) and arylpiperazine-
arylamide (II) illustrating the importance of naphthyl ring. (C) Design of newer 4-
arylpiperazine- and 4-benzylpiperidine naphthyl ethers 1–39.

Upon close analysis of the monoamine neurotransmitters reuptake inhibitors reported by us,
especially the ones with arylpiperazine (Ar2), specific relationships between the activity and
functional group (FG) are observed. Arylpiperazines with tetrazole (e.g. I, Table 1) irrespective
of variation in Ar2 region are inefficient in inhibiting the reuptake of 5-HT.27 Likewise,
arylpiperazines with amide (e.g. II) are ineffective towards DA despite of large number of
changes made in both Ar1 and Ar2 ends.30 On the other hand, 1,4-disubstituted piperazines with
ether (e.g. III) potently inhibit reuptake of all three neurotransmitters - 5-HT, NE and DA.28
Table 1: IC50 value of compounds previously studied by our group.
IC50 (µM)
Compd Structure
5-HT
NE
DA
>10
0.51
0.82
I
0.74
0.57
0.26
0.60
>10
II
0.98
III
Development of triple reuptake inhibitor is one of our prime research goal. As ethers are
generally active against all three neurotransmitters we decided to incorporate O as FG in new
series of proposed monoamine neurotransmitters inhibitors. Our decision to design ether
derivatives was further supported by docking study of arylpiperazine-arylamide II (Figure 1B).30
Ether can be an alternative of amide FG because the O can be expected to occupy the position of
carbonyl (C=O) of compound II and possibly have H-bond contact with Tyr95 of hSERT.
Furthermore, based on the docking model, naphthyl was chosen as Ar1 group as it is suitably
placed within the ligand binding pocket (LBP) to have hydrophobic interaction with Tyr95,
Ile172 and Tyr176. In addition to our findings, the importance of the group is also supported by

the presence of 2-naphthyl group in other monoamine reuptake inhibitors under investigation
(Fig. S1).31-38 Finally, 4-arylpiperazine and 4-arylpiperidine were selected as Ar2 region based
on the potency exhibited by reported antidepressants with the functional group (Fig. S2).39-45
Thus, incorporating the components which were responsible for potent activity of reported
monoamine neurotransmitters reuptake inhibitors we designed, synthesized and performed
pharmacological evaluation and docking study of a new series of 4-arylpiperazine- and 4-
benzylpiperidine naphthyl ethers (1–39, Figure 1C).
2. Chemistry
2-Naphthol 40 was refluxed overnight with excess dialkylhalide to obtain haloxynaphthalenes
41–43. In contrast, various aromatic amines 44a–44m were reacted with bis(2-chloroethyl)amine
hydrochloride to obtain 4-arylpiperazines hydrochloride salts and 4-benzylpiperidines 45a–45m
(Scheme 1) (45i–45m were commercially available). Finally, the substitution reaction of 41–43
with 4-substituted phenylpiperazine and 4-benzylpiperidines (45a–45m) produced various ether
derivatives 1–39.

Scheme 1: Synthesis of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers 1–39. Reagents
and conditions: (i) Br(CH2)nCl, acetone, reflux; (ii) diethylene glycol monomethyl ether, 150 °C;
(iii) DMSO, TEA, 100 °C.
3. Results and discussion
The in vitro neurotransmitter reuptake inhibition experiments of the synthesized compounds
were conducted in human embryonic kidney 293 (HEK-293) cells transfected with human
serotonin transporter (hSERT) or human norepinephrine transporter (hNET) or human dopamine
transporter (hDAT) by using a neurotransmitter uptake assay. Initially, 4-arylpiperazine–and 4-
benzylpiperidine naphthyl ethers (1–13) were prepared and examined for their inhibition of

neurotransmitters reuptake (5-HT, NE and DA). The majority of compounds were able to inhibit
5-HT and NE. Unfortunately, the dopamine reuptake inhibitory activity of compounds was not
effective at 1 µM. Thus, only the inhibition of 5-HT and NE reuptake was determined for any
further synthesized derivatives (14–26 and 27–39). The inhibition of neurotransmitters reuptake
by the compounds is presented in Table 2.
Table 2. Serotonin (5-HT), Norepinephrine (NE) and dopamine (DA) reuptake inhibition by 4-
arylpiperazine- and 4-benzylpiperidine naphthyl ethers 1–39.
R1
Compd 5-HTa
NEb
28.0
74.9
21
DAa
9
Compd 5-HTa
NEb
79.6
86.5
85.3
NA
23.3
25.7
80
Compd 5-HTa
NEb
86.4
74.4
68
Phenyl
7.2
27
41.2
38.3
51.3
27.5
71
1
14
15
16
17
18
19
20
21
22
23
24
27
28
29
30
31
32
33
34
35
36
37
2,6-Me2-Phenyl
2-OMe-Phenyl
3-Cl-Phenyl
4-F-Phenyl
4-Cl-Phenyl
4-Br-Phenyl
2,4-(Cl)2-Phenyl
4-CF3-Phenyl
2,3-(Cl)2-Phenyl
2-Pyridyl
24.6
48.7
85.3
60.5
20.1
9
19
35.1
56.4
NA
2
19
3
83.1
80.8
28
NR
35.6
2
63.7
74.3
69.3
66.3
67.7
68.3
60.7
59
4
45.4
28.4
54.9
NA
5
49.0
66.3
51
6
52.8
47.3
23.1
20
19
7
61.4
8.2
48.5
31.3
NR
NR
NA
NA
45
8
NA
59.2
36.8
45.3
9
26.7
54
37.5
46.2
10
11
66
68.7

2-Pyrimidyl
57
NA
NR
NR
-
23.8
47.3
32
31
12
25
26
-
38
39
-
Benzylpiperidine
12.1
68.6
-
NR
51
-
92.2
31.9
80.7
13
-
Stdc
Stdd
52.6
61.5
-
-
-
-
-
-
-
78.3
-
-
aReuptake inhibition at 1 µM by synthesized compounds
bReuptake inhibition at 10 µM by synthesized compounds
cReuptake inhibition at 1 µM by venlafaxine HCl
dReuptake inhibition at 10 µM by bupropion
NR: Negative response
NA: Not applicable
The inhibition of monoamine reuptake by the derivatives varied mainly on the length of the
linker. The majority of 4-arylpiperazine naphthyl ethers with a longer linker were more active
than those with a shorter linker. However, 4-benzylpiperidine naphthyl ether (26), with a three–
carbon linker, showed better inhibition of 5-HT and NE than the compounds with two and four
carbon units (13, 39). The 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers 4, 5, 11, 16,
20, 26, 29, 31, and 33–35 demonstrating 50% inhibition for (5-HT at 1 µM) and 57% inhibition
for (NE at 10 µM) were further analyzed to determine the IC50 values. The IC50 values of 5-HT
and NE reuptake inhibition of the selected compounds are presented in Table 3.
Table 3: IC50 values of the synthesized compounds for 5-HT and NE reuptake inhibition.
Compound
n
2
2
2
3
3
3
R1
5-HT (µM) NE (µM)
3-Cl-Phenyl
4-F-Phenyl
2-Pyridyl
1.86
2.80
1.08
1.04
0.83
0.99
5.83
5.13
23.8
1.20
2.85
2.54
4
5
11
16
20
26
2-OMe-Phenyl
4-Br-Phenyl
4-Benzylpiperidine

4
4
4
4
4
-
2-OMe-Phenyl
4-F-Phenyl
4-Br-Phenyl
2,4-(Cl)2-Phenyl
4-CF3-Phenyl
-
5.16
3.15
10.7
4.32
0.68
0.20
29.7
3.71
25.9
9.74
20.5
2.55
29
31
33
34
35
Venlafaxine·HCl
In general, compounds with a 3-carbon linker displayed more potent inhibition of 5-HT than 2-
or 4-carbon linker. However, the most potent compound was 35 (n = 4, IC50 = 0.68 µM), with a
longer linker. 4-Benzylpiperidine naphthyl ether (26, n = 3, IC50 = 0.99 µM) exerted greater
inhibition than all other derivatives except 20 (n = 3, IC50 = 0.83 µM) and 35. Among the mono-
halogen substitution compounds, 20 (4-Br, n = 3, IC50 = 0.83 µM) displayed greater inhibition
than other derivatives, such as 4 (3-Cl, n = 2, IC50 = 1.86 µM), 5 (4-F, n = 2, IC50 = 2.80 µM), 31
(4-F, n = 4, IC50 = 3.15 µM) and 33 (4-Br, n = 4, IC50 = 10.7 µM). The inhibition of 5-HT
reuptake by compounds containing a fluoro-substituent (31, 4-F, n = 4, IC50 = 3.15 µM) with a 4-
carbon linker was greater than compounds containing a bromo-substituent (33, 4-Br, n = 4, IC50
= 10.7 µM).
The inhibition of NE reuptake by compounds with 3–carbon linker was greater than that by 2- or
4–carbon linker. Derivatives 16 (n = 3, IC50 = 1.20 µM) and 26 (n = 3, IC50 = 2.54 µM) exhibited
greater inhibition of NE than the standard drug, venlafaxine HCl (IC50 = 2.55 µM). Moreover,
compound 16 was the most potent inhibitors of NE. 4-Benzylpiperidine naphthyl ether (26)
showed greater inhibition than all other derivatives except 16. Among the mono-halogen
substituted compounds, 20 (4-Br, n = 3, IC50 = 2.85 µM) was better than derivatives 4 (3-Cl, n =
2, IC50 = 5.83 µM), 5 (4-F, n = 2, IC50 = 5.13 µM), 31 (4-F, n = 4, IC50 = 3.71 µM), and 33 (4-Br,
n = 4, IC50 = 25.9 µM).

3.2. Docking study
Compound 35 was selected for the docking study as it is active towards 5-HT. A hypothetical
binding mode of hSERT and compound 35 is shown in Figure 2B. The docking study showed
that the compound 35 interacted with hSERT in the same manner as paroxetine. The naphthalene
moiety of the compound occupied the central binding site, permitting hydrophobic interactions
with Ile172 and Tyr176. As expected the O of the ether had a H-bond with Tyr95. The four–
carbon linker was particularly important as it bends the compound to achieve optimal placement
in the L-shaped pocket. Compounds with longer linker (3/4-carbon) easily attains angular
conformation necessary to fit into the LBP than relatively linear derivative with shorter linker.23
The linker was optimally placed in the region of the pocket walled by Phe335, Gly338, and
Val501. The terminal phenyl group faced the allosteric site. The trifluoromethyl group formed a
non-classical H-bond with Trp103 which in turn may be responsible for greater potency of
compound than derivatives 29 (2-OMe-phenyl), 33 (4-Br-phenyl) and 34 (2,4-(Cl)2-phenyl)
which lack functional group capable of forming either classical and non-classical H-bonds.
Figure 2. (A) The binding mode of hSERT-paroxetine (PDB ID: 5I6X). (B) Hypothetical
binding mode of hSERT-35. The H-bonds are displayed as brown discontinuous lines and ionic
bonds are displayed as solid red lines.

4. Conclusion
This report describes the design, synthesis, and evaluation of the biological activity of 4-
arylpiperazine- and 4-benzylpiperidine naphthyl ethers as monoamine neurotransmitters reuptake
inhibitors. Unfortunately, the synthesized compounds did not display strong inhibition of DA
reuptake. However, some promising compounds for the inhibition of 5-HT and NE were
obtained, characterized by low IC50. A molecular docking study of compound 35 was performed
with the surflex-Dock program to verify monoamine reuptake inhibitory activity and to
demonstrate the ideal interaction of the compound in the binding sites of the hSERT.
Collectively, these findings have provided significant information to researchers for the
development of antidepressant agents using SAR and docking.
5. Experimental Section
5.1. Chemistry
A Thomas Hoover melting point apparatus was used for the determination of melting point (MP)
by the capillary method, and the reported values are uncorrected. Varian Unity Plus 300 MHz
1
was used to obtain H NMR spectra, which are reported in ppm downfield from the peak of the
internal standard, tetramethylsilane. The data are reported as chemical shift, multiplicity (s:
singlet, d: doublet, t: triplet, q: quartet, quin: quintet, m: multiplet, dd: doublet of doublets),
coupling constant in Hz, and the number of protons. Mass spectra, obtained by using an Advion
Expression CMS and Shimadzu UFLC-MS liquid chromatograph mass spectrometer, were
recorded in positive ion mode using the electron spray ionization (ESI) method. Merck silica gel
60 (70–230 mesh) was used for column chromatography. Plates coated with silica gel 60 F254
(Merck) were used for thin-layer chromatography. Reagents were purchased from Sigma–
Aldrich and Alfa Aesar and used without further purification.
5.1.1. 2-(2-Chloroethoxy)naphthalene (41)

The mixture of 2-naphthol 40 (99 mg, 0.68 mmol), 1-bromo 2 chloro-ethane (0.1 mL, 1.37
mmol), and K2CO3 (1 g, 7.23 mmol) in acetone (6 mL) was refluxed overnight. After the
reaction was completed, the reaction mixture was filtered and concentrated. The obtained
product was purified by column chromatography with n-hexane: ethyl acetate (EtOAc) = 12:1 to
obtain 41 (110 mg, 77%) as a white solid. Rf = 0.85 (n-hexane: EtOAc = 1:1). MP = 98–100 °C.
1H NMR (300 MHz, CDCl3): δ 7.78–7.71 (m, 3H), 7.47–7.41 (m, 2H), 7.19–7.13 (m, 2H), 4.37–
4.33 (m, 2H), 3.88 (t, J = 6 Hz, 2H).
5.1.2. 2-(3-Chloropropoxy)naphthalene (42)
The procedure described for the preparation of 41 was used with compound 40 (1 g, 6.93 mmol),
1-bromo 3 chloro-propane (1.37 mL, 13.86 mmol), and K2CO3 (10 g, 72.3 mmol) in acetone (50
mL) to obtain 42 (1.07 g, 70%) as a white solid. Rf = 0.83 (n-hexane: EtOAc: = 2:1). MP = 43–
45 °C. 1H NMR (300 MHz, CDCl3): δ 7.72–7.66 (m, 3H), 7.42–7.26 (m, 2H), 7.11–7.07 (m, 2H),
4.12–4.08 (m, 2H), 3.69 (t, J = 6.3 Hz, 2H), 2.22–2.14 (m, 2H).
5.1.3. 2-(4-Chlorobutoxy)naphthalene (43)
The procedure described for the preparation of 41 was used with compound 40 (1 g, 6.93 mmol),
1-bromo 4 chloro-butane (1.59 mL, 13.86 mmol), and K2CO3 (10 g, 72.3 mmol) in acetone (50
mL) to obtain 43 (1.35 g, 83%) as a white solid. Rf = 0.83 (n-hexane: EtOAc: = 2:1). MP = 41–
43 °C. 1H NMR (300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.30 (m, 2H), 7.15–7.11 (m, 2H),
4.11 (t, J = 6 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.16–1.95 (m, 4H).
5.1.4. 1-Phenylpiperazine hydrochloride (45a)
A mixture of aniline 44a (279.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg,
3 mmol), and diethylene glycol monomethyl ether (0.75 mL) was heated at 150 °C for
approximately 12 h. The reaction mixture was cooled to room temperature and dissolved in

methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was
recovered by filtration and washed with diethyl ether to obtain 45a as an HCl salt (530 mg, 89%).
The HCl salt was used without further purification for the next reaction.
5.1.5. 1-(2,6-Dimethylphenyl)piperazine hydrochloride(45b)
The procedure described for the preparation of 45a was used with compound 44b (363.5 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45b as an HCl salt (540 mg, 79%). The HCl salt was used
without further purification for the next reaction.
5.1.6. 1-(2-Methoxyphenyl)piperazine hydrochloride (45c)
The procedure described for the preparation of 45a was used with compound 44c (369.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL to obtain 45c as an HCl salt (510 mg, 74%). The HCl salt was used
without further purification for the next reaction.
5.1.7. 1-(3-Chlorophenyl)piperazine hydrochloride(45d)
The procedure described for the preparation of 45a was used with compound 44d (321.5 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45d as an HCl salt (490 mg, 70%). The HCl salt was used
without further purification for the next reaction.
5.1.8. 1-(4-Fluorophenyl)piperazine hydrochloride (45e)
The procedure described for the preparation of 45a was used with compound 44e (333.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45e as an HCl salt (550 mg, 85%). The HCl salt was used
without further purification for the next reaction.
5.1.9. 1-(4-Chlorophenyl)piperazine hydrochloride (45f)

The procedure described for the preparation of 45a was used with compound 44f (321.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45f as an HCl salt (630 mg, 90%). The HCl salt was used
without further purification for the next reaction.
5.1.10. 1-(4-Bromophenyl)piperazine hydrochloride (45g)
The procedure described for the preparation of 45a was used with compound 44g (516.1 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45g as an HCl salt (540 mg, 65%). The HCl salt was used
without further purification for the next reaction.
5.1.11. 1-(2,4-Dichlorophenyl)piperazine hydrochloride (45h)
The procedure described for the preparation of 45a was used with compound 44h (486.1 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 45h as an HCl salt (640 mg, 80%). The HCl salt was used
without further purification for the next reaction.
5.1.12. 1-(2-(Naphthalen-2-yloxy)ethyl)-4-phenylpiperazine (1)
The mixture of compound 41 (204 mg, 1.16 mmol), 45a (200 mg, 0.97 mmol), TEA (TEA; 0.40
o
mL, 2.91 mmol), and DMSO (2 mL) was stirred at 100 C. After the reaction was completed,
water was added to the reaction mixture and an ethyl acetate extraction was performed. The
organic layer was dried over MgSO4, filtered and concentrated. The obtained product was
purified by column chromatography on silica gel with n-hexane: EtOAc: MeOH (10:1.5:0.5) to
to obtain 1 (97 mg, 30%) as a white solid. Rf = 0.66 (n-hexane: EtOAc = 1:1). MP = 114–116 °C.
1H NMR (300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.15 (m, ≈6H, overlapped with CHCl3
peak), 6.94–6.82 (m, 3H), 4.25 (t, J = =5.7 Hz, 2H), 3.24–3.21 (m, 4H), 2.94–2.90 (t, J = 5.7 Hz,
2H), 2.78–2.75(m, 4H). MS (ESI): m/z 333.4 (M+H) +.
5.1.13. 1-(2,6-Dimethylphenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazine (2)

The procedure described for the preparation of 1 was used with compound 41 (200 mg, 0.97
mmol), 45b (236 mg, 0.84 mmol), TEA (0.41 mL, 2.91 mmol), and DMSO (2 mL) to obtain 10c
(108 mg, 30%) as a light brown liquid. Rf = 0.69 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.73–7.67 (m, 3H), 7.42–7.29 (m, 2H), 7.17–7.12 (m, 2H), 6.98–6.89 (m, 3H), 4.26–
4.22 (m, 2H),3.15–3.12 (m, 4H), 2.93–2.90 (m, 2H), 2.71–2.67 (m, 4H), 2.31 (s, 6H). MS (ESI):
m/z 361.2 (M+H) +.
5.1.14. 1-(2-Methoxyphenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazine (3)
The procedure described for the preparation of 1 was used with compound 41 (120 mg, 0.58
mmol), 45c (230 mg, 0.69 mmol), TEA (0.24 mL, 1.74 mmol), and DMSO (2 mL) to obtain 10d
(100 mg, 47%) as a light brown liquid. Rf = 0.5 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.76–7.70 (m, 3H), 7.45–7.29 (m, 2H), 7.19–7.14 (m, 2H), 7.02–6.83 (m, 4H), 4.26 (t,
J = 6 Hz, 2H), 3.85 (s, 3H), 3.14 (s, 4H), 2.97–2.93 (m, 2H), 2.84–2.81 (m, 4H). MS (ESI): m/z
385.6 (M+Na) +.
5.1.15. 1-(3-Chlorophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazine (4)
The procedure described for the preparation of 1 was used with compound 41 (210 mg, 0.70
mmol), 45d (282 mg, 1.21 mmol), TEA (0.42 mL, 3.03 mmol), and DMSO (2 mL) to obtain 4
1
(141 mg, 38%) as a white solid. Rf = 0.41 (n-hexane: EtOAc = 1:1). MP = 78–81 °C. H NMR
(300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.30 (m, 2H), 7.18–7.11 (m, 3H), 6.87–6.75 (m,
3H), 4.24 (t, J = 5.7 Hz, 2H), 3.21 (t, J = 5.1 Hz, 4H), 2.91 (t, J = 5.7 Hz, 2H), 2.75–2.72 (m, 4H).
HRMS (ESI): m/z 367.15744 (M+H) + (calcd for C22H23ClN2O, 367.14989).
5.1.16. 1-(4-Fluorophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazines (5)
The procedure described for the preparation of 1 was used with compound 41 (210 mg, 1.01
mmol), 45e (262 mg, 1.21 mmol), TEA (0.42 mL, 3.03 mmol), and DMSO (2 mL) to obtain

1
5(127 mg, 36%) as a white solid. Rf = 0.66 (n-hexane: EtOAc = 1:1). MP = 114–117 °C. H
NMR (300 MHz, CDCl3): δ 7.75–7.69 (m, 3H), 7.44–7.28 (m, 2H), 7.20–7.13 (m, 2H), 6.97–
6.81 (m, 4H), 4.24–4.20 (m, 2H), 3.13–3.09 (m, 4H), 2.91–2.87 (m, 2H), 2.75–2.71 (m, 4H). MS
HRMS (ESI): m/z 351.18707 (M+H) + (calcd for C22H23FN2O, 351.17944).
5.1.17. 1-(4-Chlorophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazines (6)
The procedure described for the preparation of 1 was used with compound 41 (200 mg, 0.97
mmol), 45f (244 mg, 1.16 mmol), TEA (0.4 mL, 2.91 mmol), and DMSO (2 mL) to obtain 6 (99
mg, 28%) as white solid. Rf = 0.60 (n-hexane: EtOAc = 1:1). MP = 136–138 °C. 1H NMR (300
MHz, CDCl3): δ 7.77–7.71 (m, 3H), 7.45–7.32 (m, 2H), 7.21–7.32 (m, 4H), 6.84 (d, J = 5.4 Hz,
2H), 4.28–4.26 (m, 2H), 2.20 ( t, J = 3 Hz, 4H), 2.95–2.93 (m, 2H), 2.77 (t, J = 3 Hz, 4H). MS
(ESI): m/z 389.3 (M+Na) +.
5.1.18. 1-(4-Bromophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazine (7)
The procedure described for the preparation of 1 was used with compound 41 (200 mg, 0.97
mmol), 45g (295 mg, 0.84 mmol), TEA (0.4 mL, 2.91 mmol), and DMSO (2 mL) to obtain 7 (99
mg, 25%) as a white solid. Rf = 0.57 (n-hexane: EtOAc = 1:1). MP = 134–136 °C. 1H NMR (300
MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.46–7.41 (m, 4H), 7.18–7.15 (m, 2H), 6.81–6.76 (m, 2H),
4.28–4.24 (m, 2H), 3.22–3.18 (m, 4H), 2.94 (t, J = 5.7 Hz, 2H), 2.79–2.75 (m, 4H). MS (ESI):
m/z 411.8 (M+H) +.
5.1.19. 1-(2,4-Dichlorophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazine (8)
The procedure described for the preparation of 1 was used with compound 41 (210 mg, 1.01
mmol), 45h (324 mg, 1.21 mmol), TEA (0.42 mL, 3.03 mmol), and DMSO (2 mL) to obtain 8
(121 mg, 30%) as a white solid. Rf = 0.64 (n-hexane: EtOAc = 1:1). MP = 115–118 °C. 1H NMR
(300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.30 (m, 6H), 6.99 (d, J = 8.7 Hz, 1H), 4.25 (t, J

= 5.7 Hz, 2H), 3.08–3.05 (m, 4H), 2.94 (t, J = 5.7 Hz, 2H), 2.80–2.79 (m, 4H). MS (ESI): m/z
423.2 (M+Na) +.
5.1.20. 1-(2-(Naphthalen-2-yloxy)ethyl)-4-(4-(trifluoromethyl)phenyl)piperazines (9)
The procedure described for the preparation of 1 was used with compound 41 (210 mg, 1.01
mmol), 45i (279 mg, 1.21 mmol), TEA (0.42 mL, 3.03 mmol), and DMSO (2 mL) to obtain 9
(182 mg, 45%) as a white solid. Rf = 0.71 (n-hexane: EtOAc = 1:1). MP = 155–158 °C. 1H NMR
(300 MHz, CDCl3): δ 7.78–7.71 (m, 3H), 7.49–7.31 (m, 4H), 7.19–7.15 (m, 2H), 6.92 (d, J = 8.7
Hz, 2H), 4.29–4.26 (m, 2H), 3.34–3.31 (m, 4H), 2.94 (t, J = 5.7 Hz, 2H), 2.80–2.76 (m, 4H). MS
(ESI): m/z 401.8 (M+H) +.
5.1.21. 1-(2,3-Dichlorophenyl)-4-(2-(naphthalen-2-yloxy)ethyl)piperazines (10)
The procedure described for the preparation of 1 was used with compound 41 (70 mg, 0.34
mmol), 45j (182 mg, 0.68 mmol), TEA (0.19 mL, 1.36 mmol), and DMSO (1 mL) to obtain 10
(40 mg, 29%) as a white solid. Rf = 0.63 (n-hexane: EtOAc = 1:1). MP = 104–106 °C. 1H NMR
(300 MHz, CDCl3): δ 7.77–7.71 (m, 3H), 7.46–7.10 (m, 6H), 6.99–6.94 (m, 1H), 4.28–4.24 (m,
2H), 3.10 (t, J = 4.5 Hz, 4H), 2.96 (t, J = 5.7 Hz, 2H), 2.81(s, 4H). MS (ESI): m/z 423.8 (M+Na)
+
.
5.1.22. 1-(2-(Naphthalen-2-yloxy)ethyl)-4-(pyridin-2-yl)piperazines (11)
The procedure described for the preparation of 1 was used with compound 41 (70 mg, 0.34
mmol), 45k (0.1 mL, 0.68 mmol), TEA (0.19 mL, 1.36 mmol), and DMSO (1 mL) to obtain 11
(35 mg, 31%) as a white solid. Rf = 0.56 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). MP = 102–
1
105 °C. H NMR (300 MHz, CDCl3): δ 8.20–8.18 9m, 1H), 7.76–7.70 (m, 3H), 7.48–7.15 (m,
5H), 6.63–6.58 (m, 2H), 4.26–4.23 (m, 2H), 3.59–3.55 (m, 4H), 2.92–2.89 (m, 2H), 2.72–2.69
(m, 4H). HRMS (ESI): m/z 334.19110 (M+H) + (calcd for C21H23N3O, 334.18411).
5.1.23. 2-(4-(2-(Naphthalen-2-yloxy)ethyl)piperazin-1-yl)pyrimidine (12)

The procedure described for the preparation of 1 was used with compound 41 (100 mg, 0.48
mmol), 45l (0.14 mL, 1 mmol), TEA (0.2 mL, 2.1 mmol), and DMSO (1 mL) to obtain 12 (75
mg, 46%) as a white solid. Rf = 0.41 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). MP = 74–76 °C. 1H
NMR (300 MHz, CDCl3): δ 8.28 (d, J = 4.8 Hz, 2H), 7.75–7.70 (m, 3H), 7.44–7.14 (m, 4H),
6.45–6.42 (m, 1H), 4.24–4.21 (m, 2H), 3.88–3.85 (m, 4H), 2.90–2.86 (m, 2H), 2.66–2.63 (m,
4H). MS (ESI): m/z 335.5 (M+H) +.
5.1.24. 4-Benzyl-1-(2-(naphthalen-2-yloxy)ethyl)piperidine (13)
The procedure described for the preparation of 1 was used with compound 41 (250 mg, 1.21
mmol), 45m (0.26 mL, 1.45 mmol), TEA (0.50 mL, 3.63mmol), and DMSO (2 mL) to obtain 13
(250 mg, 60%) as a sticky white solid. Rf = 0.61 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H
NMR (300 MHz, CDCl3): δ 7.78–7.7 (m, 3H), 7.44–7.09 (m, ≈9H, overlapped with CHCl3 peak),
4.50–4.47 (m, 2H), 4.32–4.29 (m, 2H), 4.13–4.11 (m, 2H), 2.72–2.65 (m, 2H), 2.50 (d, J = 6.9
Hz, 2H), 1.71–1.58 (m, 4H), 1.28–1.26 (m, 1H). MS (ESI): m/z 368.0 (M+Na) +.
5.1.25. 1-(3-(Naphthalen-2-yloxy)propyl)-4-phenylpiperazine (14)
The procedure described for the preparation of 1 was used with compound 42 (200, 0.9 mmol),
45a (189 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (mL).to obtain 14 (422 mg,
80%) as a sticky white solid. 1H NMR (300 MHz, CDCl3): δ 7.76–7.70 (m, 3H), 7.45–7.23 (m,
5H), 7.16–7.13 (m, 2H), 6.94–6.82 (m, 3H), 4.15 (t, J = 6.3 Hz, 2H), 3.23–3.20 (m, 4H), 2.66–
2.60 (m, 6H), 2.12–2.02 (m, 2H). MS (ESI): m/z 369.9 (M+Na) +.
5.1.26. 1-(2,6-Dimethylphenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (15)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45b (219 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 15
(105 mg, 28%) as a light brown liquid. Rf = 0.40 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.76–7.70 (m, 3H), 7.44–7.28 (m, 2H), 7.16–7.12 (m, 2H), 7.03–6.91 (m, 3H), 4.15 ( t,

J = 6.3 Hz, 2H), 3.15–3.12 (m, 4H), 2.66–2.58 (m, 6H), 2.32 (s, 6H), 2.13–2.04 (m, 2H). MS
(ESI): m/z 397.6 (M+Na) +.
5.1.27. 11-(2-Methoxyphenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (16)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45c (207 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 16
(108 mg, 32%) as a light brown liquid. Rf = 0.46 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.76–7.70 (m, 3H), 7.45–7.29 (m, 2H), 7.17–7.13 (M, 2H), 7.07–6.84 (m, 4H), 4.15 (t,
J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.12 (s, 4H), 2.70–2.62 (m, 6H), 2.13–2.03 (m, 2H). HRMS (ESI):
m/z 377.22177 (M+H) + (calcd for C24H28N2O2, 377.21508).
5.1.28. 1-(3-Chlorophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (17)
The procedure described for the preparation of 1 was used with compound 42 (230 mg, 1.04
mmol), 45d (0.43 mL, 1.24 mmol), TEA (0.43 mL, 3.12 mmol), and DMSO (2 mL) to obtain 17
(158 mg, 40%) as a white solid. Rf = 0.71 (n-hexane: EtOAc = 1:1). MP = 125–128 °C. 1H NMR
(300 MHz, CDCl3): δ 7.76–7.69 (m, 3H), 7.45–7.29 (m, 2H), 7.17–7.11 (m, 3H), 6.87–6.74 (m,
3H), 4.14 (t, J = 6.3 Hz, 2H), 3.21–3.17 (m, 4H), 2.62–2.58 (m, 6H), 2.10–2.01 (m, 2H). MS
(ESI): m/z 403.1 (M+Na) +.
5.1.29. 1-(4-Fluorophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (18)
The procedure described for the preparation of 1 was used with compound 42 (220 mg, 0.99
mmol), 45e (257 mL, 1.18 mmol), TEA (0.41 mL, 2.97 mmol), and DMSO (2 mL) to obtain 18
(144 mg, 40%) as a white solid. Rf = 0.68 (n-hexane: EtOAc= 1:1). MP = 142–144 °C. 1H NMR
(300 MHz, CDCl3): δ 7.78–7.69 (M, 3H), 7.45–7.29 (m, 2H), 7.16–7.13 (m, 2H), 6.98–6.83 (m,
4H), 4.14 (t, J = 6.3 Hz, 2H), 3.14–3.11 (m, 4H), 2.65–2.59 (m, 6H), 2.11–2.02 (m, 2H). MS
(ESI): m/z 387.7 (M+Na) +.
5.1.30. 1-(4-Chlorophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (19)

The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45f (226 mL, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 19
1
(96mg, 30%) as a white solid. Rf = 0.46 (n-hexane: EtOAc = 1:1). MP = 152–154 °C. H NMR
(300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.14 (m, ≈6H, overlapped with CHCl3 peak),
6.84 (d, J = 8.7 Hz, 2H), 4.18–4.14 (m, 2H), 3.19 (m, 4H), 2.66–2.62 (m, 6H), 2.10–2.06 (m, 2H).
MS (ESI): m/z 403.7 (M+Na) +.
5.1.31. 1-(4-Bromophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (20)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.9
mmol), 45g (274 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 20
(115 mg, 30%) as a white solid. Rf = 0.60 (n-hexane: EtOAc = 1:1). MP = 110–112 °C. 1H NMR
(300 MHz, CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.13 (m, ≈6H, overlapped with CHCl3 peak),
6.95–6.71 (m, 2H), 4.18–4.14 (m, 2H), 3.25–3.16 (m, 4H) 2.68–2.60 (m, 6H), 2.13–2.02 (m, 2H).
HRMS (ESI): m/z 425.12195 (M+H) + (calcd for C23H2579BrN2O, 425.11503), 427.11951 (M+H)
+ (calcd for C23H2581BrN2O, 427.11298).
5.1.32. 1-(2,4-Dichlorophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (21)
The procedure described for the preparation of 1 was used with compound 42 (220 mg, 0.99
mmol), 45h (318 mL, 1.18 mmol), TEA (0.41 mL, 2.97 mmol), and DMSO (2 mL) to obtain 21
(131 mg, 32%) as a white solid. Rf = 0.64 (n-hexane: EtOAc= 1:1). MP = 107–110 °C. 1H NMR
(300 MHz, CDCl3): δ 7.75–7.69 (m, 3H), 7.44–7.28 (m, 3H), 7.17–7.13 (m, 3H), 6.92 (d, J = 8.7
Hz, 1H), 4.13 (t, J = 6.3 Hz, 2H), 3.03 (s, 4H), 2.65–2.60 (m, 6H), 2.10–2.00 (m, 2H). MS (ESI):
m/z 415.8 (M+H) +.
5.1.33. 1-(3-N-2-yloxy)propyl)-4-(4-(trifluoromethyl)phenyl)piperazinea (22)
The procedure described for the preparation of 1 was used with compound 42 (220 mg, 0.99
mmol), 45i (273 mg, 1.18 mmol), TEA (0.41 mL, 2.97 mmol), and DMSO (2 mL) to obtain 22
(197 mg, 48%) as a white solid. Rf = 0.7 (n-hexane: EtOAc = 1:1). MP = 158–160 °C. 1H NMR
(300 MHz, CDCl3): δ 7.76–7.70 (m, 3H), 7.48–7.29 (m, 4H), 7.16–7.12 (m, 2H), 6.90 (d, J = 8.4

Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 3.28 (t, J = 5.1 Hz, 4H), 2.64–2.59 (m, 6H), 2.11–2.02 (m, 2H).
MS (ESI): m/z 415.7 (M+H) +.
5.1.34. 1-(2,3-Dichlorophenyl)-4-(3-(naphthalen-2-yloxy)propyl)piperazines (23)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45j (289 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 23
(112 mg, 30%) as a light brown liquid. Rf = 0.49 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.76–7.69 (m, 3H), 7.42 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.31 (ddd, J = 8.1, 6.9, 1.2 Hz,
1H), 7.16–7.11 (m, 4H), 6.95–6.92 (m, 1H), 4.14–4.12 (m, 2H), 3.07 (s, 4H), 2.66–2.61 (m, 6H),
2.11–2.02 (m, 2H). MS (ESI): m/z 438.2 (M+Na) +.
5.1.35. 1-(3-(Naphthalen-2-yloxy)propyl)-4-(pyridin-2-yl)piperazines (24)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45k (177 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 24
(94 mg, 30%) as a white solid. Rf = 0.50 (n-hexane: EtOAc = 1:1). MP = 112–115 °C. 1H NMR
(300 MHz, CDCl3): δ 8.20–8.18 (m, 1H), 7.77–7.70 (m, 3H), 7.50–7.30 (m, 3H), 7.16–7.12 (m,
2H), 6.66–6.60 (m, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.59–3.55 (m, 4H), 2.63–2.59 (m, 6H), 2.13–
2.04 (m, 2H). MS (ESI): m/z 348.0 (M+H) +.
5.1.36. 2-(4-(3-(Naphthalen-2-yloxy)propyl)piperazin-1-yl)pyrimidine (25)
The procedure described for the preparation of 1 was used with compound 42 (200 mg, 0.90
mmol), 45l (177 mg, 1.08 mmol), TEA (0.37 mL, 2.7 mmol), and DMSO (2 mL) to obtain 25
1
(109 mg, 45%) as a white solid. Rf = 0.38 (n-hexane: EtOAc = 1:1). MP = 85–88 °C. H NMR
1
(300 MHz, CDCl3): δ H NMR (300 MHz, CDCl3): δ 8.29 (d, J = 4.8 Hz, 2H), 7.75–7.69 (m,
3H), 7.41 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.39–7.28 (m, 1H), 7.16–7.12 (m, 2H), 6.46–6.43 (m,
1H), 4.14 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 5.1 Hz, 4H), 2.61–2.51 (m, 6H), 2.10–2.01 (m, 2H).
MS (ESI): m/z 371.1 (M+Na) +.
5.1.37. 4-benzyl-1-(3-(Naphthalen-2-yloxy)propyl)piperidine (26)

The procedure described for the preparation of 1 was used with compound 42 (220 mg, 0.99
mmol), 45m (0.21 mL, 1.18 mmol), TEA (0.41 mL, 2.97 mmol), and DMSO (2mL) to obtain 26
(185 mg, 52%) as a white solid. Rf = 0.56 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). MP = 91–
1
94 °C. H NMR (300 MHz, CDCl3): δ 7.72–7.65 (m, 3H), 7.41–7.09 (m, ≈9H, overlapped with
CHCl3 peak), 4.06–4.02 (m, 2H), 2.88 (d, J = 11.4 Hz, 2H), 2.51–2.44 (m, 4H), 2.02–1.80 (m,
4H), 1.63–1.42 (m, 3H), 1.35–1.21 (m, 2H). HRMS (ESI): m/z 360.23141 (M+H) + (calcd for
C25H29NO, 360.22491).
5.1.38. 1-(4-(Naphthalen-2-yloxy)butyl)-4-phenylpiperazine (27)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45a (169 mg, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 27
(84 mg, 33%) as a white solid. Rf = 0.64 (n-hexane: EtOAc = 1:1). MP = 75–78 °C. 1H NMR
(300 MHz, CDCl3): δ 7.76–7.69 (m, 3H), 7.44–7.22 (m, 4H), 7.16–7.12 (m, 2H), 6.93–6.82 (m,
3H), 4.09 (t, J = 6.3 Hz, 2H), 3.21–3.18 (m, 4H), 2.63–2.59 (m, 4H), 2.50–2.45 (t, J = 7.5 Hz,
2H), 1.93–1.70 (m, 4H). MS (ESI): m/z 383.4 (M+Na) +.
5.1.39. 1-(2,6-Dimethylphenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (28)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45b (173 mg, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 28
(91 mg, 33%) as a light brown liquid. Rf = 0.41 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.76–7.79 (m, 3H),7.44–7.28 (m, 2H), 7.16–7.12 (m, 2H), 6.99–6.90 (m, 3H), 4.10 (t,
J = 6.3 Hz, 2H), 3.12 (t, J = 4.8 Hz, 4H), 2.58–2.47 (m, 6H), 2.31 (s, 6H), 1.94–1.71 (m, 4H).
MS (ESI): m/z 389.3 (M+H) +.
5.1.40. 1-(2-Methoxyphenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (29)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45c (164 mL, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 29
(83 mg, 30%) as a light brown liquid. Rf = 0.44 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,

CDCl3): δ 7.77–7.70 (m, 3H), 7.45–7.29 (m, 2H), 7.16–7.12 (m, 2H), 7.10–6.84 (m, 4H), 4.11 (t,
J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.11 (s, 4H), 2.69 (s, 4H), 2.51 (t, J = 7.5 Hz, 2H), 1.94–1.72 (m,
4H). MS (ESI): HRMS (ESI): m/z 391.23679 (M+H) + (calcd for C25H30N2O2, 391.23073).
5.1.41. 1-(3-Chlorophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (30)
The procedure described for the preparation of 1 was used with compound 43 (251 mg, 1.07
mmol), 45d (299 mg, 1.28 mmol), TEA (0.44 mL, 3.21 mmol), and DMSO (2 mL) to obtain 30
(173 mg, 41%) as white solid. Rf = 0.71 (n-hexane: EtOAc= 1:1). MP = 65–67 °C. 1H NMR (300
MHz, CDCl3): δ 7.75–7.68 (m, 3H), 7.44–7.28 (m, 2H), 7.15–7.09 (m, 3H), 6.86–6.71 (m, 3H),
4.08 (t, J = 6.3 Hz, 2H), 3.17–3.14 (m, 4H), 2.57–2.41 (m, 6H), 1.91–1.82 (m, 2H), 1.77–1.67 (m,
2H). MS (ESI): m/z 417.8 (M+Na) +.
5.1.42. 1-(4-Fluorophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (31)
The procedure described for the preparation of 1 was used with compound 43 (251 mg, 1.07
mmol), 45e (278 mg, 1.28 mmol), TEA (0.44 mL, 3.21 mmol), and DMSO (2 mL) to obtain 31
(154 mg, 38%) as a white solid. Rf = 0.68 (n-hexane: EtOAc = 1:1). MP = 72–75 °C. 1H NMR
(300 MHz, CDCl3): δ 7.76–7.69 (m, 3H), 6.97–6.83 (m, 2H), 7.16–7.12 (m, 2H), 7.44–7.29 (m,
4H), 4.12–4.08 (m, 2H), 3.13–3.09 (m, 4H), 2.63–2.45 (m, 6H), 1.93–1.70 (m, 4H). HRMS
(ESI): m/z 379.21719 (M+H) + (calcd for C24H27FN2O, 379.21074).
5.1.43. 1-(4-Chlorophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (32)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45f (178 mg, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 32
(78 mg, 28%) as a white solid. Rf = 0.46 (n-hexane: EtOAc = 1:1). MP = 91–95 °C. 1H NMR
(300 MHz, CDCl3): δ 7.77–7.69 (m, 3H), 7.44–7.12 (m, ≈6H, overlapped with CHCl3 peak),
6.85–6.81 (m, 2H), 4.13–4.09 (m, 2H), 3.16 (t, J = 5.1 Hz, 4H), 2.62–2.59 (m, 4H), 2.51–2.46 (m,
2H), 1.94–1.70 (m, 4H). MS (ESI): m/z 395.9 (M+H) +.
5.1.44. 1-(4-Bromophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (33)

The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45g (147 mL, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 33
(94 mg, 30%) as a white solid. Rf = 0.59 (n-hexane: EtOAc = 1:1). MP = 140–144 °C. 1H NMR
(300 MHz, CDCl3): δ 7.77–7.68 (m, 3H), 7.45–7.28 (m, 4H), 7.15–7.12 (m, 2H), 6.79–6.74 (m,
2H), 4.12–4.08 (m, 2H), 3.17–3.13 (m, 4H), 2.61–2.45 (m, 6H), 1.94–1.70 (m, 4H). HRMS
(ESI): m/z 439.13776 (M+H) + (calcd for C24H2779BrN2O, 439.13068), 441.13477 (M+H)+ (calcd
for C24H2781BrN2O, 441.12863).
5.1.45. 1-(2,4-Dichlorophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (34)
The procedure described for the preparation of 1 was used with compound 43 (251 mg, 1.07
mmol), 45h (343 mg, 1.28 mmol), TEA (0.44 mL, 3.21 mmol), and DMSO (2 mL) to obtain 34
(142 mg, 31%) as a white solid. Rf = 0.64 (n-hexane: EtOAc = 1:1). MP = 82–84 °C. 1H NMR
(300 MHz, CDCl3): δ 7.71–7.70 (m, 3H), 7.45–7.29 (m, ≈6H, overlapped with CHCl3 peak),
6.93 ( d, J = 8.4 Hz, 1H), 4.11 (t, J = 8.4 Hz, 2H), 3.04 (s, 4H), 2.65 (s, 4H), 2.50 (t, J = 7.5 Hz,
2H), 1.94–1.85 (m, 2H), 1.80–1.71(m, 2H). HRMS (ESI): m/z 429.14874 (M+H) + (calcd for C
24H26 Cl2N2O, 429.14222).
5.1.46. 1-(4-(Naphthalen-2-yloxy)butyl)-4-(4-(trifluoromethyl)phenyl)piperazines (35)
The procedure described for the preparation of 1 was used with compound 43 (251 mg, 1.07
mmol), 45i (295 mg, 1.28 mmol), TEA (0.44 mL, 3.21 mmol), and DMSO (2 mL) to obtain 35
(202 mg, 44%) as a white solid. Rf = 0.71 (n-hexane: EtOAc = 1:1). MP = 112–114 °C. 1H NMR
(300 MHz, CDCl3): δ 7.76–7.69 (m, 3H), 7.47–7.29 (m, 4H), 7.16–m, 2H), 6.87 (d, J = 9 Hz,
2H), 4.11–4.07 (m, 2H), 3.25 ( t, J = 5.1 Hz, 4H), 2.60–2.44 (m, 6H), 1.94–1.85 (m, 2H), 1.79–
1.69 (m, 2H). HRMS (ESI): m/z 429.21390 (M+H) + (calcd for C25H27F3N2O, 429.20755).
5.1.47. 1-(2,3-Dichlorophenyl)-4-(4-(naphthalen-2-yloxy)butyl)piperazines (36)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45j (289 mg, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 36
1
(88 mg, 29%) as a light brown liquid. Rf = 0.49 (n-hexane: EtOAc = 1:1). H NMR (300 MHz,

CDCl3): δ 7.75–7.69 (m, 3H), 7.45–7.39 (m, 1H), 7.31 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.15–7.07
(m, 4H), 6.91 (dd, J = 7.2, 2.4 Hz, 1H), 4.09 ( t, J = 6.3 Hz, 2H), 3.05 (s, 4H), 2.64 (s, 4H), 2.52–
2.47 (m, 2H), 1.93–1.70 (m, 4H). MS (ESI): m/z 429.1 (M+H) +.
5.1.48. 1-(4-(Naphthalen-2-yloxy)butyl)-4-(pyridin-2-yl)piperazines (37)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45k (139 mg, 0.84 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 37
(85 mg, 47%) as a light brown liquid. Rf = 0.49 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 8.19–8.17 (m, 1H), 7.74–7.69 (m, 3H), 7.45–7.30 (m, 3H), 7.15–7.10 (m, 2H), 6.60–
6.56 (m, 2H), 4.08–4.04 (m, 2H), 3.52 (t, J = 5.1 Hz, 4H), 2.55–2.40 (m, 6H), 1.90–1.67 (m, 4H).
MS (ESI): m/z 362.5 (M+H) +.
5.1.49. 2-(4-(4-(Naphthalen-2-yloxy)butyl)piperazin-1-yl)pyrimidine (38)
The procedure described for the preparation of 1 was used with compound 43 (166 mg, 0.71
mmol), 45l (139 mg, 0.85 mmol), TEA (0.29 mL, 2.13 mmol), and DMSO (2 mL) to obtain 38
(83 mg, 32%) as a light brown liquid. Rf = 0.38 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 8.29 (d, J = 4.5 Hz, 2H), 7.76–7.70 (m, 3H), 7.45–7.39 (m, 1H), 7.34–7.29 (m, 1H),
7.16–7.12 (m, 2H), 6.48 ( t, J = 4.8 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.85–3.82 (m, 4H), 2.54–
2.44 (m, 6H), 1.95–1.71 (m, 4H). MS (ESI): m/z 385.5 (M+Na) +.
5.1.50. 4-Benzyl-1-(4-(naphthalen-2-yloxy)butyl)piperidine (39)
The procedure described for the preparation of 1 was used with compound 43 (251 mg, 1.07
mmol), 45m (0.23 mL, 1.23 mmol), TEA (0.44 mL, 3.21 mmol), and DMSO (2 mL) to obtain 39
(232 mg, 58%) as a white solid. Rf = 0.55 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). MP = 78–
81 °C. 1H NMR (300 MHz, CDCl3): δ 7.76–7.69 (m, 3H), 7.44–7.11 (m, ≈9H, overlapped with
CHCl3 peak), 4.10–4.05 (m, 2H), 2.91 (d, J = 11.4 Hz, 2H), 2.52 (d, J = 6.9 Hz, 2H), 2.40–2.33
(m, 2H), 1.90–1.80 (m, 4H), 1.75–1.46 (m, 5H), 1.37–1.24 (m, 2H). MS (ESI): m/z 396.8
(M+Na) +.

5.2. Neurotransmitter uptake assay
The assay was performed in accordance with the method described in the literature with a slight
modification.25 HEK-293 cells were cultured in a medium supplemented with fetal bovine serum
and transfected with hSERT, or hNET, or hDAT. Radiolabeled [3H]-5-HT (PerkinElmer,
Waltham, MA, USA), [3H]-NE (PerkinElmer, Waltham, MA, USA), and [3H]-DA (PerkinElmer)
were used at a concentration of 20 nM in the assay. Radioactivity was measured using a Wallac
1450 MicroBeta® TriLux liquid scintillation counter (PerkinElmer). Venlafaxine hydrochloride,
bupropion, and GBR12909 were used as reference inhibitors of neurotransmitters reuptake.
5.3. Docking
The docking study was computed by Sybyl-X 2.1.1 (winnt_os5x) using the Surflex-Dock
program. The structure of hSERT-paroxetine was downloaded from Protein Data Bank (PDB ID:
5I6X).46 Maltose, cholesterol, N-acetylglucosamine, and the chloride ion were deleted. The
ligand (paroxetine) was extracted. Hydrogens were added and minimized by using the MMFF94s
force field with MMFF94 charges, using a conjugate gradient method, distance-dependent
dielectric constant and convergence to 0.01 kcal/mol·Å. Protomol, an idealized representation of
a ligand that makes every potential interaction with the binding site, was generated on the basis
of the ligand model. Compounds intended for the docking study including 35 and paroxetine
were constructed in Sybyl; energy was minimized by using the MMFF94s force field and
MMFF94 charged and stored in the Sybyl database. The compounds in the Sybyl database were
docked into the binding site by Surflex-Dock on the basis of the Protomol representation
constructed earlier. The extracted paroxetine was considered as a reference molecule. The
docking protocol was able to reproduce the position of paroxetine (manually constructed and
stored in the Sybyl database) in the binding site with a root-mean-square deviations (RMSD) of
0.43 Å for the heavy atoms of the extracted paroxetine.
Acknowledgment
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (grant No.
2012R1A1A2006613) and the Bio & Medical Technology Development Program of the National

Research Foundation (NRF) & funded by the Korean government (MSIT) (NRF-
2017M3A9G2077568). The authors would like to thank the Korea basic science institute
Gwangju center for performing the 1H NMR.
References and notes
1.
2.
3.
Weinberger, A. H.; Gbedemah, M.; Martinez, A. M.; Nash, D.; Galea, S.; Goodwin, R. D.
Psychological Medicine. 2018, 48, 1308.
Lim, G. A.; Tam, W. W.; Lu, Y.; Ho, C. S.; Zhang, M. W.; Ho, R. C. Scientific reports.
2018, 8, 2861
Yang, T.; Zhao, G.; Mao, R.; Huang, J.; Xu, X.; Su, Y.; Zhu, Na, Zhou, R.; Lin, X.; Xia,
W.; Wang. F.; Liu, R.; Wang, X.; Huang, Z.; Wang, Y.; Hu, Y.; Cao, L.; Yaun, C, Wang,
Z, lam, R. W.; Chen, J.; Fang, Y. Journal of Affective Disorders. 2018, 238, 412.
4.
5.
6.
7.
8.
9.
Felgium, V. L.; Vos, T. Lancet Neurology. 2017, 16, 877
Disease, G. B. D.; Ward, J.; Inquiry, I.; Prevalence, C. Lancet, 2016, 388, 1545.
Silberberg, D.; Anand, N. P.; Michels, K. Kalaria, R. N. Nature. 2015, 527, 7578.
Doucet, M. V.; Harkin, A.; Dev, K. K. Pharmacology & Therapeutic. 2012, 133, 218
Artigas, A.; Adell, A.; Celada, P. Current Drug Targets. 2006, 7, 139.
Kessler, R.; Chiu, W.; Demler, O.; Walters, E. E. Archives of General Psychiatry. 2005,
62, 617.
10.
11.
Murray, C. J.; Lopez, A. D. Lancet. 1997, 349, 1436.
Dilasaver, S.C.; Chen, Y. W.; Swann, A. C.; Shoaib, A. M.; Krajewski, K. J. American
Journal of Psychiatry. 1994, 151, 1312.
12.
13.
Murray, C. J.; Lopez, A. D. Science. 1996, 274, 740.
Lane, R. M. J. Psychopharmacol. 2015, 29, 526.

14.
15.
Grouleff, J.; Ladefoged, L. K.; Koldso, H.; Schiott, B. Frontiers in Pharmacology. 2015,
6, 235
Liming, S.; Li, W.; Xie, Q.; Yin, H. Expert Opinion on Therapeutic Patents. 2014, 24,
131.
16.
Kristensen, A. S.; Andersen, J.; Jorgensen,T. N.; Sorensen, L.; Eriksen, J.; Loland, C.
Pharmacological Reviews. 2011, 63, 585.
17.
18.
Schultz, W. Annual Review of. Neuroscience. 2007, 30, 259.
Torres, G. E.; Gainetdinov, R. R.; Caron, M. G. Nature Reviews Neuroscience. 2003, 4,
13.
19.
20.
Iversen, L. Molecular Psychiatry. 2000, 5, 357.
Stahl, S. M. Stahl’s Essential Psychopharmacology: Neuroscientific Basic and Practical
Applications; 4th ed.; Cambridge University Press: Newyork, 2013.
Marks, D. M.; Pae, C. U.; Patkar, A. A. Current Neuropharmacology. 2008, 6, 338.
Subbaiah, M. A. M. Journal of. Medicinal Chemistry.2018, 61, 2133.
Berton, O.; Nestler. E. J.; Nature Reviews Neuroscience. 2006, 7, 137.
Zhu, W. Ma, S.; Qu. R.; Kang, D. Life Sciences. 2006, 79, 749.
Paudel, S.; Cao, Y.; Guo, S.; An, B.; Kim, K. M.; Cheon, S. H. Bioorganic & Medicinal
Chemistry. 2015, 23, 6418.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Paudel, S.; Acharya, S.; Kim, K.M.; Cheon, S.H. Bioorganic & Medicinal Chemistry.
2016, 24, 2137.
Paudel, S.; Acharya, S.; Yoon, G.; Kim, K.M.; Cheon, S.H. Bioorganic & Medicinal
Chemistry. 2016, 24, 5546.
Paudel, S.; Acharya, S.; Yoon, G.; Kim, K.M.; Cheon, S.H. Bioorganic & Medicinal
Chemistry. 2017, 25, 2266.
Paudel, S.; Min, X.; Acharya, S.; Khadka, D.B., Yoon, G.; Kim, K.M.; Cheon, S.H.
Bioorganic & Medicinal Chemistry. 2017, 25, 5278.
30. Paudel, S.; Sun, N.; Acharya, S.; Khadka, D.B., Yoon, G.; Kim, K.M.; Cheon, S.H.
Bioorganic & Medicinal Chemistry, 2018, 26, 4127.