Discovery and SAR study of 3-(tert-butyl)-4-hydroxyphenyl benzoate and benzamide derivatives as novel farnesoid X receptor (FXR) antagonists

Article abstract of DOI:10.1016/j.bmc.2015.08.021

3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) was discovered in our in-house high throughput screening as a moderate FXR antagonist. To improve the potency and the stability of the hit 1, forty derivatives were synthesized and SAR was systematically explored. The results turn out that replacing the 2,4-dichlorophenyl with 2,6-dichloro-4-amidophenyl shows great improvement in potency, replacing the benzoate with benzamide shows improvement in stability and slight declining of potency and 3-(tert-butyl)-4-hydroxyphenyl unit is essential in obtaining the FXR antagonistic activity.

Full text of DOI:10.1016/j.bmc.2015.08.021

Accepted Manuscript
Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin and
norepinephrine reuptake inhibitors
Suresh Paudel, Yongkai Cao, Shuohan Guo, Byeongkwan An, Kyeong-Man
Kim, Seung Hoon Cheon
PII:
S0968-0896(15)30003-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.08.021
BMC 12525
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 July 2015
17 August 2015
19 August 2015
Please cite this article as: Paudel, S., Cao, Y., Guo, S., An, B., Kim, K-M., Cheon, S.H., Design and synthesis of 4-
benzylpiperidine carboxamides as dual serotonin and norepinephrine reuptake inhibitors, Bioorganic & Medicinal
Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.08.021
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Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin
and norepinephrine reuptake inhibitors
Suresh Paudela, Yongkai Caoa, Shuohan Guoa, Byeongkwan Anb, Kyeong-Man Kima*, Seung
Hoon Cheona*
aCollege of Pharmacy and Research Institute of Drug Development, Chonnam National
University, Gwangju 61186, Republic of Korea
bJeonnam Development Institute for Korean Traditional Medicine 288, Udeuraendeu-gil,
Anyang-myeon, Jangheung-gun, Jeollanam-do, 59338, 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:
A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their
dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine
carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon
linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted
derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine
HCl.
Keywords: 4-Benzylpiperidine carboxamide, serotonin reuptake inhibitor, norepinephrine
reuptake inhibitor

1. Introduction:
Depression is a common and severe illness.1, 2 Chronic sadness, loss of interest, disruption in
sleep patterns, fatigue and sometimes suicidal intension are common features observed in
depressed individuals.3-5 The primary cause of depression is deficiency of monoamine
neurotransmitters, serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in the brain.
Monoamine reuptake inhibitors maintain the concentration of neurotransmitters in the brain
through inhibition of presynaptic monoamine reuptake transporter.6-10 Drugs that inhibit dual (5-
HT and NE) neurotransmitters reuptake are prescribed for the treatment of several central
nervous system (CNS) illnesses including depression.11-16
Drawbacks of the selective 5-HT reuptake inhibitors fluoxetine (1), paroxetine (2) and sertraline
(3) include delayed onset of action and side effects of insomnia and sexual dysfunction (Fig. 1).17
Trazodone (4), which has a different chemical scaffold than the other antidepressant drugs,
works as a 5-HT reuptake inhibitor and is devoid of these limitations and side effects.18, 19 The
drug essentially consists of heterocyclic amine (A), linker (B) and aromatic region (C) (Fig. 2).
Arylpiperazine-containing pyrimidine 4-carboxamide derivatives 5 that have three fundamental
components also display good binding affinity for 5-HT transporter and may work as serotonin
reuptake inhibitors.20 Furthermore, arylalkanol-piperidine derivatives 6 with similar structural
moieties also possess serotonin and norepinephrine reuptake inhibition.21 Thus, considering the
structure of trazodone, 5 and 6, we designed 4-benzylpiperidine carboxamides 7, 8 as possible
dual reuptake inhibitors (Fig. 2). 4-Benzylpiperidine carboxamides 7 and 8 which differ in the
length of linker were considered to explore their impact on inhibition of neurotransmitters
reuptake. The synthesis, biological evaluation and detailed structure-activity relationship (SAR)
of the 4-benzylpiperidine carboxamides are detailed below.

Figure 1. Some marketed antidepressants (selective 5-HT reuptake inhibitors) - Fluoxetine (1),
paroxetine (2) and sertraline (3)
A
B
A
B
C
C
O
O
N
N
N
N
N
H
Ar
N
N
7
8
4
5
N
N
Cl
Cl
H
N
O
Ar
N
H
O
N
N
HO
6
N
S
Figure 2. Design of 4-benzylpiperidine carboxamides
2. Chemistry
Various aromatic carboxylic acids 9a–9i were refluxed overnight with excess thionyl chloride
and the residue obtained by evaporating the solvent was further reacted with 3-
bromopropylamine hydrobromide or 2-chloroethylamine hydrochloride in the presence of
triethylamine (TEA) to give different amides 10a–10i and 11a–11i (Scheme 1). Alternatively,
amidation reaction between aromatic carboxylic acid 9j–9l and 3-bromopropylamine
hydrobromide or 2-chloroethylamine hydrochloride using 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDCI.HCl) as a coupling reagent gave corresponding amides 10j–
10l and 11j–11l. The substitution reaction of 10a–10l and 11a–11l with 4-benzylpiperidine gave
carboxamides derivatives 7a–7l and 8a–8l.

Scheme 1. Reagents and conditions: (i) SOCl2, benzene/toluene/tetrahydrofuran, reflux (ii)
CH2Cl2, TEA, 0 °C–r.t. (iii) EDCI.HCl, DMAP, TEA, r.t. (iv) DMSO, TEA, 100 °C.
3. Result and discussion
3.1 Biological Screening
Serotonin and norepinephrine reuptake activities were measured by a neurotransmitter uptake
assay. In the assay, human embryonic kidney 293 (HEK-293) cells were stably transfected with
human serotonin transporter (hSERT) and human norepinephrine transporter (hNET). The
serotonin and norepinephrine inhibitory activities of the synthesized compounds are presented in
Table 1.

Table 1: Serotonin and norepinephrine reuptake inhibition by 4-benzylpiperidine carboxamides
7a–l and 8a–l.
Compd
7a
R1
RIa
0.83
0.84
0.84
1.10
1.01
0.26
0.19
0.85
0.6
RIb
Compd
8a
R1
RIa
RIb
3,5-dichlorophenyl
2-indolyl
1.12
1.72c
1.54c
1.80c
1.59c
1.19c
1.37c
0.62c
1.32
1.03
0.94
1.00
3,5-dichlorophenyl
2-indolyl
0.64 1.00
0.58 1.49c
0.78 1.09c
0.77 1.92c
0.98 1.49c
0.29 1.04c
7b
7c
8b
8c
benzo(b)furanyl
benzo(b)thiophenyl
4-biphenyl
benzo(b)furanyl
benzo(b)thiophenyl
4-biphenyl
7d
7e
8d
8e
diphenylacetyl
bis(4-chlorophenyl)acetyl
2-quinolyl
diphenylacetyl
7f
8f
bis(4-chlorophenyl)acetyl 0.40 1.54c
7g
8g
2-quinolyl
1-naphthyl
1.03 0.53
0.91 0.10
7h
7i
8h
8i
1-naphthyl
2-naphthyl
0.95
1.11
0.98
2-naphthyl
0.8
1.27
7j
8j
6-bromo-2-naphthyl
6-methoxy-2-naphthyl
6-bromo-2-naphthyl
6-methoxy-2-naphthyl
0.51 0.83
0.63 1.97c
7k
7l
8k
8l
a Relative inhibition (serotonin reuptake inhibition at 1 µM by compound under test/venlafaxine HCl)
b Relative inhibition (norepinephrine reuptake inhibition at 1 µM by compound under test/GBR-12909)
c Relative inhibition (norepinephrine reuptake inhibition at 3 µM by compound under test/venlafaxine HCl)
Generally, 4-benzylpiperidine carboxamide derivatives with three carbon units in the linker
showed better serotonin reuptake inhibitory activities than the compounds with two carbon units.
However, compounds 7h and 7i with longer linkers were less active than analogs 8h and 8i with
shorter linkers. The serotonin reuptake inhibition of derivatives 7f–7g and 8f–8g with bulky
diphenyl acetyl groups was very low irrespective of the length of the linker. The remaining
derivatives possessed moderate to potent serotonin reuptake inhibitory activity compared to
venlafaxine (RI: 0.5–1.11).
Inhibition of reuptake of norepinephrine by 4-benzylpiperidine carboxamides also varied mainly
on the length of linker. The compounds with a three-carbon linker showed better activity than
compounds with a two-carbon linker. Interestingly, the activity of 1-naphthyl compound 7i was
increased significantly by 13-fold when the length of linker was extended from two to three
carbons. Majority of 4-benzylpiperidine carboxamides displayed equipotent or more potent
inhibition of norepinephrine reuptake than venlafaxine and GBR-12909.

4-Benzylpiperidine carboxamides 7a, 7b, 7c, 7d, 7e, 7j, 7k, 7l, 8e, and 8h with potent relative
serotonin/norepinephrine reuptake inhibitory activities (RI > 0.8) were further analyzed to
determine IC50 values. The IC50 values of serotonin and norepinephrine reuptake inhibitory
activity of the selected compounds are presented in Table 2.
Table 2: IC50 value for serotonin and norepinephrine reuptake inhibition of the compounds
Compd
n
3
3
3
3
3
3
3
3
2
2
-
R1
3,5-dichlorophenyl
2-indolyl
hSERT (µM)
0.422
hNET (µM)
0.267
0.268
0.621
4.75
7a
0.546
7b
benzo(b)furanyl
benzo(b)thiophenyl
4-biphenyl
0.500
7c
0.449
7d
0.056
0.153
0.342
0.885
0.238
0.472
0.275
2.553
7e
2-naphthyl
0.108
7j
6-bromo-2-naphthyl
6-methoxy-2-naphthyl
4-biphenyl
1.914
7k
0.323
7l
0.986
8e
8h
2-quinolyl
0.786
Venlafaxine HCl
-
0.204
The fact that serotonin reuptake inhibition by 4-benzylpiperidine carboxamides with a three-
carbon linker is better than the compounds with a two-carbon linker was reinforced by the IC50
values of 4-biphenyl derivatives 7e and 8e. The activity of 7e was 17-times better than of 8e. The
serotonin reuptake inhibitory activities of compounds containing fused heterocyclic ring were in
the following increasing order: 2-indolyl (7b) < benzo(b)furanyl (7c) < benzo(b)thiophenyl (7d).
Furthermore, the activity of unsubstituted naphthyl derivative 7j was greater than 6-bromo- 7k
and 6-methoxy-substituted 7l naphthyl compounds. Among 10, 4-benzylpiperidine carboxamides,
compounds 7e and 7j showed 3.5- and 2-times better serotonin reuptake inhibitory activity than
the standard drug, venlafaxine HCl.
Norepinephrine reuptake inhibition by all 4-benzylpiperidine carboxamides, except 7d (IC50:
4.75 µM), was greater than the standard drug, venlafaxine HCl. The norepinephrine reuptake
inhibitory activity of 4-biphenyl derivative 7e is additional evidence of the greater activity
achieved with a three-carbon linker than with a two-carbon linker.

4. Conclusion
In summary, we developed 4-benzylpiperidine carboxamide-based dual reuptake inhibitors.
Compounds with various linker lengths and aromatic rings were synthesized by amidation and
substitution reactions. Primary screening at a single concentration and IC50 values showed that
the compounds having a three-carbon linker were more active than the ones with a two-carbon
linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed better dual reuptake
inhibition than the standard drug, venlafaxine HCl. Thus, based on the presented results, 4-
benzylpiperidine carboxamide can be the basis for the further development of promising
antidepressant drugs.
5. Experimental Section
5.1. Chemistry
Melting points were determined by the capillary method on Thomas Hoover melting point
apparatus and were uncorrected. Infrared (IR) spectra were recorded on a JASCO-FT IR
1
13
spectrometer using KBr pellets. H and C NMR data were collected on a Varian 75, 125 and
300 MHz spectrometer and are reported in ppm, downfield from the peak of the internal standard,
tetramethylsilane. Data are reported as chemical shift, number of protons, multiplicity (s: singlet,
d: doublet, t: triplet, q: quartet, quin: quintet, m: multiplet). Mass spectra were obtained on a
Shimadzu UFLC-MS liquid chromatograph mass spectrometer using the electron spray
ionization (ESI) method. Column chromatography was performed on Merck silica gel 60 (70–
230 mesh). Thin-layer chromatography was performed using plates coated with silica gel 60
F254 (Merck). Chemical reagents were purchased from Sigma-Aldrich and Alfa Aesar, and were
used without further purification.
5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (10a). Compound 9a (191 mg, 1 mmol)
was refluxed in excess of thionyl chloride (3 mL) overnight. Excess of thionyl chloride was
evaporated and the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328
mg, 1.5 mmol was added followed by triethylamine (TEA; 0.42 mL, 3 mmol). The reaction
mixture was stirred at room temperature. After the reaction was completed, the reaction mixture
was diluted with CH2Cl2 and sequentially washed with water, 1N HCl and saturated NaHCO3.

The organic layer was dried over MgSO4, filtered and concentrated. The obtained product was
purified by column chromatography with n-hexane: Ethyl acetate (EtOAc) = 4:1 to obtain 10a,
(236 mg, 76%) as white solid. Retention factor Rf = 0.85 (n-hexane: EtOAc = 1:1). Mp = 98 °C.
1H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 1.8 Hz, 2H, Ar-H), 7.49 (s, J = 1.8 Hz, 1H, Ar-H),
6.38 (s, 1H, -CONH), 3.62 (q, J = 6.4 Hz, -CONH-CH2), 3.49 (t, J = 6.3 Hz, 2H, -CH2Br), 2.21
(quin, J = 6.5 Hz, 2H, -CH2CH2Br).
5.1.2 N-(3-Bromopropyl)-1H-indole-2-carboxamide (10b). The procedure described for the
preparation of 10a was used with compound 9b (400 mg, 2.48 mmol), thionyl chloride (8 mL) in
presence of THF (10 mL), 3-bromopropylamine hydrobromide (814 mg, 3.71 mmol) and TEA (1
mL, 7.44 mmol) to obtain 10b (314 mg, 45%) as light yellow solid. Rf = 0.75 (n-hexane: EtOAc
= 1:1). Mp = 97 °C. 1H NMR (300 MHz, CDCl3 ): δ 9.27 (s, 1H, -NH), 7.65 (dd, J = 8.1, 0.9 Hz,
1H, Ar-H), 7.44 (dd, J = 8.4, 0.9 Hz, 1H, Ar-H), 7.32–7.26 (m, ≈ 3H, Ar-H, overlapped with
CHCl3 peak), 7.17–7.12 (m, 1H, Ar-H), 6.84 (dd, J = 2.1, 0.9 Hz, 1H, Ar-H), 6.37 (s, 1H, -
CONH), 3.66 (q, J = 6.5 Hz, 2H, -CONH-CH2), 3.51 (t, J = 6.45 Hz, 2H, -CH2Br), 2.33 (quin, J
= 6.45 Hz, 2H, -CH2CH2Br).
5.1.3 N-(3-Bromopropyl)benzo(b)furan-2-carboxamide (10c). The procedure described for
the preparation of 10a was used with compound 9c (300 mg, 1.85 mmol), thionyl chloride (5 mL)
in presence of benzene (10 mL), 3-bromopropylamine hydrobromide (607mg, 2.77 mmol), TEA
(0.77 mL, 5.55 mmol) to obtain 10c (480 mg, 92%) as white solid. Rf = 0.72 (n-hexane: EtOAc =
1
1:1). Mp = 88 °C. H NMR (300 MHz, CDCl3): δ 7.63 (ddd, J = 7.8, 1.2, 0.6 Hz, 1H, Ar-H),
7.48–7.45 (m, 2H, Ar-H), 7.39 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, Ar-H), 7.29–7.24 (m, 1H, Ar-H),
7.04 (s, 1H, -CONH), 3.64 (q, J = 6.5 Hz, 2H, -CONH-CH2), 3.49 (t, J = 6.6 Hz, 2H, -CH2Br),
2.21 (quin, J = 6.5 Hz, 2H, - CH2CH2Br).
5.1.4 N-(3-Bromopropyl)benzo[b]thiophene-2-carboxamide (10d). The procedure described
for the preparation of 10a was used with compound 9d (220 mg, 1.23 mmol), thionyl chloride (3
mL) in presence of toluene (5 mL), 3-bromopropylamine hydrobromide (402mg, 1.84 mmol) and
TEA (0.51 mL, 3.69 mmol to obtain 10d (325 mg, 89%) as white solid. Rf = 0.74 (n-hexane:
1
EtOAc = 1:1). Mp = 122 °C. H NMR (300 MHz, CDCl3): δ 7.86–7.79 (m, 3H, Ar-H), 7.43–

7.38 (m, 2H, Ar-H), 6.47 (s, 1H,-CONH), 3.64 (q, J = 6.4 Hz, 2H, -CONH-CH2), 3.51 (t, J = 6.3
Hz, 2H, -CH2Br), 2.23 (quin, J = 6.4 Hz, 2H, - CH2CH2Br).
5.1.5 N-(3-Bromopropyl)-1,2-dihydro-[1,1′-biphenyl]-4-carboxamide (10e). The procedure
described for the preparation of 10a was used with compound 9e (1000mg, 4.99 mmol), thionyl
chloride (20 mL) in presence of benzene (20 mL), 3-bromopropylamine hydrobromide (1637 mg,
7.48 mmol and TEA (2 mL, 14.97 mmol) to obtain 10e (952 mg, 60%) as white solid. Rf = 0.62
1
(n-hexane: EtOAc = 1:1). Mp = 135 °C. IR (cm-1): 3324 (NH). H NMR (300 MHz, CDCl3): δ
7.87–7.82 (m, 2H, Ar-H), 7.67–7.58 (m, 4H, Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.42 (s, 1H, -
CONH), 3.69–3.61 (m, 2H), 3.51 (t, J = 6.4 Hz, 2H, -CH2Br), 2.20 (quin, J = 6.5, 2H, -
CH2CH2Br).
5.1.6 N-(3-Bromopropyl)-2,2-diphenylacetamide (10f). The procedure described for the
preparation of 10a was used with compound 9f (600 mg, 2.82 mmol), thionyl chloride (10 mL)
in presence of benzene (10 mL), 3-bromopropylamine hydrobromide (926mg, 4.23mmol and
TEA (1.17 (10 mL), 8.46 mmol) to obtain 10f (563 mg, 63%) as light brown liquid. Rf = 0.82 (n-
1
hexane: EtOAc = 1:1). H NMR (300 MHz, CDCl3): δ 7.43–7.32 (m, ≈ 11H, Ar-H, overlapped
with CHCl3), 7.16 (s, 1H, -CONH), 3.51 (q, J = 6.4 Hz, 2H, -CONH-CH2), 3.38 (t, J = 6.4 Hz,
2H, -CH2Br), 2.17–2.10 (m, 2H, -CH2CH2Br).
5.1.7 N-(3-Bromopropyl)-2,2-bis(4-chlorophenyl)acetamide (10g). The procedure described
for the preparation of 10a was used with compound 9g (300mg, 1.06 mmol), thionyl chloride (5
mL), 3-bromopropylamine hydrobromide (348 mg, 1.59 mmol and TEA (0.44 mL, 3.18 mmol)
to obtain 10g (175 mg, 43%) as white solid Rf = 0.83 (n-hexane: EtOAc = 1:1). Mp = 109 °C. IR
(cm-1): 3448 (NH). 1H NMR (300 MHz, CDCl3): δ 7.36–7.25 (m, ≈ 11H, overlapped with CHCl3
peak), 3.56–3.43 (m, 2H, -CONH-CH2), 3.37 (t, J = 6.45, 2H, -CH2Br), 2.11 (q, J = 6.5, 2H, -
CH2CH2Br).
5.1.8 N-(3-Bromopropyl)quinoline-2-carboxamide (10h). The procedure described for the
preparation of 10a was used with compound 9h (550 mg, 3.17 mmol), thionyl chloride (8 mL),
3-bromopropylamine hydrobromide (1040 mg, 4.75mmol and TEA (1.32 mL, 9.51 mmol) to
obtain 10h (697 mg, 75%) as white solid Rf = 0.87 (n-hexane: EtOAc = 1:1). Mp = 94 °C. IR
1
(cm-1): 3526 (NH). H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H, -CONH), 8.30 (s, 2H, Ar-H),

7.88 (ddd, J = 8.1, 1.5, 0.6 Hz, 1H, Ar-H), 7.77 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, Ar-H), 7.62 (ddd,
J = 8.1, 6.9, 1.2 Hz, 1H, Ar-H), 7.59 (d, J = 6.9 Hz, 1H, Ar-H), 3.74–3.66 (m, 2H, -CONH-CH2),
3.53 (t, J = 6.6 Hz, 2H, -CH2Br), 2.27 (quin, J = 6.6, 2H, -CH2CH2Br).
5.1.9 N-(3-Bromopropyl)-1-naphthamide (10i). The procedure described for the preparation
of 10a was used with compound 9i (500 mg, 2.90 mmol), thionyl chloride (10 mL) in presence
of toluene (10 mL), 3-bromopropylamine hydrobromide (952mg, 4.35) and TEA (1.21 mL, 8.7
mmol) to obtain 10i (626 mg 74%) as white solid. Rf = 0.74 (n-hexane: EtOAc = 1:1). Mp =
1
104 °C. H NMR (300 MHz, CDCl3): δ 8.24–8.21 (m, 1H, Ar-H), 7.88–7.82 (m, 2H, Ar-H),
7.52–7.49 (m, 3H, Ar-H),7.40–7.35 (m, 1H, Ar-H), 6.41 (s, 1H, -CONH), 3.59 (q, J = 6.4 Hz, 2H,
-CONHCH2), 3.46 (t, J = 6.4 Hz, 2H, -CH2Br), 2.18 (quin, J = 6.4 Hz, 2H, -CH2CH2Br).
5.1.10 N-(3-Bromopropyl)-2-naphthamide (10j). The 9j (250 mg, 1.45 mmol) was dissolved
in CH2Cl2 (5 mL). EDCI.HCl (333 mg, 1.74 mmol) was added to reaction mixture followed by
DMAP (8.9 mg, 0.07mmol). To the reaction solution 3-bromopropylamine hydrobromide (317
mg, 1.45 mmol) was added and stirred for 30 minutes. TEA (0.66 mL, 4.78 mmol) was poured
slowly drop wise and stirred reaction at room temperature. After the reaction was completed, the
reaction mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried
over MgSO4, filtered and concentrated. The obtained product was purified by column
chromatography with Hexane: EtOAc (4:1) to obtain 10j (266 mg, 63%) as white solid. Rf = 0.79
(n-hexane: EtOAc = 1:1). Mp = 124 °C. 1H NMR (300 MHz, CDCl3): δ 8.28 (s, 1H, 1-H), 7.92–
7.80 (m, 4H, Ar-H), 7.60–7.51 (m, 2H, Ar-H), 6.54 (s, 1H, -CONH), 3.68 (q, J = 6.4 Hz, 2 Hz, -
CONH-CH2), 3.53 (t, J = 6.3, 2H, -CH2Br), 2.25 (quin, J = 6.6 Hz, 2H, -CH2CH2Br).
5.1.11 6-Bromo-N-(3-chloropropyl)-2-naphthamide (10k). The procedure described for the
preparation of 10j was used with compound 9k (300 mg, 1.19 mmol), EDCI.HCl (272 mg, 1.42
mmol), DMAP (11.31mg, 0.06 mmol), 3-bromopropylamine hydrobromide (260 mg, 1.19 mmol)
and TEA (0.54 mL, 3.92 mmol) to obtain 10k (242 mg, 55%) as white solid. Rf = 0.71 (n-hexane:
1
EtOAc = 1:1). Mp = 98 °C. H NMR (300 MHz, CDCl3): δ 8.25 (s, 1H, Ar-H), 8.04 (d, J = 1.8
Hz, 1H, Ar-H), 7.86–7.77 (m, 3H, Ar-H), 7.61 (dd, J = 8.7, 1.8 Hz, 1H, 7-H), 6.5 (s, 1H, -
CONH), 3.68 (q, J = 6.4, 2H, -CONH-CH2), 3.53 (t, J = 6.45, 2H, -CH2Br), 2.26 (quin, J = 6.45,
2H, -CH2CH2Br).

5.1.12 N-(3-Bromopropyl)-6-methoxy-2-naphthamide (10l). The procedure described for the
preparation of 10j was used with compound 9l (500 mg, 2.47 mmol), EDCI.HCl (567 mg, 2.96
mmol), DMAP (14.6 mg, 0.12 mmol), 3-bromopropylamine hydrobromide (540 mg, 2.47 mmol)
and TEA (1.1 mL, 8.15 mmol) to obtain 10l (493 mg, 62 %) as white solid. Rf = 0.54 (n-hexane:
EtOAc = 1:1). Mp = 118 °C. 1H NMR (300 MHz, CDCl3) ): δ 8.20 (s, 1H, Ar-H), 7.81–7.74 (m,
3H, Ar-H), 7.20–7.13 (m, 2H, Ar-H), 6.54 (s, 1H, -CONH), 3.93 (s, 1H, -OCH3), 3.66 (q, J = 6.4
Hz, 2H, -CONHCH2), 3.52 (t, J = 6.4 Hz, 2H, -CH2Br), 2.24 (quin, J = 6.4 Hz, 2H, -CH2CH2Br).
5.1.13. 3, 5-Dichloro-N-(2-chloroethyl)benzamide (11a). The procedure described for the
preparation of 10a was used with compound 9a (400 mg, 2.09 mmol), thionyl chloride (5 mL),
2-chloroethylamine hydrochloride (365 mg, 3.14 mmol) and triethylamine (TEA; 0.87 mL, 6.27
mmol) to obtain 11a (422 mg, 80%) as white solid. Rf = 0.85 (n-hexane: EtOAc = 1:1). Mp =
135 °C. IR (cm-1): 1634 (C=O). 1H NMR (300 MHz, CDCl3): δ 8.90 (s, 1H, -CONH), 7.87 (d, J
= 1.8 Hz, 2H, Ar-H), 7.83 (t, J = 1.95 Hz, 1H, Ar-H), 3.73 (t, J = 11.7 Hz, -CONH-CH2).
5.1.14 N-(2-Chloroethyl)-1H-indole-2-carboxamide (11b). The procedure described for the
preparation of 10a was used with compound 9b (500mg, 3.10 mmol), thionyl chloride (10 mL)
in presence of THF (10 mL), 2-chloroethylamine hydrochloride (835 mg, 4.65 mmol) and TEA
(1.3 mL, 9.3 mmol) to obtain 11b (345 mg, 50%) as light yellow solid. Rf = 0.74 (n-hexane:
EtOAc = 1:1). Mp = 158 °C. IR (cm-1): 3444 (NH). 1H NMR (300 MHz, CDCl3 ): δ 10.43 (s, 1H,
-NH), 7.65 (dd, J = 8.1, 0.9 Hz, 1H, Ar-H), 7.57 (t, J = 5.4 Hz, 1H, -CONH), 7.41 (m, 1H, Ar-H),
7.31 (m, 1H, Ar-H), 7.24 s, 1H, Ar-H), 7.20 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H, Ar-H), 3.94 (q, J =
5.7 Hz, 2H, -CONH-CH2), 3.78 (t, J = 5.8 Hz, 2H, -CH2Cl).
5.1.15 N-(2-Chloroethyl)benzo(b)furan-2-carboxamide (11c). The procedure described for
the preparation of 10a was used with compound 9c (324 mg, 2 mmol), thionyl chloride (5 mL) in
presence of benzene (10 mL), 2-chloroethylamine hydrochloride (348 mg, 3 mmol) and TEA
(0.83 mL, 6 mmol) to obtain 11c (402 mg, 90%) as white solid. Rf = 0.72 (n-hexane: EtOAc =
1:1). Mp = 115 °C. IR (cm-1): 3691 (NH). 1H NMR (300 MHz, CDCl3): δ 7.69–7.66 (m, 1H, Ar-
H), 7.54–7.49 (m, 2H, Ar-H), 7.46–7.4 (m, 1H, Ar-H), 7.33–7.27 (m, 1H, Ar-H), 7.04 (s, 1H, -
CONH), 3.88–3.82 (m, 2H), 3.78–3.73 (m, 2H).

5.1.16 N-(2-Chloroethyl)benzo[b]thiophene-2-carboxamide (11d). The procedure described
for the preparation of 10a was used with compound 9d (200 mg, 1.12 mmol), thionyl chloride (3
mL) in presence of toluene (5 mL), 2-chloroethylamine hydrochloride (195mg, 1.68 mmol) and
TEA (0.46 mL, 3.36 mmol) to obtain 11d (228 mg, 85%) as white solid. Rf = 0.73 (n-hexane:
EtOAc = 1:1). Mp = 144 °C. IR (cm-1): 3316 (NH). 1H NMR (300 MHz, CDCl3): δ 7.87–7.80 (m,
3H, Ar-H), 7.46–7.37 (m, 2H, Ar-H), 6.62 (s, 1H,-CONH), 3.86–3.80 (m, 2H), 3.77–3.73 (m,
2H).
5.1.17 N-(2-Chloroethyl)-1,2-dihydro-[1,1′-biphenyl]-4-carboxamide (11e). The procedure
described for the preparation of 10a was used with compound 9e (1000 mg, 4.99 mmol), thionyl
chloride (20 mL) in presence of benzene (20 mL), 2-chloroethylamine hydrochloride (867mg,
7.48 mmol and TEA (2 mL, 14.97 mmol) to obtain 11e (718 mg, 55%) as white solid. Rf = 0.61
(n-hexane: EtOAc = 1:1). Mp = 172 °C. 1H NMR (300 MHz, CDCl3): δ 7.89–7.84 (m, 2H, Ar-H),
7.70–7.60 (m, 4H, Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.58 (s, 1H,-CONH), 3.87–3.75 (m, 4H).
5.1.18 N-(2-Chloroethyl)-2,2-diphenylacetamide (11f). The procedure described for the
preparation of 10a was used with compound 9f (530 mg, 2.49 mmol), thionyl chloride (10 mL)
in presence of benzene, 2-chloroethylamine hydrochloride (432mg, 3.73 mmol and TEA (1 mL,
7.47 mmol) to obtain 11f (386 mg, 60%) as light yellow liquid. Rf = 0.82 (n-hexane: EtOAc =
1:1). 1H NMR (300 MHz, CDCl3): δ 7.43–7.33 (m, 11H), 3.73–3.65 (m, 4H).
5.1.19 N-(2-Chloroethyl)-2,2-bis(4-chlorophenyl)acetamide (11g). The procedure described
for the preparation of 10a was used with compound 9g (300 mg, 1.06 mmol), thionyl chloride (5
mL), 2-chloroethylamine hydrochloride (184 mg, 1.59 mmol and TEA (0.44 mL), 3.18 mmol) to
1
obtain 11g (138 mg, 40%) as white solid. Rf = 0.85 (n-hexane: EtOAc = 1:1). Mp = 129 °C. H
NMR (300 MHz, CDCl3): δ 7.48–7.42 (m, 1H, -CONH), 7.37–7.30 (m, ≈ 9H, Ar-H, overlapped
with CHCl3 peak), 3.73–3.64 (m, 4H).
5.1.20 N-(2-Chloroethyl)quinoline-2-carboxamide (11h). The procedure described for the
preparation of 10a was used with compound 9h (200 mg, 1.15 mmol), thionyl chloride (3 mL),
2-chloroethylamine hydrochloride (200 mg, 1.72 mmol and TEA (0.48 mL, 3.45 mmol) to obtain
1
11h (200 mg, 74%) as white solid. Rf = 0.68 (n-hexane: EtOAc = 1:1). Mp = 85 °C. H NMR
(300 MHz, CDCl3): δ 8.65 (s, 1H, -CONH), 8.30 (d, J = 2.1 Hz, 2H, Ar-H), 8.14–8.11 (m, 1H,

Ar-H), 7.8 (dd, J = 8.1, 0.9 Hz, 1H, Ar-H), 7.75 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, Ar-H), 7.62 (ddd,
J = 8.1, 6.9, 1.5 Hz, 1H, Ar-H), 3.93–3.86 (m, 2H), 3.80–3.76 (m, 2H).
5.1.21 N-(2-Chloroethyl)-1-naphthamide (11i). The procedure described for the preparation of
10a was used with compound 9i (600 mg, 3.48 mmol), thionyl chloride (10 mL) in presence of
toluene (10 mL), 2-chloroethylamine hydrochloride (605 mg, 5.22 mmol) and TEA (1.45 ml, 8.7
mmol) to obtain 11i (528 mg (65%) as white solid. Rf = 0.60 (n-hexane: EtOAc = 1:1). Mp =
104 °C. IR (cm-1): 3310(NH). 1H NMR (300 MHz, CDCl3): δ 8.21–8.18 (m, 1H, 1-H), 7.82–7.77
(m, 2H, Ar-H), 7.48–7.44 (m, 3H, Ar-H), 7.32–7.27 (m, 1H, Ar-H), 6.80 (s, 1H,-CONH), 3.68–
3.58 (m, 4H).
5.1.22 N-(2-Chloroethyl)-2-naphthamide (11j). The procedure described for the preparation of
10j was used with compound 9j (320 mg, 1.85 mmol), EDCI.HCl (425 mg, 2.22 mmol), DMAP
(11 mg, 0.01mmol), 2-chloroethylamine hydrochloride (214 mg, 1.85 mmol) and TEA (0.85 mL,
6.10 mmol) to obtain 11j (259 mg, 60%) as white solid. Rf = 0.60 (n-hexane: EtOAc = 1:1). Mp
1
= 138 °C. IR (cm-1): 3058 (NH). H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H, Ar-H), 7.95–7.82
(m, 4H, Ar-H), 7.61–7.52 (m, 2H, Ar-H), 6.71 (s, 1H, -CONH), 3.91–3.77 (m, 4H).
5.1.23 6-Bromo-N-(2-chloroethyl)-2-naphthamide (11k). The procedure described for the
preparation of 10j was used with compound 9k (251 mg, 0.99 mmol), EDCI.HCl (226 mg, 1.18
mmol), DMAP (6 mg, 0.05 mmol), 2-chloroethylamine hydrochloride (115 mg, 0.99 mmol) and
TEA (0.45 mL, 3.26 mmol) to obtain 11k (161 mg, 52%) as white solid. Rf = 0.77 (n-hexane:
EtOAc = 1:1). Mp = 150°C. IR (cm-1): 307 (NH). 1H NMR (300 MHz, CDCl3): δ 8.27 (s, 1H, Ar-
H), 8.04 (s, 1H, Ar-H), 7.88–7.77 (m, 3H, Ar-H), 7.63–7.59 (m, 1H, Ar-H), 6.75 (s, 1H, -CONH),
3.90–3.76 (m, 4H).
5.1.24 N-(2-Chloroethyl)-6-methoxy-2-naphthamide (11l). The procedure described for the
preparation of 10j was used with compound 9l (500 mg, 2.47 mmol), EDCI.HCl (567 mg, 2.96
mmol), DMAP (14.6 mg, 0.12 mmol), 2-chloroethylamine hydrochloride (286 mg, 2.47 mmol)
and TEA (1.1 mL, 8.15 mmol) to obtain 11l (390 mg, 60%) as white solid .Rf = 0.57 (n-hexane:
EtOAc = 1:1). Mp = 133 °C. IR (cm-1): 3657 (NH). 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H,
Ar-H), 7.83–7.76 (m, 3H, Ar-H), 7.22–7.15 (m, 2H, Ar-H), 6.69 (s, 1H, -CONH), 3.94 (s, 1H, -
OCH3), 3.89–3.83 (m, 2H), 3.80–3.76 (m, 2H).

5.1.25 N-(3-(4-Benzylpiperidin-1-yl)propyl)-3, 5-dichlorobenzamide (7a). The mixture of
compound 10a (130 mg, 0.41 mmol), 4-benzylpiperidine (0.15 mL, 0.83 mmol), TEA (0.23 mL,
o
1.67 mmol) and DMSO (1 mL) was stirred at 100 C. After the reaction was completed, the
water was added to the reaction mixture and extracted with ethyl acetate .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 obtain 7a (101 mg,
60%) as white solid. Rf = 0.51 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 105 °C. IR (cm-1):
3311 (NH). 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1H, -CONH), 7.73 (d, J = 2.1Hz, 2-H), 7.51
(t, J = 1.8 Hz, 1H, 4-H), 7.30–7.17 (m, ≈ 6H, Ar-H, overlapped with CHCl3), 3.55 (q, J = 5.2 Hz,
2H, -CONH-CH2), 3.00 (d, J = 11.7 Hz, 2H, -CH2Ph), 2.58–2.52 (m, 4H), 1.85 (t, J = 10.95, 2H,
13
-CH2N), 1.78–1.49 (m, 5H), 1.31–1.18 (m, 2H); C NMR (125 MHz, CDCl3): δ 164.5, 140.6,
138.0, 135.2, 131.0, 129.0, 128.2, 125.9, 125.8, 59.5, 54.3, 42.8, 42.0, 38.1, 32.5, 23.5. HRMS
(ESI): m/z 405.1443 (M+H)+ (calcd for C22H27Cl2N2O, 405.1500).
5.1.26 N-(3-(4-Benzylpiperidin-1-yl)propyl)-1H-indole-2-carboxamide (7b). The procedure
described for the preparation of 7a was used with compound 10b (400 mg, 1.42 mmol), 4-
benzylpiperidine (0.50 mL, 2.84 mmol), TEA (0.79 mL, 5.68 mmol) and DMSO (3 mL) to
obtain 7b (239 mg, 45%) as light yellow solid. Rf = 0.42 (n-hexane: EtOAc: MeOH = 2.5:1.5:1).
1
Mp = 113 °C. IR (cm-1): 3344 (NH). H NMR (300 MHz, CDCl3) ): δ 7.65 (d, J = 8.1 Hz, 1H,
Ar-H), 7.57 (t, J = 5.6 Hz, 1H, -CONH), 7.46 ( d, J = 8.4 Hz, 1H, Ar-H), 7.35–7.08 (m, 9H),
3.65 (q, J = 6.3 Hz, 2H, -CONH-CH2), 2.91 (d, J = 11.7 Hz, 2H, -CH2Ph), 2.51–2.43 (m, 4H),
1.89–1.81 (m, 4H), 1.62–1.45 (m, 3H), 1.36–1.25 (m, 2H); 13C NMR (125 MHz, CDCl3): 160.9,
140.6, 134.6, 129.1, 128.2, 125.8, 125.7, 125.3, 125.9, 121.0, 119.2, 112.7, 105.1, 56.6, 54.1,
43.2, 38.2, 37.9, 31.9, 29.8, 26.3.
5.1.27 N-(3-(4-Benzylpiperidin-1-yl)propyl)benzo(b)furan-2-carboxamide
(7c).
The
procedure described for the preparation of 7a was used with compound 10c (300 mg, 1.06 mmol),
4-benzylpiperidine (0.37 mL, 2.12 mmol), TEA (0.59 mL, 4.24 mmol) and DMSO (2.5 mL) to
obtain 7c (183 mg, 46%) as white solid. Rf = 0.40 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
104 °C. IR (cm-1): 3203 (NH). H NMR (300 MHz, CDCl3): δ 8.71 (s, 1H, -CONH), 7.68–7.65
(m, 1H, Ar-H), 7.55 (dd, J = 8.4, 0.9 Hz, 1H, Ar-H), 7.45–7.38 (m, 2H, Ar-H), 7.31–7.11 (m, ≈
7H, Ar-H, overlapped with CHCl3), 3.58 (q, J = 5.6 Hz, 2H, -CONH-CH2), 2.98 (d, J = 11.7 Hz,

2H, -CH2Ph), 2.60 (d, J = 6.6 Hz, 2H), 2.49 (t, J = 5.8 Hz, 2H, -CH2N), 1.92–1.38 (m, 9H); 13C
NMR (125 MHz, CDCl3): δ 158.8, 154.8, 149.6, 140.6, 129.0, 128.3, 127.8, 126.5, 125.9, 123.6,
122.7, 111.5, 109.9, 58.6, 54.2, 43.3, 40.2, 38.2, 32.3, 24.7. HRMS (ESI): m/z 377.2162 (M+H)+
(calcd for C24H29N2O2, 377.2229).
5.1.28 N-(3-(4-Benzylpiperidin-1-yl)propyl)benzo[b]thiophene-2-carboxamide (7d). The
procedure described for the preparation of 7a was used with compound 10d (310 mg, 1.04
mmol), 4-benzylpiperidine (0.37 mL, 2.08 mmol), TEA (0.58 mL, 4.16 mmol) and DMSO (2.5
mL) to obtain 7d (221 mg, 54%) as white solid. Rf = 0.31 (n-hexane: EtOAc: MeOH = 2.5:1.5:1).
Mp = 111 °C. IR (cm-1): 3225 (NH). 1H NMR (300 MHz, CDCl3): δ 8.75 (s,1H, -CONH), 7.90–
7.81 (m, 3H, Ar-H), 7.46–7.38 (m, 2H, Ar-H), 7.29–7.07 (m, ≈ 6H, Ar-H, overlapped with
CHCl3), 3.57 (q, J = 5.4 Hz, 2H, -CONH-CH2), 3.00 (d, J = 12 Hz, 2H, -CH2Ph), 2.52–2.50 (m,
13
4H), 1.91–1.83 (m, 2H), 1.79–1.72 (m, 2H), 1.69–1.51 (m, 3H), 1.43–1.30 (m, 2H); C NMR
(125 MHz, CDCl3): δ 162.3, 140.8, 140.4, 139.6, 139.2, 129.0, 128.3, 126.1, 125.9, 124.9, 124.8,
122.7, 58.8, 54.2, 43.5, 41.3, 37.8, 32.4, 24.4. HRMS (ESI): m/z 393.1943 (M+H)+ (calcd for
C24H29N2OS, 393.2000).
5.1.29 N-(3-(4-Benzylpiperidin-1-yl)propyl)-[1,1′-biphenyl]-4-carboxamide
(7e).
The
procedure described for the preparation of 7a was used with compound 10e (300 mg, 0.94 mmol),
4-benzylpiperidine (0.33 mL, 1.88 mmol), TEA (0.52 mL, 3.76 mmol) and DMSO (3 mL) to
obtain 7e (213 mg, 55%) as white solid. Rf = 0.28 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
108 °C. IR (cm-1): 3103 (NH). 1H NMR (300 MHz, CDCl3) ): δ 8.62 (s, 1H, -CONH), 7.92–7.88
(m, 2H, Ar-H), 7.67–7.61 (m, 4H, Ar-H), 7.50–7.30 (m, 3H, Ar-H), 7.27–7.08 (m, ≈ 7H, Ar-H,
overlapped with CHCl3), 3.58 (q, J = 5.4 Hz, 2H, -CONH-CH2), 2.99 (d, J = 11.7 Hz, 2H, -
CH2Ph), 2.55–2.52 (m, 4H), 1.92–1.73 (m, 4H), 1.66–1.52 (m, 3H), 1.31–1.25 (m, 2H); 13C
NMR (125 MHz, CDCl3): δ 167.1, 143.9, 140.4, 140.2, 133.9, 129.1, 129.0, 128.3, 128.0, 127.8,
127.2, 127.0, 125.9, 58.7, 54.1, 43.5, 41.0, 37.8, 32.4, 24.6. HRMS (ESI): m/z 413.2527 (M+H)+
(calcd for C28H33N2O, 413.2593).

5.1.30 N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-diphenylacetamide (7f). The procedure
described for the preparation of 7a was used with compound 10f (350 mg, 1.05 mmol), 4-
benzylpiperidine (0.37 mL, 2.1 mmol), TEA (0.58 mL, 4.2 mmol) and DMSO (3 mL) to obtain
°
1
7f (237 mg, 53%) as white solid. Rf = 0.40 (n-hexane: EtOAc = 1:1). Mp = 115 C. H NMR
(300 MHz, CDCl3): δ 7.54–7.01 (m, ≈ 17H, overlapped with CHCl3), 4.79 (s, 1H, -CH), 3.29 (q,
J = 5.7 Hz, 2H, -CONH-CH2), 2.75 (d, J = 10.8 Hz, 2H, -CH2Ph), 2.49 (d, J = 6.6 Hz, 2H), 2.29
13
(t, J = 6.3 Hz, 2H, -CH2N), 1.74 (t, J = 11.1, Hz),1.59–1.43 (m, 5H), 1.14–1.03 (m, 2H); C
NMR (125 MHz, CDCl3): δ 171.8, 140.9, 139.6, 128.9, 128.7, 128.4, 128.0, 126.9, 125.7, 59.0,
57.2, 53.7, 42.9, 39.4, 37.6, 31.9, 25.1.
5.1.31 N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-bis(4-chlorophenyl) acetamide (7g). The
procedure described for the preparation of 7a was used with compound 10g (200 mg, 0.49
mmol), 4-benzylpiperidine (0.17 mL, 0.98 mmol), TEA (0.27 mL, 2.96 mmol) and DMSO (2 mL)
1
to obtain 7g (84 mg, 35%) as light brown liquid. Rf = 0.30, (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 7.64 (t, J = 4.0 Hz, 1H, -CONH), 7.36–7.25 (m, ≈ 7H, Ar-H, overlapped
with CHCl3), 7.20–7.16 (m, 2H, Ar-H), 3.35 (q, J = 5.7Hz, 2H, -CONH-CH2), 2.80 (d, J = 11.7
Hz, 2H, -CH2Ph), 2.51 (d, J = 6.9 Hz, 2H), 2.36 (t, J = 6.1, 2H, -CH2N), 1.83–1.75 (m, 2H),
1.66–1.45 (m, 5H), 1.11–1.02 (m, 2H); 13C NMR (75 MHz, CDCl3): δ170.7, 140.2, 137.9, 133.2,
130.0, 129.1, 128.8, 128.2, 125.9, 57.70, 57.66, 53.8, 43.0, 40.0, 37.7, 32.0, 24.6.
5.1.32 N-(3-(4-Benzylpiperidin-1-yl)propyl)quinoline-2-carboxamide (7h). The procedure
described for the preparation of 7a was used with compound 10h (100 mg, 0.34 mmol), 4-
benzylpiperidine (0.12 mL, 0.68 mmol), TEA (0.19 mL, 1.36 mmol) and DMSO (2 mL) to
obtain 7h (70 mg, 53%) as white solid. Rf = 0.34 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
130 °C. IR (cm-1): 3280 (NH). 1H NMR (300 MHz, CDCl3): δ 8.87 (s, 1H, -CONH), 8.30 (t, J =
9 Hz, 1H, Ar-H), 8.18 (d, J = 8.4 Hz, 2H, Ar-H), 7.88 (d, J = 8.4 Hz, 1H, Ar-H), 7.80–7.75 (m,
1H, Ar-H), 7.61 (t, J = 7.5 Hz, 1H, Ar-H), 7.27–7.08 (m, 5H, Ar-H), 3.62 (q, J = 9.3 Hz, 2H, -
CONH-CH2), 2.97 (d, J = 11.4 Hz, 2H, -CH2Ph), 2.53–2.47 (m, 4H), 1.91–1.64 (M, 4H), 1.60–
13
1.35 (m, 5H); C NMR (125 MHz, CDCl3): δ 164.8, 150.0, 146.5, 140.2, 137.2, 130.0, 129.8,

129.3, 129.0, 128.2, 127.85, 127.75, 125.9, 118.9, 56.8, 53.8, 42.7, 41.0, 38.5, 37.6, 31.1, 29.7,
25.8.
5.1.33 N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-naphthamide (7i). The procedure described for
the preparation of 7a was used with compound 10i (100 mg, 0.34 mmol), 4-benzylpiperidine
(0.12 mL, 0.68 mmol), TEA (0.19 mL, 1.36 mmol) and DMSO (1 mL) to obtain 7i (59 mg, 45%)
1
as white solid. Rf = 0.66 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 125°C. H NMR (300
MHz, CDCl3): δ 8.59 (s, 1H, -CONH), 8.38–8.35 (m, 1H, Ar-H), 7.94–7.86 (m, 2H, Ar-H),
7.64–7.49 (m, 4H, Ar-H), 7.25–7.12 (m, 3H, Ar-H), 6.97–6.95 (m, 2H, Ar-H), 3.63 (q, J = 5.5
Hz, 2H, -CONH-CH2), 2.81 (d, J = 11.4 Hz, 2H, -CH2Ph), 2.47 (t, J = 5.8, 2H), 2.15 (d, J = 5.8
Hz, 2H), 1.79–1.69 (m, 4H), 1.36–1.25 (m, 3H), 0.66–0.53 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 169.4, 140.5, 135.4, 133.7, 130.3, 130.2, 129.0, 128.3, 128.1, 126.9, 126.3, 125.8,
125.7, 125.0, 124.7, 58.3, 53.7, 43.0, 40.8, 37.5,32.0, 29.7, 24.6.
5.1.34 N-(3-(4-Benzylpiperidin-1-yl)propyl)-2-naphthamide (7j). The procedure described
for the preparation of 7a was used with compound 10j (100 mg, 0.52 mmol), 4-benzylpiperidine
(0.19 mL, 1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO (1 mL) to obtain 7j (100 mg,
50%) as white solid. Rf = 0.36 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 118 °C. IR (cm-1):
1
3226 (NH). H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H, -CONH), 8.34 (s, 1H, 1-H), 7.99–7.87
(m, 4H, Ar-H), 7.59–7.53 (m, 2H, Ar-H), 7.26–7.11 (m, 2H, Ar-H, overlapped with CHCl3),
7.03–7.01(m, 2H, Ar-H), 3.62 (q, J = 5.3 Hz, 2H, -CONHCH2), 3.00 (d, J = 11.7 Hz, 2H,-
CH2Ph), 2.55 (t, J = 5.7 Hz, 2H, -CH2N), 2.43 (d, J = 6.9 Hz, 2H), 1.91–1.75 (m, 4H), 1.64–1.49
13
(m, 3H), 1.29–1.17 (m, 2H); C NMR (300 MHz, CDCl3): δ 167.5, 140.4, 134.7, 132.7, 132.6,
129.0, 128.9, 128.23, 128.15, 127.8, 127.4, 127.3, 126.6, 125.9, 124.2, 58.9, 54.1, 43.2, 41.3,
37.8, 32.4, 24.4. HRMS (ESI): m/z 387.2329 (M+H)+ (calcd for C26H31N2O, 387.2436).
5.1.35 N-(3-(4-Benzylpiperidin-1-yl)propyl)-6-bromo-2-naphthamide (7k). The procedure
described for the preparation of 7a was used with compound 10k (120 mg, 0.32 mmol), 4-
benzylpiperidine (0.11 mL, 0.64 mmol), TEA (0.18 mL, 1.28 mmol) and DMSO (1 mL) to
obtain 7k (65 mg, 44%) as white solid. Rf = 0.38 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
100 °C. IR (cm-1): 3286 (NH). H NMR (300 MHz, CDCl3): δ 8.85 (t, J = 4.3 Hz, 1H, -CONH),

8.08 (d, J = 1.8Hz, 1H, Ar-H), 7.94 (d, J = 1.5Hz, 1H, Ar-H), 7.85–7.77 (m, 2H, Ar-H), 7.63 (dd,
J = 8.7 Hz, 1.8 Hz, 1H, Ar-H), 7.29–7.14 (m, ≈ 4H, Ar-H, overlapped with CHCl3), 7.05–7.02
(m, 2H, Ar-H), 3.61 (q, J = 5.4 Hz, 2H, -CONH-CH2), 2.30 (d, J = 11.7 Hz, 2H, -CH2Ph), 2.55 (t,
J = 5.5 Hz, 2H), 2.45 (d, J = 6.9, 2H), 1.91–1.70 (m, 4H), 1.66–1.50 (m, 3H), 1.25–1.17 (m, 2H);
13C NMR (125 MHz, CDCl3): δ167.1, 140.1, 135.6, 132.7, 131.0, 130.4, 130.0, 129.9, 128.9,
128.2, 127.3, 127.2, 125.9, 125.1, 121.6, 58.5, 53.9, 43.0, 40.9, 37.6, 32.0, 24.1. HRMS (ESI):
m/z 465.1505 (M+H)+ (calcd for C26H3079BrN2O, 465.1542), 467.1478 (M+H)+ (calcd for
C26H3081BrN2O, 467.1521).
5.1.36 N-(3-(4-Benzylpiperidin-1-yl)propyl)-6-methoxy-2-naphthamide (7l). The procedure
described for the preparation of 7a was used with compound 10l (200 mg, 0.62 mmol), 4-
benzylpiperidine (0.22 mL, 1.24 mmol), TEA (0.34 mL, 2.48 mmol) and DMSO (2 mL) to
obtain 7l (129 mg, 50%) as brown solid. Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
118 °C. IR (cm-1): 3277 (NH). 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H, CONH), 8.38 (d, J =
1.2Hz, 1H, Ar-H), 8.28 (d, J = 8.7 Hz, 1H, Ar-H),7.98 (dd, J = 9.1, 8.1 Hz, 1H, Ar-H), 7.91 (d, J
= 9.3Hz, 1H, Ar-H), 7.38 (d, J = 9 Hz, 1H, Ar-H), 7.28–7.15 (m, ≈ 5H, Ar-H, overlapped with
CHCl3), 7.07–7.04 (m, 2H, Ar-H), 4.06 (s, 3H, -OCH3), 3.62 (q, J = 5.3 Hz, 2H, -CONH-CH2),
3.01 (d, J = 11.1 Hz, 2H, -CH2Ph), 2.56 (t, J = 5.5 Hz, 2H), 2.47 (d, J = 6.9 Hz, 2H), 1.92–1.75
13
(m, 4H), 1.66–1.48 (m, 3H), 1.30–1.25 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.5, 158.9,
140.4, 136.1, 130.33, 130.28, 129.0, 128.2, 128.0, 127.2, 126.8, 125.9, 124.8, 119.5, 105.7, 58.7,
55.3, 54.0, 43.2, 41.0, 37.8, 32.3, 24.6. HRMS (ESI): m/z 417.2480 (M+H)+ (calcd for
C27H33N2O2, 417.2542).
5.1.37 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-3,5-dichlorobenzamide (8a). The procedure
described for the preparation of 7a was used with compound 11a (100 mg, 0.40 mmol), 4-
benzylpiperidine (0.14 mL, 0.80 mmol) and TEA (0.22 mL, 1.6 mmol) in DMSO (1 mL) to
obtain 8a (101 mg, 60%) as white solid. Rf = 0.61 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
109 °C. H NMR (300 MHz, CDCl3): δ 7.63 (d, J = 1.8 Hz, 2H, Ar-H), 7.48 (t, J = 1.8 Hz, 1H,
Ar-H), 7.30–7.25 (m, ≈ 6H, Ar-H, overlapped with CHCl3), 6.84 (s, 1H, -CONH), 3.49 (q, J =
5.6 Hz, 2H, -CONH-CH2), 2.88 (d, J = 11.7 Hz, 2H,- CH2Ph), 2.56–2.52 (m, 4H),1.97 (ddd, J =
11.7, 2.1 Hz, 2H, -CH2N), 1.69–1.48 (m, 3H), 1.35–1.21 (m, 2H); 13C NMR (125 MHz, CDCl3):
δ 164.9, 140.5, 137.7, 135.3, 131.1, 129.1, 128.2, 125.9, 125.7, 56.6, 53.7, 43.1, 37.9, 36.9, 32.2.

5.1.38 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-1H-indole-2-carboxamide (8b). The procedure
described for the preparation of 7a was used with compound 11b (300 mg, 1.34 mmol), 4-
benzylpiperidine (0.47 mL, 2.68 mmol), TEA (0.74 mL, 5.36 mmol) and DMSO (2 mL) to
obtain 8b (208 mg, 43%) as light yellow solid. Rf = 0.45 (n-hexane: EtOAc: MeOH = 2.5:1.5:1).
Mp = 169 °C. 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 7.2, 1H, Ar-H), 7.46–7.43 (m, 1H, Ar-
H). 7.30–7.10 (m, ≈ 10H, Ar-H, overlapped with CHCl3), 7.03 (s, J = 4.5 Hz, 1H, -CONH), 6.84
(d, J = 1.2Hz, 1H, Ar-H), 3.5 (q, J = 5.7 Hz, 2H, -CONH-CH2), 2.92 (d, J = 11.7, 2H, -CH2Ph),
2.62–2.48 (m, 4H), 2.02–1.94 (m, 2H), 1.69–1.51 (m, 3H), 1.38–1.30 (m, 2H); 13C NMR (75
MHz, CDCl3): δ 161.8, 140.4, 136.3, 130.9, 129.0, 128.2, 127.6, 125.9, 124.2, 121.8, 120.4,
112.0, 102.3, 56.8, 53.6, 43.0, 37.8, 36.1, 31.9.
5.1.39 N-(2-(4-Benzylpiperidin-1-yl)ethyl)benzo(b)furan-2-carboxamide (8c). The procedure
described for the preparation of 7a was used with compound 11c (400 mg, 1.78 mmol), 4-
benzylpiperidine (0.63 mL, 3.56 mmol), TEA (1.0 mL, 7.12 mmol) and DMSO (3 mL) to obtain
8c (342 mg, 53%) as white solid .Rf = 0.45 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 125 °C.
1H NMR (300 MHz, CDCl3): δ 7.67 (ddd, 7.8, 1.2, 0.6 Hz, 1H), 7.54–7.51 (m, 1H), 7.44-7.38 (m,
2H), 7.31–7.14 (m, ≈ 8H, overlapped with CHCl3), 3.55 (q, J = 5.8 Hz, 2H, -CONH-CH2), 2.91
(d, J = 11.7 Hz, 2H, -CH2Ph), 2.58–2.55 (m, 4H), 2.02–1.93 (m, 2H), 1.68–1.48 (m, 3H), 1.39–
13
1.30 (m, 2H); C NMR (125 MHz, CDCl3): δ 158.9, 154.8, 149.1, 140.6, 129.1, 128.2, 127.7,
126.7, 125.8, 123.6, 122.6, 111.8, 110.1, 56.8, 53.8, 43.2, 37.9, 36.3, 32.3.
5.1.40 N-(2-(4-Benzylpiperidin-1-yl)ethyl)benzo[b]thiophene-2-carboxamide (8d). The
procedure described for the preparation of 7a was used with compound 11d (250 mg, 1.04
mmol), 4-benzylpiperidine (0.37 mL, 2.08 mmol), TEA (0.58 mL, 4.16 mmol) and DMSO (2 mL)
to obtain 8d (204 mg, 52%) as white solid. Rf = 0.45 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp
1
= 117 °C. H NMR (300 MHz, CDCl3): δ 7.84–7.77 (m, 3H, Ar-H), 7.42–7.11 (m, ≈ 8H, Ar-H,
overlapped with CHCl3), 7.08 (s, 1H, -CONH), 3.51 (q, J = 5.7 Hz, 2H, -CONH-CH2), 2.88 (d, J
= 11.7 Hz, 2H, -CH2Ph), 2.52–2.51 (m, 4H), 1.99–1.91 (m, 2H), 1.67–1.48 (m, 3H), 1.35–1.26
(m, 2H); 13C NMR (125 MHz, CDCl3): δ 162.3, 140.8, 140.5, 139.2, 138.8, 129.1, 128.2, 126.2,
125.9, 125.1, 125.0, 124.8, 122.7, 56.8, 53.6, 43.1, 37.9, 36.7, 32.3.

5.1.41 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-[1,1′-biphenyl]-4-carboxamide
(8e).
The
procedure described for the preparation of 7a was used with compound 11e (250 mg, 0.96 mmol),
4-benzylpiperidine (0.34 mL, 1.92 mmol), TEA (0.53 mL, 3.84 mmol) and DMSO (2 mL) to
obtain 8e (191 mg, 50%) as white solid. Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
148 °C. IR (cm-1): 3027(NH). H NMR (300 MHz, CDCl3): δ 7.87–7.84 (m, 2H, Ar-H), 7.68–
7.39 (m, 4H, Ar-H), 7.49–7.35(m, 3H, Ar-H), 7.31–7.16 (m, ≈ 6H, Ar-H, overlapped with
CHCl3), 7.02 (s, 1H, -CONH), 3.54 (q, J = 5.6 Hz, 2H, -CONH-CH2), 2.90 (d, J = 11.7, 2H, -
CH2Ph), 2.59–2.51 (m, 6H), 2.10–1.93 (m, 2H), 1.68–1.51 (m, 3H), 1.35–1.24 (m, 2H); 13C
NMR (125 MHz, CDCl3): δ 167.2, 144.0, 140.6, 140.1, 133.5, 129.2, 129.0, 128.3, 128.0, 127.7,
127.20, 127.15, 125.9, 56.9, 53.7, 43.2, 37.9, 36.9, 32.4. HRMS (ESI): m/z 399.2386 (M+H)+
(calcd for C27H31N2O, 399.2436).
5.1.42 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-diphenylacetamide (8f). The procedure
described for the preparation of 7a was used with compound 11f (150 mg, 0.54 mmol), 4-
benzylpiperidine (0.19 mL, 1.08 mmol), TEA (0.30 mL, 2.16 mmol) and DMSO (2 mL) to
1
obtain 8f (111 mg, 50%) as light brown liquid. Rf = 0.31 (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 7.45–7.42 (m, 1H, Ar-H), 7.29–7.20 (m, 12H, Ar-H overlapped with
CHCl3), 7.10–7.08 (m, 3H, Ar-H), 6.51 (s, 1H, -CONH), 3.30–3.23 (m, 2H), 2.62 (d, J = 11.1 Hz,
2H, -CH2Ph), 2.46 (d, J = 6.9 Hz, 2H), 2.29 (t, J = 6.15, 2H), 1.78 (t, J = 10.8 Hz, 2H), 1.51–1.38
13
(m, 3H), 1.10–0.95 (m, 2H); C NMR (125 MHz, CDCl3): δ 171.8, 140.5, 139.7, 129.1, 129.0,
128.7, 128.4, 128.2, 127.9, 127.6, 127.1, 125.9, 59.2, 56.2, 53.4, 43.2, 37.7, 36.4, 32.0.
5.1.43 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-bis(4-chlorophenyl)acetamide
(8g). The
procedure described for the preparation of 7a was used with compound 11g (180 mg, 0.52
mmol), 4-benzylpiperidine (0.18 mL, 1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO (2 mL)
1
to obtain 8g (82 mg, 33%) as white solid. Rf = 0.35 (n-hexane: EtOAc = 1:1). Mp = 107 °C. H
NMR (300 MHz, CDCl3): δ 7.29–7.24 (m, 6H, Ar-H), 7.18–7.12 (m, 7H, Ar-H), 6.50 (s, 1H, -
CONH), 4.83 (s, 1H, -CH), 3.28 (q, J = 5.5 Hz, 2H, CONH-CH2), 2.64 (d, J = 11.4 Hz, 2H, -
CH2Ph), 2.50 (d, J = 6.9 Hz, 2H), 2.33 (t, J = 5.8 Hz, 2H, -CH2N), 1.81 (t, J = 10.8 Hz, 2H),

1.55–1.37 (m, 3H), 1.04–0.95 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.0, 160.8, 140.6,
137.9, 133.3, 130.3, 129.1, 128.9, 128.2, 125.9, 57.1, 56.1, 53.4, 43.2, 37.8, 36.4, 32.2.
5.1.44 N-(2-(4-Benzylpiperidin-1-yl)ethyl)quinoline-2-carboxamide (8h). The procedure
described for the preparation of 7a was used with compound 11h (100 mg, 0.43 mmol), 4-
benzylpiperidine (0.15 mL, 0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO (2 mL) to
obtain 8h (112 mg, 55%) as white solid. Rf = 0.78 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
86 °C. H NMR (300 MHz, CDCl3): δ 8.58 (t, J = 4.8 Hz, 1H, -CONH), 8.23–8.26 (m, 2H, Ar-
H), 8.10 (d, J = 8.7 Hz, 1H, 5-H), 7.85 (d, J = 8.1 Hz, 1H, 3-H), 7.79–7.73 (m, 1H, Ar-H), 7.63–
7.57 (m, 1H, Ar-H), 7.30–7.14 (m, ≈ 6H, Ar-H, overlapped with CHCl3), 3.62 (q, J = 6.20 Hz,
2H, CONH-CH2), 2.96 (d, J = 11.4 Hz, 2H, -CH2Ph), 2.62 (t, J = 6.4Hz, 2H), 2.56 (d, J = 6.9Hz,
2H), 2.04–1.96 (m, 2H), 1.68–1.49 (m, 3H), 1.41–1.30 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
164.4, 149.9, 146.4, 140.6, 137.3, 129.9, 129.7, 129.2, 129.0, 128.1, 127.7, 127.6, 125.7, 118.8,
57.1, 53.8, 43.1, 37.9, 36.6, 32.2. HRMS (ESI): m/z 374.2221 (M+H)+ (calcd for C24H28N3O,
374.2232).
5.1.45 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-1-naphthamide (8i). The procedure described for
the preparation of 7a was used with compound 11i (100 mg, 0.43 mmol), 4-benzylpiperidine
(0.15 mL, 0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO (1 mL) to obtain 8i (69 mg, 43%)
as brown solid. Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 80 °C. 1H NMR (300
MHz, CDCl3): δ 8.37–8.32 (m, 1H, Ar-H), 7.93–7.85 (m, 2H, Ar-H), 7.61 (dd, J = 7.2, 1.2 Hz,
1H, Ar-H), 7.56–7.4 (m, 3H, Ar-H), 7.29–7.10 (m, ≈ 6H, Ar-H, overlapped with CHCl3), 6.60 (s,
1H,-CONH), 3.61 (q, J = 5.7 Hz, 2H, -CONH-CH2), 2.89 (d, J = 11.4 Hz, 2H, -CH2Ph), 2.57 (t, J
= 6 Hz, 2H), 2.50 (d, J = 6.9 Hz, 2H), 2.00–1.91 (m, 2H), 1.65–1.49 (m, 3H), 1.29–1.20 (m, 2H);
13C NMR (125 MHz, CDCl3): δ 169.5, 140.5, 134.7, 133.7, 130.4, 130.2, 129.1, 128.3, 128.2,
127.0, 126.3, 125.9, 125.5, 125.1, 124.8, 56.8, 53.7, 43.1, 37.9, 36.8, 32.1, 29.7.
5.1.46 N-(2-(4-Benzylpiperidin-1-yl) ethyl)-2-naphthamide (8j). The procedure described for
the preparation of 7a was used with compound 11j (100 mg, 0.43 mmol), 4-benzylpiperidine
(0.15 mL, 0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO (1 mL) to obtain 8j (77 mg, 48%)
1
as white solid. Rf = 0.72 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 110 °C. H NMR (300

MHz, CDCl3): δ 8.30 (s, 1H, Ar-H), 7.95–7.81 (m, 4H, Ar-H), 7.59–7.52 (m, 2H, Ar-H), 7.30–
7.25 (m, ≈ 3H, Ar-H, overlapped with CHCl3), 7.21–7.13 (m, 3H, Ar-H), 3.58 (q, J = 5.6 Hz, 2H,
-CONH-CH2), 2.93 (d, J = 11.7, 2H, -CH2Ph), 2.62–2.54 (m, 4H), 2.04–1.96 (m, 2H,-CH2N),
13
1.70–1.50 ((m, 3H), 1.37–1.28 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.5, 140.6, 134.7,
132.7, 132.0, 129.1, 129.0, 128.4, 128.2, 127.7, 127.5, 126.7, 125.9, 123.7, 56.8, 53.7, 43.2, 37.9,
36.9, 32.3.
5.1.47 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-6-bromo-2-naphthamide (8k). The procedure
described for the preparation of 7a was used with compound 11k (100 mg, 0.32 mmol), 4-
benzylpiperidine (0.11 mL, 0.64 mmol), TEA (0.18 mL, 1.28 mmol) and DMSO (1 mL) to
obtain 8k (60 mg, 42%) as white solid. Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
151 °C. 1H NMR (300 MHz, CDCl3): δ 8.28 (s, 1H, Ar-H), 8.04 (d, J = 1.8 Hz, 1H, Ar-H), 7.87–
7.78 (m, 3H, Ar-H), 7.30–7.13 (m, ≈ 7H, overlapped with CHCl3), 3.58 (q, J = 5.5 Hz, 2H, -
CONH-CH2), 2.94 (d, J = 11.7 Hz, 2H, -CH2Ph), 2.62–2.54 (m, 4H), 2.05–1.96 (m, 2H), 1.70–
13
1.51 (m, 3H), 1.38–1.28 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.3, 139.9, 135.6, 131.8,
131.0, 130.7, 130.0, 129.7, 129.0, 128.3, 127.8, 127.3, 126.1, 124.9, 121.8, 57.0, 53.6, 42.7, 37.2,
36.2, 31.0.
5.1.48 N-(2-(4-Benzylpiperidin-1-yl)ethyl)-6-methoxy-2-naphthamide (8l). The procedure
described for the preparation of 7a was used with compound 11l (350 mg, 1.33 mmol), 4-
benzylpiperidine (0.47 mL, 2.66 mmol), TEA (0.74 mL, 5.32 mmol) and DMSO (3 mL) to
obtain 8l (256 mg, 48%) as white solid. Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp =
1
155 °C. H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H, 1-H), 7.83–7.74 (m, 3H, Ar-H), 7.30–7.12
(m, ≈ 8H, Ar-H, overlapped with CHCl3), 7.06 (t, J = 4.2 Hz, 1H, -CONH), 3.92 (s, 1H, -OCH3),
3.56 (q, J = 5.6 Hz, 2H, -CONH-CH2), 2.91 (d, J = 11.4 Hz, 2H, -CH2Ph), 2.59–2.53 (m, 4H),
2.01–1.92 (m, 2H), 1.68–1.48 (m, 3H), 1.36–1.27 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
167.5, 159.0, 140.5, 136.2, 130.5, 129.7, 129.1, 128.2, 128.1, 127.3, 127.0, 125.9, 124.2, 119.6,
105.6, 56.8, 55.4, 53.7, 43.1, 37.9, 36.6, 32.2.
6. Neurotransmitter uptake assay
Human embryonic kidney 293 (HEK-293) cells were subcultured in fetal bovine serum (FBS) in
a 100 mm x 20 mm polystyrene dish (Corning, Corning, NY, USA) and incubated in a

humidified 5% CO2 incubator at 37 °C (Sanyo Electric Biomedical, Osaka, Japan) for 48 hr.
When the confluency was 60–70%, the cells were transfected with human serotonin transporter
(hSERT) and human norepinephrine transporter (hNET) (cDNA: 3 µg/100 mm dish, PEI: 10 µL)
and maintained in a humidified 5% CO2 incubator at 37 °C for 24 hr. The prepared HEK293
cells were subseeded in 24-well plates (poly-L-lysine coated, clear flat-bottomed, round well
shaped, volume 3.4 mL; Corning) and incubated for 24 hr. The medium was removed and cells
were washed once with 200 µL of uptake buffer/well prior to the addition of 180 µL of uptake
buffer (5 mM Tris base, 7.5 mM HEPES, 120 mM NaCl, 5.4 mM KCl, 1.2 mM CaCl2, 1.2 mM
MgSO4, 1 mM ascorbic acid and 5 mM glucose; pH 7.1) to every wells followed by addition of
drugs/compound under test dissolved in 20 µL uptake buffer. The 24-well plates were incubated
3
at 37 °C in a slide warmer for 15–20 min. After 15 min, 100 µL of the radiolabeled 60 nM H-
SERT (PerkinElmer, Waltham, MA, USA) or 60 nM 3H-NET (PerkinElmer) per well was added
(final concentration/well, 20 nM) and incubated for about 5 min at 37 °C using a slide warmer
(Fisher, Pittsburgh, PA, USA). Prepared cells were washed three times with ice cold uptake
buffer (200 µL/ well). Cell lysis was done by 0.3 mL of 1% sodium dodecyl sulfate per well with
shaking in a KMC-1205S shaker (Vision Scientific, Daejeon, South Korea) for about 2 hr.
Radioactivity was measured using a Wallac 1450 MicroBeta® TriLux liquid scintillation counter
(PerkinElmer). Venlafaxine hydrochloride was used as a standard dual (5-HT and NA) reuptake
inhibitor and GBR 12909 was used as the standard NA reuptake inhibitor.
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 KM Kim was funded by KRF- 2014R1A2A2A01002547. The authors
would like to thank the Korea basic science institute Gwangju center for performing the 1H NMR
and 13C NMR.
References and notes
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Graphical Abstract
Design and synthesis of 4-benzylpiperidine
carboxamides as dual serotonin and
norepinephrine reuptake inhibitors
Suresh Paudela, Yongkai Caoa, Shuohan Guoa, Byeongkwan Anb, Kyeong-Man Kima*, Seung Hoon Cheona*
aCollege of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju
61186, Republic of Korea
bJeonnam Development Institute for Korean Traditional Medicine 288, Udeuraendeu-gil, Anyang-myeon,
Jangheung-gun, Jeollanam-do, 59338, Republic of Korea
7e
7j
IC50 (nM):
IC50 (nM):
56 (5-HT), 153 (NE)
108 (5-HT), 342 (NE)