Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype

Article abstract of DOI:10.1016/j.ejmech.2015.07.047

A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC₅₀ values ～ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.

Full text of DOI:10.1016/j.ejmech.2015.07.047

Accepted Manuscript
Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype
Sofia A. Santos, Amanda K. Lukens, Lis Coelho, Fátima Nogueira, Dyann F. Wirth,
Ralph Mazitschek, Rui Moreira, Alexandra Paulo
PII:
S0223-5234(15)30179-3
10.1016/j.ejmech.2015.07.047
EJMECH 8031
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 3 March 2015
Revised Date: 24 July 2015
Accepted Date: 28 July 2015
Please cite this article as: S.A. Santos, A.K. Lukens, L. Coelho, F. Nogueira, D.F. Wirth, R. Mazitschek,
R. Moreira, A. Paulo, Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial
chemotype, European Journal of Medicinal Chemistry (2015), doi: 10.1016/j.ejmech.2015.07.047.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
a, b
c, d
e
e
c, d
Sofia A. Santos , Amanda K. Lukens , Lis Coelho , Fátima Nogueira , Dyann F. Wirth
,
b, c, d
a
a
Ralph Mazitschek
, Rui Moreira , Alexandra Paulo *
a
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor
Gama Pinto, 1640-003, Lisbon, Portugal
b
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
c
The Broad Institute, Infectious Diseases Initiative, Cambridge, MA 02142, USA
d
Harvard School of Public Health, Department of Immunology and Infectious Disease, Boston, MA 02115, USA
e
UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira,
1
00, P-1349-008 Lisboa, Portugal.
Title:
EXPLORING THE 3-PIPERIDIN-4-YL-1H-INDOLE SCAFFOLD AS A NOVEL
ANTIMALARIAL CHEMOTYPE
Abstract:
A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a
hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight
compounds were obtained following a three-step synthetic approach and evaluated for anti-
parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-
piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with
lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-
resistant and sensitive strains (EC50 values ∼ 3 µM), selectivity for malaria parasite and no cross-
resistance with chloroquine, thus representing a potential new chemotype for further optimization
towards novel and affordable antimalarial drugs.
Keywords: antimalarial, drug lead, indole, reagent-based diversity
1
. Introduction:
Malaria is one of the most life-threatening diseases, with almost one-third of the world’s population
at risk it represents a major public health problem due to its morbidity and mortality.[1, 2] An estimated
98 million cases led to nearly 584,000 deaths in 2013, 90% of which were reported in sub-Saharan
1
Africa.[1] Malaria has a broad impact throughout tropical and subtropical areas of the globe, affecting
indigenous populations as well as an increasing number of travelers [3-5]. According to the 2014 World
Health Organization (WHO) Malaria Report, about 78% of deaths attributed to malaria occur in African

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children under age of 5 [1]. In addition to the human cost of malaria, the economic burden of the disease
is significant with a huge impact upon individual households due to lost wages and healthcare costs as
well as detrimental affect on the national scale with about 40% of African health budgets spent on
malaria every year [6].
Five Plasmodium species are known to infect humans and cause malaria: P. vivax, P. ovale, P.
malariae, P. knowlesi and P. falciparum [7]. Of these species, P. falciparum is the most widespread in
nearly all malaria endemic countries and is responsible for the majority of malaria mortality.[8]. The
parasite has a complex life cycle, which involves alternate developmental stages within the human host
and the female Anopheles mosquito [2, 9]. Within the human host, the asexual erythrocytic stage of the
infection accounts for the clinical symptoms and constitutes the target for most chemotherapeutics used
in the clinic, such as chloroquine (1) (Figure 1) and artemisin combination therapies (ACTs) [9-11].
The emergence of drug resistance has already rendered once-effective malaria treatments less
reliable. Today, ACTs are the front line therapies for treatment of symptomatic malaria, however, we are
at risk of losing their utility due to the emergence and spread of resistance [12-14]. The Plasmodium
parasite has demonstrated an ability to evolve and adapt to every drug introduced thus far, and with this
in mind, it is crucial that efforts are made to develop new analogues active against resistant strains, to
identify new drugs, or even identify new therapeutic targets in the parasite [11, 15].
The strategies currently used for the development of novel antimalarial drugs include many
approaches such as: the discovery of new active molecules from natural sources [16-23], repurposing of
commercially available drugs, the development of hybrid compounds [24], and rational drug design with
chemical modifications of existing antimalarials and hits [25-27], amongst others. Also, a great number
of drug discovery and development programs from both public and private institutions, and public-
private partnerships, using phenotypic screening with sensitive and resistant strains of P. falciparum
have been pursued in the past recent years. Among them were large libraries from Novartis, St. Jude
Children’s Research Hospital and GlaxoSmithKline (GSK) [28, 29].
Joining these international efforts, we analyzed the recently disclosed Tres Cantos Antimalarial Set
(TCAMS) from GSK to identify novel indole-based antimalarials as starting points for the development
of next –generation antimalarial drugs. Indoles are an emerging antimalarial fragment present in several
lead drug candidates with new mechanisms of action, such as the spiroindolone (2) [30-34] and
aminoindoles classes [33, 35]. We were intrigued by TCMDC-134281 (3) (Figure 1), which emerged as
a very potent antiplasmodial compound, with a reported EC50 of 34 nM against the chloroquine-sensitive

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P. falciparum 3D7 strain. Additionally, compound 3 did not demonstrate measurable cytotoxicity as its
EC against the human HepG2 hepatoma cell line was greater than 10 µM [28].
50
However, this compound showed poor drug-like properties and cross-resistance with
chloroquine, possibly due to the presence of the 4-aminoquinolinyl fragment, which is the
essential pharmacophore of chloroquine (CQ). To address these liabilities, we decided to remove
one of the piperidin-4-yl fragments and to replace the 4-aminoquinoline fragment. This resulted
in an overall reduction of the compound’s LogP and MW and chemically differentiates the
molecule from the 4-aminoquinoline antimalarials, which we hypothesized would overcome the
observed cross-resistance with CQ. We herein report a structure-activity study aiming to explore
the antimalarial potential of the 3-piperidin-4-yl-1H-indole scaffold (Figure 1). We synthesized
three series of derivatives following a reagent-based diversity approach, in a total of 38
compounds, and assayed them against the multidrug resistant P. falciparum Dd2 strain at a fixed
5
µM concentration. The most potent derivatives were further profiled in dose-response against
both P. falciparum drug-resistant (Dd2) and sensitive (3D7) strains to determine activity and
parasite selectivity.
2
. Results and Discussion:
.1. Chemistry
We first resynthesized the original hit compound 3, following a six-step synthesis, as shown
2
in scheme 1. Starting with the condensation of the indole with N-benzyl-4-piperidone in the
presence of a base, compound 4 was obtained in high yield (98%). Subsequent debenzylation
with concurrent olefin reduction afforded the common intermediate 3-piperidin-4-yl-1H-indole
(5) with 96% yield. Compound 5 was coupled with 1-(tert-butoxycarbonyl)piperidine-4-
carboxylic acid to give the amide intermediate 6 in moderate yield (60%). Reduction of the
carbonyl group afforded compound 7, followed by Boc-deprotection to yield the amine
compound 8. Compound 3 was obtained by nucleophilic aromatic substitution of 4,6-
dichloroquinoline with the amine intermediate 8 (Scheme 1).
The first series of derivatives was designed to explore the structure-activity relationship
(SAR) of N-piperidinyl modifications. These compounds were obtained by reductive

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amination[36] of the amine intermediate 5 with the corresponding aldehydes to give the title
compounds 9a-s (Scheme 2), with yields ranging from 25%-100% (Table 1). All but two
derivatives from this series were obtained using commercially available aldehydes. Aldehydes A
and B, used in the synthesis of compounds 9o and 9n, were previously obtained by reductive
amination of terephthalaldehyde with piperidine or morpholine, respectively (Scheme 2).
We next synthesized a series of amide derivatives to assess the importance of the basic
amine versus an amide linkage and resulting rotational hindrance. These compounds were
synthesized by coupling the amine intermediate 5 with commercially available acid chlorides
under standard Schotten Baumann conditions to afford the desired compounds 10a-f (Scheme 2),
in 25% to quantitative (Quant.) yields (Table 1). To access the derivatives 10g-j (Scheme 2) in
high yields we screened several coupling reagents and found PyBOP to give the best results
(Table 1). Analogue 10j, which consisted of the bis-amide compound with a benzyl linker, was
synthesized by reacting excess of the amine intermediate 5 with terephthalic acid using PyBOP
coupling conditions, with quantitative yield (Scheme 2; Table 1). Next we examined the
importance of the 4-aminoquinoline fragment, the essential pharmacophore of chloroquinoline.
We synthesized derivative 11, which was obtained through a nucleophilic substitution between
4
,6-dichloroquinoline and the amine intermediate 5 (Scheme 2; Table 1).
As a part of our SAR studies an additional series of derivatives was designed in order to
maintain both the second piperidinyl group, as well as the amide linkages, while exploring the
chemical variation at the terminal piperidinyl fragment. To synthesize this set of analogues the
intermediate compound 6 was Boc-deprotected, followed by acylation of the free amine 12 with
commercially available acid chlorides using standard Schotten Baumann conditions to obtain the
desired compounds 13a-f (Scheme 3), in 25% to quantitative yields (Table 1).
All synthesized compounds were purified by flash chromatography and the purity was
assessed with HPLC-ELSD-MS prior to profiling for antiparasitic activity (purity was >90%).
1
13
The structures of all compounds were confirmed by NMR spectroscopy using H-NMR, C-
1
1
NMR and twodimensional experiments, including H- H COSY, HMQC and HMBC (see details
in Methods).

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2
.2. In vitro antimalarial activity
The synthesized derivatives were first evaluated at 5 µM fixed concentration for their growth
inhibitory activity against the erythrocytic stage of the CQ-resistant P. falciparum strain Dd2
(Table 1). Lipophilicity of the synthesized indole compounds, expressed in terms of their
partition coefficient values (clog P), molecular weight in g/mol and violations of Lipinski's rule
of 5 (Ro5) were calculated in Instant JChem (Chemaxon) and considered as a preliminary test of
the drug-likeness of the compounds (Table 1).
Table 1: Final step yield of synthesized compounds, their drug-like properties (MW, cLogP and
compliance with “Lipinski’s Rule of 5”) and results from antimalarial activity screening.
%
5µM
P. falciparum Dd2
Inhibition at
Yield MW
%) (g/mol)
Ro5
(≤2 violations)
Compound
R
cLogP
(
3
5
8
-
-
-
15
96
459.03 5.70
200.28 2.18
Yes
Yes
Yes
100
<10
< 10
Quant. 297.44 2.66
O
7
9
N
9
a
400.52 3.41
Yes
<10
N
N
O
9
b
76
371.47 3.70
Yes
70
N
9
9
c
99
55
357.45 3.98
346.49 5.16
Yes
Yes
<10
16
HO
S
d
9
9
e
f
53
55
290.40 4.28
304.43 4.80
Yes
Yes
15
11
O
9
9
9
g
h
i
42
99
60
366.45 3.47
350.45 3.44
419.34 5.18
Yes
Yes
Yes
<10
<10
<10
OH
O
O
OH
Cl
O
F
Cl
O
9
9
9
j
72
69
25
308.39 4.43
358.40 5.16
318.41 4.00
Yes
Yes
Yes
14
F
k
l
F
<10
20
F
O
NH
9
m
30
502.69 6.60
Yes
100
N

ACCEPTED MANUSCRIPT
9
9
9
n
o
p
O
38
54
389.53 4.01
387.56 5.08
Yes
Yes
Yes
66
N
N
100
<10
N
97
65
291.39 3.07
296.43 4.20
9
9
q
r
Yes
Yes
<10
<10
S
Quant. 296.45 4.67
9
1
s
98
55
340.55 5.10
304.39 3.64
Yes
Yes
17
0a
<10
O
O
1
0b
Quant. 364.44 3.33
Yes
<10
1
1
0c
95
25
322.38 3.78
305.37 2.42
Yes
Yes
<10
100
F
0d
N
Yes
1
1
1
0e
0f
66
73
60
310.41 3.55
242.32 1.79
305.37 2.42
<10
<10
14
S
CH3
Yes
Yes
0g
N
Yes
Yes
1
1
0h
0i
95
305.37 2.81
<10
<10
N
N
Quant. 306.36 1.59
N
NH
1
0j
Quant. 530.66 5.31
Yes
80
N
O
1
1
1
-
25
80
361.87 5.21
415.53 3.35
Yes
Yes
32
3a
<10
O
Yes
1
3b
75
475.58 3.04
10
O
Yes
Yes
1
1
3c
75
10
433.52 3.50
416.52 2.14
<10
30
F
3d
N
Yes
Yes
1
1
3e
3f
73
40
415.53 3.35
475.58 3.04
<10
10
S
CH3
Compounds inhibiting more than 95% of parasite growth at 5µM concentration were further
profiled for dose-response to determine half maximal effective concentrations (EC ) against
5
0
CQ-resistant Dd2 and CQ-sensitive 3D7. The reference antimalarials chloroquine, atovaquone,
amodiaquine and artesunate were included as controls and resulted in EC s in agreement with
5
0
published results. The original hit molecule 3 and its simplified derivative 11 were also tested
for comparison to the newly synthesized compounds (Table 2). Cytotoxicity (EC50) of selected

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compounds for human cells (HepG2) and selectivity index for CQ-resistant Dd2 (SIres) and CQ-
sensitive 3D7 strains (SI ) are reported in Table 2.
sen
Table 2: In vitro antimalarial activity (EC ) and cytotoxicity (EC ) of selected compounds.
50
50
P. falciparum
HepG2
EC (µM) ±SD
Selectivity Index
Compound
3
EC ( M) ±SD
ꢀ
0
5
50
a
b
Dd2
3D7
SIres
SIsen
0.94±0.51
0.21±0.05
2.91±0.35
2.95±0.30
5.01±1.50
0.24±0.08
0.08±0.03
1.35±0.45
3.80±0.50
6.30±1.50
3.86±0.50
0.46±0.03
n.d.
4.10
2.19
n.d.
4.33
0.85
n.d.
n.d.
n.d.
n.d.
16.08
5.75
n.d.
9
9
1
1
m
o
0d
1
12.80±0.28
4.24±0.21
n.d.
3.37
0.67
n.d.
c
c
Chloroquine
Atovaquone
285±58
23±1
c
c
c
c
0.19±0.06
0.35±0.14
5.85±2.20
1.97±0.29
n.d.
n.d.
c
Amodiaquine 12.30±4.21
n.d.
n.d.
c
Artesunate
1.76±0.43
n.d.
n.d.
a
b
c
SI = EC HepG2 / IC PfDd2; SI = EC HepG2 / EC Pf3D7; n.d.= not determined; EC
res
50
50
sen
50
50
50
values in nM; n.d.= not determined.
The hit compound 3 was resynthesized and tested against the Dd2 and 3D7 strains and
exhibited an EC of 0.94 ꢀM (Dd2) and 0.24 µM (3D7), which confirmed the previously
50
observed cross-resistance with CQ (resistance index (RI) calculated as EC50 Dd2/EC50 3D7 = 4).
Interestingly, we found significantly decreased activity for this compound in our assay compared
to that reported (EC 3D7 = 0.03 ꢀM) [28]. This discrepancy in activities could be the
5
0
consequence of different assays conditions, or possibly the result of inaccurate compound assay
concentration, or presence of a biological active contaminent in the original HTS assay plates.
In a first approach to determine the requirement of each fragment of hit 3 for its antimalarial
activity, we tested intermediates 5 and 8, and concluded that the 4-amino-chloroquinoline moiety
is essential for activity. Next, we investigated the requirement of the distal piperidinyl fragment

ACCEPTED MANUSCRIPT
for the antimalarial activity of 3. Removal of this fragment leads to a compound (11), which had
substantially decreased antimalarial activity when compared to compound 3 (Tables 1 and 2).
We then further explored the 3-piperidin-4-yl-1H-indole scaffold. The effect of chemically
diverse substituents linked to the N-piperidinyl group was investigated within the first series of
amine derivatives (9a-s). Various aromatic fragments, including bicyclic (9a-d), monocyclic (9e-
l) and mono heterocyclic (9p-q), as well as alkyl fragments (9r-s) were introduced in place of the
4
-aminoquinoline. The results indicate that, with the exception of the N-acyl indole fragment
(9b), none of the smaller fragments tested lead to compounds with anti-parasitic activity.
However, the introduction of a second 3-piperidin-4-yl-1H-indole group linked through the p-
position of the benzyl ring afforded a compound (9m) with significant antimalarial activity
against both Dd2 and 3D7 strains of P. falciparum (EC50s of 0.21 and 0.08 ꢀM, respectively).
Due to the increased lipophilic properties of 9m, simplification of the latter benzyl substitution
was investigated. The introduction of a basic piperidine group resulted in a compound (9o) with
some antimalarial activity against both strains of P. falciparum (Dd2 EC50 = 2.91 and 3D7 EC50
=
1.35 ꢀM), whereas the introduction of a less basic morpholine group decreases the activity
(9n). Overall, the results indicate that in the amine series the antimalarial activity depends mostly
on lipophilicity and the basic characteristics of the compounds, which may be a nonspecific
antiproliferative effect as compound 9m also showed an equivalent EC (0.46 µM) against the
5
0
HepG2 cell line.
We next investigated the effect of an amide linkage in place of the basic amine, conferring
rotational hindrance to the molecules, decreased basicity, as well as providing a hydrogen bond
acceptor. A series of N-acyl substituted 3-piperidin-4-yl-1H-indoles with a wide variety of
aromatic groups was synthesized. However, only one of the tested amide derivatives (10a-j) was
active against Dd2. Compound 10d, which was derived from N-acyl pyridin-3-yl substitution,
demonstrated antimalarial activity (EC = 2.95 ꢀM) comparable to analogue 9o. Notably 10d
5
0
has a significantly improved cLogP compared to 9o (2.42 vs 5.08). Moreover, 10d did not show
cross-resistance with CQ (RI = 1.3) and was modestly selective (4x) for P. falciparum over the
tested human cell line (EC = 12.8 µM). Interestingly, the activity was highly susceptible to the
50
substitution position of the pyridinyl moiety, with the N-acyl pyridine-4-yl (10g) and N-acyl
pyridine-2-yl (10h) derivatives being inactive against the parasite, suggesting that the relative
spatial disposition of the carbonyl group and the nitrogen atom is required for activity.

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Comparison of the activity of bis-3-piperidin-4-yl-1H-indole compound 9m and its bis-amide
counterpart 10j, suggests that the amide bond significantly reduces the antimalarial activity (10j
with EC > 5 ꢀM). To broaden our structure-activity relationship study we also examined a
50
small series of analogues containing the 4-(piperidine-1-carbonyl)piperidin-1-yl) scaffold with
structurally diverse N-acyl substituents (13a-f). No significant antimalarial activity was observed
for the tested N-acyl derivatives, (13a-f with EC50 > 5 ꢀM). Moreover, when comparing the N-
acyl pyridin-3-yl substitution in the 3-piperidin-4-yl-1H-indole series (10d) to the same N-acyl
substitution in the 4-(4-piperidine-1-carbonyl)piperidin-1-yl-1H-indole series (13d), the
introduction of the second piperidinyl group results in loss of antimalarial activity.
3
. Conclusion:
Despite efforts to protect the useful lifespan of frontline therapies, antimalarial drug
resistance remains an ever-present threat. This challenge demands new drugs, preferably new
chemotypes active against drug resistant parasites, with a good pharmacologic profile and
affordable to endemic areas. Here we applied a rational fragment-based approach to design three
related series of 3-piperidin-4-yl-1H-indoles around TCMDC-134281 (3), which was previously
idenfied by GSK in a HTS campaign, to develop robust SAR and to validate this chemotype for
further preclinical development. Altogether, 38 compounds were synthesized and evaluated for
antimalarial activity. Compounds that demonstrate promising activity against the multidrug-
resistant P. falciparum Dd2 strain were also tested in the 3D7 parasite strain and counterscreened
in human HepG2 cells.
The SAR study revealed that the 4-aminoquinolinyl moiety present in hit 3 can be replaced
by some smaller groups without significantly affecting activity. Compounds, which retained
activity in spite of the absence of the chloroquine motif, demonstrate the potential of the 3-
piperidin-4-yl-1H-indole scaffold as a new class of antimalarial drugs independent from the 4-
aminoquinolines.
Our results suggest that the 3-piperidin-4-yl-1H-indole scaffold is very sensitive to most N-
piperidinyl modifications. Out of the analogues synthesized, only three were active (9m, 9o and
1
0d). While 9o showed cross-resistance to chloroquine and 9m was not selective in HepG2
cytotoxicity assays, the (4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-3-yl)methanone (10d) showed
in vitro antimalarial activity (EC values ∼ 3 µM), no cross-resistance with chloroquine,
5
0

ACCEPTED MANUSCRIPT
selectivity for the parasite, and lead-like properties (cLogP ≤ 3; MW ≤ 300). This represents a
promising new antimalarial chemotype with a potential novel mechanism of action. Further
medicinal chemistry efforts are underway to improve the potency of compound 10d and disclose
its antimalarial mechanism of action.
4
. Experimental:
4
.1. Chemistry
.1.1. General
All chemicals were purchased from Chem-Impex International, Aldrich, Fluka, and
4
Sigma- Aldrich Co. and used without further purification unless otherwise noted. All solvents for
syntheses were anhydrous. Thin layer chromatography was performed with precoated aluminum-
backed TLC plates obtained from VWR: Aluminum Oxide 60, Neutral F254 & Silica Gel 60,
Neutral F254. Visualization of TLC plates was performed with ninhydrin, iodine, or an UVGL-
2
5 Compact UV Lamp 254/365 UV (UVP 115V~60Hz/0.16 Amps). Purifications were
performed on a Biotage Isolera 4 Purification System equipped with a 200-400 nm diode array
detector. For flash purifications, Biotage SNAP Flash Chromatography Cartridges were used.
Purity of compounds was determined by analytical LC-ELSD-MS performed on a Waters 2545
HPLC equipped with a 2998 diode array detector, a Waters 3100 ESI-MS module, using a
XTerraMS C18 5 ꢀm, 4.6 x 50 mm column at a flow rate of 5 mL/minute with a linear gradient
(95% A: 5% B to 100% B with 90 seconds and 30 seconds hold at 100% B, solvent A = water +
0
.1% formic acid, solvent B = acetonitrile + 0.1% formic acid). Proton and carbon nuclear
TM
1
13
magnetic resonance ( H and C NMR spectra) were recorded on a Bruker Ascend instrument
at 400 and 101 MHz, respectively. Chemical shifts for protons are reported in parts per million
(
ppm) and are referenced to residual solvent peaks for DMSO (2.5 ppm), CHCl (7.26 ppm),
3
H O (4.79 ppm) and CH OH (3.31 ppm). Data is reported as follows: chemical shift,
2
3
multiplicity (s= singlet, d= doublet, t= triplet, q= quadruplet, m= multiplet, br=broad), coupling
constants (Hz) and integration. Instant JChem was used for structure database management,
search and prediction, Instant JChem 5.9.3, 2012, ChemAxon (http://www.chemaxon.com).

ACCEPTED MANUSCRIPT
4
.1.2. Synthesis
3
-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (4)
5
g (42.7 mmol) of indole were dissolved in isopropanol (50 mL). To this solution, potassium
hydroxide (7.18 g, 128 mmol) in isopropanol (50 mL) was added, followed by the addition of 1-
benzypiperidine-4-one (20 mL, 108 mmol) in isopropanol (50 mL). The reaction refluxed for 6h,
after which it was cooled to room temperature. Solvent was removed under reduced pressure.
The crude product was purified using flash chromatography using a gradient elution of
Hexane/Ethyl Acetate. The desired product was obtained as a yellow solid (12.01 g, 98%).
+
1
ESI-MS: C20
H
20
N
2
, m/z calculated for [M+H] : 289.16, Found: 289.18. H NMR δ (MeOD) 7.84
d, J = 8.1 Hz, 1H), 7.47 – 7.31 (m, 6H), 7.28 (s, 1H), 7.14 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.07
ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.20 (tt, J = 3.5, 1.5 Hz, 1H), 3.70 (s, 2H), 3.26 (m, 2H), 2.80 (t,
(
(
1
3
F = 5.8 Hz, 2H), 2.67 (m, 2H); C NMR δ (MeOD) 138.8, 138.3, 131.7, 130.9, 129.4, 128.5,
1
26.4, 123.1, 122.5, 121.2, 120.4, 118.3, 117.7, 112.5, 63.8, 54.1, 51.1, 29.6.
3
-(piperidin-4-yl)-1H-indole (5)
4
g (13.8 mmol) of compound 4 were dissolved in 10% acetic acid in ethyl acetate (160 mL). To
this solution, 1.2 g of 10% palladium over activated carbon were added. The reaction was placed
under 1 atm of H (balloon) and stirred for 50 h, at r.t. Reaction mixture was filtered over
2
Celite™ and washed with ethyl acetate followed by acetonitrile:water:methanol (1:1:1). Solvent
was removed under reduced pressure and the crude product purified with flash chromatography
using a gradient elution of ethyl acetate/acetonitrile:water:methanol (1:1:1) with 1% ammonium
hydroxide to afford compound 5 as a yellow solid (2.66 g, 96%).
+
1
ESI-MS: C13
H
16
N
2
, m/z calculated for [M+H] : 201.13, Found: 201.42. H NMR δ (MeOD)
.60 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.09 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.06 (s,
H), 7.01 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.46 (dt, J = 12.8, 3.1 Hz, 2H), 3.22 – 3.06 (m, 3H),
7
1
2
1
1
3
.23 (d, J = 12.3 Hz, 2H), 1.99 (m, 2H), 1.92 (s, NH); C NMR δ (MeOD) 136.9, 126.0, 121.1,
19.9, 118.3, 118.0, 117.9, 111.1, 44.2, 31.5, 29.7.
tert-butyl 4-(4-(1H-indol-3-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (6)
To 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 g , 4.36 mmol) in acetonitrile (25 mL)
was added compound 5 (873.2 mg, 4.36 mmol) in acetonitrile (25 mL), followed by N,N'-

ACCEPTED MANUSCRIPT
dicyclohexylcarbodiimide (899.6 mg, 4.36 mmol) and 1-hydroxybenzotriazole (589.1 mg, 4.36
mmol). The reaction stirred at room temperature for 2 h. Suspension was filtered and solvent
removed under reduced pressure. The crude product was purified using reverse phase flash
chromatography using a gradient elution of water/acetonitrile to afford compound 6 as a white
solid (1.08 g, 60%).
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 412.25, Found: 412.42. H NMR δ (MeOD)
2
4
33
3
3
7
6
3
1
1
3
.61 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.12 (ddd, J = 8.1, 7.9, 1.2 Hz, 1H), 7.08 –
.99 (m, 2H), 4.69 (d, J = 13.2 Hz, 1H), 4.21 (d, J = 13.2 Hz, 1H), 4.15 (d, J = 13.4 Hz, 2H),
.34-3.31 (m, 1H), 3.21-3.13 (tt, J = 12.8, 3.5 Hz, 1H), 2.97 (m, 2H), 2.85 (m, 2H), 2.21 (d, J =
1
3
2.9 Hz, 1H), 2.12 (d, J = 13.0 Hz, 1H), 1.79 – 1.60 (m, 6H), 1.50 (s, 9H); C NMR δ (MeOD)
73.7, 155.0, 136.9, 126.3, 120.9, 119.9, 119.8, 119.0, 118.1, 110.9, 79.7, 45.9, 42.5, 37.9, 33.7,
2.5, 28.2, 27.3.
tert-butyl 4-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (7)
To a solution of 6 (100 mg, 0.24 mmol) in THF (3 mL) at -78°C was added DIBAL in THF (730
ꢀ
L of 1M solution, 0.73 mmol). The reaction stirred at -78°C for 1 h and then quenched with
MeOH followed by addition of 1M aq. sodium potassium tartrate. The reaction mixture stirred
until clear and was extracted with ethyl acetate. Organic phase was washed with brine and dried
over anhydrous Na SO . Solvent was removed under reduced pressure and the crude product
2
4
purified with flash chromatography using a gradient elution of ethyl
acetate/acetonitrile:water:methanol (1:1:1) to afford compound 7 as a beige solid (33.4 mg,
3
5%).
+
1
ESI-MS: C24
H
35
N
3
O
2
, m/z calculated for [M+H] : 398.27, Found: 398.47. H NMR δ (CDCl
.05 (s, NH), 7.64 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.17 (ddd, J = 7.9, 7.1, 1.2 Hz,
H), 7.09 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 4.10 (d, J = 11.4 Hz, 2H), 2.99
3
)
8
1
(d, J = 11.5 Hz, 2H), 2.82 (m, 1H), 2.71 (t, J = 12.3 Hz, 2H), 2.23 (d, J = 6.9 Hz, 2H), 2.11 (td, J
=
11.9, 1.9 Hz, 2H), 2.03 (d, J = 12.4 Hz, 2H), 1.87 – 1.64 (m, 5H), 1.46 (s, 9H), 1.11 (qd, J =
1
3
1
1
3
2.1, 3.4 Hz, 2H); C NMR δ (CDCl ) 154.8, 136.2, 126.5, 121.7, 121.4, 119.5, 118.9, 118.8,
11.0, 79.0, 64.9, 54.8, 33.7, 33.4, 32.8, 30.8, 28.3, 28.2.
3
-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indole (8)

ACCEPTED MANUSCRIPT
Compound 7 (30 mg, 0.075 mmol) was dissolved in a solution of 2M HCl in MeOH (3 mL) and
stirred at room temperature for 20 min. The solvent was removed under reduced pressure and the
crude product was purified by reverse phase flash chromatography using a gradient elution of
water/acetonitrile to afford the desired product as a yellow solid (22.4 mg, qtt yield).
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 298.22, Found: 298.45. H NMR δ (D O) 7.75
1
9
27
3
2
(
d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.29 (dd, J = 8.2, 8.1 Hz, 1H), 7.25 (s, 1H), 7.20
dd, J =8.2, 8.0 Hz, 1H), 3.71 (d, J = 12.5 Hz, 2H), 3.53 (d, J = 13.2 Hz, 2H), 3.24 – 3.05 (m,
(
7
2
3
H), 2.32 (d, J = 12.9 Hz, 2H), 2.16 – 1.97 (m, 4H), 1.94 – 1.77 (m, 1H), 1.60 (q, J =11.9 Hz,
1
3
H); C NMR δ (D
2
O) 136.3, 125.4, 122.1, 121.3, 119.3, 118.7, 117.5, 112.1, 61.3, 53.7, 43.2,
0.5, 29.6, 28.7, 26.2.
4
-(4-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)piperidin-1-yl)-6-chloroquinoline (3)
To a solution of compound 8 (20 mg, 0.067 mmol) and DIPEA (35.21 ꢀL, 0.202 mmol) in
isopropanol (2 mL) was added 4,6-dichloroquinoline (19.80 mg, 0.10 mmol). The reaction
mixture stirred under reflux for 56 h. The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography using a gradient elution of ethyl
acetate/acetonitrile:water:methanol (1:1:1) to afford compound 3 as a beige oil (4.6 mg, 15%).
+
1
ESI-MS: C H ClN , m/z calculated for [M+H] : 459.22, Found: 459.37. H NMR δ (MeOD)
2
8
31
4
8
.68 (d, J = 5.1 Hz, 1H), 8.46 (br, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.73
(dd, J = 9.0, 2.3 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.17 – 7.11 (m, 3H),
7
2
.05 (dd, J = 8.0, 7.9 Hz, 1H), 3.67-3.81 (m, 4H), 3.24-3.29 (m, 5H), 3.04 (t, J = 12.1 Hz, 2H),
.37 (d, J = 13.4 Hz, 2H), 2.28-2.16 (m, 3H), 2.11 (d, J = 13.3 Hz, 2H), 1.79 (qd, J = 12.5, 3.7
Hz, 2H).
General Procedure A:
Aldehyde (1.5 eq.) and amine (1 eq.) were mixed in 1,2-dichloroethane, followed by addition of
sodium triacetoxyborohydride (1.4 eq.). The reaction was stirred at room temperature under inert
atmosphere for 4 h. The reaction mixture was quenched with sat. aq. NaHCO
3
, and the product
was extracted with ethyl acetate. The organic phase was dried (Na SO ), and the solvent was
2
4
removed under reduced pressure. The crude product was purified by flash chromatography with
ethyl acetate/acetonitrile:water:methanol (1:1:1) to afford the desired product.

ACCEPTED MANUSCRIPT
General Procedure B:
To a solution of acid chloride (1 eq.) in DCM (3 mL) was added a suspension of compound 5
1.1 eq.) in sat. aq. NaHCO (3 mL). The reaction mixture stirred vigorously at room temperature
for 10 min. The organic phase was washed with HCl (aq., 10%), sat. aq. NaHCO and brine,
(
3
3
dried over anhydrous Na
product was purified by flash chromatography with ethyl acetate/acetonitrile:water:methanol
1:1:1) to afford the desired product.
2 4
SO and the solvent was removed under reduced pressure. The crude
(
General Procedure C:
To a solution of acid chloride (1 eq.) in DCM (2 mL) was added a solution of compound 5 (1.1
eq.) and DIPEA (3 eq.) in DCM (2 mL). The reaction mixture stirred at room temperature for 1 h
and the solvent was removed under reduced pressure. The crude product was purified by flash
chromatography with ethyl acetate/acetonitrile:water:methanol (1:1:1) to afford the desired
product.
General Procedure D:
To a solution of carboxylic acid (1 eq.) in DCM (2 mL) was added a solution of compound 5 (1
eq.) and DIPEA (3 eq.) in DCM (2 mL) followed by PyBOP (1.1 eq.). The reaction mixture
stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography ethyl acetate/acetonitrile:water:methanol
(1:1:1) to afford the desired product.
4
-(piperidin-1-ylmethyl)benzaldehyde
Reaction of terephthaldehyde (235.2 mg, 1.75 mmol), piperidine (100 mg, 1.17 mmol) and
sodium triacetoxyborohydride (348.6 mg, 1.64 mmol) according to general procedure A, gave
1
66.25 mg (70 %) of desired aldehyde as a light yellow oil.
+
1
ESI-MS: C H NO, m/z calculated for [M+H] : 204.13, Found: 204.33. H NMR δ (MeOD)
1
3
17
1
4
1
0.01 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 3.64 (s, 2H), 2.52 – 2.46 (m,
1
3
H), 1.70 – 1.60 (m, 4H), 1.53 – 1.49 (m, 2H); C NMR δ (MeOD) 192.4, 144.6, 135.8, 129.9,
29.3, 62.8, 54.1, 25.1, 23.7.

ACCEPTED MANUSCRIPT
4
-(morpholinomethyl)benzaldehyde
Reaction of terephthaldehyde (231.2 mg, 1.73 mmol), morpholine (100 mg, 1.15 mmol) and
sodium triacetoxyborohydride (340.6 mg, 1.60 mmol) according to general procedure A, gave
1
36.80 mg (58 %) of desired aldehyde as a light yellow oil.
+
1
ESI-MS: C12
H15NO
2
, m/z calculated for [M+H] : 206.11, Found: 206.71. H NMR δ (MeOD)
1
2
5
0.01 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 3.77 – 3.71 (m, 4H), 3.65 (s,
13
H), 2.55 – 2.48 (m, 4H); C NMR δ (MeOD) 192.4, 144.8, 135.8, 129.6, 125.7, 66.4, 62.4,
3.3.
4
-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-
one (9a)
Reaction of compound 5 (20 mg, 0.10 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carbaldehyde (32.4 mg, 0.15 mmol) and sodium triacetoxyborohydride (29.7 mg,
0
.14 mmol) according to general procedure A, gave 28.4 mg (79 %) of desired compound as a
yellow oil.
ESI-MS: C H N O, m/z calculated for [M+H] : 401.23, Found: 401.14. H NMR δ (MeOD)
+
1
2
5
28
4
7
.61 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.47 (ddd, J = 7.6, 7.2, 1.2 Hz, 1H), 7.42 (dd, J
8.4, 1.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.10 (ddd, J = 8.0, 7.2, 1.2 Hz 1H), 7.04 (s, 1H),
.00 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 3.53 (s, 2H), 3.26 (s, 3H), 3.22 (d, J = 10.5 Hz, 2H), 2.90
m, 1H), 2.49 (t, J = 10.7 Hz, 2H), 2.43 (s, 3H), 2.11 (d, J = 12.6 Hz, 2H), 1.92 (qd, J = 12.1, 3.4
=
7
(
1
3
Hz, 2H); C NMR δ (MeOD) 166.0, 154.4, 136.9, 134.2, 129.2, 127.9, 126.4, 125.9, 120.8,
1
19.7, 119.4, 118.2, 117.9, 110.9, 101.4, 53.3, 49.3, 33.7, 32.9, 32.0, 10.0.
1
-(3-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-1H-indol-1-yl)ethan-1-one (9b)
Reaction of compound 5 (20 mg, 0.10 mmol), 1-acetyl-1H-indole-3-carbaldehyde (28.1 mg, 0.15
mmol) and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general procedure
A, gave 25.3 mg (76 %) of desired amine as a beige solid.
+
1
ESI-MS: C24
H
25
N
3
O, m/z calculated for [M+H] : 372.21, Found: 372.41. H NMR δ (CDCl
.45 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 –
.28 (m, 4H), 7.17 (ddd, J = 8.4, 8.2, 1.2 Hz 1H), 7.10 (ddd, J = 8.4, 8.0, 1.0 Hz, 1H), 6.97 (d, J
3
)
8
7

ACCEPTED MANUSCRIPT
=
=
2.1 Hz, 1H), 3.75 (s, 2H), 3.15 (d, J = 11.8 Hz, 2H), 2.87 (tt, J = 12.9, 3.6 Hz, 1H), 2.30 (td, J
1
3
11.8, 2.1 Hz, 2H), 2.07 (d, J = 12.9 Hz, 2H), 1.88 (qd, J = 12.3, 3.6 Hz, 2H); C NMR δ
(CDCl3) 169.0, 136.9, 136.4, 131.3, 127.1, 125.7, 124.8, 124.6, 123.9, 123.5, 122.4, 121.8,
1
20.1, 119.6, 117.0, 111.9, 111.7, 54.9, 54.0, 33.9, 33.4, 24.5.
2
-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)quinolin-8-ol (9c)
Reaction of compound 5 (50 mg, 0.25 mmol), 8-hydroxyquinoline-2-carbaldehyde (64.8 mg,
.375 mmol) and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general
0
procedure A, gave 92.6 mg (99 %) of desired amine as a light yellow oil.
+
1
ESI-MS: C H N O, m/z calculated for [M+H] : 358.18, Found: 358.20. H NMR δ (MeOD)
2
3
23
3
8
1
7
1
1
1
.17 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.6 Hz,
H), 7.36 – 7.24 (m, 2H), 7.11 (dd, J = 7.5, 1.3 Hz, 1H), 7.05 (ddd, J = 7.5, 6.9, 1.3 Hz, 1H),
.01 (s, 1H), 6.96 (ddd, J = 7.9, 6.9, 1.0 Hz, 1H), 4.22 (s, 2H), 3.28 – 3.25 (m, 2H), 2.97 (tt, J =
1
3
1.4, 4.1 Hz, 1H), 2.75 (td, J = 11.6, 1.6 Hz, 2H), 2.14 – 1.96 (m, 4H); C NMR δ (MeOD)
54.2, 153.7, 139.4, 138.5, 138.3, 129.6, 128.9, 127.7, 122.6, 122.4, 121.3, 119.9, 119.6, 119.0,
18.4, 112.54, 112.4, 63.6, 55.2, 33.5, 32.2.
3
-(1-(benzo[b]thiophen-3-ylmethyl)piperidin-4-yl)-1H-indole (9d)
Reaction of compound 5 (50 mg, 0.25 mmol), benzo[b]thiophene-3-carbaldehyde (60.7 mg,
.375 mmol) and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general
0
procedure A, gave 47.6 mg (55 %) of desired amine as a light yellow oil.
+
1
ESI-MS: C H N S, m/z calculated for [M+H] : 347.15, Found: 347.16. H NMR δ (DMSO)
2
2
22
2
1
1
1
0.77 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.5 Hz,
H), 7.45 – 7.31 (m, 3H), 7.10 – 7.01 (m, 2H), 6.95 (t, J = 7.4 Hz, 1H), 3.77 (s, 2H), 3.00 (d, J =
1.2 Hz, 2H), 2.77 (tt, J = 12.0, 3.7 Hz, 1H), 2.18 (t, J = 10.8 Hz, 2H), 1.98 – 1.89 (m, 2H), 1.69
1
3
(
qd, J = 12.3, 3.7 Hz, 2H); C NMR δ (DMSO) 139.9, 138.8, 136.4, 133.4, 126.3, 124.8, 124.3,
1
23.9, 122.8, 122.7, 120.8, 120.5, 119.6, 118.5, 118.0, 111.4, 56.2, 53.9, 33.1, 32.8.
3
-(1-benzylpiperidin-4-yl)-1H-indole (9e)
Reaction of compound 5 (100 mg, 0.50 mmol), benzaldehyde (79.4 mg, 0.7 mmol) and sodium
triacetoxyborohydride (118.6 mg, 0.75 mmol) according to general procedure A, gave 76.2 mg

ACCEPTED MANUSCRIPT
(53 %) of desired amine as a dark yellow solid.
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 291.18, Found: 291.12. H NMR δ (MeOD)
2
0
22
2
7
.58 (d, J = 7.8 Hz, 1H), 7.38 – 7.26 (m, 6H), 7.08 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.03 – 6.96
(m, 2H), 3.56 (s, 2H), 3.00 (d, J = 12.2 Hz, 2H), 2.80 (tt, J = 11.9, 3.8 Hz, 1H), 2.18 (td, J = 12.2,
1
3
2
1
.6 Hz, 2H), 2.02 – 1.96 (m, 2H), 1.84 (qd, J = 12.1, 3.3 Hz, 2H); C NMR δ (MeOD) 136.9,
32.8, 129.6, 128.0, 127.9, 127.1, 126.5, 120.8, 119.7, 118.4, 117.9, 110.9, 63.1, 53.8, 33.4, 32.3.
3
-(1-(2-methylbenzyl)piperidin-4-yl)-1H-indole (9f)
Reaction of compound 5 (50 mg, 0.25 mmol), 2-methylbenzaldehyde (44.9 mg, 0.375 mmol) and
sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
4
1.8 mg (55 %) of desired amine as a light orange solid.
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 305.19, Found: 305.17. H NMR δ (CDCl )
2
1
24
2
3
8
6
2
.15 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.22 – 7.13 (m, 4H), 7.09 (m, 1H),
.96 (d, J = 2.3 Hz, 1H), 3.62 (s, 2H), 3.09 (d, J = 12.1 Hz, 2H), 2.87 (tt, J = 12.0, 3.8 Hz, 1H),
.41 (s, 3H), 2.28 (td, J = 12.1, 2.6 Hz, 2H), 2.12 – 1.98 (m, 2H), 1.84 (qd, J = 12.2, 3.3 Hz, 2H);
1
3
3
C NMR δ (CDCl ) 137.7, 136.5, 130.5, 130.3, 130.3, 127.4, 126.8, 125.8, 121.9, 121.3, 119.9,
1
19.2, 119.1, 111.3, 60.7, 54.3, 33.5, 32.8, 19.6.
4
-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-3,5-dimethoxyphenol (9g)
Reaction of compound 5 (20 mg, 0.10 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (27.3 mg,
.15 mmol) and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general
0
procedure A, gave 13.6 mg (42 %) of desired amine as a yellow solid.
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 367.19, Found: 367.12. H NMR δ (DMSO)
2
2
26
2
3
1
2
3
1
0.91 (s, 1H), 10.12 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.13 – 7.02 (m,
H), 6.96 (m, 1H), 6.21 (s, 2H), 4.08 (s, 2H), 3.79 (s, 6H), 3.40 – 3.34 (m, 2H), 3.11 – 2.94 (m,
13
H), 2.22 – 1.92 (m, 4H); C NMR δ (DMSO) 161.1, 160.1, 136.4, 125.8, 120.9, 120.8, 118.8,
18.2, 117.7, 111.5, 91.9, 55.8, 55.4, 51.9, 48.8, 43.5, 31.0, 30.7, 29.5, 29.0.
2
-(3-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)phenoxy)ethan-1-ol (9h)
Reaction of compound 5 (50 mg, 0.25 mmol), 3-(2-hydroxyethoxy)benzaldehyde (62.3 mg,
.375 mmol) and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general
0

ACCEPTED MANUSCRIPT
procedure A, gave 86.7 mg (99 %) of desired amine as an orange oil.
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 351.20, Found: 351.21. H NMR δ (CDCl )
2
2
26
2
2
3
8
2
.36 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.27 (m, 1H), 7.19 – 7.12 (m,
H), 7.08 (ddd, J = 7.9, 7.1, 1.1 Hz, 1H), 6.97 (m, 2H), 6.87 (dd, J = 8.2, 2.5 Hz, 1H), 4.13 (dd, J
5.3, 4.0 Hz, 2H), 3.96 (dd, J = 5.3, 4.0 Hz, 2H), 3.71 (s, 2H), 3.15 (d, J = 11.5 Hz, 2H), 2.88
=
1
3
(
3
tt, J = 11.4, 4.3 Hz, 1H), 2.36 (t, J = 10.9 Hz, 2H), 2.13 – 1.93 (m, 4H); C NMR δ (CDCl )
1
6
59.1, 136.5, 129.5, 126.6, 122.6, 121.9, 120.6, 120.1, 119.2, 119.0, 115.9, 114.4, 111.4, 69.4,
2.8, 61.5, 53.9, 33.1, 32.1.
3
-(1-(2,6-dichloro-3,4-dimethoxybenzyl)piperidin-4-yl)-1H-indole (9i)
Reaction of compound 5 (50 mg, 0.25 mmol), 2,6-dichloro-3,4-dimethoxybenzaldehyde (87.6
mg, 0.375 mmol) and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general
procedure A, gave 62.9 mg (60 %) of desired amine as red solid.
+
1
ESI-MS: C22
H24Cl
2
N
2
O
2
, m/z calculated for [M+H] : 419.12, Found: 419.33. H NMR δ
(DMSO) 10.74 (s, 1H), 7.52 (dd, J = 7.8, 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.09
–
7.01 (m, 2H), 6.94 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.68 (s, 2H), 2.92
(d, J = 11.1 Hz, 2H), 2.77 (tt, J = 12.0, 3.6 Hz, 1H), 2.35 (t, J = 11.1 Hz, 2H), 1.92 (d, J =13.7
1
3
Hz, 2H), 1.62 (qd, J = 12.2, 3.5 Hz, 2H); C NMR δ (DMSO) 152.6, 143.9, 136.3, 130.3, 130.2,
1
26.3, 120.7, 120.4, 119.5, 118.5, 117.9, 112.6, 111.4, 60.1, 56.5, 56.4, 53.7, 32.8.
3
-(1-(4-fluorobenzyl)piperidin-4-yl)-1H-indole (9j)
Reaction of compound 5 (50 mg, 0.25 mmol), 4-fluorobenzaldehyde (46.4 mg, 0.375 mmol) and
sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave 55
mg (72 %) of desired amine as yellow oil.
+
1
ESI-MS: C H FN , m/z calculated for [M+H] : 309.17, Found: 309.09. H NMR δ (MeOD)
2
0
21
2
7
–
1
1
1
.60 (d, J = 7.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.17 – 7.07 (m, 3H), 7.05
6.96 (m, 2H), 3.81 (s, 2H), 3.17 (d, J = 12.1 Hz, 2H), 2.94 (tt, J = 11.9, 3.8 Hz, 1H), 2.51 (t, J =
1
3
1.1 Hz, 2H), 2.11 (d, J =12.9 Hz, 2H), 1.93 (qd, J = 12.1, 3.3 Hz, 2H); C NMR δ (MeOD)
1
64.1 (d, JCF = 245 Hz), 138.3, 133.3, 127.7, 122.3, 121.2, 120.3, 119.6, 119.5, 116.4, 116.2,
12.4, 62.6, 54.7, 34.0, 32.9.

ACCEPTED MANUSCRIPT
3
-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1H-indole (9k)
Reaction of compound 5 (20 mg, 0.10 mmol), 4-(trifluoromethyl)benzaldehyde (26.1 mg, 0.15
mmol) and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general procedure
A, gave 22.2 mg (69 %) of desired amine as a beige oil.
+
1
ESI-MS: C H F N , m/z calculated for [M+H] : 359.17, Found: 359.32. H NMR δ (MeOD)
2
1
21
3
2
7
7
.72 – 7.55 (m, 5H), 7.34 (d, J = 8.1 Hz, 1H), 7.09 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.03 (s, 1H),
.00 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 3.72 (s, 2H), 3.06 (d, J = 12.3 Hz, 2H), 2.88 (tt, J = 12.3, 3.9
1
3
Hz, 1H), 2.31 (td, J = 12.3, 2.5 Hz, 2H), 2.07 (m, 2H), 1.89 (qd, J = 12.3, 3.6 Hz, 2H); C NMR
δ (MeOD) 143.3, 138.3, 131.3, 127.9, 126.2, 126.2, 126.1, 122.2, 121.1, 121.0, 119.6, 119.3,
1
12.3, 63.7, 55.3, 34.7, 33.8.
4
-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)benzaldehyde (9l)
Reaction of compound 5 (50 mg, 0.25 mmol), terephthaldehyde (50.3 mg, 0.37 mmol) and
sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
1
9.9 mg (25 %) of desired amine as beige solid.
+
1
ESI-MS: C21
H
22
N
2
O, m/z calculated for [M+H] : 319.17, Found: 319.23. H NMR δ (CDCl
3
)
1
2
1
1
0.00 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.1 Hz,
H), 7.35 (d, J = 8.2 Hz, 1H), 7.18 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.10 (ddd, J = 7.9, 7.0, 1.1 Hz,
H), 6.97 (d, J = 1.2 Hz, 1H), 3.66 (s, 2H), 3.01 (d, J = 11.8 Hz, 2H), 2.86 (tt, J = 11.9, 3.8 Hz,
H), 2.23 (td, J = 11.8, 2.5 Hz, 2H), 2.05 (d, J = 13.9 Hz, 2H), 1.86 (qd, J = 11.9, 3.3 Hz, 2H);
1
3
3
C NMR δ (CDCl ) 191.9, 145.7, 136.2, 135.2, 129.6, 129.5, 126.8, 121.7, 121.1, 119.5, 118.9,
1
11.0, 62.9, 54.2, 33.2, 32.7.
1
,4-bis((4-(1H-indol-3-yl)piperidin-1-yl)methyl)benzene (9m)
Reaction of compound 5 (50 mg, 0.25 mmol), terephthaldehyde (50.3 mg, 0.375 mmol) and
sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
3
7.7 mg (30 %) of desired amine as beige solid.
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 503.31, Found: 503.29. H NMR δ (DMSO)
3
4
38
4
1
0.74 (s, 2H), 7.53 (d, J = 7.6 Hz, 2H), 7.39 – 7.25 (m, 6H), 7.08 (s, 2H), 7.04 (dd, J = 7.5, 1.1
Hz, 2H), 6.94 (dd, J = 7.6, 1.2 Hz, 2H), 3.49 (s, 4H), 2.91 (d, J = 12.1 Hz, 4H), 2.75 (tt, J = 12.2,
.8 Hz, 2H), 2.11 (td, J = 11.8, 2.5 Hz, 4H), 1.96 – 1.86 (m, 4H), 1.69 (qd, J = 12.0, 3.4 Hz, 4H);
3

ACCEPTED MANUSCRIPT
1
3
C NMR δ (DMSO) 137.2, 136.3, 128.6, 126.3, 120.7, 120.5, 119.6, 118.5, 117.9, 111.4, 62.4,
5
3.8, 33.1, 32.8.
4
-(4-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)benzyl)morpholine (9n)
Reaction of compound 5 (20 mg, 0.10 mmol), 4-(morpholinomethyl)benzaldehyde (30.8 mg,
.15 mmol) and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general
0
procedure A, gave 14.8 mg (38 %) of desired amine as a beige solid.
+
1
ESI-MS: C H N O, m/z calculated for [M+H] : 390.25, Found: 390.17. H NMR δ (CDCl )
2
5
31
3
3
8
7
3
.25 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.44 – 7.32 (m, 5H), 7.16 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H),
.08 (ddd, J = 7.8, 7.1, 1.1 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 3.81 (s, 2H), 3.76 – 3.67 (m, 4H),
.51 (s, 2H), 3.22 (d, J = 11.5 Hz, 2H), 2.90 (m, 1H), 2.52 – 2.37 (m, 6H), 2.10 – 2.06 (m, 4H);
1
3
C NMR δ (CDCl ) 136.5, 130.4, 130.3, 129.6, 129.6, 126.6, 122.1, 120.1, 119.3, 118.9, 111.5,
3
6
7.1, 63.2, 62.2, 53.7, 32.8, 31.7.
3
-(1-(4-(piperidin-1-ylmethyl)benzyl)piperidin-4-yl)-1H-indole (9o)
Reaction of compound 5 (20 mg, 0.10 mmol), 4-(piperidin-1-ylmethyl)benzaldehyde (30.5 mg,
.15 mmol) and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general
0
procedure A, gave 20.9 mg (54 %) of desired amine as a beige solid.
+
1
ESI-MS: C26
H
33
N
3
, m/z calculated for [M+H] : 388.27, Found: 388.43. H NMR δ (CDCl
3
)
8
.02 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.32 – 7.24 (m, 4H), 7.18 (ddd, J
=
8.1, 6.9, 1.2 Hz, 1H), 7.10 (ddd, J = 7.9, 6.9, 1.1 Hz, 1H), 6.96 (d, J = 1.8 Hz, 2H), 3.56 (s,
2
2
4
1
H), 3.47 (s, 2H), 3.03 (d, J = 11.9 Hz, 2H), 2.84 (tt, J = 11.9, 3.8 Hz, 1H), 2.45 – 2.31 (m, 4H),
.17 (td, J = 11.9, 2.4 Hz, 2H), 2.08 – 1.98 (m, 2H), 1.83 (qd, J = 12.0, 3.5 Hz, 2H), 1.58 (m,
1
3
3
H), 1.44 (m, 2H); C NMR δ (CDCl ) 137.2, 137.1, 136.4, 129.1, 129.0, 126.7, 121.9, 121.7,
19.6, 119.0, 111.1, 63.7, 63.4, 54.5, 54.4, 33.5, 33.1, 25.9, 24.4.
3
-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1H-indole (9p)
Reaction of compound 5 (50 mg, 0.25 mmol), isonicotinaldehyde (40.1 mg, 0.37 mmol) and
sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
7
0.6 mg (97 %) of desired amine as orange oil.

ACCEPTED MANUSCRIPT
+
1
ESI-MS: C19
H
21
N
3
, m/z calculated for [M+H] : 292.17, Found: 292.36. H NMR δ (MeOD) 8.49
(d, J = 6.0 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 6.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H),
7
1
2
1
.08 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.02 – 6.92 (m, 2H), 3.63 (s, 2H), 3.01 (m, 2H), 2.84 (tt, J =
1.9, 3.9 Hz, 1H), 2.27 (t, J = 11.9 Hz, 2H), 2.04 (d, J = 13.8 Hz, 2H), 1.86 (qd, J = 12.0, 3.5 Hz,
1
3
H); C NMR δ (MeOD) 150.0, 149.8, 149.7, 138.3, 127.9, 126.0, 122.7, 122.2, 121.1, 120.9,
19.7, 119.4, 112.3, 62.8, 55.4, 34.6, 33.8.
3
-(1-(thiophen-2-ylmethyl)piperidin-4-yl)-1H-indole (9q)
Reaction of compound 5 (20 mg, 0.10 mmol), thiophene-2-carbaldehyde (16.8 mg, 0.15 mmol)
and sodium triacetoxyborohydride (29.7 mg, 0.14 mmol) according to general procedure A, gave
1
9.24 mg (65 %) of desired amine as a light yellow oil.
+
1
ESI-MS: C H N S, m/z calculated for [M+H] : 297.13, Found: 297.37. H NMR δ (CDCl )
1
8
20
2
3
8
.00 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.18
ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.10 (ddd, J = 7.9, 7.1, 1.1 Hz, 1H), 6.99 – 6.95 (m, 3H), 3.82 (s,
H), 3.08 (d, J = 12.9 Hz, 2H), 2.84 (tt, J = 11.9, 3.8 Hz, 1H), 2.24 (t, J = 11.8 Hz, 2H), 2.06 (d,
(
2
1
3
J = 12.9 Hz, 2H), 1.86 (qd, J = 11.8, 3.3 Hz, 2H); C NMR δ (CDCl
3
) 142.0, 136.8, 127.2,
1
26.9, 126.7, 125.4, 122.4, 121.9, 120.1, 119.6, 119.5, 111.6, 57.9, 54.4, 33.9, 33.4.
3
-(1-(cyclohexylmethyl)piperidin-4-yl)-1H-indole (9r)
Reaction of compound 5 (50 mg, 0.25 mmol), (S)-3,7-dimethyloct-6-enal (42.1 mg, 0.375 mmol)
and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
7
4.1 mg (qtt yield) of desired amine as orange oil.
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 298.23, Found: 298.20. H NMR δ (CDCl ) 8.19
2
0
28
2
3
(
s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.18 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H),
.10 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 3.03 (d, J = 11.6 Hz, 2H), 2.83 (tt,
J = 11.9, 3.8 Hz, 1H), 2.21 (d, J = 6.9 Hz, 2H), 2.15 – 1.97 (m, 4H), 1.95 – 1.79 (m, 4H), 1.78 –
7
1
3
1
1
.62 (m, 3H), 1.36 – 1.08 (m, 4H), 1.02 – 0.82 (m, 2H); C NMR δ (CDCl ) 136.5, 126.8,
3
21.9, 121.6, 119.9, 119.2, 119.1, 111.3, 66.3, 55.1, 35.3, 33.7, 32.9, 32.3, 26.9, 26.3.
3
-(1-((S)-3,7-dimethyloct-6-en-1-yl)piperidin-4-yl)indoline (9s)
Reaction of compound 5 (50 mg, 0.25 mmol), (S)-3,7-dimethyloct-6-enal (57.7 mg, 0.375 mmol)

ACCEPTED MANUSCRIPT
and sodium triacetoxyborohydride (74.1 mg, 0.35 mmol) according to general procedure A, gave
8
3.4 mg (98 %) of desired amine as a dark orange oil.
+
1
ESI-MS: C H N , m/z calculated for [M+H] : 341.29, Found: 341.28. H NMR δ (DMSO)
2
3
36
2
1
7
7
1
1
1
0.75 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.09 – 7.00 (m, 2H), 6.94 (t, J =
.4 Hz, 1H), 5.01 (m, 1H), 2.94 (d, J = 9.3 Hz, 2H), 2.72 (tt, J = 11.9, 3.8 Hz, 1H), 2.30 (t, J =
.3 Hz, 2H), 2.11 – 1.80 (m, 6H), 1.67 (m, 1H), 1.65 (s, 3H), 1.58 (s, 3H), 1.46 (m, 2H), 1.39 –
1
3
.07 (m, 4H), 0.87 (d, J = 6.3 Hz, 3H); C NMR δ (DMSO) 136.4, 130.4, 126.3, 124.7, 120.7,
20.4, 119.7, 118.5, 117.9, 111.4, 58.8, 56.3, 54.3, 53.9, 36.7, 33.6, 33.3, 32.9, 30.2, 25.5, 24.9,
9.6, 17.5.
(4-(1H-indol-3-yl)piperidin-1-yl)(phenyl)methanone (10a)
Reaction of compound 5 (78.6 mg, 0.39 mmol) and benzoyl chloride (50 mg, 0.36 mmol)
according to general procedure B, gave 59.9 mg (55 %) of desired amide as a beige solid.
+
1
ESI-MS: C20
H
20
N
2
O, m/z calculated for [M+H] : 305.16, Found: 305.13. H NMR δ (DMSO)
1
2
1
0.81 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47 – 7.40 (m, 5H), 7.34 (d, J = 7.9 Hz, 1H), 7.14 (d, J =
.3 Hz, 1H), 7.06 (dd, J = 7.9, 1.4 Hz, 1H), 6.96 (dd, J = 7.8, 1.3 Hz, 1H), 4.61 (br, 1H), 3.68 (br,
H), 3.23 (br, 1H), 3.08 (tt, J = 3.4, 12.2 Hz, 1H), 2.95 (br, 1H), 2.15 – 1.80 (m, 2H), 1.68 – 1.58
1
3
(
m, 2H); C NMR δ (DMSO) 169.4, 137.0, 136.8, 129.7, 128.9, 127.1, 126.6, 121.4, 121.3,
1
19.4, 118.9, 118.6, 111.9, 48.2, 42.6, 33.6.
(4-(1H-indol-3-yl)piperidin-1-yl)(2,5-dimethoxyphenyl)methanone (10b)
Reaction of compound 5 (54.9 mg, 0.27 mmol) and 2,5-dimethoxybenzoyl chloride (50 mg, 0.25
mmol) according to general procedure B, gave 91.04 mg (qtt yeild) of desired amide as a white
solid.
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 365.18, Found: 365.16. H NMR δ (CDCl )
2
2
24
2
3
3
8
1
.37 (s, NH), 7.62 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.19 (ddd, J = 8.1, 7.0, 1.2 Hz,
H), 7.11 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 2.3 Hz, 2H), 6.51
(t, J = 2.3 Hz, 1H), 4.85 (br, 1H), 3.91 (br, 1H), 3.80 (s, 6H), 3.20 (br, 1H), 3.13 (tt, J = 11.8, 3.6
1
3
Hz, 1H), 2.98 (br, 1H), 2.18 (br, 1H), 2.06 (br, 1H), 1.82 (br, 1H), 1.66 (br, 1H); C NMR δ
CDCl ) 170.1, 160.9, 138.3, 136.6, 126.4, 122.1, 120.2, 119.9, 119.3, 118.9, 111.5, 104.8,
(
3
1
01.6, 55.6, 48.4, 42.9, 33.9, 32.6, 29.8.

ACCEPTED MANUSCRIPT
(4-(1H-indol-3-yl)piperidin-1-yl)(4-fluorophenyl)methanone (10c)
Reaction of compound 5 (69.6 mg, 0.35 mmol) and 4-fluorobenzoyl chloride (50 mg, 0.32
mmol) according to general procedure B, gave 97.9 mg (95%) of desired amide as a yellow oil.
+
1
ESI-MS: C H FN O, m/z calculated for [M+H] : 323.15, Found: 323.33. H NMR δ (DMSO)
2
0
19
2
1
0.73 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.30 – 7.16 (m, 3H), 7.06 (d, J = 2.4
Hz, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 4.52 (br, 1H), 3.59 (br, 1H), 3.10 (br, 1H), 3.01 (tt, J =
1
3
1
1.8, 3.7 Hz, 1H), 2.91 (br, 1H), 1.91 (br, 2H), 1.57 (m, 2H); C NMR δ (DMSO) 168.5, 162.9
1
(
d, JCF = 246 Hz), 136.8, 133.4, 129.8, 126.6, 121.3, 119.4, 118.9, 118.6, 115.9, 111.9, 48.4,
4
2.7, 33.6, 33.2, 29.5.
(4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-3-yl)methanone (10d)
Reaction of compound 5 (78.1 mg, 0.39 mmol), nicotinoyl chloride (50 mg, 0.35 mmol) and
DIPEA (182.9 ꢀL, 1.05 mmol) according to general procedure C, gave 26.7 mg (25%) of desired
amide as a beige solid.
+
1
ESI-MS: C19
H
19
N
3
O, m/z calculated for [M+H] : 306.15, Found: 306.38. H NMR δ (CDCl
3
)
8
1
7
1
.73 (d, J = 2.2 Hz, 1H), 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 8.46 (s, NH), 7.80 (dd, J = 7.8, 1.9 Hz,
H), 7.62 (d, J = 7.7 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.19 (dd, J = 7.7, 1.1 Hz, 1H), 7.12 (dd, J =
.8, 1.2 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 4.88 (br, 1H), 3.85 (br, 1H), 3.28 (br, 1H), 3.15 (tt, J =
1
3
1.9, 3.7 Hz, 1H), 3.01 (br, 1H), 2.20 (br, 1H), 2.08 (br, 1H), 1.83 (br, 1H), 1.70 (br, 1H); C
) 167.8, 150.7, 147.9, 136.6, 135.0, 132.3, 126.4, 123.6, 122.2, 120.0, 119.9,
19.3, 118.9, 111.5, 48.6, 43.2, 33.8, 33.7, 32.5.
NMR δ (CDCl
3
1
(4-(1H-indol-3-yl)piperidin-1-yl)(thiophen-2-yl)methanone (10e)
Reaction of compound 5 (76.1 mg, 0.38 mmol) and 2-thiophenecarbonyl chloride (50 mg, 0.35
mmol) according to general procedure B, gave 71.1 mg (66%) of desired amide as a beige solid.
+
1
ESI-MS: C H N OS, m/z calculated for [M+H] : 311.11, Found: 311.29. H NMR δ (CDCl )
1
8
18
2
3
8
7
.12 (s, NH), 7.64 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H),
.33 (dd, J = 3.7, 1.2 Hz, 1H), 7.20 (ddd, J = 7.9, 7.1, 1.2 Hz, 1H), 7.12 (ddd, J = 8.1, 7.1, 1.1
Hz, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 4.59 (br, 2H), 3.25 – 3.08 (m,

ACCEPTED MANUSCRIPT
1
3
3
1
3
H), 2.17 (br, 1H), 2.14 (br, 1H), 1.79 (m, 2H); C NMR δ (CDCl ) 163.8, 137.7, 136.6, 128.7,
28.4, 126.8, 126.5, 122.3, 120.5, 119.9, 119.5, 119.0, 111.5, 34.0, 33.3, 29.9, 22.9, 14.3.
1
-(4-(1H-indol-3-yl)piperidin-1-yl)ethan-1-one (10f)
Reaction of compound 5 (140.4 mg, 0.70 mmol) and acetyl chloride (50 mg, 0.64 mmol)
according to general procedure B, gave 112.8 mg (73%) of desired amide as a yellow solid.
+
1
ESI-MS: C H N O, m/z calculated for [M+H] : 243.14, Found: 243.37. H NMR δ (CDCl )
1
5
18
2
3
8
1
3
2
1
.04 (s, NH), 7.63 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.1, 7.1, 1.2 Hz,
H), 7.12 (ddd, J = 7.9, 7.1, 1.1 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 4.77 (m, 1H), 3.92 (m, 1H),
.26 (ddd, J = 13.4, 12.9, 2.7 Hz, 1H), 3.09 (tt, J = 11.8, 3.8 Hz, 1H), 2.75 (ddd, J = 13.4, 12.9,
1
3
.9 Hz, 1H), 2.15 (s, 3H), 1.76 – 1.60 (m, 4H); C NMR δ (CDCl
3
) 168.9, 136.4, 126.4, 122.2,
20.5, 119.7, 119.3, 118.9, 111.3, 47.1, 42.3, 33.8, 33.6, 32.3, 21.6.
(
4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-4-yl)methanone (10g)
Reaction of compound 5 (20 mg, 0.10 mmol), isonicotinic acid (12.3 mg, 0.10 mmol), DIPEA
52.3 ꢀL, 0.3 mmol) and PyBOP (57.2 mg, 0.11 mmol) according to general procedure D, gave
(
1
8.30 mg (60 %) of desired amide as a yellow oil.
+
1
ESI-MS: C H N O, m/z calculated for [M+H] : 306.15, Found: 306.09. H NMR δ (CDCl )
1
9
19
3
3
8
7
6
2
1
1
.71 (dd, J = 5.9, 1.6 Hz, 2H), 8.06 (s, NH), 7.62 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H),
.33 (d, J = 5.9 Hz, 2H), 7.21 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.13 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H),
.98 (d, J = 2.5 Hz, 1H), 4.86 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 15.9 Hz, 1H), 3.27 (td, J = 12.5,
.3 Hz, 1H), 3.16 (tt, J = 3.7, 11.9 Hz, 1H), 3.0 (td, J = 12.9, 2.8 Hz, 1H), 2.23 (d, J = 13.3 Hz,
1
3
H), 2.08 (d, J = 13.0 Hz, 1H), 1.84 (m, 1H), 1.63 (m, 1H); C NMR δ (CDCl ) 167.5, 150.1,
3
43.9, 136.3, 126.1, 122.1, 120.9, 119.9, 119.5, 119.2, 118.7, 111.2, 48.0, 42.6, 33.6, 32.2, 29.5.
(
4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-2-yl)methanone (10h)
Reaction of compound 5 (20 mg, 0.10 mmol), picolinic acid (12.3 mg, 0.10 mmol), DIPEA (52.3
L, 0.3 mmol) and PyBOP (57.2 mg, 0.11 mmol) according to general procedure D, gave 28.98
mg (95 %) of desired amide as a beige solid.
ESI-MS: C H N O, m/z calculated for [M+H] : 306.15, Found: 306.38. H NMR δ (CDCl )
ꢀ
+
1
1
9
19
3
3
8
.71 (s, 2H), 8.22 (s, NH), 7.62 (d, J = 8.0 Hz, 1H), 7.39 – 7.31 (m, 3H), 7.20 (ddd, J = 8.2, 7.1,

ACCEPTED MANUSCRIPT
1
1
3
1
1
.2 Hz, 1H), 7.12 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 4.86 (d, J = 12.8 Hz,
H), 3.73 (d, J = 13.0 Hz, 1H), 3.27 (td, J = 12.7, 2.9 Hz, 1H), 3.15 (tt, J = 11.9, 3.7 Hz, 1H),
.01 (td, J = 12.9, 2.7 Hz, 1H), 2.23 (d, J = 13.1 Hz, 1H), 2.08 (d, J = 13.0 Hz, 1H), 1.85 (m,
1
3
H), 1.60 (m, 1H); C NMR δ (CDCl
3
) 167.7, 150.3, 144.0, 136.4, 126.3, 122.2, 121.1, 119.9,
19.8, 119.3, 118.8, 111.4, 48.2, 42.8, 33.7, 33.6, 32.4.
(4-(1H-indol-3-yl)piperidin-1-yl)(pyrazin-2-yl)methanone (10i)
Reaction of compound 5 (20 mg, 0.10 mmol), pyrazine-2-carbonyl chloride (14.19 mg, 0.10
mmol), DIPEA (52.3 ꢀL, 0.3 mmol) and PyBOP (57.2 mg, 0.11 mmol) according to general
procedure D, gave 30.62 mg (qtt yield) of desired amide as a yellow solid.
+
1
ESI-MS: C18
H
18
N
4
O, m/z calculated for [M+H] : 307.15, Found: 307.38. H NMR δ (CDCl
.94 (d, J = 1.5 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.56 (dd, J = 2.5, 1.5 Hz, 1H), 8.10 (s, NH),
.64 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.12 (ddd,
3
)
8
7
J = 7.9, 7.0, 1.1 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 4.89 (d, J = 13.3 Hz, 1H), 4.05 (d, J = 13.5
Hz, 1H), 3.31 (td, J = 12.7, 2.8 Hz, 1H), 3.18 (tt, J = 11.8, 3.7 Hz, 1H), 3.04 (td, J = 12.9, 2.9 Hz,
1
3
1
H), 2.23 (d, J = 13.2 Hz, 1H), 2.08 (d, J = 12.9 Hz, 1H), 1.95 – 1.76 (m, 2H); C NMR δ
(
CDCl ) 165.7, 150.4, 145.7, 145.6, 143.2, 138.2, 126.8, 122.6, 120.7, 120.3, 119.8, 119.3,
3
1
11.8, 48.5, 43.8, 34.2, 33.9, 32.9.
1
,4-phenylenebis((4-(1H-indol-3-yl)piperidin-1-yl)methanone) (10j)
Reaction of compound 5 (20 mg, 0.10 mmol), terephthalic acid (8.30 mg, 0.05 mmol), DIPEA
52.3 ꢀL, 0.3 mmol) and PyBOP (57.2 mg, 0.11 mmol) according to general procedure D, gave
(
5
3.02 mg (qtt yield) of desired amide as a white solid.
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 531.27, Found: 531.45. H NMR δ (DMSO)
3
4
34
4
2
1
2
0.81 (s, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.50 (s, 4H), 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 2.3 Hz,
H), 7.05 (ddd, J = 8.1, 7.0, 1.2 Hz, 2H), 6.96 (ddd, J = 7.9, 7.0, 1.1 Hz, 2H), 4.61 (br, 2H), 3.70
(br, 2H), 3.26 (br, 2H), 3.09 (tt, J = 11.9, 3.6 Hz, 2H), 2.97 (br, 2H), 2.07 (br, 1H), 1.93 (br, 1H),
1
3
1
1
.70 – 1.60 (m, 4H); C NMR δ (DMSO) 168.8, 137.8, 136.8, 127.3, 126.6, 121.4, 121.3, 119.4,
18.9, 118.6, 111.9, 49.1, 48.2, 33.6, 33.1, 14.4.
4
-(4-(1H-indol-3-yl)piperidin-1-yl)-6-chloroquinoline (11)

ACCEPTED MANUSCRIPT
To a solution of compound 5 (20 mg, 0.10 mmol) and DIPEA (52.3 ꢀL, 0.3 mmol) in
isopropanol (2 ml) was added 4,6-dichloroquinoline (19.80 mg, 0.10 mmol). The reaction
mixture stirred under reflux for 56h. The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography using a gradient elution of ethyl
acetate/acetonitrile:water:methanol (1:1:1) to afford compound 11 as a yellow oil (9.05 mg,
2
5%).
+
1
ESI-MS: C H ClN , m/z calculated for [M+H] : 362.13, Found: 361.14. H NMR (DMSO)
2
2
20
3
1
0.89 (s, NH), 8.66 (d, J = 6.9 Hz, 1H), 8.22 – 8.09 (m, 2H), 8.02 (dd, J = 9.1, 1.3 Hz, 1H), 7.63
(d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H),
7
2
2
1
.08 (ddd, J = 7.8, 7.0, 1.3 Hz, 1H), 7.00 (m, 1H), 4.28 (d, J = 13.1 Hz, 2H), 3.70 (td, J = 12.8,
.9 Hz, 2H), 3.29 (tt, J = 11.4, 3.8 Hz, 1H), 2.20 (dd, J = 11.9, 2.0 Hz, 2H), 2.02 (qd, J = 12.9,
1
3
.4 Hz, 2H); C NMR δ (DMSO) 159.5, 142.0, 138.5, 136.4, 133.5, 131.9, 130.3, 126.1, 125.3,
21.0, 120.9, 120.0, 118.6, 118.4, 118.2, 111.5, 106.2, 52.4, 32.4.
(4-(1H-indol-3-yl)piperidin-1-yl)(piperidin-4-yl)methanone (12)
Compound 6 (200 mg, 0.49 mmol) was dissolved in a solution of 2M HCl in MeOH (6 mL) and
stirred at room temperature for 40 min. The solvent was removed under reduced pressure and the
crude product was purified by reverse phase flash chromatography using a gradient elution of
water/acetonitrile to afford the desired product as a yellow solid (151.2 mg, qtt yield).
+
1
ESI-MS: C H N O, m/z calculated for [M+H] : 312.20, Found: 312.41. H NMR δ (MeOD)
1
9
25
3
8
1
1
2
.49 (s, NH), 7.59 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.10 (ddd, J = 8.1, 6.9, 1.2 Hz,
H), 7.04 (s, 1H), 7.01 (ddd, J = 7.9, 6.9, 1.1 Hz, 1H), 4.66 (d, J = 13.3 Hz, 1H), 4.21 (d, J =
3.7 Hz, 1H), 3.49 (m, 2H), 3.39 (m, 1H), 3.24 – 3.08 (m, 4H), 2.87 (td, J = 12.9, 2.8 Hz, 1H),
1
3
.21 (d, J = 13.1 Hz, 2H), 2.12 (d, J = 13.9 Hz, 2H), 2.07 – 1.86 (m, 4H), 1.70 (m, 2H); C
NMR δ (MeOD) 173.7, 138.3, 127.7, 122.3, 121.2, 120.3, 119.5, 119.4, 112.3, 47.5, 44.4, 43.9,
6.7, 35.2, 34.9, 33.9, 26.8, 26.6, 25.9.
3
(4-(1H-indol-3-yl)piperidin-1-yl)(1-benzoylpiperidin-4-yl)methanone (13a)
Reaction of compound 12 (20 mg, 0.06 mmol) and benzoyl chloride (7.56 mg, 0.054 mmol)
according to general procedure B, gave 22.4 mg (80 %) of desired product as a beige solid.

ACCEPTED MANUSCRIPT
+
1
ESI-MS: C26
H
29
N
3
O
2
, m/z calculated for [M+H] : 416.23, Found: 416.22. H NMR δ (CDCl
3
)
8
1
.66 (s, NH), 7.60 (m, 1H), 7.47 – 7.36 (m, 5H), 7.33 (d, J = 8.2 Hz, 1H), 7.17 (ddd, J = 8.2, 7.0,
.2 Hz, 1H), 7.10 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.90 (s, 1H), 4.76 (m, 1H), 4.52 (br, 1H), 4.03
(m, 1H), 3.87 (br, 1H), 3.25 (t, J = 12.1 Hz, 2H), 3.09 (tt, J = 11.9, 3.7 Hz, 1H), 2.96 – 2.70 (m,
1
3
5
1
1
H), 2.23 – 2.05 (m, 2H), 1.92 – 1.80 (m, 2H), 1.74 – 1.59 (m, 2H); C NMR δ (CDCl ) 172.6,
3
70.7, 136.6, 135.9, 133.1, 129.7, 128.6, 128.4, 126.9, 126.3, 121.9, 120.0, 119.8, 119.1, 118.8,
11.5, 51.9, 47.4, 46.3, 42.9, 42.0, 40.9, 38.4, 33.9, 32.5, 28.9.
(
4-(1H-indol-3-yl)piperidin-1-yl)(1-(3,5-dimethoxybenzoyl)piperidin-4-yl)methanone (13b)
Reaction of compound 12 (20 mg, 0.06 mmol) and 3,5-dimethoxybenzoyl chloride (10.8 mg,
.054 mmol) according to general procedure B, gave 19.24 mg (75 %) of desired product as a
beige oil.
ESI-MS: C H N O , m/z calculated for [M+H] : 476.25, Found: 476.42. H NMR δ (MeOD)
0
+
1
2
8
33
3
4
7
7
4
1
.61 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.11 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.07 –
.00 (m, 2H), 6.61 (dd, J = 2.9, 2.3 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 4.70 (d, J = 13.6 Hz, 2H),
.24 (d, J = 13.1 Hz, 1H), 3.84 (s, 6H), 3.80 (br, 1H), 3.30 – 3.07 (m, 3H), 3.01 (d, J = 11.6 Hz,
1
3
H), 2.90 (m, 1H), 2.22 (d, J = 12.6 Hz, 1H), 2.14 (d, J = 12.6 Hz, 1H), 1.99 – 1.55 (m, 7H); C
NMR δ (MeOD) 174.8, 172.1, 162.6, 138.9, 138.3, 127.7, 122.3, 121.2, 120.4, 119.5, 119.4,
12.3, 105.5, 102.5, 56.0, 47.4, 43.9, 39.3, 35.3, 35.1, 33.9.
1
(4-(1H-indol-3-yl)piperidin-1-yl)(1-(4-fluorobenzoyl)piperidin-4-yl)methanone (13c)
Reaction of compound 12 (20 mg, 0.06 mmol) and 4-fluorobenzoyl chloride (8.53 mg, 0.054
mmol) according to general procedure B, gave 17.54 mg (75 %) of desired product as a beige
solid.
+
1
ESI-MS: C H FN O , m/z calculated for [M+H] : 434.22, Found: 434.23. H NMR δ (CDCl )
2
6
28
3
2
3
8
.11 (s, NH), 7.62 (d, J = 7.9 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.20 (dd, J
7.5, 7.1 Hz, 1H), 7.14 – 7.06 (m, 3H), 6.95 (d, J = 2.4 Hz, 1H), 4.78 (d, J = 12.4 Hz, 1H), 4.67
br, 1H), 4.03 (d, J = 12.4 Hz, 1H), 3.89 (br, 1H), 3.27 (t, J = 12.9 Hz, 1H), 3.12 (tt, J = 11.9, 3.7
Hz, 1H), 3.01 (br, 1H), 2.93 – 2.69 (m, 2H), 2.19 (d, J = 12.3 Hz, 1H), 2.12 (d, J = 12.9 Hz, 1H),
=
(
1
3
1
1
.96 – 1.56 (m, 7H); C NMR δ (CDCl ) 172.3, 169.6, 163.4 (d, J = 248 Hz), 136.4, 132.0,
3 CF

ACCEPTED MANUSCRIPT
1
3
29.2, 126.3, 122.2, 120.2, 119.7, 119.3, 118.8, 115.7, 115.5, 111.4, 46.2, 42.7, 40.9, 38.4, 33.9,
2.4.
(4-(1H-indol-3-yl)piperidin-1-yl)(1-nicotinoylpiperidin-4-yl)methanone (13d)
Reaction of compound 12 (20 mg, 0.06 mmol), nicotinoyl chloride (7.61 mg, 0.054 mmol) and
DIPEA (52.3 ꢀL, 0.16 mmol) according to general procedure C, gave 5.6 mg (25%) of desired
product as a beige solid.
+
1
ESI-MS: C H N O , m/z calculated for [M+H] : 417.22, Found: 417.41. H NMR δ (CDCl )
2
5
28
4
2
3
8
7
.73 – 8.60 (m, 2H), 8.23 (s, NH), 7.76 (dt, J = 8.0, 1.9 Hz, 1H), 7.61 (dd, J = 8.2, 1.2 Hz, 1H),
.36 (m, 2H), 7.20 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.11 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.95 (d, J
=
2.9 Hz, 1H), 4.78 (d, J = 12.9 Hz, 1H), 4.69 (br, 1H), 4.02 (d, J = 12.7 Hz, 1H), 3.79 (br, J =
1
2
3
1
H), 3.28 (m, 1H), 3.12 (tt, J = 11.9, 3.8 Hz, 1H), 3.01 (br, 1H), 2.86 (td, J = 9.1, 4.6 Hz, 1H),
.77 (t, J = 11.7 Hz, 1H), 2.19 (d, J = 12.4 Hz, 1H), 2.12 (d, J = 12.7 Hz, 1H), 1.95 – 1.79 (m,
1
3
H), 1.77 – 1.58 (m, 4H); C NMR δ (CDCl
3
) 172.1, 167.8, 150.7, 147.8, 136.5, 134.9, 131.9,
26.3, 123.5, 122.1, 120.1, 119.8, 119.3, 118.8, 111.4, 50.8, 46.2, 42.7, 38.2, 33.9, 32.4.
(
4-(1H-indol-3-yl)piperidin-1-yl)(1-(thiophene-2-carbonyl)piperidin-4-yl)methanone (13e)
Reaction of compound 12 (20 mg, 0.06 mmol) and thiophene-2-carbonyl chloride (7.88 mg,
.054 mmol) according to general procedure B, gave 16.6 mg (73 %) of desired product as a
0
white solid.
+
1
27 3 2 3
ESI-MS: C24H N O S, m/z calculated for [M+H] : 422.18, Found: 422.19. H NMR δ (CDCl )
8
.19 (s, NH), 7.62 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 5.0 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.30 (d,
J = 3.7 Hz, 1H), 7.20 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.12 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 7.04
(dd, J = 5.0, 3.7 Hz, 1H), 6.96 (s, 1H), 4.47 (d, J = 13.9 Hz, 2H), 3.18–3.01 (m, 4H), 2.91–2.84
1
3
(
m, 2H), 2.16 (d, J = 12.2 Hz, 2H), 2.03–1.52 (m, 8H); C NMR δ (CDCl ) 172.8, 164.2, 137.6,
3
1
2
36.9, 129.1, 128.9, 127.1, 126.8, 122.6, 120.6, 120.2, 119.7, 119.3, 111.8, 52.4, 41.4, 38.8, 34.3,
9.2, 28.7.
1
-(4-(4-(1H-indol-3-yl)piperidine-1-carbonyl)piperidin-1-yl)ethan-1-one (13f)
Reaction of compound 12 (20 mg, 0.06 mmol) and acetyl chloride (4.21 mg, 0.054 mmol)
according to general procedure B, gave 7.62 mg (40 %) of desired product as a white solid.