Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

Article abstract of DOI:10.1016/j.ejmech.2020.112149

Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT_2A and dopamine D₂ receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT₆Rs and 5-HT₇Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M₃R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pK_i = 8.32–9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pK_B = 7.41–9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.

Full text of DOI:10.1016/j.ejmech.2020.112149

Journal Pre-proof
Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting
behavioral and psychological symptoms of dementia (BPSD)
Adam Bucki, Monika Marcinkowska, Joanna Śniecikowska, Agnieszka Zagórska,
Marek Jamrozik, Maciej Pawłowski, Monika Głuch-Lutwin, Agata Siwek, Magdalena
Jakubczyk, Karolina Pytka, Magdalena Jastrzębska-Więsek, Anna Partyka, Anna
Wesołowska, Paweł Mierzejewski, Marcin Kołaczkowski
PII:
S0223-5234(20)30116-1
DOI:
https://doi.org/10.1016/j.ejmech.2020.112149
EJMECH 112149
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 13 November 2019
Revised Date: 12 February 2020
Accepted Date: 13 February 2020
Please cite this article as: A. Bucki, M. Marcinkowska, J. Śniecikowska, A. Zagórska, M. Jamrozik, M.
Pawłowski, M. Głuch-Lutwin, A. Siwek, M. Jakubczyk, K. Pytka, M. Jastrzębska-Więsek, A. Partyka,
A. Wesołowska, Paweł. Mierzejewski, M. Kołaczkowski, Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-
yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD),
European Journal of Medicinal Chemistry (2020), doi: https://doi.org/10.1016/j.ejmech.2020.112149.
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2020 Published by Elsevier Masson SAS.

Lead compound of
drug-like properties
Computer-aided drug design
In vitro affinity
Behavioral studies
In vivo activity:
5
-HT6
✓ Antipsychotic-like
✓ Anxiolytic-like
1
0
9
8
7
6
5
4
5-HT2A
5-HT7
pKi
✓
Antidepressant-like
Cause no:
M3
D2
✓
✓
memory deficits
hERG
motor impairments
Pharmacological profile combining high affinity
for the 5-HT2A, 5-HT6, 5-HT7 and D2 receptors
CNS MPO 4.4
Antagonist functional
activity
Potential application in
BPSD
Clint = 88 µL/min/mg HLM

Multifunctional 6-Fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles
Targeting Behavioral And Psychological Symptoms Of Dementia (BPSD)
a,c*
a
a,c
a
Adam Bucki , Monika Marcinkowska , Joanna Śniecikowska , Agnieszka Zagórska , Marek
a
a
a
a
a
Jamrozik , Maciej Pawłowski , Monika Głuch-Lutwin , Agata Siwek , Magdalena Jakubczyk ,
a
a
a
a
Karolina Pytka , Magdalena Jastrzębska-Więsek , Anna Partyka , Anna Wesołowska ,
b
a,c
Paweł Mierzejewski and Marcin Kołaczkowski
a
Faculty of Pharmacy, Jagiellonian University Medical College,
Medyczna Street, 30-688 Kraków, Poland
9
b
Institute of Psychiatry and Neurology, 9 Sobieskiego Street, 02-957 Warsaw, Poland
c
Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152 Czosnów, Poland
*
Corresponding Author Information:
Phone: (+48)126205460; Fax: (+48)126205458
E-mail: adam.bucki@uj.edu.pl

ABSTRACT
Patients suffering from dementia experience cognitive deficits and 90% of them show
non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of
BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine,
have been commonly used off-label to control the burdensome symptoms, though they
cause serious side effects and further cognitive impairment. Therefore, the development of
targeted therapy for BPSD, suitable for elderly patients, remains relevant.
A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D receptors
2
(
R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT Rs and 5-
6
HT Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising
7
strategy for the treatment of BPSD. Antitargeting muscarinic M R and hERG channel is
3
expected to reduce the risk of side effects. We obtained a series of stereoisomeric
compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment
through pyrrolidin-1-yl-propyl linker.
N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-
2
-sulfonamide showed a substantial affinity for the targets of interest (pK = 8.32 – 9.35) and
i
no significant interaction with the antitargets. Functional studies revealed its antagonist
efficacy (pK = 7.41 – 9.03). The lead compound showed a promising profile of antipsychotic-
B
like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg),
antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in
the forced swim and four-plate tests, respectively). Notably, the novel compound didn’t
affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-
through passive avoidance test) in therapeutically relevant doses, which proved its benign
safety profile. The overall pharmacological characteristics of the lead compound

outperformed the reference drug quetiapine, making it a promising option for evaluation in
the treatment of BPSD.
KEYWORDS: MTDL; BPSD; psychosis in dementia; Alzheimer’s disease; serotonin receptors;
arylsulfonamide.
ABBREVIATIONS: BPSD, behavioral and psychological symptoms of dementia; AD,
Alzheimer’s disease; MTDL, multitarget-directed ligand; MED, minimum effective dose; 5-
HT R, 5-HT serotonin receptor; 5-HT R, 5-HT serotonin receptor; 5-HT R, 5-HT serotonin
2
A
2A
6
6
7
7
receptor; D R, D dopamine receptor; M R, M muscarinic receptor; CNS-MPO, central
2
2
3
3
nervous system multiparameter optimization.

INTRODUCTION
According to the World Health Organization (WHO), dementia affects 47.5 million
people worldwide and each year there are approximately 7.7 million new reports [1].
Dementia is typically associated with cognitive impairment and memory loss, however, the
most burdensome signs are so-called behavioral and psychological symptoms of dementia
(BPSD). The spectrum of BPSD includes agitation, irritability, psychosis, depression and
anxiety. These symptoms not only affect the quality of life of patients living with the disease
but also poses a heavy burden for their families and caregivers [2].
It is estimated that at least one or more symptoms of psychological or behavioral
disturbances will manifest in almost all (about 90%) of dementia patients in the course of
their disease. Approximately 50% of patients with Alzheimer’s disease (AD) and other
dementias develop psychosis manifesting mainly in hallucinations and delusions [3]. The first
th
patient, reported by Alois Alzheimer in the early 20 century, experienced psychotic
symptoms in fact [4]. The remaining signs and symptoms occur equally often; depression
affects 40-60% of dementia patients, while over 20% suffer from anxiety disorders. These
rates were 3 to 4 times higher than those estimated for people aged 65 and elder without
dementia [5,6]. Treatment of psychological and behavioral abnormalities in dementia
patients is exceptionally intractable because no pharmacotherapy has been designed and
approved in this indication to date. Given the lack of dedicated therapies, available atypical
antipsychotics have been commonly used off-label for psychosis and severe agitation in
dementia. However, these medications show limited clinical effectiveness and cause many
serious side effects such as weight gain, type II diabetes, QTc interval prolongation,
hyperlipidemia, myocarditis, extrapyramidal syndrome (EPS), and anticholinergic effects.
Moreover, long-term treatment with the present antipsychotics causes cognitive impairment

that is particularly undesirable regarding elderly patients who already suffer from memory
deficits [7]. Therefore, only short-term use of the lowest doses is acceptable for selected
antipsychotics, e.g. risperidone and quetiapine [8–10]. Depressive disorders in dementia
patients are treated with known classes of antidepressants, nevertheless, results from
different studies are contradictory. Only a few antidepressants (e.g. citalopram and
sertraline) appear to be effective and well-tolerated in patients suffering from major
depression in AD. On the other hand, antidepressants were ineffective in patients with mild
to moderate depression. Moreover, there is no specific data on the treatment of depression
in vascular dementia or other non-Alzheimer types of dementia [5]. Therefore, the
development of more effective and safe therapeutic option that does not cause further
cognitive impairment and therefore is suitable for elderly patients, remains an unmet clinical
need.
It’s been demonstrated that serotoninergic, dopaminergic and cholinergic systems are
particularly involved in the pathogenesis of BPSD, and the role of serotoninergic 5-HT6,
5
-HT , 5-HT receptors and dopamine D receptors as therapeutic targets appear to be
2A 7 2
evident [2]. The relevance of serotoninergic modulation in the treatment of psychosis and
cognitive impairment was investigated as a favourable component of the mechanism of
action of atypical antipsychotic drugs [11]. The validity of this approach was confirmed in
clinical trials, as pimavanserin, the 5-HT2A receptors antagonist, proved its positive efficacy in
patients with dementia-related psychosis. It showed antipsychotic activity and acceptable
tolerability without negative effect on cognition in phase 2 placebo-controlled study [12].
Treatment with pimavanserin resulted in statistically significant longer time to relapse of
psychosis compared to placebo in phase 3 clinical study [13,14].
A growing body of evidence testifies that selective antagonists of serotoninergic 5-HT6

receptors exhibit procognitive effect due to enhancing cholinergic transmission in the
prefrontal cortex. Therapeutic potential of 5-HT receptor antagonists has been studied in
6
clinical trials. The most encouraging results were obtained in phase II clinical trials with 5HT6
receptor antagonists: SB 742457 and Lu AE58054, which improved cognitive functions in
patients with Alzheimer’s disease [15]. These results gave hope for the therapeutic potential
of 5-HT receptor antagonists in dementia patients. Besides the procognitive properties, 5-
6
HT receptor antagonists have shown significant antidepressant activity related to an
6
enhancement of dopaminergic and noradrenergic transmission, as well as an anxiolytic
effect due to interaction with GABAergic system [16]. Similar pharmacological effects were
observed after administration of selective 5-HT receptor antagonist SB-269970. Serotonin
7
5
-HT receptors are located in brain regions associated with the processes of learning and
7
memory. Preclinical studies with selective 5-HT receptor antagonists exposed their ability to
7
elicit antipsychotic and antidepressant-like effects [17]. Moreover, it’s been proven that
blockade of the 5-HT2A and 5-HT receptors can alleviate EPS induction caused by e.g.
6
dopamine antagonism [18]. The abovementioned data suggest possible efficacy of the
selected serotonin receptors antagonists in the management of BPSD.
It has been widely accepted that one of the most advantageous approaches in the
modern drug discovery for diseases of complex aetiology, is the development of a
multitarget-directed ligand (MTDL). This strategy relies on the design of a single molecule
that interacts simultaneously with a range of biological targets of high therapeutic relevance.
Such a multifunctional ligand offers several advantages over a pharmacological cocktail,
made up from several separate drugs, in terms of pharmacokinetics and safety. Following
this strategy, we identified specific molecular targets, modulation of which might contribute
to effective pharmacotherapy of BPSD. The interaction with the 5-HT2A and D receptors is
2

supposed to provide anti-aggressive and antipsychotic activity, while antagonism of the 5-
HT and 5-HT receptors is expected to contribute to the pro-cognitive, antidepressant and
6
7
anxiolytic activity of the designed MTDLs.
Herein we present the computer-aided design, chemical synthesis and biological
evaluation of innovative ligands aimed as a potential treatment of behavioral and
psychological symptoms in the fragile population of elderly patients.
MATERIALS AND METHODS
Molecular modeling
Computer-aided design was based on molecular property analysis and prediction of
ligand-target interactions. To this end, docking to the previously developed homology
models of the 5-HT , 5-HT , 5-HT and D receptors was performed. Procedure for obtaining
2
A
6
7
2
ligand-optimized models of high predictive value, utilizing Induced-fit docking (IFD), was
characterized in detail previously [19–21]. The 5-HT R model was based on the 5-HT R
2
A
2B
crystal structure 4IB4 [22]. The alignment of the 5-HT R amino acid sequence (UniProt
1A
P28223) was predicted by hhsearch model via Genesilico Metaserver (overall amino acid
sequence identity 48%) [23]. Homology model was obtained via SwissModel platform [24]
and was validated by processing in Protein Preparation Wizard. Ligand-based optimization of
the binding site, performed using IFD protocol, as well as cross docking-based (Glide XP)
assessment of model predictive value, were carried out using various chemical classes of
high affinity 5-HT R ligands and resulted in a variety of conformational models that served
2A
as molecular targets in docking studies. Glide XP flexible docking procedure was carried out
using OPLS3 force field and default parameters. H-bond constraint, as well as centroid of a

grid box for docking to the receptor models were located on Asp3.32. Selection of the best
complex was based on scoring function and visual analysis of binding mode. Ligand
structures were optimized using LigPrep tool. Glide, induced fit docking (IFD), LigPrep and
Protein Preparation Wizard were implemented in Small-Molecule Drug Discovery Suite
(Schrödinger, Inc.), which was licensed for Adamed Pharma S.A.
Instant JChem was used for structure database management, search and property
prediction, Instant JChem 15.12.14.0, 2015, ChemAxon (http://www.chemaxon.com).
Metabolic pathways and clearance prediction was conducted using ADMET Predictor
(Simulations Plus Inc.).
The designed structures were tested for compliance with rules evaluating
bioavailability of a compound after oral administration – Lipinski’s rule of five and Veber
filter. The first one assumes that compounds having LogPo/w (octanol/water partition
coefficient) lower than 5, molecular weight (MW) below 500, less than 10 H-bond acceptors
(HBA), and less than 5 H-bond donors (HBD) are more likely to show favourable
bioavailability [25]. The Veber rule extends the range of parameters by rotatable bonds
2
(
preferably RB < 10) and topological polar surface area (preferably TPSA < 140 A ) [26].
Molecules that obey the above restrictions and are characterized by low basicity (the most
favourable pK values below 8, due to P-gp interactions and ionization issues) are more likely
a
to show preferable membrane permeability [27]. CNS MPO values were calculated using the
above data in CNS MPO calculator [28]. Moreover, the designed structures were examined
using SwissADME [29] tool for known classes of reactive assay interference compounds
(PAINS), that would disturb biological in vitro studies.
Chemical synthesis

General chemistry information
Unless otherwise indicated, all the starting materials were purchased from
commercial suppliers and were used for synthesis without further purification. Analytical
thin-layer chromatography (TLC) was performed on Merck Kieselgel 60 F254 (0.25 mm) pre-
coated aluminium sheets (Merck, Darmstadt, Germany). Chromatograms were visualized
using a 254 nm UV lamp. Column chromatography was performed using silica gel (particle
size 0.063–0.200 mm; 70–230 Mesh ATM) purchased from Merck. The UPLC-MS or UPLC-
MS/MS analyses were run on UPLC-MS/MS system comprising Waters ACQUITY UPLC
(
Waters Corporation, Milford, MA, USA) coupled with Waters TQD mass spectrometer
electrospray ionization mode ESI with tandem quadrupole). Chromatographic separations
(
were carried out using the ACQUITY UPLC BEH (bridged ethyl hybrid) C18 column: 2.1 × 100
mm and 1.7 µm particle size. The column was maintained at 40 °C and eluted under gradient
conditions using 95% to 0% of eluent A over 10 min, at a flow rate of 0.3 mL/min. Eluent A:
0
.1% solution of formic acid in water (v/v); eluent B: 0.1% solution of formic acid in
acetonitrile (v/v). A total of 10 µl of each sample were injected, and chromatograms were
recorded using Waters eλ PDA detector. The spectra were analyzed in the range of 200–700
nm with 1.2 nm resolution and at a sampling rate of 20 points/s. MS detection settings of
Waters TQD mass spectrometer were as follows: source temperature 150 °C, desolvation
temperature 350 °C, desolvation gas flow rate 600 l/h, cone gas flow 100 L/h, capillary
potential 3.00 kV, and cone potential 20 V. Nitrogen was used for both nebulizing and
drying. The data were obtained in a scan mode ranging from 50 to 1000 m/z at 0.5 s
intervals; 8 scans were summed up to obtain the final spectrum. Collision activated
dissociation (CAD) analyses were carried out with the energy of 20 eV, and all the
fragmentations were observed in the source. Consequently, the ion spectra were obtained in

the range from 50 to 500 m/z. MassLynx V 4.1 software (Waters) was used for data
acquisition. Standard solutions (1 mg/mL) of each compound were prepared in a mixture
comprising analytical grade acetonitrile/water (1/1, v/v). The UPLC/MS purity of all the test
1
13
19
compounds and key intermediates was determined to be >95%. H NMR, C NMR, and
F
NMR spectra were obtained in a Varian Mercury spectrometer (Varian Inc., Palo Alto, CA,
1
13
USA), in CDCl CD OD or DMSO-d operating at 300 MHz ( H NMR), 75 MHz ( C NMR), and
3
,
3
6
1
9
2
82 MHz ( F NMR). Chemical shifts are reported in terms of δ values (ppm) relative to TMS
1
δ = 0 ( H) as internal standard. The J values are expressed in Hertz (Hz). Signal multiplicities
are represented by the following abbreviations: s (singlet), br s (broad singlet), d (doublet),
dd (doublet of doublets), dt (doublet of triplets), dtd (doublet of triplet of doublets), t
(
triplet), td (triplet of doublets), tdd (triplet of doublet of doublets), q (quartet), quin
quintet), m (multiplet).
(
Synthetic procedures
General procedure for the synthesis of R or S enantiomer of tert-butyl (1-(3-(6-
fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)carbamate (I – II).
A mixture of 3-(3-chloropropyl)-6-fluorobenzo[d]isoxazole (1.0 equiv, 10.0 mmol),
appropriate tert-butyl pyrrolidin-3-ylcarbamate (R or S enantiomer), (1.1 equiv, 11.0 mmol),
potassium carbonate (3.0 equiv, 30.0 mmol) and catalytic amount of potassium iodide in
acetonitrile (60 mL) was stirred at 60 °C for 48 h. After that time, reaction mixture was
cooled to the room temperature, the solid was filtrated and the solvent was evaporated
under the reduced pressure. Next, the crude product was purified by column
chromatography over silica gel using dichloromethane/methanol (95/5, v/v) as eluent.

(R)-tert-butyl (1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)carbamate (I).
The
title compound was prepared starting from 3-(3-chloropropyl)-6-
fluorobenzo[d]isoxazole (1.0 equiv, 10.0 mmol, 2.13 g), (R)-tert-butyl pyrrolidin-3-
1
ylcarbamate (1.1 equiv, 11.0 mmol, 2.05 g) and potassium iodide. Yield 36%, yellow oil, H
NMR (300 MHz, CDCl , δ): 7.61 (dd, J = 5.0, 8.8 Hz, 1H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.06 (dt,
3
J = 2.2, 8.8 Hz, 1H), 4.90 (br s, 1H), 4.18 (br s, 1H), 3.03 (t, J = 7.4 Hz, 2H), 2.92 (br s, 1H),
2
1
2
.73–2.57 (m, 4H), 2.47–2.35 (m, 1H), 2.26 (dt, J = 8.3, 13.1 Hz, 1H), 2.16–2.02 (m, 2H), 1.73–
1
3
.57 (m, 1H), 1.42 (s, 9H); C NMR (75 MHz, CDCl , δ): 163.6 (d, J = 13.8 Hz), 164.3 (d, J =
3
50.2 Hz), 157.9, 155.3, 122.2 (d, J = 11.1 Hz), 118.2 (d, J = 1.7 Hz), 112.5 (d, J = 25.4 Hz), 97.3
(
d, J = 27.0 Hz), 79.4, 60.7, 55.0, 52.7, 49.6, 32.2, 28.4 (3C), 26.0, 22.9; Formula C H FN O ;
19 26 3 3
+
+
MS (ESI ): m/z 364 [M+H]
(S)-tert-butyl
(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)carbamate
(II). The title compound was prepared starting from 3-(3-chloropropyl)-6-
fluorobenzo[d]isoxazole (1.0 equiv, 10.0 mmol, 2.13 g), (R)-tert-butyl pyrrolidin-3-
1
ylcarbamate (1.1 equiv, 11.0 mmol, 2.05 g) and potassium iodide. Yield 48%, yellow oil, H
NMR (300 MHz, CDCl , δ): 7.61 (dd, J = 5.0, 8.8 Hz, 1H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.06 (dt,
3
J = 2.2, 8.8 Hz, 1H), 4.90 (br s, 1H), 4.18 (br s, 1H), 3.03 (t, J = 7.4 Hz, 2H), 2.92 (br s, 1H),
2
1
2
.73–2.57 (m, 4H), 2.47–2.35 (m, 1H), 2.26 (dt, J = 8.3, 13.1 Hz, 1H), 2.16–2.02 (m, 2H), 1.73–
1
3
.57 (m, 1H), 1.42 (s, 9H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 13.8 Hz), 163.6 (d, J =
3
50.2 Hz), 157.9, 155.3, 122.2 (d, J = 11.1 Hz), 118.2 (d, J = 1.7 Hz), 112.5 (d, J = 25.4 Hz), 97.3
(d, J = 27.0 Hz), 79.4, 60.7, 55.0, 52.7, 49.6, 32.2, 28.4, 26.0, 22.9; Formula C H FN O ; MS
19 26 3 3
+
+
(
ESI ): m/z 364 [M+H]
General procedure for the deprotection of the tert-butyloxycarbonyl group (III - IV).

The appropriate enantiomer of 3-(BOC-amino)pyrrolidine (I or II) (1.0 equiv, 4.26
mmol) was mixed with 1.0 M solution of hydrochloric acid in ethyl acetate (80 ml), and
stirred for 18 h (until the disappearance of starting materials - TLC monitoring). Then ethyl
acetate was removed under reduced pressure to obtain dark oil, which was washed with
ethyl acetate and dried under the vacuum. The intermediates III and IV were used in the
next step without further purification.
(R)-1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-amine hydrochloride (III).
The title compound was prepared using intermediate I (1.0 equiv, 4.26 mmol, 1.55 g) and 80
1
ml of 1.0 M HCl in EtOAc. Yield 96%, brown oil, H NMR (300 MHz, CD OD, δ): 7.85 (dd, J =
3
5
3
2
.3, 8.8 Hz, 1H), 7.36 (dd, J = 1.9, 8.8 Hz, 1H), 7.15 (dt, J = 2.2, 9.0 Hz, 1H), 4.24–4.04 (m, 1H),
.99–3.77 (m, 1H), 3.68–3.38 (m, 3H), 3.27 (td, J = 1.7, 3.3 Hz, 2H), 3.15 (t, J = 7.2 Hz, 2H),
.76–2.44 (m, 1H), 2.39–2.15 (m, 3H), NH protons not detected; Formula C H ClFN O; MS
1
4
19
3
+
+
(
ESI ): m/z 264 [M+H]
(S)-1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-amine hydrochloride (IV).
The title compound was prepared using intermediate II (1.0 equiv, 4.26 mmol, 1.55 g) and 80
1
ml of 1.0 M HCl in EtOAc. Yield 91%, brown oil, H NMR (300 MHz, CDCl , δ): 7.87 (dd, J = 5.1,
3
8
4
8
.7 Hz, 1H), 7.26 (dd, J = 2.1, 8.7 Hz, 1H), 7.20 (dt, J = 2.2, 9.0 Hz, 1H), 4.30–4.08 (m, 2H),
.03–3.80 (m, 2H), 3.73–3.70 (m, 2H), 3.48–3.46 (m, 3H), 2.95 (t, J = 7.3 Hz, 2H), 2.88 (dd, J =
.6, 16.5 Hz, 2H), 2.17 (td, J = 7.6, 15.5 Hz, 1H), 1.70-1.41 (br s,1H); 1.51 (br s, 1H); Formula
+
+
C H ClFN O; MS (ESI ): m/z 264 [M+H]
1
4
19
3
General procedure for the preparation of sulfonamide derivatives 1 – 36.

Cesium carbonate (2.0 equiv), catalytic amount of DMAP and suitable arylsulfonyl
chloride {1–18} (1.2 equiv) were added to a suspension of the amine III or IV (1.0 equiv) in
dry dichloromethane at room temperature. The reaction mixture was stirred for 12 hours,
then the cesium carbonate was filtrated and the solvent was evaporated under the reduced
pressure. Crude sulfonamides were purified by column chromatography over silica gel using
n-hexane/diethyl ether/dichloromethane/methanol (20/20/55/5, v/v) as eluent. The final
compounds were obtained with good overall yield (46 – 80%).
(R)-3-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (1). The title compound was prepared using intermediate III (1.0
equiv, 0.44 mmol, 0.132 g), 3-chlorobenzene-1-sulfonyl chloride (1.2 equiv, 0.53 mmol,
0
.112 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.88 mmol, 0.288 g) in
1
DCM (5 mL). Yield 58%, yellow oil, H NMR (300 MHz, CDCl , δ): 7.86 (t, J = 2.1 Hz, 1H), 7.75
3
(td, J = 1.3, 7.9 Hz, 1H), 7.58 (dd, J = 5.0, 8.5 Hz, 1H), 7.55–7.50 (m, 1H), 7.48–7.40 (m, 1H),
7
2
2
.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.07 (dt, J = 2.3, 8.8 Hz, 1H), 5.08 (br s, 1H), 3.89–3.79 (m, 1H),
.98 (t, J = 7.3 Hz, 2H), 2.76 (dt, J = 3.5, 8.5 Hz, 1H), 2.52–2.43 (m, 3H), 2.43–2.34 (m, 1H),
1
3
.22–2.12 (m, 1H), 2.12–2.02 (m, 1H), 2.01–1.89 (m, 2H), 1.60–1.47 (m, 1H); C NMR (75
MHz, CDCl , δ): 163.5 (d, J = 13.8 Hz), 164.2 (d, J = 250.2 Hz), 158.1, 142.7, 135.3, 132.7,
3
1
30.4, 127.1, 125.1, 122.1 (d, J = 10.4 Hz), 118.2 (d, J = 1.7 Hz), 112.5 (d, J = 26.0 Hz), 97.4 (d,
+
J = 27.0 Hz), 60.5, 54.5, 52.9, 51.8, 32.5, 26.2, 22.9; Formula C H ClFN O S; MS (ESI ): m/z
2
0
21
3 3
+
4
38 [M+H]
(S)-3-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (2). The title compound was prepared using intermediate IV (1.0
equiv, 0.44 mmol, 0.132 g), 3-chlorobenzene-1-sulfonyl chloride (1.2 equiv, 0.53 mmol,
0
.112 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.88 mmol, 0.288 g) in

1
DCM (5 mL). Yield 48%, yellow oil, H NMR (300 MHz, CDCl , δ): 7.86 (t, J = 2.1 Hz, 1H), 7.74
3
(td, J = 1.3, 7.9 Hz, 1H), 7.61–7.51 (m, 3H), 7.47–7.42 (m, 1H), 7.25 (dd, J = 2.1, 8.5 Hz, 1H),
7
.07 (dt, J = 2.3, 8.8 Hz, 1H), 3.85–3.73 (m, 1H), 2.99 (t, J = 7.3 Hz, 2H), 2.76 (dt, J = 3.5, 8.5
1
3
Hz, 1H), 2.52–2.46 (m, 3H), 2.41–2.39 (m, 1H), 2.14–1.92 (m, 4H), 1.55–1.49 (m, 1H);
C
NMR (75 MHz, CDCl , δ): 165.9 (d, J = 13.8 Hz), 163.5 (d, J = 250.2 Hz), 158.1, 142.6, 135.3,
3
1
9
32.7, 130.4, 127.1, 125.1, 122.1 (d, J = 10.4 Hz), 118.2 (d, J = 1.7 Hz), 112.5 (d, J = 26.0 Hz),
7.4 (d, J = 27.0 Hz), 60.5, 54.5, 52.9, 51.8, 32.4, 26.1, 22.8; Formula C H ClFN O S; MS
2
0
21
3 3
+
+
(
ESI ): m/z 438 [M+H]
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-3-
methylbenzenesulfonamide (3). The title compound was prepared using intermediate III (1.0
equiv, 0.33 mmol, 0.100 g), 3-methylbenzene-1-sulfonyl chloride (1.2 equiv, 0.40 mmol,
0
.076 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in
1
DCM (5 mL). Yield 58%, brown oil, H NMR (300 MHz, CDCl , δ): 7.70–7.63 (m, 2H), 7.59 (dd, J
3
=
1
2
1
1
5.0, 8.5 Hz, 1H), 7.39–7.33 (m, 2H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.07 (dt, J = 2.3, 8.8 Hz,
H), 4.89 (br s, 1H), 3.83 (br s, 1H), 2.97 (t, J = 7.3 Hz, 2H), 2.74 (dt, J = 4.1, 8.8 Hz, 1H), 2.51–
.43 (m, 3H), 2.42–2.35 (m, 4H), 2.24–2.14 (m, 1H), 2.13–1.99 (m, 1H), 1.99–1.89 (m, 2H),
1
3
.59–1.46 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.6 (d, J = 13.8 Hz),
3
58.1, 140.6, 139.3, 133.4, 129.0, 127.4, 124.1, 122.1 (d, J = 10.4 Hz), 118.2, 112.5 (d, J = 26.0
Hz), 97.4 (d, J = 27.0 Hz), 60.5, 54.6, 52.7, 52.0, 32.5, 26.2, 22.9, 21.3; Formula C H FN O S;
2
1
24
3 3
+
+
MS (ESI ): m/z 418 [M+H]
(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-3-
methylbenzenesulfonamide (4). The title compound was prepared using intermediate IV (1.0
equiv, 0.33 mmol, 0.100 g), 3-methylbenzene-1-sulfonyl chloride (1.2 equiv, 0.40 mmol,

0
.076 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in
1
DCM (5 mL). Yield 67%, brown oil, H NMR (300 MHz, CDCl , δ): 7.66–7.60 (m, 2H), 7.57 (dd, J
3
=
1
2
5.0, 8.5 Hz, 1H), 7.38–7.31 (m, 3H), 7.22 (dd, J = 2.1, 8.5 Hz, 1H), 7.07 (dt, J = 2.3, 8.8 Hz,
H), 3.82 (br s, 1H), 2.95 (t, J = 7.3 Hz, 2H), 2.70 (dt, J = 4.1, 8.8 Hz, 1H), 2.50–2.38 (m, 7H),
1
3
.22–2.19 (m, 1H), 2.06–1.88 (m, 4H), 1.59–1.41 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9
3
(d, J = 13.8 Hz), 163.6 (d, J = 250.2 Hz), 158.1, 140.6, 139.3, 133.4, 129.0, 127.4, 124.1, 122.2
(d, J = 10.4 Hz), 118.2, 112.5 (d, J = 26.0 Hz), 97.1 (d, J = 27.0 Hz), 60.4, 54.6, 52.6, 52.1, 32.3,
+
+
2
6.2, 22.8, 21.3; Formula C H FN O S; MS (ESI ): m/z 418 [M+H]
21 24 3 3
(R)-4-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (5). The title compound was prepared using intermediate III (1.0
equiv, 0.42 mmol, 0.126 g), 4-fluorobenzene-1-sulfonyl chloride (1.2 equiv, 0.51 mmol, 0.098
g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.84 mmol, 0.275 g) in DCM (5
1
mL). Yield 54%, brown oil, H NMR (300 MHz, CDCl , δ): 7.93–7.84 (m, 2H), 7.58 (dd, J = 5.0,
3
8
.5 Hz, 1H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.20–7.12 (m, 2H), 7.06 (dt, J = 1.8, 8.8 Hz, 1H), 5.02
(br s, 1H), 3.81 (br s, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.74 (dt, J = 4.4, 8.6 Hz, 1H), 2.51–2.43 (m,
3
2
2
H), 2.42–2.33 (m, 1H), 2.23–2.13 (m, 1H), 2.07 (tdd, J = 4.2, 8.6, 12.9 Hz, 1H), 2.01–1.89 (m,
1
3
H), 1.59–1.46 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.0 (d, J = 254.0 Hz), 164.2 (d, J =
3
50.2 Hz), 163.6 (d, J = 15.0 Hz), 158.1, 136.9 (d, J = 4.3 Hz), 129.7 (d, J = 9.2 Hz, 2C), 122.1 (d,
J = 11.5 Hz), 118.2, 116.3 (d, J = 22.0 Hz, 2C), 112.5 (d, J = 26.0 Hz), 97.4 (d, J = 27.0 Hz), 60.5,
+
+
5
4.5, 52.7, 51.9, 32.5, 26.2, 22.9; Formula C H F N O S; MS (ESI ): m/z 422 [M+H]
20 21 2 3 3
(S)-4-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (6). The title compound was prepared using intermediate IV (1.0
equiv, 0.42 mmol, 0.126 g), 4-fluorobenzene-1-sulfonyl chloride (1.2 equiv, 0.51 mmol, 0.098
g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.84 mmol, 0.275 g) in DCM (5

1
mL). Yield 57%, brown oil, H NMR (300 MHz, CDCl , δ): 7.91–7.85 (m, 2H), 7.58 (dd, J = 5.0,
3
8
2
2
.5 Hz, 1H), 7.25–7.14 (m, 3H), 7.07 (dt, J = 1.8, 8.8 Hz, 1H), 5.03 (br s, 1H), 3.83 (br s, 1H),
.98 (t, J = 7.6 Hz, 2H), 2.75 (dt, J = 4.4, 8.6 Hz, 1H), 2.51–2.46 (m, 3H), 2.40–2.35 (m, 1H),
1
3
.20–1.92 (m, 5H), 1.59–1.42 (m, 1H); C NMR (75 MHz, CDCl , δ): 166.7, 165.9 (d, J = 254.0
3
Hz), 163.6 (d, J = 250.2 Hz),163.2 (d, J = 15.0 Hz), 162.6, 137.1, 136.9 (d, J = 4.3 Hz), 129.7 (d,
J = 9.2 Hz), 122.2 (d, J = 11.5 Hz), 118.2, 116.3 (d, J = 22.0 Hz), 112.5 (d, J = 26.0 Hz), 97.4 (d, J
+
=
27.0 Hz), 60.5, 54.5, 52.7, 51.9, 32.4, 26.1, 22.9; Formula C H F N O S; MS (ESI ): m/z 422
2
0 21 2 3 3
+
[
M+H]
(R)-3-chloro-4-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (7). The title compound was prepared using intermediate III (1.0
equiv, 0.51 mmol, 0.152 g), 3-chloro-4-fluorobenzene-1-sulfonyl chloride (1.2 equiv, 0.61
mmol, 0.140 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 1.02 mmol,
1
0
6
1
1
.331 g) in DCM (5 mL). Yield 46%, brown oil, H NMR (300 MHz, CDCl , δ): 7.95 (dd, J = 2.3,
3
.4 Hz, 1H), 7.81–7.73 (m, 1H), 7.58 (dd, J = 4.7, 8.8 Hz, 1H), 7.30–7.20 (m, 2H), 7.11–7.02 (m,
H), 5.11 (br s, 1H), 3.83 (tdd, J = 3.0, 5.7, 8.2 Hz, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.84–2.74 (m,
H), 2.54–2.45 (m, 3H), 2.43–2.34 (m, 1H), 2.22–2.14 (m, 1H), 2.13–2.03 (m, 1H), 2.02–1.90
1
3
(
m, 2H), 1.62–1.48 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.3 (d, J = 250.2 Hz), 163.6 (d, J =
3
1
1
6
3.8 Hz), 160.5 (d, J = 257.0 Hz), 158.1, 138.1 (d, J = 4.1 Hz), 130.0 (2C), 127.4 (d, J = 8.1 Hz),
22.1 (d, J = 10.4 Hz), 118.2, 117.4 (d, J = 22.0 Hz), 112.5 (d, J = 26.0 Hz), 97.4 (d, J = 27.0 Hz),
+
+
0.5, 54.4, 52.9, 51.8, 32.5, 26.1, 22.9; Formula C H ClF N O S; MS (ESI ): m/z 456 [M+H]
2
0
20
2 3 3
(S)-3-chloro-4-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzenesulfonamide (8). The title compound was prepared using intermediate IV (1.0
equiv, 0.51 mmol, 0.152 g), 3-chloro-4-fluorobenzene-1-sulfonyl chloride (1.2 equiv, 0.61
mmol, 0.140 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 1.02 mmol,

1
0
6
1
.331 g) in DCM (5 mL). Yield 41%, brown oil, H NMR (300 MHz, CDCl , δ): 7.95 (dd, J = 2.3,
3
.4 Hz, 1H), 7.81–7.73 (m, 1H), 7.58 (dd, J = 4.7, 8.8 Hz, 1H), 7.27-7.24 (m, 2H), 7.09–7.08 (m,
H), 3.73 (tdd, J = 3.0, 5.7, 8.2 Hz, 1H), 2.99 (t, J = 7.6 Hz, 2H), 2.84–2.35 (m, 5H), 2.23–1.86
1
3
(
m, 5H), 1.69–1.43 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.6 (d, J =
3
1
3.8 Hz), 162.6 (d, J = 257.0 Hz), 158.8, 157.8, 137.8 (d, J = 4.1 Hz), 130.0, 127.4 (d, J = 8.1
Hz), 122.2 (d, J = 10.4 Hz), 117.6, 117.3 (d, J = 22.0 Hz), 112.7 (d, J = 26.0 Hz), 97.5 (d, J = 27.0
+
Hz), 60.2, 54.5, 52.6, 51.2, 32.1, 25.5, 22.8; Formula C H ClF N O S; MS (ESI ): m/z 456
2
0
20
2 3 3
+
[
M+H]
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)naphthalene-1-
sulfonamide (9). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), naphtalene-1-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.090 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 80%, brown oil, H NMR (300 MHz, CDCl , δ): 8.62 (d, J = 8.8 Hz, 1H), 8.27 (dd, J = 1.2,
3
7
3
2
1
2
.0 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.69–7.60 (m, 1H), 7.58–7.47 (m,
H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.05 (dt, J = 2.1, 8.9 Hz, 1H), 5.20 (br s, 1H), 3.79 (br s, 1H),
.87 (dt, J = 1.2, 7.6 Hz, 2H), 2.66 (dt, J = 4.4, 8.6 Hz, 1H), 2.47–2.25 (m, 3H), 2.24–2.15 (m,
H), 2.08 (dt, J = 7.0, 8.8 Hz, 1H), 1.93 (dtd, J = 4.4, 8.8, 13.2 Hz, 1H), 1.79 (quin, J = 7.3 Hz,
13
H), 1.52–1.37 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8
3
Hz), 158.1, 135.3, 134.3, 134.2, 129.6, 129.1, 128.4, 128.1, 126.8, 124.3, 124.2, 122.2 (d, J =
1
2
1.5 Hz), 118.2, 112.5 (d, J = 26.0 Hz), 97.3 (d, J = 27.0 Hz), 60.1, 54.4, 52.9, 51.9, 32.3, 26.2,
+
+
2.8; Formula C H FN O S; MS (ESI ): m/z 454 [M+H]
2
4
24
3 3
(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)naphthalene-1-
sulfonamide (10). The title compound was prepared using intermediate IV (1.0 equiv, 0.33

mmol, 0.100 g), naphtalene-1-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.090 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 83%, brown oil, H NMR (300 MHz, CDCl , δ): 8.62 (d, J = 8.8 Hz, 1H), 8.26 (dd, J = 1.2,
3
7
2
.0 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.66–7.50 (m, 3H), 7.24 (dd, J =
.1, 8.5 Hz, 2H), 7.06 (dt, J = 2.1, 8.9 Hz, 1H), 3.72 (br s, 1H), 2.88 (dt, J = 1.2, 7.6 Hz, 2H), 2.67
(dt, J = 4.4, 8.6 Hz, 1H), 2.46–2.31 (m, 3H), 2.22–2.01 (m, 3H), 1.92 (dtd, J = 4.4, 8.8, 13.2 Hz,
1
3
1
2
1
5
H), 1.79 (quin, J = 7.3 Hz, 2H), 1.52–1.33 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J =
3
50.2 Hz), 163.4 (d, J = 13.8 Hz), 162.6, 158.1, 135.3, 134.2, 129.6, 129.1, 126.8, 128.1, 124.3,
22.1 (d, J = 11.5 Hz), 118.1, 112.6 (d, J = 26.0 Hz), 112.3, 97.4 (d, J = 27.0 Hz), 97.1, 60.1,
+
+
4.4, 52.8, 51.9, 32.1, 26.1, 22.7; Formula C H FN O S; MS (ESI ): m/z 454 [M+H]
2
4
24
3 3
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)naphthalene-2-
sulfonamide (11). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), naphthalene-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.090 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 68%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.43 (d, J = 1.8 Hz, 1H), 8.01–7.76 (m, 4H),
3
7
8
1
1
1
.67–7.58 (m, 2H), 7.55 (dd, J = 5.3, 8.8 Hz, 1H), 7.21 (dd, J = 2.1, 8.5 Hz, 1H), 7.03 (dt, J = 2.3,
.8 Hz, 1H), 5.18 (br s, 1H), 3.87 (br s, 1H), 2.94 (t, J = 7.3 Hz, 2H), 2.72 (dt, J = 4.4, 8.6 Hz,
H), 2.52–2.30 (m, 4H), 2.14–2.08 (m, 1H), 2.08–1.97 (m, 1H), 1.91 (quin, J = 7.2 Hz, 2H),
1
3
.60–1.47 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz),
3
58.1, 137.6, 134.7, 132.2, 129.5, 129.2, 128.8, 128.3, 127.9, 127.6, 122.3, 122.1 (d, J = 11.5
Hz), 118.2, 112.5 (d, J = 26.0 Hz), 97.3 (d, J = 27.0 Hz), 60.5, 54.5, 52.8, 52.0, 32.5, 26.2, 22.8;
+
+
Formula C H FN O S; MS (ESI ): m/z 454 [M+H]
2
4
24
3 3

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)naphthalene-2-
sulfonamide (12). The title compound was prepared using intermediate IV (1.0 equiv, 0.33
mmol, 0.100 g), naphthalene-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.090 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 68%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.43 (d, J = 1.8 Hz, 1H), 7.96–7.81 (m, 4H),
3
7
2
1
1
.67–7.53 (m, 2H), 7.23 (dd, J = 2.1, 8.5 Hz, 2H), 7.04 (dt, J = 2.3, 8.8 Hz, 1H), 3.88 (br dd, 1H),
.95 (t, J = 7.3 Hz, 2H), 2.74 (dt, J = 4.4, 8.6 Hz, 1H), 2.52–2.34 (m, 4H), 2.20–1.87 (m, 5H),
1
3
.56–1.52 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.6 (d, J = 13.8 Hz),
3
62.5, 158.1, 137.6, 134.7, 132.1, 129.5, 128.8, 128.3, 127.6, 127.4, 122.3, 122.1 (d, J = 11.5
Hz), 118.2, 112.6 (d, J = 26.0 Hz), 97.3 (d, J = 27.0 Hz), 60.4 54.5, 52.7, 52.0, 32.4, 26.2, 22.8;
+
+
Formula C H FN O S; MS (ESI ): m/z 454 [M+H]
2
4
24
3 3
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-6-
methoxynaphthalene-2-sulfonamide (13). The title compound was prepared using
intermediate III (1.0 equiv, 0.33 mmol, 0.100 g), 6-methoxynaphthalene-2-sulfonyl chloride
(1.2 equiv, 0.40 mmol, 0.103 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv,
1
0
.67 mmol, 0.218 g) in DCM (5 mL). Yield 75%, brown oil, H NMR (300 MHz, CDCl , δ): 8.34
3
(
s, 1H), 7.88–7.75 (m, 3H), 7.55 (dd, J = 4.7, 8.8 Hz, 1H), 7.26–7.18 (m, 2H), 7.16 (d, J = 2.3 Hz,
H), 7.04 (dt, J = 2.1, 8.9 Hz, 1H), 5.11 (br s, 1H), 3.95 (s, 3H), 3.86 (br s, 1H), 2.94 (t, J = 7.6
Hz, 2H), 2.72 (dt, J = 4.1, 8.8 Hz, 1H), 2.52–2.40 (m, 3H), 2.40–2.32 (m, 1H), 2.22–2.11 (m,
1
13
1
H), 2.10–1.98 (m, 1H), 1.92 (quin, J = 7.3 Hz, 2H), 1.60–1.47 (m, 1H); C NMR (75 MHz,
CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 159.9, 158.1, 136.5, 135.1, 130.7,
3
1
9
28.2, 128.1, 127.5, 123.0, 122.1 (d, J = 11.5 Hz), 120.5, 118.2, 112.5 (d, J = 26.0 Hz), 105.8,
7.3 (d, J = 27.0 Hz), 60.5, 55.5, 54.6, 52.7, 52.0, 32.5, 26.2, 22.8; Formula C H FN O S; MS
2
5
26
3 4
+
+
(
ESI ): m/z 484 [M+H]

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-6-
methoxynaphthalene-2-sulfonamide (14). The title compound was prepared using
intermediate IV (1.0 equiv, 0.33 mmol, 0.100 g), 6-methoxynaphthalene-2-sulfonyl chloride
(1.2 equiv, 0.40 mmol, 0.103 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv,
1
0
.67 mmol, 0.218 g) in DCM (5 mL). Yield 78%, brown oil, H NMR (300 MHz, CDCl , δ): 8.34
3
(s, 1H), 7.83–7.79 (m, 3H), 7.54 (dd, J = 4.7, 8.8 Hz, 1H), 7.26–7.19 (m, 2H), 7.15 (d, J = 2.3 Hz,
1
2
H), 7.03 (dt, J = 2.1, 8.9 Hz, 1H), 3.94 (s, 3H), 3.87 (d, J = 4.7 Hz, 1H), 2.93 (t, J = 7.6 Hz, 2H),
1
3
.50–2.48 (m, 1H), 2.46–2.42 (m, 5H), 2.20–1.92 (m, 4H), 1.37–1.25 (m, 1H); C NMR (75
MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.4 (d, J = 13.8 Hz), 162.6, 159.9, 158.1, 136.5,
3
1
1
35.1, 130.7, 128.1, 127.5, 123.0, 122.5, 120.5 (d, J = 11.5 Hz), 118.2, 112.5 (d, J = 26.0 Hz),
05.8, 97.3 (d, J = 27.0 Hz), 60.5, 55.5, 54.6, 52.7, 52.0, 32.4, 26.1, 22.8; Formula
+
+
C H FN O S; MS (ESI ): m/z 484 [M+H]
2
5
26
3 4
(
R)-6-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)naphthalene-2-sulfonamide (15). The title compound was prepared using intermediate III
1.0 equiv, 0.33 mmol, 0.100 g), 6-chloronaphthalene-2-sulfonyl chloride (1.2 equiv, 0.40
(
mmol, 0.104 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol,
1
0
7
5
.218 g) in DCM (5 mL). Yield 53%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.41 (s, 1H), 7.95–
3
.80 (m, 4H), 7.59–7.50 (m, 2H), 7.22 (dd, J = 2.1, 8.5 Hz, 1H), 7.05 (dt, J = 2.3, 8.8 Hz, 1H),
.38 (br s, 1H), 3.88 (br s, 1H), 2.95 (t, J = 7.6 Hz, 2H), 2.76 (dt, J = 4.1, 8.8 Hz, 1H), 2.54–2.40
(m, 3H), 2.40–2.32 (m, 1H), 2.22–2.09 (m, 1H), 2.08–1.99 (m, 1H), 1.93 (quin, J = 7.3 Hz, 2H),
1
3
1
1
.62–1.46 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz),
3
58.0, 138.1, 135.3, 134.8, 130.7, 130.4, 128.6, 128.6, 128.1, 126.7, 123.5, 122.1 (d, J = 11.5
Hz), 118.1, 112.5 (d, J = 26.0 Hz), 97.4 (d, J = 26.5 Hz), 60.5, 54.5, 52.8, 51.9, 32.4, 26.1, 22.8;
+
+
Formula C H ClFN O S; MS (ESI ): m/z 489 [M+H]
2
4
23
3 3

(
S)-6-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)naphthalene-2-sulfonamide (16). The title compound was prepared using intermediate IV
1.0 equiv, 0.33 mmol, 0.100 g), 6-chloronaphthalene-2-sulfonyl chloride (1.2 equiv, 0.40
(
mmol, 0.104 g), DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol,
1
0
7
3
1
.218 g) in DCM (5 mL). Yield 48%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.41 (s, 1H), 7.93–
3
.84 (m, 4H), 7.56–7.53 (m, 2H), 7.23 (dd, J = 2.1, 8.5 Hz, 1H), 7.06 (dt, J = 2.3, 8.8 Hz, 1H),
.95 (br s, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.75 (dt, J = 4.1, 8.8 Hz, 1H), 2.59–2.39 (m, 4H), 2.77–
.94 (m, 5H), 1.42–1.18 (m, 1H);
1
3
C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 162.6, 158.0,
3
1
1
38.1, 135.3, 134.8, 130.7, 130.4, 128.6, 128.1, 126.7, 123.5, 122.1 (d, J = 11.5 Hz), 118.1,
12.5 (d, J = 26.0 Hz), 97.4 (d, J = 26.5 Hz), 60.5, 54.5, 52.8, 51.9, 32.4, 26.1, 22.8; Formula
+
+
C H ClFN O S; MS (ESI ): m/z 489 [M+H]
2
4
23
3 3
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-1-methyl-1H-indole-
4
-sulfonamide (17). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), 1-methyl-1H-indole-4-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.092 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 61%, brown oil, H (300 MHz, CDCl , δ): 7.72–7.66 (m, 1H), 7.59–7.49 (m, 2H),
3
7
.29–7.25 (m, 1H), 7.24–7.20 (m, 1H), 7.15 (d, J = 3.5 Hz, 1H), 7.09–7.01 (m, 1H), 6.88–6.84
(m, 1H), 5.03 (br d, J = 8.8 Hz, 1H), 3.81 (s, 4H), 2.93–2.83 (m, 2H), 2.64 (dt, J = 4.1, 8.8 Hz,
1
1
1
H), 2.47–2.18 (m, 4H), 2.09 (dt, J = 6.7, 8.9 Hz, 1H), 1.99–1.87 (m, 1H), 1.86–1.77 (m, 2H),
1
3
.49–1.35 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz),
3
58.2, 137.5, 131.3, 130.7, 124.5, 122.2 (d, J = 11.5 Hz), 120.6, 120.6, 118.2, 114.1, 112.5 (d,
J = 26.0 Hz), 100.6, 97.3 (d, J = 26.5 Hz), 60.2, 54.6, 52.7, 52.1, 33.2, 32.3, 26.2, 22.8; Formula
+
+
C H FN O S; MS (ESI ): m/z 457 [M+H]
2
3
25
4 3

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-1-methyl-1H-indole-
4
-sulfonamide (18). The title compound was prepared using intermediate IV (1.0 equiv, 0.33
mmol, 0.100 g), 1-methyl-1H-indole-4-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.092 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 68%, brown oil, H (300 MHz, CDCl , δ): 7.72–7.66 (m, 1H), 7.59–7.49 (m, 3H),
3
7
2
1
.30–7.19 (m, 2H), 7.15 (d, J = 3.5 Hz, 1H), 7.09–7.01 (m, 1H), 6.88–6.84 (m, 1H), 3.81 (s, 4H),
.93–2.83 (m, 2H), 2.64 (dt, J = 4.1, 8.8 Hz, 1H), 2.47–2.18 (m, 4H), 2.09 (dt, J = 6.7, 8.9 Hz,
1
3
H), 2.00–1.77 (m, 3H), 1.49–1.35 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2
3
Hz), 163.5 (d, J = 13.8 Hz), 158.2, 137.5, 131.3, 130.7, 124.5, 122.2 (d, J = 11.5 Hz), 120.6,
1
3
20.6, 118.2, 114.1, 112.5 (d, J = 26.0 Hz), 100.6, 97.3 (d, J = 26.5 Hz), 60.2, 54.6, 52.7, 52.1,
+
+
3.2, 32.3, 26.2, 22.8; Formula C H FN O S; MS (ESI ): m/z 457 [M+H]
2
3
25
4 3
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-1-methyl-1H-indole-
5
-sulfonamide (19). The title compound was prepared using intermediate III (1.0 equiv, 0.84
mmol, 0.250 g), 1-methyl-1H-indole-5-sulfonyl chloride (1.2 equiv, 1.00 mmol, 0.230 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 1.67 mmol, 0.545 g) in DCM (15
1
mL). Yield 72%, brown oil, H NMR (300 MHz, CDCl , δ): 8.19 (d, J = 1.8 Hz, 1H), 7.67 (dd, J =
3
1
1
4
1
1
1
5
.8, 8.8 Hz, 1H), 7.57 (dd, J = 5.3, 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 2.1, 8.5 Hz,
H), 7.16 (d, J = 2.9 Hz, 1H), 7.09–7.00 (m, 1H), 6.60–6.56 (m, 1H), 4.88 (br s, 1H), 3.83 (s,
H), 2.94 (t, J = 7.3 Hz, 2H), 2.69 (dt, J = 4.1, 8.8 Hz, 1H), 2.52–2.30 (m, 4H), 2.22–2.11 (m,
1
3
H), 2.09–1.96 (m, 1H), 1.95–1.85 (m, 2H), 1.58–1.43 (m, 1H); C NMR (75 MHz, CDCl , δ):
3
64.2 (d, J = 250.2 Hz),163.5 (d, J = 13.8 Hz), 158.1, 138.3, 131.1 (2C), 127.8, 122.2 (d, J =
0.4 Hz), 121.5, 119.9, 118.2, 112.5 (d, J = 26.0 Hz), 109.8, 102.7, 97.3 (d, J = 27.0 Hz), 60.5,
+
+
4.6, 52.6, 52.1, 33.1, 32.4, 26.3, 22.8; Formula C H FN O S; MS (ESI ): m/z 457 [M+H]
2
3
25
4 3

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-1-methyl-1H-indole-
5
-sulfonamide (20). The title compound was prepared using intermediate IV (1.0 equiv, 0.84
mmol, 0.250 g), 1-methyl-1H-indole-5-sulfonyl chloride (1.2 equiv, 1.00 mmol, 0.230 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 1.67 mmol, 0.545 g) in DCM (15
1
mL). Yield 70%, brown oil, H NMR (300 MHz, CDCl , δ): 8.17 (d, J = 1.8 Hz, 1H), 7.68 (dd, J =
3
1
1
3
1
.8, 8.8 Hz, 1H), 7.56 (dd, J = 5.3, 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 2.1, 8.5 Hz,
H), 7.15 (d, J = 2.9 Hz, 1H), 7.02–6.99 (m, 2H), 6.56–6.55 (m, 1H), 5.21 (br s, 1H), 3.80 (s,
H), 2.89 (t, J = 7.3 Hz, 2H), 2.66 (dt, J = 4.1, 8.8 Hz, 1H), 2.43–2.40 (m, 4H), 2.19–2.16 (m,
1
3
H), 1.87–1.83 (m, 3H), 1.26–1.23 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.8 (d, J = 250.2
3
Hz), 163.5 (d, J = 13.8 Hz), 162.5, 158.1, 138.2, 131.1, 127.8, 122.4 (d, J = 10.4 Hz), 121.4,
1
3
19.9, 112.6, 112.3 (d, J = 26.0 Hz), 109.8, 102.6, 97.3 (d, J = 27.0 Hz), 60.4, 54.6, 52.6, 52.1,
+
+
3.1, 32.3, 26.2, 22.8; Formula C H FN O S; MS (ESI ): m/z 457 [M+H]
2
3
25
4 3
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzofuran-2-
sulfonamide (21). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), benzofuran-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.087 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 61%, brown oil, H NMR (300 MHz, CDCl , δ): 7.67 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 5.0,
3
8
1
2
1
1
.5 Hz, 1H), 7.54–7.48 (m, 1H), 7.48–7.41 (m, 1H), 7.39–7.29 (m, 2H), 7.23 (dd, J = 2.1, 8.5 Hz,
H), 7.06 (dt, J = 1.8, 8.8 Hz, 1H), 5.36 (br s, 1H), 4.07–3.93 (m, 1H), 2.97 (t, J = 7.3 Hz, 2H),
.86–2.75 (m, 1H), 2.62–2.35 (m, 4H), 2.23–2.04 (m, 2H), 1.95 (quin, J = 7.2 Hz, 2H), 1.69–
13
.52 (m, 1H); C NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz),
3
58.1, 155.6, 150.6, 127.6, 126.0, 124.2, 122.9, 122.1 (d, J = 11.5 Hz), 118.2, 112.5 (d, J = 25.4
Hz), 112.2, 112.1, 97.4 (d, J = 26.5 Hz), 60.5, 54.5, 53.2, 51.9, 32.5, 26.2, 22.9; Formula C H
2 22
2
+
+
FN O S; MS (ESI ): m/z 444 [M+H]
3
4

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzofuran-2-
sulfonamide (22). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), benzofuran-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.087 g), DMAP
(catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL).
1
Yield 66%, brown oil, H NMR (300 MHz, CDCl , δ): 7.67-7.05 (m, 7H), 7.05-6.98 (m, 2H),
3
4
.04–3.99 (m, 1H), 2.96 (t, J = 7.3 Hz, 2H), 2.84–2.77 (m, 1H), 2.61–2.39 (m, 4H), 2.21–2.12
1
3
(
m, 2H), 1.95 (quin, J = 7.2 Hz, 2H), 1.64–1.60 (m, 1H); C NMR (75 MHz, CDCl , δ): 165.9 (d, J
3
=
1
5
250.2 Hz), 163.6 (d, J = 13.8 Hz), 162.6, 158.1, 155.6, 150.6, 127.6, 126.0, 124.2, 122.9,
22.2 (d, J = 11.5 Hz), 118.2, 112.5 (d, J = 25.4 Hz), 112.1, 97.5 (d, J = 26.5 Hz), 60.5, 54.6,
+
+
3.1, 52.0, 32.5, 26.1, 22.9; Formula C H FN O S; MS (ESI ): m/z 444 [M+H]
2
2
22
3 4
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzo[b]thiophene-3-
sulfonamide (23). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), benzo[b]thiophene-3-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.093 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 78%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.23 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H),
3
7
.86 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 5.3, 8.8 Hz, 1H), 7.50–7.36 (m, 2H), 7.23 (dd, J = 2.3, 8.8
Hz, 1H), 7.05 (dt, J = 2.1, 8.9 Hz, 1H), 5.18 (br s, 1H), 3.86 (br s, 1H), 2.95–2.86 (m, 2H), 2.76–
2
1
2
.65 (m, 1H), 2.52–2.22 (m, 4H), 2.18–1.93 (m, 2H), 1.84 (quin, J = 7.2 Hz, 2H), 1.55–1.40 (m,
1
9
13
H); F NMR (282 MHz, CDCl , δ): -109.6 (s, 1F); C NMR (75 MHz, CDCl , δ): 164.2 (d, J =
3
3
50.2 Hz), 163.5 (d, J = 13.8 Hz), 158.0, 140.4, 134.3, 134.2, 133.5, 125.8, 125.7, 123.0, 122.1
(d, J = 11.5 Hz), 118.2, 112.5 (d, J = 26.0 Hz), 110.0, 97.3 (d, J = 26.5 Hz), 60.1, 54.4, 52.9,
+
+
5
1.9, 32.4, 26.1, 22.7; Formula C H FN O S ; MS (ESI ): m/z 460 [M+H]
22 22 3 3 2

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzo[b]thiophene-3-
sulfonamide (24). The title compound was prepared using intermediate IV (1.0 equiv, 0.33
mmol, 0.100 g), benzo[b]thiophene-3-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.093 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 79%, yellow oil, H NMR (300 MHz, CDCl , δ): 8.23 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H),
3
7
7
1
.87 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 5.3, 8.8 Hz, 1H), 7.47–7.35 (m, 2H), 7.25-7.22 (m, 1H),
.06 (dt, J = 2.1, 8.9 Hz, 1H), 5.20 (br s, 1H), 3.64 (br s, 1H), 2.97–2.90 (m, 3H), 2.89–2.51 (m,
1
9
H), 2.47–2.43 (m, 4H), 2.14–2.14 (m, 2H), 1.89 (quin, J = 7.2 Hz, 2H); F NMR (282 MHz,
1
3
CDCl , δ): -109.6 (s, 1F); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.5 (d, J = 13.8
3
3
Hz), 157.8, 140.2, 134.3, 133.8, 125.7, 122.9, 122.1 (d, J = 11.5 Hz), 118.2, 112.5 (d, J = 26.0
Hz), 110.0, 97.5 (d, J = 26.5 Hz), 97.1, 60.2, 54.5, 52.8, 51.9, 32.3, 29.7, 25.9, 22.8; Formula
+
+
C H FN O S ; MS (ESI ): m/z 460 [M+H]
2
2
22
3 3 2
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzo[b]thiophene-2-
sulfonamide (25). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), benzo[b]thiophene-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.093 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 69%, brown oil, H NMR (300 MHz, CDCl , δ): 7.87–7.71 (m, 3H), 7.52 (dd, J = 5.3,
3
8
1
1
.8 Hz, 1H), 7.47–7.35 (m, 2H), 7.18 (dd, J = 2.1, 8.5 Hz, 1H), 7.04–6.96 (m, 1H), 5.45 (br s,
H), 3.99–3.88 (m, 1H), 2.92 (t, J = 7.6 Hz, 2H), 2.82–2.70 (m, 1H), 2.57 (dd, J = 2.6, 9.7 Hz,
1
3
H), 2.50–2.34 (m, 3H), 2.20–2.03 (m, 2H), 1.97–1.86 (m, 2H), 1.68–1.54 (m, 1H); C NMR
(
75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 158.0, 141.9, 141.7, 137.6,
3
1
29.2, 127.2, 125.6, 125.5, 122.7, 122.1 (d, J = 10.4 Hz), 118.2, 112.5 (d, J = 26.0 Hz), 97.3 (d,
+
J = 26.5 Hz), 60.4, 54.6, 53.1, 52.0, 32.3, 26.1, 22.9; Formula C H FN O S ; MS (ESI ): m/z
2
2
22
3 3 2
+
4
60 [M+H]

(S)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzo[b]thiophene-2-
sulfonamide (26). The title compound was prepared using intermediate III (1.0 equiv, 0.33
mmol, 0.100 g), benzo[b]thiophene-2-sulfonyl chloride (1.2 equiv, 0.40 mmol, 0.093 g),
DMAP (catalytic amount) and cesium carbonate (2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5
1
mL). Yield 67%, brown oil, H NMR (300 MHz, CDCl , δ): 7.89–7.80 (m, 3H), 7.56 (dd, J = 5.3,
3
8
1
3
1
1
5
.8 Hz, 1H), 7.48–7.42 (m, 2H), 7.24 (dd, J = 2.1, 8.5 Hz, 1H), 7.13–6.99 (m, 1H), 4.04–3.96 (m,
H), 2.97 (t, J = 7.6 Hz, 2H), 2.89–2.76 (m, 1H), 2.59 (dd, J = 2.6, 9.7 Hz, 1H), 2.52–2.35 (m,
1
3
H), 2.23–2.02 (m, 2H), 2.01–1.91 (m, 3H), 1.67–1.65 (m, 1H); C NMR (75 MHz, CDCl , δ):
3
65.9 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 162.6, 158.0, 141.9, 141.7, 137.6, 129.2, 127.2,
25.6, 122.7, 122.2 (d, J = 10.4 Hz), 112.5 (d, J = 26.0 Hz), 112.3, 97.3 (d, J = 26.5 Hz), 60.4,
+
+
4.5, 53.1, 51.9, 32.7, 26.1, 22.9; Formula C H FN O S ; MS (ESI ): m/z 460 [M+H]
2
2
22
3 3 2
(R)-6-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzo[b]thiophene-2-sulfonamide (27). The title compound was prepared using
intermediate III (1.0 equiv, 0.33 mmol, 0.100 g), 6-chlorobenzo[b]thiophene-2-sulfonyl
chloride (1.2 equiv, 0.40 mmol, 0.107 g), DMAP (catalytic amount) and cesium carbonate
1
(
2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL). Yield 76%, yellow oil, H NMR (300 MHz,
CDCl , δ): 7.84–7.67 (m, 3H), 7.53 (dd, J = 5.3, 8.8 Hz, 1H), 7.36 (dd, J = 2.1, 8.5 Hz, 1H), 7.21–
3
7
.14 (m, 1H), 7.01 (dt, J = 2.3, 8.8 Hz, 1H), 5.30 (br s, 1H), 3.97–3.88 (m, 1H), 2.93 (t, J = 7.6
Hz, 2H), 2.82–2.70 (m, 1H), 2.53 (dd, J = 2.9, 10.0 Hz, 1H), 2.49–2.31 (m, 3H), 2.18–2.03 (m,
1
9
13
2
H), 1.99–1.85 (m, 2H), 1.67–1.51 (m, 1H); F NMR (282 MHz, CDCl , δ): -109.4 (s, 1F); C
3
NMR (75 MHz, CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 158.1, 142.5, 136.0,
3
1
9
33.5, 132.3, 128.6, 126.6, 126.4, 122.3, 122.1 (d, J = 11.5 Hz), 118.2, 112.5 (d, J = 26.0 Hz),
7.4 (d, J = 26.5 Hz), 60.4, 54.5, 53.2, 51.9, 32.4, 26.2, 22.9; Formula C H ClFN O S ; MS
22
21
3 3 2
+
+
(
ESI ): m/z 494 [M+H]

(S)-6-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzo[b]thiophene-2-sulfonamide (28). The title compound was prepared using
intermediate IV (1.0 equiv, 0.33 mmol, 0.100 g), 6-chlorobenzo[b]thiophene-2-sulfonyl
chloride (1.2 equiv, 0.40 mmol, 0.107 g), DMAP (catalytic amount) and cesium carbonate
1
(
2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL). Yield 71%, yellow oil, H NMR (300 MHz,
CDCl , 7.82–7.80 (m, 2H), 7.78-7.76 (m, 1H), 7.57-7.43 (m, 1H), 7.41 (dd, J = 2.1, 8.5 Hz, 1H),
3
7
2
.2-7.54 (m,1H), 7.06–6.96 (m, 1H), 4.00–3.93 (m, 1H), 3.51-3.44 (m, 1H), 3.03-2.80 (m, 3H),
1
9
.55-2.40 (m, 3H), 2.17-2.15 (m, 2H), 1.33-1.18(m, 3H); F NMR (282 MHz, CDCl , δ): -109.4
3
1
3
(
s, 1F); C NMR (75 MHz, CDCl , δ): 165.9 (d, J = 250.2 Hz), 163.5 (d, J = 13.8 Hz), 158.1,
3
1
42.6, 136.0, 133.6, 133.6, 128.6, 126.6, 126.4, 122.3, 122.1 (d, J = 11.5 Hz), 118.2, 112.4 (d,
J = 26.0 Hz), 97.6 (d, J = 26.5 Hz), 60.4, 54.5, 53.2, 51.8, 32.4, 26.2, 22.8; Formula
+
+
C H ClFN O S ; MS (ESI ): m/z 494 [M+H]
2
2
21
3 3 2
(R)-6-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzo[b]thiophene-2-sulfonamide (29). The title compound was prepared using
intermediate III (1.0 equiv, 0.33 mmol, 0.100 g), 6-fluorobenzo[b]thiophene-2-sulfonyl
chloride (1.2 equiv, 0.40 mmol, 0.100 g), DMAP (catalytic amount) and cesium carbonate
1
(
2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL). Yield 67%, brown oil, H NMR (300 MHz,
CDCl , δ): 7.87–7.78 (m, 2H), 7.58 (dd, J = 5.3, 8.8 Hz, 1H), 7.51 (dd, J = 2.3, 8.8 Hz, 1H), 7.26–
3
7
.15 (m, 2H), 7.06 (dt, J = 1.8, 8.8 Hz, 1H), 5.20 (br s, 1H), 4.01–3.92 (m, 1H), 2.98 (t, J = 7.6
Hz, 2H), 2.86–2.76 (m, 1H), 2.58 (dd, J = 2.9, 10.0 Hz, 1H), 2.53–2.45 (m, 2H), 2.41 (dd, J = 5.9,
1
3
1
0.0 Hz, 1H), 2.23–2.07 (m, 2H), 2.03–1.90 (m, 2H), 1.71–1.56 (m, 1H); C NMR (75 MHz,
CDCl , δ): 164.2 (d, J = 250.2 Hz), 163.6 (d, J = 13.8 Hz), 161.9 (d, J = 249.0 Hz), 158.1, 134.1
3
(d, J = 2.2 Hz), 133.1, 128.7, 127.3, 127.0(d, J = 9.3 Hz), 122.1 (d, J = 11.5 Hz), 118.2, 115.1 (d,

J = 24.3 Hz), 112.5 (d, J = 26.0 Hz), 108.8 (d, J = 25.2 Hz), 97.4 (d, J = 26.5 Hz), 60.4, 54.5, 53.2,
+
+
5
1.8, 32.4, 26.2, 22.9; Formula C H F N O S ; MS (ESI ): m/z 478 [M+H]
22 21 2 3 3 2
(S)-6-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-
yl)benzo[b]thiophene-2-sulfonamide (30). The title compound was prepared using
intermediate IV (1.0 equiv, 0.33 mmol, 0.100 g), 6-fluorobenzo[b]thiophene-2-sulfonyl
chloride (1.2 equiv, 0.40 mmol, 0.100 g), DMAP (catalytic amount) and cesium carbonate
1
(
2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL). Yield 69%, brown oil, H NMR (300 MHz,
CDCl , δ): 7.87–7.80 (m, 2H), 7.60–7.55 (m, 2H), 7.28–7.21 (m, 2H), 7.05 (dt, J = 1.8, 8.8 Hz,
3
1
2
H), 3.97 (br s, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.86–2.80 (m, 1H), 2.56 (dd, J = 2.9, 10.0 Hz, 1H),
1
3
.51–2.40 (m, 3H), 2.18–1.93 (m, 5H), 1.66–1.42 (m, 1H); C NMR (75 MHz, CDCl , δ): 171.8
3
(d, J = 250.2 Hz), 163.6 (d, J = 13.8 Hz), 162.6 (d, J = 249.0 Hz), 158.1, 154.0 (d, J = 2.2 Hz),
1
1
2
37.6, 128.7, 127.1, 126.9 (d, J = 9.3 Hz), 122.0 (d, J = 11.5 Hz), 118.2, 115.1 (d, J = 24.3 Hz),
12.5 (d, J = 26.0 Hz), 108.8 (d, J = 25.2 Hz), 97.4 (d, J = 26.5 Hz), 60.4, 54.5, 53.2, 51.9, 32.4,
+
+
6.2, 22.9; Formula C H F N O S ; MS (ESI ): m/z 478 [M+H]
2
2 21 2 3 3 2
(R)-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-5-
methylbenzo[b]thiophene-2-sulfonamide (31). The title compound was prepared using
intermediate III (1.0 equiv, 0.33 mmol, 0.100 g), 5-methylbenzo[b]thiophene-2-sulfonyl
chloride (1.2 equiv, 0.40 mmol, 0.099 g), DMAP (catalytic amount) and cesium carbonate
1
(
2.0 equiv, 0.67 mmol, 0.218 g) in DCM (5 mL). Yield 62%, brown oil, H NMR (300 MHz,
CDCl , δ): 7.78 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 4.7, 8.8 Hz, 1H), 7.29
3
(dd, J = 1.8, 8.2 Hz, 1H), 7.22 (dd, J = 2.1, 8.5 Hz, 1H), 7.10–7.00 (m, 1H), 5.47 (br s, 1H), 4.04–
3
2
.92 (m, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.88–2.76 (m, 1H), 2.62 (dd, J = 2.6, 9.7 Hz, 1H), 2.55–
1
3
.38 (m, 6H), 2.25–2.06 (m, 2H), 2.02–1.91 (m, 2H), 1.73–1.57 (m, 1H); C NMR (75 MHz,