5-Cyclic amine-3-arylsulfonylindazoles as novel 5-HT6 receptor antagonists

Article abstract of DOI:10.1021/jm901674f

Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT ₆ receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.

Full text of DOI:10.1021/jm901674f

J. Med. Chem. 2010, 53, 2521–2527 2521
DOI: 10.1021/jm901674f
5-Cyclic Amine-3-arylsulfonylindazoles as Novel 5-HT6 Receptor Antagonists
Simon N. Haydar,*,† Heedong Yun,† Patrick M. Andrae,† James Mattes,† Jean Zhang,‡ Angela Kramer,‡ Deborah L. Smith,‡
Christine Huselton,§ Radka Graf,‡ Suzan Aschmies,‡ Lee E. Schechter,‡ Thomas A. Comery,‡ and Albert J. Robichaud†
§
†Chemical Sciences, and ‡Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, and Drug Safety and Metabolism,
Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426
Received November 13, 2009
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class
have been identified as high-affinity 5-HT6 receptor ligands with improved pharmacokinetic and
pharmacological properties. One selected example, 18b, showed good brain penetrability and a
generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recogni-
tion assay. The synthesis and structure-activity relationship of this potent class are discussed.
Introduction
5-HT6 receptor antagonists reported, Cole et al. replaced the
indole backbone with an indazole core exemplified by WAY-
101 (6).8-10 In a marked departure from the sulfonamide or
tryptamine moieties of the compounds listed previously,
scientists at Hoffmann-LaRoche and Pharmacia-Upjohn re-
ported analogues (7)11 and (8),12 respectively, bearing an
aromatic sulfone, showing the nondiscriminative nature of
the serotonin receptor subtype.
The serotonin-6 receptor (5-HT6) is a G-protein-coupled
receptor (GPCRa) predominantly expressed in the central
nervous system (CNS). In particular, it is widely reported to
be located in brain regions associated with learning and
memory such as the cerebral cortex, the hippocampus, and
the striatum.1 It has been demonstrated that antagonism of
the 5-HT6 receptor modulates the release of a wide variety of
neurotransmitters including elevating extracellular levels of
both glutamate and acetylcholine in brain regions such as the
medial prefrontal cortex (mPFC) and the hippocampal for-
mation (HPC).2,3 This modulatory activity suggests potential
utility for 5-HT6 receptor antagonists in the treatment of
cognitive impairments associated with Alzheimer’s disease
and schizophrenia.
Research efforts in this area have led to the discovery of a
number of potent and selective 5-HT6 agonists and antago-
nists over the past decade. In 1998, scientists at Roche
described a series of pyrimidinyl- and pyridinylsulfonamides,
Ro 04-6790 (1) and Ro 63-0563 (2),4 respectively (Figure 1),
which were among the first selective 5-HT6 receptor antago-
nists reported. Shortly thereafter, Bromidge and co-workers
further reported a series of sulfonamides, including SB-
271046 (3)5 and SB-357134 (4)6 as potent and selective 5-
HT6 receptor antagonists. A series of compounds, such as
MS-245(5), built on a tryptamine backbone7 werereported by
Russell and co-workers. One can not help but note the similar
structural features of these ligands, with each of these novel
antagonists sharing a common sulfonamide moiety. Further
progress in this area led to an increase in the diversity of the
structure types being identified. In a second generation of
There is an impressive preclinical proof-of-concept support
for the utility of the 5-HT6 receptor. In a variety of animal
studies, antagonism of the 5-HT6 receptor has been demon-
strated to increase acetylcholine- and glutamate-mediated
neurotransmission in brain regions such as the cortex and
hippocampus.2,3,13-15 The observed increase in these neuro-
transmitters, in brain regions associated with cognition, are
consistent with potential procognitive effects of selective 5-
HT6 receptor antagonists. However, despite the high affinity
and selectivity of many of these chemotypes, several of these
leads suffered from poor penetration across the blood-brain
barrier,6,12 potentially impeding their further development
although providing excellent tools for proof-of-concept stu-
dies. Clinical proof-of-concept is encouraging, as recent phase
II clinical data with SB-742457 (9) have demonstrated efficacy
incognitiontrials. Positiveeffects have been reported with this
selective 5-HT6 receptor antagonist in blocking a scopola-
mine-induced cognitive deficit in healthy volunteers.16 Con-
tinued clinical research and the optimization of advanced
compounds will further explore the potential utility of these
ligands for the treatment of Alzheimer’s disease, schizophre-
nia, and other cognitive disorders.
The purpose of our present research was to identify novel,
potent 5-HT6 antagonists with enhanced selectivity against
neighboring GPCR receptors with good brain-penetrating
properties that might be useful as potential therapeutics.
Our early research8-10 identified several potent compounds
that demonstrated activity in a variety of rodent cognitive
models. These compounds, although excellent tools, suffered
from modest brain exposure, limiting their potential utility.
To further expand our chemical diversity and identify higher
affinity scaffolds, we adapted the principals of a pharmaco-
phore model developed by Holenz et al.17 to our discovery
*To whom correspondence should be addressed. Phone: (732) 274-
4518. Fax: (732) 274-4505. E-mail: Haydars@wyeth.com; simonhaydar@
hotmail.com.
a Abbreviations: GPCR, G-protein coupled receptor; CNS, central
nervous system; 5-HT, 5-hydroxytryptamine; mPFC, medial prefrontal
cortex; HPC, hippocampus; VNS, vicarious nucleophilic substitution;
Boc, tert-butyl carbonyl; cAMP, cyclic adenosine monophosphate;
SAR, structure-activity relationship; NOESY, nuclear Overhauser
effect spectroscopy; HMBC, heteronuclear multiple bond correlation;
IP, intraperitoneal.
r
2010 American Chemical Society
Published on Web 02/19/2010
pubs.acs.org/jmc

2522 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6
Haydar et al.
Figure 1. Structures of selected 5-HT6 receptor antagonists.
cyclization. The nitro intermediates (11) are readily prepared
via vicarious nucleophilic substitution (VNS) of commercially
available 4-fluoronitrobenzene (12) with the appropriately
substituted arylchloromethylsulfones, a process we have pre-
viously utilized and described in detail.19
To expand the diversity, key intermediates 11 can be
prepared via two possible routes to allow access to multi-
functional analogues. In the first route, commercially avail-
able 4-fluoronitrobenzene (12) can be reacted with tert-
butylcarbonyl (Boc)-protected cyclic amine under basic con-
ditionstogive4-aminoalkylsubstitutednitrobenzenes(13) via
SNAr displacement (Scheme 2). The latter intermediates are
then subjected to vicarious nucleophilic substitution (VNS)20
at the ortho position of the nitro group to yield intermediates
(11). The arylchloromethylsulfone building blocks can be
prepared from the reaction of commercially available arylsul-
fonyl chlorides with chloromethyl bromide in the presence of
tetrabutylammonium bromide, Na2SO3, and NaHCO3 in
good yields. This route generally gave good yields with the
exception of when the amine reactant was a pyrrolidine or an
azetidine derivative. In these cases, a much more efficient
conversion was achieved withreversal of the order ofthe SNAr
and VNS steps. Thus, intermediates 14 were prepared from 4-
fluoronitrobenzene (12) using the VNS conditions described
above. Subsequent SNAr displacement with the correspond-
ing cyclic amines led to the desired chemotype 11.
Catalytic hydrogenation of nitroaryls 11 afforded anilines
15 in good to excellent yields. These key intermediates were
then diazotized and cyclized in acetic acid to give the target
indazole 16 (Scheme 3). In cases where the amine component
Y was protected by a Boc group, it was readily hydrolyzed in
the presence of TFA or HCl to give the final target 10
(Scheme 3).
With a varied array of analogues prepared, we examined
the structure-activity relationship of these indazole core
ligands and their potential as 5-HT6 receptor antagonists.
All compounds were evaluated for human 5-HT6 receptor
binding affinity by competitive inhibition of [3H]LSD bind-
ing. Selected compounds were further evaluated for 5-HT6
receptor antagonist activity in a functional cyclic adenosine
monophosphate (cAMP) assay using HeLa cells stably trans-
fected with the human 5-HT6 receptor. Upon identification of
Figure 2. Structural model for 5-HT6 pharmacophore.
Figure 3. Strategy for SAR of indazole series.
platform. The authors reported a hypothetical framework
model based on the structure and biological activity of
reference ligands (Figure 2). In his model, he proposed that
active compounds possessed two hydrophobic regions flank-
ing a double hydrogen bond acceptor (often sulfonamide or
sulfone). Furthermore, the authors noted that one of the
hydrophobic sites is terminated by a proton donor (such as
amine which can be protonated at physiological pH).
Past reports have demonstrated that the most potent
ligands known have structural features in common, such as
the presence of a hydrophobic site connected to a sulfone (or
sulfonamide) moiety and the presence of a distal amine that
can be a hydrogen donor/acceptor.17 These features have
served as a point of departure for further target discovery by
medicinal chemists. In particular, our efforts centered around
exploring the structure-activity relationship (SAR) of the
distal amine (Figure 3).18
Results and Discussion
Targeted analogues based on this hypothesis were prepared
according to the approach depicted in Scheme 1. Retrospec-
tively, indazole core derivatives (10) can be formed from 11 by
reduction of the nitro group followed by diazotization and

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6 2523
Scheme 1. Retrosynthesis of Compounds 10
Scheme 2. Synthesis of Compound 11a
that the selectivity over 5-HT2B is enhanced by the steric
effects caused by substitution at the 4-position of the phenyl-
or naphthyl sulfones. In summary, for the examination of the
sulfone moiety SAR, the substituted 4-methylnaphthyl ana-
logue 10c was the most potent 5-HT6 receptor antagonist with
greater than 136-fold selectivity over the 5-HT2B receptor.
We next moved on to a more detailed examination of the
SAR of the cyclic amine (Y). In this arm of the SAR
examination, we maintained the sulfone as the 1-naphthyl
substituent. The activity of representative analogues at the 5-
HT6 and 5-HT2B receptors prepared in this effort is detailed in
Table 2.
From the data in Table 2, one can infer that the ring size of
exocyclic amine, contracting from six-membered ring (10a) to
four-membered ring (10i), had no effect on potency but
selectivity was most optimal for the five-membered ring with
R-stereochemistry (10h). Alkylation of the distal amine (10j,
k), led to increased selectivity over parent analogues (10g,h). It
is noteworthy that only in the case of 10j with the R-stereo-
chemistry the alkylation of the distal amine led to improved
potency over the parent analogue 10h. Among all compounds
prepared, the (R)-dimethylaminopyrrolidine analogue 10j
had the highest binding affinity; however, it did not display
the best functional potency in this class of molecules. Its
enantiomer (S)-dimethylaminopyrrolidine analogue (10k)
was 50-fold less potent in the binding assay relative to 10j
but surprisingly more potent in the functional assay. The
optimized derivative 10h had excellent binding and most
improved functional activity while maintaining selectivity
against the 5-HT2B receptor and was selected for additional
in vitro and in vivo profiling .
Compound 10h showed good selectivity against other
serotonin receptors (>100-fold). However, this analogue
and others from this series were hampered by their potency
as inhibitors of CYP3A4 and CYP2C9 (%inhibition of
>50% at 3 μM). Upon further examination of the pharma-
cokinetics of 10h, it was also found that the drug-brain
concentration following a single intraperitoneal dose of 10
mg/kg was below quantifiable levels. To improve this prop-
erty, alkylation of the nitrogen of the indazole was proposed.
The removal of H-bond donors is a well documented tactic to
improve CNS penetration.22,23 To that end, the Boc-protected
intermediate 17 was treated with cesium carbonate and an
appropriate alkyl halide, followed by deprotection with tri-
fluoroacetic acid to give a mixture of N-1 and N-2 alkylated
indazoles (18a-c and 19a-c, respectively)(Scheme 4).
The regioisomeric alkylated derivatives were unambigu-
ously assigned by high field NMR studies (nuclear Over-
hauser effect spectroscopy (NOESY), heteronuclear multi-
ple bond correlation (HMBC)). Details are provided in
Supporting Information.
a Conditions: (i) K2CO3; DMF, (ii) KOt-Bu, THF -78 to 0 °C; (iii)
ClCH2Br, NaHCO3, Na2SO3, TBAB, H2O, reflux.
compounds demonstrating high affinity and full antagonist
function at the 5-HT6 receptor, selectivity of compounds
versus the 5-HT2B receptor was first determined. Further
liability was assessed in 5-HT2B functional assay. All com-
pounds reported here were antagonists and showed no agon-
ism at 5-HT2B (data not included). High selectivity for the 5-
HT6 receptor over the 5-HT2B for ligands was of particular
interest because of the potential cardiovascular liability asso-
ciated with this target.21 Ligands with good binding, func-
tional activity, and selectivity over the 5-HT2B receptor were
further advanced to screening against an array of dopaminer-
gic, adrenergic, and other 5-HT receptor subtypes.
Representative compounds describing the structure-activ-
ity relationship with regard to changes around the sulfone
moietyaredetailed inTable1. Initially, westructured the SAR
around examination of compounds with the 4-aminopiper-
idine substitution as the amine component (Y) to allow for an
empirical analysis (Table 1). In general, these derivatives were
found to have high 5-HT6 receptor affinity and to be potent
antagonists as determined by the functional assay. From
binding data, it can be seen that the 1-naphthylsulfone (10a)
is 4- to 5-fold more potent than 2-naphthyl analogue 10b but
had less selectivity over the 5-HT2B receptor. Compound (10c)
with additional substitution at the 4-position of the 1-
naphthyl group retained similar potency as the parent com-
pound but possessed higher selectivity against the 5HT2B
receptor. In a similar fashion, substitution at the 5-position
with chlorine (10d) had deleterious effects on potency and
functional efficacy with only moderate selectivity against the
5-HT2B receptor. From this limited set of data, it appeared
Unfortunately these alkylated compounds 18 and 19 were
found to have weaker 5-HT6 receptor affinity and to be less
potent antagonists for 5-HT6 receptor-dependent cyclase
assay (Table 3).

2524 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6
Scheme 3. Synthesis of Indazole 10a
Haydar et al.
a Conditions: (i) Pd/C, H2 (40 psi); (ii) NaNO2, HOAc, H2O; (iii) TFA/CH2Cl2.
Table 1. SAR of the Arylsulfone Group of 10a-fa
a The asterisk (*) indicates n = 1.
Despite the weaker potency, these alkylated analogues did
display improved pharmacokinetics compared to the unsub-
stituted indazole analogues. Specifically and by design, 18b
showed improved blood-brain penetration (B/P = 0.85;
based on AUC ratio) following a single intraperitoneal (ip)
dose of 3 mg/kg as compared to the desalkyl congener.
Encouraged by this significantly improved CNS exposure,
we examined the effects of this ligand in a rat behavioral novel
object recognition assay (assay details and literature refer-
encesareprovidedinthe SupportingInformation). Treatment
with 18b (3 mg/kg, ip) 1 h prior to the learning trial produced
enhanced recognition memory when evaluated during the
testing trial 48 h later (Figure 4). The enhanced recogni-
tion memory, during the memory trial, is reflected by the
significantly greater amount of time (*, p < 0.05) spent
exploring the novel object compared to the familiar one in
the group treated with 3 mg/kg ip of 18b, an effect not
observed in animals treated with vehicle. These results con-
firmed the cognitive enhancing capability of selective CNS
penetrant 5-HT6 antagonists. Continued efforts in this area to
improve the potency of this and other related compound
classes will be the subject of future communications.
Conclusions
In summary, we have identified a series of novel, potent,
selective small molecule antagonists of the 5-HT6 receptor.
One selected example, 18b, showed good brain exposure when

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6 2525
Table 2. SAR of the Cyclic Aminea
a The symbol “z” indicates “not determined”.
Scheme 4. N-Alkylation of Compounds 17
Table 3. SAR of N-1/N-2 Alkylated Indazolesa
5-HT6 functional
cyclase assay
binding ki (nM)
5-HT2B
compd
alkyl group
5-HT6
IC50 (nM) (( SEM)
Imax (%) ((SEM)
18a
18b
18c
19a
19b
19c
methyl
21.1b
13.7b
36.9*
54.3b
48.7b
75.8b
185b
191b
316c
92c
83 ((0)
91 ((0.5)
92c
isopropyl
isobutyl
methyl
157 ((0.032)
203 ((0.029)
444c
>3300b
455b
isopropyl
isobutyl
>3300b
260*
380 ((0.045)
433 ((0.043)
75 ((1)
77 ((2.5)
a The asterisk (*) indicates n = 1. b n = 1. c SEM not determined.
the compound was administered ip and a generally favorable
pharmacokinetic profile with procognitive efficacy in the rat
novel object recognition assay. These data further support the
potential utility of 5-HT6 receptor antagonists for the treat-
mentof psychiatricand neurologicaldisorders withassociated
cognitive dysfunction.

2526 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6
Haydar et al.
7.48-7.56 (m, 1 H) 7.56-7.66 (m, 4 H) 8.07-8.14 (m, 1 H) 8.25
(s, 2 H) 8.43 (d, J = 7.6 Hz, 1 H) 8.75-8.81 (m, 1 H) 14.21 (s, 1
H). MS (ESI) m/z 421.2, [M þ H]þ.
1-{3-[(5-Chloro-1-naphthyl)sulfonyl]-1H-indazol-5-yl}piperi-
din-4-amine (10d). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94
(d, J = 9.3 Hz, 2 H) 2.16 (d, J = 11.0 Hz, 2 H) 3.19 (s, 1 H) 3.35
(s, 1 H) 3.72 (d, J = 11.0 Hz, 2 H) 7.69 (dd, J = 8.8, 7.6 Hz, 1 H)
7.83 (dd, J = 7.6, 1.0 Hz, 1 H) 7.95 (dd, J = 8.1 Hz, 1 H)
8.28-8.44 (m, 3 H) 8.58 (d, J = 8.5 Hz, 1 H) 8.71 (dd, J = 7.4,
1.1 Hz, 1 H) 8.84 (d, J = 8.8 Hz, 1 H) 14.44 (s, 1 H). MS (ESI) m/
z 441.1, [M þ H]þ.
1-Piperidin-4-amine (10e). 1H NMR (400 MHz, DMSO-d6) δ
ppm 1.97-2.13 (m, 2 H) 2.21 (d, J = 9.5 Hz, 2 H) 3.24-3.51 (m,
3 H) 3.77 (d, J = 11.2 Hz, 2 H) 3.91 (s, 5 H) 7.59-7.72 (m, J =
8.3, 8.3 Hz, 2 H) 7.71-7.87 (m, 2 H) 8.45 (s, 2 H) 14.63 (s, 1 H).
MS (ESI) m/z 391.1, [M þ H]þ.
1-{3-[(4-Isopropylphenyl)sulfonyl]-1H-indazol-5-yl}piperidin-
4-amine (10f). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.08
(m, 6 H) 2.11-2.23 (m, J=11.0 Hz, 2 H) 2.84-3.03 (m, J=20.7,
13.7, 6.8 Hz, 1 H) 3.18-3.44 (m, J=7.1, 7.1, 7.1 Hz, 3 H) 3.54-
3.96 (m, J=11.5 Hz, 8 H) 7.49 (dt, J=8.5, 2.0 Hz, 2 H) 7.64-7.75
(m, 1 H) 7.82-7.99 (m, 1 H) 7.95 (dt, J=8.5, 2.1 Hz, 1 H) 8.32-
8.44 (m, 2 H) 14.39 (s, 1 H). MS (ESI) m/z 399.2, [M þ H]þ.
(3S)-1-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-
amine (10g). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.15
(m, 1 H) 2.28-2.42 (m, 1 H) 3.27-3.41 (m, 2 H) 3.44-3.60 (m, 3
H) 4.00 (br s, 1 H) 6.78 (d, J = 1.7 Hz, 1 H) 6.98 (dd, J = 9.3, 2.2
Hz, 1 H) 7.53 (d, J = 9.0 Hz, 1 H) 7.58-7.69 (m, 2 H) 7.76 (dd,
J = 7.8 Hz, 1 H) 8.03-8.12 (m, J = 7.3, 2.0 Hz, 4 H) 8.30 (d, J =
8.3 Hz, 1 H) 8.53 (dd, J = 7.6, 1.2 Hz, 1 H) 8.80 (dd, J = 8.4, 1.3
Hz, 1 H) 13.95-14.00 (m, 1 H). MS (ESI) m/z 393.1, [M þ H]þ.
(3R)-1-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-
amine (10h). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06-2.19
(m, J = 4.9 Hz, 1 H) 2.28-2.42 (m, 1 H) 3.27-3.41 (m, 2 H)
3.49-3.61 (m, 2 H) 3.96 (br s, 1 H) 6.77 (d, J = 2.0 Hz, 1 H) 6.97
(dd, J = 9.0, 2.2 Hz, 1 H) 7.52 (d, J = 9.0 Hz, 1 H) 7.56-7.68 (m,
2 H) 7.76 (dd, J = 7.8 Hz, 1 H) 8.03-8.10 (m, 1 H) 8.25-8.37 (m,
3 H) 8.52 (dd, J = 7.3, 1.2 Hz, 1 H) 8.80 (d, J = 8.8 Hz, 1 H)
14.02 (br s, 1H). MS (ESI) m/z 392.9, [M þ H]þ.
Figure 4. Compound 18b efficacy in a 48 h novel object recogni-
tion: (*) p < 0.05.
Experimental Section
General Procedure. All manipulations were conducted under
an inert atmosphere of dried nitrogen. All solvents as well as
organic acids and bases were reagent grade. All reagents were
commercial compounds of the highest purity available and used
without further purification. Analytical thin-layer chromatog-
raphy (TLC) was performed on silica gel 60 F-264 (0.25 mm
thickness) plates precoated with a fluorescent indicator (1.00
mm thickness plates were used for preparatory thin-layer
chromatography). Visualization was accomplished using ultra-
violet light (λ, nm) or Vaughn’s stain reagent. Flash column
chromatography was carried out with the use of standard
220-400 mesh silica gel or Biotage Flash 40 cartridges/appara-
tus. Proton magnetic resonance spectra (1H NMR) were deter-
mined in cited solvent on a Varian Unity Plus system (300, 400,
and 500 MHz) Fourier transform spectrometer, and chemical
shifts were expressed in parts per million (δ) relative to tetra-
methylsilane (TMS-0 ppm) as an internal reference. Multipli-
cities are designated as singlet (s), broad singlet (bs), doublet (d),
doublet of doublets (dd), doublet of triplets (dt), triplet (t),
quartet (q), and multiplet (m). Mass spectra were obtained on
either a Finnigan single quadrapole SSQ710C or a Finnigan
MAT900 high resolution magnetic sector. HPLC spectra were
obtained on Agilent 1100. Sample was disssolved in DMSO with
sample concentration of 0.002 g/mL. Flow rate was 1.0 mL/min
and injection volume was 0.2 μL. Two detection wavelengths
were 215 and 254 nm. Two Coupled Onyx Monolithic C18, 0.2
cm ꢀ 5 cm column was used. Water and acetonitrile with formic
acid were used as mobile phase. HPLC was used to determine
purity of all tested compounds (at least 95%).
1-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]azetidin-3-amine
(10i). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.82 (d, J=4.6 Hz,
2 H) 4.11-4.19 (m, 3 H) 6.73 (d, J = 2.0 Hz, 1 H) 6.83 (dd,
J=9.0, 2.2 Hz, 1 H) 7.53 (dd, J=9.0, 0.5 Hz, 1 H) 7.59-7.68 (m,
2 H) 7.73-7.78 (m, J=7.8, 7.8 Hz, 1 H) 8.05-8.09 (m, 1 H)
8.27-8.36 (m, J=8.3 Hz, 3 H) 8.55 (dd, J=7.3, 1.2 Hz, 1 H)
8.76-8.81 (m, 1 H) 14.01 (s, 1 H). MS (ESI) m/z 379.1, [M þ H]þ.
(3R)-N,N-Dimethyl-1-[3-(1-naphthylsulfonyl)-1H-indazol-5-
1
yl]pyrrolidin-3-amine (10j). H NMR (400 MHz, DMSO-d6) δ
ppm 1.75-1.88 (m, 1 H) 2.11-2.19 (m, 1 H) 2.21 (s, 6 H)
2.74-2.86 (m, 1 H) 3.05 (t, J = 8.4 Hz, 1 H) 3.18-3.47 (m, 3 H)
6.67 (d, J = 1.7 Hz, 1 H) 6.92 (dd, J = 9.2, 2.3 Hz, 1 H) 7.46 (d,
J = 9.0 Hz, 1 H) 7.56-7.67 (m, 2 H) 7.76 (t, J = 8.1, 7.6 Hz, 1 H)
8.05 (dd, J = 8.2, 1.1 Hz, 1 H) 8.27 (d, J = 8.3 Hz, 1 H) 8.55 (dd,
J = 7.4, 1.1 Hz, 1 H) 8.80 (d, J = 8.5 Hz, 1 H) 13.85 (br s, 1 H).
MS (ESI) m/z 421.2, [M þ H]þ.
1-[3-(1-Naphthylsulfonyl)-1H-indazol-5-yl]piperidin-4-amine
(10a). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96-2.15 (m, 2
H) 2.22 (d, J = 11.0 Hz, 2 H) 3.23-3.50 (m, 2 H) 3.73 (d, J =
11.5 Hz, 2 H) 3.88 (s, 3 H) 7.58-7.64 (m, 1 H) 7.65-7.71 (m, 1 H)
7.71-7.81 (m, 3 H) 8.07 (d, J = 7.8 Hz, 2 H) 8.31 (d, J = 8.3 Hz,
1 H) 8.47 (s, 2 H) 8.60 (dd, J = 7.3, 1.0 Hz, 1 H) 8.81 (d, J = 8.5
Hz, 1 H) 14.53 (s, 1 H). MS (ESI) m/z 407.2, [M þ H]þ.
(3S)-N,N-Dimethyl-1-[3-(1-naphthylsulfonyl)-1H-indazol-5-
yl]pyrrolidin-3-amine (10k). 1H NMR (400 MHz, DMSO-d6) δ
ppm 1.76-1.92 (m, 1 H) 2.13-2.20 (m, 1 H) 2.22 (s, 6 H)
2.76-2.88 (m, 1 H) 3.06 (t, J = 8.7 Hz, 1 H) 3.33-3.46 (m, 3 H)
6.67 (d, J = 1.5 Hz, 1 H) 6.93 (dd, J = 9.3, 2.0 Hz, 1 H) 7.46 (d,
J = 9.0 Hz, 1 H) 7.57-7.67 (m, 2 H) 7.76 (t, J = 7.8 Hz, 1 H)
8.06 (d, J = 7.3 Hz, 1 H) 8.28 (d, J = 8.5 Hz, 1 H) 8.55 (d, J = 7.8
Hz, 1 H) 8.79 (d, J = 8.5 Hz, 1 H) 13.85 (br s, 1 H). MS (ESI) m/z
421.2, [M þ H]þ.
1-[3-(2-Naphthylsulfonyl)-1H-indazol-5-yl]piperidin-4-amine
(10b). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.07 (m, 2
H) 2.09-2.25 (m, 2 H) 3.18-3.31 (m, 1 H) 3.32-3.43 (m, J =
7.1, 7.1, 7.1 Hz, 1 H) 3.43-3.90 (m, 7 H) 7.60-7.76 (m, 3 H) 7.97
(dd, J = 8.7, 1.8 Hz, 1 H) 8.03 (d, J = 7.8 Hz, 1 H) 8.13 (d, J =
8.8 Hz, 1 H) 8.27 (d, J = 7.8 Hz, 1 H) 8.36 (s, 2 H) 8.77-8.83 (m,
1 H) 14.40 (s, 1 H). MS (ESI) m/z 407.2, [M þ H]þ.
(3R)-1-[1-Methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-
1
yl]pyrrolidin-3-amine (18a). H NMR (400 MHz, DMSO-d6) δ
ppm 1.7 (m, 1H) 2.1 (m, 2H) 2.9 (m, 1H) 3.4 (m, 2H) 3.6 (m, 1H)
6.6 (m, 1H) 6.9 (m, 1H) 7.6 (m, 3H) 7.7 (t, J = 8.0 Hz, 1H) 8.0 (m,
1H) 8.25 (m, 1H) 8.5 (m, 1H) 8.8 (m, 1H). MS (ESI) m/z 407.1,
[M þ H]þ.
1-{3-[(4-Methyl-1-naphthyl)sulfonyl]-1H-indazol-5-yl}piperi-
din-4-amine (10c). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-
1.94 (m, 2 H) 2.02-2.14 (m, 2 H) 2.69 (s, 3 H) 3.34-3.79 (m, 8 H)

Article
(3R)-1-[1-(1-Methylethyl)-3-(naphthalen-1-ylsulfonyl)-1H-in-
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6 2527
H.; Smith, D. R. Phenyl benzenesulfonamides are novel and
selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-
fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide
(SB-357134). Bioorg. Med. Chem. Lett. 2001, 11 (1), 55–58.
(7) Russell, M. G. N.; Baker, R. J.; Barden, L.; Beer, M. S.; Bristow, L.;
Broughton, H. B.; Knowles, M.; McAllister, G.; Patel, S.; Castro,
J. L. N-Arylsulfonylindole derivatives as serotonin 5-HT6 receptor
ligands. J. Med. Chem. 2001, 44 (23), 3881–3895.
(8) Cole, D. C.; Lennox, W. J.; Stock, J. R.; Ellingboe, J. W.;
Mazandarani, H.; Smith, D. L.; Zhang, G.; Tawa, G. J.; Schechter,
L. E. Conformationally constrained N(1)-arylsulfonyltryptamine
derivatives as 5-HT6 receptor antagonists. Bioorg. Med. Chem.
Lett. 2005, 15 (21), 4780–4785.
(9) Cole, D. C.; Ellingboe, J. W.; Lennox, W. J.; Mazandarani, H.;
Smith, D. L.; Stock, J. R.; Zhang, G.; Zhou, P.; Schechter, L. E.
N1-Arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole de-
rivatives are potent and selective 5-HT6 receptor antagonists.
Bioorg. Med. Chem. Lett. 2005, 15 (2), 379–383.
(10) (a) Cole, D. C.; Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.;
Bernotas, R. C.; Tawa, G. J.; Mazandarani, H.; Smith, D. L.;
Zhang, G.; Coupet, J.; Schechter, L. E. Discovery of 5-Arylsulfo-
namido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent,
selective 5-HT6 receptor agonists and antagonists. J. Med. Chem.
2005, 48 (2), 353–356. (b) Liu, K. G.; Robichaud, A. J. 5-HT6
antagonists as potential treatment for cognitive dysfunction. Drug
Dev. Res. 2009, 70 (2), 145–168.
(11) Riemer, C.; Borroni, E.; Levet-Trafit, B.; Martin, J. R.; Poli, S.;
Porter, R. H. P.; Boes, M. Influence of the 5-HT6 Receptor on
Acetylcholine Release in the Cortex: Pharmacological Character-
ization of 4-(2-Bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)pheny-
lamine, a Potent and Selective 5-HT6 Receptor Antagonist. J. Med.
Chem. 2003, 46 (7), 1273–1276.
(12) Slassi, A.; Isaac, M.; O’Brien, A. Recent progress in 5-HT6
receptor antagonists for the treatment of CNS diseases. Expert
Opin. Ther. Pat. 2002, 12 (4), 513–527.
(13) East, S. Z.; Burnet, P. W. J.; Leslie, R. A.; Roberts, J. C.; Harrison,
P. J. 5-HT6 receptor binding sites in schizophrenia and following
antipsychotic drug administration: autoradiographic studies with
[125I]SB-258585. Synapse (N. Y., NY, U. S.) 2002, 45 (3), 191–199.
(14) Marcos, B.; Gil-Bea Francisco, J.; Hirst Warren, D.; Garcia-
Alloza, M.; Ramirez Maria, J. Lack of localization of 5-HT6
receptors on cholinergic neurons: implication of multiple neuro-
transmitter systems in 5-HT6 receptor-mediated acetylcholine
release. Eur. J. Neurosci. 2006, 24 (5), 1299–1306.
(15) Dawson, L. A.; Nguyen, H. Q.; Li, P. The 5-HT6 receptor
antagonist SB-271046 selectively enhances excitatory neurotrans-
mission in the rat frontal cortex and hippocampus. Neuropsycho-
pharmacology 2001, 25 (5), 662–668.
dazol-5-yl]pyrrolidin-3-amine (18b). 1H NMR (400 MHz,
DMSO-d6) δ ppm 1.4 (d, J=6.5 Hz, 6H) 1.7 (m, 1H) 2.0 (m,
2H) 2.8 (m, 1H) 3.2 (m, 1H) 3.4 (m, 1H) 3.6 (m, 1H) 5.0 (m, 1H)
6.6 (m, 1H) 6.8 (m, 1H) 7.6 (m, 3H) 7.7 (t, J = 8.0 Hz, 1H) 8.0 (m,
1H) 8.2 (m, 1H) 8.5 (m, 1H) 8.9 (m, 1H). MS (ESI) m/z 435.2,
[M þ H]þ.
(3R)-1-[1-(2-Methylpropyl)-3-(naphthalen-1-ylsulfonyl)-1H-
indazol-5-yl]pyrrolidin-3-amine (18c). 1H NMR (400 MHz,
DMSO-d6) δ ppm 0.7 (d, J = 6.75 Hz, 6H) 1.7 (m, 1H) 2.1
(m, 2H) 2.9 (m, 1H) 3.1 (m, 1H) 3.4 (m, 2H) 3.6 (m, 1H) 4.2 (m,
2H) 6.6 (m, 1H) 6.9 (m, 1H) 7.6 (m, 3H) 7.8 (t, J=8.0 Hz, 1H)
8.0 (m, 1H) 8.3 (m, 1H) 8.5 (m, 1H) 8.9 (m, 1H). MS (ESI) m/z
449.2, [M þ H]þ.
(3R)-1-[2-Methyl-3-(naphthalen-1-ylsulfonyl)-2H-indazol-5-
yl]pyrrolidin-3-amine (19a). 1H NMR (400 MHz, DMSO-d6) δ
ppm 1.75 (m, 1H) 2.1 (m, 2H) 3.0 (m, 1H) 3.5 (m, 2H) 3.6 (m, 1H)
4.1 (s, 3H) 6.6 (m, 1H) 7.0 (m, 1H) 7.6 (m, 3H) 7.8 (t, J = 8.0 Hz,
1H) 8.1 (m, 1H) 8.3 (m, 1H) 8.4 (m, 1H) 8.5 (m, 1H). MS (ESI) m/
z 407.1, [M þ H]þ.
(3R)-1-[2-(1-Methylethyl)-3-(naphthalen-1-ylsulfonyl)-2H-
indazol-5-yl]pyrrolidin-3-amine (19b). 1H NMR (400 MHz,
DMSO-d6) δ ppm 1.1 (d, J=6.5 Hz, 6H) 1.8 (m, 1H) 2.1 (m,
2H) 3.0 (m, 1H) 3.5 (m, 2H) 3.7 (m, 1H) 5.2 (m, 1H) 6.7 (m, 1H)
7.0 (m, 1H) 7.6 (m, 3H) 7.7 (t, J = 8.0 Hz, 1H) 8.1 (m, 1H) 8.3 (m,
1H) 8.5 (m, 2H). MS (ESI) m/z 435.1, [M þ H]þ.
(3R)-1-[2-(2-Methylpropyl)-3-(naphthalen-1-ylsulfonyl)-2H-
indazol-5-yl]pyrrolidin-3-amine (19c). 1H NMR (400 MHz,
DMSO-d6) δ ppm 0.6 (d, J=6.5 Hz, 6H) 0.8 (m, 1H) 1.8 (m,
1H) 2.2 (m, 2H) 3.0 (m, 1H) 3.5 (m, 2H) 3.6 (m, 1H) 4.2 (m, 2H)
6.6 (m, 1H) 7.0 (m, 1H) 7.6 (m, 3H) 7.8 (t, J = 8.0 Hz, 1H) 8.1 (m,
1H) 8.4 (m, 1H) 8.5 (m, 2H). MS (ESI) m/z 449.2, [M þ H]þ.
Acknowledgment. We gratefully acknowledge the support
of our colleagues in the Wyeth Compound Properties Group.
Supporting Information Available: In vitro and in vivo
biological assay protocols; in vitro profile of 10h; HPLC data
of 10a-k, 18a-c, and 19a-c. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Upton, N.; Chuang, T. T.; Hunter, A. J.; Virley, D. J. 5-HT6
receptor antagonists as novel cognitive enhancing agents for
Alzheimer’s disease. Neurotherapeutics 2008, 5 (3), 458–469.
(17) Holenz, J.; Merce, R.; Diaz, J. L.; Guitart, X.; Codony, X.; Dordal,
A.; Romero, G.; Torrens, A.; Mas, J.; Andaluz, B.; Hernandez, S.;
Monroy, X.; Sanchez, E.; Hernandez, E.; Perez, R.; Cubi, R.;
Sanfeliu, O.; Buschmann, H. Medicinal chemistry driven ap-
proaches toward novel and selective serotonin 5-HT6 receptor
ligands. J. Med. Chem. 2005, 48 (6), 1781–1795.
(18) Haydar, S. N.; Andrae, P. Aminoazacyclyl-3-sulfonylindazoles as
5-hydroxytryptamine-6 ligands. U.S. Pat. Appl. Publ. (2008), US
2008293688 A1 20081127, 2008
(19) Antane, S.; Bernotas, R.; Li, Y.; McDevitt, R.; Yan, Y. Chloro-
methyl sulfones from sulfonyl chlorides via a one-pot procedure.
Synth. Commun. 2004, 34 (13), 2443–2449.
(20) Makosza, M.; Lemek, T.; Kwast, A.; Terrier, F. Elucidation of the
vicarious nucleophilic substitution of hydrogen mechanism via
studies of competition between substitution of hydrogen, deuter-
ium, and fluorine. J. Org. Chem. 2002, 67 (2), 394–400.
(21) Fitzgerald, L. W.; Burn, T. C.; Brown, B. S.; Patterson, J. P.;
Corjay, M. H.; Valentine, P. A.; Sun, J.-H.; Link, J. R.; Abbaszade,
I.; Hollis, J. M.; Largent, B. L.; Hartig, P. R.; Hollis, G. F.;
Meunier, P. C.; Robichaud, A. J.; Robertson, D. W. Possible role
of valvular serotonin 5-HT2B receptors in the cardiopathy asso-
ciated with fenfluramine. Mol. Pharmacol. 2000, 57 (1), 75–81.
(22) Di, L.; Kerns, E. H. Application of physicochemical data to
support lead optimization by discovery teams. Biotechnol.: Pharm.
Aspects 2006, 4, 167–193.
References
(1) Gerard, C.; Martres, M. P.; Lefevre, K.; Miquel, M. C.; Verge, D.;
Lanfumey, L.; Doucet, E.; Hamon, M.; el Mestikawy, S. Immuno-
localization of serotonin 5-HT6 receptor-like material in the rat
central nervous system. Brain Res. 1997, 746 (1-2), 207–219.
(2) Dawson, L. A.; Nguyen, H. Q.; Li, P. The 5-HT(6) receptor
antagonist SB-271046 selectively enhances excitatory neurotrans-
mission in the rat frontal cortex and hippocampus. Neuropsycho-
pharmacology 2001, 25 (5), 662–668.
(3) Hirst, W. D.; Stean, T. O.; Rogers, D. C.; Sunter, D.; Pugh, P.;
Moss, S. F.; Bromidge, S. M.; Riley, G.; Smith, D. R.; Bartlett, S.;
Heidbreder, C. A.; Atkins, A. R.; Lacroix, L. P.; Dawson, L. A.;
Foley, A. G.; Regan, C. M.; Upton, N. SB-399885 is a potent,
selective 5-HT6 receptor antagonist with cognitive enhancing
properties in aged rat water maze and novel object recognition
models. Eur. J. Pharmacol. 2006, 553 (1-3), 109–119.
(4) Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.; Riemer, C.;
Bourson, A. Characterization of Ro 04-6790 and Ro 63-0563:
potent and selective antagonists at human and rat 5-HT6 receptors.
Br. J. Pharmacol. 1998, 124 (3), 556–562.
(5) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.;
Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.; King,
F. D.; Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.;
Routledge, C.; Wyman, P. 5-Chloro-N-(4-methoxy-3-piperazin-
1-ylphenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046):
A potent, selective, and orally bioavailable 5-HT6 receptor antago-
nist. J. Med. Chem. 1999, 42 (2), 202–205.
(23) Abraham, M. H.; Ibrahim, A.; Zissimos, A. M.; Zhao, Y. H.;
Comer, J.; Reynolds, D. P. Application of hydrogen bonding
calculations in property based drug design. Drug Discovery Today
2002, 7 (20), 1056–1063.
(6) Bromidge, S. M.; Clarke, S. E.; Gager, T.; Griffith, K.; Jeffrey, P.;
Jennings, A. J.; Joiner, G. F.; King, F. D.; Lovell, P. J.; Moss, S. F.;
Newman, H.; Riley, G.; Rogers, D.; Routledge, C.; Serafinowska,