Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists

Article abstract of DOI:10.1016/j.bmc.2009.05.055

A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT₆ ligands. The best compounds were high affinity, full agonists at 5-HT₆ receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.

Full text of DOI:10.1016/j.bmc.2009.05.055

Bioorganic & Medicinal Chemistry 17 (2009) 5153–5163
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent
5-HT6 agonists
b
b
c
b
Ronald C. Bernotas a, , Steven Lenicek , Schuyler Antane , Derek C. Cole , Boyd L. Harrison ,
Albert J. Robichaud b, Guo Ming Zhang d, Deborah Smith d, Brian Platt d, Qian Lin d, Ping Li d, Joseph Coupet d,
Sharon Rosenzweig-Lipson d, Chad E. Beyer d, Lee E. Schechter d
*
a Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
b Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
c Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA
d Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a–z was prepared as novel 5-HT6
ligands. The best compounds were high affinity, full agonists at 5-HT6 receptors. Several agonists demon-
strated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of
selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This
compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, pos-
sibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 February 2009
Revised 21 May 2009
Accepted 22 May 2009
Available online 29 May 2009
Keywords:
Serotonin
5-Hydroxytryptamine-6 receptor
7-Azaindole
Agonist
Adenylyl cyclase assay
Binding
Sulfone
Pyrrolo[2,3-b]pyridine
1. Introduction
side chain was incorporated with an indole in 6 to give 5-HT6 ago-
nists7 while Alcalde has recently shown that even indenes 7 have
Considerable attention has been focused on the 5-HT6 receptor
due to its CNS localization and the therapeutic implications of its
proposed role in learning and memory.1 This intense interest in
the 5-HT6 receptor has led to the discovery of several classes of
high affinity ligands from Roche, SmithKline, and others. Roche
identified sulfonamides including Ro 04-6790 (1) as selective 5-
HT6 antagonists (Fig. 1).2 In 1998, scientists at SmithKline de-
scribed a series of arylsulfonamide-substituted arylpiperazines
from which SB-271046 (2) was identified as a potent, selective 5-
HT6 antagonist.3 These compounds incorporate a common feature
of many 5-HT6 selective ligands: an arylsulfonyl group.
agonist activity.8 Various 1-arylsulfonyl-tryptamines 8 are also 5-
HT6 agonists.9 Such agonists may help elucidate the biological roles
of 5-HT6 receptors and may possibly be therapeutic agents in their
own right.
One approach to developing novel 5-HT6 ligands, and one we
have undertaken, is to reverse the relative roles of the 1- and 3-
positions on the indole ring. In such ligands, the location of the
H
N
Several series of 5-HT6 agonists based on an indole core have
also been identified in the last decade (Fig. 2). Among these are
moderately selective 2-alkyl-5-methoxy-tryptamines 3a and 3b,4
1-aminoethyl-6-arylsulfonamido-indoles 4,5 and 5-arylsulfonami-
do-3-(2-(R)-pyrrolidinomethyl)-indoles 5.6 A constrained basic
NHMe
N
N
MeO
O
O
Me
MeHN
N
NH
S
S
N
O
H
S
Cl
O
NH2
1
2
* Corresponding author. Tel.: +1 484 865 2168.
E-mail address: bernotr@wyeth.com (R.C. Bernotas).
Figure 1. Early 5-HT6 antagonists.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.055

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R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
H
NMe2
NR1R2
N
R
ArSO2NH
MeO
ArSO2NH
N
R
NH
NH
3a R = Me
3b R = Et
4
5 R = H, Me
H
N
NR1R2
NMe2
R
ArSO2NH
Cl
Me
N
SO2Ar
N
H
6
7 R = H, Me
Figure 2. 5-HT6 agonists.
8
ble affinity for 5-HT6 receptors relative to tryptamines 8. We have
extended this approach to pyrrolo[2,3-b]pyridines 10, which
incorporate an additional nitrogen in the core heterocycle. This
replacement of a pyrrolo[2,3-b]pyridine for an indole led to a series
of high affinity 5-HT6 ligands, many of which performed as full
agonists in a 5-HT6 functional assay.
NR1R2
NR1R2
R3
N
N
SO2Ar
SO2Ar
8
9
2. Chemistry
NR1R2
Our initial target in this series was 1-(N,N-dimethylamino-
ethyl)-3-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine 10a, which
should form upon alkylation of 3-phenylsulfonyl-1H-pyrrolo[2,3-
b]pyridine. However, when we began this work, 3-(arylsulfonyl)-
1H-pyrrolo[2,3-b]pyridines were essentially unknown. The first
synthesis of this system relied on direct arylthiolation of pyrrol-
o[2,3-b]pyridine 11 using methylphenylsulfoxide under Pummer-
er-type conditions. This approach has been used on indole to
provide 3-(phenylthio)-1H-indole.11 However, only a low yield
(13%) of 3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine (12a Ar = Ph,
R3 = H) was realized (Scheme 1). 2-Methyl-3-(thiophenyl)-1H-pyr-
rolo[2,3-b]pyridine 12b was prepared in 20% yield by a Fischer in-
dole approach starting with 2-hydrazinopyridine 13. An alternative
N
N
R3
SO2Ar
10
Figure 3. Genesis of pyrrolo[2,3-b]pyridines 10 as 5-HT6 ligands.
aminoethyl side chain is reversed or ‘flipped’ from the carbon at
the 3-position of the indole ring to the indole nitrogen itself.
Recently, we described the application of this method to
1-arylsulfonyl-tryptamines 8 to provide 1-aminoethyl-3-arylsulfo-
nyl-1H-indoles 9 (Fig. 3).10 Compounds 9 proved to have compara-
NR1R2
NHR1
H
N
H
N
H
N
N
N
N
N
a (Z = SPh) or
c (Z = I)
N
N
N
h
i
f or g
R3
R3
Ar
R3
Ar
R3
Ar
Z
S
O
S
O
S
O
O
O
O
11
12 Z = SAr
d or e
15
14 Z = I, R3 = H
10 R1, R2 = alkyl
10 R1 = Me, R2 = H
b
m
j
NHNH2
N
X
NH2
N
N
N
N
l
R3
Ar
R3
13
Ar
S
O
S
O
O
O
16 X = Cl
17 X = NPhth
10 R1, R2 = H
k
Scheme 1. Reagents and conditions: (a) PhS(O)CH3, TFAA, CH2Cl2, À78 °C, then Et3N, rt, 3 d; (b) PhSCH2C(O)Me, EtOH, reflux, then 1,3-propanediol, reflux; (c) I2, KI, EtOH; (d)
ArSH, K2CO3, CuI, DMF, 65 °C, 4 h; (e) ArSH, NaOtBu, Pd(PPh)3, EtOH, heat; (f) MnSO4, 30% H2O2, aq NaHCO3, tBuOH; (g) OXONEÒ, aq NaHCO3, acetone; (h) NaH,
R1R2NCH2CH2Hal, DMF; (i) CH3CHClOC(O)Cl, DCE, reflux, 3 h, then EtOH, reflux, 2 h; (j) DCE, CH3N[(CH2)7CH3]3Cl, NaOH, H2O, 60 °C; (k) potassium phthalimide, DMF, 115 °C;
(l) hydrazine, dioxane, heat; (m) ClCH2CH2NH2ÁHCl, NaOH, (n-Bu)4NHSO4.

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
5155
Table 1
method tried was Harris’ arylthiolation procedure developed for
5-HT6 receptor binding and adenylyl cyclase activation assays18,9
indoles.12 Treatment of 11 and thiophenol with iodine and potas-
sium iodide afforded only trace amounts of 12a, accompanied by
large amounts of 3-iodo-1H-pyrrolo[2,3-b]pyridine 14. Ready iso-
lation of 14 suggested it could serve as an intermediate for the
preparation of 12. Thus, treatment of 14 with arylthiols in the pres-
ence of copper iodide gave 12d and 12e in moderate to good
yield.13 Alternatively, the coupling could be accomplished using
Pd(PPh3)4 as a catalyst and NaOtBu as the base in hot ethanol to
give 12. Oxidation of sulfides 12 to sulfones 15 was accomplished
using MnSO4/H2O2 or, preferably, OXONEÒ.14
Ar
R1
R2 R3 5-HT6
cAMP assay for 5-HT6
Ki (nM)
EC50 or
Emax or
Imax (%)
IC50 (nM)
9a
9b
Ph
Ph
Me
H
Me
H
Me
H
Me
H
H
H
H
H
20 ( 0.2) 366 ( 23)
63
67
94
100
85
25 ( 2)
23 ( 2)
178 ( 19)
25 ( 0.1)
10a Ph
10b Ph
5.5 ( 0.6) 27 ( 4)
10c
Ph
H
H
Me 4.2 ( 0.4) 20 ( 0.3)
10d Ph
10e 3-FPh
Me
Me
Me
Me Me 4.7 ( 0.1) 47 ( 19)
100
100
93
(ant)
100
Not
tested
86
100
(ant)
94
Not
tested
84
100
97
83
80
65
97
(ant)
66
63
65
Me
H
H
H
4.8 ( 0.3) 7.3 ( 1.6)
1.0 ( 3.4) 6.2 ( 0.1)
(ant)
With the core 3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines in
hand, we turned to installation of the basic side chain. In the pres-
ence of NaH, direct alkylation of 15 with aminoethylchlorides or bro-
mides (R1R2N(CH2)2Hal), as the HCl or HBr salts, provided targets 10
(R1, R2 = alkyl), sometimes accompanied by a small amount of the
regioisomer from alkylation at the other nitrogen. Secondary amines
10 (R1 = Me, R2 = H) were prepared from tertiary amines 10 (R1,
R2 = Me) by monodealkylation with 1-chloroethyl chloroformate
as described by Olofson.15 Initially, primary amines 10 (R1, R2 = H)
were prepared by Gabriel synthesis via chloroethyl intermediates
16, which were converted to the corresponding phthalimides 17
and deprotected using hydrazine to afford 10 (R1, R2 = H). Direct
alkylation using sodium hydroxide, 2-aminoethylchloride hydro-
chloride with (n-Bu)4NHSO4 as a phase transfer catalyst, as reported
by Alvarez-Builla for pyrroles,16 proved much more efficient and
was used to prepare most of the primary amines.
To facilitate SAR studies, a direct sulfonylation approach was
developed to more quickly prepare tertiary amines 10 (Scheme
2). Commercial pyrrolo[2,3-b]pyridine 11 was alkylated with
N,N-dimethylaminoethylchloride to provide 18 which was treated
with arylsulfonyl chloride at elevated temperatures in nitroben-
zene in the presence of silver triflate.17 This two-step approach
provided targets 10 (R1, R2 = Me) in poor to good yield and allowed
the rapid expansion of the arylsulfonyl SAR to include more substi-
tuted phenyl rings as well as heterocycles such as thiophenes. Sec-
ondary amines 10 (R1 = Me, R2 = H) were prepared as described in
Scheme 1.
10f
3-FPh
10g 3-FPh
10h 3-FPh
H
H
H
H
4.7 ( 0.6) 24 ( 3)
–(CH2)4–
88 ( 3)
Not tested
10i
10j
3-ClPh
3-ClPh
Me
Me
Me
H
H
H
2.3 ( 0.2) 15 ( 0.4)
0.3 ( 0)
8.3 ( 0.6)
(ant)
10k 3-ClPh
10l 3-ClPh
H
H
H
H
2.0 ( 0.3) 18 ( 5)
–(CH2)4–
45 ( 1)
Not tested
10m 4-FPh
10n 4-FPh
10o 2-CF3Ph
10p 3-CF3Ph
10q 3,5-DiClPh
Me
H
H
H
Me
H
Me
H
H
H
Me
H
H
H
H
H
H
H
H
45 ( 5)
22 ( 3)
30 ( 3)
166 ( 2)
2.1 ( 0.1) 85 ( 4)
2.1 ( 0.1) 110 ( 0.3)
4.3 ( 0.4) 28 ( 6)
2.9 ( 0.4) 35 ( 10)
11.7 ( 4) 15 ( 2)
(ant)
10r
10s
3,5-DiClPh
2,5-DiClPh
Me
Me
10t
2,6-DiClPh
Me
Me
H
Me
Me
Me
Me
H
Me
Me
Me
H
H
H
H
H
H
9.0 ( 2)
1.0 ( 0.2) 51 ( 3)
1.6 ( 0)
15 ( 2)
3.3 ( 0)
31 ( 11)
10u 1-Naphthyl
10v 1-Naphthyl
10w 2-Thienyl
10x 5-Cl-thien-2-yl
10y 6-Cl-imidazo[2,1- Me
b][1,3]thiazo-5-yl
63 ( 23)
154 ( 32)
32 ( 8)
74
93
71
0.9 ( 0.1) 120 ( 5)
10z
6-Cl-imidazo[2,1- Me
H
H
0.9 ( 0.2) 5.4 ( 7.2)
(ant)
89
(ant)
b][1,3]thiazo-5-yl
5-HT6 receptors were human clones stably expressed in Hela cells using [3H]LSD as
the radioligand. IC50 and Imax values for antagonists in the adenylyl cyclase assay are
indicated by ‘ant’ following the value.
ity. Interestingly, secondary amine 10f had particularly high affinity
with a Ki = 1 nM. 3-Chloro substitution (10i–k) provided a 2–3-fold
increase in affinity relative to the 3-fluoro compounds and the same
trend toward higher affinity for monomethylamines (10j) was ob-
served. In fact, 10j had a Ki = 0.3 nM, the best 5-HT6 affinity for any
compound described here. In contrast, larger basic groups such as
pyrrolidine (10h, 10l) or substitution at the 4-position of the aryl-
sulfonyl (10m, 10n) resulted in compounds with considerably
weaker 5-HT6 receptor affinity. Other modifications including tri-
fluoromethyl (10o, 10p) and dichloro substitution (10q–t) were well
tolerated by the receptor. Replacing the phenyl with a 1-naphthyl
groupgave high affinity ligands 10uand 10v, a result consistent with
trends seen in the 1-(aminoethyl)-3-phenylsulfonyl-1H-indole ser-
ies we reported earlier.10 Finally, heterocycles including thiophenes
(10w, 10x) and imidazothiazoles (10y, 10z) also provided ligands
with excellent 5-HT6 affinity.
3. In vitro biological assays
Final compounds 10 were tested for 5-HT6 affinity in a standard
radioligand binding assay18 using human-cloned 5-HT6 receptors
stably transfected in Hela cells (Table 1). Comparison of 1-(amino-
ethyl)-3-phenylsulfonyl-1H-indoles 9a and 9b with their direct ana-
logs (10a and 10b, respectively) demonstrates that introduction of
the second (pyridyl) nitrogen gave comparable or increased affinity
for 5-HT6 receptors. In this instance, the primary amine had mod-
estly higher affinity compared to the tertiary amine but, in general,
there was little difference in affinity between these basic groups.
Methyl substitution at the 2-position (10c, 10d) also provided high
affinity ligands. Several modifications of the arylsulfonyl by halogen
substitution were examined. Introduction of a meta-fluorine (10e–
g) on the arylsulfonyl group maintained or slightly increased affin-
NMe2
R1R2
R1R2
H
N
N
N
N
N
a
b
c
N
N
N
SO2Ar
10 R1, R2 = Me, Me
SO2Ar
10 R1 = Me, R2 = H
11
18
Scheme 2. Reagents and conditions: (a) NaH, Me2NCH2CH2Cl, DMF, rt, 18 h; (b) ArSO2Cl, AgOTf, PhNO2, 100–125 °C, 20–25 h; (c) CH3CHClOC(O)Cl, DCE, reflux, concentrate,
then EtOH, reflux.

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R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
Nearly all the compounds were further tested in an adenylyl cy-
500
400
300
200
100
0
clase assay19 to determine whether the pyrrolo[2,3-b]pyridine li-
gands were able to modulate 5-HT6 function in vitro. Remarkably,
most of the primary (R1, R2 = H) and tertiary amines (R1, R2 = Me)
in the series were potent and efficacious agonists. Thus, introduction
of the additional nitrogen provided full agonists in the adenylyl cy-
clase assay compared to the parent indole-based series (9), which
at best were weak partial agonists. Favored substitutions for the
most potent agonists were the 3-fluorophenylsulfonyl and 3-chlo-
rophenylsulfonyl groups, which resulted in potent, full agonists.
Among these compounds, 10e (WAY-208466) was a standout with
an EC50 = 7.3 nM and Emax = 100% and was chosen for further stud-
ies.20 Most other substitution patterns in the primary and tertiary
amines still provided agonists except for 2,5-dichlorophenylsulfo-
nyl 10s, which was an antagonist. Interestingly, high affinity
monomethylamines 10 (R1 = Me, R2 = H) were potent antagonists
in the adenylyl cyclase assay, regardless of the arylsulfonyl group.
For example, in the 3-fluorophenyl and 3-chlorophenyl series, pri-
mary amines were full, potent agonists, secondary amines were
full, potent antagonists, and tertiary amines reverted back to being
full agonists. The reasons for this empirical observation are under
investigation.
GABA
-100
0
50
100
150
Time (min)
200
250
300
350
500
400
300
200
100
0
Glutamate
Vehicle + Vehicle
WAY-208466 (30 mg/kg, s.c.)
Selected compounds were further tested for binding selectivity
against other serotonergic and dopaminergic receptors (Table 2).
Binding selectivity of >50-fold for 5-HT6 receptors compared to
other serotonin and dopamine receptors was observed for four
compounds. In contrast, 10k was less selective, especially against
5-HT2 receptors.
4. In vivo biological assays
The in vivo activity of 10e (WAY-208466) was also evaluated.21
Microdialysis techniques were used to show the neurochemical ef-
fects of WAY-208466 in vivo. In the rat frontal cortex, acute treat-
ment with WAY-208466 (30 mg/kg, sc) significantly (P < 0.05)
increased extracellular GABA concentrations (Fig. 4, top panel)
without altering levels of glutamate (Fig. 4, bottom panel). These
results show a unique profile of WAY-208466 to preferentially ele-
vate cortical GABA levels, which is consistent with the in vivo
activity of other selective 5-HT6 receptor agonists.9c,20 Consistent
with this neurochemical effect, WAY-208466 was shown to reduce
adjunctive drinking behavior in the rat schedule-induced polydip-
sia (SIP) assay (Fig. 5), a model considered to be predictive for effi-
cacy in obsessive compulsive disorder (OCD) and related anxiety
disorders. In a non-scheduled control comparing vehicle to WAY-
208466, the test compound did not increase water intake.
-100
0
50
100
150
Time (min)
200
250
300
350
Figure 4. GABA and glutamate levels in the rat frontal cortex following acute
treatment with WAY-208466. Arrows represent time of 5-HT6 agonist administra-
tion. *P < 0.05 compared to vehicle treatment.
120
100
80
Table 2
Binding affinity for serotonin and dopamine receptors (IC50 values in nM, or
%
inhibition at 1 lM)
10b
10e
10i
10k
10u
60
5-HT6
5-HT1B
5-HT1D
5-HT1F
5-HT2A (ag)
5-HT2C (ag)
5-HT7
D2
5.5
11%
16%
14%
>5000
>5000
>5000
>5000
>5000
>5000
4.8
30%
16%
22%
351
644
4764
>5000
>5000
>5000
2.3
46%
10%
29%
131
477
1217
>5000
>5000
>5000
2.0
nt
nt
nt
11
44
1362
>5000
>5000
>5000
1.0
40%
0%
10%
938
1135
511
>5000
1558
>5000
*
40
20
ED50 = 89.46 mg/kg p.o.
D3
D4
0
Receptors were all human clones stably expressed in CHO cells (5-HT receptors) or
CHO-K1 cells (dopamine receptors) except 5-HT6 receptors (Hela cells). Radioli-
gands were as follows: 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2C: [3H]-5-HT: 5-HT2A: [1-(2,5-
dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI); 5-HT6, 5-HT7: [3H]LSD;
dopamine D2, D3, and D4: [3H]spiperone. ag = agonist.
veh
30
56
100
WAY-208466 (mg/kg, p.o.)
Figure 5. Schedule-induced polydipsia (SIP) in rats after oral dosing with WAY-
208466. *P < 0.05 compared to vehicle treatment.

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
5157
tion was heated at 50 °C for 3 h and concentrated in vacuo. The res-
idue was diluted with H2O (150 mL) and extracted with CH2Cl2
(3 Â 150 mL). The extracts were dried over MgSO4 and concen-
trated in vacuo to a clear gum. Chromatography, eluting with
10:90 methanol/CH2Cl2, gave the free amine of 10b as a clear
gum (2.90 g, 92%, Rf ꢀ 0.6 in 15:85 methanol/CH2Cl2). The free
amine was dissolved in ethanol and acidified with 2 N aqueous
HCl (15 mL, 30 mmol). Concentration in vacuo to dryness and crys-
tallization from ethanol/ether gave the dihydrochloride of 10b as a
white solid (3.20 g, 81%). Mp: 195–197 °C. 1H NMR (DMSO-d6):
8.51 (1H, s), 8.42 (1H, d, J = 4.7 Hz), 8.21 (1H, d, J = 8.0 Hz), 8.2
(3H, br s), 8.01 (2H, d, J = 7.9 Hz), 7.66–7.55 (3H), 7.35 (1H, dd,
J = 4.7, 7.9 Hz), 4.60 (2H, t, J = 6.0 Hz), 3.36 (2H, m). MS (ES+):
302 (100%, M+H). Anal. Calcd for C15H15N3O2SÁ2HCl: C, 48.13; H,
4.58; N, 11.23. Found: C, 47.95; H, 4.59; N, 10.95.
5. Conclusions
In summary, novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrol-
o[2,3-b]pyridines 10 were prepared by several routes. These com-
pounds invert the relative positions of the basic side chain and
arylsulfonyl group in known indole-based 5-HT6 ligands and then
introduce an additional nitrogen to the core structure. Binding as-
says indicated these compounds had generally high affinity for the
target receptors, especially 10f, 10j, 10y and 10z with Ki values of
1.0 nM or less. Some exhibited excellent selectivity versus dopami-
nergic and other serotonergic receptors. All but one of the primary
and N,N-dimethyl amines were agonists with intrinsic activity of
63% or better, including several full, potent agonists. Of particular
note is compound 10e (WAY-208466), which was a selective, full
agonist of excellent potency in a 5-HT6 functional assay (adenylyl
cyclase activation) with an EC50 = 7.3 nM and Emax = 100%. More-
over, this compound displayed in vivo activity consistent with
other selective 5-HT6 receptor agonists. Further explorations of this
and related series will be reported in the near future.
6.1.3. 2-[2-Methyl-3-(phenylsulfonyl)-1H-pyrrolo[2,3-
b]pyridin-1-yl]ethylamine hydrochloride (10c)
Prepared from 15b in a manner analogous to that of 10g afford-
ing 10c as a hygroscopic white solid in 40% yield. Mp >250 °C. 1H
NMR (DMSO-d6): 8.34 (1H, d, J = 4.7 Hz), 8.27 (1H, d, J = 8.0 Hz),
8.20 (3H, v br s), 7.95 (2H, d, J = 7.5 Hz), 7.62 (1H, app t,
J = 6.6 Hz), 7.57 (2H, app t, J = 7.0 Hz), 7.32 (1H, m), 4.52 (2H, t,
J = 6.7 Hz), 3.24 (2H, m), 2.81 (3H, s). MS (ES+): 316 (M+H). Anal.
Calcd for C16H17N3O2SÁ2HCl: C, 49.49; H, 4.93; N, 10.82. Found: C,
49.74; H, 4.80; N, 10.82.
6. Experimental
6.1. General experimental
Solvents and chemicals were purchased from EM Sciences, VWR,
and Aldrich Chemical Co. and used without further purification.
High-resolution mass spectra were obtained on a Waters LC-TOFMS
instrumentandweremeasuredtowithin5 ppmofcalculatedvalues.
1H NMRspectra were taken on a BrukerDPX300 (300 MHz)or Varian
(400 MHz) instruments. NMR data are given as delta values (d) ppm
using tetramethylsilane as an internal standard (d = 0 ppm). In the
peak shape descriptions, v is very, br is broad, fc indicates very fine
coupling, and app is apparent. Chromatographyrefers topurification
on flash silica gel. Compounds with HRMS data were also run on an
Agilent 1200H-MSD2 reverse phase analytical HPLC column (Xterra
RP18, 3.5 u, 150 Â 4.6 mm), detecting at 210–370 nM, and eluting
with a 85:15–5:95 gradient of 10 mM aq ammonium formate/
50:50 acetonitrile/water. Purity in this assay is given as HPLC purity.
6.1.4. N,N-Dimethyl-N-{2-[2-methyl-3-(phenylsulfonyl)-1H-
pyrrolo[2,3-b]pyridin-1-yl]ethyl}amine hydrochloride (10d)
Prepared from 15b by the procedure of 10a except purifying by
chromatography eluting with 3:5:92 methanol/concd NH4OH/
dichloromethane, then by chromatography eluting with 2:1:97
ethanol/triethylamine/ethyl acetate to afford the free amine of
10d (128 mg, 51%). The free amine was converted to the hydro-
chloride by dissolving in ethanol, treating with excess 1 M aqueous
HCl, and concentrating to dryness. The residue was crystallized
from ether/ethanol to afford the title compound as a hygroscopic
white solid (138 mg). Mp: 210–214 °C. 1H NMR (DMSO-d6):
10.53 (1H, br s), 8.36 (1H, dd, J = 1.5, 4.7 Hz), 8.29 (1H, dd, J = 1.5,
7.9 Hz), 7.96 (2H, d, J = 7.3 Hz), 7.63 (1H, app t, J = 7.3 Hz), 7.57
(2H, app t, J = 7.8 Hz), 7.33 (1H, dd, J = 4.7, 7.9 Hz), 4.69 (2H, t,
J = 6.9 Hz), 3.46 (2H, m), 2.84 (9H, m). MS (ES+): 343 (M+H). Anal.
Calcd for C18H21N3O2SÁ1.5HClÁ0.4H2O: C, 53.34; H, 5.79; N, 10.37.
Found: C, 53.00; H, 5.33; N, 10.11.
6.1.1. N,N-Dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-
b]pyridin-1-yl]ethyl}amine hydrochloride (10a)
Compound 15a (400 mg, 1.55 mmol) in dry DMF (5 mL) stirred
at 0 °C was treated with sodium hydride (60% in oil, 97 mg,
2.43 mmol). The reaction was stirred 3 h at 20 °C, then cooled to
À20 °C and treated with 2-(dimethylamino)ethyl chloride hydro-
chloride (336 mg, 2.33 mmol). After heating at 60 °C for 16 h, the
reaction was cooled, quenched with H2O (150 mL), and extracted
with ethyl acetate (3 Â 150 mL). The organic phases were washed
with brine and dried over MgSO4. Concentration in vacuo afforded
the free amine 10a as a yellowish gum (150 mg, 29%, Rf ꢀ 0.1 in
1:49 methanol/CH2Cl2), which was dissolved in ethanol and trea-
ted with 1 N aqueous HCl (4 mL, 4 mmol). Concentration in vacuo
to dryness followed by crystallization of the residue from ethanol/
ether gave 10a dihydrochloride as a light tan solid (111 mg). Mp:
214–217 °C. 1H NMR (DMSO-d6): 10.4 (1H, br s), 8.59 (1H, s),
8.44 (1H, d, J = 4.7 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.01 (2H, d,
J = 8.4 Hz), 7.55–7.65 (3H, m), 7.36 (1H, m), 4.74 (2H, t,
J = 6.5 Hz), 3.64 (2H, m), 2.81 (6H, d, J = 4.8 Hz). MS (ES+): 330
(100%, M+H). Anal. Calcd for C17H19N3O2SÁ2HCl: C, 50.75; H, 5.26;
N, 10.44. Found: C, 50.88; H, 5.35; N, 10.25.
6.1.5. N-(2-{3-[(3-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N,N-dimethylamine hydrochloride (10e)
A stirred solution of 18 (1.66 g, 8.8 mmol) in nitrobenzene
(30 mL) under nitrogen was treated with 3-fluorophenylsulfonyl
chloride (1.88 g, 9.7 mmol). Silver trifluoromethylsulfonate (2.94 g,
11.4 mmol) was added, producing an immediate precipitate. The
reaction was heated at 100 °C for 22 h, then cooled and filtered
through a cotton plug. The filtrate was treated with water (30 mL)
and saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2
(2 Â 100 mL). The extracts were dried (MgSO4) and concentrated
in vacuo. The residue was chromatographed eluting with 2:98 con-
centrated ammonium hydroxide/ethanol, isolating the component
with Rf ꢀ 0.2 as a viscous oil which solidified (1.25 g, 41%). The free
amine was dissolved in warm ethanol (25 mL), treated with 4 M
HCl in dioxane (2.5 mL) and the resulting pale yellow solid was suc-
tion filtered to afford 10e as the dihydrochloride (1.07 g, 29%). Mp:
191–192 °C. 1H NMR (DMSO-d6): 10.53 (1H, br s), 8.60 (1H, s), 8.41
(1H, dd, J = 1.6, 4.8 Hz), 8.22 (1H, dd, J = 1.6, 7.9 Hz), 7.83 (1H, app
d, J = 6.8 Hz), 7.79 (1H, app dt, J = 1.6, 8.4 Hz), 7.61 (1H, m), 7.47
(1H, m), 7.33 (1H, dd, J = 4.8, 7.9 Hz), 4.72 (2H, t, J = 6.5 Hz), 3.61
(2H, m), 2.78 (6H, d, J = 4.8 Hz). MS (ES+): 348 (M+H). Anal. Calcd
6.1.2. 2-[3-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-1-
yl]ethylamine hydrochloride (10b)
A solution of 17a (4.54 g, 10.5 mmol) in dioxane (80 mL) was
treated with anhydrous hydrazine (8.3 mL, 265 mmol). The solu-

5158
R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
for C17H18FN3O2SÁ2HCl: C, 48.58; H, 4.80; N, 10.00. Found: C, 48.55;
mate (0.40 mL, 3.7 mmol). The reaction was heated at reflux for
2 h, cooled, and concentrated in vacuo. The residue was treated
with ethanol (10 mL), heated at reflux for 2 h, and concentrated
in vacuo. The residue was chromatographed using 2:98 concen-
trated ammonium hydroxide/ethanol as eluent, isolating the com-
ponent with Rf ꢀ 0.2 as a semi-solid (311 mg, 60%). The free amine
was dissolved in ethanol (10 mL), treated with 4 M HCl in dioxane
(0.50 mL) and the resulting pale yellow solid was suction filtered to
afford 10j hydrochloride (274 mg, 48%). Mp: 263–265 °C (dec.). 1H
NMR (DMSO-d6): 8.79 (2H, v br s), 8.53 (1H, s), 8.40 (1H, dd, J = 1.5,
4.6 Hz), 8.22 (1H, dd, J = 1.5, 7.9 Hz), 7.97 (2H, m), 7.68 (1H, ddd,
J = 1.2, 2.1, 8.0 Hz), 7.58 (1H, app t, J = 8.1 Hz), 7.34 (1H, dd,
J = 4.6, 7.9 Hz), 4.62 (2H, t, J = 6.0 Hz), 3.43 (2H, br m), 2.53 (3H,
br t, J = 5.1 Hz). MS (ES+): 348 (100%, M+H). Anal. Calcd for
C16H16ClN3O2SÁHCl: C, 49.75; H, 4.44; N, 10.88. Found: C, 49.73;
H, 4.11; N, 10.75.
H, 4.73; N, 9.90.
6.1.6. N-(2-{3-[(3-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N-methylamine hydrochloride (10f)
Compound 10f was prepared from the free amine of 10e by the
procedure of 10j to give a white solid in 57% yield. Mp 260–262 °C.
1H NMR (DMSO-d6): 8.80 (2H, v br s), 8.52 (1H, s), 8.40 (1H, dd,
J = 1.5, 4.7 Hz), 8.22 (1H, dd, J = 1.5, 7.9 Hz), 7.84 (1H, ddd, J = 0.9,
1.7, 7.8 Hz), 7.78 (1H, d with fc, J = 8.3 Hz), 7.62 (1H, m), 7.47
(1H, m), 7.33 (1H, dd, J = 4.8, 7.9 Hz), 4.62 (2H, t, J = 5.8 Hz), 3.45
(2H, br t, J = 5.6 Hz), 2.53 (3H, s). MS (ES+): 334.1 (M+H). Anal.
Calcd for C16H16FN3O2SÁHCl: C, 51.96; H, 4.63; N, 11.36. Found: C,
51.55; H, 4.71; N, 11.15.
6.1.7. 2-{3-[(3-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethylamine hydrochloride (10g)
Essentially following the general procedure of Alvarez-Builla,16
compound 15c (270 mg, 0.98 mmol), 2-chloroethylamine hydro-
chloride (147 mg, 1.27 mmol), tetrabutylammonium sulfate
(85 mg, 0.25 mmol), and powdered NaOH (157 mg, 3.92 mmol) in
dioxane (3.0 mL) was heated at reflux for 22 h. The reaction was
cooled and diluted with ethyl acetate and filtered. The filtrate
was concentrated in vacuo and the residue purified by chromatog-
raphy eluting with 4:5:91 methanol/concd NH4OH/dichlorometh-
ane to give the free amine of 10g as a light yellow solid (154 mg,
49%). The hydrochloride was prepared to give 10g as a white,
hygroscopic solid (158 mg). Mp: 202–204 °C. 1H NMR (DMSO-d6):
8.55 (1H, s), 8.43 (1H, dd, J = 1.4, 4.7 Hz), 8.24 (1H, dd, J = 1.6,
7.9 Hz), 8.14 (3H, v br s), 7.87 (1H, dd, J = 0.9, 7.8 Hz), 7.81 (1H,
sl. br d, J = 8.4 Hz), 7.64 (1H, m), 7.50 (1H, app dt, J = 2.4, 8.5 Hz),
7.36 (1H, dd, J = 4.7, 7.9 Hz), 4.60 (2H, t, J = 6.0 Hz), 3.37 (2H, m).
MS (ES+): 320 (M+H). Anal. Calcd for C15H14FN3O2SÁ1.5HCl: C,
48.17; H, 4.18; N, 11.23. Found: C, 48.43; H, 4.33; N, 11.07.
6.1.11. 2-{3-[(3-Chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethylamine hydrochloride (10k)
Compound 10k was prepared from 17b (778 mg, 1.67 mmol) in
the same manner as 10b to give an off-white solid (369 mg,
1.10 mmol, 66%, Rf ꢀ 0.3 in 10:90 methanol/CH2Cl2). The dihydro-
chloride salt of 10k was prepared as in 10a to afford a white solid
(353 mg, 52%). Mp: 203–206 °C. 1H NMR (DMSO-d6): 8.56 (1H, s),
8.44 (1H, d, J = 4.7 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.1 (3H, br s),
7.95–8.05 (2H, m), 7.70–7.75 (1H, m), 7.63 (1H, t, J = 8.2 Hz), 4.60
(2H, t, J = 6.0 Hz), 3.38 (2H, m). MS (ES+): 336 (100%, M+H). Anal.
Calcd for C15H14ClN3O2SÁ2HCl: C, 44.08; H, 3.95; N, 10.28. Found:
C, 44.37; H, 3.96; N, 10.33.
6.1.12. 3-[(3-Chlorophenyl)sulfonyl]-1-(2-pyrrolidin-1-ylethyl)-
1H-pyrrolo[2,3-b]pyridine hydrochloride (10l)
Prepared from 15d in the same manner as 10h to afford the free
amine as an amber solid (155 mg, 73%) and the dihydrochloride as
a white solid. Mp: 183–185 °C. 1H NMR (DMSO-d6): 10.67 (1H, br
s), 8.67 (1H, s), 8.47 (1H, dd, J = 1.4, 4.6 Hz), 8.28 (1H, dd, J = 1.5,
8.1 Hz), 8.02 (2H, m), 7.73 (1H, d with fc, J = 7.2 Hz), 7.64 (1H,
app t, J = 8.1 Hz), 7.39 (1H, dd, J = 4.7, 7.9 Hz), 4.75 (2H, t,
J = 6.4 Hz), 3.73 (2H, m, partly obscured by water peak), 3.56 (2H,
m), 3.05 (2H, m), 1.98 (2H, m), 1.84 (2H, m). MS (ES+): 390
(M+H). Anal. Calcd for C19H20ClN3O2SÁ2HClÁ0.4H2O: C, 48.55; H,
4.89; N, 8.94. Found: C, 48.54; H, 4.84; N, 8.85.
6.1.8. 3-[(3-Fluorophenyl)sulfonyl]-1-(2-pyrrolidin-1-ylethyl)-
1H-pyrrolo[2,3-b]pyridine hydrochloride (10h)
Prepared as in 10a except using 15c and 1-(2-chloroethyl)pyr-
rolidine hydrochloride as reactants and crystallizing from etha-
nol/ether to afford 10h as an off-white solid (66% yield). Mp:
198–200 °C. 1H NMR (DMSO-d6): 10.64 (1H, br s), 8.66 (1H, s),
8.46 (1H, dd, J = 1.4, 4.7 Hz), 8.28 (1H, dd, J = 1.5, 7.9 Hz), 7.88
(1H, d with fc, J = 8.1 Hz), 7.84 (1H, d with fc, J = 8.2 Hz), 7.66
(1H, m), 7.52 (1H, m), 7.39 (1H, dd, J = 4.7, 7.9 Hz), 4.75 (2H, t,
J = 6.6 Hz), 3.70 (2H, m, obscured by water peak), 3.56 (2H, m),
3.05 (2H, m), 2.00 (2H, m), 1.83 (2H, m). MS (ES+): 374.1 (M+H).
Anal. Calcd for C19H20FN3O2SÁ2HCl: C, 51.13; H, 4.97; N, 9.41.
Found: C, 51.03; H, 5.14; N, 9.20.
6.1.13. N,N-Dimethyl-N-(2-{3-[(4-fluorophenyl)sulfonyl]-1H-
pyrrolo[2,3-b]pyridin-1-yl}ethyl)amine hydrochloride (10m)
Compound 10m was prepared from 15e (160 mg, 0.60 mmol) in
a manner analogous to that of compound 10a to give the free
amine as an off-white solid (109 mg, 52%). The dihydrochloride
of 10m was made in the same manner as compound 10b affording
an off-white solid (119 mg). Mp: 189–192 °C. 1H NMR (DMSO-d6):
10.3 (1H, br s), 8.60 (1H, s), 8.45 (1H, d, J = 4.7 Hz), 8.23 (1H, d,
J = 8.1 Hz), 8.15–8.05 (2H, m), 7.43 (2H, app t, J = 8.8 Hz), 7.37
(1H, m), 4.74 (2H, app t, J = 6.5 Hz), ꢀ3.6 (2H, obscured by H2O),
2.83 (6H, d, J = 4.8 Hz). MS (ES+): 348 (100%, M+H). Anal. Calcd
for C17H18N3O2SÁ2HCl: C, 48.58; H, 4.80; N, 10.00. Found: C,
48.40; H, 4.89; N, 9.77.
6.1.9. N,N-Dimethyl-N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-
pyrrolo[2,3-b]pyridin-1-yl}ethyl)amine hydrochloride (10i)
Prepared from 15d (170 mg, 0.58 mmol) in a manner analogous
to that of 10a affording the free amine 10i as an off-white solid
(140 mg, 66%). The HCl salt was made in the same manner as in
10b to give 10i dihydrochloride as an off-white solid (106 mg).
Mp: 182–186 °C. 1H NMR (DMSO-d6): 10.3 (1H, br s), 8.60 (1H,
s), 8.45 (1H, d, J = 4.7 Hz), 8.23 (1H, d, J = 8.1 Hz), 8.15–8.05 (2H,
m), 7.43 (2H, t, J = 8.8 Hz), 7.37 (1H, m), 4.74 (2H, t, J = 6.5 Hz),
ꢀ3.6 (2H, obscured by H2O), 2.83 (6H, d, J = 4.8 Hz). MS (ES+):
364 (100%, M+H). Anal. Calcd for C17H18ClN3O2SÁ2HCl: C, 46.75;
H, 4.62; N, 9.62. Found: C, 47.06; H, 4.41; N, 9.34.
6.1.14. 2-{3-[(4-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethylamine hydrochloride (10n)
A suspension of 17c (723 mg, 1.61 mmol) and anhydrous hydra-
zine (1.00 mL, 1.02 g, 32 mmol) in dioxane (20 mL) was stirred for
16 h at 20 °C. The reaction mixture was concentrated in vacuo, di-
luted with H2O (50 mL) and extracted with CH2Cl2 (3 Â 50 mL). The
combined CH2Cl2 phases were dried over MgSO4 and concentrated
to a white gum. This intermediate product was resubmitted to
reaction by dissolving in ethanol (20 mL), treating with anhydrous
6.1.10. N-(2-{3-[(3-Chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N-methylamine hydrochloride (10j)
To a stirred solution under nitrogen of 10i (0.540 g, 1.49 mmol)
in 1,2-dichloroethane (10 mL) was added 1-chloroethyl chlorofor-

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
5159
hydrazine (0.50 mL, 0.50 g, 16 mmol), and heating for 4 h at 40 °C.
The cooled reaction mixture was concentrated in vacuo, diluted
with H2O (50 mL) and extracted with CH2Cl2 (3 Â 50 mL). The com-
bined CH2Cl2 phases were dried over MgSO4 and concentrated in
vacuo. The crude product was chromatographed eluting with
3:97 methanol/CH2Cl2 to afford the free amine as an off-white solid
(375 mg, 73%, Rf ꢀ 0.3 in 10:90 methanol/CH2Cl2). The hydrochlo-
ride was made as in 10b, to obtain the title compound as a white
solid (385 mg). Mp: 193–197 °C. 1H NMR (DMSO-d6): 8.51 (1H,
s), 8.43 (1H, d, J = 4.7 Hz), 8.22 (1H, d, J = 7.9 Hz), 8.05–8.15 (5H),
7.43 (2H, app t, J = 8.9 Hz), 7.36 (1H, m), 4.59 (2H, t, J = 6.0 Hz),
3.38 (2H, m). MS (ES+): 320 (M+H). Anal. Calcd for
C15H14FN3O2SÁ1.5HClÁ0.5H2O: C, 47.03; H, 4.34; N, 10.97. Found:
C, 47.11; H, 4.24; N, 10.95.
scopic solid (8%). Mp: 136–140 °C. 1H NMR (DMSO-d6): 10.35 (1H,
br s), 8.75 (1H, s), 8.42 (1H, dd, J = 1.5, 4.8 Hz), 8.29 (1H, d,
J = 2.6 Hz), 8.13 (1H, dd, J = 1.6, 7.9 Hz), 7.72 (1H, dd, J = 2.6,
8.5 Hz), 7.60 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 4.7, 7.9 Hz), 4.75
(2H, t, J = 6.3), 3.62 (2H, br t, 6.1 Hz), 2.78 (6H, s). MS (ES+):
397.9 (M+H). HRMS: calcd for C17H17Cl2N3O2S + H+, 398.0491;
found (ESI, [M+H]+), 398.0491. HPLC purity = 100%.
6.1.20. N-(2-{3-[(2,6-Dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N,N-dimethylamine hydrochloride (10t)
Compound 10t was prepared from 2,6-dichlorophenylsulfonyl
chloride and 18 using the procedure of 10e to give a white solid
(19%). 1H NMR (DMSO-d6): 10.35 (1H, br s), 8.75 (1H, s), 8.42
(1H, dd, J = 1.5, 4.8 Hz), 8.29 (1H, d, J = 2.6 Hz), 8.13 (1H, dd,
J = 1.6, 8.1 Hz), 7.74 (1H, dd, J = 2.6, 8.5 Hz), 7.60 (1H, d,
J = 8.5 Hz), 7.33 (1H, dd, J = 4.6, 7.9 Hz), 4.72 (2H, t, J = 5.5), 3.60
(2H, m), 2.79 (6H, s). MS (ES+): 397.9 (M+H). HRMS: calcd for
C17H17Cl2N3O2S + H+, 398.0491; found (ESI, [M+H]+), 398.0489.
HPLC purity = 100%.
6.1.15. 2-(3-{[2-(Trifluoromethyl)phenyl]sulfonyl}-1H-
pyrrolo[2,3-b]pyridin-1-yl)ethylamine hydrochloride (10o)
The free amine 10o was prepared in 32% yield from 15f using
the procedure for 10g. The dihydrochloride was obtained as a
white hygroscopic solid. Mp: 182–185 °C. 1H NMR (DMSO-d6):
8.52 (1H, s), 8.46 (1H, dd, J = 1.4, 4.7 Hz), 8.40 (1H, d, J = 7.5 Hz),
8.19 (1H, dd, J = 1.5, 8.1 Hz), 8.05 (3H, v br s), 8.01 (1H, d,
J = 7.5 Hz), 7.92–7.85 (2H), 7.38 (1H, dd, J = 4.7, 7.9 Hz), 4.63 (2H,
t, J = 6.1 Hz), 3.39 (2H, t, J = 5.9 Hz). MS (ES+): 370 (M+H). HRMS:
calcd for C16H14F3N3O2S + H+, 370.0831; found (ESI, [M+H]+),
370.0826. HPLC purity = 100%.
6.1.21. N,N-Dimethyl-N-{2-[3-(1-naphthylsulfonyl)-1H-
pyrrolo[2,3-b]pyridin-1-yl]ethyl}amine hydrochloride (10u)
Prepared as in the procedure of 10a by alkylation of 15i to af-
ford a white, hygroscopic solid in 68% yield. Mp: 203–206 °C. 1H
NMR (DMSO-d6): 10.35 (1H, br s), 8.86 (1H, s), 8.73 (1H, d,
J = 8.6 Hz), 8.49 (1H, dd, J = 1.2, 7.5 Hz), 8.35 (1H, dd, J = 1.5,
4.6 Hz), 8.22 (1H, d, J = 8.2 Hz), 8.05–8.02 (2H), 7.71–7.63 (2H),
7.59 (1H, m), 7.25 (1H, dd, J = 4.7, 8.1 Hz), 4.71 (2H, t, J = 6.3 Hz),
3.60 (2H, m), 2.75 (6H, d, J = 4.7 Hz). MS (ES+): 380 (M+H). HRMS:
calcd for C21H21N3O2S+H+, 380.1426; found (ESI, [M+H]+),
380.1426. HPLC purity = 100%.
6.1.16. 2-(3-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-
pyrrolo[2,3-b]pyridin-1-yl)ethylamine hydrochloride (10p)
The free amine of 10p was prepared in 51% yield as a light yel-
low gum from 15g using the procedure for 10g. The hydrochloride
was obtained as a white hygroscopic solid. Mp: 179–183 °C. 1H
NMR (DMSO-d6): 8.62 (1H, s), 8.45 (1H, dd, J = 1.4, 4.7 Hz), 8.30
(1H, dd, J = 1.5, 8.1 Hz), 8.27 (1H, s), 8.09 (3H, v br s), 8.06 (1H, d,
J = 7.9 Hz), 7.87 (1H, app t, J = 7.9 Hz), 7.40 (1H, dd, J = 4.6,
7.9 Hz), 4.61 (2H, t, J = 6.0 Hz), 3.39 (2H, m). MS (ES+): 370
(M+H). HRMS: calcd for C16H14F3N3O2S + H+, 370.0831; found
(ESI, [M+H]+), 370.0828. HPLC purity = 97.4%.
6.1.22. 2-[3-(1-Naphthylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-1-
yl]ethylamine hydrochloride (10v)
Prepared as in 10g by alkylation of 15i to afford a white solid in
59% yield. 1H NMR (DMSO-d6): 8.77 (1H, s), 8.76 (1H, d, partly
overlapping with 8.77 singlet), 8.46 (1H, dd, J = 1.1, 7.3 Hz), 8.34
(1H, dd, J = 1.6, 4.7 Hz), 8.21 (1H, d, J = 8.3 Hz), 8.10 (3H, v br s),
8.04 (2H, m), 7.70–7.64 (2H), 7.59 (1H, app t with fc, J = 7.0 Hz),
7.25 (1H, dd, J = 4.6, 7.9 Hz), 4.57 (2H, t, J = 6.1 Hz), 3.36 (2H, m,
partly obscured by water peak). MS (ES+): 352 (M+H). HRMS: calcd
for C19H17N3O2S + H+, 352.1113; found (ESI, [M+H]+), 352.1111.
HPLC purity = 99.3%.
6.1.17. N-(2-{3-[(3,5-Dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N,N-dimethylamine hydrochloride (10q)
Compound 10q was prepared from 15h by the procedure of 10a
affording a white hygroscopic solid in 50% yield. Mp: 227–232 °C.
1H NMR (DMSO-d6): 10.32 (1H, br s), 8.70 (1H, s), 8.34 (1H, dd,
J = 1.5, 7.9 Hz), 8.04 (1H, app t, J = 0.7 Hz), 7.96 (1H, s with fc),
7.41 (1H, dd, J = 4.7, 7.9 Hz), 4.76 (2H, t, J = 6.4 Hz), 3.68 (2H, m),
2.84 (6H, d, J = 4.7 Hz). MS (ES+): 398 (M+H). Anal. Calcd for
C17H17Cl2N3O2SÁ2HCl: C, 43.33; H, 4.06; N, 8.92. Found: C, 42.96;
H, 3.89; N, 8.69.
6.1.23 N,N-Dimethyl-N-{2-[3-(thien-2-ylsulfonyl)-1H-
pyrrolo[2,3-b]pyridin-1-yl]ethyl}amine hydrochloride (10w)
Prepared by alkylation of 15j according to the procedure of 10a
to afford 10w in 72% yield as a white solid. Mp: 212–216 °C. 1H
NMR (DMSO-d6): 10.38 (1H, br s), 8.59 (1H, s), 8.46 (1H, dd,
J = 1.5, 4.7 Hz), 8.25 (1H, dd, J = 1.5, 7.9 Hz), 7.98 (1H, dd, J = 1.4,
5.0 Hz), 7.85 (1H, dd, J = 1.4, 3.8 Hz), 7.39 (1H, dd, J = 4.7, 7.9 Hz),
7.17 (1H, dd, J = 3.8, 4.9 Hz), 4.74 (2H, t, J = 6.6 Hz), 3.64 (2H, m),
2.82 (6H, d, J = 4.9 Hz). MS (ES+): 336 (M+H). HRMS: calcd for
C15H17N3O2S2 + H+, 336.0835; found (ESI, [M+H]+), 336.0842. HPLC
purity = 100%.
6.1.18. 2-{3-[(3,5-Dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethylamine hydrochloride (10r)
The free amine 10r was prepared in 53% yield from 15h using
the procedure for 10g except using acetonitrile as the solvent.
The hydrochloride was obtained as a white hygroscopic solid.
Mp: 136–140 °C. 1H NMR (DMSO-d6): 8.61 (1H, s), 8.46 (1H, dd,
J = 1.4, 4.7 Hz), 8.32 (1H, dd, J = 1.5, 8.1 Hz), 8.12 (3H, v br s), 8.02
(2H, d, J = 1.8 Hz), 7.96 (1H, t, J = 1.9 Hz), 7.40 (1H, dd, J = 4.7,
7.9 Hz), 4.62 (2H, t, J = 6.0 Hz), 3.40 (2H, m). MS (EI+): 370
(M+H). Anal. Calcd for C15H13Cl2N3O2SÁHClÁH2O: C, 42.42; H, 3.80;
N, 9.89. Found: C, 42.20; H, 3.67; N, 9.77.
6.1.24. N-(2-{3-[(5-Chlorothien-2-yl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N,N-dimethylamine hydrochloride (10x)
The free amine of 10x was prepared in 42% yield from 5-chlo-
rothien-2-ylsulfonyl chloride and 18 using the procedure of 10e.
The dihydrochloride was obtained by treating an ethanolic solution
of the free amine with 3 equiv of 4 N HCl in dioxane and isolating
the white solid precipitate that formed after several hours by suc-
tion filtration. Mp: 169–171 °C. 1H NMR (DMSO-d6): 10.53 (1H, br
s), 8.59 (1H, s), 8.44 (1H, dd, J = 1.6, 4.7 Hz), 8.21 (1H, dd, J = 1.5,
7.9 Hz), 7.74 (1H, d, J = 4.0 Hz), 7.38 (1H, dd, J = 4.7, 8.1 Hz), 7.21
6.1.19. N-(2-{3-[(2,5-Dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-N,N-dimethylamine hydrochloride (10s)
Using the procedure for 10e, compound 10s was prepared from
2,5-dichlorophenylsulfonyl chloride and 18 to give a white hygro-

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R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
(1H, d, J = 4.0 Hz), 4.72 (2H, t, J = 5.5 Hz), 3.60 (2H, m), 2.78 (6H, d,
J = 4.9). MS (ES+): 370 (M+H). Anal. Calcd for C15H16ClN3O2S2Á2HCl:
C, 40.69; H, 4.10; N, 9.49. Found: C, 40.54; H, 3.98; N, 9.40.
6.1.29. 3-[(3-Fluorophenyl)thio]-1H-pyrrolo[2,3-b]pyridine
(12c)
A stirred mixture 14 (500 mg, 2.05 mmol), 3-fluorothiophenol
(395 mg, 3.08 mmol), sodium tert-butoxide (591 mg, 6.15 mmol),
and Pd(PPh3)4 (118 mg, 0.10 mmol) in ethanol (20 mL) was heated
at reflux for 16 h. The reaction was concentrated to dryness and then
treated with ethyl acetate. The resulting suspension was filtered
through a bed of CeliteÒ and the filtrate washed with water (20 mL)
and then brine (20 mL). The ethyl acetate layer was dried over MgSO4
and concentrated in vacuo. The residue was crystallized from a mix-
tureofdichloromethaneand hexanestoafford 12c asanoff-whiteso-
lid (277 mg, 55%). Mp: 158–160 °C. 1HNMR (DMSO-d6):12.34(1H, br
s), 8.32 (1H, dd, J = 11.5, 4.7 Hz), 7.96 (1H, s), 7.79 (1H, dd, J = 1.5,
7.9 Hz), 7.25 (1H, m), 7.14 (1H, dd, J = 4.7, 7.0 Hz), 6.90 (1H, m),
6.86 (1H, d, J = 7.9 Hz), 6.77 (1H, finely coupled doublet, J = 9.8 Hz).
MS (ESÀ): 243 (100%, MÀH). HRMS: calcd for C13H9FN2S + H+,
245.0542; found (ESI, [M+H]+), 245.0540. HPLC purity = 100%.
6.1.25. N-(2-{3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-
yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}ethyl)-N,N-
dimethylamine hydrochloride (10y)
Prepared from 6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl
chloride and 18 using the procedure of 10e to afford the free amine
after chromatography eluting with 2:98 triethylamine/ethanol and
crystallizing the compound from hot ethyl acetate (45% yield). A
portion of the free amine was dissolved in warm ethyl acetate,
treated with 4 N HCl in dioxane (2.4 equiv), and concentrated in
vacuo to obtain the dihydrochloride as a white hygroscopic solid.
Mp: 180–182 °C. 1H NMR (DMSO-d6): 10.41 (1H, br s), 8.80 (1H,
s), 8.42 (1H, m), 8.23–8.20 (2H, m), 7.63 (1H, d, J = 4.4 Hz), 7.36
(1H, dd, J = 4.8, 7.9 Hz), 4.72 (2H, t, J = 6.3 Hz), 3.60 (2H, m), 2.76
(6H, d, J = 4.8). MS (EIÀ): 410 (MÀH). Anal. Calcd for
C16H16ClN5O2S2Á2HClÁ0.25H2O: C, 39.43; H, 3.83; N, 14.37. Found:
C, 39.34; H, 3.74; N, 13.98.
6.1.30. 3-[(3-Chlorophenyl)thio]-1H-pyrrolo[2,3-b]pyridine
(12d)
The title compound was prepared from 14 (3.00 g, 12.3 mmol)
and 3-chlorobenzenethiol (2.68 g, 18.5 mmol) in a manner analo-
gous to 12e except heating at 75 °C for 5 h. Chromatography
(1:99 methanol/CH2Cl2) gave a pinkish solid (2.60 g, Rf ꢀ 0.2 in
1:99 methanol/CH2Cl2) which was shown by NMR to be a mixture
of 12d (60%) along with 11 (40%). This mixture was used in the
subsequent oxidation. A small portion (140 mg) of impure product
was crystallized from CH2Cl2/hexane to afford an analytically pure
sample (90 mg) of 12d as a tan solid. Mp: 156–158 °C. 1H NMR
(DMSO-d6): 12.4 (1H, br s), 8.33 (1H, br s), 7.97 (1H, d,
J = 2.8 Hz), 7.80 (1H, dd, J = 1.1, 7.8 Hz), 7.24 (1H, dt, J = 1.2,
7.9 Hz), 7.16–7.13 (2H, m), 7.04–6.98 (2H, m). MS (ES+): 262
(100%, M+H). Anal. Calcd for C13H9ClN2SÁ0.5H2O: C, 57.88; H,
3.74; N, 10.38. Found: C, 57.94 H, 3.20; N, 10.28.
6.1.26. N-(2-{3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-
yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}ethyl)-N-
methylamine hydrochloride (10z)
Compound 10z was prepared from 10y as in the procedure of
10j except using 4 equiv of 1-chloroethyl chloroformate to afford
an off-white solid in 71% yield. Mp: 182–186 °C (foamed on melt-
ing, darkens, not well-defined). 1H NMR (DMSO-d6): 8.98 (2H, v br
s), 8.77 (1H, s), 8.41 (1H, dd, J = 1.5, 4.8 Hz), 8.23 (1H, dd, J = 1.6,
7.9 Hz), 8.20 (1H, d, J = 4.5 Hz), 7.61 (1H, d, J = 4.7 Hz), 7.36 (1H,
dd, J = 4.6, 8.0 Hz), 4.64 (2H, t, J = 5.9 Hz), 3.43 (2H, m), 2.51 (3H,
t, J = 5.3 Hz). MS (ES+): 396 (M+H). Anal. Calcd for
C15H14ClN5O2S2Á2HClÁ0.25H2O: C, 38.06; H, 3.51; N, 14.80. Found:
C, 38.25; H, 3.61; N, 14.41.
6.1.31. 3-[(4-Fluorophenyl)thio]-1H-pyrrolo[2,3-b]pyridine
(12e)
6.1.27. 3-(Phenylthio)-1H-pyrrolo[2,3-b]pyridine (12a)
A solution of methyl phenyl sulfoxide (8.33 g, 59.4 mmol) in
CH2Cl2 (175 mL) was chilled to À78 °C and treated dropwise with
trifluoroacetic anhydride (4.1 mL, 5.3 mmol). After 30 min, a solu-
tion of 11 (5.20 g, 44.0 mmol) in CH2Cl2 (25 mL) was added fol-
lowed 30 min later by triethylamine (74 mL, 534 mmol). The
reaction was stirred at ambient temperature for 84 h, then con-
centrated in vacuo, treated with saturated aqueous NaHCO3
(300 mL), and extracted with CH2Cl2 (2 Â 300 mL). The extracts
were dried (MgSO4) and concentrated in vacuo. The residue was
crystallized from methanol/water and then crystallized from
CH2Cl2/hexane. Vacuum drying gave 12a as an off-white solid
(1.26 g, 13%, Rf ꢀ 0.5 in ethyl acetate). Mp: 188–189 °C. 1H NMR
(DMSO-d6): 12.3 (1H, br s), 7.91 (1H, s), 7.78 (1H, d, J = 7.9 Hz),
7.25–7.17 (2H, m), 7.15–7.00 (4H, m). MS (ES+): 227 (100%,
M+H). MS (ESÀ): 225 (100%, MÀH). Anal. Calcd for
C13H10N2SÁ0.1H2O: C, 68.45; H, 4.51; N, 12.28. Found: C, 68.39;
H, 4.37; N, 12.22.
A solution of 14 (4.0 g, 16.4 mmol) in DMF (40 mL) was treated
with 4-fluorobenzenethiol (2.09 mL, 19.7 mmol), potassium carbon-
ate (3.40 g, 24.6 mmol), and copper iodide (4.21 g, 22.1 mmol). The
reaction mixture was heated at 65 °C for 4 h, then cooled and diluted
with concd aqueous NH4OH (100 mL). The mixture was extracted
with ethyl acetate (3 Â 200 mL) and the extracts were washed with
brine, dried over MgSO4 and concentrated in vacuo. Chromatography
(1:50 methanol/CH2Cl2) followed by crystallization from methanol/
H2O gave 12e as an off-white solid (3.56 g, 89%). Mp: 183–184 °C.
1H NMR (DMSO-d6): 12.26 (1H, br s), 8.30 (1H, dt, J = 1.5, 5.5 Hz),
7.92 (1H, s), 7.79 (1H, dd, J = 1.5, 7.6 Hz), 7.15–7.03 (5H). MS (ESÀ):
243 (60%, MÀH). Anal. Calcd for C13H9FN2S: C, 63.92; H, 3.71; N,
11.47. Found: C, 63.59; H, 3.66; N, 11.35.
6.1.32. 3-{[2-(Trifluoromethyl)phenyl]thio}-1H-pyrrolo[2,3-
b]pyridine (12f)
Prepared essentially as in 12c in 48% yield except using 2-(tri-
fluoromethyl)benzenethiol and recrystallizing from dichlorometh-
ane/hexane to give an orange solid. Mp: 222–225 °C. 1H NMR
(DMSO-d6): 12.38 (1H, br s), 8.29 (1H, d, J = 4.8 Hz), 7.98 (1H, m),
7.70–7.67 (2H), 7.34 (1H, app t, J = 7.3 Hz), 7.11 (1H, dd, J = 4.7,
7.9 Hz), 6.84 (1H, d, J = 8.1 Hz). MS (ESÀ): 293 (100%, MÀH). Anal.
Calcd for C14H9F3N2SÁ0.3H2O: C, 56.11; H, 3.23; N, 9.35. Found: C,
56.19; H, 3.02; N, 9.25.
6.1.28. 2-Methyl-3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine
(12b)
1-(Phenylthio)-2-propanone and 13 were heated in ethanol at
reflux for 24 h, then concentrated in vacuo. The resulting mixture
was treated with 1,3-propanediol and heated at reflux for 3 h,
affording 12b as an off-white solid. Mp: 180–181 °C. 1H NMR
(CDCl3): 11.91 (1H, br s), 8.30 (1H, dd, J = 1.4, 4.7 Hz), 7.87 (1H,
dd, J = 1.4, 7.8 Hz), 7.17 (2H, app t, J = 7.3 Hz), 7.12 (1H, dd,
J = 4.7, 7.8 Hz), 7.08–7.03 (3H), 2.65 (3H, s). MS (ESÀ): 239 (100%,
MÀH). Anal. Calcd for C14H12C2S: C, 69.97; H, 5.03; N, 11.66.
Found: C, 69.90; H, 4.95; N, 11.57.
6.1.33. 3-{[3-(Trifluoromethyl)phenyl]thio}-1H-pyrrolo[2,3-
b]pyridine (12g)
Prepared in 59% yield essentially as in 12c except using 3-(tri-
fluoromethyl)benzenethiol and recrystallizing from dichlorometh-

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
5161
ane/hexanes to give an light yellow solid. Mp: 132–133 °C. 1H NMR
(DMSO-d6): 12.33 (1H, br s), 8.29 (1H, dd, J = 1.6, 4.7 Hz), 7.96 (1H,
s), 7.76 (1H, dd, J = 1.6, 7.8 Hz), 7.43–7.38 (2H), 7.29 (1H, s), 7.24
(1H, m), 7.16–7.13 (2H, m), 7.11 (1H, dd, J = 4.6, 7.9 Hz). MS
(ESÀ): 293 (100%, MÀH). Anal. Calcd for C14H9F3N2S: C, 57.14; H,
3.08; N, 9.52. Found: C, 56.88; H, 2.97; N, 9.34.
7.9 Hz). MS (ES+): 300 (100%, M+CH3CN (carrier solvent)+H), 259
(20%, M+H). MS (ESÀ): 257 (100%, MÀH). Anal. Calcd for
C13H10N2O2S: C, 60.45; H, 3.90; N, 10.85. Found: C, 60.11; H,
3.68; N, 10.82.
6.1.39. 2-Methyl-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
(15b)
6.1.34. 3-[(3,5-Dichlorophenyl)thio]-1H-pyrrolo[2,3-b]pyridine
(12h)
Prepared from 12b using the procedure of 15e to give a 32%
yield of 15b as a white solid. Mp: 252–253 °C. 1H NMR (DMSO-
d6): 12.70 (1H, br s), 8.26 (1H, dd, J = 1.5, 4.8 Hz), 8.17 (1H, dd,
J = 1.5, 7.9 Hz), 7.92 (1H, app d, J = 7.5 Hz), 7.61 (1H, t, J = 7.2 Hz),
7.55 (2H, app t, J = 7.4 Hz), 7.21 (1H, dd, J = 4.7, 7.9 Hz), 2.68 (3H,
s). MS (ESÀ): 271 (100%, MÀH). Anal. Calcd for C14H12N2O2S: C,
61.75; H, 4.44; N, 10.29. Found: C, 61.34; H, 4.46; N, 10.17.
Prepared essentially as in 12c except using 3,5-dichloroben-
zenethiol to give 12h as an orange solid in 59% yield. Mp: 206–
208 °C. 1H NMR (DMSO-d6): 12.45 (1H, br s), 8.35 (1H, dd, J = 1.5,
4.7 Hz), 8.03 (1H, s), 7.84 (1H, dd, J = 1.5, 7.8 Hz), 7.33 (1H, m),
7.18 (1H, dd, J = 4.7, 7.9 Hz), 7.10 (2H, s). MS (ESÀ): 293 (100%,
MÀH). Anal. Calcd for C13H8Cl2N2SÁ0.2H2O: C, 52.26; H, 2.83; N,
9.37. Found: C, 52.30; H, 2.81; N, 9.29.
6.1.40. 3-[(3-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine
(15c)
6.1.35. 3-(1-Naphthylthio)-1H-pyrrolo[2,3-b]pyridine (12i)
Prepared essentially as in 12c except using naphthalene-1-thiol
to give 12i as an orange solid in 77% yield. Mp: 197–199 °C. 1H
NMR (DMSO-d6): 12.32 (1H, br s), 8.37 (1H, d, J = 8.4 Hz), 8.30 (1H,
dd, J = 1.5, 4.7 Hz), 8.00 (1H, d, J = 1.5 Hz), 7.94 (1H, d, J = 8.1 Hz),
7.76 (1H, dd, J = 1.2, 7.8 Hz), 7.67 (1H, app t, J = 8.2 Hz), 7.63 (1H, d,
J = 8.2 Hz), 7.58 (1H, app t, J = 7.0 Hz), 7.27 (1H, app t, J = 7.7 Hz),
7.10 (1H, dd, J = 4.7, 7.9 Hz), 6.89 (1H, d, J = 7.3 Hz). MS (ESÀ): 275
(100%, MÀH). Anal. Calcd for C17H12N2SÁ0.2H2O: C, 73.41; H, 4.42;
N, 10.07. Found: C, 73.14; H, 4.48; N, 10.00.
Prepared from 12c using the procedure of 15e to give 15c as a
white solid in 27% yield. Mp: >250 °C. 1H NMR (DMSO-d6): 12.97
(1H, br s), 8.41 (1H, s), 8.37 (1H, dd, J = 1.5, 4.7 Hz), 8.22 (1H, dd,
J = 1.5, 8.0 Hz), 7.83 (2H), 7.63 (1H, m), 7.48 (1H, app dt, J = 4.7,
8.1 Hz), 7.28 (1H, dd, J = 4.7, 8.1 Hz). MS (ES+): 277 (100%, M+H).
MS (ESIÀ): 275 (MÀH). Anal. Calcd for C13H9FN2O2S: C, 56.51; H,
3.28; N, 10.14. Found: C, 56.09; H, 3.40; N, 10.04.
6.1.41. 3-[(3-Chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine
(15d)
Prepared from 12d by the procedure of 15e to give 15d as an
off-white solid in 24% yield. The crude filtered solid was triturated
with CH2Cl2, washed with hexane, and vacuum dried to afford 15d.
Mp: 232–233 °C. 1H NMR (DMSO-d6): 13.0 (1H, br s), 8.43 (1H, s),
8.38 (1H, d, J = 4.7 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.01 (1H, t,
J = 1.9 Hz), 7.97 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 9.2 Hz), 7.60
(1H, app t, J = 7.9 Hz), 7.25–7.30 (1H, m). MS (ESÀ): 291 (100%,
MÀH). Anal. Calcd for C13H9ClN2O2S: C, 53.34; H, 3.10; N, 9.57.
Found: C, 53.01; H, 2.86; N, 9.41.
6.1.36. 3-(Thien-2-ylthio)-1H-pyrrolo[2,3-b]pyridine (12j)
Prepared essentially as in 12c except using thiophene-2-thiol to
give 12j as a pink solid in 65% yield. Mp: 192–193 °C. 1H NMR
(DMSO-d6): 12.14 (1H, br s), 8.28 (1H, dd, J = 1.4, 4.7 Hz), 7.99
(1H, dd, J = 1.5, 7.9 Hz), 7.89 (1H, s), 7.45 (1H, dd, J = 1.2, 5.3 Hz),
7.20 (1H, dd, J = 1.2, 2.5 Hz), 7.16 (1H, dd, J = 4.6, 7.9 Hz), 6.5 (1H,
dd, J = 3.5, 5.2 Hz). MS (ES+): 233 (M+H). Anal. Calcd for
C11H8N2S2. 0.1 H2O: C, 56.43; H, 3.53; N, 11.97. Found: C, 56.32;
H, 3.37; N, 11.81.
6.1.42. 3-[(4-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine
(15e)
6.1.37. 3-Iodo-1H-pyrrolo[2,3-b]pyridine (14)
A solution of 11 (20.0 g, 169 mmol) in ethanol (800 mL) was
treated with iodine (57.9 g, 228 mmol), potassium iodide (37.8 g,
228 mmol), and 1 N aqueous NaOH (204 mL, 204 mmol). After stir-
ring for 4 h at 20 °C, the reaction was diluted with H2O (500 mL)
and extracted with ethyl acetate (3 Â 1 L). The organic phases were
combined and concentrated in vacuo. The residue was crystallized
from methanol/H2O. Vacuum drying gave 14 as a pink-white solid
(35.4 g, 86%). Mp: 201–204 °C. 1H NMR (DMSO-d6): 12.1 (1H, br s),
8.25 (1H, d, J = 4.7 Hz), 7.70 (1H, s), 7.67 (1H, d, J = 7.9 Hz), 7.15
(1H, m). MS (ES+): 245 (100%, M+H). MS (ESÀ): 243 (100%,
MÀH). Anal. Calcd for C7H5IN2: C, 34.45; H, 2.07; N, 11.48. Found:
C, 34.58; H, 1.96; N, 11.40.
A solution of 12e (3.36 g, 13.8 mmol) in acetone (200 mL) was
treated with NaHCO3 (2.90 g, 34.5 mmol) dissolved in H2O
(175 mL). The reaction was then treated with OxoneÒ (25.5 g,
41.4 mmol) and stirred for 3 h at 20 °C. The reaction mixture was
diluted with H2O and chilled in an ice-water bath. The solids were
filtered, washed with H2O and vacuum dried to give 15e as a white
solid (1.73 g, 45%). Mp: 212–213 °C. 1H NMR (DMSO-d6): 12.9 (1H,
s), 8.35 (2H, m), 8.18 (1H, d, J = 8.0 Hz), 8.0–8.1 (2H, m), 7.40 (2H, t,
J = 8.9 Hz), 7.27 (1H, m). MS (ESÀ): 275 (100%, MÀH). HRMS: calcd
for C13H9FN2O2S + H+, 277.0441; found (ESI, [M+H]+), 277.0439.
HPLC purity = 98.5%.
6.1.43. 3-{[2-(Trifluoromethyl)phenyl]sulfonyl}-1H-
pyrrolo[2,3-b]pyridine (15f)
6.1.38. 3-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (15a)
A solution of 12a (100 mg, 0.44 mmol) in t-butyl alcohol
(10 mL) was treated with MnSO4ÁH2O (4 mg, 0.020 mmol) and
cooled to 0 °C. A mixture of 30% aqueous hydrogen peroxide
(500 mg, 4.41 mmol) and 0.2 N aqueous NaHCO3 (7.5 mL) was
added dropwise. The reaction was stirred for 23 h at 20 °C, then di-
luted with saturated aqueous NaHCO3 (20 mL) and extracted with
ethyl acetate (3 Â 25 mL). The combined organic phases were dried
over MgSO4 and concentrated in vacuo. Chromatography (1:50
methanol/CH2Cl2) gave crude product which was crystallized from
CH2Cl2/hexane. Vacuum drying gave 15a as a pink-white solid
(58 mg, 50%, Rf ꢀ 0.4 in ethyl acetate). Mp: >250 °C. 1H NMR
(DMSO-d6): 12.9 (1H, br s), 8.35 (2H, m), 8.18 (1H, d, J = 7.9 Hz),
8.00 (2H, d, J = 8.1 Hz), 7.65–7.55 (3H, m), 7.26 (1H, dd, J = 4.7,
Prepared from 12f using the procedure of 15e to give 15f as a
pale orange solid in 37% yield. Mp: 222–223 °C. 1H NMR (DMSO-
d6): 13.03 (1H, s), 8.40–8.37 (2H), 8.33 (1H, s), 8.35 (2H, m), 8.11
(1H, dd, J = 1.3, 8.0 Hz), 7.96 (1H, d, J = 7.2 Hz), 7.27 (1H, ddd,
J = 1.1, 4.7, 8.1 Hz). MS (ESI-): 325 (MÀH). HRMS: calcd for
C14H9F3N2O2S + H+, 327.0409; found (ESI, [M+H]+), 327.0405. HPLC
purity = 97.5%.
6.1.44. 3-{[3-(Trifluoromethyl)phenyl]sulfonyl}-1H-
pyrrolo[2,3-b]pyridine (15g)
Prepared from 12g using the procedure of 15e to give 15g as a
white solid. Mp: 214–217 °C. 1H NMR (DMSO-d6): 13.02 (1H, s),
8.49 (1H, s), 8.38 (1H, dd, J = 1.4, 4.6 Hz), 8.32 (1H, d, J = 7.8 Hz),

5162
R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
8.26 (1H, s), 8.23 (1H, dd, J = 1.5, 7.9 Hz), 8.01 (1H, d, J = 7.8 Hz),
7.82 (1H, app t, J = 7.6 Hz), 7.30 (1H, m). MS (ESI-): 325 (MÀH).
Anal. Calcd for C14H9F3N2O2S: C, 51.53; H, 2.78; N, 8.51. Found:
C, 51.28; H, 2.71; N, 8.41.
anes), characterized only by NMR. 1H NMR (DMSO-d6): 8.52 (1H,
s), 8.39 (1H, app d), 8.18 (1H, m), 8.00 (2H, m), 7.42–7.23 (3H),
4.63 (2H, m), 4.06 (2H, m).
6.1.51. 2-{2-[3-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-1-
yl]ethyl}-1H-isoindole-1,3(2H)-dione (17a)
6.1.45. 3-[(3,5-Dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridine (15h)
A solution of 16a (3.84 g, 12.0 mmol) and potassium phthali-
mide (2.78 g, 15.0 mmol) in DMF (50 mL) was heated at 115 °C
for 16 h. The cooled reaction was diluted with H2O (200 mL), ex-
tracted into ethyl acetate (3 Â 200 mL), and the combined ex-
tracts were washed with brine (100 mL) and dried (MgSO4).
Concentration in vacuo followed by crystallization from CH2Cl2/
hexane gave 17a as a white solid (4.54 g, 88%, Rf ꢀ 0.5 in 1:1
ethyl acetate/hexanes). The product was characterized only by
1H NMR and then carried on. 1H NMR (DMSO-d6): 8.48 (1H, s),
8.00 (2H, m), 7.80–7.42 (9H, m), 7.12 (1H, m), 4.55 (2H, m),
3.98 (2H, m).
Prepared from 12h using the procedure of 15e to give 15h as an
off-white solid in 64% yield. Mp: >250 °C. 1H NMR (DMSO-d6):
13.07 (1H, br s), 8.51 (1H, s), 8.41 (1H, dd, J = 1.5, 4.7 Hz), 8.29
(1H, app d, J = 8.1 Hz), 8.03 (2H, s), 7.93 (1H, m), 7.32 (1H, dd,
J = 4.7, 8.1 Hz). MS (ESI-): 325 (MÀH). Anal. Calcd for C13H8
Cl2N2O2S: C, 47.72; H, 2.46; N, 8.56. Found: C, 47.67; H, 2.41; N,
8.53.
6.1.46. 3-(1-Naphthylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (15i)
Prepared from 12i using the procedure of 15e except using
3 equivalents of OxoneÒ to give 15i as a tan solid in 57% yield, crys-
tallized from methylene chloride/hexanes. Mp: 234–236 °C. 1H
NMR (DMSO-d6): 12.90 (1H, s), 8.79 (1H, d, J = 8.7 Hz), 8.66 (1H,
s), 8.51 (1H, dd, J = 1.2, 7.5 Hz), 8.30 (1H, dd, J = 1.6, 4.5 Hz), 8.23
(1H, d, J = 8.4 Hz), 8.03 (2H, m), 7.72 (1H, app t, J = 7.7 Hz), 7.66
(1H, m), 7.60 (1H, app t, J = 7.0 Hz), 7.20 (1H, dd, J = 4.7, 7.9 Hz).
MS (ESIÀ): 307 (MÀH). HRMS: calcd for C17H12N2O2S + H+,
309.0691; found (ESI, [M+H]+), 309.0690. HPLC purity = 98.1%.
6.1.52. 2-(2-{3-[(3-Chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-1H-isoindole-1,3(2H)-dione (17b)
Prepared from 16b (790 mg, 2.22 mmol) in a similar manner to
17a. The crude product is crystallized from CH2Cl2/hexane to afford
a white solid (89%). Mp: 155–157 °C. 1H NMR (DMSO-d6): 8.60 (1H,
s), 8.10 (1H, d, J = 8.0 Hz), 8.07 (1H, d, J = 4.7 Hz), 7.89 (1H, t,
J = 1.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.75–7.80 (2H, m), 7.65–7.72
(3H, m), 7.60 (1H, t, J = 8.0 Hz), 7.15–7.20 (1H, m), 4.59 (2H, t,
J = 1.6 Hz), 4.04 (2H, t, J = 1.5 Hz). MS (ES+): 466 (100%, M + H).
Anal. Calcd for C23H16ClN3O4SÁ0.4H2O: C, 58.39; H, 3.58; N, 8.88.
Found: C, 58.47; H, 3.36; N, 8.82.
6.1.47. 3-(Thien-2-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (15j)
Prepared from 12j using the procedure of 15e to give 15j as a
pink solid crystallized from methylene chloride/hexane in 62%
yield. Mp: 249–250 °C. 1H NMR (DMSO-d6): 12.94 (1H, s), 8.40
(1H, dd, J = 1.5, 4.6 Hz), 8.37 (1H, s), 8.21 (1H, dd, J = 1.5, 7.9 Hz),
7.95 (1H, dd, J = 1.3, 4.9 Hz), 7.82 (1H, dd, J = 1.3, 3.6 Hz), 7.31
(1H, dd, J = 4.6, 8.0 Hz), 7.16 (1H, dd, J = 3.8, 4.9 Hz). MS (ESI-):
263 (MÀH). HRMS: calcd for C11H8N2O2S2 + H+, 265.0099; found
(ESI, [M+H]+), 265.0097. HPLC purity = 100%.
6.1.53. 2-(2-{3-[(4-Fluorophenyl)sulfonyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl}ethyl)-1H-isoindole-1,3(2H)-dione (17c)
Prepared from 16c in a manner analogous to that of 17a, except
crystallizing from CH2Cl2/hexane to give a white solid in 80% yield.
Mp: 164–165 °C. 1H NMR (DMSO-d6): 8.54 (1H, s), 8.08–8.03 (2H,
m), 7.98–7.93 (2H, dd, J = 5.0, 9.0 Hz), 7.80–7.75 (2H, m), 7.73–
7.65 (2H, m), 7.40 (2H, t, J = 8.9 Hz), 7.15 (1H, dd, J = 4.7, 7.8 Hz),
4.59 (2H, m), 4.03 (2H, m). MS (ES+): 450 (100%, M + H). Anal. Calcd
for C23H16FN3O4S Á 0.2 H2O: C, 60.97; H, 3.65; N, 9.27. Found: C,
60.89; H, 3.66; N, 9.18.
6.1.48. 1-(2-Chloroethyl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-
b]pyridine (16a)
A solution of 15a (4.30 g, 16.6 mmol) in 1,2-dichloroethane
(33 mL, 420 mmol) was treated with trioctylmethylammonium
chloride (6.9 g) and 50% aqueous NaOH (1.6 g, 20 mmol) and
heated 6 h at 45 °C. The cooled solution was diluted with H2O
(200 mL) and extracted with CH2Cl2 (3 Â 250 mL). The combined
extracts were dried over MgSO4 and concentrated in vacuo to a
brown gum. The gum was chromatographed eluting with 1:4 ethyl
acetate/hexanes and crystallized from ethyl acetate/hexane to give
a white solid (3.84 g, 72%, Rf ꢀ 0.6 in 1:1 ethyl acetate/hexanes).
Mp: 117–119 °C. 1H NMR (DMSO-d6): 8.55 (1H, s), 8.42 (1H, d,
J = 4.7 Hz), 8.22 (1H, d, J = 7.9 Hz), 7.99 (2H, d, J = 7.3 Hz), 7.65–
7.55 (3H), 7.33 (1H, m), 4.68 (2H, t, J = 6.0 Hz), 4.11 (2H, t,
J = 6.0 Hz). MS (ES+): 321 (100%, M+H); HRMS: calcd for
C15H13ClN2O2S + H+, 321.0458; found (ESI, [M+H]+), 321.0456.
HPLC purity = 100%.
6.1.54. N,N-Dimethyl-N-[2-(1H-pyrrolo[2,3-b]pyridin-1-
yl)ethyl]amine (18)
A stirred solution of 11 (2.50 g, 21.2 mmol) in DMF (100 mL)
under nitrogen treated with sodium hydride (3.00 g, 75 mmol) in
portions over about 2 min (gas evolved). After 1 h, the reaction
was treated with 2-(dimethylamino)ethyl chloride hydrochloride
(3.20 g, 22.2 mmol). Gas evolved. After 18 h, the reaction was trea-
ted with water (10 mL) and saturated aqueous NH4OAc (5 mL).
After gas evolution ceased, the reaction was concentrated in vacuo
at ca. 50 °C, to reduce the volume to 25 mL. Half-saturated brine
(100 mL) was added and the mixture extracted with ethyl acetate
(2 Â 100 mL). The dried (MgSO4) extracts were concentrated in va-
cuo, then chromatographed with a gradient of 10:90:0 to 100:0:0
to 95:0:5 ethanol/ethyl acetate/concd NH4OH. The resulting oil
was dissolved in dichloromethane and filtered through a pad of
MgSO4 on a filter to remove any impurities from the column,
affording 18 as a nearly colorless liquid (2.55 g, 64%). 1H NMR
(DMSO-d6): 8.23 (1H, dd, J = 1.5, 4.7 Hz), 7.94 (1H, dd, J = 1.5,
7.8 Hz), 7.56 (1H, d, J = 3.5 Hz), 7.06 (1H, dd, J = 4.6, 7.8 Hz), 6.44
(1H, d, J = 3.5 Hz), 4.34 (2H, t, J = 6.7 Hz), 2.65 (2H, t, J = 6.7 Hz),
2.18 (6H, s). MS (ES+): 190.1 (100%, M+H). HRMS: calcd for
C11H15N3 + H+, 190.1339; found (ESI, [M+H]+), 190.1340. HPLC
purity = 98.9%.
6.1.49. 1-(2-Chloroethyl)-3-[(3-chlorophenyl)sulfonyl]-1H-
pyrrolo[2,3-b]pyridine (16b)
Prepared from 15d (0.85 g, 2.90 mmol) by the procedure of 16a,
giving a colorless gum (77%, Rf ꢀ 0.5 in 1:1 ethyl acetate/hexane),
characterized only by NMR. 1H NMR (DMSO-d6): 8.57 (1H, s),
8.38 (1H, m), 8.23 (1H, m), 7.97–7.85 (2H), 7.65 (2H, m), 7.58
(1H, m), 4.64 (2H, m), 4.10 (2H, m).
6.1.50. 1-(2-Chloroethyl)-3-[4-(fluorophenyl)sulfonyl]-1H-
pyrrolo[2,3-b]pyridine (16c)
Prepared from 15e in a manner analogous to the preparation of
16a to give a white solid (78%, Rf ꢀ 0.5 in 1:1 ethyl acetate/hex-

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 5153–5163
5163
11. Jain, S.; Shukla, K.; Mukhopadhyay, A.; Suryawanshi, S. N.; Bhakuni, D. S. Synth.
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data, except intermediates 16b, 16c, and 17a, which were analyzed only by 1H
NMR. Tested compounds (10a–z) were generally isolated as hydrochloride
salts and provided satisfactory CHN analysis (though often as partial hydrates),
or gave satisfactory HRMS with analytical HPLC. For further details, see also
Bernotas, R. C.; Lenicek, S. E.; Antane, S. A. in US patent 6825212 B2.
14. Webb, K. S. Tetrahedron Lett. 1994, 35, 3457.
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18. Binding assays were run using [3H]-LSD as the radioligand. For conditions see:
Bernotas, R. C.; Lenicek, S. E.; Antane, S. A.; Zhou, P.; Li, Y. WO patent
application 2003101962 and the supporting information for Ref. 9c.
19. Adenylyl cyclase assay: HeLa cells transfected with the human 5-HT6 receptor
were washed with Krebs buffer and incubated at 37 °C in Krebs supplemented
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with 500 lM IBMX for 5 min at 37 °C. Cells were then stimulated with test
compound in the concentration range 0.1–10000 nM for an additional 10 min
at 37 °C. Serotonin was also tested to determine the maximal response of
endogenous ligand. The agonist potency was determined from the resulting
concentration–response curves and the percent efficacy determined relative to
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