Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3 H)-yl]-1-(methylamino)butan-2- ols (WYE-103231)

Article abstract of DOI:10.1021/jm100053t

Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol- 1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC₅₀ = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.

Full text of DOI:10.1021/jm100053t

J. Med. Chem. 2010, 53, 4511–4521 4511
DOI: 10.1021/jm100053t
Discovery of Novel Selective Norepinephrine Reuptake Inhibitors:
4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols
(WYE-103231)
David J. O’Neill,*,† Adedayo Adedoyin,§ Peter D. Alfinito,‡ Jenifer A. Bray,‡ Scott Cosmi,‡ Darlene C. Deecher,‡
Andrew Fensome,† Jim Harrison, Liza Leventhal, Charles Mann,† Casey C. McComas,†
Nicole R. Sullivan, Taylor B. Spangler, Albert J. Uveges, Eugene J. Trybulski,†
Garth T. Whiteside, and Puwen Zhang†
§
†Chemical Sciences, ‡Musculoskeletal Biology, and Drug Safety and Metabolism, Pfizer Global Research & Development, 500 Arcola Road,
Collegeville, Pennsylvania 19426, and Neuroscience, PGRD, CN 8000, Princeton, New Jersey 08543
Received January 14, 2010
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-
dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective
inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One
representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC50=1.2 nM) and
excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally
had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-
induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal
nerve ligation (SNL) models of acute and neuropathic pain.
Introduction
treatment of chronic pain including fibromyalgia and lower
back pain.7,8
The norepinephrine transporter (NETa) is a membrane
bound protein which regulates the uptake of the neurotrans-
mitter norepinephrine (NE) from the presynaptic cleft of nor-
adrenergic neurons during synaptic transmission.1,2 It there-
fore plays an important role in regulating the physiological
functions of NE, the deficiency of which has been implicated
in a number of neurological disorders. NE reuptake inhibitors
(NRIs) block the return of NE to the axon terminal, thereby
maintaining itssynaptic concentration resulting ina treatment
for a range of CNS disorders.3 Inthe last 20years, a number of
monoamine neurotransmitter reuptake inhibitors have been
approved for the treatment of neurological disorders such as
depression and pain.4 More recently, selective NRIs such as
reboxetine 1 and atomoxetine 2 have been used clinically for
the alleviation of major depressive disorder and attention
deficit hyperactivity disorder (ADHD), respectively.5,6 There
is also evidence that these compounds may have efficacy in the
*To whom correspondence should be addressed. Phone: (860) 715-
6627. Fax: (860) 686-5256. E-mail: david.oneill@pfizer.com. Address:
Pfizer Global Research & Development, MS: 8220-3445, Eastern Point
Road, Groton, Connecticut 06340.
Our previous reports have detailed efforts which resulted in
the discovery of selective NRIs including cycloalkanol ethyl-
amines,9 e.g. 3, benzimidazol-2-ones,10 e.g. 4, and indolin-2-ones
5.11 In our continuing effort to search for novel and selective
NRIs, we have identified the N-aryl 2,2-dioxido-2,1,3-benzo-
thiadiazol-1(3H)-yl core, 6, via virtual screening and rational
drug design approaches.12 Extensive SAR studies of this core
have led to potent and selective NRI series. This report will
cover the 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-1-(methylamino)butan-2-ols, their synthesis, in vitro SAR,
and the in vivo efficacy of lead compound S-17b. Additional
a Abbreviations: NE, norepinephrine; NET, norephinephrine trans-
porter; NRI, norepinephrine reuptake inhibitor; CNS, central nervous
system; SERT, serotonin transporter; DAT, dopamine transporter;
hNET, human norepinephrine transporter; hSERT, human serotonin
transporter; hDAT, human dopamine transporter; SAR, structure-
activity relationship; LMS, liver microsomal stability; CYP450, cyto-
chrome P450; hERG, human ether-a-go-go related gene; QTc, heartrate-
corrected QT interval; pk, pharmacokinetics; Clp, clearance; Vss, steady
state volume of distribution; Cmax, maximum concentration; Tmax, timeto
maximum concentration; F%, percent bioavailability; AUC, area under
the curve; OVX, ovariectomized; TST, tail-skin temperature; SNL, spinal
nerve ligation.
r
2010 American Chemical Society
Published on Web 05/12/2010
pubs.acs.org/jmc

4512 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
O’Neill et al.
Scheme 1. Synthesis of N-Aryl-2,2-Dioxido-2,1,3-benzothiadiazol-1(3H)-yl Cores and Targets 9-15a
a Reagents and conditions: (a) 2-fluoronitrobenzene, NaH, DMF; (b) H2, Pd/C, EtOAc; (c) sulfamide, sulfamic acid, diglyme, 190 °C; (d) HO-
R2alkyl-Br, DIAD, PPh3, THF; (e) MeNH2, EtOH, sealed tube, rt.
Scheme 2. Synthesis of 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(alkylamino)butan-2-ols 17-22a
a Reagents and conditions: (a) but-3-en-1-ol, DIAD, PPh3, THF, rt; (b) m-CPBA, DCM, rt; (c) R3R4NH, EtOH, 100 °C, 3 min, microwave.
Scheme 3. Asymmetric Synthesis of 4-[3-Aryl-2,2-dioxido-2,1,3-
benzothiadiazol-1(3H)-yl]-1- (methylamino)butan-2-ols R-17a-j
and S-17a-ja
work incorporating this core to produce other chemical series
will be disclosed in due course.
Chemistry
A synthetic route toward the preparation of the N-aryl 2,2-
dioxido-2,1,3-benzothiadiazol-1(3H)-yl cores and targets 9-15
is described in Scheme 1. Amine deprotonation of the substitu-
ted anilines 7a-j followed by addition of 2-fluoronitrobenzene
resulted in nucleophilic substitution of the fluorine. Hydro-
genation of the nitrobenzene intermediates resulted in diani-
lines 8a-j. Ring closure of 8a-j with sulfamide furnished
cyclic 2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yls 6a-j. With
these key cores in hand, target compounds 9-15 were easily
accessible employing a Mitsonobu N-alkylation. This was
exemplified with the N-2-fluorophenyl 2,2-dioxido-2,1,3-benzo-
thiadiazol-1(3H)-yl core 6b, which can be treated with a
variety of substituted bromoalkyl alcohols. Subsequent halogen-
amine substitution with methylamine furnished target com-
pounds 9-15.
Mitsonobu N-alkylation of cores 6a-j with but-3-en-1-ol,
Scheme 2, provided the intermediate alkenes 16a-j, which
were epoxidized with m-CPBA, then typically used without
isolation and ring-opened with alkylamines to provide targets
17-22.
Compounds 17a-b were separated into the R- and S-enan-
tiomers utilizing chiral preparative HPLC. The absolute
configuration of each enantiomer was determined by asym-
metric synthesis utilizing intermediates of known chirality,
Scheme 3. This route was also used to prepare additional
a Reagents and conditions: (a) (R)-4-tosyloxy-1,2-epoxybutane, K2CO3,
acetone, rt; (b) (S)-4-bromo-1,2-epoxybutane, K2CO3, acetone, rt; (c) Me-
NH2, EtOH, 100 °C, 3 min, microwave.
analogues. Mitsonobu N-alkylation of a 2,2-dioxido-2,1,3-
benzothiadiazol-1(3H)-yl core with either the R or the S chiral
epoxide provided R-24a-j and S-24a-j. Ring-opening with

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4513
Table 1. Monoamine Reuptake Inhibition and Rat Metabolic Stability of N-2-Fluorophenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yls 9-23
a Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human norepinephrine transporter (hNET). Desipramine (IC50
=
3.4 ( 1.6 nM) was used as a standard. b Inhibition of [3H] nisoxetine binding to MDCK-Net6 cells stably transfected with hNET. Desipramine (Ki =
2.1 ( 0.6 nM) was used as a standard. Compounds without standard errors are reported as an n of 1. c Inhibition of serotonin uptake in JAR cells,
natively expressing human serotonin transporter (hSERT). Fluoxetine (IC50 =9.4 ( 3.1 nM) was used as a standard. d Inhibition of [3H]WIN-35,428
binding to membranes from CHO cells expressing recombinant human dopamine transporter (hDAT). Mazindol (Ki =22.1 ( 6.5 nM) was used as a
standard. e Values in the parentheses are IC50 (nM). f LMS, liver microsomal stability.15
methylamine provided the desired targets R-17a-j and S-17a-j,
respectively.
Final compounds were converted to their hydrochloride
salt prior to in vitro and in vivo testing.
incorporation of the methyl group at the center carbon of
the propyl chain resulted in the greatest drop in potency (12,
hNET IC50=602 nM). The distal methyl analogue 13 caused
the smallest reduction in hNET functional potency (IC50
=
7 nM). Incorporation of electronegative groups in the side
chain, such as the β-fluoro analogue 14, reduced hNET
potency (IC50 = 238 nM) without any improvement in rat
metabolic stability. Extending the propyl side chain to four
carbons provided compound 15 (IC50 = 4 nM), which had
comparable in vitro potency and reduced hDAT selectivity
when compared to 9. Interestingly, compound 17b, a four-
carbon chain analogue with a β-hydroxy group had im-
proved rat LMS (t1/2=9 min) while maintaining good hNET
potency (IC50 =10 nM) and excellent selectivity. Attempted
introduction of the β-hydroxy substitution into the propyl
chain led to degradation of the target compound. Oxidation
of the alcohol, 17b, to the ketone, 23, led to an equally potent
NRI with reduced metabolic stability.
Compound 17b demonstrated improved metabolic stabi-
lity while maintaining good hNET potency and selectivity
versus hSERT and hDAT. In addition, introduction of the
β-hydroxy group had a significant impact on clogP and tPSA
values, which improved the drug-like properties of the series.16
A variety of β-hydroxy substituted analogues were synthe-
sized on the N-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl core (Tables 2 and 3). As shown in Table 2, increasing the
Results and Discussion
In Vitro Characterization. Initial optimization of the N-aryl
2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl scaffold led to the
identification of 9. This initial lead had excellent potency for
hNET (IC50 = 1 nM) and good selectivity over hDAT and
hSERT, Table 1, however 9 also displayed a low rodent meta-
bolic half-life. The primary sites of metabolism were predicted13
and confirmed experimentally as demethylation of the amine
as well as oxidation of the benzo and pendant phenyl rings. To
address the metabolic instability in rodents, various structural
modifications were made to block these sites of metabolism.
Modification of the electronic and steric character of the amine
side chain aimed at reducing dealkylation while maintaining or
improving the hNET potency and selectivity was the focus of
the work described in this report. Detailed experimental pro-
tocols for all assays discussed were reported previously.9,14
Analogues incorporating a methyl group along the propyl
side chain, 10-13, resulted in an overall 7-600-fold drop in
hNET functional potency with no increase in rat liver micro-
somal stability (LMS). While substitution proximal to the amine,
10, gave a 70-fold drop in hNET potency (IC50 = 72 nM),

4514 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
O’Neill et al.
Table 2. NE Reuptake Inhibition and Rat Metabolic Stability of 4-[3-
Phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(alkylamino)butan-
2-ols
inhibition (IC50 = >30 μM), which suggests a low poten-
tial for QTc prolongation.17 Compounds S-17a, S-17h, and
S-17i, however were not as selective at hERG with IC50’s of
8, 13, and 20 μM, respectively.
In Vivo Characterization. Compound S-17b was selected
based on its in vitro profile for complete in vivo charac-
terization.18 Table 4 highlights the male, intact female, and
ovariectomized female (OVX) rat pharmacokinetic para-
meters of S-17b using both intravenous and oral adminis-
tration. In general, S-17b showed high to moderate clearance,
high volume of distribution, and long terminal half-life.
Overall, the compound exhibited an acceptable pK profile
with bioavailability ranging from 41% to 100%. In addition,
S-17b had good brain penetration, with a brain/plasma ratio
of 3.6 in OVX rats.
compd
R
R1
hNET IC50 (nM)a
rat LMS t1/2 (min) b
Compound S-17b was profiled in a series of in vivo models
to assess its effects on norepinephrine neurobiology. It is
widely believed that fluctuations in estrogen levels due to
menopause result in corresponding changes to norepineph-
rine levels in the brain.19 In particular, norepinephrine has
been reported to regulate temperature control via stimula-
tion of areas of the hypothalamus.20,21 Hormone depletion
causes thermoregulatory dysfunction (hot flush), which has
been shown to be alleviated by NRIs.22,23 Compound S-17b
was therefore characterized in several predictive disease
models for vasomotor symptoms (VMS).22 We have previ-
ously shown that selective NRIs can significantly reduce
the tail-skin temperature (TST) in a telemetric rat model of
ovariectomized-induced thermoregulatory dysfunction.9,10
The effect of S-17b on temperature homeostasis was evalua-
ted in this telemetric rat model over a 12 h period (Figure 1).
When administered orally, compound S-17b significantly
reduced TST, with an immediate onset and a maximum tem-
perature reduction of 4.5° at a dose of 30 mg/kg. The com-
pound lowered the TST in a dose-dependent manner with a
minimum efficacious dose of 0.1 mg/kg.
The regulation of TST was further confirmed in a second
in vivo thermoregulatory efficacy model where the effect of
acute oral doses of S-17b on the abatement of morphine
dependent flush was evaluated in OVX rats (Figure 2).22 In
this model, morphine dependent OVX rats were treated
sequentially with a single oral dose of the test compound
followed by a 1 mg/kg of the nonselective opioid antagonist
naloxone 90 min later, resulting in an immediate rise in TST.
Dose-dependently, S-17b abated the increase in TST caused
by naloxone treatment. At 30 mg/kg, compound S-17b aba-
ted the flush by 90% and had an ED50 of 1 mg/kg.
NE has also been implicated in the modulation of noci-
ceptive processing,24 which is a component of the endogen-
ous descending pain inhibitory system. Reduced levels of NE
may in part contribute to the establishment and/or main-
tenance of chronic pain states.25-27 It was reported that by
blocking reuptake of NE, NRIs increase NE levels which
subsequently activate descending inhibitory pathways.24 The
rat hot plate assay of acute analgesia was used to investigate
the efficacy of S-17b on alleviating pain.28,29 In this assay,
rats are placed on a metal plate maintained at a temperature
of 52 °C. The latency to exhibit a response to this thermal
stimulus, such as hind paw lift, flutter, licking, or escape
behavior, was measured with a cutoff of 30 s to avoid tissue
damage. Upon oral administration, S-17b significantly in-
creased latency at both 3 and 10 mg/kg 1 and 3 h postdosing
(Figure 3). These data suggest that compound S-17b was
efficacious in treating acute pain.
17a
18
19
20
21
22
Me
Et
H
2 ( 0.2
196 ( 76
2255 ( 1489
9 ( 1.8
853 ( 298
481 ( 161
12
9
H
i-Pr
c-Pr
t-Bu
Me
H
6
H
6
H
Me
6
3
a Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably
transfected with human norepinephrine transporter (hNET). Desipra-
mine (IC50 = 3.4 ( 1.6 nM) was used as a standard. b LMS, liver micro-
somal stability.
size of the N-alkyl group reduced hNET potency as well as
rat LMS. The dimethylamino compound 22 showed minimal
rat microsomal stability as might be expected. Interestingly,
the cyclopropylamino derivative 20 demonstrated the smal-
lest drop in hNET potency with an IC50 of 9 nM in the hNET
functional assay while its isopropyl analogue 19 was over
100-fold less potent.
The SAR of substitution around the pendant aryl ring was
examined (Table 3). Compounds in this series were tested as
single enantiomers. In general, the R-enantiomers were 2-
9-fold less potent in the hNET assays than the corresponding
S-enantiomers. While both enantiomers showed comparable
hSERT selectivity, the R-enantiomers were less selective
for hDAT. Compound S-17b was the most potent of the
S-enantiomers tested (IC50=1 nM) with excellent hNET selec-
tivity versus hSERT (>1300-fold) and hDAT (>600-fold).
Analogues S-17h and S-17i displayed similar profiles to
S-17b (hNET IC50 <5 nM), and all three compounds had rat
LMS half-lives that were improved over 9b (t1/2=9, 6, 6 min
respectively vs 2 min). Incorporation of a 4-F group hindered
metabolism and further increased the rat metabolic stability,
exemplified by S-17f, S-17g, and S-17j, which display half-
lives greater than 30 min. Incorporation of the 4-fluorophe-
nyl substituent impacted hNET activity, with a 15-122-fold
drop in potency, and for S-17f and g a drop of 7-fold and 167-
fold, respectively, in hDAT selectivity. Alternate substitu-
tion at the 2-phenyl position such as chlorine and methyl,
S-17c and d, showed decreased hNET potency (IC50 =28 and
64 nM) and rat LMS (t1/2 = 6 and 5 min.). Incorporating
an electron-donating group such as methoxy to the phenyl
3-position, S-17e, led to decreased metabolism (t1/2 =14 min.)
relative to 9b but decreased hNET potency (IC50 = 25 nM)
and selectivity over hDAT (∼135-fold). Several lead com-
pounds, S-17a, S-17b, S-17h, and S-17i, demonstrated the
desired in vitro profile and improved rat LMS relative to 9b
and were profiled further. In general, each compound showed
a low potential for drug-drug interaction with low CYP450
inhibition against multiple isozymes (generally <15% inhi-
bition @ 3 μM). Compound S-17b demonstrated low hERG

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4515
Table 3. Monoamine Reuptake Inhibition and Rat Metabolic Stability of 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols
a Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human norepinephrine transporter (hNET). Desipramine (IC50
=
3.4 ( 1.6 nM) was used as a standard. b Inhibition of [3H] nisoxetine binding to MDCK-Net6 cells stably transfected with hNET. Desipramine (Ki =
2.1 ( 0.6 nM) was used as a standard. Compounds without standard errors are reported as an n of 1. c Inhibition of serotonin uptake in JAR cells,
natively expressing human serotonin transporter (hSERT). Fluoxetine (IC50 =9.4 ( 3.1 nM) was used as a standard. d Inhibition of [3H]WIN-35,428
binding to membranes from CHO cells expressing recombinant human dopamine transporter (hDAT). Mazindol (Ki =22.1 ( 6.5 nM) was used as a
standard. e Values in the parentheses are IC50 (nM). f ND: not determined. g LMS: liver microsomal stability.
The activity of compound S-17b was also evaluated in a
rat spinal nerve ligation (SNL) model of neuropathic pain.
In this model,30,31 surgery was performed to tightly ligate
the left L5 spinal nerve. Assessment of mechanical thresh-
olds was then measured as the hind paw withdrawal thres-
hold to a noxious mechanical stimulus as determined using
the paw pressure technique (Randall-Selitto). The cutoff
was set at 250 g of pressure, and the end point was com-
plete paw withdrawal. Thresholds were evaluated prior
to surgery to act as an internal control and reassessed three
to four weeks after recovery from SNL surgery. Com-
pound S-17b was administered orally in 0.5% methylcel-
lulose plus 2% Tween in water, and the ability to reverse
SNL-induced mechanical hyperalgesia with this agent
was assessed. Compound S-17b significantly and dose-
dependently reversed mechanical hyperalgesia at 5, 7, 10,
and 30 mg/kg, suggesting efficacy in treating neuropathic
pain (Figure 4).

4516 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
O’Neill et al.
Table 4. Pharmacokinetic Parameters of Compound S-17b in the Male, Intact Female, and OVX Rats after Intravenous and Oral Administrationsa
Clp
(mL/min/kg)
AUC0-inf
(h ng/mL)
rat
dose (mg/kg)
Vss (L/kg)
Cmax (ng/mL)
Tmax (h)
t1/2 (h)
F%
3
M
F
OVX
2 (iv)
2 (iv)
2 (iv)
170
36
36.3
11.3
25.3
2.9
4.7
6.3
199
929
505
66
M
F
OVX
10 (po)
5 (po)
5 (po)
154
135
125
1.38
0.56
1.63
3.2
4.4
4.7
1038
959
100
41.3
95.2
1200
a 2% Tween-80/0.5% methylcellulose in water and DMSO/80%PEG200 were used as vehicles for oral and intravenous administrations, respectively.
Three rats were used in each study.
(silica gel, 60 F-254), and spots were visualized with UV light
and stained in iodine. Solvents were purchased as anhydrous
grade and were used without further purification. Crude reaction
products were purified using the ISCO Rf purification system.
Preparative HPLC purifications were performed on a preparative
Gilson HPLC system using a CombiPrep Pro C18 column with
acetonitrile (0.1% TFA) and water (0.1% TFA) as solvents at a
flow rate of 20 mL/min. Chiral HPLC separations were carried
out using supercritical fluid chromatography conditions using a
250 mm ꢀ 4.6 mm i.d. column at 2.0 mL/min flow rate using
Chiralpak AS-H 5 analytical supercritical fluid chromatography
(Berger Instruments, Inc. Newark, DE). Compound purity was
1
assessed by H NMR and analytical HPLC as described in the
Supporting Information. Biological results were obtained on com-
pounds of >95% chemical purity as determined by the above
methods.
Figure 1. Oral activity of compound S-17b in a telemetric rat model
of ovariectomized-induced thermoregulatory dysfunction. Com-
pound was dosed in 2% Tween-80/0.5% methylcellulose in water.
1-Phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (6a).
Compound 6a was prepared following the general procedure for
6b with N-(2-fluorophenyl)benzene-1,2-diamine being replaced
with N-phenyl-o-phenylenediamine.
The onset of an effect was defined as the first half-hour interval of
two consecutive significant (p < 0.05) half-hour intervals following
any number of nonsignificant half-hour intervals. The treatment
effect was considered to have ended when two consecutive non-
significant half-hour intervals followed any number of significant
half-hour intervals. Mean temperature change was calculated from
half-hour TST averages obtained over the treatment duration.
MS (ES) m/z 245.2 ([M - H]þ). HRMS: calcd for C12H10-
N2O2S þ Hþ, 247.0536; found (ESI, [M þ H]þ), 247.0541. 1H
NMR (DMSO-d6) δ 11.62 (br s, 1H), 7.49 (m, 5H), 6.91 (m, 3H),
6.57 (d, J=7.54 Hz, 1H).
Conclusion
General Procedure for the Synthesis of the Sulfamide Cores. 1-(2-
Fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-Dioxide (6b).
2-Fluoroaniline (1.45 mL, 15 mmol) was dissolved in DMF (10 mL),
and sodium hydride (0.58 g, 15 mmol) was added and the mixture
was stirred for 30 min. 2-Fluoronitrobenzene (1.05 mL, 10 mmol)
was added, and the mixture was stirred for 16 h. The mixture was
quenched with saturated NH4Cl and diluted with ether. The mix-
ture was washed with water, brine, dried over anhydrous magne-
sium sulfate, and concentrated. The crude product was purified via
chromatography (Redisep, silica, gradient 5-30% ethyl acetate in
hexane) to afford 1.4 g of 2-fluoro-N-(2-nitrophenyl)aniline (MS
(ES) m/z 232.9), which was dissolved in ethyl acetate (20 mL), and
10% palladium on activated carbon (150 mg) was added. The
mixture was shaken under a hydrogen atmosphere (40 psi) for 2 h.
The mixture was filtered through a pad of celite and concentrated to
give 1.2 g of N-(2-fluorophenyl)benzene-1,2-diamine (MS (ES)
m/z 203.0) that was carried on directly to the next step. Dry diglyme
(10 mL) was added to a flask equipped with a dropping funnel
under a nitrogen atmosphere and brought to a vigorous reflux.
N-(2-Fluorophenyl)benzene-1,2-diamine (1.2 g, 5.9 mmol) and
sulfamide (0.68 g, 7.1 mmol) were dissolved in 5 mL of diglyme
and placed in the dropping funnel. The mixture was added dropwise
to the flask over 15 min, and then refluxing was continued for an
additional 15 min. The mixture was cooled to ambient temperature
and diluted with ether, washed with water, 2N HCl, water, and
brine, dried over anhydrous magnesium sulfate, and concentrated.
The crude product was purified via chromatography (Redisep,
silica, gradient 5-50% (ethyl acetate containing 2% formic acid) in
hexane) to afford 0.37 g of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-
benzothiadiazole 2,2-dioxide 6b (28%).
The lead optimization efforts toward the improvement
of compound 9b resulted in the discovery of a new series of
N-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methyl-
amino)butan-2-ols, which are potent and selective for the
inhibition of norepinephrine transportwithout effects on both
serotonin and dopamine transport. The lead compound de-
monstrated good pharmacokinetic and pharmaceutical pro-
files. Compound S-17b was orally efficacious toward alleviat-
ing behavioral symptoms associated with NE deficiency in
four in vivo models. In the telemetric rat model and in the
morphine dependent flush model, S-17b dose-dependently
reduced tail skin temperature in OVX rats and was the most
potent NRI seen in these models to date. This compound also
showed good activity in both the rat hot plate and spinal nerve
ligation models, demonstrating an additional potential to
treat acute and neuropathic pain. On the basis of this profile,
S-17b (WYE-103231) advanced into development for the treat-
ment of vasomotor symptoms and pain.
Experimental Section
1H NMR spectra were recorded on a Varian INOVA 400 or
Bruker AVANCEII 400instrument. Chemical shiftsare reported
in δ values (parts per million, ppm) relative to an internal stan-
dard of tetramethylsilane in CDCl3 or DMSO-d6. Electrospray
(ESI) mass spectra were recorded using a Hewlett-Packard 5989B
MS engine or Waters Alliance-ZMD mass spectrometer. Elec-
tron impact ionization (EI, EE=70 eV) mass spectra were recor-
ded on a Finnigan Trace mass spectrometer. Analytical thin-layer
chromatography (TLC) was carried out on precoated plates
MS (ES) m/z 262.9 ([M - H]þ); HRMS: calcd for C12H9-
FN2O2S þ Hþ, 265.0442; found (ESI, [M þ H]þ), 265.0444;

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4517
Figure 2. Abatement of compound S-17b on morphine dependent flush in OVX Rats. Compound was dosed in accordance with the previously
published protocol.22 N = 10 rats per dose.
MS (ES) m/z 263.0 ([M - H]þ). HRMS: calcd for C12H9-
FN2O2S - Hþ, 263.0296; found (ESI, [M - H]þ), 263.0295. 1H
NMR (DMSO-d6) δ 11.65 (br s, 1H), 7.48 (m, 2H), 7.39 (m, 2H),
6.91 (m, 3H), 6.54 (d, J =7.69 Hz, 1H).
1-(2,4-Difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6g). Compound 6g was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being re-
placed with 2,4-difluoroaniline.
MS (ES) m/z 281.0 ([M - H]þ). HRMS: calcd for C12H8-
F2N2O2S - Hþ, 281.0202; found (ESI, [M - H]þ), 281.0207. 1H
NMR (DMSO-d6) δ 11.80 (br s, 1H), 7.65 (m, 2H), 7.33 (m, 1H),
6.50 (m, 3H), 6.53 (d, J =7.66 Hz, 1H).
1-(2,5-Difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6h). Compound 6h was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being
Figure 3. Oral activity of compound S-17b on hot plate latency. Male,
Sprague-Dawley rats, wt = 181-215 g, (n = 10/group). The hot
replaced with 2,5-difluoroaniline.
MS (ES) m/z 280.9 ([M - H]þ). HRMS: calcd for C12H8-
plate was set at 52 °C and cut off was set at 30 s. Latency to nocifensive
F2N2O2S - Hþ, 281.0202; found (ESI, [M - H]þ), 281.0204. 1H
response was measured. S-17b was administered (po) as a solution in
2% Tween/0.5% methylcellulose (vehicle). Morphine was adminis-
NMR (DMSO-d6) δ 11.82 (br s, 1H), 7.61 (m, 1H), 7.52 (m, 2H),
tered (sc) as a solution in 0.9% saline. Data shown are means ( SEM.
6.98 (m, 3H), 6.60 (d, J =7.80 Hz, 1H).
1-(2,6-Difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6i). Compound 6i was prepared following the general
1H NMR (DMSO-d6) δ 7.54 (m, 3H), 7.40-7.35 (m, 1H), 6.90
(m, 3H), 6.44 (d, J =7.81 Hz, 1H).
procedure for sulfamide synthesis with 2-fluoroaniline being
replaced with 2,6-difluoroaniline.
1-(2-Chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-Dioxide
(6c). Compound 6c was prepared following the general proce-
dure for sulfamide synthesis with 2-fluoroaniline being replaced
with 2-chloroaniline.
MS (ES) m/z 281.3 ([M - H]þ). HRMS: calcd for C12H8-
F2N2O2S þ Hþ, 283.0347; found (ESI, [M þ H]þ), 283.0347.; 1H
NMR (DMSO-d6) δ 11.88 (br s, 1H), 7.73 (m, 1H), 7.42 (m, 2H),
6.98 (m, 3H), 6.56 (d, J =7.80 Hz, 1H).
MS (ES) m/z 278.8 ([M - H]þ). HRMS: calcd for C12H9-
ClN2O2S - Hþ, 279.0000; found (ESI, [M - H]þ), 279.0002. 1H
NMR (DMSO-d6) δ 7.72 (m, 1H), 7.56 (m, 3H), 6.90 (m, 3H),
6.28 (d, J = 7.55 Hz, 1H).
1-(3,4-Difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6j). Compound 6j was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being
replaced with 3,4-difluoroaniline.
1-(2-Methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6d). Compound 6d was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being
replaced with 2-methylaniline.
MS (ES) m/z 280.8 ([M - H]þ). HRMS: calcd for C12H8-
F2N2O2S - Hþ, 281.0202; found (ESI, [M þ H]þ), 281.0203. 1H
NMR (DMSO-d6) δ 11.78 (br s, 1H), 7.63 (m, 2H), 7.34 (m, 1H),
6.92(m, 3H), 6.65 (d, J =7.95 Hz, 1H).
MS (ES) m/z 261.0 ([M þ H]þ). HRMS: calcd for C13H12-
N2O2S - Hþ, 259.0547; found (ESI, [M - H]þ), 259.0546. 1H
NMR (DMSO-d6) δ 11.62 (br s, 1H), 7.51 (m, 2H), 7.42 (m, 2H),
6.92 (m, 3H), 6.25 (d, J =7.54 Hz, 1H), 2.21 (s, 3H).
1-(3-Methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6e). Compound 6e was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being
replaced with 3-methoxyaniline.
3-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-N-methylpropan-1-amine (9). 6b (0.37 g, 1.4 mmol) was dis-
solved in THF (10 mL). Triphenylphosphine (440 mg, 1.68 mmol)
and 3-bromopropanol (0.12 mL, 1.4 mmol) were added, fol-
lowed by diisopropylazodicarboxylate (0.33 mL, 1.68 mmol).
The mixture was stirred for 16 h and then concentrated. Puri-
fication via chromatography (Redisep, silica, gradient 5-50%
ethyl acetate in hexane) afforded 0.41 g of 1-(3-bromopropyl)-
3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
which was immediately carried on to the next step. 1-(3-Bromo-
propyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.4 g, 1.04 mmol) was dissolved in 8N methylamine
in methanol (20 mL) and stirred for 16 h in a sealed flask. The mix-
ture was concentrated in vacuo to give the crude product. The
crude product was purified via chromatography (silica, 5% methanol
MS (ES) m/z 276.9 ([M þ H]þ). HRMS: calcd for C13H12-
N2O3S - Hþ, 275.0496; found (ESI, [M - H]þ), 275.0494. 1H
NMR (DMSO-d6) δ 11.64 (br s, 1H), 7.44 (m, 1H), 7.02 (m, 2H),
6.90 (m, 4H), 6.63 (m, 1H), 3.75 (s, 3H).
1-(4-Fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-
Dioxide (6f). Compound 6f was prepared following the general
procedure for sulfamide synthesis with 2-fluoroaniline being
replaced with 4-fluoroaniline.

4518 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
O’Neill et al.
Figure 4. Oral activity of compound S-17b on SNL-induced mechanical hyperalgesia. Male, Sprague-Dawley rats (238-304 g, 9-10/group),
3 weeks postsurgery. Threshold to paw withdrawal was measured. S-17b was administered orally as a suspension of 0.5% methylcellulose plus
2% Tween in water. Gabapentin was used as a positive control and administered (ip) as a solution in 0.9% saline. Data shown are means (
SEM. * indicates a p value of e0.05 vs SNL/vehicle (ANOVA).
saturated with ammonia in chloroform) to give 350 mg of
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-N-methylpropan-1-amine. The free base was dissolved in
ether (10 mL) and treated with 1N hydrochloric acid in ether
(1 equiv). The white precipitate was collected and dried under
vacuum to provide 9.
J=7.82 Hz, 1H), 3.02 (m, 2H), 2.53 (m, 3H), 2.31 (m, 2H), 2.11
(m, 1H), 1.48 (d, J =6.92 Hz, 3H).
2,2-Difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]-N-methylpropan-1-amine (14). Compound 14
was prepared following the procedure for compound 9 with
3-bromopropanol being replaced with 2,2-difluoro-3-hydroxy-
N-methylpropanamide. The resulting impure solid was treated
with borane-tetrahyrofuran complex (1 M in THF, 3 equiv) at
0 °C and then stirred for 2 h, quenched with dilute hydrochloric
acid, basified (NaOH), and extracted with ethyl acetate. The
organic layer was washed with water, dried (MgSO4), and eva-
porated. The residue was purified first via chromatography (Redisep,
silica, gradient 0-100% ethyl acetate in hexane) and then by
reverse phase HPLC.
MS (ES) m/z 335.9 ([M þ H]þ). HRMS: calcd for C16H18-
FN3O2S þ Hþ, 336.1177; found (ESI, [M þ H]þ), 336.1177. 1H
NMR (DMSO-d6) δ 8.85 (br s, 2H), 7.57 (m, 2H), 7.41 (m, 1H),
7.20 (m, 1H), 7.06 (m, 1H), 6.93 (m, 1H), 6.52 (d, J = 7.82 Hz,
1H), 3.95 (m, 2H), 2.99 (m, 2H), 2.5 (s, 3H), 2.09 (m, 2H).
3-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-N-methylbutan-2-amine (10). Compound 10 was prepared
following the procedure for compound 9 with 3-bromopropanol
being replaced with 3-bromobutan-1-ol.
MS (ES) m/z 372.0 ([M þ H]þ). HRMS: calcd for C16H16-
F3N3O2S þ Hþ, 372.09881; found (ESI, [M þ H]þ), 372.0982.
1H NMR (DMSO-d6) δ 9.45 (br s, 2H), 7.59 (m, 3H), 7.42 (m,
1H), 7.18 (m, 1H), 7.08 (m, 1H), 7.99 (m, 1H), 6.55 (d, J=7.95
Hz, 1H), 4.58 (t, J=5.89 Hz, 2H), 3.82 (t, J=7.82 Hz, 2H), 2.31
(s, 3H).
MS (ES) m/z 350.0 ([M þ H]þ). HRMS: calcd for C17H15-
1
FN2O þ Hþ, 350.1339; found (ESI, [M þ H]þ), 350.1338. H
NMR (DMSO-d6) δ 8.82 (br s, 2H), 7.64 (m, 3H), 7.46 (m, 1H),
7.26 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 6.58 (d, J = 7.82 Hz,
1H), 3.38 (m, 1H), 2.55 (m, 3H), 2.26 (m, 2H), 1.98 (m, 2H), 1.33
(d, J =6.54 Hz, 3H).
4-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-N-methylbutan-1-amine (15). Compound 15 was prepared
following the procedure for compound 9 with 3-bromopropanol
being replaced with 4-bromobutan-1-ol.
(2R)-3-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-N,2-dimethylpropan-1-amine (11). Compound 11
was prepared following the procedure for compound 9 with
3-bromopropanol being replaced with (S)-3-bromo-2-methylpro-
pan-1-ol.
MS (ESI) m/z 350.1 ([M þ H]þ). HRMS: calcd for C17H20-
FN3O2S þ Hþ, 350.13330; found (ESI-FTMS, [M þ H]þ),
MS (ES) m/z 350.0 ([M þ H]þ). HRMS: calcd for C17H15-
350.13369. H NMR (DMSO-d6) δ 8.26 (br s, 2H), 7.53 (m,
1
1
FN2O þ Hþ, 350.1339; found (ESI, [M þ H]þ), 350.1335. H
4H), 7.14 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.51 (d, J=6.92
Hz, 1H), 3.86 (t, J=6.92 Hz, 2H), 2.90 (t, J=7.56 Hz, 2H), 2.49
(s, 3H), 1.79 (m, 2H), 1.66 (m, 2H).
NMR (DMSO-d6) δ 8.79 (br s, 2H), 7.57 (m, 3H), 7.43 (m, 1H),
7.21 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 6.52 (d, J = 7.81 Hz,
1H), 3.88 (m, 1H), 3.72 (m, 1H), 3.02 (m, 1H), 2.89 (m, 1H), 2.52
(m, 3H), 1.06 (d, J =6.67 Hz, 3H).
Achiral Route toward 17a and b. 1-(But-3-enyl)-3-(2-fluoro-
phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-Dioxide (16b). 6b
(0.45 g, 1.7 mmol) was dissolved in tetrahydrofuran (20 mL),
and triphenylphosphine (0.54 g, 2 mmol) was added followed by
3-buten-1-ol (0.16 mL, 1.87 mmol) and diisopropyl azodicar-
boxylate (0.39 g, 2 mmol). The mixture was stirred for 18 h at
23 °C. The mixture was concentrated and purified via chromato-
graphy (Redisep, silica, gradient 0-50% ethyl acetate in hexane)
to afford 0.44 g of 1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-
2,1,3-benzothiadiazole 2,2- dioxide.
(2S)-3-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-N,2-dimethylpropan-1-amine (12). Compound 12 was
prepared following the procedure for compound 9 with 3-bromo-
propanol being replaced with (R)-3-bromo-2-methylpropan-1-ol.
MS (ES) m/z 350.0 ([M þ H]þ). HRMS: calcd for C17H15-
1
FN2O þ Hþ, 350.1339; found (ESI, [M þ H]þ), 350.1337. H
NMR (DMSO-d6) δ 8.79 (br s, 2H), 7.57 (m, 3H), 7.43 (m, 1H),
7.21 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 6.52 (d, J = 7.81 Hz,
1H), 3.88 (m, 1H), 3.72 (m, 1H), 3.02 (m, 1H), 2.89 (m, 1H), 2.52
(m, 3H), 1.06 (d, J =6.67 Hz, 3H).
MS (ESI) m/z 318.8 ([M þ H]þ). HRMS: calcd for C16H15-
FN2O2S þ Naþ, 341.07304; found (ESI, [M þ Na]þ), 341.0727.
1H NMR (DMSO-d6) δ 7.56 (m, 3H), 7.41 (m, 1H), 7.15 (m, 1H),
7.03 (m, 1H), 6.91 (m, 1H), 6.51 (d, J = 7.82 Hz, 1H), 5.87 (m,
1H), 5.16 (m, 1H), 5.06 (m, 1H), 3.88 (m, 2H), 2.51 (m, 2H).
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
1-(methylamino)butan-2-ol (17a). Compound 17a was prepared
following the procedure for compound 17b.
(2S)-3-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-N,2-dimethylpropan-1-amine (13). Compound 13 was
prepared following the procedure for compound 9 with 3-bromo-
propanol being replaced with 4-bromobutan-2-ol.
MS (ES) m/z 350.0 ([M þ H]þ). HRMS: calcd for C17H15-
1
FN2O þ Hþ, 350.1339; found (ESI, [M þ H]þ), 350.1335. H
NMR (DMSO-d6) δ 8.47 (br s, 2H), 7.64 (m, 1H), 7.52 (m, 1H),
7.41 (m, 1H), 7.20 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.53 (d,
MS (ESI) m/z 348.1 ([M þ H]þ). HRMS: calcd for C17H21-
N3O3S þ Hþ, 348.1376; found (ESI, [M þ H]þ), 348.1381.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4519
1H NMR (DMSO-d6) δ 8.69 (br s, 2H), 7.61 (m, 3H), 7.51 (m,
2H), 7.18 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.66 (d, J=6.91
Hz, 1H), 5.69 (m, 1H), 3.96 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H),
2.55 (m, 3H), 2.00 (m, 1H), 1.85 (m, 1H).
MS (ESI) m/z 381.6 ([M þ H]þ). HRMS: calcd for C17H20-
ClN3O3S þ Hþ, 382.0987; found (ESI, [M þ H]þ), 382.0990. 1H
NMR (DMSO-d6) δ 8.61 (br s, 2H), 7.80 (m, 1H), 7.67 (m, 1H),
7.60 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.93 (m, 1H), 6.41 (d,
J=7.55 Hz, 1H), 5.68 (m, 1H), 3.96 (m, 3H), 3.03 (m, 1H), 2.88
(m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.86 (m, 1H).
4-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
yl]-1-(methylamino)butan-2-ol (17b). 16b (0.44 g, 1.64 mmol) was
dissolved in CH2Cl2 (10 mL) at 23 °C. 3-Chlorobenzoperoxoic acid
(1.02 g, 3.9 mmol) was added and the mixture allowed to stir for
18 h and then filtered and concentrated. The residue was diluted
with EtOAc and washed with 10% NaHCO3 solution then brine.
After drying with Na2SO4, the solution was concentrated and then
300 mg of the residue was dissolved in 10 mL of MeNH2 solution
(8 M in EtOH). The solution was irradiated in a microwave cuvette
at 100 °C for 3 min. The reaction mixture was concentrated and
then loaded directly onto silica gel and purified via chromatogra-
phy (Redisep, silica, gradient 0-10% 7 M ammonia/MeOH solu-
tion in dichloromethane) to afford 300 mg of racemic 17b.
MS (ESI) m/z 366.6 ([M þ H]þ). HRMS: calcd for C17H20-
FN3O3S þ Hþ, 366.1288; found (ESI, [M þ H]þ), 366.1269. 1H
NMR (DMSO-d6) δ 8.51 (br s, 2H), 7.53 (m, 4H), 7.12 (m, 1H),
7.07 (m, 1H), 6.91 (m, 1H), 6.51 (d, J = 7.82 Hz, 1H), 5.60 (m,
1H), 3.91 (m, 3H), 3.00 (m, 1H), 2.85 (m, 1H), 2.51 (s, 3H), 1.95
(m, 1H), 1.80 (m, 1H).
(2R)-(4-[3-(2-Methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17d). Compound R-17d
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 361.7 ([M þ H]þ). HRMS: calcd for C18H23-
N3O3S þ Hþ, 362.1533; found (ESI, [M þ H]þ), 362.1538. 1H
NMR (DMSO-d6) δ 8.63 (br s, 2H), 7.54 (m, 2H), 7.44 (m, 1H),
7.38 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.92 (m, 1H), 6.31 (d,
J=7.82 Hz, 1H), 5.67 (m, 1H), 3.97 (m, 3H), 3.03 (m, 1H), 2.88
(m, 1H), 2.55 (m, 3H), 2.21 (s, 3H), 2.01 (m, 1H), 1.86 (m, 1H).
(2R)-(4-[3-(3-Methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17e). Compound R-17e
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 377.7 ([M þ H]þ). HRMS: calcd for C18H23-
N3O4S þ Hþ, 378.1482; found (ESI, [M þ H]þ), 378.1490. 1H
NMR (DMSO-d6) δ 8.54 (br s, 2H), 7.54 (m, 1H), 7.18 (m, 2H),
7.09 (m, 2H), 6.99 (m, 2H), 6.73 (d, J=7.80 Hz, 1H), 5.66 (d, J=
5.97 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m,
1H), 2.55 (s, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2R)-(4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17f). Compound R-17f
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 365.6 ([M þ H]þ). HRMS: calcd for C17H20-
FN3O3S þ Hþ, 366.1282; found (ESI, [M þ H]þ), 378.1291. 1H
NMR (DMSO-d6) δ 8.62 (br s, 2H), 7.57 (m, 2H), 7.48 (m, 2H),
7.18 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.62 (m, 1H), 5.68 (m,
1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m, 1H), 2.55
(m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2R)-(4-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]-1-(methylamino)butan-2-ol (R-17g). Compound
R-17g was prepared following the procedure for compound R-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1193. 1H
NMR (DMSO-d6) δ 8.62 (br s, 2H), 7.69 (m, 2H), 7.37 (m, 1H),
7.18 (m, 1H), 7.11 (m, 1H), 6.98 (m, 1H), 6.61 (d, J = 7.84 Hz,
1H), 5.68 (d, J=5.84 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m,
1H), 2.88 (m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2R)-(4-[3-(2,5-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17h). Compound R-17h
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1189. 1H
NMR (DMSO-d6) δ 8.59 (br s, 2H), 7.60 (m, 3H), 7.18 (m, 1H),
7.12 (m, 1H), 6.98 (m, 1H), 6.68 (d, J=7.87 Hz, 1H), 5.67 (d, J=
6 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m, 1H),
2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2R)-(4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17i). 6i (0.15 g, 0.5 mmol)
was dissolved in acetone (5 mL), and potassium carbonate (0.14 g,
1.0 mmol) was added followed by (R)-2-(oxiran-2-yl)ethyl 4-tosy-
late (0.24 g, 1.0 mmol). The mixture was stirred for 18 h at 50 °C in
a sealed vial and then diluted with EtOAc (100 mL) and washed
with water (2ꢀ) and brine and then dried (Na2SO4). After con-
centration, the residue was dissolved in 10 mL of MeNH2 solution
(8 M in EtOH). The solution was irradiated in a microwave cuvette
at 100 °C for 3 min. The reaction mixture was concentrated and
then loaded directly onto silica gel and purified via chromatogra-
phy (Redisep, silica, gradient 0-100% of 10% 7 M ammonia in
MeOH/dichloromethane) to afford 59 mg of R-17i.
(2R)-4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
1-(methylamino)butan-2-ol (R-17a) and (2S)-4-(2,2-Dioxido-3-
phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol
(S-17a). Compounds R-17a and S-17a were prepared following
the procedure for compounds R-17b and S-17b.
R-17a: MS (ESI) m/z 348.1 ([M þ H]þ). HRMS: calcd for
C17H21N3O3S þ Hþ, 348.1376; found (ESI, [M þ H]þ), 348.1381.
1H NMR (DMSO-d6) δ 8.65 (br s, 2H), 7.66 - 7.56 (m, 3H), 7.51
(m, 2H), 7.18 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.67 (d, J =
7.81 Hz, 1H), 5.68 (m, 1H), 3.96 (m, 3H), 3.05 (m, 1H), 2.90 (m,
1H), 2.55 (m, 3H), 2.00 (m, 1H), 1.85 (m, 1H).
S-17a: MS (ESI) m/z 348.1 ([M þ H]þ). HRMS: calcd for
C17H21N3O3S þ Hþ, 348.1376; found (ESI, [M þ H]þ), 348.1381.
1H NMR (DMSO-d6) δ 8.65 (br s, 2H), 7.66 - 7.56 (m, 3H), 7.51
(m, 2H), 7.18 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.67 (d, J =
7.81 Hz, 1H), 5.68 (m, 1H), 3.96 (m, 3H), 3.05 (m, 1H), 2.90 (m,
1H), 2.55 (m, 3H), 2.00 (m, 1H), 1.85 (m, 1H).
(2R)-(4-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17b) and (2S)-(4-[3-(2-
Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
1-(methylamino)butan-2-ol (S-17b). Approximately 300 mg of
racemic 17b was dissolved in 4 mL of methanol. Then 200 μL of
the resulting solution was repetitively injected onto the super-
critical fluid chromatography instrument, and the baseline
resolved enantiomers were separately collected using the condi-
tions described below. The chiral purity of each enantiomer was
determined under the same supercritical fluid chromatography
conditions using a 250 mmꢀ4.6 mm i.d. column at 2.0 mL/min
flow rate using Chiralpak AS-H 5 analytical supercritical fluid
chromatography (Berger Instruments, Inc. Newark, DE). Both
enantiomers were found to be >99.9% enantiomerically pure.
R-17b: MS (ESI) m/z 366.1 ([M þ H]þ). HRMS: calcd for
C17H20FN3O3Sþ Hþ, 366.1288; found (ESI, [M þ H]þ), 366.1289.
1H NMR (DMSO-d6) δ 8.47 (br s, 2H), 7.63 (m, 1H), 7.54 (m,
2H), 7. 42 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 6.93 (m, 1H), 6.52
(d, J=7.95 Hz, 1H), 5.60 (d, J=6.02 Hz, 1H), 3.91 (m, 3H), 3.00
(m, 1H), 2.85 (m, 1H), 2.51 (s, 3H), 1.95 (m, 1H), 1.80 (m, 1H).
S-17b: MS (ESI) m/z 365.9 ([M þ H]þ). HRMS: calcd for
C
17H20FN3O3S þ Hþ, 366.1288; found (ESI, [M þ H]þ),
1
366.1290. H NMR (DMSO-d6) δ 8.47 (br s, 2H), 7.63 (m, 1H),
7.54 (m, 2H), 7. 42 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 6.93 (m, 1H),
6.52 (d, J=7.95 Hz, 1H), 5.60 (d, J=6.02 Hz, 1H), 3.91 (m, 3H),
3.00 (m, 1H), 2.85 (m, 1H), 2.51 (s, 3H), 1.95 (m, 1H), 1.80 (m, 1H).
Asymmetric Route to Compounds R-17c-j. (2R)-(4-[3-(2-Chloro-
phenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methyl-
amino)butan-2-ol (R-17c). Compound R-17c was prepared follow-
ing the procedure for compound R-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1191. 1H
NMR (DMSO-d6) δ 8.65 (br s, 2H), 7.77 (m, 1H), 7.45 (m, 2H),
7.21 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 6.64 (d, J = 7.80 Hz,
1H), 5.69 (d, J=5.97 Hz, 1H), 3.96 (m, 3H), 3.05 (m, 1H), 2.90
(m, 1H), 2.55 (m, 3H), 2.00 (m, 1H), 1.85 (m, 1H).

4520 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
O’Neill et al.
(2R)-(4-[3-(3,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17j). Compound R-17j
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1190. 1H
NMR (DMSO-d6) δ 8.61 (br s, 2H), 7.70 (m, 2H), 7.41 (m, 1H),
7.18 (m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 6.75 (d, J = 7.85 Hz,
1H), 5.68 (d, J=5.99 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m,
1H), 2.88 (m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
Asymmetric Route to Compounds S-17c-j. (2S)-(4-[3-(2-Chloro-
phenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methyl-
amino)butan-2-ol (S-17c). Compound S-17c was prepared follow-
ing the procedure for compound S-17i.
water (2ꢀ) and brine and then dried (Na2SO4). After concentra-
tion, the residue was dissolved in 10 mL of MeNH2 solution(8Min
EtOH). The solution was irradiated in a microwave cuvette at 100 °C
for 3 min. The reaction mixture was concentrated and then loaded
directly onto silica gel and purified via chromatography (Redisep,
silica, gradient 0-100% of 10% 7 M ammonia in MeOH/dichloro-
methane) to afford 69 mg of S-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1194. 1H
NMR (DMSO-d6) δ 8.65 (br s, 2H), 7.77 (m, 1H), 7.45 (m, 2H),
7.21 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 6.64 (d, J = 7.80 Hz,
1H), 5.69 (d, J=5.97 Hz, 1H), 3.96 (m, 3H), 3.05 (m, 1H), 2.90
(m, 1H), 2.55 (m, 3H), 2.00 (m, 1H), 1.85 (m, 1H).
MS (ESI) m/z 381.6 ([M þ H]þ). HRMS: calcd for C17H20-
ClN3O3S þ Hþ, 382.0987; found (ESI, [M þ H]þ), 382.0993. 1H
NMR (DMSO-d6) δ 8.61 (br s, 2H), 7.80 (m, 1H), 7.67 (m, 1H),
7.60 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.93 (m, 1H), 6.41 (d,
J=7.55 Hz, 1H), 5.68 (m, 1H), 3.96 (m, 3H), 3.03 (m, 1H), 2.88
(m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.86 (m, 1H).
(2S)-(4-[3-(3,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17j). Compound S-17j
was prepared following the procedure for compound S-17j.
MS (ESI) m/z 384.2 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1192. 1H
NMR (DMSO-d6) δ 8.61 (br s, 2H), 7.70 (m, 2H), 7.41 (m, 1H),
7.18 (m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 6.75 (d, J = 7.85 Hz,
1H), 5.68 (d, J=5.99 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m,
1H), 2.88 (m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethyl-
amino)butan-2-ol (18). Compound 18 was prepared following the
procedure for compound 17b, replacing MeNH2 with EtNH2.
MS (ESI) m/z 362.1 ([M þ H]þ). HRMS: calcd for C18H23-
N3O3S þ Hþ, 362.1533; found (ESI, [M þ H]þ), 362.1540. 1H
NMR (DMSO-d6) δ 8.51 (br s, 2H), 7.61 (m, 3H), 7.50 (m, 2H),
7.18 (m, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 6.67 (d, J = 6.92 Hz,
1H), 5.64 (d, J=6.02 Hz, 1H), 3.97 (m, 3H), 3.05 (m, 1H), 2.94
(m, 2H), 2.89 (m, 1H), 2.01 (m, 1H), 1.78 (m, 1H), 1.20(t, J =
7.31 Hz, 3H).
(2S)-(4-[3-(2-Methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17d). Compound S-17d
was prepared following the procedure for compound S-17i.
MS (ESI) m/z 361.8 ([M þ H]þ). HRMS: calcd for C18H23-
N3O3S þ Hþ, 362.1533; found (ESI, [M þ H]þ), 362.1538. 1H
NMR (DMSO-d6) δ 8.63 (br s, 2H), 7.54 (m, 2H), 7.44 (m, 1H),
7.38 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.92 (m, 1H), 6.31 (d,
J=7.82 Hz, 1H), 5.67 (m, 1H), 3.97 (m, 3H), 3.03 (m, 1H), 2.88
(m, 1H), 2.55 (m, 3H), 2.21 (s, 3H), 2.01 (m, 1H), 1.86 (m, 1H).
(2S)-(4-[3-(3-Methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (R-17e). Compound R-17e
was prepared following the procedure for compound R-17i.
MS (ESI) m/z 378.1 ([M þ H]þ). HRMS: calcd for C18H23-
N3O4S þ Hþ, 378.1482; found (ESI, [M þ H]þ), 378.1484. 1H
NMR (DMSO-d6) δ 8.54 (br s, 2H), 7.54 (m, 1H), 7.18 (m, 2H),
7.09 (m, 2H), 6.99 (m, 2H), 6.73 (d, J=7.80 Hz, 1H), 5.66 (d, J=
5.97 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m,
1H), 2.55 (s, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2S)-(4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17f). Compound S-17f
was prepared following the procedure for compound S-17i.
MS (ESI) m/z 365.7 ([M þ H]þ). HRMS: calcd for C17H20-
FN3O3S þ Hþ, 366.1282; found (ESI, [M þ H]þ), 378.1287. 1H
NMR (DMSO-d6) δ 8.62 (br s, 2H), 7.57 (m, 2H), 7.48 (m, 2H),
7.18 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.62 (m, 1H), 5.68 (m,
1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m, 1H), 2.55
(m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(iso-
propylamino)butan-2-ol (19). Compound 19 was prepared fol-
lowing the procedure for compound 17b, replacing MeNH2 with
iPrNH2.
MS (ESI) m/z 376.1 ([M þ H]þ). HRMS: calcd for C19H25-
N3O3S þ Hþ, 376.1689; found (ESI, [M þ H]þ), 376.1695. 1H
NMR (DMSO-d6) δ 8.41 (br s, 2H), 7.62 (m, 3H), 7.50 (m, 2H),
7.18 (m, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 6.67 (d, J = 7.82 Hz,
1H), 5.62 (d, J=6.02 Hz, 1H), 3.97 (m, 3H), 3.29 (m, 1H), 3.05
(m, 1H), 2.88 (m, 1H), 2.03 (m, 1H), 1.89 (m, 1H), 1.22 (m, 6H).
1-(Cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothia-
diazol-1(3H)-yl)butan-2-ol (20). Compound 20 was prepared
following the procedure for compound 17b, replacing MeNH2
with cPrNH2.
MS (ESI) m/z 374.1 ([M þ H]þ). HRMS: calcd for C19H23-
N3O3S þ Hþ, 374.1533; found (ESI, [M þ H]þ), 374.1537. 1H
NMR (DMSO-d6) δ 8.82 (br s, 2H), 7.62 (m, 3H), 7.50 (m, 2H),
7.19 (m, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 6.67 (d, J = 7.81 Hz,
1H), 5.62 (m, 1H), 3.97 (m, 3H), 3.18 (m, 1H), 2.99 (m, 1H), 2.69
(m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 0.86 (m, 2H), 0.71(m, 2H).
1-(tert-Butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothia-
diazol-1(3H)-yl)butan-2-ol (21). Compound 21 was prepared
following the procedure for compound 17b, replacing MeNH2
with tBuNH2.
(2S)-(4-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17g). Compound S-17g
was prepared following the procedure for compound S-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1194. 1H
NMR (DMSO-d6) δ 8.62 (br s, 2H), 7.69 (m, 2H), 7.37 (m, 1H),
7.18 (m, 1H), 7.11 (m, 1H), 6.98 (m, 1H), 6.61 (d, J = 7.84 Hz,
1H), 5.68 (d, J=5.84 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m,
1H), 2.88 (m, 1H), 2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
(2S)-(4-[3-(2,5-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17h). Compound S-17h
was prepared following the procedure for compound S-17i.
MS (ESI) m/z 383.6 ([M þ H]þ). HRMS: calcd for C17H19-
F2N3O3S þ Hþ, 384.1188; found (ESI, [M þ H]þ), 384.1194. 1H
NMR (DMSO-d6) δ 8.59 (br s, 2H), 7.60 (m, 3H), 7.18 (m, 1H),
7.12 (m, 1H), 6.98 (m, 1H), 6.68 (d, J=7.87 Hz, 1H), 5.67 (d, J=
6 Hz, 1H), 3.96 (m, 3H), 3.8 (s, 3H), 3.03 (m, 1H), 2.88 (m, 1H),
2.55 (m, 3H), 1.99 (m, 1H), 1.85 (m, 1H).
MS (ESI) m/z 390.2 ([M þ H]þ). HRMS: calcd for C20H27-
N3O3S þ Hþ, 390.1846; found (ESI, [M þ H]þ), 390.1850. 1H
NMR (DMSO-d6) δ 8.60 (br s, 1H), 8.40 (br s, 1H), 7.62 (m, 3H),
7.50 (m, 2H), 7.20 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.67 (d,
J=7.94 Hz, 1H), 5.62 (m, J=5.90 Hz, 1H), 3.97 (m, 3H), 3.05
(m, 1H), 2.83 (m, 1H), 2.07 (m, 1H), 1.90 (m, 1H), 1.29 (s, 9H).
1-(Dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothia-
diazol-1(3H)-yl)butan-2-ol (22). Compound 22 was prepared
following the procedure for compound 17b, replacing MeNH2
with Me2NH.
(2S)-(4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
1(3H)-yl]-1-(methylamino)butan-2-ol (S-17i). 6i (0.15 g, 0.5 mmol)
was dissolved in acetone (5 mL), and potassium carbonate (0.14 g,
1 mmol) was added followed by S(-)-4-bromo-1,2-epoxybutane
(0.15 g, 1 mmol). The mixture was stirred for 18 h at 50 °C in a
sealed vial and then diluted with EtOAc (100 mL) and washed with
MS (ESI) m/z 362.1 ([M þ H]þ). HRMS: calcd for C18H23-
N3O3S þ Hþ, 362.1533; found (ESI, [M þ H]þ), 362.1536. 1H
NMR (DMSO-d6) δ 9.41 (br s, 1H), 7.62 (m, 3H), 7.50 (m, 2H),
7.18 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.67 (d, J = 7.95 Hz,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11 4521
1H), 5.78 (m, J=6.15 Hz, 1H), 4.08 (m, 1H), 3.95 (m, 2H), 3.13
(m, 2H), 2.79(s, 6H), 1.96 (m, 1H), 1.86 (m, 1H).
Efficacious Norepinephrine Reuptake Inhibitors. J. Med. Chem.
2009, 52 (18), 5703–5711.
(11) McComas, C. C.; Vu, A. T.; Mahaney, P. E.; Cohn, S. T.; Fensome,
A.; Marella, M. A.; Nogle, L.; Trybulski, E. J.; Ye, F.; Zhang, P.;
Alfinito, P.; Bray, J.; Johnston, G.; Koury, E.; Deecher, D. C.
Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-
ones: a new class of selective norepinephrine reuptake inhibitors.
Bioorg. Med. Chem. Lett. 2008, 18, 4929–4931.
(12) This work shall be disclosed in a separate communication.
(13) Cruciani, G.; Carosati, E.; De Boeck, B.; Ethirajulu, K.; Mackie,
C.; Howe, T.; Vianello, R. MetaSite: Understanding Metabolism in
Human Cytochromes from the Perspective of the Chemist. J. Med.
Chem. 2005, 48, 6970–6979.
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
1-(methylamino)butan-2-one (23). 17b (90 mg, 0.25 mmol) and
di-tert-butyl dicarbonate (59 mg, 0.26 mmol) were stirred in
dichloromethane (5 mL) in a sealed vial at room temperature for
18 h. The reaction mixture was concentrated and then loaded
directly onto silica gel and purified via chromatography, pro-
viding a clear oil of which 50 mg (0.11 mmol) was stirred with
Dess-Martin periodinane (68 mg, 0.16 mmol) in dichloro-
methane (5 mL) in a sealed vial at room temperature for 18 h.
The reaction mixture was concentrated and then loaded directly
onto silica gel and purified via chromatography to afford a clear
oil, which was dissolved in diethyl ether/methanol. 4N HCl in
dioxane was added and a precipitate slowly formed. The reac-
tion was filtered to afford 23 mg of 23 as a white solid.
(14) Di, L.; Kerns, E. H.; Ma, X. J.; Huang, Y.; Carter, G. T. Applica-
tions of high throughput microsomal stability assay in drug
discovery. Comb. Chem. High Throughput Screening 2008, 11 (6),
469–476.
(15) This was used as a screening assay (n of 1) to rank compounds and
assess their potential for further characterization.
MS (ESI) m/z 346.0 ([M þ H]þ). HRMS: calcd for C17H19-
N3O3S þ Hþ, 346.1220; found (ESI, [M þ H]þ), 346.1223. 1H
NMR (DMSO-d6) δ 8.91 (br s, 2H), 7.61 (m, 3H), 7.50 (m, 2H),
7.20 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.67 (d, J = 7.94 Hz,
1H), 4.12 (m, 4H), 3.10 (m, 2H), 2.52(s, 3H).
(16) Gleeson, M. P. Generation of a Set of Simple, Interpretable
ADMET Rules of Thumb. J. Med. Chem. 2008, 51 (4), 817–834.
(17) Holbrook, M.; Malik, M.; Shah, R. R.; Valentin, J.-P. Drug induced
shortening of the QT/QTc interval: An emerging safety issue warrant-
ing further modelling and evaluation in drug research and develop-
ment? J. Pharmacol. Toxicol. Methods 2009, 59 (1), 21–28.
(18) Experimental protocols for in vivo pK work discussed was reported
in: Gavrin, L. K.; Mahaney, P. E.; Jenkins, D.; Nogle, L. M.;
Mugford, C. A.; Huselton, C.; Leiter, J.; Johnston, G. H.; Bray,
J. A.; Burroughs, K. D.; Cosmi, S. A.; Alfinito, P.; Ho, D. M.;
Deecher, D. C.; Trybulski, E. J., Discovery of WAY-260022, a
Potent and Selective Inhibitor of the Norepinephrine Transporter.
ACS Med. Chem. Lett. 2010, DOI: 10.1021/ml100009p.
Acknowledgment. We thank the Wyeth scientists whose
workcontributed tothe programdescribed inthis manuscript:
The Women’s Health & Musculoskeletal Biology and Neuro-
science departments provided assay data,the Chemical Tech-
nologies group provided stability data and performed chiral
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Supporting Information Available: Analytical HPLC purity
data is provided for all tested compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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