1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors

Article abstract of DOI:10.1021/jm901559e

Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3, 3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC₅₀= 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.

Full text of DOI:10.1021/jm901559e

J. Med. Chem. 2010, 53, 2051–2062 2051
DOI: 10.1021/jm901559e
1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake
Inhibitors
An T. Vu,*,† Stephen T. Cohn,† Puwen Zhang,† Callain Y. Kim,† Paige E. Mahaney,† Jenifer A. Bray,‡ Grace H. Johnston,‡
Elizabeth J. Koury,‡ Scott A. Cosmi,‡ Darlene C. Deecher,‡ Valerie A. Smith,§ James E. Harrison,§ Liza Leventhal,§
Garth T. Whiteside,§ Jeffrey D. Kennedy,§ and Eugene J. Trybulski†
†Chemical Sciences, and ‡Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, and §Neuroscience,
Wyeth Research, CN 8000, Princeton, New Jersey 08543
Received October 21, 2009
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple
indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaf-
fold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9).
Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3
position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the
serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring,
9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC50=2.7-6.5 nM) and excellent selectivity over
both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly
selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermo-
regulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal
nerve ligation (SNL) model of neuropathic pain.
Introduction
selective NRI, was approved for attention deficit hyperacti-
vitydisorder(ADHD),5 andracemic reboxetine (4), a selective
NRI, is marketed in Europe for the treatment of major
depressive disorder (MDD).6 In addition, recent studies sug-
gest other clinical implications for these two drugs in treating
chronic pain disorders such as fibromyalgia and low back
pain.7 Furthermore, dual acting serotonin and norepine-
phrine reuptake inhibitors (SNRI) such as venlafaxine (5)
and duloxetine (6) have emerged as another class of inhibitors
with improved antidepressant efficacy and/or faster onset of
action relative to SSRIs.8 Duloxetine has also demonstrated
efficacy in other therapeutic indications including neuro-
pathic pain7a,9 and stress urinary incontinence (SUI).10
Accordingly, considerable research efforts continue to focus
onthe development ofnovel therapeuticsthatinhibit reuptake
of norepinephrine.11,12
Biogenic monoamine neurotransmitters such as serotonin
(5-HTa), norepinephrine (NE), and dopamine (DA) play a
crucial role in various central nervous system (CNS) func-
tions, and deficiency in the levels of these neurotransmitters in
the brain has been implicated in the pathophysiology of a
variety of neuropsychiatric disorders.1 A strategy to enhance
monoaminergic neurotransmission is to inhibit reuptake after
release into the synaptic cleft by blocking presynaptic trans-
porters.2 Inhibition of monoamine reuptake has been an
effective pharmacological treatment for various CNS dis-
orders.3 Selective serotonin reuptake inhibitors (SSRI) such
as fluoxetine (1) and sertraline (2) have been widely prescribed
for depression (Figure 1). In recent years increasing efforts
have focused on norepinephrine reuptake inhibition, and to
date, two selective norepinephrine reuptake inhibitors (NRI)
have been in clinical use.4 Atomoxetine (3), a moderately
As part of our continuing interest to identify novel NRIs11
for multiple therapeutic utilities, we recently reported a series
of 3-(arylamino)-3-phenylpropan-2-olaminesasa new class of
SNRIs.11c Two compounds in this series, 7 with an ortho
methyl group on the phenylamino moiety and 8 with a meta
fluoro group on the phenyl ring, exhibited preferential affinity
for the norepinephrine transporter (NET) over the serotonin
transporter (SERT). Forming a ring between the ortho methyl
group and the N-methyl group of the phenylamino moiety
generated a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-
2-olamines 9 as potentiallyselectiveNRIs (Figure2). Explora-
tion of this new scaffold led to a number of compounds that
were potent and highly selective NRIs. Herein, we describe
the synthesis, structure-activity relationships (SAR) of the
1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines 9 and reveal
several lead compounds that displayed oral efficacy in various
*To whom correspondence should be addressed. Phone: 484-865-
8432. Fax: 484-865-9399. E-mail: vua@wyeth.com.
a Abbreviations: 5-HT, serotonin; ADHD, attention deficit hyper-
activity disorder; ANOVA, analysis of variance; CHO, Chinese hamster
ovary; cLogP, calculated octanol-water log P; CNS, central nervous
system; DA, dopamine; hDAT, human dopamine transporter; hNET,
human norepinephrine transporter; hSERT, human serotonin transpor-
ter; ip, intraperitoneal; JAR, human placental choriocarcinoma cell;
MDCK, Madin-Darby canine kidney; MDD, major depressive dis-
order; NE, norepinephrine; NET, norephinephrine transporter; NRI,
norepinephrine reuptake inhibitor; OVX, ovariectomized; po, oral;
PPQ, p-phenylquinone; SAR, structure-activity relationship; SEM,
standard error of the mean; SERT, serotonin transporter; SNL, spinal
nerve ligation; SNRI, serotonin and norepinephrine reuptake inhibitor;
SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake
inhibitor; SUI, stress urinary incontinence; TST, tail-skin temperature;
VMS, vasomotor symptoms.
r
2010 American Chemical Society
Published on Web 02/02/2010
pubs.acs.org/jmc

2052 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Vu et al.
with excellent enantioselectivity (>96% ee). The thermal17 or
titanium tetraisopropoxide18 induced epoxide ring-opening
reaction of 17 by 13 occurred stereospecifically and regiose-
lectively at the C3 position of 17 to provide (2S,3S)-diols 18.19
Selective tosylation of the primary hydroxyl group followed
by displacement of the tosylate with excess methylamine
furnished (1S,2R)-amines 9.19 Finally, amines 9 were con-
verted to their hydrochloride salts prior to biological evaluation.
Results and Discussion
As mentioned, the new 1-(indolin-1-yl)-1-phenyl-3-propan-
2-olamine series (9) was investigated as single (1S,2R)-enan-
tiomers. The 1S,2R stereochemistry was chosen on the basis
of the stereochemical preference that was established in
a closely related 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-
2-ol series.11b In addition, the secondary N-methylamine
group was selected as the side chain amino moiety of 9, since
it provided the optimal norepinephrine reuptake inhibition
in the related 3-(arylamino)-3-phenylpropan-2-olamine and
1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series.11b,c
The 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines 9 were
initially evaluated in vitro for their ability to inhibit the uptake
of norepinephrine in MDCK-Net6 cells stably transfected
with human norepinephrine transporter (hNET), and seroto-
nin in JAR cells natively expressing the human serotonin
transporter (hSERT). A small selected group of compounds
were also tested for their inhibition of [3H]nisoxetine binding
to MDCK-Net6 cells stably transfected with hNET. Com-
pounds were further evaluated for their inhibition of
[3H]WIN-35428 radioligand binding to the human dopamine
transporter (hDAT). Detailed experimental protocols for
these inhibitory assays were reported previously.11f Results
of the in vitro screening are presented in Table 1.
Figure 1. Chemical structures of known monoamine reuptake
inhibitor drugs.
The unsubstituted 1-(indolin-1-yl)-1-phenyl-3-propan-2-
olamine 9a displayed high norepinephrine reuptake inhibition
(hNET IC50 =9.7 nM), demonstrating the potential of this
new series as potent NRIs. Surprisingly, 9a also exhibited
significant serotonin reuptake inhibition, thus engendering a
low selectivity for hNET over hSERT. Introduction of a
m-fluoro group on phenyl ring (9b) led to a subtle increase
in both the hNET potency and selectivity. A similar enhance-
ment effect has been observed in other closely related
series.11a,c Consequently the SAR of the indoline ring was
investigated while maintaining the m-fluorophenyl group
constant. Incorporating a small substituent such as methyl,
ethyl, isopropyl, chloro, or benzyloxy group at various posi-
tions of the indoline ring (9c-j) offered essentially no further
improvement on the hNET potency relative to their unsub-
stituted congener 9b. A few analogues, 9d and 9g,h, however
showed comparable norepinephrine reuptake inhibition to
that of 9b. In contrast, indoline ring substitution exerted
marked effects on the hSERT potency. For example, the
5-chloro group substantially increased the hSERT potency
(versus 9b) while maintaining NE reuptake inhibition, thus
rendering compound 9h a potent SNRI exhibiting single-digit
nanomolar IC50 values at both hNET and hSERT. Conver-
sely, methyl substitution at the C3 position (9d) caused a
significant decrease in the inhibitory activity for serotonin but
not for norepinephrine, thus resulting in greater than 50-fold
selectivity for hNET over hSERT. This selectivity enhance-
ment was consistent with that observed in the closely related
1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series.11a
Separating 9d into its enantiomers, 9d isomers 1 and 2, or
elongating the C3 alkyl substituent from methyl to ethyl (9e)
Figure 2. Designing novel 1-(indolin-1-yl)-1-phenyl-3-propan-2-
olamine series 9.
predictive animal models of noradrenergic-related CNS dis-
orders.
Chemistry
All 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines 9 in
Table 1 were prepared as single (1S,2R)-enantiomers according
to Scheme 1. The synthesis features a regioselective and
stereospecific epoxide ring-opening reaction of optically
pure (R,R)-3-phenylglycidols 17 by indolines 13 as the key
synthetic step. The 3,3-disubstituted indolines were pre-
pared by double C3-alkylation of oxindoles 1013 followed
by reduction of the resulted 3,3-disubstituted oxindoles 11
using sodium bis(2-methoxyethoxy)aluminum hydride.14
All other substituted indolines either were commercially
available or were prepared by reduction of the correspond-
ing indoles 12 using sodium cyanoborohydride.15 The
unsubstituted (R,R)-3-phenylglycidol was commercially avail-
able, whereas fluorine-substituted (R,R)-3-phenylglycidols
were prepared from fluorine-substituted trans-cinnamic
acids 14. Thus, O-methylation of the carboxylic acid group
of 14 (R3=3-F and 3,5-di-F) followed by reduction of the
resulted methyl trans-cinnamate esters 15 using diisobutyl-
aluminium hydride provided trans-cinnamyl alcohols 16.
Subsequent Sharpless asymmetric expoxidation reaction16
of 16 furnished fluorine-substituted (R,R)-3-phenylglycidols

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2053
Table 1. Inhibitory Activity of the 1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines 9 at the Human Monoamine Transporters
hNET uptake hNET binding hSERT uptake (hSERT IC50)/ hDAT binding % inh
d
compd
R1
R2
R3
IC50 (nM)a
IC50 (nM)b
IC50 (nM)c
(hNET IC50
)
at 1 μMe (IC50 nM) cLogPf
reboxetine (4)
9a
3.2 ( 1.0
9.7 ( 0.9
4.6 ( 0.4
72 ( 42
6.2 ( 0.9
8.5 ( 6.4
3.7 ( 0.1
14 ( 1.9
23 ( 16
2.3 ( 2.4
7.6 ( 10
15 ( 3.6
170 ( 114
6.3 ( 2.1
150 ( 16
21 ( 2.4
39 ( 50
242 ( 39
29 ( 4.2
21 ( 2.5
84 ( 75
329 ( 10
154 ( 88
194 ( 40
499 ( 62
1123 ( 1006
5.5 ( 7.2
2.8 ( 3.9
813 ( 606
280 ( 78
4519 ( 565
8971 ( 990
1969 ( 642
4917 ( 4095
2871 ( 408
5293 ( 498
364 ( 281
4992 ( 5723
1099 ( 350
1614 ( 348
76
H
H
H
H
H
H
H
H
H
H
3.0
4.5
1.2
53
8
14
2.8
2.9
3.5
3.5
3.5
3.5
4.0
4.4
3.4
3.8
4.7
3.4
4.0
5.0
4.4
4.9
3.8
4.1
4.3
4.3
4.1
4.3
9b
9c
H
3-F
3-F
3-F
3-F
3-F
3-F
3-F
2-Me
3-Me
3-Me
3-Me
3-Et
3-i-Pr
H
33
9d
9d-isomer 1
9d-isomer 2
0
23
18
51
10
20
9e
9f
35
49
31
2
9g
9h
9i
5-Me 3-F
5-Cl 3-F
2.4
0.4
54
H
4
45
H
5-OBn 3-F
7-Me 3-F
9j
H
1.6
717
60
2
9k
9l
3,3-di-Me
3,3-di-Et
H
3-F
3-F
3-F
3-F
H
2.6 ( 0.6
4.1 ( 0.9
0
H
3
9m
9n
9o
9p
9q
9r
9s
9t
3,3-cyclopentyl
3,3-cyclohexyl
3,3-di-Me
3,3-di-Me
3,3-di-Me
3,3-di-Me
3,3-di-Me
3,3-di-Me
H
92
2
39
H
136
504
814
19
H
5.7 ( 1.0
6.5 ( 2.4
19 ( 13
17 ( 3.5
2.7 ( 1.0
5.5 ( 1.8
18
H
3,5-di-F
3-F
3-F
H
4
14
5-F
6-F
7-F
7-F
294
407
293
22
7 (20927)
2 (22834)
1.6 ( 0.03
1.4 ( 1.7
3-F
a Inhibition of norepinephrine uptake in MDCK-Net6 cells stably transfected with 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 (IC50 = 3.3 ( 1.1 nM) was used as a standard.
c Inhibition of serotonin uptake in JAR cells natively expressing hSERT. Fluoxetine (IC50 = 9.4 ( 3.1 nM) was used as a standard. d Unitless value as a
ratio of (hSERT uptake IC50)/(hNET uptake IC50) in which higher values represent greater NET selectivity, a value of 1 represents no selectivity, and
values approaching 0 represent SERT selectivity. e Inhibition of [3H]WIN-35,428 binding to membranes from CHO cells expressing recombinant hDAT.
Mazindol (IC50 = 22 ( 6.5 nM) was used as a standard. Values in the parentheses are IC50 (nM). f Calculated log P by Daylight engine, version 4.81.
Scheme 1. Synthesis of (1S,2R)-1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines 9a
a Reagents and conditions: (a) n-BuLi, LiCl, THF, 0 °C, then R1-I, room temp, 16 h, 41-50%; (b) Red-Al, toluene, 80 °C, 1 h, 79-93%; (c)
NaBH3CN, AcOH, 71-96%; (d) MeI, Cs2CO3, acetone, 65 °C, 1.5 h, 97-99%; (e) DIBAL-H, CH2Cl2, -78 to -30 °C, 1 h, 90-95%; (f) t-BuOOH, (-)-
ꢀ
˚
DIPT, Ti(O-i-Pr)4, 4 A molecular sieves, CH2Cl2, -25 °C, 70-90%, >96% ee; (g) 110 °C, neat, 5 h, 55-93%; (h) Ti(O-i-Pr)4, CH2Cl2, 0 °C to room
temp, 12 h, 74-82%; (i) p-TsCl, TEA, CH2Cl2, 0 °C to room temp, 5 h, then CH3NH2, EtOH, sealed tube, room temp, 12 h, 17-73%.
or isopropyl (9f) group showed no improvement on the hNET
selectivity versus 9d. However, a geminal dimethyl group at
the C3 position caused a drastic reduction in the 5-HT
reuptake inhibition while preserving the hNET potency, thus

2054 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Vu et al.
engendering compound 9k a potent and highly selective NRI
(hNET IC50=6 nM with greater than 700-fold selective over
hSERT). The remarkable selectivity enhancement of 9k
prompted ustofocuson the C3dialkyl substitution. However,
larger geminal dialkyl groups such as diethyl (9l), cyclopentyl
(9m), and cyclohexyl (9n) lowered both hNET potency and
selectivity relative to 9k. Exploring other 3,3-dimethyl ana-
logues (9o-t) by fluorine modification of the phenyl ring and/
or the indoline ring led to several other analogues (9o,p
and 9s,t) with similar inhibitory activities as that of 9k.
Compounds 9k, 9o,p, and 9s,t exhibited potent inhibition of
hNET(IC50=2.7-6.5nM) andgreater than290-fold selective
Table 2. Effects of 9k, 9o,p, and 9s,t in the Telemetric Rat Model of
Ovariectomized-Induced Thermoregulatory Dysfunctiona
mean
oral dose onset of duration of reduction
maximun
reduction
compd (mg/kg) activity (h) action (h) in TST (°C) in TST (°C)
9o
9k
9p
9s
9t
10
10
10
10
10
30
1
2.5
6.5
-1.84
-2.14
-2.69
-2.52
-2.08
-2.16
-2.01
-2.75
-4.04
-3.77
-3.27
-3.15
0.5
0.5
1
8.5
7
1
>11.5
3
19
1
a Compounds were dosed orally in 2% Tween-0.5% methylcellu-
lose (vehicle). 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 will be considered to have ended when two con-
secutive nonsignificant half-hour intervals follow any number of
significant half-hour intervals. Mean temperature change is calcu-
lated from half-hour TST averages obtained over the treatment
duration.
over hSERT, with 9s being the most potent (hNET IC50
=
2.7 nM) and 9p the most selective (814-fold).
A small selected group of compounds were also evaluated
for their ability to bind to hNET, and generally their binding
affinities were in good agreement with their hNET functional
potencies. The 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines
were further evaluated for their dopamine transporter
binding affinity. Overall, the compounds were found to be
weak ligands for hDAT (e45% inhibition at 1 μM), indicat-
ing high selectivity over the dopamine transporter. Com-
pounds 9s,t displayed 1.4-1.6 nM hNET binding IC50
versus greaterthan 20μMhDAT bindingIC50, demonstrating
complete hNET selectivity against hDAT. The most selective
compounds, 9k, 9o,p, and 9s,t, were also found to be weak
ligands for the 5-HT2B, dopamine D2, R1-adrenergic (<40%
inhibition at 10 μM), and 5-HT6 (<40% inhibition at 5 μM)
receptors.
maximum temperature reduction of -4.0 °C. Despite their
similar hNET potencies (IC50 = 2.7-6.5 nM), analogues
9k, 9p, and 9s,t bearing fluorine substitution on the indo-
line ring and/or phenyl ring achieved considerably greater
maximum TST reduction and longer duration of action than
their des-fluoro congener 9o. Furthermore, compounds 9p
and 9s at 10 mg/kg po were substantially more effica-
cious in both TST reduction and duration than the previ-
ously reported cyclohexanol ethylpiperazine derivative 19, at
30 mg/kg po.11f
A number of neurotransmitters, peptides, and ion channel
modulators have been implicated in the modulation of noci-
ceptive processing. NE and 5-HT are major components of
the endogenous descending pain inhibitory system from the
rostral ventral medulla to the spinal cord.27 It has been
suggested that altered or decreased activity of endogenous
NE and 5-HT at both the spine and supraspine may in part
lead to chronic pain.28 Consequentially, it is presumed that
NRIs and SRIs can attenuate pain by blocking reuptake of
NE/5-HT leading to increased postsynaptic NE/5-HT levels
and sustained activation of the descending pain inhibitory
pathway.29 However, clinical evidence suggests that com-
pounds with greater NRI versus SRI activity would be more
effective for the treatment of pain than those with only SRI
activity.30 This observation was also supported by preclinical
data.31 In addition to small molecules, the conopeptide
Xen2174, a structuralanalogue of Mr1A anda highlyselective
NRI, reversed tactile allodynia following intrathecal admin-
istration to neuropathic rats.32 Accordingly, the most hNET
selective 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamine 9p
was selected to be evaluated in models of acute visceral and
neuropathic pain to examine its antinociceptive effects.
Detailed experimental protocols for these two pain models
were reported previously.33
Compounds 9k, 9o,p, and 9s,t exhibit desirable druglike
properties that are favorable for CNS penetration.20 These
include moderate lipophilicity (cLogP=3.8-4.3), low mole-
cular weights (310-346), and low polar surface area (TPSA=
2
˚
36 A ). Consequently, they were selected for further in vivo
characterization.
Neurotransmitters NE and 5-HT are thought to play an
important role in the maintenance of temperature home-
ostasis in the hypothalamus, and alterations or reductions in
the levels of these neurotransmitters have been implicated in
thermoregulatory dysfunction that causes vasomotor symp-
toms (VMS) such as hot flushes.21 Clinical studies have
demonstrated the efficacy of paroxetine22 (an SSRI), venla-
faxine,23 and desvenlafaxine succinate24 (SNRIs) in allevia-
ting hot flushes, suggesting that these drugs may provide
effective nonhormonal therapies for the treatment of
VMS.25 Furthermore, we recently reported a selective NRI,
WAY-256805 (19), from a series of cyclohexanol ethylpipera-
zines that alleviated thermoregulatory dysfunction in a pre-
clinical rodent model of temperature regulation.11f The ability
of a compound to restore the lowering of the tail-skin
temperature (TST) during the dark phase in the rat model
of ovariectomized (OVX) induced thermoregulatory dysfunc-
tion suggests efficacy toward alleviating vasomotor symp-
toms.21b Accordingly, potent and highlyselectiveNRIs9k, 9o,
p, and 9s,t were evaluated in this model26,11f for their effects on
temperature homeostasis. An oral dose of 10 mg/kg (com-
pared to 30 mg/kg po dose for 19) was selected because these
compounds were more potent at hNET (IC50=2.7-6.5 nM)
than 19 (IC50 = 82 nM). As shown in Table 2, all five
compounds were orally efficacious and significantly reduced
TST with maximum temperature reduction between -2 to
In the mouse p-phenylquinone (PPQ) model of acute
visceral (abdominal) pain,34 PPQ administered via intra-
peritoneal (ip) injection acts as a localized irritant resulting
in an abdominal constriction response (i.e., writhing) that can
be quantified. The ability of a compound to reduce the
number of abdominal constrictions suggests efficacy toward
attenuating visceral pain. As shown in Figure 3, compound 9p
was orally efficacious at 30 mg/kg and significantly reduced
the number of PPQ-induced abdominal constrictions relative
to vehicle (p < 0.05, ANOVA), with peak effects observed
-4 °C. Note that compound 9p, a potent (hNET IC50
=
6.5 nM) and the most selective NRI among the 1-(indolin-
1-yl)-1-phenyl-3-propan-2-olamines, displayed the highest

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2055
reversal of pain behavior at only 30 mg/kg, the highest dose
tested.
Conclusion
Ring constraint of the previous 3-(arylamino)-3-phenyl-
propan-2-olaminescaffold ledtoa novelseries of 1-(indolin-1-
yl)-1-phenyl-3-propan-2-olamines 9. The compounds in this
class ranged from potent SNRI (9h) to potent and selective
NRIs (9k, 9o,p, and 9s,t) depending on the indoline ring
substitution. Moreover, the weak dopamine binding affinity
of this series indicated high selectivity over the dopamine
transporter. Compounds 9k, 9o,p, and 9s,t, bearing a 3,3-
dimethyl group on the indoline ring, exhibited low nanomolar
hNET potency (hNET IC50 = 2.7-6.5 nM) and excellent
selectivity over hSERT (superior to that of reboxetine 4) and
hDAT. The best analoguefromthis series, 9p, a potent (hNET
IC50=6.5nM) andhighlyselectiveNRI, was orallyefficacious
in a rat thermoregulatory dysfunction model, a mouse PPQ
model of acute visceral pain, and a rat SNL model of neuro-
pathic pain. These preclinical data suggest the potential
efficacy of 9p in alleviating vasomotor symptoms as well as
attenuating acute and neuropathic pain.
Figure 3. Effect of 9p in the mouse PPQ model of acute visceral
pain. Male CD-1 mice (weight 25-30 g, 10/group) were used.
Compound 9p and S-duloxetine (6) were administered orally at
30 mg/kg as a suspension in 2% Tween-0.5% methylcellulose
(vehicle). Data shown are the mean ( SEM for each dose (N =
10 per group). The asterisk (/) indicates a p value of e0.05 vs
vehicle-treated mice (ANOVA).
Experimental Section
Indoline, 2-methylindoline, 5-methylindoline, 5-chloroindo-
line, 5-benzyloxyindoline, 7-methylindoline, and (2R,3R)-3-phe-
nylglycidol were purchased from commercial sources. 3,3-
Dimethylindoline, 3,3-diethylindoline, 10,20-dihydrospiro[cyclo-
pentane-1,30-indole], and 10,20-dihydrospiro[cyclohexane-1,30-in-
dole] were prepared according to literature procedure.14 All
reaction reagents and solvents (anhydrous grade) were purchased
1
and were used without further purification. H NMR spectra
were recorded on a Varian INOVA 400 or a Varian INOVA 500
instrument. Chemical shifts are reported in δ values (parts per
million, ppm) relativeto an internal standard 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. Electron impact ionization
(EI, EE=70 eV) mass spectra were recorded on a Finnigan Trace
mass spectrometer. Analytical thin-layer chromatography (TLC)
was carried out on precoated plates (silica gel, 60 F-254), and
spots were visualized with UV light or staining with a solution of
phosphomolybdic acid in ethanol or potassium permanganate in
water. 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. Compound purity was
determined by analytical HPLC method, which was performed
on an Agilent 1100 HPLC instrument using photodiode array
detection (210-370 nm), a Waters Xterra RP18 HPLC column
(150 mm length ꢀ 4.6 mm i.d., 3.5 μm), 40 °C column oven
temperature, 1.2 mL/min flow rate, linear mobile phase gradient
of 15% to 95% B over 10 min, holding 5 min at 95% B (mobile
phase A is10 nM ammonium formate in water, pH 3.5; mobile
phase B is 1:1 methanol/acetonitrile). Biological results were
obtained on compounds of >95% chemical purity as determined
by the above HPLC method.
Figure 4. Effect of 9p in the SNL-induced mechanical hyperalgesia.
Male Sprague-Dawley rats (weight 235-300 g, 8-9/group) were
used 3 weeks postsurgery. Threshold to paw withdrawal was
measured. Compound 9p and S-duloxetine (6) were administered
orally as a solution in 2% Tween-0.5% methylcellulose (vehicle).
Gabapentin was used as a positive control and administered (ip) as a
solution in 0.9% saline. Data shown are the mean ( SEM. The
asterisk (/) indicates a p value of e0.05 vs SNL/vehicle (ANOVA).
following a 30 min pretreatment. The magnitude of effect was
greater for 9p compared to the clinical comparator S-dulo-
xetine (6) when administered at the same dose with a 60 min
pretreatment.
Compound 9p was also evaluated in a rat spinal nerve
ligation (SNL) model of neuropathic pain. Briefly in this
model,35 nerve injury was produced by tight ligation of the
left L5 spinal nerve. Assessment of mechanical thresholds was
measured as the hind paw withdrawal threshold to a noxious
mechanical stimulus as determined using the paw pressure
technique (Randall-Selitto). The cutoff was set at 250 g and
the end point taken as complete paw withdrawal. Thresholds
were evaluated prior to surgery and reassessed 3-4 weeks
after SNL surgery. The ability of a compound to reverse SNL-
induced mechanical hyperalgesia predicts efficacy toward
attenuating neuropathic pain. As shown in Figure 4, com-
pound 9p significantly and dose-dependently reversed
mechanical hyperalgesia at doses of 10 and 30 mg/kg po.
In contrast, S-duloxetine provided a statistically significant
General Methods for the Synthesis of 1-(Indolin-1-yl)-1-phenyl-
3-propan-2-olamines (9). Method a: Double C3-Alkylation of
Oxindoles 10.13 To a mixture of 5-fluorooxindole (2.000 g,
13.23 mmol) and lithium chloride (1.39 g, 33.0 mmol) in tetra-
hydrofuran (40 mL) at 0 °C was added dropwise n-butyllithium
(2.5 M in hexanes, 10.6 mL, 26.5 mmol, 2 equiv), and the mixture
was stirred for 20 min. Iodomethane (1.65 mL, 26.5 mmol, 2
equiv) was added slowly, and the mixture was stirred at 0 °C for
2 h, then at ambient temperature for 16 h. The reaction was
quenched with a saturated aqueous solution of ammonium

2056 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Vu et al.
chloride, diluted with ethyl ether, and washed with water and
brine. The organic layer was dried (anhydrous magnesium
sulfate), filtered, and concentrated. The residue was purified
by Isco silica gel chromatography (0-50% ethyl acetate/
hexane) to give 3,3-dimethyl-5-fluorooxindole (11a) as white
crystals. Yield: 1.18 g (50%).
addition funnel. The resulting mixture was stirred at -25 °C for
30 min. trans-3-Fluorocinnamyl alcohol (16a, 25.0 g, 164 mmol)
in dry dichloromethane (50 mL) was added dropwise via an
addition funnel while maintaining the temperature at -25 °C.
After the addition, the reaction mixture was stirred at -25 °C for
another 3 h. After the reaction was complete, cooled 30%
aqueous sodium hydroxide solution (20 mL) saturated with
sodium chloride was added slowly at -25 °C. Diethyl ether
(150 mL) was added. The cold bath was removed, and the
mixture was allowed to warm to ∼5 °C and stirred for 1 h.
Magnesium sulfate (anhydrous, 50 g) was added and the mixture
stirred for 20 min, then filtered through a pad of silica gel and
rinsed with diethyl ether. The filtrate was concentrated, and
toluene was used to azeotropically remove excess tert-butyl
hydroperoxide. The residual oil was purified on silica gel
(0-30% ethyl acetate/hexane) to give (2R,3R)-3-(3-fluorophe-
nyl)glycidol (17a) as a viscous, colorless oil. Yield: 24.40 g (90%,
96.5% ee).
Method g: Thermally Induced Epoxide Ring-Opening of (R,R)-
3-Phenylglycidols 17. A mixture of 3,3-dimethylindoline14 (5.89
g, 40.0 mmol) and (2R,3R)-3-phenylglycidol (6.00 g, 40.0 mmol)
was heated neat at 110 °C for 5 h in a sealed reaction vessel.
When the mixture was cooled, the crude product was dissolved
in ethyl acetate, absorbed on Fluorocil, and purified by Isco
column chromatography (silica, 0-60% ethyl acetate/hexane)
to give (2S,3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-
phenylpropane-1,2-diol (18o) as a viscous amber liquid. Yield:
11.02 g (93%). Chiral purity: 99.9% (99.8% ee).
Method h: Ti(O-i-Pr)4-Induced Epoxide Ring-Opening of
(R,R)-3-Phenylglycidols 17. To a solution of (2R,3R)-3-phenyl-
glycidol (9.01 g, 60 mmol) in dichloromethane (80 mL) under
nitrogen was added titanium(IV) isopropoxide (19.3 mL, 66
mmol, 1.1 equiv) slowly via a syringe, and the mixture was stirred
for 15 min at room temperature. After the mixture was cooled to
0 °C in an ice bath, 7-fluoro-3,3-dimethylindoline (13f, 9.91 g, 60
mmol) was added small-portionwise and the mixture was stirred
overnight while warming to room temperature. The reaction
mixture was poured into aqueous hydrochloric acid solution
(2 N, 400 mL) and then extracted with ethyl acetate (2 ꢀ 200 mL).
The combined organic extracts were washed with water, brine,
then dried (anhydrous sodium sulfate), filtered, and concen-
trated. The crude brown liquid was purified by silica gel chroma-
tography (10-70% ethyl acetate/hexane) to give pure (2S,3S)-
3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenyl-
propane-1,2-diol (18s) as an ivory foam. Yield: 15.55 g (82%).
Method i: Tosylation and Amination of Diols 18. To a solution
of (2S,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-phenylpropane-1,2-diol (18s, 13.63 g, 43.22 mmol) in dichloro-
methane (150 mL) under nitrogen was added triethylamine (15.2
mL, 109 mmol), and the mixture was cooled to 0 °C in an ice bath.
p-Toluenesulfonyl chloride (11.13 g, 58.35 mmol) was added small-
portionwise, and the mixture was stirred at 0 °C for 1 h and then at
room temperature for 5 h. Methylamine (33 wt % in ethanol,
200 mL) was added, and the mixture was stirred at room
temperature overnight. All volatiles were removed, and the
resulting liquid residue was dissolved in ethyl acetate (300 mL).
This solution was washed with aqueous potassium carbonate
solution, water, brine, then dried (anhydrous sodium sulfate),
filtered, and concentrated. The crude liquid was purified by Isco
silica gel chromatography (0-20% methanol/dichloromethane
with added 1% triethylamine) to give a viscous, colorless liquid.
To a solution of this free base in ethanol (50 mL) was added a
solution of hydrochloric acid (1.0 M in ethyl ether, 30 mL)
slowly with stirring. Isopropyl ether was added until the
mixture became slightly cloudy and then cooled to -25 °C
overnight. The white precipitate formed was collected by
decatation, washed with isopropyl ether, and dried in vacuo
to give (1S,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-(methylamino)-1-phenylpropan-2-ol hydrochloride (9s). Yield:
8.44 g (54%).
Method b: Red-Al Reduction of 3,3-Disubstituted Oxindoles
11.14 A mixture of 3,3-dimethyl-7-fluorooxindole (11c, 23.30 g
130 mmol) in toluene (250 mL) under nitrogen was heated at
80 °C. A solution of sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al, 65 wt % in toluene, 63 mL, 202 mmol) in
toluene (75 mL) was added dropwise via an addition funnel. The
resulting solution, which turned from light-yellow to dark-
brown, was stirred at 80 °C for an additional 1 h, then cooled
in an ice bath. Aqueous sodium hydroxide solution (1 N, 80 mL)
was added slowly to quench the reaction. The reaction mixture
was diluted with toluene (100 mL) and then washed with water
(200 mL), brine, dried (anhydrous sodium sulfate), filtered
through a pad of Celite, and concentrated under reduced
pressure to give 7-fluoro-3,3-dimethylindoline (13f) as a brown
solid. Yield 19.89 g (93%).
Method c: NaBH3CN Reduction of Substituted Indoles 12.15
To a solution of 3-methylindole (5.25 g, 40.0 mmol) in glacial
acetic acid (15 mL) at 0 °C was added portionwise sodium
cyanoborohydride (5.03 g, 80.0 mmol, 2 equiv), and the mixture
was stirred for 2 h at room temperature. After cooling in an ice
bath, the reaction mixture was diluted with water (100 mL) and
basified with 40% aqueous NaOH, then extracted with dichloro-
methane (2 ꢀ 100 mL). The combined organic extracts were dried
(anhydrous sodium sulfate), filtered through a pad of silica gel, and
concentrated to give 3-methylindoline (13a) as a colorless liquid
which was used in subsequent reactions without further purifica-
tion. Yield: 5.12 g (96%).
Method d: Esterification of trans-Cinnamic Acids 14. To a
mixture of trans-3-fluorocinnamic acid (62.69 g, 377 mmol) and
iodomethane (100 mL) in acetone (600 mL) was added portion-
wise cesium carbonate (150 g, 460 mmol, 1.2 equiv), and the
mixture was heated at 65 °C for 1.5 h in a sealed reaction vessel.
Upon cooling to room temperature, the reaction mixture was
filtered through a pad of silica gel, rinsed with ethyl acetate, and
concentrated to give trans-3-fluorocinnamic acid methyl ester
(15a) as a colorless oil. Yield: 66.17 g (97%).
Method e: DIBAL-H Reduction of trans-Cinnamate Esters 15.
To a solution of trans-3-fluorocinnamic acid methyl ester (15a,
69.61 g, 386 mmol) in dry dichloromethane (1 L) at -78 °C
under nitrogen was added dropwise diisobutylaluminum
hydride (neat, 172 mL, 965 mmol, 2.5 equiv) via an addition
funnel. After the addition was complete, the reaction mixture
was allowed to warm to -30 °C and stirred for an additional 1 h,
then quenched with methanol (150 mL). Upon warming to room
temperature, the reaction mixture was treated with a saturated
aqueous solution of sodium/potassium tartrate (300 mL) and
stirred for 30 min. The organic layer was washed sequentially
with 1 N aqueous hydrochloric acid solution, saturated aqueous
sodium bicarbonate solution, brine, then dried (anhydrous
sodium sulfate), filtered, and concentrated. The crude oil was
purified by silica gel chromatography (0-50% ethyl acetate/
hexane) to give trans-3-fluorocinnamyl alcohol (16a) as a color-
less oil. Yield: 53.07 g (90%).
Method f: Sharpless Asymmetric Expoxidation of trans-
Cinnamyl Alcohols 16.16 An oven-dried, three-neck, 2 L
round-bottom flask fitted with two oven-dried addition funnels
and a rubber septum was charged with diisoproyl D-tartrate
˚
(11.55 g, 49.3 mmol, 0.30 equiv), 4 A activated molecular sieves
powder (40 g), and dry dicloromethane (800 mL) under nitro-
gen. After the mixture was cooled to -25 °C, titanium isoprop-
oxide (9.6 mL, 33 mmol, 0.20 equiv) was added slowly via a
hypodermic syringe. After the mixture was stirred for 10 min,
anhydrous tert-butyl hydroperoxide (5.5 M in decane, 75.0 mL,
413 mmol, 2.5 equiv) was added at a moderate rate via an

Article
3,3-Dimethyl-5-fluorooxindole (11a). This compound was
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2057
trans-3-Fluorocinnamyl Alcohol (16a). This compound was
prepared as described in method e. Colorless oil. Yield: 90%. 1H
NMR (400 MHz, CDCl3): δ 1.49 (t, J=5.6 Hz, 1H), 4.34 (t, J=
4.5 Hz, 2H), 6.37 (td, J=15.9, 5.5 Hz, 1H), 6.60 (d, J=15.9 Hz,
1H), 6.93 (ddt, J=8.7, 2.6, 0.7 Hz, 1H), 7.08 (ddd, J=10.1, 2.2,
1.7 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.27 (td, J=7.9, 6.0 Hz,
1H). MS (ES) m/z 152.0 (Mþ).
prepared as described in method a. White crystals. Yield: 1.18
g (50%). 1H NMR (400 MHz, DMSO-d6): δ 1.25 (s, 6H), 6.82
(dd, J=8.5, 4.4 Hz, 1H), 6.98 (ddd, J=9.7, 8.5, 2.7 Hz, 1H), 7.24
(dd, J=8.6, 2.7 Hz, 1H), 10.32 (s, 1H). HRMS (ESI): m/z calcd
for [C10H10FNO þ H]þ, 180.0825; found, 180.0832.
3,3-Dimethyl-6-fluorooxindole (11b). This compound was
prepared from 6-fluorooxindole according to method a. Yellow-
ish solid. Yield: 41%. 1H NMR (400 MHz, DMSO-d6): δ 1.24 (s,
6H), 6.65 (dd, J=9.4, 2.4 Hz, 1H), 6.75 (m, 1H), 7.29 (dd, J=8.2,
5.6 Hz, 1H), 10.45 (s, 1H). HRMS (EI): m/z calcd for
[C10H10FNO]þ, 179.0746; found, 179.0742.
trans-3,5-Difluorocinnamyl Alcohol (16b). This compound
was prepared from trans-3,5-difluorocinnamic acid methyl ester
(15b) according to method e. Colorless oil. Yield: 95%. 1H
NMR (400 MHz, CDCl3): δ 1.52 (t, J=5.7 Hz, 1H), 4.35 (t, J=
5.2 Hz, 2H), 6.37 (td, J=15.9, 5.2 Hz, 1H), 6.56 (d, J=15.9 Hz,
1H), 6.68 (tt, J=8.9, 2.2 Hz, 1H), 6.88 (dd, J=8.6, 2.0 Hz, 2H).
MS (ES) m/z 153.1 [M þ H - H2O]þ).
3,3-Dimethyl-7-fluorooxindole (11c). This compound was
prepared from 7-fluorooxindole according to method a. White
1
solid. Yield: 48%. H NMR (400 MHz, DMSO-d6): δ 1.26 (s,
(2R,3R)-3-(3-Fluorophenyl)glycidol (17a). This compound
was prepared as described in method f. Colorless liquid. Yield:
6H), 6.97 (m, 1H), 7.07 (ddd, J=10.4, 8.4, 0.9 Hz, 1H), 7.14 (dd,
J=7.3, 0.9 Hz, 1H), 10.81 (s, 1H). HRMS (ESI): m/z calcd for
[C10H10FNO þ H]þ, 180.0825; found, 180.0831.
1
90%. Percent ee: 96.5%. H NMR (400 MHz, CDCl3): δ 1.77
(dd, J=7.9, 5.2 Hz, 1H), 3.18 (m, 1H), 3.81 (ddd, J=13.8, 7.9, 3.7
Hz, 1H), 3.93 (d, J=2.0 Hz, 1H), 4.05 (ddd, J=12.8, 5.1, 2.3 Hz,
1H), 6.98 (m, 2H), 7.10 (m, 1H), 7.31 (m, 1H). MS (ESI) m/z
169.1 ([M þ H]þ).
3-Methylindoline (13a). This compound was prepared as
described in method c. Colorless liquid. Yield: 5.12 g (96%).
1H NMR (400 MHz, CDCl3): δ 1.32 (d, J=6.9 Hz, 3H), 3.11 (t,
J=8.6 Hz, 1H), 3.37 (m, 1H), 3.70 (t, J=8.6 Hz, 1H), 3.68-3.71
(br, 1H), 6.64 (d, J=7.7 Hz, 1H), 6.73 (dt, J=7.4, 0.9 Hz, 1H),
7.02 (dt, J = 7.7, 0.8 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H).
HRMS (ESI): m/z calcd for [C9H11N þ H]þ, 134.0964; found,
134.0964.
(2R,3R)-3-(3,5-Difluorophenyl)glycidol (17b). This com-
pound was prepared from trans-3,5-difluorocinnamyl alcohol
(16b) according to method f. Viscous, colorless liquid. Yield:
1
70%. Percent ee: 97.9%. H NMR (400 MHz, CDCl3): δ 1.77
(dd, J=7.9, 5.1 Hz, 1H), 3.15 (m, 1H), 3.83 (ddd, J=12.6, 8.1, 3.5
Hz, 1H), 3.93 (d, J=1.4 Hz, 1H), 4.06 (ddd, J=12.9, 4.9, 2.3 Hz,
1H), 6.74 (m, 1H), 6.84 (m, 2H). HRMS (EI): m/z calcd for
[C9H8F2O2]þ, 186.0492; found, 186.0501.
3-Ethylindoline (13b). This compound was prepared from 3-
ethylindole36 according to method c. Colorless liquid. Yield:
89%. 1H NMR (400 MHz, DMSO-d6): δ 0.92 (t, J=7.4 Hz, 3H),
1.44 (m, 1H), 1.75 (m, 1H), 3.07 (m, 2H), 3.52 (m, 1H), 5.37 (br s,
1H), 6.46 (d, J=7.7 Hz, 1H), 6.51 (dt, J=7.4, 1.0 Hz, 1H), 6.89
(dt, J=7.5, 0.9 Hz, 1H), 6.99 (d, J=7.3 Hz, 1H). HRMS (EI):
m/z calcd for [C10H13N]þ, 147.1048; found, 147.1043.
3-Isopropylindoline (13c). This compound was prepared from
3-isopropylindole36 according to method c. Colorless liquid.
Yield: 71%. 1H NMR (400 MHz, DMSO-d6): δ 0.80 (d, J=6.8
Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 1.95 (m, 1H), 3.10 (m, 1H), 3.21
(ddd, J=11.4, 6.3, 2.1 Hz, 1H), 3.40 (dt, J=9.4, 2.3 Hz, 1H), 5.33
(br s, 1H), 6.45 (d, J=7.8 Hz, 1H), 6.50 (dt, J=7.3, 1.0 Hz, 1H),
6.89 (m, 1H), 6.99 (d, J=7.3 Hz, 1H). MS (ES) m/z 162.2 [M þ
H]þ.
5-Fluoro-3,3-dimethylindoline (13d). This compound was pre-
pared from 3,3-dimethyl-5-fluorooxindole (11a) according to
method b. Amber liquid. Yield: 86%. 1H NMR (400 MHz,
DMSO-d6): δ 1.21 (s, 6H), 3.17 (d, J=2.2 Hz, 2H), 5.32 (br s,
1H), 6.43 (dd, J=8.4, 4.5 Hz, 1H), 6.70 (m, 1H), 6.84 (dd, J=8.8,
2.7 Hz, 1H). HRMS (ESI): m/z calcd for [C10H12FN þ H]þ,
166.1032; found, 166.1024.
(2S,3S)-3-(2,3-Dihydro-1H-indol-1-yl)-3-phenylpropane-1,2-
diol (18a). This compound was prepared from indoline and
(2R,3R)-3-phenylglycidol according to method g. Viscous color-
less liquid. Yield: 80%. 1H NMR (400 MHz, DMSO-d6): δ 2.80
(m, 2H), 3.21 (q, J=9.2 Hz, 1H), 3.40 (p, J=5.6 Hz, 1H), 3.52
(m, 2H), 4.22 (m, 1H), 4.58 (q, J=5.6 Hz, 2H), 4.71 (d, J=5.6
Hz, 1H), 6.43 (dt, J=7.3, 0.9 Hz, 1H), 6.52 (d, J=7.8 Hz, 1H),
6.90 (m, 2H), 7.20 (m, 1H), 7.28 (m, 2H), 7.38 (m, 2H). HRMS
(ESI): m/z calcd for [C17H19NO2 þ H]þ, 270.1489; found,
270.1493.
(2S,3S)-3-(2,3-Dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)-
propane-1,2-diol (18b). This compound was prepared from
indoline and (2R,3R)-3-(3-fluorophenyl)glycidol (17a) accord-
ing to method g. Viscous, colorless liquid. Yield: 75%. 1H NMR
(400 MHz, DMSO-d6): δ 2.81 (m, 2H), 3.25 (q, J=9.4 Hz, 1H),
3.40 (p, J=5.6 Hz, 1H), 3.52 (m, 2H), 4.21 (m, 1H), 4.63 (m, 2H),
4.82 (d, J=5.6 Hz, 1H), 6.46 (t, J=7.4 Hz, 1H), 6.51 (d, J=8.0
Hz, 1H), 6.92 (m, 2H), 7.04 (m, 1H), 7.21 (d, J=7.6 Hz, 2H), 7.32
(q, J=7.7 Hz, 1H). MS (ESI) m/z 288.1 ([M þ H]þ).
(2S,3S)-3-(3-Fluorophenyl)-3-(2-methyl-2,3-dihydro-1H-indol-
1-yl)propane-1,2-diol (18c). This compound was prepared from
2-methylindoline and (2R,3R)-3-(3-fluorophenyl)glycidol (17a)
according to method g. Viscous, amber liquid. Yield: 63%. 1H
NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=5.8 Hz, 1.5H), 1.21
(d, J=6.5 Hz, 1.5H), 2.44 (m, 1H), 3.01 (dd, J=15.5, 9.1 Hz,
0.5H), 3.11 (dd, J=15.8, 9.1 Hz, 0.5H), 3.39 (p, J=5.5 Hz, 0.5H),
3.48 (p, J=5.5 Hz, 0.5H), 3.58 (m, 1.5H), 3.89 (m, 0.5H), 4.29
(m, 0.5H), 4.37 (m, 0.5H), 4.44 (m, 0.5H), 4.62 (m, 1.5H), 4.82 (d,
J=5.9 Hz, 0.5H), 4.90 (d, J=5.1 Hz, 0.5H), 6.47 (m, 1.5H), 6.62
(d, J=7.6 Hz, 0.5H), 6.90 (m, 2H), 7.05 (m, 1H), 7.14 (d, J=8.5
Hz, 1H), 7.29 (m, 2H). HRMS (ESI): m/z calcd for
[C18H20FNO2 þ H]þ, 302.1551; found, 302.1556.
6-Fluoro-3,3-dimethylindoline (13e). This compound was pre-
pared from 3,3-dimethyl-6-fluorooxindole (11b) according to
method b. Colorless liquid. Yield: 79%. H NMR (400 MHz,
1
DMSO-d6): δ 1.20 (s, 6H), 3.21 (d, J=1.8 Hz, 2H), 5.72 (br s,
1H), 6.23 (m, 2H), 6.91 (dd, J=7.9, 6.0 Hz, 1H). HRMS (ESI):
m/z calcd for [C10H12FN þ H]þ, 166.1032; found, 166.1048.
7-Fluoro-3,3-dimethylindoline (13f). This compound was pre-
1
pared as described in method b. Brown solid. Yield: 93%. H
NMR (400 MHz, DMSO-d6): δ 1.22 (s, 6H), 3.22 (s, 2H), 5.59
(br s, 1H), 6.55 (m, 1H), 6.82 (m, 2H). HRMS (ESI): m/z calcd
for [C10H12FN þ H]þ, 166.1032; found, 166.1040.
trans-3-Fluorocinnamic Acid Methyl Ester (15a). This com-
pound was prepared as described in method d. Colorless oil.
Yield: 97%. 1H NMR (400 MHz, CDCl3): δ 3.82 (s, 3H), 6.43 (d,
J=16.1 Hz, 1H), 7.08 (m, 1H), 7.29 (m, 3H), 7.64 (d, J=16.0 Hz,
1H). MS (ES) m/z 180.0 (Mþ).
(2S,3S)-3-(3-Fluorophenyl)-3-(3-methyl-2,3-dihydro-1H-indol-
1-yl)propane-1,2-diol (18d). This compound was prepared from
3-methylindoline (13a) and (2R,3R)-3-(3-fluorophenyl)glycidol
(17a) according to method g. Viscous, amber liquid. Yield: 75%.
1H NMR (400 MHz, DMSO-d6): δ 1.11 (d, J=6.8 Hz, 1.5H),
1.17 (d, J=6.5 Hz, 1.5H), 2.74 (t, J=9.1 Hz, 0.5H), 3.13 (m, 2H),
3.34-3.56 (m, 4H), 3.69 (t, J=8.8 Hz, 0.5H), 4.20 (m, 1H), 4.58
(d, J=7.3 Hz, 0.5H), 4.65 (d, J=7.9 Hz, 0.5H), 6.47 (m, 1.5H),
6.58 (d, J=7.8 Hz, 0.5H), 6.92 (m, 2H), 7.04 (m, 1H), 7.20 (m,
trans-3,5-Difluorocinnamic Acid Methyl Ester (15b). This
compound was prepared from trans-3,5-difluorocinnamic acid
according to method d. White solid. Yield: 99%. 1H NMR (400
MHz, CDCl3): δ 3.82 (s, 3H), 6.42 (d, J=16.0 Hz, 1H), 6.84 (m,
1H), 7.03 (m, 2H), 7.58 (d, J=16.0 Hz, 1H). HRMS (EI): m/z
calcd for [C10H8F2O2]þ, 198.0492; found, 198.0489.

2058 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Vu et al.
2H), 7.31 (m, 1H). HRMS (ESI): m/z calcd for [C18H20FNO2 þ
H]þ, 302.1551; found, 302.1539.
HRMS (ESI): m/z calcd for [C18H20FNO2 þ H]þ, 302.1551;
found, 302.1551.
(2S,3S)-3-(3-Ethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoro-
phenyl)propane-1,2-diol (18e). This compound was prepared
from 3-ethylindoline (13b) and (2R,3R)-3-(3-fluorophenyl)-
glycidol (17a) according to method g. Viscous, colorless liquid.
Yield: 78%. 1H NMR (400 MHz, DMSO-d6): δ 0.81 (t, J=7.4
Hz, 1.5H), 0.90 (t, J=7.4 Hz, 1.5H), 1.27 (m, 0.5 H), 1.45 (m, 0.5
H), 1.61 (m, 0.5 H), 1.71 (m, 0.5 H), 2.91 (t, J=8.8 Hz, 0.5H),
2.96 (m, 0.5H), 3.06 (m, 0.5 H), 2.23 (dd, J=7.5, 5.1 Hz, 0.5H),
3.38 (m, 1.5H), 3.48 (m, 1H), 3.68 (t, J=7.4 Hz, 0.5H), 4.22
(m, 1H), 4.63 (m, 2H), 4.81 (t, J=5.5 Hz, 1H), 6.48 (m, 2H),
6.93 (m, 2H), 7.04 (m, 1H), 7.20 (m, 2H), 7.32 (m, 1H). HRMS
(ESI): m/z calcd for [C19H22FNO2 þ H]þ, 316.1707; found,
316.1699.
(2S,3S)-3-(3,3-Dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoro-
phenyl)propane-1,2-diol (18k). This compound was prepared
from 3,3-dimethylindoline14 and (2R,3R)-3-(3-fluorophenyl)-
glycidol (17a) according to method g. Viscous, colorless liquid.
1
Yield: 85%. H NMR (400 MHz, DMSO-d6): δ 1.13 (s, 3H),
1.17 (s, 3H), 3.01 (d, J=8.7 Hz, 1H), 3.29 (d, J=8.7 Hz, 1H), 3.41
(dd, J=10.9, 5.9 Hz, 1H), 3.51 (dd, J=10.9, 4.2 Hz, 1H), 4.20 (m,
1H), 4.63 (br s, 1H), 4.64 (d, J=7.8 Hz, 1H), 4.79 (br s, 1H), 6.46
(dt, J=7.4, 0.9 Hz, 1H), 6.53 (d, J=7.9 Hz, 1H), 6.92 (m, 2H),
7.04 (m, 1H), 7.20 (m, 2H), 7.33 (m, 1H). HRMS (ESI): m/z
calcd for [C19H22FNO2 þ H]þ, 316.1713; found, 316.1713.
(2S,3S)-3-(3,3-Diethyl-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoro-
phenyl)propane-1,2-diol (18l). This compound was prepared
from 3,3-diethylindoline14 and (2R,3R)-3-(3-fluorophenyl)gly-
cidol (17a) according to method g. Viscous, colorless liquid.
Yield: 55%. 1H NMR (400 MHz, DMSO-d6): δ 0.48 (t, J=7.4
Hz, 3H), 0.72 (t, J=7.4 Hz, 3H), 1.35-1.57 (m, 4H), 3.09 (d, J=
9.4 Hz, 1H), 3.28 (d, J=9.4 Hz, 1H), 3.40 (p, J=5.5 Hz, 1H), 3.51
(m, 1H), 4.21 (m, 1H), 4.63 (m, 2H), 4.80 (d, J=5.8 Hz, 1H), 6.47
(t, J=7.4 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 6.81 (dd, J=7.2, 1.0
Hz, 1H), 6.91 (dt, J=7.8, 1.3 Hz, 1H), 7.04 (m, 1H), 7.17 (m,
2H), 7.32 (m, 1H). HRMS (ESI): m/z calcd for [C21H26FNO2 þ
H]þ, 344.2020; found, 344.2019.
(2S,3S)-3-(3-Fluorophenyl)-3-(3-isopropyl-2,3-dihydro-1H-indol-
1-yl)propane-1,2- diol (18f). This compound was prepared from
3-isopropylindoline (13c) and (2R,3R)-3-(3-fluorophenyl)glyci-
dol (17a) according to method g. Viscous, colorless liquid. Yield:
1
82%. H NMR (400 MHz, DMSO-d6): δ 0.55 (d, J=6.8 Hz,
1.5H), 0.80 (d, J=6.8 Hz, 1.5H), 0.83 (d, J=6.8 Hz, 1.5H), 0.89
(d, J=6.8 Hz, 1.5H), 1.86 (m, 1H), 2.95 (m, 0.5H), 3.08 (m,
0.5H), 3.17 (t, J=9.1 Hz, 0.5H), 3.24 (t, J=9.7 Hz, 0.5H), 3.37
(m, 1.5H), 3.46 (m, 0.5H), 3.52 (m, 1H), 4.22 (m, 1H), 4.62 (m,
2H), 4.78 (d, J=5.6 Hz, 0.5H), 4.84 (d, J=5.6 Hz, 0.5H), 6.46 (m,
1.5H), 6.54 (d, J=7.9 Hz, 0.5H), 6.92 (m, 2H), 7.03 (m, 1H), 7.18
(m, 2H), 7.31 (m, 1H). HRMS (ESI): m/z calcd for
[C20H24FNO2 þ H]þ, 330.1864; found, 330.1855.
(2S,3S)-3-(3-Fluorophenyl)-3-spiro[cyclopentane-1,30-indol]-
10(20H)-ylpropane-1,2-diol (18m). This compound was prepared
from 10,20-dihydrospiro[cyclopentane-1,30-indole]14 and (2R,
3R)-3-(3-fluorophenyl)glycidol (17a) according to method g.
(2S,3S)-3-(3-Fluorophenyl)-3-(5-methyl-2,3-dihydro-1H-indol-
1-yl)propane-1,2-diol (18g). This compound was prepared from
5-methylindoline and (2R,3R)-3-(3-fluorophenyl)glycidol (17a)
according to method g. Viscous, amber liquid. Yield: 68%. 1H
NMR (400 MHz, DMSO-d6): δ 2.11 (s, 3H), 2.77 (m, 2H), 3.20
(q, J=9.2 Hz, 1H), 3.39 (p, J=5.6 Hz, 1H), 3.49 (m, 2H), 4.19
(m, 1H), 4.56 (d, J=7.4 Hz, 1H), 4.60 (t, J=5.5 Hz, 1H), 4.79 (d,
J=5.6 Hz, 1H), 6.40 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H),
6.76 (s, 1H), 7.02 (m, 1H), 7.18 (m, 2H), 7.30 (m, 1H). HRMS
(ESI): m/z calcd for [C18H20FNO2 þ H]þ, 302.1551; found,
302.1551.
1
Amber gum. Yield: 80%. H NMR (400 MHz, DMSO-d6): δ
1.43-1.82 (m, 8H), 3.03 (d, J=8.9 Hz, 1H), 3.35 (d, J=8.9 Hz,
1H), 3.39 (m, 1H), 3.50 (m, 1H), 4.20 (m, 1H), 4.63 (d, J=7.7 Hz,
2H), 4.79 (d, J=5.4 Hz, 1H), 6.50 (m, 2H), 6.91 (m, 2H), 7.04 (m,
1H), 7.19 (m, 2H), 7.32 (m, 1H). HRMS (ESI): m/z calcd for
[C21H24FNO2 þ H]þ, 342.1864; found, 342.1862.
(2S,3S)-3-(3-Fluorophenyl)-3-spiro[cyclohexane-1,30-indol]-
10(20H)-ylpropane-1,2-diol (18n). This compound was prepared
from 10,20-dihydrospiro[cyclohexane-1,30-indole]14 and (2R,
3R)-3-(3-fluorophenyl)glycidol (17a) according to method g.
White solid. Yield: 78%. 1H NMR (400 MHz, CDCl3): δ
1.13-1.74 (m, 10H), 2.19 (br, 2H), 2.98 (d, J =8.9 Hz, 1H),
3.33 (d, J=8.9 Hz, 1H), 3.76 (dd, J=11.2, 5.9 Hz, 1H), 3.91 (dd,
J=11.2, 3.5 Hz, 1H), 4.45 (m, 1H), 4.72 (d, J=9.2 Hz, 1H), 6.63
(d, J = 7.9 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.98 (m, 2H),
7.03-7.18 (m, 3H), 7.32 (m, 1H). HRMS (ESI): m/z calcd for
[C22H26FNO2 þ H]þ, 356.2020; found, 356.2031.
(2S,3S)-3-(5-Chloro-2,3-dihydro-1H-indol-1-yl)-3-(3-fluoro-
phenyl)propane-1,2-diol (18h). This compound was prepared
from 5-chloroindoline and (2R,3R)-3-(3-fluorophenyl)glycidol
(17a) according to method g. Viscous, amber liquid. Yield: 61%.
1H NMR (400 MHz, DMSO-d6): δ 2.85 (m, 2H), 3.30 (q, J=9.1
Hz, 1H), 3.38 (p, J=5.6 Hz, 1H), 3.46 (m, 1H), 3.60 (q, J=8.7
Hz, 1H), 4.18 (m, 1H), 4.60 (d, J=7.4 Hz, 1H), 4.64 (t, J=5.5 Hz,
1H), 4.86 (d, J=5.6 Hz, 1H), 6.48 (d, J=8.5 Hz, 1H), 6.92 (dd,
J=8.3, 2.2 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 7.06 (m, 1H), 7.19
(m, 2H), 7.34 (m, 1H). HRMS (ESI): m/z calcd for
[C17H17ClFNO2 þ H]þ, 322.1005; found, 322.1005.
(2S,3S)-3-(3,3-Dimethyl-2,3-dihydro-1H-indol-1-yl)-3-phenyl-
propane-1,2-diol (18o). This compound was prepared as des-
cribed in method g. Viscous amber liquid. Yield: 93%. Chiral
1
purity: 99.9% (99.8% ee). H NMR (400 MHz, DMSO-d6): δ
(2S,3S)-3-[5-(Benzyloxy)-2,3-dihydro-1H-indol-1-yl]-3-(3-fluoro-
phenyl)propane-1,2-diol (18i). This compound was prepared
from 5-benzyloxyindoline and (2R,3R)-3-(3-fluorophenyl)gly-
cidol (17a) according to method g. Viscous, amber liquid. Yield:
61%. 1H NMR (400 MHz, DMSO-d6): δ 2.78 (m, 2H), 3.20 (q,
J=9.1 Hz, 1H), 3.39 (p, J=5.6 Hz, 1H), 3.48 (m, 2H), 4.18 (m,
1H), 4.51 (d, J=7.3 Hz, 1H), 4.59 (t, J=5.5 Hz, 1H), 4.77 (d, J=
5.5 Hz, 1H), 4.93 (s, 2H), 6.40 (d, J=8.8 Hz, 1H), 6.58 (dd, J=
8.3, 2.2 Hz, 1H), 6.70 (s, 1H), 7.02 (m, 1H), 7.19 (d, J=7.7 Hz,
2H), 7.26-7.40 (m, 6H). HRMS (ESI): m/z calcd for
[C24H24FNO3 þ H]þ, 394.1813; found, 394.1808.
1.11 (s, 3H), 1.16 (s, 3H), 2.99 (d, J=8.7 Hz, 1H), 3.27 (d, J=8.7
Hz, 1H), 3.41 (p, J=5.9 Hz, 1H), 3.54 (m, 1H), 4.21 (m, 1H), 4.58
(d, J=5.6 Hz, 1H), 4.61 (d, J=8.5 Hz, 1H), 4.68 (d, J=5.6 Hz,
1H), 6.47 (dt, J=7.4, 0.9 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.90
(m, 2H), 7.20 (m, 1H), 7.29 (m, 2H), 7.38 (m, 2H). HRMS (ESI):
m/z calcd for [C19H23NO2 þ H]þ, 298.1807; found, 298.1807.
(2S,3S)-3-(3,5-Difluorophenyl)-3-(3,3-dimethyl-2,3-dihydro-
1H-indol-1-yl)propane-1,2-diol (18p). This compound was pre-
pared from 3,3-dimethylindoline14 and (2R,3R)-3-(3,5-difluoro-
phenyl)glycidol (17b) according to method g. Viscous, amber
liquid. Yield: 84%. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (s,
3H), 1.18 (s, 3H), 3.04 (d, J=8.7 Hz, 1H), 3.31 (d, J=8.7 Hz,
1H), 3.41 (p, J=5.6 Hz, 1H), 3.49 (m, 1H), 3.18 (m, 1H), 4.66 (m,
2H), 4.88 (d, J=5.6 Hz, 1H), 6.53 (m, 2H), 6.92 (m, 2H), 7.08 (m,
3H). HRMS (ESI): m/z calcd for [C19H21F2NO2 þ H]þ,
334.1613; found, 334.1619.
(2S,3S)-3-(3-Fluorophenyl)-3-(7-methyl-2,3-dihydro-1H-indol-
1-yl)propane-1,2-diol (18j). This compound was prepared from
7-methylindoline and (2R,3R)-3-(3-fluorophenyl)glycidol (17a)
according to method g. White solid. Yield: 65%. 1H NMR (400
MHz, DMSO-d6): δ 2.28 (m, 1H), 2.40 (s, 3H), 2.53 (m, 1H), 3.35
(m, 2H), 3.62 (p, J=5.6 Hz, 1H), 3.73 (m, 1H), 4.21 (m, 1H), 4.42
(t, J=5.5 Hz, 1H), 4.70 (d, J=8.6 Hz, 1H), 4.78 (d, J=6.2 Hz,
1H), 6.59 (t, J=7.4 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.84 (d, J=
7.4 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.01 (m, 2H), 7.22 (m, 1H).
(2S,3S)-3-(5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-(3-fluorophenyl)propane-1,2-diol (18q). This compound was
prepared from 5-fluoro-3,3-dimethylindoline (13d) and (2R,
3R)-3-(3-fluorophenyl)glycidol (17a) according to method g.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2059
Viscous, colorless liquid. Yield: 82%. 1H NMR (400 MHz,
DMSO-d6): δ 1.13 (s, 3H), 1.18 (s, 3H), 3.04 (d, J = 8.8 Hz,
1H), 3.30 (d, J=8.8 Hz, 1H), 3.40 (p, J=5.6 Hz, 1H), 3.49 (m,
1H), 4.17 (m, 1H), 4.58 (d, J=7.5 Hz, 1H), 4.63 (t, J=5.6 Hz,
1H), 4.79 (d, J=5.6 Hz, 1H), 6.46 (dd, J=8.6, 4.2 Hz, 1H), 6.72
(ddd, J=11.3, 8.6, 2.7 Hz, 1H), 6.82 (dd, J=8.6, 2.7 Hz, 1H),
7.04 (m, 1H), 7.20 (m, 2H), 7.32 (m, 1H). HRMS (ESI): m/z
calcd for [C19H21F2NO2 þ H]þ, 334.1613; found, 334.1606.
(2S,3S)-3-(6-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-(3-fluorophenyl)propane-1,2-diol (18r). This compound was
prepared from 6-fluoro-3,3-dimethylindoline (13e) and (2R,
3R)-3-(3-fluorophenyl)glycidol (17a) according to method g.
Viscous, amber liquid. Yield: 89%. 1H NMR (400 MHz,
DMSO-d6): δ 1.10 (s, 3H), 1.17 (s, 3H), 3.06 (d, J = 9.0 Hz,
1H), 3.36 (d, J=9.0 Hz, 1H), 3.39 (m, 1H), 3.48 (m, 1H), 4.18 (m,
1H), 4.62 (d, J=7.7 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 4.83 (d, J=
5.6 Hz, 1H), 6.21 (ddd, J=11.9, 8.0, 2.3 Hz, 1H), 6.35 (dd, J=
11.2, 2.2 Hz, 1H), 6.86 (dd, J=7.9, 5.9 Hz, 1H), 7.07 (m, 1H),
7.24 (m, 2H), 7.34 (m, 1H). HRMS (ESI): m/z calcd for
[C19H21F2NO2 þ H]þ, 334.1613; found, 334.1597.
2.96 (dd, J=15.7, 8.8 Hz, 0.5H), 3.11 (dd, J=15.9, 9.2 Hz, 0.5H),
3.15 (m, 0.5H), 3.27 (m, 0.5H), 3.38 (m, 0.5H), 3.80 (m, 0.5H),
4.32 (d, J=9.4 Hz, 0.5H), 4.64 (dt, J=9.4, 2.1 Hz, 0.5H), 4.76 (d,
J=9.9 Hz, 0.5H), 4.88 (dt, J=9.4, 2.1 Hz, 0.5H), 5.43 (br, 1H),
6.54 (t, J=7.3 Hz, 0.5H), 6.58 (t, J=7.3 Hz, 0.5H), 6.70 (d, J=8.1
Hz, 0.5H), 6.74 (d, J=7.9 Hz, 0.5H), 6.94 (m, 1H), 7.03 (t, J=7.8
Hz, 0.5H), 7.06-7.14 (m, 2.5H), 7.28 (m, 1H), 7.36 (m, 1H), 8.57
(br, 0.5H), 8.63 (br, 0.5H), 8.79 (br, 1H). HRMS (ESI): m/z calcd
for [C19H23FN2O þ H]þ, 315.1867; found, 315.1850.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-(3-methyl-
2,3-dihydro-1H-indol-1-yl)propan-2-ol Hydrochloride (9d). This
compound was prepared from 18d according to method i. White
powder. Yield: 33%. 1H NMR (400 MHz, DMSO-d6): δ 1.11 (d,
J=6.6 Hz, 1.5H), 1.16 (d, J=6.8 Hz, 1.5H), 2.53 (m, 0.5H), 2.59
(t, J=5.3 Hz, 1.5H), 2.60 (t, J=5.3 Hz, 1.5H), 2.90 (m, 1H),
3.05-3.21 (m, 2H), 3.27 (t, J=8.8 Hz, 0.5H), 3.30 (m, 0.5H),
3.67 (t, J=8.6 Hz, 0.5H), 4.61 (m, 1H), 4.69 (m, 1H), 6.08 (br,
1H), 6.54 (t, J=7.4 Hz, 0.5H), 6.56 (t, J=7.4 Hz, 0.5H), 6.71 (d,
J=7.8 Hz, 0.5H), 6.82 (d, J=7.9 Hz, 0.5H), 6.94-7.02 (m, 2H),
7.10 (m, 1H), 7.20 (m, 2H), 7.37 (m, 1H), 8.73 (br, 1H), 8.97 (br,
1H). HRMS (ESI): m/z calcd for [C19H23FN2O þ H]þ,
315.1867; found, 315.1881.
(2S,3S)-3-(7-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-phenylpropane-1,2-diol (18s). This compound was prepared as
described in method h. Ivory foam. Yield: 82%. 1H NMR (400
MHz, DMSO-d6): δ 0.99 (s, 3H), 1.14 (s, 3H), 2.91 (d, J=9.2 Hz,
1H), 3.24 (d, J=9.2 Hz, 1H), 3.37 (br, 1H), 3.51 (dd, J=10.9, 6.1
Hz, 1H), 3.69 (dd, J=10.9, 3.4 Hz, 1H), 4.22 (m, 1H), 4.63 (br,
1H), 4.99 (dd, J=9.1, 1.7 Hz, 1H), 6.53 (ddd, J=8.1, 7.3, 4.3 Hz,
1H), 6.75 (dd, J=7.3, 1.0 Hz, 1H), 6.85 (ddd, J=13.4, 8.2, 1.0
Hz, 1H), 7.22 (m, 1H), 7.31 (m, 4H). HRMS (ESI): m/z calcd for
[C19H22FNO2 þ H]þ, 316.1707; found, 316.1690.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-[(3S)-3-methyl-
2,3-dihydro-1H-indol-1-yl]propan-2-ol Hydrochloride (9d-Isomer
1). Diastereomeric mixture of (1S,2R)-1-(3-fluorophenyl)-3-
(methylamino)-1-(3-methyl-2,3-dihydro-1H-indol-1-yl)propan-
2-ol hydrochloride (9d) was dissolved in methanol, and the
resulting solution was injected onto the supercritical fluid
chromatography (SFC) instrument with a volume of 1.0 mL
per injection. The baseline resolved diastereomers were collected
using a Berger MultiGram Prep SFC (Berger Instruments, Inc.,
Newark, DE) under the following conditions: Chiralpak AD-H
SFC column (5 μm, 250 mm length ꢀ 20 mm i.d., Chiral Techno-
logies, Inc., Exton, PA), 35 °C column temperature, 10% MeOH
with 0.2% DEA as CO2 modifier, 50 mL/min flow rate, 100 bar
outlet pressure, 254 nm UV detection. The chiral purity of each
diastereomer was determined under the same SFC conditions
using a Chiralcel OD column (10 μm, 250 mm length ꢀ 4.6 mm
i.d.) at 2.0 mL/min flow rate on a Berger Analytical SFC instru-
ment. (1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-[(3S)-3-
methyl-2,3-dihydro-1H-indol-1-yl]propan-2-ol was isolated as
peak 1 with >99.8% diastereomeric purity and was subjected to
hydrochloride salt formation in an analogous manner described
in method i to give 9d-isomer 1 as a white powder. The
stereochemistry at the C3 position of the indoline ring was
(2S,3S)-3-(7-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-(3-fluorophenyl)propane-1,2-diol (18t). This compound was
prepared from 7-fluoro-3,3-dimethylindoline (13f) and (2R,
3R)-3-(3-fluorophenyl)glycidol (17a) according to method h.
Viscous, amber liquid. Yield: 74%. 1H NMR (400 MHz,
DMSO-d6): δ 1.02 (s, 3H), 1.15 (s, 3H), 2.92 (d, J = 9.4 Hz,
1H), 3.28 (d, J=9.4 Hz, 1H), 3.51 (p, J=5.6 Hz, 1H), 3.64 (m,
1H), 4.20 (m, 1H), 4.61 (t, J=5.6 Hz, 1H), 4.80 (d, J=6.2 Hz,
1H), 5.02 (dd, J=8.8, 1.5 Hz, 1H), 6.55 (ddd, J=8.1, 7.3, 4.2 Hz,
1H), 6.78 (dd, J=7.3, 1.0 Hz, 1H), 6.86 (ddd, J=13.3, 8.2, 1.0
Hz, 1H), 7.06 (m, 1H), 7.14 (m, 2H), 7.35 (m, 1H). HRMS (ESI):
m/z calcd for [C19H21F2NO2 þ H]þ, 334.1613; found, 334.1616.
(1S,2R)-1-(2,3-Dihydro-1H-indol-1-yl)-3-(methylamino)-1-
phenylpropan-2-ol Hydrochloride (9a). This compound was pre-
pared from 18a according to method i. White powder. Yield:
28%. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (t, J=5.4 Hz, 3H),
2.76-2.96 (m, 3H), 3.03 (dd, J=18.8, 10.1 Hz, 1H), 3.32 (m,
1H), 3.51 (dt, J=8.7, 4.4 Hz, 1H), 4.60 (dt, J=9.4, 2.2 Hz, 1H),
4.65 (d, J=9.4 Hz, 1H), 5.82 (br, 1H), 6.50 (t, J=7.2 Hz, 1H),
6.75 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.98 (t, J=7.8
Hz, 1H), 7.26 (m, 1H), 7.33 (m, 4H), 8.62 (br, 1H), 8.77 (br, 1H).
HRMS (ESI): m/z calcd for [C18H22N2O þ H]þ, 283.1805;
found, 283.1810.
1
arbitrarily assigned. H NMR (400 MHz, DMSO-d6): δ 1.11
(d, J=6.8 Hz, 3H), 2.53 (m, 1H), 2.61 (t, J=5.3 Hz, 3H), 2.92 (m,
1H), 3.18 (m, 1H), 3.31 (m, 1H), 3.66 (t, J=8.6 Hz, 1H), 3.81 (br,
1H), 4.61 (t, J=7.8 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 6.56 (t, J=
7.3 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 7.00
(t, J=7.6 Hz, 1H), 7.10 (dt, J=8.6, 1.9 Hz, 1H), 7.20 (m, 2H),
7.38 (m, 1H), 8.73 (br, 1H), 8.92 (br, 1H). HRMS (ESI): m/z
calcd for [C19H23FN2O þ H]þ, 315.1867; found, 315.1869.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-[(3R)-3-methyl-
2,3-dihydro-1H-indol-1-yl]propan-2-ol Hydrochloride (9d-Isomer
2). (1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-[(3R)-3-
methyl-2,3-dihydro-1H-indol-1-yl]propan-2-ol was isolated
as peak 2 from the above HPLC separation of diastereomers
with >99.8% diastereomeric purity and was subjected to
hydrochloride salt formation in an analogous manner de-
scribed in method i to give 9d-isomer 2 as a white powder. The
stereochemistry at the C3 position of the indoline ring was
arbitrarily assigned. 1H NMR (400 MHz, DMSO-d6): δ 1.16
(d, J=6.5 Hz, 3H), 2.60 (t, J=5.3 Hz, 3H), 2.90 (m, 1H),
3.11-3.17 (m, 3H), 3.27 (t, J=8.6 Hz, 1H), 3.80 (br, 1H), 4.61
(t, J=7.6 Hz, 1H), 4.67 (d, J=8.8 Hz, 1H), 6.54 (t, J=7.3 Hz,
1H), 6.71 (d, J=7.8 Hz, 1H), 6.96 (d, J=7.4 Hz, 1H), 6.99 (t,
J=8.2 Hz, 1H), 7.10 (m, 1H), 7.22 (m, 2H), 7.37 (m, 1H), 8.69
(br, 1H), 8.93 (br, 1H). HRMS (ESI): m/z calcd for
[C19H23FN2O þ H]þ, 315.1867; found, 315.1867.
(1S,2R)-1-(2,3-Dihydro-1H-indol-1-yl)-1-(3-fluorophenyl)-
3-(methylamino)propan-2-ol Hydrochloride (9b). This com-
pound was prepared from 18b according to method i. White
powder. Yield: 41%. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (t,
J=5.4 Hz, 3H), 2.75-2.97 (m, 3H), 3.03 (dd, J=18.7, 10.0 Hz,
1H), 3.30 (m, 1H), 3.54 (dt, J=8.6, 4.6 Hz, 1H), 4.60 (dt, J=9.4,
2.2 Hz, 1H), 4.69 (d, J=9.2 Hz, 1H), 6.18 (br, 1H), 6.52 (dt, J=
7.3, 0.7 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H),
6.99 (d, J=7.7 Hz, 1H), 7.10 (m, 1H), 7.20 (m, 2H), 7.37 (m, 1H),
8.68 (br, 1H), 8.84 (br, 1H). HRMS (ESI): m/z calcd for
[C18H21FN2O þ H]þ, 301.1711; found, 301.1716.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-(2-methyl-
2,3-dihydro-1H-indol-1-yl)propan-2-ol Hydrochloride (9c). This
compound was prepared from 18c according to method i. White
powder. Yield: 57%. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d,
J=6.1 Hz, 1.5H), 1.25 (d, J=6.1 Hz, 1.5H), 2.45 (m, 1H), 2.60 (t,
J=5.6 Hz, 1.5H), 2.62 (t, J=5.6 Hz, 1.5H), 2.88-3.05 (m, 1H),

2060 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Vu et al.
(1S,2R)-1-(3-Ethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoro-
phenyl)-3-(methylamino)propan-2-ol Hydrochloride (9e). This
compound was prepared from 18e according to method i. White
powder. Yield: 61%. 1H NMR (400 MHz, DMSO-d6): δ 0.74 (t,
J=7.4 Hz, 1.5H), 0.85 (t, J=7.4 Hz, 1.5H), 1.18 (m, 1H), 1.43
(m, 1H), 2.54 (t, J=5.4 Hz, 1.5H), 2.56 (t, J=5.4 Hz, 1.5H), 2.85
(m, 2H), 2.99-3.28 (m, 2.5H), 3.58 (t, J=8.8 Hz, 0.5H), 4.55 (m,
1H), 4.63 (m, 1H), 5.70 (br, 1H), 6.47 (t, J=6.8 Hz, 0.5H), 6.49 (t,
J=6.9 Hz, 0.5H), 6.69 (d, J=7.8 Hz, 0.5H), 6.73 (d, J=7.9 Hz,
0.5H), 6.89-6.96 (m, 2H), 7.03 (m, 1H), 7.13 (m, 2H), 7.32 (m,
1H), 8.58 (br, 1H), 8.68 (br, 0.5H), 8.79 (br, 0.5H). HRMS (ESI):
m/z calcd for [C20H25FN2O þ H]þ, 329.2024; found, 329.2023.
(1S,2R)-1-(3-Fluorophenyl)-1-(3-isopropyl-2,3-dihydro-1H-
indol-1-yl)-3-(methylamino)propan-2-ol Hydrochloride (9f). This
compound was prepared from 18f according to method i. White
powder. Yield: 65%. 1H NMR (400 MHz, DMSO-d6): δ 0.37 (d,
J=6.9 Hz, 1.5H), 0.75 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz,
1.5H), 1.75 (m, 0.5H), 1.86 (m, 0.5H), 2.53 (t, J=5.6 Hz, 1.5H),
2.55 (t, J=5.5 Hz, 1.5H), 2.80-2.93 (m, 2H), 3.03 (t, J=9.6 Hz,
0.5H), 3.06 (m, 1H), 3.19 (m, 0.5H), 3.31 (m, 0.5H), 3.42 (t, J=
9.6 Hz, 0.5H), 4.52-4.67 (m, 2H), 5.73 (br, 1H), 6.47 (t, J=7.3
Hz, 1H), 6.69 (d, J=8.0 Hz, 0.5H), 6.72 (d, J=8.0 Hz, 0.5H),
6.89 (d, J=7.3 Hz, 1H), 6.94 (m, 1H), 7.03 (m, 1H), 7.14 (m, 2H),
7.31 (m, 1H), 8.63 (br, 1H), 8.74 (br, 0.5H), 8.94 (br, 0.5H).
HRMS (ESI): m/z calcd for [C21H27FN2O þ H]þ, 343.2180;
found, 343.2191.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-(5-methyl-
2,3-dihydro-1H-indol-1-yl)propan-2-ol Hydrochloride (9g). This
compound was prepared from 18g according to method i. White
powder. Yield: 57%. 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s,
3H), 2.61 (t, J=5.4 Hz, 3H), 2.73-2.82 (m, 2H), 2.91 (m 1H),
2.98 (dd, J=18.7, 10.1 Hz, 1H), 3.30 (m, 1H), 3.48 (dt, J=8.6, 4.6
Hz, 1H), 4.57 (dt, J=9.2, 2.1 Hz, 1H), 4.63 (d, J=9.2 Hz, 1H),
5.61 (br, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.79 (m, 2H), 7.09 (m, 1H),
7.18 (m, 2H), 7.36 (m, 1H), 8.63 (br, 1H), 8.77 (br, 1H). HRMS
(ESI): m/z calcd for [C19H23FN2O þ H]þ, 315.1867; found,
315.1869.
powder. Yield: 56%. 1H NMR (400 MHz, DMSO-d6): δ 1.11 (s,
3H), 1.17 (s, 3H), 2.60 (t, J=5.4 Hz, 3H), 2.81 (d, J=8.7 Hz, 1H),
2.95 (m, 1H), 3.18 (m, 1H), 3.28 (d, J=8.7 Hz, 1H), 4.19 (br, 1H),
4.61 (dt, J=9.4, 2.2 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 6.56 (dt, J=
7.4, 0.7 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.94 (dd, J=7.3, 1.1 Hz,
1H), 6.99 (dt, J=7.8, 1.2 Hz, 1H), 7.10 (m, 1H), 7.20 (m, 2H),
7.38 (m, 1H), 8.72 (br, 1H), 8.98 (br, 1H). HRMS (ESI): m/z
calcd for [C20H25FN2O þ H]þ, 329.2024; found, 329.2026.
(1S,2R)-1-(3,3-Diethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoro-
phenyl)-3-(methylamino)propan-2-ol Hydrochloride (9l). This
compound was prepared from 18l according to method i. White
powder. Yield: 54%. 1H NMR (400 MHz, DMSO-d6): δ 0.41 (t,
J=7.4 Hz, 3H), 0.72 (t, J=7.4 Hz, 3H), 1.37 (m, 1H), 1.46 (m,
1H), 1.51 (q, J=7.4 Hz, 2H), 2.61 (t, J=5.4 Hz, 3H), 2.91 (d, J=
9.4 Hz, 1H), 2.97 (m, 1H), 3.12 (m, 1H), 3.21 (d, J=9.2 Hz, 1H),
4.58 (t, J=9.0 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 5.68 (br, 1H),
6.55 (t, J=7.3 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.84 (dd, J=7.2,
1.0 Hz, 1H), 7.00 (dt, J=7.8, 1.2 Hz, 1H), 7.10 (m, 1H), 7.20 (m,
2H), 7.37 (m, 1H), 8.60 (br, 1H), 8.69 (br, 1H). HRMS (ESI): m/z
calcd for [C22H29FN2O þ H]þ, 357.2337; found, 357.2340.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-spiro[cyclo-
pentane-1,30-indol]-10(20H)-ylpropan-2-ol Hydrochloride (9m).
This compound was prepared from 18m according to method i.
1
White powder. Yield: 17%. H NMR (400 MHz, DMSO-d6): δ
1.44 (m, 2H), 1.63 (m, 1H), 1.68-1.90 (m, 5H), 2.60 (t, J=5.4 Hz,
3H), 2.81 (d, J=8.7 Hz, 1H), 2.93 (m, 1H), 3.20 (m, 1H), 3.38 (d,
J=8.7 Hz, 1H), 4.22 (br, 1H), 4.62 (dt, J=9.4, 2.0 Hz, 1H), 4.71 (d,
J=9.2 Hz, 1H), 6.56 (t, J=7.3 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H),
6.94 (dd, J=7.3, 0.9 Hz, 1H), 6.99 (dt, J=7.8, 1.2 Hz, 1H), 7.11 (m,
1H), 7.20 (m, 2H), 7.36 (m, 1H), 8.72 (br, 1H), 9.06 (br, 1H).
HRMS (ESI): m/z calcd for [C22H27FN2O þ H]þ, 355.2180;
found, 355.2178.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-spiro[cyclo-
hexane-1,30-indol]-10(20H)-ylpropan-2-ol Hydrochloride (9n).
This compound was prepared from 18n according to method i.
White powder. Yield: 46%. 1H NMR (400 MHz, DMSO-d6): δ
1.17-1.38 (m, 4H), 1.47-1.68 (m, 6H), 2.60 (t, J=5.4 Hz, 3H),
2.86 (d, J=9.2 Hz, 1H), 2.94 (m, 1H), 3.14 (m, 1H), 3.50 (d, J=
9.4 Hz, 1H), 4.68 (m, 2H), 5.59 (br, 1H), 6.54 (t, J=7.3 Hz, 1H),
6.75 (d, J=7.9 Hz, 1H), 6.93 (dd, J=7.3, 0.9 Hz, 1H), 6.98 (dt, J
=7.8, 1.2 Hz, 1H), 7.10 (m, 1H), 7.22 (m, 2H), 7.38 (m, 1H), 8.73
(br, 1H), 9.01 (br, 1H). HRMS (ESI): m/z calcd for
[C23H29FN2O þ H]þ, 369.2337; found, 369.2332.
(1S,2R)-1-(5-Chloro-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoro-
phenyl)-3-(methylamino)propan-2-ol Hydrochloride (9h). This
compound was prepared from 18h according to method i. White
powder. Yield: 59%. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (t,
J=5.4 Hz, 3H), 2.81-2.94 (m, 3H), 3.08 (dd, J=19.0, 10.0 Hz,
1H), 3.27 (m, 1H), 3.56 (m, 1H), 4.57 (dt, J=9.4, 2.2 Hz, 1H),
4.67 (d, J=9.1 Hz, 1H), 4.92 (br, 1H), 6.76 (d, J=8.2 Hz, 1H),
7.00 (m, 2H), 7.12 (m, 1H), 7.20 (m, 2H), 7.37 (m, 1H), 8.63 (br,
1H), 8.72 (br, 1H). HRMS (ESI): m/z calcd for [C18H20ClFN2O þ
H]þ, 335.1321; found, 335.1325.
(1S,2R)-1-(3,3-Dimethyl-2,3-dihydro-1H-indol-1-yl)-3-(methyl-
amino)-1-phenylpropan-2-ol Hydrochloride (9o). This compound
was prepared from 18o according to method i. White powder.
Yield: 59%. Chiral purity: 99.3% (98.6%ee). 1H NMR (400
MHz, DMSO-d6): δ 1.09 (s, 3H), 1.16 (s, 3H), 2.60 (t, J=5.4 Hz,
3H), 2.80 (d, J=8.7 Hz, 1H), 2.95 (m, 1H), 3.20 (m, 1H), 3.26 (d,
J=8.7 Hz, 1H), 4.61 (dt, J=9.4, 2.2 Hz, 1H), 4.67 (d, J=9.4 Hz,
1H), 5.42 (br, 1H), 6.54 (dt, J=7.4, 0.6 Hz, 1H), 6.76 (d, J=7.8
Hz, 1H), 6.92 (dd, J=7.2, 1.0 Hz, 1H), 6.99 (dd, J=7.8, 1.3 Hz,
1H), 7.26 (m, 1H), 7.34 (m, 4H), 8.70 (br, 1H), 8.98 (br, 1H).
HRMS (ESI): m/z calcd for [C20H26N2O þ H]þ, 311.2118;
found, 311.2122.
(1S,2R)-1-[5-(Benzyloxy)-2,3-dihydro-1H-indol-1-yl]-1-(3-fluoro-
phenyl)-3-(methylamino)propan-2-ol Hydrochloride (9i). This
compound was prepared from 18i according to method i. White
powder. Yield: 73%. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (t,
J=5.4 Hz, 3H), 2.77 (m, 2H), 2.89 (m, 1H), 2.98 (dd, J=18.7, 9.9
Hz, 1H), 3.32 (m, 1H), 3.46 (m, 1H), 4.56 (m, 2H), 4.95 (m, 2H),
5.79 (br, 1H), 6.63-6.72 (m, 2H), 7.10 (m, 2H), 7.18 (m, 2H),
7.29 (m, 1H), 7.33-7.41 (m, 4H), 7.47 (d, J=8.1 Hz, 1H), 8.61
(br, 1H), 8.73 (br, 1H). HRMS (ESI): m/z calcd for [C25H27-
FN2O2 þ H]þ, 407.2129; found, 407.2131.
(1S,2R)-1-(3,5-Difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-
1H-indol-1-yl)-3-(methylamino)propan-2-ol Hydrochloride (9p).
This compound was prepared from 18p according to method i.
White powder. Yield: 60%. 1H NMR (400 MHz, DMSO-d6): δ
1.13 (s, 3H), 1.17 (s, 3H), 2.60 (t, J=5.4 Hz, 3H), 2.84 (d, J=8.8
Hz, 1H), 2.94 (m, 1H), 3.17 (m, 1H), 3.28 (d, J=8.7 Hz, 1H), 4.52
(br, 1H), 4.58 (dt, J=9.5, 2.3 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H),
6.58 (t, J=7.3 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.96 (dd, J=7.3,
1.0 Hz, 1H), 7.00 (dt, J=7.8, 1.2 Hz, 1H), 7.08-7.18 (m, 3H),
8.70 (br, 1H), 8.88 (br, 1H). HRMS (ESI): m/z calcd for
[C20H24F2N2O þ H]þ, 347.1929; found, 347.1929.
(1S,2R)-1-(3-Fluorophenyl)-3-(methylamino)-1-(7-methyl-
2,3-dihydro-1H-indol-1-yl)propan-2-ol Hydrochloride (9j). This
compound was prepared from 18j according to method i. White
1
powder. Yield: 64%. H NMR (400 MHz, DMSO-d6): δ 2.21
(m, 1H), 2.42 (s, 3H), 2.54 (m, 1H), 2.66 (t, J=5.4 Hz, 3H), 3.07
(m, 1H), 3.37 (m, 2H), 3.53 (m, 1H), 4.61 (m, 2H), 6.69 (t, J=7.0
Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.92 (d, J=7.2 Hz, 2H), 6.95
(br, 1H), 6.98 (d, J=10.3 Hz, 1H), 7.08 (dt, J=8.6, 2.2 Hz, 1H),
7.27 (m, 1H), 8.77 (br, 1H), 8.95 (br, 1H). HRMS (ESI): m/z
calcd for [C19H23FN2O þ H]þ, 315.1867; found, 315.1862.
(1S,2R)-1-(3,3-Dimethyl-2,3-dihydro-1H-indol-1-yl)-1-(3-fluoro-
phenyl)-3-(methylamino)propan-2-ol Hydrochloride (9k). This
compound was prepared from 18k according to method i. White
(1S,2R)-1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
1-(3-fluorophenyl)-3-(methylamino)propan-2-ol Hydrochloride
(9q). This compound was prepared from 18q according to
method i. White powder. Yield: 57%. 1H NMR (400 MHz,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2061
DMSO-d6): δ 1.11 (s, 3H), 1.17 (s, 3H), 2.61 (t, J=5.4 Hz, 3H),
2.83 (d, J=8.8 Hz, 1H), 2.94 (m, 1H), 3.19 (m, 1H), 3.26 (d, J=
8.7 Hz, 1H), 3.96 (br, 1H), 4.55 (m, 1H), 4.65 (d, J=9.1 Hz, 1H),
6.74 (dd, J=8.6, 4.3 Hz, 1H), 6.79 (m, 1H), 6.84 (m, 1H), 7.11 (m,
1H), 7.20 (m, 2H), 7.37 (m, 1H), 8.61 (br, 1H), 8.71 (br, 1H).
HRMS (ESI): m/z calcd for [C20H24F2N2O þ H]þ, 347.1929;
found, 347.1940.
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(1S,2R)-1-(6-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
1-(3-fluorophenyl)-3-(methylamino)propan-2-ol Hydrochloride (9r).
This compound was prepared from 18r according to method i.
White powder. Yield: 24%. 1H NMR (400 MHz, DMSO-d6): δ
1.09 (s, 3H), 1.17 (s, 3H), 2.60 (t, J=5.4 Hz, 3H), 2.87 (d, J=9.0
Hz, 1H), 2.94 (m, 1H), 3.14 (m, 1H), 3.35 (d, J=8.8 Hz, 1H), 4.58
(t, J=9.1, 1H), 4.72 (d, J=9.1 Hz, 1H), 5.75 (br, 1H), 6.28 (ddd,
J=10.1, 8.1, 2.3 Hz, 1H), 6.66 (dd, J=11.2, 2.2 Hz, 1H), 6.90 (dd,
J=8.1, 6.0 Hz, 1H), 7.13 (dt, J=9.1, 2.0 Hz, 1H), 7.24 (m, 2H),
7.39 (m, 1H), 8.68 (br, 1H), 8.86 (br, 1H). HRMS (ESI): m/z calcd
for [C20H24F2N2O þ H]þ, 347.1929; found, 347.1914.
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(1S,2R)-1-(7-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
3-(methylamino)-1-phenylpropan-2-ol Hydrochloride (9s). This
compound was prepared as described in method i. White
1
powder. Yield: 54%. H NMR (400 MHz, DMSO-d6): δ 0.94
(s, 3H), 1.16 (s, 3H), 2.63 (t, J=5.3 Hz, 3H), 2.81 (d, J=9.4 Hz,
1H), 2.93 (m, 1H), 3.29 (d, J=9.2 Hz, 1H), 3.30 (m, 1H), 4.55 (m,
1H), 4.92 (dd, J=10.1, 2.0 Hz, 1H), 5.57 (br, 1H), 6.61 (dt, J=
8.1, 4.3 Hz, 1H), 6.79 (dd, J=7.3, 0.9 Hz, 1H), 6.92 (ddd, J=
13.4, 8.2, 0.9 Hz, 1H), 7.22 (m, 3H), 7.30 (m, 2H), 8.65 (br, 1H),
9.04 (br, 1H). HRMS (ESI): m/z calcd for [C20H25FN2O þ H]þ,
329.2024; found, 329.2021.
(1S,2R)-1-(7-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-
1-(3-fluorophenyl)-3-(methylamino)propan-2-ol Hydrochloride
(9t). This compound was prepared from 18t according to
method i. White powder. Yield: 68%. 1H NMR (400 MHz,
DMSO-d6): δ 0.97 (s, 3H), 1.16 (s, 3H), 2.64 (t, J=5.4 Hz, 3H),
2.82 (d, J=9.2 Hz, 1H), 3.00 (m, 1H), 3.29 (d, J=9.2 Hz, 1H),
3.34 (m, 1H), 4.57 (m, 1H), 4.92 (dd, J=10.0, 2.0 Hz, 1H), 5.64
(d, J=7.7 Hz, 1H), 6.64 (dt, J=8.1, 4.3 Hz, 1H), 6.82 (dd, J=7.4,
0.9 Hz, 1H), 6.93 (ddd, J=13.3, 8.2, 0.9 Hz, 1H), 7.13 (m, 3H),
7.40 (m, 1H), 8.67 (br, 1H), 8.88 (br, 1H). HRMS (ESI): m/z
calcd for [C20H24F2N2O þ H]þ, 347.1929; found, 347.1935.
Acknowledgment. The authors thank the Wyeth Discovery
Analytical Chemistry Department for the spectral data and
compound analysis. We also thank our management, Drs.
Ronald Magolda, Magid Abou-Gharbia, Leonard Freed-
man, and Menelas Pangalos for their support of this work.
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