5-piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists

Article abstract of DOI:10.1021/jm1007825

As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT₆ antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described.

Full text of DOI:10.1021/jm1007825

J. Med. Chem. 2010, 53, 7639–7646 7639
DOI: 10.1021/jm1007825
5-Piperazinyl-3-sulfonylindazoles as Potent and Selective 5-Hydroxytryptamine-6 Antagonists
Kevin G. Liu,*,† Albert J. Robichaud,*,† Ronald C. Bernotas,† Yinfa Yan,† Jennifer R. Lo,† Mei-Yi Zhang,†
Zoe A. Hughes,‡ Christine Huselton,§ Guo Ming Zhang,‡ Jean Y. Zhang,‡ Dianne M. Kowal,‡ Deborah L. Smith,‡
Lee E. Schechter,‡ and Thomas A. Comery‡
†Chemical Sciences, and ‡Discovery Neurosciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543, United States, and
§Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, United States
Received June 24, 2010
As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT6 receptor in
order to identify potent and selective ligands for cognitive enhancement. Herein we report the
identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT6
antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the
compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or
SAM-315) will be described.
Introduction
provided 10. Vicarious nucleophilic substitution with readily
available chloromethylsulfones introduced the sulfonyl group
to the core molecules (11). Reduction of the nitro group of 11
with Sn/HCl or catalytic hydrogenation followed by diazotiza-
tion and cyclication under basic conditions afforded the final
indozole compounds 14. The indazoles 14 were further alky-
lated at the 1-position to provide additional substituted com-
pounds such as 15. In the case of the substitution reaction at the
1-position of the indazoles, alkylation at the 2-position occa-
sionally was observed. However, the undesired isomer can be
easily separated from the desired product through chromatog-
raphy. In order to prepare the N-unsubstituted piperazine
derivatives 16, 15 was treated initially with ACECl followed
by decomposition with MeOH. Although we successfully pre-
pared a number of compounds 16 through this synthesis, in
general the reaction required harsh reaction conditions (reflux
with ACECl) and long reaction time (2 days) and often provided
poor yields or no desired product. To address this issue, an
improved synthesis of N-unsubstituted periazines 16 was devel-
oped and is depicted in Scheme 2. In this synthesis, the
piperazine was initially protected with a carboxybenzyl (Cbz)
group. The acid labile Cbz protecting group was chosen with the
consideration that it can survive the subsequent diazotization
conditions and yet be removed easily at the completion of the
synthesis. Initially we attempted the vicarious nucleophilic
substitution on 4-N-Cbz-piperazinyl substituted nitrobenzene
(structure not shown). Failure to identify any desired product
led us to modify the sequence of the functionalization of the
nitrobenzene. In this case vicarious nucleophilic substitu-
tion on fluorobenzene 9 was carried out first, followed by
addition of the substituted piperazine to 17 to afford the
desired indazole precursors 18. A similar reaction sequence
to that depicted in Scheme 1 was then followed to provide
the final compounds 16.
a
The 5-hydroxytryptamine-6 (5-HT6 ) receptor, first iden-
tifiedby molecular biologyinearly 1990s, hasbeena subjectof
intense research because of its CNS-selective location and
unique pharmacology.1 Over the past decade, a great number
of 5-HT6 ligands of both agonists and antagonists have been
reported.2-4 These compounds have served as excellent tools
to investigate the functional role of the 5-HT6 receptor in
greater detail. Selected ligands are depicted in Figure 1 (1,5,6
2,7,8 3,9,10 4,11 5,12 6,13,14 and 715,16) showing the diversity of
structural types in this area. Currently a number of com-
pounds from these classes are believed to be active in phase I
and phase II clinical trials for cognitive impairment in AD and
schizophrenia.12,17
As part of our continuing efforts in a multitargeted ap-
proach to identifying therapeutics for CNS diseases such as
schizophrenia and Alzheimer’s disease (AD), we have been
focused on several monoamine ligand receptors, the 5-HT6
receptor being one of them, in order to identify potent and
selective ligands as potential treatments for cognitive
dysfunction.18-21 Herein we report a series of 3-sulfonylpi-
perazinylindazoles of general type 8 (Figure 1) as potent and
selective 5-HT6 antagonists. The synthesis, SAR, and phar-
macokinetic and pharmacological activities of this potent
class of compounds will be described.
Chemistry
The general synthesis of 5-N-alkyl piperazinyl-3-sulfonyl-
indazoles of type 8 is depicted in Scheme 1. Nucleophilic sub-
stitution of 4-fluoronitrobenzenes 9 with N-alkylpiperazine
*To whom correspondence should be addressed. For K.G.L.: phone,
þ1-201-350-0129; fax, þ1-201-261-0623; e-mail, liuk@lundbeck.com.
For A.J.R.: phone, þ1-201-350-0357; fax, þ1-201-261-0623; e-mail, ajr@
lundbeck.com. Current address for K.G.L. and A.J.R.: Lundbeck
Research, 215 College Road, Paramus, NJ 07652.
a Abbreviations: ACECl, 1-chloroethyl chloroformate; 5-HT6, 5-hydro-
xytryptamine-6; AD, Alzheimer’s disease; Cbz, carboxybenzyl; MED, mini-
mum effective dose.
Syntheses of compounds with the piperazine substituted at
other positions of the aromatic core (4-, 6-, 7-) are depicted in
Schemes 3-5. For the synthesis of 4-piperazyl analogues 26,
commercially available 2,6-difluorobenzaldehyde 21 was
r
2010 American Chemical Society
Published on Web 10/08/2010
pubs.acs.org/jmc

7640 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Liu et al.
Figure 1. Selected 5-HT6 ligands.
Scheme 1a
a Reagents and conditions: (a) N-alkylpiperazine, K2CO3, DMF (85-98%); (b) ArCH2Cl, t-BuOK, THF (85-90%); (c) Sn, HCl or H2, Pd/C
(95-98%); (d) NaNO2, HCl; (e) K2CO3 (80-95%, two steps); (f) R2X, K2CO3 (50-90%); (g) ACECl, MeOH (20-50%).
Scheme 2a
a Reagents and conditions: (a) ArCH2Cl, t-BuOK, THF (80-90%); (b) N-Cbz-piperazine, K2CO3, DMF (85-98%); (c) SnCl2/HCl, EtOH;
(d) (i) NaNO2, HCl, (ii) K2CO3 (60-85%, three steps) (e) HBr in HOAc (70-90%); (f) (i) HBr in HOAr, (ii) Boc2O, (iii) R2X, K2CO3, (iv) TFA
(50-80%, three steps).

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7641
Scheme 3a
a Reagents and conditions: (a) N-Boc-piperazine, K2CO3 (71%); (b) NH2NH2, DMSO (57%); (c) I2, KOH, DMF (35%); (d) ArSO2Na, CuI, DMF
(15-50%); (e) HCl, MeOH/Et2O (40-90%).
Scheme 4a
a Reagents and conditions: (a) (i) (ClCH2CH2)NH HCl, K2CO3, n-BuOH; (ii) Boc2O, KOH, 1,4-dioxane (38%, two steps); (b) I2, KOH, DMF
3
(38%); (c) ArSO2Na, CuI, DMF (15-50%); (d) HCl, MeOH/Et2O (40-90%).
Scheme 5a
a Reagents and conditions: (a) N-alkylpiperazine, K2CO3, DMF (80%); (a) ArCH2Cl, t-BuOK, THF (85-90%); (c) (i) Sn, HCl or H2, Pd/C,
(ii) NaNO2, HCl, (iii) K2CO3 (60-80%, three steps); (d) H2, PtO2/C (60-70%); (e) ACECl, MeOH (20-30%).
chosen as the starting point. Nucleophilic substitution with 1
equiv of N-Boc-piperazine provided the monosubstituted
product 22, which was then treated with NH2NH2 to form
indazole 23. Iodonation at the 3-position of indazole 23 under
strong basic conditions afforded 24. Coupling of 24 with a
variety of sodium arylsulfinates provided compounds 25,
which readily furnished final compounds 26 by facile removal
of the Boc protecting group.
For the preparation of 6-substituted piperazyl analogues
31, shown in Scheme 4, commercially available 6-aminoinda-
zole 27 was reacted with bis(chloroethyl)amine followed by
capture of the product with a Boc protecting group. A
reaction sequence similar to that utilized for the 4-substituted
analogues (iodination, sulfination, deprotection) was then
followed to provide the final compounds 31.
For the synthesis of the 7-substituted piperazinyl deriva-
tives 37 (Scheme 5) we had to overcome issues with regiospe-
cific functionalization of the aromatic core. To that end, a
chloro group was used to block one of the possible substitu-
tion sites. Addition of the N-alkylpiperazine to 4-chloro-2-
fluoronitrobenzene afforded 2-substituted derivatives 33.
Now with the 4-position effectively blocked from nucleophilic
substitution, the addition of the sulfonyl moiety is uncompli-
cated and carried out in excellent yields to afford 34. Cycliza-
tion as before affords indazoles 35, and removal of the chloro
group is effected under standard dehalogenating reductive
conditions. Removalofthe alkyl groupofthe piperazine36, as
before, afforded the desired 7-substituted indazoles 37.
Results and Discussion
With access to all possible regioisomeric piperazinylinda-
zoles 8 at hand, evaluation of their binding affinity to the
target receptor, human 5-HT6 receptor, in a standard competi-
tion binding assay was conducted.22 Potent compounds (Ki<
20 nM) were further investigated for their functional activity in
a 5-HT6 receptor cyclase assay.22 The results are summarized in
Tables 1 and 2.
Initially we carried out extensive SAR of the arylsulfonyl
groups with the piperazine substitution at the 5-position (8af-8at,
Table 1). In general, this chemical series has a relatively flat SAR
in this region. A variety of arylsulfonyl group substitution
provided very potent compounds including the unsubstituted
phenyl derivative 8af (Ki = 1.9 nM). Nonetheless, there is a
clear trend that the 3-substituted phenylsulfonyl groups such
as 3-F-PhSO2 (8ah, Ki = 1.7 nM), 3-Cl-PhSO2 (8ak, Ki = 1.0
nM), 3-MeO-PhSO2 (8am, Ki = 1.1 nM), and 3-Me-Ph-SO2
(8ao, Ki = 0.9 nM) are preferred over other their 2- or
4-substituted counterparts. Heterocyclic and disubstituted
phenylsulfonyl groups were also tolerated and afforded po-
tent analogues (e.g., 8aq and 8ar). One of the more preferred
sulfonyl groups identified was 1-naphthalenesulfonyl group
(8at) with Ki = 1.1 nM. In general, and in alliance with our
experience with other active 5-HT6 series, the majority of
compounds (8af -at) in the molecular binding assay with
good potency also showed excellent activity in the cell-based
5-HT6 receptor cyclase assay. Although in general there is a

7642 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Table 1. SAR of Piperazine Positions and ArSO2 Groupsa
Liu et al.
Table 2. SAR of the N1-Substitutiona
compd position R1
Ar
Ki (nM) IC50 (nM) Imax (%)
compd
R1
R2
Ar
Ph
Ki (nM)
IC50 (nM)
Imax (%)
8aa
8ab
8ac
8ad
8ae
8af
8ag
8ah
8ai
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
7
H
H
H
H
H
3-F-Ph
134
125
134
88
8bb
8bc
8bd
8be
8bf
8bg
8bh
8bi
H
Me
Et
3.2
2.9
1.7
1.6
1.7
1.9
1.8
2.2
1.8
2.9
1.4
4.6
2
46
108
16
80
18
92
18
40
17
52
8
100
100
100
99
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
1-Naph
H
Ph
Me
H
Me
Me
Et
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
48
Me
H
100
100
100
99
Me Ph
1.9
5.5
1.7
5.2
4.0
1.0
8.1
1.1
12
8.8
54
99
Et
Me 2-F-Ph
Me 3-F-Ph
Me 4-F-Ph
Me 2-Cl-Ph
Me 3-Cl-Ph
Me 4-Cl-Ph
Me 3-MeO-Ph
Me 4-MeO-Ph
Me 3-Me-Ph
Me 4-Me-Ph
Me 2-thienyl
Me 2,6-diCl-Ph
Me 1-Naph
100
99
Me
H
n-Pr
n-Pr
i-Pr
i-Pr
i-Bu
i-Bu
Bn
132
467
101
62
98
8bj
Me
H
98
8aj
100
100
100
100
100
100
100
96
8bk
8bl
100
100
100
100
100
8ak
8al
Me
H
108
57
8bm
8bn
8bo
50
7.2
32
8am
8an
8ao
8ap
8aq
8ar
8as
8at
8au
8av
8aw
8ax
8ay
8bz
8ba
Me
H
544
38
Bn
7.5
0.9
4.9
7.8
2.6
1.6
1.1
11
a Displacement of [3H]LSD binding to cloned human 5-HT6 receptors
stably expressed in HeLa cells.22 All compounds tested were HCl salts.
Ki values were determined in triplicate.
112
331
40
100
100
100
8
13
(Ki = 1.1 and 1.6 nM, IC50 = 13 and 8 nM, respectively).
However, larger alkyl and benzyl substituted derivatives
afforded compounds with significantly reduced potency at the
5-HT6 receptor (data not shown).
Next we investigated the SAR of the N1-substitution,
shown in Table 2. In general, substitution at this position
resulted in a slight loss of potency with larger alkyl groups in
particular. Although the compounds were less potent, we did
discover that these N1-substituted compounds possess im-
proved pharmacokinetic properties worthy of additional
interest (vide infra).
H
H
H
H
H
H
H
1-Naph
3-F-Ph
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
4-CF3-Me
1-Naph
110
27
124
207
22
Me 1-Naph
4.6
17
100
a Displacement of [3H]LSD binding to cloned human 5-HT6 receptors
stably expressed in HeLa cells.22 All compounds tested were HCl salts.
Ki values were determined in triplicate.
A number of selected compounds that displayed satisfac-
tory potency in both the binding and cyclase functional assays
were further profiled for their selectivity against a panel of
receptors including several other 5-HT receptor subtypes,
adrenergic R2A and dopamine D2 receptors, and the data
are summarized in Table 3. In general, these compounds
showed >200-fold selectivity over all the receptors examined
with the exception of 5-HT2B. This was initially some concern
to us, as 5-HT2B agonism activity has been indicted by several
studies to possibly be responsible for adverse cardiovascular
effects associated with some serotonin ligands.23 To rule out
the adverse potential of these analogues, they were then
screened for their potential functional agonist activity in a
5-HT2B FLIPR assay.24 To our satisfaction, no agonist activity
was observed for all compounds at 0.1 nM to 10 μM in this
functional assay.
In pharmacokinetic studies 8as displayed 5% bioavailabil-
ity following oral administration in rats at a 10 mg/kg dose.
However, the des-methyl derivative 8at (WAY-255315, later
designated SAM-315), an independently synthesized ana-
logue as well as the metabolite of 8as, was identified as having
optimized pharmacokinetic properties. To our satisfaction,
8at showed improved bioavailability relative to 8as in both
rodents and dogs (F>20%), although it maintained relatively
poor brain exposure properties (brain/plasma of <0.20).
Compound 8at has excellent water solubility (>100 μg/mL)
and low brain and plasma protein binding (80-85%) and
correlation between the data of the binding and functional
assays, exceptions happened more than sporadically. In these
cases, unfortunately, wedo nothave good explanations. Inthe
past we have seen differential functional efficacy within a
series of compounds. However, all the compounds in this
chemical series tested in the functional assay demonstrated
full antagonism. Worthy of note is that alkylsulfonyl groups
were not tolerated in this region and often provided signifi-
cantly less active compounds (data not shown).
With the 1-naphthalenesulfonyl group (8at, Ki = 1.1 nM)
identifiedasthepreferredaryl substituent within5-piperazinyl
series derivatives, we then prepared the corresponding com-
pounds with the piperazine at other alternative positions
(4-, 6-, and 7-) on the phenyl ring. One can easily see that
5-piperazinyl derivative defines the optimal position for these
arylsulfonyl substituted analogues. Compound 8ba with the
piperazine at the 7-position (Ki = 4.6 nM) is nearly 5-fold less
potent than the 5-substituted analogue, 8at, while compounds
8ae (Ki = 48 nM) and 8az (Ki = 22 nM), with a piperazine at
4- and 6-positions, respectively, are much less potent than 8at.
This trend of the 5-piperazinyl analogues being preferred was
further affirmed by the decreased potency of other com-
pounds with the piperazine at the 4- or 6-position (8aa-ad,
8au-ay) compared to their 5-position counterparts. In addi-
tion, it was observed that unsubstituted piperazine and N-Me
piperazine derivatives 8at and 8as have comparable potency

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7643
Table 3. Selectivity of Selected 5-Piperazinyl-3-sulfonylindazole Derivativesa
compd
5-HT6 (nM)
5-HT1a (nM)
5-HT1b (nM)
5-HT1d (nM)
5-HT2b (nM)
5-HT2c (nM)
5-HT7 (nM)
R2a (nM)
D2 (nM)
8af
1.9
1.6
1.1
1.6
2.9
4.6
7.5
>5000
>5000
573
>5000
>5000
>5000
3624
>5000
>5000
>5000
2761
978
601
236
87
3067
>5000
>5000
3648
753
579
>5000
>5000
>5000
>5000
>5000
>5000
>5000
355
334
8as
8at
1563
>5000
2243
2036
1903
605
8be
8bk
8bm
8bo
1780
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
96
1075
1880
281
141
1070
a Ki values were determined in triplicate.
Figure 3. 8at enhances memory after a 48 h delay in a novel object
recognition task in rats.
Figure 2. 8at blocks a scopolamine-induced memory deficit in a
novel object recognition task in rats.
displayed over 200-fold selectivity over more than 80 other
receptors, enzymes, and ion channels. In the novel object
recognition assay (NOR) in rats,25 8at significantly blocked
scopolamine-induced memory deficit with an MED of 0.03 mg/
kg (Figure 2) and enhanced retention after a 48 h delay with an
MED of 3 mg/kg (Figure 3) in a dose-dependent manner. In the
in vivo microdialysis studies in rats,26 8at significantly increased
acetylcholine and glutamate release in hippocampus of the
brain in a time-course study (Figures 4 and 5).
To further improve the physical properties of the 5-piper-
azinyl-3-sulfonylindazoles series, compounds with N1-alkyl
substitution were synthesized. As mentioned previously,
N1-alkyl compounds (e.g., 8bk, 8bm, and 8bo) displayed
improved pharmacokinetic properties including both oral bio-
availability and brain penetration. For example, compound
8bo showed >50%oral bioavailability in rodents and a brain/
plasma ratio greater than 0.5 following oral administration.
Further profiling of these N1-alkylated compounds will be
reported in due course.
Figure 4. 8at increases in acetylcholine (ACh) release in rat brains.
In summary, we have identified a novel series of 5-piper-
azinyl-3-sulfonylindazoles as potent, selective, orally avail-
able, and brain-penetrant 5-HT6 antagonists. Synthesis and
detailed SAR of this class of compounds have been reported.
Compound 8at has been identified as an advanced candidate
with greater than 200-fold selectivity verses more than 80
receptors, ion channels, and enzymes and desired physical and
pharmacokinetic properties. Compound 8at displayed good
efficacy in a variety of cognitive behavioral assays and
increased release of neurotransmitters such as acetylcholine
and glutamate in the brain as measured by microdialysis.
Figure 5. 8at increases glutamate release in rat brains.
recorded on a Varian instrument in the cited deuterated sol-
vents. Chemical shifts are given in ppm, and coupling constants
are in hertz. All final compounds were purified by flash chro-
matography using 220-400 mesh silica gel or reverse-phase
HPLC with CH3CN/water as the solvents. Thin-layer chroma-
tography was done on silica gel 60 F-254 (0.25 nm thickness)
Experimental Section
General. All solvents and reagents were obtained commer-
cially and used as received. 1H and 13C NMR spectra were

7644 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Liu et al.
plates. Visualization was accomplished with UV light and/or
10% phosphomolybdic acid in ethanol. Nominal (low resolution)
mass spectra were acquired on either a Waters LCT oran Applied
Biosystems API 3000 mass spectrometer. High resolution mass
spectra (HRMS) were acquired on either a Waters LCT or an
Agilent TOF mass spectrometer. All other LC-MS experiments
were done on an Agilent 1100 HPLC coupled with an Agilent
single quadrupole mass spectrometer. Compound purity was
determined by a LC-MS with 230 and 254 nm wavelengths.
All final compounds reported here have purity of g95%.
1-Me-4-(4-nitrophenyl)piperazine (10, R1 = Me). A stirred
solution of 1-methylpiperazine (3.55 g, 35.4 mmol), 4-fluoro-
nitrobenzene (5.0 g, 35.4 mmol), and K2CO3 (4.9 g, 35.4 mmol)
in DMF is heated at 70 °C under nitrogen for 18 h, cooled, diluted
with water, and extracted with EtOAc. The combined extracts
are dried over MgSO4 and concentrated in vacuo to give a solid
residue. The solid is triturated with 20:80 ethyl acetate-hexanes
and filtered. The filtercake is air-dried to afford the title com-
pound as orange crystals, 7.8 g (89% yield). 1H NMR (400
MHz, DMSO-d6) δ ppm 2.19 (d, 3 H), 2.40 (t, J = 5.1 Hz, 4H),
3.47 (t, J = 5.0, 4H), 7.00 (d, J = 9.9 Hz, 2H), 8.01 (d, J = 9.8
Hz, 2H). MS (ESþ) m/e 222 (M þ H)þ.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.15-3.4
(m, 8H), 7.27 (d, J = 1.7 Hz, 1H), 7.25-7.50 (m, 4H), 8.00-8.10
(m, 2H). MS (ESþ) m/e 375 (M þ H)þ.
3-(2-Chlorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8aj). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 3.00-3.20
(m, 8H), 7.05-7.21 (m, 2H), 7.50-7.65 (m, 4H), 8.16 (dd, J =
7.7 and 1.4 Hz, 1H). MS (ESþ) m/e 391 (M þ H)þ.
3-(3-Chlorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8ak). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.10-3.20 (m,
8H), 7.20-7.30 (m, 2H), 7.51-7.95 (m, 5H). MS (ESþ) m/e 391
(M þ H)þ.
3-(4-Chlorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8al). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.20-3.40 (m,
8H), 7.15-7.55 (m, 3H), 7.63 (d, J = 8.5 Hz, 2H), 7.95 (d, J =
8.4 Hz, 2H). MS (ESþ) m/e 391 (M þ H)þ.
3-(3-Methoxyphenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-
indazole (8am). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H NMR
(400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.85 (s, 3H), 3.15-3.40
(m, 8H), 7.15-7.55 (m, 7H). MS (ESþ) m/e 387 (M þ H)þ.
3-(4-Methoxyphenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-
indazole (8an). The title compound was prepared using essen-
tially the same procedure as described for the preparation of 8as.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.16-3.38
(m, 8H), 3.76 (s, 3H), 7.06 (d, J = 9.0 Hz, 2H), 7.15-7.45 (m,
3H), 7.87 (d, J = 9.0 Hz, 2H). MS (ESþ) m/e 387 (M þ H)þ.
5-(4-Methylpiperazin-1-yl)-3-(m-tolylsulfonyl)-1H-indazole (8ao).
The title compound was prepared using essentially the same proce-
dure as described for the preparation of 8as. 1H NMR (400 MHz,
DMSO-d6) δppm2.20(s, 3H), 2.33(s, 3H),3.10-3.20(m, 8H),7.18
(d, J = 2.1 Hz, 1H), 7.28 (dd, J = 9.2 and 2.1 Hz, 1H), 7.40-7.80
(m, 5H). MS (ESþ) m/e 371 (M þ H)þ.
1-Methyl-4-{4-nitro-3-[(1-naphthalenesulfonyl)methyl]phenyl}-
piperazine (11, R1 = Me, Ar = 1-Naph). A stirred solution of
1-methyl-4-(4-nitrophenyl)piperazine (4.0 g, 18.1 mmol) and
chloromethyl-1-naphthalenesulfonyl (4.35 g, 18.1 mmol) in dry
THF under nitrogen at -60 °C is treated with 1.0 M KO-t-Bu in
THF (40 mL, 40 mmol), warmed to -20 °C over a 1 h period,
quenched with acetic acid, and treated sequentially with water,
saturated aqueous NaHCO3, and ether. The phases are separated,
and the aqueous phase is extracted with ether. The combined ethers
are washed with water and brine, dried over MgSO4, and concen-
trated in vacuo. The resultant residue is chromatographed (silica
gel, 1:1 and 1:0 ethyl acetate-hexanes as eluent) to give the title
1
compound as a yellow solid, 6.72 g (87% yield). H NMR (400
MHz, DMSO-d6) δ ppm 2.20 (d, 3 H), 2.23 (t, J = 5.1 Hz, 4H),
3.10 (t, J = 5.0, 4H), 5.22 (s, 2H), 6.82-8.60 (m, 10H). MS (ESþ)
m/e 426 (M þ H)þ.
5-(4-Methylpiperazin-1-yl)-3-tosyl-1H-indazole (8ap). The title
compound was prepared using essentially the same procedure as
described for the preparation of 8as. 1H NMR (400 MHz,
DMSO-d6) δ ppm 2.20 (s, 3H), 2.30 (s, 3H), 3.09-3.11 (m, 8H),
7.20-7.30 (m, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 7.5 Hz,
1H), 7.82 (d, J = 8.3 Hz, 2H). MS (ESþ) m/e 371 (M þ H)þ.
5-(4-Methylpiperazin-1-yl)-3-(thiophen-2-ylsulfonyl)-1H-indazole
(8aq). The title compound was prepared using essentially the
same procedure as described for the preparation of 8as. 1H NMR
(400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.10-3.20 (m, 8H),
7.15-7.35 (m, 3H), 7.50 (d, J = 9.1 Hz, 1H), 7.80-8.00 (m, 2H).
MS (ESþ) m/e 363 (M þ H)þ.
4-(4-Methylpiperazine-1-yl)-2-[(1-naphthalenesulfonyl)methyl]-
aniline (12, R1 = Me, Ar = 1-Naph). A mixture of 1-benzyl-4-{4-
nitro-3-[(1-naphthalenesulfonyl)methyl]phenyl}piperazine (6.77 g,
15.0 mmol) and granular tin (7.48 g, 63.0 mmol) in methanol and
concentrated hydrochloric acid is heated at 45 °C for 4 h, stirred
at ambient temperature for 18 h, carefully poured into saturated
aqueous NaHCO3, treated with ether, and stirred for 0.5 h. The
phases are separated, and the aqueous phase is extracted sequen-
tially with ether and CH2Cl2. The extracts and organic phase are
combined, dried over MgSO4, and concentrated in vacuo. The
resultant residue is dissolved in CH2Cl2 and filtered through
Celite. The filtrate is concentrated in vacuo to afford the title
compound as a pale yellow solid, 6.11 g (97% yield). 1H NMR
(400 MHz, DMSO-d6) δ ppm 2.10 (d, 3 H), 2.20 (t, J = 5.1 Hz,
4H), 2.37 (t, J = 5.0, 4H), 4.60 (s, 2H), 6.40-6.50 (m, 2H),
7.61-8.62 (m, 8H). MS (ESþ) m/e 396 (M þ H)þ.
3-(2,6-Dichlorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-
indazole (8ar). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 3.10-3.40 (m,
8H), 7.12 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 9.3 and 2.2 Hz, 1H),
7.50-7.65 (m, 4H). MS (ESþ) m/e 425 (M þ H)þ.
3-(2-Fluorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8ag). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.85 (b, 3H), 3.11-3.30 (m,
4H), 3.53 (b, 2H), 3.78 (b, 2H), 7.32 (s, 1H), 7.39-7.48 (m, 2H),
7.50-7.51 (m, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.75-7.85 (m, 1H),
8.1-8.2 (m, 1H). MS (ESþ) m/e 375 (M þ H)þ.
5-(4-Methylpiperazin-1-yl)-3-(1-naphthalenesulfonyl)-1H-inda-
zole (8as, R1 = Me, Ar = 1-Naph). A stirred solution of 4-(4-
methylpiperazine-1-yl)-2-[(1-naphthalenesulfonyl)methyl]aniline
(5.0 g, 12.6 mmol) in 4.0 M aqueous hydrochloric acid is cooled in
an ice bath, treated dropwise with NaNO2 (1.31 g, 19.0 mmol) in
water, stirred for 40 min, treated with 2.5 M aqueous NaOH to
pH ∼14, and filtered. The filtercake is dissolved in CH2Cl2 and
chromatographed (silica gel, ethyl acetate as eluent) to afford the
free indazole of the title product as a yellow solid (4.7 g, 91%). 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 3.10 (b, 2H),
3.20 (b, 2H), 3.53 (b, 2H), 3.80 (b, 2H), 7.27 (d, J = 1.8 Hz, 1H),
7.37(dd, J = 9.2and2.1 Hz, 1H), 7.60-7.80 (m, 4H), 8.09(d, J =
7.9 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.59 (d, J = 8.6 Hz, 1H),
8.82 (d, J = 8.4 Hz, 1H). MS (ESþ) m/e 407 (M þ H)þ.
3-(3-Fluorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8ah). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as. H
1
NMR (400 MHz, DMSO-d6) δ ppm 2.86 (d, J = 4.6 Hz, 3H),
3.10-3.25 (m, 4H), 3.54-3.56 (m, 2H), 3.85-3.86 (m, 2H), 7.36
(d, J = 2.2, 1H), 7.36-7.88 (m, 6H). MS (ESþ) m/e 375 (M þ H)þ.
3-(4-Fluorophenylsulfonyl)-5-(4-methylpiperazin-1-yl)-1H-in-
dazole (8ai). The title compound was prepared using essentially
the same procedure as described for the preparation of 8as.

Article
3-(Naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (8at,
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7645
1H), 7.11 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 9.3 and 2.2 Hz, 1H),
7.55-7.74 (m, 4H), 8.01 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.2 Hz,
1H), 8.52 (dd, J = 7.4 and 1.1 Hz, 1H), 8.86 (d, J = 8.8 Hz, 1H),
8.98 (b, 2H). MS (ESþ) m/e 435 (MHþ).
1-Isobutyl-5-(4-methylpiperazin-1-yl)-3-(naphthalen-1-ylsulfonyl)-
1H-indazole (8bl). The title compound was prepared using essen-
tially the same procedure as described for the preparation of 8bf. 1H
NMR (400 MHz, DMSO-d6) δ ppm 0.68 (d, J = 6.7 Hz, 6H), 2.20
(s,3H),2.26-2.29 (m, 1H), 3.20 (b, 3H), 3.30-3.40 (m, 8H), 4.22 (d,
J = 7.2 Hz, 2H), 7.00-7.75 (m, 6H), 8.01-8.80 (m, 4H). MS (ESþ)
m/e 463 (M þ H)þ.
Ar = 1-Naph). A mixture of benzyl 4-(3-(naphthalen-1-ylsul-
fonyl)-1H-indazol-5-yl)piperazine-1-carboxylate (2.50 g, 4.75 mmol)
and 30% HBr in HOAc (13.6 mL) was stirred at room temperature
for 2 h. Et2O (80 mL) was added. The brown precipitate was
filtered, washed with Et2O, treated with NaOH (1 N, 20 mL), and
extracted with 20% MeOH in EtOAc. Combined extracts were
dried over Na2SO4 and concentrated in vacuo to provide the title
compound (1.48 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm
3.22 (b, 4H), 3.32-3.33 (m, 4H), 7.21-7.32 (m, 2H), 7.52-7.74
(m, 3H), 8.03 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.52
(d, J = 7.3 Hz, 1H), 8.76 (d, J = 7.5 Hz, 1H), 9.15 (b, 1H).
MS (ESþ) m/e 393 (MHþ).
1-Isobutyl-3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-
indazole Dihydrochloride (8bm). tert-Butyl 4-(1-isobutyl-3-(naph-
thalen-1-ylsulfonyl)-1H-indazol-5-yl)piperazine-1-carboxylate
(0.40 g, 0.73 mmol) was treated with TFA (20 mL) at room
temperature for 1 h. The reaction mixture was concentrated to
dryness. The residue was dissolved in EtOAc and was added to
Et2O. The precipitate was filtered and washed with Et2O and
dried in vacuo to provide the title compound (0.34 g, 69%). 1H
NMR (400 MHz, CDCl3) δ ppm 0.66 (d, J = 6.6 Hz, 6H),
2.05-2.12 (m, 1H), 3.20 (b, 4H), 3.31-3.34 (m, 4H), 4.23 (d,
J = 7.2 Hz, 2H), 7.12 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 9.4 and
2.2 Hz, 1H), 7.54 (m, 2H), 7.70-7.74 (m, 2H), 8.00-8.02 (m,
1H), 8.23 (d, J = 8.4 Hz, 1H), 8.54 (dd, J = 7.4 and 1.0 Hz, 1H),
8.75 (dd, J = 9.6 and 1.6 Hz, 1H), 9.29 (b, 2H). MS (ESþ) m/e
449 (MHþ).
1-Benzyl-5-(4-methylpiperazin-1-yl)-3-(naphthalen-1-ylsulfonyl)-
1H-indazole (8bn). The title compound was prepared using essen-
tially the same procedure as described for the preparation of 8bf.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 2.45-2.47
(m, 4H), 3.03-3.06 (m, 4H), 5.66 (s, 2H), 7.00-7.74 (m, 11H),
8.01-8.77 (m, 4H). MS (ESþ) m/e 497 (M þ H)þ.
1-Methyl-5-(4-methylpiperazin-1-yl)-3-(naphthalen-1-ylsulfonyl)-
1H-indazole (8bd). The title compound was prepared using essen-
tially the same procedure as described for the preparation of 8bf. 1H
NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 3.15-3.41 (m,
8H), 4.02 (s, 3H), 7.10-7.75 (m, 6H), 8.05-8.80 (m, 4H). MS
(ESþ) m/e 421 (M þ H)þ.
1-Methyl-3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-inda-
zole Dihydrochloride (8be). The title compound was prepared using
essentially the same procedure as described for the preparation of
1
7.39 (61%). H NMR (400 MHz, CDCl3) δ ppm 3.32-3.52 (m,
8 H), 4.03 (s, 3 H), 7.22 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 9.4 and
2.3 Hz, 1H), 7.55-7.73 (m, 2H), 8.02 (d, J = 8.7 Hz, 1H), 8.26 (d,
J = 8.2 Hz, 1H), 8.51 (d, J = 7.4 Hz, 1H), 8.75 (d, J = 8.5 Hz, 1H),
9.18 (b, 2H). MS (ESþ) m/e 407 (MHþ).
1-Ethyl-5-(4-methylpiperazin-1-yl)-3-(naphthalen-1-ylsulfonyl)-
1H-indazole Hydrochloride (8bf, R1 = Me, Ar = 1-Naph). A
mixture of 5-(4-methylpiperazin-1-yl)-3-(1-naphthalenesulfonyl)-
1H-indazole hydrochloride (70 mg, 0.17 mmol), bromoethane
(27 mg, 0.17 mmol), and KOtBu in THF (0.2 mL, 0.2 mmol) in
DMF is stirred for 16 h at room temperature and diluted with water
and EtOAc. The organic phase is separated, dried over MgSO4, and
concentrated in vacuo. The resultant residue is chomatographed
(SiO2,80:20,then90:10EtOAc-hexanes as eluent) to afford the free
amine of the title product as a white solid (30 mg). 1H NMR (400
MHz, DMSO-d6) δ ppm 1.30 (t, J = 7.2 Hz, 3H), 2.19 (s, 3H),
3.15-3.40 (m, 8H), 4.45 (q, J = 7.2 Hz, 2H), 7.05-7.80 (m, 6H),
8.00-8.50 (m, 4H). MS (ESþ) m/e 435 (M þ H)þ.
1-Benzyl-3-(naphthalene-1-sulfonyl)-5-piperazin-1-yl-1H-indazole
Dihydrochloride (8bo). The title compound was prepared using
essentially the same procedure as described for the preparation of
8bm (0.35 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.29
(b, 4H), 3.23-3.36 (m, 4H), 7.10-7.20 (m, 5H), 7.32 (dd, J = 9.4
and 2.3 Hz, 1H), 7.58-7.64 (m, 2H), 7.69-7.74 (m, 2H), 8.00-8.04
(m, 1H), 8.25(d, J=8.2 Hz, 1H), 8.55 (dd, J=7.4and1.0Hz, 1H),
8.75-8.78 (m, 1H), 9.23 (b, 2H). MS (ESþ) m/e 483 (MHþ).
1-(5-Fluoro-2-nitrobenzylsulfonyl)naphthalene (17, Ar = 1-Naph).
To a stirred mixture of 4-fluoronitrobenzene (4.80 g, 34.1 mmol) and
1-(chloromethylsulfonyl)naphthalene (Aldrich, 8.20 g, 34.1 mmol)
in THF (75 mL) at -78 °C was slowly added KO-t-Bu (1 M in THF,
75 mL). The stirred mixture was allowed to warm to room
temperature for 2 h, quenched with water, and concentrated. The
residue was taken into water and extracted with EtOAc. The organic
layer was dried over Na2SO4 and concentrated in vacuo to provide
the title compound (9.50 g, 81%). MS (ESþ) m/e 346 (MHþ).
Benzyl 4-(3-((Naphthalen-1-ylsulfonyl)methyl)-4-nitrophenyl)-
piperazine-1-carboxylate (18, Ar = 1-Naph). A mixture of benzyl
piperazine-1-carboxylate (3.19 g, 14.5 mmol), 1-(5-fluoro-2-ni-
trobenzylsulfonyl)naphthalene (5.00 g, 14.5 mmol), and K2CO3
(4.00 g, 29.0 mmol) in DMF (32 mL) was stirred at 100 °C for 3 h,
cooled to room temperature, diluted with water, and extracted
with EtOAc. The organic layer was washed with water (3ꢀ),
dried over Na2SO4, and concentrated in vacuo to provide the title
compound (7.82 g, 94%), characterized by NMR and mass
spectral analyses. MS (ESþ) m/e 546 (MHþ).
1-Ethyl-3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-in-
dazole Dihydrochloride (8bg). The title compound was prepared
using essentially the same procedure as described for the prep-
aration of 8bm (57%). 1H NMR (400 MHz, CDCl3) δ ppm 1.29
(t, J = 7.2 Hz, 3H), 3.2 (b, 4H), 3.30-3.32 (m, 4H), 4.43 (t, J =
7.2 Hz, 2H), 7.16 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 9.3 and
2.1 Hz, 1H), 7.55-7.73 (m, 4H), 8.02 (d, J = 7.6 Hz, 1H), 8.25
(d, J = 8.2 Hz, 1H), 8.52 (dd, J = 7.4 and 1.2 Hz, 1H), 8.79 (d, J =
8.6 Hz, 1H), 9.10 (b, 2H). MS (ESþ) m/e 421 (MHþ).
3-(Naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1-propyl-1H-
indazole Dihydrochloride (8bi). The title compound was pre-
pared using essentially the same procedure as described for the
preparation of 8bm (70%). 1H NMR (400 MHz, CDCl3) δ ppm
0.62 (t, J = 7.6 Hz, 3H), 1.73 (q, J = 7.0 Hz, 2H), 3.21 (b, 4H),
3.26-3.32 (m, 4H), 4.38 (t, J = 6.7 Hz, 2H), 7.14 (d, J =
2.1 Hz, 1H), 7.33 (dd, J = 9.4 and 2.2 Hz, 1H), 7.55-7.73 (m,
4H), 8.02 (d, J = 9.3 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.53
(dd, J = 7.3 and 1.2 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 9.09 (b,
2H). MS (ESþ) m/e 435 (MHþ).
1-Isopropyl-5-(4-methylpiperazin-1-yl)-3-(naphthalen-1-ylsulfonyl)-
1H-indazole (8bj). The title compound was prepared using essentially
the same procedure as described for the preparation of 8bf. 1H NMR
(400 MHz, DMSO-d6) δ ppm 1.41 (d, J = 6.6 Hz, 6H), 2.20 (s, 3H),
3.20-3.41 (m, 8H), 4.96-5.03 (m, 1H), 7.00-7.75 (m, 6H),
8.00-8.90 (m, 4H). MS (ESþ) m/e 449 (M þ H)þ.
Benzyl 4-(4-Amino-3-((naphthalen-1-ylsulfonyl)methyl)phenyl)-
piperazine-1-carboxylate (19, Ar = 1-Naph). A mixture of benzyl
4-(3-((naphthalen-1-ylsulfonyl)methyl)-4-nitrophenyl)piperazine-1-
carboxylate (7.82 g, 14.3 mmol), SnCl2 (16.2 g, 71.7 mmol), and
concentrated HCl (1.8 mL) in EtOH (191 mL) was heated at 80 °C
overnight, diluted with CH2Cl2, and neutralized with Na2CO3 to
basic condition. The mixture was passed through a pad of Celite. The
solution was concentrated in vacuo to provide the crude title com-
pound (7.72 g), which was carried forward into the next step of the
reaction without further purification. MS (ESþ) m/e 516 (MHþ).
1-Isopropyl-3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-
1H-indazole dihydrochloride (8bk). The title compound was
prepared using essentially the same procedure as described for
1
the preparation of 8bm (30%). H NMR (400 MHz, CDCl3) δ
ppm 1.40 (d, J = 6.6 Hz, 6H), 3.21-3.30 (m, 8H), 4.99-5.03 (m,

7646 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Liu et al.
Benzyl 4-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-5-yl)piperazine-
1-carboxylate (20, Ar = 1-Naph). To a solution of crude benzyl 4-(4-
amino-3-((naphthalen-1-ylsulfonyl)methyl)phenyl)piperazine-
1-carboxylate (7.72 g) in 1 N HCl (249 mL) and MeOH (500 mL) at
0°C was added NaNO2 solution (2.07 g, 29.9 mmol in 20 mL water)
dropwise over a period of 10 min. The mixture was stirred for an
additional 30 min, and carefully neutralized with NaHCO3 solution
to pH ∼10. The brown precipitate was filtered and washed with
water and dried in vacuo to provide the title compound (5.8 g, 77%
overall, two steps), characterized by NMR and mass spectral
analyses. MS (ESþ) m/e 527 (MHþ).
tert-Butyl 4-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-5-yl)pi-
perazine-1-carboxylate. A mixture of 3-(naphthalen-1-ylsulfonyl)-
5-(piperazin-1-yl)-1H-indazole dihydrochloride salt (2.00 g, 4.00
mmol), Boc2O (1.02 g, 4.66 mmol), and triethylamine (1.65 g,
16.3 mmol) in DMF (15.5 mL) was heated at 50 °C overnight,
diluted with water, and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated in vacuo to provide the
title compound (2.00 g, 99%), characterized by NMR and mass
spectral analyses. MS (ESþ) m/e 493 (MHþ).
tert-Butyl 4-(1-Isobutyl-3-(naphthalen-1-ylsulfonyl)-1H-inda-
zol-5-yl)piperazine-1- carboxylate. To a solution of tert-butyl
4-(3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl)piperazine-1-carboxy-
late (0.50 g, 1.02 mmol) in DMF (5.1 mL) was added KO-t-Bu (1 M
THF solution, 1.5 mL) followed by isobutyl iodide (0.139 g, 1.02
mmol). The mixture was stirred overnight, diluted with water, and
extracted with EtOAc. The organic layer was washed with water
(3ꢀ), dried over Na2SO4, concentrated in vacuo, and purified by
chromatography with EtOAc-hexanes to provide the title com-
pound (0.401 g, 73%), characterized by NMR and mass spectral
analyses. MS (ESþ) m/e 549 (MHþ).
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Acknowledgment. We thank James Mattes, Yanxuan Cai,
Donald Herold, Sergio Anis, and Alvin Bach for their ana-
lytical chemistry support.
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