Reactions of functionalized sulfonamides: Application to lowering the lipophilicity of cytosolic phospholipase A2α inhibitors

Article abstract of DOI:10.1021/jm8009876

The cPLA₂α inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD _7.4. To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA₂α inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA₂α inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD_7.4 values 3- 4 units lower than previously synthesized compounds and yet maintain in vitro potency.

Full text of DOI:10.1021/jm8009876

1156
J. Med. Chem. 2009, 52, 1156–1171
Reactions of Functionalized Sulfonamides: Application to Lowering the Lipophilicity of
Cytosolic Phospholipase A2r Inhibitors|
Lihren Chen,†,| Weiheng Wang,† Katherine L. Lee,† Marina W. H. Shen,‡ Elizabeth A. Murphy,‡ Wen Zhang,‡ Xin Xu,§
Steve Tam,† Cheryl Nickerson-Nutter,‡ Debra G. Goodwin,‡ James D. Clark,‡ and John C. McKew*,†
Departments of Chemical and Screening Sciences, Inflammation, and Drug Safety and Metabolism, Wyeth Research,
200 CambridgePark DriVe, Cambridge, Massachusetts 02140
ReceiVed August 4, 2008
The cPLA2R inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays
but have high plogD7.4. To address these issues, reactions of electrophilic sulfonamides 9-12 were employed
to incorporate various heterocyclic or heteroatom-based reagents into cPLA2R inhibitors. For example,
reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues
that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10
and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided
an efficient way to introduce polarity into cPLA2R inhibitors. Finally, we report the first application of
(2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides
allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD7.4
values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
Introduction
guideline,7 our highly lipophilic, high molecular weight inhibi-
torshaveshownloworalbioavailabilityinstandardformulations.4a-c
In the work reported here, our overall goal was to improve the
bioavailability of these compounds. Since those inhibitors have
comparable potency in both enzymatic and RWB assays, cell
permeability is not a concern. We hypothesized that increased
solubility might lead to higher exposure, and we focused our
medicinal chemistry efforts on the synthesis of analogues with
lower lipophilicity. Throughout this effort, we hoped to maintain
the in vitro potency of these cPLA2R inhibitors. Introduction
of heteroatoms into the inhibitors was the route taken for this
effort of lowering lipophilicity, and the region most amenable
toheteroatomincorporationappearedtobetheC2 sulfonamide.4a-c
Cytosolic phospholipase A2R (cPLA2R,a group IVA phos-
pholipase) is the only phospholipase with specificity for sn-2
arachidonyl containing membrane phospholipids.1 Its enzymatic
action generates arachidonic acid (AA) and a lysophospholipid,
both of which are precursors to proinflammatory molecules
including prostaglandins (PGs), leukotrienes (LTs), and platelet-
activating factor (PAF).1,2 Inhibition of this enzyme is thus
envisaged to be a powerful way to lower the production of many
important downstream inflammatory mediators with a single
therapeutic agent. An inhibitor of cPLA2R would be a novel
therapeutic for the treatment of arthritis, pain, asthma, multiple
sclerosis, stroke, atherosclerosis, or other diseases where these
mediators play a role.3
Chemistry
We have recently discovered a class of potent and selective
indole-based cPLA2R inhibitors containing three pharmacoph-
ores, i.e., N1-benzhydryl, C2-primary sulfonamide, and C3-linked
benzoic acid such as compounds 1-5 in Figure 1.4c The
compounds in Figure 1 are potent in isolated enzyme and whole
The most common approach to prepare sulfonamides is a
direct coupling of an amine with a sulfonyl chloride. In our
published work,4a-c we employed commercially available
sulfonyl chlorides or prepared them from the corresponding alkyl
halides by formation of the sulfonate followed by chlorination.4a,8
However, these methods are of limited use for the work reported
here, since most commercial sulfonyl chlorides and alkyl halides
are hydrocarbon-based and few contain heteroatoms, especially
nitrogens. In addition, preparing sulfonyl chlorides individually
can be tedious and hazardous because of the corrosive nature
of chlorinating reagents such as chlorine gas, oxalyl chloride,
or thionyl chloride.
blood assays but have high calculated plogD7.4 of 7-9. Other
4a-e
previously reported Wyeth inhibitors
and the only other
class of compounds with activity in blood reported by Shionogi5
have similarly high plogD7.4 values.
The tendency to select for a lipophilic inhibitor is consistent
with the fact that cPLA2R works at the membrane-cytosol
interface and binds arachidonyl glycerol phospholipid (6, MW
768.1, plogD7.4 ) 10.44) as one of its natural substrates (Figure
2) in a deep active site.6 In accord with Lipinski’s “rule of five”
An alternative approach of making sulfonamide analogues
entails reactions of nucleophiles with sulfonamides containing
electrophilic centers, i.e., electrophilic sulfonamides, such as
9-12 in Scheme 1. This approach allows various heteroatom-
bearing nucleophiles to be introduced directly to a late stage
intermediate. The use of activated sulfonamides would assuage
the need to protect the sulfonamide NH, one of our key
pharmacophores.4c A survey of the literature revealed that
reactions of chloromethanesulfonamides containing an unpro-
tected NH, such as 8, with heteroatom nucleophiles typically
result in ring formation.9
|
Dedicated to Professor Chi-Huey Wong on the occasion of his 60th
birthday.
* To whom correspondence should be addressed. Phone: (617) 665-5603.
Fax: (617) 665-5682. E-mail: jmckew@wyeth.com.
†
Department of Chemical and Screening Sciences.
Department of Inflammation.
Department of Drug Safety and Metabolism.
‡
§
a Abbreviations: cPLA2R, cytosolic phospholipase A2R; GLU, 7-hy-
droxycoumarinyl γ-linolenate; RWB, rat whole blood; HWB, human whole
blood; PG, prostaglandin; LT, leukotriene; TX, thromboxane; PAF, platelet-
activating factor; CPE, carrageenan paw edema; ESI, electrospray ionization;
LC-MS, liquid chromatography-mass spectroscopy; AA, arachidonic acid.
10.1021/jm8009876 CCC: $40.75
2009 American Chemical Society
Published on Web 01/29/2009

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1157
Figure 1. Wyeth cPLA2R inhibitors.
Schiff base formation rather than formation of the desired
sulfonamide 11. We found, howeVer, that by performance of
the reaction in a biphasic system, Schiff base formation was
deterred, and we were able to demonstrate the first synthetic
application of this important and Versatile (2-formylphenyl)-
methanesulfonyl chloride 13.
Figure 2. Representative natural substrate of cPLA2R.
Chloromethanesulfonamide 9 was prepared by the reaction
of indole amine 74c with chloromethanesulfonyl chloride
(Scheme 1). Reactions of chloromethanesulfonamide 9 with
nitrogen, oxygen, and sulfur nucleophiles were scanned. When
treated with morpholine, 9 reverted to indole amine 7, which
might result from cleavage of the sulfonamide product (Scheme
2) as suggested in the literature with related compounds.10
Reaction of chloromethanesulfonamide 9 with phenol gave
a complex mixture from which a minor component was
identified as the desired product by LC-MS. On the other hand,
reactions of 9 with an array of substituted thiophenols went
smoothly to provide thioethers (Scheme 3). Oxidation of
thioether 24 using mCPBA resulted in the corresponding
sulfoxide 25, which after ester hydrolysis, afforded 38, which
has a significant lower plogD7.4 than the thioether analogue 36
(plogD7.4 for 36/38 ) 9.3/7.2). Attempts to further oxidize 25
to the corresponding sulfone, however, led to decomposition.
The desired product might not be stable under oxidative
conditions, as has been reported with 1,3-dicarbonyl deriva-
tives.11 The vastly different reaction profiles among nitrogen,
oxygen, and sulfur nucleophiles were quite intriguing. We
postulate that the nitrogen and oxygen atoms of the respective
nucleophilic addition products might have better σ* overlap with
the neighboring carbon compared to the corresponding sulfur,
and this might contribute to their instability compared to the
sulfur analogue.
Vinylsulfonamide 10 was prepared by the reaction of 7 with
chloroethanesulfonyl chloride (Scheme 1). Michael reactions
of vinylsulfonamide 10 with aromatic heterocycles in most cases
progressed smoothly at elevated temperature without additional
activators (Scheme 4). The reaction of 10 with 1H-tetrazole
occurred after heating at 100 °C overnight to afford, after
hydrolysis, two regioisomers, 83 and 84. In contrast, reaction
of 10 with 1H-1,2,3-triazole predominantly afforded 82. The
reaction of 10 with aliphatic amines was more efficient, as
expected, and most reactions were facile at room temperature.
In some cases, performing the reactions in refluxing 1-butanol
was necessary to promote complete conversion.
Results and Discussion
The assays used to characterize the inhibitors have been
previously described.4b,c Briefly, the GLU micelle uses purified
human cPLA2R with the substrate 7-hydroxycoumarinyl-γ-
linolenate (GLU) presented in a micelle containing a high
concentration of detergent and lipid to limit artifacts due to
disruption of the membrane interface by compounds that could
inhibit without directly interacting with cPLA2R. The rat whole
blood (RWB) assay monitors thromboxane production, which
is dependent on cPLA2R to release arachidonic acid, which is
then processed by the COX-1 pathway. This assay requires that
the inhibitors are membrane permeable to reach cPLA2R in the
cytosol and still active in the presence of serum albumin.
Additional supporting assays are the human whole blood (HWB)
assay and the murine MC-9 mast cell assay, which provide
additional information on possible species selectivity, cellular
permeability, and the effect of serum albumin binding.
Thioether Series. All of the sulfonamide analogues we
synthesized were evaluated in the GLU and RWB assays.4b,c
In general, the thioether derivatives gave good correlation
between these assays. The introduction of thioether linkage was
tolerated, since 26 compared favorably in potency with the
phenethyl analogue 75.4c Compound 31 emerged as the most
potent inhibitor in this series, with whole blood activity
comparable to that of lead compound 4 (Table 1). In contrast
to the phenylmethanesulfonamide series,4a-c monosubstitution
at the 2-position (27, 28) did not improve in vitro activity.
Furthermore, 2,6-disubstitution (29, 33), found previously to
lead to potent analogues,4a instead led to a 2- to 3-fold decrease
in activity in both assays.
We next examined the effect of different oxidation states of
the sulfur on activity. By comparison of thioether 36 and the
corresponding sulfoxide 38 (Table 1), the GLU activity of 38
was essentially unchanged, while the RWB activity decreased
by 4-fold. The sulfoxide was also marginally less potent in the
MC-9 cellular assay (Table 6) and HWB (data not shown). Thus,
the modest improvement in plogD7.4 was offset by the apparent
loss in cellular activity. The sulfonylsulfonamide 40, with a
remarkably low plogD7.4 value of 4.5, was well tolerated.
Nitrogen Series. Introduction of basic nitrogen atoms is an
effective means to lower the lipophilicity of an inhibitor. Indeed,
we observed that reactions of 10 with various nitrogen-
containing heteroaromatics and subsequent hydrolysis of the
esters afforded new analogues with plogD7.4 up to 3 log units
lower than that of 75 (Table 2). Interestingly, the GLU activities
for this series were all quite similar, ranging from 0.32 to 0.76
Lastly, we incorporated small basic amines into the phenyl-
methanesulfonamide. Although Buchwald-Hartwig amination
of aryl bromide has been widely used,12 the resulting aniline
analogues would not be basic enough to lower plogD. Therefore,
our strategy was to prepare aldehyde 12 and subsequently
perform reductive amination reactions as depicted in Scheme
5. The synthesis of (2-formylphenyl)methanesulfonyl chloride
13 has been reported;13 to our knowledge, there are no reports
in the literature of its reaction with amines. We speculated that
the reaction of amine 8 and sulfonyl chloride 13 might lead to

1158 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Scheme 1. Synthesis of Electrophilic Sulfonamidesa
Chen et al.
a Reagents: (a) ClSO2CH2Cl, DCM/NaHCO3/H2O; (b) ClSO2CH2CH2Cl, Et3N, THF; (c) 13, DCM/NaHCO3/H2O.
Scheme 2. Reaction of 9 with Morpholinea
a Reagents: (a) ClSO2CH2Cl, DCM/NaHCO3/H2O; (b) morpholine, K2CO3, MeCN.
Scheme 3. Synthesis of Thioether Analogues 26-36a
Scheme 5. Introduction of Nitrogen Nucleophiles by Reductive
Amination of 12a
a Reagents: (a) HNR1R2, NaBH(OAc)3, DCE; (b) NaOH, MeOH, THF.
a Reagents: (a) ArSH, K2CO3, MeCN; (b) NaOH, MeOH, THF.
84 is essentially inactive in the MC-9 cellular assay, which
suggests the drop in potency is due to loss of cellular activity.
Sulfonamide 76 is an example of a compound with nanomolar
potency in the RWB assay and a plogD7.4 of 4.65.
Scheme 4. Addition of Nitrogen Nucleophiles to
Vinylsulfonamides 10 and 11a
Reactions of aliphatic amines with compound 10 were also
examined (Table 3). In general, the piperidine analogues were
more potent than the corresponding pyrrolidine counterparts in
the RWB assay. Since the former also have slightly higher
plogD7.4 values, this might indicate that better activities were
conferred by higher lipophilicity, a reflection of the natural
substrate. We observed that in pyrrolidine, piperidine, and
morpholine derivatives, a 2-alkyl group on the heterocycles
improved the activity in both assays. The 2-methyl (87 and 103)
and 2,6-dimethyl (90 and 104) piperidine and pyrrolidine
analogues were among the most active inhibitors, although they
also had relatively high plogD7.4 values. Of the three methylpi-
peridine isomers, the 2-methyl derivative (87) was more potent
than the corresponding 3- and 4-counterparts (88 and 89,
respectively). The existence of polar groups such as hydroxyl,
carboxamide, or thiocarboxamide on the heterocycles appeared
to reduce the potency in both assays as exemplified by 92 vs
89, 98 vs 87, and 109 vs 103. The effect was more pronounced
in the RWB in the five-membered heterocycles such as 109 and
110 where the carboxamide or thiocarboxamide group was
adjacent to the linking nitrogen. The diminished level of activity
seen in the RWB was also seen in the HWB assay and in the
a Reagents: (a) HNR1R2, BuOH; (b) NaOH, MeOH, THF.
µM, despite varied numbers of heteroatoms (two to four)
introduced. The two tetrazole analogues 83 and 84 demonstrate
how regioisomers can have dramatic differences in activity.
Despite similar potency in the cell free assay, 83 and 84 differed
12-fold in their RWB activities. Similarly, the HWB IC50 of 83
is ∼2.0 µM, whereas 84 gives <25% inhibition at 10 µM and

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1159
Table 2. Heteroaryl Analogues
Table 1. Thioether Analogues
IC50 (µM)
RWB TXB2
b
compd
X
R
GLUa
plogD7.4
1
2
Ph
3,4-Cl2 Ph
Ph
Ph
2-Cl Ph
2-Me Ph
2,6-Me2 Ph
2,5-(OMe)2 Ph
2,4-F2 Ph
2,4-Cl2 Ph
2,6-Cl2 Ph
3,5-Cl2 Ph
3-Cl-4-F Ph
3,4-Cl2 Ph
3,4-Cl2 Ph
Me
0.11
0.15
0.50
0.19
0.15
0.15
0.33
0.33
0.14
0.30
0.60
0.20
0.17
0.24
0.18
0.15
0.12
0.11
0.63
0.075
0.090
0.080
0.30
6.9
8.4
7.4
7.9
8.6
8.4
8.9
8.0
8.3
9.3
9.3
9.3
8.8
9.3
7.2
4.5
75
26
27
28
29
30
31
32
33
34
35
36
38
40
CH2
S
S
S
S
S
S
S
S
S
S
S
SdO
SO2
0.24
0.030
0.080
0.16
0.14
0.070
0.14
0.56
0.48
a Assay protocol reported previously;4b,c values are generated from at
least two runs, and each run consists of a mean value generated from
duplicate assays. b Assay protocol reported previously;4b,c values are
generated from at least two runs, and each run consists of a mean value
generated from triplicate assays.
MC-9 cellular assay. Compounds 80, 84, and 109 have the
largest shift in IC50 between our enzymatic and whole blood
assays among the hundreds of compounds prepared for this
program. It is noteworthy that compounds 110 and 95, with
plogD7.4 of less than 4, had IC50 of ∼1 µM in the GLU but
much higher RWB activities. On the other hand, some modi-
fications to introduce more heteroatoms or heterocycles were
tolerated, such as 91 and 94, although these did not lower the
plogD7.4 to the same extent. Remarkably, 93 is of comparable
potency to compound 2, and yet it has a plogD7.4 of 4.3, 4 log
units lower than 2. This demonstrates that it is possible to modify
the sulfonamide region of these compounds to greatly reduce
the lipophilicity of the cPLA2R inhibitors while maintaining the
in vitro activity.
Next, the effect of the C3 linker was examined. Selected pairs
of heterocycles at C2 were prepared with different linker atoms
at the benzoic acid moiety (Table 4). In agreement with the
SAR we reported earlier,4a it was found that our inhibitors with
the all-carbon linker at C3 consistently give better activities in
both assays. This increase in potency might be reflective of the
higher plogD7.4 values of derivatives bearing the all-carbon
linker compared to the ether-linked analogues: typically, the
plogD7.4 values differ by 1 log unit.
(2-Formylphenyl)methanesulfonamide Series. Although we
had succeeded in lowering the lipophilicity of our cPLA2R
inhibitors synthesized via the Michael reaction strategy, potency
remained a hurdle. Since ortho substitution of the phenyl-
methanesulfonamide moiety had a positive impact on potency,4a
we sought to further explore this area. All of the new analogues,
compared to their 2-methyl counterpart, 124,4a have lower
plogD7.4 as well as comparable or improved activity in the GLU
and comparable or slightly inferior activity in the RWB assay
(Table 5). Compound 129 emerged as the most potent inhibitor
a Assay protocol reported previously;4b,c values are generated from at
least two runs, and each run consists of a mean value generated from
duplicate assays. b Assay protocol reported previously;4b,c values are
generated from at least two runs, and each run consists of a mean value
generated from triplicate assays.
in GLU in this series but suffered a 5-fold loss in RWB.
Similarly, compound 130, with a plogD7.4 of 3.95, was potent
in GLU but lost more activity than expected in the RWB assay.
In general, the measured IC50 values in HWB are higher than
that seen in RWB. This could be because a higher concentration
of calcium ionophore A23187 is used to give reproducible
stimulation of blood in humans. Interestingly, 128-131 were
all essentially equipotent in RWB and HWB (data not shown),
indicating that these compounds could have better potency in
humans than predicted preclinically.
MC-9 Assay Data.4b,.c In order to evaluate whether the new
inhibitors prepared in this work are acting on cPLA2R intrac-
ellularly, compounds were subjected to the MC-9 assay4b,c
(Table 6). In this murine mast cell-like cell line, cross-linking
of the IgE receptor with antigen activates cPLA2R, resulting in
the release of AA, which is converted into both PGs via the

1160 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Table 3. Aliphatic Amine Analogues
Chen et al.
a Assay protocol reported previously;4b,c values are generated from at least two runs, and each run consists of a mean value generated from duplicate
assays. b Assay protocol reported previously;4b,c values are generated from at least two runs, and each run consists of a mean value generated from triplicate
assays.
COX-1 pathway and LTs via the 5-LO pathway. Addition of
exogenous AA will bypass cPLA2R and be processed by the
COX-1 pathway to generate PGF2R. Thus, N-[1-(1-benzothien-
2-yl)ethyl]-N-hydroxyurea (zileuton),14 a 5-LO inhibitor, blocks
only LTB4 production, while (2S)-2-(6-methoxy-2-naphthyl)-
propanoic acid (naproxen), an inhibitor of COX-1 and -2, and
(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-
1H-pyrazole) 132 (SC-560),15 a COX-1 inhibitor, block PGF2R
from both IgE stimulation and exogenously added AA. 4-[5-
(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide (celecoxib)16 is also active despite being a selective
COX-2 inhibitor because at this concentration it inhibits COX-
1. The cPLA2R inhibitors block both PG and LT production
upon IgE cross-linking and are inactive with addition of
exogenous AA, thus demonstrating selective inhibition of
cPLA2R versus COX-1 and -2. Data from representative
compounds of the thioether (31, 36, 38, 40), heteroaryl (79,
83, 84), and aliphatic amine (87, 93, 103, 104) series are
presented.
As noted above, the MC-9 assay was also used to interpret
poor RWB activity for compounds that were active in cell-free
assays. For example, compounds 84 and 109 are poorly active
in both RWB and MC-9 assays, suggesting that the loss in RWB
potency is due to poor cellular permeability and not to an
increase in serum binding.
Rat Carrageenan Paw Edema (CPE) Model.17 Three of
the aliphatic amine analogues and compound 3 were tested in
the rat CPE model,14 an acute inflammation model, and were

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1161
Table 4. Effect of C-3 Linkers on Potency and plogD7.4
Table 6. MC-9 Assay Data for Selected Compoundsa
% inhibition @ µM inhibitorb
compd
LTB4
PGF2R
PGF2R AA feed
40
38
36
31
79
83
84
87
100 @ 0.5
55 @ 0.11
64 @ 0.037
94 @ 0.037
89 @ 0.11
80 @ 0.333
59 @ 1.0
62 @ 0.037
76 @ 0.11
62 @ 0.11
80 @ 0.11
41 @ 0.33
69 @ 0.11
50 @ 0.55
not active
not active
not active
100 @ 0.5
45 @ 0.11
48 @ 0.037
77 @ 0.037
83 @ 0.11
71 @ 0.33
19 @ 1.0
45 @ 0.037
66 @ 0.11
56 @ 0.11
69 @ 0.11
41 @ 0.33
71 @ 0.11
not active
79 @ 0.0005
50 @ 0.40
50 @ 0.20
-47 @ 0.5
1.4 @ 1.0
33 @ 1.0
47 @ 1.0
5 @ 1.0
4 @ 1.0
-5 @ 1.0
14 @ 1.0
6 @ 1.0
13 @ 1.0
-2 @ 1.0
8 @ 1.0
91
93
104
109
115
zileuton
132
celecoxib
naproxen
9 @ 1.0
not active
79 @ 0.0005
50 @ 0.30
50 @ 0.33
a Assay protocol reported previously.4b,c b Most compounds were assayed
at 0.037, 0.11, 0.33, and 1 µM, and the % inhibition at the concentration
that gave >50% inhibition is reported.
Table 7. Rat CPE Data for Selected Compoundsa
dose % inhibition plasma concnb
plasma concnb
compd (mg/kg) of edema
(ng/mL)
SD
(µM)
naproxen
3
10
15
15
15
15
50
51
27.9
37.0
23.5
3970
193.6
165.6
114.2
1000
80.1
10.7
15.8
5.3
91c
0.270
0.232
0.163
104d
115d
a Assay protocol reported previously;4b,c values are generated from at
least two runs, and each run consists of a mean value generated from
duplicate assays. b Assay protocol reported previously;4b,c values are
generated from at least two runs, and each run consists of a mean value
generated from triplicate assays.
a Assay protocol reported previously.4b,c b End bleed concentration with
iv dosing using 50/50 PEG/DMSO formulation; mean values from five mice.
c Data derived from one single dose, with 10 mice per group. d Data derived
from one dose response experiment for each compound, with 10 mice per
group.
Table 5. Sulfonamide Analogues with Basic Amines
compared to naproxen, which was used to determine the
maximum % inhibition (Table 7). These analogues and 3 have
similar potency in rat whole blood. cPLA2R inhibitors were
dosed at 15 mg/kg iv, and the plasma concentration and
inhibition of paw edema was determined 3 h later. All
compounds were effective, but 3 and naproxen inhibited paw
swelling by 50%, which is the maximal response generally seen.
The superior activity of 3 can be attributed to the significantly
higher level of exposure.
Summary. We have demonstrated the utility of electrophilic
sulfonamides 9-12 as efficient and versatile intermediates in
the preparation of cPLA2R inhibitors with lower lipophilicity.
Thiophenols have been added to chloromethanesulfonamide 9
to prepare thioether analogues and a corresponding sulfoxide.
Various aromatic heterocycles and aliphatic amines have been
added to vinylsulfonamide 10 in Michael fashion to provide
new inhibitors with lower lipophilicity. We have shown that it
is possible to retain comparable RWB activity and lower the
lipophilicity by 3-4 orders of magnitude (e.g., compounds 77,
78, 93, and 130). Polar substituents such as hydroxyl, carboxa-
mide, or thiocarboxamide had a negative impact on the RWB
activity. Low molecular weight amines have been reacted with
formyl derivative 12 to lead to new analogues with lower
lipophilicity and good potency in both assays. There appears
to be a fine balance between plogD7.4 and in vitro activity.
Overall, we have demonstrated the utility of electrophilic
sulfonamides in the preparation of cPLA2R inhibitors with
reduced lipophilicity. The SAR in the cell free and RWB assays
diverged for a small subset of compounds, but the MC-9 assay
and HWB assays suggested that these compounds were not cell
permeable. The aliphatic amine analogues were efficacious in
a Assay protocol reported previously;4b,c values are generated from at
least two runs, and each run consists of a mean value generated from
duplicate assays. b Assay protocol reported previously;4b,c values are
generated from at least two runs, and each run consists of a mean value
generated from triplicate assays.

1162 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Chen et al.
1H-indol-3-yl]propyl}benzoate4a 8 (63 mg, 0.12 mmol) in DCM
(1.4 mL) were added (2-formylphenyl)methanesulfonyl chloride6
(13, 36 mg, 0.16 mmol) and saturated NaHCO3 (1 mL), and the
reaction mixture was allowed to stir at room temperature for
4 h followed by extractive workup. Purification by flash column
chromatography using EtOAc/hexanes (20-35%) afforded 34
mg (40%) of sulfonamide 12, a yellow solid. 1H NMR (400 MHz,
acetone-d6) δ 1.82-1.89 (m, 2 H), 2.62-2.74 (m, 6 H), 3.72 (s,
3 H), 4.75 (s, 2 H), 6.25 (t, J ) 6.1 Hz, 1 H), 6.39 (d, J ) 8.8
Hz, 1 H), 6.62 (dd, J ) 8.8, 2.3 Hz, 1 H), 6.97 (s, 1 H),
6.98-7.04 (m, J ) 7.5, 2.1 Hz, 4 H), 7.20-7.27 (m, 9 H), 7.34
(d, J ) 2.3 Hz, 2 H), 7.39-7.48 (m, 2 H), 7.76-7.84 (m, 2 H),
10.10 (s, 1 H).
the rat CPE model at 15 mg/kg iv, but the efficacy was not as
robust as past compounds because of lower plasma concentra-
tions. Multiple examples of compounds with significantly lower
plogD7.4 that maintained nanomolar potency in the RWB assay
were discovered in this effort. Compounds 77, 78, 93, and 130
are among the most polar cPLA2R inhibitors to have ever
demonstrated this level of potency in a whole blood assay.
Experimental Section
General Procedures. All solvents and reagents were used as
obtained. All reaction mixtures were stirred using a magnetic stir
bar, and reactions were conducted at room temperature unless
otherwise noted. Solutions were dried with MgSO4 unless otherwise
noted. Proton NMR spectra were recorded at 300 MHz on a Varian
Gemini 2000 or on a 400 MHz Bruker AV-400 spectrometer using
TMS (δ 0.0) as a reference. Combustion analyses were obtained
using a Perkin-Elmer series II 2400 CHNS/O analyzer. CHN
analyses were carried out by Robertson-Microlit. Low resolution
mass spectra were obtained using a Micromass Platform electro-
spray ionization quadrapole mass spectrometer. High resolution
mass spectra were obtained using a Bruker (Billerica, MA) APEXIII
Fourier transform ion cyclotron resonance (FT-ICR) mass spec-
trometer equipped with an actively shielded 7 T superconducting
magnet (Magnex Scientific Ltd., U.K.) and an external Bruker
APOLLO electrospray ionization (ESI) source. Flash chromatog-
raphy was performed using EM Science 230-400 mesh silica gel
or Biotage flash columns packed with KP-SIL 60 Å silica gel. Thin-
layer chromatography (TLC) was performed using EMD 250 µm
prescored silica gel 60 F254 plates. Preparative HPLC was run using
a Waters Prep 4000 LC system or a Waters 2525 binary gradient
system. Purity in two solvent systems (H2O-CH3CN and
H2O-MeOH) was determined using an Agilent 1100 HPLC
instrument, and all final compounds were >95% pure.
Procedure for Chloromethylsulfonamide Formation. Methyl 4-{2-
[1-Benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-
1H-indol-3-yl]ethoxy}benzoate (9). To a solution of methyl 4-{2-[2-
(2-aminoethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-
yl]ethoxy}benzoate4c 7 (304 mg, 0.564 mmol) in DCM (3.6 mL)
were added chloromethanesulfonyl chloride (92 mg, 0.62 mmol)
and saturated NaHCO3 (1.8 mL). The reaction mixture was stirred
at room temperature overnight followed by extractive workup to
give the crude product (367 mg), a white foam, which was used
without further purification.
Representative Procedure for Vinylsulfonamide Synthesis (10
and 11). Methyl 4-[2-(5-Chloro-1-(diphenylmethyl)-2-{2-[(vinylsulfo-
nyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (10). To a solution
of 74c (330 mg, 0.612 mmol) in THF (4 mL) were added Et3N
(0.196 mL, 1.41 mmol) and 2-chloroethanesulfonyl chloride (0.072
mL, 0.73 mmol). The reaction mixture was allowed to stir at room
temperature for 4 h followed by extractive workup and column
chromatography using EtOAc/hexanes (30-35%) to give 262 mg
(68%) of the title product as a solid. 1H NMR (300 MHz, acetone-
d6) δ 3.12-3.22 (m, 2 H), 3.24-3.35 (m, 4 H), 3.82 (s, 3 H), 4.34
(t, J ) 6.7 Hz, 2 H), 5.85 (d, J ) 10.2 Hz, 1 H), 5.98 (d, J ) 16.5
Hz, 1 H), 6.49-6.55 (m, 1 H), 6.58 (d, J ) 9.3 Hz, 1 H), 6.79 (dd,
J ) 8.8, 2.2 Hz, 1 H), 7.01 (d, J ) 9.1 Hz, 2 H), 7.14-7.20 (m,
5 H), 7.32-7.40 (m, 6 H), 7.69 (d, J ) 1.6 Hz, 1 H), 7.92 (d, J )
8.8 Hz, 2 H).
Methyl 4-[3-(5-Chloro-1-(diphenylmethyl)-2-{2-[(vinylsulfonyl)ami-
no]ethyl}-1H-indol-3-yl)propyl]benzoate (11). Compound 11 was
prepared from 84a in a similar manner to 10 in 63% yield. 1H NMR
(300 MHz, acetone-d6) δ 1.93-2.02 (m, 2 H), 2.78-2.90 (m, 4
H), 3.03-3.21 (m, J ) 20.9, 7.1 Hz, 4 H), 3.86 (s, 3 H), 5.86 (d,
J ) 10.2 Hz, 1 H), 5.91-6.04 (m, 1 H), 6.44 (s, 1 H), 6.48-6.61
(m, 2 H), 6.76 (dd, J ) 8.8, 1.9 Hz, 1 H), 7.12-7.20 (m, 5 H),
7.32-7.40 (m, 8 H), 7.49 (d, J ) 1.9 Hz, 1 H), 7.92 (d, J ) 8.2
Hz, 2 H).
Representative Procedures. Procedure A: Thiophenol dis-
placement. See synthesis of 14; Procedure B: Ester hydrolysis,
see synthesis of 26; Procedure C: Michael addition, see synthesis
of 99; Procedure D: Reductive animation, see synthesis of 120.
Procedure A: Thiophenol Displacement. Methyl 4-(2-{1-Ben-
zhydryl-5-chloro-2-[2-({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-
1H-indol-3-yl}ethoxy)benzoate (14). A solution of compound 9 (96
mg, 0.147 mmol), PhSH (0.018 mL, 0.18 mmol), and K2CO3 (24.8
mg, 0.179 mmol) in acetonitrile (1.2 mL) was stirred overnight
and then heated to reflux for 3 h. The reaction mixture was diluted
with EtOAc, washed with cold NH4Cl, dried over MgSO4, and
evaporated. The residue was purified by silica gel chromatography
(1% MeOH/DCM) to afford the thioether intermediate 14 (51 mg,
48%). 1H NMR (300 MHz, acetone-d6) δ 3.19-3.34 (m, 6 H), 3.83
(s, 3 H), 4.31 (t, J ) 6.7 Hz, 2 H), 4.41 (s, 2 H), 6.54 (d, J ) 8.8
Hz, 1 H), 6.70 (t, J ) 5.5 Hz, 1 H), 6.78 (dd, J ) 8.8, 2.2 Hz, 1
H), 7.01 (d, J ) 8.5 Hz, 2 H), 7.12-7.17 (m, 5 H), 7.21-7.30 (m,
3 H), 7.32-7.39 (m, 6 H), 7.45-7.54 (m, 2 H), 7.68 (d, J ) 1.9
Hz, 1 H), 7.92 (d, J ) 8.5 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2-chlorophenyl)sul-
fanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (15).
Reaction of 9 with 2-chlorothiophenol afforded 15 in 53% yield.
1H NMR (300 MHz, CDCl3) δ 2.94-3.03 (m, 2 H), 3.08-3.17
(m, 2 H), 3.22 (t, J ) 6.6 Hz, 2 H), 3.88 (s, 3 H), 4.08 (s, 2 H),
4.22 (t, J ) 6.5 Hz, 2 H), 4.55 (t, J ) 6.0 Hz, 1 H), 6.54 (d, J )
8.8 Hz, 1 H), 6.80-6.88 (m, 3 H), 6.92 (s, 1 H), 7.08 (d, J ) 3.8
Hz, 4 H), 7.13-7.20 (m, 2 H), 7.28-7.38 (m, 7 H), 7.49 (dd, J )
7.4, 1.9 Hz, 1 H), 7.55 (d, J ) 1.9 Hz, 1 H), 7.95 (d, J ) 8.8 Hz,
2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2-methylphenyl)sul-
fanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (16).
Reaction of 9 with 2-methylthiophenol afforded 16 in 45% yield.
1H NMR (300 MHz, CDCl3) δ 2.36 (s, 3 H), 2.93 (q, J ) 6.7 Hz,
2 H), 3.05-3.16 (m, 2 H), 3.20 (t, J ) 6.5 Hz, 2 H), 3.88 (s, 3 H),
4.01 (s, 2 H), 4.21 (t, J ) 6.5 Hz, 2 H), 4.44 (t, J ) 6.0 Hz, 1 H),
6.53 (d, J ) 8.8 Hz, 1 H), 6.78-6.88 (m, 3 H), 6.91 (s, 1 H),
7.02-7.12 (m, 5 H), 7.12-7.18 (m, 2 H), 7.23-7.35 (m, 6 H),
7.39 (d, J ) 7.4 Hz, 1 H), 7.54 (d, J ) 1.9 Hz, 1 H), 7.95 (d, J )
9.1 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,6-dimethylphenyl)-
sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (17). Reaction of 9 with 2,6-dimethylthiophenol afforded 17
in 32% yield. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 6 H),
2.82-2.95 (m, 2 H), 3.09 (t, J ) 7.6 Hz, 2 H), 3.20 (t, J ) 6.9 Hz,
2 H), 3.88 (s, 3 H), 4.21 (t, J ) 6.6 Hz, 2 H), 4.31 (t, J ) 6.5 Hz,
1 H), 6.53 (d, J ) 9.1 Hz, 1 H), 6.79-6.94 (m, 4 H), 7.01-7.16
(m, 7 H), 7.22-7.35 (m, 6 H), 7.55 (s, 1 H), 7.96 (d, J ) 8.2 Hz,
2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,5-dimethoxyphenyl)-
sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (18). Reaction of 9 with 2,5-dimethoxythiophenol afforded
1
18 in 65% yield. H NMR (300 MHz, CDCl3) δ 2.87-3.01 (m, 2
H), 3.00-3.13 (m, 2 H), 3.19 (t, J ) 6.6 Hz, 2 H), 3.67 (s, 3 H),
3.73 (s, 3 H), 3.88 (s, 3 H), 4.06-4.15 (m, 2 H), 4.20 (t, J ) 6.6
Hz, 2 H), 4.77 (t, J ) 5.8 Hz, 1 H), 6.50 (d, J ) 8.8 Hz, 1 H),
6.68-6.93 (m, 7 H), 7.00-7.13 (m, 5 H), 7.23-7.37 (m, 5 H),
7.54 (s, 1 H), 7.95 (d, J ) 8.5 Hz, 2 H).
Methyl 4-{3-[5-Chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)-
sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (12). To a solu-
tion of methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1163
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,4-difluorophenyl)-
thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (19).
Reaction of 9 with 2,4-difluorothiophenol afforded 19 in 27% yield.
1H NMR (300 MHz, CDCl3) δ 2.98-3.08 (m, 2 H), 3.10-3.28
(m, 4 H), 3.88 (s, 3 H), 3.91 (s, 2 H), 4.24 (t, J ) 6.3 Hz, 2 H),
4.57 (t, J ) 6.0 Hz, 1 H), 6.54 (d, J ) 9.1 Hz, 1 H), 6.72-6.80
(m, 1 H), 6.81-6.90 (m, 4 H), 6.93 (s, 1 H), 7.09 (d, J ) 3.6 Hz,
4 H), 7.32 (d, J ) 3.0 Hz, 6 H), 7.40-7.50 (m, 1 H), 7.56 (s, 1 H),
7.95 (d, J ) 9.1 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)-
sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (20). Reaction of 9 with 2,4-dichlorothiophenol afforded 20
in 50% yield. 1H NMR (300 MHz, CDCl3) δ 2.96-3.30 (m, 6 H),
3.88 (d, J ) 2.2 Hz, 3 H), 4.01 (d, J ) 1.9 Hz, 2 H), 4.24 (t, J )
6.5 Hz, 2 H), 4.58 (t, J ) 6.2 Hz, 1 H), 6.49-6.59 (m, 1 H),
6.80-6.89 (m, 3 H), 6.92 (s, 1 H), 7.04-7.16 (m, 5 H), 7.22-7.48
(m, 8 H), 7.52-7.59 (m, 1 H), 7.89-8.00 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)meth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (133). A mix-
ture of methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-
indol-3-yl]ethoxy}benzoate (100 mg, 0.19 mmol), (methanesulfonyl)-
methanesulfonyl chloride (46 mg, 0.24 mmol), pyridine (0.045 mL,
0.56 mmol), and CH2Cl2 (4 mL) was stirred at room temperature
for 2 h and then at 65 °C for 1 h. The mixture was cooled to room
temperature, and saturated aqueous NH4Cl (10 mL) was added, and
the mixture was extracted with CH2Cl2 (2 × 10 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated. Purification by flash chromatography (20-50%
EtOAc/hexane) afforded 26 as a white foam (56 mg, 43% yield).
1H NMR (300 MHz, CDCl3) δ 2.98-3.13 (m, 5 H), 3.13-3.30
(m, 4 H), 3.87 (s, 3 H), 4.17 (s, 2 H), 4.24 (t, J ) 6.5 Hz, 2 H),
5.23-5.36 (m, 1 H), 6.54 (d, J ) 9.1 Hz, 1 H), 6.78-6.90 (m, 3
H), 6.93 (s, 1 H), 7.09 (dd, J ) 5.6, 3.4 Hz, 4 H), 7.28-7.39 (m,
5 H), 7.56 (d, J ) 1.9 Hz, 1 H), 7.95 (d, J ) 8.8 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,6-dichlorophenyl)-
sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (21). Reaction of 9 with 2,6-dichlorothiophenol afforded 21
in 16% yield. 1H NMR (300 MHz, CDCl3) δ 2.89-3.02 (m, 2 H),
3.09-3.20 (m, 2 H), 3.24 (t, J ) 6.6 Hz, 2 H), 3.88 (d, J ) 1.6
Hz, 3 H), 4.03 (s, 2 H), 4.23 (t, J ) 6.5 Hz, 2 H), 4.92 (t, J ) 6.2
Hz, 1 H), 6.54 (d, J ) 9.1 Hz, 1 H), 6.79-6.95 (m, 4 H), 7.04-7.22
(m, 6 H), 7.23-7.43 (m, 7 H), 7.57 (d, J ) 2.2 Hz, 1 H), 7.96 (dd,
J ) 9.1, 1.6 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,5-dichlorophenyl)-
sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (22). Reaction of 9 with 3,5-dichlorothiophenol afforded 22
in 40%. 1H NMR (300 MHz, CDCl3) δ 3.00-3.10 (m, 2 H),
3.13-3.27 (m, 4 H), 3.88 (s, 3 H), 4.01 (s, 2 H), 4.24 (t, J ) 6.5
Hz, 2 H), 4.53 (t, J ) 6.2 Hz, 1 H), 6.55 (d, J ) 8.8 Hz, 1 H), 6.85
(d, J ) 8.5 Hz, 3 H), 6.94 (s, 1 H), 7.09 (d, J ) 4.9 Hz, 4 H),
7.24-7.36 (m, 9 H), 7.55 (d, J ) 1.6 Hz, 1 H), 7.95 (d, J ) 9.1
Hz, 2 H).
Procedure D: Michael Addition. Methyl 4-(2-{1-Benzhydryl-5-
chloro-2-[2-({[2-(4-morpholinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-
3-yl}ethoxy)benzoate (63). A solution of 10 (70.0 mg, 0.111 mmol)
and morpholine (0.100 mL, 1.14 mmol) in ethanol (1 mL) was
stirred for 5 h. The solvent was evaporated and the residue was
dissolved in EtOAc and washed with water and brine to give 63
1
(71 mg, 89%). H NMR (300 MHz, acetone-d6) δ 2.20-2.40 (m,
4 H), 2.64 (t, J ) 7.1 Hz, 2 H), 3.01-3.15 (m, 2 H), 3.27-3.38
(m, 3 H), 3.41-3.58 (m, 4 H), 3.82 (s, 3 H), 4.34 (t, J ) 6.7 Hz,
2 H), 6.29-6.40 (m, 1 H), 6.57 (d, J ) 9.1 Hz, 1 H), 6.79 (dd, J
) 8.9, 2.1 Hz, 1 H), 6.97-7.04 (m, 2 H), 7.13-7.24 (m, 5 H),
7.27-7.41 (m, 6 H), 7.69 (d, J ) 1.9 Hz, 1 H), 7.92 (d, J ) 9.1
Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-pyrazol-1-yl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (41). Reaction
of 10 with pyrazole afforded 41 in 90% yield. 1H NMR (300 MHz,
CD3OD) δ 2.95-3.05 (m, 2 H), 3.07-3.16 (m, 2 H), 3.26 (t, J )
6.6 Hz, 2 H), 3.38 (t, J ) 6.7 Hz, 2 H), 3.86 (s, 3 H), 4.29 (t, J )
6.5 Hz, 2 H), 4.44 (t, J ) 7.0 Hz, 2 H), 6.21 (t, J ) 2.2 Hz, 1 H),
6.34 (t, J ) 1.8 Hz, 1 H), 6.47 (d, J ) 9.1 Hz, 1 H), 6.73 (dd, J )
8.9, 2.1 Hz, 1 H), 6.94 (d, J ) 9.1 Hz, 2 H), 7.04-7.13 (m, 5 H),
7.27-7.34 (m, 6 H), 7.43 (d, J ) 1.6 Hz, 1 H), 7.56 (dd, J ) 17.2,
2.1 Hz, 2 H), 7.91 (d, J ) 8.8 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyra-
zol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (42).
Reaction of 10 with 3-methylpyrazole afforded 42 in 88% yield.
1H NMR (300 MHz, CDCl3) δ 2.34-2.39 (m, 3 H), 2.72-2.91
(m, 2 H), 3.00-3.11 (m, 2 H), 3.14-3.24 (m, 2 H), 3.27-3.38
(m, 2 H), 3.84-3.91 (m, 3 H), 4.15-4.26 (m, 2 H), 4.39 (t, J )
5.1 Hz, 2 H), 4.50-4.67 (m, 1 H), 5.94 (d, J ) 15.4 Hz, 1 H),
6.13 (s, 1 H), 6.50 (dd, J ) 8.8, 1.9 Hz, 1 H), 6.76-6.92 (m, 4 H),
7.01-7.13 (m, 4 H), 7.25-7.36 (m, 5 H), 7.53 (d, J ) 4.7 Hz, 2
H), 7.93-8.01 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyra-
zol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (43).
Reaction of 10 with 4-methylpyrazole afforded 43 in 81% yield.
1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3 H), 2.80-2.91 (m, 2 H),
3.06 (t, J ) 7.1 Hz, 2 H), 3.21 (t, J ) 6.5 Hz, 2 H), 3.32 (t, J )
5.9 Hz, 2 H), 3.88 (s, 3 H), 4.21 (t, J ) 6.3 Hz, 2 H), 4.40 (t, J )
5.8 Hz, 2 H), 4.48-4.56 (m, 1 H), 6.50 (d, J ) 8.8 Hz, 1 H),
6.77-6.91 (m, 4 H), 7.01-7.15 (m, 4 H), 7.24-7.34 (m, 7 H),
7.48-7.57 (m, 2 H), 7.96 (d, J ) 8.8 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-fluorophe-
nyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (23). Reaction of 9 with 3-chloro-4-fluorothiophenol afforded
1
23 in 70% yield. H NMR (300 MHz, CDCl3) δ 2.95-3.09 (m, 2
H), 3.10-3.28 (m, 4 H), 3.88 (s, 3 H), 3.97 (s, 2 H), 3.99-4.05
(m, 1 H), 4.23 (t, J ) 6.0 Hz, 2 H), 4.63 (t, J ) 5.8 Hz, 1 H), 6.54
(d, J ) 8.8 Hz, 1 H), 6.79-6.88 (m, 4 H), 6.93 (s, 1 H), 7.04-7.12
(m, 4 H), 7.12-7.16 (m, 1 H), 7.27-7.35 (m, 6 H), 7.49-7.58
(m, 1 H), 7.90-7.98 (m, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)-
thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (24).
Reaction of 9 with 3,4-dichlorothiophenol afforded 24 in 61% yield.
1H NMR (300 MHz, CDCl3) δ 2.98-3.30 (m, 6 H), 3.88 (s, 3 H),
3.99 (s, 2 H), 4.24 (t, J ) 6.5 Hz, 2 H), 4.54 (t, J ) 5.9 Hz, 1 H),
6.55 (d, J ) 8.8 Hz, 1 H), 6.85 (d, J ) 9.1 Hz, 3 H), 6.94 (s, 1 H),
7.04-7.13 (m, 4 H), 7.21-7.38 (m, 8 H), 7.54 (dd, J ) 8.7, 1.8
Hz, 2 H), 7.95 (d, J ) 8.8 Hz, 2 H).
Methyl 4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)-
sulfinyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (25). To a solution of methyl 4-[2-(1-benzhydryl-5-chloro-2-
{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-
indol-3-yl)ethoxy]benzoate (150 mg, 0.19 mmol) in THF (1 mL)
at -78 °C was added 3-chloroperoxybenzoic acid (47 mg, 77%
max, 0.21 mmol) in THF (2 mL) dropwise, and the mixture was
stirred at -78 °C for 90 min and room temperature for 2 h. The
reaction mixture was diluted with EtOAc, washed with saturated
NaHCO3, water and brine, and dried over MgSO4. The volatiles
were removed and the residue was purified by flash column
chromatography (30% EtOAc-hexanes) to give 25 (64 mg, 42%)
along with unreacted starting material (32 mg, 21%). 1H NMR (400
MHz, CDCl3) δ 3.11-3.21 (m, 4 H), 3.24 (t, J ) 6.6 Hz, 2 H),
3.83-4.00 (m, 5 H), 4.25 (t, J ) 6.6 Hz, 2 H), 5.18-5.23 (m, 1
H), 6.49-6.53 (m, 1 H), 6.80-6.84 (m, 1 H), 6.84-6.89 (m, 2 H),
6.95 (s, 1 H), 7.06-7.12 (m, 4 H), 7.26-7.34 (m, 7 H), 7.54 (t, J
) 2.5 Hz, 1 H), 7.55-7.60 (m, 1 H), 7.66 (t, J ) 2.5 Hz, 1 H),
7.90-7.98 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-
pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzo-
ate (44). Reaction of 10 with 3,5-dimethylpyrazole afforded 44 in
1
95% yield. H NMR (300 MHz, CDCl3) δ 2.08-2.13 (m, 3 H),
2.15-2.22 (m, 3 H), 2.82-2.93 (m, 2 H), 3.03-3.13 (m, 2 H),
3.20 (t, J ) 6.6 Hz, 2 H), 3.25-3.34 (m, 2 H), 3.85-3.90 (m, 3
H), 4.21 (t, J ) 6.5 Hz, 2 H), 4.34 (t, J ) 5.9 Hz, 1 H), 5.78 (s, 1
H), 6.45-6.53 (m, 1 H), 6.77-6.93 (m, 4 H), 7.07 (dd, J ) 3.8,
1.6 Hz, 4 H), 7.22-7.34 (m, 7 H), 7.53 (s, 1 H), 7.92-7.99 (m, 2
H).

1164 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Chen et al.
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-imidazol-1-yl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (45). Reaction
of 10 with imidazole afforded 45 in 87% yield. 1H NMR (300 MHz,
CDCl3) δ 2.85-2.98 (m, 2 H), 3.01-3.17 (m, 4 H), 3.20 (t, J )
6.5 Hz, 2 H), 3.86 (s, 3 H), 4.20 (q, J ) 6.8 Hz, 4 H), 5.33 (t, J )
4.8 Hz, 1 H), 6.52 (d, J ) 8.8 Hz, 1 H), 6.71-7.00 (m, 6 H),
7.01-7.12 (m, 4 H), 7.23-7.38 (m, 7 H), 7.54 (d, J ) 1.6 Hz, 1
H), 7.94 (d, J ) 8.8 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (46). Re-
action of 10 with 1,2,4-triazole afforded 46 in 64% yield. 1H NMR
(300 MHz, CDCl3) δ 2.84-2.97 (m, 2 H), 3.05-3.35 (m, 6 H),
3.87 (s, 3 H), 4.18-4.30 (m, 2 H), 4.43-4.54 (m, 2 H), 4.80 (s, 1
H), 6.47-6.59 (m, 1 H), 6.77-6.94 (m, 4 H), 7.07 (d, J ) 2.5 Hz,
4 H), 7.21-7.38 (m, 6 H), 7.54 (s, 1 H), 7.82 (s, 1 H), 7.96 (d, J
) 8.5 Hz, 2 H), 8.19 (s, 1 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-
1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (53).
Reaction of 10 with 4-methylpiperidine afforded 53 in 95% yield.
1H NMR (300 MHz, CDCl3) δ 0.78 (d, J ) 6.6 Hz, 3 H), 0.86-1.01
(m, 2 H), 1.21-1.35 (m, 1 H), 1.28-1.35 (m, 1 H), 1.54 (d, J )
12.9 Hz, 2 H), 1.90 (t, J ) 11.3 Hz, 2 H), 2.65-2.76 (m, 4 H),
2.96 (t, J ) 6.2 Hz, 2 H), 3.00-3.08 (m, 2 H), 3.16-3.30 (m, 4
H), 3.88 (s, 3 H), 4.23 (t, J ) 6.6 Hz, 2 H), 5.62 (s, 1 H), 6.51 (d,
J ) 8.8 Hz, 1 H), 6.81 (dd, J ) 8.9, 2.1 Hz, 1 H), 6.84-6.91 (m,
2 H), 6.98 (s, 1 H), 7.11 (dd, J ) 3.6, 2.2 Hz, 4 H), 7.28-7.34 (m,
5 H), 7.55 (s, 1 H), 7.96 (d, J ) 9.1 Hz, 2 H).
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-
piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (54). Reaction of 10 with cis-2,6-dimethylpiperidine afforded 54
in 54% yield. 1H NMR (300 MHz, CDCl3) δ 0.93-1.38 (m, J ) 72.5
Hz, 12 H), 1.58 (d, J ) 30.8 Hz, 2 H), 2.18 (s, 2 H), 2.86 (s, 2 H),
2.99-3.31 (m, 6 H), 3.88 (s, 3 H), 4.25 (t, J ) 6.6 Hz, 2 H), 6.54 (d,
J ) 8.5 Hz, 1 H), 6.84 (t, J ) 8.4 Hz, 3 H), 6.96 (s, 1 H), 7.09 (s, 4
H), 7.21-7.37 (m, 6 H), 7.55 (s, 1 H), 7.95 (d, J ) 8.5 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-thiomorpholinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (55). Reac-
tion of 10 with thiomorpholine afforded 55 in 93% yield. 1H NMR
(300 MHz, acetone-d6) δ 2.48-2.61 (m, 8 H), 2.69 (t, J ) 7.1 Hz,
2 H), 3.03-3.12 (m, 2 H), 3.26-3.37 (m, 6 H), 3.83 (s, 3 H), 4.34
(t, J ) 6.9 Hz, 2 H), 6.31 (br s, 1 H), 6.57 (d, J ) 8.8 Hz, 1 H),
6.79 (dd, J ) 8.9, 2.1 Hz, 1 H), 7.02 (d, J ) 8.8 Hz, 2 H),
7.14-7.22 (m, J ) 7.4, 3.6 Hz, 5 H), 7.34-7.41 (m, 6 H), 7.69 (d,
J ) 1.6 Hz, 1 H), 7.93 (d, J ) 9.1 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-hydroxy-1-piperi-
dinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (56).
Reaction of 10 with 4-hydroxypiperidine afforded 56 in 95% yield.
1H NMR (300 MHz, CDCl3) δ 1.21-1.47 (m, 2 H), 1.66-1.87
(m, 2 H), 2.07-2.32 (m, 2 H), 2.72 (d, J ) 39.0 Hz, 4 H),
2.95-3.11 (m, 4 H), 3.14-3.31 (m, 4 H), 3.64 (s, 1 H), 3.88 (s, 3
H), 4.24 (t, J ) 6.5 Hz, 2 H), 5.45 (s, 1 H), 6.53 (d, J ) 8.8 Hz,
1 H), 6.78-6.91 (m, 3 H), 6.99 (s, 1 H), 7.10 (d, J ) 1.1 Hz, 4 H),
7.24-7.28 (m, 1 H), 7.28-7.36 (m, 6 H), 7.56 (d, J ) 1.9 Hz, 1
H), 7.92-8.00 (m, 2 H).
4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-{2-[(dimethylamino)methyl]-
1-piperidinyl}ethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzo-
ate (57). Reaction of 10 with N-(2-piperidylmethyl)dimethylamine
afforded 57 in 65% yield. 1H NMR (300 MHz, CDCl3) δ 1.08-1.45
(m, 3 H), 1.61 (s, 2 H), 1.80 (d, J ) 4.1 Hz, 2 H), 2.02-2.34 (m,
7 H), 2.51-2.74 (m, 3 H), 2.74-3.06 (m, 7 H), 3.09-3.32 (m, 4
H), 3.88 (s, 3 H), 4.22 (t, J ) 6.7 Hz, 2 H), 6.48 (d, J ) 8.8 Hz,
1 H), 6.78 (d, J ) 8.8 Hz, 1 H), 6.88 (d, J ) 8.8 Hz, 2 H), 7.00 (s,
1 H), 7.12 (s, 4 H), 7.28 (d, J ) 10.2 Hz, 6 H), 7.54 (s, 1 H), 7.96
(d, J ) 8.2 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,3-triazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (47). Re-
1
action of 10 with 1H-1,2,3-triazole afforded 47 in 23% yield. H
NMR (300 MHz, CDCl3) δ 2.92 (br s, 2 H), 3.07-3.16 (m, 2 H),
3.17-3.26 (m, 2 H), 3.30-3.39 (m, 2 H), 3.85 (s, 3 H), 4.17-4.28
(m, 2 H), 4.61-4.73 (m, 3 H), 6.48-6.57 (m, 1 H), 6.76-6.94
(m, 4 H), 7.07 (dd, J ) 6.2, 2.9 Hz, 4 H), 7.23-7.36 (m, 5 H),
7.54 (t, J ) 2.5 Hz, 2 H), 7.60-7.65 (m, 1 H), 7.90-7.99 (m, 2
H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2H-tetrazol-2-yl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (48) and Meth-
yl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-tetrazol-1-yl)ethyl]sul-
fonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (49). Reaction of
1
10 with 1H-tetrazole afforded 48 (41%) and 49 (52%). H NMR
for 48 (300 MHz, CDCl3) δ 2.89 (q, J ) 6.8 Hz, 2 H), 3.13 (t, J
) 7.6 Hz, 2 H), 3.23 (t, J ) 6.0 Hz, 2 H), 3.43 (t, J ) 6.9 Hz, 2
H), 3.88 (s, 3 H), 4.25 (t, J ) 6.3 Hz, 2 H), 4.39 (t, J ) 5.9 Hz, 1
H), 4.93 (t, J ) 6.9 Hz, 2 H), 6.55 (d, J ) 8.8 Hz, 1 H), 6.80-6.94
(m, 4 H), 7.03-7.11 (m, 4 H), 7.23-7.37 (m, 6 H), 7.55 (d, J )
1.6 Hz, 1 H), 7.96 (d, J ) 9.1 Hz, 2 H), 8.38 (s, 1 H). 1H NMR for
49 (300 MHz, CDCl3) δ 2.88-2.99 (m, 2 H), 3.14 (t, J ) 7.1 Hz,
2 H), 3.18-3.31 (m, 4 H), 3.87 (s, 3 H), 4.25 (t, J ) 6.2 Hz, 2 H),
4.59 (t, J ) 6.0 Hz, 1 H), 4.68 (t, J ) 6.3 Hz, 2 H), 6.55 (d, J )
9.1 Hz, 1 H), 6.78-6.93 (m, 4 H), 7.01-7.17 (m, 4 H), 7.20-7.40
(m, 6 H), 7.55 (d, J ) 1.6 Hz, 1 H), 7.87-8.05 (m, 2 H), 8.57 (s,
1 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1-piperidinyl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (50). Reaction of
10 with piperidine afforded 50 in 99% yield. 1H NMR (300 MHz,
acetone-d6) δ 1.32-1.39 (m, 2 H), 1.41-1.53 (m, 4 H), 2.31-2.48
(m, 4 H), 2.64-2.78 (m, 2 H), 3.03-3.21 (m, 2 H), 3.25-3.38
(m, 6 H), 3.82 (s, 3 H), 4.34 (t, J ) 6.7 Hz, 2 H), 6.57 (d, J ) 8.8
Hz, 1 H), 6.78 (dd, 1 H), 7.02 (d, J ) 8.8 Hz, 2 H), 7.13-7.24 (m,
5 H), 7.29-7.42 (m, 6 H), 7.69 (d, J ) 2.2 Hz, 1 H), 7.92 (d, J )
8.8 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-1-piperi-
dinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (51).
Reaction of 10 with 2-methylpiperidine afforded 51 in 91% yield.
1H NMR (300 MHz, acetone-d6) δ 0.95 (d, J ) 6.3 Hz, 1 H),
1.09-1.38 (m, 4 H), 1.40-1.60 (m, 2 H), 1.95-2.03 (m, 1 H),
2.11-2.22 (m, 1 H), 2.62-2.78 (m, 2 H), 2.94-3.10 (m, 3 H),
3.24-3.37 (m, 6 H), 3.83 (s, 3 H), 4.34 (t, J ) 6.6 Hz, 2 H), 6.35
(s, 1 H), 6.57 (d, J ) 8.8 Hz, 2 H), 6.79 (dd, J ) 8.9, 2.1 Hz, 1 H),
7.01 (d, J ) 8.8 Hz, 2 H), 7.08-7.25 (m, 5 H), 7.31-7.43 (m, 6
H), 7.69 (d, J ) 1.9 Hz, 1 H), 7.92 (d, J ) 9.1 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-
1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (52).
Reaction of 10 with 3-methylpiperidine afforded 52 in 94% yield.
1H NMR (300 MHz, CDCl3) δ 0.76 (d, J ) 6.6 Hz, 3 H), 1.11-1.38
(m, 3 H), 1.45-1.61 (m, 4 H), 1.71-1.85 (m, 1 H), 2.59-2.76
(m, 4 H), 2.91-3.07 (m, 4 H), 3.16-3.29 (m, 4 H), 3.88 (s, 3 H),
4.23 (t, J ) 6.6 Hz, 2 H), 5.72 (s, 1 H), 6.51 (d, J ) 9.1 Hz, 1 H),
6.81 (dd, J ) 8.8, 1.9 Hz, 1 H), 6.87 (d, J ) 8.8 Hz, 2 H), 6.99 (s,
1 H), 7.05-7.14 (m, 4 H), 7.27-7.35 (m, 5 H), 7.55 (d, J ) 2.2
Hz, 1 H), 7.92-7.99 (m, 2 H).
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazin-
yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (58). Re-
action of 10 with 1-(2-pyridyl)piperazine afforded 58 in 86% yield.
1H NMR (300 MHz, CDCl3) δ 2.46 (s, 4 H), 2.74-2.93 (m, 2 H),
3.03 (s, 4 H), 3.17-3.54 (m, J ) 23.6 Hz, 4 H), 3.88 (s, 3 H),
3.89-4.00 (m, 1 H), 4.15-4.33 (m, 2 H), 5.19-5.28 (m, 1 H),
6.44-6.95 (m, 7 H), 6.97 (s, 1 H), 7.09 (d, J ) 3.3 Hz, 4 H),
7.24-7.43 (m, 6 H), 7.44-7.62 (m, 1 H), 7.94 (d, J ) 8.5 Hz, 2
H), 8.15-8.29 (m, 1 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(cis-3,5-dimethylpip-
erazin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzo-
ate (59). Reaction of 10 with cis-2,6-dimethylpiperazine afforded
1
59 in 97% yield. H NMR (300 MHz, acetone-d6) δ 0.94 (d, J )
6.0 Hz, 6 H), 1.51-1.63 (m, J ) 10.2, 10.2 Hz, 2 H), 2.61-2.69
(m, 4 H), 2.69-2.80 (m, 2 H), 3.09 (t, J ) 6.9 Hz, 2 H), 3.25-3.35
(m, 6 H), 3.82 (s, 3 H), 4.34 (t, J ) 6.6 Hz, 2 H), 6.35 (br s, 1 H),
6.56 (d, J ) 8.8 Hz, 1 H), 6.79 (dd, J ) 8.9, 2.1 Hz, 1 H), 7.02 (d,
J ) 9.1 Hz, 2 H), 7.14-7.23 (m, 5 H), 7.32-7.39 (m, 6 H), 7.69
(d, J ) 1.9 Hz, 1 H), 7.92 (d, J ) 9.1 Hz, 2 H).
4-(2-{2-[2-({[2-(4-Acetyl-cis-3,5-dimethylpiperazin-1-yl)ethyl]sulfonyl}-
amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoate (60).
To a solution of 59 (31 mg, 0.042 mmol) in DCM (1 mL) were
added Et3N (0.1 mL, mmol) and Ac2O (0.060 mL, mmol). The

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1165
reaction mixture was stirred at room temperature for 5 h followed
by an extractive workup and silica gel chromatography (3.5%
MeOH/CHCl3) to give 60 (17.3 mg, 52%). H NMR (300 MHz,
acetone-d6) δ 1.23 (d, J ) 6.3 Hz, 6 H), 1.97-2.03 (m, 2 H), 2.00
(s, 3 H), 2.59-2.72 (m, 4 H), 2.83-2.89 (m, 2 H), 3.07-3.18 (m,
2 H), 3.28-3.37 (m, 6 H), 3.83 (s, 3 H), 4.34 (t, J ) 6.7 Hz, 2 H),
6.42 (t, J ) 4.8 Hz, 1 H), 6.57 (d, J ) 9.1 Hz, 1 H), 6.79 (dd, J )
8.9, 2.1 Hz, 1 H), 7.02 (d, J ) 8.8 Hz, 2 H), 7.15-7.22 (m, 5 H),
7.33-7.40 (m, 6 H), 7.69 (d, J ) 2.2 Hz, 1 H), 7.92 (d, J ) 9.1
Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2,5-dimethyl-1-pyr-
rolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate
(68). Reaction of 10 with 2,5-dimethylpyrrolidine afforded 68 in
81% yield. 1H NMR (300 MHz, acetone-d6) δ 0.96 (d, J ) 6.0 Hz,
6 H), 1.16-1.29 (m, 2 H), 1.67-1.77 (m, 2 H), 2.45-2.55 (m, 2
H), 2.98 (s, 4 H), 3.19-3.38 (m, 6 H), 3.83 (s, 3 H), 4.34 (t, J )
6.7 Hz, 2 H), 6.41 (t, J ) 6.0 Hz, 1 H), 6.57 (d, J ) 9.1 Hz, 1 H),
6.79 (dd, J ) 8.9, 2.1 Hz, 1 H), 6.97-7.04 (m, 2 H), 7.14-7.22
(m, 5 H), 7.33-7.41 (m, 6 H), 7.69 (d, J ) 2.2 Hz, 1 H), 7.92 (d,
J ) 8.5 Hz, 2 H).
1
4-(2-{2-[2-({[2-(4-Acetylpiperazin-1-yl)ethyl]sulfonyl}amino)ethyl]-
1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoate (61). Reaction
of 10 with 1-acetylpiperazine afforded 61 in 91% yield. H NMR
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (69). Re-
action of 10 with thiazolidine afforded 69 in 33% yield. H NMR
1
1
(300 MHz, acetone-d6) δ 1.95 (s, 3 H), 2.21-2.30 (m, 2 H),
2.30-2.36 (m, 2 H), 2.68 (t, J ) 7.0 Hz, 2 H), 3.10 (t, J ) 7.0 Hz,
2 H), 3.27-3.42 (m, 10 H), 3.82 (s, 3 H), 4.34 (t, J ) 6.6 Hz, 2
H), 6.34 (br s, 1 H), 6.57 (d, J ) 8.5 Hz, 1 H), 6.79 (dd, J ) 8.9,
2.1 Hz, 1 H), 7.01 (d, J ) 9.1 Hz, 2 H), 7.13-7.23 (m, 5 H),
7.29-7.41 (m, 6 H), 7.69 (d, J ) 1.9 Hz, 1 H), 7.92 (d, J ) 8.8
Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopi-
perazin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzo-
ate (62). Reaction of 10 with 3-methyl-2-piperazinone afforded 62
in 80% yield. 1H NMR (400 MHz, CDCl3) δ 1.27-1.31 (m, 3 H),
2.38-2.49 (m, 1 H), 2.79 (dd, J ) 12.6, 5.3 Hz, 2 H), 2.89-3.10
(m, 6 H), 3.10-3.27 (m, 6 H), 3.87 (s, 3 H), 4.25 (t, J ) 6.4 Hz,
2 H), 4.94 (t, J ) 5.7 Hz, 1 H), 5.88 (s, 1 H), 6.53 (d, J ) 8.8 Hz,
1 H), 6.82 (dd, J ) 9.0, 2.1 Hz, 1 H), 6.84-6.90 (m, 2 H), 6.96 (s,
1 H), 7.10 (d, J ) 2.8 Hz, 4 H), 7.28-7.35 (m, 6 H), 7.55 (d, J )
2.0 Hz, 1 H), 7.92-7.98 (m, 2 H).
(300 MHz, CDCl3) δ 2.70-3.08 (m, 10 H), 3.12-3.28 (m, 4 H),
3.74-3.79 (m, 2 H), 3.88 (s, 3 H), 4.18-4.29 (m, 2 H), 4.83 (s, 1
H), 6.49-6.56 (m, 1 H), 6.77-6.89 (m, 3 H), 6.96 (s, 1 H),
7.05-7.14 (m, 4 H), 7.23-7.35 (m, 6 H), 7.55 (d, J ) 1.9 Hz, 1
H), 7.92-7.99 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-hydroxy-1-pyrroli-
dinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (70).
1
Reaction of 10 with 3-pyrrolidinol afforded 70 in 90% yield. H
NMR (300 MHz, CDCl3) δ 1.23-1.29 (m, 1 H), 2.02-2.43 (m, 4
H), 2.71-2.90 (m, 2 H), 2.93-3.28 (m, 11 H), 3.88 (s, 3 H), 4.23
(t, J ) 6.5 Hz, 2 H), 4.30 (s, 1 H), 6.50 (d, J ) 9.1 Hz, 1 H),
6.76-6.83 (m, 1 H), 6.88 (dd, J ) 8.9, 1.8 Hz, 2 H), 6.97 (s, 1 H),
7.06-7.14 (m, 4 H), 7.26 (d, J ) 1.9 Hz, 2 H), 7.28-7.34 (m, 4
H), 7.55 (d, J ) 1.9 Hz, 1 H), 7.96 (dd, J ) 8.8, 1.9 Hz, 2 H).
4-{2-[5-Chloro-2-{2-[({2-[3-(dimethylamino)pyrrolidin-1-yl]ethyl}-
sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-
yl]ethoxy}benzoate (71). Reaction of 10 with 3-(dimethylamino)py-
rrolidine afforded 71 in 90% yield. 1H NMR (300 MHz, CDCl3) δ
1.56-1.85 (m, 2 H), 2.16 (s, 6 H), 2.31-2.62 (m, 4 H), 2.62-2.72
(m, 1 H), 2.72-2.82 (m, 1 H), 2.83-2.91 (m, 1 H), 2.96 (q, J )
6.0 Hz, 2 H), 3.01-3.13 (m, 2 H), 3.15-3.31 (m, 4 H), 3.88 (s, 3
H), 4.23 (t, J ) 6.6 Hz, 2 H), 5.30 (s, 1 H), 6.51 (d, J ) 8.8 Hz,
1 H), 6.76-6.91 (m, 3 H), 6.99 (s, 1 H), 7.11 (d, J ) 2.5 Hz, 4 H),
7.22-7.37 (m, 6 H), 7.56 (d, J ) 1.9 Hz, 1 H), 7.96 (d, J ) 8.5
Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-((1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}ethoxy)benzoate (64). Reaction of 10 with (1S,4S)-(+)-2-aza-5-
1
oxabicyclo[2,2,1]heptane afforded 64 in 85% yield. H NMR (400
MHz, CDCl3) δ 1.55-1.71 (m, 2 H), 2.41 (d, J ) 10.9 Hz, 1 H), 2.64
(d, J ) 7.8 Hz, 1 H), 2.88-3.11 (m, 6 H), 3.15-3.29 (m, 4 H), 3.37
(s, 1 H), 3.56 (dd, J ) 8.2, 1.6 Hz, 1 H), 3.83 (d, J ) 8.1 Hz, 1 H),
3.88 (s, 3 H), 4.24 (t, J ) 6.7 Hz, 2 H), 4.29 (s, 1 H), 5.08 (br s, 1 H),
6.53 (d, J ) 8.8 Hz, 1 H), 6.82 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.85-6.89
(m, 2 H), 6.97 (s, 1 H), 7.06-7.12 (m, 4 H), 7.28-7.35 (m, 6 H),
7.55 (d, J ) 1.8 Hz, 1 H), 7.93-7.98 (m, 2 H).
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(3R,5S)-3,5-dimethylmorpho-
lin-4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate (65).
Reaction of 10 with (3R,5S)-3,5-dimethylmorpholine afforded 65 in
78% yield. 1H NMR (400 MHz, CDCl3) δ 0.86-0.96 (m, 1 H), 1.08
(d, J ) 6.3 Hz, 6 H), 1.28-1.38 (m, 1 H), 1.70 (t, J ) 10.6 Hz, 2 H),
2.54 (d, J ) 10.6 Hz, 2 H), 2.70 (t, J ) 6.4 Hz, 2 H), 2.92-3.06 (m,
4 H), 3.17-3.28 (m, 4 H), 3.33-3.44 (m, 2 H), 3.88 (s, 3 H), 4.24 (t,
J ) 6.6 Hz, 2 H), 5.07 (t, J ) 5.9 Hz, 1 H), 6.53 (d, J ) 8.8 Hz, 1 H),
6.82 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.87 (d, J ) 8.8 Hz, 2 H), 6.96 (s, 1
H), 7.09 (dd, J ) 6.3, 2.8 Hz, 4 H), 7.28-7.35 (m, 6 H), 7.55 (d, J )
1.8 Hz, 1 H), 7.96 (d, J ) 8.8 Hz, 2 H).
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(2S)-2-(methoxymethyl)pyr-
rolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]ben-
zoate (72). Reaction of 10 with (S)-(+)-2-(methoxymethyl)pyrroli-
1
dine afforded 72 in 87% yield. H NMR (400 MHz, CDCl3) δ
1.38-1.84 (m, 5 H), 2.50-2.64 (m, 2 H), 2.75-3.35 (m, 14 H),
3.46 (dd, J ) 10.0, 3.2 Hz, 1 H), 3.88 (s, 3 H), 4.23 (t, J ) 6.9 Hz,
2 H), 6.37 (s, 1 H), 6.49 (d, J ) 8.8 Hz, 1 H), 6.79 (dd, J ) 8.8,
2.0 Hz, 1 H), 6.84-6.91 (m, 2 H), 6.96-7.00 (m, 1 H), 7.06-7.16
(m, 4 H), 7.27-7.35 (m, 5 H), 7.55 (d, J ) 2.3 Hz, 1 H), 7.91-7.99
(m, 2 H).
4-{2-[2-{2-[({2-[(2S)-2-(Aminocarbonyl)pyrrolidin-1-yl]ethyl}sulfo-
nyl)amino]ethyl}-5-chloro-1-(diphenylmethyl)-1H-indol-3-
yl]ethoxy}benzoate (73). Reaction of 10 with L-prolinamide afforded
1
73 in 86% yield. H NMR (400 MHz, CDCl3) δ 1.63-1.89 (m, 4
H), 2.06-2.21 (m, 2 H), 2.62-2.73 (m, 1 H), 2.79-2.90 (m, 1 H),
2.91-3.14 (m, 6 H), 3.14-3.29 (m, 4 H), 3.88 (s, 3 H), 4.24 (t, J
) 6.6 Hz, 2 H), 5.42 (s, 1 H), 6.52 (d, J ) 8.8 Hz, 1 H), 6.82 (dd,
J ) 8.8, 2.3 Hz, 1 H), 6.87 (d, J ) 8.8 Hz, 2 H), 6.96 (s, 1 H),
7.04-7.13 (m, 4 H), 7.28-7.34 (m, 6 H), 7.55 (d, J ) 2.0 Hz, 1
H), 7.92-7.98 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidaz-
olidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (74).
Reaction of 10 with 2-imidazolinethione afforded 74 in 17% yield.
1H NMR (300 MHz, CDCl3) δ 3.00-3.13 (m, 4 H), 3.15-3.29
(m, 4 H), 3.48-3.59 (m, 2 H), 3.62-3.73 (m, 2 H), 3.84-3.93
(m, 5 H), 4.20-4.29 (m, 2 H), 5.72 (s, 1 H), 5.77-5.85 (m, 1 H),
6.47-6.55 (m, 1 H), 6.77-6.84 (m, 1 H), 6.85-6.93 (m, 2 H),
6.97 (s, 1 H), 7.06-7.18 (m, 4 H), 7.23-7.38 (m, 6 H), 7.51-7.59
(m, 1 H), 7.89-8.01 (m, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1-pyrrolidinyl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (66). Reaction of
10 with pyrrolidine afforded 66 in 92% yield. 1H NMR (300 MHz,
CDCl3) δ 1.67 (s, 4 H), 2.48 (s, 4 H), 2.90 (t, J ) 6.0 Hz, 2 H),
2.95-3.12 (m, 4 H), 3.12-3.32 (m, 4 H), 3.88 (s, 3 H), 4.23 (t, J
) 6.3 Hz, 2 H), 5.44 (s, 1 H), 6.52 (d, J ) 9.1 Hz, 1 H), 6.75-6.91
(m, 3 H), 6.98 (s, 1 H), 7.10 (d, J ) 1.1 Hz, 4 H), 7.22-7.40 (m,
6 H), 7.55 (d, J ) 1.1 Hz, 1 H), 7.96 (d, J ) 9.1 Hz, 2 H).
Methyl 4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-1-pyrroli-
dinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoate (67).
Reaction of 10 with 2-methylpyrrolidine afforded 67 in 91% yield.
1H NMR (300 MHz, acetone-d6) δ 0.98 (d, J ) 6.0 Hz, 3 H),
1.16-1.31 (m, 2 H), 1.54-1.64 (m, 2 H), 1.82-2.00 (m, 2 H),
2.19-2.32 (m, 1 H), 2.35-2.47 (m, 1 H), 2.90-3.00 (m, 1 H),
3.04-3.13 (m, 2 H), 3.24-3.37 (m, 6 H), 3.83 (s, 3 H), 4.34 (t, J
) 6.7 Hz, 2 H), 6.30 (br s, 1 H), 6.57 (d, J ) 9.1 Hz, 1 H), 6.79
(dd, J ) 8.8, 2.2 Hz, 1 H), 7.01 (d, J ) 8.8 Hz, 2 H), 7.14-7.23
(m, 5 H), 7.31-7.40 (m, 6 H), 7.69 (d, J ) 1.9 Hz, 1 H), 7.92 (d,
J ) 9.1 Hz, 2 H).
Methyl 4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-
pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzo-
ate (111). Reaction of 11 with 3,5-dimethylpyrazole afforded 111
1
in 100% yield. H NMR (300 MHz, acetone-d6) δ 2.00-2.06 (m,

1166 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Chen et al.
2 H), 2.18 (s, 3 H), 2.20 (s, 3 H), 2.69-2.92 (m, 4 H), 3.08-3.16
(m, 4 H), 3.42 (t, J ) 6.9 Hz, 2 H), 3.85 (s, 3 H), 4.31 (t, J ) 6.9
Hz, 2 H), 5.81 (s, 1H), 6.42 (s, 1 H), 6.52 (d, J ) 8.8 Hz, 1 H),
6.76 (dd, J ) 8.8, 2.2 Hz, 1 H), 7.08-7.20 (m, 5 H), 7.28-7.39
(m, 7 H), 7.60 (dd, J ) 5.8, 3.3 Hz, 1 H), 7.77-7.85 (m, 1 H),
7.88-7.97 (m, 2 H).
Methyl 4-[3-(5-Chloro-1-(diphenylmethyl)-2-{2-[({2-[(4-methylpip-
erazin-1-yl)methyl]benzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propy-
l]benzoate (123). Compound 12 was reacted with 1-methylpiperazine
to afford 123 in 84% as a white solid.
Procedure B: Ester Hydrolysis. 4-(2-{1-Benzhydryl-5-chloro-
2-[2-({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}ethoxy)benzoic Acid (26). Ester 14 (30 mg, 0.041 mmol) was
hydrolyzed in 15%NaOH/THF/MeOH (2.4 mL, 1:1:1, v/v) over-
night. The reaction mixture was acidified to ∼pH 3 with HCl,
extracted with EtOAc, dried (MgSO4), and evaporated to give the
Methyl 4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-morpholinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoate (112). Re-
action of 11 with morpholine afforded 112 in 100% yield. 1H NMR
(300 MHz, acetone-d6) δ 1.93-2.03 (m, 2 H), 2.26-2.35 (m, 4
H), 2.65 (t, J ) 7.1 Hz, 2 H), 2.69-2.75 (m, 2 H), 2.77-2.93 (m,
4 H), 3.08 (t, J ) 7.0 Hz, 2 H), 3.44-3.55 (m, 6 H), 3.85 (s, 3 H),
6.31 (br s, 1 H), 6.53 (d, J ) 8.8 Hz, 1 H), 6.76 (dd, J ) 8.8, 2.2
Hz, 1 H), 7.14-7.22 (m, J ) 4.9, 2.2 Hz, 5 H), 7.31-7.42 (m, 8
H), 7.50 (d, J ) 2.2 Hz, 1 H), 7.92 (d, J ) 8.2 Hz, 2 H).
Methyl 4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(2,6-dimethyl-1-
piperidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}propyl)benzoate (113). Reaction of 11 with cis-2,6-dimethylpip-
1
title acid (27 mg, 93%) as a solid. H NMR (300 MHz, acetone-
d6) δ 3.22-3.33 (m, 6 H), 4.31 (t, J ) 6.7 Hz, 2 H), 4.40 (s, 2 H),
6.54 (d, J ) 8.8 Hz, 1 H), 6.71 (t, J ) 5.4 Hz, 1 H), 6.78 (dd, J )
8.8, 2.2 Hz, 1 H), 7.01 (d, J ) 9.1 Hz, 2 H), 7.12-7.18 (m, 5 H),
7.21-7.29 (m, 3 H), 7.33-7.39 (m, 6 H), 7.46-7.54 (m, 2 H),
7.68 (d, J ) 1.6 Hz, 1 H), 7.95 (d, J ) 8.8 Hz, 2 H), 709.11.
HRMS calcd for [C39H35ClN2O5S2 - H] 709.160 31; found
709.159 99.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2-chlorophenyl)sulfanyl]meth-
yl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (27). Ester
15 was hydrolyzed to afford 27 in 100% yield. 1H NMR (300 MHz,
CDCl3) δ 3.00 (d, J ) 6.8 Hz, 2 H), 3.07-3.35 (m, 4 H), 4.09 (s,
2 H), 4.24 (t, J ) 6.3 Hz, 2 H), 4.78 (t, 1 H), 6.53 (d, J ) 9.1 Hz,
1 H), 6.73-6.98 (m, 4 H), 7.02-7.21 (m, 6 H), 7.22-7.41 (m, 7
H), 7.49 (dd, J ) 7.1, 1.9 Hz, 1 H), 7.55 (d, J ) 1.9 Hz, 1 H), 7.99
(d, J ) 8.7 Hz, 2 H). HRMS calcd for [C39H34Cl2N2O5S2 - H]
743.121 34; found 743.121 11.
1
eridine afforded 113 in 59% yield. H NMR (300 MHz, acetone-
d6) δ 0.82 (s, 3 H), 0.85 (s, 3 H), 0.92-1.21 (m, 4 H), 1.30-1.49
(m, 2 H), 1.82-1.92 (m, 2 H), 1.97-2.11 (m, 2 H), 2.66-2.85
(m, 6 H), 2.91-3.10 (m, 4 H), 3.10-3.20 (m, 2 H), 3.74 (s, 3 H),
6.26 (t, J ) 5.8 Hz, 1 H), 6.41 (d, J ) 8.8 Hz, 1 H), 6.65 (dd, J )
8.9, 2.1 Hz, 1 H), 7.00-7.09 (m, 5 H), 7.18-7.30 (m, 8 H), 7.38
(d, J ) 1.9 Hz, 1 H), 7.81 (d, J ) 8.0 Hz, 2 H).
Representative Procedure for Reductive Amination. Methyl
4-(3-{5-Chloro-1-(diphenylmethyl)-2-[2-({[2-(morpholin-4-ylmethyl)-
benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoate (120). To
compound 12 (58 mg, 0.081 mmol) in DCE (2 mL) at 0 °C were
added morpholine (0.0092 mL, 0.105 mmol) and NaBH(OAc)3 (27
mg, 0.13 mmol), and the reaction mixture was allowed to warm to
room temperature overnight. The reaction was quenched with
saturated NaHCO3, extracted with EtOAc, and dried over MgSO4.
Purification by flash column chromatography (35-50% EtOAc/
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2-methylphenyl)sulfanyl]meth-
yl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (28). Ester
1
16 was hydrolyzed to afford 28 in 98% yield. H NMR (300 MHz,
CDCl3) δ 2.36 (s, 3 H), 2.89-3.01 (m, 2 H), 3.07-3.16 (m, 2 H),
3.21 (t, J ) 6.3 Hz, 2 H), 4.02 (s, 2 H), 4.22 (t, J ) 6.5 Hz, 2 H), 4.63
(t, J ) 5.5 Hz, 1 H), 6.53 (d, J ) 8.8 Hz, 1 H), 6.79-6.94 (m, 4 H),
7.01-7.17 (m, 7 H), 7.27-7.35 (m, J ) 2.7 Hz, 6 H), 7.39 (d, J )
8.0 Hz, 1 H), 7.54 (s, 1 H), 8.00 (d, J ) 9.1 Hz, 2 H). HRMS calcd
for [C40H37ClN2O5S - H] 723.175 96; found 723.175 96.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,6-dimethylphenyl)sulfanyl]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (29).
Ester 17 was hydrolyzed to afford 29 in 80% yield. 1H NMR (300
MHz, CDCl3) δ 2.46 (s, 6 H), 2.84-2.96 (m, 2 H), 3.05-3.15 (m,
2 H), 3.22 (t, J ) 6.5 Hz, 2 H), 3.80 (s, 2 H), 4.23 (t, J ) 6.6 Hz,
2 H), 4.46 (t, J ) 5.4 Hz, 1 H), 6.53 (d, J ) 8.8 Hz, 1 H), 6.79-6.92
(m, 4 H), 7.02-7.14 (m, 7 H), 7.24-7.36 (m, 7 H), 7.55 (d, J )
1.9 Hz, 1 H), 8.01 (d, J ) 8.8 Hz, 2 H). HRMS calcd for
[C39H33ClF2N2O5S2 + H+], 739.2067; found 739.2056.
1
hexanes) gave compound 120 as a white solid (41 mg, 64%). H
NMR (400 MHz, acetone-d6) δ 1.82-1.89 (m, 4 H), 2.13-2.21
(m, 4 H), 2.61-2.74 (m, 6 H), 3.35-3.44 (m, 4 H), 3.48 (s, 2 H),
3.72 (s, 3 H), 4.51 (s, 2 H), 6.38 (d, J ) 9.1 Hz, 1 H), 6.62 (dd, J
) 8.8, 2.3 Hz, 1 H), 6.97 (s, 1 H), 7.01 (dd, J ) 7.6, 2.0 Hz, 4 H),
7.03-7.07 (m, 1 H), 7.10-7.14 (m, 2 H), 7.15-7.19 (m, 1 H),
7.21-7.27 (m, 8 H), 7.34 (d, J ) 2.3 Hz, 1 H), 7.80 (d, J ) 8.3
Hz, 2 H).
Methyl4-{3-[5-Chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfo-
nyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate
(118) and Methyl 4-(3-{5-Chloro-1-(diphenylmethyl)-2-[2-({[2-
(hydroxymethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}propyl)benzoate (119). Compound 12 was reacted with HNEt2 to
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,5-dimethoxyphenyl)sulfa-
1
nyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid
afford 118 (41%) and 119 (15%), both as white solids. H NMR
1
(30). Ester 18 was hydrolyzed to afford 30 in 100% yield. H NMR
for 118 (400 MHz, acetone-d6) δ 1.06 (t, J ) 7.1 Hz, 6 H),
1.79-1.89 (m, 4 H), 2.62-2.73 (m, 11 H), 3.72 (s, 3 H), 4.30 (s,
2 H), 4.57-4.65 (m, 2 H), 6.39 (d, J ) 8.8 Hz, 1 H), 6.62 (dd, J
) 8.8, 2.0 Hz, 1 H), 6.98 (s, 1 H), 6.99-7.07 (m, 5 H), 7.12-7.17
(m, 2 H), 7.20-7.31 (m, 9 H), 7.34 (d, J ) 1.8 Hz, 1 H), 7.79 (d,
(300 MHz, CDCl3) δ2.90-3.01 (m, 2 H), 3.02-3.12 (m, 2 H), 3.20
(t, J ) 6.2 Hz, 2 H), 3.67 (s, 3 H), 3.73 (s, 3 H), 4.13 (s, 2 H), 4.22
(t, J ) 6.3 Hz, 2 H), 4.91-4.99 (m, 1 H), 6.50 (d, J ) 9.1 Hz, 1 H),
6.68-6.93 (m, 6 H), 7.00-7.12 (m, 5 H), 7.27-7.35 (m, J ) 3.3 Hz,
7 H), 7.55 (s, 1 H), 7.99 (d, J ) 8.5 Hz, 2 H). HRMS calcd for
[C41H39ClN2O7S2 - H] 769.181 44; found 769.181 21.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,4-difluorophenyl)thio]meth-
yl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (31). Ester
19 was hydrolyzed to afford 31 in 100% yield. 1H NMR (300 MHz,
CDCl3) δ 2.99-3.09 (m, 2 H), 3.12-3.20 (m, 2 H), 3.24 (t, J )
6.0 Hz, 2 H), 3.92 (d, J ) 1.1 Hz, 2 H), 4.25 (t, J ) 6.3 Hz, 2 H),
4.73 (t, J ) 5.9 Hz, 1 H), 6.50-6.58 (m, 1 H), 6.72-6.97 (m, 6
H), 7.03-7.13 (m, J ) 4.1 Hz, 4 H), 7.28-7.36 (m, 6 H), 7.56 (d,
J ) 1.6 Hz, 1 H), 7.96-8.04 (m, 2 H). HRMS calcd for
[C39H33ClF2N2O5S2 + H+], 747.1566; found 747.1556.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (32).
Ester 20 was hydrolyzed to afford 32 in 100% yield. 1H NMR (300
MHz, CDCl3) δ2.98-3.11 (m, 2 H), 3.12-3.20 (m, 2 H), 3.24 (t,
J ) 6.3 Hz, 2 H), 4.03 (s, 2 H), 4.25 (t, J ) 6.5 Hz, 2 H), 4.84 (t,
J ) 5.8 Hz, 1 H), 6.54 (d, J ) 9.1 Hz, 1 H), 6.80-6.96 (m, 6 H),
7.04-7.15 (m, 5 H), 7.27-7.34 (m, 5 H), 7.43 (d, J ) 8.5 Hz, 1
1
J ) 8.3 Hz, 2 H). H NMR for 119: (400 MHz, acetone-d6) δ
1.78-1.89 (m, 2 H), 2.61-2.75 (m, 8 H), 3.72 (s, 3 H), 4.31 (s, 2
H), 4.62 (s, 2 H), 6.28 (t, J ) 6.1 Hz, 1 H), 6.39 (d, J ) 8.8 Hz,
1 H), 6.62 (dd, J ) 8.8, 2.3 Hz, 1 H), 6.98 (s, 1 H), 6.99-7.07 (m,
5 H), 7.11-7.18 (m, 2 H), 7.20-7.30 (m, 9 H), 7.34 (d, J ) 2.0
Hz, 1 H), 7.79 (d, J ) 8.3 Hz, 2 H).
Methyl 4-{3-[2-{2-[({2-[(4-Acetylpiperazin-1-yl)methyl]benzyl}sulfo-
nyl)amino]ethyl}-5-chloro-1-(diphenylmethyl)-1H-indol-3-
yl]propyl}benzoate (121). Compound 12 was reacted with 1-acetylpip-
erazine to afford sulfonamide 121 in 75% as a white foam. 1H NMR
(400 MHz, acetone-d6) δ 1.80-1.88 (m, 4 H), 2.09-2.15 (m, 2
H), 2.16-2.24 (m, 2 H), 2.62-2.75 (m, 8 H), 3.22-3.27 (m, 2 H),
3.27-3.32 (m, 2 H), 3.50 (s, 2 H), 3.72 (s, 3 H), 4.51 (s, 2 H),
6.33 (t, J ) 5.4 Hz, 1 H), 6.38 (d, J ) 8.8 Hz, 1 H), 6.62 (dd, J )
8.8, 2.3 Hz, 1 H), 6.97 (s, 1 H), 6.99-7.03 (m, J ) 7.6, 1.8 Hz, 4
H), 7.04-7.09 (m, J ) 5.3 Hz, 1 H), 7.11-7.15 (m, 2 H), 7.18 (d,
J ) 7.6 Hz, 1 H), 7.22-7.26 (m, 8 H), 7.35 (d, J ) 1.8 Hz, 1 H),
7.80 (d, J ) 8.3 Hz, 2 H).

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1167
H), 7.55 (d, J ) 1.9 Hz, 1 H), 7.99 (d, J ) 8.8 Hz, 2 H). HRMS
calcd for [C39H33Cl3N2O5S2 + H+], 779.0974; found 779.0961.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(2,6-dichlorophenyl)sulfanyl]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (33).
Ester 21 was hydrolyzed to afford 33 in 98% yield. 1H NMR (300
MHz, CDCl3) δ 2.91-3.02 (m, 2 H), 3.10-3.20 (m, 2 H), 3.25 (t,
J ) 6.2 Hz, 2 H), 4.03 (s, 2 H), 4.25 (t, J ) 6.3 Hz, 2 H), 4.96 (t,
J ) 6.6 Hz, 1 H), 6.54 (d, J ) 8.8 Hz, 1 H), 6.81-6.94 (m, 4 H),
7.05-7.13 (m, 4 H), 7.19 (d, J ) 8.0 Hz, 1 H), 7.32 (dd, J ) 6.5,
2.1 Hz, 8 H), 7.58 (s, 1 H), 8.01 (d, J ) 8.8 Hz, 2 H). HRMS
calcd for [C39H33Cl3N2O5S2 - H] 777.082 37; found 777.082 05.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,5-dichlorophenyl)sulfanyl]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (34).
Ester 22 was hydrolyzed to afford 34 in 98% yield. 1H NMR (300
MHz, CDCl3) δ 3.00-3.30 (m, 6 H), 4.02 (s, 2 H), 4.21-4.30 (m,
2 H), 4.70-4.79 (m, 1 H), 6.55 (d, J ) 8.8 Hz, 1 H), 6.80-6.90
(m, 3 H), 6.94 (s, 1 H), 7.03-7.13 (m, J ) 3.8 Hz, 4 H), 7.20-7.24
(m, 1 H), 7.27-7.35 (m, 8 H), 7.55 (s, 1 H), 7.95-8.04 (m, 2 H).
HRMS calcd for [C39H33Cl3N2O5S2 - H] 777.082 37; found
777.081 59.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-fluorophenyl)thio]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (35).
Ester 23 was hydrolyzed to afford 35 in 89% yield. 1H NMR (300
MHz, CDCl3) δ2.95-3.30 (m, 6 H), 3.98 (s, 2 H), 4.25 (t, J ) 5.6
Hz, 2 H), 4.80-4.91 (m, 1 H), 6.54 (d, J ) 8.8 Hz, 1 H), 6.78-6.95
(m, 4 H), 7.03-7.11 (m, 4 H), 7.27-7.34 (m, 9 H), 7.55 (s, 1 H),
7.94-8.03 (m, 2 H). HRMS calcd for C39H33Cl2FN2O5S2, 762.1192;
found [M + H]1+ 763.1258.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]meth-
yl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (36). Ester
24 was hydrolyzed to afford 36 in 97% yield. 1H NMR (300 MHz,
CDCl3) δ 3.01-3.11 (m, J ) 9.6 Hz, 2 H), 3.12-3.20 (m, J ) 7.4
Hz, 2 H), 3.23 (t, J ) 5.6 Hz, 2 H), 4.00 (s, 2 H), 4.25 (t, J ) 6.0
Hz, 2 H), 4.78 (s, 1 H), 6.55 (d, J ) 8.8 Hz, 1 H), 6.79-6.90 (m,
3 H), 6.94 (s, 1 H), 7.08 (d, J ) 4.1 Hz, 4 H), 7.28-7.36 (m, 8 H),
7.50-7.57 (m, 2 H), 7.99 (d, J ) 8.8 Hz, 2 H). HRMS calcd for
C39H33Cl3N2O5S2, 778.0896; found [M + H]1+ 779.0966.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinyl]-
methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid (38).
Ester 25 was hydrolyzed to afford 38 in 93% yield. 1H NMR (400
MHz, CDCl3) δ 3.08-3.29 (m, J ) 14.4 Hz, 6 H), 4.13 (s, 2 H),
4.19-4.27 (m, J ) 6.3 Hz, 2 H), 5.77 (s, 1 H), 6.48-6.53 (m, 1
H), 6.78-6.86 (m, 3 H), 6.96 (s, 1 H), 7.06-7.15 (m, 4 H),
7.25-7.39 (m, 7 H), 7.54-7.62 (m, 2 H), 7.66-7.71 (m, 1 H),
7.88-7.94 (m, 2 H). HRMS calcd for C39H33Cl3N2O6S2 + Na+,
817.0744; found 817.0732.
H), 7.69 (d, J ) 1.7 Hz, 1 H), 7.95 (d, J ) 9.0 Hz, 2 H). HRMS
calcd for [C37H35ClN4O5S - H] 681.194 39; found 681.194 07.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (77).
Ester 42 was hydrolyzed to afford 77 in 86% yield. 1H NMR (300
MHz, CDCl3) δ 1.25 (s, 3 H), 2.18 (d, J ) 2.2 Hz, 1 H), 2.25 (d,
J ) 2.4 Hz, 1 H), 2.44 (d, J ) 2.2 Hz, 1 H), 2.91 (m, 2 H), 3.07
(m, 2 H), 3.21 (t, J ) 6.4 Hz, 2 H), 3.37 (t, J ) 6.4 Hz, 2 H), 4.19
(t, J ) 6.4 Hz, 2 H), 4.43 (m, 2 H), 4.74 (m, 1 H), 6.49 (d, J ) 8.7
Hz, 1 H), 6.80 (m, 2 H), 6.90 (s, 1 H), 7.08 (s, 3 H), 7.27 (m, 7 H),
7.58 (m, 2 H), 7.95 (m, 2 H). HRMS calcd for [C38H37ClN4O5S -
H] 695.210 04; found 695.209 51.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (78).
Ester 43 was hydrolyzed to afford 78 in 93%. 1H NMR (300 MHz,
CDCl3) δ 1.97 (s, 3 H), 2.85-2.97 (m, 2 H), 3.02-3.13 (m, J )
8.0, 8.0 Hz, 2 H), 3.36 (t, J ) 6.2 Hz, 2 H), 4.20 (t, J ) 6.5 Hz,
2 H), 4.44 (t, J ) 6.2 Hz, 2 H), 4.79 (s, 1 H), 6.50 (d, J ) 8.8 Hz,
1 H), 6.76-6.85 (m, J ) 8.5 Hz, 3 H), 6.89 (s, 1 H), 7.02-7.18
(m, 6 H), 7.30 (dd, J ) 3.0, 1.6 Hz, 6 H), 7.57 (d, J ) 1.1 Hz, 1
H), 7.94 (d, J ) 8.8 Hz, 2 H). HRMS calcd for [C38H37ClN4O5S -
H] 695.210 04; found 695.209 54.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (79).
Ester 44 was hydrolyzed to afford 79 in 62% yield. 1H NMR (300
MHz, acetone-d6) δ 1.93 (s, 5 H), 2.08 (s, 3 H), 3.06-3.14 (m, 4
H), 3.19 (t, J ) 6.9 Hz, 2 H), 3.30 (t, J ) 6.7 Hz, 2 H), 4.20 (q,
J ) 7.1 Hz, 4 H), 6.31 (s, 1 H), 6.44 (d, J ) 8.8 Hz, 1 H), 6.66 (d,
J ) 10.4 Hz, 1 H), 6.88 (d, J ) 8.8 Hz, 2 H), 6.99-7.11 (m, 5 H),
7.17-7.29 (m, 5 H), 7.56 (s, 1 H), 7.82 (d, J ) 8.8 Hz, 2 H).
HRMS calcd for [C39H39ClN4O5S - H] 709.225 69; found
709.225 32.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-imidazol-1-yl)ethyl]sul-
fonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (80). Ester 45
1
was hydrolyzed to afford 80 in 60% yield. H NMR (300 MHz,
DMSO-d6) δ 3.81 (s, 4 H), 3.89-3.99 (m, 2 H), 4.00-4.23 (m, 6
H), 4.90-5.05 (m, J ) 6.9 Hz, 4 H), 7.21 (d, J ) 8.8 Hz, 1 H),
7.51-7.60 (m, 2 H), 7.61-7.69 (m, J ) 8.5 Hz, 2 H), 7.80-7.88
(m, J ) 7.7 Hz, 5 H), 7.91 (s, 1 H), 8.04-8.15 (m, 5 H), 8.34-8.45
(m, 3 H), 8.56 (d, J ) 8.8 Hz, 2 H). HRMS calcd for
[C37H35ClN4O5S - H] 681.194 39; found 681.194 09.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-yl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (81). Ester
46 was hydrolyzed to afford 81 in 100% yield. 1H NMR (300 MHz,
DMSO-d6) δ 2.99-3.11 (m, 4 H), 3.14-3.26 (m, 2 H), 3.44-3.55
(m, 2 H), 4.17-4.30 (m, 2 H), 4.44-4.55 (m, 2 H), 5.76 (s, 1 H),
6.47 (d, J ) 8.0 Hz, 1 H), 6.81 (d, J ) 6.0 Hz, 1 H), 6.98 (d, J )
8.2 Hz, 1 H), 7.03-7.15 (m, 5 H), 7.26-7.43 (m, 6 H), 7.53-7.71
(m, J ) 23.9 Hz, 2 H), 7.85 (d, J ) 8.8 Hz, 2 H), 7.93 (s, 1 H),
8.50 (s, 1 H). HRMS calcd for [C36H34ClN5O5S - H] 682.189 64;
found 682.189 64.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,3-triazol-1-yl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (82). Ester
47 was hydrolyzed to afford 82 in 100% yield. 1H NMR (300 MHz,
CDCl3) δ 2.85-3.00 (m, 2 H), 3.07-3.25 (m, J ) 25.0 Hz, 4 H),
3.31-3.40 (m, 2 H), 4.17-4.26 (m, 2 H), 4.61-4.71 (m, 2 H),
5.06 (s, 1 H), 6.45-6.55 (m, 1 H), 6.76-6.94 (m, 4 H), 7.07 (d, J
) 2.5 Hz, 4 H), 7.25-7.33 (m, J ) 4.4, 1.9 Hz, 6 H), 7.50-7.56
(m, 2 H), 7.58-7.64 (m, 1 H), 7.90-7.99 (m, 2 H). HRMS calcd
for [C36H34ClN5O5S - H] 682.189 64; found 682.189 33.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)methyl]sulfo-
nyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (40). Ester 133
1
was hydrolyzed to afford 40 in 95% yield. H NMR (300 MHz,
CD3OD) δ 2.99-3.43 (m, 9 H), 4.29 (t, J ) 6.2 Hz, 2 H), 4.67-4.83
(m, 2 H), 6.46 (d, J ) 9.1 Hz, 1 H), 6.72 (dd, J ) 9.1, 1.9 Hz, 1 H),
6.93 (d, J ) 9.1 Hz, 2 H), 7.11 (dd, J ) 6.6, 2.5 Hz, 5 H), 7.23-7.41
(m, 6 H), 7.59 (d, J ) 1.6 Hz, 1 H), 7.91 (d, J ) 8.8 Hz, 2 H). HRMS
calcd for C34H33ClN2O7S2, 680.1418; found [M + H]1+ 681.1477.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-morpholinyl)ethyl]sulfo-
nyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (99). Ester 63 (36
mg, 0.050 mmol) was hydrolyzed to give 99 in 89% yield. 1H NMR
(300 MHz, acetone-d6) δ 2.87 (br s, 4 H), 3.13 (m, 2 H), 3.32 (m,
6 H), 3.47 (br s, 2 H), 3.78 (br s, 4 H), 4.33 (t, J ) 6.5 Hz, 2 H),
6.55 (d, J ) 8.7 Hz, 1 H), 6.78 (dd, J ) 8.9, 2.0 Hz, 1 H), 7.01 (d,
J ) 7.1 Hz, 2 H), 7.18-7.20 (m, 4 H), 7.24 (s, 1 H), 7.34-7.36
(m, 6 H), 7.70 (d, J ) 2.2 Hz, 1 H), 7.94 (d, J ) 8.7 Hz, 2 H).
HRMS calcd for [C38H40ClN3O6S - H] 700.2535; found 700.225 00.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-pyrazol-1-yl)ethyl]sulfo-
nyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (76). Ester 41 was
hydrolyzed to afford 76 in 61% yield. 1H NMR (300 MHz, acetone-
d6) δ 2.85 (br s, 2 H), 3.15-3.25 (m, 2 H), 3.31 (t, J ) 6.3 Hz, 2
H), 3.49 (t, J ) 7.5 Hz, 2 H), 4.33 (t, J ) 6.5 Hz, 2 H), 4.50 (t, J
) 6.8 Hz, 2 H), 6.17 (m, 1 H), 6.42 (m, 1 H), 6.56 (d, J ) 8.7 Hz,
1 H), 6.79 (dd, J ) 8.7, 2.20 Hz, 1 H), 7.02 (d, J ) 8.7 Hz, 2 H),
7.13-7.20 (m, 4 H), 7.36-7.45 (m, 6 H), 7.63 (d, J ) 1.7 Hz, 1
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2H-tetraazol-2-yl)ethyl]sul-
fonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (83). Ester 48
1
was hydrolyzed to afford 83 in 92% yield. H NMR (300 MHz,
CDCl3) δ 2.84-2.96 (m, 2 H), 3.09-3.18 (m, 2 H), 3.23 (t, J )
5.5 Hz, 2 H), 3.39-3.49 (m, 2 H), 4.26 (t, J ) 5.5 Hz, 2 H),
4.57-4.65 (m, 1 H), 4.88-4.97 (m, 2 H), 6.52-6.58 (m, 1 H),
6.80-6.93 (m, 4 H), 7.07 (dd, J ) 6.2, 2.9 Hz, 4 H), 7.27-7.37
(m, 6 H), 7.55 (d, J ) 1.9 Hz, 1 H), 7.95-7.96 (m, 2 H), 8.37-8.41
(m, 1 H). HRMS calcd for [C35H33ClN6O5S - H] 683.184 89; found
683.184 35.

1168 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Chen et al.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1H-tetraazol-1-yl)ethyl]sul-
fonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (84). Ester 49
was hydrolyzed to afford 84 in 83% yield. H NMR (300 MHz,
8.42 (s, 1 H), 8.60 (d, J ) 8.5 Hz, 2 H). HRMS calcd for
[C39H42ClN3O6S - H] 714.241 00; found 714.240 85.
1
4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-{2-[(dimethylamino)methyl]-
1-piperidinyl}ethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}ben-
zoic Acid (93). Ester 57 was hydrolyzed to afford 93 in 79% yield.
1H NMR (300 MHz, DMSO-d6) δ 2.18 (m, 4 H), 3.30 (m, 4 H),
3.46 (m, 2 H), 3.70 (m, 2 H), 3.88 (m, 4 H), 3.96 (m, 2 H), 4.15
(m, 2 H), 5.04 (m, 1 H), 7.27 (d, J ) 9.0 Hz, 1 H), 7.61 (dd, J )
8.9, 2.0 Hz, 1 H), 7.79 (m, 2 H), 7.91 (m, 5 H), 8.15 (m, 6 H),
8.48 (d, J ) 1.9 Hz, 1 H), 8.65 (d, J ) 8.7 Hz, 2 H). HRMS calcd
for [C42H49ClN4O5S - H] 755.303 94; found 755.303 44.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-
piperazinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzo-
ic Acid (94). Ester 58 was hydrolyzed to afford 94 in 100% yield.
1H NMR (300 MHz, CDCl3) δ 2.43-2.55 (m, 4 H), 2.76-2.87
(m, 2 H), 2.96-3.11 (m, 4 H), 3.13-3.29 (m, J ) 6.6 Hz, 4 H),
3.31-3.43 (m, 4 H), 4.15-4.26 (m, 2 H), 6.45-6.58 (m, 2 H),
6.66 (d, J ) 6.6 Hz, 1 H), 6.74-6.85 (m, 3 H), 6.93-6.99 (m, 1
H), 7.08 (d, J ) 7.4 Hz, 5 H), 7.21-7.34 (m, 5 H), 7.42-7.56 (m,
2 H), 7.88-7.97 (m, 2 H), 8.14-8.22 (m, J ) 4.9 Hz, 1 H). HRMS
calcd for [C43H44ClN5O5S - H] 776.267 89; found 776.267 50.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethylpiperazin-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (95).
Ester 59 was hydrolyzed to afford 95 in 39% yield. 1H NMR (300
MHz, DMSO-d6) δ 0.98 (d, J ) 6.3 Hz, 6 H), 1.61 (t, J ) 10.9
Hz, 2 H), 2.52-2.56 (m, 2 H), 2.61-2.67 (m, 2 H), 2.79-2.89
(m, 2 H), 3.00-3.10 (m, 6 H), 3.16-3.23 (m, 2 H), 4.24 (t, J )
6.2 Hz, 2 H), 6.47 (d, J ) 9.1 Hz, 1 H), 6.81 (dd, J ) 8.8, 1.9 Hz,
1 H), 6.96 (d, J ) 9.1 Hz, 2 H), 7.07-7.13 (m, J ) 7.4, 1.9 Hz,
5 H), 7.31-7.39 (m, 6 H), 7.67 (d, J ) 1.9 Hz, 1 H), 7.84 (d, J )
8.8 Hz, 2 H). HRMS calcd for C40H45ClN4O5S, 728.2799; found
[M + H]1+ 729.2873.
4-(2-{2-[2-({[2-(4-Acetyl-3,5-dimethylpiperazin-1-yl)ethyl]sulfonyl}-
amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic Acid
(96). Ester 60 was hydrolyzed to afford 96 in 96% yield. 1H NMR
(300 MHz, acetone-d6) δ 1.18 (d, 6 H), 1.95-1.97 (m, 3 H), 1.98
(d, J ) 3.3 Hz, 2 H), 2.62-2.74 (m, 2 H), 2.82-2.93 (m, 4 H),
3.08-3.23 (m, 2 H), 3.27-3.38 (m, J ) 6.6, 6.6 Hz, 6 H), 4.35 (t,
J ) 6.7 Hz, 2 H), 6.56 (d, J ) 9.1 Hz, 1 H), 6.79 (dd, J ) 8.9, 2.1
Hz, 1 H), 7.03 (d, J ) 8.8 Hz, 2 H), 7.16-7.24 (m, 5 H), 7.37 (dd,
J ) 5.1, 1.8 Hz, 6 H), 7.70 (d, J ) 1.9 Hz, 1 H), 7.95 (d, J ) 9.1
Hz, 2 H). HRMS calcd for C42H47ClN4O6S, 770.2905; found [M
+ H]1+ 771.2975.
4-(2-{2-[2-({[2-(4-Acetylpiperazin-1-yl)ethyl]sulfonyl}amino)ethyl]-
1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic Acid (97). Ester
61 was hydrolyzed to afford 97 in 19% yield. 1H NMR (300 MHz,
acetone-d6) δ 1.93-2.00 (m, J ) 2.2 Hz, 3 H), 2.22-2.31 (m, J )
4.9, 4.9 Hz, 2 H), 2.31-2.39 (m, 2 H), 2.64-2.74 (m, 2 H), 3.11
(t, J ) 6.9 Hz, 2 H), 3.27-3.42 (m, 10 H), 4.35 (t, J ) 6.7 Hz, 2
H), 6.57 (d, J ) 8.8 Hz, 1 H), 6.79 (dd, J ) 9.1, 1.9 Hz, 1 H), 7.02
(d, J ) 8.8 Hz, 2 H), 7.14-7.23 (m, J ) 7.8, 4.8 Hz, 5 H),
7.32-7.42 (m, 6 H), 7.69 (d, J ) 2.2 Hz, 1 H), 7.95 (d, J ) 8.8
Hz, 2 H). HRMS calcd for C40H43ClN4O4S, 742.2592; found
743.2664.
DMSO-d6) δ 3.02-3.13 (m, 4 H), 3.15-3.25 (m, 2 H), 3.54-3.69
(m, 2 H), 4.18-4.31 (m, 2 H), 4.78 (t, J ) 6.5 Hz, 2 H), 6.47 (d,
J ) 8.8 Hz, 1 H), 6.81 (dd, J ) 8.9, 2.1 Hz, 1 H), 6.98 (d, J ) 8.8
Hz, 2 H), 7.04-7.15 (m, 5 H), 7.29-7.42 (m, 6 H), 7.67 (d, J )
1.9 Hz, 2 H), 7.85 (d, J ) 8.8 Hz, 2 H). HRMS calcd for
[C35H33ClN6O5S - H] 683.184 89; found 683.184 35.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1-piperidinyl)ethyl]sulfonyl}-
amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (86). Ester 50 was
hydrolyzed to afford 86 in 92% yield. 1H NMR (300 MHz, acetone-
d6) δ 1.39 (s, 2 H), 1.53 (s, 4 H), 2.48 (s, 4 H), 2.72-2.86 (m, 2
H), 3.26-3.38 (m, 8 H), 4.29 (s, 2 H), 6.55 (d, J ) 8.7 Hz, 1 H),
6.77 (d, J ) 9.0 Hz, 1 H), 6.97 (m, 2 H), 7.19 (m, 5 H), 7.33 (m,
6 H), 7.69 (s, 1 H), 7.91 (d, J ) 7.4 Hz, 2 H). HRMS calcd for
[C39H42ClN3O5S - H] 698.246 09; found 698.245 70.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-1-piperidinyl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (87). Ester
51 was hydrolyzed to afford 87 in 96% yield. 1H NMR (300 MHz,
acetone-d6) δ 1.30-1.50 (m, 5 H), 1.65-85 (m, 4 H), 2.8-3.2 (m,
2 H), 3.0-3.2 (m, 2 H), 3.25-3.45 (m, 6 H), 3.5-3.8 (m, 3 H),
4.34 (t, J ) 6.5 Hz, 2 H), 6.53 (d, J ) 8.7 Hz, 1 H), 6.77 (dd, J )
8.9, 2.0 Hz, 1 H), 7.02 (d, J ) 8.7 Hz, 2 H), 7.18-7.23 (m, 4 H),
7.29 (s, 1 H), 7.3-7.4 (m, 6 H), 7.69 (d, J ) 2.2 Hz, 1 H), 7.94 (d,
J ) 8.7 Hz, 2 H). HRMS calcd for [C40H44ClN3O5S - H]
712.261 74; found 712.261 13.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (88).
Ester 52 was hydrolyzed to afford 88 in 87% yield. 1H NMR (300
MHz, DMSO-d6) δ 0.69-0.84 (m, 3 H), 1.25-1.83 (m, 4 H),
2.40-2.65 (m, 4 H), 2.97-3.17 (m, 6 H), 3.21 (t, J ) 5.8 Hz, 2
H), 3.27-3.44 (m, 6 H), 4.25 (t, J ) 6.3 Hz, 2 H), 6.48 (d, J ) 8.8
Hz, 1 H), 6.81 (dd, J ) 8.8, 1.9 Hz, 1 H), 6.99 (d, J ) 8.8 Hz, 2
H), 7.10 (d, J ) 7.7 Hz, 4 H), 7.31-7.43 (m, 6 H), 7.68 (d, J )
1.9 Hz, 1 H), 7.85 (d, J ) 8.8 Hz, 2 H). HRMS calcd for
C40H44ClN3O5S, 713.2690; found [M + H]1+ 714.2765.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (89).
Ester 53 was hydrolyzed to afford 89 in 62% yield. 1H NMR (300
MHz, DMSO-d6) δ 0.83 (d, J ) 4.1 Hz, 3 H), 0.91-1.13 (m, 2
H), 1.37-1.87 (m, J ) 87.6 Hz, 4 H), 2.54-2.71 (m, 2 H),
2.98-3.15 (m, 6 H), 3.21 (t, J ) 6.5 Hz, 2 H), 3.27-3.45 (m, 4
H), 4.24 (t, J ) 6.3 Hz, 2 H), 6.48 (d, J ) 8.8 Hz, 1 H), 6.81 (dd,
J ) 8.8, 2.2 Hz, 1 H), 6.99 (d, J ) 8.8 Hz, 2 H), 7.05-7.18 (m,
5 H), 7.31-7.43 (m, 6 H), 7.68 (d, J ) 1.9 Hz, 1 H), 7.85 (d, J )
8.8 Hz, 2 H). HRMS calcd for C40H44ClN3O5S, 713.2690; found
714.2755.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-
piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzo-
ic Acid (90). Ester 54 was hydrolyzed to afford 90 in 79% yield. 1H
NMR (300 MHz, CDCl3) δ 0.74-1.78 (m, 12 H), 2.43-2.68 (m,
2 H), 2.95-3.44 (m, 10 H), 4.05-4.17 (m, 2 H), 6.42-6.65 (m, 4
H), 6.73-6.84 (m, 1 H), 6.96-7.17 (m, 6 H), 7.20-7.35 (m, 4 H),
7.55-7.63 (m, 1 H), 7.71-7.82 (m, J ) 7.8, 7.8 Hz, 2 H). HRMS
calcd for [C41H46ClN3O5S - H] 726.277 39; found 726.277 20.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-thiomorpholinyl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (91). Ester
55 was hydrolyzed to afford 91 in 90% yield. 1H NMR (300 MHz,
acetone-d6) δ 2.55 (app s, 4 H), 2.59 (app s, 4 H), 2.70 (t, J ) 6.8
Hz, 2 H), 3.08 (t, J ) 6.87 Hz, 2 H), 3.32 (m, 6 H), 4.33 (m, 2 H),
6.57 (d, J ) 9.0 Hz, 1 H), 6.78 (dd, J ) 9.1, 2.2 Hz, 2 H),
6.98-7.03 (m, 2 H), 7.13-7.22 (m, 5 H), 7.33-7.40 (m, 6 H),
7.69 (s, 1 H), 7.96 (m, 2 H). HRMS calcd for [C38H40ClN3O5S2 -
H] 716.202 51; found 716.202 17.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperazin-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (98).
Ester 62 was hydrolyzed to afford 98 in 29% yield. 1H NMR (400
MHz, CDCl3) δ 1.24-1.31 (m, 3 H), 2.71-2.81 (m, 1 H),
2.89-3.27 (m, 14 H), 4.24 (t, J ) 6.4 Hz, 2 H), 5.14 (none, 1 H),
6.53 (d, J ) 8.8 Hz, 1 H), 6.78-6.85 (m, 3 H), 6.97 (s, 1 H),
7.07-7.13 (m, 4 H), 7.28-7.34 (m, 6 H), 7.55 (d, J ) 2.0 Hz, 1
H), 7.90-7.97 (m, 2 H). HRMS calcd for C39H41ClN4O6S,
728.2435; found [M + H]1+ 729.2501.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]-
hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid
1
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-hydroxy-1-piperidinyl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (92). Ester
56 was hydrolyzed to afford 92 in 42% yield. 1H NMR (300 MHz,
DMSO-d6) δ 1.74-2.80 (m, 4 H), 3.69-4.39 (m, 16 H), 4.92-5.04
(m, 2 H), 7.21 (d, J ) 9.1 Hz, 1 H), 7.56 (d, J ) 9.1 Hz, 1 H),
7.74 (d, J ) 8.8 Hz, 2 H), 7.85 (d, J ) 7.1 Hz, 5 H), 8.10 (s, 6 H),
(100). Ester 64 was hydrolyzed to afford 100 in 100% yield. H
NMR (400 MHz, CD3OD) δ 1.60-1.75 (m, 2 H), 2.54 (d, J )
10.6 Hz, 1 H), 2.70 (dd, J ) 10.5, 1.4 Hz, 1 H), 2.77-3.08 (m, 9
H), 3.17 (t, J ) 6.4 Hz, 2 H), 3.44-3.49 (m, 2 H), 3.77 (t, J ) 8.0
Hz, 1 H), 4.20 (t, J ) 6.3 Hz, 2 H), 4.27 (s, 1 H), 6.38 (d, J ) 8.8
Hz, 1 H), 6.63 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.78-6.84 (m, 2 H),

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1169
6.97-7.04 (m, 5 H), 7.18-7.25 (m, 6 H), 7.50 (d, J ) 2.0 Hz, 1
H), 7.78-7.83 (m, 2 H). HRMS calcd for C39H40ClN3O6S,
713.2326; found [M + H]1+ 714.2397.
(m, 1 H), 2.60-2.74 (m, 2 H), 2.88-3.41 (m, 15 H), 3.48 (dd, J )
10.1, 3.3 Hz, 1 H), 4.24 (t, J ) 6.8 Hz, 2 H), 6.51 (d, J ) 8.8 Hz,
1 H), 6.81 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.88 (d, J ) 8.8 Hz, 2 H),
6.98-7.02 (m, 1 H), 7.08-7.18 (m, 5 H), 7.29-7.36 (m, 5 H),
7.58 (d, J ) 2.0 Hz, 1 H), 8.00 (d, J ) 8.8 Hz, 2 H). HRMS calcd
for C40H44ClN3O6S, 729.2639; found [M + H]1+ 730.2709.
4-{2-[2-{2-[({2-[(2S)-2-(Aminocarbonyl)pyrrolidin-1-yl]ethyl}sulfo-
nyl)amino]ethyl}-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}-
benzoic Acid (109). Ester 73 was hydrolyzed to afford 109 in 43%
yield. 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.67 (m, 4 H),
1.87-2.14 (m, 2 H), 2.51-3.47 (m, 12 H), 4.24 (t, J ) 6.8 Hz, 2 H),
6.48 (d, J ) 8.8 Hz, 1 H), 6.80 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.96-7.01
(m, 2 H), 7.05-7.14 (m, 5 H), 7.27-7.52 (m, 7 H), 7.67 (d, J ) 2.0
Hz, 1 H), 7.82-7.87 (m, 2 H), 8.16 (s, 1 H). HRMS calcd for
C39H41ClN4O6S, 728.2435; found [M + H]1+ 729.2510.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (110).
Ester 74 was hydrolyzed to afford 110 in 88% yield. 1H NMR (300
MHz, CDCl3) δ 2.98-3.30 (m, 8 H), 3.45-3.72 (m, J ) 31.3 Hz,
4 H), 3.81-3.94 (m, 2 H), 4.18-4.32 (m, 2 H), 5.92 (s, 1 H), 6.51
(d, J ) 8.8 Hz, 1 H), 6.75-7.00 (m, 3 H), 7.02-7.16 (m, 4 H),
7.22-7.37 (m, 6 H), 7.55 (dd, J ) 5.2, 2.2 Hz, 1 H), 7.92-8.03
(m, 2 H). HRMS calcd for [C37H37ClN4O5S - H] 715.182 11; found
715.181 61.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(3R,5S)-3,5-dimethylmorpho-
lin-4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic Acid
(101). Ester 65 was hydrolyzed to afford 101 in 8% yield. 1H NMR
(400 MHz, CD3OD) δ 0.98 (d, J ) 6.1 Hz, 6 H), 1.51 (t, J ) 10.7
Hz, 2 H), 2.45-2.53 (m, 4 H), 2.91-2.97 (m, J ) 8.5, 6.4 Hz, 2
H), 3.05-3.11 (m, 2 H), 3.18-3.26 (m, 5 H), 3.38-3.45 (m, J )
3.0 Hz, 1 H), 4.24 (t, J ) 5.8 Hz, 2 H), 6.41 (d, J ) 9.1 Hz, 1 H),
6.66 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.85 (d, J ) 9.1 Hz, 2 H), 7.04
(dd, J ) 6.9, 2.7 Hz, 5 H), 7.21-7.28 (m, 6 H), 7.54 (d, J ) 1.8
Hz, 1 H), 7.84 (d, J ) 8.8 Hz, 2 H), 8.32 (s, 1 H). HRMS calcd for
[C40H44ClN3O6S + H] 730.2717; found 730.2708.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1-pyrrolidinyl)ethyl]sulfo-
nyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (102). Ester 66
1
was hydrolyzed to afford 102 in 94% yield. H NMR (300 MHz,
DMSO-d6) δ 2.37-2.63 (m, J ) 2.7 Hz, 4 H), 3.44-4.26 (m, 14
H), 4.85-5.00 (m, 2 H), 7.14 (dd, J ) 8.8, 2.5 Hz, 1 H), 7.44-7.51
(m, 1 H), 7.66 (dd, J ) 8.9, 2.6 Hz, 2 H), 7.72-7.85 (m, 5 H),
7.97-8.12 (m, J ) 4.4 Hz, 6 H), 8.31-8.38 (m, 1 H), 8.43-8.60
(m, J ) 8.8, 2.5 Hz, 2 H). HRMS calcd for [C38H40ClN3O5S - H]
684.230 44; found 684.230 09.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-methyl-1-pyrrolidinyl)eth-
yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (103). Es-
4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-
yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic Acid (114).
1
ter 67 was hydrolyzed to afford 103 in 99% yield. H NMR (300
1
MHz, acetone-d6) δ 1.48 (br s, 3 H), 1.76 (m, 1 H), 1.96 (m, 2 H),
2.21 (m, 1 H), 3.01 (m, 2 H), 3.25-3.45 (m, 6 H), 3.5-3.7 (m, 4
H), 3.91 (br s, 1 H), 4.34 (t, J ) 6.4 Hz, 2 H), 6.53 (d, J ) 8.7 Hz,
1 H), 6.77 (dd, J ) 8.9, 2.0 Hz, 1 H), 7.02 (d, J ) 8.5 Hz, 2 H),
7.21 (m, 4 H), 7.29 (s, 1 H), 7.36 (m, 6 H), 7.69 (d, J ) 1.9 Hz,
1 H), 7.94 (d, J ) 8.7 Hz, 2 H). HRMS calcd for [C39H42ClN3O5S
- H] 698.246 09; found 698.245 72.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(2,5-dimethyl-1-pyrrolidinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (104).
Ester 68 was hydrolyzed to afford 104 in 96% yield. 1H NMR (300
MHz, acetone-d6) δ 0.9-1.2 (m, 6 H), 1.2-1.5 (m, 2 H), 1.7-1.9
(m, 2 H), 2.7-3.2 (m, 6 H), 4.35 (t, J ) 6.6 Hz, 2 H), 6.56 (d, J )
8.7 Hz, 1 H), 6.75-6.81 (m, 1 H), 6.98-7.03 (m, 2 H), 7.16-7.23
(m, 5 H), 7.33-7.38 (m, 6 H), 7.69 (s, 1 H), 7.92-7.97 (m, 2 H).
HRMS calcd for [C40H44ClN3O5S - H] 712.261 74; found 712.261 14.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]-
sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (105). Ester
69 was hydrolyzed to afford 105 in 93% yield. 1H NMR (300 MHz,
CDCl3) δ 2.70-3.31 (m, 14 H), 3.78 (s, 2 H), 4.25 (t, J ) 6.7 Hz,
2 H), 6.54 (d, J ) 9.1 Hz, 1 H), 6.78-6.92 (m, 3 H), 6.97 (s, 1 H),
7.05-7.16 (m, 5 H), 7.28-7.37 (m, 5 H), 7.56 (s, 1 H), 7.99 (d, J
) 8.8 Hz, 2 H). HRMS calcd for [C37H38ClN3O5S2 - H]
702.186 86; found 702.186 59.
4-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(3-hydroxy-1-pyrrolidinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic Acid (106).
Ester 70 was hydrolyzed to afford 106 in 84% yield. 1H NMR (300
MHz, DMSO-d6) δ 3.30-3.51 (m, 2 H), 3.67-4.40 (m, 14 H),
4.82-4.91 (m, 1 H), 4.93-5.05 (m, 2 H), 5.52 (s, 1 H), 7.21 (d, J
) 8.5 Hz, 1 H), 7.55 (dd, J ) 8.9, 2.1 Hz, 1 H), 7.73 (d, J ) 8.8
Hz, 2 H), 7.79-7.91 (m, J ) 4.9 Hz, 5 H), 8.02-8.20 (m, 6 H),
8.41 (d, J ) 1.9 Hz, 1 H), 8.59 (d, J ) 8.8 Hz, 2 H). HRMS calcd
for [C38H40ClN3O6S - H] 700.225 35; found 700.224 90.
4-{2-[5-Chloro-2-{2-[({2-[3-(dimethylamino)pyrrolidin-1-
yl]ethyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-
yl]ethoxy}benzoic Acid (107). Ester 71 was hydrolyzed to afford 107
in 73% yield. 1H NMR (300 MHz, DMSO-d6) δ 2.97-3.48 (m, 8
H), 3.73-4.01 (m, J ) 26.9 Hz, 12 H), 4.28-4.42 (m, 4 H),
4.93-5.05 (m, 2 H), 7.22 (d, J ) 8.8 Hz, 1 H), 7.52-7.59 (m, J
) 2.2 Hz, 1 H), 7.72 (d, J ) 8.5 Hz, 2 H), 7.79-7.90 (m, 5 H),
8.09 (s, 6 H), 8.42 (d, J ) 1.9 Hz, 1 H), 8.59 (d, J ) 8.8 Hz, 2 H).
HRMS calcd for C40H45ClN4O5S + H+, 729.2877; found 729.2872.
4-[2-(1-Benzhydryl-5-chloro-2-{2-[({2-[(2S)-2-(methoxymethyl)pyr-
rolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzo-
ic Acid (108). Ester 72 was hydrolyzed to afford 108 in 87% yield.
1H NMR (400 MHz, CDCl3) δ 1.49-1.90 (m, 4 H), 2.11-2.21
Ester 111 was hydrolyzed to afford 114 in 89% yield. H NMR
(300 MHz, acetone-d6) δ 1.95-2.10 (m, 2H), 2.18 (s, 3H), 2.20
(s, 3 H), 2.84 (m, 4 H), 3.12 (app d, J ) 2.4 Hz, 4 H), 3.42 (m, 2
H), 4.30 (t, J ) 6.8 Hz, 2 H), 5.76 (m, 1 H) 6.37 (m, 1 H), 6.52 (d,
J ) 8.7 Hz, 1 H), 6.76 (dd, J ) 8.7, 2.2 Hz, 1 H), 7.15 (m, 4 H),
7.36 (m, 6 H), 7.50 (m, 1 H), 7.63 (dd, J ) 5.7, 3.3 Hz, 1 H), 7.79
(dd, J ) 5.7, 3.3 Hz, 1 H), 7.96 (m, 2 H). HRMS calcd for
[C40H41ClN4O4S - H] 707.246 42; found 707.245 97.
4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(4-morpholinyl)ethyl]sulfo-
nyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic Acid (115). Ester 112
1
was hydrolyzed to afford 115 in 85% yield. H NMR (300 MHz,
acetone-d6) δ 1.95-2.05 (m, 2H), 2.85 (m, 4 H), 3.05-3.25 (m, 6
H), 3.25-3.40 (m, 4 H), 3.62 (br s, 2 H), 3.89 (br s, 4 H), 6.50 (d,
J ) 8.7 Hz, 1 H), 6.75 (dd, J ) 8.7, 2.2 Hz, 1 H), 7.197-7.23 (m,
6 H), 7.32-7.40 (m, 7 H), 7.51 (d, J ) 2.2 Hz, 1 H), 7.94 (d, J )
7.9 Hz, 2 H). HRMS calcd for [C39H42ClN3O5S - H] 698.246 09;
found 698.245 81.
4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(2,6-dimethyl-1-piperidinyl)-
ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic Acid (116).
1
Ester 113 was hydrolyzed to afford 116 in 86% yield. H NMR
(300 MHz, acetone-d6) δ 1.35 (d, J ) 6.3 Hz, 6 H), 1.75-1.86 (m,
J ) 7.7 Hz, 4 H), 1.91-2.02 (m, 2 H), 2.75-2.91 (m, 4 H),
3.09-3.20 (m, J ) 7.7 Hz, 4 H), 3.23-3.32 (m, 2 H), 3.37-3.55
(m, 4 H), 3.61-3.71 (m, 2 H), 6.51 (d, J ) 9.1 Hz, 1 H), 6.73-6.78
(m, 1 H), 7.12-7.17 (m, 5 H), 7.31-7.36 (m, 8 H), 7.49 (d, J )
2.2 Hz, 1 H), 7.92 (d, J ) 8.2 Hz, 2 H). HRMS calcd for
C42H48ClN3O4S + H+, 726.3132; found 726.3125.
4-{3-[5-Chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]-
amino}ethyl)-1H-indol-3-yl]propyl}benzoic Acid (125). Ester 12 was
1
hydrolyzed to afford 125 in 62% as a white solid. H NMR (400
MHz, acetone-d6) δ 1.82-1.89 (m, 2 H), 2.59-2.74 (m, 8 H), 4.76
(s, 2 H), 6.26 (t, J ) 5.2 Hz, 1 H), 6.39 (d, J ) 8.6 Hz, 1 H), 6.62
(dd, J ) 8.8, 2.3 Hz, 1 H), 6.97 (s, 1 H), 6.99-7.04 (m, 4 H),
7.18-7.29 (m, 8 H), 7.31-7.38 (m, 2 H), 7.41-7.45 (m, 2 H),
7.74-7.79 (m, 1 H), 7.83 (d, J ) 8.3 Hz, 2 H), 10.10 (s, 1 H).
HRMS calcd for C41H37ClN2O5S + H+, 705.21845; found [M +
H]1+ 705.2168.
4-{3-[5-Chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)-
amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid
(126). Ester 118 was hydrolyzed to afford 126 in 66% as a white
solid. 1H NMR (400 MHz, acetone-d6) δ 1.07 (t, J ) 7.0 Hz, 6 H),
1.79-1.89 (m, 4 H), 2.63-2.75 (m, 6 H), 2.93-3.05 (m, 4 H),
3.82-3.98 (m, 2 H), 4.61 (s, 2 H), 6.38 (d, J ) 8.8 Hz, 1 H), 6.62
(dd, J ) 8.8, 2.2 Hz, 1 H), 7.00-7.06 (m, J ) 7.4, 1.6 Hz, 5 H),
7.15-7.21 (m, 3 H), 7.21-7.27 (m, 9 H), 7.35 (d, J ) 2.0 Hz, 1

1170 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4
Chen et al.
H), 7.83 (d, J ) 8.0 Hz, 2 H). HRMS calcd for C45H48ClN3O4S +
H+, 762.312 68; found 762.3133.
References
(1) (a) Clark, J. D.; Schievella, A. R.; Nalefski, E. A.; Lin, L.-L. Cytosolic
phospholipase A2. J. Lipid Mediators Cell Signalling 1995, 12, 83–
117. (b) Hanel, A. M.; Schuttel, S.; Gelb, M. H. Processive interfacial
catalysis by mammalian 85-kilodalton phospholipase A2 enzymes on
product-containing vesicles: application to the determination of
substrate preferences. Biochemistry 1993, 32, 5949–5958.
(2) (a) Magrioti, V.; Kokotos, G. Synthetic inhibitors of group IVA and
group VIA phospholipase A2. Anti-Inflammatory Anti-Allergy Agents
Med. Chem. 2006, 5 (2), 189–203. (b) Kokotos, G.; Six, D. A.; Loukas,
V.; Smith, T.; Constantinou-Kokotou, V.; Hadjipavlou-Litina, D.;
Kotsovolou, S.; Chiou, A.; Beltzner, C. C.; Dennis, E. A. Inhibition
of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in
vitro, in cells, and in vivo. J. Med. Chem. 2004, 47 (14), 3615–3628.
4-(3-{5-Chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)ben-
zyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic Acid (127).
Ester 119 was hydrolyzed to afford 127 in 61% as a white solid.
1H NMR (400 MHz, acetone-d6) δ 1.80-1.90 (m, 2 H), 2.60-2.76
(m, 6 H), 4.31 (s, 2 H), 4.62 (s, 2 H), 6.28 (t, J ) 6.1 Hz, 1 H),
6.36-6.41 (m, 1 H), 6.62 (dd, J ) 8.8, 2.3 Hz, 1 H), 6.98 (s, 1 H),
6.99-7.07 (m, 5 H), 7.12-7.18 (m, 2 H), 7.12-7.18 (m, 2 H),
7.21-7.30 (m, 9 H), 7.35 (d, J ) 2.0 Hz, 1 H), 7.83 (d, J ) 8.3
Hz, 2 H). HRMS calcd for C41H39ClN2O5S + H+, 707.234 10; found
707.2356.
4-(3-{5-Chloro-1-(diphenylmethyl)-2-[2-({[2-(morpholin-4-
ylmethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic
Acid (128). Ester 120 was hydrolyzed to afford 128 in 83% as a
(3) (a) Uozumi, N.; Kume, K.; Nagase, T.; Nakatani, N.; Ishii, S.; Tashiro,
F.; Komagata, Y.; Maki, K.; Ikuta, K.; Ouchi, Y.; Miyazaki, J.-i.;
Shimizu, T. Role of cytosolic phospholipase A2 in allergic response
and parturition. Nature 1997, 390 (6660), 618–622. (b) Hegen, M.;
Sun, L.; Uozumi, N.; Kume, K.; Goad, M. E.; Nickerson-Nutter, C. L.;
Shimizu, T.; Clark, J. D. Cytosolic phospholipase A2R-deficient mice
are resistant to collagen-induced arthritis. J. Exp. Med. 2003, 197 (10),
1297–1302. (c) Tabuchi, S.; Uozumi, N.; Ishii, S.; Shimizu, Y.;
Watanabe, T.; Shimizu, T. Mice Deficient in Cytosolic Phospholipase
A2 Are Less Susceptible to Cerebral Ischemia/Reperfusion Injury Brain
Edema XII, Proceedings of the 12th International Symposium, Hakone,
Japan, Nov 10-13, 2002; Springer: Berlin, 2003; pp 169-172. (d)
Marusic, S.; Leach, M. W.; Pelker, J. W.; Azoitei, M. L.; Uozumi,
N.; Cui, J.; Shen, M. W. H.; De Clercq, C. M.; Miyashiro, J. S.; Carito,
B. A.; Thakker, P.; Simmons, D. L.; Leonard, J. P.; Shimizu, T.; Clark,
J. D. Cytosolic phospholipase A2R-deficient mice are resistant to
experimental autoimmune encephalomyelitis. J. Exp. Med. 2005, 202
(6), 841–851. (e) Bonventre, J. V.; Huang, Z.; Taheri, M. R.; O’Leary,
E.; Li, E.; Moskowitz, M. A.; Sapirstein, A. Reduced fertility and
postischemic brain injury in mice deficient in cytosolic phospholipase
A2. Nature (London) 1997, 390 (6660), 622–625. (f) Hong, K. H.;
Bonventre, J. C.; O’Leary, E.; Bonventre, J. V.; Lander, E. S. Deletion
of cytosolic phospholipase A2 suppresses ApcMin-induced tumori-
genesis. Proc. Natl. Acad. Sci. U.S.A. 2001, 98 (7), 3935–3939.
(4) (a) McKew, J. C.; Lee, K. L.; Shen, M. W. H.; Thakker, P.; Foley,
M. A.; Behnke, M. L.; Hu, B.; Sum, F.-W.; Tam, S.; Hu, Y.; Chen,
L.; Kirincich, S. J.; Michalak, R.; Thomason, J.; Ipek, M.; Wu,
K.; Wooder, L.; Ramarao, M. K.; Murphy, E. A.; Goodwin, D. G.;
Albert, L.; Xu, X.; Donahue, F.; Ku, M. S.; Keith, J.; Nickerson-
Nutter, C. L.; Abraham, W. M.; William, C.; Hegen, M.; Clark,
J. D. Discovery and in vitro and in vivo characterization of 4-{3-
[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphe-
nylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib. J. Med.
Chem. 2008, 51, 3388–3413. (b) Lee, K. L.; Behnke, M. L.; Foley,
M A.; Chen, L.; Wang, W.; Vargas, R.; Nunez, J.; Tam, S.; Mollova,
N.; Xu, X.; Shen, M. W. H.; Ramarao, M. K.; Goodwin, D. G.;
Nickerson-Nutter, C. L.; Abraham, W. M.; Williams, C.; Clark, J. D.;
McKew, J. C. Benzenesulfonamide indole inhibitors of cytosolic
phospholipase A2R: optimization of in vitro potency and rat pharma-
cokinetics for oral efficacy. Bioorg. Med. Chem. 2008, 16, 1345–1358.
(c) Lee, K. L.; Foley, M. A.; Chen, L.; Behnke, M. L.; Lovering,
F. E.; Kirincich, S. J.; Wang, W.; Shim, J.; Tam, S.; Shen, M. W. H.;
Khor, S. P.; Xu, X.; Goodwin, D. G.; Ramarao, M. K.; Nickerson-
Nutter, C.; Donahue, F.; Ku, M. S.; Clark, J. D.; McKew, J. C.
Discovery of ecopladib, an indole inhibitor of cytosolic phospholipase
A2R. J. Med. Chem. 2007, 50, 1380–1400. (d) McKew, J. C.; Foley,
M. A.; Thakker, P.; Behnke, M. L.; Lovering, F. E.; Sum, F.-W.; Tam,
S.; Wu, K.; Shen, M. W. H.; Zhang, W.; Gonzalez, M.; Liu, S.;
Mahadevan, A.; Sard, H.; Khor, S. P.; Clark, J. D. Inhibition of
cytosolic phospholipase A2R: hit to lead optimization. J. Med. Chem.
2006, 49 (1), 135–158. (e) McKew, J. C.; Lovering, F.; Clark, J. D.;
Bemis, J.; Xiang, Y.; Shen, M.; Zhang, W.; Alvarez, J. C.; Joseph-
McCarthy, D. Structure-activity relationships of indole cytosolic
phospholipase A2R inhibitors: substrate mimetics. Bioorg. Med. Chem.
Lett. 2003, 13 (24), 4501–4504.
1
white solid. H NMR (400 MHz, acetone-d6) δ 1.78-1.90 (m, 4
H), 2.18 (brs, 2 H), 2.62-2.76 (m, 6 H), 2.97 (br s, 2 H), 3.44 (d,
J ) 6.3 Hz, 6 H), 4.53 (br s, 2 H), 6.38 (d, J ) 8.8 Hz, 1 H), 6.62
(dd, J ) 8.8 Hz, 1 H), 6.97-7.27 (m, 17 H), 7.35 (d, J ) 2.3 Hz,
1 H), 7.83 (d, J ) 8.3 Hz, 2 H). HRMS calcd for C45H46ClN3O5S
+ H+, 776.291 95; found [M + H]1+ 776.2921.
4-{3-[2-{2-[({2-[(4-Acetylpiperazin-1-yl)methyl]benzyl}sulfonyl)ami-
no]ethyl}-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic
Acid (129) and 4-(3-{5-Chloro-1-(diphenylmethyl)-2-[2-({[2-(piperazin-
1-ylmethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}propyl)benzoic Acid (130). Ester 121 was hydrolyzed to afford,
after preparative HPLC separation, 129 (21%) and 130 (21%), both
1
as solids. 129: H NMR (400 MHz, acetone-d6) δ 1.84 (s, 3 H),
1.85-1.90 (m, 4 H), 2.12-2.19 (m, 2 H), 2.20-2.27 (m, 2 H),
2.64-2.76 (m, 4 H), 3.24-3.29 (m, 2 H), 3.29-3.34 (m, 2 H),
3.53 (s, 2 H), 3.71 (d, J ) 1.5 Hz, 1 H), 4.52 (s, 2 H), 6.39 (d, J
) 8.8 Hz, 1 H), 6.63 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.99 (s, 1 H),
7.00-7.04 (m, J ) 7.6, 1.8 Hz, 4 H), 7.04-7.11 (m, J ) 8.8 Hz,
1 H), 7.12-7.17 (m, 2 H), 7.18-7.26 (m, 8 H), 7.35-7.38 (m, 1
H), 7.84 (d, J ) 8.6 Hz, 2 H), 8.00 (s, 1 H). HRMS calcd for
C47H49ClN4O5S + H+, 817.318 49; found [M + H]1+ 817.3199.
130: 1H NMR (400 MHz, acetone-d6) δ 1.85-1.90 (m, 4 H), 1.96
(s, 3 H), 2.12-2.19 (m, 2 H), 2.23 (none, 1 H), 2.20-2.27 (m, 2
H), 2.64-2.76 (m, 4 H), 3.24-3.29 (m, 2 H), 3.29-3.34 (m, 2 H),
3.53 (s, 2 H), 3.71 (d, J ) 1.5 Hz, 1 H), 4.52 (s, 2 H), 6.39 (d, J
) 8.8 Hz, 1 H), 6.63 (dd, J ) 8.8, 2.0 Hz, 1 H), 6.99 (s, 1 H),
7.00-7.04 (m, J ) 7.6, 1.8 Hz, 4 H), 7.04-7.11 (m, J ) 8.8 Hz,
1 H), 7.12-7.17 (m, 2 H), 7.18-7.26 (m, 8 H), 7.35-7.38 (m, 1
H), 7.84 (d, J ) 8.6 Hz, 2 H), 8.00 (s, 1 H). HRMS calcd for
C45H47ClN4O4S + H+, 775.307 93; found [M + H]1+), 775.3073.
4-[3-(5-Chloro-1-(diphenylmethyl)-2-{2-[({2-[(4-methylpiperazin-1-
yl)methyl]benzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzo-
ic Acid (131). Ester 123 was hydrolyzed to afford 131 in 69% as a
1
white solid. H NMR (400 MHz, acetone-d6) δ 1.89-1.97 (m, 2
H), 2.54-2.66 (m, 2 H), 2.70-2.76 (m, 4 H), 2.78 (s, 3 H),
2.80-2.92 (m, 4 H), 3.09-3.16 (m, 4 H), 3.31-3.34 (m, 2 H),
3.66 (s, 2 H), 4.52 (s, 2 H), 6.40 (d, J ) 8.8 Hz, 1 H), 6.68 (dd, J
) 8.8, 2.0 Hz, 1 H), 6.96 (s, 1 H), 7.06 (dd, J ) 6.6, 2.4 Hz, 4 H),
7.14-7.20 (m, 1 H), 7.22-7.26 (m, 2 H), 7.27 (d, J ) 8.3 Hz, 2
H), 7.31-7.35 (m, 7 H), 7.37 (d, J ) 2.0 Hz, 1 H), 7.93 (d, J )
8.3 Hz, 2 H). HRMS calcd for C46H49ClN4O4S - H+, 787.309 03;
found [M - H]1- 787.3101.
All assays including GLU micelle, rat whole blood, human whole
blood, and MC-9 assays were described previously; the CPE model
was also described previously.4b,c
All plogD7.4 values were calculated from CompuDrug prologD
program.
(5) Ono, T.; Yamada, K.; Chikazawa, Y.; Ueno, M.; Nakamoto, S.; Okuno,
T.; Seno, K. Characterization of a novel inhibitor of cytosolic
phospholipase A2R, pyrrophenone. Biochem. J. 2002, 363 (3), 727–
735.
(6) Dessen, A.; Tang, J.; Schmidt, H.; Stahl, M.; Clark, J. D.; Seehra, J.;
Somers, W. S. Crystal structure of human cytosolic phospholipase
A2 reveals a novel topology and catalytic mechanism. Cell 1999, 97,
349–360.
Acknowledgment. The authors thank Ning Pan, Ying Ge,
Nelson Huang, and Walter Massefski for analytical support.
We also thank Molly Hoke, Wei Li, Jianchang Li, and Dianne
DeVincentis for the preparation of chemical intermediates.
(7) (a) Lipinski, C. A. Integration of physicochemical property consid-
erations into the design of combinatorial libraries. Pharm. News 2002,
9, 195–202. (b) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Experimental and computational approaches to estimate solubility
Supporting Information Available: Purity data from HPLC
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.

Reactions of Functionalized Sulfonamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1171
and permeability in drug discovery and development settings. AdV.
Drug DeliVery ReV. 1997, 23, 3–25.
(14) (a) Abraham, W. M.; Ahmed, A.; Cortes, A.; Sielczak, M. W.; Hinz,
W.; Bouska, J.; Lanni, C.; Bell, R. L. The 5-lipoxygenase inhibitor
zileuton blocks antigen-induced late airway responses, inflammation
and airway hyperresponsiveness in allergic sheep. Eur. J. Pharmacol.
1992, 217 (2-3), 119–126. (b) Bell, R. L. The development of zileuton
(ZYFLO) and the N-hydroxyurea class of 5-lipoxygenase inhibitors.
NoVel Inhibitors Leukotrienes 1999, 235–249.
(15) Smith, C. J.; Zhang, Y.; Koboldt, C. M.; Muhammad, J.; Zweifel,
B. S.; Shaffer, A.; Talley, J. J.; Masferrer, J. L.; Seibert, K.; Isakson,
P. C. Pharmacological analysis of cyclooxygenase-1 in inflammation.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95 (22), 13313–13318.
(16) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,
P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang,
Y. Y.; Isakson, P. C. Synthesis and biological evaluation of the
1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identifica-
tion of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide (SC-58635, celecoxib). J. Med. Chem. 1997,
40 (9), 1347–1365.
(8) Michalak, R. S.; Helom, J. L.; Zeldis, J. Process for the Synthesis of
Sulfonyl Halides and Sulfonamides from Sulfonic Acid Salts. U.S.
Pat. Appl. Publ. US 2007021614 A1 20070125, 2007; 13 pp.
(9) (a) Hromatka, O.; Knollmueller, M.; Binder, D. Syntheses of 1,3-
dihydro-2,1,4-benzothiadiazepines. Monatsh. Chem. 1969, 100, 872–
878. (b) Griffiths, D.; Hull, R.; Seden, T. P. The chemistry of
o-phenylenediisothiocyanate. Part 3. Studies on the syntheses of
heterocyclic compounds. J. Chem. Soc., Perkin Trans 1 1980, (11),
2608–2611.
(10) (a) Frankel, M.; Moses, P. Syntheses of amino alkyl sulphonic acids
and their peptide analogues. Tetrahedron 1960, 9, 289–294. (b) Moe,
G. R.; Sayre, L. M.; Portoghese, P. S. An explanation for the failure
of aminomethanesulfonic acid to form sulfonamides. Acyl chloride-
promoted generation of R-carboxamidoalkylating electrophiles. Tet-
rahedron Lett. 1981, 22, 537–540.
(11) Ashford, S. W.; Grega, K. C. Oxidative cleavage of 1,3-dicarbonyls
to carboxylic acids with oxone. J. Org. Chem. 2001, 66, 1523–1524.
(12) (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
Simple, efficient catalyst system for the palladium-catalyzed amination
of aryl chlorides, bromides, and triflates. J. Org. Chem. 2000, 65,
1158–1174. (b) Hartwig, J. F. Transition metal catalyzed synthesis of
arylamines and aryl ethers from aryl halides and triflates: scope and
mechanism. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
(13) King, J. F.; Hawson, A.; Huston, B. L.; Danks, L. J.; Komery, J.
Chlorination of heterocyclic and acyclic sulfonhydrazones. Can.
J. Chem. 1971, 49, 943–955.
(17) (a) Mukherjee, A.; Hale, V. G.; Borga, O.; Stein, R. Predictability
of the clinical potency of NSAIDs from the preclinical pharma-
codynamics in rats. Inflammation Res. 1996, 45 (11), 531–540. (b)
Otterness, I. G.; Bliven, M. L. Laboratory Models for Testing
Nonsteroidal Antiinflammatory Drugs; John Wiley & Sons: New York,
1985; pp 111-251.
JM8009876