Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group

Article abstract of DOI:10.1021/jm070650e

The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a s

Full text of DOI:10.1021/jm070650e

J. Med. Chem. 2007, 50, 6535–6544
6535
Design and Synthesis of Human Immunodeficiency Virus Entry Inhibitors: Sulfonamide as an
Isostere for the r-Ketoamide Group
Rong-Jian Lu,*,† John A. Tucker,*,‡ Tatiana Zinevitch,§ Olga Kirichenko,§ Vitalii Konoplev,§ Svetlana Kuznetsova,§
Sergey Sviridov,§ Jason Pickens,‡ Sagun Tandel,‡ Enugurthi Brahmachary,‡ Yang Yang,‡ Jian Wang,‡ Stephanie Freel,†
Shelly Fisher,† Alana Sullivan,† Jiying Zhou,† Sherry Stanfield-Oakley,† Michael Greenberg,† Dani Bolognesi,† Brian Bray,†
Barney Koszalka,† Peter Jeffs,† Alisher Khasanov,‡ You-An Ma,‡ Cynthia Jeffries,‡ Changhui Liu,‡ Tatiana Proskurina,‡
Tong Zhu,‡ Alexander Chucholowski,‡ Rongshi Li,‡ and Connie Sexton†
Trimeris, Inc., 3500 Paramount Parkway, MorrisVille, North Carolina 27560, ChemBridge Research Laboratories, Suite K, 16981 Via Tazon,
San Diego, California 92127, and ChemBridge Corporation, Suite G, 16981 Via Tazon, San Diego, California 92127
ReceiVed June 6, 2007
The crystal structures of many tertiary R-ketoamides reveal an orthogonal arrangement of the two carbonyl
groups. Based on the hypothesis that the R-ketoamide HIV attachment inhibitor BMS 806 (formally
BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized
a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most
potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped
antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed
a single conformation of each that gave significantly better overlap of key pharmacophore features than
other conformations and thus suggest a possible binding conformation for each class.
Introduction
BMS378806, 26, Table 1) and BMS 043 (formally BMS488043,
27, Table 1) that have demonstrated the ability to reduce viral
loads in man.8–10
In highly active antiretroviral therapy (HAART), potent
combinations of three or more reverse transcriptase and protease
inhibitors are used to suppress replication of the human
immunodeficiency virus (HIV).1 HAART has provided an
effective means of prolonging the survival of AIDS patients
and controlling disease progression of HIV-infected patients.2
Nonetheless, HAART has important limitations, including
incomplete efficacy,2 toxicity3 of the component antiviral agents,
and the eventual emergence of resistant virus.4 There is,
therefore, an urgent need for the development of anti-HIV agents
with novel mechanisms of action.
One promising area of investigation is the identification of
agents that inhibit viral attachment and entry into host cells.5
HIV-1 entry is a dynamic process beginning with viral attach-
ment to the host cell via interactions between the viral gp120
molecule and its primary (CD4) and secondary receptors
(typically the CCR5 and CXCR4 members of the chemokine
receptor family). Following gp120 attachment to CD4 and
coreceptor binding, the viral gp41 molecule undergoes a series
of structural rearrangements leading ultimately to fusion between
viral and host cell membranes. Drugs targeting attachment to
either CD4 or the CCR5 coreceptor or fusion have been shown
to inhibit viral infection both in vitro and in vivo.6 The recent
approval of the first fusion inhibitor, enfuvirtide, has demon-
strated the therapeutic potential of targeting these early stages
in the virus lifecycle.7 Additional evidence supporting virus entry
as a target comes from several CCR5-binding inhibitors that
have shown antiviral efficacy in the clinic6 and from gp120-
binding viral attachment inhibitors BMS 806 (formally
The small molecule attachment inhibitor, 26, has been shown
to bind within the CD4-binding pocket of the viral gp120
molecule.11 Crystallographic analysis of compounds containing
an Ar-(CdO)-(CdO)-NRR′ fragment12 suggest a preferred
conformation of the ketoamide group in which the two CdO
bonds adopt a roughly orthogonal arrangement. This structural
arrangement is likely to be an important component in the ability
of this molecule to interfere with the CD4-binding pocket and
thus prevent HIV infection. Based on the hypothesis that an
SO2 group could mimic the arrangement of the ketoamide
oxygens in such a conformation, we undertook the synthesis of
a series of analogs in which the two carbonyls of the previously
reported ketoamide inhibitors are replaced by a sulfonyl group.
This manuscript describes our discovery of sulfonamide HIV
entry inhibitors exhibiting nanomolar potency and improved
breadth of activity over related ketoamide analogs against clade
B HIV-1 isolates. The isosteric replacement demonstrated in
this work may prove generally useful in the optimization of
lead structures containing the ketoamide group.
Synthesis. Indole-3-sulfonyl chlorides were prepared by
sulfonylation of the corresponding indoles with pyridine-sulfur
trioxide complex, followed by chlorination with thionyl chloride
or phosphorus oxychloride, as described in Scheme 1 (method
A). Azaindole-3-sulfonyl chlorides were prepared by chloro-
sulfonylation of the corresponding azaindole with a 5-fold or
greater excess of chlorosulfonic acid (method C). The rates of
the sulfonylation and chlorosulfonylation reactions are substrate-
dependent, and the best results were obtained by performing
the reactions at the lowest temperature at which a convenient
reaction rate could be achieved. The sulfonyl chlorides thus
obtained were treated with secondary amines in the presence
of Hunig’s base to provide sulfonamides (method B). Mono-
N-acylated piperazines were prepared using literature proto-
cols.13 Many of the sulfonyl chlorides prepared in this work
decomposed on storage, and were therefore normally converted
* To whom correspondence should be addressed. Rong Jian Lu: current
address, Sequoia Pharmaceuticals, Inc., 401 Professional Dr., Gaithersburg,
MD 20879. Tel.: 240-632-0094 x113. Fax: 240-632-0497. E-mail:
rongjian.lu@sequoiapharma.com. John A. Tucker: Tel.: 650-245-7315.
E-mail: john.alan.tucker@gmail.com.
†
Trimeris, Inc.
ChemBridge Research Laboratories, Suite K.
ChemBridge Corporation.
‡
§
10.1021/jm070650e CCC: $37.00
2007 American Chemical Society
Published on Web 12/04/2007

6536 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Table 1. M33 Pseudotyped Assay IC50 Values for Ketoamide Inhibitors
Lu et al.
Scheme 1
Scheme 2
to sulfonamides immediately without characterization. The
indole and azaindole starting materials used in this work were
commercially available or were prepared from nitropyridines
using literature methods.14
For SAR studies involving variation of the benzoyl group or
substitution on the piperazine ring, certain compounds were
prepared by acylation of intermediates of general structure 11,
as described in Scheme 2 (method E). These intermediates were
in turn prepared by cleavage of the tert-butoxycarbonyl protect-
ing group from intermediates of general structure 10 (method
D). The mono-Boc piperazines used in this work were com-
mercially available.
Scheme 3
Nucleophilic aromatic substitution reactions were used to
prepare a number of analogs of general structures 14 and 16
from intermediates of structures 13 and 15, as described in
Scheme 3. In this Scheme, Y-H is a five-member aromatic
heterocycle having a free N-H group. Intermediates 13 and 15
were prepared according to Scheme 1.
The palladium-catalyzed cyanation15 of chloride 13a provided
the nitrile 17, which was used to prepare a number of analogs
having C-linked heterocycles attached to C-7 of the azaindole
ring (Scheme 4). Alternatively, treating 13a with sodium azide
under microwave heating gave the aryl azide 21, which was
used to prepare certain analogs containing an N-linked 1,2,3-
triazole substituent (Scheme 5).
Ketoamide inhibitors 24–29 (Table 1) were prepared using
methods described previously by others.10
Palladium-catalyzed coupling reactions between chloride 13a
and heteroaromatic boronic acids and trialkyltin derivatives were
used to prepare several analogs, as described in Scheme 6.16
Structure–Activity Relationships. The potency of the
compounds described in this work was examined using an anti-
HIV-1 pseudotyped viral assay, as described previously.17 In

Human Immunodeficiency Virus Entry Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6537
Scheme 6
Scheme 4
assessed against U87, CD4, and CXCR4 cells. None of the
compounds showed noticeable toxicity (CC50 > 40000 nM).
To facilitate comparison between the sulfonamides prepared
in the course of this work and compounds reported previously
by others,10 we first examined the series of ketoamide inhibitors
described in Table 1. Compounds 26 and 27 are clinical
development compounds from Bristol-Myers-Squibb. Com-
pound 25 differs from 24 by the addition of an (R)-configured
methyl group to the piperazine ring adjacent to the ketoamide
linker. This change led to a 17-fold enhancement in potency.
Other comparisons, for example, 28 versus 27, indicate that the
effect of adding an (R)-methyl substituent on the piperazine ring
is dependent on the nature of the azaindole ring. The addition
of a methoxy group to the 4-position of the azaindole ring of
25 as in compound 26 provides a 4-fold improvement in potency
in the psuedotype assay. Compound 29 and its prodrugs are
the subject of several recently published patent applications from
Bristol- Myers-Squibb.10
Scheme 5
In the original test of our hypothesis that a sulfonyl group
could replace the ketoamide group of the Bristol-Myers-Squibb
entry inhibitors, we synthesized compound 12a (Table 2) and
examined its activity in the pseudotype assay. Compound 12a
exhibits an IC50 value of 860 nM, approximately 30-fold less
potent than the corresponding ketoamide 25. To explore SAR
differences that might potentially arise from replacing the two
atom linker of the ketoamide series with a single atom linker,
as in the sulfonamides, two parallel synthesis libraries were
prepared. In the first of these, more than 150 sulfonamides were
prepared by treating the sulfonyl chloride 6a with a diverse set
of cyclic secondary amines. None of the resulting sulfonamides
exhibited IC50 < 15000 nM.
A second library was prepared by acylation of the amine 11a
(or its racemate) with a set of 285 carboxylic acids. The set of
carboxylic acid building blocks for this library contained a
diverse set of optionally substituted aromatic, heteroaromatic,
arylalkyl, heteroarylalkyl, heterocyclic, alkyl, and cycloalkyl
carboxylic acids. Representative analogs from this library
exhibiting IC50 < 20000 nM are shown in Table 2. Most of the
analogs from this library exhibiting measurable activity were
derived from five-member heteroaromatic carboxylic acids
having one or no substituents attached to the heteroaromatic
ring. Only representative examples of these five-membered
heteroaromatic analogs are shown in the table. Other active
analogs were derived from fused heteroaromatic rings or
optionally substituted six-member aromatic and heteroaromatic
brief, the anti-HIV-1 activity of inhibitors was determined by
measuring the 50% inhibitory dose against pseudovirions
containing an R5-using envelope that was cloned from a primary
virus isolate. The specificity of inhibitors was assessed by their
ability to prevent infection of pseudotyped viruses expressing
a CD4-independent amphotropic murine leukemia virus (AMLV)
envelope. Inhibitors that were shown to prevent infection of
the M33 pseudovirus, but were not able to inhibit AMLV
pseudovirus infection at concentrations more than 100× their
M33 IC50 were considered to be specific for inhibition of HIV.
The toxicity of the compounds described in this work was

6538 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Lu et al.
Table 3. M33 Pseudotyped Assay IC50 Values for Analogs of the
Table 2. M33 Pseudotyped Assay IC50 Values for Compounds of the
General Structure I
General Structure II
We then turned our attention to the more synthetically
challenging task of evaluating changes to the azaindole ring.
Our first effort in this arena was to synthesize compound 8j,
the sulfonamide analog of the BMS clinical compound 26. We
were disappointed to find that 8j is substantially less active than
the prototype 12a, a result that contrasts with the potency-
enhancing effect of this substitution in the ketoamide series.
a Racemic analog.
rings. Notably, none of these analogs is significantly more potent
than 12a, and the most potent analogs contain acyl groups that
are approximately isosteric with benzoyl.
The effect of varying the piperazine ring substituents is
described in Table 3. Compound 8b is the enantiomer of 12a.
It exhibits an IC50 > 20000 nM, demonstrating that the preferred
configuration of the piperazine methyl group is the same as that
previously reported for ketoamide entry inhibitors. Complete
elimination of the piperazine methyl substituent led to a 25-
fold reduction in potency (compound 8a), similar to the 17-
fold potency difference between ketoamide inhibitors 24 and
25. These results, combined with those described in the previous
paragraph, suggest a similar binding mode for the two series.
Increasing the size of the substituent, as in compounds 8d–8g,
adding a second methyl group, as in compound 8c, or moving
the methyl group to a different position on the piperazine ring
(compounds 8h, 8i) had a negative effect on potency, which
might indicate limited binding space in the corresponding pocket
area of gp120.
Table 4 shows the SAR of a series of analogs in which the
7-azaindole ring of 12a is replaced by an indole ring. The
unsubstituted indole ring of 4a gave a 2-fold improvement in
potency relative to 12a, and the addition of a fluorine substituent
in the 4-position gave a further reduction of the IC50 to 200
nM (compound 4b). Examining a variety of other indole ring
substitution patterns failed to provide significant improvements
in potency. Compounds 4c and 16a-c, having a fluorine in the
4-position and a fluorine or heterocyclic group in the 7-position,
exhibited potency approximately similar to or less than that of
4a. The 4-methoxy indole derivative 4e exhibited a dramatically
reduced potency relative to the unsubstituted indole 4a, in close
analogy to what was observed in the 7-azaindole series.
The SAR of 6-azaindole sulfonamide analogs is described
in Table 5. Analogs 8j and 8k, substituted in the 5-position of

Human Immunodeficiency Virus Entry Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6539
Table 4. M33 Pseudotyped Assay IC50 Values for Analogs of the
General Structure III
Table 5. M33 Pseudotype Assay IC50 Values for Analogs of the
General Structure IVa
the azaindole ring, failed to exhibit detectable activity. Analog
8l, which is monosubstituted with chlorine in the 7-position,
gave only marginally better results. We then decided to direct
our efforts toward the synthesis of analogs having a heteroaro-
matic substituent in the 7-position of the 6-azaindole ring.
Among the C-linked heteroaromatic rings examined, the best
results were obtained with a pyrazol-3-yl substituent (compound
23a), which provided an IC50 value of 140 nM. Several N-linked
heteroaromatic substituents were then examined. Pyrazole,
imidazole, 1,2,4-triazole, and 1,2,3-triazole substituents in the
7-position of the azaindole ring increased potency from 4-fold
to 32-fold relative to 12a, with 1,2,3-triazole providing an IC50
value of 27 nM (compound 14e). In hope of building on this
result, we prepared a series of analogs 22a–22e bearing a
functionalized 1,2,3-triazole substituent. None of these analogs
exhibited properties superior to those of 14e. Lastly, we
examined the effect of combining 4-fluoro and 7-heterocycle
substitution on the azaindole ring. Fluorinated compounds
14f–14i exhibit potency improvements of 2- to 4-fold relative
to their nonfluorinated counterparts. The best of these, compound
14i exhibits an IC50 of 7 nM.
The racemic version of compound 14e was evaluated against
a panel of laboratory-adapted strains in a viral replication assay.
The data from this study are presented along with the Bristol-
Myers-Squibb clinical development compound 26 in Table 6.
Overall, racemic 14e is somewhat less potent than 26 and
exhibits a slightly different profile, with up to 2∼10× improved
potency against certain individual strains.
Conformational Modeling of Sulfonamide and Ketoam-
ide Entry Inhibitors. To obtain a better understanding of the
structural features required for binding, flexible overlay calcula-
tions were performed for the sulfonamide inhibitor 12a and the
ketoamide inhibitor 25 using the algorithm and default param-
eters incorporated in the MOE software suite.18,19 In this
protocol, each atom is assigned a pharmocophore descriptor
a Racemic analog.
(aromatic, donor, acceptor, hydrophobe) according to the
PATTY rules,20 and the overlay scoring function is based on a
method that approximates molecular shape as a sum of Guassian
densities. The conformation of each molecule is randomly
perturbed and then optimized against a function that includes
terms describing both the extent of overlap of pharmacorphore
features and the conformational energy of the individual
molecules. Conformational searching is continued until a

6540 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Lu et al.
Table 6. IC50 Values (nM) for Compounds 26 and (+/-)-14e in Viral
Replication Assays vs a Panel of Laboratory-Adapted HIV Strains
entry
virus
26
14e
1
2
3
4
5
6
7
8
584.000220
584.000063P1B
208.000923
589.000049
589.000821
589.000033
584.000016
584.000030
584.000039
584.000058
584.000088
584.000241
geometric mean
4
2
37
1400
6
2800
28
40
31
400
58
14
460
465
46
330
492
513
267
1800
1400
116
8
Figure 1
9
10
11
12
against a panel of laboratory-adapted strains. Parallels between
the structure–activity relationship of the sulfonamides described
in the present work and that of the ketoamide inhibitors
described previously suggest a similar binding mode for the
two series. Flexible overlay calculations revealed essentially a
single conformer of each series that can mutually overlay and
thus suggest possible binding conformations for each inhibitor
type.
In addition to the implications of this work for the develop-
ment of novel HIV entry inhibitors, our demonstration of the
successful application of a sulfonamide group as an isosteric
replacement for the R-ketoamide group may prove useful in
other drug discovery programs. A search of the MDDR21 for
R-ketoamides that are currently marketed or in clinical develop-
ment as human therapeutics revealed only compounds in which
the ketone carbonyl of the ketoamide group is sterically hindered
or conjugated to a strongly electron-donating aromatic ring. A
possible explanation for this result is that the electrophilic
carbonyl group of other R-ketoamides has prevented their
advancement through preclinical development. The isosteric
replacement demonstrated in this work may prove generally
useful in the optimization of lead structures containing this
group.
118
64
178
predetermined (in this case, 1000) number of successive attempts
to generate novel overlays provides only duplicates of previously
identified configurations.
The highest-ranked overlay between 12a and 25 is shown in
Figure 1. In this alignment, the piperazine ring and the
benzamide groups of the two compounds are tightly overlaid.
The sulfonamide group of 12a is in close proximity to the
ketoamide group of 25, with one sulfonamide oxygen tightly
overlaid on the amide oxygen. The other sulfonamide oxygen
lies about 1.1 Å from the ketone oxygen. The azaindole rings
of the two molecules are closely superimposed. A second highly
ranked overlay differs from the one shown only in that there is
a 180° rotation around the bond between the piperazine ring
and the benzoyl group in each inhibitor. Other overlays provided
a much poorer overlap of the azaindole rings, of the benzoylpip-
erazine groups, or of the piperazine ring methyl substituents.
These results are congruent with the close similarity of the SAR
trends observed in the two series.
The calculated steric energies of the sulfonamide and keto-
amide conformers in Figure 1 are 9.5 and 10.5 kcal/mol,
respectively, relative to their global conformational minima.
When these conformers are individually minimized without
similarity constraints, the resulting local conformational minima
exhibit Erel values of 0.2 and 0.6 kcal/mole compared to their
respective global conformational energy minima. An overlay
of these minimized structures is shown in Figure S1 (Supporting
Information). Overall, the results of these calculations support
the hypothesis that certain energetically accessible conformations
of the sulfonamide 12a and the ketoamide 25 have similar
dispositions of potentially pharmacophoric aromatic, lipophilic,
and hydrogen bond-acceptor groups. The single atom SO2 linker
of the sulfonamide is able to direct its attached azaindole and
piperazine rings in a manner remarkably similar to that of the
two-atom ketoamide group. These results provide a rationale
for the activity of the sulfonamide compounds prepared in this
work and suggest plausible binding conformations for the
sulfonamide 12a and the ketoamide 25.
Experimental Section
General Chemistry. HPLC purification: Compounds requiring
HPLC purification were purified on a system using a Sedex 75
ELSD as the fraction-determining detector, the Gilson 215 as
autosampler and fraction collector, and Gilson 321 pumps. Mobile
phases used were one of the following: (1) water/acetonitrile/0.05%
trifluoroacetic acid; (2) 20 mM ammonium formate at pH 4–6 and
acetonitrile; or (3) 0.1% ammonium hydroxide and acetonitrile at
pH 9.0. Columns used were either Phenomenex Gemini, 5 µm, 21.2
× 50 mm or Peeke Scientific Ultro 60 C18 5 µm, 20 mm × 50
mm.
Analytical LCMS. Compounds were analyzed on an Applied
Biosystems/Sciex 150EX single quad mass spectrometer in positive
ion mode using either an ESI (electrospray ionization) source or
an APCI (atmospheric pressure chemical ionization) source. The
scan range is 100–1000 amu. The mobile phase used was one of
the above, as described in General Chemistry. Sedex 75 ELSD and
Agilent PDA (photodiode array) UV detection was used. The
column most commonly used was the Phenomenex Gemini, 5 µm,
4.6 × 50 mm. When necessary to achieve greater separation of
close-eluting impurities, other columns were used, including the
Phenomenex Gemini, 5 um, 4.6 × 100 or 250 mm, the Kromasil
100, C18, 5 µm, 4.6 × 100 or 250, and the DuraGel HS, 5 µm,
phenyl 4.6 × 250 mm from Peeke Scientific. Mass calculations
were made using the monoisotopic mass for the compound.
7-Bromo-4-fluoro-1H-indole-3-sulfonyl Chloride (Method
A). A mixture of 7-bromo-4-fluoro-1H-indole (3.71 g, 0.017 mol)
and sulfur trioxide-pyridine complex (2.76 g, 0.017 mol) in
anhydrous pyridine (200 mL) was refluxed under stirring for 2 h
and then was cooled to RT, diluted with water (400 mL), and
washed with Et2O (2 × 250 mL). The aqueous phase was
Conclusions
Based on the hypothesis that the R-ketoamide linker of
previously reported HIV entry inhibitors adopts a twisted
conformation similar to that observed in the crystal structures
of related compounds, we designed and synthesized a series of
analogs in which the ketoamide group is replaced by a
sulfonamide group. The most potent of these analogs, compound
14i, exhibits an IC50 value of 7 nM in the M33 pseudotyped
viral attachment assay. A related analog, (+/-)-14e, exhibited
approximately one-half the potency of the Bristol-Myers-Squibb
clinical development compound 26 in viral replication assays

Human Immunodeficiency Virus Entry Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6541
evaporated to give crude 7-bromo-4-fluoro-1H-indole-3-sulfonic
acid pyridinium salt, which was used in the next step without further
purification.
[3-Methyl-4-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridine-
3-sulfonyl)-piperazin-1-yl]-phenyl-methanone and [3-Methyl-
4-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-
piperazin-1-yl]-phenyl-methanone, Method F. A mixture of 4-(7-
chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-piperazin-
1-yl]-phenyl-methanone (0.21 g, 0.5 mmol), Cu powder (0.064 g,
1 mmol), 1,2,3-triazole (1.04 g, 0.87 mL, 15 mmol), and powdered
KOH (0.056 g, 1 mmol) was heated to 160 °C and kept (under an
argon atmosphere) under stirring at this temperature until the starting
sulfonamide disappeared (∼3 h, TLC monitoring, 5% MeOH/
CHCl3). The reaction mixture was then cooled to RT, diluted with
EtOAc (∼2 mL), placed onto a silica gel column, and eluted with
EtOAc/hexane (9:1). Fractions containing the first product (together
with 1,2,3-triazole) were collected, evaporated, and diluted with
water. The precipitate was filtered, washed with water and ether,
and dried to give [3-methyl-4-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl)-piperazin-1-yl]-phenyl-methanone (0.075 g,
30%). Then eluent was changed to 10% MeOH/CHCl3 and fractions
containing the second product were collected, and evaporated to
give [3-methyl-4-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[2,3-c]pyridine-
3-sulfonyl)-piperazin-1-yl]-phenyl-methanone(0.075g,30%).[3-Meth-
yl-4-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-
piperazin-1-yl]-phenyl-methanone: 1H NMR (DMSO-d6): δ 12.68
(s, 1H, H-indole), 9.05 (d, J ) 1.0 Hz, 1H), 8.30 (d, J ) 5.6 Hz,
1H), 8.15 (s, 1H), 8.12 (d, J ) 1.0 Hz, 1H), 7.87 (d, J ) 5.6 Hz,
1H), 7.39 (m, 3H, C6H5), 7.30 (m, 2H, C6H5), 4.40–4.00 (br signal,
2H), 3.84–3.39 (br signal, 2H), 3.25–3.14 (m, 1H), 3.10–2.69 (br
signal, 2H), 1.06–0.89 (br signal, 3H, CH3). LC/MS calcd for
C21H21N7O3S [M + 1]+, 452; found, 452. [3-Methyl-4-(7-
[1,2,3]triazol-2-yl-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-piperazin-
1-yl]-phenyl-methanone: 1H NMR (DMSO-d6): δ 12.50 (s, 1H,
H-indole), 8.33 (s, 2H), 8.28 (d, J ) 5.4 Hz, 1H), 8.15 (s, 1H),
7.84 (d, J ) 5.4 Hz, 1H), 7.39 (m, 3H, C6H5), 7.30 (m, 2H, C6H5),
4.38–4.00 (br signal, 2H), 3.84–3.35 (br signal, 2H), 3.24–3.10 (m,
1H), 3.07–2.69 (br signal, 2H), 1.10–0.89 (br signal, 3H, CH3).
LC/MS calcd for C21H21N7O3S [M + 1]+, 452; found, 452.
[4-(4-Fluoro-7-[1,2,4]triazol-1-yl-1H-indole-3-sulfonyl)-3-methyl-
piperazin-1-yl]-phenyl-methanone, Method G. [4-(4-Fluoro-7-
[1,2,4]triazol-1-yl-1H-indole-3-sulfonyl)-3-methyl-piperazin-1-yl]-
phenyl-methanone (55.6%) was prepared according to the procedure
above, using [4-(7-bromo-4-fluoro-1H-indole-3-sulfonyl)-3-methyl-
piperazin-1-yl]-phenyl-methanone and 1,2,4-triazole, and 0f3%
MeOH in CH2Cl2 as eluent. 1H NMR (DMSO-d6): δ 12.25 (s, 1H,
H-indole), 9.25 (s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.70 (dd, JH-H
) 8.6 Hz, JH-F ) 3.9 Hz, 1H), 7.39 (m, 3H, C6H5), 7.30 (m, 2H,
C6H5), 7.19 (dd, JH-H ) 8.6 Hz, JH-F ) 10.3 Hz, 1H), 4.58–3.85
(br signal, 2H), 3.81–3.40 (br signal, 2H), 3.22–2.64 (br signal,
3H), 1.05 (br signal, 3H, CH3). LC/MS calcd for C22H21FN6O3S
[M + 1]+, 469; found, 469.
Crude 7-bromo-4-fluoro-1H-indole-3-sulfonic acid pyridinium
salt from the previous step was dissolved in 30 mL of a 1:1
sulfolane-acetonitrile mixture. The solution was cooled to 0 °C,
and phosphorus oxychloride (3.5 mL) was added dropwise under
stirring. Then the reaction mixture was heated to 70 °C, kept under
stirring for 40 min, and then cooled to 0 °C. Cold water (50 mL)
was added dropwise. The precipitate was filtered, washed with
water, and dried under reduced pressure to afford 7-bromo-4-fluoro-
1H-indole-3-sulfonyl chloride (2.84 g, 53% per two steps). 1H NMR
(CDCl3): δ 9.06 (s, 1H, H-indole), 8.04 (d, J ) 3.2 Hz, 1H), 7.49
(dd, JH-H ) 8.6 Hz, JH-F ) 4.7 Hz, 1H) 7.02 (dd, JH-H ) 8.6 Hz,
JH-F ) 9.8 Hz, 1H).
(+/-)-[4-(7-Chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-
methyl-piperazin-1-yl]-phenyl-methanone (Method B). A mix-
ture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (1.5
g, 6.0 mmol), (3-methyl-piperazin-1-yl)-phenyl-methanone (1.33
g, 6.5 mmol), and NEt3 (0.66 g, 6.5 mmol) in CH2Cl2 (50 mL)
was refluxed under stirring until the starting sulfonyl chloride
disappeared (TLC monitoring, MeOH/CHCl3 5:95). The solution
was cooled to RT, washed with brine, and dried with Na2SO4. The
solvent volume was reduced by 75% by evaporation at reduced
pressure. The residue was passed through a thin layer of silica gel
(eluent: 10% MeOH/CHCl3). The solvent was evaporated to give
[4-(7-chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-piper-
1
azin-1-yl]-phenyl-methanone (2.0 g, 81%). H NMR (DMSO-d6):
δ 13.11 (s, 1H, H-indole), 8.29 (s, 1H), 8.11 (d, J ) 5.4 Hz, 1H),
7.73 (d, J ) 5.4 Hz, 1H), 7.40 (m, 3H, C6H5), 7.30 (m, 2H, C6H5),
4.37–3.87 (br signal, 2H), 3.79–3.38 (br signal, 2H), 3.22–3.09 (m,
1H), 3.06–2.64 (br signal, 2H), 1.08–0.79 (br signal, 3H, CH3).
LCMS: calcd for C19H19ClN4O3S·H+, 419.1; found, 419.0.
7-Chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl
Chloride
(Method C). 7-Chloro-6-azaindole (8.0 g, 0.0524 mol) was added
in small portions to chlorosulfonic acid (40 mL) at 0 °C under
stirring. Then the reaction mixture was slowly heated to 120 °C
(higher temperatures reduced the yield) and kept until the starting
7-chloro-6-azaindole disappeared (1.5–2 h). The reaction was
monitored by TLC (5% MeOH/CHCl3). To do this, a sample of
the reaction mixture was treated with ice–water. The precipitate
was filtered, washed with water, dissolved in methanol and analyzed
by TLC. The reaction mixture was cooled and poured into
ice–water. The precipitate was separated by filtration, washed with
water several times, and vacuum-dried under P2O5 to give 7-chloro-
1H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (8.3 g, 62%). 1H
NMR (DMSO-d6): δ 12.46 (s, 1H, H-indole), 8.02 (d, J ) 5.9 Hz,
1H), 7.81 (m, 2H).
Parallel Synthesis of Amides (Method D and E), (+)-[4-((7-
Azaindole)-1H-3-sulfonyl)-3-methyl-piperazin-1-yl]-t-butyl-car-
boamide. Compound 10 from method B was dissolved in 20 mL
of 4 M HCl in dioxane and stirred at room temperature for 2 h.
The mixture was concentrated to ¼ the original volume and diluted
with 12 mL of diethyl ether. The precipitate was filtered and dried
under high vacuum to offer amine HCl salt (compound 11). LCMS:
calcd for C12H16N4O2S·H+, 281.1; found, 281.3. Purity (ELSD):
98%. The above compound was dissolved in DMF to give ∼0.5
M solutions. The acids (95 uMol) were placed in 48-well plates.
N-methylmorpholine (75 uL), a 0.5 M solution of HBTU in DMF
(95 uM), and a 0.5 M solution of amine 1 in DMF (80 uM) were
added sequentially into each tube. The plates were covered with a
Cap Mat. The reaction mixtures were agitated for 10–20 s with the
use of a Vortex shaker and kept at 40 °C for 24 h on a J-Chem
heater. Water (50 uL) was added to each well, and the solvents
were evaporated in a Savant evaporator for ∼5 h at 65 °C. DCM
(2 mL) and 5% NaOH in water (500 uL) were added to each well.
The reaction mixtures were thoroughly stirred on a Vortex shaker
and then passed through Celite columns packed in DCM. The DCM
solutions were evaporated in an oven at 45 °C for 5 h. The residues
were dissolved in DMSO and purified by reverse-phase chromato-
graphy.
1-[3-(4-Benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyrrolo[2,3-
c]pyridin-7-yl]-ethanone, Method H. [4-(7-Chloro-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl-metha-
none (0.6 g, 1.4 mmol), Zn(CN)2 (0.089 g, 0.76 mmol), Zn dust
(0.01 g, 0.15 mmol), Pd2(dba)3 (0.023 g, 0.025 mmol), dppf (0.028
g, 0.038 mmol), and anhydrous dimethylacetamide (6.5 mL) were
placed into a pressure-capped glass reactor (10 mL) filled with
argon. The mixture was kept in a microwave oven (CEM Discovery
System, 908010) at 130 °C for 1 h, cooled to RT, and diluted with
water (50 mL). The precipitate was filtered, washed with water
and then Et2O, and dried under reduced pressure to give 3-(4-
benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyrrolo[2,3-c]pyridine-
7-carbonitrile (0.45 g, 71%), which was used for the next step
without additional purification. LC/MS calcd for C20H19N5O3S·H+,
410.1; found, 410.1. 1H NMR (DMSO-d6): δ 13.58 (s, 1H,
H-indole), 8.47 (d, J ) 5.4 Hz, 1H), 8.44 (s, 1H), 8.05 (d, J ) 5.4
Hz, 1H), 7.40 (m, 3H), 7.30 (m, 2H), 4.37–3.36 (br signal, 4H),
3.20–2.82 (br signal, 3H), 0.98 (br signal, 3H, CH3).
1-[3-(4-Benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyrrolo[2,3-
c]pyridin-7-yl]-3-dimethylamino-propenone, Method I. To a
suspension of 3-(4-benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyr-
rolo[2,3-c]pyridine-7-carbonitrile (1.78 g, 4.3 mmol) in anhydrous

6542 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Lu et al.
THF (40 mL) cooled to -20 °C, a 22% solution of MeMgBr (5.9
mL, 17.4 mmol) in THF was slowly added dropwise. The reaction
mixture was stirred at this temperature for 40 min, treated (at the
same temperature) with a 5% solution of H2SO4 until complete
1-yl]-phenyl-methanone (2.0 g, 4.78 mmol) and NaN3 (1.6 g, 24.6
mmol) in HMPT (15 mL) was kept under stirring at 150–160 °C
for 1 h using a Biotage microwave reactior, cooled to RT, and
diluted with water (70 mL). The precipitate was filtered, washed
with water, and dried under reduced pressure to give [4-(7-azido-
1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-piperazin-1-yl]-
phenyl-methanone (1.7 g, 83%), which was used for the next step
without additional purification. LC/MS calcd for C19H19N7O3S·H+,
426.1; found, 426.1. Purity (ELSD): 100%. 1H NMR (DMSO-d6):
δ 14.05 (s, 1H, H-indole), 8.95 (m, 1H), 8.27 (s, 1H), 7.69 (m,
1H), 7.39 (m, 3H), 7.29 (m, 2H), 4.34–3.58 (br signal, 4H),
3.20–2.75 (br signal, 3H), 0.99 (br signal, 3H, CH3).
{4-[7-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-metha-
none, Method M. A mixture of [4-(7-azido-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl-
methanone (0.4 g, 0.94 mmol), propargyl alcohol (0.5 g, 8.9 mmol),
sodium ascorbate (0.04 g, 0.2 mmol), CuSO4 (0.03 g, 0.47 mmol),
and NaHCO3 (0.079 g, 0.94 mmol) in DMF (6 mL) and water (2
mL) was kept under stirring at 100–120 °C for 40 min (TLC
monitoring, CHCl3/MeOH 9:1), cooled to RT, and evaporated. The
residue was purified by chromatography (silica gel, eluent Et2O/
MeOH 9:1, then CHCl3/MeOH 9:1) to give {4-[7-(4-hydroxym-
ethyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-
methyl-piperazin-1-yl}-phenyl-methanone (0.36 g, 79%). 1H NMR
(DMSO-d6): δ 12.64 (s, 1H, H-indole), 8.84 (s, 1H), 8.29 (d, J )
5.6 Hz, 1H), 8.13 (s, 1H), 7.85 (d, J ) 5.6 Hz, 1H), 7.42–7.36 (m,
3H), 7.30 (m, 2H), 5.37 (t, J ) 5.6 Hz, 1H, OH), 4.70 (d, J ) 5.6
Hz, 2H), 4.34–3.37 (br signal, 4H), 3.21–2.74 (br signal, 3H), 0.98
(br signal, 3H, CH3). LC/MS calcd for C22H23N7O4S·H+, 482.1;
found, 482.1.
{(R)-4-[7-(4-Fluoromethyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-metha-
none, Method N. To a solution of {4-[7-(4-hydroxymethyl-
[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-methyl-
piperazin-1-yl}-phenyl-methanone (0.23 g, 0.48 mmol) in DCM
(40 mL) cooled to -80 °C, Et2NSF3 (0.3 mL, 2.27 mmol) was
added dropwise. The reaction mixture was allowed to warm to RT
(LC/MS monitoring). Water (40 mL) and DCM (20 mL) were
added, the mixture obtained was filtered, the organic phase was
separated, washed with water, dried with Na2SO4, and evaporated,
and the residue was purified by chromatography (silica gel, eluent
CHCl3/MeOH 9:1) to afford {(R)-4-[7-(4-fluoromethyl-[1,2,3]tria-
zol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-methyl-piperazin-
1-yl}-phenyl-methanone (0.015 g, 6.5%). 1H NMR (DMSO-d6): δ
12.70 (s, 1H, H-indole), 9.25 (m, 1H), 8.30 (m, 1H), 8.16 (s, 1H),
7.88 (m, 1H), 7.41 (m, 3H), 7.30 (m, 2H), 5.65 (d, JH-F ) 48 Hz,
2H, CH2F), 4.37–3.40 (br signal, 4H), 3.21–2.69 (br signal, 3H),
1.00 (br signal, 3H, CH3). LC/MS calcd for C22H22FN7O3S [M +
1]+, 484; found, 484.
{4-[7-(4-Dimethylaminomethyl-[1,2,3]triazol-1-yl)-1H-pyrro-
lo[2,3-c]pyridine-3-sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-
methanone, Method O. A solution of methanesulfonyl chloride
(0.08 mL, 1.0 mmol) in DCM (2 mL) was added dropwise under
stirring to a solution of {4-[7-(4-hydroxymethyl-[1,2,3]triazol-1-
yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-methyl-piperazin-1-yl}-
phenyl-methanone (0.2 g, 0.41 mmol) and NEt3 (0.15 mL, 1.0
mmol) in DCM (20 mL) at 0 °C. The reaction mixture was kept at
0 °C for 1 h and then allowed to warm to RT (TLC monitoring,
CHCl3/MeOH 9:1). Water (20 mL) was added, the product was
extracted with DCM (20 mL), the organic phase was dried with
Na2SO4 and evaporated, and the residue was purified by chroma-
tography (silica gel, eluent EtOAc/n-hexane 9:1, then CHCl3/MeOH
9:1) to afford methanesulfonic acid 1-[3-(4-benzoyl-2-methyl-
piperazine-1-sulfonyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1H-[1,2,3]tri-
azol-4-ylmethyl ester (0.1 g, 43%). LC/MS calcd for C23H25N7O6S2
[M + 1]+, 560.5; found, 560, 561. 1H NMR (DMSO-d6): δ 12.69
(s, 1H, H-indole), 9.20 (s, 1H), 8.31 (m, 1H), 8.17 (s, 1H), 7.89
(m, 1H), 7.38 (m, 3H), 7.30 (m, 2H), 5.53 (s, 2H), 4.38–3.36 (br
signal, 4H), 3.29 (s, 3H), 3.21–2.68 (br signal, 3H), 1.00 (br signal,
3H, CH3).
1
precipitate dissolution, allowed to warm to RT, evaporated to /3
of the volume, made basic with aqueous NH3, and extracted with
CHCl3 (4 × 50 mL). The organic phase was washed with water
and brine, dried with Na2SO4, and evaporated. The residue was
purified by chromatography (silica gel, eluent CHCl3/MeOH 50:1)
to afford 1-[3-(4-benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyr-
rolo[2,3-c]pyridin-7-yl]-ethanone (0.66 g, 36%). LC/MS calcd for
C21H22N4O4S [M + 1]+, 427.5; found, 427, 428. 1H NMR (DMSO-
d6): δ 12.56 (s, 1H, H-indole), 8.48 (d, J ) 5.4 Hz, 1H), 8.10 (m,
1H), 8.02 (d, J ) 5.4 Hz, 1H), 7.40 (m, 3H), 7.31 (m, 2H),
4.38–3.37 (br signal, 4H), 3.17–2.82 (br signal, 3H), 2.76 (s, 3H,
CH3), 0.94 (br signal, 3H, CH3).
A solution of 1-[3-(4-benzoyl-2-methyl-piperazin-1-sulfonyl)-
1H-pyrrolo[2,3-c]pyridin-7-yl]-ethanone (0.78 g, 1.8 mmol) and
dimethylformamide dimetylacetal (6.3 mL) in anhydrous DMF (6.5
mL) was stirred at 55–60 °C for 6 h (TLC-monitoring, CHCl3/
MeOH 9:1) and evaporated to give crude 1-[3-(4-benzoyl-2-methyl-
piperazine-1-sulfonyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-3-dimethy-
lamino-propenone (quantitative yield), which was used for the next
step without additional purification. LC/MS calcd for C24H27
1
N5O4S·H+, 482.5; found, 482.1. H NMR (DMSO-d6): δ 11.05
(s, 1H, H-indole), 8.38 (d, J ) 5.4 Hz, 1H), 8.00 (s, 1H), 7.85 (d,
J ) 5.4 Hz, 1H), 7.40–7.30 (m, 6H), 6.53 (m, 1H), 4.44–3.51 (br
signal, 4H), 3.29–3.03 (br signal, 3H), 3.22 (s, 3H, NCH3), 2.97
(s, 3H, NCH3), 0.94 (br signal, 3H, CH3).
{4-[7-(2-Amino-pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-
sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-methanone, Method
J. {4-[7-(2-Amino-pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-sul-
fonyl]-3-methyl-piperazin-1-yl}-phenyl-methanone (15%) was re-
moved according to the procedure above, using 1-[3-(4-benzoyl-
2-methyl-piperazin-1-sulfonyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-3-
dimethylamino-propenone and guanidine hydrochloride. The product
was purified by chromatography (silica gel, first column, eluent
CHCl3/MeOH 20:1f9:1; second column, eluent Et2O/MeOH 9:1).
1H NMR (DMSO-d6): δ 12.50 (s, 1H, H-indole), 8.46 (d, J ) 5.4
Hz, 2H), 8.23 (m, 1H), 7.88 (d, J ) 5.4 Hz, 1H), 7.63 (d, J ) 5.1
Hz, 1H), 7.41–7.29 (m, 5H), 6.97 (br s, 2H), 4.34–4.04 (br signal,
2H), 3.79–3.33 (br signal, 2H), 3.18–2.91 (m, 3H), 3.07–2.69 (br
signal, 2H), 0.98 (br signal, 3H, CH3). LC/MS calcd for
C23H23N7O3S [M + 1]+, 478; found, 478.
[3-Methyl-4-(7-[1,2,4]oxadiazol-3-yl-1H-pyrrolo[2,3-c]pyridine-
3-sulfonyl)-piperazin-1-yl]-phenyl-methanone, Method K. Hy-
droxylamine hydrochloride (0.03 g, 4.3 mmol), Na2CO3 (0.023 g,
2.2 mmol), and BF3 ·Et2O (two drops) were added to a suspension
of 3-(4-benzoyl-2-methyl-piperazin-1-sulfonyl)-1H-pyrrolo[2,3-
c]pyridine-7-carbonitrile (0.17 g, 4.2 mmol) in a water-ethanol
mixture (1:1, 10 mL). The mixture was stirred for 3 h at RT, then
diluted with water (10 mL), and extracted with DCM (3 × 10 mL),
the organic layers were combined, dried over sodium sulfate, and
concentrated to give crude 3-(4-benzoyl-2-methyl-piperazin-1-
sulfonyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-7-carboxamidine,
which was used for the next step without further purification. LC/
MS calcd for C21H20N6O4S [M + 1]+, 443; found, 443.
A mixture of the product from the previous step and BF3 ·Et2O
(5 drops) in triethyl orthoformate (10 mL) was refluxed under
stirring for 1 h and then evaporated. The residue was purified by
HPLC to give [3-methyl-4-(7-[1,2,4]oxadiazol-3-yl-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl)-piperazin-1-yl]-phenyl-methanone (0.06 g,
32% per two steps). 1H NMR (DMSO-d6): δ 12.35 (s, 1H,
H-indole), 9.97 (s, 1H), 8.53 (d, J ) 5.4 Hz, 1H), 8.15 (m, 1H),
7.96 (d, J ) 5.4 Hz, 1H), 7.39 (m, 3H, C6H5), 7.30 (m, 2H, C6H5),
4.46–3.92 (br signal, 2H), 3.89–3.40 (br signal, 2H), 3.20–2.67 (br
signal, 3H), 0.98 (br signal, 3H, CH3). LC/MS calcd for
C21H20N6O4S [M + 1]+, 453; found, 453.
[4-(7-Azido-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-
piperazin-1-yl]-phenyl-methanone, Method L. A mixture of [4-(7-
chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-piperazin-

Human Immunodeficiency Virus Entry Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6543
A mixture of 1-[3-(4-benzoyl-2-methyl-piperazine-1-sulfonyl)-
1H-pyrrolo[2,3-c]pyridin-7-yl]-1H-[1,2,3]triazol-4-ylmethyl ester
(0.1 g, 0.18 mmol) and 40% aqueous solution of dimethylamine
(0.15 mL) in DMF (4 mL) was stirred at RT for 30 min (TLC
monitoring, CHCl3/MeOH 9:1). Solvent was evaporated, and the
residue was purified by chromatography (silica gel, eluent CHCl3/
MeOH 9:1) to afford methanesulfonic acid {4-[7-(4-dimethylami-
nomethyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-
3-methyl-piperazin-1-yl}-phenyl-methanone (0.04 g, 43%). 1H
NMR (DMSO-d6): δ 12.63 (s, 1H, H-indole), 8.87 (s, 1H), 8.28
(d, J ) 5.4 Hz, 1H), 8.13 (s, 1H), 7.85 (d, J ) 5.4 Hz, 1H),
7.41–7.35 (m, 3H), 7.29 (m, 2H), 4.38–3.92 (br signal, 2H),
3.83–3.37 (br signal 2H), 3.21–2.69 (br signal, 3H), 2.23 (s, 6H,
N(CH3)2), 0.98 (br signal, 3H, CH3). LC/MS calcd for C24H28N8O3S
[M + 1]+, 509; found, 509.
{3-Methyl-4-[7-(4-methyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-
c]pyridine-3-sulfonyl]-piperazin-1-yl}-phenyl-methanone, Method
P. A solution of methanesulfonyl chloride (0.08 mL, 1.0 mmol) in
DCM (2 mL) was added dropwise under stirring to a solution of
{4-[7-(4-hydroxymethyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyri-
dine-3-sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-methanone (0.2
g, 0.41 mmol) and NEt3 (0.15 mL, 1.0 mmol) in DCM (20 mL) at
RT. The reaction mixture was kept at RT for 2 h (TLC monitoring,
CHCl3/MeOH 9:1). Water (20 mL) was added, the product was
extracted with DCM (20 mL), and the organic phase was dried
with Na2SO4, evaporated to give crude {4-[7-(4-chloromethyl-
[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-methyl-
piperazin-1-yl}-phenyl-methanone (∼0.1 g), which was used for
the next step without purification. LC/MS calcd for C22H22ClN7O3S
[M + 1]+, 501; found, 501, 502.
Sodium borohydride (0.03 g, 0.79 mmol) was added to a solution
of crude (from the previous step) {4-[7-(4-chloromethyl-[1,2,3]tria-
zol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-3-methyl-piperazin-
1-yl}-phenyl-methanone (∼0.1 g) in DMF (3.5 mL) under stirring
at 0 °C. Then the mixture was heated to 50–60 °C, stirred for 6 h
(TLC monitoring, CHCl3/MeOH 2:1), and cooled to RT. A 15%
aqueous solution of H2SO4 was added dropwise until a homoge-
neous solution was obtained. Solvent was evaporated, and the
residue was purified by chromatography (silica gel, eluent CHCl3/
MeOH 9:1), followed by HPLC, to afford {3-methyl-4-[7-(4-
methyl-[1,2,3]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl]-
piperazin-1-yl}-phenyl-methanone (0.03 g, 32%). 1H NMR (DMSO-
d6): δ 12.60 (s, 1H, H-indole), 8.78 (s, 1H), 8.27 (d, J ) 5.4 Hz,
1H), 8.12 (s, 1H), 7.83 (d, J ) 5.4 Hz, 1H), 7.41–7.36 (m, 3H),
7.30 (m, 2H), 4.41–3.42 (br signal, 4H), 3.20–2.67 (br signal, 3H),
2.42 (s, 3H, CH3), 0.99 (br signal, 3H, CH3). LC/MS calcd for
C22H23N7O3S [M + 1]+, 466; found, 466.
[3-Methyl-4-(7-thiazol-2-yl-1H-pyrrolo[2,3-c]pyridine-3-sul-
fonyl)-piperazin-1-yl]-phenyl-methanone, Method R. [4-(7-
Chloro-1H-pyrrolo[2,3-c]pyridine-3-sulfonyl)-3-methyl-piperazin-
1-yl]-phenyl-methanone (0.1 g, 0.24 mmol), Pd(PPh3)4 (0.2 g, 0.17
mmol), 2-tributylstannylthiazole (0.2 mL, 0.63 mmol), and anhy-
drous dioxane (6.5 mL) were placed into a pressure-capped glass
reactor (10 mL) filled with argon. The mixture was kept in a
microwave oven (CEM Discover System, 908010) at 150 °C for
20 min, cooled to RT, diluted with water (50 mL), and extracted
with EtOAc (3 × 40 mL). The organic solution was dried with
Na2SO4 and evaporated, and the residue was purified by chroma-
tography (silica gel, EtOAc/n-hexane 9:1) and then additionally by
HPLC to afford [3-methyl-4-(7-thiazol-2-yl-1H-pyrrolo[2,3-c]py-
ridine-3-sulfonyl)-piperazin-1-yl]-phenyl-methanone (0.035 g, 31%).
1H NMR (DMSO-d6): δ 12.38 (s, 1H, H-indole), 8.39 (d, J ) 5.6
Hz, 1H), 8.17 (d, J ) 3.2 Hz, 1H), 8.10 (m, 1H), 7.99 (d, J ) 3.2
Hz, 1H), 7.84 (d, J ) 5.4 Hz, 1H), 7.39 (m, 3H, C6H5), 7.30 (m,
2H, C6H5), 4.40–3.63 (br signal, 4H), 3.19–2.72 (br signal, 3H),
0.97 (br signal, 3H, CH3). LC/MS calcd for C22H21N5O3S2 [M +
1]+, 468; found, 468.
Supporting Information Available: Overlay of minimized
structures of 12a and 25. Characterization data (NMR, LC-MS,
and elemental analysis) for newly synthesized compounds and
protocol for single cycle antiviral assay and cytotoxicity assay. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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fonyl)-piperazin-1-yl]-phenyl-methanone, Method Q. Toluene
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Pd(PPh3)4 (0.14 g, 0.12 mmol) was added. The reaction mixture
was stirred under reflux (48 h; TLC monitoring, CHCl3/MeOH 9:1),
then cooled to RT, and diluted with water (50 mL). The product
was extracted with benzene (2 × 50 mL). The organic solution
was washed with water (3 × 100 mL), dried with Na2SO4, and
evaporated, and the residue was purified by chromatography (silica
gel, EtOAc/n-hexane 1:1, then 3:1, then EtOAc), then additionally
by HPLC to afford [3-methyl-4-(7-pyridin-3-yl-1H-pyrrolo[2,3-
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1
salt (0.115 g, 16.7%). H NMR (DMSO-d6): δ 13.33 (br s, 1H,
H-indole), 9.16 (s, 1H), 8.87 (m, 1H), 8.52 (m, 2H), 8.47 (m, 1H),
7.99 (m, 1H), 7.81 (m, 1H), ∼7.50 (br signal, CF3COOH·H2O),
7.42 (m, 3H, C6H5), 7.32 (m, 2H, C6H5), 4.49–3.91 (br signal, 2H),
3.88–3.33 (br signal, 2H), 3.20 (m, 1H), 3.10–2.70 (br signal, 2H),
1.02 (br signal, 3H, CH3). LC/MS calcd for C24H23N5O3S [M +
1]+, 462.5; found, 462, 463.

6544 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
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