Inhibitors of HIV-1 attachment. Part 10. the discovery and structure-activity relationships of 4-azaindole cores

Article abstract of DOI:10.1016/j.bmcl.2012.10.120

A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7.

Full text of DOI:10.1016/j.bmcl.2012.10.120

Bioorganic & Medicinal Chemistry Letters 23 (2013) 213–217
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibitors of HIV-1 attachment. Part 10. The discovery and structure–activity
relationships of 4-azaindole cores
⇑
Tao Wang , Zhong Yang, Zhongxing Zhang, Yi-Fei Gong, Keith A. Riccardi, Pin-Fang Lin, Dawn D. Parker,
Sandhya Rahematpura, Marina Mathew, Ming Zheng, Nicholas A. Meanwell, John F. Kadow,
⇑
John A. Bender
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 7 November 2012
A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort
to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile
of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core
modulated potency significantly and SAR showed that certain compounds with a 5-membered ring het-
eroaryl group at that position were the most potent. Four of the compounds with the best profiles were
evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance
when compared with 7.
Keywords:
HIV-1
Entry
Attachment
4-Azaindole
BMS-378806
Ó 2012 Elsevier Ltd. All rights reserved.
An array of single antiviral agents and fixed-dose combinations
representing six mechanistic classes is now available for use in the
treatment of HIV-1 infection.1 HIV-1 has been transformed from an
acute to a chronic disease but, unfortunately, a cure is not on the
horizon and there is an expanding population of HIV-1 patients
relying on existing therapies whose medical needs are not com-
pletely satisfied.2 The need for new, mechanistically distinct, non
cross-resistant drugs remains due to the occurrence of drug-
resistant strains and the emergence of comorbidities associated
with long-term usage of highly active combination antiretroviral
therapy (cART).3 The initial entry step, HIV-1 attachment, involves
the binding of viral envelope gp120 to CD-4 receptors on T-cells.4
This binding event effects a conformational change that facilitates
binding of the viral envelope to co-receptors. This step triggers a
rearrangement of the fusion protein gp41 which then mediates
host and viral membrane coalescence and virion entry to the cell.5
Two drugs that inhibit the HIV-1 entry process have been ap-
proved: maraviroc, a CCR5 chemokine co-receptor antagonist,
and enfuvirtide, an injectible polypeptidic inhibitor of gp41-
mediated fusion. HIV-1 attachment inhibitors (AIs) are a previously
disclosed class of orally bioavailable, small molecules that bind
to and induce conformational changes within the HIV-1 viral
envelope gp120 protein. These changes interfere with binding to
the cellular CD4 receptor, thus inhibiting entry at the initial point
of host cell engagement by the virus.6–11 Potent and selective
inhibition has been observed in vitro against macrophage-, T-,
and dual-tropic HIV-1 strains by members of this class.9,12,13
Mechanistically, HIV AIs are attractive because they target a viral,
not a host receptor, they inhibit HIV-1 independent of viral co-
receptor usage, and they lack cross resistance with existing drug
classes. In addition, several preclinical in vitro studies suggest
the potential for this class of compound to exhibit benefits beyond
reduction in viral load, including T-cell protection, although the
potential for these effects to manifest in the clinic will need to be
determined experimentally.14–16
Indole diketo benzoylpiperazines such as 1 (Fig 1) represent the
initial lead chemotype that was discovered through high through-
put compound screening of the Bristol-Myers Squibb corporate
collection. The structure–activity relationship (SAR) data that has
been published on indole-based HIV-1 attachment inhibitors de-
fines basic aspects of the pharmacophore and also highlights mar-
ginal pharmaceutical and metabolic stability properties.17–19 These
observations led to a focused effort on azaindole inhibitors, all of
which offered improved physical properties.13 Unsubstituted ana-
logs of the 4-azaindole 2 and 7-azaindole 3 series demonstrated
moderate potency improvements over the unsubstituted indole
chemotype, while the 5-azaindole 4 and 6-azaindole 5 analogs
exhibited reduced potency. Incorporation of a 4-methoxy substitu-
ent led to a 6-fold boost in potency in the indole 6 series and a
ꢀtwo fold improvement in the 7-azaindole series
7 (BMS-
378806). BMS-378806 (7) was the first small molecule inhibitor
of HIV-1 attachment to enter into clinical trials, but failed to show
sufficient exposure to merit proceeding into an efficacy trial.12,20
The 4-methoxy substituent also provided a substantial (17-fold)
improvement in potency in the 6-azaindole (8) series which lead
⇑
Corresponding authors.
E-mail address: john.bender@bms.com (J.A. Bender).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.120

214
T. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 213–217
O
O
O
O
O
O
N
N
N
N
N
N
a
N
N
N
Ph
Ph
N
N
H
O
H
O
O
O
OH
N
N
20
21
N
H
N
H
N
H
N
H
Scheme 2. Reagents and conditions: (a) SeO2, pyridine, dioxane, H2O, reflux, 35%.
3
1
2
4
EC50 = 1.7 nM
EC50 = 4.9 nM
EC50 = 1.6 nM
EC50 = 580 nM
CC50 = 280 µM
CC50 = 195 µM
CC50 = > 300 µM
CC50 = > 300 µM
carboxylic acids 13 and 14 with known benzoyl piperazines using
DEPBT resulted in the desired diketobenzoyl piperazine 4-azain-
dole derivatives 15–19.24,25 Dehalogenation of 15 and 16 under
hydrogenation conditions yielded 20 and 38, respectively.
The 7-methyl compound 20 was oxidized with selenium diox-
ide in the presence of pyridine to yield the 7-carboxylic acid com-
pound 21 (Scheme 2). The acid was converted directly to amides 22
and 30 using standard amine coupling conditions, or to a pentaflu-
orophenyl ester intermediate which was reacted with heteroaryl
amines to form compounds 28 and 29.
O
O
O
N
N
N
N
N
N
H
N
H
H
H
5
7
6
8
EC50 = 22 nM
CC50 = > 300 µM
EC50 = 1.0 nM
CC50 = > 300 µM
EC50 = 0.8 nM
CC50 = 250 µM
EC50 = 1.3 nM
CC50 = 6 µM
Figure 1. Lead HIV attachment molecules, azaindole comparison.
The 7-chloro functionality in compounds 17–19 was converted
to a 7-alkoxy substituent to afford 23 and 40 by displacement with
potassium alkoxide under microwave irradiation conditions
(Scheme 3). Similarly, all C-linked heterocycles were prepared via
a Pd(PPh3)4-catalyzed cross-coupling reaction using the appropri-
ate stannane or boronic acid at elevated temperatures. The N-
linked heterocycles were prepared by nucleophilic displacement
of the 7-chloro substituent with the appropriate heterocycle either
directly or via copper(0) catalysis at 160 °C, again under micro-
wave irradiation conditions.
All compounds were tested using a single cycle, HIV-1 pseudo-
virus assay which included an envelope DNA expression vector and
a proviral cDNA (JR-FL) containing an envelope deletion mutation
and a luciferase reporter gene.7–9 This assay was designed to detect
inhibition of early steps in the HIV-1 life cycle up to and including
integration of viral DNA into the cell genome. All compounds were
also tested for cytotoxicity. All potency and cytotoxicity assays
were performed at a minimum in duplicate and the data are re-
ported as an average. Analogs that demonstrated targeted potency
and exhibited a therapeutic index equal to or greater than that of 7
were further evaluated using in vitro assays designed to assess
their potential for a good pharmacokinetic profile or to manifest
off-target liabilities. Molecules judged to display the potential for
a profile superior to 7 were subsequently evaluated in a rat phar-
macokinetic model.
to the discovery of BMS-488043, the molecule that first demon-
strated clinical proof-of-concept for the HIV-1 attachment
mechanism.13 Since the 4-azaindole 2 exhibited potency compara-
ble to the 4-methoxyindole 6 and the 4-methoxy-6-azaindole 8
and emerging SAR indicated that significant potency enhance-
ments were attainable by substitution at the 7-position, a survey
of this aspect of structural modification was pursued as part of
the search for molecules with both improved potency and in vivo
exposure compared to 7.
The synthetic approach for preparing the key intermediates is
illustrated in Scheme 1. The 4-azaindole cores 11 and 12 were pre-
pared from the commercially available 3-nitropyridines 9 and 10
via a Bartoli reaction using an excess of vinyl Grignard reagent.21,22
The 3-position of the 4-azaindole was selectively acylated with
methyl chlorooxoacetate using AlCl3 to yield 13 or 14. This Fri-
edel–Crafts acylation could be done traditionally to yield a ketoes-
ter intermediate which was then hydrolyzed to the carboxylic acid,
or the reaction could be performed using an ionic liquid as solvent,
which afforded the acid product directly.23 Coupling the b-keto-
O
O
Compound 2 was the starting point in the 4-azaindole research
effort. Since SAR development in the indole and 6-azaindole series
had typically noted a moderate potency improvement with the 2R-
methyl piperazine over the unsubstituted piperazine this moiety
was initially employed (Table 1).19
R2
N
R2
N
R2
N
OH
b
a
N
H
NO2
N
H
R1
R1
R1
1 = CH3, R2 = Cl
11 R1 = CH3, R2 = Cl
12 R1 = Cl, R2 = H
13 R1 = CH3, R2 = Cl
14 R1 = Cl, R2 = H
9
R
10 R1 = Cl, R2 = H
Small modifications at the 7-position of the 4-azaindole from
hydrogen (2) to chloro (17), methyl (20), carboxylic acid (21) or
the simple amide 22 resulted in no or minimal losses in potency
in the HIV-1 pseudotype assay. However, the 7-methoxy com-
pound 23 exhibited subnanomolar potency. It is also worth noting
that methylation of the indole NH, as in compound 24, resulted in a
>10-fold loss in potency. Introduction of a 4-methoxyphenyl (25)
also resulted in an increase in potency when compared with 2, as
did other 6-membered heteroaromatics, represented by 26 and
27. Cytotoxicity in the initial assay became measurable for the het-
eroaromatics 26 and 27 but at a level not considered to preclude
further study in compounds with otherwise compelling profiles.
Amides such as 28, 29 and 30 demonstrated a wide range of potency,
but the best molecule in this series (28) was only slightly more
potent than the unsubstituted compound 2. The incorporation of
d
15 R1 = CH3, R2 = Cl,
R3
HN
O
20
38
R
R
R
3 = CH3, R4 = H
1 = CH3, R2 = Cl,
3 = H, R4 = H
R3
O
Ph
d
16
N
N
R2
N
O
R4
17 R1 = Cl, R2 = H,
R3 = CH3, R4 = H
18 R1 = Cl, R2 = H,
R3 = H, R4 = H
N
Ph
N
R4
H
c
R1
O
1 = Cl, R2 = H,
19
R
R3 = H, R4 = CH3
Scheme 1. Reagents and conditions: (a) CH2@CHMgBr, THF, À20 °C, 20–40% (b) (i)
ClCOCO2CH3, AlCl3, CH2Cl2 (ii) K2CO3, MeOH, H2O 82% (for 13) or ClCOCO2CH3, AlCl3,
1-ethyl-3-methyl-1H-imidazol-3-ium chloride, 80% (for 14) (c) DEBPT, iPr2EtN,
DMF, 50–80% d) 10% Pd/C, H2, 40 psi, 90%.

T. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 213–217
215
Table 2
O
O
O
R3
N
O
R3
N
Potency and cytotoxicity of 4-azaindole analogs with an unsubstituted benzoyl
piperazine
N
N
N
a, b or c
N
X
O
O
Ph
N
Ph
N
N
N
H
R4
H
R4
O
Cl
O
N
Ph
N
H
17 R3 = CH3, R4 = H
X = heteroaryl
O
18
19
R
R
3 = H, R4 = H
R3 = H, R4 = CH3
Compd
R
HIV-1 EC50 (nM) CC50 (uM)
Scheme 3. Reagents and conditions: (a) R3Sn-heteroaryl, Pd(Ph3)4, dioxane 140 °C;
(b) (HO)2B-heteroaryl, Pd(Ph3)4, dioxane 140 °C; (c) heteroaryl (free NH), Cu(0),
K2CO3, 160 °C.
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
CH3
Cl
CH3O
46.3
18.4
12.3
0.02
0.29
0.21
0.39
0.09
0.20
0.52
0.93
1.71
7.40
0.32
0.64
0.88
0.89
0.21
23.6
>300
>300
>300
85
268
150
>300
>300
23
251
231
4-Methylthiophen-2-yl
5-Acetylthiophen-2-yl
Thiazol-2-yl
Oxazol-2-yl
Thiazol-5-yl
4-Methylthiazol-2-yl
5-Methylthiazol-2-yl
Pyridin-2-yl
Table 1
Potency and cytotoxicity of 4-azaindole analogs with 2R-methyl benzoyl piperazine
O
O
N
N
R
Pyrazin-2-yl
>300
174
N
6-Methoxypyridin-2-yl
2H-1,2,3-Triazol-2-yl
1H-1,2,4-triazol-1-yl
1H-1,2,3-triazol-1-yl
pyrazol-1-yl
2H-benzo[d][1,2,3]-triazol-2-yl
1H-benzo[d][1,2,3]-triazol-1-yl
3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 10.6
Ph
N
H
>300
>300
>300
>300
124
O
Compd
R
HIV EC50 (nM)
CC50 (uM)
2
17
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
H
Cl
CH3
COOH
CONHMe
CH3O
CH3O (w/NMe)
4-Methoxyphenyl
Pyrimidin-5-yl
Pyrazin-2-yl
1.56
1.22
3.06
3.38
2.48
0.63
7.37
0.32
0.68
0.27
0.43
3.4
61.1
0.02
0.18
0.10
0.04
0.10
0.18
1.05
>300
>300
>300
>300
>300
>300
>300
>300
35.3
246
>300
the methyl group on the piperazine ring as a potency-enhancing
substituent was next investigated. An unsubstituted piperazine
in this series would be synthetically more accessible than a
methyl-substituted piperazine if the potency could be maintained
(Table 2). Once again, simple 7-substituents such as methyl (38),
chloro (39) and methoxy (40) were prepared and tested. All
showed significant decreases in potency, exemplifying the impor-
tance of the 2R-methyl group on the piperazine. However, once
5-membered heteroaryls were installed at the 7-position, the ben-
eficial impact of this methyl group on potency was muted. In fact,
the 4-methyl-2-thiophenyl 41, 2-thiazole 43 and 2-oxazole 44 ana-
logs were equipotent in the desmethyl series when compared with
the 2R-methylpiperazine series (34, 35, and 36, respectively).
Introducing an acetyl group to the thiophene (42) resulted in an
improved CC50 but reduced potency compared with 41. Addition-
ally, shifting the attachment point of the 2-thiazole 43 to the 5-po-
sition (45) produced a molecule with an EC50 of 90 pM and a CC50
15.3
thiazol-2-ylcarbamoyl
>300
>300
>300
>300
94.5
170.5
48.9
>300
>300
>300
4-Methylthiazol-2-ylcarbamoyl
Methoxy(methyl)carbamoyl
Thiophen-2-yl
Thiophen-3-yl
Benzo[b]thiophen-2-yl
4-Methylthiophen-2-yl
Thiazol-2-yl
Oxazol-2-yl
3,5-Dimethylisoxazol-4-yl
C-linked 5-membered heteroaromatic rings provided the first
significant enhancement in potency. The 2-thiophenyl compound
31 displayed an EC50 of 20 pM in the pseudotype assay,
representing a 75-fold potency increase compared to 2. Replacing
the 2-thiophene with 3-thiophene (32), 2-benzothiophene (33) or
4-methyl-2-thiophene (34) resulted in compounds that were still
several fold more potent than 2. The 2-thiazolyl derivative 35
and 2-oxazolyl analog 36 each provided an EC50 value that was a
>10-fold improvement over compound 2 and had no notable cyto-
toxicity. Interestingly, when the 3,5-dimethylisoxazol-4-yl moiety
was attached to the 7-position (37), the improved potency that had
been observed with other 5-membered ring heteroaromatics was
no longer apparent. A possible explanation for this result is that
substituents on the heteroaryl ring adjacent to the point of attach-
ment to the 4-azaindole may prevent the heteroaromatic from
achieving coplanarity with the 4-azaindole due to allylic 1,3-
strain.26 Although the bound conformation of attachment inhibi-
tors has not been definitively established, a mnemonic in which
substitution around the attached heteroaromatic that allows
coplanarity with the 4-azaindole has generally proven to be a use-
ful guide as a predictor of optimal potency within a series.27–30
Since potency of less than 200 pM had been demonstrated in a
number of compounds in the 4-azaindole series, the necessity of
of >300 lM. A methyl group on the 4-position of the 2-substituted
thiazole (46) maintained the potency of the unsubstituted 2-thia-
zole, but with a measurable increase in cytotoxicity. Moving the
methyl group to the 5-position (47) decreased the cytotoxicity,
but potency was also moderately reduced. 6-Membered heteroaro-
matics were also investigated and analogs such as pyridin-2-yl
(48), pyrazin-2-yl (49) and 6-methoxypyridin-2-yl (50) were gen-
erally found to be less potent than C-linked 5-membered hetero-
aromatics. The N-linked heteroaromatics were explored for the
first time in this series. The most potent molecules within this
group were the 2-linked, 1,2,3 triazole 51 and the 2-linked 1,2,3-
benzotriazole 55. These molecules have nitrogen atoms flanking
the site of attachment to the core. Consequently, there is no steric
encumbrance that would hinder coplanarity between the two het-
eroaromatic rings. Replacing one of these flanking nitrogens with a
CH, as in 52, 53, or 54 lead to a moderate loss in potency across the
series, consistent with the coplanarity argument. If a fused aro-
matic ring was placed into one of these flanking positions, as in
56 or 57, significant, 50 to 100-fold reductions in potency were
observed.

216
T. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 213–217
Table 4
Analogs with a 3R-methyl-piperazine were prepared and evalu-
Rat pharmacokinetic properties of compounds 51, 61, 62 and 65 compared with BMS-
378806 (7)
ated to determine if they offered potency (Table 3) and/or pharma-
cokinetic advantages.31 Within this series, the 2-thiophene 59 and
the 4-methyl-2-thiophene 60 each resulted in good EC50 values of
ꢀ200 pM. The 2-oxazole 61 and the 2-thiazole 62 derivatives were
each about equipotent with the desmethyl and 2R-methyl pipera-
zine analogs. Methyl substitution on the 2-thiazole was also toler-
ated, although the 4-methyl 64 was slightly more potent than the
5-methyl isomer 63. Interestingly, a similar shift of the methyl
group from the 3-methylpyrazol-1-yl analog 66, which had an
EC50 value of 460 pM, to the 4-methylpyrazol-1-yl 67, again
afforded a loss of potency. As anticipated based on the coplanarity
mnemonic, within the N-linked 5-membered heteroaryl analogs,
the 2-linked 1,2,3-triazole 65 and the 2-linked 1,2,3-benzotriazole
68 proved to be the most potent, but within the 3R-methyl series
the 3-methylpyrazo-l-yl analog 66 was equal in potency to 68.
The importance of avoiding allylic 1,3-strain between the
7-heteroaryl and the 4-azaindole was again demonstrated in this
series.26 When comparing the 2-benzotriazole 68 to the 1-benzo-
triazole 69 and the 3-methyl-1,2,4-triazol-1-yl 70 to 5-methyl-
1,2,4-triazol-1-yl 71, the more sterically encumbered molecule
was nearly 20-fold less potent. This loss in potency may be attrib-
uted to interference with a coplanar conformation between the
heteroaryl ring and the 4-azaindole. Although collectively the
3R-methyl piperazine series displayed slightly diminished potency
when compared with the desmethyl or 2R-methyl series, this ser-
ies generally demonstrated superior predicted and balanced prop-
erties from in vitro assays (including metabolic stability and
permeability) (unpublished results). Overall, optimal potency in
all three 4-azaindole series at the key 7-position was obtained
using 5-membered ring heteraromatics which possessed structural
elements that would enhance (or not hinder) coplanarity between
the heteroaromatic elements. Also, the 2R-methyl-piperazine did
not offer a significant potency advantage over the unsubstituted
piperazine or the 3R-methyl-piperazine in the most potent
analogs.
7
51
61
62
65
F%
19
1.3
32
65
9.6
5.4
60
5.6
7.4
41
1.3
11.2
78
3.3
13.9
AUC po.(uM⁄hr)
CL iv (mL/min/kg)
properties in rats that were superior to 7 (see Table 4). However,
both the 1,2,3-triazol-2-yl compound in the desmethyl piperazine
series (51) and the 2-oxazole in the 3R-methyl piperazine series
(61) displayed higher AUC values and lower clearance than that
exhibited by 62 and 65 in the 3R-methyl piperazine series.
In summary, a series of novel and potent 4-azaindole core con-
taining compounds was prepared and evaluated for potential util-
ity as inhibitors of HIV-1 attachment and infection in vitro.
Synthetic chemical approaches were successfully developed that
allowed for the investigation of SAR around the key 7-position of
this core. Many aromatic heterocyclic compounds that conformed
to a model in which coplanarity between the C-7 substituent and
the core heterocycle was accessible were found to have improved
potency when compared with 7 from which two compounds, 51
and 61, exhibited superior PK profiles in the rat. Thus, the goal of
an improvement in combined potency and exposure was achieved
in this series, and 4-azaindole core molecules were considered for
advancement. Ultimately, however, more promising candidates
were discovered in a related 6-azaindole core series a member of
which provided clinical proof-of-concept for the attachment mech-
anism.13,32–35 A prodrug of a second more potent compound within
the 6-azaindole series has been advanced into Phase II clinical
studies.36–40
Acknowledgments
The authors would like to gratefully acknowledge Dr. Gregory
Yamanaka (deceased) for providing the antiviral data presented
in this manuscript. Greg was both a thoughtful and thought-pro-
voking scientist and he is dearly missed.
Four molecules within the 4-azaindole series demonstrated suf-
ficiently potent antiviral activity and in vitro ADME properties
along with limited off-target liabilities to merit investigation in a
rat pharmacokinetic study. Compounds were administered as a
single dose (IV at 1 mg/kg and PO at 5 mg/kg) and plasma concen-
trations assessed. All of the molecules displayed pharmacokinetic
References and notes
1. De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307.
2. Taiwo, B.; Hicks, C.; Eron, J. J. Antimicrob. Chemother. 2010, 65, 1100.
3. Mehellou, Y.; De Clercq, E. J. Med. Chem. 2010, 53, 521.
Table 3
4. For references on CD4 mimics see: (a) Zhao, Q.; Ma, L.; Jiang, S.; Lu, H.; Liu, S.;
He, Y.; Strick, N.; Neamati, N.; Debnath, A. K. Virology 2005, 339, 213; (b) Schön,
A.; Madani, N.; Klein, J. C.; Hubicki, A.; Ng, D.; Yang, X.; Smith, A. B., III;
Sodroski, J.; Freire, E. Biochemistry 2006, 45, 10973; (c) Yoshimura, K.; Harada,
S.; Shibata, J.; Hatada, M.; Yamada, Y.; Ochiai, C.; Tamamura, H.; Matsushita, S.
J. Virol. 2010, 84, 7558; (d) Yamada, Y.; Ochiai, C.; Yoshimura, K.; Tanaka, T.;
Ohashi, N.; Narumi, T.; Nomura, W.; Harada, S.; Matsushita, S.; Tamamura, H.
Bioorg. Med. Chem. Lett. 2010, 20, 354.
5. (a) Derdeyn, C. A.; Hunter, E. HIV Chemotherapy 2005, 195; (b) Ryser, H. J.-P.;
Fluckiger, R. Drug Discovery Today 2005, 10, 1085; (c) Castagna, A.; Biswas, P.;
Beretta, A.; Lazzarin, A. Drugs 2005, 65, 879; (d) Vermeire, K.; Schols, D. Exp.
Opin. Invest. Drugs 2005, 14, 1199; (e) Rusconi, S.; Scozzafava, A.;
Mastrolorenzo, A.; Supuran, C. T. Curr. Top. Med. Chem. 2007, 7, 1273; (f)
Veiga, A. S.; Santos, N. C.; Castanho, M. A. R. B. Recent Pat. Anti-Infect. Drug
Discov. 2006, 1, 67; (g) Vermeire, K.; Schols, D.; Bell, T. W. Curr. Med. Chem.
2006, 13, 731.
6. Kadow, J.; Wang, H.-G. H.; Lin, P.-F. Curr. Opin. Invest. Drugs 2006, 7, 721.
7. Guo, Q.; Ho, H.-T.; Dicker, I.; Fan, L.; Zhou, N.; Friborg, J.; Wang, T.; McAuliffe, B.
V.; Wang, H.-G. H.; Rose, R. E.; Fang, H.; Scarnati, H. T.; Langley, D. R.; Meanwell,
N. A.; Abraham, R.; Colonno, R. J.; Lin, P.-F. J. Virol. 2003, 77, 10528.
8. Ho, H.-T.; Fan, L.; Nowicka-Sans, B.; McAuliffe, B.; Li, C.-B.; Yamanaka, G.; Zhou,
N.; Fang, H.; Dicker, I.; Dalterio, R.; Gong, Y.-F.; Wang, T.; Yin, Z.; Ueda, Y.;
Matiskella, J.; Kadow, J.; Clapham, P.; Robinson, J.; Colonno, R.; Lin, P.-F. J. Virol.
2006, 80, 4017.
9. Lin, P.-F.; Blair, W.; Wang, T.; Spicer, T.; Guo, Q.; Zhou, N.; Gong, Y.-F.; Wang,
H.-G. H.; Rose, R.; Yamanaka, G.; Robinson, B.; Li, C.-B.; Fridell, R.; Deminie, C.;
Demers, G.; Yang, Z.; Zadjura, L.; Meanwell, N.; Colonno, R. Proc. Natl. Acad. Sci.
U. S. A. 2003, 100, 11013.
Potency and cytotoxicity of 4-azaindole analogs with 3R-methyl benzoyl piperazine.
O
O
N
N
N
Ph
N
H
O
R
Compd
R
HIV EC50 (nM)
CC50 (uM)
58
59
60
61
62
63
64
65
66
67
68
69
70
71
Cl
11.6
0.24
0.21
0.34
0.31
0.71
0.19
0.44
0.46
1.59
0.31
5.34
0.59
10.8
300
168
123
135
35
28
30
300
300
>150
74
Thiophen-2-yl
4-Methylthiophen-2-yl
Oxazol-2-yl
Thiazol-2-yl
5-Methylthiazol-2-yl
4-Methylthiazol-2-yl
2H-1,2,3-Triazol-2-yl
3-Methyl-1H-pyrazol-1-yl
4-Methyl-1H-pyrazol-1-yl
2H-Benzo[d][1,2,3]-triazol-2-yl
1H-Benzo[d][1,2,3]-triazol-1-yl
3-Methyl-1H-1,2,4-triazol-1-yl
5-Methyl-1H-1,2,4-triazol-1-yl
71
>300
>300

T. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 213–217
217
10. Lin, P.-F.; Kadow, J.; Alexander, L. In Entry Inhibitors in HIV Therapy; Reeves, J.
D.; Derdeyn, C. A.; Birkhäuser, V., Eds.; Birkhäuser Basel, 2007, pp 49.
11. Si, Z.; Madani, N.; Cox, J. M.; Chruma, J. J.; Klein, J. C.; Schoen, A.; Phan, N.;
Wang, L.; Biorn, A. C.; Cocklin, S.; Chaiken, I.; Freire, E.; Smith, A. B., III;
Sodroski, J. G. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5036.
12. Wang, T.; Zhang, Z.; Wallace, O. B.; Deshpande, M.; Fang, H.; Yang, Z.; Zadjura,
L. M.; Tweedie, D. L.; Huang, S.; Zhao, F.; Ranadive, S.; Robinson, B. S.; Gong, Y.-
F.; Ricarrdi, K.; Spicer, T. P.; Deminie, C.; Rose, R.; Wang, H.-G. H.; Blair, W. S.;
Shi, P.-Y.; Lin, P.-F.; Colonno, R. J.; Meanwell, N. A. J. Med. Chem. 2003, 46, 4236.
13. Wang, T.; Yin, Z.; Zhang, Z.; Bender, J. A.; Yang, Z.; Johnson, G.; Yang, Z.;
Zadjura, L. M.; D’Arienzo, C. J.; Parker, D. D.; Gesenberg, C.; Yamanaka, G. A.;
Gong, Y.-F.; Ho, H.-T.; Fang, H.; Zhou, N.; McAuliffe, B. V.; Eggers, B. J.; Fan, L.;
Nowicka-Sans, B.; Dicker, I. B.; Gao, Q.; Colonno, R. J.; Lin, P.-F.; Meanwell, N. A.;
Kadow, J. F. J. Med. Chem. 2009, 52, 7778.
S.; Qiu, Z.; Yang, Z.; Zadjura, L.; D’Arienzo, C. J.; Browning, M.R.; Hansel, S.;
Huang, X.; Eggers, B.; Riccardi, K.; Lin, P.-F.; Meanwell, N. A.; Kadow, J. F. Bioorg.
Med. Chem. Lett. 9, in press.
28. Bender, J. A.; Yang, Z.; Eggers, B.; Gong, Y-.F.; Lin, P.-F.; Parker, D. D.;
Rahematpure, S.; Zheng, M.; Meanwell, N.; Kadow, J. F. Bioorg. Med. Chem. Lett.
11, in press.
29. (a) Regueiro-Ren, A.; Xue, Q. M.; Ueda, Y.; Yamanaka, G.; Swidorski, J. J.; Chen,
C. -P.; Wang, T.; Gong, Y. -F.; Mathew, M.; Parker, D. D.; Yang, Z.; Eggers, B.;
Darienzo, C.; Malinowski, J.; Zheng, M.; Lin, P.-F.; Meanwell, N. A.; Kadow, J. F.
238th ACS National Meeting: Washington, DC, United States, 2009; MEDI-450.;
(b) Regueiro-Ren, A.; Xue, Q. M.; Swidorski, J. J.; Gong, Y.-F.; Mathew, M.;
Parker, D. D.; Yang, Z.; Eggers, B.; Darienzo, C.; Sun, Y.; Malinowski, J.; Gao, Q.;
Wu, D.; Langley, D. R.; Colonno, R. J.; Grasela, D.; Zheng, M.; Lin, P. -F.;
Meanwell, N. A.; Kadow, J. F. Manuscript in preparation.
14. Alexander, L.; Zhang, S.; McAuliffe, B.; Connors, D.; Zhou, N.; Wang, T.; Agler,
M.; Kadow, J.; Lin, P.-F. Antimicrob. Agents Chemother. 2009, 53, 4726.
15. Zhou, N.; Fan, L.; Ho, H.-T.; Nowicka-Sans, B.; Sun, Y.; Zhu, Y.; Hu, Y. a.;
McAuliffe, B.; Rose, B.; Fang, H.; Wang, T.; Kadow, J.; Krystal, M.; Alexander, L.;
Colonno, R.; Lin, P.-F. Virology 2010, 402, 256.
30. Wang, T.; Ueda, Y.; Zhang, Z.; Yin, Z.; Matiskella, J.; Pearce, B.; Bender, J. A.;
Yang, Z.; Yang, Z.; Zheng, M.; Parker, D. D.; Gong, Y.-F.; Ho, H.-T.; Gao, Q.;
Colonno, R.J.; Lin, P.-F.; Meanwell, N. A.; Kadow, J. F. Manuscript in preparation.
31. Analogs in other core series possessing 3R-methyl-piperazines demonstrated a
potency advantage over 3S-methyl-piperazine analogs (unpublished results).
32. Hanna, G. J.; Lalezari, J.; Hellinger, J. A.; Wohl, D. A.; Nettles, R.; Persson, A.;
Krystal, M.; Lin, P.-F.; Colonno, R.; Grasela, D. M. Antimicrob. Agents Chemother.
2011, 55, 722.
33. Zhou, N.; Nowicka-Sans, B.; Zhang, S.; Fan, L.; Fang, J.; Fang, H.; Gong, Y.-F.;
Eggers, B.; Langley, D. R.; Wang, T.; Kadow, J.; Grasela, D.; Hanna, G. J.;
Alexander, L.; Colonno, R.; Krystal, M.; Lin, P.-F. Antimicrob. Agents Chemother.
2011, 55, 729.
16. Zhang, S.; Alexander, L.; Wang, T.; Agler, M.; Zhou, N.-N.; Fang, H.; Kadow, J.;
Clapham, P.; Lin, P.-F. Arch. Virol. 2010, 155, 777.
17. Meanwell, N. A.; Wallace, O. B.; Fang, H.; Wang, H.; Deshpande, M.; Wang, T.;
Yin, Z.; Zhang, Z.; Pearce, B. C.; James, J.; Yeung, K.-S.; Qui, Z.; Wright, J. J. K.;
Yang, Z.; Zadjura, L.; Tweedie, D. L.; Yeola, S.; Zhao, F.; Ranadive, S.; Robinson,
B. A.; Gong, Y.-F.; Wang, H.-G. H.; Blair, W. S.; Shi, P.-Y.; Colonno, R. J.; Lin, P.-F.
Bioorg. Med. Chem. Lett. 2009, 19, 1977.
18. Meanwell, N. A.; Wallace, O. B.; Wang, H.; Deshpande, M.; Pearce, B. C.; Trehan,
A.; Yeung, K.-S.; Qiu, Z.; Wright, J. J. K.; Robinson, B. A.; Gong, Y.-F.; Wang, H.-G.
H.; Blair, W. S.; Shi, P.-Y.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009, 19, 5136.
19. Wang, T.; Kadow, J. F.; Zhang, Z.; Yin, Z.; Gao, Q.; Wu, D.; Parker, D. D.; Yang, Z.;
Zadjura, L.; Robinson, B. A.; Gong, Y.-F.; Spicer, T. P.; Blair, W. S.; Shi, P.-Y.;
Yamanaka, G.; Lin, P.-F.; Meanwell, N. A. Bioorg. Med. Chem. Lett 2009, 19, 5140.
20. (a) Yang, Z.; Zadjura, L.; D’Arienzo, C.; Marino, A.; Santone, K.; Klunk, L.; Greene,
D.; Lin, P.-F.; Colonno, R.; Wang, T.; Meanwell, N.; Hansel, S. Biopharma. Drug
Dispos. 2005, 26(9), 387–402; (b) Xue, Y.-J.; Yan, J.-H.; Arnold, M.; Grasela, D.;
Unger, S. J. Sep. Sci. 2007, 30, 1267.
21. (a) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163; (b) Zhang, Z.; Yang, Z.;
Meanwell, N. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 2345.
22. For an alternative preparation of the 4-azaindole core see: Zhu, J.; Wong, H.;
Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Tetrahedron Lett. 2006,
47, 5653.
34. Yang, Z.; Zadjura, L. M.; Marino, A. M.; D’Arienzo, C. J.; Malinowski, J.;
Gesenberg, C.; Lin, P.-F.; Colonno, R. J.; Wang, T.; Kadow, J. F.; Meanwell, N. A.;
Hansel, S. B. J. Pharm. Sci. 2010, 99, 2135.
35. Kadow, J. F.; Ueda, Y.; Meanwell, N. A.; Connolly, T. P.; Wang, T.; Chen, C.-P.;
Yeung, K.-S.; Zhu, J.; Bender, J. A.; Yang, Z.; Parker, D.; Lin, P.-F.; Colonno, R. J.;
Mathew, M.; Morgan, D.; Zheng, M.; Chien, C.; Grasela, D. J. Med. Chem. 2012,
55, 2048.
36. Nettles, R.; Schurmann, D.; Zhu, L.; Stonier, M.; Huang, S.-P.; Chien, C.; Krystal,
M.; Wind-Rotolo, M.; Bertz, R.; Grasela, D. 18th Conf. Retroviruses
Opportunistic Infections, Boston, M. A, February 27–March 2, 2011, Paper 49.
37. Nettles, R.; Schürmann, D.; Zhu, L.; Stonier, M.; Huang, S.-P.; Chang, I.; Chien,
C.; Krystal, M.; Wind-Rotolo, M.; Ray, N.; Hanna, G. J.; Bertz, R.; Grasela, D. J.
Infect. Dis. 2012, 206, 1002.
38. Kadow, J. F.; Ueda, Y.; Connolly, T. P.; Wang, T.; Chen, C.P.; Yeung, K.-S.; Bender,
J.; Yang, Z.; Zhu, J.; Matiskella, J.; Regueiro-Ren, A.; Yin, Z.; Zhang, Z.; Farkas, M.;
Yang, X.; Wong, H.; Smith, D.; Raghaven, K.S.; Pendri, Y.; Staab, A.;
Soundararajan, N.; Meanwell, N.; Zheng, M.; Parker, D. D.; Adams, S.; Ho, H-
T; Yamanaka, G.; Nowicka-Sans, B.; Eggers, B.; McAuliffe, B.; Fang, H.; Fan, L.;
Zhou, N.; Gong, Y. -F; Colonno, R. J .; Lin, P.-F.; Brown, J.; Grasela, D. M.; Chen,
C.; Nettles, R.E. 241st ACS National Meeting & Exposition: Anaheim, CA, United
States. March 27–31, 2011; MEDI-29.
23. (a) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell, N. A.; Kadow, J. F.; Wang, T.
J. Org. Chem. 2002, 67, 6226; (b) Yeung, K.-S.; Farkas, M. E.; Qiu, Z.; Yang, Z.
Tetrahedron Lett. 2002, 43, 5793.
24. Wang, T.; Zhang, Z.; Meanwell, N. A. J. Org. Chem. 2000, 65, 4740.
25. Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org. Lett. 2002, 4,
1103.
26. Johnson, F. Chem. Rev. 1968, 68(4), 375.
39. Nowicka-Sans, B.; Gong, Y.-F.; McAuliffe, B.; Dicker, I.; Ho, H.-T.; Zhou, N.;
Eggers, B.; Lin, P.-F.; Ray, N.; Wind-Rotolo, M.; Zhu, L.; Majumdar, A.; Stock, D.;
Lataillade, M.; Hanna, G. J.; Matiskella, J. D.; Ueda, Y.; Wang, T.; Kadow, J. F.;
Meanwell, M. A.; Krystal, M. Antimicrob. Agents Chemother. 2012, 56, 349.
40. Nowicka-Sans, B.; Gong, Y.-F.; Ho, H. -T.; Colonno, R.; Lin, P.-F.; Wind-Rotolo,
M.; Kadow, J.; Meanwell, N.; Nettles, R.; Krystal, M. 18th CROI, Feb 27–Mar 2,
2011, Poster 518.
27. (a) Yeung, K.-S.; Qiu, Z.; Xue, Q.; Fang, H.; Yang, Z.; Zadjura, L.; D’Arienzo, C. J.;
Eggers, B.; Riccardi, K.; Shi, P.-Y.; Gong, Y-.F.; Browning, M. R.; Gao, Q.; Hansel,
S.; Santone, K.; Lin, P. -F.; Meanwell, N. A.; Kadow, J. F. Bioorg. Med. Chem. Lett.
7, in press.; (b) Yeung, K.-S.; Qiu, Z.; Yin, Z.; Trehan, A.; Fang, H.; Pearce, B.;
Yang, Z.; Zadjura, L.; D’Arienzo, C. J.; Riccardi, K.; Shi, P.-Y.; Spicer, T.; Gong, Y-
.F.; Browning, M. R.; Hansel, S.; Santone, K.; Barker, J.; Coulter, T.; Lin, P. -F.;
Meanwell, N. A.; Kadow, J. F. Bioorg. Med. Chem. Lett. 8, in press.; (c) Yeung, K.-