Inhibitors of HIV-1 attachment. Part 11: The discovery and structure-activity relationships associated with 4,6-diazaindole cores

Article abstract of DOI:10.1016/j.bmcl.2012.10.118

A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibit

Full text of DOI:10.1016/j.bmcl.2012.10.118

Bioorganic & Medicinal Chemistry Letters 23 (2013) 218–222
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibitors of HIV-1 attachment. Part 11: The discovery
and structure–activity relationships associated with 4,6-diazaindole cores
⇑
John A. Bender , Zhong Yang, Betsy Eggers, Yi-Fei Gong, Pin-Fang Lin, Dawn D. Parker,
Sandhya Rahematpura, Ming Zheng, Nicholas A. Meanwell, John F. Kadow
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 5 November 2012
A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to
identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-
488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this
mechanism in human clinical studies but required high doses and concomitant administration of a high
fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR
investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the dis-
covery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure
over 2 in a rat PK studies.
Keywords:
HIV-1
Entry
Attachment
4,6-Diazaindole
BMS-488043
Ó 2012 Elsevier Ltd. All rights reserved.
Although a cure continues to be elusive, significant advances
have been made in the treatment of patients infected with HIV-1
over the past decade. Presently, there are more than 25 FDA-ap-
proved drugs from six mechanistic classes, and drug combination
therapies (combination antiretroviral therapy, cART) have become
the standard of care for the treatment of HIV-1 infection.1 These
advances have transformed HIV-1 infection into a manageable
disease for many patients, but there are still a number of unmet
medical needs for those undergoing treatment.2 These include
drug-resistant HIV-1 strains which continue to appear and increase
in prevalence. As a result, the development of drugs with new
mechanisms or which lack cross resistance to drugs with
established mechanisms remains an important objective in this
arena of research.3 Current combination therapies continue to
emphasize protease and reverse transcriptase (both nucleoside
and non-nucleoside) inhibitors but approved HIV-1 drugs such as
enfuvirtide (an injectible fusion inhibitor), raltegravir (an integrase
inhibitor) and maraviroc (a CCR5 chemokine co-receptor antago-
nist) provide mechanistic alternatives.
HIV-1 attachment inhibitors interfere with the first step of the
well-defined, three step HIV entry process in which the initial inter-
action is binding of the viral envelope protein gp120 to the host cell
CD4 receptor.4 This association triggers conformational rearrange-
ments in gp120 that sequentially facilitate chemokine co-receptor
binding and gp41 rearrangement, which then leads to 6-helix bun-
dle formation, virus-host cell membrane fusion and delivery of the
virus capsid to the cytosol.5 The bulk of the published mechanistic
evidence suggests that HIV-1 attachment inhibitors bind directly to
the viral gp120 and prevent the initial binding interaction with CD4
on the surface of T-cells.5–9 However, studies conducted under
alternative in vitro conditions have led to the suggestion that the
binding of the attachment inhibitor and CD4 to gp120 occurs simul-
taneously, with virus entry prevented by interference with gp41
activation.10 Although there are currently no marketed HIV-1
attachment inhibitors, research into this mechanism remains
important due to the demonstrated antiviral activity in clinical
studies and recently reported in vitro data revealing the potential
possibility of unique beneficial properties in addition to the ex-
pected direct antiviral effects. These properties include evidence
that attachment inhibitors may provide a level of protection against
CD4+ T-cell apoptosis, which has been shown to be induced by
binding of HIV-1 envelope protein.11 Also, viruses with mutations
which demonstrated resistance to attachment inhibitors were
shown to have increased sensitivity to certain broadly neutralizing
antibodies.12,13 Early structure–activity relationship (SAR) studies
in both the indole and azaindole class of attachment inhibitor led
to the selection of a clinical candidate that provided proof-of-con-
cept for this antiviral mechanism in infected patients.14–16
The first small molecule inhibitor of HIV-1 attachment to enter
clinical trials was BMS-378806 (1) (Fig. 1) which did not show suf-
ficient exposure to merit further studies.17–19 This molecule was
followed by BMS-488043 (2), which was the first HIV-1 attachment
inhibitor to establish clinical proof-of-concept for this mecha-
nism.20–23 The mechanism of inhibition, spectrum of activity and
resistance profile of 2 have been described in detail.7,20,21 Although
2 demonstrated an acceptable safety profile, a predicted high BID
dose and a requirement for a concomitant high fat meal to take
⇑
Corresponding author. Tel.: +1 203 677 7662.
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.2012.10.118

J. A. Bender et al. / Bioorg. Med. Chem. Lett. 23 (2013) 218–222
219
O
O
OMe
OMe
O
N
OMe
N
O
N
N
N
O
N
O
N
H
N
H
1
2
EC50 = 1.0 nM
EC50 = 1.0 nM
CC50 = > 300 µM
HLM t1/2 = 37 min
Caco-2 Pc = 51 nm/s
CC50 = > 300 µM
HLM t1/2 = 100 min
Caco-2 Pc = 178 nm/s
Figure 1. Lead HIV-1 Attachment molecules.
advantage of a positive food effect on exposure were needed to
achieve good efficacy.24 Further optimization resulted in this com-
pound being replaced in development by BMS-663068, the phos-
phonooxymethyl prodrug of BMS-626529, a 6-azaindole with an
improved pre-clinical virologic profile.25–30 As part of the effort to
identify HIV-1 attachment inhibitors with improved physicochem-
ical and pharmacokinetic properties, a series of 4,6-diazaindole
analogs of 2 was explored. In this report, the SARs associated with
this series, with a particular emphasis on analogs substituted at
the C-7 position, are described.
The original synthetic route to prepare the desired 4,6-diazain-
dole analogs involved the initial preparation of 7-chloro-4,6-diaz-
aindole.31 Unfortunately, attempts to functionalize the 3-position
of this molecule and analogs proved unsuccessful, necessitating
an alternate strategy that circumvented this limitation. This strat-
egy, captured in Scheme 1, incorporated the desired ester function-
ality at an early step and carried it through the diazaindole core
synthesis. The route started from commercially-available ethyl
(ethoxymethylene)-cyanoacetate which was condensed with
diethyl 2-aminomalonate to yield the 3-aminopyrazole 6.32 This
molecule was regioselectively cyclized with formamidine acetate
to afford a pyrrolopyrimidinone. Chlorination with POCl3 provided
the desired key intermediate 7-chloro-4,6-diazaindole derivative 7
which possessed an ethyl ester at the 3-position. Ester hydrolysis
followed by acid chloride formation with oxalyl chloride and
DMF resulted in the reactive intermediate 8. Treatment of 8 with
the potassium anion of the piperazinyl acetonitrile 11 (prepared
in three steps from commercially-available BOC-piperazine)33 led
to the enol intermediate 9, which was isolated as a mixture of ole-
fin isomers or directly oxidized with peracetic acid to yield the keto
amide intermediate 10. The 7-chloro functionality was converted
to a 7-alkoxy (13 and 14) or a 7-cyano (15) by displacement with
the appropriate potassium counterion under microwave irradia-
tion conditions. The 7-ketomethyl analog 16 was prepared by the
coupling of ethoxyvinyl stannane with 10 using Pd(PPh3)4 under
microwave irradiation conditions, and then hydrolyzing the result-
ing enol ether. Similarly, the C-linked heterocycles 17–24 were
prepared using a Pd(PPh3)4-catalyzed coupling with the appropri-
ate stannane at elevated temperatures. The N-linked heterocycles
25–40 were prepared by nucleophilic displacement of the 7-chloro
substituent with the appropriate heterocycle, either directly or cat-
alyzed by copper(0) at 140–160 °C, again under microwave irradi-
ation conditions.
The effects of the surveyed structural modifications were ini-
tially evaluated using an in vivo HIV-1 pseudotype assay to deter-
mine entry inhibitory potency (EC50) and in a cellular assay to
determine cytotoxicity (CC50) and establish a therapeutic index.7,8
Analogs that demonstrated good potency and had a therapeutic in-
dex equal to or greater than that of 2 were then further evaluated
for in vitro CYP and hERG inhibition, PXR activation, cell perme-
ability and liver microsomal stability. Molecules lacking assessed
off-target liabilities and demonstrating potential for a good phar-
macokinetic profile compared with 2 were then explored in a rat
pharmacokinetic model.
O
O
O
O
OEt
H2N
EtO
NC
a
OEt
EtO
O
OEt
+
N
H
NH2
EtO
O
6
O
Cl
OEt
N
N
d, e
b, c
N
N
N
N
H
H
8
Cl
Cl
f
7
NC
O
h, i, j
N
N
BOC
N
NH
Ph
11
The studies reported here were initiated to determine if the 4,6-
diazaindole core would offer improved potency, exposure and/or
solubility over 6- or 7-azaindole cores. Initially, the 7-methoxy-
4,6-diazaindole analog 13, the closest analog of 1 and 2, was pre-
pared and found to be ꢀfour-fold less potent than the 7-azaindole
2 (Table 1). Other substituents at the 7-position, including ethoxy,
cyano and acyl, incurred a further 10- to 40-fold reduction in po-
tency compared to 2. However, azaindole cores, including 4,6-diaz-
aindole analogs, were typically found to be more soluble than the
corresponding indole core analogs (unpublished results).
CN
O
HO
O
N
N
N
N
N
g
N
N
O
N
N
O
N
H
H
Ph
Cl
Ph
Cl
9
10
Scheme 1. Reagents and conditions: (a) NaOEt, EtOH, reflux, 80%; (b) formamidine
acetate, EtOH, reflux; (c) POCl3, 65% (over two steps); (d) LiOH, H2O, THF, 90 °C, 90%;
(e) oxalyl chloride, CH2Cl2, DMF; (f) KHMDS, THF, ꢁ78 °C; (g) AcOOH, KHMDS, THF,
ꢁ78 °C to rt (28% over three steps) (h) BzCl, Et3N, THF; (i) TFA, CH2Cl2; (j) ClCH2CN,
Et3N, THF (90% over three steps).
Heterocycles at the 7-position of the diazaindole core were
investigated based on observations in the indole series where this
substitution enhanced potency. While non-aromatic heterocycles

220
J. A. Bender et al. / Bioorg. Med. Chem. Lett. 23 (2013) 218–222
Table 1
Potency and cytotoxicity of 4,6-diazindole core analogs of 2
N
N
N
O
O
N
N
N
N
N
H
N
N
H
N
H
H
N
H
H
X
X
X
N
N
O
N
H
Ph
R
Observed loss
in potency
Optimal
potency
Observed loss
in potency
a
b
Compound
R
HIV-1 EC50 (nM) CC50 (lM)
Figure 2. Optimal HIV-1 antiviral activity is observed when the 7-position
heteroaryls is configured so it may lie coplanar with the 4,6-diazaindole core.
10
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Cl
CH3O
CH3CH2O
CN
CH3CO
2-Pyridinyl
3-Pyridinyl
4-Pyridinyl
2-Pyrazinyl
4-Pyridazinyl
5-Pyrimidinyl
3-Pyrazolyl
5-(3-Methyl)isoxazolyl
1-Pyrazolyl
2-(1,2,3-Triazolyl)
1-(1,2,4-Triazolyl)
11
4.1
12
44
18
0.34
1.3
12
0.25
5.2
2.7
0.31
0.88
0.05
11
>300
>300
>150
>300
>300
6
>300
>300
78
>300
>300
>300
177
>300
>150
>300
>150
>300
>300
>300
present. Interestingly, the two most potent molecules within the
C-linked six membered heteroaromatic series, 17 and 20, had mea-
surable cytotoxicities; however, both still maintained a therapeutic
index of >15,000.
The predictive value of the coplanarity mnemonic held as five-
membered ring heteroaryl substituents within this series were
investigated. Both the 3-pyrazolyl 23 and 5-(3-methyl)isoxazolyl
24 analogs, which are C-linked heteroaromatics, proved to be more
potent than 13, although 24 had similar potency to 2. However,
when looking at a series of N-linked, 5-membered heteroaromatic
rings, the N1-pyrazole 25 and the N1-1,2,4-triazole 27 emerged as
very potent compounds, with EC50 values of 50 pM and 100 pM,
respectively. The N2-1,2,3-triazole 26 exhibited significantly re-
duced potency (11 nM) in comparison, possibly due to the lack of
a second hydrogen bonding interaction and/or an electron pair
repulsion with the 6-aza heteroatom, which may limit the hetero-
cycle from populating the desired coplanarity state with the 4,6-
diazaindole core. The addition of a methyl group at the 3-position
of the potent triazole 27 and pyrazole 31 was tolerated with only a
modest loss in potency; however, the 4-methyl pyrazole com-
pound 30 is ꢀ20-fold lower in potency when compared with the
unsubstituted pyrazole, making it equipotent with 2. With com-
pounds in hand that had similar therapeutic indexes when com-
pared with 2 but were 10- to 20-fold more potent, the 3-position
of the most potent N1-pyrazole series was next explored in an at-
tempt to optimize in vitro ADME properties.
In an effort to increase exposure by improving solubility within
the pyrazole series, functional groups at the 3-position which
would be amenable to salt formation were investigated. These in-
cluded the carboxylic acid 32 and the tertiary amine 34 linked
through an amide moiety (Table 2). Although both of these mole-
cules achieved higher solubility in their respective salt forms, both
showed significant erosion in intrinsic potency in the pseudotype
assay. The dimethylamide analog 33 was also 40-fold weaker com-
pared with the parent pyrazole. Next, a series of 3-aryl pyrazoles
with varying electron-donating and -withdrawing groups were
tested (compounds 35–40). Although the varied functionality
around the aromatic ring exerted little influence on the potency,
these molecules were found to be more potent as a group than
the amide series; however, they were three- to seven-fold less po-
tent than the parent pyrazole and did not demonstrate a solubility
advantage
0.10
1-(3-Methyl-1,2,4-Triazolyl) 0.36
1-(4-Methylpiperidinyl)
1-(4-Methylpyrazolyl)
1-(3-Methylpyrazolyl)
>5000
1.1
0.15
a
HIV-1 pseudotype assay performed in duplicate (Refs. 6,7).
Cellular assay performed in duplicate (Refs. 6,7).
b
such as the 1-(4-methylpiperidinyl) derivative 29 showed consid-
erably diminished potency in the HIV-1 pseudotype assay, hetero-
aromatics were found to offer the desired potency increases. The
effect of incorporation of heteroaromatic rings at C-7 of indoles
and azaindoles has been described, but the SARs are unique within
each indole core series.27,30,34–37 When C-linked, six-membered
heteroaromatics were incorporated into the 4,6-diazaindole
chemotype, two molecules, the 2-pyridinyl derivative 17 and the
2-pyrazinyl analog 20, were found to be at least 10-fold more po-
tent than the 7-methoxy analog 13 and moderately more potent
than 2. As the nitrogen of the pyridine ring was moved away from
the bond coupling to the diazaindole heterocycle, activity was re-
duced, as can be noted by the 3-pyridinyl analog 18 and 4-pyridi-
nyl 19 congeners which had EC50 values of 1.3 and 12 nM,
respectively. This trend was also observed in the C-linked, six-
membered heteroaryl series that probed incorporation of two
nitrogen atoms into the heteroaryl moiety. Thus, the 5-pyrimidinyl
derivative 22 and 4-pyridazinyl analog 21 were 10-fold and 20-fold
less potent than the 2-pyrazine 20, respectively. While the bound
conformation of these compounds in gp120 has not been estab-
lished, these results and potency data within this series can be ex-
plained by a mnemonic that relies upon coplanarity between the
C-7 substituent and the core heterocycle. This mnemonic predicts
superior potency for heteroaryl rings attached to C-7 of the diaz-
aindole that can readily achieve coplanarity with the 4,6-diazain-
dole core.38 The coplanarity of the heteroaryl ring with the
azaindole may be enforced by the two potential hydrogen bonding
interactions depicted in Fig. 2. One is found between the indole NH
and a heteroatom (without a hydrogen or substitution) at the 2-po-
sition of the heteroaryl ring. The other is found between the 6-aza
nitrogen and a 20-CH (or NH) on the heteroaryl ring.39,40 Generally,
analogs lacking one or both of these potential interactions were
found to be less potent than similar analogs in which both were
Four molecules within the 4,6-diazaindole core series demon-
strated sufficient antiviral potency and in vitro ADME properties
to merit investigation in a rat pharmacokinetic experiment. The
compounds were each administered to rats as a single dose (IV
at 1 mg/kg and PO at 5 mg/kg) and plasma concentrations were
subsequently measured. The PK profile of the 1-(1,2,4-triazolyl)
derivative 27 proved to be markedly inferior to 2 while the 1-(3-
methyl-1,2,4-triazolyl) analog 28, although superior to 27, did
not show an improved PK profile compared with 2 (see Table 3).

J. A. Bender et al. / Bioorg. Med. Chem. Lett. 23 (2013) 218–222
221
Table 2
Potency and solubility of 4,6-diazindole core analogs with a 7-position 30-substituted N-linked pyrazole
O
O
N
N
N
N
O
N
H
Ph
N
N
R'
Compound
R0
HIV-1 EC50 (nM)
Solubilitya (mg/mL)
25
31
32
33
34
35
36
37
38
39
40
H
CH3
CO2H
CON(CH3)2
CON(CH2CH2)2NCH3
Ph
4-Fluorophenyl
4-Methoxyphenyl
2-Methoxyphenyl
0.05
0.15
0.76
2.0
0.054
0.008
1.07
ND
1.73
0.001
ND
0.001
0.004
0.060
0.008
4.8
0.28
<0.16
0.24
0.36
0.37
0.15
3-(Trifluoromethyl)-phenyl
2-Pyridinyl
a
Solubility of amorphous solids measured at pH 6.5.
More encouraging results were observed with the pyrazole com-
pounds where the 1-pyrazole derivative 25 and the 1-(3-meth-
ylpyrazoly) analog 31 demonstrated seven-fold and three-fold
increases in AUC and five-fold and three-fold decreases in the rate
of clearance, respectively.
achieved with the 4,6-diazaindole core, more promising molecules
were discovered in the 6-azaindole core series and as a result a
prodrug of a compound from that series, designated as BMS-
663068, was selected for advancement into clinical studies.25–30
In summary, the development of novel antiviral drugs with un-
ique mechanisms and resistance profiles remains an important
goal of HIV-1 research. One such approach seeks HIV-1 attachment
inhibitors, a class where additional potentially beneficial attributes
have been identified preclinically, and compounds have demon-
strated efficacy in humans in clinical studies. The utility of the pio-
neering representative of this class, BMS-488043 (2) was limited
by a predicted high BID dose that relied upon a food effect to pro-
vide targeted exposure. An effort to discover molecules with supe-
rior potency and/or exposure when compared with 2 led to studies
described here that probed a 4,6-diazaindole core. From these
studies, it was found that small heteroaryl substituents at the
key 7-position of the 4,6-diazaindole core provided the most po-
tent analogs, and five-membered ring heteroaromatics provided
the highest therapeutic indexes. The discovery that certain hetero-
aromatic analogs, such as 2-pyridine 17, N-linked pyrazole 25, and
N1-linked 1,2,4-triazole 27, were more potent than others (such as
4-pyridine 12, and N2-linked 1,2,3-triazole 26) is consistent with a
mnemonic in which the ability of the 7-substituent and the core
heterocycle to attain a coplanar arrangement can be used to pre-
dict relative potency. Aromatic heterocyclic compounds that fit
this mnemonic were found to have improved potency when com-
pared with 2, and two compounds, 25 and 31, exhibited a superior
rat pharmacokinetic profile. Although the goal of realizing an
improvement in the combined exposure and potency of 2 was
Acknowledgment
The authors would like to gratefully acknowledge the contribu-
tions of Dr. Gregory Yamanaka to the antiviral data presented in
this manuscript.
References and notes
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Table 3
Rat pharmacokinetic properties of compounds 25, 27, 28 and 31 compared with BMS-
488043 (2)
2
25
27
28
31
F%
90
6.3
13
60
47
2.6
15
0.83
35
19
4.9
7.6
45
17.8
4.8
AUC p.o. (uM⁄hr)
CL iv (mL/min/kg)
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