Inhibitors of HIV-1 attachment. Part 8: The effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.10.117

As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.

Full text of DOI:10.1016/j.bmcl.2012.10.117

Bioorganic & Medicinal Chemistry Letters 23 (2013) 203–208
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibitors of HIV-1 attachment. Part 8: The effect of C7-heteroaryl substitution
on the potency, and in vitro and in vivo profiles of indole-based inhibitors
Kap-Sun Yeung a, , Zhilei Qiu a, Zhiwei Yin a, Ashok Trehan a, Haiquan Fang a, Bradley Pearce a,
⇑
Zheng Yang a, Lisa Zadjura a, Celia J. D’Arienzo a, Keith Riccardi a, Pei-Yong Shi a, Timothy P. Spicer a,
Yi-Fei Gong a, Marc R. Browning a, Steven Hansel a, Kenneth Santone a, Jonathan Barker b,
Thomas Coulter b, Ping-Fang Lin a, Nicholas A. Meanwell a, John F. Kadow a
a Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA
b Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK
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
As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment
inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered
heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a pri-
mary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory
activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained
the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmaco-
kinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV
clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability
as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the
highest exposure.
Keywords:
HIV-1 attachment inhibitors
Indole glyoxamide
Heterocycles
Ligand efficiency
Lipophilic ligand efficiency
Ó 2012 Elsevier Ltd. All rights reserved.
Despite the fact that highly active anti-retroviral combination
therapy (HAART) has substantially decreased mortality and trans-
formed human immunodeficiency virus-1 (HIV-1) infection into a
chronic disease,1 issues associated with the persistence of drug-
resistant HIV-1 mutant viruses, drug toxicity and patient non-com-
pliance related to the long-term therapy as well as the appearance
of co-morbidities remain.2 Therefore efforts to discover clinically
effective inhibitors that act at new viral targets and are not cross-
resistant to current drugs are much needed in order to help over-
come these enduring problems in the treatment of HIV-1 infection.3
The attachment of the HIV-1 envelope glycoprotein gp120 to
the CD4 receptor expressed on the host cell surface is essential
for the viral entry into the host cells. The completion of this first
step initiates the binding of the gp120/CD4 complex to a co-recep-
tor (CCR5 or CXCR4), which is followed by rearrangement of the
viral transmembrane protein gp41. The formation of a six helical
bundle between N- and C-terminal heptad repeats of gp41 pro-
motes fusion between the viral and host cell membranes. This se-
quence of events eventually results in the release of the viral
genetic material into the host cell.4 Indole- and azaindole-oxoace-
tic piperazinyl benzamide HIV-1 attachment inhibitors, which
interfere with the protein-protein interaction between gp120 to
CD4 by binding to the CD4 binding site in gp120, were previously
reported from these laboratories.5–10 Clincial proof-of-concept for
an antiviral effect of this novel inhibition mechanism has been
demonstrated by the 6-azaindole BMS-488043 in HIV-1-infected
patients.7e,8
An initial structure-activity-relationship (SAR) survey of the ef-
fect of variation of simple substitutions on the indole nucleus of 17b
led to the identification of the early lead compound 2 (Table 1) that
achieved a >100-fold increase in potency and accompanied by a
marked improvement in ligand efficiency. Following that work,
substitution at the C7 position of 2 was explored in order to further
define the SAR around this region of the molecule, and as an ave-
nue to modulate the physicochemical property of the inhibitors.
The SAR associated with a series of C7 amide analogs of 2 has been
disclosed7g and the results of studies with a variety of elaborated
5- and 6-membered heterocycles are described herein. As shown
in Table 2, the initial indication that substitution at the C7 position
of 2 with an aryl ring may be beneficial was provided by the simple
phenyl analog 3, which showed a modest 3-fold increase in po-
tency compared to 2 in a single cycle infection assay against
JRFL-envelope-expressing pseudotyped virus.11 Follow-up probing
with 4-methoxyphenyl and pyridine rings (4–6) suggested that a
>10-fold potency enhancement was feasible. Subsequent substitu-
tion using a range of 5-membered heterocycles was even more
⇑
Corresponding author.
E-mail address: kapsun.yeung@bms.com (K.-S. Yeung).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.117

204
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 203–208
Table 1
HIV attachment inhibitors
O
R
O
N
N
O
N
1: R = H; 2: R = F
H
11
11
Compound
EC50 (nM)
CC50
(lM)
cLogP
LE
1
2
153
1.24
275
>300
2.21
2.43
0.25
0.32
Chart 1. Scatter plot of pEC50 against cLogP of the inhibitors shown in Table 2.
Table 2
encouraging, providing inhibitors 7–16 that exhibited sub-nano-
molar to picomolar potency in the primary assay. The thiazole ana-
log 9 and the oxazole analog 11 were especially potent as they
exhibited single-digit picomolar inhibitory activity. It appeared
that compounds with more lipophilic heterocycles, for example 3
and 7, had a propensity to exhibit higher levels of cytotoxicity, a
potential liability. However, highly potent compounds with
Antiviral activity and cytotoxicity of 4-F, 7-heteroaryl-indoles
F
O
O
N
N
R
HN
O
11
11
Compound
R =
EC50 (nM)
CC50
(lM)
cLogP
CC50 >300
sufficient selectivity window could be obtained from potent com-
pounds with CC50 <100 M. For example, the oxadiazole analog
lM were identified, for example, 11, 12 and 14, and a
3
0.43
6.8
4.32
l
13 had a ꢀ1500-fold safety index. Less productive was substitution
with [5,6]-fused heterocycles, as exemplified by compounds 17
and 18 that were >10-fold less potent than the best analogs.
An analysis and closer examination of the relationship of activ-
ity to cLogP values revealed that the potency of this series of inhib-
itors was not driven by intrinsic lipophilicity. Indeed, a plot of
pEC50 against cLogP (Chart 1) suggested that less lipophilic com-
pounds (cLogP <3) provided better potency. As represented in Ta-
ble 3, the ligand effeciency LE13 of 2 (0.32) was in general
maintained in these compounds with heterocycle substitution at
C7, despite an increase of approximately 20% in heavy atom count.
This is particular encouraging considering that the LE for inhibitors
of a protein-protein interaction is typically about 0.24.14 Moreover,
consistent with the observed general trend of potency versus lipo-
philicity, the lipophilic ligand efficiency (LLE)15 was substantially
improved. Remarkably, as suggested by lipophilicity-corrected LE
(LELP),16 about one Log unit less of lipophilicity was used per unit
of LE in these attachment inhibitors, for example, 11, 13, 15 and 16,
compared to the C7-unsubstituted 2. The phenomenon and the
improvement in LLE and LELP reflect that the putative binding
pocket surrounding the C7 substitutent is more polar in character
and that, rather than relying on non-specific hydrophobic contacts,
the interactions between the heterocycle and the pocket are likely
highly specific in nature.
MeO
4
5
0.04
0.12
21
17
4.24
3.03
N
6
0.06
10
2.82
N
7
8
0.06
0.01
5.3
4.17
3.96
S
27
23
S
N
S
9
0.0067
2.87
N
10
11
0.05
192
2.21
2.21
O
O
0.0054
>300
N
N
12
0.06
>300
2.36
N
H
N
13
14
0.05
0.05
74
1.88
0.98
O
N
N
N
The highly efficient 1,2,4-oxadiazole 13 and the tetrazole 16
were chosen as representative analogs to evaluate for activity
against several M-tropic and T-tropic viruses in cell culture. The
enhanced activity against JRFL-pseudotyped virus in a single cycle
>300
O
N
N
15
0.03
199
2.1112
N
H
Table 3
N
N
Efficiency of representative inhibitors as measured by ligand efficiency (LE), lipophilic
ligand efficiency (LLE) and lipophilicity-corrected LE (LELP)
N
HN
16
17
0.08
0.88
245
27
1.93
3.80
Compound
LE
LLE
LELP
N
2
9
11
13
15
16
0.32
0.34
0.34
0.31
0.32
0.31
6.5
8.3
9.1
8.4
8.4
8.2
7.4
8.4
6.5
O
N
6.1
18
0.53
11
3.95
6.612
6.2
N
H

K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 203–208
205
Table 4
2 against Bal and NL4-3 viruses was significantly improved by het-
eroaryl substitution at C7.
Antiviral potency of compounds 13 and 16 against M-tropic and T-tropic viruses in
cell culture
Encouraged by the potent antiviral activity in cell culture of
these analogs, the effect of substitution of the C7 heterocycle ring
on potency was next examined in order to further probe the struc-
tural requirements of this region. This exercise was performed pri-
marily on the oxadiazole 13 and representative examples are
shown in Table 5. Substitution of the oxadiazole ring of 13 with
simple alkyl moieties, as exemplified by the methyl analog 19, lar-
gely maintained potency, while the isomeric methyloxadiazole 20
showed a similar level of activity. Introduction of heteroatoms was
not well tolerated as shown by the methoxy analog 21 and the
dimethylamino derivative 24. However, the presence of a hydro-
gen-bond donor (i.e., NH, as in 22 and 23) was associated with in-
creased potency with the aminooxadiazole 22 showing a 6-fold
improvement over 13. This requirement was also evident in amide
analogs 25 and 26, although steric encumberance around the NH
a
Compound
EC50 (nM)
pdt-JRFL11
EC50 (nM)
BRU
Bal
NL4-3
1500
2
13
16
1.24
0.05
0.08
700
7.61
0.37
90
3.38
6.38
8.66
9.41
a
JRFL-pseudotyped virus.
infection assay shown by 13 and 16 compared to 2 extended to
their activities in cell culture. As shown in Table 4, analogs 13
and 16 displayed single digit nanomolar to sub-nanomolar potency
toward the M-tropic Bal virus as well as the T-tropic viruses BRU
and NL4-3 in cell culture. In particular, the inhibitory potency of
Table 5
Antiviral activity and cytotoxicity of substituted analogs of compounds 13, 15 and 16
X
O
N
O
N
R
HN
O
Y
11
11
Compound
R =
X
F
Y
EC50 (nM)
CC50
(lM)
cLogP
N
19
H
0.06
226
2.15
O
N
N
20
21
F
F
H
H
0.094
>300
2.15
2.81
N
O
MeO
N
N
3.55
44
43
O
H2N
N
22
23
F
F
H
H
0.0082
1.86
2.61
O
O
N
H
N
N
N
0.04
0.30
0.10
26
23
N
N
N
24
25
F
F
H
H
2.78
2.01
O
H
N
N
N
229
O
O
NH2
N
O
26
27
F
F
H
0.10
0.16
154
159
1.49
O
N
N
N
H
H
2.3712
N
H
N
28
29
30
OMe
0.16
0.04
0.07
22
125
1.72
2.40
2.45
O
O
N
N
F
F
Me
Me
N
N
N
HN
>300
N

206
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 203–208
Table 7
group and its position appeared to contribute to the slight decrease
in potency compared to 13. In contrast to the methyloxadiazoles
20 and 21, the methyltriazole 27 was about 5-fold less potent than
the parent triazole 15. The general relationship between potency
and lipophilicity as described above was again observed with these
substituted heterocycle analogs, and highly lipophilic ligand effi-
cient compounds could once more be achieved (e.g., 22: LE 0.33,
LLE 9.2 and LELP 5.6). Earlier SAR studies on 1 had shown that in
addition to a fluorine atom,7b a methoxy group at C4 conferred po-
tency to the indole chemotype and was another preferred substitu-
ent at this site. The introduction of an (R)-methyl group to the
piperazine ring generally provided a beneficial effect on potency
of C7-unsubstituted indole inhibitors.7d These two modifications
were incorporated into the C7-heteroaryl series to determine the
effect on potency. The 4-OMe derivatives of C7-heteroaryl com-
pounds were in general equipotent to the analogs in the 4-F series,
although modest changes in potency were observed with some
analogs. For example, the 4-methoxy-7-oxadiazolyl analog 28
was 3-fold less potent than the 4-F analog 13. The effect of the
addition of an (R)-methyl group to the piperazine ring on potency
of 4-F-7-heteroaryl-indole inhibitors was more dependent on the
heterocycle substituent at C7. For example, the (R)-methylpipera-
zine analogs of oxadiazole 29 and tetrazole 30 were equipotent
to the corresponding piperazine analogs 13 and 16, respectively.
When dosed orally to rats, the extremely potent oxazole 11 and
the oxadiazole 13 showed better oral bioavailability (F%) than 2. In
contrast, triazole 15 and tetrazole 16 showed low to negligible oral
bioavailability (Table 6). The highly permeable 13 provided the
highest exposure among these analogs, while the tetrazole 16 that
exhibited limited membrane permeability was at the opposite end
of spectrum. The oral exposure in rats appeared to be dependent
on the membrane permeability of the compound as measured in
Caco-2 cells at pH 6.5 (Table 7) which improved with increasing
lipophilicity at pH 6.5, as suggested by their calculated ACDLogDpH
6.5 values. For example, the oxadiazole analog 13 is more liphophil-
ic than the oxazole 11 at pH 6.5 (ACDLogDpH 6.5 0.00 vs À0.11) and
thus apparently more permeable than 11, although intrinsically 13
is more polar than 11 according to their cLogP values (1.88 and
2.21, respectively). The increase in lipophilicity of 13 at pH 6.5
compared to 11 is consistent with a stronger hydrogen bonding
Human liver microsomal (HLM) stability and Caco-2 permeability (Pc) of C7-
heteroaryl-indoles
X
O
O
N
N
R
HN
O
Y
Compound
R
X
Y
HLM
T1/2 (min)
Caco-2 Pca
pH 6.5 (nm/s)
2
H
F
F
H
H
>100
100
O
11
2.9
122
N
N
12
F
H
16
37
N
H
N
13
14
28
F
H
H
H
17
10
16
>300
N.D.
148
O
N
N
N
F
O
N
OMe
O
N
H2N
N
N
22
15
F
F
H
H
17
32
69
19
O
N
N
N
N
H
N
27
F
H
25
89
N
H
N
N
16
30
F
F
H
>200
>100
17
HN
N
N
N
Me
<15
HN
N
a
Metoprolol and mannitol were used as reference agents; N.D. = not determined.
Table 6
capacity of the oxazole nitrogen atom based on the pKBHX scale.17
Due to the acidicity of the NH of the tetrazole analog 16 (calculated
pKa = 4.2), the compound likely partitions in its ionized state at pH
6.5. The tetrazole analog 16 is therefore very polar at pH 6.5 (ACD-
LogDpH 6.5 = À1.71, cLogP = 1.92) and hence showed poor mem-
brane permeability.
Rat oral pharmacokinetic parameters of C7-heteroaryl-indoles
F
O
O
N
N
R
HN
O
Also as shown in Table 6, the C7-heteroaryl-indole analogs
demonstrated a substantial improvement in intravenous clearance
(IV CL) and half-life in rats compared to 2. In contrast to these
in vivo findings in rats, heterocycle substitution at C7 of 2 dramat-
ically changed the metabolic stability of the compound in human
liver microsomes (HLM) (Table 7). In the molecular context of 2,
it appeared that the half-life (T1/2) in human liver microsomes of
these compounds did not correlerate with their inherent lipophil-
icity but rather depends on the type of heterocycle present at C7.18
The more polar and less oxidation-prone heterocycles, for example,
a triazole (15 and 27) and a tetrazole (16 and 30), provided reason-
able to excellent stability. Analog 11, which contains an oxazole
ring that is more susceptible to oxidative metabolism, was poorly
stable in HLM. The 1,2,4-oxadiazole analog 13, its 5’-amino analog
22 and 4-methoxy analog 28 all exhibited a modest stability in
HLM. Recent studies have shown that 1,3,4-oxadiazoles are in gen-
eral about one Log unit less lipophilic than 1,2,4-oxadiazoles and
Compound
R
Rat oral
F (%)
Cmax
(ng/ml)
IV CL
(ml/min/kg)
IV T1/2
(min)
2
H
a17
649
444
48
17
28
65
O
N
11
47
N
13
15
16
89
14
2.3
2606
369
95
3.9
3.7
3.1
120
187
67
O
N
N
N
N
H
N
N
HN
N
Rat: IV 1 mg/kg, PO 5 mg/kg, vehicle 90% PEG400/10% EtOH.
a
IV 5 mg/kg, PO 25 mg/kg.

K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 203–208
207
are more stable in HLM.19 Indeed, the equipotent, matched 1,3,4-
oxadiazole analog 14 of 13 is more polar than 13 (cLogP values
are 0.98 and 1.88, respectively). However, interestingly, 14 was
less stable than 13 in the same HLM assay. The 1,2,4-oxadiazole
analog 13, which possessed excellent Caco-2 permeability (Pc
(pH 6.5) >300 nm/s), showed the best pharmacokinetic properties
and displayed the highest oral exposure and bioavailability in rats
amongst this series of compounds. This compound also exhibited
activity against M- and T-tropic viruses in cell culture at nanomo-
lar concentrations. However, inhibitor 13 was predicted to be a
high clearance compound in human based on its half-life of
17 min in human liver microsomes, and thus further characteriza-
tion of this molecule was not pursued.
tween this acid chloride and benzoylpiperazine afforded the
pivotal intermediate 34, which was derivatized to the various 5-
membered C7-heterocycle analogs, for example, the oxadiazole
13 and the tetrazole 16, under conventional conditions. Com-
pounds 3 to 9 were synthesized via Stille or Suzuki coupling under
standard conditions using the 7-bromo counterpart of 34 as the
key intermediate. The 4-methoxy and (R)-methylpiperazine ana-
logs compiled in Table 5 were prepared in a similar manner.
References and notes
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at the C7 position of the lead indole-based compound 2. Many
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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; Part 7: (g)
Yeung, K.-S.; Qiu, Z.; Xue, Q.; Fang, H.; Yang, Z.; Zadjura, L.; D’Arienzo, C. J.;
Eggers, B. J.; 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.
2012, 22 accepted for publication.
aryl substituent that was advanced to clinical studies as
a
phosphonoxymethyl prodrug, BMS-663068.9,10
The syntheses of compounds 13 and 16 were accomplished by
the routes shown in Scheme 1 which are representative of the syn-
theses of the series of 5-membered C7-heterocycle analogs that
have been described.20 Accordingly, 7-bromo-4-fluoroindole 31
was converted to the 7-cyano analog 32, which underwent Fri-
edel–Crafts acylation to provide the acid chloride 33. Coupling be-
8. Hanna, G. J.; Lalezari, J.; Hellinger, J. A.; Wohl, D. A.; Nettles, R.; Persson, A.;
Krystal, M.; Lin, P.; Colonno, R.; Grasela, D. M. Antimicrob. Agents Chemother.
2011, 55, 722.
9. (a) Nettles, R.; Schurmann, D.; Zhu, L.; Stonier, M.; Huang, S.-P.; Chien, C.;
Krystal, M.; Wind-Rotolo, M.; Bertz, R.; Grasela, D. Abstract 49, 18th Conference
Retroviruses Opportunistic Infections, Boston, MA, Feb 27–Mar 2, 2011.; (b)
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. M. J.
Infect. Dis. 2012, 206, 1002.
10. 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. 241th ACS National Meeting & Exposition, Anaheim, CA, United
States, Mar 27–31, 2011; MEDI-29.
11. The EC50 of test compounds in the single cycle infectivity assay against HIV
JRFL pseudotyped virus and the CC50 of the inhibitors were determined as
previously described in Ref. 6. Data reported were the means of two or more
experiments.
12. Molecular conformation as well as tautomeric form can have significant impact
on the lipophilicity calculations. The three tautomeric pairs of triazole analogs
O
Cl
F
F
F
O
a
b
O
+
N
N
H
N
H
HN
N
H
Br
CN
CN
31
32
33
O
O
N
N
O
O
N
O
N
O
F
F
c
d
e
13
N
H
N
H
35
f
CN
H2N
N
34
16
OH
15 and 27 and their cLogP and ACDLogDpH
values are shown below, and
6.5
those of T2 weere used in this paper. Tautomeric imidazole and tetrazole
analogs do not show a marked difference in calculated lipophilicity. This trend
of triazole T3 being more polar than T1 and T2 is consistent with the reported
general trend that 1,3,4-oxadiazoles being about 1 unit lower in LogP than
1,2,4-oxadiazoles; see Ref. 19.
Scheme 1. Synthesis of compounds 13 and 16. Reagents and conditions: (a) CuCN,
DMF, 145 °C, 17 h; (b) (ClCO)2, CH2Cl2, reflux, 3 days; (c) i-Pr2EtN, THF, rt, 16 h;
(d) HONH2ÁHCl, Et3N, EtOH, rt, 36 h; (e) HC(OEt)3 105 °C, 16 h; (f) NaN3, NH4Cl,
DMF, 85 °C; 12 h.

208
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 203–208
T1
T2
HN
T3
13. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
14. Wells, J. A.; McClendon, C. L. Nature 2007, 450, 1001.
15. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881.
16. Keserü, G. M.; Makara, G. M. Nat. Rev. Drug Disc. 2009, 8, 203.
17. Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. J. Med. Chem.
2009, 52, 4073.
N
N
HN
N
N
N
N
NH
1.49
−0.24
cLogP
2.11
2.11
0.24
18. Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J.
P. Chem. Res. Toxicol. 2002, 15, 269.
ACDLogDpH6.5 0.01
The three tautomers of triazole analog 15
19. Boström, J.; Hogner, A.; Llina`s, A.; Wellner, E.; Plowright, A. T. J. Med. Chem.
2012, 55, 1817; (b) Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.;
MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney, J.
Med. Chem. Commun. 2012, 3, 600.
20. For experimental procedures and analytical data of the compounds described
in this paper, see: Wallace, O. B.; Wang, T.; Yeung, K.-S.; Pearce, B. C.;
Meanwell, N. A.; Qiu, Z.; Fang, H.; Xue, Q. M.; Yin Z. U.S. Patent 6,573,262,
2003.
N
HN
N
N
HN
N
N
N
NH
cLogP
ACDLogDpH6.5
2.37
0.01
2.37
0.01
1.76
1.09
−
The three tautomers of triazole analog 27