Nucleotide competing reverse transcriptase inhibitors: Discovery of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.02.021

A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2- one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.

Full text of DOI:10.1016/j.bmcl.2013.02.021

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2781–2786
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Nucleotide competing reverse transcriptase inhibitors: Discovery
of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived
inhibitors
⇑
Clint A. James , Patrick DeRoy, Martin Duplessis, Paul J. Edwards, Teddy Halmos, Joannie Minville,
⇑
Louis Morency , Sébastien Morin, Bruno Simoneau , Martin Tremblay, Richard Bethell,
Michael Cordingley, Jianmin Duan, Louie Lamorte, Alex Pelletier, Daniel Rajotte, Patrick Salois,
Sonia Tremblay, Claudio F. Sturino
Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5
a r t i c l e i n f o
a b s t r a c t
Article history:
A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon
further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor
(NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when com-
bined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic
amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated
excellent antiviral potency and improved physicochemical properties.
Received 17 December 2012
Revised 24 January 2013
Accepted 1 February 2013
Available online 13 February 2013
This manuscript is dedicated to the memory
of a respected friend and colleague, Dr. Louis
Morency.
Ó 2013 Published by Elsevier Ltd.
Keywords:
Reverse transcriptase
NcRTI
HIV-1
Benzofuranopyrimidone
Nucleotide competing
In 2011, the United Nations estimated that 34 million people
worldwide were infected with the Human Immunodeficiency Virus
(HIV).1 Additionally, more than 2 million new cases of infection
were reported, and the number of AIDS related deaths was
estimated at 1.7 million.2 Currently marketed treatments for HIV
fall into six major categories: chemokine antagonists,3 fusion
inhibitors,4 integrase inhibitors,5 protease inhibitors,6 nucleoside/
nucleotide (NRTI)7 and non-nucleoside inhibitors (NNRTI).8
Together the two classes of reverse transcriptase (RT) inhibitors
make up almost half of all the available treatments. A few years
ago, a new class of RT inhibitors has been reported.9 Similar to
the NRTI’s, biochemical studies showed these compounds to be
competitive with the next incoming nucleotide and consequently
they were termed nucleotide-competing reverse transcriptase
inhibitors (NcRTI’s).10 Like the NNRTI class, these inhibitors are
structurally distinct from the deoxyribonucleotide triphosphates
(dNTPs), and in contrast to the NRTI’s they are not chain termina-
tors. As a result of these differences relative to the established clas-
ses of RT inhibitors, the NcRTI class presents a distinct resistance
profile, rendering this an attractive mode of inhibition of this
enzyme.
The tricyclic urea 1 (Fig. 1) arose as a promising lead based on
initial optimization of the potency and cytotoxicity index of a hit
derived from a high throughput screening campaign. Early SAR
around this core revealed that all three pharmacophores were tol-
erant of basic functionality and this resulted in improved antiviral
activity. Profiling data of inhibitor 1 showed promising metabolic
stability in human and rat liver microsomal preparations but poor
apical to basolateral (AB) permeability in Caco-2 monolayers,
presumably as a result of the highly basic nature of two of the
three pharmacophores.11 Sequential removal of the basic amines
showed that the presence of only one was sufficient to maintain
satisfactory levels of antiviral potency. With this knowledge of
the SAR, the initial strategy to optimize the series was to maintain
⇑
Corresponding authors. Tel.: +1 450 682 4641x4154 (C.A.J.); tel.: +1 450 682
4641x4228; fax: +1 450 682 4189 (B.S.).
E-mail addresses: clint.james@boehringer-ingelheim.com (C.A. James), bruno.si-
moneau@boehringer-ingelheim.com (B. Simoneau).
Dr. Louis Morency passed away suddenly on July 24, 2012.
0960-894X/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.02.021

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C. A. James et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2781–2786
whereas a significant increase was observed with the five-atom
O
n-pentyl group (entry 10). Interestingly, compound 10 containing
an n-butyl group was found to be significantly more active than
the corresponding ether analogue 2, however, there was no differ-
ence between the 5-atom analogues 3 and 11. The addition of
branching substituents seemed to be less well tolerated as illus-
trated by the four fold loss of potency observed between the
n-Bu analogue 10 and 12 (entries 9 and 11). This effect was also ob-
served in the ether series as demonstrated by 14 (entry 13) and 15
(entry 14) which incorporated a methyl group on the chain and
showed a 5 to 15-fold loss in activity. Interestingly, an eutomer ef-
fect was observed with these two analogues, the analogue with R
stereochemistry being more potent. Further exploration demon-
strated that larger substituents such as 3-phenylpropyl (entry
15) and substituents containing a polar group such as acid (entry
16) and ester (entry 17), were poorly tolerated. Aromatic substitu-
tions at the N-1 position resulted in very potent analogues;
however, these compounds generally displayed unsatisfactory lev-
els of cytotoxicity (entry 19). Taken together, these results demon-
strated a clear preference for straight chain lipophilic groups at the
N-1 position and that both the n-pentyl and 3-methoxypropyl
groups would serve as useful substituents to elucidate the SAR at
other positions.
Having demonstrated that the N-1 position allowed significant
improvements in potency while maintaining a single basic amine,
efforts were undertaken in order to improve the in vitro profile of
monobasic analogues. Previous SAR had shown that the presence
of a basic amine at the C8 position was associated with significant
hERG inhibition as well as an increase in the number of hits in an
off-target pharmacology panel. Since these issues were substan-
tially less pronounced for analogues containing a basic group at
C4, the initial strategy was to maintain the basic amine at this po-
sition in conjunction with the 3-methoxypropyl group at N-1 as
the key pharmacophores to drive the potency (Table 2). Prelimin-
ary SAR demonstrated that constricting the N-ethylglycineamide
into an alkylpiperazine (22–23) maintained potency and also affor-
ded a modest increase in permeability. Therefore, subsequent SAR
was aimed at decreasing the pKa of the amine to further improve
the Caco-2 permeability. More than sixty compounds covering a
range of pKa values were prepared, several of which demonstrated
significant improvements in Caco-2 permeability (e.g., entries 4, 5
and 7). In fact, consideration of a series of these compounds
showed a trend indicating a dependence of the Caco-2 permeabil-
ity on the calculated pKa (data not shown).13 Analogs with a calcu-
lated pKa of 8 or higher were associated with Caco-2 permeability
less than 5 Â 10À6 cm/s. Unfortunately, while it was clear that
attenuating the pKa of the compounds could afford significant
improvements in permeability, no compounds were discovered
that maintained both metabolic stability and acceptable
permeability in this series. Additionally, the less basic compounds
generally displayed reduced antiviral activity (entry 3 vs 7). Inter-
estingly, it was shown that the piperazinyl pyridine analogues (e.g.,
27) possessed similar activity and in vitro profiles relative to their
non-aza counterparts (entry 2). Consequently, this modification
was adopted in further SAR studies in order to mitigate the poten-
tial for genotoxicity associated with the presence of an aniline.14
Concurrent SAR focused at C-8 revealed that small heterocycles
were viable replacements for the basic amine of 1 or the halogen of
22. A number of heterocycles were introduced including various
regioisomers of substituted pyrazoles, thiazoles, oxazoles and pyr-
idines. The five-membered heterocycles were generally well toler-
ated and the 4-substituted regioisomers were usually preferred. In
particular 1-methylpyrazole-4-yl became a preferred substituent
at this position (e.g., 29, Table 3). Not only did this group result
in an analogue with excellent enzyme and cell based antiviral
O
Me
N
1
N
N
8
4
O
1
O
IC50 : 4 nM
EC50 : 30 nM
N
H
NHEt
CC50 : 4.1 µM
HLM CL (%QH) : 29%
RLM CL (%QH) : 11%
Caco-2 AB (10-6 cm/s) : <0.1
Figure 1. Benzofurano[3,2-d]pyrimidin-2-one lead scaffold.
a single basic amine to drive the potency and attenuate the basicity
of the inhibitors in order to improve the in vitro profile, in partic-
ular the permeability. This would also reduce the potential risk for
undesirable off-target activities associated with highly basic and
lipophilic compounds (e.g., phospholipidosis12).
Initially, the optimization of the series began with a detailed
investigation of the N-1 position for which previous investigations
had demonstrated the potential to improve potency. To facilitate
generation of SAR, a model analogue was selected containing a
benzylamine moiety at C8 as the only basic functional group (Table
1). The parent analogue 2 containing the 2-methoxyethyl substitu-
ent at N-1 (entry 1) showed weak activity on this unoptimized
scaffold. Remarkably, extending the ether chain by one methylene
unit resulted in a 60-fold increase in activity (entry 2). Further
extending the chain resulted in 4, which showed no additional
advantage. In the hydrocarbon series, a more detailed investigation
could be undertaken. Shorter analogues ranging from methyl to i-
Bu (entries 4–8) showed relatively poor but similar potency
Table 1
N-1 SAR
N
O
1
N
R
N
8
O
Entry
Compd
R
IC50 (nM)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
–(CH2)2OMe
–(CH2)3OMe
–(CH2)4OMe
Me
2330
39
86
645
890
>685 (45%)
800
655
42
27
190
55
635
195
>365 (25%)
>4700 (46%)
>1100 (14%)
245
Et
n-Pr
i-Pr
i-Bu
n-Bu
n-Pentyl
–(CH2)2CHMe2
–(CH2)3CHMe2
(S)-CH2CH(Me)CH2OMe
(R)-CH2CH(Me)CH2OMe
–(CH2)3Ph
–(CH2)3CO2H
–(CH2)3CO2Et
Ph
p-Nitrophenyl
4-Methyl-3-cyanophenyl
1.7
7.3
a
Values in parentheses are the percent inhibition at the highest concentration
achieved.
activity,
a significant improvement in cytotoxicity was also

C. A. James et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2781–2786
2783
Table 2
C4 SAR directed toward improving Caco-2 permeability
OMe
O
N
Cl
N
4
O
X
R
M)c
HLM CL (%QH)b
Caco-2 (10À6 cm/s)
a
Entry
1
Compd
X
R
cpKa
IC50 (nM)
2.8
EC50 (nM)
33
CC50
>8.6
(
l
O
N
H
22
CH
7.8
46
<0.1
2.7
NHEt
N
2
3
4
23
24
25
CH
CH
CH
8.2
8.8
8.1
9.1
1.7
13
35
25
2.3
2.7
51
28
52
N
N
N
0.3
8.9
N
H
290
>3.6 (20)
N
N
N
5
6
7
26
27
28
CH
N
7.0
8.0
6.9
10
130
37
>4.2
61
59
78
8.0
2.6
12
OMe
N
N
3
>3.2
N
N
N
8
56
NDd
OMe
pKa Values were calculated using ACD/PhysChem Suite version 12, ACD Labs, Toronto.
Microsomal clearance is reported as the measured t1/2 normalized with respect to the hepatic blood flow of the given species.
Values in parentheses are the percent inhibition at the highest concentration achieved.
ND = not determined.
a
b
c
d
observed. The excellent antiviral activity observed with the combi-
nation of optimized N-1 and C-8 substituents, along with the chal-
lenges encountered during our efforts to improve the
physicochemical properties of the series by attenuating the basi-
city of the amine (vide supra), prompted us to consider the trunca-
tion of the C-4 piperazine group thereby completely eliminating
the basic amine. Application of this strategy to piperazine 29
resulted in 30 which demonstrated a level of antiviral activity
which while reduced was nonetheless encouraging for a non-basic
inhibitor. Incorporation of the more potent n-pentyl fragment re-
sulted in 31 which for the first time gave a compound with excel-
lent antiviral activity but no strongly basic centers. Further
profiling of these analogues revealed that the methoxypropyl frag-
ment imparts good aqueous solubility whereas the n-pentyl ana-
logue 31 results in significantly increased lipophilicity as well as
poor solubility at pH 6.8. Given the disparity in the antiviral and
solubility data between analogues containing these N-1 substitu-
ents, a hybrid structure was sought which would maintain the
favorable properties of both. Further contemplation of the
structural similarity of these two fragments led to the tetra-
hydrofurylethyl moiety as in 32. Upon synthesis of the racemic
analogue 32 we were delighted to observe that this compound,
containing no basic amine, showed an EC50 value of 13 nM and
excellent aqueous solubility at both pH 2 and 6.8.
Encouraged by these results we initiated a synthesis of the indi-
vidual enantiomers of 32 (see Schemes 1 and 2). Given the poor
metabolic stability of 32, the chiral N-1 fragments were grafted
onto the more optimized 6-aza core (Table 4). Previous SAR
indicated that this modification had a beneficial effect on both
the lipophilicity and microsomal stability of the series. In the

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C. A. James et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2781–2786
Table 3
Discovery of non-basic inhibitors
O
O
O
O
N
N
N
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
29
30
31
32
NH
NH
NH
N
Compd
29
30
31
32
IC50 (nM)
EC50 WT (nM)
3
6
4
2
1.5
13
3.8
61
148
>17
50
18
4.0
81
9.8
CC50
(
l
M)
>21.7
67
0.4
HLM CL (%QH)a
Caco-2 (10À6 cm/s)
1.6
3.1
Sol. pH 2/6.8 (
logD
lg/mL)
>1000/>1000
3.0
>1000/>1000
>1000/0.27
4.7
>1000/>984
3.4
NDb
MW
513
444
442
470
a
Microsomal clearance is reported as the measured t1/2 normalized with respect to the hepatic blood flow of the given species.
ND = not determined.
b
event, an eutomer effect was observed and the S enantiomer 33
proved to be slightly more potent. Additionally, the 6-aza modifi-
cation showed the expected improvement in the metabolic stabil-
ity in human liver microsomes and the excellent aqueous solubility
of 32 was retained in the chiral analogue 33. Despite the relatively
poor Caco-2 permeability, the promising overall profile and good
potency without the necessity of a basic functional group repre-
sented a significant advancement of the series.
inhibitors (Table 5). As expected, the potency of analogue 33 was
not affected by the NNRTI-induced resistance mutation Y188L.
Similarly, the NNRTI-resistance mutation K103N/Y181C was fully
susceptible to inhibition by analogue 33. Consistent with observa-
tions made for other NcRTI’s,9b,c the K65R RT mutant virus (resis-
tance mutation to NRTI’s such as tenofovir) was hypersusceptible
to inhibition by compound 33 compared to wild type virus. Limited
cross-resistance was observed between compound 33 and the NRTI
class. Viruses harboring the M184V mutation, displayed a fourfold
shift in EC50 values. In addition, the thymidine associated muta-
Compound 33 was profiled against a number of recombinant
viruses with resistant mutations to known reverse transcriptase
O
H
N
OEt
NH2
O
Br
O
a
Br
CN
Cl
Br
O
b
+
HO
OEt
O
(40%)
OEt
(90%)
N
O
OEt
N
N
37
36
35
O
O
O
O
O
O
N
N
N
N
N
OEt
O
B
N
OEt
O
c
Br
e
d
OH
O
OEt
N
O
OEt
N
O
(S)-40 (43%, 2 steps)
(R)-40 (10%, 2 steps)
(S)-39
(R)-39
(S)-38
(R)-38
O
O
O
O
N
N
N
N
N
N
N
OEt
O
f
O
N
O
N
N
N
F
NHMe
(S)-33 (52%)
(R)-34 (20%)
(S)-41 (61%)
(R)-41 (85%)
Scheme 1. Reagents and conditions: (a) Cs2CO3, DMF, 90 °C; (b) ClCO2Et, Na2CO3, toluene, reflux; (c) DIAD, PPh3, THF; (d) K2CO3, Pd(dppf)Cl2, dioxane, H2O, 90 °C; (e) 2-
bromo-5-fluoropyridine, n-BuLi, THF, À78 °C; (f) (i) MeNH2, DMSO, 90 °C; then (ii) NH4OAc, 130 °C.

C. A. James et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2781–2786
2785
O
O
O
a
b
c
O
O
O
N+
N
O
HO
OMe
OH
(S)-42
(R)-42
(S)-43 (79%)
(R)-43 (83%)
(S)-44 (62%)
(R)-44 (56%)
(S)-38 (50%)
(R)-38 (91%)
Scheme 2. Reagents and conditions: (a) (i) Ethyl chloroformate, Et3N,THF, À20 °C; (ii) CH2N2 (b) PhCO2Ag, Et3N, MeOH, 0 °C; (c) LiAlH4, THF.
then incorporated via the Mitsunobu15 reaction of either (R)- or (
S)-2-(tetrahydrofuryl-2-yl)ethanol (Scheme 2). Suzuki–Miyaura16
coupling allowed introduction of the C-8 pyrazole in low to modest
yield over two steps. The lower yield at this stage is presumably a
consequence of the Mitsunobu reaction, the product of which was
invariably contaminated with significant amounts of DIAD related
by-products even after repeated chromatography. Consequently,
purification was best achieved after the Suzuki–Miyaura cou-
pling.17 Incorporation of the C-4 pyridine ring was accomplished
by treatment of a mixture of 40 and 2-fluoro-5-bromopyridine in
THF with n-BuLi followed by quench at low temperature (HOAc
in THF) to afford ketone 41. Treatment with methylamine was fol-
lowed by heating the resulting product in fused NH4OAc at 130 °C
to accomplish the formation of the pyrimidone ring. Analogues
contained in Tables 1–3 were prepared using similar methods.18
The preparation of the required chiral alcohols 38 was carried
out as shown in Scheme 2. The Arndt–Eistert19 protocol was
utilized as the key step of the sequence. Conversion of the commer-
cially available acid 42 to the mixed anhydrides followed by treat-
ment with excess diazomethane gave the diazoketones 43 in good
yield. Silver mediated Wolff rearrangement19a of 43 in MeOH gave
the corresponding methyl esters in acceptable yield. Finally, LAH
reduction of 44 afforded the desired chiral alcohols 38 in good
yield.
Table 4
In vitro profiles of 33 and 34
O
O
(R)
(S)
O
O
N
N
N
N
N
N
N
N
O
O
N
N
N
N
33
34
N
H
N
H
Compd
33
34
IC50 (nM)
EC50 WT (nM)
CC50
HLM CL (%QH)a
Caco-2 (10À6 cm/s)
Sol. pH 2, 6.8 ( g/mL)
2
6.0
116
—
29
19.7
>8.2
25
2.8
>844, >928
(
lM)
2
l
>871, 1.2
a
Microsomal clearance is reported as the measured t1/2 normalized with respect
to the hepatic blood flow of the given species.
Table 5
In conclusion, we have optimized a series of benzofurano[3,2-
d]pyrimidin-2-one derived nucleotide-competing reverse trans-
criptase inhibitors. Incorporation of appropriate substitution at
the N-1 position in combination with heterocycles at C-8 gener-
ated analogues with excellent antiviral potency and obviated the
necessity for a basic amine. Further modifications showed that
the (S)-2-(tetrahydrofuryl-2-yl)ethyl group provided a potent ana-
logue with improved aqueous solubility. Efforts toward the further
optimization of the in vitro profile of the series as well as the im-
pact on the susceptibility to M184V and TAM-1 complex will be re-
ported elsewhere.
Antiviral profile of 33 versus RT resistant mutations
Virus
EC50 (nM)
Fold (vs WT)
WT
Y188L
19.7
20
—
1
2
0.19
3.9
7.4
1.4
0.19
K103N/Y181C
K65R
39
3.7
M184V
78.3
147.5
27
TAM-1a
TAM-2b
Q151M complexc
3.7
a
b
c
TAM-1 = M41L/T67N/L210W/T215Y/K219E.
TAM-2 = M41L/D67N/K70R/T215F/K219E.
Q151M complex = A62V/V75I/F77L/F116Y/Q151M.
Acknowledgements
tions (TAM-1) complex displayed a sevenfold loss in susceptibility
to compound 33 while a mutant bearing the Q151M mutation
complex was hypersusceptible (fivefold) to inhibition. Overall,
compound 33 displays minimal to no cross-resistance with both
NRTI and NNRTI classes which suggests that an NcRTI may be
appropriate for dosing in combination with other HIV RT
inhibitors.
We gratefully acknowledge the following: Patrick Salois and
Alex Pelletier for IC50 data, Hugo Poirier for Caco-2 permeability
data, Josie DeMarte and Frederico Colombo for microsomal stabil-
ity data, Dr. Laibin Luo, Danhui Sun and Eduard Bugan for solubility
and LogD determinations.
Supplementary data
Synthesis
Supplementary data (a description of the enzymatic and cell
based assays (antiviral and cytotoxicity), as well as methods for
Caco-2 permeability, solubility, metabolic stability in microsomes,
logD and solubility. Schemes describing the general synthesis of
the compounds not covered in Schemes 1 and 2 are also included)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2013.02.021. These data include
The synthesis of compounds 33 and 34 is outlined in Scheme 1.
A one-pot condensation–cyclization sequence of ethyl glycolate
with the commercially available chloropyridine 35, afforded the
aminobenzofuran 36 in modest to good yield. Carbamoylation with
ethyl chloroformate gave 37 onto which the N-1 substituent was

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C. A. James et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2781–2786
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MOL files and InChiKeys of the most important compounds
described in this article.
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6. Ghosh, A. K.; Andersen, D. D.; Weber, I. T.; Mitsuya, H. Angew. Chem., Int. Ed.
2012, 51, 1778.
17. A preparation of 32 (the racemic analogue of 33) was carried out using the
corresponding mesylate in an alkylative process which resulted in good yields
of alkylated product and straightforward purification of 39. This sequence also
demonstrated that the cross coupling was a high yielding process:
7. Cihlar, T.; Ray, A. S. Antiviral Res. 2010, 85, 39.
O
Cs2CO3, DMSO,
O
O
O
O
O
O
rt, 24h
N
N
H
B
N
N
OEt
O
N
N
OEt
O
N
OEt
O
Br
Br
OMs
O
PdCl2dppf, NaHCO3
O
OEt
N
O
O
OEt
OEt
N
N
DMF, 90°C
(94%)
(79%)
rac-39
37
rac-40
8. Jochmans, D. Virus Res. 2008, 134, 171.
18. For general schemes for the preparation of these compounds see the
Supplementary data. For further details see: Sturino, C.; Deroy, P.; Duplessis,
M.; Edwards, P. J.; Faucher, A.-M.; Halmos, T.; James, C.; Lacoste, J.-E.;
Malenfant, E.; Minville, J.; Morency, L.; Morin, S.; Tremblay, M.; Yoakim, C.
WO 2010115264, 2010.
9. For a review see: (a) Maga, G.; Radi, M.; Gerard, M.-A.; Botta, M.; Ennifar, E.
Viruses 2010, 2, 880; For the original publications see: (b) Jochmans, D.; Deval,
J.; Kesteleyn, B.; Van Marck, H.; Bettens, E.; De Baere, I.; Dehertogh, P.; Ivens, T.;
Van Ginderen, M.; Van Schoubroeck, B.; Ehteshami, M.; Wigerinck, P.; Götte,
M.; Hertogs, K. J. Virol. 2006, 80, 12283; (c) Zhang, Z.; Walker, M.; Xu, W.; Shim,
J. H.; Girardet, J.-L.; Hamatake, R. K.; Hong, Z. Antimicrob. Agents Chemother.
2006, 50, 2772.
19. (a) Kirmse, W. Eur. J. Org. Chem. 2002, 14, 2193; (b) Ye, T.; McKervery, M. A.
Chem. Rev. 1994, 94, 1091.