Design and synthesis of benzenesulfonamide derivatives as potent anti-influenza hemagglutinin inhibitors

Article abstract of DOI:10.1021/ml2000627

Structural optimization of salicylamide-based hemagglutinin (HA) inhibitor 1 resulted in the identification of cis-3-(5-hydroxy-1,3,3- trimethylcyclohexylmethylamino)benzenesulfonamide 28 and its derivatives as potent anti-influenza agents. The lead compo

Full text of DOI:10.1021/ml2000627

LETTER
pubs.acs.org/acsmedchemlett
Design and Synthesis of Benzenesulfonamide Derivatives as Potent
Anti-Influenza Hemagglutinin Inhibitors
Guozhi Tang,*,† Xianfeng Lin,† Zongxing Qiu,† Wentao Li,† Lei Zhu,† Lisha Wang,† Shaohua Li,‡
Haodong Li,‡ Wenbin Lin,‡ Mei Yang,‡ Tao Guo,‡ Li Chen,† Daniel Lee,† Jim Z. Wu,† and Wengang Yang†
†Roche R&D Center China, Shanghai, 201203, China
‡WuXi Apptec Co., Ltd., Shanghai, 200131, China
S Supporting Information
b
ABSTRACT: Structural optimization of salicylamide-based hemagglutinin (HA) inhibitor 1 resulted
in the identification of cis-3-(5-hydroxy-1,3,3-trimethylcyclohexylmethylamino)benzenesulfonamide
28 and its derivatives as potent anti-influenza agents. The lead compound 28 and its 2-chloro
analogue 40 can effectively prevent cytopathic effects (CPE) caused by infection of influenza A/
Weiss/43 strain (H1N1) with EC50 values of 210 and 86 nM, respectively. Mechanism of action
studies indicate that 40 and its analogues inhibit the virus fusion with host endosome membrane by
binding to HA and stabilizing the prefusion HA structure. With significantly improved metabolic
stability, the reported series represents the first generation of orally bioavailable HA inhibitors that
have a good selectivity window and potential for further development as novel anti-influenza agents.
KEYWORDS: Anti-influenza, hemagglutinin, benzenesulfonamide, inhibitor
nfluenza-caused acute respiratory diseases in humans, birds,
and other mammals represent one of the major threats to
As with many other enveloped viruses, membrane fusion of
the influenza virus with a host cell is a key biological process
required for the successful release of viral genome into the cyto-
plasm.6 Hemagglutinin (HA), one of the influenza envelope
proteins, is a mushroomlike glycoprotein on the surface of viruses
that plays a pivotal role in host cell recognition and membrane
fusion. It has long been regarded as a potential target for anti-
influenza therapies. The stalk region of HA is genetically stable
among all 16 HA subtypes, and it constitutes the core fusion
machinery that undergoes irreversible structural rearrangements
and facilitates the fusion of viral envelope with host cell endo-
some membrane. It has been recently demonstrated that human
monoclonal antibodies binding to the stalk region of HA are able
to inhibit the fusion process and demonstrate broad spectrum
activities against HA phenotype group 1 influenza A viruses,
including human H1N1 and avian H5N1 strains.7,8 Besides new
vaccine strategies based on the consensus sequence of HA, there
has been particular interest in identifying and developing novel
small molecule HA inhibitors as well as antibodies against a broad
variety of flu viruses.9
I
public health.1 As a genus of the Orthomyxoviridae family, the
influenza A viruses have eight segmented RNA genomes and are
the most virulent human pathogens among the three types of
influenza viruses. Through frequent genetic drift and reassort-
ment of different viral strains, influenza A viruses rapidly and
continuously accumulate mutations to evade prevailing immu-
nities in the general population. Influenza A viruses not only
cause seasonal epidemics in the winter but also are able to un-
leash a major pandemic with a greater mortality and morbidity. In
the most recent influenza pandemic, the 2009 influenza A/H1N1
strain likely emerged from a genetic reassortment of human,
swine, and avian strains.2 Beyond those seasonal flu epidemics
and the recent H1N1 pandemic, there also have been concerns
about the far more lethal H5N1 avian flu strains and the possi-
bility of breakthrough of interspecies and interhuman transmis-
sion barriers through viral genetic mutations, which could have a
devastating effect on public health.3
Currently, the prevention and treatment of influenza A in-
fection rely on vaccination and a limited number of antiflu drugs
that inhibit two viral targets, M2 ion channel and neuraminidase.
Amantadine and rimantadine block the M2 ion channel but have
limited clinical use due to rapid emergence of drug resistance.4
Among the marketed neuraminidase inhibitors, oseltamivir is the
sole oral drug that has been widely used for the treatment of flu.
Nevertheless, the recently emerged oseltamivir-resistant H1N1
strain in the 2008ꢀ2009 flu season has been a cause for concern.5
In light of the persistent threat posed by influenza A viruses to the
public, there is an urgent need to develop new anti-influenza
agents with different mechanisms of action for therapeutic or
prophylactic purpose.
The development of orally bioavailable small molecule HA
inhibitors, especially those targeting the conserved stalk region of
HA, is expected to have enormous value for the treatment of
drug-resistant influenza infections. Many small molecule HA in-
hibitors such as cis-2-hydroxy-N-(5-hydroxy-1,3,3-trimethyl-cy-
clohexylmethyl)-benzamide (1),10 podocarpate ester (2),11 tri-
periden analogue (3),12 and 1-phenyl-cycloalkane carbamide
(4)13 have been implicated to have potential anti-influenza
Received: April 7, 2011
Accepted: June 7, 2011
Published: June 07, 2011
r
2011 American Chemical Society
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effects by stabilizing the HA structure and preventing its con-
formational change during the membrane fusion process
(Figure 1). On the basis of affinity-labeling studies and docking
predictions, 1 and its analogues were claimed to bind to a hydro-
phobic pocket in the stalk region of HA and demonstrated good
anti-influenza potency.14 In this study, we aim to identify highly
potent HA inhibitors with 1 as a starting point and address
potential DMPK liabilities of the salicylamide functional group.
Our preliminary structureꢀactivity relationship (SAR) studies of
1 suggested that the salicylamide group is more important for
conformational control of the molecule versus a role in potential
hydrogen bonding with HA protein. Thus, we designed ring-
cyclized analogues, such as 1H-indazol-3-ylamine 7, which could
mimic the salicylamide structure while retaining antiviral activity
and exhibiting better metabolic stability than 1.
We explored bicyclic aryl derivatives first while keeping the cis-
aliphatic amino group constant. The synthesis of 7 was carried
out from cis-amine 510 as shown in Scheme 1. Briefly, the
coupling reaction of 5 and 2-fluoro-benzoic acid with HATU
afforded the amide intermediate, which was then treated
with Lawesson's reagent to give thioamide 6. A mixture of 6
and hydrazine hydrate in DMSO was heated at 150 °C to
yield designed indazole analogue 7. It was evaluated for anti-
influenza activity in the CPE assay using MadinꢀDarby canine
kidney (MDCK) cells. Indazole 7 was found to be able to
inhibit the replication of the influenza A/Weiss/43 strain and
prevent the viral cytopathic effect with an EC50 of 6.9 μM
(Table 1). Because 7 also demonstrated improved mouse liver
microsomal stability (MLM = 45.2 mL/min/kg) as compared
to 1 (MLM = 76.7 mL/min/kg),15 it was used as a template for
additional structural modifications.
To test the influence of geometry and the substitution pattern
of the aromatic rings on the antiviral activity, analogues 8ꢀ11
were made by nucleophilic replacement of various bicyclic aryl
chlorides with amine 5 in pyridine. Those bicyclic aromatic
analogues were tested for their antiviral potency and cytotoxicity
in MDCK cells using the CPE assay. It quickly became apparent
that analogues with quinazoline or benzothiazole replacements
have moderate activity, and the substitution on the aromatic
groups is generally not tolerated, thus leaving little space for
further structural optimizations. For example, analogue 11 with
6-Cl substitution was inactive in the CPE assay, but 9 and 10 (R =
H and F) showed an EC50 around 2 μM. In addition, many
analogues had a marginal selectivity window and a high intrinsic
clearance probably due to increased hydrophobicity. Therefore,
new scaffolds with a less lipophilic ring such as pyridine or phenyl
were synthesized to evaluate the possibility to increase potency
and metabolic stability.
Among the aminopyridine analogues, 14 with 6-CF3 is over 15
times more potent than analogues 12 and 13 but demonstrated
poor microsomal stability. The synthesis of aniline analogues
15ꢀ28 was carried out by the copper-catalyzed cross-coupling of
substituted phenyl bromides with 5.16 Aniline analogues 17 and
20 with 3-Cl and 3-CF3 substitution groups demonstrated much
better antiviral potencies than others with an EC50 of 57 and 42 nM,
respectively (see 12ꢀ20). When a second small hydrophobic
group was introduced, it gave highly potent analogues 22 and 23
with EC50 below 20 nM. Both bulky hydrophobic groups and
polar substituents such as amides abolished anti-influenza activ-
ity. Further chemistry explorations led to sulfonamide 28, which
showed submicromolar antiviral activities and a good selectivity
window in MDCK cells. As compared to other derivatives, 28
also showed good water solubility (141 μg/mL in phosphate
buffer, pH 6.5) and a significantly improved stability in human
Figure 1. Structures of HA inhibitors 1ꢀ4.
Scheme 1. General Synthesis for HA Inhibitors 7ꢀ28a
a Reagents and conditions: (a) 2-Fluorobenzoic acid, HATU, NEt3, DCM, room temperature. (b) Lawesson's reagent, toluene, refluxing.
(c) NH2NH2 H2O, DMSO, 150 °C. (d) Pyridine, DMSO, microwave, 150 °C. (e) CuI, K3PO4, L-proline, microwave, DMSO, 80ꢀ120 °C.
3
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Table 1. Anti-Influenza Activities of Compounds 7ꢀ28
compd ID
Ar
R
EC50 (CPE, μM) a
CC50 (μM) b
MLM CLh (mL/min/kg) c
1
salicylamide
H
0.030
6.90
8.5
>50
>100
26.7
36.8
16.2
4.2
76.7
45.2
82.9
85.4
78.2
7
1H-indazol-3-yl
H
8
quinazolin-2-yl
H
9
benzothiazol-2-yl
H
2.12
2.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
benzothiazol-2-yl
6-F
6-Cl
H
benzothiazol-2-yl
>50
pyridin-2-yl
4.43
3.39
0.22
0.43
0.52
0.057
0.44
0.15
0.042
0.044
0.015
0.018
0.25
>100
37.9
0.93
0.21
>100
30.5
13.5
37
80.6
pyridin-2-yl
5-CF3
pyridin-2-yl
6-CF3
82.3
85.6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
2-Cl
6.9
3-Cl
9.7
86.1
4-Cl
8.1
2-CF3
6.6
3-CF3
7.8
83.8
49.8
85.1
62.4
84
3-CF3, 5-Cl
3-Cl, 5-F
3-CF3, 4-Cl
3-CN
6.7
4.4
2.8
46.9
6.0
3-PhO
3-CONH2
3-SO2Me
3-SO2NH2
>100
>50
>100
43.0
65.3
37.2
a Compound concentration to inhibit 50% of the cytopathic effect based on OD measurement. Values are the average of gtwo determinations run in
duplicate, SD ( 15%. b Compound concentration to inhibit 50% of MDCK cell growth relative to control. c In vitro mouse liver microsome clearance
calculated using the well-stirred model. See ref 15 for details.
and mouse liver microsomes with HLM of 6.6 mL/min/kg and
MLM of 37.2 mL/min/kg, respectively.
both 31 and 40 showed over 600-fold selectivity (CC50/EC50)
against MDCK cells in the CPE assay.
On the basis of the SAR and metabolite analysis of the aniline
series, disubstituted benzenesulfonamide analogues were de-
signed and synthesized (Scheme 2). Substituted benzenesulfo-
namide 30 was prepared from aniline 29 by a Sandmeyer reaction
and subsequent treatment of the resulting benzenesulfonyl
chloride with ammonia. The cross-coupling of 30 with 5 was
carried out with CuI, L-proline, and K3PO4 in DMSO at 120 °C
to give compounds 31ꢀ35. However, because of favorable
ortho-substitution of 30 (R = 2-Cl), an alternative method was
developed for the synthesis of 40. Briefly, sulfonamide 37 was
prepared from 5-fluoro-2-nitro-phenylamine 36, and it was
treated with amine 5 under basic conditions to afford aniline
38. Then, the nitro group of 38 was reduced by tin(II)
chloride under refluxing conditions to benzene-1,4-diamine
39. A selective Sandmeyer reaction of 39 with copper(II)
chloride and tert-butyl nitrite gave 2-chloride analogue 40 in
moderate yield.
To confirm the novel series indeed targets influenza HA
protein and blocks virus fusion as expected, the inhibitory effect
of representative analogues on the hemolysis of chicken red
blood cells (RBCs) was tested. As one of the most potent com-
pounds in the CPE assay, 23 effectively blocked the hemolysis of
RBCs with an IC50 of 0.06 μM. In accord with the CPE results,
analogues 11, 25, and 26 did not have an obvious impact on the
hemolysis with IC50 values above 31.6 μM. Sulfonamide 40
showed potent hemolysis inhibition with an IC50 of 0.25 μM but
did not have an effect on hemagglutination, in which only viral
HA-cellular receptor binding is involved. This result suggests that
40 prevents hemolysis very likely by binding to the stalk region of
HA and thus interfering with crucial conformational changes of
HA normally triggered by a low pH environment.
It has been well-documented that the low pH-triggered con-
formational changes of HA expose its internal trypsin cleavage sites
and render HA sensitive to trypsin. Thus, the mechanism of action
of 40 was further verified in an HA trypsin sensitivity assay with 1 as
a positive control (Figure 2). The purified HA, in the presence or
absence of compounds, was subjected to a brief low pH treat-
ment followed by trypsin digestion. It was clearly demonstrated
that 40 protects HA from low pH-induced trypsin degradation
As expected, the derivatives 31, 32, and 40 with additional F- or
Cl-substitution showed a 3ꢀ5-fold increase in inhibitory potency
as compared to the parent compound 28 (Table 2). On the other
hand, extra substitutiongroups such as methyl, methoxyl, and CF3
generally led to reduced antiviral activities. It is noteworthy that
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Scheme 2. Synthesis of Substituted Benzenesulfonamides 31ꢀ35 and 40a
a Reagents and conditions: (a) (1) NaNO2, HCl; (2) CuCl, AcOH, SO2. (b) NH3, DCM. (c) CuI, K3PO4, L-proline, microwave, DMSO, 120 °C.
(d) Compound 5, K2CO3, DMSO, 50 °C, 43%. (e) SnCl2 H2O, EtOH, reflux, 99%. (f) CuCl2 2H2O, t-BuONO, DMF, 45 °C, 22%.
3
3
Table 2. Anti-Influenza Activities of Sulfonamide Analogues and Their DMPK Profiles
compd
R
EC50 (CPE, μM) a
CC50 (μM) b
IC50 (μM) c
HLM CLh (mL/min/kg) d
MLM CLh (mL/min/kg) b
31
32
33
34
35
40
3-F
0.089
0.044
1.36
55.0
8.4
0.58
0.23
2.91
1.13
4.16
0.25
7.2
12.1
5.1
42.3
51.8
39.6
43.7
66.4
42.5
3-Cl
3-CF3
2-Me
2-OMe
2-Cl
19.5
81.5
>100
71.2
0.56
8.5
2.62
10.0
0.086
8.4
a Compound concentration to inhibit the cytopathic effect based on OD measurement. Values are means of three determinations run in duplicate,
SD ( 15%. b See the notes in Table 1. c Half maximal inhibition concentration to prevent hemolysis of chicken RBCs; values are the average of two
duplicate experiments, SD ( 20%. d In vitro human liver microsome clearance calculated using the well-stirred model.
(Figure 2, lane 6). Taken together, the mechanism of action studies
and the CPE data indicate that 40 inhibits the virus fusion with host
endosome membrane by binding to HA and preventing the con-
formational changes of the prefusion HA structure.
The single dose pharmacokinetic properties of a few sulfon-
amide analogues were analyzed in CD-1 mice. They all demon-
strated good oral availabilities with F g 55% and significantly
improved in vivo stability and longer terminal half-life as com-
pared to 1. The chloro substitution on the phenyl ring resulted in
reduced clearance of 32 (CL = 42 mL/min/kg) and 40 (CL =
53 mL/min/kg) when compared to the parent compound 28,
which had a clearance of 82 mL/min/kg in mice. Furthermore,
32 and 40 did not significantly inhibit five major CYP isoforms,
with IC50 values above 10 μM.
Viral specificity studies showed that 40 had similar anti-
viral potency against another group 1 influenza strain A/PR/8/
34 (H1N1) but was inactive against influenza A/Hongkong/8/
68 virus, a H3N2 strain that belongs to the HA phenotype group
2 influenza viruses. This selectivity between group 1 and 2 viruses
is probably due to the structural difference at the binding site in
the HA stalk region, as revealed by recent cocrystal studies of HA
complexed with group 1 broadly neutralizing antibodies7,8 and
group 2 specific HA inhibitor tert-butyl hydroquinone.17 Addi-
tional biostructure analysis of the stalk region of HA proteins
indicates that this region is highly conserved and stable within
each group and thus provides an attractive target for antiviral
drug discovery. Highly potent HA inhibitors with sufficient meta-
bolic stability and selectivity window like 40 could be very
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J. S. M.; Guan, Y.; Rambaut, A. Origins and evolutionary genomics of the
2009 swine-origin H1N1 influenza A epidemic. Nature 2009, 459, 1122.
(3) Fauci, A. S. Pandemic influenza threat and preparedness. Emerging
Infect. Dis. 2006, 12, 73.
(4) Bright, R. A.; Shay, D. K.; Shu, B.; Cox, N. J.; Klimov, A. I.
Adamantane resistance among influenza A viruses isolated early during
the 2005ꢀ2006 influenza season in the United States. J. Am. Med. Assoc.
2006, 295, 891.
(5) Weinstock, D. M.; Zuccotti, G. The evolution of influenza
resistance and treatment. J. Am. Med. Assoc. 2009, 301, 1066.
(6) Dimitrov, D. S. Virus entry: Molecular mechanisms and biome-
dical applications. Nat. Rev. Microbiol. 2004, 2, 109.
(7) Sui, J.; Hwang, W.; Perez, S.; Wei, G.; Aird, D.; Chen, L.; Santelli,
E.; Stec, B.; Cadwell, G.; Ali, M.; Wan, H.; Murakami, A.; Yammanuru,
A.; Han, T.; Cox, N. J.; Bankston, L. A.; Donis, R. O.; Liddington, R. C.;
Marasco, W. A. Structural and functional bases for broad-spectrum
neutralization of avian and human influenza A viruses. Nat. Struct. Mol.
Biol. 2009, 16, 265.
(8) Ekiert, D. C.; Bhabha, G.; Elsliger, M.; Friesen, R. H. E.;
Jongeneelen, M.; Throsby, M.; Goudsmit, J.; Wilson, I. A. Antibody
recognition of a highly conserved influenza virus epitope. Science 2009,
324, 246.
(9) Boriskin, Y. S.; Leneva, I. A.; Pecheur, E.-I.; Polyak, S. J. Arbidol:
A broad-spectrum antiviral compound that blocks viral fusion. Curr.
Med. Chem. 2008, 15, 997.
(10) Deshpande, M. S.; Wei, J.; Luo, G.; Cianci, C.; Danetz, S.; Torri,
A.; Tiley, L.; Krystal, M.; Yu, K.; Huang, S.; Gao, Q.; Meanwell, N. A. An
approach to the identification of potent inhibitors of influenza virus
fusion using parallel synthesis methodology. Bioorg. Med. Chem. Lett.
2001, 11, 2393.
(11) Staschke, K. A.; Hatch, S. D.; Tang, J. C.; Hornback, W. J.;
Munroe, J. E.; Colacino, J. M.; Muesing, M. A. Inhibition of influenza
virus hemagglutinin-mediated membrane fusion by a compound related
to podocarpic acid. Virology 1998, 248, 264.
(12) Oka, M.; Ishiwata, Y.; Iwata, N.; Honda, N.; Kakigami, T.
Synthesis and anti-influenza virus activity of tricyclic compounds with a
unique amine moiety. Chem. Pharm. Bull. 2001, 49, 379.
(13) Tang, G.; Qiu, Z.; Lin, X.; Li, W.; Zhu, L.; Li, S.; Li, H.; Wang,
L.; Chen, L.; Wu, Z. J.; Yang, W. Discovery of novel 1-phenyl-cycloalk-
ane carbamides as potent and selective influenza fusion inhibitors.
Bioorg. Med. Chem. Lett. 2010, 20, 3507.
(14) Cianci, C.; Yu, K.; Dischino, D.; Harte, W.; Deshpande, M.;
Luo, G.; Colonno, R.; Meanwell, N.; Krystal, M. pH-dependent changes
in photoaffinity labeling patterns of the H1 influenza virus hemaggluti-
nin by using an inhibitor of viral fusion. J. Virol. 1999, 73, 1785.
(15) Obach, R. B.; Baxter, J. G.; Liston, T. E.; Silber, B. M.; Jones,
B. C.; MacIntyre, F.; Rance, D. J.; Wastall, P. The prediction of human
pharmacokinetic parameters from preclinical and in vitro metabolism
data. J. Pharmacol. Exp. Ther. 1997, 283, 46.
Figure 2. SDS-PAGE analysis of trypsin sensitivity assay showing 1 and
40 protected purified HA from trypsin digestion. Lane 1, purified HA;
lane 2, HA treated with trypsin without a prior acidification step; lane 3,
acidified HA without trypin treatment; lane 4, DMSO control; lane 5,
compound 1 (10 μM); lane 6, compound 40 (10 μM); lane 7, ribavirin
(10 μM); lane 8, trypsin only; and lane 9, molecular markers. Lanes 4ꢀ7
included all steps and components in a typical trypsin sensitivity assay.
Positions of HA1 and HA2 are marked.
valuable in the ongoing battle against the vicious influenza A
pathogens including seasonal H1N1 and avian H5N1 strains.
In summary, a novel series of potent and orally available anti-
influenza inhibitors were identified through structural modifica-
tions of salicylamide 1. The representative analogue 40 demon-
strated potent antiviral activities with an adequate selectivity
window and had significantly improved metabolic stability in
mouse PK studies. The identification of benzenesulfonamide-
based HA inhibitors and their mechanism of action studies
warrant further structural optimizations and development for
the treatment of flu.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures for the synthesis of compounds 7, 28, 31ꢀ35, and 40 and
the biological assays (CPE, RBC hemolysis, and trypsin sensitivity).
This material is available free of charge via the Internet at http://
pubs.acs.org.
(16) Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted CuI-catalyzed
C-N bond formation between aryl halides and amines or N-containing
heterocycles. J. Org. Chem. 2005, 70, 5164.
(17) Russell, R. J.; Kerry, P. S.; Stevens, D. J.; Steinhauer, D. A.;
Martin, S. R.; Gamblin, S. J.; Skehel, J. J. Structure of influenza
hemagglutinin in complex with an inhibitor of membrane fusion. Proc.
Natl. Acad. Sci. U.S.A. 2008, 105, 17736.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ86 21 38954910 ext. 3350. Fax: þ86 21 50790291.
E-mail: gordon.tang@roche.com.
’ ACKNOWLEDGMENT
We acknowledge Jason Wong and Shuhai Zhao for many
scientific discussions. We also thank Yongguo Li, Wenzhi Chen,
Peilan Ding, Qingshan Gao, Rong Zhao, and Sheng Zhong for
their analytical assistance.
’ REFERENCES
(1) World Health Organization, http://www.who.int.
(2) Smith, G. J. D.; Vijaykrishna, D.; Bahl, J.; Lycett, S. J.; Worobey,
M.; Pybus, O. G.; Ma, S. K.; Cheung, C. L.; Raghwani, J.; Bhatt, S.; Peiris,
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