Heterobiaryl human immunodeficiency virus entry inhibitors

Article abstract of DOI:10.1021/jm900330x

Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS 806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC₅₀ values of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit potency and selectivity similar to those of 1 against a panel of clinical viral isolates. Moreover, current structure-activity relationship studies of these novel biaryl gp120 inhibitors revealed that around the biaryl, a fine crevice might exist in the gp120 binding site. Taken in sum, these data reveal a hitherto unsuspected flexibility in the structure-activity relationships for these inhibitors and suggest new avenues for exploration and gp120 inhibitor design. 2009 American Chemical Society.

Full text of DOI:10.1021/jm900330x

J. Med. Chem. 2009, 52, 4481–4487 4481
DOI: 10.1021/jm900330x
Heterobiaryl Human Immunodeficiency Virus Entry Inhibitors
Rong-Jian Lu,*,§ John A. Tucker,*,† Jason Pickens,† You-An Ma,† Tatiana Zinevitch,‡ Olga Kirichenko,‡ Vitalii Konoplev,‡
Svetlana Kuznetsova,‡ Sergey Sviridov,‡ Enugurthi Brahmachary,† Alisher Khasanov,† Charles Mikel,† Yang Yang,†
Changhui Liu,† Jian Wang,† Stephanie Freel,§ Shelly Fisher,§ Alana Sullivan,§ Jiying Zhou,§ Sherry Stanfield-Oakley,§
Brian Baker,§ Jeff Sailstad,§ Michael Greenberg,§ Dani Bolognesi,§ Brian Bray,§ Barney Koszalka,§ Peter Jeffs,§
Cynthia Jeffries,† Alexander Chucholowski,† and Connie Sexton§
§Trimeris, Inc., 3500 Paramount Parkway, Morrisville, North Carolina 27560, †ChemBridge Research Laboratories, Inc.,
16981 Via Tazon, Suite K, San Diego, California 92127, and ‡ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, California
Received March 16, 2009
Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS
806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to
a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the
discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of
previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC50 values
of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit
potency and selectivity similar to those of 1 against a panel of clinical viral isolates. Moreover, current
structure-activity relationship studies of these novel biaryl gp120 inhibitors revealed that around the
biaryl, a fine crevice might exist in the gp120 binding site. Taken in sum, these data reveal a hitherto
unsuspected flexibility in the structure-activity relationships for these inhibitors and suggest new
avenues for exploration and gp120 inhibitor design.
Introduction
demonstratedthe therapeutic potentialoftargeting theseearly
stages in the virus life cycle.7 Additional evidence supporting
virus entry as a target comes from several CCR5-binding
inhibitors that have shown antiviral efficacy in the clinic,6
including maraviroc, which was approved in 2007. A third
class of viral entry inhibitors that has been shown to reduce
viral load in man is represented by BMSa 806 (formally
BMS378806, 1, Table 1) and BMS 043 (formally BMS488043,
2, Table 1).8-10 1 has been shown to prevent viral attachment
by binding within the CD4-binding pocket of the viral gp120
molecule.11
In highly active antiretroviral therapy (HAART), potent
combinations of three or more reverse transcriptase and
protease inhibitors are used to suppress replication of the
human immunodeficiency virus (HIV).1 HAART has pro-
vided an effective means of prolonging the survival of AIDS
patients and controlling disease progression of HIV-infected
patients.2 Nonetheless, HAART has important limitations
including incomplete efficacy,2 toxicity3 of the component
antiviral agents, and the eventual emergence of resistant
virus.4 There is therefore an urgent need for the development
of anti-HIV agents with novel mechanisms of action.
One promising area of investigation is the identification of
agents that inhibit viral attachment and entry into host cells.5
HIV-1 entry is a dynamic process beginning with viral attach-
ment to the host cell via interactions between the viral gp120
molecule and its primary (CD4) and secondary receptors
(typically the CCR5 and CXCR4 members of the chemokine
receptor family). Following gp120 attachment to CD4 and
coreceptor binding, the viral gp41 molecule undergoes a series
of structural rearrangements leading ultimately to fusion
between viral and host cell membranes. Drugs targeting
attachment to either CD4 or the CCR5 coreceptor or fusion
have been shown to inhibit viral infection both in vitro and in
vivo.6 The approval of the first fusion inhibitor, enfuvirtide,
In spite of the high level of interest in 1 and its analogues
as the only known family of potent small molecule viral
attachment inhibitors that act through binding to gp120,
relatively little detailed structure-activity relationship
data have been published. Potent inhibitors have been
described that are derived from 1 by relatively conservative
changes such as replacing the 4-azaindole ring with an
indole or isomeric azaindole ring.10 Certain variations
in the substitution pattern of the azaindole or indole
ring are tolerated, and in some cases elimination of the
methyl substituent from the piperazine ring has been
shown to result in only a modest decrease in potency.12
A
recent publication from these laboratories disclosed a
series of potent inhibitors in which the R-ketoamide
group of the aforementioned compounds is replaced by a
*To whom correspondence should be addressed. For J.A.T.: (phone)
650-245-7315; (fax) 650-245-7315; (e-mail) john.alan.tucker@gmail.
com. For R.J.-L.: (current address) Sequoia Pharmaceuticals Inc., 401
Professional Drive, Gaithersburg, MD 20879; (phone) 240-632-0094,
extension 113; (fax) 240-632-0497; (e-mail) rongjian.lu@sequoiapharma.
com.
a Abbreviations: BMS, Bristol-Myers Squibb; ELISA, enzyme-linked
immunosorbent assay; ELSD, evaporative light scattering detection;
NaHMDS, sodium bis(trimethylsilyl)amide; LiHMDS, lithium bis-
(trimethylsilyl)amide; MCPBA, 3-chloroperoxybenzoic acid; DME,
ethylene glycol dimethyl ether; DCM, dichloromethane; Tosmic, tosyl-
methyl isocyanide; DMSO, dimethyl sulfoxide.
r
2009 American Chemical Society
Published on Web 06/17/2009
pubs.acs.org/jmc

4482 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Table 1. Previously Disclosed Inhibitors
Lu et al.
CD4, and CXCR4 cells. None of the compounds showed
noticeable toxicity (CC50 > 40 000 nM). Selected compounds
were also examined in a competitive ELISA format to assess
their ability to inhibit the binding interaction between soluble
CD4 and gp120 from the IIIB subtype of HIV. The activity
was determined by measuring the 50% inhibitory dose against
CD4 allowed to bind to gp120 (IIIB) via an anti-CD4 mono-
clonal antibody followed by a peroxidase-labeled antimouse
antibody.
The activities of several previously reported inhibitors in
our assays are shown in Table 1. Compound 1 exhibits single
digit nanomolar potency in the M33 assay. The second
generation inhibitor 2, having an isomeric azaindole ring
and a second methoxyl substituent, is slightly less potent in
this assay. The incorporation of a triazole ring in the 7-
position of the azaindole ring (BMS compound 310b) provided
a compound with an IC50 less than 5 nM in the M33 assay.
In the ELISA this compound was >11-fold more potent
thanthe clinical development compounds1 and 2. Compound
4, the most potent inhibitor identified in our recent study
of analogues having a sulfonamide replacement for the
ketoamide linker of the Bristol-Myers-Squibb compounds,
exhibited potency greater than that of 1 and 2 but less than
that of 3.
As part of our exploration of the structure-activity rela-
tionships of sulfonamide inhibitors related to 4,13 we under-
took the preparation of a parallel synthesis library in which
the amine 5 was treated with a diverse set of 90 commercially
available sulfonyl chlorides. Among the most promising
analogues arising from this effort were compounds 6a and
6b, which exhibit IC50 values of 1-5 μM in the M33 pseudo-
typed assay. In an effort to exploit these initially promising
results, we then synthesized a series of 57 analogues of general
structure 6 and 20 analogues of general structure 7, but this
effort did not lead to the discovery of compounds having
significantly improved potency.
We then turned our efforts to the synthesis of biaryl
analogues in the ketoamide series. Compound 8, which is
the ketoamide analogue of sulfonamide 6b, failed to exhibit
interesting activity in the M33 pseudotyped assay (Table 2).
We then prepared the meta and para biaryls 9 and 12a. We
were gratified to find that 12a exhibited potency approxi-
mately 5-fold greater than any previous compound in this
series.
a Reference 11. b M33 pseudotyped assay.14
sulfonamide group.13 Flexible overlay calculations of a
ketoamide inhibitor with a sulfonamide inhibitor revealed
a single conformation of each that gave significantly better
overlap of key pharmacophore features than other low
energy conformations, thus suggesting a possible binding
conformation for each class of inhibitor.
In the present manuscript we describe our discovery of
potent HIV entry inhibitors in which the azaindole ring of
previously described inhibitors is replaced by a heterobiaryl
group. Among these, compound 13k was shown to exhibit
potency comparabletothatof1 against a panel of clinical viral
isolates.
Structure-Activity Relationships
The potency of the compounds described in this work was
examined using an anti-HIV-1 pseudotyped viral assay as
described previously.14 In brief, the anti-HIV-1 activity of
inhibitors was determined by measuring the 50% inhibitory
dose against pseudovirions containing an R5-using envelope
that was cloned from a primary virus isolate. The specificity of
inhibitors was assessed by their ability to prevent infection of
pseudotyped viruses expressing a CD4-independent ampho-
tropic murine leukemia virus (AMLV) envelope. Inhibitors
that were shown to prevent infection of the M33 pseudovirus
but were not able to inhibit AMLV pseudovirus infection at
concentrations more than 100ꢀ their M33 IC50 were consid-
ered to be specific for inhibition of HIV. The toxicity of the
compounds described in this work was assessed against U87,
In order to rapidly map out the structure-activity rela-
tionships around the heteroaryl ring of 12a, we prepared a
library of 73 analogues of general structure 12 by perform-
ing palladium-catalyzed aryl-aryl coupling reactions on
the boronic acid 10 or the aryl bromide 11.20,21 Each
product was purified by HPLC. Purity (>95% by ELSD)
and identity were established by LCMS. The 10 most active
analogues from this library are shown in Table 3. These
data suggest a relatively small binding pocket around

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4483
Table 2. M33 Pseudotyped Assay IC50 Values
Table 3. M33 Pseudotyped Assay IC50 Values for Parallel Synthesis-
Derived Analogues 12
the oxazole ring of 12a that prefers five-member rings
with minimal substitution.
a Racemic analogue.
In order to better understand the structure-activity relation-
ships observed in this series, we compared the MM2-minimized
structures of 12a and the potent Bristol-Myers-Squibb inhibi-
tor 3. This overlay is shown in Figure 1. In this model we have
assumed that the ketoamide and benzoylpiperazine groups of
the two inhibitors interact with the gp120 protein in a similar
manner. The trajectory of the aryl-carbonyl bond of 12a,
combined with the linear geometry of the para-substituted
phenyl ring, places the oxazole ring of 12a in a position similar
to that occupied by the triazole ring of 3. The phenyl ring
closely overlays the pyrrole moiety of the azaindole ring. The
model further suggests that substituents in the 2- or 3-position
of the phenyl ring of 12a could occupy a position similar to that
of the pyridine moiety of the azaindole ring of 3. We therefore
decided to prepare a series of heterobiaryl analogues of general
structure 13. The screening data for these analogues are shown
in Table 5.
The addition of 2- or 3-substituents to the phenyl group
of our heterobiaryl inhibitors had widely varying effects
on potency. In the pyrazole and methylisoxazole series, the
addition of a 2-methoxyl group (13e, 13k) provided a >30-
fold enhancement in potency to give analogues with M33 IC50
values of less than 5 nM. The effect of 3-methoxyl (13i) on
pyrazole serieswith3-foldpotency enhancement iscontrary to
that on methylisoxazole series with >2.5-fold activity de-
crease (13l). In the oxazole series, the addition of a 3-chloro
substituent provided a >50-fold enhancement in potency,
Further evaluation of the SAR around the terminal hetero-
cycle was performed by the synthesis of discrete ana-
logues. The data for these analogues are shown in Table 4.
Overall, these data support the results from the parallel
synthesis-derived analogues, suggesting a relatively small
binding pocket in this region. The results for compounds
12u and 12v suggest a preference for R to be an unsatura-
ted ring. Small changes in the steric profile of this part of the
molecule are demonstrated by the 10-fold potency dif-
ference between 12l and 12r. In spite of the negative effect
observed for methyl substitution in this pair, similar substitu-
tion appears to be well-tolerated when the pyra-
zole has an isomeric mode of attachment to the phenyl ring,
as in 12b.

4484 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Table 4. M33 IC50 Data for Discretely Synthesized Analogues 12
Lu et al.
Table 5. M33 PT and HIV IIIb ELISA IC50 Values for Analogues 13
and 14
a Racemic analogue.
a Racemic analogue.
in the pyrazole and methylisoxazole series. To prove this
hypothesis, we made compound 15 with MeO at position 6,
which led to a 7.5-fold enhancement in potency with
IC50 = 134nM.
Figure 1
Compound 13k was tested against a panel of clinical HIV
isolate strains derived from phase II clinical trials of enfuvir-
tide. The derivation of the isolates for the panel and the
method used for testing compound 13k against the panel
of primary isolates are described in the ref 14b. The activity
of compound 13k in a viral replication assay against a panel of
clinical HIV isolate strains is shown in Table 6 along with
similar data for 1 and 2. The geometric mean IC50 values for 1,
2, and 13k are 190, 83, and 155 nM, respectively. Heterobiaryl
leading to a third analogue having IC50<5 nM in the M33
assay. The presence of a 2-hydroxyl group had a highly
deleterious effect on potency in analogues 13d and 13j.
Replacing the phenyl ring of inhibitor 12l with a pyridine ring
as in 14 led to a substantial reduction in potency, which
might suggest an electronrich aromatic ring system is required
for excellent potency. This is consistent with the pre-
sence of 2-MeO leading to a >30-fold potency enhancement

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4485
Scheme 3a
Table 6. IC50 Values (nM) for Compounds 1, 2, and 13k in Viral
Replication Assays vs a Panel of Clinical HIV Isolates Strains
entry
virus
1
2
13k
1
584.000 017
584.000 030
584.000 031
584.000 054
584.000 058
584.000 060
584.000 063
584.000 066
584.000 098
584.000 220
584.000 227
589.000 033
>10000
29
>10000
30
>10000
13
2
3
8016
5533
38
240
7131
60
8975
3514
22
4
5
6
24
46
14
17
17
25
7
8
190
394
5
11
273
301
3
9
425
4
10
11
12
423
27
22
34
1,817
11
geometric mean
Scheme 1a
190
83
155
a Reagents: (a) NaHMDS, THF; (b) aq NaOCl; (c) 4,4,5,5,40,40,50,50-
octamethyl[2,20]bi[[1,3,2]dioxaborolanyl], KOAc, PdCl2dppf, 75 °C; (d)
NaIO4, NH4OAc, acetone/H2O, room temp; (e) PdCl2(PPh3)2, THF,
reflex; (f) tetrakis(triphenylphosphine)palladium(0), 2 M Na2CO3 (aq),
t-Bu4NBr, toluene/H2O (1:1); (g) Cu, KOH, 160 °C; (h) Pd(OAc)2, o-
Tol3P, K2CO3, DME/H2O 5:1; (i) Cu(OAc)2, Et3N, DCM, room temp.
a Reagents: (a) (CH3O)2SO2, LiOH H2O, THF; (b) NaHMDS, THF;
(c) aq NaOCl.
3
Scheme 2a
Scheme 4a
a Reagents. D-1: (a) NaHMDS, THF; (b) aq NaOCl. D-2: (a)
LiHMDS, THF; (b) MCPBA, THF.
inhibitor 13k exhibits a spectrum of activity closely compar-
able to that of 1. Bristol-Myers-Squibb’s second generation
inhibitor 2 exhibits better potency against several strains
3, 8, and 11 that are resistant to inhibition by 1 and 13k.
Synthesis
Compounds 6a and 6b were prepared by treating commer-
cially available sulfonyl chlorides with the amine 5 (method
A). Compound 8 was prepared by the route shown in
Scheme 1.
a Reagents: (a) PdCl2(PPh3)2, THF, ref; (b) Tosmic, Na2CO3, MeOH.
Most of the other compounds described in this manuscript
were prepared by one of two general strategies. The first of
these involved preparing heterobiaryl carboxylic acid ester 17
and performing an oxidative coupling15 with 18 as outlined in
Scheme 2. Many of the heterobiaryl carboxylic esters were
commercially available. The syntheses of others were per-
formed using literature methods or relatively straightforward
modifications of literature methods for the synthesis of related
compounds.16-18 These are described in detail in the Support-
ing Information.
using method E.19 Intermediates of types 20 and 21 were
then used to prepare the final analogues using a variety of
transformation types. In method F, halides 20 were coupled
with arylstannanes under Stille conditions to provide final
analogues.20 In methods G and I aryl-aryl bonds were
formed using the Suzuki protocol.21 Compounds 12o, 12p,
12u, and 12v were prepared by copper-mediated coupling
reactions between an aromatic or aliphatic amine and inter-
mediates of general structure 20 or 21 using literature proce-
dures (methods H and J).22 All of the arylstannanes,
arylboronic acid, aryl halides, and amines required for these
transformations were commercially available or were synthe-
sized using literature procedures.
The second general strategy involved using this same
oxidative coupling method to prepare a ketoamide of general
structure 20 (Scheme 3). Palladium-catalyzed conversion
of 20 to the corresponding boronic acids 21 was achieved

4486 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Lu et al.
Scheme 5a
Acknowledgment. We thank Steve Wring, Cornelia Smith,
Adam Silverstein, Doug Ahrens, John Dwyer, Xuefang Bai,
Justin Green, Donna Davison, Lei Jin, Robyn Medinas,
Sarah Mosier, Scott Webb, Tony Picking, Sheila Whight,
Warren Marquitta, Bill Mahony, Marlene Scobell, Marina
Abdurakhmanova, Simone Ferguson, and Cosina Mui for
their contributions.
a Reagents: (a) amines (NH3 H2O, 26a; MeNH2, 26b), DMSO,
3
Supporting Information Available: Experimental procedures
and characterization data for newly synthesized compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
80 °C.
Scheme 6a
References
(1) (a) Hammer, S. M.; Saag, M. S.; Schechter, M.; Montaner, J. S.;
Schooley, R. T.; Jacobsen, D. M.; Thompson, M. A.; Carpenter,
C. C.; Fischl, M. A.; Gazzard, B. G.; Gatell, J. M.; Hirsch, M. S.;
Katzenstein, D. A.; Richman, D. D.; Vella, S.; Yeni, P. G.;
Volberding, P. A. International AIDS Society;USA panel. Treat-
ment for adult HIV infection: 2006 recommendations of the
International AIDS Society-USA panel. JAMA, J. Am. Med.
Assoc. 2006, 296, 827–843. (b) Gulick, R. M.; Ribaudo, H. J.;
Shikuma, C. M.; Lalama, C.; Schackman, B. R.; Meyer, W. A.;
Acosta, E. P.; Schouten, J.; Squires, K. E.; Pilcher, C. D.; Murphy,
R. L.; Koletar, S. L.; Carlson, M.; Reichman, R. C.; Bastow, B.;
Klingman, K. L.; Kuritzkes, D. R. Three- vs four-drug antiretro-
viral regimens for the initial treatment of HIV-1 infection: a
randomized controlled trial. JAMA, J. Am. Med. Assoc. 2006,
296, 769–781. (c) Rathbun, R. C.; Lockhart, S. M.; Stephens, J. R.;
Current HIV treatment guidelines. An overview. Curr. Pharm. Des.
2006, 12, 1045–1063.
(2) (a) Kumar, A.; Kilaru, K. R.; Forde, S.; Roach, T. C. Changing
HIV infection-related mortality rate and causes of death among
persons with HIV infection before and after the introduction of
highly active antiretroviral therapy. J. Int. Assoc. Physicians AIDS
Care 2006, 5, 109–114. (b) Crum, N. F.; Riffenburgh, R. H.;
Wegner, S.; Agan, B. K.; Tasker, S. A.; Spooner, K. M.; Arm-
strong, A. W.; Fraser, S.; Wallace, M. R. Comparisons of causes of
death and mortality rates among HIV-infected persons: analysis of
the pre-, early, and late HAART (highly active antiretroviral
therapy) era. J. Acquir Immune Defic Syndr. 2006, 41, 194–200.
(c) Palella, F. J.; Baker, R. K.; Moorman, A. C.; Chmiel, J. S.;
Wood, K. C.; Brooks, J. T.; Holmberg, S. D. Mortality in the
highly active antiretroviral therapy era: changing causes of death
and disease in the HIV outpatient study. J Acquired Immune Defic.
Syndr. 2006, 43, 27–34.
(3) (a) Roling, J.; Schmid, H.; Fischereder, M.; Draenert, R.; Goebel,
F. D. HIV-associated renal diseases and highly active antiretro-
viral therapy-induced nephropathy. Clin. Infect. Dis. 2006, 42,
1488–1495. (b) Wyatt, C. M.; Klotman, P. E. Antiretroviral
therapy and the kidney: balancing benefit and risk in patients
with HIV infection. Expert. Opin. Drug Safety 2006, 5, 275–287.
(c) Haugaard, S. B. Toxic metabolic syndrome associated with
HAART. Expert Opin. Drug Metab. Toxicol. 2006, 2, 429–445.
(4) (a) Vaclavikova, J.; Weber, J.; Machala, L.; Reinis, M.; Linka, M.;
Bruckova, M.; Vandasova, J.; Stankova, M.; Konvalinka, J.
Long-term analysis of the resistance development in HIV-1 positive
patients treated with protease and reverse transcriptase inhibitors:
correlation of the genotype and disease progression. Acta Virol.
2005, 49, 29–36. (b) Liu, H.; Miller, L. G.; Hays, R. D.; Golin, C.
E.; Wu, T.; Wenger, N. S.; Kaplan, A. H. Repeated measures
longitudinal analyses of HIV virologic response as a function of
percent adherence, dose timing, genotypic sensitivity, and other
factors. J. Acquired Immune Defic. Syndr. 2006, 41, 315–322.
(5) (a) Briz, V.; Poveda, E; Soriano, V. HIV entry inhibitors: mechan-
isms of action and resistance pathways. J. Antimicrob. Chemother.
2006, 57, 619–627. (b) Rusconi, S.; Scozzafava, A.; Mastrolorenzo,
A.; Supuran, C. T. New advances in HIV entry inhibitors devel-
opment. Curr. Drug Targets Infect. Disord. 2004, 4, 339–355.
(c) Shaheen, F.; Collman, R. G. Co-receptor antagonists as
HIV-1 entry inhibitors. Curr. Opin. Infect. Dis. 2004, 17, 7–16.
(d) Markovic, I. Advances in HIV-1 entry inhibitors: strategies to
interfere with receptor and coreceptor engagement. Curr. Pharm.
Des. 2006, 12, 1105–1119.
a Reagents: (a) BnOH, K2CO3, DMSO; (b) pyrazole-3-boronic
acid, tetrakis(triphenylphosphine)palladium(0), 2 M Na2CO3(aq),
t-Bu4NBr, toluene/H2O (1:1); (c) H2/Pd-C, THF; (d) AlCl3, DCM,
room temp.
Most of the intermediates 17 used in this work are known
in the literature, and many others were prepared by ester-
ification of previously described carboxylic acids. The
previously unknown ester 17a was prepared by a Stille
coupling, and previously unknown ester 17b was prepared
by formation of the oxazole ring.17-18 These routes are
shown in Scheme 4.
Intermediates 26a,b were prepared by nucleophlic aromatic
substitution reactions of 25 in DMSO at 80 °C (Scheme 5).
Hydroxylated analogues 13d and 13j were formed by deben-
zylationanddemethylationreactions, respectively(Scheme6).
Conclusions
Aspart of a research effort directed atthe discoveryof novel
inhibitors of viral entry that target the interaction of the viral
gp120 protein with its primary coreceptor CD4, we have
examined the utility of heterobiaryl groups as replacements
for the indole and azaindole rings that are invariant motifs in
previouslydescribedinhibitors. Thiseffortledtothe discovery
of a novel series of inhibitors having a 4-heteroaryl-substi-
tuted phenyl in place of the azaindole ring of the previously
described inhibitor. Optimization of the identity of the hetero-
aryl ring and of the substitution pattern on the phenyl ring led
to several inhibitors with IC50 < 5 nM in the M33 pseudo-
typed antiviral assay. Compound 13k exhibited potency and
selectivity comparable to that of 1 against a panel of clinical
viral isolates. Moreover, current structure-activity relation-
ship studies of these novel biaryl gp120 inhibitors revealed
that around the biaryl, a fine crevice might exist in the gp120
binding site. Taken in sum, these data reveal a hitherto
unsuspected flexibility in the structure-activity relationships
for these inhibitors and suggest new avenues for exploration
and inhibitor design.
(6) (a) Fatkenheuer, G.; Pozniak, A. L.; Johnson, M. A.; Plettenberg,
A.; Staszewski, S.; Hoepelman, A. I.; Saag, M. S.; Goebel, F. D.;
Rockstroh, J. K.; Dezube, B. J.; Jenkins, T. M.; Medhurst, C.;
Sullivan, J. F.; Ridgway, C.; Abel, S.; James, I. T.; Youle, M.; van

Article
der Ryst, E. Efficacy of short-term monotherapy with maraviroc, a
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 4487
novel human immunodeficiency virus type 1 inhibitor that blocks
gp120-CD4 interactions. J. Virol. 2003, 77, 10528–10536. (c) Kong,
R.; Tan, J. J.; Ma, X. H; Chen, W.; Wang, C. X. Prediction of the
binding mode between BMS-378806 and HIV-1 gp120 by docking
and molecular dynamics simulation. Biochim. Biophys. Acta 2006,
1764 (4), 766–767.
new CCR5 antagonist, in patients infected with HIV-1. Nat. Med.
2005, 11, 1170–1172.(b) Greaves, W.; Landovitz, R.; Fatkenheuer,
G.; Hoffmann, C.; Antunes, F; Angel, J.; Boparai, N.; Knepp, D.;
Keung, A; Dunkle, L. Late Virologic Breakthrough in Treatment-
Naive Patients on a Regimen of Combivir plus Vicriviroc. Pre-
sented at the 13th Conference on Reteroviruses and Opportunistic
Infections, 2006; Abstract 161LB. (c) Lalezari, J.; Thompson, M.;
Kumar, P.; Piliero, P.; Davey, R.; Murtaugh, T.; Patterson, K.;
Shachoy-Clark, A.; Adkison, K.; Demarest, J.; Sparks, S.; Fang,
L.; Lou, Y.; Berrey, M.; Piscitelli, S. 873140, a Novel CCR5
Antagonist: Antiviral Activity and Safety during Short-Term
Monotherapy in HIV-Infected Adults. Presented at the 44th
Interscience Conference on Antiretroviral Agents and Chemother-
apy, Washington, DC, 2004; Abstract H-1137b.
(12) Wang, J.; Le, H.; Heredia, A.; Song, H.; Redfield, R.; Wang, L.-X.
Modification and structure-activity relationship of
a small
molecule HIV-1 inhibitor targeting the viral envelope glycoprotein
gp120. Org. Biomol. Chem. 2005, 3 (9), 1781–1786.
(13) Lu, R.-J.; Tucker, J. A.; Zinevitch, T.; Kirichenko, O.; Konoplev,
V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.; Tandel, S.; Brahmach-
ary, E.; Yang, Y.; Wang, J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou,
J.; Stanfield-Oakley, S.; Greenberg, M.; Bolognesi, D.; Bray, B.;
Koszalka, B.; Jeffs, P.; Khasanov, A.; Ma, Y.-A.; Jeffries, C.; Liu,
C.; Proskurina, T.; Zhu, T.; Chucholowski, A.; Li, R.; Sexton, C.
Design and synthesis of human immunodeficiency virus entry
inhibitors: sulfonamide as an isostere for the R-ketoamide group.
J. Med. Chem. 2007, 50 (26), 6535–6544.
(14) (a) Hu, Q. X.; Perkins, A. G.; Wang, Z.-X.; Connolly, S. M.; Peiper,
S. C.; Greenberg, M. L. Evolution of the HIV-1 envelope during
infection reveals molecular corollaries of specificity for corecep-
tor utilization and AIDS pathogenesis. J. Virol. 2000, 74, 11858–
11872. (b) Mink, M.; Mosier, S. M.; Janumpalli, S.; Davison, D.;
Jin, L.; Melby, T.; Sista, P.; Erickson, J.; Lambert, D.; Stanfield-
Oakley, S. A.; Salgo, M.; Cammack, N.; Matthews, T.; Greenberg,
M. L. Impact of human immunodeficiency virus type 1 gp41 amino
acid substitutions selected during enfuvirtide treatment on gp41
binding and antiviral potency of enfuvirtide in vitro. J. Virol. 2005,
79, 12447–12454.
(15) Yang, Z; Zhang, Z; Meanwell, N. A.; Kadow, J. F.; Wang, T. A
strategy for the Synthesis of aryl alpha-ketoamides based upon the
acylation of anions derived from cyanomethylamines followed
by oxidative cleavage. Org. Lett. 2002, 4 (7), 1103–1105.
(16) Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.;
Sawada, M; Takasugi, H.; Tanaka, H. Inhibitors of Acyl-CoA:
cholesterol O-acyltransferase. 2. Identification and structure-
activity relationships of a novel series of N-alkyl-N-(heteroaryl-
substituted benzyl)-N0-arylureas. J. Med. Chem. 1998, 13, 2390–
2410.
(7) (a) Poveda, E.; Briz, V.; Soriano, V. Enfuvirtide, the first fusion
inhibitor to treat HIV infection. AIDS Rev. 2005, 7, 139–147.
(b) Oldfield, V.; Keating, G. M.; Plosker, G. Enfuvirtide: a review
of its use in the management of HIV infection. Drugs 2005, 65,
1139–1160. (c) Lazzarin, A. Enfuvirtide: the first HIV fusion
inhibitor. Expert Opin. Pharmacother. 2005, 6, 453–464. (d) Clotet,
B.; Raffi, F.; Cooper, D.; Delfraissy, J. F.; Lazzarin, A.; Moyle, G.;
Rockstroh, J.; Soriano, V.; Schapiro, J. Clinical management
of treatment-experienced, HIV-infected patients with the fusion
inhibitor enfuvirtide: consensus recommendations. AIDS 2004, 18,
1137–1146.
(8) Hanna, G.; Lalezari, J.; Hellinger, J.; Wohl, D.; Masterson, T.;
Fiskel, W.; Kadow, J.; Lin, P.; Giordano, M.; Colonnol, R.;
Grasela, D. Antiviral Activity, Safety, and Tolerability of a
Novel, Oral Small-Molecule HIV-1 Attachment Inhibitor,
BMS488043, in HIV-1-Infected Subjects. Presented at the 11th
Conference on Retroviruses and Opportunistic Infections, 2004;
Abstract 141.
(9) (a) Wang, H.-G. H.; Williams, R. E.; Lin, P.-F. A novel class of
HIV inhibitors that targets the viral envelope and inhibits CD4
receptor binding. Curr. Pharm. Des. 2004, 10, 1785–1793. (b) 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. Biochemical and genetic characterizations of
a novel human immunodeficiency virus type 1 inhibitor that blocks
gp120-CD4 interactions. J. Virol. 2003, 77, 10528–10536.
(17) Bombrun, A. N-Cinnamoyl Derivatives of Beta-Carboline. U.S.
Patent 6,306,870B1, 2001.
(10) (a) 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.; Riccardi, K.; Spicer,
T. P.; Deminie, C.; Rose, R.; Wang, H. G.; Blair, W. S.; Shi, P. Y.;
Lin, P. F.; Colonno, R. J.; Meanwell, N. A. Discovery of 4-benzoyl-
1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-
methylpiperazine (BMS378806): a novel HIV-1 attachment
inhibitor that interferes with CD4-gp120 interactions. J. Med.
Chem. 2003, 46, 4236–4239. (b) Yasutsugu, U.; Connolly, T.;
Kadow, J.; Wang, T.; Meanwell, N.; et al. Prodrugs of Piper-
azine and Substituted Piperazine Antiviral Agents. U.S. Patent
Appl. 2005/0209246A1, 2005.
(18) Kajino M.; Hird, N. W.; Tarui, N.; Banno, H.; Kawano, Y.;
Inatomi, N. Fused Quinoline Derivative and Use Thereof.
WO2005105802 A1, 2005.
(19) Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed
cross-coupling reaction of alkoxydiboron with haloarenes:
a direct procedure for arylboronic esters. J. Org. Chem. 1995, 60,
7508–7510.
(20) (a) Stille, J. K. Palladium catalyzed coupling of organotin reagents
with organic electrophiles. Pure Appl. Chem. 1985, 57, 1771–1780.
(b) Stille, J. K. The palladium-catalyzed cross-coupling reactions of
organotin reagents with organic electrophiles. Angew. Chem., Int.
Ed. Engl. 1986, 25, 508–524.
(11) (a) Lin, P.-F.; Blair, W.; Tao, W.; Spicer, T.; Guo, Q.; Zhou, N.;
Gong, Y.-F.; Wang, H. H.-G.; Rose, R.; Yamanaka, G.; Robin-
son, B.; Li, C.-B.; Fridell, R.; Deminie, C.; Demers, G.; Yang, Z.;
Zadjura, L.; Meanwell, N.; Colonno, R. A small molecule HIV-1
inhibitor that targets the HIV envelope and inhibits CD4 receptor
binding. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11013–11018.
(b) Guo, Q.; Ho, H.-T.; Dicker, I.; Fan, Li; Zhou, N.; Friborg, J.;
Wang, T.; McAuliffe, B. V.; Wang, H. H.-G.; Rose, R. E.; Fang,
H.; Scarnati, H. T.; Langley, D. R.; Meanwell, N. A.; Abraham, R.;
Colonno, R. J. Biochemical and genetic characterizations of a
(21) (a) Suzuki, A. Organoborates in new synthetic reactions. Acc.
Chem. Res. 1982, 15, 178–184. (b) Suzuki, A. Organoboron com-
pounds in new synthetic reactions. Pure Appl. Chem. 1985, 57,
1749–1758. Suzuki, A. Synthetic studies via the cross-coupling
reaction of organoboron derivatives with organic halides. Pure
Appl. Chem. 1991, 63, 419–422. Suzuki, A. New synthetic trans-
formations via organoboron compounds. Pure Appl. Chem. 1994,
66, 213–222.
(22) Bernd, R. Direct N-arylation of amides: an improvement of the
Goldberg-reaction. Synthesis 1985, 9, 856–860.