Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Article abstract of DOI:10.1016/j.bmcl.2012.10.115

A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.

Full text of DOI:10.1016/j.bmcl.2012.10.115

Bioorganic & Medicinal Chemistry Letters 23 (2013) 198–202
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent
and orally bioavailable antiviral agents
⇑
Kap-Sun Yeung , Zhilei Qiu, Quifen Xue, Haiquan Fang, Zheng Yang, Lisa Zadjura, Celia J. D’Arienzo,
Betsy J. Eggers, Keith Riccardi, Pei-Yong Shi, Yi-Fei Gong, Marc R. Browning, Qi Gao, Steven Hansel,
Kenneth Santone, Ping-Fang Lin, Nicholas A. Meanwell, John F. Kadow
Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 6 November 2012
A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-
substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl
carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype
virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a
promising in vitro profile, with its favorable HLM stability and membrane permeability translating into
favorable pharmacokinetic properties in preclinical species.
Keywords:
Antivirals
HIV-1 attachment inhibitors
Indole glyoxamide
Amides
Ó 2012 Elsevier Ltd. All rights reserved.
Molecular conformation
Although the mortality rate resulting from human immunodefi-
ciency virus-1 (HIV-1) infection/AIDS has been reduced by highly
active anti-retroviral therapy (HAART),1 which uses drug combina-
tions containing nucleoside and non-nucleoside reverse transcrip-
tase inhibitors, as well as protease and integrase inhibitors, the
emergence of drug-resistant HIV-1 mutant viruses, drug toxicity
and patient non-compliance associated with long-term therapy
remain significant medical challenges.2 Inhibitors of new viral
targets that are not cross-resistant to the current drugs thus
continue to be pursued in order to surmount these major obstacles
to the treatment of HIV-1 infection.3
proof-of-concept for an antiviral effect by inhibition of binding of
gp120 to CD4 was established by 2 during a Phase-1b, 8-day
monotherapy trial in HIV-1-infected patients.6e,7
One aspect of the early stage lead optimization in the medicinal
chemistry program of HIV-1 attachment inhibitors was aimed at
exploring the SAR associated with substitution at the indole C7
position of the early lead compound 1 with various carboxamide
moieties.6b It was anticipated that substitutions on the amide
element may offer additional interactions with gp120 and that
the amide group may also modulate the physicochemical property
of these compounds. In this Letter, the SAR resulting from a survey
of substituted amides in the 4-substituted indole series is described
along with the in vitro and in vivo profiles of key compounds.
As shown in Table 2, the introduction of a primary amide to the
C7 position of 1 maintained potency as exemplified by 3, while the
secondary methyl amide analog 4 was slightly more potent than 1.
A tertiary N,N-dimethyl amide 5 was poorly tolerated, although po-
tency appeared to be restored in a tertiary amide with a larger sub-
stitutent, as noted for the C7 piperazinyl benzamide 6. The
methoxy amide 7 and the hydrazide analog 8 were equipotent to
1; however, erosion of potency was observed in analogs of these
two compounds (9–13) that contained a basic amine or a more ex-
tended amide moiety. This trend also holds for the benzyl amide 14
which showed a >80-fold reduction in potency compared to 1.
Interestingly, replacing the phenyl ring in 14 with heterocycles
(15–18) improved potency to be comparable to 1. It appeared from
this survey that the presence of a heteroatom coupled with an aro-
matic ring deployed at the correct position with respect to the
Indole- and azaindole-oxoacetic piperazinyl benzamide-based
HIV-1 attachment inhibitors, as exemplified by an early indole
lead compound 1 and
a development candidate 6-azaindole
BMS-488043 (2) (Table 1), have previously been described by these
laboratories.4–9 These inhibitors interfere with the attachment of
the viral envelope glycoprotein gp120 to host cell receptor CD4,
which is an essential first step in the process of HIV-1 entry into
host cells. The binding of gp120 to CD4 and the ensuing association
of this binary complex with a co-receptor (CCR5 or CXCR4) triggers
the membrane fusion process that proceeds via the formation of a
six helical bundle of the viral transmembrane protein gp41,
ultimately culminating in the release of the viral genetic material
into the host cell cytosol to initiate viral replication.10 Clinical
⇑
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.2012.10.115

K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 198–202
199
Table 1
Table 2
Antiviral activity of HIV-1 attachment inhibitors
Antiviral activity of 4-fluoroindole-7-carboxamides and sulfonamides
O
O
F
O
O
F
OMe
O
N
O
N
N
H
N
N
N
N
N
R
HN
O
O
O
O
N
H
N
H
MeO
1
BMS-488043 (2)
Compound
R
EC50 (nM)11
1.24
CC50 (l
M)11
Compound
EC50 (nM)11
CC50 (l
M)11
1
—
>300
1
2
1.24
0.75
>300
>300
3
4
2.03
0.52
>300
>300
H
Me
Me
amide nitrogen was important for optimal potency. This observa-
tion is also reflected in the potency of the acyl sulfonamides 19
and 20, with the latter about four-fold more potent than 1. How-
ever, of particular note, was the approximately 800-fold increase
in potency in methyl amide analog 4 compared to the dimethyl
amide 5. The co-planar conformation of 4, stabilized by an intra-
molecular hydrogen-bond between the amide carbonyl and the in-
dole NH as observed in its single crystal X-ray structure (Fig. 1),
likely contributed significantly to the observed potency enhance-
ment. The dimethyl amide moiety in 5 is likely to adopt an out
of plane conformation due to the severe A(1,3) strain that would
develop between the amide methyl group and the C6-H if it as-
sumes a co-planar arrangement with the indole ring. An extensive
review of structural information has revealed that this kind of
highly stable, planar, conjugated system resulting from intramo-
lecular, resonance-assisted hydrogen-bonding occurs with high
frequency and often has an impact on molecular properties.12
Since the simple primary amide 3 and the secondary methyl
amide 4 were the more potent analogs identified in this amide sur-
vey, analogs of these two compounds with modifications in other
areas of the molecule were synthesized. As depicted in Table 3,
the 4-methoxy group, another preferred substituent at C4,6b con-
ferred increased potency over amide 3 but not the methyl amide
4 (compare 21 and 22). Introduction of an (R)-methyl to the piper-
azine ring, a modification that was previously found to increase po-
tency,6d also improved the potency of the primary amide 3 but not
4 (compare 23 and 24). The picolinamide analogs 25 and 26, pre-
pared with the intent of increasing solubility, showed a 3- and
10-fold reduction in potency compared to 3 and 23, respectively.
A hypothesis derived from the SAR studies presented in Table 2
was that heteroatom(s) in an aromatic ring within several atoms
distance of the C7 carboxamide nitrogen appeared to contribute
to good potency, exemplified by 16–18. Heteroaryl carboxamides
were therefore investigated and the results are shown in Table 4.
Satisfyingly, a range of carboxamides incorporating heterocycles,
including pyridine, tetrazole, thiadiazole, isoxazole, thiazole, ben-
zothiazole and benzimidazole (29–31 and 33–39), showed sub-
nanomolar to picomolar antiviral potency in the pseudotype infec-
C7
N
5
6
407
>300
145
Me
O
O
C7
O
N
N
2.68
Ph
7
8
3.83
2.69
>300
>300
MeO
H2N
9
18.82
12.83
298
135
MeO
H2N
10
11
12
315.7
7.95
>300
>300
N
O
O
N
13
14
11.24
109.1
>300
>300
N
Ph
H
N
15
6.73
>300
N
O
S
16
17
1.30
1.06
71
44
H
N
18
19
20
1.08
2.64
0.29
>300
>300
>300
O
S
O
O
S
O
Ph
tivity assay. Heterocycles with a N atom
a to the amide nitrogen
were the most potent (compare 29 with 27 and 28), with the thia-
zol-2-yl analogs35–36 and the benzimidazol-2-yl analog 38 exhib-
iting half-maximal inhibition at pM concentrations. Moreover, the
Figure 1. Single crystal X-ray structure of methyl amide 4.

200
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 198–202
Table 3
Table 4
Antiviral activity of analogs of the indole C7 primary and methyl carboxamides 3 and
Antiviral activity of heteroaryl indole-7-carboxamides
4
F
O
X
O
O
O
N
H
N
N
N
H
N
Z
N
HetAr
HN
O
O
R
HN
O
O
Y
Compound
HetAr
EC50 (nM)11
3.37
CC50 (l
M)11
Compound
R
X
Y
Z
EC50 (nM)11
CC50 (l
M)11
N
27
>300
3
4
H
Me
H
Me
H
Me
H
F
F
H
H
H
H
Me
Me
H
C
C
C
C
C
C
N
N
2.03
0.52
0.76
0.76
0.14
0.75
7.59
1.42
>300
>300
244
>300
141
>300
>300
>300
21
22
23
24
25
26
OMe
OMe
F
F
F
F
28
29
9.09
0.65
132
69
N
N
H
H
Me
N
N
N
30
31
32
0.40
0.19
3.07
>300
1.74
166
N
S
N
N
coplanar conformation observed with methyl amide 4 is unlikely
to be perturbed in these molecules, whilst additional interactions
between the heterocycle and the protein may explain the marked
improvement in potency observed with these heterocyclic amide
analogs.
N
N
O
N
33
34
35
36
37
0.94
>300
>300
89
Key compounds from each series were evaluated in vitro for hu-
man liver microsomal (HLM) stability and Caco-2 permeability and
in vivo for oral exposure in rats, with the results compared to the
parent indole 1 (Table 5). The more stable primary amide 3,
although intrinsically less permeable, showed 2.3-fold better oral
bioavailability in rat than 1. Phenylsulfonamide 20 and tetrazol-
5-ylamide 30 possessed greater HLM stability compared to other
amide analogs, but were poorly permeable and showed poor oral
exposure in rat, presumably a function of their overt acidic nature.
The highly potent thiazol-2-ylamide 35 displayed high permeabil-
ity but was unstable in HLM while analogs 22 and 23 showed no
advantageous in vitro properties. Interestingly, the methyl amide
4 exhibited a satisfactory balance of metabolic stability and perme-
ability amongst these analogs. This compound afforded a higher
oral exposure in rats compared to 1 as reflected in the seven-fold
improvement in oral bioavailability and 15-fold increase in Cmax
(843 vs 57 ng/ml). It is apparent from this study that the Caco-2
permeability correlates with the in vivo rat oral exposure for this
S
0.02
N
S
0.057
0.0058
0.32
N
S
N
29
S
N
81
H
N
38
39
0.04
0.21
9.2
N
S
>300
N
Ph
Table 5
Human liver microsomal (HLM) stability, Caco-2 permeability and rat oral exposure associated with indole-7-carboxamides
X
O
O
N
H
N
N
R
HN
O
O
Y
Compound
R
X
Y
HLM T1/2 (min)
Caca-2 Pc pH 6.5a (nm/s)
100
Rat oral Fb (%)
9
1
—
—
—
H
>100
3
4
F
F
>100
81
24
21
65
H
H
H
112
Me
O
S
Ph
20
F
>100
15
<2
O
22
23
OMe
F
H
40
25
39
51
N.D.
N.D.
Me
H
Me

K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 198–202
201
Table 5 (continued)
Compound
R
X
F
Y
HLM T1/2 (min)
Caca-2 Pc pH 6.5a (nm/s)
<15
Rat oral Fb (%)
H
N
N
N
30
35
H
>100
<1%
N.D.
N
S
F
H
4.1
>300
N
N.D. = not determined.
a
Metoprolol and mannitol were used as reference agents.
Rat: IV 1 mg/kg, PO 5 mg/kg, vehicle 90% PEG 400/10% EtOH.
b
strated a substantial improvement in IV clearance (12 vs 48 mL/
min/kg) and half-life (131 vs 28 min) in rats compared to 1.
The favorable pharmacokinetic properties of the methyl amide
4 as observed in rat also extended to both the dog and monkey,
as shown in Table 6. In addition, compound 4 exhibited a favorable
in vitro profile: the predicted human clearance was 5.7 mL/min/kg
based on its half-life in human liver microsomes, IC50s for CYP 450
Table 6
Animal pharmacokinetic parameters of methyl amide 4 (dosing vehicle 90% PEG 400/
10% EtOH)a
Oral F (%)
IV T1/2 (min)
Cmax (ng/ml)
AUC (lgÁmin/ml)
277
422
206
Rat
Dog
Monkey
65
93
70
131
139
251
843
1556
1329
inhibition were >90
lM and in vitro hepatotoxicity IC50s were
aRat: IV 1 mg/kg, PO 5 mg/kg; dog and monkey: IV 1 mg/kg, PO 2.5 mg/kg.
>57 M against immortalized human liver cell lines expressing
l
CYP3A4, 2C9, 2C19 and 2D6. However, methyl amide 4 was
not considered for further advancement since it possessed insuffi-
cient potency against a range of HIV-1 clinical isolates and labora-
tory strains when tested in the presence of human serum in cell
culture. This deficiency was attributed to its high protein binding
(98.9%).13
series of C7 amide indole analogs. Further development of 1 was
hampered by its poor aqueous solubility which resulted in poor
oral absorption following dosing of aqueous suspensions.6b The
improvement in oral bioavailability seen with amides 3 and 4
when compared to 1 is likely a result of the increase in solubility
in the amide analogs. For example, a crystalline sample of methyl
In summary, incorporation of substituted amides at the C7 po-
sition of the early lead compound 1 provided inhibitors of HIV-1
attachment with improved potency. Picomolar inhibitors were ob-
tained in the heteroaryl carboxamide series, as exemplified by
compounds 34, 35, 36 and 38. However, the simple methyl amide
analog 4 provided enhanced HLM stability and Caco-2 cell perme-
amide 4 showed an aqueous solubility of 33 lg/mL at pH 6.5,
which is almost four Log10 higher than the 5 ng/mL solubility
exhibited by 1. The solubility of an amorphous sample of 4 in
PEG 400 is approximately four-fold better than 1 (18 mg/mL and
4.6 mg/mL, respectively).6b In addition, methyl amide 4 demon-
O
Cl
F
F
F
F
O
O
+
b
c
N
a
HN
N
H
N
H
N
H
N
H
Br
CN
MeO
O
MeO
O
43
40
41
42
F
O
N
O
N
O
O
N
O
N
O
F
d
e
N
H
N
H
4
44
N
H
O
MeO
O
f
O
N
O
N
O
amine
ref 14
F
3
20
27 39
to
to
and
N
H
45
HO
O
Scheme 1. Synthesis of methyl amide 4 and analogs. Reagents and conditions: (a) CuCN, DMF, 145 °C, 17 h, 61%; (b) (i) HCl, MeOH, rt, 18 h then reflux 12 h; (ii) TMSCHN2,
MeOH/PhH, rt, 35 min, 100%; (c) (ClCO)2, CH2Cl2, 65 °C, 14 h; (d) i-Pr2EtN, THF, rt, 15 h, 76% (2 steps); (e) 40% MeNH2/H2O, rt, 83%; (f) aq NaOH, MeOH, rt 10 h, 86%.

202
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 198–202
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Zadjura, L. M.; Tweedie, D. L.; Huang, S.; Zhao, F.; Ranadive, S.; Robinson, B. S.;
Gong, Y.-F.; Ricarrdi, K.; Spicer, T. P.; Deminie, C.; Rose, R.; Wang, H.-G. H.; Blair,
W. S.; Shi, P.-Y.; Lin, P.-F.; Colonno, R. J.; Meanwell, N. A. J. Med. Chem. 2003, 46,
4236; Part 2: (b) Meanwell, N. A.; Wallace, O. B.; Fang, H.; Wang, H.;
Deshpande, M.; Wang, T.; Yin, Z.; Zhang, Z.; Pearce, B. C.; James, J.; Yeung, K.-S.;
Qiu, Z.; Wright, J. J. K.; Yang, Z.; Zadjura, L.; Tweedie, D. L.; Yeola, S.; Zhao, F.;
Ranadive, S.; Robinson, B. A.; Gong, Y.-F.; Wang, H.-G. H.; Blair, W. S.; Shi, P.-Y.;
Colonno, R. J.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009, 19, 1977; Part 3: (c)
Meanwell, N. A.; Wallace, O. B.; Wang, H.; Deshpande, M.; Pearce, B. C.; Trehan,
A.; Yeung, K.-S.; Qiu, Z.; Wright, J. J. K.; Robinson, B. A.; Gong, Y.-F.; Wang, H.-G.
H.; Blair, W. S.; Shi, P.-Y.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009, 19, 5136; Part
4: (d) Wang, T.; Kadow, J. F.; Zhang, Z.; Yin, Z.; Gao, Q.; Wu, D.; Digiugno Parker,
D.; Yang, Z.; Zadjura, L.; Robinson, B. A.; Gong, Y.-F.; Blair, W. S.; Shi, P.-Y.;
Yamanaka, G.; Lin, P.-F.; Meanwell, N. A. Bioorg. Med. Chem. Lett. 2009, 19, 5140;
Part 5: (e) Wang, T.; Yin, Z.; Zhang, Z.; Bender, J. A.; Yang, Z.; Johnson, G.; Yang,
Z.; Zadjura, L. M.; D’Arienzo, C. J.; Parker, D. D.; Gesenberg, C.; Yamanaka, G. A.;
Gong, Y.-F.; Ho, H.-T.; Fang, H.; Zhou, N.; McAuliffe, B. V.; Eggers, B. J.; Fan, L.;
Nowicka-Sans, B.; Dicker, I. B.; Gao, Q.; Colonno, R. J.; Lin, P-F.; Meanwell, N. A.;
Kadow, J. F. J. Med. Chem. 2009, 52, 7778; Part 6: (f) Kadow, J. F.; Ueda, Y.;
Meanwell, N. A.; Connolly, T. P.; Wang, T.; Chen, C.-P.; Yeung, K.-S.; Zhu, J.;
Bender, J. A.; Yang, Z.; Parker, D.; Lin, P.-F.; Colonno, R. J.; Mathew, M.; Morgan,
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2011, 55, 722.
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Krystal, M.; Wind-Rotolo, M.; Bertz, R.; Grasela, D. 18th Conference Retroviruses
Opportunistic Infections, Boston, MA, February 27–March 2, 2011, Abstract 49.;
(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. J. Infect. Dis. 2012, 206, 1002.
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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. 241st ACS National Meeting & Exposition, Anaheim, CA, United
States, March 27–31, 2011, MEDI 29.
ability which translated into favorable pharmacokinetic properties
in rat, dog and monkey. The insight that the intramolecular hydro-
gen bonding-stabilized, coplanar conformation of the secondary
methyl amide 4 apparently contributed to the dramatic increase
in potency compared to the dimethyl amide 5 was subsequently
assimilated into the design of second generation inhibitors in
related heterocycle core series. That work ultimately led to the
identification of BMS-626529,
a 6-azaindole analog that is
currently in clinical studies as the phosphonoxymethyl prodrug,
BMS-663068.8,9
Chemistry
The synthesis of the methyl amide 4 is depicted in Scheme 1.
Cyanation of 7-bromo-4-fluoroindole 40 was followed by hydro-
lytic conversion of the 7-cyanoindole 41 to the methyl ester 42.
Installation of the diketo moiety on 42 by a Friedel–Crafts acylation
using oxalyl chloride provided the acid chloride 43, which was cou-
pled with benzoylpiperazine to form the penultimate intermediate
44. Direct conversion of the 7-methyl ester to the methylamide
was achieved by using 40% aqueous methylamine to furnish analog
4. Basic hydrolysis of the methyl ester 44 gave the pivotal acid 45,
which was coupled with various amines under common amide
coupling conditions to provide the C7-carboxamide analogs ( 3–
20 and27–39) in Tables 2 and 4, as previously described.14 Analogs
21–26 in Table 3 were prepared in a similar manner.
References and notes
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13. The resolution of this issue will be the subject of a separate report.
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Fang, H.; Xue, Q. M.; Yin Z. U.S. Patent 6,573,262, June 3, 2003.