1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position

Article abstract of DOI:10.1016/j.bmcl.2009.01.089

The use of a 1,3,4-oxadiazole in combination with an 8-hydroxy-1,6-naphthyridine ring system has been shown to deliver potent enzyme and antiviral activity through inhibition of viral DNA integration. This report presents a detailed structure-activity inv

Full text of DOI:10.1016/j.bmcl.2009.01.089

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1807–1810
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors.
Part 2: SAR of the C5 position
a
a
a
b
Brian A. Johns a, , Jason G. Weatherhead , Scott H. Allen , James B. Thompson , Edward P. Garvey ,
*
Scott A. Foster b, Jerry L. Jeffrey b, Wayne H. Miller b
a Department of Medicinal Chemistry, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709, USA
b Department of Virology, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of a 1,3,4-oxadiazole in combination with an 8-hydroxy-1,6-naphthyridine ring system has been
shown to deliver potent enzyme and antiviral activity through inhibition of viral DNA integration. This
report presents a detailed structure–activity investigation of the C5 position resulting in low nM potency
for several analogs with an excellent therapeutic index.
Received 10 December 2008
Accepted 15 January 2009
Available online 30 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
HIV-1 integrase
Integration
Two-metal chelation
According to UNAIDS estimates for 2007 over 33 million people
globally were living with the virus that causes AIDS. These esti-
mates include 2.5 million individuals that became newly infected
with HIV and tragically 2.1 million have perished during 2007
alone.1 In the preceding paper,2 the design of a novel 2-metal bind-
ing naphthyridine series was presented where oxadiazole and tri-
azole heterocyclic groups were part of the metal chelation motif.
That work not only showed the heterocycles to be a viable chelat-
ing isostere for the amido group, but also showed a series of C5-
sultam containing compounds (e.g. 2) having potency approaching
such as 2 upon deprotection of the methyl ether5 (Table 2). This
was a marked advance over the Cu2O conditions previously de-
scribed to make 2 primarily due to avoidance of copper complexed
intermediates (Scheme 1).
Bromo intermediate 6 was also useful in amine couplings either
employing contemporary Pd(0) catalyzed methods or by simple
thermal displacement of the bromide with a 2° amine to provide
27 (Scheme 2). Interestingly, this was not able to be accomplished
with 1° amines as it resulted in displacement of the methoxy group
rather than the halide. However, masking a 1° amine with a remov-
able group (p-methoxybenzyl) facilitated the desired selectivity to
give 28 which could be converted to the 5-mono substituted amino
intermediate en route to analogs such as amide 11 and amine 29
(Table 3).
that of the validated clinical candidate L-870,810 (3). In this paper
we expand the effects of 5-substitution on the biological activity of
the 1,3,4-oxadiazole series 1 (Fig. 1).
We decided that the encouraging potency of the 5-sultam con-
taining analog 2 justified a broader set of nitrogen containing ana-
logs. Beginning with 5-bromo naphthyridine derivative 5,3
hydrolysis and coupling of the bromo containing core to 4-fluor-
ophenylmethyl hydrazide and subsequent ring condensation pro-
vided the versatile late stage intermediate 6. The amide coupling
protocol of Buchwald4 was employed with various amido, urea,
carbamate, sulfonyl urea and sulfonamide coupling partners to
smoothly provide 5-N containing analogs 7–20 (Table 1). During
these coupling investigations, we also found that subjecting 6 to
these conditions (Pd2(dba)3) in the presence of the corresponding
sultam or sulfonamides coupled smoothly to provide sulfonamides
N
N
OH
7
N
N
O
O
OH
N
1
N
5
N
R
H
F
F
N
N
O
F
N
OH
N
3 (L-870,810)
SO2
N
2
N
SO2
* Corresponding author. Tel.: +1 919 483 6006; fax: +1 919 483 6053.
E-mail address: brian.a.johns@gsk.com (B.A. Johns).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.089

1808
B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1807–1810
Table 1
N
O
O
N
OMe
Amide, urea and carbamate substituents
N
CO2Me
N
a,b,c
N
O
OH N
N
N
N
Br
6
Br
F
F
N
d
5
R
N
O
F
OH N
N
N
O
OH N
N
N
T.I.8
6
7
Compound
R
IC50
(
lM)
EC50 (lM)
d
N
O
N
2
7
N
SO2
7
0.019
0.088
0.089
0.087
>156
O
F
N
Scheme 1. Reagents and conditions: (a) LiOH (aq), THF (85%); (b) F-
C6H4CH2C(O)NHNH2, EDCI, HOBt, CH2Cl2 (95%); (c) PPh3, I2, Et3N, CH2Cl2 (87%);
(d) Pd(OAc)2 or Pd2(dba)3, xantphos, pyrrolidinone or sultam, Cs2CO3, dioxane, 65
then TMSCl, NaI, MeCN, °C (92% for 7), (68% for 2).
O
N
8
>160
>411
127
428
10
O
N
9
0.025
0.072
0.028
0.033
0.085
0.038
0.023
0.015
0.012
0.013
0.013
0.011
0.034
0.11
Table 2
Sulfonamide and sulfonyl urea substitutents
N
O
OH
N
H
N
O
10
11
12
13
14
15
16
17
18
19
20
N
N
R
F
N
O
O
0.18
6
7
Compound
R
IC50
(lM)
EC50 (lM)
T.I.8
198
H
N
1.3
N
N
OEt
N
2
0.002
0.008
0.019
0.015
0.006
0.004
0.042
0.013
0.11
SO2
SO2
O
O
O
N
0.31
>40
58
21
22
23
24
25
26
>129
131
127
294
137
74
O
N
O
S
0.24
HN
HN
0.11
NH
O
O
O
N
O
N
O
S
0.087
0.030
0.045
0.094
0.021
0.056
120
>466
311
148
>666
>250
N
NMe
NH
N
0.084
0.031
0.063
0.19
N
O
N
N
SO2
N
N
O
SO2
N
N
O
OH
HN
N
SO2Tol
O
O
N
Similarly, the 5-halo intermediate 6 coupled smoothly with sev-
eral aryl boronic acids to yield 5-aryl substituents using standard
Suzuki conditions to provide a series of aryl derivatives (32–60)
(Scheme 3 and Table 4). A related method was also effective in pro-
viding the N-pyrazolyl substituted analog 61.
O
N
H
N

B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1807–1810
1809
Table 4
Aryl substitutents
N
O
OH N
N
O
a
N
O
OH N
N
N
6
N
F
N
27
F
b
Ar
N
H
F
N
O
OH N
N
N
O
O
N
c,d,e
6
7
N
Compound
Ar
IC50
(
lM)
EC50 (lM)
T.I.8
N
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
–Ph
0.029
0.030
0.011
0.008
0.020
0.002
0.010
0.015
0.080
0.008
0.002
0.006
0.004
0.018
0.004
0.004
0.018
0.004
0.012
0.004
0.004
0.003
0.011
0.006
0.009
0.015
0.023
0.012
0.004
0.021
0.036
0.056
0.036
0.035
0.17
49
40
194
200
24
>60
182
546
1400
435
241
1220
780
668
95
OMe
N
–2-Pyridyl
–3-Pyridyl
–4-Pyridyl
O
N
11
N
F
28
–2-Pyrazinyl
3-C6H4–CO2H
3-C6H4–CONHiPr
3-C6H4–NH2
0.23
Scheme 2. Reagents and conditions: (a) piperazinone, dioxane,
D, 2 h (53%); (b) 4-
MeOC6H4CH2NHCH3, NMP, 70–80 °C (68%); (c) TFA (99%); (d) Ac2O, CH2Cl2, 55 °C
0.028
0.015
0.010
0.014
0.058
0.010
0.012
0.012
0.013
0.029
0.009
0.022
0.008
0.015
0.006
0.009
0.023
0.013
0.008
0.026
0.10
(61%); (e) TMSCl, NaI, MeCN (57%).
3-C6H4–NHAc
3-C6H4–NHSO2Me
4-C6H4–CO2H
4-C6H4–CONH2
4-C6H4–CONHMe
4-C6H4–CONMe2
4-C6H4–CONHiPr
2-C6H4–SO2NMe2
4-C6H4–SO2NMe2
2-C6H4–SO2NHMe
2-C6H4–SO2NHiPr
4-C6H4–SO2NHiPr
4-C6H4–NHAc
4-C6H4–NHSO2Me
2-C6H4–SO2Me
3-C6H4–SO2Me
4-C6H4–SO2Me
4-C6H4–CN
Table 3
Amine substitutents
N
O
OH N
N
67
N
R
218
173
295
118
591
915
243
234
301
72
F
T.I.8
844
6
7
Compound
R
IC50
(
l
M)
EC50 (lM)
N
27
0.007
0.074
0.017
0.40
N
H
O
3-Furyl
2-Pyrrolyl
2-Pyrazolyl
1-(3-Methylpyrazolyl)
116
31
546
23
0.16
0.016
0.38
29
30
30
NH
N
N
R
N
O
O
N
0.019
0.012
0.038
0.043
162
c
N
a
SO2Me
6
N
CN
F
N
N
62 R=Me
63 R=H
31
205
b
F
CH2C(O)NMe2
N
O
N
N
OH N
O
N
N
b
N
O
OH N
N
N
O
N
O
N
O
a,b
F
R
6
R
32
64 R=NH2
65 R=OMe
66 R=OH
68 R=NH2
69 R=OH
70 R=NMe
F
d
e
f
c,b
N
O
OH N
67 R=NHMe
N
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4, Zn(CN)2, DMF 85 °C, (91%); (b)
TMSCl, NaI, MeCN; (c) urea H2O2, K2CO3, acetone/H2O (84%); (d) DMF–DMA, MeOH
(81%); (e) LiOH, THF (89%); (f) EDCI, HOBt, MeNH2, CH2Cl2 (63%).
N
N
N
F
61
The final area we chose to exploit was 5-carbonyl substituted
analogs including several 5-amido analogs. These were accessed
through a Negishi coupling of Zn(CN)2 under Pd(0) mediated con-
ditions to provide nitrile 62 (Scheme 4). Mild hydrolysis conditions
Scheme 3. Reagents and conditions: (c) PdCl2(PPh3)2, Na2CO3 (aq), phenylboric
acid, DMF 90 °C, (70%); (b) TMSCl, NaI, MeCN; (c) Pd2(dba)3, xantphos, 3-
methylpyrazole, Cs2CO3, dioxane, 65 °C (89%).

1810
B. A. Johns et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1807–1810
Table 5
ity. All of the data from the sub-100 nM compounds showed
5-Nitrile, acid and amide substituents
excellent separation from cytotoxicity clearly establishing the
antiviral effect for these series of analogs. It also became appar-
ent that the size of the C5 substituent was quite independent
from activity. Both amides and amino groups at C5 were well
tolerated and the relatively smaller derivatives such as carba-
mate 19 compared nearly equally to the amino analog 31 con-
N
O
OH N
N
N
R
F
taining
a somewhat extended chain on a piperazinyl ring
6
7
system. This trend of tolerance of size and polarity is also evi-
dent in the 5-aryl series shown in Table 4. Little difference is
noted when phenyl is replaced with the pyridyl isomers (33–
35). Not surprisingly the carboxylic acid analogs 37 and 42 show
a modest
fall-off between the enzyme and cellular data suggesting perhaps
limited penetration due to decreased membrane permeability.
Overall, the 5-aryl series showed excellent antiviral potency with
several analogs in the single digit nM range very much in line
with some of the more potent drug candidates from other
groups.
Finally, the C5-amide series shown in Table 5 displayed slightly
less potency in both the enzyme and cellular systems. It is unclear
if this trend is due to an increased acidity of the phenolic group of
the two-metal binding motif due to conjugation through the ring
or other effects of the amido group itself but in general these ana-
logs were around an order of magnitude less potent than some of
the 5-aryl and 5-N substituted derivatives.
In summary, we have presented significant data to support the
potency profile of C5 substituted 7-(1,3,4-oxadiazole)-1,6-naph-
thyridine integrase inhibitors. A preference for 5-amido, sulfon-
amido and aryl substitutions is clear from the data that was
obtained. Many of these analogs have a potency profile consistent
with previously reported clinical compounds that have been effica-
cious in human trials. The above results continue to show the oxa-
diazole can serve as an amide isostere for metal coordination
within the integrase two-metal binding pharmacophore.
Compound
R
IC50
(
lM)
EC50
(lM)
T.I.8
63
68
69
70
71
72
73
74
–CN
–CONH2
–CO2H
–CONHMe
–CONHiPr
–CONH(CH2)2OH
–CONH(CH2)3OH
0.24
0.10
0.86
0.12
0.19
0.13
>35
n.d.
75
>3
43
22
>9
>30
139
0.16
4.4
0.15
0.098
1.49
0.47
0.071
0.19
–CONH(CH2)2OMe
0.072
75
76
0.13
0.097
0.097
134
O
O
N
N
O
0.044
>144
NMe
O
O
N
N
77
78
0.027
0.074
0.22
>65
n.d.
OH
O
>14
NH
were employed using urea–hydrogen peroxide to produce the cor-
responding 1° amide 64. From the amide, treatment with DMF–
DMA smoothly converted the material to the methyl ester 65
which was then hydrolyzed and coupled using carbodiimide condi-
tions to provide the desired substituted amide 67. The amide 67
and its precursors were deprotected using the standard TMSI con-
ditions to provide the free phenols shown in Table 5.
The compounds presented in Tables 1–5 were evaluated in
for strand transfer activity against the recombinant enzyme6
and for antiviral activity in a pseudotyped HIV cell-based assay
(PHIV).7 It was clear when we started that 5-amido groups
would be promising based on the initial activity of sultam deriv-
ative 2. As can be seen from Tables 1 and 2, many of the 5-ami-
do and sulfonamide analogs are well below 100 nM potency in
the antiviral assay. There do not appear to be major trends
amongst the derivatives that were made other than nearly all
of the compounds showed very encouraging enzyme potency
that for the most part translated very closely into antiviral activ-
References and notes
1. United Nations program on HIV/AIDS (UNAIDS), AIDS epidemic update 2007,
December, 2007. Available from: www.UNAIDS.org.
2. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster,
S. A.; Jeffrey, J. L.; Miller, W. H. Bioorg. Med. Chem. Lett. 2009, 19, 1802.
3. Anthony, N. J.; Gomez, R. P.; Bennett, J. J.; Young, S. D.; Egbertson, M.; Wai, J. S.
WO 02/30426; Chem. Abstr. 2002, 136, 325438.
4. Buchwald, S. L.; Yin, J. J. Am. Chem. Soc. 2002, 124, 6043.
5. (a) Jung, M. E.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99, 968; (b) Jung, M. E.; Lyster,
M. A. J. Org. Chem. 1977, 42, 3761.
6. Boros, E. E.; Johns, B. A.; Garvey, E. P.; Koble, C. S.; Miller, W. H. Bioorg. Med.
Chem. Lett. 2006, 16, 5668.
7. Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster, S. A.; Miller, W. H.; Ferris, R. G.;
Hazen, R. J.; Underwood, M. R.; Boros, E. E.; Thompson, J. B.; Weatherhead, J. G.;
Koble, C. S.; Allen, S. H.; Schaller, L. T.; Sherrill, R. G.; Yoshinaga, T.; Kobayashi,
M.; Wakasa-Morimoto, C.; Miki, S.; Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T.
Antimicrob. Agents Chemother. 2008, 52, 901.
8. Therapeutic index (CC50/EC50).