The design and development of 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides as inhibitors of human cytomegalovirus polymerase

Article abstract of DOI:10.1016/j.bmcl.2010.01.094

Discovery efforts were focused on identifying a non-nucleoside antiviral for treating infections caused by human cytomegalovirus (HCMV) with equal or better potency and diminished toxicity compared to current therapeutics. This Letter describes the HCMV D

Full text of DOI:10.1016/j.bmcl.2010.01.094

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1994–2000
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The design and development of 2-aryl-2-hydroxy ethylamine substituted
1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides as inhibitors of human
cytomegalovirus polymerase
b,
c
c
b
Steven P. Tanis a, , Joseph W. Strohbach , Timothy T. Parker , Malcom W. Moon , Suvit Thaisrivongs ,
William R. Perrault c, Todd A. Hopkins a, Mary L. Knechtel c, Nancee L. Oien c, Janet L. Wieber c,
Kevin J. Stephanski c, Michael W. Wathen c
*
*
a Global Research and Development, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA
b Global Research and Development, Pfizer Inc., 700 Chesterfield Parkway West, St. Louis, MO 63017, USA
c Global Research and Development, Pfizer, Inc., 7000 Portage Road, Kalamazoo, MI 49007, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Discovery efforts were focused on identifying a non-nucleoside antiviral for treating infections caused by
human cytomegalovirus (HCMV) with equal or better potency and diminished toxicity compared to current
therapeutics. This Letter describes the HCMV DNA polymerase inhibition and in vitro antiviral activity of
various 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 7 December 2009
Revised 15 January 2010
Accepted 19 January 2010
Available online 25 January 2010
Keywords:
Inhibitors
HCMV
VZV
DNA polymerase
Pyrido-quinoxalines
Amino ethanol
Antiviral activity
The Herpesviridae family of viruses are ubiquitous worldwide
and these viruses are frequent causative agents of viral infections.
The members of the Herpes family of viruses which infect humans
are the herpes simplex viruses (HSV-1 and HSV-2), varicella zoster
virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus
(EBV), and human herpes viruses (HHV-6, HHV-7 and HHV-8).1,2
While many in the immunocompetent population might be in-
fected with members of this viral family, these infections generally
remain latent in the host but can be reactivated by immunosup-
pression or stress. Evidence of infection by human cytomegalovirus
(HCMV) can be found in ca. 90% of the population, however in
immunocompetent individuals this infection is asymptomatic.
HCMV infection in the immunocompromised (e.g., AIDS, post-
transplant, cancer) is often associated with clinical symptoms such
as pneumonia and graft rejection. HCMV infection in neonates can
be associated with congenital birth defects.3 Current treatments
for HCMV infections such as ganciclovir, valganciclovir, foscarnet,
and cidofovir suffer from shortcomings which include toxicity
(hematologic, renal, CNS) and/or poor oral bioavailability.4 When
coupled with emerging drug resistance, especially in the immuno-
compromised population, these limitations provide a strong impe-
tus for the discovery of new classes of antiviral agents which are
safer and more effective.
The project team had previously reported the utility of 4-oxo-
dihydroquinolines such as 1 (Fig. 1) as inhibitors of HCMV poly-
merase (HCMV pol IC50) with broad spectrum antiviral activity
(e.g., HCMV plaque reduction assay = HCMV pra IC50, VZV pra
IC50) and good selectivity versus human
a
-DNA polymerase.5,6
The team found that select structural changes were well tolerated
leading to broad spectrum antiviral agents such as the 4-oxo-4,7-
dihydrothieno[2,3-b]pyridine 2.6 Further modification of the thie-
nyl side chain led to a breakthrough in polymerase enzymatic
inhibitory activity and antiviral activity as exemplified by the 4-
oxo-4,7-dihydrothieno[2,3-b]pyridine 3 bearing a chiral amino
ethanol at the thienyl-a
-position.7a Additional structural modifica-
tions led to 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamides
4 with a small loss of enzymatic and antiviral activity, and a signif-
icant improvement in aqueous solubility relative to 3.7b During the
course of the studies leading to compounds 1–4 investigations into
substitution at the pyridone nitrogen suggested a neutral to
* Corresponding authors. Tel.: +1 760 918 2484 (S.P.T.).
E-mail addresses: sptanis@sbcglobal.net (S.P. Tanis), joseph.w.strohbach@pfizer.
com (J.W. Strohbach).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.094

S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
1995
OH
O
O
O
O
O
O
CH3
HO
O
N
N
N
N
N
H
H
H
O
S
S
N
Cl
N
Cl
N
Cl
CH3
CH3
CH3
1 HCMVpol IC50 = 690nM
HCMVpra IC50 = 300nM
2 HCMVpol IC50 = 400nM
HCMVpra IC50 = 600nM
3 HCMVpol IC50 = 35nM
HCMVpra IC50 = 7nM
Aq. sol. = 0.19μg/mL
OH
N
N
O
O
O
O
O
N
O
CH3
O
N
N
N
N
N
N
H
H
H
OH CH3
O
O
N
Cl
Cl
N
Cl
CH3
OH
OH
4 HCMVpol IC50 = 76nM
HCMVpra IC50 = 26nM
Aq. sol. = 28.2μg/mL
5 HCMVpol IC50 = 350nM
HCMVpra IC50 = 40nM
Aq. sol. = 0.6μg/mL
6 HCMVpol IC50 = 14nM
HCMVpra IC50 = 10nM
Aq. sol. = 17μg/mL
Figure 1. The development of pyridone amides as Herpes antiviral agents.
negative impact with the possibility of utilizing this substitution to
alter the physical properties of the various series. The team wished
to further investigate the vectors emanating from this southern re-
gion of the molecule to determine if high levels of enzymatic/anti-
viral activity might be melded with improved physical properties.
This led to the preparation of a series of 6-oxo-6H-pyrrolo[3,2,1-
i,j]quinoline-5-carboxamides as exemplified by 58 and the amino
ethanol substituted 6.9 It is clear from a perusal of compounds
1–6 that one can realize good antiviral potency and reasonable sol-
ubility in a single entity via the choice of side chain (amino ethanol
versus morpholinomethyl), alteration of the nucleus (thienyl ver-
sus furyl), and modification in the southern region (hydroxy-
ethyl–pyrrolyl). Also, during the study leading to 4 Schnute
et al.7b have discussed the fit of the p-Cl-benzamide moiety into
the lipophilic pocket in the crystal structure of HSV-1 DNA poly-
merase and a study of p-Cl-benzamide replacements suggests that
this group is preferred.
nitrobenzene was brominated (NBS, AIBN, 57%) and the resulting
bromide alkylated with morpholine to provide amine 8 (87%).
The fluorine was replaced with methyl amine, the nitro was re-
duced (50 psi H2, Pd-C), and the crude diamine was bis-acylated
(ClCH2COCl) to give 9 (76% from 8). Treatment with aq. NaOH in
THF closed the lactam ring and cleaved the more accessible amide
moiety to provide the intermediate lactam.11 Treatment of the lac-
tam with diethyl ethoxymethylene malonate (DEEM) (toluene
110 °C) gave methylenemalonate 10 (78% over two steps) which
was smoothly cyclized upon treatment with Eaton’s reagent (11a,
90 °C, 89%).11,12 The sequence was completed by heating 11a in
the presence of 4-Cl-benzyl amine to afford the target pyridoqui-
noxaline 11b in an unoptimized 26% yield from the ester. Prelimin-
ary evaluation of 11b suggested that the alteration in the southern
region of the molecule was tolerated as 11b was associated with
The data of Figure 1 demonstrates that the nature of the side
chain (amino ethanol strongly preferred) is a crucial element in
the synthesis of a potent Herpes antiviral. The amino ethanol seg-
ment improves solubility as does substitution on the pyridone
nitrogen.7 To date, pyridone N-substitution has been limited and
we were drawn to compounds such as those shown in Fig. 2. We
reasoned that 1,9-disubstituted 1H,7H-pyrido[1,2,3-de]quinoxa-
line-6-carboxamides such as 7, with a simple morpholino-side
chain or a more complex amino ethanol side chain at the 9-posi-
tion, would allow us to further alter the characteristics of the mol-
ecule by variation of R1 at the 1-position.
Our initial target in the pyridoquinoxaline series was the 1-
methyl-9-morpholinomethyl pyridoquinoxaline 11 (Scheme 1).
The choice of the 9-morpholinomethyl entity is based upon prece-
dent with respect to antiviral activity5–9 as well as the demon-
strated ability of the morpholinomethyl to serve as a placeholder
for the reactive chloromethyl7,9 via a chlorinative deamination
with a chloroformate.10 Commercially available 2-fluoro-4-methyl
c, d, e
N
a, b
O
NO2
NO2
F
F
8
N
O
N
O
Cl
O
CO2Et
CO2Et
f, g
N
H
N
ClCH2CO2H
N
N
Cl
O
O
9
10
O
O
N
R
h, i
O
N
N
O
11a R = OEt
11b R =
HN
O
N
O
Cl
N
R2
N
H
HCMV pol IC50 = 620nM
HCMV pra IC50 = 100nM
O
R2
=
Cl
N
Scheme 1. Synthesis of 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides 11a,
11b. Reagents and conditions: (a) NBS, DCE, AIBN, , 57%; (b) morpholine, MeOH,
87%; (c) aq MeNH2, DMSO, , 97%; (d) H2 (50 psi), 5% Pd-C, THF; (e) chloroacetic
R1
N
N
D
OH CH3
O
D
7
anhydride, THF 79%; (f) aq 1 N NaOH, THF; (g) diethyl ethoxymethylene malonate,
toluene, 110 °C, 78%; (h) Eaton’s reagent, 89%; (i) 4-ClPhCH2NH2, ethylene glycol,
120 °C, 26%.
Figure 2. Proposed 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide Herpes
antivirals.

1996
S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
modest enzymatic activity (HCMV pol IC50 = 620 nM) and quite
reasonable antiviral activity (HCMV pra IC50 = 100 nM).
heat).17 We initiated our search for a general and mild Pd-medi-
ated thioester formation unaware of the work of Alper18 which
has led to the formation of phenylthioesters from aryl iodides uti-
lizing an ionic liquid (trihexyl(tetradecyl)phosphonium hexa-
fluorophosphate), Pd(OAc)2, Ph3P, and CO at 200 psi and 100 °C.
We examined Pd(OAc)2 (5 mol %)/Ph3P and Pd(PPh3)4 as palladium
sources, THF and DMF as solvents, CO at 1 atm and at pressures up
to 400 psi, and PhSH and NaSPh as thiol sources for this conversion.
We discovered19 that 12 can be smoothly converted to 13 in 91%
yield upon treatment with Pd(PPh3)4, PhSH (1.1 equiv), i-Pr2NEt,
and CO (1 atm via gas dispersion tube), in DMF at 90 °C on a
100 mmol scale. Reduction (LiBH4, THF, EtOH, 82%), conversion to
the related chloride (MsCl, LiCl, s-collidine, 89%)20 and treatment
with morpholine (i-Pr2NEt, DMF, 80%) then provided amine 14.
Alkylation of 14 with phenyl bromoacetate (Cs2CO3, DMF, 60 °C)
gave the relatively reactive quinolone phenyl ester 15 which was
easily converted to the abnormal SNAr substrate 16 (93% from
14) after exposure to methylamine in THF at room temperature.
A number of conditions were examined for their ability to effect
the desired abnormal SNAr ring closure with KO-t-Bu in THF pro-
viding 11b (50%) from 22. Surprisingly, alternate bases and
Despite the reasonable enzymatic and antiviral activity associ-
ated with the first member of the pyridoquinoxaline series, we
were concerned with the synthetic sequence. A nine step sequence
which provided 11b in ca. 6.9% overall yield and calls for the intro-
duction of the amide substituent R1 (see: 7 Fig. 2) in the third step
is of concern for an analog program. Also of note will be the addi-
tional two steps required to convert compounds 7 (R2 = morpho-
line) to target amnioethanols (vide supra, Fig. 2).7,9 As a result of
these concerns we elected to examine a new synthetic sequence
which was initiated as the chemistry of Scheme 1 was being com-
pleted. It was our desire to develop a route which would allow the
introduction of groups R1 (Fig. 2) at a later stage of the sequence,
enabling greater flexibility in analog design while potentially pro-
viding higher overall yields.
Two major variations were considered for this modified route,
the first an abnormal intramolecular SNAr reaction13 to construct
the tricycle from a hydroxyquinoline, while the second major
change was the introduction of the morpholinomethyl moiety. In
this route we planned to construct the hydroxyquinoline nucleus
via a standard Gould–Jacob11,12 cyclization, affording an 8-fluoro-
4-hydroxy quinoline which should serve as a substrate for the
abnormal intramolecular SNAr reaction, while an iodide in the 6-
position was viewed as a precursor to the desired morpholinom-
ethyl via a Pd-mediated carbonylation. These efforts are presented
in Scheme 2.
Commercially available 2-fluoro-4-iodoaniline was heated with
DEEM to afford the related methylene malonate (83%) which was
smoothly cyclized in Gould–Jacob fashion upon heating in diphe-
nyl ether (250 °C, sparge with nitrogen, 91%). The resulting ester
was then converted to amide 12 upon treatment with 4-Cl-benzyl
amine (NaOMe, MeOH, DMSO, 120 °C, 90%) setting the stage for the
Pd-mediated carbonylation. In our initial plan, we wished to con-
vert 12 to a carbonylated product which would be readily trans-
formed into an alcohol, ester, amide, or aldehyde in a single step
from said intermediate. These desires led us to consider developing
a simple Pd-mediated thioester formation as this entity is ideally
suited for conversion into an alcohol under mild conditions
(LiBH4),14 and has been converted directly to aldehydes (Pd-C, Et3-
SiH),15 esters (ROH, base, mild heat),16 and amides (amine, mild
Table 1
HCMV polymerase inhibition for compounds 17b, 23–26
O
N
O
N
N
H
O
Cl
N
R1
O
R1
HCMV pol IC50 (nM) HCMV pra IC50 (nM)
a
a
11b CH3
620
1280
830
100
ND
700
ND
17
18
19
CH3CH2
HOCH2CH2
HOCH2CH2CH2
1840
20
O
N CH2CH2CH2 4410
ND
a
Ref. 6.
OH O
O
OH O
I
I
a, b, c
N
d
e, f, g
PhS
N
H
H
N
Cl
N
Cl
i
NH2
F
F
F
12
13
OH O
N
O
N
O
h
N
N
N
O
N
H
H
O
O
Cl
Cl
F
F
CO2Ph
15
14
O
O
O
O
j
N
N
N
N
H
H
O
N
Cl
N
F
Cl
H
N
N
O
O
16
11b
Scheme 2. Synthesis of 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide 11b. Reagents and conditions: (a) diethyl ethoxymethylene malonate, 120 °C, 83%; (b) Ph2O,
250 °C, 91%; (c) 4-ClPhCH2NH2, NaOMe–MeOH, DMSO, 120°, 90%; (d) Pd(PPh3)4, CO, PhSH, i-Pr2NEt, 90 °C, 91%; (e) LiBH4, THF, EtOH, 82%; (f) MsCl, LiCl, s-collidine, DMAP,
THF, DMF, 89%; (g) morpholine, i-Pr2NEt, DMF, 80%; (h) BrCH2CO2Ph, Cs2CO3, DMF, 60 °C; (i) RNH2, THF, (R = CH3, 93%); (j) KO-t-Bu, THF, rt, 50%.

S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
1997
Table 2
HCMV pol/pra IC50 and cLog P/cLog D for compounds 11b, 22–35
O
N
O
R2
N
H
Cl
N
O
R2
HCMV pol IC50 (nM)
HCMV pra IC50 (nM)
100
cLog Pb (cLog Db)
LipEd
a
a
N
11b
22c
620
0.80 (0.78)
6.20
3.10
O
130
100
ND
20
3.10 (2.74)
1.61 (1.40)
1.61 (1.38)
N
OH Me
23
9160
300
N
OH Me
24c
25
6.08
N
N
N
OH Me
5250
150
ND
10
N
OH Me
26c
27
6.39
N
N
N
OH Me
4550
ND
N
OH Me
N
N
N
N
28
29
260
200
ND
0.61 (0.43)
6.08
N
OH Me
7700
N
OH Me
30c
31
110
10
2.26 (2.04)
2.78 (2.48)
3.14 (3.04)
5.74
4.22
3.86
O
N
OH Me
4930
190
ND
100
ND
100
O
N
OH Me
S
32c
33
N
OH Me
S
5720
490
N
OH Me
N
34
S
N
OH Me
(continued on next page)

1998
S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
Table 2 (continued)
R2
HCMV pol IC50 (nM)
HCMV pra IC50 (nM)
cLog Pb (cLog Db)
LipEd
a
a
N
35
6200
42
ND
ND
S
N
OH Me
36c
2.97 (2.75)
5.27 (5.06)
N
N
OH Me
S
37c
38c
97
8
100
ND
1.73
N
OH Me
3.56 (3.33)
3.56 (3.33)
3.56 (3.33)
O
N
OH Me
39c
40c
4
1
5.44
3.48
O
O
N
OH Me
180
90
N
OH Me
a
Ref. 6.
b
Calculated utilizing ACD Labs 12.0 software.
c
CC50 > 15
Ref. 21.
lM (Ref. 6).
d
O
N
O
preserving the bulk of the activity of the parent 11b. Moving for-
ward, we will examine changes at R2 while keeping R1 (7, Fig. 2)
as a methyl group.
Cl
N
N
H
EtOCOCl
CHCl3, Δ
11b
Cl
Cl
Variation of the R2 substituent of 7 (Fig. 2) calls for us to employ
the chiral amino ethanols7c as side chains. These entities have
afforded high levels of enzymatic and antiviral activity while alter-
ing the properties of the final molecules.6–9 Toward that end,
amine 11b will serve as the starting material, affording the desired
chloromethyl intermediate 21 (92%, Scheme 3) after treatment
with ethyl chloroformate.6,7,9,10 Alkylation of 21 with (S)-2-(meth-
ylamino)-1-phenylethanol21 (THF, i-Pr2NEt, activated 4 Å molecu-
lar sieves) then afforded the target analog 22 in 85% yield.
Utilizing the chemistry of Scheme 3, the compounds of Table 2
were prepared.
N
H3C
O
21
O
O
N
H
N
H
OH
OH
i-Pr2NEt
4Åsieves, THF
N
N
H3C
O
22
Scheme 3. Synthesis of side chain modified 1H,7H-pyrido[1,2,3-de]quinoxaline-6-
carboxamide 22.
An examination of Table 2 indicates that the impact of the ami-
no ethanol side chain is apparent in the pyridoquinoxaline series
and that the preferred asymmetry of the amino ethanol remains
the same as previous studies.7,9 Potent HCMV pol activity
(IC50 < 500 nM) and excellent antiviral activity (HCMV pra
IC50 < 200 nM) are associated with each of the favored monocy-
clic-aminomethanol enantiomers (compounds 22, 24, 26, 28, 30,
32, and 34). The most potent compounds of this series furan 30
(HCMV pol IC50 = 110 nM; HCMV pra IC50 = 10 nM) and pyridine
26 (HCMV pol IC50 = 150 nM; HCMV pra IC50 = 10 nM) present a
solvents proved ineffective in this cyclization during our initial tri-
als. The alternate route to 11b afforded the target material in 10
steps and 17% overall yield. As a result of the higher overall yield
and the late introduction of the pyridoquinoxaline N-substituent
(15–16), we were well positioned for our planned studies of the
impact both the R1 and R2 substituents.
hydrogen bond acceptor
a- or b-to the point of attachment. An
Utilizing the chemistry of Scheme 2, but altering the amine used
in the conversion of ester 15 to the cyclization substrate 16, we
prepared the compounds of Table 1. Despite our initial desire to al-
ter the physical characteristics of the pyridoquinoxaline series by
varying the R1 group of compound 7 (Fig. 2), it is clear from an
inspection of Table 2 that the modification of the R1 group to larger
than a methyl, with or without added polarity, is neutral to detri-
mental, with only the hydroxyethyl containing compound 18
extension of this series to a small set of bicyclic-aminoethanols7a
was next examined. These had proven useful in the dihydrothie-
no[2,3-b]pyridine series but had not provided optimal physical
characteristics in that series. Three bicyclic aryl-aminoethanols
were selected, each with a heteroatom
attachment to the carbinol carbon: 2-quinolinyl-, benzothienyl-,
and benzofuranyl. As shown in Table 2 all of the racemic bicyclic
a- or b- to the point of

S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
1999
Table 3
Broad spectrum activity for compounds 11b and 43 and comparison with established therapies
Solubilityc
g/mL)
b
b
HCMV pol
IC50 (nM)
HCMV pra
IC50 (nM)
VZV pol IC50
(nM)
VZV pra IC50
(nM)
Human
IC50 (nM)
a
-pol
b
b
b
(l
O
N
O
N
N
H
O
620
100
180
20
>5000
8.6
Cl
N
H3C
11b
O
N
O
N
O
O
N
H
4
1
29
4
>5000
0.94
OH CH3
Cl
N
H3C
39
O
Ganciclovir
Acyclovir
Foscarnet
Aphidicolin
AZT-TPa
1300
>20,000
8100
2500
487
22,100
473
5800
a
b
c
AZT-TP: zidovudine triphosphate.
Ref. 6.
Ref. 22.
aryl-aminoethanols afforded analogs which are as potent (36, 37)
or more potent (38) in the HCMV pol assay than any of the preced-
ing compounds of Table 2. The HCMV pol IC50 = 8 nM associated
with rac-benzofuranyl containing 38 is noteworthy, suggesting
the utility of the chiral congeners. Utilization of (R)-1-(benzofu-
ran-2-yl)-2-(methylamino)ethanol7c and (S)-1-(benzofuran-2-yl)-
2-(methylamino)ethanol7c led to 39 and 40 respectively. Of special
interest is the notable HCMV pol activity (IC50 = 4 nM) and HCMV
antiviral activity (HCMV pra IC50 = 1 nM) associated with the (R)-
1-(benzofuran-2-yl)-2-(methylamino)ethanol containing com-
pound 39. The enzymatic and antiviral activity exhibited by the
(S)-1-(benzofuran-2-yl)-2-(methylamino)ethanol containing 40
(HCMV pol IC50 = 180 nM; HCMV pra IC50 = 90 nM) is surprising
(23, 25, 27, 29, 31, 33, 35: HCMV pol IC50 P 4550 nM.7a,b,9) in light
of the data of Table 2 and earlier reports,7,9 however, given the po-
tency exhibited by 39, it is possible that this is the result of the ca.
1% contaminant of the antipodal (R)-aminoethanol ((S)-1-(benzo-
furan-2-yl)-2-(methylamino)ethanol, 98% ee).
We have examined calculated Log P and Log D values for the
compounds of Table 2 in an attempt to associate the level of ob-
served activity with a particular lipophilicity (Log P) and/or Log D.
The cLog P and cLog D values for 39 and 40 (cLog P = 3.56,
cLog D = 3.33) are higher than the most lipophilic momocyclic-
compound of Table 2 (compound 34; cLog P = 3.14, cLogD = 3.04)
and lower than that calculated for 37 (cLog P = 5.27, cLog D = 5.06)
the antiviral data for these compounds does not appear to correlate
solely with cLog P. If we compare 39 to the most potent monocy-
clic-compound of Table 2, furan containing 30 (cLog P = 2.26,
cLog D = 2.04) we cannot attribute the difference in activity as
being exclusively due to increased lipophilicity (viz. 37). We have
also evaluated the properties of potency and lipophilicity for com-
pounds of Table 2 using the Lipophilic Efficiency paradigm (LipE)
recently reported by Ryckmans.21 If the analysis above re: cLog P
and cLog D is valid, we would expect the most efficient compounds
to be clustered near the same LipE line. Should we be gaining po-
tency solely through added lipophilicity, then those compounds
should fall off from this line significantly. Utilizing the HCMV pra
IC50 data of Table 2, LipE values were calculated. The benchmark
morpholinomethyl containing 11b is associated with LipE = 6.20,
while 2-pyridyl 24, 3-pyridyl 26, 2-furyl 30, and 2-benzofuranyl
39 are associated with LipE = 6.08, 6.39, 5.74 and 5.44, respectively.
Thus, the most interesting compounds of this study are clustered
around a similar LipE line = 6 placing them in a highly optimized
grouping as described by Ryckmans et al.21
In conclusion, the pyridoquinoxaline nucleus has proven to be
a useful core for the construction of novel herpes antiviral agents,
providing compounds such as 39 which compare favorably to
established therapies (Table 3). The standard morpholinomethyl
side chain affords reasonable levels of enzymatic and antiviral
activity exemplified by compound 11b. The application of the
SAR previously described7,9 for the 2-aryl-2-hydroxyethylamine
motif to the pyridoquinoxaline nucleus has provided analogs of
good to excellent enzymatic and antiviral activity. Of significance
was the impact of the benzofuran moiety in compound 39, which
resulted in extremely potent enzymatic and antiviral activity
with a small impact on LipE. Future activities should attempt to
maintain the desirable aspects of compounds such as 39 while
improving solubility,22 toward and beyond that exhibited by
11b, while continuing to improve other biopharmaceutical
properties.
References and notes
1. (a) Villarreal, E. C. Prog. Drug Res. 2003, 60, 263. and 2001, 56, 77; (b) Wathen,
M. W. Rev. Med. Virol. 2002, 12, 167.
2. Brideau, R. J.; Knetchel, M. L.; Huang, A.; Vaillancourt, V. A.; Vera, E. E.; Oien, N.
L.; Hopkins, T. A.; Wieber, J. L.; Wilkinson, K. F.; Rush, B. D.; Schwende, F. J.;
Wathen, W. M. Antiviral Res. 2002, 54, 19.
3. Alford, C. A.; Stagno, S.; Pass, R. F.; Britt, W. J. Rev. Infect. Res. 1990, 12,
S75.
4. (a) Faulds, D.; Heel, R. C. Drugs 1990, 39, 597; (b) Lalezari, J. P. J. AIDS Hum.
Retrov. 1997, 14, S22; (c) Chrisp, P.; Clissold, S. P. Drugs 1991, 41, 104; (d)
Sobera, L. A.; Radasseda, X.; Castaner, J. Drugs Future 1998, 23, 1168.
5. Brideau, R. J.; Knechtel, M. L.; Huang, A.; Vaillancourt, V. A.; Vera, E. E.; Oien, N.
L.; Hopkins, T. A.; Wieber, J. L.; Wilkinson, K. F.; Rush, B. D.; Schwende, F. J.;
Wathen, M. W. Antiviral Res. 2002, 54, 19; Oien, N. L.; Brideau, R. J.; Hopkins, T.
A.; Wieber, J. L.; Knechtel, M. L.; Shelly, J. A.; Anstadt, R. A.; Wells, P. A.;
Poorman, R. A.; Huang, A.; Vaillancourt, V. A.; Clayton, T. L.; Tucker, J. A.;
Wathen, M. W. Antimicrob. Agents Chemother. 2002, 46, 724.

2000
S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1994–2000
6. Schnute, M. E.; Cudahy, M. M.; Brideau, R. J.; Homa, F. L.; Hopkins, T. A.;
Knechtel, M. L.; Oien, N. L.; Pitts, T. W.; Poorman, R. A.; Wathen, M. W.; Wieber,
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19. A representative procedure for the conversion of 12–13 follows: Iodide 12
(45.66 g, 0.1 mol) was added to a three neck 1 L round-bottomed flask, and it
was covered with anhydrous DMF (0.4 L). The flask was equipped with a
magnetic stir bar, a 125 mL pressure equalized addition funnel, a medium sized
cold finger condenser, and a coarse frit gas dispersion tube. The set up was
swept with a flow of argon (addition funnel inlet, cold finger condenser outlet)
while i-Pr2NEt (27.14 g, 0.21 mol, 36.6 mL) was added to the reaction flask. The
addition funnel was charged with anhydrous DMF (0.1 L) and PhSH (12.12 g,
0.11 mol, 1.1 equiv, 11.3 mL). The argon flow is replaced by a flow of argon
through a 20 gauge syringe needle, bubbling through the DMF/PhSH mixture in
the addition funnel. The CO flow (vigorous through the gas dispersion tube)
into the mixture in the round-bottom flask is initiated and the vessel is
lowered into a preheated 90 °C oil bath. Bubbling (CO and Ar) is continued for
10 min while the solution warms and 12 gradually dissolves. During this
period the cold finger condenser is charged with a dry ice/i-PrOH mixture. At
the end of the 10 min period the addition funnel was capped with a serum cap
and the argon inlet was switched to a 20 gauge 1.5 inch syringe needle placed
into the open outlet of the cold finger condenser. With a vigorous flow of CO
bubbling through the DMF solution of 12 and i-Pr2NEt, the center joint of the
3 N RB flask was unstoppered and Pd(PPh3)4 (0.86 g, 0.75 mmol) was added in
one portion. The solution became lemon yellow as the Pd(PPh3)4 dissolved.
After complete dissolution of Pd(PPh3)4 the PhSH/DMF was added over 75 min.
As the addition progressed the reaction mixture turned orange, then red, and
finally after ca. 90% of the PhSH had been added, the solution became red–
black. HPLC analysis after 75 min indicated that the reaction was complete
(17 min gradient, 5:95 CH3CN/H2O[H3PO4–NaH2PO4 buffer] to 95:5): 12
tR = 7.29 min; 13 tR = 10.87 min). The mixture was cooled to room
temperature and the DMF was removed on a cold finger rotary evaporator
(vacuum pump pressure) with warming in a 40 °C oil bath to afford a red–black
solid. The crude material was triturated with CH2Cl2–pentane (0.5 L, 3:1) to
furnish a red–black solution and a cream colored solid. The mixture was chilled
in an ice-water bath for 30 min, then the solid was isolated by filtration. The
solid was rinsed with CH2Cl2–pentane (3 Â 100 mL, 3:1) to provide 28.92 g of
the thioester 13 after drying in a vacuum oven (70 °C). The triturate was
concentrated in vacuo to give a sticky red–black solid that was triturated with
CH2Cl2–pentane (0.25 L, 3:1) to give a red–black solution and a cream colored
solid. Isolation of the solid by filtration, washing with CH2Cl2–pentane
(3 Â 75 mL, 3:1) and drying in vacuo (70 °C) gave an additional 9.21 g of
thioester 13. The lots were combined to realize 38.13 g (82%) of 13. A portion
was recrystallized from CH2Cl2–MeOH to yield 13 as fine, cream colored
needles. Mp 222–223 °C.
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