Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8- Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild- type and mutant enzymes

Article abstract of DOI:10.1021/jm9707028

Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.

Full text of DOI:10.1021/jm9707028

2960
J . Med. Chem. 1998, 41, 2960-2971
Novel Non n u cleosid e In h ibitor s of HIV-1 Rever se Tr a n scr ip ta se. 7.
8-Ar yleth yld ip yr id od ia zep in on es a s P oten t Br oa d -Sp ectr u m In h ibitor s of
Wild -Typ e a n d Mu ta n t En zym es
J anice M. Klunder,*,†,# MaryAnn Hoermann,† Charles L. Cywin,† Eva David,§,| J anice R. Brickwood,§
Racheline Schwartz,§ Kevin J . Barringer, Daniel Pauletti,§ Cheng-Kon Shih,§ David A. Erickson,
Christopher L. Sorge, David P. J oseph, Susan E. Hattox, J ulian Adams,†,‡ and Peter M. Grob§
Departments of Medicinal Chemistry, Inflammatory Diseases, and Drug Metabolism and Pharmacokinetics, Research and
Development Center, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877
Received October 16, 1997
Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone
nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and
in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is
associated with resistance to most reported nonnucleoside inhibitors. Introduction of an
arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers
enhanced potency against Y181C RT. Several analogues of this series display good broad
spectrum potency against a panel of mutant enzymes.
In tr od u ction
In the quest for effective therapies for treatment of
human immunodeficiency virus (HIV) infection, dem-
onstrated clinical benefit has now been achieved with
drugs that target the viral protease1 or reverse tran-
scriptase2 enzymes. As monotherapies, however, cur-
rently available agents provide only transient benefit,
due to the rapid emergence of drug-resistant viral
strains.3 Combinations of drugs have been tried in an
attempt to avoid the problem of resistance, with some
promising results,4,5 and combination therapy now
represents the standard of care. However, there is a
continuing need to identify improved agents within each
class in order to provide the optimum clinical benefit.
Among reverse transcriptase inhibitors that have
undergone clinical development, the majority are nu-
cleoside analogues. However, a number of structurally
diverse nonnucleoside reverse transcriptase (RT) inhibi-
tors have also been reported, all of which are character-
ized by specificity for HIV-1. The dipyridodiazepinone
nevirapine6 (Viramune, 1) is the first such nonnucleo-
side RT inhibitor to achieve regulatory approval. Like
the other nonnucleoside RT inhibitors, nevirapine se-
lects for drug resistant variants of HIV-1, both in cell
culture and in patients. In particular, the mutation of
residue 181 from tyrosine to cysteine (Y181C) is associ-
ated with resistance to nevirapine7 and to most reported
nonnucleoside inhibitors.8 Other mutations associated
with resistance to nevirapine include K103N, V106A,
G190A, and Y188L.
inhibitory activity against a variety of mutated, yet
enzymatically competent, viruses. As revealed by crys-
tallographic studies,9 the nonnucleoside RT inhibitors
bind at an allosteric site adjacent to the active site of
the enzyme. Many of the residues surrounding this
binding pocket are highly variable, including many of
those identified in connection with nonnucleoside drug
resistance. However, also located in this same region
are a number of other residues that are more highly
conserved, including in particular the catalytic aspartic
acid residues (Asp110, Asp185, Asp186). Mutation of
these residues results in inactive RT enzymes.10 The
side chains of several of these conserved residues face
nevirapine, suggesting that binding interactions with
these residues might be possible, given appropriate
substitution on the tricyclic skeleton. In addition, by
achieving multiple interactions with the enzyme, we
hoped both to enhance potency and to lessen the impact
of mutation at any given residue.
Successful application of this approach has already
been reported for compounds in the 2-aryldipyridodi-
azepinone series.11 We now report that dipyridodiaz-
epinone analogues bearing arylalkyl substituents at the
8-position of the tricyclic nucleus exhibit good potency
against both wild-type and mutant HIV-1 reverse tran-
scriptase enzymes. In the following paper,12 we report
that 8-aryloxymethyl and 8-arylthiomethyl dipyridodi-
azepinones are also potent broad spectrum inhibitors
of wild-type and mutant enzymes.
Our primary goal in the design of second generation
RT inhibitors, therefore, was to achieve broad-spectrum
† Department of Medicinal Chemistry.
#
Current address: Hale and Dorr LLP, 60 State St., Boston, MA
02109.
‡ Current address: ProScript, Inc., 38 Sidney St., Cambridge, MA
02139.
§ Department of Inflammatory Diseases.
| Deceased August 19, 1995.
Department of Drug Metabolism and Pharmacokinetics.
S0022-2623(97)00702-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/09/1998

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2961
Sch em e 1a
a
(a) Et2NH, xylenes, 105 °C; (b) SnCl2‚2H2O, HOAc, HCl; (c) DIEA, THF; (d) xylenes, 140 °C; (e) NaH, MeI, DMF; (f) SnCl2‚2H2O,
HOAc, HCl; (g) NaNO2, NaI.
Sch em e 2
8-substituents attached to the tricyclic nucleus by
means of a two-carbon tether provided good activity
(vide infra), the Heck reaction15 appeared to offer an
especially convenient alternative (Scheme 3, method B).
Indeed, coupling of methyl acrylate or acrylamide with
compound VIIIa (Cl2Pd(PPh3)4, Et3N, DMF, 100 °C)
proceeded smoothly to afford the corresponding 8-sub-
stituted dipyridodiazepinones in 70% and 90% yields,
respectively. A variety of vinylaromatic compounds also
served as suitable coupling partners. Although dimer-
ization was in some cases a troubling side reaction, the
trans-olefin XI was the only geometrical isomer or
regioisomer observed in any of these reactions. Hydro-
genation then afforded the saturated analogues XII.
Ch em istr y
The synthesis of 8-iodo dipyridodiazepinones VIIIa
and VIIIb is illustrated in Scheme 1. These compounds
served as precursors for the majority of compounds
reported here, with the 8-iodo substituent offering a
versatile handle for introduction of a variety of groups
at this position. In some of the chemistry that follows,
the 8-bromo derivative corresponding to VIIIb was used
in its place, with similar results. The synthesis of this
compound is reported in the following paper.
Stille13 methodology was first explored (Scheme 2,
method A); in the presence of Pd0, VIIIa coupled
efficiently both with allyltributylstannane and with
vinyltributylstannane. Subsequent functional group
transformations then provided analogues 7-10 (Table
1). The 8-benzyl analogue 15 and 8-anisyl derivative
16 were also prepared by Stille coupling, but in those
cases, dimerization of the dipyridodiazepinone repre-
sented the predominant reaction pathway. Coupling
reactions of VIIIa with organozinc reagents14 were also
briefly explored, with the phenylpropyl analogue 18
being synthesized by this method.
Surprisingly, many of the olefinic compounds XI
proved remarkably resistant to standard hydrogenation
conditions. For example, elevated temperatures and
pressures and extended reaction times (150 psi, 60 °C,
48 h) were required in order to achieve reduction of the
(4-pyridyl)ethenyl side chain. Such forcing conditions
were obviously unsuitable for the synthesis of 8-aryl-
ethyldipyridodiazepinones bearing a 2-chloro substitu-
ent. The use of platinum catalysts in an attempt to
minimize hydrogenolysis of the 2-chloro substituent
served instead to retard hydrogenation of the side chain.
Ultimately, transfer hydrogenation16 provided a solu-
tion to this problem and significantly simplified isolation
and purification of the product. Sodium hypophosphite
was employed as hydrogen donor, on the basis of
literature reports that its use minimizes hydrogenolysis
of aryl chlorides.17 In fact, at reaction temperatures of
70-80 °C, selective reduction of the olefin was achieved,
and 37 was isolated in 75% yield. However, rapid
Despite its successful application in the synthesis of
8-allyl and 8-vinyl analogues, the Stille approach suffers
the limitation that all but the simplest stannanes must
be prepared in a separate step. With the discovery that

2962 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Klunder et al.
Ta ble 1. Inhibition of HIV-1 Wild-Type RT and HIV-1 Y181C RT by 8-Substituted Dipyridodiazepinones
IC50 (µM)
no.
R
method
mp (°C)
recryst solvent
EtOAc/hexanes
triturated with petroleum ether
hexanes
1,2-dichloroethane/hexanes
MeOH/ether
EtOH/ether
ether/petroleum ether
ether/petroleum ether
ether
EtOAc/hexanes
EtOAc/hexanes
EtOAc/hexanes
EtOAc/hexanes
ether/petroleum ether
ether/petroleum ether
EtOAc/hexanes
EtOAc/hexanes
ether/petroleum ether
EtOAc/hexanes
formula
14H14N4O
C15H16N4O
14H13ClN4O
C14H15N5O‚0.4H2O
C15H16N6O2
C15H14N4O3
C15H16N4O2
C16H18N4O2
C17H20N4O2
C17H17N5O
C17H19N5O2
C18H20N4O3
C18H18N4O3
C21H21N4O
C21H20N4O2
C22H22N4O
C23H24N4O
WT RT
Y181C RT
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
CH3
Cl
ref 6b
NAa
ref 6b
NAa
NAb
Ac
130-132
95-95.5
105-106
193-194
235-237
148-250
129-131
114-115
109-111
157
C
0.09
0.75
0.54
0.10
1.1
NT
>>1
>>1
NT
NT
NT
0.74
2.50
2.90
2.16
6.1
C
NH2
NHC(O)NH2
CO2H
>>1
CH2OH
(CH2)2OH
(CH2)3OH
(CH2)2CN
Ad
Ae
0.05
0.43
0.30
0.21
0.62
0.09
Af
B
B
B
B
A
A
B
A
(CH2)2CONH2
(CH2)2CO2Me
trans-CHdCHCO2Me
CH2Ph
(3-OMe)Ph
(CH2)2Ph
177-179
98-99
0.14
NT
183-185
oil
>>1
0.12
>>1
1.20
>>1
0.13
1.17
0.58
>1
127-129
129-131
100-102
oil
0.05
0.12
0.25
3.0
(CH2)3Ph
cis-CHdCHPh
trans-CHdCH(4-pyr)
C
B
C
C
22H20N4O
21H19N5O‚0.5H2O
151-153
a
b
Prepared by methods analogous to those described in ref 6b. Prepared from 5 (KCNO, HOAc/H2O). c prepared by coupling VIIIa
d
with (n-Bu)3Sn(CHdCH2) to produce the 8-vinyl derivative followed by oxidative cleavage (RuCl3, NaIO4, CCl4, CH3CN, H2O). Prepared
from 7 [(i) ClCO2Et, TEA, THF; (ii) NaBH4, H2O]. e Prepared by hydroboration/oxidation of the 8-vinyl derivative. f Prepared by coupling
VIIIa with (n-Bu)3Sn(CH2CHdCH2) to produce the 8-allyl derivative followed by hydroboration/oxidation.
Sch em e 3
Sch em e 4
hydrogenolysis of the 2-chloro substituent was observed
when the temperature was allowed to climb above 85-
90 °C.
ners in reactions with VIII (Scheme 4, method C). The
reaction conditions (Cl2Pd(PPh3)2, Et3N, DMF, 100 °C)
used for reactions of vinylaromatics were suitable also
for arylacetylenes, and yields were generally high. This
route offered the advantage that hydrogenation of the
acetylenes XIV appeared to proceed more smoothly than
did hydrogenation of the corresponding olefins XI.
Preparation of cis-olefin 19 was achieved by Lindlar
reduction of the corresponding acetylene, itself prepared
in 80% yield according to method C (Ar ) phenyl).
As an alternative to methods B and C, the nature of
the coupling reaction was reversed, with the dipyridodi-
azepinone serving as the acetylene partner (Scheme 5,
method D). Synthesis of the requisite 8-ethynyldipyri-
dodiazepinones XVIII was accomplished in two steps
by coupling 8-iodo derivatives VIII with trimethylsilyl-
acetylene, followed by fluoride-induced cleavage of the
silyl group. With compounds XVIII in hand, the scope
The 2-fluoro analogues 39 and 42 were prepared
analogously to method B, by Heck reaction of the
2-fluoro-8-bromo precursor12 with the corresponding
vinylaromatics. Other compounds with varied substit-
uents at the 2-position were prepared from the corre-
sponding 2-chloro analogues. Compound 37 was con-
verted to the 2-iodo derivative 40, via the 2-trimeth-
ylstannane intermediate, by reaction with hexameth-
ylditin under palladium catalysis, followed by treatment
with iodine. The preparation of 2-cyano derivative 38
was accomplished by treatment of 37 with sodium
cyanide impregnated silica gel under palladium cataly-
sis.18 Coupling of 36 with N-Boc-pyrrole ((Ph3P)4Pd,
KOAc, DMF),19 afforded 2-pyrrolyl analogue 35.
Arylacetylenes were also employed as coupling part-

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2963
Sch em e 5
of compounds XV accessible by this methodology was
greatly expanded, due to the wide variety of com-
mercially available aryl halides. Coupling reactions and
hydrogenation proceeded analogously to methods B and
C.
According to method D, compound XVIII was coupled
with 4-bromo-2-picoline N-oxide to produce the acety-
lene in 95% yield. N-Oxide rearrangement (Ac2O, 105
°C),20 followed by hydrogenation (Pd, NaH2PO2, 1,4-
dioxane, 80-90 °C), then afforded compound 53. In a
similar fashion, coupling of XVIII with 4-bromo-2-
picolinic acid21 and hydrogenation of the resultant
acetylene afforded the acid 57. Curtius rearrangement
((PhO)2P(O)N3, Et3N, t-BuOH) of 57 produced 56, while
esterification and aminolysis provided compounds 54-
55.
virtually identical to that of the ester 13, and further
efforts focused exclusively on the 8-arylalkyl series.
Variations in the connecting chain (15-18) revealed
that a two-carbon linker is optimum for 8-arylalkyl
substituents, although a one-carbon linker is preferred
in the 8-hydroxyalkyl series. As noted above, trans-
unsaturation in the linking chain virtually abolishes
activity (e.g., 20). However, significant potency is
retained by compounds with cis-olefinic linkers (e.g., 19),
and cis-epoxides are also active (data not shown). This
suggests that the 8-arylalkyl side chain is bent in the
bioactive conformation of the inhibitor. A variety of
aromatic substituents were examined in place of the
phenyl group, with largely consistent results (Table 2).
However, ortho substitution on the aromatic ring is not
well tolerated by the Y181C mutant enzyme (e.g., 28,
33).
Biologica l Resu lts
Substitution at the 2-position of the dipyridodiazepi-
none nucleus was previously shown to confer potency
against the Y181C mutant enzyme.11 It was therefore
of some interest to determine if the effects of 2- and
8-substitution might be additive. In the event, the
2-pyrrolyl-8-phenethyl derivative 35 was found to suffer
a 10-fold reduction in potency as compared to the
corresponding compounds bearing either substituent
alone. Surprisingly, however, this compound exhibited
measurable activity against the highly refractory Y188L
mutant enzyme. Encouragingly, 2-chloro-8-phenethyl
disubstitution (36) also afforded inhibition of the Y188L
mutant enzyme, while at the same time retaining
potency against both the wild-type and the Y181C
mutant enzymes.
Compounds bearing 2-fluoro or 2-iodo substituents,
as exemplified by compounds 39 and 40, also exhibited
good potencies against wild-type and mutant enzymes.
However, the 2-cyano derivative 38 displayed a marked
decrease in potency against all three enzymes. Hydroxy
and amino substituents at the 2-position also led to
decreased activity (data not shown).
At the outset of the project, available SAR at the
8-position was not promising, with most simple substi-
tuents at this position leading to a decrease in potency
(Table 1, 3-5). Compounds bearing an 8-amino sub-
stituent (e.g., 5) provided a notable exception to this
trend, being roughly equipotent to the corresponding
unsubstituted compounds. Interestingly, comparably
positioned amino substituents were found to enhance
potency in related series of tricyclic oxazepinones.22
These data offered some hope that polar functionalities,
such as those intended to interact with the conserved
aspartate residues, might be tolerated at this position.
In fact, the 8-hydroxymethyl analogue 8 was found to
exhibit enhanced activity against the wild-type enzyme,
as well as submicromolar potency against the Y181C
mutant enzyme.
Esters, amides, nitriles and alcohols were all exam-
ined in the attempt to achieve electrostatic or hydrogen
bonding interactions with D185 or D186. Ester 13
represented a significant breakthrough, exhibiting good
potency against both wild-type and Y181C mutant
enzymes. By contrast, compound 14, in which the ester
is connected to the tricyclic core by means of a trans-
olefin linker, is almost completely inactive. Concerned
that the ester moiety in 13 might prove metabolically
unstable, we replaced it with a phenyl substituent. The
resultant analogue, 17, displayed an inhibitory profile
In general, 2-chloro derivatives and the corresponding
2-unsubstituted analogues are roughly equipotent against
wild-type enzyme (compare, for example, compounds 17
and 36 or 21 and 37). A notable exception to this trend
is compound 41, which is 10-fold less active than 30.
Apparently, in this case, the steric requirements of the

2964 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Klunder et al.
Ta ble 2. Inhibition of HIV-1 Wild-Type RT, HIV-1 Y181C RT, and HIV-1 Y188L RT by 8-Arylethyl Dipyridodiazepinones
IC50 (µM)
no.
Ar
phenyl
4-pyridyl
3-pyridyl
2-pyridyl
5-pyrimidyl
2-thiazolyl
4-tolyl
method
mp (°C)
recryst solvent
EtOAc/hexanes
EtOAc/hexanes
ether/petroleum ether
EtOAc/hexanes
formula
22H22N4O
21H21N5O
21H21N5O
WT RT
Y181C RT
Y188L
17
21
22
23
24
25
26
27
28
29
30
31
32
33
34
C
B
D
C
D
D
C
B
D
D
B
B
B
D
B
129-131
109-110
79-80
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
0.05
0.03
0.13
0.19
0.54
0.04
0.10
0.11
0.20
0.03
0.08
0.06
0.04
0.08
0.12
0.13
0.11
0.32
>1
>>1
>>1
>>1
>>1
>>1
>>1
>1
68-72
21H21N5O‚0.25H2O
142-143
EtOAc/hexanes
20H20N6O
>1
oil
19H19N5OSa,b
23H23N4O
0.44
0.25
0.28
1.6
0.09
0.15
0.20
0.07
1.7
120-122
103-104
151-152
128-129
136-137
157-158
129-130
157-158
130-131
EtOAc/petroleum ether
EtOAc/ether/petroleum ether
EtOAc/hexanes
ether/petroleum ether
EtOAc/hexanes
EtOH/hexanes
EtOAc/hexanes
EtOH/hexanes
EtOAc/hexanes
3-tolyl
2-tolyl
23H24N4O
23H24N4O
22H23N5O‚0.25H2O
26H24N4O
22H23N5O
22H23N5O
22H23N5O
22H21N4F
>>1
>1
4-(2-picolyl)
2-naphthyl
4-anilinyl
3-anilinyl
2-anilinyl
3-fluorophenyl
>>1
>>1
>>1
>1
>1
>>1
0.37
a
b
C: calcd, 62.45; found 63.07. N: calcd, 19.16; found, 16.69.
naphthylethyl side chain are such that the 2-chloro
substituent cannot be simultaneously accommodated by
the enzyme. Replacement of the 2-chloro group with a
smaller fluoro substituent (42) achieves the desired
increase in potency against mutant enzymes while at
the same time also maintaining potency against the
wild-type enzyme.
Limited exploration was made of SAR in the side
chain aromatic group. As already noted, ortho substitu-
tion is not well tolerated by the Y181C mutant, and in
combination with a 2-chloro substituent the 8-(2-tolyl)-
ethyl substituent (e.g., 45) abolishes activity against
wild-type enzyme as well. By contrast, substitution at
the position meta to the point of attachment is well
tolerated. An amino group at this position is particu-
larly favorable, especially for activity against the Y188L
mutant enzyme. Indeed, compounds 47 and 56 are
among the most potent analogues reported here against
all three enzymes of our primary assay.
patients undergoing monotherapy with nevirapine, but
it does appear in patients being treated with both
nevirapine and AZT. The good activity exhibited by
compounds such as 39, 47, and 56 against this mutant
was therefore very encouraging.
Having optimized the 8-arylethyldipyridodiazepino-
nes for potency against wild-type, Y181C, and Y188L
RT enzymes, however, we fully appreciated that alter-
native mutations might arise equally readily and result
in resistance to these new agents. Selected compounds
were therefore tested against an expanded panel of
mutant RT enzymes (Table 5). Represented in this
panel were mutations associated with resistance to
BHAP derivatives including delavirdine (P236L)23 and
to the pyridinones (K103N),24 as well as additional
mutations associated with resistance to nevirapine
(V106A, G190A). The enzymes of this panel were also
selected to be representative of possible mutations in
various regions of the nonnucleoside binding pocket.
All compounds tested potently inhibited the K103N
and G190A mutant enzymes. Structural analysis of
binding interactions between nevirapine and HIV-1
RT25 suggested that mutations at Gly 190 confer resis-
tance to the inhibitor due to repulsive steric interaction
between the amino acid side chain and the cyclopropyl
ring of nevirapine. This negative interaction and there-
fore resistance are less profound for compounds, such
as those reported here, with an N-ethyl substituent in
place of the cyclopropyl ring. Interactions of the dipyr-
idodiazepinones with Lys 103, which points toward the
C-ring nitrogen atom, are more complex. Although
conferring modest resistance to nevirapine, mutation of
this residue has little impact on sensitivity to many
dipyridodiazepinones.
Secon d a r y Assa ys
Selected compounds active in the primary assay were
tested for their ability to inhibit syncytia formation in
cell cultures infected with wild-type HIV-1IIIB virus
(Table 4). Consistent with the enzyme inhibitory po-
tency of this series of compounds, all compounds tested
were also effective antiviral agents in culture. An MTT
assay was conducted as a measure of the cytotoxic
effects of the compounds. In general, the 8-substituted
dipyridodiazepinone series is characterized by relatively
low cytotoxicity, and most compounds reported here
displayed CC30 values above 60 µM (data not shown).
Ironically, although the Y181C mutation confers
cross-resistance to many nonnucleoside inhibitors of
varied chemical structure, it has proven relatively easy
to identify dipyridodiazepinone analogues, including the
8-arylethyl derivatives reported here, with good potency
against Y181C RT. By contrast, as is evident from the
results presented in Table 1, the Y188L mutation
represents a significantly greater challenge. This mu-
tation is not typically observed in cell culture or in
The 8-phenethyl analogue 36 exhibits a 10-fold reduc-
tion in potency against the P236L mutant enzyme as
compared to wild-type enzyme. This finding is note-
worthy, since the P236L mutation, although conferring
resistance to BHAP derivatives, generally has no effect
on enzyme sensitivity to inhibition by dipyridodiazepi-
nones. The data are consistent with crystallographic

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2965
Ta ble 3. Inhibition of HIV-1 Wild-Type RT, HIV-1 Y181C RT, and HIV-1 Y188L RT by 2,8-Disubstituted Dipyridodiazepinones
IC50 (µM)
WT
RT
Y181C Y188L
no.
X
Ar
method mp (°C)
recryst solvent
formula
22H22N4O
C26H25N5O
22H21ClN4O
21H20ClN5O
C22H20N6O
21H20FN5O
C21H20IN5O‚0.25H2O
26H23ClN4O
26H23FN4O
23H23ClN4O‚0.25H2O
23H23ClN4O
23H23ClN4O
22H22ClN5O
22H22ClN5O
RT RT
17
H
phenyl
C
129-131
82-84
EtOAc/hexanes
ether
C
0.05
0.13 >>1
35 2-pyrrolyl phenyl
Ca
C
0.59
0.05
0.08
0.46
0.05
0.09
1.02
0.02
0.23
0.11
0.52
0.15
0.12
1.28
0.96
1.85
36 Cl
37 Cl
38 CN
39
40
phenyl
128-129.5 EtOAc/hexanes
C
C
4-pyridyl
4-pyridyl
4-pyridyl
4-pyridyl
2-naphthyl
2-naphthyl
4-tolyl
3-tolyl
2-tolyl
4-anilinyl
3-anilinyl
B
152-153
149-150
109-111
174
EtOAc/hexanes
EtOAc/hexanes
ether/petroleum ether
EtOAc/hexanes
ether/hexanes
EtOAc/hexanes
EtOAc/hexanes
ether/petroleum ether
EtOAc/hexanes
EtOH/hexanes
EtOH/petroleum ether
EtOAc/petroleum ether C23H23ClN6O2‚0.2H2O
EtOH/hexanes
EtOAc/hexanes
ether/petroleum ether C22H20ClN7O
Bb
B
0.29 >>1
F
I
C
0.08
0.18
0.25
0.43
Bb
B
41 Cl
42
115-117
112-114
120-122
100-102
180-182
191-192
121-123
121-123
199-204
131-132
104-105
94-96
C
C
C
C
C
C
C
2.88 >>1
F
B
0.03 >1
43 Cl
44 Cl
45 Cl
46 Cl
47 Cl
48 Cl
49 Cl
50 Cl
51 Cl
52 Cl
53 Cl
54 Cl
55 Cl
56 Cl
57 Cl
D
D
D
B
1.18 >>1
0.46
>>1
>1
>>1
>>1
0.16
0.12
0.06
0.33
0.14
0.08
0.06
0.16
0.15
0.05
0.02
1.5
0.36 >>1
B
0.23
0.08
0.56
0.14
0.16
0.14 >>1
0.28 >>1
0.48
0.25
0.07
0.25
0.23
>1
>1
>1
3-ureidophenyl
Bc
Bd
Be
Bf
D
D
D
D
D
D
4-(methylsulfonamido)phenyl
3-(methylsulfonamido)phenyl
3-azidophenyl
C23H24ClN5O3S‚0.25H2O
C23H24ClN5O3S
4-(2-picolyl)
ether/petroleum ether
C
C
C
C
C
22H22N5OCl‚0.5H2O
22H22N5O2Cl
4-(2-hydroxymethylpyridyl)
4-(2-carbomethoxypyridyl)
4-(2-amidopyridyl)
4-(2-aminopyridyl)
4-(2-carboxypyridyl)
133-134.5 ether/petroleum ether
149
EtOAC/ether
23H22N5O3Cl‚0.25H2O
22H21N6O2Cl‚0.25EtOAc
21H21N6OCl
6.0
4.0
0.16
145-147
95 dec
244-246
EtOAc/hexanes
ether/petroleum ether
CH2Cl2/hexanes
C22H20N5O3Clg
3.8 >>1
a
b
Prepared from 36; see Experimental Section. Prepared from 37; see Experimental Section. c Prepared from 47 (KCNO, HOAc/H2O).
Prepared from 46 (MsCl, pyr, CH2Cl2). e Prepared from 47 (MsCl, pyr, CH2Cl2). f Prepared from 47 (NaNO2, NaN3). C: calcd, 60.34;
d
g
found, 59.66. N: calcd, 16.00; found, 14.79.
Ta ble 4. Inhibition of HIV-1IIIB Replication in C8166 Cells
mutation at codon 106 is the most commonly identified
mutation in viral strains resistant to dipyridodiazepi-
none inhibitors. Indeed, viral selection in the presence
of 37 resulted in emergence of the V106A mutant.26
no.
IC50 (nM)a
21
36
37
48
25
12
9
Compounds 36, 37, 39, and 47 were additionally
evaluated for in vitro metabolic stability in human liver
microsomes.27 In comparison to nevirapine (1), which
exhibits a very slow rate of metabolism (2 (pmol/min)/
mg of microsomal protein) in this assay, compound 36
was rapidly metabolized (266 (pmol/min)/mg). Com-
pounds 37, 39, and 47 were all metabolized at a rate of
approximately 145 (pmol/min)/mg. Metabolites of these
compounds were found to be oxidized at both ring and
benzylic positions of the 8-arylethyl substituent (data
not shown).
39
a
Inhibitory concentration of compound producing a 50% reduc-
tions in the centers of syncytia. See ref 6a.
Ta ble 5. Inhibition of HIV-1 Mutant RT Enzymes
IC50 (µM)
no.
K103N
V106A
G190A
P236L
1
36
37
39
47
56
1.9
0.08
0.71
0.11
0.05
0.04
0.10
0.05
0.12
0.02
0.01
0.01
0.84
0.55
0.25
0.09
0.19
0.12
0.03
0.06
0.01
0.03
Con clu sion s
Introduction of an arylethyl substituent at the 8-posi-
tion of the tricyclic dipyridodiazepinone skeleton confers
enhanced potency against Y181C RT, and several
analogues of this series with good broad spectrum
potency against a panel of mutant enzymes were identi-
fied. The factors responsible for the improved inhibitory
profile of these compounds remain to be elucidated. The
fact that dramatic enhancements in potency against
wild-type enzyme were not observed suggests that one
set of binding interactions has been substituted for
another. Inspection of the crystal structure of HIV-1
RT reveals the presence of a number of aromatic amino
acid residues in the nonnucleoside binding pocket that
appear to be within reach of the 8-arylethyl substituent,
including Phe 227, Trp 229, and Tyr 232. Favorable
information showing the 8-position of nevirapine to be
pointed toward Pro 236 and provide additional confir-
mation that nonnucleoside inhibitors of diverse chemical
structures occupy overlapping regions of the same
binding pocket. Note, however, that the 8-pyridylethyl
analogue 37 shows little loss in potency against P236L
RT. The reasons for the different resistance profiles of
36 and 37 are not clear.
Consistent with their potency against enzymes of the
primary assay, compounds 39, 47, and 56 exhibit good
potency against the entire panel of mutant enzymes. For
all three compounds, as well as for compounds 36 and
37, inhibitory potency is weakest against the V106A
mutant. After the Y181C mutation, a valine to alanine

2966 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Klunder et al.
1
186 °C; H NMR (DMSO-d6) δ 10.06 (s, 1 H), 9.36 (d, J ) 2.8
Hz, 1 H), 9.13 (d J ) 2.8 Hz, 1 H), 7.97 (dd, J ) 2, 4.9 Hz, 1
H), 7.59 (dd, J ) 2, 8 Hz, 1 H), 6.60 (dd, J ) 4.9, 8 Hz, 1 H),
6.09 (t, J ) 5 Hz, 1 H), 3.39 (dq, J ) 7, 5 Hz, 2 H), 1.16 (t, J
) 7 Hz, 3 H); MS (CI) m/z 321 (MH+).
interactions between the side chain aryl substituent of
the inhibitor with these aromatic residues may contrib-
ute to binding affinity and diminish the importance of
interactions with residues such as Tyr 181. It should
be noted that Trp 229 in particular is highly conserved,
and mutation of this residue to alanine results in a
substantial decrease in RT activity.28 The analogues
reported here may therefore accomplish our goal of
achieving binding interactions with conserved residues
at the expense of interactions with more variable
residues. Whether this will result in prolonged efficacy
remains to be determined. Unfortunately, in vivo
studies with the compounds reported here are likely to
be hindered by their rapid metabolism and poor bio-
availability. The design of broad-spectrum inhibitors
with improved metabolic stability is described in the
following paper.
(d ) 5,11-Dih yd r o-11-et h yl-8-n it r o-6H -d ip yr id o[3,2-b:
2′,3′-e][1,4]d ia zep in -6-on e. A solution of 1.80 g of 2-chloro-
N-(2-ethylamino-3-pyridinyl)-5-nitro-3-pyridinecarboxamide in
25 mL of xylenes was heated at reflux for 4 h. After
concentration in vacuo, the residue was purified on a silica
gel column, eluting with 50% EtOAc/hexane, to give 0.93 g of
1
the title compound: mp 214-216 °C; H NMR (DMSO-d6) δ
10.73 (br s, 1 H), 9.24 (d, J ) 2.8 Hz, 1 H), 8.68 (d, J ) 2.8 Hz,
1 H), 8.23 (dd, J ) 2.5 Hz, 1 H), 7.55 (dd, J ) 2, 8 Hz, 1 H),
7.27 (dd, J ) 5, 8 Hz, 1 H), 4.25 (q, J ) 7 Hz, 2 H), 1.23 (t, J
) 7 Hz, 3 H); MS (CI) m/z 285 (MH+).
(e) 5,11-Dih ydr o-11-eth yl-5-m eth yl-8-n itr o-6H-dipyr ido-
[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e. Sodium hydride (60% oil
dispersion, 1.0 g, 0.025 mol) was added to a solution of 5,11-
dihydro-11-ethyl-8-nitro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-
6-one (7.0 g, 0.025 mol) in 120 mL of DMF. After 1 h,
iodomethane (1.6 mL, 0.026 mol) was added, and the reaction
mixture was stirred at room temperature overnight. The
reaction mixture was diluted with water and extracted with
EtOAc. The crude product was purified by flash chromatog-
raphy, eluting with EtOAc/CH2Cl2, to give 6.4 g of the title
compound: 1H NMR (DMSO-d6) δ 9.23 (d, J ) 2.8 Hz, 1 H),
8.66 (d, J ) 2.8 Hz, 1 H), 8.29 (dd, J ) 4.6, 2 Hz, 1 H), 7.94
(dd, J ) 2, 8 Hz, 1 H), 7.39 (dd, J ) 4.6, 8 Hz, 1 H), 4.23 (q, J
) 7 Hz, 2 H), 3.45 (s, 3 H), 1.24 (t, J ) 7 Hz, 3 H).
(f) 8-Am in o-5,11-d ih yd r o-11-eth yl-5-m eth yl-6H-d ip yr -
id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (5). Following a pro-
cedure analogous to that described in (b) above, 6.2 g of 5,11-
dihydro-11-ethyl-5-methyl-8-nitro-6H-dipyrido[3,2-b:2′,3′-e]-
[1,4]diazepin-6-one was reduced to give, after recrystallization,
4.4 g of the title compound as a yellow powder: 1H NMR
(DMSO-d6) δ 8.19 (dd, J ) 2, 5 Hz, 1 H), 7.83 (d, J ) 3 Hz, 1
H), 7.82 (dd, J ) 2, 8 Hz, 1 H), 7.30 (d, J ) 3 Hz, 1 H), 7.23
(dd, J ) 5, 8 Hz, 1 H), 5.27 (s, 2 H), 3.97 (br q, J ) 7 Hz, 2 H),
3.43 (s, 3 H), 1.15 (t, J ) 7 Hz, 3 H); MS (CI) m/z 270 (MH+).
Anal. (C14H15N5O‚0.4H2O) C, H, N.
Exp er im en ta l Section
Gen er a l. The procedures for the reverse transcriptase wild-
type and mutant enzyme, inhibition of HIV-1IIIB replication
in C8166 cells, the in vitro metabolism, and MTT toxicity
assays have appeared elsewhere.6a,11b,12 Short-path chroma-
tography was performed with EM-Science silica gel 60 (finer
than 230 mesh). Melting points were determined on a Bu¨chi
510 melting point apparatus and are uncorrected. 1H NMR
spectra were recorded on
a Bruker WM-250 (250 MHz)
spectrometer with Me4Si as the internal standard. Mass
spectra were recorded on a Finnegan 4023 GC/MS/DS spec-
trometer. Elemental analyses were determined by Midwest
Laboratories, Indianapolis, IN, and are within 0.4% of theo-
retical values unless otherwise noted.
5,11-Dih yd r o-11-et h yl-8-iod o-5-m et h yl-6H -d ip yr id o-
[3,2-b:2′,3′-e][1,4]diazepin -6-on e (VIIIa). (a) 2-Eth ylam in o-
3-n itr op yr id in e. A stirred mixture of 2-chloro-3-nitropyri-
dine (50.0 g, 0.32 mol), ethylamine (33.5 g, 0.74 mol), and
xylenes (85 mL) was heated at 105 °C in a sealed vessel for 3
h. After cooling, the solvent was removed in vacuo, and water
was added to the residue. The product was extracted with
CH2Cl2, dried (MgSO4), and concentrated in vacuo to give 56.8
g of the title compound as a brown oil, suitable for use in the
next reaction: 1H NMR (DMSO-d6) δ 8.46 (m, 2 H), 8.38 (dd,
J ) 1, 8 Hz, 1 H), 8.72 (dd, J ) 4, 8 Hz, 1 H), 3.58 (dq, J ) 7,
7 Hz, 2 H), 8.18 (t, J ) 7 Hz, 3 H); MS (CI) m/z 168 (MH+).
(b) 3-Am in o-2-eth yla m in op yr id in e. A solution of 160 g
(1.05 mol) of SnCl2‚H2O in 200 mL of concentrated HCl was
added to 2-ethylamino-3-nitropyridine (52.7 g, 0.32 mol) in 650
mL of AcOH, and the resultant mixture was stirred overnight
at room temperature. The white precipitate was collected and
washed with AcOH. The collected solid was dissolved in 300
mL of water, and the mixture was basified with 12 N NaOH.
The product was extracted with CH2Cl2, and the organic layer
was washed with saturated aqueous NaCl, dried (Na2SO4), and
concentrated to give 34 g of solid. Recrystallization (EtOAc)
afforded 28 g of 3-amino-2-ethylaminopyridine: mp 106 °C;
1H NMR (DMSO-d6) δ 7.35 (dd, J ) 1.5, 5 Hz, 1 H), 6.65 (dd,
J ) 1.5, 7 Hz, 1 H), 6.31 (dd, J ) 5, 7 Hz, 1 H), 5.45 (t, J ) 5
Hz, 1 H), 4.65 (br s, 2 H), 3.34 (m, 2 H), 1.15 (t, J ) 7 Hz, 3
H); MS (CI) m/z 137 (MH+).
(c) 2-Ch lor o-N-(2-eth ylam in o-3-pyr idin yl)-5-n itr o-3-pyr -
id in eca r boxa m id e. A solution of 2.21 g of 2-chloro-5-
nitronicotinoyl chloride22 (obtained by nitration of 2-hydroxy-
nicotinic acid, followed by conversion to 2-chloro-5-nitronico-
tinic acid, which was then treated with thionyl chloride) in 10
mL of THF was slowly added over 15 min to a cooled, stirred
mixture of 1.34 g of 3-amino-2-ethylaminopyridine, 1.29 g of
diisopropylethylamine, and 40 mL of THF. The resulting
mixture was allowed to stir overnight at room temperature
and then was concentrated in vacuo. The title compound (2.30
g), which precipitated out when the residue was treated with
CH2Cl2, was suitable for use in the next reaction: mp 185-
(g) 5,11-Dih yd r o-11-eth yl-8-iodo-5-m eth yl-6H-d ip yr id o-
[3,2-b:2′,3′-e][1,4]diazepin -6-on e (VIIIa). A solution of NaNO2
(0.14 g, 2.0 mmol) was added at 0 °C to 0.5 g (1.9 mmol) of
8-amino-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one in 4 mL of 10% H2SO4. After 20 min,
NaI (0.39 g, 2.6 mmol) was added and the mixture was warmed
to room temperature. Extraction with CH2Cl2 and purification
of the crude product by flash chromatography, eluting with
EtOAc/CH2Cl2, afforded 0.45 g of the title compound: mp 167-
1
169 °C; H NMR (DMSO-d6) δ 8.64 (d, J ) 2.3 Hz, 1 H), 8.25
(d, J ) 2.3 Hz, 1 H), 8.23 (dd, J ) 2, 5 Hz, 1 H), 7.86 (dd, J )
2, 8 Hz, 1 H), 7.30 (dd, J ) 5, 8 Hz, 1 H), 4.05 (q, J ) 7 Hz, 2
H), 3.42 (s, 3 H), 1.17 (t, J ) 7 Hz, 3 H); MS (CI) m/z 381
(MH+). Anal. (C14H13IN4O) C, H, N.
2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyr-
id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (VIIIb). By procedures
analogous to those described in a-g above, the title compound
was prepared: mp 220-222 °C; 1H NMR (CDCl3) δ 8.55 (d, J
) 2 Hz, 1 H), 8.33 (d, J ) 2 Hz, 1 H), 7.43 (d, J ) 3 Hz, 1 H)
7.11 (d, J ) 8.3 Hz, 1 H), 4.13 (q, J ) 7 Hz, 2 H), 3.46 (s, 3 H),
1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 415 (MH+). Anal. (C14
H12ClIN4O) C, H, N.
Met h od A. 8-Ben zyl-5,11-d ih yd r o-11-et h yl-5-m et h yl-
6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (15). (a) Ben -
zyltr ibu tyltin . To a solution of benzylmagnesium chloride
(2.0 M in THF, 1.32 mmol) in 5 mL of THF at -78 °C under
argon was added tributyltin chloride (0.36, 1.27 mmol). After
15 min, the reaction mixture was allowed to warm to room
temperature. After 3 h, solvent was removed, and the residue
was purified by flash chromatography, eluting with CH2Cl2/
hexanes, to give 0.45 g of a clear, colorless oil, which was used
directly in the next reaction: 1H NMR (CDCl3) δ 7.16 (m, 2

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2967
H), 6.98 (m, 3 H), 2.30 (s, 2 H), 1.43 (m, 6 H), 1.31 (m, 6 H),
crystals: 1H NMR (CDCl3) δ 8.49 (d, J ) 5 Hz, 2 H), 8.21 (dd,
J ) 2, 5 Hz, 1 H), 8.18 (d, J ) 3 Hz, 1 H), 7.93 (d, J ) 3 Hz,
1 H), 7.49 (dd, J ) 2, 8 Hz, 1 H), 7.12 (d, 2 H), 7.10 (dd, J )
5, 8 Hz, 1 H), 4.17 (q, J ) 7 Haz, 2 H), 3.52 (s, 3 H), 2.90 (s, 3
H), 1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 360 (MH+). Anal.
(C21H21N5O) C, H, N.
2-Ch lor o-5,11-d ih yd r o-11-eth yl-5-m eth yl-8-[2-(p yr id -4-
yl)eth yl]-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (37).
(a ) 2-Ch lor o-5,11-d ih yd r o-11-eth yl-8-[tr a n s-2-(4-p yr id yl)-
eth en -1-yl]-5-m eth yl-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -
6-on e. 2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-
dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (0.5 g, 1.2 mmol) was
coupled with 4-vinylpyridine in the presence of (Ph3P)2PdCl2
and Et3N as described above to give 0.28 g of the title
compound as brown crystals, which was used directly in the
next reaction: mp 150-152 °C.
(b) 2-Ch lor o-5,11-dih ydr o-11-eth yl-8-[2-(4-pyr idyl)eth yl]-
5-m eth yl-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (37).
To a mixture of 2-chloro-5,11-dihydro-11-ethyl-8-[trans-2-(4-
pyridyl)ethen-1-yl]-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]-
diazepin-6-one (2.3 g, 5.9 mmol) and palladium black (0.25 g)
in 30 mL of 1,4-dioxane was added a solution of NaH2PO2 (0.82
g, 7.7 mmol) in 15 mL of water. The reaction mixture was
heated at 80-90 °C for 3 h. The reaction mixture was then
filtered through Celite and extracted with EtOAc. The product
was purified by chromatography over silica gel, eluting with
MeOH/CH2Cl2, and recrystallized to give 1.75 g of the title
compound as colorless crystals: 1H NMR (CDCl3) δ 8.50 (d, J
) 6 Hz, 2 H), 8.19 (d, J ) 2.5 Hz, 1 H), 7.91 (d, J ) 2.5 Hz, 1
H), 7.43 (d, J ) 8.3 Hz, 1 H), 7.15 (d, J ) 6 Hz, 2 H), 7.10 (d,
J ) 8.3 Hz, 1 H), 4.15 (q, J ) 7 Hz, 2 H), 3.48 (s, 3 H), 2.93 (s,
4 H), 1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 394 (MH+). Anal.
(C21H20N5OCl) C, H, N.
2-Cya n o-5,11-d ih yd r o-11-eth yl-8-[2-(4-p yr id yl)eth yl]-5-
m eth yl-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (38).
A solution of 2-chloro-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)-
ethyl]-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (37)
(78 mg, 0.2 mmol), sodium cyanide impregnated alumina (2
g/4 g, 0.44 g, 4.5 mmol),29 and (Ph3)4Pd (45 mg, 0.04 mmol) in
5 mL of toluene was heated at 100 °C under argon for 8 h.
The reaction mixture was filtered, and the collected solid was
washed with EtOAc. The filtrate was concentrated to give a
yellow oil, which was purified by flash chromatography (elution
with 2-propanol/hexanes) and recrystallization to afford 11.5
mg (15%) of the title compound: 1H NMR (CDCl3) δ 8.49 (v br
s, 2 H), 8.23 (d, J ) 2.5 Hz, 1 H), 7.92 (d, J ) 2.5 Hz, 1 H),
7.54 (d, J ) 8.1 Hz, 1 H), 7.48 (d, J ) 8.1 Hz, 1 H), 7.08 (br d,
J ) 6 Hz, 2 H), 4.18 (q, J ) 7 Hz, 2 H), 3.52 (s, 3 H), 2.91 (s,
4 H), 1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 385 (MH+). Anal.
(C22H20N6O) C, H, N.
0.83 (m, 15 H); MS (CI) m/z 325 (MH+).
(b) 8-Ben zyl-5,11-d ih yd r o-11-eth yl-5-m eth yl-6H-d ip yr -
id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (15). To a solution of
5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one (0.3 g, 0.79 mmol), (Ph3P)2PdCl2 (18 mg,
0.03 mmol), and 2,6-di-tert-butyl-4-methylphenol (BHT) (1
crystal) in 5 mL of DMF was added benzyltributylstannane
(0.36 g, 0.94 mmol). The resultant reaction mixture was
heated at 100 °C under argon for 5 h. An aqueous solution of
potassium fluoride was added, and the mixture was stirred
for 5 h. The product was extracted with CH2Cl2 and purified
by flash chromatography, eluting with EtOAc/CH2Cl2, to give
20 mg of the title compound as an oil: 1H NMR (CDCl3) δ 8.25
(d, J ) 2.5 Hz, 1 H), 8.19 (dd, J ) 2, 5 Hz, 1 H), 7.90 (d, J )
2.5 Hz, 1 H), 7.45 (dd, J ) 2, 8 Hz, 1 H), 7.20 (m, 5 H), 7.07
(dd, J ) 5, 8 Hz, 1 H), 4.17 (q, J ) 7 Hz, 2 H), 3.92 (s, 2 H),
3.49 (s, 3 H), 1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 345 (MH+);
HRMS (MH+, C21H22N4O) calcd 345.1715, found 345.1726.
5,11-Dih yd r o-11-eth yl-5-m eth yl-8-(3-p h en ylp r op yl)-6H-
d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (18). A solution
of naphthalene (0.65 g, 5.07 mmol) in 2 mL of THF was added
to lithium wire (35 mg, 5.04 mmol), and the mixture was
stirred overnight at room temperature under argon. A solution
of zinc chloride in THF (0.5 M, 5.25 mL, 2.63 mmol) was then
added. After 20 min, 1-bromo-3-phenylpropane (0.18 mL, 1.15
mmol) was added, and the reaction mixture was stirred at
room temperature for 4.5 h. Unreacted zinc was allowed to
settle, and the supernatant was added by cannula to a solution
of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:
2′,3′-e][1,4]diazepin-6-one (0.22 g, 0.58 mmol) and (Ph3)4Pd (70
mg, 0.06 mmol) in 3 mL of THF. The reaction mixture was
allowed to stir overnight at room temperature under argon.
The reaction was quenched by the addition of saturated
aqueous ammonium chloride, and the product was extracted
with EtOAc. The organic layer was washed with saturated
aqueous NaCl, dried over MgSO4, and concentrated. Purifica-
tion by flash chromatography, eluting with EtOAc/CH2Cl2, and
recrystallization afforded 16 mg of the title compound as off-
white crystals: 1H NMR (CDCl3) δ 8.21 (d, J ) 2 Hz, 1 H),
8.20 (dd, J ) 2, 5 Hz, 1 H), 7.92 (d, J ) 2 Hz, 1 H), 7.48 (dd,
J ) 2, 8 Hz, 1 H), 7.20 (m, 5 H), 7.09 (dd, J ) 5, 8 Hz, 1 H),
4.17 (q, J ) 6 Hz, 2 H), 3.52 (s, 3 H), 2.63 (t, J ) 8 Hz, 2 H),
2.60 (t, J ) 8 Hz, 2 H), 1.92 (m, 2 H), 1.26 (t, J ) 7 Hz, 3 H);
MS (CI) m/z 373 (MH+). Anal. (C23H24N4O) C, H, N.
Meth od B. 5,11-Dih yd r o-11-eth yl-5-m eth yl-8-[2-(p yr id -
4-yl)et h yl]-6H -d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e
(21). (a ) 5,11-Dih yd r o-11-et h yl-5-m et h yl-8-[tr a n s-2-(4-
pyr idyl)eth en -1-yl]-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -
6-on e (20). A mixture containing 5,11-dihydro-11-ethyl-8-
iodo-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (0.7
g, 1.9 mmol), 4-vinylpyridine (0.3 mL, 2.9 mmol), (Ph3P)2PdCl2
(60 mg, 0.09 mmol), Et3N (1.8 mL, 12.8 mmol), and 1 crystal
of BHT in 4 mL of DMF was heated at 125 °C under argon for
3 h. The reaction mixture was then cooled to room tempera-
ture, diluted with water, and extracted with EtOAc. The
organic layer was washed with saturated aqueous NaCl, dried
(MgSO4), and concentrated to give a yellow oil. Purification
by flash chromatography, eluting with EtOAc/hexanes, and
recrystallization provided the 0.5 g of the title compound as
yellow crystals: 1H NMR (CDCl3) δ 8.59 (br d, J ) 5.5 Hz, 2
H), 8.50 (d, J ) 2.4 Hz, 1 H), 8.32 (d, J ) 2.4 Hz, 1 H), 8.23
(dd, J ) 1.5, 4.6 Hz, 1 H), 7.52 (dd, J ) 1.5, 8 Hz, 1 H), 7.40
(br d, J ) 5.5 Hz, 2 H), 7.26 (d, J ) 16 Hz, 1 H), 7.14 (dd, J )
4.6, 8 Hz, 1 H), 7.00 (d, J ) 16 Hz, 1 H), 4.24 (q, J ) 7 Hz, 2
H), 3.54 (s, 3 H), 1.30 (t, J ) 7 Hz, 3 H); MS (CI) m/z 358
(MH+). Anal. (C21H19N5O‚0.5H2O) C, H, N.
5,11-Dih yd r o-11-et h yl-2-iod o-8-[2-(4-p yr id yl)et h yl]-5-
m eth yl-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (40).
(a )
5,11-Dih yd r o-11-et h yl-8-[2-(4-p yr id yl)et h yl]-2-t r i-
m eth ylsta n n yl-5-m eth yl-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d i-
a zep in -6-on e. To a solution of 2-chloro-5,11-dihydro-11-ethyl-
8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]-
diazepin-6-one (37) (60 mg, 0.15 mmol) in 3.5 mL of THF under
argon were added hexamethylditin (45µL, 0.15 mmol) and
(Ph3)4Pd (10 mg, 0.0085 mmol), and the resultant mixture was
heated at 85 °C in a sealed tube. After 22 h, additional catalyst
(10 mg) was added. (Ph3P)2PdCl2 (10 mg) was added after an
additional 7 h, and the temperature was increased to 100 °C.
After 40 h total reaction time, the reaction mixture was diluted
with water and extracted with EtOAc. Purification by flash
chromatography (elution with MeOH/CH2Cl2) afforded 47 mg
of the title compound, which was used directly in the next
reaction: 1H NMR (CDCl3) δ 8.49 (d, J ) 6 Hz, 2 H), 8.18 (d,
J ) 2.5 Hz, 1 H), 7.93 (d, J ) 2.5 Hz, 1 H), 7.32 (d, J ) 7.7 Hz,
1 H), 7.23 (d, J ) 7.7 Hz, 1 H), 7.11 (d, J ) 6 Hz, 2 H), 4.21 (q,
J ) 7 Hz, 2 H), 3.49 (s, 3 H), 2.89 (s, 4 H), 1.25 (t, J ) 7 Hz,
3 H), 0.31 (s, 9 H); MS (CI) m/z 522 (MH+).
(b ) 5,11-Dih yd r o-11-et h yl-5-m et h yl-8-[2-(p yr id -4-yl)-
eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (21).
The title compound was prepared from 5,11-dihydro-11-ethyl-
5-methyl-8-[trans-2-(4-pyridyl)ethen-1-yl]-6H-dipyrido[3,2-b:
2′,3′-e][1,4]diazepin-6-one (0.38 g, 1.0 mmol) by catalytic
hydrogenation over PtO2 in EtOAc at 150 psi and 60 °C.
Recrystallization afforded 0.18 g of the product as off-white
(b) 5,11-Dih yd r o-11-eth yl-2-iod o-8-[2-(4-p yr id yl)eth yl]-
5-m eth yl-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (40).
To a solution of 5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-

2968 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Klunder et al.
2-trimethylstannyl-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]-di-
azepin-6-one (47 mg, 0.09 mmol) in chloroform was added a
solution of iodine in chloroform (0.1 M, 4 mL, 0.4 mmol). After
24 h, the reaction mixture was washed with saturated aqueous
KF, 5% NaHSO3, and saturated aqueous NaCl. Purification
by flash chromatography (elution with MeOH/CH2Cl2) and
recrystallization afforded 15 mg of the title compound: 1H
NMR (CDCl3) δ 8.5 (br s, 2 H), 8.18 (d, J ) 2.5 Hz, 1 H), 7.89
9d, J ) 2.5 Hz, 1 H), 7.48 (d, J ) 8 Hz, 1 H); 7.26 (br s, 2 H),
7.09 (d, J ) 8 Hz, 1 H), 4.13 (q, J ) 7 Hz, 2 H), 3.46 (s, 3 H),
2.95 (s, 4 H), 1.24 (t, J ) 7 Hz, 3 H); MS (CI) m/z 486 (MH+).
Anal. (C21H20IN5O‚1/4H2O) C, H, N.
Meth od C. 5,11-Dih yd r o-11-eth yl-5-m eth yl-8-(2-p h en -
yleth yl)-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (17).
(a ) 5,11-Dih yd r o-11-eth yl-5-m eth yl-8-p h en yleth yn yl-6H-
d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e. A mixture of
5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one (0.20 g, 0.53 mmol), phenylacetylene (0.06
mL, 0.55 mmol), (Ph3P)2PdCl2 (25 mg, 0.04 mmol), and Et3N
(0.16 mL, 1.14 mmol) in 3 mL of DMF was heated at 95 °C
under argon for 19 h. The reaction mixture was then cooled
to room temperature, diluted with water, and extracted with
EtOAc. The organic layer was washed with saturated aqueous
NaCl, dried (MgSO4), and concentrated. Purification by flash
chromatography, eluting with EtOAc/CH2Cl2, afforded 0.1 g
of the title compound, which was used directly in the next
reaction: 1H NMR (CDCl3) δ 8.5 (d, J ) 2 Hz, 1 H), 8.25 (d, J
) 2 Hz, 1 H), 8.25 (dd, J ) 1, 4 Hz, 1 H), 7.55 (dd, J ) 1, 8 Hz,
1 H), 7.5 (m, 2 H), 7.35 (m, 3 H), 7.15 (dd, J ) 4, 8 Hz, 1 H),
4.25 (q, J ) 7 Hz, 2 H), 3.55 (s, 3 H), 1.25 (t, J ) 7 Hz, 3 H);
MS (CI) m/z 355 (MH+).
(b) 5,11-Dih yd r o-11-eth yl-5-m eth yl-8-(2-p h en eth yl)-6H-
d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e. 5,11-Dihydro-11-
ethyl-5-methyl-8-(2-phenylethynyl)-6H-dipyrido[3,2-b:2′,3′-e]-
[1,4]diazepin-6-one (70 mg, 0.2 mmol) was hydrogenated over
PtO2 in EtOAc under 50 psi of hydrogen. The reaction mixture
was filtered through Celite and concentrated. Purification by
flash chromatography and preparative TLC, eluting with
EtOAc/CH2Cl2, afforded 31 mg of the title compound as yellow
crystals: 1H NMR (CDCl3) δ 8.21 (dd, J ) 2, 5 Hz, 1 H), 8.19
(d, J ) 3 Hz, 1 H), 7.95 (d, J ) 3 Hz, 1 H), 7.49 (dd, J ) 2, 8
Hz, 1 H), 7.22 (m, 5 H), 7.09 (dd, J ) 5, 8 Hz, 1 H), 4.17 (q, J
) 7 Hz, 2 H), 3.52 (s, 3 H), 2.88 (s, 4 H), 1.26 (t, J ) 7 Hz, 3
H); MS (CI) m/z 359 (MH+). Anal. (C22H22N4O) C, H, N.
5,11-Dih yd r o-11-eth yl-5-m eth yl-8-(cis-2-p h en yleth en -
1-yl)-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (19). 5,-
11-Dihydro-11-ethyl-5-methyl-8-phenylethynyl-6H-dipyrido-
[3,2-b:2′,3′-e][1,4]diazepin-6-one (0.12 g, 0.34 mmol) was
hydrogenated over Lindlar catalyst in ethanol under 50 psi of
hydrogen. The reaction mixture was filtered through Celite
and concentrated. Purification by flash chromatography and
preparative TLC, eluting with EtOAc/CH2Cl2, afforded 20 mg
of the title compound as a yellow-orange oil: 1H NMR (CDCl3)
δ 8.25 (d, J ) 2 Hz, 1 H), 8.22 (dd, J ) 2, 8 Hz, 1 H), 7.97 (d,
J ) 2 Hz, 1 H), 7.48 (dd, J ) 2, 8 Hz, 1 H), 7.20 (m, 5 H), 6.68
(d, J ) 12.2 Hz, 1 H), 6.44 (d, J ) 12.2 Hz, 1 H), 4.16 (q, J )
7 Hz, 2 H), 3.48 (s, 3 H), 1.24 (t, J ) 7 Hz, 3 H); MS (CI) m/z
357 (MH+); HRMS (MH+, C22H21N4O) calcd 357.171 54; found
357.172 05.
A mixture containing 2-chloro-5,11-dihydro-11-ethyl-5-methyl-
8-(2-phenylethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-
one (0.10 g, 0.26 mmol), potassium acetate (0.05 g, 0.51 mmol),
N-(tert-butyloxycarbonyl)pyrrole (0.078 g, 0.47 mmol), and
(Ph3)4Pd (20 mg, 0.02 mmol) in 2 mL of DMF was heated in a
sealed tube at 125 °C for 10 h. Additional potassium acetate
(50 mg), N-(tert-butyloxycarbonyl)pyrrole (0.08 g), and (Ph3)4-
Pd (15 mg) were added, and the reaction mixture was heated
at 140 °C for an additional 8 h. The reaction mixture was
diluted with water and extracted with EtOAc. The organic
layer was washed with saturated aqueous NaCl, dried over
MgSO4, and concentrated. Purification by flash chromatog-
raphy, eluting with EtOAc/hexanes, provided 20 mg of the title
compound, as a foam: 1H NMR (CDCl3) δ 9.39 (b s, 1 H), 8.17
(d, J ) 2.4 Hz, 1 H), 7.96 (d, J ) 2.4 Hz, 1 H), 7.43 (d, J ) 8.4
Hz, 1 H), 7.30 (d, J ) 8.4 Hz, 1 H), 7.22 (m, 5 H), 6.91 (m, 1
H), 6.66 (m, 1 H), 6.28 (m, 1 H), 4.21 (q, J ) 7 Hz, 2 H), 3.51
(s, 3 H), 2.88 (s, 4 H), 1.28 (t, J ) 7 Hz, 3 H); MS (CI) m/z 424
(MH+). Anal. (C26H25N5O‚0.25H2O) C, H, N.
Meth od D. 2-Ch lor o-5,11-d ih yd r o-11-eth yl-8-eth yn yl-
5-m eth yl-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e. A
mixture containing 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-
methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (1.37 g,
0.37 mmol), trimethylsilylacetylene (0.59 mL, 4.2 mmol),
(Ph3P)2PdCl2 (0.53 g, 0.76 mmol), Et3N (1.1 mL, 7.8 mmol),
CuI (0.1 g, 0.53 mmol), and 1-2 crystals of BHT in 40 mL of
THF was heated at 80 °C under argon in a sealed tube for 2
h. The reaction mixture was cooled to room temperature,
diluted with water, and extracted with EtOAc. The organic
layer was washed with saturated aqueous NaCl, dried over
MgSO4, and concentrated. Purification by flash chromatog-
raphy, eluting with EtOAc/hexanes, provided 0.92 g of the
coupled product, which was then dissolved in THF (10 mL)
and treated at room temperature with a 1.1 M solution of
Bu4NF in THF (2.2 mL, 2.39 mmol). After 30 min, solvent
was removed at reduced pressure and the residue was purified
by flash chromatography, eluting with EtOAc/hexanes, to give
0.64 g of the title compound as a beige solid: mp 157-159 °C;
1H NMR (CDCl3) δ 8.47 (d, J ) 2 Hz, 1 H), 8.18, d, J ) 2 Hz,
1 H), 7.44 (d, J ) 8 Hz, 1 H), 7.12 (d, J ) 8 Hz, 1 H), 4.18 (q,
J ) 7 Hz, 2 H), 3.47 (s, 3 H), 3.15 (s, 1 H), 1.26 (t, J ) 7 Hz,
3 H); MS (CI) m/z 313 (MH+). Anal. (C16H13N4OCl) C, H, N.
5,11-Dih yd r o-11-eth yl-5-m eth yl-8-[2-(2-m eth ylp yr id -4-
yl)eth yl]-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (52).
(a ) 2-Ch lor o-5,11-d ih yd r o-11-eth yl-5-m eth yl-8-[2-(2-m eth -
ylpyrid-4-yl)ethynyl]-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-
6-on e. A mixture containing 48 mg (0.15 mmol) of 2-chloro-
5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:
2′,3′-e][1,4]diazepin-6-one, 4-bromo-2-picoline21 (31 mg, 0.15
mmol), (Ph3)4Pd (9.7 mg, 0.008 mmol), Et3N (0.2 mL), and 1
crystal of BHT in 1.0 mL of DMF was heated at 105 °C in a
sealed tube for 3 h. The reaction mixture was cooled to room
temperature and extracted with EtOAc. The organic layer was
washed with saturated aqueous NaCl, dried (MgSO4), and
concentrated. The residue was purified by flash chromatog-
raphy, eluting with EtOAc/hexanes, to give 0.051 g of the title
compound as a yellow foam: 1H NMR (CDCl3) δ 8.53 (d, J )
2 Hz, 1 H), 8.50 (d, J ) 6 Hz, 1 H), 8.24 (d, J ) 2 Hz, 1 H),
7.46 (d, J ) 8 Hz, 1 H), 7.26 (s, 1 H), 7.18 (d, J ) 6 Hz, 1 H),
7.14 (d, J ) 8 Hz, 1 H), 4.23 (q, J ) 7 Hz, 2 H), 3.49 (s, 3 H),
2.57 (s, 3 H), 1.29 (t, J ) 7 Hz, 3 H); MS (CI) m/z 404 (MH+).
(b ) 2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-[2-(2-
m eth ylp yr id -4-yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]-d i-
a zep in -6-on e (52). 2-Chloro-5,11-dihydro-11-ethyl-5-methyl-
8-[trans-2-(2-methylpyrid-4-yl)ethynyl]-6H-dipyrido[3,2-b:2′,3′-
e]-[1,4]diazepin-6-one (50 mg, 0.12 mmol) was hydrogenated
over PtO2, as described for the synthesis of 17, to afford 18
mg (37%) of the title compound: 1H NMR (CDCl3) δ 8.37 (d, J
) 5 Hz, 1 H), 8.18 (d, J ) 2.5 Hz, 1 H), 7.90 (d, J ) 2.5 Hz, 1
H), 7.42 (d, J ) 8 Hz, 1 H), 7.09 (d, J ) 8 Hz, 1 H), 6.95 (s, 1
H), 6.90 (d, J ) 5 Hz, 1 H), 4.14 (q, J ) 7 Hz, 2 H), 3.47 (s, 3
H), 2.86 (m, 4 H), 2.50 (s, 3 H), 1.24 (t, J ) 7 Hz, 3 H); MS
(CI) m/z 408 (MH+). Anal. (C22H22ClN5O‚1/2H2O) C, H, N.
2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-(2-p h en yl-
eth yl)-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e (36).
From 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-phenylethyn-
yl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (0.33 g) (pre-
pared from 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-
dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one and phenylacetylene)
by procedures analogous to those described for the preparation
of 17. The title compound was obtained as white needles: 1H
NMR (CDCl3) δ 8.18 (d, J ) 2 Hz, 1 H), 7.94 (d, J ) 2 Hz, 1
H), 7.42 (d, J ) 8 Hz, 1 H), 7.15-7.35 (m, 5 H), 7.09 (d, J ) 8
Hz, 1 H), 4.15 (q, J ) 7 Hz, 2 H), 3.48 (s, 3 H), 2.88 (s, 4 H),
1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 393 (MH+). Anal. (C22H21
ClN4O) C, H, N.
-
5,11-Dih yd r o-11-eth yl-5-m eth yl-8-(2-p h en yleth yl)-2-(2-
pyr r olyl)-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -6-on e (35).
2-Ch lor o-5,11-d ih yd r o-11-e t h yl-5-m e t h yl-8-[2-(2-h y-

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2969
d r oxym eth yl-4-p yr id yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e]-
[1,4]d ia zep in -6-on e (53). (a ) 4-Br om o-2-p icolin e N-Oxid e.
A mixture of 4-nitro-2-picoline N-oxide (1.0 g, 6.5 mmol) and
AcBr (3.5 mL, 47 mmol) was heated at reflux under argon for
8 h. The reaction mixture was poured onto ice, neutralized
with NaHCO3, and extracted with EtOAc and CH2Cl2. The
organic layer was washed with 5% aqueous NaHSO3 and
saturated aqueous NaCl, dried (MgSO4), and concentrated. The
residue was purified by flash chromatography, eluting with
MeOH/CH2Cl2, EtOAc/hexanes, EtOAc, and MeOH/CH2Cl2 to
afford the title compound (0.38 g, 31%) as an orange-brown
oil: 1H NMR (CDCl3) δ 8.09 (dd, J ) 4, 8 Hz, 1 H), 7.40 (d, J
) 2 Hz, 1 H), 7.26 (dd, J ) 2, 4 Hz, 1 H), 2.49 (s, 3 H); MS (CI)
m/z 188 (MH+).
(b) 2-Ch lor o-5,11-d ih yd r o-11-eth yl-5-m eth yl-8-(N-oxo-
2-m eth ylp yr id -4-yl)eth yn yl-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]-
d ia zep in -6-on e. 2-Chloro-5,11-dihydro-11-ethyl-8-ethynyl-5-
methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (0.2 g, 0.64
mmol) was coupled with 4-bromo-2-picoline N-oxide (0.12 g,
0.64 mmol) by a procedure analogous to that described for the
synthesis of 52 to provide the title compound (0.26 g, 95%),
which was used directly in the next reaction: 1H NMR (CDCl3)
δ 8.50 (d, J ) 2.3 Hz, 1 H), 8.21 (d, J ) 2.3 Hz, 1 H), 8.19 (d,
J ) 6 Hz, 1 H), 7.46 (d, J ) 8 Hz, 1 H), 7.37 (d, J ) 2 Hz, 1 H),
7.22 (dd, J ) 2, 6 Hz, 1 H), 7.14 (d, J ) 8 Hz, 1 H), 4.21 (q, J
) 7 Hz, 2 H), 3.84 (s, 3 H), 2.50 (s, 3 H), 1.28 (t, J ) 7 Hz, 3
H).
(c) 2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-(2-h y-
d r oxym eth ylp yr id -4-yl)eth yn yl-6H-d ip yr id o [3,2-b:2′,3′-
e][1,4]d ia zep in -6-on e. 2-Chloro-5,11-dihydro-11-ethyl-5-
methyl-8-(N-oxo-2-methylpyrid-4-yl)ethynyl-6H-dipyrido[3,2-
b:2′,3′-e][1,4]diazepin-6-one (0.26 g, 0.61 mmol) was dissolved
in Ac2O (5 mL) and heated at 105 °C in a sealed tube. After
3.5 h, excess Ac2O was removed by rotary evaporation, the
residue was neutralized with aqueous NaHCO3, and the
product was extracted with EtOAc. The organic layer was
concentrated, the residue was dissolved in 12 mL of MeOH,
and a solution of K2CO3 (0.18 g, 1.3 mmol) in 1 mL of water
was added. After 30 min, the reaction mixture was concen-
trated, and the residue was diluted with CH2Cl2, filtered, and
concentrated. Purification by flash chromatography (elution
with MeOH/CH2Cl2) afforded the title compound (0.07 g, 27%)
as a yellow oil: 1H NMR (CDCl3) δ 8.54 (br s, 1 H), 8.53 (d, J
) 2.3 Hz, 1 H), 8.24 (d, J ) 2.3 Hz, 1 H), 7.47 (d, J ) 8 Hz, 1
H), 7.37 (br s, 1 H), 7.27 (br s, 1 H), 7.15 (d, J ) 8 Hz, 1 H),
4.79 (br s, 2 H), 4.22 (q, J ) 7 Hz, 2 H), 3.50 (s, 3 H), 1.29 (t,
J ) 7 Hz, 3 H); MS (CI) m/z 420 (MH+).
(d ) 2-Ch lor o-5,11-d ih yd r o-11-eth yl-5-m eth yl-8-[2-(2-h y-
d r oxym eth ylp yr id -4-yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e]-
[1,4]d ia zep in -6-on e (53). 2-Chloro-5,11-dihydro-11-ethyl-5-
methyl-8-(2-hydroxymethylpyrid-4-yl)ethynyl-6H-dipyrido[3,2-
b:2′,3′-e][1,4]diazepin-6-one (66 mg, 0.16 mmol) was
hydrogenated, according to the procedure described for the
synthesis of 37, to provide the title compound (34 mg, 50%):
1H NMR (CDCl3) δ 8.44 (d, J ) 5 Hz, 1 H), 8.19 (d, J ) 2.5 Hz,
1 H), 7.85 (d, J ) 2.5 Hz, 1 H), 7.43 (d, J ) 8.2 Hz, 1 H), 7.10
(d, J ) 8.2 Hz, 1 H), 7.03 (s, 1 H), 7.01 (d, J ) 5 Hz, 1 H), 4.71
(s, 2 H), 4.15 (q, J ) 7 Hz, 2H), 3.71 (br s, 1 H), 3.48 (s, 3 H),
2.90 (s, 4 H), 1.26 (t, J ) 7 Hz, 3 H); MS (CI) m/z 424 (MH+).
Anal. (C22H22ClN5O2) C, H, N.
(DMSO-d6) δ 8.73 (apparent s, 1 H), 8.28 (d, J ) 2 Hz, 1 H),
8.21 (apparent s, 1 H), 8.12 (s, 1 H), 7.95 (d, J ) 8.4 Hz, 1 H),
7.66 (br s, 1 H), 7.44 (d, J ) 8.4 Hz, 1 H), 4.09 (apparent d, J
) 7 Hz, 2 H), 3.43 (s, 3 H), 1.22 (t, J ) 7 Hz, 3 H).
(b ) 2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-[2-(2-
ca r bom eth oxyp yr id -4-yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e]-
[1,4]d ia zep in -6-on e (54). The mixture obtained above was
dissolved in 50 mL of MeOH containing a few drops of
concentrated H2SO4, and the resultant solution was heated
at reflux under argon for 15 h. The reaction mixture was
diluted with water, neutralized with NaHCO3, and extracted
with CH2Cl2 and EtOAc. Purification by flash chromatogra-
phy, radial chromatography, and preparative TLC (elution
with MeOH/CH2Cl2) afforded the title compound (0.20 g, 46%).
A portion of this material was recrystallized to afford the pure
product as off-white crystals: 1H NMR (CDCl3) δ 8.62 (d, J )
5 Hz, 1 H), 8.19 (d, J ) 2 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J )
2 Hz, 1 H), 7.43 (d, J ) 8 Hz, 1 H), 7.24 (m, 1 H), 7.10 (d, J )
8 Hz, 1 H), 4.15 (q, J ) 7 Hz, 2 H), 4.00 (s, 3 H), 3.48 (s, 3 H),
2.96 (s, 4 H), 1.25 (t, J ) 7 Hz, 3 H); MS (CI) m/z 452 (MH+).
Anal. (C23H22ClN5O3‚1/4H2O) C, H, N.
2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-[2-(2-ca r -
boxa m id op yr id -4-yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e][1,4]-
diazepin -6-on e (55). 2-Chloro-5,11-dihydro-11-ethyl-5-methyl-
8-[2-(2-carbomethoxypyrid-4-yl)ethyl]-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one (32 mg, 0.07 mmol) was dissolved in 5
mL of MeOH, and the solution was saturated with NH3. After
6 h, solvents were removed and the residue was purified by
flash chromatography (elution with MeOH/CH2Cl2). Recrys-
tallization afforded the title compound (25 mg, 82%) as white
crystals: 1H NMR (CDCl3) δ 8.45 (d, J ) 5 Hz, 1 H), 8.17 (d,
J ) 2.5 Hz, 1 H), 8.07 (s, 1 H), 7.93 (d, J ) 2.5 Hz, 1 H), 7.85
(br s, 1 H), 7.43 (d, J ) 8.2 Hz, 1 H), 7.21 (dd, J ) 2, 5 Hz, 1
H), 7.10 (d, J ) 8.2 Hz, 1 H), 5.54 (br s, 1 H), 4.12 (q, J ) 7
Hz, 2 H), 3.49 (s, 3 H), 2.96 (s, 4 H), 1.25 (t, J ) 7 Hz, 3 H);
MS (CI) m/z 437 (MH+). Anal. (C22H21ClN6O2‚1/4EtOAc) C,
H, N.
2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-[2-(2-ca r -
b oxyp yr id -4-yl)et h yl]-6H -d ip yr id o[3,2-b:2′,3′-e][1,4]d i-
a zep in -6-on e (57). 2-Chloro-5,11-dihydro-11-ethyl-5-methyl-
8-[2-(2-carbomethoxypyrid-4-yl)ethyl]-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one (0.15 g, 0.33 mmol) was dissolved in 30
mL of THF, aqueous LiOH (1.0 M, 1.0 mL, 1.0 mmol) was
added, and the reaction mixture was heated at reflux under
argon. After 1 h, additional LiOH (0.5 mL) was added, and
heating was continued for an additional 3 h. The reaction
mixture was concentrated, acidified with 2 N HCl, saturated
with NaCl, and extracted with chloroform/ethanol (3:1). Con-
centration afforded a yellow foam, which was recrystallized
to provide the title compound (58 mg, 40%) as a pale yellow
solid: 1H NMR (DMSO-d6) δ 8.57 (d, J ) 5 Hz, 1 H), 8.36 (d,
J ) 2 Hz, 1 H), 8.00 (d, J ) 2 Hz, 1 H), 7.97 (s, 1 H), 7.90 (d,
J ) 8.4 Hz, 1 H), 7.52 (dd, J ) 2, 5 Hz, 1 H), 7.37 (d, J ) 8.4
Hz, 1 H), 4.01 (app. br s, 2 H), 3.41 (s, 3 H), 2.94 (s, 4 H), 1.17
(t, J ) 7 Hz, 3 H); MS (CI) m/z (MH+)438; HRMS (MH+, C22H21
ClN5O3) calcd 438.133 29, found 438.131 57.
-
2-Ch lor o-5,11-d ih yd r o-11-et h yl-5-m et h yl-8-[2-(2-a m i-
n opyr id-4-yl)eth yl]-6H-dipyr ido[3,2-b:2′,3′-e][1,4]diazepin -
6-on e (56). To a solution of 2-chloro-5,11-dihydro-11-ethyl-
5-methyl-8-[2-(2-carboxypyrid-4-yl)ethyl]-6H-dipyrido[3,2-b:
2′,3′-e][1,4]diazepin-6-one (92 mg, 0.21 mmol) and Et3N (0.03
mL, 0.22 mmol) in tert-butyl alcohol (20 mL) was added
diphenylphosphoryl azide (0.046 g, 0.21 mmol). The reaction
mixture was heated at reflux under argon for 16 h. Solvents
were removed by rotary evaporation, and the residue was
dissolved in EtOAc, washed with saturated aqueous NaHCO3,
dried (MgSO4), and concentrated. The residue was treated
with 2 N HCl in ethanol at 25-50 °C for 30 h. The reaction
mixture was concentrated, basified with 6 N NaOH, and
extracted with EtOAc. Purification by flash chromatography
(elution with MeOH/CH2Cl2) and recrystallization afforded 14
mg (16%) of the title compound: 1H NMR (CDCl3) δ 8.19 (d, J
) 2 Hz, 1 H), 7.95 (d, J ) 5.1 Hz, 1 H), 7.92 (d, J ) 2 Hz, 1 H),
7.43 (d, J ) 8 Hz, 1 H); 7.09 (d, J ) 8 Hz, 1 H); 6.48 (d, J )
2-C h lo r o -5,11-d i h y d r o -11-e t h y l-5-m e t h y l-8-[2-(2-
ca r bom eth oxyp yr id -4-yl)eth yl]-6H-d ip yr id o[3,2-b:2′,3′-e]-
[1,4]d ia zep in -6-on e (54). (a ) 2-Ch lor o-5,11-d ih yd r o-11-
eth yl-5-m eth yl-8-[2-(2-ca r boxyp yr id -4-yl)eth yl]-6H-d ip y-
r id o[3,2-b:2′,3′-e][1,4]d ia zep in -6-on e. By procedures analo-
gous to those described for the synthesis of 52, 2-chloro-5,11-
dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2′,3′-
e][1,4]diazepin-6-one (0.83 g, 2.64 mmol) was coupled with
4-bromopicolinic acid21 (0.53 g, 2.62 mmol) and hydrogenated
to provide 0.4 g of the title compound, as a mixture containing
the corresponding des-chloro analogue. The mixture was used
directly in the next reaction. Data for 2-chloro-5,11-dihydro-
11-ethyl-5-methyl-8-[2-(2-carboxypyrid-4-yl)ethynyl]6H-dipyr-
ido[3,2-b:2′,3′-e][1,4]diazepin-6-one: mp >300 °C; 1H NMR

2970 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Klunder et al.
Kohlstaedt, L. A.; Friedman, J . M.; Rice, P. A.; Steitz, T. A.
Structure of the Binding Site for Non-nucleoside Inhibitors of
the Reverse Transcriptase of Human Immunodeficiency Virus
Type 1. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3911-3915. (c)
Esnouf, R.; Ren, J .; Ross, C.; J ones, Y.; Stammers, D.; Stuart,
D. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by
Nonnucleoside Inhibitors. Struct. Biol. 1995, 2, 303-308.
(10) Larder, B. A.; Purifoy, D. J . M.; Powell, K. L.; Darby, G. Site-
specific Mutagenesis of AIDS Virus Reverse Transcriptase.
Nature 1987, 327, 716.
(11) (a) Proudfoot, J . R.; Hargrave, K. D.; Kapadia, S. R.; Patel, U.
R.; Grozinger, K. G.; McNeil, D. W.; Cullen, E.; Cardozo, M.;
Tong, L.; Kelly, T. A.; Rose, J .; David, E.; Mauldin, S. C.; Fuchs,
V. U.; Vitous, J .; Hoermann, M.; Klunder, J . M.; Raghavan, P.;
Skiles, J . W.; Mui, P.; Richman, D. D.; Sullivan, J . L.; Shih, C.-
K.; Grob, P. M.; Adams, J . Novel Nonnucleoside Inhibitors of
Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Tran-
scriptase. 4. 2-Substituted Dipyridodiazepinones as Potent
Inhibitors of Both Wild-Type and Cysteine-181 HIV-1 Reverse
Transcriptase Enzymes. J . Med. Chem. 1995, 38, 4830-4838.
(b) Kelly, T. A.; McNeil, D. W.; Rose, J . M.; David, E.; Shih, C.-
K.; Grob, P. M Novel Non-Nucleoside Inhibitors of HIV-1 Reverse
Transcriptase. 6. 2-Indol-3-yl and 2-azaindol-3-yl Dipyridodiaz-
epinones. J . Med. Chem. 1997, 40, 2430-2433.
(12) Cywin, C. L.; Klunder, J . M.; Hoermann, M.; Brickwood, J . R.;
David, E.; Grob, P. M.; Schwartz, R.; Pauletti, D.; Barringer, K.
J .; Shih, C.-K.; Sorge, C. L.; Erickson, D. A.; J oseph, D. P.;
Hattox, S. E. Novel Nonnucleoside Inhibitors of HIV-1 Reverse
Transcriptase. 8. 8-Aryloxymethyl- and 8-Arylthiomethyldipy-
ridodiazepinones. J . Med. Chem. 1998, 41, 2972-2984.
(13) Stille, J . K. The Palladium-Catalyzed Cross-Coupling Reactions
of Organotin Reagents with Organic Electrophiles. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508-524.
(14) (a) Negishi, E. Palladium- or Nickel-Catalyzed Cross-Coupling.
A New Selective Method for Carbon-Carbon Bond Formation.
Acc. Chem. Res. 1982, 15, 340-348. (b) Sakamoto, T. Nishimura,
S.; Kondo, Y.; Yamanaka, H. Palladium-Catalyzed Coupling
Reaction of N-Heteroaryl Halides with Functionalized Alkylzinc
Iodides. Synthesis 1988, 485-486.
(15) Heck, R. F. Palladium Catalyzed Reactions of Organic Halides
with Olefins. Acc. Chem. Res. 1979, 12, 146-151.
(16) J ohnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Heterogeneous
Catalytic Transfer Hydrogenation and Its Relation to Other
Methods for Reduction of Organic Compounds. Chem. Rev. 1985,
85, 129-170.
(17) Entwistle, I. D.; J ackson, A. E.; J ohnstone, R. A. W.; Telford, R.
P. Reduction of Nitro-compounds. J . Chem. Soc., Perkin Trans.
1 1977, 443-444.
(18) Dalton, J . R.; Regen, S. L. Alumina-Assisted Aryl Cyanation. J .
Org. Chem. 1979, 44, 4443-4444.
(19) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.;
Gohma, K.; Komatsu, J .; Sekine, K.; Miyafuji, A.; Kunoh, J .;
Honma, R.; Akita, Y.; Ohta, A. Paladium-Catalyzed Cross-
Coupling Reactions of Chloropyrazines with Aromatic Hetero-
cycles. Heterocycles 1992, 33, 257-272.
(20) Oae, S.; Ogino, K. Rearrangements of t-Amine Oxides. Hetero-
cycles 1977, 6, 583.
(21) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;
Watanabe, M.; Yokoyama, K. Novel 1,4-Dihydropyridine Cal-
cium Antagonists. I. Synthesis and Hypotensive Activity of
4-(Substituted pyridyl)-1,4-dihydropyridine Derivatives. Chem.
Pharm. Bull. 1990, 38, 2446.
5.1 Hz, 1 H), 6.28 (s, 1 H), 4.37 (br s, 2 H), 4.15 (q, J ) 7 Hz,
2 H), 3.48 (s, 3 H), 2.81 (m, 4 H), 1.25 (t, J ) 7 Hz, 3 H); MS
(CI) m/z 409 (MH+); HRMS (MH+, C21H22ClN6O) calcd
409.154 36, found 409.154 69.
Ack n ow led gm en t. The authors thank Roger Di-
nallo, Keith McKellop, and Walter Davidson for provid-
ing MS data. J ohn L. Sullivan and Frank Brewster of
the University of Massachusetts are acknowledged for
performing the HIV-1 syncytia assay. Additionally, J ohn
Proudfoot, Usaha Patel, Suresh Kapadia, Terence Kelly,
Daniel McNeil, Vittorio Farina, and Karl Hargrave are
acknowledged for very helpful discussions and critical
input as members of the second generation NNRTI
chemistry project team.
Refer en ces
(1) (a) Kempf, D. J .; Sham, H. L. HIV Protease Inhibitors. Curr.
Pharm. Res. 1996, 2, 225-246. (b) Deeks, S. G.; Smith, M.;
Holdniy, M.; Kahn, J . O. HIV-1 Protease Inhibitors. A Review
for Clinicians. J . Am. Med. Assoc. 1997, 277, 145-153. (c) Lewis,
J . S. 2nd Protease Inhibitors: A Therapeutic Breakthrough for
the Treatment of Patients with Human Immunodeficiency Virus.
Clin. Ther. 1997, 19, 187-214.
(2) (a) Saunders: J .; Storer, R. New Developments in RT Inhibitors.
Drug News Perspect. 1992, 5, 153-169. (b) Tucker, T. J .; Lumma,
W. C.; Culberson, J . C. Development of Nonnucleoside HIV
Reverse Transcriptase Inhibitors. Methods Enzymol. 1996, 275,
440-472. (c) Balzarini, J .; De Clercq, E. Methods Enzymol. 1996,
275, 472-502.
(3) Richman, D. D. Antiretroviral Drug Resistance: Mechanisms,
Pathogenesis, Clinical Significance. Adv. Exp. Med. Biol. 1996,
394, 383-395.
(4) For general reviews, see: (a) Collier, A. C. Efficacy of Combina-
tion Antiretroviral Therapy. Adv. Exp. Med. Biol. 1996, 394,
355-372. (b) Vella, S.; Franca Pirillo, M. Combination Therapy
in the Management of HIV Infection. Methods Find. Exp. Clin.
Pharm. 1996, 18 (Suppl. C), 23-26.
(5) For clinical trials involving nevirapine, see: (a) Carr, A.; Cooper,
D. A. Current Clinical Experience with Nevirapine for HIV
Infection. Adv. Exp. Med. Biol. 1996, 394. (b) Luzuriaga, K.;
Bryson, Y.; Krostad, P.; Robinson, J .; Stechenberg, B.; Lamson,
M.; Cort, S.; Sullivan, J . L. Combination Treatment with
Zidovudine, Didanosine, and Nevirapine in Infants with Human
Immunodeficiency Virus Type 1 Infection. N. Engl. J . Med. 1997,
336, 1343-1349. (c) D’Aquila, R. T.; Hughes, M. D.; J ohnson,
V. A.; Fischl, M. A.; Sommadossi, J .-P.; Liou, S.; Timpone, J .;
Myers, M.; Basgoz, N.; Niu, M.; Hirsch, M. S.; and the National
Institute of Allergy and Infections Diseases AIDS Clinical Trials
Group 241 Investigators. Nevirapine, Zidovudine, and Didanosine
Compared with Zidovudine and Didanosine in Patients with
HIV-1 Infection. Ann. Int. Med. 1996, 124, 1019-1030.
(6) (a) Merluzzi, V. J .; Hargrave, K. D.; Labadia, M.; Grozinger, K.;
Skoog, M.; Wu, J . C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams,
J .; Rosenthal, A. S.; Faanes, R.; Eckner, R. J .; Koup, R. A.;
Sullivan, J . L. Inhibition of HIV-1 Replication by
a Non-
Nucleoside Reverse Transcriptase Inhibitor. Science 1990, 250,
1411-1413. (b) Hargrave, K. D.; Proudfoot, J . R.; Grozinger, K.
G.; Kapadia, S. R.; Patel, U. R.; Fuchs, V. U.; Mauldin, S. C.;
Vitous, J . Behnke, M. L.; Klunder, J . M.; Pal, K.; Skiles, J . W.;
McNeil, D. W.; Rose, J . M.; Chow, G. C.; Skoog, M. T.; Wu, J .
C.; Schmidt, G.; Engel, W.; Eberlein, W. G.; Saboe, T. D.;
Campbell, S. J .; Rosenthal, A. S.; Adams, J . Novel Non-
Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 1. Tri-
cyclic Pyridobenzo- and Dipyridodiazepinones. J . Med. Chem.
1991, 34, 2231-2241.
(22) Klunder, J . M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.;
Behnke, M. L.; Kapadia, S. R.; McNeil, D. W.; Wu, J . C.; Chow,
G. C.; Adams, J . Novel Non-Nucleoside Inhibitors of HIV-1
Reverse Transcriptase. 2. Tricyclic Pyridobenzoxazepinones and
Dibenzoxazepinones. J . Med. Chem. 1992, 35, 1887-1897.
(23) Dueweke, T. J .; Pushkarskaya, T.; Poppe, S. M.; Swaney, S. M.;
Zhao, J . Q.; Chen, I. S. Y.; Stevenson, M.; Tarpley, W. G. A
Mutation in Reverse Transcriptase of Bis(heteroaryl)piperazine-
resistant Human Immunodeficiency Virus Type 1That Confers
Increased Sensitivity to Other Nonnucleoside Inhibitors. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 4713.
(24) Nunberg, J . H.; Schleif, W. A.; Boots, E. J .; O’Brien, J . A.;
Quintero, J . C.; Hoffman, J . M.; Emini, E. A.; Goldman, M. E.
Viral resistance to Human Immunodeficiency Virus Type 1-spe-
cific Pyridinone Reverse Transcriptase Inhibitors. J . Virol. 1991,
65, 4887-4892.
(7) (a) Richman, D.; Shih, C.-K.; Lowy, I.; Rose, J .; Prodanovich,
P.; Goff, S.; Griffin, J . Human Immunodeficiency Virus Type 1
Mutants Resistant to Nonnucleoside Inhibitors Of Reverse
Transcriptase Arise In Tissue Culture. Proc. Natl. Acad. Sci.
U.S.A. 1991, 88, 11241-11245. (b) Richman, D.; Havlir, D.;
Corbeil, J .; Looney, D.; Ignacio, C.; Spector, S. A.; Sullivan, J .;
Cheeseman, S.; Barringer, K.; Pauletti, D.; Shih, C.-K.; Myers,
M.; Griffin, J . Nevirapine Resistance Mutations of Human
Immunodeficiency Virus Type 1 Selected During Therapy. J .
Virol. 1994, 68, 1660-1666.
(25) Tong, L.; Cardozo, M.; J ones, P.-J .; Adams, J . Preliminary
Structural Analysis of the Mutations Selected by Non-Nucleoside
Inhibitors of HIV-1 Reverse Transcriptase. Bioorg. Med. Chem.
Lett. 1993, 3, 721-726.
(8) de Clercq, E. Non-nucleoside Reverse Transcriptase Inhibitors
(NNRTIs) for the Treatment of Human Immunodeficiency Virus
Type 1 (HIV-1) Infections: Strategies to Overcome Drug Resis-
tance Development. Med. Res. Rev. 1996, 16, 125.
(26) The time and number of passages required for isolation of
resistant virus varied from experiment to experiment, but was
only modestly increased relative to nevirapine. Shih, C.-K.;
Schwartz, R.; Barringer, K. Unpublished results.
(9) (a) Kohlstaedt, L. A.; Wang, J .; Friedman, J . M.; Rice, P. A.;
Steitz, T. A. Crystal Structure at 3.5 Å Resolution of HIV-1
Reverse Transcriptase Complexed With An Inhibitor. Science
1992, 256, 1783-1790. (b) Smerdon, S. J .; J ager, J .; Wang, J .;

Inhibitors of HIV-1 Reverse Transcriptase. 7
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 2971
(27) (a) Powis, G.; J ardine, I.; Van Dyke, R.; Weishilboum, R.; Moore,
D.; Wilke, T.; Rhodes, W.; Nelson, R.; Benson, L.; Szumlanski,
C. Foreign Compound Metabolism Studies With Human Liver
Obtained as Surgical Waste, Relation To Donor Characteristics
And Effects Of Tissue Storage. Drug Metab. Dispos. 1988, 16,
582-589. (b) details of assay are reported in ref 12.
(28) Shih, C.-K.; Brickwood, J . R. Unpublished results.
(29) Regen, S. L.; Wuici, S.; Liaw, S.-J . Impregnated Cyanide
Reagents. Convenient Synthesis of Nitriles. J . Org. Chem. 1979,
44, 2029-2030.
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