Targeting delavirdine/atevirdine resistant HIV-1: Identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jm960158n

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.

Full text of DOI:10.1021/jm960158n

J . Med. Chem. 1996, 39, 3769-3789
3769
Ta r getin g Dela vir d in e/Atevir d in e Resista n t HIV-1: Id en tifica tion of
(Alk yla m in o)p ip er id in e-Con ta in in g Bis(h eter oa r yl)p ip er a zin es a s Br oa d
Sp ectr u m HIV-1 Rever se Tr a n scr ip ta se In h ibitor s
Donna L. Romero,* Robert A. Olmsted,† Toni J o Poel, Raymond A. Morge, Carolyn Biles, Barbara J . Keiser,‡
Laurice A. Kopta,† J an M. Friis,§ J ohn D. Hosley,§ Kevin J . Stefanski,∇ Donn G. Wishka,| David B. Evans,
J oel Morris,| Randy G. Stehle,∇ Satish K. Sharma, Yoshihiko Yagi,‡ Richard L. Voorman,§ Wade J . Adams,§
W. Gary Tarpley,† and Richard C. Thomas
Medicinal Chemistry Research, Cancer and Infectious Diseases Research, Chemical and Biological Screening, Drug Metabolism
Research, DDR&D Pharmaceutics, Discovery Chemistry Research, and Biochemistry, Pharmacia & Upjohn, Inc., 301 Henrietta
Street, Kalamazoo, Michigan 49001
Received February 26, 1996X
A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit
NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse
transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted
screening. Further investigation of the structure-activity relationships of close congeners of
these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several
compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying
the Y181C and P236L substitutions). Further structural modifications were required to inhibit
metabolism and modulate solubility in order to obtain compounds with the desired biological
profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most
suitable characteristics were compounds 7, 15, and 36.
In tr od u ction
Nucleoside HIV-1 reverse transcriptase inhibitors
(RTIs) such as AZT, ddI, and 3TC1 benefit HIV-1-
infected patients and have been approved by the FDA
for the treatment of acquired immune deficiency syn-
drome (AIDS). A major limitation of such treatment is
the emergence of resistant virus with specific mutations
in the RT gene.2,5 A major thrust of more recent
research targets non-nucleoside HIV-1 reverse tran-
scriptase inhibitors (NNRTIs) because theory held that
a viable treatment of AIDs would involve coadminis-
tration of drugs which inhibit RT via disparate mech-
anisms. Our efforts along these lines led to the iden-
tification of two clinical candidates of the bis-
(heteroaryl)piperazine (BHAP) class of NNRTIs, atevir-
dine mesylate (1, U-87201E)6 and delavirdine mesylate
NNRTI are not resistant to all other NNRTIs but, in
(2, U-90152T).7 Thus far, clinical trials of several
fact, can exhibit increased sensitivity.14 For example,
NNRTIs as monotherapies have also demonstrated
serial HIV-1 passage in vitro in the presence of increas-
ing concentrations of the BHAP NNRTIs U-87201E or
rapid emergence of resistant virus.8-12
Early experiments indicated that several structurally
U-90152S15 causes a proline to leucine substitution at
diverse NNRTIs interact at a common site on RT, giving
amino acid 236 of RT (P236L). Mutations which arise
rise to the thought that resistance against one type of
upon serial passage in the presence of NNRTIs in cell
NNRTI would engender cross-resistance to all others.
culture are usually, but not always, found in human
This was supported by the observation that HIV-1
patients receiving that particular NNRTI.16 The P236L
variants generated via serial passage in the presence
substitution conferred resistance against atevirdine and
of one NNRTI exhibited substantial cross-resistance to
delavirdine as expected but caused sensitization to other
all other NNRTIs. In addition, the construction of
NNRTIs (e.g., TIBO R82913 and L-697,661). This
recombinant RTs, which contained the mutations at
intriguing property of the BHAPs indicates that HIV-1
amino acids 103, 181, or 188 responsible for resistance,
resistant to one NNRTI will not necessarily be cross-
showed that cross-resistance was engendered to the
resistant to other NNRTIs and, furthermore, empha-
other NNRTIs.13 More recently, it was demonstrated
sizes the need to investigate combinations (sequentially
that in some cases HIV-1 variants resistant to one
and simultaneously) of various RTIs in HIV-1-infected
patients.17 In particular, could sequential treatment
† Cancer and Infectious Diseases Research.
with delavirdine followed by another drug with en-
hanced activity against delavirdine resistant virus
result in effective anti-HIV therapy? To answer this
question, we undertook a project to determine whether
a BHAP of a different structural type might be a
‡ Chemical and Biological Screening.
§ Drug Metabolism Research.
∇ DDR&D Pharmaceutics.
| Discovery Chemistry Research.
Biochemistry.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(96)00158-6 CCC: $12.00 © 1996 American Chemical Society

3770 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Ta ble 1. In Vitro Inhibition of Recombinant HIV-1IIIB RT Mutants
Romero et al.
dec
dec

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3771
Ta ble 1. (Continued)
a
RNA-dependent DNA polymerase activity of mutant RTs was assayed as described in the Experimental Section. IC50 values were
b
determined by nonlinear least-squares fit of data from duplicate points at six drug concentrations. Analyses for C, H, and N are within
(0.4% of theoretical values unless otherwise indicated. c Highest concentration tested. Satisfactory HRMS data were obtained.
d
Ta ble 2. Comparison of the Antiviral Activities of U-90152 vs
suitable partner for use in just such a combination with
the Lead (Alkylamino)piperidine BHAP Analog
delavirdine.
IC90 (µM)c
U-90152R
HIV-1MF
L-697,661R
HIV-1IIIB
WT
HIV-1IIIB
Biologica l Resu lts a n d Discu ssion
a
b
no.
Since we had already synthesized a diverse set of
analogs related to atevirdine and delavirdine, we
screened a subset of these analogs versus a panel of
recombinant RTs to identify compounds that retained
activity against the P236L RT. Although none of the
screened compounds possessed the sensitization phe-
notype, we were successful in identifying a subclass of
analogs, the (methylamino)piperidines, which were
more active than either atevirdine or delavirdine against
the P236L mutant enzyme (Table 1). We were pleased
to find that these compounds were also more active
against other recombinant RTs containing known NNR-
TI resistance mutations, such as the mutant RT enzyme
containing a tyrosine to cysteine substitution at amino
acid 181 (Y181C), a substitution known to confer broad
cross-resistance to most NNRTIs currently in develop-
ment.16 Confirmation of these results in cell culture
assays employed resistant virus generated by serial
passage in the presence of either delavirdine or Merck's
L-697,661. Compound 3 demonstrated enhanced anti-
viral activity against both resistant viruses as compared
to delavirdine (Table 2).
U-90152
3
>10
5.2
1.0
0.05
0.02
5.3
a
Delavirdine was used for the selection of the BHAP resistant
b
MF HIV-1 variant. L-697,661 was used for the selection of the
L-drug resistant IIIB HIV-1 variant. c IC90 ) concentration of drug
that inhibited p24 production in the antiviral assay by 90%.
due to high clearance rates (Table 9). Therefore we
began a program to expand upon the scope of our initial
SAR effort by focusing on the synthesis of a variety of
(alkylamino)piperidines. We sought to design com-
pounds with increased inhibitory activity against mu-
tant RTs (P236L and Y181C), with the appropriate
pharmaceutical properties required for an anti-HIV-1
drug.
Analysis of HPLC traces obtained from plasma of rats
dosed with 3 revealed the presence of one major more
polar metabolite which was subsequently shown to be
the N-desisopropyl metabolite.18 N-Dealkylation of the
pyridine 3-alkylamino substituent is a predominant
pathway for metabolism of the BHAPs.19-21 Unfortu-
nately, it appeared that the novel (methylamino)-
piperidine spacer which linked the two heterocyclic
portions of the template facilitated metabolic N-dealk-
ylation of the 3-(isopropylamino)pyridine substituent,
relative to the corresponding piperazine analog (i.e.,
U-90152). Consequently, the analogs in Table 3 were
synthesized in hopes of boosting metabolic stability. For
example, the isopropylamino substituent of 3 was
replaced with a tert-butylamino substituent in com-
Since the (alkylamino)piperidines had previously
demonstrated excellent activity against the WT virus,
we had already evaluated the pharmacokinetic param-
eters of several such compounds as part of our original
structure-activity relationship (SAR) program. How-
ever, neither 3 nor 4 possessed the desired pharmaco-
kinetic profile when administered orally to rats. Both
compounds exhibited low oral bioavailabilities primarily

3772 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
Ta ble 3. Alterations in the 3-Pyridine Substituent for the Purpose of Gaining Metabolic Stability
IC50(µM)
no.
Y
WT
P236L
Y181C
mp (oC)
formulaa
3
7
8
9
10
11
i-Pr
t-Bu
t-amyl
CH2-c-Pr
c-Pr
0.5
1.5
1.46
3.33
14.6
0.21
1.45
1.1
217-220 dec
130-132
-
187-189
175 dec
201-204
C24H32N6O3Sb
C25H34N6O3S
C26H36N6S1O3
0.39
0.35
0.52
0.09
0.16
0.51
0.53
2.91
0.28
0.37
b
C25H32N6O3S‚0.625H2O
C
C
24H30N6O3S‚0.6H2O
25H32N6O3S‚0.1H2O
1-Me-c-Pr
a
b
Analyses for C, H, and N are within (0.4% of theoretical values unless otherwise indicated. Satisfactory HRMS data were obtained.
pound 7 or a tert-amylamino substituent in compound
8 because the lack of an abstractable hydrogen atom R
to nitrogen should alter the mechanism of dealkylative
metabolism, possibly decreasing the rate.22-24 Cyclo-
propylmethyl-substituted amines (e.g., 9) are reportedly
more resistant to oxidative N-dealkylation.25 Experi-
ence with nevirapine suggested that a cyclopropyl-
amine26,27 (10) might also be advantageous in terms of
reducing the rate of metabolic N-dealkylation. Fur-
thermore, compound 11 was designed to take advantage
of both of these structural features. Thus, it contains
a cyclopropyl group in which the postion R to nitrogen
is blocked by a methyl substitutuent on the ring. In
terms of the effect of the 3-pyridine substituent on
activity, the bulky tert-butyl analog 7 demonstrated
inhibitory activity superior to the isopropyl parent 3,
particularly with respect to activity against the Y181C
mutant enzyme. Further increases in steric bulkiness
as in the tert-amyl case (8) were detrimental to activity
against the P236L RT mutant. The enzyme inhibitory
activity of the cyclopropyl compound 10 was better than
that of 3, but it possessed very poor antiviral activity
in cell culture (Table 8). Moreover, the cyclopropyl
group did not appear to enhance the metabolic stability
in an in vitro metabolism study in rat liver microsomes
where it was determined that its half-life was 16% of
that of U-90152. Likewise, the 1-methylcyclopropyl
analog 11 exhibited slightly enhanced potency compared
to 3 but was much less inhibitory of the BHAP resistant
mutant enzyme (P236L) relative to WT. It also pos-
sessed poor antiviral activity (Table 7). Accordingly, 7
was the only compound of this group selected to undergo
further evaluation.
Pharmacokinetic evaluation of 7 in rats (iv) demon-
strated that it too possessed a high clearance rate but
possessed a slightly increased po bioavailability (10
times) relative to 3. LC/MS examination of the metabo-
lites formed indicated the desired absence of the N-
(desalkylamino)pyridine metabolite. However, substan-
tial pyridine ring hydroxylation as well as small amounts
of N-dealkylation of the linker and hydroxylation of the
tert-butyl group occurred (Scheme 1). Nonlinear phar-
macokinetics, similar to those observed for the pipera-
zine U-90152, suggested that the increase in oral
bioavailability observed with 7 at the higher dose was
likely due to inhibition of a capacity-limited clearance
process rather than increased absorption efficiency.
Meanwhile, efforts aimed at improving both the
pharmacokinetic profile and spectrum of activity con-
Sch em e 1. Metabolic Fate of Compound 7
tinued. Fortunately, incorporation of the tert-butyl-
amino group on the pyridine ring increased the inhibi-
tion of the mutant RT containing the Y181C substi-
tution, although as demonstrated above it was clear that
further increases in the steric bulk of the 3-pyridine
substituent were not leading to the desired enhance-
ments in activity. In order to determine whether
further enhancement of inhibitory activity could be
garnered by increasing the lipophilicity in the vicinity
of this region of the molecule, the effect of shifting
lipophilicity to the alkyl substituent on the aminopip-
eridine linker was explored in both the 3-(isopropyl-
amino)- and 3-(tert-butylamino)pyridine series (Table 4).
It was gratifying to find that progressing from a
(methylamino)piperidine linker to an (ethylamino)- or
(n-propylamino)piperidine linker in the 3-(isopropylami-
no)pyridine series (3 vs 12, 13) improved the enzyme
inhibitory activity against all three enzymes. (Cyclo-
propylamino)piperidine 14 offered no advantages in
terms of activity. The results in the 3-(tert-butylamino)-
pyridine series were comparable, in that the (ethyl-
amino)- and (n-propylamino)piperidines 15 and 16 were
more active than the (methylamino)piperidine com-
pound 7. However, in the tert-butyl series (ethylamino)-
piperidine 15 appeared more inhibitory than the (n-
propylamino)piperidine 16 in both the P236L and
Y181C mutant enzymes, perhaps indicative of an upper
limit on lipophilicity. Nevertheless, antiviral activities
appeared virtually identical for these two compounds,
and both proved advantageous over 7 in cell culture
(Table 8).

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3773
Ta ble 4. Effect of Varying the Lipophilicity of (Alkylamino)piperidine BHAPs
IC50 (µM)
no.
R
Y
Z
WT
P236L
Y181C
mp (°C)
formulaa
3
12
13
14
7
15
16
17
18
19
20
21
22
CH3
Et
n-Pr
c-Pr
CH3
Et
n-Pr
Et
Et
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Et
Et
Et
Et
Et
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
i-Pr
CH3
CH3
CH3
0.5
1.5
0.2
0.24
0.7
1.46
0.46
1.45
0.54
0.26
0.33
0.52
2.6
1.1
217-220 dec
215-216
C24H32N6O3Sb
C25H34N6O3S
C26H36N6O3S
C26H34N6O3S
C25H34N6O3S
C26H36N6O3S
C27H38N6O3S
C24H32N6O3S‚0.33H2O
0.25
0.24
0.23
0.39
0.32
0.48
0.46
0.40
0.45
0.15
0.38
0.13
0.40
0.61
0.94
0.51
0.66
2.48
0.88
0.48
0.66
0.95
3.6
177-179 dec
138-140 dec
130-132
193-194
195-197 dec
204-205
211-213
206-207
C
C
25H34N6O3S‚0.33H2O
26H36N6O3S‚0.25H2O
Et
n-Pr
i-Pr
Et
133-135 dec
115-117
C25H34N6O3S
C25H34N6O3S
C25H34N6O3S
Pr
0.28
0.45
209-210
a
b
Analyses for C, H, and N are within (0.4% of theoretical values unless otherwise indicated. Satisfactory HRMS data were obtained.
Selection of 14 and 15 for pharmacokinetic evaluation
in rats followed (Table 9). Replacing ethyl for methyl
on the aminopiperidine linker slightly worsened the
pharmacokinetic parameters (i.e., 15 vs 7). As in the
case of U-90152 and compound 7, nonlinear pharmaco-
kinetics were observed. However, higher doses of 15,
relative to 7, were required to cause the same degree of
saturation of systemic clearance. The cyclopropyl sub-
stituent on the 4-aminopiperidine, as in compound 14,
only resulted in lowering the oral bioavailability. Thus,
the trend appeared to be that increasing the number of
carbons on the 4-aminopiperidine substituent led to
compounds with poorer pharmacokinetic profiles.
Since previous experience with atevirdine analogs had
shown that a 3-(ethylamino)pyridine substituent was
more metabolically stable than a 3-isopropylamino
substituent,28 a series of analogs in which the 3-(ethyl-
amino)pyridine substituent was held constant while the
lipophilicity was shifted to other parts of the template
were synthesized (compounds 17-21). As anticipated
from the studies previously detailed, it was demon-
strated that the 3-ethylamino substituent (17) slightly
diminished the RT enzyme inhibitory activities relative
to the 3-isopropyl- and 3-tert-butylamino-substituted
compounds 12 and 15. Shifting lipophilicity to the left-
hand side in the form of a 5-isopropyl- or 5-ethylsul-
fonamide-substituted indole did not appreciably alter
the activity. Although shifting lipophilicity to the linker
may have offered a slight advantage in the case of 20
which contained an (n-propylamino)piperidine, this
approach was definitely detrimental in the case of 21
which contained an (isopropylamino)piperidine. One
last attempt involved synthesis of a compound with a
3-(n-propylamino)pyridine substituent (22), which sur-
prisingly, in light of past experience in the piperazine-
linked series,19 exhibited enzyme inhibitory activity
comparable to the 3-isopropyl- and 3-tert-butyl-substi-
tuted parents 12 and 15. In contrast to the pharma-
cokinetic results obtained in the [3-(ethylamino)pyridyl]-
piperazine series, the presence of the N-ethyl moiety did
not result in enhanced metabolic stabilities in the
(alkylamino)piperidine series. The in vitro half-life of
17 in the presence of liver microsomes was one-fourth
that of 7. Poor in vivo clearances and oral bioavail-
abilities were also observed in rats (compound 17 vs 7,
Table 9).
Next we investigated the effect of decreasing the
lipophilicity of these molecules, in order to probe
whether a corresponding decrease in the rate of me-
tabolism would result. It was thought that decreasing
the lipophilicity of these compounds would diminish
their interactions with the lipophilic active sites of the
enzymes responsible for their metabolism. Thus polar
water-solubilizing groups were introduced as substitu-
ents on the indole ring (Table 5). We had successfully
utilized this approach previously to solubilize BHAPs
while retaining activity.29 In all cases, the compounds
containing the water-solubilizing urea substituents were
more inhibitory than those containing the sulfamoyl
substituents against the panel of RTs. In general, the
compounds appeared to be less inhibitory of the Y181C
mutant RT than their methylsulfonamide parents.
Evaluation in the antiviral assays revealed that com-
pounds 25-28 possessed comparable activities. Thus,
they were submitted to the in vitro metabolism assay
to compare metabolic stabilities. These results indi-
cated that 26 was by far the most stable with a half-
life 6.7 times longer than that of 15. Compounds 25-
28 were selected for pharmacokinetic evaluation in rats.
In spite of their enhanced in vitro metabolic stability,
the systemic clearances of compounds 26-28 were
increased relative to their parent 15, which lacked the
water-solubilizing substituent, possibly due to their
enhanced aqueous solubility (Table 9).
The next approach to improve pharmacokinetic per-
formance was an attempt to suppress the pyridine ring
hydroxylation which occurred when N-dealkylation was
hindered by the presence of the tert-butylamino moiety.
Since it had been conclusively demonstrated that delavir-
dine underwent hydroxylation at C-6,30 that position of
the AAP-BHAPs was targeted for blocking. Therefore,
a compound (30) containing a pyridazine ring wherein
a nitrogen atom replaced C-6 was synthesized, in
addition to several compounds containing a halogen

3774 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
Ta ble 5. Effect of Adding Water-Solubilizing Substituents on the Indole Ring
IC50 (µM)
no.
Y
R
Z
WT
P236L
Y181C
formulaa
23
24
25
26
27
28
29
Et
Et
Et
Et
Et
Et
Et
Et
n-Pr
-CO-
-SO2-
-CO-
-SO2-
-CO-
-SO2-
-CO-
0.14
0.24
0.14
0.38
0.22
0.79
0.19
0.24
0.44
0.18
0.57
0.37
1.25
0.40
1.23
1.11
0.41
0.77
0.61
1.83
0.86
C25H34N6O3Sb
C25H34N6O3Sb
C30H42N8O2‚0.4H2O
C29H42N8O3S
i-Pr
i-Pr
t-Bu
t-Bu
i-Pr
C
31H44N8O2‚0.5H2O
C30H44N8O3S‚0.3H2O
31H44N8O2‚0.8H2O
C
a
All compounds were amorphous. Analyses for C, H, and N are within (0.4% of theoretical values unless otherwise indicated.
Satisfactory HRMS data were obtained.
b
Ta ble 6. Effect of C-6-Modified Pyridines on HIV-1 WT and Mutant RT Enzyme Inhibitory Activities
IC50 (µM)
no.
X
R
Y
WT
P236L
Y181C
mp (°C)
formulaa
30
31
32
33
34
35
N
C-Cl
C-F
C-F
C-Cl
C-F
CH3
CH3
CH3
Et
Et
Et
i-Pr
i-Pr
t-Bu
i-Pr
t-Bu
t-Bu
0.74
0.36
0.53
0.46
1.02
0.73
4.56
1.7
1.9
0.54
1.52
1.05
1.31
2.13
0.72
0.88
3.0
193-194
101-102
203-204
166-168
206-207
221-223
C23H31N7O3S‚0.7H2O
C24H31N6O3ClS
C25H33N6O3FS
C
C
C
25H33N6O3FS
26H35N6O3ClS
26H35N6O3FS
1.06
a
Analyses for C, H, and N are within (0.4% of theoretical values.
atom substituent (fluorine or chlorine) at the C-6
position of the pyridine ring (compounds 31-35, Table
6).
results with the fluorinated compounds were confirmed
upon pharmacokinetic evaluation of 35, which was
selected because of its superior antiviral activity. The
iv clearance of 35 in rats was approximately one-half
that of 15; nevertheless, the oral bioavailability was
lower than anticipated and was ascribed to malabsorp-
tion due to extremely poor solubility (Table 9).31 In
general, there was a reasonably good inverse correlation
between systemic (iv) clearance and absolute oral bio-
availability for this class of AAP-BHAP analogs. Excep-
tions, as in the case of compound 35, arose when
aqueous solubility was low and absorption efficiency was
poor. Apparently, the addition of the fluorine atom in
compound 35 dramatically decreased the aqueous solu-
bility due to either the increase in lipophilicity and/or
the anticipated decreased basicity of the 3-(tert-butyl-
amino)pyridine substituent.32 In order to counteract
this effect, we attempted to increase the solubility of
these compounds in the manner described above (Table
7).
Comparison of the fluoro-containing analogs 36 and
37 in the enzyme assay confirmed the trend observed
previously, in that the urea-containing compound 36
was more effective at inhibiting the RT enzymes. In
fact in this fluorinated series, the urea-based water-
solubilizing indole substituent does not adversely effect
the RT enzyme activities compared to the methane-
sulfonamido-substituted indole. Regardless, both com-
pounds possessed very comparable antiviral activities
(Table 8). The sulfamide-linked methylpiperazine 37
was cleared rapidly upon iv administration to rats,
although it demonstrated relatively good oral bioavail-
In all cases introduction of the halogen atom caused
slight to moderate increases in the IC50s against the
three RT enzymes tested. The presence of the py-
ridazine ring (30) also decreased inhibitory activities
relative to 3, especially against the P236L recombinant
RT. All of these results were not necessarily paralleled
in the antiviral assays. For example, 32 and 35 pos-
sessed antiviral activities comparable to their deshalo
parents 7 and 15, respectively. In vitro metabolism
studies of the 3-(tert-butylamino)-6-fluoropyridines 32
and 35 and the pyridazine 30 demonstrated substantial
improvements in metabolic stability. For example, 32
which contains the (methylamino)piperidine linker had
a half-life 2.8 times greater than that of the nonfluori-
nated parent 7. Furthermore, 35, which contains the
(ethylamino)piperidine linker, had a half-life 5.2 times
that of the nonfluorinated parent 15 and 0.78 times that
of U-90152. The pyridazine analog contained the (me-
thylamino)piperidine linker and a 3-isopropylamino
substituent on the pyridine ring. Even with the pres-
ence of the more metabolically labile 3-isopropylamino
moiety, 30 possessed an in vitro half-life 3 times longer
than that of the analogous compound 3, which lacks the
additional nitrogen in the ring. According to calculated
log P values, incorporation of the pyridazine ring should
decrease the lipophilicity of 30 relative to the analogous
pyridine 3. Apparently, this alteration was not well
tolerated as indicated by pharmacokinetic studies which
demonstrated that 30 was not absorbed. The in vitro

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3775
Ta ble 7. Enzyme Inhibitory Activities of Fluorinated Pyridine
AAP-BHAPs Containing a Water-Solubilizing Substituent on
the 5-Indole Position
Ta ble 9. Selected Pharmacokinetic Parameters of Some
Indole-Substituted (Alkylamino)piperidine HIV-1 RT Inhibitors
in Male Sprague-Dawley Ratsa
dose (mg/kg)
iv clearance
(mL/min/kg)
absolute oral
bioavailability (%)
compd
iv
po
U-87201
U-90152
12
23
15
28
30.2
35
29.1
31.4
30
60
120
240
30
30
30
30
30
13.0 ( 1.3
13.6 ( 0.3
13.6 ( 0.3
44 ( 6
75 ( 14
64 ( 8
14
14
15
16
15
15.7
15
15
15
15
15
15
15
15
15
15.6
15
15
15
169 ( 25b
4.3 ( 4.2
12.3 ( 1.8
44 ( 3
3
4
7
14
15
42 ( 4
46.0 ( 1.9
22.6(1.3
50 ( 10
50 ( 10
50 ( 10
50 ( 10
66.6 ( 1.7
50 ( 7
IC50 (µM)
1.6 ( 0.4
14 ( 10
42 ( 17
124 ( 35
240 ( 90
2.8 ( 0.7
21.3 ( 1.2
8 ( 3
35.1 ( 2.9
32 ( 24
0
17.1 ( 1.6
42 ( 16
54 ( 29
no.
Z
X
WT P236L Y181C mp (°C)
formulaa
36 -CO-
37 -SO2-
F
F
0.21 0.43
0.83 1.09
0.79 203-204 C29H38N8O2F
2.07 181-183 C30H43N8O3FS
a
Analyses for C, H, and N are within (0.4% of theoretical
17
25
26
27
28
30
35
36
37
values.
89 ( 3
61 ( 7
Ta ble 8. Antiviral Activities of Selected Compounds Against
Resistant Viruses
73.7 ( 2.1
40 ( 7
31.2
IC90 (µM)a
30
30
30
27 ( 3
U-90152R
HIV-1MF
U-90152R
HIV-1IIIB
L-697,661R
HIV-1IIIB
16 ( 4
b
c
c
61 ( 12
no.
(P236L)
(L100I, M230L)
(Y181C)
a
Compounds were administered as solutions in propylene
glycol/water (80/20, v/v) acidified with a molar excess of methane-
sulfonic acid. Doses were administered to fasted animals in a
crossover design with a 1 week washout period between treatments
90152T
L-697,661
>10
0.43
5.3
>10
4.0
NT
0.83
NT
NT
5.2
>10
3
7
1.0
0.22
4.4
2.3
0.06
0.03
0.03
0.18
0.14
0.05-0.1
0.17
∼0.05-0.10
<0.03
0.44
b
5.4
(N ) 3). The nonlinear pharmacokinetics of U-90152 result in
an apparent bioavailability >100%.
10
11
13
15
16
17
22
25
26
27
28
32
33
34
35
36
37
>10
>0.3
0.22
0.19
0.32
0.31
0.4
0.24
0.3
0.16
0.34
2.6
0.3-1.0
0.24
0.22
0.16
0.29
noncompetitive inhibitor with respect to poly(rA):(dT)10
and dTTP. Delavirdine mesylate,35 on the other hand,
acts as a mixed inhibitor regardless of template:primer
in that it binds more tightly to the enzyme-substrate
complexes than to the free enzyme. The Ki values for
all three (alkylamino)piperidines were quite similar for
all three enzymes (Table 10). Interestingly, the relative
ordering of Ki values was not consistent between
enzymes.
NT
0.08
0.11
0.08
NT
0.11
NT
0.16
0.14
1.6
0.11
NT
0.14
Resistance selection studies were conducted with
compounds 7 and 15.36 Selection of HIV-1 variants
resistant to these compounds was prolonged relative to
other NNRTIs. The derived virus stocks were of lower
infectious titer and grew more slowly than wild type
virus in cell culture. Analysis of the DNA sequence of
the RT gene indicated that high-level resistance to 7
required simultaneous multiple amino acid substitu-
tions, including a glycine to glutamate substitution at
amino acid 190 (G190E). Furthermore, genotypic analy-
sis of the HIV-1 variant resistant to 15 revealed one
other substitution (Leu214 f Phe) in addition to G190E.
The G190E mutation has been reported to drastically
reduce the enzyme activity, and preliminary data sug-
gested that the corresponding HIV-1 variant exhibited
impeded growth in tissue culture.37 Analogous results
were obtained in our labs when the G190E substitution
was incorporated into recombinant HIV-1IIIB RT. The
reduced replicative capacity of the HIV-1IIIB variants
resistant to 7 and 15 also supports the notion that the
G190E mutation compromises virus growth. Genera-
tion of such a mutation in patients treated with these
types of (alkylamino)piperidines could be beneficial,
since selection of a virus population with diminished
replication might lead to a decrease in the steady-state
level of virus.
>0.3
e 0.03
0.13
0.12
0.14
0.29
0.15
a
IC90 ) concentration of drug that inhibited p24 production in
the antiviral assay by 90%. b Delavirdine was used for the selection
of BHAP resistant MF and IIIB HIV-1 variants. c L-697,661 was
used for the selection of the L-drug resistant IIIB HIV-1 variant.
ability (Table 9). The urea-linked methylpiperazine 36
possessed a greatly diminished iv clearance relative to
7 and the nonfluorinated 27, and it possessed an oral
bioavailability similar to that of 7. Thus it appears that
incorporation of the 6-fluorine to inhibit pyridine ring
hydroxylation and incorporation of the 5-methylpipera-
zine urea indole substituent to counteract the effect of
the fluorine on solubility enhanced the pharmacokinetic
properties of the (ethylamino)piperidine template with-
out negatively effecting the activity.
Experiments designed to determine the kinetics of
inhibition of HIV-1 WT, P236L, and Y181C RTs were
conducted with compounds 7, 15, and 36. All three
compounds are noncompetitive inhibitors with respect
to dGTP, dTTP, and poly(rA):(dT)10. Previous experi-
ments with the BHAP atevirdine mesylate33 revealed
that it acts as a noncompetitive inhibitor with respect
to deoxyribonucleotide triphosphate (dNTP) irrespective
of the template:primer [poly(rA):(dT)10 or poly(rC):
(dG)10] used. The BHAP U-88204E34 acts as a mixed
inhibitor with respect to poly(rC):(dG)10 and as a
Ch em istr y
The (alkylamino)piperidine-linked template could be
easily prepared starting with 4-amino-1-benzylpiperi-

3776 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
Ta ble 10. Ki Values for Compounds 7, 15, and 36 Against HIV-1 WT, P236L, and Y181C RTs
Ki (µM) versus dTTPa
Ki (µM) versus poly(rA)300:oligo(dT)10
no.
WT
P236L
Y181C
WT
P236L
Y181C
7
15
36
0.714 (0.046)
1.033 (0.113)
1.262 (0.061)
2.759 (0.213)
1.114 (0.046)
2.022 (0.105)
1.046 (0.086)
1.922 (0.171)
2.547 (0.194)
0.853 (0.052)
1.380 (0.039)
1.640 (0.144)
2.515 (0.119)
1.603 (0.077)
1.739 (0.148)
1.790 (0.088)
3.089 (0.295)
3.025 (0.195)
a
Data shown were generated in a single experiment which involved two determinations at a total of four substrate and four inhibitor
concentrations (16 data points). The experiments were repeated at least three times with consistent results.
Sch em e 2
Sch em e 3a
a(i) Acetone, NaCNBH3, AcOH, methanol; (ii) acetone, TMSCN,
ZnCl2; (iii) CH3Li, toluene; (iv) 2-methoxypropene, PPTS; (v)
CH3Li‚LiBr, toluene; (vi) 3-chloro-3-methyl-1-butyne, Cu, CuCl;
(vii) Raney Ni, H2.
39 via hydrogenation over palladium or platinum oxide
was uneventful and provided the desired 3-aminopyr-
idines 40. Functionalization of the 3-amino moiety of
these pyridines is outlined in Schemes 3 and 4. Re-
moval of the piperidine-protecting group (generally
hydrogenation over palladium on carbon in the case of
the benzyl protecting group41 or treatment with TFA
in methylene chloride in the case of the BOC protecting
group) provided the 4-functionalized piperidines 50
suitable for coupling with the desired 5-substituted-
indole-2-carboxylic acid (usually 5-methanesulfonamido)
utilizing 1-[3-(dimethylamino)propyl]-3-ethylcarbodiim-
ide hydrochloride (EDC) or 1,1′-carbonyldiimidazole
(CDI) as coupling agents.
Scheme 3 describes the sequence of reactions utilized
to generate the isopropylamino, tert-butylamino, and
tert-amylamino groups at the 3-position of the pyridine
ring. (Isopropylamino)pyridines 41 were synthesized by
treating the 3-aminopyridine 40 with acetone and
sodium cyanoborohydride in acetic acid/methanol sol-
vent. The 3-(ethylamino)- and 3-(propylamino)pyridines
were synthesized similarly. The tert-butylamine con-
geners were synthesized as previously described.42 In
short, treatment of the 3-aminopyridine 40 with acetone
and trimethylsilyl cyanide in the presence of catalytic
zinc chloride afforded the R-aminonitrile 42, which upon
treatment with excess methyllithium in toluene afforded
the desired tert-butylamine intermediate 44. An alter-
nate route involves formation of the acetonylimine 43
dine or 1-(tert-butoxycarbonyl)-4-piperidone (Scheme 2).
Formylation or acylation of the primary amine of
4-amino-1-benzylpiperidine followed by reduction with
lithium aluminum hydride provided 4-(alkylamino)-1-
benzylpiperidines 38 (PG ) benzyl). A more expedient
route to 38 involved reductive amination of amino-
protected 4-piperidones (PG ) benzyl or BOC) which
occurred upon treatment with alkylamines and sodium
cyanoborohydride. Even more conveniently, hydrogena-
tion of a solution of aqueous methyl- or ethylamine and
N-benzyl-4-piperidone over palladium on carbon in THF
provided the desired intermediates 38 (PG ) benzyl, R
) methyl or ethyl) in excellent yields.38 The secondary
amines produced via these methods were used as
nucleophiles in a nucleophilic aromatic substitution of
2-chloro-3-nitropyridines or 2,6-dichloro- or 2,6-difluoro-
3-nitropyridines.39,40 In the case of (methylamino)- or
(ethylamino)piperidines, these reactions were typically
conducted in refluxing acetonitrile with 1 equiv of
potassium carbonate to scavage the acid byproduct.
When more hindered (alkylamino)piperidines were em-
ployed, such as isopropyl or n-propyl, the reactions were
very sluggish, and thus they were conducted using
Hunig’s base as solvent or neat in a sealed tube at high
temperature. Reduction of the resultant nitropyridines

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3777
Sch em e 4
Sch em e 5
were prepared similarly, but ethyl- or isopropylsulfonyl
chloride was employed.
by treating the 3-aminopyridine with 2-methoxypropene
and 10 mol % of pyridinium p-toluenesulfonic acid.43
Subsequent addition of methyllithium-lithium bromide
complex to the imine also affords the desired tert-
butylamine analogs. The tert-amyl analogs were pre-
pared in a manner similar to literature precedent.44
3-Chloro-3-methyl-1-butyne45 could be coupled with the
3-aminopyridine moiety (40) upon treatment with ap-
proximately stoichiometric quantities of copper powder
and cuprous chloride in DMF, providing intermediate
45. The alkyne product was reduced with hydrogen
over Raney nickel to provide the desired (tert-amylami-
no)pyridine intermediate 46.
Cyclopropylamines were prepared by treating 3-ami-
nopyridine 40 with 1-bromo-1-ethoxycyclopropane and
triethylamine in THF at reflux to afford the intermedi-
ate (ethoxyamino)cyclopropane 47 (Scheme 4).46 Reduc-
tion with lithium aluminum hydride was capricious but
afforded the desired aminocyclopropane product 48.
Reaction of the 1-amino-1-ethoxycyclopropane with me-
thyllithium in toluene afforded the desired 1-amino-1-
methylcyclopropane 49.
Nucleophilic aromatic substitution of 3,4,5-trichloro-
pyridazine with isopropylamine in refluxing toluene
provided two regioisomeric products in an approxi-
mately 1:1 ratio (Scheme 5).47 Chromatography af-
forded the desired isomer 51 which was treated with
1-benzyl-4-(methylamino)piperidine and heated (neat)
to 155 °C in a sealed tube. The coupled product 52 was
hydrogenated over palladium hydroxide on carbon to
dechlorinate the pyridazine and remove the benzyl
protecting group providing 53. Standard coupling to the
indole-2-carboxylic acid afforded 30.
Introduction of the water-solubilizing substituents
was accomplished by treating the 5-aminoindole inter-
mediate 55, available via reduction of nitroindoles 54,
with 4-methyl-1-piperazinylcarbamoyl chloride hydro-
chloride or 4-methyl-1-piperazinylsulfamoyl chloride
hydrochloride and pyridine (Scheme 6). These reagents
were prepared by treating excess phosgene or excess
sulfuryl chloride with N-methylpiperazine in methylene
chloride at 0 °C, and concentrating in vacuo after
strirring for 3 h at room temperature. The ethyl- and
isopropylsulfonamide-containing compounds 18 and 19
Con clu sion
In summary, investigation of the SAR surrounding
the bis(heteroaryl)(alkylamino)piperidine template re-
sulted in the synthesis of a number of compounds with
the desired phenotypes. In particular, substituting an
ethyl for a methyl group on the aminopiperidine spacer
enhanced the desired activities against both Y181C and
P236L mutant RTs. Several of the (alkylamino)piperi-
dine analogs described herein demonstrate excellent
activities against both mutant RT enzymes and viruses.
Once the activity barrier was hurdled, the primary
strategy became synthetic manipulation of the chemical
structure with the object of obtaining a suitable phar-
macokinetic profile in the rat. The strategies pursued
involved substituting the more stable tert-butylamino
group (15) for a metabolically labile isopropylamino
group, introduction of a heteroaromatic fluorine sub-
stituent to thwart ring hydroxylation (35), and intro-
duction of water-solubilizing substituents to counteract
the decreased solubility attributed to the fluorine atom
(36). Investigations which define the pharmacokinetic
parameters and safety profiles of three of these analogs,
7, 15, and 36, in laboratory animals will be detailed
elsewhere.
Exp er im en ta l Section
Flash chromatography utilized E. Merck silica gel (230-
400 mesh). Melting points were taken on a Thomas-Hoover
capillary melting point apparatus and are uncorrected. Mass
spectra, infrared spectra, and combustion analyses were
obtained by the Structural, Analytical and Medicinal Chem-
istry Department of Pharmacia & Upjohn, Inc. Unless oth-
erwise indicated, proton NMR spectra were recorded with a
Brucker Aspect 3000 300 MHz spectrometer. Tetrahydrofuran
(THF) was distilled from sodium and benzophenone. All other
solvents were Burdick and J ackson or Fisher reagent grade.
In cases where synthetic intermediates or products were
isolated by “aqueous workup (organic solvent, drying agent)”,
the procedure was to quench the reaction with water, dilute
the mixture with the indicated organic solvent, separate the
organic layer, extract the aqueous layer several times with the
organic solvent, dry the combined organic layers with the
indicated drying agent, and remove the solvent with a rotary
evaporator at reduced pressure. When “basic workup (organic
solvent, aqueous base, drying agent)” is indicated, the proce-

3778 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
Sch em e 6
dure was similar to the aqueous workup, except the indicated
aqueous base was used instead of water.
concentrated in vacuo. Basic workup (CH2Cl2, aqueous KOH
to pH 12, Na2SO4) and chromatography (ammonium hydroxide/
CH3OH/CH2Cl2, 0.5/4.5/95-0.5/14.5/85) afforded a residue
which was dissolved in CH2Cl2 (100 mL), washed with 5%
aqueous NaOH (20 mL) and brine (20 mL), dried over Na2-
SO4, and concentrated in vacuo to provide 23.7 g (96%) of the
product as a pale amber oil: 1H NMR (CDCl3) δ 7.31 (m, 4H),
7.24 (m, 1H), 3.50 (s, 2H), 2.85 (br d, J ) 11.7 Hz, 2H), 2.59 (t,
J ) 7.4 Hz, 2H), 2.46 (m, 1H), 2.02 (br t, J ) 11.5 Hz, 2H),
1.85 (br d, J ) 12.6 Hz, 2H), 1.50 (sext, J ) 7.4 Hz, 2H), 1.39
(m, 2H), 0.92 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 139.1, 129.4, 128.5, 127.2, 63.5, 55.4, 52.9, 49.2, 33.3, 23.9,
12.2.
1-Ben zyl-4-[(1-m eth yleth yl)a m in o]p ip er id in e, 38d (P G
) ben zyl, R ) isop r op yl): prepared in a manner analogous
to 38c to afford 45% of the title amine; 1H NMR (CDCl3) δ
7.20 (m, 5H) 3.40 (s, 2H), 2.99 (m, 1H), 2.78 (br d, J ) 12.1
Hz, 2H), 2.58 (m, 1H), 1.92 (t, J ) 11.8 Hz, 2H), 1.79 (m, 2H),
1.35 (m, 2H), 1.04 (d, J ) 4.2 Hz, 6H); MS-EI m/ e (rel
intensity) 232 (4), 189 (4), 173 (60), 146 (11), 91 (100).
1-[(1,1-Dim eth yleth oxy)ca r bon yl]-4-(cyclop r op yla m i-
n o)p ip er id in e, 38e (P G ) BOC, R ) cyclop r op yl): pre-
pared in a manner analogous to 38c to afford 84% of the title
amine as a colorless oil; IR (atr) 3316 (w), 3087 (w), 2976 (m),
2933 (m), 2855 (m), 1685 (s) cm-1; 1H NMR (CDCl3) δ 4.02 (br
m, 2H), 2.75 (m, 3H), 2.13 (m, 1H), 1.90 (br d, J ) 10.9 Hz,
2H), 1.59 (s, 1H), 1.45 (s, 9H), 1.25 (m, 2H), 0.45 (m, 2H), 0.32
(m, 2H); MS-EI m/ e 240 (M+), 184, 169, 155, 110, 84, 82, 57,
40. Anal. (C13H24N2O2) C, H, N.
Gen er a l P r oced u r e for th e Nu cleop h ilic Su bstitu tion
of Nitr op yr id in es w ith 1-P r otected -4-(a lk yla m in o)p ip -
er id in es. 1-Ben zyl-4-[N-et h yl-(N-3-n it r o-2-p yr id in yl)-
a m in o]p ip er id in e, 39a (P G ) ben zyl, R ) Et, X ) H). 38a
(12.91 g, 59.1 mmol), 2-chloro-3-nitropyridine (9.37 g, 59.1
mmol), and K2CO3 (8.17 g, 59.1 mmol) were placed in 118 mL
of CH3CN and heated to reflux for 72 h. Then the reaction
mixture was cooled to room temperature. Aqueous workup
(CHCl3, Na2SO4) and purification by flash column chromatog-
raphy (10% EtOAc/hexane) afforded 13.7 g (69%) of the title
compound: 1H NMR (CDCl3) δ 8.20 (dd, J ) 4.5, 1.6 Hz, 1H),
7.92 (dd, J ) 8.1, 1.8 Hz, 1H), 7.12-7.24 (m, 5H), 6.58 (dd, J
) 7.7, 4.5 Hz, 1H), 3.55-3.70 (m, 1H), 3.47 (s, 2H), 3.35 (q, J
) 7.1 Hz, 2H), 2.89-2.93 (br m, 2H), 1.80-2.10 (m, 4H), 1.65-
1.73 (br m, 2H), 0.93 (t, J ) 7.1 Hz, 3H).
Gen er a l P r oced u r e for th e Acyla tion a n d Su bsequ en t
Red u ction of 4-Am in o-1-ben zylp ip er id in e. 1-Ben zyl-4-
a ceta m id op ip er id in e. 4-Amino-1-benzylpiperidine (20.0 g,
105.1 mmol) was dissolved in 210 mL of CH2Cl2 and cooled to
0 °C. Then pyridine (10.29 mL, 127.2 mmol) was added
followed by the dropwise addition of acetyl chloride (9.06 mL,
127.4 mmol). The reaction mixture was stirred for 30 min at
0 °C and slowly warmed to room temperature. When complete
by TLC, basic workup (CHCl3, 1 N aqueous NaOH, Na2SO4)
and recrystallization from EtOAc afforded 19.09 g (78%) of the
title compound: 1H NMR (CDCl3) δ 7.29-7.36 (m, 5H), 5.57
(br s, 1H), 3.75-3.90 (m, 1H), 3.59 (s, 2H), 2.89-2.93 (br m,
2H), 2.21 (t, J ) 9.5 Hz, 2H), 1.98 (s, 3H), 1.93-1.98 (m, 2H),
1.51-1.63 (m, 2H).
1-Ben zyl-4-(eth yla m in o)p ip er id in e, 38a (P G ) ben zyl,
) Et). 1-Benzyl-4-acetamidopiperidine (19.09 g, 82.17
R
mmol) was dissolved in 164.3 mL of anhydrous THF and cooled
to 0 °C. Then LAH in THF (1 M, 82.17 mL, 82.17 mmol) was
added dropwise via an addition funnel. When the addition
was complete, the reaction mixture was warmed to room
temperature and heated to reflux for 16 h. TLC of an aliquot
quenched with 1 N NaOH and partitioned in CHCl3 showed
complete reduction. The reaction was cooled to 0 °C and
quenched by the dropwise addition of 3.12 mL of water, 3.12
mL of 15% aqueous NaOH, and 9.36 mL of water. The
reaction mixture was filtered through a pad of Celite/sodium
sulfate and concentrated in vacuo to afford 14.98 g (84%) of
the title compound which was used without further purifica-
tion: 1H NMR (CDCl3) δ 7.06-7.14 (m, 5H), 3.33 (s, 2H), 2.65-
2.71 (m, 2H), 2.52 (q, J ) 7.2 Hz, 2H), 2.27-2.37 (m, 1H), 1.80-
1.88 (m, 3H), 1.68-1.72 (m, 2H), 1.18-1.31 (m, 2H), 0.96 (t, J
) 7.1 Hz, 3H).
Gen er a l P r oced u r es for th e Red u ctive Am in a tion of
N-P r otected -p ip er id on es. 1-Ben zyl-4-(m eth yla m in o)p i-
p er id in e, 38b (P G ) ben zyl, R ) Me). 1-Benzyl-4-piperi-
done (10.0 g, 52.8 mmol) was dissolved in 200 mL of methanol
and cooled to 0 °C. Then methylamine hydrochloride (3.57 g,
52.8 mmol) and 4 Å molecular sieves were added followed by
3.32 g of NaCNBH3 (52.8 mmol). The reaction mixture was
warmed to room temperature and stirred for 24 h. Basic
workup (CHCl3, NaHCO3, Na2SO4) afforded a residue which
was dissolved in CHCl3, washed with 1 N HCl, basified with
1 N NaOH, and extracted with CHCl3. The extract was dried
over Na2SO4 and concentrated in vacuo to provide 8.1 g of the
title amine (76%): 1H NMR (CDCl3) δ 7.24 (m, 5H), 3.49 (s,
2H), 2.83 (m, 2H), 2.41 (s, 3H), 2.33 (m, 1H), 2.01 (m, 2H),
1.83 (m, 2H), 1.31 (m, 2H).
1-Ben zyl-4-(p r op yla m in o)p ip er id in e, 38c (P G ) ben -
zyl, R ) p r op yl). A solution of 1-benzyl-4-piperidone (20.0
g, 106 mmol) in CH3OH (200 mL) maintained at 0 °C was
treated with n-propylamine (12.2 mL, 148 mmol) and NaC-
NBH3 (3.33 g, 53 mmol), adjusted to pH 7 with glacial acetic
acid as determined on moistened pH test paper, warmed to
room temperature, and stirred at room temperature for 20 h.
The mixture was then adjusted to pH 3 using 3 M HCl and
1-Ben zyl-4-[N-m eth yl-N-(3-n itr o-2-p yr id in yl)a m in o]p i-
p er id in e, 39b (P G ) ben zyl, R ) m eth yl, X ) H).
A
mixture of 38b (10.80 g, 52.8 mmol), 2-chloro-3-nitropyridine
(6.70 g, 42.2 mmol, 0.8 equiv), and anhydrous K2CO3 (14.6 g,
106 mmol, 2 equiv) in dry CH3CN (211 mL) was stirred at room
temperature for 5 days and then concentrated to remove
solvent. Aqueous workup (CH2Cl2, Na2SO4), concentration in
vacuo, and chromatography (50% EtOAc/hexane) afforded
13.10 g (95%) of the product as a yellow solid: mp 92-95 °C;
1
IR (mull) 2926 (s), 1597 (s), 1556 (s), 1501 (s) cm-1; H NMR
(CDCl3) δ 8.27 (dd, J ) 1.7, 4.4 Hz, 1H), 8.09 (dd, J ) 1.7, 8.0
Hz, 1H), 7.29 (m, 5H), 6.63 (dd, J ) 4.4, 8.0 Hz, 1H), 4.45 (m,
1H), 3.54 (s, 2H), 2.99 (br d, J ) 11.6 Hz, 2H), 2.69 (s, 3H),

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3779
2.15 (td, J ) 2.7, 11.6 Hz, 2H), 1.90 (m, 2H), 1.81 (m, 2H).
EI-MS m/ z (rel intensity) 326 (M+, 1), 280 (6), 172 (100), 91
(100). Anal. (C18H22N4O2) C, H, N.
1-Ben zyl-4-[N-(1-m eth yleth yl)-N-(3-n itr o-2-p yr id in yl)-
a m in o]p ip er id in e, 39h (P G ) ben zyl, R ) isop r op yl, X )
H). 38d (7.55 g, 32.49 mmol) and 2-chloro-3-nitropyridine
(5.15 g, 32.49 mmol) were heated in a sealed tube under
nitrogen to 160 °C for 3 h. The mixture was then applied to
the top of a 400 g silica gel column in a few milliliters of
chloroform and eluted with 15% EtOAc in hexane to yield 1.66
g (14%) of product as an oil: 1H NMR (CDCl3) δ 8.51 (dd, J )
1.7, 4.7 Hz, 1H), 8.10 (dd, J ) 1.7, 8.1 Hz, 1H), 7.34 (dd, J )
4.7, 8.1 Hz, 1H), 7.18 (m, 5H), 3.48 (m, 1H), 3.39 (m, 2H), 2.85
(m, 3H), 2.15 (m, 2H), 1.85 (m, 2H), 1.67 (m, 2H), 1.25 (d, J )
6.6 Hz, 6H); MS-EI m/ e (rel intensity) 354 (1), 337 (2), 308
(8), 172 (100), 146 (15), 91 (99).
1-[(1,1-Dim eth yleth oxy)ca r bon yl]-4-[N-cyclop r op yl-N-
(3-n itr o-2-p yr id in yl)a m in o]p ip er id in e, 39c (P G ) BOC,
R ) cyclop r op yl, X ) H). A mixture of 38e (100 mg, 0.42
mmol), 2-chloro-3-nitropyridine (53 mg, 0.33 mmol), and 145
µL of diisopropylethylamine (0.83 mmol) in 1.5 mL of N-meth-
yl-2-pyrrolidinone was stirred at room temperature for 1 day,
at 90 °C for 4 days, and again at room temperature for 1 day.
Aqueous workup (CH2Cl2, Na2SO4), concentration, and chro-
matography (10-20% EtOAc/hexane) afforded 54 mg of a
yellow film which was chromatographed on one 2000 µm
preparative silica gel plate, eluting with 10% and 25% EtOAc/
hexane. The band with Rf ) 0.38-0.50 was extracted with
5% MeOH/CHCl3 and concentrated to give 48 mg (40%) of the
title compound as a yellow film: IR (atr) 2974 (m), 2934 (m),
2863 (m), 1689 (s), 1594 (s) cm-1; 1H NMR (CDCl3) δ 8.28 (dd,
J ) 1.7, 4.5 Hz, 1H), 8.05 (dd, J ) 1.7, 8.0 Hz, 1H), 6.72 (dd,
J ) 4.5, 8.0 Hz, 1H), 4.50 (m, 1H), 4.23 (br m, 2H), 2.83 (br t,
J ) 10.8 Hz, 2H), 2.57 (m, 1H), 2.06 (m, 4H), 1.49 (s, 9H),
0.70 (m, 2H), 0.45 (m, 2H); MS-EI m/ e 289, 178, 164, 126, 82,
57; HRMS (FAB) calcd for C18H26N4O4 + H1 363.2032, found
363.2037.
1-Ben zyl-4-[N-m eth yl-N-(6-ch lor o-3-n itr o-2-p yr id in yl)-
a m in o]p ip er id in e, 39i (P G ) ben zyl, R ) m eth yl, X ) Cl):
prepared in a manner analogous to 39b but employing 2,6-
dichloro-3-nitropyridine and 38b to afford 69% of the title
1
compound; H NMR (CDCl3) δ 7.92 (d, J ) 8.3 Hz, 1H), 7.14
(m, 5H), 6.47 (d, J ) 8.3 Hz, 1H), 4.23 (sept J ) 6.2 Hz, 1H),
3.40 (s, 2H), 2.85 (m, 2H), 2.57 (s, 3H), 2.02 (m, 2H), 1.72 (m,
2H); HRMS (EI) calcd for C18H21N4O2Cl + H 361.1431, found
361.1447.
Nu cleop h ilic Ar om a tic Su bstitu tion of P yr id a zin es.
4-(Isop r op yla m in o)-3,5-d ich lor op yr id a zin e, 51. 3,4,5-
Trichloropyridazine (9.2 g 0.05 mol) was dissolved in 24 mL
of toluene. Isopropylamine (16.5 g 0.28 mol) was added and
the solution refluxed for 3 hours. Basic workup (CHCl3, 1 N
NaOH, Na2SO4) and chromatography (30% EtOAc/hexane)
yielded 4.33 g of 4-(isopropylamino)-3,5-dichloropyridazine (the
1-Ben zyl-4-[N-et h yl-N-(6-ch lor o-3-n it r o-2-p yr id in yl)-
a m in o]p ip er id in e, 39d (P G ) ben zyl, R ) eth yl, X ) Cl):
prepared in a manner analogous to 39b but employing 28a
and 2,6-dichloro-3-nitropyridine in place of 2-chloro-3-nitro-
pyridine afforded 74% of the title compound; 1H NMR (CDCl3)
δ 7.82 (d, J ) 8.4 Hz, 1H), 7.11 (m, 5H), 6.45 (d, J ) 8.4 Hz,
1H), 3.44 (m, 1H), 3.33 (s, 2H), 3.31 (m, 2H), 2.79 (m, 2H),
1.86 (m, 2H), 1.72 (m, 2H), 1.65 (m, 2H), 0.90 (t, J ) 7.0 Hz,
3H).
desired product) plus 4.73
g
of 5-(isopropylamino)-
3,4-dichloropyridazine: 1H NMR (CDCl3) δ 8.50 (s, 1H), 4.74
(br s, 1H), 4.47 (m, 1H), 1.20 (d, J ) 6.4 Hz, 6H).
1-Ben zyl-4-[N-m et h yl-N-[3-[(1-m et h ylet h yl)a m in o]-4-
ch lor o-2-p yr id a zin yl]a m in o]p ip er a zin e, 52. 38b (2.30 g,
11.4 mmol) and 51 (1.0 g, 4.8 mmol) were heated in a sealed
tube under a nitrogen atmosphere to 155 °C for 3 h. The
mixture was chromatographed (50-100% EtOAc/hexane) to
yield 320 mg (18%) of the title compound as an oil: 1H NMR
(CD3OD) δ 8.43 (s, 1H), 7.30 (m, 5H), 4.5 (m, 1H), 3.51 (s, 2H),
2.90 (br d, 2H), 2.72 (s, 3H), 2.05 (m, 2H), 1.75 (m, 4H), 1.21
(d, J ) 6.3 Hz, 6H).
Gen er a l P r oced u r es for R ed u ct ion of 3-Nit r op yr -
id in es. 1-Ben zyl-4-[N-et h yl-N-(3-a m in o-6-ch lor o-2-p yr -
id in yl)a m in o]p ip er id in e, 40a (P G ) ben zyl, R ) Et, X )
Cl). 39d (14.7 g, 39.21 mmol) and platinum oxide (6.0 g) in
130 mL of THF was hydrogenated on a Parr apparatus under
10 psi of hydrogen for 1 h. Filtration and evaporation of the
solvent gave 14.4 g of the title compound as an oil: 1H NMR
(CD3OD) δ 7.38 (m, 5H), 7.12 (d, J ) 8.1 Hz, 1H), 6.93 (d, J )
8.1 Hz, 1H), 3.60 (s, 2H), 3.41 (s, 2H), 3.21 (q, J ) 7.1 Hz,
2H), 3.17 (m, 1H), 2.98 (d, J ) 12.1 Hz, 2H), 2.15 (t, J ) 8.7
Hz, 2H), 1.78 (m, 4H), 0.94 (t, J ) 7.1 Hz, 3H).
1-Ben zyl-4-[N-m eth yl-N-(3-a m in o-2-p yr id in yl)a m in o]-
p ip er id in e, 40b (P G ) ben zyl, R ) Me, X ) H, Y )
isop r op yl). A mixture of 39b (4.50 g, 13.8 mmol, 1 equiv)
and aqueous titanium(III) chloride (19 wt % in 20 wt %
aqueous hydrochloric acid, 56 mL, 82.7 mmol, 6 equiv) was
stirred for 21 h at room temperature under reduced pressure
and then added to concentrated aqueous ammonium hydroxide
(500 mL) with cooling. The resulting mixture was extracted
with CH2Cl2 (5 × 100 mL), and the combined organic phase
was washed with brine (50 mL), dried over sodium sulfate,
and concentrated in vacuo to give 4.14 g (100%) of the product
as a dark green, viscous oil which was used without further
purification: 1H NMR (CDCl3) δ 7.80 (dd, J ) 1.7, 4.7 Hz, 1H),
7.25 (m, 5H), 6.93 (dd, J ) 1.7, 7.7 Hz, 1H), 6.82 (dd, J ) 4.7,
7.7 Hz, 1H), 3.85 (br s, 2H), 3.48 (s, 2H), 3.14 (m, 1H), 2.88
(br d, J ) 11.8 Hz, 2H), 2.68 (s, 3H), 2.00 (td, J ) 3.1, 11.3
Hz, 2H), 1.74 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 152.0,
138.4, 137.5, 137.0, 129.2, 128.1, 126.9, 121.6, 119.7, 63.1, 57.3,
52.9, 34.4, 29.5.
1-Ben zyl-4-[N-m eth yl-N-(3-n itr o-6-flu or o-2-p yr id in yl)-
a m in o]p ip er id in e, 39e (P G ) ben zyl, R ) m eth yl, X )
F ): prepared in a manner analogous to 39b but employing 2,6-
difluoro-3-nitropyridine39,40 instead of 2-chloro-3-nitropyridine
to afford 55% of the title compound; 1H NMR (CD3OD) δ 8.47
(dd, J ) 7.2, 8.6 Hz, 1H), 7.43-7.51 (m, 5H), 6.49 (dd, J ) 3.5,
8.6 Hz, 1H), 4.42-4.51 (m, 1H), 3.72 (s, 2H), 3.19 (br d, J )
11.8 Hz, 2H), 2.86 (s, 3H), 2.30-2.37 (m, 2H), 2.04-2.12 (m,
2H), 1.95 (m, 2H).
1-Ben zyl-4-[N-et h yl-N-(3-n it r o-6-flu or o-2-p yr id in yl)-
a m in o]p ip er id in e, 39f (P G ) ben zyl, R ) eth yl, X ) F ):
prepared in a manner similar to 39b but employing 38a and
2,6-difluoro-3-nitropyridine instead of 38b and 2-chloro-3-
nitropyridine; reaction was run at 0 °C to room temperature
1
for 6 h to afford 54% of the title compound; H NMR (CDCl3)
δ 8.01 (dd, J ) 7.4, 8.6 Hz, 1H), 7.11 (m, 5H), 6.04 (dd, J )
3.9, 8.6 Hz, 1H), 3.43 (m, 1H), 3.31 (q, J ) 7.0 Hz, 2H), 3.32
(s, 2H), 1.78 (m, 2H), 1.85 (m, 2H), 1.72 (m, 2H), 1.66 (m, 2H),
0.88 (t, J ) 7.0 Hz, 3H).
1-Ben zyl-4-[N-p r op yl-N-(3-n itr o-2-p yr id in yl)a m in o]p i-
p er id in e, 39g (P G ) ben zyl, R ) p r op yl, X ) H).
A
mixture of 38c (4.00 g, 17.2 mmol) and 2-chloro-3-nitropyridine
(1.36 g, 8.61 mmol) was stirred at 110 °C in a sealed tube for
5 min, diluted with CH2Cl2 (40 mL), washed with water (10
mL) and brine (10 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was chromatographed (25-50% EtOAc/
CH2Cl2) to afford 2.77 g (91%) of the product as a deep yellow
1
oil: IR (neat) 2963 (m), 1595 (s), 1553 (s), 1512 (s) cm-1; H
NMR (CDCl3) δ 8.30 (dd, J ) 1.8, 4.5 Hz, 1H), 8.02 (dd, J )
1.8, 8.0 Hz, 1H), 7.32 (m, 4H), 7.26 (m, 1H), 6.68 (dd, J ) 4.5,
7.9 Hz, 1H), 3.61 (m, 1H), 3.50 (s, 2H), 3.34 (m, 2H), 2.95 (br
d, J ) 11.4 Hz, 2H), 2.02 (m, 2H), 1.91 (m, 2H), 1.80 (m, 2H),
1.44 (sext, J ) 7.4 Hz, 2H), 0.83 (t, J ) 7.3 Hz, 3H); EI-MS
m/ z (rel intensity) 308 (3), 172 (73), 90 (100). Anal.
(C20H26N4O2) C, H, N.
Gen er a l P r oced u r e for Red u ction a n d Alk yla tion of
3-Nitr op yr id in es. 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-4-
[N-cyclopr opyl-N-[3-((1-m eth yleth yl)am in o]-2-pyr idin yl]-
a m in o]p ip er id in e, 41a (P G ) BOC, R ) cyclop r op yl, X
) H, Y ) isop r op yl). To a solution of 39c (965 mg, 2.66

3780 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
mmol) in CH3OH (20 mL) under N2 was added 10% Pd/C (567
mg), and the mixture was stirred under a hydrogen atmo-
sphere (balloon) for 2 h. The mixture was then filtered through
Celite and concentrated in vacuo to give 828 mg (94%) of the
crude aminopyridine intermediate (Rf ) 0.14 by TLC, EtOAc/
hexane, 25/75). This intermediate was dissolved in absolute
ethanol (10 mL) and treated with acetone (2.74 mL, 37.4 mmol)
and NaCNBH3 (78 mg, 1.24 mmol). The pH was adjusted to
5 with glacial CH3COOH as measured on moistened pH test
paper, and the mixture was stirred at room temperature for 6
days, during which additional NaCNBH3 (312 mg) and acetone
(5.48 mL) were added, the pH being adjusted after each
addition. The mixture was then adjusted to pH 3 with 10%
hydrochloric acid (aqueous), neutralized with 5% NaOH (aque-
ous), and concentrated to remove EtOH. The residue was
diluted with water (20 mL) and extracted with CH2Cl2 (2 ×
25 mL), and the combined organic phase was washed with
brine (10 mL), dried over Na2SO4, concentrated, and chro-
matographed (5-15% EtOAc/hexane) to afford 497 mg (53%,
50% overall) of the product as an oil: 1H NMR (CDCl3) δ 7.75
(dd, J ) 1.7, 4.7 Hz, 1H), 6.95 (dd, J ) 4.7, 8.0 Hz, 1H), 6.80
(dd, J ) 1.7, 8.0 Hz, 1H), 4.48 (d, J ) 8.4 Hz, 1H), 4.05 (br m,
2H), 3.51 (m, 1H), 3.20 (tt, J ) 3.6, 11.2 Hz, 1H), 2.68 (br t, J
) 12.2 Hz, 2H), 2.57 (m, 1H), 1.85 (m, 2H), 1.54 (m, 2H), 1.45
(s, 9H), 1.17 (d, J ) 6.3 Hz, 6H), 0.51 (m, 2H), 0.34 (m, 2H);
(q, J ) 7.0 Hz, 2H), 3.14-2.85 (m, 3H), 2.59 (m, 2H), 1.76 (m,
2H), 1.58 (m, 2H), 1.18 (d, J ) 6.3 Hz, 6H), 0.85 (t, J ) 7.0
Hz, 3H).
1-Be n zyl-4-[N -(1-m e t h yle t h yl)-N -[3-(e t h yla m in o)-2-
p yr id in yl]a m in o]p ip er id in e, 41g (P G ) ben zyl, R ) i-P r ,
X ) H, Y ) Et). 39h (2.1 g, 5.9 mmol) and platinum oxide
(1.0 g) in 50 mL of THF were hydrogenated on a Parr
apparatus at 10 psi for 1 h. Filtration and evaporation of the
solvent gave 1.95 g of oil. The oil was dissolved in methanol
(0.4 M) and chilled to 0 °C. Acetaldehyde (0.5 mL, 8.9 mmol)
and then sodium cyanoborohydride (558 mg, 8.9 mmol) were
added, and the reaction mixture was stirred at room temper-
ature overnight. It was then poured into 1 N NaOH solution
and extracted with chloroform and the extract dried over
sodium sulfate, filtered, and evaporated to an oil. Chroma-
tography (20% EtOAc/hexane) yielded 900 mg (43%) of the title
compound as an oil: 1H NMR (CDCl3) δ 7.64 (m, 1H), 7.19
(m, 5H), 6.84 (dd, J ) 4.7, 7.9 Hz, 1H), 6.67 (dd, J ) 7.9 Hz,
1H), 4.98 (m, 1H), 3.46 (m, 3H), 3.15 (m, 1H), 2.96 (q, J ) 7.1
Hz, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.40 (m,
2H), 1.12 (t, J ) 7.1 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 6H); MS-EI
m/ e (rel intensity) 352 (7), 293 (10), 219 (24), 203 (14), 190
(24), 173 (45), 172 (44), 91 (100).
1-Ben zyl-4-[N-eth yl-N-[3-(eth ylam in o)-2-pyr idin yl]am i-
n o]p ip er id in e, 41h (P G ) ben zyl, R ) Et, X ) H, Y ) Et):
prepared in a manner analogous to 41g to afford 83% of the
IR (neat) 3370 (w), 2969 (m), 1694 (s), 1577 (m), 1481 (s) cm-1
;
EI-MS m/ z (rel intensity) 374 (M+, 24), 318 (4), 301 (8), 190
(60), 176 (26), 162 (18), 148 (100). Anal. (C21H34N4O2) C, H,
N.
1
title compound; H NMR (CDCl3) δ 7.74 (dd, J ) 1.5, 4.7 Hz,
1H), 7.33 (m, 5H), 6.95 (dd, J ) 4.7, 7.9 Hz, 1H), 6.82 (dd, J )
1.5, 7.9 Hz, 1H), 4.75 (br t, 1H), 3.55 (s, 2H), 3.16 (m, 4H),
3.05 (m, 1H), 2.92 (m, 2H), 2.05 (m, 2H), 1.86-1.68 (m, 4H),
1.28 (t, J ) 7.1 Hz, 3H), 0.89 (t, J ) 7.0 Hz, 3H).
1-Ben zyl-4-[N-m et h yl-N-[3-[(1-m et h ylet h yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 41b (P G ) ben zyl, R ) Et,
X ) H, Y ) i-P r ): prepared in a manner analogous to 41a but
reducing with platinum oxide for 50 min instead of Pd/C (see
1-Ben zyl-4-[N-p r op yl-N-[3-[(1-m et h ylet h yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 41i (P G ) ben zyl, R ) P r ,
X ) H, Y ) i-P r ). A mixture of 39g (2.61 g, 7.36 mmol, 1
equiv) in aqueous TiCl3 (30.0 mL, 19 wt % in 20% aqueous
HCl, 44.2 mmol, 6 equiv) was stirred under reduced pressure
for 20 h and then added carefully to concentrated aqueous
ammonium hydroxide (250 mL). The resulting mixture was
extracted with CH2Cl2 (4 × 100 mL), and the combined organic
phase was washed with brine (50 mL), dried over Na2SO4, and
concentrated in vacuo to give the crude product which was
then chromatographed, eluting with a gradient of CH3OH/CH2-
Cl2 (2.5/97.5-5/95). Fractions with an Rf ) 0.17 by TLC
(methanol/chloroform, 5/95) were pooled and concentrated in
vacuo to give 1.51 g (63%) of the product as a faint green
solid: mp 73-74 °C; IR (mull) 3400 (m), 3174 (m), 3073 (m),
2926 (s), 1621 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (dd,
J ) 1.6, 4.8 Hz, 1H), 7.30 (m, 4H), 7.25 (m, 1H), 6.95 (dd, J )
1.6, 7.8 Hz, 1H), 6.84 (dd, J ) 4.8, 7.8 Hz, 1H), 3.94 (s, 2H),
3.50 (s, 2H), 3.12 (m, 2H), 3.00 (m, 1H), 2.90 (br d, J ) 11.3
Hz, 2H), 1.98 (m, 2H), 1.75 (m, 4H), 1.29 (sext, J ) 7.3 Hz,
2H), 0.81 (t, J ) 7.3 Hz, 3H); EI-MS m/ z (rel intensity) 324
(M+, 6), 265 (8), 191 (21), 173 (63), 91 (100). Anal. (C20H28N4)
C, H, N.
1
compound 40a ) to afford 63% of the title compound; H NMR
(CD3OD) δ 7.41 (m, 5H), 7.07 (m, 2H), 3.71 (sept, J ) 6.3 Hz,
1H), 3.63 (s, 2H), 3.24 (m, 1H), 3.02 (m, 2H), 2.72 (s, 3H), 2.17
(m, 2H), 1.90-1.72 (m, 4H), 1.33 (d, J ) 6.3 Hz, 6H); HRMS
calcd for C21H29N4Cl 372.2081, found 372.2079.
1-Ben zyl-4-[N-et h yl-N-[3-(p r op yla m in o)-2-p yr id in yl]-
a m in o]p ip er id in e, 41c (P G ) ben zyl, R ) m eth yl, Y )
p r op yl, X ) H): prepared in a manner analogous to 41a but
the reduction of the nitro intermediate was conducted with
1
platinum oxide to afford 90% of the title compound; H NMR
(400 MHz, CDCl3) δ 7.72 (dd, J ) 1.4, 4.7 Hz, 1H), 7.27 (m,
5H), 6.91 (dd, J ) 4.7, 7.9 Hz, 1H), 6.78 (dd, J ) 1.4, 7.9 Hz,
1H), 4.79 (m, 1H), 3.48 (br s, 2H), 3.14 (q, J ) 7.3 Hz, 2H),
3.04 (q, J ) 7.0 Hz, 2H), 3.02 (m, 1H), 2.86 (m, 2H), 1.98 (m,
2H), 1.75 (m, 2H), 1.68 (m, 4H), 1.00 (t, J ) 7.3 Hz, 3H), 0.87
(t, J ) 7.0 Hz, 3H).
1-[(1,1-Dim et h ylet h oxy)ca r b on yl]-4-[N-m et h yl-N-[3-
[(cyclop r op ylm et h yl)a m in o]-2-p yr id in yl]a m in o]p ip er i-
d in e, 41d (P G ) BOC, R ) Me, X ) H, Y ) CH 2-c-P r ):
prepared in a manner analogous to 41a to afford 75% of the
title compound; 1H NMR (CD3OD) δ 7.39 (dd, J ) 2.8, 3.7 Hz,
1H), 6.79 (m, 2H), 3.79 (br d, J ) 13.1 Hz, 2H), 3.07 (m, 1H),
2.80 (d, J ) 6.7 Hz, 2H), 2.63 (m, 2H), 2.44 (s, 3H), 1.52 (m,
2H), 1.33 (m, 2H), 1.27 (s, 9H), 0.93 (m, 1H), 0.35 (m, 2H),
0.05 (m, 2H).
1-Be n zyl-4-[N -e t h yl-N -[3-[(1-m e t h yle t h yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 41e (P G ) ben zyl, R ) Et,
X ) H, Y ) i-P r ): prepared in a manner analogous to 41a to
afford 73% of the title compound; 1H NMR (CDCl3) δ 7.49 (dd,
J ) 4.7, 1.6 Hz, 1H), 7.03-7.10 (m, 5H), 6.68 (dd, J ) 7.9, 4.7
Hz, 1H), 6.58 (dd, J ) 8.0, 1.7 Hz, 1H), 4.49 (d, J ) 8.4 Hz,
1H), 3.30-3.38 (m, 3H), 2.89 (q, J ) 7.1 Hz, 2H), 2.75-2.86
(m, 1H), 2.67-2.70 (br m, 2H), 1.77-1.84 (br m, 2H), 1.40-
1.53 (br m, 4H), 0.97 (d, J ) 6.3 Hz, 6H), 0.64 (t, J ) 7.1 Hz,
3H).
A solution of 1-benzyl-4-[N-propyl-N-(3-amino-2-pyridinyl)-
amino]piperidine (0.35 g, 1.08 mmol, 1 equiv) in absolute
ethanol (4.3 mL) under N2 was treated with acetone (1.19 mL,
16.2 mmol, 15 equiv) and NaCNBH3 (135 mg, 2.16 mmol, 2
mol equiv), and the pH was adjusted to 5 with glacial acetic
acid as measured on moistened pH test paper. The resulting
mixture was stirred at room temperature for 65 h, during
which additional acetone (2.38 mL, 32.4 mmol) and NaCNBH3
(152 mg, 2.42 mmol) were added. Then the reaction mixture
was adjusted to pH 3 with 3 N HCl (aqueous), neutralized with
5% aqueous NaOH, and concentrated in vacuo. The residue
was chromatographed eluting with a gradient of CH3OH/CH2-
Cl2 (1/99-2/98), and those fractions with an Rf ) 0.13 by TLC
(5% CH3OH/CHCl3) were pooled and concentrated in vacuo to
give 298 mg (75%) of the product as a faint green, viscous oil:
1-Ben zyl-4-[N-eth yl-N-[6-flu or o-3-[(1-m eth yleth yl)a m i-
n o]-2-p yr id in yl]a m in o]p ip er id in e, 41f (P G ) ben zyl, R
) Et, X ) F , Y ) i-P r ): prepared in a manner analogous to
41a but the reduction of the nitro intermediate was carried
out using palladium hydroxide to afford 93% of the title
1
IR (neat) 3361 (w), 2961 (s), 1577 (s), 1481 (s) cm-1; H NMR
(CDCl3, 400 MHz) δ 7.70 (dd, J ) 1.5, 4.7 Hz, 1H), 7.31-7.24
(m, 5H), 6.90 (dd, J ) 4.7, 7.9 Hz, 1H), 6.79 (m, 1H), 4.66 (br
d, J ) 8.3 Hz, 1H), 3.53 (m, 3H), 3.06 (m, 2H), 2.91 (br m,
3H), 1.98 (br m, 2H), 1.73 (br m, 4H), 1.26 (sext, J ) 7.3 Hz,
2H), 1.20 (d, J ) 6.3 Hz, 6H), 0.80 (t, J ) 7.3 Hz, 3H); EI-MS
1
compound; H NMR (CDCl3) δ 6.93 (dd, J ) 7.7, 8.5 Hz, 1H),
6.55 (dd, J ) 3.5, 8.5 Hz, 1H), 4.30 (m, 1H), 3.51 (m, 1H), 3.09

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3781
m/ z (rel intensity) 366 (M+, 34), 307 (27), 233 (55), 216 (15),
173 (90), 172 (82), 91 (100). Anal. (C23H34N4) C, H, N.
1-Ben zyl-4-[N-m et h yl-N-[6-ch lor o-3-[(1-m et h ylet h yl)-
a m in o]p yr id in yl]a m in o]p ip er id in e, 41j (P G ) ben zyl, R
) Me, X ) Cl, Y ) i-P r ). The reductive alkylation was
conducted in a manner similar to that described for 41a ,
starting with 40a to afford 63% of the title compound: 1H NMR
(CD3OD) δ 7.44 (m, 5H), 7.07 (m, 2H), 3.71 (sept, J ) 6.3 Hz,
1H), 3.63 (s, 2H), 3.24 (sept, 1H), 3.02 (m, 2H), 2.72 (s, 3H),
2.18 (m, 2H), 1.85 (m, 4H), 1.33 (d, J ) 6.3 Hz, 6H); HRMS
calcd for C21H29N4Cl 372.2081, found 372.2079.
1-Ben zyl-4-[N-m eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-
6-flu or o-2-p yr id in yl]a m in o]p ip er id in e, 44c (R ) Me, X
) F ): prepared according to literature ref 42 from 42c to afford
33% of the title tert-butylamine; 1H NMR (CD3OD) δ 7.55 (m,
1H), 7.48 (m, 5H), 6.78 (m, 1H), 3.68 (s, 2H), 3.25 (m, 1H),
3.10 (br d, 2H), 2.74 (s, 3H), 2.20-2.30 (m, 2H), 1.75-1.90 (m,
4H), 1.52 (s, 9H).
[2-[N-Eth yl-N-[1-(p h en ylm eth yl)p ip er id in -4-yl]a m in o]-
6-flu or o-p yr id in -3-yl](1-m eth yleth ylid en e)a m in e, 43d (R
) Et, X ) F ): prepared according to literature ref 43 to afford
1
99% of the title compound; H NMR (CDCl3) δ 1.01 (t, J ) 7
Hz, 3H), 1.51 (m, 2H), 1.72 (s, 3H), 1.77-1.85 (m, 2H), 1.96-
2.08 (m, 2H), 2.16 (s, 3H), 2.90 (m, 2H), 3.30 (q, J ) 7, 13.9
Hz, 2H), 3.48 (s, 2H), 3.62-3.70 (m, 1H), 6.26 (dd, J ) 3.7, 8.0
Hz, 1H), 6.82 (t, J ) 7.9 Hz, 1H), 7.22-7.31 (m, 5H). Anal.
(C22H29FN4) C, H, N.
Gen er a l P r oced u r es for th e Syn th esis of 3-(ter t-Bu -
t yla m in o)p yr id in es. 1-Ben zyl-4-[N-m et h yl-N-[3-[(1-cy-
a n o-1-m e t h yle t h yl)a m in o]-2-p yr id in yl]a m in o]p ip e r i-
d in e, 42a (R ) Me, X ) H): prepared according to literature
ref 42 but starting with compound 40b to afford 85% of the
title compound; 1H NMR (CD3OD) δ 7.76 (dd, J ) 1.5, 4.8 Hz,
1H), 7.41 (dd, J ) 1.5, 8.1 Hz, 1H), 7.29 (m, 5H), 7.08 (dd, J )
4.8, 8.1 Hz, 1H), 3.49 (s, 2H), 3.07 (m, 1H), 2.85 (m, 2H), 2.51
(s, 3H), 2.03 (m, 2H), 1.74 (s, 6H), 1.74-1.55 (m, 4H); HRMS
(EI) calcd for C23H31N4 377.2579, found 377.2581.
1-Ben zyl-4-[N-m eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-
2-p yr id in yl]a m in o]p ip er id in e, 44a (R ) Me, X ) H). 42a
(1.94 g, 5.35 mmol) was dissolved in 10 mL of toluene and
cooled to -78 °C. In a separate flask, 38 mL of CH3Li (53.5
mmol, 1.4 M in ether) was dissolved in 10 mL of toluene and
cooled to -78 °C. Then the toluene solution of the cyanoamine
42a was cannulated to the CH3Li solution, and the reaction
mixture was allowed to warm gradually to 0 °C. The reaction
was quenched by the dropwise addition of water and the
mixture extracted with CH2Cl2, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
(40% EtOAc/hexane) provided 1.45 g of the tert-butylamine
(84%): 1H NMR (CD3OD) δ 7.64 (dd, J ) 1.5, 4.8 Hz, 1H), 7.37
(m, 5H), 7.29 (dd, J ) 1.5, 8.1 Hz, 1H), 7.03 (dd, J ) 4.8, 8.1
Hz, 1H), 3.57 (s, 2H), 3.09 (s, 1H), 2.93 (m, 2H), 2.64 (s, 3H),
2.12 (m, 2H), 1.80-1.62 (m, 4H), 1.44 (s, 9H); HRMS (EI) calcd
for C23H34N4 366.2783, found 366.2779.
1-Ben zyl-4-[N-eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-6-
flu or o-2-p yr id in yl]a m in o]p ip er id in e, 44d (R ) Et, X )
F ): prepared according to literature ref 43 from 43d to afford
72% of the title tert-butylamine; 1H NMR (400 MHz, CDCl3) δ
7.17 (m, 5H), 7.21 (dd, J ) 7.8, 8.6 Hz, 1H), 6.52 (dd, J ) 3.5,
8.6 Hz, 1H), 4.77 (s, 1H), 3.47 (s, 2H), 3.09 (q, J ) 7.1 Hz,
2H), 2.92 (m, 1H), 2.87 (m, 2H), 1.95 (m, 2H), 1.71 (m, 2H),
1.65 (m, 2H), 1.33 (s, 9H), 0.87 (t, J ) 7.1 Hz, 3H); HRMS
calcd for C23H33N4F 385.2767, found 385.2777. Anal. (C23H33
FN4) C, H, N.
-
1-Ben zyl-4-[N-eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-6-
ch lor o-2-p yr id in yl]a m in o]p ip er id in e, 44e (R ) Et, X )
Cl): prepared according to literature ref 43 from 40a to afford
1
31% of the title compound as an oil; H NMR (CDCl3) δ 7.28
(m, 5H), 7.01 (d, J ) 8.4 Hz, 1H), 6.86 (d, J ) 8.4 Hz, 1H),
5.01 (s, 1H), 3.47 (s, 2H), 3.07 (q, J ) 7.1 Hz, 2H), 2.87 (m,
3H), 1.96 (m, 2H), 1.69 (m, 4H), 1.32 (s, 9H), 0.85 (t, J ) 7.1
Hz, 3H).
1-Ben zyl-4-[N-p r op yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-
2-p yr id in yl]a m in o]p ip er id in e, 44f (R ) P r , X ) H):
prepared according to literature ref 42 from 1-benzyl-4-[N-
propyl-N-(3-amino-2-pyridinyl)amino]piperidine (prepared from
39g via hydrogenation over Pd/C, see beginning portion of
preparation of compound 41a ) to afford 63% of the title
compound as a pale green, viscous oil; IR (neat) 3338 (w), 2960
(s), 1575 (s), 1488 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.69
(dd, J ) 1.6, 4.8 Hz, 1H), 7.31 (m, 4H), 7.25 (m, 1H), 7.05 (dd,
J ) 1.6, 8.0 Hz, 1H), 6.85 (dd, J ) 4.8, 8.0 Hz, 1H), 5.13 (s,
1H), 3.49 (br s, 2H), 3.05 (m, 2H), 2.89 (m, 3H), 1.97 (br m,
2H), 1.73 (br m, 4H), 1.36 (s, 9H), 1.25 (sext, J ) 7.3 Hz, 2H),
0.81 (t, J ) 7.3 Hz, 3H); EI-MS m/ z (rel intensity) 380 (M+
31), 321 (24), 289 (10), 247 (46), 203 (29), 173 (100), 172 (80),
91 (94); HRMS (FAB) calcd for C24H36N4 + H 381.3018, found
381.3021.
1-Ben zyl-4-[N-eth yl-N-[3-[(1-cya n o-1-m eth yleth yl)a m i-
n o]-2-p yr id in yl]a m in o]p ip er id in e, 42b (R ) Et, X ) H):
prepared according to literature ref 42, starting with compound
40, to afford 85% of the title compound; 1H NMR (CDCl3) δ
7.94 (dd, J ) 1.7, 4.8 Hz, 1H), 7.32 (m, 6H), 7.03 (dd, J ) 4.8,
8.0 Hz, 1H), 5.39 (s, 1H), 3.51 (s, 2H), 3.14 (q, J ) 7.1 Hz,
2H), 2.98 (m, 1H), 2.88 (m, 2H), 1.99 (m, 2H), 1.75 (s, 6H),
1.75 (m, 2H), 1.65 (m, 4H), 0.89 (t, J ) 7.1 Hz, 3H).
[2-[N-Eth yl-N-[1-(p h en ylm eth yl)p ip er id in -4-yl]a m in o]-
p yr id in -3-yl](1-m eth yleth ylid en e)a m in e, 43b (R ) Et, X
) H): prepared according to literature ref 43, starting with
,
1
compound 40, to afford 100% of the title compound; H NMR
(CDCl3) δ 0.98 (t, J ) 6.9 Hz, 3H), 1.49-1.52 (m, 2H), 1.69 (s,
3H), 1.77-2.02 (m, 4H), 2.16 (s, 3H), 2.88-2.92 (m, 2H), 3.02
(q, J ) 6.9, 13.9 Hz, 2H), 3.45-3.59 (m, 3H), 6.71-6.83 (m,
2H), 7.22 -7.31 (m, 5H), 7.97-7.99 (m, 1H); HRMS calcd for
C22H30N4 + H1 351.2549, found 351.2558.
Syn th esis of ter t-Am yl-Su bstitu ted Com pou n ds. 1-[(1,1-
Dim e t h yle t h oxy)ca r b on yl]-4-[N -m e t h yl-N -[3-[(1,1-d i-
m e t h ylp r op -2-yn yl)a m in o]-2-p yr id in yl]a m in o]p ip e r i-
d in e, 45. To a solution of 1-[(1,1-dimethylethoxy)carbonyl]-
4-[N-methyl-N-(3-nitro-2-pyridinyl)amino]piperidine (5.00 g,
14.9 mmol) in 85 mL of MeOH was added 800 mg of 10% Pd/
C. The mixture was hydrogenated at 40 psi (Parr) for 5.5 h,
filtered through Celite, and concentrated in vacuo to give 4.50
g (99%) of the amine intermediate as an off-white solid (Rf )
0.23, 50% EtOAc/hexane). This intermediate was then dis-
solved in 20 mL of dry DMF under N2 at 0 °C, and 750 mg
(11.8 mmol) of copper powder and 750 mg (7.58 mmol) of
cuprous chloride were added. To this was added a solution of
1.51 g (14.7 mmol) of 3-chloro-3-methyl-1-butyne in 4 mL of
dry DMF in 5 portions over 15 min. The resulting mixture
was stirred at room temperature for 2 h and concentrated to
remove DMF. Aqueous workup (CH2Cl2, Na2SO4) and chro-
matography (10-40% EtOAc/hexane) provided 2.42 g (44%)
of the title compound as an orange oil: IR (atr) 3300 (w), 2976
(m), 1692 (s), 1577 (m) cm-1; 1H NMR (CDCl3) δ 7.79 (dd, 1H,
J ) 1.5, 4.8 Hz, 1H), 7.51 (d, J ) 6.8 Hz, 1H), 6.95 (dd, J )
4.8, 8.0 Hz, 1H), 4.92 (br s, 1H), 4.05 (br m, 2H), 3.19 (m, 1H),
2.75 (br t, J ) 12.6 Hz, 2H), 2.61 (s, 3H), 2.38 (s, 1H), 1.75 (m,
2H), 1.62 (s, 6H), 1.49 (m, 2H), 1.45 (s, 9H); MS-EI m/ e 372
(M+), 299, 271, 214, 188, 174, 57; HRMS calcd for C21H32N4O2
372.2525, found 372.2525.
1-Ben zyl-4-[N-eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 44b (R ) Et, X ) H): pre-
pared according to literature ref 42 from 42b (see also
preparation of 44a ) or according to literature ref 43 from 43b
to afford 69% or 61%, respectively, of the title tert-butylamine;
1H NMR (CDCl3) δ 7.74 (dd, J ) 1.5, 4.7 Hz, 1H), 7.30 (m,
5H), 7.09 (dd, J ) 1.5, 8.1 Hz, 1H), 6.89 (dd, J ) 4.7, 8.1 Hz,
1H), 5.21 (s, 1H), 3.52 (s, 2H), 3.14 (q, J ) 7.1 Hz, 1H), 2.97
(m, 1H), 2.90 (m, 2H), 2.01 (m, 2H), 1.80-1.65 (m, 4H), 1.39
(s, 9H), 0.89 (t, J ) 7.1 Hz, 3H). Anal. (C23H34N4) C, H, N.
1-Ben zyl-4-[N-m et h yl-N-[3-[(1-cya n o-1-m et h ylet h yl)-
a m in o]-6-flu or o-2-p yr id in yl]a m in o]p ip er id in e, 42c (R )
Me, X ) F ): prepared according to literature ref 42 from
1-benzyl-4-[N-methyl-N-(3-amino-6-fluoro-2-pyridinyl)amino]-
piperidine (prepared from 39e via hydrogenation over Pd/C,
see beginning portion of preparation of compound 41a ) to
1
afford 43% of the title cyanoamine; H NMR (CD3OD) δ 7.64
(dd, J ) 7.3, 8.4 Hz, 1H), 7.36-7.41 (m, 5H), 6.73 (dd, J ) 3.3,
8.4 Hz, 1H), 3.60 (s, 2H), 3.35 (m, 1H), 3.00 (br d, J ) 12.5
Hz, 2H), 2.74 (s, 3H), 2.10-2.20 (m, 2H), 1.81 (m, 4H), 1.77
(s, 6H).

3782 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
1-[1,1-Dim eth yleth oxy)car bon yl]-4-[N-m eth yl-N-[3-[(1,1-
dim eth ylpr opyl)am in o]-2-pyr idin yl]am in o]piper idin e, 46.
To a solution of 2.41 g (6.48 mmol) of 45 in 40 mL of absolute
EtOH under N2 was added 620 mg of wet Raney nickel. The
mixture was hydrogenated at 40 psi (Parr) for 21 h, filtered
through Celite, and concentrated to give 2.52 g of a yellow
viscous oil which was chromatographed, eluting with a gradi-
ent of 10-35% EtOAc/hexane. Pooling of fractions giving an
Rf ) 0.31 by TLC (25% EtOAc/hexane) and removal of solvent
in vacuo gave 2.43 g (99%) of the title compound as a pale
green viscous oil: IR (atr) 3357 (w), 2971 (s), 1695 (s), 1576
Gen er a l P r oced u r es for th e Dep r otection of Ben zylp i-
p er id in es. 4-[N-Meth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-
2-p yr id in yl]a m in o]p ip er id in e, 50a (Y ) ter t-bu tyl, R )
Me, X ) H). 44a (1.84 g, 5.2 mmol) was dissolved in 60 mL
of EtOH. Then 800 mg of 10% Pd/C was added, and the
reaction mixture was placed on a Parr hydrogenator for 7 h
at 40 psi. Filtration and concentration in vacuo afforded 1.3
g of the desired product (96%) which was used without further
purification: 1H NMR (CD3OD) δ 7.47 (dd, J ) 1.5, 4.8 Hz,
1H), 7.13 (dd, J ) 1.5, 8.1 Hz, 1H), 6.86 (dd, J ) 4.8, 8.1 Hz,
1H), 2.99 (m, 1H), 2.93 (m, 2H), 2.50 (s, 3H), 2.42 (m, 2H),
1.61 (m, 2H), 1.42 (m, 2H), 1.29 (s, 9H).
(s) cm-1 1H NMR (CDCl3) δ 7.67 (dd, J ) 1.5, 4.8 Hz, 1H),
;
7.04 (dd, J ) 1.5, 8.0 Hz, 1H), 6.87 (dd, J ) 4.8, 8.0 Hz, 1H),
4.87 (s, 1H), 4.04 (br m, 2H), 3.20 (m, 1H), 2.76 (br t, J ) 11.9
Hz, 2H), 2.61 (s, 3H), 1.71 (m, 4H), 1.50 (m, 2H), 1.45 (s, 9H),
1.31 (s, 6H), 0.86 (t, J ) 7.4 Hz, 3H); MS (EI) m/ e 376 (M+),
347, 305, 303, 275, 249, 233, 191, 164, 148, 122, 57; HRMS
calcd for C21H36N4O2 376.2838, found 376.2838.
4-[N-E t h yl-N-[(3-(et h yla m in o)-2-p yr id in yl]a m in o]p i-
p er id in e, 50b (R ) Et, Y ) Et, X ) H): prepared in a manner
analogous to 50a using 41h but employing Pd(OH)2/C to afford
1
84% of the title amine; H NMR (CDCl3) δ 7.60 (dd, J ) 1.5,
4.7 Hz, 1H), 6.81 (dd, J ) 4.7, 7.9 Hz, 1H), 6.69 (dd, J ) 1.5,
7.9 Hz, 1H), 4.52 (m, 1H), 3.27 (m, 2H), 3.01 (m, 4H), 2.88 (m,
1H), 2.64 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H), 1.14 (t, J ) 7.1
Hz, 1H), 0.75 (t, J ) 7.0 Hz, 3H).
Syn th esis of 3-(Cyclop r op yla m in o)p yr id in es. 1-Ben z-
yl-4-[N -m e t h yl-N -[3-[(1-e t h oxycyclop r op yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 47. A mixture of 40b (825 mg,
2.78 mmol), 1-bromo-1-ethoxycyclopropane (919 mg, 5.57
mmol), and triethylamine (0.78 mL, 5.57 mmol) in dry tet-
rahydrofuran (1.4 mL) under N2 was refluxed for 48 h and
cooled to room temperature. Aqueous workup (CH2Cl2, Na2-
SO4) and chromatography (1-5% methanol/CH2Cl2) afforded
185 mg (17%) of the product as a pale yellow oil. An additional
279 mg (26%) of slightly impure product was also isolated: 1H
NMR (CDCl3) δ 7.80 (dd, J ) 1.7, 4.7 Hz, 1H), 7.41 (dd, J )
1.7, 8.0 Hz, 1H), 7.25 (m, 5H), 6.93 (dd, J ) 4.8, 7.9 Hz, 1H),
5.62 (s, 1H), 3.51 (q, J ) 7.0 Hz, 2H), 3.48 (s, 2H), 3.03 (m,
1H), 2.87 (br d, J ) 11.8 Hz, 2H), 2.60 (s, 3H), 1.98 (br t, J )
11.5 Hz, 2H), 1.71 (m, 2H), 1.64 (m, 2H), 1.13 (m, 5H), 0.85
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 151.2, 138.2, 136.8, 129.2,
128.2, 127.0, 120.5, 120.0, 68.2, 63.1, 61.0, 58.2, 52.8, 36.1, 30.0,
15.3, 14.6.
4-[N-Eth yl-N-[(3-(p r op yla m in o)-2-p yr id in yl]a m in o]p i-
p er id in e, 50c (R ) Et, Y ) p r op yl, X ) H): prepared in a
manner analogous to 50a but employing Pd(OH)2/C to afford
99% of the title amine; 1H NMR (400 MHz, CDCl3) δ 7.71 (dd,
J ) 1.5, 4.7 Hz, 1H), 6.94 (dd, J ) 4.7, 7.9 Hz, 1H), 6.82 (dd,
J ) 1.5, 7.9 Hz, 1H), 4.65 (br, 1H), 3.43 (m, 3H), 3.09 (m, 4H),
2.88 (m, 2H), 2.05-1.85 (m, 2H), 1.66 (m, 2H), 1.00 (t, J ) 7.4
Hz, 3H), 0.88 (t, J ) 7.01 Hz, 3H).
4-[N -E t h yl-N -[6-flu or o-3-[(1-m e t h yle t h yl)a m in o]-2-
-p yr id in yl]a m in o]p ip er id in e, 50d (R ) Et, Y ) p r op yl, X
) F ): prepared in a manner analogous to 50a but employing
1
Pd(OH)2/C to afford 93% of the title amine; H NMR (CDCl3)
δ 6.93 (dd, J ) 8.1, 8.5 Hz, 1H), 6.54 (dd, J ) 3.5, 8.5 Hz, 1H),
4.30 (br d, 1H), 3.50 (m, 1H), 3.09 (m, 4H), 3.00 (br, 1H), 2.59
(m, 2H), 1.80 (m, 2H), 1.55 (m, 2H), 1.18 (d, J ) 6.3 Hz, 1H),
0.86 (t, J ) 7.0 Hz, 3H).
1-B e n zy l-4-[N -m e t h y l-N -[3-(c y c lo p r o p y la m in o )-2-
p yr id in yl]a m in o]p ip er id in e, 48. A solution of 47 (178 mg,
0.468 mmol) in dry THF (4.7 mL) under N2 was treated with
LAH (18 mg), and the resulting mixture was stirred at room
temperature for 1 h, the reaction was quenched with saturated
aqueous ammonium chloride (5 mL), and the mixture was
diluted with water (30 mL) and CH2Cl2 (20 mL) and filtered
through Celite. The layers of the filtrate were separated, the
aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and
the combined organic phase was washed with saline (10 mL),
dried over Na2SO4, and concentrated in vacuo. The crude
product was then chromatographed (2.5-5% MeOH/CHCl3) to
give 93 mg (59%) of the product as an amber film: IR (neat)
3363 (w), 2946 (m), 2926 (m), 1578 (s) cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.75 (dd, J ) 1.6, 4.8 Hz, 1H), 7.31 (m, 4H), 7.24
(m, 1H), 7.21 (dd, J ) 1.6, 7.9 Hz, 1H), 6.92 (dd, J ) 4.8, 7.9
Hz, 1H), 4.92 (s, 1H), 3.50 (s, 2H), 3.04 (m, 1H), 2.89 (br d, J
) 11.2 Hz, 2H), 2.62 (s, 3H), 2.35 (m, 1H), 1.99 (m, 2H), 1.70
(m, 4H), 0.75 (m, 2H), 0.51 (m, 2H); EI-MS m/ z (rel intensity)
336 (M+, 6), 280 (3), 173 (73), 91 (100); HRMS calcd for
C21H28N4 336.2314, found 336.2329.
1-Ben zyl-4-[N-m eth yl-N-[3-[(1-m eth ylcyclop r op yl)a m i-
n o]-2-p yr id in yl]a m in o]p ip er id in e, 49. To a solution of
CH3Li‚LiBr (1.5 M in diethyl ether, 2.28 mL, 3.42 mmol) in
dry toluene (6.3 mL) at -78 °C under N2 in a flame-dried flask
was added a solution of 47 (325 mg, 0.854 mmol) in dry toluene
(8.5 mL) at -78 °C. The mixture was stirred at -78 °C for 1
h, the reaction was quenched carefully with saturated aqueous
ammonium chloride (10 mL), and water (10 mL), and the
mixture as warmed to room temperature. Aqueous workup
(EtOAc, MgSO4) and chromatography (1-4% MeOH/CHCl3)
gave 232 mg (78%) of the product as a faint green, oily film:
IR (neat) 3366 (w), 2949 (m), 1577 (s), 1476 (s) cm-1; 1H NMR
(CDCl3, 400 MHz) δ 7.72 (dd, J ) 1.6, 4.8 Hz, 1H), 7.31 (m,
5H), 7.17 (dd, J ) 1.6, 7.9 Hz, 1H), 6.91 (dd, J ) 4.8, 7.9 Hz,
1H), 5.02 (s, 1H), 3.50 (br s, 2H), 3.05 (br m, 1H), 2.88 (br m,
2H), 2.59 (s, 3H), 2.01 (br m, 2H), 1.71 (br m, 4H), 1.32 (s,
3H), 0.76 (m, 2H), 0.65 (m, 2H); EI-MS m/ z (rel intensity) 350
(M+, 9), 335 (3), 280 (4), 174 (46), 173 (100), 172 (35), 91 (84);
HRMS (FAB) calcd for C22H30N4 + H 351.2549, found 351.2542.
4-[N-Meth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-6-flu or o-
2-p yr id in yl]a m in o]p ip er id in e, 50e (R ) Me, Y ) ter t-
bu tyl, X ) F ): prepared in a manner analogous to 50a to
afford 99% of the title compound; 1H NMR (CD3OD) δ 7.38
(dd, J ) 7.4, 8.5 Hz, 1H), 6.61 (dd, J )3.3, 8.7 Hz, 1H), 3.16-
3.27 (m, 3H), 2.71-2.79 (m, 2H), 2.56 (s, 3H), 1.84 (d, J ) 12.0
Hz, 2H), 1.61-1.66 (m, 2H), 1.33 (s, 9H).
4-[N-Eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-6-flu or o-2-
p yr id in yl]a m in o]p ip er id in e, 50f (R ) Et, Y ) ter t-Bu , X
) F ): prepared in a manner analogous to 50a but employing
Pd(OH)2/C to afford 99% of the title compound; 1H NMR
(CDCl3) δ 7.19 (dd, J ) 8.1, 8.6 Hz, 1H), 6.51 (dd, J ) 3.5, 8.6
Hz, 1H), 4.24 (br s, 1H), 3.08 (m, 4H), 2.95 (m, 1H), 2.52 (m,
2H), 1.72 (m, 2H), 1.50 (m, 2H), 1.32 (s, 9H), 0.85 (t, J ) 7.1
Hz, 3H).
4-[N-E t h yl-N-[3-[(1-m et h ylet h yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 50g (Y ) isop r op yl, R ) Et, X ) H):
prepared in a manner analogous to 50a but employing Pd-
(OH)2/C to afford 93% of the title compound as a green oil; 1H
NMR (CDCl3, 400 MHz) δ 7.72 (dd, J ) 1.5, 4.7 Hz, 1H), 6.91
(m, 1H), 6.80 (m, 1H), 4.70 (m, 1H), 3.56 (m, 1H), 3.10 (m,
5H), 2.61 (m, 2H), 1.83 (m, 2H), 1.55 (m, 2H), 1.20 (d, J ) 6.2
Hz, 6H), 0.86 (t, J ) 7.0 Hz, 3H).
4-[N-Eth yl-N-[3-[(1,1-dim eth yleth yl)am in o]-2-pyr idin yl]-
a m in o]p ip er id in e, 50h (R ) Et, Y ) ter t-bu tyl, X ) H):
prepared in a manner analogous to 50a to afford 93% of the
amine as an amber oil; 1H NMR (CDCl3, 400 MHz) δ 7.71 (m,
1H), 7.06 (d, J ) 8.1 Hz, 1H), 6.87 (dd, J ) 4.7, 8.0 Hz, 1H),
5.18 (s, 1H), 3.11 (m, 4H), 3.00 (m, 1H), 2.57 (m, 2H), 1.80 (m,
2H), 1.52 (m, 2H), 1.36 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H).
4-[N -Me t h yl-N -[3-[(1-m e t h ylcyclop r op yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 50i (R ) Me, Y ) CH2-c-P r ,
X ) H): prepared in a manner analogous to 50a but starting
with compound 49 and employing Pd(OH)2/C to afford 100%
1
of the amine; H NMR (CDCl3, 400 MHz) δ 7.72 (dd, J ) 1.5,
4.8 Hz, 1H), 7.20 (dd, J ) 1.5, 8.0 Hz, 1H), 6.94 (dd, J ) 4.8,
8.0 Hz, 1H), 5.20 (br s, 1H), 3.30 (m, 3H), 2.80 (br t, J ) 11.4
Hz, 2H), 2.56 (s, 3H), 1.93 (m, 2H), 1.77 (m, 2H), 1.32 (s, 3H),
0.77 (m, 2H), 0.67 (m, 2H).

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3783
manner analogous to 50o from
4-[N-Met h yl-N-[6-ch lor o-3-[(1-m et h ylet h yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 50j (R ) Me Y ) isop r op yl,
X ) Cl). 1-Benzyl-4-[N-methyl-N-[3-[(1-methylethyl)amino]-
6-chloro-2-pyridinyl]amino]piperidine (41j) (1.60 g, 4.84 mmol)
was dissolved in CH2Cl2 (0.2 M) and cooled to 0 °C. 1-Chlo-
roethyl chloroformate (0.57 mL, 5.32 mmol) was added drop-
wise. The solution was allowed to warm to room temperature
and then refluxed for 0.5 h. The solvent was evaporated to
one-third volume, 15 mL CH3OH was added, and the solution
was refluxed for 2 h. Aqueous workup (CHCl3, Na2SO4) and
evaporation of the solvent gave 1.5 g of an oil. Chromatog-
raphy (10% MeOH/CHCl3) yielded 432 mg (31%) of the title
compound: 1H NMR (CD3OD) δ 6.88 (d, J ) 2.3 Hz, 2H), 3.49
(m, 1H), 3.23 (m, 2H), 2.87 (m, 2H), 2.50 (s, 3H), 1.95 (br d,
2H), 1.70 (m, 2H), 1.12 (d, J ) 6.3 Hz, 6H).
X ) H): prepared in a
compound 46 to afford 94% of the title amine as a yellow oil;
1
IR (atr) 3349 (w), 2966 (s), 1574 (s), 1489 (s) cm-1; H NMR
(CDCl3) δ 7.66 (dd, J ) 1.6, 4.7 Hz, 1H), 7.02 (dd, J ) 1.6, 8.0
Hz, 1H), 6.84 (dd, J ) 4.7, 8.0 Hz, 1H), 4.86 (s, 1H), 3.39 (br
s, 1H), 3.13 (m, 3H), 2.63 (m, 5H), 1.81-1.52 (m, 6H), 1.31 (s,
6H), 0.87 (t, J ) 7.4 Hz, 3H); MS-EI m/ e 276 (M+), 205, 191,
164, 150, 124; HRMS calcd for C16H28N4 276.2314, found
276.2314.
4-[N -Me t h y l-N -[3-[(c y c lo p r o p y lm e t h y l)a m in o ]-2-
p yr id in yl]a m in o]p ip er id in e, 50q (R ) Me, Y ) CH2-c-P r ,
X ) H). 41d (1.46 g, 4.05 mmol) was dissolved in 10 mL of
dioxane, and 30 mL of hydrochloric acid (4.0 M in dioxane)
was added. The solvent was removed by evaporation, and the
residue was suspended in water. The water was adjusted to
pH 12 with 1 N NaOH and extracted with chloroform/
methanol. The organic phase was dried over Na2SO4 and the
solvent evaporated to yield 1.22 g (100%) of the title com-
pound: 1H NMR (CD3OD) δ 7.37 (dd, J ) 2.7, 6.4 Hz, 1H),
6.77 (dd, J ) 1.0, 3.7 Hz, 2H), 3.3-3.5 (m, 1H), 2.85 (br d, J )
12.8 Hz, 2H), 2.79 (d, J ) 6.7 Hz, 2H), 2.45 (s, 3H), 2.36 (m,
2H), 1.53 (m, 2H), 1.40 (m, 2H), 0.92 (m, 1H), 0.33 (m, 2H),
0.56 (m, 2H).
Gen er a l Meth od for Cou p lin g to In d ole-2-ca r boxylic
Acid s Usin g 1,1′-Ca r bon yld iim id a zole (CDI). 1-[(5-Meth -
an esu lfon am idoin dol-2-yl)car bon yl]-4-[N-eth yl-N-[3-[(1,1-
d im eth yleth yl)a m in o]-2-p yr id in yl]a m in o]p ip er id in e, 15.
5-Methanesulfonamidoindole-2-carboxylic acid (1.66 g, 6.52
mmol) and CDI (1.06 g, 6.52 mmol) were stirred together for
1 h at room temperature in 6.5 mL of THF. Then the reaction
mixture was cooled to 0 °C, and 50h (0.90 g, 3.26 mmol)
dissolved in 6.52 mL of THF was added. The reaction mixture
was warmed to room temperature and stirred overnight.
Standard workup, chromatography (2.5% CH3OH/CHCl3), and
crystallization afforded 1.33 g (80%) of the title piperidine: mp
193-194 °C; 1H NMR (CD3OD) δ 7.76 (dd, J ) 1.5, 4.8 Hz,
1H), 7.66 (d, J ) 2.0 Hz, 1H), 7.53 (d, J ) 8.7 Hz, 1H), 7.38
(dd, J ) 1.5, 8.2 Hz, 1H), 7.28 (dd, J ) 2.0, 0.7 Hz, 2H), 3.25-
3.20 (br, 2H), 3.01 (s, 3H), 2.01 (br, 2H), 1.72 (m, 2H), 1.51 (s,
9H), 1.00 (t, J ) 7.0 Hz, 3H); HRMS calcd for C26H36N6O3S
512.2569, found 512.2569. Anal. calcd for C26H36N6O3S: C,
60.91; H, 7.08; N, 16.39; S, 6.25. Found C, 60.64; H, 7.10; N,
16.16; S, 6.12.
4-[N-Eth yl-N-[6-ch lor o-3-[(1,1-d im eth yleth yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 50k (Y ) ter t-bu tyl, R ) Et,
X ) Cl): prepared analogous to 50j to afford 31% of the title
1
compound; H NMR (CDCl3) δ 7.04 (d, J ) 8.5 Hz, 1H), 6.89
(d, J ) 8.5 Hz, 1H), 4.91 (s, 1H), 3.35 (m, 2H), 3.20 (m, 1H),
3.03 (q, J ) 7.0 Hz, 2H), 2.81 (m, 2H), 1.92 (m, 4H), 1.32 (s,
9H), 0.85 (t, J ) 7.0 Hz, 3H).
4-[N-Meth yl-N-[3-[(1-m eth yleth yl)am in o]-2-pyr idazin yl]-
a m in o]p ip er id in e, 53: prepared in a manner analogous to
50a but starting with compound 52 and employing Pd(OH)2
to afford 63% of the title compound; 1H NMR (CD3OD) δ 8.54
(d, J ) 5.9 Hz, 1H), 6.84 (d, J ) 5.9 Hz, 1H), 3.89 (m, 1H),
3.67 (m, 1H), 3.54 (m, 2H), 3.15 (m, 2H), 2.86 (s, 3H), 2.26 (m,
2H), 2.05 (m, 2H), 1.42 (d, J ) 6.3 Hz, 6H).
Red u ction Em p loyin g Am m on iu m F or m a te a s Red u c-
in g Agen t .
4-[N-Met h yl-N-[3-(cyclop r op yla m in o)-2-
p yr id in yl]a m in o]p ip er id in e, 50l (Y ) cyclop r op yl, R)
Me, X ) H). A mixture of 48 (135 mg, 0.401 mmol),
ammonium formate (76 mg, 1.20 mmol, 3 equiv), and 10% Pd/C
(135 mg) in methanol (8 mL) under N2 was degassed and
placed in an oil bath maintained at 60-65 °C. The mixture
was refluxed for 45 min, cooled to room temperature, filtered
through Celite, and concentrated in vacuo to provide 120 mg
(100%) of the title amine: 1H NMR (MeOD, 400 MHz) δ 7.66
(m, 1H), 7.37 (d, J ) 7.9 Hz, 1H), 7.06 (dd, J ) 4.8, 7.9 Hz,
1H), 3.43 (m, 3H), 3.01 (br t, J ) 11.8 Hz, 2H), 2.62 (s, 3H),
2.38 (m, 1H), 2.00 (m, 2H), 1.90 (m, 2H), 0.80 (m, 2H), 0.54
(m, 2H).
4-[N-P r op yl-N-[3-[(1-m eth yleth yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 50m (Y ) isop r op yl, R ) p r op yl, X )
H): prepared in a manner analogous to 50l to afford 81% of
1-[(5-Nitr oin d ol-2-yl)ca r bon yl]-4-[N-m eth yl-N-[3-[(1,1-
dim eth ylpr opyl)am in o]-2-pyr idin yl]am in o]piper idin e, 54a
(Y ) ter t-a m yl, R ) Me, X ) H): prepared in a manner
analogous to 15 to afford 72% of the title compound as a pale
yellow solid; mp 205.5-207.5 °C; IR (atr) 3240 (m), 2967 (m),
1
the title amine; H NMR (CDCl3) δ 7.70 (dd, J ) 1.6, 4.7 Hz,
1H), 6.91 (dd, J ) 4.7, 7.9 Hz, 1H), 6.80 (m, 1H), 5.24 (br s,
1H), 4.63 (d, J ) 8.4 Hz, 1H), 3.53 (m, 1H), 3.21 (br d, J )
12.6 Hz, 2H), 3.04 (m, 3H), 2.66 (br t, J ) 12.1 Hz, 2H), 1.84
(m, 2H), 1.70 (m, 2H), 1.25 (m, 2H), 1.20 (d, J ) 6.3 Hz, 6H),
0.80 (t, J ) 7.4 Hz, 3H).
1
1603 (s) cm-1; H NMR (CDCl3) δ 11.12 (s, 1H), 8.61 (d, J )
2.1 Hz, 1H), 8.13 (dd, J ) 2.2, 9.1 Hz, 1H), 7.70 (dd, J ) 1.4,
4.7 Hz, 1H), 7.47 (d, J ) 9.1 Hz, 1H), 7.09 (m, 1H), 6.91 (m,
2H), 4.93 (s, 1H), 4.66 (br m, 2H), 3.50 (m, 1H), 3.48-3.05 (m,
2H), 2.65 (s, 3H), 2.03 (m, 2H), 1.70 (m, 4H), 1.33 (s, 6H), 0.87
(t, J ) 7.3Hz, 3H); MS-EI m/ e 464 (M+), 449, 435, 393, 189,
164, 143, 122. Anal. (C25H32N6O3) C, H, N.
1-[(5-Nit r oin d ol-2-yl)ca r b on yl]-4-[N -e t h yl-N -[3-[(1-
m eth yleth yl)a m in o]-2-p yr id in yl]a m in o]p ip er id in e, 54b
(Y ) isop r op yl, R ) Et, X ) H): prepared in a manner
analogous to 15 to afford 67% of the title compound as a yellow
solid; mp 198-200 °C; 1H NMR (CDCl3, 400 MHz) δ 10.25 (s,
1H), 8.62 (d, J ) 2.0 Hz, 1H), 8.16 (dd, J ) 2.2, 9.0 Hz, 1H),
7.76 (dd, J ) 1.5, 4.7 Hz, 1H), 7.47 (d, J ) 9.2 Hz, 1H), 6.99
(m, 1H), 6.91 (d, J ) 1.4 Hz, 1H), 6.87 (d, J ) 7.8 Hz, 1H),
4.74 (m, 1H), 4.64 (m, 2H), 3.56 (m, 1H), 3.44 (m, 1H), 3.30-
2.90 (m, 2H), 3.16 (m, 2H), 2.01 (m, 2H), 1.64 (m, 2H), 1.22 (d,
J ) 6.2 Hz, 6H), 0.92 (t, J ) 7.0 Hz, 3H); EI-MS m/ z (rel
intensity) 450 (M+, 55), 435 (6), 421 (22), 407 (8), 216 (37),
189 (33), 178 (100). Anal. (C24H30N6O3) C, H, N.
1-[(5-Nit r oin d ol-2-yl)ca r b on yl]-4-[N-et h yl-N-[3-[(1,1-
dim eth yleth yl)a m in o]-2-pyr idin yl]a m in o]p iper id in e, 54c
(Y ) ter t-bu tyl, R ) Et, X ) H): prepared in a manner
analogous to 15 to provide 30% yield of an an off-white solid;
mp 182-184 °C; IR (mull) 1605 (s) cm-1; 1H NMR (CDCl3, 400
MHz) δ 10.18 (s, 1H), 8.62 (s, 1H), 8.16 (dd, J ) 2.2, 9.1 Hz,
1H), 7.75 (m, 1H), 7.47 (d, J ) 9.1 Hz, 1H), 7.13 (d, J ) 7.9
Hz, 1H), 6.95 (m, 1H), 6.92 (s, 1H), 5.18 (s, 1H), 4.64 (m, 2H),
4-[N-P r op yl-N-[3-[(1,1-d im et h ylet h yl)a m in o]-2-p yr i-
d in yl]a m in o]p ip er id in e, 50n (Y ) ter t-bu tyl, R ) p r op yl,
X ) H): prepared in a manner analogous to 50l to afford 94%
of the title amine; 1H NMR (CDCl3, 400 MHz) δ 7.69 (dd, J )
1.5, 4.7 Hz, 1H), 7.05 (dd, J ) 1.5, 8.0 Hz, 1H), 6.85 (dd, J )
4.7, 8.0 Hz, 1H), 5.14 (s, 1H), 3.05 (m, 4H), 2.90 (m, 1H), 2.54
(br t, J ) 12.2 Hz, 2H), 1.75 (m, 2H), 1.52 (m, 2H), 1.35 (s,
9H), 1.25 (m, 2H), 0.81 (t, J ) 7.4 Hz, 3H).
Gen er a l P r oced u r es for Dep r otection of 1-BOC-4-[N-
alkyl-N-[3-(alkylam in o)pyr idin yl]am in o]piper idin es. 4-[N-
Cyclop r op yl-N-[3-[(1-m et h ylet h yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 50o (R ) cyclop r op yl, Y ) isop r op yl,
X ) H). A solution of 41a (430 mg, 1.15 mmol, 1 equiv) in
dry CH2Cl2 (5.7 mL) under N2 was treated with TFA (1.15 mL,
14.9 mmol, 13 equiv). The mixture was stirred at room
temperature. Basic workup (CH2Cl2, NaOH, Na2SO4) afforded
290 mg (92%) of the deprotected piperidine: 1H NMR (CDCl3)
δ 7.74 (dd, J ) 1.6, 4.7 Hz, 1H), 6.93 (dd, J ) 4.7, 8.0 Hz, 1H),
6.79 (dd, J ) 1.5, 8.0 Hz, 1H), 4.51 (d, J ) 8.6 Hz, 1H), 3.51
(m, 1H), 3.13 (m, 1H), 3.07 (br d, J ) 11.0 Hz, 2H), 2.62-2.52
(m, 3H), 1.95-1.80 (m, 3H), 1.61 (qd, J ) 3.9, 11.9 Hz, 2H),
1.17 (d, J ) 6.3 Hz, 6H).
4-[N -Me t h y l-N -[3-[(1,1-d im e t h y lp r o p y l)a m in o ]-2-
p yr id in yl]a m in o]p ip er id in e, 50p (R ) Me, Y ) ter t-a m yl,

3784 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
3.39 (m, 1H), 3.30-2.95 (m, 2H), 3.14 (m, 2H), 2.01 (m, 2H),
1.64 (m, 2H), 1.38 (s, 9H), 0.92 (t, J ) 7.0 Hz, 3H); EI-MS m/ z
(rel intensity) 464 (M+, 82), 449 (16), 435 (22), 407 (43), 189
(50), 178 (49), 174 (50), 136 (100); HRMS (FAB) calcd for
C25H32N6O3 + H 465.2614, found 465.2634.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
eth yl-N-[3-[(1-m eth yleth yl)a m in o]-2-p yr id in yl]a m in o]p i-
p er id in e, 12: prepared in a manner analogous to 15 to provide
77% of the title piperidine; mp 215-216 °C; 1H NMR (CDCl3)
δ 9.51 (s, 1H), 7.68 (dd, J ) 1.3, 4.8 Hz, 1H), 7.37 (s, 1H), 7.34
(d, J ) 8.7 Hz, 1H), 7.09 (dd, J ) 1.9, 8.7 Hz, 1H), 6.90 (dd, J
) 4.8, 7.9 Hz, 1H), 6.77 (d, J ) 7.4 Hz, 1H), 6.61 (s, 1H), 4.60
(br m, 3H), 3.33 (br, 1H), 3.16 (m, 2H), 3.07 (m, 5H), 1.87 (m,
2H), 1.53 (m, 2H), 1.29 (d, J ) 6.9 Hz, 6H), 1.18 (t, J ) 7.1
Hz, 3H), 0.82 (t, J ) 6.8 Hz, 3H); HRMS calcd for C25H34N6O3S
498.2413, found 498.2427. Anal. (C25H34N6O3S) C, H, N.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
cyclopr opyl-N-[3-[(1-m eth yleth yl)am in o]-2-pyr idin yl]am i-
n o]p ip er id in e, 13: prepared in a manner analogous to 15 to
provide 68% yield of the title compound as an off-white powder;
mp 138-140 °C dec; 1H NMR (CDCl3) δ 10.11 (s, 1H), 7.77
(m, 1H), 7.58 (s, 1H), 7.40 (m, 2H), 7.15 (d, J ) 8.7 Hz, 1H),
6.99 (dd, J ) 4.8, 8.0 Hz, 1H), 6.84 (d, J ) 7.5 Hz, 1H), 6.71
(s, 1H), 4.68 (br d, J ) 12.9 Hz, 2H), 4.49 (d, J ) 8.4 Hz, 1H),
3.58-3.40 (m, 2H), 3.40-2.80 (br m, 2H), 2.95 (s, 3H), 2.60
(m, 1H), 2.01 (m, 2H), 1.68 (m, 2H), 1.17 (d, J ) 6.3 Hz, 6H),
0.52 (m, 2H), 0.37 (m, 2H); EI-MS m/ z (rel intensity) 510 (M+,
74), 495 (5), 481 (23), 237 (33), 190 (100), 148 (97). Anal.
(C26H34N6O3S) C, H, N.
1-[(5-Nit r oin d ol-2-yl)ca r b on yl]-4-[N-et h yl-N-[3-[(1,1-
d im e t h yle t h yl)a m in o]-6-flu or o-2-p yr id in yl]a m in o]p i-
p er id in e, 54d (Y ) ter t-bu tyl, R ) Et, X ) F ): prepared in
a manner analogous to 15 to provide 63% of the title com-
pound; IR (mull) 3292 (s), 1602 (s), 1584 (s) cm-1 1H NMR
;
(CDCl3) δ 8.54 (d, J ) 2.1 Hz, 1H), 8.07 (dd, J ) 2.3, 9.1 Hz,
1H), 7.39 (d, J ) 9.1 Hz, 1H), 7.19 (dd, J ) 7.6, 8.6 Hz, 1H),
6.84 (m, 1H), 6.52 (dd, J ) 3.4, 8.6 Hz, 1H), 4.73 (s, 1H), 4.60
(m, 2H), 3.27 (m, 1H), 3.04 (q, J ) 7.1 Hz, 2H), 3.05-2.80 (br,
2H), 1.93 (m, 2H), 1.59 (m, 2H), 1.27 (s, 9H), 0.84 (t, J ) 7.1
Hz, 3H); MS-EI m/ z (rel intensity) 482 (M+, 93), 482 (93), 211
(30), 194 (40), 192 (32), 189 (56), 155 (28), 154 (99); HRMS
(FAB) calcd for C25H31N6O3F + H 483.2520, found 483.2522.
Anal. (C25H31FN6O3) C, H, N.
1-[(5-Nit r oin d ol-2-yl)ca r b on yl]-4-[N-et h yl-N-[3-(et h -
yla m in o)-2-p yr id in yl]a m in o]p ip er id in e, 54e (Y ) Et, R
) Et, X ) H): prepared in a manner analogous to 15 to provide
1
65% of the title compound; H NMR (CD3OD) δ 8.71 (s, 1H),
8.19 (dd, J ) 1.5, 9.0 Hz, 1H), 7.73 (m, 1H), 7.62 (d, J ) 9.0
Hz, 1H), 7.12 (m, 3H), 4.55 (m, 2H), 3.48 (m, 1H), 2.27 (m,
4H), 3.25-2.95 (br, 2H), 2.01 (m, 2H), 1.72 (m, 2H), 1.33 (t, J
) 7.1 Hz, 3H), 0.98 (t, J ) 7.0 Hz, 3H).
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
p r op yl-N-[3-[(1-m eth yleth yl)a m in o]-2-p yr id in yl]a m in o]-
p ip er id in e, 14: prepared in a manner analogous to 15 to
provide 69% yield of an off-white solid; mp 177-179 °C dec;
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m eth yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-2-p yr id in yl]a m i-
n o]p ip er id in e, 7: prepared in a manner analogous to 15 to
1
IR (mull) 1578 (s) cm-1; H NMR (CDCl3, 400 MHz) δ 10.10
(s, 1H), 7.73 (dd, J ) 1.4, 4.7 Hz, 1H), 7.58 (s, 1H), 7.39 (d, J
) 8.7 Hz, 1H), 7.35 (s, 1H), 7.15 (dd, J ) 1.9, 8.7 Hz, 1H), 6.95
(dd, J ) 4.7, 8.0 Hz, 1H), 6.84 (m, 1H), 6.71 (s, 1H), 4.67 (m,
3H), 3.55 (m, 1H), 3.28 (m, 1H), 3.20-2.80 (br m, 2H), 3.05
(m, 2H), 2.95 (s, 3H), 1.94 (m, 2H), 1.65 (m, 2H), 1.28 (m, 2H),
1.21 (d, J ) 6.3 Hz, 6H), 0.81 (t, J ) 7.3 Hz, 3H); EI-MS m/ z
(rel intensity) 512 (M+, 65), 483 (34), 275 (7), 237 (41), 216
(44), 192 (100), 178 (47), 163 (37). Anal. (C26H36N6O3S) C, H,
N, S.
1
provide 34% yield of the title compound; mp 192-193 °C; H
NMR (CD3OD) δ 7.48 (dd, J ) 1.5, 4.8 Hz, 1H), 7.41 (d, J )
1.8 Hz, 1H), 7.29 (d, J ) 8.8 Hz, 1H), 7.12 (dd, J ) 1.5, 8.2 Hz,
1H), 7.02 (dd, J ) 2.1, 8.8 Hz, 1H), 6.87 (dd, J ) 4.8, 8.2 Hz,
1H), 6.66 (s, 1H), 4.33 (br d, 2H), 3.2-2.9 (br m, 2H), 2.76 (s,
3H), 2.50 (s, 3H), 1.74 (br d, 2H), 1.47 (m, 2H), 1.26 (s, 9H).
Anal. (C25H34N6O3S) C, H, N.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m eth yl-N-[3-[(cyclopr opylm eth yl)am in o]-2-pyr idin yl]am i-
n o]p ip er id in e, 9: prepared in a manner analogous to 15 to
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
p r op yl-N-[3-[(1,1-d im eth yleth yl)a m in o]-2-p yr id in yl]a m i-
n o]p ip er id in e, 16: prepared in a manner analogous to 15 to
provide 74% of a white solid; mp 195-197 °C dec; IR (mull)
1
provide 53% yield of the title compound; mp 187-189 °C; H
NMR (CD3OD) δ 7.59 (m, 1H), 7.53 (m, 1H), 7.41 (d, J ) 8.8
Hz, 1H), 7.14 (d, 1H, J ) 8.8 Hz), 7.00 (d, J ) 3.4 Hz, 2H),
6.78 (s, 1H), 4.45 (br d, 2H), 3.45 (m, 1H), 3.00 (d, 2H, J ) 6.7
Hz), 2.88 (s, 3H), 2.66 (s, 3H), 1.85 (br d, 2H), 1.70 (m, 2H),
1.10 (m, 1H), 0.55 (m, 2H), 0.25 (m, 2H); EI-MS m/ z (rel
intensity) 496 (84), 259 (17), 237 (47), 228 (36), 217 (27), 204
(21), 176 (100). Anal. (C25H32N6SO3‚0.625H2O) C, H, N.
1
1580 (s), 1456 (m) cm-1; H NMR (CDCl3, 400 MHz) δ 10.15
(s, 1H), 7.72 (dd, J ) 1.4, 4.7 Hz, 1H), 7.58 (s, 1H), 7.48 (s,
1H), 7.39 (d, J ) 8.7 Hz, 1H), 7.15 (dd, J ) 2.0, 8.7 Hz, 1H),
7.09 (dd, J ) 1.4, 8.0 Hz, 1H), 6.91 (dd, J ) 4.7, 8.0 Hz, 1H),
6.71 (s, 1H), 5.15 (s, 1H), 4.68 (br d, J ) 12.4 Hz, 2H), 3.23
(m, 1H), 3.20-2.80 (br m, 2H), 3.04 (m, 2H), 2.95 (s, 3H), 1.94
(m, 2H), 1.65 (m, 2H), 1.37 (s, 9H), 1.29 (m, 2H), 0.82 (t, J )
7.4 Hz, 3H); EI-MS m/ z (rel intensity) 526 (M+, 83), 511 (12),
497 (27), 483 (16), 469 (38), 441 (11), 237 (67), 206 (60), 192
(61), 174 (56), 150 (100), 130 (52). Anal. (C27H38N6O3S) C, H,
N, S.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m et h yl-N-[3-(cyclop r op yla m in o)-2-p yr id in yl]a m in o]p i-
p er id in e, 10: prepared in a manner analogous to 15 to provide
57% yield of the product as a faint yellow solid; mp 175 °C
dec; 1H NMR (CDCl3, 400 MHz) δ 10.02 (s, 1H), 7.78 (dd, J )
1.6, 4.8 Hz, 1H), 7.58 (d, J ) 1.7 Hz, 1H), 7.39 (d, J ) 8.7 Hz,
1H), 7.33 (s, 1H), 7.25 (m, 1H), 7.15 (dd, J ) 2.9, 8.7 Hz, 1H),
6.98 (dd, J ) 4.8, 7.9 Hz, 1H), 6.71 (d, J ) 1.5 Hz, 1H), 4.95
(s, 1H), 4.62 (br d, J ) 13.0 Hz, 2H), 3.45 (m, 1H), 3.15 (br m,
2H), 2.95 (s, 3H), 2.61 (s, 3H), 2.36 (m, 1H), 1.93 (m, 2H), 1.63
(bq, J ) 11.3 Hz, 2H), 0.77 (m, 2H), 0.53 (m, 2H); EI-MS m/ z
(rel intensity) 482 (M+, 13), 440 (3), 426 (5), 237 (68), 162 (100),
130 (90); HRMS calcd for C24H30N6O3S 482.2100, found
482.2086. Anal. (C24H30N6S1O3‚0.6H2O) C, H, N.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m eth yl-N-[3-[(1-m eth ylcyclop r op yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 11: prepared in a manner analogous to
15 to provide 62% yield of the title compound; mp 201-204
°C dec; 1H NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 7.76 (m,
1H), 7.59 (s, 1H), 7.40 (d, J ) 8.7 Hz, 1H), 7.25 (m, 1H), 7.15
(br d, J ) 8.7 Hz, 1H), 6.90 (m, 1H), 6.74 (s, 1H), 6.50 (s, 1H),
5.04 (s, 1H), 4.60 (br d, J ) 13.0 Hz, 2H), 3.47 (m, 1H), 3.30-
3.00 (br m, 2H), 2.97 (s, 3H), 2.62 (s, 3H), 1.94 (m, 2H), 1.60
(m, 2H), 1.34 (s, 3H), 0.78 (m, 2H), 0.69 (m, 2H); EI-MS m/ z
(rel intensity) 496 (M+, 22), 237 (43), 176 (100), 158 (35), 148
(32), 130 (62); HRMS calcd for C25H32N6O3S 496.2256, found
496.2258. Anal. (C25H32N6O3S‚0.1H2O) C, H, N.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
eth yl-N-[3-(eth ylam in o)-2-pyr idin yl]am in o]piper idin e, 17:
prepared in a manner analogous to 15 to provide 59% of the
1
title piperidine; mp 204-205 °C; H NMR (CDCl3) δ 9.38 (s,
1H), 7.57 (d, J ) 3.3 Hz, 1H), 7.37 (m, 1H), 7.18 (m, 1H), 6.95
(dd, J ) 2.1, 8.7 Hz, 1H), 6.81 (m, 1H), 6.65 (m, 2H), 6.50 (s,
1H), 4.52 (m, 1H), 4.42 (br d, 2H), 3.25 (br, 1H), 2.95 (br m,
6H), 2.76 (s, 3H), 1.75 (m, 2H), 1.42 (m, 2H), 1.07 (t, J ) 7.0
Hz, 3H), 0.71 (t, J ) 6.9 Hz, 3H); HRMS calcd for C24H32N6O3S
484.2252, found 484.2256. Anal. (C24H32N6O3S‚0.33H2O) C,
H, N.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
e t h yl-N -[3-(p r op yla m in o)-2-p yr id in yl]a m in o]p ip e r i-
d in e, 22: prepared in a manner analogous to 15 to provide
37% yield of the title compound; mp 208-209 °C; 1H NMR
(DMSO-d6) δ 11.42 (s, 1H), 9.19 (s, 1H), 7.45 (d, J ) 2.9 Hz,
1H), 7.30 (s, 1H), 7.21 (d, J ) 8.7 Hz, 1H), 6.93 (d, J ) 8.7 Hz,
1H), 6.77 (m, 1H), 6.73 (m, 1H), 6.59 (s, 1H), 4.86 (m, 1H),
4.20 (br d, 2H), 2.91 (m, 4H), 271 (s, 2H), 1.64 (m, 2H), 1.37
(m, 4H), 0.76 (t, J ) 7.3 Hz, 3H), 0.64 (t, J ) 6.9 Hz, 3H);
EI-MS m/ z (rel intensity) 498 (39), 469 (10), 261 (8), 237 (27),
216 (47), 178 (100). Anal. (C25H34N6O3S) C, H, N, S.

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3785
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m et h yl-N-[3-(isop r op yla m in o)-2-p yr id a zin yl]a m in o]p i-
p er id in e, 30: prepared in a manner analogous to 15 to provide
39% yield of the title compound; mp 193-194 °C; IR (mull)
3253, 1600, 1579, 1560, 1532, 1495, 1448 cm-1; 1H NMR (CD3-
OD) δ 8.17 (d, J ) 5.8 Hz, 1H), 7.34 (d, J ) 1.6 Hz, 1H) 7.21
(d, J ) 8.7 Hz, 1H), 6.95 (dd, J ) 2.0, 8.7 Hz, 1H), 6.59 (s,
1H), 6.47 (d, J ) 5.9 Hz, 1H), 4.35 (br d, 2H), 3.53 (m, 1H),
3.32 (m, 1H), 2.68 (s, 3H), 2.53 (s, 3H), 1.75 (br d, 2H), 1.55
(m, 2H), 1.07 (d, J ) 6.3 Hz, 6H); EI-MS m/ z (rel intensity)
485 (100), 470 (27), 442 (21), 406 (26), 237 (30), 167 (77). Anal.
(C23H31N7O3S‚0.7H2O) C, H, N, S.
carboxylic acid (77 mg, 3.0 mmol) was added, and the solution
was chilled to 0 °C. EDC (582 mg, 3.0 mmol) was added, and
the reaction mixture was stirred overnight at room tempera-
ture. It was then poured into 1 N NaOH solution and
extracted with CHCl3/CH3OH, breaking emulsions with the
addition of brine. The extract was dried over Na2SO4, filtered,
and evaporated to an oil. Chromatography on a silica gel
column with 5% CH3OH/CHCl3 followed by chromatography
with 75-100% EtOAc in hexane yielded 585 mg (47%) of the
title compound as an amorphous solid: IR (mull) 3255, 1600,
1
1578, 1533, 1478, cm-1; H NMR (CD3OD) 7.69 (dd, J ) 1.6,
4.7 Hz, 1H), 7.56 (d, J ) 2.0 Hz, 1H), 7.43 (d, J ) 8.7 Hz, 2H),
7.17 (dd, J ) 2.0, 8.7 Hz, 1H), 7.11 (dd, J ) 4.7, 8.0 Hz, 1H),
7.00 (d, J ) 8.1 Hz, 1H), 6.76 (s, 1H), 4.53 (br d, 2H), 3.66 (m,
2H), 3.19 (q, J ) 7.1 Hz, 2H), 2.92 (s, 3H), 2.00 (br d, 2H),
1.46 (m, 2H), 1.25 (t, J ) 7.1 Hz, 3H), 1.07 (d, J ) 6.4 Hz,
6H); MS-EI m/ e (rel intensity) 498 (11), 483 (13), 455 (33),
237 (39), 202 (83), 178 (100). Anal. (C25H34N6O3S) C, H, N,
S.
Gen er a l P r oced u r e for Red u ction of 5-Nitr oin d oles.
1-[(5-Am in oin d ol-2-yl)ca r b on yl]-4-[N -e t h yl-N -[3-[(1,1-
dim eth yleth yl)am in o]-2-pyr idin yl]am in o]piper idin e, 55a
(Y ) ter t-bu tyl, R ) Et, X ) H). To a solution of 54c (1.24
g, 2.67 mmol) in DMF/MeOH (25/75, 80 mL) under N2 was
added 10% Pd/C (0.570 g). The mixture was put under a
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
m e t h yl-N -[6-ch lor o-3-[(1-m e t h yle t h yl)a m in o]-2-p yr i-
d in yl]a m in o]p ip er id in e, 31: prepared in a manner analo-
gous to 15 to provide 54% yield of the title compound; mp 101-
1
102 °C; H NMR (CD3OD) δ 7.37 (d, J ) 2.1 Hz, 1H), 7.25 (d,
J ) 8.7 Hz, 1H), 7.00 (dd, J ) 2.1, 8.7 Hz, 1H), 6.80 (d, J )
2.2 Hz, 2H), 6.62 (s, 1H), 4.30 (br d, 2H), 3.43 (m, 1H), 3.30
(m, 1H), 2.8-3.0 (m, 2H), 2.72 (s, 3H), 2.46 (s, 3H), 1.73 (br d,
2H), 1.50 (m, 2H), 1.05 (d, 6H, J ) 6.3 Hz, 6H); EI-MS m/ z
(rel intensity) 518 (100), 281 (14), 250 (12), 237 (28), 198 (32).
Anal. (C24H31N6O3ClS) C, H, N, Cl, S.
1-[(5-Met h a n esu lfon a m id oin d o-2-yl)ca r b on yl]-4-[N-
m et h yl-N-[3-[(1,1-d im et h ylet h yl)a m in o]-6-flu or o-2-p yr -
id in yl]a m in o]p ip er id in e, 32: prepared in a manner analo-
gous to 15 to provide 67% yield of the title compound; mp 203-
204 °C; IR (mull) 3301, 1600, 1531, 1492, 1461, 1447 cm-1; 1H
NMR (CD3OD) δ 7.57 (d, J ) 1.6 Hz, 1H), 7.43 (m, 2H), 7.19
(m, 1H), 6.82 (s, 1H), 6.65 (dd, J ) 3.3, 8.5 Hz, 1H), 4.55 (br d,
2H), 3.2-3.4 (br m, 2H), 2.92 (s, 3H), 2.65 (s, 3H), 1.90 (br d,
2H), 1.70 (m, 2H), 1.39 (s, 9H); EI-MS m/ e (rel intensity) 516
(73), 501 (4), 459 (5), 237 (86), 223 (18), 197 (41), 180 (52), 158
(61). Anal. (C25H33N6O3SF) C, H, N, S, F.
hydrogen atmosphere (balloon) for 2 h and N2
for 16 h, filtered
through Celite, and concentrated in vacuo to give the crude
product which was then triturated with diethyl ether (50 mL)
and filtered to give 0.88 g (76%) of the product (Rf
TLC, methanol/chloroform, 5/95) as a pale yellow solid: mp
) 0.22 by
104 °C dec; IR (mull) 3286 (m), 2924 (s), 1580 (s), 1530 (s) cm-1
1H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 7.74 (dd, J ) 1.6,
4.8 Hz, 1H), 7.22 (d, J ) 8.6 Hz, 1H), 7.10 (dd, J ) 1.6, 8.1 Hz,
1H), 6.92 (dd, J ) 4.8, 8.1 Hz, 1H), 6.89 (d, J ) 1.9 Hz, 1H),
6.75 (dd, J ) 2.1, 8.6 Hz, 1H), 6.57 (d, J ) 1.6 Hz, 1H), 5.18
(s, 1H), 4.63 (br d, J ) 13.2 Hz, 2H), 3.65 (m, 2H), 3.31 (m,
1H), 3.13 (q, J ) 7.1 Hz, 2H), 3.20-3.00 (m, 2H), 1.93 (m, 2H),
1.61 (m, 2H), 1.37 (s, 9H), 0.90 (t, J ) 7.1 Hz, 3H); EI-MS m/ z
(rel intensity) 434 (M+, 94), 419 (7), 377 (18), 230 (51), 192
(46), 174 (36), 159 (100); HRMS (FAB) calcd for C25H34N6O +
H 435.2872, found 435.2883.
;
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
eth yl-N-[6-flu or o-3-[(1-m eth yleth yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 33: prepared in a manner analogous to
1
15 to provide 85% of the title piperidine; mp 166-168 °C; H
NMR (CD3OD) δ 7.35 (d, J ) 1.8 Hz, 1H), 7.23 (d, J ) 8.8 Hz,
1H), 6.97 (m, 2H), 6.59 (s, 1H), 6.48 (dd, J ) 3.2, 8.5 Hz, 1H),
4.32 (m, 2H), 3.41 (sept, J ) 6.3 Hz, 1H), 3.16 (m, 1H), 2.95
(q, J ) 7.0 Hz, 2H), 2.95-2.72 (br, 2H), 2.70 (s, 3H), 1.70 (m,
2H), 1.43 (m, 2H), 1.01 (d, J ) 6.3 Hz, 6H), 0.70 (t, J ) 7.0
Hz, 3H); HRMS calcd for C25H33N6O3SF 516.2319, found
516.2320. Anal. (C25H33N6O3SF) C, H, N, S, F.
1-[(5-Am in oin d ol-2-yl)ca r bon yl]-4-[N-m eth yl-N-[3-[(1,1-
dim eth ylpr opyl)am in o]-2-pyr idin yl]am in o]piper idin e, 55b
(Y ) ter t-bu tyl, R ) Me, X ) H): prepared in a manner
similar to 55a , starting with 54a , to afford 57% of the title
amine as a pale yellow film; IR (atr) 3269 (m), 2967 (m), 1597
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
et h yl-N-[6-ch lor o-3-[(1,1-d im et h ylet h yl)a m in o]-2-p yr i-
d in yl]a m in o]p ip er id in e, 34: prepared in a manner analo-
gous to 15 to provide 70% yield of the title compound; mp 206-
207 °C; IR (mull) 1608, 1531 cm-1; 1H NMR (DMSO-d6) δ 11.44
(s, 1H), 9.21 (s, 1H), 7.33 (s, 1H), 7.23 (d, J ) 8.7 Hz, 1H),
7.10 (d, J ) 8.4 Hz, 1H), 6.64 (s, 1H), 4.78 (s, 1H), 4.27 (br d,
2H), 2.92 (q, J ) 7.0 Hz, 2H), 2.73 (s, 3H), 1.64 (br d, 2H),
1.40 (m, 2H), 1.18 (s, 9H), 0.68 (t, J ) 7.0 Hz, 3H); MS-EI m/ z
(rel intensity) 546 (61), 489 (20), 309 (16), 264 (25), 237 (100),
226 (44), 210 (59). Anal. (C26H35N6O3SCl) C, H, N, S, Cl.
1-[(5-Met h a n esu lfon a m id oin d ol-2-yl)ca r b on yl]-4-[N-
et h yl-N-[3-[(1,1-d im et h ylet h yl)a m in o]-6-flu or o-2-p yr i-
d in yl]a m in o]p ip er id in e, 35: prepared in a manner analo-
gous to 15 to provide 72% of the title piperidine; mp 221-223
°C; 1H NMR (DMSO-d6) δ 7.47 (m, 1H), 7.37 (m, 2H), 7.09 (dd,
J ) 1.9, 8.7 Hz, 1H), 6.77 (m, 1H), 6.70 (dd, J ) 3.5, 8.6 Hz,
1H), 4.67 (s, 1H), 4.42 (br d, J ) 12.8, 2H), 3.20 (m, 1H), 3.05
(q, J ) 6.9 Hz, 2H), 3.05-2.92 (br, 2H), 2.87 (s, 3H), 1.78 (m,
2H), 1.54 (m, 2H), 1.31 (s, 9H), 0.82 (t, J ) 6.9 Hz, 3H); HRMS
calcd for C26H35FN6O3S 531.2553, found 531.2550. Anal.
(C26H35FN6O3S) C, H, N, S.
Gen er a l P r oced u r e for Cou p lin g w ith EDC. 1-[(5-
Meth a n esu lfon a m id oin d ol-2-yl)ca r bon yl]-4-[N-(1-m eth -
yle t h yl)-N -[3-(e t h yla m in o)-2-p yr id in yl]a m in o]p ip e r i-
d in e, 21. 41g (900 mg, 2.55 mmol) and palladium hydroxide
on carbon (500 mg) in 50 mL of ethanol were hydrogenated
on a Parr apparatus under 40 psi hydrogen for 48 h. Filtration
and evaporation of solvent yielded 700 mg of oil. Without
purification this oil was dissolved in a mixture of 12 mL of
THF and 2.5 mL of DMF. 5-Methanesulfonamidoindole-2-
1
(s), 1577 (s), 1451 (s) cm-1; H NMR (CDCl3) δ 9.95 (s, 1H),
7.69 (dd, J ) 1.5, 4.7 Hz, 1H), 7.20 (d, J ) 8.7 Hz, 1H), 7.05
(dd, J ) 1.5, 8.1 Hz, 1H), 6.88 (m, 2H), 6.71 (dd, J ) 2.1, 8.7
Hz, 1H), 6.55 (d, J ) 1.2 Hz, 1H), 4.91 (s, 1H), 4.64 (d, J )
13.2 Hz, 2H), 3.86 (br s, 2H), 3.40 (m, 1H), 3.11 (br s, 2H),
2.62 (s, 3H), 1.91 (m, 2H), 1.63 (m, 4H), 1.31 (s, 6H), 0.86 (t, J
) 7.3 Hz, 3H); MS-EI m/ e 434 (M+), 419, 405, 363, 275, 244,
191, 159, 131; HRMS calcd for C25H34N6O1 434.2794, found
434.2796.
1-[(5-Am in oin d ol-2-yl)ca r b on yl]-4-[N-et h yl-N-[3-[(1-
m eth yleth yl)a m in o]-2-p yr id in yl]a m in o]p ip er id in e, 55c
(Y ) isop r op yl, R ) Et, X ) H): prepared in a manner similar
to 55a , starting with 54b, to afford 89% of the product (Rf )
0.22 by TLC, MeOH/CHCl3, 5/95) as a pale yellow solid; mp
159-162 °C dec; IR (mull) 3431 (w), 3263 (m), 2924 (s), 1586
(s), 1530 (s), 1445 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.92
(s, 1H), 7.75 (dd, J ) 1.5, 4.7 Hz, 1H), 7.22 (d, J ) 8.6 Hz,
1H), 6.96 (m, 1H), 6.88 (s, 1H), 6.85 (m, 1H), 6.75 (dd, J ) 2.1,
8.6 Hz, 1H), 6.57 (d, J ) 1.3 Hz, 1H), 4.70 (m, 1H), 4.64 (br d,
J ) 13.2 Hz, 2H), 3.70 (br m, 2H), 3.57 (m, 1H), 3.36 (m, 1H),
3.14 (m, 2H), 3.10 (br m, 2H), 1.94 (m, 2H), 1.62 (m, 2H), 1.22
(d, J ) 6.2 Hz, 6H), 0.90 (t, J ) 7.0 Hz, 3H); EI-MS m/ z (rel
intensity) 420 (M+, 85), 405 (4), 377 (5), 261 (18), 216 (50),
178 (100); HRMS (FAB) calcd for C24H32N6O + H 421.2716,
found 421.2707.
1-[(5-Am in oin d ol-2-yl)ca r bon yl]-4-[N-eth yl-N-[3-[(1,1-
d im e t h yle t h yl)a m in o]-6-flu or o-2-p yr id in yl]a m in o]p i-
p er id in e, 55d (Y ) ter t-bu tyl, R ) Et, X ) F ): prepared in
a manner similar to 55a , starting with 54d and using THF as
solvent, to afford 54% of the title compound; 1H NMR (CDCl3)

3786 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
δ 7.42 (m, 2H), 7.06 (d, J ) 2.1 Hz, 1H), 6.92 (dd, J ) 2.1, 8.7
Hz, 1H), 6.75 (m, 2H), 4.96 (s, 1H), 4.83 (m, 2H), 3.73 (br, 1H),
3.46 (m, 1H), 3.27 (t, J ) 7.1 Hz, 2H), 3.28-3.12 (m, 2H), 2.09
(m, 2H), 1.79 (m, 2H), 1.52 (s, 9H), 1.07 (t, J ) 7.1 Hz, 3H).
1-[(5-Am in oin d ol-2-yl)ca r b on yl]-4-[N-et h yl-N-[3-(et h -
yla m in o)-2-p yr id in yl]a m in o]p ip er id in e, 55e (Y ) eth yl,
R ) Et, X ) H): prepared in a manner similar to 55a , starting
with 54e and using ethanol/ethyl acetate as solvent, to afford
reaction mixture was stirred for a further 6 h. Then it was
poured into H2O, extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and concentrated in vacuo. Purification
by flash column chromatography (5% CH3OH/CHCl3) and
crystallization from EtOAc/hexane afforded 0.28 g of the title
1
piperidine (75%): mp 203-204 °C; H NMR (CD3OD) δ 7.35
(d, J ) 2.1 Hz, 1H), 7.22 (dd, J ) 7.5, 8.6 Hz, 1H), 7.16 (d, J
) 8.7 Hz, 1H), 6.97 (dd, J ) 3.0, 8.6 Hz, 1H), 6.54 (s, 1H), 6.45
(dd, J ) 2.0, 8.7 Hz, 1H), 4.34 (br d, 2H), 3.37 (m, 4H), 3.07
(m, 1H), 2.93 (q, J ) 7.0 Hz, 2H), 2.95 (br, 2H), 2.30 (m, 4H),
2.14 (s, 3H), 1.72 (m, 2H), 1.41 (m, 2H), 1.16 (s, 9H), 0.69 (t, J
) 7.0 Hz, 3H); HRMS calcd for C29H38N8O2F 578.3493, found
578.3503. Anal. (C29H38N8O2F) C, H, N.
1
93% of the title amine; H NMR (CDCl3) δ 7.56 (dd, J ) 1.6,
4.8 Hz, 1H), 7.31 (d, J ) 8.6 Hz, 1H), 7.07 (dd, J ) 4.8, 7.9 Hz,
1H), 6.99 (d, J ) 2.1 Hz, 1H), 6.93 (dd, J ) 1.6, 7.9 Hz, 1H),
6.84 (dd, J ) 2.1, 8.6 Hz, 1H), 6.65 (d, J ) 1.6 Hz, 1H), 4.73
(m, 2H), 3.49 (m, 1H), 3.24 (m, 4H), 2.7 (br, 2H), 2.03 (m, 2H),
1.71 (m, 2H), 1.33 (t, J ) 7.1 Hz, 3H), 0.99 (t, J ) 7.0 Hz, 3H).
Gen er a l P r oced u r e for Su lfon yla tin g Am in oin d oles.
1-[[5-[(Meth ylsu lfon yl)a m in o]in d ol-2-yl]ca r bon yl]-4-[N-
m et h yl-N-[3-[(1,1-d im et h ylp r op yl)a m in o]-2-p yr id in yl]-
a m in o]p ip er id in e, 8. A mixture of 508 mg (1.17 mmol) of
55b, 189 µL (2.34 mmol) of pyridine, 91 µL (1.17 mmol) of
methanesulfonyl chloride, and 5 mL of CH2Cl2 was prepared
and stirred at room temperature for 20 h. The mixture was
diluted with 25 mL of CH2Cl2 and 10 mL of water, the layers
were separated, and the organic layer was washed with 10
mL of brine, dried over Na2SO4, and concentrated in vacuo to
give 532 mg of an orange residue which was then chromato-
graphed on 70 g of 230-400 mesh silica gel, eluting with 3%
MeOH/CHCl3. Pooling of fractions giving an Rf ) 0.25 by TLC
(3 × 5% MeOH/CHCl3) and removal of solvent in vacuo gave
345 mg (58%) of the title compound as an amorphous solid:
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)su lfon yl]a m in o]in d ol-
2-yl]car bon yl]-4-[N-eth yl-N-[3-[(1,1-dim eth yleth yl)am in o]-
6-flu or o-2-p yr id in yl]a m in o]p ip er id in e, 37. 55d (0.30 g,
0.663 mmol) was dissolved in 2.2 mL of CH2Cl2 and cooled to
0 °C. Then pyridine (0.11 mL, 1.4 mmol) was added followed
by 0.19 g of 4-methyl-1-piperazinylsulfamoyl chloride (0.80
mmol). The reaction mixture was slowly warmed to room
temperature and stirred for 4 days. Then a further 0.094 g of
4-methyl-1-piperazinylsulfamoyl chloride and 0.056 mL of
pyridine were added, and the reaction mixture was stirred for
a further 6 h. Then it was poured into H2O, extracted with
CH2Cl2, washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Purification by flash column chromatography
(5% CH3OH/CHCl3), a second chromatography (5% CH3OH/
EtOAc), and crystallization from EtOAc/hexane afforded 0.20
g of the title piperidine (50%): mp 181-183 °C; 1H NMR (CD3-
OD) δ 7.43 (d, J ) 1.8 Hz, 1H), 7.33 (d, J ) 7.5 Hz, 1H), 7.27
(d, J ) 8.2 Hz, 1H), 7.07 (dd, J ) 2.1, 8.7 Hz, 1H), 6.65 (s,
1H), 6.55 (dd, J ) 3.3, 8.7 Hz, 1H), 4.42 (br d, 2H), 3.19 (m,
1H), 3.11 (m, 4H), 3.02 (q, J ) 7.0 Hz, 2H), 3.02-2.95 (br m,
2H), 2.26 (m, 4H), 2.10 (s, 3H), 1.80 (m, 2H), 1.55 (m, 2H),
1.26 (s, 9H), 0.79 (t, J ) 7.0 Hz, 3H); HRMS calcd for
C30H43N8O3F 615.3248, found 615.3241. Anal. (C30H43N8O3F)
C, H, N.
1
IR (atr) 3262 (m), 2966 (m), 1602 (s), 1450 (s) cm-1; H NMR
(CDCl3) δ 10.06 (s, 1H), 7.70 (dd, J ) 1.4, 4.8 Hz, 1H), 7.58 (s,
1H), 7.39 (m, 2H), 7.16 (dd, J ) 2.0, 8.7 Hz, 1H), 7.08 (m, 1H),
6.91 (dd, J ) 4.8, 8.1 Hz, 1H), 6.71 (s, 1H), 4.90 (s, 1H), 4.63
(d, J ) 13.1 Hz, 2H), 3.45 (m, 1H), 3.20 (br m, 2H), 2.95 (s,
3H), 2.64 (s, 3H), 1.94 (m, 2H), 1.68 (m, 4H), 1.32 (s, 6H), 0.87
(t, J ) 7.3 Hz, 3H); MS-EI m/ e 512 (M+), 497, 483, 441, 237,
158, 157, 130, 43; HRMS calcd for C26H36N6S1O3 512.2569,
found 512.2584.
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)ca r bon yl]a m in o]in d ol-
2-yl]ca r bon yl]-4-[N-eth yl-N-[3-(eth yla m in o)-2-p yr id in yl]-
a m in o]p ip er id in e, 23: prepared in a manner analogous to
36, starting with 55e, to provide 63% of a hygroscopic foam;
1H NMR (CDCl3) δ 9.41 (br s, 1H), 7.68 (m, 1H), 7.57 (s, 1H),
7.19 (d, J ) 8.7 Hz, 1H), 7.03 (br d, J ) 8.7 Hz, 1H), 6.85 (dd,
J ) 4.7, 7.8 Hz, 1H), 6.76 (br d, J ) 7.8 Hz, 1H), 6.56 (br s,
1H), 6.52 (br s, 1H), 4.63 (m, 1H), 4.52 (br d, 2H), 3.45 (m,
4H), 3.29 (m, 1H), 3.12-2.70 (m, 6H), 2.37 (m, 4H), 2.24 (s,
3H), 1.83 (m, 2H), 1.53 (m, 2H), 1.19 (t, J ) 7.1 Hz, 3H), 0.82
(t, J ) 6.9 Hz, 3H); MS-EI m/ z (rel %) 532 (M+, 0), 432 (40),
406 (31), 202 (39), 185 (39), 164 (99), 159 (28), 150 (35); HRMS
(FAB) calcd for C29H40N8O2 + H1 533.3352, found 533.3338.
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)su lfon yl]a m in o]in d ol-
2-yl]ca r bon yl]-4-[N-eth yl-N-[3-(eth yla m in o)-2-p yr id in yl]-
a m in o]p ip er id in e, 24: prepared in a manner analogous to
37, starting with 55e, to provide 17% of a hygroscopic foam;
1H NMR (CDCl3) δ 10.1 (s, 1H), 7.65 (dd, J ) 1.5, 4.7 Hz, 1H),
7.56 (br, 1H), 7.41 (d, J ) 1.5 Hz, 1H), 7.16 (d, J ) 8.7 Hz,
1H), 7.00 (dd, J ) 1.9, 8.7 Hz, 1H), 6.85 (dd, J ) 4.7, 7.9 Hz,
1H), 6.72 (dd, J ) 1.5, 7.9 Hz, 1H), 6.55 (br s, 1H), 4.59 (t, J
) 4.3 Hz, 1H), 4.52 (br d, J ) 12.6 Hz, 2H), 3.27 (m, 1H), 3.13
(m, 4H), 3.00 (m, 6H), 2.23 (m, 4H), 2.10 (s, 3H), 1.82 (br d, J
) 10.7 Hz, 2H), 1.49 (m, 2H), 1.13 (t, J ) 7.1 Hz, 3H), 0.77 (t,
J ) 7.0 Hz, 3H); MS-EI m/ z (rel intensity) 568 (M+, 7), 406
(54), 202 (54), 164 (99), 159 (58), 158 (49), 150 (35); HRMS
(FAB) calcd for C28H40N8O3S + H1 569.3022, found 569.3010.
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)ca r bon yl]a m in o]in d ol-
2-yl]ca r bon yl]-4-[N-eth yl-N-[3-[(1-m eth yleth yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 25: prepared in a manner
analogous to 36, starting with 55c, to afford 49% of the title
compound as a green solid; IR (mull) 3288 (m), 2924 (s), 1633
(s), 1600 (s), 1530 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.25
(s, 1H), 7.75 (m, 1H), 7.66 (s, 1H), 7.29 (d, J ) 8.8 Hz, 1H),
7.13 (d, J ) 8.7 Hz, 1H), 6.95 (m, 1H), 6.84 (d, J ) 8.0 Hz,
1H), 6.66 (s, 1H), 6.44 (s, 1H), 4.71 (d, J ) 8.3 Hz, 1H), 4.62
(d, J ) 13.1 Hz, 2H), 3.54 (m, 5H), 3.35 (m, 1H), 3.13 (m, 2H),
3.20-2.90 (br m, 2H), 2.46 (m, 4H), 2.33 (s, 3H), 1.92 (m, 2H),
1.61 (m, 2H), 1.21 (d, J ) 6.2 Hz, 6H), 0.89 (t, J ) 7.0 Hz,
1-[[5-[(Eth ylsu lfon yl)a m in o]in d ol-2-yl]ca r bon yl]-4-[N-
eth yl-N-[3-(eth ylam in o)-2-pyr idin yl]am in o]piper idin e, 18:
prepared in a manner analogous to 8 but starting with 55e
and employing ethanesulfonyl chloride in place of methane-
sulfonyl choride to provided 42% of the title compound; mp
211-213 °C; IR (mull) 3256 (s), 1606 (s), 1580 cm-1; 1H NMR
(DMSO-d6) δ 7.46 (m, 1H), 7.29 (m, 1H), 7.18 (d, J ) 8.7 Hz,
1H), 6.92 (m, 1H), 6.78 (m, 1H), 6.73 (m, 1H), 6.57 (br s, 1H),
4.21 (br, 2H), 3.21 (br, 2H), 2.92 (m, 4H), 2.79 (q, J ) 7.3 Hz,
2H), 1.65 (m, 2H), 1.37 (m, 2H), 1.03 (t, J ) 7.3 Hz, 3H), 0.99
(t, J ) 6.9 Hz, 3H), 0.63 (t, J ) 6.9 Hz, 3H); MS-EI m/ z (rel
intensity) 498 (M+, 64), 202 (47), 165 (22), 164 (99), 157 (25),
150 (36); HRMS (EI) calcd for C25H34N6O3S 498.2413, found
498.2419. Anal. (C25H34N6O3S‚0.33H2O) C, H, N.
1-[[5-[(Isop r op ylsu lfon yl)a m in o]in d ol-2-yl]ca r bon yl]-
4-[N-eth yl-N-[3-(eth yla m in o)-2-p yr id in yl]a m in o]p ip er i-
d in e, 19: prepared in a manner analogous to 8, starting with
55e and employing 2-propanesulfonyl chloride in place of
methanesulfonyl choride, to provided 20% of the title com-
pound; mp 206-207 °C; 1H NMR (CD3OD) δ 7.70 (m, 1H), 7.57
(d, J ) 2.0 Hz, 1H), 7.52-7.48 (m, 4H), 7.19 (m, 1H), 6.80 (s,
1H), 4.61 (br d, 2H), 4.03 (dq, J ) 7.2 Hz, 1H), 3.62 (m, 1H),
3.35 (m, 4H), 3.21 (m, 2H), 2.00 (br d, 2H), 1.75 (m, 2H), 1.35
(d, J ) 6.9 Hz, 6H), 1.30 (t, J ) 7.2 Hz, 3H), 1.02 (t, J ) 7.2
Hz, 3H); MS-EI m/ z (rel %) 512 (M+, 46), 512 (46), 202 (55),
165 (22), 164 (99), 158 (30), 157 (37), 150 (37); HRMS (EI) calcd
for C26H36N6O3S 512.2569, found 512.2576. Anal. (C26H36N6-
O3S1‚0.25H2O) C, H, N.
Wa ter -Solu bilizin g Su bstitu en ts. 1-[[5-[[(4-Meth yl-1-
p ip er a zin yl)ca r b on yl]a m in o]in d ol-2-yl]ca r b on yl]-4-[N-
ethyl-N-[3-[(1,1-dimethylethyl)amino]-6-fluoro-2-pyridinyl]-
am in o]piper idin e, 36. 55d (0.30 g, 0.663 mmol) was dissolved
in 2.2 mL of CH2Cl2 and cooled to 0 °C. Then pyridine (0.11
mL, 1.4 mmol) was added followed by 0.19 g of 4-methyl-1-
piperazinylcarbonyl chloride (0.95 mmol). The reaction mix-
ture was slowly warmed to room temperature and stirred for
4 days. Then a further 0.094 g of 4-methyl-1-piperazinylcar-
bonyl chloride and 0.056 mL of pyridine were added, and the

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3787
3H); FAB-MS m/ z (rel intensity) 1094 ([2M + 2H]+, 8), 547
([M + H]+, 100), 447 (6), 285 (17), 185 (24), 101 (92); HRMS
calcd for C30H42N8O2 + H 547.3509, found 547.3501. Anal.
(C30H42N8O2‚0.4H2O). C, H, N.
cultures was 0.1%. At 4 days postinfection culture fluid
samples were collected for HIV-1 p24 core antigen quantitation
to determine antiviral effects. Linear regression analysis was
used to calculate the drug concentration necessary to inhibit
90% of nondrug p24 antigen production.
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)su lfon yl]a m in o]in d ol-
2-yl]ca r bon yl]-4-[N-eth yl-N-[3-[(1-m eth yleth yl)a m in o]-2-
p yr id in yl]a m in o]p ip er id in e, 26: prepared in a manner
analogous to 37, starting with 55c, to provide 56% of an off-
Selection of Dr u g Resista n t Va r ia n ts. MT4 cells were
infected with HIV-1IIIB or HIV-1MF as described for the antiviral
assay and initially treated with a concentration of NNRTI
approximating its IC50. Infected cells were serially passaged
(1:4) typically every 3-4 days. Each passage was initiated
by pelleting one-quarter of the cells, resuspending in fresh
medium with drug, and supplementing with uninfected cells
to yield a cell density of ∼3-5 × 105/mL. The infections were
monitored by the progression of the cytopathic effect (i.e.,
syncytium formation) as well as p24 productions. Inhibitor
concentrations were increased by 0.5 log 10 increments during
the passage series when p24 antigen levels approached 1 ×
106 pg/mL. Resistant virus stocks were harvested once growth
was sustained in 10 µM of the respective NNRTI.
white solid, amorphous solid; IR (mull) 1607 (s), 1455 (s) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 9.50 (s, 1H), 7.75 (dd, J ) 1.5,
4.7 Hz, 1H), 7.54 (s, 1H), 7.33 (d, J ) 8.7 Hz, 1H), 7.14 (dd, J
) 2.0, 8.7 Hz, 1H), 6.96 (dd, J ) 4.7, 7.9 Hz, 1H), 6.85 (d, J )
8.1 Hz, 1H), 6.70 (m, 2H), 4.70 (m, 1H), 4.63 (br d, J ) 13.2
Hz, 2H), 3.55 (m, 1H), 3.37 (m, 1H), 3.28 (m, 4H), 3.13 (q, J )
7.0 Hz, 2H), 3.10 (br m, 2H), 2.40 (m, 4H), 2.26 (s, 3H), 1.96
(m, 2H), 1.62 (m, 2H), 1.22 (d, J ) 6.3 Hz, 6H), 0.90 (t, J ) 7.0
Hz, 3H); EI-MS m/ z (rel intensity) 582 (M+, 19), 420 (64), 261
(12), 216 (43), 178 (100), 159 (56), 100 (36), 58 (88). Anal.
(C29H42N8O3S) C, H, N.
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)ca r bon yl]a m in o]in d ol-
2-yl]car bon yl]-4-[N-eth yl-N-[3-[(1,1-dim eth yleth yl)am in o]-
2-p yr id in yl]a m in o]p ip er id in e, 27: prepared in a manner
analogous to 36, starting with 55a , to provide 41% of the
product as a faint green, amorphous solid; additional 216 mg
(48%) of slightly impure product also isolated; IR (mull) 1628
(s), 1530 (s), 1455 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.20
(s, 1H), 7.74 (d, J ) 4.6 Hz, 1H), 7.67 (s, 1H), 7.30 (d, J ) 8.7
Hz, 1H), 7.14 (d, J ) 8.0 Hz, 1H), 7.10 (d, J ) 8.1 Hz, 1H),
6.91 (dd, J ) 4.7, 8.1 Hz, 1H), 6.66 (s, 1H), 6.42 (s, 1H), 5.18
(s, 1H), 4.62 (d, J ) 13.1 Hz, 2H), 3.55 (m, 4H), 3.30 (m, 1H),
3.11 (q, J ) 7.0 Hz, 2H), 3.20-2.95 (m, 2H), 2.47 (m, 4H), 2.34
(s, 3H), 1.92 (m, 2H), 1.62 (m, 2H), 1.37 (s, 9H), 0.90 (t, J )
7.0 Hz, 3H); EI-MS m/ z (rel intensity) 460 (31), 230 (25), 185
(52), 174 (46), 136 (74), 58 (100); HRMS (FAB) calcd for
Assa y for Meta bolic Sta bility. Analogs were screened
for metabolic stability in the presence of hepatic microsomal
cytochrome P450 by measuring loss of the parent drug in the
following manner. Hepatic microsomes (0.4 mg), obtained
from untreated rats, were diluted into 1 mL (final volume) of
50 mM potassium phosphate buffer, pH 7.4, 0.1 mM EDTA.
Drug was added from 1 mM stock in MeOH to a final
concentration of 5 µM. Following a preincubation at 37 °C,
reaction was started by addition of an NADPH-generating
system consisting of (final concentration) 0.5 mM NADPH, 5
mM isocitrate, 5 mM MgCl2, and 0.4 U of isocitrate dehydro-
genase. At 2 min intervals between 0 and 12 min from start
of reaction, 100 µL aliquots of incubation were removed and
quenched with 100 µL of acetonitrile followed by addition of
an appropriate internal standard contained in 10 µL of
acetonitrile. Samples were vortex, mixed, and centrifuged to
pellet protein. The supernatant was diluted 1:1 with HPLC
buffer, and a 100 µL sample was assayed by reverse phase
HPLC using a Zorbax Rx-C8 column (15 × 0.49 cm). The
mobile phase consisted of a 12 min gradient of 20-60%
acetonitrile balanced by 100 mM ammonium acetate, pH 4.0,
flowing at 1 mL/min. Detection was by UV absorbance at 295
nM. Drug concentration was estimated by peak height ratio
to the internal standard. Concentration data were fitted to a
monoexponential equation, yielding the rate constant (k) for
loss of drug, which was converted to half-life by t1/2 ) ln 2/k.
Delavirdine and/or atevirdine were run as controls in each
assay.
C31H44N8O2 + H 561.3665, found 561.3663. Anal. (C31H14
N8O2‚0.5H2O).
-
1-[[5-[[(4-Meth yl-1-p ip er a zin yl)su lfon yl]a m in o]in d ol-
2-yl]car bon yl]-4-[N-eth yl-N-[3-[(1,1-dim eth yleth yl)am in o]-
2-p yr id in yl]a m in o]p ip er id in e, 28: prepared in a manner
analogous to 37, starting with 55a , to provide 56% of an off-
white, amorphous solid: IR (mull) 1612 (s), 1455 (s) cm-1; 1H
NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 7.74 (dd, J ) 1.5, 4.8
Hz, 1H), 7.54 (s, 1H), 7.32 (d, J ) 8.7 Hz, 1H), 7.14 (dd, J )
2.0, 8.7 Hz, 1H), 7.10 (dd, J ) 1.5, 8.1 Hz, 1H), 6.92 (dd, J )
4.8, 8.1 Hz, 1H), 6.85 (br s, 1H), 6.70 (s, 1H), 5.18 (s, 1H), 4.62
(br d, J ) 13.1 Hz, 2H), 3.32 (m, 1H), 3.27 (m, 4H), 3.12 (q, J
) 7.0 Hz, 2H), 3.20-3.00 (m, 2H), 2.38 (m, 4H), 2.25 (s, 3H),
1.95 (m, 2H), 1.61 (m, 2H), 1.37 (s, 9H), 0.90 (t, J ) 7.0 Hz,
3H); FAB-MS m/ z (rel intensity) 1194 ([2M + 2H]+, 4), 597
([M + H]+, 100), 433 (7), 101 (24), 99 (34), 97 (38), 57 (25);
HRMS calcd for C30H44N8O3S + H 597.3335, found 597.3332.
Anal (C30H44N8O3S‚0.3H2O) C, H, N.
HIV RT Assa y P r otocol. The RT assays were carried out
at 28 °C for 10 min in a 100 µL reaction mixture consisting of
2 mM dithiothreitol, 60 mM NaCl, 10 mM MgCl2, 50 mM Tris-
HCl (pH 8.3), 0.05% Nonidet P-40, 50 µM thymidine triphos-
phate with 12 µCi/mL [methyl-3H]thymidine 5′-triphosphate
(Amersham), 200 nM template:primer (poly(rA)600:oligo(dT)10
from Pharmacia), and 4 µg/mL purified HIV RT. The RT
enzymes (WT, P236L, and Y181C) were used as the ho-
modimers and obtained as previously described.14,48,49 The
reaction was stopped with 100 µL of 10% (v/v) trichloroacetic
acid. The acid-precipitated materials, recovered on glass fiber
filters, were analyzed for radioactivity. Non-nucleoside drugs
were added from DMSO stocks. In all cases the final DMSO
concentration was 1% (v/v).
Ack n ow led gm en t. We thank Brian G. Conway,
Azhwarsamy J eganathan, David O. Pearson, Rick J .
Imbordino, Moses W. McMillan, and Mark R. Guthaus
for supplying various chemical intermediates and the
large scale preparation of compounds 7, 15, 16, and 36.
We are indebted to Herman W. Smith for synthesizing
a sample of L-697,661. We also thank Barbara A. Leone
and Debra J . Bevis for their technical involvement
conducting the mutant RT assays in the early stages of
this investigation. Our thanks is also extended to Steve
M. Maio for assistance in the determination of half-lives
in liver microsomes and to Philip E. Sanders for the LC/
MS analysis of metabolites. Lastly, we thank J ean L.
Sarcich and Alfredo G. Tomesselli for helping during
the large scale isolation of mutant enzymes.
An tivir a l Assa y.50 Assessment of the antiviral activities
of the NNRTIs versus the panel of viruses used in these studies
was carried out mainly in MT4 cells. Cells were batch-infected
with the appropriate virus stock at a multiplicity of infection
of 0.001-0.005 TCID50 per cell for 2 h at 37 °C. The cells were
washed, resuspended in RPMI/FBS, and plated in 24-well
dishes at a final concentration of 1.5 × 105 cells/mL to which
were added 2× drug treatments prepared in RPMI/FBS. All
treatment concentrations were tested in duplicate. The final
DMSO concentration for all treatments or vehicle control
Refer en ces
(1) Scrip. US panel clears GW’s Epivir and Roche’s Invirase; Nov.
14, 1995; p 22.
(2) Kellam, P.; Boucher, C. A. B.; Larder, B. A. Fifth mutation in a
human immunodeficiency virus type 1 reverse transcriptase
contributes to the development of high-level resistance to
zidovudine. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 1934-1938.
(3) Larder, B. A.; Darby, G.; Richman, D. D. Multiple Mutations in
HIV-1 Reverse Transcriptase Confer High-Level Resistance to
Zidovudine (AZT). Science 1989, 243, 1731-1734.

3788 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Romero et al.
(23) Pettit, F. H.; Ziegler, D. M. The Catalytic Demethylation of N,N-
dimethylaniline-N-oxide by Liver Microsomes. Biochem. Biophys.
Res. Commun. 1963, 13, 193-197.
(24) Karki, S. B.; Dinnocenzo, J . P.; J ones, J . P.; Korzekwa, K. R.
Mechanism of Oxidative Amine Dealkylation of Substituted N,N-
dimethylanilines by Cytochrome P-450: Application of Isotope
Effect Profiles. J . Am. Chem. Soc. 1995, 117, 3657-3664.
(25) Foye, W. O. Principles of Medicinal Chemistry; Lea & Febiger:
Philadelphia, 1981; p 101.
(26) Hargrave, K. D.; Proudfoot, J . R.; Grozinger, K. G.; Cullen, E.;
Kapadia, S. R.; Pate, 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. 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. Tricyclic Pyridobenzo- and
Dipyridodiazepinones. J . Med. Chem. 1991, 34, 2231-2241.
(27) Skoog, M. T.; Hargrave, K. D.; Miglietta, J . J .; Kopp, E. B.;
Merluzzi, V. Inhibition of HIV-1 Reverse Transcriptase and
Virus Replication by a Non-Nucleoside Dipyridodiazepinone BI-
RG-587 (Nevirapine). Med. Res. Rev. 1992, 12, 27-40.
(28) Anstadt, R. A.; Schwende, F. J .; Sedlock, M. L.; Voorman, R.;
Wurzer, G. M. Preclinical Pharmacokinetic Evaluation of Several
Bis(heteroaryl)piperazine (BHAP) analogs, non-nucleoside re-
verse transcriptase inhibitors (RTI). 31st Interscience Confer-
ence on Antimicrobial Agents and Chemotherapy, Chicago, IL,
Sept. 29-Oct. 2, 1991; Poster 1337.
(4) Larder, B. A.; Darby, G.; Richman, D. D. HIV with Reduced
Sensitivity to Zidovudine (AZT) Isolated During Prolonged
Therapy. Science 1989, 243, 1731-1734.
(5) St. Clair, M. H.; Martin, J . L.; Tudor-Williams, G.; Bach, M. C.;
Vavro, C. L.; King, D. M.; Kellam, P.; Kemp, S. D.; Larder, B.
A. Resistance to ddI and Sensitivity to AZT Induced by a
Mutation in HIV-1 Reverse Transcriptase. Science 1991, 253,
1557-1559.
(6) Romero, D. L. Atevirdine Mesylate. Drugs Future 1994, 19 (1),
9-12.
(7) Romero, D. L. Delavirdine Mesylate. Drugs Future 1994, 19 (3),
238-242.
(8) 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-Specific Pyridinone Reverse Transcriptase Inhibitors. J . Virol.
1991, 65, 4887-4892.
(9) Richman, D.; Shih, C.-K.; Lowry, I.; Rose, J .; Prodanovich, P.;
Goff, S.; Griffin, J . Human immunodeficiency virus type 1
mutants resistant to nonnucleoside inhibitors of reverse tran-
scriptase arise in tissue culture. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 11241-11245.
(10) De Vreese, K.; Debyser, Z.; VanDamme, A.-M.; Pauwels, R.;
Desmter, J .; DeClerq, E.; Anne, J . Resistance of human immu-
nodeficiency virus type 1 reverse transcriptase to TIBO deriva-
tives induced by site-directed mutagenesis. Virology 1992, 188,
900-904.
(11) Mellors, J . W.; Dutschman, G. E.; Im, G.-J .; Tramontano, E.;
Winkler, S. R.; Cheng, Y.-C. In vitro selection and molecular
characterization of human immunodeficiency virus-1 resistant
to non-nucleoside inhibitors of reverse transcriptase. Mol. Phar-
macol. 1992, 41, 446-451.
(12) (a) Freimuth, W. W. Delavirdine mesylate a potent non-nucleo-
side reverse transcriptase inhibitor of HIV-1: virology, phar-
macokinetics, safety and clinical surrogate marker response. In
Proceedings of the Fourth Triennial Symposium on New Direc-
tions in Antiviral Chemotherapy; Mills, J . Ed.; Plenum Press:
New York, in press. (b) Wathen, L. K.; Freimuth, W. W.; Batts,
D. H.; Cox, S. R. Phenotypic and genotypic characterization of
HIV-1 viral isolates from patients treated with combined AZT
and delavirdine mesylate therapy. Third International HIV Drug
Resistance Workshop, Kauai, Hawaii, Aug. 2-5, 1994; Abstract
42. (c) Aristoff, P. A. BHAPs. DN&P 1995, 8 (3), 151-155.
(13) Sardana, V. V.; Emini, E. A.; Gotlib, L.; Graham, D. J .;
Lineberger, D. W.; Long, W. J .; Schlabach, A. J .; Wolfgang, J .
A.; Condra, J . H. Functional Analysis of HIV-1 Reverse Tran-
scriptase Amino Acids Involved in Resistance to Multiple Non-
nucleoside Inhibitors. J . Biol. Chem. 1992, 267, 17526-17530.
(14) 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 1 that confers
increased sensitivity to other nonnucleoside inhibitors. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 4713-4717.
(29) T. J . Poel, R. C.; Thomas, D. L.; Romero, M. J .; Hosley, R. A.;
Morge, C.; Biles, F.; Reusser, I. W.; Althaus, W. C.; Schinzer, D.
J .; Platzer. Second Generation Bisheteroarylpiperazine (BHAP)
HIV-1 Reverse Transcriptase Inhibitors. Enhancement of An-
tiviral Activity and Aqueous Solubility via 5- and 6-Substitution
of the Indole Ring. 205th American Chemical Society National
Meeting, Denver, CO, Mar. 28-Apr. 2, 1993.
(30) Mayland Chang, et. al., Pharmacia
& Upjohn, Inc., Drug
Metabolism Research, unpublished results.
(31) Compound 35 was poorly soluble in the standard 80% PG vehicle.
Randall G. Stehle and Kevin J . Stefanski, Pharmacia & Upjohn,
Inc., DDR&D Pharmaceutics, private communication.
(32) Streitwieser, A.; Heathcock, C. H. Introduction to Organic
Chemistry; Macmillan Publishing Co.: New York, 1981; pp 736-
737.
(33) Althaus, I. W.; Chou, J . J .; Gonzales, A. J .; Deibel, M. R.; Chou,
K.-C.; Kezdy, F. J .; Romero, D. L.; Aristoff, P. A.; Tarpley, W.
G.; Reusser, F. Steady-State Kinetic Studies with the Non-
nucleoside HIV-1 Reverse Transcriptase Inhibitor U-87201E. J .
Biol. Chem. 1993, 268, 6119-6124.
(34) Althaus, I. W.; Chou, J . J .; Gonzales, A. J .; Deibel, M. R.; Chou,
K.-C.; Kezdy, F. J .; Romero, D. L.; Palmer, J . R.; Thomas, R. C.;
Aristoff, P. A.; Tarpley, W. G.; Reusser, F. Kinetic studies with
the non-nucleoside HIV-1 reverse transcriptase inhibitor
U-88204E. Biochemistry 1993, 32, 6548-6554.
(35) Althaus, I. W.; Chou, J . J .; Gonzales, A. J .; Deibel, M. R.; Chou,
K.-C.; Kezdy, F. J .; Thomas, R. C.; Aristoff, P. A.; Tarpley, W.
G.; Reusser, F. Kinetic Studies with the Non-nucleoside Human
Immunodeficiency Virus Type-1 Reverse Transcriptase Inhibitor
U-90152E. Biochem. Pharmacol. 1994, 47, 2017-2028.
(36) Olmsted, R. A.; Slade, D. E.; Kopta, L. A.; Poppe, S. M.; Poel, T.
J .; Newport, S. W.; Rank, K. B.; Biles, S. C.; Morge, R. A.;
Dueweke, T. J .; Yagi, Y.; Romero, D. L.; Thomas, R. C.; Sharma,
S. K.; Tarpley, W. G. (Alkylamino)Piperidine BHAP Analogs are
Potent Broad-Spectrum Nonnucleoside Reverse Transcriptase
Inhibitors of Drug-Resistant Isolates of HIV-1 and Select for
(15) U-90152S, U-90152E, and U-90152T are different crystal forms
of the mesylate salt of U-90152 (delavirdine).
(16) Mellors, J . W.; Larder, B. A.; Schinazi, R. F. Mutations in the
HIV-1 Reverse Transcriptase and Protease Associated with Drug
Resistance. Int. Antiviral News 1995, 3, 8-13.
(17) De Clercq, E. How to overcome resistance of HIV-1 to HIV-1-
specific reverse transcriptase inhibitors. AIDS 1994, 8 (7), 1020-
1021.
(18) Adams, W. J .; Voorman, R. Unpublished results.
(19) Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May,
P. D.; Palmer, J . R.; J ohnson, P. D.; Smith, H. W.; Busso, M.;
Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey,
K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.; Aristoff, P. A.
Discovery, Synthesis and Bioactivity of Bis(heteroaryl)pipera-
zines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse
Transcriptase Inhibitors. J . Med. Chem. 1994, 37, 999-1014.
(20) Romero, D. L.; Morge, R. A.; Genin, M. J .; Biles, C.; Busso, M.;
Resnick, L.; Althaus, I. W.; Reusser, F.; Thomas, R. C.; Tarpley,
W. G. Bis(heteroaryl)piperazine (BHAP) Reverse Transcriptase
Inhibitors: Structure-Activity Relationships of Novel Substi-
tuted Indole Analogues and the Identification of 1-[(5-Methane-
sulfonamido-1H-indol-2-yl)carbonyl]-4-[3-[(1-methylethyl)amino]-
Drug Resistant Variants of HIV-1IIIB
Phenotypes. J . Virol. 1996, 70, 3699-3705.
(37) Kleim, J .-P.; Bender, R.; Billhardt, U.-M.; Meichsner, C.; Riess,
G.; Rosner, M.; Winkler, I.; Paessens, A. Activity of a Novel
Quinoxaline Derivative against Human Immunodeficiency Virus
Type 1 Reverse Transcriptase and Viral Replication. Antimicrob.
Agents Chemother. 1993, 37, 1659-1664.
(38) Conway, B. G.; J eganathan, A.; Gage, J . R. Chemical Research
Preparations, Pharmacia & Upjohn, Inc., private communication.
(39) Kroon, C.; Maassen van den Brink, A.; Vlietstra, E. J .; Salemink,
C. A. Deazapurine derivatives XV. Syntheses of some mono- and
difluoroimidazo[4,5-b]- and [4,5-c]pyridines. Recl. Trav. Chim.
Pay-Bas 1976, 95, 127-156.
(40) Clark, J . H.; Macquarrie, D. J . The Synthesis of Organofluorine
Compounds using Potassium Fluoride-tetraphenylphosphonium
Bromide Systems. Tetrahedron Lett. 1987, 28, 111-114.
(41) When chlorine was present in the pyridine ring, a dealkylative
deprotection employing 1-chloroethyl chloroformate was used to
debenzylate; see: Olofson, R. A.; Martz, J . T.; Senet, J .-P.;
Piteau, M.; Malfroot, T. J . Org. Chem. 1984, 49, 2081. DeShong,
P.; Kell, D. A. Tetrahedron Lett. 1986, 27, 3979.
with Reduced Replication
pyridinyl]piperazine Monomethanesulfonate (U-90152S),
a
Second-Generation Clinical Candidate. J . Med. Chem. 1993, 36,
1505-1508.
(21) Staton, B. A.; J ohnson, M. G.; Friis, J . M.; Adams, W. J . Simple,
rapid and sensitive high-performance liquid chromatographic
determination of delavirdine and its N-desisopropyl metabolite
in human plasma. J . Chromatogr. 1995, B668, 99-106.
(22) Miwa, G. T.; Walsh, J . S.; Kedderis, G. L.; Hollenberg, P. F. The
Use of Intramolecular Isotope Effects to Distinguish between
Deprotonation and Hydrogen Atom Abstraction Mechanisms in
Cytochrome P-450- and Peroxidase-catalyzed N-Demethylation
Reactions. J . Biol. Chem. 1983, 258, 14445-14449.
(42) Genin, M. J .; Biles, C.; Romero, D. L. A Novel Method for the
t-Butylation of Aromatic Amines. Tetrahedron Lett. 1993, 4301-
4304.
(43) Morris, J .; Wishka, D. G. An Efficient Synthesis of Aromatic
Acetonyl Imines. J . Org. Chem. 1995, 60, 2642-2644.

Targeting Delavirdine/ Atevirdine Resistant HIV-1
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3789
(44) Hennion, G. F.; Hanzel, R. S. The Alkylation of Amines with
t-Acetylenic Chlorides. Preparation of Sterically Hindered Amines.
J . Am. Chem. Soc. 1960, 82, 4908.
Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase
Produced by in vitro Processing of p66 with Recombinant HIV-1
Protease. J . Biol. Chem. 1992, 267, 14227-14232.
(50) In the in vitro enzyme assay, the inhibition of RT activity is
measured directly by the reduction in radiolabel incorporation
into DNA, whereas in cell culture the inhibition is measured
indirectly by assay of viral p24 production. Differences in the
IC values between the two systems can be explained by the fact
that reverse transcription of the RNA genome into full length
proviral DNA is a vital stage in the viral replication cycle. If
the intracellular viral RT activity were inhibited by just 5-10%,
that low level of inhibition could conceivably have a profound
effect on the full length proviral DNA synthesis that is necessary
for productive infection and replication over the 4 day assay
period. However, a 5-10% reduction in radiolabel incorporation
in the enzyme assay would not be meaningful. In addition, the
outcome of the cell-based assays can be dependent upon factors
such as cell type, amount of infectious innocula, method of end
point determination, strain of virus, and time line of the assay.
These explanations most likely account for the lower IC90 values
observed in the viral spread assay as compared to IC50 values
obtained in the enzyme assays.
(45) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. Preparation of a
Series of Highly Hindered Secondary Amines, Including Bis-
(trimethylcarbinyl)amine. J . Org. Chem. 1980, 45, 4616-4622.
(46) Kang, J .; Kim, K. S. N-Cyclopropylation of Aromatic Amines. J .
Chem. Soc. Chem. Comm. 1987, 897-898. For a newer method
published subsequent to our work, see: Gillaspy, M. L.; Lefker,
B. A.; Hada, W. A.; Hoover, D. J . A Simple Method for the
Formation of Cyclopropylamines: The First Synthesis of Tricy-
clopropylamine. Tet. Lett. 1995, 36, 7399-7402.
(47) Kuraiski, T.; Castle, R. N. J . Het. Chem. 1964, 1, 42.
(48) Sharma, S. K.; Evans, D. B.; Vosters, A. F.; McQuade, T. J .;
Tarpley, W. G. Metal Affinity Chromatography of Recombinant
HIV-1 Reverse Transcriptase Containing a Human Renin Cleav-
able Metal Binding Domain. Biotechnol. Appl. Biochem. 1991,
14, 69-81.
(49) Chattopadhyay, D.; Evans, D. B.; Deibel, M. R., J r.; Vosters, A.
F.; Eckenrode, F. M.; Einspahr, H. M.; Hui, J . O.; Tomasselli,
A. G.; Zurcher-Neely, H. A.; Heinrikson, R. L.; Sharma, S. K.
Purification and Characterization of Heterodimeric Human
J M960158N