Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: Effect of 3-alkylpyridine ring substitution

Article abstract of DOI:10.1021/jm990051a

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nuc

Full text of DOI:10.1021/jm990051a

4140
J . Med. Chem. 1999, 42, 4140-4149
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of th e
(Alk yla m in o)p ip er id in e-Con ta in in g BHAP Cla ss of Non -Nu cleosid e Rever se
Tr a n scr ip ta se In h ibitor s: Effect of 3-Alk ylp yr id in e Rin g Su bstitu tion
Michael J . Genin,† Toni J . Poel,† Paul D. May,† Laurice A. Kopta,‡ Yoshihiko Yagi,§ Robert A. Olmsted,‡
J anice M. Friis,∇ Richard L. Voorman,∇ Wade J . Adams,∇ Richard C. Thomas,† and Donna L. Romero*,†
Medicinal Chemistry Research, Infectious Diseases Research, Discovery Technologies, and Drug Metabolism Research,
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001
Received J anuary 28, 1999
Development of resistance to currently approved HIV therapies has continued to fuel research
efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-
containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase
inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent
on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity
against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of
the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted
congeners. Testing of representative analogues in an in vitro liver microsome assay indicated
that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-
BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results
in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657,
possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug
delavirdine which is currently on the market for the treatment of HIV infection.
In tr od u ction
had previously embarked upon a program to identify
compounds complimentary to delavirdine.12-14 In short,
screening of formerly identified NNRTIs from our
compound collection and structurally diverse delavir-
dine analogues was conducted against a panel of re-
combinant RTs to target compounds with enhanced
activity against a mutant which contained a proline to
leucine substitution at amino acid 236 (P236L RT)
relative to wild-type (WT) RT. (The P236L mutant arises
upon serial HIV-1 passage in vitro in the presence of
increasing concentrations of delavirdine.11) These efforts
resulted in the discovery that certain delavirdine ana-
logues, namely those of the (alkylamino)piperidine
(AAP-BHAP) variety (e.g., 2 and 3), possessed better
activity than delavirdine against the P236L mutant
enzyme. In addition, these compounds were also more
active against other recombinant RTs containing known
NNRTI resistance mutations, such as the mutant RT
enzyme containing a tyrosine to cysteine substitution
at amino acid 181 (Y181C).
A number of drugs which target either the viral
protease1 or reverse transcriptase (RT) enzymes2 of
human immunodeficiency virus (HIV) are now available
for the treatment of acquired immune deficiency syn-
drome (AIDS). Due to the facility with which HIV can
mutate, therapy with one of the approved drugs usually
results in emergence of drug-resistant viral strains.3
Thus, current best practice generally involves treatment
with combinations of drugs in order to delay emergence
of resistance.4,5 Of the approved drugs, only three are
reverse transcriptase inhibitors of the non-nucleoside
(NNRTIs) class: Rescriptor (delavirdine mesylate, 1),6
Viramune (nevirapine),7,8 and Sustiva (DMP-266).9
On the basis of the hypothesis that sequential treat-
ment with delavirdine followed by a compound with
enhanced activity against delavirdine-resistant virus
might result in an effective anti-HIV therapy,10,11 we
Investigation of the pharmaceutical properties of the
AAP-BHAPs revealed that this structural series suf-
fered the same metabolic fate as the BHAPs: oxidative
N-dealkylation of the 3-(alkylamino)pyridine substitu-
† Medicinal Chemistry Research.
‡ Infectious Diseases Research.
§ Discovery Technologies.
∇ Drug Metabolism Research.
10.1021/jm990051a CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/10/1999

Synthesis and SAR of AAP-BHAPs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4141
Ch a r t 1
logues containing ethers in the alkyl substituent to
investigate the effect of the oxygen atom on the activity
as well as the pharmacokinetics (Scheme 3). Nucleo-
philic aromatic substitution of commercially available
methyl nicotinate with the 4-(alkylamino)piperidines 8a
and 8b afforded the pyridinyl esters 24a and 24b in
modest yield. LAH reduction of the ester afforded the
hydroxymethyl-substituted intermediates, which could
be methylated upon treatment with methyl iodide and
potassium hydroxide in DMSO. Deprotection of the
benzylamine and coupling with the indole-2-carboxylic
acid proceeded uneventfully to afford 27 and 28. An
ester-substituted pyridine analogue was synthesized by
deprotecting intermediate 24a and coupling with the
indole-2-carboxylic acid to afford 29 (Scheme 4). Simi-
larly, hydroxymethyl-substituted derivative 30 was
prepared from intermediate 25a .
ent, albeit at a more rapid rate. A number of structural
modifications were explored in attempts to enhance the
metabolic stability of the AAP-BHAP template while
maintaining the desired activity profile. These included
replacing the usual 3-isopropylamino substituent on the
pyridine ring with a tert-butylamino moiety (4)12 or an
alkoxy group (5).15 Herein, we describe further inves-
tigation of the SAR of the 3-pyridyl substituent via the
synthesis of AAP-BHAPs containing 3-alkyl or ether-
containing 3-alkyl substituents which afforded another
opportunity to circumvent metabolism at this site.
Biologica l Resu lts a n d Discu ssion
Compounds were evaluated in an in vitro assay
against a panel of recombinant RTs which included WT
RT and the P236L and Y181C mutant RTs. Compounds
were further tested in cell culture against resistant virus
selected by serial passage in the presence of delavirdine
or Merck’s L-697,661. Table 1 presents the results of
the in vitro RT assay against the panel of RTs for a
variety of alkylpyridine analogues as well as for three
parent (alkylamino)pyridine congeners (2, 31, 32). Sev-
eral trends can be discerned from these results. For
example, analogues containing the 3-alkyl substituent
retain activity comparable to that of the parent in the
assays against the P236L mutant or WT RT. However,
potency against the Y181C mutant RT is less than that
of the alkylamino counterparts (e.g., comparison of
compound 2 to 13 and comparison of compound 15 to
32). In addition, the (ethylamino)piperidine-linked ana-
logues are more potent against P236L and Y181C
mutant RTs than the corresponding (methylamino)-
piperidine-linked compounds (21 vs 20 and 15 vs 13).
This trend was observed previously in the 3-(alkylami-
no)pyridine series.12 (Propylamino)piperidine-linked com-
pound 22 was 2-fold less potent than the analogous
(ethylamino)piperidine 21 against P236L and Y181 RTs.
Table 2 shows the effect of placing oxygen atoms in
the 3-alkylpyridine side chain. (Methylamino)piperidine
27 which contains a methyl ether in the 3-pyridine side
chain lost considerable potency against P236L and
Y181C RTs as compared to its WT potency. On the other
hand, the analogous (ethylamino)pyridine compound 28
retained good potency against all three enzymes and
compared favorably to the n-propyl compound 14. The
presence of an ester at the 3-position, as in compound
29, was not well tolerated by the P236L and Y181C RT
enzymes. Last, a 3-hydroxymethyl-substituted pyridine
30 exhibited decreased activity for all three enzymes
as compared to the corresponding ethyl-substituted
pyridine 21.
Syn th esis
Synthesis of the desired 3-alkylpyridine analogues
was straightforward and began with 2-bromo-3-formylpy-
ridine (7) which was available according to literature
precedent via deprotonation of 2-bromopyridine with
lithium diisopropylamide and subsequent quenching of
the resulting anion with dimethylformamide (Scheme
1).16 Nucleophilic aromatic substitution of 7 with an
(alkylamino)piperidine in the presence of N-ethyldiiso-
propylamine base at 100 °C in a sealed tube provided
compounds 9a and 9b. Olefination and subsequent
reduction served to introduce the desired 3-alkyl sub-
stituent while simultaneously deprotecting the piperi-
dine. Coupling to 5-methanesulfonamidoindole-2-car-
boxylic acid afforded compounds 12-15. Alternatively,
a BOC group could be employed as a protecting group
for the piperidine nitrogen (see Experimental Section
for preparation of compound 13).
In an effort to avoid the synthesis of the 2-bromo-3-
formylpyridine and improve upon the previous route,
we investigated an alternate route which employed the
commercially available 2-bromo-3-cyanopyridine (16) as
a partner in the nucleophilic aromatic substitution
(Scheme 2). Reaction of the desired (alkylamino)piperi-
dine spacer groups with the cyanopyridine was con-
ducted neat at 115-120 °C and resulted in moderate
yields of the desired products. Elaboration of the cyano
group was accomplished by treatment with methyl-
lithium to provide the methyl ketones 18a -c which
were reduced under Wolff-Kischner conditions to pro-
vide the 3-ethylpyridine intermediates 19a -c in good
yields. Deprotection and coupling with the desired
substituted indole-2-carboxylic acid under previously
described conditions provided analogues 20-22.
Antiviral activities of selected 3-alkylpyridine AAP-
BHAPs and comparator compounds (delavirdine (1),
L-697,661, and 2) against BHAP and L-drug-resistant
viral strains are presented in Table 3.12 Three of the
five 3-alkylpyridine-substituted compounds tested pos-
sessed good activities against the delavirdine and L-
drug-resistant viruses. Compounds 14 and 15, contain-
In addition to the alkyl-substituted pyridine ana-
logues described above, we also prepared some ana-

4142 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Genin et al.
Sch em e 1
Sch em e 2
Sch em e 3
ing the (ethylamino)piperidine, were the most potent
against the viruses tested and confirmed the importance
of this substituent in conferring enhanced potency over
that observed for the (methylamino)piperidine homo-
logues. The two compounds that demonstrated the
weakest activities against the Y181C RT-containing
virus each had a (methylamino)piperidine and either
an 3-alkyl ether (27) or a 3-isobutyl (13) pyridine
substituent.
Next, compounds of interest were evaluated for in
vitro metabolic stability in the presence of hepatic
cytochrome P450 (Table 4). Clinical candidates atevir-

Synthesis and SAR of AAP-BHAPs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4143
Sch em e 4
Ta ble 1. RT Inhibitory Activities of AAP-BHAP Analogues
Ta ble 3. Antiviral Activities of Selected Compounds against
Containing a 3-Alkylpyridine
Resistant Viruses
EC90 (µM)a
U-90152R
HIV-1MF
U-90152R
HIV-1IIIB
L-697,661R
HIV-1IIIB
b
b
c
no.
(P236L)
(L100I, M230L)
(Y181C)
1
>10
0.43
5.3
1.8
0.10
1.0
>10
4.0
NT
NT‘
0.04
0.03-0.05
NT
5.2
>10
1.0
d
0.09
0.03-0.1
f
IC (µM)a
L-697,661
2
no.
R
R′
WT
P236L
Y181C
13
14
15
27
28
1 (delavirdine)
2
0.26
0.50
0.43
0.25
0.061
b
0.51
0.098
0.27
0.41
0.13
18.0
1.5
0.36
0.17
1.1
b
1.1
0.21
0.37
0.43
0.54
8.32
1.1
0.39
0.40
2.0
b
2.6
0.43
0.45
0.88
0.91
CH3
Et
Et
CH3
CH3
CH3
Et
Et
Et
nPr
NH-iPr
NHEt
NH-iPr
Et
nPr
iBu
Et
nPr
iBu
Et
31
32
20
12
13
21
14
15
22
e
0.77
NT
1.0
a
EC90, concentration of drug that inhibited p24 production in
b
the antiviral assay by 90%. Delaviridine was used for the
selection of BHAP-resistant MF and IIIB HIV-1 variants as
described in ref 12. c L-697,661 was used for the selection of the
L-drug-resistant IIIB HIV-1 variant. EC50 ) >1 µM. e EC50
)
d
0.3-3 µM. f EC50 ) >3 µM. NT, not tested.
a
Ta ble 4. In Vitro t1/2 of Selected Compounds
RNA-dependent DNA polymerase activity of mutant RTs was
assayed as described in the Experimental Section of ref 12 using
poly(rA)600:oligo(dT)10 as template:primer. IC50 values were de-
termined by nonlinear least-squares fit of data from duplicate
no.
t1/2 (min)a
Atevirdine (PNU-87201)
1
2
13
14
15
14.7
10.8
1.40
5.90
1.68
2.29
b
points at 6 drug concentrations. At 1 µM compound 12 exhibited
the following percent inhibitions: WT ) 84%; P236L ) 40%;
Y181C ) 25%.
Ta ble 2. RT Inhibitory Activities of Compounds Containing
Oxygen in the 3-Alkylpyridine Side Chain
a
Half-life of parent compound upon microsomal incubation in
the presence of hepatic microsomal cytochrome P450 (see Experi-
mental Section of ref 12 for a description of the assay).
substituted compounds containing the (ethylamino)-
piperidine linker were metabolized more quickly than
those containing the (methylamino)piperidine linker (15
vs 13).17 The analogue with a 3-propylpyridine substitu-
ent was metabolically less stable than the one which
contained a 3-isobutylpyridine substituent (14 vs 15).
The in vivo administration of 13 and 14 to rats allowed
determination of the systemic clearances and oral
bioavailabilities and confirmed the in vitro metabolic
results (Table 5).
The systemic clearances of compounds 2 and 13 were
the same (Table 5). However, oral bioavailability of 13,
the alkylpyridine AAP-BHAP, was better than that of
2. Comparison of a 15 mg/kg oral dose of 13 to the 30
mg/kg oral dose indicated nonlinear pharmacokinetic
behavior (data not shown). Since the volumes of distri-
bution (Vss) for 2 and 13 were also similar, it is likely
that differences in the nonlinear pharmacokinetics are
responsible for the differences in bioavailabilities ob-
IC50 (µM)a
no.
R
R′
WT
P236L
Y181C
27
29
28
30
CH3
CH3
CH2CH3
CH3
CH2OCH3
C(O)OCH3
CH2OCH3
CH2OH
0.14
0.25
0.14
b
6.8
13
0.30
b
11
21
0.84
b
a
RNA-dependent DNA polymerase activity of mutant RTs was
assayed as described in the Experimental Section of ref 12. IC50
values were determined by nonlinear least-squares fit of data from
duplicate points at 6 drug concentrations. At 50 µM compound
30 exhibited the following percent inhibitions: WT ) 50%; P236L
) 7%; Y181C ) 15%.
b
dine and delavirdine (1) were run as comparator com-
pounds. The in vitro metabolism data indicates that, in
general, the 3-alkylpyridine AAP-BHAPs possess half-
lives substantially shorter than 1. As in the 3-(alkyl-
amino)pyridine AAP-BHAP series, 3-alkylpyridine-

4144 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Genin et al.
Ta ble 5. Selected Pharmacokinetic Parameters of 3-Alkylpyridine AAP-BHAPs and Selected Comparator Compounds in Male
Sprague-Dawley Ratsa
dose (mg/kg)
IV clearance
(mL/min/kg)
absolute oral
bioavailability (%)
no.
iv
14
po
VSS (L/kg)
IVt1/2â (h)
1
15
28
30.2
30.3
30
1.21 ( 0.11
1.00 ( 0.096
13.6 ( 0.3
64 ( 8
169 ( 25b
4.3 ( 4.2
64 ( 7
14
2
13
14
15
15.2
15
2.5 ( 0.4
2.73 ( 0.22
3.2 ( 0.5
0.67 ( 0.026
0.89 ( 0.04
0.82 ( 0.12
44 ( 6
45 ( 4
67 ( 4
9.8
a
Compounds were administered as solutions in propylene glycol/water (80/20, v/v) acidified with a molar excess of methanesulfonic
b
acid. Doses were administered to fasted animals in a crossover design with a 1-week washout period between treatments (N ) 3). The
nonlinear pharmacokinetics of 1 (PNU-90152) result in an apparent bioavailability >100%. VSS, steady-state volume of distribution;
IVt1/2â, apparent terminal disposition half-life.
diisopropylethylamine (0.92 mL, 5.3 mmol) were heated in a
sealed tube at 100 °C for 2 days. The reaction was cooled and
partitioned between H2O and CHCl3. The organic layer was
washed with brine and dried (Na2SO4). The solvent was
removed in vacuo and the residue was chromatographed on a
2- × 40-cm column with EtOAc/hexane (1:3 to 1:1). The product
was isolated as an oil (0.44 g, 26%): 1H NMR (CDCl3) δ 0.90
(t, 3H), 1.55-1.64 (m, 2H), 1.68-1.83 (m, 4H), 2.69-2.75 (m,
2H), 3.15-3.25 (m, 1H), 3.29 (s, 2H), 3.33 (q, 2H), 6.68 (dd,
1H), 7.03-7.16 (m, 5H), 7.81 (dd, 1H), 8.20 (dd, 1H); MS (EI)
m/z (rel intensity) 323 (M+, 3), 294 (11), 173 (35), 172 (83),
152 (8), 151 (80), 146 (9), 92 (12), 91 (99), 82 (11), 41 (11).
HRMS (EI) calcd for C20H25N3O: 323.1997. Found: 323.1997.
1-Ben zyl-4-(N-m eth yl-N-(3-for m yl-2-p yr id in yl)a m in o)-
p ip er id in e (9a ). Prepared as described above for 9b using
2-bromo-3-formylpyridine (5.0 g, 26.9 mmol), 1-benzyl-4-(me-
thylamino)piperidine12 (5.49 g, 26.9 mmol), and diisopropyl-
ethylamine (4.7 mL, 26.9 mmol). The product was isolated as
an oil (3.4 g, 41%): 1H NMR (CDCl3) δ 1.80-1.86 (m, 2H),
1.94-2.07 (m, 2H), 2.09-2.18 (m, 2H), 2.99 (s, 3H), 3.00-3.05
(m, 2H), 3.57 (s, 2H), 3.99-4.09 (m, 1H), 6.81 (dd, 1H), 7.27-
7.40 (m, 5H), 7.99 (dd, 1H), 8.34 (dd, 1H); MS (EI) m/z (rel
intensity) 309 (M+, 3), 280 (9), 173 (32), 172 (97), 137 (60), 92
(12), 91 (99), 82 (13), 65 (8), 43 (8), 41 (12). HRMS (EI) calcd
for C19H23N3O: 309.1841. Found: 309.1845.
1-ter t-Bu t oxyca r b on yl-4-(N-m et h yl-N-(3-for m yl-2-p y-
r id in yl)a m in o)p ip er id in e. Prepared as described above for
9b using 2-bromo-3-formylpyridine (2.67 g, 14.4 mmol), 1-tert-
butoxycarbonyl-4-(methylamino)piperidine (2.8 g, 13.1 mmol),
and diisopropylethylamine (2.3 mL). The product was isolated
as an oil which solidified on standing (2.0 g, 48%): mp 90-91
°C; MS (EI) m/z (rel intensity) 319 (M+, 8), 290 (36), 246 (14),
234 (25), 161 (20), 137 (50), 108 (15), 82 (21), 57 (99), 41 (16),
40 (32). HRMS (EI) calcd for C17H25N3O3: 319.1896. Found:
319.1909.
1-Ben zyl-4-(N-m eth yl-N-(3-(p r op en -1-yl)-2-p yr id in yl)-
a m in o)p ip er id in e (10a ). n-BuLi (1.6 M, 1.51 mL, 2.42 mmol)
was added to a suspension of ethyltriphenylphosphonium
bromide (0.9 g, 2.42 mmol) in dry THF. The reaction was
stirred for 45 min at room temperature under N2 before a
solution of 9a (0.5 g, 1.62 mmol) in dry THF was added. The
reaction was stirred an additional 30 min before being
quenched with water and extracted with CHCl3. The extracts
were washed with brine and dried (Na2SO4). Removal of
solvent gave a residue which was purified by flash chroma-
tography eluting with EtOAc/hexane (1:3 to 1:1). The product
was isolated as an oil which was a 2:3 ratio of geometrical
isomers (0.47 g, 90%): 1H NMR (CDCl3) δ 8.05 (dd, J ) 1.8,
4.8 Hz, 1H), 7.49 (dd, J ) 1.8, 7.5 Hz, 0.4H), 7.33 (dd, J ) 1.7,
7.4 Hz, 0.6H), 7.23 (m, 5H), 6.71 (m, 1H), 3.32 (d, J ) 15.9
Hz, 0.4H), 6.20 (d, J ) 11.3 Hz, 0.6 H), 6.05 (dq, J ) 6.5, 15.9
Hz, 0.4H), 5.70 (dq, J ) 7.0, 11.3 Hz, 0.6H), 3.44 (m, 0.6H),
3.40 (s, 2H), 3.31 (m, 0.4H), 2.86 (m, 2H), 2.74 (s, 0.6H), 2.72
(s, 0.4H), 1.91-1.75 (m, 7H), 1.57(m, 2H); MS (EI) m/z (rel
intensity) 321 (M+, 28), 321 (28), 230 (27), 174 (25), 173 (99),
172 (45), 149 (25), 92 (11), 91 (99), 82 (18). HRMS (EI) calcd
for C21H27N3: 321.2205. Found: 321.2220.
served for the 30 mg/kg oral dose. Such nonlinearity was
also observed for delavirdine but to a much greater
degree (Table 5). Compound 14 possessed increased
clearance and decreased oral bioavailability relative to
compound 13. Thus the short half-lives (IV t1/2â) ob-
served for compounds 2, 13, and 14 in the in vitro liver
microsome assay are correlated with the high IV clear-
ances observed in vivo.
Con clu sion s
A variety of 3-alkylpyridine-substituted AAP-BHAPs
were successfully synthesized. In general, compounds
containing a 3-ethyl-, n-propyl-, or isobutylpyridine
substituent were active against the P236L, Y181C, and
WT RTs. However, relative to their 3-ethylamino or
3-isopropylamino counterparts, these compounds dem-
onstrated a slight reduction in activities against the
P236L and WT RTs, whereas the reduction in activity
against the Y181C RT was more pronounced. Com-
pounds containing an ether or ester in the 3-alkyl side
chain were significantly less active against all three
enzymes, except in the case of compound 28, an (ethyl-
amino)piperidine containing a 3-(methoxymethyl)pyri-
dine. The antiviral activities observed in cell culture
assays for selected compounds (13-15, 28) were con-
sistent with their relative potencies measured in the in
vitro RT assays. Several compounds were selected for
evaluation in an in vitro liver microsome assay. While
one compound, 13, possessed a half-life 4.2 times longer
than that of 2 (PNU-92884), the AAP-BHAP containing
a 3-(isopropylamino)pyridine, none of the compounds
possessed half-lives as long as delavirdine. Administra-
tion (iv and po) of compounds 13 and 14 to rats indicated
that these compounds both had high clearances relative
to delavirdine. Only the 3-isobutylpyridine analogue 13
had an oral bioavailability which approached that of
delavirdine.
Ma ter ia ls a n d Meth od s
Flash chromatography utilized E. Merck silica gel (230-
400 mesh) unless otherwise indicated. 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, Analyti-
cal and Medicinal Chemistry Department of Pharmacia and
Upjohn. Unless otherwise indicated, proton NMR spectra were
recorded with a Brucker Aspect 3000 300-MHz spectrometer.
Tetrahydrofuran (THF) was distilled from sodium and ben-
zophenone. All other solvents were Burdick and J ackson or
Fisher reagent grade.
1-Ben zyl-4-(N-eth yl-N-(3-for m yl-2-p yr id in yl)a m in o)p i-
p er id in e (9b). 2-Bromo-3-formylpyridine16 (0.98 g, 5.3 mmol),
1-benzyl-4-(ethylamino)piperidine12 (1.15 g, 5.3 mmol), and
1-Ben zyl-4-(N-m et h yl-N-(3-(2-m et h ylp r op yl-1-en e)-2-
p yr id in yl)a m in o)p ip er id in e (10b). Prepared in a manner

Synthesis and SAR of AAP-BHAPs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4145
analogous to 10a using n-BuLi (1.6 M, 8.1 mL, 12.93 mmol),
isopropyltriphenylphosphonium iodide (5.6 g, 12.93 mmol), and
9a (2.0 g, 6.5 mmol). The product was isolated as an oil (1.7 g,
78%): 1H NMR (CDCl3) δ 1.55-1.65 (m, 2H), 1.74 (s, 3H),
1.79-1.85 (m, 2H), 1.85 (s, 3H), 2.75 (s, 3H), 2.87-2.90 (m,
2H), 3.40-3.48 (m, 1H), 3.42 (s, 2H), 5.97 (s, 1H), 6.69 (dd,
1H), 7.16-7.28 (m, 6H), 8.04 (dd, 1H).
1-Ben zyl-4-(N-et h yl-N-(3-(1-p r op ylen e)-2-p yr id in yl)-
a m in o)p ip er id in e (10c). Prepared as above for 10a making
noncritical variations using n-BuLi (1.6 M, 1.16 mL, 1.86
mmol), ethyltriphenylphosphonium bromide (0.69 g, 1.86
mmol), and 9b (0.40 g, 1.24 mmol). The product was isolated
as an oil in a 2:3 ratio of geometrical isomers (0.40 g, 96%):
1H NMR (CDCl3) δ 8.15 (dd, J ) 2.0, 4.8 Hz, 1H), 7.60 (dd, J
) 2.0, 7.5 Hz, 0.4H), 7.43 (dd, J ) 1.7, 7.4 Hz, 0.6H), 7.30-
7.20 (m, 5H), 6.83 (dd, J ) 4.8, 7.5 Hz, 0.4H), 6.79 (dd, J )
4.8, 7.4 Hz, 0.6H), 6.50 (d, J ) 15.8 Hz, 0.4H), 6.29 (d, J )
11.4 Hz, 0.6H), 6.11(dd, J ) 6.6, 15.8 Hz, 0.4H), 5.76 (dq, J )
7.1, 11.4 Hz, 0.6H), 3.45 (s, 2H), 3.30 (m, 2H), 3.26 (m, 1H),
2.87 (m, 2H), 1.95-1.60 (m, 9H), 0.92 (m, 3H); MS (EI) m/z
(rel intensity) 335 (M+, 9), 244 (13), 217 (17), 178 (20), 174
(19), 173 (69), 172 (26), 146 (20), 135 (14), 92 (19), 91 (99).
HRMS (EI) calcd for C22H29N3: 335.2361. Found: 335.2368.
1-Ben zyl-4-(N-eth yl-N-(3-(2-m eth ylp r op yl-1-en e)-2-p y-
r id in yl)a m in o)p ip er id in e (10d ). Prepared in a manner
analogous to 10a using n-BuLi (1.6 M, 4.3 mL, 6.8 mmol),
isopropyltriphenylphosphonium iodide (2.9 g, 6.8 mmol), and
9b (1.1 g, 3.4 mmol). The product was isolated as an oil (0.67
g, 56%): 1H NMR (CDCl3) δ 1.08 (t, 3H), 1.71-1.80 (m, 2H),
1.90 (s, 3H), 1.90-2.00 (m, 2H), 2.01 (s, 3H), 2.98-3.03 (m,
2H), 3.30-3.45 (m, 1H), 3.43 (q, 2H), 3.57 (s, 2H), 6.18 (s, 1H),
6.89 (dd, 1H), 7.32-7.45 (m, 5H), 7.46 (dd, 1H), 8.24 (dd, 1H);
MS (EI) m/z (rel intensity) 349 (M+, 8), 278 (21), 277 (40), 263
(20), 262 (99), 184 (17), 183 (79), 173 (44), 108 (36), 107 (19),
91 (45). HRMS (EI) calcd for C23H31N3: 349.2518. Found:
349.2516.
1-ter t-Bu t oxyca r b on yl-4-(N-m et h yl-N-(3-isobu t ylen e-
2-p yr id in yl)a m in o)p ip er id in e. Prepared in a manner analo-
gous to 10b using n-BuLi (1.6 M, 3.9 mL, 6.26 mmol),
isopropyltriphenylphosphonium iodide (2.71 g, 6.26 mmol), and
1-tert-butoxycarbonyl-4-(N-methyl-N-(3-formyl-2-pyridinyl)-
amimo)piperidine (1.0 g, 3.13 mmol). The product was isolated
as an oil (1.05 g, 97%): 1H NMR (CDCl3) δ 1.30 (s, 9H), 1.50-
1.59 (m, 2H), 1.64 (s, 3H), 1.75 (s, 3H), 2.42-2.50 (m, 2H), 2.61
(s, 3H), 3.40-3.50 (m, 1H), 3.95-4.06 (m, 1H), 5.88 (s, 1H),
6.62 (dd, 1H), 7.18 (dd, 1H), 7.95 (dd, 1H).
1-[5-Me t h a n e su lfon a m id oin d ol-2-ylca r b on yl]-4-(N -
m eth yl-N-(3-p r op yl-2-p yr id in yl)a m in o)p ip er id in e (12).
To a stirred solution of 10a (0.35 g, 0.11 mmol) in MeOH (50
mL) was added 10% Pd(OH)2-C (100 mg) and the resulting
mixture was hydrogenated at 40 psi overnight. The resulting
mixture was filtered through Celite and the solvent was
evaporated to afford a brown oil (117 mg, 0.05 mmol) which
was contaminated with unreacted N-benzylalkane-reduced
material. The resulting oil was taken up in CH2Cl2/THF/DMF
(10/5/2 v/v/v 17 mL), the temperature was reduced to 0 °C,
and the resulting solution was treated with 5-methanesulfona-
midoindole-2-carboxylic acid (0.13 g 0.05 mmol) and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC;
0.097 g, 0.05 mmol). The mixture was stirred overnight
allowing the solution to warm to ambient temperature. The
resulting mixture was poured into H2O (50 mL) and extracted
with EtOAc (3 × 25 mL). The organic layers were combined,
dried over Na2SO4, and concentrated in vacuo. The resulting
residue was purified by flash column chromatography with
EtOAc/hexane to yield pure product as a foam: 1H NMR
(CDCl3) δ 10.36 (s, 1H), 8.10 (dd, J ) 1.8, 4.8 Hz, 1H), 7.73 (s,
1H), 7.51 (d, J ) 1.7 Hz, 1H), 7.39 (dd, J ) 1.8, 7.5 Hz, 1H),
7.30 (d, J ) 8.7 Hz, 1H), 7.07 (dd, J ) 2.0, 8.8 Hz, 1H), 6.83
(dd, J ) 4.8, 7.5 Hz, 1H), 6.62 (d, J ) 1.4 Hz, 1H), 4.60 (d, J
) 12.8 Hz, 2H), 3.48 (m, 1H), 3.07 (br, 2H), 2.85 (s, 3H), 2.61
(s, 3H), 2.52 (m, 2H), 1.85 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H),
0.87 (t, J ) 7.3 Hz, 3H); MS (EI) m/z (rel intensity) 469 (M+,
7), 190 (84), 189 (99), 175 (49), 158 (44), 157 (71), 151 (97),
149 (68), 130 (91), 96 (64), 82 (53). HRMS (EI) calcd for
C24H31N5O3S: 469.2148. Found: 469.2138. Anal. (C24H31N5O3S‚
1.5H2O) C, N; H: calcd, 6.90; found, 6.28.
1-ter t-Bu toxyca r bon yl-4-(N-m eth yl-N-(3-(2-m eth ylp r o-
p yl)-2-p yr id in yl)a m in o)p ip er id in e. 1-tert-Butoxycarbonyl-
4-(N-methyl-N-(3-isobutylene-2-pyridinyl)amino)piperidine (1.07
g, 3.1 mmol) was hydrogenated on a Parr shaker at 20 psi of
hydrogen overnight using 10% Pd/C (0.1 g) as catalyst. The
reaction was filtered and the solvent was evaporated in vacuo
to an oil which was used without further purification (1.08 g,
100%): 1H NMR (CDCl3) δ 0.66 (d, 6H), 1.25 (s, 9H), 1.34-
1.42 (m, 2H), 1.50-1.56 (m, 2H), 1.72-1.81 (m, 1H), 2.28 (d,
2H), 2.46 (s, 3H), 2.50-2.56 (m, 2H), 3.50-3.13 (m, 1H), 3.88
(br, 2H), 6.70 (dd, 1H), 7.21 (dd, 1H), 7.98 (dd, 1H).
1-[5-Me t h a n e su lfon a m id oin d ol-2-ylca r b on yl]-4-(N -
m eth yl-N-(3-(2-m eth ylp r op yl)-2-p yr id in yl)a m in o)p ip er i-
d in e (13). 1-tert-Butoxycarbonyl-4-(N-methyl-N-(3-(2-meth-
ylpropyl)-2-pyridinyl)amino)piperidine (1.08 g, 3.1 mmol) was
deprotected in 4 N HCl/dioxane for 15 min. The solvent was
removed in vacuo and the residue was taken up in CH2Cl2 and
stripped of solvent. The foam was dried under high vacuum
for 1 h. In a separate flask a solution of 5-methanesulfonami-
doindole-2-carboxylic acid (1.6 g, 6.2 mmol) and CDI (1.0 g,
6.2 mmol) were stirred for 1 h in dry THF. This was cooled to
0 °C and a solution of the above foam and NEt3 (0.45 mL, 3.2
mmol) in dry THF was added. The reaction was stirred at room
temperature overnight and partitioned between CHCl3 and 1
N NaOH. The organic layer was washed with brine, dried (Na2-
SO4), and concentrated in vacuo. Purification by flash column
chromatography with EtOAc afforded the product as a white
1
solid (0.7 g, 67%): mp 200-201 °C; H NMR (CDCl3) δ 9.58
(s, 1H), 8.21 (dd, J ) 1.9, 4.8 Hz, 1H), 7.57 (m, 1H), 7.55 (m,
1H), 7.39 (d, J ) 8.7 Hz, 1H), 7.14 (dd, J ) 1.9, 7.5 Hz, 1H),
6.93 (dd, J ) 4.8, 7.5 Hz, 1H), 6.74 (m, 2H), 4.67 (d, J ) 13.3
Hz, 2H), 3.55 (m, 1H), 3.20 (br, 2H), 2.95 (s, 3H), 2.69 (s, 3H),
2.51 (d, J ) 7.3 Hz, 2H), 1.97 (m, 3H), 1.69 (m, 2H), 0.87 (d, J
) 6.6 Hz, 6H). Anal. (C25H33N5O3S‚0.2H2O) C, H, N.
1-[5-Meth an esu lfon am idoin dol-2-ylcar bon yl]-4-(N-eth yl-
N-(3-p r op yl-2-p yr id in yl)a m in o)p ip er id in e (14). 10c (0.60
g, 1.8 mmol) was reduced and deprotected simultaneously on
a Parr Shaker at 40 psi of H2 in MeOH for 24 h using Pd-
(OH)2-C (0.1 g). The reaction was filtered and concentrated
in vacuo to afford an oil: 1H NMR (CDCl3) δ 8.01 (dd, J ) 1.9,
4.7 Hz, 1H), 7.28 (dd, J ) 1.9, 7.5 Hz, 1H), 6.74 (dd, J ) 4.7,
7.5 Hz, 1H), 3.10-2.90 (m, 7H), 2.41 (m, 4H), 1.62 (m, 2H),
1.42 (m, 2H), 0.76 (t, J ) 7.3 Hz, 3H), 0.71 (t, J ) 7.0 Hz, 3H).
In a separate flask CDI (0.33 g, 2.04 mmol) and 5-methane-
sulfonamidoindole-2-carboxylic acid (0.52 g, 2.04 mmol) were
stirred in dry THF at room temperature for 1 h. This solution
was then cooled to 0 °C, a solution of the above oil (0.27 g,
1.03 mmol) in dry THF was added, and the reaction was stirred
at room temperature overnight. The reaction was partitioned
between 0.5 N NaOH and CHCl3. The organic layer was
washed with brine and dried (Na2SO4). The solvent was
removed in vacuo and the residue was purified by flash column
chromatography with EtOAc/hexane (50% to 100% EtOAc).
The product was isolated as a foam (0.32 g, 65%): 1H NMR
(CDCl3) δ 9.59 (s, 1H), 8.16 (dd, J ) 1.9, 4.7 Hz, 1H), 7.51 (m,
1H), 743 (dd, J ) 1.9, 7.5 Hz, 1H), 7.32 (d, J ) 8.6 Hz, 1H),
7.07 (dd, J ) 2.1, 8.7 Hz, 1H), 6.89 (dd, J ) 4.7, 7.5 Hz, 1H),
6.76 (s, 1H), 6.65 (m, 1H), 4.58 (d, J ) 13.5 Hz, 2H), 3.36 (m,
1H), 3.12 (q, J ) 7.1 Hz, 2H), 2.88 (s, 3H), 2.56 (m, 2H), 1.88
(m, 2H), 1.72-1.50 (m, 5H), 0.88 (t, J ) 7.3 Hz, 3H), 0.83 (t,
J ) 7.1 Hz, 3H); MS (EI) m/z (rel intensity) 483 (M+, 8), 203
(39), 201 (26), 189 (26), 165 (27), 164 (22), 163 (99), 158 (26),
157 (41), 130 (58), 82 (27). HRMS (EI) calcd for C25H33N5O3S:
483.2304. Found: 483.2303. Anal. (C25H33N5O3S‚1.0H2O) C,
H; N: calcd, 13.96; found, 13.51.
1-[5-Meth an esu lfon am idoin dol-2-ylcar bon yl]-4-(N-eth yl-
N-(3-(2-m eth ylpr opyl)-2-pyr idin yl)am in o)piper idin e (15).
Prepared in a manner analogous to 12 using 10d (0.67 g, 1.92
mmol) and Pearlman’s catalyst (0.1 g) to afford the amine: 1H
NMR (CDCl3) δ 8.00 (dd, J ) 1.9, 4.8 Hz, 1H), 7.24 (dd, J )
1.9, 7.4 Hz, 1H), 6.72 (dd, J ) 4.8, 7.4 Hz, 1H), 5.31 (br, 1H),

4146 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Genin et al.
3.02 (m, 4H), 2.80 (m, 1H), 2.50 (m, 2H), 2.29 (m, 2H), 1.85
(m, 1H), 1.75-1.50 (m, 4H), 0.68 (d, J ) 6.5 Hz, 6H), 0.68 (t,
3H). The amine was coupled with 5-methanesulfonamidoin-
dole-2-carboxylic acid (0.53 g, 2.06 mmol) using 1,1′-carbon-
yldiimidazole (CDI; 0.33 g, 2.06 mmol). The product was
isolated as a foam (0.31 g, 60%): 1H NMR (CDCl3) δ 9.73 (s,
1H), 8.14 (dd, J ) 1.8, 4.8 Hz, 1H), 7.47 (m, 1H), 7.38((m, 1H),
7.28 (d, J ) 8.7 Hz, 1H), 7.05 (dd, J ) 2.0, 8.7 Hz, 1H), 6.86
(dd, J ) 4.8, 7.4 Hz, 1H), 6.60 (m, 1H), 4.58 (br d, 2H), 3.35
(br m, 1H), 3.11 (q, J ) 7.0 Hz, 2H), 2.84 (s, 3H), 2.41 (d, J )
7.3 Hz, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.61 (m, 2H), 0.83 (t,
J ) 7.0 Hz, 3H), 0.77 (d, J ) 6.6 Hz, 6H); MS (EI) m/z (rel
intensity) 497 (M+, 27), 497 (27), 468 (26), 440 (24), 218 (27),
217 (44), 215 (31), 179 (27), 177 (99), 157 (25), 130 (29). HRMS
calcd for C26H35N5O3S: 497.2460. Found: 497.2472. Anal.
(C26H35N5O3S‚0.5H2O) C, H, N.
h, quenched with 2 N aqueous H2SO4 (3.9 mL), and stirred at
room temperature for 2 h. The biphasic mixture was then
adjusted to pH 10-11 with 5% aqueous NaOH and diluted
with Et2O (10 mL) and H2O (10 mL), and the layers were
separated. The aqueous phase was extracted with additional
Et2O (30 mL), and the combined organic phase was washed
with brine (10 mL), dried over anhydrous MgSO4, concentrated
in vacuo, and purified by flash column chromatography eluting
with ethyl acetate/hexane (50/50) to afford 0.99 g (78%) of the
product as a pale yellow solid: mp 93-94 °C; IR (mull, cm-1
)
2926 (s), 1674 (s), 1587 (s), 1541 (s), 1493 (s), 1410 (s), 1363
1
(s), 1239 (s); H NMR (CDCl3, 400 MHz) δ 8.22 (dd, J 1 ) 4.6
Hz, J 2 ) 2.0 Hz, 1H), 7.72 (dd, J 1 ) 7.5 Hz, J 2 ) 1.9 Hz, 1H),
7.33 (m, 4H), 7.26 (m, 1H), 6.67 (dd, J 1 ) 7.6 Hz, J 2 ) 4.7 Hz,
1H), 4.14 (m, 1H), 3.53 (s, 2H), 2.98 (bd, J ) 11.4 Hz, 2H),
2.74 (s, 3H), 2.51 (s, 3H), 2.12 (bd, J ) 11.1 Hz, 2H), 1.89 (m,
2H), 1.77 (m, 2H); EI-MS (m/z, rel abundance) 323 (M+, 1),
308 (1), 280 (9), 173 (34), 172 (38), 151 (100), 91 (81). Anal.
(C20H25N3O) C, H, N.
1-Ben zyl-4-(N-m eth yl-N-(3-cya n o-2-p yr id in yl)a m in o)-
p ip er id in e (17a ). A mixture of 8a (10.97 g, 53.7 mmol, 2
equiv) and 2-chloro-3-cyanopyridine (3.72 g, 26.8 mmol) were
placed in two sealed tubes and maintained at 115-120 °C for
2 h. The residue was diluted with CH2Cl2 (125 mL), washed
with H2O (2 × 50 mL) and brine (20 mL), dried over Na2SO4,
and concentrated in vacuo. The resulting semisolid was then
purified by flash column chromatography eluting with a
gradient of EtOAc/hexane (25/75-50/50) to afford 5.38 g (65%)
of the product as a pale yellow, low-melting solid: mp 58-60
°C; IR (mull, cm-1) 2950 (s), 2209 (s), 1584 (s), 1549 (s), 1500
1-Ben zyl-4-(N-eth yl-N-(3-a cetyl-2-p yr id in yl)a m in o)p i-
p er id in e (18b). Prepared in a manner analogous to 18a with
methyllithium (1.5 M in diethyl ether as complexed with
lithium bromide, 2.66 mL, 3.99 mmol) and 17b (640 mg, 2.00
mmol) to provide 634 mg (94%) of the product as a faint yellow,
partially crystalline oil: IR (neat, cm-1) 2961 (m), 2801 (m),
1682 (s), 1580 (s), 1427 (s), 1351 (m), 1285 (m), 1246 (m), 1093
(m), 1030 (m), 741 (m), 699 (m); 1H NMR (CDCl3, 400 MHz) δ
8.30 (dd, J 1 ) 4.8 Hz, J 2 ) 1.9 Hz, 1H), 7.66 (dd, J 1 ) 7.5 Hz,
J 2 ) 1.9 Hz, 1H), 7.30 (m, 4H), 7.27 (m, 1H), 6.81 (dd, J 1 ) 7.5
Hz, J 2 ) 4.7 Hz, 1H), 3.48 (s, 2H), 3.40 (m, 3H), 2.90 (m, 2H),
2.56 (s, 3H), 1.98 (m, 2H), 1.82 (m, 2H), 1.76 (m, 2H), 1.04 (t,
J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 202.5, 158.8,
149.5, 137.8, 129.1, 128.2, 127.1, 127.0, 115.2, 63.0, 61.2, 53.3,
39.4, 29.7, 28.2, 14.0; EI-MS (m/z, rel abundance) 337 (M+, 2),
294 (11), 246 (1), 217 (2), 173 (34), 165 (100), 91 (80). HRMS
calcd for C21H27N3O: 337.2154. Found: 337.2133.
1
(s), 1458 (m), 1413 (s), 1241 (m); H NMR (CDCl3, 400 MHz)
δ 8.27 (dd, J 1 ) 4.8 Hz, J 2 ) 2.0 Hz, 1H), 7.72 (dd, J 1 ) 7.6
Hz, J 2 ) 2.0 Hz, 1H), 7.33 (m, 4H), 7.28 (m, 1H), 6.61 (dd, J 1
) 7.6 Hz, J 2 ) 4.7 Hz, 1H), 4.42 (tt, J 1 ) 11.8 Hz, J 2 ) 4.0 Hz,
1H), 3.54 (s, 2H), 3.13 (s, 3H), 2.99 (bd, J ) 11.1 Hz, 2H), 2.16
(bt, J ) 11.3 Hz, 2H), 1.93 (m, 2H), 1.77 (m, 2H); EI-MS (m/z,
rel abundance) 306 (M+, 15), 173 (98), 146 (51), 91 (100), 82
(30). Anal. (C19H22N4) C, H, N.
1-Ben zyl-4-(N-eth yl-N-(3-cya n o-2-p yr id in yl)a m in o)p i-
p er id in e (17b). Prepared in a manner analogous to 17a using
8b (11.10 g, 50.8 mmol) and 2-chloro-3-cyanopyridine (3.52 g,
25.4 mmol) to afford 3.24 g (40%) of the product as a pale
yellow, viscous oil: IR (neat, cm-1) 2941 (m), 2802 (m), 2762
(m), 2208 (m), 1588 (s), 1547 (s), 1487 (s), 1445 (s), 1237 (s);
1H NMR (CDCl3, 400 MHz) δ 8.29 (dd, J 1 ) 4.7 Hz, J 2 ) 2.0
Hz, 1H), 7.72 (dd, J 1 ) 7.6 Hz, J 2 ) 2.0 Hz, 1H), 7.33 (m, 4H),
7.26 (m, 1H), 6.60 (dd, J 1 ) 7.6 Hz, J 2 ) 4.6 Hz, 1H), 4.47 (m,
1H), 3.66 (q, J ) 7.0 Hz, 2H), 3.53 (s, 2H), 2.98 (m, 2H), 2.16
(m, 2H), 1.93 (m, 2H), 1.80 (m, 2H), 1.21 (t, J ) 7.0 Hz, 3H);
EI-MS (m/z, rel abundance) 320 (M+, 15), 305 (1), 229 (3), 174
(23), 173 (77), 172 (37), 146 (29), 91 (100). Anal. (C20H24N4) C,
H, N.
1-Ben zyl-4-(N-p r op yl-N-(3-cya n o-2-p yr id in yl)a m in o)-
p ip er id in e (17c). Prepared in a manner analogous to 17a
using 8c (4.00 g, 17.2 mmol) and 2-chloro-3-cyanopyridine (1.19
g, 8.61 mmol). The resulting semisolid was then purified by
flash column chromatography eluting with a gradient of CH3-
OH/CH2Cl2 (1/99-2/98) to afford 894 mg (31%) of the product
as a pale yellow, viscous oil: IR (neat, cm-1) 2962 (m), 2208
(m), 1589 (s), 1547 (s), 1485 (s), 1442 (s), 1367 (m), 1234 (s);
1H NMR (CDCl3, 400 MHz) δ 8.28 (dd, J 1 ) 4.6 Hz, J 2 ) 2.0
Hz, 1H), 7.71 (dd, J 1 ) 7.6 Hz, J 2 ) 2.0 Hz, 1H), 7.34 (m, 4H),
7.26 (m, 1H), 6.61 (dd, J 1 ) 7.6 Hz, J 2 ) 4.7 Hz, 1H), 4.42 (m,
1H), 3.54 (s, 2H), 3.50 (m, 2H), 2.99 (m, 2H), 2.15 (m, 2H),
1.89 (m, 2H), 1.81 (m, 2H), 1.60 (sext, J ) 7.8 Hz, 2H), 0.92 (t,
J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 158.7, 151.9,
144.6, 129.2, 128.2, 127.1, 119.2, 112.1, 92.0, 63.1, 57.2, 53.2,
45.7, 30.4, 22.6, 10.9; EI-MS (m/z, rel abundance) 334 (M+, 4),
173 (43), 146 (13), 91 (100). HRMS (FAB) calcd for C21H26N4
+ H: 335.2236. Found: 335.2240.
1-Ben zyl-4-(N-p r op yl-N-(3-a cetyl-2-p yr id in yl)a m in o)-
p ip er id in e (18c). Prepared in a manner analogous to 18a
with methyllithium (1.5 M in diethyl ether as complexed with
lithium bromide, 2.52 mL, 3.77 mmol) and 17c (650 mg, 1.89
mmol) to afford 405 mg (61%) of the product as a faint yellow,
oily film. An additional 46 mg (7%) of slightly impure product
was also isolated: IR (neat, cm-1) 2960 (m), 1682 (s), 1581 (s),
1
1554 (m), 1425 (s), 1367 (m), 1261 (m); H NMR (CDCl3, 400
MHz) δ 8.28 (dd, J 1 ) 4.7 Hz, J 2 ) 1.9 Hz, 1H), 7.65 (d, J )
5.7 Hz, 1H), 7.31 (m, 4H), 7.27 (m, 1H), 6.80 (dd, J 1 ) 7.4 Hz,
J 2 ) 4.7 Hz, 1H), 3.49 (s, 2H), 3.40 (m, 1H), 3.30 (m, 2H), 2.92
(m, 2H), 2.56 (s, 3H), 1.98 (m, 2H), 1.88 (m, 2H), 1.75 (m, 2H),
1.46 (m, 2H), 0.85 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 202.7, 159.3, 149.8, 138.2, 129.5, 128.6, 127.4, 127.1,
115.4, 63.3, 62.6, 53.6, 46.8, 30.1, 28.5, 22.1, 12.0; EI-MS (m/
z, rel abundance) 351 (M+, 2), 308 (12), 179 (100), 173 (37),
172 (29), 91 (77). HRMS (FAB) calcd for C22H29N3O + H:
352.2389. Found: 352.2397.
1-Ben zyl-4-(N-m eth yl-N-(3-eth yl-2-p yr id in yl)a m in o)p i-
p er id in e (19a ). A mixture of 18a (260 mg, 0.804 mmol, 1
equiv), hydrazine monohydrate (0.78 mL, 16.1 mmol, 20 equiv),
and powdered KOH (0.90 g, 16.1 mmol, 20 equiv) in triethylene
glycol (16 mL) was stirred at 120 °C for 2 h. The condenser
was removed, the mixture was heated to approximately 185-
190 °C, the condenser was reattached, and the mixture was
stirred at 190 °C for 3 h. After cooling to room temperature,
the mixture was added to water (50 mL) and extracted with
CH2Cl2 (2 × 50 mL), and the organic phase was washed with
H2O (20 mL) and brine (20 mL), dried Na2SO4, concentrated
in vacuo, and purified by flash column chromatography eluting
with EtOAc/hexane (25/75-50/50) to afford 193 mg (78%) of
the product as a colorless, viscous oil: IR (neat, cm-1) 2942
(s), 2799 (m), 1584 (s), 1438 (s, br), 1410 (s), 1282 (m), 1083
1-Ben zyl-4-(N-m eth yl-N-(3-a cetyl-2-p yr id in yl)a m in o)-
p ip er id in e (18a ). To a flame-dried flask containing a mixture
of CH3Li (1.5 M in diethyl ether as complexed LiBr, 5.2 mL,
7.83 mmol, 2 equiv) in anhydrous Et2O (5.2 mL) at -78 °C
under N2 was added a solution of 17a (1.20 g, 3.92 mmol, 1
equiv) in anhydrous Et2O (5.3 mL) over 5 min. The resulting
mixture was allowed to warm to 0 °C over approximately 2.25
1
(m), 791 (m), 737 (m), 698 (m); H NMR (CDCl3, 400 MHz) δ
8.16 (m, 1H), 7.46 (d, J ) 9.0 Hz, 1H), 7.31 (m, 4H), 7.26 (m,
1H), 6.88 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz, 1H), 3.50 (bs, 2H),
3.15 (m, 1H), 2.92 (m, 2H), 2.73 (s, 3H), 2.63 (q, J ) 7.5 Hz,
2H), 2.00 (m, 2H), 1.82 (m, 2H), 1.73 (m, 2H), 1.23 (t, J ) 7.5

Synthesis and SAR of AAP-BHAPs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4147
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.0, 145.3, 138.9,
137.4, 132.4, 129.5, 128.5, 127.3, 118.4, 63.5, 59.8, 53.7, 34.7,
29.6, 24.3, 14.5; EI-MS (m/z, rel abundance) 309 (M+, 7), 280
(8), 173 (100), 91 (72). HRMS calcd for C20H27N3: 309.2205.
Found: 309.2222.
58.3, 45.0 (broad), 38.5, 35.8, 30.0, 23.9, 14.1; EI-MS (m/z, rel
abundance) (M+, 74), 440 (10), 426 (43), 240 (44), 189 (55), 176
(100), 175 (98), 157 (72), 130 (91). HRMS (FAB) calcd for
C23H29N5O3S + H: 456.2069. Found: 456.2073. Anal. (C23H29N5-
O3S‚2H2O) C, N; H: calcd, 6.77; found, 6.05.
1-Ben zyl-4-(N-et h yl-N-(3-et h yl-2-p yr id in yl)a m in o)p i-
p er id in e (19b). Prepared in a manner analogous to 19a with
18b (300 mg, 0.889 mmol), hydrazine monohydrate (0.86 mL,
17.8 mmol), and powdered potassium hydroxide (1.00 g, 17.8
mmol) to afford 207 mg (72%) of the product as a colorless,
viscous oil: IR (neat, cm-1) 2964 (s), 1583 (m), 1428 (s), 1092
(m); 1H NMR (CDCl3, 300 MHz) δ 8.20 (m, 1H), 7.47 (m, 1H),
7.30 (m, 5H), 6.92 (dd, J 1 ) 7.5 Hz, J 2 ) 4.8 Hz, 1H), 3.47 (s,
2H), 3.22 (q, J ) 7.0 Hz, 2H), 3.05 (m, 1H), 2.90 (m, 2H), 2.65
(q, J ) 7.5 Hz, 2H), 1.94 (m, 2H), 1.74 (m, 4H), 1.21 (t, J ) 7.5
Hz, 3H), 0.88 (t, J ) 7.0 Hz, 3H). Anal. (C21H29N3) C, H, N.
1-Ben zyl-4-(N-p r op yl-N-(3-eth yl-2-p yr id in yl)a m in o)p i-
p er id in e (19c). Prepared in a manner analogous to 19a with
18c (320 mg, 0.910 mmol), hydrazine monohydrate (0.88 mL,
18.2 mmol), and powdered KOH (1.02 g, 18.2 mmol) to afford
265 mg (86%) of the product as a colorless, viscous oil: IR
(neat, cm-1) 2961 (s), 1584 (m), 1455 (s), 1427 (s); 1H NMR
(CDCl3, 400 MHz) δ 8.19 (m, 1H), 7.48 (d, J ) 7.3 Hz, 1H),
7.31 (m, 4H), 7.27 (m, 1H), 6.91 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz,
1H), 3.49 (s, 2H), 3.16 (m, 2H), 2.93 (m, 3H), 2.65 (q, J ) 7.5
Hz, 2H), 1.95 (m, 2H), 1.82 (m, 2H), 1.59 (m, 2H), 1.29 (sext,
J ) 7.2 Hz, 2H), 1.22 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 161.3, 144.9, 137.0, 134.2, 129.2, 128.2, 127.0,
118.5, 63.1, 60.4, 53.4, 47.2, 29.6, 23.5, 21.5, 14.1, 11.8; EI-
MS (m/z, rel abundance) 337 (M+, 5), 308 (7), 173 (100), 91
(47). HRMS (FAB) calcd for C22H31N3 + H: 338.2596. Found:
338.2610.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
m eth yl-N-(3-eth yl-2-p yr id in yl)a m in o)p ip er id in e (20). A
mixture containing 19a (160 mg, 0.517 mmol, 1 equiv),
ammonium formate (98 mg, 1.55 mmol, 3 equiv), and 10% Pd/C
(160 mg) in CH3OH (10 mL) under N2 was degassed, heated
to reflux, and refluxed for 1 h. The catalyst was then removed
by filtration through Celite and the filtrate was concentrated
in vacuo to give 108 mg (96%) of the debenzylated intermediate
4-(N-methyl-N-(3-ethyl-2-pyridinyl)amino)piperidine as a col-
orless film: 1H NMR (CDCl3, 400 MHz) δ 8.15 (dd, J 1 ) 4.7
Hz, J 2 ) 1.7 Hz, 1H), 7.45 (dd, J 1 ) 7.4 Hz, J 2 ) 1.7 Hz, 1H),
6.88 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz, 1H), 3.24 (m, 1H), 3.13 (bd,
J ) 12.4 Hz, 2H), 2.72 (s, 3H), 2.62 (m, 4H), 2.26 (bs, 1H),
1.76 (m, 2H), 1.67 (m, 2H), 1.22 (t, J ) 7.6 Hz, 3H). To a flame-
dried flask under N2 were added 5-(methanesulfonylamino)-
indole-2-carboxylic acid (145 mg, 0.569 mmol, 1.15 equiv), CDI
(88 mg, 0.543 mmol, 1.10 equiv), and dry THF (3 mL) and the
mixture was stirred at room temperature for 1.5 h. Then a
solution of the intermediate (108 mg, 0.492 mmol, 1 equiv) in
dry THF (4 mL) was added and the resultant mixture was
stirred at room temperature for 19 h and concentrated in vacuo
to remove solvent. The residue was diluted CH2Cl2 (25 mL),
washed with H2O (10 mL), saturated aqueous NaHCO3 (10
mL), and brine (10 mL), dried over Na2SO4, concentrated in
vacuo, and flushed through a pad of silica gel (10 g), eluting
with CH3OH/CH2Cl2 (5/95); concentration in vacuo gave the
crude product which was purified by radial chromatography
(4000-µm silica gel plate), eluting with CH3OH/CH2Cl2 (5/95),
to give 166 mg (74%, 71% overall) of the product as a faint
yellow, amorphous solid. An additional 49 mg (22%) of slightly
impure product was also isolated: IR (mull, cm-1) 3253 (m),
2924 (s), 1598 (s), 1533 (s), 1447 (s), 1411 (s), 1325 (s), 1153
(s), 1012 (m), 975 (m), 806 (m), 760 (m); 1H NMR (CDCl3, 300
MHz) δ 10.38 (s, 1H), 8.20 (dd, J 1 ) 4.8 Hz, J 2 ) 1.8 Hz, 1H),
7.72 (s, 1H), 7.59 (d, J ) 1.8 Hz, 1H), 7.50 (dd, J 1 ) 7.6 Hz, J 2
) 1.8 Hz, 1H), 7.39 (d, J ) 8.7 Hz, 1H), 7.15 (dd, J 1 ) 8.8 Hz,
J 2 ) 2.0 Hz, 1H), 6.95 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz, 1H), 6.72
(d, J ) 1.5 Hz, 1H), 4.67 (bd, J ) 12.7 Hz, 2H), 3.57 (m, 1H),
3.17 (bm, 2H), 2.94 (s, 3H), 2.71 (s, 3H), 2.67 (q, J ) 7.5 Hz,
2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.24 (t, J ) 7.5 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 162.3, 162.1, 145.1, 137.5, 134.3,
132.6, 130.7, 129.6, 127.6, 120.7, 118.9, 115.9, 112.9, 105.0,
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
eth yl-N-(3-eth yl-2-p yr id in yl)a m in o)p ip er id in e (21). Pre-
pared in a manner analogous to 20 using 19b (144 mg, 0.445
mmol), ammonium formate (84 mg, 1.34 mmol), and 10% Pd/C
(140 mg) in CH3OH (9 mL) afforded 98 mg (94%) of the
debenzylated intermediate 4-(N-ethyl-N-(3-ethyl-2-pyridinyl)-
amino)piperidine as a colorless film: 1H NMR (CDCl3, 400
MHz) δ 8.20 (dd, J 1 ) 4.8 Hz, J 2 ) 1.8 Hz, 1H), 7.48 (dd, J 1
)
7.5 Hz, J 2 ) 1.8 Hz, 1H), 6.92 (dd, J 1 ) 7.5 Hz, J 2 ) 4.8 Hz,
1H), 3.21 (q, J ) 7.0 Hz, 2H), 3.13 (m, 4H), 2.65 (q, J ) 7.5
Hz, 2H), 2.58 (bt, J ) 12.1 Hz, 2H), 1.80 (m, 2H), 1.64 (qd, J 1
) 11.8 Hz, J 2 ) 3.7 Hz, 2H), 1.21 (t, J ) 7.5 Hz, 3H), 0.89 (t,
J ) 7.0 Hz, 3H). Coupling to 5-(methanesulfonylamino)indole-
2-carboxylic acid (125 mg, 0.490 mmol) as described for 20 with
CDI (76 mg, 0.467 mmol) afforded 175 mg (89%, 83% overall)
of the product as a faint yellow, amorphous solid: IR (mull,
cm-1) 3254 (m), 2923 (s), 1600 (s), 1533 (s), 1448 (s), 1428 (s),
1324 (s), 1152 (s), 972 (m), 805 (m), 760 (m); 1H NMR (CDCl3,
400 MHz) δ 9.65 (s, 1H), 8.27 (d, J ) 3.4 Hz, 1H), 7.59 (s, 1H),
7.55 (d, J ) 7.2 Hz, 1H), 7.40 (d, J ) 8.7 Hz, 1H), 7.16 (d, J )
8.7 Hz, 1H), 7.00 (dd, J 1 ) 7.2 Hz, J 2 ) 4.9 Hz, 1H), 6.85 (s,
1H), 6.73 (s, 1H), 4.65 (bd, J ) 13.1 Hz, 2H), 3.47 (m, 1H),
3.22 (m, 2H), 3.15 (bm, 2H), 2.97 (s, 3H), 2.71 (q, J ) 7.5 Hz,
2H), 1.96 (m, 2H), 1.72 (m, 2H), 1.24 (t, J ) 7.5 Hz, 3H), 0.92
(t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 162.7, 160.9,
145.6, 137.7, 135.6, 134.7, 131.1, 130.0, 128.1, 121.1, 119.9,
116.4, 113.3, 105.4, 58.7, 46.0 (broad), 41.8, 39.0, 30.6, 24.0,
14.5, 13.4; EI-MS (m/z, rel abundance) 469 (M+, 33), 440 (52),
390 (s), 237 (22), 189 (56), 149 (100), 130 (35). HRMS (FAB)
calcd for C24H31N5O3S + H: 470.2226. Found: 470.2240. Anal.
(C24H31N5O3S‚0.5H2O) C, H, N.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
p r op yl-N-(3-eth yl-2-p yr id in yl)a m in o)p ip er id in e (22). Pre-
pared in a manner analogous to 20 using 19c (210 mg, 0.622
mmol), ammonium formate (118 mg, 1.87 mmol), and 10%
Pd/C (200 mg) provided 144 mg (93%) of the debenzylated
intermediate 4-(N-propyl-N-(3-ethyl-2-pyridinyl)amino)piperi-
dine as a colorless film: 1H NMR (CDCl3, 400 MHz) δ 8.21
(dd, J 1 ) 4.7 Hz, J 2 ) 1.9 Hz, 1H), 7.51 (dd, J 1 ) 7.4 Hz, J 2
)
1.9 Hz, 1H), 6.94 (dd, J 1 ) 7.4 Hz, J 2 ) 4.7 Hz, 1H), 3.23 (bd,
J ) 12.5 Hz, 2H), 3.15 (m, 3H), 2.66 (m, 4H), 1.80 (m, 4H),
1.29 (m, 2H), 1.23 (t, J ) 7.6 Hz, 3H), 0.81 (t, J ) 7.4 Hz, 3H).
Coupling of the intermediate with 5-(methanesulfonylamino)-
indole-2-carboxylic acid (178 mg, 0.698 mmol) as described for
20 afforded 264 mg (94%, 87% overall) of the product as a faint
yellow, amorphous solid: IR (mull, cm-1) 3255 (m), 2926 (s),
1601 (s), 1455 (s), 1533 (s), 1428 (s), 1324 (s); 1H NMR (CDCl3,
400 MHz) δ 9.54 (s, 1H), 8.25 (d, J ) 3.2 Hz, 1H), 7.59 (s, 1H),
7.56 (d, J ) 7.1 Hz, 1H), 7.41 (d, J ) 8.7 Hz, 1H), 7.16 (dd, J 1
) 8.7 Hz, J 2 ) 2.0 Hz, 1H), 7.00 (m, 1H), 6.83 (s, 1H), 6.74 (s,
1H), 4.69 (bd, J ) 13.1 Hz, 2H), 3.39 (m, 1H), 3.10 (m, 4H),
2.97 (s, 3H), 2.71 (q, J ) 7.5 Hz, 2H), 1.96 (m, 2H), 1.75 (m,
2H), 1.31 (sext, J ) 7.3 Hz, 2H), 1.25 (t, J ) 7.5 Hz, 3H), 0.82
(t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 162.7, 161.1,
145.5, 137.7, 135.0, 134.7, 131.1, 130.0, 128.1, 121.1, 119.7,
116.4, 113.3, 105.4, 59.7, 48.7, 39.0, 30.5 (broad), 23.9, 21.5,
14.5, 12.1; EI-MS (m/z, rel abundance) 483 (M+, 15), 454 (23),
440 (18), 318 (10), 237 (34), 203 (45), 163 (100), 130 (50). HRMS
(FAB) calcd for C25H33N5O3S + H: 484.2382. Found: 484.2394.
Anal. (C25H33N5O3S‚H2O) C, H, N.
1-Ben zyl-4-(N-m eth yl-N-(3-m eth oxyca r bon yl-2-p yr id i-
n yl)a m in o)p ip er id in e (24a ). A mixture of 1-benzyl-4-(me-
thylamino)piperidine (8.00 g, 39.2 mmol) and methyl 2-chloro-
3-nicotinate (3.36 g, 19.6 mmol) was placed in a sealed tube
and maintained at 115-120 °C for 2 h. The residue was diluted
with CH2Cl2 (125 mL), washed with H2O (2 × 50 mL) and brine
(25 mL), dried over Na2SO4, and concentrated in vacuo. The
resulting semisolid was then chromatographed on silica gel
(230-400 mesh, 350 g), eluting with a gradient of EtOAc/

4148 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20
Genin et al.
hexane (25/75-50/50) to afford 4.44 g (67%) of the product as
a white solid: mp 109-110 °C; IR (mull, cm-1) 2925 (s), 2872
400 MHz) δ 8.22 (dd, J 1 ) 4.8 Hz, J 2 ) 1.8 Hz, 1H), 7.67 (dd,
J 1 ) 7.4 Hz, J 2 ) 1.6 Hz, 1H), 7.31 (m, 4H), 7.25 (m, 1H), 6.89
(dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz, 1H), 4.40 (s, 2H), 3.50 (s, 2H),
3.41 (s, 3H), 3.28 (m, 1H), 2.94 (bd, J ) 11.5 Hz, 2H), 2.77 (s,
3H), 2.01 (bt, J ) 11.3 Hz, 2H), 1.86 (bq, J ) 11.7 Hz, 2H),
1.70 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.9, 146.6, 137.9,
129.2, 128.2, 127.0, 125.1, 117.2, 70.9, 63.1, 59.5, 58.5, 53.2,
33.7, 29.2; EI-MS (m/z, rel abundance) 325 (M+, 2), 280 (5),
173 (96), 91 (100), 82 (20). HRMS calcd for C20H27N3O:
325.2154. Found: 325.2155.
1
(m), 1708 (s), 1588 (s), 1496 (s), 1462 (s), 1410 (s); H NMR
(CDCl3, 400 MHz) δ 8.21 (dd, J 1 ) 4.6 Hz, J 2 ) 1.9 Hz, 1H),
7.87 (dd, J 1 ) 7.5 Hz, J 2 ) 1.8 Hz, 1H), 7.33 (m, 4H), 7.26 (m,
1H), 6.60 (dd, J 1 ) 7.6 Hz, J 2 ) 4.6 Hz, 1H), 4.15 (tt, J 1 ) 11.7
Hz, J 2 ) 4.1 Hz, 1H), 3.87 (s, 3H), 3.53 (s, 2H), 2.98 (bd, J )
11.5 Hz, 2H), 2.79 (s, 3H), 2.11 (bt, J ) 11.6 Hz, 2H), 1.89 (qd,
J 1 ) 12.0 Hz, J 2 ) 3.5 Hz, 2H), 1.79 (m, 2H); EI-MS (m/z, rel
abundance) 339 (M+, 1), 308 (1), 280 (7), 173 (100), 91 (61).
Anal. (C20H25N3O2) C, H, N.
1-Ben zyl-4-(N-eth yl-N-(3-m eth oxym eth yl-2-p yr id in yl)-
a m in o)p ip er id in e (26b). Prepared in a manner analogous
to 26a using KOH (276 mg, 4.92 mmol), 25b (400 mg, 1.23
mmol), and CH3I (92 µL, 1.48 mmol) afforded 240 mg (58%) of
the product as an amber oil: IR (neat, cm-1) 2935 (m), 2802
(m), 1585 (m), 1429 (s); 1H NMR (CDCl3, 400 MHz) δ 8.28 (m,
1-Ben zyl-4-(N-eth yl-N-(3-m eth oxyca r bon yl-2-p yr id in -
yl)a m in o)p ip er id in e (24b). Prepared in a manner analogous
to 24a using 1-benzyl-4-(ethylamino)piperidine (7.69 g, 35.2
mmol) and methyl 2-chloro-3-nicotinate (3.02 g, 17.6 mmol)
afforded 2.05 g (33%) of the product as an amber oil: IR (neat,
cm-1) 2947 (m), 2800 (m), 2758 (m), 1720 (s), 1585 (s), 1553
(s), 1445 (s), 1475 (s), 1431 (s), 1287 (s), 1236 (s), 1119 (s), 1084
1H), 7.73 (m, 1H), 7.31 (m, 4H), 7.27 (m, 1H), 6.97 (dd, J 1
)
7.5 Hz, J 2 ) 4.8 Hz, 1H), 4.46 (s, 2H), 3.48 (s, 2H), 3.41 (s,
3H), 3.24 (q, J ) 7.0 Hz, 2H), 3.05 (m, 1H), 2.90 (m, 2H), 1.95
(m, 2H), 1.73 (m, 4H), 0.90 (t, J ) 6.9 Hz, 3H); EI-MS (m/z,
rel abundance) 339 (M+, 3), 294 (6), 173 (100), 91 (73). HRMS
calcd for C21H29N3O: 339.2310. Found: 339.2316.
1
(s), 800 (m), 741 (m), 699 (m); H NMR (CDCl3, 400 MHz) δ
8.24 (dd, J 1 ) 4.6 Hz, J 2 ) 1.9 Hz, 1H), 7.81 (dd, J 1 ) 7.5 Hz,
J 2 ) 1.9 Hz, 1H), 7.31 (m, 4H), 7.26 (m, 1H), 6.64 (dd, J 1 ) 7.5
Hz, J 2 ) 4.7 Hz, 1H), 3.86 (s, 3H), 3.46 (m, 4H), 2.95 (bd, J )
10.4 Hz, 2H), 1.95 (m, 2H), 1.88 (m, 2H), 1.75 (m, 2H), 1.09 (t,
J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 157.9,
149.9, 139.8, 138.5, 129.1, 128.2, 127.0, 114.5, 112.7, 63.7, 60.6,
53.6, 52.1, 38.1, 29.8, 14.5; EI-MS (m/z, rel abundance) 353
(M+, 1), 322 (3), 294 (17), 173 (100), 91 (85). Anal. (C21H27N3O2)
C, H, N.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
m et h yl-N-(3-m et h oxym et h yl-2-p yr id in yl)a m in o)p ip er i-
d in e (27). Prepared in a manner analogous to 20 using 26a
(150 mg, 0.461 mmol), ammonium formate (87 mg, 1.38 mmol),
and 10% Pd/C (150 mg) to give 102 mg (94%) of the debenzy-
lated intermediate 4-(N-methyl-N-(3-methoxymethyl-2-pyridi-
nyl)amino)piperidine as a colorless film: 1H NMR (CDCl3, 400
1-Ben zyl-4-(N-m eth yl-N-(3-h yd r oxym eth yl-2-p yr id in -
yl)a m in o)p ip er id in e (25a ). To a flame-dried flask containing
24a (750 mg, 2.21 mmol, 1 equiv) in dry THF (22 mL) at 0 °C
under N2 was added LAH (84 mg, 1 mol-equiv) in two portions.
The mixture was stirred at 0 °C for 1.5 h, quenched carefully
with 5% aqueous NaOH (5 mL), diluted with H2O (10 mL),
and filtered through a pad of Celite. The filtrate was then
extracted with CH2Cl2 (2 × 30 mL) and the combined organic
phase was washed with brine (10 mL), dried over Na2SO4, and
concentrated in vacuo to give 687 mg (100%) of the product as
a colorless, viscous oil: IR (neat, cm-1) 3287 (br, m), 2944 (s),
2806 (s), 1587 (s), 1568 (m), 1447 (s), 1412 (s); 1H NMR (CDCl3,
400 MHz) δ 8.28 (dd, J 1 ) 4.7 Hz, J 2 ) 1.7 Hz, 1H), 7.53 (dd,
J 1 ) 7.5 Hz, J 2 ) 1.7 Hz, 1H), 7.31 (m, 4H), 7.24 (m, 1H), 6.99
(dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz, 1H), 4.90 (bs, 1H), 4.71 (s, 2H),
3.48 (s, 2H), 3.16 (m, 1H), 2.91 (bd, J ) 11.9 Hz, 2H), 2.74 (s,
3H), 1.99 (m, 2H), 1.74 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ 161.4, 146.9, 138.3, 136.9, 129.7, 129.1, 128.2, 127.0, 119.3,
63.04, 63.00, 59.7, 52.9, 35.4, 29.5; EI-MS (m/z, rel abundance)
311 (M+, 2), 280 (8), 191 (2), 173 (100), 91 (58).
1-Ben zyl-4-(N-eth yl-N-(3-h yd r oxym eth yl-2-p yr id in yl)-
a m in o)p ip er id in e (25b). Prepared in a manner analogous
to 25a with 24b (600 mg, 1.70 mmol) and LAH (64 mg, 1 mol-
equiv) in dry THF (17 mL) to afford 486 mg (88%) of the
product as a colorless oil: IR (neat, cm-1) 3306 (br, w), 2935
(m), 1585 (m), 1429 (s); 1H NMR (CDCl3, 300 MHz) δ 8.34 (m,
1H), 7.48 (m, 1H), 7.27 (m, 5H), 7.03 (dd, J 1 ) 7.5 Hz, J 2 ) 4.8
Hz, 1H), 5.75 (bs, 1H), 4.75 (s, 2H), 3.47 (s, 2H), 3.26 (q, J )
7.1 Hz, 2H), 3.05 (m, 1H), 2.89 (bd, J ) 11.2 Hz, 2H), 1.95 (m,
2H), 1.75 (m, 4H), 0.93 (t, J ) 7.0 Hz, 3H); EI-MS (m/z, rel
abundance) 325 (M+, 2), 294 (6), 173 (100), 91 (65). HRMS calcd
for C20H27N3O: 325.2154. Found: 325.2149.
1-Ben zyl-4-(N-m eth yl-N-(3-m eth oxym eth yl-2-p yr id in -
yl)a m in o)p ip er id in e (26a ). To a mixture of powdered KOH
(356 mg, 6.34 mmol, 4 equiv) in dry DMSO (2 mL) under N2
was added a solution of 25a (494 mg, 1.58 mmol, 1 equiv) in
dry DMSO (1.2 mL) followed by CH3I (118 µL, 1.90 mmol).
The resulting mixture was stirred at room temperature for
30 min, then diluted with water (15 mL), and extracted with
CH2Cl2 (2 × 20 mL). The combined organic phase was washed
with H2O (2 × 10 mL) and brine (10 mL), dried over Na2SO4,
and concentrated in vacuo to give an oil which was then
purified by flash chromatography by eluting with a gradient
of EtOAc/hexane (20/80-40/60) to afford 313 mg (61%) of the
product as a colorless, viscous oil: IR (neat, cm-1) 2940 (s),
2900 (s), 1587 (s), 1448 (s), 1412 (s), 1115 (s); 1H NMR (CDCl3,
MHz) δ 8.19 (dd, J 1 ) 4.8 Hz, J 2 ) 1.7 Hz, 1H), 7.65 (dd, J 1
)
7.4 Hz, J 2 ) 1.7 Hz, 1H), 6.87 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz,
1H), 4.39 (s, 2H), 3.39 (s, 3H), 3.32 (m, 1H), 3.10 (bd, J ) 12.3
Hz, 2H), 2.75 (s, 3H), 2.58 (td, J 1 ) 12.0 Hz, J 2 ) 2.9 Hz, 2H),
2.12 (bs, 1H), 1.68 (m, 4H). The intermediate amine was
coupled to 5-(methanesulfonylamino)indole-2-carboxylic acid
(116 mg, 0.456 mmol) using CDI (74 mg, 0.456 mmol) as
described for 20 to give 159 mg (76%, 73% overall) of the
product as a faint yellow, amorphous solid: IR (mull, cm-1
)
3251 (m), 2924 (s), 2855 (s), 1590 (s), 1533 (m), 1447 (s), 1413
1
(s), 1322 (s), 1152 (s), 804 (w), 761 (w); H NMR (CDCl3, 400
MHz) δ 9.40 (s, 1H), 8.27 (m, 1H), 7.72 (m, 1H), 7.60 (s, 1H),
7.41 (d, J ) 8.7 Hz, 1H), 7.16 (d, J ) 8.7 Hz, 1H), 6.97 (m,
1H), 6.77 (s, 1H), 6.57 (s, 1H), 4.71 (bd, J ) 12.2 Hz, 2H), 4.45
(s, 2H), 3.80 (m, 1H), 3.45 (s, 3H), 3.15 (bm, 2H), 2.97 (s, 3H),
2.78 (s, 3H), 1.97 (m, 2H), 1.81 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 162.1, 161.8, 147.0, 138.3, 134.2, 130.8, 129.5, 127.9,
125.6, 120.9, 117.9, 116.3, 112.8, 105.0, 70.9, 58.6, 38.8, 34.8,
29.7; EI-MS (m/z, rel abundance) 471 (M+, 37), 426 (21), 237
(37), 192 (50), 177 (36), 151 (100), 130 (76), 92 (41). HRMS
calcd for C23H29N5O4S: 471.1940. Found: 471.1939. Anal.
(C23H29N5O4S‚0.25H2O) C, H, N.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
e t h yl-N -(3-m e t h oxym e t h yl-2-p yr id in yl)a m in o)p ip e r i-
d in e (28). Prepared in a manner analogous to 20 using 26b
(110 mg, 0.324 mmol), ammonium formate (61 mg, 0.972
mmol), and 10% Pd/C (110 mg) to give 66 mg (82%) of the
debenzylated intermediate 4-(N-ethyl-N-(3-methoxymethyl-2-
pyridinyl)amino)piperidine as a colorless film: 1H NMR (CDCl3,
400 MHz) δ 8.25 (dd, J 1 ) 4.7 Hz, J 2 ) 1.8 Hz, 1H), 7.72 (dd,
J 1 ) 7.5 Hz, J 2 ) 1.8 Hz, 1H), 6.96 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8
Hz, 1H), 4.45 (s, 2H), 3.39 (s, 3H), 3.22 (q, J ) 7.0 Hz, 2H),
3.11 (m, 1H), 3.07 (bd, J ) 12.2 Hz, 2H), 2.52 (td, J 1 ) 12.2
Hz, J 2 ) 2.1 Hz, 2H), 2.02 (bs, 1H), 1.75 (m, 2H), 1.57 (qd, J 1
) 12.0 Hz, J 2 ) 4.0 Hz, 2H), 0.88 (t, J ) 7.0 Hz, 3H). Coupling
of the intermediate amine with 5-(methanesulfonylamino)-
indole-2-carboxylic acid (71 mg, 0.279 mmol) using CDI (45
mg, 0.279 mmol) as described for 20 afforded 94 mg (73%, 60%
overall) of the product as a faint yellow, amorphous solid: IR
(mull, cm-1) 3251 (m), 2925 (s), 2856 (s), 1600 (s), 1448 (s),
1
1430 (s), 1227 (s); H NMR (CDCl3, 400 MHz) δ 9.50 (s, 1H),
8.34 (m, 1H), 7.78 (m, 1H), 7.59 (s, 1H), 7.40 (d, J ) 8.7 Hz,
1H), 7.16 (d, J ) 8.7 Hz, 1H), 7.05 (m, 1H), 6.74 (s, 1H), 6.65
(s, 1H), 4.67 (bd, J ) 12.9 Hz, 2H), 4.50 (s, 2H), 3.55 (m, 1H),
3.45 (s, 3H), 3.23 (m, 2H), 3.15 (bm, 2H), 2.97 (s, 3H), 1.94 (m,

Synthesis and SAR of AAP-BHAPs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 20 4149
(7) Merluzzi, V. J .; Hargrave, K. D.; Labadia, M.; Grozinger, K.;
Skoog, M.; Wu, J . C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams,
J .; Rosenthal, A. S.; Faanes, R.; Eckner, R. J .; Koup, R. A.;
2H), 1.74 (m, 2H), 0.93 (t, J ) 6.9 Hz, 3H); EI-MS (m/z, rel
abundance) 485 (M+, 44), 470 (6), 456 (10), 440 (27), 237 (31),
205 (35), 191 (23), 165 (100), 130 (39). Anal. (C24H31N5O4S) C,
H, N.
Sullivan, J . L. Inhibition of HIV-1 Replication by
a Non-
Nucleoside Reverse Transcriptase Inhibitor. Science 1990, 250,
1411-1413.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
m eth yl-N-(3-m eth oxyca r bon yl-2-p yr id in yl)a m in o)p ip e-
r id in e (29). Prepared as described for 14 using 24a (250 mg,
0.736 mmol) and 20% Pd(OH)2 on carbon (45% moisture, 100
mg) in CH3OH (14 mL) provided 112 mg (61%) of the
debenzylated intermediate 4-(N-methyl-N-(3-methoxycarbonyl-
2-pyridinyl)amino)piperidine: 1H NMR (CDCl3, 400 MHz) δ
8.22 (dd, J 1 ) 4.6 Hz, J 2 ) 1.9 Hz, 1H), 7.88 (dd, J 1 ) 7.6 Hz,
J 2 ) 1.9 Hz, 1H), 6.61 (dd, J 1 ) 7.6 Hz, J 2 ) 4.6 Hz, 1H), 4.25
(m, 1H), 3.87 (s, 3H), 3.17 (bd, J ) 12.2 Hz, 2H), 2.79 (s, 3H),
2.73 (bt, J ) 12.0 Hz, 2H), 1.75 (m, 4H). Coupling of the
intermediate amine with 5-(methanesulfonylamino)indole-2-
carboxylic acid (135 mg, 0.529 mmol) using CDI (754 mg, 0.463
mmol) as described for 14 afforded 179 mg (84%, 51% overall)
of the product as a white solid: mp 223-224 °C; IR (mull,
cm-1) 3291 (s), 2924 (s), 2855 (s), 1715 (s), 1595 (s), 1459 (m),
(8) Hargrave, K. D.; Proudfoot, J . R.; Grozinger, K. G.; Kapadia, S.
R.; Patel, U. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, J .; Behnke,
M. L.; Klunder, J . M.; Pal, K.; Skiles, J . W.; McNeil, D. W.; Rose,
J . M.; Chow, G. C.; Skoog, M. T.; Wu, J . C.; Schmidt, G.; Engel,
W.; Eberlein, W. G.; Saboe, T. D.; Campbell, S. J .; Rosenthal, A.
S.; Adams, J . Novel Non-Nucleoside Inhibitors of HIV-1 Reverse
Transcriptase. 1. Tricyclic Pyridobenzo- and Dipyridodiazepi-
nones. J . Med. Chem. 1991, 34, 2231-2241.
(9) (a) Graul, A.; Rabasseda, X.; Castaner, J . Efavirenz. Drugs
Future 1998, 23 (2), 133-141. (b) Young, S. D.; Britcher, S. F.;
Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J . R.;
Anderson, P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J .;
O’Brien, J . A.; Ball, R. G.; Balani, S. K.; Lin, J . H.; Chen, I-W.;
Schleif, W. A.; Sardana, V. V.; Long, W. J .; Byrnes, V. W.; Emini,
E. A. L-743,726 (DMP-266): a Novel, Highly Potent Nonnucleo-
side Inhibitor of the Human Immunodeficiency Virus Type 1
Reverse Transcriptase. Antimicrob. Agents Chemother. 1995, 39
(12), 2602-2605.
(10) (a) de Clercq, E. How to overcome resistance of HIV-1 to HIV-1
specific reverse transcriptase inhibitors. AIDS 1994, 8 (7), 1020-
1021. (b) de Clercq, E. Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs) for the Treatment of Human Immunode-
ficiency Virus Type 1 (HIV-1) Infections: Strategies to Overcome
Drug Resistance Development. Med. Res. Rev. 1996, 16, 125.
(11) 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 immundeficiency virus type 1 that confers
increased sensitivity to other nonnucleoside inhibitors. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 4813-4717.
(12) Romero, D. L.; Olmsted, R. A.; Poel, T. J .; Morge, R. A.; Biles,
C.; Keiser, B. J .; Kopta, L. A.; Friis, J . M.; Hosley, J . D.;
Stefanski, K. J .; Wishka, D. G.; Evans, D. B.; Morris, J ., Stehle,
R. G.; Sharma, S. K.; Yagi, Y.; Voorman, R. L.; Adams, W. J .;
Tarpley, W. G.; Thomas, R. C. Targeting Delavirdine/Atevirdine
Resistant HIV-1: Identification of (Alkylamino)piperidine-
Containing Bis(heteroaryl)piperazines as Broad Spectrum HIV-1
Reverse Transcriptase Inhibitors. J . Med. Chem. 1996, 39,
3769-3789.
1
1413 (m); H NMR (CDCl3, 400 MHz) δ 9.65 (s, 1H), 8.25 (m,
1H), 7.93 (d, J ) 6.6 Hz, 1H), 7.61 (s, 1H), 7.42 (d, J ) 8.7 Hz,
1H), 7.17 (d, J ) 8.7 Hz, 1H), 6.81 (s, 1H), 6.78 (s, 1H), 6.68
(m, 1H), 4.84 (bd, J ) 12.3 Hz, 2H), 4.63 (m, 1H), 3.89 (s, 3H),
3.15 (bm, 2H), 2.97 (s, 3H), 2.76 (s, 3H), 2.02 (m, 2H), 1.86 (m,
2H); EI-MS (m/z, rel abundance) 485 (M+, 27), 470 (7), 426
(80), 319 (29), 240 (82), 237 (47), 219 (47), 206 (96), 205 (100),
191 (45), 157 (89), 130 (88). Anal. (C23H27N5O5S) C, H, N.
1-(5-(Meth a n esu lfon yla m in o)in d ol-2-ylca r bon yl)-4-(N-
m et h yl-N-(3-h yd r oxym et h yl-2-p yr id in yl)a m in o)p ip er i-
d in e (30). Prepared in a manner analogous to 20 with 25a
(50 mg, 0.160 mmol), ammonium formate (30 mg, 0.482 mmol),
and 10% Pd/C (50 mg) afforded 35 mg (100%) of the debenzy-
lated intermediate 4-(N-methyl-N-(3-hydroxymethyl-2-pyridi-
nyl)amino)piperidine as an opaque film: 1H NMR (CDCl3, 400
MHz) δ 8.29 (dd, J 1 ) 4.8 Hz, J 2 ) 1.8 Hz, 1H), 7.55 (dd, J 1
)
7.4 Hz, J 2 ) 1.8 Hz, 1H), 7.00 (dd, J 1 ) 7.4 Hz, J 2 ) 4.8 Hz,
1H), 4.73 (s, 2H), 3.24 (m, 1H), 3.11 (bd, J ) 12.4 Hz, 2H),
2.75 (s, 3H), 2.60 (td, J 1 ) 12.3 Hz, J 2 ) 2.3 Hz, 2H), 1.78 (m,
2H), 1.58 (qd, J 1 ) 12.1 Hz, J 2 ) 4.0 Hz, 2H). Coupling of the
intermediate amine to 5-(methanesulfonylamino)indole-2-car-
boxylic acid (43 mg, 0.168 mmol) with EDC (32 mg, 0.168
mmol) as described for 12 afforded 40 mg (55%) of the product
as a faint yellow, amorphous solid: IR (mull, cm-1) 3253 (m,
(13) Wishka, D. G.; Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis,
J . M.; Hosley, J . D.; Adams, W. J .; Seest, E. P.; Castle, T. M.;
Dolak, L. A.; Keiser, B. J .; Yagi, Y.; Azhwarsamy, J .; Schlachter,
S. T.; Murphy M. J .; Cleek, G. J .; Nugent, R. A.; Poppe, S. M.;
Swaney, S. M.; Han, F.; Watt, W.; White, W. L.; Poel, T.-J .;
Thomas, R. C.; Voorman, R. L.; Stefanski, K. J .; Stehle, R. G.;
Tarpley, W. G.; Morris, J . (-)-6-Chloro-2-[(1-furo[2,3-c]pyridin-
5-ylethyl)thio]-4-pyrimidinamine, PNU-142721, a New Broad
Spectrum HIV-1 Non-Nucleoside Reverse Transcriptase Inhibi-
tor. J . Med. Chem. 1998, 41, 1357-1360.
1
br), 2923 (s), 1589 (s), 1446 (s), 1323 (s); H NMR (MeOH-d4,
400 MHz) δ 8.19 (dd, J 1 ) 4.7 Hz, J 2 ) 1.7 Hz, 1H), 7.89 (d, J
) 6.4 Hz, 1H), 7.56 (d, J ) 1.7 Hz, 1H), 7.43 (d, J ) 8.7 Hz,
1H), 7.18 (dd, J 1 ) 8.7 Hz, J 2 ) 2.0 Hz, 1H), 7.08 (dd, J 1 ) 7.4
Hz, J 2 ) 4.9 Hz, 1H), 6.81 (s, 1H), 4.69 (s, 2H), 4.56 (bd, J )
12.3 Hz, 2H), 3.64 (m, 1H), 3.15 (bm, 2H), 2.91 (s, 3H), 2.78
(s, 3H), 1.82 (m, 4H); 13C NMR (MeOH-d4, 100 MHz) δ 163.7,
161.3, 146.0, 138.1, 134.9, 131.1, 130.7, 130.4, 127.9, 120.6,
118.6, 115.7, 112.5, 104.7, 60.1, 59.2, 37.5, 34.0, 29.7; FAB-
MS (m/z, rel abundance) 458 ([M + H]+, 100), 237 (25), 139
(25), 121 (39). HRMS calcd for C22H27N5O4S + H: 458.1868.
Found: 458.1862. Anal. (C22H27N5O4S‚H2O) C, H, N.
(14) Nugent, R. A.; Schlachter, S. T.; Murphy, M. J .; Cleek, G. J .;
Poel, T. J .; Wishka, D. G.; Graber, D. R.; Yagi, Y.; Keiser, B. J .;
Olmsted, R. A.; Kopta, L. A.; Swaney, S. M.; Poppe, S. M.; Morris,
J .; Tarpley, W. G.; Thomas, R. C. Pyrimidine Thioethers:
A
Novel Class of HIV-1 Reverse Transcriptase Inhibitors with
Activity Against BHAP Resistant HIV. J . Med. Chem. 1998, 41,
3793-3803.
Ack n ow led gm en t. We would like to thank Barbara
J . Keiser for valuable technical assistance.
(15) Genin, M. J .; Poel, T. J .; Yagi, Y.; Biles, C.; Althaus, I.; Keiser,
B. J .; Kopta, L. A.; Friis, J . M.; Reusser, F.; Adams, W. J .;
Olmsted, R. A.; Voorman, R. L.; Thomas, R. C.; Romero, D. L.
Synthesis and Bioactivity of Novel Bis(heteroaryl)piperazine
(BHAP) Reverse Transcriptase Inhibitors: Structure-Activity
Relationships and Increased Metabolic Stability of Novel Sub-
stituted Pyridine Analogues. J . Med. Chem. 1996, 39, 5267-
5275.
(16) Melnyk, P.; Gasche, J .; Thal, C. Improved syntheses of 2-bro-
monicotinaldehyde and acid. Synth. Commun. 1993, 23 (19),
2727-2730.
(17) Metabolites of the alkylpyridine-substituted AAP-BHAPs tend
to be hydroxylated in the side chain or on the pyridine ring.
There was also some N-dealkylation of the 4-(alkylamino)-
piperidine nitrogen. In general, compounds with these modifica-
tions have not shown good inhibition of HIV RT.
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(3) Richman, D. D. Antiretroviral Drug Resistance: Mechanisms,
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J M990051A