Studies toward the discovery of the next generation of antidepressants. Part 6: Dual 5-HT1A receptor and serotonin transporter affinity within a class of arylpiperazinyl-cyclohexyl indole derivatives

Article abstract of DOI:10.1016/j.bmc.2008.05.075

Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors

Full text of DOI:10.1016/j.bmc.2008.05.075

Bioorganic & Medicinal Chemistry 16 (2008) 6707–6723
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Studies toward the discovery of the next generation of antidepressants.
Part 6: Dual 5-HT1A receptor and serotonin transporter affinity within
a class of arylpiperazinyl-cyclohexyl indole derivatives
a
a
a
a
a
Dahui Zhou a, , Ping Zhou , Deborah A. Evrard , Kristin Meagher , Michael Webb , Boyd L. Harrison ,
*
Donna M. Huryn a, Jeannette Golembieski b, Geoffrey A. Hornby b, Lee E. Schechter b, Deborah L. Smith b,
Terrance H. Andree b, Richard E. Mewshaw a,
*
a Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
b Neuroscience’ Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-
5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized
then evaluated as 5-HT transporter inhibitors and 5-HT1A receptor antagonists. The investigation of the
structure–activity relationships revealed the optimal pharmacophoric elements required for activities
in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited
equal binding affinities at 5-HT transporter (Ki = 4.9 nM), 5-HT1A receptor (Ki = 6.2 nM) and functioned as
a 5-HT1A receptor antagonist.
Received 6 March 2008
Revised 29 May 2008
Accepted 29 May 2008
Available online 5 June 2008
Keywords:
Serotonin transporter
5-HT1A receptor
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
observed with acute fluoxetine treatment alone.5–7 In support of
this hypothesis, clinical trials performed by Artigas8 and Blier9
Selective serotonin reuptake inhibitors (SSRIs) have achieved
great success in treating depression and related illnesses and have
fewer and less-severe side effects than first generation drugs, such
as tricyclic antidepressants (TCAs) and non-selective monoamine
oxide (MAO) inhibitors. However, clinical efficacy is seen only after
prolonged treatment with SSRIs.1 It is speculated that this delayed
onset of action is attributed to the SSRI-induced increase in seroto-
nin (5-HT) levels in the vicinity of the serotonergic cell bodies. The
excess serotonin activates somatodendritic 5-HT1A autoreceptors,
causing a decrease in neuronal firing, which in turn decreases the
release of serotonin in major forebrain areas. In practice, sustained
treatment with SSRIs can effectively desensitize the pre-synaptic
5-HT1A autoreceptor and allow for the desired increase in 5-HT lev-
els in the forebrain.2–4
It has been proposed that the addition of a 5-HT1A receptor
antagonist component to the action of a SSRI can limit the negative
feedback through blockade of the 5-HT1A autoreceptor, allowing an
immediate increase in synaptic 5-HT levels in desired post-synap-
tic brain regions. Preclinical evidence using in vivo microdialysis
has shown that co-administration of fluoxetine and the selective
5-HT1A receptor antagonist WAY-100635 produces an immediate
increase in 5-HT levels in rat frontal cortex. This effect is not
demonstrated that the combination of ( )-pindolol, a non-selective
5-HT1A partial agonist, with the SSRI paroxetine shortened the on-
set of antidepressant action to a period of 3–7 days, in contrast to
2–3 weeks required with the SSRI alone. Therefore, the concept of
developing a dual-acting agent that combines blockade of both the
5-HT1A receptor and 5-HT transporter in one molecule has been
proposed. Several groups have reported their efforts and design
strategies toward the construction of such a hybrid 5-HT1A recep-
tor antagonist and 5-HT transporter inhibitor.10–14
The current study expands efforts initiated in 2001 to incorpo-
rate 5-HT transporter and 5-HT1A receptor activity into a single
molecule. 4-(1H-Indol-3-yl)cyclohexylamines were used as a start-
ing point to introduce the 5-HT1A pharmacophore, resulting in a
novel class of indolylcyclohexylamines (1, Fig. 1).10 Disappoint-
ingly, incorporation of the methoxy-substituted tetrahydroiso-
quinoline as
a 5-HT1A receptor pharmacophore resulted in
compounds having only weak affinity for the 5-HT1A receptor. As
a continuation of our investigation, we decided to replace the tet-
rahydroisoquinoline moiety with 1-(4-indolyl)piperazine, a more
optimal 5-HT1A receptor pharmacophoric group. As a result, cis-
1-(4-indolyl)piperazine analog cis-2 (Fig. 1), which exhibited high
binding affinity for 5-HT transporter (Ki = 5.3 nM) and moderate
affinity for 5-HT1A receptor (Ki = 36.6 nM), was chosen as a new
discovery lead.15 In order to further advance this series, we then
turned our attention to the Regions A and B of the compound
* Corresponding authors. Tel.: +1 732 274 4423; fax: +1 732 274 4505.
E-mail address: zhoud@wyeth.com (D. Zhou).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.05.075

6708
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
O
X
R
O
N
1
a
NH
b
R3
R1
R3
R1
R = H, 5-OMe, 6-OMe, 7-OMe and 8-OMe
X = H, F and CN
N
N
H
H
25a: R1 = H, R3 = H
25b: R1 = 5-F, R3 = H
25c: R1 = 6-F, R3= H
25d: R1 = 5-CN, R3 = H
NH
25e: R1 = 5-OMe, R3 = H
N
N
25f:
R
1 = 4-F, R3 = H
25g: R1 = 5-Cl, R3 = H
25h: R1 = H, R3 = Me
O
HN
cis-2
F
A
O
O
B
R3
R2
Z
c
R3
R1
R3
R1
N
N
N
Ar
N
N
H
H
26a-h
28a-h
R1
3
d
Figure 1. Compound design.
O
O
O
cis-2, in attempts to further enhance the potency at both 5-HT
transporter and 5-HT1A receptor sites. Our strategy was to system-
atically explore different 4-(indol-3-yl)cyclohexyl moieties (B-re-
gion, exemplified by generic structure 3, Fig. 1) and alternative
aryl piperazines (A-region) as replacements for the 1-(4-indo-
lyl)piperazine. Herein, we describe the synthesis and biological
c
R3
R1
R3
R1
N
N
R2
R2
28i-m
27i-m
evaluation of
a series of arylpiperazin-4-yl-cyclohexyl indole
28i: R1= 5-F, R2= Me, R3 = H
28j: R1 = 5-CN, R2 = Me, R3 = H
28k: R1 = 5-CN, R2= Et, R3 = H
derivatives (3) that demonstrated potent and selective dual activ-
ities as 5-HT reuptake inhibitors and 5-HT1A receptor antagonists.
28l: R1 = 5-CN, R2=
28m: R1 = 5-CN, R2=
n
-pr, R3 = H
-pr, R3= H
2. Chemistry
i
Scheme 1. Reagents: (a) 1,4-cyclohexanedione mono-ethylene ketal, KOH, meth-
anol; (b) Pd–C 10%, ethanol–EtOAc or PtO2, ethanol when R1 = Cl; (c) 1 N HCl/THF
(1:1); (d) NaH, R2Br, DMF.
The current SAR study began with an evaluation of the effect of
various cyclohexyl-3-indoles on the binding affinities at the 5-HT
transporter and the 5-HT1A receptor. The synthesis began with
the preparation of several 4-(indol-3-yl)-cyclohexanones 28a–
28m as shown in Scheme 1. Condensation of the requisite indoles
with 1,4-cyclohexanedione mono-ethylene ketal under basic con-
ditions afforded compounds 25a–25h. Reduction of the resulting
alkenes 25a–25h and deketalization of compounds 26a–26h pro-
vided the 4-(1H-indol-3-yl)-cyclohexanones 28a–28h.16 N-Alkyl-
ation of compounds 26b and 26d with alkyl halides, followed by
hydrolysis of compounds 27i–28m under acidic conditions gener-
ated 4-(indol-3-yl)cyclohexanones 28i–28m.
butyl-4-piperazine carboxylate afforded compound 32. Deprotec-
tion and reductive alkylation of 5-(piperazin-1-yl)quinoline (33)
with 4-(indol-3-yl)cyclohexanones 28b and 28d generated the tar-
get compounds 19 and 20.
Next, 8-(piperazin-1-yl)quinoline analogs 21 and 22 were
prepared (Scheme 5). Reaction of commercially available 8-amino-
quinoline with bis-(2-chloroethyl)-benzylamine afforded com-
pound 34. Debenzylation with vinyl chloroformate followed by
reductive alkylation with 4-(indol-3-yl)-cyclohexanones 28b and
28d provided compounds 21 and 22 (Scheme 5).
Finally, in order to further expand our SAR, quinoxaline 23, 1-
naphthalenyl-piperazine 24 and the 7-azoindole analog 25 were
prepared (Schemes 6 and 7). Reductive alkylation of compound
4020 and 2915 with cyclohexanones 28b and 4-(1H-pyrrolo[2,3-
b]pyridin-3-yl)cyclohexanone 41 afforded compounds 24 and 25.
Reductive alkylation of 4-(piperazin-1-yl)-1H-indole (29)15
with the 4-(indol-3-yl)-cyclohexanones 28a–28m afforded target
compounds 2 and 4–15 in excellence yield (Scheme 2). The cis
and trans isomers were separated by column chromatography.
To investigate of the effects of different heteroaryl piperazines
(A-region) on affinities at 5-HT transporter and 5-HT1A receptor
sites, (piperazin-1-yl)-1H-benzo[d]imidazole analogs 16–18 were
prepared by reductive alkylation of (piperazin-1-yl)-1H-
benzo[d]imidazoles 30a–30c17,18 with 4-(1H-indol-3-yl)-cyclohex-
anone 28a (Scheme 3).
3. Results and discussion
To further expand the SAR, 5-quinoline analogs 19 and 20 were
synthesized in a 4-step sequence starting from commercially
available 5-hydroxyquinoline (Scheme 4). Buchwald coupling19 be-
tween the 5-(trifluoromethylsulfonyloxy)quinoline (31) and 1-tert-
Both the B-region indole moiety and the A-region heteroaryl
moiety of the compound cis-2 (Fig. 1) were systematically varied
to establish the structure–activity relationship (SAR) of this series

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6709
R1
N
N
N
R2
b
a
a
N
N
NH
N
N
NH2
N
N
Bn
N
NH
HN
HN
34
35
29
R
N
2: R = 5-F, R1 = R2 = H
4: R = H, R1 = R2 = H
c
NH
R1
N
N
5: R = H, R1 = H, R2 = Me
6: R = 6-F, R1 = R2 = H
7: R = 4-F, R1 = R2 = H
8: R = 5-CN, R1 = R2 = H
9: R = 5-CN, R1 = H, R2 = Me
21: R1 = F
22: R1 = CN
Scheme 5. Reagents: (a) bis-(2-chloroethyl)-benzylamine, 1-butanol; (b) vinyl
chloroformate followed by HCl (12 N)/dioxane (1:1) then ethanol reflux; (c) 4-
(indol-3-yl)cyclohexaones, NaBH(OAc)3, HOAc, 1,2-dichloroethane.
10: R = 5-CN, R1 = H, R2 = Et
11: R = 5-CN, R1 = H, R2 =
12: R = 5-CN, R1 = H, R2 =
n
-Pr
i-Pr
13: R = 5-OMe, R1 = R2 = H
14: R = 5-Cl, R1 = R2 = H
15: R = H, R1 = Me, R2 = H
H2N
NH2
NO2
N
N
N
N
a
b
NH2
NO2
Scheme 2. Reagents: (a) 4-(1H-indol-3-yl)-cyclohexanone, NaBH(OAc)3, HOAc, 1,2-
dichloroethane.
36
37
N
N
N
N
c
d
e
R1
R1
N
N Bn
N
NH
HN
N
HN
N
38
a
NH
39
N
N
N
N
N
NH
NH
N
N
30a: R1 = H
16: R1 = H
30b: R1 = Me
30c: R1 = CF3
17: R1 = Me
18: R1 = CF3
23
NC
Scheme 3. Reagents: (a) 4-(1H-indol-3-yl)-cyclohexanone, NaBH(OAc)3, HOAc, 1,2-
dichloroethane.
Scheme 6. Reagents: (a) glyoxal; (b) Fe, HOAc; (c) bis(2-chloroethyl)-benzylamine,
1-butanol; (d) Pd–C 10%, ammonium formate, ethanol; (e) 3-(4-oxocyclohexyl)-1H-
indole-5-carbonitrile, NaBH(OAc)3, HOAc, 1,2-dichloroethane.
N
N
NH
N
a
a
Ar
N
N
b
Ar
N
NH
40 and 29
40: Ar =
Z
OH
OTf
N
N
N
BOC
24 and 25
31
R
32
24: Ar =
and R = F, Z = CH
N
d
c
NH
R1
N
N
29: Ar = HN
25: Ar = HN
N
NH
and R =H, Z = N
19: R1 = F
20: R1 = CN
33
Scheme 7. Reagents: (a) 4-(5-fluoro-1H-indol-3-yl)cyclohexanone or 4-(1H-pyr-
rolo[2,3-b]pyridin-3-yl)cyclohexanone, NaBH(OAc)3, HOAc, 1,2-dichloroethane.
Scheme 4. Reagents: (a) Tf2O, Et3N, dichloromethane; (b) tert-butyl piperazine-1-
carboxylate, Pd(OAc)2, BINAP, Cs2CO3, tetrahydrofuran; (c) TFA, dichloromethane;
(d) 4-(indol-3-yl)cyclohexaones, NaBH(OAc)3, HOAc, 1,2-dichloroethane.
As noted previously, cis-3-(4-(4-(1H-indole-4-yl)piperazin-1-
yl)cyclohexyl)-5-fluoro-1H-indole (cis-2) was identified as
a
promising lead, but this observation was based only on the 4-(5-
fluoro-1H-indol-3-yl) moiety in the B-region. Therefore, to more
completely probe the effect of the B-region indolyl moiety on the
affinities at the 5-HT transporter and 5-HT1A receptor, we decided
to systematically examine substituents at various positions in this
region, while maintaining the 1-(4-indolyl)piperazine (29) as the
5-HT1A receptor pharmacophore in the A-region.
As shown in Table 1, within each pair of geometric isomers in
the 3-{4-[4-(1H-indol-4-yl)-piperazin-4-yl]cyclohexyl}-indole ser-
ies (i.e., 2, 4–15), the cis isomers were more potent for 5-HT trans-
porter affinity than their corresponding trans isomers. Also,
of compounds,. The following SAR Tables 1–6 examine each of
these variables in turn. Compounds were evaluated in vitro to
determine the binding affinities for both the serotonin transporter
(r-5-HT-T) and 5-HT1A receptor (h-5-HT1A). Compounds that
exhibited high binding affinity at both the 5-HT1A receptor and
the 5-HT transporter were further evaluated for their 5-HT1A
receptor intrinsic activity (GTPc
S35 Emax) and selectivity over the
a1 adrenergic receptor. WAY-100635 (a 5-HT1A receptor antago-
nist) and fluoxetine (a 5-HT transporter inhibitor) are shown as ref-
erence standards (Table 1).

6710
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
Table 1
3-{4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl}indoles 2, 4–16a
R3
R2
N
N
N
HN
R1
Compound
R1
R2
R3
r-5-HT-T Kib (nM)
trans
h-5-HT1A Kic (nM)
cis
cis
trans
Fluoxetine
WAY-100635
2
4
5
6
7
8
2.7 (racemic)
nd
nd
0.9 (achiral)
4.62
5-F
H
5-F
6-F
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
5.3
38
11.6
12.7
27% at 100 nM
1.6
3.3
13.4
26.7
48.5
155
67.5
35% at 100 nM
0% at 100 nM
8.5
102
58.2
62.5
16% at 100 nM
45% at 1 lM
20% at 100 nM
36.7
32
124
5.3
90
5.4
22.2
3.5
53.2
827.6
46% at 1
46% at 1
2.9
58.3
13
33.5
117.3
69.6
232.9
563.5
819.8
694.2
60.3
4-F
5-CN
5-CN
5-CN
5-CN
5-CN
5-OMe
5-Cl
H
H
9
Me
Et
Pr
i-Pr
H
10
11
12
13
14
15
l
l
M
M
38.5
25% at 100 nM
28% at 100 nM
4% at 100 nM
H
H
325.7
87.1
12% at 100 nM
nd, not determined.
a
Ki values are the mean of at least two experiments performed in triplicate, determined from nine concentrations and all Ki values were calculated from IC50 values using
the method of Cheng and Prusoff.21 Percentages represent inhibition of binding at the concentration indicated.
b
Binding affinity at rat cortical 5-HT reuptake sites labeled with [3H]paroxetine.22
Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-OH-DPAT.23
c
Table 2
Table 3
Intrinsic activity at 5-HT1A receptor and the selectivity over a1 adrenergic receptor
Benzimidazolepiperazines 16–18a
R1
NH
N
N
HN
N
HN
R1
N
N
NH
Compound
R1
h-5-HT1A
Ki (nM)
GTP
Emax (%)
c
S35
r-a1
a
Compound
R1
r-5-HT-T
h-5-HT1A
GTP
Emax (%)
c
S35
r-a1
Kib (nM)
d
Kib (nM)
Kic (nM)
Kie (nM)
cis-2
trans-2
cis-4
cis-6
cis-8
5-F
5-F
H
6-F
5-CN
5-CN
36.7
4.6
32
33.5
69.6
3.5
10
43
0
0
0
196
16% at 100 nM
2430
266
65
cis-16
trans-16
cis-17
trans-17
cis-18
trans-18
H
H
Me
Me
CF3
CF3
13
75
61
115
105
75
7.9
1.7
10.7
3
16.1
3.6
0
0
0
0
0
34
4.2
23.1
3
118
11
trans-8
11
26
29
a
Stimulation of GTPc
S35 binding in CHO cells expressing 5-HT1A receptor.24 Emax
a
Ki values are the mean of at least two experiments performed in triplicate,
determined from nine concentrations and all Ki values were calculated from IC50
values using the method of Cheng and Prusoff.21
refers to maximal agonist effect relative to 5-HT.
b
Binding affinity at rat cortical a1 adrenergic receptors labeled with
[3H]prazosin.25
b
Binding affinity at rat cortical 5-HT reuptake sites labeled with
[3H]paroxetine.22
Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-
c
OH-DPAT.23
substituents at the C5-position of the B-region indole moiety had a
significant influence on the binding affinity for the 5-HT trans-
porter in both cis and trans isomeric series. For example, the C5-cy-
ano analogs showed a 24-fold (cis-8) and an 18-fold (trans-8)
increase in binding affinity compared to the non-substituted ana-
logs (cis-4 and trans-4). The C5-fluoro derivatives showed a seven-
fold (cis-2) and 23-fold (trans-2) increase in binding affinity
compared to the corresponding non-substituted analogs (cis-4
and trans-4). In contrast, the C5-methoxy analogs (cis-13 and
trans-13) and C5-chloro analogs (cis-14 and trans-14) were almost
devoid of the transporter affinity compared to the corresponding
non-substituted analogs (cis-4 and trans-4). A consistent trend
was followed by both cis and trans isomers demonstrating that
C5-CN > C5-F > H ꢀ C5-Cl ꢁ C5-OMe with respect to 5-HT trans-
porter binding affinity.
d
Stimulation of GTPc
S35 binding in CHO cells expressing 5-HT1A receptor.24 Emax
refers to maximal agonist effect relative to 5-HT.
e
Binding affinity at rat cortical a1 adrenergic receptors labeled with
[3H]prazosin.25
The presence of fluorine at the C4-, C5-, and C6- positions of the
B-region indole moiety was also found to have great impact on 5-
HT transporter affinity for both cis and trans isomers. The C5-fluoro
analogs (cis-2 and trans-2) had optimized 5-HT transporter binding
affinity compared to their corresponding C6-fluoro (cis-6 and trans-
6) and C4-fluoro analogs (cis-7 and trans-7). In fact, compounds
bearing a C4-fluoro at the B-region indole moiety (cis-7 and
trans-7) displayed dramatically lower binding affinity for 5-HT
transporter.

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6711
Table 4
Table 6
5-(Piperazin-1-yl)quinoline Analogs 19–20a
Other piperazine analogs 23–25a
R1
R1
N
Z
N
N
Ar
N
N
NH
GTP
NH
Compound
R1
r-5-HT-T
h-5-HT1A
c
S35
r-a1
Kib (nM)
Kic (nM)
Emax (%)
Kie (nM)
d
Compound Ar
R1
Z
r-5-HT-T
h-5-HT1A
GTP
Emax
(%)
c
S35 r-a1
d
Kib (nM)
Kic (nM)
Kie
cis-19
trans-19
cis-20
F
F
CN
CN
13.8
73
3.5
4.9
97.2
8.3
58.1
6.2
0
0
0
3
nd
156
522
293
(nM)
trans-20
N
N
N
cis-23
CN
CN
F
C
C
C
C
N
N
1.1
156.2
9.1
0
11
34
71
nd
nd
60.5
47.6
nd
nd, not determined.
a
Ki values are the mean of at least two experiments performed in triplicate,
determined from nine concentrations and all Ki values were calculated from IC50
values using the method of Cheng and Prusoff.21
N
b
Binding affinity at rat cortical 5-HT reuptake sites labeled with
trans-23
13.6
[3H]paroxetine.22
c
Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-
OH-DAPT.23
Stimulation of GTPc
S35 binding in CHO cells expressing 5-HT1A receptor.24 Emax
d
refers to maximal agonist effect relative to 5-HT.
cis-24
640
46% at 1
e
Binding affinity at rat cortical a1 adrenergic receptors labeled with
l
M
[3H]prazosin.25
trans-24
F
38% at 1
42.6
15.8
7.8
nd
Table 5
8-(Piperazin-1-yl)quinoline Analogs 21–22a
l
M
R1
HN
N
cis-25
H
0% at
100 nM
nd
N
N
NH
HN
trans-25
H
18% at
100 nM
nd
Compound
R1
r-5-HT-T
h-5-HT1A
GTP
Emax (%)
c
S35
r-a1
Kib (nM)
Kic (nM)
Kie (nM)
d
cis-21
trans-21
cis-22
F
F
CN
CN
4.6
39.3
1.3
69.7
6.5
43.9
2.9
20
66
23
0
177.0
82.0
78.0
66.0
nd, not determined.
a
Ki values are the mean of at least two experiments performed in triplicate,
determined from nine concentrations and all Ki values were calculated from IC50
values using the method of Cheng and Prusoff.21 Percentages represent inhibition of
binding at the concentration indicated.
trans-22
20.0
a
Ki values are the mean of at least two experiments performed in triplicate,
determined from nine concentrations and all Ki values were calculated from IC50
values using the method of Cheng and Prusoff.21
b
Binding affinity at rat cortical 5-HT reuptake sites labeled with
[3H]paroxetine.22
Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-
c
b
Binding affinity at rat cortical 5-HT reuptake sites labeled with
OH-DPAT.23
[3H]paroxetine.22
d
Stimulation of GTPc
S35 binding in CHO cells expressing 5-HT1A receptor.24 Emax
Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-
c
refers to maximal agonist effect relative to 5-HT.
OH-DAPT.23
e
Binding affinity at rat cortical a1 adrenergic receptors labeled with
d
Stimulation of GTPc
S35 binding in CHO cells expressing 5-HT1A receptor.24 Emax
[3H]prazosin.2
refers to maximal agonist effect relative to 5-HT.
e
Binding affinity at rat cortical a1 adrenergic receptors labeled with
[3H]prazosin.25
on understanding the effects of these modifications on affinity at
the 5-HT1A receptor.
Introduction of a C2-methyl group to the B-region indole moi-
ety also had a detrimental effect on the binding affinity for 5-HT
transporter in both cis and trans isomeric series (i.e., cis-15 and
trans-15), with only 4% and 12% inhibition in r-5-HT transporter
binding assay at 100 nM, respectively.
Further exploration of the SAR of the N-alkylations of the B-re-
gion indole moiety revealed that replacement of the N-proton with
N-alkyl substitutents showed a consistent trend toward decreased
5-HT transporter binding affinity for both cis and trans isomers
(e.g., cis- and trans-8 vs cis- and trans-9, 10, 11, and 12), suggesting
that the binding pocket of the 5-HT transporter appears to be sen-
sitive to steric bulk.
As summarized in Table 1, within each pair of geometric iso-
mers in the 3-{4-[4-(1H-indol-4-yl)-piperazin-4-yl]cyclohexyl}-in-
dole series (i.e., 2, 4–15), the trans isomers always demonstrated
more potent binding affinity for the 5-HT1A receptor than their
corresponding cis isomers. Changing different substituents at C5-
position of B-region indole moiety (e.g., non-substituted, C5-fluoro,
C5-cyano and C5-methoxy) had minimal impact on the binding
affinity at 5-HT1A receptor for both cis and trans isomers (cis- and
trans-4 vs 2, 8 and 13), suggesting that there exists a large toler-
ance of the 5-HT1A receptor toward electronic effects at C5-posi-
tion of B-region indole moiety. For example, cis- and trans-8
isomers were equipotent to the corresponding cis- and trans-13
isomers in the h-5-HT1A receptor binding assay.
Having investigated the effects of modifying the B-region indole
moiety on 5-HT transporter affinity, we next focused our attention

6712
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
The C5- and C6-fluoro substituted analogs (cis- and trans-2 vs
8-(Piperazin-1-yl)quinoline replacement for the 5-(piperazin-1-
yl)quinoline was likewise well-tolerated (Table 5) with respect to
the binding affinities at 5-HT transporter and 5-HT1A receptor, with
the exception of trans-22 that showed a fourfold loss of the binding
affinity for 5-HT transporter compared to trans-20. As a conse-
quence, none of the compounds proved superior to the trans-20
analog. In addition, replacement of 5-(piperazin-1-yl)quinoline
with 8-(piperazin-1-yl)-quinoline resulted in decreased selectivity
for the 5-HT1A receptor over the a1 adrenergic receptor.
For completeness, 5-(piperazin-1-yl)quinoxaline analogs were
also explored, albeit to a lesser extent (Table 6). Replacement of
5-(piperazin-1-yl)quinoline and 8-(piperazin-1-yl)quinoline with
5-(piperazin-1-yl)quinoxaline provided no improvement in bind-
ing affinities for the 5-HT transporter and 5-HT1A receptor, as well
as the selectivity over the a1 adrenergic receptor (cis- and trans-
23).
To further examine the effect of the heteroatoms in the aro-
matic ring (A-region), we prepared the naphthalenyl-piperazine
analogs cis- and trans-24. A deterioration of binding affinities at
both the 5-HT transporter and the 5-HT1A receptor was observed
when heteroaryl piperazines (29, 30, 33, 35, and 39) were replaced
by naphthalenyl-piperazine 40. The cis- and trans-24 analogs also
showed an increase in 5-HT1A receptor intrinsic activity. Both cis-
24 and trans-24 functioned as partial 5-HT1A receptor agonists.
The reduction in binding affinities at the 5-HT transporter and
the 5-HT1A receptor, and increase in agonism at 5-HT1A receptor
for compounds cis- and trans-24 may be due to the elimination
of the hydrogen-bonding interaction between the ligand and the
5-HT transporter and 5-HT1A receptor, suggesting that hydrogen-
bonding interaction in the A-region is critical for achieving activi-
ties at both 5-HT transporter and 5-HT1A receptor sites in this class
of molecules.
cis- and trans-6) showed comparable potency with respect to the
binding affinity at the 5-HT1A receptor. However, the C4-fluoro
analogs (cis- and trans-7) demonstrated reduced binding affinity
at the 5-HT1A receptor.
Furthermore, as depicted in Table 1, replacement of N-proton of
the B-region indole moiety with N-alkyls led to a decrease in the
binding affinity at the 5-HT1A receptor for both cis and trans iso-
mers (cis- and trans-8 vs 9, 10, 11, and 12).
We further examined six compounds (i.e., cis-2, trans-2, cis-4,
cis-6, cis-8, and trans-8) selected from Table 1, which exhibited
good binding affinities at both 5-HT1A receptor and the 5-HT trans-
porter, for their intrinsic activity at the 5-HT1A receptor as well as
selectivity against the a1 adrenergic receptor (Table 2).
These six compounds were tested in vitro using a GTPc
S35 bind-
ing assay to determine their agonist/antagonist properties at the
5-HT1A receptor. Four cis analogs (cis-2, cis-4, cis-6, and cis-8) ap-
peared to be antagonists or very weak partial agonists (Emax values
expressed as a percentage of the maximal activity of 5-HT), indicat-
ing that antagonism of the 5-HT1A receptor was more readily
achieved for cis isomers in this series. With respect to the selectiv-
ity for the 5-HT1A receptor over the a1 adrenergic receptor, cis-4
was observed to have the best profile. The C5-fluoro (cis-2 and
trans-2), C6-fluoro (cis-6), and C5-cyano (trans-8) analogs exhib-
ited moderate selectivity (5- to 8-fold).
By now we had developed a clear picture of the B-region indole
moiety requirements for potent binding at 5-HT transporter and 5-
HT1A receptor when employing the 1-(4-indolyl)piperazine motif
as a 5-HT1A receptor pharmacophore. Most critical was to have a
C5-fluoro or a C5-cyano substitution on the B-region indole ring.
With respect to a1 adrenergic receptor selectivity, no substitution
on the B-region indole ring was optimal, although the correspond-
ing cis-4 analog was less potent for 5-HT transporter binding affin-
ity when compared to C5-fluoro (cis-2) or C5-cyano (cis-8) analogs.
Having identified the cis-4 analog to be selective for the 5-HT1A
receptor over the a1 adrenergic receptor, we set out to further
increase the binding affinities at 5-HT transporter and 5-HT1A
receptor by modifying the A-region aryl moiety while maintaining
the 4-(1H-indol-3-yl)cyclohexyl moiety constant. As a result, a 7-
(piperazin-1-yl)benzo-[d]imidazole moiety was introduced as a
surrogate for the 1-(4-indolyl)piperazine. As shown in Table 3,
compared to the 1-(4-indolyl)piperazine analog cis-4, benzoimi-
dazole analogs cis- and trans-16–18 exhibited a trend toward the
improvement of the binding affinity for the 5-HT1A receptor (e.g.,
2- to 18-fold), but failed to improve the binding affinity for the
5-HT transporter, with the exception of compound cis-16, which
showed a threefold increase in binding affinity for the 5-HT trans-
porter. As noted previously (Table 2), all the cis isomers (cis-16–18)
appeared as 5-HT1A receptor antagonists. Interestingly, three trans
isomers (trans-16–18) also had low 5-HT1A receptor intrinsic activ-
ity. Benzoimidazole analog cis-16 demonstrated potent and bal-
anced affinity for 5-HT transporter and 5-HT1A receptor and
functioned as a 5-HT1A receptor antagonist, albeit at the cost of
reduction of the selectivity for the 5-HT1A receptor over the a1
adrenergic receptor (e.g., cis-16: fourfold).
The final SARs examined in this investigation entailed replace-
ment the B-region 3-cyclohexyl-indole moiety with 3-cyclohexyl-
7-azoindole 41 (Table 6). Both isomers (cis- and trans-25) were
devoid of 5-HT transporter affinity, but maintained potent binding
affinity for 5-HT1A receptor, strongly indicating that 3-cyclohexyl-
7-azoindole moiety was not a desirable 5-HT transporter pharma-
cophoric modification.
4. Conclusion
In this study, we synthesized a class of arylpiperazine-4-yl-
cyclohexyl indole derivatives (4–25). The goal of creating a single
molecular entity with dual activities as both a 5-HT transporter
inhibitor and a 5-HT1A receptor antagonist has been achieved.
Through structural modifications of 3-(cis-4-(4-(1H-indol-4-yl)pip-
erazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (cis-2), we have devel-
oped a thorough understanding of the interactions between the
arylpiperazineyl-indole derivatives and the 5-HT transporter and
5-HT1A receptor. The heteroaryl piperazines of A-region and the
3-cyclohexyl-indoles of B-region in the structure 3 are clearly crit-
ical, as the naphthalenyl-piperazine (cis- and trans-24) and 3-
cyclohexyl-azoindole (cis- and trans-25) replacements significantly
decreased the dual activities at both 5-HT transporter and 5-HT1A
receptor. Furthermore, our studies demonstrated that the substitu-
tion pattern on the B-region indole ring in structure 3 was very
important and that C5-cyano and C5-fluoro were preferred with
respect to the binding affinities at 5-HT transporter and 5-HT1A
receptor. Finally, selectivity for the 5-HT1A receptor over the a1
adrenergic receptor in this series of compounds spans a wide
range, with selectivity ratios from 0.2- to 75-fold. The most
interesting compound identified from this study is the 5-(pipera-
zin-1-yl)quinoline analog trans-20, which exhibited nearly equal
potencies at both 5-HT transporter (Ki = 4.9 nM) and 5-HT1A recep-
Further exploration of the SAR of A-region of cis-2 is revealed in
Tables 4–6. Compared to the 1-(4-indolyl)piperazine analogs (cis-
and trans-2 and 8), 5-(piperazin-1-yl)quinoline analogs (cis- and
trans-19 and 20) gave no improvement in binding affinity for 5-
HT transporter and 5-HT1A receptor. However, the selectivity for
the 5-HT1A receptor over the a1 adrenergic receptor was improved
in the analogs of cis- and trans-20. 5-(Piperazin-1-yl)quinoline ana-
log trans-20 exhibited nearly equal potencies for both 5-HT trans-
porter and 5-HT1A receptor. In addition, analog trans-20 showed
nearly 50-fold 5-HT1A receptor selectivity over the a1 adrenergic
receptor.

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6713
tor (Ki = 6.2 nM), and functioned as a full 5-HT1A receptor antago-
nist. In addition, trans-20 showed nearly 50-fold 5-HT1A receptor
selectivity over the a1 adrenergic receptor.
5.1.5. 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-2-methyl-1H-
indole (25h)
This compound was prepared in a similar fashion as described
above (25c) by replacing 6-fluoroindole with 2-methylindole
(4.76 g, 30.4 mmol) to afford 2.35 g (62%) of the title product as a
white solid: mp 136–137 °C; 1H NMR (400 MHz, DMSO-d6) d 1.81
(t, J = 6.36 Hz, 2H), 2.33 (s, 3H), 2.38 (m, 2H), 2.50–2.54 (m, 2H),
3.92 (s, 4H), 6.88–6.92 (m, 2H), 6.94–6.98 (m, 1H), 7.21 (d,
J = 7.92 Hz, 1H), 7.40 (d, J = 7.68 Hz, 1H), 10.84 (s, 1H). Anal. Calcd
for C17H19NO2: C, 75.81; H, 7.11; N, 5.70. Found: C, 75.47; H, 7.26;
N, 5.13.
5. Experimental
5.1. General method: Chemistry
Melting points were determined on a Thomas-Hoover melting
point apparatus and are uncorrected. 1H NMR spectra were re-
corded on a Varian Unity Plus 400 instrument. Chemical shifts
are reported in d values (part per million, ppm) relative to an inter-
nal standard of tetramethylsilane in CDCl3 or DMSO-d6. Mass spec-
5.1.6. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-6-fluoro-1H-indole (26c)
A mixture of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-6-fluoro-1H-
indole 25c (9.54 g, mmol) and 10% palladium on carbon (0.35 g) in
ethanol (80 mL) was hydrogenated under 45 Psi for 18 h. The cata-
lyst was filtered off, and then a solution of methylene/methanol
(80 mL) was used to dissolve any solids within the Celite. The was
solvent removed in vacuo to afford 5.83 g (60%) of the title product
as an off-white solid, which was triturated with ethyl ether
tra were recorded on
a Micromass LCT spectrometer. CHN
combustion analyses were determined on either a Perkin-Elmer
2400 analyzer or were performed by Robertson Microlit (Madison,
NJ). Solvents and reagents were used as purchased.
5.1.1. 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-6-fluoro-1H-indole
(25c)
(40 mL) to afford
a
white solid: mp 158–159 °C; 1H NMR
A solution of 6-fluoro-indole (5.14 g, 38 g, 38 mmol), 1,4-cyclo-
hexanedione mono-ethylene ketal (5.9 g, 38 mmol), and potassium
hydroxide (7.6 g, 190 mol) in 50 mL methanol was heated to reflux
for 18 h. The mixture was poured into water (150 mL) and ex-
tracted with methylene chloride (2Â 200 mL). The organic layer
was dried over anhydrous magnesium sulfate, filtered, and solvent
was removed in vacuo. Chromatography (25% ethyl acetate/hex-
anes) afforded 10 g (96.3%) of the title product as a white solid:
mp 196–197 °C; 1H NMR (400 MHz, DMSO-d6) d 1.78–1.82 (m,
2H), 2.38 (m, 2H), 2.54–2.57 (m, 2H), 3.91 (s, 4H), 5.99–6.01 (m,
1H), 6.83–6.88 (m, 1H), 7.12 (dd, J = 10.12, 2.64 Hz, 1H), 7.35 (d,
J = 2.40 Hz, 1H), 7.70–7.76 (m, 1H), 11.13 (br, 1H). Anal. Calcd for
(400 MHz, DMSO-d6) d 1.61–1.76 (6H, m), 1.90–1.93 (2H, m),
2.77–2.82 (1H, m), 3.88 (4H, s), 6.77–6.82 (1H, m), 7.05–7.09 (1H,
m), 7.49–7.52 (1H, m), 10.81 (1H, br). Anal. Calcd for C16H18FNO2:
C, 69.80; H, 6.59; N, 5.09. Found: C, 69.74; H, 6.48; N, 5.13.
5.1.7. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (26d)
This compound was prepared in a similar fashion as described
above (26c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-6-
fluoro-1H-indole with 3-(1,4-dioxa-spiro[4,5]-dec-7-en-8-yl)-5-
cyano-1H-indole (54.6 g) to afford 52.1 g (95%) of the title
compound as a white solid in 95% (52.1 g) yield: mp 153–155 °C;
MS (ESI) m/z 281 ([M+H]+); 1H NMR (400 MHz, DMSO-d6) d 1.64–
1.76 (m, 6H), 1.94 (m, 2H), 2.88 (m, 1H), 3.88 (s, 4H), 7.30 (s,
1H), 7.38 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 8.09 (s, 1H),
11.36 (br, 1H).
C16H16FNO2: C, 70.32; H, 5.90; N, 5.13. Found: C, 70.62; H, 5.91;
N, 5.08.
5.1.2. 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole
(25d)
5.1.8. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-4-fluoro-1H-indole (26f)
This compound was prepared in a similar fashion as described
above (26c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-6-
fluoro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-4-flu-
oro-1H-indole (6.3 g) to afford 4.44 g (70%) of the title compound
as a white solid: mp 161–162 °C; MS (EI) m/z 275 (M+); 1H NMR
(400 MHz, CDCl3) d 1.72–1.90 (m, 6H), 2.12–2.15 (m, 2H), 3.03–
3.06 (m, 1H), 3.99 (s, 4H), 6.71–6.76 (m, 1H), 6.93 (m, 1H), 7.04–
7.12 (m, 2H), 8.02 (br, 1H). Anal. Calcd for C16H18FNO2: C, 69.08;
H, 6.59; N, 5.09. Found: C, 69.05; H, 6.56; N, 4.87.
This compound was prepared in a similar fashion as described
above (25c) by replacing 6-fluoroindole with 5-cyanoindole
(29.98 g, 0.21 mol) to afford 29.32 g (50%) of the title compound
as a white solid: mp 158–160 °C; MS (ESI) m/z 279 ([M+H]+); 1H
NMR (400 MHz, DMSO-d6) d 1.82 (t, J = 4.0 Hz, 2H), 2.41 (m, 2H),
2.58 (t, J = 4.0 Hz, 2H), 3.92 (s, 4H), 6.08 (m, 1H), 7.43 (d,
J = 4.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H), 8.25 (s, 1H), 11.66 (br, 1H).
5.1.3. 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-4-fluoro-1H-indole
(25f)
This compound was prepared in a similar fashion as described
above (25c) by replacing 6-fluoroindole with 4-fluoroindole (3 g,
22 mmol) to afford the title compound in quantitative yield as a
white solid: mp at 140 °C sublimated; MS (EI) m/z 273 (M+); 1H
NMR (400 MHz, CDCl3) d1.95 (t, J = 6.56 Hz, 2H), 2.02 (t,
J = 7.24 Hz, 2H), 2.70 (m, 2H), 4.03 (s, 4H), 5.94 (m, 1H), 7.06–
7.14 (m, 2H), 8.10 (br, 1H).
5.1.9. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-chloro-1H-indole
(26g)
A mixture of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-chloro-
1H-indole (0.18 g) and platinum oxide (0.02 g) in ethanol (20 mL)
with ten drops of acetic acid was hydrogenated under 45 Psi over-
night. The catalyst was filtered off and the solvent removed in va-
cuo. Chromatography (25% ethyl acetate/hexanes) afforded 0.16 g
(88%) of the title product as a white solid: mp 205–206.5 °C; MS
(FAB) m/z 291 ([M+H]+); 1H NMR (400 MHz, CDCl3) d 1.71–1.79
(m, 4H), 1.81–1.87 (m, 2H), 2.04–2.083 (m, 2H), 2.82–2.86 (m,
1H), 3.99 (s, 3H), 6.99 (m, 1H), 7.12 (dd, J = 8.56, 1.96 Hz, 1H),
7.26 (t, J = 4.30 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 8.02 (br, 1H).
5.1.4. 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-chloro-1H-indole
(25g)
This compound was prepared in a similar fashion as described
above (25c) by replacing 6-fluoroindole with 5-chloroindole (5 g,
33 mmol) to afford 9.14 g (96%) of the title compound as a white
solid: mp 178–181 °C; MS (EI) m/z 273 (M+); 1H NMR (400 MHz,
CDCl3) d 1.96 (t, J = 6.6 Hz, 2H), 2.53 (m, 2H), 2.65–2.70 (m, 2H),
4.04 (s, 4H), 6.06–6.09 (m, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.15 (dd,
J = 5.24, 2.6 Hz, 1H), 7.25 (m, 1H), 7.84 (d, J = 2.0 Hz, 1H), 8.11
(br, 1H).
5.1.10. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-2-methyl-1H-indole
(26h)
This compound was prepared in a similar fashion as de-
scribed above (26c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-

6714
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
en-8-yl)-6-fluoro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-
en-8-yl)-2-methyl-1H-indole (2.39 g, 8.9 mmol) to afford 2.34 g
5.1.13. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-N-propyl-
indole (27l)
(97%) of the title compound as
a
white solid: mp 166–
This compound was prepared in a similar fashion as described
above (27k) by replacing ethylbromide with n-propylbromide
(13.1 g, 11 mmol) to afford 4.33 g (75%) of the title compound as
an oil: MS (EI) m/z 324 (M+); 1H NMR (400 MHz, DMSO-d6) d
0.79 (t, J = 7.24 Hz, 3H), 1.62–1.78 (m, 8H), 1.92–1.96 (m, 2H),
2.88 (m, 1H), 3.87 (s, 4H), 4.11 (t, J = 7.00 Hz, 2H), 7.35 (s, 1H),
7.42 (dd, J = 8.56, 1.52 Hz, 1H), 7.62 (d, J = 8.56 Hz, 1H), 8.10 (m,
1H).
168 °C; MS (EI) m/z 271 (M+); The mother liquor was concen-
trated to afford another 1.2 g of the title product as a yellow
solid. 1H NMR (400 MHz, DMSO-d6)
d 1.58–1.65 (m, 4H),
1.74–1.77 (m, 2H), 2.06–2.13 (m, 2H), 2.31 (s, 3H), 2.74–2.80
(m, 1H), 3.86–3.95 (m, 4H), 6.84–6.99 (m, 2H), 7.18–7.20 (m,
1H), 7.46 (d, J = 7.68 Hz, 1H), 10.61 (s, 1H). Anal. Calcd for
C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.17; H,
7.99; N, 5.12.
5.1.14. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-iso-propyl-
indole (27m)
5.1.11. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-
indole (27j)
This compound was prepared in a similar fashion as described
above (27k) by replacing ethylbromide with isopropylbromide
(10.2 g, 83 mmol) in 62% yield (6.44 g) as a white solid: mp
114.5–116 °C; MS (EI) m/z 324 (M+); 1H NMR (400 MHz, DMSO-
d6) d 1.41–1.45 (m, 6H), 1.65–1.94 (m, 8H), 2.86 (m, 1H), 3.88 (s,
4H), 4.75 (m, 1H), 7.43 (m, 1H), 7.46(m, 1H), 7.60–7.65 (m, 1H),
8.09 (s, 1H).
(a) To
0.073 mol) in anhydrous N,N-dimethylformamide (100 mL) was
added 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole
a suspension of sodium hydride (60%, 1.74 g,
(9.9 g, 0.035 mol) at room temperature. The mixture was stirred
for 30 min at room temperature, then methyl iodide (9 mL,
0.14 mol) was added at room temperature. The reaction was al-
lowed to stir for 1 h, then quenched with water (50 mL). The
mixture was extracted with methylene chloride (3Â 150 mL)
and water (3Â 150 mL). The organic layer was dried over
anhydrous magnesium sulfate and filtered. The solvent was re-
moved in vacuo. Chromatography (5% methanol/methylene
chloride) afforded 2.54 g (24%) of 3-(1,4-dioxa-spiro[4,5]dec-7-
en-8-yl)-5-cyano-1-methyl-indole as a light yellow solid: mp
65–67 °C; 1H NMR (400 MHz, DMSO-d6) d 1.81 (t, J = 6.60 Hz,
2H), 2.39–2.46 (m, 2H), 2.53–2.56 (m, 2H), 2.84–2.90 (m, 1H),
3.79 (s, 3H), 3.91 (s, 4H), 6.46 (s, 1H), 6.07 (m, 1H), 7.50 (dd,
J = 8.56, 1.56 Hz, 1H), 7.56 (s, 1H), 7.60 (d, J = 8.56 Hz, 1H),
8.25 (m, 1H). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N,
9.52. Found: C, 73.17; H, 6.24; N, 9.43. (b) A mixture of 3-
(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1-methyl-indole (3.77
g) and 10% palladium on carbon (0.99 g) in ethanol/tetrahydro-
furan (200:80 mL) was hydrogenated under 45 Psi for 5 h. The
catalyst was filtered off and the solvent was removed in vacuo
to afford a white powder which was washed with ethanol/hex-
anes (1:1) and dried under vacuum for 4 h to afford 2.75 g
(12%) of the title product: mp 170–172 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.62–1.76 (m, 6H), 1.92–1.94 (m, 2H), 2.88 (m,
1H), 3.77 (s, 3H), 3.88 (s, 4H), 7.30 (m, 1H), 7.45 (dd, J = 8.56,
1.52 Hz, 1H), 7.55 (d, J = 8.56 Hz, 1H), 8.10–8.11 (m, 1H). Anal.
Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
72.79; H, 6.82; N, 9.35.
5.1.15. 4-(6-Fluoro-1H-3-indolyl)-cyclohexanone (28c)
A solution of 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-fluoro-indole
(5.4 g) in 150 mL (1:1) tetrahydrofuran/hydrochloric acid (1 N)
was allowed to stir at room temperature for 16 h, followed by
the addition of 4.49 g sodium bicarbonate. The mixture was ex-
tracted with methylene chloride (3Â 100 mL), washed with brine
(3Â 150 mL). The organic layer was dried over anhydrous magne-
sium sulfate and filtered. The solvent was removed to afford a light
brown solid that was boiled in ethyl acetate/hexanes (1:1). The
mixture was cooled to room temperature, and solid was collected
and dried under vacuum to afford 19.3 g (99%) of the title com-
pound as a white solid: mp 102–105 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.79–1.90 (m, 2H), 2.22–2.29 (m, 4H), 2.57–2.66 (m,
2H), 3.25–3.32 (m, 1H), 6.80–6.85 (m, 1H), 7.08–7.13 (m, 1H),
7.58–7.62 (m, 1H), 10.89 (br, 1H). Anal. Calcd for C14H14NOF: C,
72.71; H, 6.10; N, 6.06. Found: C, 72.77; H, 5.98; N, 5.96.
5.1.16. 3-(4-Oxo-cyclohexyl)-1H-indole-5-carbo-nitrile (28d)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-in-
dole (6 g) to afford 4.0 g (81%) of the title compound as a white
solid: mp 162.5–164 °C; 1H NMR (400 MHz, DMSO-d6): d1.82–
1.93 (m, 2H), 2.22–2.30 (m, 4H), 2.58–2.67 (m, 2H), 3.33–3.39
(m, 1H), 7.34 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 8.24 (s, 1H),
11.42 (s, 1H). Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N,
11.76. C, 75.82; H, 6.06; N, 11.72.
5.1.12. 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-ethyl-indole
(27k)
To a suspension of sodium hydride (60%, 1.63 g, 0.068 mol) in
anhydrous N,N-dimethylformamide (150 mL) was added 3-(1,4-
dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (9.0 g, 0.032 mol) at
room temperature. The mixture was stirred for 30 min at room
temperature then ethylbromide (14.6 g, 0.13 mol) was added at
room temperature. The reaction was allowed to stir overnight,
and then quenched with water (50 mL). The mixture was extracted
with methylene chloride (3Â 150 mL) and water (3Â 150 mL). The
organic layer was dried over anhydrous magnesium sulfate and fil-
tered. The solvent was removed in vacuo. Chromatography (hex-
anes) afforded 5.5 g (69%) of the title product as a white solid:
5.1.17. 4-(5-Methoxy-1H-3-indolyl)-cyclohexanone (28e)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-methoxy-1H-
indole (5.9 g) to afford 4.2 g (85%) of the title compound as a white
solid: mp 103–106 °C; MS (EI) m/z 243 (M+); 1H NMR (400 MHz,
CDCl3): d 1.92–2.03 (m, 2H), 2.40–2.47 (m, 2H), 2.49–2.63 (m,
4H), 3.27–3.34 (m, 1H), 3.89 (s, 3H), 6.88 (dd, J = 8.80, 2.40 Hz,
1H), 6.97 (d, J = 2.40 Hz, 1H), 7.07 (d, J = 2.40 Hz, 1H), 7.27 (d,
J = 8.8 Hz, 1H), 7.93 (s, 1H).
mp 124–126 °C; 1H NMR (400 MHz, DMSO-d6)
d 1.32 (t,
5.1.18. 4-(4-Fluoro-1H-3-indolyl)-cyclohexanone (28f)
J = 7.24 Hz, 3H), 1.63–1.76 (m, 6H), 1.93–1.94 (m, 2H), 2.83 (m,
1H), 3.88 (s, 4H), 4.18 (q, J = 7.04 Hz, 2H), 7.37 (s, 1H), 7.43 (dd,
J = 8.56, 1.52 Hz, 1H), 7.60 (d, J = 8.56 Hz, 1H), 8.10 (m, 1H). Anal.
Calcd for C19H20N2O2: C, 73.52; H, 7.14; N, 9.02. Found: C, 73.56;
H, 6.93; N, 8.95.
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-4-fluoro-1H-
indole (4.0 g) to afford 3.7 g (63%) of the title compound as a white

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6715
solid: mp 104–106 °C; MS (EI) m/z 231 (M+); 1H NMR (400 MHz,
CDCl3) d 1.82–1.95 (m, 2H), 2.43–2.63 (m, 6H), 3.46–3.54 (m,
1H), 6.75–6.80 (m, 1H), 6.94 (m, 1H), 7.07–7.15 (m, 2H), 8.14 (br,
1H).
5.1.24. 4-(5-Cyano-1-n-propyl-3-indolyl)-cyclo-hexanone (28l)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-n-
propyl-indole (2.6 g, 8.2 mmol) to afford 1.7 g (73%) of the title
compound as a white solid: mp 103–104 °C; MS (EI) m/z 280
(M+); 1H NMR (400 MHz, DMSO-d6) d 0.80 (t, J = 7.48 Hz, 3H),
1.71–1.76 (m, 2H), 1.82–1.92 (m, 2H), 2.22–2.29 (m, 4H), 2.58–
2.66 (m, 2H), 3.31 (m, 1H), 4.12 (t, J = 7.00 Hz, 2H), 7.40 (s, 1H),
7.44 (dd, J = 8.56, 1.52 Hz, 1H), 7.64 (d, J = 8.56 Hz, 1H), 8.25 (m,
1H). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found:
C, 76.80; H, 7.10; N, 9.82.
5.1.19. 4-(5-Chloro-1H-3-indolyl)-cyclohexanone (28g)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-chloro-1H-
indole (2.1 g) to afford 1.1 g (60%) of the title compound as a clear
oil. MS (FAB) m/z 248 ([M+H]+); 1H NMR (400 MHz, CDCl3) d 1.90–
2.00 (m, 2H), 2.39–2.45 (m, 2H), 2.50–2.62 (m, 4H), 3.26–3.30 (m,
1H), 7.02 (d, J = 2.44 Hz, 1H), 7.16 (dd, J = 8.80, 1.96 Hz, 1H), 7.29
(d, J = 8.56 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 8.04 (br, 1H).
5.1.25. 4-(5-Cyano-1-isopropyl-3-indolyl)-cyclo-hexanone
(28m)
5.1.20. 4-(2-Methyl-1H-3-indolyl)-cyclohexanone (28h)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-iso-
propyl-indole (5.86 g, 16 mmol) to afford 3.5 g (63%) of the title
compound as a white solid: mp 106–107 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.41 (d, J = 6.6 Hz, 6H), 1.45–1.94 (m, 2H), 2.22–2.29
(m, 4H), 2.58–2.67 (m, 2H), 3.34–3.39 (m, 1H), 4.78 (m, 1H), 7.44
(dd, J = 8.56, 1.32 Hz, 1H), 7.52 (s, 1H), 7.65 (d, J = 8.56 Hz, 1H),
8.25 (m, 1H). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.0.
Found: C, 76.85; H, 7.16; N, 9.
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-2-methyl-
1H-indole (2.2 g) to afford 1.6 g (88%) of the title compound as a
yellow thick oil: MS (EI) m/z 227 (M+); 1H NMR (400 MHz,
DMSO-d6) d 1.95–1.99 (m, 2H), 2.21–2.30 (m, 4H), 2.37 (s, 3H),
2.56–2.64 (m, 2H), 3.27–3.32 (m, 1H), 6.84–6.88 (m, 1H), 6.91–
6.95 (m, 1H), 7.19–7.20 (m, 1H), 7.50–7.52 (m, 1H), 10.68 (s, 1H).
5.1.21. 4-(5-Fluoro-1-methyl-1H-indol-3-yl)cyclo-hexanone
(28i)
5.1.26. 5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (cis-2)
To a suspension of sodium hydride (60%, 0.18 g, 4.5 mmol) in
anhydrous N,N-dimethylformamide (10 mL) at room tempera-
ture was added 4-(5-fluoro-1H-indol-3-yl) cyclohexasnone
(0.7 g, 3.0 mmol), and the mixture was stirred for 0.5 h. Then
to the above solution was added iodomethane (0.21 mL,
3.3 mmol) at room temperature, and the resulting mixture was
stirred for another 0.5 h and quenched with water. The mixture
was extracted with methylene chloride (3Â 50 mL), and the or-
ganic layer was dried over anhydrous sodium sulfate and fil-
tered. Chromatography (30% ethyl acetate/hexanes) afforded
0.35 g (46%) of the title product as a yellow solid: mp 102.5–
104.5 °C; MS (EI) m/z 245 (M+); 1H NMR (400 MHz, DMSO-d6)
d 1.89 (m, 2H), 2.37–2.43 (m, 2H), 2.50–2.62 (m, 4H), 3.25–
3.31 (m, 1H), 3.76 (s, 3H), 6.89 (s, 1H), 6.96–7.02 (m, 1H),
7.20–7.23 (m, 1H), 7.27–7.31 (m, 1H).
A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.56 g,
2.5 mmol), 1-(indol-4-yl)piperazine (0.5 g, 2.5 mmol), sodium tri-
acetoxyborohydride (0.78 g, 3.5 mmol), and acetic acid (0.14 mL,
2.5 mmol) in 1,2-dichloroethane (11 mL) was allowed to stir at
room temperature overnight. The reaction was quenched with
1 N sodium hydroxide (10 mL), extracted with methylene chloride
(3Â 60 mL), and washed with brine (3Â 60 mL). The organic layer
was dried over anhydrous sodium sulfate and filtered. Chromatog-
raphy (10% methanol/ethyl acetate) afforded 0.54 g (52%) of the ti-
tle product as a white solid: mp 85–87 °C. The HCl salt was
prepared in ethyl acetate: mp 215–217 °C; 1H NMR (400 MHz,
DMSO-d6)d 1.81–1.92 (m, 4H), 2.01–2.04 (m, 2H), 2.16–2.19 (m,
2H), 3.18–3.39 (m, 6H), 3.60–3.69 (m, 4H), 6.43–6.44 (m, 1H),
6.48 (d, J = 7.3 Hz, 1H), 6.87–6.92 (m, 1H), 6.98 (t, J = 7.9 Hz, 1H),
7.08 (d, J = 7.9 Hz, 1H), 7.26–7.35 (m, 3H), 7.43–7.44 (m, 1H),
10.41 (br s, 1H), 11.05 (s, 1H), 11.14 (s, 1H). Anal. Calcd for
5.1.22. 4-(5-Cyano-1-methyl-3-indolyl)-cyclo-hexanone (28j)
This compound was prepared in a similar fashion as described
above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-flu-
oro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-
methyl-indole (5.5 g) to afford 2.1 g of the title compound as a
white solid: mp 150–152 °C; 1H NMR (400 MHz, DMSO-d6) d 1.32
(t, J = 7.24 Hz, 3H), 1.81–1.88 (m, 2H), 2.22–2.30 (m, 4H), 2.58–
2.66 (m, 2H), 3.32–3.39 (m, 1H), 4.19 (q, J = 7.24 Hz, 2H), 7.42 (m,
1H), 7.45 (dd, J = 8.60, 1.52 Hz, 1H), 7.62 (d, J = 8.60 Hz, 1H), 8.23
(m, 1H). Anal. Calcd for C15H15N2O: C, 76.16; H, 6.39; N, 11.10.
Found: C, 75.84; H, 6.34; N, 10.9.
C
26H29FN4ÁHClÁ0.36C4H8O2: C, 67.37; H, 6.88; N, 11.45. Found: C,
67.18; H, 6.72; N, 11.18.
5.1.27. 5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (trans-2)
The trans compound was isolated at the same time as the cis-2
isomer in 30% yield (0.31 g) as a white solid: mp 112–114 °C. The
HCl salt was prepared in ethanol: mp 280 °C (decomposed); 1H
NMR (400 MHz, DMSO-d6) d 1.54–1.62 (m, 2H), 1.71–1.80 (m,
2H), 2.12–2.15 (m, 2H), 2.29–2.32 (m, 2H), 2.72–2.78 (m, 1H),
3.23–3.43 (m, 5H), 3.56–4.03 (m, 4H), 6.47–6.48 (m, 1H), 6.52
(d, J = 7.5 Hz, 1H), 6.86–6.92 (m, 1H), 7.00 (t, J = 7.9 Hz, 1H),
7.10 (d, J = 7.9 Hz, 1H), 7.18–7.19 (m, 1H), 7.28–7.38 (m, 3H),
10.78 (br s, 1H), 10.94 (s, 1H), 11.17 (s, 1H). Anal. Calcd for
5.1.23. 4-(5-Cyano-1-ethyl-3-indolyl)-cyclo-hexanone (28k)
This compound was prepared in a similar fashion as de-
scribed above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-
yl)-6-fluoro-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cya-
no-1-ethyl-indole (6.77 g, 22 mmol) to afford 4.33 g (75%) of
C
26H29FN4ÁHCl: Calcd C, 66.81; H, 6.81; N, 11.99. Found: C,
66.44; H, 6.66; N, 11.74.
the title compound as
a
white solid: mp 124 °C; 1H NMR
(400 MHz, DMSO-d6) d 1.86 (m, 2H), 2.21–2.30 (m, 4H), 3.32–
3.35 (m, 1H), 3.77 (s, 3H), 7.34 (s, 1H), 7.47 (dd, J = 8.56,
1.52 Hz, 1H), 7.57 (d, J = 8.56 Hz, 1H), 8.26 (m, 1H). Anal. Calcd
for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C, 76.30; H,
6.82; N, 10.25.
5.1.28. 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]-cyclo-hexyl]-
1H-indole (cis-4)
A
solution of 4-(1H-indol-3-yl)-cyclohexanone10 (0.53 g,
2.5 mmol), 1-(indol-4-yl)piperazine (0.5 g, 2.5 mmol), sodium

6716
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
triacetoxyborohydride (0.78 g, 3.5 mmol), and acetic acid (0.14 mL,
2.5 mmol) in 1,2-dichloroethane (11 mL) was allowed to stir at
room temperature overnight. The reaction was quenched with
1 N sodium hydroxide (10 mL), extracted with methylene chloride
(3Â 60 mL), and washed with brine (3Â 60 mL). The organic layer
was dried over anhydrous sodium sulfate and filtered. Chromatog-
raphy (10% methanol/ethyl acetate) afforded 0.52 g (53%) of the ti-
tle product as a white solid: mp 85–87 °C. The HCl salt was
prepared in ethyl acetate: mp 198–200 °C (off-white solid); MS
(FAB) m/z 399 ([M+H]+); 1H NMR (400 MHz, DMSO-d6) d 1.82–
1.93 (m, 4H), 1.98–2.10 (m, 2H), 2.17–2.23 (m, 2H), 3.20–3.40
(m, 6H), 3.60–3.70 (m, 4H), 6.42–6.48 (m, 1H), 6.50 (d,
J = 7.47 Hz, 1H), 6.94–7.10 (m, 4H), 7.26–7.35 (m, 3H), 7.53 (d,
J = 7.91 Hz, 1H), 10.47 (br, 1H), 10.92 (s, 1H), 11.16 (s, 1H); Anal.
Calcd. for C26H30N4Á1HClÁ1.25H2O: C, 68.25; H, 7.38; N, 12.25.
Found: C, 68.12; H, 7.16; N, 11.93.
was prepared in ethanol: mp 250–252 °C (decomposed); 1H NMR
(400 MHz, DMSO-d6) d 1.81–1.91 (m, 4H), 1.97–2.02 (m, 2H),
2.17–2.19 (m, 2H), 3.27–3.39 (m, 6H), 3.61–3.69 (m, 4H), 6.49
(br, 1H), 6.54 (m, 1H), 6.79–6.80 (m, 1H), 6.99 (t, J = 7.68 Hz, 1H),
7.08–7.09 (m, 1H), 7.11 (m, 1H), 7.28 (t, J = 2.84 Hz, 1H), 7.35 (d,
J = 1.52 Hz, 1H), 7.52 (dd, J = 8.76, 5.72 Hz, 1H), 10.63 (br, 1H),
11.02 (s, 1H), 11.78 (s, 1H). Anal. Calcd for C26H29FN4Á2HClÁ
0.75H2O: C, 62.09; H, 6.51; N, 11.14. Found: C, 62.20; H, 6.50; N,
11.16.
5.1.33. 6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-pipera-zinyl]
cyclohexyl]-1H-indole (trans-6)
The trans compound was isolated at the same time as the cis-6
isomer in 27% yield (0.55 g) as a white foam. The HCl salt was pre-
pared in ethanol: mp 319–320 °C (decomposed); 1H NMR
(400 MHz, DMSO-d6) d 1.52–1.62 (m, 2H), 1.72–1.81 (m, 2H),
2.13–2.16 (m, 2H), 2.30–2.32 (m, 2H), 2.74–2.80 (m, 1H), 3.28–
3.42 (m, 5H), 3.59–3.62 (m, 2H), 3.71–3.74 (m, 2H), 6.50 (br, 1H),
6.54 (m, 1H), 6.79–6.84 (m, 1H), 7.00 (t, J = 7.68 Hz, 1H), 7.08–
7.12 (m, 3H), 7.30 (t, J = 2.88 Hz, 1H), 7.526 (dd, J = 8.76, 5.48 Hz,
1H), 10.90 (br, 1H), 10.91 (s, 1H), 11.18 (s, 1H). Anal. Calcd for
5.1.29. 3-[trans-4-[4-(1H-Indol-4-yl)-1-pipera-zinyl]-cyclohexyl]-
1H-indole (tans-4)
The trans compound was isolated at the same time as the cis-4
isomer in 21% yield (0.21 g) as a white solid: mp 105–107 °C. The
HCl salt (off-white solid) was prepared in ethyl acetate: mp
305 °C (decomposed); 1H NMR (400 MHz, DMSO-d6)d 1.54–1.64
(m, 2H), 1.73–1.82 (m, 2H), 2.15–2.18 (m, 2H), 2.30–2.33 (m,
2H), 2.76–2.83 (m, 1H), 3.25–3.42 (m, 5H), 3.59–3.79 (m, 4H),
6.48–6.50 (m, 1H), 6.54 (d, J = 7.47 Hz, 1H), 6.94–7.12 (m, 5H),
7.29–7.34 (m, 2H), 7.58 (d, J = 7.69 Hz, 1H), 10.81–10.82 (m, 2H),
11.17 (s, 1H); MS (FAB) m/z 399 ([M+H]+); Anal. Calcd for
C
26H29FN4Á1.5HClÁ0.25H2O: C, 65.64; H, 6.57; N, 11.78. Found: C,
65.62; H, 6.59; N, 11.64.
5.1.34. 4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (cis-7)
A solution of 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (0.88 g,
3.8 mmol), 1-(indol-4-yl)piperazine (0.7 g, 3.5 mmol), sodium tri-
acetoxy-borohydride (1.1 g, 5.2 mmol), and acetic acid (0.4 mL,
7 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room
temperature overnight. The reaction was quenched with 1 N so-
dium hydroxide (10 mL), extracted with methylene chloride (3Â
60 mL), and washed with brine (3Â 60 mL). The organic layer
was dried over anhydrous sodium sulfate and filtered. Chromatog-
raphy (5–7% methanol/ethyl acetate) afforded 1.14 g (79%) of the
title product as a white foam. The HCl salt was prepared in ethanol:
mp 283–285 °C; 1H NMR (400 MHz, DMSO-d6) d 1.83–2.04 (m, 6H),
2.14–2.17 (m, 2H), 3.15–3.18 (m, 2H), 3.21–3.37 (m, 4H), 3.62–3.74
(m, 4H), 6.44 (s, 1H), 6.48 (d, J = 7.24 Hz, 1H), 6.67–6.72 (m, 1H),
7.00–7.09 (m, 2H), 7.08 (d, J = 8.36 Hz, 1H), 7.17 (d, J = 7.88 Hz,
1H), 7.26–7.28 (m, 1H), 7.36–7.34 (m, 1H), 10.14 (br, 1H), 1113
(br, 1H), 11.24 (br, 1H). Anal. Calcd for C26H29FN4ÁHClÁ0.25H2O: C,
68.26; H, 6.72; N, 12.25. Found: C, 68.16; H, 6.74; N, 12.04.
C
26H30N4ÁHClÁ1.25H2O: C, 68.25; H, 7.38; N, 12.25. Found: C,
68.12; H, 7.16; N, 11.93.
5.1.30. 5-Fluoro-3-{cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl}-1-methyl-1H-indole (cis-5)
This compound was prepared in a similar fashion as described
above (cis-4) by replacing 4-(1H-3-indolyl)-cyclohexone with 4-
(5-fluoro-1-methyl-3-indolyl)-cyclohexone (0.34 g, 1.4 mmol) to
afford 0.24 g (34%) of the title product as a clear oil. HCl salt was
prepared in ethanol: mp 247–249 °C; 1H NMR (400 MHz, DMSO-
d6): d 1.84–1.89 (m, 2H), 2.03–2.05 (m, 2H), 2.13–2.16 (m, 2H),
3.24–3.38 (m, 6H), 3.61–3.71 (m, 4H), 3.76 (s, 3H), 6.48 (m, 1H),
6.53 (d, J = 7.44 Hz, 1H), 6.95–7.01 (m, 2H), 7.10 (d, J = 8.12 Hz,
1H), 7.28–7.34 (m, 2H), 7.39 (dd, J = 8.80, 4.40 Hz, 1H), 7.48 (m,
1H), 10.59 (br, 1H), 11.17 (s, 1H). Anal. Calcd for
C
27H31FN4Á2HClÁ0.25H2O: C, 63.84; H, 6.65; N, 11.03. Found: C,
63.88; H, 6.51; N, 10.77.
5.1.35. 4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (trans-7)
5.1.31. 5-Fluoro-3-{trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl}-1-methyl-1H-indole (trans-5)
The trans compound was isolated at the same time as the cis-7
isomer in 17% yield (0.24 g) as a white solid: mp 206–208 °C. The
HCl salt was prepared in ethanol: mp 297–299 °C; 1H NMR
(400 MHz, DMSO-d6) d1.49–1.58 (m, 2H), 1.70–1.79 (m, 2H), 2.17
(m, 2H), 2.30 (m, 2H), 2.84–2.90 (m, 1H), 3.18–3.24 (m, 2H),
3.34–3.42 (m, 3H), 3.52–3.89 (m, 4H), 6.46 (s, 1H), 6.52 (t,
J = 7.48 Hz, 1H), 6.68–6.73 (m, 1H), 7.00–7.04 (m, 2H), 7.09 (m,
1H), 7.14–7.17 (m, 2H), 7.28–7.30 (m, 1H), 10.50 (br, 1H), 11.1
(br, 1H). Anal. Calcd for C26H29FN4ÁHClÁH2O: C, 66.30; H, 6.85; N,
11.90. Found: C, 66.17; H, 6.51; N, 11.70.
The trans compound was isolated at the same time as the cis-5
isomer as a white solid. The HCl salt was prepared in ethanol: mp
275–277 °C; MS (EI) m/z 430 (M+); 1H NMR (400 MHz, DMSO-d6):
1H NMR (400 MHz, DMSO-d6): d 1.52–1.61 (m, 2H), 1.72–1.80
(m, 2H), 2.11–2.14 (m, 2H), 2.30–2.32 (m, 2H), 2.72–2.78 (m,
1H), 3.28–3.45 (m, 5H), 3.59–3.62 (m, 2H), 3.72 (s, 3H), 3.74 (m,
1H), 6.51 (M, 1H), 6.56 (d, J = 7.48 Hz, 1H), 6.94–7.03 (m, 2H),
7.12 (d, J = 8.12 Hz, 1H), 7.18 (s, 1H), 7.30 (t, J = 2.64 Hz, 1H),
7.36–7.40 (m, 2H), 10.84 (br, 1H), 11.18 (s, 1H). Anal. Calcd for
C
27H31FN4Á2HCl: C, 64.41; H, 6.61; N, 11.13. Found: C, 64.10, H,
5.1.36. 3-{4-[(1,4-cis)-4-(1H-Indol-4-yl)-pipera-zinyl-1-yl]-
cyclohexyl}-1H-indole-5-carbonitrile (cis-8)
6.57, N, 10.77.
This compound was prepared in a similar fashion as described
above (cis-4) by replacing 4-(4-fluoro-1H-indol-3-yl)-cyclohexa-
none with 4-(5-cyano-1H-indol-3-yl)-cyclohexanone10 (0.71 g,
3.0 mmol) to afford 0.38 g (30%) of the title product. The HCl salt
(off-white solid) was prepared in ethyl acetate: mp 216–218 °C;
MS (EI) m/z 423 (M+); 1H NMR (400 MHz, DMSO-d6) d 1.83–1.93
(m, 4H), 2.03–2.04 (m, 2H), 2.18–2.21 (m, 2H), 3.19–3.40 (m,
5.1.32. 6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]
cyclohexyl]-1H-indole (cis-6)
This compound was prepared in a similar fashion as described
above (cis-4) by replacing 4-(1H-indol-3-yl)-cyclohexanone with
4-(6-fluoro-1H-indol-3-yl)-cyclohexanone (1.15 g, 5.0 mmol) to af-
ford 1.06 g (51%) of the title product as a white foam. The HCl salt

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6717
7H), 3.52–3.70 (m, 5H), 6.40–6.46 (m, 1H), 6.49 (d, J = 7.47 Hz, 1H),
6.98 (t, J = 7.91 Hz, 1H), 7.08 (d, J = 7.91 Hz, 1H), 7.28 (t, J = 2.70 Hz,
1H), 7.40–7.42 (m, 1H), 7.50–7.52 (m, 1H), 7.58–7.60 (m, 1H),
8.11–8.12 (m, 1H), 10.42 (br, 1H), 11.15 (s, 1H), 11.58 (s, 1H). Anal.
Calcd for C27H29N5ÁHClÁ1.5H2O: C, 66.25; H, 6.94; N, 13.64. Found:
C, 66.05; H, 6.54; N, 13.28.
ganic layer was dried over anhydrous sodium sulfate and filtered.
Chromatography (2.5% methanol/ethyl acetate) afforded 0.98 g
(39%) of the title product as a white solid: mp decomposed at
226 °C. The HCl salt was prepared in ethyl acetate: mp 245 °C
(dec); 1H NMR (400 MHz, DMSO-d6) d 1.38 (t, J = 7.2 Hz, 3H),
1.82–1.99 (m, 4H), 2.01–2.10 (m, 2H), 2.13–2.18 (m, 2H), 3.26–
3.41 (m, 6H), 3.62–3.75 (m, 4H), 4.25 (t, J = 7.24 Hz, 2H), 6.48 (m,
1H), 6.54 (d, J = 7.24 Hz, 1H), 6.99 (d, J = 7.92 Hz, 1H), 7.10 (t,
J = 8.12 Hz, 1H), 7.30 (t, J = 2.44 Hz, 1H), 7.48 (dd, J = 8.56,
1.52 Hz, 1H), 7.65 (d, J = 8.56 Hz, 1H), 7.70 (s, 1H), 8.14 (m, 1H),
5.1.37. 3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-pipera-zinyl-1-
yl]cyclohexyl}-1H-indole-5-carbonitrile (trans-8)
The trans compound was isolated at the same time as the cis-8
isomer in 25% yield (0.32 g). The HCl salt (white solid) was pre-
pared in ethyl acetate: mp 310 °C (dec); MS FAB m/z 424
([M+H]+); 1H NMR (400 MHz, DMSO-d6) d 1.58–1.81 (m, 4H),
2.14–2.18 (m, 2H), 2.29–2.32 (m, 2H), 2.82–2.88 (m, 1H), 3.18–
3.24 (m, 2H), 3.34–3.46 (m, 3H), 3.60–3.63(m, 2H), 3.72–3.76 (m,
2H), 6.45–6.48 (m, 1H), 6.51 (d, J = 7.47 Hz, 1H), 7.00(t,
J = 7.47 Hz, 1H), 7.08–7.11 (m, 1H), 7.29–7.33 (m, 2H), 7.38–7.41
(m, 1H), 7.49–7.51 (m, 1H), 8.20–8.22 (m, 1H), 10.47 (br, 1H),
11.15 (s, 1H), 11.45 (s, 1H). Anal. Calcd for C27H29N5ÁHClÁ0.75H2O:
C, 68.48; H, 6.71; N, 14.79. Found: C, 68.43; H, 6.54; N, 14.63.
10.06
29H33N5Á2HClÁ0.25H2O: C, 65.84; H, 6.76; N, 13.24. Found: C,
65.97; H, 6.74; N, 13.40.
(br,
1H),
11.18
(br,
1H).
Anal.
Calcd
for
C
5.1.41. 1-Ethyl-3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-
yl]-cyclohexyl}-1H-indole-5-carbonitrile (trans-10)
The trans compound was isolated at the same time as the cis-
10 isomer in 19% yield (0.48 g) as a light brown solid: mp
decomposed at 110 °C. The HCl salt was prepared in ethyl ace-
tate: mp 250 °C (decomposed); 1H NMR (400 MHz, DMSO-d6) d
1.34 (t, J = 7.24 Hz, 3H), 1.58–1.64 (m, 2H), 1.67–1.81 (m, 2H),
2.16 (m, 2H), 2.34 (m, 2H), 2.82–2.89 (m, 1H), 3.41–3.47 (m,
5H), 3.62–3.65 (m, 2H), 3.74–3.76 (m, 2H), 4.22 (q, J = 7.24 Hz,
2H), 6.56 (m, 1H), 6.62 (d, J = 7.68 Hz, 1H), 7.03 (d, J = 7.68 Hz,
1H), 7.15 (d, J = 8.12 Hz, 1H), 7.33 (t, J = 2.64 Hz, 1H), 7.41 (s,
1H), 7.47 (dd, J = 8.56, 1.52 Hz, 1H), 7.64 (d, J = 8.80 Hz, 1H),
8.24 (m, 1H), 11.07 (br, 1H), 11.20 (br, 1H). Anal. Calcd for
5.1.38. 3-{(1,4-cis)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-
cyclohexyl}-1-methyl-1H-indole-5-carbonitrile (cis-9)
A solution of 4-(5-cyano-1-methyl-3-indolyl)cyclohexa-none
(0.75 g, 3 mmol), 1-(indol-4-yl)piperazine (0.6 g, 3 mmol), sodium
triacetoxyborohydride (0.95 g, 4.5 mmol), and acetic acid
(0.34 mL, 6 mmol) in 1,2-dichloroethane (20 mL) was allowed to
stir at room temperature overnight. The reaction was quenched
with 1 N sodium hydroxide (10 mL), extracted with methylene
chloride (3Â 60 mL), and washed with brine (3Â 60 mL). The or-
ganic layer was dried over anhydrous sodium sulfate and filtered.
Chromatography (10% methanol/ethyl acetate) afforded 0.73 g
(56%) of the title product as a white solid: mp 274–275 °C. The
HCl salt was prepared in ethyl acetate: mp 285.5–288 °C; 1H
NMR (400 MHz, DMSO-d6): d 1.83–1.93 (m, 4H), 2.00–2.07 (m,
2H), 2.15–2.17 (m, 2H), 3.20–3.42 (m, 6H), 3.61–3.71 (m, 4H),
3.82 (s, 3H), 6.45 (m, 1H), 6.50 (d, J = 7.44 Hz, 1H), 6.98 (t,
J = 7.92 Hz, 1H), 7.09 (d, J = 8.12 Hz, 1H), 7.28 (t, J = 2.64 Hz, 1H),
7.48 (dd, J = 8.56, 1.52 Hz, 1H), 7.58–7.62 (m, 2H), 8.14 (m, 1H),
C
29H33N5Á2HCl: C, 66.40; H, 6.73; N, 13.35. Found: C, 66.32; H,
6.67; N, 13.10.
5.1.42. 3-{(1,4-cis)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-
cyclohexyl}-1-propyl-1H-indole-5-carbonitrile (cis-11)
A
solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexa-
none (1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol),
sodium triacetoxyborohydride (1.84 g, 8.9 mmol), and acetic acid
(0.94 mL, 16 mmol) in 1,2-dichloroethane (80 mL) was allowed to
stir at room temperature overnight. The reaction was quenched
with 1 N sodium hydroxide (20 mL), extracted with methylene
chloride (3Â 100 mL), and washed with brine (3Â 100 mL). The or-
ganic layer was dried over anhydrous sodium sulfate and filtered.
Chromatography (10% methanol/ethyl acetate) afforded 0.42 g
(15%) of the title product as a white powder. The HCl salt was pre-
pared in ethanol: mp 200–206 °C; 1H NMR (400 MHz, DMSO-d6) d
0.84 (t, J = 7.44 Hz, 3H), 1.76–1.96 (m, 6H), 2.04–2.08 (m, 2H),
2.15–2.18 (m, 2H), 3.33–3.43 (m, 6H), 3.64–3.71 (m, 4H), 4.18 (t,
J = 7.04 Hz, 2H), 6.50 (m, 1H), 6.56 (d, J = 7.48 Hz, 1H), 7.01 (d,
J = 7.72 Hz, 1H), 7.12 (t, J = 8.12 Hz, 1H), 7.30 (t, J = 2.64 Hz, 1H),
7.47 (dd, J = 8.56, 0.88 Hz, 1H), 7.66 (d, J = 8.56 Hz, 1H), 7.70 (s,
1H), 8.14 (m, 1H), 10.76 (br, 1H), 11.19 (br, 1H). Anal. Calcd for
10.40
28H31N5Á1.0HClÁ1.0H2O: C, 68.35; H, 6.96; N, 14.23. Found: C,
68.02; H, 6.40; N, 14.18.
(br,
1H),
11.14
(s,
1H).
Anal.
Calcd
for
C
5.1.39. 3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-
cyclohexyl}-1-methyl-1H-indole-5-carbonitrile (tran-9)
The trans compound was isolated at the same time as the cis-9
isomer in 33% yield (0.42 g) as a white solid: mp 239–240 °C. The
HCl salt was prepared in ethyl acetate: mp 286–288 °C; 1H NMR
(400 MHz, DMSO-d6): d 1.58–1.64 (m, 2H), 1.73–1.82 (m, 2H),
2.12–2.15 (m, 2H), 2.31–2.34 (m, 2H), 2.82–2.88 (m, 1H), 3.31–
3.46 (m, 5H), 3.60–3.63 (m, 2H), 3.72–3.75 (m, 2H), 3.79 (s, 3H),
6.52 (m, 1H), 6.58 (d, J = 7.48 Hz, 1H), 7.01 (t, J = 7.72 Hz, 1H),
7.12 (d, J = 8.12 Hz, 1H), 7.30 (t, J = 2.84 Hz, 1H), 7.33 (s, 1H), 7.47
(dd, J = 8.60, 1.56 Hz, 1H), 7.57 (d, J = 8.60 Hz, 1H), 8.23 (m, 1H),
10.96 (br, 1H), 11.20 (s, 1H). Anal. Calcd for C28H31N5Á2HClÁ0.5H2O:
C, 64.73; H, 6.60; N, 13.65. Found: C, 64.55; H, 6.42; N, 13.41.
C
30H35N5Á2HClÁ0.75H2O: C, 65.27; H, 7.03; N, 12.69. Found: C,
65.18; H, 6.97; N, 12.68.
5.1.43. 3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-pipera-zin-1-yl]-
cyclohexyl}-1-propyl-1H-indole-5-carbonitrile (trans-11)
The trans compound was isolated at the same time as the cis-11
isomer in 14% yield (0.39 g) as a white foam. The HCl salt was pre-
pared in ethanol: mp decomposed >245 °C; 1H NMR (400 MHz,
DMSO-d6) d 0.83 (t, J = 7.24 Hz, 3H), 1.57–1.66 (m, 2H), 1.60–1.68
(m, 4H), 2.15–2.17 (m, 2H), 2.31–2.34 (m, 2H), 2.84–2.89 (m,
1H), 3.25–3.29 (m, 2H), 3.30–3.39 (m, 3H), 3.62–3.64 (m, 2H),
3.74–3.77 (m, 2H), 4.15 (t, J = 7.04 Hz, 2H), 6.51 (m, 1H), 6.56 (d,
J = 7.28 Hz, 1H), 7.02 (d, J = 7.68 Hz, 1H), 7.12 (t, J = 8.16 Hz, 1H),
7.31 (t, J = 2.84 Hz, 1H), 7.40 (s, 1H), 7.45–7.47 (m, 1H), 7.65 (d,
J = 8.36 Hz, 1H), 8.24 (m, 1H), 10.70 (br, 1H), 11.19 (s, 1H). Anal.
Calcd for C30H35N5Á2HCl: C, 66.90; H, 6.93; N, 13.00. Found: C,
66.68; H, 6.97; N, 12.96.
5.1.40. 1-Ethyl-3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-
yl]-cyclohexyl}-1H-indole-5-carbonitrile (cis-10)
A
solution of 4-(5-cyano-1-ethyl-indol-3-yl)-cyclohexanone
(1.5 g, 5.6 mmol), 1-(indol-4-yl)piperazine (1.19 g, 5.9 mmol), so-
dium triacetoxyborohydride (1.73 g, 8.2 mmol), and acetic acid
(0.9 mL, 15 mmol) in 1,2-dichloroethane (30 mL) was allowed to
stir at room temperature overnight. The reaction was quenched
with 1 N sodium hydroxide (10 mL), extracted with methylene
chloride (3Â 80 mL), and washed with brine (3Â 80 mL). The or-

6718
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
5.1.44. 3-{(1,4-cis)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-
(s, 1H), 6.51 (d, J = 7.47 Hz, 1H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H),
6.98–7.11 (m, 4H), 7.22 (d, J = 8.8 Hz, 1H), 7.29–7.30 (m, 1H),
10.37 (br, 1H), 10.64 (s, 1H), 11.15 (s, 1H). Anal. Calcd for
cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile (cis-12)
A solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexanone
(1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol), so-
dium triacetoxyborohydride (1.84 g, 8.9 mmol), and acetic acid
(0.94 mL, 16 mmol) in 1,2-dichloroethane (80 mL) was allowed to
stir at room temperature overnight. The reaction was quenched
with 1 N sodium hydroxide (20 mL), extracted with methylene
chloride (3Â 100 mL), and washed with brine (3Â 100 mL). The or-
ganic layer was dried over anhydrous sodium sulfate, and filtered.
Chromatography (10% methanol/ethyl acetate) afforded 0.49 g
(18%) of the title product as a white powder. The HCl salt was pre-
pared in ethanol: mp 285–286 °C; 1H NMR (400 MHz, DMSO-d6) d
1.49 (d, J = 6.59 Hz, 6H), 1.81–1.87 (m, 2H), 1.92–1.98 (m, 4H),
2.03–2.08 (m, 2H), 3.27–3.40 (m, 6H), 3.67–3.69 (m, 4H), 4.81
(m, 1H), 6.44 (m, 1H), 6.49 (d, J = 7.47 Hz, 1H), 6.99 (t, J = 7.69 Hz,
1H), 7.09 (d, J = 8.13 Hz, 1H), 7.28 (m, 1H), 7.45 (dd, J = 8.56,
1.54 Hz, 1H), 7.67 (d, J = 8.55 Hz, 1H), 7.76 (m, 1H), 8.13 (m, 1H),
10.72 (br, 1H), 11.14 (s, 1H). Anal. Calcd for C30H35N5ÁHClÁ0.5H2O:
C, 70.50; H, 7.30; N, 13.70. Found: C, 70.86; H, 7.12; N, 13.56.
C
27H32N4OÁHClÁ1.5H2O: C, 66.65; H, 7.15; N, 11.52. Found: C,
66.65; H, 7.06; N, 11.44.
5.1.48. 5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (cis-14)
A solution of 4-(5-chloro-1H-indol-3-yl)-cyclohexanone (0.78 g,
3.1 mmol), 1-(indol-4-yl)piperazine (0.6 g, 3 mmol), sodium tri-
acetoxy-borohydride (0.95 g, 4.5 mmol), and acetic acid (0.34 mL,
6 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room
temperature overnight. The reaction was quenched with 1 N so-
dium hydroxide (10 mL), extracted with methylene chloride (3Â
60 mL), and washed with brine (3Â 60 mL). The organic layer
was dried over anhydrous sodium sulfate and filtered. Chromatog-
raphy (5% methanol/ethyl acetate) afforded 0.84 g (65%) of the title
product as a white foam. The HCl salt was prepared in ethanol: mp
279–281 °C; 1H NMR (400 MHz, DMSO-d6) d1.85 (m, 4H), 2.03 (m,
2H), 2.60 (m, 2H), 3.16 (m, 2H), 3.22–3.45 (m, 4H), 3.61–3.70 (m,
4H), 6.43–6.49 (m, 2H), 6.98 (t, J = 7.9 Hz, 1H), 7.02–7.09 (m, 2H),
7.27 (t, J = 2.8 Hz, 1H), 7.36 (m, 1H), 7.42 (m, 1H), 7.56 (m, 1H),
10.10 (br, 1H), 11.13 (br, 1H), 11.15 (br, 1H). Anal. Calcd for
5.1.45. 3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-
cyclohexyl}-1-isopropyl-1H-indole-5-carbo-nitrile (trans-12)
The trans compound was isolated at the same time as the cis-12
isomer in 12% yield (0.34 g) as a white foam. The HCl salt was pre-
pared in ethanol: mp decomposed >245 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.42 (s, 3H), 1.44 (s, 3H), 1.62–1.68 (m, 2H), 1.72–
1.74 (m, 2H), 2.13–2.16 (m, 2H), 2.30–2.33 (m, 2H), 2.82–2.85
(m, 1H), 3.20–3.26 (m, 2H), 3.35–3.42 (m, 3H), 3.59–3.62 (m,
2H), 3.71–3.75 (m, 2H), 4.77–4.80 (m, 1H), 6.47 (m, 1H), 6.51 (d,
J = 7.24 Hz, 1H), 7.00 (d, J = 8.16, Hz, 1H), 7.09 (t, J = 7.72 Hz, 1H),
7.29 (t, J = 2.84 Hz, 1H), 7.43 (d, J = 1.52 Hz, 1H), 7.45 (d,
J = 1.54 Hz, 1H), 7.49 (s, 1H), 7.66 (d, J = 8.56 Hz, 1H), 8.22 (m,
1H), 10.67 (br, 1H), 11.15 (s, 1H). Anal. Cacld for C30H35N5Á2HCl:
C, 66.90; H, 6.93; N, 13.00. Found: C, 66.68; H, 6.97; N, 12.96.
C
26H29ClN4ÁHClÁ0.25H2O: C, 65.46; H, 6.69; N, 11.45. Found: C,
65.14; H, 6.73; N, 11.33.
5.1.49. 5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (tans-14)
The trans compound was isolated at the same time as the cis-14
isomer in 24% yield (0.32 g) as a white foam. The HCl salt was pre-
pared in ethanol: mp 314–315.5 °C; 1H NMR (400 MHz, DMSO-d6)
d1.53–1.63 (m, 2H), 1.65–1.80 (m, 2H), 2.12–2.15 (m, 2H), 2.30–
2.33 (m, 2H), 2.75–2.79 (m, 1H), 3.18–3.28 (m, 2H), 3.34–3.46
(m, 3H), 3.59–3.62 (m, 2H), 3.72–3.76 (m, 2H), 6.46 (s, 1H), 6.51
(m, 1H), 6.98–7.10 (m, 3H), 7.19–7.20 (m, 1H), 7.27–7.30 (m,
1H), 7.33–7.36 (m, 1H), 7.64 (m, 1H), 10.37 (br, 1H), 11.03 (br,
1H), 11.14 (br, 1H). Anal. Calcd for C26H29ClN4ÁHClÁ0.25H2O: C,
65.65; H, 6.60; N, 11.62. Found: C, 65.50; H, 6.50; N, 11.30.
5.1.46. 5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (cis-13)
A
solution of 4-(5-methoxy-1H-indol-3-yl)-cyclohexanone
5.1.50. 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]-cyclohexyl]-
2-methyl-1H-indole (cis-15)
(1.2 g, 5 mmol), 1-(indol-4-yl)piperazine (1 g, 5 mmol), sodium tri-
acetoxy-borohydride (1.47 g, 6.2 mmol), and acetic acid (0.28 mL,
4 mmol) in 1,2-dichloroethane (20 mL) was allowed to stir at room
temperature overnight. The reaction was quenched with 1 N so-
dium hydroxide (10 mL), extracted with methylene chloride (3Â
60 mL) and washed with brine (3Â 60 mL). The organic layer
was dried over anhydrous sodium sulfate and filtered. Chromatog-
raphy (2.5% methanol/ethyl acetate) afforded 1.18 g (55%) of the ti-
tle product as a white solid: mp 105–108 °C. The HCl salt was
prepared in ethyl acetate: mp 280–281 °C; 1H NMR (400 MHz,
DMSO-d6) d1.84–1.86 (m, 4H), 2.02 (m, 2H), 2.16–2.19 (m, 2H),
3.14–3.20 (m, 3H), 3.25–3.40 (m, 3H), 3.60–3.71 (m, 4H), 3.75 (s,
3H), 6.44 (s, 1H), 6.48 (d, J = 7.48 Hz, 1H), 6.70–6.73 (m, 1H),
6.96–7.00 (m, 2H), 7.08 (d, J = 7.92 Hz, 1H), 7.23 (d, J = 8.8 Hz,
1H), 7.26–7.30 (m, 2H), 10.15 (br, 1H), 10.75 (br, 1H), 11.13 (br,
1H). Anal. Calcd for C27H32N4OÁHClÁ0.25H2O: C, 69.07; H, 7.19; N,
11.93. Found: C, 69.18; H, 7.19; N, 11.80.
A
solution of 4-(1H-indol-3-yl)-cyclohexanone (1.44 g,
6.33 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.33 mmol), so-
dium triacetoxyborohydride (1.88 g, 8.86 mmol), and acetic acid
(0.76 mg, 12.6 mmol) in 1,2-dichloroethane (100 mL) was al-
lowed to stir at room temperature overnight. The reaction
was quenched with 1 N sodium hydroxide (80 mL), extracted
with methylene chloride (3Â 300 mL), and washed with brine
(150 mL). The organic layer was dried over anhydrous sodium
sulfate and filtered. The solvent was removed under vacuum
to afford an off-white solid. Trituration of the solid with warm
methylene chloride (80 mL) followed by filtration afforded
0.88 g of the title product as a white solid. The mother liquor
was concentrated and chromatographed (2% methanol/methy-
lene chloride) to afford another 0.18 g (total 40.7%) of the title
product as a white solid: mp 279–280 °C; 1H NMR (400 MHz,
DMSO-d6) d1.65–1.68 (m, 2H), 1.89–1.96 (m, 2H), 2.27–2.36
(m, 4H), 2.40 (s, 3H), 2.91–2.97 (m, 1H), 3.37–3.45 (m, 2H),
3.50–3.52 (m, 1H), 3.60–3.70 (m, 4H), 3.79–3.83 (m, 2H),
6.59 (m, 1H), 6.64–6.67 (m, 1H), 6.85–6.98 (m, 1H), 6.91–
6.96 (m, 1H), 7.03 (t, J = 7.68 Hz, 1H), 7.14–7.20 (m, 2H),
7.32 (t, J = 2.88 Hz, 1H), 7.78 (d, J = 7.68 Hz, 1H), 10.48 (br,
1H), 10.67 (br, 1H), 11.24 (br, 1H). The HCl salt was prepared
5.1.47. 5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]-
cyclohexyl]-1H-indole (trans-13)
The trans compound was isolated at the same time as the cis-13
isomer in 20% yield (0.43 g) as a white foam. The HCl salt was pre-
pared in ethyl acetate: mp 194–196 °C; 1H NMR (400 MHz, DMSO-
d6) d1.55–1.61 (m, 2H), 1.72–1.78 (m, 2H), 2.15–2.18 (m, 2H),
2.28–2.31 (m, 2H), 2.73–2.79 (m, 1H), 3.16–3.22 (m, 2H), 3.34–
3.45 (m, 3H), 3.58–3.65 (m, 2H), 3.72 (m, 2H), 3.76 (s, 3H), 6.46
in ethanol: mp 200–203 °C. Anal. Calcd for
C
27H32N4Á
2HClÁ0.75H2O: C, 64.99; H, 7.17; N, 11.23. Found: C, 65.05;
H, 7.07; N, 11.23.

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6719
5.1.51. 3-[trans-4-[4-(1H-Indol-4-yl)-1-pipera-zinyl]-
cyclohexyl]-2-methyl-1H-indole (trans-15)
1.74–1.83 (m, 2H), 2.16–2.19 (m, 2H), 2.30–2.32 (m, 2H), 2.77 (s,
3H), 2.75–2.83 (m, 1H), 3.32–3.46 (m, 5H), 3.52–3.63 (m, 2H),
3.72–3.84 (m, 2H), 6.94–6.98 (m, 2H), 7.03–7.10 (m, 2H), 7.32–
7.37 (m, 3H), 7.58–7.60 (m, 1H), 10.81 (s, 1H), 10.99 (br, 1H),
14.65 (br, 1H). Anal. Calcd for C26H31N5Á2HClÁ1H2O: C, 61.90; H,
6.99; N, 13.88. Found: C, 61.88; H, 7.17; N, 13.44.
The trans compound was isolated at the same time as the cis-15
isomer in 25.7% yield (0.67 g) as a white foam; 1H NMR (400 MHz,
DMSO-d6) d1.73–1.85 (m, 4H), 1.98–2.04 (m, 2H), 2.30 (m, 2H),
2.34 (s, 3H), 2.74–2.75 (m, 1H), 3.46–3.62 (m, 7H), 3.73–3.75 (m,
2H), 6.59 (m, 1H), 6.65–6.67 (m, 1H), 6.85–6.89 (m, 1H), 6.92–
6.96 (m, 1H), 7.02 (t, J = 7.68 Hz, 1H), 7.16 (d, J = 8.16 Hz, 1H),
7.21 (d, J = 7.88 Hz, 1H), 7.33 (t, J = 2.84 Hz, 1H), 10.72 (br, 1H),
11.26 (br, 2H). The HCl salt was prepared in ethanol: mp >310 °C.
Anal. Calcd for C27H32N4Á2HCl: C, 66.80; H, 7.06; N, 11.54. Found:
C, 66.84; H, 6.87; N, 11.37.
5.1.56. 4-{cis-4-[4-(1H-Indol-3-yl)cyclohexyl]-piperazin-1-yl}-
2-(trifluoromethyl)-1H-benzimidazole (cis-18)
This compound was prepared as described for cis-16 by replac-
ing 4-piperazin-1-yl-1H-benzoimidazole with 4-piperazin-1-yl-2-
(trifluoro-methyl)-1H-benzoimida-zole (0.4 g, 1.48 mmol) to
afford 0.17 g (25%) of the title product as a white solid. The HCl salt
was generated from ethyl acetate yielding a white solid: mp above
207 °C; 1H NMR (400 MHz, DMSO-d6) d 1.79–1.92 (m, 4H), 1.98–
2.08 (m, 2H), 2.18–2.24 (m, 2H), 3.23–3.48 (m, 4H), 3.66–3.68
(m, 2H), 3.98 (m, 2H), 4.34 (m, 2H), 6.72–6.76 (m, 1H), 6.93–6.98
(m, 1H), 7.02–7.08 (m, 1H), 7.19–7.21 (m, 1H), 7.24–7.30 (m,
1H), 7.33–7.35 (m, 2H), 7.52–7.54 (m, 1H), 10.36 (br, 1H), 10.9 (s,
1H), 14.0 (br, 1H). Anal. Calcd for C26H28F3N5ÁHClÁH2O: C, 59.82;
H, 5.99; N, 13.42. Found: C, 60.18; H, 5.84; N, 13.29.
5.1.52. 4-{cis-4-[4-(1H-Indol-3-yl)cyclohexyl]-piperazin-1-yl}-
1H-benzimidazole (cis-16)
To a solution of 4-piperazin-1-yl-1H-benzoimidazole (0.51 g,
2.5 mmol), 4-(1H-3-indolyl)-cyclohexanone (0.53 g, 2.5 mmol),
and sodium tracetoxyborohydride (0.79 g, 3.7 mmol) in dichloro-
ethane (30 mL) was added acetic acid (0.29 mL, 5.0 mmol), and
stirred overnight at room temperature. The reaction was quenched
with 1 N NaOH (50 mL) and extracted in methylene chloride (2Â
100 mL) and 50% ethyl acetate/methanol (3Â 100 mL). The organic
fractions were combined, dried over sodium sulfate, concentrated,
filtered and chromatographed twice (5% methanol/ethyl acetate)
yielding 0.35 g (34%) of the title product as a white solid. The
HCl salt was generated from ethyl acetate yielding a white solid:
mp 217–219 °C; 1H NMR (400 MHz, DMSO-d6) d 1.57–1.68 (m,
4H), 1.86–2.03 (m, 4H), 2.28 (m, 1H), 2.62–2.69 (m, 4H), 2.95–
2.69 (m, 4H), 2.95–3.05 (m, 2H), 3.43–3.49 (m, 3H), 6.45 (d,
J = 6.49 Hz, 1H), 6.88 (t, J = 7.42 Hz, 1H), 6.97–7.04 (m, 3H), 7.06
(m, 1H), 7.27 (d, J = 8.11 Hz, 1H), 7.55 (d, J = 7.77 Hz, 1H), 7.99 (s,
1H), 10.67 (s, 1H), 12.29 (s, 1H). Anal. Calcd for C25H29N5: C,
75.16; H, 7.32; N, 17.53. Found: C, 74.82; H, 7.21; N, 17.05.
5.1.57. 4-{trans-4-[4-(1H-Indol-3-yl)cyclohexyl]-piperazin-1-
yl}-2-(trifluoromethyl)-1H-benzimidazole (trans-18)
The trans isomer was isolated at the same time as cis-18 afford-
ing 0.18 g (9%) of the title product as a beige solid. The HCl salt was
generated from ethyl acetate yielding a white solid: mp above
200 °C; 1H NMR (400 MHz, DMSO-d6) d 1.54–1.60 (m, 2H), 1.63–
1.77 (m, 2H), 2.15–2.18 (m, 2H), 2.29–2.32 (m, 2H), 2.76–2.82
(m, 1H), 3.17–3.19 (m, 2H), 3.28–3.40 (m, 3H), 3.66–3.68 (m,
2H), 4.43 (m, 2H), 6.75 (d, J = 5.93 Hz, 1H), 6.96 (m, 1H), 7.03–
7.10 (m, 2H), 7.21–7.28 (m, 1H), 7.30–7.35 (m, 2H), 7.54–7.58
(m, 1H), 10.5 (br, 1H), 10.89 (s, 1H), 14.0 (m, 1H). Anal. Calcd for
C
26H28F3N5ÁHClÁ0.75H2O: C, 60.34; H, 5.94; N, 13.53. Found: C,
60.37; H, 5.68; N, 13.43.
5.1.53. 4-{trans-4-[4-(1H-Indol-3-yl)cyclohexyl]-piperazin-1-
yl}-1H-benzimidazole (trans-16)
5.1.58. 5-(Trifluoromethylsulfonyloxy)-quinoline (31)
The trans isomer was isolated at the same time as cis-16 afford-
ing 0.2 g (20%) of the title product as a white solid. The HCl salt was
generated from Et2O/EtOH to give white solid: mp dec >215 °C; 1H
NMR (400 MHz, DMSO-d6) d 1.53–1.62 (m, 2H), 1.69–1.76 (m, 2H),
2.13–2.16 (m, 2H), 2.25–2.29 (m, 2H), 2.75–2.81 (m, 1H), 3.20–3.49
(m, 4H), 3.57–3.66 (m, 2H), 3.86–4.01 (m, 2H), 6.88–6.95 (m, 1H),
7.06 (m, 1H), 7.29–7.52 (m, 3H), 7.30 (m, 1H), 7.55 (d, J = 8.0 Hz,
1H), 8.98 (br, 1H), 10.63 (br, 1H), 10.87 (s, 1H). Anal. Calcd for
A solution of 5-hydroxy-quinoline (8 g, 55 mmol) and potas-
sium carbonate (15.2 g, 110 mmol) in anhydrous pyridine
(60 mL) under nitrogen was cooled to À20 °C. Tf2O (13.97 mL,
83 mmol) was added drop-wise via syringe. The reaction mixture
was stirred 1 h at À20 °C, then warmed to 0 °C for 1 h then stirred
at room temperature for 48 h. The reaction mixture was then
poured into water (200 mL) and extracted in methylene chloride
(2Â 200 mL). The aqueous layer was acidified with 1 N HCl
(100 mL) and back extracted with methylene chloride (2Â
200 mL). The organic fractions were dried over anhydrous sodium
sulfate and concentrated and purified by column chromatography
(40% ethyl acetate/hexanes) affording 13.97 g (90%) of the title
product as a pink oil; MS (EI) m/z 277 (M+). 1H NMR (400 MHz,
DMSO-d6) d 7.77–7.82 (m, 2H), 7.90 (t, J = 7.92 Hz, 1H), 8.17–8.20
(m, 1H), 8.37–8.40 (m, 1H), 9.07 (m, 1H).
C
25H29N5Á0.5H2O: C, 73.50; H, 7.40; N, 17.14. Found: C, 73.79; H,
7.11; N, 17.02.
5.1.54. 4-{cis-4-[4-(1H-Indol-3-yl)cyclohexyl]-piperazin-1-yl}-
2-methyl-1H-benzimidazole (cis-17)
This compound was prepared as described for cis-16 by replac-
ing 4-piperazin-1-yl-1H-benzoimidazole with 4-piperazin-1-yl-2-
methyl-1H-benzoimidazole (0.34 g, 1.6 mmol) to afford 0.35 g
(54%) of the title compound as a white foam: mp dec >190 °C; 1H
NMR (400 MHz, DMSO-d6) d 1.86–1.88 (m, 4H), 1.98–2.03 (m,
2H), 2.23–2.32 (m, 2H), 2.76 (s, 3H), 3.34–3.40 (m, 6H), 3.53–
3.61 (m, 2H), 3.68–3.78 (m, 2H), 6.94–6.98 (m, 2H), 7.04–7.12
(m, 1H), 7.32–7.55 (m, 4H), 7.58 (m, 1H), 10.82 (br, 1H), 10.93 (s,
1H), 14.8 (br, 1H). Anal. Calcd for C26H31N5Á2HClÁ0.45H2O: C,
63.14; H, 6.91; N, 14.16. Found: C, 63.41; H, 7.30; N, 13.65.
5.1.59. 1-tert-Butyl-4-(5-quinolinyl)piperazine carboxylate (32)
To an oven-dried 200 mL flask was added cesium carbonate
(19.87 g, 61 mmol), palladium acetate (0.49 g, 2.2 mmol) and BIN-
AP (1.18 g, 1.9 mmol). The solids were flushed with nitrogen for
10 min.
A solution of 5-(trifluoromethylsulfonyl-oxy)quinoline
(12 g, 43 mmol) and 1-tert-butyl-4-piperazine carboxylate
(9.67 g, 52 mmol) in THF was then added slowly to the reaction
flask. The reaction mixture was stirred at room temperature for
0.5 h then at 65 °C overnight. The resulting solution was diluted
with ether, filtered through a bed of Celite, washed with ether
(50 mL) and ethyl acetate (50 mL). The organic fractions were com-
bined, dried over anhydrous sodium sulfate, filtered, and chroma-
tography three times (10% methanol/methylene chloride) yielding
5.1.55. 4-{trans-4-[4-(1H-Indol-3-yl)cyclohexyl]piperazin-1-
yl}-2-methyl-1H-benzimidazole (trans-17)
The trans isomer was isolated at the same time as cis-17 afford-
ing 0.11 g (17%) of the title product as a white solid: mp dec
>220 °C; 1H NMR (400 MHz, DMSO-d6) d 1.52–1.66 (m, 2H),

6720
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
1.57 g (12%) of pure product as a beige solid: mp 116–118 °C; 1H
NMR (400 MHz, DMSO-d6) d 1.43 (s, 9H), 3.00 (m, 4H), 3.60 (m,
4H), 7.19 (dd, J = 7.24, 1.12 Hz, 1H), 7.52 (dd, J = 8.56, 4.20 Hz,
1H), 7.63–7.72 (m, 2H), 8.50–8.53 (m, 1H), 8.86–8.88 (m, 1H). Anal.
Calcd for C18H23N3O2: C, 68.98; H, 7.40; N, 13.41. Found: C, 69.09;
H, 7.33; N, 13.08.
1H), 7.80 (d, J = 8.57 Hz, 1H). Anal. Calcd for C28H29N5ÁHClÁH2O: C,
68.63; H, 6.58; N, 14.29. Found: C, 68.99; H, 6.54; N, 14.06.
5.1.64. 3-[(1,4-trans)-4-(4-Quinolin-5-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (trans-20)
The trans isomer was isolated at the same time as the cis-20 iso-
mer affording 0.18 g (18%) as a beige solid. The HCl salt was gener-
ated from ethyl acetate yielding a white solid: mp 210–211 °C
(dec); 1H NMR (400 MHz, DMSO-d6) d 1.85–1.95 (m, 4H), 2.04–
2.06 (m, 2H), 2.20–2.23 (m, 2H), 3.34–3.56 (m, 6H), 3.61–3.64
(m, 4H), 7.27 (d, J = 7.28 Hz, 1H), 7.41 (dd, J = 8.36, 1.32 Hz, 1H),
7.51 (d, J = 8.56 Hz, 1H), 7.58–7.61 (m, 2H), 7.74 (t, J = 8.36 Hz,
1H), 7.80 (d, J = 8.60 Hz, 1H), 8.12 (d, J = 0.64 Hz, 1H), 8.63 (d,
J = 8.36 Hz, 1H), 8.95 (dd, J = 4.20, 1.32 Hz, 1H), 10.71 (br, 1H),
11.58 (s, 1H). Anal. Calcd for C28H29N5ÁHClÁ0.40H2O: C, 70.18; H,
6.48; N, 14.61. Found: C, 70.23; H, 6.21; N, 14.45.
5.1.60. 5-(1-Piperazinyl)-quinoline (33)
To a solution of 1-tert-butyl-4-(5-quinolinyl)piperazine carbox-
ylate (1.57 g, 5 mmol) in methylene chloride (2 mL) at 0 °C were
added a per-cooled, premixed, solution of TFA (10 mL), methylene
chloride (20 mL) and methanol (10 drops). The reaction was
warmed slowly to room temperature and allowed to stir overnight.
The resulting solution was concentrated, dissolved in water (5 mL),
and methylene chloride (5 mL) and made alkaline with sodium
bicarbonate to pH 9. The aqueous portion was extracted ethyl ace-
tate (6Â 100 mL) and concentrated yielding 1.0 g (100%) of a yel-
low oil which solidified upon standing and was not purified
further. 1H NMR (400 MHz, DMSO-d6) d 3.06 (m, 4H), 3.17 (m,
4H), 3.62 (br, 1H), 7.19 (dd, J = 7.0, 1.08 Hz, 1H), 7.50 (dd, J = 8.56,
4.16 Hz, 1H), 7.64–7.72 (m, 2H), 8.50 (m, 1H), 8.87 (m, 1H).
5.1.65. 8-(4-Benzyl-piperazin-1-yl)quinoline (34)
A solution of 8-amino-quinoline (12.9 g, 89 mmol) and bis(2-
chloroethyl)-benzylamine (26.0 g, 112 mmol) in n-butanol
(65 mL) was allowed to heat at 85 °C for 11 h. The mixture was
poured into 50% sodium hydroxide, extracted with methylene
chloride and water. The organic layer was dried over anhydrous
magnesium sulfate, and filtered. The solvent was removed in va-
cuo. Chromatography (5% methanol/methylene chloride) afforded
12.3 g of the title product as a solid: mp 116.5–118 °C. The HCl salt
was prepared in ethyl acetate: mp 209–210 °C; 1H NMR (400 MHz,
DMSO-d6) d 3.36–3.58 (m, 6H), 3.69–3.73 (m, 2H), 4.41 (s, 2H),
7.45–7.49 (m, 3H), 7.57–7.58 (m, 1H), 7.70–7.74 (m, 3H), 7.84–
7.89 (m, 1H), 8.80 (br, 1H), 9.06 (m, 1H), 11.72 (br, 1H). Anal. Calcd
for C20H21N3Á2HClÁ0.5H2O: C, 62.34; H, 6.28; N, 10.91. Found: C,
62.37; H, 6.55; N, 10.80.
5.1.61. 5-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-
piperazin-1-yl}-quinoline (cis-19)
To a solution of 5-(1-piperazinyl)quinoline (0.5 g, 2.35 mmol),
4-(5-fluoro-1H-3-indolyl)-cyclohexanone (0.54 g, 2.35 mmol) and
sodium traxetoxyborohydride (0.74 g, 3.5 mmol) in dichloroethane
(20 mL) was added acetic acid (0.27 mL, 4.7 mmol) and stirred
overnight at room temperature. The reaction was quenched with
1 N NaOH (50 mL) and extracted in methylene chloride (3Â
100 mL). The organic fractions were combined, dried over anhy-
drous sodium sulfate, concentrated, filtered, and chromatographed
(5% methanol/ethyl acetate) yielding 0.41 g (41%) of the title prod-
uct as a pale yellow solid: mp 220–223 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.58–1.70 (m, 4H), 1.94–2.04 (m, 4H), 2.37 (m, 1H),
2.75 (m, 4H), 2.92–2.97 (m, 1H), 3.07 (m, 4H), 6.88 (m, 1H), 7.18
(m, 1H), 7.29 (dd, J = 8.76, 4.80 Hz, 1H), 7.35 (dd, J = 10.52,
2.44 Hz, 1H), 7.49 (dd, J = 8.56, 4.20 Hz, 1H), 7.63–7.69 (m, 2H),
8.47 (dd, J = 8.56, 1.56 Hz, 1H), 8.86 (dd, J = 3.92, 1.52 Hz, 1H),
10.82 (br, 1H). Anal. Calcd for C27H29FN4Á0.12C4H8O2: C, 75.16; H,
6.88; N, 12.76. Found: C, 74.83; H, 6.86; N, 12.60.
5.1.66. 8-(Piperazin-1-yl)-quinoline (35)
To a solution of 8-(4-benzyl-piperazin-1-yl)quinoline (2.6 g,
8.7 mmol) in methylene chloride (30 mL) was added vinyl chloro-
formate (1.1 mL, 13 mmol) at room temperature slowly. The reac-
tion mixture was refluxed for 2 h, and then concentrated in vacuo.
The residue was dissolved in hydrochloric acid (12 N, 20 mL) and
stirred at room temperature for 1 h. The mixture was concen-
trated; the residue was taken up with 40 mL ethanol and heated
up to 50 °C for 2 h. The solvent was removed in vacuo, the residue
was dissolved in 1.0 N sodium hydroxide/ethyl acetate, and ex-
tracted with ethyl acetate and washed with water. The organic
layer was dried over anhydrous sodium sulfate. The solvent was re-
moved in vacuo. Chromatography (10–30% methanol/methylene
chloride plus ammonium hydroxide) afforded 1.86 g (90%) of the
title product as a yellow oil. The HCl salt was prepared in ethanol;
MS (EI) m/z 213 (M)+; 1H NMR (400 MHz, DMSO-d6) d 3.41 (br, 4H),
3.47 (br, 4H), 7.46 (m, 1H), 7.63–7.68 (m, 1H), 7.74–7.77 (m, 2H),
8.63 (m, 1H), 9.00–9.17 (m, 1H), 9.25 (br, 2H). Anal. Calcd for
5.1.62. 5-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-
cyclohexyl]-piperazin-1-yl}-quinoline (trans-19)
The trans isomer was isolated at the same time as the cis-19 iso-
mer affording 0.18 g (18%) of the title product as a white solid: mp
210–211 °C; 1H NMR (400 MHz, DMSO-d6) d 1.46–1.56 (m, 4H),
2.00–2.06 (m, 4H), 2.52–2.69 (m, 1H), 2.83 (m, 4H), 3.04 (m, 4H),
6.88 (m, 1H), 7.15 (d, J = 2.20 Hz, 1H), 7.18 (dd, J = 6.60, 1.56 Hz,
1H), 7.27–7.33 (m, 2H), 7.50 (dd, J = 8.56, 4.16 Hz, 1H), 7.63–7.69
(m, 2H), 8.47 (m, 1H), 8.86 (m, 1H), 10.83 (s, 1H). Anal. Calcd for
C
13H15N3Á2HClÁH2O: C, 51.30; H, 6.30; N, 13.81. Found: C, 51.67;
C
27H29FN4Á0.20C4H8O2: C, 74.84; H, 6.91; N, 12.56. Found: C,
H, 6.36; N, 13.32.
74.45; H, 6.79; N, 12.35.
5.1.67. 8-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-
piperazin-1-yl}-quinoline (cis-21)
5.1.63. 3-[(1,4-cis)-4-(4-Quinolin-5-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (cis-20)
This compound was prepared in the same manner as the cis-19
isomer by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohexanone with
A solution of 4-(5-fluoro-1-indol-3-yl)-cyclohexanone (0.54 g,
2.3 mmol), 8-(piperazin-1-yl)-quinoline (0.5 g, 2.3 mmol), sodium
triacetoxyborohydride (0.75 g, 3.5 mmol), and acetic acid
(0.27 mL, 4.7 mmol) in 1,2-dichloroethane (20 mL) was allowed
to stir at room temperature overnight. The reaction was quenched
with 1 N sodium hydroxide (20 mL), extracted with methylene
chloride (3Â 100 mL), and washed with brine (3Â 100 mL). The or-
ganic layer was dried over anhydrous sodium sulfate and filtered.
Chromatography (5% methanol/ethyl acetate) afforded 0.46 g
(46%) of the title product as a white solid: mp 122–125 °C. The
4-(5-cyano-1H-3-indolyl)-cyclohexanone (0.54 g,
2.35 mmol)
afforded 0.41 (41%) of the cis isomer as a white solid. The HCl salt
was generated from ethyl acetate yielding a white solid: mp
>270 °C (dec); 1H NMR (400 MHz, DMSO-d6) d 1.85–1.92 (m, 4H),
2.01–2.06 (m, 2H), 2.21–2.26 (m, 2H), 3.34–3.51 (m, 6H), 3.56–
3.64 (m, 4H), 7.28 (d, J = 7.25 Hz, 1H), 7.41 (dd, J = 8.57, 1.32 Hz,
1H), 7.51 (d, J = 8.57 Hz, 1H), 7.59 (m, 2H), 7.74 (t, J = 8.35 Hz,

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6721
HCl salt was prepared in ethanol: mp 209–212 °C; 1H NMR
(400 MHz, DMSO-d6) d 1.55–1.64 (m, 2H), 1.74–1.82 (m, 2H),
2.13–2.16 (m, 2H), 2.32–2.35 (m, 2H), 2.73–2.80 (m, 1H), 3.34–
3.45 (m, 4H), 3.58–3.74 (m, 5H), 6.86–6.92 (m, 1H), 7.19 (m, 1H),
7.30–7.38 (m, 2H), 7.48 (m, 1H), 7.66 (m, 1H), 7.76–7.79 (m, 2H),
8.65 (m, 1H), 9.0 (m, 1H), 10.79 (br, 1H), 10.93 (br, 1H). Anal. Calcd
for C27H29FN4Á3HCl: C, 60.28; H, 6.00; N, 10.42. Found: C, 60.23; H,
6.29; N, 10.21.
which was recrystallized from ethyl acetate/hexanes to give
10.96 g (96%) of the title product as a solid mp: 90–92 °C; 1H
NMR (400 MHz, DMSO-d6) d 8.00–8.04 (m, 1H), 8.39–8.43 (m,
1H), 9.10–9.14 (m, 1H). Anal. Calcd for C8H5N3O2:C, 54.86; H,
2.88; N, 23.99. Found: C, 55.12; H, 3.05; N, 24.05.
5.1.72. 5-Amino-quinoxaline (37)
To a three-neck 250 mL round-bottomed flask equipped with
a reflux condenser, and nitrogen inlet was added 5-nitro-quin-
oxaline (4 g, 22.8 mmol) dissolved in acetic acid (60 mL). The
mixture was heated to boiling, removed from heat, and solid
iron powder (3.83 g, 68.6 mmol) was added. Vigorous boiling
was observed. The reaction mixture was heated at reflux for
10 min and them poured into water (100 mL) and ice. The aque-
ous solution was filtered and basified to pH > 10 with 1 M so-
dium hydroxide, and extracted in ethyl acetate (3Â 200 mL).
The organic layers were combined and washed again with water
(500 mL), dried over sodium sulfate and concentrated. The
resulting oil was purified by column chromatography (40% ethyl
acetate/hexanes) yielding a bright orange solid 2.03 g (61%);
mp: 87–90 °C; 1H NMR (MHz, DMSO-d6) d 6.13 (s, 2H), 6.90
(dd, J = 7.68, 1.32 Hz, 1H), 7.16 (dd, J = 8.12, 1.12 Hz, 1H), 7.52
(t, J = 8.12 Hz, 1H), 8.71 (s, 1H), 8.84 (s, 1H). Anal. Calcd for
C8H7N3: C, 66.19; H, 4.86 N, 28.95. Found: C, 66.25; H, 4.96;
N, 29.26.
5.1.68. 8-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-
cyclohexyl]-piperazin-1-yl}-quinoline (trans-21)
The trans compound was isolated at the same time as the cis-
21 isomer in 25% yield (0.25 g) as a white solid: mp 207.5–
209 °C. The HCl salt was prepared in ethanol: mp 286–288 °C;
1H NMR (400 MHz, DMSO-d6) d 1.82–1.94 (m, 4H), 2.04–2.07
(m, 2H), 2.17–2.19 (m, 2H), 3.24 (m, 1H), 3.34–3.59 (m, 6H),
3.64–3.71 (m, 3H), 6.87–6.92 (m, 1H), 7.28–7.34 (m, 2H), 7.44
(m, 1H), 7.63–7.67 (m, 1H), 7.74–7.79 (m, 2H), 8.64 (br, 1H),
9.00 (br, 1H), 10.55 (br, 1H), 11.05 (br, 1H). Anal. Calcd for
C
27H29FN4ÁHCl: C, 64.67; H, 6.23; N, 11.17. Found: C, 64.74; H,
6.27; N, 11.06.
5.1.69. 3-[(1,4-cis)-4-(4-Quinolin-8-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (cis-22)
A solution of 4-(5-cyano-1-indol-3-yl)-cyclohexanone (1.47 g,
6.2 mmol), 8-(piperazin-1-yl)-quinoline (1.32 g, 6.2 mmol), so-
dium triacetoxyborohydride (2.0 g, 7.2 mmol), and acetic acid
(0.71 mL, 12 mmol) in 1,2-dichloroethane (40 mL) was allowed
to stir at room temperature overnight. The reaction was
quenched with 1 N sodium hydroxide (20 mL), extracted with
methylene chloride (3Â 100 mL), and washed with brine (3Â
100 mL). The organic layer was dried over anhydrous sodium
sulfate and filtered. Chromatography (5% methanol/ethyl acetate)
afforded 1.48 g (55%) of the title product as a white solid: mp
149–151 °C. The HCl salt was prepared in ethanol: mp 282–
5.1.73. 5-(1-Piperazinyl)quinoxaline (39)
To a solution of 5-amino-quinoxaline (2.8 g, 19.3 mmol) in
BuOH (50 mL) were added bis(2-chloroethyl)-benzylamine
(8.42 g, 38.6 mmol) and triethyl amine (5.34 mL, 38.6 mmol). The
reaction was stirred at 100 °C overnight. A second portion of tri-
ethyl amine (5.34 mL, 38.6 mmol) was added and the reaction stir-
red at 100 °C an additional 24 h. The cooled solution was made
alkaline with NaOH (2.5 N, 500 mL) and extracted with ethyl ace-
tate (3Â 200 mL). The organic fractions were combined, dried over
sodium sulfate, concentrated and chromatography (40% ethyl
acetate/hexanes) yielding 1.0 g (17%) of 1-benzyl-4-(quinoxalin-
yl)piperazine 38 as a gold oil. To a solution of 1-benzyl-4-(quinox-
alin-yl)piperazine 38 (1.0 g, 3.3 mmol) in anhydrous methylene
chloride at room temperature under nitrogen was added vinyl
chloroformate (0.34 mL, 3.9 mmol) drop-wise. The reaction mix-
ture was heated at reflux for 2 h. The reaction was cooled, concen-
trated to dryness, and concentrated HCl (25 mL) and 1,4-dioxane
(25 mL) were added. The resulting solution was stirred at ambient
temperature overnight. The solution was basified with sodium
hydroxide (2.5 N, 300 mL) and extracted into ethyl acetate (3Â
200 mL). The organic layers were combined, dried over sodium
sulfate, concentrated, and chromatographed (10% MeOH/CH2Cl2/
NH4OH) to give 0.45 g (64%) of the title product as an orange solid:
mp 106–108 °C; MS (ESI) m/z 215 (M+H)+; 1H NMR (400 MHz,
DMSO-d6) d 2.93–2.95 (m, 4H), 3.24–3.36 (m, 4H), 7.15–7.17 (m,
1H), 7.58–7.60 (m, 1H), 7.67–7.72 (m, 1H), 8.85 (m, 1H), 8.88 (m,
1H).
283 °C; 1H NMR (400 MHz, DMSO-d6)
d 1.84–1.96 (m, 4H),
2.05–2.07 (m, 2H), 2.19–2.21 (m, 2H), 3.33 (m, 1H), 3.39–3.44
(m, 3H), 3.53–3.55 (m, 2H), 3.65–3.67 (m, 2H), 3.78 (m, 2H),
7.40 (dd, J = 8.36, 1.32 Hz, 1H), 7.50 (m, 2H), 7.59 (m, 1H), 7.68
(m, 1H), 7.82 (m, 2H), 8.12 (m, 1H), 8.72 (br, 1H), 9.04 (m,
1H), 10.71 (br, 1H), 11.58 (s, 1H). Anal. Calcd for
C
28H29N5Á2HClÁ0.75H2O: C, 66.43; H, 6.28; N, 13.42. Found: C,
64.46; H, 6.29; N, 13.37.
5.1.70. 3-[(1,4-trans)-4-(4-Quinolin-8-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (trans-22)
The trans compound was isolated at the same time as the cis-22
isomer in 26% yield (0.55 g) as a white solid: mp 276–278 °C. The
HCl salt was prepared in ethanol: mp 286–288 °C; 1H NMR
(400 MHz, DMSO-d6) d 1.57–1.66 (m, 2H), 1.73–1.82 (m, 2H),
2.14–2.17 (m, 2H), 2.33–2.35 (m, 2H), 2.83–2.89 (m, 1H), 3.14–
3.20 (m, 2H), 3.38–3.50 (m, 3H), 3.62–3.65 (m, 3H), 3.62–3.65
(m, 2H), 4.00–4.08 (m, 2H), 7.33 (m, 2H), 7.40 (dd, J = 8.36,
1.56 Hz, 1H), 7.50 (d, J = 8.36 Hz, 1H), 7.56–7.69 (m, 3H), 8.20 (s,
1H), 8.45 (br, 1H), 8.93 (m, 1H), 10.59 (br, 1H), 11.45 (s, 1H). Anal.
Calcd for C28H29FN5Á2HClÁ0.5H2O: C, 64.98; H, 6.23; N, 13.53.
Found: C, 65.28; H, 5.96; N, 13.30.
5.1.74. 3-[(1,4-cis)-4-(4-Quinoxalin-5-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (cis-23)
A solution of 4-(5-cyano-1H-indolyl)-cyclo-hexanone (0.43 g,
1.87 mmol), 5-(1-piperazinyl)-quinoxaline (0.4 g, 1.87 mmol), ace-
tic acid (0.22 mL, 3.7 mmol), and sodium triacetoxyborohydride
(0.59 g, 2.8 mmol) in dichloroethane (50 mL) was stirred at room
temperature overnight. The reaction was quenched with NaOH
(1 N, 100 mL) and extracted with methylene chloride (3Â
100 mL). The organic fractions were combined, dried over sodium
sulfate, and filtered. The resulting oil was purified by column chro-
matography (5% MeOH in EtOAc) yielding 0.13 g (16%) of the title
5.1.71. 5-Nitro-quinoxaline (36)
To a room temperature solution of 3-nitro-o-phenylenediamine
(10 g, 65.3 mmol) in ethanol (50 mL) was added glyoxal (40% in
water, 22.47 mL). The reaction mixture was heated at reflux for
1 h, then diluted with water (100 mL). The cooled mixture was ex-
tracted with methylene chloride (2Â 300 mL) and the organic lay-
ers were combined and washed again with water (500 mL), dried
over sodium sulfate and concentrated yield a bright orange solid

6722
D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
product as a yellow solid: mp 223–225 °C; MS (ESI) m/z 437
([M+H]+); 1H NMR (400 MHz, DMSO-d6) d1.62–1.67 (m, 4H),
1.71–2.06 (m, 4H), 2.31–2.35 (m, 1H), 2.65–2.72 (s, 3H), 3.03–
3.06 (m, 1H), 3.21–3.40 (m, 5H), 7.19–7.21 (m, 1H), 7.33–7.39
(m, 2H), 7.47–7.50 (m, 1H), 7.60–7.62 (m, 1H), 7.68–7.72 (m,
1H), 8.15 (s, 1H), 8.85–8.89 (m, 2H), 11.34 (br, 1H). Anal. Calcd
for C27H28N6H2O: C, 71.34; H, 6.65; N, 18.49. Found: C, 71.65; H,
6.11; N, 18.18.
250 °C (dec); 1H NMR (MHz, DMSO-d6) d 1.82–1.96 (m, 4H),
2.03–2.06 (m, 2H), 2.27–2.28 (m, 2H), 3.33–3.60 (m, 6H),
3.64–3.70 (m, 4H), 6.54 (m, 1H), 6.61(d, J = 6.80 Hz, 1H), 7.00
(t, J = 7.72 Hz, 1H), 7.13 (d, J = 8.12 Hz, 1H), 7.29–7.31 (m, 1H),
7.42–7.46 (m, 1H), 7.76 (m, 1H), 8.42 (d, J = 5.08 Hz, 1H), 8.68
(d, J = 7.92 Hz, 1H), 11.16 (br, 1H), 11.25 (s, 1H), 12.78 (s, 1H).
Anal. Calcd for
C25H29N5Á3HCl: C, 58.49; H, 6.38; N, 13.64.
Found: C, 58.47; H, 6.52; N, 12.91.
5.1.75. 3-[(1,4-trans)-4-(4-Quinoxalin-5-yl-piperazin-1-yl)-
cyclohexyl]-1H-indole-5-carbonitrile (trans-23)
5.1.80. 3-{(1,4-trans)-4-[4-(1H-Indole-4-yl)-piperazin-1-yl]-
cyclohexyl}-1H-pyrrolo[2,3-b]pyridine (trans-25)
The trans isomer was isolated at the same time as the cis-23 iso-
mer affording 0.24 g (29%) of a pale yellow cis-23 isomer solid: mp
257–259 °C; MS (ESI) m/z 437 [(M+H]+); 1H NMR (MHz, DMSO-d6)
d 1.53–1.59 (m, 4H), 1.97–2.07 (m, 4H), 2.80–2.82 (m, 4H), 3.34–
3.44 (m, 6H), 7.19–7.21 (m, 1H), 7.29 (m, 1H), 7.37–7.39 (m, 1H),
7.47–7.49 (m, 1H), 7.61–7.63 (m, 1H), 7.69–7.73 (m, 1H), 8.14 (s,
1H), 8.87–8.90 (m, 2H), 11.36 (br, 1H). Anal. Calcd for
The trans compound was isolated at the same time as the cis-25
isomer in 9% yield (0.26 g) as a white solid: mp >228 °C. Its hydro-
chloride salt was prepared in ethanol: mp >250 °C (dec); 1H NMR
(400 MHz, DMSO-d6) d 1.57–1.67 (m, 2H), 1.74–1.84 (m, 2H),
2.14–2.17 (m, 2H), 2.34–2.37 (m, 2H), 2.86–2.92 (m, 1H), 3.36–
3.45 (m, 5H), 3.58–3.63 (m, 2H), 3.72–3.74 (m, 2H), 6.55 (m, 1H),
6.61–6.63 (m, 1H), 7.01 (t, J = 7.68 Hz, 1H), 7.14 (d, J = 8.12 Hz,
1H), 7.31 (m, 1H), 7.41–7.44 (m, 1H), 7.50 (m, 1H), 8.40–8.42 (m,
1H), 8.67–8.68 (m, 1H), 11.24 (s, 1H), 11.38 (br, 1H), 12.58 (s,
1H). Anal. Calcd for C25H29N5Á3HCl: C, 56.50; H, 6.54; N, 13.18.
Found: C, 56.45; H, 6.63; N, 12.98.
C
27H28N6Á0.75H2O: C, 72.05; H, 6.61; N, 18.67. Found: C, 72.32;
H, 6.14; N, 18.25.
5.1.76. 5-Fluoro-3-[(1,4-cis)-4-(4-naphthalen-1-yl-piperazin-1-
yl)-cyclohexyl]-1H-indole (cis-24)
This compound was prepared by the manner shown in cis-19 by
replacing 5-(1-piperazinyl)-quinoline with 1-(1-naphthyl)pipera-
zine (0.41 g, 1.9 mmol). 0.24 g (29%) of the title product was ob-
tained as a white solid: mp 195–197 °C; 1H NMR (400 MHz,
DMSO-d6) d 1.55–1.66 (m, 4H), 1.93–2.01 (m, 4H), 2.26–2.29 (m,
1H), 2.62–2.78 (m, 4H), 2.83–2.94 (m, 1H), 2.96–3.10 (m, 4H),
6.83 (m, 1H), 7.09 (d, J = 6.73 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H),
7.27 (dd J = 8.80, 4.63 Hz, 1H), 7.32 (dd, J = 10.32, 2.55 Hz, 1H),
7.38(t, J = 7.54 Hz, 1H), 7.42–7.47 (m, 2H), 7.51 (m, 1H), 7.84 (m,
1H), 8.09 (m, 1H). Anal. Calcd for C28H30FN3: C, 78.66; H, 7.07; N,
9.83. Found: C, 78.24; H, 7.06; N, 9.59.
Acknowledgments
The authors thank the Discovery Analytical Chemistry-Chemi-
cal and Screening Sciences at Wyeth Research for providing 1H
NMR, MS, and CHN elemental analysis data reported here in the
experimental section.
References and notes
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5.1.77. 5-Fluoro-3-[(1,4-trans)-4-(4-naphthalen-1-yl-piperazin-
1-yl)-cyclohexyl]-1H-indole (trans-24)
The trans isomer was isolated at the same time as the cis-25
affording 70 mg (9%) of the title compound as a white solid: mp
179–181 °C; 1H NMR (400 MHz, DMSO-d6) d 1.58–1.70 (m, 4H),
1.96–2.04 (m, 4H), 2.37 (m, 1H), 2.74 (m, 3H), 2.93–2.97 (m, 1H),
3.07 (m, 3H), 6.86 (m, 1H), 7.11 (d, J = 7.04 Hz, 1H), 7.19 (d,
J = 2.2 Hz, 1H), 7.30 (dd J = 8.76, 4.60 Hz, 1H), 7.36 (dd, J = 10.32,
2.40 Hz, 1H), 7.41(t, J = 7.72 Hz, 1H), 7.46–7.49 (m, 2H), 7.51 (d,
J = 5.04 Hz, 1H), 7.57 (d, J = 8.12 Hz, 1H), 7.86–7.88 (m, 1H), 8.11–
8.13 (m, 1H), 10.83 (br, 1H). Anal. Calcd for C28H30FN3: C, 78.66;
H, 7.07; N, 9.83. Found: C, 78.28; H, 7.05; N, 9.79.
7. Hjorth, S.; Westlin, D.; Bengtsson, H. J. Neuropharmacology 1997, 36, 461–
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H. K.; Riley, G. J.; Scott, C. M.; Shaw, T. E.; Starr, K. R.; Stemp, G.; Thewlis, K. M.;
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16. (a) Wustrow, D. J.; Smith, W. J., III; Corbin, A. E.; Davis, M. D.; Georgic, L. M.;
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5.1.78. 4-(1H-3-Pyrrolo[2,3-b]pyridyl)-cyclohexanone (41)
This compound was prepared in a similar fashion as de-
scribed above (28c) by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-
yl)-6-fluoro-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-
azaindole (2.48 g). 1.96 g (95%) of the title compound was ob-
tained as
a
white solid: mp 162–164 °C; MS (EI) m/z 214
1.83–1.94 (m, 2H),
(M+); 1H NMR (400 MHz, DMSO-d6)
d
2.22–2.29 (m, 4H), 2.56–2.65 (m, 2H), 3.26–3.30 (m, 1H),
7.00–7.03 (m, 1H), 7.24 (s, 1H), 8.02–8.05 (m, 1H), 8.16–8.18
(m, 1H), 11.36 (s, 1H).
5.1.79. 3-{(1,4-cis)-4-[(1H-Indole-4-yl)-piperazin-1-yl]-
cyclohexyl}-1H-pyrrolo[2,3-b]pyridine (cis-25)
This compound was prepared in a similar fashion as de-
scribed above (cis-4) by replacing 4-(1H-indol-3-yl)-cyclohexa-
none with 4-(1H-3-pyrrolo[2,3-b]-pyridyl)cyclohexanone (41)
(1.52 g, 7.1 mmol). 0.79 g (27%) of the title product was ob-
tained. Its hydrochloride salt was prepared in ethanol. mp
17. Lopez-Rodriguez, M. L. ; Benhamu, B. ; Ayala, D. ; Rominguera, J. L. ; Murcia, M.
; Ramos, J. A. ; Viso, A. Tetrahedron 2000, 56, 3245–3253.
18. Guerret, P.; Tisne-Versailles, J.; Ancher, J. F.; Langlois, M. Brit. UK Pat. Appl.
1982, GB 2097790.

D. Zhou et al. / Bioorg. Med. Chem. 16 (2008) 6707–6723
6723
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