Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier

Article abstract of DOI:10.1016/j.ejmech.2010.03.003

By employing pharmacophore-based design and the privileged fragments reassembly, a series of piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an efficient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure. Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel scaffolds for further development of potent CCR5 inhibitors.

Full text of DOI:10.1016/j.ejmech.2010.03.003

European Journal of Medicinal Chemistry 45 (2010) 2827e2840
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5
antagonists with variation on the basic center carrier
,
,
,
Xing Fan a 1, Hu-Shan Zhang a 1, Li Chen b, Ya-Qiu Long a
*
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, 555 Zuchongzhi Road, Shanghai 201203, China
b Shanghai TargetDrug Co. Ltd, 500 Caobao Road, Shanghai 200233, China
a r t i c l e i n f o
a b s t r a c t
Article history:
By employing pharmacophore-based design and the privileged fragments reassembly, a series of
piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an effi-
cient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure.
Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were
identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel
scaffolds for further development of potent CCR5 inhibitors.
Received 14 August 2009
Received in revised form
25 February 2010
Accepted 2 March 2010
Available online 7 March 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
CCR5 antagonist
Propane-1,3-diamine
Convergent synthesis
(S)-b-amino-b-arylpropanal
4-Amino-4-methylpiperidine
Basic center carrier
1. Introduction
CCR5 belongs to the seven-transmembrane G protein-coupled
receptor (GPCR) superfamily. The GPCRs are structural trans-
Human immunodeficiency virus (HIV) infection with its clinical
progression to AIDS has become one of the fatal diseases in the
world. Though highly active antiretroviral therapy (HAART) has
been successful in reducing HIV-1-associated mortality and
morbidity, the emergence of multi-drug resistant viral strains and
intolerance to available agents render a compelling need to
discover new drugs or targets for effective therapeutic intervention.
The CeC chemokine receptor 5 (CCR5), an essential co-receptor for
HIV-1 recognition and entry into CD4þ macrophages and T-cells [1]
but not essential for human functions [2] is an attractive target for
antiretroviral intervention [3]. Many pharmaceutical companies
and academic institutions have been enthusiastically investigating
novel antagonists against CCR5 as novel anti-HIV agents [4,5]. As
a result, several small-molecule CCR5 antagonists (Sch-D [6], UK-
427857 [7], GW-873140 [8], TAK 220 [9] as shown in Fig. 1) are now
being evaluated in clinical trials, in which the UK-427857 (Mar-
aviroc) has become the first FDA-approved CCR5 inhibitor as anti-
HIV drug, further validating the CCR5 as an anti-HIV therapeutic
target.
membrane polypeptides that typically contain seven loops and
mediate various intracellular events when triggered by extracel-
lular ligands. Based on the structural and molecular interactions of
CCR5 inhibitors with CCR5 [10], the molecular modeling-guided
mutagenesis study using homology-based approach suggested that
the binding pocket of CCR5 is located within a predominantly
lipophilic cavity near the extracellular surface formed by trans-
membrane helices 2, 3, 6, and 7. And the residue E283 within TM7,
which is highly conserved in CC-chemokine receptors, was proved
to be critically important for the interaction of the antagonists with
CCR5 protein [11e13].
Correspondingly, the literature-reported CCR5 antagonists are
generally characterized by two hydrophobic domains and a basic
centre within the framework. As depicted in Fig. 2, we deduced
a general pharmacophore model for CCR5 inhibition. The propane-
1,3-diamine served as the bridge to link the two hydrophobic
domains, which preferred for aryl group on one side and the
heterocycle or polar group substituted aryl portion on the other
side. The incorporation of heterocycle was recognized to improve
the antiviral activity and pharmacokinetic properties in the context
of CCR5 inhibitors [14]. The basic centre afforded electronic inter-
actions with the key residue E283, usually in the form of aliphatic
tertiary amine which is part of the 1,3-propanediamine core
* Corresponding author. Tel.: þ86 21 50806876; fax: þ86 21 50807088.
E-mail address: yqlong@mail.shcnc.ac.cn (Y.-Q. Long).
1
These authors equally contributed to this work.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.003

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X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
Fig. 1. Representative structures of small molecule CCR5 antagonists, sharing the common propane-1,3-diamino skeleton flanked by two hydrophobic domains.
structure and supplied by piperdine, tropane or piperizine. Since
the basic center is critical for the CCR5 binding, and the con-
formationally constrained amine linker can orient the relative
positioning of the two hydrophobic domains, the optimal basic
center carrier was especially investigated in this study to search for
new scaffold.
According to our proposed pharmacophore model for the CCR5
inhibition, we selected some privileged fragments as the modular
structure to assemble new structure CCR5 inhibitors. Privileged
structure-based drug discovery recently gained particular attention
and has been widely applied to finding new drugs in a shorter time
[15]. In this study, we employed phenyl ring, heteroaromatic ring
and aliphatic ring as the hydrophobic group, and the conforma-
tionally constrained amine as the linker to fulfill the putative 3-
domain pharmacophore model, providing novel and rational
approach for the discovery of new structure CCR5 inhibitors.
We applied lead deconstruction strategy to a range of literature-
reported potent CCR5 antagonists, in combination with analyzing
the structural features of the CCR5 binding pocket. Hence, we
deduced a general 3-domain pharmacophore model for the CCR5
inhibition, and selected an amine and an aldehyde as the key
building blocks to build focused library with structural diversity. As
described in Scheme 1, a convergent synthesis strategy was
employed to construct the propane-1,3-diamino bridged CCR5
antagonists from two building blocks of (S)-
b-amino-b-arylpropa-
nal (6aec) and the piperidine-/tropane/piperazine-substituted
heteroaromatics (5-1 to 5-6) via a reductive amination reaction
[16]. Alkylation or acylation of the amino group in the intermediate
7 resulted in the desired products 1e4(aei) with structural varia-
tion on the basic center carrier and hydrophobic groups.
In this work, efficient synthesis was developed to prepare the
two building blocks, namely the
hyde and the piperidine-/tropane-substituted heteroaromatics. The
synthesis of (S)- -amino- -arylpropanal (6aec) was achieved by
b-aryl substituted b-amino alde-
b
b
employing Davies protocol as the key step [17e20]. As depicted in
Scheme 2, the aryl aldehyde was treated with Horner-Emmons
2. Chemistry
reagent to generate aryl substituted (E)-a,b-unsaturated esters
Since CCR5 antagonist represents a promising new class of
antiretroviral agents for the treatment of ART-experienced patients,
furthermore, the emergence of viral strains resistant to clinically
studied CCR5 inhibitors and the dynamic nature of the HIV-1
genome demand a continued effort toward the discovery of novel
inhibitors, we were intrigued to design and discover new structure
CCR5 antagonists by combining the pharmacophore-based
approach and the privileged structures.
(8aec) [21,22]. Subsequent asymmetric conjugate addition by the
chiral reagent (R)-N-benzyl-1-phenylethanamine produced one
predominant diastereoisomer (9aec) [17e20]. The resulting (S)-3-
aryl-3-(benzyl((R)-1-phenylethyl)amino)-propanoate was sub-
jected to a one-pot N-protecting group exchange (N-Bn -> N-Boc)
(10aec), followed by DIBAL-H reduction [23] to yield the final chiral
b-aryl substituted b-amino aldehyde (6aec).
Fig. 2. Our deduced general pharmacophore model for effective CCR5 binding and the design of the propane-1,3-diamine bridged CCR5 antagonists by using the privileged
fragments.

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2829
Scheme 1. The convergent synthesis strategy to construct the propane-1,3-diamine bridged CCR5 antagonists, categorized by the structure type of the basic centre carrier. Reagents
and conditions: (a) NaBH(OAc)3, ClCH2CH2Cl; (b) CF3COOH/CH2Cl2; (c) R2COOH, EDCI, HOAt, DIPEA, CH2Cl2; (d) LiAlH4,THF, ꢀ78 ꢁC (for the conversion of compounds 3ae3b); (e)
10% PdeC, then Ac2O, 60 ꢁC, 3e5 h (for the conversion of compounds 2ae2b).
Prior to the synthesis of another building block of piperidine-/
tropane-substituted heteroaromatics (5-1 to 5-6), the precursors N-
protected piperidine and endo-tropanamine were prepared. As
shown in Scheme 3, tropinone was conveniently converted into
endo-tropanamine by sequential N-demethylation with ethyl
chloroformate [24] and reductive amination with ammonium
formate in the presence of 10% PdeC catalyst [25,26]. The resulting
endo-tropanamine (12) was coupled with isobutyric acid to afford
Scheme 4. It is worthwhile to note that the choice of N-ethox-
ycarbonyl protecting group is of significance for the production
of the heterocycle-substituted 1,2,4-triazole derivatives. On one
hand, the tropinone was demethylated by treatment with ethyl
chloroformate; on the other hand, the resulting ethyl carbamate
functioned as the N-protecting group. Furthermore, the presence
of the ethoxycarbonyl group was beneficial for the formation of
the tropane-substituted 1,2,4-triazole. As shown in Scheme 4,
the 1,2,3-triazole (19, 20) was synthesized under acidic condi-
tions [27], so the basic nature of the tropane might interfere
with this reaction. Then, the ethoxycarbonyl group dispersed the
electron density of the nitrogen bridge by conjugation effect,
resulting in neutralized basicity of the tropane alkaloid thus
securing the formation of the 1,2,4-triazole functionality. As
a comparison, the N-benzyl protected analog failed to produce
the endo-tropane-substituted 1,2,4-triazole under the same
conditions.
the
N-(8-ethylcarbamate-8-aza-bicyclo[3.2.1]octan-3-yl)
iso-
butyramide (13) which served as the starting material for the
synthesis of endo-tropane-substituted 1,2,4-triazole.
For the synthesis of piperidine-substituted 1,2,4-triazole, similar
strategy was employed, as shown in Scheme 3. Starting from the
commercially available 1-benzylpiperidin-4-one, the reductive
amination with hydroxylamine hydrochloride and sodium in n-
propanol afforded the 1-benzylpiperidin-4-amine 14 in high yield.
Introduction of the isobutyroyl group on the 4-amino of the
piperidine ring (15) provided the handle to generate 1,2,4-triazole.
The subsequent N-protecting group exchange yielded the precursor
16, in which the ethyl carbamate served as the optimal protective
group for the following conversion reaction into triazole.
Meanwhile, the synthesis of N1-Boc-4-amino-4-methyl-piperi-
dine was conveniently achieved by employing isonipecotate as
a starting material and Curtius rearrangement as a key step, which
was previously reported by our laboratory [28]. Thus the piperi-
dine-/4-amino-4-mthyl-piperidine-/piperazine-substituted
aromatics (5-4, 5-5 and 5-6aee) were readily prepared by
employing reductive amination [28], alkylation or acylation as the
key reactions, as depicted in Scheme 5.
With the N-protected-piperidine/-tropanamine in hand, endo-
tropane-substituted 3H-imidazo[4,5-b]pyridine (5-1) or piperi-
dine-/endo-tropane-substituted 1,2,4-triazole (5-2 and 5-3) were
synthesized by using our modified methodology, as indicated in
Scheme 2. The synthesis of the (S)-b-amino-b
-arylpropanal by employing the Davies protocol as the key step. Reagents and conditions: 9a) t-BuOK/THF, 0 ꢁC -rt, 4 h, 81e84%; (b) n-
BuLi/THF, ꢀ78 ꢁC, 70e89%; (c) 20% Pd(OH)2eC/H2/EtOH; (d) (Boc)2O, two steps overall yield 83e87%; (e) TFA/CH2Cl2, rt, 66%; (f) cyclohexanecarboxylic acid, EDCI/HOBt/NMM/
CH2Cl2, rt, two steps overall yield 66%; (g) DIBAL-H/CH2Cl2, ꢀ78 ꢁC, 60e76%.

2830
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
Scheme 3. The synthesis of the N-protected piperidine and endo-tropanamine which served as the starting materials to prepare piperidine-/tropane-substituted heteroaromatics.
Reagents and conditions: (a) ClCOOEt/K2CO3, CHCl3, reflux, 88e90%; (b) HCOONH4/10%PdeC, CH3OH-H2O, rt, 84%; (c) isobutyric acid, DCC/THF, rt, 60e85%; (d) HONH2.HCl/EtOH/Py,
reflux, 99%; (e) Na/n-PrOH, reflux, 95%; (f) 10% PdeC, H2, EtOH, 90%.
After the successful preparation of the building block sets,
convergent synthesis proceeded smoothly between the (S)-
amino- -arylpropanal (6a,b) and the piperidine/tropane/pipera-
was determined in the absence of agonists, and nonspecific binding
was obtained in the presence of 10 mM GTPgS (Sigma).
b
-
b
zine-substituted heteroaromatics (5-1 to 5-5), followed by coupling
reaction with carboxylic acid or acyl chloride, affording the
propane-1,3-diamino bridged CCR5 antagonists 1e3(aec), as indi-
cated in Scheme 1. For the synthesis of 4-amino-4-methylpiper-
idine-linked CCR5 inhibitors, the acidic removal of N1-Boc of 5e6
4. Results and discussion
As we expected, the conformationally constrained amino linker
played an important role in the interaction with CCR5 protein.
Among the propane-1,3-diamino bridged CCR5 inhibitors, the
endo-tropane-substituted heteroaromatics containing compounds,
(aei) followed by the reductive amination with (S)-
arylpropanal 6c furnished the desired products 4aei.
b-amino-b-
exemplified by 1a (IC50 ¼ 0.253
mM), were found to exhibit high
affinity binding to CCR5, while the piperazine-containing analogs
(2a and 2b) turned out inactive. Piperidino-linked analogs dis-
played moderate or weak inhibition against CCR5 (3a,
3. Biological assay
IC50 ¼ 10
mM). However, the 4-amino-4-methyl-piperidino linker
These pharmacophore-based compounds were evaluated for
their inhibitory effects on RANTES-stimulated [35S]-GTP
S binding
displayed a remarkable activity-enhancing effect, which consti-
tuted a new class of small molecule CCR5 inhibitors with an IC50
value varying in the range of 300 to 30 nM (4b, 4eei). In terms of
the hydrophobic group at the left side of the 3-feature pharmaco-
phore model, 4-trifluoromethylphenyl or 3-fluorophenyl was
preferred over the bulky naphthalenyl moiety.
g
to CCR5-expressing CHO cell membranes. The results are summa-
rized in Table 1 as IC50 values or inhibition rates at the concentra-
tions of 300 nM and 30 nM.
SPA-WGA based
(GTP
S)-binding assay. Exchange of [35S]GTP
was measured using a scintillation proximity assay (SPA) in 100
reaction volume. 10 g of CHO/CCR5 cell membranes, 0.1 mg of
WGA-coated SPA beads,10
M GDP,10 nM RANTES and 0.5 nM [35S]
GTP S (Amersham Biosciences) in SPA binding buffer (50 mM
[
35S] guanosine 50-[
g-thio] triphosphate
g
gS (>1000 Ci/mmol)
For this novel 4-amino-4-methyl-piperidino-bridged series,
a preliminary SAR study was conducted with respect to the right
side hydrophobic group. The 4’-substituted phenyl (4a, 4d), the
pyridinyl (4b), the cyclohexyl (4c), the adamantylmethyl (4e), and
the substituted benzyl (4f-i) rings were investigated. As the activity
data indicated (Table 1), the aromatic ring was an optimal group for
the right side hydrophobic domain (4a, 4b vs. 4c, 4f-i vs. 4e) to
achieve effective CCR5 inhibition. In addition, the electron-nega-
tivity and hydrphobicity of the aromatic group were favored for the
interaction with CCR5 protein (4a, 4b and 4f-i), while the electron-
withdrawing group on the phenyl ring was detrimental to the
binding (4d). Furthermore, one more methylene extention of the
aromatic ring away from the basic center was beneficial for the
potency (4eei), thus the benzyl group was obviousely advantageous
over the phenyl group acylated with the 4-amino-4-methylpiper-
idine linker in the context of CCR5 inhibition (4eei vs. 4aed).
So, based on our proposed 3-feature pharmacophore model and
the priviledged structure re-assembly, we discovered potent new
structure CCR5 inhibitors (1a and 4fei), which in turn positively
supported our hypothesis about the pharmacophore model for
CCR5 inhibition. More significantly, the identification of 4-amino-
4-methylpiperidine-bridged CCR5 antagonists via the pharmaco-
phore-based design and the efficient synthesis provides promising
new scaffold for further lead optimization and development of new
structure CCR5 antagonists.
ml
m
m
g
HEPES, 10 mM MgCl2, 1 mM EDTA, 100 mM NaCl, 0.1% BSA, pH 7.6)
were incubated with compounds in 96-well plate for 30 min at
25 ꢁC. The incubation was then continued at room temperature
with 0.5 nM [35S]GTP
GTP
g
S for another 30 min, membrane-bound [35S]
S was measured using a scintillation counter. Basal binding
g
Scheme 4. The synthesis of the piperidine-/tropane-substituted heteroaromatics.
Reagents and conditions: 9a) K2CO3/CH3CN, reflux, 24 h, 99%; (b) 10% PdeC/H2,THF,
22 h, 94%; c) Ac2O/165 ꢁC, 24 h,; (d) HCl, reflux, 70% in two steps; (e) PCl5/CH2Cl2,
0e20 ꢁC, 10 h; (f) CH3CONHNH2/CH2Cl2/t-amyl alcohol, 0 ꢁC, 12 h; g) PhMe/TsOH,
reflux, 20 h; (h) (Boc)2O/NaOH (aq).
5. Conclusion
Based on the putative three-feature pharmacophore model, we
designed and synthesized a new class of CCR5 inhibitors by

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2831
Scheme 5. The synthesis of the piperidine-/piperazine-substituted aromatics. Reagents and conditions: (a) NaB(OAc)3H/HOAc, CH3COCH3, rt, 96%; (b) BnBr/K2CO3, CH3CN. rt, 93%;
(c) CF3COOH/CH2Cl2, rt, 1 h, 99%; (d) SOCl2/CH3OH, rt; (e) (Boc)2O/CH2Cl2/TEA, rt, 99%; (f) LDA/THF, ꢀ78 ꢁC, 87%; (g) aryl-/alkyl-carboxylic acid, EDCI/HOBt/NMM/CH2Cl2, rt, 60e80%.
selecting privileged fragments for the three functional domains,
focused on the basic center carrier structure which is critical for the
CCR5 binding due to the electronic interaction with the key residue
E283 and the orientation effect. Efficient synthesis was developed
to build the target molecules and construct the building block sets
in this work. Evaluation of these analogues in the RANTES-stimu-
6.3. (E)-Ethyl 3-(naphthalen-1-yl)acrylate (8b) [30]
8b was prepared in a similar fashion as described for 8a,
colorless oil, yield 81.6%. 1H NMR (300 MHz, CDCl3):
d 8.52 (d, 1H,
J ¼ 15.9 Hz), 8.19e8.20 (m, 1H), 7.86e7.90 (m, 2H), 7.74e7.77 (m,
1H), 7.48e7.56 (m, 3H), 6.52 (d, 1H, J ¼ 16.2 Hz), 4.31 (q, 2H,
J ¼ 7.2 Hz), 1.38 (t, 3H, J ¼ 7.2 Hz). TLC Rf ¼ 0.7 (petroleum ether/
EtOAc ¼ 10/1).
lated [35S]-GTP
gS binding assay resulted in the discovery of new
structure nanomolar CCR5 inhibitors. Especially, the 4-amino-4-
methylpiperidine containing compounds represent a new class of
CCR5 antagonists identified via the pharmacophore-based design
and the efficient synthesis strategy, affording novel scaffolds for
further development of the potent CCR5 inhibitors.
6.4. (E)-Ethyl 3-(3-fluorophenyl)acrylate (8c)
8c was prepared in a similar fashion as described for 8a, color-
less oil, yield 95%. 1H NMR (300 MHz, CDCl3):
d 7.63 (d, 1H,
J ¼ 15.9 Hz), 7.19e7.39 (m, 3H), 7.04e7.10 (m, 1H), 6.42 (d, 1H,
6. Experimental protocols
J ¼ 15.9 Hz), 4.27 (q, 2H, J ¼ 7.2 Hz), 1.34 (t, 3H, J ¼ 7.2 Hz).
6.1. General
6.5. (S)-Ethyl 3-(N-benzyl-N-((R)-1-phenylethyl)amino)-3-(4-
(trifluoromethyl)phenyl) propanoate (9a)
Solvents were distilled and dried according to standard proce-
dures. 1H NMR spectra were recorded on a Varian 300-MHz or 400-
MHz spectrometer. 13C NMR spectra were recorded on a Varian
Mercury VX 400-MHz spectrometer. Melting points (uncorrected)
were determined on a Buchi-510 capillary apparatus. Specific
rotations (uncorrected) were determined in a Perkin-Elmer 241
polarimeter. Low and high-resolution mass spectra were deter-
mined on Finnigan MAT-95 mass spectrometer. TLC was performed
on 0.25 mm HSGF 254 silica gel plates. The key products were
characterized by NMR, MS and high-resolution mass spectra.
Under N2 protection, n-butyllithiumm 1.6 M in hexane (10.5 mL,
16.8 mmol) was added dropwise to the solution of (R)-N-benzyl-1-
phenylethyl ethanamine (2.88 g, 13.6 mmol) in dry THF (40 mL) at
ꢀ15 ꢁC. After stirring for 30 min, the mixture was allowed to warm
to room temperature for 10 min, then cooled to ꢀ78 ꢁC. The solu-
tion of compound 8a (2.56 g, 10.5 mmol) in THF (10 mL) was
introduced via syringe. After 3 hours of stirring at ꢀ78 ꢁC, the
reaction was quenched with saturated NH4Cl aqueous solution
(5 mL) and warmed to room temperature. The aqueous phase was
separated and extracted with EtOAc (3 ꢂ 50 mL). The combined
organic phases were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuum. The crude product was puri-
fied by silica gel column chromatography with eluent of petroleum
ether/EtOAc ¼ 40/1 to afford the compound 9a (3.337 g, yield
6.2. (E)-Ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (8a) [29]
To the solution of triethyl phosphonoacetate (3.3 mL,
16.5 mmol) in dry THF (50 mL) was added NaH (0.72 g, 30 mmol) at
0 ꢁC. The reaction mixture was gently stirred for 45 min at 0 ꢁC,
then was added 4-(trifluoromethyl)benzaldehyde (2.61 g,15 mmol)
in dry THF (2 mL) dropwise. After 3 hours of stirring at 0 ꢁC and 1 h
at room temperature, the mixture was quenched with saturated
aqueous solution of ammonium chloride, filtered and washed with
EtOAc (2 ꢂ 50 mL). The combined organic phases were concen-
trated under vacuum, and the residue was purified by silica gel
column chromatography with the eluent of petroleum ether/
EtOAc ¼ 40/1 to give compound 8a (2.74 g, yield 84.1%) as colorless
69.8%) as colorless oil. 1H NMR (CDCl3, 300 MHz):
d 7.58e7.67 (m,
4H), 7.23e7.48 (m,10H), 4.56e4.60 (m, 1H), 3.96e4.06 (m, 3H), 3.75
(q, 2H, J ¼ 5.7 Hz), 2.63e2.67 (m, 2H), 1.34 (d, 3H, J ¼ 6.9 Hz), 1.10 (t,
3H, J ¼ 6.9 Hz). TLC Rf ¼ 0.35 (petroleum ether/EtOAc ¼ 20/1).
6.6. (S)-Ethyl-3-(N-benzyl-N-((R)-1-phenylethyl)amino)-3-
(naphthalen-1-yl) propanoate (9b)
oil. 1H NMR (300 MHz, CDCl3):
d
7.68 (d, 1H, J ¼ 15.6 Hz), 7.63 (s,
9b was prepared in a similar fashion as described for 9a,
4H), 6.50 (d, H, J ¼ 16.2 Hz), 4.27 (q, 2H, J ¼ 7.2 Hz), 1.34 (t, 3H,
colorless oil, yield 80 %. 1H NMR (CDCl3, 300 MHz):
d
8.29 (brs, 1H)
J ¼ 7.2 Hz). TLC Rf ¼ 0.55 (petroleum ether/EtOAc ¼ 20:1).
7.69e7.83 (m, 3H), 7.41e7.49 (m, 5H), 7.14e7.29 (m, 8H), 5.11e5.56

2832
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
Table 1
CCR5 inhibition activity of 1,3-propanediamine bridged compounds with variation on the basic center carrier.
Entry
Compounds
Structures
IC50, m
Ma or inhibition rate
1
1a
0.253
2
1b
w10
3
2a
>10
4
2b
>10
5
3a
w10
6
3b
>10
7
3c
>10

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2833
Table 1 (continued)
Entry
Compounds
Structures
IC50
33% at 300 nM, 9% at 30 nM
, m
Ma or inhibition rate
8
4a
9
4b
44% at 300 nM, 35% at 30 nM
10
4c
29% at 300 nM, 6% at 30 nM
11
4d
7% at 300 nM, 3% at 30 nM
12
4e
46% at 300 nM, 21% at 30 nM
13
4f
91% at 300 nM, 28% at 30 nM
14
4g
97% at 300 nM, 36% at 30 nM
15
4h
95% at 300 nM, 31% at 30 nM
(continued on next page)

2834
Table 1 (continued)
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
Entry
Compounds
Structures
IC50
98% at 300 nM, 22% at 30 nM
, m
Ma or inhibition rate
16
4i
a
Inhibition of RANTES-stimulated [35S]-GTP
g
S binding to CCR5-expressing CHO cell membranes.
(m, 1H), 3.96e4.03 (m, 1H), 3.77e3.92 (m, 2H), 3.73 (q, 2H,
(br,1H), 5.09 (br,1H), 4.07 (q, 2H, J ¼ 7.1 Hz), 2.79e2.80 (m, 2H),1.42
(s, 9H), 1.17 (t, 3H, J ¼ 7.1 Hz).
J ¼ 7.2 Hz), 2.92e2.74 (m, 2H), 1.22 (d, 3H, J ¼ 6.9 Hz), 0.80 (t, 3H,
20
J ¼ 7.2 Hz). [
a
]
¼ þ45.8ꢁ (c ¼ 1.02, CHCl3). TLC Rf ¼ 0.4 (petroleum
D
ether/EtOAc ¼ 20/1).
6.10. tert-Butyl-(S)-1-(4-(trifluoromethyl)phenyl)-2-
formylethylcarbamate (6a) [31]
6.7. tert-Butyl-(S)-2-(ethoxycarbonyl)-1-(4-(trifluoromethyl)
phenyl)ethylcarbamate (10a)
To the solution of the compound 10a (0.723 g, 2 mmol) in dry
CH2Cl2 (20 mL) was added DIBAl-H (1 M in toluene, 3 mL) at ꢀ78 ꢁC
under N2 protection and the resulting solution was stirred at
ꢀ78 ꢁC for 3 h until the starting material disappeared. The reaction
was quenched with saturated NH4Cl aqueous solution (2 mL) and
water (10 mL). After extraction with CH2Cl2 (4 ꢂ 20 mL), the
combined organic layers were washed with brine and dried over
Na2SO4, filtered and concentrated under reduced pressure to give
compound 6a (0.38 g, yield 60.2%). TLC Rf ¼ 0.4 (petroleum ether/
EtOAc ¼ 4/1). The crude product was not purified and used directly
for the next step.
The suspension of compound 9a (3.337 g, 7.33 mmol), 20% Pd
(OH)2 on carbon (0.4 g) and di-tert-dicarbonate (3.21 g,1 4.7 mmol)
in ethanol (40 mL) was hydrogenated at room temperature for 70 h
until the reaction was completed. The slurry was filtered, rinsed
with CH3OH (50 mL), and concentrated to an oil. The crude product
was purified by silica gel column chromatography with eluent of
petroleum ether/EtOAc ¼ 8/1 to give the compound 10a (2.303 g,
yield 86.9%) as white solid. M.p.75e78 ꢁC. 1H NMR (CDCl3,
300 MHz):
d
7.59 (d, 2H, J ¼ 8.1 Hz), 7.41 (d, 2H, J ¼ 8.1 Hz), 5.67 (brs,
1H), 4.06 (q, 2H, J ¼ 6.9 Hz), 2.82e2.84 (m,2H), 1.42 (s, 9H), 1.16
22
(t, J ¼ 6.9 Hz, 3H). EI-MS (m/z): 361 (Mþ). [
a]
¼ ꢀ14.6ꢁ (c ¼ 0.64,
6.11. (S)-Ethyl 3-(cyclohexanecarboxamido)-3-(3-fluorophenyl)
propanoate (10d)
D
CHCl3). TLC Rf ¼ 0.3 (petroleum ether/EtOAc ¼ 8/1).
To a stirred solution of 10c (1.127 g, 3.6 mmol) in 20 mL DCM
was added TFA (1.4 mL, 18 mmol), the mixture was stirred at rt for
12 h. Evaporated to remove the solvent and TFA, the residue was
dissolved in 20 mL DCM. To the solution was added cyclo-
hexanecarboxylic acid (0.52 mL, 4.3 mmol), EDCI (1.038 g,
5.4 mmol), HOBt (0.734 g, 5.4 mmol) and DIPEA (2.53 ml,
14.5 mmol). The mixture was stirred at rt for another 12 h. Usual
work-up and purification by column chromatography (PE/EA ¼ 3:1)
gave 10d as colorless oil (0.75 g, 66% yield). 1H NMR (300 MHz,
6.8. tert-Butyl-(S)-2-(ethoxycarbonyl)-1-(naphthalen-1-yl)
ethylcarbamate (10b)
10b was prepared in a similar fashion as described for 10a, white
solid, yield 83%. M.p.88e90 ꢁC. 1H NMR (CDCl3, 300 MHz): dd 8.13
(d, 1H, J ¼ 8.1 Hz), 7.77e7.98 (m, 2H), 7.41e7.59 (m, 4H), 5.96 (brs,
1H), 5.55 (brs, 1H), 4.05 (q, 2H, J ¼ 6.9 Hz), 2.98e3.00 (m, 2H), 1.43
20
(s, 9H), 1.12 (t, 3H, J ¼ 6.9 Hz). EI-MS (m/z): 343 (Mþ). [
a]
¼ ꢀ13.6ꢁ
D
(c ¼ 0.99, CHCl3). TLC Rf ¼ 0.4 (petroleum ether/EtOAc ¼ 8/1).
CDCl3):
d 7.26e7.33 (m, 1H), 7.05e7.08 (m, 1H), 6.92e7.01 (m, 2H),
6.75e6.78 (m, 1H), 5.39e5.45 (m, 1H), 4.09 (q, 2H, J ¼ 7.2 Hz),
2.77e2.92 (m, 2H), 2.12e2.22 (m, 1H), 1.89e1.94 (m, 2H), 1.78e1.84
(m, 2H), 1.66e1.71 (m, 1H), 1.40e1.52 (m, 2H), 1.23e1.37 (m, 3H),
1.19 (t, 3H, J ¼ 7.2 Hz).
6.9. (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(3-fluorophenyl)
propanoate (10c)
To
a stirred solution of (R)-N-benzyl-1-phenylethanamine
(9.8 g, 46.5 mmol) in 100 mL dry THF at ꢀ78 ꢁC was added nBuLi
(32 mL, 50.7 mmol). The resulting mixrture was allowed to rt over
10 min before re-cooling to ꢀ78 ꢁC, then was added the solution of
8c (8.195 g, 42.4 mmol) in 80 mL dry THF. The resulting mixture
was stirred at ꢀ78 ꢁC for 2 h then quenched by the addition of
saturated aqueous NH4Cl solution. After warming to rt, the organic
phase was washed with water and brine, dried over Na2SO4 and
concentrated. The crude product was purified by column chroma-
6.12. (S)-N-(1-(3-Fluorophenyl)-3-oxopropyl)
cyclohexanecarboxamide (6c)
Compound 6c was prepared from 10d in a similar fashion as
described for 6a, colorless oil in yield of 56%. 1H NMR (300 MHz,
CDCl3):
d
9.71 (s, 1H), 7.27e7.30 (m, 1H), 7.05 (d, 1H, J ¼ 7.8 Hz),
6.92e6.97 (m, 2H), 6.40e6.43 (m, 1H), 5.48 (dd, 1H, J ¼ 6.6 Hz,
13.8 Hz), 2.87e3.06 (m, 2H), 2.04e2.13 (m, 2H), 1.75e1.84 (m, 4H),
1.38e1.42 (m, 2H), 1.19e1.24 (m, 3H).
tography (PE/EA ¼ 30:1) to afford the product 9c as colorless oil
23
(11.68 g, 68% yield). [
a
]
¼ þ2.3ꢁ(c ¼ 1.0, CHCl3). To the stirred
D
solution of 9c (4.05 g, 10 mmol) in 100 mL EtOH was added Boc2O
(4.36 g, 20 mmol) and 10% Pd(OH)2/C (400 mg). The mixture was
hydrogenated at rt for 24 h then filtered, evaporated to remove the
solvent. The crude product was purified by column chromatog-
raphy (PE/EA ¼ 5:1) to give 10c as colorless oil (2.36 g, 76% yield). 1H
6.13. Ethyl 8-carboxylate-8-aza-bicyclo[3.2.1]octan-3-one (11) [32]
A suspension of tropinone (27.84 g, 200 mmol), ethyl chlor-
oformate (43.41 g, 38.2 mL, 400 mmol) and anhydrous K2CO3
(110 g, 800 mmol) in CHCl3 (300 mL) was heated to reflux for 3 h.
TLC monitored the reaction progress until the reaction was
NMR (300 MHz, CDCl3): d 7.25e7.31 (m, 1H), 6.91e7.08 (m, 3H),5.58

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2835
completed. The slurry was filtered, rinsed with 100 mL of CH2Cl2.
The organic layer was treated with saturated NaHCO3 solution and
extracted with CH2Cl2 (2 ꢂ 100 mL). The organic layer was washed
with brine and concentrated in vacuum. The residue was purified
by silica gel chromatography with eluent of CH2Cl2/CH3OH ¼ 20/1
to afford the compound 11 (34.7 g, yield 88.1%) as colorless oil. 1H
3 h until the reaction completed. The solvent was removed under
vaccum and the residue was dissolved in saturated NaCl aq. under
ice-bath. The solution was extracted with CH2Cl2 followded by
usual work-up to give compound 14 as brown oil (8.43 g, yield
95.1%).
NMR (CDCl3, 300 MHz):
(brs, 2H), 2.27e2.34 (m, 2H), 2.05e2.07 (m, 2H), 1.63e1.67 (m, 2H),
1.25 (t, 3H, J ¼ 6.9 Hz). TLC Rf ¼ 0.8 (CH2Cl2/CH3OH ¼ 10/1).
d
4.51 (brs, 2H), 4.15 (q, 2H, J ¼ 6.9 Hz), 2.62
6.17. N-(1-Benzylpiperidin-4-yl)isobutyramide (15) [35]
To the solution of 14 (3.8 g, 20 mmol) in THF (20 mL) was added
the solution of isobutyric acid (3.5 g, 40 mmol) and DCC (8.26 g,
40 mmol) in 30 mL of THF at room temperature. The reaction
mixture was stirred for 10 h, then filtered to remove the white solid.
The filtrate was concentrated under vaccum and extracted with
CH2Cl2. The combined organic layers was washed with saturated
NaCl aq. and dried over anhydrous Na2SO4. Evaporation afforded 15
as yellow solid (6.73 g, yield 83%). M.p.126e127 ꢁC. 1H NMR
6.14. 8-(Ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octan-3-amine (12)
(endo-) [33]
The solution of 11 (1.97 g, 10 mmol) in MeOH (50 mL) was
treated with ammonium formate (6.4 g, 100 mol) and water (6 mL)
under vigorous stirring. After complete dissolution, 10% Pd/C (1 g)
was added carefully and the reaction mixture was stirred overnight
at room temperature. After TLC indicated a complete consumption
of the starting material, the catalyst was filtered off on Celite and
the solution was concentrated under reduced pressure. The oily
residue was basified with saturated aqueous NaHCO3 to pH 9e10
and the mixture was extracted with CH2Cl2 (3 ꢂ 50 mL). The
combined organic layer was washed with brine and dried over
Na2SO4, concentrated in vacuum. The crude product was purified
by column chromatography with eluent of CH2Cl2/MeOH ¼ 50/1 to
20/1 to afford the compound 12 (1.583 g, 80.1 yield) as colorless oil.
After standing at room temperature, the oil turns into light yellow
(300 MHz, CDCl3):
d 7.24e7.32 (m, 5H), 5.26e5.29 (brs, 1H),
3.77e3.82 (m, 1H), 3.50 (s, 2H), 2.79e2.83 (m, 2H), 2.24e2.33 (m,
1H), 2.08e2.17 (m, 2H), 1.37e1.47 (m, 2H), 1.25 (m, 2H), 1.09 (d, 6H,
J ¼ 6.6 Hz). EI-MS: m/z 260 (Mþ).
6.17.1. Ethyl 4-(isobutyramido)piperidine-1-carboxylate (16)
Compound 16 was prepared in a similar fashion as described for
11 (yield 93.8%) as white solid. M.p.128e130 ꢁC. 1H NMR (300 MHz,
CDCl3):
d 5.38 (s, 1H), 4.08e4.15 (m, 4H), 3.38e3.97 (m, 1H), 2.88
(t, 2H, J ¼ 12 Hz), 2.29 (sep, 1H, J ¼ 6.6 Hz,), 1.88e1.95 (m, 2H),
1.22e1.35 (m, 5H), 1.12 (d, 6H, J ¼ 6.6 Hz). TLC Rf ¼ 0.5 (CH2Cl2/
CH3OH ¼ 20/1).
solid. M.p.64e68 ꢁC. 1H NMR (CDCl3, 300 MHz):
d 4.22 (brs, 2H),
4.12 (q, 4H, J ¼ 7.2 Hz), 3.324 (t, 1H, J ¼ 6.0 Hz), 2.10e2.17 (m, 4H),
1.91e1.96 (m, 2H), 1.43 (d, 2H, J ¼ 13.2 Hz), 1.24 (t, 3H, J ¼ 7.2 Hz).
TLC Rf ¼ 0.3 (CH2Cl2/MeOH ¼ 10/1).
6.18. Ethyl 3-(3-nitropyridin-2-ylamino)-8-aza-bicyclo[3.2.1]
octan-8-carboxylate (17) (endo-)
6.15. N-(8-Ethoxycarbonyl-8-aza-bicyclo[3.2.1]octan-3-yl)
isobutyramide (13)
A suspension of compound 12 (1.28 g, 8.09 mmol), 2-chloro-3-
nitropyridine (1.603 g, 8.09 mmol) and K2CO3 (4.5 g, 32.4 mmol) in
100 mL of dry CH3CN was heated at refluxing for 10 h until the
reaction was complete. The mixture was concentrated to driness
and 50 mL of water was added. Extracted with EtOAc (2 ꢂ 30 mL),
the combined organic phases were washed with saturated NaCl
aqueous solution (40 mL). After drying over Na2SO4 and evapora-
tion, the crude product was purified by silica gel chromatography
with petroleum ether/EtOAc ¼ 2/1 to afford 17 (2.134 g, yield 82.4%)
To a stirred solution of isobutyric acid (1.76 g, 20 mmol) and DCC
(4.76 g, 20 mmol) in dry THF (30 mL) at room temperature for
30 min was added the compound 12 (3.9 g, 20 mmol). The mixture
was stirred for another 24 h until reaction was completed. The
slurry was filtrated, rinsed with THF. The organic layer was
concentrated and extracted with EtOAc (3 ꢂ 50 mL). The organic
layer was washed with brine and concentrated. The crude product
was purified by silica gel chromatography with eluent of PE:
EtOAc ¼ 2:1 to afford 13 (4.8 g, 90% yield) as white solid. M.
as yellow solid. M.p.140e144 ꢁC. 1H NMR (CDCl3, 300 MHz):
d 8.92
p.99e100 ꢁC.1H NMR (CDCl3, 300 MHz):
d 5.87 (brs, 1H), 5.28 (s,
(brs, 1H), 8.07e8.11 (m, 1H), 6.33e6.36 (m, 1H), 6.03e6.05 (m, 1H),
4.28 (brs, 2H), 4.07e4.13 (m, 3H), 2.24 (brs, 2H), 1.91e2.05 (m, 4H),
1.76e1.80 (m, 2H), 1.21 (t, 3H, J ¼ 6.9 Hz). TLC Rf ¼ 0.5 (petroleum
ether/EtOAc ¼ 1/1).
1H), 4,28 (brs, 2H), 4.12 (q, 2H, J ¼ 7.2 Hz), 2.30 (sep, 1H, J ¼ 6.9 Hz),
2.18 (brs, 2H), 2.05e2.10 (m, 2H), 1.80e1.83 (m, 2H), 1.64e1.69 (m,
2H), 1.24 (t, 3H, J ¼ 7.2 Hz), 1.13 (d, 6H, J ¼ 6.6 Hz). EI-MS (m/z): 268
(Mþ). TLC Rf ¼ 0.75 (CH2Cl2/CH3OH ¼ 10:1).
6.16. 1-Benzylpiperidin-4-amine (14) [34]
6.19. Ethyl 3-(3-aminopyridin-2-ylamino)-8-aza-bicyclo[3.2.1]
octan-8-carboxylate (18) (endo-)
To the solution of 1-benzylpiperidin-4-one (9.45 g, 50 mmol) in
anhydrous EtOH (150 mL) was added NH2OH.HCl (7 g, 100 mmol)
under ice bath, then added pyridine (17 mL) with vigorous stirring.
The reaction mixture was heated to reflux for 5 h until the starting
material disappeared. The reaction mixture was evaporated and the
residue was dissoved in saturated NaCl aqueous solution and was
adjusted by 1 N NaOH to pH 9e10, then extracted with ethyl
acetate. Usual work-up gave yellow solid which was chromatog-
raphied with eluent of PE:EtOAc ¼ 2:1 to afford 1-benzylpiperidin-
4-one oxime as white solid (10.7 g, yield 99%). The intermediate
(9.5 g, 46 mmol) was dissolved in n-PrOH (150 mL), and sodium
piece (10.6 g, 460 mmol) was added to the solution under ice-bath.
After stirring for 0.5 h, the reaction mixture was heated to reflux for
The mixture of compound 17 (2.140 g, 6.7 mmol) and 10%
palladium-C (0.03 g) in dry CH3OH (50 mL) was stirred under
hydrogen for 8 h at room temperature. After filtration and removal
of the solvent under reduced pressure, the crude product was
purified by silica gel chromatography with eluent CH2Cl2/
CH3OH ¼ 20/1 to 10/1 to afford 18 (1.81 g, yield 93.7%) as brown
solid. M.p.9e95 ꢁC. 1H NMR (CDCl3, 300 MHz):
d 7.64e7.65 (m, 1H),
6.92e6.96 (m, 1H), 6.19e6.22 (m, 1H), 4.26 (brs, 2H), 4.11 (q, 1H,
J ¼ 6.9 Hz), 3.75 (brs, 1H), 3.03 (brs, 2H), 2.20 (brs, 2H), 1.99 (s, 4H),
1.72e1.78 (m, 2H), 1.23 (t, 3H, J ¼ 6.9 Hz). TLC Rf ¼ 0.1 (CH2Cl2/
CH3OH ¼ 50/1).

2836
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
6.20. endo-3-(8-Aza-bicyclo[3.2.1]octan-3-yl)-2-methyl-3H-
imidazo[4,5-b]pyridine (5-1)
(300 MHz, CDCl3):
d
4.34e4.38 (brs, 2H), 4.13 (q, 2H, J ¼ 7.2 Hz),
3.98e4.0 (m, 1H), 2.94e3.01 (m, 1H), 2.82 (t, 2H, J ¼ 12 Hz), 2.46
(s, 3H), 1.97e2.09 (m, 2H),1.79e1.84 (m, 2H), 1.35 (d, 6H, J ¼ 6.6 Hz),
1.25 (t, 3H, J ¼ 7.2 Hz). TLC Rf ¼ 0.1 (CH2Cl2/CH3OH ¼ 20/1).
The compound 18 (1.45 g, 5 mmol) was heated with acetic
anhydride (10 mL) at 165 ꢁC for 24 hs until the reaction completed.
The resultant solution was concentrated under reduced pressure
and the residue was dissolved in Na2CO3 aqueous solution to adjust
pH 9e10. Usual work-up afforded the intermediate of ethyl-3-(2-
methyl-3H-imidazo[4,5-b]pyridin-3-yl)-8-aza-bicyclo[3.2.1]octan-
8-carboxylate (endo-).
6.24. tert-Butyl 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)
piperidine-1-carboxylate (5-3)
Compound 5-3 was prepared in a similar fashion as described
for 5-2 as white solid. M.p. 148e152 ꢁC. 1H NMR (300 MHz, CDCl3):
d
4.29e4.30 (brs, 2H), 3.97e4.01 (m,1H), 2.97 (sep, 1H, J ¼ 6.9 Hz),
6.21. Ethyl-3-(2-Methyl-3H-imidazo[4,5-b]pyridin-3-yl)-8-aza-
bicyclo[3.2.1]octan-8-carboxylate (endo-)
2.74e2.82 (m, 2H), 2.48 (s, 3H), 1.97e2.10 (m, 2H), 1.78e1.83 (m,
2H), 1.46 (s, 9H), 1.36 (d, 6H, J ¼ 6.6 Hz). EI-MS: m/z 308 (Mþ). TLC
Rf ¼ 0.15 (CH2Cl2/CH3OH ¼ 20/1).
As light brown solid. M.p.91e93 ꢁC. 1H NMR (CDCl3, 300 MHz):
d
8.22 (d, 1H, J ¼ 1.5 Hz), 7.86 (d, 1H, J ¼ 1.5 Hz), 7.09 (q, 1H,
6.25. tert-Butyl 4-(4-(N-benzyl-N-isopropylamino)phenyl)
piperazine-1-carboxylate (21)
J ¼ 1.5 Hz), 4.47 (brs, 2H), 4.16e4.32 (m, 3H), 2.52 (s, 3H), 2.41e2.55
(m, 2H), 2.42 (m, 2H), 2.04e2.08 (m, 4H), 1.28 (t, 3H, J ¼ 6.9 Hz). TLC
Rf ¼ 0.4 (CH2Cl2/CH3OH ¼ 20/1).
To a stirred solution of tert-butyl 4-(4-aminophenyl)piperazine-
1-carboxylate (1.748 g, 6.16 mmol) and glacial acetic acid (1.19 g,
18.5 mmol) in dry acetone (30 mL) was added NaB(OAc)3H (3.90 g,
18.5 mmol) at room temperature, stirred for another 7 h at room
temperature. The mixture was concentrated and the residue was
dissolved in NaHCO3 solution to pH 9e10 and extracted with
CH2Cl2 (3 ꢂ 50 mL), The organic extracts were combined, the
organic layer was washed with brine, dried over Na2SO4, concen-
trated to afford the intermediate of tert-butyl 4-(4-(iso-
The intermediate was dissolved in 6 N HCl (5 mL) and stirred at
reflux for 12 h. After cooling, the mixture was extracted with CH2Cl2,
basified, and the aqueous layer was treated with 10% aqueous NaOH
solution and extracted with CH2Cl2 (3 ꢂ 30 mL). The combined
organic layers werewashedwithbrineandconcentrated.Theresidue
was purified by silica gel column chromatography with eluent
CH2Cl2/CH3OH ¼ 10/1 to 1/1 to afford compound 5-1 as light brown
solid (0.848 g, yield 70.1% in two steps). M.p.170e174 ꢁC. 1H NMR
(CDCl3, 300 MHz):
d
8.22e8.24 (m, 1H), 7.83e7.86 (m,1H), 7.07e7.11
propylamino)phenyl)piperazine-1-carboxylate
96.5%) as light brown solid. M.p. 67e68 ꢁC. 1H NMR (CDCl3,
300 MHz): 6.84 (brs, 2H), 6.58 (brs, 2H), 3.54e3.58 (m, 5H), 2.96
(1.897 g,
yield
(m,1H), 4.64e4.68(m,1H), 3.68e3.72 (m, 2H), 2.60(s, 3H), 2.26e2.43
(m, 4H), 1.99e2.01 (m, 2H), 1.80e1.84 (m, 2H). 13C NMR (CDCl3,
d
75 MHz,):
d
153.1,148.5,142.3,135.1,125.8,117.4, 52.0, 46.4, 34.5, 33.7,
(s, 4H), 1.48 (s, 9H), 1.19 (d, 6H, J ¼ 6.0 Hz).
15.2. EI-MS (m/z): 242 (Mþ). TLC Rf ¼ 0.5 (CH2Cl2/CH3OH ¼ 1/1).
At 0 ꢁC, 1-(bromomethyl)benzene (0.96 g, 5.62 mmol) was
added dropwise to the suspension of the intermediate (1.494 g,
4.68 mmol), K2CO3 (2.58 g, 18.72 mmol) in dry CH3CN (30 mL) over
30 min, the mixture was stirred for another 5 h, TLC monitor
reaction progress until the reaction was complete, filtered and
concentrated, Extracted with EtOAc (3 ꢂ 50 mL), washed with brine
and dried over Na2SO4, the crude was purified by column chro-
matography with elute DCM/CH3OH ¼ 50/1 to afford the compound
21 (1.773 g, yield 92.8%) as a brown oil. 1H NMR (CDCl3, 300 MHz):
6.22. endo-tert-Butyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-
yl)-8-aza-bicyclo[3.2.1] octan-8-carboxylate (5-2)
To a stirred solution of the compound 13 (0.96 g, 3.56 mmol) and
N,N-dimethylbenzenamine (0.05 g, 0.4 mmol) in dry CH2Cl2 (15 mL)
at 0 ꢁC was added PCl5 (1.11 g, 5.35 mmol) in three portions. After 2 h
stirring at 0 ꢁC, acetic hydrazide (1.31 g, 17.8 mmol) in 10 mL of
t-Amyl alcohol was added and the reaction mixture was stirred for
another 12 h, then allowed to warm to room temperature. The
solvent was removed in vacuo, and the residue was mixed with p-
TsOH (0.06 g, 0.4 mmol) in toluene (10 mL). The resultant solution
was heated to reflux for 6 h. After cooling, the solvent was removed.
The crude product 19 was stirred with 6 N HCl (10 mL) at refluxing
for 12 h, then the mixture was basified to pH 10e11 with 10%
aqueous NaOH solution at room temperature. Boc2O (1.1 g,
5.2 mmol) was added and the resulting solution was stirred for 24 h.
Extracted with CH2Cl2 (5 ꢂ 20 mL), the combined organic layers
were washed with brine and concentrated in vacuo. The residue was
purified by silica gel column chromatography with eluent of CH2Cl2/
CH3OH ¼ 20/1 to afford 5-2 (0.771 g, yield 64.7% in three steps) as
d
7.29e7.37 (m, 5H), 6.80e6.83 (m, 2H), 6.67e6.69 (m, 2H), 4.34 (s,
2H), 4.09e4.15 (m, 1H), 3.52e3.55 (m, 4H), 2.94 (s, 4H), 1.47 (s, 9H),
1.18 (d, 6H, J ¼ 6.6 Hz).
6.26. N-benzyl-N-isopropyl-4-(piperazin-1-yl)benzenamine (5-4)
At 0 ꢁC, TFA 0.2 mL in dry CH2Cl2 (1 mL) was added dropwise to
the solution of compound 21 (0.409 g, 10 mmol) in dry CH2Cl2
(4 mL). The resultant solution was stirred at room temperature for
1 h. Both the solvent and TFA were removed under vacuum. The
residue of light brown solid was used directly into next step
without further purification.
white solid. M.p.183e185 ꢁC.1H NMR (CDCl3,300 MHz):
d
4.36e4.44
6.27. 1-tert-Butyl 4-methyl 4-benzylpiperidine-1,4-dicarboxylate
(m, 2H), 3.96e4.03 (m, 1H), 2.89e2.95 (m, 1H), 2.47e2.57 (m, 2H),
2.50 (s, 3H), 2.16e2.19 (m, 2H),1.69e1.77 (m, 4H),1.50 (s, 9H),1.37 (d,
(23) [28]
6H, J ¼ 6.9 Hz). 13C NMR (75 MHz, CDCl3):
d
159.4, 154.5, 150.7, 50.4,
To a solution of diisopropylamine (2.1 mL) in anhydrous THF
(10 mL) was added n-butyllithium in hexanes (1.6 M, 10 mL) via
syringe at ꢀ15 ꢁC under N2 protection. After 30 min stirring at
ꢀ15 ꢁC, the mixture was added dropwise to the solution of
compound 22 (2.43 g, 10 mmol) [36] in anhydrous THF (50 mL) via
syringe over 30 min at ꢀ78 ꢁC. The reaction mixture was then
stirred at ꢀ78 ꢁC for 1 more hour. The solution of 1-(bromomethyl)
benzene (3.4 g, 20 mmol) in anhydrous THF (10 mL) was added
dropwise via syringe over 30 min. The resultant mixture was
49.7, 45.3, 35.6, 34.8, 32.1, 31.5, 28.2, 25.6, 21.3, 13.1; EI-MS:
C18H30N4O2 m/z 334 (Mþ). TLC Rf ¼ 0.35 (CH2Cl2/CH3OH ¼ 10/1).
6.23. Ethyl 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)
piperidine-1-carboxylate (20)
Compound 20 was prepared from the starting marterial 16 in
a similar fashion as described for 19 as light yellow oil. 1H NMR

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2837
stirred for 2 h at ꢀ78 ꢁC, then warmed to room temperature. The
reaction was quenched with saturated aqueous solution of NH4Cl
and extracted with EtOAc (3 ꢂ 50 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and solvents
removed in vacuo. The residue was purified by silica gel column
chromatography with elute PE/EtOAc ¼ 50/1 to 10/1 to afford 23 as
colorless oil (3.03 g, yield 87.3%). 1H NMR (CDCl3, 300 MHz):
according to the same procedure as 10d, colorless oil, 51% yield. 1H
NMR (CDCl3, 300 MHz) : 4.99 (br, 1H), 3.63e3.68 (m, 2H),
3.10e3.19 (m, 2H),1.97e1.98 (m, 4H),1.88 (s, 2H),1.69e1.73 (m, 4H),
1.61e1.64 (m, 7H), 1.50e1.57 (m, 2H), 1.46 (s, 9H), 1.41 (s, 3H),
1.26e1.28 (m, 2H).
d
6.34. tert-Butyl 4-(2-(4-chlorophenyl)acetamido)-4-
d
7.21e7.28 (m, 3H), 7.01e7.03 (m, 2H), 3.88e3.96 (s, 2H), 3.63
methylpiperidine-1-carboxylate (5e6f)
(s, 3H), 2.81 (brs, 4H), 2.05e2.10 (m, 2H), 1.44(s, 9H), 1.40e1.46 (m,
2H). TLC Rf ¼ 0.32 (petroleum ether/EtOAc ¼ 10/1).
Compound 5e6f was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 2-(4-chlorophenyl)acetic acid
according to the same procedure as 10d, colorless oil, 80% yield. 1H
6.28. Methyl 4-benzylpiperidine-4-carboxylate (5-5)
NMR (300 MHz, CDCl3):
d
7.34 (d, 2H, J ¼ 8.7 Hz), 7.19 (d, 2H,
Starting from compound 23, acidic removal of the Boc group
yielded 5-5, in a similar fashion as described for 5-4. Without
further purification, the intermediate 5-5 was used directly for the
next coupling reaction.
J ¼ 8.7 Hz), 5.03 (br, 1H), 3.60e3.65 (m, 2H), 3.49 (s, 2H), 2.85e2.95
(m, 2H), 1.91e1.96 (m, 2H), 1.48e1.54 (m, 2H), 1.44 (s, 9H), 1.37
(s, 3H).
6.35. tert-Butyl 4-(2-(3,4-dichlorophenyl)acetamido)-4-
6.29. tert-Butyl 4-(4-methoxybenzamido)-4-methylpiperidine-1-
methylpiperidine-1-carboxylate (5e6g)
carboxylate (5e6a)
Compound 5e6g was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 2-(3,4-dichlorophenyl)acetic
acid according to the same procedure as 10d, white foam, 67% yield.
Compound 5e6a was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 4-methoxybenzoic acid in
a similar fashion as described for compound 10d, colorless oil,
1H NMR (CDCl3, 300 MHz)
d
: 7.42 (d, 1H, J ¼ 8.1 Hz), 7.37 (d, 1H,
yield 78%. 1H NMR (300 MHz, CDCl3):
d
7.70 (d, 2H, J ¼ 9.0 Hz), 6.92
J ¼ 2.1 Hz), 7.11 (dd, 1H, J ¼ 2.1 Hz, 8.1 Hz), 5.18 (br, 1H), 3.57e3.65
(m, 2H), 3.46 (s, 2H), 2.97e3.06 (m, 2H), 1.95e1.99 (m, 2H),
1.49e1.58 (m, 2H), 1.45 (s, 9H), 1.38 (s, 3H).
(d, 2H, J ¼ 9.0 Hz), 5.75 (br, 1H), 3.86 (s, 3H), 3.71e3.76 (m, 2H),
3.16e3.25 (m, 2H), 2.18e2.22 (m, 2H), 1.62e1.72 (m, 2H), 1.53
(s, 3H), 1.47 (s, 9H).
6.36. tert-Butyl 4-(2-(4-fluorophenyl)acetamido)-4-
methylpiperidine-1-carboxylate (5e6h)
6.30. tert-Butyl 4-methyl-4-(nicotinamido)piperidine-1-
carboxylate (5e6b)
Compound 5e6h was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 2-(4-fluorophenyl)acetic acid
according to the same procedure as 10d, colorless oil, 63% yield. 1H
Compound 5e6b was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and nicotinic acid according to the
same procedure as 10d. Colorless oil, yield 70%. 1H NMR (300 MHz,
NMR (CDCl3, 300 MHz)
5.03 (br, 1H), 3.61e3.68 (m, 2H), 3.51 (s, 2H), 2.84e2.93 (m, 2H),
1.93e1.97 (m, 2H), 1.48e1.55 (m, 2H), 1.45 (s, 9H), 1.38 (s, 3H).
d
: 7.22e7.26 (m, 2H), 7.07 (t, 2H, J ¼ 8.7 Hz),
CDCl3):
d
9.11 (s, 1H), 8.74 (d, 1H, J ¼ 5.1 Hz), 8.21 (d, 1H, J ¼ 7.8 Hz),
7.49 (dd, 1H, J ¼ 5.1 Hz, 7.8 Hz), 6.15 (br, 1H), 3.71e3.75 (m, 2H),
3.21e3.31 (m, 2H), 2.21e2.26 (m, 2H), 1.67e1.76 (m, 2H), 1.56 (s,
3H), 1.48 (s, 9H).
6.37. tert-Butyl 4-(2-(3,4,5-trimethoxyphenyl)acetamido)-4-
methylpiperidine-1-carboxylate (5e6i)
6.31. tert-Butyl 4-(cyclohexanecarboxamido)-4-methylpiperidine-
1-carboxylate (5e6c)
Compound 5e6i was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 2-(3,4,5-trimethoxyphenyl)
acetic acid according to the same procedure as 10d, white foam,
Compound 5e6c was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and cyclohexanecarboxylic acid
according to the same procedure as 10d, colorless oil, yield 75%. 1H
46% yield. 1H NMR (CDCl3, 300 MHz)
d: 6.47 (s, 2H), 5.15 (br, 1H),
3.86 (s, 9H), 3.64e3.68 (m, 2H), 3.48 (s, 2H), 2.85e2.95 (m, 2H),
1.96e2.00 (m, 2H), 1.49e1.55 (m, 2H), 1.45 (s, 9H), 1.39 (s, 3H).
NMR (300 MHz, CDCl3) :
d 5.11 (br, 1H), 3.65e3.73 (m, 2H),
3.03e3.12 (m, 2H), 1.98e2.07 (m, 3H), 1.69e1.86 (m, 6H), 1.49e1.58
(m, 3H), 1.45 (s, 9H), 1.38 (s, 3H), 1.21e1.32 (m, 3H).
6.38. endo-N-((S)-1-(4-(Trifluoromethyl)phenyl)-3-(3-(3-
isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1]
octan-8-yl)propyl)-2-phenoxyacetamide (1a)
6.32. tert-Butyl 4-methyl-4-(4-(trifluoromethyl)benzamido)
piperidine-1-carboxylate (5e6d)
At 0 ꢁC, TFA (0.2 mL) in dry CH2Cl2 (1 mL) was added dropwise
to the solution of compound 5-2 (0.034 g, 0.1 mmol) in dry CH2Cl2
(1 mL). The resultant solution was stirred at room temperature for
1 h till the starting material disappeared. Then the solvent and TFA
was removed under reduced pressure. The residue was dissolved in
5 mL of dry 1,2-dichloromethane and basified by adding Et3N
(1 mL). To the solution were added compound 6a (0.032 g,
0.1 mmol), HOAc (0.012 g) and sodium triacetoxyborohydride
(0.043 g, 0.2 mmol). The reaction mixture was stirred for 24 h at
room temperature. Concentrated and the residue was dissolved in
NaHCO3 solution to adjust the pH 9e10 and extracted with CH2Cl2
(3 ꢂ 20 mL). Usual work-up gave the crude product of tert-butyl (S)-
3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-aza-bicyclo
Compounds 5e6d were prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 4-(trifluoromethyl)benzoic
acid according to the same procedure as 10d, white foam, 68% yield.
1H NMR (300 MHz, CDCl3):
d
7.83 (d, 2H, J ¼ 8.1 Hz), 7.70 (d, 2H,
J ¼ 8.1 Hz), 5.81 (br, 1H), 3.67e3.75 (m, 2H), 3.18e3.27 (m, 2H),
2.15e2.20 (m, 2H), 1.66e1.75 (m, 2H), 1.54 (s, 3H), 1.46 (s, 9H).
6.33. tert-Butyl 4-(2-(adamantylacetamido))-4-methylpiperidine-
1-carboxylate (5e6e)
Compound 5e6e was prepared from tert-butyl 4-amino-4-
methylpiperidine-1-carboxylate and 2-adamantylacetic acid

2838
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
[3.2.1]octan-8-yl)-1-(4-(trifluoromethyl)phenyl) propylcarbamate
(0.038 g, yield 70.3%) as light brown solid.
(s, 2H), 4.05e4.16 (m, 1H), 3.03e3.06 (m, 4H), 2.54e2.65 (m, 4H),
2.35e2.39 (m, 4H), 1.85e1.98 (m, 2H), 1.17 (d, 6H, J ¼ 6.9 Hz). TLC
Rf ¼ 0.4e0.5(CH2Cl2/CH3OH ¼ 10:1).
The precursor (0.038 g, 0.07 mmol) was treated by TFA in dry
CH2Cl2 (20% v/v) at room temperature for 1 h, then concentrated.
The residue was dissolved in 10 mL of dry CH2Cl2 and basified by
adding Et3N (1 mL). To the solution were added 2-phenoxyacetic
acid (0.012 g, 0.084 mmol), EDCI (0.016 g, 0.084 mmol), HOAt
(0.011 g, 0.084 mmol) and DIPEA (0.1 mL). The mixture was stirred
overnight at room temperature and was quenched by adding
saturated aqueous NaHCO3 (10 mL). Usual work-up followed by
flash chromatography purification with eluent of CH2Cl2/
CH3OH ¼ 10/1 produced 1a as light brown solid (0.035 g, yield
The intermediate (0.12 g, 0.25 mmol) was mixed with DCC
(0.062 g, 0.3 mmol) and cyclohexanecarboxylic acid (0.038 g,
0.3 mmol) in dry THF (10 mL) at 0 ꢁC. The mixture was stirred for
24 h until the reaction was complete. Filtrated and concentrated,
basified with saturated NaHCO3 aqueous solution to pH 8e9,
extracted with CH2Cl2 (3 ꢂ 30 mL). Usual work-up followed by the
column chromatography purification with eluent CH2Cl2/
CH3OH ¼ 20/1 afforded compound 2a (0.123 g, yield 79.4%) as light
brown colloidal solid. 1H NMR (CDCl3, 300 MHz):
d 8.18 (brs, 1H),
88.0%). M.p.79.5e81 ꢁC. 1H NMR (CDCl3, 300 MHz):
d
7.56e7.59 (m,
7.26e7.37 (m, 2H), 7.34e7.36 (m, 2H), 7.15e7.31 (m, 5H), 6.81e6.84
(m, 2H), 6.67e6.70 (m, 2H), 5.08e5.14 (m, 1H), 4.35 (s, 2H),
4.10e4.19 (m, 1H), 3.12 (s, 4H), 2.66e2.73 (m, 4H), 2.46 (s, 2H),
1.39e2.22 (m, 14H), 1.18 (d, 6H, J ¼ 6.9 Hz). TLC Rf ¼ 0.75 (CH2Cl2/
CH3OH ¼ 20:1).
2H), 7.25e7.39 (m, 7H), 6.11e6.14 (m, 1H), 5.19e5.26 (m, 1H),
4.48e4.54 (m, 1H), 3.59 (s, 2H), 3.26e3.28 (m, 2H), 2.96e3.05 (m,
1H), 2.46 (s, 3H), 2.38e2.42 (m, 2H), 2.11e2.16 (m, 2H), 2.03e2.06
(m, 2H), 1.83e1.88 (m, 2H), 1.54e1.58 (m, 4H), 1.36 (d, 6H,
J ¼ 6.9 Hz). 13C NMR (DMSO-d6, 100 MHz):
d 169.7, 158.8, 150.2,
149.2, 136.6, 128.9, 128.2, 127.2, 126.4, 125.2, 57.2, 55.6, 50.0, 48.6,
6.41. N-((S)-1-(4-(trifluoromethyl)phenyl)-3-(4-(4-
(isopropylamino)phenyl)piperazin-1-yl)propyl)
cyclohexanecarboxamide (2b)
22
44.9, 42.6, 36.8, 35.6, 29.7, 29.3, 24.8, 21.9, 21.6, 12.7. [
a
]
¼ ꢀ2.1ꢁ
D
(c ¼ 0.45, CHCl3). EI-MS (m/z) 568 (M ꢀ 1)ꢀ. TLC Rf ¼ 0.45(CH2Cl2/
CH3OH ¼ 10/1).
The mixture of compound 2a (0.14 g, 0.173 mmol) and palla-
dium (10% on carbon, 0.05 g) in dry EtOH (20 mL) was stirred under
hydrogen for 10 h at room temperature until the reaction was
complete. After filtration and removal of the solvent under reduced
pressure, the crude product was purified by silica gel chromatog-
raphy with eluent of CH2Cl2/CH3OH ¼ 20/1 to give the precursor,
namely (S)-N-(3-(4-(4-(isopropylamino)phenyl) piperazin-1-yl)-1-
6.39. endo-4-Fluoro-N-((S)-3-(3-(2-methyl-3H-imidazo[4,5-b]
pyridin-3-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)-1-(naphthalen-1-yl)
propyl)benzamide (1b)
Starting from the building blocks 5-1 and 6b, compound 1b was
prepared in a similar fashion as described for 1a. Grey solid, 61%
yield in two steps. 1H NMR (CDCl3, 300 MHz):
d
8.32e8.34 (m, 1H),
(4-(trifluoromethyl)phenyl)propyl)cyclohexanecarboxamide
light brown colloidal solid (0.083 g, yield 90.2%). 1H NMR(CDCl3,
300 MHz): 8.27e8.29 (m, 1H), 7.56e7.59 (m, 2H), 7.34e7.36 (m,
as
7.24e8.31 (m, 4H), 8.16e8.19 (m, 1H), 7.90e7.93 (m, 1H), 7.75e7.80
(m, 5H), 7.51e7.54 (m, 1H), 7.26e7.29 (m, 1H), 5.21 (brs, 1H),
4.08e4.13 (m, 1H), 3.37e3.42 (m, 2H), 2.82e2.85 (m, 2H), 2.63
(s, 3H), 2.35e2.46 (m, 2H), 1.83e1.87 (m, 2H), 1.68e1.74 (m, 2H),
1.28e1.37 (m, 4H). EI-MS (m/z) 547 (Mþ). TLC Rf ¼ 0.4e0.45(CH2Cl2/
CH3OH ¼ 20/1).
d
2H), 6.84e6.86 (m, 2H), 6.56e6.60 (m, 2H), 5.11e5.17 (m, 1H),
3.54e3.60 (m, 1H), 3.10 (s, 4H), 2.57e2.71 (m, 4H), 2.35e2.42 (m,
2H), 2.07e2.16 (m, 2H), 1.39e1.92 (m, 12H), 1.19 (d, 6H, J ¼ 6.9 Hz).
TLC Rf ¼ 0.3 (CH2Cl2/CH3OH ¼ 20:1).
The precursor of compound 1b: endo-tert-butyl (S)-3-(3-(2-
methyl-3H-imidazo[4,5-b]pyridin-3-yl)-8-aza-bicyclo[3.2.1]octan-
8-yl)-1-(naphthalen-1-yl)propylcarbamate. 1H NMR (CDCl3,
To the stirred solution of the precursor (0.061 g, 0.11 mmol) in
toluene (10 mL) was added Ac2O (0.102 g, 1.1 mmol). The resultant
solution was refluxed for 3 h, then concentrated and basified with
saturated aqueous NaHCO3 to pH 8e9, extracted with EtOAc
(3 ꢂ 30 mL). Usual work-up followed by flash chromatography
purification with DCM/CH3OH ¼ 50/1 to 20/1 gave 2b as light
brown solid (0.059 g, yield 93.6%). M.p.73e75 ꢁC. 1H NMR (CDCl3,
300 MHz):
d
8.25 (d, 1H, J ¼ 1.5 Hz), 7.87 (d, 1H, J ¼ 1.5 Hz), 7.84
(d, 1H, J ¼ 1.5 Hz), 7.46e7.53 (m, 4H), 7.10e7.14 (m, 1H), 6.08 (brs,
1H), 5.81 (brs, 1H), 4.86e4.94 (m, 1H), 3.39e3.46 (m, 2H), 2.70
(s, 3H), 2.49e2.57 (m, 4H), 2.11e2.12 (m, 4H), 1.89e1.93 (m, 4H),
1.43 (s, 9H). TLC Rf ¼ 0.8 (CH2Cl2/CH3OH ¼ 10/1).
300 MHz):
d 7.74e7.76 (m, 1H), 7.56e7.59 (m, 2H), 7.34e7.36 (m,
2H), 6.97e6.99 (m, 2H), 6.87e6.91 (m, 2H), 4.96e5.04 (m, 1H),
3.18e3.28 (m, 3H), 2.58e2.69 (m, 2H), 2.32e2.43 (m, 2H), 2.01e2.18
(m, 2H), 1.87e1.91 (m, 2H), 1.74 (s, 3H), 1.61e1.73 (m, 8H), 1.39e1.51
(m, 2H), 1.02 (d, 6H, J ¼ 6.9 Hz). 13C NMR (DMSO-d6, 100 MHz):
6.40. N-((S)-3-(4-(4-(N-benzyl-N-isopropylamino)phenyl)
piperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)propyl)
cyclohexanecarboxamide (2a)
d
174.8, 169.1, 150.2, 148.9, 130.6, 129.5, 127.2, 125.8, 125.2, 115.2,
To the solution of compound 5-4 (0.9 mmol) in 5 mL of dry 1,2-
dichloromethane and Et3N (1 mL) were added compound 6a
(0.095 g, 0.3 mmol), HOAc (0.054 g, 0.9 mmol) and sodium tri-
acetoxyborohydride (0.19 g, 0.9 mmol). The resultant solution was
stirred for 22 h at room temperature, then concentrated under
reduced pressure. The residue was dissolved in NaHCO3 solution to
adjust pH to 9e10 and extracted with CH2Cl2 (3 ꢂ 50 mL). The
usual-workup afforded 0.173 g solid which was dissolved in dry
CH2Cl2 and treated with TFA (20% v/v) for 1 h at room temperature.
Removal of the solvent in vacuo produced the residue. Purification
by column chromatography with eluent of DCM/CH3OH ¼ 10/1
gave the intermediate of (S)-4-(4-(3-amino-3-(4-(trifluoromethyl)
phenyl)propyl)piperazin-1-yl)-N-benzyl-N- isopropylbenzenamine
as light brown colloidal solid (0.121 g, yield 79% in two step). 1H
54.6, 52.7, 50.6, 47.7, 44.7, 44.0, 33.0, 29.3, 29.2, 26.1, 25.5, 25.3, 23.2,
20.8. EI-MS (m/z) 572 (Mþ) . TLC Rf ¼ 0.6 (CH2Cl2/CH3OH ¼ 10/1).
6.42. Methyl-4-benzyl-1-((S)-3-(cyclobutanecarboxamido)-3-(4-
(trifluoromethyl)phenyl)propyl)piperidine-4-carboxylate (3a)
Starting from the building blocks of 5-5 and 6a, compound 3a
was prepared in a similar fashion as described for 1a as colorless oil
(yield 85.6%). 1H NMR (CDCl3, 300 MHz):
d 7.92e7.95 (brs, 1H),
7.54e7.57 (m, 2H), 7.24e7.34 (m, 5H), 7.02e7.05 (m, 2H), 4.97e5.03
(m, 1H), 3.65 (s, 3H), 2.98e3.17 (m, 6H), 2.85 (s, 2H), 2.43e2.51 (m,
2H), 1.64e2.15 (m, 11H). 13C NMR (DMSO-d6, 100 MHz):
d 174.9,
173.5, 148.8, 136.6, 129.7, 128.0, 127.5, 127.2, 126.6, 125.8, 125.2,
123.1, 54.7, 51.4, 50.9, 50.5, 37.5, 32.8, 24.8, 24.7, 24.6, 17.9, 17.8. EI-
20
NMR (CDCl3, 300 MHz):
d
7.57e7.60 (m, 2H), 7.45e7.48 (m, 2H),
MS (m/z) 516 (Mþ). [
(CH2Cl2/CH3OH ¼ 20:1).
a]
¼ ꢀ26.4ꢁ (c ¼ 0.36, CHCl3). TLC Rf ¼ 0.3
D
7.15e7.31 (m, 5H), 6.79e6.82 (m, 2H), 6.66e6.69 (m, 2H), 4.33

X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2839
6.43. N-((S)-3-(4-benzyl-4-(hydroxymethyl)piperidin-1-yl)-1-(4-
(trifluoromethyl)phenyl)propyl)cyclobutanecarboxamide (3b)
(m, 2H), 1.88e1.96 (m, 2H), 1.68e1.78 (m, 6H), 1.63 (s, 3H),
1.39e1.44 (m, 3H); 13C NMR (DMSO-d6, 100 MHz)
d
: 175.1, 166.4,
1
162.2 (d, JCF ¼ 241.8 Hz), 151.7, 148.8, 146.1, 135.7, 130.9, 130.4,
2
2
To the cold solution of LiAlH4 (0.005 g, 0.13 mmol) in dry THF
(1 mL) was added compound 3a (0.052 g, 0.1 mmol) in dry THF
(1 mL) via syringe under N2 protection at ꢀ15 ꢁC. The mixture was
stirred for an hour at ꢀ15 ꢁC until TLC indicated complete
consumption of the starting material. The reaction was quenched
with saturated aqueous NH4Cl (0.5 mL) followed by the usual work-
up. The crude product was purified by column chromatography
with eluent of CH2Cl2/CH3OH ¼ 10/1 to give compound 3b as
colorless colloidal solid (0.041 g, yield 83.6%). M.p.71e73 ꢁC. 1H
123.3, 122.4, 113.9 (d, JCF ¼ 14.2 Hz), 113.1 (d, JCF ¼ 14.6 Hz), 50.1,
49.5, 48.5, 43.8, 33.2, 30.5, 30.1, 29.1, 29.0, 28.7, 25.7, 25.4, 25.2, 22.1.
6.46.1. (S)-N-(1-(3-(cyclohexanecarboxamido)-3-(3-fluorophenyl)
propyl)-4-methylpiperidin-4-yl)cyclohexanecarboxamide (4c)
Compound 4c was prepared from 5e6c and 6c according to the
same procedure as 4a. 4c was a white solid. Mp: 83e85 ꢁC;
21
[a
]
¼ ꢀ25.2ꢁ (c ¼ 0.75, CHCl3); EI-MS (m/z): 485(Mþ); 1H NMR
D
(300 MHz, CDCl3):
d 8.09e8.11 (m, 1H), 7.02e7.04 (m, 1H),
NMR (CDCl3, 300 MHz):
7.24e7.34 (m, 5H), 7.16e7.19 (m, 2H), 5.05e5.11 (m, 1H), 3.45 (s,
d
8.12e8.14 (m, 1H), 7.56e7.59 (m, 2H),
6.92e6.95 (m, 2H), 5.09 (br, 2H), 2.76e2.81 (m, 1H), 2.61e2.65 (m,
1H), 2.35e2.43 (m, 3H), 2.12e2.27 (m, 7H), 1.78e1.89 (m, 17H),
3H), 2.99e3.04 (m, 1H), 2.73 (s, 2H), 1.88e2.00 (m, 6H), 1.60e1.74
1.68e1.72 (m, 5H), 1.42 (s, 3H). 13C NMR (DMSO-d6, 100 MHz)
d :
22
(m, 12H). EI-MS (m/z): 488 (Mþ). [
Rf ¼ 0.15 (CH2Cl2/CH3OH ¼ 20/1).
a
]
¼ ꢀ29ꢁ (c ¼ 0.16, CHCl3). TLC
175.3, 174.6, 162.2 (d, 1JCF ¼ 241.8 Hz), 147.0, 130.1 (d, 3JCF ¼ 8.9 Hz),
D
2
2
122.4, 113.4 (d, JCF ¼ 20.1 Hz), 112.9 (d, JCF ¼ 21.6 Hz), 54.4, 50.3,
49.6, 49.0, 44.4, 44.0, 34.6, 32.6, 29.4, 29.3, 29.2, 25.5, 25.3.
6.44. Methyl-4-benzyl-1-((S)-3-(cyclobutanecarboxamido)-3-
(naphthalen-4-yl)propyl)piperidine-4-carboxylate (3c)
6.47. (S)-N-(1-(3-(cyclohexanecarboxamido)-3-(3-fluorophenyl)
propyl)-4-methylpiperidin-4-yl)-4-(trifluoromethyl)benzamide (4d)
Starting from the building blocks of 5-5 and 6b, compound 3c
was prepared in a similar fashion as described for 1a as colorless
solid in yield of 90% for two steps. 1H NMR (CDCl3, 300 MHz):
Compound 4d was prepared from 5e6d and 6c according to the
same procedure as 4a, white solid, yield 68%. Mp: 93e95 ꢁC;
21
[a
]
¼ ꢀ19.0ꢁ (c ¼ 1.05, CHCl3); EI-MS (m/z): 547 (Mþ); 1H NMR
d
8.04e8.06 (m, 1H), 7.84e7.86 (m, 1H), 7.52e7.83 (m, 1H),
D
7.42e7.51 (m, 4H), 7.24e7.28 (m, 3H), 7.02e7.05 (m, 2H), 5.81e5.83
(m, 1H), 3.64 (s, 3H), 2.99e3.17 (m, 4H), 2.86 (s, 2H), 2.57e2.60 (m,
2H), 2.10e2.36 (m, 11H), 1.82e1.99 (m, 2H). 13C NMR (DMSO-d6,
(300 MHz, CDCl3):
d
7.92e7.95 (m, 1H), 7.84 (d, 2H, J ¼ 7.5 Hz), 7.70
(d, 2H, J ¼ 7.5 Hz), 6.92e7.03 (m, 3H), 5.99 (br, 1H), 5.03e6.08 (m,
1H), 2.83e2.86 (m, 1H), 2.70e2.72 (m, 1H), 2.36e2.44 (m, 7H),
2.12e2.26 (m, 2H),1.80e1.93 (m, 8H),1.68e1.71 (m,1H),1.55 (s, 3H),
100 MHz) d: 173.6, 148.4, 138.0, 130.6, 127.8, 127.6, 127.2, 125.9,
1.42e1.49 (m, 3H); 13C NMR (DMSO-d6, 100 MHz)
d: 174.7,
125.7, 125.2, 123.0, 54.4, 50.8, 48.7, 38.7, 36.1, 30.4, 24.6, 17.9. EI-MS
20
(m/z): 498 (Mþ). [
a]
¼ ꢀ18ꢁ (c ¼ 0.074, CHCl3). TLC Rf ¼ 0.3
1
2
D
165.7, 162.2 (d, JCF ¼ 241.8 Hz), 139.6, 130.8 (d, JCF ¼ 32.0 Hz),
(CH2Cl2/CH3OH ¼ 20/1).
3
3
130.1 (d, JCF ¼ 8.2 Hz), 128.4, 125.1 (d, JCF ¼ 2.9 Hz), 124.0
(d, 1JCF ¼ 270.8 Hz), 122.4, 113.4 (d, 2JCF ¼ 21.6 Hz), 113.0
(d, 2JCF ¼ 21.5 Hz), 51.2, 50.2, 49.0, 43.9, 29.2, 29.1, 25.4, 25.3.
6.45. (S)-N-(1-(3-(cyclohexanecarboxamido)-3-(3-fluorophenyl)
propyl)-4-methylpiperidin-4-yl)-4-methoxybenzamide (4a)
6.48. (S)-N-(3-(4-(2-adamantylacetamido)-4-methylpiperidin-1-
yl)-1-(3-fluorophenyl)propyl)cyclohexanecarboxamide (4e)
To a stirred solution of 5-6a (191 mg, 0.55 mmol) in 5 mL DCM
was added TFA (0.42 mL, 5.5 mmol). The mixture was stirred at rt
for 8 h, then evaporated to remove the solvent and TFA. The residue
was treated with 20 mL DCE, NaBH(OAc)3 (171 mg, 0.81 mmol) and
6c (112 mg, 0.4 mmol). The resultant mixture was stirred at rt for
22 h, then evaporated to remove the solvent. The crude product
was purified by column chromatography (DCM/MeOH ¼ 20:1) to
Compound 4e was prepared from 5e6e and 6c according to the
same procedure as 4a, white solid, 23% yield. Mp: 108e110 ꢁC;
21
[a
]
¼ ꢀ23.2ꢁ(c ¼ 0.25, CHCl3); EI-MS (m/z): 552(M þ 1)þ; 1H NMR
D
(CDCl3, 300 MHz)
d
: 8.04e8.07 (m, 1H), 7.01 (d, 1H, J ¼ 7.2 Hz),
6.90e6.93 (m, 2H), 5.05e5.07 (m, 1H), 5.01 (br, 1H), 2.74e2.76 (m,
1H), 2.59e2.62 (m, 1H), 2.34e2.40 (m, 4H), 2.10e2.26 (m, 7H), 1.87
(s, 2H), 1.62e1.82 (m, 23H), 1.42 (s, 3H), 1.23e1.31 (m, 4H); 13C NMR
give 4a as white solid (140 mg, 69% yield). Mpþ: 67e69 ꢁC;
21
[
a]
¼ ꢀ15.1ꢁ(c ¼ 0.95, CHCl3); EI-MS (m/z): 509 (M ); 1H NMR
D
(300 MHz, CDCl3)
d
: 7.95 (d, 1H, J ¼ 7.5 Hz), 7.69 (d, 2H, J ¼ 8.7 Hz),
(DMSO-d6, 100 MHz)
d
: 176.8, 174.7, 162.2 (d, 1JCF ¼ 241.8 Hz), 146.2,
7.23e7.30 (m, 1H), 7.01 (d, 1H, J ¼ 7.5 Hz), 6.89e6.94 (m, 3H), 5.91
(br, 1H), 4.95e5.01 (m, 1H), 3.84 (s, 3H), 2.86e2.90 (m, 1H),
2.76e2.80 (m, 1H), 2.50e2.54 (m, 3H), 2.36e2.46 (m, 3H),
2.07e2.22 (m, 2H), 1.77e1.90 (m, 7H), 1.66e1.69 (m, 1H), 1.52 (s,
2
130.1, 122.3, 113.3, 112.9 (d, JCF ¼ 14.2 Hz), 50.6, 50.0, 48.6, 43.9,
42.2, 36.5, 32.3, 29.2, 29.1, 28.0, 25.4, 25.2.
3H), 1.41e1.48 (m, 2H), 1.17e1.30 (m, 3H); 13C NMR (CD3OD,
6.49. (S)-N-(3-(4-(2-(4-chlorophenyl)acetamido)-4-
methylpiperidin-1-yl)-1-(3-fluorophenyl)propyl)
cyclohexanecarboxamide (4f)
1
100 MHz)
d
: 179.4, 171.0, 164.8 (d, JCF ¼ 243.6 Hz), 164.3, 146.6
3
3
(d, JCF ¼ 6.4 Hz), 132.0 (d, JCF ¼ 8.2 Hz), 130.8, 129.2, 124.0, 115.7
2
2
(d, JCF ¼ 21.4 Hz), 115.1, 114.9 (d, JCF ¼ 22.4 Hz), 56.4, 56.1, 52.5,
52.4, 51.1, 50.9, 46.7, 35.2, 32.6, 31.2, 31.1, 27.3, 27.2, 27.1.
Compound 4f was prepared from 5-6f and 6c according to the
same procedure as 4a, white solid, 75% yield. Mp: 66e68 ꢁC;
21
6.46. (S)-N-(1-(3-(cyclohexanecarboxamido)-3-(3-fluorophenyl)
propyl)-4-methylpiperidin-4-yl)nicotinamide (4b)
[a
]
¼ ꢀ18.8ꢁ (c ¼ 0.8, CHCl3); EI-MS (m/z): 527(Mþ); 1H NMR
D
(300 MHz, CDCl3) :
d
7.92 (d, 1H, J ¼ 6.9 Hz), 7.18e7.34 (m, 4H), 7.00
(d, 1H, J ¼ 8.4 Hz), 6.92 (d, 2H, J ¼ 9.0 Hz), 5.41 (br, 1H), 4.96e5.02
(m, 1H), 3.47 (s, 2H), 2.72e2.77 (m, 1H), 2.61e2.65 (m, 1H),
2.40e2.42 (m, 2H), 2.11e2.19 (m, 6H), 1.85e1.90 (m, 3H), 1.77e1.81
(m, 3H), 1.68e1.71 (m, 3H), 1.43e1.47 (m, 2H), 1.38 (s, 3H), 1.21e1.29
Compound 4b was prepared from 5e6b and 6c according to the
same procedure as 4a. White solid, 70% yield. Mpþ: 58e60 ꢁC;
22
[
a]
¼ ꢀ34.4ꢁ(c ¼ 0.45, CHCl3); EI-MS (m/z): 480 (M ); 1H NMR
D
(300 MHz, CDCl3):
d
9.28 (br, 1H), 8.70e8.72 (m, 1H), 8.41 (br, 2H),
(m, 2H); 13C NMR (CD3OD, 100 MHz)
d
: 179.4, 174.2, 164.7 (d,
3
8.26 (d, 1H, J ¼ 7.5 Hz), 7.09e7.13 (m, 3H), 6.77e6.81 (m, 1H),
1JCF ¼ 243.7 Hz), 146.5 (d, JCF ¼ 6.8 Hz), 136.6, 134.2, 132.2, 132.1
3
2
5.18e5.21 (m, 2H), 3.12e3.19 (m, 2H), 2.26e2.31 (m, 8H), 2.07e2.12
(d, JCF ¼ 8.2 Hz), 130.0, 124.0, 115.8 (d, JCF ¼ 21.4 Hz), 114.9 (d,

2840
X. Fan et al. / European Journal of Medicinal Chemistry 45 (2010) 2827e2840
2JCF ¼ 21.8 Hz), 52.4, 51.9, 50.8, 50.6, 50.4, 46.7, 44.3, 34.9, 32.4, 31.2,
(07QH14018, 08JC1422200) and National Science and Technology
Major Project (2009ZX09301-001) are greatly appreciated for the
financial supports.
31.1, 27.3, 27.2.
6.50. (S)-N-(3-(4-(2-(3,4-dichlorophenyl)acetamido)-4-
methylpiperidin-1-yl)-1-(3-fluorophenyl)propyl)
cyclohexanecarboxamide (4g)
References
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Compound 4g was prepared from 5e6g and 6c according to the
same procedure as 4a, white solid, 31% yield. Mpþ: 86e88 ꢁC;
21
[
a]
¼ ꢀ22.5ꢁ(c ¼ 0.75, CHCl3); EI-MS (m/z): 561 (M ); 1H NMR
D
(CDCl3, 300 MHz) d: 8.06e8.08 (m, 1H), 7.38e7.43 (m, 2H), 7.12 (d,
1H, J ¼ 8.4 Hz), 7.00 (d, 1H, J ¼ 7.8 Hz), 6.89e6.93 (m, 2H), 5.31 (br,
1H), 5.03e5.07 (m, 1H), 3.45 (s, 2H), 2.68e2.71 (m, 1H), 2.51e2.54
(m, 1H), 2.28e2.37 (m, 2H), 2.08e2.17 (m, 7H), 1.89e1.93 (m, 2H),
1.79e1.82 (m, 3H),1.65e1.72 (m, 3H),1.44e1.48 (m,1H),1.40 (s, 3H),
1.23e1.29 (m, 3H); 13C NMR (DMSO-d6, 100 MHz)
d : 174.6, 169.1,
162.2 (d, 1JCF ¼ 241.9 Hz),147.0,138.1,131.0,130.6,130.2,130.1,129.4,
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2
2
128.9, 122.4, 113.3 (d, JCF ¼ 21.6 Hz), 112.9 (d, JCF ¼ 21.6 Hz), 54.5,
50.3, 48.9, 44.0, 42.0, 29.3, 29.2, 26.1, 25.5, 25.3.
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6.51. (S)-N-(3-(4-(2-(4-fluorophenyl)acetamido)-4-
methylpiperidin-1-yl)-1-(3-fluorophenyl)propyl)
cyclohexanecarboxamide (4h)
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same procedure as 4a, white solid, 64% yield. Mp: 65e67 ꢁC;
21
[
a]
¼ ꢀ22.6ꢁ (c ¼ 1.05, CHCl3); EI-MS (m/z): 511 (Mþ); 1H NMR
D
(CDCl3, 300 MHz)
d
: 7.88 (d, 1H, J ¼ 7.2 Hz), 7.22 (dd, 2H, J ¼ 5.4 Hz,
8.7 Hz), 7.00e7.06 (m, 3H), 6.93 (d, 2H, J ¼ 9.0 Hz), 5.45 (br, 1H),
4.95e5.01 (m, 1H), 3.47 (s, 2H), 2.74e2.80 (m, 1H), 2.65e2.71
(m, 1H), 2.46 (t, 2H, J ¼ 6.3 Hz), 2.07e2.24 (m, 6H), 1.91e1.98
(m, 1H), 1.66e1.88 (m, 8H), 1.43e1.47 (m, 1H), 1.38 (s, 3H), 1.21e1.29
(m, 3H); 13C NMR (DMSO-d6, 100 MHz)
d: 174.7, 170.0, 162.2
(d, 1JCF ¼ 241.8 Hz), 160.9 (d, 1JCF ¼ 240.3 Hz), 146.8, 133.1, 130.7 (d,
3JCF ¼ 8.2 Hz), 130.1 (d, 3JCF ¼ 8.2 Hz), 122.4, 114.8 (d, 2JCF ¼ 20.8 Hz),
2
2
113.4 (d, JCF ¼ 20.9 Hz), 113.0 (d, JCF ¼ 21.6 Hz), 54.2, 50.2, 48.5,
43.9, 42.2, 29.2, 29.1, 25.5, 25.3.
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6.52. (S)-N-(3-(4-(2-(3,4,5-trimethoxyphenyl)acetamido)-4-
methylpiperidin-1-yl)-1-(3-fluorophenyl)propyl)
cyclohexanecarboxamide (4i)
Compound 4i was prepared from 5e6i and 6c according to the
same procedure as 4a, white solid, 35% yield. Mp: 68e70 ꢁC;
22
[
a]
¼ ꢀ6.3ꢁ(c ¼ 0.3, CHCl3); EI-MS (m/z): 583 (Mþ); 1H NMR
D
(CDCl3, 300 MHz)
d
7.31e7.35 (m, 1H), 7.04 (d, 1H, J ¼ 6.9 Hz), 6.95
(d, 2H, J ¼ 6.9 Hz), 6.48 (s, 2H), 5.32 (s, 1H), 5.01 (br, 1H), 3.87(s, 6H),
3.85 (s, 3H), 3.48 (s, 2H), 2.77e2.82 (m, 1H), 2.59e2.66 (m, 1H),
2.12e2.23 (m, 4H), 1.78e1.91 (m, 6H), 1.65e1.71 (m, 4H), 1.46e1.56
(m, 4H), 1.42 (s, 3H), 1.30e1.37 (m, 3H); 13C NMR (CD3OD, 100 MHz)
d
: 179.3, 174.6, 163.7 (d, 1JCF ¼ 243.6 Hz), 154.9, 147.0, 138.4, 134.0,
3
2
132.0 (d, JCF ¼ 6.4 Hz), 124.0, 115.6 (d, JCF ¼ 20.9 Hz), 114.9 (d,
2JCF ¼ 22.3 Hz),107.9, 61.6, 57.2, 56.3, 52.7, 52.1, 50.8, 50.7, 46.8, 45.4,
35.3, 32.8, 31.2, 31.1, 27.4, 27.3, 27.2.
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Acknowledgements
National Natural Science Foundation of China (30672528),
Science and Technology Commission of Shanghai Municipality