Benzofuran derivatives as anticancer inhibitors of mTOR signaling

Article abstract of DOI:10.1016/j.ejmech.2014.05.014

A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.

Full text of DOI:10.1016/j.ejmech.2014.05.014

European Journal of Medicinal Chemistry 81 (2014) 181e191
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Benzofuran derivatives as anticancer inhibitors of mTOR signaling
Christophe Salomé a, Nigel Ribeiro a, Thierry Chavagnan a, Frédéric Thuaud a,
Maria Serova b, Armand de Gramont b, Sandrine Faivre c, Eric Raymond c,
,
Laurent Désaubry a
*
a Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France
b AAREC Filia Research, 1 Place Paul Verlaine, 92100 Boulogne-Billancourt, France
c Departments of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their
cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were
significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt
signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with
rapamycin derivatives currently used in clinic.
Received 6 February 2014
Received in revised form
14 March 2014
Accepted 2 May 2014
Available online 5 May 2014
Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
Benzofuran
Cytotoxicity
mTOR
Cancer
Rapamycin
1. Introduction
2. Results and discussions
The mammalian Target of Rapamycin (mTOR) is a key protein
that controls cell growth, metabolism, autophagy and angiogenesis
[1,2]. Its signaling is one of the most frequently altered in cancer
cells, which makes mTOR an important target in oncology. In their
quest to identify inhibitors of mTOR signaling, William Sellers,
Pamela Silver and coworkers at Harvard University identified the
hit 1 by high-throughput screening (Fig. 1) [3,4]. We recently re-
ported the first hit to lead optimization of this compound and
demonstrated that the replacements of the dimethylamine and
benzyl moieties by a 4-piperidino-piperidine and a phenyl (com-
pound 2) significantly improve cytotoxicity [5]. We also showed
that this new class of compounds interacts with the complex
mTORC1 to inhibit its activity. Importantly, as far as we know, prior
to this study, no benzofuran derivatives had been previously
explored as inhibitors of Akt/mTOR signaling. Herein, we report our
endeavor to complete the SAR study of this class of compounds and
provide new insight on their mechanism of action.
2.1. Chemical synthesis
The 2-phenylbenzofuran derivatives 5aem were synthesized in
a convergent manner from the phosphonium 4 [6] and an acid
chloride by a tandem esterification-intramolecular Wittig reaction
[7] followed by a saponification (Scheme 1). Next, a Mannich re-
action afforded the expected adducts 6aem. Compound 10 was
synthesized similarly, starting from 9. The adduct 8 was obtained
by sulfonylation of the benzofuran derivative 2 [8].
To introduce a methyl in position 3, phenol 11 was condensed
with desyl chloride 12 to generate the benzofuran 13 following
Hajela’s procedure [9]. This adduct was transformed as previously
into the Mannich base 14 after phenol deprotection (Scheme 2).
The derivatives and analogues 17aee were synthesized by a
Mannich reaction from easily prepared hydroxyindoles 16a and 16b
(from known ethers 15a [10] and 15b [11]) and from described
compounds 16c,d [12] (Scheme 3). Moreover, ester 17d was quan-
titatively reduced to alcohol 17e.
The benzoxazole 20a and benzimidazole 20b analogues were
prepared from the anilines 18a and 18b [13] by a cyclisation/
demethylation step followed by a Mannich reaction (Scheme 4).
* Corresponding author.
E-mail address: desaubry@unistra.fr (L. Désaubry).
http://dx.doi.org/10.1016/j.ejmech.2014.05.014
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

182
C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
Our approach to O-substituted derivatives began with a tandem
Sonogashira coupling/5-endo-dig-cyclization [18] using Fu’s cata-
lytic system [19] to afford hydroxybenzofurans 29a,b that were
alkylated into ethers (Scheme 7). Nucleophilic aromatic substitu-
tion displacement of fluoroarene 29b afforded benzyl ether 29c
[20]. Subsequent reductive amination yielded the expected com-
pounds 30a,b. Dehydroxy analogue 32, was prepared similarly from
bromophenol derivative 31.
Fig. 1. Structures of HTS hit 1 and lead 2.
2.2. Biological results
The synthesis of isostere 24 started from pyridone 21. Optimi-
First, we focused our efforts on the substituent on the phenyl
moiety (Table 1). The cytotoxicity of benzofuran derivatives was
assessed after 72 h of exposure in HNSCC SQ20B cell line and
compared to that of everolimus. Overall, chloro- and methox-
yphenyl derivatives 6aeh displayed a similar activity as unsub-
stituted 2. Replacement of the phenyl by a 2-furyl (6i), a 2-
thiophenyl (6j), a 1-naphtyl (6k) or a 2-naphtyl (6l) did not
change also greatly the activity. Introduction of a methyl (14) or a
carbethoxy (17d) in position 3 was well tolerated, while a more
polar hydroxymethyl was slightly detrimental (17e).
Isosteric modifications of the benzofuran scaffold were next
examined. The introduction of a nitrogen atom into the furan
ring of 2 to give the oxazole 20a was less detrimental to the
activity than shifting the oxygen within the 5-membered ring to
provide 10. This latter compound was more active than
zation of the published iodination conditions (NaOH, I2) [14]
afforded principally a mono-iodinated compound, which upon a
Sonogashira reaction with phenylacetylene coupled to a 5-endo-
dig ring closure [15] affording directly the furo[3,2-c]pyridine 22
(Scheme 5). Metalation of 22 with Fort’s procedure (nBuLi/DMAE)
[16] followed by a quenching with DMF lead to the aldehyde 23
(15% yield). Finally, expected adduct 24 was obtained by reductive
amination of 23.
Compound 27, a bioisostere of benzofuran derivative 2, was
synthesized in three steps from the known 2-phenylbenzofuran-5-
amine (25) [17] by the introduction of the triflyl moiety followed by
a Mannich reaction (Scheme 6). All the attempts to introduce ni-
trogen in this position by a Pd-cross coupling reaction on the triflate
8 were unsuccessful.
Scheme 1. Synthesis of 2ephenylbenzofuran derivatives 6aem, 7g, 8 and 10.
Scheme 2. Synthesis of 2ephenylbenzofuran derivative 14.

C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
183
Scheme 3. Synthesis of indole and 2ephenyl-3-subtituted benzofuran derivatives 17aee.
benzimidazole 20b and N-methylindole 17a. Interestingly, isos-
3. Conclusion
teric replacement coupled to a migration of the phenyl moiety
yielded indole 17b that was as cytotoxic as 17a. Migration of the
phenyl ring from the 2- to the 3-position (14c) decreased also
cytotoxicity.
In a previous study, we performed the first hit to lead optimi-
zation of 1 discovered by William Sellers, Pamela Silver and co-
workers at Harvard [3]. We found that 2 displayed an enhanced
cytotoxicity compared to 1 and demonstrated that, this new family
of anticancer agents interacts with the complex mTORC1 to inhibit
its activity [5]. Herein, we continued our optimization program
based on 2. The seven isosteric replacement of the benzofuran
scaffold that we examined were detrimental to the activity. We also
showed that methylation of the phenolic hydroxyl and replacement
of the 4epiperidinopiperidine by a 4-dimethylaminopiperidine is
well tolerated. Importantly, substitution of the phenyl by a benzy-
loxy significantly improved the cytotoxicity in cancer cells. Com-
bination of these data resulted in 30b, which has an IC50 10 fold
lower than 2. Both compounds display a similar profile of cyto-
toxicity on a panel of human cancer cell lines, suggesting a related
mechanism of action. Importantly, 30b was shown to inhibit both
mTORC1 and Akt signaling, suggesting that it should overcome the
resistance associated to Akt overactivation observed with rapa-
mycin derivatives.
Next, we examined the contribution of the phenolic hydroxy to
cytotoxicity. Replacing the phenol moiety of 2 by a H-bond acceptor
to give the furo[3,2-c]pyridine 24 altered the activity. Exchanging
the phenolic hydroxyl by another H-bond donor such as a tri-
flylamide (27) conserved the cytotoxicity. Surprisingly, the intro-
duction of a triflate ester (8), which cannot donate an H-bond, was
also well tolerated, while the deletion of the phenolic hydroxy
reduced cytotoxicity (32). Next, we showed that the piper-
idinopiperidine moiety can be replaced by a dimethylamino moiety
(7g) without loss of activity, resulting in a significant gain in ligand
efficiency.
In the following experiments we observed a drift in the sensi-
tivity of the cells toward the cytotoxicity induced by this class of
agents, probably because of origin of the cells or of the culture
medium. To meaningfully compare our compounds, we tested one
more time the most significant compounds and observed the same
trends of activities (Table 2). Finally, we observed that the intro-
duction of a hydrophobic benzyloxy moiety on the phenyl ring (6m)
significantly improves cytotoxicity. Methylation of the phenolic
hydroxy (30a) did not alter the activity but gratefully enhanced
solubility. We combined all these data to design 30b, which dis-
played an enhanced cytotoxicity. We then compared this optimized
lead compound 30bwith 2, 6m, everolimus and OZI027 on a panel of
cell lines (Fig. 2). The pattern of sensitivity of 30b is close to 6m as
expected, but significantly different from everolimus or OZI027.
Interestingly, HOP62 HNSCC cell line was the most sensitive to 30b,
2, 6m and OZI027 but not to everolimus, whereas Colo205 colon
cancer cell line was resistant to all tested compounds. Next, we
examined the effect of 30b on inhibition of mTOR signaling. We
observed a decrease in phosphorylation of S6 ribosomal protein and
4-EBP1 protein, the main targets of mTORC1. In contrast to mTORC1
specific inhibitor everolimus, we did not see the recurrent Akt
hyperactivation (Fig. 3). Indeed, mTOR exerts its activity through
two functional complexes, mTORC1 and mTORC2 (Fig. 3) [1,2]. Akt,
also known as protein kinase B (PKB) activates mTORC1 and is
activated by mTORC2. Rapamycin and its analogues selectively
inhibit mTORC1, which decreases the phosphorylation of down-
stream proteins, such as S6, and also increases Akt activity through a
feed-back mechanism, resulting in resistance to treatment. In fact,
4. Experimental protocol
4.1. Biology
4.1.1. Cell lines
Hepatocarcinoma SK-HEP1, prostate DU145, renal CAKI1 and
ovarian OVCAR3 cell lines were obtained from the ATCC (Rockville,
MD). Colon Colo205, HCT116, HT29, and HSCLC HOP62 cell lines
were purchased from NCI cell line bank. SQ20B was kindly provided
by Prof. E. Deutsch (Institute Gustave Roussy, France). ColoR was
developed in our laboratory. Cells were grown as monolayers in
RPMI medium supplemented with 10% fetal calf serum (Invitrogen,
Cergy-Pontoise, France), 2 mM glutamine, 100 units/ml penicillin
and 100 m
g/ml streptomycin at 37 ꢀC in a humidified 5% CO2 at-
mosphere, and regularly checked for the absence of Mycoplasma.
4.1.2. Cell cytotoxicity assay
Cell survival was determined using the MTT assay (3e(4,5e
dimethylthiazole2eyl)e2,5ediphenyltetrazolium bromide; Sigma,
Saint-Quentin Fallavier, France). The conversion of yellow water-
soluble tetrazolium MTT into purple insoluble formazan is cata-
lyzed by mitochondrial dehydrogenases and used to estimate the
number of viable cells. In brief, cells were seeded in 96-well tissue
culture plates at a density of 2 ꢁ 103 cells/well. After drug exposure,
cells were incubated with 0.4 mg/ml MTT for 4 h at 37 ꢀC. After
inhibition of mTORC1 induces
a compensatory activation of
mTORC2 which stimulates Akt through its phosphorylation at serine
473 [21].

184
C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
Scheme 4. Synthesis of benzoxazole and benzimidazole derivatives 20aeb.
incubation, the supernatant was discarded, insoluble formazan
precipitates were dissolved in 0.1 mL of DMSO and the absorbance
was measured at 560 nm by use of a microplate reader (Thermo,
France). Wells with untreated cells or with drug-containing me-
dium without cells were used as positive and negative controls
respectively. Everolimus and OZI027 were purchased from Selleck
Chemicals (Munich, Germany).
4.2.1. General procedure for the Mannich reaction (Method A)
The secondary amine (2 eq) was added to an EtOH (0.1e0.2 M)
solution of 5ehydroxyebenzofuran derivative (1 eq) and formalde-
hyde (37% inwater, 2 eq). The solutionwas stirred at reflux (3 he16 h)
and concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel or by recrystallization in EtOH.
4.2.2. 4e([1,40eBipiperidin]e10eylmethyl)e2e(2echlorophenyl)
benzofurane5eol (6a)
4.1.3. Western blot analysis
Using Method A, formaldehyde (37% in water, 54 mL, 0.7 mmol),
Cells were lysed in buffer containing 50 mM HEPES (pH 7.6),
150 mM NaCl, 1% Triton X-100, 2 mM sodium vanadate, 100 mM
NaF, and 0.4 mg/ml phenylmethylsulfonyl fluoride. Equal amounts
4epiperidinopiperidine (120 mg, 0.7 mmol) and 5ehydroxye2e
(2echlorophenyl)benzofuran 5a (86 mg, 0.3 mmol) gave 105 mg
(70%) of 6a as a white solid after recrystallization in ethanol:
of protein (30 mg/lane) were subjected to SDS-PAGE and transferred
Rf ¼ 0.16 (acetone); 1H NMR (400 MHz, CDCl3)
d 1.34e1.37 (m, 2H),
to nitrocellulose membranes. Membranes were blocked with 5%
milk in 0.05% Tween 20/phosphate-buffered saline and then incu-
bated with the primary antibody overnight. Membranes were then
washed and incubated with the secondary antibody conjugated to
horseradish peroxidase. Bands were visualized by using the
enhanced chemiluminescence Western blotting detection system.
Densitometric analysis was performed under conditions that yiel-
ded a linear response.
1.51e1.64 (m, 6H),1.79 (d, J ¼ 12.8 Hz, 2H), 2.06e2.12 (br m, 2H), 2.26
(t, J ¼ 11.6 Hz,1H), 2.40e2.45 (m, 4H), 3.06 (d, J ¼ 12.0 Hz, 2H), 3.84 (s,
NCH2), 6.75 (d, J ¼ 8.8 Hz, 1H), 7.16e7.32 (m, 4H), 7.40 (d, J ¼ 8.0 Hz,
1H), 7.94 (d, J ¼ 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 26.4,
29.7, 50.3, 53.2, 57.9, 62.3,105.0,110.4,111.8,114.5,127.0,128.4,128.9,
129.0,130.8,131.0,148.2,152.2,153.8,1 peak is missing and believed
to overlap with peaks nearby; HRMS (M þ Hþ)(ESIþ) 425.2007
[M þ Hþ] (calcd for C25H29ClN2O2Hþ 425.1990).
4.2. Chemistry
4.2.3. 4e([1,40eBipiperidin]e10eylmethyl)e2e(3echlorophenyl)
benzofurane5eol (6b)
All reagents and solvents for synthesis were purchased from
SigmaeAldrich, Fluka, or Acros and used without further purifica-
tion. Column chromatography was carried out on silica gel 60
(Merck, 70ꢂ230 mesh). 1H NMR spectra at 300 MHz or 400 MHz
and 13C NMR spectra at 75 MHz or 100 MHz were recorded with
Brucker spectrometers 300 and 400 with the deuterated solvent as
the lock and residual solvent as the internal reference. All chemical
shift values, coupling constants J and the multiplicity (s ¼ singlet,
d ¼ doublet, t ¼ triplet, m ¼ multiplet, br ¼ broad) are quoted in
ppm, in Hz and in Hz, respectively. High resolution mass spectra
(HRMS) were obtained using a Agilent Q-TOF (time of flight) 6520
and low resolution mass spectra using an Agilent MSD 1200 SL (ESI/
APCI). Analytical RP-HPLC-MS was performed using a C18 column
Using Method A, formaldehyde (37% in water, 56 mL, 0.7 mmol),
4ePiperidinopiperidine (121 mg, 0.7 mmol) and 5ehydroxye2e
(3echlorophenyl)benzofuran 5b (90 mg, 0.4 mmol) gave 90 mg
(58%) of 6b as a white solid after recrystalisation in ethanol: Rf ¼ 0.15
(acetone); 1H NMR (400 MHz, CDCl3)
d 1.35e1.39 (m, 2H), 1.50e1.65
(m, 6H), 1.79 (d, J ¼ 12.4 Hz, 2H), 2.06e2.11 (m, 2H), 2.28 (m, 1H),
2.42e2.45 (m, 4H), 3.05 (d, J ¼ 12.0 Hz, 2H), 3.82 (s, NCH2), 6.74 (d,
J ¼ 8.8 Hz,1H), 6.86 (s,1H), 7.21e7.31 (m, 3H), 7.62 (d, J ¼ 7.6 Hz,1H),
7.74 (d, J ¼ 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.7, 26.3, 27.9,
50.3, 53.2, 57.9, 62.3, 100.2, 110.6, 111.5, 114.3, 122.8, 124.8, 128.2,
128.3, 130.1, 132.3, 134.9, 149.1, 153.9, 154.7; HRMS (M þ Hþ)(ESIþ)
425.2003 [M þ Hþ] (calcd for C25H29ClN2O3Hþ 425.1990).
(30 mm ꢁ 1 mm; 1.9
mm) using the following parameters: (1) the
solvent system A (acetonitrile) and B (0.05% TFA in H2O); (2) the
linear gradient t ¼ 0 min with 98% B, t ¼ 5 min with 5% B, t ¼ 6 min
with 5% B, t ¼ 7 min with 98% B, and t ¼ 9 min with 98% B; (3) flow
rate of 0.3 mL/min; (4) column temperature 50 ꢀC; (5) ratio of
products determined by integration of spectra recorded at 210 or
254 nm; (6) ionization mode ESI.
4.2.4. 4e([1,40eBipiperidin]e10eylmethyl)e2e(4echlorophenyl)
benzofurane5eol (6c)
Using Method A, formaldehyde (37% in water, 62 mL, 0.8 mmol),
4epiperidinopiperidine (138 mg, 0.8 mmol) and 5ehydroxye2e
(4echlorophenyl)benzofuran 5c (100 mg, 0.4 mmol) gave 110 mg
(63%) of 6c as a white solid after recrystalisation in ethanol:

C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
185
Scheme 5. Synthesis of the furopyridine derivative 24.
Scheme 6. Synthesis of the bioisostere 27.
Scheme 7. Synthesis of O-substituted derivatives 30aeb and 32.
Rf ¼ 0.12 (acetone); 1H NMR (400 MHz, CDCl3)
d
1.36e1.38 (m, 2H),
of 6d as a white solid after column (acetone): Rf ¼ 0.14 (acetone); IR
1.49e1.64 (m, 6H), 1.79 (d, J ¼ 12.8 Hz, 2H), 2.05e2.11 (br m, 2H),
2.23e2.30 (m, 1H), 2.42e2.45 (m, 4H), 3.05 (d, J ¼ 12.0 Hz, 2H), 3.81
(s, NCH2), 6.72 (d, J ¼ 8.8 Hz,1H), 6.82 (s,1H), 7.19e7.22 (m,1H), 7.32
(d, J ¼ 8.6 Hz, 2H), 7.67 (d, J ¼ 8.6 Hz, 2H); 13C NMR (100 MHz,
(cmꢂ1) 2933, 2809, 1602, 1498, 1443, 1145, 1105; 1H NMR (400 MHz,
CDCl3)
d
1.44e1.48 (m, 2H),1.59e1.72 (m, 6H), 1.88 (d, J ¼ 12.8 Hz, 2H),
2.13e2.19 (br m, 2H), 2.32e2.38 (m, 1H), 2.50e2.53 (m, 4H), 3.14 (d,
J ¼ 12.0 Hz, 2H), 3.88(s, NCH2), 6.83(d, J ¼ 8.8 Hz,1H), 6.93(s,1H), 7.29
(m, 1H), 7.49 (d, J ¼ 8.4 Hz, 1H), 7.63 (dd, J ¼ 2.0, 8.4 Hz, 1H), 7.90 (d,
CDCl3) d 24.6, 26.2, 27.8, 50.2, 53.1, 57.8, 62.4, 99.5, 110.5, 111.4, 114.1,
126.0, 128.4, 129.0, 129.1, 134.2, 149.0, 153.9, 155.1; HRMS
(M þ Hþ)(ESIþ) 425.2011 [M þ Hþ] (calcd for C25H29ClN2O3Hþ
425.1990).
J ¼ 2.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 25.0, 26.6, 28.1, 50.5, 53.4,
58.0, 62.4, 100.7, 110.8, 111.7, 114.8, 124.0, 126.6, 128.4, 130.7, 131.0,
132.3, 133.3, 149.3, 153.8, 154.2; HRMS (M þ Hþ)(ESIþ) 459.16148
[M þ Hþ] (calcd for C25H28Cl2N2O2Hþ 459.16006).
4.2.5. 4e([1,40eBipiperidin]e10eylmethyl)e2e(3,4e
dichlorophenyl)benzofurane5eol (6d)
4.2.6. 4e([1,40eBipiperidin]e10eylmethyl)e2e(2emethoxyphenyl)
benzofurane5eol (6e)
Using Method A, formaldehyde (37% inwater, 55 mL, 0.7 mmol), 4e
piperidinopiperidine (118 mg, 0.7 mmol) and 5ehydroxye2e(3,4e
dichlorophenyl)benzofuran5d(100 mg, 0.35 mmol) gave 95 mg (73%)
Using Method A, formaldehyde (37% in water, 64
4epiperidinopiperidine (71 mg, 0.4 mmol) and 5ehydroxye2e(2e
mL, 0.8 mmol),

186
C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
Table 1
Cytotoxicity of benzofuran derivatives in SQ20B cancer cells (72 h treatment).
cpd
R1
Ar
X
Y
NR2R3
IC50 (mM)
2
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Ph
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
NMe2
1.4 ꢃ 0.24
2.6 ꢃ 0.49
0.92 ꢃ 0.21
0.86 ꢃ 0.44
2.3 ꢃ 0.47
1.3 ꢃ 0.51
2.0 ꢃ 0.33
0.85 ꢃ 0.28
1.1 ꢃ 0.44
4.0 ꢃ 1.4
6a
6b
6c
6d
6e
6f
6g
6h
6i
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
3,4-Cl2-Ph
2-OMe-Ph
3-OMe-Ph
4-OMe-Ph
2,6-(OMe)2-Ph
2-Furyl
2-Thiophenyl
1-Naphtyl
2-Naphtyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
6j
6k
6l
2.7 ꢃ 0.63
0.86 ꢃ 0.08
2.8 ꢃ 0.73
1.2 ꢃ 0.14
1.5 ꢃ 0.22
3.4 ꢃ 0.38
6.5 ꢃ 0.56
11 ꢃ 2.7
CH
14
17d
17e
20a
10
20b
17a
17b
14c
24
27
8
CMe
CeCOOEt
CeCH2OH
N
O
N
CH
CH
C-Ph
O
CH
NH
NMe
NBn
O
21 ꢃ 5.2
19 ꢃ 4.5
17 ꢃ 4.9
11 ꢃ 3.6
2-Phenyl-furo[3,2-c]pyridine
18 ꢃ 4.2
NHTf
OTf
H
Ph
Ph
Ph
CH
CH
CH
CH
O
O
O
O
2.1 ꢃ 0.44
2.8 ꢃ 0.28
7.5 ꢃ 2.1
32
7g
OH
4-OMe-Ph
1.2 ꢃ 0.38
Table 2
120.9, 127.1, 129.1, 129.2, 147.9, 152.5, 153.5, 156.3; HRMS
(M þ Hþ)(ESIþ) 421.2503 [M þ Hþ] (calcd for C26H32N2O3Hþ
421.2485).
Cytotoxicity of benzofuran derivatives in SQ20B cancer cells (72 h treatment).
4.2.7. 4e([1,40eBipiperidin]e10eylmethyl)e2e(3emethoxyphenyl)
benzofurane5eol (6f)
Using Method A, formaldehyde (37% in water, 54 mL, 0.7 mmol),
4epiperidinopiperidine (120 mg, 0.7 mmol) and 5ehydroxye2e
(3emethoxyphenyl)benzofuran 5f (85 mg, 0.35 mmol) gave
120 mg (82%) of 6f as a white solid after flash column chroma-
tography on silica gel: Rf ¼ 0.33 (acetone); 1H NMR (400 MHz,
cpd
R1
Ar
NR2R3
IC50 (mM)
CDCl3)
d
1.36e1.38 (m, 2H), 1.49e1.65 (m, 6H), 1.79 (d, J ¼ 12.4 Hz,
2H), 2.06e2,12 (br m, 2H), 2.23e2.30 (m, 1H), 2.42e2.45 (m, 4H),
3.07 (d, J ¼ 12.4 Hz, 2H), 3.81 (s, NCH2), 3.82 (s, OCH3), 6.71 (d,
J ¼ 8.8 Hz, 1H), 6.80e6.83 (m, 2H), 7.19e7.35 (m, 3H), 8.05 (d,
RAD001 (everolimus)
1
2
6g
7g
6m
30a
30b
7.3 ꢃ 3.1
32 ꢃ 1.7
OH
OH
OH
OH
OH
OMe
OMe
Ph
Piperidine
Piperidine
NMe2
Piperidine
Piperidine
NMe2
2.5 ꢃ 1.3
4-OMe-Ph
4-OMe-Ph
2-OBn-Ph
Ph
0.72 ꢃ 0.48
1.5 ꢃ 0.9
J ¼ 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 26.4, 27.9, 50.1,
53.2, 55.5; 57.9, 62.4, 104.0, 110.1, 111.0, 111.5, 113.5, 119.4, 120.9,
127.1, 129.1, 129.2, 147.9, 152.5, 153.5, 156.3; HRMS (M þ Hþ)(ESIþ)
421.2503 [M þ Hþ] (calcd for C26H32N2O3Hþ 421.2485).
0.38 ꢃ 0.22
2.5 ꢃ 1.7
2-OBn-Ph
0.46 ꢃ 0.25
4.2.8. 4e([1,40eBipiperidin]e10eylmethyl)e2e(4emethoxyphenyl)
benzofurane5eol (6g)
methoxyphenyl)benzofuran 5e (100 mg, 0.4 mmol) gave 105 mg
(60%) of 6e as a white solid after recrystalisation in ethanol:
Using Method A, formaldehyde (37% in water, 54 mL, 0.7 mmol),
Rf ¼ 0.36 (acetone); 1H NMR (400 MHz, CDCl3)
d
1.46e1.78 (m, 2H),
4epiperidinopiperidine (120 mg, 0.7 mmol) and 5ehydroxye2e
(4emethoxyphenyl)benzofuran 5g (85 mg, 0.35 mmol) gave
105 mg (72%) of 6g as a white solid after flash column chroma-
tography on silica gel: Rf ¼ 0.37 (acetone); 1H NMR (400 MHz,
1.61e1.74 (m, 6H), 1.88 (d, J ¼ 12.4 Hz, 2H), 2.17e2.23 (br m, 2H),
2.37 (t, J ¼ 11.2 Hz, 1H), 2.52e2.55 (m, 4H), 3.17 (d, J ¼ 11.6 Hz, 2H),
3.95 (s, NCH2), 4.04 (s, OCH3), 6.80 (d, J ¼ 8.4 Hz, 1H), 7.02e7.11 (m,
2H), 7.28e7.36 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
24.8, 26.4, 27.9,
CDCl3)
d
1.34e1.37 (m, 2H), 1.48e1.60 (m, 6H), 1.77 (d, J ¼ 12.8 Hz,
50.1, 53.2, 55.5; 57.9, 62.4, 104.0, 110.1, 111.0, 111.5, 113.5, 119.4,
2H), 2.04e2.10 (br m, 2H), 2.23e2.30 (m, 1H), 2.41e2.45 (m, 4H),

C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
187
Fig. 2. Cytotoxicity of benzofuran derivatives in a panel of cancer cell lines. The indicated values are calculated as follows: log(IC50 individual cell line) - mean (log IC50). Negative
values indicate that the cell line is more sensitive than the average, whereas positive values indicate that the cell line is more resistant than the average.
3.05 (d, J ¼ 12.0 Hz, 2H), 3.77 (s, OCH3), 3.80 (s, NCH2), 6.66e6.70
(m, 2H), 6.88 (d, J ¼ 9.0 Hz, 2H), 7.18e7.20 (d, J ¼ 8.8 Hz, 1H), 7.67 (d,
of 6i as a white solid after flash chromatography on silica gel
(acetone): Rf ¼ 0.15 (acetone); 1H NMR (400 MHz, CDCl3)
d 1.44e
J ¼ 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
24.7, 26.4, 27.9, 50.3,
1.46 (m, 2H), 1.58e1.68 (m, 6H), 1.85 (d, J ¼ 12.8 Hz, 2H), 2.11e2.17
(m, 2H), 2.30e2.36 (m, 1H), 2.48e2.53 (br m, 4H), 3.12 (d,
J ¼ 11.6 Hz, 2H), 3.87 (s, NCH2), 6.51 (dd, J ¼ 1.6, 3.2 Hz, 1H), 6.76e
6.80 (s, 3H), 7.27 (d, J ¼ 9.2 Hz, 1H), 7.49 (d, J ¼ 1.6 Hz, 1H); 13C NMR
53.1, 55.4; 57.9, 62.3, 97.5, 110.3, 111.2, 113.1, 114.2, 123.5, 126.3,
148.8, 153.7, 156.4, 159.9, 1 carbon peak is missing and believed to
overlap with peaks nearby; HRMS (M þ Hþ)(ESIþ) 421.2502
[M þ Hþ] (calcd for C26H32N2O3Hþ 421.2485).
(100 MHz, CDCl3) d 24.8, 26.4, 27.9, 50.3, 53.1, 57.8, 62.3, 99.0, 107.4,
110.4, 111.5, 111.7, 113.8, 128.1, 142.9, 146.3, 148.4, 148.6, 154.0; LCe
MS (M þ Hþ)(ESIþ) 381.21877 [M þ Hþ] (calcd for C23H28N2O2SHþ
381.21726).
4.2.9. 4e([1,40eBipiperidin]e10eylmethyl)e2e(2,4e
methoxyphenyl)benzofurane5eol (6h)
Using Method A, formaldehyde (37% in water, 140 mL, 1.5 mmol),
4epiperidinopiperidine (125 mg, 0.5 mmol) and 5ehydroxye2e
(2,4edimethoxyphenyl)benzofuran 5h (200 mg, 0.75 mmol) gave
195 mg (56%) of 6h as a white solid after column (acetone): Rf ¼ 0.14
4.2.11. 4e([1,40eBipiperidin]e10eylmethyl)e2e(thiophene2eyl)
benzofurane5eol (6j)
Using Method A, formaldehyde (37% in water, 200 mL, 2.1 mmol),
(acetone); 1H NMR (400 MHz, CDCl3)
d
1.34e1.36 (m, 2H),1.48e1.60
4epiperidinopiperidine (358 mg, 2.1 mmol) and 5ehydroxye2e
(thiophene2eyl)benzofuran 5j (230 mg, 1.1 mmol) gave 130 mg
(50%) of 6j as a white solid after flash chromatography on silica gel
(m, 6H), 1.76 (d, J ¼ 12.4 Hz, 2H), 2.04e2.10 (m, 2H), 2.22e2.28 (m,
1H), 2.41e2.44 (m, 4H), 3.04 (d, J ¼ 12.0 Hz, 2H), 3.77 (s, OCH3), 3.82
(s, NCH2), 3.90 (s, OCH3), 6.47 (d, J ¼ 2.0 Hz, 1H), 6.52 (dd, J ¼ 2.0,
8.4 Hz, 1H), 6.66 (d, J ¼ 8.4 Hz, 1H), 6.97 (s, 1H), 7.18 (d, J ¼ 9.6 Hz,
(acetone): Rf ¼ 0.15 (acetone); 1H NMR (400 MHz, CDCl3)
d 1.43e
1.47 (m, 2H), 1.57e1.71 (m, 6H), 1.86 (d, J ¼ 12.4 Hz, 2H), 2.10e2.18
(br m, 2H), 2.30e2.36 (m, 1H), 2.48e2.54 (br m, 4H), 3.12 (d,
J ¼ 12.4 Hz, 2H), 3.56 (s, NCH2), 6.75 (s, 1H), 6.79 (d, J ¼ 8.4 Hz, 1H),
7.09 (dd, J ¼ 3.6, 5.2 Hz, 1H), 7.27 (d, J ¼ 8.4 Hz, 1H), 7.32 (dd, J ¼ 1.2,
5.2 Hz, 1H), 7.45 (dd, J ¼ 1.2, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
1H), 7.86 (d, J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 26.4,
27.9, 50.2, 53.1, 55.5, 55.6 (2 OCH3), 57.9, 62.4, 98.8, 102.0, 104.9,
109.8, 111.3, 112.9, 128.0, 129.3, 147.7, 152.8, 153.5, 157.6, 160.9, 1
carbon peak is missing and believed to overlap with peaks nearby;
HRMS (M þ Hþ)(ESIþ) 451.2608 [M þ Hþ] (calcd for C27H34N2O4Hþ
451.2591).
d
24.8, 26.4, 27.9, 50.3, 53.1, 57.9, 62.3, 99.0, 110.3, 111.3, 113.7, 124.4,
125.6, 127.9, 128.5, 133.5, 148.6, 151.6, 153.9; LCeMS (M þ Hþ)(ESIþ)
397.19574 [M þ Hþ] (calcd for C23H28N2O2SHþ 397.19442).
4.2.10. 4e([1,40eBipiperidin]e10eylmethyl)e2e(furane2eyl)
benzofurane5eol (6i)
4.2.12. 4e([1,40eBipiperidin]e10eylmethyl)e2e(naphthalene1e
yl)benzofurane5eol (6k)
Using Method A, formaldehyde (37% in water, 130 mL, 1.6 mmol),
4epiperidinopiperidine (270 mg, 1.6 mmol) and 5ehydroxye2e
(furane2eyl)benzofuran 5i (200 mg, 0.8 mmol) gave 170 mg (56%)
Using Method A, formaldehyde (37% in water, 108
4epiperidinopiperidine (240 mg, 1.4 mmol) and 5ehydroxye2e
mL, 1.4 mmol),

188
C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
4.2.14. 4e([1,40eBipiperidin]e10eylmethyl)e2e(2ebenzyloxy)
benzofurane5eol (6m)
Using Method A, formaldehyde (37% in water, 47 mL, 0.5 mmol),
4epiperidinopiperidine (84 mg, 0.5 mmol) and 5ehydroxye2e(2e
benzyloxy)benzofuran 5m (80 mg, 0.25 mmol) gave 70 mg (56%) of
6m as a colorless oil after column (acetone): Rf ¼ 0.20 (acetone); 1H
NMR (400 MHz, CDCl3) d 1.45e1.49 (m, 2H), 1.61e1.73 (m, 6H), 1.88
(d, J ¼ 12.4 Hz, 2H), 2.05e2.11 (br m, 2H), 2.33e2.41 (m, 1H), 2.53e
2.56 (m, 4H), 3.12 (d, J ¼ 12.0 Hz, 2H), 3.75 (s, NCH2), 5.28 (s, OCH2),
6.79 (d, J ¼ 8.8 Hz,1H), 7.06e7.13 (m, 2H), 7.24 (s, 1H), 7.28e7.34 (m,
2H), 7.40e7.48 (m, 3H), 7.54e7.58 (m, 2H), 8.07 (dd, J ¼ 1.6, 8.0 Hz,
H); 13C NMR (100 MHz, CDCl3)
d 24.7, 26.3, 27.8, 50.2, 53.2, 57.7,
62.4, 70.6 (OCH2), 104.5, 110.1, 111.5, 112.4, 113.5, 119.8, 121.2, 127.0,
127.7, 128.2, 128.7, 129.1, 129.1, 136.8, 147.9, 152.4, 153.4, 155.5;
HRMS (M
C
þ
Hþ)(ESIþ) 405.25482 [M
þ
Hþ] (calcd for
26H32N2O2Hþ 405.25365).
4.2.15. 4e((4e(Dimethylamino)piperidine1eyl)methyl)e2e(4e
methoxyphenyl)benzofurane5eol (7g)
Using Method A, formaldehyde (37% in water, 70 mL, 0.7 mmol),
N,Nedimethylpiperidine4eamine (85 mg, 0.7 mmol) and 5ehy-
droxye2e(4emethoxyphenyl)benzofuran (5g) (80 mg, 0.35 mmol)
gave 90 mg (72%) of 7g as a white solid after flash chromatography
on silica gel (acetone): Rf ¼ 0.15 (acetone); 1H NMR (400 MHz,
CDCl3)
d 1.54e1.60 (m, 2H), 1.77e1.82 (m, 2H), 2.08e2.23 (m, 9H),
3.05 (d, J ¼ 12.0 Hz, 2H), 3.79 (s, OCH3), 3.82 (s, NCH2), 6.66e6.70
(m, 2H), 6.89 (d, J ¼ 8.8 Hz, 2H), 7.18e7.22 (m, 1H), 7.69 (d,
J ¼ 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 28.2, 41.6, 52.7, 55.4
(OCH3), 57.9 (CH2N), 61.8, 110.3, 111.1, 113.1, 114.2, 114.3, 123.5, 126.3,
128.8, 148.7, 153.7, 156.4, 159.9; LCeMS (M þ Hþ)(ESIþ) 381.21877
[M þ Hþ] (calcd for C23H28N2O3Hþ 381.21726).
Fig. 3. Inhibition of mTORC1 and Akt signaling. SK-HEP1 and Colo205 cells were
treated with 30b, everolimus or OZI027 for 24 h and were immunoblotted with an-
tibodies against p-S6, p-4EBP1 (downstream targets of mTORC1) and p-Akt (S473).
4.2.16. 4-([1,40-Bipiperidin]-10-ylmethyl)-2-phenylbenzofuran-5-yl
trifluoromethanesulfonate (8)
At 0 ꢀC, Tf2O (97
mL, 0.58 mmol) was added to a toluene (1 mL)
solution of 5-hydroxybenzofuran derivative 2 (125 mg, 0.32 mmol)
and an aqueous solution of K3PO4 (30% w/w, 0.7 mL, 0.96 mmol).
The biphasic solution was stirred vigorously at room temperature
(6 h). H2O was added and the layers were separated. The aqueous
layer was washed with CH2Cl2 (2 ꢁ 10 mL). The organic layers were
combined, dried and concentrated under vacuum to obtain 180 mg
(naphthalene1eyl)benzofuran 5k (185 mg, 0.7 mmol) gave 155 mg
(50%) of 6k as a yellow solid after flash column chromatography on
silica gel: Rf ¼ 0.17 (acetone); 1H NMR (400 MHz, CDCl3)
d 1.40e1.52
(m, 2H), 1.59e1.77 (m, 6H), 1.90 (d, J ¼ 12.8 Hz, 2H), 2.17e2.23 (m,
2H), 2.33e2.39 (m, 1H), 2.50e2.56 (br m, 4H), 3.18 (d, J ¼ 12.0 Hz,
2H), 3.97 (s, NCH2), 6.87 (d, J ¼ 8.8 Hz, 1H), 6.97 (s, 1H), 7.39 (d,
J ¼ 8.8 Hz, 1H), 7.54e7.60 (m, 3H), 7.86e7.94 (m, 3H), 8.49 (d,
(33%) of
a
white solid corresponding to the tri-
1.44e1.44
fluoromethanesulfonate 8: 1H NMR (400 MHz, CDCl3)
d
J ¼ 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 26.5, 28.0, 50.3,
(m, 2H), 1.56e1.68 (m, 6H), 1.78 (d, J ¼ 12.0 Hz, 2H), 2.04 (t,
J ¼ 11.8 Hz, 2H), 2.47e2.50 (m, 5H), 2.90 (d, J ¼ 12.0 Hz, 2H), 3.70 (s,
CH2N), 7.07 (d, J ¼ 8.8 Hz, 1H), 7.16e7.21 (m, 2H), 7.32e7.42 (m, 3H),
53.2, 58.0, 62.3, 103.6, 110.6, 111.5, 113.8, 125.3, 125.6126.1, 126.8,
127.2, 128.4, 128.5, 128.6, 129.4, 130.7, 134.0, 149.1, 153.8, 156.1;
HRMS (M
þ
Hþ)(ESIþ) 441.25504 [M
þ
Hþ] (calcd for
7.81 (d, J ¼ 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
23.8, 25.0, 27.0,
C
29H32N2O2Hþ 441.25365).
50.3, 52.9, 54.7, 63.5, 100.8, 111.2, 117.3, 118.7 (q, J ¼ 316.8 Hz, CF3),
124.5, 125.2, 128.9, 129.3, 129.7, 131.3, 144.4, 153.0, 158.1; MS
(M þ Hþ)(ESIþ) 523.2 [M þ Hþ] (calcd for C26H29F3N2O4SHþ 523.2).
4.2.13. 4e([1,40eBipiperidin]e10eylmethyl)e2e(naphthalene2e
yl)benzofurane5eol (6l)
Using Method A, formaldehyde (37% in water, 75
m
L, 0.8 mmol),
4.2.17. 7e([1,40eBipiperidin]e10eylmethyl)e2e
phenylbenzofurane6eol (10)
Employing Method A, using 2ephenylbenzofurane6eol (S-1)
(65 mg, 0.31 mmol), 4epiperidinopiperidine (104 mg, 0.62 mmol),
4epiperidinopiperidine (134 mg, 0.8 mmol) and 5ehydroxye2e
(naphthalene2eyl)benzofuran 5l (100 mg, 0.4 mmol) gave 65 mg
(50%) of 6l as a white solid after recrystallization in ethanol:
Rf ¼ 0.16 (acetone); IR (cmꢂ1) 2938, 2814, 1599, 1444, 1419, 1101,
formaldehyde (50
mL, 0.62 mmol, 40% in water) gave 40 mg (33%) of
788; 1H NMR (400 MHz, CDCl3)
d 1.45e1.49 (m, 2H), 1.59e1.72 (m,
a white solid corresponding to the 7: 1H NMR (400 MHz, CDCl3)
6H), 1.90 (d, J ¼ 12.4 Hz, 2H), 2.17e2.11 (br m, 2H), 2.33e2.41 (m,
1H), 2.51e2,57 (br m, 4H), 3.18 (d, J ¼ 12.4 Hz, 2H), 3.95 (s, NCH2),
6.84 (d, J ¼ 8.8 Hz,1H), 7.05 (s,1H), 7.36 (d, J ¼ 8.8 Hz,1H), 7.49e7.56
(m, 2H), 7.85e7.96 (m, 4H), 8.36 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
1.43e1.49 (m, 2H), 1.60e1.74 (m, 6H), 1.89 (d, J ¼ 12.8 Hz, 2H), 2.25
(t, J ¼ 12.2 Hz, 2H), 2.34e2.41 (m, 1H), 2.50e2.55 (m, 4H), 3.18 (d,
J ¼ 12.2 Hz, 2H), 4.10 (s, CH2N), 6.79 (d, J ¼ 8.4 Hz, 1H), 6.94 (s, 1H),
7.28e7.34 (m, 2H), 7.44 (t, J ¼ 7.8 Hz, 2H), 7.80 (d, J ¼ 7.8 Hz, 2H); 13
C
d
24.7, 26.4, 27.8, 50.3, 53.2, 57.9, 62.4, 99.7, 110.5, 111.4, 113.9, 122.7,
NMR (100 MHz, CDCl3) d 24.8, 26.4, 28.0, 50.3, 53.2, 54.4, 62.3,101.7,
123.7, 126.4, 126.6, 127.8, 127.9, 128.4, 128.5, 128.6, 133.2, 133.5,
149.1, 153.8, 156.3; HRMS (M þ Hþ)(ESIþ) 441.25497 [M þ Hþ]
(calcd for C29H32N2O2Hþ 441.25365).
104.7, 113.0, 119.9, 121.1, 124.3, 127.9, 128.7, 130.9, 153.7, 154.3, 156.3;
HRMS (M
Hþ)(ESIþ) 391.23800 [M Hþ] (calcd for
25H30N2O2Hþ 391.23855).
þ
þ
C

C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
189
4.2.18. 4e([1,40ebipiperidin]e10eylmethyl)e3emethyle2e
piperidinopiperidine (1.2 g, 7.1 mmol), formaldehyde (535 mL,
phenylbenzofurane5eol (14)
Employing Method A, using benzofuran derivative 13 (70 mg,
0.31 mmol), 4epiperidinopiperidine (105 mg, 0.62 mmol), form-
7.1 mmol, 40% in water) gave 1.20 g (75%) of 17d as an orange oil
after column (acetone): Rf ¼ 0.32 (Acetone); 1H NMR (400 MHz,
CDCl3)
d
1.29 (t, J ¼ 7.2 Hz, OCH2CH3), 1.42e1.48 (m, 2H), 1.57e1.73
aldehyde (48
m
L, 0.62 mmol, 40% in water) gave 65 mg (52%) of 14 as
(m, 6H), 1.86 (d, J ¼ 12.9 Hz, 2H), 2.14e2.23 (m, 2H), 2.31e2.36 (m,
1H), 2.39e2.53 (m, 4H), 3.13 (d, J ¼ 12.0 Hz, 2H), 3.99 (s, CH2N), 4.35
(q, J ¼ 7.2 Hz, OCH2CH3), 6.82 (d, J ¼ 8.8 Hz, 1H), 7.32 (d, J ¼ 8.8 Hz,
1H), 7.43e7.47 (m, 3H), 7.72e7.76 (m, 2H); 13C NMR (100 MHz,
a white solid after column (acetone): Rf ¼ 0.18 (Acetone); 1H NMR
(400 MHz, CDCl3)
d 1.46e1.49 (m, 2H), 1.60e1.75 (m, 6H), 1.91 (d,
J ¼ 12.8 Hz, 2H), 2.16e2.23 (m, 2H), 2.38e2.45 (m, 1H), 2.51e2.56
(m, 7H), 3.19 (d, J ¼ 11.6 Hz, 2H), 4.16 (s, CH2N), 6.82 (d, J ¼ 8.8 Hz,
1H), 7.27e7.31 (m, 1H), 7.39 (t, J ¼ 7.4 Hz, 1H), 7.49 (t, J ¼ 7.4 Hz, 2H),
CDCl3) d 14.0 (CH3), 24.8, 26.4, 27.9, 50.3, 53.0, 57.2, 61.4, 62.2, 110.1,
110.8, 112.3, 115.2, 125.4, 127.9, 128.3, 129.5, 130.0, 148.2, 155.4,
7.69 (d, J ¼ 7.4 Hz, 2H); 13C NMR (100 MHz, CD3OD)
d
13.0 (CH3),
156.9, 166.3; HRMS (M þ Hþ)(ESIþ) 463.2607 [M þ Hþ] (calcd for
24.7, 26.3, 27.8, 50.2, 53.1, 56.5, 62.4 (NCH), 110.6, 110.9, 113.0, 114.0,
127.8, 128.1, 128.5, 131.2, 148.5, 154.2, 2 peaks are missing and
believed to overlap nearby; HRMS (M þ Hþ)(ESIþ) 405.2557
[M þ Hþ] (calcd for C26H32N2O2Hþ 405.2536).
C
28H34N2O4Hþ 463.2591).
4.2.23. 4e([1,40eBipiperidin]e10eylmethyl)e3e(hydroxymethyl)e
2ephenylbenzofurane5eol (17e)
A THF solution (3 mL) of ethyl 4e([1,40ebipiperidin]e10e
ylmethyl)e5ehydroxye2ephenylbenzofurane3ecarboxylate
(17d) (140 mg, 0.3 mmol) was added dropwisely to a THF suspen-
sion (10 mL) of LiAlH4 (80 mg, 2.1 mmol). The mixture was stirred at
4.2.19. 4e([1,40eBipiperidin]e10eylmethyl)e1emethyle2e
phenyle1Heindole5eol (17a)
Employing Method A, using 5ehydroxye1emethyle2e
phenyle1Heindole (16a) (25 mg, 0.11 mmol), 4epiperidinopiper-
room temperature (3 h). 625
m
L of H2O was added dropwisely at
idine (21 mg, 0.22 mmol), formaldehyde (18
m
L, 0.22 mmol, 40% in
0 ꢀC followed by 625
mL of a 1 M NaOH solution and 625 m
L of H2O.
water) gave 10 mg (33%) of a brown solid corresponding to the 17a:
CH2Cl2 (10 mL) was added and the mixture was filtered. The filtrate
was concentrated under vacuum to obtain the alcohol 17e (125 mg,
Rf ¼ 0.48 (Acetone/MeOH 9/1); 1H NMR (400 MHz, CDCl3)
d 1.44e
1.49 (m, 2H), 1.57e1.71 (m, 6H), 1.87 (d, J ¼ 12.8 Hz, 2H), 2.15 (t,
J ¼ 11.2 Hz, 2H), 2.36e2.42 (m, 1H), 2.52e2.56 (m, 4H), 3.18 (d,
J ¼ 12.6 Hz, 2H), 3.70 (s, NCH3), 3.95 (s, CH2N), 6.40 (s, 1H), 6.83 (d,
J ¼ 8.7 Hz, 1H), 7.17 (d, J ¼ 8.7 Hz, 1H) 7.40e7.53 (m, 5H); 13C NMR
quant.) as a white solid: 1H NMR (400 MHz, CDCl3)
d 1.42e1.48 (m,
2H), 1.57e1.73 (m, 6H), 1.85 (d, J ¼ 12.0 Hz, 2H), 2.20e2.27 (m, 2H),
2.35e2.42 (m, 1H), 2.51e2.54 (m, 4H), 3.14 (d, J ¼ 12.0 Hz, 2H), 4.19
(s, CH2N), 4.8 (s, OCH2), 6.83 (d, J ¼ 8.6 Hz, 1H), 7.31 (d, J ¼ 8.6 Hz,
1H), 7.42e7.53 (m, 3H), 7.72e7.75 (m, 2H); 13C NMR (100 MHz,
(100 MHz, CD3OD) d 24.9, 26.3, 28.5, 31.6 (CH3), 49.7, 51.3, 57.7, 62.3,
99.7,110.6,112.9,128.9,129.2,129.6,130.3,134.3,134.8143.3,152.1,1
carbon peak is missing and believed to overlap with peaks nearby;
HRMS (M þ Hþ)(ESIþ) 404.2702 [M þ Hþ] (calcd for C26H33N3OHþ
404.2696).
CDCl3) d 24.5, 26.0, 29.7, 50.1, 52.6, 56.0, 62.4, 70.6, 110.8, 113.2,
114.2, 115.1, 127.5, 128.1, 128.7, 129.0, 130.3, 148.8, 154.1, 155.0;
HRMS (M þ Hþ)(ESIþ) 421.2510 [M þ Hþ] (calcd fo C26H32N2O3Hþ
421.2485).
4.2.20. 4-([1,40-Bipiperidin]-10-ylmethyl)-1-benzyl-1H-indol-5-ol
(17b)
4.2.24. 4e([1,40eBipiperidin]e10eylmethyl)e2ephenylbenzo[d]
oxazole5eol (20a)
Using Method A with formaldehyde (80
m
L, 0.90 mmol), 16b
Employing Method A, using 5ehydroxye2ephenylbenzoxazole
(19a) (100 mg, 0.47 mmol), 4epiperidinopiperidine (160 mg,
(100 mg, 0.45 mmol) and 4epiperidinopiperidine (152 mg,
0.90 mmol), 17b [23] (79 mg, 44%) was obtained as a white solid
after purification by column chromatography on silica gel using
CH2Cl2/MeOH (7/3) as solvent; Rf ¼ 0.43 (EtOAc/MeOH 8/2); 1H
0.95 mmol), formaldehyde (72
140 mg (75%) of a white solid corresponding to the 20a: Rf ¼ 0.10
(acetone); 1H NMR (400 MHz, CDCl3)
1.44e1.47 (m, 2H), 1.58e1.74
mL, 0.95 mmol, 40% in water) gave
d
NMR (300 MHz, CDCl3)
d
1.47e1.51 (m, 2H), 1.62e1.75 (m, 6H), 1.91
(m, 6H), 1.90 (d, J ¼ 13.2 Hz, 2H), 2.24e2.40 (m, 3H), 2.52e2.55 (m,
4H), 3.16 (d, J ¼ 12.0 Hz, 2H), 4.19 (s, CH2N), 6.85 (d, J ¼ 8.8 Hz, 1H),
7.35 (d, J ¼ 8.8 Hz, 1H), 7.51e7.54 (m, 3H), 8.21e8.24 (m, 2H); 13C
(d, J ¼ 12.3 Hz, 2H), 2.13e2.21 (m, 2H), 2.40e2.60 (m, 5H), 3.16 (d,
J ¼ 12.0 Hz, 2H), 3.96 (s, NCH3), 5.24 (s, NCH2), 6.38 (d, J ¼ 3.0 Hz,
1H), 6.75 (d, J ¼ 8.7 Hz, 1H), 7.04e7.16 (m, 4H), 7.25e7.33 (m, 3H);
NMR (100 MHz, CDCl3) d 24.8, 26.4, 28.0, 50.3, 53.1, 55.7, 62.2, 109.3,
13C NMR (75 MHz, CDCl3)
d
24.7, 26.2, 27.7, 50.2, 53.1, 57.8, 62.2,
111.7, 113.8, 127.5, 127.5, 128.8, 131.2, 141.3, 144.3, 155.4, 163.2;
HRMS (M þ Hþ)(ESIþ) 392.23389[M þ Hþ] (calcd for C24H29N3O2Hþ
392.23380).
70.5, 101.6, 110.6, 111.7, 113.6, 126.8, 127.4, 128.2, 128.6, 140.7, 149.1,
153.6, 159.4.
4.2.21. 4e([1,40eBipiperidin]e10eylmethyl)e3e
phenylbenzofurane5eol (17c)
4.2.25. 4e([1,40eBipiperidin]e10eylmethyl)e2ephenyle1He
benzo[d]imidazole5eol (20b)
Using Method A, formaldehyde (37% in water, 205
m
L, 2.2 mmol),
Employing Method A, using benzimidazole tautomers (19b)
(105 mg, 0.50 mmol), 4epiperidinopiperidine (168 mg, 1.00 mmol),
4epiperidinopiperidine (370 mg, 2.2 mmol) and 5ehydroxye3e
phenylbenzofuran (16c) [24] (230 mg, 1.1 mmol) gave 170 mg (56%)
of 17c as a white solid after flash chromatography on silica gel
formaldehyde (76 mL, 1.00 mmol, 40% in water) gave 60 mg (31%) of
a white solid corresponding to the 20b: Rf ¼ 0.05 (acetone); 1H
(acetone): Rf ¼ 0.16 (acetone); 1H NMR (400 MHz, CDCl3)
d
1.40e
NMR (400 MHz, CDCl3) d 1.43e1.46 (m, 2H), 1.58e1.71 (m, 6H), 1.83
1.46 (m, 2H), 1.54e1.63 (m, 6H), 1.78 (d, J ¼ 12.4 Hz, 2H), 1.88 (m,
2H), 2.21e2.29 (m, 1H), 2.45e2.49 (m, 4H), 3.01 (d, J ¼ 12.0 Hz, 2H),
3.59 (s, NCH2), 6.87 (d, J ¼ 8.8 Hz, 1H), 7.33e7.48 (s, 7H); 13C NMR
(d, J ¼ 11.6 Hz, 2H), 2.14e2.34 (m, 3H), 2.48e2.53 (m, 4H), 3.11 (d,
J ¼ 9.2 Hz, 2H), 4.09e4.33 (s, CH2N), 6.80 (d, J ¼ 8.8 Hz, 1H), 7.05e
7.29 (br m, 1H), 7.42e7.47 (m, 3H), 7.98e8.08 (m, 2H); HRMS
(M þ Hþ)(ESIþ) 391.24932 [M þ Hþ] (calcd for C24H30N4OHþ
391.24978).
(100 MHz, CDCl3) d 24.8, 26.4, 27.7, 50.2, 52.7, 56.3, 62.2, 111.0, 112.8,
114.3, 122.5, 125.9, 127.7, 128.2, 130.2, 133.8, 143.0, 154.7.
4.2.22. Ethyl 4e([1,40ebipiperidin]e10eylmethyl)e5ehydroxye2e
phenylbenzofurane3ecarboxylate (17d)
4.2.26. 4-([1,40-Bipiperidin]-10-ylmethyl)-2-phenylfuro[3,2-c]
pyridine (24)
Employing Method A, using ethyl 5ehydroxye2ephenyl-
benzofurane3ecarboxylate [25] (16d) (1.00 g, 3.5 mmol), 4e
NaBH(OAc)3 (94 mg, 0.4 mmol) was added to an anhydrous DCE
(1 mL) solution of aldehyde 23 (45 mg, 0.2 mmol) and 4e

190
C. Salomé et al. / European Journal of Medicinal Chemistry 81 (2014) 181e191
piperidinopiperidine (37 mg, 0.22 mmol). The mixture was stirred
at room temperature (24 h). The volatiles were evaporated under
vacuum. H2O and CH2Cl2 were added and the layers were sepa-
rated. The aqueous layer was washed with CH2Cl2 (30 mL). The
organic layers were combined and concentrate under vacuum. The
crude residue was purified by flash column chromatography on
silica gel with CH2Cl2/MeOH (7/3) as eluant to obtain 24 as a white
solid (7 mg, 10%): Rf ¼ 0.16 (CH2Cl2/MeOH; 2/8); 1H NMR (300 MHz,
3.61 (s, 2H), 3.75 (s, 3H), 5.12 (s, 2H), 6.78 (d, J ¼ 8.9 Hz, 1H), 6.98e
7.03 (br m, 2H), 7.18e7.27 (m, 2H), 7.33e7.39 (m, 3H), 7.44e7.49 (br
d, J ¼ 7.2 Hz, 2H), 7.98 (d, J ¼ 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
26.8, 39.9, 52.2, 53.1, 57.3, 61.9, 70.8, 106.4,109.5,110.1, 112.3,117.3,
119.8, 121.2, 127.2, 128.3, 128.6, 128.9, 129.4, 132.0, 136.7, 148.9,
153.0, 154.3, 155.8; LRMS (M þ Hþ)(ESIþ) 471.2 [M þ Hþ] (calcd for
C
30H34N2O3Hþ 471.2).
CD3OD)
d 1.55e1.60 (m, 2H), 1.70e1.80 (m, 4H), 1.92e2.01 (m, 4H),
4.2.30. 10-((2-Phenylbenzofuran-4-yl)methyl)-1,40-bipiperidine
(32)
2.19e2.27 (br m, 2H), 2.68e2.76 (m,1H), 2.86e2.96 (m, 4H), 3.09 (d,
J ¼ 10.0 Hz, 2H), 3.96 (s, CH2N), 7.45e7.59 (m, 5H), 7.97 (d,
J ¼ 8.0 Hz, 2H), 8.37 (d, J ¼ 5.2 Hz, 1H); HRMS (M þ Hþ)(ESIþ)
376.2395 [M þ Hþ] (calcd for C24H29N3OHþ 376.2383).
NaBH3CN (33 mg, 0.46 mmol) was added to an anhydrous MeOH
(1 mL) solution of aldehyde S-15 (see supporting information)
(50 mg, 0.23 mmol), AcOH (cat., 1 drop) and 4epiperidinopiper-
idine (42 mg, 0.25 mmol). The mixture was stirred at room tem-
perature (16 h) then evaporated under vacuum. The crude residue
was purified by flash column chromatography on silica gel with
acetone/MeOH (10/0 to 9/1) as the eluant to obtain a white solid
corresponding to 32 (42 mg, 50%): Rf ¼ 0.20 (acetone/MeOH); 1H
4.2.27. Ne(4e([1,40eBipiperidin]e10eylmethyl)e2e
phenylbenzofurane5eyl)methanesulfonamide (27)
In
anesulfonamide (26) (130 mg, 0.46 mmol), 4epiperidinopiperidine
(306 mg, 1.82 mmol), formaldehyde (175 L, 2.28 mmol, 37% in
a
sealed tube, Ne(2ephenylbenzofurane5eyl)meth-
m
NMR (400 MHz, CDCl3) d 1.32e1.36 (m, 2H), 1.48e1.55 (m, 6H), 1.72
water) were added followed by EtOH (1 mL). The mixture was
stirred at 110 ꢀC (3 days). H2O and CH2Cl2 were added. The layers
were separated and the aqueous layer was washed with CH2Cl2. The
organic layers were combined, and concentrated under vacuum.
The crude residue was purified by flash column chromatography on
silica gel with acetone/MeOH (10/0 to 8/2) as the eluant to obtain
27 as a white solid (80 mg, 38%): Rf ¼ 0.09 (acetone); 1H NMR
(d, J ¼ 12.4 Hz, 2H), 1.90e1.97 (m, 2H), 2.15e2.26 (m, 1H), 2.41e2.45
(m, 4H), 2.92 (d, J ¼ 11.6 Hz, 2H), 3.66 (s, CH2N), 7.07 (d, J ¼ 7.2 Hz,
1H), 7.13e7.18 (m, 2H), 7.25e7.29 (m, 1H), 7.33e7.40 (m, 3H), 7.90
(d, J ¼ 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 24.8, 26.3, 28.2, 50.3,
53.7, 60.9, 62.9, 101.0, 110.0, 123.4, 124.1, 125.2, 128.6, 129.0, 129.3,
130.8, 132.0, 155.2, 155.6; HRMS (M þ Hþ)(ESIþ) 375.2436 [M þ Hþ]
(calcd for C25H30N2OHþ 375.2436).
(400 MHz, CDCl3)
d 1.43e1.47 (m, 2H), 1.57e1.70 (m, 6H), 1.86 (d,
J ¼ 12.4 Hz, 2H), 2.12e2.20 (m, 2H), 2.31e2.36 (m, 1H), 2.51e2.54
(m, 4H), 3.00e3.05 (m, 5H), 3.86 (s, CH2N), 7.03 (s, 1H), 7.39e7.51
Acknowledgment
(m, 5H), 7.88 (d, J ¼ 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 24.7,
26.2, 27.8, 40.1, 50.3, 53.0, 57.7, 62.4, 99.2, 110.8, 117.2, 118.3, 128.9,
129.0, 129.9, 130.0, 133.7, 151.7, 157.0, 1 carbon peak is missing and
believed to overlap with peaks nearby; HRMS (M þ Hþ)(ESIþ)
468.2341 [M þ Hþ] (calcd for C26H33N3O3SHþ 468.2315).
We are grateful to region Alsace and MNESR for fellowships to
Christophe Salomé and Frédéric Thuaud. We thank also the SATT
Ile-de-France Innov for financial support.
Appendix A. Supplementary data
4.2.28. 10-((5-Methoxy-2-phenylbenzofuran-4-yl)methyl)-1,40-
bipiperidine (30a)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.05.014.
NaBH3CN (27 mg, 0.4 mmol) was added to an anhydrous MeOH
(5 mL) solution of aldehyde S-13 (see supporting information)
(50 mg, 0.2 mmol), AcOH (cat., 1 drop) and 4epiperidinopiperidine
(37 mg, 0.2 mmol). The mixture was stirred at room temperature
(16 h), then evaporated under vacuum. The crude residue was
purified by flash column chromatography on silica gel with
acetone/MeOH (10/0 to 8/2) as the eluant to obtain a yellow oil
corresponding to 30a (40 mg, 50%): Rf ¼ 0.10 (acetone/MeOH; 9/1);
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