Synthesis and biological evaluation of benzimidazole derivatives as potent AMP-activated protein kinase activators

Article abstract of DOI:10.1016/j.bmc.2006.02.028

Design, synthesis and structure-activity relationships of benzimidazole derivatives as activators of the AMP-activated protein kinase (AMPK) are presented in this paper. AMPK is the central component of a protein kinase cascade that plays a key role in the regulation of energy balance. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance of the cell and recent studies have indicated that AMPK plays an important role in regulation of the whole-body energy metabolism. The following study based on the lead compound S27847 involved modification of three regions of this compound. Preliminary structure-activity relationships are being described.

Full text of DOI:10.1016/j.bmc.2006.02.028

Bioorganic & Medicinal Chemistry 14 (2006) 4490–4518
Synthesis and biological evaluation of benzimidazole derivatives
as potent AMP-activated protein kinase activators
Julie Charton,a,* Sophie Girault-Mizzi,a Marie-Ange Debreu-Fontaine,a
Fabienne Foufelle,b Isabelle Hainault,b Jean-Guy Bizot-Espiard,c
Daniel-Henri Caignardc and Christian Sergheraerta
aUMR CNRS 8525, Universite de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
B.P. 447, 59021 Lille cedex, France
bU671 INSERM, 15 rue de l’Ecole de Medecine, 75270 Paris Cedex 06, France
cInstitut de Recherches Servier, 125 Chemin de ronde, 78290 Croissy sur Seine, France
Received 2 December 2005; revised 8 February 2006; accepted 14 February 2006
Available online 2 March 2006
Abstract—Design, synthesis and structure–activity relationships of beU:/AP/DTD501/BMC/4818nzimidazole derivatives as activa-
tors of the AMP-activated protein kinase (AMPK) are presented in this paper. AMPK is the central component of a protein kinase
cascade that plays a key role in the regulation of energy balance. Once activated, AMPK initiates a series of responses that are aimed
at restoring the energy balance of the cell and recent studies have indicated that AMPK plays an important role in regulation of the
whole-body energy metabolism. The following study based on the lead compound S27847 involved modification of three regions of
this compound. Preliminary structure–activity relationships are being described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and cholesterol synthesis) and switching-on the ATP-
generating pathways (e.g., fatty acid oxidation and gly-
colysis).5,9–11
The AMP-activated protein kinase (AMPK) is the cen-
tral component of a protein kinase cascade that plays
a major role in energy sensing. AMPK itself plays a
key role in the regulation of metabolism within the mus-
cle cell and has been already identified as a potential tar-
get for type 2 diabetes mellitus and obesity.1–4 AMPK is
activated following depletion of cellular ATP together
with a concomitant rise in AMP.5,6 AMP increases
AMPK activity by direct allosteric activation and by
promoting the phosphorylation of AMPK by an up-
stream kinase, AMPK kinase (AMPKK). Recently, sev-
eral studies have demonstrated that AMPK is activated
by a second mechanism that does not appear to involve
changes in adenine nucleotides. However, the molecular
basis for this activation is not yet understood.7,8 Once
activated, AMPK phosphorylates several downstream
substrates, with an overall effect of switching-off the
ATP-consuming pathways (e.g., fatty acid synthesis
A major development in AMPK research came with the
finding that 5-amino-4-imidazolecarboxamide (AICA)
riboside (Fig. 1) could be used to activate AMPK phar-
NH2
NH2
NH2
N
N
N
O
N
N
O
N
N
H2N
H2N
N
H
O
P
O
P
HO
O
O
O
O
O
O
O
H
H
H
O
H
H
H
O
H
H
H
H
H
OH
OH
OH
ZMP
OH
OH
OH
AMP
AICAR
4
3
N
5
6
2
N
H
7
1
Keywords: AMP-activated protein kinase; Benzimidazole derivatives.
*
S27847
Corresponding author. Tel.: +33 3 20 96 49 28; fax: +33 3 20 96 47
09; e-mail: julie.charton@univ-lille2.fr
Figure 1. Structures of AMP, ZMP, AICAR and compound S27847.
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.02.028

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4491
macologically in cells.12,13 AICA riboside (AICAR) is
Table 1. AMP-Kinase activity for compounds 1–32 (A series)
converted in cells to the monophosphate derivative,
ZMP, which can accumulate to high levels, and mimics
the effects of AMP on the AMPK cascade. Until recent-
ly, AICAR was the only pharmacological activator of
AMPK to be described and many studies investigating
the physiological consequences of AMPK activation re-
lied solely on its use. In this paper, we describe the syn-
thesis and biological evaluation of benzimidazole
derivatives as potent AMPK activators. A screening of
a general library afforded S27847 as a better mediator
of AMPK activation in primary cultured hepatocytes
and in muscle cells H-2K than the reference AMPK acti-
vator AICAR. The benzimidazole scaffold of S27847
made it attractive in terms of possible diversifications.
N
R
N
H
Compound
R
REAa at 100 lM
1 or S27847
4.5
1.1
1.1
2
3
4
5
1.1
1.1
Here we report our efforts to improve AMPK activation
starting from the lead compound S27847 (racemate
compound): first, by modification of the cyclohexylphe-
nyl moiety and second, by introducing diversity on the
aromatic moiety of the benzimidazole ring. These results
will provide a useful aid for further work on the poten-
tial benefit of therapeutic agents aimed at targeting
AMPK in disease such as type 2 diabetes or other obes-
ity-related diseases.
6
7
2.8
1.4
8
1.2
N
H
9
1.3
1.2
S
2. Chemistry
10
Synthesis of S27847 analogs (compounds 2–74, Tables
1–6) is depicted in Schemes 1–13. In the A series, com-
pounds 2–32 have been modified at the C-2 position
with the aim of evaluating the optimal substituent
(Table 1, Fig. 2). Several aromatic and/or alicyclic
groups replaced the cyclohexylphenylmethyl moiety. In
the B series (compounds 33–38, Table 2, Fig. 2), the
replacement of the cyclohexyl group by an amine was
carried out in order to enhance activity and optimize
solubility simultaneously. In addition, two compounds
in which the C2 atom was replaced with a nitrogen atom
were synthesized (compounds 39–40, C series, Table 3,
Fig. 2). In addition, replacement of the imidazole moiety
with other heterocycles was attempted to evaluate the
importance of this pattern on activity (compounds 41–
43, D series, Table 4, Fig. 2). In the E series (compounds
44–67, Table 5, Fig. 2), diversity was introduced on the
phenyl moiety of the benzimidazole core while maintain-
ing the cyclohexylphenylmethyl substituent at C-2 posi-
tion. It consisted in various substitutions of phenyl
moiety (compounds 44–48 and 51–67) or in the replace-
ment of the latter by a purine (compound 49) or a pyr-
idine (compound 50). In the F series (compounds 68–74,
Table 6, Fig. 2), the combination of the methoxy group
at the C-5 position and several other substituents at the
C-2 position (compounds 68–72) was realized. Two ana-
logs with an amino substituent in N-1 position (com-
pounds 73 and 74) were also synthesized while
preserving cyclohexylphenylmethyl group at the C-2
position.
11
12
13
1.2
1.0
1.0
CH3
CH3
14
15
1.2
1.0
H3C
CH3
16
17
18
1.4
1.1
0.8
I
19
20
7.1
5.4
21
22
0.9
The presence of bulky substituents led us logically to
consider a two-step procedure. Substituted or unsubsti-
tuted 1,2-phenylenediamine was first treated with the
1.1
N
H
(continued on next page)

4492
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
Table 3. AMP-Kinase activity for compounds 39 and 40 (C series)
Table 1 (continued)
Compound
R
REAa at 100 lM
Compound
Structure
REAa at 100 lM
N
23
24
5.1
N
39
4.3
N
H
1.1
N
40
3.1
N
N
25
26
7.2
H
N
H
1 or S27847
AICAR
4.5
2.3b
0.9
O
a Relative enzyme activity (enzyme activity relative to buffer blank).
b Relative enzyme activity at 500 lM.
27
28
1.1
F
Table 4. AMP-Kinase activity for compounds 41–43 (D series)
4.7
REAa at 100 lM
S
Compound
Structure
N
O
29
30
31
0.6
1.1
1.2
41
0.6
H3C
NH
N
42
43
1.8
0.8
N
O
32
0.8
Br
AICAR
2.3b
1 or S27847
AICAR
4.5
2.3b
a Relative enzyme activity (enzyme activity relative to buffer blank).
b Relative enzyme activity at 500 lM.
a Relative enzyme activity (enzyme activity relative to buffer blank).
b Relative enzyme activity at 500 lM.
Table 2. AMP-Kinase activity for compounds 33–38 (B series)
appropriate activated carboxylic acid. Cyclodehydration
of the resulting monoacylated derivative led to the benz-
imidazole derivative (Scheme 1). Under optimal condi-
tions, the DCC coupling in THF or DMF between an
appropriate carboxylic acid and substituted or unsubsti-
tuted o-phenylenediamine, followed by reflux of the
monoacylated derivative in neat acetic acid, led to the
isolation of desired compounds with good yields.14
N
N
NRR'
H
Compound
-NRR0
REAa at 100 lM
N
N
N
33
6.1
O
34
35
36
37
38
1.0
1.0
0.9
1.2
5.8
In the case of expensive or commercially unavailable
acids, the use of more than two equivalents of acid with
regard to o-phenylenediamine was a major inconve-
nience. A coupling using PyBrop activation15 and an ex-
cess of amine, to avoid formation of diacylated
derivatives, has been preferred for compounds 3i, 6i,
8i, 9i, 19i, 22i, 25–29i, 33–36i and 38i (Scheme 1). In this
case, diisopropylethylamine (DIEA) was used as a base
with that coupling reagent.
NH2
N
N
OH
N
H
1 or S27847
AICAR
4.5
2.3b
Synthesis of monoacylated precursor 37i necessitated a
coupling using EDC/HOBt activation and DIEA as a
base to avoid reaction with the hydroxy group (Scheme 1).
a Relative enzyme activity (enzyme activity relative to buffer blank).
b Relative enzyme activity at 500 lM.

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
Table 5. AMP-Kinase activity for compounds 44–67 (E series)
4493
R1
R2
R3
N
Y
N
H
X
Compound
R1
R2
R3
X
Y
REAa at 100 lM
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
1
NO2
NH2
H
H
CH
CH
CH
CH
CH
N
C
C
C
C
C
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
H
1.0
4.3
3.2
0.7
2.1
0.9
1.1
2.0
6.9
1.8
4.0
1.7
0.8
0.6
1.2
2.1
5.0
4.6
1.9
0.8
3.7
2.7
4.4
2.2
4.5
2.3b
H
H
NHEt
NHCOMe
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
—
H
H
H
Me
H
N
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
H
OMe
F
Cl
H
H
H
CF3
COOMe
COOH
OCOMe
Me
H
H
H
H
H
Me
OMe
Cl
Me
OMe
Cl
Phenyl
Piperidine
H
H
H
H
H
Methylpiperazine
Morpholine
Thiomorpholine
H
AICAR
a Relative enzyme activity (enzyme activity relative to buffer blank).
b Relative enzyme activity at 500 lM.
Compounds 49i and 50i were synthesized starting,
respectively, from 4,5-diaminopyrimidine and 2,3-diami-
nopyridine by reaction, in the presence of DIEA, with
acyl chloride of cyclohexylphenylacetic acid, prepared
beforehand using thionyl chloride (Scheme 1).
of compound 3j using p-toluenesulfonic acid in refluxing
toluene (Scheme 2), conditions previously reported for
the preparation of 2-substituted benzoxazoles and benz-
imidazoles, when starting from the corresponding sym-
metrical diacylated precursors.14,17
Two different acidic conditions of cyclization were ap-
plied: refluxing in neat AcOH or in the presence of
HCl. Compound 50 was obtained by treating the corre-
sponding monoacylated precursor 50i with p-toluene-
sulfonic acid in toluene at reflux (Scheme 1).
Nitrothiourea 39i and 40i were obtained starting from
2-nitrophenylisothiocyanate by reaction with the appro-
priate amine, N-cyclohexylaniline and 2-(1-piperidi-
no)aniline, respectively, in THF.18 Then treatment
with tin chloride in ethanol at reflux led to reduction
of nitro group and consecutive cylization affording
benzimidazoles 39 and 40 (Scheme 3).
For several compounds, the starting material was 2-nitro-
aniline, both substituted or not, which was reacted with
commercially available or previously synthesized acyl
chlorides. In most cases, reduction of the nitro group fol-
lowed by the cyclodehydration step of the resulting mono-
acylated derivative was realized ‘one pot’ using iron in
refluxing neat acetic acid,16 tin chloride in the presence
of 12 N HCl in refluxing ethanol or iron in the presence
of 12 N HCl in refluxing ethanol (Scheme 1).
The compounds 41–43 (D series) were synthesized under
conditions described previously. In the case of com-
pound 41, coupling between 2-aminophenol and cyclo-
hexylphenylacetic acid, using DCC activation in THF,
and treatment with p-toluenesulfonic acid in refluxing
toluene were applied to afford the expected benzoxazole
(Scheme 4).17,19
In the case of dicyclohexylmethyl benzimidazole 3, no
cyclization was observed in refluxing neat acetic acid
from monoacylated precursor 3i. Under these condi-
tions the acetylated derivative 3j was obtained. The
benzimidazole 3 was finally synthesized by cyclization
For compound 42, coupling between 2-aminobenzyl-
amine and cyclohexylphenylacetic acid, using DCC acti-
vation and DIEA as a base in DMF, and consecutive
reflux in neat acetic acid led to the obtention of the
expected dihydroquinazoline (Scheme 5).

4494
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
Table 6. AMP-kinase activity for compounds 68–74 (F series)
N
R
H
N
H
N
NH2
NH2
N
MeO
a
b
R'
O
O
NH
NH2
Compound
R
R0
H
REAa at 100 lM
3j
3i
O
CH3
c
68
3.1
N
N
H
O
69
H
1.8
3
Scheme 2. Reagents and conditions: (a) dicyclohexylacetic acid,
PyBrop, DIEA, CH2Cl2, rt, 12 h; (b) neat AcOH, reflux, 5 h; (c) p-
TsOH, toluene, reflux, 24 h.
HN
70
71
72
H
H
H
1.0
4.7
6.9
S
H
N
NRR'
N
N
a
b
NRR'
S
N
H
NO2
NO2
39i-40i
39-40
Scheme 3. Reagents and conditions: (a) RR0NH, THF, rt, 12 h; (b)
SnCl2, EtOH, reflux, 5 h.
N
N
73
74
O
0.9
1.0
H
N
NH2
OH
N
O
a
b
O
OH
N
41
Scheme 4. Reagents and conditions: (a) cyclohexylphenylacetic acid,
DCC, THF, rt, 12 h; (b) p-TsOH, toluene, reflux, 8 h.
1 or S27847
AICAR
4.5
2.3b
a Relative enzyme activity (enzyme activity relative to buffer blank).
O
b Relative enzyme activity at 500 lM.
NH2
NH2
NH
a
N
b
H
N
NH2
42i
H
42
NH2
NH2
N
R
N
b
d
a
Y
Y
Y
R
O
N
H
X
X
X
R'
R'
R'
NH2
Scheme 5. Reagents and conditions: (a) cyclohexylphenylacetic acid,
DCC, DIEA, DMF, rt, 12 h; (b) neat AcOH, reflux, 24 h.
H
N
R
N
NH2
NO2
c
R
O
NO2
N
R'
R'
H
R'
Scheme 1. Reagents and conditions: (a) RCOOH, DCC, DIEA, DMF
or THF, rt, 12 h or RCOOH, PyBrop, DIEA, CH2Cl2, rt, 12 h or
EDC, HOBt, DIEA, DCM, rt, 12 h; (b) neat AcOH, reflux, 5 h or 4 N
HCl, MeOH/dioxane 1:1, reflux, 8 h or p-TsOH, toluene, reflux, 72 h;
(c) RCOCl, pyridine, THF, rt, 4 h or RCOCl, DIEA, CH2Cl2, 12 h; (d)
Fe, neat AcOH, reflux, 5 h or SnCl2, 12 N HCl, EtOH, reflux, 24 h or
Fe, 12 N HCl, EtOH, reflux, 8 h.
N
NH
O
43
Scheme 6. Reagents and conditions: cyclohexylphenylacetic acid,
PyBrop, DIEA, CH2Cl2, rt, 12 h.
Tetrahydroquinoline 43 was prepared by a coupling
between cyclohexylphenylacetic acid and 1,2,3,4-tetra-
hydroquinoline using PyBrop activation and DIEA as
a base in dichloromethane (Scheme 6).
The reaction between 3-nitro-o-phenylenediamine and
the acyl chloride of cyclohexylphenylacetic acid led to
expected compound 44i, which was cyclized in benz-
imidazole 44 in neat acetic acid at reflux (Scheme 7).

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4495
NH2
NO2
NO2
NO2
NH2
NH2
NH2
N
N
a
b
c
H
N
N
H
N
H
44i
O
45
44
e
d
O
HN
CH3
N
HN
N
N
H
N
H
47
46
Scheme 7. Reagents and conditions: (a) cyclohexylphenylacetyl chloride, DIEA, CH2Cl2, rt, 12 h; (b) neat AcOH, reflux, 5 h; (c) Fe, 12 N HCl,
EtOH, reflux, 6 h; (d) CH3CHO, NaBH3CN, MeOH, rt, 24 h; (e) Fe, neat AcOH, reflux, 5 h.
X
H
Cl
NH2
NO2
NH2
NO2
N
N
+
COOMe
a
b
X
COOMe
COOH
64a X = CH2
65a X = N-Me
66a X = O
67a X = S
19a
Scheme 12. Reagents and conditions: K2CO3, DMF, reflux, 24 h.
Scheme 8. Reagents and conditions: (a) 1-bromohexane, NaH, THF,
rt, 12 h; (b) NaOH 1 M/MeOH 1:1, reflux, 4 h.
COOH
X
N
COOMe
+
B(OH)2
N
a, b
N
+
N
MeO
N
MeO
H
25a
Br
Cl
N
52
73 X = O
74 X = CH2
COOH
X
COOMe
B(OH)2
a, b
+
Scheme 13. Reagents and conditions: NaH, KI, THF, reflux, 12 h
(compound 73) or 6 h (compound 74).
Br
R
26-29a
R
Scheme 9. Reagents and conditions: (a) KF, Pd(OAc)2, 2-(di-tert-
butylphosphino)biphenyl, THF, N2, rt, 24 h; (b) NaOH, MeOH,
reflux, 6 h.
When the cyclization conditions adoped for monoacy-
lated precursors from 2-nitroaniline: neat acetic acid at
reflux in the presence of iron, were used, only compound
47, in which the newly formed amino group is acylated,
was obtained. The amino derivative 45 was eventually
synthesized by action of iron and 12 N HCl in refluxing
ethanol. Functionalization of the amino group in com-
pound 45 by an ethyl group was performed using acetal-
dehyde and sodium cyanoborohydride in MeOH and led
to analog 46 (Scheme 7).
Br
NRR'
COOMe
NRR'
COONa
COOMe
a
b
33-38a
Scheme 10. Reagents and conditions: (a) RR0NH, DIEA, CH3CN, rt,
4 h; (b) NaOH, MeOH, reflux, 8 h.
N
N
N
N
a
H
b
COONa
N
N
H
MeO
O
MeO
NH2
33a
72
Scheme 11. Reagents and conditions: (a) 3-methoxy-o-phenylenediamine, PyBroP, DIEA, CH2Cl2, rt, 12 h; (b) 4 N HCl, MeOH/dioxane 1:1, reflux,
72 h.

4496
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
ary amine in the presence of potassium carbonate in
refluxing DMF led to corresponding amines 64–67a
(Scheme 12).22
R
N
N
N
R
N
N
H
N
H
N
H
R'
NRR'
Both analogs 73 and 74, with a substituent in N-1 posi-
tion, were synthesized by substitution of the chlorine
atom of N-(2-chloroethyl)morpholine or 1-(2-chloroeth-
yl)piperidine, respectively, by the amino group of com-
pound 52 in the presence of sodium hydride and
potassium iodide in refluxing THF (Scheme 13).
A series
C series
B series
NH
N
O
N
N
O
D series
3. Results and discussion
R1
N
N
3.1. Activation of the AMP-kinase
R2
N
R
Y
MeO
N
H
R3
X
Compounds were assayed for activation of the AMP-ki-
nase on fresh rat hepatocytes. Compounds were incu-
bated with hepatocytes during 1 h. The level of
AMPK activation was determined on cell lysates by
measurement of phosphorylation of a peptide substrate
(SAMS peptide, a synthetic peptide substrate with the
amino acid sequence HMRSAMSGLHLVKRR).23
The biochemical results are presented as relative enzyme
activity (enzyme activity relative to buffer blank) (Tables
1–6).
R'
F series
E series
Figure 2. Structures of S27847 analogs.
The saponification of the methyl ester in compound 56,
by treatment with aqueous NaOH 1 M in refluxing
methanol, led to benzimidazole 57.
Some starting materials, which were not commercially
available, were synthesized for the purpose of this study.
In the case of compound 19, the acid 19a was obtained
by reaction between methylphenylacetate and 1-bromo-
hexane (Scheme 8). The acidic hydrogen in the a-posi-
tion of the ester group was removed in the presence of
sodium hydride as a base to form the corresponding
carbanion, which was reacted with 1-bromohexane.20
A treatment with a mixture of NaOH 1 M/MeOH
allowed the formation of the carboxylate.
Compounds 2–32 of series A (Table 1) were designed
with the aim of evaluating the optimal substituent at
the C-2 position. Three compounds showed activities
higher than that of the lead compound S27847 (or 1):
compounds 19 (R: 1-phenylheptyl), 20 (R: trans-2-phe-
nylcyclopropyl) and 23 (R: biphenyl-2-yl). In some
cases, minor structural modifications led to a complete
loss of activity, for example in the case of compound
18 that differs from 1 only by the cyclopentyl/cyclohexyl
replacement. Activation of AMPK is slightly increased
for the linear analog 19 of benzimidazole S27847 (or
1). As compound 23 possessed the advantage of being
more favourable for modifications, several other analogs
were synthesized (compounds 24–32) and revealed dif-
ferent behaviours. The para biphenyl derivative 24 was
totally inactive whereas the meta analog 25 revealed an
activity slightly greater than that of the ortho variant
23. Among compounds 26–32, where the second phenyl
moiety was modified, only the replacement by a thiophe-
nyl group (compound 28) resulted in an unaffected activ-
ity in comparison with those of the lead compound
S27847 (or 1) and with compound 23. An interesting
structure–activity relationship could be deduced from
this series of compounds: a phenyl group associated
with another group whether cyclohexyl (compound 1),
cyclopropyl (compound 20), hexyl (compound 19) or
aromatic (compounds 23, 25 and 28), in C-2 position ap-
pears to impact an AMPK activity.
Acids 25–29a, commercially unavailable, were obtained
using a Suzuki coupling starting from the corresponding
boronic acid derivatives and methyl 3-bromobenzoate
for compound 25a or methyl 2-bromobenzoate for com-
pounds 26–29a (Scheme 9). The conditions described by
Buchwald and co-workers were applied using potassium
fluoride as a base, palladium acetate as a catalyser and
2-(di-tert-butylphosphino)biphenyl as
a
ligand in
THF.21 A final basic treatment using aqueous NaOH
in refluxing methanol led to saponification of the ester
function.
The substitution of the bromine atom of methyl-
a-bromophenyl acetate by the appropriate amine,
protected if necessary, in the presence of DIEA in aceto-
nitrile, and subsequent basic treatment in methanol
afforded the corresponding sodium salts 33–38a com-
mercially unavailable (Scheme 10).
The coupling reaction between the sodium salt 33a and 3-
methoxy-o-phenylenediamine using PyBroP activation
andDIEAasbaseindichloromethaneaffordedtheexpect-
edmonocylatedprecursor,whichwascyclizeddirectlyinto
compound72at reflux in the presence ofHCl(Scheme 11).
With the aim of introducing minor structural modifica-
tions on S27847 (or 1), a series of compounds, in which
the phenyl group was conserved and the cyclohexyl
group replaced by an amine, was designed (B series,
compounds 33–38, Table 2). Compounds 33 and 38,
piperidine and cyclohexylamine analogs, respectively,
possessed an interesting activity with respect to the lead
Another substitution reaction of the chlorine atom of 5-
chloro-2-nitroaniline by the appropriate cyclic second-

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4497
compound, including an improvement of solubility.
However, like in the preceding series, minor structural
modifications resulted in a complete loss of activity,
for example, the replacement of piperidine by homopi-
peridine (compound 35) or by morpholine (compound
34) clearly illustrates that effect. In the two series A
and B the structural modifications around S27847 (or
1) led to the introduction of preliminary SAR and to
the identification of novel activators of AMPK (com-
pounds 33 and 38) presenting more ‘lead-like’ properties
(better solubility, lower lipophilicity (clogP)) than those
of compound S27847.
ine and pyridine derivatives 49 and 50 were also inactive.
An additional phenyl group on the benzimidazole pat-
tern (compound 63) affected strongly the activity. Com-
pound 45, which possessed a primary amino group in
position 7, presented a good activity as compared to that
of the lead compound S27847 (or 1). The ethyl analog
46, synthesized with the aim of avoiding the potential
toxicity of benzimidazole 45 due to aromatic amine
function, demonstrated a slightly lower activity, whereas
its acetyl derivative 47 was totally inactive. With com-
pounds 64–67, which possessed an alicyclic amine in po-
sition 5, the activation of AMPK was equivalent to the
lead compound S27847 (or 1), only in the case of the
morpholine derivative 66.
In the series C, the carbon atom in position 2 of benz-
imidazole was replaced by a nitrogen atom (compounds
39 and 40, Table 3). Two aromatic amines were selected:
one primary with 2-(1-piperidino)aniline (compound 40)
and one secondary with N-cyclohexylaniline (compound
39), while the phenyl group was preserved in position 2
of benzimidazole, as with active compounds of series A.
Benzimidazole 39, analog of compound S27847 (or 1)
with a nitrogen atom in position 2, possessed an activity
similar to that of the latter. Compound 40 showed a
slightly lower activity. Consequently, the replacement
of the carbon atom in position 2 of benzimidazole by
a secondary or tertiary amine seemed to be a favourable
outcome though activity was unaffected.
In the last series of compounds (E series, compounds 44–
67), the benzimidazole 52, possessing a methoxy group in
position 5, was the more potent activator of AMPK.
With the aim of increasing activity, a combination of
methoxy group in position 5 and optimal groups in C-2
position from A series was evaluated: with an ortho-bi-
phenyl group for compound 68 and with phenylpiperid-
inylmethyl group for compound 72 (F series, Table 6). In
parallel, several analogs of compound 68 were synthe-
sized (compounds 69–71, F series, Table 6). Compared
with the lead compound S27847 (or 1), only compounds
71 and 72 presented a better activation of AMPK. In the
case of analog 72, a combination of compounds 33 and
52, the replacement of the cyclohexyl group by a piperi-
dine did not improve activity when compared with com-
pound 52. The effect of the alkylation of nitrogen atom in
position 1 was studied by substitution of compound 52
with amino chains: 1-ethylmorpholine group for com-
pound 73 and 1-ethylpiperidinyl group for compound
74. In both cases, the modification led to a complete loss
of activity. This result confirmed the requirement for the
presence of a hydrogen bond donating atom at position 1
to preserve activity.
With the aim of studying the influence of benzimidazolyl
pattern on activity, isosteric replacements were tested.
Three compounds were synthesized: a benzoxazolyl ana-
log in which one of the nitrogen atoms was replaced by
an oxygen atom, a 3,4-dihydroquinazolinyl analog with
a six-membered ring and a 1,2,3,4-tetrahydroisoquinoli-
nyl analog with a larger cycle and only one cyclic nitro-
gen atom (compounds 41–43, respectively, D series,
Table 4). These attempts to replace benzimidazole led
to a total loss of activity. These results showed that there
was an activity-contribution of the nitrogen atom donor
of the hydrogen bound in position 1 (replaced by an
oxygen atom, acceptor of hydrogen bound in compound
41) and of the aromaticity of the structure (which was
absent in compound 42) as well.
In conclusion, the overall function of AMPK in regulat-
ing energy balance makes it an attractive target for ther-
apeutic agents aimed at reducing body weight. However
studies investigating the physiological consequences of
AMPK activation relied until now solely on few very
weak pharmacological AMPK activators like AICAR.
Here, we described new activators of higher potency of
this kinase and structure–activity relationships. Their
exact molecular mode of action still remains to be eluci-
dated. However, being either direct or indirect25 activa-
tors of AMPK, this novel class of AMPK activators
might facilitate the elucidation of a role of AMPK in
the regulation of cellular processes and might represent
a promising therapeutic potential in the treatment of
obesity and type 2 diabetes mellitus.
In a second step, our research consisted in the study of
the influence of structural modifications of the phenyl
moiety of benzimidazole while maintaining the cyclo-
hexylphenylmethyl group at C-2 position (compounds
44–67, E series, Table 5). In this series, a methoxy group
in position 5 only (equivalent to position 6 when N-1 is
not substituted, compound 52) or in both positions 5
and 6 (compound 61) proved favourable for activity.
For the methyl group, only the substitution in positions
5 and 6 simultaneously was favourable (compound 60).
A methyl group in position 4 (compound 48), in position
5 (compound 51) or in positions 4 and 5 (compound 59)
led to a loss of activity. The introduction of electron-
withdrawing groups appeared to be detrimental to activ-
ity (compounds 44: NO2, 55: CF3, 56: COOMe and 57:
COOH). Except for the case of compound 54 (Cl in po-
sition 5), the introduction of electrodonating mesomer
groups proved unfavourable for activity (compounds
53: F, 58: OCOMe and 62: Cl in positions 5 and 6). Pur-
4. Experimental
4.1. Chemistry
All reactions were monitored using thin-layer chroma-
tography carried out on 0.2 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent.

4498
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
1H- and 13C NMR spectra were measured in DMSO-d6
using a Brucker 300 MHz spectrometer. Mass spectra
¨
(di-tert-butylphosphino)biphenyl (3 mol %) and appro-
priate boronic acid (3 mmol, 2 equiv). After stirring
the mixture for 24 h under N2 and at room temperature,
the solvent was evaporated, the residue diluted with
CH2Cl2, the organic layer washed with aqueous NaH-
CO3 5%, dried over MgSO4 and concentrated. The res-
idue was diluted with 10 mL of methanol in the presence
of aqueous NaOH 2.5 M (900 lL, 2.25 mmol,
1.5 equiv). Following reflux of the mixture for 6 h, the
methanol was evaporated, the residue acidified with
aqueous HCl 1 M and the expected acid extracted with
CH2Cl2. The solvent was evaporated to give expected
compound, directly used for synthesis of corresponding
monoacylated precursor.
were recorded on a Maldi mass spectrometer (MAL-
DI-TOF-MS). Chromatography was carried out using
silica gel 60 (230–400 mesh ASTM) from Macherey-
Nagel. Thick-layer chromatography (TLC) was per-
formed using silica gel from Merck and the compounds
were extracted from silica gel using the following sol-
vent system: CH2Cl2/MeOH 80:20. The melting point
(mp) of benzimidazoles was determined on a Buchi
¨
535 capillary mp apparatus and is uncorrected. The
purity of final compounds was checked by high pres-
sure liquid chromatography (PHPLC) with a C18 Xterra
or TSK GEL column. Analytical HPLC was per-
formed on a Shimadzu system equipped with a UV
detector set at 254 nm. Compounds were dissolved in
MeOH and injected through a 50 lL loop. The follow-
ing eluent systems were used: A (H2O/TFA, 100:0.05)
and B (CH3CN/H2O/TFA, 80:20:0.05). HPLC reten-
tion times (tR) were obtained at flow rates of 1 mL/
min using different methods: a gradient run from
100% eluent A to 100% eluent B in 7 min 30 s for
method A and in 10 min for method B.
4.1.4. General procedure D for synthesis of non-commer-
cially available sodium salts 33–38a. To a solution of
methyl-a-bromophenyl acetate (500 mg, 2.18 mmol,
1 equiv) in 5 mL of acetonitrile were added DIEA
(970 lL, 2.18 mmol, 1 equiv) and appropriate amine
(2.62 mmol, 1.2 equiv). After stirring the mixture for
4 h at room temperature, the solvent was evaporated.
To a solution of this residue in 5 mL of methanol was
added aqueous NaOH 2.5 M (1.75 mL, 4.36 mmol,
2 equiv). Following reflux of the mixture for 8 h, the sol-
vent was evaporated to afford expected acid which was
not isolated.
4.1.1. General procedure A for synthesis of monoacylated
precursors 1i, 4–5i, 7i, 10–11i, 14–15i, 17–18i, 20i, 23i
and 30–32i. To
a solution of appropriate acid
(5.77 mmol, 1 equiv) in 23 mL of DMF were added a
solution of DCC 1 M in CH2Cl2 (2.89 mL, 2.89 mmol,
0.5 equiv), DIEA (1.1 mL, 6.35 mmol, 1.1 equiv) and
o-phenylenediamine (250 mg, 2.31 mmol, 0.4 equiv).
After stirring for 12 h at room temperature, the mixture
was filtered and the solvent evaporated. The residue was
diluted with CH2Cl2, washed with aqueous NaHCO3
5%, dried over MgSO4, concentrated and the residue
purified by TLC or by trituration in Et2O to afford
expected monoacylated compound.
4.1.5. General procedure E for synthesis of monoacylated
precursors 3i, 6i, 22i, 25–29i, 33–36i and 38i. To a solu-
tion of appropriate acid (3.0 mmol, 1 equiv) in 12 mL
of dry CH2Cl2 were added DIEA (1.25 mL, 7.5 mmol,
2.5 equiv), PyBrop (2.1 g, 4.5 mmol, 1.5 equiv), and then
o-phenylenediamine (650 mg, 6.0 mmol, 2 equiv). After
stirring for 12 h at room temperature, the mixture was
washed with aqueous NaHCO3 5%, dried over MgSO4,
concentrated and the residue purified by TLC or by trit-
uration in a Et2O/pentane mixture to afford expected
monoacylated compound.
4.1.2. General procedure B for synthesis of monoacylated
precursors 2i, 12–13i and 24i. To a solution of acid
(0.94 mmol, 1 equiv) in 5 mL of dry CH2Cl2 was add-
ed thionyl chloride (172 lL, 2.35 mmol, 2.5 equiv).
Following reflux of the mixture for 1 h 30 min, the
solvent and the excess of thionyl chloride were evapo-
rated. To a solution of this residue in 3 mL of dry
THF was added a solution of 2-nitroaniline (195 mg,
1.41 mmol, 1.5 equiv) and pyridine (380 lL, 4.7 mmol,
5 equiv) in 3 mL of dry THF. After stirring the mix-
ture for 4 h at room temperature, the solvent was
evaporated, the residue diluted with CH2Cl2 and
washed with aqueous KHSO4 5%, aqueous NaHCO3
5% and aqueous saturated NaCl. The organic layer
was dried over MgSO4, concentrated and the residue
purified by trituration in a Et2O/pentane mixture or
by TLC to afford expected compound. In the case
of commercially available acyl chloride, the first step
was not necessary.
4.1.6. General procedure F for synthesis of monoacylated
precursors 48i, 51–52i, 54–56i, 59–63i and 68–71i. To a
solution of appropriate acid (2.47 mmol, 2.4 equiv) in
10 mL of THF were added a solution of DCC 1 M in
CH2Cl2 (1.24 mL, 1.24 mmol, 1.2 equiv), DIEA
(430 lL, 2.47 mmol, 2.4 equiv) and appropriate substi-
tuted o-phenylenediamine (1.03 mmol, 1 equiv). After
stirring for 12 h at room temperature, the mixture was
filtered and the solvent evaporated. The residue was
diluted with CH2Cl2, washed with aqueous NaHCO3
5%, dried over MgSO4, concentrated and the residue
purified by TLC to afford expected monoacylated
compound.
4.1.7. General procedure G for synthesis of commercially
unavailable substituted 2-nitroanilines 64–67a. To a solu-
tion of 5-chloro-2-nitroaniline (500 mg, 2.9 mmol,
1 equiv) in 10 mL of DMF were added appropriate
amine (11.6 mmol, 4 equiv) and K2CO3 (812 mg,
5.8 mmol, 2 equiv). Following reflux of the mixture for
24 h, the solvent was evaporated, the residue diluted
with CH2Cl2, washed with aqueous NaHCO3 5%, dried
over MgSO4, concentrated and the residue purified by
4.1.3. General procedure C for synthesis of non-commer-
cially available acids 25–29a. To a solution of methyl 2-
bromobenzoate or methyl 3-bromobenzoate (1.5 mmol,
1 equiv) in 10 mL of THF were added KF (261 mg,
4.5 mmol, 3 equiv), palladium acetate (1.5 mol %), 2-

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4499
TLC or by trituration in a Et2O/pentane mixture to af-
ford expected substituted 2-nitroaniline.
dure A starting from phenylacetic acid and was
obtained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 51%; white solid; Rf (CH2Cl2/MeOH
9.7:0.3): 0.55; tR (C18 Xterra, method B): 4.02 min,
4.1.8. General procedure H for synthesis of monoacylated
precursors 53i, 58i and 64–67i. To a solution of cyclo-
hexylphenylacetic acid (785 mg, 3.6 mmol, 1.2 equiv) in
5 mL of dry CH2Cl2 was added thionyl chloride
(1.3 mL, 18 mmol, 6 equiv). After stirring the mixture
for 1 h at room temperature, the solvent and the excess
of thionyl chloride were evaporated. To a solution of
this residue in 20 mL of dry CH2Cl2 were added DIEA
(1.04 mL, 6 mmol, 2 equiv) and appropriate substituted
2-nitroaniline (3 mmol, 1 equiv). After stirring for 12 h
at room temperature, the mixture was washed with
aqueous NaHCO3 5%. The organic layer was dried over
MgSO4, concentrated and the residue purified by TLC
to afford expected compound.
1
PHPLC: 99%; H NMR d: 9.35 (s, 1H, NH), 7.32–7.21
(m, 5H, H phenyl), 7.12 (m, 1H, ArH), 6.87 (m, 1H,
ArH), 6.69 (m, 1H, ArH), 6.50 (m, 1H, ArH), 4.80 (s,
2H, NH2), 3.62 (s, 2H, CH2); 13C NMR d: 169.9,
142.8, 137.2, 129.9, 129.1, 127.3, 126.8, 126.1, 124.1,
117.0, 116.7, 43.5; MALDI-TOF-MS m/z: 227 [M+H]+.
4.1.13. N-(2-Aminophenyl)-2-cyclohexylacetamide (5i).
Compound 5i was prepared according to the general
procedure A starting from cyclohexylacetic acid and
was obtained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 76%; white solid; Rf (CH2Cl2/MeOH
9.7:0.3): 0.80; tR (C18 Xterra, method B): 4.83 min,
1
PHPLC: 95%; H NMR d: 9.10 (s, 1H, NH), 7.14 (m,
4.1.9.
N-(2-Aminophenyl)-2-cyclohexyl-2-phenylaceta-
1H, ArH), 6.88 (m, 1H, ArH), 6.69 (m, 1H, ArH),
6.53 (m, 1H, ArH), 4.78 (s, 2H, NH2), 2.18
(d, J = 6.8 Hz, 2H, CH2), 1.73–0.95 (m, 11H, H cyclo-
hexyl); 13C NMR d: 171.2, 157.5, 142.7, 126.5, 126.1,
117.1, 116.8, 44.5, 35.7, 34.2, 33.4, 26.7, 26.5, 25.3;
MALDI-TOF-MS m/z: 233 [M+H]+.
mide (1i). Compound 1i was prepared according to the
general procedure A starting from cyclohexylphenylace-
tic acid and was obtained after purification by TLC
(CH2Cl2/MeOH 9.9:0.1). Yield: 42%; white solid; Rf
(CH2Cl2/MeOH 9.9:0.1): 0.50; tR (TSK gel, method
B): 6.82 min, PHPLC: 99%; 1H NMR d: 9.30 (s, 1H,
NH), 7.33–7.30 (m, 2H, ArH), 7.26–7.21 (m, 2H,
ArH), 7.18–7.12 (m, 1H, ArH), 7.02 (m, 1H, ArH),
6.80 (m, 1H, ArH), 6.60 (m, 1H, ArH), 6.43 (m, 1H,
ArH), 4.60 (s, 2H, NH2), 3.31 (d, J = 10.7 Hz, 1H,
CH), 1.95–1.00 (m, 11H, H cyclohexyl); 13C NMR d:
172.3, 142.5, 140.4, 129.1, 127.5, 126.7, 125.9, 124.1,
117.1, 116.9, 59.2, 40.6, 32.1, 31.1, 26.8, 26.3; MAL-
DI-TOF-MS m/z: 309 [M+H]+.
4.1.14. N-(2-Aminophenyl)-2-naphthalen-2-ylacetamide
(6i). Compound 6i was prepared according to the gener-
al procedure E starting from 2-naphthylacetic acid, but
was not purified and directly cyclized.
4.1.15. N-(2-Aminophenyl)-2-naphthalen-1-ylacetamide
(7i). Compound 7i was prepared according to the general
procedure A starting from 1-naphthylacetic acid and was
obtained after purification by TLC (AcOEt/cyclohexane
7:3). Yield: 58%; light yellow solid; Rf (CH2Cl2/MeOH
4.1.10. N-(2-Nitrophenyl)-2,2-diphenylacetamide (2i).
Compound 2i was prepared according to the general
procedure B starting from diphenylacetic acid and was
obtained after purification by trituration in Et2O. Yield:
70%; yellow solid; Rf (cyclohexane/AcOEt 8:2): 0.50; tR
(C18 Xterra, method B): 8.54 min, PHPLC: 99%; 1H
NMR d: 10.40 (s, 1H, NH), 8.86 (dd, J = 1.3, 8.5 Hz,
1H, ArH), 8.16 (dd, J = 1.5, 8.5 Hz, 1H, ArH), 7.63
(m, 1H, ArH), 7.36 (m, 10H, ArH), 7.16 (m, 1H,
ArH), 5.16 (s, 1H, CH); 13C NMR d: 186.8, 136.3,
129.5, 129.4, 128.6, 128.2, 126.2, 123.9, 122.5, 61.5;
MALDI-TOF-MS m/z: 333 [M+H]+.
9.8:0.2): 0.30; tR (TSK gel, method B): 5.32 min, PHPLC
:
1
99%; H NMR d: 9.48 (s, 1H, NH), 8.16 (d, J = 8.9 Hz,
1H, ArH naphthyl), 7.92 (d, J = 7.4 Hz, 1H, ArH naph-
thyl), 7.83 (d, J = 6.3 Hz, 1H, ArH naphthyl), 7.58–7.44
(m, 4H, ArH naphthyl), 7.14 (d, J = 7.8 Hz, 1H, ArH),
6.88 (t, J = 7.8 Hz, 1H, ArH), 6.70 (d, J = 7.9 Hz, 1H,
ArH), 6.49 (t, J = 7.7 Hz, 1H, ArH), 4.84 (s, 2H, NH2),
4.14 (s, 2H, CH2); 13C NMR d: 169.9, 142.8, 134.2,
133.6, 132.9, 129.3, 128.0, 126.9, 126.8, 126.5, 126.4,
126.2, 125.1, 124.2, 117.0, 116.7, 41.2; MALDI-TOF-
MS m/z: 277 [M+H]+.
4.1.11.
N-(2-Aminophenyl)-2,2-dicyclohexylacetamide
4.1.16. N-(2-Aminophenyl)-2-(1H-indol-3-yl)acetamide
(8i). To a solution of 3-indoleacetic acid (737 mg,
4.21 mmol, 1.3 equiv) in 16 mL of dry CH2Cl2 were add-
ed DIEA (1.12 mL, 6.48 mmol, 2 equiv), PyBroP
(1.96 g, 4.21 mmol, 1.3 equiv) and then o-phenylenedi-
amine (350 mg, 3.24 mmol, 1 equiv). After stirring the
mixture for 12 h at room temperature, the expected
product was precipitated in DCM, filtered and washed
with Et2O to afford compound 8i. Yield: 42%; white sol-
id; Rf (CH2Cl2/MeOH 9.6:0.4): 0.55; tR (TSK gel, meth-
(3i). Compound 3i was prepared according to the gener-
al procedure E starting from dicyclohexylacetic acid and
was obtained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 30%; white solid; Rf (CH2Cl2/MeOH
9.8:0.2): 0,65; tR (C18 Xterra, method B): 7.31 min,
1
PHPLC: 99%; H NMR d: 9.11 (s, 1H, NH), 7.07 (m,
1H, ArH), 6.88 (m, 1H, ArH), 6.70 (m, 1H, ArH),
6.53 (m, 1H, ArH), 4.71 (s, 2H, NH2), 2.09 (t,
J = 7.2 Hz, 1H, CH), 1.68 (m, 12H, CH + CH2), 1.10
(m, 10H, CH2); 13C NMR d: 173.,2, 142.8, 126.6,
126.2, 124.6, 117.2, 116.9, 57.3, 36.9, 31.8, 29.9, 27.1,
27.0, 26.9; MALDI-TOF-MS m/z: 315 [M+H]+.
1
od B): 4.42 min, PHPLC: 99%; H NMR d: 10.85 (s, 1H,
NH indolyl), 9.22 (s, 1H, NH), 7.58 (d, J = 7.7 Hz, 1H,
ArH indolyl), 7.31 (d, J = 8.0 Hz, 1H, ArH indolyl),
7.21 (d, J = 2.3 Hz, 1H, ArH indolyl), 7.10 (dd,
J = 1.3, 7.8 Hz, 1H, ArH), 7.02 (td, J = 1.2, 7.8 Hz,
1H, ArH indolyl), 6.93 (td, J = 0.9, 7.9 Hz, 1H, ArH
4.1.12. N-(2-Aminophenyl)-2-phenylacetamide (4i). Com-
pound 4i was prepared according to the general proce-

4500
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
indolyl), 6.83 (td, J = 1.5, 7.9 Hz, 1H, ArH), 6.65 (dd,
J = 1.3, 7.9 Hz, 1H, ArH), 6.47 (td, J = 1.3, 7.6 Hz,
1H, ArH), 4.75 (s, 2H, NH2), 3.69 (s, 2H, CH2); 13C
NMR d: 170.5, 142.7, 136.9, 126.6, 126.0, 124.7, 121.8,
119.5, 119.2, 117.1, 116.7, 112.2, 33.9; MALDI-TOF-
MS m/z: 266 [M+H]+.
chloride and was obtained after purification by TLC
(cyclohexane/AcOEt 7:3). Yield: 33%; yellow solid; Rf
(cyclohexane/AcOEt 8:2): 0.50; tR (TSK gel, method
1
A): 7.58 min, PHPLC: 99%; H NMR d: 10.70 (s, 1H,
NH), 8.02 (m, 1H, ArH), 7.88 (m, 2H, ArH), 7.83–
7.72 (m, 2H, ArH), 7.44–7.37 (m, 3H, ArH), 2.64 (t,
J = 7.4 Hz, 2H, CH2), 1.64 (m, 2H, CH2), 0.90 (t,
J = 7.3 Hz, 3H, CH3); 13C NMR d: 165.8, 147.6, 143.3,
134.6, 132.3, 131.6, 129.2, 128.4, 126.4, 126.0, 125.6,
37.6, 24.5, 14.2; MALDI-TOF-MS m/z: 285 [M+H]+.
4.1.17. N-(2-Aminophenyl)-2-benzo[b]thiophen-3-ylaceta-
mide (9i). To a solution of benzothiophene-3-acetic acid
(533 mg, 2.77 mmol, 1.2 equiv) in 16 mL of dry CH2Cl2
were added DIEA (0.80 mL, 4.62 mmol, 2 equiv), PyB-
roP (1.29 g, 2.77 mmol, 1.2 equiv) and then o-phenylen-
ediamine (250 mg, 2.31 mmol, 1 equiv). After stirring
the mixture for 12 h at room temperature, the expected
product was precipitated in DCM, filtered, washed with
Et2O and purified by TLC (CH2Cl2/MeOH 9.6:0.4) to
afford compound 9i. Yield: 37%; white solid; Rf
(CH2Cl2/MeOH 9.6:0.4): 0.30; tR (TSK gel, method
B): 5.34 min, PHPLC: 99%; 1H NMR d: 9.37 (s, 1H,
NH), 7.88 (m, 2H, ArH benzothiophenyl), 7.51 (s, 1H,
ArH benzothiophenyl), 7.33 (m, 2H, ArH benzothi-
ophenyl), 7.07 (m, 1H, ArH), 6.79 (m, 1H, ArH), 6.61
(m, 1H, ArH), 6.44 (m, 1H ArH), 4.77 (s, 2H, NH2),
3.85 (s, 2H, CH2); 13C NMR d: 169.1, 162.7, 142.8,
131.4, 126.8, 126.2, 125.4, 125.1, 124.9, 124.1, 123.7,
122.9, 117.0, 116.7, 36.7; MALDI-TOF-MS m/z: 283
[M+H]+.
4.1.21. N-(2-Nitrophenyl)-2-phenylbutyramide (13i).
Compound 13i was prepared according to the general
procedure B starting from commercial 2-phenylbutyryl
chloride, but was not purified and directly cyclized.
4.1.22. N-(2-Aminophenyl)-3-phenylbutyramide (14i).
Compound 14i was prepared according to the general
procedure A starting from 3-phenylbutyric acid and
was obtained after purification by trituration in Et2O.
Yield: 88%; white solid; Rf (CH2Cl2/MeOH 9.7:0.3):
0.55; tR (C18 Xterra, method B): 4.95 min, PHPLC
:
1
99%; H NMR d: 9.10 (s, 1H, NH), 7.33–7.16 (m, 5H,
ArH), 7.03 (dd, J = 1.4, 7.8 Hz, 1H, ArH), 6.87 (td,
J = 1.5, 7.9 Hz, 1H, ArH), 6.67 (dd, J = 1.4, 8.0 Hz,
1H, ArH), 6.50 (td, J = 1.4, 7.7 Hz, 1H, ArH), 4.66 (s,
2H, NH2), 3.26 (m, 1H, CH), 2.58 (m, 2H, CH2), 1.26
(d, J = 6.9 Hz, 3H, CH3); 13C NMR d: 170.4, 146.9,
142.7, 128.9, 127.4, 126.7, 126.5, 126.1, 123.9, 116.7,
116.4, 44.8, 37.0, 22.4; MALDI-TOF-MS m/z: 255
[M+H]+.
4.1.18. 1,2,3,4-Tetrahydronaphthalene-2-carboxylic acid
(2-aminophenyl)amide (10i). Compound 10i was pre-
pared according to the general procedure A starting
from 1,2,3,4 tetrahydro-2-naphthoic acid and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 70%; white solid; Rf (CH2Cl2/MeOH
9.7:0.3): 0.65; tR (C18 Xterra, method B): 5.19 min,
4.1.23. N-(2-Aminophenyl)-2-phenylpropionamide (15i).
Compound 15i was prepared according to the general
procedure A starting from 2-phenylpropionic acid and
was obtained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 72%; white solid; Rf (CH2Cl2/MeOH
9.7:0.3): 0.55; tR (C18 Xterra, method B): 4.42 min,
1
PHPLC: 99%; H NMR d: 9.22 (s, 1H, NH), 7.22 (m,
1H, ArH), 7.19–7.08 (m, 4H, ArH naphthyl), 6.88 (m,
1H, ArH), 6.75 (m, 1H, ArH), 6.56 (m, 1H, ArH),
4.84 (s, 2H, NH2), 2.95-2.77 (m, 5H, CH + 2CH2),
2.10 (m, 2H, CH2); 13C NMR d: 174.5, 142.8, 136.5,
136.3, 129.7, 129.4, 126.7, 126.5, 126.2, 124.3, 117.1,
116.8, 41.6, 32.8, 29.1, 27.3; MALDI-TOF-MS m/z:
267 [M+H]+.
1
PHPLC: 99%; H NMR d: 9.21 (s, 1H, NH), 7.35–7.31
(m, 2H, ArH), 7.28–7.22 (m, 2H, ArH), 7.19–7.13 (m,
1H, ArH), 7.06–7.02 (m, 1H, ArH), 6.83–6.78 (m, 1H,
ArH), 6.64–6.60 (m, 1H, ArH), 6.47–6.42 (m, 1H,
ArH), 4.68 (s, 2H, NH2), 3.80 (q, J = 7.0 Hz, 1H, CH),
1.34 (d, J = 7.0 Hz, 3H, CH3); 13C NMR d: 173.1,
143.1, 142.7, 129.2, 128.3, 128.1, 127.5, 126.7, 126.1,
124.1, 117.1, 116.7, 46.2, 19.5; MALDI-TOF-MS m/z:
241 [M+H]+.
4.1.19. 9H-Fluorene-9-carboxylic acid (2-aminophenyl)
amide (11i). Compound 11i was prepared according to
the general procedure A starting from 9-fluorenecarb-
oxylic acid and was obtained after purification by tritur-
ation in Et2O. Yield: 63%; white solid; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.65; tR (C18 Xterra, method B):
4.1.24. N-(2-Aminophenyl)-2-iodobenzamide (16i). To a
solution of 2-iodobenzoic acid (6.2 g, 25 mmol, 1 equiv)
in 100 mL THF were added a solution of DCC 1 M in
CH2Cl2 (12.5 mL, 12.5 mmol, 0.5 equiv), DIEA
(4.3 mL, 25 mmol, 1 equiv) and o-phenylenediamine
(1.08 g, 10 mmol, 0.4 equiv). After stirring for 12 h at
room temperature, the mixture was filtered and the sol-
vent evaporated. The residue was diluted with CH2Cl2,
washed with aqueous NaHCO3 5%, dried over MgSO4
and concentrated. Compound 16i was not purified and
directly cyclized.
1
5.85 min, PHPLC: 99%; H NMR d: 9.86 (s, 1H, NH),
7.88 (m, 2H, ArH), 7.65 (m, 2H, ArH), 7.44–7.34 (m,
4H, ArH), 7.17 (m, 1H, ArH), 6.94–6.89 (m, 1H,
ArH), 6.76 (m, 1H, ArH), 6.57–6.51 (m, 1H, ArH),
5.07 (s, 1H, CH), 4.90 (s, 2H, NH2), 2.95-2.77 (m, 5H,
CH + 2 CH2), 2.10 (m, 2H, CH2); 13C NMR d: 169.5,
143.8, 142.9, 142.3, 128.6, 128.1, 127.1, 126.4, 125.8,
124.1, 121.0, 117.1, 116.8, 55.7; MALDI-TOF-MS m/z:
301 [M+H]+.
4.1.20. N-(2-Nitrophenyl)-4-propylbenzamide (12i). Com-
pound 12i was prepared according to the general proce-
dure B starting from commercial 4-propylbenzoyl
4.1.25. 1-Phenylcyclopentanecarboxylic acid (2-amino-
phenyl) amide (17i). Compound 17i was prepared
according to the general procedure A starting from 1-

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4501
phenyl-1-cyclopentanecarboxylic acid, but was not puri-
fied and directly cyclized.
60%; light yellow solid; Rf (CH2Cl2/MeOH 9.7:0.3):
0.70; tR (TSK gel, method A): 4.75 min, PHPLC: 99%;
1H NMR d: 9.24 (s, 1H, NH), 7.10 (d, J = 7.9 Hz, 1H,
ArH), 6.92 (td, J = 1.4, 7.9 Hz, 1H, ArH), 6.74 (dd,
J = 1.4, 7.9 Hz, 1H, ArH), 6.56 (td, J = 1.3, 7.7 Hz,
1H, ArH), 4.70 (s, 2H, NH2), 3.80 (d, J = 12.5 Hz, 1H,
CH), 2.13 (d, J = 13.7 Hz, 1H, CH2), 1.74–1.58 (m,
3H, CH2), 1.38 (m, 13H, CH2 + CH3); 13C NMR d:
126.9, 126.4, 117.4, 117.0, 41.6, 28.9, 28.4, 25.1, 20.5;
MALDI-TOF-MS m/z: 320 [M+H]+ and 220 [MꢀBoc].
4.1.26. N-(2-Aminophenyl)-2-cyclopentyl-2-phenylaceta-
mide (18i). Compound 18i was prepared according to
the general procedure A starting from a-phenylcycl-
opentylacetic acid and was obtained after purification
by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 56%; white sol-
id; Rf (CH2Cl2/MeOH 9.8:0.2): 0.55; tR (TSK gel, meth-
1
od B): 6.19 min, PHPLC: 99%; H NMR d: 9.38 (s, 1H,
NH), 7.44 (m, 2H, ArH), 7.32 (m, 3H, ArH), 7.24 (m,
1H, ArH), 7.09 (m, 1H, ArH), 7.88 (m, 1H, ArH),
6.69 (m, 1H, ArH), 6.52 (m, 1H, ArH), 4.70 (s, 2H,
NH2), 3.44 (d, J = 11.0 Hz, 1H, CH), 2.57 (m, 1H, CH
cyclopentyl), 1.64–1.33 (m, 8H, CH2 cyclopentyl); 13C
NMR d: 172.5, 142.6, 141.4, 129.1, 128.9, 127.5, 126.7,
125.9, 124.1, 117.1, 116.8, 58.4, 43.5, 31.8, 31.1, 25.5,
25.2; MALDI-TOF-MS m/z: 295 [M+H]+.
4.1.30. Biphenyl-2-carboxylic acid (2-aminophenyl)amide
(23i). Compound 23i was prepared according to the gen-
eral procedure A starting from 2-biphenylcarboxylic
acid and was obtained after purification by TLC
(CH2Cl2/MeOH 9.7:0.3). Yield: 47%; white solid; Rf
(CH2Cl2/MeOH 9.7:0.3): 0.50; tR (C18 Xterra, method
1
B): 5.35 min, PHPLC: 95%; H NMR d: 7.63–7.31 (m,
9H, ArH), 7.99 (m, 1H, ArH), 6.88 (m, 1H, ArH),
6.67 (m, 1H, ArH), 6.50 (m, 1H, ArH), 4.66 (s, 2H,
NH2); 13C NMR d: 168.9, 143.3, 141.1, 140.1, 138.1,
130.7, 130.4, 129.3, 129.2, 128.8, 128.2, 128.0, 127.1,
126.5, 123.8, 116.8, 116.6; MALDI-TOF-MS m/z: 289
[M+H]+.
4.1.27. 2-Phenyloctanoic acid (2-aminophenyl)amide
(19i). To a solution of methylphenylacetate (500 mg,
3.33 mmol, 1 equiv) in 10 mL THF were added NaH
(60% suspension, 200 mg, 4.99 mmol, 1.5 equiv), washed
previously with hexane, and 1-bromohexane (560 lL,
3.99 mmol, 1.2 equiv). After stirring the mixture for
12 h at room temperature, the solvent was evaporated,
the residue diluted with CH2Cl2, washed with aqueous
HCl 1 M and with water, dried over MgSO4 and concen-
trated. The ester was diluted with 10 mL of a NaOH
1 M/MeOH 1:1 mixture. Following reflux for 4 h, the
mixture was concentrated, acidified with aqueous HCl
1 M, extracted with CH2Cl2, the organic layer dried over
MgSO4 and concentrated to afford compound 19a. To a
solution of the crude acid 19a (3.3 mmol, 1 equiv) in
15 mL of CH2Cl2 were added DIEA (1.4 mL,
8.25 mmol, 2.5 equiv), PyBrop (2 g, 4.3 mmol, 1.3 equiv)
and o-phenylenediamine (464 mg, 4.3 mmol, 1.3 equiv).
After stirring for 12 h at room temperature, the mixture
was washed with aqueous NaHCO3 5%, dried over
MgSO4 and concentrated to afford compound 19i,
which was not purified and directly cyclized.
4.1.31. Biphenyl-4-carboxylic acid (2-nitrophenyl)amide
(24i). Compound 24i was prepared according to the gen-
eral procedure B starting from commercial 4-biphenyl-
carbonyl chloride, but was not purified and directly
cyclized.
4.1.32. Biphenyl-3-carboxylic acid (2-aminophenyl)amide
(25i). Compound 25i was prepared according to the gen-
eral procedure E starting from biphenyl-3-carboxylic
acid 25a, synthesized according to the general procedure
C and was obtained after purification by TLC (CH2Cl2/
MeOH 9.9:0.1). Yield: 73%; white solid; Rf (CH2Cl2/
MeOH 9.9:0.1): 0.60; tR (TSK gel, method A):
1
5.16 min, PHPLC: 99%; H NMR d: 9.88 (s, 1H, NH),
8.29 (s, 1H, ArH biphenyl), 7.97 (d, J = 7.7 Hz, 1H,
ArH biphenyl), 7.88 (d, J = 7.7 Hz, 1H, ArH biphenyl),
7.79 (m, 2H, ArH biphenyl), 7.61 (t, J = 7.7 Hz, 1H,
ArH biphenyl), 7.51 (m, 2H, ArH biphenyl), 7.41 (m,
1H, ArH biphenyl), 7.20 (dd, J = 1.1, 7.8 Hz, 1H,
ArH), 7.03 (td, J = 1.5, 7.4 Hz, 1H, ArH), 6.87 (dd,
J = 1.4, 7.9 Hz, 1H, ArH), 6.70 (td, J = 1.0, 7.6 Hz,
1H, ArH), 4.80 (s, 2H, NH2); 13C NMR d: 140.8,
140.2, 135.8, 130.2, 129.6, 128.4, 127.6, 127.5, 127.3,
126.6, 118.1, 117.5; MALDI-TOF-MS m/z: 289
[M+H]+.
4.1.28. 2-Phenylcyclopropanecarboxylic acid (2-amino-
phenyl)amide (20i). Compound 20i was prepared accord-
ing to the general procedure
A using trans-2-
phenylcyclopropane-1-carboxylic acid and was obtained
after purification by TLC (CH2Cl2/MeOH 9.8:0.2).
Yield: 54%; light yellow solid; Rf (CH2Cl2/MeOH
9.8:0.2): 0.55; tR (TSK gel, method A): 4.31 min, PHPLC
:
1
95%; H NMR d: 9.48 (s, 1H, NH), 7.32–7.16 (m, 6H,
5H phenyl + 1H ArH), 6.88 (td, J = 1.4, 7.9 Hz, 1H,
ArH), 6.71 (dd, J = 1.4, 7.9 Hz, 1H, ArH), 6.53 (td,
J = 1.3, 7.7 Hz, 1H, ArH), 4.84 (s, 2H, NH2), 2.35 (m,
1H, CH), 2.15 (m, 1H, CH), 1.44 (m, 1H, CH2), 1.31
(m, 1H, CH2); 13C NMR d: 170.7, 162.7, 142.3, 141.9,
129.2, 126.9, 126.8, 126.4, 125.5, 124.5, 117.1, 116.8,
27.0, 25.4, 16.7; MALDI-TOF-MS m/z: 253 [M+H]+.
4.1.33. N-(2-Aminophenyl)-2-furan-2-ylbenzamide (26i).
Compound 26i was prepared according to the general
procedure E starting from 2-furan-2-ylbenzoic acid
26a, synthesized according to the general procedure C.
Compound 26i was not isolated and directly cyclized.
4.1.34. 40-Fluorobiphenyl-2-carboxylic acid (2-aminophe-
nyl)amide (27i). Compound 27i was prepared according
to the general procedure E starting from 40-fluorobiphe-
nyl-2-carboxylic acid 27a, synthesized according to the
general procedure C. Compound 27i was not isolated
and directly cyclized.
4.1.29. 2-(2-Aminophenylcarbamoyl)piperidine-1-carbox-
ylic acid tert-butyl ester (22i). Compound 22i was pre-
pared according to the general procedure E starting
from N-Boc-pipecolinic acid and was obtained after
purification by TLC (CH2Cl2/MeOH 9.8:0.2). Yield:

4502
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4.1.35.
N-(2-Aminophenyl)-2-thiophen-2-ylbenzamide
(dd, J = 1.2, 8.0 Hz, 1H, ArH), 6.51 (td, J = 1.3,
7.7 Hz, 1H, ArH), 4.85 (s, 2H, NH2), 4.10 (s, 2H,
CH2); 13C NMR d: 168.9, 143.4, 141.8, 139.8, 132.5,
132.2, 131.2, 130.5, 129.7, 129.5, 129.2, 128.6, 127.2,
126.9, 126.8, 126.6, 124.0, 117.1, 116.9, 38.7; MALDI-
TOF-MS m/z: 303 [M+H]+.
(28i). Compound 28i was prepared according to the gen-
eral procedure E starting from 2-thiophen-2-ylbenzoic
acid 28a, synthesized according to the general procedure
C, and was obtained after purification by TLC (CH2Cl2/
MeOH 9.8:0.2). Yield: 86%; white solid; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.60; tR (TSK gel, method A):
1
4.48 min, PHPLC: 99%; H NMR d: 9.71 (s, 1H, NH),
4.1.39. N-(2-Aminophenyl)-3-bromobenzamide (32i).
Compound 32i was prepared according to the general
procedure A starting from 3-bromobenzoic acid and
was obtained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 46%; white solid; Rf (CH2Cl2/MeOH
7.62–7.44 (m, 5H, 4H ArH phenyl + 1H ArH thiophe-
nyl), 7.28 (dd, J = 1.3, 3.6 Hz, 1H, ArH thiophenyl),
7.20 (dd, J = 1.4, 7.9 Hz, 1H, ArH), 7.10 (dd, J = 3.6,
5.2 Hz, 1H, ArH thiophenyl), 6.97 (td, J = 1.4, 8.1 Hz,
1H, ArH), 6.80 (d, J = 7.9 Hz, 1H, ArH), 6.65 (t,
J = 7.6 Hz, 1H, ArH), 5.35 (s, 2H, NH2); 13C NMR d:
173.1, 168.6, 168.5, 146.3, 141.8, 137.5, 132.0, 130.3,
128.7, 128.4, 128.2, 127.4, 127.0, 126.9, 126.2, 125.8,
118.5, 117.7; MALDI-TOF-MS m/z: 295 [M+H]+.
9.8:0.2): 0.70; tR (TSK gel, method A): 4.57 min, PHPLC
:
1
99%; H NMR d: 9.74 (s, 1H, NH), 8.17 (s, 1H, ArH
phenyl), 7.97 (d, J = 7.8 Hz, 1H, ArH phenyl), 7.77 (d,
J = 7.9 Hz, 1H, ArH phenyl), 7.48 (t, J = 7.8 Hz, 1H,
ArH phenyl), 7.13 (dd, J = 1.0, 7.7 Hz, 1H, ArH), 6.97
(td, J = 1.5, 7.9 Hz, 1H, ArH), 6.77 (dd, J = 1.4,
7.9 Hz, 1H, ArH), 6.58 (td, J = 1.3, 7.6 Hz, 1H, ArH),
4.94 (s, 2H, NH2); 13C NMR d: 144.2, 137.7, 134.9,
131.3, 127.7, 127.6, 123.6, 116.9, 116.8; MALDI-TOF-
MS m/z: 292 [M+H]+.
4.1.36. 40-Methylbiphenyl-2-carboxylic acid (2-aminophe-
nyl)amide (29i). Compound 29i was prepared according
to the general procedure E starting from 40-methylbi-
phenyl-2-carboxylic acid 29a, synthesized according to
the general procedure C, and was obtained after purifi-
cation by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 63%;
white solid; Rf (CH2Cl2/MeOH 9.8:0.2): 0.50; tR (TSK
gel, method A): 5.03 min, PHPLC: 99%; 1H NMR d:
9.43 (s, 1H, NH), 7.61 (dd, J = 1.0, 7.1 Hz, 1H, ArH
biphenyl), 7.52 (dd, J = 1.5, 7.4 Hz, 1H, ArH biphenyl),
7.47–7.41 (m, 2H, ArH biphenyl), 7.39 (d, J = 8.0 Hz,
2H, ArH biphenyl), 7.22 (d, J = 7.9 Hz, 2H, ArH biphe-
nyl), 7.05 (dd, J = 1.4, 7.8 Hz, 1 H, ArH), 6.90 (td,
J = 1.5, 8.0 Hz, 1H, ArH), 6.69 (dd, J = 1.4, 8.0 Hz,
1H, ArH), 6.52 (td, J = 1.4, 7.6 Hz, 1H, ArH), 4.68 (s,
2H, NH2), 2.33 (s, 3H, CH3); 13C NMR d: 168.7,
142.9, 139.8, 137.9, 137.7, 137.2, 130.4, 130.2, 129.5,
128.9, 128.6, 127.5, 126.8, 126.3, 123.6, 116.6, 116.4,
21,3; MALDI-TOF-MS m/z: 303 [M+H]+.
4.1.40. N-(2-Aminophenyl)-2-phenyl-2-piperidin-1-ylace-
tamide (33i). Compound 33i was prepared according to
the general procedure E starting from phenylpiperidin-
1-ylacetic acid 33a, synthesized according to the general
procedure D, and was obtained after purification by
TLC (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1). Yield: 90%;
white solid; Rf (CH2Cl2/MeOH/NH4OH 9.7:0.3:0.1):
0.65; tR (TSK gel, method A): 3.59 min, PHPLC: 99%;
1H NMR d: 9.49 (s, 1H, NH), 7.48 (m, 2H, ArH phen-
yl), 7.37–7.26 (m, 3H, ArH phenyl), 7.17 (m, 1H, ArH),
6.93–6.87 (m, 1H, ArH), 6.73 (m, 1H, ArH), 6.58–6.53
(m, 1H, ArH), 4.65 (s, 2H, NH2), 4.03 (s, 1H, CH),
2.37 (m, 4H, 2 CH2), 1.54 (m, 4H, 2 CH2), 1.23 (m,
2H, CH2); 13C NMR d: 170.3, 142.5, 138.1, 129.6,
129.0, 128.5, 126.7, 125.7, 124.5, 117.5, 117.2, 76.0,
52.8, 26.4, 24.9; MALDI-TOF-MS m/z: 310 [M+H]+.
4.1.37. N-(2-Aminophenyl)-2-phenethylbenzamide (30i).
Compound 30i was prepared according to the general
procedure A starting from 2-bibenzylcarboxylic acid
and was obtained after purification by TLC (CH2Cl2/
MeOH 9.9:0.1). Yield: 98%; white solid; Rf (CH2Cl2/
MeOH 9.8:0.2): 0.75; tR (TSK gel, method B):
4.1.41. N-(2-Aminophenyl)-2-morpholin-4-yl-2-phenylac-
etamide (34i). Compound 34i was prepared according to
the general procedure E starting from morpholin-4-
ylphenylacetic acid 34a, synthesized according to the
general procedure D, but was not isolated.
1
6.67 min, PHPLC: 99%; H NMR d: 9.55 (s, 1H, NH),
7.44 (m, 1H, ArH bibenzyl), 7.31–7.03 (m, 9H, 1
ArH + 8 ArH bibenzyl), 6.85 (t, J = 8.5 Hz, 1H, ArH),
6.67 (dd, J = 1.3, 8.0 Hz, 1H, ArH), 6.49 (td, J = 1.3,
7.8 Hz, 1H, ArH), 4.81 (s, 2H, NH2), 2.92 (m, 2H, 1H
CH2 + 1H CH2), 2.77 (m, 2H, 1H CH2 + 1H CH2);
13C NMR d: 168.9, 143.3, 142.5, 140.3, 137.8, 130.7,
130.4, 129.1, 128.5, 127.1, 126.7, 126.3, 124.2, 117.2,
117.1, 38.2, 36.0; MALDI-TOF-MS m/z: 317 [M+H]+.
4.1.42. N-(2-Aminophenyl)-2-azepan-1-yl-2-phenylaceta-
mide (35i). Compound 35i was prepared according to
the general procedure E starting from azepan-1-ylphe-
nylacetic acid 35a, synthesized according to the general
procedure D, and was obtained after purification by
TLC (CH2Cl2/MeOH/NH4OH 9.9:0.1:0.1). Yield: 44%;
white solid; Rf (CH2Cl2/MeOH 9.9:0.1): 0.50; tR (TSK
gel, method A): 3.78 min, PHPLC: 99%; 1H NMR d:
9.44 (s, 1H, NH), 7.50 (m, 2H, ArH phenyl), 7.41–7.31
(m, 3H, ArH phenyl), 7.18 (d, J = 7.8 Hz, 1H, ArH),
6.90 (t, J = 7.3 Hz, 1H, ArH), 6.72 (d, J = 8.0 Hz, 1H,
ArH), 6.55 (t, J = 7.4 Hz, 1H, ArH), 4.66 (s, 2H,
NH2), 4.38 (s, 1H, CH), 2.65 (m, 4H, 2 CH2), 1.58 (m,
8H, 4 CH2); 13C NMR d: 170.7, 142.3, 139.1, 129.2,
128.9, 128.7, 128.1, 126.5, 126.1, 125.5, 124.2, 117.2,
116.9, 74.4, 53.3, 29.1, 26.9; MALDI-TOF-MS m/z:
324 [M+H]+.
4.1.38. N-(2-Aminophenyl)-2-benzylbenzamide (31i).
Compound 31i was prepared according to the general
procedure A starting from a-phenyl-o-toluic acid and
was obtained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 62%; white solid; Rf (CH2Cl2/MeOH
9.8:0.2): 0.60; tR (TSK gel, method B): 6.08 min, PHPLC
:
1
95%; H NMR d: 9.57 (s, 1H, NH), 7.50 (m, 1H, ArH
phenyl-o-toluic), 7.38–7.07 (m, 9H, 1H ArH + 8H ArH
phenyl-o-toluic), 6.89 (t, J = 8.0 Hz, 1H, ArH), 6.69

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4503
4.1.43. {1-[(2-Aminophenylcarbamoyl)phenylmethyl]pyrr-
olidin-3-yl}carbamic acid tert-butyl ester (36i). Com-
pound 36i was prepared according to the general
procedure E starting from (3-tert-butoxycarbonylami-
nopyrrolidin-1-yl)phenylacetic acid 36a, synthesized
according to the general procedure D, and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 54%; white solid; Rf (CH2Cl2/MeOH
9.8:0.2): 0.35; tR (TSK gel, method A): 4.50 min,
33.5, 33.4, 26.4, 24.9; MALDI-TOF-MS m/z: 324
[M+H]+.
4.1.46. 1-Cyclohexyl-3-(2-nitrophenyl)-1-phenylthiourea
(39i). To a solution of 2-nitrophenylisothiocyanate
(500 mg, 2.77 mmol, 1 equiv) in 10 mL THF was added
N-cyclohexylaniline (969 mg, 5.54 mmol, 2 equiv). After
stirring the mixture for 12 h at room temperature, the
solvent was evaporated, the residue diluted with
CH2Cl2, washed with aqueous NaHCO3 5%, dried over
MgSO4, concentrated and the residue purified by TLC
(cyclohexane/AcOEt 9:1) to afford compound 39i. Yield:
89%; white solid; Rf (CH2Cl2): 0.50; tR (TSK gel, meth-
1
PHPLC: 99%; H NMR d: 9.56 (s, 1H, NH), 7.57 (m,
2H, ArH), 7.43–7.34 (m, 3H, ArH), 7.14-7.06 (m, 2H,
ArH + NH), 6.98–6.93 (m, 1H, ArH), 6.76 (m, 1H,
ArH), 6.62–6.56 (m, 1H, ArH), 4.63 (s, 2H, NH2),
4.03 (m, 2H, 2 CH), 2.83–2.53 (m, 2H, CH2), 2.49–
2.32 (m, 2H, CH2), 2.11 (m, 1H, CH2), 1.61 (m, 1H,
CH2), 1.14 (m, 9H, 3 CH3); 13C NMR d: 143.3,
139.2, 129.1, 128.7, 127.2, 126.7, 125.7, 123.9, 117.4,
117.1, 74.8, 58.7, 51.5, 51.1, 31.8, 29.1; MALDI-
TOF-MS m/z: 411 [M+H]+.
1
od A): 7.71 min, PHPLC: 99%; H NMR d: 8.65 (s, 1H,
NH thiourea), 7.95 (dd, J = 1.5, 8.0 Hz, 1H, ArH nitro-
phenyl), 7.91 (dd, J = 1.2, 8.2 Hz, 1H, ArH nitrophen-
yl), 7.75 (td, J = 1.5, 7.5 Hz, 1H, ArH nitrophenyl),
7.56–7.49 (m, 3H, ArH), 7.30 (td, J = 1.4, 8.5 Hz, 1H,
ArH nitrophenyl), 7.27 (m, 2H, ArH), 5.23 (m, 1H,
CH), 1.95 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.52 (m,
1H, CH2), 1.33-1.28 (m, 2H, CH2), 0.95-0.87 (m, 3H,
CH2); 13C NMR d: 180.9, 143.9, 138.2, 135.5, 133.9,
130.5, 130.4, 129.9, 129.7, 129.5, 126.3, 125.1, 60.1,
31.7, 25.9, 25.5; MALDI-TOF-MS m/z: 356 [M+H]+.
4.1.44. N-(2-Aminophenyl)-2-(4-hydroxypiperidin-1-yl)-
2-phenylacetamide (37i). To a solution of (4-hydroxypi-
peridin-1-yl)phenylacetic acid 37a (430 mg, 2.18 mmol,
1 equiv), synthesized according to the general procedure
D, in 10 mL CH2Cl2 were added EDC (627 mg,
3.27 mmol, 1.5 equiv), HOBt (441 mg, 3.27 mmol,
1.5 equiv), DIEA (570 lL, 3.27 mmol, 1.5 equiv), and
4.1.47. 1-(2-Nitrophenyl)-3-(2-piperidin-1-ylphenyl)thio-
urea (40i). To a solution of 2-nitrophenylisothiocyanate
(500 mg, 2.77 mmol, 1 equiv) in 10 mL THF was added
2-(1-piperidino)aniline (586 mg, 3.33 mmol, 1.2 equiv).
After stirring the mixture for 12 h at room temperature,
the solvent was evaporated, the residue diluted with
CH2Cl2, washed with aqueous NaHCO3 5%, dried over
MgSO4, concentrated and the residue purified by TLC
(cyclohexane/AcOEt 9:1) to afford compound 40i. Yield:
81%; yellow solid; Rf (CH2Cl2): 0.80; tR (TSK gel, method
A): 4.97 min, PHPLC: 99%; 1H NMR d: 10.24 (s, 1H, NH
thiourea), 9.50 (s, 1H, NH thiourea), 8.01 (d, J = 8.2 Hz,
1H, ArH nitrophenyl), 7.90 (d, J = 8.1 Hz, 1H, ArH
nitrophenyl), 7.75 (m, 1H, ArH), 7.73 (t, J = 7.3 Hz, 1H,
ArH nitrophenyl), 7.43 (t, J = 7.3 Hz, 1H, ArH nitro-
phenyl), 7.16–7.04 (m, 3H, ArH), 2.81 (t, J = 4.7 Hz,
4H, 2 CH2), 1.65 (m, 4H, 2 CH2), 1.51 (m, 2H, CH2);
13C NMR d: 180.5, 147.5, 144.6, 134.2, 133.8, 132.7,
129.9, 126.9, 126.7, 126.6, 125.4, 123.1, 120.1, 53.0, 26.5,
24.4; MALDI-TOF-MS m/z: 357 [M+H]+.
then
o-phenylenediamine
(588 mg,
5.45 mmol,
2.5 equiv). After stirring for 12 h at room temperature,
the mixture was washed with aqueous NaHCO3 5%,
dried over MgSO4, concentrated and the residue purified
by TLC (CH2Cl2/MeOH 9.6:0.4) to afford compound
37i. Yield: 31%; white solid; Rf (CH2Cl2/MeOH
9.6:0.4): 0.35; tR (TSK gel, method A): 3.26 min, PHPLC
:
1
99%; H NMR d: 9.49 (s, 1H, NH), 7.48–7.45 (m, 2H,
ArH phenyl), 7.37–7.25 (m, 3H, ArH phenyl), 7.17
(dd, J = 1.4, 7.9 Hz, 1H, ArH), 6.89 (td, J = 1.5,
7.9 Hz, 1H, ArH), 6.72 (dd, J = 1.4, 7.9 Hz, 1H, ArH),
6.55 (td, J = 1.4, 7.7 Hz, 1H, ArH), 4.64 (s, 2H, NH2),
4.53 (d, J = 3.4 Hz, 1H, OH), 4.01 (s, 1H, CH), 3.45
(m, 1H, CH), 2.77 (m, 1H, CH2), 2.59 (m, 1H, CH2),
2.17 (m, 1H, CH2), 2.01 (m, 1H, CH2), 1.70 (m, 2H,
CH2), 1.44 (m, 2H, CH2); 13C NMR d: 170.1, 142.3,
138.1, 129.3, 129.0, 128.8, 128.3, 126.5, 125.5, 124.2,
117.3, 117.0, 75.1, 66.7, 49.7, 49.1, 34.9; MALDI-
TOF-MS m/z: 326 [M+H]+.
4.1.48. N-(2-Aminobenzyl)-2-cyclohexyl-2-phenylaceta-
mide (42i). To a solution of cyclohexylphenylacetic acid
(1.78 g, 8.17 mmol, 1 equiv) in 32 mL DMF were added
a solution of DCC 1 M in CH2Cl2 (4.09 mL, 4.09 mmol,
0.5 equiv), DIEA (1.56 mL, 8.99 mmol, 1.1 equiv) and
2-aminobenzylamine (400 mg, 3.27 mmol, 0.4 equiv).
After stirring for 12 h at room temperature, the mixture
was filtered and the solvent evaporated. The residue was
diluted with CH2Cl2, washed with aqueous NaHCO3
5%, dried over MgSO4, concentrated and the residue
purified by TLC (CH2Cl2/MeOH 9.8:0.2) to afford com-
pound 42i. Yield: 79%; white solid; Rf (CH2Cl2/MeOH
4.1.45. N-(2-Aminophenyl)-2-cyclohexylamino-2-pheny-
lacetamide (38i). Compound 38i was prepared according
to the general procedure E starting from cyclohexylam-
inophenylacetic acid 38a, synthesized according to the
general procedure D, and was obtained after purifica-
tion by TLC (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1).
Yield: 82%; white solid; Rf (CH2Cl2/MeOH/NH4OH
9.7:0.3:0.1): 0.70; tR (TSK gel, method A): 3.92 min,
1
PHPLC: 99%; H NMR d: 9.53 (s, 1H, NH), 7.49 (m,
2H, ArH phenyl), 7.37–7.24 (m, 3H, ArH phenyl),
7.19 (dd, J = 1.4, 7.8 Hz, 1H, ArH), 6.90 (td, J = 1.4,
8.0 Hz, 1H, ArH), 6.72 (dd, J = 1.3, 7.9 Hz, 1H, ArH),
6.55 (td, J = 1.2, 7.2 Hz, 1H, ArH), 4.72 (s, 2H, NH2),
4.54 (s, 1H, CH), 2.38 (m, 1H, CH), 1.89–1.13 (m,
10H, CH2 cyclohexyl); 13C NMR d: 171.9, 142.0,
128.9, 128.7, 126.4, 125.0, 117.2, 116.8, 63.6, 54.7,
9.8:0.2): 0.50; tR (TSK gel, method B): 6.72 min, PHPLC
:
1
99%; H NMR d: 8.42 (t, J = 5.9 Hz, 1H, NH), 7.34–
7.20 (m, 5H, ArH phenyl), 6.91 (td, J = 1.5, 7.0 Hz,
1H, ArH), 6.42 (td, J = 0.9, 7.4 Hz, 1H, ArH), 5.01 (s,
2H, NH2), 4.17 (dd, J = 6.6, 15.0 Hz, 1H, CH2), 3.95

4504
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
(dd, J = 5.5, 15.0 Hz, 1H, CH2), 3.14 (d, J = 10.7 Hz,
1H, CH), 1.96 (m, 1H, CH), 1.79–1.56 (m, 4H, H cyclo-
hexyl), 1.23–0.92 (m, 5H, H cyclohexyl), 0.70 (m, 1H, H
cyclohexyl); 13C NMR d: 173.7, 146.9, 140.6, 129.6,
129.1, 128.9, 128.6, 127.4, 116.4, 115.3, 59.2, 40.9,
39.9, 32.1, 30.1, 28.5, 26.8, 26.4, 26.3; MALDI-TOF-
MS m/z: 323 [M+H]+.
ture for 12 h at room temperature, the product was pre-
cipitated, filtered and washed with Et2O to afford
compound 49i. Yield: 88%; light yellow solid; Rf
(CH2Cl2/MeOH 9.7:0.3): 0.55; tR (TSK gel, method
1
B): 6.72 min, PHPLC: 99%; H NMR d: 10.70 (s, 1H,
NH), 8.27 (s, 1H, ArH), 8.22 (s, 1H, ArH), 7.40–7.22
(m, 5H, ArH), 5.03 (s, 2H, NH2), 3.60 (d, J = 10.7 Hz,
1H, CH), 2.02 (m, 1H, CH), 1.84 (m, 1H, H cyclohexyl),
1.70 (m, 1H, H cyclohexyl), 1.26 (m, 2H, H cyclohexyl),
1.27–1.05 (m, 6H, H cyclohexyl); 13C NMR d: 173.3,
147.4, 145.9, 144.4, 139.3, 135.4, 129.0, 128.9, 127.6,
58.4, 40.5, 31.9, 30.6, 26.5, 26.0, 25.9; MALDI-TOF-
MS m/z: 311 [M+H]+.
4.1.49. N-(2-Amino-6-nitrophenyl)-2-cyclohexyl-2-pheny-
lacetamide (44i). To a solution of cyclohexylphenylacetic
acid (713 mg, 3.27 mmol, 1 equiv) in 15 mL of dry
CH2Cl2 was added thionyl chloride (600 lL, 8.17 mmol,
2.5 equiv). After stirring the mixture for 1 h at room
temperature, the solvent and the excess of thionyl chlo-
ride were evaporated. To a solution of this residue in
10 mL of dry CH2Cl2 were added DIEA (835 lL,
4.9 mmol, 1.5 equiv) and 3-nitro-o-phenylenediamine
(200 mg, 1.30 mmol, 0.4 equiv). After stirring for 12 h
at room temperature, the mixture was washed with
aqueous NaHCO3 5%, dried over MgSO4, concentrated
and the residue purified by TLC (CH2Cl2) to afford
compound 44i. Yield: 96%; yellow solid; Rf (CH2Cl2):
0.35; tR (TSK gel, method B): 8.39 min, PHPLC: 99%;
1H NMR d: 9.46 (s, 1H, NH), 7.78 (d, J = 8.7 Hz, 1H,
ArH), 7.41 (d, J = 7.6 Hz, 1H, ArH), 7.34-7.16 (m,
5H, ArH), 6.71 (s, 2H, NH2), 6.56 (t, J = 7.6 Hz, 1H,
ArH), 3.37 (d, J = 10.6 Hz, 1H, CH), 1.92 (m, 1H,
CH), 1.78–1.50 (m, 4H, H cyclohexyl), 1.22–1.00 (m,
6H, H cyclohexyl); 13C NMR d: 173.2, 140.9, 139.9,
132.8, 129.1, 127.7, 126.7, 123.6, 115.5, 59.2, 32.1,
31.0, 26.8, 26.3, 26.2; MALDI-TOF-MS m/z: not
observed.
4.1.52. N-(3-Amino-pyridin-2-yl)-2-cyclohexyl-2-phenyl-
acetamide (50i). To a solution of cyclohexylphenylacetic
acid (1.25 g, 5.75 mmol, 1 equiv) in 30 mL of dry
CH2Cl2 was added thionyl chloride (2.1 mL,
28.75 mmol, 5 equiv). After stirring the mixture for
30 min at room temperature, the solvent and the excess
thionyl chloride were evaporated. To a solution of this
residue in 10 mL of dry CH2Cl2 were added DIEA
(1.5 mL, 8.62 mmol, 1.5 equiv) and 2,3-diaminopyridine
(250 mg, 2.3 mmol, 0.4 equiv). After stirring for 12 h at
room temperature, the mixture was washed with aque-
ous NaHCO3 5%, dried over MgSO4 and concentrated.
Compound 50i was not purified and directly cyclized.
4.1.53.
N-(2-Amino-4-methylphenyl)-2-cyclohexyl-2-
phenylacetamide and N-(2-amino-5-methylphenyl)-2-cy-
clohexyl-2-phenylacetamide (51i). Compound 51i was
prepared according to the general procedure F starting
from cyclohexylphenylacetic acid and 3,4-diaminotolu-
ene and was obtained in melange after purification by
TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 63%; brown solid;
Rf (CH2Cl2/MeOH 9.7:0.3): 0.65; tR (TSK gel, method
B): 6.96 min (33%)–7.16 min (67%), PHPLC: 99%; 1H
NMR d: 9.38 (s, 0.33H, NH), 9.34 (s, 0.67H, NH),
7.42 (m, 2H, ArH phenyl), 7.35–7.30 (m, 2H, ArH phen-
yl), 7.27–7.20 (m, 1H, ArH phenyl), 6.98 (s, 0.33H,
ArH), 6.95 (s, 0.67H, ArH), 6.70 (m, 0.33H, ArH),
6.62 (m, 0.33H, ArH), 6.52 (m, 0.67H, ArH), 6.36 (m,
0.67H, ArH), 4.62 (s, 2H, NH2), 3.40 (m, 1H, CH),
2.15 (s, 0.67· 3H, CH3), 2.12 (s, 0.33· 3H, CH3), 2.02
(m, 1H, CH), 1.84 (m, 1H, H cyclohexyl), 1.73 (m,
1H, H cyclohexyl), 1.60 (m, 2H, H cyclohexyl), 1.27–
1.09 (m, 6H, H cyclohexyl); 13C NMR d: 172.2, 142.3,
140.5, 139.7, 135.7, 129.1, 127.5, 127.2, 126.1, 125.9,
124.3, 121.8, 117.9, 117.3, 117.1, 59.2, 40.9, 32.1, 31.0,
26.9, 26.4, 26.3, 21.6, 20.9; MALDI-TOF-MS m/z: 323
[M+H]+.
4.1.50.
N-(2-Amino-3-methylphenyl)-2-cyclohexyl-2-
phenylacetamide (48i). Compound 48i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 2,3-diaminotoluene
and was obtained after purification by TLC (CH2Cl2/
MeOH 9.7:0.3). Yield: 45%; white solid; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.65; tR (TSK gel, method B):
1
7.76 min, PHPLC: 99%; H NMR d: 9.33 (s, 1H, NH),
7.39 (m, 2H, ArH phenyl), 7.30 (m, 2H, ArH phenyl),
7.22 (m, 1H, ArH phenyl), 6.90 (d, J = 6.8 Hz, 1H,
ArH), 6.79 (d, J = 6.8 Hz, 1H, ArH), 6.43 (t,
J = 7.6 Hz, 1H, ArH), 4.37 (s, 2H, NH2), 3.46 (d,
J = 16.8 Hz, 1H, CH), 2.04 (s, 3H, CH3), 2.02 (m, 1H,
CH), 1.86 (m, 1H, H cyclohexyl), 1.82 (m, 1H, H cyclo-
hexyl), 1.57 (m, 2H, H cyclohexyl), 1.25–1.04 (m, 6H, H
cyclohexyl); 13C NMR d: 172.5, 162.7, 140.7, 140.4,
129.1, 128.0, 127.5, 124.3, 123.6, 123.5, 116.6, 59.2,
34.2, 32.1, 26.8, 26.3, 25.3, 18.6; MALDI-TOF-MS
m/z: 323 [M+H]+.
4.1.54.
N-(2-Amino-4-methoxyphenyl)-2-cyclohexyl-2-
4.1.51. N-(5-Aminopyrimidin-4-yl)-2-cyclohexyl-2-pheny-
lacetamide (49i). To a solution of cyclohexylphenylacetic
acid (450 mg, 2.04 mmol, 1 equiv) in 10 mL of dry
CH2Cl2 was added thionyl chloride (370 lL, 5.1 mmol,
2.5 equiv). After stirring the mixture for 1 h at room
temperature, the solvent and the excess of thionyl chlo-
ride were evaporated. To a solution of this residue in
10 mL of dry CH2Cl2 were added DIEA (530 lL,
3.06 mmol, 1.5 equiv) and 4,5-diaminopyrimidine
(150 mg, 1.36 mmol, 0.67 equiv). After stirring the mix-
phenylacetamide (52i). Compound 52i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 4-methoxy-o-phenylen-
ediamine.2HCl and was obtained after purification by
TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 50%; white solid;
Rf (CH2Cl2/MeOH 9.7:0.3): 0.55; tR (TSK gel, method
B): 7.27 min, PHPLC: 99%; 1H NMR d: 9.26 (s, 1H,
NH), 7.40–7.37 (m, 2H, ArH phenyl), 7.33–7.30 (m,
2H, ArH phenyl), 7.24–7.20 (m, 1H, ArH phenyl),
6.90 (d, J = 8.6 Hz, 1H, ArH), 6.25 (d, J = 2.7 Hz, 1H,

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4505
ArH), 6.10 (dd, J = 2.8, 8.6 Hz, 1H, ArH), 4.66 (s, 2H,
NH2), 3.62 (s, 3H, CH3), 3.34 (m, 1H, CH), 1.99 (m,
1H, CH), 1.84 (m, 1H, H cyclohexyl), 1.72 (m, 1H, H
cyclohexyl), 1.58 (m, 2H, H cyclohexyl), 1.23–1.05 (m,
6H, H cyclohexyl); 13C NMR d: 172.1, 158.3, 143.9,
140.2, 128.9, 128.8, 127.2, 127.0, 125.3, 117.3, 102.5,
101.4, 58.9, 55.4, 40.5, 30.8, 26.6, 26.0; MALDI-TOF-
MS m/z: 339 [M+H]+.
59.3, 41.2, 32.1, 31.0, 26.8, 26.3, 26.2; MALDI-TOF-
MS m/z: 377 [M+H]+.
4.1.58.
4-Amino-3-(2-cyclohexyl-2-phenylacetylami-
no)benzoic acid methyl ester (56i). Compound 56i was
prepared according to the general procedure F starting
from cyclohexylphenylacetic acid and methyl-3,4-diam-
inobenzoate and was obtained after purification by
TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 67%; white solid;
Rf (CH2Cl2/MeOH 9.8:0.2): 0.45; tR (TSK gel, method
B): 8.17 min, PHPLC: 99%; 1H NMR d: 9.36 (s, 1H,
NH), 7.86 (d, J = 2.0 Hz, 1H, ArH), 7.50 (dd, J = 2.0,
8.4 Hz, 1H, ArH), 7.39 (m, 2H, ArH phenyl), 7.33
(m, 2H, ArH phenyl), 7.24 (m, 1H, ArH phenyl),
6.71 (d, J = 8.4 Hz, 1H, ArH), 5.57 (s, 2H, NH2),
3.73 (s, 3H, OCH3), 3.40 (d, J = 10.7 Hz, 1H, CH),
2.02 (m, 1H, CH), 1.85-1.71 (m, 2H, H cyclohexyl),
1.59 (m, 2H, H cyclohexyl), 1.31–1.06 (m, 6H, H cyclo-
hexyl); 13C NMR d: 172.7, 166.9, 162.7, 146.9, 140.1,
129.1, 128.4, 127.6, 127.1, 122.8, 117.2, 115.5, 59.3,
52.2, 40.9, 32.1, 31.0, 26.8, 26.3; MALDI-TOF-MS
m/z: 367 [M+H]+.
4.1.55. 2-Cyclohexyl-N-(4-fluoro-2-nitrophenyl)-2-pheny-
lacetamide (53i). Compound 53i was prepared accord-
ing to the general procedure H starting from 3-
fluoro-2-nitroaniline and was obtained after purifica-
tion by TLC (cyclohexane/AcOEt 9:1). Yield: 70%;
light yellow solid; Rf (CH2Cl2/MeOH 9.9:0.1): 0.40;
tR (TSK gel, method B): 9.95 min, PHPLC: 99%; 1H
NMR d: 10.42 (s, 1H, NH), 7.88-7.84 (m, 1H, ArH),
7.57–7.51 (m, 2H, ArH), 7.36–7.21 (m, 5H, ArH),
3.37 (d, J = 10.6 Hz, 1H, CH), 2.03 (m, 1H, CH),
1.82 (m, 1H, H cyclohexyl), 1.64 (m, 1H, H cyclohex-
yl), 1.56 (m, 5H, H cyclohexyl), 1.37–0.70 (m, 6H, H
cyclohexyl); 13C NMR d: 172.1, 160.0, 156.8, 138.9,
128.9, 128.8, 128.2, 128.1, 127.5, 121.7, 121.4, 112.8,
58.9, 40.9, 31.7, 30.7, 26.5, 26.0, 25.9; MALDI-TOF-
MS m/z: 357 [M+H]+.
4.1.59.
2-Cyclohexyl-N-(4-hydroxy-2-nitrophenyl)-2-
phenylacetamide (58i). Compound 58i was prepared
according to the general procedure H starting from
4-amino-3-nitrophenol and was obtained after purifi-
cation by TLC (CH2Cl2). Yield: 62%; yellow solid;
Rf (CH2Cl2): 0.55; tR (TSK gel, method B):
6.98 min, PHPLC: 99%; 1H NMR d: 7.52–7.48 (m,
2H, NH + ArH), 7.39–7.28 (m, 6H, OH + ArH), 7.10
(m, 1H, ArH), 7.02 (m, 1H, ArH), 3.58 (d,
J = 10.3 Hz, 1H, CH), 2.02 (m, 1H, CH), 1.97–1.04
(m, 10H, H cyclohexyl); 13C NMR d: 173.1, 145.3,
139.5, 137.7, 131.3, 129.7, 129.5, 129.3, 128.3, 121.1,
117.5, 58.9, 41.3, 32.1, 30.5, 26.6, 26.3, 26.1;
MALDI-TOF-MS m/z: not observed.
4.1.56.
N-(2-Amino-4-chlorophenyl)-2-cyclohexyl-2-
phenylacetamide and N-(2-amino-5-chlorophenyl)-2-cy-
clohexyl-2-phenylacetamide (54i). Compound 54i was
prepared according to the general procedure F starting
from cyclohexylphenylacetic acid and 4-chloro-o-pheny-
lenediamine and was obtained in melange after purifica-
tion by TLC (CH2Cl2/MeOH 9.9:0.1). Yield: 48%; white
solid; Rf (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1): 0.55; tR
(TSK gel, method A): 6.79 min (25%)–6.92 min (75%),
1
PHPLC: 99%; H NMR d: 9.36 (s, 1H, NH), 7.40–7.20
(m, 5H, ArH phenyl + 0.25H, ArH), 7.17 (d,
J = 8.5 Hz, 0.75H, ArH), 6.89 (dd, J = 2.4, 8.5 Hz,
0.25H, ArH), 6.73 (d, J = 2.4 Hz, 0.75H, ArH), 6.68
(d, J = 8.5 Hz, 0.25H, ArH), 6.51 (dd, J = 2.4, 8.5 Hz,
0.75H, ArH), 5.01 (s, 0.75· 2H, NH2), 4.94 (s, 0.25·
2H, NH2), 3.39 (d, J = 10.6 Hz, 0.25H, CH), 3.37 (d,
J = 10.7 Hz, 0.75H, CH), 2.02 (m, 1H, CH), 1.80-1.07
(m, 10H, H cyclohexyl); 13C NMR d: 172.3, 143.6,
139.9, 130.1, 128.9, 127.4, 126.8, 124.2, 117.4, 116.1,
115.4, 59.0, 40.4, 31.9, 30.8, 26.6, 26.0; MALDI-TOF-
MS m/z: 343 [M+H]+.
4.1.60. N-(2-Amino-3,4-dimethylphenyl)-2-cyclohexyl-2-
phenylacetamide (59i). Compound 59i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 3,4-dimethyl-o-pheny-
lenediamine and was obtained after purification by
TLC (CH2Cl2/MeOH 9.9:0.1). Yield: 61%; light yellow
solid; Rf (CH2Cl2/MeOH 9.9:0.1): 0.45; tR (TSK gel,
method B): 7.46 min, PHPLC: 99%; 1H NMR d: 9.29
(s, 1H, NH), 7.39 (m, 2H, ArH phenyl), 7.31 (m,
2H, ArH phenyl), 7.23 (m, 1H, ArH phenyl), 6.77
(d, J = 7.9 Hz, 1H, ArH), 6.37 (d, J = 8.0 Hz, 1H,
ArH), 4.32 (s, 2H, NH2), 3.38 (d, J = 10.7 Hz, 1H,
CH), 2.13 (s, 3H, CH3), 1.98 (m, 1H, CH), 1.96 (s,
3H, CH3), 1.85 (m, 1H, H cyclohexyl), 1.74 (m, 1H,
H cyclohexyl), 1.59 (m, 2H, H cyclohexyl), 1.25–0.73
(m, 6H, H cyclohexyl); 13C NMR d: 172.5, 140.8,
140.5, 129.1, 127.5, 123.7, 121.9, 121.6, 118.6, 59.2,
39.8, 32.1, 31.0, 26.9, 26.3, 21.0; MALDI-TOF-MS
m/z: 337 [M+H]+.
4.1.57. N-(2-Amino-5-trifluoromethylphenyl)-2-cyclohex-
yl-2-phenylacetamide (55i). Compound 55i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 4-trifluoromethyl-o-
phenylenediamine and was obtained after purification
by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 63%; orange
solid; Rf (CH2Cl2/MeOH 9.8:0.2): 0.75; tR (TSK gel,
1
method B): 8.82 min, PHPLC: 99%; H NMR d: 9.39 (s,
1H, NH), 7.64 (m, 1H, ArH), 7.42 (m, 2H, ArH phenyl),
7.32 (m, 2H, ArH phenyl), 7.25 (m, 1H, ArH phenyl),
7.18 (m, 1H, ArH), 6.80 (m, 1H, ArH), 5.48 (s, 2H,
NH2), 3.42 (d, J = 10.7 Hz, 1H, CH), 2.02 (m, 1H,
CH), 1.79–1.58 (m, 5H, H cyclohexyl), 1.27–1.09 (m,
5H, H cyclohexyl); 13C NMR d: 172.8, 162.7, 145.1,
140.0, 129.5, 129.1, 128.8, 127.7, 123.3, 121.8, 115.9,
4.1.61. N-(2-Amino-4,5-dimethylphenyl)-2-cyclohexyl-2-
phenylacetamide (60i). Compound 60i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 4,5-dimethyl-o-pheny-
lenediamine and was obtained after purification by

4506
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
TLC (CH2Cl2/MeOH 9.9:0.1). Yield: 74%; white solid;
Rf (CH2Cl2/MeOH 9.9:0.1): 0.40; tR (TSK gel, method
B): 6.98 min, PHPLC: 99%; 1H NMR d: 9.31 (s, 1H,
NH), 7.40–7.37 (m, 2H, ArH), 7.33–7.24 (m, 3H,
ArH), 6.83 (s, 1H, ArH), 6.48 (s, 1H, ArH), 4.50 (s,
2H, NH2), 3.37 (m, 1H, CH), 2.05 (s, 3H, CH3),
2.01 (s, 3H, CH3), 1.57–1.13 (m, 11H, H cyclohexyl);
13C NMR d: 172.1, 162.7, 140.5, 140.2, 134.2, 129.2,
129.0, 128.2, 127.7, 124.5, 121.9, 118.3, 59.2, 32.1,
26.9, 26.3, 19.9, 19.2; MALDI-TOF-MS m/z: 337
[M+H]+.
4.1.65. 2-Nitro-5-piperidin-1-ylphenylamine (64a). Com-
pound 64a was prepared according to the general proce-
dure G starting from piperidine (1.15 mL, 11.6 mmol,
4 equiv) and was obtained after purification by TLC
(CH2Cl2). Yield: 87%; yellow solid; Rf (CH2Cl2): 0.45;
tR (TSK gel, method B): 6.59 min, PHPLC: 99%; 1H
NMR d: 7.78 (d, J = 9.8 Hz, 1H, ArH), 7.22 (s, 2H,
NH2), 6.36 (dd, J = 2.7, 9.8 Hz, 1H, ArH), 6.18 (d,
J = 2.7 Hz, 1H, ArH), 3.35 (t, J = 5.8 Hz, 4H, 2 CH2),
1.57(m, 6H, 3CH2);MALDI-TOF-MSm/z:222[M+H]+.
4.1.66. 2-Cyclohexyl-N-(2-nitro-5-piperidin-1-ylphenyl)-
2-phenylacetamide (64i). Compound 64i was prepared
according to the general procedure H starting from
compound 64a and was obtained after purification by
TLC (cyclohexane/AcOEt 8:2). Yield: 75%; orange sol-
id; Rf (cyclohexane/AcOEt 8:2): 0.50; tR (TSK gel, meth-
od B): 11.30 min, PHPLC: 99%; 1H NMR d: 10.80 (s, 1H,
NH), 7.95 (d, J = 9.6 Hz, 1H, ArH), 7.84 (d, J = 2.7 Hz,
1H, ArH), 7.40–7.22 (m, 5H, ArH phenyl), 6.73 (dd,
J = 2.6, 9.7 Hz, 1H, ArH), 3.47–3.44 (m, 5H, CH +
CH2 piperidinyl), 2.04 (m, 1H, CH cyclohexyl), 1.84–
1.58 (m, 10H, CH2 cyclohexyl + CH2 piperidinyl),
1.30–0.84 (m, 6H, CH2 cyclohexyl); 13C NMR d:
137.4, 129.3, 129.2, 127.9, 109.4, 103.6, 61.2, 48.6,
40.9, 32.1, 30.7, 26.7, 26.3, 25.8, 24.6; MALDI-TOF-
MS m/z: 422 [M+H]+.
4.1.62. N-(2-Amino-4,5-dimethoxyphenyl)-2-cyclohexyl-
2-phenylacetamide (61i). Compound 61i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 4,5-dimethoxy-o-
phenylenediamine.2HCl and was obtained after purifi-
cation by TLC (CH2Cl2/MeOH 9.5:0.5). Yield: 94%;
white solid; Rf (CH2Cl2/MeOH 9.5:0.5): 0.50; tR (TSK
gel, method B): 6.50 min, PHPLC: 99%; 1H NMR d:
9.31 (s, 1H, NH), 7.39–7.19 (m, 5H, ArH), 6.69 (s, 1H,
ArH), 6.36 (s, 1H, ArH), 4.35 (s, 2H, NH2), 3.63 (s,
3H, OCH3), 3.56 (s, 3H, OCH3), 3.32 (d, J = 10.7 Hz,
1H, CH), 1.99 (m, 1H, CH cyclohexyl), 1.85–1.01 (m,
10H, H cyclohexyl); 13C NMR d: 172.0, 162.7, 140.4,
136.8, 129.1, 129.0, 127.5, 125.5, 111.9, 102.1, 59.2,
57.4, 56.2, 40.9, 34.2, 32.2, 26.8, 26.3; MALDI-TOF-
MS m/z: 369 [M+H]+.
4.1.67.
5-(4-Methylpiperazin-1-yl)-2-nitrophenylamine
4.1.63. N-(2-Amino-4,5-dichlorophenyl)-2-cyclohexyl-2-
phenylacetamide (62i). Compound 62i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 4,5-dichloro-o-pheny-
lenediamine and was obtained after purification by
TLC (CH2Cl2/MeOH 9.9:0.1). Yield: 45%; white sol-
id; Rf (CH2Cl2): 0.40; tR (TSK gel, method B):
9.25 min, PHPLC: 99%; 1H NMR d: 9.34 (s, 1H,
NH), 7.50 (s, 1H, ArH), 7.34–7.15 (m, 5H, ArH),
6.84 (s, 1H, ArH), 5.19 (s, 2H, NH2), 3.34 (d,
J = 10.6 Hz, 1H, CH), 1.95 (m, 1H, CH), 1.70-1.11
(m, 10H, H cyclohexyl); 13C NMR d: 172.7, 142.0,
132.9, 129.1, 127.7, 125.6, 124.1, 116.7, 59.3, 32.1,
31.0, 26.8, 26.3, 26.2; MALDI-TOF-MS m/z: 377
[M+H]+.
(65a). Compound 65a was prepared according to the
general procedure G starting from 1-methylpiperazine
(1.29 mL, 11.6 mmol, 4 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 75%; yellow solid; Rf (cyclohexane/AcOEt 7:3):
0.55; tR (TSK gel, method B): 3.47 min, PHPLC: 99%;
1H NMR d: 7.70 (d, J = 9.7 Hz, 1H, ArH), 7.17 (s,
2H, NH2), 6.29 (dd, J = 2.7, 9.8 Hz, 1H, ArH), 6.12
(d, J = 2.7 Hz, 1H, ArH), 3.21 (t, J = 5.0 Hz, 4H, 2
CH2), 2.30 (t, J = 5.0 Hz, 4H, 2 CH2), 2.10 (s, 3H,
CH3); MALDI-TOF-MS m/z: 237 [M+H]+.
4.1.68.
2-Cyclohexyl-N-[5-(4-methylpiperazin-1-yl)-2-
nitrophenyl]-2-phenylacetamide (65i). Compound 65i
was prepared according to the general procedure H
starting from compound 65a and was obtained after
purification by TLC (cyclohexane/AcOEt 8:2). Yield:
28%; orange solid; Rf (CH2Cl2/MeOH 9:1): 0.40; tR
(TSK gel, method A): 6.25 min, PHPLC: 99%; 1H
NMR d: 11.06 (s, 1H, NH), 8.24 (d, J = 2.8 Hz, 1H,
ArH), 8.00 (d, J = 9.7 Hz, 1H, ArH), 7.33–7.15 (m,
5H, ArH phenyl), 6.42 (dd, J = 2.8, 9.7 Hz, 1H, ArH),
3.37 (t, J = 5.0 Hz, 4H, CH2 piperazinyl), 3.12 (d,
J = 10.5 Hz, 1H, CH cyclohexyl), 2.40 (t, J = 5.0 Hz,
4H, CH2 piperazinyl), 2.20 (s, 3H, CH3), 2.11–2.06 (m,
1H, CH cyclohexyl), 1.89–1.04 (m, 10H, CH2 cyclohex-
yl); 13C NMR d: 127.8, 127.7, 127.5, 126.5, 106.8, 101.5,
62.3, 52.7, 45.8, 44.9, 39.6, 31.3, 25.4, 25.3; MALDI-
TOF-MS m/z: 437 [M+H]+.
4.1.64.
N-(3-Aminonaphthalen-2-yl)-2-cyclohexyl-2-
phenylacetamide (63i). Compound 63i was prepared
according to the general procedure F starting from
cyclohexylphenylacetic acid and 2,3-diaminonaphtha-
lene and was obtained after purification by TLC
(CH2Cl2/MeOH 9.8:0.2). Yield: 34%; ligth yellow sol-
id; Rf (CH2Cl2/MeOH 9.8:0.2): 0.65; tR (TSK gel,
method B): 8.14 min, PHPLC: 99%; 1H NMR d:
9.43 (s, 1H, NH), 7.82 (s, 1H, ArH), 7.55 (d,
J = 8.0 Hz, 1H, ArH), 7.44 (d, J = 8.0 Hz, 1H,
ArH), 7.39 (m, 2H, ArH), 7.28 (m, 2H, ArH),
7.19 (m, 2H, ArH), 7.07 (m, 2H, ArH), 6.94 (s,
1H, ArH), 5.03 (s, 2H, NH2), 3.43 (d, J = 10.7 Hz,
1H, CH), 2.01 (m, 1H, CH), 1.93–1.10 (m, 10H,
H cyclohexyl); 13C NMR d: 172.9, 140.2, 129.1,
127.9, 127.6, 126.8, 126.1, 125.6, 122.6, 109.4, 59.4,
40.9, 34.2, 32.2, 31.1, 26.8; MALDI-TOF-MS m/z:
not observed.
4.1.69. 5-Morpholin-4-yl-2-nitrophenylamine (66a). Com-
pound 66a was prepared according to the general proce-
dure G starting from morpholine (1.01 mL, 11.6 mmol,
4 equiv) and was obtained after purification by trituration

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4507
in a Et2O/pentane mixture. Yield: 56%; yellow solid; Rf
(cyclohexane/AcOEt 7:3): 0.60; tR (TSK gel, method B):
5.15 min, PHPLC: 99%; H NMR d: 7.73 (d, J = 9.7 Hz,
acid and 4-methoxy-o-phenylenediamine.2HCl and was
obtained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 38%; red-orange oil; Rf (CH2Cl2/MeOH
1
1H, ArH), 7.20 (s, 2H, NH2), 6.30 (dd, J = 2.7, 9.7 Hz,
1H, ArH), 6.12 (d, J = 2.7 Hz, 1H, ArH), 3.61 (t,
J = 4.8 Hz, 4H, 2 CH2), 3.18 (t, J = 5.0 Hz, 4H, 2 CH2);
MALDI-TOF-MS m/z: 224 [M+H]+.
9.7:0.3): 0.55; tR (TSK gel, method B): 6.54 min, PHPLC:
1
99%; H NMR d: 9.37 (s, 1H, NH), 7.73 (m, 1H, ArH),
7.49–7.36 (m, 3H, ArH), 7.24 (m, 1H, ArH), 7.14 (m,
1H, ArH), 7.07 (m, 2H, ArH), 6.97 (m, 1H, ArH),
6.92 (m, 1H, ArH), 6.27 (m, 1H, ArH), 6.10 (m, 1H,
ArH), 4.82 (s, 2H, NH2), 3.63 (s, 3H, CH3); 13C NMR
d: 163.5, 145.3, 134.8, 133.2, 131.6, 128.4, 125.3, 125.2,
120.5, 120.3, 103.4, 102.2, 98.7, 56.4; MALDI-TOF-
MS m/z: 335 [M+H]+.
4.1.70. 2-Cyclohexyl-N-(5-morpholin-4-yl-2-nitrophenyl)-
2-phenylacetamide (66i). Compound 66i was prepared
according to the general procedure H starting from
compound 66a, but was not purified and directly re-
duced and cyclized.
4.1.75. N-(2-Amino-4-methoxyphenyl)-2-phenylaminob-
enzamide (70i). Compound 70i was prepared according
to the general procedure F starting from N-phenylanth-
ranilic acid and 4-methoxy-o-phenylenediamine.2HCl
and was obtained after purification by TLC (CH2Cl2/
MeOH 9.7:0.3). Yield: 33%; white solid; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.75; tR (TSK gel, method B):
4.1.71. 2-Nitro-5-thiomorpholin-4-ylphenylamine (67a).
Compound 67a was prepared according to the general
procedure G starting from thiomorpholine (1.10 mL,
11.6 mmol, 4 equiv) and was obtained after purification
by TLC (CH2Cl2). Yield: 74%; yellow solid; Rf
(CH2Cl2): 0.60; tR (TSK gel, method B): 5.97 min,
PHPLC: 99%; 1H NMR d: 7.80 (d, J = 9.7 Hz, 1H,
ArH), 7.23 (s, 2H, NH2), 6.35 (dd, J = 2.7, 9.8 Hz, 1H,
ArH), 6.20 (d, J = 2.7 Hz, 1H, ArH), 3.74 (t,
J = 5.0 Hz, 4H, 2 CH2), 2.60 (t, J = 5.0 Hz, 4H, 2
CH2); MALDI-TOF-MS m/z: 240 [M+H]+.
1
6.85 min, PHPLC: 99%; H NMR d: 9.55 (s, 1H, NH),
9.48 (s, 1H, NH), 7.85 (m, 1H, ArH), 7.38–7.25 (m,
4H, ArH), 7.13 (m, 2H, ArH), 6.99–6.84 (m, 3H,
ArH), 6.33 (m, 1H, ArH), 6.14 (m, 1H, ArH), 4.92 (s,
2H, NH2), 3.66 (s, 3H, CH3); 13C NMR d: 132.8,
130.5, 130.2, 128.9, 122.5, 120.1, 119.1, 116.9, 116.0,
102.7, 101.4, 55.7; MALDI-TOF-MS m/z: 334 [M+H]+.
4.1.72. 2-Cyclohexyl-N-(2-nitro-5-thiomorpholin-4-ylphe-
nyl)-2-phenylacetamide (67i). Compound 67i was pre-
pared according to the general procedure H starting
from compound 67a and was obtained after purification
by TLC (CH2Cl2). Yield: 83%; yellow solid; Rf (CH2Cl2):
0.80; tR (TSK gel, method A): 8.53 min, PHPLC: 99%; 1H
NMR d: 10.73 (s, 1H, NH), 7.96 (d, J = 9.6 Hz, 1H,
ArH), 7.78 (d, J = 2.8 Hz, 1H, ArH), 7.40–7.21 (m, 5H,
ArH phenyl), 6.75 (dd, J = 2.8, 9.6 Hz, 1H, ArH), 3.80
(m, 4H, 2 CH2 thiomorpholinyl), 3.47 (d, J = 10.4 Hz,
1H, CH), 2.64 (m, 4H, 2 CH2 thiomorpholinyl), 2.04
(m, 1H, CH cyclohexyl), 1.83 (m, 1H, CH2 cyclohexyl),
1.69 (m, 1H, CH2 cyclohexyl), 1.58 (m, 2H, CH2 cyclo-
hexyl), 1.26–0.76 (m, 6H, CH2 cyclohexyl); 13C NMR
d: 173.1, 154.4, 139.2, 137.2, 129.3, 129.2, 129.0, 127.9,
109.8, 104.5, 50.4, 40.9, 32.1, 30.7, 26.7, 26.3, 26.1; MAL-
DI-TOF-MS m/z: 440 [M+H]+.
4.1.76. N-(2-Amino-4-methoxyphenyl)-2-cyclohexylben-
zamide (71i). Compound 71i was prepared according
to the general procedure F starting from 2-cyclohexyl-
benzoic acid and 4-methoxy-o-phenylenediamine.2HCl
and was obtained after purification by TLC (CH2Cl2/
MeOH 9.7:0.3). Yield: 77%; white solid; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.45; tR (TSK gel, method B):
1
7.06 min, PHPLC: 93%; H NMR d: 9.43 (s, 1H, NH),
7.38 (m, 3H, ArH), 7.20 (m, 1H, ArH), 7.00 (d,
J = 8.6 Hz, 1H, ArH), 6.30 (d, J = 2.8 Hz, 1H, ArH),
6.15 (dd, J = 2.8, 8.6 Hz, 1H, ArH), 4.85 (s, 2H, NH2),
3.63 (s, 3H, CH3), 2.86 (m, 1H, CH), 1.81–1.26 (m,
10H, CH2); 13C NMR d: 169.3, 158.9, 145.4, 144.8,
138.2, 130.1, 127.9, 127.7, 126.9, 126.2, 125.8, 117.5,
102.9, 101.8, 55.7, 41.2, 34.6, 27.4, 26.5; MALDI-
TOF-MS m/z: 325 [M+H]+.
4.1.73. Biphenyl-2-carboxylic acid (2-amino-4-methoxy-
phenyl)amide (68i). Compound 68i was prepared accord-
ing to the general procedure F starting from 2-
biphenylcarboxylic acid and 4-methoxy-o-phenylenedi-
amineÆ2HCl and was obtained after purification by
TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 45%; light yellow
solid; Rf (CH2Cl2/MeOH 9.7:0.3): 0.35; tR (TSK gel,
4.1.77. General procedure I for synthesis of benzimidaz-
oles 1, 3i0, 4–11, 14–15, 17–18, 20, 23, 32–35, 44, 48–49,
51–52, 54–56 and 59–63. The monoacylated precursor
was diluted with neat acetic acid (0.2 M). Following re-
flux of the mixture for 5 h, the solvent was evaporated,
the residue diluted with CH2Cl2, washed with aqueous
NaHCO3 5%, dried over MgSO4 and concentrated.
The expected benzimidazole was obtained after purifica-
tion by trituration in a Et2O/pentane or hexane/AcOEt
mixture or by TLC.
1
method B): 5.92 min, PHPLC: 91%; H NMR d: 9.20 (s,
1H, NH), 7.57 (m, 1H, ArH), 7.46–7.32 (m, 9H, ArH
biphenyl), 6.75 (d, J = 8.6 Hz, 1H, ArH), 6.20 (d,
J = 2.8 Hz, 1H, ArH), 6.04 (dd, J = 2.8, 8.6 Hz, 1H,
ArH), 4.61 (s, 2H, NH2), 3.58 (s, 3H, CH3); 13C NMR
d: 169.0, 158.8, 144.8, 141.2, 140.0, 138.2, 130.6, 130.3,
129.5, 129.3, 129.1, 128.8, 128.1, 127.9, 127.8, 117.1,
102.5, 101.4, 55.7; MALDI-TOF-MS m/z: 319 [M+H]+.
4.1.78. General Procedure J for synthesis of benzimidaz-
oles 2, 12–13, 24, 47, 53 and 58. To a solution of mono-
acylated precursor in neat acetic acid (0.2 M) was added
iron (2 equiv). Following reflux of the mixture for 5 h,
the solvent was evaporated, the residue diluted with
CH2Cl2, washed with aqueous NaHCO3 5%, dried over
MgSO4 and concentrated. The expected benzimidazole
4.1.74. N-(2-Amino-4-methoxyphenyl)-2-phenoxybenza-
mide (69i). Compound 69i was prepared according to
the general procedure F starting from 2-phenoxybenzoic

4508
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
was obtained after purification by trituration in a Et2O/
pentane mixture or by TLC.
4.1.84. 2-Dicyclohexylmethyl-1H-benzoimidazole (3). To
a solution of compound 3i0 (130 mg, 0.36 mmol, 1 equiv)
in 3.5 mL of toluene was added p-toluenesulfonic acid
(135 mg, 0.72 mmol, 2 equiv). Following reflux of the
mixture for 24 h, the solvent was evaporated, the residue
diluted with CH2Cl2, washed with aqueous NaHCO3
5%, dried over MgSO4 and concentrated. The residue
was purified by TLC (CH2Cl2/MeOH 9.6:0.4) to afford
compound 3. Yield: 65%; white solid; mp 205–207 ꢁC;
Rf (CH2Cl2/MeOH 9.6:0.4): 0.50; tR (TSK gel, method
4.1.79. General procedure K for synthesis of benzimidaz-
oles 16, 19, 25–31, 36–38 and 68–71. To a solution of
monoacylated precursor in a MeOH/dioxane 1:1 mix-
ture (0.1 M) was added aqueous HCl 4 N (10 equiv).
Following reflux of the mixture for 8 h, the solvents were
evaporated, the residue diluted with CH2Cl2, washed
with aqueous NaHCO3 5%, dried over MgSO4 and con-
centrated. The expected benzimidazole was obtained
after purification by trituration in a Et2O/pentane mix-
ture or by TLC.
1
B): 6.44 min, PHPLC: 99%; H NMR d: 12.16 (s, 1H,
NH), 7.68 (m, 1 H, ArH), 7.55 (m, 1H, ArH), 7.25 (m,
2H, ArH), 2.69 (t, J = 7.5 Hz, 1H, CH), 2.09 (m, 2H,
CH), 1.93–0.85 (m, 20H, H cyclohexyl); 13C NMR d:
176.3, 156.9, 121.9, 121.4, 118.9, 111.5, 57.4, 51.8,
32.2, 31.6, 30.1, 30.0, 26.9; MALDI-TOF-MS m/z: 297
[M+H]+.
4.1.80. General procedure L for synthesis of benzimidaz-
oles 64–65 and 67. To a solution of nitro monoacylated
precursor (2 mmol, 1 equiv) in 10 mL of absolute EtOH
were added SnCl2 (4 mmol, 2 equiv) and HCl 12 N
(20 mmol, 10 equiv). Following reflux of the mixture
for 24 h, the solvent was evaporated, the residue diluted
with CH2Cl2, washed with aqueous NaHCO3 5%, dried
over MgSO4 and concentrated. The expected benzimid-
azole was obtained after purification by TLC.
4.1.85. 2-Benzyl-1H-benzoimidazole (4). Compound 4
was prepared according to the general procedure I start-
ing from compound 4i (150 mg, 0.66 mmol, 1 equiv) and
was obtained after purification by trituration in a Et2O/
pentane mixture. Yield: 75%; white solid; mp 179–
180 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.45; tR (C18 Xter-
ra, method B): 4.30 min, PHPLC: 99%; 1H NMR d: 12.27
(s, 1H, NH), 7.52–7.10 (m, 9H, ArH), 4.17 (s, 2H, CH2);
13C NMR d: 154.4, 138.5, 129.6, 129.3, 127.4, 122.5,
121.8, 119.2, 111.8, 35.8; MALDI-TOF-MS m/z: 209
[M+H]+.
4.1.81. 2-(Cyclohexylphenylmethyl)-1H-benzoimidazole
(1). Compound 1 was prepared according to the general
procedure I starting from compound 1o (250 mg,
0.81 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 51%; white solid;
mp 195–197 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2): 0.45; tR
1
(TSK gel, method B): 5.06 min, PHPLC: 99%; H NMR
4.1.86.
2-Cyclohexylmethyl-1H-benzoimidazole
(5).
d: 12.18 (s, 1H, NH), 7.53 (m, 1H, ArH), 7.45 (m, 1H,
ArH), 7.37 (m, 1H, ArH), 7.25 (m, 2H, ArH), 7.17 (m,
1H, ArH), 7.07 (m, 2H, ArH), 3.80 (d, J = 10.7 Hz, 1H,
CH), 2.29 (m, 1H, CH), 1.58–0.91 (m, 10H, CH2 cyclohex-
yl); 13C NMR d: 157.2, 144.2, 141.7, 134.7, 129.2, 129.1,
127.4, 122.3, 121.7, 119.2, 53.3, 41.9, 32.3, 31.6, 29.8,
26.8, 26.4; MALDI-TOF-MS m/z: 291 [M+H]+.
Compound 5 was prepared according to the general pro-
cedure I starting from compound 5i (150 mg, 0.64 mmol,
1 equiv) and was obtained after purification by tritur-
ation in a Et2O/pentane mixture. Yield: 84%; white sol-
id; mp 195–197 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.45; tR
(C18 Xterra, method B): 4.89 min, PHPLC: 99%; 1H
NMR d: 7.49–7.44 (m, 2H, ArH), 7.14–7.10 (m, 2H,
ArH), 2.69 (d, J = 7.1 Hz, 2H, CH2), 1.69–1.16
(m, 11H, CH + CH2 cyclohexyl); 13C NMR d: 154.9,
121.7, 118.8, 111.5, 48.3, 37.1, 34.2, 33.5, 26.5;
MALDI-TOF-MS m/z: 215 [M+H]+.
4.1.82. 2-Benzhydryl-1H-benzoimidazole (2). Compound
2 was prepared according to the general procedure J
starting from compound 2i (200 mg, 0.6 mmol,
1 equiv) and was obtained after purification by TLC
(cyclohexane/AcOEt 7:3). Yield: 58%; white solid;
mp 210–212 ꢁC; Rf (cyclohexane/AcOEt 7:3): 0.45; tR
(C18 Xterra, method B): 5.35 min, PHPLC: 99%; 1H
NMR d: 12.31 (s, 1H, NH), 7.40–7.11 (m, 14H,
ArH), 5.74 (s, 1H, CH); 13C NMR d: 156.1, 142.3,
129.5, 129.3, 122.7, 121.9, 119.4, 112.0, 51.6; MAL-
DI-TOF-MS m/z: 285 [M+H]+.
4.1.87. 2-Naphthalen-2-ylmethyl-1H-benzoimidazole (6).
Compound 6 was prepared according to the general pro-
cedure I starting from crude compound 6i (1.07 mmol,
1 equiv) and was obtained after purification by tritur-
ation in a Et2O/pentane mixture. Yield: 34% global;
white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5):
0.65; tR (TSK gel, method A): 4.72 min, PHPLC: 92%;
1H NMR d: 12.20 (s, 1H, NH), 7.88–7.83 (m, 4H,
ArH), 7.53–7.42 (m, 5H, ArH), 7.14–7.09 (m, 2H,
ArH), 4.35 (s, 2H, CH2); 13C NMR d: 154.3, 134.4,
132.5, 129.3, 128.3, 127.1, 126.6, 126.5, 124.9, 122.5,
121.8, 119.1, 111.8, 33.6; MALDI-TOF-MS m/z: 259
[M+H]+.
4.1.83. N-(2-Acetylaminophenyl)-2,2-dicyclohexylaceta-
mide (3i0). Compound 3i0 was prepared according to
the general procedure I starting from compound 3i
(150 mg, 0.48 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH 9.6:0.4). Yield:
47%; white solid; Rf (CH2Cl2/MeOH 9.6:0.4): 0.55; tR
1
(TSK gel, method B): 8.87 min, PHPLC: 99%; H NMR
4.1.88. 2-Naphthalen-1-ylmethyl-1H-benzoimidazole (7).
Compound 7 was prepared according to the general
procedure I starting from compound 7i (370 mg,
1.34 mmol, 1 equiv) and was obtained after purifica-
tion by trituration in a Et2O/pentane mixture. Yield:
78%; light yellow solid; mp > 225 ꢁC; Rf (CH2Cl2/
d: 9.22 (s, 1H, NH), 9.21 (s, 1H, NH), 7.34–7.25 (m,
2H, ArH), 7.08–7.04 (m, 2H, ArH), 3.19 (s, 3H, CH3),
1.95 (m, 1H, CH), 1.58–1.54 (m, 12H, H cyclohexyl),
1.62–0.83 (m, 10H, H cyclohexyl); MALDI-TOF-MS
m/z: 357 [M+H]+.

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4509
MeOH 9.6:0.4): 0.40; tR (TSK gel, method B):
5.21 min, PHPLC: 99%; 1H NMR d: 12.17 (s, 1H,
NH), 8.15 (m, 1H, ArH), 7.88 (m, 1H, ArH), 7.80
(m, 1H, ArH), 7.46 (m, 5H, ArH), 7.33 (m, 1H,
ArH), 7.05 (m, 2H, ArH), 4.59 (s, 2H, CH2); 13C
NMR d: 154.3, 134.4, 132.5, 129.3, 128.3, 127.1,
126.6, 126.5, 124.9, 122.5, 121.8, 119.1, 111.8, 33.6;
MALDI-TOF-MS m/z: 259 [M+H]+.
2.90 (m, 2H, CH2); 13C NMR d: 158.8, 143.9, 136.5,
136.2, 135.2, 129.8, 129.6, 126.6, 126.5, 122.4, 121.7,
119.2, 111.7, 48.4, 35.2, 34.5, 29.2; MALDI-TOF-MS
m/z: 283 [M+H]+.
4.1.93.
2-(4-Propylphenyl)-1H-benzoimidazole
(12).
Compound 12 was prepared according to the general
procedure J starting from compound 12i (500 mg,
1.76 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.6:0.4). Yield: 75%; white sol-
id; mp 197–198 ꢁC; Rf (CH2Cl2/MeOH 9.6:0.4): 0.50; tR
(C18 Xterra, method B): 5.65 min, PHPLC: 99%; 1H
NMR d: 12.74 (s, 1H, NH), 8.01 (m, 2H, ArH), 7.54
(m, 2H, ArH), 7.27 (m, 2H, ArH), 7.11 (m, 2H, ArH),
2.53 (t, J = 7.3 Hz, 2H, CH2), 1.56 (m, 2H, CH2), 0.83
(t, J = 7.3 Hz, 3H, CH3); 13C NMR d: 152.3, 145.0,
129.7, 128.6, 127.2, 123.1, 122.4, 119.5, 112.0, 37.9,
26.4, 14.5; MALDI-TOF-MS m/z: 237 [M+H]+.
4.1.89. 2-(1H-Indol-3-ylmethyl)-1H-benzoimidazole (8).
Compound 8 was prepared according to the general pro-
cedure I starting from compound 8i (300 mg, 1.13 mmol,
1 equiv) and was obtained after purification by tritur-
ation in a Et2O/pentane mixture. Yield: 78%; white sol-
id; mp 173–175 ꢁC; Rf (CH2Cl2/MeOH 9.6:0.4): 0.25; tR
1
(TSK gel, method B): 4.65 min, PHPLC: 99%; H NMR
d: 12.03 (s, 1H, NH), 10.91 (s, 1H, NH), 7.45 (m, 2H,
ArH), 7.30 (m, 2H, ArH), 7.23 (m, 1H, ArH), 7.02 (m,
3H, ArH), 6.87 (m, 1H, ArH), 4.22 (s, 2H, CH2); 13C
NMR d: 162.7, 155.2, 144.2, 137.1, 135.3, 127.8, 124.6,
122.2, 121.9, 121.6, 119.3, 118.9, 112.3, 110.7, 26.3;
MALDI-TOF-MS m/z: 248 [M+H]+.
4.1.94.
Compound 13 was prepared according to the general
procedure starting from crude compound 13i
2-(1-Phenylpropyl)-1H-benzoimidazole
(13).
J
(1.85 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH/NH4OH 9.9:0.1:0.1). Yield:
40% global; white solid; mp 178–180 ꢁC; Rf (CH2Cl2/
MeOH/NH4OH 9.9:0.1:0.1): 0.45; tR (C18 Xterra, meth-
od B): 5.22 min, PHPLC: 99%; 1H NMR d: 7.31–7.02 (m,
9H, ArH), 4.00 (t, J = 7.7 Hz, 1H, CH), 2.25-2.18 (m,
1H, CH2), 2.01–1.91 (m, 1H, CH2), 0.79 (t, J = 7.3 Hz,
1H, CH3); 13C NMR d: 157.5, 143.1, 129.8, 128.6,
127.4, 122.0, 119.3, 111.8, 48.1, 28.4, 13.3; MALDI-
TOF-MS m/z: 237 [M+H]+.
4.1.90. 2-Benzo[b]thiophen-3-ylmethyl-1H-benzoimidaz-
ole (9). Compound 9 was prepared according to the gen-
eral procedure I starting from compound 9i (220 mg,
0.78 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 97%;
white solid; mp 217–219 ꢁC; Rf (CH2Cl2/MeOH
9.8:0.2): 0.45; tR (TSK gel, method B): 5.14 min, PHPLC
:
1
99%; H NMR d: 12.28 (s, 1H, NH), 7.96 (m, 1H, ArH
benzothiophenyl), 7.84 (m, 1H, ArH benzothiophenyl),
7.57 (s, 1H, ArH benzothiophenyl), 7.52 (m, 1H,
ArH), 7.40-7.32 (m, 3H, ArH benzothiophenyl + ArH),
7.10 (m, 2H, ArH), 4.42 (s, 2H, CH2); 13C NMR d:
140.6, 139.3, 125.5, 125.2, 124.9, 123.8, 122.9, 122.5,
121.8, 119.1, 118.7, 111.8, 29.3; MALDI-TOF-MS m/z:
265 [M+H]+.
4.1.95.
2-(2-Phenylpropyl)-1H-benzoimidazole
(14).
Compound 14 was prepared according to the general
procedure I starting from compound 14i (250 mg,
0.98 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 78%;
white solid; mp 152–154 ꢁC; Rf (CH2Cl2/MeOH
9.5:0.5): 0.55; tR (C18 Xterra, method B): 4.67 min,
4.1.91. 2-(1,2,3,4-Tetrahydronaphthalen-2-yl)-1H-benzo-
imidazole (10). Compound 10 was prepared according to
the general procedure I starting from compound 10i
(200 mg, 0.75 mmol, 1 equiv) and was obtained after puri-
fication by trituration in a Et2O/pentane mixture. Yield:
75%; white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH
9.5:0.5): 0.45; tR (C18 Xterra, method B): 5.06 min,
1
PHPLC: 99%; H NMR d: 12.18 (s, 1H, NH), 7.47–7.07
(m, 9H, ArH), 3.42 (m, 1H, CH), 3.13–2.98 (m, 2H,
CH2), 1.23 (d, J = 6.9 Hz, 3H, CH3); 13C NMR d:
176.4, 154.6, 147.1, 129.2, 127.6, 126.9, 122.2, 121.7,
118.9, 111.6, 39.2, 37.9, 22.6; MALDI-TOF-MS m/z:
237 [M+H]+.
1
PHPLC: 99%; H NMR d: 7.55 (m, 1H, ArH), 7.43 (m,
1H, ArH), 7.24–7.10 (m, 6H, ArH), 3.32 (m, 3H,
4.1.96. 2-(1-Phenylethyl)-1H-benzoimidazole (15). Com-
pound 15 was prepared according to the general proce-
dure I starting from compound 15i (250 mg, 1.04 mmol,
1 equiv) and was obtained after purification by tritur-
ation in a Et2O/pentane mixture. Yield: 87%; white sol-
id; mp 197–199 ꢁC; Rf (CH2Cl2/MeOH 9.7:0.3): 0.40; tR
(C18 Xterra, method B): 4.28 min, PHPLC: 99%; 1H
NMR d: 12.18 (s, 1H, NH), 7.57–7.07 (m, 9H, ArH),
4.37 (q, J = 7.2 Hz, 1H, CH), 1.69 (d, J = 7.2 Hz, 3H,
CH3); 13C NMR d: 158.2, 144.5, 129.3, 128.2, 127.4,
122.5, 121.7, 119.2, 111.8, 40.2, 21.3; MALDI-TOF-
MS m/z: 223 [M+H]+.
CH + CH2), 3.17 (m, 2H, CH2), 2.90 (m, 2H, CH2); 13
C
NMR d: 158.8, 143.9, 136.5, 136.2, 135.2, 129.8, 129.6,
126.6, 126.5, 122.4, 121.7, 119.2, 111.7, 48.4, 35.2, 34.5,
29.2; MALDI-TOF-MS m/z: 249 [M+H]+.
4.1.92. 2-(9H-Fluoren-9-yl)-1H-benzoimidazole (11).
Compound 11 was prepared according to the general
procedure I starting from compound 11i (110 mg,
0.36 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.5:0.5). Yield: 95%; white sol-
id; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.50; tR
(C18 Xterra, method B): 5.36 min, PHPLC: 99%; 1H
NMR d: 12.16 (s, 1H, NH), 7.96 (m, 2H, ArH), 7.52–
7.42 (m, 5H, ArH), 7.35–7.28 (m, 3H, ArH), 7.11–7.08
(m, 2H, ArH), 5.53 (s, 1H, CH), 3.17 (m, 2H, CH2),
4.1.97. 2-(2-Iodophenyl)-1H-benzoimidazole (16). Com-
pound 16 was prepared according to the general proce-
dure K starting from crude compound 16i (5 mmol,

4510
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
1 equiv) and was obtained after purification by tritur-
ation in a Et2O/pentane mixture. Yield: 78% global;
white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5):
0.65; tR (TSK gel, method B): 4.65 min, PHPLC: 99%;
1H NMR d: 12.73 (s, 1H, NH), 8.09 (m, 1H, ArH),
7.66–7.54 (m, 4H, ArH), 7.32–7.22 (m, 3H, ArH); 13C
NMR d: 153.4, 140.5, 137.4, 132.2, 132.0, 129.0, 122.9,
98.2; MALDI-TOF-MS m/z: 321 [M+H]+.
7.30 (m, 2H, ArH phenyl), 7.22–7.16 (m, 3H, ArH phen-
yl), 7.13–7.07 (m, 2H, ArH), 2.53 (m, 1H, CH), 2.34 (m,
1H, CH), 1.78 (m, 1H, CH2), 1.59 (m, 1H, CH2); 13C
NMR d: 141.7, 129.0, 126.6, 126.3, 121.7, 27.5, 22.1,
17.9; MALDI-TOF-MS m/z: 235 [M+H]+.
4.1.102. 2-Phenyl-1H-benzoimidazole (21). White solid
(commercially available). Mp > 225 ꢁC; Rf (CH2Cl2/
MeOH 9.5:0.5): 0.40; tR (TSK gel, method B):
1
4.1.98. 2-(1-Phenylcyclopentyl)-1H-benzoimidazole (17).
Compound 17 was prepared according to the general
3.48 min, PHPLC: 100%; H NMR d: 8.21-8.16 (m, 2H,
ArH), 7.64–7.46 (m, 5H, ArH), 7.24–7.20 (m, 2H,
ArH); 13C NMR d: 154.0, 151.8, 145.9, 130.8, 130.5,
129.6, 127.1, 122.7; MALDI-TOF-MS m/z: 195
[M+H]+.
procedure
I starting from crude compound 17i
(1.85 mmol, 1 equiv) and was obtained after purification
by trituration in a hexane/AcOEt mixture. Yield: 30%
global; white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH
9.5:0.5): 0.65; tR (C18 Xterra, method B): 5.37 min,
PHPLC: 99%; 1H NMR d: 7.57–7.54 (m, 1H, ArH),
7.36–7.25 (m, 5H, ArH), 7.19–7.06 (m, 3H, ArH), 2.88
(m, 2H, CH2), 2.15-2.07 (m, 2H, CH2), 1.75–1.48 (m,
5H, CH + CH2); 13C NMR d: 129.1, 127.4, 127.0,
122.5, 121.6, 119.3, 111.7, 38.1, 34.2, 23.9; MALDI-
TOF-MS m/z: 263 [M+H]+.
4.1.103. 2-Piperidin-2-yl-1H-benzoimidazole (22). To a
solution of compound 22i (550 mg, 1.70 mmol,
1 equiv) in 10 mL of a MeOH/dioxane 1:1 mixture
was added 5 mL of aqueous HCl 4 N. Following re-
flux of the mixture for 20 h, the solvent was evaporat-
ed, the residue diluted with CH2Cl2, washed with
aqueous NaHCO3 5%, dried over MgSO4 and con-
centrated. The benzimidazole 22 was obtained after
purification by TLC (CH2Cl2/MeOH 9:1). Yield:
44%; white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH
4.1.99. 2-(Cyclopentylphenylmethyl)-1H-benzoimidazole
(18). Compound 18 was prepared according to the gen-
eral procedure I starting from compound 18i (250 mg,
0.88 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1). Yield:
63%; white solid; mp 208–210 ꢁC; Rf (CH2Cl2/MeOH/
NH4OH 9.8:0.2:0.1): 0.55; tR (TSK gel, method B):
9:1): 0.40; tR (TSK gel, method A): 2.82 min, PHPLC
:
1
99%; H NMR d: 7.48–7.45 (m, 2H, ArH), 7.13–7.01
(m, 2H, ArH), 3.88 (dd, J = 2.8, 10.0 Hz, 1H, CH),
3.03 (m, 1H, CH2), 2.70 (m, 1H, CH2), 1.94 (m,
1H, CH2), 1.81 (m, 1H, CH2), 1.64–1.43 (m, 4H,
CH2); 13C NMR d: 160.2, 157.8, 145.3, 121.7, 55.7,
46.6, 32.1, 26.2, 24.6; MALDI-TOF-MS m/z: 202
[M+H]+.
1
5.60 min, PHPLC: 99%; H NMR d: 12.26 (s, 1H, NH),
7.50–7.31 (m, 4H, ArH), 7.26 (m, 2H, ArH), 7.16 (m,
1H, ArH), 7.07 (m, 1H, ArH), 3.85 (d, J = 11.2 Hz,
1H, CH), 2.85 (m, 1H, CH), 1.64-1.42 (m, 6H, CH2
cyclopentyl), 1.10 (m, 2H, CH2 cyclopentyl); 13C
NMR d: 157.8, 142.9, 129.2, 128.9, 127.4, 122.3, 121.7,
119.2, 111.7, 52.5, 44.6, 32.2, 25.6, 25.5; MALDI-
TOF-MS m/z: 277 [M+H]+.
4.1.104. 2-Biphenyl-2-yl-1H-benzoimidazole (23). Com-
pound 23 was prepared according to the general proce-
dure I starting from compound 23i (200 mg, 0.70 mmol,
1 equiv) and was obtained after purification by TLC
(CH2Cl2/MeOH 9.7:0.3). Yield: 74%; white solid; mp
212–213 ꢁC; Rf (CH2Cl2/MeOH 9.7:0.3): 0.40; tR (C18
4.1.100. 2-(1-Phenylheptyl)-1H-benzoimidazole (19).
Compound 19 was prepared according to the general pro-
cedure K starting from crude compound 19i (3.33 mmol,
1 equiv) and was obtained after purification by TLC
(CH2Cl2/MeOH 9.8:0.2). Yield: 20% global; white solid;
mp 107–115 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2): 0.80; tR
1
Xterra, method B): 5.06 min, PHPLC: 99%; H NMR d:
12.07 (s, 1H, NH), 7.72–7.69 (m, 1H, ArH), 7.63–7.48
(m, 4H, ArH), 7.33–7.25 (m, 1H, ArH), 7.24–7.10 (m,
7H, ArH); 13C NMR d: 152.9, 144.3, 141.8, 140.9,
135.4, 131.9, 131.3, 131.0, 130.7, 129.6, 128.9, 128.2,
127.9, 122.9, 122.1, 119.7, 112.1; MALDI-TOF-MS m/
z: 271 [M+H]+.
1
(TSK gel, method A): 5.74 min, PHPLC: 99%; H NMR
d: 12.21 (s, 1H, NH), 7.55 (m, 1H, ArH), 7.39–7.35 (m,
3H, ArH), 7.32–7.27 (m, 2H, ArH), 7.21 (m, 1H, ArH),
7.13–7.06 (m, 2H, ArH), 4.15 (t, J = 7.7 Hz, 1H, CH),
2.28 (m, 1H, CH2), 2.01 (m, 1H, CH2), 1.29–1.18 (m,
8H, 4 CH2), 0.81 (t, J = 6.7 Hz, 3H, CH3); 13C NMR d:
157.4, 143.8, 143.0, 129.0, 128.3, 127.2, 122.2, 121.5,
118.9, 111.5, 46.0, 35.1, 31.7, 29.1, 27.9, 22.6, 14.5; MAL-
DI-TOF-MS m/z: 293 [M+H]+.
4.1.105. 2-Biphenyl-4-yl-1H-benzoimidazole (24). Com-
pound 24 was prepared according to the general proce-
dure J starting from crude compound 24o (1.85 mmol,
1 equiv) and was obtained after purification by TLC
(CH2Cl2/MeOH/NH4OH 9.8:0.1:0.1). Yield: 60% glob-
al; white solid; mp 178–180 ꢁC; Rf (CH2Cl2/MeOH/
NH4OH 9.9:0.1:0.1): 0.40; tR (C18 Xterra, method B):
1
4.1.101. 2-(trans-2-Phenylcyclopropyl)-1H-benzoimidaz-
ole (20). Compound 20 was prepared according to the
general procedure I starting from compound 20i
(350 mg, 1.38 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH 9.6:0.4). Yield:
74%; white solid; mp 150–154 ꢁC; Rf (CH2Cl2/MeOH
6.16 min, PHPLC: 99%; H NMR d: 8.27 (d, J = 8.4 Hz,
2H, ArH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.78 (d,
J = 7.2 Hz, 2H, ArH biphenyl), 7.62 (m, 2H, ArH biphe-
nyl), 7.51 (t, J = 7.1 Hz, 2H, ArH biphenyl), 7.41 (m,
1H, ArH biphenyl), 7.24–7.18 (m, 2H, ArH biphenyl);
13C NMR d: 151.8, 142.1, 140.1, 129.9, 128.7, 128.0,
127.9, 127.5, 122.9, 115.3; MALDI-TOF-MS m/z: 271
[M+H]+.
9.6:0.4): 0.70; tR (TSK gel, method B): 4.99 min, PHPLC
:
99%; 1H NMR d: 12.28 (s, 1H, NH), 7.44 (m, 2H, ArH),

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4511
4.1.106. 2-Biphenyl-3-yl-1H-benzoimidazole (25). Com-
pound 25 was prepared according to the general proce-
(TSK gel, method A): 4.68 min, PHPLC: 99%; 1H
NMR d: 12.07 (s, 1H, NH), 7.70-7.67 (m, 1H, ArH),
7.62–7.56 (m, 4H, ArH), 7.34 (m, 1H, ArH), 7.13 (m,
2H, ArH), 7.11–7.03 (m, 4H, ArH), 2.24 (s, 3H, CH3);
13C NMR d: 152.8, 144.1, 141.5, 137.8, 136.9, 135.1,
131.7, 131.0, 130.7, 130.4, 129.4, 129.2, 127.7, 122.6,
121.8, 119.4, 111.9, 21.2; MALDI-TOF-MS m/z: 277
[M+H]+.
dure
K
starting from compound 25i (300 mg,
1.04 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 78%; white sol-
id; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2): 0.50; tR
(TSK gel, method A): 4.94 min, PHPLC: 99%; 1H
NMR d: 13.00 (s, 1H, NH), 8.48 (t, J = 1.6 Hz, 1H,
ArH), 8.19 (dt, J = 1.2, 7.8 Hz, 1H, ArH), 7.81–7.77
(m, 3H, ArH), 7.69–7.61 (m, 2H, ArH), 7.56–7.50 (m,
3H, ArH), 7.46–7.40 (m, 1H, ArH), 7.22 (m, 2H,
ArH); 13C NMR d: 130.3, 129.7, 128.6, 128.5, 127.4,
126.1, 125.2, 123.3, 111.9; MALDI-TOF-MS m/z: 271
[M+H]+.
4.1.111. 2-(2-Phenethylphenyl)-1H-benzoimidazole (30).
Compound 30 was prepared according to the general
procedure K starting from compound 30i (800 mg,
2.53 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 44%;
white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2):
0.55; tR (TSK gel, method B): 5.88 min, PHPLC: 97%;
1H NMR d: 12.59 (s, 1H, NH), 7.64–7.60 (m, 2H,
ArH), 7.43 (m, 1H, ArH), 7.31–7.26 (m, 3H, ArH),
7.15–7.08 (m, 6H, ArH), 7.05–7.02 (m, 1H, ArH), 3.20
(m, 2H, CH2), 2.69 (m, 2H, CH2); 13C NMR d: 152.6,
144.7, 142.8, 142.1, 135.2, 131.6, 130.6, 130.5, 130.3,
129.2, 129.0, 127.1, 126.6, 123.2, 122.3, 119.7, 112.1,
37.9, 26.9; MALDI-TOF-MS m/z: 299 [M+H]+.
4.1.107. 2-(2-Furan-2-ylphenyl)-1H-benzoimidazole (26).
Compound 26 was prepared according to the general
procedure K starting from compound 26i (400 mg,
1.43 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 54%; light yel-
low solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.7:0.3):
0.45; tR (TSK gel, method A): 3.92 min, PHPLC: 99%;
1H NMR d: 12.53 (s, 1H, NH), 7.85 (dd, J = 1.6,
8.0 Hz, 1H, ArH), 7.64–7.48 (m, 4H, ArH), 7.47 (m,
2H, ArH), 7.24–7.18 (m, 2H, ArH), 6.40 (m, 1H,
ArH), 5.84 (m, 1H, ArH); 13C NMR d: 143.8, 132.2,
130.8, 128.3, 127.4, 123.1, 112.7, 109.4; MALDI-TOF-
MS m/z: 261 [M+H]+.
4.1.112. 2-(2-Benzylphenyl)-1H-benzoimidazole (31).
Compound 31 was prepared according to the general
procedure K starting from compound 31i (450 mg,
1.49 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 61%;
white solid; mp 196–198 ꢁC; Rf (CH2Cl2/MeOH
4.1.108.
2-(40-Fluorobiphenyl-2-yl)-1H-benzoimidazole
(27). Compound 27 was prepared according to the gen-
eral procedure K starting from crude compound 27i
(1.1 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 30% global;
white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.7:0.3):
0.50; tR (TSK gel, method A): 4.45 min, PHPLC: 99%;
1H NMR d: 12.10 (s, 1H, NH), 7.74 (d, J = 7.4 Hz,
1H, ArH), 7.61–7.49 (m, 5H, ArH), 7.38–7.33 (m, 1H,
ArH), 7.23–7.06 (m, 5H, ArH); 13C NMR d: 140.7,
137.4, 131.9, 131.7, 131.5, 131.4, 131.0, 130.7, 128.4,
123.0, 122.1, 119.7, 115.9, 115.7, 112.1; MALDI-TOF-
MS m/z: 289 [M+H]+.
9.8:0.2): 0.80; tR (TSK gel, method B): 5.49 min, PHPLC:
1
99%; H NMR d: 12.68 (s, 1H, NH), 7.72–7.67 (m, 2H,
ArH), 7.53 (m, 1H, ArH), 7.45–7.31 (m, 3H, ArH),
7.22–7.05 (m, 7H, ArH), 4.54 (m, 2H, CH2); 13C
NMR d: 141.9, 141.3, 131.6, 130.4, 130.1, 129.3, 128.8,
126.9, 126.4, 38.6; MALDI-TOF-MS m/z: 285 [M+H]+.
4.1.113. 2-(3-Bromophenyl)-1H-benzoimidazole (32).
Compound 32 was prepared according to the general
procedure I starting from compound 32i (480 mg,
1.65 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 86%;
white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.7:0.3):
0.60; tR (TSK gel, method A): 4.17 min, PHPLC: 99%;
1H NMR d: 12.80 (s, 1H, NH), 8.37 (s, 1H, ArH),
8.18 (d, J = 7.8 Hz, 1H, ArH), 7.68 (d, J = 8.0 Hz, 1H,
ArH), 7.61 (m, 2H, ArH), 7.51 (m, 1H, ArH), 7.22 (m,
2H, ArH); 13C NMR d: 150.2, 133.0, 131.8, 129.5,
125.9, 123.0, 97.7; MALDI-TOF-MS m/z: 274 [M+H]+.
4.1.109. 2-(2-Thiophen-2-ylphenyl)-1H-benzoimidazole
(28). Compound 28 was prepared according to the gen-
eral procedure K starting from compound 28i (700 mg,
2.38 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 56%; white sol-
id; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2): 0.60; tR
(TSK gel, method A): 4.19 min, PHPLC: 99%; 1H
NMR d: 12.42 (s, 1H, NH), 7.69 (d, J = 7.8 Hz, 1H,
ArH), 7.63–7.55 (m, 3H, ArH), 7.52–7.43 (m, 3H,
ArH), 7.19 (m, 2H, ArH), 6.96–6.90 (m, 2H, ArH);
13C NMR d: 152.1, 142.0, 134.4, 131.9, 130.7, 130.4,
128.1, 128.0, 127.6, 127.0, 121.9; MALDI-TOF-MS
m/z: 277 [M+H]+.
4.1.114. 2-(Phenylpiperidin-1-ylmethyl)-1H-benzoimidaz-
ole (33). Compound 33 was prepared according to the
general procedure I starting from compound 33i
(450 mg, 1.45 mmol, 1 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 64%; white solid; mp 197–201 ꢁC; Rf (CH2Cl2/
MeOH/NH4OH 9.8:0.2:0.1): 0.45; tR (TSK gel, method
1
4.1.110. 2-(40-Methylbiphenyl-2-yl)-1H-benzoimidazole
(29). Compound 29 was prepared according to the gen-
eral procedure K starting from compound 29i (600 mg,
1.98 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.8:0.2). Yield: 42%; white sol-
id; mp > 225 ꢁC; Rf (CH2Cl2/MeOH 9.8:0.2): 0.55; tR
A): 4.25 min, PHPLC: 99%; H NMR d: 12.21 (s, 1H,
NH), 7.44 (m, 3H, ArH), 7.33 (m, 1H, ArH), 7.25 (m,
2H, ArH), 7.17 (m, 1H, ArH), 7.02 (m, 2H, ArH),
4.54 (s, 1H, CH), 2.27 (m, 2H, CH2), 2.15 (m, 2H,
CH2), 1.44 (m, 4H, CH2), 1.30 (m, 2H, CH2); 13C
NMR d: 155.6, 143.6, 140.1, 135.2, 129.2, 128.3, 122.7,

4512
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
121.8, 119.3, 112.1, 71.1, 53.2, 26.4, 24.9; MALDI-TOF-
(m, 2H, CH2), 1.45 (m, 2H, CH2); 13C NMR d: 155.7,
140.3, 129.3, 129.1, 128.3, 122.7, 121.8, 119.3, 112.2,
70.5, 67.0, 50.2, 50.0, 35.1; MALDI-TOF-MS m/z: 308
[M+H]+.
MS m/z: 292 [M+H]+.
4.1.115. 2-(Morpholin-4-ylphenylmethyl)-1H-benzoimi-
dazole (34). Compound 34 was prepared according to
the general procedure I starting from crude compound
34i (2 mmol, 1 equiv) and was obtained after purifica-
tion by trituration in a Et2O/pentane mixture. Yield:
25% global; white solid; mp > 225 ꢁC; Rf (cyclohexane/
AcOEt 8:2): 0.65; tR (TSK gel, method A): 4.29 min,
4.1.119. [(1H-Benzoimidazol-2-yl)phenylmethyl]cyclohex-
ylamine (38). Compound 38 was prepared according to
the general procedure K starting from compound 38i
(450 mg, 1.4 mmol, 1 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 30%; white solid; mp 174–175 ꢁC; Rf (CH2Cl2/
MeOH/NH4OH 9.6:0.4:0.1): 0.45; tR (TSK gel, method
1
PHPLC: 99%; H NMR d: 12.38 (s, 1H, NH), 7.58–7.44
(m, 3H, ArH), 7.37–7.32 (m, 2H, ArH), 7.29–7.23 (m,
2H, ArH), 7.11 (m, 2H, ArH), 4.64 (s, 1H, CH), 3.60
(m, 4H, 2 CH2), 2.40 (m, 2H, CH2), 2.29 (m, 2H,
CH2); 13C NMR d: 129.1, 128.3, 70.7, 66.8, 52.5; MAL-
DI-TOF-MS m/z: 294 [M+H]+.
1
A): 4.51 min, PHPLC: 99%; H NMR d: 12.26 (s, 1H,
NH benzimidazolyl), 7.47 (m, 4H, ArH), 7.34 (m, 2H,
ArH), 7.22 (m, 1H, ArH), 7.11 (m, 2H, ArH), 5.24 (s,
1H, CH), 2.33 (m, 1H, CH), 1.86 (m, 2H, CH2), 1.64
(m, 2H, CH2), 1.49 (m, 1H, CH2), 1.10 (m, 5H, CH2);
13C NMR d: 128.9, 128.0, 127.9, 58.7, 54.5, 33.2, 26.3,
25.0; MALDI-TOF-MS m/z: 307 [M+H]+.
4.1.116. 2-(Azepan-1-ylphenylmethyl)-1H-benzoimidazole
(35). Compound 35 was prepared according to the gen-
eral procedure I starting from compound 35i (300 mg,
0.92 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 68%;
white solid; mp 191–194 ꢁC; Rf (CH2Cl2/MeOH
4.1.120. (1H-Benzoimidazol-2-yl)cyclohexylphenylamine
(39). To
a solution of compound 39i (300 mg,
0.84 mmol, 1 equiv) in 7 mL of absolute EtOH was add-
ed tin chloride (316 mg, 1.68 mmol, 2 equiv). Following
reflux of the mixture for 5 h, the solvent was evaporated
and the residue purified by TLC (CH2Cl2/MeOH/
NH4OH 9.8:0.2:0.1) to afford compound 39. Yield:
41%; white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH/
NH4OH 9.8:0.2:0.1): 0.40; tR (TSK gel, method A):
9.6:0.4): 0.45; tR (TSK gel, method A): 4.61 min, PHPLC
:
99%; 1H NMR d: 12.23 (s, 1H, NH), 7.52 (m, 3H, ArH),
7.43 (m, 1H, ArH), 7.33 (m, 2H, ArH), 7.23 (m, 1H,
ArH), 7.11 (m, 2H, ArH), 4.99 (s, 1H, CH), 2.64 (m,
4H, 2 CH2), 1.58 (m, 8H, 4 CH2); 13C NMR d: 162.7,
156.0, 143.6, 141.2, 135.2, 129.1, 129.0, 128.2, 122.7,
121.8, 119.4, 112.1, 69.6, 53.7, 29.0, 27.2; MALDI-
TOF-MS m/z: 306 [M+H]+.
1
5.18 min, PHPLC: 99%; H NMR d: 10.37 (s, 1H, NH
benzimidazolyl), 7.50–7.37 (m, 3H, ArH), 7.28–7.20
(m, 5H, ArH), 4.41 (m, 1H, CH cyclohexyl), 1.94 (m,
2H, CH2 cyclohexyl), 1.71 (m, 2H, CH2 cyclohexyl),
1.54 (m, 1H, CH2 cyclohexyl), 1.42–1.32 (m, 2H, CH2
cyclohexyl), 1.13–1.06 (m, 2H, CH2 cyclohexyl), 0.91
(m, 1H, CH2 cyclohexyl); 13C NMR d: 155.8, 140.4,
131.4, 130.5, 128.5, 57.7, 32.2, 26.3, 26.0; MALDI-
TOF-MS m/z: 292 [M+H]+.
4.1.117. 1-[(1H-Benzoimidazol-2-yl)phenylmethyl]pyrroli-
din-3-ylamine (36). Compound 36 was prepared accord-
ing to the general procedure K starting from compound
36i (450 mg, 1.09 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH/NH4OH 9:1:0.1).
Yield: 20%; white solid; mp 74–80 ꢁC; Rf (CH2Cl2/
MeOH/NH4OH 9.6:0.4:0.1): 0.30; tR (TSK gel, method
1
A): 3.38–3.45 min, PHPLC: 99%; H NMR d: 12.23 (s,
4.1.121. (1H-Benzoimidazol-2-yl)-(2-piperidin-1-ylphe-
nyl)amine (40). To a solution of compound 40i
(750 mg, 2.1 mmol, 1 equiv) in 10 mL of absolute EtOH
was added tin chloride (792 mg, 4.2 mmol, 2 equiv). Fol-
lowing reflux of the mixture for 5 h, the solvent was
evaporated and the residue purified by two successive
TLC (CH2Cl2/MeOH 9.8:0.2, then cyclohexane/
AcOEt/NH4OH 7:3:0.05) to afford compound 40. Yield:
25%; white solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH
1H, NH), 7.48 (d, J = 7.7 Hz, 2H, ArH phenyl), 7.33
(m, 2H, ArH), 7.24 (t, J = 7.2 Hz, 2H, ArH phenyl),
7.16 (d, J = 7.2 Hz, 1H, ArH phenyl), 7.02 (m, 2H,
ArH), 4.60 (m, 3H, CH + NH2), 3.35 (m, 1H, CH),
2.52 (m, 2H, CH2), 2.30 (m, 1H, CH2), 2.15 (m, 1H,
CH2), 1.96 (m, 1H, CH2), 1.40 (m, 1H, CH2); 13C
NMR d: 156.2, 156.1, 141.0, 129.0, 128.6, 128.1, 121.9,
115.6, 69.7, 69.6, 61.9, 61.7, 51.9, 50.8, 34.1; MALDI-
TOF-MS m/z: 293 [M+H]+.
9.9:0.1): 0.25; tR (TSK gel, method A): 4.25 min, PHPLC
:
1
99%; H NMR d: 11.59 (s, 1H, NH benzimidazolyl),
8.59 (dd, J = 1.4, 8.1 Hz, 1H, ArH), 8.28 (s, 1H, NH),
7.35–7.29 (m, 2H, ArH benzimidazolyl), 7.18 (dd,
J = 1.4, 7.8 Hz, 1H, ArH), 7.12 (td, J = 1.2, 7.9 Hz,
1H, ArH), 7.02–6.98 (m, 2H, ArH benzimidazolyl),
6.92 (td, J = 1.5, 7.6 Hz, 1H, ArH), 2.78 (t, J = 5.0 Hz,
4H, 2 CH2), 1.78 (m, 4H, 2 CH2), 1.59 (m, 2H, CH2);
13C NMR d: 151.2, 141.9, 135.5, 125.1, 121.5, 120.9,
120.4, 117.3, 116.6, 53.8, 26.6, 24.3; MALDI-TOF-MS
m/z: 293 [M+H]+.
4.1.118. 1-[(1H-Benzoimidazol-2-yl)phenylmethyl] piperi-
din-4-ol (37). Compound 37 was prepared according to
the general procedure K starting from compound 37i
(220 mg, 0.67 mmol, 1 equiv) and was obtained after
purification
by
TLC
(CH2Cl2/MeOH/NH4OH
9.6:0.4:0.1). Yield: 40%; white solid; mp > 225 ꢁC; Rf
(CH2Cl2/MeOH/NH4OH 9.6:0.4:0.1): 0.40; tR (TSK
gel, method A): 3.94 min, PHPLC: 99%; 1H NMR d:
12.29 (s, 1H, NH), 7.53 (m, 3H, ArH), 7.43 (m, 1H,
ArH), 7.34 (m, 2H, ArH), 7.25 (m, 1H, ArH), 7.12 (m,
2H, ArH), 4.64 (s, 1H, CH), 4.57 (d, J = 4.0 Hz, 1H,
OH), 3.45 (m, 1H, CH), 2.67 (m, 1H, CH2), 2.51 (m,
1H, CH2), 2.12 (m, 1H, CH2), 1.99 (m, 1H, CH2), 1.72
4.1.122. 2-(Cyclohexylphenylmethyl)benzooxazole (41).
To a solution of 2-aminophenol (300 mg, 2.75 mmol,
1 equiv) in 10 mL of THF were added cyclohexylphenyl-

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4513
acetic acid (660 mg, 3.02 mmol, 1.1 equiv) and a solu-
tion of DCC 1 M in CH2Cl2 (3.02 mL, 3.02 mmol,
1.1 equiv). After stirring for 12 h at room temperature,
the mixture was flitrated and the solvents were evaporat-
ed. The residue was diluted with CH2Cl2, washed with
aqueous NaHCO3 5%, dried over MgSO4 and concen-
trated. To a solution of the residue in 10 mL of toluene
126.2, 124.6, 117.2, 116.9, 57.3, 36.9, 31.8, 29.9, 27.1,
27.0, 26.9; MALDI-TOF-MS m/z: 334 [M+H]+.
4.1.125. 2-(Cyclohexylphenylmethyl)-4-nitro-1H-benzo-
imidazole (44). Compound 44 was prepared according
to the general procedure I starting from compound 44i
(200 mg, 0.56 mmol, 1 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 95%; yellow solid; mp 167-169 ꢁC; Rf (CH2Cl2/
MeOH 9.8:0.2): 0.80; tR (TSK gel, method B):
was
added
para-toluenesulfonic
acid
(2.61 g,
13.75 mmol, 5 equiv). Following reflux of the mixture
for 8 h, the solvent was evaporated, the residue was
diluted with CH2Cl2, washed with aqueous NaHCO3
5%, dried over MgSO4, and concentrated, and the resi-
due purified by TLC (cyclohexane/AcOEt 8:2) to afford
compound 41. Yield: 40%; white solid; mp 87–89 ꢁC; Rf
(cyclohexane/AcOEt 8:2): 0.70; tR (TSK gel, method B):
10.48 min, PHPLC: 99%; 1H NMR d: 7.62 (m, 1H, ArH),
7.55 (m, 1H, ArH), 7.34 (m, 2H, ArH), 7.22 (m, 4H,
ArH), 7.13 (m, 1H, ArH), 3.95 (d, J = 10.3 Hz, 1H,
CH), 2.14 (m, 1H, CH), 1.55-0.80 (m, 10H, CH2 cyclo-
hexyl); 13C NMR d: 168.2, 150.8, 141.5, 139.3, 129.5,
129.3, 128.0, 125.7, 125.2, 120.3, 111.5, 52.4, 41.9,
32.0, 31.1, 26.6, 26.3; MALDI-TOF-MS m/z: 292
[M+H]+.
1
7.72 min, PHPLC: 99%; H NMR d: 13.02 (s, 1H, NH),
7.99 (m, 2H, ArH), 7.43 (m, 2H, ArH), 7.31–7.19 (m,
3H, ArH), 7.10 (m, 1H, ArH), 4.10 (d, J = 10.7 Hz,
1H, CH), 2.24 (m, 1H, CH), 1.50-0.97 (m, 10H, H cyclo-
hexyl); 13C NMR d: 161.2, 147.5, 141.2, 133.5, 129.5,
129.1, 128.5, 127.5, 127.2, 121.8, 118.9, 51.6, 42.4,
32.2, 31.5, 26.7, 26.2; MALDI-TOF-MS m/z: not
observed.
4.1.126. 2-(Cyclohexylphenylmethyl)-1H-benzoimidazol-
4-ylamine (45). To a solution of compound 44 (300 mg,
0.89 mmol, 1 equiv) in 5 mL of EtOH were added iron
(299 mg, 5.34 mmol, 6 equiv) and HCl 12 N (200 lL,
2.3 mmol, 2.5 equiv). Following reflux of the mixture
for 6 h, the solvent was evaporated, the residue diluted
with CH2Cl2, washed with aqueous NaHCO3 5%, dried
over MgSO4, concentrated and the residue purified by
TLC (CH2Cl2/MeOH 9.6:0.4) to afford compound 45.
Yield: 44%; grey-green solid; mp 96–99 ꢁC; Rf (CH2Cl2/
MeOH 9.6:0.4): 0.50; tR (TSK gel, method B): 6.02 min,
4.1.123. 2-(Cyclohexylphenylmethyl)-3,4-dihydroquinazo-
line (42). Compound 42i (400 mg, 1.24 mmol, 1 equiv)
was diltued in 10 mL of neat acetic acid. Following re-
flux of the mixture for 24 h, the solvent was evaporated,
the residue diluted with CH2Cl2, washed with aqueous
NaHCO3 5%, dried over MgSO4, concentrated and the
residue purified by TLC (CH2Cl2/MeOH 9.5:0.5) to af-
ford compound 42. Yield: 40%; light yellow solid; mp
117–119 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.35; tR (TSK
gel, method B): 6.26 min, PHPLC: 99%; 1H NMR d:
10.83 (s, 1H, NH), 7.68 (m, 1H, ArH phenyl), 7.37 (m,
2H, ArH), 7.31 (m, 2H, ArH), 7.22 (m, 2H, ArH phen-
yl), 7.15 (m, 1H, ArH phenyl), 7.01 (m, 1H, ArH phen-
yl), 3.67 (d, J = 5.6 Hz, 2H, CH2), 3.18 (d, J = 10.7 Hz,
1H, CH), 2.11 (m, 1H, CH), 1.89 (m, 1H, H cyclohexyl),
1.72 (m, 1H, H cyclohexyl), 1.58 (m, 2H, H cyclohexyl),
1.26-1.05 (m, 6H, H cyclohexyl); 13C NMR d: 171.9,
140.1, 138.1, 129.3, 129.2, 129.0, 127.9, 127.7, 124.7,
123.2, 60.9, 44.5, 40.9, 32.2, 30.9, 26.8, 26.3; MALDI-
TOF-MS m/z: 305 [M+H]+.
1
PHPLC: 99%; H NMR d (isomere mixture 75:25): 11.70
(s, 0.75H, NH), 11.44 (s, 0.25H, NH), 7.21 (m, 2H,
ArH), 7.04 (m, 2H, ArH), 6.93 (m, 1H, ArH), 6.56-6.32
(m, 2H, ArH), 6.03 (m, 1H, ArH), 5.05 (s, 1.5H, NH2),
5.00 (s, 0.5H, NH2), 3.52 (d, J = 10.9 Hz, 0.75H, CH),
3.50 (d, J = 10.6 Hz, 0.25H, CH), 2.02 (m, 1H, CH),
1.35–0.81 (m, 10H, H cyclohexyl); 13C NMR d: 154.1,
142.0, 140.2, 129.2, 127.3, 123.4, 122.6, 107.8, 106.4,
104.9, 99.7, 53.6, 41.8, 32.4, 31.7, 26.8, 26.4; MALDI-
TOF-MS m/z: 306 [M+H]+.
4.1.127. [2-(Cyclohexylphenylmethyl)-1H-benzoimidazol-
4-yl]ethylamine (46). To a solution of compound 45
(250 mg, 0.82 mmol, 1 equiv) in 2.5 mL of methanol
were added, at 0 ꢁC, acetaldehyde (46 lL, 0.82 mmol,
1 equiv) and sodium cyanoborohydride (51.5 mg,
0.82 mmol, 1 equiv). After stirring the mixture for 24 h
at room temperature, the solvent was evaporated and
the residue purified by TLC (cyclohexane/AcOEt 6:4)
to afford compound 46. Yield: 30%; white solid; mp
90–98 ꢁC; Rf (cyclohexane/AcOEt 6:4): 0.65; tR (TSK
gel, method A): 5.77 min, PHPLC: 99%; 1H NMR d:
12.00 (s, 1H, NH), 7.44 (d, J = 7.4 Hz, 2H, ArH phenyl),
7.27 (t, J = 7.2 Hz, 2H, ArH phenyl), 7.15 (t, J = 7.3 Hz,
1 H, ArH phenyl), 6.85 (t, J = 7.9 Hz, 1H, ArH), 6.58 (d,
J = 7.2 Hz, 1H, ArH), 6.15 (d, J = 7.5 Hz, 1H, ArH),
5.21 (t, J = 5.8 Hz, 1H, NH), 3.22 (m, 2H, CH2 ethyl),
2.28 (m, 1H, CH cyclohexyl), 1.61–1.50 (m, 4H, H cyclo-
hexyl), 1.30 (m, 1H, H cyclohexyl), 1.22 (t, J = 7.1 Hz,
3H, CH3 ethyl), 1.21–1.07 (m, 5H, H cyclohexyl); 13C
NMR d: 141.8, 128.9, 127.1, 53.3, 41.6, 32.1, 31.5,
26.6, 26.2, 15.3; MALDI-TOF-MS m/z: 334 [M+H]+.
4.1.124. 2-Cyclohexyl-1-(3,4-dihydro-1H-isoquinolin-2-
yl)-2-phenyl-ethanone (43). To a solution of cyclohexyl-
phenylacetic acid (394 mg, 1.8 mmol, 1.2 equiv) in
10 mL of dry CH2Cl2 were added PybroP (838 mg,
1.8 mmol, 1.2 equiv), DIEA (520 lL, 3 mmol, 2 equiv)
and 1,2,3,4-tetrahydroquinoline (200 mg, 1.5 mmol,
1 equiv). After stirring for 12 h at room temperature,
the mixture was washed with aqueous NaHCO3 5%,
dried over MgSO4, concentrated and the residue purified
by TLC (CH2Cl2) to afford compound 43. Yield: 75%;
white solid; mp 106–108 ꢁC; Rf (CH2Cl2): 0.65; tR
(TSK gel, method B): 9.45 min, PHPLC: 100%; 1H
NMR d: 7.27–7.11 (m, 9H, ArH) 7.29–7.07 (m, 7H,
ArH), 7.07 (m, 1H, ArH), 6.88 (m, 1H, ArH), 6.70 (m,
1H, ArH), 6.53 (m, 1H, ArH), 4.71 (s, 2H, NH2), 2.09
(t, J = 7.2 Hz, 1H, CH), 1.68 (m, 12H, CH + CH2),
1.10 (m, 10H, CH2); 13C NMR d: 173.2, 142.8, 126.6,

4514
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4.1.128.
N-[2-(Cyclohexylphenylmethyl)-1H-ben-
0.3H, ArH), 8.19 (dd, J = 1.5, 4.8 Hz, 0.7H, ArH),
7.93 (dd, J = 1.4, 7.9 Hz, 0.7H, ArH), 7.79 (dd,
J = 1.5, 7.9 Hz, 0.3H, ArH), 7.47 (m, 2H, ArH phenyl),
7.32–7.22 (m, 2H, ArH phenyl), 7.21–7.12 (m, 2H, Ar-
H + ArH phenyl), 3.85 (d, J = 10.6 Hz, 0.3H, CH),
3.83 (d, J = 10.8 Hz, 0.7H, CH), 2.34 (m, 1H, CH cyclo-
hexyl), 1.59–1.36 (m, 5H, H cyclohexyl), 1.22–1.08 (m,
5H, H cyclohexyl); 13C NMR d: 159.6, 143.3, 142.9,
141.0, 135.6, 128.9, 128.8, 126.8, 126.1, 119.1, 117.5,
53.3, 41.4, 32.1, 31.3, 26.5, 26.1; MALDI-TOF-MS
m/z: 292 [M+H]+.
zoimidazol-4-yl]acetamide (47). Compound 47 was pre-
pared according to the general procedure J starting
from compound 44i (198 mg, 0.56 mmol, 1 equiv) and
was obtained after purification by TLC (CH2Cl2/MeOH
9.7:0.3). Yield: 75%; white solid; mp > 225 ꢁC; Rf
(CH2Cl2/MeOH 9.7:0.3): 0.40; tR (TSK gel, method
1
B): 5.74 min, PHPLC: 99%; H NMR d (isomere mixture
70:30): 12.37 (s, 0.7H, NH), 11.64 (s, 0.3H, NH), 9.76 (s,
0.3H, NHCOCH3), 9.63 (s, 0.7H, NHCOCH3), 7.45 (m,
2H, ArH), 7.20-7.08 (m, 2H, ArH), 7.01 (m, 1H, ArH),
3.88 (d, J = 10.6 Hz, 0.3H, CH), 3.83 (d, J = 11.1 Hz,
0.7H, CH), 2.27 (m, 1H, CH), 2.14 (s, 2.1H, CH3),
2.08 (s, 0.9H, CH3), 1.57–0.8 (m, 10H, H cyclohexyl);
13C NMR d: 156.1, 141.6, 135.3, 129.9, 129.3, 129.2,
127.4, 124.0, 122.6, 121.7, 115.6, 115.2, 106.9, 53.8,
52.6, 42.3, 32.4, 32.3, 31.7, 26.7, 26.4, 24.9, 24.4; MAL-
DI-TOF-MS m/z: 348 [M+H]+.
4.1.132. 2-(Cyclohexylphenylmethyl)-6-methyl-1H-benzo-
imidazole (51). Compound 51 was prepared according to
the general procedure I starting from compound 51i
(400 mg, 1.24 mmol, 1 equiv) and was obtained after
purification
by
TLC
(CH2Cl2/MeOH/NH4OH
9.7:0.3:0.1). Yield: 56%; orange solid; mp 202–204 ꢁC;
Rf (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1): 0.75; tR (TSK
gel, method B): 6.53 min, PHPLC: 99%; 1H NMR d:
12.03 (s, 1H, NH), 7.37 (m, 2H, ArH), 7.23 (m, 4H,
ArH), 7.09 (m, 1H, ArH), 6.83 (m, 1H, ArH), 3.69 (d,
J = 10.7 Hz, 1H, CH), 2.28 (s, 3H, CH3), 2.18 (m, 1H,
CH), 1.51–0.71 (m, 10H, H cyclohexyl); 13C NMR d:
156.9, 141.8, 129.3, 129.1, 127.3, 123.3, 111.7, 53.3,
42.8, 32.3, 31.7, 31.4, 26.8, 26.4, 22.1; MALDI-TOF-
MS m/z: 305 [M+H]+.
4.1.129. 2-(Cyclohexylphenylmethyl)-4-methyl-1H-benzo-
imidazole (48). Compound 48 was prepared according to
the general procedure I starting from compound 48i
(180 mg, 0.56 mmol, 1 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 90%; light brown solid; mp 95–97 ꢁC; Rf
(CH2Cl2/MeOH 9.7:0.3): 0.55; tR (TSK gel, method
1
B): 6.52 min, PHPLC: 99%; H NMR d: 12.10 (s, 1H,
NH), 7.42 (m, 2H, ArH), 7.33–7.21 (m, 3H, ArH),
7.12 (m, 1H, ArH), 6.93 (m, 1H, ArH), 6.83 (m, 1H,
ArH), 3.76 (m, 1H, CH), 2.38 (s, 3H, CH3), 2.21 (m,
1H, CH), 1.54-0.84 (m, 10H, H cyclohexyl); 13C NMR
d: 141.9, 130.5, 129.3, 129.1, 127.3, 122.8, 122.2, 116.6,
109.1, 53.2, 42.1, 32.4, 31.7, 26.8, 26.4, 18.0; MALDI-
TOF-MS m/z: 305 [M+H]+.
4.1.133. 2-(Cyclohexylphenylmethyl)-6-methoxy-1H-ben-
zoimidazole (52). Compound 52 was prepared according
to the general procedure I starting from compound 52i
(450 mg, 1.33 mmol, 1 equiv) and was obtained after
purification
by
TLC
(CH2Cl2/MeOH/NH4OH
9.8:0.2:0.1). Yield: 45%; white solid; mp 75–77 ꢁC; Rf
(CH2Cl2/MeOH/NH4OH 9.7:0.3:0.1): 0.50; tR (TSK
gel, method B): 6.26 min, PHPLC: 99%; 1H NMR d:
12.02 (s, 1H, NH), 7.42 (m, 2H, ArH), 7.35–7.23 (m,
3H, ArH), 7.17–7.12 (m, 1H, ArH), 6.96 (m, 1H,
ArH), 6.69 (m, 1H, ArH), 3.74 (d, J = 13.0 Hz, 1H,
CH), 3.71 (s, 3H, CH3), 2.24 (m, 1H, CH), 1.57–1.06
(m, 10H, H cyclohexyl); 13C NMR d: 156.8, 156.0,
141.8, 129.2, 129.1, 127.3, 111.3, 56.3, 53.3, 42.0, 32.3,
31.7, 26.8, 26.4; MALDI-TOF-MS m/z: 321 [M+H]+.
4.1.130. 8-(Cyclohexylphenylmethyl)-9H-purine (49).
Compound 49 was prepared according to the general
procedure I starting from compound 49i (300 mg,
0.96 mmol, 1 equiv) and was obtained after purification
by trituration in a Et2O/pentane mixture. Yield: 98%;
white solid; mp 208–210 ꢁC; Rf (CH2Cl2/MeOH
9.7:0.3): 0.45; tR (TSK gel, method B): 6.16 min, PHPLC
:
1
99%; H NMR d: 13.00 (s, 1H, NH), 8.97 (s, 1H, ArH),
8.80 (s, 1H, ArH), 7.22 (m, 2H, ArH phenyl), 7.06 (m,
2H, ArH phenyl), 6.96 (m, 1H, ArH phenyl), 3.89 (d,
J = 10.8 Hz, 1H, CH), 2.33 (m, 1H, CH), 1.59–0.98
(m, 10H, H cyclohexyl); 13C NMR d: 152.4, 140.5,
129.3, 127.8, 53.5, 41.7, 32.2, 31.4, 26.7, 26.3;
MALDI-TOF-MS m/z: 293 [M+H]+.
4.1.134. 2-(Cyclohexylphenylmethyl)-6-fluoro-1H-benzo-
imidazole (53). Compound 53 was prepared according
to the general procedure J starting from compound
53i (300 mg, 0.84 mmol, 1 equiv) and was obtained
after purification by TLC (CH2Cl2/MeOH 9.8:0.2).
Yield: 73%; light brown solid; mp 207–209 ꢁC; Rf
(CH2Cl2/MeOH 9.8:0.2): 0.55; tR (TSK gel, method
4.1.131.
2-(Cyclohexylphenylmethyl)-3H-imidazo[4,5-
1
b]pyridine (50). To a solution of crude compond 50i
(5.75 mmol, 1 equiv) in 10 mL of toluene was added
p-toluenesulfonic acid (2.19 g, 11.5 mmol, 2 equiv).
Following reflux of the mixture for 72 h, the solvent
was evaporated, the residue diluted with CH2Cl2, the
organic layer washed with aqueous NaHCO3 5%, dried
over MgSO4, concentrated and the residue purified by
TLC (CH2Cl2/MeOH 9.7:0.3) to afford compound 50.
Yield: 40%; white solid; mp 221–223 ꢁC; Rf (CH2Cl2/
MeOH 9.8:0.2): 0.40; tR (TSK gel, method B):
B): 6.39 min, PHPLC: 99%; H NMR d: 7.62–7.18 (m,
8H, ArH), 4.36 (d, J = 10.3 Hz, 1H, CH), 2.50 (m,
1H, CH), 1.69–0.90 (m, 10H, H cyclohexyl); 13C
NMR d: 128.8, 128.6, 127.8, 113.6, 100.5, 51.2, 40.2,
31.6, 30.5, 25.8, 25.6; MALDI-TOF-MS m/z: 309
[M+H]+.
4.1.135. 6-Chloro-2-(cyclohexylphenylmethyl)-1H-benzo-
imidazole (54). Compound 54 was prepared according to
the general procedure I starting from compound 54i
(175 mg, 0.51 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH 9.9:0.1). Yield:
1
5.66 min, PHPLC: 88%; H NMR d (isomeres mixture
70:30): 12.93 (s, 1H, NH), 8.29 (dd, J = 1.5, 4.8 Hz,

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4515
60%; white solid; mp 198–200 ꢁC; Rf (CH2Cl2): 0.50; tR
(TSK gel, method B): 6.47 min, PHPLC: 99%; H NMR
4.1.139. Acetic acid 2-(cyclohexylphenylmethyl)-3H-ben-
zoimidazol-5-yl ester (58). Compound 58 was prepared
according to the general procedure J starting from com-
pound 58i (430 mg, 1.28 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.3:0.7). Yield: 46%; white solid; mp > 225 ꢁC; Rf
(CH2Cl2/MeOH 9.8:0.2): 0.45; tR (TSK gel, method
1
d: 12.47 (s, 1H, NH), 7.58-7.40 (m, 4H, ArH), 7.24 (m,
2H, ArH), 7.19–7.08 (m, 2H, ArH), 3.79 (d,
J = 10.7 Hz, 1H, CH), 2.24 (m, 1H, CH), 1.56-0.88 (m,
10H, H cyclohexyl); 13C NMR d: 141.4, 129.2, 127.5,
122.2, 118.6, 111.6, 53.2, 41.9, 32.3, 31.5, 26.7, 26.3;
MALDI-TOF-MS m/z: 325 [M+H]+.
1
B): 7.44 min, PHPLC: 99%; H NMR d: 12.10 (s, 1H,
NH), 7.37–7.23 (m, 6H, ArH), 6.90 (m, 1H, ArH),
6.58 (m, 2H, ArH), 3.52 (d, J = 10.3 Hz, 1H, CH),
2.37 (s, 3H, CH3), 1.89 (m, 1H, H cyclohexyl), 1.72
(m, 1H, H cyclohexyl), 1.53 (m, 2H, H cyclohexyl),
1.17–1.05 (m, 6H, H cyclohexyl); 13C NMR d: 137.9,
129.2, 129.1, 128.0, 104.1, 58.0, 41.1, 38.3, 31.9, 30.3,
26.4, 25.9; MALDI-TOF-MS m/z: 349 [M+H]+.
4.1.136. 2-(Cyclohexylphenylmethyl)-6-trifluoromethyl-
1H-benzoimidazole (55). Compound 55 was prepared
according to the general procedure I starting from com-
pound 55i (440 mg, 1.17 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 78%; white solid; mp 200–203 ꢁC; Rf
(CH2Cl2/MeOH 9.9:0.1): 0.45; tR (TSK gel, method
1
B): 7.25 min, PHPLC: 99%; H NMR d: 12.73 (s, 1H,
4.1.140. 2-(Cyclohexylphenylmethyl)-4,5-dimethyl-1H-
benzoimidazole (59). Compound 59 was prepared
according to the general procedure I starting from com-
pound 59i (430 mg, 1.28 mmol, 1 equiv) and was ob-
tained after purification by trituration in a Et2O/
pentane mixture. Yield: 81%; white solid; mp 209–
212 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.50; tR (TSK gel,
NH), 7.92 (m, 1H, ArH), 7.73 (m, 1H, ArH), 7.58 (m,
1H, ArH), 7.43 (m, 2H, ArH), 7.28 (m, 2H, ArH),
7.17 (m, 1H, ArH), 3.86 (d, J = 10.7 Hz, 1H, CH),
2.30 (m, 1H, CH), 2.19 (m, 1H, CH), 1.60–0.83 (m,
10H, H cyclohexyl); 13C NMR d: 160.5, 159.9, 141.2,
129.3, 128.8, 127.6, 119.9, 119.1, 118.6, 116.5, 112.6,
109.4, 53.2, 41.9, 32.3, 31.5, 26.7, 26.3; MALDI-TOF-
MS m/z: 321 [M+H]+.
1
method B): 7.05 min, PHPLC: 99%; H NMR d: 12.05
(s, 1H, NH), 7.47 (m, 2H, ArH), 7.30-7.21 (m, 2H,
ArH), 7.19–7.13 (m, 2H, ArH), 6.90 (m, 1H, ArH),
3.80 (d, J = 10.7 Hz, 1H, CH), 2.37–2.25 (m, 7H, 1
CH + 2 CH3), 2.19 (m, 1H, CH), 1.58–0.81 (m, 10H,
H cyclohexyl); 13C NMR d: 141.9, 129.3, 129.1, 128.6,
127.3, 124.1, 53.4, 41.9, 32.3, 31.7, 26.8, 26.4, 19.8;
MALDI-TOF-MS m/z: 319 [M+H]+.
4.1.137. 2-(Cyclohexylphenylmethyl)-3H-benzoimi-daz-
ole-5-carboxylic acid methyl ester (56). Compound 56
was prepared according to the general procedure I start-
ing from compound 56i (500 mg, 1.36 mmol, 1 equiv)
and was obtained after purification by TLC (CH2Cl2/
MeOH/NH4OH 9.6:0.4:0.1). Yield: 80%; white solid;
mp 117–119 ꢁC; Rf (CH2Cl2/MeOH 9.5:0.5): 0.60; tR
4.1.141. 2-(Cyclohexylphenylmethyl)-5,6-dimethyl-1H-
benzoimidazole (60). Compound 60 was prepared
according to the general procedure I starting from com-
pound 60i (400 mg, 1.19 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH/
NH4OH 9.7:0.3:0.1). Yield: 55%; white solid; mp 210–
213 ꢁC; Rf (CH2Cl2/MeOH 9.6:0.4): 0.50; tR (TSK gel,
1
(TSK gel, method B): 6.45 min, PHPLC: 99%; H NMR
d: 12.51 (s, 1H, NH), 7.94 (s, 1H, ArH), 7.60 (m, 1H,
ArH), 7.40 (m, 1H, ArH), 7.30 (m, 2H, ArH phenyl),
7.13 (m, 2H, ArH phenyl), 7.02 (m, 1H, ArH phenyl),
3.70 (d, J = 10.7 Hz, 1H, CH), 3.67 (s, 3H, CH3), 2.13
(m, 1H, CH), 1.42–0.83 (m, 10H, H cyclohexyl); 13C
NMR d: 167.7, 141.2, 129.3, 127.5, 123.5, 123.4, 53.3,
52.7, 41.9, 32.3, 31.5, 26.7, 26.3; MALDI-TOF-MS
m/z: 349 [M+H]+.
1
method B): 6.79 min, PHPLC: 99%; H NMR d: 12.09
(s, 1H, NH), 7.43 (m, 2H, ArH), 7.27 (m, 3H, ArH),
7.16 (m, 2H, ArH), 3.74 (d, J = 10.7 Hz, 1H, CH),
2.24 (m, 7H, 1 CH + 2 CH3), 1.57-1.05 (m, 10H, H
cyclohexyl); 13C NMR d: 156.3, 142.8, 141.9, 133.2,
130.6, 129.7, 129.3, 129.1, 127.3, 119.4, 111.8, 53.3,
42.1, 32.3, 31.7, 26.8, 26.4, 20.7; MALDI-TOF-MS m/
z: 319 [M+H]+.
4.1.138. 2-(Cyclohexylphenylmethyl)-3H-benzoimidazole-
5-carboxylic acid (57). Compound 56 (150 mg,
0.43 mmol, 1 equiv) was diluted with 10 mL of a aque-
ous NaOH 2.5 N/MeOH 1:1 mixture. Following reflux
of the mixture for 2 h, the methanol was evaporated,
the aqueous layer acidified with aqueous HCl 1 M and
extracted with CH2Cl2, the organic layer dried over
MgSO4 and concentrated to afford compound 57. Yield:
97%; white solid; mp 210–213 ꢁC; Rf (CH2Cl2/MeOH
4.1.142. 2-(Cyclohexylphenylmethyl)-5,6-dimethoxy-1H-
benzoimidazole (61). Compound 61 was prepared
according to the general procedure I starting from com-
pound 61i (330 mg, 0.89 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH/
NH4OH 9.5:0.5:0.1). Yield: 38%; white solid; mp 76–
80 ꢁC; Rf (CH2Cl2/MeOH/NH4OH 9.5:0.5:0.1): 0.50;
tR (TSK gel, method B): 6.33 min, PHPLC: 99%; 1H
NMR d: 11.97 (s, 1H, NH), 7.45 (m, 2H, ArH), 7.30
(m, 2H, ArH), 7.21–6.96 (m, 3H, ArH), 3.77 (m, 4H,
CH + CH3), 3.35 (s, 3H, CH3), 2.27 (m, 1H, CH),
1.71–1.07 (m, 10H, H cyclohexyl); 13C NMR d: 155.5,
146.6, 142.1, 129.2, 129.1, 127.2, 56.8, 53.1, 48.4, 42.2,
34.2, 32.3, 31.7, 26.8, 26.4, 26.2, 25.3; MALDI-TOF-
MS m/z: 351 [M+H]+.
9.2:0.8): 0.40; tR (TSK gel, method B): 5.98 min, PHPLC
:
1
99%; H NMR d: 8.17 (s, 1H, ArH), 7.89 (dd, J = 1.3,
8.5 Hz, 1H, ArH), 7.67 (d, J = 8.5 Hz, 1H, ArH), 7.50
(d, J = 7.2 Hz, 2H, ArH phenyl), 7.34 (t, J = 7.2 Hz,
2H, ArH phenyl), 7.24 (m, 1H, ArH phenyl), 4.07 (d,
J = 10.9 Hz, 1H, CH), 2.43 (m, 1H, CH), 1.61–1.49
(m, 4H, H cyclohexyl), 1.42–1.37 (m, 1H, H cyclohexyl),
1.27–0.90 (m, 5H, H cyclohexyl); 13C NMR d: 167.9,
158.6, 139.5, 129.3, 129.0, 127.9, 126.3, 125.0, 116.8,
114.9, 52.1, 48.4, 31.9, 31.1, 26.4, 25.9; MALDI-TOF-
MS m/z: 335 [M+H]+.

4516
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4.1.143.
5,6-Dichloro-2-(cyclohexylphenylmethyl)-1H-
113.6, 67.1, 55.6, 53.3, 50.9, 46.5, 43.2, 32.3, 31.7, 26.8,
benzoimidazole (62). Compound 62 was prepared
according to the general procedure I starting from com-
pound 62i (220 mg, 0.58 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 72%; white solid; mp 211–214 ꢁC; Rf
(CH2Cl2/MeOH 9.8:0.2): 0.40; tR (TSK gel, method
26.4; MALDI-TOF-MS m/z: 389 [M+H]+.
4.1.147. 2-(Cyclohexylphenylmethyl)-6-morpholin-4-yl-
1H-benzoimidazole (66). To a solution of crude com-
pound 66i (1.57 mmol, 1 equiv) in 10 mL of EtOH were
added iron (132 mg, 2.35 mmol, 1.5 equiv) and HCl
12 N (1.3 mL, 15.7 mmol, 10 equiv). Following reflux
of the mixture for 8 h, the solvent was evaporated, the
residue diluted with CH2Cl2, washed with aqueous
NaHCO3 5%, dried over MgSO4 and concentrated.
The expected benzimidazole 66 was obtained after puri-
fication by TLC (CH2Cl2/MeOH 9:1). Yield: 25%; light
green solid; mp 114–116 ꢁC; Rf (CH2Cl2/MeOH 9.2:0.8):
0.60; tR (TSK gel, method B): 6.40 min, PHPLC: 99%; 1H
NMR d: 12.00 (s, 1H, NH), 7.43 (m, 2H, ArH), 7.28 (m,
3H, ArH), 7.16 (m, 1H, ArH), 6.83 (m, 2H, ArH), 3.76–
3.71 (m, 5H, CH + 2 CH2), 3.01 (t, J = 4.7 Hz, 4H, 2
CH2), 2.23 (m, 1H, CH), 1.58–1.01 (m, 10H, H cyclo-
hexyl); 13C NMR d: 141.9, 129.2, 129.1, 127.3, 67.1,
53.3, 51.4, 42.0, 32.3, 31.7, 26.8, 26.4; MALDI-TOF-
MS m/z: 376 [M+H]+.
1
B): 7.31 min, PHPLC: 99%; H NMR d: 12.52 (s, 1H,
NH), 7.79–7.65 (m, 2H, ArH), 7.42–7.39 (m, 2H,
ArH), 7.29–7.22 (m, 2H, ArH), 7.19–7.14 (m, 1H,
ArH), 3.81 (d, J = 10.7 Hz, 1H, CH), 2.24 (m, 1H,
CH), 1.56–1.08 (m, 10H, H cyclohexyl); 13C NMR d:
160.2, 141.1, 129.9, 129.3, 127.6, 124.5, 120.4, 113.4,
53.1, 41.9, 32.2, 31.5, 26.7, 26.3; MALDI-TOF-MS m/
z: 359 [M+H]+.
4.1.144.
2-(Cyclohexylphenylmethyl)-1H-naphtho[2,3-
d]imidazole (63). Compound 63 was prepared according
to the general procedure I starting from compound 63i
(250 mg, 0.69 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH 9.8:0.2). Yield:
63%; brown solid; mp > 225 ꢁC; Rf (CH2Cl2/MeOH
9.8:0.2): 0.45; tR (TSK gel, method B): 7.26 min, PHPLC
:
1
99%; H NMR d: 12.37 (s, 1H, NH), 8.09 (s, 1H, ArH),
7.93 (m, 2H, ArH), 7.86 (s, 1H, ArH), 7.51 (m, 2H,
ArH), 7.37–7.29 (m, 4H, ArH), 7.20 (m, 1H, ArH),
3.90 (d, J = 10.7 Hz, 1H, CH), 2.37 (m, 1H, CH), 1.77-
0.91 (m, 10H, H cyclohexyl); 13C NMR d: 144.9,
141.3, 135.7, 130.5, 130.2, 129.3, 129.2, 128.8, 128.1,
127.6, 124.3, 123.6, 115.5, 106.9, 53.6, 41.9, 32.3, 31.6,
26.8, 26.4; MALDI-TOF-MS m/z: 341 [M+H]+.
4.1.148. 2-(Cyclohexylphenylmethyl)-6-thiomorpholin-4-
yl-1H-benzoimidazole (67). Compound 67 was prepared
according to the general procedure L starting from com-
pound 67i (700 mg, 1.6 mmol, 1 equiv) and was obtained
after purification by TLC (cyclohexane/AcOEt/NH4OH
6:4:0.1). Yield: 32%; white solid; mp 109–117 ꢁC; Rf
(cyclohexane/AcOEt/NH4OH 7:3:0.1): 0.35; tR (TSK
gel, method A): 5.61 min, PHPLC: 99%; 1H NMR d:
7.44 (m, 2H, ArH), 7.35–7.26 (m, 3H, ArH), 7.20–7.14
(m, 1H, ArH), 6.96 (m, 1H, ArH), 6.82 (m, 1H, ArH),
3.76 (d, J = 10.7 Hz, 1H, CH), 3.35 (t, J = 4.9 Hz, 4H,
2 CH2), 2.71 (t, J = 5.0 Hz, 4H, 2 CH2), 2.25 (m, 1H,
CH), 1.59-1.50 (m, 4H, H cyclohexyl), 1.36 (m, 1H, H
cyclohexyl), 1.23–0.96 (m, 5H, H cyclohexyl); 13C
NMR d: 156.3, 148.3, 141.6, 129.0, 128.9, 127.1, 115.6,
115.3, 54.1, 52.9, 41.7, 31.4, 27.3, 26.6, 26.1; MALDI-
TOF-MS m/z: 392 [M+H]+.
4.1.145.
2-(Cyclohexylphenylmethyl)-6-piperidin-1-yl-
1H-benzoimidazole (64). Compound 64 was prepared
according to the general procedure L starting from com-
pound 64i (750 mg, 1.78 mmol, 1 equiv) and was obtained
after purification by TLC (cyclohexane/AcOEt/NH4OH
6:4:0.1). Yield: 33%; white solid; mp 115–120 ꢁC; Rf
(CH2Cl2/MeOH 9.6:0.4): 0.55; tR (TSK gel, method A):
1
5.56 min, PHPLC: 99%; H NMR d: 12.00 (s, 1H, NH),
7.44 (m, 2H, ArH phenyl), 7.31–7.25 (m, 3H, 1 ArH + 2
ArH phenyl), 7.20–7.14 (m, 1H, ArH phenyl), 6.90 (s,
1H, ArH), 6.82 (m, 1H, ArH), 3.74 (d, J = 10.7 Hz, 1H,
CH), 3.00 (t, J = 5.1 Hz, 4H, CH2 piperidinyl), 2.24 (m,
1H, CH), 1.67–1.47 (m, 10H, CH2 cyclohexyl + CH2 pipe-
ridinyl), 1.39–0.95 (m, 6H, CH2 cyclohexyl); 13C NMR d:
156.3, 149.1, 141.2, 129.2, 129.1, 127.3, 114.9, 53.3, 52.8,
41.9, 32.3, 31.7, 26.8, 26.5, 26.4, 24.8; MALDI-TOF-
MS m/z: 374 [M+H]+.
4.1.149. 2-Biphenyl-2-yl-6-methoxy-1H-benzoimidazole
(68). Compound 68 was prepared according to the gen-
eral procedure K starting from compound 68i (300 mg,
0.94 mmol, 1 equiv) and was obtained after purification
by TLC (CH2Cl2/MeOH 9.7:0.3). Yield: 38%; white sol-
id; mp 92–94 ꢁC; Rf (CH2Cl2/MeOH/NH4OH
9.6:0.4:0.1): 0.55; tR (TSK gel, method B): 5.48 min,
1
PHPLC: 99%; H NMR d: 11.75 (s, 1H, NH), 7.63 (m,
1H, ArH), 7.54 (m, 1H, ArH), 7.46 (m, 2H, ArH),
7.29 (m, 1H, ArH), 7.22–7.11 (m, 5H, ArH), 6.87 (m,
1H, ArH), 6.70 (m, 1H, ArH), 3.69 (s, 3H, OCH3);
13C NMR d: 175.2, 141.1, 131.9, 131.3, 131.1, 130.5,
129.6, 128.9, 128.2, 127.9, 112.0, 98.1, 56.2; MALDI-
TOF-MS m/z: 301 [M+H]+.
4.1.146. 2-(Cyclohexylphenylmethyl)-6-(4-methylpipera-
zin-1-yl)- 1H-benzoimidazole (65). Compound 65 was
prepared according to the general procedure L starting
from compound 65i (500 mg, 2.1 mmol, 1 equiv) and
was obtained after purification by TLC (CH2Cl2/
MeOH/NH4OH 9:1:0.1). Yield: 15%; white solid; mp
98–103 ꢁC; Rf (CH2Cl2/MeOH/NH4OH 9:1:0.1): 0.30;
tR (TSK gel, method A): 5.48 min, PHPLC: 99%; 1H
NMR d: 12.00 (s, 1H, NH), 7.42 (m, 2H, ArH), 7.27 (m,
3H, ArH), 7.17 (m, 1H, ArH), 6.82 (m, 2H, ArH), 3.75
(d, J = 10.7 Hz, 1H, CH), 3.04 (m, 4H, 2 CH2), 2.50 (m,
4H, 2 CH2), 2.23 (m, 4H, CH + CH3), 1.59-1.07 (m,
10H, H cyclohexyl); 13C NMR d: 129.2, 129.1, 127.3,
4.1.150. 6-Methoxy-2-(2-phenoxyphenyl)-1H-benzoimi-
dazole (69). Compound 69 was prepared according to
the general procedure K starting from compound 69i
(240 mg, 0.72 mmol, 1 equiv) and was obtained after
purification by TLC (CH2Cl2/MeOH 9.7:0.3). Yield:
80%; white solid; mp 62–72 ꢁC; Rf (CH2Cl2/MeOH
9.7:0.3): 0.65; tR (TSK gel, method B): 6.25 min, PHPLC
:

J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
4517
99%; 1H NMR d: 12.10 (s, 1H, NH), 8.34 (m, 1H, ArH),
7.54–7.40 (m, 4H, ArH), 7.30–7.18 (m, 5H, ArH), 6.90
(m, 1H, ArH), 6.85 (m, 1H, ArH), 3.79 (s, 3H, OCH3);
13C NMR d: 156.5, 155.6, 131.7, 131.1, 130.9, 125.3,
124.3, 121.6, 121.1, 120.2, 118.7, 113.0, 112.5, 56.2;
MALDI-TOF-MS m/z: 317 [M+H]+.
140.0, 128.9, 128.0, 119.5, 112.1, 110.9, 95.2, 70.9,
56.0, 52.9, 26.1, 24.7; MALDI-TOF-MS m/z: 322
[M+H]+.
4.1.154.
2-(Cyclohexylphenylmethyl)-6-methoxy-1-(2-
morpholin-4-ylethyl)-1H-benzoimidazole (73). To a solu-
tion of compound 52 (250 mg, 0.78 mmol, 1 equiv) in
5 mL of THF were added sodium hydride (60% suspen-
sion in oil, 187 mg, 4.68 mmol, 6 equiv), previously
washed with hexane, potassium iodide (39 mg,
0.23 mmol, 0.3 equiv) and N-(2-chloroethyl)morpho-
lineÆHCl (174 mg, 0.93 mmol, 1.2 equiv). Following re-
flux of the mixture for 12 h, compound 73 was directly
purified by TLC (CH2Cl2/MeOH/NH4OH 9.9:0.1:0.1).
Yield: 53%; yellow oil; Rf (CH2Cl2/MeOH/NH4OH
9.8:0.2:0.1): 0.65; tR (TSK gel, method B): 5.47 min,
4.1.151.
[2-(6-Methoxy-1H-benzoimidazol-2-yl)phen-
yl]phenylamine (70). Compound 70 was prepared
according to the general procedure K starting from
compound 70i (230 mg, 0.69 mmol, 1 equiv) and was ob-
tained after purification by TLC (CH2Cl2/MeOH
9.8:0.2). Yield: 83%; white solid; mp 64–75 ꢁC; Rf
(CH2Cl2/MeOH 9.8:0.2): 0.60; tR (TSK gel, method
1
B): 6.05 min, PHPLC: 99%; H NMR d (isomere mixture
60:40): 12.79 (s, 1H, NH), 11.21 (s, 0.4H, NH), 11.15 (s,
0.6H, NH), 7.99 (m, 1H, ArH), 7.80 (m, 0.6H, ArH),
7.60 (m, 0.4H, ArH), 7.39–7.27 (m, 6.4H, ArH), 7.05-
7.00 (m, 1.6H, ArH), 6.95–6.89 (m, 2H, ArH), 6.85
(m, 1H, ArH), 3.81 (s, 3H, OCH3); 13C NMR d: 157.0,
151.5, 143.9, 142.1, 134.8, 130.9, 130.8, 130.1, 128.3,
122.9, 121.1, 119.5, 118.6, 114.9, 113.9, 113.4, 112.0,
111.8, 101.4, 94.9, 56.1; MALDI-TOF-MS m/z: 316
[M+H]+.
1
PHPLC: 99%; H NMR d (isomere mixture 60:40): 7.46
(m, 0.6H, ArH), 7.38–7.32 (m, 2H, ArH phenyl), 7.27–
7.20 (m, 2.4H, 0.4H ArH + 2H ArH phenyl), 7.17–7.10
(m, 1.4H, 0.4H ArH + 1H ArH phenyl), 6.91 (m,
0.6H, ArH), 6.75–6.70 (m, 1H, ArH), 4.21–4.07 (m,
2H, CH2), 3.92 (d, J = 10.0 Hz, 1H, CH), 3.72 (s, 3H,
CH3), 3.52–3.44 (m, 4H, CH2), 2.38–2.22 (m, 7H, 1H
CH + 6H CH2), 2.09 (m, 1H, CH2), 1.67–0.99 (m, 9H,
CH2 cyclohexyl); 13C NMR d: 156.3, 129.5, 129.2,
127.4, 119.9, 111.9, 111.3, 102.3, 94.8, 66.9, 58.2, 58.1,
54.4, 53.9, 49.8, 42.8, 40.9, 32.5, 31.5, 26.9, 26.6;
MALDI-TOF-MS m/z: 434 [M+H]+.
4.1.152. 2-(2-Cyclohexylphenyl)-6-methoxy-1H-benzoim-
idazole (71). Compound 71 was prepared according to
the general procedure K starting from compound 71i
(400 mg, 1.23 mmol, 1 equiv) and was obtained after
purification by trituration in a Et2O/pentane mixture.
Yield: 80%; white solid; mp 76–84 ꢁC; Rf (CH2Cl2/
MeOH 9.7:0.3): 0.40; tR (TSK gel, method B):
4.1.155. 2-(Cyclohexylphenylmethyl)-6-methoxy-1-(2-pip-
eridin-1- ylethyl)-1H-benzoimidazole (74). To a solution
of compound 52 (250 mg, 0.78 mmol, 1 equiv) in 5 mL
of THF were added sodium hydride (60% suspension
in oil, 187 mg, 4.68 mmol, 6 equiv), previously washed
with hexane, potassium iodide (39 mg, 0.23 mmol,
1
6.39 min, PHPLC: 97%; H NMR d: 12.37 (s, 1H, NH),
7.51–7.23 (m, 5H, ArH), 7.15 (m, 1H, ArH), 6.78 (m,
1H, ArH), 3.77 (s, 3H, OCH3), 3.29 (m, 1H, CH),
1.70–1.16 (m, 10H, CH2); 13C NMR d: 147.7, 130.7,
130.2, 127.4, 126.4, 125.5, 120.3, 112.9, 112.3, 111.7,
102.2, 95.1, 56.3, 48.3, 39.8, 34.6, 34.2, 27.3, 26.5, 25.3;
MALDI-TOF-MS m/z: 307 [M+H]+.
0.3 equiv)
and
1-(2-chloroethyl)piperidine.HCl
(286 mg, 1.56 mmol, 2 equiv). Following reflux of the
mixture for 6 h, compound 74 was directly purified by
TLC (CH2Cl2/MeOH/NH4OH 9.8:0.2:0.1). Yield: 95%;
yellow oil; Rf (CH2Cl2/MeOH/NH4OH 9.9:0.1:0.1):
0.60; tR (TSK gel, method B): 5.57 min (50%)–
4.1.153. 6-Methoxy-2-(phenylpiperidin-1-ylmethyl)-1H-
benzoimidazole (72). To a solution of phenylpiperidin-
1-ylacetic acid 33a (2.18 mmol, 1 equiv), synthesized
according to the general procedure D, in 10 mL of dry
CH2Cl2 were added DIEA (760 lL, 4.36 mmol, 2 equiv),
PyBrop (1.32 g, 2.83 mmol, 1.3 equiv) and 3-methoxy-o-
phenylenediamineÆ2HCl (690 mg, 3.27 mmol, 1.5 equiv).
After stirring for 12 h at room temperature, the mixture
was washed with aqueous NaHCO3 5%, dried over
MgSO4, concentrated and the residue diluted with
9 mL of an aqueous HCl 4 N/MeOH/dioxane 1:1:1 mix-
ture. Following reflux of the mixture for 72 h, the sol-
vents were evaporated, the residue was diluted with
CH2Cl2, washed with aqueous NaHCO3 5%, dried over
MgSO4, concentrated and the residue purified by TLC
(CH2Cl2/MeOH 9.5:0.5) to afford compound 72. Yield:
20% global; white solid; mp 174–175 ꢁC; Rf (CH2Cl2/
MeOH 9.5:0.5): 0.75; tR (TSK gel, method A):
1
5.66 min (50%), PHPLC: 99%; H NMR d (isomere mix-
ture 50:50): 7.47 (m, 0.5H, ArH), 7.36–7.31 (m, 2H, ArH
phenyl), 7.25–7.19 (m, 2.5H, 0.5H ArH + 2H ArH phen-
yl), 7.17–7.10 (m, 1.5H, 0.5H ArH + 1H ArH phenyl),
6.90 (m, 0.5H, ArH), 6.74–6.69 (m, 1H, ArH), 4.15-
4.02 (m, 2H, CH2), 3.94 (d, J = 10.0 Hz, 1H, CH),
3.72 (s, 3H, CH3), 2.32–2.03 (m, 8H, 1H CH + 7H
CH2), 1.70–0.99 (m, 15H, CH2); 13C NMR d: 164.4,
143.9, 141.3, 137.6, 129.4, 129.2, 127.4, 119.9, 111.9,
111.2, 102.3, 94.8, 58.6, 56.4, 56.2, 55.2, 54.7, 49.8,
42.6, 41.2, 32.5, 31.4, 26.9, 26.6, 26.3, 24.6; MALDI-
TOF-MS m/z: 432 [M+H]+.
4.2. Biological testing
4.2.1. Animals. Animal studies were conducted accord-
ing to the French Guidelines for the Care and Use of
Experimental Animals. Female Wistar rats (200–300 g
body weight) from Iffa-Credo (L’Arbresle, France) were
used. They were housed in plastic cages at a constant
temperature (22 ꢁC) with light from 07.00 to 19.00 h
for at least 1 week before the experiments.
1
4.31 min, PHPLC: 99%; H NMR d: 12.10 (s, 1H, NH),
7.52 (m, 2H, ArH), 7.38–7.21 (m, 4H, ArH), 6.90 (m,
1H, ArH), 6.77–6.69 (m, 1H, ArH), 4.58 (s, 1H, CH),
3.74 (s, 3H, CH3), 2.36–2.21 (m, 4H, 2 CH2), 1.52 (m,
4H, 2 CH2), 1.38 (m, 2H, CH2); 13C NMR d: 154.3,

4518
J. Charton et al. / Bioorg. Med. Chem. 14 (2006) 4490–4518
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100-mm Petri dishes in medium M199 with Earle’s
salts (Life Technologies, Inc., Paisley, UK) supple-
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Acknowledgments
21. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J.
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Bioorg. Med. Chem. 2001, 9, 2905–2919.
Thanks are due to Gerard Montagne for NMR spectra
and Herve Drobecq for MALDI-TOF-MS experiments.
Julie Charton was a recipient of fellowships from the
Ministere de l’Education Nationale et de la Recherche.
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25. Indirect activation could be the result of ATP synthesis
blockade or elevation of ATP consumption.