Synthesis and structure-activity relationship of 1,2,4-triazole-containing diarylpyrazolyl carboxamide as CB1 cannabinoid receptor-ligand

Article abstract of DOI:10.1016/j.bmc.2009.12.040

Numerous research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, proved to be efficacious in human for the treatment of obesity. In the present study, a series of 1,2,4-triazole-containing diarylpyrazolyl carboxamides based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. The structure-activity relationship studies demonstrated that incorporation of 1,2,4-triazole ring onto the pyrazole scaffold via a methylene linker led to a significant improvement for CB1 receptor binding affinity. Importantly, these analogues also exhibited excellent selectivity for CB1 receptor over CB2 receptor.

Full text of DOI:10.1016/j.bmc.2009.12.040

Bioorganic & Medicinal Chemistry 18 (2010) 1149–1162
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure–activity relationship of 1,2,4-triazole-containing
diarylpyrazolyl carboxamide as CB1 cannabinoid receptor–ligand
Hee Jeong Seo, Min Ju Kim, Suk Ho Lee, Sung-Han Lee, Myung Eun Jung, Mi-Soon Kim, Kwangwoo Ahn,
*
Jeongmin Kim, Jinhwa Lee
Central Research Laboratories, Green Cross Corporation, 303 Bojeong-Dong, Giheung-Gu, Yongin, Gyeonggi-Do 446-770, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Numerous research groups have been engaged in searching for novel CB1 receptor antagonists, since
SR141716A (rimonabant), a CB1 receptor antagonist, proved to be efficacious in human for the treatment
of obesity. In the present study, a series of 1,2,4-triazole-containing diarylpyrazolyl carboxamides based
on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding
affinity. The structure–activity relationship studies demonstrated that incorporation of 1,2,4-triazole ring
onto the pyrazole scaffold via a methylene linker led to a significant improvement for CB1 receptor bind-
ing affinity. Importantly, these analogues also exhibited excellent selectivity for CB1 receptor over CB2
receptor.
Received 12 October 2009
Revised 11 December 2009
Accepted 15 December 2009
Available online 22 December 2009
Keywords:
CB1 receptor
Rimonabant
Triazole
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrazole
Carboxamide
1. Introduction
system appears to be closely related to the abdominal obesity
and the development of the metabolic syndrome.8 The particular
The prevalence of obesity is rapidly increasing globally. Obesity
has reached epidemic proportions in developed countries. It is now
widely accepted that obesity is not a cosmetic issue, but is a major
health issue. At last, the World Health Organization (WHO) offi-
cially declared obesity a disease in 1998.1,2 Obesity has received
significant attention due to its high prevalence and association
with serious health risks, especially metabolic syndrome including
insulin resistance, hypertension, and heart disease.3–5 Obesity is
defined as a body mass index of more than 30 kg/m.2 This index
gives a measure of weight and body fat in relation to height. More-
over, obesity is included in the pathogenesis of metabolic syn-
drome, which can lead to cardiovascular diseases and type II
diabetes. Currently only two drugs are approved by FDA in the Uni-
ted States for the long-term treatment of obesity, that is, sibutr-
amine and orlistat. However, both of these agents suffer from
variable efficacy or undesirable side effects that have restricted
their therapeutic potential. Accordingly, there are still unmet med-
ical needs for novel target developments for antiobesity drug.1,6,7
Under these circumstances, the endocannabinoid system pro-
vided the good clue for a new approach to the antiobesity drug
development. This endogenous signaling system has been known
to play a key role in the regulation of food intake, fat accumulation,
and energy balance. The over activation of the endocannabinoid
interest has been focused on the characteristic role of CB1 receptor,
which could effectively modulate endocannabinoid system. The
down-regulation of the endocannabinoid system by the specific
blockage of CB1 receptors could induce body weight reduction.
Accordingly, a number of research groups have attempted to find
clinically useful CB1 receptor antagonists and eventually, rimona-
bant, the first commercial CB1 receptor antagonist, was identified
by Sanofi-Aventis. Since then, antagonism against CB1 receptor
has been regarded as a highly promising strategy for the treatment
of obesity and various CB1 receptor antagonists have been discov-
ered and developed by many pharmaceutical companies.9–11
Although several CB1 receptor inverse agonists or antagonists
including rimonabant (1),12 taranabant (2),13 and otenabant (3)14
were recently withdrawn from clinical development, many re-
search groups and pharmaceutical companies are still searching
for novel CB1 antagonists such as ibipinabant (4) or AVE-1625
(5), bearing improved physicochemical properties and decreased
adverse effects involving depression, anxiety or suicidality (Fig. 1).
The main objective of this study was the search for novel CB1
receptor antagonists. A pharmacophore model for the binding of
a low energy conformation of rimonabant in the CB1 receptor
has been well-documented.15a,15b The key receptor–ligand interac-
tion is reported to be a hydrogen bond between the carbonyl group
of rimonabant and the Lys192-Asp366 residue of the CB1 receptor,
thereby exerting a stabilizing effect on the Lys192-Asp366 salt
bridge as shown in Figure 2.15a
* Corresponding author. Tel.: +82 31 260 9892; fax: +82 31 260 9020.
E-mail address: jinhwalee@greencross.com (J. Lee).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.12.040

1150
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
O
NH2
NH
N
N
NH
N
O
Me
O
N
O
N
NC
Cl
N
N
H
N
N
CF3
Cl
N
Cl
Cl
Cl
2 (taranabant, MK-0364)
3 (otenabant, CP-945598)
Cl
1 (rimonabant)
O
S
NH
Cl
O
N
Cl
N
Me
O
S
N
O
N
N
F
Cl
F
Cl
5 (AVE-1625)
4 (ibipinabant, SLV-319)
Figure 1. Structures of CB1R antagonists or inverse agonists.
As shown in Figure 4, we envisioned that incorporation of 1,2,4-
Trp255
triazolylmethyl moiety onto the pyrazole 3-carboxamide could
lead to more potent CB1 receptor antagonists based on the encour-
aging observation made in our previous study.17 In this article, we
describe the synthesis and biological evaluation of 1,2,4-triazole-
containing diarylpyrazolyl carboxamides as novel CB1 receptor–li-
gands. Through a process of lead optimization, we successfully
identified a promising compound showing strong binding affinity
for CB1 receptor (IC50 = 1.1 nM).
Asp366-Lys192
Tyr 275
Cl
Val196
A
D
Phe278
O
Phe170
Leu387
C
N
N
HN
N
B
Trp279
Cl
Met384
Cl
2. Chemistry
Trp356
The synthetic pathway toward a series of 1,2,4-triazole-contain-
ing diarylpyrazolyl carboxamide is outlined in Scheme 1. The com-
pounds containing 1,2,4-triazole were obtained by a reaction
sequence involving key intermediate bromide 11. Thus, the generic
ester 1012 underwent a benzylic bromination-type reaction (NBS,
catalytic amount AIBN)19 to produce 11, which was reacted with
triazole in the presence of cesium carbonate to generate 12. Hydro-
lysis of ester 12 with lithium hydroxide, activation of acid 13, fol-
lowed by coupling with an amine in the presence of triethylamine
provided the corresponding target carboxamide 9. Alternatively,
acid 13 was directly coupled with requisite amines by use of cou-
pling reagents such as EDCI, HOBt, NMM in a suitable solvent such
as DMF or CH2Cl2 to generate 9.
Phe200
Figure 2. Rimonabant and its receptor–ligand interaction.
In our previous studies,17,18 we investigated a series of diarylpy-
razolyl oxadiazole derivatives as antagonists for the cannabinoid
CB1 and CB2 receptors. A few of compounds (e.g., 6, Fig. 3) in this
series exhibited better binding affinity of known CB1 antagonists,
validating the hypothesis that a 1,3,4-oxadiazole16,17 could act as
a CB1 bioisostere of the amide moiety in rimonabant (1). Along
the line, both imidazole23 and tetrazole24 replacements for the
amide functionality have been reported. Subsequently, we intro-
duced a triazolyl ring onto the C4 methyl group of the pyrazole
scaffold via a methylene linker (7, Fig. 3) leading to a potent CB1
receptor antagonist with a significant antiobesity effect in animal
model. A subsequently conducted modeling study revealed that
the N2 of triazole substituent forms a bidentate H-bond with side
chain OH and backbone NH of Thr 197, which is an exclusive inter-
action observed in the binding model of 7 (GCC2469).17
3. Results and discussion
The target 1,2,4-triazole-containing diarylpyrazolyl carboxam-
ides were evaluated in vitro at a rat CB1 binding assay,21,26 and ini-
N
N
Cl
Cl
N
Cl
*
*
A
A
O
N
N
A
*
N
N
C
CF3
O
N
N
HN
N
N
N
O
N
N
B
B
Cl
Cl
B
Cl
7 (GCC2469)
Figure 3. Rimonabant 1, its bioisostere compound 6, and compound 7 evolved from earlier form 6 (ꢀ = C4 methyl group).
Cl
Cl
Cl
1
6

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1151
carbon chain is increased, a slight decrease in binding affinity is ob-
served (32 and 33). Similarly, 1-(trifluoromethyl)cyclopropyl 34a
or 1-(trifluoromethyl)cyclobutyl 35a which possibly acts as a
gem-dimethyl surrogate, also showed nanomolar level of activity
against rCB1 receptor (IC50 = 4.5 nM for 34a and IC50 = 4.67 nM
for 35a). Trifluoromethylcyclopropyl 34a should confer lower lipo-
philicity and possibly enhanced water solubility. Acylhydrazides
36, 37 only showed modest rCB1 receptor binding affinity, respec-
tively, indicating that additional carbonyl functionality in 36, 37
does not appear to be well tolerated. Moreover, substitution with
(1-ethylpyrrolidin-2-yl)methyl 38 demonstrated a dramatic loss
of activity, suggesting that isolated amine functionality in the re-
gion is not tolerated. Additionally, substitution with polar piperi-
dine moiety14 39 demonstrated loss of activity in two orders of
magnitude against rCB1 receptor (IC50 = 3.83 nM for 19a and
IC50 = 878 nM for 39a), indicating the importance of lipophilicity
at this region for the improvement of in vitro activity.
It was encouraging to observe that significant rCB1 receptor
binding affinity was already evident in this series. At this juncture,
we proceeded to explore the effect of halogen atoms on diphenyl
rings connected to the pyrazole against rCB1 receptor binding
affinities. We focused on branched alkyls, trifluoromethylcyclopro-
pyl, trifluoromethylcyclobutyl and cyclic moieties including cyclo-
hexyl, cycloheptyl or piperidine for the SAR studies as shown in
Table 2. First, the compounds lacking the para chlorine atom at
the N-1 pyrazole phenyl substituent were prepared and evaluated.
Comparison of des-chloro analogues 34b (IC50 = 4.75 nM) and 35b
(IC50 = 5.14 nM) with 34a (IC50 = 4.5 nM) and 35a (IC50 = 4.67 nM),
respectively, exhibited that there would be little impact on their
in vitro profiles. Next, in order to explore the effect of substitution
of 5-(4-chlorophenyl)pyrazole with the corresponding 5-(4-
bromophenyl)pyrazole, a small set of bromo dichloro analogues
were prepared. Comparison of bromo dichloro analogues 34c
(IC50 = 3.31 nM) and 35c (IC50 = 3.87 nM) with 34a (IC50 = 4.5 nM)
and 35a (IC50 = 4.67 nM), respectively, demonstrated a marginally
improved binding affinity against rCB1 receptor. Subsequently,
bromo des-chloro (R1 = Br, R2 = H in Table 2) analogues were pre-
pared and evaluated. The structure–activity relationship in this
set of analogues was less obvious, but branched chains (34d,
35d) appear to diminish rCB1 receptor binding affinity, while cyclic
analogue 19c retains similar level of binding affinity
(IC50 = 5.23 nM). Interestingly, the best result for bromo des-chloro
analogues was obtained when cyclohexyl was substituted (21d,
IC50 = 1.6 nM), indicating that cyclohexyl moiety in this analogue
binds optimally to a hydrophobic pocket consisting of residues
Phe174, Phe177, Phe189, Val263, Tyr365 and Phe379.17,18b
N
N
N
Cl
Cl
A
A
O
O
R
N
R
N
N
N
N
N
R'
R'
B
B
Cl
Cl
Cl
Cl
8
9
Figure 4. Exploration of 1,2,4-triazole-containing diarylpyrazolyl carboxamide
series 9.
tial results are shown in Table 1. The structure–activity relation-
ship (SAR) work presented in Table 1 was performed with the 5-
(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
amide. Initial SAR studies were performed with alkyls, carbocycles,
and piperidine derivatives. Aryl or heteroaryl groups were not at-
tempted for the region, since our previous study exhibited that a
phenyl or heteroaryls such as furan, thiophene, pyridine or pyra-
zine did not appear to be tolerated, showing dramatic decrease
in binding affinity to rCB1 receptor.17 Substitution of the NH2 with
piperidin-1-yl resulted in a slight improvement over rimonabant
(1) in binding affinity against a rat CB1 receptor (IC50 = 3.83 nM
for 19a vs. IC50 = 4.53 nM for 1), implying that there might be in-
deed promising structure–activity relationship (SAR) potential via
incorporation of 1,2,4-triazolylmethyl moiety onto the pyrazole
3-carboxamide. For cyclic analogues, the size of the carbocycle ap-
pears to affect binding affinity. Thus, six-membered ring (21a) is
slightly more potent than the corresponding five- or seven-mem-
bered carbocycle (20a and 22a). Addition of methyl group alpha
to cyclohexyl ring diminished binding affinity to rCB1 receptor in
sixfold (23a, IC50 = 22.8 nM vs 21a, IC50 = 3.77 nM), suggesting that
there might be a size requirement for the alkyl carboxamide region
to bind with high affinity to the rCB1 receptor. Introduction of
methyl group or dimethyl group on cyclohexyl or piperidinyl moi-
ety has a three- to fivefold impact on rCB1 binding affinities (24–
28). Moreover, hydroxycyclohexyl 29 demonstrated a 16-fold loss
of activity, implying that polar functionality in the region is not tol-
erated. For acyclic analogues, branched aliphatic chains were pre-
pared and evaluated, since our prior work showed that branched
aliphatic chains are usually more potent than the corresponding
non-branched counterparts.17 Substitution with tert-butyl 30a or
tert-pentyl 31a exhibited nanomolar activity against rCB1 receptor
(IC50 = 4.9 nM for 30a and IC50 = 3.01 nM for 31a). As the size of the
O
O
O
O
O
O
Br
N
N
N
X
N
N
N
(b)
(a)
N
N
N
Cl
Cl
Cl
X
X
10
11
12
Y
Y
Y
R
N
O
O
OH
R'
N
N
N
N
N
N
X
N
N
(d)
(c)
N
N
Cl
Cl
X
9
13
Y
Y
Scheme 1. Reagents: (a) NBS, AIBN, CCl4; (b) 1,2,4-triazole, Cs2CO3, DMF; (c) LiOH, THF–H2O; (d) (i) (COCl)2, (ii) NHRR0, Et3N, CH2Cl2.

1152
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
Table 1
Table 2
Structures and binding affinities of selected ligands to rat CB1 receptorsa,b
Structures and binding affinities of selected ligands to rat CB1 receptorsa,b
N
N
N
N
N
N
Cl
R1
O
O
R1
R3
N
H
N
N
N
N
N
H
Cl
Cl
Cl
R2
Compound R1
Receptor affinity
(IC50, nM)
rCB1
Compound
R1
R2
R3
Receptor affinity
(IC50, nM)
rCB1
1
6
4.53
7.59
3.83
6.9
1
4.53
6.6
9.7
21b
22b
23b
34b
35b
31b
32b
19b
40
21c
22c
23c
34c
35c
30b
31c
32c
19c
21d
22d
34d
35d
30c
31d
32d
41
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
Cyclohexyl
Cycloheptyl
Cyclohexylmethyl
1-(Trifluoromethyl)cyclopropyl
1-(Trifluoromethyl)cyclobutyl
t-Pentyl
3,3-Dimethylbutan-2-yl
Piperidin-1-yl
Homopiperidin-1-yl
Cyclohexyl
19a
20a
21a
22a
23a
24
25
26
27
28
Piperidin-1-yl
Cyclopentyl
Cyclohexyl
Cycloheptyl
12.2
4.75
5.14
11.9
6.22
5.11
8.23
4.38
8.49
20.5
3.31
3.87
2.9
3.77
11.2
22.8
11.4
17.1
14.2
18.3
12.9
60.7
4.9
3.01
8.44
20.2
4.5
4.67
189
Cyclohexylmethyl
(2,6-Dimethyl)piperidin-1-yl
cis-4-Methylcyclohexyl
trans-4-Methylcyclohexyl
cis-2-Methylcyclohexyl
trans-2-Methylcyclohexyl
trans-2-Hydroxycyclohexyl
t-Butyl
t-Pentyl
3,3-Dimethylbutan-2-yl
2-Ethylhexyl
Cycloheptyl
29
Cyclohexylmethyl
1-(Trifluoromethyl)cyclopropyl
1-(Trifluoromethyl)cyclobutyl
t-Butyl
t-Pentyl
3,3-Dimethylbutan-2-yl
Piperidin-1-yl
Cyclohexyl
Cycloheptyl
1-(Trifluoromethyl)cyclopropyl
1-(Trifluoromethyl)cyclobutyl
t-Butyl
30a
31a
32a
33
34a
35a
36
37
38
39
3.67
4.1
5.23
1.6
1-(Trifluoromethyl)cyclopropyl
1-(Trifluoromethyl)cyclobutyl
Cyclohexylcarboxamido
Trifluoromethylcyclopropylcarboxamido 126
2.7
1-Ethylpyrrolidinylmethyl
(4-Carboxamido-4-
ethylamino)piperidin-1-yl
4020
878
9.15
7.48
7.9
8.99
6.0
t-Pentyl
3,3-Dimethylbutan-2-yl
1-Cyanocyclopropyl
a
These data were obtained by single determinations.
Compound 1 was evaluated to have CB1 binding affinity via in-house assay.
b
19.6
a
These data were obtained by single determinations.
Compound 1 was evaluated to have CB1 binding affinity via in-house assay.
b
Next, we decided to investigate piperazine analogues as carbox-
amide substituents since it has structural similarity to piperidine
or cyclohexyl moiety and presents a cyclic motif which has conve-
nient synthetic access to a variety of analogues. The distal nitrogen
atom (4 N) of the piperazine ring provided the desired site for SAR
work in Table 3. Substitution of NH in piperazine with small alkyl
such as methyl or ethyl showed a dramatic lost of binding potency
against rCB1 (42b, IC50 = 961 nM; 48a, IC50 = 1050 nM). However,
substitution with a phenyl group as in 43b (IC50 = 11.5 nM) signif-
icantly altered the in vitro profile of the simple N-alkylamines.
Replacement of a phenyl with a substituted phenyl even increased
binding potency against rCB1 receptor as displayed in 3-chloro-
phenyl 44b (IC50 = 4.08 nM) or 2,3-dimethylphenyl 46b
(IC50 = 6.09 nM). Substitution of the NH in piperazine with hetero-
cycle such as 2-pyrimidyl did not improve the binding potency
against rCB1 receptor (47a, IC50 = 56.0 nM), implying the impor-
tance of non-polar moiety in order to optimally bind to a hydro-
phobic area of rCB1 receptor. The in vitro profile of the
piperazine-based ligands was quite sensitive to the changes in
both steric and electronic environments. Among the compounds
tested in this piperazine series, bromophenyl des-chlorophenyl
compounds 44d, 45c, and 46d showed the best binding affinity
against rCB1 in this particular series to date (IC50 = 2.07–2.28 nM).
Following the prior examples in Table 1–3, we undertook sub-
stitution of NH with benzyl, or more lipophilic benzyl analogues
such as methylbenzyl and gem-dimethylbenzyl groups as well as
spiro-cyclopropylphenyl for the focused SAR studies around
1,2,4-triazole-containing diarylpyrazolyl carboxamide as shown
in Table 4. Our previous studies illustrated usefulness of gem-di-
methyl and spiro-cyclopropyl groups at the lipophilic region for
the in vitro and in vivo profile of the CB1 ligands.17 Substitution
of benzyl with gem-dimethylbenzyl improved binding potency
against rCB1 receptor in about threefold (IC50 = 7.4 nM for 50a).
Substitution of gem-dimethylbenzyl with 4-chloro-a,a-dimethyl-
benzyl 51a ameliorated rCB1 receptor binding potency in twofold
(IC50 = 3.3 nM). Spiro-cyclopropyl groups such as phenylcyclopro-
pyl 54a and (4-chlorophenyl)cyclopropyl 55a did not significantly
affect binding affinity against rCB1, respectively. Heteroaryl groups
such as 2-pyridylmethyl 56a diminished binding potency against
rCB1 receptor, suggesting the importance of lipophilicity at the
region.
Next, the des-chloro compounds on the N1 phenyl group in the
series were prepared and evaluated. As shown in 52b and 53b,
these ligands did not lead to any loss of affinity, but rather en-
hanced their binding potency (IC50 = 1.8 nM for 52b; IC50 = 2.0 nM
for 53b). This phenomenon was observed in 5-(4-bromophenyl)-
pyrazole series as well. Thus, 4-bromo-a-methylbenzyl 52d dem-
onstrated the best binding affinity in the series prepared to date
(IC50 = 1.1 nM). Binding affinity was also measured for the CB2 can-
nabinoid receptor expressed in chinese hamster ovary (CHO) cells,
employing [3H]-WIN55,212-2 as a radioligand.22 Virtually all of our
triazole-containing diarylpyrazole carboxamides were devoid of
noticeable activity in this hCB2, resulting in excellent selectivity
for rCB1 over hCB2 for these analogues (i.e., 52c, hCB2/
rCB1 = 4629; 52d, hCB2/rCB1 = 1627).

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1153
Table 3
Table 4
Structures and binding affinities of selected ligands to rat CB1 and human CB2
Structures and binding affinities of selected ligands to rat CB1 and human CB2
receptors and hCB2/rCB1 selectivity of the ligandsa,b
receptors and hCB2/rCB1 selectivity of the ligandsa,b
N
N
N
N
N
N
R1
R1
O
O
R3
N
N
N
N
N
N
H
N
R3
Cl
Cl
R2
R2
Compound R1 R2 R3
Receptor affinity hCB2/rCB1
Compound R1 R2 R3
Receptor
affinity
hCB2/
rCB1
(IC50, nM)
selectivity
(IC50, nM) selectivity
rCB1
hCB2
rCB1 hCB2
1
21d
4.53
1.6
1420
8.88
7.33
5.50
1760
4060
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
296
582
547
—
389
2538
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
130
262
264
—
1
4.53 1760 389
42a
43a
44a
45a
46a
47a
42b
48a
43b
44b
46b
42c
48b
43c
44c
45b
46c
47b
42d
48c
43d
44d
45c
46d
47c
Cl Cl Methyl
Cl Cl Phenyl
Cl Cl 3-Chlorophenyl
49a
50a
51a
52a
53a
54a
55a
56a
57
Cl Cl Benzyl
Cl Cl -Dimethylbenzyl
Cl Cl 4-Chloro-
19.2
7.4
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
a,a
a,a-dimethylbenzyl 3.33
Cl Cl 2,3-Dichlorophenyl
Cl Cl 4-Bromo-
a-methylbenzyl
2.6
Cl Cl 2,3-Dimethylphenyl 11.5
Cl Cl 2,4-Dichloro-
a
-methylbenzyl 2.6
Cl Cl 2-Pyrimidyl
56.0
961
1050
11.5
4.08
Cl Cl Phenylcyclopropyl
Cl Cl (4-Chlorophenyl)cyclopropyl 5.09
Cl Cl 2-Pyridylmethyl 74.8
5.1
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Methyl
Ethyl
Phenyl
3-Chlorophenyl
Cl Cl (4-Chlorophenyl)cyclopropyl- 44.5
carboxamido
2,3-Dimethylphenyl 6.09
49b
50b
51b
52b
53b
54b
55b
49c
51c
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
Benzyl
a,a-dimethylbenzyl
4-Chloro-
14.1
12.9
—
—
—
—
—
—
Br Cl Methyl
Br Cl Ethyl
Br Cl Phenyl
Br Cl 3-Chlorophenyl
Br Cl 2,3-Dichlorophenyl
1340
285
12.5
7.22
5.74
a,a-dimethylbenzyl 7.70
4-Bromo-
a-methylbenzyl
1.8
3510 1950
3330 1665
2,4-Dichloro-
a
-methylbenzyl 2.0
Phenylcyclopropyl
5.81
—
—
—
—
—
—
—
—
Br Cl 2,3-Dimethylphenyl 3.8
Br Cl 2-Pyrimidyl 27.7
(4-Chlorophenyl)cyclopropyl 9.03
Br Cl Benzyl
Br Cl 4-Chlroro-a,a-
13.0
2.99
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
Methyl
Ethyl
Phenyl
3-Chlorophenyl
2,3-Dichlorophenyl
901
303
8.01
2.28
2.22
dimethylbenzyl
52c
53c
54c
55c
50c
52d
53d
54d
55d
56b
Br Cl 4-Bromo-
a-methylbenzyl
1.4
6480 4629
Br Cl 2,4-Dichloro-
a
-methylbenzyl 2.2
7.86
Br Cl (4-Chlorophenyl)cyclopropyl 2.8
—
—
—
—
—
—
—
—
Br Cl Phenylcyclopropyl
2,3-Dimethylphenyl 2.07
2-Pyrimidyl 22.3
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
a
,a
-Dimethylbenzyl
4-Bromo- -methylbenzyl
2,4-Dichloro-
Phenylcyclopropyl
(4-Chlorophenyl)cyclopropyl 1.7
2-Pyridylmethyl 63.4
6.1
a
1.1
1790 1627
2420 1100
a
These data were obtained by single determinations.
Compound 1 was evaluated to have CB1 binding affinity via in-house assay.
a
-methylbenzyl 2.2
b
1.98 3200 1616
2570 1512
—
—
The analogues 52c, 52d were also shown to be highly potent in
a
the CHO-hCB1R-luciferase assay,27,28 with IC50 values being
28.2 nM, 2.51 nM, respectively (for comparison, IC50 = 108 nM for
rimonabant), thus demonstrating inverse agonism activity of this
series. In vivo efficacy was evaluated on DIO (diet-induced obesity)
mice in order to confirm proof-of-concept on animal model of the
current scaffold.25 Male C57BL/6 J mice weighing over 38 g were
housed one per cage on a 12-/12-h light/dark cycle, had free access
to food (rodent sterilized diet) and water, and were experimentally
native before testing. Mice were allowed at least 7 days to habitu-
ate to the experimental room prior to testing, and testing was con-
ducted during the light period. Mice were maintained and
experiments were conducted in accordance with the Institutional
Animal Care. The selected compounds 52c and 52d were prepared
fresh daily by dissolving it in de-ionized water containing 10%
DMSO. By oral administration, animals received at a volume of
10 mL/kg for 7 days. All control animals received 10% DMSO dis-
solved in de-ionized water. The vehicles 10% DMSO-treated groups
were comprised of five mice in oral test. There were five mice in
each of the other experimental groups (n = 5 in each group). By oral
administration, the losing weight was checked everyday for the
drug treated group and the control group.17,18b
These data were obtained by single determinations.
Compound 1 was evaluated to have CB1 binding affinity via in-house assay.
b
52d compound. Each value is the mean S.E.M. of
5 mice.
*P <0.05 versus corresponding vehicle (ANOVA with Dunnett’s
test). Figure 5 shows that compound 52d is substantially more effi-
cacious in in vivo efficacy study on the DIO mice model
(15.04 2.00% reduction in body weight after 7 days), while 52c re-
duces body weight moderately (7.99 0.98%). This is a notable
piece of information that this series of compounds are indeed
CB1 receptor antagonists or inverse agonists.
4. Conclusion
We investigated a series of 1,2,4-triazole-containing diarylpy-
razolyl carboxamides based on the 1,5-diarylpyrazole template of
rimonabant for their binding affinity against rCB1 and hCB2 recep-
tors. We have identified a novel series of small molecule rCB1 li-
gands that demonstrate binding affinity superior to that of
reported rCB1 antagonists. Several compounds in this series exhib-
ited potent rCB1 receptor binding affinities, confirming the
hypothesis that incorporation of 1,2,4-triazolylmethyl moiety onto
the pyrazole 3-carboxamide could lead to more potent CB1 recep-
tor antagonists. Of note is 52d was shown to possess the highest
Figure 5 shows chronic effects of compounds 52c and 52d in
DIO mice. Body weight change from day 0 was observed on all days
at 10 mg/kg of example 52c compound, at 10 mg/kg of example

1154
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
2
0
Day
1
2
3
4
5
6
7
-2
-4
-6
Vehicle
52c @ 10mg/kg
52d @ 10mg/kg
-8
-10
-12
-14
-16
-18
-20
N
N
N
O
Br
N
H
N
N
Br
Cl
R2
52c (R2 = Cl)
52d (R2 = H)
Figure 5. In vivo efficacy study of compounds 52c and 52d on DIO mice.
binding affinity with a significant antiobesity effect in this 1,2,4-
triazole-containing diarylpyrazolyl carboxamide series prepared
to date. Importantly, these analogues also demonstrate excellent
selectivity for rCB1 over hCB2. The analogue 52d was shown to
be highly potent in the CHO-hCB1R-luciferase assay, with IC50 va-
lue being 2.51 nM, thus demonstrating inverse agonism activity of
this series. Therefore, diarylpyrazolyl carboxamide class of com-
pounds bearing a triazolylmethyl as the optimal side chain pos-
sesses a therapeutic potential as a CB1 receptor antagonist or
inverse agonist for the treatment of obesity. The structural unit
of triazolylmethyl might be considered to be included in new de-
sign of CB1 receptor antagonists based on diarylpyrazole scaffold.
and hexane. Flash chromatography was carried using Merck Silica
Gel 60 (230–400 mesh). Most of the reactions were monitored by
thin-layer chromatography on 0.25 mm E. Merck Silica Gel plates
(60F-254), visualized with UV light using a 5% ethanolic phospho-
molybdic acid or p-anisaldehyde solution.
5.2. Chemistry
5.2.1. Preparation of amines20
O
H
N
DPPA, TEA
F3C
O
F3C
OH
t-BuOH, reflux
5. Experimental
O
14
15
HCl
5.1. General methods
1N-HCl
All reactions are conducted under an inert atmosphere at room
temperature unless otherwise noted, and all solvents are of the
highest available purity unless otherwise indicated. Microwave
reaction was conducted with a Biotage Initiator™ microwave reac-
tor. 1H NMR spectra were recorded on 400 MHz Fourier Transform-
Nuclear Magnetic Resonance; Varian, 400-MR. Chemical shifts
were expressed in parts per million (ppm, d units). Coupling con-
stants are in units of hertz (Hz). Splitting patterns describe appar-
ent multiplicities and are designated as s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
Mass spectra were obtained with either a Micromass, Quattro LC
Triple Quadruple Tandem Mass Spectometer, ESI or Agilent,
F3C
NH2
reflux to rt
16
5.2.1.1. tert-Butyl
(15). To a solution of 1-(trifluoromethyl)cyclopropanecarbox-
1-(trifluoromethyl)cyclopropylcarbamate
ylic acid (14, 3.26 g, 21.1 mmol), triethylamine (2.95 mL,
21.1 mmol) in t-BuOH (12.5 mL) was added dropwise diphenyl-
phosphoryl azide (5.05 mL, 23.3 mmol) at room temperature. The
reaction mixture was stirred at 83 °C for 12 h and then added
diethyl ether (50 mL). The mixture was stirred for 2 h and filtered
to give a biphasic solution. The ether layer was isolated, and the
oily liquid was extracted with ether (25 mL ꢁ 4). The combined
ether phase was washed with 5% citric acid (25 mL), saturated
NaHCO3 solution (15 mL ꢁ 2) and saturated NaCl solution
(15 mL). The organic layer was dried over anhydrous MgSO4, fil-
tered and concentrated in vacuo. The obtained product (3.4 g,
white solid) was used for the next step without purification. 1H
NMR (400 MHz, DMSO-d6) d 1.34 (s, 9H), 1.12–1.11 (m, 2H),
0.98–0.96 (m, 2H).
1200LC/MSD, system equipped with XTerraÒ MS C18 3.5
lm
2.1 ꢁ 50 mm column with a 12 min gradient from 10% CH3CN to
90% CH3CN in H2O with 0.05% TFA. For preparative HPLC, ca
100 mg of a product was injected in 1 mL of DMSO onto a SunFire™
Prep C18 OBD 5
l
m 19 ꢁ 100 mm Column with a 10 min gradient
from 10% CH3CN to 90% CH3CN in H2O. BiotageÒ SP1 Flash purifica-
tion system or BiotageÒ Isolera™ Flash purification system was
used for normal phase column chromatography with ethyl acetate

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1155
5.2.1.2. 1-(Trifluoromethyl)cyclopropanamine
(16). To a mixture of tert-butyl 1-(trifluoromethyl)cyclopro-
hydrochloride
(m, 2H), 1.77–1.74 (m, 2H), 1.66–1.60 (m, 2H), 1.45–1.37 (m,
2H), 1.29–1.13 (m, 2H); MH+ 529.
pylcarbamate (15, 3.3 g, 14.65 mmol) in 1 N-HCl (120 mL) was stir-
red at 100 °C for 2 h and then at room temperature for 12 h. The
reaction mixture was concentrated under reduced pressure. The
residue was triturated with acetone (25 mL) at 0 °C, and filtered
affording 800 mg (23%) of title compound 16 as white solid. 1H
NMR (400 MHz, DMSO-d6) d 9.58 (br s, 1H), 1.43–1.39 (m, 2H),
1.29–1.22 (m, 2H); MH+ 126.
5.2.3. General method II
N
N
N
O
Cl
OH
HCl
HN
N
N
N
5.2.2. General method I
Cl
N
N
N
N
Cl
N
N
Cl
Cl
13a
18
O
O
LiOH.H2O
N
O
OH
N
N
N
N
N
THF/MeOH/H2O
rt
N
O
Cl
Cl
Cl
N
EDCI, HOBt, NMM
DMF, rt
Cl
Cl
N
N
N
12a
13a
Cl
N
N
N
Cl
Cl
H2N
O
46a
17
oxalyl chloride
N
N
N
cat.DMF
CH2Cl2, rt
CH2Cl2, rt
H
Cl
5.2.3.1. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dimethylphen-
Cl
yl)piperazin-1-yl)methanone (46a).
1,2,4-triazol-1-yl)methyl)-5-(4-chlorophenyl)-1-(2,4-dichloroph-
To a mixture of 4-((1H-
21a
enyl)-1H-pyrazole-3-carboxylic acid (13a, 150 mg, 0.33 mmol), 1-
(2,3-dimethylphenyl)piperazine
0.43 mmol), EDCI (96 mg, 0.50 mmol) and HOBt (54 mg,
0.40 mmol) in anhydrous DMF (2 mL) was added NMM (221 L,
hydrochloride
(18,
84 mg,
5.2.2.1. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-1-
(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid
(13a). To solution of ethyl 4-((1H-1,2,4-triazol-1-yl)-
l
2.01 mmol). The reaction mixture was stirred at room temperature
for 15 h. The mixture was concentrated under reduced pressure.
The residue was diluted with CH2Cl2, and washed with water.
The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by prepara-
tive HPLC (purification system, Gilson) to provide the title com-
pound (150 mg, 73%) as a white solid. 1H NMR (400 MHz, CDCl3)
d 8.30 (s, 1H), 7.91 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.36–7.34 (m,
2H), 7.30–7.23 (m, 4H), 7.10–7.06 (t, J = 8.0 Hz, 1H), 6.90 (dd,
J = 18.0, 8.0 Hz, 2H), 5.40 (s, 2H), 3.92 (m, 4H), 2.91 (m, 2H), 2.75
(m, 2H), 2.25 (d, J = 14.4 Hz, 6H); MH+ 620.
a
methyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-
3-carboxylate17 (12a, 2.37 g, 4.97 mmol) and LiOHꢂH2O (625 mg,
14.91 mmol) in THF/CH3OH/H2O (20/20/2 mL) was stirred at room
temperature for 2 h. The reaction mixture was concentrated under
reduced pressure. The residue was diluted with EtOAc and washed
with 1 N-HCl solution. The organic layer was dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The obtained product
(2.2 g, white solid) was used for the next step without purification.
MH+ 448.
5.2.2.2. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-cyclohexyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxam-
5.2.3.2. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-1-
(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carbox-
amide (19a).
1H), 7.72 (br s, 1H), 7.46–7.41 (m, 3H), 7.36–7.23 (m, 4H), 5.44 (s,
2H), 2.93–2.81 (m, 4H), 1.83–1.72 (m, 4H), 1.48–1.37 (m, 2H); MH+
530
ide (21a).
To a mixture of 4-((1H-1,2,4-triazol-1-yl)methyl)-
1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 7.89 (s,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
ylic acid (13a, 200 mg, 0.44 mmol) in CH2Cl2 (5 mL) was added
oxalyl chloride (77 lL, 0.88 mmol) and the catalytic amount of
DMF at room temperature and stirred at room temperature for
1 h. The reaction mixture was concentrated under reduced pres-
sure. The residue (acyl chloride) was diluted with CH2Cl2
5.2.3.3. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-car-
(10 mL), to which cyclohexylamine (17, 150 lL, 1.32 mmol) was
boxamide (19b).
1H NMR (400 MHz, CDCl3) d 8.69 (s, 1H),
added and stirred for 1 h at room temperature. The resultant was
concentrated under reduced pressure, diluted with EtOAc and
washed with saturated NaHCO3 solution. The organic layer was
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The crude product was purified by preparative HPLC (purification
system, Gilson) to provide the title compound (157 mg, 67%) as a
pale yellow solid. 1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89
(s, 1H), 7.45–7.40 (m, 3H), 7.36–7.32 (m, 2H), 7.30–7.25 (m, 1H),
6.84 (d, J = 8.4 Hz, 1H), 5.49 (s, 2H), 3.96–3.87 (m, 1H), 2.01–1.98
8.10 (br s, 1H), 7.93 (s, 1H), 7.63–7.41 (m, 2H), 7.45–7.42 (d,
J = 1.8 Hz, 1H), 7.37–7.26 (m, 4H), 5.44 (s, 2H), 3.15–3.00 (m, 4H),
1.90–1.79 (m, 4H), 1.55–1.46 (m, 2H); MH+ 574.
5.2.3.4. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carbox-
amide (19c).
1H), 7.67 (br s, 1H), 7.49–7.43 (m, 3H), 7.39–7.35 (m, 3H), 7.33–
1H NMR (400 MHz, CDCl3) d 8.67 (s, 1H), 7.89 (s,

1156
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
7.29 (m, 2H), 5.47 (s, 2H), 2.83–2.81 (m, 4H), 1.79–1.74 (m, 4H),
1.44–1.42 (m, 2H); MH+ 540.
(m, 4H), 1.56–1.54 (m, 1H), 1.28–1.18 (m, 4H), 1.02–0.96 (m,
2H); MH+ 543.
5.2.3.5. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-cyclopentyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
amide (20).
5.2.3.14. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(cyclohexylmethyl)-1H-pyrazole-3-car-
boxamide (23b).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s,
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H),
1H), 7.45 (m, 1H), 7.42–7.40 (m, 2H), 7.36–7.34 (m, 2H), 7.32–7.26
(m, 2H), 6.89 (d, J = 7.6 Hz, 1H), 5.49 (s, 2H), 4.38–4.33 (m, 1H),
2.09–2.04 (m, 2H), 1.72–1.48 (m, 6H); MH+ 515.
7.90 (s, 1H), 7.46–7.37 (m, 4H), 7.37–7.27 (m, 4H), 7.06 (m, 1H),
5.52 (s, 2H), 3.28–3.25 (m, 2H), 1.79–1.66 (m, 5H), 1.26–1.19 (m,
2H), 1.03–0.97 (m, 2H); MH+ 509.
5.2.3.6. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-5-
(4-chlorophenyl)-N-cyclohexyl-1H-pyrazole-3-carboxamide
(21b).
5.2.3.15. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-(cyclohexylmethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-
carboxamide (23c).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s, 1H),
1H NMR (400 MHz, CDCl3) d 8.56 (s, 1H),
7.44–7.37 (m, 4H), 7.36–7.30 (m, 4H), 6.87 (d, J = 8.4 Hz, 1H),
5.50 (s, 2H), 3.94–3.91 (m, 1H), 2.02–1.98 (m, 2H), 1.77–1.74 (m,
2H), 1.43–1.37 (m, 2H), 1.29–1.16 (m, 4H); MH+ 495.
7.89 (s, 1H), 7.53–7.49 (m, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.36–7.24
(m, 5H), 7.02 (t, J = 6.4 Hz, 1H), 5.49 (s, 2H), 3.25 (t, J = 6.8 Hz,
2H), 1.78–1.65 (m, 4H), 1.57–1.50 (m, 2H), 1.29–1.11 (m, 3H),
1.02–0.92 (m, 2H); MH+ 587.
5.2.3.7. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-cyclohexyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxam-
ide (21c).
1H), 7.52–7.49 (m, 2H), 7.45 d, J = 2.4 Hz, 1H), 7.36–7.25 (m, 4H),
6.84 (d, J = 8.4 Hz, 1H), 5.49 (s, 2H), 3.96–3.87 (m, 1H), 2.17–1.99
(m, 2H), 1.97–1.73 (m, 2H), 1.66–1.63 (m, 2H), 1.47–1.36 (m,
2H), 1.29–1.13 (m, 2H); MH+ 573.
5.2.3.16. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(2,6-dimethylpiperidin-1-yl)-1H-pyr-
azole-3-carboxamide (24).
(s, 1H), 7.87 (s, 1H), 7.47 (m, 2H), 7.38–7.36 (m, 2H), 7.34–7.24
(m, 3H), 7.07 (m, 1H), 5.49 (s, 2H), 2.38 (m, 2H), 1.70–1.63 (m,
4H), 1.32 (m, 2H), 1.11 (d, J = 6.0 Hz, 6H); MH+ 558.
1H NMR (400 MHz, CDCl3) d 8.56 (s, 1H), 7.88 (s,
1H NMR (400 MHz, CDCl3) d 8.63
5.2.3.8. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-cyclohexyl-1H-pyrazole-3-carboxamide
(21d).
5.2.3.17. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1S,4S)-4-methylcyclohexyl)-1H-pyr-
azole-3-carboxamide (25).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s, 1H),
1H NMR (400 MHz, CDCl3) d 8.56
7.49–7.43 (m, 3H), 7.40–7.36 (m, 1H), 7.35–7.30 (m, 4H), 6.88 (d,
J = 8.4 Hz, 1H), 5.50 (s, 2H), 3.96–3.89 (m, 1H), 2.05–1.98 (m, 2H),
1.77–1.73 (m, 2H), 1.66–1.63 (m, 2H), 1.51–1.36 (m, 2H), 1.28–
1.13 (m, H); MH+ 539.
(s, 1H), 7.89 (s, 1H), 7.46–7.40 (m, 3H), 7.36–7.27 (m, 3H), 7.06
(d, J = 8.0 Hz, 1H), 5.49 (s, 2H), 4.16–4.11 (m, 1H), 1.76–1.60 (m,
5H), 1.28–1.21 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H); MH+ 543.
5.2.3.18. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1R,4R)-4-methylcyclohexyl)-1H-pyr-
azole-3-carboxamide (26).
(s, 1H), 7.88 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.41–7.39 (m, 2H),
7.35–7.33 (m, 2H), 7.31–7.25 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H),
5.48 (s, 2H), 3.90–3.80 (m, 1H), 2.04–2.01 (m, 2H), 1.75–1.72 (m,
2H), 1.36–1.30 (m, 1H), 1.28–1.18 (m, 2H), 1.14–1.04 (m, 2H),
0.90 (d, J = 6.4 Hz, 3H); MH+ 543.
5.2.3.9. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-cycloheptyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
amide (22a).
1H), 7.45 (m, 1H), 7.42–7.40 (m, 2H), 7.36–7.34 (m, 2H), 7.32–7.26
(m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 5.49 (s, 2H), 4.11–4.10 (m, 1H),
2.05–1.99 (m, 2H), 1.70–1.53 (m, 10H); MH+ 543.
1H NMR (400 MHz, CDCl3) d 8.56
1H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 7.90 (s,
5.2.3.10. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-cycloheptyl-1H-pyrazole-3-carboxamide
(22b).
7.44–7.37 (m, 4H), 7.36–7.30 (m, 4H), 6.94 (d, J = 8.0 Hz, 1H),
5.51 (s, 2H), 4.10 (m, 1H), 2.05–1.99 (m, 2H), 1.70–1.53 (m, 10H);
MH+ 509.
5.2.3.19. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1R,2S)-2-methylcyclohexyl)-1H-pyr-
azole-3-carboxamide (27).
(s, 1H), 7.88 (s, 1H), 7.45 (m, 1H), 7.42–7.40 (m, 2H), 7.36–7.34
(m, 2H), 7.32–7.26 (m, 2H), 6.74 (d, J = 9.2 Hz, 1H), 5.49 (dd,
J = 23.2 Hz, 2H), 3.64–3.61 (m, 1H), 2.03–2.00 (m, 1H), 1.80–1.67
(m, 4H), 1.40–1.33 (m, 2H), 1.25–1.12 (m, 3H), 0.95 (d, J = 6.8 Hz,
3H); MH+ 543.
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s, 1H),
1H NMR (400 MHz, CDCl3) d 8.57
5.2.3.11. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-cycloheptyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
amide (22c).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s,
1H), 7.51 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.35–7.25 (m,
4H), 6.91 (d, J = 8.4 Hz, 1H), 5.49 (s, 2H), 4.11–4.09 (m, 1H), 2.04–
1.98 (m, 2H), 1.70–1.63 (m, 4H), 1.55–1.52 (m, 6H); MH+ 587.
5.2.3.20. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1R,2R)-2-methylcyclohexyl)-1H-pyr-
azole-3-carboxamide (28).
1H NMR (400 MHz, CDCl3) d 8.57
(s, 1H), 7.89 (s, 1H), 7.45 (m, 1H), 7.42–7.40 (m, 2H), 7.36–7.34
(m, 2H), 7.32–7.25 (m, 2H), 7.06 (d, J = 8.8 Hz, 1H), 5.49 (dd,
J = 24 Hz, 2H), 4.24–4.20 (m, 1H), 2.00–1.88 (m, 1H), 1.77–1.46
(m, 6H), 1.37–1.26 (m, 3H), 0.91 (d, J = 6.8 Hz, 3H); MH+ 543.
5.2.3.12. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-cycloheptyl-1H-pyrazole-3-carboxamide
(22d).
1H NMR (400 MHz, CDCl3) d 8.60 (s, 1H), 7.92 (s, 1H),
7.51–7.42 (m, 3H), 7.40–7.38 (m, 1H), 7.36–7.29 (m, 4H), 6.94 (d,
J = 8.0 Hz, 1H), 5.53 (s, 2H), 4.11–4.10 (m, 1H), 2.05–1.99 (m, 2H),
1.70–1.67 (m, 4H), 1.54–1.48 (m, 6H); MH+ 553.
5.2.3.21. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-
pyrazole-3-carboxamide (29).
1H NMR (400 MHz, CDCl3) d
5.2.3.13. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-(cyclohexylmethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-
carboxamide (23a).
7.90 (s, 1H), 7.42–7.40 (m, 1H), 7.36–7.34 (m, 2H), 7.32–7.25 (m,
2H), 7.03 (m, 1H), 5.50 (s, 2H), 3.26 (t, J = 6.4 Hz, 2H), 1.78–1.66
8.52 (s, 1H), 7.89 (s, 1H), 7.46–7.40 (m, 3H), 7.36–7.32 (m, 2H),
7.30–7.26 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 5.58 (d, J = 14.0 Hz,
1H), 5.56 (d, J = 14.4 Hz, 1H), 3.86–3.79 (m, 1H), 3.43 (td, J = 10.0,
4.4 Hz, 1H), 2.17–2.02 (m, 2H), 1.78–1.73 (m, 2H), 1.45–1.24 (s,
4H); MH+ 545.
1H NMR (400 MHz, CDCl3) d 8.58 (s, 1H),

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1157
5.2.3.22. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-tert-butyl-5-(4-
chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
amide (30a).
5.2.3.32. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(3,3-dimethylbutan-2-yl)-1H-pyrazole-3-
carboxamide (32d).
1H NMR (400 MHz, CDCl3) d 8.55 (s, 1H), 7.86 (s,
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H),
1H), 7.42 (m, 1H), 7.37–7.29 (m, 4H), 7.27–7.23 (m, 2H), 6.79 (s,
1H), 5.48 (s, 2H), 1.43 (s, 9H); MH+ 503.
7.89 (s, 1H), 7.49–7.43 (m, 3H), 7.40–7.29 (m, 4H), 6.89 (d,
J = 9.6 Hz, 1H), 5.54 (d, J = 14.0 Hz, 1H), 5.48 (d, J = 14.0 Hz, 1H),
4.09–4.02 (m, 1H), 1.15 (d, J = 6.4 Hz, 2H), 0.95 (s, 9H); MH+ 541.
5.2.3.23. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-tert-butyl-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxam-
ide (30b).
5.2.3.33. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(2-ethylhexyl)-1H-pyrazole-3-carbox-
amide (33).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.88 (s, 1H),
7.51–7.49 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.33–7.29 (m, 2H), 7.27–
1H NMR (400 MHz, CDCl3) d 8.56 (s, 1H), 7.89 (s,
7.25 (m, 2H), 6.81 (br s, 1H), 5.30 (s, 2H), 1.45 (s, 9H); MH+ 547.
1H), 7.46 (m, 1H), 7.42–7.40 (m, 2H), 7.36–7.34 (m, 2H), 7.31–7.24
(m, 2H), 6.92–6.93 (m, 1H), 5.50 (s, 2H), 3.37–3.34 (m, 2H), 1.55–
1.52 (m, 1H), 1.40–1.26 (m, 8H), 0.94–0.89 (m, 6H); MH+ 559.
5.2.3.24. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-tert-butyl-1-(2-chlorophenyl)-1H-pyrazole-3-carboxamide
(30c).
1H NMR (400 MHz, CDCl3) d 8.58 (s, 1H), 7.88 (s, 1H),
5.2.3.34. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(trifluoromethyl)cyclopropyl)-1H-
7.48–7.42 (m, 3H), 7.40–7.34 (m, 1H), 7.33–7.30 (m, 4H), 6.84 (s,
1H), 5.51 (s, 2H), 1.46 (s, 9H); MH+ 513.
pyrazole-3-carboxamide (34a).
1H NMR (400 MHz, CDCl3) d
8.54 (s, 1H), 7.88 (s, 1H), 7.46–7.43 (m, 4H), 7.37–7.35 (m, 2H),
7.33–7.26 (m, 1H), 5.47 (s, 2H), 1.43–1.35 (m, 2H), 1.21 (m, 2H);
MH+ 555.
5.2.3.25. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-tert-pentyl-1H-pyrazole-3-carboxam-
ide (31a).
1H NMR (400 MHz, CDCl3) d 8.54 (s, 1H), 7.86 (s,
1H), 7.42 (m, 1H), 7.37–7.29 (m, 4H), 7.27–7.23 (m, 2H), 6.71 (s,
1H), 5.47 (s, 2H), 1.81 (q, J = 7.6 Hz, 2H), 1.38 (s, 6H), 0.87 (t,
J = 7.2 Hz, 3H); MH+ 517.
5.2.3.35. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(1-(trifluoromethyl)cyclopropyl)-1H-pyr-
azole-3-carboxamide (34b).
1H NMR (400 MHz, CDCl3) d
8.55 (s, 1H), 7.89 (s, 1H), 7.46–7.41 (m, 4H), 7.36–7.32 (m, 4H),
5.48 (s, 2H), 1.35 (m, 2H), 1.21 (m, 2H); MH+ 521.
5.2.3.26. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-tert-pentyl-1H-pyrazole-3-carboxamide
(31b).
7.42 (m, 1H), 7.40–7.30 (m, 7H), 6.77 (s, 1H), 5.51 (s, 2H), 1.83
(q, J = 7.6 Hz, 2H), 1.41 (s, 6H), 0.90 (t, J = 7.6 Hz, 3H); MH+ 483.
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s, 1H),
5.2.3.36. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(trifluoromethyl)cyclopropyl)-1H-
pyrazole-3-carboxamide (34c).
1H NMR (400 MHz, CDCl3) d
8.54 (s, 1H), 7.88 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.46 (d,
J = 2.0 Hz, 1H), 7.42 (br s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.32 (dd,
J = 8.4, 2.0 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 5.46 (s, 2H), 1.43–1.39
(m, 2H), 1.26–1.25 (m, 2H); MH+ 599.
5.2.3.27. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-tert-pentyl-1H-pyrazole-3-carboxam-
ide (31c).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.89 (s,
1H), 7.53–7.50 (m, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.34–7.26 (m,
4H), 6.73 (br s, 1H), 5.50 (s, 2H), 1.83 (q, J = 7.6 Hz, 2H), 1.41 (s,
6H), 0.90 (d, J = 7.6 Hz, 3H); MH+ 561.
5.2.3.37. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-(trifluoromethyl)cyclopropyl)-1H-pyr-
azole-3-carboxamide (34d).
1H NMR (400 MHz, CDCl3) d
5.2.3.28. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-tert-pentyl-1H-pyrazole-3-carboxamide
(31d).
8.54 (s, 1H), 7.89 (s, 1H), 7.50–7.43 (m, 4H), 7.41–7.29 (m, 5H),
5.48 (s, 2H), 1.42–1.39 (m, 2H), 1.21–1.19 (m, 2H); MH+ 565.
1H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 7.90 (s, 1H),
7.49–7.42 (m, 3H), 7.34–7.27 (m, 4H), 6.77 (s, 1H), 5.51 (s, 2H),
1.84 (q, J = 7.2 Hz, 2H), 1.41 (s, 6H), 0.90 (t, J = 7.2 Hz, 3H); MH+ 527.
5.2.3.38. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(trifluoromethyl)cyclobutyl)-1H-
pyrazole-3-carboxamide (35a).
8.53 (s, 1H), 7.90 (s, 1H), 7.46–7.42 (m, 3H), 7.38–7.33 (m, 2H),
7.31–7.27 (m, 1H), 7.09 (s, 1H), 5.48 (s, 2H), 2.68–2.56 (m, 4H),
2.11–2.03 (m, 2H); MH+ 569.
1H NMR (400 MHz, CDCl3) d
5.2.3.29. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(3,3-dimethylbutan-2-yl)-1H-pyra-
zole-3-carboxamide (32a).
1H NMR (400 MHz, CDCl3) d 8.54
(s, 1H), 7.86 (s, 1H), 7.43 (m, 1H), 7.40–7.38 (m, 2H), 7.34–7.32
(m, 2H), 7.29–7.23 (m, 2H), 6.84 (d, J = 10.0 Hz, 1H), 5.47 (dd,
J = 24.8 Hz, 2H), 4.04–4.00 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H), 0.93
(s, 9H); MH+ 531.
5.2.3.39. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(1-(trifluoromethyl)cyclobutyl)-1H-pyra-
zole-3-carboxamide (35b).
1H NMR (400 MHz, CDCl3) d 8.53
(s, 1H), 7.90 (s, 1H), 7.45–7.37 (m, 4H), 7.34–7.30 (m, 4H), 5.49 (s,
2H), 2.68–2.56 (m, 4H), 2.11–2.02 (m, 2H); MH+ 535.
5.2.3.30. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(3,3-dimethylbutan-2-yl)-1H-pyrazole-3-
carboxamide (32b).
7.89 (s, 1H), 7.45–7.35 (m, 4H), 7.34–7.29 (m, 4H), 6.89 (d,
J = 10.0 Hz, 1H), 5.51 (dd, J = 25.6 Hz, 2H), 4.09–4.01 (m, 1H), 1.15
(d, J = 6.8 Hz, 3H), 0.95 (s, 9H); MH+ 497.
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H),
5.2.3.40. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(trifluoromethyl)cyclobutyl)-1H-
pyrazole-3-carboxamide (35c).
1H NMR (400 MHz, CDCl3) d
8.53 (s, 1H), 7.89 (s, 1H), 7.53–7.50 (m, 2H), 7.46 (d, J = 2.0 Hz,
1H), 7.37–7.27 (m, 4H), 7.08 (br s, 1H), 5.47 (s, 2H), 2.68–2.56
(m, 4H), 2.11–2.02 (m, 2H); MH+ 613.
5.2.3.31. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(3,3-dimethylbutan-2-yl)-1H-pyra-
zole-3-carboxamide (32c).
1H NMR (400 MHz, CDCl3) d 8.56
5.2.3.41. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-(trifluoromethyl)cyclobutyl)-1H-pyra-
(s, 1H), 7.89 (s, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.46 (br s, 1H), 7.35–
7.25 (m, 4H), 6.86 (d, J = 10.0 Hz, 1H), 5.53 (d, J = 14.4 Hz, 1H),
5.47 (d, J = 14.0 Hz, 1H), 4.07–4.00 (m, 1H), 1.15 (d, J = 6.0 Hz,
3H), 0.94 (s, 9H); MH+ 575.
zole-3-carboxamide (35d).
(s, 1H), 7.89 (s, 1H), 7.49–7.47 (m, 2H), 7.47–7.43 (m, 1H), 7.41–
1H NMR (400 MHz, CDCl3) d 8.53

1158
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
7.31 (m, 5H), 7.12 (br s, 1H), 2.68–2.56 (m, 4H), 2.10–2.02 (m, 2H);
MH+ 579.
5.2.3.51. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-
yl)methanone (42d).
1H NMR (400 MHz, CDCl3) d 8.30 (s,
5.2.3.42. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N0-(cyclohexanecarbonyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-
3-carbohydrazide (36).
1H), 7.92 (s, 1H), 7.49–7.43 (m, 3H), 7.39–7.34 (m, 1H), 7.32–
7.28 (m, 2H), 7.21–7.18 (m, 2H), 3.83–3.79 (m, 4H), 2.45 (t,
J = 4.8 Hz, 2H), 2.29 (s, 3H), 2.25 (t, J = 4.8 Hz, 2H); MH+ 540.
1H NMR (400 MHz, CDCl3) d 9.47 (s,
1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.44–7.27 (m, 7H),
5.53 (s, 2H), 2.39–2.22 (m, 1H), 1.96–1.63 (m, 5H), 1.59–1.19 (m,
6H); MH+ 572.
5.2.3.52. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-phenylpiperazin-1-
yl)methanone (43a).
1H NMR (400 MHz, CDCl3) d 8.29 (s, 1H),
5.2.3.43. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N0-(1-(trifluoromethyl)cyclopropane-
carbonyl)-1H-pyrazole-3-carbohydrazide (37).
7.88 (s, 1H), 7.47 (m, 1H), 7.36–7.34 (m, 2H), 7.30–7.22 (m, 6H),
6.93–6.88 (m, 3H), 5.39 (s, 2H), 4.00–3.98 (m, 2H), 3.94–3.91 (m,
2H), 3.25–3.22 (m, 2H), 3.09–3.07 (m, 2H); MH+ 592.
1H NMR
(400 MHz, CDCl3) d 9.26 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 8.23 (s,
1H), 7.45–7.26 (m, 7H), 5.59 (s, 2H), 1.58–1.51 (m, 2H), 1.39–
1.33 (m, 2H); MH+ 598.
5.2.3.53. (4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-1H-pyrazol-3-yl)(4-phenylpiperazin-1-
yl)methanone (43b).
1H NMR (400 MHz, CDCl3) d 8.32 (s,
5.2.3.44. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-((1-ethylpyrrolidin-2-yl)methyl)-1H-
pyrazole-3-carboxamide (38).
1H), 7.89 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40–7.35 (m, 1H), 7.34–
7.25 (m, 8H), 6.93–6.88 (m, 3H), 5.40 (s, 2H), 4.03–4.01 (m, 2H),
3.95–3.92 (m, 2H), 3.25–3.23 (m, 2H), 3.11–3.08 (m, 2H); MH+ 558.
1H NMR (400 MHz, CDCl3) d
8.52 (s, 1H), 7.89 (s, 1H), 7.44 (m, 1H), 7.40–7.34 (m, 4H), 7.29 (m,
2H), 5.47 (dd, J = 17.2, 2H), 3.75–3.70 (m, 1H), 3.49 (m, 2H), 3.00 (m,
2H), 2.60–2.48 (m, 2H), 1.85–1.74 (m, 4H), 1.18 (m, 3H); MH+ 558.
5.2.3.54. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-phenylpipera-
zin-1-yl)methanone (43c).
1H NMR (400 MHz, CDCl3) d 8.30
5.2.3.45. 1-(4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chloro-
phenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbonyl)-4-
(s, 1H), 7.89 (s, 1H), 7.52–7.51 (m, 2H), 7.50–7.47 (m, 1H), 7.31–
7.24 (m, 4H), 7.22–7.18 (m, 2H), 6.93–6.88 (m, 3H), 3.99–3.98
(m, 2H), 3.92–3.91 (m, 2H), 3.23 (t, J = 5.2 Hz, 2H), 3.07 (t,
J = 5.2 Hz, 2H); MH+ 636.
(ethylamino)piperidine-4-carboxamide
(39).
1H
NMR
(400 MHz, CDCl3) d 8.30 (s, 1H), 7.92 (s, 1H), 7.45 (d, J = 2.4 Hz,
1H), 7.37–7.34 (m, 2H), 7.29–7.26 (m, 3H), 7.24–7.22 (m, 1H),
5.46 (d, J = 14.4 Hz, 1H), 5.29 (d, J = 14.8 Hz, 1H), 3.95–3.87 (m,
2H), 3.79–3.71 (m, 2H), 2.54 (q, J = 7.2 Hz, 2H), 1.94–1.88 (m,
4H), 1.13 (t, J = 6.8 Hz, 3H); MH+ 601.
5.2.3.55. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-phenylpiperazin-1-
yl)methanone (43d).
1H NMR (400 MHz, CDCl3) d 8.28 (s,
1H), 7.86 (s, 1H), 7.47–7.42 (m, 3H), 7.38–7.33 (m, 1H), 7.28–
7.23 (m, 4H), 7.18–7.16 (m, 2H), 6.91–6.87 (m, 3H), 5.38 (s, 2H),
3.99 (t, J = 4.8 Hz, 2H), 3.92 (t, J = 4.8 Hz, 2H), 3.22 (t, J = 4.8 Hz,
2H), 3.07 (t, J = 4.8 Hz, 2H); MH+ 602.
5.2.3.46. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-(azepan-1-yl)-5-
(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-car-
boxamide (40).
1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 8.06
(br s, 1H), 7.88 (s, 1H), 7.53–7.49 (m, 2H), 7.46 (d, J = 2.0 Hz, 1H),
7.39–7.37 (m, 2H), 7.32–7.20 (m, 2H), 5.47 (s, 2H), 3.13–3.11 (m,
4H), 1.75–1.72 (m, 4H), 1.68–1.62 (m, 4H); MH+ 588.
5.2.3.56. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(3-chloro-
phenyl)piperazin-1-yl)methanone
(44a).
1H
NMR
5.2.3.47. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-cyanocyclopropyl)-1H-pyrazole-3-car-
boxamide (41).
(s, 1H), 7.48–7.42 (m, 4H), 7.39–7.23 (m, 4H), 5.46 (s, 2H), 1.61–
1.59 (m, 2H), 1.34–1.31 (m, 2H); MH+ 522.
(400 MHz, CDCl3) d 8.29 (s, 1H), 7.88 (s, 1H), 7.47 (d, J = 2.0 Hz,
1H), 7.35 (d, J = 8.4 Hz, 2H), 7.30–7.21 (m, 4H), 7.17 (t, J = 8.0 Hz,
1H), 6.86–6.84 (m, 2H), 6.79–6.76 (m, 1H), 5.39 (s, 2H), 4.00–3.99
(m, 2H), 3.92–3.90 (m, 2H), 3.26–3.24 (m, 2H), 3.10–3.08 (m,
2H); MH+ 626.
1H NMR (400 MHz, CDCl3) d 8.55 (s, 1H), 7.88
5.2.3.48. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-
yl)methanone (42a).
5.2.3.57. (4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-1H-pyrazol-3-yl)(4-(3-chlorophenyl)pipera-
zin-1-yl)methanone (44b).
1H NMR (400 MHz, CDCl3) d 8.28 (s, 1H),
1H NMR (400 MHz, CDCl3) d 8.29
7.90 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.36–7.33 (m, 2H), 7.29–7.24
(m, 3H), 7.23–7.21 (m, 1H), 5.37 (s, 2H), 3.82–3.77 (m, 4H), 2.45–
2.43 (m, 2H), 2.29 (s, 3H), 2.26–2.22 (m, 2H); MH+ 530.
(s, 1H), 7.89 (s, 1H), 7.47–7.45 (m, 1H), 7.40–7.36 (m, 1H), 7.33–
7.25 (m, 8H), 7.17 (t, J = 8.0 Hz, 1H), 6.87–6.83 (m, 2H), 6.77 (dd,
J = 8.0, 1.6 Hz, 1H), 5.40 (s, 2H), 4.02–4.00 (m, 2H), 3.93–3.90 (m,
2H), 3.26–3.23 (m, 2H), 3.11–3.08 (m, 2H); MH+ 592.
5.2.3.49. (4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-5-
(4-chlorophenyl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)meth-
anone (42b).
5.2.3.58. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(3-chloro-
phenyl)piperazin-1-yl)methanone (44c).
1H NMR (400 MHz, CDCl3) d 8.30 (s, 1H), 7.92 (s,
1H), 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.39 (td, J = 8.0, 0.8 Hz, 1H), 7.34–
1H NMR (400 MHz,
7.30 (m, 2H), 7.28–7.24 (m, 4H), 5.39 (s, 2H), 2.80 (s, 3H); MH+ 496.
CDCl3) d 8.30 (s, 1H), 7.89 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.47 (d,
J = 2.4 Hz, 1H), 7.30–7.15 (m, 5H), 6.87–6.84 (m, 2H), 6.80–6.78
(m, 1H), 5.39 (s, 2H), 4.00–3.99 (m, 2H), 3.93–3.92 (m, 2H), 3.25
(t, J = 4.8 Hz, 2H), 3.09 (t, J = 4.8 Hz, 2H); MH+ 670.
5.2.3.50. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-methylpipera-
zin-1-yl)methanone (42c).
1H NMR (400 MHz, CDCl3) d 8.30
(s, 1H), 7.92 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 2.0 Hz,
1H), 7.31–7.28 (m, 1H), 7.25–7.19 (m, 3H), 5.38 (s, 2H), 3.81–
3.79 (m, 4H), 2.45 (t, J = 4.4 Hz, 2H), 2.30 (s, 3H), 2.25 (t,
J = 4.4 Hz, 2H); MH+ 574.
5.2.3.59. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-(3-chlorophenyl)pipera-
zin-1-yl)methanone (44d).
(s, 1H), 7.88 (s, 1H), 7.49–7.44 (m, 3H), 7.40–7.35 (m, 1H), 7.33–
1H NMR (400 MHz, CDCl3) d 8.29

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1159
7.28 (m, 2H), 7.21–7.15 (m, 3H), 6.87–6.83 (m, 2H), 6.78 (dd,
J = 8.4, 2.0 Hz, 1H), 5.40 (s, 2H), 4.01 (t, J = 4.8 Hz, 2H), 3.91 (t,
J = 4.8 Hz, 2H), 3.24 (t, J = 4.8 Hz, 2H), 3.09 (t, J = 4.8 Hz, 2H);
MH+ 636.
CDCl3) d 8.30 (d, J = 4.8 Hz, 2H), 8.28 (s, 1H), 7.87 (s, 1H), 7.49
(dd, J = 6.8, 2.0 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.27–7.24 (m, 1H),
7.21–7.17 (m, 3H), 6.52 (t, J = 4.8 Hz, 1H), 5.37 (s, 2H), 3.91–3.81
(m, 6H), 3.75–3.72 (m, 2H); MH+ 638.
5.2.3.60. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dichloro-
5.2.3.68. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-(pyrimidin-2-
yl)piperazin-1-yl)methanone (47c).
phenyl)piperazin-1-yl)methanone
(45a).
1H
NMR
1H NMR (400 MHz,
(400 MHz, CDCl3) d 8.30 (s, 1H), 7.90 (s, 1H), 7.46 (d, J = 2.0 Hz,
1H), 7.37–7.34 (m, 2H), 7.30–7.25 (m, 2H), 7.22–7.13 (m, 4H),
6.92 (dd, J = 7.6, 1.6 Hz, 1H), 5.40 (s, 2H), 3.96–3.95 (m, 4H),
3.08–3.06 (m, 2H), 2.90–2.88 (m, 2H); MH+ 660.
CDCl3) d 8.35 (d, J = 4.8 Hz, 2H), 8.33 (s, 1H), 7.90 (s, 1H), 7.49–
7.44 (m, 3H), 7.40–7.35 (m, 1H), 7.32–7.27 (m, 2H), 7.21–7.19
(m, 2H), 6.58 (t, J = 4.8 Hz, 1H), 5.40 (s, 2H), 3.95–3.92 (m, 4H),
3.87–3.81 (m, 4H); MH+ 604.
5.2.3.61. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dichloro-
5.2.3.69. (4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-1H-pyrazol-3-yl)(4-ethylpiperazin-1-
yl)methanone (48a).
phenyl)piperazin-1-yl)methanone
(45b).
1H
NMR
1H NMR (400 MHz, CDCl3) d 8.29 (s, 1H),
(400 MHz, CDCl3) d 8.30 (s, 1H), 7.90 (s, 1H), 7.51 (d, J = 8.0 Hz,
2H), 7.46 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 7.24–
7.13 (m, 5H), 6.93 (dd, J = 7.6, 1.6 Hz, 1H), 5.39 (s, 2H), 3.97–3.95
(m, 4H), 3.07 (t, J = 4.8 Hz, 2H), 2.88 (t, J = 4.8 Hz, 2H); MH+ 704.
7.90 (s, 1H), 7.43 (m, 1H), 7.39–7.34 (m, 1H), 7.32–7.24 (m, 6H),
5.38 (s, 2H), 3.85–3.79 (m, 4H), 2.49–2.47 (m, 2H), 2.41 (q,
J = 7.2 Hz, 2H), 2.31–2.28 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); MH+ 510.
5.2.3.70. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-ethylpiperazin-
1-yl)methanone (48b).
1H), 7.91 (s, 1H), 7.52–7.49 (m, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.30–
7.27 (m, 2H), 7.24–7.18 (m, 2H), 5.37 (s, 2H), 3.82–3.79 (m, 4H),
2.48 (t, J = 4.8 Hz, 2H), 2.42 (q, J = 7.2 Hz, 2H), 2.28 (t, J = 4.8 Hz,
2H), 1.08 (t, J = 7.2 Hz, 3H); MH+ 588.
5.2.3.62. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dichloro-
phenyl)piperazin-1-yl)methanone (45c).
CDCl3) d 8.32 (s, 1H), 7.92 (s, 1H), 7.50–7.45 (m, 3H), 7.41–7.37 (m,
1H), 7.32–7.31 (m, 2H), 7.23–7.15 (m, 4H), 6.94 (dd, J = 7.6, 2.0 Hz,
1H), 5.42 (s, 2H), 4.00–3.96 (m, 4H), 3.10–3.07 (m, 2H), 2.91–2.89
(m, 2H); MH+ 670.
1H NMR (400 MHz, CDCl3) d 8.30 (s,
1H NMR (400 MHz,
5.2.3.71. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-ethylpiperazin-1-
yl)methanone (48c).
7.91 (s, 1H), 7.49–7.43 (m, 3H), 7.40–7.34 (m, 1H), 7.32–7.29 (m,
2H), 7.21–7.18 (m, 2H), 5.38 (s, 2H), 3.85–3.78 (m, 4H), 2.48 (t,
J = 4.8 Hz, 2H), 2.42 (q, J = 6.8 Hz, 2H), 2.28 (t, J = 4.8 Hz, 2H), 1.08
(t, J = 6.8 Hz, 3H); MH+ 554.
5.2.3.63. (4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dimethyl-
1H NMR (400 MHz, CDCl3) d 8.30 (s, 1H),
phenyl)piperazin-1-yl)methanone
(46b).
1H
NMR
(400 MHz, CDCl3) d 8.31 (s, 1H), 7.92 (s, 1H), 7.45–7.43 (m, 1H),
7.39–7.34 (m, 1H), 7.33–7.25 (m, 8H), 7.07 (t, J = 8.0 Hz, 1H), 6.90
(dd, J = 15.2, 7.6 Hz, 1H), 5.41 (s, 2H), 3.94 (m, 4H), 2.91 (m, 2H),
2.76 (m, 2H), 2.25 (d, J = 13.6 Hz, 6H); MH+ 586.
5.2.3.72. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-benzyl-5-(4-chlo-
rophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxamide
(49a).
5.2.3.64. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dimethyl-
phenyl)piperazin-1-yl)methanone (46c).
1H NMR (400 MHz, CDCl3) d 8.57 (s, 1H), 7.90 (s, 1H),
1H NMR (400 MHz,
7.43–7.40 (m, 2H), 7.36–7.31 (m, 6H), 7.30–7.22 (m, 4H), 5.51 (s,
CDCl3) d 8.30 (s, 1H), 7.91 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.45 (d,
J = 2.0 Hz, 1H), 7.34–7.19 (m, 4H), 7.08 (t, J = 7.6 Hz, 1H), 6.92 (d,
J = 7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.39 (s. 2H), 3.96–3.91 (m,
4H), 2.93–2.91 (m, 2H), 2.75–2.74 (m, 2H), 2.27 (s, 3H), 2.23 (s,
3H); MH+ 664.
2H), 4.60 (d, J = 6.0 Hz, 2H); MH+ 537.
5.2.3.73. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-benzyl-1-(2-chlo-
rophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide
(49b).
1H NMR (400 MHz, CDCl3) d 8.58 (s, 1H), 7.91 (s, 1H),
7.43–7.40 (m, 4H), 7.39–7.26 (m, 9H), 5.53 (s, 2H), 4.60 (d,
5.2.3.65. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)(4-(2,3-dimethyl-
J = 5.6 Hz, 2H); MH+ 509.
phenyl)piperazin-1-yl)methanone
(46d).
1H
NMR
5.2.3.74. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-benzyl-5-(4-
bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbox-
(400 MHz, CDCl3) d 8.31 (s, 1H), 7.92 (s, 1H), 4.48–4.43 (m, 3H),
7.39–7.33 (m, 1H), 7.31–7.29 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H),
7.07 (d, J = 15.6 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 7.6 Hz,
1H), 5.40 (s, 2H), 3.95–3.93 (m, 4H), 2.92–2.90 (m, 2H), 2.76–2.74
(m, 2H). 2.27 (s, 3H), 2.23 (s, 3H); MH+ 630.
amide (49c).
1H NMR (400 MHz, CDCl3) d 8.58 (s, 1H), 7.90 (s,
1H), 7.51 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.36–7.33 (m,
5H), 7.29–7.23 (m, 4H), 5.51 (s, 2H), 4.61 (d, J = 6.0 Hz, 2H); MH+
581.
5.2.3.66. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(pyrimidin-2-yl)pip-
erazin-1-yl)methanone (47a).
5.2.3.75. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(2-phenylpropan-2-yl)-1H-pyrazole-
3-carboxamide (50a).
1H NMR (400 MHz, CDCl3) d
1H NMR (400 MHz, CDCl3) d 8.39 (s,
8.31 (d, J = 4.8 Hz, 2H), 8.29 (s, 1H), 7.89 (s, 1H), 7.47 (d,
J = 2.0 Hz, 1H), 7.36–7.34 (m, 2H), 7.29–7.25 (m, 3H), 7.23–7.21
(m, 1H), 6.53 (t, J = 4.8 Hz, 1H), 5.39 (s, 2H), 3.93–3.83 (m, 6H),
3.76–3.74 (m, 2H); MH+ 543.
1H), 7.86 (s, 1H), 7.46–7.34 (m, 9H), 7.34–7.25 (m, 4H), 5.45 (s,
2H), 1.79 (s, 6H); MH+ 565.
5.2.3.76. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(2-phenylpropan-2-yl)-1H-pyrazole-3-
5.2.3.67. (4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophe-
nyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)(4-(pyrimidin-2-
carboxamide (50b).
1H NMR (400 MHz, CDCl3) d 8.40 (s, 1H),
7.87 (s, 1H), 7.46–7.44 (m, 3H), 7.41–7.30 (m, 10H), 5.46 (s, 2H),
1.79 (s, 6H); MH+ 531.
yl)piperazin-1-yl)methanone (47b).
1H NMR (400 MHz,

1160
H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
5.2.3.77. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(2-phenylpropan-2-yl)-1H-pyrazole-3-
carboxamide (50c).
(s, 1H), 7.89 (s, 1H), 7.47–7.45 (m, 1H), 7.42–7.37 (m, 4H), 7.36–
7.31 (m, 6H), 5.57 (d, J = 14.4 Hz, 1H), 5.53–5.48 (m, 1H), 5.37 (d,
J = 14.4 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H); MH+ 585.
1H NMR (400 MHz, CDCl3) d 8.40 (s, 1H),
7.87 (s, 1H), 7.49–7.43 (m, 4H), 7.41–7.32 (m, 8H), 7.28–7.24 (m,
1H), 5.46 (s, 2H), 1.79 (s, 6H); MH+ 575.
5.2.3.87. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(2,4-dichlorophenyl)ethyl)-1H-
pyrazole-3-carboxamide (53c).
8.48 (s, 1H), 7.87 (s, 1H), 7.52–7.50 (m, 2H), 7.47 (d, J = 2.0 Hz,
1H), 7.40 (d, J = 2.4 Hz, 1H), 7.35–7.29 (m, 5H), 7.23 (dd, J = 8.4,
2.4 Hz, 1H), 5.55 (d, J = 14.4 Hz, 1H), 5.51–5.46 (m, 1H), 5.35 (d,
J = 14.4 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H); MH+ 663.
5.2.3.78. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-(2-(4-chlorophenyl)propan-2-yl)-1-(2,4-dichlorophenyl)-1H-
1H NMR (400 MHz, CDCl3) d
pyrazole-3-carboxamide (51a).
1H NMR (400 MHz, CDCl3) d
8.40 (s, 1H), 7.87 (s, 1H), 7.47 (m, 1H), 7.41–7.31 (m, 10H), 5.44
(s, 2H), 1.76 (s, 6H); MH+ 599.
5.2.3.79. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(2-(4-chlorophenyl)propan-2-yl)-1H-pyr-
azole-3-carboxamide (51b).
5.2.3.88. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-(2,4-dichlorophenyl)ethyl)-1H-pyra-
zole-3-carboxamide (53d).
1H NMR (400 MHz, CDCl3) d
1H NMR (400 MHz, CDCl3) d 8.48
8.39 (s, 1H), 7.87 (s, 1H), 7.46–7.44 (m, 1H), 7.41–7.32 (m, 6H),
7.31–7.29 (m, 5H), 5.45 (s, 2H), 1.75 (s, 6H); MH+ 565.
(s, 1H), 7.88 (s, 1H), 7.49–7.45 (m, 3H), 7.42–7.38 (m, 2H), 7.34–
7.31 (m, 5H), 7.24–7.21 (m, 1H), 5.56 (d, J = 14.4 Hz, 1H), 5.52–
5.47 (m, 1H), 5.37 (d, J = 14.4 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H);
MH+ 629.
5.2.3.80. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-(2-(4-chlorophenyl)propan-2-yl)-1-(2,4-dichlorophenyl)-1H-
pyrazole-3-carboxamide (51c).
1H NMR (400 MHz, CDCl3) d
5.2.3.89. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(1-phenylcyclopropyl)-1H-pyrazole-
8.39 (s, 1H), 7.86 (s, 1H), 7.52–7.50 (m, 2H), 7.46–7.40 (m, 1H),
7.38–7.26 (m, 8H), 5.43 (s, 2H), 1.75 (s, 6H); MH+ 643.
3-carboxamide (54a).
1H NMR (400 MHz, CDCl3) d 8.53 (s,
1H), 7.86 (s, 1H), 7.60 (s, 1H), 7.44–7.39 (m, 3H), 7.35–7.29 (m,
2H), 7.27–7.23 (m, 6H), 7.23–7.17 (m, 1H), 5.46 (s, 2H), 1.35 (m,
4H); MH+ 563.
5.2.3.81. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-(1-(4-bromophe-
nyl)ethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyra-
zole-3-carboxamide (52a).
1H NMR (400 MHz, CDCl3) d 8.51
(s, 1H), 7.89 (s, 1H), 7.48–7.45 (m, 3H), 7.42–7.40 (m, 2H), 7.36–
7.34 (m, 2H), 7.32–7.24 (m, 3H), 7.19–7.17 (m, 1H), 5.56 (d,
J = 14.4 Hz, 1H), 5.37 (d, J = 14.4 Hz, 1H), 5.24–5.20 (m, 1H), 1.55
(d, J = 6.8 Hz, 3H); MH+ 509.
5.2.3.90. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(1-phenylcyclopropyl)-1H-pyrazole-3-
carboxamide (54b).
7.88 (s, 1H), 7.65 (s, 1H), 7.46–7.36 (m, 4H), 7.33–7.26 (m, 8H),
7.22–7.19 (m, 1H), 5.50 (s, 2H), 1.40–1.33 (m, 4H); MH+ 529.
1H NMR (400 MHz, CDCl3) d 8.56 (s, 1H),
5.2.3.82. 4-((1H-1,2,4-Triazol-1-yl)methyl)-N-(1-(4-bromophe-
nyl)ethyl)-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-
3-carboxamide (52b).
1H), 7.90 (s, 1H), 7.48–7.46 (m, 2H), 7.43–7.36 (m, 4H), 7.34–
7.26 (m, 4H), 7.25–7.21 (m, 2H), 5.58 (d, J = 14.0 Hz, 1H), 5.39 (d,
J = 14.0 Hz, 1H), 5.27–5.20 (m, 1H), 1.55 (d, J = 7.2 Hz, 3H); MH+
509.
5.2.3.91. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2,4-dichlorophenyl)-N-(1-phenylcyclopropyl)-1H-pyrazole-
3-carboxamide (54c).
1H), 7.87 (s, 1H), 7.61 (br s, 1H), 7.52–7.50 (m, 2H), 7.46 (d,
J = 2.0 Hz, 1H), 7.37–7.35 (m, 2H), 7.33–7.25 (m, 6H), 7.23–7.19
(m, 1H), 5.48 (s, 2H), 1.37–1.36 (m, 4H); MH+ 607.
1H NMR (400 MHz, CDCl3) d 8.52 (s,
1H NMR (400 MHz, CDCl3) d 8.55 (s,
5.2.3.83. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-(1-(4-bromophenyl)ethyl)-1-(2,4-dichlorophenyl)-1H-pyra-
zole-3-carboxamide (52c).
5.2.3.92. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-phenylcyclopropyl)-1H-pyrazole-3-
carboxamide (54d).
1H NMR (400 MHz, CDCl3) d 8.51
1H NMR (400 MHz, CDCl3) d 8.55 (s, 1H),
(s, 1H), 7.88 (s, 1H), 7.52–7.45 (m, 4H), 7.35–7.24 (m, 6H), 7.18–
7.16 (m, 1H), 5.55 (d, J = 14.0 Hz, 1H), 5.37 (d, J = 14.4 Hz, 1H),
5.26–5.18 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H); MH+ 673.
7.88 (s, 1H), 7.65 (br s, 1H), 7.49–7.43 (m, 3H), 7.41–7.28 (m, 9H),
7.22–7.18 (m, 1H), 5.49 (s, 2H), 1.40–1.33 (m, 4H); MH+ 573.
5.2.3.93. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N-(1-(4-chlorophenyl)cyclopropyl)-1-(2,4-dichlorophenyl)-1H-
pyrazole-3-carboxamide (55a).
8.51 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.44–7.39 (m, 3H), 7.34–
7.32 (m, 2H), 7.28–7.24 (m, 3H), 7.23–7.19 (m, 3H), 5.45 (s, 2H),
1.35–1.30 (m, 4H); MH+ 597.
5.2.3.84. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-(1-(4-bromophenyl)ethyl)-1-(2-chlorophenyl)-1H-pyrazole-
3-carboxamide (52d).
1H), 7.89 (s, 1H), 7.48–7.43 (m, 5H), 7.40–7.38 (m, 1H), 7.37–7.30
(m, 4H), 7.24–7.20 (m, 2H), 5.57 (d, J = 14.4 Hz, 1H), 5.39 (d,
J = 14.4 Hz, 1H), 5.27–5.19 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H); MH+
639.
1H NMR (400 MHz, CDCl3) d
1H NMR (400 MHz, CDCl3) d 8.51 (s,
5.2.3.94. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(1-(4-chlorophenyl)cyclopropyl)-1H-pyr-
5.2.3.85. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(1-(2,4-dichlorophenyl)ethyl)-1H-
azole-3-carboxamide (55b).
1H NMR (400 MHz, CDCl3) d
8.54 (s, 1H), 7.89 (s, 1H), 7.63 (m, 1H), 7.46–7.36 (m, 4H), 7.33–
7.31 (m, 3H), 7.28–7.21 (m, 5H), 5.48 (s, 2H), 1.39–1.30 (m, 4H);
MH+ 503.
pyrazole-3-carboxamide (53a).
1H NMR (400 MHz, CDCl3) d
8.48 (s, 1H), 7.87 (s, 1H), 7.46 (m, 1H), 7.42–7.40 (m, 3H), 7.36–
7.26 (m, 6H), 7.24–7.22 (m, 1H), 5.56 (d, J = 14.4 Hz, 1H), 5.52–
5.46 (m, 1H), 5.35 (d, J = 14.4 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H);
MH+ 619.
5.2.3.95. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
N-(1-(4-chlorophenyl)cyclopropyl)-1-(2,4-dichlorophenyl)-1H-
pyrazole-3-carboxamide (55c).
1H NMR (400 MHz, CDCl3) d
5.2.3.86. 4-((1H-1,2,4-Triazol-1-yl)methyl)-1-(2-chlorophenyl)-
5-(4-chlorophenyl)-N-(1-(2,4-dichlorophenyl)ethyl)-1H-pyra-
zole-3-carboxamide (53b).
8.53 (s, 1H), 7.88 (s, 1H), 7.59 (br s, 1H), 7.53–7.50 (m, 2H), 7.46–
7.45 (m, 1H), 7.37–7.34 (m, 2H), 7.32–7.21 (m, 6H), 5.47 (s, 2H),
1.39–1.30 (m, 4H); MH+ 641.
1H NMR (400 MHz, CDCl3) d 8.49

H. J. Seo et al. / Bioorg. Med. Chem. 18 (2010) 1149–1162
1161
5.2.3.96. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(1-(4-chlorophenyl)cyclopropyl)-1H-pyr-
azole-3-carboxamide (55d).
8.54 (s, 1H), 7.89 (s, 1H), 7.63 (br s, 1H), 7.49–7.44 (m, 3H), 7.41–
7.32 (m, 5H), 7.28–7.21 (m, 4H), 5.48 (s, 2H), 1.39–1.36 (m, 2H),
1.33–1.25 (m, 2H); MH+ 607.
as the difference between the binding that occurred in the pres-
ence and absence of 1 M concentrations of 1 or WIN55,212-2
and was 70–80% of the total binding. IC50 was determined by non-
linear regression analysis using GraphPad PRISM
l
1H NMR (400 MHz, CDCl3) d
.
5.4. Measurements of in vivo activity analysis
5.2.3.97. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-3-
carboxamide (56a).
7.93–7.90 (m, 1H), 7.87 (s, 1H), 7.65 (td, J = 7.6, 2.0 Hz, 1H), 7.43–
7.38 (m, 3H), 7.34–7.27 (m, 6H), 7.19–7.16 (m, 1H), 5.49 (s, 2H),
4.72 (d, J = 5.6 Hz, 2H); MH+ 538.
Male C57BL/6J mice weighing over 38 g were housed one per
cage on a 12 h/12 h light/dark cycle, had free access to food (rodent
sterilizable diet) and water, and were experimentally native before
testing. Mice were allowed 7 days to habituate to the experimental
room prior to testing, and testing was conducted during the light
period. Mice were maintained and experiments were conducted
in accordance with the Institutional Animal Care. The compounds
52c and 52d were prepared daily by dissolving them in deionized
water containing 10% DMSO. By oral administration, animals re-
ceived a volume of 10 ml/kg for 7 days. All control animals received
10% DMSO dissolved in deionized water. The vehicles 10% DMSO
treated group were comprised of five mice in oral test. There were
five mice in each of the other experimental groups (n = 5 in each
group). By oral administration, the losing weight was checked
everyday for the drug treated group and the control group.
1H NMR (400 MHz, CDCl3) d 8.53 (s, 1H),
5.2.3.98. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-bromophenyl)-
1-(2-chlorophenyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-3-car-
boxamide (56b).
1H NMR (400 MHz, CDCl3) d 8.58–8.57 (m,
1H), 8.55 (s, 1H), 8.02–7.98 (m, 1H), 7.91 (s, 1H), 7.99–7.76 (m,
1H), 7.50–7.28 (m, 9H), 5.52 (s, 2H), 4.81 (s, 2H); MH+ 548.
5.2.3.99. 4-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-chlorophenyl)-
N0-(1-(4-chlorophenyl)cyclopropanecarbonyl)-1-(2,4-dichloro-
phenyl)-1H-pyrazole-3-carbohydrazide
(57).
1H
NMR
(400 MHz, CDCl3) d 9.11 (s, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.16 (s,
1H), 7.53 (d, J = 4.4 Hz, 1H), 7.48–7.29 (m, 11H), 5.46 (s, 2H),
1.74–1.68 (m, 2H), 1.19–1.13 (m, 2H); MH+ 640.
Acknowledgements
We thank Dr. Chong-Hwan Chang for his leadership in R&D at
Green Cross Corporation (GCC). Also we are grateful to Dr. Eun Chul
Huh, Mr. Jung Ho Kim, and Mr. Jung-Won Jeon at GCC Office of R&D
planning and coordination for their supports and services.
5.3. CB1 and CB2 receptor binding assay
For CB1 receptor binding studies, rat cerebellar membranes
were prepared as previously described by the methods of Kuster
et al.21 Male Sprague Dawley rats (200–300 g) were sacrificed by
decapitation and the cerebella rapidly removed. The tissue was
homogenized in 30 volumes of TME buffer (50 mM Tris–HCl,
1 mM EDTA, 3 mM MgCl2, pH = 7.4) using a Dounce homogenizer.
The crude homogenates were immediately centrifuged (48,000g)
for 30 min at 4 °C. The resultant pellets were resuspended in 30
volumes of TME buffer and protein concentration was determined
by the method of Bradford and stored at ꢃ70 °C until use.
For CB2 receptor binding studies, CHO K-1 cells were transfec-
ted with human CB2 receptor as previously described, and cell
membranes were prepared as described above.22
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.12.040.
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