Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo

Article abstract of DOI:10.1016/j.ejmech.2016.02.009

It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. In order to carry out more rational design, based on structure-based drug design, several series of N-substituted-dihydropyrazole derivatives, totally 78 compounds as potential human telomerase inhibitors were designed and synthesized. The results demonstrated that some compounds had potent anticancer activity against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells. By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity against telomerase with an IC₅₀ value of 0.98 μM. In vivo evaluation results indicated that compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further studies to assess rational design of more efficient telomerase inhibitors in the future.

Full text of DOI:10.1016/j.ejmech.2016.02.009

Accepted Manuscript
Dihydropyrazole derivatives as telomerase inhibitors: structure-based design,
synthesis, SAR and anticancer evaluation in vitro and in vivo
Yang Wang, Fei Xiong Cheng, Xiao Long Yuan, Wen Jian Tang, Jing Bo Shi, Chen
Zhong Liao, Xin Hua Liu
PII:
S0223-5234(16)30079-4
10.1016/j.ejmech.2016.02.009
EJMECH 8360
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 24 November 2015
Revised Date: 3 February 2016
Accepted Date: 4 February 2016
Please cite this article as: Y. Wang, F.X. Cheng, X.L. Yuan, W.J. Tang, J.B. Shi, C.Z. Liao, X.H. Liu,
Dihydropyrazole derivatives as telomerase inhibitors: structure-based design, synthesis, SAR and
anticancer evaluation in vitro and in vivo, European Journal of Medicinal Chemistry (2016), doi: 10.1016/
j.ejmech.2016.02.009.
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Graphical abstract
Dihydropyrazole derivatives as telomerase inhibitors: structure-based design,
synthesis, SAR and anticancer evaluation in vitro and in vivo
a
,#
b
,#
c
a
a
Yang Wang , Fei Xiong Cheng , Xiao Long Yuan , Wen Jian Tang , Jing Bo Shi ,
a
a,
Chen Zhong Liao , Xin Hua Liu *
a
b
School of Pharmacy, Anhui Medical University, Hefei, 230032, P. R. China
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
University of Technology, Shanghai 200237, P. R. China
c
The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, P. R. China
Based on structure-based drug design, 78 compounds as potential human telomerase
inhibitors were designed. In vivo studies showed that compound 13i displayed potent
anticancer activity with inhibition tumor growth of S180 and HepG2 tumor-bearing
mice. It also significantly enhanced the survival rate of EAC tumor-bearing mice.

ACCEPTED MANUSCRIPT
Dihydropyrazole derivatives as telomerase inhibitors: structure-based design,
synthesis, SAR and anticancer evaluation in vitro and in vivo
a
,#
b
,#
c
a
a
Yang Wang , Fei Xiong Cheng , Xiao Long Yuan , Wen Jian Tang , Jing Bo Shi ,
a
a,
Chen Zhong Liao , Xin Hua Liu *
a
b
School of Pharmacy, Anhui Medical University, Hefei, 230032, P. R. China
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
University of Technology, Shanghai 200237, P. R. China
c
The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, P. R. China
Abstract: It is of our interest to generate and identify novel compounds with regulation
telomerase for cancer therapy. In order to carry out more rational design, based on
structure-based drug design, several series of N-substituted-dihydropyrazole derivatives,
totally 78 compounds as potential human telomerase inhibitors were designed and
synthesized. The results demonstrated that some compounds had potent anticancer activity
against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells.
By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity
against telomerase with an IC value of 0.98 ꢀM. In vivo evaluation results indicated that
5
0
compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also
significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in
vivo confirmed that it could significantly improve pathological changes of
N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further
studies to assess rational design of more efficient telomerase inhibitors in the future.
Keywords: Dihydropyrazole; selective anticancer activity; telomerase; inhibitor
_
________________
#
These authors contributed equally to this work.
*Corresponding author.
Tel.: +86 551 65161115; fax: +86 551 65161115. E-mail: xhliuhx@163.com.

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1
. Introduction
Telomerase plays important roles in early stage of life-maintaining telomere and
chromosomal integrity of frequently dividing cells. It turns dormant in most somatic cells
during adulthood [1]. However, in cancer cells telomerase gets reactivated and works
tirelessly to maintain the short length of telomeres, resulting in immortality [2]. About
8
0-90% of various cancer cells have detectable telomerase activity, telomerase is hence
believed as a potential anticancer target [3-6]. Human telomerase consists of two parts: a
template-encoding RNA named TER (telomerase RNA), and a primary protein component
TERT (telomerase reverse transcriptase) which includes several functional domains: TEN
(
telomerase essential N-terminal domain), TRBD (telomerase RNA binding domain), RT
reverse transcriptase domain), and the C-terminal extension [7, 8]. In the past decade,
(
several types of telomerase inhibitors were reported, including 2’-O-MeRNA
oligonucleotides and peptide nucleic acids targeting the telomerase RNA template [9],
ligands targeting telomeric DNA [10], and nucleosidic reverse transcriptase inhibitors [11].
Recently, a number of G-quadruplex stabilizing compounds were also designed and
extensively studied as telomerase inhibitors [12-13].
Among the whole structure of human telomerase, the expression level of human
TERT (hTERT) is the rate-limiting factor for telomerase activity, and most human somatic
cells do not show detectable telomerase activity due to lack of hTERT, hTERT is hence
regarded as the key part of telomerase in discovery of anticancer drug [14]. Several hTERT
inhibitors with good anticancer effects, including BIBR1532 [15], symmetrical
bis-substituted derivatives of anthraquinone [16], rhodacyanine FJ5002 [17], MST-312 [18]
and isothiazolone derivative TMPI [19] were reported. Among them, BIBR1532 was
defined as a novel class of selective hTERT inhibitor with the mechanism of action similar
to non-nucleosidic inhibitors of HIV-1 reverse transcriptase. However, most of the reported
hTERT inhibitors also exhibited potential toxicities against somatic cells, and so far there
are no inhibitors targeting hTERT have been approved by FDA. Therefore, design of
potent hTERT inhibitors with high selectivity against tumor cells and low toxicity against
somatic cells is a very urgent task.
Dihydropyrazole [20-22] and coumarin [23-28] moieties are prominent structural

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motifs presented in numerous drugs. In our previous studies [29-30], several
dihydropyrazole derivatives (LXH-1~LXH-5, Figure 1) showed potent telomerase
inhibition activity, in which these compounds can be divided into two basic scaffolds
phenyl-dihydropyrazole colored by blue, and courmarin colored by red. Based on
structure-activity relationships (SAR), there are some motivations provided in the design
process. For example, in order to compare the activity of 4,5-dihydropyrazole moiety with
carbonyl or sulfone, some sulfonyl-4,5-dihydropyrazole derivatives were synthesized.
Meanwhile, because coumarin derivatives showed potent anti-HIV-1 activity, some
dihydropyrazole-coumarin derivatives were designed and synthesized, mainly due to the
mechanistic and structural similarities between hTERT and HIV-1 reverse transcriptase.
Figure 1
Structure-based drug design has played very important roles for hits identification
and optimization [31]. However, to date, for hTERT, there are no X-ray crystal structures
available. Based on our above SAR, in order to carry out more rational drug design, in this
report, we employed a three-dimension human telomerase model [7] to explore the binding
mode of BIBR1532, and then designed drug-like hTERT inhibitor scaffolds which
incorporate dihydropyrazole and courmarin, two motifs presented in many drugs to try to
discover novel potent hTERT inhibitors.
The antiproliferative activity of the title compounds against gastric cancer cell
(MGC-803), breast cancer cell (Bcap-37), prostate cancer cell (PC3) and human hepatoma
cell (HepG2) will be assayed. In order to determine the selective cancer cell toxicity of
some compounds, proliferative inhibition assay against human normal cells will be
conducted. Compounds with good antiproliferative activity will be further evaluated on
telomerase to validate the antitumor. In order to further confirm anticancer activity in vivo,
sarcoma cells S180, hepatoma cells HepG2 and ehrlich ascites cells EAC models will
select to evaluate their antitumor pharmacodynamics, the effect on DEN-induced rat
hepatic tumor will be explored to find pathological changes.

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2
. Results and discussion
2
.1 Modeling and scaffold design
To date, there are no X-ray crystal structures available for hTERT. Recently, the X-ray
structures of the full length T. castaneum telomerase alone (PDB IDs: 3DU5 and 3DU6)
and in complex with a TNA: DNA hairpin (PDB ID: 3KYL) have been published [32].
Based on this information and the crystal structures for separate TRBD and TEN domains
from T. castaneum, Steczkiewicz et al. has constructed a three-dimension human
telomerase model by employing computational methods for distant homology detection,
comparative modeling and molecular docking, guided by available experimental data [7].
In order to employ structure-based drug design methods for identifying novel hTERT
inhibitors, we decided to use this model to explore the binding mode of BIBR1532 (Figure
2
A), a promising and potent hTERT inhibitor with an IC value of 0.093 ꢀM. Considering
50
the model is an apoprotein, in silico induced fit docking (IFD) of Schrödinger was
employed to dock BIBR1532 and BIBR1591 (Figure 2B, IC = 0.47 ꢀM) into the active
5
0
site. IFD can consider the flexibility both of the receptor and the ligand so that it may give
us more reasonable docking poses. In our IFD study, a docking pose which can account for
the limited SAR of BIBR1532 and BIBR1591 were chosen and submitted to do a 10 ns
molecular dynamics (MD) simulation employing the program of Desmond, which was
developed at D. E. Shaw Research to perform high-speed molecular dynamics simulations
of biological systems on conventional commodity clusters.
The MD simulation result shows that BIBR1532 binds to hTERT mainly with a
hydrogen bond (the carboxylic acid group with Lys 710) and several hydrophobic
interactions: the naphthalene ring with Phe 568 and Tyr 949; the methyl group with Pro
2
67 and the benzene ring with Lys 902 and Val 904 (Figure 2B). This model can explain
why BIBR1591 has less potent inhibition against hTERT than BIBR1532 since the
introduction of the morpholine in the meta-position of the benzoic acid may have
confliction with the backbone of the protein.
Figure 2

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Based on the structure of BIBR1532, preliminary analysis of SAR about our earlier
reported hTERT inhibitors [33-34] and the volume of the active site of hTERT, we
designed dozens of synthesizable drug-like scaffolds which incorporate the moieties of
dihydropyrazole and courmarin. The prinicipal is that the designed scaffolds should have
an aromatic ring on which a hydrogen bond receptor is to mimic the benzoic acid of
BIBR1532; additionaly, the other end of the designed scaffolds should be a hydrophobic
moiety to mimic the naphthalene ring of BIBT1532. All these designed scaffolds were then
docked into the active site of the hTERT-BIBR1532 complex. Only the scaffolds whose
docking poses have similar interactions with hTERT as BIBR1532 were considered for
further synthesis. At last, a small library of 78 novel dihydropyrazole derivatives were
designed and synthesized as potential telomerase inhibitors in this study (Figure 3).
Figure 3
2
.2 Chemistry
7 N-substituted-dihydropyrazoles and 31 dihydropyrazole-coumarin derivatives were
4
designed and synthesized. The synthesis of compound 1 (Scheme 1) started from
o
salicylaldehyde and acetone catalyzed by NaOH at 20 C. The synthesis of α, β-unsaturated
ketone 5 (Scheme 2) started from salicylaldehyde and acetoacetate catalyzed by piperidine
o
at 50~60 C. Claisen-Schmidt condensation of 3-acetyl-2H-chromen-2-one with
substituted-benzaldehyde was catalyzed by piperidine. Catalysts tosyl chloride and DMAP
were proved to be efficient alternatives for the synthesis of compounds 7, 9 and 11.
However, piperazine was a better catalyst for the synthesis of compound 13. In the process
of synthesis of compounds 5, 6, 11, 12, 13 the pH value should be less than 8.2. Otherwise,
the coumarin ring will open.
Schemes 1-2

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2
.3 Structural Determination of Compounds
2
0 compounds (7d, 7f, 7j, 7l, 7m, 7n, 7o, 7t, 7u, 8d, 9d, 9g, 9l, 9n, 9r, 9s, 13f, 13x,
1
3y and 13z) were determined by X-ray diffraction analysis. Representative compounds
(7j, 8d, 9d, 9n, 13x, 13y) crystallographic and experimental data were presented in Tables
1
~3. Another data were presented in Supporting Information (Tables S1~S8). Structures of
the compounds 7j, 8d, 9d, 9n, 13x, 13y were shown in Figure 4, another structures of the
compounds were shown in Supporting Information (Figures S1~S15). Crystallographic
data (excluding structure factors) for the structures were deposited into the Cambridge
Crystallographic Data Center (Registered No. CCDC-814973, CCDC-813726,
CCDC-813727, CCDC-819490, CCDC-819491, CCDC-824623, CCDC-824625,
CCDC-837389, CCDC-836556, CCDC-836555, CCDC-834936, CCDC-826456,
CCDC-837388, CCDC-837390, CCDC-861071, CCDC-861072, CCDC-834938,
CCDC-861070, CCDC-861075, CCDC-883316, respectively).
Tables 1~3
Figure 4
2
.4 Anticancer Activity
At first, compounds 7~13 were evaluated for their antiproliferative activity against
PC3, Bcap-37, MGC-803 and HepG2 cell lines. The cells were allowed to proliferate in
presence of tested material for 48 h, and the results were reported in terms of IC values
5
0
(Table 4). From Table 4 it is obvious to see that compounds 10i, 10n, 11i and 13i exhibited
high activity against MGC-803 with IC values at 3.51±0.21, 3.01±0.13, 2.02±0.23 and
5
0
2
.96±0.15 µM, respectively. Compounds 9c, 10n, 11i and 13i possesseded potent activity
against HepG2 with IC50 = 3.02±0.33, 2.52±0.09, 2.98±0.19 and 2.45±0.11 µM,
respectively. Compounds 11i, 13c and 13f occupied high activity against PC3 with IC =
5
0
2
.98±0.15, 1.87±0.11 and 1.92±0.13 µM, respectively. Compounds 13c, 13i and 13w
showed high activity against Bcap-37 with IC50 values at 2.21±0.10, 3.37±0.30 and

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3
.50±0.99 µM respectively, which is comparable with the positive control AMD.
As given in Table 4, compounds 7~10 (phenyl-4,5-dihydropyrazole moiety) and
11~13 (phenyl-coumarin-4,5-dihydropyrazole moiety) exhibited similar antiproliferative
activity against the above cancer cells. The introduction of N-sulfonyl group did not
improve the activity (8d, 8e, 8f, 12k and 12l) obviously, neither did the coumarin unit. We
then investigated the SAR profiles of the N-acetyl substituted group of dihydropyrazole (9,
1
0 and 13) to find a permissive region. Transformation of acetyl group could significantly
improve the anticancer activity (10o, 11h, 11i, 13f, 13d, 13w and 13z). Further, the
introduction of short-chain aliphatic amine group in the N-acetyl part played an important
role (such as 13f, 13d, 13w and 13y).
Table 4
2
.5 Inhibition assay of human normal cell
In order to determine wether the title compounds have selective activity on cancer
cells. We subsequently conducted a proliferative inhibition assay against human normal
gastric mucosa cell (GES-1) and liver cell (L-02). As shown in Table 5, all compounds
manifested obvious un-toxic effect on GES-1 and L-02 with IC from 1.2 to 2.5 mM. The
5
0
data indicated that the compounds have good selectivity against tumor cells over somatic
cells (Tables 4 and 5).
Table 5
2
.6 Anticancer activity evaluation in vivo
Mice sarcoma cells S180 model, hepatoma cells HepG2 model and ehrlich ascites
cells EAC model are recognized as the reliable research models for study of antitumor
pharmacodynamics. Pathological changes of N,N-diethylnitrosamine (DEN)-induced rat
hepatic tumor is also a classic induced tumor model as for antitumor pharmacodynamics
study. Based on the results of tables 4 and 5, the compounds 9c and 13i showed good

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selectivity on HepG2 cells over GES-1 cells in vitro. To further verify the inhibitory effect
on the growth of tumor cells in vivo, sarcoma cells S180, hepatoma cells HepG2 and
ehrlich ascites cells EAC were selected to evaluate effects of compounds 9c and 13i.
2
.6.1 Antitumor effects of title compounds against tumor growth
The inhibitory effects of title compounds against growth of transplanted S180 or
HepG2 carcinoma were presented in Table 6 and Figure 5. The results revealed that title
compounds significantly decreased the tumor weights of S180 and HepG2 tumor-bearing
mice. The potent activity was showed by compound 13i with inhibitory rates 48.9% and
4
6.1% for S180 and HepG2 tumor-bearing mice, respectively.
Table 6
Figure 5
2
.6.2 Effects of title compounds against the survival of EAC-bearing mice
EAC tumor-bearing mice were observed for mean survival time. Based on the
mortality, the effect of percentage increases in life span was calculated. Survival response
of untreated EAC-bearing mice died within 16.6 days (Table 7). A similar phenomenon
with above was observed that mice displayed longer survival times treated with
compounds 9c and 13i. Among them, the compound 13i was observed to enhance the
survival rate to about 44%.
Table 7
2
.6.3 Histopathology effect of title compound
In order to further reveal the pathological effects of the title compounds in vivo, the
histopathology effect on DEN-induced rat hepatic tumor was explored. Microscopic
features of the liver were examined. In the control group, as expected, integral liver cell
structure, hepatic lobular architecture and hepatic nuclei were clearly observed (Figure 6A).
In the DEN model group, normal liver lobular structure was completely destroyed. The
tumor cells showed low differentiation and evident atypia (including multinuclear,
karyopyknosis, nuclear vacuoles, etc.), with larger nuclei and nucleoli, chromatin rough. In

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addition, tumor giant cells and cancer nests infiltrating surrounding tissues were also
observed (Figure 6B). The experimental group markedly abated pathological changes of
hepatic lobules. The hepatic cells exhibited evidently reduced atypia, high differentiation
and full cytoplasm. The cells were also observed similar multinuclear, karyopyknosis and
nuclear vacuoles to those of normal cells. These results showed that title compound 13i
could significantly improve pathological changes of DEN-induced rat hepatic tumor
(Figure 6C).
Figure 6
2
.7 Telomerase Activity
To confirm if the synthesized compounds performed anticancer activities via
telomerase inhibition as designed, some title compounds were evaluated by a modified
TRAP assay using an extraction from MGC-803 cells. Modified TRAP is a powerful
technique to determine small molecules inhibiting telomere elongation qualitatively and
quantitatively [35]. The results were summarized in Table 8. Among them, compounds 7l,
9
c, 9o, 10e, 10n, 11i, 13a and 13f showed potent inhibitory activity against telomerase
with IC values less than 5 µM, better than positive control staurosporine. In particular,
5
0
compound 13i showed the most potent activity against telomerase with IC = 0.98 µM.
5
0
In primary SAR analysis, the nine series compounds are divided into two types, one is
-aryl-dihydropyrazole skeleton (compounds 7~10), the other is
-coumarin-5-aryl-dihydropyrazole skeleton (compounds 11~13). In general, the
5
3
introduction of the coumarin moiety in the dihydropyrazole ring (compounds 11~13)
significantly increased the inhibitory activity (compounds 11h, 11i, 13a, 13b, 13c, 13f, 13j,
1
3x, 13z). When piperidine ring was replaced by substituted-piperidine (compounds 13u,
3v, 13p, 13r), compound 13p lost activity against telomerase and the inhibitory activity
1
of compound 13u decreased 41 times. Furthermore, compounds 13p and 13u did not show
any antiproliferative activity against PC3, Bcap-37 and MGC-803 cells (Table 8).
Further SAR analysis was focused on different substitutes of 5-aryl. For the
5
-aryl-dihydropyrazole skeleton (compounds 7~10), the phenyl bromine substitution

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(
compounds 7 and 9) showed a little increasing effect on the activity against telomerase
compounds 7l, 9c, 9d, 9o and 7q). The un-substitution at the 5-aryl resulted in
(
considerable loss of potency (compound 7j). For 3-coumarin-5-aryl-dihydropyrazole
skeleton (compounds 11~13), the introduction of an electron-withdrawing (trifluoromethyl)
group in the phenyl ring increased the activity (compounds 13x and 13y) comparing to
those with un-substituted phenyl ring. Therefore the presence of trifluoromethyl group in
the phenyl ring played an important role for the telomerase activity. These SAR
observations could offer the useful information for further structural optimiztion.
Table 8
2
.8 Proposed Binding Model
In this study, a three-dimension human telomerase model [7] and an advanced
docking method–IFD were employed to explore the binding mode of BIBR1532, a potent
hTERT inhibitor. The docked complex was then done a 10 ns MD simulation. Our
designed scaffolds were docked into the active site of the modelled hTERT– BIBR1532
complex to see if these designed scaffolds have common interactions with the hTERT as
BIBR1532. Based on these criteria, a library compounds were synthesized, and some of
them showed good inhibition against hTERT. Among them, compound 13i has an IC50
value of 0.98±0.07 ꢀM against human telomerase.
Compound 13i was docked into the complex of hTERT-BIBR1532, which was
gotten by the induced fit docking method as discussed. Modeling showed that compound
1
3i has similar active site as BIBR1532 shown in Figure 7: the moiety of courmarin of 13i
can mimic benzoic acid of BIBR1532 and form a hydrogen bond with Lys 710 and have
hydrophobic interactions with Lys 902, Val 904 and Pro 929; one fatty chain has
hydrophobic interactions mainly with Phe 568; the dihydropyrazole ring and the benzene
ring have hydrophobic interactions mainly with Pro 627.
Figure 7

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3
. Conclusions
In this study, nine series of N-substituted-dihydropyrazoles and
dihydropyrazole-coumarin derivatives were designed, synthesized and evaluated as
potential telomerase inhibitors. Among the 78 compounds, compounds 10i, 10n, 11i and
1
3i exhibited potent activity against MGC-803 cell with lower toxicity on normal cells in
vitro. In vivo studies showed that compound 13i displayed potent anticancer activity with
inhibition tumor growth of S180 and HepG2 tumor-bearing mice. It also significantly
enhanced the survival rate of EAC tumor-bearing mice. Furthermore, compound 13i could
significantly improve pathological changes of DEN-induced rat hepatic tumor. Moreover,
compound 13i showed high inhibitory activity against telomerase with IC = 0.98±0.07
50
µM. The binding modes of several inhibitors on hTERT indicated that the conserved
residue Lys710 is important for ligand binding via hydrogen bond interaction, which could
explain the SAR of these compounds and match reported mutation data. These results are
of help in rational design of more efficient telomerase TERT inhibitors for cancer therapy.
4
. Experimental section
4
.1 Chemistry
All reagents were purchased from Aldrich (U.S.A) and Sinopharm Chemical Reagent
Co., Ltd (China). Separation of the compounds by column chromatography was carried out
with silica gel 60 (200~300 mesh ASTM, E. Merck). The quantity of silica gel used was
3
0~70 times the weight charged on the column. Then, the reactions were monitored using
TLC. Melting points (uncorrected) were determined on a XT4 MP apparatus (Taike Corp.,
1
Beijing, China). H NMR spectra were recorded on a Bruker DPX400 or DPX300
spectrometer at 25 °C with TMS and solvent signals allotted as internal standards.
Chemical shifts were reported in ppm (δ). Elemental analyses were performed on a
CHN-O-Rapid instrument and were within ± 0.4 % of the theoretical values.
4
.1.1 General procedure for preparation of compounds 7c~7u
Carboxylic acid (12 mmol) was dissolved in 20 mL of chloroform, at room

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temperature was added tosyl chloride (12 mmol) and DMAP (12 mmol), then the
substituted-2-(3-methyl-4,5-dihydro-1H-pyrazol-5-yl) phenol 2 (10 mmol) was added, the
reaction mixture was refluxed for 3 h. The mixture was cooled, washed with water, and
allowed to stand at 0~5 ˚C over night. The product was collected by filtration and the crude
residue was purified by chromatography on SiO (acetone/petroleum, v:v=2:1) to give title
2
compounds 7c~7u (Scheme 1) as colorless solids.
7
c: 1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-3-phenylprop-2-en-1
o
1
-
one, colorless crystals, yield, 66%; mp 265~267 C; H NMR (CDCl , 300 MHz): δ 2.25
3
(
3H, s, -Me), 3.13 (1H, dd, J= 18.0 and 3.0 Hz, pyrazole, 4-H ), 3.40 (1H, dd, J= 12.0 and
a
1
8.0 Hz, pyrazole, 4-H ), 5.80 (1H, dd, J= 12.0 and 3.0 Hz, pyrazole, 5-H), 6.88-7.75 (11H,
b
1
3
m, -CH=CH- and ArH) , 9.69 (1H, brs, -OH); C NMR (CDCl , 125 MHz): δ 16.3, 31.0,
3
4
3.5, 53.3, 117.3, 119.7, 121.3, 126.2, 128.3, 128.9, 130.0, 133.5, 134.4, 135.0, 143.2,
55.6; Anal. calcd for C H N O : C, 74.49; H, 5.92; N, 9.14%. Found: C, 74.78; H, 6.13;
1
19
18
2
2
N, 9.00%.
7
d: 1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)(4-nitrophenyl)]methan-one,
o
1
colorless crystals, yield, 80%; mp 224~225 C; H NMR (CDCl , 300 MHz): δ 2.21 (3H, s,
3
-
Me), 3.12 (1H, dd, J= 18.9 and 3.6 Hz, pyrazole, 4-H ), 3.46 (1H, dd, J= 11.3 and 18.8
a
Hz, pyrazole, 4-H ), 5.94 (1H, dd, J= 11.4 and 3.9 Hz, pyrazole, 5-H), 6.93-8.29 (8H, m,
b
1
3
ArH), 8.76 (1H, brs, -OH); C NMR (CDCl , 125 MHz): δ 16.3, 43.8, 54.7, 119.1, 121.4,
3
1
22.9, 126.0, 126.7, 130.1, 131.1, 139.4, 149.1, 155.0, 160.8, 164.8; Anal. calcd for
C H N O : C, 62.76; H, 4.65; N, 12.92%. Found: C, 63.02; H, 4.80; N, 12.61%.
17
15
3
4
7
f:1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-3-phenylpropan-1-one,
o
1
colorless crystals, yield, 81%; mp 202~203 C; H NMR (CDCl , 300 MHz): δ 2.08 (3H, s,
3
-
Me), 2.88 (4H, m, -2CH -), 2.96 (1H, dd, J= 18.5 and 3.3 Hz, pyrazole, 4-H ), 3.22 (1H,
2
a
dd, J= 11.2 and 18.5 Hz, pyrazole, 4-H ), 5.57 (1H, dd, J= 11.2 and 3.5 Hz, pyrazole, 5-H),
b
1
3
6
.81-7.18 (9H, m, ArH), 9.00 (1H, brs, -OH); C NMR (CDCl , 125 MHz): δ 16.2, 30.8,
3
3
5.6, 39.9, 43.5, 55.1, 115.7, 119.3, 125.7, 126.4, 128.3, 128.8, 128.9, 141.8, 154.3, 157.8,
68.9; Anal. calcd for C H N O : C, 74.00; H, 6.54; N, 9.08%. Found: C, 74.32; H, 6.80;
1
19
20
2
2
N, 9.35%.
7
g: 5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)(p-tolyl)methanone, colorless

ACCEPTED MANUSCRIPT
o
1
crystals, yield, 54%; mp 232~233 C; H NMR (CDCl , 300 MHz): δ 2.23 (3H, s, -Me),
3
2
.46 (3H, s, -Me), 3.15 (1H, dd, J= 18.0 and 3.5 Hz, pyrazole, 4-H ), 3.49 (1H, dd, J= 11.2
a
and 18.0 Hz, pyrazole, 4-H ), 5.77 (1H, dd, J= 11.2 and 3.6 Hz, pyrazole, 5-H), 6.80-7.86
b
(
8H, m, ArH), 9.20 (1H, brs, -OH); Anal. calcd for C H N O : C, 73.45; H, 6.16; N,
18 18 2 2
9
7
.52%. Found: C, 73.17; H, 6.32; N, 9.88%.
i: 2-chlorophenyl)(5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)methan- one,
o
1
colorless crystals, yield, 62%; mp 207~209 C; H NMR (CDCl , 300 MHz): δ 2.10 (3H, s,
3
-
Me), 3.08 (1H, dd, J= 18.6 and 3.3 Hz, pyrazole, 4-H ), 3.45 (1H, dd, J= 11.1 and 18.6
a
Hz, pyrazole, 4-H ), 5.90 (1H, dd, J= 11.1 and 3.3 Hz, pyrazole, 5-H), 6.74-7.40 (8H, m,
b
1
3
ArH), 8.97 (1H, brs, -OH); C NMR (CDCl , 125 MHz): δ 16.2, 44.2, 55.9, 121.1, 125.9,
3
1
4
7
26.6, 128.7, 129.6, 130.7, 155.0, 160.2, 165.9; Anal. calcd for C H ClN O : C, 64.87; H,
17 15 2 2
.80; N, 8.90%. Found: C, 65.06; H, 4.92; N, 9.11%.
j: 2-[(4-chlorophenoxy)-1-(5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)]
o
1
ethanone, colorless crystals, yield, 80%; mp 198~199 C; H NMR (CDCl , 300 MHz): δ
3
2
.11 (3H, s, -Me), 2.82 (1H, dd, J= 18.5 and 4.5 Hz, pyrazole, 4-H ), 3.39 (1H, dd, J= 11.0
a
and 18.0 Hz, pyrazole, 4-H ), 4.12 (2H, s, -CH -), 5.68 (1H, dd, J= 11.5 and 4.5 Hz,
b
2
1
3
pyrazole, 5-H), 6.79-7.22 (8H, m, ArH); C NMR (CDCl , 125 MHz): δ 16.2, 39.9, 45.1,
3
5
1
5
7
5.7, 66.0, 115.8, 116.8, 119.4, 124.9, 126.2, 127.9, 128.6, 129.6, 154.3, 157.5, 159.1,
64.3; Anal. calcd for C H ClN O : C, 62.70; H, 4.97; N, 8.12%. Found: C, 63.06; H,
1
8
17
2
3
.13; N, 8.44%.
l: 1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-chloroethan-one,
o
1
colorless crystals, yield, 88%; mp 160~161 C; H NMR (CDCl , 300 MHz): δ 2.21 (3H, s,
3
-
Me), 3.00 (1H, dd, J= 18.9 and 3.6 Hz, pyrazole, 4-H ), 3.42 (1H, dd, J= 11.7 and 19.2
a
Hz, pyrazole, 4-H ), 4.49 (2H, m, -CH -), 5.67 (1H, dd, J= 11.4 and 3.9 Hz, pyrazole, 5-H),
b
2
6
.76-7.28 (3H, m, ArH), 8.65 (1H, brs, -OH); Anal. calcd for C H BrClN O : C, 43.47;
12 12 2 2
H, 3.65; N, 8.45%. Found: C, 43.68; H, 4.02; N, 8.17%.
7
m:
1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)]propan-1-one,
o
1
colorless crystals, yield, 75%; mp 180~181 C; H NMR (CDCl , 300 MHz): δ 1.14 (3H, t,
3
J= 7.5 Hz, -CH ), 2.18 (3H, s, -Me), 2.67 (2H, m, -CH -), 2.96 (1H, dd, J= 18.6 and 3.3
3
2
Hz, pyrazole, 4-H ), 3.35 (1H, dd, J= 11.4 and 18.9 Hz, pyrazole, 4-H ), 5.60 (1H, dd, J=
a
b

ACCEPTED MANUSCRIPT
1
1.1 and 3.6 Hz, pyrazole, 5-H), 6.74-7.26 (3H, m, ArH), 9.53 (1H, brs, -OH); Anal. calcd
for C H BrN O : C, 50.18; H, 4.86; N, 9.00%. Found: C, 50.00; H, 5.07; N, 8.81%.
1
3
15
2
2
7
n: 5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl(p-tolyl)methan- one,
o
1
colorless crystals, yield, 68%; mp 208~210 C; H NMR (CDCl , 300 MHz): δ 2.20 (3H,
3
m, -CH ), 2.38 (3H, s, -Me), 3.04 (1H, dd, J= 18.9 and 3.6 Hz, pyrazole, 4-H ), 3.40 (1H,
3
a
dd, J= 11.1 and 18.9 Hz, pyrazole, 4-H ), 5.83 (1H, dd, J= 11.1 and 3.9 Hz, pyrazole, 5-H),
b
6
.83-7.82 (7H, m, ArH); Anal. calcd for C H BrN O : C, 57.92; H, 4.59; N, 7.51%.
18 17 2 2
Found: C, 58.21; H, 4.52; N, 7.89%.
7
o: 1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-3-phenylpro- pan-
o
1
1
-one, colorless crystals, yield, 82%; mp 179~180 C; H NMR (CDCl , 300 MHz): δ 2.06
3
(
3H, s, -Me), 2.86 (1H, dd, J= 16.8 and 3.6 Hz, pyrazole, 4-H ), 2.88 (4H, m, -2CH -),
a 2
3
.22 (1H, dd, J= 10.8 and 18.6 Hz, pyrazole, 4-H ), 5.51 (1H, dd, J= 11.4 and 3.3 Hz,
b
pyrazole, 5-H), 6.67-7.19 (8H, m, ArH); Anal. calcd for C H BrN O : C, 58.93; H, 4.95;
1
9
19
2
2
N, 7.23%. Found: C, 59.07; H, 4.60; N, 7.45%.
p:1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(4-
7
o
1
chlorophenoxy)ethanone, colorless crystals, yield, 77%; mp 211~212 C; H NMR (CDCl ,
3
3
00 MHz): δ 2.14 (3H, s, -Me), 2.93 (1H, dd, J= 18.6 and 3.3 Hz, pyrazole, 4-H ), 3.32
a
(
1H, dd, J= 11.1 and 18.9 Hz, pyrazole, 4-H ), 4.88 (2H, s, -CH -), 5.59 (1H, dd, J= 11.4
b 2
and 3.9 Hz, pyrazole, 5-H), 6.64-7.34 (7H, m, ArH); Anal. calcd for C H BrClN O : C,
1
8
16
2
3
5
1.03; H, 3.81; N, 6.61%. Found: C, 51.00; H, 4.17; N, 6.21%.
q: 2-chloro-1-[5-(3,5-dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-
7
o
1
ethanone, colorless crystals, yield, 89%; mp 136~137 C; H NMR (CDCl , 300 MHz): δ
3
2
.07 (3H, s, -Me), 2.79 (1H, dd, J= 18.6 and 4.2 Hz, pyrazole, 4-H ), 3.32 (1H, dd, J= 11.7
a
and 18.3 Hz, pyrazole, 4-H ), 4.37 (2H, s, -CH -), 5.54 (1H, dd, J= 11.4 and 4.2 Hz,
b
2
pyrazole, 5-H), 6.96-7.50 (3H, m, ArH); Anal. calcd for C H Br ClN O : C, 35.11; H,
1
2
11
2
2
2
2
.70; N, 6.82%. Found: C, 35.44; H, 3.03; N, 7.10%.
r: 1-[5-(3,5-dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]propan-1-one,
7
o
1
colorless crystals, yield, 68%; mp 124~125 C; H NMR (CDCl , 300 MHz): δ 1.07 (3H, t,
3
J= 7.5 Hz -Me), 2.10 (3H, s, -Me), 2.59 (2H, m, -CH -), 2.85 (1H, dd, J= 18.6 and 3.9 Hz,
2
pyrazole, 4-H ), 3.28 (1H, dd, J= 11.4 and 18.6 Hz, pyrazole, 4-H ), 5.51 (1H, dd, J= 11.4
a
b

ACCEPTED MANUSCRIPT
and 3.9 Hz, pyrazole, 5-H), 6.91-7.52 (2H, m, ArH), 9.12 (1H, brs, -OH); Anal. calcd for
C H Br N O : C, 40.03; H, 3.62; N, 7.18%. Found: C, 39.91; H, 3.99; N, 6.87%.
13
14
2
2
2
7
s: 1-[5-(3,5-dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-3-
o
1
phenylpropan-1-one, colorless crystals, yield, 70%; mp 143~144 C; H NMR (CDCl , 300
3
MHz): δ 2.12 (3H, s, -Me), 2.88 (1H, dd, J= 18.6 and 3.9 Hz, pyrazole, 4-H ), 2.96 (4H, m,
a
-
2CH -), 3.31 (1H, dd, J= 11.1 and 18.6 Hz, pyrazole, 4-H ), 5.56 (1H, dd, J= 11.4 and 3.9
2
b
Hz, pyrazole, 5-H), 6.74-7.60 (7H, m, ArH), 9.05 (1H, brs, -OH); Anal. calcd for
C H Br N O : C, 48.95; H, 3.89; N, 6.01%. Found: C, 49.21; H, 4.04; N, 5.76%.
19
18
2
2
2
7
t: 2-(4-chlorophenoxy)-1-[5-(3,5-dibromo-2-hydroxyphenyl)-3-methyl-4,5
o
1
-
dihydropyrazol-1-yl]ethanone, colorless crystals, yield, 93%; mp 208~210 C; H NMR
(
CDCl , 300 MHz): δ 2.16 (3H, s, -Me), 2.87 (1H, dd, J= 18.6 and 4.5 Hz, pyrazole, 4-H ),
3
a
3
.38 (1H, dd, J= 10.8 and 17.7 Hz, pyrazole, 4-H ), 4.99 (2H, m, -CH -), 5.63 (1H, dd, J=
b 2
1
1.7 and 4.5 Hz, pyrazole, 5-H), 6.85-7.57 (6H, m, ArH); Anal. calcd for C H Br ClN O :
18 15 2 2 3
C, 43.02; H, 3.01; N, 5.57%. Found: C, 43.00; H, 3.32; N, 6.00%.
7
u:
5-(3,5-dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl](p-tolyl)-
o
1
methanone, colorless crystals, yield, 81%; mp 164~165 C; H NMR (CDCl , 300 MHz): δ
3
2
3
.17 (3H, s, -Me), 2.38 (3H, s, -Me), 2.94 (1H, dd, J= 18.6 and 4.2 Hz, pyrazole, 4-Ha),
.40 (1H, dd, J= 11.1 and 18.3 Hz, pyrazole, 4-H ), 5.82 (1H, dd, J= 11.4 and 4.2 Hz,
b
pyrazole, 5-H), 7.09-7.84 (6H, m, ArH) , 8.92 (1H, brs, -OH); Anal. calcd for
C H Br N O : C, 47.82; H, 3.57; N, 6.20%. Found: C, 48.11; H, 3.85; N, 5.92%.
18
16
2
2
2
4
.1.2 General procedure for preparation of compounds 8d~8g
Substituted-2-(3-methyl-4,5-dihydro- 1H-pyrazol-5-yl) phenol 2 (10 mmol) was
dissolved in 20 mL of chloroform, at room temperature was added tosyl chloride (10 mmol)
or nitrophenyl chloride (10 mmol), the reaction mixture was refluxed for 1 h. The mixture
was cooled, washed with water, and allowed to stand at 0~5 ˚C over night. The product
was collected by filtration and the crude residue was purified by chromatography on SiO2
(
ethyl acetate/petroleum, v:v=3:1) to give title compounds 8d~8g (Scheme 1) as colorless
solids.
d: 4-bromo-2-(3-methyl-1-tosyl-4,5-dihydro-1H-pyrazol-5-yl)phenol, colorless crystals,
8
o
1
yield, 89%; mp 184~186 C; H NMR (CDCl , 300 MHz): δ 1.93 (3H, s, -Me), 2.38 (3H, s,
3

ACCEPTED MANUSCRIPT
-
Me), 2.70 (1H, dd, J= 9.6 and 17.7 Hz, pyrazole, 4-H ), 2.99 (1H, dd, J= 11.1 and 17.7
a
Hz, pyrazole, 4-H ), 4.78 (1H, dd, J= 9.6 and 10.8 Hz, pyrazole, 5-H), 6.66-7.71 (7H, m,
b
ArH); Anal. calcd for C H BrN O S: C, 49.89; H, 4.19; N, 6.84%. Found: C, 50.12; H,
1
7
17
2
3
4
8
5
.31; N, 7.15%.
e: 2,4-dibromo-6-[3-methyl-1-(4-nitrophenylsulfonyl)-4,5-dihydro-1H-pyrazol-
o
1
-yl]phenol, colorless crystals, yield, 85%; mp 230~231 C; H NMR (CDCl , 300 MHz):
3
δ 1.93 (3H, s, -Me), 2.60 (1H, dd, J= 8.6 and 18.0 Hz, pyrazole, 4-H ), 3.12 (1H, dd, J=
a
1
1.7 and 18.3 Hz, pyrazole, 4-H ), 5.09 (1H, dd, J=8.7 and 11.4 Hz, pyrazole, 5-H),
b
7
.18-8.29 (6H, m, ArH); Anal. calcd for C H Br N O S: C, 37.02; H, 2.52; N, 8.09%.
1
6
13
2
3
5
Found: C, 36.89; H, 2.80; N, 8.17%.
8
f: 2,4-dibromo-6-(3-methyl-1-tosyl-4,5-dihydro-1H-pyrazol-5-yl)phenol, colorless crystals,
o
1
yield, 82%; mp 217~219 C; H NMR (CDCl , 300 MHz): δ 1.94 (3H, s, -Me), 2.17 (3H, s,
3
-
Me), 2.75 (1H, dd, J= 8.6 and 18.0 Hz, pyrazole, 4-H ), 3.17 (1H, dd, J= 11.4 and 18.3
a
Hz, pyrazole, 4-H ), 4.89 (1H, dd, J=8.6 and 11.4 Hz, pyrazole, 5-H), 7.05-7.60 (6H, m,
b
ArH); Anal. calcd for C H Br N O S: C, 41.82; H, 3.30; N, 5.74%. Found: C, 42.03; H,
1
7
16
2
2
3
3
.51; N, 5.52%.
g: 4-chloro-2-[3-methyl-1-(4-nitrophenylsulfonyl)-4,5-dihydro-1H-pyrazol-5-yl] phenol,
8
o
1
colorless crystals, yield, 80%; mp 223~224 C; H NMR (CDCl , 300 MHz): δ 2.02 (3H, s,
3
-
Me), 2.78 (1H, dd, J= 9.0 and 18.3 Hz, pyrazole, 4-H ), 3.17 (1H, dd, J= 11.1 and 18.3
a
Hz, pyrazole, 4-H ), 5.08 (1H, dd, J=9.0 and 11.1 Hz, pyrazole, 5-H), 6.74-8.36 (7H, m,
b
ArH); Anal. calcd for C H ClN O S: C, 48.55; H, 3.57; N, 10.62%. Found: C, 48.70; H,
16
14
3
5
3
.21; N, 10.99%.
.1.3 General procedure for preparation of compounds 9a~9u
-chloro-1-(5-(2-substituted-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)
4
2
ethanone 3 (10 mmol) was dissolved in 20 mL of acetone, at room temperature was added
amine (12 mmol), DMAP (12 mmol) and catalytic KI, the reaction mixture was allowed to
stand at 40 ˚C for 2 h. The mixture was cooled, washed with water. The product was
collected by filtration and the crude residue was purified by chromatography on SiO2
(dichloromethane/methanol, v:v= 68:1) to give compounds 9a~9u (Scheme 1) as colorless
solids. Acetylation of the hydroxyl of compound 3, then according to the general procedure

ACCEPTED MANUSCRIPT
for preparation of compounds 9a~9u, compounds 10b~10p were synthesized.
9
a: 2-(diethylamino)-1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]- ethanone,
o
1
colorless crystals, yield, 60%; mp 203~204 C; H NMR (400 MHz, CDCl ) δ (ppm): 1.02
3
(
t, 6H, J = 7.2 Hz), 2.18 (s, 3H), 2.65 (q, 4H, J = 7.2 Hz), 3.02 (dd, 1H, J = 18.4 Hz, J =
1 2
2
.8 Hz, pyrazole, 4-H ), 3.32 (dd, 1H, J = 18.4 Hz, J = 11.6 Hz, pyrazole, 4-H ), 3.61 (m,
a 1 2 b
2
H), 5.62 (dd, 1H, J = 11.6 Hz, J = 2.8 Hz, pyrazole, 5-H), 6.85-6.93 (m, 3H), 7.14-7.18
1
2
1
3
(
m, 1H), 9.29 (brs, 1H). C NMR (CDCl , 125 MHz): δ 12.0, 16.2, 44.0, 47.9, 53.8, 53.9,
3
1
6
9
18.4, 120.3, 125.3, 127.1, 129.3, 154.9, 158.7, 169.4; Anal. calcd for C H N O : C,
16 23 3 2
6.41; H, 8.01; N, 14.52%. Found: C, 66.06; H, 7.89; N, 14.70%.
b: 2-(diisopropylamino)-1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-
o
1
yl]- ethanone, colorless crystals, yield, 75%; mp 211~212 C; H NMR (400 MHz, CDCl )
3
δ (ppm): 0.97-1.00 (m, 12H), 2.20 (s, 3H), 3.01-3.10 (m, 3H, containing pyrazole 4-Ha),
3
.32 (dd, 1H, J = 18.4 Hz, J = 11.2 Hz, pyrazole, 4-H ), 3.58 (s, 2H), 5.65 (dd, 1H,
1 2 b
pyrazole, 4-H ), 6.85-6.97 (m, 3H), 7.15-7.19 (m, 1H), 9.34 (brs, 1H, -OH). Anal. calcd for
b
C H N O : C, 68.11; H, 8.57; N, 13.24%. Found: C, 67.85; H, 8.80; N, 13.02%.
18
27
3
2
9
c: l-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(piperidin-1-yl)
o
1
ethan one, colorless crystals, yield, 80%; mp 225~227 C; H NMR (400 MHz, CDCl ) δ
3
(ppm): 1.41-1.42 (m, 2H), 1.57-1.63 (m, 4H), 2.17 (s, 3H), 2.50-2.51 (m, 4H), 3.01 (dd, 1H,
J = 18.4 Hz, J = 2.8 Hz, pyrazole, 4-H ), 3.31 (dd, 1H, J = 18.4 Hz, J = 11.2 Hz,
1
2
a
1
2
pyrazole, 4-H ), 3.49 (m, 2H), 5.66 (dd, 1H, J = 11.6 Hz, J = 2.8 Hz, pyrazole, 5-H),
b
1
2
1
3
6
.84-6.93 (m, 3H), 7.14-7.18 (m, 1H), 9.25 (brs, 1H). C NMR (CDCl , 125 MHz): δ 16.2,
3
2
4.1, 25.8, 43.8, 53.7, 55.0, 59.8, 118.9, 120.7, 125.7, 127.2, 129.6, 155.1, 158.7, 168.4;
Anal. calcd for C H N O : C, 67.75; H, 7.69; N, 13.94%. Found: C, 68.06; H, 7.44; N,
1
7
23
3
2
1
4.22%.
d:1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(pyrrolidin-1-yl) ethanone,
9
o
1
colorless crystals, yield, 65%; mp 200~201 C; H NMR (400 MHz, CDCl ) δ (ppm):
3
1
.73-1.78 (m, 4H), 2.17 (s, 3H), 2.61-2.65 (m, 4H), 3.02 (dd, 1H, J = 18.4 Hz, J = 2.8 Hz,
1 2
pyrazole, 4-H ), 3.29 (dd, 1H, J = 18.4 Hz, J = 11.2 Hz, pyrazole, 4-H ), 3.65 (m, 2H),
a
1
2
b
5
1
.67 (dd, 1H, J = 11.2 Hz, J = 2.8 Hz, pyrazole, 5-H), 6.84-6.92 (m, 3H), 7.14-7.18 (m,
1 2
1
3
H). C NMR (CDCl , 125 MHz): δ 16.2, 23.7, 43.6, 53.5, 54.6, 56.9, 119.4, 120.9, 125.8,
3

ACCEPTED MANUSCRIPT
1
1
9
27.3, 129.7, 155.3, 158.7, 168.8; Anal. calcd for C H N O : C, 66.88; H, 7.37; N,
1
6
21
3
2
4.62%. Found: C, 67.05; H, 7.33; N, 14.99%.
g: 1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(4-
o
1
methoxyphenyl amino)ethanone, colorless crystals, yield, 82%; mp 225~226 C; H NMR
(
400 MHz, CDCl ) δ (ppm): 2.20 (s, 3H), 3.01 (dd, 1H, J = 18.4 Hz, J = 2.8 Hz, pyrazole,
3 1 2
4
-H ), 3.36 (dd, 1H, J = 18.4 Hz, J = 11.2 Hz, pyrazole, 4-H ), 3.74 (s, 3H), 4.17 (m, 2H,
a 1 2 b
-
CH - ), 5.71 (dd, 1H, J = 11.2 Hz, J = 2.8 Hz, pyrazole, 5-H), 6.62-6.64 (m, 2H),
2 1 2
1
3
6
.76-6.78 (m, 3H), 6.84-7.13 (m, 4H), 8.79 (brs, 1H, -NH). C NMR (CDCl , 125 MHz):
3
δ 16.2, 43.9, 46.9, 53.8, 55.9, 114.6, 114.9, 118.8, 121.0, 125.6, 126.7, 129.8, 141.7, 152.5,
1
6
9
54.8, 159.6, 168.4; Anal. calcd for C H N O : C, 67.24; H, 6.24; N, 12.38%. Found: C,
19 21 3 3
7.00; H, 6.45; N, 12.05%.
j: 1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(4-phenylpiperidin-1
o
1
-
yl)ethanone, colorless crystals, yield, 59%; mp 198~200 C; H NMR (400 MHz, CDCl )
3
δ (ppm): 1.34-1.49 (m, 2H), 1.50-1.60 (m, 2H), 2.04-2.10 (m, 4H), 2.17 (s, 3H), 2.92-3.05
(
m, 2H, containing pyrazole, 4-H ), 3.36 (dd, 1H, J = 18.4 Hz, J = 11.2 Hz, pyrazole,
a 1 2
4
3
7
9
-H ), 3.49 (m, 2H), 5.65 (dd, 1H, J = 11.2 Hz, J = 3.2 Hz, pyrazole, 5-H), 6.85-6.95 (m,
b 1 2
H), 7.11-7.18 (m, 4H), 7.24-7.28 (m, 2H), 9.21 (brs, 1H). Anal. calcd for C H N O : C,
23
27
3
2
3.18; H, 7.21; N, 11.13%. Found: C, 73.57; H, 7.44; N, 11.01%.
l: 2-(4-chloropiperidin-1-yl)-1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-
o
1
yl]ethanone, colorless crystals, yield, 80%; mp 220~222 C; H NMR (400 MHz, CDCl ) δ
3
(ppm): 1.89-1.97 (m, 2H), 2.08-2.14 (m, 2H), 2.16 (s, 3H), 2.43-2.48 (m, 2H), 2.82-2.84
(
m, 2H, containing pyrazole, 4-H ), 3.00 (dd, 1H, J = 18.4 Hz, J = 3.6 Hz, pyrazole,
a
1
2
4
-H ), 3.28-3.36 (m, 1H), 3.54 (m, 2H), 4.05 (brs, 1H, - piperidine-Cl), 5.66 (dd, 1H, J =
b 1
1
1.2 Hz, J = 3.6 Hz, pyrazole, 5-H), 6.84-6.92 (m, 3H), 7.13-7.17 (m, 1H), 9.09 (brs, 1H,
2
1
3
-
OH). C NMR (CDCl , 125 MHz): δ 16.2, 35.3, 43.5, 51.4, 53.3, 57.2, 58.9, 119.6, 121.2,
3
1
26.0, 127.2, 129.9, 155.3, 159.0, 168.3; Anal. calcd for C H ClN O : C, 60.80; H, 6.60;
17 22 3 2
N, 12.51%. Found: C, 61.17; H, 6.94; N, 12.50%.
9
m: 2-(3,5-dimethylpiperidin-1-yl)-1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol
o
1
-
1-yl]ethanone, colorless crystals, yield, 83%; mp 217~218 C; H NMR (400 MHz,
CDCl ) δ (ppm): 0.87-0.92 (m, 6H), 2.08-2.14 (m, 2H), 2.13 (s, 3H), 2.17-2.22 (m, 2H),
3

ACCEPTED MANUSCRIPT
2
.36-2.48 (m, 2H), 2.91 (dd, 1H, J = 18.8 Hz, J = 4.4 Hz pyrazole, 4-H ), 3.23-3.27 (m,
1
2
a
2
H), 3.40 (dd, 1H, J = 18.4 Hz, J = 11.6 Hz pyrazole, 4-H ), 3.98 (m, 2H), 5.67 (dd, 1H,
1
2
b
J = 11.6 Hz, J = 4.4 Hz pyrazole, 5-H), 6.87-6.95 (m, 2H), 7.05-7.07 (m, 1H), 7.14-7.18
1
2
(
m, 1H). Anal. calcd for C H N O : C, 69.27; H, 8.26; N, 12.76%. Found: C, 69.05; H,
19 27 3 2
8
.34; N, 13.02%.
9
n:Tert-butyl4-{2-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-oxo
o
1
ethyl}piperazine-1-carboxylate, colorless crystals, yield, 80%; mp 189~190 C; H NMR
(
400 MHz, CDCl ) δ (ppm): 1.44 (s, 9H), 2.17 (s, 3H), 2.52-2.52 (m, 4H), 3.02 (dd, 1H, J1
3
=
18.8 Hz, J = 3.2 Hz pyrazole, 4-H ), 3.33 (dd, 1H, J = 18.8 Hz, J = 11.6 Hz pyrazole,
2 a 1 2
4
-H ), 3.44-3.47 (m, 4H), 3.53 (m, 2H), 5.66 (dd, 1H, J = 11.2 Hz, J = 3.6 Hz pyrazole,
b 1 2
1
3
5
-H ), 6.86-6.92 (m, 3H), 7.14-7.19 (m, 1H), 9.04 (brs, 1H). C NMR (CDCl , 125 MHz):
3
δ 16.2, 28.5, 43.5, 53.3, 53.4, 59.0, 79.7, 119.6, 121.3, 126.0, 127.2, 130.0, 154.8, 155.2,
1
59.0, 168.0; Anal. calcd for C H N O : C, 62.67; H, 7.51; N, 13.92%. Found: C, 63.01;
21 30 4 4
H, 7.22; N, 13.61%.
9
o: 1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(4-methylpiperazin-1-
o
1
yl)ethanone, colorless crystals, yield, 69%; mp 184~185 C; H NMR (400 MHz, CDCl ) δ
3
(ppm): 2.13 (s, 3H), 2.56 (s, 3H), 2.87-2.88 (m, 4H), 2.92-2.96 (m, 5H, containing pyrazole,
4
-H ), 3.33 (dd, 1H, J = 18.4 Hz, J = 11.6 Hz pyrazole, 4-H ), 3.61 (m, 2H), 5.61 (dd, 1H,
a
1
2
b
J = 11.6 Hz, J = 4.0 Hz pyrazole, 5-H), 6.82-6.86 (m, 1H), 6.88-6.92 (m, 2H), 7.10-7.14
1
2
(
m, 1H). Anal. calcd for C H N O : C, 64.53; H, 7.65; N, 17.71%. Found: C, 64.81; H,
17 24 4 2
7
9
1
.94; N, 18.10%.
q:1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(3-methylpiperidin-
o
1
-yl)ethanone, colorless crystals, yield, 65%; mp 200~201 C; H NMR (400 MHz, CDCl )
3
δ (ppm): 0.80-0.83 (m, 3H), 1.56-1.66 (m, 2H), 1.69-1.73 (m, 4H), 1.94-2.03 (m, 1H), 2.16
(s, 3H), 2.86-2.95 (m, 2H), 3.00 (dd, 1H, J = 18.4 Hz, J = 3.2 Hz pyrazole, 4-H ), 3.31
1 2 a
(
dd, 1H, J = 18.8 Hz, J = 11.2 Hz pyrazole, 4-H ), 3.49 (m, 2H), 5.66 (dd, 1H, J = 11.2
1
2
b
1
1
3
Hz, J = 18.4 Hz pyrazole, 5-H), 6.84-6.92 (m, 3H), 7.13-7.17 (m, 1H). C NMR (CDCl ,
2
3
1
1
1
25 MHz): δ 16.2, 19.7, 25.5, 31.0, 32.8, 43.5, 53.3, 54.4, 59.5, 62.4, 119.5, 121.1, 126.0,
27.4, 129.8, 155.3, 158.6, 168.6; Anal. calcd for C H N O : C, 68.54; H, 7.99; N,
1
8
25
3
2
3.32%. Found: C, 68.17; H, 8.22; N, 13.07%.

ACCEPTED MANUSCRIPT
9
r:1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-thiomorpholino- ethanone,
o
1
colorless crystals, yield, 86%; mp 177~178 C; H NMR (400 MHz, CDCl ) δ (ppm): 2.20
3
(s, 3H), 2.71 (4H, d, J= 4.0 Hz), 2.83 (4H, d, J= 4.0 Hz), 3.07 (1H, dd, J= 3.2 and 18.6 Hz,
pyrazole, 4-H ), 3.40 (1H, dd, J= 11.2 and 18.8 Hz, pyrazole, 4-H ), 3.55 (2H, m), 5.65
a
b
(1H, dd, J= 12.0 and 4.0 Hz, pyrazole, 5-H), 6.90-7.23 (4H, m), 9.09 (1H, brs, -OH). Anal.
calcd for C H N O S: C, 60.16; H, 6.63; N, 13.16%. Found: C, 60.01; H, 6.87; N,
1
6
21
3
2
1
3.40%.
s: 2-(diisobutylamino)-1-[5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]
9
o
1
ethanone, colorless crystals, yield, 81%; mp 172~173 C; H NMR (400 MHz, CDCl ) δ
3
(ppm): 0.81 (m, 12H), 1.64 (m, 2H), 2.18 (s, 3H), 2.30 (4H, d, J= 8.0 Hz), 3.04 (1H, dd,
J= 4.0 and 20.0 Hz, pyrazole, 4-H ), 3.30 (1H, dd, J= 12.0 and 20.0 Hz, pyrazole, 4-H ),
a
b
3
.59 (2H, m), 5.65 (1H, dd, J= 12.0 and 4.0 Hz, pyrazole, 5-H), 6.87-7.20 (4H, m), 9.48
(
1H, brs, -OH). Anal. calcd for C H N O : C, 69.53; H, 9.04; N, 12.16%. Found: C,
2
0
31
3
2
6
9
9.17; H, 8.85; N, 12.44%.
t: 1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(dipropylamino)
o
1
ethanone, colorless crystals, yield, 74%; mp 180~181 C; H NMR (CDCl , 400 MHz): δ
3
0
.85 (6H, t, J= 8.0 Hz), 1.46 (4H, m), 2.16 (3H, s, -Me), 2.55 (4H, m), 2.89 (1H, dd, J=
0.0 and 4.0 Hz, pyrazole, 4-H ), 3.32 (1H, dd, J= 12.0 and 20.0 Hz, pyrazole, 4-H ), 3.67
2
a
b
(
2H, m, -CH -), 5.62 (1H, dd, J= 12.0 and 4.0 Hz, pyrazole, 5-H), 6.67-7.18 (3H, m, ArH);
2
Anal. calcd for C H BrN O : C, 54.55; H, 6.61; N, 10.60%. Found: C, 54.19; H, 6.35; N,
1
8
26
3
2
1
0.91%.
u: 1-[5-(5-bromo-2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(diallylamino)
9
o
1
ethanone, colorless crystals, yield, 80%; mp 167~168 C; H NMR (CDCl , 400 MHz): δ
3
2
.00 (3H, s, -Me), 2.59 (1H, dd, J= 20.0 and 4.0 Hz, pyrazole, 4-H ), 3.26 (5H, m,
a
containing pyrazole, 4-H ), 3.74 (2H, m, -CH -), 5.12 (4H, m), 5.60 (1H, dd, J= 12.0 and
b
2
4
.0 Hz, pyrazole, 5-H), 5.84 (2H, m), 6.28-6.94 (3H, m, ArH); Anal. calcd for
C H BrN O : C, 55.11; H, 5.65; N, 10.71%. Found: C, 55.34; H, 5.89; N, 10.42%.
18
22
3
2
1
0b: 2-(1-(2-(diethylamino)acetyl)-3-methyl-4,5-dihydro-1H-pyrazol-5-yl)phenyl acetate,
o
1
colorless crystals, yield, 81%; mp 228~230 C; H NMR (400 MHz, CDCl ) δ (ppm): 1.17
3
(t, 6H, J = 7.2 Hz), 2.06 (s, 3H), 2.29 (s, 3H), 2.67-2.73 (m, 1H), 2.91 (m, 4H, containing

ACCEPTED MANUSCRIPT
pyrazole, 4-H ), 3.27 (dd, 1H, J = 18.4 Hz, J = 12.8 Hz pyrazole, 4-H ), 3.85 (s, 2H),
a
1
2
b
5
.46 (dd, 1H, J = 12.0 Hz, J = 5.2 Hz pyrazole, 5-H), 7.02-7.04 (m, 1H), 7.18-7.20 (m,
1 2
2
H), 7.27-7.31 (m, 1H). Anal. calcd for C H N O : C, 65.23; H, 7.60; N, 12.68%. Found:
18 25 3 3
C, 65.01; H, 7.25; N, 13.04%.
1
0c:2-[1-(2-(diisopropylamino)acetyl)-3-methyl-4,5-dihydro-1H-pyrazol-5-yl]phenyl
o
1
acetate, colorless crystals, yield, 80%; mp 218~219 C; H NMR (400 MHz, CDCl ) δ
3
(
ppm): 1.39-1.43 (m, 12H), 2.17 (s, 3H), 2.34 (s, 3H), 2.84 (dd, 1H, J = 18.4 Hz, J = 4.4
1 2
Hz pyrazole, 4-H ), 3.47 (dd, 1H, J = 18.4 Hz, J = 12.4 Hz pyrazole, 4-H ), 3.69-3.75
a
1
2
b
(m, 3H), 4.33-4.70 (m, 1H), 5.42-5.54 (m, 1H, pyrazole, 5-H), 7.03-7.15 (m, 1H),
7
1
1
.23-7.27 (m, 2H), 7.33-7.36 (m, 1H). Anal. calcd for C H N O : C, 66.83; H, 8.13; N,
20 29 3 3
1.69%. Found: C, 66.45; H, 8.52; N, 12.02%.
0d: 2-(diisopropylamino)-1-[5-(2-methoxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]
o
1
ethanone, colorless crystals, yield, 64%; mp 210~212 C; H NMR (400 MHz, CDCl ) δ
3
(ppm): 1.43-1.62 (m, 12H), 2.11 (d, 3H, J = 6.8 Hz), 2.58-2.79 (m, 1H), 3.28 (s, 1H),
3
6
6
1
.37-3.47 (m, 1H), 3.82 (s, 3H), 4.14 (s, 1H), 4.29-4.62 (m, 2H), 5.51-5.64 (m, 1H),
.87-6.92 (m, 2H), 6.98-7.08 (m, 1H), 7.25-7.26 (m, 1H). Anal. calcd for C H N O : C,
19
29
3
2
8.85; H, 8.82; N, 12.68%. Found: C, 69.17; H, 9.07; N, 12.99%.
0e: 2-[3-methyl-1-(2-(piperidin-1-yl)acetyl)-4,5-dihydro-1H-pyrazol-5-yl]phenyl acetate,
o
1
colorless crystals, yield, 85%; mp 225~227 C; H NMR (400 MHz, CDCl ) δ (ppm):
3
1
.40-1.42 (m, 2H), 1.57-1.62 (m, 4H), 2.03 (s, 3H), 2.28 (s, 3H), 2.59-2.61 (m, 4H), 2.65
(
dd, 1H, J = 19.2 Hz, J = 5.6 Hz), 3.18-3.26 (m, 1H), 3.56 (s, 2H), 5.46 (dd, 1H, J = 12.0
1
2
1
Hz, J = 5.6 Hz), 7.01-7.03 (m, 1H), 7.13-7.19 (m, 2H), 7.24-7.27 (m, 1H). Anal. calcd for
2
C H N O : C, 66.45; H, 7.34; N, 12.24%. Found: C, 66.31; H, 7.22; N, 12.01%.
19
25
3
3
1
0g: 2-[3-methyl-1-(2-(pyrrolidin-1-yl)acetyl)-4,5-dihydro-1H-pyrazol-5-yl]phenyl acetate,
o
1
colorless crystals, yield, 76%; mp 220~221 C; H NMR (400 MHz, CDCl ) δ (ppm):
3
1
.59-1.78 (m, 4H), 2.10-2.12 (m, 3H), 2.29 (s, 3H), 2.67-2.81 (m, 1H), 3.21-3.40 (m, 3H),
.48-3.53 (m, 2H), 4.11-4.72 (m, 2H), 5.42-5.46 (m, 1H), 7.00-7.04 (m, 1H), 7.18-7.25 (m,
H), 7.27-7.33 (m, 1H). Anal. calcd for C H N O : C, 65.63; H, 7.04; N, 12.76%. Found:
3
2
1
8
23
3
3
C, 66.02; H, 7.41; N, 12.51%.
1
0i: 2-{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-3-methyl-4,5-dihydro-1H-pyrazol-5-yl}

ACCEPTED MANUSCRIPT
o
1
phenyl acetate, colorless crystals, yield, 67%; mp 220~221 C; H NMR (400 MHz, CDCl )
3
δ (ppm): 1.63-1.69 (m, 2H), 1.92-1.94 (m, 2H), 2.07 (s, 3H), 2.31 (s, 3H), 2.42-2.47 (m,
2
H), 2.69 (dd, 1H, J = 18.8 Hz, J = 5.2 Hz), 2.92-2.94 (m, 2H), 3.26 (dd, 1H, J = 18.8
1 2 1
Hz, J = 12.4 Hz), 3.61 (s, 2H), 3.70-3.72 (m, 1H), 5.49 (dd, 1H, J = 12.0 Hz, J = 5.2 Hz),
2
1
2
7
6
1
.04-7.06 (m, 1H), 7.16-7.22 (m, 2H), 7.27-7.30 (m, 1H). Anal. calcd for C H N O : C,
19 25 3 4
3.49; H, 7.01; N, 11.69%. Found: C, 63.11; H, 7.39; N, 12.38%.
0j: 2-{3-methyl-1-[2-(4-acetylpiperidin-1-yl)acetyl]-4,5-dihydro-1H-pyrazol-5-yl}-
o
1
phenyl acetate, colorless crystals, yield, 81%; mp 208~209 C; H NMR (400 MHz,
CDCl ) δ (ppm): 1.70-1.78 (m, 2H), 1.89-1.934 (m, 2H), 2.02 (s, 3H), 2.03 (s, 3H), 2.28 (s,
3
3
H), 2.53-2.58 (m, 2H), 2.66 (dd, 1H, J = 18.8 Hz, J = 5.2 Hz), 2.92-2.95 (m, 2H), 3.23
1 2
(
dd, 1H, J = 18.4 Hz, J = 12.0 Hz), 3.63 (s, 2H), 4.75-4.80 (m, 1H), 5.45 (dd, 1H, J =
1
2
1
1
2.0 Hz, J = 5.2 Hz), 7.01-7.03 (m, 1H), 7.13-7.20 (m, 2H), 7.24-7.28 (m, 1H). Anal.
2
calcd for C H N O : C, 65.44; H, 7.06; N, 10.90%. Found: C, 65.31; H, 7.01; N, 10.67%.
2
1
27
3
4
1
0k: 1-(5-(2-methoxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl)-2-(4-methoxypiper-
o
1
idin-1-yl)ethanone, colorless crystals, yield, 80%; mp 203~204 C; H NMR (400 MHz,
CDCl ) δ (ppm): 2.10 (s, 3H), 2.14-2.18 (m, 4H), 2.69 (dd, 1H, J = 18.4 Hz, J = 4.0 Hz),
3
1
2
3
4
.41 (dd, 1H, J = 18.4 Hz, J = 11.6 Hz), 3.51 (s, 3H), 3.85 (s, 3H), 3.89-4.04 (m, 4H),
1 2
.28-4.29 (m, 1H), 4.73-4.80 (m, 2H), 5.61 (dd, 1H, J = 11.6 Hz, J = 4.4 Hz), 6.90-6.97
1
2
(
m, 2H), 7.02-7.04 (m, 1H), 7.26-7.30 (m, 1H). Anal. calcd for C H N O : C, 66.06; H,
19 27 3 3
7
1
.88; N, 12.16%. Found: C, 66.00; H, 8.17; N, 12.45%.
0l: 2-{3-methyl-1-[2-(2-methylpiperidin-1-yl)acetyl]-4,5-dihydro-1H-pyrazol-5- yl}phenyl
o
1
acetate, colorless crystals, yield, 62%; mp 211~212 C; H NMR (400 MHz, CDCl ) δ
3
(
ppm): 1.24-1.28 (m, 3H), 1.38-1.42 (m, 2H), 1.69-1.75 (m, 4H), 1.90-1.96 (m, 1H), 2.07
s, 3H), 2.28 (s, 3H), 2.69-2.78 (m, 1H), 3.09-3.10 (m, 2H), 3.24-3.31 (m, 1H), 3.88 (dd,
(
1
7
1
1
H, J = 16.8 Hz, J = 8.0 Hz), 4.10-4.13 (m, 1H), 5.40-5.43 (m, 1H), 7.01-7.04 (m, 1H),
1 2
.18-7.20 (m, 2H), 7.28-7.31 (m, 1H). Anal. calcd for C H N O : C, 67.20; H, 7.61; N,
2
0
27
3
3
1.76%. Found: C, 67.38; H, 8.00; N, 11.43%.
0n: 2-[1-(2-chloroacetyl)-3-methyl-4,5-dihydro-1H-pyrazol-5-yl]phenyl acetate, colorless
o
1
crystals, yield, 70%; mp 205~206 C; H NMR (400 MHz, CDCl ) δ (ppm): 2.09 (s, 3H),
3
2
.32 (s, 3H), 2.75 (dd, 1H, J = 18.0 Hz, J = 5.6 Hz), 3.31 (dd, 1H, J = 18.0 Hz, J = 12.0
1 2 1 2

ACCEPTED MANUSCRIPT
Hz), 4.43 (s, 2H), 5.51 (dd, 1H, J = 12.4 Hz, J = 5.6 Hz), 7.07-7.09 (m, 1H), 7.17-7.24
1
2
(
m, 2H), 7.28-7.32 (m, 1H). Anal. calcd for C H ClN O : C, 57.05; H, 5.13; N, 9.50%.
14 15 2 3
Found: C, 56.87; H, 5.44; N, 9.22%.
1
0o: N,N-diethyl-2-[5-(2-methoxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-N-
o
1
methyl-2-Oxoethanaminium, colorless crystals, yield, 80%; mp 227~229 C; H NMR (400
MHz, CDCl ) δ (ppm): 1.38 (6H, t, J = 7.2 Hz), 2.08 (s, 3H), 2.68 (1H, dd, J= 4.4 and 18.4
3
Hz, pyrazole, 4-H ), 3.40 (1H, dd, J= 11.6 and 18.4 Hz, pyrazole, 4-H ), 3.46 (3H, s),
a
b
3
6
6
1
.79-3.94 (7H, m), 4.64 (2H, m), 5.58 (1H, dd, J= 11.6 and 4.8 Hz, pyrazole, 5-H),
+
.88-6.94 (2H, m), 6.98-7.01 (1H, m), 7.24-7.29 (1H, m). Anal. calcd for C H N O : C,
18
28
3
2
7.89; H, 8.86; N, 13.20%. Found: C, 68.14; H, 9.13; N, 12.98%.
0p: 1-[5-(2-methoxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl]-2-(pyrrolidin-1-
o
1
yl) ethanaminium, colorless crystals, yield, 70%; mp 219~221 C; H NMR (400 MHz,
CDCl ) δ (ppm): 2.06 (s, 3H), 2.21-2.24 (m, 2H), 2.34-2.37 (m, 2H), 2.66 (1H, dd, J = 18.0
3
and 4.8 Hz, pyrazole, 4-H ), 3.38 (1H, dd, J = 18.8 and 11.6 Hz, pyrazole, 4-H ), 3.44 (3H,
a
b
s), 3.85 (3H, s), 4.03-4.13 (4H, m), 4.98 (2H, m), 5.60 (1H, dd, J = 11.6 and 4.8 Hz,
+
pyrazole, 5-H), 6.88-6.95 (2H, m), 7.01-7.29 (2H, m). Anal. calcd for C H N O : C,
18
26
3
2
6
8.33; H, 8.28; N, 13.28%. Found: C, 68.60; H, 8.41; N, 13.31%.
4
.1.4 General procedure for preparation of compounds 11f~11j
A solution of carboxylic acid (12 mmol) and nitropheny chloride (12 mmol) in
chloroform (20 mL) was stirred, 3-(5-substituted-phenyl-4,5-dihydro-1H-pyrazol- 3-yl)-
H-chromen-2-one (10 mmol) and DMAP (14 mmol) were added, then the reaction
2
mixture was refluxed for 5 h. The mixture was cooled, washed with water, and allowed to
stand at 0 ˚C over night. The product was collected by filtration and the crude residue was
purified by chromatography on SiO (acetone/petroleum, v:v=4:1) to give title compounds
2
1
1f~11j (Scheme 2) as colorless solids.
1
1f: 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one, colorless
o
1
crystals, yield, 62%; mp 220~222 C; H NMR (CDCl , 300 MHz): δ 3.49 (1H, dd, J=
3
1
8.9 and 5.1 Hz , pyrazole, 4-H ), 4.03 (1H, dd, J= 12.0 and 18.9 Hz, pyrazole, 4-H ), 5.83
a b
(1H, dd, J= 12.0 and 5.4 Hz , pyrazole, 5-H), 7.25-8.03 (14H, m, C -H and ArH ), 8.35
5-8
1
3
(
1H, s, C -H); C NMR (CDCl , 125 MHz): δ 43.8, 61.8, 116.7, 118.8, 119.7, 125.0, 125.7,
4
3

ACCEPTED MANUSCRIPT
1
27.9, 128.9, 129.0, 130.1, 131.2, 133.0, 134.3, 141.3, 141.5, 151.7, 154.2, 159.3, 166.7;
Anal. calcd for: C H N O : C, 76.13; H, 4.60; N, 7.10%. Found: C, 76.42; H, 4.91; N,
2
5
18
2
3
7
.00%.
1
1g: 3-[1-(4-methylbenzoyl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2H-chromen
o
1
-
2- one, colorless crystals, yield, 69%; mp 197~198 C; H NMR (CDCl , 300 MHz): δ
3
2
.42 (3H, s, -Me), 3.45 (1H, dd, J= 18.9 and 5.1 Hz , pyrazole, 4-H ), 4.00 (1H, dd, J=
a
1
2.0 and 18.9 Hz, pyrazole, 4-H ), 5.81 (1H, dd, J= 12.0 and 5.4 Hz , pyrazole, 5-H),
b
1
3
7
.24-7.92 (13H, m, C -H and ArH ), 8.34 (1H, s, C -H); C NMR (CDCl , 125 MHz): δ
5-8 4 3
2
1.7, 43.7, 61.8, 116.7, 117.9, 118.9, 119.8, 125.0, 125.4, 125.7, 127.8, 128.6, 128.9, 129.0,
30.2, 131.3, 132.9, 141.2, 141.6, 151.4, 154.2, 159.3, 166.6; Anal. calcd for: C H N O :
1
2
6
20
2
3
C, 76.45; H, 4.94; N, 6.86%. Found: C, 76.71; H, 5.21; N, 7.09%.
1
1h: 3-(5-phenyl-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one, colorless
o
1
crystals, yield, 78%; mp 217~218 C; H NMR (CDCl , 300 MHz): δ 1.22 (3H, t, J= 7.5
3
Hz, -Me), 2.84 (2H, q, J= 7.5 Hz, -CH -), 3.41 (1H, dd, J= 18.9 and 5.1 Hz , pyrazole,
2
4
-H ), 3.96 (1H, dd, J= 12.0 and 18.9 Hz, pyrazole, 4-H ), 5.59 (1H, dd, J= 12.0 and 4.8
a b
1
3
Hz , pyrazole, 5-H), 7.21-7.64 (9H, m, C -H and ArH ), 8.44 (1H, s, C -H); C NMR
5
-8
4
(
CDCl , 125 MHz): δ 9.0, 27.6, 44.2, 60.6, 116.7, 118.9, 119.9, 125.0, 125.6, 127.7, 128.9,
3
1
7
1
29.0, 132.9, 140.9, 141.8, 150.5, 154.2, 159.3, 172.4; Anal. calcd for: C H N O : C,
21 18 2 3
2.82; H, 5.24; N, 8.09%. Found: C, 73.04; H, 5.02; N, 8.43%.
1i: 3-[1-(2-chloroacetyl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2H-chromen
o
1
-
2-one, colorless crystals, yield, 93%; mp 210~212 C; H NMR (CDCl , 300 MHz): δ
3
3
.49 (1H, dd, J= 18.9 and 4.8 Hz , pyrazole, 4-H ), 3.99 (1H, dd, J= 12.0 and 19.2 Hz,
a
pyrazole, 4-H ), 4.55 (2H, s, -CH -), 5.59 (1H, dd, J= 11.7 and 4.8 Hz , pyrazole, 5-H),
b
2
1
3
7
.21-7.65 (9H, m, C -H and ArH ), 8.46 (1H, s, C -H); C NMR (DMSO-d , 125 MHz):
5-8 4 6
δ 42.9, 44.4, 60.4, 116.6, 119.1, 125.5, 126.0, 128.0, 129.3, 129.9, 133.8, 141.9, 143.2,
1
52.8, 154.0, 158.4, 164.0; Anal. calcd for: C H ClN O : C, 65.49; H, 4.12; N, 7.64%.
20 15 2 3
Found: C, 65.70; H, 3.95; N, 8.00%.
1
1j: 3-[1-(2-chlorobenzoyl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2H-chromen
o
1
-
2- one, colorless crystals, yield, 63%; mp 194~195 C; H NMR (CDCl , 300 MHz): δ
3
3
.50 (1H, dd, J= 19.2 and 5.1 Hz , pyrazole, 4-H ), 4.08 (1H, dd, J= 12.0 and 18.9 Hz,
a

ACCEPTED MANUSCRIPT
pyrazole, 4-H ), 5.78 (1H, dd, J= 12.0 and 5.1 Hz , pyrazole, 5-H), 7.26-7.55 (13H, m,
b
1
3
C -H and ArH ), 8.22 (1H, s, C -H); C NMR (DMSO-d , 125 MHz): δ 44.6, 60.6, 116.6,
5
-8
4
6
1
18.9, 119.5, 125.4, 126.2, 127.6, 128.0, 129.3, 129.5, 130.0, 130.5, 131.4, 133.7, 136.2,
42.1, 142.5, 153.6, 154.0, 158.5, 164.8; Anal. calcd for: C H ClN O : C, 70.01; H, 4.00;
1
2
5
17
2
3
N, 6.53%. Found: C, 70.39; H, 3.90; N, 6.47%.
4
.1.5 General procedure for preparation of compounds 12k~12l
-(5-substituted-phenyl-4,5-dihydro-1H- pyrazol-3-yl)-2H-chromen-2-one 6 (10
3
mmol) was dissolved in 20 mL of chloroform, at room temperature was added tosyl
chloride (10 mmol) or nitrophenyl chloride (10 mmol) and DMAP (10 mmol), the reaction
mixture was refluxed for 2 h. The mixture was cooled, washed with water, and allowed to
stand at 0~5 ˚C over night. The product was collected by filtration and the crude residue
was purified by chromatography on SiO (acetone/petroleum, v:v=2:1) to give title
2
compounds 12k~12l (Scheme 2) as colorless solids.
1
2k: 3-[1-(4-nitrophenylsulfonyl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2H-chromen-2
o
1
-
one, colorless crystals, yield, 89%; mp 217~219 C; H NMR (CDCl , 300 MHz): δ 3.46
3
(
1H, dd, J= 18.6 and 7.5 Hz , pyrazole, 4-H ), 3.94 (1H, dd, J= 11.7 and 18.9 Hz, pyrazole,
a
4
-H ), 5.19 (1H, dd, J= 11.4 and 7.5 Hz , pyrazole, 5-H), 7.23-8.26 (13H, m, C -H and
b 5-8
ArH ), 8.49 (1H, s, C -H); Anal. calcd for: C H N O S: C, 60.63; H, 3.60; N, 8.84%.
4
24 17
3
6
Found: C, 61.02; H, 3.41; N, 9.12%.
1
2l:3-(5-phenyl-1-tosyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one,colorless crystals,
o
1
yield, 91%; mp 208~210 C; H NMR (CDCl , 300 MHz): δ 2.42 (3H, s, -Me), 3.27 (1H,
3
dd, J= 18.6 and 9.3 Hz , pyrazole, 4-H ), 3.85 (1H, dd, J= 11.7 and 18.6 Hz, pyrazole,
a
4
-H ), 4.95 (1H, dd, J= 11.7 and 9.3 Hz , pyrazole, 5-H), 7.26-7.74 (13H, m, C -H and
b 5-8
13
ArH ), 8.53 (1H, s, C -H); C NMR (CDCl , 125 MHz): δ 21.7, 45.7, 65.9, 116.7, 118.8,
4
3
1
1
6
4
18.9, 125.2, 126.8, 128.2, 128.5, 128.9, 129.1, 129.7, 133.2, 140.6, 141.9, 142.3, 144.5,
53.7, 154.3, 159.3; Anal. calcd for: C H N O S: C, 67.55; H, 4.54; N, 6.30%. Found: C,
2
5
20
2
4
7.19; H, 4.50; N, 6.02%.
.1.6 General procedure for preparation of compounds 13a~13z
-(1-(2-chloroacetyl)-5-substituted-phenyl-4,5-Dihydro-1H-pyrazol-3-yl)-2H-chrome
n-2-one 6’ (10 mmol) was dissolved in 20 mL of acetone, at room temperature was added
3

ACCEPTED MANUSCRIPT
amine (12 mmol), piperazine (10 mmol) and catalytic KI, the reaction mixture was allowed
to stand at 50 ˚C for 5 h. The mixture was cooled, washed with water. The product was
collected by filtration and the crude residue was purified by chromatography on SiO2
(
dichloromethane /methanol, v:v= 70:1) to give title compounds 13a~13z (Scheme 2) as
colorless solids.
3a:3-{1-[2-(methylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-
1
o
1
chromen-2-one, colorless crystals, yield, 68%; mp 208~209 C; H NMR (400 MHz,
CDCl ) δ (ppm): 2.46 (s, 3H), 3.43 (dd, 1H, J = 19.2 Hz, J = 4.8 Hz pyrazole, 4-H ),
3
1
2
a
3
.87-4.00 (m, 3H, containing pyrazole, 4-H ), 5.57 (dd, 1H, J = 11.6 Hz, J = 5.2 Hz
b 1 2
pyrazole, 5-H), 7.19-7.24 (m, 3H), 7.26-7.36 (m, 4H), 7.57-7.68 (m, 2H), 8.35 (1H, s,
C -H), 9.28 (1H, brs, -NH); Anal. calcd for: C H N O : C, 69.79; H, 5.30; N, 11.63%.
4
21 19
3
3
Found: C, 70.05; H, 4.99; N, 12.02%.
1
3b: 3-{1-[2-(ethylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-chro- men-
o
1
2
-one, colorless crystals, yield, 62%; mp 206~207 C; H NMR (400 MHz, CDCl ) δ
3
(
ppm): 2.46 (t, 3H, J = 7.2 Hz), 2.64-2.73 (m, 2H), 3.43 (dd, 1H, J = 19.2 Hz, J = 4.8 Hz
1 2
pyrazole, 4-H ), 3.90-4.00 (m, 3H, containing pyrazole, 4-H ), 5.58 (dd, 1H, J = 12.0 Hz,
a
b
1
J2 = 4.8 Hz pyrazole, 5-H ), 7.19-7.27 (m, 3H), 7.30-7.37 (m, 4H), 7.57-7.65 (m, 2H), 8.45
1H, s, C -H); Anal. calcd for: C H N O : C, 70.38; H, 5.64; N, 11.19%. Found: C, 70.65;
(
4
22 21
3
3
H, 6.01; N, 11.54%.
3c: 3-{1-[2-(isopropylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-
1
o
1
chromen-2-one, colorless crystals, yield, 60%; mp 202~204 C; H NMR (400 MHz,
CDCl ) δ (ppm): 1.07-1.11 (m, 6H), 2.81 (m, 1H), 3.43 (dd, 1H, J = 18.8 Hz, J = 4.8 Hz
3
1
2
pyrazole, 4-H ), 3.90-4.01 (m, 3H, -CH and containing pyrazole, 4-H ), 5.58 (dd, 1H, J =
a
2
b
1
1
2.0 Hz, J = 5.2 Hz pyrazole, 5-H), 7.20-7.25 (m, 3H), 7.30-7.37 (m, 4H), 7.58-7.66 (m,
2
2
H), 8.45 (1H, s, C -H); Anal. calcd for: C H N O : C, 70.93; H, 5.95; N, 10.79%. Found:
4
23 23
3
3
C, 71.21; H, 6.24; N, 11.10%.
1
3d: 3-{3-phenyl-1-[2-(propylamino)acetyl]-4,5-dihydro-1H-pyrazol-5-yl}-
o
1
2
H-chromen-2-one, colorless crystals, yield, 67%; mp 212~214 C; H NMR (400 MHz,
CDCl ) δ (ppm): 0.92 (t, 3H, J = 7.2 Hz), 1.54 (q, 2H), 2.57-2.64 (m, 2H), 3.44 (dd, 1H, J1
3
=
19.2 Hz, J = 4.8 Hz pyrazole, 4-H ), 3.89-4.01 (m, 3H, containing pyrazole, 4-H ), 5.58
2 a b

ACCEPTED MANUSCRIPT
(
dd, 1H, J = 11.6 Hz, J = 4.8 Hz pyrazole, 5-H), 7.20-7.24 (m, 3H), 7.31-7.37 (m, 4H),
1
2
7
1
1
2
.58-7.65 (m, 2H), 8.45 (1H, s, C -H); Anal. calcd for: C H N O : C, 70.93; H, 5.95; N,
4
23 23
3
3
0.79%. Found: C, 71.05; H, 5.68; N, 10.59%.
3e: 3-{1-[2-(cyclopropylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-
o
1
H-chromen-2-one, colorless crystals, yield, 55%; mp 208~209 C; H NMR (400 MHz,
CDCl ) δ (ppm): 0.44-0.52(m, 4H), 2.26 (t, 1H, J = 5.2 Hz ), 3.44 (dd, 1H, J = 18.8 Hz,
3
2
1
J = 4.8 Hz pyrazole, 4-H ), 3.92-4.02 (m, 3H, containing pyrazole, 4-H ), 5.59 (dd, 1H, J
1
2
a
b
=
12.0 Hz, J = 4.8 Hz pyrazole, 5-H), 7.19-7.25 (m, 3H), 7.27-7.37 (m, 4H), 7.58-7.66 (m,
2
1
3
2
1
1
5
1
H), 8.45 (1H, s, C -H); C NMR (CDCl , 125 MHz): δ 6.3, 6.5, 30.5, 44.1, 51.1, 60.9,
4 3
16.8, 118.8, 119.5, 125.1, 125.7, 127.9, 129.0, 133.1, 141.2, 141.4, 151.7, 154.3, 159.3,
69.6; Anal. calcd for: C H N O : C, 71.30; H, 5.46; N, 10.85%. Found: C, 71.66; H,
2
3
21
3
3
.19; N, 10.48%.
3f: 3-{1-[2-(isobutylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-
o
1
chromen-2-one, colorless crystals, yield, 62%; mp 214~216 C; H NMR (400 MHz,
CDCl ) δ (ppm): 0.92-0.94 (m, 6H), 1.74-1.81 (m, 1H), 2.45-2.48 (m, 2H), 3.44 (dd, 1H, J1
3
=
19.2 Hz, J = 4.8 Hz pyrazole, 4-H ), 3.89-4.01 (m, 3H, containing pyrazole, 4-H ), 5.59
2 a b
(
dd, 1H, J = 12.0 Hz, J = 4.8 Hz pyrazole, 5-H), 7.21-7.24 (m, 3H), 7.27-7.37 (m, 4H),
1 2
7
1
1
.58-7.64 (m, 2H), 8.45 (1H, s, C -H); Anal. calcd for: C H N O : C, 71.44; H, 6.25; N,
4
24 25
3
3
0.41%. Found: C, 71.20; H, 5.97; N, 10.75%.
3g: 3-{1-[2-(tert-butylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-
o
1
chromen-2-one, colorless crystals, yield, 69%; mp 202~203 C; H NMR (400 MHz,
CDCl ) δ (ppm): 1.15 (s, 9H), 3.43 (dd, 1H, J = 19.2 Hz, J = 5.2 Hz pyrazole, 4-H ),
3
1
2
a
3
.89-4.01 (m, 3H, containing pyrazole, 4-H ), 5.57 (dd, 1H, J = 12.0 Hz, J = 4.8 Hz
b 1 2
pyrazole, 5-H), 7.20-7.24 (m, 3H), 7.29-7.37 (m, 4H), 7.58-7.67 (m, 2H), 8.45 (1H, s,
C -H); Anal. calcd for: C H N O : C, 71.44; H, 6.25; N, 10.41%. Found: C, 71.69; H,
4
24 25
3
3
6
1
2
.38; N, 10.70%.
3h: 3-{1-[2-(cyclohexylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-
o
1
H-chromen-2-one, colorless crystals, yield, 60%; mp 212~214 C; H NMR (400 MHz,
CDCl ) δ (ppm): 1.09-1.25 (m, 4H), 1.66-1.71 (m, 4H), 1.89-1.91 (m, 2H), 2.40-2.46 (m,
3
1
H), 3.44 (dd, 1H, J = 18.2 Hz, J = 4.8 Hz pyrazole, 4-H ), 3.91-3.98 (m, 3H, containing
1 2 a

ACCEPTED MANUSCRIPT
pyrazole, 4-H ), 5.56-5.59 (m, 1H, pyrazole, 5-H), 7.20-7.25 (m, 3H), 7.30-7.37 (m, 4H),
b
7
9
1
.58-7.65 (m, 2H), 8.45 (1H, s, C -H); Anal. calcd for: C H N O : C, 72.71; H, 6.34; N,
4
26 27
3
3
.78%. Found: C, 73.08; H, 6.30; N, 9.46%.
3i: 3-{1-[2-(dibutylamino)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl}-2H-chromen-2
o
1
-
one, colorless crystals, yield, 69%; mp 207~208 C; H NMR (400 MHz, CDCl ) δ (ppm):
3
0
.90 (t, 6H, J = 7.2 Hz,), 1.25-1.34 (m, 4H), 1.58-1.64 (m, 4H), 2.92-2.96 (m, 4H), 3.45
1
(
dd, 1H, J = 19.6 Hz, J = 4.8 Hz pyrazole, 4-H ), 3.94-4.23 (m, 3H, containing pyrazole,
1 2 a
4
-H ), 5.56 (dd, 1H, J = 12.0 Hz, J = 4.8 Hz pyrazole, 5-H), 7.18-7.24 (m, 2H), 7.26-7.37
b 1 2
(
m, 5H), 7.58-7.62 (m, 1H), 7.69-7.72 (m, 1H), 8.59 (1H, s, C -H); Anal. calcd for:
4
C H N O : C, 73.18; H, 7.24; N, 9.14%. Found: C, 73.51; H, 7.00; N, 9.41%.
28
33
3
3
1
3j: 3-{3-phenyl-1-[2-(pyrrolidin-1-yl)acetyl]-4,5-dihydro-1H-pyrazol-5-yl}-2H-
o
1
chromen-2-one, colorless crystals, yield, 59%; mp 211~212 C; H NMR (400 MHz,
CDCl ) δ (ppm): 1.84-1.84 (m, 4H), 2.78-2.84 (m, 4H), 3.42 (dd, 1H, J = 19.2 Hz, J = 4.8
3
1
2
Hz pyrazole, 4-H ), 3.85-4.01 (m, 3H, containing pyrazole, 4-H ), 5.59 (dd, 1H, J = 12.0
a
b
1
Hz, J = 4.8 Hz pyrazole, 5-H), 7.19-7.24 (m, 3H), 7.26-7.37 (m, 4H), 7.57-7.66 (m, 2H),
2
8
7
1
5
.46 (1H, s, C -H); Anal. calcd for: C H N O : C, 71.80; H, 5.77; N, 10.47%. Found: C,
4
24 23
3
3
2.17; H, 6.09; N, 10.65%.
3l: 3-{1-[2-(2-methylpiperidin-1-yl)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-
o
1
-yl}- 2H-chromen-2-one, colorless crystals, yield, 57%; mp 212~213 C; H NMR (400
MHz, CDCl ) δ (ppm): 1.22-1.25 (m, 3H), 1.37-1.40 (m, 1H), 1.57-1.76 (m, 4H), 2.70-3.20
3
(
m, 4H), 3.41-3.47 (m, 1H, pyrazole, 4-H ), 3.67-4.27 (m, 3H, containing pyrazole, 4-H ),
a
b
5
5
.57 (dd, 1H, J = 12.0 Hz, J = 4.8 Hz pyrazole, 5-H), 7.19-7.22 (m, 2H), 7.25-7.37 (m,
1 2
H), 7.57-7.69 (m, 2H), 8.52 (1H, s, C -H); Anal. calcd for: C H N O : C, 72.71; H, 6.34;
4
26 27
3
3
N, 9.78%. Found: C, 72.40; H, 6.61; N, 10.11%.
1
3m: 3-{1-[2-(3-methylpiperidin-1-yl)acetyl]-3-phenyl-4,5-dihydro-1H-pyrazol-
o
13
5
-yl}-2H-chromen-2-one, colorless crystals, yield, 50%; mp 218~219 C; C NMR
(
CDCl , 125 MHz): δ 19.5, 24.8, 24.9, 30.6, 32.0, 44.2, 53.7, 58.8, 60.9, 61.2, 116.7, 118.8,
3
1
25.2, 125.7, 128.0, 129.0, 129.2, 133.2, 141.1, 141.9, 152.1, 154.3, 159.3, 166.1; Anal.
calcd for: C H N O : C, 72.71; H, 6.34; N, 9.78%. Found: C, 72.89; H, 6.20; N, 9.54%.
2
6
27
3
3
1
3n: 3-{1-[2-(3,5-dimethylpiperidin-1-yl)acetyl]-3-phenyl-4,5-dihydro-1H-