Synthesis and antifungal evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase

Article abstract of DOI:10.1016/j.ejmech.2010.07.002

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted- 2-propanols (1a-v, 2a-w), which are analogues of fluconazole, have been designed and synthesized as the potential antifungal agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3-triazolyl linked triazole antifungal derivatives 1a-v, 2a-w was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl group was inserted into the side chain of the target molecule which can increase the antifungal activity of compounds.

Full text of DOI:10.1016/j.ejmech.2010.07.002

European Journal of Medicinal Chemistry 45 (2010) 4435e4445
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antifungal evaluation of novel triazole derivatives as inhibitors
of cytochrome P450 14 -demethylase
a
Shichong Yu 1, Xiaoyun Chai 1, Honggang Hu, Yongzheng Yan, Zhongjun Guan, Yan Zou, Qingyan Sun,
*
Qiuye Wu
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1aev, 2aew),
which are analogues of fluconazole, have been designed and synthesized as the potential antifungal
agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3-
triazolyl linked triazole antifungal derivatives 1aev, 2aew was achieved by Cu(I)-catalyzed 1,3-dipolar
cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl
group was inserted into the side chain of the target molecule which can increase the antifungal activity of
compounds.
Received 12 March 2010
Received in revised form
29 June 2010
Accepted 2 July 2010
Available online 3 August 2010
Keywords:
Triazole
Ó 2010 Elsevier Masson SAS. All rights reserved.
Synthesis
Click reaction
Antifungal activity
CYP51
1. Introduction
ergosterol, through a mechanism in which the heterocyclic
nitrogen atom (N-4 of triazole) binds to the heme iron atom.
However, the increasing administration of these antifungal agents
has led to the development of fungal resistance. Survey reveals
genetic mutations that result in resistance to clinically used drugs,
especially to fluconazole, may also result in resistance to new
structurally related azoles such as voriconazole and ravuconazole
[11e13]. The emergence of resistance shows the necessity of
discovering new antifungal agents with broader antifungal spectra,
low toxicity, and higher therapeutic indexes. This report describes
the design, synthesis and biological evaluation of a series of triazole
derivatives that show promising antifungal properties.
In recent years, life-threatening systemic fungal infections have
become increasingly common in the immunocompromised hosts
suffering from cancer, AIDS, and other diseases, or in organ-trans-
plant patients [1,2]. Currently, there are three major clinical fungal
infections caused by Candidosis, aspergillosis, and cryptococcosis,
respectively [3,4]. Several clinical drugs, including azoles such as
fluconazole, voriconazole and itraconazole (Fig. 1) [5], polyenes
such as amphotericin B [6], echinocandins such as caspofungin [7]
and micafungin [8], and allylamines such as naftifine [9] and ter-
binafine [10], have been developed to reduce the impact of fungal
diseases. Among those antifungal drugs, azoles, especially triazole
agents such as fluconazole, voriconazole and itraconazole, are
proved to be more effective and thus are more widely used for the
treatment of invasive fungal infections. These antigugal drugs act
by inhibiting CYP51, a necessary enzyme in the biosynthesis of
It has been demonstrated that triazole antifungal drugs act
through inhibiting cytochrome P450 14
a-demethylase (CYP51), an
enzyme involved in ergosterol biosynthesis, and that their func-
tional mechanism is to have the N-4 of triazole interacting with the
heme iron atom of CYP51 [14]. This binding pattern was further
verified by our 3D computer modeling of the interaction between
fluconazole and CYP51 of Candida albicans [15], as shown in Fig. 2.
In addition, the difluorophenyl group of fluconazole is located in
the hydrophobic cleft interacting with Gla114, Phe126, Leu139,
Met140, Phe145, Ile304, Met306 and Gly307. Several residues,
including Leu121, Thr122, Phe228, Thr311, Pro375, Leu376, His377,
Ser378, Met508, Val509 and Val510 of CYP51, were further
observed to form nonbonding interactions with the other triazolyl
Abbreviations: C. alb., C. albicans; C. neo., C. neoformans; A. fum., A. fumigatus;
T. rub., T. rubrum; C. tro., C. tropicalis; C. par., C. parapsilosis; C. kef., C. kefyr; ICZ,
itraconazole; TRB, terbinafine; KCZ, ketoconazole; AMB, amphotericin B; VCZ,
voriconazole; FCZ, fluconazole.
* Corresponding author. Tel./fax: þ86 21 81871225.
E-mail address: wuqy6439@sohu.com (Q. Wu).
Shichong Yu and Xiaoyun Chai contributed equally to this work.
1
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.002

4436
S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
Fig. 1. Triazole antifungal agents used in clinical therapy.
ring [16]. These results, as well as literature structureeactivity
relationship studies [17], indicate that the triazole ring, the
difluorophenyl group, the hydroxyl group, and potentially another
heterocyclic group are important pharmacophores of this type of
antifungal drugs. Moreover, the side chain located in the narrow
hydrophobic cleft is also important.
After the key intermediate 6 was prepared by a reported proce-
dure [16], the title compound 7 was obtained by ring-open
reaction of oxirane 6 with isopropylamine or cyclopropylamine.
Then, compound 7 was transformed into 8 by reacting with
propargyl bromide in the presence of KI and K2CO3 in acetonitrile.
Synthesis of all the target triazole antifungal derivatives 1aev,
2aew was achieved using Cu(I)-catalyzed sharpless click chem-
Based on the above-discussed results and discoveries, we have
designed
a
series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluor-
istry [18] approach from propargylated intermediate 8 and
ophenyl)-3-substituted-2-propanols (1, 2 Fig. 3) as fluconazole
analogues that contain a triazole ring, a difluorophenyl group,
a hydroxyl group, and a side chain with another triazole group.
While these compounds contain all the essential pharmacophores,
the introduction of an additional triazole group was expected to
enhance the interaction between these molecules and CYP51 to
potentially result in systemic antifungal compounds that are less
possible to develop drug resistance. Moreover, we systematically
altered the side chain structure, which is oriented to interact with
the narrow hydrophobic cleft, to explore how it may further affect
the antifungal activity.
substituted azidomethyl benzene. The addition of Cu(I) catalyst
strongly activates terminal acetylenes toward 1,3-dipole in
organic azides, exclusively forming the 1,4-disubstituted regio-
isomer.
3. Pharmacology
The in vitro antifungal activities of all the target compounds
were evaluated against eight human pathogenic fungi, Candida
albican SC5314 and Y0109, Cryptococcus neoformans, Candida para-
psilosis, Candida tropicalis, Trichophyton rubrum, Candida kefyr, and
Aspergillus fumigatus, which are frequently encountered in clinic.
The results were compared with positive controls itraconazole,
terbinafine, ketoconazole, amphotericin B, voriconazole and flu-
conazole. C. albican SC5314 and C. neoformans, purchased from
ATCC, were provided by Shanghai Changzheng Hospital;
2. Chemistry
Compounds 1aev, 2aew were synthesized according to an
efficient route based on click reaction, as outlined in Scheme 1.
Fig. 2. Computed fluconazole binding to the heme iron atom at the active site of CYP51.

S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
4437
Fig. 3. Generic structure of the designed fluconazole analogues.
C. parapsilosis, C. albican Y0109, C. tropicalis, T. rubrum, C. kefyr and
A. fumigatus, which are clinic isolates, were provided by Shanghai
Changhai Hospital. Fluconazole, itraconazole, ketoconazole, vor-
iconazole, amphotericin B and terbinafine served as the positive
control were obtained from their respective manufacturers.
inoculated and incubated at 35 ꢀC. Growth MIC was determined at
24 h for C. albican and at 72 h for C. neoformans. The results of assays
are summarized in Table 1. These data are the mean of three
replicate tests performed with each antifungal agent.
The in vitro minimal inhibitory concentrations (MICs) of the title
compounds were determined by the micro-broth dilution method
in 96-well microtestplates according to the methods defined by the
National Committee for Clinical Laboratory Standards (NCCLS) [19].
The MIC80 was defined as the first well with an approximate 80%
reduction in growth compared to the growth of the drug-free well.
For assays, the title compounds to be tested were dissolved in
dimethyl sulfoxide (DMSO), serially diluted in growth medium,
4. Results and discussion
In our approach to synthesize title compounds, we have per-
formed click reaction to connect the key intermediate 8 con-
taining terminal alkynyl and the substituted azidomethyl
benzene in the presence of Cu(I)-catalyst in dimethyl sulfoxide
(DMSO) at room temperature to form the title compounds in
good yields.
Scheme 1. Synthesis of the target compounds 1aev, 2aew. Conditions: (a) ClCH2COCl, AlCl3, 50 ꢀC, 5 h, 80%; (b) 1H-1,2,4-triazole, NaHCO3, toluene, reflux, 5 h, 42%; (c) (CH3)3SOI,
NaOH, centylmethylammonium bromide, toluene, 60 ꢀC, 3 h, 53%; (d) CH3SO3H, 0 ꢀC, 1 h, 89%; (e) Et3N, isopropylamine or cyclopropylamine, EtOH, reflux, 6 h, 80%; (f) propargyl
bromide, KI, K2CO3, CH3CN, rt, 5e6 h, 70%; (g) NaN3, substituted benzyl bromide or alkyl bromide, DMSO, CuSO4$5H2O, sodium ascorbate, rt, 12 h, 60e70%.

4438
S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
Table 1
Antifungal activities of the target compounds in vitro.
Compound no.
MICa
(mg/mL)
C. alb SC5314
C. alb Y0109
C. neo
T. nru
C. tro
C. pra
C. kef
A. fum
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
<0.125
<0.125
0.25
<0.125
<0.125
<0.125
<0.125
0.25
<0.125
1
<0.125
<0.125
<0.125
0.25
<0.125
1
<0.125
4
0.0039
<0.125
<0.125
<0.125
0.5
<0.125
1
<0.125
1
0.25
0.25
0.0156
0.25
0.0625
0.5
<0.125
16
4
0.0156
0.0156
0.25
0.0039
0.0156
0.0625
0.0156
1
0.0625
0.0625
0.0625
0.0625
0.0039
0.0156
0.0625
0.0156
0.0039
0.0156
<0.125
0.25
0.0625
0.0625
0.0625
0.0625
0.25
2
4
8
16
32
4
1
1
8
8
32
32
16
64
64
16
8
0.25
0.25
4
2
4
2
<0.125
0.0156
4
2
8
2
4
8
16
0.5
0.25
0.5
0.0625
1
2
0.5
<0.125
<0.125
1
1
2
0.5
<0.125
0.25
1
0.25
2
4
1
1
16
<0.125
<0.125
0.25
0.0156
2
0.5
<0.125
0.5
<0.125
1
<0.125
4
0.5
2
4
0.5
4
<0.125
<0.125
4
4
0.25
1
1
4
4
2
16
0.25
1
<0.0625
<0.125
<0.125
0.25
<0.125
<0.125
<0.125
<0.125
2
<0.125
2
0.5
<0.125
0.0625
1
0.25
1
1
2
2
16
<0.125
<0.125
0.25
0.0156
1
1
0.25
0.25
<0.125
2
<0.125
4
2
2
0.25
1
0.0625
0.0625
0.25
0.25
0.25
>64
>64
>64
>64
>64
>64
16
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
64
0.25
0.0156
0.0039
0.25
1
0.0625
0.25
0.25
1
0.25
0.25
0.0625
0.25
0.0156
0.25
0.25
8
1s
1t
0.0625
32
16
2
1u
1v
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
0.25
8
1
0.0156
0.0156
0.0625
0.0156
0.0156
0.0156
0.0625
0.0625
0.0156
0.25
0.0156
0.0156
0.0625
0.0156
0.0039
1
1
1
0.25
0.25
1
0.25
0.25
>64
16
4
64
16
64
0.25
16
0.0625
2
1
64
64
16
64
64
64
64
1
4
32
2
0.125
8
0.5
4
<0.125
8
<0.125
4
0.25
8
2
2
0.25
1
0.0625
0.0156
0.25
16
0.0156
0.0156
0.0156
0.0156
0.0156
0.0625
0.0625
0.25
4
1
<0.125
<0.125
4
8
1
2
4
4
4
4
0.25
0.5
1
0.0625
<0.125
<0.125
0.125
<0.125
2
<0.125
<0.125
4
0.25
0.5
2
4
4
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
<0.125
0.25
4
1
4
16
4
0.0625
0.0625
0.25
<0.125
0.0625
0.0625
0.0625
2
<0.125
4
<0.125
0.5
2s
2t
1
2
4
4
2u
2v
2w
ICZ
TBR
KCZ
AMB
VCZ
FCZ
0.0625
<0.125
4
<0.0625
16
<0.125
8
32
<0.125
2
0.0625
<0.125
<0.125
1
0.0625
0.0625
0.0625
0.25
0.0039
1
2
0.25
0.125
32
<0.125
>64
0.25
<0.125
0.5
a
Minimum inhibitory concentration for 80% inhibition of growth.
The results of Table 1 clearly show that the in vitro antifungal
activities of all the target compounds 1aev, 2aew were active
against nearly all fungi tested, except for A. fumigatus. Among the
compounds tested, 1d, 1h, 1m, 1q, 1s, 2h, 2i, 2j, 2k and 2o showed
higher activity against C. albican SC5314, C. albican Y0109, C. par-
apsilosis and C. kefyr than FCZ. Most of the target compounds
exhibited higher activities against C. albican SC5314 and C. albican
Y0109 than all six positive controls. Especially, the MIC values of
compounds 1d, 1m and 1q were 128 times lower than that of FCZ
against C. albican Y0109, and the MIC value of compound 1s was
128 times lower than that of FCZ against C. albican SC5314. The
MIC values of compounds 2h, 2i, 2j, 2k and 2l were 32 times lower
than that of FCZ against C. albican Y0109, and the MIC value of
compound 2o was 256 times lower than that of FCZ against
C. kefyr.
To explain the results, a likely binding mode of 2h in the active
site of CYP51 is proposed based on computational docking results
(Fig. 4). As usual, the N(4) atom of the 1,2,4-triazole moiety of 2h
coordinates with the heme Fe-atom, while the 2,4-difluorophenyl
group in the designed compound could be placed into the hydro-
phobic pocket formed by Phe126, Phe145, Met306, Gly307. The
hydroxyl group and the vicinal His310 which is a highly conserved
residue in the CYP51 family have been found to form a hydrogen
bond. The 1,2,3-triazole group in the side chain would generate pep
stacking interactions with the Tyr118. Finally, the substituted benzyl
could interact with a hydrophobic pocket formed by Ala114, Phe126,
Gln142 and Phe145. In addition, the side chains were the pharma-
cophores, and the spatial orientations of the pharmacophores were
just oriented in the hydrophobic pocket. The side chains of inhibi-
tors were not the determinants for activity, but were very important.

S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
4439
Fig. 4. Computed binding geometry of the new inhibitor 2h in the active site of CYP51.
5. Conclusion
lowest energy conformation was selected. All the other parameters
were default value.
In conclusion, the current endeavor enables a practical, reliable
and efficient synthesis of a series of 1-(1H-1,2,4-triazole-1-yl)-2-
(2,4-difluorophenyl)-3-substituted-2-propanols as analogues of
fluconazole by ‘click chemistry’ approach. Their antifungal activi-
ties were screened for eight human pathogenic fungi. Biological
evaluations of the target compounds 1aev, 2aew showed that
they had strong antifungal activities against nearly all the fungi
tested, except for A. fumigatus and C. neoformans. The antifungal
activities of compounds 1aev are just the same as compounds
2aew. The 1,2,3-triazole group was inserted into the side chain of
the target molecule which can increase the antifungal activity of
compounds. The obtained results indicated that for antifungal
activity of these novel triazole derivatives it is very helpful to
introduce the 1,2,3-triazole group and the substituted benzyl as
Melting points were measured on a Yamato MP-21 melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 unless otherwise indicated with a Bruker AC-
300P spectrometer or a Bruker Avance II 600 spectrometer, using
TMS as internal standard. ESI mass spectra were performed on an
API-3000 LCeMS spectrometer. The solvents and reagents were
purchased from commercial vendors and were used either as
received or dried prior to use as needed.
6.1. 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-
isopropylamino-2-propanol (7)
A
mixture of compound 6 (33.3 g, 0.10 mol), CH3CH2OH
(500 mL) and Et3N (50 mL), isopropylamine (9.0 g, 0.15 mol) was
stirred and refluxed for 6 h. The reaction was monitored by TLC.
After filtration, the filtrate was evaporated under reduced pressure.
Water was added to the residue, extracted with ethylacetate twice,
combinate the organic layer, washed with saturated NaCl solution
twice, dried over anhydrous Na2SO4 and evaporated to get
side chains to generate a
pep stacking interactions with the
Tyr118 and interact with a hydrophobic pocket. The research has
led to the discovery of
optimization.
a series of compounds for further
compound 7 (22.5 g, 80%). 1H NMR (600 MHz, CDCl3)
d: 8.07 (1H, s,
6. Experimental part
triazole-H), 7.77 (1H, s, triazole-H), 6.73e7.53 (3H, m, Ar-H),
4.35e4.51 (2H, d, J ¼ 14.0 Hz, triazole-CH2e), 2.83e3.06 (2H, d,
J ¼ 14.0 Hz, CH2), 2.59e2.62 (1H, m, CH), 0.81e0.88 (6H, d,
In our studies, we constructed a 3D model of C. albicans CYP51
on the basis of Ji et al. [17]. All the molecular modeling calculations
were performed using SYBYL 6.9 version. And the structures of the
compounds were assigned with Gasteiger-Hückle partial atomic
charges. Energy minimization was performed using the Tripos force
field, Powell optimization method, and MAXIMIN2 minimizer with
a convergence criterion 0.001 kcal/mol Å. Simulated annealing was
then performed. The system was heated to 1000 K for 1.0 ps and
then annealed to 250 K for 1.5 ps. The annealing function was
exponential; 50 such cycles of annealing were run and the resulting
50 conformers were optimized using methods described above. The
J ¼ 6.8 Hz, 2 ꢁ CH3); 13C NMR(150 MHz, CDCl3)
d: 160.2, 158.3, 151.2,
144.2, 131.5, 129.6, 110.2, 104.3, 68.9, 61.9, 57.4, 48.5, 23.5; MS (ESI)
m/z calcd. for C14H18F2N4O 296.1, found [M ꢂ H]þ 296.5.
6.2. 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(N-
isopropyl-N-propargyl amino)-2-propanol (8)
A mixture of compound 7 (2.96 g, 0.01 mol), propargyl bromide
(2.36 g, 0.02 mol), KI (166 mg, 0.001 mol), K2CO3 (3.45 g,

4440
S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
0.025 mol) and CH3CN (100 mL) was stirred at room temperature
for 6 h. The reaction was monitored by TLC. After reaction, filtrated
off the solid, washed with CH3CN, the filtrate was concentrated in
52.37, 49.17, 48.04, 37.66, 20.77, 20.34. MS (ESI) m/z calcd. for
C24H26F3N7O 485.2, found [M ꢂ H]þ 484.7.
a
vacuum. Column chromatography of the residue afforded
compound 8 as a white solid (2.0 g, 61%). 1H NMR (600 MHz, CDCl3)
: 8.05 (1H, s, triazole-H), 7.72 (1H, s, triazole-H), 6.77e7.51 (3H, m,
6.4.3. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-fluorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1c)
d
Ar-H), 4.30e4.51 (2H, d, J ¼ 14.0 Hz, triazole-CH2e), 3.11e3.20 (2H,
d, J ¼ 14.0 Hz, CH2), 2.81e3.02 (2H, d, J ¼ 14.0 Hz, CH2), 2.65 (1H, s,
CH), 2.45e2.57 (1H, m, CH), 0.80e0.88 (6H, d, J ¼ 6.8 Hz, 2 ꢁ CH3);
Mp: 119.3e120.7 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.09 (1H, s,
triazole-H), 7.79 (1H, s, triazole-H), 7.54e7.58 (1H, m, Ar-H),
7.23e7.29 (3H, m, Ar-H), 7.03e7.11 (3H, m, Ar-H, triazole-H),
6.74e6.82 (3H, m, Ar-H), 5.49 (2H, s, Ar-CH2e), 4.52 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 4.36 (1H, d, J ¼ 14.1 Hz, triazole-CH2e),
3.41e3.54 (2H, m, triazole-CH2e), 3.13 (1H, d, J ¼ 14.4 Hz, CH2), 2.73
(1H, d, J ¼ 14.1 Hz, CH2), 2.56e2.60 (1H, m, CH), 0.84e0.87 (6H, m,
13C NMR(150 MHz, CDCl3)
d: 160.0, 158.1, 151.5, 144.7, 131.4, 129.2,
110.1, 104.5, 78.2, 73.9, 68.4, 61.5, 57.3, 48.1, 44.5, 23.2; MS (ESI) m/z
calcd. for C14H18F2N4O 334.2, found [M ꢂ H]þ 334.6.
The
propylamine-2-propanol
difluorophenyl)-3-(N-cyclopropyl-N-propargyl
1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-cyclo-
and
1-(1H-1,2,4-triazole-1-yl)-2-(2,4-
amino)-2-propanol
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 163.06, 162.34, 157.65,
156.45, 150.41, 143.48, 140.22, 126.08, 122.51, 113.07, 111.41, 109.47,
103.33, 72.52, 60.33, 59.47, 57.72, 55.38, 52.14, 49.00, 47.79, 36.61,
20.50, 20.38. MS (ESI) m/z calcd. for C24H26F3N7O 485.2, found
[M ꢂ H]þ 484.7.
were synthesized by the same procedure as the above respectively.
6.3. General procedure for the target compound 1a
6.4.4. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2-chlorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1d)
A mixture of NaN3 (100 mg, 1.4 mmol), 2-fluorobenzyl bromide
(200 mg, 1.2 mmol) and DMSO (15 mL) was stirred at room
temperature for 6 h. Then added the compound 7 (200 mg,
0.6 mmol), sodium ascorbate (20 mg), CuSO4$5H2O (25 mg), H2O
(1 mL), were stirred at room temperature for 2 h, then put the
reaction solution into NH3$H2O, extracted with ethylacetate, the
organic layer was acidificated with dilute hydrochloric acid, then
the aqueous layer was adjusted to pH about 7 by saturation sodium
bicarbonate, extracted with ethylacetate, washed with water, dried
with Na2SO4 concentrated in a vacuum to afford compound 1a
(189 mg, 65%).
Mp: 104.2e105.1 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.12 (1H, s,
triazole-H), 7.77 (1H, s, triazole-H), 7.51e7.56 (1H, m, Ar-H),
7.43e7.46 (1H, m, Ar-H), 7.15e7.36 (4H, m, Ar-H, triazole-H),
6.71e6.81 (2H, m, Ar-H), 5.64 (2H, s, Ar-CH2e), 4.50 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 3.40 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
3.54 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.42 (1H, d, J ¼ 14.7 Hz,
triazole-CH2e), 3.13 (1H, d, J ¼ 14.1 Hz, CH2), 2.76 (1H, d,
J ¼ 14.1 Hz, CH2), 2.60e2.66 (1H, m, CH), 0.84e0.88 (6H, m,
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.17, 160.79, 157.32,
The target compounds 1bev and 2aew were synthesized by
same procedure as the compound 1a.
156.33, 150.08, 145.27, 141.08, 124.69, 122.54, 113.10, 112.09, 109.52,
103.79, 72.82, 60.64, 59.28, 58.71, 55.27, 52.18, 50.15, 47.63, 36.14,
20.79, 20.54. MS (ESI) m/z calcd. for C24H26ClF2N7O 501.2, found
[M ꢂ H]þ 500.7.
6.4. The title compounds were characterized as follows
6.4.1. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2-fluorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1a)
6.4.5. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(3-chlorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1e)
Mp: 94.5e95.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.09 (1H, s,
Mp: 106.5e107.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.08 (1H, s,
triazole-H), 7.77 (1H, s, triazole-H), 7.53e7.59 (1H, m, triazole-H),
6.72e7.38 (7H, m, Ar-H), 5.57 (2H, s, Ar-CH2e), 4.47 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 4.43 (1H, d, J ¼ 14.1 Hz, triazole-CH2e),
3.53 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.41 (1H, d, J ¼ 14.1 Hz,
triazole-CH2e), 2.83 (1H, d, J ¼ 14.1 Hz, CH2), 2.75 (1H, d,
J ¼ 13.8 Hz, CH2), 2.59e2.61 (1H, m, CH), 0.83e0.92 (6H, m,
triazole-H), 7.78 (1H, s, triazole-H), 7.34e7.60 (1H, m, Ar-H),
7.18e7.32 (4H, m, Ar-H), 7.01 (1H, s, triazole-H), 6.75e6.81 (2H, m,
Ar-H), 5.50 (2H, s, Ar-CH2e), 4.53 (1H, d, J ¼ 14.1 Hz, triazole-
CH2e), 4.36 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.42e3.55 (2H, m,
triazole-CH2e), 3.14 (1H, d, J ¼ 14.4 Hz, CH2), 2.73 (1H, d,
J ¼ 14.1 Hz, CH2), 2.53e2.62 (1H, m, CH), 0.82e0.95 (6H, m,
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 163.32, 161.58, 159.60, 157.96,
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.19, 160.82, 157.30,
150.74, 143.48, 140.40, 126.10, 122.20, 115.88, 111.06, 108.52, 103.78,
72.26, 60.10, 59.89, 58.52, 56.34, 53.04, 49.01, 48.67, 37.64, 20.97,
20.76. MS (ESI) m/z calcd. for C24H26F3N7O 485.2, found [M ꢂ H]þ
484.7.
156.21, 150.01, 145.45, 141.21, 124.54, 122.68, 113.10, 112.11, 109.52,
103.68, 72.87, 60.25, 59.39, 58.71, 55.68, 52.20, 50.26, 47.41, 36.03,
20.65, 20.59. MS (ESI) m/z calcd. for C24H26ClF2N7O 501.2, found
[M ꢂ H]þ 500.7.
6.4.2. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(3-fluorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1b)
6.4.6. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-chlorobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1f)
Mp: 78.5e79.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d
: 8.08 (1H, s,
Mp: 105.9e107.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.07 (1H, s,
triazole-H), 7.78 (1H, s, triazole-H), 7.54e7.60 (1H, m, Ar-H),
7.32e7.39 (1H, m, Ar-H), 6.74e7.09 (6H, m, Ar-H, triazole-H), 5.52
(2H, s, Ar-CH2e), 4.52 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.37 (1H,
d, J ¼ 14.1 Hz, triazole-CH2e), 3.52 (1H, d, J ¼ 14.8 Hz, triazole-
CH2e), 3.47 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 3.14 (1H, d,
J ¼ 14.1 Hz, CH2), 2.73 (1H, d, J ¼ 14.1 Hz, CH2), 2.55e2.60 (1H, m,
triazole-H), 7.78 (1H, s, triazole-H), 7.55e7.59 (1H, m, Ar-H),
7.20e7.23 (4H, dd, J ¼ 6.3 Hz, Ar-H), 7.12 (1H, s, triazole-H),
6.73e6.82 (2H, m, Ar-H), 5.50 (2H, s, Ar-CH2e), 4.53 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 4.38 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
3.43e3.55 (2H, m, triazole-CH2e), 3.13 (1H, d, J ¼ 14.1 Hz, CH2),
3.13 (1H, d, J ¼ 14.1 Hz, CH2), 2.56e2.60 (1H, m, CH), 0.84e0.88
CH), 0.84e0.92 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d:
(6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 163.16, 161.57,
162.76, 161.50, 158.63, 157.45, 150.43, 143.45, 140.31, 126.14, 122.67,
114.54, 111.87, 109.15, 103.08, 72.66, 60.25, 59.57, 58.52, 55.68,
158.53, 157.05, 150.83, 143.05, 140.11, 126.14, 121.67, 114.34, 111.86,
109.13, 103.68, 72.16, 60.35, 59.52, 58.12, 55.28, 52.57, 49.11, 48.07,

S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
4441
37.16, 21.37, 20.44. MS (ESI) m/z calcd. for C24H26ClF2N7O 501.2,
found [M ꢂ H]þ 500.7.
47.18, 36.10, 20.94, 20.78, 20.17. MS (ESI) m/z calcd. for C25H29F2N7O
481.2, found [M ꢂ H]þ 480.6.
6.4.7. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2-bromobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1g)
6.4.11. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1k)
Mp: 101.9e103.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d
: 8.14 (1H,
Mp: 126.3e127.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.12e8.16
s, triazole-H), 7.77 (1H, s, triazole-H), 7.53e7.64 (1H, m, Ar-H),
7.15e7.35 (4H, m, Ar-H, triazole-H), 6.72e6.81 (2H, m, Ar-H),
5.65 (2H, s, Ar-CH2e), 4.51 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
4.44 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 3.60 (1H, d, J ¼ 14.7 Hz,
triazole-CH2e), 3.54 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.18
(1H, d, J ¼ 13.8 Hz, CH2), 2.76 (1H, d, J ¼ 14.1 Hz, CH2),
2.04e2.40 (1H, m, CH), 0.85e0.98 (6H, m, 2 ꢁ CH3); 13C NMR
(1H, m, Ar-H), 8.10 (1H, s, triazole-H), 7.79 (1H, s, triazole-H),
7.36e7.66 (3H, m, Ar-H), 7.35 (1H, s, triazole-H), 6.76e7.19 (3H, m,
Ar-H), 5.90 (2H, s, Ar-CH2e), 4.56 (1H, s, OH), 4.54 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 4.40 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 3.56 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 3.47 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 3.15 (1H, d, J ¼ 1.9 Hz, CH2), 2.78 (1H,
d, J ¼ 14.1 Hz, CH2), 2.58e2.67 (1H, m, CH), 0.84e0.89 (6H, m,
(75 MHz, CDCl3)
d
: 162.20, 160.82, 157.40, 156.52, 150.14, 14530,
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 163.44, 161.78, 159.75,
141.08, 124.52, 122.43, 113.18, 112.04, 109.40, 103.63, 72.71,
60.57, 59.28, 58.57, 55.17 52.24 50.20, 47.52, 36.19, 20.58, 20.54.
MS (ESI) m/z calcd. for C24H26BrF2N7O 545.1, found [M ꢂ H]þ
544.7.
158.11, 148.03, 144.14, 141.67, 129.75, 128.43, 126.24, 124.25,
122.66, 111.41, 104.20, 72.45, 65.75, 58.74, 56.43, 55.21, 52.97,
49.33, 37.90, 21.12, 20.56. MS (ESI) m/z calcd. for C24H26F2N8O3
512.2, found [M ꢂ H]þ 511.6.
6.4.8. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(3-bromobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1h)
6.4.12. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(3-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1l)
Mp: 105.3e107.2 ꢀC; 1H NMR (300 MHz, CDCl3)
d
: 8.08 (1H, s,
Mp: 113.1e114.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.21e8.25
triazole-H), 7.79 (1H, s, triazole-H), 7.48e7.58 (3H, m, Ar-H),
7.17e7.28 (2H, m, Ar-H), 7.01 (1H, s, triazole-H), 6.75e6.81 (2H, m,
Ar-H), 5.50 (2H, s, Ar-CH2e), 4.53 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 4.36 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.47e3.55 (2H, m,
triazole-CH2e), 3.13 (1H, d, J ¼ 14.1 Hz, CH2), 2.73 (1H, d,
J ¼ 14.1 Hz, CH2), 2.55e2.59 (1H, m, CH), 0.84e0.88 (6H, m,
(2H, m, Ar-H), 8.07 (1H, s, triazole-H), 7.80 (1H, s, triazole-H),
7.56e7.63 (3H, m, Ar-H), 7.11 (1H, s, triazole-H), 6.76e6.83 (2H, m,
Ar-H), 5.65 (2H, s, Ar-CH2e), 5.45 (1H, s, OH), 4.56 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 4.34 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
3.47e3.52 (2H, m, triazole-CH2e), 3.16 (1H, d, J ¼ 14.1 Hz, CH2),
2.71 (1H, d, J ¼ 14.4 Hz, CH2), 2.52e2.56 (1H, m, CH), 0.85e0.88
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.14, 160.74, 157.45,
(6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.16, 160.64,
156.29, 150.04, 145.19, 141.15, 124.61, 122.48, 113.21, 112.11, 109.47,
103.65, 72.63, 60.58, 59.22, 58.52, 55.17, 52.14, 50.18, 47.63, 36.26,
20.62, 20.50. MS (ESI) m/z calcd. for C24H26BrF2N7O 545.1, found
[M ꢂ H]þ 544.7.
157.03, 156.42, 150.15, 145.05, 141.16, 124.60, 122.53, 113.23, 112.08,
109.65, 103.48, 72.81, 60.25, 59.12, 58.56, 55.18, 52.06, 50.23, 47.68,
36.26, 20.80, 20.59. MS (ESI) m/z calcd. for C24H26F2N8O3 512.2,
found [M ꢂ H]þ 511.7.
6.4.9. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-bromobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1i)
6.4.13. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1m)
Mp: 120.5e122.0 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.08 (1H, s,
Mp: 134.1e135.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.10e8.15 (2H,
triazole-H), 7.79 (1H, s, triazole-H), 7.53e7.56 (1H, m, Ar-H),
7.13e7.52 (4H, dd, Ar-H), 7.03 (1H, s, triazole-H), 6.75e6.79 (2H, m,
Ar-H), 5.51 (1H, s, OH), 5.48 (2H, s, Ar-CH2e), 4.53 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 4.36 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
3.11e3.48 (2H, m, triazole-CH2e), 3.13 (1H, d, J ¼ 14.1 Hz, CH2), 2.73
(1H, d, J ¼ 14.1 Hz, CH2), 2.50e2.59 (1H, m, CH), 0.84e0.88 (6H, m,
d, Ar-H), 8.08 (1H, s, triazole-H), 7.79 (1H, s, triazole-H), 7.56e7.64
(1H, m, Ar-H), 7.39e7.42 (2H, d, Ar-H), 7.08 (1H, s, triazole-H),
6.77e6.83 (2H, m, Ar-H), 5.66 (2H, s, Ar-CH2e), 5.43 (1H, s, OH),
4.57 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 4.35 (1H, d, J ¼ 14.1 Hz,
triazole-CH2e), 3.47e3.52 (2H, m, triazole-CH2e), 3.16 (1H, d,
J ¼ 14.1 Hz, CH2), 3.16 (1H, d, J ¼ 14.1 Hz, CH2), 2.52e2.56 (1H, m,
2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 163.20, 160.57, 157.46,156.42,
CH), 0.85e0.88 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d:
150.15, 145.27, 141.17, 124.45, 122.68, 113.10, 112.24, 109.01, 103.57,
72.38, 60.46, 59.18, 58.45, 55.16, 52.18, 50.21, 47.82, 36.24, 20.53,
20.49. MS (ESI) m/z calcd. for C24H26BrF2N7O 545.1, found [M ꢂ H]þ
544.6.
163.26, 161.70, 158.64, 157.65, 150.43, 142.45, 141.31, 126.16, 122.17,
114.547, 111.86, 109.95, 103.28, 72.46, 60.21, 59.51, 58.51, 55.18,
52.37, 49.12, 48.05, 37.76, 21.34, 20.79. MS (ESI) m/z calcd. for
C24H26F2N8O3 512.2, found [M ꢂ H]þ 511.7.
6.4.10. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-methylbenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1j)
6.4.14. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2-cyanobenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1n)
Mp: 133.5e135.2 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.08 (1H, s,
Mp: 116.1e117.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.10 (1H, s,
triazole-H), 7.77 (1H, s, triazole-H), 7.52e7.57 (1H, m, Ar-H),
7.14e7.20 (4H, m, Ar-H), 7.03 (1H, s, triazole-H), 6.69e6.80 (2H, m,
Ar-H), 5.57 (1H, s, OH), 5.46 (2H, s, Ar-CH2e), 4.48 (1H, d,
J ¼ 13.8 Hz, triazole-CH2e), 4.37 (1H, d, J ¼ 14.1 Hz, triazole-CH2e),
3.38e3.54 (2H, m, triazole-CH2e), 3.11 (1H, d, J ¼ 14.1 Hz, CH2), 2.74
(1H, d, J ¼ 14.1 Hz, CH2), 2.58e2.62 (1H, m, CH), 2.36 (3H, s, CH3),
triazole-H), 7.80 (1H, s, triazole-H), 7.42e7.77 (5H, m, Ar-H), 7.34
(1H, s, triazole-H), 6.76e6.82 (2H, m, Ar-H), 5.72 (2H, s, Ar-CH2e),
5.50 (1H, s, OH), 4.52 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 4.38 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 3.54 (1H, d, J ¼ 14.1 Hz, triazole-CH2e),
3.43 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.13 (1H, d, J ¼ 14.4 Hz,
CH2), 2.75 (1H, d, J ¼ 14.1 Hz, CH2), 2.58e2.63 (1H, m, CH),
0.83e0.87 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.87,
0.83e0.88 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 162.15,
160.74, 157.09, 156.12, 151.07, 145.45, 141.39, 124.59, 122.02, 113.79,
112.12,109.05,103.48, 73.12, 60.23, 59.52, 58.09, 55.48, 52.14, 50.65,
160.87, 157.46, 156.52, 150.16, 145.28, 141.20, 124.80, 122.65, 113.48,
112.24, 109.51, 103.16, 72.23, 60.72, 59.06, 58.69, 55.18, 52.26, 50.16,

4442
S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
47.35, 36.15, 21.68, 20.52. MS (ESI) m/z calcd. for C25H26F2N8O 492.2,
found [M ꢂ H]þ 491.7.
6.4.19. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2,6-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1s)
6.4.15. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(3-cyanobenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1o)
Mp: 109.2e111.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.18 (1H, s,
triazole-H), 7.81 (1H, s, triazole-H), 7.31e7.58 (3H, m, Ar-H), 7.18
(1H, s, triazole-H), 6.76e6.87 (2H, m, Ar-H), 5.83 (2H, s, Ar-CH2e),
4.62 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 4.48 (1H, d, J ¼ 14.1 Hz,
triazole-CH2e), 3.00e3.26 (2H, m, triazole-CH2e), 2.80e2.95 (2H,
m, CH2), 2.57e2.60 (1H, m, CH), 0.83e0.90 (6H, m, 2 ꢁ CH3); 13C
Mp: 117.8e118.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.07 (1H, s,
triazole-H), 7.80 (1H, s, triazole-H), 7.50e7.53 (4H, m, Ar-H), 7.07
(1H, s, triazole-H), 6.77e6.83 (2H, m, Ar-H), 5.58 (2H, s, Ar-CH2e),
5.44 (1H, s, OH), 4.55 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 4.35 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 3.50 (2H, s, triazole-CH2e), 3.16 (1H, d,
J ¼ 14.4 Hz, CH2), 2.70 (1H, d, J ¼ 14.1 Hz, CH2), 2.51e2.56 (1H, m,
NMR (75 MHz, CDCl3)
d: 163.16, 161.30, 157.63, 157.45, 150.63,
143.46, 140.31, 126.34, 122.77, 114.94, 111.67, 109.95, 103.06, 72.65,
60.25, 59.57, 58.55, 55.67, 52.47, 49.14, 48.54, 37.67, 20.72, 20.54. MS
(ESI) m/z calcd. for C24H25Cl2F2N7O 535.2, found [M ꢂ H]þ 534.9.
CH), 0.86e0.88 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d:
163.76, 161.52, 158.13, 157.75, 150.44, 143.65, 140.21, 126.54, 122.77,
114.84, 111.88, 109.95, 103.09, 72.46, 60.22, 59.57, 58.55, 55.63,
52.34, 49.87, 48.05, 37.26, 20.57, 20.35. MS (ESI) m/z calcd. for
C25H26F2N8O 492.2, found [M ꢂ H]þ 491.7.
6.4.20. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-tertbutylbenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1t)
Mp: 119.5e120.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.09 (1H, s,
6.4.16. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-cyanobenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1p)
triazole-H), 7.77(1H, s, triazole-H), 7.49e7.58(1H, m, Ar-H), 7.18e7.41
(4H, dd, J ¼ 8.1 Hz, Ar-H), 7.04 (1H, s, triazole-H), 6.68e6.80 (2H, m,
Ar-H), 5.58 (1H, s, OH), 5.47 (2H, s, Ar-CH2e), 4.51 (1H, d, J ¼ 14.1 Hz,
triazole-CH2e), 4.37 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 3.38e3.54
(2H, m, triazole-CH2e), 3.12 (1H, d, J ¼ 14.1 Hz, CH2), 2.74 (1H, d,
J ¼ 14.1 Hz, CH2), 2.59e2.64 (1H, m, CH), 1.29e1.33 (9H, m, 3 ꢁ CH3),
Mp: 75.1e76.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.06 (1H, s,
triazole-H), 7.77 (1H, s, triazole-H), 7.67e7.70 (2H, d, Ar-H),
7.55e7.66 (1H, m, Ar-H), 7.32e7.35 (2H, d, Ar-H), 7.06 (1H, s, tri-
azole-H), 6.76e6.82 (2H, m, Ar-H), 5.60 (2H, s, Ar-CH2e), 5.44 (1H, s,
OH), 4.55 (1H, d, J ¼ 14.1 Hz, triazole-CH2e), 4.34 (1H, d, J ¼ 14.1 Hz,
triazole-CH2e), 3.45e3.52 (2H, m, triazole-CH2e), 3.16 (1H, d,
J ¼ 14.1 Hz, CH2), 2.70 (1H, d, J ¼ 14.1 Hz, CH2), 2.51e2.55 (1H, m,
0.83e0.87 (6H, m, 2 ꢁ CH3); 13C NMR(75 MHz, CDCl3)
d: 162.74,
160.58, 157.35, 156.46, 151.36, 145.54, 141.31, 124.49, 121.11, 113.43,
112.64, 109.50, 103.72, 73.23, 61.12, 59.23, 57.78, 55.04, 52.27, 50.12,
47.33, 36.45, 33.25, 22.87, 22.70, 20.61, 20.49. MS (ESI) m/z calcd. for
C28H35F2N7O 523.3, found [M ꢂ H]þ 522.8.
CH), 0.85e0.90 (6H, m, 2 ꢁ CH3); 13C NMR(75 MHz, CDCl3)
d:
162.83, 161.10, 158.65, 157.35, 150.42, 143.41, 140.37, 126.12, 122.47,
114.64, 111.84, 109.17, 103.05, 72.64, 60.25, 59.37, 58.22, 55.68,
52.34, 49.15, 48.54, 37.76, 20.78, 20.31. MS (ESI) m/z calcd. for
C25H26F2N8O 492.2, found [M ꢂ H]þ 491.6.
6.4.21. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-cyclohexyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1u)
Mp: 84.1e85.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.13 (1H, s, tri-
6.4.17. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amino}-2-
propanol (1q)
azole-H), 7.77 (1H, s, triazole-H), 7.58e7.76 (1H, m, Ar-H), 7.21 (1H, s,
triazole-H), 6.76e6.84 (2H, m, Ar-H), 5.76 (1H, s, OH), 4.41e4.54 (2H,
m, triazole-CH2e), 4.38e4.39 (1H, m, triazole-CHe), 3.57 (1H, d,
J ¼ 14.4 Hz, triazole-CH2), 3.43 (1H, d, J ¼ 14.7 Hz, triazole-CH2), 3.13
(1H, d, J ¼ 13.8 Hz, CH2), 2.67 (1H, d, J ¼ 13.2 Hz, CH2), 2.65e2.69 (1H,
Mp: 100.1e102.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.08 (1H, s,
triazole-H), 7.75 (1H, s, triazole-H), 7.39e7.55 (1H, m, Ar-H),
7.37e7.40 (3H, m, Ar-H), 7.24e7.26 (2H, m, Ar-H), 7.05 (1H, s, tri-
azole-H), 6.73e6.80 (2H, m, Ar-H), 5.52 (2H, s, Ar-CH2e), 4.49 (1H,
d, J ¼ 14.1 Hz, triazole-CH2e), 4.37 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 3.47e3.54 (2H, m, triazole-CH2e), 3.12 (1H, d, J ¼ 12.9 Hz,
CH2), 2.74 (1H, d, J ¼ 14.1 Hz, CH2), 2.58e2.62 (1H, m, CH),
m, CH),1.26e2.22 (10H, m, 5 ꢁ CH2), 0.83e0.88 (6H, m, 2 ꢁ CH3); 13
C
NMR (75 MHz, CDCl3) d: 163.47,160.25,156.29,141.28,124.37,121.10,
113.44, 109.55, 73.20, 61.17, 59.28, 57.70, 55.06, 52.18, 50.26, 47.44,
36.95, 35.26, 34.17, 24.63, 23.58, 20.65, 20.43. MS (ESI) m/z calcd. for
C23H31F2N7O 459.3, found [M ꢂ H]þ 458.7.
0.83e0.88 (6H, m, 2 ꢁ CH3); 13C NMR (75 MHz, CDCl3)
d: 164.06,
161.30, 158.63, 157.75, 150.33, 143.25, 140.32, 126.24, 122.57, 114.14,
111.83, 109.17, 103.28, 72.67, 60.21, 59.55, 58.42, 55.38, 52.31, 49.27,
48.05, 37.66, 20.76, 20.34. MS (ESI) m/z calcd. for C24H27F2N7O
467.2, found [M ꢂ H]þ 466.8.
6.4.22. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(4-hexadecyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1v)
Mp: 73.4e74.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.11 (1H, s, tri-
azole-H), 7.78 (1H, s, triazole-H), 7.56e7.64 (1H, m, Ar-H), 7.14 (1H,
s, triazole-H), 6.76e6.84 (2H, m, Ar-H), 5.65 (1H, s, OH), 4.39e4.57
(2H, m, triazole-CH2e), 4.28e4.33 (2H, m, triazole-CH-), 3.41e3.58
(2H, m, triazole-CH2), 2.63e3.16 (2H, m, CH2), 2.60e2.65 (1H, m,
6.4.18. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
isopropyl-N-[(1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (1r)
Mp: 119.5e120.9 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.10 (1H, s,
CH), 1.00e1.90 (28H, m, 14 ꢁ CH2), 0.84e0.98 (9H, m, 3 ꢁ CH3); 13
C
triazole-H), 7.79 (1H, s, triazole-H), 7.54e7.62 (1H, m, Ar-H),
7.46e7.48 (1H, m, Ar-H), 7.12e7.28 (3H, m, Ar-H), 6.74e6.83 (2H,
m, Ar-H), 5.60 (2H, s, Ar-CH2e), 4.53 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 4.38 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.45e3.56 (2H, m,
triazole-CH2e), 3.13 (1H, d, J ¼ 14.1 Hz, CH2), 2.75 (1H, d,
J ¼ 14.1 Hz, CH2), 2.57e2.61 (1H, m, CH), 0.84e0.90 (6H, m,
NMR (75 MHz, CDCl3) d: 160.21, 158.32, 151.52, 143.82, 131.31,
130.73, 129.43, 122.59, 110.84, 104.45, 67.77, 65.57, 64.70, 55.67,
52.74, 40.73, 29.30, 29.24, 29.22, 28.67, 28.63, 26.12, 26.01, 24.23,
24.23, 23.12, 23.12, 22.45, 22.10, 21.12, 20.14 19.18,14.15. MS (ESI) m/
z calcd. for C33H53F2N7O 601.4, found [M ꢂ H]þ 600.8.
2 ꢁ CH3); 13C NMR(75 MHz, CDCl3)
d
: 162.06, 161.30, 158.53,
6.4.23. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N- [(1-(2-fluorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2a)
157.44, 150.43, 143.35, 140.33, 126.12, 122.65, 114.56, 111.86, 109.25,
103.28, 72.76, 60.35, 59.58, 58.32, 55.67, 52.39, 49.37, 48.05, 37.46,
20.77, 20.32. MS (ESI) m/z calcd. for C24H25Cl2F2N7O 535.2, found
[M ꢂ H]þ 534.9.
Mp: 71.0e72.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.08 (1H, s,
triazole-H), 7.79 (1H, s, triazole-H), 7.44e7.52 (1H, m, Ar-H),

S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
4443
7.05e7.37 (5H, m, Ar-H, triazole-H), 6.64e6.74 (2H, m, Ar-H), 5.56
(2H, s, Ar-CH2e), 4.45e4.58 (2H, m, triazole-CH2e), 3.70 (1H, d,
J ¼ 14.7 Hz, triazole-CH2e), 3.58 (1H, d, J ¼ 14.1 Hz, triazole-CH2e),
3.34 (1H, d, J ¼ 13.8 Hz, CH2), 2.87 (1H, d, J ¼ 13.8 Hz, CH2),
1.98e2.15 (1H, m, NCH), 0.15e0.41 (4H, m, 2*CH2); 13C NMR
(150 MHz, CDCl3) d: 162.46, 160.18, 157.68, 156.53, 150.87, 145.19,
141.48, 124.29, 122.26, 113.11, 112.30, 109.68, 103.57, 72.61, 60.68,
59.35, 58.64, 55.30, 52.54, 50.24, 47.62, 36.16, 20.27, 20.41. MS (ESI)
m/z calcd. for C24H24ClF2N7O 499.2, found [M ꢂ H]þ 498.6.
(75 MHz, CDCl3)
d
: 162.06, 160.48, 157.20, 156.18, 150.64, 145.05,
6.4.28. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-chlorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2f)
141.18, 124.89, 122.44, 113.31, 112.02, 109.68, 103.99, 72.62, 60.64,
59.26, 58.48, 55.52, 52.38, 50.19, 47.48, 36.12, 21.80, 21.59. MS (ESI)
m/z calcd. for C24H24F3N7O 483.2, found [M ꢂ H]þ 482.6.
Mp: 105.2e107.6 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.13 (1H, s,
triazole-H), 7.78 (1H, s, triazole-H), 7.44e7.53 (1H, m, Ar-H),
7.13e7.30 (4H, m, Ar-H), 7.06 (1H, s, triazole-H), 6.62e6.74 (2H, m,
Ar-H), 5.43 (2H, s, Ar-CH2e), 4.38e4.49 (2H, m, triazole-CH2e), 3.70
(1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.50 (1H, d, J ¼ 14.7 Hz, triazole-
CH2e), 3.33 (1H, d, J ¼ 14.4 Hz, CH2), 2.90 (1H, d, J ¼ 14.4 Hz, CH2),
1.93e2.00 (1H, m, NCH), 0.13e0.34 (4H, m, 2 ꢁ CH2); 13C NMR
6.4.24. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N- [(1-(3-fluorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2b)
Mp: 75.6e77.7 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.10 (1H, s, tri-
azole-H), 7.72 (1H, s, triazole-H), 6.88e7.52 (6H, m, Ar-H, triazole-
H), 6.65e6.77 (2H, m, Ar-H), 5.47 (2H, m, Ar-CH2e), 5.15 (1H, s, OH),
4.44e4.50 (2H, m, triazole-CH2e), 3.70 (1H, d, J ¼ 14.7 Hz, triazole-
CH2e), 3.51 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.40 (1H, d,
J ¼ 14.1 Hz, CH2), 2.87 (1H, d, J ¼ 14.1 Hz, CH2), 1.99e2.01 (1H, m,
(75 MHz, CDCl3) d: 163.04, 162.50, 158.65, 157.35, 150.23, 143.75,
140.21, 126.13, 122.57, 114.53, 111.83, 109.13, 103.68, 72.56, 60.23,
59.52, 58.54, 55.28, 52.34, 49.15, 48.03, 37.64, 20.77, 20.32. MS (ESI)
m/z calcd. for C24H24ClF2N7O 499.2, found [M ꢂ H]þ 498.6.
NCH), 0.15e0.35 (4H, m, 2 ꢁ CH2); 13C NMR (75 MHz, CDCl3)
d:
162.31, 160.86, 157.16, 156.25, 150.18, 145.35, 141.24, 124.46, 122.62,
113.53, 112.14, 109.62, 103.24, 72.58, 60.68, 59.54, 58.49, 55.84,
52.15, 50.26, 47.37, 36.20, 20.81, 20.16. MS (ESI) m/z calcd. for
C24H24F3N7O 483.2, found [M ꢂ H]þ 482.6.
6.4.29. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2-bromobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2g)
Mp: 117.2e119.5 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.25 (1H, s,
triazole-H), 7.85 (1H, s, triazole-H), 7.62e7.64 (1H, m, Ar-H),
7.22e7.45 (5H, m, Ar-H, triazole-H), 6.81e6.88 (2H, m, Ar-H),
5.56e5.63 (2H, m, Ar-CH2e), 4.56e4.62 (2H, m, triazole-CH2e),
3.88 (1H, d, J ¼ 15.0 Hz, triazole-CH2e), 3.69 (1H, d, J ¼ 14.4 Hz,
triazole-CH2e), 3.50 (1H, d, J ¼ 13.8 Hz, CH2), 3.06 (1H, d,
J ¼ 13.8 Hz, CH2), 2.13e2.15 (1H, m, NCH), 0.29e0.48 (4H, m,
6.4.25. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-fluorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2c)
Mp: 95.3e97.5 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.07 (1H, s,
triazole-H), 7.68 (1H, s, triazole-H), 7.47e7.48 (1H, m, Ar-H),
7.18e7.20 (2H, m, Ar-H), 7.04 (1H, s, triazole-H), 7.00e7.01 (2H, m,
Ar-H), 6.64e6.72 (2H, m, Ar-H), 5.41 (2H, dd, J ¼ 25.8 Hz, 15.0 Hz,
Ar-CH2e), 5.15 (1H, s, OH), 4.42 (2H, dd, J ¼ 24.0 Hz, 14.4 Hz, tri-
azole-CH2e), 3.49e3.70 (2H, dd, J ¼ 15.0 Hz, triazole-CH2e),
2.87e3.34 (2H, dd, J ¼ 14.4 Hz, CH2), 1.95e1.97 (1H, m, NCH),
2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 163.26, 161.53, 158.65,
157.15, 150.45, 143.45, 140.41, 126.12, 122.67, 114.64, 111.27, 109.16,
103.28, 72.61, 60.27, 59.51, 58.55, 55.68, 52.36, 49.11, 48.03, 37.61,
20.57, 20.31. MS (ESI) m/z calcd. for C24H24BrF2N7O 543.1, found
[M ꢂ H]þ 542.6.
0.12e0.30 (4H, m, 2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 163.36,
161.52, 158.64, 157.44, 150.23, 143.65, 140.71, 126.15, 122.63, 114.54,
111.86, 109.13, 103.48, 72.26, 60.25, 59.67, 58.32, 55.68, 52.47, 49.67,
48.05, 37.66, 20.67, 20.36. MS (ESI) m/z calcd. for C24H24F3N7O
483.2, found [M ꢂ H]þ 482.8.
6.4.30. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(3-bromobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2h)
Mp: 92.8e94.6 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.12 (1H, s,
triazole-H), 7.75 (1H, s, triazole-H), 7.19e7.53 (5H, m, Ar-H), 7.11
(1H, s, triazole-H), 6.69e6.81 (2H, m, Ar-H), 5.48 (2H, dd,
J ¼ 18.6 Hz, 15.0 Hz, Ar-CH2e), 5.16 (1H, s, OH), 4.52 (1H, d,
J ¼ 14.1 Hz, triazole-CH2e), 4.45 (1H, d, J ¼ 14.4 Hz, triazole-CH2e),
3.76 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.56 (1H, d, J ¼ 14.7 Hz,
triazole-CH2e), 3.39 (1H, d, J ¼ 14.1 Hz, CH2), 2.95 (1H, d,
J ¼ 14.1 Hz, CH2), 2.01e2.06 (1H, m, NCH), 0.19e0.39 (4H, m,
6.4.26. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2-chlorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2d)
Mp: 124.1e126.8 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.11 (1H, s,
triazole-H), 7.15 (1H, s, triazole-H), 7.14e7.51 (6H, m, Ar-H, triazole-
H), 6.67e6.77 (2H, m, Ar-H), 5.60 (2H, s, Ar-CH2e), 4.45e4.50 (2H,
m, triazole-CH2e), 3.72 (1H, d, J ¼ 15.0 Hz, triazole-CH2e), 3.50 (1H,
d, J ¼ 15.0 Hz, triazole-CH2e), 3.36 (1H, d, J ¼ 13.8 Hz, CH2), 2.90
(1H, d, J ¼ 14.4 Hz, CH2), 2.00e2.16 (1H, m, NCH), 0.15e0.43 (4H, m,
2 ꢁ CH2); 13C NMR(75 MHz, CDCl3)
d: 162.03, 161.10, 153.65, 157.35,
150.45, 143.41, 140.37, 126.12, 122.47, 114.74, 111.84, 109.17, 103.05,
72.62, 60.25, 59.37, 58.42, 55.68, 52.14, 49.15, 48.54, 37.56, 20.78,
20.31. MS (ESI) m/z calcd. for C24H24BrF2N7O 543.1, found [M ꢂ H]þ
542.6.
2 ꢁ CH2); 13C NMR (75 MHz, CDCl3)
d: 164.06, 161.50, 158.63, 157.45,
150.43, 143.45, 140.31, 126.14, 122.67, 114.54, 111.87, 109.15, 103.08,
72.66, 60.25, 59.57, 58.52, 55.68, 52.37, 49.17, 48.04, 37.66, 21.77,
21.34. MS (ESI) m/z calcd. for C24H24ClF2N7O 499.2, found [M ꢂ H]þ
498.6.
6.4.31. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-bromobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2i)
6.4.27. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N- [(1-(3-chlorobe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2e)
Mp: 121.3e122.5 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.09 (1H, s,
triazole-H), 7.72 (1H, s, triazole-H), 7.47e7.53 (3H, m, Ar-H),
7.09e7.10 (23H, m, Ar-H), 7.05 (1H, s, triazole-H), 6.66e6.76 (2H, m,
Ar-H), 5.40e5.47 (2H, m, Ar-CH2e), 5.16 (1H, s, OH), 4.42e4.51 (2H,
m, triazole-CH2e), 3.72 (1H, d, J ¼ 15.0 Hz, triazole-CH2e), 3.53 (1H,
d, J ¼ 15.0 Hz, triazole-CH2e), 3.35 (1H, d, J ¼ 13.8 Hz, CH2), 2.90
(1H, d, J ¼ 13.8 Hz, CH2), 2.01e2.06 (1H, m, NCH), 0.19e0.39 (4H, m,
Mp: 104.4e106.7 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.22 (1H, s,
triazole-H), 7.79 (1H, s, triazole-H), 7.22e7.66 (6H, m, Ar-H, tri-
azole-H), 6.67e6.71 (2H, m, Ar-H), 5.62e5.68 (2H, dd, J ¼ 15.6 Hz,
Ar-CH2e), 4.42e4.47 (2H, m, triazole-CH2e), 3.48e3.69 (2H, dd,
J ¼ 14.4 Hz, triazole-CH2e), 2.85e3.35 (2H, dd, J ¼ 13.8 Hz, CH2),
2.15e2.16 (1H, m, NCH), 0.12e0.31 (4H, m, 2 ꢁ CH2); 13C NMR
2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 164.46, 161.52, 158.13,
157.75, 150.44, 143.65, 140.21, 126.54, 122.77, 114.84, 111.78, 109.95,

4444
S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
103.09, 72.46, 50.22, 59.57, 58.55, 55.63, 52.34, 49.87, 49.03, 37.26,
21.57, 21.25. MS (ESI) m/z calcd. for C24H24BrF2N7O 543.1, found
[M ꢂ H]þ 542.8.
21.30, 20.98. MS (ESI) m/z calcd. for C24H24F2N8O3 510.2, found
[M ꢂ H]þ 509.8.
6.4.36. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(3-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2n)
6.4.32. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2-methylbe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2j)
Mp: 102.6e104.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.12e8.15
Mp: 112.5e114.0 ꢀC; 1H NMR (300 MHz, CDCl3)
d
: 8.12 (1H, s,
(2H, m, Ar-H), 8.11 (1H, s, triazole-H), 7.66 (1H, s, triazole-H),
7.21e7.52 (4H, m, Ar-H, triazole-H), 6.63e6.72 (2H, m, Ar-H), 5.58
(2H, s, Ar-CH2e), 5.07 (1H, s, OH), 4.45 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 4.38 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.70 (1H, d,
J ¼ 14.7 Hz, triazole-CH2e), 3.52 (1H, d, J ¼ 14.7 Hz, triazole-CH2e),
3.37 (1H, d, J ¼ 14.7 Hz, CH2), 2.86 (1H, d, J ¼ 14.1 Hz, CH2),
1.93e1.96 (1H, m, NCH), 0.06e0.29 (4H, m, 2 ꢁ CH2); 13C NMR
triazole-H), 7.74 (1H, s, triazole-H), 7.14e7.57 (5H, m, Ar-H), 6.86
(1H, s, triazole-H), 6.56e6.79 (2H, m, Ar-H), 5.55 (1H, d,
J ¼ 14.7 Hz, Ar-CH2e), 5.46 (1H, d, J ¼ 15.0 Hz, Ar-CH2e), 5.20
(1H, s, OH), 4.46e4.47 (2H, m, triazole-CH2e), 3.73 (1H, d,
J ¼ 14.7 Hz, triazole-CH2e), 3.48 (1H, d, J ¼ 14.7 Hz, triazole-
CH2e), 3.35 (1H, d, J ¼ 13.8 Hz, CH2), 2.91 (1H, d, J ¼ 13.8 Hz, CH2),
2.25 (1H, s, CH3), 2.07e2.10 (1H, m, NCH), 0.18e0.39 (4H, m,
(75 MHz, CDCl3) d: 162.16, 161.57, 158.53, 157.05, 150.83, 144.05,
2 ꢁ CH2); 13C NMR(75 MHz, CDCl3)
d
: 163.07, 160.54, 157.21,
140.11, 126.14, 121.67, 114.34, 111.73, 109.13, 103.68, 72.16, 60.35,
59.52, 54.12, 55.28, 52.57, 49.11, 47.07, 37.16, 21.37, 20.64. MS (ESI)
m/z calcd. for C24H24F2N8O3 510.2, found [M ꢂ H]þ 509.8.
156.34, 151.31, 145.68, 141.50, 124.54, 121.98, 113.44, 112.54,
109.57, 103.35, 73.18, 60.29, 59.67, 57.93, 55.41, 52.18, 50.45,
47.28, 36.16, 20.77, 20.59, 20.21. MS (ESI) m/z calcd. for
C25H27F2N7O 479.2, found [M ꢂ H]þ 478.6.
6.4.37. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2o)
6.4.33. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(3-methylbe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2k)
Mp: 114.3e116.1 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.22 (2H, d,
J ¼ 8.4 Hz, Ar-H), 8.10 (1H, s, triazole-H), 7.77 (1H, s, triazole-H),
7.53e7.55 (1H, m, Ar-H), 7.38 (2H, d, J ¼ 8.4 Hz, Ar-H), 7.17 (1H, s,
triazole-H), 6.72e6.80 (2H, m, Ar-H), 5.63 (2H, s, Ar-CH2e),
4.44e4.53 (2H, m, triazole-CH2e), 3.77 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 3.59 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.40 (1H, d,
J ¼ 13.8 Hz, CH2), 2.93 (1H, d, J ¼ 13.8 Hz, CH2), 2.00e2.01 (1H, m,
Mp: 97.5e98.7 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.07 (1H, s,
triazole-H), 7.68 (1H, s, triazole-H), 7.44e7.48 (1H, m, Ar-H),
7.08e7.25 (5H, m, Ar-H), 6.54e6.68 (2H, m, Ar-H), 5.40e5.50 (2H,
m, Ar-CH2e), 4.41e4.42 (2H, m, triazole-CH2e), 3.68 (1H, d,
J ¼ 15.0 Hz, triazole-CH2e), 3.45 (1H, d, J ¼ 15.0 Hz, triazole-CH2e),
3.29 (1H, d, J ¼ 13.8 Hz, CH2), 2.87 (1H, d, J ¼ 13.8 Hz, CH2), 2.20 (1H,
s, CH3), 2.00e2.03 (1H, m, NCH), 0.12e0.32 (4H, m, 2 ꢁ CH2); 13C
NCH), 0.15e0.38 (4H, m, 2 ꢁ CH2); 13C NMR(150 MHz, CDCl3)
d:
163.04, 161.30, 158.63, 157.75, 150.33, 143.25, 140.32, 126.24, 122.57,
114.14, 111.83, 108.17, 103.28, 72.37, 60.21, 59.55, 58.42, 55.38, 52.31,
49.27, 48.05, 37.66, 20.76, 20.33. MS (ESI) m/z calcd. for
C24H24F2N8O3 510.2, found [M ꢂ H]þ 509.8.
NMR (150 MHz, CDCl3) d: 163.14, 160.45, 157.65, 156.73, 151.57,
145.82, 141.50, 124.37, 121.98, 113.41, 112.54, 109.46, 103.77, 73.45,
60.23, 59.45, 57.86, 55.54, 52.24, 50.19, 47.33, 36.52, 20.82, 20.76,
20.25. MS (ESI) m/z calcd. for C25H27F2N7O 479.2, found [M ꢂ H]þ
478.8.
6.4.38. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2-cyanoben-zyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2p)
6.4.34. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-methylbe-nzyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2l)
Mp: 89.5.3e91.7 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.12 (1H, s,
triazole-H), 7.71 (1H, s, triazole-H), 7.46e7.50 (1H, m, Ar-H), 7.39
(1H, s, triazole-H), 7.06e7.21 (4H, m, Ar-H), 6.66e6.73 (2H, m, Ar-
H), 5.51e5.57 (2H, m, Ar-CH2e), 5.14 (1H, s, OH), 4.41e4.47 (2H, m,
triazole-CH2e), 3.70 (1H, d, J ¼ 15.0 Hz, triazole-CH2e), 3.52 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 3.33 (1H, d, J ¼ 13.8 Hz, CH2), 2.89
(1H, d, J ¼ 13.8 Hz, CH2), 1.96e1.98 (1H, m, NCH), 0.14e0.33 (4H, m,
Mp: 93.6e95.8 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.13 (1H, s,
triazole-H), 7.74 (1H, s, triazole-H), 7.48e7.57 (1H, m, Ar-H),
7.03e7.22 (3H, m, Ar-H), 7.01 (1H, s, triazole-H), 6.63e6.79 (2H, m,
Ar-H), 5.40e5.52 (2H, m, Ar-CH2e), 5.26 (1H, s, OH), 4.47e4.54
(2H, m, triazole-CH2e), 3.74 (1H, d, J ¼ 15.0 Hz, triazole-CH2e), 3.52
(1H, d, J ¼ 14.70 Hz, triazole-CH2e), 3.38 (1H, d, J ¼ 15.0 Hz, CH2),
2.92 (1H, d, J ¼ 13.8 Hz, CH2), 2.36 (1H, s, CH3), 2.02e2.07 (1H, m,
2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 164.04, 162.50, 158.65,
157.35, 150.23, 143.75, 140.21, 126.13, 122.58, 114.53, 111.83, 109.33,
103.68, 72.56, 60.23, 59.52, 58.54, 55.28, 52.34, 49.15, 48.03, 37.64,
20.95, 20.12. MS (ESI) m/z calcd. for C25H24F2N8O 490.2, found
[M ꢂ H]þ 489.7.
NCH), 0.18e0.39 (4H, m, 2 ꢁ CH2); 13C NMR(75 MHz, CDCl3)
d:
163.44, 160.71, 157.23, 156.54, 151.57, 145.69, 141.38, 124.52, 121.14,
113.55, 112.62, 109.59, 103.73, 73.25, 60.28, 59.42, 57.86, 55.04,
52.27, 50.12, 47.43, 36.45, 20.87, 20.70, 20.21. MS (ESI) m/z calcd. for
C25H27F2N7O 479.2, found [M ꢂ H]þ 478.7.
6.4.39. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(3-cyanoben-zyl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2q)
6.4.35. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2-nitrobenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2m)
Mp: 97.5e98.8 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.05 (1H, s,
triazole-H), 7.67 (1H, s, triazole-H), 7.40e7.59 (5H, m, Ar-H), 7.15
(1H, s, triazole-H), 6.6e6.73 (2H, m, Ar-H), 5.50 (2H, s, Ar-CH2e),
5.06 (1H, s, OH), 4.36e4.47 (2H, m, triazole-CH2e), 3.70 (1H, d,
J ¼ 14.7 Hz, triazole-CH2e), 3.50 (1H, d, J ¼ 14.7 Hz, triazole-CH2e),
3.33 (1H, d, J ¼ 14.4 Hz, CH2), 2.87 (1H, d, J ¼ 14.1 Hz, CH2),
1.98e2.00 (1H, m, NCH), 0.15e0.36 (4H, m, 2 ꢁ CH2); 13C NMR
Mp: 105.3e107.8 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.05e8.10
(2H, m, Ar-H, triazole-H), 7.67 (1H, s, triazole-H), 7.43e7.61 (4H, m,
Ar-H), 7.36 (1H, s, triazole-H), 7.03e7.08 (1H, m, Ar-H), 6.66e6.73
(2H, m, Ar-H), 5.84 (2H, s, Ar-CH2e), 5.14 (1H, s, OH), 4.39e4.49
(2H, m, triazole-CH2e), 3.51e3.75 (2H, m, triazole-CH2e),
2.87e3.43 (2H, m, CH2), 1.96e1.98 (1H, m, NCH), 0.27e0.32 (4H, m,
(75 MHz, CDCl3) d: 163.56, 161.52, 157.13, 157.75, 150.44, 143.65,
2 ꢁ CH2); 13C NMR (75 MHz, CDCl3)
d
: 163.64, 161.30, 158.53,
140.21, 126.54, 122.77, 114.84, 112.88, 109.95, 103.09, 72.46, 60.22,
59.67, 58.55, 55.63, 52.34, 49.87, 48.45, 37.26, 20.57, 20.37. MS (ESI)
m/z calcd. for C25H24F2N8O 490.2, found [M ꢂ H]þ 489.6.
157.44, 150.43, 143.35, 140.33, 126.12, 122.65, 114.56, 111.86, 109.25,
103.28, 72.76, 60.35, 59.58, 58.32, 55.67, 52.39, 49.37, 48.05, 37.46,

S. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 4435e4445
4445
6.4.40. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-cyanoben-zyl)-1H-1,2,3-triazol-4-yl)methyl]
6.4.44. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-pentyl-1H-1,2,3-triazol-4-yl)methyl]amino}-2-
propanol (2v)
amino}-2-propanol (2r)
Mp: 109.5e111.2 ꢀC; 1H NMR(600 MHz, CDCl3)
d
: 8.15 (1H, s,
Mp: 71.2e73.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.17 (1H, s,
triazole-H), 7.81 (1H, s, triazole-H), 7.73 (2H, d, J ¼ 8.4 Hz, Ar-H),
7.60e7.62 (1H, m, Ar-H), 7.40 (2H, d, J ¼ 8.4 Hz, Ar-H), 7.27 (1H, s,
triazole-H), 6.78e6.86 (2H, m, Ar-H), 5.66 (2H, m, Ar-CH2e), 5.18
(1H, s, OH), 4.58 (1H, d, J ¼ 13.8 Hz, triazole-CH2e), 4.53 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 3.83 (1H, d, J ¼ 15.0 Hz, triazole-CH2e),
3.66 (1H, d, J ¼ 14.4 Hz, triazole-CH2e), 3.46 (1H, d, J ¼ 14.4 Hz,
CH2), 3.01 (1H, d, J ¼ 14.4 Hz, CH2), 2.06e2.09 (1H, m, NCH),
triazole-H), 7.75 (1H, s, triazole-H), 7.55e7.61 (1H, m, Ar-H), 7.26
(1H, s, triazole-H), 6.76e6.85 (2H, m, Ar-H), 5.41 (1H, s, OH),
4.53e4.56 (2H, m, triazole-CH2e), 4.31e4.36 (2H, t, trazole-
CH*2CH2CH2CH2CH3), 3.79 (1H, d, J ¼ 14.7 Hz, triazole-CH2e),
3.62 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.43 (1H, d, J ¼ 13.8 Hz,
CH2), 3.00 (1H, d, J ¼ 14.1 Hz, CH2), 1.94e2.04 (1H, m, NCH),
1.87e1.92 (2H, m, trazole-CH2CH*2CH2CH2CH3), 1.23e1.38 (4H,
m, trazole-CH2CH2CH*2CH*2CH3), 0.88e0.92 (3H, t, trazole-
CH2CH2CH2CH2CH*3), 0.23e0.41 (4H, m, 2 ꢁ CH2); 13C NMR
0.23e0.44 (4H, m, 2 ꢁ CH2); 13C NMR(150 MHz, CDCl3)
d: 163.17,
161.30, 157.63, 157.45, 150.63, 143.56, 140.31, 126.34, 122.79, 114.94,
111.37, 109.95, 103.06, 72.64, 60.25, 59.54, 58.55, 55.67, 52.47, 49.12,
48.54, 37.67, 20.72, 20.67. MS (ESI) m/z calcd. for C25H24F2N8O
490.2, found [M ꢂ H]þ 489.7.
(75 MHz, CDCl3) d: 163.67, 161.09, 155.56, 141.24, 128.32, 121.57,
117.34, 115.20, 110.51, 74.21, 61.17, 59.37, 57.65, 55.29, 50.14,
47.44, 28.35, 24.80, 23.34, 20.39, 20.05, 14.68. MS (ESI) m/z calcd.
for C22H29F2N7O 445.2, found [M ꢂ H]þ 444.7.
6.4.41. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(2,6-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl]amino}-2-propanol (2s)
6.4.45. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-cyclohexyl-1H-1,2,3-triazol-4-yl)methyl]amino}-
2-propanol (2w)
Mp: 103.5e105.4 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.12 (1H, s,
triazole-H), 7.80 (1H, s, triazole-H), 7.16e7.50 (4H, m, Ar-H), 7.08
(1H, s, triazole-H), 6.62e6.74 (2H, m, Ar-H), 5.78 (2H, s, Ar-CH2e),
4.60 (2H, s, triazole-CH2e), 3.68 (1H, d, J ¼ 14.7 Hz, triazole-CH2e),
3.44 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.33 (1H, d, J ¼ 13.8 Hz,
CH2), 2.92 (1H, d, J ¼ 13.8 Hz, CH2), 1.93e2.02 (1H, m, NCH),
Mp: 83.4e85.5 ꢀC; 1H NMR (600 MHz, CDCl3)
d: 8.07 (1H, s,
triazole-H), 7.65 (1H, s, triazole-H), 7.45e7.49 (1H, m, Ar-H), 7.16
(1H, s, triazole-H), 6.68e6.73 (2H, m, Ar-H), 5.34 (1H, s, OH), 4.43
(2H, s, triazole-CH2e), 4.31e4.32 (1H, m, trazole-CH-), 3.68 (1H, d,
J ¼ 14.4 Hz, triazole-CH2e), 3.51 (1H, d, J ¼ 15.0, Hz, triazole-CH2e),
3.33 (1H, d, J ¼ 14.4 Hz, CH2), 2.90 (1H, d, J ¼ 13.8 Hz, CH2),
1.93e1.94 (1H, m, NCH),1.15e2.11 (10H, m, 5 ꢁ CH2), 0.13e0.30 (4H,
0.14e0.34 (4H, m, 2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 164.37,
161.52, 158.64, 157.44, 150.23, 143.65, 140.71, 126.15, 122.63, 114.54,
111.86, 109.13, 103.48, 72.26, 60.25, 59.67, 58.32, 55.68, 52.47, 49.67,
48.05, 37.66, 21.65, 21.36. MS (ESI) m/z calcd. for C24H23Cl2F2N7O
533.1, found [M ꢂ H]þ 532.8.
m, 2 ꢁ CH2); 13C NMR (150 MHz, CDCl3)
d: 165.13, 161.25, 155.20,
143.25, 124.17, 121.57, 113.34, 110.51, 74.21, 61.17, 59.37, 57.65, 55.29,
52.18, 50.14, 47.44, 36.82, 35.35, 34.28, 24.80, 23.34, 20.39, 20.05.
MS (ESI) m/z calcd. for C23H29F2N7O 457.2, found [M ꢂ H]þ 456.8.
6.4.42. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-ethylbenz-yl)-1H-1,2,3-triazol-4-yl)methyl]
amino}-2-propanol (2t)
Acknowledgment
Mp: 121.5e123.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.12 (1H, s,
This work was supported by the National Natural Science Foun-
dation of China (Nos. 20772153), the Eleventh Five Year Military
Medicine and Public Health Research Projects (Nos. 06MB206) and
by Shanghai Leading Academic Discipline Project Number: B906.
triazole-H), 7.71 (1H, s, triazole-H), 7.47e7.51 (1H, m, Ar-H),
7.12e7.28 (4H, m, Ar-H), 7.02 (1H, s, triazole-H), 6.60e6.75 (2H, m,
Ar-H), 5.48 (2H, s, Ar-CH2e), 4.44 (2H, s, triazole-CH2e), 3.72 (1H, d,
J ¼ 15.0 Hz, triazole-CH2e), 3.50 (1H, d, J ¼ 14.7 Hz, triazole-CH2e),
3.35 (1H, d, J ¼ 13.5 Hz, CH2), 2.90 (1H, d, J ¼ 13.8 Hz, CH2),
2.58e2.66 (2H, m, phCH*2CH3), 1.99e2.04 (1H, m, NCH), 1.19e1.24
(3H, m, phCH2CH*3), 0.17e0.35 (4H, m, 2 ꢁ CH2); 13C NMR (75 MHz,
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CDCl3)
d: 164.35, 161.28, 157.41, 156.67, 151.32, 145.60, 141.45,
124.22, 121.05, 113.48, 112.83, 108.97, 103.55, 73.78, 61.39, 59.32,
57.55, 55.13, 52.14, 50.26, 47.25, 36.38, 34.50, 22.35, 20.97, 20.65. MS
(ESI) m/z calcd. for C26H29F2N7O 493.2, found [M ꢂ H]þ 492.7.
6.4.43. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-
cyclopropyl-N-[(1-(4-tert-butyl-benzyl)-1H-1,2,3-triazol-4-yl)
methyl]amino}-2-propanol (2u)
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Wayne, PA, 2002.
Mp: 104.3e106.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 8.15 (1H, s,
triazole-H), 7.76 (1H, s, triazole-H), 7.52e7.58 (1H, m, Ar-H), 7.42
(2H, d, J ¼ 1.8 Hz, Ar-H), 7.20 (2H, d, J ¼ 1.8 Hz, Ar-H), 7.03 (1H, s,
triazole-H), 6.62e6.79 (2H, m, Ar-H), 5.51 (1H, d, J ¼ 14.7 Hz, Ar-
CH2e), 5.43 (1H, d, J ¼ 14.7 Hz, Ar-CH2e), 5.24 (1H, s, OH), 4.51 (1H,
d, J ¼ 14.4 Hz, triazole-CH2e), 4.45 (1H, d, J ¼ 14.4 Hz, triazole-
CH2e), 3.74 (1H, d, J ¼ 14.7 Hz, triazole-CH2e), 3.53 (1H, d,
J ¼ 14.7 Hz, triazole-CH2e), 3.38 (1H, d, J ¼ 14.1 Hz, CH2), 2.93
(1H, d, J ¼ 13.8 Hz, CH2), 2.03e2.10 (1H, m, NCH), 1.26e1.38 (9H, m,
3 ꢁ CH3), 0.19e0.39 (4H, m, 2 ꢁ CH2); 13C NMR (75 MHz, CDCl3)
d:
163.14, 160.25, 157.30, 156.29, 151.37, 145.64, 141.28, 124.37, 121.10,
113.44,112.53,109.55,103.75, 73.20, 61.17, 59.28, 57.70, 55.06, 52.18,
50.26, 47.44, 36.95, 34.39, 22.94, 22.77, 20.65, 20.43. MS (ESI) m/z
calcd. for C28H33F2N7O 521.3, found [M ꢂ H]þ 520.8.