Synthesis and evaluation of structurally constrained imidazolidin derivatives as potent dipeptidyl peptidase IV inhibitors

Article abstract of DOI:10.1016/j.ejmech.2009.03.021

To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine derivatives with constrained imidazolidin ring and tested their activities against DPP-IV. Most of them exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound among these is (S)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxoimidazolidin-1-yl)ethyl-amino)acetyl)pyrrolidine-2-carbonitrile (6n), which is a 2 nM DPP-IV inhibitor.

Full text of DOI:10.1016/j.ejmech.2009.03.021

European Journal of Medicinal Chemistry 44 (2009) 3318–3322
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and evaluation of structurally constrained imidazolidin derivatives
as potent dipeptidyl peptidase IV inhibitors
,
Liutang Wang a b, Bin Zhang b, Jianxin Ji b, Bogang Li b, Jufang Yan b, Weiyu Zhang b,
,
b,
*
Yong Wu a , Xuechao Wang
*
a West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
b Department of Research and Development, Di’ao Co. Ltd, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-
cyanopyrrolidine derivatives with constrained imidazolidin ring and tested their activities against DPP-
IV. Most of them exhibited submicromolar inhibitory activities against DPP-IV. The most potent
compound among these is (S)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxoimidazolidin-1-yl)ethyl-amino)-
acetyl)pyrrolidine-2-carbonitrile (6n), which is a 2 nM DPP-IV inhibitor.
Received 21 October 2008
Received in revised form
22 February 2009
Accepted 10 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Dipeptidyl peptidase IV inhibitors
Imidazolidin derivatives
2-Cyanopyrrolidine
Anti-diabetic agent
1. Introduction
a promising new target for drugs. In fact, a clinical investigation has
already demonstrated the benefits of DPP-IV inhibition in type II
The incretin hormone glucagon-like peptide 1(GLP-1 (7-36
amide or 7-37)) is a 30-amino acid peptide hormone produced by
L-cells of the small intestine in response to food intake [1]. GLP-1
has been shown in mammals to stimulate the secretion of insulin in
a glucose-dependent manner, inhibit glucagon release, slow gastric
emptying, induce satiety, and stimulate the regeneration and
diabetes [5]. A number of small molecule inhibitors of DPP-IV have
been described [6] and several of these, including Vildagliptin (LAF-
237) [7], Saxagliptin (BMS477118) [8], Sitagliptin (MK-0431) [9] and
Alogliptin (SYR-322) [10], Fig. 1 are in late-stage of clinical devel-
opment or approved by the U.S. Food and Drug Administration. In
our laboratory, we focused on substitutions of 2-cyanopyrrolidine,
because 2-cyanopyrrolidine derivatives are one of the most potent
inhibitors. In this paper, we reported a new series of structurally
constrained imidazolidin2-cyanopyrrolidine derivatives 6.
differentiation of islet b-cells, with all of these actions promoting
the control of glucose homeostasis in patients with type II diabetes
[2]. However, active GLP-1 is rapidly degraded to give inactive GLP-
1 (9-36 amide or 9-37) by the serine protease dipeptidyl peptidase
IV (DPP-IV) which catalyzes the cleavage of dipeptides from the
N-terminus of proteins with the preference to proline (Pro) or
alanine (Ala) as the penultimate (P1) amino acid [3]. DPP-IV is
widely distributed in mammalian tissues and body fluids, and is
found in great abundance in the kidney, liver, intestinal epithelium,
and placenta [4]. Thus, inhibition of DPP-IV could increase the half-
life of active GLP-1, lead to the persistence of circulating GLP-1
levels, and prolong the beneficial effects of this incretin hormone,
which would enhance insulin secretion and improve glucose
tolerance. Therefore much attention has been paid to DPP-IV as
2. Chemistry
The DPP-IV inhibitors were prepared as described in Scheme 1.
Amine (1) was heated with triphosgene in toluene to afford
isocyanate compound (2), then reacted with diethanolamine in
dichloromethane at room temperature to provide substituted
urea derivatives (3) in excellent yield. 3 was brominated with tri-
bromophosphine in dichloromethane under ice-water conditions
to yield the desired intermediates (4) followed to cyclize at based
conditions to obtain the key imidazolidin-2-one derivatives (5). 5
was coupled with (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile
to provide the desired 2-cyanopyrrolidine derivatives (6).
* Corresponding authors. Tel.: þ86 28 82900431; fax: þ86 28 85181150.
E-mail address: huaxiwanglt@163.com (X. Wang).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.03.021

L. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 3318–3322
3319
Table 1
OH
DPP-IV inhibitory activity.a
OH
CN
CN
O
O
H
N
N
N
N
N
N
N
H
R
NH2
vildagliptin
(LAF-237)
IC50 = 3.5 nM
O
saxagliptin
(BMS-477118)
Ki = 0.6 nM
O
O
CN
Compd
R
IC50 (nM)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
n-Butyl
53.5
68.1
47.8
68.6
34.8
29.3
82.4
65.1
25.8
44.5
60.1
133.6
20.4
2.0
F
F
tert-Butyl
Isopropyl
Cyclohexyl
Phenyl
N
F
NH2
O
H2N
N
N
O
N
p-tolyl
N
N
4-Methoxyphenyl
3-Methoxyphenyl
4-Chlorophenyl
4-Fluorophenyl
3-Fluorophenyl
N
CF3
NC
alogliptin
(SYR-322)
IC50 < 10 nM
sitagliptin
(MK-0431)
IC50 = 18 nM
2-Fluorophenyl
6m
6n
6o
LAF-237
3,5-Dimethoxyphenyl
3,4-Dimethoxyphenyl
3,4,5-Trimethoxyphenyl
165.6
16.6
Fig. 1. Structures of selected DPP-IV inhibitors.
a
Values are IC50 (nM) expressed as the mean of three independent
determinations.
3. Results and discussion
Compounds 6a–o were evaluated in vitro for their inhibition of
DPP-IV extracted from human plasma (Table 1). LAF-237 was used
as a reference compound. Among compounds 6a–e, 6e showed the
most active with an IC50 value of 34.8 nM. Changing phenyl to
cyclohexyl or tert-butyl resulted in a 2-fold decrease in potency (6e
vs. 6d; 6e vs. 6b). Changing phenyl to n-butyl or isopropyl resulted
only in a slight decrease in potency, respectively (6e vs. 6a; 6e vs.
6c). To increase the inhibitory activity, we introduced several
substituents on the phenyl ring. The influence of electron-donating
or electron-withdrawing substituents on enzyme inhibition was
investigated. The introduction of electron-donating methyl (6f) or
electron-withdrawing chloro (6i) into the 4-position of the phenyl
ring causes a slight increase in potency, respectively (6e vs. 6f; 6e
vs. 6i). However, the introduction of electron-donating methoxyl
(6g, 6h) or electron-withdrawing fluoro (6j–l) into the 2-, 3-or 4-
position of the phenyl ring causes a modest decrease in potency,
Table 2
DPP-IV inhibition and selectivity assays of 6n.
DPP-IV
2.0 nM
DPP-VII
>100
DPP-VIII
53
DPP-IX
>100 mM
m
M
m
M
respectively (6e vs. 6g–h; 6e vs. 6j–l). The introduction of two
methoxyl substituents into the phenyl ring gave generally more
active compounds. For instance, a 3,5-dimethoxyphenyl or a 3,4-
dimethoxyphenyl substituent caused a 2-fold (6e vs. 6m) or a 17-
fold (6e vs. 6n) improvement in activity, respectively. However, the
introduction of three methoxyl substituents into the phenyl ring
gave less active compounds. For instance, a 3,4,5-trimethoxyphenyl
substituent caused a 5-fold (6e vs. 6o) drop in activity. It was shown
that the optimum substituent is 3,4-dimethoxyphenyl substituent
which results in an improved, low nanomolar inhibitor (6n) with an
IC50 of 2.0 nM which is 17 times as potent as 6e.
Another criteria for DPP-IV inhibitor development are selectivity
against the closely related enzymes. There are a number of other
dipeptidyl peptidases in the body, and although the function of
most of these peptidases remains unknown at present, there is
evidence indicating that selectivity over other peptidases may be
important. We screened 6n for selectivity against DPP-VII (also
known as DPP-II and QPP) [11], DPP-VIII [12], DPP-IX [13] (Table 2)
6n displays more than 10 000-fold selectivity against these
enzymes. In addition, the specificity of 6n was profiled in over 20
receptor and enzyme assays in vitro and no significant binding was
OH
OH
Br
Br
O
O
R
i
ii
iii
R
R
NH2
R
NCO
N
H
N
N
H
N
1
2
4
3
iv
N
N
N
N
N
v
N
R
R
Br
H
CN
O
O
O
5
6
observed (10 mM).
a R= n-butyl;
i R= 4-chlorophenyl;
j R= 4-fluorophenyl;
k R= 3-fluorophenyl;
l R= 2-fluorophenyl;
b R= tert-butyl;
c R= isopropyl;
d R= cyclohexyl;
e R= phenyl;
4. Conclusions
m R= 3,5-dimethoxyphenyl;
n R= 3,4-dimethoxyphenyl;
o R= 3,4,5-trimethoxyphenyl.
In summary, we have synthesized a series of 2-cyanopyrrolidine
derivatives with constrained imidazolidin ring and evaluated their
ability to inhibit DPP-IV. All of them exhibited submicromolar
inhibitory activities against DPP-IV. The most potent compound is
6n, which is a 2 nM DPP-IV inhibitor with good selectivity over
related proline peptidases. These preliminary results suggest that
6n needs further study in next step.
f R= p-tolyl;
g R= 4-methoxyphenyl;
h R= 3-methoxyphenyl;
Scheme 1. Reagent and conditions: (i) triphosgene, toluene, heated, 4-8 h; (ii) dieth-
anolamine, CH2Cl2, rt, overnight; (iii) PBr3, CH2Cl2, 10 ꢀC, 5 h; (iv) NaHCO3, PH z 10,
overnight; (v) (S)-1-(2- aminoacetyl)pyrrolidine-2-carbonitrile, K2CO3, CH3CN, rt,
overnight.

3320
L. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 3318–3322
5. Experimental
5.2.7. 1-(2-Bromoethyl)-3-(4-methoxyphenyl)imidazolidin-2-one
(5g)
1H NMR
J ¼ 9.2 Hz); 3.81 (t, 2H, J ¼ 7.5 Hz); 3.78 (s, 3H); 3.70 (t, 2H, J ¼ 6.4);
3.62 (t, 2H, J ¼ 7.6 Hz); 3.53 (t, 2H, J ¼ 6.4 Hz). ESI-MS: 298, 300
(M þ Hþ).
5.1. General
d
(CDCl3): 7.43 (d, 2H, J ¼ 9.0 Hz); 6.88 (d, 2H,
1H NMR and 13C NMR spectra were obtained at 600 MHz on
a Bruker Avance 600 instrument using CDCl3 or DMSO-d6 as solvent
and tetramethylsilane as internal standard. Mass spectra were
measured on an Agilent 1946B ESI-MS instrument. All commer-
cially available reagents were used without purification.
5.2.8. 1-(2-Bromoethyl)-3-(3-methoxyphenyl)imidazolidin-2-one
(5h)
1H NMR
d
(CDCl3): 7.33 (t, 1H, J ¼ 2.4 Hz); 7.22 (t, 1H, J ¼ 8.0 Hz);
5.2. General procedure for the synthesis of 5
7.00 (dd, 1H, J ¼ 8.2, 2.0 Hz); 6.61 (dd, 1H, J ¼ 8.2, 2.3 Hz); 3.84 (t,
2H, J ¼ 8.4 Hz); 3.82 (s, 3H); 3.71 (t, 2H, J ¼ 6.5 Hz); 3.64 (t, 2H,
J ¼ 8.5 Hz); 3.54 (t, 2H, J ¼ 6.5 Hz). ESI-MS: 209,301 (M þ Hþ).
In toluene (200 mL), triphosgene (85 mmol) was dissolved, the
solution of 1 (100 mmol) in toluene was added in drop with ice
cooling. The temperature was gradually increased. The mixture was
stirred for an hour at room temperature, then was heated to 100 ꢀC
for 3 h. The mixture was concentrated to about 80 mL, added to the
solution of the diethanolamine (200 mmol) in CH2Cl2 (200 mL) and
continued to stir overnight. The reacting solution was diluted with
CH2Cl2, washed with brine, dried over Na2SO4 and concentrated in
vacuo to afford 2, which can be used for next reaction without
purification.
To the solution of 2 in CH2Cl2 (200 mL) was added tri-
bromophosphine (120 mmol) in drop in ice-water bath. The
mixture was stirred for 3 h at room temperature, followed to be
basified with saturated NaHCO3 solution and continued stirring
overnight. The organic phase was isolated and the aqueous layer
was extracted with CH2Cl2 two times. The combined organic phase
was washed with brine and dried over Na2SO4. Concentration was
followed by purification by chromatography using silica gel (eluting
sequentially with petroleum ether/ethyl acetate ¼ 10/1 to 3/1) to
afford 5. Rate (four steps): 15%–35%.
5.2.9. 1-(2-Bromoethyl)-3-(4-chlorophenyl)imidazolidin-2-one (5i)
1H NMR
d
(CDCl3): 7.49 (d, 2H, J ¼ 9.0 Hz); 7.29 (d, 2H,
J ¼ 8.8 Hz); 3.83 (t, 2H, J ¼ 8.4 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.66 (t,
2H, J ¼ 8.7 Hz); 3.54 (t, 2H, J ¼ 6.1 Hz). ESI-MS: 302, 304, 306
(M þ Hþ).
5.2.10. 1-(2-Bromoethyl)-3-(4-fluorophenyl)imidazolidin-2-one
(5j)
1H NMR
d (CDCl3): 7.50–7.47 (m, 2H); 7.05–7.00 (m, 2H); 3.83 (t,
2H, J ¼ 8.6 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.64 (t, 2H, J ¼ 8.4 Hz); 3.54
(t, 2H, J ¼ 6.4 Hz). ESI-MS: 287, 289 (M þ Hþ).
5.2.11. 1-(2-Bromoethyl)-3-(3-fluorophenyl)imidazolidin-2-one
(5k)
1H NMR
d
(CDCl3): 7.44 (d, 1H, J ¼ 11.8 Hz); 7.28–7.23 (m, 2H);
6.73 (t, 1H, J ¼ 8.8 Hz); 3.84 (t, 2H, J ¼ 8.0 Hz); 3.72 (t, 2H,
J ¼ 6.4 Hz); 3.66 (t, 2H, J ¼ 8.4 Hz); 3.54 (t, 2H, J ¼ 6.2 Hz). ESI-MS:
287, 289 (M þ Hþ).
5.2.1. 1-(2-Bromoethyl)-3-butylimidazolidin-2-one (5a)
5.2.12. 1-(2-Bromoethyl)-3-(2-fluorophenyl)imidazolidin-2-one
1H NMR
d
(CDCl3): 3.59 (t, 2H, J ¼ 6.4 Hz); 3.48–3.44 (m, 4H), 3.33
(5l)
(t, 2H, J ¼ 8.4 Hz); 3.19 (t, 2H, J ¼ 7.4 Hz); 1.51–1.46 (m, 2H); 1.38–
1H NMR
d
(CDCl3): 7.53(t, 1H, J ¼ 7.9 Hz); 7.18–7.08 (m, 3H); 3.89
1.30 (m, 2H); 0.93 (t, 3H, J ¼ 7.4 Hz). ESI-MS: 249, 251 (M þ Hþ).
(t, 2H, J ¼ 7.4 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.66 (t, 2H, J ¼ 7.6 Hz);
3.55 (t, 2H, J ¼ 6.4 Hz). ESI-MS: 287, 289 (M þ Hþ).
5.2.2. 1-(2-Bromoethyl)-3-tert-butylimidazolidin-2-one (5b)
1H NMR
d
(CDCl3): 3.55 (t, 2H, J ¼ 6.5 Hz); 3.46 (t, 2H, J ¼ 6.2 Hz);
5.2.13. 1-(2-Bromoethyl)-3-(3,5-dimethoxyphenyl)imidazolidin-2-
3.34 (s, 4H); 1.35 (s, 9H). ESI-MS: 249, 251 (M þ Hþ).
one (5m)
1H NMR
d
(CDCl3): 6.81 (d, 2H, J ¼ 2.2 Hz); 6.18 (t, 1H, J ¼ 2.2 Hz);
5.2.3. 1-(2-Bromoethyl)-3-isopropylimidazolidin-2-one (5c)
3.82 (t, 2H, J ¼ 8.5 Hz); 3.79 (s, 6H); 3.70 (t, 2H, J ¼ 6.4); 3.63 (t, 2H,
1H NMR
d
(CDCl3): 4.14 (m, 1H); 3.59 (t, 2H, J ¼ 6.6 Hz); 3.47 (t,
J ¼ 8.3 Hz); 3.53 (t, 2H, J ¼ 6.4). ESM-MS: 329, 331 (M þ Hþ).
2H, J ¼ 6.4 Hz); 3.43 (t, 2H, J ¼ 7.4 Hz); 3.29 (t, 2H, J ¼ 7.2 Hz); 1.12
(d, 6H, J ¼ 6.8 Hz). ESI-MS: 235, 237 (M þ Hþ).
5.2.14. 1-(2-Bromoethyl)-3-(3,4-dimethoxyphenyl)imidazolidin-2-
one (5n)
5.2.4. 1-(2-Bromoethyl)-3-cyclohexylimidazolidin-2-one (5d)
1H NMR
d
(CDCl3): 7.63 (d,1H, J ¼ 2.6 Hz); 6.82 (d,1H, J ¼ 8.6 Hz),
1H NMR
d
(CDCl3): 3.72–3.67 (m, 1H); 3.59 (t, 2H, J ¼ 6.5 Hz);
6.65 (dd, 1H, J ¼ 8.6, 2.4 Hz); 3.90 (s, 3H); 3.85 (s, 3H); 3.83 (t, 2H,
J ¼ 7.4 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.62 (t, 2H, J ¼ 7.8 Hz); 3.54 (t,
2H, J ¼ 6.2 Hz). ESI-MS: 351, 353 (M þ Hþ).
3.47 (t, 2H, J ¼ 6.7 Hz); 3.42 (t, 2H, J ¼ 8.7 Hz); 3.31 (t, 2H,
J ¼ 8.4 Hz); 1.79 (d, 2H, J ¼ 12 Hz); 1.72 (d, 2H, J ¼ 9.5 Hz); 1.65 (d,
2H, J ¼ 13 Hz); 1.40–1.29 (m, 4H); 1.10–1.04 (m, 1H). ESI-MS: 275,
277 (M þ Hþ).
5.2.15. 1-(2-Bromoethyl)-3-(3,4,5-trimethoxyphenyl)imidazolidin-
2-one (5o)
5.2.5. 1-(2-Bromoethyl)-3-phenylimidazolidin-2-one (5e)
1H NMR
d
(CDCl3): 6.93 (s, 2H); 3.8 (t, 2H, J ¼ 7.5 Hz); 3.74 (s,
1H NMR
d
(CDCl3): 7.54 (d, 2H, J ¼ 8.7 Hz); 7.33 (t, 2H, J ¼ 7.4 Hz);
6H); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.68 (s, 3H); 3.62 (t, 2H, J ¼ 7.8 Hz); 3.54
7.04 (t,1H, J ¼ 7.4 Hz); 3.86 (t, 2H, J ¼ 7.6 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz);
3.65 (t, 2H, J ¼ 7.5 Hz); 3.54 (t, 2H, J ¼ 6.2 Hz). MS: 269, 271
(M þ Hþ).
(t, 2H, J ¼ 6.2 Hz). ESI-MS: 381, 383 (M þ Hþ).
5.3. General procedure for the synthesis of 6
5.2.6. 1-(2-Bromoethyl)-3-p-tolylimidazolidin-2-one (5f)
(S)-1-(2-Aminoacetyl)pyrrolidine-2-carbonitrile trifluoroacetate
(24 mmol) was dissolved in acetonitrile, K2CO3 (64 mmol) was
added, the mixture stirred for 30 min to liberate free amine. Then 5
(8 mmol) was added and continued stirring for 48 h at room
temperature. Themixturewasfilteredtoremoveinsolublesubstance
1H NMR
d
(CDCl3): 7.42 (d, 2H, J ¼ 8.6 Hz); 7.14 (d, 2H, J ¼ 8.6 Hz);
3.83 (t, 2H, J ¼ 7.6 Hz); 3.71 (t, 2H, J ¼ 6.4 Hz); 3.63 (t, 2H,
J ¼ 7.6 Hz); 3.54 (t, 2H, J ¼ 6.4 Hz); 2.31 (s, 3H). ESI-MS: 283, 285
(M þ Hþ).

L. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 3318–3322
3321
and concentrated in vacuo. Purification by flash column chroma-
tography (eluted with CHCl3/MeOH ¼ 10/1) yielded 6 as a viscous oil.
The free base was dissolved in isopropanol, the solution of oxalic acid
inisopropanolwasaddedindrop, andprecipitateoccurred. Filtration
was followed dried in vacuo over P2O5. Rate: 15%–30%.
(m, 2H) 3.81–3.76 (t, 2H, J ¼ 8.34 Hz); 3.73 (s, 3H); 3.60 (s, 1H); 3.49
(s, 4H); 3.44–3.40 (m, 1H); 3.09 (s, 2H); 2.17 (s, 2H); 2.08–2.00 (m,
2H). ESI-MS: 372 (M þ Hþ).
5.3.9. (S)-1-(2-(2-(3-(4-chlorophenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6i)
5.3.1. (S)-1-(2-(2-(3-Butyl-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6a)
1H NMR
d
(DMSO-d6): 7.61 (d, 2H, J ¼ 9.0 Hz); 7.37 (d, 2H,
J ¼ 9.0 Hz); 4.81 (dd, 1H, J ¼ 7.4, 4.0 Hz); 4.00–3.91 (m, 2H); 3.80 (t,
2H, J ¼ 7.4 Hz); 3.61–3.57 (m, 1H); 3.51–3.47 (m, 4H); 3.43–3.39 (m,
1H); 3.80 (t, 2H, J ¼ 5.6 Hz); 2.17–2.15 (m, 2H); 2.06–1.99. ESI-MS:
376, 378 (M þ Hþ).
1H NMR
d
(DMSO-d6): 4.83 (dd, 1H, J ¼ 7.4, 3.8 Hz); 4.04–4.01
(m, 2H); 3.61–3.57 (m, 1H); 3.43–3.39 (m, 1H); 3.60 (t, 2H,
J ¼ 5.8 Hz); 3.29 (s, 4H); 3.08–3.05 (m, 4H); 2.20–2.17 (m, 2H);
2.07–2.03 (m, 2H). ESI-MS: 322 (M þ Hþ).
5.3.10. (S)-1-(2-(2-(3-(4-Fluorophenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6j)
5.3.2. (S)-1-(2-(2-(3-Tert-butyl-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6b)
1H NMR
d
(DMSO-d6): 7.60–7.58 (m, 2H); 7.17 (t, 2H, J ¼ 9 Hz);
1H NMR
d
(DMSO-d6): 4.77 (dd, 1H, J ¼ 4.4, 7.2 Hz); 4.09–4.03
4.83 (dd, 1H, J ¼ 6.2, 4.6 Hz); 4.05–3.95 (m, 2H); 3.80 (t, 2H,
J ¼ 7.4 Hz); 3.72–3.67 (m, 1H); 3.51–3.48 (m, 4H); 3.45–3.40 (m,
1H); 3.11 (s, 2H); 2.20–2.16 (m, 2H); 2.10–2.00 (m, 2H). ESI-MS: 360
(M þ Hþ).
(m, 2H); 3.61–3.57 (m, 1H); 3.46–3.40 (m, 5H); 3.29–3.26 (m, 4H);
2.28–2.24 (m, 2H); 2.14–2.09 (m, 2H); 1.26 (s, 9H). ESI-MS: 322
(M þ Hþ).
5.3.3. (S)-1-(2-(2-(3-Isopropyl-2-oxoimidazolidin-1-
5.3.11. (S)-1-(2-(2-(3-(3-Fluorophenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6k)
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6c)
1H NMR
d
(DMSO-d6): 4.82 (dd, 1H, J ¼ 7.4,3.8 Hz); 3.95–3.88 (m,
1H NMR
d
(DMSO-d6): 7.44 (d, 1H, J ¼ 12.4 Hz); 7.38–7.34 (m,
3H); 3.59–3.56 (m, 1H); 3.43–3.39 (m, 1H); 3.32 (t, 2H, J ¼ 5.9 Hz);
3.27 (t, 2H, J ¼ 7.3 Hz); 3.22 (t, 2H, J ¼ 7.1 Hz); 3.00 (t, 2H, J ¼ 5.5 Hz);
2.18–2.16 (m, 2H); 2.06–2.01 (m, 2H); 1.04 (d, 6H, J ¼ 6.9 Hz). ESI-
MS: 308 (M þ Hþ).
1H); 7.31 (d, 1H, J ¼ 8.1 Hz); 6.81 (t, 1H, J ¼ 7.8 Hz); 4.82 (dd, 1H,
J ¼ 7.2, 4.0 Hz); 4.01–3.91 (m, 2H); 3.83 (t, 2H, J ¼ 7.8 Hz); 3.62–3.59
(m, 1H); 3.51 (t, 4H, J ¼ 8.8 Hz); 3.44–3.40 (m, 1H); 3.09 (t, 2H,
J ¼ 5.8 Hz); 2.20–2.16 (m, 2H); 2.07–2.02 (m, 2H). ESI-MS: 360
(M þ Hþ).
5.3.4. (S)-1-(2-(2-(3-Cyclohexyl-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6d)
1H NMR
d
(DMSO-d6): 4.83 (dd,1H, J ¼ 7.1, 4.0 Hz); 4.00–3.90 (m,
5.3.12. (S)-1-(2-(2-(3-(2-Fluorophenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6l)
2H); 3.60–3.57 (m, 1H); 3.51–3.46 (m, 1H); 3.43–3.39 (m, 1H); 3.34
(t, 2H, J ¼ 6.0 Hz); 3.27 (s, 4H); 3.03 (t, 2H, J ¼ 5.1 Hz); 2.20–2.17 (m,
2H); 2.07–2.00 (m, 2H); 1.74 (d, 2H, J ¼ 12.9 Hz); 1.58 (d, 3H,
J ¼ 9.7 Hz); 1.39–1.33 (m, 2H); 1.30–1.24 (m, 2H); 1.09–1.03 (m, 1H).
ESI-MS: 348 (M þ Hþ).
1H NMR
d
(DMSO-d6): 7.51 (t, 1H, J ¼ 9.1 Hz); 7.28–7.18 (m, 3H);
4.83 (dd, 1H, J ¼ 7.4, 4.0 Hz); 4.09–4.00 (m, 2H); 3.80 (t, 2H,
J ¼ 7.6 Hz); 3.62–3.59 (m, 1H); 3.52 (t, 2H, J ¼ 7.9 Hz); 3.49 (t, 2H,
J ¼ 6.0 Hz); 3.44–3.42 (m, 1H); 3.10 (t, 2H, J ¼ 6.0 Hz); 2.20–2.17 (m,
2H); 2.09–2.01 (m, 2H). ESI-MS: 360 (M þ Hþ).
5.3.5. (S)-1-(2-(2-(2-Oxo-3-phenylimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6e)
5.3.13. (S)-1-(2-(2-(3-(3,5-Dimethoxyphenyl)-2-oxoimidazolidin-
1-yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6m)
1H NMR
d
(DMSO-d6): 7.59 (d, 2H, J ¼ 8.0 Hz); 7.33 (t, 2H,
J ¼ 7.9 Hz); 7.01 (t, 1H, J ¼ 7.4 Hz); 4.82 (dd, 1H, J ¼ 7.1, 4.2 Hz); 4.05–
3.93 (m, 2H); 3.81 (t, 2H, J ¼ 7.9 Hz); 3.62–3.59 (m, 1H); 3.51 (t, 4H,
J ¼ 6.0 Hz); 3.44–3.40 (m, 1H); 3.10 (t, 2H, J ¼ 5.0 Hz); 2.21–2.16 (m,
2H); 2.05–2.00 (m, 2H). ESI-MS: 342 (M þ Hþ).
1H NMR
d
(DMSO-d6): 6.81 (d, 2H, J ¼ 2.0 Hz); 6.19 (t, 1H,
J ¼ 2.0 Hz); 4.82 (dd, 1H, J ¼ 7.0, 4.0 Hz); 4.01–3.92 (m, 2H); 3.79–
3.75 (m, 3H); 3.72 (s, 3H); 3.61–3.59 (m, 1H); 3.50–3.46 (m, 4H);
3.44–3.42 (m, 1H); 3.09 (t, 2H, J ¼ 5.82 Hz); 2.19–2.16 (m, 2H); 2.07–
2.00 (m, 2H). ESI-MS: 402 (M þ Hþ).
5.3.6. (S)-1-(2-(2-(2-Oxo-3-p-tolylimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6f)
1H NMR
d
(DMSO-d6): 7.45 (d, 2H, J ¼ 8.5 Hz); 7.13 (d, 2H,
5.3.14. (S)-1-(2-(2-(3-(3,4-Dimethoxyphenyl)-2-oxoimidazolidin-
1-yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6n)
J ¼ 8.5 Hz); 4.82 (dd, 1H, J ¼ 7.3, 4.0 Hz); 4.03–3.94 (m, 2H); 3.78 (t,
2H, J ¼ 7.5 Hz); 3.61–3.58 (m, 1H); 3.50–3.47 (m, 4H); 3.44–3.40 (m,
1H); 3.10 (t, 2H, J ¼ 5.9 Hz); 2.25 (s, 3H); 2.20–2.16 (m, 2H); 2.07–
2.00 (m, 2H). ESI-MS: 356 (M þ Hþ).
1H NMR
d
(DMSO-d6): 7.46 (d, 1H, J ¼ 2.4 Hz); 6.91 (d, 1H,
J ¼ 8.6 Hz); 6.85 (dd, 1H, J ¼ 8.7, 2.6 Hz); 4.82 (dd, 1H, J ¼ 7.0,
4.0 Hz); 4.08–4.00 (m, 2H); 3.78 (t, 2H, J ¼ 8.2 Hz); 3.74 (s, 3H); 3.71
(s, 3H); 3.62–3.58 (m, 1H); 3.52–3.48 (m, 4H); 3.44–3.40 (m, 1H);
3.09 (t, 2H, J ¼ 5.0 Hz); 2.19–2.16 (m, 2H); 2.08–1.98 (m, 2H). 13C
5.3.7. (S)-1-(2-(2-(3-(4-Methoxyphenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6g)
NMR
d (DMSO-d6): 165.7, 164.8, 158.1, 149.2, 144.7, 134.9, 119.4,
1H NMR
d
(DMSO-d6): 7.48 (d, 2H, J ¼ 9.2 Hz); 6.92 (d, 2H,
112.7, 109.3, 103.6, 56.3, 55.9, 47.9, 46.7, 45.9, 45.2, 43.0, 41.8, 41.1,
29.9, 25.1. ESI-MS: 402 (M þ Hþ). HRMS (ESþ): 402.2136 (M þ Hþ),
calcd. for C20H28N5O4.
J ¼ 9.2 Hz); 4.83 (dd, 1H, J ¼ 7.2, 4.0 Hz); 4.02–3.92 (m, 1H); 3.77 (t,
2H, J ¼ 7.1 Hz); 3.72 (s, 3H); 3.61–3.58 (m, 1H); 3.49–3.47 (m, 4H);
3.46–3.42 (m, 1H); 3.10 (t, 2H, J ¼ 5.6 Hz); 2.18–2.16 (m, 2H); 2.07–
2.00 (m, 2H). ESI-MS: 372 (M þ Hþ).
5.3.15. (S)-1-(2-(2-(2-Oxo-3-(3,4,5-trimethoxyphenyl)imidazolidin-
1-yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6o)
5.3.8. (S)-1-(2-(2-(3-(3-Methoxyphenyl)-2-oxoimidazolidin-1-
yl)ethylamino)acetyl)pyrrolidine-2-carbonitrile oxalate (6h)
1H NMR
d
(DMSO-d6): 6.90 (s, 2H); 4.80 (dd, 1H, J ¼ 7.0, 4.4 Hz);
3.98–3.86 (m, 2H); 3.8 (t, 2H, J ¼ 7.5 Hz); 3.74 (s, 6H); 3.60 (s, 3H);
3.46–3.38 (m, 6H); 3.06 (s, 2H); 2.12–2.14 (m, 2H); 2.04–1.99 (m,
2H). ESI-MS: 432 (M þ Hþ).
1H NMR
d
(DMSO-d6): 7.28 (s,1H); 7.22 (t,1H, J ¼ 8.3 Hz); 7.09 (d,
1H, J ¼ 7.3 Hz); 6.60 (d, 1H, J ¼ 8.2 Hz); 4.82 (s, 1H); 4.05–3.94

3322
L. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 3318–3322
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