Synthesis and in vitro/in vivo antibacterial activity of oxazolidinones having thiocarbamate at C-5 on the A-ring and an amide- or urea-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane as the C-ring

Article abstract of DOI:10.1016/j.ejmech.2013.08.002

Oxazolidinones bearing a seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane heterocycle substituted with an amide or urea functionality as the C-ring and having a [1,2,3]triazole, a thiocarbamate, an isoxazole-3-ylamino, or a thioacetamide C-5 side chain unit on the A-ring instead of the typical acetamide were synthesized and their in vitro antibacterial activities towards various pathogens were evaluated. Several derivatives exhibited potent in vitro antibacterial activity toward not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. The in vivo therapeutic effects of amide 11a and ureas 16e, 17a were 2- to 3-fold greater than that of linezolid in a systemic mouse infection model treated by intravenous administration. Furthermore, compounds 11a and 17a showed lower monoamine oxidase (MAO)-inhibitory activity than our previously reported potent oxazolidinone antibacterials 3a and 3b.

Full text of DOI:10.1016/j.ejmech.2013.08.002

European Journal of Medicinal Chemistry 69 (2013) 262e277
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro/in vivo antibacterial activity of oxazolidinones
having thiocarbamate at C-5 on the A-ring and an amide- or urea-
substituted [1,2,5]triazepane or [1,2,5]oxadiazepane as the C-ring
,
a
a
b
b
Hideyuki Suzuki a , Iwao Utsunomiya , Koichi Shudo , Norio Fukuhara , Tsutomu Iwaki ,
*
Tatsuro Yasukata c
a Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan
b Medicinal Research Laboratories, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
c Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxazolidinones bearing
a seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane heterocycle
Received 9 April 2013
Received in revised form
11 July 2013
Accepted 4 August 2013
Available online 13 August 2013
substituted with an amide or urea functionality as the C-ring and having a [1,2,3]triazole, a thio-
carbamate, an isoxazole-3-ylamino, or a thioacetamide C-5 side chain unit on the A-ring instead of the
typical acetamide were synthesized and their in vitro antibacterial activities towards various pathogens
were evaluated. Several derivatives exhibited potent in vitro antibacterial activity toward not only Gram-
positive, but also Gram-negative and linezolid-resistant pathogens. The in vivo therapeutic effects of
amide 11a and ureas 16e, 17a were 2- to 3-fold greater than that of linezolid in a systemic mouse
infection model treated by intravenous administration. Furthermore, compounds 11a and 17a showed
lower monoamine oxidase (MAO)-inhibitory activity than our previously reported potent oxazolidinone
antibacterials 3a and 3b.
Keywords:
Antibacterial
Oxazolidinone
Methicillin-resistant Staphylococcus aureus
[1,2,5]Triazepane
Ó 2013 Elsevier Masson SAS. All rights reserved.
[1,2,5]Oxadiazepane
1. Introduction
analogous to the conventional pharmaceutical structural units
piperazine and morpholine [9]. We have also investigated the ef-
Linezolid (1) was the first oxazolidinone antibiotic to be
approved by the US Food and Drug Administration (FDA) in 2000,
and has been used for the treatment of serious infections caused by
Gram-positive bacteria such as methicillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant Enterococcus faecalis
(VRE) [1,2]. However, linezolid-resistant bacteria have already been
reported [3e5], and although this problem is not yet serious, it may
become serious in the near future. Although other oxazolidinone
antibiotic candidates have been reported, none of them has yet
been approved. However, tedizolid 2 (formerly called torezolid
phosphate; Fig. 1) developed by Trius Therapeutics recently suc-
cessfully completed a Phase III clinical trial [6,7]. Thus, there is great
interest in new types of oxazolidinone antibiotics [8]. We have
recently synthesized oxazolidinones in which the C-ring (see
fects of various side chain units at the 5-position of the oxazolidi-
none ring in eperezolid-type antibacterials, and found that the
analogs 3a and 3b bearing a thiocarbamate-type side chain unit at
the C-5 position in the A-ring showed potent in vitro and in vivo
antibacterial efficacy (Fig. 2) [10]. However, derivatives other than
the hydroxyacetamide were not explored, and analogs with other
functional groups at the nitrogen atom of the seven-membered
heterocyclic C-ring were not examined. Therefore, in the present
work, we focused on the synthesis of a series of oxazolidinone
analogs containing our seven-membered heterocycles substituted
with an amide or urea functionality as the C-ring. Although 3a and
3b have a thiocarbamate side chain unit in the A-ring, we consid-
ered that a change of the C-ring functionality might alter the
preferred C-5 side chain unit in the A-ring. Therefore, we synthe-
sized and evaluated compounds containing other previously
examined side chain units, [1,2,3]triazole, isoxazol-3-ylamino, and
thioacetamide, as well as thiocarbamate on the A-ring. Evaluation
of in vitro and in vivo antibacterial activities indicated that several of
the new compounds are more potent than linezolid (1). It was
confirmed that a thiocarbamate side chain unit at C-5 of the A-ring
below) consists of
a seven-membered heterocycle, [1,2,5]tri-
azepane or [1,2,5]oxadiazepane, which can be considered
* Corresponding author.
E-mail address: hsuzuki@itsuu.or.jp (H. Suzuki).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.08.002

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
263
O
O
F
F
N
N
N
O
N
N
O
H
N
O
N
N
N
Me
O
ONa
ONa
P
O
Me
O
Linezolid (1)
Tedizolid (2)
Fig. 1. Linezolid (1) and Tedizolid (2).
chain unit in the A-ring substructure [11]. Here, we focused on
seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane het-
erocycles modified with amide or urea functionality as the C-ring
unit. We previously examined the hydroxyacetamide functionality,
and in this work we examined three other types of amide func-
tional groups. The oxazolidinone intermediates 4e8 were pre-
pared in accordance with our previous report [10]. Since the
choice of C-5 side chain unit in the A-ring strongly influences
in vitro antibacterial activity, we mainly adopted thiocarbamate
[12], thioacetamide [13], [1,2,3]triazole [14] and isoxazol-3-
ylamino [15] units, in contrast to typical acetamide [16]. For the
amide functionality on the seven-membered heterocycle, we
chose orthodox formamide 9, acetamide 10, and difluor-
oacetamide 11. As shown in Table 1, formamide 9 and difluor-
oacetamide 11 were obtained by deprotection of the tert-
butoxycarbonyl (Boc) group in appropriate intermediates under
acidic conditions, followed by condensation with the appropriate
carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (EDCI)/1-hydroxybenzotriazole (HOBt). Acetamide 10 was
also obtained by Ac2O/pyridine treatment, followed by
deprotection.
O
O
F
X
HN
N
H
N
N
N
OMe
HO
O
S
3a (X = H)
3b (X = F)
Fig. 2. Potent oxazolidinone analogs, 3a and 3b, having [1,2,5]triazepane bearing a
hydroxyacetyl group as the C-ring unit.
is optimum for potent in vitro and in vivo antibacterial activities in
these compounds. Initial safety evaluation showed that 11a and 17a
had low inhibitory activity towards four cytochrome P450 (CYP)
isoforms, like our previously reported compounds 3a and 3b, while
their inhibitory activity towards monoamine oxidase (MAO)-A,B
was markedly lower than that of 3a and 3b.
2. Results and discussion
2.1. Chemistry
Furthermore, oxazolidinones (12e15) bearing a fused-type C-
ring were also synthesized in the [1,2,5]triazepane heterocycle
series, as shown in Table 2. As simple structures with no sub-
stituent on the terminal pyridine ring, we synthesized compound
The oxazolidinone family of antibiotics is composed of an A-
ring (oxazolidinone), B-ring (phenyl), and C-ring (an appropriate
heterocycle, such as morpholine or piperazine), with a C-5 side
Table 1
Synthesis of oxazolidinone analogs bearing amide functionalities 9e11.
O
O
F
F
Y1
HN
O
Y2
N
O
Reagents
yield
N
N
N
N
R1
R2
R1
X
X
O
4c (X = F, Y1 = O, R1 = NHC(=O)Me)
5c (X = F, Y1 = O, R1 = NHC(=S)Me)
6a (X = H, Y1 = NBoc, R1 = NHC(=S)OMe)
6b (X = F, Y1 = NBoc, R1 = NHC(=S)OMe)
9-11
7b (X = F, Y1 = NBoc, R1 = [1,2,3]triazol-1-yl)
8ba (X = F, Y1 = NBoc)
Substrateb
Reagentsc
X
Y2
R1
NHC(]S)OMe
[1,2,3]Triazol-1-yl
Isoxazol-3-ylamino
NHC(]O)Me
NHC(]S)OMe
NHC(]S)Me
NHC(]S)OMe
[1,2,3]Triazol-1-yl
NHC(]S)OMe
R2
Product
Yield (%)
6a
7b
8ba
4c
6a
5c
6b
7b
6a
7b
8ba
a
a
a
b
b
b
b
b
c
H
F
F
F
H
F
F
F
H
F
F
NH
NH
NH
O
NH
O
NH
NH
NH
NH
NH
H
H
H
9a
9b
9c
53
55
31
96
71
98
75
85
58
45
30
Me
Me
Me
Me
Me
CHF2
CHF2
CHF2
10a
10b
10c
10d
10e
11a
11b
11c
c
c
[1,2,3]Triazol-1-yl
Isoxazol-3-ylamino
a
R1 of compound 8b ¼ tert-butoxycarbonyl-isoxazol-3-yl-amino.
b
c
Substrates 4c, 5c, 6a, 6b, 7b, and 8b are known compounds, see Ref. [10].
a) i) conc. HCl, 1,4-dioxane; ii) EDCI, HOBt, i-Pr2NEt, HCO2H, DMF; b) i) Ac2O, pyridine, CH2Cl2; ii) conc. HCl, 1,4-dioxane (except for synthesis of 10a and 10c); iii) EDCI,
HOBt, i-Pr2NEt, CH3CO2H, DMF; c) i) conc. HCl, 1,4-dioxane; ii) EDCI, HOBt, i-Pr2NEt, CHF2CO2H, DMF.

264
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
Table 2
Synthesis of oxazolidinone analogs bearing fused ring structure 12e15.
O
O
F
N
O
F
X
Y
Boc
Reagents
yield
N
O
N
N
O
N
N
N
N
HN
R
R
X
4a (X = H,R = NHC(=O)Me)
4b (X = F, R = NHC(=O)Me)
12-15
6a (X = H,R = NHC(=S)OMe)
6b (X = F, R = NHC(=S)OMe)
7a (X = H,R = [1,2,3]triazol-1-yl)
7b (X = F, R = [1,2,3]triazol-1-yl)
Substratea
Reagentsb
X
R
Y
Product
Yield (%)
4a
4b
6a
6b
7a
7b
4b
4b
4b
7b
a
a
a
a
a
a
b
c
H
F
H
F
H
F
F
F
F
F
NHC(]O)Me
NHC(]O)Me
NHC(]S)OMe
NHC(]S)OMe
[1,2,3]Triazol-1-yl
[1,2,3]Triazol-1-yl
NHC(]O)Me
NHC(]O)Me
NHC(]O)Me
[1,2,3]Triazol-1-yl
H
H
H
H
H
H
Cl
Br
NH2
NH2
12a
12b
12c
12d
12e
12f
13
14
15a
15b
87
100
90
88
84
90
76
85
45
d
d
48
a
Substrates 4a, 4b, 6a, 6b, 7a, and 7b are known compounds, see Ref. [10].
a) i) 2-Chloronicotinoyl chloride, pyridine, CH2Cl2; ii) CF3CO2H, CH2Cl2; b) i) 2,5-dichloronicotinoyl chloride, pyridine, CH2Cl2; ii) CF3CO2H, CH2Cl2; c) i) 5-bromo-2-
b
chloronicotinoyl chloride, pyridine, CH2Cl2; ii) CF3CO2H, CH2Cl2; d) i) conc. HCl, 1,4-dioxane; ii) EDCI, HOBt, i-Pr2NEt, 5-t-butoxycarbonylamino-2-chloronicotinic acid,
DMF; iii) CF3CO2H, CH2Cl2.
12 with six kinds of combinations of B ring (monofluorophenyl or
difluorophenyl) and C-5 side chain unit in the A-ring (acetamide,
thiocarbamate, and [1,2,3]triazole). Furthermore, in order to
examine the effect of substitution on the pyridine ring, we chose
Cl (13), Br (14), and NH2 (15) as substituents. Compounds 12e15
were synthesized via conversion of the appropriate intermediate
to 2-chloronicotinic acid amide, followed by acid treatment.
Then, we examined the synthesis of oxazolidinones 16e19
bearing a sterically simple urea functionality on the seven-
membered heterocycle (Table 3). In order to evaluate antibacte-
rial potential, the orthodox urea 16 was modified with four kinds
of C-5 side chain unit of the A-ring in place of conventional
acetamide. The analogs 17e19 bearing the other types of urea
functionality on the seven-membered heterocycle were synthe-
sized mainly with a thiocarbamate side chain in the A-ring. Ureas
16e19 were obtained by triphosgene/Et3N treatment of the
appropriate intermediate, followed by deprotection of the Boc
group.
On the other hand, pyridine- and benzene-insertion types of
oxazolidinone antibacterials have recently been synthesized and
evaluated [6,17]. Because compound 2, which is currently under-
going clinical trial, resembles these oxazolidinones, we decided to
synthesize similar analogs. As the terminal hetero ring substructure
(D-ring), we focused on the [1,2,5]oxadiazepane ring, and as the C-5
side chain of the A-ring, we selected both acetamide and [1,2,3]
triazole. As shown in Scheme 1, commercially available 5-bromo-2-
hydroxypyridine (20) was converted to triflate 21, followed by
treatment with [1,2,5]oxadiazepane-2-carboxylic acid tert-butyl
ester [18] in hexamethylphosphoric triamide to afford the
seven-membered heterocycle 22 in good yield. SuzukieMiyaura
coupling reaction of the known boronic acid ester [19,20] with
compound 22 afforded the oxazolidinone intermediates 23a and
23b, respectively. Deprotection of the Boc group in 23 gave amine
24, which was converted to the hydroxyacetamide compounds 25a
and 25b in two steps using standard techniques.
2.2. Pharmacology
All the new synthesized oxazolidinones bearing seven-
membered heterocycles, 9e19 and 24 and 25, were evaluated
for in vitro antibacterial activity against Gram-positive (S. aureus,
E. faecalis, Enterococcus faecium, and Streptococcus pneumoniae)
and Gram-negative (Moraxella catarrhalis and Haemophilus
influenzae) pathogens using the conventional agar-dilution
method. Linezolid-resistant S. aureus NRS271 (a clinical isolate)
was also used. As shown in Table 4, the oxazolidinones bearing a
formamide functionality on the seven-membered heterocycle 9
generally showed 4- to 16-fold more potent antibacterial activity
than linezolid (1). Thiocarbamate 9a exhibited clinically appro-
priate minimum inhibitory concentration (MIC) values (2e4 mg/
mL) against Gram-negative strains, like the previously reported
potent analogs 3a and 3b. The analog 10a with acetamide func-
tionality on the seven-membered heterocycle showed in vitro
activities slightly weaker than those of the above formamide, but
similar to those of linezolid, even with the orthodox acetamide-
type C-5 side chain in the A-ring. The difluoroacetamide de-
rivatives 11 also exhibited good antibacterial activity. In partic-
ular, compound 11a bearing a thiocarbamate-type C-5 side chain
in the A-ring showed the strongest antibacterial activity
(0.125
mg/mL) against S. aureus SR20549, as well as sufficient
in vitro activity toward Gram-negative strains, and its antibac-
terial activity pattern was similar to those of 3a and 3b. The
in vitro antibacterial activities of analogs 12 bearing a fused ring
as a C-ring substructure were investigated with various combi-
nations of B-ring unit and C-5 side chain in the A-ring. Though
the analog 12a, which has the same structure as 1, except for the
C-ring scaffold, exhibited nearly the same levels of in vitro anti-
bacterial activity as 1, compound 12b, in which the B-ring
monofluorophenyl was replaced with difluorophenyl, showed 2-
fold greater in vitro antibacterial activity compared to 12a. The
analogs 12c and 12d bearing thiocarbamate as the C-5 side chain

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
265
Table 3
Synthesis of oxazolidinone analogs bearing urea functionalities 16e19.
O
O
F
F
Y1
HN
O
Y2
N
O
Reagents
yield
N
N
N
N
R1
R2HN
R1
X
X
O
5a (X = H, Y1 = NBoc, R1 = NHC(=S)Me)
5b (X = F, Y1 = NBoc, R1 = NHC(=S)Me)
5c (X = F, Y1 = O, R1 = NHC(=S)Me)
16-19
6a (X = H, Y1 = NBoc, R1 = NHC(=S)OMe)
6b (X = F, Y1 = NBoc, R1 = NHC(=S)OMe)
6c (X = F, Y1 = O, R1 = NHC(=S)OMe)
7b (X = F, Y1 = NBoc, R1 = [1,2,3]triazol-1-yl)
7c (X = F, Y1 = O, R1 = [1,2,3]triazol-1-yl)
8ba (X = F, Y1 = NBoc)
Substrateb
Reagentsc
X
Y2
R1
R2
Product
Yield (%)
5a
5b
5c
6a
6b
6c
7b
7c
8ba
6a
6b
6c
7c
6a
7b
7c
6a
6b
6c
a
a
a
a
a
a
a
a
a
b
b
b
b
c
H
F
F
H
F
F
F
F
F
H
F
F
F
H
F
F
H
F
F
NH
NH
O
NH
NH
O
NH
O
NH
NH
NH
O
NH(C]S)Me
NH(C]S)Me
NH(C]S)Me
NH(C]S)OMe
NH(C]S)OMe
NH(C]S)OMe
[1,2,3]Triazol-1-yl
[1,2,3]Triazol-1-yl
Isoxazol-3-ylamino
NH(C]S)OMe
H
H
H
H
H
H
H
H
16a
16b
16c
16d
16e
16f
16g
16h
16i
17a
17b
17c
17d
18a
18b
18c
19a
19b
19c
37
66
99
89
83
89
70
94
94
81
83
99
62
86
69
79
80
70
92
H
Me
Me
Me
Me
OH
OH
OH
OMe
OMe
OMe
NH(C]S)OMe
NH(C]S)OMe
O
[1,2,3]Triazol-1-yl
NH(C]S)OMe
[1,2,3]Triazol-1-yl
[1,2,3]Triazol-1-yl
NH(C]S)OMe
NH
NH
O
NH
NH
O
c
c
d
d
d
NH(C]S)OMe
NH(C]S)OMe
a
R1 of compound 8b ¼ tert-butoxycarbonyl-isoxazol-3-yl-amino.
b
c
Substrates 5a, 5b, 5c, 6a, 6b, 6c, 7b, 7c, and 8b are known compounds, see Ref. [10].
a) i) triphosgene, Et3N, THF, then NH4OH; ii) conc. HCl, 1,4-dioxane (except for synthesis of 16c, 16f, and 16h); b) i) triphosgene, Et3N, THF, then CH3NH2; ii) conc. HCl, 1,4-
dioxane (except for synthesis of 17c and 17d); c) i) triphosgene, Et3N, THF, then hydroxylamine hydrochloride; ii) conc. HCl, 1,4-dioxane (except for synthesis of 18c);
d) i) triphosgene, Et3N, THF, then O-methylhydroxylamine hydrochloride; ii) conc. HCl, 1,4-dioxane (except for synthesis of 19c).
unit in the A-ring exhibited superior antibacterial activity against
Gram-positive strains, and were also active against the linezolid-
resistant strain, like 3a and 3b. The antibacterial activities of the
analogs 12e and 12f bearing a [1,2,3]triazole side chain unit were
similar to those of acetamides 12a and 12b, respectively. On the
other hand, analogs 13e15 with a halogen or amino substituent
on the terminal pyridine ring did not show enhanced antibac-
terial activity compared to non-substituted 12b or 12f. The most
basic compounds 16 bearing an urea functionality on the C-ring
were also investigated with various structural combinations,
O
F
N
N
N
N
a
b
c
O
N
O
N
O
HO
Br
TfO
Br
N
Br
N
N
R
Boc
N
98%
88%
Boc
R
20
21
22
23a (R = NH(C=O)Me) 57%
23b (R = [1,2,3]triazol-1-yl) 31%
O
O
F
F
N
d
e
O
HN
O
O
N
O
N
N
N
N
R
HO
O
24a (R = NH(C=O)Me) 90%
24b (R = [1,2,3]triazol-1-yl) 98%
25a (R = NH(C=O)Me) 75%
25b (R = [1,2,3]triazol-1-yl) 92%
Scheme 1. Synthesis of pyridine insertion-type oxazolidinone analogs 24 and 25. Reagents: (a) Tf2O, pyridine; (b) [1,2,5]oxadiazepane-2-carboxylic acid tert-butyl ester, i-Pr2NEt,
HMPA; (c) (S)-N-((3-(3-fluoro-4-(3,3,4,4-tetramethylborolan-1-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (for 23a) or (5R)-3-(3-fluoro-4-(3,3,4,4-tetramethylborolan-1-yl)
phenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (for 23b), Pd(PPh3)4, Na2CO3, 1,4-dioxane, H2O; (d) conc. HCl, 1,4-dioxane; (e) i) acetoxyacetyl chloride, pyridine, CH2Cl2; ii)
K2CO3, MeOH.

266
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
Table 4
Table 5
In vitro antibacterial activities of amide and fused-ring analogs 9e15.
In vitro antibacterial activities of urea analogs 16e19.
Compound
Minimum inhibitory concentration (
m
g/mL)
M. c.f
Compound Minimum inhibitory concentration (
m
g/mL)
S. a.a
S. a.b
S. a.c
E. f.d
E. f.e
S. p.g
H. i.h
S. a.a
S. a.b S. a.c E. f.d E. f.e
M. c.f S. p.g
H. i.h
1
2
2
32
2
2
4
2
8
2
1
2
8
8
4
4
2
2
16
2
8
4
16
4
2
1
32
8
1
16
4
4
4
8
1
2
2
32
2
2
8
4
4
4
2
2
32
32
16
8
2
4
32
16
64
64
16
4
4
2
8
2
1
4
1
2
2
0.5
1
4
8
8
2
1
2
1
16
4
4
4
4
3ai
0.25
0.25
0.25
0.25
0.5
2
0.5
0.25
0.5
1
0.25
0.25
0.25
1
1
4
1
1
1
2
0.5
0.25
0.25
1
1
2
0.5
0.5
1
2
0.25
1
0.5
2
1
0.5
0.5
4
1
2
2
2
0.25
0.25
0.25
1
1
4
0.5
0.5
0.5
2
0.25
1
0.5
2
1
0.25
0.25
4
1
1
1
2
2
0.125
&0.063
0.063
&0.063
0.25
1
0.063
0.125
0.125
1
0.063
0.125
0.125
0.5
0.25
0.125
0.125
1
3ai
0.25
0.25
0.25
0.25
0.25
0.25
0.5
0.25
0.5
0.25
0.25
0.25
0.5
0.25
2
4
1
0.5
0.25
1
4
1
8
4
0.5
0.5
1
0.25
0.25
0.5
0.25
0.5
0.125
0.125
0.125
4
4
1
0.25
0.25
0.5
2
0.125
&0.063
0.063
0.063
0.063
&0.063
&0.063 16
&0.063
0.5
3bi
9a
9b
3bi
4
16a
16b
16c
16d
16e
16f
16g
16h
16i
17a
17b
17c
17d
18a
18b
18c
19a
19b
19c
16
16
32
8
4
4
16
4
16
8
16
8
2
0.125 0.25
9c
16
32
16
8
32
32
4
16
16
32
16
16
>64
32
32
64
64
32
32
0.25
0.25
0.25
0.25
1
0.5
0.25
0.25
0.25
1
2
1
0.5
0.25
0.5
8
1
4
2
1
0.5
1
8
4
10a
10b
10c
10d
10e
11a
11b
11c
12a
12b
12c
12d
12e
12f
13
8
16
16
16
16
8
32
32
4
16
16
16
16
16
1
1
0.125
0.5
0.5
2
0.5
1
1
0.5
0.25
0.25
0.5
2
0.5
2
2
0.125
0.25
&0.063
0.125
1
&0.063
0.5
0.5
1
1
0.5
0.25
0.25
4
2
1
1
0.5
1
16
0.25
0.25
2
0.5
1
1
1
1
1
8
4
0.5
0.25
0.5
4
8
8
4
2
2
2
64
8
8
8
0.5
1
0.5
0.5
0.25
0.25
0.125
4
4
8
16
0.25
0.25
0.25
0.25
14
15a
15b
8
8
16
a
Staphylococcus aureus SR20549.
Staphylococcus aureus Smith.
2
b
c
d
e
f
a
Staphylococcus aureus SR20549.
Staphylococcus aureus Smith.
Linezolid-resistant Staphylococcus aureus NRS271.
Enterococcus faecalis SR1004.
Enterococcus faecium SR7940.
Moraxella catarrhalis SR26840.
Streptococcus pneumoniae SR26207.
Haemophilus influenzae SR27914.
See Ref. [10].
b
c
d
e
f
Linezolid-resistant Staphylococcus aureus NRS271.
Enterococcus faecalis SR1004.
Enterococcus faecium SR7940.
Moraxella catarrhalis SR26840.
Streptococcus pneumoniae SR26207.
Haemophilus influenzae SR27914.
See Ref. [10].
g
h
i
g
h
i
difference between compounds containing [1,2,5]triazepane and
[1,2,5]oxadiazepane structures. As for the B-ring unit, a difluor-
ophenyl group seemed to afford higher activity than a mono-
fluorophenyl group, and a thiocarbonyl-type C-5 side chain in the
A-ring was also favorable for potent in vitro antibacterial activity.
As the next step, selected potent in vitro-active analogs were
tested for in vivo therapeutic effect via intravenous administration
in a lethal systemic mouse infection model employing S. aureus
SR3637. The results are summarized in Table 7. The MIC values of all
the selected compounds against S. aureus SR3637 were less than
except for the acetamide side chain, which seemed unfavorable
for antibacterial activity.
As shown in Table 5, analogs 16aef having thioacetamide or
thiocarbamate as the C-5 side chain moiety exhibited 4- to 16-fold
more potent in vitro antibacterial activity than 1, and the antibac-
terial activity was almost equivalent to those of the potent analogs
3a and 3b. In particular, 16e and 16f showed clinically appropriate
levels of antibacterial activity against Gram-negative and linezolid-
resistant strains. Although derivatives 16gei with a [1,2,3]triazole
or an isoxazol-3-ylamino C-5 side chain in the A-ring also showed
greater antibacterial activity than 1, they were less potent than the
compounds bearing a thiocarbonyl C-5 side chain in the A-ring. The
MIC values of compound 17 indicated that methyl substitution on
the terminal urea functionality had little or no effect on the anti-
bacterial activity. The analogs 18 having a hydroxamic acid-type
terminal unit on the C-ring also exhibited moderate antibacterial
activities, though these were slightly lower as compared to the
basic 16 series. The conversion of hydroxyl group to a methoxy
group slightly decreased the antibacterial activity (18a vs 19a).
As shown in Table 6, the pyridine insertion-type derivatives 24a
and 24b with [1,2,5]oxadiazepane as the D-ring exhibited 2-fold
greater antibacterial activities than 1, but without any especially
noteworthy feature. The antibacterial activity of analog 25 with a
hydroxyacetamide group on the seven-membered heterocycle
showed no change from those of non-substituted 24a and 24b.
Thus, we have found several potent in vitro active oxazolidinone
analogs without complicated structural ornamentation on the C-
ring unit. The present synthesis and evaluation of oxazolidinone
analogs with various substituent groups on our seven-membered
heterocyclic [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring struc-
ture yielded the following results. Broadly speaking, there was little
0.5 mg/mL. Formamides 9a, b and acetamide 10b exhibited similar
levels of therapeutic effect to 1. Because the in vivo effects of these
Table 6
In vitro antibacterial activities of pyridine insertion-type analogs 24 and 25.
Compound
Minimum inhibitory concentration (
m
g/mL)
M. c.f
S. a.a
S. a.b
S. a.c
E. f.d
E. f.e
S. p.g
H. i.h
1
2
2
32
2
2
8
8
4
2
8
2
1
16
8
16
8
1
16
4
4
16
32
16
32
3ai
3bi
24a
24b
25a
25b
0.25
0.25
1
1
1
0.25
0.25
2
2
2
0.5
0.25
1
2
1
0.25
0.25
1
1
1
0.125
&0.063
0.125
0.25
0.125
0.25
8
8
1
2
2
1
a
Staphylococcus aureus SR20549.
Staphylococcus aureus Smith.
b
c
d
e
f
Linezolid-resistant Staphylococcus aureus NRS271.
Enterococcus faecalis SR1004.
Enterococcus faecium SR7940.
Moraxella catarrhalis SR26840.
Streptococcus pneumoniae SR26207.
Haemophilus influenzae SR27914.
See Ref. [10].
g
h
i

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
267
Table 7
antibacterial activities. Selected compounds were tested in an
in vivo mouse model employing S. aureus SR3637, and among them,
11a, 16e, and 17a showed a potent in vivo therapeutic effect similar
to that of our previously reported potent oxazolidinone analogs 3a
and 3b. Our results indicate that a thiocarbamate side chain unit at
C-5 of the A-ring is optimum for potent in vitro and in vivo anti-
bacterial activities, regardless of the kind of substituent at the ni-
trogen atom on the C-ring. Compounds 11a and 16a showed
markedly weaker inhibitory activity toward MAO-A and -B as
compared to 3a and 3b, while all of these compounds showed
similar levels of CYP-inhibitory activity (IC50 > 20 mM) towards
four selected isoforms. Therefore, 11a and 16a may be better drug
candidates than 3a and 3b from the viewpoint of safety profile.
Thus, we consider that our substituted seven-membered hetero-
cycles are promising structural units to replace conventional het-
erocyclic units, such as piperazine or morpholine, in the search for
new, highly potent oxazolidinone antibiotics.
In vivo antibacterial efficacies (ED50) of selected oxazolidinones in a systemic mouse
infection model.
Compound
MIC (
m
g/mL)
Therapeutic effect ED50 (mg/kg)
3aa
3ba
9a
0.25
0.25
0.25
0.25
0.5
0.25
0.25
0.25
0.25
0.25
0.5
0.94 (1: 3.26)
0.77 (1: 2.13)
2.95 (1: 3.31)
2.50 (1: 1.94)
2.85 (1: 3.31)
0.77 (1: 2.13)
3.17 (1: 2.13)
9.83 (1: 4.98)
5.71 (1: 2.02)
1.23 (1: 2.13)
0.86 (1: 2.07)
3.17 (1: 2.07)
3.05 (1: 2.07)
9b
10b
11a
12c
12d
16c
16e
17a
17b
19b
0.25
0.5
a
See Ref. [10].
analogs did not fully reflect the in vitro activities, these compounds
may have non-optimal pharmacokinetic or metabolic properties.
However, difluoroacetamide 11a had a 3-fold stronger therapeutic
effect than 1. The analogs bearing fused ring structure, 12c and 12d,
showed moderate efficacy. The urea analog 16c showed poor in vivo
antibacterial potential, possibly due to chemical instability of the
thioamide C-5 side chain moiety. On the other hand, compound
16e, having a more stable thiocarbamate side chain unit, showed a
good in vivo therapeutic effect. Compound 17a showed a superior
in vivo antibacterial activity to 1, although 17b, which is structurally
rather similar, showed only a weak therapeutic effect. This result
may indicate that the hydrophobicity of the oxazolidinone mole-
cule influences the pharmacokinetic profile.
Thus, among the analogs examined, 11a, 16e, and 17a showed
promising in vivo activity, comparable to that of our previously
reported hydroxyacetamides 3a and 3b. In order to further evaluate
11a and 17a as candidate antibiotics from the viewpoint of safety, as
we discussed previously [10], we examined their inhibitory activ-
ities towards four CYP isozymes and MAO-A and -B. The results are
shown in Table 8. The thiocarbamates 11a and 17a had similar
levels of CYP-inhibitory activity (IC50 > 20 mM for the four selected
isoforms) to linezolid (1), 3a, and 3b, and this profile is considered
satisfactory for this class of antibiotics. Importantly, the thio-
carbamates 11a and 17a showed remarkably improved values of
MAO-A, B inhibition index compared to 3a and 3b. In particular,
these two compounds hardly inhibited MAO-B. Thus, compounds
11a and 17a appear to be superior to 3a and 3b in terms of their
safety profile.
4. Experimental protocols
4.1. Chemistry
Melting points were determined with a Yanagimoto micro
melting point apparatus (hot plate) and are uncorrected. Elemental
analyses were determined by a Yanaco CHN MT-5 instrument and
were within ꢀ0.4% of the theoretical values. Low-resolution elec-
tron ionization mass spectra (EI-LRMS) and high-resolution elec-
tron ionization mass spectra (EI-HRMS) were recorded on a JEOL
JMS-AX505HA. Low-resolution electrospray ionization mass
spectra (ESI-LRMS) were recorded on a Waters 3100 Mass Detector.
High-resolution electrospray ionization mass spectra (ESI-HRMS)
were recorded on a Thermo Fisher Scientific LTQ-Orbitrap. Proton
nuclear magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were measured with a
Varian Mercury at 300 MHz and at 75 MHz, respectively. The
chemical shifts are recorded in ppm, and coupling constants (J) in
Hz. 1H NMR and 13C NMR chemical shifts were calculated on the
basis of tetramethylsilane (0 ppm for 1H NMR in CDCl3 or CD3OD/
CDCl3) and residual solvent (77 ppm for 13C NMR in CDCl3 or
CD3OD/CDCl3, 2.49 ppm for 1H NMR in DMSO-d6, and 39.5 ppm for
13C NMR in DMSO-d6) as internal standards. Splitting patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br; broad peak. Column chromatography was carried out
with silica gel [Fuji Davison BW200] as an absorbent. Thin layer
chromatography (TLC) was carried out on Merck Silica gel 60 PF254
.
Solutions were dried over anhydrous sodium sulfate or anhydrous
magnesium sulfate and the solvent was removed by rotary evap-
oration under reduced pressure.
3. Conclusion
Oxazolidinones bearing a seven-membered heterocycle [1,2,5]
triazepane or [1,2,5]oxadiazepane substituted with an amide or
urea functionality as the C-ring were synthesized and their in vitro
antibacterial activities were evaluated. Examination of compounds
with various combinations of partial structures resulted in the
identification of several compounds with potent in vitro
4.1.1. (S)-N-((3-(3-Fluoro-4-(1-formyl[1,2,5]triazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate (9a)
To a solution of 6a (323.0 mg, 0.668 mmol) in 1,4-dioxane (3 mL)
was added dropwise concentrated hydrochloric acid (1.0 mL). The
mixture was stirred for 2 h at ambient temperature, and then
concentrated in vacuo. The residue was used for the next reaction
without further purification. Formic acid (90.2 mg, 1.960 mmol)
Table 8
was added to
a mixture of the residue, EDCI (140.3 mg,
Values of CYP450 and MAO-A, B inhibition index of potent in vivo active analogs 11a
and 17a.
0.732 mmol), HOBt (18.6 mg, 0.138 mmol) and i-Pr2NEt (112.5 mg,
0.870 mmol) in DMF (3 mL), and the whole was stirred for 16 h at
ambient temperature. The reaction was quenched by the addition
of 10% potassium carbonate aqueous solution (20 mL), and the
mixture was extracted with ethyl acetate. The organic solution
was dried and evaporated. Silica gel (10 g) column chromatography
of the residue using CHCl3/MeOH (99:1 to 99:3) as the eluent
afforded 9a (146.2 mg, 53%). Amorphous solid; 1H NMR (CDCl3)
Compound
CYP450 isoform, IC50
(m
M)
MAO inhibition (%)
1A2
2C9
2D6
3A4
A
B
3aa
3ba
11a
17a
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
48.2
12.4
9.2
10.1
10.6
0.1
3.4
3.1

268
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
d
¼ 3.10e4.12 (12H, m, eCH2e), 4.00 (3H, s, eOCH3), 4.84e4.96 (1H,
1.058 mmol). The mixture was stirred for 30 min at ambient tem-
perature. The reaction was quenched by the addition of 10% po-
tassium carbonate aqueous solution (10 mL), and the mixture was
extracted with 10% MeOH/CHCl3. The organic solution was dried
and evaporated. Silica gel (8 g) column chromatography of the
residue using CHCl3/MeOH (99:1 to 96:4) as the eluent afforded 10a
(105.4 mg, 96%). Colorless needles (EtOH); mp 149e151 ꢁC; 1H NMR
m, oxazolidinone-H5), 6.85 (0.6H, t, J ¼ 9.1 Hz, Ar-H6), 6.89 (0.4H, t,
J ¼ 9.1 Hz, Ar-H6), 7.00 (0.6H, dd, J ¼ 2.4, 9.1 Hz, Ar-H5), 7.03 (0.4H,
dd, J ¼ 2.4, 9.1 Hz, Ar-H5), 7.39 (1H, dd, J ¼ 2.4, 15.3 Hz, Ar-H6), 7.88
(0.6H, s, eCH]O), and 8.33 (0.4H, s, eCH]O); 13C NMR (CDCl3)
d
¼ 47.58 (0.6C), 47.69 (0.4C), 48.75 (1C), 49.75 (1C), 51.10 (0.4C),
51.52 (0.6C), 52.03 (1C), 53.94 (0.4C), 54.06 (0.6C), 57.51 (1C), 71.17
(1C), 107.88 (0.4C, d, JCeF ¼ 26.6 Hz), 108.06 (0.6C, d, JCeF ¼ 26.6 Hz),
114.20 (0.4C), 114.40 (0.6C), 118.30 (0.6C), 119.08 (0.4C), 130.89
(0.6C, d, JCeF ¼ 12.8 Hz),131.72 (0.4C, d, JCeF ¼ 12.8 Hz),134.68 (0.6C,
d, JCeF ¼ 8.8 Hz), 135.99 (0.4C, d, JCeF ¼ 8.8 Hz), 153.38 (0.6C, d,
JCeF ¼ 245 Hz), 154.22 (1C), 154.26 (0.4H, d, JCeF ¼ 245 Hz), 160.54
(0.6C), 165.13 (0.4C), and 192.75 (1C); ESI-MS (m/z): 412 (Mþ).
HRMS-ESI (m/z): Calcd. for C17H23FN5O4S (Mþ þ H): 412.1449;
Found 412.1450.
(CDCl3)
d
¼ 2.03 (3H, s, CH3eC]O), 2.19 (3H, s, CH3eC]O), 3.38e
3.45 (4H, m, eCH2e), 3.62e3.70 (2H, m, eCH2e), 3.74 (1H, dd,
J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 3.90 (2H, t, J ¼ 5.3 Hz, eCH2e),
3.99 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.12 (2H, t, J ¼ 4.9 Hz,
eCH2e), 4.73e4.83 (1H, m, oxazolidinone-H5), 6.36 (1H, t,
J ¼ 6.0 Hz, -NH-C]O), and 7.10 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6);
13C NMR (CDCl3)
d
¼ 19.88 (1C), 22.83 (1C), 41.79 (1C), 47.40 (1C),
49.43 (1C), 52.34 (1C), 54.39 (1C), 71.96 (1C), 76.72 (1C), 102.35 (2C,
d, JCeF ¼ 30.2 Hz), 124.53 (1C, t, JCeF ¼ 15.5 Hz), 133.98 (1C, t, JCe
4.1.2. 5(R)-3-(4-(1-Formyl[1,2,5]triazepan-5-yl)-3,5-
¼ 12.1 Hz), 154.03 (1C), 158.20 (2C, dd, JCeF ¼ 8.9, 246 Hz), and
F
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (9b)
Compound 9b (148.7 mg, 55%) was prepared from 7b (318.1 mg,
0.663 mmol) in the same manner as described for 7a. White
powder (EtOH); mp 124e126 ꢁC; 1H NMR (CDCl3 þ CD3OD)
171.31 (2C); LRMS-EI (m/z): 412 (Mþ). HRMS-EI (m/z): Calcd. for
C
C
18H22F2N4O5 (Mþ): 412.1558; Found 412.1568. Anal. Calcd for
18H22F2N4O5: C, 52.42; H, 5.38; N, 13.59. Found: C, 52.30; H, 5.34;
N, 13.57.
d
¼ 3.00e3.06 (0.8H, m), 3.15e3.22 (1.2H, m, eCH2e), 3.26e3.42
(3H, m, eCH2e), 3.48e3.55 (0.8H, m, eCH2e), 3.58e3.66 (1.2H, m,
eCH2e), 3.72e3.78 (1H, m, eCH2e), 3.86e3.96 (1H, m, eCH2e),
4.16 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.80 (1H, dd, J ¼ 5.0,
14.8 Hz, eCHHe[1,2,3]triazole), 4.84 (1H, dd, J ¼ 3.8, 14.8 Hz, e
CHHe[1,2,3]triazole), 5.05e5.16 (1H, m, oxazolidinone-H5), 7.01
(0.8H, d, J ¼ 10.7 Hz, Ar-H2 and H6), 7.03 (1.2H, d, J ¼ 10.7 Hz, Ar-H2
and H6), 7.74 (1H, s, [1,2,3]triazole-H), 7.89 (1H, s, [1,2,3]triazole-H),
8.02 (0.4H, s, eCH]O), and 8.32 (0.6H, s, eCH]O); 13C NMR
4.1.5. (S)-N-((3-(3-Fluoro-4-(1-acetyl[1,2,5]triazepan-5-yl)phenyl)-
2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate (10b)
To a solution of 6a (264.8 mg, 0.548 mmol) and Et3N (0.5 mL,
3.558 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.3 mL,
3.174 mmol). The mixture was stirred for 30 min at ambient tem-
perature. The reaction was quenched by the addition of 10% po-
tassium carbonate aqueous solution (10 mL), and the mixture was
diluted with ethyl acetate. The organic layer was washed with
brine, dried and evaporated. The residue was used for the next
reaction without further purification. To a solution of the residue in
1,4-dioxane (3 mL) was added concentrated hydrochloric acid
(0.5 mL). The mixture was stirred for 2 h at ambient temperature.
The reaction was quenched by the addition of 10% potassium car-
bonate aqueous solution (10 mL), and the mixture was extracted
with 5% MeOH/CHCl3. The organic solution was dried and evapo-
rated. Silica gel (10 g) column chromatography of the residue using
CHCl3/MeOH (99:1 to 99:2) as the eluent afforded 10b (164.8 mg,
(CDCl3 þ CD3OD) ¼ 46.97 (1C), 49.53 (1C), 51.12 (1C), 51.71 (0.6C),
d
51.92 (0.4C), 52.67 (0.6C), 53.11 (0.4C), 55.28 (0.6C), 56.12 (0.4C),
70.46 (1C), 102.45 (2C, d, JCeF ¼ 31.0 Hz), 124.99 (1C, t, JCeF ¼ 15 Hz),
125.24 (1C), 133.47 (1C, t, JCeF ¼ 14 Hz), 133.79 (1C), 153.28 (1C),
157.90 (0.8C, dd, JCeF ¼ 8.3, 244 Hz), 158.26 (1.2C, dd, JCeF ¼ 8.3,
244 Hz), 160.79 (0.4C), and 165.33 (0.6C); LRMS-EI (m/z): 407 (Mþ).
HRMS-EI (m/z): Calcd. for C17H19F2N7O3 (Mþ): 407.1517; Found
407.1526.
4.1.3. 5(S)-(Isoxazol-3-ylaminomethyl)-3-(3,5-difluoro-4-(1-formyl
[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (9c)
71%). Amorphous solid; 1H NMR (CDCl3)
d
¼ 1.96 (1.5H, s, CH3e
C]O), 2.20 (1.5H, s, CH3eC]O), 3.06e4.14 (12H, m, eCH2e), 4.01
(3H, s, eOCH3), 4.85e4.96 (1H, m, oxazolidinone-H5), 6.88 (1H, br t,
J ¼ 6 Hz, eNHeC]S), 6.88 (0.5H, t, J ¼ 9.1 Hz, Ar-H5), 6.89 (0.5H, t,
J ¼ 9.1 Hz, Ar-H5), 6.99 (0.5H, dd, J ¼ 2.4, 9.1 Hz, Ar-H6), 7.03 (0.5H,
dd, J ¼ 2.4, 9.1 Hz, Ar-H6), 7.39 (0.5H, dd, J ¼ 2.4,14.8 Hz, Ar-H2), and
Compound 9c (78.9 mg, 31%) was prepared from 8b (357.5 mg,
0.601 mmol) in the same manner as described for 9a. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 3.00e3.06 (1H, m, eCH2e), 3.18e3.41
(4H, m, eCH2e), 3.48e3.54 (1H, m, eCH2e), 3.56e3.67 (2H, m, e
CH2e), 3.69e3.85 (3H, m, eCH2e), 4.03 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.39 (1H, t, J ¼ 6.5 Hz, eNHeisoxazole), 4.89e
5.00 (1H, m, oxazolidinone-H5), 5.87 (1H, d, J ¼ 1.8 Hz, isoxazole-
H), 7.09 (1.2H, d, J ¼ 10.8 Hz, Ar-H2 and H6), 7.11 (0.8H, d,
J ¼ 10.8 Hz, Ar-H2 and H6), 8.04 (0.6H, s, eCH]O), 8.07 (1H, d,
J ¼ 1.8 Hz, isoxazole-H), and 8.36 (0.4H, s, eCH]O); 13C NMR
7.43 (0.5H, dd, J ¼ 2.4, 14.8 Hz, Ar-H2); 13C NMR (CDCl3)
d
¼ 20.67
(1C), 47.62 (1C), 49.49 (0.5C), 49.56 (0.5C), 50.44 (0.5C), 50.73
(0.5C), 51.19 (1C), 51.77 (0.5C), 51.85 (0.5C), 53.66 (0.5C), 53.91
(0.5C), 57.50 (1C), 71.15 (1C), 107.88 (1C, d, JCeF ¼ 26.6 Hz), 114.23
(1C), 118.44 (0.5C), 118.89 (0.5C), 131.02 (0.5C, d, JCeF ¼ 12.2 Hz),
131.54 (0.5C, d, JCeF ¼ 12.2 Hz), 135.20 (0.5C, d, JCeF ¼ 8.3 Hz),136.23
(0.5C, d, JCeF ¼ 8.3 Hz), 153.63 (1C, d, JCeF ¼ 241 Hz), 154.23 (1C),
168.74 (0.5C), 173.68 (0.5C), and 192.75 (1C); LRMS-EI (m/z): 425
(Mþ). HRMS-EI (m/z): Calcd. for C18H24FN5O4S (Mþ): 425.1533;
Found 425.1483.
(CDCl3)
d
¼ 46.43 (1C), 47.47 (1C), 48.72 (0.6C), 49.55 (0.4C), 51.52
(0.6C), 52.38 (0.4C), 52.96 (0.6C), 53.38 (0.4C), 55.54 (0.6C), 56.42
(0.4C), 71.46 (1C), 96.38 (1C), 102.31 (2C, d, JCeF ¼ 30.4 Hz),124.73
(0.6C, t, JCeF ¼ 14.3 Hz), 125.02 (0.4C, t, JCeF ¼ 14.3 Hz), 133.68 (0.4C,
t, JCeF ¼ 13.6 Hz), 134.32 (0.6C, t, JCeF ¼ 13.6 Hz), 154.08 (1C), 158.07
(0.8C, dd, JCeF ¼ 8.3, 245 Hz), 158.17 (1C), 158.49 (1.2C, dd, JCeF ¼ 8.3,
245 Hz), 160.60 (1C), 163.65 (0.6C), and 165.17 (0.4C); LRMS-EI (m/
z): 422 (Mþ). HRMS-EI (m/z): Calcd. for C18H20F2N6O4 (Mþ):
422.1514; Found 422.1506.
4.1.6. (S)-N-((3-(3,5-Difluoro-4-(2-acetyl[1,2,5]oxadiazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)thioacetamide (10c)
Compound 10c (111.1 mg, 98%) was prepared from 5c (101.6 mg,
0.263 mmol) in the same manner as described for 10a.
White powder (EtOH); mp 121e123 ꢁC; 1H NMR (CDCl3)
d
¼ 2.19
4.1.4. (S)-N-((3-(3,5-Difluoro-4-(2-acetyl[1,2,5]oxadiazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (10a)
To a solution of 4c (99.2 mg, 0.268 mmol) and Et3N (0.2 mL,
1.423 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.1 mL,
(3H, s, CH3eC]O), 2.60 (3H, s, CH3eC]S), 3.38e3.46 (4H, m,
eCH2e), 3.80 (1H, dd, J ¼ 6.9, 9.1 Hz, oxazolidinone-H4), 3.90
(2H, t, J ¼ 5.6 Hz, eCH2e), 4.04 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.09e4.15 (3H, m, eCH2e), 4.24 (1H, ddd, J ¼ 2.9, 5.8,

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
269
14.4 Hz, eCHHeNHeC]S), 4.94e5.04 (1H, m, oxazolidinone-H5),
7.08 (2H, d, J ¼ 10.9 Hz, Ar-H2 and H6), and 8.24 (1H, br t,
6.95 (1H, t, J ¼ 9.1 Hz, Ar-H5), 7.06 (1H, dd, J ¼ 2.2, 9.1 Hz, Ar-H6),
7.40 (1H, dd, J ¼ 2.2, 14.7 Hz, Ar-H2), and 8.56 (1H, br t, J ¼ 6 Hz, e
J ¼ 6 Hz, eNHeC]S); 13C NMR (CDCl3)
d
¼ 19.96 (1C), 33.74 (1C),
NHeC]O); 13C NMR (CDCl3 þ CD3OD)
d
¼ 47.27 (1C), 47.70 (1C),
47.57 (1C), 47.89 (1C), 49.50 (1C), 52.33 (1C), 54.44 (1C), 71.15 (1C),
50.00 (1C), 50.19 (1C), 50.95 (1C), 53.62 (1C), 57.03 (1C), 71.34 (1C),
105.98 (1C, t, JCeF ¼ 242 Hz), 107.83 (1C, d, JCeF ¼ 26.0 Hz), 114.28
(1C), 119.14 (1C), 131.73 (1C, d, JCeF ¼ 14.1 Hz), 136.04 (1C, d, JCe
76.88 (1C), 102.52 (2C, d, JCeF ¼ 29.8 Hz), 124.75 (1C, t, JCe
¼ 13.3 Hz), 133.73 (1C, t, JCeF ¼ 12.7 Hz), 154.08 (1C), 158.18 (2C,
F
dd, JCeF ¼ 8.9, 246 Hz), 171.50 (1C), and 203.85 (1C); LRMS-ESI (m/
z): 429 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C18H23F2N4O4S
(Mþ þ H): 429.1403; Found 429.1404.
¼ 9.4 Hz), 154.27 (1C, d, JCeF ¼ 247 Hz), 154.78 (1C), 164.33 (1C, t,
F
JCeF ¼ 26.9 Hz), and 192.78 (1C); LRMS-EI (m/z): 461 (Mþ). HRMS-EI
(m/z): Calcd. for C18H22F3N5O4S (Mþ): 461.1345; Found 461.1347.
Anal. Calcd for C18H22F3N5O4S: C, 46.85; H, 4.81; N, 15.18. Found: C,
46.82; H, 4.78; N, 15.15.
4.1.7. (S)-N-((3-(3,5-Difluoro-4-(1-acetyl[1,2,5]triazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate
(10d)
Compound 10d (174.6 mg, 75%) was prepared from 6b
(262.8 mg, 0.524 mmol) in the same manner as described for 10b.
4.1.10. 5(R)-3-(4-(1-(Difluoroacetyl)[1,2,5]triazepan-5-yl)-3,5-
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (11b)
Compound 11b (131.0 mg, 45%) was prepared from 7b
(303.0 mg, 0.632 mmol) in the same manner as described for
11a. Colorless needles (EtOH); mp 157.5e159.5 ꢁC; 1H NMR
Amorphous solid; 1H NMR (CDCl3)
d
¼ 2.12 (1.2H, s, CH3eC]O),
2.22 (1.8H, s, CH3eC]O), 2.96e4.16 (12H, m, eCH2e), 4.01 (3H, s, e
OCH3), 4.87e4.98 (1H, m, oxazolidinone-H5), 6.86 (0.4H, br t,
J ¼ 6 Hz, eNHeC]S), 6.89 (0.6H, br t, J ¼ 9.1 Hz, eNHeC]S), and
(CDCl3 þ CD3OD) ¼ 3.14e3.21 (2H, m, eCH2e), 3.25e3.32 (2H, m,
d
eCH2e), 3.36e3.43 (2H, m, eCH2e), 3.82e3.89 (2H, m, eCH2e),
3.92 (1H, dd, J ¼ 5.9, 9.1 Hz, oxazolidinone-H4), 4.18 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.81 (1H, dd, J ¼ 5.0, 14.8 Hz, eCHHe
[1,2,3]-triazole), 4.85 (1H, dd, J ¼ 3.8, 14.8 Hz, eCHHe[1,2,3]tri-
azole), 5.11 (1H, dddd, J ¼ 3.8, 5.0, 5.9, 9.1 Hz, oxazolidinone-H5),
6.67 (1H, t, J ¼ 54.3 Hz, CHF2eC]O), 7.04 (2H, d, J ¼ 10.6 Hz, Ar-
H2 and H6), 7.74 (1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-H), and 7.91
(1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-H); 13C NMR (CDCl3 þ CD3OD)
7.10 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6); 13C NMR (CDCl3)
d
¼ 20.75
(1C), 47.41 (2C), 50.54 (1C), 51.67 (0.6C), 52.38 (0.4C), 52.83 (0.6C),
53.26 (0.4C), 55.30 (0.6C), 55.91 (0.4C), 57.53 (1C), 71.23 (1C),102.37
(2C, d, JCeF ¼ 29.9 Hz), 125.08 (0.4C, t, JCeF ¼ 13.7 Hz), 125.41 (0.6C, t,
JCeF ¼ 13.7 Hz), 133.82 (0.4C, t, JCeF ¼ 14.0 Hz), 134.19 (0.6C, t, JCe
¼ 14.0 Hz), 153.85 (1C),158.21 (0.8C, dd, JCeF ¼ 8.8, 246 Hz),158.48
F
(1.2C, dd, JCeF ¼ 8.8, 246 Hz),168.68 (0.4C),173.76 (0.6C), and 192.87
(1C); LRMS-EI (m/z): 443 (Mþ). HRMS-EI (m/z): Calcd. for
d
¼ 46.92 (1C), 50.97 (1C), 51.32 (1C), 51.69 (1C), 51.84 (1C), 55.03
C
18H23F2N5O4S (Mþ): 443.1439; Found 443.1449.
(1C), 70.49 (1C), 102.39 (2C, d, JCeF ¼ 30.4 Hz), 106.01 (1C, t, JCe
¼ 242 Hz), 124.80 (1C, t, JCeF ¼ 14.3 Hz), 125.29 (1C), 133.60 (1C, t,
F
4.1.8. 5(R)-3-(4-(1-Acetyl[1,2,5]triazepan-5-yl)-3,5-
JCeF ¼ 12.8 Hz), 133.71 (1C), 153.34 (1C), 158.27 (2C, dd, JCeF ¼ 9.4,
247 Hz), and 164.30 (1C, t, JCeF ¼ 26.6 Hz); LRMS-EI (m/z): 457 (Mþ).
HRMS-EI (m/z): Calcd. for C18H19F4N7O3 (Mþ): 457.1486; Found
457.1500.
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (10e)
Compound 10e (185.2 mg, 85%) was prepared from
7b (247.2 mg, 0.516 mmol) in the same manner as described
for 10b. Colorless needles (EtOH); mp 161e162.5 ꢁC; 1H NMR
(CDCl3 þ CD3OD)
d
¼ 2.13 (1.2H, m, CH3eC]O), 2.22 (1.8H, s, CH3e
4.1.11. 5(S)-(Isoxazol-3-ylaminomethyl)-3-(3,5-difluoro-4-(1-
(difluoroacetyl)[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (11c)
Compound 11c (80.9 mg, 30%) was prepared from 8b (342.7 mg,
0.576 mmol) in the same manner as described for 11a. White
powder (EtOH); mp 122e124 ꢁC; 1H NMR (CDCl3 þ CD3OD)
C]O), 2.96e3.03 (0.8H, m, eCH2e), 3.09e3.16 (1.2H, m, eCH2e),
3.25e3.38 (3H, m, eCH2e), 3.50 (0.8H, t, J ¼ 5.8 Hz, eCH2e), 3.69
(1.2H, t, J ¼ 5.8 Hz, eCH2e), 3.78e3.85 (1H, m, eCH2e), 3.91 (1H,
dd, J ¼ 5.9, 9.1 Hz, oxazolidinone-H4), 4.17 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.81 (1H, dd, J ¼ 4.8, 14.6 Hz, eCHHe[1,2,3]
triazole), 4.85 (1H, dd, J ¼ 3.9, 14.6 Hz, eCHHe[1,2,3]triazole), 5.11
(1H, dddd, J ¼ 3.9, 4.8, 5.9, 9.1 Hz, oxazolidinone-H5), 7.03 (2H, d,
J ¼ 10.6 Hz, Ar-H2 and H6), 7.74 (1H, s, [1,2,3]triazole-H), and 7.90
d
¼ 3.15e3.22 (2H, m, eCH2e), 3.26e3.33 (2H, m, eCH2e), 3.37e
3.43 (2H, m, eCH2e), 3.56 (1H, dd, J ¼ 5.6, 14.7 Hz, eCHHeNHe
isoxazole), 3.64 (1H, dd, J ¼ 3.6, 14.7 Hz, eCHHeNHeisoxazole),
3.78e3.89 (3H, m, eCH2e), 4.06 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.87e4.98 (1H, m, oxazolidinone-H5), 5.92 (1H, d, J ¼ 1.8 Hz,
isoxazole-H), 6.66 (1H, t, J ¼ 53.4 Hz, CHF2eC]O), 7.14 (2H, d,
J ¼ 10.8 Hz, Ar-H2 and H6), and 8.07 (1H, d, J ¼ 1.8 Hz, isoxazole-H);
(1H, s, [1,2,3]triazole-H); 13C NMR (CDCl3 þ CD3OD)
d
¼ 20.14 (1C),
46.93 (1C), 50.27 (0.6C), 50.37 (0.4C), 51.30 (0.6C), 51.68 (1C), 51.93
(0.4C), 52.16 (0.6C), 52.84 (0.4C), 55.02 (0.6C), 55.51 (0.4C), 70.46
(1C), 102.41 (2C, d, JCeF ¼ 30.4 Hz), 125.07 (0.6C, t, JCeF ¼ 15.3 Hz),
125.23 (0.4C, t, JCeF ¼ 15.3 Hz), 125.24 (1C), 133.26 (0.6C, t, JCe
13C NMR (CDCl3 þ CD3OD)
d
¼ 46.11 (1C), 47.45 (1C), 51.08 (1C),
51.57 (1C), 51.90 (1C), 55.16 (1C), 71.58 (1C), 96.23 (1C), 102.28 (2C,
¼ 14.3 Hz), 133.34 (0.4C, t, JCeF ¼ 14.3 Hz), 133.72 (1C), 153.31 (1C),
d, JCeF ¼ 30.4 Hz), 106.10 (1C, t, JCeF ¼ 243 Hz), 124.51 (1C, t, JCe
F
158.03 (0.8C, dd, JCeF ¼ 9.1, 245 Hz), 158.25 (1.2C, dd, JCeF ¼ 9.1,
245 Hz), 169.07 (0.4C), and 174.26 (0.6C); LRMS-EI (m/z): 421 (Mþ).
HRMS-EI (m/z): Calcd. for C18H21F2N7O3 (Mþ): 421.1674; Found
421.1664. Anal. Calcd for C18H21F2N7O3: C, 51.30; H, 5.02; N, 23.27.
Found: C, 51.29; H, 5.02; N, 23.23.
¼ 14.4 Hz), 134.42 (1C, t, JCeF ¼ 12.3 Hz), 154.42 (1C), 158.04 (1C),
F
158.44 (2C, dd, JCeF ¼ 8.8, 246 Hz), 163.66 (1C), and 164.31 (1C, t, JCe
¼ 26.6 Hz); LRMS-EI (m/z): 472 (Mþ). HRMS-EI (m/z): Calcd. for
F
C
19H20F4N6O4 (Mþ): 472.1482; Found 472.1467.
4.1.12. (S)-N-((3-(3-Fluoro-4-(10-oxo-5,6,8,9-tetrahydro-10H-
4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)phenyl)-2-oxo-5-
oxazolidinyl)methyl)acetamide (12a)
4.1.9. (S)-N-((3-(3-Fluoro-4-(1-(difluoroacetyl)[1,2,5]triazepan-5-
yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate
(11a)
To a solution of 4a (218.7 mg, 0.484 mmol) and pyridine
(0.1 mL, 1.241 mmol) in CH2Cl2 (2 mL) was added 2-
chloronicotinoyl chloride (130.8 mg, 0.743 mmol). The mixture
was stirred for 1 h at ambient temperature, and then concentrated
in vacuo. The residue was used for the next reaction without
further purification. To a solution of the residue in CH2Cl2 (5 mL)
was added trifluoroacetic acid (0.5 mL). The mixture was stirred
for 18 h at ambient temperature, then neutralized with 10%
Compound 11a (171.6 mg, 58%) was prepared from 6a (310.7 mg,
0.643 mmol) in the same manner as described for 9a, except that
difluoroacetic acid was used instead of formic acid. White powder
(EtOH); mp 133e135 ꢁC; 1H NMR (CDCl3 þ CD3OD)
d
¼ 3.20e3.26
(2H, m, eCH2e), 3.33e3.39 (2H, m, eCH2e), 3.43e3.49 (2H, m, e
CH2e), 3.81e4.15 (6H, m, eCH2e), 4.00 (3H, s, CH3Oe), 4.88e4.99
(1H, m, oxazolidinone-H5), 6.65 (1H, t, J ¼ 53.4 Hz, CHF2eC]O),

270
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
potassium carbonate aqueous solution (10 mL), and extracted with
10% MeOH/CHCl3. The organic solution was dried and evaporated.
Silica gel (8 g) column chromatography of the residue using CHCl3/
MeOH (98:2 to 94:6) as the eluent afforded 12a (190.7 mg, 87%).
Colorless needles (EtOH); mp 212.5e213.5 ꢁC; 1H NMR
4.1.15. (S)-N-((3-(3,5-Difluoro-4-(10-oxo-5,6,8,9-tetrahydro-10H-
4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)phenyl)-2-oxo-5-
oxazolidinyl)methyl)-O-methylthiocarbamate (12d)
Compound 12d (230.1 mg, 88%) was prepared from 6b
(258.8 mg, 0.516 mmol) in the same manner as described for
12a. Colorless needles (EtOH); mp 220e223 ꢁC; 1H NMR
(CDCl3 þ CD3OD)
d
¼ 2.01 (3H, s, CH3eC]O), 3.41e3.54 (4H, m, e
CH2e), 3.53e3.68 (2H, m, eCH2e), 3.78 (1H, dd, J ¼ 6.6, 9.1 Hz,
oxazolidinone-H4), 4.08 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4),
4.41e4.54 (4H, m, eCH2e), 4.73e4.83 (1H, m, oxazolidinone-H5),
7.05 (1H, t, J ¼ 8.8 Hz, Ar-H5), 7.11 (1H, dd, J ¼ 2.4, 8.8 Hz, Ar-
H6), 7.15 (1H, dd, J ¼ 4.7, 7.9 Hz, fused ring-H2), 7.49 (1H, dd,
J ¼ 2.4, 14.1 Hz, Ar-H2), 7.97 (1H, t, J ¼ 5.9 Hz, eNHeC]O), 8.21
(1H, dd, J ¼ 1.5, 7.9 Hz, fused ring-H1), and 8.57 (1H, dd, J ¼ 1.5,
(CDCl3 þ CD3OD) ¼ 3.40e3.54 (4H, m, eCH2e), 3.86e4.12 (4H, m,
d
eCH2e), 4.01 (3H, s, CH3Oe), 4.38e4.54 (4H, m, eCH2e), 4.91e5.01
(1H, m, oxazolidinone-H5), 7.15 (1H, dd, J ¼ 4.8, 7.9 Hz, fused ring-
H2), 7.18 (2H, d, J ¼ 10.7 Hz, Ar-H2 and H6), 8.22 (1H, dd, J ¼ 1.7,
7.9 Hz, fused ring-H1), and 8.56 (1H, dd, J ¼ 1.7, 4.8 Hz, fused ring-
H3); 13C NMR (CDCl3 þ CD3OD)
d
¼ 45.31 (1C), 47.09 (1C), 47.25
(1C), 48.85 (1C), 54.21 (1C), 54.45 (1C), 57.03 (1C), 71.35 (1C),102.24
4.7 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
d
¼ 21.94 (1C),
(2C, d, JCeF ¼ 29.4 Hz), 108.16 (1C), 116.79 (1C), 124.30 (1C, t, JCe
41.68 (1C), 44.47 (1C), 47.59 (1C), 48.15 (1C), 53.58 (1C), 53.71 (1C),
71.83 (1C), 107.39 (1C, d, JCeF ¼ 26.6 Hz), 108.31 (1C), 113.90 (1C),
116.90 (1C), 120.92 (1C), 133.23 (1C), 133.41 (1C, d, JCeF ¼ 10.0 Hz),
136.09 (1C, d, JCeF ¼ 9.4 Hz), 152.72 (1C), 153.95 (1C), 154.66 (1C),
155.26 (1C, d, JCeF ¼ 246 Hz), 157.94 (1C), and 172.06 (1C); LRMS-EI
(m/z): 454 (Mþ). HRMS-EI (m/z): Calcd. for C22H23FN6O4 (Mþ):
454.1765; Found 454.1768.
¼ 14.6 Hz), 133.27 (1C), 134.89 (1C, t, JCeF ¼ 13.6 Hz), 152.71 (1C),
F
153.60 (1C), 154.23 (1C), 157.75 (1C), 158.42 (2C, dd, JCeF ¼ 8.5,
243 Hz), and 192.86 (1C); LRMS-EI (m/z): 504 (Mþ). HRMS-EI (m/z):
Calcd. for C22H22F2N6O4S (Mþ): 504.1391; Found 504.1413. Anal.
Calcd for C22H22F2N6O4S: C, 52.37; H, 4.40; N, 16.66. Found: C,
52.15; H, 4.45; N, 16.40.
4.1.16. 5(R)-3-(4-(10-Oxo-5,6,8,9-tetrahydro-10H-4,4b,7,9a-
tetraazabenzo[a]azulen-7-yl)-3-fluorophenyl)-5-(1,2,3-tri-azol-1-
ylmethyl)oxazolidin-2-one (12e)
4.1.13. (S)-N-((3-(3,5-Difluoro-4-(10-oxo-5,6,8,9-tetrahydro-10H-
4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)phenyl)-2-oxo-5-
oxazolidinyl)methyl)acetamide (12b)
Compound 12b (114.4 mg, 100%) was prepared from 4b
(113.9 mg, 0.243 mmol) in the same manner as described for 12a.
Colorless needles (EtOH); mp 204e206 ꢁC; 1H NMR (CDCl3)
Compound 12e (84.2 mg, 84%) was prepared from 7a (99.3 mg,
0.215 mmol) in the same manner as described for 12a. Colorless
needles (EtOH); mp 166.5e168.5 ꢁC; 1H NMR (CDCl3)
d
¼ 3.37e
3.50 (4H, m, eCH2e), 3.92 (1H, dd, J ¼ 5.9, 9.1 Hz, oxazolidinone-
H4), 4.14 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.37e4.47 (4H, m, e
CH2e), 4.80 (2H, d, J ¼ 4.4 Hz, eCH2e[1,2,3]triazole), 5.07 (1H, ddt,
J ¼ 5.9, 9.1, 4.4 Hz, oxazolidinone-H5), 6.92e7.00 (2H, m, Ar-H5
and H6), 7.08 (1H, dd, J ¼ 4.7, 7.6 Hz, fused ring-H2), 7.33 (1H,
dd, J ¼ 2.2, 13.5 Hz, Ar-H2), 7.75 (1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-
H), 7.79 (1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-H), 8.17 (1H, dd, J ¼ 1.8,
7.6 Hz, fused ring-H1), and 8.54 (1H, dd, J ¼ 1.8, 4.7 Hz, fused ring-
d
¼ 2.03 (3H, s, CH3eC]O), 3.38e3.51 (4H, m, eCH2e), 3.57e3.73
(2H, m, eCH2e), 3.74 (1H, dd, J ¼ 6.8, 9.1 Hz, oxazolidinone-H4),
4.00 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.37e4.48 (4H, m, e
CH2e), 4.73e4.84 (1H, m, oxazolidinone-H5), 6.00 (1H, br t,
J ¼ 6 Hz, eNHeC]O), 7.07 (1H, dd, J ¼ 4.7, 7.6 Hz, fused ring-H2),
7.14 (2H, d, J ¼ 10.9 Hz, Ar-H2 and H6), 8.18 (1H, dd, J ¼ 1.8,
7.6 Hz, fused ring-H1), and 8.53 (1H, dd, J ¼ 1.8, 4.7 Hz, fused
ring-H3); 13C NMR (CDCl3)
47.44 (1C), 49.33 (1C), 54.56 (1C), 54.72 (1C), 71.99 (1C), 102.35
d
¼ 22.89 (1C), 41.89 (1C), 45.48 (1C),
H3); 13C NMR (CDCl3)
(1C), 53.75 (1C), 53.85 (1C), 70.37 (1C), 107.89 (1C, d, JCe
d
¼ 44.65 (1C), 47.35 (1C), 48.69 (1C), 51.95
(2C, d, JCeF ¼ 29.4 Hz), 108.93 (1C), 116.80 (1C), 124.72 (1C, t, JCe
¼ 25.4 Hz), 109.15 (1C), 114.30 (1C), 116.95 (1C), 120.93 (1C),
F
¼ 14.6 Hz), 133.29 (1C), 134.97 (1C, t, JCeF ¼ 13.6 Hz), 152.74
125.04 (1C), 132.80 (1C, d, JCeF ¼ 8.8 Hz), 133.30 (1C), 134.33 (1C),
136.75 (1C, d, JCeF ¼ 10.0 Hz), 152.75 (1C), 153.32 (1C), 155.17 (1C),
155.36 (1C, d, JCeF ¼ 245 Hz), and 158.34 (1C); LRMS-EI (m/z): 464
(Mþ). HRMS-EI (m/z): Calcd. for C22H21FN8O3 (Mþ): 464.1721;
Found 464.1710.
F
(1C), 153.98 (1C), 154.73 (1C), 158.11 (1C), 158.70 (2C, dd, JCe
¼ 8.3, 246 Hz), and 171.31 (1C); LRMS-EI (m/z): 472 (Mþ).
F
HRMS-EI (m/z): Calcd. for C22H22F2N6O4 (Mþ): 472.1671; Found
472.1689.
4.1.14. (S)-N-((3-(3-Fluoro-4-(10-oxo-5,6,8,9-tetrahydro-10H-
4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)phenyl)-2-oxo-5-
oxazolidinyl)methyl)-O-methylthiocarbamate (12c)
4.1.17. 5(R)-3-(4-(10-Oxo-5,6,8,9-tetrahydro-10H-4,4b,7,9a-
tetraazabenzo[a]azulen-7-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-
1-ylmethyl)oxazolidin-2-one (12f)
Compound 12c (228.3 mg, 90%) was prepared from 6a
(253.4 mg, 0.524 mmol) in the same manner as described for 12a.
Colorless needles (EtOH); mp 203e205 ꢁC; 1H NMR
Compound 12f (64.7 mg, 90%) was prepared from 7b (71.4 mg,
0.149 mmol) in the same manner as described for 12a. Colorless
needles (EtOH); mp 209e211 ꢁC; 1H NMR (CDCl3 þ CD3OD)
(CDCl3 þ CD3OD)
d
¼ 3.42e3.54 (4H, m, eCH2e), 3.87e4.07 (3H, m,
d
¼ 3.40e3.52 (4H, m, eCH2e), 3.93 (1H, dd, J ¼ 6.1, 9.1 Hz,
eCH2e), 4.00 (3H, s, eOCH3), 4.09 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.41e4.54 (4H, m, eCH2e), 4.90e5.00 (1H, m, oxazolidinone-
H5), 7.05 (1H, t, J ¼ 8.8 Hz, Ar-H5), 7.12 (1H, dd, J ¼ 2.3, 8.8 Hz,
Ar-H6), 7.15 (1H, dd, J ¼ 4.7, 7.9 Hz, fused ring-H2), 7.47 (1H, dd,
J ¼ 2.4, 13.8 Hz, Ar-H2), 8.21 (1H, dd, J ¼ 1.8, 7.9 Hz, fused ring-H1),
and 8.57 (1H, dd, J ¼ 1.8, 4.7 Hz, fused ring-H3); 13C NMR
oxazolidinone-H4), 4.18 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.39e
4.52 (4H, m, eCH2e), 4.81 (1H, dd, J ¼ 4.9, 14.8 Hz, eCHHe[1,2,3]
triazole), 4.86 (1H, dd, J ¼ 4.9, 14.8 Hz, eCHHe[1,2,3]triazole), 5.12
(1H, ddt, J ¼ 6.1, 9.1, 4.9 Hz, oxazolidinone-H5), 7.08 (2H, d,
J ¼ 10.8 Hz, Ar-H2 and H6), 7.14 (1H, dd, J ¼ 4.8, 7.8 Hz, fused ring-
H2), 7.75 (1H, br s, [1,2,3]triazole-H), 7.91 (1H, br s, [1,2,3]triazole-
H), 8.21 (1H, dd, J ¼ 1.5, 7.8 Hz, fused ring-H1), and 8.56 (1H, dd,
(CDCl3 þ CD3OD)
d
¼ 44.50 (1C), 47.24 (1C), 47.58 (1C), 48.15 (1C),
53.59 (1C), 53.75 (1C), 57.00 (1C), 71.34 (1C), 107.53 (1C, d, JCe
J ¼ 1.5, 4.8 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
¼ 45.32
d
¼ 26.0 Hz), 108.35 (1C), 114.05 (1C), 116.92 (1C), 120.94 (1C),
(1C), 46.91 (1C), 48.89 (1C), 51.68 (1C), 54.18 (1C), 54.41 (1C), 70.48
(1C), 102.37 (2C, d, JCeF ¼ 29.9 Hz), 108.24 (1C), 116.80 (1C), 124.60
(1C, t, JCeF ¼ 14.7 Hz), 125.25 (1C), 133.26 (1C), 133.76 (1C), 134.30
(1C, t, JCeF ¼ 13.5 Hz), 152.72 (1C), 153.26 (1C), 153.80 (1C), 157.86
(1C), and 158.38 (2C, dd, JCeF ¼ 10.0, 248 Hz); LRMS-EI (m/z): 482
(Mþ). HRMS-EI (m/z): Calcd. for C22H20F2N8O3 (Mþ): 482.1626;
F
133.27 (1C), 133.41 (1C, d, JCeF ¼ 10.6 Hz), 136.15 (1C, d, JCe
¼ 9.9 Hz), 152.74 (1C), 153.97 (1C), 154.63 (1C), 155.28 (1C, d, JCe
F
¼ 246 Hz), 158.00 (1C), and 192.82 (1C); LRMS-EI (m/z): 486 (Mþ).
F
HRMS-EI (m/z): Calcd. for C22H23FN6O4S (Mþ): 486.1486; Found
486.1506.

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
271
Found 482.1627. Anal. Calcd for C22H20F2N8O3: C, 54.77; H, 4.18; N,
23.23. Found: C, 54.57; H, 4.25; N, 22.97.
and evaporated. The residue was used for the next reaction without
further purification. To a solution of the residue in CH2Cl2 (5 mL)
was added trifluoroacetic acid (1.0 mL). The mixture was stirred for
7 h at ambient temperature, then neutralized with 10% potassium
carbonate aqueous solution (15 mL), and extracted with 10% MeOH/
CHCl3. The organic solution was dried and evaporated. Silica gel
(10 g) column chromatography of the residue using CHCl3/MeOH
(95:5 to 90:10) as the eluent afforded 15a (149.0 mg, 45%). Amor-
4.1.18. (S)-N-((3-(3,5-Difluoro-4-(2-chloro-10-oxo-5,6,8,9-
tetrahydro-10H-4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)-phenyl)-2-
oxo-5-oxazolidinyl)methyl)acetamide (13)
Compound 13 (102.9 mg, 76%) was prepared from 4b (125.0 mg,
0.266 mmol) in the same manner as described for 12a, except
that 2,5-dichloronicotinoyl chloride was used instead of 2-
chloronicotinoyl chloride. Colorless needles (EtOH); mp 247e
phous powder; 1H NMR (CDCl3 þ CD3OD)
d
¼ 2.02 (3H, s, CH3e
C]O), 3.36e3.54 (4H, m, eCH2e), 3.56e3.64 (2H, m, eCH2e), 3.76
(1H, dd, J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 4.06 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.24e4.36 (4H, m, eCH2e), 4.75e4.85 (1H, m,
oxazolidinone-H5), 7.17 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6), 7.47 (1H,
d, J ¼ 2.6 Hz, fused ring-H1), 8.04 (1H, t, J ¼ 5.9 Hz, eNHeC]O), and
8.16 (1H, d, J ¼ 2.6 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
249 ꢁC; 1H NMR (CDCl3 þ CD3OD)
¼ 2.01 (3H, s, CH3eC]O), 3.40e
d
3.52 (4H, m, eCH2e), 3.56 (1H, dd, J ¼ 5.6, 14.5 Hz, eCHHeNHe
C]O), 3.61 (1H, dd, J ¼ 4.1,14.5 Hz, eCHHeNHeC]O), 3.75 (1H, dd,
J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 4.04 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.39e4.51 (4H, m, eCH2e), 4.78 (1H, dddd,
J ¼ 4.1, 5.6, 6.7, 9.1 Hz, oxazolidinone-H5), 7.18 (2H, d, J ¼ 10.6 Hz,
Ar-H2 and H6), 8.17 (1H, d, J ¼ 2.4 Hz, fused ring-H1), and 8.50 (1H,
d
¼ 21.99 (1C), 41.71 (1C), 45.69 (1C), 47.35 (1C), 50.60 (1C), 53.60
(1C), 54.03 (1C), 71.85 (1C), 102.15 (2C, d, JCeF ¼ 29.8 Hz), 109.21
(1C), 116.15 (1C), 124.37 (1C, t, JCeF ¼ 15.5 Hz), 134.67 (1C, t, JCe
d, J ¼ 2.4 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
d
¼ 22.07
(1C), 41.66 (1C), 45.52 (1C), 47.41 (1C), 48.99 (1C), 54.30 (1C), 54.46
(1C), 71.94 (1C), 102.24 (2C, d, JCeF ¼ 29.9 Hz), 108.70 (1C), 124.28
(1C, t, JCeF ¼ 14.7 Hz), 124.40 (1C), 132.18 (1C), 135.02 (1C, t, JCe
¼ 13.6 Hz), 139.21 (1C), 142.59 (1C), 150.29 (1C), 154.32 (1C),
F
158.39 (2C, dd, JCeF ¼ 8.9, 246 Hz), 158.61 (1C), and 172.25 (1C);
LRMS-ESI (m/z): 488 (Mþ þ H). HRMS-ESI (m/z): Calcd. for
¼ 14.0 Hz), 151.77 (2C), 154.32 (1C), 156.92 (1C), 158.45 (2C, dd, JCe
C
22H24F2N7O4 (Mþ þ H): 488.1852; Found 488.1855.
F
¼ 8.8, 255 Hz), and 172.14 (1C); LRMS-EI (m/z): 506 (Mþ). HRMS-EI
F
(m/z): Calcd. for C22H21ClF2N6O4 (Mþ): 506.1281; Found 506.1289.
Anal. Calcd for C22H21ClF2N6O4: C, 52.13; H, 4.18; N, 16.58. Found: C,
51.93; H, 4.23; N, 16.42.
4.1.21. 5(R)-3-(4-(2-Amino-10-oxo-5,6,8,9-tetrahydro-10H-
4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)-3,5-difluorophenyl)-5-
(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (15b)
Compound 15b (152.1 mg, 48%) was prepared from 7b
(305.7 mg, 0.638 mmol) in the same manner as described for 15a.
4.1.19. (S)-N-((3-(3,5-Difluoro-4-(2-bromo-10-oxo-5,6,8,9-
tetrahydro-10H-4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)phenyl)-2-
oxo-5-oxazolidinyl)methyl)acetamide (14)
Amorphous powder; 1H NMR (CDCl3 þ CD3OD)
¼ 3.34e3.52 (4H,
d
m, eCH2e), 3.93 (1H, dd, J ¼ 5.9, 9.1 Hz, oxazolidinone-H4), 4.19
(1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.23e4.35 (4H, m, eCH2e),
4.82 (1H, dd, J ¼ 5.0, 14.8 Hz, eCHHe[1,2,3]triazole), 4.87 (1H, dd,
J ¼ 3.9, 14.8 Hz, eCHHe[1,2,3]triazole), 5.14 (1H, dddd, J ¼ 3.9, 5.0,
5.9, 9.1 Hz, oxazolidinone-H5), 7.07 (2H, d, J ¼ 10.7 Hz, Ar-H2 and
H6), 7.46 (1H, d, J ¼ 2.6 Hz, fused ring-H1), 7.75 (1H, d, J ¼ 0.9 Hz,
[1,2,3]triazole-H), 7.92 (1H, d, J ¼ 0.9 Hz, [1,2,3]triazole-H), and 8.16
(1H, d, J ¼ 2.6 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
Compound 14 (140.7 mg, 85%) was prepared from 4b (141.6 mg,
0.302 mmol) in the same manner as described for 12a, except that
5-bromo-2-chloronicotinoyl chloride was used instead of 2-
chloronicotinoyl chloride. Colorless needles (EtOH); mp 256e
258 ꢁC; 1H NMR (CDCl3 þ CD3OD)
¼ 2.01 (3H, s, CH3eC]O), 3.39e
d
3.51 (4H, m, eCH2e), 3.56 (1H, dd, J ¼ 5.6, 14.4 Hz, eCHHeNHe
C]O), 3.61 (1H, dd, J ¼ 3.8, 14.4 Hz, eCHHeNHeC]O), 3.75 (1H,
dd, J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 4.04 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.38e4.52 (4H, m, eCH2e), 4.78 (1H, dddd,
J ¼ 3.8, 5.6, 6.7, 9.1 Hz, oxazolidinone-H5), 7.18 (2H, d, J ¼ 10.9 Hz,
Ar-H2 and H6), 8.31 (1H, d, J ¼ 2.2 Hz, fused ring-H1), and 8.58 (1H,
d
¼ 45.70 (1C), 46.90 (1C), 50.62 (1C), 51.68 (1C), 53.56 (1C), 53.99
(1C), 70.48 (1C), 102.35 (2C, d, JCeF ¼ 29.9 Hz), 109.25 (1C), 116.19
(1C), 124.68 (1C, t, J ¼ 15.2 Hz), 125.28 (1C), 133.79 (1C), 134.05 (1C,
t, J ¼ 13.1 Hz), 139.17 (1C), 142.59 (1C), 150.30 (1C), 153.27 (1C),
158.32 (2C, dd, JCeF ¼ 8.9, 246 Hz), and 158.66 (1C); LRMS-ESI (m/z):
498 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C22H22F2N9O3 (Mþ þ H):
498.1808; Found 498.1809.
d, J ¼ 2.2 Hz, fused ring-H3); 13C NMR (CDCl3 þ CD3OD)
d
¼ 22.05
(1C), 41.68 (1C), 45.49 (1C), 47.41 (1C), 48.87 (1C), 54.34 (1C), 54.47
(1C), 71.94 (1C), 102.26 (2C, d, JCeF ¼ 29.9 Hz), 109.45 (1C), 111.66
(1C), 124.26 (1C, t, JCeF ¼ 14.5 Hz), 135.05 (1C, t, JCeF ¼ 14.0 Hz),
135.16 (1C), 151.88 (1C), 153.69 (1C), 154.33 (1C), 156.58 (1C), 158.52
(2C, dd, JCeF ¼ 8.3, 247 Hz), and 172.16 (1C); LRMS-EI (m/z): 550
(Mþ). HRMS-EI (m/z): Calcd. for C22H21BrF2N6O4 (Mþ): 550.0776;
Found 550.0802. Anal. Calcd for C22H21BrF2N6O4: C, 47.93; H, 3.84;
N, 15.24. Found: C, 47.94; H, 3.91; N, 15.27.
4.1.22. (S)-N-((3-(3-Fluoro-4-(1-carbamoyl-[1,2,5]triazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)thioacetamide (16a)
To a solution of 5a (95.4 mg, 0.204 mmol) and triphosgene
(30.6 mg, 0.103 mmol) in tetrahydrofuran (4 mL) was added
dropwise Et3N (0.09 mL, 0.640 mmol) at 0 ꢁC. The mixture was
stirred for 10 min at the same temperature, and then concentrated
NH3 aqueous solution (0.2 mL) was added. Stirring was continued
for 20 h at ambient temperature. The mixture was diluted with
water (10 mL) and then extracted with 10% MeOH/CHCl3. The
organic solution was dried and evaporated. The residue was used
for the next reaction without further purification. To a solution of
the residue in 1,4-dioxane (2 mL) was added concentrated hydro-
chloric acid (0.2 mL). The mixture was stirred for 1 h at ambient
temperature. The reaction was quenched by the addition of 10%
potassium carbonate aqueous solution (5 mL), and the mixture was
extracted with 10% MeOH/CHCl3. The organic solution was dried,
and evaporated. Silica gel (8 g) column chromatography of the
residue using CHCl3/MeOH (97:3 to 92:8) as the eluent afforded 16a
(30.8 mg, 37%). White powder (EtOH); mp 176.5e178.5 ꢁC (dec.); 1H
4.1.20. (S)-N-((3-(3,5-Difluoro-4-(2-amino-10-oxo-5,6,8,9-
tetrahydro-10H-4,4b,7,9a-tetraazabenzo[a]azulen-7-yl)pheny-l)-2-
oxo-5-oxazolidinyl)methyl)acetamide (15a)
To a solution of 4b (316.9 mg, 0.675 mmol) in 1,4-dioxane (3 mL)
was added concentrated hydrochloric acid (0.5 mL). The mixture
was stirred for 1 h at ambient temperature and then concentrated
in vacuo. The residue was used for the next reaction without further
purification. To
a mixture of the residue, EDCI (155.0 mg,
0.809 mmol), HOBt (15.8 mg, 0.117 mmol) and i-Pr2NEt (132.1 mg,
1.022 mmol) in DMF (3 mL) was added 5-tert-butoxy-
carbonylamino-2-chloronicotinic acid (221.1 mg, 0.811 mmol). The
mixture was stirred for 19 h at ambient temperature, then 10% citric
acid aqueous solution (10 mL) was added, and the whole was
extracted with 10% MeOH/CHCl3. The organic solution was dried
NMR (CDCl3 þ CD3OD)
d
¼ 2.57 (3H, s, CH3eC]S), 3.15e3.23 (2H,

272
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
m, eCH2e), 3.36e3.44 (4H, m, eCH2e), 3.80e3.88 (3H, m, eCH2e),
3.93e4.04 (1H, m, eCH2e), 4.10 (1H, t, J ¼ 9.1 Hz, oxazolidinone-
H4), 4.12e4.22 (1H, m, eCH2e), 4.94e5.04 (1H, m, oxazolidinone-
H5), 6.94 (1H, t, J ¼ 9.1 Hz, Ar-H5), 7.04 (1H, dd, J ¼ 2.4, 9.1 Hz,
Ar-H6), and 7.40 (1H, dd, J ¼ 2.4, 14.7 Hz, Ar-H2); 13C NMR
4.1.26. (S)-N-((3-(3,5-Difluoro-4-(1-carbamoyl-[1,2,5]triazepan-5-
yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate
(16e)
Compound 16e (151.7 mg, 83%) was prepared from 6b
(205.4 mg, 0.410 mmol) in the same manner as described for 16a.
White powder (EtOH); mp 178.5e180.5 ꢁC; 1H NMR
(CDCl3 þ CD3OD)
d
¼ 32.63 (1C), 47.94 (2C), 48.95 (1C), 49.93 (1C),
51.56 (1C), 53.51 (1C), 71.00 (1C), 107.90 (1C, d, JCeF ¼ 29.3 Hz),
114.32 (1C), 118.82 (1C), 130.99 (1C, d, JCeF ¼ 12.8 Hz), 136.42 (1C, d,
JCeF ¼ 8.9 Hz), 154.07 (1C, d, JCeF ¼ 244 Hz), 154.85 (1C), 160.63 (1C),
and 203.23 (1C); LRMS-EI (m/z): 410 (Mþ). HRMS-EI (m/z): Calcd.
for C17H23FN6O3S (Mþ): 410.1536; Found 410.1539.
(CDCl3 þ CD3OD)
d
¼ 3.11e3.18 (2H, m, eCH2e), 3.28e3.37 (4H, m,
eCH2e), 3.74e3.80 (2H, m, eCH2e), 3.87 (1H, dd, J ¼ 6.8, 9.1 Hz,
oxazolidinone-H4), 3.93e4.11 (3H, m, eCH2e), 4.00 (3H, s, eOCH3),
4.89e5.00 (1H, m, oxazolidinone-H5), and 7.12 (2H, d, J ¼ 10.8 Hz,
Ar-H2 and H6); 13C NMR (CDCl3 þ CD3OD)
¼ 47.06 (1C), 47.23 (1C),
d
49.90 (1C), 50.83 (1C), 53.10 (1C), 54.84 (1C), 57.05 (1C), 71.28 (1C),
102.22 (2C, d, JCeF ¼ 30.4 Hz), 124.99 (1C, t, JCeF ¼ 14.3 Hz), 133.68
(1C, t, JCeF ¼ 13.2 Hz),154.30 (1C),158.23 (2C, dd, JCeF ¼ 8.9, 246 Hz),
160.72 (1C), and 192.75 (1C); LRMS-ESI (m/z): 445 (Mþ þ H). HRMS-
ESI (m/z): Calcd. for C17H23F2N6O4S (Mþ þ H): 445.1464; Found
445.1464. Anal. Calcd for C17H22F2N6O4S: C, 45.94; H, 4.99; N, 18.91.
Found: C, 45.68; H, 4.97; N, 18.60.
4.1.23. (S)-N-((3-(3,5-Difluoro-4-(1-carbamoyl-[1,2,5]triazepan-5-
yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)thioacetamide (16b)
Compound 16b (109.4 mg, 66%) was prepared from 5b
(186.3 mg, 0.384 mmol) in the same manner as described for 16a.
White powder (EtOH); mp 181.5e183.5 ꢁC (dec.); 1H NMR
(CDCl3 þ CD3OD)
d
¼ 2.57 (3H, s, CH3eC]S), 3.11e3.18 (2H, m, e
CH2e), 3.27e3.38 (4H, m, eCH2e), 3.73e3.80 (2H, m, eCH2e),
3.83 (1H, dd, J ¼ 6.8, 9.1 Hz, oxazolidinone-H4), 3.97e4.05 (1H, m,
eCH2e), 4.08 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.15 (1H, dd,
4.1.27. (S)-N-((3-(3,5-Difluoro-4-(2-carbamoyl-[1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (16f)
Compound 16f (126.7 mg, 89%) was prepared from 6c
(128.8 mg, 0.320 mmol) in the same manner as described for
16c. Colorless needles (EtOH); mp 163.5e165 ꢁC; 1H NMR
J
¼
3.4, 14.4 Hz, eCHHeNHeC]S), 4.95e5.06 (1H, m,
oxazolidinone-H5), and 7.11 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6); 13
C
NMR (CDCl3 þ CD3OD) ¼ 32.70 (1C), 47.55 (1C), 47.76 (1C), 49.97
d
(1C), 50.88 (1C), 53.20 (1C), 54.88 (1C), 70.97 (1C), 102.32 (2C, d,
JCeF ¼ 29.9 Hz), 125.13 (1C, t, JCeF ¼ 14.7 Hz), 133.66 (1C, t, JCe
(CDCl3 þ CD3OD)
d
¼ 3.42 (2H, t, J ¼ 5.3 Hz, eCH2e), 3.46 (2H, t,
¼ 12.8 Hz), 154.28 (1C), 158.30 (2C, dd, JCeF ¼ 8.6, 245 Hz), 160.68
J ¼ 5.3 Hz, eCH2e), 3.80 (2H, t, J ¼ 5.3 Hz, eCH2e), 3.87 (1H, dd,
J ¼ 7.0, 9.1 Hz, oxazolidinone-H4), 3.94e4.16 (5H, m, eCH2e), 4.00
(3H, s, eOCH3), 4.90e5.01 (1H, m, oxazolidinone-H5), and 7.13 (2H,
F
(1C), and 203.33 (1C); LRMS-ESI (m/z): 428 (Mþ þ H). HRMS-ESI
(m/z): Calcd. for C17H23F2N6O3S (Mþ þ H): 429.1515; Found
429.1515.
d, J ¼ 10.8 Hz, Ar-H2 and H6); 13C NMR (CDCl3 þ CD3OD)
d
¼ 47.08
(1C), 47.24 (1C), 50.31 (1C), 53.19 (1C), 54.23 (1C), 57.07 (1C), 71.32
4.1.24. (S)-N-((3-(3,5-Difluoro-4-(2-carbamoyl-[1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)
thioacetamide (16c)
(1C), 74.99 (1C), 102.32 (2C, d, JCeF ¼ 30.4 Hz), 124.56 (1C, t, JCe
¼ 14.4 Hz), 133.37 (1C, t, JCeF ¼ 13.3 Hz), 154.34 (1C), 157.80 (2C,
F
dd, JCeF ¼ 8.3, 246 Hz), 160.33 (1C), and 192.82 (1C); LRMS-ESI (m/
Compound 16c (143.5 mg, 99%) was prepared from 5c
(130.7 mg, 0.338 mmol) in the same manner as described for 16a,
except that hydrochloric acid treatment was omitted. Colorless
needles (EtOH); mp 182e184 ꢁC (dec.); 1H NMR (CDCl3 þ CD3OD)
z): 446 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C17H22F2N5O5S
(Mþ
þ
H): 446.1304; Found 446.1302. Anal. Calcd for
C17H21F2N5O5S: C, 45.84; H, 4.75; N, 15.72. Found: C, 45.88; H, 4.75;
N, 15.73.
d
¼ 2.57 (3H, s, CH3eC]S), 3.39e3.51 (4H, m, eCH2e), 3.77e3.87
(3H, m, eCH2e), 3.93e4.21 (5H, m, eCH2e), 4.95e5.06 (1H, m,
4.1.28. 5(R)-3-(4-(1-Carbamoyl-[1,2,5]triazepan-5-yl)-3,5-
oxazolidinone-H5), and 7.12 (2H, d, J ¼ 10.7 Hz, Ar-H2 and H6); 13
C
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (16g)
Compound 16g (137.0 mg, 70%) was prepared from 7b
(223.4 mg, 0.466 mmol) in the same manner as described for 16a.
White powder (CH2Cl2/EtOH); mp 193e195 ꢁC; 1H NMR (DMSO-d6)
NMR (CDCl3 þ CD3OD)
d
¼ 32.74 (1C), 47.49 (1C), 47.82 (1C), 50.34
(1C), 53.22 (1C), 54.24 (1C), 70.98 (1C), 75.03 (1C), 102.36 (2C, d, JCe
¼ 30.4 Hz), 124.66 (1C, t, JCeF ¼ 14.4 Hz), 133.23 (1C, t, JCe
F
¼ 13.8 Hz), 154.33 (1C), 157.81 (2C, dd, JCeF ¼ 8.8, 245 Hz), 160.30
d
¼ 2.90e2.99 (2H, m, eCH2e), 3.12e3.27 (4H, m, eCH2e), 3.55e
F
(1C), and 203.38 (1C); LRMS-ESI (m/z): 430 (Mþ þ H). HRMS-ESI (m/
z): Calcd. for C17H22F2N5O4S (Mþ þ H): 430.1355; Found 430.1355.
3.63 (2H, m, eCH2e), 3.85 (1H, dd, J ¼ 5.8, 9.4 Hz, oxazolidinone-
H4), 4.18 (1H, t, J ¼ 9.4 Hz, oxazolidinone-H4), 4.81 (2H, d,
J ¼ 5.0 Hz, eCH2e[1,2,3]triazole), 5.04 (1H, t, J ¼ 5.9 Hz, NH), 5.13
(1H, ddt, J ¼ 5.8, 9.4, 5.0 Hz, oxazolidinone-H5), 6.05 (2H, br s, NH2),
7.19 (2H, d, J ¼ 11.1 Hz, Ar-H2 and H6), 7.75 (1H, s, [1,2,3]triazole-H),
4.1.25. (S)-N-(((3-[3-Fluoro-4-(1-carbamoyl-[1,2,5]triazepan-5-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-methylthiocarbamate
(16d)
Compound 16d (172.4 mg, 89%) was prepared from 6a
(220.6 mg, 0.456 mmol) in the same manner as described for 16a.
White powder (EtOH); mp 166e168 ꢁC; 1H NMR (CDCl3 þ CD3OD)
and 8.15 (1H, s, [1,2,3]triazole-H); 13C NMR (DMSO-d6)
d
¼ 46.98
(1C), 49.12 (1C), 51.28 (1C), 51.61 (1C), 52.64 (1C), 54.97 (1C), 70.82
(1C), 102.25 (2C, d, JCeF ¼ 30.4 Hz), 124.70 (1C, t, JCeF ¼ 16.6 Hz),
125.79 (1C), 133.33 (1C), 133.85 (1C, t, JCeF ¼ 14.0 Hz), 153.27 (1C),
157.68 (2C, dd, JCeF ¼ 8.8, 244 Hz), and 159.37 (1C); LRMS-ESI (m/z):
423 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C17H21F2N8O3 (Mþ þ H):
423.1699; Found 423.1699.
d
¼ 3.15e3.22 (2H, m, eCH2e), 3.35e3.43 (4H, m, eCH2e), 3.60e
3.76 (3H, m, eCH2e), 3.80e4.11 (3H, m, eCH2e), 4.00 (3H, s, e
OCH3), 4.87e4.98 (1H, m, oxazolidinone-H5), 6.93 (1H, t, J ¼ 9.1 Hz,
Ar-H5), 7.03 (1H, dd, J ¼ 2.4, 9.1 Hz, Ar-H6), and 7.38 (1H, dd, J ¼ 2.4,
14.8 Hz, Ar-H2); 13C NMR (CDCl3 þ CD3OD)
d
¼ 47.38 (1C), 47.63
4.1.29. 5(R)-3-(4-(2-Carbamoyl-[1,2,5]oxadiazepan-5-yl)-3,5-
difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (16h)
Compound 16h (98.0 mg, 94%) was prepared from 7c (93.0 mg,
0.245 mmol) in the same manner as described for 16c. White
powder (CH2Cl2/EtOH); mp 179e181 ꢁC; 1H NMR (CDCl3 þ CD3OD)
(1C), 48.91 (1C), 49.90 (1C), 51.47 (1C), 53.46 (1C), 57.10 (1C), 71.30
(1C), 107.78 (1C, d, JCeF ¼ 27.1 Hz), 114.22 (1C), 118.68 (1C), 131.08
(1C, d, JCeF ¼ 10.5 Hz), 136.27 (1C, d, JCeF ¼ 9.4 Hz), 153.96 (1C, d, JCe
¼ 244 Hz), 154.77 (1C), 160.54 (1C), and 192.75 (1C); LRMS-ESI (m/
F
z): 427 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C17H24FN6O4S
(Mþ þ H): 427.1558; Found 427.1559.
d
¼ 3.38e3.49 (4H, m, eCH2e), 3.80 (2H, t, J ¼ 5.9 Hz, eCH2e),
3.91 (1H, dd, J ¼ 6.2, 9.1 Hz, oxazolidinone-H4), 4.10 (2H,

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
273
t, J ¼ 5.3 Hz, eCH2e), 4.18 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.81
(1H, dd, J ¼ 5.0,14.7 Hz, eCHHe[1,2,3]triazole), 4.86 (1H, dd, J ¼ 3.8,
14.7 Hz, eCHHe[1,2,3]triazole), 5.12 (1H, dddd, J ¼ 3.8, 5.0, 6.2,
9.1 Hz, oxazolidinone-H5), 7.04 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6),
(m/z): 441 (Mþ þ H). HRMS-ESI (m/z): Calcd. for C18H26FN6O4S
(Mþ þ H): 441.1715; Found 441.1715.
4.1.32. (S)-N-((3-(3,5-Difluoro-4-(1-(methylcarbamoyl)[1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (17b)
Compound 17b (168.5 mg, 83%) was prepared from 6b
(221.1 mg, 0.441 mmol) in the same manner as described for 17a.
Colorless prisms (EtOH); mp 175.5e177.5 ꢁC; 1H NMR
7.74 (1H, s, [1,2,3]triazole-H), and 7.92 (1H, s, [1,2,3]triazole-H); 13
C
NMR (CDCl3 þ CD3OD)
d
¼ 46.92 (1C), 50.32 (1C), 51.71 (1C), 53.18
(1C), 54.18 (1C), 70.47 (1C), 74.96 (1C), 102.46 (2C, d, JCeF ¼ 30.9 Hz),
124.84 (1C, t, JCeF ¼ 14.0 Hz), 125.29 (1C), 132.79 (1C, t, JCe
¼ 12.1 Hz), 133.76 (1C), 153.35 (1C), 157.76 (2C, dd, JCeF ¼ 8.8,
F
246 Hz), and 160.31 (1C); LRMS-ESI (m/z): 424 (Mþ þ H). HRMS-ESI
(CDCl3 þ CD3OD)
d
¼ 2.80 (3H, s, CH3eNHeC]O), 3.06e3.14 (2H,
(m/z): Calcd. for
C
17H20F2N7O4 (Mþ
þ
H): 424.1539; Found
m, eCH2e), 3.26e3.38 (4H, m, eCH2e), 3.72e3.81 (2H, m, eCH2e),
3.87 (1H, dd, J ¼ 6.9, 9.1 Hz, oxazolidinone-H4), 3.93e4.12 (3H, m, e
CH2e), 4.00 (3H, s, eOCH3), 4.89e5.00 (1H, m, oxazolidinone-H5),
424.1538.
4.1.30. 5(S)-(Isoxazol-3-yl-aminomethyl)-3-(3,5-difluoro-4-(1-
carbamoyl-[1,2,5]triazepan-5-yl)phenyl)oxazolidin-2-one (16i)
Compound 16i (139.4 mg, 94%) was prepared from 6c
(200.9 mg, 0.338 mmol) in the same manner as described for 16a.
White powder (EtOH); mp 161e162.5 ꢁC; 1H NMR
and 7.12 (2H, d,
J
¼
10.8 Hz, Ar-H2 and H6); 13C NMR
(CDCl3 þ CD3OD)
d
¼ 26.08 (1C), 47.10 (1C), 47.27 (1C), 50.29 (1C),
50.71 (1C), 53.58 (1C), 54.85 (1C), 57.08 (1C), 71.31 (1C), 102.27 (2C,
d, JCeF ¼ 30.4 Hz), 125.13 (1C, t, JCeF ¼ 14.4 Hz), 133.64 (1C, t, JCe
¼ 13.3 Hz), 154.32 (1C), 158.25 (2C, dd, JCeF ¼ 9.2, 246 Hz), 160.22
F
(CDCl3 þ CD3OD)
d
¼ 3.10e3.18 (2H, m, eCH2e), 3.26e3.39 (4H,
(1C), and 192.81 (1C); LRMS-ESI (m/z): 459 (Mþ þ H). HRMS-ESI (v):
Calcd. for C18H25F2N6O4S (Mþ þ H): 459.1621; Found 459.1620.
Anal. Calcd for C18H24F2N6O4S: C, 47.15; H, 5.28; N, 18.33. Found: C,
47.17; H, 5.34; N, 18.05.
m, eCH2e), 3.57 (1H, d, J ¼ 5.6, 14.7 Hz, eCHHeNHeisoxazole),
3.63 (1H, dd, J ¼ 4.0, 14.7 Hz, eCHHeNHeisoxazole), 3.73e3.81
(2H, m, eCH2e), 3.83 (1H, dd, J ¼ 6.7, 9.1 Hz, oxazolidinone-H4),
4.07 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.93 (1H, dddd, J ¼ 4.0,
5.6, 6.7, 9.1 Hz, oxazolidinone-H5), 5.94 (1H, d, J ¼ 1.8 Hz,
isoxazole-H), 7.13 (2H, d, J ¼ 10.7 Hz, Ar-H2 and H6), and 8.07
(1H, d, J ¼ 1.8 Hz, isoxazole-H); 13C NMR (CDCl3 þ CD3OD)
4.1.33. (S)-N-((3-(3,5-Difluoro-4-(2-(methylcarbamoyl)-[1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (17c)
Compound 17c (138.7 mg, 99%) was prepared from 6c
(122.2 mg, 0.304 mmol) in the same manner as described for 17a,
except that hydrochloric acid treatment was omitted. Colorless
d
¼ 46.13 (1C), 47.50 (1C), 50.06 (1C), 50.98 (1C), 53.29 (1C), 55.01
(1C), 71.62 (1C), 96.33 (1C), 102.31 (2C, d, JCeF ¼ 30.9 Hz), 125.04
(1C, t, JCeF ¼ 14.6 Hz), 134.03 (1C, t, JCeF ¼ 13.9 Hz), 154.57 (1C),
158.09 (1C), 158.42 (2C, dd, JCeF ¼ 9.4, 246 Hz), 160.86 (1C), and
163.74 (1C); LRMS-EI (m/z): 437 (Mþ). HRMS-EI (m/z): Calcd. for
C
C
prisms (EtOH); mp 162.5e164.5 ꢁC; 1H NMR (CDCl3)
d
¼ 2.85 (3H,
d, J ¼ 4.8 Hz, CH3eNHeC]O), 3.39 (2H, t, J ¼ 5.3 Hz, eCH2e), 3.46
(2H, t, J ¼ 5.3 Hz, eCH2e), 3.75e3.81 (2H, m, eCH2e), 3.83 (1H, dd,
J ¼ 7.0, 9.1 Hz, oxazolidinone-H4), 3.97e4.09 (5H, m, eCH2e), 4.00
(3H, s, eOCH3), 4.88e4.99 (1H, m, oxazolidinone-H5), 5.87 (1H, q,
J ¼ 4.8 Hz, CH3eNHeC]O), 7.08 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6),
18H21F2N7O4 (Mþ): 437.1623; Found 437.1621. Anal. Calcd for
18H21F2N7O4: C, 49.43; H, 4.84; N, 22.42. Found: C, 49.07; H,
4.93; N, 22.11.
4.1.31. (S)-N-((3-(3-Fluoro-4-(1-(methylcarbamoyl)-[1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (17a)
and 7.32 (1H, t, J ¼ 6.3 Hz, eNHeC]S); 13C NMR (CDCl3)
¼ 26.65
d
(1C), 47.27 (1C), 47.41 (1C), 51.60 (1C), 54.04 (1C), 54.36 (1C), 57.59
(1C), 71.18 (1C), 74.22 (1C), 102.42 (2C, d, JCeF ¼ 30.9 Hz), 124.85
(1C, t, JCeF ¼ 14.1 Hz), 133.24 (1C, t, JCeF ¼ 13.6 Hz), 153.84 (1C),
157.86 (2C, dd, J ¼ 9.1, 245 Hz), 160.33 (1C), and 192.84 (1C);
LRMS-EI (m/z): 459 (Mþ). HRMS-EI (m/z): Calcd. for
To a solution of 6a (229.8 mg, 0.475 mmol) and triphosgene
(70.0 mg, 0.236 mmol) in tetrahydrofuran (5 mL) was added
dropwise Et3N (0.20 mL, 1.423 mmol) at 0 ꢁC. The mixture was
stirred for 10 min at the same temperature, and then 40%
methylamine aqueous solution (0.2 mL) was added. Stirring was
continued for 2 h at ambient temperature. The mixture was
diluted with water (10 mL) and extracted with 10% MeOH/CHCl3.
The organic solution was dried and evaporated. The residue was
used for the next reaction without further purification. To a so-
lution of the residue in 1,4-dioxane (3 mL) was added concen-
trated hydrochloric acid (0.4 mL). The mixture was stirred for 1 h
at ambient temperature. The reaction was quenched by the
addition of 10% potassium carbonate aqueous solution (10 mL),
and the mixture was extracted with 10% MeOH/CHCl3. The organic
solution was dried, and evaporated. Silica gel (10 g) column
chromatography of the residue using CHCl3/MeOH (98:2 to 95:5)
as the eluent afforded 17a (172.4 mg, 89%). Amorphous powder;
C
C
18H23F2N5O5S (Mþ): 459.1388; Found 459.1389. Anal. Calcd for
18H23F2N5O5S: C, 47.05; H, 5.05; N, 15.24. Found: C, 47.12; H, 5.06;
N, 14.97.
4.1.34. 5(R)-3-(4-(2-Methylcarbamoyl[1,2,5]oxadiazepan-5-yl)-
3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethy-l)oxazolidin-2-one
(17d)
Compound 17d (97.5 mg, 62%) was prepared from 7c (137.5 mg,
0.362 mmol) in the same manner as described for 17c. Amorphous
solid; 1H NMR (CDCl3)
d
¼ 2.85 (3H, d, J ¼ 4.8 Hz, CH3eNHeC]O),
3.40 (2H, br t, J ¼ 5 Hz, eCH2e), 3.46 (2H, br t, J ¼ 5 Hz, eCH2e),
3.79 (2H, br t, J ¼ 5 Hz, eCH2e), 3.89 (1H, dd, J ¼ 6.2, 9.1 Hz,
oxazolidinone-H4), 4.02 (2H, br t, J ¼ 5 Hz, eCH2e), 4.10 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.78 (2H, d, J ¼ 4.1 Hz, eCH2e[1,2,3]
triazole), 5.06 (1H, ddt, J ¼ 6.2, 9.1, 4.1 Hz, oxazolidinone-H5), 5.81
(1H, q, J ¼ 4.8 Hz, CH3eNHeC]O), 6.92 (2H, d, J ¼ 10.7 Hz, Ar-H2
and H6), 7.75 (1H, br s, [1,2,3]triazole-H), and 7.77 (1H, br s, [1,2,3]
1H NMR (CDCl3 þ CD3OD)
d
¼ 2.78 (3H, s, CH3eNHeC]O), 3.11e
3.18 (2H, m, eCH2e), 3.34e3.43 (4H, m, eCH2e), 3.78e4.15 (6H,
m, eCH2e), 4.00 (3H, s, eOCH3), 4.87e4.98 (1H, m, oxazolidinone-
H5), 6.93 (1H, t, J ¼ 9.1 Hz, Ar-H5), 7.03 (1H, dd, J ¼ 2.4, 9.1 Hz, Ar-
H6), and 7.38 (1H, dd, J ¼ 2.4, 14.7 Hz, Ar-H2); 13C NMR
triazole-H); 13C NMR (CDCl3)
d
¼ 26.56 (1C), 47.12 (1C), 51.52 (1C),
51.84 (1C), 53.93 (1C), 54.25 (1C), 70.38 (1C), 74.14 (1C), 102.58
(2C, d, JCeF ¼ 29.8 Hz), 125.04 (1C), 125.08 (1C, t, JCeF ¼ 14.3 Hz),
132.62 (1C, t, JCeF ¼ 13.6 Hz), 134.20 (1C), 153.02 (1C), 157.76 (2C,
dd, JCeF ¼ 9.4, 248 Hz), and 160.20 (1C); LRMS-EI (v): 437 (Mþ).
HRMS-EI (v): Calcd. for C18H21F2N7O4 (Mþ): 437.1623; Found
437.1617.
(CDCl3 þ CD3OD)
d
¼ 26.03 (1C), 47.24 (1C), 47.68 (1C), 49.17 (1C),
49.79 (1C), 51.74 (1C), 53.46 (1C), 56.99 (1C), 71.26 (1C), 107.82
(1C, d, JCeF ¼ 27.1 Hz), 114.27 (1C), 118.64 (1C), 131.00 (1C, d, JCe
¼ 10.2 Hz), 136.30 (1C, d, JCeF ¼ 8.8 Hz), 153.91 (1C, d, JCe
F
¼ 244 Hz), 154.78 (1C), 160.03 (1C), and 192.70 (1C); LRMS-ESI
F

274
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
4.1.35. (S)-N-((3-(3-Fluoro-4-(1-(hydroxycarbamoyl)[1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (18a)
J ¼ 5.9, 9.3 Hz, oxazolidinone-H4), 3.99e4.11 (2H, m, eCH2e), 4.19
(1H, t, J ¼ 9.3 Hz, oxazolidinone-H4), 4.35 (1H, t, J ¼ 5.0 Hz, eCH2e),
4.82 (2H, d, J ¼ 5.0 Hz, eCH2e[1,2,3]triazole), 5.08e5.19 (1H, m,
oxazolidinone-H5), 7.22 (2H, d, J ¼ 11.0 Hz, Ar-H2 and H6), 7.75 (1H,
s, [1,2,3]triazole-H), and 8.15 (1H, s, [1,2,3]triazole-H); 13C NMR
To a solution of 6a (251.2 mg, 0.519 mmol) and triphosgene
(76.2 mg, 0.257 mmol) in tetrahydrofuran (5 mL) was added
dropwise Et3N (0.44 mL, 3.131 mmol) at 0 ꢁC. The mixture was
stirred for 10 min at the same temperature, and then hydrox-
yammonium chloride (117.8 mg, 2.559 mmol) was added. Stirring
was continued for 7.5 h at ambient temperature. The mixture was
diluted with water (10 mL) and extracted with 10% MeOH/CHCl3.
The organic solution was dried and evaporated. The residue was
used for the next reaction without further purification. To a solution
of the residue in 1,4-dioxane (3 mL) was added concentrated hy-
drochloric acid (0.4 mL). The mixture was stirred for 1.5 h at
ambient temperature. The reaction was quenched by the addition
of 10% potassium carbonate aqueous solution (5 mL), and the
mixture was extracted with 10% MeOH/CHCl3. The organic solution
was dried and evaporated. Silica gel (10 g) column chromatography
of the residue using CHCl3/MeOH (97:3 to 90:10) as the eluent
afforded 18a (196.9 mg, 86%). White powder (CHCl3/MeOH); mp
(DMSO-d6)
d
¼ 46.97 (1C), 50.48 (0.5C), 51.25 (0.5C), 51.58 (1C),
52.53 (0.5C), 52.92 (0.5C), 54.37 (0.5C), 55.97 (0.5C), 70.82 (1C),
75.73 (0.5C), 75.91 (0.5C), 102.26 (2C, d, JCeF ¼ 30.4 Hz), 123.95
(0.5C, t, JCeF ¼ 14.3 Hz), 124.04 (0.5C, t, JCeF ¼ 14.3 Hz), 125.77 (1C),
133.32 (1C), 134.18 (0.5C, t, JCeF ¼ 13.7 Hz), 134.22 (0.5C, t, JCe
¼ 13.7 Hz), 153.26 (1C), 154.45 (0.5C), 157.51 (2C, dd, JCeF ¼ 9.1,
F
243 Hz), and 157.94 (0.5C); LRMS-ESI (m/z): 440 (Mþ þ H). HRMS-
ESI (m/z): Calcd. for C17H20F2N7O5 (Mþ þ H): 440.1488; Found
440.1493.
4.1.38. (S)-N-((3-(3-Fluoro-4-(1-(methoxycarbamoyl)[1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (19a)
To a solution of 6a (244.1 mg, 0.505 mmol) and triphosgene
(75.9 mg, 0.256 mmol) in tetrahydrofuran (5 mL) was added
dropwise Et3N (0.43 mL, 3.060 mmol) at 0 ꢁC. The mixture was
stirred for 10 min at the same temperature, and then O-methyl-
hydroxylamine hydrochloride (206.5 mg, 2.472 mmol) was added.
Stirring was continued for 24 h at ambient temperature. The
mixture was diluted with water (10 mL) and extracted with 10%
MeOH/CHCl3. The organic solution was dried and evaporated. The
residue was used for the next reaction without further purification.
To a solution of the residue in 1,4-dioxane (3 mL) was added
concentrated hydrochloric acid (0.4 mL), and the mixture was
stirred for 2 h at ambient temperature. The reaction was quenched
by the addition of 10% potassium carbonate aqueous solution
(10 mL), and the mixture was extracted with 10% MeOH/CHCl3. The
organic solution was dried and evaporated. Silica gel (10 g) column
chromatography of the residue using CHCl3/MeOH (98:2 to 96:4) as
the eluent afforded 19a (184.5 mg, 80%). White powder (EtOH); mp
191e193.5 ꢁC (dec.); 1H NMR (DMSO-d6)
d
¼ 2.89e3.00 (2H, m, e
CH2e), 3.22e3.42 (4H, m, eCH2e), 3.59e3.80 (5H, m, eCH2e), 3.87
(3H, s, eOCH3), 4.08 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.80e4.91
(1H, m, oxazolidinone-H5), 4.99 (1H, t, J ¼ 6.0 Hz, NH), 6.98 (1H, t,
J ¼ 9.7 Hz, Ar-H5), 7.09 (1H, dd, J ¼ 2.1, 9.7 Hz, Ar-H6), 7.40 (1H, dd,
J ¼ 2.1, 15.5 Hz, Ar-H2), 8.09 (1H, br s, eNHeOH), 8.90 (1H, s, eNHe
OH), and 9.50 (1H, br t, J ¼ 6 Hz, NH); 13C NMR (DMSO-d6)
¼ 47.33
d
(1C), 47.60 (1C), 48.53 (1C), 49.68 (1C), 50.31 (1C), 53.30 (1C), 56.71
(1C), 70.24 (1C), 107.14 (1C, d, JCeF ¼ 24.9 Hz), 114.42 (1C), 118.53
(1C), 131.09 (1C, d, JCeF ¼ 10.6 Hz), 134.95 (1C, d, JCeF ¼ 9.1 Hz),
152.88 (1C, d, JCeF ¼ 241 Hz), 153.89 (1C), 160.27 (1C), and 191.69
(1C); LRMS-ESI (m/z): 443 (Mþ þ H). HRMS-ESI (v): Calcd. for
C
C
17H24FN6O5S (Mþ þ H): 443.1507; Found 443.1510. Anal. Calcd for
17H23FN6O5S: C, 46.15; H, 5.24; N, 18.99. Found: C, 46.05; H, 5.19;
N, 18.83.
146e148 ꢁC; 1H NMR (CDCl3 þ CD3OD)
d
¼ 3.11e3.19 (2H, m, e
4.1.36. 5(R)-3-(4-(1-(Hydroxycarbamoyl)[1,2,5]triazepan-5-yl)-
3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one
(18b)
Compound 18b (134.1 mg, 69%) was prepared from 7b
(212.7 mg, 0.444 mmol) in the same manner as described for 18a.
White powder (CH2Cl2/MeOH); mp 182e184 ꢁC (dec.); 1H NMR
CH2e), 3.32e3.44 (4H, m, eCH2e), 3.72 (3H, s, eNHeOCH3), 3.77e
4.16 (6H, m, eCH2e), 4.00 (3H, s, eOCH3), 4.88e4.99 (1H, m,
oxazolidinone-H5), 6.93 (1H, t, J ¼ 9.1 Hz, Ar-H5), 7.04 (1H, dd,
J ¼ 2.5, 9.1 Hz, Ar-H6), 7.39 (1H, dd, J ¼ 2.5, 14.7 Hz, Ar-H2), and 8.58
(1H, br t, J ¼ 6 Hz, eNHeC]S); 13C NMR (CDCl3 þ CD3OD)
¼ 47.36
d
(1C), 47.65 (1C), 49.31 (1C), 49.89 (1C), 51.20 (1C), 53.45 (1C), 57.02
(1C), 63.99 (1C), 71.26 (1C), 107.79 (1C, d, JCeF ¼ 27.6 Hz), 114.23
(1C), 118.78 (1C), 131.21 (1C, d, JCeF ¼ 9.6 Hz), 136.14 (1C, d, JCe
(DMSO-d6)
d
¼ 2.87e2.98 (2H, m, eCH2e), 3.11e3.19 (2H, m, e
CH2e), 3.21e3.29 (2H, m, eCH2e), 3.54e3.63 (2H, m, eCH2e),
3.79e3.89 (1H, m, oxazolidinone-H4), 4.19 (1H, t, J ¼ 9.4 Hz,
oxazolidinone-H4), 4.82 (2H, br s, eCH2e[1,2,3]triazole), 4.99 (1H,
t, J ¼ 5.8 Hz, NH), 5.08e5.19 (1H, m, oxazolidinone-H5), 7.19 (2H, d,
J ¼ 11.1 Hz, Ar-H2 and H6), 7.75 (1H, s, [1,2,5]triazole-H), 8.12 (1H, s,
[1,2,5]triazole-H), 8.15 (1H, s, eNHeOH), and 8.91 (1H, s, eNHe
¼ 8.8 Hz), 154.00 (1C, d, JCeF ¼ 247 Hz), 154.77 (1C), 160.25 (1C),
F
and 192.74 (1C); LRMS-ESI (m/z): 457 (Mþ þ H). HRMS-ESI (m/z):
Calcd. for C18H26FN6O5S (Mþ þ H): 457.1664; Found 457.1662. Anal.
Calcd for C18H25FN6O5S: C, 47.36; H, 5.52; N, 18.41. Found: C, 47.39;
H, 5.50; N, 18.28.
OH); 13C NMR (DMSO-d6)
51.59 (1C), 52.28 (1C), 54.98 (1C), 70.82 (1C), 102.26 (2C, d, JCe
d
¼ 46.97 (1C), 49.85 (1C), 51.30 (1C),
4.1.39. (S)-N-((3-(3,5-Difluoro-4-(1-(methoxycarbamoyl)[1,2,5]
triazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)-methyl)-O-
methylthiocarbamate (19b)
Compound 19b (205.2 mg, 70%) was prepared from 6b
(309.7 mg, 0.617 mmol) in the same manner as described for 19a.
White powder (EtOH); mp 176e180 ꢁC; 1H NMR (CDCl3 þ CD3OD)
¼ 29.8 Hz), 124.60 (1C, t, JCeF ¼ 14.7 Hz), 125.77 (1C), 133.31 (1C),
F
133.89 (1C, t, JCeF ¼ 14.3 Hz), 153.26 (1C), 157.67 (2C, dd, JCeF ¼ 8.9,
244 Hz), and 160.44 (1C); LRMS-ESI (m/z): 439 (Mþ þ H). HRMS-ESI
(m/z): Calcd. for
439.1650.
C
17H21F2N8O4 (Mþ
þ
H): 439.1648; Found
d
¼ 3.08e3.14 (2H, m, eCH2e), 3.25e3.39 (4H, m, eCH2e), 3.71e
4.1.37. 5(R)-3-(4-(2-(Hydroxycarbamoyl)[1,2,5]oxadiazepan-5-yl)-
3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one
(18c)
Compound 18c (82.8 mg, 79%) was prepared from 7c (90.8 mg,
0.239 mmol) in the same manner as described for 18a, except that
hydrochloric acid treatment was omitted. Amorphous powder; 1H
3.80 (2H, m, eCH2e), 3.74 (3H, s, eNHeOCH3), 3.87 (1H, dd, J ¼ 6.8,
9.1 Hz, oxazolidinone-H4), 3.94e4.01 (2H, m, eCH2e), 4.00 (3H, s,
eOCH3), 4.06 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.90e5.01 (1H,
m, oxazolidinone-H5), 7.13 (2H, d, J ¼ 10.8 Hz, Ar-H2 and H6), and
8.59 (1H, br t, J ¼ 6 Hz, eNHeC]S); 13C NMR (CDCl3 þ CD3OD)
d
¼ 47.27 (2C), 50.37 (1C), 50.85 (1C), 52.80 (1C), 54.87 (1C), 57.03
NMR (DMSO-d6)
J ¼ 5 Hz, eCH2e), 3.76 (1H, br t, J ¼ 5 Hz, eCH2e), 3.85 (1H, dd,
d
¼ 3.30e3.48 (3H, m, eCH2e), 3.65 (1H, br t,
(1C), 63.99 (1C), 71.29 (1C), 102.27 (2C, d, JCeF ¼ 29.8 Hz), 124.88
(1C, t, JCeF ¼ 14.2 Hz), 133.84 (1C, t, JCeF ¼ 12.8 Hz), 154.30 (1C),

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
275
158.29 (2C, dd, JCeF ¼ 9.1, 246 Hz), 160.38 (1C), and 192.89 (1C);
4.1.43. (S)-N-((3-(3-Fluoro-4-(2-(2-(tert-butoxycarbonyl)[1,2,5]
oxadiazepan-5-yl)pyridin-5-yl)phenyl)-2-oxo-5-oxazolidinyl)
methyl)acetamide (23a)
LRMS-ESI (m/z): 475 (Mþ þ H). HRMS-ESI (m/z): Calcd. for
C
18H25F2N6O5S (Mþ þ H): 475.1570; Found 475.1571.
A suspension of 22 (503.4 mg, 1.405 mmol), (S)-N-(3-((3-fluoro-
4-(3,3,4,4-tetramethylborolan-1-yl)phenyl)-2-oxo-5-oxazolidinyl)
methyl)acetamide (637.9 mg, 1.687 mmol), Pd(PPh3)4 (168.3 mg,
0.146 mmol), and sodium carbonate (447.2 mg, 4.219 mmol) in 1,4-
dioxane (4 mL) and H2O (1 mL) was refluxed for 1.5 h. After cooling,
the reaction mixture was diluted with H2O (30 mL). The resulting
mixture was extracted with AcOEt, and the organic solution was
washed with brine, dried and evaporated. Silica gel (20 g) column
chromatography of the residue using CHCl3/MeOH (98:1 to 97:3) as
the eluent afforded 23a (426.5 mg, 57%). Amorphous solid; 1H NMR
4.1.40. (S)-N-((3-(3,5-Difluoro-4-(2-(methoxycarbamoyl)[1,2,5]
oxadiazepan-5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-O-
methylthiocarbamate (19c)
Compound 19c (112.3 mg, 92%) was prepared from 6c (102.9 mg,
0.256 mmol) in the same manner as described for 19a, except that
hydrochloric acid treatment was omitted. White powder (Et2O/
EtOH); mp 159e161 ꢁC; 1H NMR (CDCl3 þ CD3OD)
d
¼ 3.39e3.48
(4H, m, eCH2e), 3.73e3.82 (2H, m, eCH2e), 3.76 (3H, s, eNHe
OCH3), 3.87 (1H, dd, J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 3.94e4.04
(3H, m, eCH2e), 4.00 (3H, s, eOCH3), 4.07 (2H, t, J ¼ 4.7 Hz, eCH2e),
4.90e5.01 (1H, m, oxazolidinone-H5), 7.13 (2H, d, J ¼ 10.8 Hz, Ar-H2
and H6), and 8.55 (1H, br t, J ¼ 6 Hz, eNHeC]S); 13C NMR
(CDCl3)
d
¼ 1.43 (9H, s, t-C4H9e), 2.04 (3H, s, CH3eC]O), 3.63e3.72
(2H, m, eCH2e), 3.79e3.98 (7H, m, eCH2e), 4.07 (1H, t, J ¼ 9.1 Hz,
oxazolidinone-H4), 4.14 (2H, t, J ¼ 5.3 Hz, eCH2e), 4.76e4.87 (1H,
m, oxazolidinone-H5), 6.57 (1H, t, J ¼ 6.2 Hz, eNHeC]O), 6.61 (1H,
d, J ¼ 8.8 Hz, pyridine-H3), 7.24 (1H, dd, J ¼ 2.2, 8.6 Hz, Ar-H6), 7.37
(1H, t, J ¼ 8.6 Hz, Ar-H5), 7.49 (1H, dd, J ¼ 2.2, 12.9 Hz, Ar-H2), 7.65
(1H, d, J ¼ 8.8 Hz, pyridine-H4), and 8.31 (1H, s, pyridine-H6); 13C
(CDCl3 þ CD3OD)
d
¼ 47.27 (2C), 50.79 (1C), 53.03 (1C), 54.25 (1C),
57.05 (1C), 64.01 (1C), 71.31 (1C), 75.26 (1C), 102.35 (2C, d, JCe
¼ 30.4 Hz), 124.48 (1C, t, JCeF ¼ 14.3 Hz), 133.52 (1C, t, JCe
F
¼ 12.8 Hz), 154.32 (1C), 157.84 (2C, dd, JCeF ¼ 9.1, 246 Hz), 159.70
F
(1C), and 192.87 (1C); LRMS-ESI (m/z): 476 (Mþ þ H). HRMS-ESI (m/
z): Calcd. for C18H24F2N5O6S (Mþ þ H): 476.1410; Found 476.1413.
Anal. Calcd for C18H23F2N5O6S: C, 45.47; H, 4.88; N, 14.73. Found: C,
45.54; H, 4.83; N, 14.56.
NMR (CDCl3)
d
¼ 22.98 (1C), 28.22 (3C), 41.91 (1C), 47.30 (1C), 47.49
(1C), 48.01 (1C), 48.35 (1C), 71.61 (1C), 72.01 (1C), 81.33 (1C), 105.37
(1C), 106.45 (1C, d, JCeF ¼ 28.8 Hz), 113.76 (1C), 119.59 (1C), 122.00
(1C, d, JCeF ¼ 14.9 Hz), 129.79 (1C, d, JCeF ¼ 5.5 Hz), 137.69 (1C),
137.90 (1C, d, JCeF ¼ 12.8 Hz), 147.79 (1C), 154.20 (1C), 155.12 (1C),
156.43 (1C), 159.76 (1C, d, JCeF ¼ 247 Hz), and 171.17 (1C); LRMS-EI
(m/z): 529 (Mþ). HRMS-EI (m/z): Calcd. for C26H32FN5O6 (Mþ):
529.2337; Found 529.2338.
4.1.41. Trifluoromethanesulfonic acid 5-bromo-pyridin-2-yl ester
(21)
To a solution of 20 (1.9267 g, 11.07 mmol) in pyridine (11 mL)
was added dropwise triflic anhydride (2.05 mL, 12.18 mmol) at 0 ꢁC,
and the mixture was stirred for 10 min at the same temperature
and then for 20 min at ambient temperature. The reaction mixture
was diluted with Et2O (50 mL), the organic layer was washed with
1 M CuSO4 aqueous solution, H2O, and brine, and dried. Evapora-
tion of the solvent followed by silica gel (50 g) column chroma-
tography of the residue using Et2O/n-hexane (10:90) as the eluent
4.1.44. 5(R)-3-(4-(2-(2-(tert-Butoxycarbonyl)[1,2,5]oxadiazepan-5-
yl)pyridin-5-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)
oxazolidin-2-one (23b)
Compound 23b (235.6 mg, 31%) was prepared from 22
(506.5 mg, 1.414 mmol) in the same manner as described for 23a,
except that (5R)-3-(3-fluoro-4-(3,3,4,4-tetramethylborolan-1-yl)
phenyl)-5-(1,2,3-triazol-1-yl-methyl)oxazolidin-2-one was used
instead of (S)-N-((3-(3-fluoro-4-(3,3,4,4-tetramethylborolan-1-yl)
phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide. White powder
afforded 21 (3.3320 g, 98%). Colorless oil; 1H NMR (CDCl3)
d
¼ 7.11
(1H, d, J ¼ 8.5 Hz, pyridine-H3), 8.00 (1H, dd, J ¼ 2.6, 8.5 Hz,
pyridine-H4), and 8.46 (1H, d, J ¼ 2.6 Hz, pyridine-H6); 13C NMR
(CDCl3)
d
¼ 116.68 (1C), 118.56 (1C, q, JCeF ¼ 320 Hz), 120.45 (1C),
(CH2Cl2/EtOH); mp 201e203 ꢁC; 1H NMR (CDCl3)
d
¼ 1.43 (9H, s, t-
143.45 (1C), 149.68 (1C), and 154.50 (1C); LRMS-EI (m/z): 305 (Mþ).
HRMS-EI (m/z): Calcd. for C6H3BrF3NO3S (Mþ): 304.8969; Found
304.8966.
C4H9e), 3.82e3.92 (4H, m, eCH2e), 3.92e4.01 (3H, m, eCH2e), 4.14
(2H, t, J ¼ 5.3 Hz, eCH2e), 4.19 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4),
4.81 (2H, d, J ¼ 4.2 Hz, eCH2e[1,2,3]triazole), 5.04e5.14 (1H, m,
oxazolidinone-H5), 6.62 (1H, d, J ¼ 8.8 Hz, pyridine-H3), 7.16 (1H,
dd, J ¼ 2.2, 8.5 Hz, Ar-H6), 7.36 (1H, t, J ¼ 8.5 Hz, Ar-H5), 7.38 (1H,
dd, J ¼ 2.2,12.6 Hz, Ar-H2), 7.65 (1H, d, J ¼ 8.8 Hz, pyridine-H4), 7.76
(1H, br s, [1,2,3]triazole-H), 7.80 (1H, br s, [1,2,3]triazole-H), and
4.1.42. 5-(5-Bromopyridin-2-yl)[1,2,5]oxadiazepane-2-carboxylic
acid tert-butyl ester (22)
To a solution of 21 (1.5571 g, 5.088 mmol) and i-Pr2NEt
(1.3410 g, 10.38 mmol) in hexamethylphosphoric triamide (5 mL)
was added [1,2,5]oxadiazepane-2-carboxylic acid tert-butyl ester
(1.5509 g, 7.668 mmol) at ambient temperature. The solution was
stirred for 15 h at 100 ꢁC, then cooled and diluted with H2O
(30 mL). The resulting mixture was extracted with AcOEt, and the
organic solution was dried and evaporated. Silica gel (50 g) col-
umn chromatography of the residue using n-hexane/AcOEt (85:15
to 75:25) as the eluent afforded 22 (1.6018 g, 88%). Colorless
prisms (Et2O/n-hexane); mp 102.5e104.5 ꢁC; 1H NMR (CDCl3)
8.31 (1H, br s, pyridine-H6); 13C NMR (CDCl3)
d
¼ 28.25 (3C), 47.33
(2C), 48.03 (1C), 48.39 (1C), 51.98 (1C), 70.44 (1C), 71.64 (1C), 81.32
(1C), 105.39 (1C), 106.72 (1C, d, JCeF ¼ 28.8 Hz), 114.02 (1C), 119.53
(1C), 122.51 (1C, d, JCeF ¼ 14.3 Hz), 124.99 (1C), 129.88 (1C, d, JCe
¼ 5.0 Hz), 134.48 (1C), 137.37 (1C, d, JCeF ¼ 12.8 Hz), 137.71 (1C),
F
147.83 (1C), 153.15 (1C), 155.12 (1C), 156.52 (1C), and 159.75 (1C, d,
JCeF ¼ 248 Hz); LRMS-EI (m/z): 539 (Mþ). HRMS-EI (m/z): Calcd. for
C
C
26H30FN7O5 (Mþ): 539.2293; Found 539.2285. Anal. Calcd for
26H30FN7O5: C, 57.88; H, 5.60; N, 18.17. Found: C, 57.66; H, 5.74; N,
d
¼ 1.43 (9H, s, t-C4H9e), 3.80 (4H, s, eCH2e), 3.88 (2H, t,
17.98.
J ¼ 5.3 Hz, eCH2e), 4.09 (2H, t, J ¼ 5.3 Hz, eCH2e), 6.45 (1H, d,
J ¼ 9.1 Hz, pyridine-H3), 7.51 (1H, dd, J ¼ 2.6, 9.1 Hz, pyridine-H4),
and 8.16 (1H, d, J ¼ 2.6 Hz, pyridine-H6); 13C NMR (CDCl3)
4.1.45. (S)-N-((3-(3-Fluoro-4-(2-([1,2,5]oxadiazepan-5-yl)pyridin-
5-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (24a)
d
¼ 28.22 (3C), 47.38 (1C), 47.74 (1C), 48.40 (1C), 71.32 (1C), 81.32
To a solution of 23a (111.3 mg, 0.210 mmol) in 1,4-dioxane
(2 mL) was added concentrated hydrochloric acid (0.2 mL). The
mixture was stirred for 1 h at ambient temperature, then neutral-
ized with 10% potassium carbonate aqueous solution, and extracted
with 10% MeOH/CHCl3. The organic solution was dried and evap-
orated. Silica gel (8 g) column chromatography of the residue using
(1C), 106.90 (1C), 107.18 (1C), 139.71 (1C), 148.76 (1C), 155.10 (1C),
and 155.78 (1C); LRMS-EI (m/z): 357 (Mþ). HRMS-EI (m/z): Calcd.
for C14H20BrN3O3 (Mþ): 357.0688; Found 357.0677. Anal. Calcd for
C
14H20BrN3O3: C, 46.94; H, 5.63; N, 11.73. Found: C, 46.87; H, 5.54;
N, 11.66.

276
H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
CHCl3/MeOH (97:3 to 95:5) as the eluent afforded 24a (81.3 mg,
90%). White powder (CH2Cl2/EtOH); mp 178e180 ꢁC; 1H NMR
106.21 (1C, d, JCeF ¼ 27.7 Hz), 113.68 (1C), 119.88 (1C), 121.32 (1C, d,
JCeF ¼ 13.2 Hz), 129.53 (1C, d, JCeF ¼ 5.0 Hz), 137.85 (2C), 147.27 (1C),
154.56 (1C), 155.66 (1C), 159.42 (1C, d, JCeF ¼ 248 Hz), 172.18 (1C),
and 173.58 (1C); LRMS-EI (m/z): 487 (Mþ). HRMS-EI (m/z): Calcd.
for C23H26FN5O6 (Mþ): 487.1867; Found 487.1856. Anal. Calcd for
(CDCl3 þ CD3OD) ¼ 2.02 (3H, s, CH3eC]O), 3.22 (2H, t, J ¼ 5.3 Hz,
d
eCH2e), 3.55e3.65 (2H, m, eCH2e), 3.81 (1H, dd, J ¼ 6.8, 9.1 Hz,
oxazolidinone-H4), 3.87 (2H, t, J ¼ 5.3 Hz, eCH2e), 3.91e4.03 (4H,
m, eCH2e), 4.10 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.75e4.85
(1H, m, oxazolidinone-H5), 6.66 (1H, d, J ¼ 8.8 Hz, pyridine-H3),
7.25 (1H, dd, J ¼ 2.1, 8.5 Hz, Ar-H6), 7.39 (1H, t, J ¼ 8.5 Hz, Ar-H5),
7.50 (1H, dd, J ¼ 2.1, 12.9 Hz, Ar-H2), 7.66 (1H, d, J ¼ 8.8 Hz,
pyridine-H4), 7.86 (1H, br t, J ¼ 6 Hz, eNHeC]O), and 8.28 (1H, s,
C23H26FN5O6: C, 56.67; H, 5.38; N, 14.37. Found: C, 56.28; H, 5.55; N,
14.67.
4.1.48. 5(R)-3-(4-(2-(2-(Hydroxyacetyl)[1,2,5]oxadiazepan-5-yl)
pyridin-5-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)
oxazolidin-2-one (25b)
Compound 25b (79.1 mg, 92%) was prepared from 24b (75.6 mg,
0.172 mmol) in the same manner as described for 25a. White
powder (CH2Cl2/EtOH); mp 138e139.5 ꢁC; 1H NMR
pyridine-H6); 13C NMR (CDCl3 þ CD3OD)
¼ 22.13 (1C), 41.75 (1C),
d
47.44 (1C), 48.43 (1C), 49.10 (1C), 49.99 (1C), 68.99 (1C), 71.95 (1C),
105.54 (1C), 106.25 (1C, d, JCeF ¼ 29.3 Hz), 113.69 (1C), 118.93 (1C),
121.74 (1C, d, JCeF ¼ 11.6 Hz), 129.49 (1C, d, JCeF ¼ 5.0 Hz), 137.60
(2C), 147.25 (1C), 154.56 (1C), 156.78 (1C), 159.46 (1C, d, JCe
(CDCl3 þ CD3OD) ¼ 3.90e4.06 (6H, m, eCH2e), 4.07e4.21 (3H, m,
d
¼ 248 Hz), and 172.12 (1C); LRMS-EI (m/z): 429 (Mþ). HRMS-EI (m/
eCH2e), 4.26 (1H, t, J ¼ 9.1 Hz, oxazolidinone-H4), 4.33 (2H, br s, e
CH2eOH), 4.83 (1H, dd, J ¼ 5.3, 15.0 Hz, eCHHe[1,2,3]triazole), 4.87
(1H, dd, J ¼ 3.8, 15.0 Hz, eCHHe[1,2,3]triazole), 5.08e5.19 (1H, m,
oxazolidinone-H5), 6.69 (1H, d, J ¼ 8.8 Hz, pyridine-H3), 7.19 (1H,
dd, J ¼ 2.2, 8.5 Hz, Ar-H6), 7.38 (1H, t, J ¼ 8.5 Hz, Ar-H5), 7.42 (1H,
dd, J ¼ 2.2,12.7 Hz, Ar-H2), 7.69 (1H, d, J ¼ 8.8 Hz, pyridine-H4), 7.75
(1H, br s, [1,2,3]triazole-H), 7.94 (1H, br s, [1,2,3]triazole-H), and
F
z): Calcd. for C21H24FN5O4 (Mþ): 429.1812; Found 429.1810.
4.1.46. 5(R)-3-(4-(2-[1,2,5]Oxadiazepan-5-yl)pyridin-5-yl)-3-
fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (24b)
Compound 24b (158.0 mg, 98%) was prepared from 23b
(199.0 mg, 0.369 mmol) in the same manner as described for 24a.
White powder (CH2Cl2/EtOH); mp 189.5e191.5 ꢁC; 1H NMR
8.28 (1H, s, pyridine-H6); 13C NMR (CDCl3 þ CD3OD)
¼ 45.81 (1C),
d
(CDCl3 þ CD3OD)
d
¼ 3.22 (2H, t, J ¼ 5.3 Hz, eCH2e), 3.87 (2H, t,
47.02 (2C), 47.67 (1C), 51.74 (1C), 59.43 (1C), 70.57 (1C), 74.71 (1C),
105.40 (1C), 106.36 (1C, d, JCeF ¼ 30.4 Hz), 113.84 (1C), 119.75 (1C),
122.66 (1C, d, JCeF ¼ 14.4 Hz), 125.27 (1C), 129.55 (1C, d, JCe
J ¼ 5.3 Hz, eCH2e), 3.92e4.04 (5H, m, eCH2e), 4.24 (1H, t,
J ¼ 9.1 Hz, oxazolidinone-H4), 4.82 (1H, dd, J ¼ 5.0, 14.7 Hz, eCHHe
[1,2,3]triazole), 4.86 (1H, dd, J ¼ 3.8,14.7 Hz, eCHHe[1,2,3]triazole),
5.08e5.18 (1H, m, oxazolidinone-H5), 6.67 (1H, d, J ¼ 8.8 Hz,
pyridine-H3), 7.17 (1H, dd, J ¼ 2.1, 8.5 Hz, Ar-H6), 7.37 (1H, t,
J ¼ 8.5 Hz, Ar-H5), 7.40 (1H, dd, J ¼ 2.1, 13.0 Hz, Ar-H2), 7.66 (1H, d,
J ¼ 8.8 Hz, pyridine-H4), 7.75 (1H, s, [1,2,3]triazole-H), 7.92 (1H, s,
[1,2,3]triazole-H), and 8.26 (1H, s, pyridine-H6); 13C NMR
¼ 5.0 Hz), 133.71 (1C), 137.28 (1C, d, JCeF ¼ 12.8 Hz), 137.83 (1C),
F
147.31 (1C), 153.51 (1C), 155.72 (1C), 159.35 (1C, d, JCeF ¼ 245 Hz),
and 173.62 (1C); LRMS-EI (m/z): 497 (Mþ). HRMS-EI (m/z): Calcd.
for C23H24FN7O5 (Mþ): 497.1823; Found 497.1812.
4.2. Pharmacological evaluation
(CDCl3 þ CD3OD)
d
¼ 47.04 (1C), 48.42 (1C), 49.09 (1C), 49.96 (1C),
51.80 (1C), 68.97 (1C), 70.57 (1C), 105.58 (1C), 106.44 (1C, d,
Jv ¼ 28.8 Hz), 113.89 (1C), 118.85 (1C), 122.12 (1C, d, JCeF ¼ 10.6 Hz),
125.26 (1C), 129.53 (1C, d, JCeF ¼ 5.0 Hz), 133.80 (1C), 137.07 (1C, d,
JCeF ¼ 13.3 Hz),137.65 (1C),147.22 (1C),153.53 (1C),156.82 (1C), and
159.40 (1C, d, JCeF ¼ 247 Hz); LRMS-EI (m/z): 439 (Mþ). HRMS-EI
(m/z): Calcd. for C21H22FN7O3 (Mþ): 439.1768; Found 439.1780.
The in vitro antibacterial activity, in vivo therapeutic effect of
selected compounds, and inhibitory activity of selected compounds
towards four cytochrome P450 isozymes (CYP) and MAO-A, and -B
were evaluated in the same way as reported previously [10].
Acknowledgments
4.1.47. (S)-N-((3-(3-Fluoro-4-(2-(2-(hydroxyacetyl)[1,2,5]
oxadiazepan-5-yl)pyridin-5-yl)phenyl)-2-oxo-5-oxazolidinyl)
methyl)acetamide (25a)
We are grateful to various medicinal chemists and biologists of
Shionogi & Co., Ltd. Discovery Laboratory for their contributions to
this work: Masakatsu Tsuji and Rio Nakamura (infectious diseases
section), Kenji Morimoto, Toshiaki Aoki, Mikito Asai, and Keisuke
Miyazaki (medicinal chemistry section). We are also grateful to
Professor Hiroyuki Kagechika and Dr. Hiroyuki Masuno of the
Institute of Biomaterials and Bioengineering, Tokyo Medical and
Dental University, for measurement of EI-LRMS and HRMS spectra.
Linezolid-resistant strain NRS271 was kindly provided by the
network on antimicrobial resistance in Staphylococcus aureus
(http://www.narsa.net/content/default.jsp).
To a solution of compound 24a (126.0 mg, 0.293 mmol) and
pyridine (234.1 mg, 2.960 mmol) in CH2Cl2 (5 mL) was added
acetoxyacetyl chloride (211.1 mg, 1.546 mmol). The mixture was
stirred for 2 h, and then a small amount of EtOH was added and the
solution was concentrated in vacuo. The residue was used for the
next reaction without further purification. To a solution of the
residue in MeOH (3 mL) was added potassium carbonate (406.7 mg,
2.943 mmol). The mixture was stirred for 30 min at ambient tem-
perature, diluted by the addition of H2O (5 mL), and extracted with
10% MeOH/CHCl3. The organic solution was dried and evaporated.
Silica gel (8 g) column chromatography of the residue using CHCl3/
MeOH (99:1 to 92:8) as the eluent afforded 25a (107.3 mg, 75%).
White powder (EtOH); mp 151e153 ꢁC; 1H NMR (CDCl3 þ CD3OD)
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.08.002.
d
¼ 2.02 (3H, s, CH3eC]O), 3.56e3.66 (2H, m, eCH2e), 3.83 (1H,
dd, J ¼ 6.7, 9.1 Hz, oxazolidinone-H4), 3.91e4.22 (9H, m, eCH2e),
4.34 (2H, br s, eCH2eOH), 4.76e4.87 (1H, m, oxazolidinone-H5),
6.70 (1H, d, J ¼ 8.8 Hz, pyridine-H3), 7.28 (1H, dd, J ¼ 2.1, 8.5 Hz,
Ar-H6), 7.40 (1H, t, J ¼ 8.5 Hz, Ar-H5), 7.53 (1H, dd, J ¼ 2.1, 12.9 Hz,
Ar-H2), 7.71 (1H, d, J ¼ 8.8 Hz, pyridine-H4), 8.02 (1H, br t, J ¼ 6 Hz,
eNHeC]O), and 8.30 (1H, s, pyridine-H6); 13C NMR
References
[1] C.M. Perry, B. Jarvis, Linezolid: a review of its use in the management of
serious Gram-positive infections, Drugs 61 (2001) 525e551.
[2] R.C. Moellering Jr., Linezolid: the first oxazolidinone antimicrobial, Ann.
Intern. Med. 138 (2003) 135e142.
[3] S. Tsiodras, H.S. Gold, G. Sakoulas, G.M. Eliopoulos, C. Wennersten,
L. Venkataraman, R.C. Moellering Jr., M.J. Ferraro, Linezolid resistance in a
clinical isolate of Staphylococcus aureus, Lancet 358 (2001) 207e208.
(CDCl3 þ CD3OD)
d
¼ 21.98 (1C), 41.72 (1C), 45.83 (1C), 47.07 (1C),
47.42 (1C), 47.68 (1C), 59.44 (1C), 71.92 (1C), 74.74 (1C), 105.41 (1C),

H. Suzuki et al. / European Journal of Medicinal Chemistry 69 (2013) 262e277
277
[4] S. Toh, L. Xiong, C.A. Arias, V. Villegas, K. Lolans, J. Quinn, A.S. Mankin,
Acquisition of a natural resistance gene renders a clinical strain of methicillin-
resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid,
Mol. Microbiol. 64 (2007) 1506e1514.
[5] R.D. Gonzales, P.C. Schreckenberger, M.B. Graham, S. Kelkar, K. DenBesten,
J.P. Quinn, Infections due to vancomycin-resistant Enterococcus faecium
resistant to linezolid, Lancet 357 (2001) 1179e1180.
[6] W.B. Im, S.H. Choi, J.-.Y. Park, S.H. Choi, J. Finn, S.-.H. Yoon, Discovery of tor-
ezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent, Eur. J.
Med. Chem. 46 (2011) 1027e1039.
[7] K. Michalska, I. Karpiuk, M. Król, S. Tyski, Recent development of potent an-
alogues of oxazolidinone antibacterial agents, Bioorg. Med. Chem. 21 (2013)
577e591.
[8] A. Khalaj, M. Nakhjiri, A.S. Negahbani, M. Samadizadeh, L. Firoozpour,
S. Rajabalian, N. Samadi, M.A. Faramarzi, N. Adibpour, A. Shafiee,
A. Foroumadi, Discovery of a novel nitroimidazolyl-oxazolidinone hybrid with
potent anti Gram-positive activity: synthesis and antibacterial evaluation, Eur.
J. Med. Chem. 46 (2011) 65e70.
[9] H. Suzuki, I. Utsunomiya, K. Shudo, Synthesis and application of [1,2,5]tri-
azepane and [1,2,5]oxadiazepane as versatile structural units for drug dis-
covery, Chem. Pharm. Bull. 58 (2010) 1001e1002.
[12] R. Tokuyama, Y. Takahashi, Y. Tomita, M. Tsubouchi, N. Iwasaki, N. Kado,
E. Okezaki, O. Nagata, Structureeactivity relationship (SAR) studies on oxa-
zolidinone antibacterial agents. 3.1 Synthesis and evaluation of 5-
thiocarbamate oxazolidinones, Chem. Pharm. Bull. 46 (2001) 361e367.
[13] L.M. Thomasco, R.C. Gadwood, E.A. Weaver, J.M. Ochoada, C.W. Ford,
G.E. Zurenko, J.C. Hamel, D. Stapert, J.K. Moerman, R.D. Schaadt, B.H. Yagi, The
synthesis and antibacterial activity of 1,3,4-thiadiazole phenyl oxazolidinone
analogues, Bioorg. Med. Chem. Lett. 13 (2003) 4193e4196.
[14] F. Reck, F. Zhou, M. Girardot, G. Kern, C.J. Eyermann, N.J. Hales, R.R. Ramsay,
M.B. Gravestock, Identification of 4-substituted 1,2,3-triazoles as novel oxa-
zolidinone antibacterial agents with reduced activity against monoamine
oxidase A, J. Med. Chem. 48 (2005) 499e506.
[15] S.I. Hauck, C. Cederberg, A. Doucette, L. Grosser, N.J. Hales, G. Poon,
M.B. Gravestock, New carbon-linked azole oxazolidinones with improved
potency and pharmacokinetics, Bioorg. Med. Chem. Lett. 17 (2007) 337e
340.
[16] W.A. Gregory, D.R. Brittelli, C.eL.J. Wang, M.A. Wuonola, R.J. McRipley,
D.C. Eustice, V.S. Eberly, P.T. Bartholomew, A.M. Slee, M. Forbes, Antibacterials.
Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 1. The
“B” Group, J. Med. Chem. 32 (1989) 1673e1681.
[17] K.J. Shaw, M.R. Barbachyn, The oxazolidinones: past, present, and future, Ann.
N. Y. Acad. Sci. 1241 (2011) 48e70.
[10] H. Suzuki, I. Utsunomiya, K. Shudo, N. Fukuhara, T. Iwaki, T. Yasukata, Anti-
bacterial oxazolidinone analogues having
seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit, Eur. J.
Med. Chem. 63 (2013) 811e825.
a
N-hydroxyacetyl-substituted
[18] This compound is available from Watanabe Chemical Industries, Ltd.
[19] N.J. Hales, T.P. Weber, M.B. Gravestock, D.R. Carcanague, S.I. Hauck, PCT Int.
Appl., WO200448392, 2004.
[11] M.R. Barbachyn, C.W. Ford, Oxazolidinone structureeactivity relationships
leading to linezolid, Angew. Chem. Int. Ed. 42 (2003) 2010e2023.
[20] M.B. Gravestock, H.K. Huynh, N.J. Hales, PCT Int. Appl., WO200456817,
2004.