Design, synthesis and evaluation of triazole functionalized ring-fused 2-pyridones as antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2012.06.018

Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC₅₀'s between 9 and 50 μM.

Full text of DOI:10.1016/j.ejmech.2012.06.018

European Journal of Medicinal Chemistry 54 (2012) 637e646
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and evaluation of triazole functionalized ring-fused 2-pyridones
as antibacterial agents
,b,c,
Christoffer Bengtsson a, Anders E.G. Lindgren a, Hanna Uvell b, Fredrik Almqvist a
*
a Department of Chemistry, Umeå University, Linnaeus väg 10, SE-90187 Umeå, Sweden
b Laboratories for Chemical Biology Umeå LCBU, Umeå University, SE-90187 Umeå, Sweden
c Umeå Center for Microbial Research UCMR, Umeå University, SE-90187 Umeå, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial
agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus
assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused
bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by
Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse
series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-
dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but
interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities
Received 8 May 2012
Received in revised form
3 June 2012
Accepted 9 June 2012
Available online 18 June 2012
Keywords:
Pilicide
2-Pyridone
Triazole
with EC50’s between 9 and 50 mM.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Huisgen 1,3-dipolar cycloaddition
Antibacterial
1. Introduction
latter example this is achieved by preventing polymerization of the
major curli subunit protein, CsgA, into a functional amyloid fibre
[2,7]. The bicyclic 2-pyridones are synthesized via an acid induced
acylketene/imine cyclocondensation between an acyl Meldrum’s
Considering the ever growing antibiotic resistance developed by
many bacteria, there is an immense need for new compounds with
new mode of actions, for treatment of bacterial infections. Bicyclic 2-
pyridones, named pilicides, have been designed and synthesized to
inhibit the pili assembly machinery in uropathogenic Escherichia coli
by inhibition of the chaperone/usher pathway [1]. Furthermore it
has been shown that a carboxylic acid [2,3] or a carboxylic acid
isostere [4] in position 3 is essential for biological activity. Pili are
important virulence factors for the bacteria and they need these
organelles to attach to the host cell, to withstand shear forces (in the
urinary tract), to invade the host and to establish biofilm like colo-
nies [5]. Bacterial biofilms are complex structures and are involved
in many serious bacterial infections such as urinary tract infection
(UTI). UTI by it’s own is responsible for infecting more than 900 000
women and men, severaltimes per year in U.S. alone! [6]. Depending
on the substitution pattern on the bicyclic 2-pyridones, particularly
in position 8 (Fig. 1), the biological target can be switched from
inhibition of pilus assembly to inhibition of curli formation. In the
acid derivative and a D
2-thiazoline, either via conventional heating
[8] or more convenient under microwave irradiation to yield the 7
and 8 substituted bicyclic 2-pyridones [9] (Fig. 1).
Previous biological data has revealed that small heterocycles i.e.
thiophenes and furanes can be beneficial substituents in position 8
(1) and 2 (2) of the ring-fused bicyclic 2-pyridones (Fig. 2), resulting
in increased biological activity [6,10].
These results encouraged us also to investigate other small
heterocycles like triazoles, which ultimately would allow the intro-
duction of a diverse set of substituted heterocycles to gain further
knowledge in structure activity relationships. Substituted triazoles
are scarcely commercially available as their boronic acid/ester coun-
terparts, which considerablylimit theSuzukieMiyaura coupling asan
alternative for library synthesis in this case. However, triazoles can be
synthesized via the Huisgen 1,3-dipolar cycloaddition often referred
to as “click chemistry”. This reaction allows late introduction of
diverse substituents, which is advantageous in library synthesis. Tri-
azoles are widely used as mimetics in different occasions, most well
known as peptide bond mimetics [11] but they have also served as
double bond- [12] and furan substitutes [13].
* Corresponding author. Department of Chemistry, Umeå University, Linnaeus
väg 10, SE-90187 Umeå, Sweden. Tel.: þ46 90 7866925; fax: þ46 90 7867655.
E-mail address: fredrik.almqvist@chem.umu.se (F. Almqvist).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.06.018

638
C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
A
Fig. 1. Schematic view over the acylketene/imine cyclocondensation to the 7- and 8
substituted thiazolino ring-fused bicyclic 2-pyridones. Reaction conditions: (a) TFA,
DCM, MWI 140 ꢀC for 2 min.
B
Fig. 2. Examples of biologically active, heterocycle functionalized bicyclic 2-pyridones,
the heterocycles are highlighted in red. Their respective effective concentration with
50% inhibition (EC50) of pilus dependent biofilm formation is shown. (For interpreta-
tion of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
Fig. 3. Retrosynthetic scheme over the triazole functionalizations of position 8 (A) and
2 (B).
compounds were considered to be key intermediates for the
introduction of substituted triazoles in the 8- and 2 positions
respectively as outlined in the retrosynthetic scheme (Fig. 3).
The halogenated compounds 3 and 4 have previously been
synthesized and successfully used in Pd-catalyzed cross couplings
(i.e. SuzukieMiyaura [14], and Sonogashira couplings [15]). These
Table 1
Selective Sonogashira coupling of the bromo-iodo-bicyclic 2-pyridone 3 followed by Huisgen 1,3-dipolar cycloadditions.
R
X
Product
Yield (%)
a
H
Me
Et
cPrCH2
Bn
N3
I
I
Br
Br
Br
Br
N3
N3
6a
6b
6c
6d
6e
6f
6g
6h
6i
42
79
78
54
70
82
84
66
95
pMeBn
pNO2Bn
b
a
TMSN3 was used in the reaction instead of NaN3.
The azido alcohol was made from the corresponding commercial available amino alcohol via a diazo-transfer reaction with TfN3 according to published procedures [16].
b

C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
639
Table 2
Hydrolysis of the 8-position triazole functionalized bicyclic 2-pyridones followed by reductive dehalogenation.
a
a
R
Product
Yield (%)
EC50
(m
M)
Product
Yield (%)
EC50 (mM)
H
Me
Et
cPrCH2
Bn
7a
7b
7c
7d
7e
7f
7g
7h
7i
72
73
87
93
85
82
63
77
79
>200
>200
>200
>200
100
200
35
150
>200
8a
8b
8c
8d
8e
8f
73
85
69
72
67
92
82
88
74
>200
>200
>200
>200
100
pMeBn
pNO2Bn
75
8gb
8h
8i
>200
>200
>200
a
Experiments were performed in triplicates and compared to DMSO-treated controls. The biofilm formation was studied under type-1 pili inducing conditions [5a].
The nitro group was reduced to the corresponding aniline.
b
2. Results and discussion
or bad for antibacterial activity. In the series of 8-triazolo
substituted pilicides only five out of eighteen tested compounds
2.1. Functionalization of the 8-position
had an activity with an EC50 below 200
8f). However, the best pilicide in this collection, 7g, was active in
the lower M range (EC50 at 35 M), which is comparable to the
thiophene analogue 1 with an EC50 of 39 M. Interestingly, the
analogues most similar to pilicide 1 in size (i.e. 8a and 8b) both had
EC50’s higher than 200 M.
mM (i.e. 7e, 7g, 7h, 8e and
Triazole functionalization of the 8-position started by a regio-
selective Sonogashira coupling on the 6-bromo-8-iodo bicyclic 2-
pyridone 3 [14] with trimethylsilylacetylene (TMSA). The trime-
thylsilyl (TMS) group was then deprotected by K2CO3 in THF:MeOH
1:4 to give the terminal acetylene 5 in 76% yield. The terminal
alkyne was then exposed to a Cu(I) catalyzed Huisgen 1,3-dipolar
cycloaddition with a variety of azides (either as presynthesized
azides or by in situ generation via NaN3 and alkyl halides) (Table 1).
LiOH mediated hydrolysis furnished the 6-bromo substituted
carboxylic acid intermediates 7aei in 63e93% yields (Table 2). The
following dehalogenation by ammoniumformate and Pd/C in
refluxing methanol [14] gave the final 8-triazole functionalized
bicyclic 2-pyridones 8aei in 67e92% yields (Table 2) without any
debenzylation detected (i.e. 8f and 8g, Table 2).
The compounds (7ae7i and 8ae8i) were evaluated for their
ability to inhibit the formation of pili in an uropathogenic E. coli
strain (the clinical isolate UTI89). The assay is a whole cell based
assay where the bacteria are grown under conditions where they
form a bacterial biofilm, which is dependent upon pilus assembly.
The efficacy as a whole of the compounds is not only dependent on
there direct interaction with the target (Chaperone-Usher
pathway) but also upon their ability to enter the bacteria. Hence, it
is hard to foresee and predict if a substitution pattern will be good
m
m
m
m
2.2. Functionalization of the 2-position
Triazole functionalization of the 2-position turned out to be
more demanding. Our first attempt was made with the previously
published alkyne functionalized bicyclic 2-pyridone methyl ester 9
[15]. The Huisgen 1,3-dipolar cycloaddition proceeded in 71%,
however the methyl ester 10 was shown to be very difficult to
hydrolyze and only generated the decarboxylated compound 11,
even when using the hydrolysis method previously developed for
thiophene and furane substituted compounds (i.e. 2) (Scheme 1).
The starting material was exchanged for the corresponding
alkyne functionalized trimethylsilyl ethyl ester (TMSE) 12 [15],
which can be deprotected under milder conditions. Due to higher
lipophilicity of these compounds DMSO:H2O 1:1 could not be used
as solvent for the Huisgen 1,3-dipolar cycloaddition. Instead the
DMSO content was increased to DMSO:H2O 9:1 and after subse-
quent TBAF$3H2O deprotection of the TMSE ester in THF at room
temperature the 2-position triazole functionalized bicyclic 2-

640
C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
3. Conclusion
Herein we present a synthetic route to functionalize the ring-
fused bicyclic 2-pyridones in position 8 and 2 with triazoles. This
was made via a Sonogashira coupling followed by a Huisgen 1,3-
dipolar cycloaddition. In the 8-position this strategy was effective
for a wide range of azides, both in situ generated (6beg),
commercially available (6a and 6i) and synthesized (6h). The 2-
position triazole functionalized methyl ester was proven to be
hard to hydrolyze this problem was circumvented by using the
previously developed TMSE esters 12aeb [15], which could be
deprotected under mild conditions with TBAF in THF at room
temperature without any decarboxylation observed. All together
this gave a collection of twenty-four potential pilus dependent
biofilm inhibitors. The evaluation showed that the 8-position was
difficult to vary without affecting the biofilm inhibition capacity
negatively. Here only one out of eighteen pilicides gave an EC50
Scheme 1. Synthesis of triazole substituted methyl ester and attempted hydrolysis.
Reaction conditions: (a) CuSO4, Na-ascorbate, NaN3, MeI, DMSO:H2O 1:1, 71%.
below 50
substituted triazoles can be a very attractive substituent for the
future, with the best pilicide 13e showing EC50 values below 10 M.
mM. However, in the 2 position it was shown that
pyridone acids 13aef could be isolated in 54e69% yields over two
steps (Table 3) without any decarboxylation detected.
m
Four out of six analogues showed 50% effective concentrations
Both small (methyl, 13e) and larger (benzyl, 13f) groups in the tri-
azolo substituent were allowed indicating that further fine-tuning
of the substitution pattern in this position have potential to result
in more potent pilicides. The methodologies developed in this
study are general and robust, which is a prerequisite to enable such
studies in the future.
lower than 200 mM (Table 3). As pointed out earlier, the assay in this
case is a whole cell assay, which will reflect not only the direct
interaction with the potential target but also will take into account
uptake and distributionwithin the bacteria, a clear structure activity
can be hard to predict. The trend is that a larger substituent in
position eight (e.g. R ¼ mCF3Ph) is better than a smaller (e.g. R ¼ cPr)
but interesting differences can be seenwhen the triazolo substituent
is taken into account. Here R1 ¼ H is better in combination with
a cyclopropyl substituent compared to a meta CF3-phenyl substit-
uent (compare 13a with 13d) and the opposite is seen for R1 ¼ Bn
(compare 13c with 13f). Pilicide 13e was the most potent analogue in
4. Experimental section
4.1. General synthesis
this study and had an EC50 of 9
the pilicides tested the past two years (approx. 120) [6,10,17] only
sixteen of them have shown EC50 below 10 M with the best being
mM, which is very promising. Among
Unless stated otherwise, all reagents and solvents were used as
received from commercial suppliers. CuI was purified by refluxing
with DCM for 20 h in a Soxhlet apparatus and stored under dark and
dry conditions. DMF was distilled under vaccum and stored over 3 Å
m
a pilus dependent biofilm inhibitor with an EC50 of 400 nM [10].
Table 3
Huisgen 1,3-dipolar cycloaddition in position 2 of the thiazolo ring-fused bicyclic 2-pyridones followed by TBAF deprotection of the TMSE ester.
Product
R
R1
X
Yield (%)
EC50
(m
M)f
13a
13b
13c
13d
13e
13f
cPr
cPr
cPr
mCF3Ph
mCF3Ph
mCF3Ph
H
56
75
Me
Bn
H
Me
Bn
I
Br
69a
54b
61
150
>200
>200
9
I
Br
61c,d
55e
50
a
Approx 5% of 13a was formed.
b
c
d
e
f
Approx 10% of 13a was formed.
Approx 5% of 13d was formed.
CuTC was used instead of CuSO4/Na-ascorbate.
Approx 10% of 13d was formed.
Experiments were performed in triplicates and compared to DMSO-treated controls. The biofilm formation was studied under type-1 pili inducing conditions [5a].

C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
641
molecular sieves. All HPLC was performed on a C18 reversed-phase
column with H2O:MeCN mixtures as eluent. TLC was performed on
silica gel detected with UV-light. Column chromatography was
employed on normal phase silica gel (eluents given in brackets).
Optical rotation was measured with a polarimeter at 20 ꢀC and
589 nm. IR was recorded on a spectrometer equipped with an ATR
device. 1H and 13C NMR spectra were recorded on a 400 MHz or
a 500 MHz spectrometer at 298 K and calibrated using the residual
peak of solvent as internal standard [CDCl3 (CHCl3 dH 7.26 ppm,
CDCl3 dC 77.16 ppm), d6-DMSO (d5-DMSO dH 2.49 ppm, d6-DMSO dC
39.5 ppm), d3-AcOD (d2-AcOD dH 2.00 ppm and 11.70 ppm, d3-AcOD
dC 20.0 ppm and 180.0 ppm)]. HRMS was performed using a mass
spectrometer with electrospray ionization (ESþ), sodiumformate
was used as calibration chemical. E. coli, UTI89, was inoculated in LB
over night at 37 ꢀC. The next day the culture was diluted 1:1000 in LB
The mixture was stirred for 5 min at room temperature and DMF
(0.75 ml), MeI (6
ml, 0.10 mmol) and 5 (30 mg, 0.066 mmol) were
added. The reaction mixture was stirred at 70 ꢀC for 16 h (oil bath).
Diluted with EtOAc and washed with brine. The organic layer was
dried (Na2SO4), filtered and concentrated. The crude product was
purified by column chromatography on silica gel (heptane:EtOAc
80:20 / 0:100) gave 6b (26.6 mg, 79%).[
a] 0 (c 0.50, CDCl3); IR
D
1740, 1652, 1472, 1212, 988, 792 cmꢁ1 1H NMR, (400 MHz, CHCl3)
;
d
7.89e7.80 (m, 2H), 7.75 (d, J ¼ 8.3 Hz, 1H), 7.54e7.49 (m, 2H), 7.35
(t, J ¼ 7.5 Hz, 1H), 7.03 (dd, J ¼ 7.1, 0.9 Hz, 1H), 6.64 (s, 1H), 5.76 (dd,
J ¼ 8.6, 2.5 Hz, 1H), 4.57e4.40 (m, 2H), 3.86 (s, 3H), 3.74e3.67 (m,
4H), 3.53 (dd, J ¼ 11.8, 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
168.2, 157.6, 152.0, 148.6, 142.1, 133.8, 132.7, 131.5, 128.9, 127.5,
126.5, 126.1, 125.7, 124.7, 123.7, 123.0, 114.8, 106.5, 64.9, 53.7,
37.4, 36.7, 31.9; LRMS (ES) calcd [M þ H] for C23H20BrN4O3S
512, obsd 512.
and plated into 96-well PVC plates (Falcon #353911),100 ml per well.
Compounds were added to the wells to desired concentration, the
DMSO concentration was kept constant. The plates were incubated
for 24 h in humid boxes at 26 ꢀC. The plates were washed extensively
4.2.2. (3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-(1H-[1,2,3]
triazol-4-yl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic
acid methyl ester (6a)
with water and air dried before 125
ml/well of 1% crystal violet
(Sigma C3886) was added. The plates were incubated with crystal
violet for 10 min at room temperature, washed extensively with
From 5 (40 mg, 0.088 mmol) was prepared 6a (19 mg, 42%
yield) after purification by column chromatography on silica gel
water and then air dried. 150
m
l/well of 33% acetic acid was added,
heptane:EtOAc 30:70; [
a
]
ꢁ1 (c 0.50, DMSO); IR 2355, 1744,
D
100 l from each well was transferred to a new clear bottom 96-well
m
1622, 1473, 1155, 975, 792; 1H NMR, (400 MHz, d6-DMSO)
plates (Nunc #167008). Absorbance was read at 600 nm. Growth
was monitored in separate sterile clear bottom 96-well plates. All
experiments were performed in triplicates.
Compounds 3 [14], 4 [6], 9 [15] and 12 [15] were synthesized
according to published procedures. Data in agreement with pub-
lished data.
d
8.08e8.01 (m, 1H), 7.97e7.91 (m, 1H), 7.79 (d, J ¼ 8.3 Hz, 1H),
7.59e7.51 (m, 2H), 7.40 (t, J ¼ 7.7 Hz, 1H), 7.24 (s, 1H), 6.92 (d,
J ¼ 7.2 Hz, 1H), 5.77 (dd, J ¼ 10.4, 1.7 Hz, 1H), 4.57e4.36 (m, 2H),
3.87 (dd, J ¼ 12.1, 9.4 Hz, 1H), 3.80 (s, 3H), 3.56 (dd, J ¼ 12.1,
1.6 Hz, 1H); 13C NMR (100 MHz, d6-DMSO)
d 168.5, 156.3, 151.1,
148.7, 139.7, 133.3, 132.6, 131.1, 128.7, 128.6, 126.8, 126.3, 125.9,
125.5, 123.6, 123.1, 113.0, 107.1, 64.4, 53.1, 37.1, 30.9; LRMS (ES)
calcd [M þ H] for C22H18BrN4O3S 498, obsd 498.
4.1.1. (3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-ethynyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (5)
3 (1.5 g, 2.7 mmol), CuI (51.4 mg, 0.27 mmol), Pd(PPh3)2Cl2
(94.7 mg, 0.135 mmol) and TEA (0.75 ml, 5.4 mmol) in DMF (25 ml,
degassed before use) was stirred for 5 min and TMSA (1.14 ml,
8.1 mmol) in DMF (7 ml) was added dropwise over 5 min. The flask
was sealed and stirred at room temperature under nitrogen
atmosphere for 20 h. The reaction mixture was diluted with EtOAc
and washed with brine. The organic layer was dried (Na2SO4),
filtered and concentrated. The crude material was dissolved in THF/
MeOH 1:4 (70 ml) and K2CO3 (746 mg, 5.4 mmol) was added, the
reaction was stirred at room temperature for 15 min. The reaction
mixture was diluted with EtOAc and washed with brine. The
organic layer was dried (Na2SO4), filtered and concentrated. Puri-
fication by column chromatography on silica gel (Heptane:EtOAc
4.2.3. (3R)-6-Bromo-8-(1-ethyl-1H-[1,2,3]triazol-4-yl)-7-naphthalen-
1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid methyl ester (6c)
From 5 (100 mg, 0.22 mmol) was prepared 6c (90 mg, 78%
yield) after purification by column chromatography on silica gel
heptane:EtOAc 80:20 / 0:100; [
a
;
]
D
2 (c 0.50, CHCl3); IR 1747,
1646, 1472, 1213, 1174, 792 cmꢁ1
1H NMR, (400 MHz, CDCl3)
d
7.89e7.79 (m, 2H), 7.74 (d, J ¼ 8.2 Hz, 1H), 7.53e7.46 (m, 2H),
7.35 (t, J ¼ 8.0 Hz, 1H), 7.04 (d, J ¼ 7.1 Hz, 1H), 6.54 (s, 1H), 5.76
(dd, J ¼ 8.5, 2.3 Hz, 1H), 4.55e4.39 (m, 2H), 3.97 (dq, J ¼ 2.1,
8.5 Hz, 2H), 3.86 (s, 3H), 3.71 (dd, J ¼ 11.8, 8.6 Hz, 1H), 3.52 (dd,
J ¼ 11.8, 2.4 Hz, 1H), 0.97 (t, J ¼ 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 168.2, 157.6, 152.1, 148.6, 141.8, 133.9, 132.7, 131.4, 128.9,
65:35) gave 5 (931 mg, 76%). [
2361, 1747, 1642, 1576, 1473, 1212, 999, 771 cmꢁ1
(400 MHz, CDCl3)
a
]
D ꢁ1 (c 0.50, CHCl3); IR 3226, 2952,
127.5, 126.5, 126.1, 125.7, 124.7, 123.0, 122.1, 114.9, 106.5, 64.9,
;
1H NMR,
53.7, 45.2, 37.5, 31.9, 14.7; LRMS (ES) calcd [M
C24H22BrN4O3S 526, obsd 526.
þ
H] for
d
8.13 (d, J ¼ 8.8 Hz, 1H), 7.89 (d, J ¼ 8.8 Hz, 1H),
7.75 (d, J ¼ 8.8 Hz, 1H), 7.62e7.57 (m, 1H), 7.56e7.51 (m, 1H), 7.35 (t,
J ¼ 7.6 Hz, 1H), 6.94 (dd, J ¼ 7.2, 0.8 Hz, 1H), 5.74 (dd, J ¼ 8.8, 2.4 Hz,
1H), 4.69 (s, 2H), 3.87 (s, 3H), 3.85e3.81 (m, 1H), 3.62 (dd, J ¼ 12.0,
4.2.4. (3R)-6-Bromo-8-(1-cyclopropylmethyl-1H-[1,2,3]triazol-4-
yl)-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid methyl ester (6d)
2.4 Hz, 1H), 3.15 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 167.9, 157.2,
153.4, 152.8, 133.9, 132.0, 131.8, 129.0, 127.4, 126.3, 125.9, 125.7,
124.0, 123.1, 113.7, 98.4, 85.3, 65.4, 53.8, 38.0, 32.0; LRMS (ES) calcd
[M þ H] for C22H17BrNO3S 455, obsd 455.
From 5 (40 mg, 0.088 mmol) was prepared 6d (26 mg, 54%
yield) after purification by column chromatography on silica gel
heptane:EtOAc 80:20 / 0:100; [
1646, 1472, 1432, 1212, 1170, 791 cmꢁ1
CDCl3)
(m, 2H), 7.37 (t, J ¼ 7.6 Hz, 1H), 7.05 (d, J ¼ 6.9 Hz, 1H), 6.71
(s, 1H), 5.78 (dd, J ¼ 8.5, 2.2 Hz, 1H), 4.58e4.41 (m, 2H), 3.87 (s,
3H), 3.85e3.75 (m, 2H), 3.75e3.67 (m, 1H), 3.54 (dd, J ¼ 11.8,
2.3 Hz, 1H), 0.61e0.50 (m, 1H), 0.19e0.06 (m, 2H), ꢁ0.12e0.19
a
]
ꢁ1 (c 0.50, CHCl3); IR 1738,
D
;
1H NMR, (400 MHz,
4.2. Typical procedure for the Huisgen 1,3-dipolar cycloaddition in
the 8-position (compounds 6aei)
d
7.90e7.83 (m, 2H), 7.76 (d, J ¼ 8.2 Hz, 1H), 7.53e7.47
4.2.1. (3R)-6-Bromo-8-(1-methyl-1H-[1,2,3]triazol-4-yl)-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid methyl ester (6b)
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 168.2, 157.6, 151.6,
NaN3 (25.8 mg, 0.40 mmol), Na-ascorbate (5.9 mg, 0.03 mmol)
and CuSO4 (1.6 mg, 0.01 mmol) were dissolved in water (0.75 ml).
148.5, 141.7, 134.0, 132.5, 131.4, 128.9, 127.5, 126.6, 126.1, 125.8,
124.6, 123.0, 122.1, 115.0, 106.7, 64.9, 54.9, 53.7, 37.8, 32.0, 10.2,

642
C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
3.8, 3.7; LRMS (ES) calcd [M þ H] for C26H24BrN4O3S 552,
(100 MHz, d6-DMSO)
d
168.4 (splitted, 1C), 156.4, 151.5 þ 151.4 (1C),
obsd 552.
149.6, 140.8 þ 140.6 (1C), 136.9, 133.3 (splitted, 1C), 132.5 (splitted,
1C),131.1 (splitted,1C),128.6 (splitted,1C),128.5 (splitted,1C),128.5
(splitted, 1C), 128.1 (splitted, 2C), 126.8 (splitted, 1C), 126.3 þ 126.2
(2C), 125.9 (splitted, 1C), 125.5 (splitted, 1C), 123.8 (splitted, 1C),
123.3 þ 123.1 (1C), 123.1 þ 122.9 (1C), 113.0 þ 113.0 (1C),
105.8 þ 105.7 (1C), 64.6 þ 64.5 (2C), 62.8 þ 62.7 (1C), 53.1 (splitted,
1C), 36.9 (splitted, 1C), 36.6 þ 36.5 (1C), 31.1 þ 31.0 (1C); LRMS (ES)
calcd [M þ H] for C31H28BrN4O4S 633, obsd 633.
4.2.5. (3R)-8-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-6-bromo-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid methyl ester (6e)
From 5 (40 mg, 0.088 mmol) was prepared 6e (36 mg, 70% yield)
after purification by column chromatography on silica gel hepta-
ne:EtOAc 90:10 / 20:80; [
a
]
ꢁ4 (c 0.25, DMSO); IR 1750, 1646,
D
1598, 1474, 1212, 792, 725 cmꢁ1
;
1H NMR, (400 MHz, d6-DMSO)
d
8.03e7.93 (m, 2H), 7.83 (s, 1H), 7.78 (d, J ¼ 8.2 Hz, 1H), 7.57e7.53
4.2.9. (3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-[1-(2,3,4-
tri-O-acetyl-ß-D-xylopyranosyl)-1H-[1,2,3]triazol-4-yl]-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (6i)
From 5(50mg, 0.11mmol)wasprepared6i(79mg, 95%yield)after
purification by column chromatography on silica gel heptane:EtOAc
(m, 2H), 7.36 (t, J ¼ 7.4 Hz, 1H), 7.17 (t, J ¼ 7.2 Hz, 1H), 7.05 (t,
J ¼ 7.3 Hz, 2H), 6.88 (d, J ¼ 7.1 Hz,1H), 6.77 (t, J ¼ 7.7 Hz, 2H), 5.79 (d,
J ¼ 9.0 Hz, 1H), 5.40 (s, 2H), 4.58e4.34 (m, 2H), 3.95e3.86 (m, 1H),
3.79 (s, 3H), 3.65e3.58 (m, 1H); 13C NMR (100 MHz, d6-DMSO)
d
168.4, 156.4, 151.3, 149.7, 141.2, 135.5, 133.2, 132.1, 131.0, 128.6,
85:15/ 0:100;[
a
]D ꢁ2(c0.50, CHCl3);IR1740,1646,1473,1365,1207,
128.5 (2C), 127.8, 126.9, 126.9 (2C), 126.3, 125.9, 125.5, 124.3, 123.6,
123.0, 113.1, 105.3, 64.5, 53.2, 52.6, 36.8, 31.1; LRMS (ES) calcd
[M þ H] for C29H24BrN4O3S 588, obsd 588.
1033, 746 cmꢁ1; 1H NMR, (400 MHz, CDCl3)
d
8.04e7.84 (m, 2H), 7.76
(t, J ¼ 7.8 Hz, 1H), 7.59e7.46 (m, 2H), 7.38e7.32 (m, 1H), 7.02 (t,
J ¼ 7.1 Hz, 1H), 6.97, 6.86 (s, 1H), 5.79e5.71 (m, 1H), 5.45 (dd, J ¼ 8.9,
6.3 Hz,1H), 5.22 (dt, J ¼ 9.4,1.1 Hz,1H), 4.85e4.62 (m, 2H), 4.58e4.35
(m, 2H), 3.98e3.87 (m, 1H), 3.84, 3.83 (s, 3H), 3.76e3.64 (m, 1H),
3.54e3.48 (m,1H), 3.38e3.28 (m,1H), 2.05e1.97 (m, 6H), 1.71, 1.59 (s,
4.2.6. (3R)-6-Bromo-8-[1-(4-methyl-benzyl)-1H-[1,2,3]triazol-4-
yl]-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid methyl ester (6f)
3H); 13C NMR (100 MHz, CDCl3)
d 169.7 (splitted, 1C), 169.7,
From 5 (60 mg, 0.132 mmol) was prepared 6f (65 mg, 82% yield)
after purification by column chromatography on silica gel hepta-
168.8 þ 168.7 (1C),168.1 þ168.0 (1C), 157.5 þ157.4 (1C), 151.9 þ 151.6
(1C), 148.8 þ 148.6 (1C), 142.6 þ 142.5 (1C), 134.0 þ 133.9 (1C),
132.3 þ132.2 (1C),131.4 þ131.3 (1C),129.0 þ 128.9 (1C),127.6 þ 127.5
(1C), 126.5 þ 126.4 (1C), 126.1 þ 125.9 (1C), 125.8 þ 125.7 (1C),
124.5 þ124.4 (1C), 123.4 þ123.2 (1C), 121.3 þ121.0 (1C),115.2 þ114.9
(1C),106.0 þ 105.8 (1C), 86.3 þ 86.2 (1C), 71.4 þ 71.3 (1C), 70.9 þ 70.4
(1C), 68.2 þ 68.1 (1C), 65.2, 65.0 þ 64.7 (1C), 53.6 (splitted, 1C),
37.3 þ 37.2 (1C), 32.0 þ 31.9 (1C), 20.7, 20.6 (splitted, 1C), 20.0 þ 19.8
(1C); LRMS (ES) calcd [M þ H] for C33H32BrN4O10S 757, obsd 757.
ne:EtOAc 85:15 / 0:100; [
a]
D 1 (c 0.50, CHCl3); IR 1748, 1645, 1472,
1212, 1156, 792, 770 cmꢁ1
;
1H NMR, (400 MHz, CDCl3)
d
7.89 (dd,
J ¼ 9.2, 1.3 Hz, 1H), 7.80 (d, J ¼ 8.2 Hz, 1H), 7.71 (d, J ¼ 8.2 Hz, 1H),
7.57e7.47 (m, 2H), 7.26 (t, J ¼ 7.7 Hz,1H), 6.94 (dd, J ¼ 8.0, 0.9 Hz,1H),
6.85 (d, J ¼ 7.8 Hz, 2H), 6.61 (d, J ¼ 8.0 Hz, 2H), 6.55 (s, 1H), 5.75 (dd,
J ¼ 8.6, 2.4 Hz, 1H), 5.1 (s, 2H), 4.53e4.35 (m, 2H), 3.85 (s, 3H), 3.69
(dd, J ¼ 11.8, 8.6 Hz,1H), 3.51 (dd, J ¼ 11.8, 2.4 Hz,1H), 2.27 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 168.1,157.5,151.7, 148.4,142.0,138.5,133.8,
132.3, 131.3, 130.5, 129.6 (2C), 128.9, 127.9 (2C), 127.4, 126.5, 126.0,
125.6,124.4,123.0,122.6,114.9,106.5, 64.8, 53.9, 53.7, 37.6, 31.9, 21.2;
LRMS (ES) calcd [M þ H] for C30H26BrN4O3S 603, obsd 603.
4.3. Typical procedure for hydrolysis of the 8-position triazole
functionalized bicyclic 2-pyridones (compounds 7aei)
4.3.1. (3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-(1H-[1,2,3]
triazol-4-yl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic
acid (7a)
6a (29.0 mg, 0.058 mmol) was dissolved in THF (5 ml) and 1 M
LiOH (0.174 ml) was added. The mixture was stirred at room
temperature for 17 h. The suspension was diluted with EtOAc and
brine was added.1 M HCl was added until pH ¼ 1. The organic phase
was dried (Na2SO4), filtered and concentrated. Purification by HPLC
4.2.7. (3R)-6-Bromo-7-naphthalen-8-[1-(4-nitro-benzyl)-1H-
[1,2,3]triazol-4-yl]-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-
a]pyridine-3-carboxylic acid methyl ester (6g)
From 5 (40 mg, 0.088 mmol) was prepared 6g (49 mg, 84% yield)
after purification by column chromatography on silica gel hepta-
ne:EtOAc 80:20 / 0:100; [
a
]
D 1 (c 0.50, CHCl3); IR 1747, 1644, 1416,
1472, 1342, 1213, 725 cmꢁ1; 1H NMR, (400 MHz, CDCl3)
d
7.88e7.81
(m, 3H), 7.76 (d, J ¼ 8.3 Hz,1H), 7.68 (d, J ¼ 8.3 Hz,1H), 7.57e7.44 (m,
2H), 7.26 (t, J ¼ 7.7 Hz,1H), 6.95 (d, J ¼ 7.1 Hz,1H). 6.78 (d, J ¼ 8.8 Hz,
2H), 6.64 (s, 1H), 5.76 (dd, J ¼ 8.6, 2.4 Hz, 1H), 5.30e5.19 (m, 2H),
4.52e4.33 (m, 2H), 3.86 (s, 3H), 3.73 (dd, J ¼ 11.8, 8.6 Hz, 1H), 3.54
gave 7a (20.1 mg, 72%). [
1472,1390,1158,1139, 977, 792 cmꢁ1; 1H NMR, (400 MHz, d6-DMSO)
15.05 (broad s, 1H), 8.05e7.99 (m, 1H), 7.97e7.91 (m, 1H), 7.79 (d,
a
]
D ꢁ1 (c 0.10, DMSO); IR 2936, 1722, 1619,
d
J ¼ 8.2 Hz, 1H), 7.58e7.53 (m, 2H), 7.40 (t, J ¼ 7.4 Hz, 1H), 7.33 (s, 1H,
broad), 6.93 (d, J ¼ 6.9 Hz,1H), 5.68 (dd, J ¼ 9.0,1.3 Hz,1H), 4.55e4.32
(m, 2H), 3.89 (dd, J ¼ 11.9, 9.3 Hz, 1H), 3.59 (dd, J ¼ 11.9, 4.7 Hz, 1H);
(dd, J ¼ 11.8, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 168.1, 157.5,
151.3, 148.6, 147.9, 142.7, 140.5, 133.8, 132.1, 131.2, 128.9, 128.3 (2C),
127.5, 126.6, 126.3, 125.6, 124.2 (2C), 124.2, 122.9, 122.8, 115.0, 105.9,
13C NMR (100 MHz, d6-DMSO)
d 169.2, 156.4, 150.8 (broad), 149.6,
64.8, 53.7, 53.0, 37.7, 32.0; LRMS (ES) calcd [M
C29H23BrN5O5S 633, obsd 633.
þ
H] for
141.6 (broad), 133.3, 132.7 (broad), 132.4, 131.0, 128.6, 126.9, 126.4,
125.9, 125.5, 123.7, 123.0, 113.3, 105.2 (broad), 64.7, 37.0, 31.5; HRMS
(ES) calcd [M þ Na] for C21H15BrN4NaO3S 504.9946, obsd 504.9934.
4.2.8. (3R)-8-((S)-1-Benzyl-2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-
yl)-6-bromo-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (6h)
From 5 (100 mg, 0.22 mmol) was prepared 6h (92 mg, 66% yield)
after purification by column chromatography on silica gel hepta-
4.3.2. (3R)-6-Bromo-8-(1-methyl-1H-[1,2,3]triazol-4-yl)-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (7b)
From 6b (60 mg, 0.116 mmol) was prepared 7b (42 mg, 73%
yield) after purification by column chromatography on silica gel
ne:EtOAc 75:25 / 0:100; [
1591,1475,1220,1158, 987, 791 cmꢁ1; 1H NMR, (400 MHz, d6-DMSO)
8.11e7.99 (m,1H), 7.98e7.90 (m,1H), 7.87e7.77 (m, 2H), 7.64e7.52
a
]D ꢁ222 (c 0.10, DMSO); IR 1744, 1636,
DCM:MeOH:AcOH 91:7:2; [
1606, 1531, 1307, 1127, 886, 818 cmꢁ1
DMSO)
a
]
ꢁ5 (c 0.10, DMSO); IR 1779, 1693,
D
d
;
1H NMR, (400 MHz, d6-
(m, 2H), 7.45e7.37 (m, 1H), 7.02e6.84 (m, 4H), 6.75e6.66 (m, 2H),
5.84e5.77 (m,1H), 5.04 (s,1H, broad), 4.67e4.24 (m, 3H), 3.95e3.84
(m,1H), 3.84 (s, 3H), 3.66e3.53 (m, 3H), 3.05e2.64 (m, 2H); 13C NMR
d
8.01 (d, J ¼ 7.9 Hz, 1H), 7.92 (d, J ¼ 6.8 Hz, 1H), 7.82e7.73
(m, 2H), 7.59e7.49 (m, 2H), 7.39 (t, J ¼ 7.1 Hz,1H), 6.91 (d, J ¼ 6.9 Hz,
1H), 5.67 (d, J ¼ 8.8 Hz, 1H), 4.56e4.33 (m, 2H), 3.89 (dd, J ¼ 11.2,

C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
643
9.7 Hz,1H), 3.82 (s, 3H), 3.58 (d, J ¼ 11.2 Hz,1H); 13C NMR (100 MHz,
132.6, 132.4, 131.2, 129.2 (2C), 128.8, 127.3 (2C), 127.1, 126.5, 126.1,
125.7,124.3,123.8,123.2,113.4,105.4, 64.9, 52.6, 37.0, 31.8, 20.8; HRMS
(ES) calcd [M þ Na] for C29H23BrN4NaO3S 609.0572, obsd 609.0576.
d6-DMSO) d 169.2, 156.4, 151.4, 149.7, 141.2, 133.2, 132.7, 131.1, 128.6,
126.9, 126.3, 125.8, 125.5, 124.7, 123.8, 123.1, 113.0, 105.4, 64.7, 36.5,
36.3, 31.5; HRMS (ES) calcd [M þ Na] for C22H17BrN4NaO3S
519.0102, obsd 519.0098.
4.3.7. (3R)-6-Bromo-7-naphthalen-8-[1-(4-nitro-benzyl)-1H-
[1,2,3]triazol-4-yl]-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-
a]pyridine-3-carboxylic acid (7g)
4.3.3. (3R)-6-Bromo-8-(1-ethyl-1H-[1,2,3]triazol-4-yl)-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (7c)
From 6g (67 mg, 0.106 mmol) was prepared 7g (41 mg, 63%
yield) after purification by HPLC; [
1592, 1521, 1476, 1344, 1160, 1111, 798, 777, 731 cmꢁ1
(400 MHz, d6-DMSO) 7.99e7.94 (m,1H), 7.93e7.89 (m,1H), 7.88 (s,
a
]
D
ꢁ4 (c 0.10, DMSO); IR 1734,
From 6c (88 mg, 0.167 mmol) was prepared 7c (74 mg, 87%
;
1H NMR,
yield) after purification by HPLC; [
a
]
ꢁ2 (c 0.10, DMSO); IR 1725,
d
D
1617, 1475, 1167, 768, 719 cmꢁ1 1H NMR, (400 MHz, d6-DMSO)
;
1H), 7.83 (d, J ¼ 8.7 Hz, 2H), 7.76 (d, J ¼ 8.2 Hz, 1H), 7.55e7.48 (m,
2H), 7.36 (t, J ¼ 7.9 Hz,1H), 6.95 (d, J ¼ 8.6 Hz,1H), 6.87 (d, J ¼ 7.1 Hz,
1H), 5.69 (dd, J ¼ 7.8, 1.0 Hz, 1H), 5.59 (s, 2H), 4.54e4.31 (m, 2H),
3.91 (dd, J ¼ 11.7, 9.1 Hz, 1H), 3.60 (dd, J ¼ 11.7, 1.0 Hz, 1H); 13C NMR
d
8.02e7.96 (m, 1H), 7.96e7.88 (m, 1H), 7.78 (d, J ¼ 8.0 Hz, 1H), 7.67
(s, 1H), 7.58e7.48 (m, 2H), 7.39 (t, J ¼ 7.6 Hz, 1H), 6.92 (d, J ¼ 6.9 Hz,
1H), 5.68 (d, J ¼ 8.9 Hz, 1H), 4.57e4.33 (m, 2H), 4.16e4.06 (m, 2H),
3.88 (dd, J ¼ 11.4, 9.8 Hz, 1H), 3.57 (d, J ¼ 11.4 Hz, 1H), 1.03 (t,
(100 MHz, d6-DMSO)
d 169.4, 156.6, 151.1, 150.0, 147.0, 143.2, 141.8,
J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, d6-DMSO)
d
169.4, 156.6, 151.6,
133.4, 132.3, 131.1, 128.7, 128.2 (2C), 127.1, 126.5, 126.1, 125.7, 124.8,
123.8 (2C), 123.7, 123.2, 113.4, 105.1, 64.9, 51.9, 37.0, 31.8; HRMS (ES)
calcd [M þ Na] for C28H20BrN5NaO5S 640.0266, obsd 640.0270.
149.9, 141.3, 133.4,132.8, 131.2, 128.8, 127.1, 126.5, 126.0, 125.7, 124.1,
123.4, 123.2, 113.4, 105.5, 64.9, 44.7, 36.7, 31.7, 15.1; HRMS (ES) calcd
[M þ Na] for C23H19BrN4NaO3S 533.0259, obsd 533.0255.
4.3.8. (3R)-8-((S)-1-Benzyl-2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-
yl)-6-bromo-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic acid (7h)
4.3.4. (3R)-6-Bromo-8-(1-cyclopropylmethyl-1H-[1,2,3]triazol-4-
yl)-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (7d)
From 6h (80 mg, 0.126 mmol) was prepared 7h (60 mg, 77%
From 6d (55 mg, 1 mmol) was prepared 7d (51 mg, 93% yield)
after purification by column chromatography on silica gel
yield) after purification by HPLC; [
1622, 1532, 1475, 1308, 1163, 1018, 792, 701 cmꢁ1
(400 MHz, d6-DMSO) 8.09e7.99 (m, 1H), 7.97e7.93 (m, 1H),
a
]
D ꢁ104 (c 0.10, DMSO); IR 1776,
;
1H NMR,
DCM:MeOH:AcOH 91:7:2; [
a
]
;
ꢁ2 (c 0.10, DMSO); IR 1634, 1474,
d
D
1396, 1179, 791, 768 cmꢁ1
1H NMR, (400 MHz, d6-DMSO)
7.84e7.78 (m, 2H), 7.61e7.52 (m, 2H), 7.43e7.37 (m, 1H), 6.98e6.85
(m, 4H), 6.72e6.67 (m, 2H), 5.67 (d, J ¼ 9.0 Hz, 1H), 4.66e4.24 (m,
3H), 3.94e3.83 (m, 1H), 3.62e3.50 (m, 3H), 3.03e2.89 (m, 1H),
d
8.04e7.97 (m, 1H), 7.95e7.89 (m, 1H), 7.79 (d, J ¼ 8.1 Hz, 1H), 7.58
(s, 1H), 7.56e7.49 (m, 2H), 7.40 (t, J ¼ 7.9 Hz, 1H), 6.93 (d, J ¼ 7.0 Hz,
1H), 5.56 (d, J ¼ 8.7 Hz, 1H), 4.55e4.31 (m, 2H), 4.03e3.91 (m, 2H),
3.81 (dd, J ¼ 11.4, 9.4 Hz, 1H), 3.58 (d, J ¼ 11.4 Hz, 1H), 0.83e0.71 (m,
1H), 0.20e0.06 (m, 2H), 0.04e0.07 (m, 2H); 13C NMR (100 MHz, d6-
2.80e2.63 (m, 1H); 13C NMR (100 MHz, d6-DMSO)
d 169.2 (splitted,
1C), 156.4, 151.2 þ 151.1 (1C), 149.7, 140.9 þ 140.7 (1C), 136.9, 133.3
(splitted, 1C), 132.6 (splitted, 1C), 131.1 (splitted, 1C), 128.6 (splitted,
1C), 128.5 (splitted 2C), 128.1 (2C), 126.8 (splitted, 1C), 126.3 þ 126.2
(1C), 125.9 (splitted, 1C), 125.5 (splitted, 1C), 123.8, 123.3, 123.1,
122.9, 113.1 þ 113.0 (1C), 105.6 (splitted, 1C), 64.7 (splitted, 1C),
64.6 þ 64.5 (splitted, 1C), 62.8 þ 62.7 (1C), 36.9, 36.6 þ 36.5
(splitted, 1C), 31.5 þ 31.4 (splitted, 1C); HRMS (ES) calcd [M þ Na]
for C30H25BrN4NaO4S 639.0678, obsd 639.0680.
DMSO)
d 169.4, 156.7, 150.6, 150.1, 141.4, 133.5, 132.8, 131.2, 128.7,
127.1, 126.5, 126.0, 125.7, 124.0, 123.4, 123.3, 113.5, 105.1, 66.2, 53.7,
37.0, 32.4, 11.0, 3.4 (splitted, 2C); HRMS (ES) calcd [M þ Na] for
C25H21BrN4NaO3S 559.0415, obsd 559.0420.
4.3.5. (3R)-8-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-6-bromo-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (7e)
4.3.9. (3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-[1-(2,3,4-
From 6e (79 mg, 0.135 mmol) was prepared 7e (66 mg, 85%
tri-hydroxy-ß-D-xylopyranosyl)-1H-[1,2,3]triazol-4-yl]-2,3-
yield) after purification by HPLC; [
a]
D ꢁ11 (c 0.10, DMSO); IR 1750,
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (7i)
1614, 1474, 1201, 714 cmꢁ1 1H NMR, (400 MHz, d6-DMSO)
;
From 6i (72 mg, 0.095 mmol) was prepared 7i (46 mg, 79% yield)
d
8.04e7.92 (m, 2H), 7.83 (s, 1H), 7.78 (d, J ¼ 8.3 Hz, 1H), 7.61e7.52
after purification by HPLC; [
1621, 1473, 1310, 1039, 991, 792 cmꢁ1
DMSO)
1H), 7.79 (d, J ¼ 8.2 Hz, 1H), 7.59e7.51 (m, 2H), 7.40 (dt, J ¼ 0.7,
7.7 Hz, 1H), 6.94 (d, J ¼ 7.2 Hz, 1H), 5.68 (dd, J ¼ 9.1, 1.1 Hz, 1H), 5.34
(dd, J ¼ 9.2, 1.5 Hz, 1H), 4.54e4.30 (m, 2H), 3.94e3.85 (m, 1H),
3.74e3.66 (m, 1H), 3.61e3.47 (m, 2H), 3.36e3.18 (m, 3H); 13C NMR
a
]
ꢁ21 (c 0.10, DMSO); IR 3351, 1722,
D
(m, 2H), 7.36 (t, J ¼ 7.6 Hz, 1H), 7.17 (t, J ¼ 7.3 Hz, 1H), 7.05 (t,
J ¼ 7.4 Hz, 2H), 6.89 (d, J ¼ 6.9 Hz, 1H), 6.77 (d, J ¼ 7.4 Hz, 2H), 5.68
(d, J ¼ 8.9 Hz, 1H), 5.40 (s, 2H), 4.57e4.32 (m, 2H), 3.89 (t,
J ¼ 10.4 Hz, 1H), 3.59 (d, J ¼ 5.8 Hz, 1H); 13C NMR (100 MHz, d6-
;
1H NMR, (400 MHz, d6-
d
8.09e8.04 (m, 1H), 8.00 (d, J ¼ 15.2 Hz, 1H), 7.96e7.91 (m,
DMSO)
d 169.2, 156.4, 151.0, 149.7, 141.3, 135.5, 133.2, 132.2, 131.0,
128.6, 128.5 (2C), 127.8, 126.9, 126.9 (2C), 126.3, 125.9, 125.5, 124.3,
123.6, 123.0, 113.2, 105.2, 64.7, 52.6, 36.8, 31.6; HRMS (ES) calcd
[M þ Na] for C28H21BrN4NaO3S 595.0415, obsd 595.0410.
(100 MHz, d6-DMSO)
d
169.2, 156.4, 151.2 þ 151.1 (1C), 150.0 þ 149.9
(1C), 141.1, 133.3, 132.6, 131.2, 128.6, 126.9, 126.4 þ 126.3 (1C),
125.9 þ 125.9 (1C), 125.6, 123.9, 123.3, 123.1, 113.2 þ 113.1 (1C),
105.3, 88.0 þ 87.9 (1C), 76.9, 71.9 þ 71.8 (1C), 69.0, 68.2 þ 68.1 (1C),
64.7, 36.7 þ 36.6 (1C), 31.5; HRMS (ES) calcd [M þ Na] for
C26H23BrN4NaO7S 637.0369, obsd 637.0357.
4.3.6. (3R)-6-Bromo-8-[1-(4-methyl-benzyl)-1H-[1,2,3]triazol-4-
yl]-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (7f)
From 6f (93 mg, 0.153 mmol) was prepared 7f (74 mg, 82% yield)
after purification by HPLC; [
a
]D ꢁ6 (c 0.10, DMSO); IR 1748,1612,1474,
4.4. Typical procedure for the dehalogenation of the 8-position
triazole functionalized bicyclic 2-pyridones (compounds 8aei)
1
1199, 1120, 788, 762 cmꢁ1; H NMR, (400 MHz, d6-DMSO)
d
7.99 (t,
J ¼ 8.8 Hz, 2H), 7.82e7.75 (m, 2H), 7.63e7.53 (m, 2H), 7.37 (t, J ¼ 7.7 Hz,
1H), 6.89 (d, J ¼ 7.1 Hz,1H), 6.83 (d, J ¼ 7.8 Hz, 2H), 6.68 (d, J ¼ 7.9 Hz,
2H), 5.69 (d, J ¼ 8.9 Hz, 1H), 5.34 (s, 2H), 4.55e4.31 (m, 2H), 3.89 (dd,
J ¼ 11.9, 9.4 Hz, 1H), 3.60 (d, J ¼ 11.9 Hz, 1H), 2.21 (s, 3H); 13C NMR
4.4.1. (3R)-7-Naphthalen-1-ylmethyl-5-oxo-8-(1H-[1,2,3]triazol-4-
yl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (8a)
7a(10.1 mg, 0.0209 mmol), ammoniumformate (19.7 mg,
0.313 mmol) and 10% Pd/C (5.0 mg) were dissolved in MeOH (2 ml).
(100 MHz, d6-DMSO)
d 169.4, 156.6, 151.2, 149.9, 141.5, 137.3, 133.5,

644
C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
The mixture was refluxed for 4 h after which the solvent was
d 8.41 (s, 1H), 7.98e7.93 (m, 1H), 7.87e7.79 (m, 2H), 7.55e7.47 (m,
evaporated. The residue was dissolved in DMSO and Pd/C was
2H), 7.46e7.39 (m, 1H), 7.33e7.24 (m, 4H), 7.21e7.16 (m, 2H), 5.62
(s, 2H), 5.49 (s, 1H), 5.45 (dd, J ¼ 8.9, 1.4 Hz, 1H), 4.38e4.13 (m, 2H),
3.79 (dd, J ¼ 9.2, 2.7 Hz, 1H), 3.49 (dd, J ¼ 11.9, 1.4 Hz, 1H); 13C NMR
filtered off. Purification by HPLC gave8a (6.2 mg, 73%). [
DMSO); IR 1733, 1634, 1483, 1178, 780 cmꢁ1 1H NMR, (400 MHz,
d6-DMSO)
a]D 5 (c 0.25,
;
d
8.02 (s,1H, broad), 7.99e7.92 (m,1H), 7.85 (d, J ¼ 8.3 Hz,
(100 MHz, d6-DMSO) d 169.4, 159.7, 153.5, 149.7, 141.4, 135.9, 133.9,
1H), 7.83e7.78 (m, 1H), 7.56e7.49 (m, 2H), 7.46 (t, J ¼ 7.2 Hz, 1H),
7.29 (d, J ¼ 7.0 Hz, 1H), 5.51e5.42 (m, 2H), 4.34e4.10 (m, 2H), 3.81
(dd, J ¼ 12.0, 9.1 Hz, 1H), 3.50 (dd, J ¼ 12.0, 1.4 Hz, 1H); 13C NMR
133.4, 131.3, 128.7 (2C), 128.6, 128.0, 127.5 (2C), 127.5, 127.4, 126.3,
125.8, 125.6, 124.6, 123.8, 113.9, 104.4, 63.0, 52.9, 35.7, 31.2; HRMS
(ES) calcd [M þ Na] for C28H22N4NaO3S 517.1310, obsd 517.1303.
(125 MHz, d6-DMSO)
d
169.4, 159.7, 158.1 þ 157.8 (1C), 153.7, 149.7,
134.0,133.4,131.3,128.6,127.5,127.4,126.4,125.9,125.6,123.9,113.9
(splitted, 2C), 104.3, 63.1, 35.8, 31.2; HRMS (ES) calcd [M þ Na] for
C21H16N4NaO3S 427.0841, obsd 427.0836.
4.4.6. (3R)-8-[1-(4-Methyl-benzyl)-1H-[1,2,3]triazol-4-yl]-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (8f)
From 7f (31 mg, 0.053 mmol) was prepared 8f (25 mg, 92% yield)
4.4.2. (3R)-8-(1-Methyl-1H-[1,2,3]triazol-4-yl)-7-naphthalen-1-
ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid (8b)
after purification by HPLC; [
a
]
ꢁ3 (c 0.10, DMSO); IR 1727, 1621,
D
1563, 1488, 1442, 1158, 783 cmꢁ1
;
1H NMR, (400 MHz, d6-DMSO)
d
8.36 (s,1H), 7.95 (d, J ¼ 7.9 Hz,1H), 7.88e7.78 (m, 2H), 7.56e7.47 (m,
From 7b (20 mg, 0.040 mmol) was prepared 8b (14 mg, 85%
2H), 7.42 (t, J ¼ 7.6 Hz,1H), 7.29e7.23 (m,1H), 7.10 (s, 4H), 5.55 (s, 2H),
5.48 (s,1H), 5.45 (d, J ¼ 8.9 Hz,1H), 4.36e4.11 (m, 2H), 3.83e3.74 (m,
1H), 3.49 (d, J ¼ 11.8 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, d6-
yield) after purification by HPLC; [
1622, 1566, 1492, 1441, 1183, 782 cmꢁ1
DMSO)
a
]
ꢁ3 (c 0.10, DMSO); IR 1734,
D
;
1H NMR, (400 MHz, d6-
d
8.31 (s, 1H), 7.99e7.92 (m, 1H), 7.86 (d, J ¼ 8.3 Hz, 1H),
DMSO) d 169.4, 159.7, 153.5, 149.6, 141.4, 137.4, 134.0, 133.4, 132.9,
7.83e7.75 (m, 1H), 7.56e7.43 (m, 3H), 7.33 (d, J ¼ 6.7 Hz, 1H), 5.44
(d, J ¼ 8.7 Hz, 1H), 5.38 (s, 1H), 4.36e4.10 (m, 2H), 4.07 (s, 3H), 3.79
(dd, J ¼ 11.2, 9.5 Hz, 1H), 3.49 (d, J ¼ 11.2 Hz, 1H); 13C NMR
131.3, 129.2 (2C), 128.6, 127.6 (2C), 127.5, 127.4, 126.3, 125.8, 125.6,
124.5,123.8,113.9,104.5, 63.0, 52.7, 35.7, 31.2, 20.7; HRMS (ES) calcd
[M þ Na] for C29H24N4NaO3S 531.1467, obsd 531.1463.
(100 MHz, d6-DMSO) d 169.4, 159.7, 153.9, 149.6, 141.2, 134.0, 133.4,
131.4, 128.6, 127.8, 127.4, 126.3, 125.8, 125.6, 125.2, 123.9, 113.6,
104.5, 63.1, 36.4, 35.8, 31.2; HRMS (ES) calcd [M þ Na] for
C22H18N4NaO3S 441.0997, obsd 441.1003.
4.4.7. (3R)-8-[1-(4-Amino-benzyl)-1H-[1,2,3]triazol-4-yl]-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (8g)
From 7g (32 mg, 0.052 mmol) was prepared 8g (22 mg, 82%
4.4.3. (3R)-8-(1-Ethyl-1H-[1,2,3]triazol-4-yl)-7-naphthalen-1-
ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid (8c)
yield) after purification by HPLC; [
a
]
D ꢁ11 (c 0.10, DMSO); IR 1681,
1622, 1490, 1444, 1198 cmꢁ1; 1H NMR, (400 MHz, d6-DMSO)
d
8.34
(s, 1H), 7.98e7.93 (m, 1H), 7.88e7.78 (m, 2H), 7.55e7.47 (m, 2H),
7.46e7.40 (m, 11H), 7.27 (d, J ¼ 7.0 Hz, 1H), 7.11 (d, J ¼ 8.4 Hz, 2H),
6.83 (d, J ¼ 8.3 Hz, 2H), 5.49 (s, 2H), 5.47e5.42 (m, 2H), 4.36e4.12
(m, 2H), 3.78 (dd, J ¼ 11.9, 9.2 Hz, 1H), 3.48 (dd, J ¼ 11.9, 1.4 Hz,
From 7c (38 mg, 0.075 mmol) was prepared 8c (22 mg, 69% yield)
after purification by HPLC; [
1563,1491,1443,1220,1197,1168, 781 cmꢁ1; 1H NMR, (400 MHz, d6-
DMSO)
a
]
ꢁ11 (c 0.10, DMSO); IR 1731, 1627,
D
d
8.32 (s, 1H), 7.97e7.92 (m, 1H), 7.85 (d, J ¼ 8.3 Hz, 1H),
1H); 13C NMR (100 MHz, d6-DMSO)
d 169.4, 159.7, 153.6, 149.6, 141.6
7.83e7.78 (m, 1H), 7.54e7.48 (m, 2H), 7.46 (t, J ¼ 7.9 Hz, 1H), 7.30 (d,
J ¼ 7.0 Hz, 1H), 5.46e5.41 (m, 2H), 4.38 (q, J ¼ 7.3 Hz, 2H), 4.35e4.12
(m, 2H), 3.78 (dd, J ¼ 11.8, 9.4 Hz,1H), 3.49 (d, J ¼ 11.8 Hz,1H),1.38 (t,
(broad),141.4, 134.0, 133.4, 131.3, 129.0 (2C), 128.6, 128.1
(broad),127.6, 127.4, 126.3, 125.8, 125.6, 124.3, 123.9, 117.8 (2C),
113.9, 104.5, 63.0, 52.7, 35.7, 31.2; HRMS (ES) calcd [M þ Na] for
C28H23N5NaO3S 532.1419, obsd 532.1409.
J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, d6-DMSO)
d 169.5, 159.7, 153.7,
149.6,141.2,134.0,133.4,131.4,128.6,127.7,127.4,126.3,125.8,125.6,
123.9, 123.7, 113.8, 104.6, 63.1, 44.7, 35.7, 31.3, 15.2; HRMS (ES) calcd
[M þ Na] for C23H20N4NaO3S 455.1154, obsd 455.1148.
4.4.8. (3R)-8-((S)-1-Benzyl-2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-
yl)-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (8h)
4.4.4. (3R)-8-(1-Cyclopropylmethyl-1H-[1,2,3]triazol-4-yl)-7-
naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (8d)
From 7h (34 mg, 0.056 mmol) was prepared 8h (27 mg, 88%
yield) after purification by HPLC; [
1645, 1489, 1439, 1196, 1022, 996, 782, 700 cmꢁ1
(400 MHz, d6-DMSO)
a
]
D ꢁ154 (c 0.10, DMSO); IR 1731,
;
1H NMR,
From 7d (44 mg, 0.082 mmol) was prepared 8d (26 mg, 72%
d
8.35 (d, J ¼ 16.4 Hz, 1H), 8.00e7.95 (m, 1H),
yield) after purification by HPLC; [
1621, 1489, 1444, 1197, 1167, 782 cmꢁ1
DMSO) 8.28 (s, 1H), 7.97e7.92 (m, 1H), 7.88e7.80 (m, 2H),
a]
9 (c 0.10, DMSO); IR 1731,
;
7.89 (d, J ¼ 8.2 Hz,1H), 7.81e7.71 (m, 1H), 7.57e7.46 (m, 3H), 7.33 (d,
J ¼ 6.9 Hz, 1H), 7.15e6.97 (m, 5H), 5.47e5.41 (m, 1H), 5.33 (d,
J ¼ 14.5 Hz, 1H), 4.90e4.79 (m, 1H), 4.28e3.94 (m, 3H), 3.92e3.83
(m, 2H), 3.83e3.75 (m, 1H), 3.53e3.47 (m, 1H), 3.27e3.18 (m, 1H),
D
1H NMR, (400 MHz, d6-
d
7.54e7.49 (m, 2H), 7.47 (t, J ¼ 7.2 Hz, 1H), 7.29 (d, J ¼ 7.0 Hz, 1H),
5.50 (s, 1H), 5.46 (dd, J ¼ 8.8, 1.2 Hz, 1H), 4.37e4.14 (m, 2H), 4.22 (d,
J ¼ 7.2 Hz, 2H), 3.80 (dd, J ¼ 11.9, 9.3 Hz, 1H), 3.50 (dd, J ¼ 11.9,
1.1 Hz, 1H), 1.25e1.13 (m, 1H), 0.50e0.44 (m, 2H), 0.36e0.31 (m,
3.14e3.04 (m, 1H); 13C NMR (100 MHz, d6-DMSO)
d 169.5, 159.7,
153.9 þ 153.8 (1C), 149.5 (splitted, 1C), 140.6 þ 140.5 (1C),
137.2 þ 137.1 (1C), 134.0 (splitted, 1C), 133.5, 131.4 þ 131.3 (1C),
128.8 (splitted, 2C), 128.6, 128.2 (2C), 127.9 þ 127.8 (1C), 127.5
(splitted, 1C), 126.3 (splitted, 2C), 125.8, 125.7, 124.0 (splitted, 1C),
124.0 þ 123.7 (1C), 113.5 þ 113.4 (1C), 104.6, 64.8 (splitted, 1C), 63.1
(splitted, 1C), 63.0, 37.1 þ 37.0 (1C), 35.8 (splitted, 1C), 31.2; HRMS
(ES) calcd [M þ Na] for C30H26N4NaO4S 561.1572, obsd 561.1580.
2H); 13C NMR (100 MHz, d6-DMSO)
d 169.5, 159.7, 153.6, 149.6,141.1,
134.1, 133.4, 131.3, 128.6, 127.5, 127.4, 126.3, 125.8, 125.6, 123.8 (2C),
113.9, 104.6, 63.0, 53.8, 35.8, 31.2, 11.2, 3.6 (splitted, 2C); HRMS (ES)
calcd [M þ Na] for C25H22N4NaO3S 481.1310, obsd 481.1319.
4.4.5. (3R)-8-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-7-naphthalen-1-
ylmethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid methyl ester (8e)
4.4.9. (3R)-7-Naphthalen-1-ylmethyl-5-oxo-8-[1-(2,3,4-tri-
hydroxy-ß-D-xylopyranosyl)-1H-[1,2,3]triazol-4-yl]-2,3-dihydro-
From 7e (34 mg, 0.059 mmol) was prepared 8e (20 mg, 67%
5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (8i)
yield) after purification by HPLC; [
a
]
D
ꢁ4 (c 0.10, DMSO); IR 1723,
From 7i (38 mg, 0.062 mmol) was prepared 8i (24 mg, 74% yield)
1615, 1488, 1442, 1158, 718 cmꢁ1
;
1H NMR, (400 MHz, d6-DMSO)
after purification by HPLC; [
a
]
D
ꢁ22 (c 0.10, DMSO); IR 1716, 1633,

C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
645
1490, 1416, 1064, 781 cmꢁ1; 1H NMR, (400 MHz, d6-DMSO)
d
13.49
The product was freeze dried, to give 13b (82 mg, 69%) IR
l
1717,
(broad s, 1H) 8.66 (d, J ¼ 4.0 Hz, 1H), 7.99e7.94 (m, 1H), 7.88 (d,
J ¼ 8.1 Hz, 1H), 7.81e7.76 (m, 1H), 7.55e7.46 (m, 3H), 7.37 (d,
J ¼ 6.7 Hz, 1H), 5.56 (d, J ¼ 9.2 Hz, 1H), 5.43 (d, J ¼ 8.5 Hz, 1H), 5.26
(d, J ¼ 10.0 Hz, 1H), 4.36 (d, J ¼ 17.3 Hz, 1H), 4.16e4.07 (m, 1H),
3.90e3.74 (m, 3H), 3.53e3.45 (m, 2H), 3.43e3.33 (m, 2H); 13C NMR
1636, 1558, 1472 cmꢁ1; 1H NMR (400 MHz, d6-DMSO)
d 8.37 (s, 1H),
7.99e7.93 (m, 1H), 7.93e7.85 (m, 2H), 7.55e7.45 (m, 3H), 7.40e7.35
(m, 1H), 5.53 (s, 1H), 4.57 (s, 2H), 4.14 (s, 3H), 1.95e1.86 (m, 1H),
1.08e1.01 (m, 2H), 0.83e0.76 (m, 2H) 13C NMR (100 MHz, d6-
DMSO)
d 161.4, 157.6, 153.9, 145.6, 136.0, 134.6, 133.5, 131.5, 128.6,
(100 MHz, d6-DMSO)
d
169.4, 159.6, 153.8 þ 153.7 (1C), 149.7, 141.1
127.6, 127.4, 126.8, 126.4, 125.8, 125.7, 124.0, 123.8, 117.9, 111.5, 110.0,
(splitted, 1C), 133.9 (splitted, 1C), 133.5, 131.5 þ 131.4 (1C), 128.6,
128.2 þ 128.1 (1C), 127.6, 126.4, 125.8, 125.7, 124.1 þ 124.0 (1C),
123.5 (split, 1C), 113.4 þ 113.3 (1C), 104.4 þ 104.3 (1C), 88.4 (split,
1C), 77.0 (split,1C), 72.50 þ 71.9 (1C), 69.1, 68.3, 62.9 (split,1C), 35.9,
31.2 (split, 1C); HRMS (ES) calcd [M þ Na] for C26H24N4NaO7S
559.1263, obsd 559.1250.
36.8, 35.4, 10.6, 7.6 (2C) HRMS (ES) calcd [M
C25H20N4NaO3S 479.1154, obsd 479.1156.
þ
Na] for
4.5.2. 8-Cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2-(1H-
1,2,3-triazol-4-yl)-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid
(13a)
From 12a (100 mg, 0.2 mmol) was prepared 13a (50 mg, 56%
4.4.10. Methyl 8-cyclopropyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)-7-
(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyridine-3-
carboxylate (10)
yield) after purification by HPLC; IR
NMR (400 MHz, d6-DMSO) 8.18 (s, 1H), 8.00e7.94 (m, 1H),
l ;
1716, 1636, 1464 cmꢁ1 1H
d
7.94e7.86 (m, 2H), 7.56e7.46 (m, 3H), 7.40e7.36 (m, 1H), 5.52 (s,
1H9), 4.58 (s, 2H), 1.96e1.87 (m, 1H), 1.08e0.99 (m, 2H), 0.84e0.76
NaN3 (0.72 mmol, 47 mg), Iodomethane (0.18 mmol, 11
ml),
CuSO4 (0.018 mmol, 3 mg) and Na-ascorbate (0.054 mmol, 11 mg)
were dissolved in DMSO:H2O 1:1 (1 ml) and heated to 80 ꢀC with an
oil bath for 5 min. 9 (0.12 mmol, 50 mg) dissolved in DMSO (1 ml)
was added and the reaction was stirred for 1 h. The reaction
mixture was diluted with saturated NaHCO3 (aq) and extracted
with DCM, the organic phase was dried (Na2SO4), filtered and
concentrated. The crude reaction mixture was purified by column
chromatography on silica gel (heptane:EtOAc 50:50 / 20:80). To
(m, 2H) 13C NMR (100 MHz, d6-DMSO)
d 161.6, 157.6, 153.8, 145.8,
136.0 (br), 134.6, 133.5, 131.5, 128.6, 128.3 (br), 127.5, 127.4, 126.4,
126.2 (br), 125.8, 125.7, 124.0, 116.8 (br), 111.4, 110.0, 35.4, 10.6, 7.6
(2C) HRMS (ES) calcd [M þ Na] for C24H18N4NaO3S 465.0997, obsd
465.0995.
4.5.3. 2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-8-cyclopropyl-7-
(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid (13c)
give 10 (40 mg, 71%) IR
(400 MHz, d6-DMSO) 8.34 (s, 1H), 8.03e7.94 (m, 1H), 7.94e7.84
l ;
1734, 1654, 1560, 1466 cmꢁ1 1H NMR
d
From 12a (100 mg, 0.2 mmol) was prepared 13c (58 mg, 54%
(m, 2H), 7.58e7.45 (m, 3H), 7.41e7.34 (m, 1H), 5.55 (s, 1H), 4.58
(s, 2H), 4.14 (s, 3H), 3.85 (s, 3H), 1.99e1.89 (m, 1H), 1.12e0.99 (m,
yield) after purification by HPLC; IR
l
1716, 1634, 1616, 1551, 1471,
8.53 (s, 1H), 8.00e7.94
1414 cmꢁ1; 1H NMR (400 MHz, d6-DMSO)
d
2H), 0.89e0.78 (m, 2H) 13C NMR (100 MHz, d6-DMSO)
d
160.7,157.5,
(m, 1H), 7.94e7.86 (m, 2H), 7.56e7.46 (m, 3H), 7.41e7.29 (m, 6H),
5.71 (s, 2H), 5.51 (s, 1H), 4.58 (s, 2H), 1.97e1.88 (m, 1H), 1.10e1.02
154.3, 145.3, 135.4, 134.5, 133.5, 131.5, 128.6, 127.5, 127.4, 126.4,
125.8, 125.7, 124.0, 123.9, 123.8, 119.9, 111.9, 109.9, 53.3, 36.8, 35.4,
10.6, 7.5 (2C).
(m, 2H), 0.85e0.77 (m, 2H) 13C NMR (100 MHz, d6-DMSO)
d 161.4
(br), 157.6, 153.8, 145.7, 136.3, 135.5, 134.6, 133.5, 131.5, 128.8 (2C),
128.6, 128.3, 128.1 (2C), 127.6, 127.5 (br), 127.3, 126.4, 125.8, 125.7,
124.0, 123.0, 117.4 (br), 111.4, 109.9, 53.2, 35.4, 10.6, 7.6 (2C) HRMS
(ES) calcd [M þ Na] for C31H24N4NaO3S 555.1467, obsd 555.1470.
4.4.11. 8-Cyclopropyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)-7-
(naphthalen-1-ylmethyl)-5H-thiazolo[3,2-a]pyridin-5-one (11)
IR
8.73e8.71 (m, 1H), 8.37e8.34 (m, 1H) 7.95e7.89 (m, 2H),
l ;
1637, 1558, 1472 cmꢁ1 1H NMR (500 MHz, d4-AcOH)
d
4.5.4. 7-(naphthalen-1-ylmethyl)-5-oxo-2-(1H-1,2,3-triazol-4-yl)-
8-(3-(trifluoromethyl)phenyl)-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid (13d)
7.85e7.81 (m, 1H), 7.52e7.43 (m, 3H), 7.31e7.27 (m, 1H), 6.16 (s, 1H),
4.69 (s, 2H), 4.21 (s, 3H), 2.00e1.92 (m, 1H), 1.16e1.11 (m, 2H),
0.92e0.88 (m, 2H) 13C NMR (125 MHz, d4-AcOH)
d
160.3, 155.9,
From 12b (121 mg, 0.2 mmol) was prepared 13d (68 mg, 61%
149.2, 139.2, 135.6, 135.2, 133.0, 129.8, 128.6, 128.4, 127.3, 126.8,
126.6, 124.7, 124.3, 122.9, 121.8, 116.5, 111.0, 37.6, 37.0, 11.8, 8.3 (2C).
yield) after purification by HPLC; IR
1H NMR (400 MHz, d6-DMSO)
8.20 (s, 1H), 7.93e7.87 (m, 1H),
7.86e7.68 (m, 6H), 7.51e7.37 (m, 3H), 7.29e7.24 (m, 1H), 5.87 (s,
1H), 4.16 (s, 2H) 13C NMR (100 MHz, d6-DMSO)
161.4, 157.7, 150.8,
l ;
1718, 1636, 1472, 1335 cmꢁ1
d
4.5. Typical procedure for the Huisgen 1,3-dipolar cycloaddition,
followed by TMSE deprotection, in the 2-position of the bicyclic 2-
pyridones (compounds 13aef)
d
146.2, 136.6, 135.8 (br), 134.3, 134.1, 133.3, 131.2, 130.6, 130.1 (q,
J ¼ 31 Hz, 1C), 129.0 (br), 128.5, 127.5, 127.3, 126.8 (br), 126.2, 125.7,
125.6e125.2 (m, 3C), 123.9 (q, J ¼ 271Hz, 1C), 123.7, 116.1 (br), 112.5,
110.4, 35.8; HRMS (ES) calcd [M þ Na] for C28H17F3N4NaO3S
569.0871, obsd 569.0873.
4.5.1. 8-Cyclopropyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)-7-
(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyridine-3-
carboxylic acid (13b)
NaN3 (1.56 mmol, 101 mg), CuSO4 (0.05 mmol, 8 mg), Na-
ascorbate (0.12 mmol, 24 mg) and methyliodide (0.39 mmol,
36 ml) were dissolved in DMSO:H2O 9:1 (5 ml) and stirred at rt for
4.5.5. 2-(1-Methyl-1H-1,2,3-triazol-4-yl)-7-(naphthalen-1-
ylmethyl)-5-oxo-8-(3-(trifluoromethyl)phenyl)-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (13e)
10 min. 12a (0.26 mmol, 130 mg) was added and the reaction was
stirred at rt for 18 h. The reaction mixture was diluted with water
and pH was set to approx 8 with saturated NaHCO3 (aq) and
extracted with EtOAc. The organic phase was dried (Na2SO4),
filtered and concentrated. The crude material was dissolved in THF
(5 ml) and TBAF$3H2O (0.31 mmol, 98 mg) was added and the
reaction was stirred at rt for 3 h. The reaction mixture was diluted
with water and pH was set to approx 1 with 1 M HCl (aq), and then
extracted with EtOAc. The organic phase was dried (Na2SO4),
filtered and concentrated, the crude product was purified by HPLC.
From 12b (121 mg, 0.2 mmol) was prepared 13e (68 mg, 61%
yield) after purification by HPLC; IR
l
1748, 1616, 1540, 1466,
8.42 (s, 1H), 7.93e7.88
1335 cmꢁ1; 1H NMR (400 MHz, d6-DMSO)
d
(m, 1H), 7.86e7.69 (m, 6H), 7.51e7.38 (m, 3H), 7.30e7.25 (m, 1H),
5.88 (s, 1H), 4.17 (s, 2H), 4.09 (s, 3H) 13C NMR (100 MHz, d6-DMSO)
d
161.3, 157.7, 150.8, 146.1, 136.6, 135.8, 134.3, 134.1, 133.3, 131.2,
130.6, 130.1 (q, J ¼ 31Hz, 1C), 128.5, 127.8 (br), 127.6, 127.3, 126.8 (q,
J ¼ 4Hz, 1C), 126.2, 125.7, 125.5, 125.4 (q, J ¼ 4Hz, 1C), 123.9 (q,
J ¼ 272Hz, 1C), 123.8, 123.7, 117.0, 112.6, 110.4, 36.8, 35.8 HRMS (ES)
calcd [M þ Na] for C29H19F3N4NaO3S 583.1028, obsd 583.1036.

646
C. Bengtsson et al. / European Journal of Medicinal Chemistry 54 (2012) 637e646
[5] (a) M.A. Mulvey, Y.S. Lopez-Boado, C.L. Wilson, R. Roth, W.C. Parks, J. Heuser,
S.J. Hultgren, Science 282 (1998) 1494;
4.5.6. 2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-7-(naphthalen-1-
ylmethyl)-5-oxo-8-(3-(trifluoromethyl)phenyl)-5H-thiazolo[3,2-a]
pyridine-3-carboxylic acid (13f)
(b) M.A. Mulvey, J.D. Schilling, S.J. Hultgren, Infect. Immun. 69 (2001) 4572;
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From 12b (121 mg, 0.2 mmol) was prepared 13f (70 mg, 55%
yield) after purification by HPLC; IR
l
1718, 1637, 1472, 1430,
8.55 (s, 1H), 7.93e7.87
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S. Normark, S.J. Hultgren, Science 295 (2002) 851;
1334 cmꢁ1; 1H NMR (400 MHz, d6-DMSO)
d
(m, 1H), 7.86e7.68 (m, 6H), 7.50e7.37 (m, 3H), 7.37e7.24 (m, 6H),
5.88 (s, 1H), 5.68 (s, 2H), 4.17 (s, 2H), 13C NMR (100 MHz, d6-DMSO)
(b) L. Cegelski, J.S. Pinkner, N.D. Hammer, C.K. Cusumano, C.S. Hung, E. Chorell,
V. Åberg, J.N. Walker, P.C. Seed, F. Almqvist, M.R. Chapman, S.J. Hultgren, Nat.
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d
161.2, 157.7, 150.9, 146.0, 136.5, 136.0, 135.4, 134.3, 134.1, 133.3,
131.2, 130.6, 130.1 (q, J ¼ 32Hz, 1C), 128.8 (2C), 128.5, 128.3, 128.1
(2C), 127.6, 127.4 (br), 127.3, 126.8 (q, J ¼ 3Hz, 1C), 126.2, 125.7, 125.5
(splitted, 2C), 123.9 (q, J ¼ 272Hz, 1C), 123.7, 123.1, 117.3, 112.7, 110.4,
53.2, 35.8 HRMS (ES) calcd [M þ Na] for C35H23F3N4NaO3S 659.1341,
obsd 659.1346.
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3128e3142.
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K.B. Sharpless, C.H. Wong, ChemBioChem 4 (2003) 1246e1248;
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Acknowledgements
We are grateful for financial support from the Swedish Research
Council (621-2010-4730), the Knut and Alice Wallenberg Founda-
tion, VINNOVA and the Kempe Foundation (SJCKMS).
(d) G. Appendino, S. Bacchiega, A. Minassi, M. Grazia Cascio, L. De Petrocellis,
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Appendix A. Supplementary data
(g) S.K. Maurya, D.R. Gollapalli, S. Kirubakaran, M. Zhang, C.R. Johnson,
N.N. Benjamin, L. Hedstrom, G.D. Cuny, J. Med. Chem. 52 (2009) 4623e4630.
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Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.ejmech.2012.06.018.
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