Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2010.06.076

With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.

Full text of DOI:10.1016/j.bmc.2010.06.076

Bioorganic & Medicinal Chemistry 18 (2010) 6069–6079
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors
*
Suk Youn Kang , Kwang-Seop Song , Junwon Lee, Sung-Han Lee, Jinhwa Lee
Research Center, Green Cross Corporation, 303 Bojeong-Dong, Giheung-Gu, Yongin, Gyeonggi-Do 446-770, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and
thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the
anomeric carbon of D-glucopyranose was carried out in a stereoselective fashion. On the other hand, a
series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl glucon-
olactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by
the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzyl-
thiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors use-
ful for pharmacotherapy.
Received 27 April 2010
Revised 18 June 2010
Accepted 19 June 2010
Available online 25 June 2010
Keywords:
Pyridazine
Thiazole
Ó 2010 Elsevier Ltd. All rights reserved.
SGLT2
Dapagliflozin
Glucopyranose
1. Introduction
surrogates of phenyl group. Herein, we report the chemical synthe-
sis and biological evaluation of a few of novel SGLT2 inhibitors
It has been known for a long time that substances such as the
natural product phlorizin 1 cause the renal excretion of glucose,
thereby potentially being able to improve control of diabetes
(Fig. 1). But this inhibitor was not suitable as a candidate of clinical
development due to its nonselectivity against SGLT1. More recent
studies of the physiology of renal glucose transport have allowed
the drugs that selectively target the sodium glucose co-transporter
2 (SGLT2) as potentially effective treatments for Type 2 diabetes
and other diseases.1
Dapagliflozin 2 discovered by BMS, currently the most ad-
vanced SGLT2 inhibitor in this field, is being co-developed by
BMS and AstraZeneca with 1200-fold selectivity over SGLT1
(Fig. 1).2 Its structure consists of glucoside and benzylphenyl group,
in which the bond between the glucose and the aglycone is a
carbon–carbon bond. Because of its unique molecular structure
in 2, it is rather difficult to modify its basic framework. However,
we envisioned that addition of heteroatoms to phenyl ring could
provide a valuable approach for the improvement in c log P value,
in turn possibly leading to decrease plasma protein binding of 2,
while maintaining its biological activity. Thus, replacement of phe-
nyl ring with the corresponding heterocyclic ring was anticipated
to provide a promising platform for the improvement in developa-
bility characteristics of SGLT2 inhibitor if successful. As the first
step, we considered pyridazine and thiazole group as potential
including pyridazine 3 and thiazole 4.
2. Results and discussion
2.1. Synthesis of pyridazine analog
As shown in Figure 2, the target compound 3 consists of gluco-
side part and benzyl pyridazine part as an aglycone, in which two
units are connected with b-configuration from the glucose ring.
Pyridazinyl group is substituted with chlorine at 3-position there-
in. Thus, it would be reasonable to install pyridazinyl group onto
glucose stereoselectively, and subsequent transformation from
pyridazinone 15 by two steps ((i) treatment with POCl3, (ii) depro-
tection of benzyl groups) would then provide the target 3-chloro-
pyridazine 3. From a retrosynthetic point of view, we envisioned
that pyridazine ring would be prepared from pyridazinone 15,
which could be provided by cyclization of
c-ketoester 6 with
hydrazine followed by requisite oxidation. 4-Methoxybenzylation
would then take place by alkylation of 2-carboxylated butyrolac-
tone 6, which would be generated in turn from protected vinyl glu-
cose derivative 7.
Per-benzylated
D-glucose 8 was selected as a starting mate-
rial.3,4 Lactol 8 was oxidized to lactone 9 in the presence of TPAP
and NMO at room temperature in CH2Cl2 in 95% yield (Scheme
1). Lactone 9 was then treated with vinyl magnesium bromide in
THF at À78 °C to give rise to the corresponding hemiketal. Without
further purification, b-C-vinyl glucoside 7 was obtained by reduc-
tion of the resulting hemiketal with triethylsilane and TMSOTf in
CH2Cl2 at À30 °C in 53% overall yield. Epoxidation of double bond
* Corresponding author. Tel.: +82 31 260 9892; fax: +82 31 260 9020.
E-mail addresses: jinhwalee@greencross.com, jinhwa_2_lee@hotmail.com (J.
Lee).
These authors contributed equally to this work.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.06.076

6070
S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
Cl
OEt
HO
O
OH
O
OH
O
HO
HO
O
OH
HO
HO
OH
OH
OH
1 (Phlorizin)
2 (Dapagliflozin)
X
A
R
N
Cl
OMe
N
O
O
HO
HO
HO
HO
B
OH
OH
OH
OH
4
3
(A/B=N/S or S/N; X=Cl or Br)
Figure 1. Representative SGLT2 inhibitors (1 and 2) and newly designed SGLT2 inhibitors (3 and 4).
H
N
Cl
OMe
N
O
OMe
N
N
O
O
HO
HO
BnO
BnO
OH
OBn
OH
OBn
3
15
O
O
O
O
BnO
BnO
O
BnO
BnO
OEt
OBn
OBn
OBn
OBn
6
7
Figure 2. Retrosynthetic analysis for the synthesis of compound 3.
O
O
O
O
O
OH
d
a
BnO
b, c
BnO
BnO
O
BnO
BnO
BnO
BnO
85%, ~2:1 ratio
95%
53%
BnO
OBn
OBn
O
OBn
OBn
OBn
OBn
OBn
8
OBn
9
7
10
O
O
O
O
O
O
O
OEt
g
O
f
e
O
O
BnO
BnO
BnO
BnO
BnO
OEt
88%
~100% crude
84%
OBn
OBn
BnO
OBn
OBn
OBn
OBn
OMe
MeO
6
11
12
O
OMe
OMe
O
OMe
OMe
h
O
i
BnO
BnO
OH
OBn
O
BnO
BnO
O
95%
42% (44% sm recoverd)
OBn
OBn
13
OBn
14
Scheme 1. Reagents and conditions: (a) TPAP, 4 Å MS, NMO, CH2Cl2, rt; (b) vinyl magnesium bromide, THF, À78 °C; (c) triethylsilane, trimethylsilyl trifluoromethylsulfonate,
CH2Cl2, À30 °C; (d) mCPBA, NaHCO3, CH2Cl2, rt; (e) diethylmalonate, NaOEt, EtOH, rt; (f) 4-methoxybenzyl bromide, sodium hydride, THF, rt; (g) NaCl, DMSO, reflux; (h) p-
toluenesulfonic acid, MeOH; (i) TPAP, NMO, CH3CN.

S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
6071
underwent smoothly with mCPBA and NaHCO3 in CH2Cl2 to
produce approximately 2:1 mixture of epoxides 10 in 84% com-
bined yields. The coupling reaction between epoxide 10 and dieth-
ylmalonate was accomplished using sodium ethoxide at room
temperature, which was concurrently cyclized to 2-carboxylated
butyrolactone 6 in 84% yield. In order to afford 2-(p-methoxyben-
zyl)-2-carboxylated lactone 11, 2-carboxylated butyrolactone 6
was treated with sodium hydride and p-methoxybenzyl bromide
in THF at room temperature. Subsequently, heating a mixture of
NaCl and 11 in DMSO and water, 2-carboxylated lactone 11 under-
went facile decarboxylation to provide p-methoxybenzyl lactone
12 in 88% yield. At this stage, composition of the whole carbon
framework was accomplished. The unspecified asymmetric centers
in 12 are insignificant because both of them will be incorporated
produce the target compound 3 was accomplished when TMSI
was used in acetonitrile at room temperature.6
By NMR studies, the trans-stereochemistry was evident by either
analysis of the coupling constants of Ha and Hb (JHa,Hb = 9.6 Hz) at
compound3orNOEenhancementdatabetweenhydrogensingluco-
side of acetylated compound 17 (Ha and Hc = 2.1%; Ha and Hd = 3.7%)
as shown in Figure 3.
2.2. Synthesis of thiazole analogs
We next extended a method developed by Dondoni and Scherr-
mann7 for preparation of novel thiazolyl analogs 4 as shown in
Scheme 4. The coupling reaction of D-gluconolactone 9 with 2-lith-
iothiazole prepared in situ from n-BuLi and 2-bromothiazole affor-
ded thiazolyl ketose 18 in 83% yield. The activation of the anomeric
position by O-acetylation, and subsequent removal of the acetoxy
group by reduction with excess triethylsilane in the presence of
BF3 etherate converted ketal 19 to a mixture of glucosides 20 in
good yields (73%).8 Thiazolyl C-glucosides 20 were purified by flash
column chromatography (Biotage, hexane–ethyl acetate gradient
elution) and analyzed by 1H NMR spectroscopy to confirm the ano-
meric configurations. Thus, a doublet peak, observed at 5.29 ppm
into pyridazine ring at the later stage. For the oxidation of c-hydro-
xy group, butyrolactone 12 was opened under the conditions of a
catalytic amount of p-toluenesulfonic acid in methanol. The de-
sired alcohol 13 was produced in 42% yield along with the recov-
ered starting material 12 (44% yield). c-Keto methyl ester 14 was
then generated from alcohol 13 using TPAP and NMO in acetoni-
trile at room temperature in 95% yield.
Cyclization from c-keto ester 14 to dihydropyridazinone 5 was
accomplished with hydrazine monohydrate under the conditions
of refluxing methanol (Scheme 2). Using bromine under acetic acid
at 80 °C, dihydropyridazinone 5 was oxidized to pyridazinone 15
uneventfully and two diastereoisomers became a single compound
15 in 75% yield.5 Pyridazinone 15 was then converted to 6-chloro-
5-benzylpyridazine 16 by treatment of 15 with POCl3 in refluxed
toluene in 84% yield. Final removal of the four benzyl groups to
(J = 6.0 Hz), indicated an existence of the
a-anomeric form of 20.
The -anomeric proton peak intensity was estimated as a half of
a
the proton peak intensity in 4-thiazolyl position at 7.78 ppm.
According to this 1H NMR spectral data, the thiazolyl C-glucosides
20 turned out to be a 1:1 isomeric mixture.7
Lithiation of the thiazole moiety in the 5-position was achieved
by the treatment of thiazolyl C-glucosides 20 with n-BuLi at low
O
OMe
OMe
a
H
O
N
OMe
H
N
N
O
OMe
N
O
b
BnO
BnO
O
O
BnO
BnO
O
89%
BnO
BnO
75%
OBn
OBn
OBn
OBn
OBn
OBn
15
14
5
N
Cl
OMe
N
Cl
OMe
N
N
O
d
O
HO
HO
c
BnO
42%
84%
OH
BnO
OBn
OH
OBn
3
16
Scheme 2. Reagents and conditions: (a) hydrazine monohydrate, MeOH, reflux; (b) bromine, acetic acid, 80 °C; (c) POCl3, toluene, reflux; (d) trimethylsilyl iodide,
acetonitrile, rt.
N
Cl
OMe
N
Cl
OMe
N
N
Hd Ha
O
O
AcO
AcO
HO
HO
Ha
Ac2O, Et3N, DMAP, CH2Cl2
78%
OAc
OH
Hb
Hc
OAc
OH
17
3
N
Cl
AcO
Hb
Ha
N
N
N
O
O
Cl
AcO
AcO
AcO
Hd
Ha
OH
JHa,Hb = 9.6 Hz
NOE
Ha and Hc = 2.1 %
Ha and Hd = 3.7 %
Hc
Figure 3. NMR experiments for determination of stereochemistry (analysis of coupling constants and NOE)

6072
S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
temperature (À78 °C). The subsequent reaction involved the addi-
tion of the lithiated thiazole group to the requisite benzaldehyde,
providing a mixture of diastereomers 21 in 50–60% yields.9 To
reaction. As mentioned above, the base-promoted transformation of
-anomer produced the thermodynamically more stable b-anomers
31 and 32, respectively.
a
our delight, it was observed that thiazolyl
formed into the desired b-anomer 21 during the addition reaction.
a
-C-glucoside was trans-
Lithiation of 5-bromothiazole intermediate 32 was performed
by treatment of LDA, and the resulting anion underwent metal–
halogen exchange reaction so that a bromine atom moved to a
new position (4-position) on the thiazole ring.16,17 The newly
formed lithiated intermediate 33 was subjected to subsequent cou-
pling with requisite aldehydes at low temperature (À78 °C) to pro-
duce the desired alcoholic products 34. The same conditions were
applied to 5-chlorothiazole intermediate 31 with the expectation
for the halogen dance rearrangement. However, in the 5-chloro-
thiazole case, the chlorine atom did not move to 4-position but
maintain the original position. Thus, the coupling reactions of
5-chlorothiazole intermediate 31 with requisite aldehydes pro-
duced 4-benzyl type 36. Both debenzylation and reduction of 34
and 36 were concurrently performed to prepare final products 35
and 37 in an analogous fashion as described previously.
Reductive dehalogenation was performed in order to confirm the
halogen atom positions. Two representative analogs 35a and 37a
were hydrogenated in the presence of Pd/C and the chemical struc-
tures of resulting products were analyzed by their 1H NMR spectra.
While 1H NMR spectrum of the hydrogenated product from 35a was
exactly matched to one of 22a in Scheme 4, one of the hydrogenated
products of 37a was not identical to one of 22b but one of 30a. These
results support that bromine atom is placed on 4-position of thiazole
as in 35a and chlorine atom remains on 5-position as in 37a.
The characteristic doublet signal for
a-anomeric proton was not
detected on 1H NMR spectral data of alkylated products 21. The
basic conditions derived from n-BuLi in the addition reaction are
presumed to transform the
a-anomer (axial) into the thermody-
namically more stable b-anomer (equatorial). This base-promoted
transformation through the sugar carbanion was previously
observed and reported by Dondoni and Marra.10 The reduction fol-
lowed by concomitant debenzylation of alcohol 21 was accom-
plished by warming 21 in neat TMSI at 50 °C for 12–24 h.11a At
this stage, the hydroxyl group in 5-methyl position of thiazole
was also completely reduced to the corresponding methylene at
this final step11b (Scheme 3).
As shown in Scheme 4, 2-bromo-4-((triisopropylsilyloxy)-
methyl)thiazole 23 was lithiated with n-BuLi and subsequently
coupled with D-gluconolactone 9 to produce 4-((triisopropylsilyl-
oxy)methyl)thiazolyl C-glucoside 24 in 63% yield. The hydroxyl
group at the anomeric position of 24 was reduced by acetylation
and subsequent treatment of triethylsilane in the presence of BF3
etherate in good yield (>90%). The triisopropylsilyl protecting
group of glucoside 26 was efficiently removed using TBAF.12 The
resulting alcohol of compound 27 was converted to aldehyde 28
by oxidation with Dess–Martin periodinane (DMP).13 Grignard
reactions of p-substituted phenylmagnesium bromide with the
aldehyde 28 provided the corresponding phenyl(thiazol-4-yl)
methanols 29.14 The final products were obtained by warming 29
in neat TMSI at 50 °C. The b-anomers of final products 30 were
purified by preparative HPLC equipped with a reverse phase
column.
2.3. Structure–activity relationship
The inhibitory effects of all synthesized compounds against
hSGLT2 were evaluated using the cell-based SGLT2 AMG
(methyl-a-D
-glucopyranoside) assay.18,19 The results of biological
As shown in Scheme 5, the lithiated thiazolylglucoside 20 was
converted to 5-chlorothiazolylglucoside 31 and 5-bromothiazolylg-
lucoside 32 by electrophilic halogenation using CCl4 and CBr4,
respectively.15 The intermediate 31 or 32 was carefully separated
by silica gel column chromatography in order to proceed to the next
activities are summarized in Table 1. The replacement of 4-chloro-
phenyl moiety in 2 with 6-chloropyridazinyl group in 3 resulted in
significant loss of hSGLT2 inhibitory activity. Even though the
pyridazinyl analog 3 (IC50 = 610 nM) has a similar structure to 2,
it demonstrated only moderate inhibitory activity against hSGLT2.
Ac
O
N
N
O
OH
O
O
O
S
S
BnO
BnO
BnO
BnO
BnO
BnO
b
95%
a
83%
OBn
R
OBn
OBn
OBn
OBn
OBn
19
18
9
N
N
O
O
S
BnO
BnO
S
BnO
BnO
c
d
OH
OBn
73%,
OBn
50~60%
1:1 mixture
OBn
20
OBn
21
R
N
O
S
OH
HO
HO
e
40%
OH
22
Scheme 3. Reagents and conditions: (a) n-BuLi, 2-bromothiazole, Et2O/THF, À78 °C to rt; (b) Ac2O, TEA, DCM, rt; (c) Et3SiH, BF3 etherate, 4 Å MS, DCM, 0 °C to rt; (d) n-BuLi, p-
substituted benzaldehyde, THF, À78 °C to rt; (e) TMSI (neat), at 50 °C.

S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
6073
TIPSO
TIPSO
N
N
HO
AcO
O
TIPSO
O
O
O
S
S
BnO
BnO
BnO
BnO
BnO
a
b
+
N
63%
91%
BnO
OBn
OBn
OBn
S
Br
OBn
OBn
OBn
24
25
23
9
TIPSO
HO
O
N
N
S
N
O
O
O
S
S
BnO
BnO
BnO
BnO
BnO
BnO
e
c
d
80%
82%
85%
OBn
OBn
OBn
OBn
OBn
OBn
28
26
27
HO
R
R
N
N
O
O
S
S
BnO
HO
HO
f
g
20~40%
70~80%
BnO
OBn
OH
OBn
29
OH
30
Scheme 4. Reagents and conditions: (a) n-BuLi, ether/THF, À40 °C to rt; (b) Ac2O, TEA, DCM, rt; (c) Et3SiH, BF3 etherate, 4 Å MS, DCM, 0 °C to rt; (d) TBAF, THF, 0 °C to rt; (e)
DMP, DCM, rt; (f) R-C6H4MgBr, THF, 0 °C to rt; (g) TMSI (neat), 50 °C/prep. HPLC.
A series of thiazolyl analogs also represented only moderate
inhibitory activities against hSGLT2 as shown in Table 1. Nonsub-
stituted thiazolyl analogs 22, 30 with benzyl-type moiety linked
at either 4- or 5-position of the thiazole group lacked any obvious
SGLT2 inhibitory activity. Most of the analogs exhibit IC50 values
3. Conclusion
In conclusion, we prepared novel SGLT2 inhibitors containing
benzylpyridazine and benzylthiazole moieties at the proximal ring.
Pyridazinyl functional group was installed smoothly from c-keto-
greater than 10 lM, and only one analog 22b displayed merely
ester 14, which was prepared from b-C-vinyl glucoside 7. Thiazole
group was linked to C-glucoside using 2-lithiated thiazole, and hal-
ogen atoms were introduced at either 4-position or 5-position of
thiazole ring. The analogs thus prepared were subjected to biolog-
ical evaluation involving hSGLT2 inhibition assay. While dapagli-
flozin (2) shows highly potent inhibitory activity against hSGLT2,
it was discovered that neither pyridazinyl nor thiazolyl analogs im-
proved hSGLT2 inhibition probably due to unfavorable electronic
environments around proximal ring of the current compounds.
marginal potency (IC50 = 4630 nM). In order to perform further
SAR study on thiazole moiety, 4-bromothiazole and 5-chlorothiaz-
ole analogs were prepared. On the whole, the incorporation of a
halogen atom into either 4- or 5-position of thiazole group exhib-
ited considerable improvement in inhibitory activity. Even though
a 4-bromothiazole analog 35a with nonsubstituted benzyl moiety
demonstrated no inhibitory activity (IC50 > 10,000 nM), increased
potencies were observed when p-substituted benzyl moiety
(35b–e) was incorporated into 5-position of thiazole. Especially
compound 35c with p-ethylbenzyl moiety was found to have
somewhat potent inhibitory activity (IC50 = 786 nM). However,
other p-substituted benzyl moieties in the 4-bromothiazole series
turned out to be less favorable (IC50 > 1000 nM) than 4-ethylbenzyl
moiety. Another series containing 5-chlorothiazole moiety demon-
strated more significant inhibitory activities than 4-bromothiazole
series. All tested compounds (37a–d) in this series demonstrated
less than 500 nM of IC50 values at hSGLT2. Compound 37b, contain-
ing 4-ethylbenzyl moiety at 5-position of thiazole, exhibited the
most potent inhibition (IC50 = 121 nM) in the thiazole series to
date. However, introduction of other moieties, such as 4-methyl-
benzyl 37a, 4-n-butylbenzyl 37c, biphenyl-4-ylmethyl 37d, only
slightly decreased the inhibitory activities. Nonetheless, none of
them proved to improve inhibitory activity against hSGLT2 over
dapagliflozin 2, indicating that replacement of the proximal ring
in 2 with pyridazine or thiazole is intolerant most likely due to
its unfavorable electronic environments.
4. Experimental
4.1. General
All references to ether are to diethyl ether; brine refers to a sat-
urated aqueous solution of NaCl. Unless otherwise indicated, all
temperatures are expressed in °C (degrees Centrigrade). All reac-
tions are conducted under an inert atmosphere at room tempera-
ture unless otherwise noted, and all solvents are of the highest
available purity unless otherwise indicated. 1H NMR spectra were
recorded on either a Jeol ECX-400, or a Jeol JNM-LA300 spectrom-
eter. Chemical shifts were expressed in parts per million (ppm,
units). Coupling constants are in units of hertz (Hz). Splitting
patterns describe apparent multiplicities and are designated as s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
m (multiplet), br (broad). Mass spectra were obtained with either
a
Micromass, Quattro LC Triple Quadruple Tandem Mass

6074
S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
Br
N
N
N
Li
O
X
O
O
S
BnO
BnO
S
BnO
BnO
S
BnO
BnO
b
a
OBn
OBn
18~34%
OBn
OBn
OBn
OBn
33
20
31 (X = Cl)
32 (X = Br)
c
70~84%,
overall
c
70~80%,
overall
R
HO
R
Br
N
N
Cl
O
O
S
S
BnO
BnO
BnO
BnO
OH
OBn
OBn
OBn
OBn
34
36
d
10~40%
d
10~40%
R
R
Br
N
N
Cl
O
O
S
S
HO
HO
HO
HO
OH
OH
OH
OH
37
35
Scheme 5. Reagents and conditions: (a) n-BuLi, CCl4 or CBr4, THF, À78 °C to À10 °C; (b) LDA, THF, À78 °C; (c) p-substituted benzaldehyde, THF, À78 °C to rt; (d) TMSI (neat),
50 °C.
Spectometer, ESI or Agilent, 1100LC/MSD, ESI. For preparative
HPLC, ca. 100 mg of a product was injected in 1 mL of DMSO onto
NMR (400 MHz, CDCl3) d 7.39–7.16 (m, 20H), 4.98 (d, J = 11.2 Hz,
1H), 4.74–4.44 (m, 8H), 4.12 (d, J = 6.4 Hz, 1H), 3.97–3.89 (m,
2H), 3.72 (dd, J = 10.8, 2.4 Hz, 1H), 3.67 (dd, J = 10.8, 3.2 Hz, 1H).
a SunFire™ Prep C18 OBD 5
l
m 19 Â 100 mm column with a
gradient from 10% acetonitrile to 90% acetonitrile in water. Flash
chromatography was carried out using Merck silica gel 60 (230–
400 mesh) or Biotage system equipped with a silica pre-packed
cartridge. Most of the reactions were monitored by thin-layer
chromatography on 0.25 mm Merck silica gel plates (60F-254),
visualized with UV light using a 5% ethanolic phosphomolybdic
acid or p-anisaldehyde solution.
4.3. Pyridazine analog synthesis
4.3.1. Vinyl compound 7
To a solution of lactone 9 (4.8 g, 8.9 mmol) in THF (50 mL)
at À78 °C under nitrogen atmosphere was added dropwise the
vinylmagnesium bromide (1.0 M in ether, 11.5 mL, 11.5 mmol).
After 2.5 h of stirring at À78 °C, the reaction mixture was quenched
with saturated NH4Cl and extracted with Et2O. The combined
organic layers were washed with brine, dried with MgSO4, and
concentrated to give the hemiketal. To a solution of the hemiketal
in anhydrous CH2Cl2 (50 mL) at À30 °C were added triethylsilane
(4.2 mL, 26.7 mmol) and TMSOTf (1.8 mL, 8.9 mmol). The solution
was stirred À30 °C for 1 h, then quenched with MeOH (5 mL) then
evaporated. The residue was purified with silica gel column chro-
matography (EtOAc/Hx = 1:5) to afford the desired product (2.6 g,
53% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) d 7.36–7.11
(m, 20H), 6.01–5.92 (m, 1H), 5.46 (d, J = 17.2 Hz, 1H), 5.29 (d,
J = 10.5 Hz, 1H), 4.89 (dd, J = 11.2, 19.2 Hz, 2H), 4.82 (d,
4.2. Synthesis of lactone 9
To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (8)
(1.01 g, 1.86 mmol) in dry CH2Cl2 (30 mL) under nitrogen
atmosphere, were added 3 Å molecular sieves (1 g) and 4-methyl-
morpholine-N-oxide (0.5 g, 4.26 mmol). After stirring at room tem-
perature for 10 min, tetra-n-propylammonium perruthenate
(TPAP) (64 mg, 0.18 mmol) was added. After stirring for over night,
the suspension was filtered through Celite and concentrated in va-
cuo. The residue was purified with silica gel column chromatogra-
phy (EtOAc/Hx = 1:5) to give lactone 9 as an oil (954 mg, 95%). 1H

S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
6075
Table 1
crude benzylated lactone 11 which was used for the next step
without further purification.
hSGLT2 inhibition data for a pyridazinyl analog 3 and thiazolyl analogs 22, 30, 35, and 37
X
N
NaCl (5 g, 30 mmol) was added to lactone 11 dissolved in DMSO
(10 mL) at room temperature and then it was refluxed for 1 day.
After reaction completes, the resulting solution was cooled down
to room temperature. Water and ether were added and organic
layer was extracted with ether. After evaporated the volatile sol-
vent, the residue was purified with silica gel column chromatogra-
phy (EtOAc/Hx = 1:3) to afford desire product (960 mg, 88% from
compound 12). 1H NMR (400 MHz, CDCl3) d 7.32–7.18 (m, 22H),
7.11–7.04 (m, 2H), 4.95–4.74 (m, 5H), 4.70–4.01 (m, 4H), 3.83 (s,
3H), 3.75–3.33 (m, 8H), 3.17–3.14 (m, 3H), 2.88–2.66 (m, 3H),
1.93–1.84 (m, 2H). MH+ 729.
Y
O
S
HO
HO
OH
OH
a
Code
X
Y
SGLT2 IC50
(nM)
2 (dapagliflozin)
3
—
—
H
H
H
H
—
—
Benzyl
0.49b
610
>10,000
4630
>10,000
22a
22b
22c
22d
30a
30b
30c
35a
35b
35c
35d
35e
37a
37b
37c
37d
4-Methylbenzyl
4-Chlorobenzyl
4-tert-Butylbenzyl >10,000
4.3.5. Pyridazinone 15
To a solution of dihydropyridazinone 5 (420 mg, 0.57 mmol) in
acetic acid (10 mL) was added bromine (0.5 mL) dropwise. The
reaction mixture was stirred at 80 °C overnight. After reaction
completes, water (10 mL) was added and then the organic layer
was extracted with CH2Cl2, dried with MgSO4. The volatile solvent
was evaporated under reduced pressure, and the residue was puri-
fied with silica gel column (EtOAc/Hx = 1:1) to give the desired
product (314 mg, 75% yield) as light yellow solid. 1H NMR
(400 MHz, CDCl3) d 7.42–7.22 (m, 17H), 7.22–7.18 (m, 4H), 7.05
(d, J = 9.1 Hz, 1H), 6.92 (dd, J = 1.4, 7.1 Hz, 2H), 6.78 (d, J = 9.1 Hz,
1H), 6.42 (br s, 1H), 4.87 (s, 2H), 4.85 (d, J = 10.2 Hz, 1H), 4.66 (d,
J = 10.2 Hz, 1H), 4.61 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H),
4.44 (d, J = 10.2 Hz, 2H), 4.28 (d, J = 12.3 Hz, 2H), 4.18 (d,
J = 9.3 Hz, 1H), 4.11 (s, 3H), 3.86 (d, J = 10.4 Hz, 1H), 3.82–3.74
(m, 4H), 3.57–3.53 (m, 1H), 3.42 (dt, J = 1.2, 9.2 Hz, 1H).
4-Methylbenzyl
4-Ethylbenzyl
4-n-Propylbenzyl
Br
Br
Br
Br
Br
H
H
H
>10,000
>10,000
>10,000
>10,000
1050
Benzyl
4-Methylbenzyl
4-Ethylbenzyl
4-tert-Butylbenzyl 2360
4-Chlorobenzyl
Cl
Cl
Cl
786
8640
257
121
251
411
4-Methylbenzyl
4-Ethylbenzyl
4-n-Butylbenzyl
Biphenyl-4-ylmethyl Cl
a
These data were obtained by single determinations.
The IC50 value of 2 was obtained by in-house assay.
b
J = 10.8 Hz, 1H), 4.74 (d, J = 10.4 Hz, 1H), 4.68–4.51 (m, 4H), 3.80–
3.63 (m, 5H), 3.50–3.46 (m, 1H), 3.34 (t, J = 8.8 Hz, 1H).
4.3.6. Pyridazine 16
4.3.2. Epoxide 10
To a solution of pyridazinone 15 (314 mg, 0.42 mmol) in tolu-
ene (20 mL) was added POCl3 (5 mL) slowly at 0 °C. The reaction
temperature was raised up to 100 °C and stirred for 3 h. The reac-
tion mixture was cooled down to room temperature. After quench-
ing with water carefully, the resulting solution was extracted with
CH2Cl2. The residue after evaporation was purified with silica gel
column chromatography (EtOAc/Hx = 1:3) to afford the title prod-
uct 16 (270 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) d
7.39–7.26 (m, 17H), 7.20–7.17 (m, 4H), 7.04 (d, J = 9.2 Hz, 1H), 6.89
(dd, J = 1.6, 7.2 Hz, 2H), 6.72 (d, J = 8.8 Hz, 1H), 4.89 (s, 2H), 4.85 (d,
J = 10.4 Hz, 1H), 4.62 (d, J = 10.8 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H),
4.53 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 10.4 Hz, 2H), 4.32 (d,
J = 15.6 Hz, 2H), 4.17 (d, J = 9.6 Hz, 1H), 4.08 (s, 3H), 3.84 (d,
J = 10.8 Hz, 1H), 3.79–3.71 (m, 4H), 3.58–3.55 (m, 1H), 3.43 (t,
J = 9.2 Hz, 1H).
mCPBA (1.8 g, 6.1 mmol) was added to vinyl compound 7
(2.25 g, 4 mmol) dissolved in CH2Cl2 (40 mL) at 0 °C and then stir-
red at room temperature for 1 day. After reaction complete, the
mixture was quenched with 1 N NaOH (20 mL), work-up with
Et2O, and evaporated in vacuo. The residue was purified with silica
gel column (EtOAc/Hx = 1:5) to give desired product (2.05 g, 88%
yield) with about 2:1 ratio inseparable diastereoisomer mixture.
1H NMR (400 MHz, CDCl3) d 7.34–7.26 (m, 18H), 7.17–7.15 (m,
1H), 4.91–4.86 (m, 3H), 4.84–4.79 (m, 1H), 4.76–4.69 (m, 1H),
4.63–4.50 (m, 4H), 3.75–3.33 (m, 8H), 3.17–3.14 (m, 3H),
2.88–2.66 (m, 3H). M+Na 589.2.
4.3.3. 2-Carboxylated butyrolactone 6
To a solution of epoxide 10 (500 mg, 0.88 mmol) in ethanol
(20 mL) was added diethyl malonate (212 mg, 1.32 mmol) and so-
dium ethoxide (21% wt in EtOH, 430 mg,, 1.32 mmol). The reaction
mixture was stirred for overnight, and then it was quenched with
saturated aqueous NH4Cl solution. The organic layer was extracted
with ether, dried with MgSO4, and evaporated. The residue was
purified with silica gel column chromatography (EtOA/Hx = 1:4)
to afford desired product (505 mg, 84%) as colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.38–7.19 (m, 20H), 4.96–4.84 (m, 4H), 4.80–
4.59 (m, 3H), 4.52–4.48 (m, 4H), 4.30–4.22 (m, 2H), 3.85–3.50
(m, 10), 1.34–1.16 (m, 4H). MH+ 681.31.
4.3.7. Deprotection of benzyl group of pyridazine 16
TMSI (5 mL) wad added to protected pyridazine (270 mg,
0.36 mmol) in CH3CN (20 mL) at 0 °C, and reaction temperature
was raised to room temperature. The reaction mixture was stirred
for 20 h at room temperature. The resulting solution was quenched
with MeOH (5 mL) and the volatile solvent was evaporated under re-
duced pressure. The residue was purified with silica gel column (5%
MeOHinCH2Cl2 to 10%MeOHinCH2Cl2) toproducethedesiredcom-
pound 3 (59 mg, 42%) as a white solid. 1H NMR (400 MHz, CDCl3) d
7.42–7.31 (m, 4H), 7.05 (d, J = 8.8 Hz, 1H), 4.33 (s, 2H), 4.10 (d,
J = 9.6 Hz, 1H), 4.03 (s, 3H), 3.85 (dd, J = 2.4, 12.4 Hz, 1H), 3.64 (dd,
J = 4.8, 12.0 Hz, 1H), 3.48–3.26 (m, 4H). 13C NMR (100 MHz, CDCl3)
d 164.48, 157.0, 139.1, 135.2, 133.1, 130.8, 130.4, 128.9, 127.8,
118.3, 81.3, 80.7, 78.2, 75.1, 70.4, 51.6, 53.8, 34.0.
4.3.4. 2-(p-Methoxybenzyl)-2-carboylated lactone 12
To
a
solution of 2-carboxylated butyrolactone
6
(1 g,
1.47 mmol) in THF (25 mL) was added NaH (88 mg, 60% in mineral
oil, 2.2 mmol) and p-methoxybenzyl bromide (0.5 mL, 2.2 mmol).
After stirring 3 h at room temperature, the resulting solution was
quenched with satd aqueous NH4Cl. Organic layer was extracted
with ether, dried with MgSO4, evaporated the volatile solvent
under reduced pressure. The residue was purified shortly to give
4.3.8. Acetylated compound 17
To a solution of 3 (20 mg, 0.05 mmol) in CH2Cl2 (10 mL) was
added Et3N (2 mL) and Ac2O (1 mL) with a catalytic amount of

6076
S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
DMAP. The reaction mixture was stirred for 1 h at room tempera-
ture, the reaction mixture was quenched with saturated aqueous
NH4Cl solution. The organic layer was collected with EtOAc, dried
with MgSO4, and evaporated under reduced pressure. The residue
was purified with silica gel (EtOAc/Hx = 2:1) to afford the acety-
lated compound 17 (22 mg, 78%) as colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.37 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H),
7.22 (dd, J = 2.0, 8.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.88 (d,
J = 9.2 Hz, 1H), 5.30 (t, J = 9.2 Hz, 1H), 5.19 (t, J = 9.6 Hz, 1H), 5.05
(t, J = 9.6 Hz, 1H), 4.42–4.32 (m, 3H), 4.26 (dd, J = 4.8, 12.4 Hz,
1H), 4.14 (dd, J = 2.4, 12.4 Hz, 1H), 4.11 (s, 3H), 3.83–3.78 (m,
1H), 2.08 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.77 (s, 3H).
(0.72 mL of a 2.5 M solution in hexane, 1.8 mmol) at À78 °C. After
an additional stirring 15 min at À78 °C, a solution of p-tolualde-
hyde (192 mg, 1.6 mmol) in THF (1 mL) was added dropwise. After
an additional 1 h stirring at À78 °C, the reaction mixture was al-
lowed to warm to room temperature for 3 h, and then poured into
the saturated aqueous NH4Cl solution (50 mL). The resulting mix-
ture was extracted with ethyl acetate (50 mL). The organic phase
was dried over MgSO4 and evaporated under vacuum. The residue
was further purified by silica column chromatography (Biotage) to
provide the intermediate 21b, (434 mg, 0.60 mmol, 60%). 1H NMR
(400 MHz, CDCl3) d 7.60–5.56 (m, 1H), 7.36–7.24 (m, 16H), 7.20–
7.15 (m, 6H), 7.02–6.99 (2H), 6.06–6.02 (m, 1H), 4.94–4.81 (m,
2H), 4.75–4.66 (m, 1H), 4.61–4.50 (m, 5H), 4.36–3.95 (m, 3H),
3.87–3.60 (m, 4H), 2.36 (s, 3H). MH+ 728.
4.4. Thiazole analog synthesis
The mixture of 21b (268 mg, 0.37 mmol) and TMSI (4 mL) was
heated at 50 °C for 15 h. The reaction mixture was quenched by a
slow addition of MeOH, and evaporated under vacuum. The residue
was dissolved in MeOH (3–4 mL) and further purified by prep HPLC
(C18 column) to provide the title compound 22 (30 mg,
0.085 mmol, 14%). 1H NMR (400 MHz, CD3OD3) d 7.47 (s, 1H),
7.10 (d, J = 1.2 Hz, 4H), 4.41 (d, J = 8.8 Hz, 1H), 4.10 (s, 2H), 3.84
(d, J = 14.8 Hz, 1H), 3.66–3.63 (m, 1H), 3.45–3.32 (m, 4H), 2.28 (s,
3H). 13C NMR (100 MHz, CD3OD3) d 168.14, 140.73, 138.27,
136.55, 136.13, 128.92, 128.03, 81.03,78.50, 77.84, 74.44, 69.95,
61.50, 31.95, 19.64. MH+ 352.
4.4.1. (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
2-(thiazol-2-yl)tetrahydro-2H-pyran-2-ol (18)
To a solution of n-BuLi (14.5 mL, 2.5 M in hexane) in anhydrous
ether (51 mL) was added dropwise (over a 30-min period) a solu-
tion of 2-bromothiazole (5.4 g, 32.9 mmol) in THF (15 mL) at
À78 °C. After stirring at À78 °C for 20 min, a solution of lactone 9
(15 g, 27.8 mmol) in THF (51 mL) was added slowly (over a 25-
min period) to the mixture. The reaction mixture was allowed to
warm to room temperature and stirred for 16 h. The mixture was
poured into a 1 M phosphate buffer solution (300 mL, pH 7.4)
and extracted with DCM (300 mL). The DCM extract was dried over
MgSO4 and evaporated under vacuum. The residue was further
purified by silica column chromatography (Biotage™) to provide
the title compound 18 (14.4 g, 23.0 mmol, 83%). 1H NMR
(400 MHz, CDCl3) d 7.78 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H),
7.34–7.24 (m, 14H), 7.21–7.18 (m, 4H), 7.00–6.98 (m, 2H), 4.90–
4.85 (m, 3H), 4.64–4.51 (m, 4H), 4.18 (d, J = 10.4 Hz, 2H), 4.10–
3.80 (m, 2H), 3.89–3.80 (m, 2H), 3.2 (d, J = 12.0 Hz, 1H).
4.4.5. (2R,3R,4S,5S,6R)-2-(5-Benzylthiazol-2-yl)-6-(hydroxy-
methyl)tetrahydro-2H-pyran-3,4,5-triol (22a)
The procedure described for the synthesis of 22b was applied to
20 and benzaldehyde instead of p-tolualdehyde providing the title
compound 22a. 1H NMR (400 MHz, CD3OD3) d 7.49 (s, 1H),
7.30–7.18 (m, 5H), 4.42 (d, J = 9.2 Hz, 1H), 4.16 (s, 2H), 3.84 (dd,
J = 12.0, 2.0 Hz, 1H), 3.64 (dd, J = 12.0, 5.2 Hz, 1H), 3.47–3.32 (m,
4H). MH+ 338.
4.4.2. (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
2-(thiazol-2-yl)tetrahydro-2H-pyran-2-yl acetate (19)
4.4.6. (2R,3R,4S,5S,6R)-2-(5-(4-Chlorobenzyl)thiazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (22c)
The procedure described for the synthesis of 22b was applied to
20 and p-chlorobenzaldehyde instead of p-tolualdehyde providing
the title compound 22c. 1H NMR (400 MHz, CD3OD3) d 7.51 (s, 1H),
7.30–7.22 (m, 4H), 4.42 (d, J = 8.8 Hz, 1H), 4.16 (s, 2H), 3.84 (dd,
J = 12.0, 2.0 Hz, 1H), 3.64 (dd, J = 12.0, 5.6 Hz, 1H), 3.47–3.32 (m,
4H). MH+ 372.
To a solution of 18 (14.4 g, 23.0 mmol) in DCM (43 mL) was
added TEA (27.5 mL) and Ac2O (27.5 mL) at room temperature.
After an additional stirring for 16 h, the mixture was evaporated
under vacuum. The residue was further purified by silica column
chromatography (Biotage™) to provide the title compound 19
(14.6 g, 21.9 mmol, 95%). 1H NMR (400 MHz, CDCl3) d 7.78 (d,
J = 3.6 Hz, 1H), 7.41–7.18 (m, 21H), 4.95–4.85 (m, 3H), 4.74–4.59
(m, 3H), 4.41 (d, J = 10.4 Hz, 1H), 4.15–4.09 (m, 2H), 3.96–3.80
(m, 4H), 3.59 (d, J = 9.6 Hz, 1H), 2.21 (s, 3H). MH+ 666.
4.4.7. (2R,3R,4S,5S,6R)-2-(5-(4-tert-Butylbenzyl)thiazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (22d)
4.4.3. 2-((3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymeth-
yl)tetrahydro-2H-pyran-2-yl)thiazole (20)
The procedure described for the synthesis of 22b was applied to
20 and p-tert-butylbenzaldehyde instead of p-tolualdehyde provid-
ing the title compound 22d. 1H NMR (400 MHz, CD3OD3) d 7.49 (s,
1H), 7.32 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.41 (d,
J = 9.2 Hz, 1H), 4.11 (s, 2H), 3.84 (dd, J = 12.0, 2.0 Hz, 1H), 3.64
(dd, J = 12.0, 5.6 Hz, 1H), 3.44–3.34 (m, 4H), 1.28 (s, 9H). MH+ 394.
To a stirred mixture of 19 (14.6 g, 21.9 mmol) and activated 4 Å
powdered molecular sieve (14.6 g) in anhydrous DCM (68 mL) was
added dropwise (over a 20-min period) triethylsilane (36.4 mL,
43.0 mmol) at 0 °C. After stirring at room temperature for additional
30 min, a BF3 etherate solution (7.7 mL) was added dropwise to the
mixture. The reaction mixture was stirred at room temperature for
4 h and then neutralized with TEA (6–7 mL). The resulting mixture
was filtered through Celite, and evaporated under vacuum. The res-
idue was further purified by silica column chromatography (Bio-
tage™) to provide the title compound 20 (9.72 g, 16.0 mmol, 73%).
1H NMR (400 MHz, CDCl3) d 7.84 (t, J = 3.2 Hz, 1H), 7.39–7.17 (m,
19H), 7.13–7.11 (m, 1H), 7.02–7.01 (m, 1H), 5.30–4.45 (m, 7H; dou-
4.4.8. (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
2-(4-((triisopropylsilyloxy)methyl)thiazol-2-yl)tetrahydro-2H-
pyran-2-ol (24)
To a solution of n-BuLi (3.39 mL, 2.5 M in hexane) in anhydrous
ether (11.9 mL) was added dropwise (over a 30-min period) a solu-
tion of 2-bromo-4-((triisopropylsilyloxy)methyl)thiazole 23 (2.7 g,
7.7 mmol) in THF (7.0 mL) at À40 °C. After stirring at À40 °C for
20 min, a solution of lactone 9 (3.5 g, 6.5 mmol) in THF (11.9 mL)
was added slowly (over a 25-min period) to the mixture. The reac-
tion mixture was allowed to warm to room temperature and stir-
red for 5 h. The mixture was poured into a 1 M phosphate buffer
solution (100 mL, pH 7.4) and extracted with DCM (150 mL). The
DCM extract was dried over MgSO4 and evaporated under vacuum.
blet signal of a-anomericproton was detected at5.29 with J = 6.0 Hz,
0.5H), 4.32–3.94 (m, 2H), 3.83–3.64 (m, 6H). MH+ 608.
4.4.4. (2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-(5-(4-methylben-
zyl)thiazol-2-yl)tetrahydro-2H-pyran-3,4,5-triol (22b)
To a solution of 20 (608 mg, 1 mmol) in anhydrous THF
(5–6 mL) under nitrogen atmosphere was added dropwise n-BuLi

S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
6077
The residue was further purified by silica column chromatography
(Biotage) to provide the title compound 24 (3.95 g, 4.88 mmol,
75%). MH+ 810.
at 0 °C. After an additional stirring 30 min at 0 °C, the reaction mix-
ture was allowed to warm to room temperature for 5 h, and then
quenched with a saturated aqueous NH4Cl solution (15 mL). The
resulting mixture was extracted with ethyl acetate (30 mL). The or-
ganic phase was dried over MgSO4 and evaporated under vacuum.
The residue was further purified by silica column chromatography
(Biotage) to provide the intermediate 29a (324 mg, 0.45 mmol,
74%). MH+ 728.
The mixture of 29a (324 mg, 0.45 mmol) and TMSI (4.5 mL) was
heated at 50 °C for 24 h. The reaction mixture was quenched by a
slow addition of MeOH, and evaporated under vacuum. The residue
was dissolved in MeOH (4–5 mL) and further purified by prep HPLC
(C18 column) to provide the title compound 30a (59 mg,
0.17 mmol, 37%). 1H NMR (400 MHz, CD3OD3) d 7.11–7.06 (m,
4H), 7.03 (s, 1H), 4.50–4.45 (m, 1H), 4.04 (s, 2H), 3.86 (d,
J = 12.4 Hz, 1H), 3.69–3.65 (m, 1H), 3.50–3.35 (m, 4H), 2.27 (s,
3H). MH+ 352.
4.4.9. (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
2-(4-((triisopropylsilyloxy)methyl)thiazol-2-yl)tetrahydro-2H-
pyran-2-yl acetate (25)
To a solution of 24 (3.95 g, 4.88 mmol) in DCM (4.9 mL) was
added TEA (5.8 mL) and Ac2O (5.8 mL) at room temperature. After
an additional stirring for 16 h, the mixture was evaporated under
vacuum. The residue was further purified by silica column chroma-
tography (Biotage) to provide the title compound 25 (3.80 g,
4.45 mmol, 91%). MNa+ 874.
4.4.10. 4-((Triisopropylsilyloxy)methyl)-2-((3R,4S,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl) tetrahydro-2H-pyran-2-
yl)thiazole (26)
To a stirred mixture of 25 (3.80 g, 4.45 mmol) and activated 4 Å
powdered molecular sieve (3.8 g) in anhydrous DCM (17 mL) was
added dropwise (over a 20-min period) triethylsilane (7.32 mL,
8.65 mmol) at 0 °C. After stirring at room temperature for addi-
tional 30 min, a BF3 etherate solution (1.55 mL) was added drop-
wise to the mixture. The reaction mixture was stirred at room
temperature for 4 h and then neutralized with TEA (2–3 mL). The
resulting mixture was filtered through Celite, and evaporated un-
der vacuum. The residue was further purified by silica column
chromatography (Biotage) to provide the title compound 26
(2.88 g, 3.63 mmol, 82%). 1H NMR (400 MHz, CDCl3) d 7.36–7.23
(m, 17H), 7.21–7.13 (m, 3H), 7.03–7.01 (m, 1H), 5.28–4.45 (m,
4.4.14. (2R,3R,4S,5S,6R)-2-(4-(4-Ethylbenzyl)thiazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (30b)
The procedure described for the synthesis of 30a was applied to
28 and 4-ethylphenylmagnesium bromide instead of p-toluylmag-
nesium bromide providing the title compound 30b. 1H NMR
(400 MHz, CD3OD3) d 7.14–7.09 (m, 4H), 7.04 (s, 1H), 4.49–4.46
(m, 1H), 4.05 (s, 2H), 3.86 (d, J = 12.4 Hz, 1H), 3.69–3.65 (m, 1H),
3.50–3.37 (m, 4H), 2.58 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).
MH+ 366.
4.4.15. (2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-(4-(4-propylb-
enzyl)thiazol-2-yl)tetrahydro-2H-pyran-3,4,5-triol (30c)
The procedure described for the synthesis of 30a was applied to
28 and 4-propylphenylmagnesium bromide instead of p-toluyl-
magnesium bromide providing the title compound 30c. 1H NMR
(400 MHz, CD3OD3) d 7.14–7.07 (m, 4H), 7.04 (s, 1H), 4.49–4.46
(m, 1H), 4.05 (s, 2H), 3.86 (d, J = 10.0 Hz, 1H), 3.69–3.65 (m, 1H),
3.49–3.36 (m, 4H), 2.53 (t, J = 7.6 Hz, 2H), 1.64–1.55 (m, 2H), 0.90
(t, J = 7.2 Hz, 3H). MH+ 380.
9H; doublet signal of a-anomeric proton was detected at 5.28 with
J = 5.6 Hz, 0.5H), 4.25–3.99 (m, 2H), 3.84–3.63 (m, 6H), 1.23–1.13
(m, 3H), 1.10–1.08 (m, 18H). MH+ 794.
4.4.11. (2-((3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxym-
ethyl)tetrahydro-2H-pyran-2-yl)thiazol-4-yl)methanol (27)
To a solution of 26 (2.88 g, 3.63 mmol) in anhydrous THF
(20 mL) under nitrogen atmosphere was added dropwise TBAF
(9.1 mL of a 1 solution in THF, 9.1 mmol) at 0 °C. After an additional
stirring 1 h at 0 °C, the reaction mixture was allowed to warm to
room temperature for 2 h, and then poured into water (100 mL).
The resulting mixture was extracted with ethyl acetate (150 mL).
The organic phase was dried over MgSO4 and evaporated under
vacuum. The residue was further purified by silica column chroma-
tography (Biotage) to provide the intermediate 27 (1.97 g,
3.08 mmol, 85%). 1H NMR (400 MHz, CDCl3) d 7.34–7.24 (m,
17H), 7.22–7.11 (m, 3H), 7.04–7.02 (m, 1H), 5.29–4.47 (m, 9H;
4.4.16. 5-Chloro-2-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)thiazole (31)
To a solution of 20 (4 g, 6.58 mmol) in anhydrous THF (45 mL)
was added dropwise n-BuLi (5.8 mL, 14.5 mmol, 2.5 M in hexane)
at À78 °C. After stirring for 20 min at À78 °C, a solution of carbon
tetrachloride (1.90 mL, 19.7 mmol) in anhydrous THF (5 mL) was
added dropwise over 5 min. The reaction mixture was allowed to
warm to À10 °C over a 4-h period, and then quenched with a sat-
urated aqueous NH4Cl solution (100 mL). The resulting mixture
was extracted with ethyl acetate (150 mL). The organic phase
was dried over MgSO4 and evaporated under vacuum. The residue
was further purified by silica column chromatography (Biotage) to
provide the title compound 31 (0.78 g, 1.21 mmol, 18%). 1H NMR
(400 MHz, CDCl3) d 7.55 (s, 1H), 7.37–7.23 (m, 16H), 7.20–7.16
(m, 2H), 7.09–7.06 (m, 2H), 4.94–4.83 (m, 3H), 4.64–4.52 (m,
5H), 4.31 (d, J = 10.8 Hz, 1H), 3.83–3.60 (m, 6H). MH+ 642.
doublet signal of
a-anomeric proton was detected at 5.28 with
J = 5.6 Hz, 0.5H), 4.21–4.00 (m, 2H), 3.84–3.63 (m, 6H). MH+ 638.
4.4.12. 2-((3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxym-
ethyl)tetrahydro-2H-pyran-2-yl)thiazole-4-carbaldehyde (28)
To a solution of 27 (1.96 g, 3.07 mmol) in DCM (45 mL) was
added DMP (1.56 g, 3.7 mmol) at RT for 16 h. The reaction mixture
was quenched with 1 M Na2S2O3 solution (100 mL). The resulting
mixture was extracted with DCM (2Â 100 mL), and successively
washed with saturated aqueous NaHCO3 solution and brine. The
organic phase was dried over MgSO4 and evaporated under
vacuum. The residue was further purified by silica column chroma-
tography (Biotage) to provide the title compound 28 (1.57 g,
2.47 mmol, 80%). MH+ 636.
4.4.17. (2R,3R,4S,5S,6R)-2-(4-Chloro-5-(4-methylbenzyl)thiazol-
2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (37a)
To a solution of 31 (385 mg, 0.60 mmol) in anhydrous THF
(4 mL) under nitrogen atmosphere was added dropwise a solution
of LDA (1.43 mL, 2.57 mmol, 1.8 M in heptane/THF/ethylbenzene,
Aldrich 494585) at À78 °C. After an additional stirring 30 min at
À78 °C, p-tolualdehyde (0.43 mL, 3.6 mmol) was added dropwise.
The reaction mixture was allowed to warm to room temperature
for 3 h, and then quenched with 1 M HCl (15 mL). The resulting
mixture was extracted with ethyl acetate (30 mL). The organic
phase was dried over MgSO4 and evaporated under vacuum. The
4.4.13. (2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-(4-(4-methyl-
benzyl)thiazol-2-yl)tetrahydro-2H-pyran-3,4,5-triol (30a)
To a solution of 28 (380 mg, 0.60 mmol) in anhydrous THF
(2 mL) under nitrogen atmosphere was added dropwise a solution
of p-toluylmagnesium bromide (2.38 mL, 1.19 mmol, 0.5 M in THF)

6078
S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
residue was further purified by silica column chromatography
(Biotage) to provide the title compound 36a (382 mg, 0.50 mmol,
84%). 1H NMR (400 MHz, CDCl3) d 7.38–7.20 (m, 18H), 7.19–7.16
(m, 3H), 7.10–7.00 (m, 3H), 5.87 (br, 1H), 4.94–4.82 (m, 4H),
4.70–4.45 (m, 6H), 4.27–4.01 (m, 1H), 3.80–3.56 (m, 4H), 2.33 (s,
3H). MH+ 762.
The mixture of 36a (382 mg, 0.50 mmol) and TMSI (5 mL) was
heated at 50 °C for 12 h. The reaction mixture was quenched by a
slow addition of MeOH, and evaporated under vacuum. The residue
was dissolved in MeOH (3–4 mL) and further purified by prep HPLC
(C18 column) to provide the title compound 37a (41 mg,
0.22 mmol, 11%). 1H NMR (400 MHz, CD3OD3) d 7.07 (q, J = 6.8
Hz, 4H), 4.39 (d, J = 9.2 Hz, 1H), 4.01 (s, 2H), 3.85 (dd, J = 12.0,
2.0 Hz, 1H), 3.65 (dd, J = 12.4, 5.6 Hz, 1H), 3.44–3.32 (m, 4H), 2.26
(s, 3H). 13C NMR (100 MHz, CD3OD3) d 166.15, 150.77, 135.68,
134.96, 128.68, 128.04, 121.83, 81.19, 78.63, 77.73, 74.38, 69.85,
61.43, 33.28, 19.61. MH+ 386.
4.4.23. (2R,3R,4S,5S,6R)-2-(4-Bromo-5-(4-methylbenzyl)thiazol-
2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (35b)
The procedure described for the synthesis of 37a was applied to
32 and p-tolualdehyde providing the title compound 35b. 1H NMR
(400 MHz, CD3OD3) d 7.11 (d, J = 6.0 Hz, 4H), 4.39 (d, J = 9.2 Hz,
1H), 4.05 (s, 2H), 3.84 (dd, J = 12.4, 2.0 Hz, 1H), 3.64 (dd, J = 12.4,
5.6 Hz, 1H), 3.45–3.32 (m, 4H), 2.28 (s, 3H). 13C NMR (100 MHz,
CD3OD3)
d 167.55, 136.42, 135.54, 135.45, 129.01, 128.01,
121.95, 81.09, 78.34, 77.76, 74.27, 69.81, 61.42, 34.89, 19.64.
MH+ 432.
4.4.24. (2R,3R,4S,5S,6R)-2-(4-Bromo-5-(4-ethylbenzyl)thiazol-2-
yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (35c)
The procedure described for the synthesis of 37a was applied to
32 and p-ethylbenzaldehyde providing the title compound 35c. 1H
NMR (400 MHz, CD3OD3) d 7.13 (d, J = 4.8 Hz, 4H), 4.39 (d,
J = 9.2 Hz, 1H), 4.06 (s, 2H), 3.84 (dd, J = 12.4, 2.0 Hz, 1H), 3.64
(dd, J = 12.4, 5.2 Hz, 1H), 3.43–3.31 (m, 4H), 2.59 (q, J = 7.6 Hz,
2H), 1.19 (t, J = 7.6 Hz, 3H). MH+ 446.
4.4.18. (2R,3R,4S,5S,6R)-2-(5-Chloro-4-(4-ethylbenzyl)thiazol-2-
yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (37b)
The procedure described for the synthesis of 37a was applied to
31 and p-ethylbenzaldehyde instead of p-tolualdehyde providing
the title compound 37b. 1H NMR (400 MHz, CD3OD3) d 7.09 (q,
J = 8.4 Hz, 4H), 4.40 (d, J = 9.2 Hz, 1H), 4.02 (s, 2H), 3.85 (dd,
J = 12.0, 2.0 Hz, 1H), 3.65 (dd, J = 12.4, 6.0 Hz, 1H), 3.47–3.32 (m,
4H), 2.56 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). MH+ 400.
4.4.25. (2R,3R,4S,5S,6R)-2-(4-Bromo-5-(4-tert-butylbenzyl)
thiazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (35d)
The procedure described for the synthesis of 37a was applied to
32 and p-tert-butylbenzaldehyde providing the title compound
35d. 1H NMR (400 MHz, CD3OD3) d 7.33 (d, J = 8.4 Hz, 2H), 7.16
(d, J = 8.4 Hz, 2H), 4.39 (d, J = 8.8 Hz, 1H), 4.06 (s, 2H), 3.82 (dd,
J = 12.0, 2.0 Hz, 1H), 3.64 (dd, J = 12.0, 5.6 Hz, 1H), 3.43–3.34 (m,
4H), 1.28 (s, 9H). MH+ 474.
4.4.19. (2R,3R,4S,5S,6R)-2-(4-(4-Butylbenzyl)-5-chlorothiazol-2-
yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (37c)
The procedure described for the synthesis of 37a was applied to
31 and p-butylbenzaldehyde instead of p-tolualdehyde providing
the title compound 37c. 1H NMR (400 MHz, DMSO-d6) d 7.11–
7.06 (m, 4H), 4.27 (d, J = 9.2 Hz, 1H), 3.94 (s, 2H), 3.85 (dd,
J = 12.0, 2.0 Hz, 1H), 3.64 (d, J = 10.8 Hz, 1H), 3.37 (dd, J = 12.0,
6.0 Hz, 1H), 3.32–3.21 (m, 3H), 3.14–3.09 (m, 1H), 2.48 (t,
J = 7.6 Hz, 2H), 1.51–1.43 (m, 2H), 1.29–1.20 (m, 2H), 0.84 (t,
J = 7.2 Hz, 3H). MH+ 428.
4.4.26. (2R,3R,4S,5S,6R)-2-(4-Bromo-5-(4-chlorobenzyl)thiazol-
2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (35e)
The procedure described for the synthesis of 37a was applied to
32 and p-chlorobenzaldehyde providing the title compound 35e.
1H NMR (400 MHz, CD3OD3) d 7.30 (d, J = 8.4 Hz, 2H), 7.23 (d,
J = 8.4 Hz, 2H), 4.41 (d, J = 9.2 Hz, 1H), 4.11 (s, 2H), 3.84 (dd,
J = 12.4, 2.0 Hz, 1H), 3.64 (dd, J = 12.4, 5.6 Hz, 1H), 3.46–3.31 (m,
4H), 2.28 (s, 3H). MH+ 452.
4.4.20. (2R,3R,4S,5S,6R)-2-(4-(Biphenyl-4-ylmethyl)-5-chloro-
thiazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (37d)
4.5. Inhibitory effect on human SGLT2 activities
The procedure described for the synthesis of 37a was applied to
31 and biphenyl-4-carbaldehyde instead of p-tolualdehyde provid-
ing the title compound 37d. 1H NMR (400 MHz, CD3OD3) d 7.56–
7.49 (m, 4H), 7.38 (t, J = 8.0 Hz, 2H), 7.33–7.26 (m, 3H), 4.42 (d,
J = 8.8 Hz, 1H), 4.11 (s, 2H), 3.86 (dd, J = 12.0, 2.0 Hz, 1H), 3.66
(dd, J = 12.0, 5.6 Hz, 1H), 3.47–3.32 (m, 4H). MH+ 448.
For sodium-dependent glucose transport assay, cells express-
ing hSGLT2 were seeded into a 96-well culture plate at a density
of 5 Â 104 cells/well in RPMI medium 1640 containing 10% fetal
bovine serum. The cells were used 1 day after plating. They were
incubated in pretreatment buffer (10 mM HEPES, 5 mM Tris,
140 mM choline chloride, 2 mM KCl, 1 mM CaCl2, and 1 mM
MgCl2, pH 7.4) at 37 °C for 10 min. They were then incubated
in uptake buffer (10 mM HEPES, 5 mM Tris, 140 mM NaCl,
2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, and 1 mM 14C-nonlabeled
4.4.21. 5-Bromo-2-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)thiazole (32)
The procedure described for the synthesis of 31 was applied to
20 and carbon tetrabromide instead of carbon tetrachloride pro-
viding the title compound 32. 1H NMR (400 MHz, CDCl3) d 7.64
(s, 1H), 7.34–7.22 (m, 16H), 7.19–7.17 (m, 2H), 7.08–7.05 (m,
2H), 4.94–4.83 (m, 3H), 4.62–4.53 (m, 5H), 4.30 (d, J = 10.8 Hz,
1H), 3.84–3.60 (m, 6H). MH+ 688.
AMG pH 7.4) containing 14C-labeled (8
lM) and inhibitor or di-
methyl sulfoxide (DMSO) vehicle at 37 °C for 2 h. Cells were
washed twice with washing buffer (pretreatment buffer contain-
ing 10 mM AMG at room temperature) and then the radioactivity
was measured using a liquid scintillation counter. IC50 was
determined by nonlinear regression analysis using GraphPad
PRISM.
4.4.22. (2R,3R,4S,5S,6R)-2-(5-Benzyl-4-bromothiazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (35a)
The procedure described for the synthesis of 37a was applied to
32 and benzaldehyde providing the title compound 35a. 1H NMR
(400 MHz, CD3OD3) d 7.31–7.19 (m, 5H), 4.40 (d, J = 9.2 Hz, 1H),
4.11 (s, 2H), 3.84 (dd, J = 12.0, 2.0 Hz, 1H), 3.64 (dd, J = 12.0,
5.6 Hz, 1H), 3.46–3.35 (m, 4H). MH+ 416.
Acknowledgments
The authors thank Dr. Jeongmin Kim for his scientific discussion
regarding small molecule programs at Green Cross Corp. (GCC). The
authors are also thankful to Dr. Eun Chul Huh for his leadership
and supports for R&D at GCC.

S. Y. Kang et al. / Bioorg. Med. Chem. 18 (2010) 6069–6079
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