Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

Article abstract of DOI:10.1016/j.bmc.2012.03.008

A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC₅₀ values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

Full text of DOI:10.1016/j.bmc.2012.03.008

Bioorganic & Medicinal Chemistry 20 (2012) 2982–2991
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis, and pharmacological evaluation of benzamide derivatives
as glucokinase activators
Weiwei Mao a, , Mengmeng Ning b, , Zhiqing Liu a, Qingzhang Zhu b, Ying Leng b, , Ao Zhang a,
⇑
⇑
a Synthetic Organic and Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strat-
egy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identi-
fied having a suitable balance of potency and activation profile. They showed EC50 values of 28.3 and
44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor
reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic
profiles (PK) were also observed on these two compounds.
Received 7 February 2012
Revised 1 March 2012
Accepted 1 March 2012
Available online 8 March 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Type 2 diabetes (T2D)
Glucokinase activator
Benzamide derivatives
Privileged-fragment-merging
Aminothiazole
1. Introduction
of this protein and achieve anti-hyperglycemic effects by enhanc-
ing glucose usage in the liver, and by potentiating insulin secretion
Over the past decades, incidence rate of type 1 diabetes (T1D)
has remained fairly stable, but the number of people diagnosed
with type 2 diabetes (T2D) has been steadily growing. T2D cur-
rently comprises about 90% of all diabetes cases.1 It is character-
ized by insulin resistance, excessive hepatic glucose production,
and reduced glucose-triggered insulin secretion from the pancre-
atic b-cells.2–7 The discovery of safe and effective drugs for the long
term treatment of T2D patients remains the greatest challenge in
diabetes research, predominantly owing to the continuous lack of
understanding of the complex molecular pathogenesis and genetic
basis of this disease.8 Glucokinase (GK), a unique isoform of the
from pancreatic b-cells.14–25 However, compounds with significant
GK enzyme potency were very limited, and only a few of them
have shown the capability of lowering blood glucose in animal
models of type 2 diabetes.8,19–21 Among the reported small mole-
cule GK activators (GKAs), benzamides and phenylacetamides rep-
resent the two classes of major structural scaffolds. The former
scaffold was represented by the clinical candidate compound 1
(GKA50, Fig. 1)26–28 which was developed by AstraZeneca possess-
ing good in vitro and in vivo glucose-lowering potency. Unfortu-
nately, this compound was halted in clinical trials because of its
epididymal and testicular toxicity observed in both rats and dogs.
Further study showed that the pyridine-5-carboxylic acid moiety
embedded in compound 1 was likely responsible for the toxic lia-
bility.29 The latter chemotype was exemplified by compound 3
(PSN-GK1),22,30 which was a back-up of compound 2 and currently
in phase I clinical trial.
With the aim to identify new lead compounds possessing more
efficacy and better pharmacokinetic properties, we recently initi-
ated a privileged-fragment-merging (PFM) strategy and designed
a series of new benzamides. Since the cyclopropylsulfonyl and
aminothiazolyl moieties are the key elements responsible for the
high GK potency in arylacetamides 2 and 3 where the former sub-
stituent provides the optimum potency-pharmacokinetic profile
and the aminothiazolyl function affords a pair of H-bond donor-
acceptors necessary to access the backbone hydrogen and carbonyl
oxygen of Arg63 in GK binding pockets.31 Therefore, these two
hexokinase enzymes to phosphorylate D-glucose and other hex-
oses, was identified during the past three to four decades as a
promising T2D drug target.9,10 GK serves as a glucose sensor of
the insulin-producing pancreatic islet b-cells, controlling the con-
version of glucose to glycogen in the liver and regulating hepatic
glucose production as well.11–13 Guided by this fundamental
knowledge, hundreds of small molecule compounds have been
designed in the past few years with the hypothesis that com-
pounds targeting this enzyme would activate the allosteric pocket
⇑
Corresponding authors. Tel./fax: +86 21 50806035 (A.Z.); tel./fax: +86 21
50806059 (Y.L.).
E-mail addresses: yleng@mail.shcnc.ac.cn (Y. Leng), aozhang@mail.shcnc.ac.cn
(A. Zhang).
These two authors contributed equally to this work.
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.03.008

W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
2983
COOH
O
O
HO
O
OH
O
N
H
N
H
N
S
HO
O
X
N
O
O
S
O
O
O
O
2 (X = H)
3 (PSN-GK1, X = F)
4
1 (GKA50)
2007
(Bioorg. Med. Chem.,
, 15, 3445)
privileged f ragment merging
O
O
O
O
S
O
O
S
H
N
H
N
S
R
Heterocycle
O
O
N
O
O
5
I
Figure 1. Known GKAs 1–3 and proposed new benzamides 5 and I.
privileged fragments were incorporated to the benzamide skeleton
of compound 1. Meanwhile, the 2-methylpenten-2-yl moiety, a
lipophilic fragment often found in many natural anti-diabetic
products (e.g., 432) was used to replace the 1-methoxypropan-2-
yl substituent in compound 1. With this PFM strategy, new benz-
amide 5 was designed followed by further tuning on the sulfonyl
function as the para-substituent of the side-chain phenyl ring,
and on the heterocyclic moiety in the amide portion (Fig. 1). Here-
in, we described our synthesis of these benzamide analogues I, and
their GK potency and pharmacokinetic properties.
including alkylation of 4-bromobenzenethiol with cyclopropyl bro-
mide in the presence of potassium tert-butoxide as base to afford
(4-bromophenyl)(cyclopropyl)sulfane, which was subsequently
oxidized using m-chloroperbenzoic acid (mCPBA). Methyl 3-hydro-
xy-5-(3-methylbut-2-enyloxy) benzoate (7)34 was prepared from
methyl 3,5-dihydroxybenzoate through Williamson ether synthe-
sis. Ullmann condensation35 of compounds 6 and 7 with assistance
of CuBr/Cs2CO3 resulted in ether 8, but in poor yield (<8%). Optimi-
zation of the reaction conditions disclosed that ether 8 could be
prepared in 80% yield by using 2,2,6,6-tetramethyl-3,5-heptanedi-
one (TMHD) as ligand and N-methyl-2-pyrrolidone (NMP) as the
solvent under 110 °C. Hydrolysis of benzoate 8 with LiOH afforded
benzoic acid 2 in quantitative yield. Condensation36 of 9 with 2-
aminothiazole in the presence of 2-(7-aza-1H-benzotriazole-1-
yl)-1,1,3,3-tetramethyluronium hexafluo-rophosphate (HATU)
and 1-hydroxy-7-azabenzotriazole (HOAt) under microwave
(40 W, 60 °C) afforded target compound 5 in 87% yield. However,
2. Results
2.1. Chemistry
The synthesis of compounds 5 and 10 was shown in Scheme 1.
Intermediate 633 was synthesized in two steps in 69% overall yield,
Br
Br
Br
a
b
Br
+
O
O
S
O
6
S
SH
O
S
O
d
CO2Me
O
e
8
HO
COOCH3
c
O
OH
HO
CO2Me
7
O
O
O
S
O
H
N
O
S
O
f
N
COOH
O
O
S
O
R
9
5
(R=H)
10 (R=F)
Scheme 1. Reagents and conditions: (a) t-BuOK, DMSO, rt, 24 h, 82%; (b) m-CPBA (85%), CHCl3, 2 h, 85%; (c) K2CO3, DMF, 60 °C, 24 h, 67%; (d) TMHD, CuBr, Cs2CO3, NMP,
110 °C, 80%; (e) LiOH, THF:H2O = 3:1, reflux, 2 h, 100%; (f) compound 5: 2-aminothiazole, HATU, HOAt, DMF, microwave, 40 W, 60 °C, 30 min, 87%; compound 10: (i) SOCl2,
CH2Cl2, Cat. DMF, reflux 2 h; (ii) 5-fluorothiazol-2-amine, pyridine, THF, rt, 2 h, 82%.

2984
W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
O
S
Br
a
O
O
O
O
b
Br
S
R1R2NH
Cl
+
2R1RN
2R1RN
S
O
O
S
O
12A-E
COOCH3
11A-E
O
O
O
c,d
2R1RN
H
N
N
O
S
O
R
13a,b - 17a,b
a
b
( : R=H; : R=F)
Scheme 2. Reagents and conditions: (a) pyridine, CH2Cl2, 4 h, 80–90%; (b) compound 7, TMHD, CuBr, Cs2CO3, NMP, 110 °C, 70–80%; (c) LiOH, THF:H2O = 3:1, reflux, 2 h, 100%;
(d) R = F: (i)SOCl2, CH2Cl2, cat. DMF, reflux 2 h; (ii) pyridine, THF, rt, 2 h, 70–82%; R = H: HATU, HOAt, DMF, microwave, 40 W, 60 °C, 30 min, 72–85%.
when 5-fluorothiazol-2-amine was used, subsequent condensation
with acid 9 proceeded dramatically sluggish. In this regard, acid 9
was treated firstly with refluxed SOCl2 followed by coupling with
5-fluorothiazol-2-amine and compound 10 was obtained in 82%
yield.
As indicated in Scheme 2, compounds 13a,b–17a,b were syn-
thesized in four steps. First, reaction of commercially available
amines R1R2NH with 4-bromobenzene-1-sulfonyl chloride pro-
vided sulfonylamides 11A–E, which were then condensed with
benzoate 7 affording esters 12A–E, respectively. Hydrolysis of es-
ters 12A–E with LiOH followed by amidation with aminothiazoles
yielded final compounds 13a,b–17a,b using a similar procedure36
as described in Scheme 1.
Similarly, heterocyclic amides 18–23 and 24a,b–28a,b were
prepared as shown in Scheme 3. Hydrolysis of benzoate 8 followed
by condensation with a series of heterocyclic amines provided the
expected amides 18–23 in moderate yields. Whereas compounds
24a,b–28a,b were prepared by hydrolysis of 12A–E followed by
condensation36 with 1-methyl-1H-pyrazol-3-amine or 1,5-di-
methyl-1H-pyrazol-3-amine using HATU and HOAt as the coupling
agents.
2.2. In vitro pharmacological evaluation of benzamide
derivatives
All newly synthetic compounds were evaluated in an enzymatic
glucokinase (GK) assay using purified recombinant human islet GK
following a similar procedure as we reported earlier.33,36 Known
compound 1 (GK50)27 was also synthesized and evaluated in our
assays for comparison (EC50 of 240 nM and activation fold 1.5).
To our delight, compound 5 bearing the aminothiazolyl and 2-
methylpenten-2-yl fragments displayed an EC50 value of 28.3 nM
and maximum activation fold of 2.4. It was eightfold more potent
than reference compound 1 in our assay (Table 1). Introducing a 5-
fluoro atom to the aminothiazole component led to compound 10
possessing a statistically similar EC50 value (47 nM). Encouraged by
the results, a sub-series of diversified aminosulfonyl moieties were
introduced to replace the cyclopropylsulfonyl fragment in 5 and
10. It was found that all the aminosulfonyl analogs 13a,b–17a,b re-
tained good GK potency with EC50 ranging between 48–100 nM.
Comparing the non-substituted morpholinosulfonyl analogs
13a,b with substituted morpholinosulfonyl analogs 14a,b and
15a,b, the bulky substituent on the morpholine ring slightly
Het:
O
O
N
N
S
20
N
F
S
19
O
S
S
O
H
N
a,b
18
8
Het
O
N
N
N
N
O
N
N
18-23
N
22
23
21
O
O
O
S
c,d
1R2RN
12A-E
H
N
N
N
O
O
R3
24a,b - 28a,b
3
3
a
b
( : R =Me; : R =H)
Scheme 3. Reagents and conditions: (a) LiOH, THF:H2O = 3:1, reflux, 2 h, 100%; (b) compounds 20 and 22: (i) SOCl2, CH2Cl2, cat. DMF, reflux 2 h; (ii) pyridine, THF, rt, 2 h, 70–
82%; compounds 18–19, 21, 23: HATU, HOAt, DMF, microwave, 40 W, 60 °C, 40 min, 72–76%; (c) LiOH, THF:H2O = 3:1, reflux, 2 h, 100%; (d) HATU, HOAt, DMF, microwave,
40 W, 60 °C, 40 min, 72–85%.

W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
2985
Table 1
Table 2
In vitro activation of GK by benzamide-thiazole analogs
In vitro activation of GK by benzamide-heterocycle analogs
O
O
O
O
O
S
O
S
H
N
R
N
H
N
O
Heterocycle
S
O
O
R'
O
Compda
1(GK50)
5
R
R0
—
H
EC50 (nM)
240(30c)
28.3
Activation foldb
Compda
Heterocycle
EC50 (nM)
Activation foldb
—
—
N
F
18
250
0.9
0.7
2.4
S
N
10
F
47.7
48.0
1.8
2.1
19
890
N
N
S
13a
H
O
O
O
N
13b
14a
F
52.0
62.6
1.8
1.5
20
21
22
120
90.1
165
1.5
1.5
1.6
S
N
N
N
N
H
O
O
N
N
14b
F
65.4
1.7
N
23
N
>1000
—
N
N
15a
15b
H
F
101
1.7
1.9
O
a
Six different concentrations of compounds were tested in the assay, data were
N
N
78.0
O
mean of three independent experiments.
b
Maximum fold activation of GK over control level.
16a
16b
H
F
52.3
44.8
1.9
2.2
F
N
analogue 22 having sixfold reduced potency (165 nM). The imi-
dazo[1,2-a]pyrazin-8-yl analogue 23 completely lost GK activation
potency. Although all the bioisosteres of thiazole analogs 18–23
displayed reduced potency in comparison to the parent 5, the pyr-
azolyl analogue 21 caught our attention. In general, the pyrazolyl
moiety has better chemical stability than the thiazole fragment
and may raise less metabolic concerns in vivo,24 although com-
pound 21 was threefold less potent than thiazole 5. In this regard,
we used the pyrazolyl moiety (with or without 5-methyl substitu-
ent) as an additional privileged fragment, and counter-screened
the sulfonyl fragment with the aim to find more potent GK
activators.
F
N
17a
17b
H
F
90.4
64.6
1.7
1.7
O
N
O
a
Six different concentrations of compounds were tested in the assay, data were
mean of three independent experiments.
b
Maximum fold activation of GK over control level.
Data from Ref.30
.
c
reduced the GK potency. High GK activation potency was observed
on the 3- fluoropyrrolidinylsulfonyl analogs 16a,b showing EC50
values of 52 and 44 nM, respectively. The 4-methoxy piper-
idinylsulfonyl analogs 17a,b displayed slightly lower potency and
were twofold less potent than the five-membered congeners
16a,b. However, in comparison to the good GK potency, the maxi-
mum activation fold was not improved. It was noteworthy that in
all cases, the addition of a 5-fluoro to the thiazole component did
not affect GK potency significantly.
On the basis of the results in Table 1, the cyclopropylsulfonyl
analogue 5 remains the most potent GK activator, although variant
aminosulfonyl moieties were well tolerated. Accordingly, with the
cyclopropylsulfonyl fragment intact, a small series of heterocycles
were screened as bioisosteres of the thiazole fragment, and the re-
sults were summarized in Table 2.
From the results in Table 3, a much wider range of potency was
observed than that in Table 1. Morpholinylsulfonyl analogue 24a
gave a similar EC50 value (95 nM) as compound 21, whereas the
di-methyl substituted morpholinylsulfonyl analogue 25a showed
twofold increase in GK potency. Bridged morpholinyl analogue
26a showed reduced potency indicating that much bulkier substi-
tuent was not tolerant at this position. 3-Fluoropyrrolidinyl ana-
logue 27a also showed improved potency with an EC50 value of
63 nM. Piperidinyl analogue 28a had much lower potency. Inter-
estingly, all the pyrazolyl analogs 24b–28b lacking the 5-methyl
substituent showed reduced GK potency, indicating that a small
binding pocket in the GK enzyme may exist for the 5-methyl sub-
stituent. Overall, the thiazolyl series in Table 1 are more potent
than the pyrazolyl series in Table 3.
Aminothiazoles 18 and 19 bearing
a
bulky 4-substituent
2.3. In vivo pharmacological evaluation
showed much lower potency. However, reasonable potency was
observed on the 4-oxo-4,5-dihydrothiazolyl (20) and 1,5-di-
methyl-1H-pyrazolyl (21) analogs. Replacing the thiazole fragment
On the basis of the structure–activity relationship (SAR) de-
scribed above, compounds 5 and 16b were identified as the most
potent GK activators in current studies possessing optimum
in GK activator
5 with 5-methylpyrazin-2-yl moiety led to

2986
W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
Table 3
In vitro activation of GK by benzamide-pyrazol analogs
O
O
S
O
1R2RN
H
N
N
N
O
O
R3
Compda
24a
NR1R2
O
R3
EC50 (nM)
95.1
Activation foldb
N
N
Me
H
1.5
3.0
24b
297
O
N
N
25a
25b
Me
H
44.8
265
1.6
1.8
O
O
N
26a
26b
Me
H
144
242
1.5
1.7
O
O
N
N
27a
27b
Me
H
63.1
83.5
1.9
2.1
F
N
F
N
28a
28b
Me
H
460
491
1.8
1.7
O
N
O
Figure 2. Effects of 5 and 16b on blood glucose level in ICR mice. Upper panel:
Blood glucose profiles. Lower panel: Delta blood glucose ( BG) profiles. BG
reflects the change in blood glucose concentrations from 0 min within each
a
Six different concentrations of compounds were tested in the assay, data were
D
D
mean of three independent experiments.
b
Maximum fold activation of GK over control level.
experimental group. Data were shown as mean SEM (n = 6).
Table 4
combinations of GK potency (28 vs 45 nM) and maximum activa-
tion fold (>2). Therefore, they were carried forward for further
evaluation. The hypoglycemic effect of 5 and 16b was evaluated
on imprinting control region (ICR) mice, a non-diabetic animal
model.33 It was found that administration of an oral dose of
10 mg/kg of compounds 5 and 16b resulted in 5.5% and 8.1% blood
glucose reduction of vehicle control within 1 h, respectively (Fig. 2).
Therefore, no significant hypoglycemic effects of 5 and 16b were
achieved after single oral dosing at the dose of 10 mg/kg. The
low glucose reduction of these two compounds is not in parallel
with their GK enzymatic potency, which may be due to the rela-
tively low intrinsic activity (maximum activation fold), and the
pharmacokinetic properties (PK). Accordingly, as shown in Table
4, the PK profiles of compounds 5 and 16b were evaluated in mice
after single iv (10 mg/kg) and po (20 mg/kg) administration.37 The
cyclopropylsulfonyl analogue 5 displayed reasonable half-life time
(2.3 h), and moderate oral bioavailability (38%). However, poor
plasma clearance (0.20 L/h/kg, iv) was observed. The 3-fluor-
opyrrolidinylsulfonyl analogue 16b showed longer half-life
(ꢀ6.0 h), and improved plasma clearance (1.07 L/h/kg, iv), however
poor bioavailability (less than 10%) was observed. The unfavorable
PK profiles of compounds 5 and 16b may partially explain the poor
in vivo glucose-lowering properties. Therefore, further structural
optimization will be focused on tuning the PK parameters.
Pharmacokinetic parameters of compounds 5 and 16b
iv (10 mg/kg)a
Compd
5
16b
CL(L/h/Kg)
0.20 0.02
1.07 0.15
Vss(L/kg)
0.28 1.2
1.20 0.32
po (20 mg/kg)a
Tmax (h)
T1/2(h)
2.3 0.3
5.9 0.56
Compd
5
16b
Cmax (ng/ml)
15800 2900
1086 751
AUC0–1 (ng th/ml)
39800 5800
1790 101
F (%)
38.6
9.5
1.0 0.0
1.0 0.0
a
Values are the average of three runs; vehicle: DMSO, tween-80, normal saline.
CL, clearance; Vss, volume of distribution; T1/2, half-life; Cmax, maximum concen-
tration; Tmax, time of maximum concentration; AUC0–1, area under the plasma
concentration time curve; F, oral bioavailability.
3. Conclusion
In summary, a series of benzamide derivatives were synthe-
sized and evaluated as glucokinase activators (GKs) by using the
privileged-fragment-merging (PFM) strategy. A variety of amino
groups were introduced to the sulfonyl-terminal of benzamide
derivatives to explore the electronic and spacial effects, and differ-
ent types of heterocyclic fragments were evaluated as well. Com-
pounds
5 and 16b were identified as the most potent GK

W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
2987
activators having a suitable balance of potency and activation pro-
file, with EC50 values of 28.3 and 44.8 nM, and activation fold of 2.4
and 2.2, respectively. However, these two compounds only showed
a minor reduction in plasma glucose levels on imprinting control
region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were
also observed on these two compounds. Further structural optimi-
zation will be focused on tuning the PK parameters.
4.4.1. General procedure for the synthesis of compounds 8 and
12A–E
Methyl 3-hydroxy-5-((3-methylbut-2-en-1-yl)oxy) benzo-ate
734 (1.6 g, 6.8 mmol, 1 equiv), aryl bromide 636 or 11A–E
(7.5 mmol, 1.1 equiv), copper (I) bromide (0.34 mmol, 0.5 equiv)
and cesium carbonate (3.32 g, 10.2 mmol, 1.5 equiv) were added
to a pear-shaped Schlenk flask. Degased NMP (9 mL) was added
via needle, then TMHD (0.13 mmol, 0.1 equiv) was dropped. The
reaction mixture was heated at 110 °C under nitrogen, and then
cooled to the room temperature. The reaction mixture was filtered
through a pad of celite and washed with EtOAc. Combined filtrates
were washed subsequently with 2 N HCl, 2 M NaOH, and 10% NaCl.
The resulting organic layer was dried over anhydrous NaSO4 and
concentrated. The crude product was then purified by flash column
chromatography to give the title intermediate in 70–80% yield (8
and 12A–E).
4. Experimental section
4.1. Preparation of recombinant glucokinase protein33,36
cDNA of human glucokinase (MGC: 1742, purchased from Ori-
Gene Technologies, USA) was subcloned into the pET28a (+)
expression vector, and expressed in Escherichia coli strain BL21
(DE3). The NH2 terminal end of (His)6-tag glucokinase fusion pro-
tein was purified by Ni-NTA metal chelate affinity chromatography
and stored at ꢁ80 °C in 50 mM Tris–HCl pH 7.4, 1 mM dithiothre-
itol (DTT), 50 mM NaCl, and 10% glycerol.
4.4.2. Methyl 3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methyl-
but-2-en-1-yl)oxy)benzoate (8)
Yield 80% (colorless oil); 1H NMR (300 MHz, CDCl3) d = 7.85 (d,
J = 8.5 Hz, 2H), 7.42 (s, 1H), 7.30 (s, 1H),7.09 (d, J = 8.5 Hz, 2H),
6.81 (s, 1H), 5.46 (t, J = 6.4 Hz, 1H), 4.54 (d, J = 6.8 Hz, 2H), 3.90
(s, 3H), 2.70–2.31 (td, J = 7.7, 4.0 Hz, 1H), 1.79 (s, 3H), 1.74 (s,
3H), 1.07–1.01 (m, 2H), 0.89–0.82 (m, 2H); EI-MS m/z 416 (M+).
4.2. Glucokinase enzymatic assay
The GK activity was assessed spectrometrically by a coupled
reaction with glucose-6-phosphate dehydrogenase (G6PDH).33,36
Briefly, GK catalyzes glucose phosphorylation to generate glu-
cose-6-P, which was oxidized by the G6PDH with the concomitant
reduction of NADPH. The product NADPH was then monitored by
the increase rate of absorbance at 340 nm in a plate reader (Spec-
tra-Max 190; Molecular Devices, USA). All compounds were pre-
pared in DMSO. The assay was performed in 96-well plates in a
4.4.3. Methyl 3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methyl-
but-2-en-1-yl)oxy)benzoate (12A)
Yield 80% (white solid);1H NMR (300 MHz, CDCl3) d = 7.71 (d,
J = 8.6 Hz, 2H), 7.44 (s, 1H), 7.31 (s, 1H), 7.09 (d, J = 8.6 Hz, 2H),
6.82 (s, 1H), 5.47 (t, J = 6.5 Hz, 1H), 4.55 (d, J = 6.8 Hz, 2H), 3.91
(s, 3H), 3.81–3.68 (m, 4H), 3.14–2.87 (m, 4H), 1.80 (s, 3H), 1.75
(s, 3H); EI-MS m/z 461 (M+).
final volume of 100
cose, 25 mM KCl, 2 mM MgCl2, 1 mM DTT, 1 mM ATP, 1 mM NADP,
2.5 U/mL G6PDH, 0.5 g (His)6-glucokinase, and test compounds.
lL containing 50 mM HEPES pH 7.4, 5 mM glu-
l
4.4.4. Methyl 3-(4-(((2S,6R)-2,6-dimethylmorpholino)sulfonyl)
phe-noxy)-5-((3-methylbut-2-en-1-yl)oxy)benzoate (12B)
Yield 78% (colorless oil); 1H NMR (300 MHz, CDCl3) d = 7.70 (d,
J = 8.7 Hz, 2H), 7.44 (s, 1H), 7.32 (s, 1H), 7.08 (d, J = 8.7 Hz, 2H),
6.82 (d, J = 1.9 Hz, 1H), 5.47 (t, J = 6.6 Hz, 1H), 4.55 (d, J = 6.8 Hz,
2H), 3.91 (s, 3H), 3.72 (dd, J = 8.4, 5.6 Hz, 2H), 3.55 (d, J = 11.0 Hz,
2H), 2.00 (t, J = 10.8 Hz, 2H), 1.80 (s, 3H), 1.75 (s, 3H), 1.17 (s,
3H), 1.15 (s, 3H); EI-MS m/z 489 (M+).
The velocities of the enzyme reaction were expressed as mOD/
min, and the fold activation of the enzyme was achieved by com-
paring with control (GK activation with only DMSO was considered
as 100%). For EC50 determination, six different concentrations of
compounds were tested in the assay, and the fold changes in activ-
ity versus controls were fitted to sigmoidal curve using a four
parameter logistic model in GraphPad Prism 4.
4.4.5. Methyl 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)
ph -enoxy)-5-((3-methylbut-2-en-1-yl)oxy)benzoate (12C)
Yield 78% (colorless oil); 1H NMR (300 MHz, CDCl3) d = 7.67 (d,
J = 6.1 Hz, 2H), 7.44 (d, J = 1.1 Hz, 1H), 7.31 (s, 1H), 7.06 (d,
J = 5.7 Hz, 2H), 6.82 (d, J = 1.3 Hz, 1H), 5.47 (t, J = 6.7 Hz, 1H), 4.55
(d, J = 6.7 Hz, 2H), 4.38 (s, 2H), 3.90 (s, 3H), 3.38 (d, J = 11.0 Hz,
2H), 2.64 (d, J = 11.0 Hz, 2H), 2.01–1.87 (m, 2H), 1.96-1.91 (m,
1H), 1.80 (s, 3H), 1.75 (s, 3H); EI-MS m/z 487 (M+).
4.3. Animal studies33
Male ICR mice (8 weeks old), housed with free access to diet and
reversed light cycles, were used. Before the studies, food was de-
prived for 2 h in ICR mice, while free access to water was provided.
The ICR mice were assigned to different groups based on the body
weight. Mice were then orally dosed with test compounds or vehi-
cle (0.5% carboxymethylcellulose). Blood glucose levels were mea-
sured via blood sample from tail vein by using an ACCU-CHEK
Advantage (Roche) at the indicated time after dosing.
4.4.6. (S)-Methyl 3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)
phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)benzoate (12D)
Yield 70% (colorless oil); 1H NMR (300 MHz, CDCl3) d = 7.81 (t,
J = 5.8 Hz, 2H), 7.43 (d, J = 1.0 Hz, 1H), 7.30 (s, 1H), 7.09 (t,
J = 5.8 Hz, 2H), 6.81 (t, J = 2.1 Hz, 1H), 5.47 (t, J = 6.7 Hz, 1H), 5.17
(d, J = 51.7 Hz, 1H), 4.55 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.66–3.47
(m, 3H), 3.34–3.26 (m, 1H), 2.29–1.88 (m, 3H), 1.81 (s, 3H), 1.75
(s, 3H); EI-MS m/z 463 (M+).
4.4. Chemistry
1H NMR spectral data were recorded in CDCl3 on Varian Mer-
cury 300 NMR spectrometer and 13C NMR data were recorded in
CDCl3 on Varian Mercury 400 NMR spectrometer. Low-resolution
mass spectra (MS) and high-resolution mass spectra (HRMS) were
recorded at an ionizing voltage of 70 eV on a Finnigan/MAT95
spectrometer. Column chromatography was carried out on silica
gel (200–300 mesh). Reactions using microwave irradiation was
conducted on CZM (DC-5415, CEM) instrument. All reactions were
monitored using thin-layer chromatography (TLC) on silica gel
plates.
4.4.7. Methyl 3-(4-((4-methoxypiperidin-1-yl)sulfonyl)
phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)benzoate (12E)
Yield 76% (colorless oil); 1H NMR (300 MHz, CDCl3) d = 7.71 (d,
J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.31 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.82
(t, J = 2.2 Hz, 1H), 5.47 (t, J = 6.5 Hz, 1H), 4.55 (d, J = 6.8 Hz, 2H),
3.91 (s, 3H), 3.38–3.26 (m, 4H), 3.26–3.10 (m, 2H), 2.98 (ddd,

2988
W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
J = 11.3, 7.1, 3.8 Hz, 2H), 1.90 (ddd, J = 11.8, 8.2, 3.8 Hz, 2H), 1.80 (s,
3H), 1.79–1.66 (m, 5H); EI-MS m/z 489 (M+).
CDCl3) d = 165.0, 160.8, 160.6, 160.1, 156.5, 139.4, 137.1, 135.5,
130.2, 129.6, 118.5, 118.2, 113.8, 111.6, 111.1, 110.2, 66.0, 65.4,
46.0, 25.8, 18.2 ppm; HRMS (EI) calcd for
529.1341, found 529.1339.
C25H27N3O6S2:
4.4.8. General procedure for the synthesis of compounds 5,
13a–17a, 18–19, 21, 23 and 24a,b–28a,b
4.4.12. N-(5-Fluorothiazol-2-yl)-3-((3-methylbut-2-en-1-
Method A To a solution of benzoic acid which was obtained by
hydrolysis of methyl esters 8 or 12A–E (0.22 mmol, 1.0 equiv),
aminothiazole or imidazo[1,2-a]pyrazin-8-amine or aminopyra-
zole (0.33 mmol, 1.5 equiv), HATU (0.33 mmol, 1.5 equiv) and
HOAt (0.33 mmol, 1.5 equiv) in DMF (2 mL) was added dropwise
di(isopropyl)ethylamine (DIPEA) (0.12 mL, 0.67 mmol, 3 equiv).
The reaction was run under microwave at 60 °C (40 W) for
30 min, and then cooled to room temperature and poured into
brine. The aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over anhydrous
NaSO4 and concentrated. The residue was purified by chromatog-
raphy (SiO2, petroleum ether/EtOAc = 4:1–1:1) to yield corre-
sponding amides as white or yellow powder.
Method B for compounds 10,13b–17b, 20 and 22. A mixture of
benzoic acid 9 (0.22 mmol, 1 equiv), anhydrous CH2Cl2 (4 mL)
and DMF (15 lL) was cooled to 0 °C, SOCl2 (0.66 mmol, 3 equiv)
was added dropwise. The mixture was warmed to room tempera-
ture, and then refluxed for 2 h. After cooling to room temperature,
CH2Cl2 was evacuated by vacuum under nitrogen atmosphere.
Anhydrous THF (4 mL) was added slowly, followed by addition of
a catalytic amount of pyridine, and 5-fluoroaminothiazole or 2-
yl)oxy)-5-(4-(morpholinosulfonyl)phenoxy)benzamide (13b)
Yield 74% (yellow powder); 1H NMR (300 MHz, CDCl3) d = 7.74
(d, J = 8.7 Hz, 2H), 7.30 (d, J = 1.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H),
7.13 (d, J = 1.7 Hz, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.96–6.90 (m, 1H),
6.85 (t, J = 1.8 Hz, 1H), 5.47 (t, J = 5.9 Hz, 1H), 4.56 (d, J = 6.2 Hz,
2H), 3.85–3.70 (m, 4H), 3.16–2.84 (m, 4H), 1.81 (s, 3H), 1.74 (s,
3H); 13C NMR (100 MHz, CDCl3) d = 164.3, 160.7, 160.6, 156.7,
139.5, 134.7, 130.2, 129.8, 118.4, 118.2, 117.6, 117.5, 111.1,
110.2, 66.0, 65.5, 45.9, 25.8, 18.2 ppm; HRMS (EI) calcd for
C25H26FN3O6S2: 547.1247, found 547.1245
4.4.13. 3-(4-(((2S,6R)-2,6-Dimethylmorpholino)sulfonyl)
phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)
benzamide (14a)
Yield 78% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.71
(d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 7.11 (d,
J = 8.5 Hz, 2H), 6.98 (d, J = 2.8 Hz, 1H), 6.85 (s, 1H), 5.45 (t,
J = 6.5 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 3.83–3.64 (m, 2H), 3.56 (d,
J = 11.1 Hz, 2H), 1.99 (t, J = 10.8 Hz, 2H), 1.80 (s, 3H), 1.72 (s, 3H),
1.17 (s, 3H), 1.15 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 164.9,
160.7, 160.6, 160.1, 156.6, 139.3, 136.9, 135.4, 130.0, 129.9,
118.5, 118.2, 113.7, 111.7, 111.1, 110.1, 71.3, 65.4, 50.7, 25.8,
18.6, 18.2 ppm; HRMS (EI) calcd for C27H31N3O6S2: 557.1654,
found 557.1656.
aminothiazol-4(5H)-one
or
5-methylpyr-azin-2-amine
(0.26 mmol, 1.2 equiv). The reaction was stirred for 2 h at room
temperature, quenched with water, and then extracted with EtOAc.
The combined organic layers were washed with brine, dried over
anhydrous NaSO4 and concentrated. The residue was purified by
chromatography (SiO2, petroleum ether/EtOAc = 4:1 to 1:1) to
yield corresponding amides as white or yellow powder.
4.4.14. 3-(4-(((2S,6R)-2,6-Dimethylmorpholino)sulfonyl)
phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-
yl)oxy)benzami-de (14b)
Yield 79% (yellow powder); 1H NMR (300 MHz, CDCl3) d = 7.73
(d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 7.20 (s, 1H), 7.12 (d, J = 8.6 Hz,
2H), 6.97 (s, 1H), 6.85 (s, 1H), 5.47 (t, J = 6.9 Hz, 1H), 4.57 (d,
J = 6.7 Hz, 2H), 3.83–3.66 (m, 2H), 3.57 (d, J = 11.2 Hz, 2H), 2.00
(t, J = 10.7 Hz, 2H), 1.81 (s, 3H), 1.75 (s, 3H), 1.17 (s, 3H), 1.15 (s,
3H); 13C NMR (100 MHz, CDCl3) d = 163.7, 160.8, 160.6, 156.7,
139.5, 134.4, 130.1, 118.3, 118.2, 117.7, 111.3, 111.0, 109.8, 71.3,
65.5, 50.7, 43.1, 29.6, 25.8, 18.6, 18.2 ppm; HRMS (EI) calcd for
4.4.9. 3-(4-(Cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-
en-1-yl)oxy)-N-(thiazol-2-yl)benzamide (5)
Yield 87% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.91–
7.77 (m, 2H), 7.36 (s, 1H), 7.24 (s, 1H), 7.21 (d, J = 3.5 Hz, 1H), 7.15–
7.08 (m, 2H), 6.98 (d, J = 3.5 Hz, 1H), 6.85 (t, J = 2.0 Hz, 1H), 5.45 (t,
J = 7.3 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 2.76–1.88 (m, 1H), 1.80 (s,
3H), 1.72 (s, 3H), 1.49–1.30 (m, 2H), 1.19–0.97 (m, 2H); 13C NMR
(100 MHz, CDCl3) d = 164.9, 160.9, 160.6, 160.0, 156.8, 139.3,
137.0, 135.4, 135.3, 129.9, 118.6, 118.5, 113.7, 111.3, 111.1,
110.0, 65.4, 33.1, 25.8, 18.2, 6.0 ppm; HRMS (EI) calcd for
C27H30FN3O6S2: 575.1560, found 575.1558.
4.4.15. 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)
phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)
benzamide (15a)
C24H24N2O5S2: 484.1127, found 484.1124.
Yield 84% (off white powder); 1H NMR (300 MHz, CDCl3)
d = 7.69 (d, J = 8.6 Hz, 2H), 7.37 (s, 1H), 7.27 (s, 1H), 7.20 (d,
J = 3.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 3.3 Hz, 1H),
6.84 (s, 1H), 5.45 (t, J = 7.0 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 4.37
(s, 2H), 3.38 (d, J = 10.9 Hz, 2H), 2.65 (d, J = 10.6 Hz, 2H), 2.06–
1.90 (m, 4H), 1.80 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3)
d = 164.9, 160.6, 160.1, 156.5, 139.3, 136.9, 135.5, 130.1, 129.8,
118.5, 118.1, 113.7, 111.6, 111.0, 110.2, 73.6, 65.4, 50.9, 27.7,
25.8, 18.2 ppm; HRMS (EI) calcd for C27H29N3O6S2: 555.1498,
found 555.1500.
4.4.10. 3-(4-(Cyclopropylsulfonyl)phenoxy)-N-(5-fluorothiazol-
2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide (10)
Yield 82% (yellow powder); 1H NMR (300 MHz, CDCl3) d = 7.88
(d, J = 8.6 Hz, 2H), 7.31 (s, 1H), 7.18 (s, 1H), 7.13 (d, J = 8.6 Hz,
2H), 6.86 (d, J = 6.7 Hz, 2H), 5.46 (t, J = 6.9 Hz, 1H), 4.55 (d,
J = 7.1 Hz, 2H), 2.47 (dd, J = 10.8, 6.3 Hz, 1H), 1.80 (s, 3H), 1.73 (s,
3H), 1.49–1.27 (m, 2H), 1.18–0.98 (m, 2H); 13C NMR (100 MHz,
CDCl3) d = 164.5, 160.8, 160.7, 156.9, 139.5, 135.5, 134.6, 130.0,
118.6, 118.4, 117.5, 117.4, 111, 110.9, 110.1, 65.5, 33.1, 25.8,
18.2, 6.0 ppm; HRMS (EI) calcd for C24H23FN2O5S2: 502.1032, found
502.1030.
4.4.16. 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)
phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)
oxy)benza-mide (15b)
4.4.11. 3-((3-Methylbut-2-en-1-yl)oxy)-5-(4-(morpholinosulfo
nyl)phe -noxy)-N-(thiazol-2-yl)benzamide (13a)
Yield 82% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.72
(d, J = 8.6 Hz, 2H), 7.38 (s, 1H), 7.27 (s, 1H), 7.16 (d, J = 3.6 Hz,
1H), 7.11 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 3.6 Hz, 1H), 6.85 (s, 1H),
5.45 (t, J = 6.5 Hz, 1H), 4.53 (d, J = 6.8 Hz, 2H), 3.83–3.58 (m, 4H),
3.09–2.77 (m, 4H), 1.80 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz,
Yield 74% (yellow powder); 1H NMR (300 MHz, CDCl3) d = 7.71
(d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 7.18 (s, 1H), 7.10 (d, J = 8.8 Hz,
2H), 6.97 (s, 1H), 6.84 (s, 1H), 5.46 (t, J = 7.0 Hz, 1H), 4.57 (d,
J = 6.9 Hz, 2H), 4.38 (s, 2H), 3.39 (d, J = 10.7 Hz, 2H), 2.66 (d,
J = 11.3 Hz, 2H), 2.14–1.90 (m, 4H), 1.81 (s, 3H), 1.75 (s, 3H); 13C

W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
2989
NMR (100 MHz, CDCl3) d = 163.8, 160.8, 160.5, 156.8, 139.4, 134.4,
130.3, 129.9, 118.4, 118.2, 111.2, 110.9, 109.9, 73.6, 65.5, 51.0, 27.7,
25.8, 18.2 ppm; HRMS (EI) calcd for C27H28FN3O6S2: 573.1404,
found 573.1402.
1.18 (m, 2H), 1.25–0.58 (m, 2H); 13C NMR (100 MHz, CDCl3)
d = 164.3, 163.7, 161.2, 160.8, 160.4, 158.9, 156.7, 149.1, 139.2,
135.2, 134.5, 130.1, 129.9, 127.7, 127.6, 118.5, 118.4, 115.6,
115.3, 110.9, 110.7, 109.4, 107.9, 65.2, 33.1, 25.8, 18.2, 6.0; HRMS
(EI) calcd for C30H27FN2O5S2: 578.1345, found 578.1355
4.4.17. (S)-3-(4-((3-Fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-5-
((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide (16a)
Yield 78% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.81
(d, J = 8.7 Hz, 1H), 7.37 (s, 2H), 7.22 (s, 2H), 7.10 (d, J = 8.7 Hz,
2H), 6.98 (s, 1H), 6.84 (s, 1H), 5.45 (t, J = 6.4 Hz, 1H), 5.16 (d,
J = 53.1 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 3.58 (d, J = 1.3 Hz, 1H),
3.56–3.41 (m, 2H), 3.30 (td, J = 10.2, 6.6 Hz, 1H), 2.31–1.86 (m,
2H), 1.80 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3)
d = 164.9, 160.5, 160.5, 160.2, 156.6, 139.2, 136.9, 135.4, 131.2,
129.8, 118.5, 118.3, 113.7, 111.4, 111.0, 110.1, 93.0, 91.3, 65.4,
54.4, 54.2, 45.8, 32.6, 32.4, 25.8, 18.2 ppm; HRMS (EI) calcd for
4.4.22. N-(4-(tert-Butyl)thiazol-2-yl)-3-(4-(cyclopropylsulfonyl)
phen -oxy)-5-((3-methylbut-2-en-1-yl)oxy)benzamide (19)
Yield 84% (white powder); 1H NMR (300 MHz, CDCl3) d = 9.48 (s,
1H), 7.87 (d, J = 8.5 Hz, 2H), 7.32 (s, 1H), 7.18 (s, 1H), 7.12 (d,
J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.59 (s, 1H), 5.47 (t, J = 6.1 Hz, 1H),
4.56 (d, J = 6.6 Hz, 2H), 2.68–2.38 (m, 1H), 1.81 (s, 3H), 1.75 (s,
3H), 1.45–1.34 (m, 2H), 1.30 (s, 9H), 1.06 (d, J = 7.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d = 163.3, 161.0, 160.7, 156.8, 139.4,
135.1, 134.8, 130.0, 118.5, 118.4, 111.2, 110.5, 109.3, 105.5, 65.4,
34.3, 33.1, 29.7, 25.8, 18.2, 6.0; HRMS (EI) calcd for C28H32N2O5S2:
540.1753, found 540.1757.
C25H26FN3O5S2: 531.1298, found 531.1299.
4.4.18. (S)-3-(4-((3-Fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-
N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)
benzamide (16b)
4.4.23. 3-(4-(Cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-
en-1-yl)oxy)-N-(4-oxo-4,5-dihydrothiazol-2-yl)benzamide (20)
Yield 82% (yellow powder); 1H NMR (300 MHz, CDCl3) d = 7.86
(d, J = 8.7 Hz, 2H), 7.60 (s, 1H), 7.48 (s, 1H), 7.11 (d, J = 8.7 Hz,
2H), 6.85 (s, 1H), 5.48 (t, J = 6.7 Hz, 1H), 4.58 (d, J = 6.7 Hz, 2H),
3.86 (s, 2H), 2.62–2.23 (m, 1H), 1.81 (s, 3H), 1.75 (s, 3H), 1.42–
1.31 (m, 2H), 1.12–0.98 (m, 2H); 13C NMR (100 MHz, CDCl3)
d = 177.1, 161.3, 160.5, 156.5, 139.2, 129.9, 118.7, 118.4, 113.2,
112.4, 111.2, 96.6, 65.4, 33.1, 25.8, 18.2, 6.0; HRMS (EI) calcd for
Yield 78% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.83
(d, J = 8.7 Hz, 2H), 7.30 (s, 1H), 7.11 (d, J = 8.8 Hz, 3H), 6.91 (s,
1H), 6.84 (s, 1H), 5.46 (t, J = 6.1 Hz, 1H), 5.18 (d, J = 53.2 Hz, 1H),
4.55 (d, J = 6.8 Hz, 2H), 3.63–3.58 (m, 1H), 3.58–3.42 (m, 2H),
3.30 (td, J = 10.2, 6.6 Hz, 1H), 2.23 - 2.04 (m, 1H), 1.81 (s, 3H),
1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 164.0, 160.7, 160.3,
157.0, 139.5, 134.5, 131.4, 129.8, 118.4, 118.4, 110.9, 110.6,
109.9, 93.1, 91.3, 65.5, 54.4, 54.2, 45.9, 32.6, 32.4, 25.8, 18.2 ppm;
HRMS (EI) calcd for C25H25F2N3O5S2: 549.1204, found 549.1202
C24H24N2O6S2: 500.1076, found 500.1072
4.4.24. 3-(4-(Cyclopropylsulfonyl)phenoxy)-N-(1,5-dimethyl-
1H-pyr-azol-3-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
(21)
4.4.19. 3-(4-((4-Methoxypiperidin-1-yl)sulfonyl)phenoxy)-5-
((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide (17a)
Yield 84% (white powder); 1H NMR (300 MHz, CDCl3) d = 11.55
(s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.36 (s, 1H), 7.24 (s, 1H), 7.09 (d,
J = 8.7 Hz, 2H), 6.98 (d, J = 3.6 Hz, 1H), 6.85 (t, J = 1.9 Hz, 1H), 5.46
(t, J = 6.9 Hz, 1H), 4.54 (d, J = 6.8 Hz, 2H), 3.37–3.29 (m, 1H), 3.27
(s, 3H), 3.24–3.13 (m, 2H), 2.97 (ddd, J = 8.7, 5.3, 1.9 Hz, 2H), 1.91
(ddd, J = 11.4, 7.1, 3.5 Hz, 2H), 1.80 (s, 3H), 1.76 (dd, J = 7.0,
3.3 Hz, 2H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 164.9,
160.6, 160.4, 156.6, 139.3, 136.9, 135.4, 130.9, 129.9, 118.5,
118.1, 113.7, 111.5, 111.1, 110.0, 73.9, 65.4, 55.7, 43.0, 29.7, 25.8,
18.2 ppm; HRMS (EI) calcd for C27H31N3O6S2: 557.1654, found
557.1657
Yield 81% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.92 (s,
1H), 7.85 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 7.09 (d, J = 8.0 Hz, 3H),
6.76 (s, 1H), 6.60 (s, 1H), 5.45 (t, J = 6.4 Hz, 1H), 4.52 (d,
J = 6.7 Hz, 2H), 3.60 (s, 3H), 2.59–2.37 (m, 1H), 2.26 (s, 3H), 1.79
(s, 3H), 1.73 (s, 3H), 1.37–1.31 (m, 2H), 1.07–1.01 (m, 2H); 13C
NMR (100 MHz, CDCl3) d = 163.7, 161.2, 160.5, 156.5, 145.6,
139.7, 139.1, 137.1, 135.0, 129.9, 118.6, 118.3, 110.7, 110.3,
109.4, 97.4, 65.3, 35.5, 33.1, 25.8, 18.2, 11.3, 6.0 ppm; HRMS (EI)
calcd for C26H29N3O5S: 495.1828, found 495.1825.
4.4.25. 3-(4-(Cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-
en-1-yl)oxy)-N-(5-methylpyrazin-2-yl)benzamide (22)
Yield 70% (white powder); 1H NMR (300 MHz, CDCl3) d 9.56 (s,
1H), 8.54 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.32 (s, 1H),
7.20 (s, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.83 (s, 1H), 5.47 (t,
J = 6.7 Hz, 1H), 4.58 (d, J = 7.0 Hz, 2H), 2.57 (s, 3H), 2.54–2.34 (m,
1H), 1.81 (s, 3H), 1.75 (s, 3H), 1.39–1.33 (m, 2H), 1.09–1.02 (m,
2H); 13C NMR (100 MHz, CDCl3) d = 164.2, 161.0, 160.7, 156.8,
149.5, 145.5, 141.3, 139.3, 136.3, 135.8, 135.2, 129.9, 118.5,
118.4, 110.7, 110.6, 109.6, 65.4, 33.1, 25.8, 20.8, 18.2, 6.0; HRMS
(EI) calcd for C26H27N3O5S 493.1671, found 493.1677.
4.4.20. N-(5-Fluorothiazol-2-yl)-3-(4-((4-methoxypiperidin-1-
yl)sulfo-nyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)
benzamide (17b)
Yield 84% (white powder); 1H NMR (300 MHz, CDCl3) d = 7.74
(d, J = 8.8 Hz, 2H), 7.29 (s, 1H), 7.18 (s, 1H), 7.09 (d, J = 8.7 Hz,
2H), 6.94 (s, 1H), 6.84 (s, 1H), 5.46 (t, J = 6.4 Hz, 1H), 4.56 (d,
J = 6.5 Hz, 2H), 3.40–3.29 (m, 1H), 3.28 (s, 3H), 3.25–3.13 (m, 2H),
3.05–2.93 (m, 2H), 1.98–1.85 (m, 2H), 1.80 (s, 3H), 1.78–1.69 (m,
5H); 13C NMR (100 MHz, CDCl3) d = 164.1, 160.7, 160.2, 156.9,
139.5, 134.5, 131.1, 129.9, 118.3, 118.2, 111.0, 111.0, 109.9, 73.8,
65.5, 55.7, 43.0, 29.7, 25.8, 18.2 ppm; HRMS (EI) calcd for
4.4.26. 3-(4-(Cyclopropylsulfonyl)phenoxy)-N-(imidazo[1,2-
a]pyraz in-8-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide (23)
Yield 74% (yellow powder); 1H NMR (300 MHz, CDCl3) d 9.62 (s,
1H), 7.81 (d, J = 8.6 Hz, 3H), 7.71 (s, 1H), 7.64 (d, J = 14.2 Hz, 2H),
7.40 (s, 1H), 7.30 (s, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.78 (s, 1H), 5.44
(t, J = 6.7 Hz, 1H), 4.56 (d, J = 5.0 Hz, 2H), 2.48–2.45 (m, 1H), 1.79
(s, 3H), 1.73 (s, 3H), 1.38–1.32 (m, 2H), 1.08–1.02 (m, 2H); 13C
NMR (100 MHz, CDCl3) d = 161.1, 160.5, 156.4, 139.264, 136.932,
134.878, 133.407, 129.804, 118.581, 118.2, 115.4, 111.1, 110.7,
110.2, 65.3, 33.1, 25.7, 18.1, 5.9; HRMS (EI) calcd for
C27H30FN3O6S2: 575.1560, found 575.1564.
4.4.21. 3-(4-(Cyclopropylsulfonyl)phenoxy)-N-(4-(4-fluoro
phenyl)thi -azol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)
benzamide (18)
Yield 85% (white powder); 1H NMR (300 MHz, CDCl3) d = 10.09
(s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.80–7.68 (m, 2H), 7.29 (s, 1H), 7.16
- 7.05 (m, 6H), 6.81 (t, J = 2.1 Hz, 1H), 5.47 (t, J = 6.4 Hz, 1H), 4.55 (d,
J = 6.8 Hz, 1H), 2.53–2.44 (m, 1H), 1.82 (s, 3H), 1.75 (s, 3H), 1.56–
C27H26N4O5S:518.1624, found 518.1628.

2990
W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
4.4.27. N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-((3-methylbut-2-en-
1-yl) oxy)-5-(4-(morpholinosulfonyl)phenoxy)benzamide (24a)
Yield 82% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.80 (s,
1H), 7.71 (d, J = 8.5 Hz, 1H), 7.19–7.00 (m, 3H), 6.77 (s, 1H), 6.60 (s,
1H), 5.46 (t, J = 6.6 Hz, 1H), 4.53 (d, J = 6.7 Hz, 2H), 3.84–3.70 (m,
4H), 3.63 (s, 3H), 3.13–2.95 (m, 4H), 2.27 (s, 3H), 1.80 (s, 3H),
1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 163.7, 161.0, 160.5,
156.2, 145.7, 139.7, 139.1, 137.2, 130.1, 129.3, 118.6, 117.9,
111.0, 110.4, 109.6, 97.4, 66.0, 65.3, 45.9, 35.5, 25.8, 18.2,
11.3 ppm; HRMS (EI) calcd for C27H32N4O6S: 540.2043, found
540.2045.
3H), 6.79 (s, 2H), 5.47 (t, J = 6.7 Hz, 1H), 4.56 (d, J = 6.7 Hz, 2H),
3.80 (s, 3H), 3.76–3.66 (m, 2H), 3.56 (d, J = 11.1 Hz, 2H), 2.00 (t,
J = 10.8 Hz, 2H), 1.80 (s, 3H), 1.74 (s, 3H), 1.17 (s, 3H), 1.15 (s,
3H); 13C NMR (100 MHz, CDCl3) d = 163.6, 160.9, 160.5, 156.3,
146.8, 139.1, 137.0, 131.1, 130.0, 129.6, 118.6, 118.0, 110.9,
110.5, 109.4, 97.6, 71.3, 65.3, 50.7, 38.7, 25.8, 18.6, 18.2 ppm;
HRMS (EI) calcd for C28H34N4O6S: 554.2199, found 554.2202.
4.4.33. (S)-N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-(4-((3-fluoro
pyrrolidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)
oxy) benz-amide (27a)
Yield 81% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.69 (s,
1H), 7.80 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 1.6 Hz, 1H), 7.09 (d,
J = 8.8 Hz, 3H), 6.76 (t, J = 1.9 Hz, 1H), 6.59 (s, 1H), 5.46 (t,
J = 6.8 Hz, 1H), 5.16 (d, J = 52.8 Hz, 1H), 4.54 (d, J = 6.7 Hz, 2H),
3.65 (s, 3H), 3.57 (d, J = 3.5 Hz, 1H), 3.56–3.39 (m, 2H), 3.31 (td,
J = 10.1, 6.5 Hz, 1H), 2.27 (s, 3H), 2.09–1.97 (m, 2H), 1.80 (s, 3H),
1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 163.7, 160.7, 160.4,
156.4, 145.6, 139.7, 139.0, 137.1, 130.8, 129.7, 118.6, 118.0,
110.8, 110.3, 109.4, 97.4, 93.0, 91.2, 65.3, 54.4, 54.1, 45.8, 35.4,
32.5, 32.3, 25.7, 18.1, 11.3 ppm; HRMS (EI) calcd for C27H31FN4O5S:
542.1999, found 542.2001.
4.4.28. 3-(4-(Cyclopropylsulfonyl)phenoxy)-N-(1-methyl-1H-
pyrazol-3-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide (24b)
Yield 79% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.57 (s,
1H), 7.86 (d, J = 8.5 Hz, 2H), 7.30 (s, 2H), 7.18–7.04 (m, 3H), 6.80 (s,
2H), 5.47 (t, J = 6.9 Hz, 1H), 4.56 (d, J = 6.6 Hz, 2H), 2.58–2.29 (m,
2H), 1.81 (s, 3H), 1.74 (s, 3H), 1.40–1.32 (m, 3H), 1.06 (q,
J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d = 163.7, 161.1, 160.5,
156.6, 146.9, 139.1, 137.0, 135.0, 131.1, 129.9, 118.6, 118.4,
110.6, 110.3, 109.4, 97.6, 65.3, 38.6, 33.1, 25.8, 18.2, 6.0 ppm;
HRMS (EI) calcd for C25H27N3O5S: 481.1671, found 481.1673.
4.4.29. N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-(4-(((2S,6R)-2,6-
dimethyl morpholino)sulfonyl)phenoxy)-5-((3-methylbut-2-
en-1-yl)oxy) benzamide(25a)
4.4.34. 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)
phenoxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-((3-methylbut-2-en-
1-yl)oxy) benzamide (27b)
Yield 80% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.51 (s,
1H), 7.71 (d, J = 8.3 Hz, 2H), 7.20–7.01 (m, 3H), 6.78 (s, 1H), 6.60 (s,
1H), 5.47 (t, J = 6.8 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 3.81–3.71 (m,
2H), 3.68 (s, 3H), 3.56 (d, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.01 (t,
J = 8.5 Hz, 2H), 1.80 (s, 3H), 1.74 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H);
13C NMR (100 MHz, CDCl3) d = 163.6, 160.9, 160.4, 156.2, 145.6,
139.7, 139.0, 137.2, 129.9, 129.6, 118.6, 117.9, 111.0, 110.4,
109.5, 97.4, 71.2, 65.3, 50.7, 35.4, 25.7, 18.6, 18.1, 11.3 ppm; HRMS
(EI) calcd for C29H36N4O6S: 568.2356, found 568.2353.
Yield 83% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.47 (s,
1H), 7.69 (d, J = 8.7 Hz, 2H), 7.28 (s, 1H), 7.19–6.99 (m, 3H), 6.78 (d,
J = 2.4 Hz, 2H), 5.47 (t, J = 6.5 Hz, 1H), 4.55 (d, J = 6.7 Hz, 2H), 4.37
(s, 2H), 3.80 (s, 3H), 3.38 (d, J = 11.0 Hz, 2H), 2.67 (d, J = 9.8 Hz,
2H), 2.21–1.87 (m, 4H), 1.80 (s, 3H), 1.74 (s, 3H); 13C NMR
(100 MHz, CDCl3) d = 163.6, 160.8, 160.5, 156.3, 146.8, 139.0,
137.0, 131.1, 129.8, 118.6, 117.9, 110.8, 110.4, 109.5, 97.6, 73.6,
65.3, 50.9, 38.6, 27.6, 25.7, 18.2 ppm; HRMS (EI) calcd for
C28H32N4O6S: 552.2043, found 552.2040.
4.4.30. N-(1-Methyl-1H-pyrazol-3-yl)-3-((3-methylbut-2-en-1-
yl)ox y)-5-(4-(morpholinosulfonyl)phenoxy)benzamide (25b)
Yield 75% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.84 (s,
1H), 7.71 (d, J = 8.3 Hz, 2H), 7.29 (s, 1H), 7.17–7.03 (m, 3H), 6.79 (d,
J = 7.5 Hz, 2H), 5.46 (t, J = 6.2 Hz, 1H), 4.53 (d, J = 6.6 Hz, 2H), 3.77
(m, 4H), 3.75 (s, 3H), 3.03–3.01 (m, 4H), 1.80 (s, 3H), 1.74 (s, 3H);
13C NMR (100 MHz, CDCl3) d = 163.7, 161.0, 160.5, 156.3, 146.9,
139.1, 137.1, 131.1, 130.1, 129.3, 118.6, 118.0, 110.8, 110.5,
109.6, 97.6, 66.0, 65.3, 45.9, 38.6, 25.8, 18.2 ppm; HRMS (EI) calcd
for C26H30N4O6S: 526.1886, found 526.1884.
4.4.35. N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-(4-((4-methoxypi
peridin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)
benza-mide (28a)
Yield 83% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.62 (s,
1H), 7.71 (d, J = 8.7 Hz, 2H), 7.25 (s, 1H), 7.13 (s, 1H), 7.07 (d,
J = 8.7 Hz, 2H), 6.77 (s, 1H), 6.60 (s, 1H), 5.46 (t, J = 6.5 Hz, 1H),
4.54 (d, J = 6.7 Hz, 2H), 3.65 (s, 3H), 3.34–3.29 (m, 1H), 3.28 (s,
3H), 3.25–3.18 (m, 2H), 2.93 (ddd, J = 11.5, 7.7, 3.7 Hz, 2H), 2.28
(s, 3H), 2.00–1.85 (m, 2H), 1.80 (s, 3H), 1.76 (d, J = 4.3 Hz, 2H),
1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d = 163.7, 160.6, 160.4,
156.3, 145.6, 139.7, 139.0, 137.1, 130.5, 129.8, 118.6, 117.9,
110.9, 110.3, 109.4, 97.4, 74.0, 65.3, 55.6, 43.1, 35.4, 29.7, 25.7,
18.1, 11.3 ppm; HRMS (EI) calcd for C29H36N4O6S: 568.2356, found
568.2352.
4.4.31. 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)
phenoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-((3-methylbut-2-
en-1-yl)oxy) benzamide (26a)
Yield 85% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.49 (s,
1H), 7.69 (d, J = 7.1 Hz, 2H), 7.17–6.98 (m, 3H), 6.77 (s, 1H), 6.59 (s,
1H), 5.47 (t, J = 6.1 Hz, 1H), 4.55 (d, J = 6.4 Hz, 2H), 4.37 (s, 2H), 3.66
(s, 3H), 3.38 (d, J = 10.8 Hz, 2H), 2.66 (d, J = 11.0 Hz, 2H), 2.28 (s,
3H), 2.13–1.87 (m, 4H), 1.80 (s, 3H), 1.74 (s, 3H); 13C NMR
(100 MHz, CDCl3) d = 163.6, 160.8, 160.4, 156.2, 145.6, 139.6,
139.0, 137.2, 129.8, 118.6, 117.8, 110.9, 110.3, 109.5, 97.4, 73.6,
65.3, 50.9, 35.4, 27.6, 25.7, 18.2, 11.3 ppm; HRMS (EI) calcd for
4.4.36. (S)-3-(4-((3-Fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-N-
(1-me thyl-1H-pyrazol-3-yl)-5-((3-methylbut-2-en-1-yl)oxy)
benzami-de (28b)
Yield 83% (white powder); H NMR (300 MHz, CDCl3) d = 8.76 (t,
J = 6.9 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.27 (s, 2H), 7.09 (d,
J = 8.9 Hz, 3H), 6.78 (d, J = 5.9 Hz, 2H), 5.46 (t, J = 6.6 Hz, 1H), 5.16
(d, J = 52.6 Hz, 1H), 4.54 (d, J = 6.7 Hz, 2H), 3.77 (s, 3H), 3.57 (d,
J = 3.9 Hz, 1H), 3.55–3.39 (m, 2H), 3.31 (td, J = 10.1, 6.6 Hz, 1H),
2.35–1.86 (m, 2H), 1.80 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz,
CDCl3) d = 163.7, 160.7, 160.5, 156.4, 146.9, 139.0, 136.9, 131.1,
130.9, 129.7, 118.6, 118.1, 110.7, 110.4, 109.4, 97.6, 93.0, 91.2,
65.3, 54.4, 54.1, 45.8, 38.5, 32.5, 32.3, 25.7, 18.1 ppm; HRMS (EI)
calcd for C26H29FN4O5S: 528.1843, found 528.1846.
C29H34N4O6S: 566.2199, found 566.2197.
4.4.32. 3-(4-(((2S,6R)-2,6-Dimethylmorpholino)sulfonyl) phen
oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-((3-methylbut-2-en-1-yl)
oxy) benzamide (26b)
Yield 84% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.57 (s,
1H), 7.71 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 4.2 Hz, 2H), 7.18–7.05 (m,

W. Mao et al. / Bioorg. Med. Chem. 20 (2012) 2982–2991
2991
18. Fyfe, M. C. T.; White, J.; Taylor, A.; Chatfield, R.; Wargent, E.; Printz, R. L.;
Sulpice, T.; McCormack, J. G.; Procter, M. J.; Reynet, C.; Widdowson, P. S.;
Wong-kai-in, P. Diabetologia 2007, 50, 1277.
19. Coghlan, M.; Leighton, B. Expert Opin. Investig Drugs 2008, 17, 145.
20. Grimsby, J.; Berthel, S. J.; Sarabu, R. Curr. Top. Med. Chem. 2008, 8, 1524.
21. Sarabu, R.; Berthel, S. J.; Kester, R. F. K.; Tilley, J. W. T. Expert Opin. Ther. Pat.
2008, 18, 759.
4.4.37. 3-(4-((4-Methoxypiperidin-1-yl)sulfonyl)phenoxy)-N-(1-
methyl-1H-pyrazol-3-yl)-5-((3-methylbut-2-en-1-yl)oxy)
benzamide (29b)
Yield 80% (white powder); 1H NMR (300 MHz, CDCl3) d = 8.61 (s,
1H), 7.72 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 2.8 Hz, 2H), 7.14 (s, 1H),
7.08 (d, J = 8.3 Hz, 2H), 6.78 (s, 2H), 5.46 (t, J = 6.4 Hz, 1H), 4.55
(d, J = 6.7 Hz, 2H), 3.79 (s, 3H), 3.34–3.29 (m, 1H), 3.27 (s, 3H),
3.26–3.15 (m, 2H), 2.96–2.90 (m, 2H), 1.99–1.85 (m, 2H), 1.80 (s,
2H), 1.78–1.68 (m, 5H); 13C NMR (100 MHz, CDCl3) d = 163.6,
160.6, 160.5, 156.4, 146.8, 139.1, 137.0, 131.1, 130.5, 129.8,
118.6, 117.9, 110.8, 110.4, 109.3, 97.5, 74.0, 65.3, 55.6, 43.1, 38.6,
29.7, 25.7, 18.2 ppm; HRMS (EI) calcd for C28H34N4O6S: 554.2199,
found 554.2197.
22. Pal, M. Curr. Med. Chem. 2009, 16, 3858.
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M.; Reynet, C.; Schofield, K. L.; Shah, V. K.; Spindler, F.; Taylor, A.; Turton, R.;
Williams, G. M.; Wong-Kai-In, P.; Yasuda, K. J. Med. Chem. 2008, 51, 4340.
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Grondine, M. S.; Gupta, R. C.; Kakmak, M.; Kavana, M.; Kirman, L. C.; Liang, J.;
Maniara, W. M.; Munshi, S.; Nadkarni, S. S.; Schuster, H. F.; Stams, T.; Denny, I.
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R. B.; Caulkett, P. W. R.; James, R.; Hayter, B.; Currie, G.; Hargreaves, R.;
Caulkett, P.; Hayter, R.; Currie, S.; Hargreaves, B.; Caulkett, W. World Patent
Application No. WO2003/000262.; (c) McKerrecher, D.; Allen, J. V.; Bowker, S.
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Acknowledgments
This work was supported by Grants from Chinese National Sci-
ence Foundation (81125021, 81072528), National Basic Research
Program of China (973 Program, 2009CB522300), National Science
& Technology Major Project on ‘Key New Drug Creation and Man-
ufacturing Program’, China (Numbers: 2012ZX09103-101-035).
Support of Shanghai postdoctoral research funding program (Num-
bers: 11R21417900) is also appreciated.
27. McKerrecher, D.; Allen, J. V.; Caulkett, P. W.; Donald, C. S.; Fenwick, M. L.;
Grange, E.; Johnson, K. M.; Johnstone, C.; Jones, C. D.; Pike, K. G.; Rayner, J. W.;
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