Discovery and biological evaluation of novel G protein-coupled receptor 119 agonists for type 2 diabetes

Article abstract of DOI:10.1002/ardp.201800267

G protein-coupled receptor 119 (GPR119) is a member of the GPCR family promising to be the target for type 2 diabetes mellitus (T2DM) treatment. In this work, 30 novel compounds were designed, synthesized, and evaluated by in vitro cAMP activation assay, where compounds II–14 and II–18 showed the best potency with EC₅₀ values of 69 and 99 nM, respectively. In the oral glucose tolerance test, compound II–18 showed even more efficacious activity in lowering blood excursions than MBX-2982 at a fixed dose of 30 mg/kg. Here, we report that compound II–18 with its excellent agonistic activity and its orally effective activity in decreasing blood glucose deviations may serve as a potent GPR119 agonist for the treatment of T2DM.

Full text of DOI:10.1002/ardp.201800267

Received: 7 September 2018
Revised: 2 January 2019
Accepted: 3 January 2019
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DOI: 10.1002/ardp.201800267
FULL PAPER
Discovery and biological evaluation of novel G protein-
coupled receptor 119 agonists for type 2 diabetes
Ying Zhou1
Youzhi Wang2
Leilei Zhang1
Chunlei Tang1
Bainian Feng1
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1 School of Pharmaceutical Science, Jiangnan
University, Wuxi, China
Abstract
2 Department of Medicinal Chemistry, School
of Pharmacy, China Pharmaceutical
University, Nanjing, China
G protein-coupled receptor 119 (GPR119) is a member of the GPCR family promising
to be the target for type 2 diabetes mellitus (T2DM) treatment. In this work, 30 novel
compounds were designed, synthesized, and evaluated by in vitro cAMP activation
assay, where compounds II–14 and II–18 showed the best potency with EC50 values of
69 and 99 nM, respectively. In the oral glucose tolerance test, compound II–18 showed
even more efficacious activity in lowering blood excursions than MBX-2982 at a fixed
dose of 30 mg/kg. Here, we report that compound II–18 with its excellent agonistic
activity and its orally effective activity in decreasing blood glucose deviations may
serve as a potent GPR119 agonist for the treatment of T2DM.
Correspondence
Chunlei Tang and Bainian Feng, School of
Pharmaceutical Science, Jiangnan University,
1800 Lihu Road, Wuxi, Jiangsu 214122,
China.
Email: tangcl@jiangnan.edu.cn (C.T.);
fengbainian@jiangnan.edu.cn (B.F.)
Funding information
National Natural Science Foundation of China,
Grant number: 21305051; National First-
Class Discipline Program of Food Science and
Technology, Grant number:
K E Y W O R D S
agonistic activity, biological evaluation, GPR119, synthesis, type 2 diabetes
JUFSTR20180101
many synthetic GPR119 agonists over the past several years.[11–13] For
example, AR231453 from Arena Pharmaceuticals and PSN632408
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1
INTRODUCTION
G protein-coupled receptor 119 (GPR119) is a member of the class A
(rhodopsin-type) GPCR family, which is highly expressed on only a
limited number of tissues, such as pancreatic β-cells and entero-
endocrine cells of the gastrointestinal tract in humans.[1–3] The
activation of GPR119 has the stimulatory effects of glucose-
dependent insulin secretion in pancreatic β-cells as well as intestinal
secretion of incretin hormones including glucose-dependent insulino-
tropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). Taken
from Prosidion Ltd. were two of the earlier potent and orally
efficacious GPR119 agonists with significant, published preclinical
data. However, owing to the loss of efficacy as well as indicate
tachyphylaxis, the positive results obtained in preclinical studies did
not appear in the phase II clinical trials, which brought uncertainty to
the clinical prospects of GPR119 agonists for the treatment of
T2DM.[14,15] With the expectation of discovering new drugs, a few
more novel GPR119 agonists with diverse chemical structures have
been reported to be under clinical trials (Figure 1).[16,17] Many of the
disclosed chemical structures share a common structural motif
including an aryl or heteroaryl group linked via a space group to a
piperidine moiety capped with a carbamate or heterocycle group. From
previous researches we knew that the conformational restriction of
the piperidine scaffold played an important role for bioactivity, as well
as the methylsulfonylphenyl fragment.[17,18] With the hope of
identifying a template with superior druggability, thus improving the
overall pharmacokinetic properties over existing series, we reported a
series of 2-(4-(methylsulfonyl)phenyl)pyridine derivatives as GPR119
agonists in our former studies. For further exploration, we kept the
together, these effects represented
a potential mechanism for
modulation of glucose homeostasis and an attractive approach to
the treatment of type 2 diabetes mellitus (T2DM).[4–8]
Several phospholipids and lipid amides such as lysophosphatidyl-
choline (LPC), oleoylethanolamide (OEA), and oleoyldopamine (OLDA)
have been identified as endogenous GPR119 agonists.[9,10] However,
these endogenous agonists showed low activity and poor selectivity at
GPR119 receptor in cellular assays, which led to the development of
Ying Zhou and Youzhi Wang contributed equally to this work.
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Arch Pharm Chem Life Sci. 2019;e1800267.
https://doi.org/10.1002/ardp.201800267
wileyonlinelibrary.com/journal/ardp
© 2019 Deutsche Pharmazeutische Gesellschaft
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compound I–1. In the presence of trifluoroacetic acid (TFA), compound
I–2 was achieved through the deprotection of Boc group. Following
the similar procedure, compounds II–2 and III–2 were prepared with
different starting material of 5-bromopyridin-2-alcohol (II-A) and 5-
bromopyrazin-2-alcohol (III-A), respectively. Preparation of the final
compounds I-3–I-6, II-3–II-18, III-3–III-6 was accomplished by
derivatization of the N-position of the piperidine ring with a set of
halogenated reagents (Scheme 1).
In order to evaluate the ability of our synthesized compounds in
activating GPR119, we carried out cAMP activation assays by
measuring stimulate increases in cAMP levels in CHO cells stably
expressing human GPR119. Along with the results from cAMP tests,
we also calculated ligand efficiency (LE) and ligand efficiency
dependent lipophilicity (LELP) of the synthesized compounds as
well, which are shown in Table 1. In our former studies, we found
that high lipophilicity might cause missing of target or toxic effects,
so our goal was aimed at maintaining or improving agonistic potency
while reducing lipophilicity, which was presented by lower LELP
scores. First, we explored the effects of different linkers among the
three series on the agonistic activity. With the same substituent in
the N-position of the piperidine ring, compounds III-1, III-3, and III-5
showed more activity with lower scores of LELP compared to
compounds II-1, II-13, and II-7, respectively, which indicated a
better agonistic potency and druggability with pyrazine linker than
benzene and pyridine linker. In the pyridine series, we studied the
substitutional effect in the N-positon. The carbamate substitutional
compounds were effective, while by removing it (compound II-12) or
replacing it with amide groups (compounds II-10, II-11), the agonistic
activities were lost, suggesting that the piperidine carbamate or
heterocycle region seemed to make pharmacologically very impor-
tant interaction with the receptor, which was also demonstrated by
our former study with 2-(4-(methylsulfonyl)phenyl)pyridine deriva-
tives. Gratifyingly, compounds substituted by pyrimidine ring
showed better agonistic activity than that by carbamate, and the
introduction of a substitute in the 5-position of pyrimidine brought
an improvement to the activity as well as LELP score compared with
none substitute. From the comparison of pyridine series with our
former study results, we found that in both series, the introduction
of pyrimidine ring increased activity while piperidine carbamate or
heterocycle region reduced or even eliminated activity, which
showed that the position-changing of N atom in the pyridine ring
had not as much contribution on agonistic activity changes as the
substituent of R. Here we found compounds II-14 and II-18
performed the best potency with EC50 value less than 100 nM
and ClogP lower than MBX-2982, leading to satisfying LELP score
that indicates impressive drugability.
FIGURE 1 Structures of selected GPR119 agonists under clinical
development
active pharmacophores of the common structural motif, and changed
the linker as well as the “tail group” with various moieties to produce
new benzene, pyridine, and pyrazine analogs (Figure 2). Herein, we
reported the synthesis, biological evaluation, and structure–activity
relationship of novel GPR119 agonists for the treatment of T2DM.
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RESULTS AND DISCUSSION
The synthesis of these series of compounds started from reacting 4-
bromophenol (I-A) with N-Boc-protected piperidine alcohol to provide
intermediate I-B over a Mitsunobu reaction (PPh3, DEAD, THF).
Following with
a Suzuki coupling reaction, intermediate I-B
was coupled with 4-(methylsulfonyl)phenylboronic acid to afford
In order to assess the relevance of the cAMP results in vivo, we
selected compounds II-14 and II-18 for profiling in a mouse (ICR) oral
glucose tolerance test (OGTT) at a fixed dose of 30 mg/kg. The results
are shown in Figure 3, where significant glucose-lowering effect was
observed. Compound II-18 with the best performance in cAMP assays
showed the most efficacious activity in lowering blood glucose, even
better than the positive control MBX-2982. Compound II-14 also had
FIGURE 2 Common structural motif shared by most GPR119
agonist and structure of novel GPR119 agonists in this study

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SCHEME 1 Synthesis of compounds I-1–I-6, II-1–II-18, III-1–III-6. Reagents and conditions: (a) PPh3, diethyl azodicarboxylate (DEAD),
anhydrous THF, N2, 0–25°C, 12 h; (b) K2CO3, Pd(PPh3)4, 1,4-dioxane/H2O, N2, 80°C, 6–8 h; (c) trifluoroacetic acid, DCM, reflux, 1 h; (d) R2-Cl,
Cs2CO3, acetone, 40–70°C, 12 h, (for I–3, II-13–II-16, III-3); (e) R2-Cl, NaOH, THF/H2O (v/v = 2:1), 0–25°C, 1.5 h, (for I-4–I-5, II-3–II-11, III-
4–IIII-5); (f) R2-Br, triethylamine, DCM, 25°C, 8 h, (for I-6, II-12, III-6); (g) R2-Cl, NaH, DMF, 100°C, 12 h, (for II-17–II-18)
glucose-lowering effect observed, comparing to the blank group, at the
same level with MBX-2982.
for the treatment of T2DM. Thirty novel compounds were successfully
synthesized and characterized by ESI-MS, 1H NMR and 13C NMR, and
also evaluated for their biological activity for GPR119 agonism. The
results from in vitro and in vivo tests led to the identification of
compound II-18, 5-chloro-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-
2-yl)oxy)piperidin-1-yl)pyrimidine, showing excellent agonistic activity
in in vitro cAMP assay with EC50 value of 99 nM and oral effectiveness
in lowering blood glucose level and improving glucose tolerance.
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CONCLUSION
In conclusion, we have developed three novel series of (4-(methyl-
sulfonyl)phenyl)aryl derivatives as small molecular GPR119 agonists
TABLE 1 In vitro GPR119 agonistic activities and lipophilic properties of synthesized compounds
a
a
Compd
I-1
EC50 (nM)
ClogPb
3.94
2.34
1.64
2.92
2.13
3.59
2.97
3.49
3.12
4.55
2.3
LEc (kcal/mol)
0.30
0.31
0.33
0.28
–
LELPd
12.94
7.55
4.97
12.04
–
Compd
II-12
II-13
II-14
II-15
II-16
II-17
II-18
III-1
EC50 (nM)
ClogPb
3.67
1.77
2.27
2.8
LEc (kcal/mol)
LELPd
–
320
280
130
510
NAe
930
960
350
630
270
2500
NAe
NAe
3.9
NAe
620
69
–
I-3
0.29
0.32
0.31
0.3
0.3
0.32
0.3
–
6.1
I-4
7.09
9.03
11.07
6.47
7.84
9.2
II-1
100
100
290
99
II-3
3.32
1.94
2.51
2.76
0.83
1.16
0.46
2.51
3.06
II-4
0.27
0.28
0.29
0.27
0.27
0.25
–
13.3
10.61
12.03
11.56
16.85
9.2
II-5
II-6
200
NAe
430
NAe
290
1400
II-7
III-2
–
II-8
III-3
0.3
–
3.87
–
II-9
III-4
II-10
II-11
MBX-2982
0.48
1.72
3.13
–
III-5
0.28
0.27
8.96
11.33
–
–
III-6
0.36
8.69
aConcentration for 50% cAMP stimulation of GSK 1292263 at 1 µM.
bClogP was calculated by ChemBioDraw.
cLE = 1.36pEC50/Nheavy atoms
dLELP = ClogP/LE.
eNA = not active.
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FIGURE 3 Effects of selected compounds and MBX-2982 (30 mg/kg) on glucose excursion in an OGTT in male ICR mice. (a) Blood glucose
levels at various times relative to glucose injection; (b) percentage reduction in blood glucose AUC. *p < 0.05, significantly different from
vehicle-treated mice
Additional study of pharmacokinetic properties of these compounds
will be necessary to determine if they can represent a new type of
GPR119 agonists for the orally effective treatment of T2DM or other
disorders. We are currently producing further modification of these
new agonist scaffolds that will be examined soon. The follow-up
studies will be reported as results become available.
starting material. After completion of the reaction, the solvent was
removed by two thirds under diminished pressure along with a solid
precipitation. The mixture was filtered and washed with THF (30 mL,
two times). The filtrate was concentrated under diminished pressure
and the residue was purified by column chromatography (petroleum
ether/EtOAc = 15:1) to give white solid intermediate IB (27.8 g,
67.3%). 1H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 9.2 Hz 2H, −ArH),
6.78 (dd, J = 8.8 Hz, 2H, −ArH), 4.38–4.44 (m, 1H, −CH), 3.64–3.71 (m,
2H, −CH2), 3.30–3.36 (m, 2H, −CH2), 1.86–1.92 (m, 2H, −CH2), 1.68–
1.76 (m, 2H, −CH2), 1.47 (s, 9H, OC(CH3)3).
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4
EXPERIMENTAL
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4.1 Chemistry
Intermediates II-B, III-B were prepared in a manner similar to that
described for intermediate I-B.
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4.1.1 General
All chemicals were reagent grade and used as purchased. All reactions
were performed using distilled dry solvent. Column chromatography
(CC) was carried out using silica gel 60 100–200 mesh. Thin layer
chromatography (TLC) was performed on silica gel 60 F254 plates
(250 mm; Qingdao Ocean Chemical Company, China). 1H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded on a Bruker AVIII
400 MHz/100 MHz spectrometer. The chemical shifts were given in
parts per million (ppm) using the 7.26 signal of CDCl3 (1H NMR) and the
tert-Butyl 4-((5-bromopyridin-2-yl)oxy)piperidine-1-carboxylate
(intermediate II-B)
Yield 58%. 1H NMR (400 MHz, CDCl3) δ: 8.16 (dd, J1 = 2.8 Hz,
J2 = 0.8 Hz, 1H, −ArH), 7.63 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H, −ArH),
6.63 (dd, J1 = 8.4 Hz, J2 =0.4 Hz, 1H, −ArH), 5.12–5.18 (m, 1H, −CH),
3.73–3.76 (m, 2H, −CH2), 3.24–3.31 (m, 2H, −CH2), 1.93–1.98 (m, 2H,
−CH2), 1.65–1.74 (m, 2H, −CH2), 1.47 (s, 9H, OC(CH3)3).
77.0 signal of CDCl3
(
13C NMR) as internal standards. MS data were
tert-Butyl 4-((5-bromopyrazin-2-yl)oxy)piperidine-1-carboxylate
(intermediate III-B)
Yield 61%. 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 1.6 Hz, 1H, −ArH),
7.99 (d, J = 1.2 Hz, 1H, −ArH), 5.10–5.17 (m, 1H, −CH), 3.74–3.78 (m,
2H, −CH2), 3.25–3.32 (m, 2H, −CH2), 1.94–1.99 (m, 2H, −CH2), 1.68–
1.77 (m, 2H, −CH2), 1.47 (s, 9H, −C(CH3)3).
obtained by Waters Micromass Platform LCZ mass spectrometer
utilizing electrospray ionization (ESI). Elemental analyses were
obtained using elementar vario MICRO cube.
The InChI codes of the investigated compounds together with
some biological activity data are provided as Supporting Information.
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4.1.2 Synthesis of tert-butyl 4-(4-bromophenoxy)-
4.1.3 Synthesis of tert-butyl 4-((4ʹ-(methylsulfonyl)-
piperidine-1-carboxylate (intermediate I-B)
[1,1ʹ-biphenyl]-4-yl)oxy)piperidine-1-carboxylate
(compound I–1)
A solution of diazenedicarboxylic acid (DEAD) (30.3 g, 174 mmol)
diluted by tetrahydrofuran (THF) (40 mL) was added dropwise into a
solution containing 4-bromophenol (20.0 g, 116 mmol), tert-butyl 4-
hydroxypiperidine-1-carboxylate (23.3 g, 116 mmol), triphenylphos-
phine (PPh3) (45.6 g, 174 mmol) and THF (40 mL) under the protection
of nitrogen at 0°C and then the reaction was stirred overnight at room
temperature. TLC monitoring showed complete consumption of
A mixture of (4-(methylsulfonyl)phenyl)boronic acid (6.7 g, 33.7 mmol),
compound I-B (10 g, 28.1 mmol), Pd(PPh3)4 (3.3 g, 2.81 mmol), K2CO3
(9.7 g, 70.3 mmol), 1,4-dioxane (80 mL) and water (35 mL) was reacted
by stirring at 80°C for 8 h. TLC monitoring showed complete
consumption of starting material. After completion of the reaction,
1,4-dioxane was removed under diminished pressure, the residue was

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extracted twice with a mixture of ethyl acetate (400 mL) and water
(150 mL). The organic phases were collected and washed, respectively,
with saturated sodium carbonate solution (150 mL, two times) and
saturated sodium chloride solution (100 mL, two times). The organic
phase was dried over anhydrous sodium sulfate, filtered, evaporated,
and purified by column chromatography (petroleum ether/
EtOAc = 20:1) to give white powder compound I-1 (6.1 g, 51%).
1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J = 8.4 Hz, 2H, −ArH), 7.72 (d,
J = 8.4 Hz, 2H, −ArH), 7.55 (d, J = 8.8 Hz, 2H, −ArH), 7.01 (d, J = 8.8 Hz,
2H, −ArH), 4.52–4.58 (m, 1H, −CH), 3.69 –3.75 (m, 2H, −CH2), 3.34–
3.41 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 1.93–1.98 (m, 2H, −CH2),
1.75–1.83 (m, 2H, −CH2), 1.48 (s, 9H, −OC(CH3)3); 13C NMR (100 MHz,
CDCl3) δ: 157.9, 154.8, 146.2, 138.5, 131.7, 128.6, 127.9, 127.4,
116.5, 79.7, 72.3, 44.7, 30.5, 28.5; MS (ESI): m/z calcd. for
cooled to room temperature and removed the solvent under
diminished pressure. The residue was dissolved in water (30 mL),
basified with aqua ammonia (3 mL) to pH 9–10, filtered, and washed
with water (30 mL) twice to afford white solid compound I-2 (2.85 g,
93%). 1H NMR (400 MHz, CDCl3) δ: 7.96–7.98 (m, 2H, −ArH),
7.89–7.92 (m, 2H, −ArH), 7.71–7.74 (m, 2H, −ArH), 7.13–7.17 (m,
2H, −ArH), 4.73–4.78 (m, 1H, −CH), 3.54 (br, 2H, −CH2), 3.25 (s, 3H,
−SO2CH3), 3.12 (br, 2H, −CH2), 2.09–2.16 (m, 2H, −CH2), 1.80–1.89
(m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 157.6, 145.1, 139.4,
131.6, 129.0, 128.1, 127.4, 116.8, 69.5, 44.1, 41.1, 27.7; MS (ESI): m/z
calcd. for C18H22NO3S, [M+H]+ 332.1, found 332.3 [M+H]+. Anal.
calcd. C, 65.23; H, 6.39; N, 4.23; S, 9.67, found: C, 65.17; H, 6.38; N,
4.25; S, 9.70.
Compounds II-2, III-2 were prepared in a manner similar to that
described for compound I-2.
C
23H30NO5S, [M+H]+ 432.7, found 433.7 [M+H]+. Anal. calcd. C,
64.01; H, 6.77; N, 3.25; S, 7.43, found: C, 64.15; H, 6.75; N, 3.26; S,
7.42.
5-(4-(Methylsulfonyl)phenyl)-2-(piperidin-4-yloxy)pyridine
(compound II-2)
Compounds II-1, III-1 were prepared in a manner similar to that
described for compound I-1.
Yield 92%. 1H NMR (400 MHz, CDCl3) δ: 8.40 (dd, J1 = 2.8 Hz,
J2 = 0.8 Hz, 1H, −ArH), 8.02 (d, J = 8.4 Hz, 2H, −ArH), 7.81 (dd,
J1 = 8.4 Hz, J2 = 2.8 Hz, 1H, −ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH), 6.83
(dd, J1 = 8.8 Hz, J2 = 0.8 Hz, 1H, −ArH), 5.18–5.24 (m, 1H, −CH), 3.14–
3.20 (m, 2H, −CH2), 3.10 (s, 3H, −SO2CH3), 2.79–2.86 (m, 2H, −CH2),
2.08–2.12 (m, 2H, −CH2), 1.80 (br, 2H, −CH2); 13C NMR (100 MHz,
CDCl3) δ: 162.8, 145.8, 142.4, 140.0, 138.8, 128.4, 128.2, 127.6,
112.0, 68.0, 44.0, 41.3, 27.9; MS (ESI): m/z calcd. for C17H21N2O3S, [M
+H]+ 333.1, found 333.6 [M+H]+. Anal. calcd. C, 61.42; H, 6.06; N,
8.43; S, 9.65, found: C, 61.56; H, 6.08; N, 8.41; S, 9.62.
tert-Butyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-1)
Yield 50%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 2.4 Hz, 1H, −ArH),
8.01 (d, J = 8 Hz, 2H, −ArH), 7.82 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H,
−ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH), 6.83 (d, J = 8.4 Hz, 1H, −ArH),
5.27–5.31 (m, 1H, −CH), 3.77–3.82 (m, 2H, −CH2), 3.28–3.35 (m, 2H,
−CH2), 3.09 (s, 3H, −SO2CH3), 1.98–2.04 (m, 2H, −CH2), 1.72–1.80 (m,
2H, −CH2), 1.48 (s, 9H, OC(CH3)3); 13C NMR (100 MHz, CDCl3) δ:
163.4, 154.9, 145.5, 143.5, 139.2, 137.6, 128.2, 128.0, 127.3, 112.0,
79.6, 70.8, 44.6, 30.8, 28.5; MS (ESI): m/z calcd. for C22H29N2O5S,
[M+H]+ 433.1, found 433.5 [M+H]+. Anal. calcd. C, 61.09; H, 6.52; N,
6.48; S, 7.41, found: C, 60.96; H, 6.53; N, 6.47; S, 7.38.
2-(4-(Methylsulfonyl)phenyl)-5-(piperidin-4-yloxy)pyrazine
(compound III-2)
Yield 90%. 1H NMR (400 MHz, CDCl3) δ: 8.94 (d, J = 1.6 Hz, 1H, −ArH),
8.86 (s, 1H, −NH), 8.47 (d, J = 1.6 Hz, 1H, −ArH), 8.31–8.32 (m, 1H,
−ArH), 8.29–8.30 (m, 1H, −ArH), 8.05–8.06 (m, 1H, −ArH), 8.03–8.04
(m, 1H, −ArH), 5.31–5.36 (m, 1H, −CH), 3.32–3.38 (m, 2H, −CH2), 3.28
(s, 3H, −SO2CH3), 3.15–3.21 (m, 2H, −CH2), 2.16–2.23 (m, 2H, −CH2),
1.92–2.00 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 158.9, 143.1,
141.1, 141.1, 139.1, 135.8, 128.1, 127.0, 68.9, 44.0, 41.1, 27.7; MS
(ESI): m/z calcd. for C16H20N3O3S, [M+H]+ 334.1, found 334.4 [M+H]+.
Anal. calcd. C, 57.64; H, 5.74; N, 12.60; S, 9.62, found: C, 57.78; H,
5.76; N, 12.59; S, 9.63.
tert-Butyl 4-((5-(4-(methylsulfonyl)phenyl)pyrazin-2-yl)oxy)-
piperidine-1-carboxylate (compound III-1)
Yield 47%. 1H NMR (400 MHz, CDCl3) δ: 8.56 (d, J = 1.2 Hz, 1H, −ArH),
8.30 (d, J = 1.6 Hz, 1H, −ArH), 8.14–8.15 (m, 1H, −ArH), 8.12–8.12 (m,
1H, −ArH), 8.05–8.06 (m, 1H, −ArH), 8.02–8.03 (m, 1H, −ArH), 5.24–
5.30 (m, 1H, −CH), 3.81 (br, 2H, −CH2), 3.29–3.36 (m, 2H, −CH2), 3.1 (s,
3H, −SO2CH3), 2.03 (br, 2H, −CH2), 1.75–1.83 (m, 2H, −CH2), 1.49 (s,
9H, −C(CH3)3); 13C NMR (100 MHz, CDCl3) δ: 159.2, 154.8, 142.9,
141.7, 140.2, 138.1, 135.8, 128.0, 126.8, 79.7, 71.8, 44.6, 30.5, 28.5;
MS (ESI): m/z calcd. for C21H28N3O5S, [M+H]+ 434.1, found 434.7
[M+H]+. Anal. calcd. C, 58.18; H, 6.28; N, 9.69; S, 7.40, found: C, 58.09;
H, 6.30; N, 9.72; S, 7.43.
|
4.1.5 Synthesis of 2-(4-((4ʹ-(methylsulfonyl)-[1,1ʹ-
biphenyl]-4-yl)oxy)piperidin-1-yl)pyrimidine
(compound I-3)
A mixture of compound I-2 (0.1 g, 0.3 mmol), 2-chloropyrimidine
(41 mg, 0.36 mmol), caesium carbonate (0.2 g, 0.6 mmol), and acetone
(15 mL) was stirred at 50°C overnight. TLC monitoring showed
complete consumption of starting material. After completion of the
reaction, cooled to room temperature and removed acetone under
diminished pressure. The residue was purified by column chromatog-
raphy (petroleum ether/EtOAc = 10:1) to give white solid compound I-
|
4.1.4 Synthesis of 4-((4ʹ-(methylsulfonyl)-[1,1ʹ-
biphenyl]-4-yl)oxy)piperidine (compound I-2)
Trifluoroacetic acid (5 mL) was added to a solution of compound I-1
(4 g, 9.28 mmol) and dichloromethane (20 mL). The reaction mixture
was stirred and refluxed for 30 min. TLC monitoring showed complete
consumption of starting material. After completion of the reaction,

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3 (51 mg, 41%). 1H NMR (400 MHz, CDCl3) δ: 8.32 (d, J = 4.8 Hz, 2H,
−ArH), 7.97–8.00 (m, 2H, −ArH), 7.72–7.54 (m, 2H, −ArH), 7.55–7.59
(m, 2H, −ArH), 7.04–7.07 (m, 2H, −ArH), 6.49 (t, J = 4.8 Hz, 1H, −ArH),
4.62–4.68 (m, 1H, −CH), 4.16–4.22 (m, 2H, −CH2), 3.71–3.78 (m, 2H,
−CH2), 3.09 (s, 3H, −SO2CH3), 2.03–2.10 (m, 2H, −CH2), 1.83–1.91 (m,
2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 161.6, 158.1, 157.8, 146.2,
138.5, 131.7, 128.7, 127.9, 127.4, 116.6, 109.7, 72.9, 44.7, 40.8, 30.5;
MS (ESI): m/z calcd. for C22H24N3O3S, [M+H]+ 410.1, found 410.4
[M+H]+. Anal. calcd. C, 64.53; H, 5.66; N, 10.26; S, 7.83, found: C,
64.72; H, 5.64; N, 10.27; S, 7.84.
62.99; H, 5.98; N, 12.78; S, 7.31, found: C, 63.14; H, 5.96; N, 12.82; S,
7.33.
2-(4-((5-(4-(Methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidin-1-
yl)-5-propylpyrimidine (compound II-16)
Yield 32%. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.4 Hz, 1H, −ArH),
8.17 (s, 2H, −ArH), 8.01 (d, J = 8.4 Hz, 2H, −ArH), 7.82 (dd, J1 = 8.4 Hz,
J2 = 2.4 Hz, 1H, −ArH), 7.72 (d, J = 8.4 Hz, 2H, −ArH), 6.84 (d, J = 8.8 Hz,
1H, −ArH), 5.36–5.40 (m, 1H, −CH), 4.25–4.31 (m, 2H, −CH2), 3.58–
3.64 (m, 2H, −CH2), 3.10 (s, 3H, −SO2CH3), 2.41 (t, J = 7.6 Hz, 2H,
−CH2CH2CH3), 2.10–2.16 (m, 2H, −CH2), 1.82–1.87 (m, 2H, −CH2),
1.57 (q, J = 7.6 Hz, 2H, −CH2CH2CH3), 0.94 (t, J = 7.2 Hz, 3H,
−CH2CH2CH3); 13C NMR (100 MHz, CDCl3) δ: 160.5, 157.6, 153.7,
147.7, 144.2, 139.7, 139.4, 127.8, 127.1, 123.2, 123.1, 121.6, 73.8,
44.6, 41.0, 31.5, 30.3, 24.4, 13.5; MS (ESI): m/z calcd. for
Compounds II-13–16, III-3 were prepared in a manner similar to
that described for compound I-3.
2-(4-((5-(4-(Methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidin-1-
yl)pyrimidine (compound II-13)
Yield 50%. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.4 Hz, 1H, −ArH),
8.32 (d, J = 4.8 Hz, 2H, −ArH), 8.02 (d, J = 8.4 Hz, 2H, −ArH), 7.83 (dd,
J1 = 8.4 Hz, J2 = 2.8 Hz, 1H, −ArH), 7.72 (dd, J1 = 6.4 Hz, J2 = 2 Hz, 2H,
−ArH), 6.84–6.87 (d, J = 8.8 Hz, 1H, −ArH), 6.47–6.49 (t, J = 4.8 Hz, 1H,
−ArH), 5.38–5.42 (m, 1H, −CH), 4.27–4.33 (m, 2H, −CH2), 3.63–3.69
(m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.09–2.15 (m, 2H, −CH2), 1.80–
1.88 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 163.5, 161.7, 157.8,
145.5, 143.5, 139.2, 137.6, 128.2, 128.0, 127.3, 112.0, 109.6, 71.3,
44.6, 41.2, 30.7; MS (ESI): m/z calcd. for C21H22N4O3S, [M+H]+ 410.1,
found 411.8 [M+H]+. Anal. calcd. C, 61.44; H, 5.40; N, 13.65; S, 7.81,
found: C, 61.41; H, 5.42; N, 13.59; S, 7.83.
C
24H29N4O3S, [M+H]+ 453.1, found 453.9 [M+H]+. Anal. calcd. C,
63.69; H, 6.24; N, 12.38; S, 7.09, found: C, 63.74; H, 6.26; N, 12.42; S,
7.11.
2-(4-((5-(4-(Methylsulfonyl)phenyl)pyrazin-2-yl)oxy)piperidin-1-
yl)pyrimidine (compound III-3)
Yield 45%. 1H NMR (400 MHz, CDCl3) δ: 8.58 (d, J = 1.2 Hz, 1H,
−ArH), 8.34 (s, 1H, −ArH), 8.32 (s, 1H, −ArH), 8.31 (d, J = 1.6 Hz, 1H,
−ArH), 8.14–8.15 (m, 1H, −ArH), 8.12–8.13 (m, 1H, −ArH), 8.05–
8.06 (m, 1H, −ArH), 8.03–8.04 (m, 1H, −ArH), 6.50 (t, J = 4.4 Hz, 1H,
−ArH), 5.35–5.41 (m, 1H, −CH), 4.29–4.35 (m, 2H, −CH2), 3.63–3.70
(m, 2H, −CH2), 3.10 (s, 3H, −SO2CH3), 2.10–2.17 (m, 2H, −CH2),
1.82–1.91 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 161.6,
159.3, 157.8, 142.8, 141.8, 140.2, 138.2, 135.9, 128.0, 126.8, 109.8,
72.4, 58.5, 44.6, 41.1, 30.5, 18.4; MS (ESI): m/z calcd. for
5-Methyl-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidin-1-yl)pyrimidine (compound II-14)
Yield (42%). 1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 2.8 Hz, 1H,
−ArH), 8.15 (t, J = 7.6 Hz, 4H, −ArH), 8.02 (d, J = 8.4 Hz, 2H, −ArH), 7.74
(d, J = 8.8 Hz, 1H, −ArH), 7.34(dd, J1 = 8.4 Hz, J2 = 2.8 Hz, 1H, −ArH),
4.65–4.69 (m, 1H, −CH), 4.16–4.22 (m, 2H, −CH2), 3.64–3.73 (m, 2H,
−CH2), 3.09 (s, 3H, −SO2CH3), 2.14 (s, 3H, −ArCH3), 2.05–2.11 (m, 2H,
−CH2), 1.83–1.90 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 160.6,
157.8, 153.7, 147.7, 144.2, 139.7, 139.5, 127.8, 127.1, 123.2, 121.6,
118.3, 73.9, 44.6, 41.0, 30.3, 14.6; MS (ESI): m/z calcd. for
C
20H22N5O3S, [M+H]+ 412.1, found 412.3 [M+H]+. Anal. calcd. C,
58.38; H, 5.14; N, 17.02; S, 7.79, found: C, 58.25; H, 5.16; N, 17.06;
S, 7.82.
|
4.1.6 Synthesis of cyclopropyl(4-((4ʹ(methylsulfonyl)-
[1,1ʹ-biphenyl]-4-yl)oxy)piperidin-1-yl)methanone
(compound I-4)
C
22H25N4O3S, [M+H]+ 425.1, found 425.5 [M+H]+. Anal. calcd. C,
62.24; H, 5.70; N, 13.20; S, 7.55, found: C, 62.07; H, 5.66; N, 13.21; S,
7.54.
Cyclopropanecarbonyl chloride (30.0 mg, 0.29 mmol) was added
dropwise slowly into
a solution of compound I-2 (80 mg,
0.24 mmol), NaOH (19 mg, 0.48 mmol), THF (8 mL), and water (4 mL)
at 0°C. The mixture was then reacted at room temperature for 1.5 h.
TLC monitoring showed complete consumption of starting material.
THF was removed under diminished pressure, and then the residue
was extracted twice with a mixture of ethyl acetate (50 mL) and water
(25 mL). The organic phases were collected, washed twice with
saturated sodium chloride solution (100 mL), dried over anhydrous
sodium sulfate, evaporated under diminished pressure to give white
solid compound I–4 (41 mg, 43%). 1H NMR (400 MHz, CDCl3) δ: 7.99–
8.00 (m, 1H, −ArH), 7.97–7.98 (m, 1H, −ArH), 7.74–7.75 (m, 1H, −ArH),
7.72–7.73 (m, 1H, −ArH), 7.57–7.58 (m, 1H, −ArH), 7.55–7.56 (m, 1H,
−ArH), 7.04–7.05 (m, 1H, −ArH), 7.02–7.03 (m, 1H, −ArH), 4.62–4.67
(m, 1H, −CH), 3.82–3.93 (m, 2H, −CH2), 3.65–3.71 (m, 2H, −CH2), 3.09
5-Ethyl-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidin-1-yl)pyrimidine (compound II-15)
Yield 45%. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.4 Hz, 1H, −ArH),
8.19 (s, 2H, −ArH), 8.01 (d, J = 8.4 Hz, 2H, −ArH), 7.82 (dd, J1 = 8.4 Hz,
J2 = 2.4 Hz, 1H, −ArH), 7.72 (d, J = 8.4 Hz, 2H, −ArH), 6.84 (d, J = 8.8 Hz,
1H, −ArH), 5.36–5.40 (m, 1H, −CH), 4.26–4.32 (m, 2H, −CH2), 3.58–
3.64 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.48 (q, J = 7.6 Hz, 2H,
−CH2CH3), 2.09–2.11 (m, 2H, −CH2), 1.81–1.88 (m, 2H, −CH2), 1.20 (t,
J = 7.6 Hz, 3H, −CH2CH3); 13C NMR (100 MHz, CDCl3) δ: 163.5, 160.8,
157.2, 145.5, 143.5, 139.2, 137.6, 128.2, 127.9, 127.3, 127.3, 124.3,
112.0, 71.5, 44.6, 41.5, 30.7, 22.7, 15.6; MS (ESI): m/z calcd. for
C
23H27N4O3S, [M+H]+ 439.1, found 439.5 [M+H]+. Anal. calcd. C,

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(s, 3H, −SO2CH3), 1.85–2.02 (m, 4H, −CH2), 1.76–1.82 (m, 1H, −CH),
0.98–1.02 (m, 2H, −CH2), 0.76–0.80 (m, 2H, −CH2); 13C NMR
(100 MHz, CDCl3) δ: 171.9, 157.8, 146.1, 138.6, 131.9, 128.7,
127.9, 127.4, 116.5, 72.0, 44.7, 11.0, 7.3; MS (ESI): m/z calcd. for
Isopropyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-5)
Yield 54%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (dd, J1 = 0.8 Hz,
J2 = 2.4 Hz, 1H, −ArH), 8.01 (d, J = 8.4 Hz, 2H, −ArH), 7.82 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH), 6.84
(d, J1 = 0.8 Hz, J2 = 8.8 Hz, 1H, −ArH), 5.27–5.33 (m, 1H, −CH),
4.91–4.97 (m, 1H, −CH(CH3)2), 3.81 (br, 2H, −CH2), 3.33–3.39 (m,
2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.01–2.04 (m, 2H, −CH2), 1.76–1.79
(m, 2H, −CH2), 1.26 (d, J = 6.4 Hz, 6H, −CH(CH3)2); 13C NMR (100 MHz,
CDCl3) δ: 163.3, 155.3, 145.5, 143.5, 139.2, 137.6, 128.2, 128.0,
127.3, 112.0, 70.6, 68.6, 44.6, 41.1, 30.7, 22.3; MS (ESI): m/z calcd. for
C
22H26NO4S, [M+H]+ 400.1, found 400.4 [M+H]+. Anal. calcd. C,
66.14; H, 6.31; N, 3.51; S, 8.03, found: C, 66.01; H, 6.33; N, 3.53; S,
8.05.
Compounds I-5, II-3–11, III-4–5 were prepared in a manner similar
to that described for compound I-4.
Phenyl 4-((4ʹ-(methylsulfonyl)-[1,1ʹ-biphenyl]-4-yl)oxy)-
piperidine-1-carboxylate (compound I-5)
C
21H27N2O5S, [M+H]+ 419.1, found 419.7 [M+H]+. Anal. calcd. C,
Yield 44%. 1H NMR (400 MHz, CDCl3) δ: 7.99–8.00 (m, 1H, −ArH),
7.97–7.98 (m, 1H, −ArH), 7.74–7.75 (m, 1H, −ArH), 7.72–7.73 (m,
1H, −ArH), 7.58–7.59 (m, 1H, −ArH), 7.56–7.57 (m, 1H, −ArH),
7.35–7.40 (m, 2H, −ArH), 7.19–7.23 (m, 1H, −ArH), 7.11–7.14 (m,
2H, −ArH), 7.03–7.07 (m, 2H, −ArH), 4.63–4.68 (m, 1H, −CH),
3.63–3.90 (m, 4H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.05 (br, 2H,
−CH2), 1.95 (br, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 157.8,
153.8, 151.4, 146.1, 146.1, 138.6, 132.0, 129.3, 129.3, 128.7,
127.9, 127.4, 125.3, 121.7, 116.6, 71.7, 44.7; MS (ESI): m/z calcd.
for C25H26NO5S, [M+H]+ 452.1, found 452.9 [M+H]+. Anal. calcd.
C, 66.50; H, 5.58; N, 3.10; S, 7.10, found: C, 66.72; H, 5.55; N, 3.11;
S, 7.11.
60.27; H, 6.26; N, 6.69; S, 7.66, found: C, 60.42; H, 6.25; N, 6.70; S,
7.67.
sec-Butyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-6)
Yield 67%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (dd, J1 = 2.4 Hz,
J2 = 0.8 Hz, 1H, −ArH), 8.01 (d, J = 8 Hz, 2H, −ArH), 7.82 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH),
6.84 (d, J1 = 8.8 Hz, J2 = 0.8 Hz, 1H, −ArH), 5.28–5.33 (m, 1H, −CH),
4.73–4.81 (m, 1H, −CH(CH3)CH2CH3), 3.81–3.86 (m, 2H, −CH2), 3.33–
3.40 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.02 (br, 2H, −CH2), 1.77–
1.81 (m, 2H, −CH2), 1.50–1.68 (m, 2H, −CH(CH3)CH2CH3), 1.23 (d,
J = 6.0 Hz, 3H, −CH(CH3)CH2CH3), 0.92 (t, J = 7.6 Hz, 3H, −CH(CH3)
CH2CH3); 13C NMR (100 MHz, CDCl3) δ: 163.3, 155.4, 145.4, 143.5,
139.2, 137.6, 128.2, 128.0, 127.3, 112.0, 73.2, 70.6, 44.6, 41.1, 30.7,
29.1, 19.9, 9.7; MS (ESI): m/z calcd. for C22H29N2O5S, [M+H]+ 433.1,
found 433.8 [M+H]+. Anal. calcd. C, 61.09; H, 6.52; N, 6.48; S, 7.41,
found: C, 61.02; H, 6.54; N, 6.49; S, 7.43.
Methyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-3)
Yield 60%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 2.4 Hz, 1H,
−ArH), 8.01 (d, J = 8 Hz, 2H, −ArH), 7.82 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H, −ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH), 6.84 (d, J = 8.4 Hz, 1H,
−ArH), 5.28–5.33 (m, 1H, −CH), 3.82 (br, 2H, −CH2), 3.72 (s, 3H,
−COOCH3), 3.36–3.43 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.02–
2.04 (m, 2H, −CH2), 1.78–1.80 (m, 2H, −CH2); 13C NMR (100 MHz,
CDCl3) δ: 163.3, 156.0, 145.4, 143.4, 139.2, 137.6, 128.2, 128.1,
127.3, 112.0, 70.4, 52.6, 44.6, 41.2, 30.7; MS (ESI): m/z calcd. for
Phenyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-7)
Yield 49%. 1H NMR (400 MHz, CDCl3) δ: 8.40 (dd, J1 = 2.8 Hz,
J2 = 0.8 Hz, 1H, −ArH), 8.02 (d, J = 8 Hz, 2H, −ArH), 7.84 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.72 (d, J = 8.4 Hz, 2H, −ArH),
7.34–7.40 (m, 2H, −ArH), 7.19–7.22 (m, 1H, −ArH), 7.11–7.14 (m, 2H,
−ArH), 6.87 (dd, J1 = 8.8 Hz, J2 = 0.8 Hz, 1H, −ArH), 5.35–5.41 (m, 1H,
−CH), 3.95 (d, J = 34 Hz, 2H, −CH2), 3.58 (d, J = 39.2 Hz, 2H, −CH2),
3.09 (s, 3H, −SO2CH3), 2.11 (br, 2H, −CH2), 1.90–1.93 (m, 2H, −CH2);
13C NMR (100 MHz, CDCl3) δ: 163.2, 153.8, 151.4, 145.5, 143.4,
139.3, 137.7, 129.3, 128.2, 127.4, 125.3, 121.7, 112.0, 100.0, 70.1,
44.6; MS (ESI): m/z calcd. for C24H25N2O5S, [M+H]+ 453.1, found
453.1 [M+H]+. Anal. calcd. C, 63.70; H, 5.35; N, 6.19; S, 7.09, found: C,
63.79; H, 5.37; N, 6.17; S, 7.10.
C
19H23N2O5S, [M+H]+ 391.1, found 391.6 [M+H]+. Anal. calcd. C,
58.45; H, 5.68; N, 7.17; S, 8.21, found: C, 58.57; H, 5.70; N, 7.14; S,
8.23.
Isobutyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-4)
Yield 54%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 2.4 Hz, 1H, −ArH),
8.01 (d, J = 8 Hz, 2H, −ArH), 7.82 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H,
−ArH), 7.71 (d, J = 8.4 Hz, 2H, −ArH), 6.84 (d, J = 8.4 Hz, 1H, −ArH),
5.28–5.33 (m, 1H, −CH), 3.88 (d, J = 6.0 Hz, 2H, −CH2CH(CH3)2), 3.82–
3.85 (m, 2H, −CH2), 3.36–3.43 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3),
2.01–2.04 (m, 2H, −CH2), 1.92–1.99 (m, 1H, −CH2CH(CH3)2), 1.75–
1.83 (m, 2H, −CH2), 0.95 (d, J = 6.4 Hz, 6H, −CH2CH(CH3)2); 13C NMR
(100 MHz, CDCl3) δ: 163.3, 155.7, 145.5, 143.5, 139.2, 137.6, 128.2,
128.1, 127.3, 112.0, 71.6, 70.5, 44.6, 41.2, 30.7, 29.7, 28.1, 19.1; MS
(ESI): m/z calcd. for C22H29N2O5S, [M+H]+ 433.1, found 433.5 [M+H]+.
Anal. calcd. C, 61.09; H, 6.52; N, 6.48; S, 7.41, found: C, 60.89; H, 6.55;
N, 6.47; S, 7.39.
Benzyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidine-1-carboxylate (compound II-8)
Yield 43%. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.8 Hz, 1H, −ArH),
8.13 (d, J = 8.4 Hz, 2H, −ArH), 8.00 (dd, J = 8.4 Hz, 2H, −ArH), 7.73 (d,
J = 8.8 Hz, 2H, −ArH), 7.30–7.38 (m, 6H, −ArH), 5.15 (s, 2H, −OCH2Ph),
4.59–4.64 (m, 1H, −CH), 3.74–3.81 (m, 2H, −CH2), 3.48–3.54 (m, 2H,
−CH2), 3.09 (s, 3H, −SO2CH3), 1.99 (br, 2H, −CH2), 1.85 (br, 2H, −CH2);

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13C NMR (100 MHz, CDCl3) δ: 155.3, 153.4, 147.9, 144.1, 139.8,
139.4, 136.7, 128.5, 128.1, 127.9, 127.9, 127.8, 127.1, 127.1, 123.2,
123.0, 121.6, 72.7, 67.3, 44.6, 40.6, 30.3, 30.2; MS (ESI): m/z calcd. for
5.33–5.39 (m, 1H, −CH), 3.98–4.04 (m, 2H, −CH2), 3.53–3.64 (m, 2H,
−CH2), 3.10 (s, 3H, −SO2CH3), 2.11 (br, 2H, −CH2), 1.89 (br, 1H, −CH),
1.77–1.83 (m, 2H, −CH2), 0.99–1.03 (m, 2H, −CH2), 0.77–0.81 (m, 2H,
−CH2); 13C NMR (100 MHz, CDCl3) δ: 172.0, 159.1, 143.0, 141.7,
140.3, 138.0, 135.8, 128.1, 126.8, 100.0, 71.6, 44.6, 11.0, 7.4; MS
(ESI): m/z calcd. for C20H24N3O4S, [M+H]+ 402.1, found 402.3 [M+H]+.
Anal. calcd. C, 59.83; H, 5.77; N, 10.47; S, 7.99, found: C, 59.96; H,
5.79; N, 10.45; S, 7.98.
C
25H27N2O5S, [M+H]+ 467.1, found 467.2 [M+H]+. Anal. calcd. C,
64.36; H, 5.62; N, 6.00; S, 6.87, found: C, 64.44; H, 5.64; N, 5.97; S,
6.85.
(4-((5-(4-(Methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-
(phenyl)methanone (compound II-9)
Yield 52%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 2.8 Hz, 1H, −ArH),
8.02–8.03 (m, 1H, −ArH), 8.00–8.01 (m, 1H, −ArH), 7.84 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.72–7.73 (m, 1H, −ArH), 7.70–
7.71 (m, 1H, −ArH), 7.40–7.46 (m, 5H, −ArH), 6.85 (d, J = 8.6 Hz, 1H,
−ArH), 5.37–5.43 (m, 1H, −CH), 3.40–4.12 (m, 4H, −CH2), 3.10 (s, 3H,
−SO2CH3), 1.80–2.15 (m, 4H, −CH2); 13C NMR (100 MHz, CDCl3) δ:
170.5, 163.2, 145.4, 143.4, 139.3, 137.7, 136.1, 129.7, 128.5, 128.2,
128.2, 127.4, 126.9, 112.0, 70.2, 44.6; MS (ESI): m/z calcd. for
Phenyl 4-((5-(4-(methylsulfonyl)phenyl)pyrazin-2-yl)oxy)-
piperidine-1-carboxylate (compound III-5)
Yield 52%. 1H NMR (400 MHz, CDCl3) δ: 8.58 (d, J = 1.2 Hz, 1H, −ArH),
8.34 (d, J = 1.2 Hz, 1H, −ArH), 8.15–8.16 (m, 1H, −ArH), 8.13–8.14 (m,
1H, −ArH), 8.06–8.07 (m, 1H, −ArH), 8.04–8.04 (m, 1H, −ArH), 7.35–
7.40 (m, 2H, −ArH), 7.19–7.24 (m, 1H, −ArH), 7.14–7.15 (m, 1H, −ArH),
7.11–7.12 (m, 1H, −ArH), 5.34–5.39 (m, 1H, −CH), 3.92–4.00 (m, 2H,
−CH2), 3.55–3.64 (m, 2H, −CH2), 3.10 (s, 3H, −SO2CH3), 2.12–2.16 (m,
2H, −CH2), 1.92–1.95 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ:
159.1, 153.7, 151.4, 143.1, 141.7, 140.3, 138.1, 135.8, 129.3, 128.1,
126.8, 125.3, 121.7, 71.2, 44.6; MS (ESI): m/z calcd. for C23H24N3O5S,
[M+H]+ 454.1, found 453.8 [M+H]+. Anal. calcd. C, 60.91; H, 5.11; N,
9.27; S, 7.07, found: C, 61.04; H, 5.13; N, 9.32; S, 7.06.
C
24H25N2O4S, [M+H]+ 437.1, found 437.9 [M+H]+. Anal. calcd. C,
66.03; H, 5.54; N, 6.42; S, 7.35, found: C, 66.23; H, 5.51; N, 6.39; S,
7.37.
1-(4-((5-(4-(Methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidin-1-
yl)ethan-1-one (compound II-10)
Yield 37%. 1H NMR (400 MHz, CDCl3) δ: 8.43 (d, J = 2.8 Hz, 1H, −ArH),
8.15–8.16 (m, 1H, −ArH), 8.13–8.14 (m, 1H, −ArH), 8.02–8.03 (m, 1H,
−ArH), 8.00–8.01 (m, 1H, −ArH), 7.75 (d, J = 8.8 Hz, 1H, −ArH), 7.33
(dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H, −ArH), 4.65–4.70 (m, 1H, −CH), 3.43–
3.83 (m, 4H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.14 (s, 3H, −COCH3),
1.81–2.06 (m, 4H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 169.0, 153.4,
148.0, 144.0, 139.8, 139.3, 127.9, 127.1, 123.2, 121.6, 72.5, 44.6,
42.9, 38.0, 31.0, 30.0, 21.4; MS (ESI): m/z calcd. for C19H23N2O4S,
[M+H]+ 375.1, found 375.5 [M+H]+. Anal. calcd. C, 60.94; H, 5.92; N,
7.48; S, 8.56, found: C, 61.09; H, 5.93; N, 7.50; S, 8.58.
|
4.1.7 Synthesis of 1-benzyl-4-((4ʹ-(methylsulfonyl)-
[1,1ʹ-biphenyl]-4-yl)oxy)piperidine (compound I-6)
A
mixture of compound I-2 (0.1 g, 0.3 mmol), benzyl bromide
(45.36 mg, 0.36 mmol), trimethylamine (45.45 mg, 0.45 mmol), and
dichloromethane (20 mL) was stirred at room temperature overnight.
TLC monitoring showed complete consumption of starting material.
After completion of the reaction, the mixture was extracted with
dichloromethane (30 mL) and water (20 mL), washed twice with
saturated sodium chloride solution (20 mL), dried over anhydrous
sodium sulfate, evaporated under diminished pressure to give white
solid compound I-6 (71 mg, 55%). 1H NMR (400 MHz, CDCl3) δ: 7.96–
7.98 (m, 2H, −ArH), 7.71–7.73 (m, 2H, −ArH), 7.52–7.56 (m, 2H, −ArH),
7.31–7.35 (m, 4H, −ArH), 7.27–7.29 (m, 1H, −ArH), 6.99–7.02 (m, 2H,
−ArH), 4.38–4.42 (m, 1H, −CH), 3.56 (s, 2H, −CH2), 3.08 (s, 3H,
−SO2CH3), 2.77 (br, 2H, −CH2), 2.34 (br, 2H, −CH2), 2.04 (br, 2H,
−CH2), 1.82–1.90 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 158.2,
146.3, 138.4, 131.4, 129.1, 128.6, 128.3, 127.9, 127.3, 127.1, 116.5,
63.0, 50.5, 44.7, 30.8; MS (ESI): m/z calcd. for C25H28NO3S, [M+H]+
422.1, found 421.9 [M+H]+. Anal. calcd. C, 71.23; H, 6.46; N, 3.32; S,
7.61, found: C, 71.28; H, 6.48; N, 3.33; S, 7.64.
2,2-Dimethyl-1-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-
oxy)piperidin-1-yl)propan-1-one (compound II-11)
Yield 55%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 1.6 Hz, 1H, −ArH),
8.03–8.04 (m, 1H, −ArH), 8.00–8.01 (m, 1H, −ArH), 7.83 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.72–7.73 (m, 1H, −ArH), 7.70–
7.71 (m, 1H, −ArH), 6.85 (d, J = 8.6 Hz, 1H, −ArH), 5.33–5.39 (m, 1H,
−CH), 3.97–4.03 (m, 2H, −CH2), 3.49–3.55 (m, 2H, −CH2), 3.10 (s, 3H,
−SO2CH3), 2.03–2.10 (m, 2H, −CH2), 1.76–1.85 (m, 2H, −CH2), 1.31 (s,
9H, −C(CH3)3); 13C NMR (100 MHz, CDCl3) δ: 176.3, 163.3, 145.4,
143.4, 139.2, 137.7, 128.2, 128.1, 127.3, 112.0, 70.6, 44.6, 42.4, 38.8,
31.2, 28.4; MS (ESI): m/z calcd. for C22H29N2O4S, [M+H]+ 417.1, found
417.3 [M+H]+. Anal. calcd. C, 63.44; H, 6.78; N, 6.73; S, 7.70, found: C,
63.53; H, 6.79; N, 6.74; S, 7.72.
Compounds II-12, III-6 were prepared in a manner similar to that
described for compound I-6.
2-((1-Benzylpiperidin-4-yl)oxy)-5-(4-(methylsulfonyl)phenyl)-
pyridine (compound II-12)
Yield 34%. 1H NMR (400 MHz, CDCl3) δ: 8.39 (dd, J1 = 2.8 Hz,
J2 = 0.8 Hz, 1H, −ArH), 8.00 (d, J = 8.4 Hz, 2H, −ArH), 7.80 (dd,
J1 = 8.8 Hz, J2 = 2.8 Hz, 1H, −ArH), 7.72 (d, J = 8.8 Hz, 2H, −ArH), 7.27–
7.36 (m, 6H, −ArH), 5.11–5.17 (m, 1H, −CH), 3.56 (s, 2H, −NCH2Ph),
Cyclopropyl(4-((5-(4-(methylsulfonyl)phenyl)pyrazin-2-yl)oxy)-
piperidin-1-yl)methanone (compound III-4)
Yield 50%. 1H NMR (400 MHz, CDCl3) δ: 8.57 (d, J = 1.6 Hz, 1H, −ArH),
8.32 (d, J = 1.6 Hz, 1H, −ArH), 8.14–8.15 (m, 1H, −ArH), 8.12–8.13 (m,
1H, −ArH), 8.05–8.06 (m, 1H, −ArH), 8.03–8.04 (m, 1H, −ArH),

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3.09 (s, 3H, −SO2CH3), 2.77–2.80 (m, 2H, −CH2), 2.33–2.38 (m, 2H,
−CH2), 2.06 (br, 2H, −CH2), 1.81–1.89 (m, 2H, −CH2); 13C NMR
(100 MHz, CDCl3) δ: 145.5, 143.6, 137.4, 129.2, 128.2, 128.1, 127.7,
127.3, 127.1, 112.0, 63.1, 50.9, 44.6, 31.0; MS (ESI): m/z calcd. for
J2 = 2.4 Hz, 1H, −ArH), 7.72 (d, J = 8.4 Hz, 2H, −ArH), 6.85 (d, J = 8.8 Hz,
1H, −ArH), 5.38–5.42 (m, 1H, −CH), 4.20–4.26 (m, 2H, −CH2), 3.63–
3.70 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.08–2.13 (m, 2H, −CH2),
1.81–1.86 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 163.4, 159.8,
155.9, 155.9, 145.5, 143.5, 139.2, 137.6, 128.2, 128.0, 127.3, 117.9,
112.0, 70.9, 44.6, 41.5, 30.6; MS (ESI): m/z calcd. for C21H22ClN4O3S,
[M+H]+ 425.1, found 425.5 [M+H]+. Anal. calcd. C, 56.69; H, 4.76; N,
12.59; S, 7.21, found: C, 56.60; H, 4.73; N, 12.62; S, 7.24.
C
24H27N2O3S, [M+H]+ 423.1, found 423.0 [M+H]+. Anal. calcd. C,
68.22; H, 6.20; N, 6.63; S, 7.59, found: C, 68.16; H, 6.17; N, 6.65; S,
7.62.
2-((1-Benzylpiperidin-4-yl)oxy)-5-(4-(methylsulfonyl)phenyl)-
pyrazine (compound III-6)
|
4.2 Biological evaluation
Yield 39%. 1H NMR (400 MHz, CDCl3) δ: 8.55 (d, J = 1.2 Hz, 1H, −ArH),
8.28 (d, J = 1.6 Hz, 1H, −ArH), 8.13–8.14 (m, 1H, −ArH), 8.10–8.11 (m,
1H, −ArH), 8.04–8.05 (m, 1H, −ArH), 8.02–8.02 (m, 1H, −ArH), 7.31–
7.36 (m, 4H, −ArH), 7.27–7.29 (m, 1H, −ArH), 5.10–5.16 (m, 1H, −CH),
3.56 (s, 2H, −NCH2Ph), 3.09 (s, 3H, −SO2CH3), 2.77–2.81 (m, 2H,
−CH2), 2.36 (t, J = 20.8 Hz, 2H, −CH2), 2.06 (br, 2H, −CH2), 1.84–1.92
(m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ: 159.5, 142.6, 141.9,
140.1, 138.1, 135.9, 129.1, 128.3, 128.0, 127.1, 126.7, 72.4, 63.0,
50.7, 44.6, 30.8; MS (ESI): m/z calcd. for C23H26N3O3S, [M+H]+ 424.1,
found 424.5 [M+H]+. Anal. calcd. C, 65.23; H, 5.95; N, 9.92; S, 7.57,
found: C, 65.10; H, 5.97; N, 9.94; S, 7.59.
|
4.2.1 In vitro GPR119 agonist activity
Intracellular cAMP in CHO human GPR119 stable cell line was
measured using the LANCE Ultra cAMP Detection Kit (PerkinElmer).
The assay was performed according to the manufacturer's protocol.
Compounds were tested on CHO human GPR119 stable cell line. Cells
were diluted in assay buffer (5 mM HEPES pH 7.4, Hank's Balanced
Salt Solution, 0.1% BSA, 0.5 mM IBMX) and used at 2 × 103 cells/well
in 384-well plates. Cells were incubated with compound for 60 min
before addition of 5 µL 4X Eu-cAMP tracer solution and 5 µL 4X
ULight™-anti-cAMP solution. Signal = 665 nm Raw Data/615 nm Raw
Data × 10000. %Activation = (1 − (Max signal − Compound signal)/
(Max signal − Min signal)) × 100. Min signal was obtained from the
DMSO negative control with only DMSO. Max signal was obtained
from the action of reference-positive control GSK1292263 at 1 µM.
EC50 was calculated using GraphPad Prism V5.0 software: Sigmoidal
dose-response (variable slope).[19]
|
4.1.8 Synthesis of 5-fluoro-2-(4-((5-(4-
(methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-
pyrimidine (compound II-17)
A mixture of compound I-2 (0.2 g, 0.6 mmol), sodium hydride (27.6 mg,
1.2 mmol) and dimethyl formamide (20 mL) was stirred at 100°C for
1 h. Then 2-chloro-5-fluoropyrimidine (95.04 mg, 0.72 mmol) was
added into the mixture and stirred at 100°C overnight. TLC monitoring
showed complete consumption of starting material. After completion
of the reaction, the mixture was extracted with ethyl acetate (30 mL)
and water (20 mL), washed twice with saturated sodium chloride
solution (20 mL), dried over anhydrous sodium sulfate, evaporated
under diminished pressure to give white solid compound II-17
(120 mg, 47%). 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.4 Hz, 1H,
−ArH), 8.21 (s, 2H, −ArH), 8.01 (d, J = 8.4 Hz, 2H, −ArH), 7.82 (dd,
J1 = 8.4 Hz, J2 = 2.4 Hz, 1H, −ArH), 7.72 (d, J = 8.4 Hz, 2H, −ArH), 6.85
(d, J = 8.8 Hz, 1H, −ArH), 5.36–5.40 (m, 1H, −CH), 4.20–4.26 (m, 2H,
−CH2), 3.59–3.66 (m, 2H, −CH2), 3.09 (s, 3H, −SO2CH3), 2.08–2.13 (m,
2H, −CH2), 1.81–1.86 (m, 2H, −CH2); 13C NMR (100 MHz, CDCl3) δ:
163.5, 158.9, 152.7, 150.2, 145.5, 145.3, 145.1, 143.5, 139.2, 137.6,
128.2, 128.0, 127.3, 112.0, 71.1, 44.6, 41.9, 30.6; MS (ESI): m/z calcd.
for C21H22FN4O3S, [M+H]+ 429.1, found 429.6 [M+H]+. Anal. calcd. C,
58.87; H, 4.94; N, 13.08; S, 7.48, found: C, 58.99; H, 4.96; N, 13.05; S,
7.47.
|
4.2.2 Oral glucose tolerance test (OGTT)
The animal study was performed according to the international rules
considering animal experiments and the internationally accepted
ethical principles for laboratory animal use and care. Synthesized
compounds and positive control were formulated in 0.5% methyl-
cellulose. Male ICR mice (18–22 g, obtained from Shanghai SLAC
Laboratory Animal Co. Ltd.) were fasted overnight and randomly
stratified (n = 6/group) to vehicle and test compound groups. Body
weights were recorded on the morning of the study (post-fasting) for
dose volume calculation. Blood samples were collected via the tail
vein from all mice prior to dosing with either vehicle (0.5%
methylcellulose) or test compound via oral gavage (30 mg/kg). Thirty
minutes later mice were bled and immediately dosed with oral
glucose (2 g/kg). The mice were re-bled at 30, 60, and 120 min post-
glucose load. Glucose levels were measured on a SANNUO hand-
held monitor. AUC was calculated using GraphPad Prism
software.[20,21]
7
Compound II-18 was prepared in a manner similar to that
described for compound II-17.
ACKNOWLEDGMENTS
5-Chloro-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)-
piperidin-1-yl)pyrimidine (compound II-18)
This work was supported by the National Natural Science Foundation
of China (21305051) and the National First-class Discipline Program of
Food Science and Technology (JUFSTR20180101).
Yield 39%. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 2.4 Hz, 1H, −ArH),
8.23 (s, 2H, −ArH), 8.01 (d, J = 8.4 Hz, 2H, −ArH), 7.83 (dd, J1 = 8.4 Hz,

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ZHOU ET AL.
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CONFLICT OF INTEREST
Hammarstedt, U. Smith, T. E. McGraw, A. Saghatelian, B. B. Kahn, Cell
2014, 159, 318.
The authors have declared no conflict of interest.
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How to cite this article: Zhou Y, Wang Y, Zhang L, Tang C,
Feng B. Discovery and biological evaluation of novel G
protein-coupled receptor 119 agonists for type 2 diabetes.
Arch Pharm Chem Life Sci. 2019;1–10.
https://doi.org/10.1002/ardp.201800267