Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

Article abstract of DOI:10.1080/14756366.2019.1681988

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC₅₀ values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC_0–2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

Full text of DOI:10.1080/14756366.2019.1681988

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Optimisation of novel 4, 8-disubstituted
dihydropyrimido[5,4-b][1,4]oxazine derivatives as
potent GPR 119 agonists
Yuanying Fang, Shaokun Zhang, Min Li, Lijuan Xiong, Liangxing Tu, Saisai Xie,
Yi Jin, Yanhua Liu, Zunhua Yang & Ronghua Liu
To cite this article: Yuanying Fang, Shaokun Zhang, Min Li, Lijuan Xiong, Liangxing Tu,
Saisai Xie, Yi Jin, Yanhua Liu, Zunhua Yang & Ronghua Liu (2020) Optimisation of novel 4, 8-
disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists, Journal of
Enzyme Inhibition and Medicinal Chemistry, 35:1, 50-58, DOI: 10.1080/14756366.2019.1681988
To link to this article: https://doi.org/10.1080/14756366.2019.1681988
© 2019 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 28 Oct 2019.
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2020, VOL. 35, NO. 1, 50–58
https://doi.org/10.1080/14756366.2019.1681988
RESEARCH PAPER
Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine
derivatives as potent GPR 119 agonists
Yuanying Fanga,b, Shaokun Zhangb, Min Lia, Lijuan Xionga, Liangxing Tub, Saisai Xieb, Yi Jinb, Yanhua Liua,
Zunhua Yanga and Ronghua Liua
b
aCollege of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China; National Engineering Research Center for
Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
ABSTRACT
ARTICLE HISTORY
Received 11 September 2019
Revised 10 October 2019
Accepted 10 October 2019
GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the opti-
misation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed
compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the
potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypo-
glycaemic effect of compound 15 was observed by reducing the blood glucose AUC0–2h at the dose of
30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).
KEYWORDS
Optimisation; pyrimidodihy-
drooxazine; GPR 119
agonists; type 2
diabetes mellitus
1. Introduction
agonists did not show the significant glucose-lowering effect in
oral glucose tolerance test (oGTT) in mice compared with positive
control. Therefore, we sequentially attempted to optimise the core
fragment with the aim to enhance the biological activity both
in vitro and in vivo. With this purpose, we introduced pyri-
mido[5,4-b][1,4]oxazine as the core using the strategy of scaffold
hopping. We also identified whether introduction of several con-
formation restricted azabicyclic amines were beneficial to agonistic
potency or not (Figure 1). In this paper, we described our opti-
misation to synthesise and evaluate a series of novel pyrimido[5,4-
b][1,4]oxazine derivatives as GPR119 agonists, also including an
in vivo efficacy study.
Type 2 diabetes mellitus (T2DM) is a complex chronic disease
characterised by metabolic disorder and hyperglycaemia due to
insulin resistance, hepatic glucose overproduction and/or insuffi-
cient insulin secretion1–3. Although there are a number of pharma-
cotherapy options for T2DM, most of current anti-diabetes drug
have shown known adverse effects and loss of their overall effi-
cacy in a long-term glycaemic control4–6. Thus, there is still a crit-
ical need of novel therapeutic targets or approaches for treatment
T2DM by good glycaemic control.
G protein-coupled receptor 119 (GPR119) is a member of class
A (rhodopsin-type) GPCR family, with highly expressed in pancre-
atic b-cells and the K and L cells of the gastrointestinal tract7–9
.
Activation of GPR119 increases the intracellular cyclic AMP (cAMP)
level, which in turn directly stimulate the glucose-dependent insu-
lin secretion and regulate glucagon-like peptide 1 (GLP-1), leading
to improve the glucose tolerance in T2DM patients10–14. In add-
ition, GPR119 agonists showed b-cells function preservation, which
is also an important role in current T2DM therapy15–17. As a result,
GPR119 agonists are used for discovery of anti-T2DM agents by
lowering the blood glucose level and improving b-cells function.
Indeed, numerous synthetic, small molecule GPR119 agonists were
revealed by academia and industry to date, and some of which
have advanced into clinical trials such as MBX-2982, BMS-
903452, LEZ763, ZYG-1918–30. Despite tremendous endeavours,
none of GPR119 agonists were approved to market by FDA up
to now.
2. Results and discussion
2.1. Chemistry
The intermediates amine or bicyclic amines 3–6 could be pur-
chased or synthesised according to the reported procedures33–36
.
Coupling reaction of 4,6-dichloro-5-methoxypyrimidine with 4-
amino-3-fluorobenzonitrile in DMF under basic condition afforded
compound 7, followed by demethylation using BBr3 solution in
dichloromethane under reflux condition gave hydroxyl compound
8. Cyclisation of 8 with 1-bromo-2-chloroethane and K2CO3 in
DMF generated key intermediate 9. Buchwald–Hartwig reaction of
9 and amines 3–6 with Pd2(dba)3, X-Phos and Cs2CO3 under reflux
conditions and N2 atmosphere overnight resulted in target com-
pounds 10–13 (Scheme 1).
In our efforts to discover GPR119 agonists, we previously have
evaluated some series of pyrimidine derivatives, and some com-
pounds displayed quite good agonistic potency31,32. Among them,
pyrimidopyrimidine compounds 1 and 2 exhibited single digit
Removing Boc group of derivative 10 in 3 M HCl ethanol solu-
tion obtained amine compound 14 in good yield, which was
treated with various chloro-fragments in base conditions to
EC50 values (2.2 nM and 8.1 nM respectively); however, these two receive desired final compounds 15–20 (Scheme 2).
CONTACT Zunhua Yang
joshyyy@126.com
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
51
The general synthetic procedures of the pyrimidooxazine deriv-
atives 22–25 were synthesised as shown in Scheme 3, following
similar methods with compounds 15–20.
2.2. Biological activity
2.2.1. GPR119 activation
GPR119 agonistic activity of target compounds 10–13, 15–20, and
22–25 were measured using a reporter assay with the human
GPR119 receptor stably expressed in CHO K1 cells. A GPR119
agonist GSK-1292263 was chose for the reference. The results
expressed the activity as EC50 values and the inherent activity (IA)
as percentages (%max) of response which were compared to the
reference GSK-1292263 (defined the maximal effect activation).
At first, we evaluated pyrimidooxazine derivatives 10–13 for
the GPR119 agonistic activity and intrinsic activity (Table 1). As a
Figure 1. The design of target compounds.
Scheme 1. Synthesis of compounds 10–13. Reagents and conditions: (a) 4-amino-3-fluorobenzonitrile, K2CO3, DMF, 65 ꢀC, overnight. (b) 1 M BBr3 in DCM, anhydrous
DCM, r. t. – reflux, 2 h. (c) 1-bromo-2-chloroethane, K2CO3, DMF, 40 ꢀC, overnight. (d) amines 3–6, Pd2(dba)3, X-Phos, Cs2CO3, 1,4-Dioxane, reflux, under N2 overnight.
Scheme 2. Synthesis of compounds 15–20. Reagents and conditions: (a) 3 M HCl in EtOH, r. t., overnight. (b) chloro-fragments, Et3N, DCM, r. t., overnight or Cs2CO3,
DMF, r. t., overnight.

52
Y. FANG ET AL.
Scheme 3. Synthesis of compounds 22–25. Reagents and conditions: (a) 3 M HCl in EtOH, r. t., overnight. (b) chloro-fragments, Et3N, DCM, r. t., overnight or Cs2CO3,
DMF, r. t., overnight.
Table 1. GPR119 agonistic activities of compounds 10–13.
GPR119 activation
EC50 (nM) %maxa ClogPb
2.2.2. oGTT in mice
Based on the good agonistic activity, we conducted oGTT of com-
pounds 10 and 15 with a single dose (15 and 30 mg/kg) in
C57BL/6N mice with DPP-4 inhibitor vildagliptin as a positive con-
trol. The results were outlined in Figure 2, compounds 10 and 15
both showed blood glucose reduction effect in dose-dependent
manner. Vildagliptin reduced the area under curve from 0 to
120 min (AUC0–120 min) by 17.9% (Vehicle: 24.69 3.08, Vildagliptin:
20.26 2.14) at the dose of 30 mg/kg. Meanwhile compounds 10
and 15 reduced AUC0–120 min by 10.7% (22.07 4.28) and 14.5%
(21.10 3.92) at the dosage of 15 mg/kg, respectively. However,
10 and 15 showed significant improved efficacy by the reduction
of value to 18.8% (20.05 2.27) and 23.4% (18.91 2.58) at the
dosage of 30 mg/kg, respectively.
Compound
Structure
10
13
83.9
4.0
11
12
1800
200
45.9
63.5
4.6
3.5
13
>10000
22.7
4.5
3. Conclusion
In summary, we have designed, synthesised and biologically eval-
uated a series of novel pyrimido[5,4-b][1,4]oxazine derivatives as
potent GPR119 agonists. In vitro, half derivatives exhibited strong
EC50 values (<100 nM). Among the aliphatic amine moieties of
this scaffold, the compound 10 with tropine amine ring displayed
much more potent agonistic activity than piperidine amine and
other rigid bicyclic amines. In the further optimisation of N-substi-
tution, only isopropyl carbamate of tropine ring 15 improved the
EC50 values and showed the greatest inherent activity.
Accordingly, compounds 10 and 15 were conducted the oGTT in
C57BL/6N mice. Both two agonists demonstrated blood glucose
reduction effect in a dose-dependent manner. Furthermore, the
optimised compound 15 was exerted improved 23.4% reduction
in blood glucose AUC0–2h at the dose of 30 mg/kg comparing with
Vildagliptin (17.9% reduction). Follow-up studies and their results
will be reported in due course.
GSK-1292263
6.6 100
a%max: cAMP stimulation % compared to maximal effect of GSK1292263.
bClogP was calculated using ACD software from Discovery Studio 4.5.
result, good activities were observed with compounds 10 and 12
(EC50 ¼ 13 and 200 nM respectively), which contained tropine
amine and piperidine amine scaffolds with moderate lipophilicity
(ClogP ¼ 4.0 and 3.5 respectively).
Next, we focussed on the modification of Boc group in head
part with various moieties. The biological results were shown in
Table 2, all compounds exhibited moderate to potent agonistic
activities (EC50 values range from 250 nM to 12 nM). The substitu-
tion of 2-pyrimidyl on the nitrogen of tropine ring yielded com-
pounds 16 and 17, which showed the moderate EC50 values
(130 nM and 250 nM, respectively). However, the compounds 23
and 24, bearing same substituents on the nitrogen of piperidine
ring, demonstrated significant agonistic activities (EC50 ¼ 44 nM
and 40 nM) and lower lipophilicity. But the reverse results were
observed for carbamate substituted derivatives (15 vs. 22), and
compound 15 exhibited 10 times EC50 values than compound 22.
Furthermore, compound 15 revealed the strongest inherent activ-
ity (%max 146.5%) and best agonistic activity (EC50 ¼ 12 nM) with
suitable ClogP value (3.8). Consequently, compounds 15 and 10
were selected and examined the oral glucose tolerance test
(oGTT) in vivo as promising GPR119 agonists.
4. Experimental
4.1. Chemistry
All starting materials were obtained from commercial suppliers
1
and used without further purification. H-NMR and 13C-NMR spec-
tra were recorded on a Bruker AVANCE III HD 600 (600 Hz) spec-
trometer. Chemical shifts are reported in parts per million (ppm)
downfield relative to tetramethylsilane as an internal standard.
Peak splitting patterns are abbreviated as s (singlet), br s (broad
singlet), d (doublet), t (triplet), dd (doublet of doublet), and m
(multiplet). MS spectra were recorded on a Thermo Fisher (LCQ

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
53
Table 2. GPR119 agonistic activities of compounds 15–20 and 22–25.
GPR119 activation
Compound
Structure
EC50 (nM)
12
%maxa
ClogPb
15
146.3
3.8
16
17
130
250
60.5
71.2
4.6
4.3
18
110
100
3.0
19
20
68
82
75.6
79.6
3.7
3.3
22
23
120
44
66.1
70.7
3.3
4.0
24
40
90
6.6
62.7
3.8
2.7
25
100
GSK-1292263
100
a%max: cAMP stimulation % compared to maximal effect of GSK1292263.
bClogP was calculated using ACD software from Discovery Studio 4.5.

54
Y. FANG ET AL.
ꢁ
Figure 2. Single dose of compounds 10 and 15 on oGTT in C57BL/6N mice. The results are presented as the mean SE. p < 0.05 compared to vehicle group (n ¼ 8).
Fleet). HR-MS spectra were recorded on an AB SCIEX (Triple TOF 4.1.3. 4-(4-Chloro-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-
5600þ). TLC was performed on silica F254 purchased from Branch
3-fluorobenzonitrile (9)
of Qingdao Haiyang Chemical Co. (Qingdao, China) and detected
by UV light at 254, 365 nm or by charring with sulphuric acid.
Column chromatography was performed on silica gel column
(200–300 mesh, Branch of Qingdao Haiyang Chemical Co.).
To a solution of compound 8 (0.4 g, 1.4 mmol) in DMF (10 ml), 1-
bromo-2-chloroethane (0.62 g, 4.3 mmol) and K2CO3 (0.6 g,
4.3 mmol) were added. The reaction was stirred at 40 ꢀC for over-
night. Then the mixture was poured into ice water. The mix solu-
tion was extracted with ethyl acetate for two times, washed with
brine for two times. The organic layer was dried over MgSO4, fil-
tered and evaporated. The residue was purified by column chro-
matography (petroleum ether: EtOAc ¼ 2: 1) to afford the desired
product as a claybank solid (0.68 g, 55%). 1H-NMR (600 MHz,
CDCl3) d (ppm): 8.04 (s, 1H), 8.35 (s, 1H), 7.73–7.44 (m, 3H), 4.51 (t,
J ¼ 4.4 Hz, 2H), 3.95 (t, J ¼ 4.3 Hz, 2H). MS-ESI: [M þ H]þ: 291.5.
R
Analytical HPLC was performed on a Waters AcquityV ArcTM with
2998 PDA detector and all final compounds possessed purities of
>90% after purification.
4.1.1. 4-((6-Chloro-5-methoxypyrimidin-4-yl)amino)-3-fluorobenzo-
nitrile (7)
To a solution of 4,6-dichloro-5-methoxypyrimidine (1 g, 5.7 mmol)
in DMF (20 ml), 4-amino-3-fluorobenzonitrile (0.6 g, 4.4 mmol) and
K2CO3 (2.4 g, 17 mmol) were added. The reaction was stirrd at
65 ꢀC for overnight. Then the mixture was poured into ice water.
The mix solution was extracted with ethyl acetate for two times,
washed with brine for two times. The organic layer was dried over
MgSO4, filtered and evaporated. The residue was purified by col-
umn chromatography (petroleum ether: EtOAc ¼ 3: 1) to afford
the desired product as a claybank solid (0.68 g, 55%). 1H-NMR
(600 MHz, CDCl3) d (ppm): 8.94 (t, J ¼ 8.8 Hz, 1H), 8.35 (s, 1H), 7.73
(s, 1H), 7.59 (d, J ¼ 8.8 Hz, 1H), 7.52 (d, J ¼ 10.2 Hz, 1H), 3.10 (s, 3H).
MS-ESI: [M þ H]þ: 279.3.
4.1.4. General procedure of compounds 10–13
To the solution of compound 9 (0.22 mmol) and substituted
amines (0.22 mmol) in 1,4-dioxane (2 ml), Pd2(dba)3 (0.05 mmol), X-
Phos (0.05 mmol), and Cs2CO3 (0.55 mmol) were added. The reac-
tion was heated to reflux under nitrogen gas for overnight. Then
the mixture was diluted with ethyl acetate, washed with brine,
dried over MgSO4, and evaporated. The residue was purified by
column chromatography to give the product.
4.1.5. tert-Butyl (endo)-3-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-
6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)-8-azabicyclo[3.2.1]oc-
4.1.2. 4-((6-Chloro-5-hydroxypyrimidin-4-yl)amino)-3-fluorobenzo-
nitrile (8)
To a solution of compound 7 (0.5 g, 1.9 mmol) in anhydrous
tane-8-carboxylate (10)
1
dichloromethane (15 ml), 1 M BBr3 in dichloromethane solution Yellowish solid, 52% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.93
(5.7 ml, 5.7 mmol) was added at room temperature (r. t.) The reac- (s, 1H), 7.54–7.50 (m, 1H), 7.47 (m, 2H), 5.38 (d, J ¼ 7.0 Hz, 1H),
tion was reflux for 2 h. Then the reaction was quenched by water. 4.46–4.37 (m, 2H), 4.33 (m, 2H), 4.22 (s, 1H), 3.89 (s, 2H), 2.39 (s,
The mixture was extracted with dichloromethane for two times, 1H), 2.30–2.20 (m, 1H), 2.12 (t, J ¼ 7.4 Hz, 2H), 2.07–1.92 (m, 2H),
washed by brine for two times. The organic layer was dried over 1.84 (d, J ¼ 27.1 Hz, 2H), 1.49 (s, 9H). 13C-NMR (150 MHz, CDCl3) d
MgSO4, filtered and evaporated. The residue was purified by col- (ppm): 156.4 (d, J ¼ 250.5 Hz), 153.4, 151.3, 149.8, 143.9, 135.4 (d,
umn chromatography (petroleum ether: EtOAc ¼ 1: 1) to give the J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.5 Hz), 128.4 (d, J ¼ 2.6 Hz), 121.8, 120.6
desired product as a yellow solid (0.3 g, 72%). 1H-NMR (600 MHz, (d, J ¼ 23.7 Hz), 117.6 (d, J ¼ 2.6 Hz), 109.4 (d, J ¼ 9.2 Hz), 79.5, 64.5,
CDCl3) d (ppm): 8.92 (t, J ¼ 8.4 Hz, 1H), 8.32 (s, 1H), 7.68 (s, 1H), 53.1, 52.2, 48.2 (d, J ¼ 3.9 Hz), 43.1, 35.8, 35.3, 28.5 (x3), 28.3, 27.9.
7.53 (d, J ¼ 8.6 Hz, 1H), 7.46 (d, J ¼ 10.8 Hz, 1H). MS-ESI: HRMS-TOF (m/z) calcd for C25H29FN6O3 [M þ H]þ: 481.2358,
[M þ H]þ: 265.1.
found 481.2436.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
55
4.1.6. tert-Butyl (exo)-3-(((8-(4-cyano-2-fluorophenyl)-7,8-dihydro- 128.4 (d, J ¼ 2.5 Hz), 121.8, 120.6 (d, J ¼ 23.7 Hz), 117.6 (d,
J ¼ 2.4 Hz), 109.4 (d, J ¼ 9.2 Hz), 68.1, 64.5, 53.1, 52.6, 48.2 (d,
6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)methyl)-8-azabicy-
J ¼ 4.4 Hz), 43.1, 35.9, 35.4, 28.3, 27.9, 22.3 (x2). HRMS-TOF (m/z)
clo[3.2.1]octane-8-carboxylate (11)
calcd for C24H27FN6O3 [M þ H]þ: 467.2201, found 467.2282.
1
Yellowish solid, 45% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.92
(s, 1H), 7.55–7.51 (m, 1H), 7.50–7.44 (m, 2H), 5.00 (t, J ¼ 6.1 Hz, 1H),
4.39–4.35 (m, 2H), 4.30 (s, 1H), 4.20 (s, 1H), 3.95–3.81 (m, 2H), 3.37
(d, J ¼ 23.7 Hz, 2H), 2.29–2.14 (m, 1H), 1.97 (s, 2H), 1.72–1.63 (m,
4.1.11. General procedure of compounds 16–20
4H), 1.65 (s, 2H), 1.49 (s, 9H). HRMS-TOF (m/z) calcd for
To a solution of compound 14 (0.26 mmol) in DMF (3 ml), chloro-
C26H31FN6O3 [M þ H]þ: 495.2514, found 495.2592.
fragments (0.34 mmol) and K2CO3 (1 mmol) were added. The reac-
tion was stirred at r. t. for overnight. Then the mixture was poured
into ice water. The mix solution was extracted with ethyl acetate
for two times, washed with brine for 2 times. The organic layer
was dried over MgSO4, filtered and evaporated. The residue was
purified by column chromatography to afford the desired product.
4.1.7. tert-Butyl 4-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-6H-pyri-
mido[5,4-b][1,4]oxazin-4-yl)amino)piperidine-1-carboxylate (12)
1
Yellowish solid, 76% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.93
(s, 1H), 7.56–7.51 (m, 1H), 7.48 (m, 2H), 4.83 (d, J ¼ 8.1 Hz, 1H), 4.38
(t, J ¼ 4.3 Hz, 2H), 4.17–4.11 (m, 3H), 3.89–3.87 (t, J ¼ 3.7, 2H), 2.98
(m, 2H), 2.07–2.05 (m, 2H), 1.49 (s, 9H), 1.43–1.40 (m, 2H). 13C-
NMR (150 MHz, CDCl3) d (ppm): 156.4 (d, J ¼ 250.7 Hz), 154.8,
4.1.12. 4-(4-(((endo)-8-(5-Ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oc-
151.2, 149.7, 144.2, 135.4 (d, J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.6 Hz),
tan-3-yl)amino)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-3-
128.4 (d, J ¼ 2.6 Hz), 121.7, 120.6 (d, J ¼ 23.7 Hz), 117.6 (d,
fluorobenzonitrile (16)
Yellowish solid, 47% yield. H-NMR (600 MHz, CDCl3) d (ppm): 8.22
J ¼ 2.7 Hz), 109.5 (d, J ¼ 9.0 Hz), 79.7, 64.3, 48.2 (d, J ¼ 3.8 Hz), 47.6,
1
43.0, 32.5 (x2), 28.5 (x3). HRMS-TOF (m/z) calcd for C23H27FN6O3
(s, 2H), 7.92 (s, 1H), 7.55–7.51 (m, 1H), 7.47 (m, 2H), 5.52 (d,
[M þ H]þ: 455.2201, found 455.2275.
J ¼ 7.2 Hz, 1H), 4.78 (s, 2H), 4.43–4.37 (m, 2H), 4.30 (q, J ¼ 6.6 Hz,
1H), 3.92–3.85 (m, 2H), 2.50 (q, J ¼ 7.6 Hz, 2H), 2.38 (m, 2H),
2.25–2.18 (m, 2H), 2.13 (m, 2H), 1.89 (d, J ¼ 14.2 Hz, 2H), 1.23 (t,
4.1.8. tert-Butyl 3-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-6H-pyri-
mido[5,4-b][1,4]oxazin-4-yl)amino)-9-azabicyclo[3.3.1]nonane-9-
J ¼ 7.6 Hz, 3H). 13C-NMR (150 MHz, CDCl3) d (ppm): 159.1, 157.5
(x2), 156.4 (d, J ¼ 250.7 Hz), 151.4, 149.9, 143.8, 135.5 (d,
carboxylate (13)
1
J ¼ 10.4 Hz), 128.5 (d, J ¼ 3.5 Hz), 128.4 (d, J ¼ 2.6 Hz), 124.6, 121.8,
Yellowish solid, 52% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.91
120.6 (d, J ¼ 23.7 Hz), 117.6 (d, J ¼ 2.7 Hz), 109.4 (d, J ¼ 9.2 Hz),
64.5, 52.6 (x2), 48.3 (d, J ¼ 3.9 Hz), 43.5, 34.7 (x2), 28.1 (x2), 22.8,
15.6. HRMS-TOF (m/z) calcd for C26H27FN8O [M þ H]þ: 487.2365,
found 487.2462.
(s, 1H), 7.52 (t, J ¼ 7.8 Hz, 1H), 7.50–7.43 (m, 2H), 4.71 (d, J ¼ 8.3 Hz,
1H), 4.60 (t, J ¼ 9.0 Hz, 1H), 4.46 (d, J ¼ 12.3 Hz, 1H), 4.36 (dt,
J ¼ 6.2, 4.8 Hz, 2H), 4.03 (m, 1H), 3.93–3.81 (m, 2H), 2.52 (m, 2H),
2.09–1.94 (m, 2H), 1.85 (m, 1H), 1.77–1.74 (m, 1H), 1.72–1.69 (m,
1H), 1.66-.1.61 (m, 1H), 1.58–1.57 (m, 1H), 1.50 (s, 9H), 1.43–1.41
(m, 2H). HRMS-TOF (m/z) calcd for C26H31FN6O3 [M þ H]þ:
495.2514, found 495.2600.
4.1.13.
4-(4-(((endo)-8-(5-Chloropyrimidin-2-yl)-8-azabicy-
clo[3.2.1]octan-3-yl)amino)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxa-
zin-8-yl)-3-fluorobenzonitrile (17)
Yellowish solid, 51% yield. H-NMR (600 MHz, CDCl3) d (ppm): 8.27
4.1.9. 4-(4-(((endo)-8-Azabicyclo[3.2.1]octan-3-yl)amino)-6,7-dihy-
dro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-3-fluorobenzonitrile (14)
To a solution of compound 10 (1 mmol) in 3 M HCl/EtOH (40 ml)
was stirred at r. t. for overnight. Then the mixture was filtered to
obtain the product 14, which was used for next step without puri-
fication. MS-ESI: [M þ H]þ: 381.3.
1
(s, 2H), 7.92 (s, 1H), 7.53 (t, J ¼ 7.8 Hz, 1H), 7.51–7.44 (m, 2H), 5.48
(d, J ¼ 7.1 Hz, 1H), 4.87–4.67 (m, 2H), 4.49–4.38 (m, 2H), 4.28 (q,
J ¼ 6.6 Hz, 1H), 3.95–3.83 (m, 2H), 2.34 (m, 2H), 2.26–2.19 (m, 2H),
2.14 (m, 2H), 1.96–1.88 (m, 2H). 13C-NMR (150 MHz, CDCl3) d
(ppm): 158.0, 156.4 (d, J ¼ 250.6 Hz), 156.3 (x2), 151.3, 149.9, 143.9,
135.4 (d, J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.6 Hz), 128.4 (d, J ¼ 2.5 Hz),
121.8, 120.6 (d, J ¼ 23.7 Hz), 118.1, 117.6 (d, J ¼ 2.6 Hz), 109.4 (d,
J ¼ 9.2 Hz), 64.5, 52.8 (x2), 48.2 (d, J ¼ 3.9 Hz), 43.4, 34.6 (x2), 28.1
(x2). HRMS-TOF (m/z) calcd for C24H22ClFN8O [M þ H]þ: 493.1662,
found 493.1751.
4.1.10. Isopropyl (endo)-3-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-
6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)-8-azabicyclo[3.2.1]oc-
tane-8-carboxylate (15)
To a solution of compound 14 (0.1 g, 0.26 mmol) in dichlorome-
thane (3 ml), isopropyl carbonochloridate (30 lL, 0.34 mmol) and
Et3N (73 lL, 1 mmol) were added. The reaction was stirred at r.t.
for overnight. Then mixture was diluted with dichloromethane,
washed with brine for two times. The organic layer was dried over
MgSO4, filtered and evaporated. The residue was purified by col-
umn chromatography (petroleum ether: EtOAc ¼ 1: 1) to afford
the desired product as a light yellow solid (70 mg, 58%). 1H-NMR
(600 MHz, CDCl3) d (ppm): 7.93 (s, 1H), 7.54–7.51 (m, 1H), 7.48 (m,
2H), 5.38 (d, J ¼ 6.9 Hz, 1H), 4.98 (dt, J ¼ 12.5, 6.2 Hz, 1H), 4.40–4.37
(m, 3H), 4.34 (m, 2H), 3.89 (m, 2H), 2.37 (m, 1H), 2.24 (m, 1H), 2.13
(m, 2H), 2.02 (m, 2H), 1.87 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H). 13C-
NMR (150 MHz, CDCl3) d (ppm): 156.4 (d, J ¼ 250.5 Hz), 153.6,
4.1.14.
3-Fluoro-4-(4-(((endo)-8-(2-oxo-2-(3-(trifluoromethyl)-5,6-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethyl)-8-azabicy-
clo[3.2.1]octan-3-yl)amino)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxa-
zin-8-yl)benzonitrile (18)
1
Yellowish solid, 44% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.91
(s, 1H), 7.53–7.50 (m, 1H), 7.49–7.43 (m, 2H), 5.30 (m, 2H), 5.05 (s,
1H), 4.38 (m, 2H), 4.33–4.16 (m, 4H), 4.11 (t, J ¼ 5.6 Hz, 1H), 3.87 (t,
J ¼ 4.3 Hz, 2H), 3.36 (d, J ¼ 3.8 Hz, 2H), 3.26 (m, 2H), 2.29–2.08 (m,
4H), 1.97 (m, 2H), 1.82 (m, 2H). HRMS-TOF (m/z) calcd for
151.3, 149.8, 143.9, 135.4 (d, J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.6 Hz), C28H28FN10O2 [M þ H]þ: 613.2406, found 613.2508.

56
Y. FANG ET AL.
4.1.15. tert-Butyl ((R)-1-(2-((endo)-3-((8-(4-cyano-2-fluorophenyl)- 15.7. HRMS-TOF (m/z) calcd for C24H25FN8O [M þ H]þ: 461.2208,
found 461.2318.
7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)-8-azabicy-
clo[3.2.1]octan-8-yl)acetyl)piperidin-3-yl)carbamate (19)
Yellowish solid, 50% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.92
1
4.1.20. 4-(4-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)amino)-6,7-
dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-3-fluorobenzoni-
trile (24)
(s, 1H), 7.52 (m, 1H), 7.47 (m, 2H), 5.47–5.32 (m, 2H), 4.44–4.35 (m,
2H), 4.30 (m, 1H), 3.88 (m, 2H), 3.74–3.67 (m, 3H), 3.61–3.15 (m,
6H), 2.49–2.30 (m, 2H), 2.23 (m, 2H), 1.97 (m, 2H), 1.93–1.74 (m,
6H), 1.48 (s, 9H). HRMS-TOF (m/z) calcd for C32H41FN8O4 [M þ H]þ:
621.3308, found 621.3405.
Follow the similar procedure of 16–20. Yellowish solid, 58% yield.
1H-NMR (600 MHz, CDCl3) d (ppm): 8.25 (s, 2H), 7.95 (s, 1H),
7.58–7.51 (m, 1H), 7.48 (m, 2H), 4.86 (d, J ¼ 8.1 Hz, 1H), 4.74–4.61
(m, 2H), 4.47–4.33 (m, 2H), 4.28 (m, 1H), 3.96–3.79 (m, 2H),
3.27–3.11 (m, 2H), 2.21–2.12 (m, 2H), 1.48 (m, 2H). 13C-NMR
(150 MHz, CDCl3) d (ppm): 159.8, 156.4 (d, J ¼ 250.9 Hz), 155.9 (x2),
151.3, 149.8, 144.2, 135.4 (d, J ¼ 10.4 Hz), 128.5 (d, J ¼ 3.6 Hz),
128.4 (d, J ¼ 2.5 Hz), 121.7, 120.6 (d, J ¼ 23.7 Hz), 118.0, 117.6,
109.4 (d, J ¼ 9.2 Hz), 64.3, 48.2 (d, J ¼ 3.8 Hz), 47.8, 43.2 (x2), 32.8
(x2). HRMS-TOF (m/z) calcd for C22H20ClFN8O [M þ H]þ: 467.1505,
found 467.1613.
4.1.16. tert-Butyl 4-(2-((endo)-3-((8-(4-cyano-2-fluorophenyl)-7,8-
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)-8-azabicy-
clo[3.2.1]octan-8-yl)acetyl)piperazine-1-carboxylate (20)
1
Yellowish solid, 68% yield. H-NMR (600 MHz, CDCl3) d (ppm): 7.92
(s, 1H), 7.55–7.50 (m, 1H), 7.47 (m, 2H), 5.34 (d, J ¼ 7.1 Hz, 1H),
4.44–4.35 (m, 2H), 4.26 (q, J ¼ 6.7 Hz, 1H), 3.91–3.84 (m, 2H),
3.72–3.67 (m, 2H), 3.60 (s, 2H), 3.53–3.47 (m, 2H), 3.43 (m, 2H),
3.32 (m, 2H), 3.28 (m, 2H), 2.29 (m, 2H), 2.21–2.13 (m, 2H), 1.96 (m,
2H), 1.83 (d, J ¼ 14.3 Hz, 2H), 1.50 (s, 9H). 13C-NMR (150 MHz,
CDCl3) d (ppm): 168.8, 156.4 (d, J ¼ 250.6 Hz), 154.6, 151.3, 149.8,
143.8, 135.5 (d, J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.5 Hz), 128.4 (d,
J ¼ 2.5 Hz), 121.8, 120.6 (d, J ¼ 23.7 Hz), 117.6 (d, J ¼ 2.5 Hz), 109.4
(d, J ¼ 9.1 Hz), 80.3, 70.6, 64.4, 58.8, 56.0 (x2), 48.2 (d, J ¼ 3.8 Hz),
45.8, 43.5 (x2), 42.4, 41.7, 36.9 (x2), 28.4 (x3), 26.2. HRMS-TOF (m/z)
calcd for C31H39FN8O4 [M þ H]þ: 607.3151, found 607.3239.
4.1.21. tert-Butyl 4-(2-(4-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-
6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)piperidin-1-yl)acetyl)pi-
perazine-1-carboxylate (25)
Follow the similar procedure of 16–20. Yellowish solid, 63% yield.
1H-NMR (600 MHz, CDCl3) d (ppm): 7.91 (s, 1H), 7.54–7.49 (m, 1H),
7.46 (m, 2H), 4.84 (d, J ¼ 8.1 Hz, 1H), 4.50–4.30 (m, 2H), 4.01 (m,
1H), 3.94–3.81 (m, 2H), 3.59 (s, 4H), 3.51–3.45 (m, 2H), 3.42 (s, 2H),
3.22 (s, 2H), 2.89 (m, 2H), 2.32 (m, 2H), 2.08 (m, 2H), 1.65–1.53 (m,
2H), 1.49 (s, 9H). 13C-NMR (150 MHz, CDCl3) d (ppm): 168.4, 156.4
(d, J ¼ 250.6 Hz), 154.7, 151.4, 149.8, 144.0, 135.5 (d, J ¼ 10.5 Hz),
128.5 (d, J ¼ 3.6 Hz), 128.4 (d, J ¼ 2.5 Hz), 121.7, 120.6 (d,
J ¼ 23.7 Hz), 117.6 (d, J ¼ 2.6 Hz), 109.4 (d, J ¼ 9.1 Hz), 80.3, 64.3,
61.4, 52.8, 50.8, 48.2 (d, J ¼ 3.8 Hz), 47.0, 45.5, 43.6 (x2), 41.7, 32.6
(x2), 28.4 (x3). HRMS-TOF (m/z) calcd for C29H37FN8O4 [M þ H]þ:
581.2995, found 581.3136.
4.1.17.
3-Fluoro-4-(4-(piperidin-4-ylamino)-6,7-dihydro-8H-pyri-
mido[5,4-b][1,4]oxazin-8-yl)benzonitrile (21)
Follow the similar procedure of 14. Yellow solid, 72% yield. MS-
ESI: [M þ H]þ: 355.7.
4.1.18. Isopropyl 4-((8-(4-cyano-2-fluorophenyl)-7,8-dihydro-6H-
pyrimido[5,4-b][1,4]oxazin-4-yl)amino)piperidine-1-carboxylate (22)
1
4.2. hGPR119 agonistic activity
Follow the similar procedure of 15. Yellowish solid, 70% yield. H-
NMR (600 MHz, CDCl3) d (ppm): 7.93 (s, 1H), 7.56–7.51 (m, 1H),
7.48 (m, 2H), 4.95 (dt, J ¼ 12.5, 6.2 Hz, 1H), 4.83 (d, J ¼ 8.1 Hz, 1H),
4.43–4.33 (m, 2H), 4.27–4.08 (m, 3H), 3.93–3.85 (m, 2H), 3.00 (t,
J ¼ 12.0 Hz, 2H), 2.13–2.04 (m, 2H), 1.50–1.37 (m, 2H), 1.28 (s, 3H),
1.27 (s, 3H). 13C-NMR (150 MHz, CDCl3) d (ppm): 156.4 (d,
J ¼ 250.6 Hz), 155.2, 151.2, 149.8, 144.2, 135.4 (d, J ¼ 10.4 Hz), 128.5
(d, J ¼ 3.8 Hz), 128.4 (d, J ¼ 2.6 Hz), 121.7, 120.6 (d, J ¼ 23.7 Hz),
117.6 (d, J ¼ 2.7 Hz), 109.5 (d, J ¼ 9.2 Hz), 68.7, 64.3, 48.2 (d,
J ¼ 3.9 Hz), 47.6, 42.8 (x2), 32.5 (x2), 22.3 (x2). HRMS-TOF (m/z)
calcd for C22H25FN6O3 [M þ H]þ: 441.2045, found 441.2144.
CHO K1 cells stably transfected with human GPR119 were grown
at 37 ꢀC, 95%O2 and 5% CO2 in 75 cm flasks containing DMEM/F12
R
R
(1:1) media with added 10% FBS (GibcoV), Geneticin (GibcoV) and
grown until 90% confluent. Cells were then washed (PBS), lifted
R
with cell dissociation solution (InvtrogenV), counted and used for
cAMP accumulation assays and/or passaging (1:10). Following the
R
manufacturer’s instructions for the LANCEV Ultra cAMP assay
(Perkin Elmer), cell transfected with hGPR119 were centrifuged
(1000 rpm, 5 min), re-suspended in cAMP assay buffer (HBSS, 0.1%
BSA, 0.5 mM IBMX and 5 mM HEPES) and seeded at 5000 cells/well
in optiplate-384 (Perkin Elmer). Cells were treated with com-
pounds or reference GSK1292263 over a range of concentrations
(10 lM-0.6 lM) and incubated for 1 h. Cell lysis buffers (4X Eu-
cAMP tracer solution and 4X ULightTM-anti-cAMP solution) were
added to each well, and the plates were incubated at r. t. for 1 h
before being read on Envision (Perkin Elmer). The assay was per-
4.1.19.
4-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)amino)-6,7-
dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)-3-fluorobenzoni-
trile (23)
Follow the similar procedure of 16–20. Yellowish solid, 54% yield.
1H-NMR (600 MHz, CDCl3) d (ppm): 8.20 (s, 2H), 7.95 (s, 1H), formed for three replicates for each concentration.
7.56–7.51 (m, 1H), 7.48 (m, 2H), 4.87 (d, J ¼ 8.2 Hz, 1H), 4.68 (m,
2H), 4.42–4.32 (m, 2H), 4.32–4.17 (m, 1H), 3.92–3.84 (m, 2H),
4.3. oGTT in C57BL/6N mice
3.24–3.10 (m, 2H), 2.49 (q, J ¼ 7.6 Hz, 2H), 2.21–2.12 (m, 2H), 1.50
(m, 2H), 1.21 (t, J ¼ 7.6 Hz, 3H). 13C-NMR (150 MHz, CDCl3) d (ppm):
For the acute single dose study, vehicle (0.5% carboxymethylcellu-
lose sodium, 10 ml/kg), compound 10, compound 15 (15 and
30 mg/kg) and vildagliptin (30 mg/kg) were administered to
C57BL/6N mice after 16-h starvation, then the oral glucose toler-
160.8, 157.2 (x2), 156.4 (d, J ¼ 250.9 Hz), 151.4, 149.8, 144.1, 135.4
(d, J ¼ 10.5 Hz), 128.5 (d, J ¼ 3.7 Hz), 128.4 (d, J ¼ 2.6 Hz), 124.5,
121.7, 120.6 (d, J ¼ 23.8 Hz), 117.7 (d, J ¼ 2.6 Hz), 109.4 (d,
J ¼ 9.0 Hz), 64.3, 48.2 (d, J ¼ 3.9 Hz), 48.0, 43.1 (x2), 32.5 (x2), 22.7, ance test (3 g/kg) was conducted after 4 h of the single dose, the

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
57
blood glucose level at 0, 15, 30, 60, 90, and 120 min were 14. Zhou Y, Zhu X, Zhang L, et al. Design, synthesis, and bio-
recorded for area under curve calculation (AUC0–2h).
AUC0–2h(mmol/L) ¼ (BG0þBG15)ꢂ0.25/2 þ (BG15þBG30)ꢂ0.25/2 þ
(BG30þBG60)ꢂ0.5/2 þ (BG60þBG90)ꢂ0.5/2 þ (BG90þBG120)ꢂ0.5/2.
logical evaluation of 2-(4-(methylsulfonyl)phenyl)pyridine
derivatives as GPR119 agonists. Chem Biol Drug Des 2019;
93:67–74.
15. Gao J, Tian L, Weng G, et al. Stimulating beta cell replication
and improving islet graft function by GPR119 agonists.
Transpl Int 2011;24:1124–34.
Disclosure statement
16. Fyfe MC, McCormack JG, Overton HA, et al. GPR119 agonists
as potential new oral agents for the treatment of type 2 dia-
betes and obesity. Expert Opin Drug Dis 2008;3:403–13.
17. Yoshida S, Ohishi T, Matsui T, et al. The role of small mol-
ecule GPR119 agonist, AS1535907, in glucose-stimulated
insulin secretion and pancreatic b-cell function. Diabetes
Obes Metab 2011;13:34–41.
18. Matsuda D, Kawamura M, Kobashi Y, et al. Design, synthesis
and biological evaluation of novel 7-azaspiro[3,5]nonane
derivatives as GPR119 agonists. Bioorgan Med Chem 2018;
26:1832–47.
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by National Natural Science
Foundation of China [81460526], Jiangxi Provincial Department of
Science and Technology [20171BAB205103, 20181BAB215043,
20192ACB21012], Education Department of Jiangxi Province on
Science and Technology Project Foundation [GJJ180667] and
Traditional Chinese pharmacology discipline construction of Jiangxi
University of Traditional Chinese Medicine [JXSYLXK-ZHYAO013].
19. Zhu C, Wang L, Zhu Y, et al. Discovery of phenyl acetamides
as potent and selective GPR119 agonists. Bioorg Med Chem
Lett 2017;27:1124–8.
20. Li G, Huan Y, Yuan BK, et al. Discovery of novel xanthine
compounds targeting DPP-IV and GPR119 as anti-diabetic
agents. Eur J Med Chem 2016;124:103–16.
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