4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists

Article abstract of DOI:10.1016/j.ejmech.2014.05.031

A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC₅₀ = 0.28 nM, mTGR5 EC ₅₀ = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC₅₀ of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19.

Full text of DOI:10.1016/j.ejmech.2014.05.031

Accepted Manuscript
4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available
TGR5 agonists
Qingan Zou , Hongliang Duan , Mengmeng Ning , Jia Liu , Ying Feng , Liming Zhang ,
Junjie Zhu , Ying Leng , Jianhua Shen
PII:
S0223-5234(14)00445-0
10.1016/j.ejmech.2014.05.031
EJMECH 6987
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 30 November 2013
Revised Date: 9 May 2014
Accepted Date: 11 May 2014
Please cite this article as: Q. Zou, H. Duan, M. Ning, J. Liu, Y. Feng, L. Zhang, J. Zhu, Y. Leng, J.
Shen, 4-Benzofuranyloxynicotinamide derivatives are novel potent and orally available TGR5 agonists,
European Journal of Medicinal Chemistry (2014), doi: 10.1016/j.ejmech.2014.05.031.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
-Benzofuranyloxynicotinamide derivatives are novel potent and
orally available TGR5 agonists
4
Qingan Zou, Hongliang Duan, Mengmeng Ning, Jia Liu, Ying Feng, Liming Zhang,
Junjie Zhu, Ying Leng* and Jianhua Shen*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
(
SIMM), Chinese Academy of Sciences, Shanghai 201203, China
Abstract
A series of 4-benzofuranyloxynicotinamide derivatives were identified to be
novel, potent, and orally available TGR5 agonists. Among them, compound 9r had
the highest potency in vitro (hTGR5 EC = 0.28 nM, mTGR5 EC = 0.92 nM).
5
0
50
Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but
meantime caused an increase in the gallbladder volume of mice. Subsequent research
toward eliminating the gallbladder toxicity resulted in compound 19 with low
permeability. Although the EC of mTGR5 of 19 was larger one order than that of 9r,
5
0
it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse
effects to the gallbladder. The drug levels detection disclosed that the concentration of
1
9 was only lower than that of 9r in plasma but was higher in bile and gallbladder
tissue. This result indicated that low exposure in plasma could not guarantee low
exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of
1
9.
Keywords: TGR5; 4-Benzofuranyloxynicotinamide; Gallbladder toxicity; Caco-2
permeability.
1
. Introduction
TGR5, a G-protein-coupled receptor that has been identified as a cell surface
receptor responsive to bile acids (BAs), was discovered independently by two
Japanese groups almost simultaneously [1, 2]. It is abundantly expressed in the lung,
spleen, placenta, small intestine, gallbladder, and brown adipose tissue [3]. Because of
its widespread distribution in human tissue, TGR5 plays important roles in the
1

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regulation of a multitude of physiological functions and pathological processes [4].
The activation of TGR5 has been proven to result in the stimulation of glucagon-like
peptide-1 (GLP-1) secretion from intestinal enteroendocrine cells by increasing the
intracellular cyclic adenosine monophosphate (cAMP) concentration [5]. GLP-1
influences blood glucose homeostasis by stimulating insulin release in a
glucose-dependent manner, suppressing glucagon release, slowing gastric emptying,
and suppressing appetite [6]. Therefore, small molecules that induce TGR5 activity
may be useful in reducing high blood glucose levels. In addition, it has been reported
that TGR5 agonists such as BAs can increase energy expenditure of mice, thereby
preventing obesity through action on the BA-TGR5-cAMP-D2 signaling pathway [7].
Therefore, TGR5 has immense potential to become a promising target for the
treatment of diabetes and associated metabolic disorders.
Recently, owing to the promising application of TGR5 agonists in type II
diabetes treatment, intensive research has been undertaken in the area and a variety of
potent TGR5 agonists have been reported [8–13]. Based on BAs and triterpenoid
scaffolds, a number of potent and selective TGR5 agonists, including
6
α-ethyl-23(S)-methylcholic acid (INT-777, Fig. 1) [8], have been reported. INT-777
had an acceptable pharmacokinetic profile and induced the release of GLP-1 in the
gut in a TGR5-dependent manner, with improvement of insulin sensitivity and
glucose tolerance, increased energy expenditure, and prevention of weight gain [14].
However, INT-777 significantly increased gallbladder volume in wild-type mice,
limiting its further development [15]. Our group previously reported a series of
4
-phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as
potent and selective TGR5 agonists [10]. Compound 1, with an EC of 0.72 nM
5
0
toward hTGR5 and an EC of 6.2 nM toward mTGR5, increased the release of
50
GLP-1 in a dose-dependent manner and caused a significant reduction in blood
glucose levels in both db/db and ICR mice. Nonetheless, similar to INT-777, after oral
administration at a dose of 50 mg/kg to ICR mice, the gallbladder volume was
significantly increased. It was reported that because TGR5 is highly expressed in the
gallbladder, systemic TGR5 agonists will inevitably stimulate the filling of the
2

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gallbladder with bile leading to a dramatic increase in gallbladder volume [15, 16].
Fortunately, research efforts [9] have demonstrated that systemic exposure was not
required for in vivo efficacy of TGR5 agonists. Therefore, it might be feasible to
eliminate the gallbladder toxicity of TGR5 agonists by reducing their systemic
exposure as much as possible. In addition, Roche Corp. published a patent that
disclosed a series of small molecular TGR5 agonists with a similar scaffold to
compound 1 [17]. Consequently, we initiated a search for a novel class of TGR5
agonists with low systemic exposure to reduce gallbladder toxicity as well as improve
structural novelty.
Compounds 2–4 (Fig. 2) were disclosed in a patent previously by our group [18].
Among them, compound 4 exhibited the highest potency with an EC of 2.3 nM
5
0
toward hTGR5, while compound 3 (hTGR5 EC =5.5 nM) was less potent than 2 and
50
compound 2 was almost inactive. After careful analysis of the structure of compound
, we found that the two adjacent substituents, a hydroxyl and an acetyl, could form
4
an intramolecular hydrogen bond. The formation of the hydrogen bond induced the
phenoxy moiety to form a double-ring structure, which might improve the affinity to
TGR5. In light of the positive role of the double-ring structure, we planned to
introduce a suitable benzo-fused five- or six-membered ring to replace the
3
-acetyl-4-hydroxyphenyl moiety to improve potency. More importantly, we hoped
that the structural optimizations would help to eliminate the adverse effects to the
gallbladder tissue. Herein, we report our synthetic efforts, optimizations, and the
biological evaluations of 4-benzocyclicoxypridine-3-carboxamide derivatives.
2
. Results and discussion
2
.1 Chemistry
The synthesis of compounds 9a–9s was outlined in Scheme 1, which was similar
to the procedure described in the literature [10]. First, 4-chloronicotinic acid (5) was
converted into the acid chloride by reaction with thionyl chloride, followed by
esterification with ethanol to give ethyl 4-chloronicotinate (6). Treatment of
compound 6 with various commercially available or prepared benzocyclic phenols in
3

ACCEPTED MANUSCRIPT
the presence of potassium carbonate in DMF at 90–100 °C provided the
corresponding intermediates 7a–7s in good yields. Subsequent hydrolysis of the esters
7
a–7s
-cyclopropyl-1,2,3,4-tetrahydroquinoxaline gave the target compounds 9a–9s.
-Chlorobenzofuran-5-yloxy derivatives 13a–d possessing an ethyl carboxylate
chain on the benzofuran ring were synthesized following the route depicted in Scheme
. Compound 5 was protected with a benzyl group followed by nucleophilic
yielded
the
acids
8a–8s.
Condensation
of
8a–8s
with
1
6
2
substitution with a variety of substituted 5-hydroxybenzofurans, which were prepared
according to the reported methods [19–21], yielding the key intermediates 11a–d.
Compounds 13a–d were obtained through deprotection of the benzyl group of the
esters 11a–d by catalytic hydrogenation, followed by coupling with
1
-cyclopropyl-1,2,3,4-tetrahydroquinoxaline. Hydrolysis of the esters 13a–d yielded
the compounds 14a–d which underwent condensation with glycine ethyl ester
hydrochloride to give the target compounds 15a–d.
As illustrated in Scheme 3, the preparation of compound 16 was accomplished
by a microwave-assisted Heck reaction of 9s with ethyl acrylate in excellent yield.
Reduction of the olefin moiety of compound 16 with sodium borohydride (NaBH4)
and one equivalent cuprous chloride gave compound 20. The synthesis of 17, 18, 21,
and 22 was the same as described in Scheme 2. Finally, hydrolysis of compound 18
provided compound 19.
2
.2 Results of biological evaluations and discussion
The compounds were evaluated for their ability to activate TGR5 and the results
were summarized in Table 1.
-Naphthyl analog 9a was somewhat more potent than 2-naphthyl (9b), but was
1
less potent than compound 4. The quinolyl analogs 9c–9f displayed even lower
potencies compared with compound 9a and the largest loss in potency was observed
for the 8-quinolyl derivative 9f. Pleasingly, a slight increase in potency was noted for
the 5-benzofuranyl analog 9g compared with 9a, whereas the 6-benzofuranyl analog
9
h was slightly less active. Replacing 5-benzofuranyl with 5-benzothiopenyl resulted
4

ACCEPTED MANUSCRIPT
in compound 9l, which showed comparable activity to 9a. Unfortunately, compounds
9i–9k bearing an indolyl group suffered a great loss in potency. The results indicated a
hydrogen-bond donor, like the oxygen atom of benzofuran, might be beneficial to
increase the binding affinities of compounds while the hydrogen atom on the nitrogen
of indole might blocke this interaction. 6-Thiazolyl derivative 9m showed almost the
same activity as 9l. Fortunately, a significant improvement in potency was achieved
after the introduction of 3-methyl-5-benzoisoxazolyl providing compound 9n, with
EC values of 1.4 and 5.5 nM toward hTGR5 and mTGR5, respectively. However, a
50
change in the position of the 3-methylbenzoisoxazole group led to a great reduction in
potency (9o vs 9n).
The distinct increase in potency of compound 9n attracted our attention. After
analyzing the structures of compounds 9n, 9g, and 4, we speculated that the methyl at
position 3 of the benzoisoxazole of compound 9n, which was similar to the methyl of
the actyl group of compound 4, might contribute to its excellent potency. On this basis,
we decided to introduce a methyl group at position 3 of the benzofuran ring of
compound 9g. The resulting compound 9q exhibited significant boosts in potency
with EC values of 0.45 nM and 2.4 nM toward hTGR5 and mTGR, respectively. In
50
addition, a chloro atom at position 2 of the phenoxy moiety improved the activity [13],
and hence this substituent was incorporated into the structure of 9q to give compound
9
r. 9r showed a further increase in potency, with EC values of 0.28 nM and 0.92 nM
50
toward hTGR5 and mTGR5, respectively. Moreover, the activity of compound 9p
supported the importance of the 2-chloro (vs. 9g) and 3-methyl (vs. 9r) substituents.
Brominated derivative 9s displayed a large loss in potency compared with 9r.
On account of the excellent in vitro activity of 9r, it was selected to carry out
further in vivo studies to evaluate its glucose-lowing activity and gallbladder toxicity.
First, an oral glucose tolerance test (OGTT) was conducted in ICR mice. The areas
under the curve AUC0−120 min for glucose levels versus time were calculated after a
single oral administration of 9r (50mg/kg), and it was found to caused a 33%
reduction in blood glucose AUC0−120 min (Fig. 3). Unfortunately, we simultaneously
found 9r caused an increase of the gallbladder volume by 97%. The drug levels
5

ACCEPTED MANUSCRIPT
detection showed the concentrations of 9r in plasma, bile and gallbladder tissue were
approximately 153-, 1034- and 891-fold greater than the EC50 value of mTGR5,
respectively. This result indicated that the systemic exposure of 9r was sufficient to
activate TGR5 in gallbladder tissue, and thus caused gallbladder toxicity. Therefore,
9
r should be further optimized to achieve a compound with low systemic exposure.
Systemic drug exposure is closely related to oral bioavailability which is
predominantly determined by oral absorption and liver first-pass metabolism [22],
while the intestinal permeability is a major determinant of extent of oral absorption
[
23]. Therefore, a compound with low intestinal permeability would have poor oral
absorption and low systemic exposure. Considering that the Caco-2 permeability can
be used to predict the intestinal permeability [24], the Caco-2 permeability assay was
adopted. Our subsequent work mainly focused on searching for compounds with low
Caco-2 permeability and maintaining good activity toward TGR5.
To lower the molecular Caco-2 permeability, a high polar kinetophore should be
introduced without interfering with the binding affinities to the receptor [25]. To
search for an appropriate site and a suitable linker to tolerate this polar functional
group, the effects of substitutions at positions 2 and 3 of the benzofuran ring of 9r on
potency were explored. Initially, modifications were carried out around the 3-methyl
group. Replacement of the methyl group with a carboxylic ester group provided
compound 13b, which showed excellent activity toward hTGR5 but a great loss in
potency toward mTGR5. Acid 14b, the hydrolysis product of 13b, was almost
inactive, while its amidated product 15b (EC = 1405 nM) provided a slight increase
5
0
in potency. Insertion of one or two methylenes between the carboxylic ester and
position 3 of the benzofuran ring of 13b yielded two less potent compounds (13c and
1
3d), however, an opposite tendency in potency was observed for their hydrolysis
products (14b d) and coupling products (15b d). Nonetheless, no compound with a
–
–
polar group was potent enough for further study in vivo. The unfavorable results of
these variations proved again that the 3-methyl group was essential for activity. In
view of this, polar substituents at position 2 were investigated while keeping the vital
3
-methyl intact. Compound 13a, with a carboxylic ester group directly introduced at
6

ACCEPTED MANUSCRIPT
the benzofuran ring, suffered a dramatic reduction in potency compared with 9r, and
its hydrolysis product 14a and coupling product 15a both displayed similar activity.
The incorporation of two methylenes gave an approximate one-fold increase in
potency for ester 20 as well as its hydrolysis and coupling products (21, 22) compared
with 13a–15a. Replacement of two methylenes with a vinyl group (16 vs 20) further
led to a one- and three-fold increase in activity for hTGR5 and mTGR5, respectively.
Hydrolysis product 17 displayed a slightly weaker potency toward hTGR5 while
coupling product 18 maintained activity for hTGR5 and enhanced the activity for
mTGR5. Compound 19, the hydrolysis product of 18, was a little less potent than 18
but still maintained moderate activity for both hTGR5 and mTGR5. Moreover, the
-6
Caco-2 permeability of compound 19 (Papp = 0.21×10 cm/s) was much lower than
-6
-6
9
r (Papp = 2.10×10 cm/s) and 18 (Papp = 1.04×10 cm/s) (Table 3), which might
imply it would have low systemic exposure. Therefore, compound 19 was selected to
carry out further in vivo studies.
First, the OGTT showed a single oral dose of 19 (50mg/kg) could cause a 25%
reduction in blood glucose AUC0−120min (Fig. 3). However, we also found 19 caused an
increase of gallbladder volume by 42% (Fig. 4), albeit less than 9r but still
unacceptable for further development. This undesirable result made us wonder
whether the drug concentration in plasma, bile, and gallbladder tissue decreased along
with the decrease in permeability, and hence the drug levels of 19 were detected.
Unexpectedly, the concentration of 19 was only lower than that of 9r in plasma, while
much higher in bile and gallbladder tissue (Table 4).
Next, we tried to uncover the reasons for the unexpectedly high concentration of
1
9 in bile and gallbladder tissue. The ratio of 19 in bile and plasma was 1784,
suggesting that biliary excretion should be a significant route of elimination for 19
26]. As the gallbladder can concentrate the bile [27], the drug levels of 19 became
[
higher in gallbladder bile, which resulted in a large concentration gradient between
gallbladder bile and gallbladder tissue. This concentration gradient might induce the
movement of 19 from gallbladder bile to gallbladder tissue [28, 29]. In addition, 19 in
plasma could be partially distributed to the gallbladder tissue [29]. As the
7

ACCEPTED MANUSCRIPT
concentration of 19 in gallbladder tissue gradually increased, it became sufficient to
activate TGR5. In turn, the activation of TGR5 in gallbladder tissue caused
gallbladder smooth muscle relaxation leading to the decrease of gallbladder emptying
[
18, 19], preventing timely excretion of 19 ultimately resulting in its accumulation in
gallbladder bile. On the contrary, owing to its lower polarity, 9r may not, in principle,
be excreted into the bile [30, 31]. Consequently, the concentration of 19 was much
higher than 9r in gallbladder bile. The high drug levels of 19 in gallbladder tissue
probably resulted from the extremely high concentration in gallbladder bile [28, 29].
Besides, to determine whether differences in metabolic stability contributed to the
differences in the concentrations of 9r and 19, an in vitro mouse microsomal assay
was carried out. The result indicated that there was no significant difference between
their clearances in mouse microsomes (Table 5).
3
. Conclusion
A series of 4-benzofuranyloxynicotinamide derivatives was synthesized as potent
TGR5 agonists. The most potent compound 9r (hTGR5 EC = 0.28 nM, mTGR5
5
0
EC = 0.92 nM) was selected to execute further in vivo studies. Through an OGTT, it
50
was found to cause a 33% reduction in blood glucose AUC0−120 min after a single oral
administration of 9r (50mg/kg). Yet we simultaneously found the gallbladder volume
of mice significantly increased. To eliminate the gallbladder toxicity, subsequent work
-6
resulted in 19 with low Caco-2 permeability (Papp = 0.21×10 cm/s) and moderate
potency. The OGTT showed 19 still had good glucose-lowing activity, however,
meantime it still caused adverse effects to the gallbladder. The drug levels detection
disclosed that the concentration of 19 was only lower than that of 9r in plasma but
was much higher in bile and gallbladder tissue, which indicated low exposure in
plasma could not guarantee low exposure in bile and gallbladder tissue, and thus
resulting in the gallbladder toxicity of 19. Therefore, we could arrive at a conclusion
that only low exposure in plasma was insufficient for a non-toxic TGR5 agonist, but
low exposures in bile and gallbladder tissue were also necessary. In addition, we
speculated the primary reason for the extremely high concentration of 19 in bile and
8

ACCEPTED MANUSCRIPT
gallbladder tissue might be that biliary excretion was a significant route of elimination
for 19. Hence, we thought the compounds should be designed to avoid elimination
predominantly by biliary excretion to prevent their accumulations in the gallbladder
bile. Over all, additional research is necessary to determine how the lead compound
can be further optimized to yield a non-toxic TGR5 agonist.
4
. Experiment
4
.1 Chemistry
All reagents were purchased from commercial suppliers and used without further
purification. Microwave reactions were performed in a Biotage Initiator. Column
chromatography was carried out on silica gel (200–300 mesh) or with pre-packed
silica cartridges (4–40 g) from Bonna-Agela Technologies Inc. (Tianjin, China) and
1
13
eluted with a CombiFlash® Rf 200 from Teledyne Isco. H NMR and C NMR
spectra were recorded on a Bruker AC300 or a Bruker AC400 NMR spectrometer,
using tetramethylsilane as an internal reference. Low-resolution mass spectra were
determined on a Waters ZQ2000a or Agilent LC–MS systems that consisted of an
Agilent 1260 infinity LC coupled to an Agilent 6120 Quadrupole mass spectrometer
(ESI+) using an Agilent ZORBAX 1.8 mm SB-C18 column (2.1×50 mm) or a
CAPCELL PAK C18 MGIII S3 (Shiseido Co., Ltd.) column (2.0(i.d.)×50 mm).
High-resolution mass spectra were recorded on a Q-Tof Ultima Globe mass
spectrometer (Micromass, Manchester, UK).
4
.1.1 Ethyl 4-chloronicotinate(6)
A mixture of 4-chloronicotinatic acid (7.88g, 50mmol) in dichloromethane
(100ml) was added thionyl chloride (12.7ml, 150mmol) and DMF (3 drops), and the
reaction was refluxed for 2h. After the reaction was cooled to room temperature, the
solvent and thionyl chloride was removed under reduced pressure. Then ethanol
(
80ml) and Et N (13.9ml, 100mmol) were added to the residue and the resulting
3
mixture was stirred at room temperature overnight. The solution was diluted with
water (80ml), and extracted with dichloromethane (50ml×2). The organic layers were
combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and
9

ACCEPTED MANUSCRIPT
evaporated under reduced pressure. The residue was purified by flash column
chromatography with petroleum ether/ethyl acetate (10:1) to provide 7.89g (85%) of 6
1
as a colorless oil. H NMR (300 MHz, CDCl ) δ 9.20(s, 1H), 8.82(d, J = 6.0Hz, 1H),
3
8
.08(d, J = 6.0Hz, 1H), 4.48(q, J = 7.5Hz, 2H), 1.43(t, J = 7.5Hz, 3H).
.1.2. General procedure for 7a–7s.
4
To a mixture of 6 (1mmol) and potassium carbonate (3mmol) in anhydrous DMF
(5ml) was added corresponding benzo cyclic phenol (1.1mmol). After the resulting
mixture was heated at 90–110 °C for 3–10h, the reaction was cooled to room
temperature and poured into water (15ml). The mixture was extracted with ethyl
acetate for three times, and the organic layers were combined, washed with saturated
brine (20ml×2), dried over anhydrous magnesium sulfate and evaporated under
reduced pressure. The residue was purified by flash column chromatography to yield
the desired compound.
4
.1.3 Ethyl 4-(naphthalen-1-yloxy)nicotinate (7a)
The title compound was synthesized from 6 and naphthalen-1-ol according to the
1
general procedure in yield of 89%. H NMR (300 MHz, CDCl ): δ 8.98(s, 1H),
3
8
.52(m, 1H), 8.18(d, J = 7.5Hz, 1H), 7.91(d, J = 7.5Hz, 1H), 7.75(t, J = 8.1Hz, 1H),
.61(m, 1H), 7.46(m, 2H), 7.12(m, 1H), 6.89(m, 1H), 4.39(q, J = 7.8Hz, 2H), 1.33(t, J
7
=
7.8Hz, 3H).
4
.1.4 Ethyl 4-(naphthalen-2-yloxy)nicotinate (7b)
The title compound was synthesized from 6 and naphthalen-2-ol according to the
1
general procedure in yield of 90%. H NMR (300 MHz, CHCl ): δ 8.96(s, 1H),
3
8.56(m, 1H), 7.98(m, 2H), 7.81(m, 1H), 7.55(m, 2H), 7.23(m, 1H), 6.87(m, 1H),
6.55(m, 1H), 4.38(q, J = 7.5Hz, 2H), 1.32(t, J = 7.5Hz, 3H).
4.1.5 Ethyl 4-(quinolin-5-yloxy)nicotinate (7c)
The title compound was synthesized from 6 and quinolin-5-ol according to the
1
general procedure in yield of 83%. H NMR (300 MHz, CDCl ): δ 9.08(s, 1H),
3
8
8
.97(dd, J = 3.9Hz, 1.8Hz , 1H), 8.48(d, J = 5.7Hz, 1H), 8.39(m, 1H), 8.03(d, J =
.7Hz, 1H), 7.71(dd, J = 8.7Hz, 7.5Hz, 1H), 7.43(dd, J = 5.7Hz, 3.9Hz, 1H), 7.20(dd,
J = 7.5Hz, 1.2Hz, 1H), 6.63(d, J = 5.7Hz, 1H), 4.39(q, J = 7.2Hz, 2H), 1.32(t, J =
1
0

ACCEPTED MANUSCRIPT
7
.2Hz, 3H).
4
.1.6 Ethyl 4-(quinolin-6-yloxy)nicotinate (7d)
The title compound was synthesized from 6 and quinolin-6-ol according to the
1
general procedure in yield of 85%. H NMR (300 MHz, CDCl ): δ 9.06(s, 1H), 8.91(d,
3
J = 2.4Hz, 1H), 8.47(d, J = 5.1Hz, 1H), 8.05-8.02(m, 2H), 7.51(m, 1H), 7.42(m, 1H),
7
.15(m, 1H), 6.71(m, 1H), 4.41(q, J = 7.5Hz, 2H), 1.34(t, J = 7.5Hz, 3H).
4
.1.7 Ethyl 4-(quinolin-7-yloxy)nicotinate (7e)
The title compound was synthesized from 6 and quinolin-7-ol according to the
1
general procedure in yield of 82%. H NMR (300 MHz, CDCl ): δ 9.08(s, 1H),
3
8
.96(dd, J = 3.6Hz, 1.2Hz, 1H), 8.43(d, J = 1.2Hz, 1H), 8.22(d, J = 6.3Hz, 1H), 7.91(d,
J = 7.2Hz, 1H), 7.59(m, 1H), 7.45(m, 1H), 7.24(m, 1H), 6.86(m, 1H), 4.39(q, J =
7
.2Hz, 2H), 1.32(t, J = 7.2Hz, 3H).
4
.1.8 Ethyl 4-(quinolin-8-yloxy)nicotinate (7f)
The title compound was synthesized from 6 and quinolin-8-ol according to the
1
general procedure in yield of 81%. H NMR (300MHz, CDCl ):δ 9.06(s, 1H), 8.87(m,
3
1H), 8.37(m, 1H), 8.22(m, 1H)ꢀ7.73(m, 1H), 7.51(m, 1H), 7.12(m, 1H), 7.04(m, 1H),
6.89(m, 1H), 4.38(q, J = 7.2Hz, 2H), 1.34(t, J = 7.2Hz, 3H).
4.1.9 Ethyl 4-(benzofuran-5-yloxy)nicotinate (7g)
The title compound was synthesized from 6 and benzofuran-5-ol according to the
1
general procedure in yield of 86%. H NMR (300 MHz, CDCl ): δ 9.05(s, 1H), 8.52(d,
3
J = 6.0Hz, 1H), 7.62(d, J = 1.8Hz, 1H), 7.53(m, 2H), 7.12(m, 1H), 6.74(d, J = 1.8Hz,
1
H), 6.43(d, J = 6.0Hz, 1H), 4.43(q, J = 7.5Hz, 2H), 1.40(t, J = 7.5Hz, 3H).
4
.1.10 Ethyl 4-(benzofuran-6-yloxy)nicotinate (7h)
The title compound was synthesized from 6 and benzofuran-6-ol according to the
1
general procedure in yield of 84%. H NMR (300 MHz, CDCl ): δ 9.01(s, 1H), 8.54(d,
3
J = 7.2Hz, 1H), 7.63(d, J = 7.5Hz, 1H), 7.53(m, 1H), 7.13(m, 1H), 7.02(m, 1H),
6
.92(m, 1H), 6.68(d, J = 7.2Hz, 1H), 4.42(q, J = 7.2Hz, 2H), 1.41(t, J = 7.2Hz, 3H).
4
.1.11 Ethyl 4-(1H-indol-5-yloxy)nicotinate (7i)
The title compound was synthesized from 6 and 1H-indol-5-ol according to the
1
general procedure in yield of 75%. H NMR (300 MHz, CDCl ): δ 9.00(s, 1H), 8.50(s,
3
1
1

ACCEPTED MANUSCRIPT
1
6
7
4
H), 8.40(d, J = 6.0Hz, 1H), 7.42(d, J = 8.7Hz, 1H), 7.34(m, 1H), 7.30(m, 1H),
.95(m, 1H), 6.63(d, J = 6.0Hz, 1H), 6.56(m, 1H), 4.43(q, J = 7.2Hz, 2H), 1.41(t, J =
.2Hz, 3H).
.1.12 Ethyl 4-(1H-indol-4-yloxy)nicotinate (7j)
The title compound was synthesized from 6 and 1H-indol-4-ol according to the
1
general procedure in yield of 76%. H NMR (300 MHz, CDCl ): δ 9.03(s, 1H),
3
8
1
3
4
.51(br, 1H), 8.41(d, J = 6.0Hz, 1H), 7.53(m, 1H), 7.36(m, 1H), 7.31(m, 1H), 7.05(m,
H), 6.65(d, J = 6.0Hz, 1H), 6.48(m, 1H), 4.42(q, J = 7.2Hz, 2H), 1.41(t, J = 7.2Hz,
H).
.1.13 Ethyl 4-(1H-indol-6-yloxy)nicotinate (7k)
The title compound was synthesized from 6 and 1H-indol-6-ol according to the
1
general procedure in yield of 79%. H NMR (300 MHz, CDCl ): δ 9.00(s, 1H),
3
8
1
3
4
.51(br, 1H), 8.40(d, J = 6.0Hz, 1H), 7.91(m, 1H), 7.36(m, 1H), 7.18(m, 1H), 6.95(m,
H), 6.64(d, J = 6.0Hz, 1H), 6.54(m, 1H), 4.42(q, J = 7.2Hz, 2H), 1.40(t, J = 7.2Hz,
H).
.1.14 Ethyl 4-(benzo[b]thiophen-5-yloxy)nicotinate (7l)
The title compound was synthesized from 6 and benzo[b]thiophen-5-ol
1
according to the general procedure in yield of 84%. H NMR (300 MHz, CDCl ): δ
3
9
5
2
4
.03(s, 1H), 8.36(d, J = 6.0Hz, 1H), 7.91(d, J = 8.7Hz, 1H), 7.55(m, 2H), 7.31(d, J =
.7Hz, 1H), 7.13(dd, J = 2.4Hz, 8.7Hz, 1H), 6.67(d, J = 6.0Hz, 1H), 4.41(q, J = 7.2Hz,
H), 1.39(t, J = 7.2Hz, 3H).
.1.15 Ethyl 4-(benzo[d]thiazol-6-yloxy)nicotinate (7m)
The title compound was synthesized from 6 and benzo[d]thiazol-6-ol according
1
to the general procedure in yield of 79%. H NMR (400 MHz, CDCl ): δ 9.06(s, 1H),
3
9
7
.01(s, 1H), 8.51(d, J = 6.0Hz, 1H), 8.17(d, J = 8.8Hz, 1H), 7.68(d, J = 2.4Hz, 1H),
.29 (dd, J = 2.4Hz, 8.4Hz, 1H), 6.70(d, J = 6.0Hz, 1H), 4.40(q, J = 7.2Hz, 2H), 1.37(t,
J = 7.2Hz, 3H).
4
.1.16Ethyl 4-(3-methylbenzo[d]isoxazol-5-yloxy)nicotinate (7n)
The title compound was synthesized from 6 and 3-methylbenzo[d]isoxazol-5-ol
1
according to the general procedure in yield of 82%. H NMR (300 MHz, CDCl ): δ
3
1
2

ACCEPTED MANUSCRIPT
9.05(s, 1H), 8.46(d, J = 6.0Hz, 1H), 7.63(d, J = 8.7Hz, 1H), 7.12(m, 1H), 7.02(m, 1H),
6.58(d, J = 6.0Hz, 1H), 4.42(q, J = 7.2Hz, 2H), 2.56(s, 3H), 1.41(t, J = 7.2Hz, 3H).
4.1.17 Ethyl 4-(3-methylbenzo[d]isoxazol-6-yloxy)nicotinate (7o)
The title compound was synthesized from 6 and 3-methylbenzo[d]isoxazol-6-ol
1
according to the general procedure in yield of 80%. H NMR (300 MHz, CDCl ): δ
3
9
.07(s, 1H), 8.47(d, J = 6.0Hz, 1H), 7.62(d, J = 8.1Hz, 1H), 7.21(m, 1H), 7.08(m, 1H),
6
.62(d, J = 6.0Hz, 1H), 4.41(q, J = 7.2Hz, 2H), 2.55(s, 3H), 1.42(t, J = 7.2Hz, 3H).
4
.1.18 Ethyl 4-(6-chlorobenzofuran-5-yloxy)nicotinate (7p)
The title compound was synthesized from 6 and 6-chlorobenzofuran-5-ol
1
according to the general procedure in yield of 83%. H NMR (300 MHz, CDCl ) δ
3
9
1
4
.06(s, 1H), 8.46(d, J = 6.0Hz, 1H), 7.70(m, 1H), 7.68(s, 1H), 7.42(s, 1H), 6.77(m,
H), 6.48(d, J = 6.0Hz, 1H), 4.42(q, J = 7.2Hz, 2H), 1.40(t, J = 7.2Hz, 3H).
.1.19 Ethyl 4-(3-methylbenzofuran-5-yloxy)nicotinate (7q)
The title compound was synthesized from 6 and 3-methylbenzofuran-5-ol
1
according to the general procedure in yield of 85%. H NMR (400 MHz, CDCl ) δ
3
9
1
3
4
.03(s, 1H), 8.41(d, J = 6.0Hz, 1H), 7.78(s, 1H), 7.65(m, 1H), 7.41(s, 1H), 7.08(m,
H), 6.51(d, J = 6.0Hz, 1H), 4.42(q, J = 7.2Hz, 2H), 2.19(s, 3H), 1.42(t, J = 7.2Hz,
H).
.1.20 Ethyl 4-(6-chloro-3-methylbenzofuran-5-yloxy)nicotinate (7r)
The title compound was synthesized from 6 and 6-chloro-3-methylbenzofuran-
1
5
-ol according to the general procedure in yield of 82%. H NMR (400 MHz, CDCl )
3
δ 9.05(s, 1H), 8.46(d, J = 6.0Hz, 1H), 7.61(s, 1H), 7.47(q, J = 1.2Hz, 1H), 7.34(s, 1H),
6
7
4
.48(d, J = 6.0Hz, 1H), 4.44(q, J = 7.2Hz, 2H), 2.20(d, J = 1.2Hz, 3H), 1.41(t, J =
.2Hz, 3H).
.1.21 Ethyl 4-(2-bromo-6-chloro-3-methylbenzofuran-5-yloxy)nicotinate (7s)
The title compound was synthesized from 6 and 2-bromo-6-chloro-3-methyl-
1
benzofuran-5-ol according to the general procedure in yield of 81%. H NMR (300
MHz, CDCl ) δ 9.06(s, 1H), 8.47(d, J = 6.0Hz, 1H), 7.58(s, 1H), 7.27(s, 1H), 6.46(d, J
3
=
6.0Hz, 1H), 4.43(q, J = 7.2Hz, 2H), 2.16(s, 3H), 1.41(t, J = 7.2Hz, 3H).
4
.1.22 General procedure for 9a–9h and 9l–9s
1
3

ACCEPTED MANUSCRIPT
Sodium hydroxide (1mmol) was added to a solution of 7a–7h and 7l–7s
(0.5mmol) in 1, 4-dioxane (3ml) and water (3ml), and the reaction was stirred at
ambient temperature for 2–10h. After the solvent was removed under reduced
pressure, the residue was dissolved in water (6ml) and the pH was adjusted to 3 with
2
N HCl. The formed precipitate was filtered, washed with cold water, and dried under
vacumm to obtain 8a–8h and 8l–8s, which were used in next step without any further
purification. Acid intermediate (0.3mmol) was dissolved in dichloromethane, and then
oxalyl chloride (1.2mmol) and DMF (2 drops) were added. The resulting mixture was
refluxing for 2h. After cooling to ambient temperature, the solvent and excess oxalyl
chloride were removed under reduced pressure. The residue was dissolved in
dichloromethane (5ml), followed by adding 1-cyclopropyl-1,2,3,4-tetrahydro-
quinoxaline (0.3mmol) and Et N (1mmol). The reaction was stirred at room
3
temperature for 2h, poured into water (8ml) and extract with dichloromethane. The
organic layer was washed with saturated brine, dried over anhydrous magnesium
sulfate and evaporated to dryness. The crude product was purified by flash column
chromatography to yield the desired compound.
4
.1.23 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(naphthalen-1-yloxy)pyrid-
in-3-yl)methanone (9a)
The title compound was obtained as a light yellow solid from 7a according to the
1
general procedure in yield of 85%. H NMR (300 MHz, DMSO-d6): δ 8.74(s, 1H),
8.32(m, 1H), 7.98(d, J = 7.8Hz, 1H), 7.81(d, J = 8.1Hz, 1H), 7.57(t, J = 8.1Hz, 1H),
7.27-7.44(m, 3H), 7.06(t, J = 7.2Hz, 1H), 6.91(m, 1H), 6.61(m, 1H), 6.40(m, 1H),
6.29(m, 2H), 4.71(m, 1H), 3.18-3.34(m, 3H), 2.08(m, 1H), 0.48(m, 2H), 0.08(m, 1H),
1
3
-
0.61(m, 1H). C NMR (126 MHz, CDCl ) δ 164.1, 159.9, 151.7, 150.9, 148.28,
3
1
39.9, 134.2, 127.4, 126.4, 126.1, 126.0, 125.8, 125.0, 124.9, 123.1, 122.8, 120.8,
+
1
15.29, 115.15, 112.8, 109.1, 48.3, 39.9, 30.3, 7.0. HRMS (ESI): m/z (M+H) calcd
for C H N O : 422.1869, found: 422.1866.
2
7
24
3
2
4
.1.24 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(naphthalen-2-yloxy)pyrid-
in-3-yl)methanone (9b)
1
4

ACCEPTED MANUSCRIPT
The title compound was obtained as a light yellow solid from 7b according to the
1
general procedure in yield of 88%. H NMR (300 MHz, DMSO-d6): δ 8.73(s, 1H),
8
6
0
1
1
.35(d, J = 3.3Hz, 1H), 7.90(m, 2H), 7.73(m, 1H), 7.52(m, 2H), 7.04(t, J = 7.8Hz, 1H),
.87(m, 2H), 6.43-6.55(m, 4H), 4.72(m, 1H), 3.11-3.45(m, 3H), 2.12(m, 1H),
1
3
.33-0.50(m, 3H), -0.49(m, 1H). C NMR (126MHz, CDCl ) δ 164.1, 160.0, 151.6,
3
50.9, 149.9, 140.11, 133.4, 130.7, 129.6, 127.3, 126.9, 126.3, 125.8, 125.3, 125.1,
23.1, 122.80, 119.59, 116.75, 115.2, 112.8, 109.1, 48.3, 39.9, 30.4, 7.2. HRMS (ESI):
+
m/z (M+H) calcd for C H N O : 422.1869, found: 422.1864.
2
7
24
3
2
4
.1.25 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(quinolin-5-yloxy)pyridine-
-3-yl)methanone (9c)
The title compound was obtained as a light yellow solid from 7c according to the
1
general procedure in yield of 79%. H NMR (300 MHz, CDCl ): δ 8.93(d, J = 3.6Hz,
3
1
H), 8.86(s, 1H), 8.33 (d, J = 5.1Hz, 1H), 7.95(d, J = 7.8Hz, 1H), 7.71(m, 1H), 7.51(t,
J = 9.1Hz, 1H), 7.30(m, 1H), 7.05(t, J = 7.8Hz, 1H), 6.91(d, J = 7.8Hz, 0.9Hz), 6.59(d,
J = 7.5Hz, 1H), 6.44(t, J = 7.5Hz, 1H), 6.23(m, 2H), 4.95(m, 1H), 3.40(m, 2H),
1
3
3
.20(m, 1H), 2.05(m, 1H), 0.43(m, 2H), 0.13(m, 1H), -0.64(m, 1H). C NMR (126
MHz, CDCl ) δ 164.3, 160.0, 152.3, 151.6, 151.3, 149.0, 148.3, 140.4, 130.0, 129.0,
3
1
3
4
4
3
27.0, 126.4, 125.3, 123.6, 123.4, 121.9, 121.5, 116.1, 115.8, 113.4, 109.6, 48.8, 40.3,
+
0.8, 7.5. HRMS (ESI): m/z (M+H) calcd for C H N O : 423.1821, found:
2
6
23
4
2
23.1826.
.1.26 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(quinolin-6-yloxy)pyridine-
-yl)methanone (9d)
The title compound was obtained as a light yellow solid from 7d according to the
1
general procedure in yield of 81%. H NMR (300 MHz, CDCl ): δ 8.89(d, J = 2.1Hz,
3
1
7
6
1
1
1
H), 8.85(s, 1H), 8.37(d, J = 4.8Hz, 1H), 8.00-7.97(m, 2H), 7.43-7.40(m, 1H),
.07-7.03(m, 1H), 6.89(d, J = 5.7Hz, 1H), 6.68-6.65(m, 2H), 6.53(d, J = 5.7Hz, 1H),
.45-6.42(m, 1H), 6.33-6.32(d, J = 5.1Hz, 1H), 4.94(m, 1H), 3.45(m, 2H), 3.17(m,
1
3
H), 2.1(m, 1H), 0.49(m, 3H), -0.49(m, 1H). C NMR (126 MHz, CDCl ) δ 164.4,
3
59.9, 152.3, 151.6, 150.8, 150.3, 146.0, 140.5, 135.5, 131.7, 128.7, 126.4, 125.5,
23.6, 123.6, 123.4, 121.8, 116.64, 115.69, 113.3, 109.8, 48.8, 40.4, 30.9, 7.7. HRMS
1
5

ACCEPTED MANUSCRIPT
+
(
ESI): m/z (M+H) calcd for C H N O : 423.1821, found: 423.1829.
26 23 4 2
4
.1.27 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(quinolin-7-yloxy)pyridin-3
-yl)methanone (9e)
The title compound was obtained as a light yellow solid from 7e according to the
1
general procedure in yield of 78%. H NMR (300 MHz, CDCl ): δ 8.91(dd, J = 3.0Hz,
3
1
6
6
3
1
1
.2Hz, 1H), 8.84(s, 1H), 8.35(d, J = 1.2Hz, 1H), 8.14(d, J = 6.0Hz, 1H), 7.71(d, J =
.6Hz, 1H), 7.42-7.39(m, 1H), 7.16(d, J = 1.2Hz, 1H), 7.04(m, 1H), 6.91(m, 1H),
.52(m, 1H), 6.45-6.44(m, 2H), 6.37(d, J = 4.5Hz, 1H), 4.92(m, 1H), 3.46(m, 2H),
1
3
.20(m, 1H), 2.13(m, 1H), 0.51(m, 3H),-0.4(m, 1H). C NMR (126 MHz, CDCl ) δ
3
64.4, 159.6, 153.4, 152.2, 151.7, 151.4, 148.9, 140.4, 135.8, 129.7, 126.5, 126.0,
25.4, 123.6, 123.4, 120.9, 120.7, 118.7, 115.8, 113.2, 109.8, 48.8, 40.4, 30.9, 7.8.
+
HRMS (ESI): m/z (M+H) calcd for C H N O : 423.1821, found: 423.1814.
2
6
23
4
2
4
.1.28 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(quinolin-8-yloxy)pyridin-3
-yl)methanone (9f)
The title compound was obtained as a light yellow solid from 7f according to the
1
general procedure in yield of 76%. H NMR (300MHz, CDCl ):δ 8.83(m, 1H), 8.67(s,
3
1
1
2
H), 8.27(m, 1H), 8.19(m, 1H), 7.69(m, 1H), 7.46-7.43(m, 1H), 7.02(m, 1H),7.00(m,
H), 6.96(m, 1H), 6.82(m, 1H), 6.46-6.37(m, 2H), 6.25(m, 1H), 4.58(m, 1H), 3.46(m,
1
3
H), 2.65(m, 1H), 2.14(m, 1H), 0.53(m, 2H), 0.25(m, 1H), -0.26(m, 1H). C NMR
(
126 MHz, CDCl ) δ 164.0, 162.3, 160.8, 151.2, 150.5, 150.0, 148.5, 140.4, 139.9,
3
1
35.6, 129.2, 126.0, 125.8, 125.0, 123.4, 122.6, 121.6, 119.5, 115.4, 112.6, 109.9,
+
4
8.35, 40.04, 30.43, 7.16. HRMS (ESI): m/z (M+H) calcd for C H N O : 423.1821,
2
6
23
4
2
found: 423.1831.
4
.1.29 (4-(Benzofuran-5-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxalin-1-
(2H)-yl)methanone (9g)
The title compound was obtained as a light yellow solid from 7g according to the
1
general procedure in yield of 82%. H NMR (300 MHz, CDCl ): δ 8.78(s, 1H), 8.30(d,
3
J = 4.2Hz, 1H), 7.65(d, J = 1.5Hz, 1H), 7.35(d, J = 6.6Hz, 1H), 7.07-7.03(m, 1H),
6
6
.99(d, J = 5.7 Hz, 1H), 6.68(d, J = 0.9Hz, 1H), 6.52(m, 2H), 6.40(m, 1H),
.22-6.19(m, 2H), 4.94(m, 1H), 3.47(m, 2H), 3.18(m, 1H), 2.19(m, 1H), 0.55(m, 3H),
1
6

ACCEPTED MANUSCRIPT
1
3
-
0.32(m, 1H). C NMR (126 MHz, CDCl ) δ 164.7, 161.0, 152.3, 152.2, 151.3, 148.4,
3
1
1
4
4
46.6, 140.6, 128.4, 126.2, 125.7, 123.5, 122.9, 117.3, 115.6, 113.2, 112.8, 112.25,
+
09.10, 106.7, 48.7, 40.4, 30.9, 7.9. HRMS (ESI): m/z (M+H) calcd for C H N O :
2
5
22
3
3
12.1661, found: 412.1668.
.1.30 (4-(Benzofuran-6-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxalin-1-
(2H)-yl)methanone (9h)
The title compound was obtained as a brown solid from 7h according to the
1
general procedure in yield of 80%. H NMR (300 MHz, CDCl ): δ 8.80(s, 1H), 8.32(d,
3
J = 4.5Hz, 1H), 7.62(d, J = 1.5Hz, 1H), 7.44(d, J = 6.3Hz, 1H), 7.05(m, 1H), 6.98(d, J
=
5.7Hz, 1H), 6.74(d, J = 0.9Hz, 1H), 6.51(d, J = 5.7Hz, 1H), 6.42-6.38(m, 2H),
6
3
1
.26-6.24(m, 2H), 4.94(m, 1H), 3.46(m, 2H), 3.17(m, 1H), 2.19(m, 1H), 0.61-0.49(m,
1
3
H), -0.32(m, 1H). C NMR (126 MHz, CDCl ) δ 164.7, 161.0, 152.3, 152.2, 151.3,
3
48.4, 146.6, 140.6, 128.4, 126.2, 125.7, 123.5, 122.9, 117.3, 115.6, 113.2, 112.8,
+
1
12.2, 109.1, 106.7, 48.7, 40.4, 30.9, 7.9. HRMS (ESI): m/z (M+H) calcd for
C H N O : 412.1661, found: 412.1658.
25
22
3
3
4
.1.31 (4-(Benzo[b]thiophen-5-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxa-
lin-1(2H)-yl)methanone (9l)
The title compound was obtained as an off-white solid from 7l according to the
1
general procedure in yield of 85%. H NMR (300 MHz, CDCl ): δ 8.80(s, 1H), 8.32(d,
3
J = 5.1Hz, 1H), 7.72(d, J = 8.4Hz, 1H), 7.51(d, J = 5.1Hz, 1H), 7.19(d, J = 5.4Hz, 1H),
7
6
3
1
1
4
4
.07-7.03(m, 1H), 6.98-6.95(m, 1H), 6.70(s, 1H), 6.54-6.52(m, 1H), 6.43-6.39(m, 1H),
.32-6.25(m, 2H), 4.94(m, 1H), 3.46(m, 2H), 3.19(m, 1H), 2.18(m, 1H), 0.57-0.47(m,
1
3
H), -0.35(m, 1H). C NMR (126 MHz, CDCl ) δ 164.6, 160.7, 152.2, 151.4, 150.1,
3
40.6, 136.7, 128.6, 126.2, 125.6, 123.6, 123.6, 123.1, 117.7, 115.6, 114.9, 113.2,
+
09.4, 48.75, 40.4, 30.9, 7.5. HRMS (ESI): m/z (M+H) calcd for C H N O S:
2
5
22
3
2
28.1433, found: 428.1441.
.1.32 (4-(Benzo[d]thiazol-6-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxa-
lin-1(2H)-yl)methanone (9m)
The title compound was obtained as an off-white solid from 7m according to the
1
general procedure in yield of 81%. H NMR (300 MHz, CDCl ): δ 8.98(s, 1H), 8.83(s,
3
1
7

ACCEPTED MANUSCRIPT
1
H), 8.36(d, J = 4.5Hz, 1H), 7.99(d, J = 6.6Hz, 1H), 7.05(t, J = 6.3Hz, 1H), 6.91(d, J
=
6.3Hz, 1H), 6.72(d, J = 1.5Hz, 1H), 6.52(m, 2H), 6.42(t, J = 5.4Hz, 1H), 6.30(d, J =
4
.2Hz, 1H), 4.93(m, 1H), 3.46(m, 2H), 3.16(m, 1H), 2.13(m, 1H), 0.51(m, 3H),
1
3
-
0.47(m, 1H). C NMR (126 MHz, CDCl ) δ 164.4, 160.2, 154.4, 152.3, 151.6, 150.8,
3
1
1
4
4
5
50.8, 140.6, 134.8, 126.3, 125.5, 124.6, 123.6, 123.3, 119.6, 115.7, 113.2, 113.2,
+
09.6, 48.8, 40.3, 30.9, 7.8. HRMS (ESI): m/z (M+H) calcd for C H N O S:
2
4
21
4
2
29.1385, found: 429.1393.
.1.33 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(3-methylbenzo[d]isoxazol-
-yloxy)pyridin-3-yl)methanone (9n)
The title compound was obtained as a light yellow solid from 7n according to the
1
general procedure in yield of 84%. H NMR (300 MHz, CDCl ): δ 8.83(s, 1H), 8.36(d,
3
J = 6.0Hz, 1H), 7.44(d, J = 9.0Hz, 1H), 7.04(t, J = 7.5Hz, 1H), 6.97(d, J = 8.1Hz, 1H),
6
1
.54(m, 2H), 6.42(m, 2H), 6.21(d, J = 6.0Hz, 1H), 4.96(m, 1H), 3,45(m, 2H), 3.15(m,
1
3
H), 2.51(s,3H), 2.19(m, 1H), 0.43-0.61(m, 3H), -0.44(m, 1H). C NMR (126 MHz,
CDCl ) δ 163.8, 160.0, 159.9, 154.6, 151.9, 151.1, 148.3, 140.1, 125.7, 125.3, 123.1,
3
1
23.0, 122.7, 122.5, 115.2, 112.7, 111.9, 110.5, 108.6, 48.3, 39.9, 30.4, 9.7, 7.3.
+
HRMS (ESI): m/z (M+H) calcd for C H N O : 427.1770, found: 427.1762.
2
5
23
4
3
4
6
.1.34 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(3-methylbenzo[d]isoxazol-
-yloxy)pyridin-3-yl)methanone (9o)
The title compound was obtained as a light yellow solid from 7o according to the
1
general procedure in yield of 82%. H NMR (300 MHz, CDCl ): δ 8.84(s, 1H), 8.38(d,
3
J = 6.0Hz, 1H), 7.50(d, J = 8.4Hz, 1H), 7.05(t, J = 6.0Hz, 1H), 6.94(d, J = 7.8Hz, 1H),
6
0
1
.30-6.51(m, 5H), 4.93(m, 1H), 3,45(s, 2H), 3.18(m, 1H), 2.51(s, 3H), 2.16(m, 1H),
1
3
.63(m, 3H), -0.36(m, 1H). C NMR (126 MHz, CDCl ) δ 163.6, 162.9, 159.2, 154.4,
3
54.3, 151.6, 151.1, 140.0, 126.0, 124.9, 123.1, 123.0, 121.7, 119.3, 116.2, 115.3,
+
1
12.8, 109.2, 101.4, 48.3, 39.9, 30.5, 9.5, 7.2. HRMS (ESI): m/z (M+H) calcd for
C H N O : 427.1770, found: 427.1758.
25
23
4
3
4
.1.35 (4-(6-Chlorobenzofuran-5-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquino-
xalin-1(2H)-yl)methanone (9p)
The title compound was obtained as an off-white solid from 7p according to the
1
8

ACCEPTED MANUSCRIPT
1
general procedure in yield of 84%. H NMR (300 MHz, CDCl ) δ 8.77(s, 1H),
3
8
1
3
1
1
.34(d, J = 5.4Hz, 1H), 7.65(m, 1H), 7.57(s, 1H), 7.04(m, 2H), 6.63(m, 1H), 6.58(m,
H), 6.40(m, 1H), 6.21(d, J = 5.4Hz, 1H), 6.11(s, 1H), 4.84(m, 1H), 3.49(m, 2H),
1
3
.31(m, 1H), 2.24(m, 1H), 0.59(m, 3H), -0.23(m, 1H). C NMR (126 MHz, CDCl ) δ
3
64.2, 160.0, 152.2, 151.9, 151.5, 147.0, 144.5, 140.5, 127.0, 126.1, 125.7, 123.5,
23.1, 122.8, 115.6, 113.8, 113.1, 108.9, 106.6, 48.8, 40.4, 30.9, 7.7. HRMS (ESI):
+
m/z (M+H) calcd for C H ClN O : 446.1271, found: 426.1281.
2
5
21
3
3
4
.1.36 (4-Cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-(3-methylbenzofuran-5-yl-
oxy)pyridin-3-yl)methanone (9q)
The title compound was obtained as an off-white solid from 7q according to the
1
general procedure in yield of 85%. H NMR (400 MHz, CDCl ) δ 8.79(s, 1H), 8.31(d,
3
J = 6.0Hz, 1H), 7.42(s, 1H), 7.31(d, J = 9.2Hz, 1H), 7.04(m, 2H), 6.53(d, J = 7.6Hz,
1
3
H), 6.40(m, 1H), 6.30(m, 2H), 6.20(d, J = 6.0Hz, 1H), 4.96(m, 1H), 3.47(m, 2H),
1
3
.17(m, 1H), 2.21(m, 1H), 2.16(s, 3H), 0.55(m, 3H), -0.30(m, 1H). C NMR (126
MHz, CDCl ) δ 164.7, 161.1, 152.6, 152.2, 151.3, 148.1, 143.0, 140.6, 130.1, 126.2,
3
1
7
4
4
25.8, 123.5, 122.8, 117.1, 115.9, 115.6, 113.2, 112.1, 111.3, 109.0, 48.8, 40.4, 30.9,
+
.9, 7.6. HRMS (ESI): m/z (M+H) calcd for C H N O : 426.1818, found:
2
6
24
3
3
26.1821.
.1.37 (4-(6-Chloro-3-methylbenzofuran-5-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dih-
ydroquinoxalin-1(2H)-yl)methanone (9r)
The title compound was obtained as an off-white solid from 7r according to the
1
general procedure in yield of 83%. H NMR (400 MHz, CDCl ) δ 8.78(s, 1H), 8.34(d,
3
J = 5.6Hz, 1H), 7.50(s, 1H), 7.42(s, 1H), 7.01(m, 2H), 6.57(d, J = 7.6Hz, 1H), 6.41(m,
1
2
1
1
H), 6.18(d, J = 5.6Hz, 1H), 5.96(s, 1H), 4.84(m, 1H), 3.51(m, 2H), 3.26(m, 1H),
1
3
.26(m, 1H), 2.14(s, 3H), 0.59(m, 3H), -0.25(m, 1H). C NMR (126 MHz, CDCl ) δ
3
64.2, 160.0, 152.3, 152.2, 151.5, 144.2, 143.4, 140.5, 128.8, 126.2, 125.8, 123.5,
23.0, 122.7, 115.8, 115.6, 113.1, 113.0, 112.4, 108.9, 48.9, 40.3, 31.0, 7.9, 7.8.
+
HRMS (ESI): m/z (M+H) calcd for C H ClN O : 460.9321, found: 460.9316.
2
6
23
3
3
4
.1.38 (4-(2-Bromo-6-chloro-3-methylbenzofuran-5-yloxy)pyridin-3-yl)(4-cycloprop-
yl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (9s)
1
9

ACCEPTED MANUSCRIPT
The title compound was obtained as an off-white solid from 7s according to the
general procedure in yield of 81%. 8.81(s, 1H), 8.36(d, J = 6.0Hz, 1H), 7.47(s, 1H),
6
.98(m, 2H), 6.56(d, J = 8.1Hz, 1H), 6.41(m, 1H), 6.17(d, J =6.0Hz, 1H), 5.85(s, 1H),
.90(m, 1H), 3.49(m, 2H), 3.23(m, 1H), 2.25(m, 1H), 2.08(s, 3H), 0.58(m, 3H),
4
1
3
-
0.29(m, 1H). C NMR (126 MHz, CDCl ) δ 163.9, 160.0, 152.0, 151.4, 144.8, 140.5,
3
1
1
5
4
29.0, 128.6, 126.2, 125.8, 123.5, 123.1, 122.9, 115.6, 115.5, 113.1, 112.6, 111.7,
+
08.9, 48.9, 40.4, 31.0, 8.8, 7.8. HRMS (ESI): m/z (M+H) calcd for C H BrN O :
2
6
21
3
3
37.0455, found: 537.0467.
.1.39 General procedure for 9i–9k
Sodium hydroxide (1mmol) was added to a solution of 7i–7k (0.5mmol) in 1,
4
-dioxane (3ml) and water (3ml), and the reaction was stirred at ambient temperature
for 2–10h. After the solvent was removed under reduced pressure, the residue was
dissolved in water (6ml) and the pH was adjusted to 3 with 2N HCl. The formed
precipitate was filtered, washed with cold water, and dried under vacumm to obtain
8
i–8k, which were used in next step without any further purification. Acid
intermediate (0.3mmol) was dissolved in anhydrous DMF (3ml), followed by adding
HATU (0.45mmol), Et3N (0.6mmol) and 1-cyclopropyl-1,2,3,4-tetrahydroquinoxaline
(0.3mmol). The reaction was stirred at room temperature overnight, poured into water
and extracted with ethyl acetate for three times. The organic layers were combined,
washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated
under reduced pressure. The residue was purified by flash column chromatography to
yield the desired compound.
4
.1.40 (4-(1H-indol-5-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)
-yl)methanone (9i)
The title compound was obtained as a brown solid from 7i according to the
1
general procedure in yield of 56%. H NMR (300 MHz, CDCl ): δ 8.76(s, 1H),
3
8
1
1
.45(m, 1H), 8.26(d, J = 4.2Hz, 1H), 7.23(m, 2H), 7.06(m, 2H), 6.53(m, 2H), 6.45(s,
H), 6.40(t, J = 5.1Hz, 1H), 6.22(d, J = 4.2Hz, 1H), 6.13(d, J = 6.0Hz, 1H), 4.93(m,
1
3
H), 3.47(m, 2H), 3.21(m, 1H), 2.21(m, 1H), 0.55(m, 3H), -0.23(m, 1H). C NMR
(
126 MHz, CDCl ) δ 165.0, 161.6, 152.1, 151.0, 146.3, 140.6, 133.5, 128.3, 126.2,
3
2
0

ACCEPTED MANUSCRIPT
1
3
4
4
25.7, 123.4, 122.8, 115.8, 115.4, 113.2, 112.1, 111.8, 109.7, 102.8, 48.70, 40.47,
+
8.65, 30.95, 8.0. HRMS (ESI): m/z (M+H) calcd for C H N O : 411.1821, found:
25
23
4
2
11.1828.
.1.41 (4-(1H-indol-4-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)
-yl)methanone (9j)
The title compound was obtained as a brown solid from 7j according to the
1
general procedure in yield of 52%. H NMR (300 MHz, CDCl ): δ 8.79(s, 1H),
3
8
6
5
3
1
1
.46(m, 1H), 8.27(d, J = 4.2Hz, 1H), 7.22(d, J = 5.7Hz, 1H), 7.09(s, 1H), 6.99(m, 3H),
.58(d, J = 5.4Hz, 1H), 6.40(t, J = 5.7Hz, 1H), 6.30(d, J = 4.2Hz, 1H), 5.97(s, 1H),
.89(d, J = 5.7Hz, 1H), 4.91(m, 1H), 3.50(m, 2H), 3.22(m, 1H), 2.20(m, 1H), 0.44(m,
1
3
H), -0.38(m, 1H). C NMR (126 MHz, CDCl ) δ 164.8, 160.3, 152.0, 151.0, 145.5,
3
40.3, 137.8, 126.3, 125.4, 124.3, 123.6, 123.1, 122.4, 120.6, 115.5, 113.2, 110.4,
09.6, 108.7, 99.6, 77.3, 77.3, 77.1, 76.8, 48.8, 40.5, 30.8, 7.5. HRMS (ESI): m/z
+
(
M+H) calcd for C H N O : 411.1821, found: 411.1823.
2
5
23
4
2
4
.1.42 (4-(1H-indol-6-yloxy)pyridin-3-yl)(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)
-yl)methanone (9k)
The title compound was obtained as a brown solid from 7j according to the
1
general procedure in yield of 58%. H NMR (300 MHz, CDCl ): δ 8.76(s, 1H),
3
8.46(br, 1H), 8.26(d, J = 4.5Hz, 1H), 7.46(d, J = 6.6Hz, 1H), 7.21(m, 1H), 7.02(m,
2H), 6.52(m,2H), 6.36(m, 1H), 6.34(s, 1H), 6.24(d, J = 4.5Hz, 1H), 6.04(d, J = 6.3Hz,
1H), 4.93(m, 1H), 3.50-3.42(m, 2H), 3.19(m, 1H), 2.20(m, 1H), 0.59-0.43(m, 3H),
1
3
-
0.25(m,1H). C NMR (126 MHz, CDCl ) δ 164.5, 160.9, 151.6, 150.5, 147.8, 140.2,
3
1
1
4
4
35.4, 125.7, 125.3, 125.1, 124.7, 123.0, 122.4, 121.0, 115.1, 112.8, 112.7, 108.92,
+
02.54, 102.0, 48.2, 40.0, 30.5, 7.6. HRMS (ESI): m/z (M+H) calcd for C H N O :
2
5
23
4
2
11.1821, found: 411.1825.
.1.43 Benzyl 4-chloronicotinate (10)
The title compound was synthesized from 5 by the same route as the preparation
1
of 6 except from the replacement ethanol with benzalcohol. H NMR (300 MHz,
DMSO): δ 8.90(d, J = 1.2Hz, 1H), 8.53(dd, J = 6.9Hz, 1.2Hz, 1H), 8.08(d, J = 6.9Hz,
1
H), 7.50-7.31(m, 5H), 5.34(s, 2H).
2
1

ACCEPTED MANUSCRIPT
4
.1.44 General procedure for 11a–d
To a mixture of 10 (5mmol) and potassium carbonate (15mmol) in anhydrous
DMF (15ml) was added corresponding benzo cyclic phenol (5mmol). After the
o
resulting mixture was heated at 110 C overnight, the reaction was cooled to ambient
temperature and was poured into water (45ml). The mixture was extracted with ethyl
acetate (45ml) for three times, and the organic layers were combined, washed with
saturated brine (50ml×2), dried over anhydrous magnesium sulfate and evaporated
under reduced pressure. The residue was purified by flash column chromatography to
yield the desired compound.
4
.1.45 Benzyl 4-(6-chloro-2-(ethoxycarbonyl)-3-methylbenzofuran-5-yloxy)nicotinate
11a)
The title compound was synthesized from 10 and ethyl 6-chloro-5-hydroxy-
-methylbenzofuran-2-carboxylate according to the general procedure in yield of 85%.
(
3
1
H NMR (300 MHz, CDCl ) δ 9.11(s, 1H), 8.50(d, J = 6.0Hz, 1H), 7.71(s, 1H),
3
7
.45(m, 2H), 7.43(s, 1H), 7.35(m, 3H), 6.49(d, J = 6.0Hz, 1H), 5.43(s, 2H), 4.47(q, J
=
7.2Hz, 2H), 2.53(s, 3H), 1.45(t, J = 7.2Hz, 3H).
4
.1.46 Benzyl 4-(6-chloro-3-(ethoxycarbonyl)benzofuran-5-yloxy)nicotinate (11b)
The title compound was synthesized from 10 and ethyl 6-chloro-5-hydroxy-
1
benzofuran-3-carboxylate according to the general procedure in yield of 81%. H
NMR (400 MHz, CDCl ) δ 9.08 (s, 1H), 8.45(d, J = 6.0Hz, 1H), 8.36(s, 1H), 7.69(s,
3
1
4
4
H), 7.43(m, 2H), 7.31(m, 3H), 7.01(s, 1H), 6.45(d, J = 6.0Hz, 1H), 5.44(s, 2H),
.43(q, J = 7.2Hz, 2H), 1.41(t, J = 7.2Hz, 3H).
.1.47 Benzyl 4-(6-chloro-3-(2-methoxy-2-oxoethyl)benzofuran-5-yloxy)nicotinate
(11c)
The title compound was synthesized from 10 and methyl 2-(6-chloro-5-hydroxy-
1
benzofuran-3-yl)acetate according to the general procedure in yield of 78%. H NMR
(
300 MHz, CDCl ) δ 9.10(s, 1H), 8.47(d, J = 6.0Hz, 1H), 7.71(s, 1H), 7.66(s, 1H),
3
7
2
4
.47(m, 2H), 7.39(m, 4H), 6.49(d, J = 6.0Hz, 1H), 5.44(s, 2H), 3.71(s, 3H), 3.66(s,
H).
.1.48 Benzyl 4-(6-chloro-3-(3-methoxy-3-oxopropyl)benzofuran-5-yloxy)nicotinate
2
2

ACCEPTED MANUSCRIPT
(11d)
The title compound was synthesized from 10 and methyl 3-(6-chloro-5-hydroxy-
1
benzofuran-3-yl)propanoate according to the general procedure in yield of 82%. H
NMR (300 MHz, CDCl ) δ 9.10(s, 1H), 8.47(d, J = 6.0Hz, 1H), 7.64(s, 1H), 7.52(s,
3
1
2
4
H), 7.48(m, 2H), 7.35(m, 4H), 6.48(d, J = 6.0Hz, 1H), 5.44(s, 2H), 3.67(s, 3H),
.96(t, J = 7.2Hz, 2H), 2.67(t, J = 7.2 Hz, 2H).
.1.49 General procedure for 13a–d
To a solution of 11a–d (3mmol) in methanol (10ml) was added 10% Pd/C
(100mg) and the reaction mixture was stirred under an atmosphere of hydrogen (1atm)
at room temperature for 0.5–5h. The reaction mixture was diluted with THF (20ml),
filtered over celite and the filtrate was evaporated under reduced pressure to give the
desired acids 12a–d, which were directly used in next step without any further
purification. The obtained acid was dissolved in anhydrous DMF (9mmol), followed
by adding HATU (4.5mmol), Et N (6mmol) and 1-cyclopropyl-1,2,3,4-tetrahydro-
3
quinoxaline (2.7mmol). The reaction was stirred at room temperature overnight,
poured into water and extract with ethyl acetate for three times. The organic layers
were combined, washed with saturated brine, dried over anhydrous magnesium sulfate
and evaporated under reduced pressure. The residue was purified by flash column
chromatography to yield the desired compound.
4
.1.50 Ethyl 6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)
pyridin-4-yloxy)-3-methylbenzofuran-2-carboxylate (13a)
The title compound was obtained as an off-white solid from 11a according to the
1
general procedure in yield of 76%. H NMR (300 MHz, CDCl ) δ 8.83(s, 1H), 8.38(d,
3
J = 6.0Hz, 1H), 7.60(s, 1H), 7.02(m, 1H), 6.96(m, 1H), 6.57(m, 1H), 6.42(m, 1H),
6
3
1
1
.20(d, J = 6.0Hz, 1H), 6.01(s, 1H), 4.90(m, 1H), 4.47(q, J = 7.2Hz, 2H), 3.50(m, 2H),
.23(m, 1H), 2.46(s, 3H), 2.23(m, 1H), 1.45(t, J = 7.2Hz, 3H), 0.57(m, 3H), -0.34(m,
1
3
H). C NMR (126 MHz, CDCl ) δ 164.0, 160.0, 159.67, 152.4, 151.8, 151.1, 145.0,
3
42.7, 140.5, 128.7, 126.9, 126.2, 126.2, 125.8, 125.2, 123.5, 123.5, 122.8, 115.5,
115.5, 113.9, 113.6, 113.1, 108.9, 61.6, 48.9, 40.3, 31.0, 14.4, 9.5, 7.8. HRMS (ESI):
+
m/z (M+H) calcd for C H ClN O : 532.1639, found: 532.1642.
2
9
27
3
5
2
3

ACCEPTED MANUSCRIPT
4
.1.51 Ethyl 6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)
pyridin-4-yloxy)benzofuran-3-carboxylate (13b)
The title compound was obtained as an off-white solid from 11b according to the
1
general procedure in yield of 65%. H NMR (300 MHz, CDCl ) δ 8.76(s, 1H), 8.35(d,
3
J = 5.4Hz, 1H), 8.27(s, 1H), 7.63(s, 1H), 6.98(m, 3H), 6.59(d, J = 8.4Hz, 1H), 6.42(m,
1
1
1
1
H), 6.25(m, 1H), 4.79(m, 1H), 4.41(q, J = 7.2Hz, 2H), 3.49(m, 3H), 2.26(m, 1H),
1
3
.40(t, J = 7.2Hz, 3H), 0.62(m, 3H), -0.09(m, 1H). C NMR (126 MHz, CDCl ) δ
3
62.3, 159.6, 152.5, 152.3, 152.2, 151.6, 145.4, 140.3, 126.7, 125.4, 124.5, 124.3,
23.4, 122.9, 115.7, 114.9, 114.7, 113.7, 113.0, 108.6, 60.9, 48.8, 40.4, 31.0, 14.5, 7.8.
+
HRMS (ESI): m/z (M+H) calcd for C H ClN O : 518.1483, found: 518.1471.
2
8
25
3
5
4
.1.52 Methyl 2-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carb-
onyl) pyridin-4-yloxy)benzofuran-3-yl)acetate (13c)
The title compound was obtained as an off-white solid from 11c according to the
1
general procedure in yield of 72%. H NMR (300 MHz, CDCl ) δ 8.78(s, 1H), 8.34(d,
3
J = 5.4Hz, 1H), 7.68(s, 1H), 7.55(s, 1H), 7.01(m, 2H), 6.57(d, J = 7.2Hz, 1H), 6.41(m,
1
2
1
1
H), 6.18(m, 1H), 6.00(m, 1H), 4.88(m, 1H), 3.75(s, 3H), 3.59(s, 2H), 3.40(m, 3H),
1
3
.26(m, 1H), 0.60(m, 3H), -0.21(m, 1H). C NMR (126 MHz, CDCl ) δ 170.4, 164.2,
3
60.0, 152.2, 152.1, 151.5, 145.0, 144.4, 140.5, 127.4, 126.1, 125.8, 123.6, 123.5,
22.7, 115.6, 113.3, 113.2, 113.1, 112.6, 108.8, 52.4, 48.8, 40.4, 31.0, 29.0, 7.8.
+
HRMS (ESI): m/z (M+H) calcd for C H ClN O : 518.1483, found: 518.1489.
2
8
25
3
5
4
.1.53 Methyl 3-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carb-
onyl) pyridin-4-yloxy)benzofuran-3-yl)propanoate (13d)
The title compound was obtained as an off-white solid from 11d according to the
1
general procedure in yield of 75%. H NMR (300 MHz, CDCl ) δ 8.80(s, 1H), 8.35(d,
3
J = 5.7Hz, 1H), 7.53(s, 1H), 7.47(s, 1H), 7.04(m, 2H), 6.57(d, J = 7.2Hz, 1H), 6.42(m,
1
H), 6.14(m, 1H), 5.97(m, 1H), 4.89(m, 1H), 3.72(s, 3H), 3.40(m, 3H), 2.90(t, J =
1
3
7
.2Hz, 2H), 2.65(t, J = 7.2Hz, 2H), 2.28(m, 1H), 0.59(m, 3H), -0.22(m, 1H). C
NMR (126 MHz, CDCl ) δ 172.3, 164.2, 159.9, 152.4, 152.3, 151.6, 144.1, 143.5,
3
1
1
40.5, 127.5, 126.1, 125.9, 123.5, 123.4, 122.5, 119.1, 115.7, 113.3, 113.0, 112.4,
+
08.6, 51.9, 48.8, 40.4, 33.3, 31.0, 18.8, 7.8. HRMS (ESI): m/z (M+H) calcd for
2
4

ACCEPTED MANUSCRIPT
C H ClN O : 532.1639, found: 532.1648.
29
27
3
5
4
.1.54 General procedure for 14a–d
To a solution of 13a–d (2mmol) in 1, 4-dioxane (5ml) and water (5ml) was added
sodium hydroxide (4mmol) and the reaction mixture was stirred at ambient
temperature for 2h. The reaction was evaporated to dryness, and the residue was
dissolved in water (10ml). The pH of the solution was adjusted to 3 with 2N HCl. The
formed precipitate was filtered, washed with cold water, and dried under vacumm to
provide the title compound.
4
.1.55 6-Chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrid-
in-4-yloxy)-3-methylbenzofuran-2-carboxylic acid (14a)
The title compound was obtained as an off-white solid from 13a according to the
1
general procedure in yield of 91%. H NMR (300 MHz, CDCl ) δ 8.71(s, 1H), 8.36(m,
3
1
4
H), 7.99(s, 1H), 7.03(m, 1H), 6.92(m, 1H), 6.54(m, 1H), 6.39(m, 2H), 5.99(s, 1H),
1
3
.70(m, 1H), 3.37(m, 3H), 2.38(s, 3H), 2.20(m, 1H), 0.54(m, 3H), -0.45(m, 1H). C
NMR (126 MHz, DMSO) δ 163.8, 161.7, 159.3, 152.9, 151.7, 150.7, 144.6, 140.6,
1
30.1, 129.4, 126.6, 125.6, 125.0, 123.9, 123.0, 115.6, 114.2, 113.5, 113.2, 109.4, 48.8,
+
4
0.4, 31.1, 9.6, 7.7. HRMS (ESI): m/z (M+H) calcd for C H ClN O : 504.1326,
2
7
23
3
5
found: 504.1317.
4
.1.56 6-Chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrid-
in-4-yloxy)benzofuran-3-carboxylic acid (14b)
The title compound was obtained as a white solid from 13b according to the
1
general procedure in yield of 93%. H NMR (300 MHz, CDCl ) δ 8.84(s, 1H), 8.41(d,
3
J = 5.6Hz, 1H), 8.33(s, 1H), 7.64(s, 1H), 6.98(m, 3H), 6.55(m, 1H), 6.36(m, 2H),
1
3
4
.83(m, 1H), 3.45(m, 3H), 2.25(m, 1H), 0.61(m, 3H), -0.19(m, 1H). C NMR (126
MHz, DMSO) δ 163.9, 163.8, 159.2, 154.5, 152.7, 152.6, 152.4, 151.53, 145.2, 140.4,
1
3
4
4
27.0, 125.2, 125.1, 123.7, 123.4, 123.1, 115.5, 115.3, 114.5, 113.1, 109.2, 48.7, 40.5,
+
1.2, 7.7. HRMS (ESI): m/z (M+H) calcd for C H ClN O : 490.1170, found:
26
21
3
5
90.1176.
.1.57 2-(6-Chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)py-
ridin-4-yloxy)benzofuran-3-yl)acetic acid (14c)
2
5

ACCEPTED MANUSCRIPT
The title compound was obtained as an off-white solid from 13c according to the
1
general procedure in yield of 92%. H NMR (300 MHz, DMSO) δ 8.69(s, 1H),
8
1
1
1
.34(m, 1H), 7.99(s, 1H), 7.94(s, 1H), 7.04(m, 2H), 6.53(m, 1H), 6.36(m, 1H), 6.25(m,
H), 6.05(m, 1H), 4.68(m, 1H), 3.59-3.30(m, 5H), 2.22(m, 1H), 0.60(m, 3H), -0.29(m,
1
3
H). C NMR (126 MHz, DMSO) δ 172.0, 164.0, 159.404, 152.8, 152.7, 152.0,
51.5, 146.4, 146.4, 144.0, 140.6, 128.4, 126.5, 125.6, 123.7, 122.9, 122.9, 122.4,
115.6, 115.0, 113.7, 113.4, 113.2, 109.0, 48.7, 40.5, 31.2, 29.2, 7.7. HRMS (ESI): m/z
+
(
M+H) calcd for C H ClN O : 504.1326, found: 504.1319.
27 23 3 5
4
.1.58 3-(6-Chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)py-
ridin-4-yloxy)benzofuran-3-yl)propanoic acid (14d)
The title compound was obtained as an off-white solid from 13d according to the
1
general procedure in yield of 93%. H NMR (300 MHz, DMSO) δ 8.72(s, 1H), 8.35(d,
J = 5.4Hz, 1H), 7.92(s, 1H), 7.90(s, 1H), 7.06(m, 2H), 6.54(d, J = 7.2Hz, 1H), 6.39(m,
1
2
1
1
H), 6.28(m, 1H), 5.95(m, 1H), 4.74(m, 1H), 3.25(m, 3H), 2.74(m, 2H), 2.56(m, 2H),
1
3
.24(m, 1H), 0.53(m, 3H), -0.35(m, 1H). C NMR (126 MHz, DMSO) δ 174.4, 163.9,
59.4, 152.8, 152.2, 151.6, 145.0, 14400, 140.7, 128.2, 126.4, 125.7, 123.8, 122.8,
22.5, 119.9, 115.6, 113.8, 113.2, 112.6, 109.0, 48.8, 40.4, 33.8, 31.2, 18.9, 7.9, 7.7.
+
HRMS (ESI): m/z (M+H) calcd for C H ClN O : 518.1483, found: 518.1486.
2
8
25
3
5
4
.1.59 General procedure for 15a–d
To a solution of 14a–d (1mmol) in dichloromethane (5ml) was added HATU
(
1.5mmol), followed by Et N (3mmol) and glycine ethyl ester hydrochloride
3
(1.5mmol). The resulting mixture was stirred at room temperature overnight. The
reaction mixture was diluted with water (10ml) and extracted with dichloromethane
10ml). The organic layer was washed with saturated brine, dried over anhydrous
(
magnesium sulfate, and concentrated under reduced pressure. The residue was
purified by flash chromatography to deliver the desired compound.
4
.1.60 Ethyl 2-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbon-
yl) pyridin-4-yloxy)-3-methylbenzofuran-2-carboxamido)acetate (15a)
The title compound was obtained as an off-white solid from 14a according to the
2
6

ACCEPTED MANUSCRIPT
1
general procedure in yield of 83%. H NMR (400 MHz, CDCl ) δ 8.84(s, 1H), 8.39(m,
3
1
1
2
7
1
1
9
5
4
H), 7.54(s, 1H), 7.08(m, 1H), 7.03(m, 1H), 6.95(d, J = 8.0Hz, 1H), 6.55(d, J = 7.2Hz,
H), 6.42(t, J = 7.2Hz, 1H), 6.12(m, 1H), 5.96(s, 1H), 4.93(m, 1H), 4.28(q, J = 7.2Hz,
H), 4.24(m, 2H), 3.50(m, 2H), 3.20(m, 1H), 2.48(s, 3H), 2.23(m, 1H), 1.32(t, J =
1
3
.2Hz, 3H), 0.59(m, 3H), -0.37(m, 1H). C NMR (126 MHz, CDCl ) δ 169.7, 164.0,
3
59.7, 159.5, 152.4, 151.7, 150.1, 145.0, 144.0, 140.5, 129.3, 126.3, 125.7, 123.5,
22.8, 122.8, 115.6, 113.6, 113.4, 113.1, 108.8, 61.9, 48.9, 41.0, 40.3, 38.6, 30.9, 14.2,
+
.0, 7.8. HRMS (ESI): m/z (M+H) calcd for C H ClN O : 589.1854, found:
3
1
30
4
6
89.1861.
.1.61 Ethyl 2-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbon-
yl) pyridin-4-yloxy)benzofuran-3-carboxamido)acetate (15b)
The title compound was obtained as an off-white solid from 14b according to the
1
general procedure in yield of 82%. H NMR (300 MHz, CDCl ) δ 8.76(s, 1H), 8.36(d,
3
J = 5.4Hz, 1H), 8.16(s, 1H), 7.63(s, 1H), 6.96(m, 2H), 6.74(s, 1H), 6.58(d, J = 8.4Hz,
1
H), 6.38(m, 2H), 6.26(m, 1H), 4.77(m, 1H), 4.24(m, 4H), 3.49(m, 3H), 2.25(m, 1H),
1
3
1
.30(t, J = 7.2Hz, 3H), 0.62(m, 3H), -0.15(m, 1H). C NMR (126 MHz, CDCl ) δ
3
1
69.9, 164.1, 161.8, 159.6, 152.3, 151.6, 148.9, 145.4, 140.4, 126.5, 125.5, 124.5,
24.1, 123.4, 122.8, 117.4, 115.7, 113.9, 113.8, 113.1, 108.9, 61.9, 48.9, 41.3, 40.4,
1
+
3
1.0, 29.7, 14.2, 7.8. HRMS (ESI): m/z (M+H) calcd for C H ClN O : 575.1697,
3
0
28
4
6
found: 575.1703.
4
.1.62 Ethyl 2-(2-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-car-
bonyl) pyridin-4-yloxy)benzofuran-3-yl)acetamido)acetate (15c)
The title compound was obtained as an off-white solid from 14c according to the
1
general procedure in yield of 85%. H NMR (300 MHz, CDCl ) δ 8.76(s, 1H), 8.34(m,
3
1
3
3
1
1
7
H), 7.70(s, 1H), 7.57(s, 1H), 7.00(m, 2H), 6.56(m, 1H), 6.39(m, 1H), 6.22-6.07(m,
H), 4.81(m, 1H), 4.20(m, 2H), 4.02(m, 2H), 3.55-3.44(m, 5H), 2.25(m, 1H), 1.27(m,
1
3
H), 0.60(m, 3H), -0.22(m, 1H). C NMR (126 MHz, CDCl ) δ 169.7, 169.0, 164.1,
3
56.0, 152.3, 152.2, 151.3, 145.3, 144.5, 140.5, 127.2, 126.2, 125.7, 123.8, 123.5,
22.7, 115.6, 113.9, 113.5, 113.2, 112.5, 109.0, 61.8, 48.8, 41.5, 40.4, 31.0, 14.2, 14.0,
+
.8. HRMS (ESI): m/z (M+H) calcd for C H ClN O : 589.1854, found:589.1863.
3
1
30
4
6
2
7

ACCEPTED MANUSCRIPT
4
.1.63 Ethyl 2-(3-(6-chloro-5-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-car-
bonyl) pyridin-4-yloxy)benzofuran-3-yl)propanamido)acetate (15d)
The title compound was obtained as an off-white solid from 14c according to the
1
general procedure in yield of 83%. H NMR (300 MHz, CDCl ) δ 8.79(s, 1H), 8.36(d,
3
J = 5.7Hz, 1H), 7.53(s, 1H), 7.49(s, 1H), 7.05(m, 2H), 6.56(d, J = 7.2Hz, 1H), 6.42(m,
1
4
1
H), 6.19(m, 1H), 6.04(m, 2H), 4.87(m, 1H), 4.22(q, J = 7.2Hz, 2H), 4.05(d, J =
.5Hz, 2H), 3.49(m, 2H), 3.28(m, 1H), 2.92(m, 2H), 2.57(t, J = 7.5Hz, 2H), 2.28(m,
13
H), 1.29(t, J = 7.2Hz, 3H), 0.61(m, 3H), -0.21(m, 1H). C NMR (126 MHz, CDCl )
3
δ 171.5, 170.0, 164.1, 160.0, 152.3, 152.3, 151.5, 144.2, 143.6, 140.5, 127.6, 126.3,
1
4
6
4
25.8, 123.4, 123.4, 122.6, 119.3, 115.7, 113.3, 113.2, 112.4, 108.8, 61.7, 48.8, 41.4,
+
0.4, 35.1, 31.0, 19.0, 14.2, 7.8. HRMS (ESI): m/z (M+H) calcd for C H ClN O :
3
2
32
4
6
03.2010, found:603.2017.
.1.64 (E)-Ethyl 3-(5-chloro-4-(3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-ca-
rbonyl) pyridin-4-yloxy)-3-methylbenzofuran-2-yl)acrylate (16)
To a solution of 9s (1.35g, 2.5mmol) in DMF (10ml) was added ethyl acrylate
(1.36ml, 12.5mmol), followed by palladium diacetate (56mg, 0.25mmol), benzyl
triethylammonium chloride (0.57g, 2.5mmol) and Et N (1.73mml, 12.5mmol). The
3
resulting mixture was heated using microwave reactor at 110°C for 1h. After cooling
to ambient temperature, the reaction mixture was poured into water (20ml) and
extracted with ethyl acetate (15ml×3). The organic layers were combined, washed
with saturated brine (20ml×3), dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by flash column
chromatography to afford the title compound 16 (1.24g, 2.2mmol, 89%) as a light
1
yellow solid. H NMR (300 MHz, CDCl ) δ 8.81(s, 1H), 8.36(d, J = 5.7Hz, 1H),
3
7.58(d, J = 15.3Hz, 1H), 7.49(s, 1H), 6.99(m, 2H), 6.58(m, 1H), 6.53(d, J = 15.3Hz,
1H), 6.41(m, 1H), 6.19(d, J =5.7Hz, 1H), 5.92(s, 1H), 4.90(m, 1H), 4.28(q, J = 7.2Hz,
2H), 3.49(m, 2H), 3.23(m, 1H), 2.24(m, 4H), 1.35(t, J = 7.2Hz, 3H), 0.58(m, 3H),
1
3
-
0.28(m, 1H). C NMR (126 MHz, CDCl ) δ 166.8, 164.1, 159.8, 152.3, 151.6, 150.3,
3
1
44.6, 140.5, 129.5, 128.5, 126.2, 125.8, 125.4, 123.5, 122.7, 119.8, 118.8, 115.6,
2
8