Discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4- tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel gpr119 agonists

Article abstract of DOI:10.1016/j.bmcl.2013.12.127

We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1, 2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.

Full text of DOI:10.1016/j.bmcl.2013.12.127

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1133–1137
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tet-
rahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel
gpr119 agonists
a
a
a
a
a
Yingcai Wang a, , Ming Yu , Jiang Zhu , Jian (Ken) Zhang , Frank Kayser , Julio C. Medina ,
⇑
Karen Siegler b, Marion Conn b, Bei Shan b, Mark P. Grillo c, Jiwen (Jim) Liu a, Peter Coward b
a Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
b Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
c Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-
7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2
had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation
of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline
ring constrained the rotation of the aniline C–N bond and gave compounds with increased efficacy on
human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher
free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 12 November 2013
Revised 29 December 2013
Accepted 31 December 2013
Available online 8 January 2014
Keywords:
GPR119
Agonists
Oxadiazole
Constrain
Free fraction
GPR119 is a class A GPCR that is predominantly expressed in
beta-cells of pancreas and gastrointestinal tract.1 Endogenously-
occurring phospholipids and lipid amides, such as oleoylethanola-
mide, have been identified as GPR119 ligands.2,3 Activation of the
receptor results in increased intracellular cAMP levels.2–4
Several GPR119 agonists have been studied in clinical trials,8
and many patents describing GPR119 agonists have been dis-
closed.9 However, whether GPR119 agonists will ultimately prove
to be a safe and effective treatment for metabolic diseases such
as type 2 diabetes remains to be shown.10
Activation of GPR119 causes receptor-dependent, glucose-stim-
ulated insulin secretion in isolated pancreatic beta-cells and im-
proves glucose tolerance in vivo without causing hypoglycemia.4
The improvement in glucose tolerance was specific where it was
observed in wild-type but not in GPR119 knockout mice.4 In addi-
tion, GPR119 agonists increase gastric inhibitory peptide and glu-
cagon-like protein-1 (GLP-1) secretion in a receptor-dependent
manner.5 Co-administration of GPR119 agonists and inhibitors of
dipeptidyl peptidase IV, which function to prevent degradation of
GLP-1, resulted in a greater improvement in glucose tolerance than
with either agent alone.6 Chronic administration of GPR119 agonist
APD668 to Zucker diabetic fatty rats for 8 weeks resulted in signif-
icant reduction of blood glucose and glycated hemoglobin levels
without causing hypoglycemia.7 In addition, APD668 improved
glucose tolerance in acute studies in cynomolgus monkeys (cyno).7
In this Letter we describe the optimization of a new chemical
series of GPR119 agonists, focusing on improvements in potency,
efficacy, and pharmacokinetic (PK) profile.
We previously reported the optimization of a high-throughput
screening (HTS) hit compound 1 to compound 2 (Fig. 1), which
showed an improved potency and PK profile.11 However, com-
pound 2 had lower efficacy (58%) in the cyno cAMP assay than
compound 3, a very close analog of APD668.7 As a result, we deter-
mined that this compound was not ideal for in vivo efficacy studies
in cyno and made improving the efficacy a major focus of our SAR
campaign.
We first explored a few structural modifications on compound 1
that were considered likely to be promising as observed from
examples, which included N-alkylation of the sulfonamide,
replacement of the methyl or chlorine with a cyclopropyl at the
6-pyridinyl position, or maintaining substituents such as CN at
the 3-pyridinyl position. None of these modifications were proven
to be consistent (data not shown). However, we did observe a trend
of increasing efficacy when we constrained the sulfonamide nitro-
⇑
Corresponding author.
E-mail address: yingcai02@gmail.com (Y. Wang).
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.127

1134
Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1133–1137
Table 2
Cl
Me
CN
Constraining the sulfonamide nitrogen increases efficacy of heterocycles
N
N
Cl
O
HN
S
O
Me
HN
S
O
N
O
O
S
N
Cl
O
N
Me
O
O
O
O
X
O
N
1
2
N
Cl
µ
µ
human EC50( M)/Emax(%): 0.31/105
cyno EC50(µM) /Emax(%): 3.09/71
human EC50( M)/ Emax(%): 0.02/85
cyno EC50(µM) /Emax(%): 0.08/58
R
Compds
X
Human
GPR119 cAMP
Cyno GPR119
cAMP EC50
%Fu in
plasma
r/c/hc
N
N
O
EC50
(l
M)/
(lM)/
efficacya,b (%)
efficacya,b (%)
N
N
N
O
O
S
O
O
0.5/1.2/
0.8
2 (R = iPr)
8 (R = cPr)
0.02/85
0.08/58
3
N
H
human EC50(µM)/Emax (%): 0.04/100
cyno EC50(µM)/Emax (%): 0.17/100
3.5/10/
26
0.06/109
0.21/99
N
Figure 1. HTS hit 1, previously optimized compound 2, and reference compound 3
(% efficacy relative to 3, values are means of two or more experiments).
9 (R = iPr)
0.05/108
0.05/107
0.16/96
0.14/106
NA
5.3/15/
11
10 (R = cPr)
N
Table 1
Constraining the sulfonamide nitrogen increases efficacy of pyridyl esters
11 (R = cPr)
4.3/102d
9.0/106d
NA
Cl
N
O
S
O
N
a
b
c
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
Fraction unbound (fu) values are means of three experiments using ultracen-
R
O
X
O
O
Cl
trifugation method; r for rat, c for cyno, h for human.
d
From one experiment.
Compds
X
Human GPR119 Cyno GPR119
cAMP EC50 cAMP EC50
M)/efficacya,b
M)/
(
l
(l
(%)
efficacya,b (%)
Table 3
Sulfonamide SAR
4 (R = Et)
0.02/92
0.14/50
N
H
Cl
N
5 (R = Me)
0.03/102
0.27/76
O
N
N
S
O
O
N
R
O
N
6 (R = Me)
7 (R = Et)
0.10/108
0.10/117
0.30/94
N
Compds
R
Human GPR119
Cyno GPR119
0.20/103
cAMP EC50
(
lM)/
cAMP EC50 (lM)/
efficacya,b (%)
efficacya,b (%)
a
Values are means of two or more experiments, see Ref. 11 for assay protocol
(accession numbers of the GPR119 sequences transfected in HEK cells:
human = NM_178471.2, cyno = XM_005594569.1).
12
13
14
15
16
17
18
19
20
10
21
22
23
24
25
26
H
2-CN
3-CN
3-F
0.29/87c
0.27/44c
0.55/52
0.32/90
0.54/69
0.59/65
0.18/99
0.03/98
0.09/102
0.05/107
0.09/94
0.77/55
0.08/103
0.86/43c
0.09/100
0.07/96
>30/0c
>30/0c
>30/0
b
Efficacy relative to compound 3.
0.35/5c
>30/0
3-Cl
3-OMe
3-SO2Me
4-CN
4-F
4-Cl
4-OMe
4-SO2Me
4-Me
2,4-Di F
3,4-Di F
3,4-Di Cl
>30/0
gen to the middle phenyl ring with an ester at the 4-pyridyl posi-
tion (Table 1). Compared to the unconstrained ester 4, compound 5
showed increased efficacy on both the human and cyno receptors.
Compounds 6 and 7 improved the efficacy even further.
0.63/65
0.11/122
0.33/65
0.14/106
0.28/43
>30/0
0.24/63
>30/0c
0.33/74
0.43/54
We then combined structural features that both enhanced effi-
cacy (observed by constraining the sulfonamide nitrogen as shown
in Table 1) and improved PK profiles (observed with heterocyclic
replacement of the esters, as exemplified with compound 211).
Replacement of the aniline ring of 2 with an indoline, a terahydro-
quinoline, or a tetrahydrobenzoazepine provided compounds 8–11
(Table 2), each of which showed an increase in efficacy on the cyno
GPR119 receptor. The indoline and tetrahydroquinoline-containing
compounds (8–10) offer a good balance of efficacy and potency
(8–10). In addition, fractions unbound (fu, or free fraction) in plas-
ma increased 7–33 fold across species for 8 and 10 compared to 2.
Compound 10 showed comparable potency and efficacy to com-
pound 3 in both human and cyno cAMP assays.
a
b
c
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
From one experiment.
and the para-position was quite sensitive in terms of cyno efficacy
to size of substituent: Cl (10) ꢀ CN (19) > F (20) >> H (12). Although
OMe (21) and Me (23) had good activities on the human receptor,
both showed low efficacy on the cyno receptor (43% and 63%,
respectively). Di-substitutions (24–26) and 4-SO2Me (22) were
not preferred.
The SAR around the substituted phenyl ring on the sulfonamide
was very sensitive to modifications (Table 3). Substitution at the
ortho- and meta-positions were generally not tolerated (13–18),

Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1133–1137
1135
Table 4
Table 7
SAR of 6-pyridyl substituents
SAR of substituents on the tetrahydroquinoline
R
Cl
X
N
N
O
N
S
O
O
N
S
O
O
R
N
Cl
O
N
O
Cl
Compds X
R
Human GPR119 Cyno GPR119 Rat CLc %Fu in
cAMP EC50 cAMP EC50
(L/h/kg) Plasmad
M)/efficacya,b
Compds
R
Human GPR119 cAMP EC50
M)/efficacya,b (%)
Cyno GPR119 cAMP EC50
M)/efficacya,b (%)
(l
(l
(
l
(l
M)/
r/c/h
(%)
efficacya,b (%)
10
27
28
29
30
31
Cl
F
Me
OH
0.05/107
0.10/106
0.12/98
>30/0c
0.14/106
0.31/106
0.23/87
>30/0c
N
N
10
42
H
F
0.05/107
0.04/109
0.14/106
0.09/117
1.0
0.91
NA
5.5/10/
O
N
28
OMe 0.27/122c
1.1/65c
2.6/24c
43
Cl
H
0.08/102
0.33/102
0.41
4.3/12/
14
CPr
0.13/93c
a
b
c
O
N
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
From one experiment.
2.5/8.5/
13
39
0.08/117
0.16/119
3.8
44
45
F
Cl
0.07/116
0.08/112
0.09/133
0.10/123
2.9
1.1
NA
3.0/15/
12
a
b
c
Table 5
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
Dosed intravenously at 0.5 mg/kg.
SAR of 1,2,4-oxadiazole substituents
Cl
d
Fraction unbound (fu) values are means of three experiments using ultracen-
N
trifugation method; r for rat, c for cyno, h for human.
O
N
O
N
R
Cl
S
O
N
O
Table 8
SAR of the middle fused ring
Compds
R
Human GPR119 cAMP EC50 Cyno GPR119 cAMP EC50
M)/efficacya,b (%) M)/efficacya,b (%)
(l
(l
Cl
X
32
33
34
35
36
9
Me
CF3
Et
0.18/118
0.11/101
0.08/106
0.67/128
0.66/97
0.20/101
0.44/70c
0.27/79
0.16/96
0.14/106
0.49/87
N
N
S
O
O
R
CH2CF3 0.19/98c
O
Cl
CH2CPr 0.06/109
iPr
0.05/108
0.05/107
0.05/108
10
37
CPr
tBu
Compds
Z
Human GPR119 cAMP EC50
M)/efficacya,b (%)
Cyno GPR119 cAMP EC50
(l
(l
M)/efficacya,b (%)
a
b
c
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
From one experiment.
10
46
47
48
C
O
S
0.05/107
0.06/119
0.10/111c
0.14/106
0.12/135
1.26/73c
1.19/34c
SO2 0.31/93c
a
b
c
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
From one experiment.
Table 6
SAR of 5-membered heterocycles
Cl
N
The replacement of the chlorine at the 6 position of the pyridine
N
S
O
R
with other substituents were also studied (Table 4). Overall, substi-
tution of the chlorine at the 6 position with a different group re-
sulted in a loss either potency or efficacy. The fluoro-pyridine 27
showed only a 2-fold decrease in potency, while maintaining the
same efficacy (106%). The methyl substituted pyridine compound
(28) showed a small decrease in both potency and efficacy. Intro-
duction of an OH produces an inactive compound (29). Potency
and efficacy values of the methoxy (30) and cyclopropyl (31)
substituted pyridyl compounds were far superior on the human
receptor compared to the corresponding values obtained with
the cyno receptor.
Cl
O
O
Compds
R
Human GPR119 cAMP
EC50
M)/efficacya,b (%)
Cyno GPR119 cAMP
(
l
EC50 (l
M)/efficacya,b (%)
N
10
38
39
0.05/107
0.14/93
0.14/106
0.81/27
O
N
N
O
S
N
N
O
O
0.08/117
0.16/119
N
We next explored substituents at the 3-position of the 1,2,
4-oxadiazole moiety (Table 5). Introduction of a CF3 group (33 vs
32; 35 vs 34) and increased substituent size (larger than 3 carbons:
36 and 37) are detrimental to efficacy on the cyno receptor,
although neither has a significant impact on efficacy on the human
receptor.
40
41
0.10/100
1.5/89c
0.43/95
17/25c
N
N
a
b
c
Values are means of two or more experiments, see Ref. 11 for assay protocol.
Efficacy relative to compound 3.
Other 5-membered heterocycles were explored on the 4-pyridyl
position (Table 6). While 1,3,4-oxadiazole 39 and isoxazole 40 are
From one experiment.

1136
Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1133–1137
Table 9
Pharmacokinetic propertiesa
Compds
CL (L/h/kg)
AUC (lM⁄h)
t1/2 (h)
Vdss (L/kg)
Species
%fub
2
1.86
0.91
0.41
1.1
0.74
1.00
0.35
0.54
0.99
2.09
0.79
1.26
0.92
2.86
5.1
6.8
7.9
5.9
7.8
5.8
17
5.1
4.1
1.6
6.4
3.4
2.8
2.8
rat
rat
rat
rat
rat
rat
cyno
0.5
5.5
4.3
3.8
2.9
5.3
15
42
43
45
46
10
10
a
Dosed intravenously at 0.5 mg/kg.
Fraction unbound (fu) values are means of three experiments using ultracentrifugation method.
b
4-chlorobenzene-
1-sulfonylchloride
N
S
OH
pyridine
N
H
OH
O
O
Cl
Cl
THF, 0 °C
(87% yield)
49
N
K2CO3
O
+
N
S
O
N
DMF, 80°C
(91%yield)
Cl
N-
Cl
O
O
N
Cl
hydroxycyclo
propanecarb
oximidamide
N
N
10
O
Cl
Cl
Cl
N
pyridine
toluene, reflux
N
O
50
(47%yield)
Scheme 1. Synthesis of 10.
2. Soga, T.; Ohishi, T.; Matsui, T.; Saito, T.; Matsumoto, M.; Takasaki, J.;
Matsumoto, S.; Kamohara, M.; Hiyama, H.; Yoshida, S.; Momose, K.; Ueda, Y.;
Matsushime, H.; Kobori, M.; Furuichi, K. Biochem. Biophys. Res. Commun. 2005,
326, 744.
3. Overton, H. A.; Babbs, A. J.; Doel, S. M.; Fyfe, M. C. T.; Gardner, L. S.; Griffin, G.;
Jackson, H. C.; Procter, M. J.; Rasamison, C. M.; Tang-Christensen, M.;
Widdowson, P. S.; Williams, G. M.; Reynet, C. Cell Metab. 2006, 3, 167.
4. Chu, Z.-L.; Jones, R. M.; He, H.; Carroll, C.; Gutierrez, V.; Lucman, A.; Moloney,
M.; Gao, H.; Mondala, H.; Bagnol, D.; Unett, D.; Liang, Y.; Demarest, K.; Semple,
G.; Behan, D. P.; Leonard, J. Endocrinology 2007, 148, 2601.
5. Chu, Z.-L.; Carroll, C.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Pedraza, M.;
Mondala, H.; Gao, H.; Bagnol, D.; Chen, R.; Jones, R. M.; Behan, D. P.; Leonard, J.
Endocrinology 2008, 149, 2038.
6. Ansarullah; Lu, Y.; Holstein, M.; DeRuyter, B.; Rabinovitch, A.; Guo, Z. PLoS ONE
2013, 8, e53345.
well tolerated, the 1,2,4-oxadiazole 38 and thiazole 41 show dra-
matically reduced activity on the cyno receptor.
Adding a fluoro- or chloro-substituent ortho to the oxygen on
the tetrahydroquinoline ring in two oxadiazole series maintains
potency, while decreasing the in vivo clearance in rat (10 vs 42
or 43; and 39 vs 44 or 45) (Table 7). Since the unbound fractions
are similar between 42 and 43 as well as between 39 and 45, the
decrease in clearance is not related to plasma protein binding.
The 4-position of the middle ring linker was also explored (Ta-
ble 8). This position can tolerate carbon (10) and oxygen (46), but
potency and efficacy on the cyno receptor is negatively impacted
by sulfur (47) or sulfone (48).
Compared to compound 2, many compounds showed improved
rat PK properties and fraction unbound in plasma (Table 9). Com-
pound 10 was tested in cyno and showed good cyno PK profiles.
In addition to its significantly reduced human plasma protein bind-
ing, 10 does not bind to the human ether-à-go-go-related gene
(hERG) potassium ion channel or inhibit the bile salt export pump
(BSEP) transporter.
7. Semple, G.; Ren, A.; Fioravanti, B.; Pereira, G.; Calderon, I.; Choi, K.; Xiong, Y.;
Shin, Y.-J.; Gharbaoui, T.; Sage, C. R.; Morgan, M.; Xing, C.; Chu, Z.-L.; Leonard, J.
N.; Grottick, A. J.; Al-Shamma, H.; Liang, Y.; Demarest, K. T.; Jones, R. M. Bioorg.
Med. Chem. Lett. 2011, 21, 3134 (APD668 is compound 3k in Ref. 7. We used
compound 3c in Ref. 7 as the reference compound in our assays).
8. Zhu, X.; Huang, W.; Qian, H. ‘GPR119 Agonists: A Novel Strategy for Type 2
Diabetes Treatment’, chapter
4
of ‘Diabetes Mellitus—Insights and
Perspectives’, 2013, Prof. Oluwafemi Oguntibeju (Ed.), ISBN: 978-953-51-
0939-6, InTech, DOI: 10.5772/48444.
9. Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J. Expert Opin. Ther. Patents
2009, 19, 1339.
10. Cornall, L. M.; Mathai, M. L.; Hryciw, D. H.; McAinch, A. J. Expert. Opin. Invest.
Drugs 2013, 22, 487.
Compound 10 can be prepared in three steps with good overall
yield (Scheme 1).12
In summary, we discovered 5-(2-((1-(phenylsulfonyl)-1,2,3,
4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as
a novel class of GPR119 agonists, and presented the SAR in detail.
Compounds were optimized to have good potency and efficacy on
both the human and cyno receptors. Additional characterization of
these compounds in vitro and in vivo will be necessary to deter-
mine if they can further developed for the treatment of type 2 dia-
betes or other disorders. This is particularly important given
reports of limited efficacy of other GPR119 agonists in clinical
trials.13
11. Zhang, J.; Li, A.-R.; Yu, M.; Wang, Y.; Zhu, J.; Kayser, F.; Medina, J. C.; Siegler, K.;
Conn, M.; Shan, B.; Grillo, M. P.; Eksterowicz, J.; Coward, P.; Liu, J. Bioorg. Med.
Chem. Lett. 2013, 23, 3609.
12. 1-(4-Chlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-ol (49): To a solution of
1,2,3,4-tetrahydroquinolin-7-ol (4.68 g, 31.4 mmol, Astatech) and pyridine
(3.04 mL, 37.6 mmol) in THF (30 mL) at 0 °C was added a solution of 4-
chlorobenzene-1-sulfonyl chloride (6.95 g, 32.9 mmol) in THF (15 mL)
dropwise. The reaction was stirred at 0 °C for 4 h. The reaction mixture was
concentrated with silica gel and purified by flash chromatography (10–40%
EtOAc in hexanes) to give 49 (8.8 g, 87%) as a pale-yellow solid. 1H NMR
(400 MHz, chloroform-d) d ppm 7.54–7.58 (2H, m), 7.37–7.41 (2H, m), 7.36
(1H, d, J = 2.5 Hz), 6.89 (1H, d, J = 8.4 Hz), 6.64 (1H, dd, J = 8.4, 2.5 Hz), 3.76–
3.82 (2H, m), 2.40 (2H, t, J = 6.7 Hz), 1.57–1.65 (2H, m). MS ESI (pos.) M/E: 324
(M+H).
3-Cyclopropyl-5-(2,6-dichloropyridin-4-yl)-1,2,4-oxadiazole (50): To a solution of
2,6-dichloroisonicotinoyl chloride (21.02 g, 100 mmol, Maybridge) in toluene
(300 mL), was added N-hydroxycyclopropanecarboximidamide (11.0 g,
110 mmol, Maybridge) and pyridine (24.23 mL, 300 mmol). The mixture was
References and notes
1. Fredriksson, R.; Hoglund, P. J.; Gloriam, D. E. I.; Lagerstrom, M. C.; Schioth, H. B.
FEBS Lett. 2003, 554, 381.

Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1133–1137
1137
refluxed (145 °C) with a Dean–Stark trap for 6 h, concentrated and purified by
flash chromatography (0–20% EtOAc in hexanes) to give 50 (11.9 g, 47%) as a
white solid. 1H NMR (400 MHz, chloroform-d) d ppm 7.91 (2H, s), 2.12–2.32
(1H, m), 1.05–1.24 (4H, m). MS ESI (pos.) M/E: 256 (M+H).
flash chromatography (0–20% EtOAc in hexanes) to give 10 (248 mg, 91% yield)
as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.78 (1H, d, J = 1.0 Hz),
7.59–7.72 (4 H, m), 7.55 (1H, d, J = 1.2 Hz), 7.48 (1H, d, J = 2.5 Hz), 7.19 (1H, d,
J = 8.2 Hz), 7.00 (1H, dd, J = 8.2, 2.3 Hz), 3.83 (2H, dd, J = 7.8, 3.9 Hz), 2.25 (2H,
m), 1.62 (2H, m), 1.11–1.19 (2H, m), 1.02–1.00 (2H, m). MS ESI (pos.) M/E: 543
(M+H).
5-(2-Chloro-6-(1-(4-chlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-
yloxy)pyridin-4-yl)-3-cyclopropyl-1,2,4-oxadiazole (10):
A
mixture of 49
(162 mg, 0.5 mmol), 50 (128 mg, 0.5 mmol) and potassium carbonate
(104 mg, 0.75 mmol) in DMF (1.5 mL) was stirred at 80 °C for 1 h. The
reaction mixture was loaded directly onto a silica gel cartridge and purified by
13. Katz, L. B.; Gambale, J. J.; Rothenberg, P. L.; Vanapalli, S. R.; Vaccaro, N.; Xi, L.;
Sarich, T. C.; Stein, P. P. Diabetes Obes. Metab. 2012, 14, 709.