Discovery of a potent dihydrooxadiazole series of non-ATP-competitive MK2 (MAPKAPK2) inhibitors

Article abstract of DOI:10.1021/ml200238g

Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure-activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

Full text of DOI:10.1021/ml200238g

Discovery of a potent dihydrooxadiazole series of non-ATP-
competitive MK2 (MAPKAPK2) inhibitors
Jun Qin,*,† Pawan Dhondi,† Xianhai Huang,† Robert Aslanian,† James
Fossetta,‡ Fang Tian,‡ Daniel Lundell,‡ and Anandan Palani*,†
‡
†Department of Medicinal Chemistry and Inflammatory Disease, Merck Research
Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Experimental Procedures
Analytical methods: All reactions were carried out under nitrogen atmosphere in
anhydrous conditions, unless otherwise noted. Solvents were purchased from Aldrich and
Acros without further purification. Reagents and chemicals were purchased from
commercial sources with purity ≥ 95% without further purification. Flash
chromatography was carried out with EM Science silica gel 60 (neutral, 230-400 mesh).
1H NMR and 13C NMR were recorded on a Bruker Avance 500 NMR Spectrometer.
LCMS analyses were performed on Applied Biosystem API-150. HRMS analyses were
recorded on a Micromass QT of Ultima API US Mass Spectrometer by FAB.
LC/MS conditions: Agilent 6140 Quadrupole LC/MS System; Column Zorbax SB-C18,
3.0 x 50.0 mm, 1.8 micron; Mobile phase A: H2O/0.05% TFA/0.5% acetic acid; Mobile
phase B: acetonitrile/0.5% acetic acid; Flow: 1.0 ml/min; Gradient: 0 min 10% B, 1.5 min
95% B, 2.7 min 95% B, 2.8 min 10% B, Stop 3.6 min; Column temperature: 50 oC.
All of the biologic assays and experiments with animal models performed in Merck
& CO., Inc were in accordance with all national or local guidelines and regulations.
MK2 IMAP ASSAY:
Assay Reagents
5X Reaction Buffer T (Molecular Device, R7364)
10 mM ATP (New England, P0756S)
Substrate: TAMRA labeled Glycogen Synthase-derived Peptide (5TAMRA-
KKLNRTLSVA-COOH, Molecular Device, R7277)
5X Progressive Binding Buffer A (Molecular Device, R7279)
Progressive Binding Reagent (Molecular Device, R7281)
All the components of MK2 phosphorylation reaction made as 4X concentrated in 1X
Reaction Buffer T containing 10 mM Tris, pH7.2, 10 mM MgCl2, 1 mM DTT (fresh

added), 0.05% azide and 0.01% Tween 20, and the reaction is carried in 384 well black
reaction plate (Fisher, 09-761-85) at room temperature in dark.
Reaction Setup
Mix 5 l of 4X inhibitor in 4% DMSO, l of 400 M ATP and 5 l of 200 pM MK2
kinase and incubate for 30 min. Reaction is started by adding 5 ml of 400 nM TAMRA
labeled peptide and incubating 30 min in dark. The final concentrations are: 1X inhibitor,
1% DMSO, 100 M ATP, 50 pM MK2 and 100 nM substrate.
Detection
Reaction is stopped by adding 60 l of 1:400 diluted Progressive Binding Reagent in 1X
Progressive Binding Buffer A and incubating 30 min in dark. Read plate at Analyst HT
96-384 Plate Reader (LJL BioSystem) equipped with Fluorescence Polarization module
(Excitation wavelength 530 nm and Emission wavelength 580 nm).
LPS Induced Phospho-HSP27 Serine78 Assay:
Cells: THP-1 (ATCC # TIB-202)
TNF Detection: MesoScale(Phospho-HSP27 Serine78 ) - 384 Format
Reagents and Materials
1. Complete RPMI-1640 medium
2 mM
1 mM
L-glutamine
Sodium Pyruvate
Glucose
Sodium Bicarbonate
HEPES
4.5 g/L
1.5 g/L
10 mM
0.05 mM
10%
2-mercaptoethanol
FBS
2. RPMI-1640 without FBS (Completed RPMI-1640 without FBS)
3. 10X Cell Lysis Buffer (Cell Signaling, Cat#9803)
4. Okadaic Acid Sigma, Cat#O7885, MW = 843, 1mg/ml = ~1.2mM
5. Halt Protease & Phosphotase Inhibitor Cocktail (100X) Thermo Scientific,
Cat#1861282
6. MesoScale Phospho-HSP27 (Ser78) 384-well Plate Cat#N310FOB-1
7. Flat-bottom Microtest Tissue Culture Plate (96-well) Becton Dickinson, Cat#3075
8. Glass Fiber Filter Plate (96-well) Millipore, Cat#MSFBN6B50
9. 96-well Storage Plate BD Falcon, Cat#353263
10. LPS Sigma, Cat#L3129, 1mg/ml stored at -80 oC
LPS Induction and Cell Lysate Preparation

1. Bring the THP-1 cells to Log-phase by passing the cells at proper density a day
previous to the assay (~ 1 x 105 cells/ml)
2. Spin to collect cells and suspend in fresh complete-RPMI-1640 Medium at cell
density of 2.5x106 cells/ml
3. Add equal volume of RPMI-1640 without FBS containing 40 nM Okadaic Acid
(final: 100,000 cells/80 l/well)
4. Plate 100,000 cells/80 l into flat-bottom cell culture plate and incubate at 37 oC
for 60 min
5. Add 10 l of 10X diluted-compound in 1% DMSO in 5% FBS-RPMI medium
and incubate at 37 oC for 60 min
6. Add 10 l of 10X LPS in 5% FBS-RPMI medium and incubate at 37 oC for 60
min
7. Add 25 l 5X Cell Lysis Buffer containing 5X Halt Inhibitors and incubate on ice
for 30 min
8. Transfer cell lysate to glass fiber filter plate and stack the filter plate on top of a
96-well storage plate
9. Spin stacked filter-storage plate at 3,500 rpm for 5 min at 4 oC
MesoScale pHSP27 S78 Assay: 10 ~ 20 l cell lysate was used in this assay. Follow the
manufacturer's instructions.
General procedure for the preparation of analogues:

Reagents and conditions: (a) NH2OH·HCl, Py; (b) NCS, 60 oC→rt, Et3N, DMF; (c) TFA/CH2Cl2;
(d) p-TsOH, CH2Cl2; (e) Br(CH2)3Br, Cs2CO3, DMF; (f) CDI, Cs2CO3, DMF; (g) EDC, DMAP,
o
DMF; (h) Bu3P, ADDP, N-hydroxyphthalimide, THF, 80 C; (i) NH2NH2·xH2O, CH2Cl2/MeOH;
(j) H3PO4, microwave, 120 oC.
Compound 40 was converted to oxime ether 41 by condensing with NH2OH in pyridine.
After 41 was treated with NCS to form imidoyl chloride, a subsequent [3+2]
cycloaddition with enol ether 42, alkyne 43 or imine 44, followed by removal of the Boc
group delivered analogues 2, 3 or 5 respectively. In a similar fashion, a [3+2]
cycloaddition between oxime ether 46 and imine 47 provided compound 6 after
deprotection of the Boc group. Reaction of hydroxyamidine 48 with 1,3-dibromopropane

in the presence of base through consecutive inter- and intramolecular alkylation provided
8 after removal of protection group. Compound 4 was also prepared in a similar method
to 8 using CDI. The synthesis of 7 started from coupling of 49 with 50 to give tertiary
amide 51. A subsequent two step transformation converted 51 to hydroxylamine
intermediate 52, which eventually led to the formation of dihydrooxadiazine compound 7
through a one pot cyclization and deprotection.
41
To a solution of compound 40 (15.0 g, 72.8 mmol) in pyridine (100 ml) was added
NH2OH·HCl (7.5 g, 109.2 mmol) and the mixture was stirred at room temperature
overnight. It was then concentrated to remove the pyridine. The residue was dissolved in
CH2Cl2, washed with H2O, brine, dried with Na2SO4 and filtered. The filtrate was
concentrated and the product was formed as solid during the concentration process. It was
then collected by filtration and dried by vacuum to give 41 as white solid (13.0 g, 81%).
2
To a solution of 41 (300 mg, 1.36 mmol) in DMF (10 ml) was added NCS (200 mg, 1.5
o
mmol) and was heated at 60 C for 1 h. Then 42 (319 mg, 1.0 mmol) and Et3N (227 μl,
o
1.63 mmol) were added to the mixture and was heated at 70 C for 2 d. The mixture was
diluted with EtOAc, washed with H2O, brine, dried with Na2SO4 and filtered. The filtrate
was concentrated and purified by flash chromatography (EtOAc/Hex) to provide product
70 mg, which was then dissolved in TFA/CH2Cl2 (10/10 ml) and was stirred for 2 h. The
solvent was removed and the residue was purified by HPLC to give the product 2 as
colorless oil (43 mg, 11% for two steps).
3
To a solution of 41 (442 mg, 2.0 mmol) in DMF (15 ml) was added NCS (295 mg, 2.2
o
mmol) and was heated at 60 C for 1 h. The mixture was cooled and then compound 43
(430 mg, 1.5 mmol) and Et3N (417 μl, 3.0 mmol) were added and was stirred at room
temperature overnight. It was then diluted with EtOAc, washed with H2O, brine, dried
with Na2SO4 and filtered. The filtrate was concentrated and purified by flash
chromatography (EtOAc/Hex) to provide product 200 mg, which was dissolved in

TFA/CH2Cl2 (10/10 ml) and was stirred for 2 h. The solvent was removed and the residue
was purified by flash chromatography (CH2Cl2/MeOH) to give the product 3 as colorless
oil (113 mg, 14% for two steps).
5
To a solution of 41 (1.50 g, 6.79 mmol) in DMF (15 ml) was added NCS (1.0 g, 7.46
o
mmol) and was heated at 60 C for 1 h. The mixture was cooled and then compound 44
(2.06 g, 5.66 mmol) and Et3N (1.04 ml, 7.46 mmol) were added and was stirred at room
temperature overnight. It was then diluted with EtOAc, washed with H2O, brine, dried
with Na2SO4 and filtered. The filtrate was concentrated and purified by flash
chromatography (EtOAc/Hex) to provide 900 mg product as off-white solid, which was
dissolved in TFA/CH2Cl2 (15/15 ml) and was stirred for 2 h. The solvent was removed
and the residue was purified by flash chromatography (CH2Cl2/MeOH) to give the
product 5 as yellowish solid (600 mg, 22% for two steps).
47
To a mixture of 40 (2.27 g, 11.0 mmol) and 45 (2.77 g, 11.0 mmol) in CH2Cl2 (20 ml)
was added p-TsOH (300 mg) and was stirred at room temperature overnight. It was then
diluted with CH2Cl2, washed with H2O, brine, dried with Na2SO4 and filtered. The filtrate
was concentrated and purified by flash chromatography (EtOAc/Hex, deactivated with
Et3N/Hex = 5/100) to provide product 47 as off-white solid (4.0 g, 86%).
6
To a solution of 46 (800 mg, 6.61 mmol) in DMF (10 ml) was added NCS (974 mg, 7.27
o
mmol) and was heated at 60 C for 1 h. The mixture was cooled and 47 (2.36 g, 5.08
mmol) and Et3N (1.01 ml, 7.27 mmol) were added and was stirred at room temperature
overnight. It was then diluted with EtOAc, washed with H2O, brine, dried with Na2SO4
and filtered. The filtrate was concentrated and purified by flash chromatography
(EtOAc/Hex) to provide 260 mg product as off-white solid, which was dissolved in
TFA/CH2Cl2 (5/5 ml) and was stirred for 2 h. Then the solvent was removed and the

residue was purified by flash chromatography (CH2Cl2/MeOH) to give the product 6 as
off-white powder (30 mg, 1.2% for two steps).
48
To a solution of 41 (5.0 g, 22.6 mmol) in DMF (30 ml) was added NCS (3.33 g, 24.9
o
mmol) and was heated at 60 C for 1 h. The mixture was cooled and compound 45 (3.13
g, 11.3 mmol) and Et3N (3.77 ml, 27.1 mmol) were added and was stirred at room
temperature overnight. It was then diluted with EtOAc, washed with H2O, brine, dried
with Na2SO4 and filtered. The filtrate was concentrated and purified by flash
chromatography (EtOAc/Hex) to give product 48 as brownish solid (2.3 g, 41%)
4
A mixture of 48 (300 mg, 0.60 mmol), CDI (107 mg, 0.66 mmol) and Cs2CO3 (430 mg,
1.32 mmol) in DMF (5 ml) was stirred at room temperature overnight. It was then diluted
with EtOAc, washed with H2O, brine, dried with Na2SO4 and filtered. The filtrate was
concentrated and purified by flash chromatography (EtOAc/Hex) to give product 110 mg
as off-white solid, which was then dissolved in TFA/CH2Cl2 (10/10 ml) and was stirred
for 2 h. The solvent was removed and the residue was purified by flash chromatography
(CH2Cl2/MeOH) to give the product 4 as yellowish solid (60 mg, 24% for two steps).
8
A mixture of 48 (250 mg, 0.50 mmol), Br(CH2)3Br (110 mg, 0.55 mmol) and Cs2CO3
(359 mg, 1.10 mmol) in DMF (5 ml) was stirred at room temperature overnight. It was
then diluted with EtOAc, washed with H2O, brine, dried with Na2SO4 and filtered. The
filtrate was concentrated and purified by flash chromatography (EtOAc/Hex) to give
product 90 mg as yellowish oil, which was dissolved in TFA/CH2Cl2 (5/5 ml) and was
stirred for 2 h. The solvent was removed and the residue was purified by flash

chromatography (CH2Cl2/MeOH) to give the product 8 as yellowish powder (60 mg, 28%
for two steps).
51
A mixture of compound 49 (0.33 g, 1.56 mmol), 50 (0.50 g, 1.56 mmol), EDC (0.60 g,
3.12 mmol) and DMAP (95.3 mg, 0.78 mmol) in DMF (8.0 ml) was stirred at room
temperature overnight. It was then diluted with ethyl acetate and washed with aqueous
NH4Cl, water, brine and dried (MgSO4). After filtration and solvent removal, the residue
was purified with silica gel column (EtOAc/Hex) to give product 51 as colorless oil (155
mg, 19%).
52
A mixture of compound 51 (155 mg, 0.30 mmol), ADDP (109 mg, 0.45 mmol), PBu3
(109 µl, 0.45 mmol) and N-hydroxyphthalimide (74 mg, 0.42 mmol) in THF (3.0 ml) was
o
heated at 80 C overnight. It was cooled and solid was filtered and washed with ether.
The filtrate was diluted with ethyl acetate and washed with NaHCO3, brine and dried
(MgSO4). After filtration and solvent removal, the residue was purified with silica gel
column (EtOAc/Hex) to give product (124 mg, 78%), which was then dissolved in
CH2Cl2/MeOH (1.5/1.5 ml) and NH2NH2.xH2O (23 µl, 0.47 mmol) was added to the
solution. The mixture was stirred for 1 h at room temperature. It was diluted with ethyl
acetate and washed with 0.5 N NaOH, sat. aqueous NaHCO3, brine and dried (MgSO4).
After filtration and solvent removal, the residue was used in the next step without
purification.
7

The product obtained from previous step was dissolved in EtOH (4.0 ml) followed with
addition of H3PO4 (200 μl). The mixture was heated in a microwave reactor at 120 oC for
1.5 h. Then it was cooled and diluted with ethyl acetate and basified with 1 N NaOH until
aqueous layer pH = 9. The aqueous layer was separated and extracted with ethyl acetate.
The combined organic phases were washed with water, brine and dried (MgSO4). After
filtration and solvent removal, the residue was purified with preparative TLC plate
(EtOAc/Hex) to give product 7 as white solid (24 mg, 19% for three steps).
Compound 33 was resolved to provide 38 and 39 by the following HPLC condition:
CHIRALCEL® OD preparative column, hexane : ethanol : Et2NH = 50 : 50 : 0.20
(v/v/v). Under this condition, enantiomer 38 had a shorter (92.90 minutes) retention time
than enantiomer 39 (137.85 minutes). Both enantiomers have purity of >95%
enantiomeric excess.
1H NMR and LCMS data:
2
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)isoxazole: 1H NMR
(500 MHz, CDCl3) δ 8.45 (s, 1 H), 7.59 (d, J = 8.50 Hz, 2 H), 7.42-7.35 (m, 4 H), 7.04 (d,
J = 9.00 Hz, 2 H), 6.74 (d, J = 3.50 Hz, 1 H), 6.71 (d, J = 3.50 Hz, 1 H), 3.34-3.28 (m,
4H), 3.19-3.14 (m, 4 H) ppm; ES-LCMS (M + H)+ = 406.2 (96% purity).
3
3-(5-(4-chlorophenyl)furan-2-yl)-5-(4-(piperazin-1-yl)phenyl)isoxazole: 1H NMR
(500 MHz, CDCl3) δ 7.83-7.73 (m, 4 H), 7.45 (d, J = 8.50 Hz, 2 H), 7.06 (d, J = 4.00 Hz,
1 H), 7.03 (d, J = 8.50 Hz, 2 H), 6.83 (d, J = 3.50 Hz, 1H), 6.74 (s, 1 H), 3.39-3.33 (m,
4H), 3.18-3.11 (m, 4 H) ppm; ES-LCMS (M + H)+ = 406.2 (95% purity).
4

3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-1,2,4-oxadiazol-5(4H)-
1
one: H NMR (500 MHz, DMSO) δ 7.58 (d, J = 9.00 Hz, 2 H), 7.50 (d, J = 9.00 Hz, 2
H), 7.44 (d, J = 9.00 Hz, 2 H), 7.16 (d, J = 4.00 Hz, 1 H), 7.08 (d, J = 9.00 Hz, 2H), 6.52
(d, J = 4.00 Hz, 1 H), 3.22-3.14 (m, 4H), 2.89-2.83 (m, 4 H) ppm; ES-LCMS (M + H)+ =
423.2 (100% purity).
5
3-(5-(4-chlorophenyl)furan-2-yl)-5-phenyl-4-(4-(piperazin-1-yl)phenyl)-4,5-dihydro-
1
1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ 7.64-7.58 (m, 2 H), 7.52 (d, J = 8.50
Hz, 2 H), 7.49-7.44 (m, 3 H), 7.36 (d, J = 9.00 Hz, 2 H), 7.01 (d, J = 9.00 Hz, 2 H), 6.86
(d, J = 9.00 Hz, 2 H), 6.61 (d, J = 3.50 Hz, 1 H), 6.45 (s, 1H), 6.43 (d, J = 3.50 Hz, 1 H),
3.25-3.18 (m, 4H), 3.14-3.08 (m, 4 H) ppm; ES-LCMS (M + H)+ = 485.2 (95% purity).
6
5-(5-(4-chlorophenyl)furan-2-yl)-3-phenyl-4-(4-(piperazin-1-yl)phenyl)-4,5-dihydro-
1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) δ 7.72-7.61 (m, 4 H), 7.48-7.34 (m, 5 H),
6.90 (d, J = 9.00 Hz, 2 H), 6.79 (d, J = 9.00 Hz, 2 H), 6.72 (d, J = 3.00 Hz, 1 H), 6.70 (d, J
= 3.00 Hz, 1 H), 6.59 (s, 1 H), 3.21-3.15 (m, 4H), 3.12-3.05 (m, 4 H) ppm; ES-LCMS (M
+ H)+ = 485.2 (100% purity).
7
4-(5-(4-(4-(piperazin-1-yl)phenyl)-5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)furan-2-
yl)benzonitrile: 1H NMR (500 MHz, CDCl3) 7.56 (d, J = 8.50 Hz, 2 H), 7.43 (d, J = 8.5
Hz, 2 H), 7.01 (d, J = 9.00 Hz, 2 H), 6.83 (d, J = 9.00 Hz, 2 H), 6.66 (d, J = 3.50 Hz, 1 H),
6.56 (d, J = 3.50 Hz, 1 H), 4.25 (t, J = 4.50 Hz, 2 H), 3.81 (t, J = 4.50 Hz, 2 H), 3.09-3.07
(m, 4 H), 3.04-3.02 (m, 4 H) ppm; ES-LCMS (M + H)+ = 414.2 (95% purity).

8
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-4,5,6,7-tetrahydro-
1,2,4-oxadiazepine: 1H NMR (500 MHz, CDCl3) δ 7.35-7.23 (m, 4 H), 6.88 (d, J = 9.00
Hz, 2 H), 6.75 (d, J = 9.00 Hz, 2 H), 6.66 (brs, 1 H), 6.61 (d, J = 3.50 Hz, 1 H), 4.07 (t, J
= 7.00 Hz, 2 H), 3.86 (t, J = 7.50 Hz, 2 H), 3.19-3.08 (m, 8 H), 2.46-2.36 (m, 2 H) ppm;
ES-LCMS (M + H)+ = 437.2 (90% purity).
9
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(pyridin-2-yl)-4,5-
1
dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.69-8.64 (m, 1 H), 7.89-7.82
(m, 2 H), 7.52 (d, J = 8.00 Hz, 2 H), 7.40-7.33 (m, 3 H), 7.10 (d, J = 8.50 Hz, 2 H), 6.87
(d, J = 9.00 Hz, 2 H), 6.62 (d, J = 3.50 Hz, 1 H), 6.58 (s, 1H), 6.48 (d, J = 4.00 Hz, 1 H),
3.32-3.23 (m, 4 H), 3.20-3.12 (m, 4 H) ppm; ES-LCMS (M + H)+ = 486.2 (99% purity).
10
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(pyridin-3-yl)-4,5-
1
dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.76-8.67 (m, 2 H), 8.03-7.98
(m, 1 H), 7.51 (d, J = 8.50 Hz, 2 H), 7.45-7.39 (m, 1 H), 7.35 (d, J = 8.50 Hz, 2 H), 7.03
(d, J = 9.00 Hz, 2 H), 6.87 (d, J = 9.00 Hz, 2 H), 6.62 (d, J = 3.50 Hz, 1 H), 6.49 (s, 1H),
6.43 (d, J = 3.50 Hz, 1 H), 3.34-3.27 (m, 4 H), 3.24-3.15 (m, 4 H) ppm; ES-LCMS (M +
H)+ = 486.2 (99% purity).

11
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(pyridin-4-yl)-4,5-
1
dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 9.05-8.56 (m, 2 H), 7.64-7.54
(m, 2 H), 7.51 (d, J = 8.50 Hz, 2 H), 7.35 (d, J = 8.50 Hz, 2 H), 7.06 (d, J = 8.50 Hz, 2 H),
6.89 (d, J = 8.50 Hz, 2 H), 6.63 (d, J = 4.00 Hz, 1 H), 6.48 (d, J = 3.50 Hz, 1 H), 6.43 (s,
1H), 3.49-3.41 (m, 4 H), 3.40-3.30 (m, 4 H) ppm; ES-LCMS (M + H)+ = 486.2 (99%
purity).
12
3-(5-(4-chlorophenyl)furan-2-yl)-5-(5-fluoropyridin-2-yl)-4-(4-(piperazin-1-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.55-8.48 (m, 1
H), 7.89-7.82 (m, 1 H), 7.61-7.54 (m, 1 H), 7.51 (d, J = 8.50 Hz, 2 H), 7.34 (d, J = 8.00
Hz, 2 H), 7.12 (d, J = 8.50 Hz, 2 H), 6.88 (d, J = 8.50 Hz, 2 H), 6.63 (d, J = 3.50 Hz, 1 H),
6.57 (s, 1H), 6.50 (d, J = 3.50 Hz, 1 H), 3.47-3.20 (m, 8 H) ppm; ES-LCMS (M + H)+ =
504.2 (99% purity).
13
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(pyrimidin-4-yl)-4,5-
dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) 9.50(s, 1 H), 9.12-8.76 (m, 1 H),
8.05-7.78 (m, 1 H), 7.52 (d, J = 8.00 Hz, 2 H), 7.34 (d, J = 8.00 Hz, 2 H), 7.23 (d, J =
8.00 Hz, 2 H), 6.91 (d, J = 7.50 Hz, 2 H), 6.69-6.59 (m,1 H), 6.58-6.50 (m, 1H), 6.46 (s, 1
H), 3.49-3.06 (m, 8 H) ppm; ES-LCMS (M + H)+ = 487.3 (99% purity).

14
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(pyrimidin-5-yl)-4,5-
dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) 9.53 (s, 2 H), 9.05 (s, 1 H), 7.49
(d, J = 7.50 Hz, 2 H), 7.32 (d, J = 7.00 Hz, 2 H), 7.16-7.02 (m, 2 H), 6.97-6.82 (m, 2 H),
6.67-6.58 (m,1 H), 6.54 (s, 1H), 6.49-6.41 (m, 1 H), 3.72-3.08 (m, 8 H) ppm; ES-LCMS
(M + H)+ = 487.3 (99% purity).
15
3-(5-(4-chlorophenyl)furan-2-yl)-5-(4-fluorophenyl)-4-(4-(piperazin-1-yl)phenyl)-5-
dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) 7.63-7.53 (m, 2 H), 7.49 (d, J =
8.50 Hz, 2 H), 7.39-7.29 (m, 2 H), 7.16-7.09 (m, 2 H), 7.00 (d, J = 8.00Hz, 2 H), 6.92-
6.80 (m, 2 H), 6.65-6.58 (m,1 H), 6.42 (s, 1 H), 6.41-6.39 (m, 1 H), 3.64-3.09 (m, 8 H)
ppm; ES-LCMS (M + H)+ = 503.2 (99% purity).
16
3-(5-(4-chlorophenyl)furan-2-yl)-5-(2,4-difluorophenyl)-4-(4-(piperazin-1-l)phenyl)-
4,5-dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) 7.80-7.72 (m, 1 H), 7.50 (d,
J = 8.50 Hz, 2 H), 7.34 (d, J = 8.00Hz, 2 H), 7.06 (d, J = 8.50Hz, 2 H), 7.03-6.97 (m, 1
H), 6.90-6.84 (m, 3 H), 6.80 (s, 1 H), 6.63 (d, J = 3.50Hz, 1 H), 6.48 (d, J = 3.50Hz, 1 H),
3.64-3.05 (m, 8 H) ppm; ES-LCMS (M + H)+ = 521.2 (99% purity).

17
3-(5-(4-chlorophenyl)furan-2-yl)-5-(3,5-difluorophenyl)-4-(4-(piperazin-1-l)phenyl)-
1
4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 7.51 (d, J = 8.50 Hz, 2 H),
7.35 (d, J = 8.50Hz, 2 H), 7.18-7.11 (m, 2 H), 7.03 (d, J = 9.00 Hz, 2 H), 6.92-6.89 (m, 1
H),, 6.88 (d, J = 9.00Hz, 2 H), 6.61 (d, J = 3.50Hz, 1 H), 6.43 (d, J = 3.50Hz, 1 H), 6.39
(s, 1 H), 3.24-3.18 (m, 4 H), 3.13-3.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 521.2 (99%
purity).
18
3-(5-(4-chlorophenyl)furan-2-yl)-5-(1H-imidazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)-
1
4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 7.79 (s, 1 H), 7.48 (d, J =
8.00 Hz, 2 H), 7.35-7.28 (m, 3 H), 7.09 (d, J = 8.50Hz, 2 H), 6.92 (d, J = 8.50 Hz, 2 H),
6.75 (d, J = 3.50Hz, 1 H), 6.56 (s, 1 H), 6.40 (d, J = 3.50Hz, 1 H), 3.28-3.07 (m, 8 H)
ppm; ES-LCMS (M + H)+ = 475.2 (99% purity).
19
3-(5-(4-chlorophenyl)furan-2-yl)-5-(2-phenylpyrimidin-5-yl)-4-(4-(piperazin-1-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.97 (s, 2 H),
8.55-8.46 (m, 2 H), 7.57-7.52 (m, 3 H), 7.50 (d, J = 8.50Hz, 2H), 7.34 (d, J = 8.50 Hz, 2
H), 7.09 (d, J = 8.50 Hz, 2 H), 6.88 (d, J = 9.00Hz, 2 H), 6.62 (d, J = 3.50Hz, 1 H), 6.52
(s, 1 H), 6.45 (d, J = 3.50Hz, 1 H), 3.51-3.39 (m, 4 H), 3.38-3.25 (m, 4 H) ppm; ES-
LCMS (M + H)+ = 563.2 (99% purity).

20
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(4-(pyrimidin-2-
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: ES-LCMS (M + H)+ = 563.2 (99% purity).
21
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(4-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 9.29 (s, 1 H),
9.06 (s, 2 H), 7.72 (d, J = 8Hz, 2H), 7.66 (d, J = 7.50 Hz, 2 H), 7.46 (d, J = 8.50 Hz, 2 H),
7.29 (d, J = 8.50Hz, 2 H), 7.04 (d, J = 8.50Hz, 2 H), 6.86 (d, J = 8.00 Hz, 2 H), 6.60 (d, J
= 3.50Hz, 1 H), 6.49 (s, 1 H), 6.40 (d, J = 3.50Hz, 1 H), 3.51-3.23 (m, 8 H) ppm; ES-
LCMS (M + H)+ = 563.2 (99% purity).
22
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(3-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 9.24 (s, 1 H),
8.98 (s, 2 H), 7.79-7.75 (m, 1 H), 7.71-7.65 (m, 2 H), 7.64-7.59 (m, 1 H), 7.49 (d, J =
8.50 Hz, 2 H), 7.33 (d, J = 8.50Hz, 2 H), 7.05 (d, J = 8.50Hz, 2 H), 6.87 (d, J = 9.00Hz, 2
H), 6.62 (d, J = 4.00 Hz, 1 H), 6.52 (s, 1 H), 6.45 (d, J = 3.50Hz, 1 H), 3.49-3.24 (m, 8 H)
ppm; ES-LCMS (M + H)+ = 563.3 (99% purity).

23
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 9.03 (s, 1 H),
8.59 (s, 2 H), 7.92-7.83 (m, 1 H), 7.63-7.51 (m, 2 H), 7.42 (d, J = 8.50 Hz, 2 H), 7.34-
7.24 (m, 3 H), 6.84 (q, J = 7.50Hz, 4 H), 6.67 (d, J = 3.50 Hz, 1 H), 6.44 (s, 1 H), 6.29 (d,
J = 4.00Hz, 1 H), 3.33 (p, J = 1.5 Hz, 1H), 3.15-3.03 (m, 4 H), 2.98-2.86 (m, 4 H) ppm;
ES-LCMS (M + H)+ = 563.2 (99% purity).
24
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyridin-3-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.08-7.99 (m, 1
H), 7.92-7.81 (m, 1 H), 7.65-7.58 (m, 1 H), 7.57-7.51 (m, 2 H), 7.50-7.43 (m, 3 H), 7.37-
7.25 (m, 4 H), 6.93-6.84 (m, 2 H), 6.83-6.74 (m, 2 H), 6.59 (s, 1 H), 6.44-6.30 (m, 2 H),
3.47-3.22 (m, 8 H) ppm; ES-LCMS (M + H)+ = 562.2 (99% purity).
25
5-(biphenyl-2-yl)-3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-4,5-
1
dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) 8.12-8.00 (m, 1 H), 7.58-7.43
(m, 4 H), 7.39-7.27 (m, 6 H), 7.25-7.15 (m, 2 H), ), 6.88 (d, J = 8.50Hz, 2 H), 6.76 (d, J =
9.00Hz, 2 H), 6.59 (d, J = 3.50 Hz, 1 H), 6.50 (s, 1 H), 6.42 (d, J = 3.50Hz, 1 H), 3.49-
3.12 (m, 8 H) ppm; ES-LCMS (M + H)+ = 561.2 (99% purity).

26
3-(5-(3-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ 9.20 (s, 1 H),
8.63 (s, 2 H), 8.09 (d, J = 8.00 Hz, 1 H), 7.66 (t, J = 6.50 Hz, 1 H), 7.58 (t, J = 6.50 Hz, 1
H), 7.48-7.40 (m, 2 H), 7.34-7.25 (m, 3 H), 6.92 (d, J = 9.00 Hz, 2 H), 6.83 (d, J = 9.00
Hz, 2 H), 6.64 (d, J = 3.5 Hz, 1 H), 6.48 (d, J = 3.5 Hz, 1 H), 6.42 (s, 1 H), 3.25-3.17 (m,
4 H), 3.12-3.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 562.7 (95% purity).
27
3-(5-(4-fluorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ 9.19 (s, 1 H),
8.62 (s, 2 H), 8.07 (d, J = 8.00 Hz, 1 H), 7.69-7.49 (m, 4 H), 7.29 (d, J = 6.00 Hz, 1 H),
7.07 (t, J = 9.00 Hz, 2H), 6.91 (d, J = 9.00 Hz, 2 H), 6.82 (d, J = 9.00 Hz, 2 H), 6.54 (d, J
= 3.5 Hz, 1 H), 6.40 (s, 1 H), 6.38 (d, J = 3.5 Hz, 1 H), 3.29-3.18 (m, 4 H), 3.16-3.06 (m,
4 H) ppm; ES-LCMS (M + H)+ = 547.1 (99% purity).
28
3-(5-(3,4-dichlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ 9.18 (s, 1 H),
8.65 (s, 2 H), 7.98 (d, J = 8.00 Hz, 1 H), 7.65 (t, J = 7.00 Hz, 1 H), 7.59 (t, J = 7.00 Hz, 1
H), 7.46 (s, 1H), 7.42 (d, J = 8.50 Hz, 1 H), 7.35 (d, J = 8.50 Hz, 1 H), 7.28 (d, J = 8.50
Hz, 1 H), 6.90 (d, J = 9.00 Hz, 2 H), 6.82 (d, J = 9.00 Hz, 2 H), 6.62 (d, J = 3.50 Hz, 1 H),

6.47 (d, J = 3.50 Hz, 1 H), 6.38 (s, 1 H), 3.29-3.18 (m, 4 H), 3.16-3.06 (m, 4 H) ppm; ES-
LCMS (M + H)+ = 596.7 (99% purity).
29
3-(5-(4-chloro-3-fluorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-
1
(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ
9.19 (s, 1 H), 8.68 (s, 2 H), 7.98 (d, J = 8.00 Hz, 1 H), 7.65 (t, J = 7.00 Hz, 1 H), 7.59 (t, J
= 7.00 Hz, 1 H), 7.36 (t, J = 7.50 Hz, 1 H), 7.31-7.22 (m, 2 H), 7.09 (d, J = 10.00 Hz, 1
H), 6.91 (d, J = 9.00 Hz, 2 H), 6.83 (d, J = 9.00 Hz, 2 H), 6.62 (d, J = 3.50 Hz, 1 H), 6.49
(d, J = 3.50 Hz, 1 H), 6.38 (s, 1 H), 3.49-3.28 (m, 8 H) ppm; ES-LCMS (M + H)+ = 580.7
(99% purity).
30
4-(4-(piperazin-1-yl)phenyl)-3-(5-(pyridin-4-yl)furan-2-yl)-5-(2-(pyrimidin-5-
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CD3OD) δ 9.04 (s, 1 H),
8.77 (d, J = 7.0 Hz, 2 H), 8.65 (s, 2 H), 8.08 (d, J = 6.50 Hz, 2H), 7.92-7.86 (m, 1 H),
7.71-7.61 (m, 2 H), 7.55 (d, J = 4.00 Hz, 1 H), 7.44-7.38 (m, 1 H), 6.99 (s, 4 H), 6.55 (s,
1 H), 6.53 (d, J = 4.00 Hz, 1 H), 3.47-3.40 (m, 4 H), 3.39-3.35 (m, 4 H) ppm; ES-LCMS
(M + H)+ = 529.8 (99% purity).
31

3-(5-(4-methoxyphenyl)furan-2-yl)-4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-
1
yl)phenyl)-4,5-dihydro-1,2,4-oxadiazole: H NMR (500 MHz, CDCl3) δ 9.20 (s, 1 H),
8.63 (s, 2 H), 8.10 (d, J = 8.00 Hz, 1H), 7.65 (t, J = 7.00 Hz, 1 H), 7.58 (t, J = 7.50 Hz, 1
H), 7.51 (d, J = 9.00 Hz, 2 H), 7.28 (d, J = 9.00 Hz, 1 H), 6.95-6.88 (m, 4 H), 6.83 (d, J =
9.00 Hz, 2 H), 6.48 (d, J = 4.00 Hz, 1 H), 6.40 (s, 1 H),6.35 (d, J = 4.00 Hz, 1 H), 3.87 (s,
3 H), 3.22-3.15 (m, 4 H), 3.10-3.03 (m, 4 H) ppm; ES-LCMS (M + H)+ = 558.9 (99%
purity).
32
N-methyl-4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-
1
dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzamide: H NMR (500 MHz, CDCl3) δ
9.20 (s, 1 H), 8.63 (s, 2 H), 8.10 (d, J = 8.00 Hz, 1H), 7.78 (d, J = 8.50 Hz, 2 H), 7.66 (t, J
= 7.50 Hz, 1 H), 7.62-7.54 (m, 3 H), 7.28 (d, J = 7.50 Hz, 1 H), 6.92 (d, J = 9.00 Hz, 2
H), 6.83 (d, J = 9.00 Hz, 2 H), 6.71 (d, J = 4.00 Hz, 1 H), 6.51-6.45 (m, 2 H), 6.42 (s, 1
H), 3.28-3.18 (m, 4 H), 3.13-3.08 (m, 4 H), 3.05 (d, J = 5.00 Hz, 3 H) ppm; ES-LCMS
(M + H)+ = 585.8 (99% purity).
33
4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-
oxadiazol-3-yl)furan-2-yl)benzonitrile: 1H NMR (500 MHz, CDCl3) 9.11 (s, 1 H), 8.57
(s, 2 H), 8.04-7.97 (m, 1 H), 7.60-7.53 (m, 6 H), 7.27-7.20 (m, 1 H), 6.87 (d, J = 9.00 Hz,
2 H), 6.78 (d, J = 9.00 Hz, 2 H), 6.72 (d, J = 3.50 Hz, 1 H), 6.39-6.36 (m, 2 H), 3.26-3.19
(m, 4 H), 3.12-3.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 554.2 (99% purity).

34
3-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-
1
oxadiazol-3-yl)furan-2-yl)benzonitrile: H NMR (500 MHz, CDCl3) δ 9.17 (s, 1 H),
8.63 (s, 2 H), 8.01 (d, J = 8.00 Hz, 1H), 7.71 (d, J = 8.00 Hz, 1 H), 7.65 (t, J = 8.00 Hz, 1
H), 7.58 (t, J = 8.00 Hz, 1 H), 7.52 (d, J = 8.00 Hz, 1 H), 7.49-7.41 (m, 2 H), 7.28 (d, J =
7.50 Hz, 1 H), 6.92 (d, J = 9.00 Hz, 2 H), 6.84 (d, J = 9.00 Hz, 2 H), 6.71 (d, J = 4.00 Hz,
1 H), 6.67 (d, J = 4.00 Hz, 1 H), 6.40 (s, 1 H), 3.49-3.40 (m, 4 H), 3.39-3.29 (m, 4 H),
ppm; ES-LCMS (M + H)+ = 553.8 (99% purity).
35
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperidin-4-yl)phenyl)-5-(pyridin-4-yl)-4,5-
dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3) 8.63 (d, J = 6.00 Hz, 2 H), 7.64
(d, J = 6.00 Hz, 2 H), 7.45 (d, J = 8.50 Hz, 2 H), 7.36-7.25 (m, 4 H), 7.13 (d, J = 8.50 Hz,
2 H), 6.81 (d, J = 4.00 Hz, 1 H), 6.65 (s, 1H), 6.63 (d, J = 3.50 Hz, 1 H), 3.60-3.42 (m, 2
H), 3.18-3.07 (m, 2 H), 2.96-2.87 (m, 1 H), 2.07-1.96 (m, 2 H), 1.95-1.82 (m, 2 H) ppm;
ES-LCMS (M + H)+ = 485.2 (99% purity).
36
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(4,4-difluoropiperidin-1-yl)phenyl)-5-(pyridin-
4-yl)-4,5-dihydro-1,2,4-oxadiazole: : 1H NMR (500 MHz, CDCl3) 8.71 (d, J = 5.50 Hz,
2 H), ), 7.53-7.46 (m, 4 H), 7.32 (d, J = 8.50 Hz, 2 H), 7.02 (d, J = 9.00 Hz, 2 H), 6.89 (d,
J = 9.00 Hz, 2 H), 6.61 (d, J = 3.50 Hz, 1 H), 6.45 (d, J = 4.00 Hz, 1 H), 6.41 (s, 1H), 3.38
(t, J = 5.5Hz, 4 H), 2.15-2.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 521.2 (99% purity).

37
3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperazin-1-yl)benzyl)-5-(pyridin-4-yl)-4,5-
dihydro-1,2,4-oxadiazole:3-(5-(4-chlorophenyl)furan-2-yl)-4-(4-(piperidin-4-
yl)phenyl)-5-(pyridin-4-yl)-4,5-dihydro-1,2,4-oxadiazole: 1H NMR (500 MHz, CDCl3)
8.50 (d, J = 5.00 Hz, 2 H), 7.71 (d, J = 8.00 Hz, 2 H), 7.41 (d, J = 8.50 Hz, 2 H), 7.22 (d, J
= 3.50 Hz, 1 H), 7.19 (d, J = 5.50 Hz, 2 H), 7.06 (d, J = 8.50 Hz, 2 H), 6.84 (d, J = 3.00
Hz, 1 H), 6.74 (d, J = 8.00 Hz, 2 H), 6.58 (s, 1H), 4.75 (d, J = 15.00 Hz, 1 H), 4.61 (d, J =
15.00 Hz, 1 H), 3.43-3.10 (m, 8 H) ppm; ES-LCMS (M + H)+ = 500.2 (99% purity).
38
4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-
oxadiazol-3-yl)furan-2-yl)benzonitrile: 1H NMR (500 MHz, CDCl3) 9.11 (s, 1 H), 8.57
(s, 2 H), 8.04-7.97 (m, 1 H), 7.60-7.53 (m, 6 H), 7.27-7.20 (m, 1 H), 6.87 (d, J = 9.00 Hz,
2 H), 6.78 (d, J = 9.00 Hz, 2 H), 6.72 (d, J = 3.50 Hz, 1 H), 6.39-6.36 (m, 2 H), 3.26-3.19
(m, 4 H), 3.12-3.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 554.2 (>95% ee, 98% purity).
39
4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-
oxadiazol-3-yl)furan-2-yl)benzonitrile: 1H NMR (500 MHz, CDCl3) 9.11 (s, 1 H), 8.57
(s, 2 H), 8.04-7.97 (m, 1 H), 7.60-7.53 (m, 6 H), 7.27-7.20 (m, 1 H), 6.87 (d, J = 9.00 Hz,
2 H), 6.78 (d, J = 9.00 Hz, 2 H), 6.72 (d, J = 3.50 Hz, 1 H), 6.39-6.36 (m, 2 H), 3.26-3.19
(m, 4 H), 3.12-3.05 (m, 4 H) ppm; ES-LCMS (M + H)+ = 554.2 (>95% ee, 98% purity).