Page 27 of 49
Journal of Medicinal Chemistry
9
.3 Hz, 2H), 5.37 – 5.16 (m, 1H), 3.59 – 3.35 (m, 2H), 2.54 - 2.42 (m, 1H), 2.08 – 1.86 (m, 1H), 1.47 (s,
1
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5
6
7
8
9
1
1
1
1
1
1
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1
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6
1
3
3H), 1.30 (d, J = 8.8 Hz, 5H), 0.75 – 0.47 (m, 4H). C NMR (100 MHz, CDCl ) δ 180.8, 167.7, 153.4,
3
1
32.2, 128.9, 125.8, 125.7, 80.6, 54.5, 53.7, 40.5, 28.2, 20.2, 11.9, 9.1.
tert-butyl
(S)-6-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]
heptane-5-
1
carboxylate (11j): White solid, 82% yield (three steps). H NMR (500 MHz, CDCl ) δ 8.22 (t, J = 7.9 Hz,
3
2H), 7.74 (dd, J = 13.3, 8.3 Hz, 2H), 5.29 (ddd, J = 12.4, 8.0, 3.6 Hz, 1H), 3.59 – 3.37 (m, 2H), 2.56 -
0
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0
2
.45 (m, 1H), 2.08 – 1.90 (m, 1H), 1.47 (s, 3H), 1.31 (s, 6H), 0.76 – 0.60 (m, 3H), 0.59 – 0.48 (m, 1H).
1
3
C NMR (101 MHz, CDCl ) δ 181.1, 167.3, 153.4, 127.9, 127.8, 125.9, 125.9, 80.6, 54.5, 40.5, 28.1,
3
2
0.2, 11.9, 9.1.
tert-butyl (S)-6-(3-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptane-5-
1
carboxylate (11k): White solid, 61% yield (three steps). H NMR (400 MHz, CDCl ) δ 8.10 (t, J = 6.9
3
Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 5.42 – 5.22 (m, 1H), 3.62 – 3.35 (m, 2H), 2.59
1
3
- 2.46 (m, 1H), 2.10 – 1.86 (m, 1H), 1.48 (s, 3H), 1.39 – 1.25 (m, 6H), 0.75 – 0.46 (m, 4H). C NMR
100 MHz, CDCl ) δ 180.6, 166.3, 153.3, 134.2, 132.4, 132.2, 129.5, 128.0, 123.7, 121.5, 80.6, 54.4, 40.5,
(
3
2
8.4, 28.2, 20.2, 13.4, 12.0, 9.0, 7.6.
tert-butyl (S)-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptane-5-
1
carboxylate (11l): White solid, 91% yield (three steps). H NMR (500 MHz, CDCl ) δ 8.22 (t, J = 7.4 Hz,
3
1
1
H), 7.61 – 7.48 (m, 2H), 5.41 – 5.22 (m, 1H), 3.57 - 3.39 (m, 2H), 2.57 - 2.46 (m, 1H), 2.10 – 1.88 (m,
13
H), 1.48 (s, 3H), 1.38 – 1.25 (m, 6H), 0.76 – 0.61 (m, 3H), 0.57 - 0.50 (m, 1H). C NMR (126 MHz,
CDCl ) δ 164.3, 161.4, 159.3, 153.3, 134.6, 131.7, 131.5, 126.1, 123.9, 121.8, 121.3, 121.2, 118.6, 114.4,
3
1
14.2, 80.6, 54.4, 54.2, 53.7, 40.5, 39.7, 28.3, 28.1, 20.7, 20.2, 13.3, 12.0, 9.0, 7.8.
tert-butyl (S)-6-(3-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4]heptane-5-
1
carboxylate (11m): White solid, 83% yield (three steps). H NMR (400 MHz, CDCl ) δ 7.73 (dd, J = 8.1,
3
5.1 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.30 (t, J = 7.1 Hz, 1H), 5.33 – 5.11 (m, 1H), 3.49 (d, J = 10.4 Hz,
1
1
H), 3.41-4.24 (m, 1H), 2.52-2.41 (m, 1H), 1.95 – 1.76 (m, 1H), 1.39-1.27 (m, 9H), 0.62 (d, J = 9.7 Hz,
1
3
H), 0.55 (d, J = 8.7 Hz, 2H), 0.46 - 0.35 (m, 1H). C NMR (100 MHz, CDCl3) δ 179.8, 165.8, 162.4 (d,
J = 253.7 Hz), 152.4, 133.1 (d, J = 8.5 Hz), 130.7 (dd, J = 33.2, 7.9 Hz), 122.8 (d, J = 274.0 Hz),
CF
CF
CF
CF
120.5 (t, JCF = 3.6 Hz), 118.0 (d, JCF = 21.3 Hz), 114.0 (d, JCF = 19.7 Hz), 79.6, 53.5, 39.6, 27.1, 19.1,
1.5, 7.4.
1
tert-butyl (S)-6-(3-(2,4,5-trifluorophenyl)-1,2,4-oxadiazol-5-yl)-5-azaspiro[2.4] heptane-5-carboxylate
1
(11n): White solid, 82% yield (three steps). H NMR (500 MHz, CDCl ) δ 7.92 (d, J = 5.8 Hz, 1H), 7.17
3
–
7.07 (m, 1H), 5.36 – 5.21 (m, 1H), 3.56 - 3.38 (m, 2H), 2.59 – 2.45 (m, 1H), 2.06 – 1.83 (m, 1H), 1.47
13
(s, 4H), 1.32 (s, 5H), 0.73 - 0.49 (m, 4H). C NMR (125 MHz, CDCl3) δ 180.6, 163.8, 156.2 (ddd, J =
CF
2
57.9, 9.2, 2.3 Hz), 153.3, 151.8 (ddd, J = 244.0, 14.2, 11.6 Hz), 146.9 (ddd, J = 248.8, 12.5, 3.2 Hz),
CF CF
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