X. Yang, Z. Wang, Y. Pei et al.
European Journal of Medicinal Chemistry 218 (2021) 113341
5.4 Hz, 1H), 4.25e4.07 (m, 3H), 3.88 (d, J ¼ 9.2 Hz, 1H), 3.68 (d,
J ¼ 9.1 Hz, 1H), 3.60 (t, J ¼ 5.4 Hz, 2H), 3.51e3.35 (m, 5H), 3.23 (q,
J ¼ 5.7 Hz, 2H), 3.11e2.98 (m, 2H), 2.85 (ddd, J ¼ 18.2, 13.8, 6.2 Hz,
1H), 2.66e2.45 (m, 4H), 2.42 (t, J ¼ 7.2 Hz, 2H), 2.08e1.92 (m, 1H),
1.80e1.63 (m, 3H), 1.55 (d, J ¼ 13.1 Hz, 1H), 1.21 (d, J ¼ 7.1 Hz, 3H).
NMR (151 MHz, DMSO‑d6) d 172.86, 171.06, 170.95, 170.14, 168.86,
167.35, 155.85, 153.64, 146.45, 137.39, 136.31, 135.96, 132.21, 126.95,
123.21, 122.31, 122.05, 120.35, 117.11, 113.31, 110.39, 109.06, 74.34,
73.33, 69.81, 69.76, 69.72, 69.56, 68.24, 68.08, 60.55, 48.54, 44.76,
41.36, 40.92, 35.87, 33.72, 31.01, 30.46, 29.40, 22.19, 14.93.
13C NMR (151 MHz, DMSO‑d6)
d
172.93, 171.47, 171.05, 170.20,
N1-(3-((3-amino-5-((1R,2R)-1-amino-2-methyl-8-azaspiro
[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N4-(2-(2-
((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)
ethoxy)ethyl)succinamide(12) As yellow TFA salts, UPLC-
MS:[MþH]þ ¼ 863.37/865.17 found. 1H NMR (400 MHz, DMSO‑d6)
169.06, 167.40, 155.91, 153.71, 146.47, 137.40, 136.38, 135.99, 132.14,
129.73, 127.03, 123.28, 122.40, 122.15, 120.38, 117.54, 113.28, 110.81,
109.33, 74.40, 73.39, 69.01, 68.64, 60.64, 48.64, 44.81, 41.70, 41.42,
40.98, 38.63, 33.79, 31.05, 30.40, 22.23, 14.96.
The other PROTAC molecules 9 to 21 were prepared following
the same procedures described for the synthesis of 8 in 40%e64%
yields.
d
11.07 (s, 1H), 9.57 (s, 1H), 8.05 (br, 3H), 7.98 (t, J ¼ 5.6 Hz, 1H), 7.66
(s, 1H), 7.56 (d, J ¼ 8.4 Hz, 1H), 7.46 (d, J ¼ 7.9 Hz, 1H), 7.14 (t,
J ¼ 8.0 Hz, 1H), 7.01 (d, J ¼ 2.0 Hz, 1H), 6.90 (dd, J ¼ 8.4, 2.1 Hz, 1H),
6.42 (d, J ¼ 7.8 Hz, 1H), 6.14 (s, 2H), 5.03 (dd, J ¼ 12.9, 5.4 Hz, 1H),
4.29e4.06 (m, 3H), 3.89 (d, J ¼ 9.0 Hz, 1H), 3.68 (d, J ¼ 9.0 Hz, 1H),
3.59 (t, J ¼ 5.4 Hz, 2H), 3.49e3.31 (m, 5H), 3.24 (q, J ¼ 5.7 Hz, 2H),
3.12e2.96 (m, 2H), 2.87 (ddd, J ¼ 17.4, 13.9, 5.4 Hz, 1H), 2.67e2.44
(m, 4H), 2.42 (t, J ¼ 7.2 Hz, 2H), 2.08e1.93 (m, 1H), 1.81e1.63 (m,
3H), 1.56 (d, J ¼ 12.9 Hz, 1H), 1.21 (d, J ¼ 6.4 Hz, 3H). 13C NMR
N1-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-
azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-
N4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-
4-yl)amino)ethoxy)ethoxy)ethyl)succinamide(9) As yellow TFA
salts, UPLC-MS:[MþH]þ ¼ 907.66/909.45 found. 1H NMR (400 MHz,
DMSO‑d6)
d
11.10 (s, 1H), 9.56 (s, 1H), 8.01 (br, 3H), 7.94 (t, J ¼ 5.6 Hz,
1H), 7.66 (s, 1H), 7.56 (dd, J ¼ 8.4, 7.2 Hz, 1H), 7.46 (d, J ¼ 7.9 Hz, 1H),
7.18e7.09 (m, 2H), 7.03 (d, J ¼ 7.1 Hz, 1H), 6.43 (d, J ¼ 7.9 Hz, 1H),
5.05 (dd, J ¼ 13.0, 5.5 Hz, 1H), 4.26e4.06 (m, 3H), 3.88 (d, J ¼ 9.0 Hz,
1H), 3.68 (d, J ¼ 9.1 Hz, 1H), 3.61 (t, J ¼ 5.4 Hz, 2H), 3.58e3.49 (m,
4H), 3.46 (t, J ¼ 5.4 Hz, 2H), 3.43e3.35 (m, 3H), 3.20 (q, J ¼ 5.8 Hz,
2H), 3.12e2.97 (m, 2H), 2.87 (ddd, J ¼ 17.4, 13.9, 5.4 Hz, 1H),
2.66e2.44 (m, 4H), 2.41 (t, J ¼ 7.2 Hz, 2H), 2.08e1.96 (m, 1H),
1.78e1.62 (m, 3H), 1.56 (d, J ¼ 13.0 Hz, 1H), 1.21 (d, J ¼ 6.3 Hz,
(126 MHz, DMSO‑d6) d 172.84, 171.41, 170.95, 170.19, 167.71, 167.18,
155.80, 154.43, 153.64, 137.36, 135.94, 134.18, 129.67, 126.95, 125.08,
123.32, 122.38, 122.20, 120.38, 116.19, 113.42, 74.36, 73.27, 69.08,
68.35, 60.57, 48.67, 44.74, 42.45, 41.35, 40.94, 38.54, 33.72, 31.01,
30.41, 22.26, 14.92.
N1-(3-((3-amino-5-((1R,2R)-1-amino-2-methyl-8-azaspiro
[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N4-(2-(2-
(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
amino)ethoxy)ethoxy)ethyl)succinamide(13) As yellow TFA salts,
UPLC-MS:[MþH]þ ¼ 907.24/908.95 found. 1H NMR (400 MHz,
3H).13C NMR (151 MHz, DMSO‑d6)
d 173.04, 171.55, 171.14, 170.30,
169.13, 167.49, 156.04, 153.82, 146.56, 137.42, 136.41, 136.10, 132.24,
129.81, 127.12, 123.38, 122.52, 122.27, 120.35, 117.59, 113.16, 110.87,
109.40, 74.51, 73.47, 69.85, 69.76, 69.30, 69.03, 60.75, 48.74, 44.90,
41.86, 41.52, 41.09, 38.80, 33.89, 31.15, 30.52, 22.32, 15.02.
N1-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-
azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-
N4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-
DMSO‑d6) d 11.07 (s,1H), 9.56 (s,1H), 8.04e7.93 (m, 4H), 7.66 (s,1H),
7.55 (d, J ¼ 8.4 Hz, 1H), 7.45 (d, J ¼ 7.9 Hz, 1H), 7.14 (t, J ¼ 8.0 Hz, 1H),
7.00 (d, J ¼ 2.1 Hz, 1H), 6.89 (dd, J ¼ 8.5, 2.1 Hz, 1H), 6.42 (d,
J ¼ 7.9 Hz, 1H), 5.02 (dd, J ¼ 12.9, 5.4 Hz, 1H), 4.38e3.98 (m, 3H),
3.88 (d, J ¼ 9.1 Hz, 1H), 3.68 (d, J ¼ 9.1 Hz, 1H), 3.65e3.48 (m, 6H),
3.43e3.32 (m, 5H), 3.19 (q, J ¼ 5.8 Hz, 2H), 3.11e2.97 (m, 2H), 2.86
(ddd, J ¼ 17.5, 14.1, 5.5 Hz, 1H), 2.65e2.42 (m, 4H), 2.41 (t, J ¼ 7.2 Hz,
2H), 2.04e1.94 (m, 1H), 1.79e1.63 (m, 3H), 1.55 (d, J ¼ 12.9 Hz, 1H),
dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)succi-
namide(10) As yellow TFA salts, UPLC-MS:[MþH]þ ¼ 951.61/953.44
found. 1H NMR (400 MHz, DMSO‑d6)
d
11.10 (s,1H), 9.56 (s,1H), 8.00
1.21 (d, J ¼ 6.8 Hz, 3H). 13C NMR (126 MHz, DMSO‑d6)
d 172.88,
(br, 3H), 7.95 (t, J ¼ 5.8 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J ¼ 8.4, 7.2 Hz,
1H), 7.46 (d, J ¼ 7.9 Hz, 1H), 7.17e7.09 (m, 2H), 7.03 (d, J ¼ 7.0 Hz,
1H), 6.43 (d, J ¼ 7.9 Hz,1H), 5.04 (dd, J ¼ 12.9, 5.4 Hz,1H), 4.53e4.04
(m, 3H), 3.88 (d, J ¼ 9.0 Hz, 1H), 3.68 (d, J ¼ 9.1 Hz, 1H), 3.61 (t,
J ¼ 5.3 Hz, 2H), 3.58e3.42 (m, 10H), 3.41e3.35 (m, 3H), 3.19 (q,
J ¼ 5.8 Hz, 2H), 3.10e2.98 (m, 2H), 2.87 (ddd, J ¼ 17.8, 14.4, 5.3 Hz,
1H), 2.65e2.44 (m, 4H), 2.41 (t, J ¼ 7.2 Hz, 2H), 2.07e1.91 (m, 1H),
1.77e1.64 (m, 3H), 1.55 (d, J ¼ 12.9 Hz, 1H), 1.21 (d, J ¼ 6.6 Hz, 3H).
171.40, 171.00, 170.22, 167.74, 167.21, 155.85, 154.48, 153.68, 137.35,
135.98, 134.21, 129.70, 126.99, 125.10, 123.34, 122.41, 122.21, 120.36,
116.16, 113.35, 74.37, 73.36, 69.78, 69.62, 69.16, 68.76, 60.63, 48.69,
44.78, 42.52, 41.40, 40.97, 38.66, 33.77, 31.04, 30.41, 22.29, 14.92.
N1-(3-((3-amino-5-((1R,2R)-1-amino-2-methyl-8-azaspiro
[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N4-(2-(2-
(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
amino)ethoxy)ethoxy)ethoxy)ethyl)succinamide(14) As yellow
TFA salts, UPLC-MS:[MþH]þ ¼ 951.19/953.40 found. 1H NMR
13C NMR (151 MHz, DMSO‑d6)
d 173.03, 171.54, 171.11, 170.26,
169.09, 167.47, 155.99, 153.79, 146.54, 137.41, 136.40, 136.06, 132.21,
129.79, 127.10, 123.37, 122.51, 122.24, 120.37, 117.59, 113.20, 110.86,
109.35, 74.47, 73.44, 69.92, 69.73, 69.21, 69.01, 60.73, 48.71, 44.87,
41.83, 41.49, 41.05, 38.77, 33.87, 31.12, 30.49, 22.30, 15.00.
N1-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-
azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-
N4-(3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-
(400 MHz, DMSO‑d6) d 11.07 (s, 1H), 9.56 (s, 1H), 8.03e7.93 (m, 4H),
7.66 (s, 1H), 7.55 (d, J ¼ 8.3 Hz, 1H), 7.46 (d, J ¼ 7.9 Hz, 1H), 7.14 (t,
J ¼ 8.1 Hz, 1H), 7.00 (d, J ¼ 2.1 Hz, 1H), 6.89 (dd, J ¼ 8.4, 2.1 Hz, 1H),
6.42 (d, J ¼ 7.8 Hz, 1H), 5.03 (dd, J ¼ 12.9, 5.4 Hz, 1H), 4.29e4.01 (m,
3H), 3.88 (d, J ¼ 9.1 Hz,1H), 3.68 (d, J ¼ 9.1 Hz,1H), 3.59 (t, J ¼ 5.4 Hz,
2H), 3.57e3.46 (m, 8H), 3.37 (dt, J ¼ 13.6, 5.7 Hz, 5H), 3.19 (q,
J ¼ 5.8 Hz, 2H), 3.12e2.97 (m, 2H), 2.94e2.80 (m,1H), 2.65e2.43 (m,
4H), 2.41 (t, J ¼ 7.2 Hz, 2H), 2.04e1.93 (m, 1H), 1.77e1.63 (m, 3H),
1.55 (d, J ¼ 13.4 Hz, 1H), 1.21 (d, J ¼ 7.4 Hz, 3H). 13C NMR (126 MHz,
dioxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)propyl)
succinamide(11) As yellow TFA salts, UPLC-MS:[MþH]þ ¼ 979.72/
981.41 found. 1H NMR (400 MHz, DMSO‑d6)
d
11.11 (s, 1H), 9.57 (s,
DMSO‑d6) d 172.83, 171.32, 170.94, 170.17, 167.70, 167.16, 155.81,
1H), 7.99 (s, 3H), 7.87 (t, J ¼ 5.7 Hz, 1H), 7.66 (s, 1H), 7.57 (dd, J ¼ 8.6,
7.1 Hz, 1H), 7.46 (d, J ¼ 7.9 Hz, 1H), 7.14 (t, J ¼ 8.0 Hz, 1H), 7.09 (d,
J ¼ 8.6 Hz, 1H), 7.01 (d, J ¼ 7.1 Hz, 1H), 6.68 (s, 1H), 6.41 (d, J ¼ 7.9 Hz,
1H), 5.05 (dd, J ¼ 12.9, 5.4 Hz, 1H), 4.32e4.06 (m, 3H), 3.88 (d,
J ¼ 9.0 Hz, 1H), 3.68 (d, J ¼ 9.1 Hz, 1H), 3.58e3.31 (m, 15H),
3.13e2.98 (m, 4H), 2.88 (ddd, J ¼ 17.3, 14.0, 5.4 Hz, 1H), 2.67e2.43
(m, 4H), 2.39 (t, J ¼ 7.2 Hz, 2H), 2.07e1.95 (m, 1H),1.80 (p, J ¼ 6.4 Hz,
154.45, 153.64, 137.33, 135.95, 134.17, 129.66, 126.95, 125.05, 123.29,
122.36, 122.17, 120.34, 116.11, 113.37, 74.34, 73.33, 69.80, 69.76,
69.59, 69.10, 68.74, 60.58, 48.65, 44.74, 42.47, 41.36, 40.93, 38.63,
33.73, 31.00, 30.38, 22.26, 14.89.
N1-(3-((3-amino-5-((1R,2R)-1-amino-2-methyl-8-azaspiro
[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N4-(3-(2-
(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
2H),1.75e1.64 (m, 3H),1.65e1.51 (m, 3H),1.21 (d, J ¼ 6.6 Hz, 3H). 13
C
amino)propoxy)ethoxy)ethoxy)propyl)succinamide(15)
As
11