Journal of Medicinal Chemistry
Article
N5,N6-Bis(2-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8d). Synthesized by general procedure A.
16%, yellow solid. 1H NMR (400 MHz, (CD3)2CO) δ 9.03−8.64 (m,
2H), 7.28−6.97 (m, 8H), 3.92 (s, 6H). HRMS (ESI+): calcd for
N5,N6-Bis(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo-
[3,4-b]pyrazine-5,6-diamine (8n). Synthesized by general proce-
dure A. 40%, off-white solid. 1H NMR (400 MHz, (CD3)2CO) δ 9.09
(brs, 2H), 8.03−7.55 (brm, 4H), 7.49 (d, J = 8.5 Hz, 4H); 13C NMR
(101 MHz, (CD3)2CO) δ some carbons are not visible 149.9 (br),
146.4, 138.7 (br), 124.0, 122.8, 121.5 (q, JCF = 255 Hz); 19F NMR
(376 MHz, (CD3)2CO) δ −58.78 (s, 6F). HRMS (ESI+): calcd for
+
C18H17N6O3 [M + H]+, 365.1362; found 365.1345.
N5,N6-Bis(3-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8e). Synthesized by general procedure A.
1
+
32%, off-white solid. H NMR (400 MHz, (CD3)2CO) δ 9.64 (brs,
C18H11F6N6O3 [M + H]+, 473.0797; found 473.0792.
N5,N6-Bis(2-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-
b]pyrazine-5,6-diamine (8o). Synthesized by general procedure A.
2H), 7.80−7.24 (brm, 4H), 7.34 (t, J = 8.1 Hz, 2H), 6.80−6.75 (m,
2H), 3.82 (s, 6H); 13C NMR (101 MHz, (CD3)2CO) δ some carbons
are not visible 161.3, 130.7, 114.5, 111.1, 108.1, 55.6. HRMS (ESI+):
1
52%, light yellow solid. H NMR (400 MHz, (CD3)2CO) δ 9.40 (s,
2H), 8.03−7.76 (m, 6H), 7.64 (t, J = 7.7 Hz, 2H); 19F NMR (376
MHz, (CD3)2CO) δ −61.18 (s, 6F). HRMS (ESI+): calcd for
C18H11F6N6O+ [M + H]+, 441.0899; found 441.0892.
+
calcd for C18H17N6O3 [M + H]+, 365.1362; found 365.1370.
N5,N6-Bis(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8f). Synthesized by general procedure A.
N5,N6-Bis(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-
b]pyrazine-5,6-diamine (8p). Synthesized by general procedure A.
1
47%, yellow solid. H NMR (400 MHz, (CD3)2CO) δ 9.35 (s, 2H),
7.91−7.43 (brm, 4H), 7.03−6.98 (m, 4H), 3.83 (s, 6H). HRMS
(ESI+): calcd for C18H17N6O3+ [M + H]+, 365.1362; found 365.1367.
N5,N6-Bis(2-ethoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8g). Synthesized by general procedure A.
54%, light yellow solid. 1H NMR (400 MHz, (CD3)2CO) δ 9.61 (brs,
2H), 7.95−7.06 (brm, 4H), 7.32 (t, J = 8.1 Hz, 2H), 6.80−6.71 (m,
2H), 4.08 (q, J = 7.0 Hz, 4H), 1.38 (t, J = 7.0 Hz, 6H). HRMS
(ESI+): calcd for C20H21N6O3+ [M + H]+, 393.1675; found 393.1674.
N5,N6-Bis(3-ethoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8h). Synthesized by general procedure A.
27%, yellow solid. 1H NMR (400 MHz, (CD3)2CO) δ 9.67 (brs, 2H),
7.85−7.00 (brm, 4H), 7.32 (t, J = 8.1 Hz, 2H), 6.78−6.74 (brm, 2H),
4.08 (q, J = 7.0 Hz, 4H), 1.38 (t, J = 7.0 Hz, 6H); 13C NMR (101
MHz, (CD3)2CO) δ some carbons are not visible 160.6, 130.7, 114.4,
111.7, 108.7, 64.1, 15.1. HRMS (ESI+): calcd for C20H21N6O3+ [M +
H]+, 393.1675; found 393.1656.
1
50%, off-white solid. H NMR (400 MHz, (CD3)2CO) δ 10.11 (brs,
2H), 8.28−7.84 (brm, 4H), 7.70 (t, J = 7.9 Hz, 2H), 7.55 (d, J = 7.8
Hz, 2H); 19F NMR (376 MHz, (CD3)2CO) δ −63.20 (s, 6F). HRMS
(ESI+): calcd for C18H11F6N6O+ [M + H]+, 441.0899; found
441.0887.
N5,N6-Bis(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-
b]pyrazine-5,6-diamine (8q). Synthesized by general procedure A.
1
63%, light yellow solid. H NMR (400 MHz, (CD3)2CO) δ 10.17
(brs, 2H), 8.05−7.84 (brm, 4H), 7.80 (d, J = 8.3 Hz, 4H); 13C NMR
(101 MHz, (CD3)2CO) δ some carbons are not visible 148.8 (br),
145.2 (br), 127.3 (q, JCF = 4.0 Hz), 126.9 (q, JCF = 5.6 Hz), 125.4 (q,
J
CF = 244 Hz), 122.6; 19F NMR (376 MHz, (CD3)2CO) δ −62.53 (s,
6F). HRMS (ESI+): calcd for C18H11F6N6O+ [M + H]+, 441.0899;
found 441.0875.
4,4′-([1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diylbis-
(azanediyl))dibenzonitrile (8r). Synthesized by general procedure
N5,N6-Bis(4-ethoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8i). Synthesized by general procedure A.
73%, yellow solid. 1H NMR (400 MHz, (CD3)2CO) δ 9.15 (brs, 2H),
8.01−7.50 (brm, 4H), 7.04−6.94 (m, 4H), 4.07 (q, J = 7.0 Hz, 4H),
1.38 (t, J = 6.9 Hz, 6H); 13C NMR (101 MHz, (CD3)2CO) δ 157.3,
151.0, 148.3, 131.7, 124.8 (br), 115.4, 64.2, 15.1. HRMS (ESI+): calcd
1
A. 19%, off-white solid. H NMR (400 MHz, (CD3)2CO) δ 9.78 (s,
2H), 8.25−8.17 (m, 4H), 7.92−7.85 (m, 4H); 13C NMR (101 MHz,
(CD3)2CO) δ 152.3*, 152.1*, 150.9*, 150.0*, 142.4, 134.1*, 134.0*,
123.9*, 123.8*, 119.3, 109.6. HRMS (ESI+): calcd for C18H11N8O+
[M + H]+, 355.1050; found 355.1040.
3,3′-([1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diylbis-
+
for C20H21N6O3 [M + H]+, 393.1675; found 393.1673.
(azanediyl))dibenzonitrile (8s). Synthesized following general
3,3′-([1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diylbis-
(azanediyl))diphenol (8j). Synthesized by general procedure A.
43%, light yellow solid. 1H NMR (500 MHz, (CD3)2CO) δ 8.71 (brs,
2H), 7.89−7.35 (brm, 1H), 7.35−6.95 (brm, 2H), 7.23 (t, J = 7.9 Hz,
2H), 6.70−6.66 (m, 2H); 13C NMR (126 MHz, (CD3)2CO) δ 158.9,
150.9 (br), 150.6 (br), 140.4 (br), 130.7, 113.5, 112.8, 109.4. HRMS
(ESI+): calcd for C16H13N6O3+ [M + H]+, 337.1049; found 337.1044.
N,N′-(([1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diylbis-
(azanediyl))bis(4,1-phenylene))bis(2,2,2-trifluoroacetamide)
(8k). Synthesized by general procedure A. 22%, yellow solid. 1H NMR
(400 MHz, (CD3)2CO) δ 10.38 (s, 2H), 9.61 (s, 2H), 8.00−7.94 (m,
4H), 7.86−7.81 (m, 4H); 13C NMR (101 MHz, (CD3)2CO) δ 155.6
(q, JCF = 37.3 Hz), 152.3*, 152.3*, 150.8, 149.9*, 149.8*, 135.5*,
135.4*, 135.1*, 135.0*, 124.4*, 124.3*, 122.0*, 121.9*, 116.9 (q, JCF
= 288 Hz); 19F NMR (376 MHz, (CD3)2CO) δ −76.58 (s, 6F).
HRMS (ESI+): calcd for C20H13F6N8O3+ [M + H]+, 527.1015; found
527.1009.
1
procedure A. Yellow solid (34.4 mg, 14%); H NMR (400 MHz,
(CD3)2CO) δ 10.18 (s, 2H), 8.33−7.83 (m, 4H), 7.68 (td, J = 7.7, 0.6
Hz, 2H), 7.61 (dt, J = 7.7, 1.1 Hz, 2H). HRMS (ESI−) m/z calcd for
C18H11N8O [M − H]−, 355.1050; found 355.1046.
N5,N6-Bis(4-ethylphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-
5,6-diamine (8t). Synthesized following general procedure A. 3%,
1
yellow solid: H NMR (400 MHz, (CD3)2CO) δ 9.61 (s, 2H), 7.65
(s, 4H), 7.31−7.26 (m, 4H), 2.66 (q, J = 7.6 Hz, 4H), 1.24 (t, J = 7.6
Hz, 6H). HRMS (ESI+) m/z calcd for C20H21N6O [M + H]+,
361.1771; found 361.1768.
N5,N6-Bis(3,4-dimethylphenyl)-[1,2,5]oxadiazolo[3,4-b]-
pyrazine-5,6-diamine (8u). Synthesized following general proce-
dure A. 4%, yellow solid: 1H NMR (400 MHz, (CD3)2CO) δ 9.55 (s,
2H), 7.47 (s, 4H), 7.18 (d, J = 8.0 Hz, 2H), 2.26 (d, J = 7.3 Hz, 12H).
HRMS (ESI+) m/z calcd for C20H21N6O [M + H]+, 361.1771; found
361.1769.
N5,N6-Bis(3-bromo-4-(trifluoromethoxy)phenyl)-[1,2,5]-
oxadiazolo[3,4-b]pyrazine-5,6-diamine (8v). Synthesized follow-
N5,N6-Bis(2-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo-
[3,4-b]pyrazine-5,6-diamine (8l). Synthesized by general proce-
1
ing general procedure A. 34%, yellow solid: H NMR (400 MHz,
1
dure A. 20%, off-white solid. H NMR (400 MHz, (CD3)2CO) δ
(CD3)2CO) δ 10.20 (s, 2H), 8.15 (s, 2H), 7.80 (s, 2H), 7.58 (dd, J =
8.8, 1.4 Hz, 2H). HRMS (ESI+) m/z calcd for C18H9Br2F6N6O3 [M +
H]+, 628.9002; found 628.8975.
10.23 (brs, 2H), 8.12 (brs, 2H), 7.54−7.46 (m, 4H), 7.38−7.29 (m,
2H); 19F NMR (376 MHz, (CD3−)2CO) δ −58.69 (s, 6F). HRMS
(ESI−): calcd for C18H9F6N6O3 [M − H], 471.0646; found
471.0657.
N5,N6-Bis(2-fluoro-4-(pent-1-yn-1-yl)phenyl)-[1,2,5]-
oxadiazolo[3,4-b]pyrazine-5,6-diamine (8w). Synthesized fol-
N5,N6-Bis(3-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo-
[3,4-b]pyrazine-5,6-diamine (8m). Synthesized by general proce-
dure A. 69%, yellow solid. 1H NMR (400 MHz, (CD3)2CO) δ 10.00
(brs, 2H), 8.01−7.64 (brm, 4H), 7.58 (t, J = 8.1 Hz, 2H), 7.21−7.13
(m, 2H); 13C NMR (101 MHz, (CD3)2CO) δ some carbons are not
visible 150.4, 131.6, 121.5 (q, JCF = 256 Hz), 121.1, 117.7, 114.9; 19F
NMR (376 MHz, (CD3)2CO) δ −58.47 (s, 6F). HRMS (ESI+): calcd
1
lowing general procedure A. 1%, yellow solid: H NMR (400 MHz,
(CD3)2CO) δ 9.85 (s, 2H), 8.10 (s, 2H), 7.37−7.25 (m, 4H), 2.42 (t,
J = 7.0 Hz, 4H), 1.62 (h, 4H), 1.05 (t, J = 7.4 Hz, 6H). HRMS (ESI+)
m/z calcd for C26H23F2N6O [M + H]+, 473.1895; found 473.1887.
N5,N6-Bis(4-bromo-2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-
b]pyrazine-5,6-diamine (8x). Synthesized following general
1
procedure A. 10%, yellow solid: H NMR (400 MHz, (CD3)2CO)
+
for C18H11F6N6O3 [M + H]+, 473.0797; found 473.0773.
δ 9.95 (s, 2H), 7.90 (s, 2H), 7.55 (dd, J = 10.2, 2.2 Hz, 2H), 7.51−
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J. Med. Chem. 2020, 63, 2511−2526