656 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 2
Guo et al.
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for C21H24N4O2 [M - H]- 363.1826, found 363.1837. HPLC
purity: 96.7%.
81%. H NMR (CDCl3) δ 8.71 (s, 1H), 7.55 (s, 1H), 7.45 (d,
J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 7.2 Hz,
1H), 5.25-5.10 (m, 1H), 2.80-2.60 (m, 2H), 2.45 (s, 3H),
2.20-2.00 (m, 1H), 1.95-1.75 (m, 2H), 1.75-1.55 (m, 1H);
13C NMR (CDCl3) δ 160.0, 158.1, 158.0, 147.4, 139.4, 138.4,
137.5, 123.8, 121.4, 121.3, 120.0 (q, J = 256 Hz), 118.7, 118.3,
115.7, 42.3, 29.4, 22.8, 20.0, 10.4; HRMS (ESI) calculated for
C19H17F3N4O3 [M þ H]þ 407.1326, found 407.1322. HPLC
purity: 99.3%.
(S)-2-Amino-N-[1-(4-tert-butylphenyl)-1H-4,5,6,7-tetrahydroin-
dazol-4-yl]-4-methylsulfanylbutyramide Trifluoroacetate (6i). 6i
was synthesized by method C by using crude 5a and Boc-Met-
OH as starting materials and then treated with TFA. Three-step
overall yield 71%. 1H NMR (CDCl3) δ 8.90-8.35 (m, 4H),
8.35-8.20 (m, 1H), 8.10-7.95 (m, 1H), 7.61 (s, 1H), 7.60 (s,
1H), 7.50-7.35 (m, 4H), 7.30-7.10 (m, 4H), 5.10-4.90 (m, 2H),
4.30-4.05 (m, 2H), 2.80-2.35 (m, 8H), 2.25-2.05 (m, 4H),
2.05-1.80 (m, 8H), 1.85-1.50 (m, 4H), 1.32 (s, 9H), 1.30 (s,
9H); 13C NMR (CDCl3) δ 168.1, 168.0, 162.0, 161.7, 151.0, 150.5,
140.5, 140.0, 137.9, 137.8, 136.5, 136.0, 126.2, 126.1, 123.1, 122.8,
117.9, 117.7, 53.1, 52.9, 43.1, 43.0, 34.7, 34.6, 31.2, 30.5, 30.3, 29.3,
29.2, 29.1, 22.9, 22.7, 20.3, 20.2, 14.8, 14.8; HRMS (ESI) calcu-
lated for C22H32N4OS [M þ H]þ 401.2370, found 401.2369.
HPLC purity: 95.6%.
N-[1-(4-Trifluoromethoxylphenyl)-1H-4,5,6,7-tetrahydroinda-
zol-4-yl]-2-methylbenzothiazole-5-carboxamide (6o). 6o was syn-
thesized by method C by using crude 5c and 2-methylbenzothia-
zole-5-carboxylic acid as starting materials. Two-step overall
yield 36%. 1H NMR (CDCl3) δ 8.30 (s, 1H), 7.95-7.80 (m, 2H),
7.69 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H),
6.57 (d, J = 7.2 Hz, 1H), 5.45-5.25 (m, 1H), 2.85 (s, 3H),
2.95-2.60 (m, 2H), 2.30-2.05 (m, 1H), 2.05-1.75 (m, 3H); 13
C
NMR (CDCl3) δ 168.7, 166.6, 153.1, 147.8, 139.8, 139.0, 138.1,
132.7, 124.6, 124.4, 123.6, 121.7, 121.6, 120.6, 120.3 (q, J = 256
Hz), 119.1 43.0, 29.8, 23.3, 20.3, 20.2; HRMS (ESI) calculated
for C23H19F3N4O2S [M - H]- 471.1108, found 471.1128. HPLC
purity: 96.0%.
N-[1-(4-Trifluoromethoxylphenyl)-1H-4,5,6,7-tetrahydroindaz-
ol-4-yl]-3-methylsulfanylpropionamide (6p). 6p was synthesized by
method C by using crude 5c and 3-methylsulfanylpropionic acid
as starting materials. Two-step overall yield 67%. 1H NMR
(CDCl3) δ 7.63 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.31 (d, J =
8.8 Hz, 2H), 6.00 (d, J = 7.2 Hz, 1H), 5.25-5.05 (m, 1H), 2.84
(t, J = 7.2 Hz, 2H), 2.85-2.65 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H),
2.15 (s, 3H), 2.20-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.80-1.65
(m, 1H); 13C NMR (CDCl3) δ 170.6, 147.7, 139.6, 138.9, 138.1,
124.3, 121.7, 119.2, 42.5, 36.5, 30.0, 29.8, 23.3, 20.3, 15.7; HRMS
(ESI) calculated for C18H20F3N3O2S [M - H]- 398.1156, found
398.1158. HPLC purity: 99.8%.
N-[1-(4-tert-Butylphenyl)-1H-4,5,6,7-tetrahydroindazol-4-yl]-
3-hydroxypyridine-2-carboxamide (6j). 6j was synthesized by
method C by using crude 5a and 3-hydroxypyridine-2-car-
boxylic acid as starting materials. Two-step overall yield 36%.
1H NMR (CDCl3) δ 12.25 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H),
8.10-7.95 (m, 1H), 7.66 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.42
(d, J = 7.2 Hz, 2H), 7.40-7.25 (m, 2H), 5.40-5.25 (m, 1H),
2.90-2.65 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.85 (m, 3H), 1.37
(s, 9H); 13C NMR (CDCl3) δ 168.2, 157.9, 150.4, 139.6, 139.5,
138.4, 137.1, 131.5, 128.6, 126.1, 126.1, 123.0, 117.7, 42.2, 34.6,
31.3, 29.9, 23.2, 20.3; HRMS (ESI) calculated for C23H26N4O2
[M þ H]þ 391.2129, found 391.2136. HPLC purity: 95.0%.
N-[1-(4-tert-Butylphenyl)-1H-4,5,6,7-tetrahydroindazol-4-yl]-
pyrazine-2-carboxamide (6k). 6k was synthesized by method C
by using crude 5a and pyrazine-2-carboxylic acid as starting
materials. Two-step overall yield 71%. 1H NMR (CDCl3) δ
9.55-9.40 (m, 1H), 8.80-8.65 (m, 1H), 8.55-8.40 (m, 1H), 7.99
(d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.4 Hz, 2H), 5.45-5.25 (m, 1H), 2.90-2.65 (m, 2H),
2.25-2.10 (m, 1H), 2.05-1.80 (m, 3H), 1.35 (s, 9H); 13C NMR
(CDCl3) δ 162.0, 150.0, 146.9, 144.1, 144.1, 142.1, 139.2, 137.9,
136.7, 125.7, 122.5, 117.6, 42.2, 34.3, 30.9, 29.6, 22.8, 19.9;
HRMS (ESI) calculated for C22H25N5O [M þ H]þ 376.2132,
found 376.2131. HPLC purity: 95.9%.
N-[1-(4-Trifluoromethylphenyl)-1H-4,5,6,7-tetrahydroinda-
zol-4-yl]-4-methylfurazan-3-carboxamide (6q). 6q was synthe-
sized by method C by using crude 5d and 4-methylfurazan-3-
carboxylic acid as starting materials. Two-step overall yield
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30%. H NMR (CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.68 (s,
1H), 7.66 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 5.40-
5.25 (m, 1H), 3.00-2.75 (m, 2H), 2.67 (s, 3H), 2.25-2.10 (m,
1H), 2.05-1.85 (m, 3H); 13C NMR (CDCl3) δ 156.5, 151.4,
147.7, 142.0, 139.6, 139.0, 128.6 (q, J = 33 Hz), 126.1 (q, J = 4
Hz), 123.4 (q, J = 270 Hz), 122.5, 118.1, 42.3, 29.1, 23.1, 19.8,
8.7; HRMS (ESI) calculated for C18H16F3N5O2 [M þ H]þ
392.1329, found 392.1326. HPLC purity: 98.9%.
5-[1-(4-tert-Butylphenyl)-1H-4,5,6,7-tetrahydroindazol-4-yl-
carbamoyl]isoxazole-3-carboxylic Acid Ethyl Ester (6l). 6l was
synthesized by method C by using crude 5a and isoxazole-3,5-
dicarboxylic acid 3-ethyl ester as starting materials. Two-step
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overall yield 55%. H NMR (CDCl3) δ 7.62 (s, 1H), 7.47 (d,
J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.92 (d,
J = 8.0 Hz, 1H), 5.40-5.25 (m, 1H), 4.47 (q, J = 6.8 Hz, 2H),
2.90-2.65 (m, 2H), 2.25-2.05 (m, 1H), 2.00-1.80 (m, 3H), 1.43
(t, J = 6.8 Hz, 3H), 1.35 (s, 9H); 13C NMR (CDCl3) δ 164.9,
159.0, 157.2, 154.4, 150.5, 139.7, 138.2, 137.0, 126.1, 122.9,
117.1, 107.5, 62.6, 43.0, 34.6, 31.3, 29.6, 23.1, 20.1, 14.1;
HRMS (ESI) calculated for C24H28N4O4 [M - H]- 435.2038,
found 435.2058. HPLC purity: 96.8%.
N-[1-(3-Trifluoromethylphenyl)-1H-4,5,6,7-tetrahydroindazol-
4-yl]-4-methylfurazan-3-carboxamide (6r). 6r was synthesized by
method C by using crude 5e and 4-methylfurazan-3-carboxylic
acid as starting materials. Two-step overall yield 62%. 1H NMR
(CDCl3) δ 7.85-7.75 (m, 1H), 7.75-7.64 (m, 1H), 7.65 (s, 1H),
7.62-7.55 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 5.40-5.20 (m, 1H),
2.90-2.70 (m, 2H), 2.64 (s, 3H), 2.25-2.05 (m, 1H), 2.05-1.80
(m, 3H); 13C NMR (CDCl3) δ 156.5, 151.4, 147.7, 139.6, 139.5,
138.8, 131.4 (q, J = 33 Hz), 129.5, 125.7, 123.4 (q, J = 4 Hz),
123.2 (q, J = 270 Hz), 119.6 (q, J = 33 Hz), 118.0, 42.3, 29.1,
22.8, 19.7, 8.7; HRMS (ESI) calculated for C18H16F3N5O2 [M þ
H]þ 392.1329, found 392.1328. HPLC purity: 95.7%.
N-[1-(2-Trifluoromethylphenyl)-1H-4,5,6,7-tetrahydroindazol-
4-yl]-4-methylfurazan-3-carboxamide (6s). 6s was synthesized by
method C by using crude 5f and 4-methylfurazan-3-carboxylic
acid as starting materials. Two-step overall yield 59%. 1H NMR
(CDCl3) δ 7.85-7.75 (m, 1H), 7.75-7.55 (m, 2H), 7.60 (s, 1H),
7.40-7.30 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 5.40-5.20 (m, 1H),
2.63 (s, 3H), 2.50-2.28 (m, 2H), 2.20-2.00 (m, 1H), 1.95-1.75
(m, 3H); 13C NMR (CDCl3) δ 156.5, 151.4, 147.8, 141.7, 137.8,
136.5 (q, J = 2 Hz), 132.4, 129.7, 129.4, 127.8 (q, J = 31 Hz),
127.1 (q, J = 5 Hz), 122.4 (q, J = 272 Hz), 115.9, 42.4, 29.4, 20.8,
19.4, 8.7; HRMS (ESI) calculated for C18H16F3N5O2 [M þ H]þ
392.1329, found 392.1319. HPLC purity: 98.9%.
N-[1-(4-Trifluoromethoxylphenyl)-1H-4,5,6,7-tetrahydroinda-
zol-4-yl]-4-methylfurazan-3-carboxamide (6m). 6m was synthe-
sized by method C by using crude 5c and 4-methylfurazan-3-
carboxylic acid as starting materials. Two-step overall yield
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76%. H NMR (CDCl3) δ 7.68 (s, 1H), 7.56 (d, J = 8.4 Hz,
2H), 7.35 (d, J = 8.4 Hz, 2H), 7.10-6.90 (m, 1H), 5.45-5.20 (m,
1H), 2.95-2.60 (m, 2H), 2.70 (s, 3H), 2.30-2.05 (m, 1H),
2.05-1.80 (m, 3H); 13C NMR (CDCl3) δ 156.5, 151.4, 147.7,
147.5, 139.5, 138.5, 137.7, 124.2, 121.4, 120.0 (q, J = 256 Hz),
117.6, 42.3, 29.2, 22.8, 19.7, 8.7; HRMS (ESI) calculated for
C18H16F3N5O3 [M þ H]þ 408.1278, found 408.1280. HPLC
purity: 98.0%.
N-[1-(4-Trifluoromethoxylphenyl)-1H-4,5,6,7-tetrahydroinda-
zol-4-yl]-3-methylisoxazole-4-carboxamide (6n). 6n was synthe-
sized by method C by using crude 5c and 3-methylisoxazole-4-
carboxylic acid as starting materials. Two-step overall yield