Article
SAR Compounds. Yields were given for the racemic syn
product and were based on 7 for compounds prepared by
method A or 36 for compounds prepared by method B.
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22 7051
(m, 2 H), 6.83 (dd, J=8.4, 2.2 Hz, 4 H), 6.08 (s, 1 H), 5.80 (s, 1 H),
3.53 (s, 3 H), 1.99 (s, 3 H); MS (ESIþ) m/z 508.9 (M þ H)þ; Anal.
(C28H22BrN4O) C, H, N.
(()-syn-6,7-Bis(4-fluorophenyl)-12-methyl-7,12-dihydro-6H-
chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 9: Method A
(40%), mp 187.8 ꢀC: IR (neat) cm-1 2925, 1727, 1644, 1506,
1420, 1221, 1041, 837, 769; 1H NMR (400 MHz, chloroform-d) δ
ppm 7.67 (s, 1 H), 7.54 (dd, J=7.9, 1.7 Hz, 1 H), 7.31-7.24 (m, 2
H), 7.16-7.10 (m, 1 H), 6.96-6.84 (m, 4 H), 6.79-6.67 (m, 4 H),
5.82 (s, 1 H), 5.60 (s, 1 H), 3.66 (s, 3 H); MS (ESIþ) m/z 429.0 (M
þ H)þ; Anal. (C25H19F2N4O) C, H, N.
(()-syn-7-(4-Bromophenyl)-6-(4-ethylphenyl)-12-methyl-7,12-
dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 18:
Method B (30%), mp 163.3 ꢀC: IR (neat) cm-1 2822, 1640,
1561, 1485, 1203, 1007, 814, 668; 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.72 (s, 1 H), 7.65 (d, J=7.7 Hz, 1 H), 6.72-7.27 (m, 11
H), 6.05 (s, 1 H), 5.75 (s, 1 H), 3.53 (s, 3 H), 2.42 (q, J=7.5 Hz, 2
H), 1.09 (t, J=7.6 Hz, 3 H); MS (ESIþ) m/z 499.0 (M þ H)þ;
Anal. (C27H24BrN4O H2O) C, H, N.
3
(()-syn-6,7-Bis(4-chlorophenyl)-12-methyl-7,12-dihydro-6H-
chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 10: Method A
(77%), mp 144.6 ꢀC: IR (neat) cm-1 2923, 1634, 1558, 1486,
173, 1010, 831; 1H NMR (400 MHz, chloroform-d) δ ppm 7.66
(s, 1 H), 7.54 (dd, J=7.9, 1.7 Hz, 1 H), 7.24-7.32 (m, 2 H), 7.13
(t, J=7.5 Hz, 1 H), 6.96-7.06 (m, 4 H), 6.93 (d, J=7.0 Hz, 1 H),
6.78-6.89 (m, 3 H), 5.81 (s, 1 H), 5.58 (s, 1 H), 3.66 (s, 3 H); MS
(ESIþ) m/z 460.9 (M þ H)þ; Anal. (C25H19Cl2N4O) C, H, N.
(()-syn-7-(4-Bromophenyl)-6-(4-fluorophenyl)-12-methyl-7,
12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine,
12: Method B (50%), mp 179.2 ꢀC: IR (neat) cm-1 2916, 1639,
1559, 1485, 1213, 1010, 815, 730; 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.73 (s, 1 H), 7.66 (d, J=7.9 Hz, 1 H), 7.24 (t, J=8.5
Hz, 1 H), 7.17 (d, J=8.3 Hz, 2 H), 7.11 (t, J=7.6 Hz, 1 H),
6.89-6.95 (m, 2 H), 6.81-6.87 (m, 3 H), 6.73-6.80 (m, 2 H),
6.08 (s, 1 H), 5.83 (s, 1 H), 3.53 (s, 3 H); MS (ESIþ) m/z 488.9 (M
(()-syn-6-(4-Bromophenyl)-7-(4-fluorophenyl)-12-methyl-7,12-
dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 19:
Method B (36%), mp 171.4 ꢀC: IR (neat) cm-1 3044, 1655,
1552, 1454, 1236, 1071, 1010, 821; 1H NMR (400 MHz, DMSO-
d6) δ ppm 7.73 (s, 1 H), 7.66 (d, J=7.9 Hz, 1 H), 7.27-7.21 (m, 1
H), 7.17-7.08 (m, 3 H), 6.96-6.90 (m, 2 H), 6.87-6.76 (m, 5 H),
6.10 (s, 1 H), 5.83 (s, 1 H), 3.53 (s, 3 H); MS (ESIþ) m/z 488.8 (M
þ H)þ; Anal. (C25H19BrFN4O) C, H, N.
(()-syn-6-(4-Bromophenyl)-12-methyl-7-(4-methylphenyl)-7,12-
dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 20:
Method B (10%), mp 160.5 ꢀC: IR (neat) cm-1 1641, 1558,
1415, 1215, 1010, 816, 750; 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.71 (s, 1 H), 7.65 (d, J=7.9 Hz, 1 H), 7.23 (t, J=7.8 Hz, 1
H), 7.13-7.07 (m, 3 H), 6.84 (d, J=8.1 Hz, 1 H), 6.81-6.75 (m, 4
H), 6.74-6.69 (m, 2 H), 5.99 (s, 1 H), 5.80 (s, 1 H), 3.53 (s, 3 H),
2.11 (s, 3 H); MS (ESIþ) m/z = 484.7 (M þ H)þ; Anal.
(C26H22BrN4O) C, H, N.
þ H)þ; Anal. (C25H18BrFN4O H2O) C, H, N.
3
(()-syn-7-(4-Bromophenyl)-6-(4-chlorophenyl)-12-methyl-7,
12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine,
13: Method A (8%), mp 177.8 ꢀC: IR (neat) cm-1 2922, 1643,
(()-syn-4-[6-(4-Bromophenyl)-12-methyl-7,12-dihydro-6H-
chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin-7-yl]benzonitrile,
1
21: Method B (28%); H NMR (400 MHz, DMSO-d6) δ ppm
1
1559, 1487, 1410, 1213, 1073, 967, 833; H NMR (400 MHz,
7.76 (s, 1 H), 7.67 (d, J=8.5 Hz, 1 H), 7.45 (d, J=7.7 Hz, 2 H),
7.29-7.21 (m, 1 H), 7.11 (t, J=8.60 Hz, 5 H), 6.88-6.77 (m, 3
H), 6.22 (s, 1 H), 5.85 (s, 1 H), 3.55 (s, 3 H); HPLC condition C,
4.93 min, 94.6% 210 nm, 94.3%, 250 nm; HRMS calcd for
C26H19BrN5O 496.0767, found 496.0691.
(()-syn-6,7-Bis(4-bromophenyl)-1-fluoro-12-methyl-7,12-di-
hydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 22:
Method A (28%), mp 158.2 ꢀC: IR (neat) cm-1 1639, 1460,
1253, 1171, 1009, 785, 765, 725; 1H NMR (400 MHz, DMSO-d6)
δ ppm 7.77 (s, 1 H), 7.23-7.33 (m, 1 H), 7.12-7.23 (m, 4 H),
6.95-7.02 (m, 1 H), 6.92 (d, 2 H), 6.80 (d, 2 H), 6.72 (d, 1 H), 6.20
(s, 1 H), 5.86 (s, 1 H), 3.34 (s, 3 H); MS (ESþ) m/z: 568.9 (M þ
H)þ; Anal. (C25H18Br2FN4O) C, H, N.
DMSO-d6) δ ppm 7.74 (s, 1 H), 7.64-7.69 (m, 1 H), 7.21-7.27
(m, 1 H), 7.17 (d, J=8.3 Hz, 2 H), 7.08-7.14 (m, 1 H), 7.00 (d, J=
8.5 Hz, 2 H), 6.80-6.91 (m, 5 H), 6.09 (s, 1 H), 5.83 (s, 1 H), 3.53
(s, 3 H); HPLC condition A, 7.46 min, 97.7% 210 nm, 99.3% 254
nm; HRMS calcd for C25H19BrClN4O 505.0425, found
505.0413.
(()-syn-7-(4-Bromophenyl)-12-methyl-6-(4-methylphenyl)-7,
12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine,
14: Method B (10%), mp 159.9 ꢀC: IR (neat) cm-1 2926, 1638,
1
1557, 1484, 1406, 1174, 1010, 816, 730; H NMR (400 MHz,
DMSO-d6) δ ppm 7.73 (s, 1 H), 7.65 (d, J=7.7 Hz, 2 H), 7.22 (t,
J=7.7 Hz, 1 H), 7.17-7.06 (m, 3 H), 6.85-6.76 (m, 3 H), 6.74 (s,
4 H), 6.06 (s, 1 H), 5.75 (s, 1 H), 3.53 (s, 3 H), 2.14 (s, 3 H); MS
(ESIþ) m/z 484.9 (M þ H)þ; Anal. (C26H22BrN4O) C, H, N.
(()-syn-4-[6-(4-Bromophenyl)-12-methyl-7,12-dihydro-6H-
chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin-7-yl]benzonitrile,
15: Method B (32%), mp 183.8 ꢀC: IR (neat) cm-1 2923, 1656,
(()-syn-6,7-Bis(4-bromophenyl)-12-methyl-1-(methyloxy)-7,
12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine,
23: Method B (13%): 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74
(s, 1 H), 7.30-7.09 (m, 5 H), 6.91 (d, J= 8.3 Hz, 2 H), 6.82-
6.72 (m, 3 H), 6.46 (d, J=8.1 Hz, 1 H), 6.17 (s, 1 H), 5.74 (s, 1 H),
3.92 (s, 3 H), 3.25 (s, 3 H); HPLC condition C, 5.42 min, 100%
210 nm, 100% 250 nm; HPLC condition E, 2.73 min, 88% 215 nm,
94% 254 nm; MS (ESIþ) for C26H20Br2N4O2 m/z = 578.8
(M þ H)þ.
1
1555, 1454, 1234, 1072, 1011, 821, 762; H NMR (400 MHz,
DMSO-d6) δ ppm 7.76 (s, 1 H), 7.67 (d, J=7.9 Hz, 1 H), 7.45 (d,
J=8.1 Hz, 2 H), 7.25 (t, J=7.8 Hz, 1 H), 7.11 (t, J=9.0 Hz, 5 H),
6.81 (d, J=8.3 Hz, 2 H), 6.84 (d, J=8.1 Hz, 1 H), 6.22 (s, 1 H),
5.85 (s, 1 H), 3.55 (s, 3 H); MS (ESIþ) m/z 496.0 (M þ H)þ; Anal.
(()-syn-6,7-Bis(4-bromophenyl)-1-ethoxy-12-methyl-7,12-di-
hydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 24:
Method B (12%): IR (neat) cm-1 2922, 1632, 1555, 1458,
1256, 1067, 1009, 877, 722; 1H NMR (400 MHz, DMSO-d6) δ
ppm 7.71 (s, 1 H), 7.07-7.32 (m, 5 H), 6.70-6.96 (m, 5 H), 6.48
(d, J=7.9 Hz, 1 H), 6.11 (br. s., 1 H), 5.71 (s, 1 H), 4.03-4.32 (m,
2 H), 3.27 (s, 3 H), 1.41 (t, J=6.8 Hz, 3 H); HPLC condition A
but with a 12 min gradient, 5.67 min, 100% 210 nm, 100% 250
nm; condition B, 2.84 min, 100% 215 nm, 100% 254 nm; MS
(ESIþ) for C27H22Br2N4O2 m/z 592.8 (M þ H)þ.
(C26H19BrN5O H2O) C, H, N.
3
(()-syn-7-(4-Bromophenyl)-6-(4-ethynylphenyl)-12-methyl-7,
12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine,
16: Method B (22%), mp 109.5 ꢀC: IR (neat) cm-1 2922, 1634,
1
1558, 1486, 1408, 1173, 1071, 1010, 829; H NMR (400 MHz,
DMSO-d6) δ ppm 7.74 (s, 1 H), 7.67 (d, J=7.9 Hz, 1 H), 7.23 (t,
J=7.7 Hz, 1 H), 7.15 (d, J=8.5 Hz, 1 H), 7.11 (t, J=7.0 Hz, 1 H),
7.04 (d, J=8.3 Hz, 2 H), 6.90-6.81 (m, 5 H), 6.09 (s, 1 H), 5.83 (s,
1 H), 4.14 (s, 1 H), 3.53 (s, 3 H); MS (ESIþ) m/z 494.9 (M þ H)þ;
Anal. (C27H20BrN4O 2H2O) C, H, N.
(()-syn-6,7-Bis(4-bromophenyl)-2-fluoro-12-methyl-7,12-di-
hydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine, 25:
Method B (10%), mp 199.7 ꢀC: IR (neat) cm-1 2923, 1644, 1560,
1485, 1408, 992, 736; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74
(s, 1 H), 7.55-7.48 (m, 1 H), 7.20-7.05 (m, 5 H), 6.89-6.77 (m, 5
H), 6.11 (s, 1 H), 5.82 (s, 1 H), 3.54 (s, 3 H); MS (ESIþ) m/z 556.9
3
(()-syn-7-(4-Bromophenyl)-12-methyl-6-(4-prop-1-yn-1-ylphe-
nyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyri-
midine, 17: Method B (13%), mp 180.6 ꢀC: IR (neat) cm-1 2915,
1
1631, 1560, 1485, 1407, 1174, 1070, 822; H NMR (400 MHz,
DMSO-d6) δ ppm 7.73 (s, 1 H), 7.66 (d, J=7.9 Hz, 2 H), 7.23 (s, 1
H), 7.16 (d, J=8.3 Hz, 2 H), 7.11 (d, J=7.7 Hz, 1 H), 6.91-6.98
(M þ H)þ; Anal. (C25H18Br2FN4O H2O) C, H, N.
3