738 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Contreras et al.
J ) 5.3 Hz), 6.70 (d, 1H, J ) 9.2 Hz), 7.21-7.33 (m, 5H), 7.39-
7.49 (m, 3H), 7.58 (d, 1H, J ) 9.2 Hz), 7.97 (m, 2H).
Dihydrochloride (i-PrOH): mp 268 °C. Anal. Calcd for C24H28N4‚
2HCl‚H2O: C, 62.19; H, 6.97; N, 12.09. Found: C, 62.46; H,
6.98; N, 11.90.
3 -[2 -(M o r p h o l i n -4 -y l )e t h y l a m i n o ]-6 -p h e n y l p y -
r id a zin e (3a ). The free base was purified by recrystallization
in (i-Pr)2O: yield 80%; mp 107 °C; 1H NMR (200 MHz, CDCl3)
δ 2.42 (m, 4H), 2.58 (m, 2H), 3.52 (m, 2H), 3.62-3.67 (m, 4H),
5.54 (s, 1H), 6.71 (d, 1H, J ) 9.1 Hz), 7.31-7.44 (m, 3H), 7.50
(d, 1H, J ) 9.1 Hz), 7.90 (m, 2H). Dihydrochloride (i-PrOH):
mp 231 °C. Anal. Calcd for C16H20N4O‚2HCl: C, 53.81; H, 6.16;
N, 15.69. Found: C, 53.77; H, 6.17; N, 15.69.
3-[2-(P ip er id in -1-yl)et h yla m in o]-6-p h en ylp yr id a zin e
(3b). The free base (white solid) was purified by flash chro-
matography (EtOAc-MeOH, 9:1, with 2% (v) triethylamine):
yield 81%; mp 110 °C; 1H NMR (200 MHz, CDCl3) δ 1.45-
1.65 (m, 6H), 2.38-2.50 (m, 4H), 2.63 (t, 2H, J ) 5.8 Hz), 3.56
(m, 2H), 5.45 (s, 1H), 6.74 (d, 1H, J ) 9.1 Hz), 7.35-7.51 (m,
3H), 7.59 (d, 1H, J ) 9.1 Hz), 7.95-8.00 (m, 2H). Dihydro-
chloride (i-PrOH): mp 262 °C. Anal. Calcd for C17H22N4‚2HCl‚
0.5H2O: C, 56.04; H, 6.93; N, 15.38. Found: C, 56.12; H, 6.95;
N, 15.37.
4-Meth yl-6-(4-ch lor op h en yl)-3-[2-(p ip er id in -1-yl)eth y-
la m in o]p yr id a zin e (3f). The free base was purified by
crystallization in i-PrOH: yield 80%; 1H NMR (200 MHz, D2O)
δ 1.63-2.09 (m, 6H), 2.40 (s, 3H), 3.19 (m, 2H), 3.58 (t, 2H, J
) 5.9 Hz), 3.76-3.82 (m, 2H), 4.06 (t, 2H, J ) 5.9 Hz), 7.61 (d,
2H, J ) 8.4 Hz), 7.79 (d, 2H, J ) 8.4 Hz), 7.81 (s, 1H). Oxalate
(i-PrOH): mp 221 °C. Anal. Calcd for C18H23ClN4‚C2H2O4: C,
57.06; H, 5.98; N, 13.31. Found: C, 56.77; H, 5.96; N, 13.30.
6H), 2.43-2.60 (m, 6H), 3.46 (t, 2H, J ) 5.8 Hz), 6.25 (s, 1H),
7.36-7.40 (m, 3H), 7.75-7.76 (m, 2H). Anal. Calcd for
C15H20N4S: C, 62.47; H, 6.98; N, 19.42. Found: C, 62.68; H,
7.06; N, 19.39.
3-[3-(M o r p h o li n -4-y l)p r o p y la m i n o ]-6-p h e n y lp y -
r id a zin e (3m ). The free base (white solid) was purified
by flash chromatography (EtOAc-MeOH, 9:1, with 2% (v)
triethylamine): yield 55%; mp 138 °C; 1H NMR (200 MHz,
CDCl3) δ 1.87 (quint., 2H, J ) 6.6 Hz), 2.51 (m, 6H), 3.58
(m, 2H), 3.75 (t, 4H, J ) 4.5 Hz), 5.97 (brs, 1H), 6.70 (d, 1H,
J ) 9.3 Hz), 7.38-7.50 (m, 3H), 7.59 (d, 1H, J ) 9.3), 7.97 (m,
2H). Dihydrochloride (i-PrOH): mp 276 °C. Anal. Calcd for
C
17H22N4O‚2HCl‚0.5H2O: C, 53.68; H, 6.64; N, 14.73. Found:
C, 53.67; H, 6.66; N, 14.66.
3-[1-(1-Eth ylp yr r olid in -2-yl)m eth yla m in o]-6-p h en ylp y-
r id a zin e (3n ). The free base (brown oil) was purified by flash
chromatography (EtOAc-MeOH, 9:1, with 2% (v) triethy-
1
lamine): yield 49%; H NMR (200 MHz, CDCl3) δ 1.12 (t, 3H,
J ) 7.3 Hz), 1.73-1.75 (m, 4H), 2.20-2.29 (q, 4H, J ) 7.3 Hz),
2.72-2.92 (m, 5H), 3.23 (m, 1H), 3.35-3.75 (m, 2H), 5.38 (brs,
1H), 6.74 (d, 1H, J ) 9.5 Hz), 7.37-7.49 (m, 3H), 7.58 (d, 1H,
J ) 9.5 Hz), 7.97 (m, 2H). Dihydrochloride (i-PrOH): mp 219
°C. Anal. Calcd for C17H22N4‚2HCl‚0.5H2O: C, 56.03; H, 6.93;
N, 15.38. Found: C, 55.94; H, 7.05; N, 15.19.
3-[2-(1,2,3,4-Tetr a h yd r oisoqu in olin -2-yl)eth yla m in o]-
6-p h en ylp yr id a zin e (3o). The free base (brown oil) was
purified by flash chromatography (EtOAc with 2% (v) triethy-
1
lamine): yield 10%; H NMR (200 MHz, CDCl3) δ 2.80-2.92
(m, 8H), 3.68 (s, 2H), 5.40 (brs, 1H), 6.70 (d, 1H, J ) 8.0 Hz),
7.10-7.20 (m, 4H), 7.30-7.50 (m, 3H), 7.53 (d, 1H, J ) 8.0
Hz), 7.98-8.02 (m, 2H). Dihydrochloride (i-PrOH): mp 288 °C.
Anal. Calcd for C21H22N4‚2HCl‚H2O: C, 59.80; H, 6.17; N, 13.29.
Found: C, 59.46; H, 6.10; N, 13.31.
4-Meth yl-6-(3,4-m eth ylen edioxyph en yl)-3-[2-(piper idin -
1-yl)et h yla m in o]p yr id a zin e (3g). The free base (oil) was
purified by flash chromatography (EtOAc-MeOH, 9:1, with
3-[3-(1,2,3,4-Tetr a h yd r oisoqu in olin -2-yl)p r op yla m in o]-
6-p h en ylp yr id a zin e (3p ). The free base (colorless oil) was
purified by flash chromatography (EtOAc with 2% (v) triethy-
lamine): yield 14%; 1H NMR (300 MHz, CDCl3) δ 1.96 (m, 2H),
2.64-3.95 (m, 4H), 2.94 (m, 2H), 3.50-3.63 (m, 2H), 3.67 (s,
2H), 6.22 (brs, 1H), 6.61 (d, 1H, J ) 9.0 Hz), 7.02 (m, 1H),
7.14 (m, 3H), 7.39-7.51 (m, 4H), 7.97 (m, 2H). Dihydrochloride
(i-PrOH): mp 230 °C. Anal. Calcd for C22H24N4‚2HCl‚2H2O: C,
58.27; H, 6.66; N, 12.36. Found: C, 58.12; H, 6.27; N, 13.05.
3-[4-(1,2,3,4-Tetr a h yd r oisoqu in olin -2-yl)bu tyla m in o]-
6-p h en ylp yr id a zin e (3q). The free base (colorless oil) was
purified by flash chromatography (EtOAc-MeOH, 9:1 with 2%
(v) triethylamine): yield 12%; 1H NMR (200 MHz, CDCl3) δ
1.74-1.90 (m, 4H), 2.59 (t, 2H, J ) 6.7 Hz), 2.77 (t, 2H, J )
5.6 Hz), 2.94 (t, 2H, J ) 5.6 Hz), 3.51 (m, 2H), 3,65 (s, 2H),
5.72 (brs, 1H), 6.45 (d, 1H, J ) 9.5 Hz), 7.02-7.20 (m, 4H),
7.35-7.50 (m, 4H), 7.95 (m, 2H). Dihydrochloride (i-PrOH):
mp 162 °C. Anal. Calcd for C23H26N4‚2HCl‚2H2O: C, 59.09; H,
6.91; N, 11.99. Found: C, 59.23; H, 6.60; N, 11.91.
1
2% (v) triethylamine): yield 11%; H NMR (200 MHz, CDCl3)
δ 1.5 (m, 6H), 2.1 (s, 3H), 2.4 (m, 4H), 2.7 (m, 2H), 3.6 (m,
2H), 5.4 (m, 1H), 5.9 (s, 2H), 6.8 (d, 1H), 7.3 (m, 2H), 7.5 (s,
1H). Dihydrochloride (EtOH): mp 205 °C. Anal. Calcd for
C
19H24N4O2‚2HCl‚H2O: C, 52.90; H, 6.30; N, 12.90. Found: C,
52.75; H, 6.24; N, 12.10.
4-Tr iflu or om eth yl-3-[2-(m or p h olin -4-yl)eth yla m in o]-6-
p h en ylp yr id a zin e (3j). The free base was purified by flash
chromatography (EtOAc): yield 94%; mp 82 °C; 1H NMR (200
MHz, CDCl3) δ 2.6-3.0 (m, 6H), 3.7-4.1 (m, 6H), 6.17 (s, 1H),
7.5-7.7 (m, 3H), 7.92 (s, 1H), 8.0-8.2 (m, 2H). Dihydrochloride
(i-PrOH): mp 218 °C. Anal. Calcd for C17H19F3N4O‚2HCl: C,
48.01; H, 4.98; N, 13.17. Found: C, 47.74; H, 5.15; N, 12.93.
5-P h en yl-2-[2-(p ip er id in -1-yl)eth yla m in o]p yr id in e (4).
The free base (colorless oil) was purified by flash (EtOAc-
MeOH, 9:1, with 2% (v) triethylamine): yield 39%; 1H NMR
(80 MHz, CDCl3) δ 1.53-1.71 (m, 6H), 2.30-2.50 (m, 6H), 3.10
(m, 2H), 5.10 (s, 1H), 6.40 (s, 1H), 7.20-7.50 (m, 5H), 8.26 (m,
2H).
3-[5-(1,2,3,4-Tetr a h yd r oisoqu in olin -2-yl)p en tyla m in o]-
6-p h en ylp yr id a zin e (3r ). The free base (white solid) was
purified by flash chromatography (EtOAc-MeOH, 9:1): yield
5-P h en yl-2-[2-(p ip er id in -1-yl)eth yla m in o]p yr im id in e
(5). The free base (white crystals) was purified by flash
chromatography (EtOAc with 2% (v) triethylamine): yield
1
10%; mp 272 °C; H NMR (200 MHz, CDCl3) δ 1.45-1.81 (m,
6H), 2.52 (t, 2H, J ) 7.3 Hz), 2.72 (t, 2H, J ) 5.8 Hz), 2.91 (t,
2H, J ) 5.8 Hz), 3.46 (m, 2H), 3.62 (s, 2H), 5.02 (brs, 1H),
6.64 (d, 1H, J ) 9.3 Hz), 6.98-7.15 (m, 4H), 7.30-7.51 (m,
3H), 7.55 (d, 1H, J ) 9.3 Hz), 7.96 (m, 2H). Dihydrochloride
(i-PrOH): mp 95 °C. Anal. Calcd for C24H28N4‚2HCl‚H2O: C,
62.19; H, 6.97; N, 12.09. Found: C, 62.56; H, 7.11; N, 11.88.
3-[2-(1-Ben zyl-1-m eth ylam in o)eth ylam in o]-6-ph en ylpy-
r id a zin e (3s). The free base (colorless oil) was purified by
flash chromatography (EtOAc with 2% (v) triethylamine): yield
40%; 1H NMR (200 MHz, CDCl3) δ 2.20 (s, 3H), 2.70 (m, 2H),
3.50 (m, 4H), 5.30 (brs, 1H), 6.70 (d, 1H, J ) 9.1 Hz), 7.30 (m,
3H), 7.40 (m, 5H), 7.60 (d, 1H, J ) 9.1 Hz), 8.00 (m, 2H).
Dihydrochloride (i-PrOH): mp 201 °C. Anal. Calcd for C20H22N4‚
2HCl‚0.5H2O: C, 60.00; H, 6.29; N, 14.00. Found: C, 59.90; H,
5.92; N, 14.10.
1
65%; mp 78 °C; H NMR (200 MHz, CDCl3) δ 1.56-1.58 (m,
6H), 2.43-2.60 (m, 6H), 3.51 (t, 2H, J ) 5.8 Hz), 5.86 (s, 1H),
7.26-7.46 (m, 5H), 8.52 (s, 2H). Anal. Calcd for C17H22N4: C,
72.31; H, 7.85; N, 19.84. Found: C, 72.28; H, 7.90; N, 19.75.
3-P h en yl-6-[2-(p ip er id in -1-yl)et h yla m in o]-1,2,4-t r ia z-
in e (6). The free base (brown solid) was purified by flash
chromatography (EtOAc-MeOH, 8:2, with 2% (v) triethy-
1
lamine): yield 30%; mp 105 °C; H NMR (200 MHz, CDCl3) δ
1.47-1.52 (m, 2H), 1.56-1.66 (m, 4H), 2.45 (m, 4H), 2.64 (t,
2H, J ) 5.8 Hz), 3.60 (q, 2H, J ) 5.5 Hz), 5.71 (s, 1H), 5.86 (s,
1H), 7.43-7.50 (m, 3H), 8.12 (s, 1H), 8.32-8.37 (m, 2H). Anal.
Calcd for C16H21N5‚H2O: C, 63.75; H, 7.69; N, 23.23. Found:
C, 63.66; H, 7.31; N, 22.71.
5-P h en yl-2-[2-(p ip er id in -1-yl)et h yla m in o]-1,3,4-t h ia -
d ia zole (7).30 The free base (white crystals) was purified by
flash chromatography (EtOAc with 2% (v) triethylamine): yield
3-[3-(1-Be n zyl-1-m e t h yla m in o)p r op yla m in o]-6-p h e -
n ylp yr id a zin e (3t). The free base (colorless oil) was purified
by flash chromatography (EtOAc-MeOH, 9:1, with 2% (v)
1
60%; mp 100 °C; H NMR (200 MHz, CDCl3) δ 1.56-1.58 (m,