Identification of 4-Piperazinylquinazolines as Antagonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3789
4-{7-[2-(4-Hyd r oxy-p ip er id in -1-yl)eth oxy]-6-m eth oxy-
qu in a zolin -4-yl}p ip er a zin e-1-ca r boxylic Acid (4-Cya n o-
p h en yl)a m id e (47). Yield 30 mg, 63%. H NMR (CD3OD): δ
4-[6-Meth oxy-7-(2-p ip er id in -1-yl-eth oxy)qu in a zolin -4-
yl]p ip er a zin e-1-ca r boxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (61). Yield 338 mg, 93.7%. H NMR (CD3OD): δ 8.63
1
1
8.60 (s, 1H), 7.65-7.60 (m, 4H), 7.54 (s, 1H), 7.30 (s, 1H), 4.52-
4.50 (m, 4H), 4.36-4.32 (m, 4H), 4.01 (s, 3H), 3.91-3.78 (m,
6H), 3.52-3.48 (m, 3H), 2.27-2.00 (m, 4H). MS (ES): 532.6
(M + H)+.
4-{7-[2-(1,4-Dioxa -8-a za -sp ir o[4.5]d ec-8-yl)et h oxy]-6-
m eth oxy-qu in a zolin -4-yl}p ip er a zin e-1-ca r boxylic Acid
(4-Cya n op h en yl)a m id e (48). Yield 25 mg, 48%. 1H NMR
(CD3OD): δ 8.64 (s, 1H), 7.62 (s, 4H), 7.50 (s, 1H), 7.34 (s,
1H), 4.62-4.60 (m, 2H), 4.36-4.32 (m, 4H), 4.24-4.01 (m, 6H),
3.95 (s, 3H), 3.84-3.80 (m, 4H), 3.76-3.74 (m, 4H), 2.10-2.00
(m, 4H). MS (ES): 574.64 (M + H)+.
(s, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.23 (dd, 2H, J ) 2.4 and 6.8
Hz), 6.83 (dd, 2H, J ) 2.4 and 6.8 Hz), 4.67-4.64 (m, 2H),
4.50 (hept, 1H), 4.36-4.32 (m, 4H), 4.03 (s, 3H), 3.81-3.79 (m,
4H), 3.72-3.66 (m, 4H), 3.18-3.10 (m, 2H), 1.98-1.83 (m, 6H),
1.27-1.25 (d. 6H). MS (ES): 549 (M + H)+. Exact mass (FAB,
M + 1)+ calcd, 549.3189; found, 549.3178.
4-[6-Meth oxy-7-(2-[1,2,3]tr ia zol-1-yl-eth oxy)qu in a zolin -
4-yl]p ip er a zin e-1-ca r boxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (62). Yield 147 mg, 36.87%. 1H NMR (CD3OD): δ 8.60
(s, 1H), 8.30 (s, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.24 (s, 1H),
7.18-7.16 (d, 2H), 6.82-6.80 (d, 2H), 4.98-4.97 (m, 2H), 4.65
(m, 2H), 4.50 (hept, 1H), 4.40 (m, 4H), 4.01 (s, 3H), 3.60-3.50
(m, 4H), 1.30 (d, 6H). MS (ES): 533 (M + H)+. Exact mass
(FAB, M + 1)+ calcd, 533.2624; found, 533.2631.
4-{7-[2-(4-O x o -p ip e r id in -1-y l)e t h o x y ]-6-m e t h o x y -
qu in a zolin -4-yl}p ip er a zin e-1-ca r boxylic Acid (4-Cya n o-
1
p h en yl)a m id e (49). Yield 7.8 mg, 38.4%. H NMR (CD3OD):
δ 8.61 (s, 1H), 7.58 (s, 4H), 7.48 (s, 1H), 7.28 (s, 1H), 4.60-
4.58 (m, 2H), 4.30-4.26 (m, 4H), 4.01 (s, 3H), 3.92-3.90 (m,
2H), 3.84-3.80 (m, 4H), 3.74-3.70 (m, 4H), 2.10-2.00 (m, 4H).
MS (ES): 530 (M + H)+.
4-[6-Meth oxy-7-(2-[1,2,3]tr ia zol-2-yl-eth oxy)qu in a zolin -
4-yl]p ip er a zin e-1-ca r boxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (63). Yield 145 mg, 36.8%. H NMR (CD3OD): δ 8.60
1
(s, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.24 (d, 2H), 7.10 (s, 1H),
4.98-4.97 (m, 2H), 4.65 (m, 2H), 4.50 (hept, 1H), 4.40 (m, 4H),
3.90 (s, 3H), 3.70-3.65 (m, 4H), 1.30 (d, 6H). MS (ES): 533
(M + H)+. Exact mass (FAB, M + 1)+ calcd, 533.2624; found,
533.2621.
4-[6-Meth oxy-7-(2-[1,2,3]tr ia zol-1-yl-eth oxy)qu in a zolin -
4-yl]p ip er a zin e-1-ca r b oxylic Acid (4-Cya n op h en yl)-
a m id e (64). 1H NMR (CD3OD): δ 8.60 (s, 1H), 8.30 (s, 1H),
7.72 (s, 1H), 7.60 (s, 4H), 7.46 (s, 1H), 7.14 (s, 1H), 4.66-4.62
(m, 2H), 4.36-4.30 (m, 5H), 3.98 (s, 3H), 3.82-3.80 (m, 5H).
MS (ES): 500 (M + H)+.
4-[6-Meth oxy-7-(2-p ip er a zin -1-yl-eth oxy)qu in a zolin -4-
yl]p ip er a zin e-1-ca r boxylic Acid (4-Cya n op h en yl)a m id e
1
(50). Yield 37.2 mg, 59.2%. H NMR (CD3OD): δ 8.65 (s, 1H),
7.65-7.55 (m, 6H), 7.30 (s, 1H), 4.64-4.60 (m, 2H), 4.39-4.32
(m, 6H), 3.91-3.78 (m, 12H), 3.42 (s, 3H), 2.27-2.00 (m, 4H).
MS (ES): 517 (M + H)+. Exact mass (FAB, M + 1)+ calcd,
517.2675; found, 517.2664.
4-{6-Met h oxy-7-[2-(4-m et h yl-p ip er a zin -1-yl)et h oxy]-
qu in a zolin -4-yl}p ip er a zin e-1-ca r boxylic Acid (4-Cya n o-
1
p h en yl)a m id e (51). Yield 50 mg, 80.2%. H NMR (CD3OD):
δ 8.61 (s, 1H), 7.61 (s, 4H), 7.48 (s, 1H), 7.24 (s, 1H), 4.62-
4.60 (m, 2H), 4.36-4.32 (m, 4H), 4.01 (s, 3H), 3.82-3.80 (m,
4H), 3.68-3.20 (m, 7H), 2.98 (s, 3H). MS (ES): 531.6 (M +
H)+. Exact mass (FAB, M + 1)+ calcd, 531.2832; found,
531.2819.
4-[6-Meth oxy-7-(2-[1,2,3]tr ia zol-2-yl-eth oxy)qu in a zolin -
4-yl]p ip er a zin e-1-ca r b oxylic Acid (4-Cya n op h en yl)-
a m id e (65). 1H NMR (CD3OD): δ 8.60 (s, 1H), 7.70 (s, 2H),
7.60 (s, 4H), 7.42 (s, 1H), 7.18 (s, 1H), 4.66-4.62 (m, 4H), 4.36-
4.30 (m, 4H), 3.94 (s, 3H), 3.82-3.80 (m, 4H). MS (ES): 500
(M + H)+.
4-[6-Meth oxy-7-(2-th iom or p h olin -4-yl-eth oxy)qu in a zo-
lin -4-yl]p ip er a zin e-1-ca r boxylic Acid (4-Cya n op h en yl)-
4-{7-[2-(1,1-Dioxo-1λ6-t h iom or p h olin -4-yl)et h oxy]-6-
m eth oxy-qu in a zolin -4-yl}p ip er a zin e-ca r boxylic Acid (4-
Cya n op h en yl)a m id e (66). 1H NMR (CD3OD): δ 8.60 (s, 1H),
7.6 (s, 4H), 7.42 (s, 1H), 7.18 (s, 1H), 4.36-4.30 (m, 6H), 4.26-
4.22 (m, 2H), 3.98 (s, 3H), 3.96-3.94 (m, 2H), 3.82-3.80 (m,
2H), 3.18-3.12 (m, 4H). MS (ES): 566 (M + H)+.
1
a m id e (52). Yield 43.9 mg, 75.9%. H NMR (CD3OD): δ 8.40
(s, 1H), 7.62 (d, 2H), 7.58 (d, 2H), 7.50 (s, 1H), 7.30 (s, 1H),
4.70 (m, 2H), 4.40-4.36 (m, 4H), 4.02 (s, 3H), 4.00-3.98 (m,
2H), 3.88-3.86 (m, 4H), 3.78 (m, 2H), 3.50-3.46 (m, 2H), 3.28-
3.20 (m, 2H), 2.92-2.88 (m, 2H). MS (ES): 534 (M + H)+.
Exact mass (FAB, M + 1)+ calcd, 534.2287; found, 534.2284.
4-[6-Meth oxy-7-(2-p yr r olid in -1-yl-eth oxy)qu in a zolin -4-
yl]p ip er a zin e-1-ca r boxylic Acid (4-Cya n op h en yl)a m id e
4-{7-[2-(1,1-Dioxo-1λ6-t h iom or p h olin -4-yl)et h oxy]-6-
m eth oxy-qu in a zolin -4-yl}p ip er a zin e-ca r boxylic Acid (4-
Isop r op oxyp h en yl)a m id e (67). 1H NMR (CD3OD): δ 8.40
(s, 1H), 7.62 (d, 2H), 7.58 (d, 2H), 7.50 (s, 1H), 7.30 (s, 1H),
4.70 (m, 2H), 4.56 (hept, 1H), 4.40-4.36 (m, 4H), 4.02 (s, 3H),
4.00-3.98 (m, 2H), 3.88-3.86 (m, 4H), 3.78 (m, 2H), 3.50-
3.46 (m, 2H), 3.28-3.20 (m, 2H), 2.92-2.88 (m, 2H), 1.27 (d,
6H). MS (ES): 599 (M + H)+. Exact mass (FAB, M + 1)+ calcd,
599.2651; found, 599.2655.
4-[6-Meth oxy-7-(2-tetr a zol-1-yl-eth oxy)qu in a zolin -4-yl]-
p ip er a zin e-1-ca r b oxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (68). 1H NMR (CD3OD): δ 9.30 (s, 1H), 8.60 (s, 1H),
7.46 (s, 1H), 7.20 (d, 2H), 7.18 (s, 1H), 6.80 (d, 2H), 5.02 (m,
2H), 4.70 (m, 2H), 4.50 (hept, 1H), 4.30 (m, 4H), 4.01 (s, 3H),
3.80 (m, 4H), 1.30 (d, 6H). Exact mass (FAB, M + 1)+ calcd,
534.2577; found, 534.2592.
4-[6-Meth oxy-7-(2-tetr a zol-2-yl-eth oxy)qu in a zolin -4-yl]-
p ip er a zin e-1-ca r b oxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (69). 1H NMR (CD3OD): δ 8.70 (s, 1H), 8.58 (s, 1H),
7.40 (s, 1H), 7.20 (d, 2H), 7.14 (s, 1H), 6.80 (d, 2H), 5.20 (m,
2H), 4.70 (m, 2H), 4.50 (hept, 1H), 4.30 (m, 4H), 3.90 (s, 3H),
3.75 (m, 4H), 1.20 (d, 6H). Exact mass (FAB, M + 1)+ calcd,
534.2577; found, 534.2587.
1
(53). Yield 40.9 mg, 58.2%. H NMR (CD3OD): δ 8.60 (s, 1H),
7.65 (s, 4H), 7.50 (s, 1H), 7.30 (s, 1H), 4.60 (m, 2H), 4.32-4.30
(m, 4H), 4.0 (s, 3H), 3.84-3.76 (m, 6H), 3.42 (s, 3H), 2.20-
2.10 (m, 4H). MS (ES): 502 (M + H)+. Exact mass (FAB, M +
1)+ calcd, 502.2566; found, 502.2570.
4-[7-(2-Im id a zol-1-yl-eth oxy)-6-m eth oxy-qu in a zolin -4-
yl]p ip er a zin e-1-ca r boxylic Acid (4-Cya n op h en yl)a m id e
(54). Yield 34 mg, 47.9%. 1H NMR (CD3OD): δ 9.1 (s, 1H),
8.62 (s, 1H), 7.8 (s, 1H), 7.62-7.58 (m, 5H), 7.48 (s, 1H), 7.25
(s, 1H), 4.64-4.60 (m, 2H), 4.39-4.32 (m, 4H), 4.06-4.04 (m,
2H), 4.01 (s, 3H), 3.86-3.82 (m, 4H). MS (ES): 499 (M + H)+.
4-[6-Meth oxy-7-(2-p yr r ol-1-yl-eth oxy)qu in a zolin -4-yl]-
piper azin e-1-car boxylic Acid (4-Cyan oph en yl)am ide (55).
1
Yield 21 mg, 69.8%. H NMR (CD3OD): δ 8.8 (s, 1H), 8.6 (s,
1H), 7.6 (m, 4H), 7.42 (s, 1H), 7.0 (s, 1H), 6.8 (m, 2H), 6.0 (m,
2H), 4.46-4.38 (m, 4H), 4.34-4.30 (m, 4H), 4.0 (s, 3H), 3.84-
3.80 (m, 4H). MS (ES): 498 (M + H)+. Exact mass (FAB, M +
1)+ calcd, 498.2253; found, 498.2258.
Analogues 60-69 were synthesized using method B for final
urea linkage formation.
Analogues 70-87 were synthesized as shown in Scheme 5.
The synthesis of representative examples 70 and 75 is
described as follows.
4-[6-Met h oxy-7-(2-m or p h olin -4-yl-et h oxy)q u in a zolin -
4-yl]p ip er a zin e-1-ca r boxylic Acid (4-Isop r op oxyp h en yl)-
a m id e (60). Yield 29.6 mg, 52.6%. H NMR (CD3OD): δ 8.65
1
(s, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 7.22 (d, 2H, J ) 8.7 Hz), 6.8
(d, 2H, J ) 8.7 Hz), 4.70 (m, 2H), 4.5 (hept, 1H, J ) 8 Hz),
4.39-4.32 (m, 4H), 4.10-4.04 (m, 2H), 4.01 (s, 3H), 3.91-3.78
(m, 9H), 3.42-3.36 (m, 2H), 1.27 (d, J ) 1 Hz, 3H), 1.24 (d, J
) 1 Hz, 3H). MS (ES): 551 (M + H)+.
4-[6-Meth oxy-7-(3-p ip er id in -1-yl-p r op oxy)qu in a zolin -
4-yl]p ip er a zin e-1-ca r b oxylic Acid (4-Cya n op h en yl)-
a m id e (70). (a) To a DMF solution (3 mL) of 4-(7-hydroxy-6-
methoxy-quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl
ester 43 (0.100 g, 0.28 mmol) was added Cs2CO3 (0.365 g, 1.12