Hydrazino- and Azonaphthalene TPO Mimics
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 22 3741
3-H yd r oxy-4-{N′-[3-m et h yl-1-(3-m et h ylp h en yl)-5-oxo-
1,5-d ih yd r op yr a zol-4-ylid en e]h yd r a zin o}n a p h th a len e-1-
su lfon ic Acid (25h ). Following the procedure of 2a , except
substituting pyrazole 15g for 2-naphthol, the title com-
pound was prepared as a red solid (1.18 g, 48%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.1 (br s, 1H), 8.97 (d, J ) 8.7
Hz, 1H), 8.87 (d, J ) 8.6 Hz, 1H), 7.89 (s, 1H), 7.81-7.77 (m,
2H), 7.58 (dd, J ) 8.2 and 7.0 Hz, 1H), 7.43 (t, J ) 8.2 Hz,
1H), 7.35 (t, J ) 7.9 Hz, 1H), 7.05 (d, J ) 7.5 Hz, 1H), 2.38 (s,
6H).
3-H yd r oxy-4-{N′-[1-(3,4-d im et h ylp h en yl)-3-m et h yl-5-
o x o -1,5-d ih y d r o p y r a zo l-4-y lid e n e ]h y d r a zin o}n a p h -
th a len e-1-su lfon ic Acid (25p ). Following the procedure of
2a , except substituting pyrazole 15m for 2-naphthol, the title
compound was prepared as a red solid (23.3 g, 97%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.1 (br s, 1H), 8.97 (d, J ) 8.4
Hz, 1H), 8.86 (d, J ) 8.4 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H),
7.68 (d, J ) 8.1 Hz, 1H), 7.57 (t, J ) 8.4 Hz, 1H), 7.42 (t, J )
8.4 Hz, 1H), 7.21 (d, J ) 8.1 Hz, 1H), 2.37 (s, 3H), 2.29 (s,
3H), 2.24 (s, 3H).
3-H yd r oxy-4-{N′-[3-m et h yl-1-(4-m et h ylp h en yl)-5-oxo-
1,5-d ih yd r op yr a zol-4-ylid en e]h yd r a zin o}n a p h th a len e-1-
su lfon ic Acid (25i). Following the procedure of 2a , except
substituting 5-methyl-2-(4-methylphenyl)-2,4-dihydropyrazol-
3-one for 2-naphthol, the title compound was prepared as a
red solid (2.1 g, 81%): 1H NMR (d6-DMSO) δ 14.1 (br s, 1H),
11.1 (br s, 1H), 8.97 (d, J ) 8.6 Hz, 1H), 8.87 (d, J ) 8.6 Hz,
1H), 7.90 (s, 1H), 7.85 (d, J ) 8.4 Hz, 2H), 7.58 (td, J ) 8.2
and 1.0 Hz, 1H), 7.43 (t, J ) 7.4 Hz, 1H), 7.28 (d, J ) 8.5 Hz,
1H), 2.37 (s, 3H), 2.34 (s, 3H).
3-Hydr oxy-4-{N′-{3-m eth yl-1-[4-(2-m eth yleth yl)ph en yl]-
5-oxo-1,5-d ih yd r op yr a zol-4-ylid e n e }h yd r a zin o}n a p h -
t h a len e-1-su lfon ic Acid (25q ). Following the procedure
of 2a , except substituting pyrazole 15n for 2-naphthol, the
title compound was prepared as a red solid (0.20 g, 90%): 1H
NMR (d6-DMSO) δ 14.1 (br s, 1H), 11.1 (br s, 1H), 8.97 (d, J
) 8.8 Hz, 1H), 8.87 (d, J ) 8.6 Hz, 1H), 7.91 (s, 1H), 7.82 (d,
J ) 8.5 Hz, 2H), 7.49 (m, 1H), 7.37 (m, 1H), 7.28 (d, J ) 8.5
Hz, 2H), 2.92 (m, 1H), 2.34 (s, 3H), 1.25 (d, J ) 7.3 Hz,
6H).
3-Hyd r oxy-4-{N′-{3-m et h yl-5-oxo-1-[3-(t r iflu or om et h -
yl)p h e n yl]-1,5-d ih yd r op yr a zol-4-ylid e n e }h yd r a zin o}-
n a p h th a len e-1-su lfon ic Acid (25j). Following the procedure
of 2a , except substituting pyrazole 15h for 2-naphthol, the title
compound was prepared as a red solid (1.19 g, 72%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.3 (br s, 1H), 8.98 (d, J ) 8.7
Hz, 1H), 8.87 (d, J ) 8.6 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J ) 8.3
Hz, 1H), 7.90 (s, 1H), 7.73 (t, J ) 8.0 Hz, 1H), 7.60 (m, 1H),
7.44 (t, J ) 8.2 Hz, 1H), 2.40 (s, 3H).
4-{N′-[1-(3-ter t-Bu tylp h en yl)-3-m eth yl-5-oxo-1,5-d ih y-
dr opyr azol-4-yliden e]h ydr azin o}-3-h ydr oxyn aph th alen e-
1-su lfon ic Acid (25r ). Following the procedure of 2a , except
substituting pyrazole 15o for 2-naphthol, the title compound
was prepared as a red solid (0.14 g, 64%): 1H NMR (d6-DMSO)
δ 14.1 (br s, 1H), 11.1 (br s, 1H), 8.97 (d, J ) 8.4 Hz, 1H), 8.86
(d, J ) 8.4 Hz, 1H), 8.03 (t, J ) 2.3 Hz, 1H), 7.89 (s, 1H), 7.79
(m, 1H), 7.58 (m, 1H), 7.43-7.38 (m, 2H), 7.28 (m, 1H), 2.38
(s, 3H), 1.18 (s, 9H).
3-Hyd r oxy-4-{N′-{3-m et h yl-5-oxo-1-[4-(t r iflu or om et h -
yl)p h e n yl]-1,5-d ih yd r op yr a zol-4-ylid e n e }h yd r a zin o}-
n a p h th a len e-1-su lfon ic Acid (25k ). Following the procedure
of 2a , except substituting pyrazole 15i for 2-naphthol, the title
compound was prepared as a red solid (1.64 g, 77%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.2 (br s, 1H), 8.98 (d, J ) 8.7
Hz, 1H), 8.87 (d, J ) 8.6 Hz, 1H), 8.23 (d, J ) 8.5 Hz, 2H),
7.91 (s, 1H), 7.84 (d, J ) 8.5 Hz, 2H), 7.59 (t, J ) 8.0 Hz, 1H),
7.42 (t, J ) 8.2 Hz, 1H), 2.40 (s, 3H).
4-{N′-[1-(4-ter t-Bu tylp h en yl)-3-m eth yl-5-oxo-1,5-d ih y-
dr opyr azol-4-yliden e]h ydr azin o}-3-h ydr oxyn aph th alen e-
1-su lfon ic Acid (25s). Following the procedure of 2a , except
substituting pyrazole 15p for 2-naphthol, the title compound
was prepared as a red solid (5.4 g, 98%): 1H NMR (d6-DMSO)
δ 14.1 (br s, 1H), 11.2 (br s, 1H), 8.97 (d, J ) 8.8 Hz, 1H), 8.86
(d, J ) 8.6 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J ) 8.6 Hz, 2H), 7.57
(m, 1H), 7.49 (d, J ) 8.6 Hz, 2H), 7.43 (m, 1H), 2.37 (s, 3H),
1.31 (s, 9H).
4-{N′-[1-(4-F lu or op h en yl)-3-m eth yl-5-oxo-1,5-d ih yd r o-
p yr a zol-4-ylid en e]h yd r a zin o}-3-h yd r oxyn a p h th a len e-1-
su lfon ic Acid (25l). Following the procedure of 2a , except
substituting 5-methyl-2-[4-(fluoromethyl)phenyl]-2,4-dihydro-
pyrazol-3-one for 2-naphthol, the title compound was prepared
as a red solid (2.03 g, 75%): 1H NMR (d6-DMSO) δ 14.1 (br s,
1H), 11.1 (br s, 1H), 8.97 (d, J ) 8.5 Hz, 1H), 8.87 (d, J ) 8.5
Hz, 1H), 8.01-7.96 (m, 2H), 7.89 (s, 1H), 7.58 (td, J ) 8.2 and
1.2 Hz, 1H), 7.35-7.30 (m, 2H), 2.38 (s, 3H).
3-Hydr oxy-4-{N′-{1-[4-(m eth ylsu lfon yl)p h en yl]-3-m eth -
yl-5-oxo-1,5-d ih yd r op yr a zol-4-ylid en e}h yd r a zin o}n a p h -
th a len e-1-su lfon ic Acid (25t). Following the procedure of 2a ,
except substituting pyrazole 15q for 2-naphthol, the title
compound was prepared as a red solid (0.21 g, 35%): 1H NMR
(d6-DMSO) δ 14.0 (br s, 1H), 11.1 (br s, 1H), 8.93 (d, J ) 8.6
Hz, 1H), 8.82 (d, J ) 8.6 Hz, 1H), 8.21 (d, J ) 8.9 Hz, 2H),
7.97 (d, J ) 8.9 Hz, 1H), 7.85 (s, 1H), 7.54 (m, 1H), 7.39 (m,
1H), 3.19 (s, 3H), 2.35 (s, 3H).
3-Hyd r oxy-4-{N′-[1-(4-iod op h en yl)-3-m eth yl-5-oxo-1,5-
d ih yd r op yr a zol-4-ylid en e]h yd r a zin o}n a p h th a len e-1-su l-
fon ic Acid (25m ). Following the procedure of 2a , except
substituting pyrazole 15j for 2-naphthol, the title compound
was prepared as a red solid (0.50 g, 45%): 1H NMR (d6-DMSO)
δ 14.1 (br s, 1H), 11.2 (br s, 1H), 8.97 (d, J ) 8.6 Hz, 1H), 8.86
(d, J ) 8.6 Hz, 1H), 7.85 (s, 1H), 7.82 (m, 4H), 7.58 (m, 1H),
7.42 (m, 1H), 2.38 (s, 3H).
4-{N′-{1-[4-(Ben zyloxy)p h en yl]-3-m et h yl-5-oxo-1,5-d i-
h yd r op yr a zol-4-ylid en e}h yd r a zin o}-3-h yd r oxyn a p h th a -
len e-1-su lfon ic Acid (25n ). Following the procedure of 2a ,
except substituting pyrazole 15k for 2-naphthol, the title
compound was prepared as a red solid (0.50 g, 45%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.1 (br s, 1H), 8.96 (d, J ) 8.7
Hz, 1H), 8.87 (d, J ) 8.7 Hz, 1H), 7.89 (s, 1H), 7.86 (d, J ) 8.9
Hz, 2H), 7.60-7.3 (m, 6H), 7.13 (d, J ) 8.9 Hz, 1H), 5.15 (s,
2H), 2.37 (s, 3H).
4-{N′-[1-(3,4-Dich lor op h en yl)-3-m eth yl-5-oxo-1,5-d ih y-
dr opyr azol-4-yliden e]h ydr azin o}-3-h ydr oxyn aph th alen e-
1-su lfon ic Acid (25o). Following the procedure of 2a , except
substituting pyrazole 15l for 2-naphthol, the title compound
was prepared as a red solid (1.89 g, 77%): 1H NMR (d6-DMSO)
δ 14.0 (br s, 1H), 11.3 (br s, 1H), 8.96 (d, J ) 8.7 Hz, 1H), 8.87
(d, J ) 8.5 Hz, 1H), 8.19 (d, J ) 2.3 Hz, 1H), 7.94 (dd, J ) 8.9
and 2.3 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J ) 8.9 Hz, 1H), 7.57
(dd, J ) 8.8 and 8.7 Hz, 1H), 7.42 (dd, J ) 8,8 and 8.5 Hz,
1H), 2.34 (s, 3H).
4-{N′-{1-[3-(E t h ylsu lfa m oyl)p h en yl]-3-m et h yl-5-oxo-
1,5-dih ydr opyr azol-4-yliden e}h ydr azin o}-3-h ydr oxyn aph -
th a len e-1-su lfon ic Acid (25u ). Following the procedure of
2a , except substituting N-ethyl-3-(3-methyl-5-oxo-4,5-dihydro-
pyrazol-1-yl)benzenesulfonamide for 2-naphthol, the title com-
pound was prepared as a red solid (1.92 g, 86%): 1H NMR
(d6-DMSO) δ 14.1 (br s, 1H), 11.2 (br s, 1H), 8.99 (d, J ) 8.6
Hz, 1H), 8.88 (d, J ) 8.5 Hz, 1H), 8.45 (s, 1H), 8.27 (d, J ) 7.2
Hz, 1H), 7.91 (s, 1H), 7.71 (m, 1H), 7.61 (m, 1H), 7.44 (m, 1H)
2.84 (m, 2H), 2.42 (s, 3H), 1.00 (t, J ) 7.1 Hz, 3H).
4-{4-[(2-Hyd r oxy-4-su lfon a p h th a len -1-yl)h yd r a zon o]-
3-m et h yl-5-oxo-4,5-d ih yd r op yr a zol-1-yl}b en zoic Acid
(25v). Following the procedure of 2a , except substituting 4-(3-
methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid for 2-naph-
thol, the title compound was prepared as a red solid (1.92 g,
95%): 1H NMR (d6-DMSO) δ 14.1 (br s, 1H), 11.2 (br s, 1H),
8.99 (d, J ) 8.7 Hz, 1H), 8.88 (d, J ) 8.6 Hz, 1H), 8.14 (d, J )
7.2 Hz, 2H), 8.05 (d, J ) 7.2 Hz, 2H), 7.90 (s, 1H), 7.59 (m,
1H), 7.44 (m, 1H), 2.40 (s, 3H).
3-Hyd r oxy-4-{N′-[3-m eth yl-5-oxo-1-(4-su lfop h en yl)-1,5-
d ih yd r op yr a zol-4-ylid en e]h yd r a zin o}n a p h th a len e-1-su l-
fon ic Acid (25w ). Following the procedure of 2a , except
substituting 4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benze-
nesulfonic acid for 2-naphthol, the title compound was pre-
pared as a red solid (1.82 g, 85%): 1H NMR (d6-DMSO) δ 14.1
(br s, 1H), 11.2 (br s, 1H), 8.99 (m, 1H), 8.88 (m, 1H), 7.95-
7.42 (m, 7H), 2.40 (s, 3H).