1358 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9
Penning et al.
3-chloro-4-(N,N-dimethylamino)acetophenone using the 2-step
procedure described above in 23% overall yield: 1H NMR
(CDCl3) δ 2.87 (s, 6H), 4.90 (br s, 2H), 6.72 (s, 1H), 6.96 (d, J
) 8 Hz, 2H), 7.32 (s, 1H), 7.50 (d, J ) 8 Hz, 2H), 7.94 (d, J )
8 Hz, 2H); HRMS m/ z 444.0656 (calcd for C18H16ClF3N4O2S,
444.0634).
drich) using step 2 of the 2-step procedure described above in
5% overall yield: 1H NMR (CDCl3/CD3OD) δ 6.93 (s, 1H), 7.40
(m, 3H), 7.61 (d, J ) 8 Hz, 1H), 7.97 (d, J ) 8 Hz, 2H), 8.53 (s,
1H), 8.61 (d, J ) 8 Hz, 1H).
4-[5-(4-P yr id yl)-3-(t r iflu or om et h yl)-1H -p yr a zol-1-yl]-
ben zen esu lfon a m id e (1a k ). The title compound was syn-
thesized from 4-acetylpyridine using the 2-step procedure
described above in 8% overall yield: 1H NMR (acetone-d6) δ
6.79 (s, 2H), 7.25 (s, 1H), 7.35 (d, J ) 4.6 Hz, 2H), 7.62 (d, J
) 8.5 Hz, 2H), 8.00 (d, J ) 8.5 Hz, 2H), 8.1 (m, 4H), 8.64 (d,
2H, J ) 4.4 Hz).
4-[5-(5-B r o m o -2-t h ie n y l)-3-(t r iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a l). The title com-
pound was synthesized from 2-acetyl-5-bromothiophene using
the 2-step procedure described above in 32% overall yield: 1H
NMR (CDCl3/CD3OD) δ 6.72 (d, J ) 4 Hz, 1H), 7.83 (s, 1H),
7.03 (d, J ) 4 Hz, 1H), 7.58 (d, J ) 8 Hz, 2H), 8.03 (d, J ) 8
Hz, 2H).
4-[5-(5-C h lo r o -2-t h ie n y l)-3-(t r iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a m ). The title com-
pound was synthesized from 2-acetyl-5-chlorothiophene using
the 2-step procedure described above in 46% overall yield: 1H
NMR (acetone-d6) δ 6.80 (br s, 2H), 7.06 (s, 2H), 7.14 (s, 1H),
7.75 (d, J ) 8.7 Hz, 2H), 8.05 (d, J ) 8.7 Hz, 2H); HRMS m/ z
406.9784 (calcd for C14H9ClF3N3O2S2, 406.9777).
4-[3-(Diflu or om eth yl)-5-(5-m eth yl-2-fu r yl)-1H-p yr a zol-
1-yl]b en zen esu lfon a m id e (2m ). The title compound was
synthesized from 2-acetyl-5-methylfuran and ethyl difluoro-
acetate using the 2-step procedure described above in 62%
overall yield: 1H NMR (DMSO-d6/400 MHz) δ 3.34 (s, 3H),
6.16 (d, J ) 3.2 Hz, 2H), 6.22 (d, J ) 3.2 Hz, 2H), 7.24-6.96
(m, 2H), 7.52 (s, 2H), 7.64 (d, J ) 8.8 Hz, 2H), 7.94 (d, J ) 8.8
Hz, 2H).
4-[5-(3-Ben zoth ien yl)-3-(tr iflu or om eth yl)-1H-p yr a zol-
1-yl]ben zen esu lfon a m id e (1a n ). The title compound was
synthesized from 3-acetylbenzothiophene using the 2-step
procedure described above in 36% overall yield: 1H NMR
(CDCl3/CD3OD) δ 6.98 (s, 1H), 7.47 (m, 5H), 7.87 (d, J ) 8 Hz,
2H), 7.94 (d, J ) 8 Hz, 2H).
4-[5-(Ben zofu r a n -2-yl)-3-(tr iflu or om eth yl)-1H-p yr a zol-
1-yl]ben zen esu lfon a m id e (1a o). The title compound was
synthesized from 2-acetylbenzofuran using the 2-step proce-
dure described above in 42% overall yield: 1H NMR (CDCl3/
CD3OD) δ 6.56 (s, 1H), 7.14 (s, 1H), 7.29 (d, J ) 8 Hz, 1H),
7.36 (t, J ) 8 Hz, 1H), 7.47 (d, J ) 8 Hz, 1H), 7.54 (d, J ) 8
Hz, 1H), 7.69 (d, J ) 8 Hz, 2H), 8.07 (d, J ) 8 Hz, 2H).
4-[5-(1-Cycloh exen yl)-3-(tr iflu or om eth yl)-1H-p yr a zol-
1-yl]ben zen esu lfon a m id e (1a p ). The title compound was
synthesized from 1-acetyl-1-cyclohexene using the 2-step
procedure described above in 10% overall yield: 1H NMR
(acetone-d6) δ 1.65 (m, 4H), 2.13 (m, 4H), 5.92 (m, 1H), 6.75
(br s, 3H), 7.79 (d, J ) 8.7 Hz, 2H), 8.04 (d, J ) 8.7 Hz, 2H);
HRMS m/ z 371.0918 (calcd for C16H16F3N3O2S, 371.0915).
4-[5-(5-In d a n yl)-3-(t r iflu or om et h yl)-1H-p yr a zol-1-yl]-
ben zen esu lfon a m id e (1a q). The title compound was syn-
thesized from 5-acetylindan using the 2-step procedure de-
scribed above in 22% overall yield: 1H NMR (CDCl3) δ 2.10
(m, 2H), 2.94 (m, 4H), 4.92 (s, 2H), 6.72 (s, 1H), 6.92 (d, J ) 8
Hz, 1H), 7.14 (s, 1H), 7.20 (d, J ) 8 Hz, 1H), 7.50 (d, J ) 8 Hz,
2H), 7.90 (d, J ) 8 Hz, 2H).
St ep 2: P r ep a r a t ion of 4-[5-[3-Ch lor o-4-(N-m et h yl-
a m in o)p h en yl]-3-(tr iflu or om eth yl)-1H-p yr a zol-1-yl]ben -
zen esu lfon a m id e. Demethylation of the product from step
1 using the procedure described for 1t provided 1a c in 10%
yield: 1H NMR (CDCl3) δ 2.94 (d, 3H), 4.60 (m, 1H), 4.94 (br
s, 2H), 6.56 (d, J ) 8 Hz, 1H), 6.69 (s, 1H), 6.90 (s, 1H), 7.21
(s, 1H), 7.50 (d, J ) 8 Hz, 2H), 7.90 (d, J ) 8 Hz, 2H).
4-[5-(3,5-Dich lor o-4-m eth oxyph en yl)-3-(diflu or om eth yl)-
1H-p yr a zol-1-yl]ben zen esu lfon a m id e (2j). The title com-
pound was synthesized from 3,5-dichloro-4-methoxyacetophe-
none and ethyl difluoroacetate using the 2-step procedure
described above in 66% overall yield: 1H NMR (CDCl3) δ 3.95
(s, 3H), 4.83 (s, 2H), 6.75 (s, 1H), 6.75 (t, J ) 54.5 Hz, 1H),
7.18 (s, 2H), 7.48 (d, J ) 8.7 Hz, 2H), 7.97 (d, J ) 8.7 Hz, 2H);
19F NMR (CDCl3) δ -112.91 (d, J ) 54.5 Hz).
4-[5-(3,5-Diflu or o-4-m eth oxyph en yl)-3-(diflu or om eth yl)-
1H-p yr a zol-1-yl]ben zen esu lfon a m id e (2k ). The title com-
pound was synthesized from 3,5-difluoro-4-methoxyacetophe-
none and ethyl difluoroacetate using the 2-step procedure
described above in 65% overall yield: 1H NMR (CDCl3) δ 4.06
(s, 3H), 4.87 (s, 2H), 6.93-6.57 (m, 4H), 7.47 (d, J ) 8.9 Hz,
2H), 7.96 (d, J ) 8.7 Hz, 2H); 19F NMR (CDCl3) δ -112.90 (d,
J ) 54.7 Hz), -126.69 (d, J ) 7.9 Hz).
4-[5-(3-Ch lor o-4-m et h oxy-5-m et h ylp h en yl)-3-(t r iflu o-
r om eth yl)-1H-pyr azol-1-yl]ben zen esu lfon am ide (1ad). The
title compound was synthesized from 3-chloro-4-methoxy-5-
methylacetophenone using the 2-step procedure described
above in 38% overall yield: 1H NMR (CDCl3) δ 2.27 (s, 3H),
3.87 (s, 3H), 4.87 (s, 2H), 6.76 (s, 1H), 6.94 (s, 1H), 7.14 (s,
1H), 7.52 (d, J ) 8 Hz, 2H), 7.96 (d, J ) 8 Hz, 2H).
4-[5-(3,4-D ic h lo r o p h e n y l)-3-(t r iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a e). The title com-
pound was synthesized from 3,4-dichloroacetophenone using
the 2-step procedure described above in 46% overall yield: 1H
NMR (CDCl3) δ 4.89 (s, 2H), 6.83 (s, 1H), 6.98 (d, J ) 8 Hz,
1H), 7.47 (m, 4H), 7.98 (d, J ) 8 Hz, 2H).
4-[5-(2,4-D ic h lo r o p h e n y l)-3-(t r iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a f). The title com-
pound was synthesized from 2,4-dichloroacetophenone using
the 2-step procedure described above in 62% overall yield: 1H
NMR (CDCl3) δ 6.80 (s, 1H), 7.36 (m, 5H), 7.87 (d, J ) 8 Hz,
2H).
4-[5-(2,5-D ic h lo r o p h e n y l)-3-(t r iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a g). The title com-
pound was synthesized from 2,5-dichloroacetophenone using
the 2-step procedure described above in 46% overall yield: 1H
NMR (CDCl3) δ 6.81 (s, 2H), 7.40 (m, 4H), 7.90 (d, J ) 8 Hz,
2H).
4-[5-(2,4-Dim e t h ylp h e n yl)-3-(t r iflu or om e t h yl)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (1a h ). The title com-
pound was synthesized from 2,4-dimethylacetophenone using
the 2-step procedure described above in 11% overall yield: 1H
NMR (CDCl3) δ 1.96 (s, 3H), 2.36 (s, 3H), 6.67 (s, 1H), 7.07
(m, 3H), 7.40 (d, J ) 8 Hz, 2H), 7.83 (d, J ) 8 Hz, 2H).
4-[5-(2,5-D im e t h y lp h e n y l)-3-(d iflu o r o m e t h y l)-1H -
p yr a zol-1-yl]ben zen esu lfon a m id e (2l). The title compound
was synthesized from 2,5-dimethylacetophenone and ethyl
difluoroacetate using the 2-step procedure described above in
69% overall yield: 1H NMR (DMSO-d6) δ 1.85 (s, 3H), 2.23 (s,
3H), 6.84 (s, 1H), 7.19-6.98 (m, 4H), 7.44-7.33 (m, 4H), 7.77
(d, J ) 8.7 Hz, 2H).
4-[5-(2-P yr id yl)-3-(t r iflu or om et h yl)-1H -p yr a zol-1-yl]-
ben zen esu lfon a m id e (1a i). The title compound was syn-
thesized from 2-acetylpyridine using the 2-step procedure
described above in 11% overall yield: 1H NMR (CDCl3) δ 3.72
(s, 2H), 7.05 (s, 1H), 7.43 (m, 5H), 7.80 (t, 1H), 7.94 (d, J ) 8
Hz, 2H).
4-[5-(3-P yr id yl)-3-(t r iflu or om et h yl)-1H -p yr a zol-1-yl]-
ben zen esu lfon a m id e (1a j). The title compound was syn-
thesized from 4,4,4-trifluoro-1-(3-pyridyl)-1,3-butanedione (Al-
4-[5-(3,4-Dih yd r o-2H-1-ben zoth iop yr a n -6-yl)-3-(tr iflu o-
r om eth yl)-1H-pyr azol-1-yl]ben zen esu lfon am ide (1ar ). The
title compound was synthesized from 6-acetyl-3,4-dihydro-2H-
1-benzothiopyran using the 2-step procedure described above
in 25% overall yield: 1H NMR (acetone-d6) δ 2.05 (m, 2H), 2.78
(t, J ) 5 Hz, 2H), 3.05 (t, J ) 5 Hz, 2H), 6.92 (d, 1H), 6.98 (s,
1H), 7.02 (d, J ) 10 Hz, 1H), 7.12 (s, 1H), 7.58 (d, J ) 10 Hz,
2H), 7.96 (d, J ) 10 Hz, 2H).
4-[5-(2,3-Dih yd r oben zofu r a n -5-yl)-3-(tr iflu or om eth yl)-
1H-p yr a zol-1-yl]ben zen esu lfon a m id e (1a s). The title com-
pound was synthesized from 5-acetyl-2,3-dihydrobenzofuran
using the 2-step procedure described above in 45% overall
yield: 1H NMR (CDCl3) δ 3.15 (t, J ) 6 Hz, 2H), 4.54 (t, J )
6 Hz, 2H), 5.71 (s, 2H), 6.68 (s, 1H), 6.69 (d, J ) 8 Hz, 1H),
6.92 (dd, J ) 1, 8 Hz, 1H), 7.07 (br s, 1H), 7.42 (d, J ) 8 Hz,
2H), 7.85 (d, J ) 8 Hz, 2H).