Replacement of the Pyrazole 5-Aryl Moiety
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5407
1-(2,4-Dichlorophenyl)-4-methyl-5-(5-(4-methylpent-1-ynyl)thio-
phen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (15). Us-
ing carboxylic acid 11a (130 mg, 0.30 mmol) as a starting material,
carboxamide 15 was synthesized following a similar coupling
procedure for 12 as a white solid (108 mg, 70%): mp 101.5-103
1-(2,4-Dichlorophenyl)-4-ethyl-5-(5-(4-methylpent-1-ynyl)thiophen-
2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (20). Using
1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(4-methylpent-1-ynyl)thiophen-
2-yl)-1H-pyrazole-3-carboxylic acid (134 mg, 0.30 mmol) as a
starting material, compound 20 was synthesized following a similar
coupling procedure for 12 as a white solid (103 mg, 65%): mp
92-93 °C; 1H NMR (CDCl3) δ 7.63 (s, 1H), 7.48 (d, J ) 1.5 Hz,
1H), 7.35-7.33 (m, 2H), 6.96 (d, J ) 3.9 Hz, 1H), 6.66 (d, J )
3.9 Hz, 1H), 2.87 (q, J ) 7.5 Hz, 2H), 2.86-2.84 (m, 4H), 2.30
(d, J ) 6.6 Hz, 2H), 1.89 (septet, J ) 6.6 Hz, 1H), 1.79-1.71 (m,
4H), 1.50-1.38 (m, 2H), 1.26 (t, J ) 7.5 Hz, 3H), 1.01 (d, J ) 6.6
Hz, 6H); 13C NMR (CDCl3) δ 159.4, 143.9, 136.8, 136.2, 135.8,
133.6, 131.0, 130.7, 130.2, 128.4, 128.3, 127.8, 126.7, 126.0, 95.7,
73.7, 57.0, 28.8, 28.0, 25.4, 23.3, 22.0, 17.2, 15.7. ESMS m/z: 529.2
(M + 1), 551.1 (M + 23). Anal. (C27H30Cl2N4OS) C, H, N.
1-(2,4-Dichlorophenyl)-4-methyl-5-[((E)-5-pent-1-enyl)-thiophen-
2-yl]-1H-pyrazole-3-carboxylic Acid Piperidin-1-ylamide (21). Start-
ing from the carboxylic acid 11b (130 mg, 0.30 mmol), compound
21 was synthesized following a similar coupling procedure for 12
and obtained as a white solid (110 mg, 73%): mp 71-71.5 °C; 1H
NMR (CDCl3) δ 7.61 (s, 1H), 7.49 (d, J ) 1.2 Hz, 1H), 7.35-7.33
(m, 2H), 6.71 (d, J ) 3.6 Hz, 1H), 6.64 (d, J ) 3.6 Hz, 1H), 6.39
(d, J ) 15.9 Hz, 1H), 6.02 (dt, J ) 15.9, 6.9 Hz, 1H), 2.87-2.84
(m, 4H), 2.47 (s, 3H), 2.20-2.06 (m, 2H), 1.79-1.71 (m, 4H),
1.50-1.38 (m, 4H), 0.93 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
δ 159.9, 145.4, 144.2, 138.0, 136.1, 136.0, 133.7, 132.4, 130.8,
130.2, 128.8, 127.8, 125.9, 124.1, 122.5, 118.9, 57.0, 34.9, 25.4,
23.3, 22.2, 13.7, 9.6. ESMS m/z: 503.1 (M + 1), 525.1 (M + 23).
Anal. (C25H28Cl2N4OS) C, H, N.
1
°C; H NMR (CDCl3) δ 7.61 (s, 1H), 7.49 (d, J ) 2.0 Hz, 1H),
7.34 (d, J ) 2.0 Hz, 2H), 6.97 (d, J ) 3.6 Hz, 1H), 6.68 (d, J )
3.6 Hz, 1H), 2.91-2.80 (m, 4H), 2.47 (s, 3H), 2.29 (d, J ) 6.4 Hz,
2H), 1.94-1.82 (m, 1H), 1.80-1.70 (m, 4H), 1.44-1.40 (m, 2H),
1.01 (d, J ) 6.4 Hz, 6H); 13C NMR (CDCl3) δ 159.8, 144.3, 137.3,
136.4, 135.8, 133.7, 130.9, 130.8, 130.3, 128.5, 128.2, 127.9, 126.6,
119.2, 95.7, 73.7, 57.0, 28.8, 28.0, 25.4, 23.3, 22.0, 9.9. ESMS
m/z: 515.1 (M + 1). Anal. (C26H28Cl2N4OS) C, H, N.
N-(Azepan-1-yl)-1-(2,4-dichlorophenyl)-4-methyl-5-(5-(4-meth-
ylpent-1-ynyl)thiophen-2-yl)-1H-pyrazole-3-carboxamide (16). Us-
ing carboxylic acid 11a (125 mg, 0.29 mmol) as a starting material,
carboxamide 16 was synthesized following a similar coupling
procedure for 12 as a white solid (101 mg, 66%): mp 48-49 °C;
1H NMR (CDCl3) δ 8.03 (s, 1H), 7.48 (d, J ) 1.2 Hz, 1H),
7.40-7.30 (m, 2H), 6.96 (d, J ) 3.6 Hz, 1H), 6.67 (d, J ) 3.6 Hz,
1H), 3.13 (t, J ) 5.4 Hz, 4H), 2.46 (s, 3H), 2.29 (d, J ) 6.9 Hz,
2H), 1.96-1.80 (m, 1H), 1.80-1.60 (m, 8H), 1.00 (d, J ) 6.4 Hz,
6H); 13C NMR (CDCl3) δ 160.0, 144.2, 137.2, 136.2, 135.7, 133.6,
130.9, 130.7, 130.2, 128.5, 128.1, 127.8, 126.5, 119.0, 95.7, 73.7,
58.2, 28.7, 28.0, 26.8, 26.2, 22.0, 9.6. ESMS m/z: 529.2 (M + 1).
Anal. (C27H30Cl2N4OS) C, H, N.
1-(2,4-Dichlorophenyl)-4-methyl-5-(5-pentylthiophen-2-yl)-1H-
pyrazole-3-carboxylic acid (17). A mixture of carboxylic acid 11
(0.84 g, 2.00 mmol) and 10% Pd/C (80 mg) in MeOH (10 mL)
was stirred under hydrogen (1 atm) at room temperature for 24 h.
After the reaction was complete, the mixture was filtered through
Celite, washed with MeOH, and concentrated under vacuum to
afford carboxylic acid 17 (0.38 g, 45%): mp 170-171 °C; 1H NMR
(CDCl3) δ 10.15 (br s, 1H), 7.39 (d, J ) 8.4 Hz, 1H), 7.36 (d, J )
1.8 Hz, 1H), 7.27 (dd, J ) 8.4, 1.8 Hz, 1H), 6.62 (s, 2H), 2.71 (t,
J ) 7.5 Hz, 2H), 2.34 (s, 3H), 1.61 (m, 2H), 1.40-1.20 (m, 4H),
0.88 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 166.5, 148.5, 143.5,
138.2, 136.0, 135.9, 133.4, 131.0, 129.7, 128.5, 127.7, 125.9, 124.0,
119.4, 31.1, 31.0, 29.8, 22.3, 13.9, 10.0. ESMS m/z: 423.1(M +
1), 445.1 (M + 23). Anal. (C20H20Cl2N2O2S) Calcd: C 56.74; H
4.76; N 6.62. Found: C 55.39; H 4.71; N 6.22.
1-(2,4-Dichlorophenyl)-4-methyl-5-[((E)-5-pent-1-enyl)-thiophen-
2-yl]-1H-pyrazole-3-carboxylic acid (hexahydrocyclopenta[c]pyr-
rol-2-yl)amide (22). Starting from the carboxylic acid 11b (130 mg,
0.30 mmol), compound 22 was synthesized following a similar
coupling procedure for 13 and obtained as a white solid (114 mg,
1
72%): mp 124-124.5 °C; H NMR (CDCl3) δ 7.49 (s, 1H), 7.48
(s, 1H), 7.33-7.32 (m, 2H), 6.71 (d, J ) 3.6 Hz, 1H), 6.64 (d, J
) 3.6 Hz, 1H), 6.38 (d, J ) 15.6 Hz, 1H), 6.02 (dt, J ) 15.6, 6.6
Hz, 1H), 3.28 (t, J ) 7.5 Hz, 2H), 2.56-2.47 (m, 2H), 2.47 (s,
3H), 2.16-2.07 (m, 2H), 1.78-1.42 (m, 10H), 0.93 (t, J ) 7.2
Hz, 3H); 13C NMR (CDCl3) δ 160.6, 145.4, 144.1, 138.0, 136.2,
136.0, 133.7, 132.4, 130.7, 130.2, 128.8, 127.8, 125.8, 124.1, 122.5,
118.8, 62.4, 40.4, 34.9, 32.3, 25.6, 22.2, 13.7, 9.6. ESMS m/z: 529.1
(M + 1), 551.1 (M + 23). Anal. (C27H30Cl2N4OS) C, H, N.
1-(2,4-Dichlorophenyl)-4-ethyl-5-(5-(pent-1-ynyl)thiophen-2-yl)-
N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (18). Using 1-(2,4-
dichlorophenyl)-4-ethyl-5-(5-(4-methylpent-1-ynyl)thiophen-2-yl)-
1H-pyrazole-3-carboxylic acid (104 mg, 0.24 mmol) as a starting
material, compound 18 was synthesized following a similar coupling
procedure for 12 as a white solid (80 mg, 65%): mp 88.5-89.5
1-(2,4-Dichlorophenyl)-4-methyl-5-(5-pentylthiophen-2-yl)-N-(pi-
peridin-1-yl)-1H-pyrazole-3-carboxamide (23). Starting from the
carboxylic acid 17 (127 mg, 0.30 mmol), compound 23 was
synthesized following a similar coupling procedure for 12 and
obtained as a white solid (115 mg, 75%): mp 70-71 °C; 1H NMR
(CDCl3) δ 7.61 (s, 1H), 7.48 (d, J ) 0.9 Hz, 1H), 7.35-7.31 (m,
2H), 6.62-6.68 (m, 2H), 2.85 (t, J ) 6.4 Hz, 4H), 2.72 (t, J ) 7.5
Hz, 2H), 2.47 (s, 3H), 1.79-1.71 (m, 4H), 1.70-1.58 (m, 2H),
1.50-1.36 (m, 2H), 1.36-1.22 (m, 4H), 0.88 (t, J ) 7.5 Hz, 3H);
13C NMR (CDCl3) δ 159.9, 148.6, 144.1, 138.3, 136.1, 136.0,
133.8, 130.8, 130.1, 128.4, 127.7, 125.9, 124.1, 118.5, 57.0, 31.1,
30.9, 29.8, 25.3, 23.3, 22.3, 13.9, 9.6. ESMS m/z: 505.2 (M + 1).
Anal. (C25H30Cl2N4OS) C, H, N.
1
°C; H NMR (CDCl3) δ 7.63 (s, 1H), 7.47 (dd, J ) 2.4, 1.2 Hz,
1H), 7.34-7.32 (m, 2H), 6.96 (d, J ) 3.6 Hz, 1H), 6.67 (d, J )
3.6 Hz, 1H), 2.91 (q, J ) 7.5 Hz, 2H), 2.90-2.78 (m, 4H), 2.38 (t,
J ) 7.2 Hz, 2H), 1.80-1.70 (m, 4H), 1.60 (sextet, J ) 7.2 Hz,
2H), 1.48-1.36 (m, 2H), 1.25 (t, J ) 7.5 Hz, 3H), 1.02 (t, J ) 7.2
Hz, 3H); 13C NMR (CDCl3) δ 159.4, 143.9, 136.8, 136.3, 135.8,
133.7, 131.0, 130.7, 130.2, 128.4, 128.3, 127.8, 126.7, 126.0, 96.5,
73.0, 57.0, 25.4, 23.3, 21.8, 21.6, 17.2, 15.7, 13.5. ESMS m/z: 515.1
(M + 1), 537.1 (M + 23). Anal. (C26H28Cl2N4OS) C, H, N.
N-(Azepan-1-yl)-1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(pent-1-
ynyl)thiophen-2-yl)-1H-pyrazole-3-carboxamide (19). Using 1-(2,4-
dichlorophenyl)-4-ethyl-5-(5-(4-methylpent-1-ynyl)thiophen-2-yl)-
1H-pyrazole-3-carboxylic acid (121 mg, 0.28 mmol) as a starting
material, compound 19 was synthesized following a similar coupling
procedure for 14 as a white solid (98 mg, 66%): mp 58-60 °C; 1H
NMR (CDCl3) δ 8.05 (s, 1H), 7.47 (s, 1H), 7.37-7.27 (m, 2H),
6.96 (d, J ) 3.6 Hz, 1H), 6.67 (d, J ) 3.6 Hz, 1H), 3.13 (t, J ) 5.4
Hz, 4H), 2.88 (q, J ) 7.5 Hz, 2H), 2.38 (t, J ) 7.2 Hz, 2H),
1.79-1.68 (m, 4H), 1.68-1.54 (m, 6H), 1.25 (t, J ) 7.5 Hz, 3H),
1.02 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 159.7, 143.9, 136.7,
136.2, 135.7, 133.6, 130.9, 130.6, 130.1, 128.4, 128.2, 127.8, 126.6,
125.8, 96.5, 72.9, 58.3, 26.8, 26.3, 21.8, 21.6, 17.1, 15.7, 13.5.
ESMS m/z: 529.1 (M + 1), 551.1 (M + 23). Anal. (C27H30Cl2N4OS)
Calcd: C 61.24; H 5.71; N 10.58. Found: C 61.70; H 6.17; N 10.68.
1-(2,4-Dichlorophenyl)-N-(hexahydrocyclopenta[c]pyrrol-2(1H)-
yl)-4-methyl-5-(5-pentylthiophen-2-yl)-1H-pyrazole-3-carboxam-
ide (24). Starting from the carboxylic acid 17 (127 mg, 0.30 mmol),
compound 24 was synthesized following a similar coupling
procedure for 13 and obtained as a white solid (107 mg, 67%): mp
123-123.5 °C; 1H NMR (CDCl3) δ 7.50-7.45 (m, 2H), 7.33-7.30
(m, 2H), 6.68-6.62 (m, 2H), 3.27 (t, J ) 8.1 Hz, 2H), 2.72 (t, J )
7.5 Hz, 2H), 2.70-2.62 (m, 2H), 2.53-2.47 (m, 4H), 2.47 (s, 3H),
1.75-1.40 (m, 6H), 1.38-1.21 (m, 4H), 0.88 (t, J ) 6.6 Hz, 3H);
13C NMR (CDCl3) δ 160.7, 148.6, 144.1, 138.3, 136.1, 136.0,
133.8, 130.8, 130.1, 128.4, 127.7, 125.9, 124.1, 118.4, 62.5, 40.4,
32.3, 31.1, 31.0, 29.8, 25.6, 22.2, 13.9, 9.6. ESMS m/z: 531.2 (M
+ 1). Anal. (C27H32Cl2N4OS) C, H, N.