Journal of Medicinal Chemistry
Article
7H), 2.19 (s, 6H), 2.07 (ddd, J = 13.9, 8.4, 5.5 Hz, 1H), 0.80−0.72
(m, 2H), 0.22−0.13 (m, 2H). 13C NMR (151 MHz, DMSO-d6): δ
169.81, 143.43, 139.77, 139.41 (d, J = 4.1 Hz), 136.44, 136.13,
135.89, 135.74, 129.49, 127.85, 124.64, 123.99, 51.00, 20.47, 17.48,
7.84, 6.35. LC−MS (ESI) m/z: 522.2 [M + 1]+, tR = 3.03 min, purity
>95% (UV).
1-(3-Bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxamide
(78-I1). General procedure G2 was followed starting from 63-I1 (1.00
g, 3.26 mmol). Complete conversion was seen after 22 h. After the
extraction procedure, the pale yellow solid 78-I1 (0.85 g, 2.8 mmol,
85%) was used without further purification. LC−MS (ESI) m/z:
306.0 and 308.0 [M + 1]+, tR = 1.96 min, purity >95% (UV).
1 - ( 3 - ( N - ( 2 - A m i n o - 2 - o x o e t h y l ) - 2 , 3 , 5 , 6 -
tetramethylphenylsulfonamido)phenyl)-5-cyclopropyl-1H-pyra-
zole-4-carboxylic Acid (77c). To 77c-I1 (0.250 g, 0.57 mmol) in
degassed DMF (2 mL) were added TBDMSCl and imidazole at 0 °C.
The reaction was stirred at RT for 20 h. The reaction mixture was
diluted with EtOAc and washed with water and brine, dried with
Na2SO4, filtered, and concentrated in vacuo. Hereafter, general
procedure E was applied with 2-bromoacetamide (0.22 g, 1.59 mmol).
The reaction was stirred for 3 h at 0 °C. Purification by flash column
chromatography (DCM/MeOH) afforded 77c as a yellow solid
(0.050 g, 0.10 mmol, 18%). 1H NMR (600 MHz, DMSO-d6): δ 12.12
(s, 2H), 7.92 (d, J = 2.6 Hz, 1H), 7.54−7.43 (m, 3H), 7.33 (d, J = 7.6
Hz, 2H), 7.25 (s, 1H), 7.09 (s, 1H), 4.35 (d, J = 2.0 Hz, 2H), 2.31 (s,
6H), 2.18 (s, 7H), 1.94−1.84 (m, 5H), 0.80−0.63 (m, 2H), 0.49−
0.31 (m, 2H). 13C NMR (151 MHz, DMSO-d6): δ 171.96, 168.59,
163.71, 147.04, 142.03, 139.83, 139.45, 136.39, 136.05, 135.90,
135.70, 129.23, 128.00, 125.14, 124.34, 114.24, 50.36 (d, J = 424.1
Hz), 21.03, 20.49, 17.53, 8.03, 6.79. LC−MS (ESI) m/z: 497.2 [M +
1]+, tR = 2.89 min, purity >95% (UV).
Ethyl-2-(N-(3-(5-cyclopropyl-4-(1H-tetrazol-5-yl)-1H-pyrazol-1-
yl)phenyl)-2,3,5,6-tetramethylphenylsulfonamido)-acetate (77a-
I1). 80 (0.45 g, 0.89 mmol) and TBAF (0.140 g, 0.50 mmol) were
placed in a dry bottom flask under nitrogen, then TMS-azide (0.21 g,
1.82 mmol) was added. The neat mixture was stirred at 100 °C for 24
h, diluted with HCl (2 M), and washed with EtOAc. The organic
layer was collected, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude compound is purified by flash column
chromatography (DCM/MeOH) to afford 77a-I1 (0.26 g, 0.47
mmol, 53%) as a yellowish solid. 1H NMR (600 MHz, chloroform-d):
δ 8.20 (s, 1H), 8.06 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.56−7.52 (m,
1H), 7.41 (t, J = 8.0 Hz, 1H), 7.30−7.27 (m, 1H), 7.14 (s, 1H), 4.53
(s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.39 (s, 6H), 2.22 (d, J = 3.5 Hz,
7H), 1.20 (t, J = 7.1 Hz, 3H), 1.04−0.95 (m, 2H), 0.35 (dt, J = 6.5,
3.3 Hz, 2H). 13C NMR (151 MHz, chloroform-d): δ 168.79, 149.48,
143.86, 140.41, 140.00, 139.85, 136.91, 136.80, 136.24, 136.16,
129.90, 129.39, 126.31, 124.76, 107.54, 61.79, 52.08, 21.18, 18.06,
14.18, 8.56, 6.70. LC−MS (ESI) m/z: 550.3 [M + 1]+, tR = 3.53 min,
purity >95% (UV).
5-Cyclopropyl-1-(3-(2,3,5,6-tetramethylphenylsulfonamido)-
phenyl)-1H-pyrazole-4-carboxylic Acid (77c-I1). General procedure
B1 was followed starting from aryl bromide 63-I1 (0.65 g, 2.12
mmol). Complete conversion was seen after 24 h by LC−MS.
Purification by flash column chromatography (hep/EtOAc) afforded
77c-I1 as a white solid (0.250 g, 0.57 mmol, 27%). LC−MS (ESI):
440.2 [M + 1]+, tR = 3.17 min, purity >95% (UV).
Ethyl-2-(N-(3-(4-cyano-5-cyclopropyl-1H-pyrazol-1-yl)phenyl)-
2,3,5,6-tetramethylphenylsulfonamido)acetate (80). General pro-
cedure E was followed starting from 79 (0.35 g, 0.83 mmol) and ethyl
bromoacetate (0.42 g, 2.51 mmol). Complete conversion was seen
after 20 h. Purification by flash column chromatography (hep/
EtOAc) afforded 80 as a colorless oil (0.40 g, 0.79 mmol, 95%). LC−
MS (ESI) m/z: 630.3 [M + 1]+, tR = 4.44 min, purity >95% (UV). 1H
NMR (600 MHz, DMSO-d6): δ 8.17 (d, J = 1.4 Hz, 1H), 7.62−7.50
(m, 3H), 7.42 (dt, J = 7.8, 1.7 Hz, 1H), 7.26 (s, 1H), 4.63 (s, 2H),
4.15 (t, J = 7.1 Hz, 2H), 2.29 (s, 7H), 2.18 (s, 7H), 1.82 (tt, J = 8.3,
5.3 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.89 (dt, J = 8.5, 3.2 Hz, 2H),
0.82 (dt, J = 5.6, 3.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6): δ
168.38 (d, J = 3.3 Hz), 167.17, 149.90, 142.74, 139.81, 138.50,
136.18, 136.13, 135.97, 135.80, 129.89, 128.86, 125.04, 124.52,
113.69, 90.76, 61.63, 51.12, 20.44, 17.44, 13.85, 7.17, 6.78. LC−MS
(ESI) m/z: 507.2 [M + 1]+, tR = 3.99 min, purity >95% (UV).
N-(3-(4-Cyano-5-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,3,5,6-
tetramethylbenzenesulfonamide (79). General procedure B1 was
followed starting from aryl bromide 78 (0.84 g, 2.5 mmol). Complete
conversion was seen after 24 h by LC−MS. Purification by flash
column chromatography (hep/EtOAc) afforded 79 as a white solid
1-(3-((N-(2-Amino-2-oxoethyl)-2,3,5,6-tetramethylphenyl)-
sulfonamido)phenyl)-5-(trans-2-phenylcyclopropyl)-1H-pyrazole-
4-carboxylic Acid (77d). General procedure E was followed starting
from 77d-I1 (0.14 g, 0.23 mmol) and 2-bromoacetamide (0.095 g,
0.69 mmol). Purification by preparative HPLC afforded 77h as a
white solid (0.020 g, 0.04 mmol, 16%). LC−MS (ESI) m/z: 630.3 [M
+ 1]+, tR = 4.44 min, purity >95% (UV). 1H NMR (600 MHz,
DMSO-d6): δ 12.38 (s, 1H), 7.97 (s, 1H), 7.59 (q, J = 1.6 Hz, 1H),
7.41 (dt, J = 6.3, 2.3 Hz, 1H), 7.34 (s, 1H), 7.29−7.23 (m, 2H), 7.22
(s, 1H), 7.20−7.15 (m, 2H), 7.14−7.09 (m, 2H), 6.90−6.85 (m, 2H),
4.31 (d, J = 1.0 Hz, 2H), 2.32 (s, 6H), 2.30−2.26 (m, 1H), 2.16 (s,
6H), 1.98 (dt, J = 8.9, 5.6 Hz, 1H), 1.20 (dt, J = 9.0, 5.6 Hz, 1H), 0.95
(ddd, J = 8.8, 6.2, 5.2 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ
169.17, 164.20, 146.39, 142.57, 141.52, 140.66, 139.86, 136.87,
136.63, 136.40, 136.21, 129.75, 128.41, 128.01, 126.29, 126.15,
125.41, 124.70, 114.85, 52.22, 26.19, 21.00, 18.62, 18.04, 17.45. LC−
MS (ESI) m/z: 573.3 [M + 1]+, tR = 3.33 min, purity >95% (UV).
tert-Butyldimethylsilyl 5-(trans-2-Phenylcyclopropyl)-1-(3-
((2,3,5,6-tetramethylphenyl)sulfonamido)phenyl)-1H-pyrazole-4-
carboxylate (77d-I1). To 77m (0.12 g, 0.23 mmol) in degassed DMF
(1−2 mL) were added TBDMSCl (0.069 g, 0.46 mmol) and
imidazole (0.047 g, 0.69 mmol) at 0 °C. The reaction was stirred at 0
°C for 2 h. The reaction mixture was diluted with EtOAc and washed
with water and brine, dried with Na2SO4, filtered, and concentrated in
vacuo to afford 77d-I1 (0.15 g), which was used without further
purification and characterization.
5-(trans-2-Phenylcyclopropyl)-1-(3-((2,3,5,6-tetramethylphenyl)-
sulfonamido)phenyl)-1H-pyrazole-4-carboxylic Acid (77m). Gen-
eral procedure C was followed starting from ester 81 (0.20 g, 0.38
mmol). Complete conversion was seen after 92 h. Purification by
preparative HPLC afforded 77m as a white powder (0.12 g, 61%). 1H
NMR (600 MHz, DMSO): δ 12.38 (s, 1H), 10.55 (s, 1H), 7.95 (s,
1H), 7.14 (s, 1H), 7.11 (d, J = 18.6 Hz, 2H), 7.07 (dt, J = 8.0, 1.4 Hz,
1H), 6.96 (ddd, J = 8.1, 2.2, 1.2 Hz, 1H), 6.73−6.68 (m, 2H), 2.14 (s,
7H), 1.80 (dt, J = 8.9, 5.6 Hz, 1H), 1.19 (dt, J = 9.0, 5.6 Hz, 1H), 0.97
(dt, J = 8.8, 5.6 Hz, 1H). LC−MS (ESI) m/z: 516.4 [M + 1]+, purity
>95% (UV).
1
(0.75 g, 2.1 mmol, 84%). H NMR (600 MHz, DMSO-d6): δ 10.61
(s, 1H), 8.14 (s, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.26−7.20 (m, 2H),
7.14 (t, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.3, 2.1 Hz, 1H), 2.48 (s, 6H),
2.19 (s, 6H), 1.81 (tt, J = 8.5, 5.3 Hz, 1H), 0.90−0.86 (m, 2H), 0.81−
0.77 (m, 2H). 13C NMR (151 MHz, DMSO-d6): δ 149.72, 142.63,
138.67 (d, J = 5.3 Hz), 137.64, 135.78, 135.61, 134.64, 130.00,
119.43, 118.31, 114.63, 113.74, 90.74, 59.72, 20.37, 17.48, 7.17, 6.86.
LC−MS (ESI) m/z: 419.2 [M − 1]−, tR = 3.71 min, purity >95%
(UV).
1-(3-Bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonitrile
(78). 78-I1 (0.80 g, 2.61 mmol) was dissolved in DMF (6 mL) at 0
°C then thionyl chloride (0.78 g, 6.52 mmol) was added dropwise.
The mixture was stirred at 0 °C for 30 min and quenched with
NaHCO. The mixture was extracted with EtOAc, the organic layer
was collected, dried over Na2SO4, filtered, and concentrated in vacuo
to give 78 (0.70 g, 2.4 mmol, 93%) as a yellow oil. Compound was
used without any further purification. 1H NMR (600 MHz,
chloroform-d): δ 7.83 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.60 (dd,
J = 8.0, 1.9 Hz, 1H), 7.51 (dd, J = 8.0, 2.1 Hz, 1H), 7.39 (t, J = 8.0 Hz,
1H), 1.89 (tt, J = 8.6, 5.3 Hz, 1H), 1.20−1.07 (m, 5H). 13C NMR
(151 MHz, chloroform-d): δ 150.21, 142.97, 139.70, 132.16, 130.63,
128.53, 123.87, 122.88, 113.62, 91.43, 8.42, 7.89. LC−MS (ESI) m/z:
288.0 and 290.0 [M + 1]+, tR = 3.56 min, purity >80% (UV).
Ethyl 5-(trans-2-Phenylcyclopropyl)-1-(3-((2,3,5,6-
tetramethylphenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxy-
4652
J. Med. Chem. 2021, 64, 4623−4661