Journal of Medicinal Chemistry
Article
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(CH), 128.14 (CF3, q, JCF = 277.3 Hz), 117.34 (Cq), 116.85 (Cq),
procedure 6 previously described using intermediate 54e (50 mg, 0.16
mmol) and amine 53a (33.4 mg, 0.18 mmol) in dry 1,4-dioxane (0.55
mL). Purification by silica gel flash chromatography (CH2Cl2/MeOH
from 100:0 to 98:02) followed by trituration with diethyl ether (1
mL) afforded the pure 37 (25.3 mg, 34% yield). UPLC/MS: Rt = 2.40
min (gradient 1); MS (ESI) m/z: 463.5 [M − H]−. C21H30F3N2O4S
2
112.50 (CH), 47.94 (CH2, 2C), 42.58 (CH2), 32.73 (CH2, q, JCF
=
27.2 Hz), 28.49 (CH2), 28.34 (CH2), 28.17 (CH2), 26.39 (CH2),
25.06 (CH2, 2C), 21.68 (CH2). 19F NMR (565 MHz, DMSO-d6): δ
−63.73 (t, J = 11.7 Hz). HRMS (AP-ESI) m/z: calcd for
C19H28F3N2O4S [M + H]+, 437.1722; found, 437.1728.
1
3-(1-Piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic Acid
(34). Compound 34 was synthesized following the general procedure
6 previously described using intermediate 54b (50 mg, 0.17 mmol)
and amine 53a (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 mL).
Purification by silica gel flash chromatography (CH2Cl2/MeOH from
100:0 to 99:01) followed by trituration with diethyl ether (1 mL)
afforded the pure 34 (13 mg, 17% yield) as a white solid. UPLC/MS:
Rt = 2.40 min (gradient 1); MS (ESI) m/z: 449.5 [M − H]−.
C20H28F3N2O4S [M − H]− calcd: 449.2. 1H NMR (400 MHz,
DMSO-d6): δ 8.04 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.8, 2.1 Hz, 1H),
6.89 (d, J = 9.0 Hz, 1H), 6.69 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.7 Hz,
2H), 2.98 (t, J = 5.4 Hz, 4H), 2.29−2.15 (m, 2H), 1.62−1.55 (m,
2H), 1.55−1.43 (m, 6H), 1.42−1.37 (m, 2H), 1.37−1.30 (m, 6H).
13C (101 MHz, chloroform-d): δ 170.93 (CO), 150.62 (Cq), 136.12
[M − H]− calcd: 463.2. H NMR (400 MHz, chloroform-d): δ 8.49
(d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.74 (d, J = 8.9 Hz,
1H), 6.50 (s, 1H), 4.49 (d, J = 7.9 Hz, 1H), 3.25 (t, J = 7.1 Hz, 2H),
3.18−3.07 (m, 1H), 2.14−2.00 (m, 2H), 1.79−1.66 (m, 4H), 1.66−
1.49 (m, 6H), 1.48−1.34 (m, 6H), 1.30−1.19 (m, 3H), 1.18−1.07
(m, 2H). 13C NMR (101 MHz, DMSO-d6): δ 166.53 (CO), 148.17
(Cq), 134.69 (CH), 131.51 (CH), 127.62 (CF3, q, 1JCF = 278.3 Hz),
121.48 (Cq), 116.18 (Cq), 111.25 (CH), 51.60 (CH), 42.40 (CH2),
2
33.06 (CH2, 2C), 32.36 (CF3, q, JCF = 27.14 Hz), 28.26 (CH2),
28.14 (CH2), 27.87 (CH2), 26.14 (CH2), 24.80 (CH2), 24.13 (CH2,
2C), 21.36 (CH2). 19F NMR (565 MHz, DMSO-d6): δ −63.75 (t, J =
11.7 Hz). HRMS (AP-ESI) m/z: calcd for C21H32F3N2O4S [M + H]+,
465.2035; found, 465.2046.
3-(N-(Tetrahydro-2H-pyran-4-yl)sulfamoyl)-4-((8,8,8-
trifluorooctyl)amino)benzoic Acid (38). Compound 38 was synthe-
sized following the general procedure 6 previously described using
intermediate 54f (50 mg, 0.16 mmol) and amine 53a (33.4 mg, 0.18
mmol) in dry 1,4-dioxane (0.55 mL). Purification by silica gel flash
chromatography (CH2Cl2/MeOH from 100:0 to 98:02) followed by
trituration with diethyl ether (1 mL) afforded the pure 38 (20.9 mg,
28% yield) as a white solid. UPLC/MS: Rt = 2.40 min (gradient 1);
MS (ESI) m/z: 463.5 [M − H]−. C20H28F3N2O5S [M − H]− calcd:
(CH), 133.97 (CH), 127.34 (CF3, q, 1JCF = 276.6 Hz), 117.55 (Cq),
115.75 (Cq), 111.48 (CH), 46.85 (CH2, 2C), 43.30 (CH2), 33.82
(CH2), (q, JCF = 28.16 Hz), 29.04 (CH2), 28.88 (CH2), 28.74
2
(CH2), 26.96 (CH2), 25.33 (CH2, 2C), 23.64 (CH2), 21.95 (CH2).
19F NMR (565 MHz, DMSO-d6): δ −63.69 (t, J = 11.7 Hz). HRMS
(AP-ESI) m/z: calcd for C20H30F3N2O4S [M + H]+, 451.1878; found,
451.1879.
3-Morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic Acid
(35). Compound 35 was synthesized following the general procedure
6 previously described using intermediate 54c (50 mg, 0.17 mmol)
and amine 53a (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 mL).
Purification by silica gel flash chromatography (CH2Cl2/MeOH from
100:0 to 98:02) followed by trituration with diethyl ether (1 mL)
afforded the pure 42d (28.4 mg, 37% yield) as a white solid. UPLC/
MS: Rt = 2.21 min (gradient 1); MS (ESI) m/z: 451.2 [M − H]−.
C19H26F3N2O5S [M − H]− calcd: 451.2. 1H NMR (400 MHz,
chloroform-d): δ 8.33 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.9, 2.1 Hz,
1H), 6.87 (t, J = 5.0 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.77−3.70 (m,
4H), 3.21 (q, J = 7.0 Hz, 2H), 3.12−3.06 (m, 4H), 2.14−1.99 (m,
2H), 1.73−1.63 (m, 2H), 1.61−1.50 (m, 2H), 1.48−1.32 (m, 6H).
13C NMR (101 MHz, DMSO-d6): δ 166.25 (CO), 149.50 (Cq),
1
463.2. H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J = 2.1 Hz, 1H),
7.96 (d, J = 7.6 Hz, 1H), 7.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.85 (d, J =
8.9 Hz, 1H), 6.35 (t, J = 5.6 Hz, 1H), 3.74−3.65 (m, 2H), 3.30−3.17
(m, 4H), 3.17−3.06 (m, 1H), 2.29−2.13 (m, 2H), 1.64−1.56 (m,
2H), 1.53−1.42 (m, 4H), 1.40−1.29 (m, 8H). 13C NMR (101 MHz,
DMSO-d6): δ 166.66 (CO), 148.20 (Cq), 134.95 (CH), 131.63
1
(CH), 127.82 (CF3, q, JCF = 277.1 Hz), 121.32 (Cq), 116.45 (Cq),
111.44 (CH), 65.45 (CH), 48.86 (CH2, 2C), 42.49 (CH2), 33.24
2
(CH2, 2C), 32.42 (CH2, q, JCF = 26.29 Hz), 28.35 (CH2), 28.19
(CH2), 27.96 (CH2), 26.24 (CH2), 21.46 (CH2). 19F NMR (565
MHz, DMSO-d6): δ −63.75 (t, J = 11.7 Hz). HRMS (AP-ESI) m/z:
calcd for C20H30F3N2O5S [M + H]+, 467.1828; found, 467.1835.
2-Chloro-5-(N,N-dimethylsulfamoyl)-4-fluorobenzoic Acid (56).
2-Chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid 55 (250 mg, 0.91
mmol) dissolved in 1.5 mL of THF was added dropwise to 8 mL of an
ice-cold solution of dimethylamine (0.45 mL, 0.91 mmol) in THF
and DIPEA (0.38 mL, 2.72 mmol) and stirred for 30 h. At reaction
completion, the reaction mixture was evaporated to dryness. The dry
residue was dissolved in water and treated with 2 N HCl until
reaching pH 3. The resulting precipitated solid was filtered and rinsed
with water. Final purification by silica gel flash chromatography
(CH2Cl2/MeOH from 100:0 to 98:02) afforded the pure 56 (105.1
mg, 41% yield) as a white solid. UPLC/MS: Rt = 1.04 min (gradient
1); MS (ESI) m/z: 280.0 [M − H]−. C9H8ClFNO4S [M − H]− calcd:
135.64 (CH), 132.61 (CH), 127.73 (CF3, q, 1JCF = 278.6 Hz), 116.65
(Cq), 114.65 (Cq), 112.13 (CH), 65.27 (CH2, 2C), 45.53 (CH2,
2C), 42.26 (CH2), 32.35 (CH2, q, JCF = 27.24 Hz), 28.14 (CH2),
2
27.96 (CH2), 27.83 (CH2), 26.11 (CH2), 21.33 (CH2). 19F NMR
(565 MHz, DMSO-d6): δ −63.76 (t, J = 11.7 Hz). HRMS (AP-ESI)
m/z: calcd for C19H28F3N2O5S [M + H]+, 453.1671; found, 453.1675.
3-(-N-Cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)-
benzoic Acid (36). Compound 36 was synthesized following the
general procedure 6 previously described using intermediate 54d (50
mg, 0.17 mmol) and amine 53a (35.1 mg, 0.19 mmol) in dry 1,4-
dioxane (0.6 mL). Purification by silica gel flash chromatography
(CH2Cl2/MeOH from 100:0 to 98:02) followed by trituration with
diethyl ether (1 mL) afforded the pure 36 (31.7 mg, 41% yield) as a
white solid. UPLC/MS: Rt = 2.33 min (gradient 1); MS (ESI) m/z:
1
280.1. H NMR (400 MHz, DMSO-d6): δ 8.17 (d, J = 7.5 Hz, 1H),
7.91 (d, J = 10.1 Hz, 1H), 2.76 (d, J = 1.8 Hz, 6H).
2-Chloro-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)-
amino)benzoic Acid (39). Compound 39 was synthesized following
the general procedure 6 previously described using intermediate 56
(60 mg, 0.21 mmol) and amine 53a (46.8 mg, 0.21 mmol) in dry 1,4-
dioxane (0.8 mL). Purification by silica gel flash chromatography
(CH2Cl2/MeOH from 100:0 to 97:03) followed by trituration with
diethyl ether (1 mL) afforded the pure 39 (82.2 mg, 88% yield) as a
white solid. UPLC/MS: Rt = 2.14 min (gradient 1); MS (ESI) m/z:
443.1 [M − H]−. C17H23ClF3N2O4S [M − H]− calcd: 444.2. 1H
NMR (400 MHz, chloroform-d): δ 8.37 (s, 1H), 6.88 (t, J = 5.0 Hz,
1H), 6.75 (s, 1H), 3.21−3.16 (m, 2H), 2.77 (s, 6H), 2.14−2.00 (m,
2H), 1.73−1.63 (m, 2H), 1.61−1.51 (m, 2H), 1.48−1.34 (m, 6H).
13C NMR (150 MHz, DMSO-d6): δ 164.85 (CO), 148.78 (Cq),
449.5 [M − H]−. C20H28F3N2O4S [M − H]− calcd: 449.2. H NMR
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(400 MHz, chloroform-d): δ 8.49 (d, J = 2.1 Hz, 1H), 8.08 (dd, J =
8.8, 2.1 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.53 (s, 1H), 4.63−4.51
(m, 1H), 3.63−3.53 (m, 1H), 3.25 (t, J = 7.1 Hz, 2H), 2.14−2.00 (m,
2H), 1.85−1.75 (m, 2H), 1.74−1.65 (m, 2H), 1.65−1.54 (m, 4H),
1.53−1.47 (m, 2H), 1.46−1.36 (m, 6H), 1.36−1.27 (m, 2H). 13C
NMR (101 MHz, DMSO-d6): δ 166.51 (CO), 148.28 (Cq), 134.75
(CH), 131.79 (CH), 127.71 (CF3, q, 1JCF = 268.1 Hz), 120.88 (Cq),
116.25 (Cq), 111.26 (CH), 54.06 (CH), 42.40 (CH2), 32.36 (CH2,
2
q, JCF = 26.86 Hz) 32.32 (CH2, 2C), 28.24 (CH2), 28.10 (CH2),
27.86 (CH2), 26.12 (CH2), 22.75 (CH2, 2C), 21.34 (CH2). 19F NMR
(565 MHz, DMSO-d6): δ −63.75 (t, J = 11.7 Hz). HRMS (AP-ESI)
m/z: calcd for C20H30F3N2O4S [M + H]+, 451.1878; found, 451.1891.
3-(-N-Cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic
Acid (37). Compound 37 was synthesized following the general
139.82 (Cq), 135.04 (CH), 127.76 (CF3, q, 1JCF = 276.4 Hz), 114.29
(Cq), 113.80 (CH), 42.24 (CH2), 37.29 (CH2, 2C), 32.37 (CH2, q,
2JCF = 27.89 Hz), 28.10 (CH2), 27.85 (CH2), 27.82 (CH2), 26.03
10222
J. Med. Chem. 2021, 64, 10203−10229