Journal of Medicinal Chemistry
Article
2-[2-(Trimethylacetylamino)benzoylamino]benzoic Acid (17d).
17d was synthesized by procedures A, E, F, and C.
2-[2-(4-Fluorobenzoylamino)benzoylamino]benzoic Acid (17j).
17j was synthesized by procedures A, E, F, and C.
1H NMR (500 MHz; pyridine-d5): δ 13.34 (s, 1H), 11.94 (s, 1H),
9.14 (dd, J = 8.5, 1.1 Hz, 2H), 8.51 (dd, J = 7.9, 1.6 Hz, 1H), 8.16 (dd,
J = 7.9, 1.3 Hz, 1H), 7.62−7.58 (ddd, J = 8.7, 7.1, 1.6 Hz, 1H), 7.45−
7.42 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.23−7.20 (ddd, J = 8.3, 7.3, 1.0
Hz, 1H), 7.05−7.02 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 1.39 (s, 9H).
13C NMR (126 MHz; pyridine-d5): δ 177.1, 172.3, 168.1, 141.7,
141.5, 133.8, 132.9, 132.1, 127.8, 123.2, 122.8, 121.4, 121.1, 120.5,
118.8, 27. 5.
1H NMR (360 MHz; pyridine-d5): δ 13.61 (s, 1H), 12.78 (s, 1H),
9.23 (d, J = 8.3 Hz, 1H), 9.15 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 7.7 Hz,
1H), 8.32 (dd, J = 8.0, 5.7 Hz, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.62−
7.56 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.27−7.20 (m, J = 7.5 Hz, 3H),
7.10 (t, J = 7.7 Hz, 1H).
13C NMR (91 MHz; pyridine-d5): δ 168.55, 165.35 (d, J = 251.0
Hz), 164.56, 141.96, 141.54, 134.03, 133.41, 132.54, 132.25, 130.65,
130.55, 128.42, 121.91, 121.66, 121.03, 116.40, 116. 16.
ESIMS m/z calcd for [C21H16FN2O4]+, 379.35; found, 379.43.
2-[2-(Phenylacetylamino)benzoylamino]benzoic Acid (17k). 17k
was synthesized by procedures A, E, F, and C.
ESIMS m/z calcd for [C19H21N2O4]+, 341.14; found, 341.24.
2-[[2-(Cyclohexanecarboxylamino)benzoyl]amino]benzoic Acid
(17e). 17e was synthesized by procedures A, E, F, and C.
1H NMR (400 MHz; pyridine-d5): δ 13.28 (s, 1H), 11.71 (s, 1H),
9.15 (d, J = 8.3 Hz, 1H), 9.12 (dd, J = 8.5, 1.0 Hz, 1H), 8.52 (dd, J =
7.9, 1.6 Hz, 1H), 8.17 (dd, J = 7.9, 1.3 Hz, 1H), 7.60 (ddd, J = 8.5, 7.2,
1.3 Hz, 1H), 7.45 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.23 (ddd, J = 8.0,
7.0, 1.0 Hz, 1H), 7.06 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 2.45 (tt, J = 11.4,
3.6 Hz, 1H), 2.13−2.06 (m, 2H), 1.74−1.61 (m, 4H), 1.53−1.46 (m,
1H), 1.27−1.06 (m, 3H).
1H NMR (500 MHz; pyridine-d5): δ 13.25 (s, 1H), 11.72 (s, 1H),
9.11 (dd, J = 8.4, 0.5 Hz, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.53 (dd, J =
7.9, 1.5 Hz, 1H), 8.09 (dd, J = 7.9, 1.2 Hz, 1H), 7.67−7.64 (ddd, J =
7.0, 1.6 Hz, 1H), 7.40−7.35 (m, 3H), 7.29−7.23 (m, 3H), 7.04−7.01
(ddd, J = 7.0, 1.0 Hz, 2H), 3.93 (s, 2H).
13C NMR (126 MHz; pyridine-d5): δ 172.36, 169.81, 167.73,
141.87, 140.66, 133.88, 132.72, 132.20, 129.98, 129.02, 127.85, 127.31,
123.34, 123.30, 122.18, 121.78, 120.60, 118.88, 45. 73.
ESIMS m/z calcd for [C22H19N2O4]+, 375.13; found, 375.18.
2-[2-(Benzoylamino)benzoylamino]phenylacetic Acid (23). 23
was synthesized by procedures E, D, E, F, and C.
13C NMR (126 MHz; pyridine-d5): δ 175.7, 173.4, 169.1, 142.8,
142.3, 134.8, 133.9, 133.2, 129.0, 124.3, 124.0, 122.71, 122.52, 121.6,
120.0, 48.1, 30.9, 26.96, 26. 80.
ESIMS m/z calcd for [C21H23N2O4]+, 367.16; found, 367.24.
2-[2-(4-Carboxybutanoylamido)benzoyl]aminobenzoic Acid
(17f). 17f was synthesized by procedures A, E, F, and C.
1H NMR (500 MHz; pyridine-d5): δ 13.31 (s, 1H), 11.83 (s, 1H),
9.16 (d, J = 8.3 Hz, 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 7.8 Hz,
1H), 8.13 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.8
Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.05 (m,
4H).
1H NMR (400 MHz, pyridine-d5): δ 12.94 (s, 1H), 11.59 (s, 1H),
9.29 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 7.4 Hz,
2H), 7.99 (d, J = 7.8 Hz, 1H), 7.56−7.49 (m, 2H), 7.44−7.40 (m,
1H), 7.37−7.33 (m, 3H), 7.24 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz,
1H), 4.10 (s, 2H).
13C NMR (400 MHz, pyridine-d5): δ 176.4, 169.4, 166, 142, 137.8,
133.6, 132.6, 132.2, 131.7, 129.7, 129.3, 128.6, 128.3, 127.4, 127.2,
122.0, 121.4, 40.5.
13C NMR (126 MHz; pyridine-d5): δ 175.1, 172.4, 171.0, 167.9,
141.9, 140.9, 133.9, 132.8, 132.2, 128.0, 123.1, 121.8, 120.6, 118.9,
33.3, 30. 0.
13C NMR (100 MHz, pyridine-d5): δ 175.5, 168.8, 165.3, 141.5,
137.4, 135.6, 133.1, 132.0, 131.7, 131.4, 129.1, 128.8, 128.1, 127.8,
126.82, 126.65, 123.0, 121.4, 120.8, 40.1.
ESIMS m/z calcd for [C18H17N2O6]+, 357.10; found, 357.23.
2-[2-(Benzylamino)benzoylamino]benzoic Acid (17g). 17g was
synthesized by procedures A, E, G, and C.
ESIMS m/z calcd for [C22H17N2O4]+, 373.13; found, 373.20.
2-[2-(Benzoylamino)phenylacetylamino]benzoic Acid (28). 28
was synthesized by procedures D, E, F, and C.
1H NMR (360 MHz; pyridine-d5): δ 13.13 (s, 1H), 9.21 (d, J = 8.4
Hz, 1H), 8.51 (dd, J = 7.9, 1.4 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H),
7.61−7.58 (m, 1H), 7.49 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H),
7.25 (app q, J = 7.4 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 8.4
Hz, 1H), 6.65 (t, J = 7.5 Hz, 1H), 4.46 (s, 2H).
1H NMR (400 MHz, pyridine-d5): δ 12.72 (s, 1H), 11.30 (s, 1H),
8.95 (d, J = 8.4 Hz, 1H), 8.48−8.45 (m, 2H), 8.41 (dd, J = 7.7, 1.5 Hz,
1H), 8.37 (d, J = 8.0 Hz, 1H), 7.51−7.44 (m, 5H), 7.37−7.33 (m,
1H), 7.13 (t, J = 7.5 Hz, 2H), 4.03 (s, 2H).
13C NMR (91 MHz; pyridine-d5): δ 172.4, 168.9, 150.9, 142.7,
139.8, 133.9, 133.5, 132.1, 128.9, 128.4, 127.55, 127.36, 122.5, 120.4,
118.1, 116.0, 115.6, 112.7, 47. 1.
13C NMR (100 MHz, pyridine-d5): δ 172.1, 171.3, 165.9, 141.7,
138.5, 135.6, 135.3, 133.8, 132.03, 131.90, 131.3, 128.97, 128.83,
128.28, 128.17, 125.54, 125.43, 120.5, 43. 6.
ESIMS m/z calcd for [C21H19N2O3]+, 347.13; found, 347.22.
2-[2-(2-Fluorobenzoylamino)benzoylamino]benzoic Acid (17h).
17h was synthesized by procedures A, E, F, and C.
ESIMS m/z calcd for [C22H19N2O4]+, 375.13; found, 375.22.
2-[2-(2-Fluorobenzoylamino)benzoylamino]-4-chlorobenzoic
Acid (35a). 35awas synthesized by procedures I, A, J, A, and C.
1H NMR (500 MHz; pyridine-d5): δ 14.04 (s, 1H), 12.39 (d, J = 6.1
Hz, 1H), 9.25 (d, J = 1.7 Hz, 1H), 9.14 (d, J = 8.3 Hz, 1H), 8.49 (d, J
= 8.4 Hz, 1H), 8.24−8.21 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.40−7.36
(m, 1H), 7.23−7.09 (m, 4H).
1H NMR (360 MHz; pyridine-d5): δ 13.43 (s, 1H), 12.47 (d, J = 6.1
Hz, 1H), 9.16 (d, J = 8.4 Hz, 2H), 8.52 (d, J = 7.8 Hz, 1H), 8.52 (d, J
= 7.8 Hz, 1H), 8.25 (td, J = 7.7, 1.5 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H),
7.53 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44−7.38 (m, 1H),
7.23−7.17 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H).
13C NMR (126 MHz; pyridine-d5): δ 171.89, 167.76, 162.24 (d, J =
2.5 Hz), 160.27 (d, J = 250.9 Hz), 142.56, 140.24, 138.43, 133.59 (d, J
= 8.8 Hz), 133.38, 132.73, 131.49 (d, J = 1.6 Hz), 128.07, 124.83 (d, J
= 3.4 Hz), 123.73, 122.95, 122.57, 122.47, 122.40, 119.87, 118.91,
116.58 (d, J = 23.1 Hz).
13C NMR (91 MHz; pyridine-d5): δ 173.90, 169.15, 163.70, 162.01
(d, J = 251.0 Hz), 143.25, 141.75, 137.24, 136.97, 135.22, 135.16,
134.20, 133.60, 133.15, 129.43, 126.4 (d, J = 2.7 Hz), 125.34, 125.00,
124.72, 123.99, 122.02, 120.45, 118.1 (d, J = 24 Hz).
ESIMS m/z calcd for [C21H14FN2O4]−, 377.09; found, 377.20.
2-[2-(3-Fluorobenzoylamino)benzoylamino]benzoic Acid (17i).
17i was synthesized by procedures A, E, F, and C.
ESIMS m/z calcd for [C21H13ClFN2O4]−, 411.06; found, 411.16.
2-[2-(2-Fluorobenzoylamino)benzoylamino]-5-chlorobenzoic
Acid (35b). 35b was synthesized by procedures I, A, J, A, and C.
Compound 35b was only available in very small quantities.
Consequently, some signals are lost in the noise or obscured by
solvent signals.
1H NMR (500 MHz; pyridine-d5): δ 13.90 (s, 1H), 12.82 (s, 1H),
9.10−9.07 (m, 2H), 8.56−8.52 (m, J = 1.0 Hz, 1H), 8.27 (d, J = 7.5
Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.02 (dt, J = 9.6, 2.1 Hz, 1H), 7.51
(app dt, J = 11.0, 7.9 Hz, 2H), 7.44 (app td, J = 7.9, 5.8 Hz, 1H), 7.27
(td, J = 8.4, 2.4 Hz, 1H), 7.20−7.15 (m, 2H).
1H NMR (500 MHz; pyridine-d5): δ 12.69 (s, 1H), 9.19 (d, J = 8.5
Hz, 1H), 9.12 (d, J = 8.8 Hz, 1H), 8.79 (s, 2H), 8.28 (d, J = 7.7 Hz,
1H), 8.23 (t, J = 7.1 Hz, 1H), 7.51−7.46 (m, 2H), 7.42−7.37 (m, 1H),
7.04−7.01 (m, 1H).
13C NMR (126 MHz; pyridine-d5): δ 168.04, 164.04, 164.02, 163.01
(d, J = 246.4 Hz), 140.66, 137.86, 137.81, 135.73, 135.54, 133.26,
132.97, 132.20, 131.03, 130.97, 128.17, 123.77, 123.36, 123.14, 123.12,
121.59, 120.50, 118.91 (d, J = 21.3 Hz, 3C), 114.81 (d, J = 23.0 Hz).
ESIMS m/z calcd for [C21H16FN2O4]+, 379.35; found, 379.37.
13C NMR (126 MHz; pyridine-d5): δ 168.65, 141.60, 141.33, 134.65
(d, J = 8.5 Hz), 133.43, 132.96, 132.61, 132.11, 129.38, 125.96 (d, J =
3.4 Hz), 123.28, 122.58, 117.73 (d, J = 22.9 Hz).
3179
dx.doi.org/10.1021/jm201636v | J. Med. Chem. 2012, 55, 3170−3181