Journal of Medicinal Chemistry
Article
1H), 7.08 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 5.40 (dd, J =
12.0, 4.6 Hz, 1H), 3.86 (dd, J = 18.4, 12.0 Hz, 1H), 2.90 (dd, J = 18.5,
4.6 Hz, 1H), 2.59−2.41 (m, 2H), 2.33 (t, J = 6.8 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6) δ 173.65, 173.46, 168.64, 163.55, 163.43,
161.11, 160.95, 160.11, 152.68, 148.60, 141.09, 139.05, 138.95, 138.52,
131.58, 128.55, 128.40, 127.26, 127.13, 123.41, 122.57, 118.79, 115.58,
113.31, 113.12, 112.32, 112.12, 103.85, 58.30, 45.02, 28.80, 28.37,
28.15. 19F (376 MHz, DMSO-d6) δ −109.98 to −110.05 (m). HRMS
(m/z): [M − H]− calcd for C28H19ClF2N3O4, 534.10376; found,
534.10402. Anal. Calcd for C28H20ClF2N3O4·0.50H2O: C, 61.71; H,
3.88; N, 7.71. Found: C, 61.52; H, 4.05; N, 7.42.
4-{5-(4-Chlorophenyl)-3-[4-(3,5-dichlorophenyl)-2-oxo-1,2-
dihydroquinolin-3-yl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobu-
tanoic Acid (45). Compound 45 was prepared according to general
procedure G using 87 (0.038 g, 0.384 mmol) and 45f (0.180 g, 0.384
mmol). The title compound was obtained as a yellow solid after
purifying using flash column chromatography with 0−10% MeOH/
DCM. Yield 0.080 g, 36.6%. 1H NMR (400 MHz, DMSO-d6) δ 12.33
(s, 1H), 12.10 (s, 1H), 7.84−7.71 (m, 1H), 7.64−7.56 (m, 2H), 7.51−
7.39 (m, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 (t,
J = 6.9 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 5.39 (dd, J =12.0, 4.3 Hz,
1H), 3.89−3.75 (m, 1H), 2.85−2.67 (m, 1H), 2.64−2.30 (m, 4H). 13C
NMR (100 MHz, DMSO-d6) δ 173.46, 168.66, 160.11, 152.60, 152.53,
148.48, 141.01, 138.52, 136.01, 131.77, 131.59, 131.31, 131.11, 130.39,
130.13, 129.07, 128.40, 128.33, 127.35, 127.17, 127.06, 122.55, 119.02,
115.57, 58.24, 45.09, 28.43, 28.38, 28.17. HRMS calcd for
C28H19Cl3N3O4 [M − H]−, 566.04466; found, 566.04483. Anal.
Calcd for C28H20Cl3N3O4·0.30H2O: C, 58.57; H, 3.62; N, 7.32.
Found: C, 58.58; H, 3.75; N, 7.23.
0.38 mmol). The title compound was obtained as a yellow solid after
flash column chromatography using 0−8% MeOH/DCM. Yield 0.033
1
g, 15.1%. H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.08 (s,
1H), 7.69−7.58 (m, 2H), 7.54 (dd, J = 8.2, 2.3 Hz, 1H), 7.44 (dd, J =
8.5, 2.7 Hz, 2H), 7.35−7.23 (m, 3H), 6.93 (d, J = 2.3 Hz, 1H), 6.85−
6.76 (m, 2H), 5.35 (dd, J = 12.0, 4.4 Hz, 1H), 3.72 (dd, J = 18.5, 12.0
Hz, 1H), 2.76 (dd, J = 18.5, 4.4 Hz, 1H), 2.64−2.38 (m, 2H), 2.33 (t, J
= 6.7 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 173.50, 168.71,
159.96, 152.33, 148.76, 141.00, 137.33, 133.52, 133.36, 131.61, 131.48,
131.38, 130.52, 128.52, 128.32, 127.27, 126.25, 125.91, 124.80, 120.43,
117.67, 58.25, 45.08, 28.47, 28.19. HRMS (m/z): [M + H]+ calcd for
C28H21Cl3N3O4, 568.05922; found, 568.05881. Anal. Calcd for
C28H20Cl3N3O4·0.40H2O: C, 58.38; H, 3.64; N, 7.29. Found: C,
58.29; H, 3.73; N, 7.24.
4-{3-[6-Chloro-4-(3-fluorophenyl)-2-oxo-1,2-dihydroquino-
lin-3-yl]-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl}-4-ox-
obutanoic Acid (49). Compound 49 was prepared according to
general procedure G using 87 (0.035 g, 0.35 mmol) and 49f (0.160 g,
0.35 mmol). The title compound was obtained as a yellow solid after
flash column chromatography using 0−8% MeOH/DCM. Yield 0.039
1
g, 20.0%. H NMR (600 MHz, DMSO-d6) δ 12.45 (s, 1H), 12.05 (s,
1H), 7.65 (dd, J = 8.8, 2.5 Hz, 1H), 7.63−7.53 (m, 1H), 7.45 (d, J =
8.8 Hz, 1H), 7.42−7.32 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.29−7.25
(m, 1H), 7.19 (dd, J = 9.2, 2.1 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.94
(d, J = 2.4 Hz, 1H), 6.83 (dd, J = 11.9, 8.3 Hz, 2H), 5.36 (dt, J = 12.2,
4.6 Hz, 1H), 2.88−2.80 (m, 1H), 2.51−2.44 (m, 2H), 2.31 (t, J = 6.9
Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 174.13, 169.33, 163.45,
161.82, 160.66, 153.02, 152.95, 149.14, 141.73, 137.95, 137.52, 132.03,
131.21, 129.05, 127.96, 127.78, 126.91, 126.57, 125.39, 125.30, 121.01,
118.31, 116.19, 58.96, 45.71, 29.12, 28.85. HRMS (m/z): [M − H]−
calcd for C28H19Cl2FN3O4, 550.07421; found, 550.07485. Anal. Calcd
for C28H20Cl2FN3O4·1.00H2O: C, 58.96; H, 3.89; N, 7.37. Found: C,
58.98; H, 3.78; N, 7.06.
4-{5-(4-Chlorophenyl)-3-[4-(4-chlorophenyl)-6-methyl-2-
oxo-1,2-dihydroquinolin-3-yl]-4,5-dihydro-1H-pyrazol-1-yl}-4-
oxobutanoic Acid (46). Compound 46 was prepared according to
general procedure G using 87 (0.039 g, 0.39 mmol) and 46f (0.175 g,
0.39 mmol). The title compound was obtained after flash column
chromatography using 0−8% MeOH/DCM as a yellow solid. Yield
4-{5-(4-Chlorophenyl)-3-[4-(4-chlorophenyl)-6-fluoro-2-oxo-
1,2-dihydroquinolin-3-yl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxo-
butanoic Acid (50). Compound 50 was prepared according to
general procedure G using 87 (0.035 g, 0.35 mmol) and 50f (0.19 g,
0.42 mmol). The title compound was obtained after flash column
chromatography using 0−10% MeOH/DCM as a yellow solid. Yield
1
0.114 g, 53.3%. H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H),
11.79 (s, 1H), 7.56 (dt, J = 8.2, 2.3 Hz, 1H), 7.48 (dt, J = 8.2, 2.3 Hz,
1H), 7.41−7.34 (m, 2H), 7.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.27−7.20
(m, 3H), 6.80−6.72 (m, 3H), 5.35−5.25 (m, 1H), 3.75−3.59 (m, 1H),
2.76−2.65 (m, 1H), 2.61−2.33 (m, 2H), 2.26−2.32 (m, 2H), 2.19 (s,
3H). 13C NMR (100 MHz, DMSO-d6) δ 173.54, 168.64, 160.00,
152.85, 149.66, 141.10, 136.63, 134.07, 133.16, 132.79, 131.56, 131.48,
131.40, 130.53, 128.37, 128.30, 127.30, 126.53, 123.47, 119.05, 115.59,
58.18, 45.18, 28.47, 28.19, 20.58. HRMS (m/z): [M − H]− calcd for
C29H22Cl2N3O4, 546.09929; found, 546.09872. Anal. Calcd for
C29H23Cl2N3O4·0.50H2O: C, 62.49; H, 4.34; N, 7.54. Found: C,
62.44; H, 4.55; N 7.39.
1
0.151 g, 65.1%. H NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H),
12.07 (s, 1H), 7.61 (dd, J = 8.2, 2.4 Hz, 1H), 7.56−7.41 (m, 4H),
7.34−7.25 (m, 3H), 6.85−6.78 (m, 2H), 6.71 (dd, J = 9.7, 2.9 Hz,
1H), 5.36 (dd, J = 12.0, 4.5 Hz, 1H), 3.73 (dd, J = 18.5, 12.1 Hz, 1H),
2.78 (dd, J = 18.5, 4.4 Hz, 1H), 2.62−2.54 (m, 1H), 2.53−2.40 (m,
1H), 2.33 (t, J = 6.7 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ
173.48, 168.69, 159.89, 157.84, 156.25, 152.46, 149.03, 141.01, 135.30,
133.52, 133.45, 131.59, 131.40, 130.47, 128.48, 128.30, 127.28, 124.74,
119.94, 119.78, 119.61, 117.67, 117.62, 111.93, 111.77, 58.24, 45.07,
28.46, 28.18. 19F NMR (376 MHz, DMSO-d6) δ −120.13 to −120.29
(m). HRMS (m/z): [M − H]− calcd for C28H19Cl2FN3O4, 550.07421;
found, 550.07419. Anal. Calcd for C28H20Cl2FN3O4: C, 60.88; H, 3.65;
N, 7.61. Found: C, 60.16; H, 3.98; N, 7.28. HPLC 85% MeOH/H2O
(0.1% formic acid) tR = 1.10 min; >95% purity; 75% ACN/H2O (0.1%
formic acid) tR = 0.81 min; >95% purity.
4-{5-(4-Chlorophenyl)-3-[4-(3-fluorophenyl)-6-methyl-2-
oxo-1,2-dihydroquinolin-3-yl]-4,5-dihydro-1H-pyrazol-1-yl}-4-
oxobutanoic Acid (47). Compound 47 was prepared according to
general procedure G using 87 (0.037 g, 0.37 mmol) and 47f (0.160 g,
0.37 mmol). The title compound was obtained after flash column
chromatography using 0−10% MeOH/DCM as a brown solid. Yield
1
0.094 g, 47.7%. H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H),
12.12 (s, 1H), 7.64−7.47 (m, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.40−7.32
(m, 2H), 7.32−7.22 (m, 3H), 7.11 (dd, J = 23.8, 8.5 Hz, 1H), 6.86−
6.77 (m, 3H), 5.35 (dt, J = 12.5, 3.4 Hz, 1H), 3.80 (dd, J = 18.6, 12.1
Hz, 1H), 2.81 (dt, J = 18.5, 5.2 Hz, 1H), 2.53−2.39 (m, 2H), 2.31 (t, J
= 6.8 Hz, 2H), 2.23 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ
173.46, 168.57, 162.67, 161.11, 160.03, 152.88, 152.81, 149.39, 141.15,
137.59, 136.61, 132.77, 131.58, 131.52, 131.38, 130.25, 128.36, 128.20,
127.33, 127.15, 126.57, 126.52, 125.83, 124.79, 123.38, 123.30, 118.98,
116.66, 116.52, 115.57, 115.19, 115.05, 58.25, 45.16, 28.98, 28.47,
28.19, 20.61. 19F NMR (376 MHz, DMSO-d6) δ −113.28 to −113.50
(m). HRMS (m/z): [M − H]− calcd for C29H22ClFN3O4, 530.12884;
found, 530.12883. Anal. Calcd for C29H23ClFN3O4·1.20H2O: C, 62.92;
H, 4.62; N, 7.59. Found: C, 62.82; H, 4.37; N, 7.34.
4-{5-(4-Chlorophenyl)-3-[6-fluoro-4-(3-fluorophenyl)-2-oxo-
1,2-dihydroquinolin-3-yl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxo-
butanoic Acid (51). Compound 51 was prepared according to
general procedure G using 87 (0.041 g, 0.41 mmol) and 51f (0.180 g,
0.41 mmol). The title compound was obtained after flash column
chromatography using 0−10% MeOH/DCM as a yellow solid. Yield
1
0.076 g, 34.3%. H NMR (600 MHz, DMSO-d6) δ 12.34 (s, 1H),
12.01 (s, 1H), 7.59−7.39 (m, 3H), 7.37−7.19 (m, 3H), 7.14 (t, J = 7.8
Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.83−6.75 (m, 1H), 6.74−6.63 (m,
1H), 5.40−5.33 (m, 1H), 3.81 (dd, J = 18.5, 12.1 Hz, 2H), 2.85−2.75
(m, 1H), 2.46−2.36 (m, 2H), 2.27 (t, J = 7.0 Hz, 2H). 13C NMR (150
MHz, DMSO-d6) δ 173.47, 168.66, 162.80, 161.17, 161.11, 159.93,
157.85, 156.26, 152.52, 152.44, 148.77, 141.08, 137.08, 137.02, 136.97,
135.29, 131.62, 131.56, 130.55, 128.39, 127.39, 127.25, 127.21, 127.08,
125.75, 124.69, 124.59, 119.90, 119.83, 117.66, 116.65, 115.50, 115.36,
111.87, 58.36, 58.24, 45.07, 28.46, 28.18. 19F NMR (376 MHz,
4-{3-[6-Chloro-4-(4-chlorophenyl)-2-oxo-1,2-dihydroquino-
lin-3-yl]-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl}-4-ox-
obutanoic Acid (48). Compound 48 was prepared according to
general procedure G using 87 (0.038 g, 0.38 mmol) and 48f (0.180 g,
R
dx.doi.org/10.1021/jm400652r | J. Med. Chem. XXXX, XXX, XXX−XXX