Journal of Medicinal Chemistry
Article
[M + H]+: 466.08. Found: 465.90. HRMS (ESI) Calcd for C25H20Cl-
NO4S [2M + H]+: 931.1676. Found: 931.1629.
for 1.5 h. The mixture was filtered through Celite and washed with
water, and the solvents were removed in vacuo. The resulting crude
material was acidified with 2 M HCl, extracted into EtOAc, and dried
over anhydrous Na2SO4. The solvent was evaporated in vacuo to
obtain the crude acid which was purified using automated preparative
HPLC to yield the desired compound (33 mg, 30%) as a white solid.
1H NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 8.2 Hz, 1H), 7.82 (s,
1H), 7.55−7.42 (m, 5H), 7.21−7.18 (m, 2H), 7.10 (dd, J = 8.7 Hz, J =
2.3 Hz, 1H), 5.23 (s, 2H), 4.54−4.46 (m, 1H), 4.37 (s, 2H), 3.84 (s,
3H), 1.85−1.80 (m, 2H), 1.71−1.56 (m, 6H). 13C NMR (100 MHz,
DMSO-d6): δ 167.1, 166.8, 161.0, 159.5, 143.9, 137.5, 136.6, 131.5,
130.8, 129.2, 128.8, 128.4, 128.3, 126.6, 125.5, 123.9, 115.3, 111.5,
109.1, 69.5, 55.9, 51.9, 45.6, 29.6, 23.8. HRMS: calcd for C28H27NO5
[M + H]+ 458.1962; found 458.1947.
4-Chloro-3′-((2-isobutyl-3-oxo-2,3-dihydrobenzo[d]-
isothiazol-6-yloxy)methyl)biphenyl-3-carboxylic Acid (3d). Pale
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yellow solid (97 mg, 65%). H NMR (400 MHz, CDCl3): δ 8.05 (s,
1H), 7.84−7.80 (m, 1H), 7.56−7.38 (m, 6H), 7.21(d, 1H, J = 8.4 Hz),
6.98 (d, 1H, J = 8.5 Hz), 5.17 (s, 2H), 3.58 (d, 2H, J = 7.3 Hz), 2.07−
1.96 (m, 1H), 0.88 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 167.5, 165.5, 163.5, 147.9, 143.2, 139.7, 138.9, 131.5, 130.7, 130.2,
129.4, 127.8, 127.0, 126.0, 115.1, 110.6, 70.8, 51.1, 22.9. LC-MS (ESI)
Calcd for C25H22ClNO4S [M + H]+: 468.09. Found: 467.90. HRMS
(ESI) Calcd for C25H22ClNO4S [M + H]+: 468.1031. Found: 468.1012.
4-Chloro-3′-((2-cyclopropyl-3-oxo-2,3-dihydrobenzo[d]-
isothiazol-6-yloxy)methyl)biphenyl-3-carboxylic Acid (3e). Pale
1
yellow solid (43 mg, 30%). H NMR (400 MHz, DMSO-d6): δ 8.01
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-4-
(s, 1H), 7.82−7.80 (m, 3H), 7.69 (d, 1H, J = 8.6 Hz), 7.60 (d, 1H, J =
8.5 Hz), 7.53−7.40 (m, 3H), 7.06 (d, 1H, J = 8.6 Hz), 5.23 (s, 2H),
3.00−2.98 (m, 1H), 0.96−0.92 (m, 2H), 0.87−0.83 (m, 2H). 13C
NMR (100 MHz, DMSO-d6): δ 167.7, 164.8, 161.2, 144.1, 138.8,
138.3, 137.7, 132.1, 131.4, 130.9, 130.6, 129.5, 128.7, 127.6, 126.4,
126.2, 125.7, 124.0, 115.5, 106.9, 70.2, 5.2. LC-MS (ESI) Calcd for
C24H18ClNO4S [M + H]+: 452.06. Found: 451.85. HRMS (ESI) Calcd
for C24H18ClNO4S [M + H]+: 452.0718. Found: 452.0716.
hydroxybiphenyl-3-carboxylic Acid (15b). White solid (18 mg,
1
20%). H NMR (400 MHz, DMSO-d6): δ 8.03 (dd, J = 7.3 Hz, J =
2.3 Hz, 1H), 7.85−7.39 (m, 6H), 7.24−6.94 (m, 3H), 5.24 (s, 2H),
4.55−4.47 (m, 1H), 4.37 (s, 2H), 1.86−1.56 (m, 8H). 13C NMR
(100 MHz, DMSO-d6): δ 171.7, 166.8, 161.0, 160.6, 143.9, 139.2,
137.4, 133.9, 130.9, 129.2, 127.9, 126.4, 125.8, 125.5, 123.8, 117.9,
115.3, 109.1, 69.5, 51.9, 45.6, 29.6, 23.8. HRMS calcd for C27H25NO5
[M + H]+ 444.1805; found: 444.1800.
4-Chloro-3′-((2-isopentyl-3-oxo-2,3-dihydrobenzo[d]-
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-2,6-
isothiazol-6-yloxy)methyl)biphenyl-3-carboxylic Acid (3f). Pale
dimethoxybiphenyl-4-carboxylic Acid (15c). White solid (8 mg,
1
1
yellow solid (83 mg, 55%). H NMR (400 MHz, DMSO-d6): δ 8.02
16%). H NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 8.2 Hz, 1H),
(s, 1H), 7.84−7.82 (m, 4H), 7.79 (d, 1H, J = 8.5 Hz), 7.58 (d, 1H, J =
8.6 Hz), 7.49−7.47 (m, 2H), 7.05 (d, 1H, J = 8.5 Hz), 5.32 (s, 2H),
3.76−3.72 (m, 2H), 1.51- 1.48 (m, 3H), 0.86 (d, J = 6.1 Hz, 6H). 13C
NMR (100 MHz, DMSO-d6): δ 167.8, 165.3, 149.7, 139.1, 137.8,
131.7, 131.0, 130.9, 129.9, 129.2, 127.5, 127.1, 126.9, 120.7, 112.0,
71.0, 54.8, 38.3, 25.7, 22.7. LC-MS (ESI) Calcd for C26H24ClNO4S
[M + H]+: 482.11. Found: 482.00. HRMS (ESI) Calcd for
C26H24ClNO4S [M + H]+: 482.1187. Found: 482.1173.
3-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-
phenylboronic Acid (13). To a solution of 2-cyclopentyl-5-hydro-
xyisoindolin-1-one (500 mg, 2.3 mmol) in acetone (20 mL) were added
K2CO3 (1.2 g, 8.7 mmol) and 3-(bromomethyl)phenylboronic acid
(650 mg, 3.0 mmol), and the mixture was heated with stirring at reflux for
3 h. The reaction mixture was filtered, and the solvent was evaporated in
vacuo to obtain 3-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-
phenylboronic acid as a white solid (583 mg, 72%). The crude product
was used for the next step without further purification. 1H NMR
(400 MHz, DMSO-d6): δ 7.86 (s, 1H), 7.75−7.69 (m, 2H), 7.55−7.32
(m, 4H), 7.19 (s, 1H), 7.09−7.07 (m, 1H), 5.15 (s, 2H), 4.55−4.49
(m, 1H), 4.37 (s, 2H), 1.84−1.56 (m, 8H). LRMS calcd for
C20H22BNO4 [M + H]+ 352 found: 352.
7.40−7.09 (m, 8H), 5.19 (s, 2H), 4.56−4.48 (m, 1H), 4.39 (s, 2H),
3.69 (s, 6H), 2.02−1.54 (m, 8H). 13C NMR (100 MHz, DMSO-d6):
δ 167.1, 166.9, 161.1, 156.9, 143.9, 135.9, 133.5, 129.7, 127.8, 125.4,
123.8, 122.5, 115.6, 115.3, 109.1, 105.1, 69.6, 55.8, 51.9, 45.6, 29.6,
23.8. HRMS calcd for C29H29NO6 [M + H]+ 488.2068; found:
488.2061.
6-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-
methyl)biphenyl-3-carboxylic Acid (15d). White solid (8.2 mg,
1
14%). H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.99−7.97 (m,
1H), 7.75 (d, J = 8.2 Hz, 1H), 7.55−7.41 (m, 5H), 7.06−7.04 (m,
1H), 6.99 (s, 1H), 5.17 (s, 2H), 4.77−4.69 (m, 1H), 4.28 (s, 2H),
1.99−1.55 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 168.5, 161.2,
143.2, 136.8, 133.0, 130.3, 129.1, 128.4, 126.0, 124.9, 115.4, 108.8,
70.2, 52.6, 46.0, 30.0, 24.1. HRMS calcd for C27H24ClNO4 [M + H]+
462.1467; found: 462.1466.
2-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-
methyl)biphenyl-4-carboxylic Acid (15e). White solid (14 mg,
15%). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.94−7.91 (m,
1H), 7.55−7.51 (m, 5H), 7.45−7.43 (m, 1H), 7.21−7.09 (m, 2H),
5.25 (s, 2H), 4.55−4.47 (m, 1H), 4.37 (s, 2H), 1.86−1.56 (m, 8H).
13C NMR (100 MHz, DMSO-d6): δ 167.1, 166.0, 160.9, 143.9, 137.0,
3-((2-Cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-
yloxy)methyl)phenylboronic Acid (14). Potassium carbonate (166
mg, 1.2 mmol) was added to a solution of 2-cyclopentyl-7-hydroxy-
3,4-dihydroisoquinolin-1(2H)-one (235 mg, 1 mmol) and 3-(bromo-
methyl)phenylboronic acid (257 mg, 1.2 mmol) in acetone (10 mL).
After being stirred for 1 h at 60 °C, the reaction mixture was cooled to
room temperature and filtered. The filtrate was evaporated under
reduced pressure to give crude 3-((2-cyclopentyl-3-oxo-2,3-dihydro-
benzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid as a colorless
solid (315 mg, 85%). The crude product was used for the next step
131.8, 130.4, 128.6, 128.2, 123.9, 115.3, 109.1, 69.3, 51.9, 45.2, 29.6,
23.8. HRMS calcd for C27H24ClNO4 [M + H]+ 462.1467; found:
462.1464.
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-6-methyl-
1
biphenyl-3-carboxylic Acid (15f). White solid (15 mg, 32%). H
NMR (400 MHz, CDCl3): δ 7.84−7.80 (m, 2H), 7.60−7.25 (m, 6H),
7.07−7.02 (m, 2H), 5.17 (s, 2H), 4.64−4.57 (m, 1H), 4.31 (s, 2H),
2.26 (s, 3H), 1.91−1.62 (m, 8H). 13C NMR (100 MHz, CDCl3): δ
167.8, 167.6, 161.2, 143.4, 141.1, 141.0, 140.1, 136.4, 130.3, 128.8,
128.6, 128.4, 128.3, 127.9, 126.1, 125.8, 124.1, 115.3, 108.7, 69.8, 52.2,
45.8, 29.8, 23.9, 20.5. LRMS calcd for C28H27NO4 [M + H]+ 442
found: 442. HRMS calcd for C28H27NO4 [M + H]+ 442.2013 found:
442.2000.
1
without further purification. H NMR (400 MHz, DMSO-d6): δ 8.12
(s, 2H), 7.83 (s, 1H), 7.73−7.68 (m, 2H), 7.56 (s, 1H), 7.47 (d, 1H,
J = 7.8 Hz), 7.32 (t, 1H, J = 7.8 Hz), 7.04 (d, 1H, J = 8.7 Hz), 5.25 (s,
2H), 4.85−4.81 (m, 1H), 2.01−1.98 (m, 2H), 1.75−1.59 (m, 6H). 13C
NMR (100 MHz, DMSO-d6): δ 164.4, 162.2, 143.3, 136.6, 134.4,
130.0, 128.8, 127.7, 115.6, 108.8, 70.8, 54.8, 32.2, 24.4. LC-MS (ESI)
Calcd for C19H20BNO4S [M + H]+: 370.12. Found: 369.90.
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-6-
methoxybiphenyl-3-carboxylic Acid (15a). 3-((2-Cyclopentyl-1-
oxoisoindolin-5-yloxy)methyl)phenylboronic acid (100 mg, 0.28 mmol),
3-iodo-4-methoxybenzoic acid (67 mg, 0.24 mmol), K2CO3 (83 mg,
0.6 mmol), and PdCl2(PPh3)2 (22 mg, 0.03 mmol) were dissolved in
a mixture of toluene and MeOH (3.7:0.37 mL) and heated at 80 °C
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-5-fluo-
1
robiphenyl-3-carboxylic Acid (15g). White solid (9 mg, 27%). H
NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.85−7.51 (m, 7H),
7.24−7.11 (m, 2H), 5.28 (s, 2H), 4.56−4.48 (m, 1H), 4.39 (s, 2H),
1.87−1.57 (m, 8H). 13C NMR (100 MHz, DMSO-d6): δ 166.8, 160.9,
144.0, 137.6, 129.3, 127.7, 126.5, 126.3, 125.5, 123.9, 123.3, 115.3,
109.1, 69.4, 51.9, 45.6, 29.6, 23.8. HRMS calcd for C27H24FNO4 [M +
H]+ 446.1762; found: 446.1767.
3′-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)-4-me-
thoxybiphenyl-3-carboxylic Acid (15h). White solid (12 mg, 21%).
9441
dx.doi.org/10.1021/jm3005306 | J. Med. Chem. 2012, 55, 9434−9445