Compounds useful as inhibitors of ALCAT 1
11208404 · 2021-12-28
Assignee
Inventors
- Yuguang Shi (San Antonio, TX, US)
- Daqing Che (Taizhou, CN)
- Jonathan Baell (Parkville, AU)
- Xiaoyu LIU (WUHAN, CN)
- Jiasheng Fu (Foster City, CA)
Cpc classification
C07D271/113
CHEMISTRY; METALLURGY
C07D307/56
CHEMISTRY; METALLURGY
C07D307/68
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D271/10
CHEMISTRY; METALLURGY
C07D307/52
CHEMISTRY; METALLURGY
C07F9/65586
CHEMISTRY; METALLURGY
C07D413/06
CHEMISTRY; METALLURGY
International classification
C07D413/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
C07D271/10
CHEMISTRY; METALLURGY
Abstract
Inhibitors of ALCAT1 are described having the general formula: (I). These compounds offer a treatment for aging and age-related diseases. ##STR00001##
Claims
1. A compound, being selected from the group consisting of ##STR00710## ##STR00711## ##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717## ##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722##
2. A compound according to claim 1, being selected from the group consisting of ##STR00723## ##STR00724## ##STR00725## ##STR00726## ##STR00727## ##STR00728##
3. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
4. A method of preparing a pharmaceutical composition comprising admixing a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
5. A method of treating aging or age-related diseases comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to claim 1.
6. A method of treating a disease selected from stroke, ischaemia, and reperfusion injury, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to claim 1.
Description
EXAMPLES
(1) General Synthetic Routes
(2) Schemes 1 and 2 below show the general syntheses followed to prepare compounds according to the invention:
(3) ##STR00620##
(4) ##STR00621##
(5) The syntheses of some specific compounds according to these reaction schemes are set out in the Examples below.
Example 1
(6) ##STR00622##
3-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 192
(7) According to the synthetic procedure depicted in Scheme 1, 3-bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepares as follows:
(8) a) N′-(3-nitrobenzoyl)furan-2-carbohydrazide: To a solution of 3-nitrobenzoic acid (10.0 g, 59.8 mmol) in dichloromethane (50 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (7.7 ml, 89.8 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give acid chloride.
(9) This acid chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of 2-furoic acid hydrazide (7.6 g, 60.4 mmol) and anhydrous sodium carbonate (6.3 g, 59.8 mmol) in tetrahydrofuran (50 mL) and water (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and at room temperature for 6 hr. A massive precipitation was observed. The product was harvested by filtration and washed with water, then finally dried in vacuo to afford 14.0 g (85.1% yield) of N′-(3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.
(10) b) 2-(Furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole: N′-(3-nitrobenzoyl)furan-2-carbohydrazide (14.0 g, 50.9 mmol) was dissolved in phosphorus oxychloride (70 ml) and the mixture was stirred with heating at 80° C. for 5 hr. Phosphorus oxychloride was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 12.3 g (93.9% yield) of 2-(furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole as a yellow solid.
(11) c) 3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline: A mixture of 2-(furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole (12.3 g, 47.8 mmol) and Raney-Ni (2.0 g) in methanol (100 ml) was stirred at 50° C. for 16 h under 2.0 Mpa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) gave 9.4 g (86.5% yield) of 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline as a white solid.
(12) d) 3-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide: A mixture of 3-bromo-2-methoxybenzoic acid (122.0 mg, 0.53 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (0.5 ml) was stirred with refluxing for 1 hr. The excess thionyl chloride was evaporated under reduced pressure to give acid chloride. This acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol) and triethylamine (62.3 mg, 0.62 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 12 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (175.5 mg, 90.6% yield) as a white solid.
(13) .sup.1H NMR (400 MHz, DMSO): δ 10.73 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.83-7.80 (m, 2H), 7.63-7.59 (m, 2H), 7.44 (d, J=3.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 6.85-6.84 (m, 1H), 3.84 (s, 3H);
(14) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15BrN.sub.3O.sub.4].sup.+: 440.0246, Found 440.0246.
Example 2
(15) ##STR00623##
3-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 193
(16) 3-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 3-chloro-2-methoxybenzoic acid (98.5 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (163.0 mg, 93.6% yield) as a yellow solid.
(17) .sup.1H NMR (400 MHz, DMSO): δ 10.72 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.67 (dd, J=1.2, 8.0 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57-7.55 (m, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.31-7.27 (m, 1H), 6.85-6.84 (m, 1H), 3.86 (s, 3H);
(18) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15ClN.sub.3O.sub.4].sup.+: 396.0751, Found 396.0756.
Example 3
(19) ##STR00624##
5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 120
(20) 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 5-bromo-2-methoxybenzoic acid (122.0 mg, 0.53 mmol), 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol) and triethylamine (58.7 mg, 0.58 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (184.5 mg, 95.2% yield) as a white solid.
(21) .sup.1H NMR (400 MHz, DMSO): δ 10.50 (s, 1H), 8.56 (s, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 7.68 (dd, J=2.8, 8.8 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.48 (d, J=3.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.85-6.83 (m, 1H), 3.89 (s, 3H);
(22) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15BrN.sub.3O.sub.4].sup.+: 440.0246, Found 440.0221.
Example 4
(23) ##STR00625##
5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 124
(24) 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 5-chloro-2-methoxybenzoic acid (98.5 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (162.9 mg, 93.5% yield) as a white solid.
(25) .sup.1H NMR (400 MHz, DMSO): δ 10.50 (s, 1H), 8.57 (s, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.64-7.55 (m, 3H), 7.44 (d, J=3.6 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 6.85-6.83 (m, 1H), 3.90 (s, 3H);
(26) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15ClN.sub.3O.sub.4].sup.+: 396.0751, Found 396.0749.
Example 5
(27) ##STR00626##
N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide
Compound 279
(28) N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(trifluoromethoxy)benzoic acid (124.7 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (177.9 mg, 90.8% yield) as a white solid.
(29) .sup.1H NMR (400 MHz, DMSO): δ 10.53 (s, 1H), 8.57 (s, 1H), 8.11-8.10 (m, 1H), 7.93-7.91 (m, 1H), 7.82-7.80 (m, 1H), 7.63-7.53 (m, 3H), 7.45 (dd, J=0.4, 3.6 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 3.93 (s, 3H);
(30) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.15F.sub.3N.sub.3O.sub.5].sup.+: 446.0964, Found 446.0960.
Example 6
(31) ##STR00627##
N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide
Compound 197
(32) N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide can be prepared as in Example 1, but from 2-methoxy-5-methylbenzoic acid (87.7 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (155.8 mg, 94.3% yield) as a white solid.
(33) .sup.1H NMR (400 MHz, DMSO): δ 10.39 (s, 1H), 8.60 (s, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.47-7.44 (m, 2H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 3.88 (s, 3H), 2.30 (s, 3H);
(34) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.18N.sub.3O.sub.4].sup.+: 376.1297, Found 376.1310.
Example 7
(35) ##STR00628##
5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide
Compound 123
(36) 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 1, but from 5-chloro-2-propoxybenzoic acid (113.3 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (171.8 mg, 92.1% yield) as a white solid.
(37) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.54 (dd, J=2.8, 8.8 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.08 (t, J=6.4 Hz, 2H), 1.81-1.74 (m, 2H), 0.96 (t, J=7.4 Hz, 3H);
(38) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.19ClN.sub.3O.sub.4].sup.+: 424.1064, Found 424.1078.
Example 8
(39) ##STR00629##
5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide
Compound 119
(40) 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 1, but from 5-bromo-2-propoxybenzoic acid (136.8 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (191.4 mg, 92.9% yield) as a white solid.
(41) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.58 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66 (dd, J=2.4, 8.8 Hz, 1H), 7.63-7.59 (m, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.85-6.84 (m, 1H), 4.07 (t, J=6.4 Hz, 2H), 1.80-1.73 (m, 2H), 0.96 (t, J=7.4 Hz, 3H);
(42) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.19BrN.sub.3O.sub.4].sup.+: 468.0559, Found 468.0568.
Example 9
(43) ##STR00630##
2-Ethoxy-5-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 125
(44) 2-Ethoxy-5-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-ethoxy-5-fluorobenzoic acid (97.2 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (159.4 mg, 92.1% yield) as a beige solid.
(45) .sup.1H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 8.61 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.88-7.85 (m, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.50 (dd, J=3.2, 8.8 Hz, 1H), 7.45 (d, J=3.2 Hz, 1H), 7.40-7.34 (m, 1H), 7.22 (dd, J=4.4, 9.2 Hz, 1H), 6.85-6.84 (m, 1H), 4.17 (q, J=6.8 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.17FN.sub.3O.sub.4].sup.+: 394.1203, Found 394.1200.
Example 10
(46) ##STR00631##
5-Chloro-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 122
(47) 5-Chloro-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 5-chloro-2-ethoxybenzoic acid (105.9 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (170.6 mg, 94.6% yield) as a pale-yellow solid.
(48) .sup.1H NMR (400 MHz, DMSO): δ 10.48 (s, 1H), 8.59 (s, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.18 (q, J=6.8 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H);
(49) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.17ClN.sub.3O.sub.4].sup.+: 410.0908, Found 410.0910.
Example 11
(50) ##STR00632##
5-Bromo-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 118
(51) 5-Bromo-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 5-bromo-2-ethoxybenzoic acid (129.4 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (187.9 mg, 94.0% yield) as a white solid.
(52) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.67 (dd, J=2.8, 8.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.17 (q, J=6.8 Hz, 2H), 1.38 (t, J=6.8 Hz, 3H);
(53) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.17BrN.sub.3O.sub.4].sup.+: 454.0402, Found 454.0406.
Example 12
(54) ##STR00633##
2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-iodobenzamide
Compound 200
(55) 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-iodobenzamide can be prepared as in Example 1, but from 2-ethoxy-5-iodobenzoic acid (154.2 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (197.6 mg, 89.6% yield) as a pale-yellow solid.
(56) .sup.1H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 8.58 (s, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.82-7.79 (m, 2H), 7.62-7.58 (m, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.17 (q, J=6.8 Hz, 2H), 1.38 (t, J=6.8 Hz, 3H);
(57) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.171N.sub.3O.sub.4].sup.+: 502.0264, Found 502.0264.
Example 13
(58) ##STR00634##
2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide
Compound 218
(59) 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 1, but from 2-ethoxy-5-methylbenzoic acid (95.1 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (160.4 mg, 93.6% yield) as a white solid.
(60) .sup.1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.63 (s, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.45 (d, J=2.8 Hz, 1H), 7.32 (dd, J=2.0, 8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.16 (q, J=6.8 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J=6.8 Hz, 3H); LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.20N.sub.3O.sub.4].sup.+: 390.1454, Found 390.1458.
Example 14
(61) ##STR00635##
2-Ethoxy-5-ethyl-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 219
(62) 2-Ethoxy-5-ethyl-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-ethoxy-5-ethylbenzoic acid (102.6 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (170.6 mg, 96.1% yield) as a white solid.
(63) .sup.1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.63 (s, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.35-7.33 (m, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.16 (q, J=6.8 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.40 (t, J=6.8 Hz, 3H), 1.18 (t, J=7.6 Hz, 3H);
(64) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.22N.sub.3O.sub.4].sup.+: 404.1610, Found 404.1607.
Example 15
(65) ##STR00636##
2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethoxy)benzamide
Compound 211
(66) 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethoxy)benzamide can be prepared as in Example 1, but from 2-fluoro-5-(trifluoromethoxy)benzoic acid (118.3 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (179.4 mg, 94.1% yield) as a white solid.
(67) .sup.1H NMR (400 MHz, DMSO): δ 10.87 (s, 1H), 8.53 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.78-7.76 (m, 1H), 7.68-7.61 (m, 2H), 7.58-7.54 (m, 1H), 7.45 (d, J=3.6 Hz, 1H), 6.85-6.84 (m, 1H);
(68) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.12F.sub.4N.sub.3O.sub.4].sup.+: 434.0764, Found 434.0765.
Example 16
(69) ##STR00637##
5-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 228
(70) 5-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (125.7 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (178.7 mg, 90.8% yield) as a white solid.
(71) .sup.1H NMR (400 MHz, DMSO): δ 10.54 (s, 1H), 8.56 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.87-7.84 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.49 (dd, J=3.2, 8.4 Hz, 1H), 7.45-7.41 (m, 2H), 7.36-7.32 (m, 1H), 6.85-6.84 (m, 1H), 4.86 (q, J=8.8 Hz, 2H);
(72) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14F.sub.4N.sub.3O.sub.4].sup.+: 448.0920, Found 448.0917.
Example 17
(73) ##STR00638##
5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 225
(74) 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-chloro-2-(2,2,2-trifluoroethoxy)benzoic acid (134.4 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (189.6 mg, 92.9% yield) as a white solid.
(75) .sup.1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.54 (s, 1H), 8.11-8.10 (m, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.66-7.59 (m, 3H), 7.44 (d, J=3.6 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.88 (q, J=8.8 Hz, 2H);
(76) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14ClF.sub.3N.sub.3O.sub.4].sup.+: 464.0625, Found 464.0627.
Example 18
(77) ##STR00639##
5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 226
(78) 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (157.9 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (207.5 mg, 92.8% yield) as a white solid.
(79) .sup.1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.54 (s, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.77-7.72 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.88 (q, J=8.8 Hz, 2H);
(80) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14BrF.sub.3N.sub.3O.sub.4].sup.+: 508.0120, Found 508.0105.
Example 19
(81) ##STR00640##
3-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 220
(82) 3-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 3-fluoro-2-methoxybenzoic acid (89.8 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (158.0 mg, 94.7% yield) as a off-white solid.
(83) .sup.1H NMR (400 MHz, DMSO): δ 10.66 (s, 1H), 8.59 (s, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.48-7.39 (m, 3H), 7.27-7.22 (m, 1H), 6.85-6.83 (m, 1H), 3.94 (d, J=1.2 Hz, 3H);
(84) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15FN.sub.3O.sub.4].sup.+: 380.1047, Found 380.1048.
Example 20
(85) ##STR00641##
3,5-Dibromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 168
(86) 3,5-Dibromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide an be prepared as in Example 1, but from 3,5-dibromo-2-methoxybenzoic acid (163.6 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (205.0 mg, 89.7% yield) as a white solid.
(87) .sup.1H NMR (400 MHz, DMSO): δ 10.80 (s, 1H), 8.55 (s, 1H), 8.10 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.84-7.82 (m, 2H), 7.62 (t, J=8.0 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 6.85-6.83 (m, 1H), 3.84 (s, 3H);
(88) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14Br.sub.2N.sub.3O.sub.4].sup.+: 517.9351, Found 517.9350.
Example 21
(89) ##STR00642##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 184
(90) According to the synthetic procedure depicted in Scheme 1, 5-chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepares as follows:
(91) a) N′-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide: To a solution of 4-fluoro-3-nitrobenzoic acid (10.0 g, 54.0 mmol) in dichloromethane (50 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (6.9 ml, 81.0 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give acid chloride.
(92) This acid chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of 2-furoic acid hydrazide (6.9 g, 54.5 mmol) and anhydrous sodium carbonate (5.7 g, 54.0 mmol) in tetrahydrofuran (50 mL) and water (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and at room temperature for 6 hr. A massive precipitation was observed. The product was harvested by filtration and washed with water, then finally dried in vacuo to afford 14.4 g (91.0% yield) of N′-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide as a yellow solid.
(93) b) 2-(4-Fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole: N′-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide (14.4 g, 49.1 mmol) was dissolved in phosphorus oxychloride (70 ml) and the mixture was stirred with heating at 80° C. for 5 hr. Phosphorus oxychloride was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 12.5 g (92.6% yield) of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole as a yellow solid.
(94) c) 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline: A mixture of 2-(4-Fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole (12.5 g, 45.4 mmol) and Raney Ni (2.0 g) in methanol (100 ml) was stirred at 50° C. for 16 h under 2.0 Mpa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) gave 9.3 g (83.6% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline as a white solid.
(95) d) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide: A mixture of 5-chloro-2-methoxybenzoic acid (91.3 mg, 0.49 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (0.5 ml) was stirred with refluxing for 1 hr. The excess thionyl chloride was evaporated under reduced pressure to give acid chloride.
(96) This acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol) and triethylamine (57.8 mg, 0.57 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 12 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (154.9 mg, 91.8% yield) as a white solid.
(97) .sup.1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.92-8.90 (m, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.65-7.56 (m, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.85-6.83 (m, 1H), 4.01 (s, 3H);
(98) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14ClFN.sub.3O.sub.4].sup.+: 414.0657, Found 414.0658.
Example 22
(99) ##STR00643##
5-chloro-2-ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 216
(100) 5-Chloro-2-ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-ethoxybenzoic acid (98.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (159.6 mg, 91.5% yield) as a white solid.
(101) .sup.1H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 9.08 (d, J=9.6 Hz, 1H), 8.10 (s, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.86-7.82 (m, 1H), 7.64-7.55 (m, 2H), 7.44 (d, J=3.6 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 6.84-6.83 (m, 1H), 4.27 (q, J=6.8 Hz, 2H), 1.48 (t, J=6.8 Hz, 3H);
(102) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.16ClFN.sub.3O.sub.4].sup.+: 428.0813, Found 428.0812.
Example 23
(103) ##STR00644##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 128
(104) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 21, but from 2-methoxybenzoic acid (74.5 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (140.8 mg, 91.0% yield) as a white solid.
(105) .sup.1H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 9.01 (d, J=6.0 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.99 (d, J=6.4 Hz, 1H), 7.90-7.86 (m, 1H), 7.63-7.57 (m, 2H), 7.46 (d, J=3.2 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.85-6.83 (m, 1H), 4.03 (s, 3H);
(106) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.15FN.sub.3O.sub.4].sup.+: 380.1047, Found 380.1052.
Example 24
(107) ##STR00645##
5-Bromo-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide
Compound 183
(108) 5-Bromo-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 21, but from 5-bromo-2-methoxybenzoic acid (113.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (179.5 mg, 96.0% yield) as a white solid.
(109) .sup.1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.92-8.90 (m, 1H), 8.11 (d, J=1.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.93-7.89 (m, 1H), 7.77 (dd, J=2.4, 8.8 Hz, 1H), 7.60 (dd, J=8.8, 10.4 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.26 (d, J=9.2 Hz, 1H), 6.85-6.84 (m, 1H), 4.01 (s, 3H);
(110) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14BrFN.sub.3O.sub.4].sup.+: 458.0152, Found 458.0159.
Example 25
(111) ##STR00646##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide
Compound 300
(112) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide can be prepared as in Example 21, but from 2-methoxy-5-methylbenzoic acid (81.4 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (154.4 mg, 96.2% yield) as a white solid.
(113) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.03 (d, J=5.6 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.82 (s, 1H), 7.61 (dd, J=8.8, 10.4 Hz, 1H), 7.47 (d, J=3.2 Hz, 1H), 7.44-7.41 (m, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.86-6.84 (m, 1H), 4.01 (s, 3H), 2.33 (s, 3H);
(114) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.17FN.sub.3O.sub.4].sup.+: 394.1203, Found 394.1205.
Example 26
(115) ##STR00647##
2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 215
(116) 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-methoxy-5-methylbenzoic acid (81.4 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (150.1 mg, 93.5% yield) as a white solid.
(117) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.19 (d, J=5.6 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 8.09-8.06 (m, 1H), 7.88-7.84 (m, 1H), 7.63-7.59 (m, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18-7.14 (m, 1H), 6.85-6.84 (m, 1H), 4.31 (q, J=6.8 Hz, 2H), 1.51 (t, J=6.8 Hz, 3H);
(118) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.17FN.sub.3O.sub.4].sup.+: 394.1203, Found 394.1228.
Example 27
(119) ##STR00648##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 313
(120) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 2-(2,2,2-trifluoroethoxy)benzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (160.0 mg, 87.7% yield) as a white solid.
(121) .sup.1H NMR (400 MHz, DMSO): δ 10.10 (s, 1H), 8.93 (d, J=1.6 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.92-7.85 (m, 2H), 7.63-7.57 (m, 2H), 7.46 (d, J=3.2 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.25-7.22 (m, 1H), 6.85-6.84 (m, 1H), 4.98 (q, J=8.8 Hz, 2H);
(122) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14F.sub.4N.sub.3O.sub.4].sup.+: 448.0920, Found 448.0918.
Example 28
(123) ##STR00649##
2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 314
(124) 2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)benzoic acid (99.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (156.8 mg, 89.5% yield) as a white solid.
(125) .sup.1H NMR (400 MHz, DMSO): δ 10.16 (s, 1H), 8.99 (d, J=6.0 Hz, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.95 (d, J=6.4 Hz, H), 7.91-7.87 (m, 1H), 7.63-7.58 (m, 2H), 7.46 (d, J=3.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 6.85-6.84 (m, 1H), 6.50 (tt, J=3.2, 54.6 Hz, 1H), 4.58 (dt, J=3.2, 14.4 Hz, 2H);
(126) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.15F.sub.3N.sub.3O.sub.4].sup.+: 430.1015, Found 430.1007.
Example 29
(127) ##STR00650##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide
Compound 315
(128) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 2-(2-fluoroethoxy)benzoic acid (90.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (155.8 mg, 92.8% yield) as a white solid.
(129) .sup.1H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 9.12 (d, J=5.6 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J=6.8 Hz, H), 7.91-7.88 (m, 1H), 7.65-7.60 (m, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.23-7.19 (m, 1H), 6.86-6.85 (m, 1H), 4.98-4.96 (m, 1H), 4.86-4.84 (m, 1H), 4.59-4.57 (m, 1H), 4.51-4.50 (m, 1H);
(130) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.16F.sub.2N.sub.3O.sub.4].sup.+: 412.1109, Found 412.1095.
Example 30
(131) ##STR00651##
2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide
Compound 221
(132) 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 21, but from 2-ethoxy-5-methylbenzoic acid (88.3 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (151.8 mg, 91.3% yield) as a yellow solid.
(133) .sup.1H NMR (400 MHz, DMSO): δ 10.49 (d, J=2.0 Hz, 1H), 9.16 (dd, J=1.6, 3.4 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.82-7.78 (m, 1H), 7.58-7.53 (m, 1H), 7.43 (d, J=3.2 Hz, 1H), 7.37-7.35 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.84-6.83 (m, 1H), 4.24 (q, J=6.8 Hz, 2H), 2.92 (s, 3H), 1.48 (t, J=6.8 Hz, 1H);
(134) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.19FN.sub.3O.sub.4].sup.+: 408.1360, Found 408.1356.
Example 31
(135) ##STR00652##
2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 222
(136) 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-ethoxy-5-ethylbenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol).
(137) The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (159.2 mg, 92.6% yield) as a white solid.
(138) .sup.1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 9.19 (d, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.85-7.82 (m, 1H), 7.62-7.57 (m, 1H), 7.46-7.41 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.27 (q, J=6.8 Hz, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.49 (t, J=6.8 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H);
(139) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.21FN.sub.3O.sub.4].sup.+: 422.1516, Found 422.1520.
Example 32
(140) ##STR00653##
5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide
Compound 210
(141) 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 21, but from 5-fluoro-2-propoxybenzoic acid (97.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (171.0 mg, 98.5% yield) as a pale-yellow solid.
(142) .sup.1H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.11-9.09 (m, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.87-7.83 (m, 1H), 7.74 (dd, J=3.6, 9.2 Hz, 1H), 7.61-7.56 (m, 1H), 7.46-7.41 (m, 2H), 7.31-7.28 (m, 1H), 6.84-6.83 (m, 1H), 4.18 (t, J=6.6 Hz, 2H), 1.91-1.85 (m, 2H), 1.02 (t, J=7.2 Hz, 3H);
(143) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.18F.sub.2N.sub.3O.sub.4].sup.+: 426.1265, Found 426.1273.
Example 33
(144) ##STR00654##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide
Compound 209
(145) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 21, but from 5-chloro-2-propoxybenzoic acid (105.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (169.3 mg, 93.9% yield) as a pale-yellow solid.
(146) .sup.1H NMR (400 MHz, DMSO): δ 10.41 (d, J=1.6 Hz, 1H), 9.07 (dd, J=1.6, 7.2 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.93 (d, J=2.8 Hz, 1H), 7.89-7.85 (m, 1H), 7.64-7.58 (m, 2H), 7.45 (d, J=3.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.19 (t, J=6.4 Hz, 2H), 1.91-1.86 (m, 2H), 1.02 (t, J=7.2 Hz, 3H);
(147) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.18ClFN.sub.3O.sub.4].sup.+: 442.0970, Found 442.0961.
Example 34
(148) ##STR00655##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-propoxybenzamide
Compound 208
(149) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-propoxybenzamide can be prepared as in Example 21, but from 5-methyl-2-propoxybenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (165.2 mg, 96.1% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO): δ 10.48 (d, J=1.6 Hz, 1H), 9.16 (d, J=6.4 Hz, 1H), 8.11 (s, 1H), 7.86-7.83 (m, 2H), 7.62-7.57 (m, 1H), 7.45 (d, J=3.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.17 (t, J=6.4 Hz, 2H), 2.32 (s, 3H), 1.92-1.87 (m, 2H), 1.02 (t, J=7.4 Hz, 3H);
(150) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.21FN.sub.3O.sub.4].sup.+: 422.1516, Found 422.1519.
Example 35
(151) ##STR00656##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 316
(152) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2,2,2-trifluoroethoxy)benzoic acid (124.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (191.0 mg, 97.2% yield) as a white solid.
(153) .sup.1H NMR (400 MHz, DMSO): δ 10.24 (s, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.94-7.91 (m, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.68-7.65 (m, 1H), 7.62-7.57 (m, 1H), 7.46 (d, J=3.2 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 4.95 (q, J=8.8 Hz, 2H);
(154) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.13ClF.sub.4N.sub.3O.sub.4].sup.+: 482.0531, Found 482.0518.
Example 36
(155) ##STR00657##
5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide
Compound 319
(156) 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 5-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (116.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (178.5 mg, 94.0% yield) as a white solid.
(157) .sup.1H NMR (400 MHz, DMSO): δ 10.22 (s, 1H), 8.88 (d, J=6.4 Hz, 1H), 8.11 (s, 1H), 7.94-7.91 (m, 1H), 7.63-7.58 (m, 2H), 7.50-7.45 (m, 2H), 7.39-7.36 (m, 1H), 6.85-6.84 (m, 1H), 4.94 (q, J=8.8 Hz, 2H);
(158) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.13F.sub.5N.sub.3O.sub.4].sup.+: 466.0826, Found 466.0812.
Example 37
(159) ##STR00658##
2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide
Compound 323
(160) 2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)-5-methylbenzoic acid (105.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (163.2 mg, 90.2% yield) as a white solid.
(161) .sup.1H NMR (400 MHz, DMSO): δ 10.15 (s, 1H), 9.00 (d, J=6.0 Hz, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.77 (s, 1H), 7.63-7.58 (m, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.42 (dd, J=1.6, 8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 6.49 (tt, J=3.2, 14.4 Hz, 1H), 4.54 (dt, J=2.8, 14.0 Hz, 2H), 2.34 (s, 3H);
(162) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.17F.sub.3N.sub.3O.sub.4].sup.+: 444.1171, Found 444.1170.
Example 38
(163) ##STR00659##
5-Chloro-2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 317
(164) 5-Chloro-2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2,2-difluoroethoxy)benzoic acid (115.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (169.5 mg, 89.6% yield) as a white solid.
(165) .sup.1H NMR (400 MHz, DMSO): δ 10.22 (s, 1H), 8.93-8.90 (m, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.93-7.90 (m, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.66 (dd, J=2.8, 8.8 Hz, 1H), 7.61 (dd, J=8.8, 10.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.36 (d, J=9.2 Hz, 1H), 6.85-6.84 (m, 1H), 6.47 (tt, J=3.2, 14.4 Hz, 1H), 4.56 (dt, J=3.2, 14.4 Hz, 2H);
(166) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14ClF.sub.3N.sub.3O.sub.4].sup.+: 464.0625, Found 464.0632.
Example 39
(167) ##STR00660##
2-(2,2-Difluoroethoxy)-5-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 320
(168) 2-(2,2-Difluoroethoxy)-5-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)-5-fluorobenzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (172.5 mg, 94.5% yield) as a white solid.
(169) .sup.1H NMR (400 MHz, DMSO): δ 10.24 (s, 1H), 8.96-8.94 (m, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.69 (d, J=3.2, 7.2 Hz, 1H), 7.64-7.59 (m, 1H), 7.51-7.46 (m, 2H), 7.39-7.36 (m, 1H), 6.85-6.84 (m, 1H), 6.47 (tt, J=3.2, 14.4 Hz, 1H), 4.56 (dt, J=3.2, 14.4 Hz, 2H);
(170) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14F.sub.4N.sub.3O.sub.4].sup.+: 448.0920, Found 448.0915.
Example 40
(171) ##STR00661##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide
Compound 318
(172) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2-fluoroethoxy)benzoic acid (107.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (164.6 mg, 90.5% yield) as a white solid.
(173) .sup.1H NMR (400 MHz, DMSO): δ 10.37 (s, 1H), 9.04-9.01 (m, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.92-7.89 (m, 1H), 7.67 (dd, J=2.8, 8.8 Hz, 1H), 7.62 (dd, J=8.8, 10.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 6.85-6.84 (m, 1H), 4.94-4.92 (m, 1H), 4.82-4.80 (m, 1H), 4.57-4.55 (m, 1H), 4.49-4.76 (m, 1H);
(174) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.15ClF.sub.2N.sub.3O.sub.4].sup.+: 446.0719, Found 446.0716.
Example 41
(175) ##STR00662##
2-(Difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 302
(176) 2-(Difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(difluoromethoxy)benzoic acid (92.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (150.6 mg, 88.9% yield) as a white solid.
(177) .sup.1H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 8.72 (d, J=6.0 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.95-7.91 (m, 1H), 7.76 (d, J=6.8 Hz, 1H), 7.65-7.56 (m, 2H), 7.46-7.39 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.26 (t, J=73.2 Hz, 1H), 6.84-6.83 (m, 1H);
(178) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.13F.sub.3N.sub.3O.sub.4].sup.+: 416.0858, Found 416.0825.
Example 42
(179) ##STR00663##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-propylbenzamide
Compound 281
(180) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-propylbenzamide can be prepared as in Example 21, but from 2-methoxy-5-propylbenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (146.7 mg, 85.3% yield) as a white solid.
(181) .sup.1H NMR (400 MHz, DMSO): δ 10.46 (d, J=1.2 Hz, 1H), 9.03 (d, J=5.6 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.89-7.86 (m, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.62-7.57 (m, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.43 (dd, J=2.0, 8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.01 (s, 3H), 2.58 (t, J=7.6 Hz, 2H), 1.64-1.55 (m, 2H), 0.90 (t, J=7.2 Hz, 3H);
(182) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.21FN.sub.3O.sub.4].sup.+: 422.1516, Found 422.1518.
Example 43
(183) ##STR00664##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide
Compound 301
(184) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide can be prepared as in Example 21, but from 2-(trifluoromethoxy)benzoic acid (101.0 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (160.5 mg, 90.8% yield) as a white solid.
(185) .sup.1H NMR (400 MHz, DMSO): δ 10.61 (s, 1H), 8.57 (d, J=6.0 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.81-7.79 (m, 1H), 7.71-7.67 (m, 1H), 7.62-7.55 (m, 3H), 7.46 (d, J=3.2 Hz, 1H), 6.85-6.84 (m, 1H);
(186) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.12F.sub.4N.sub.3O.sub.4].sup.+: 434.0764, Found 434.0748.
Example 44
(187) ##STR00665##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide
Compound 304
(188) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide can be prepared as in Example 21, but from 2-(trifluoromethoxy)benzoic acid (117.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (180.7 mg, 94.7% yield) as a white solid.
(189) .sup.1H NMR (400 MHz, DMSO): δ 10.73 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.99-7.95 (m, 1H), 7.92 (d, J=3.2 Hz, 1H), 7.77-7.75 (m, 1H), 7.62-7.58 (m, 2H), 7.46 (d, J=3.2 Hz, 1H), 6.85-6.84 (m, 1H);
(190) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.11ClF.sub.4N.sub.3O.sub.4].sup.+: 468.0374, Found 468.0402.
Example 45
(191) ##STR00666##
5-Chloro-2-(difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 305
(192) 5-Chloro-2-(difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-(difluoromethoxy)benzoic acid (109.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (170.4 mg, 92.9% yield) as a pale-yellow solid.
(193) .sup.1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.73-8.70 (m, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.96-7.92 (m, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.69 (dd, J=2.8, 8.8 Hz, 1H), 7.62-7.57 (m, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.26 (t, J=73.2 Hz, 1H), 6.85-6.84 (m, 1H);
(194) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.12ClF.sub.3N.sub.3O.sub.4].sup.+: 450.0468, Found 450.0468.
Example 46
(195) ##STR00667##
5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(fluoromethoxy)benzamide
Compound 306
(196) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(fluoromethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(fluoromethoxy)benzoic acid (100.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (155.6 mg, 88.3% yield) as a yellow solid.
(197) .sup.1H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 8.75-8.73 (m, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.66 (dd, J=2.8, 8.8 Hz, 1H), 7.61-7.57 (m, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.85-6.84 (m, 1H), 6.04 (s, 1H), 5.90 (s, 1H);
(198) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.13ClF.sub.2N.sub.3O.sub.4].sup.+: 432.0563, Found 432.0555.
Example 47
(199) ##STR00668##
5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide
Compound 312
(200) 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 5-fluoro-2-(2-fluoroethoxy)benzoic acid (99.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (168.4 mg, 96.2% yield) as a white solid.
(201) .sup.1H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 9.06 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 7.91-7.87 (m, 1H), 7.76 (dd, J=2.4, 9.2 Hz, 1H), 7.64-7.59 (m, 1H), 7.52-7.46 (m, 2H), 7.37-7.33 (m, 1H), 6.85-6.84 (m, 1H), 4.94-4.92 (m, 1H), 4.82-4.80 (m, 1H), 4.56-4.54 (m, 1H), 4.49-4.47 (m, 1H);
(202) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.15F.sub.3N.sub.3O.sub.4].sup.+: 430.1015, Found 430.1017.
Example 48
(203) ##STR00669##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)-5-methylbenzamide
Compound 321
(204) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)-5-methylbenzamide can be prepared as in Example 21, but from 2-(2-fluoroethoxy)-5-methylbenzoic acid (97.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (170.2 mg, 98.1% yield) as a white solid.
(205) .sup.1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 9.12 (d, J=5.6 Hz, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.88-7.86 (m, 2H), 7.60 (dd, J=8.8, 10.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.42 (dd, J=2.0, 8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.95-4.93 (m, 1H), 4.83-4.81 (m, 1H), 4.55-4.53 (m, 1H), 4.47-4.45 (m, 1H), 2.33 (s, 3H);
(206) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.18F.sub.2N.sub.3O.sub.4].sup.+: 426.1265, Found 426.1277.
Example 49
(207) ##STR00670##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide
Compound 405
(208) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 20, but from 2-methoxy-5-(trifluoromethoxy)benzoic acid (115.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (170.3 mg, 90.1% yield) as a white solid.
(209) .sup.1H NMR (400 MHz, DMSO): δ 10.45 (s, 1H), 8.93 (d, J=6.8 Hz, 1H), 8.11 (s, 1H), 7.94-7.91 (m, 1H), 7.84 (s, 1H), 7.67-7.59 (m, 2H), 7.47 (d, J=3.6 Hz, 1H), 7.40 (d, J=9.2 Hz, 1H), 6.85-6.84 (m, 1H), 4.04 (s, 3H);
(210) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14F.sub.4N.sub.3O.sub.5].sup.+: 464.0870, Found 464.0865.
Example 50
(211) ##STR00671##
N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide
Compound 416
(212) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 21, but from 2-methoxy-5-(trifluoromethyl)benzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (179.1 mg, 98.1% yield) as a white solid.
(213) .sup.1H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 8.89 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.97-7.91 (m, 2H), 7.63-7.59 (m, 1H), 7.48-7.46 (m, 2H), 6.85-6.84 (m, 1H), 4.07 (s, 3H);
(214) LC-HRMS (ESI) calcd for [M+H, C.sub.21H.sub.14F.sub.4N.sub.3O.sub.4].sup.+: 448.0920, Found 448.0913.
Example 51
(215) ##STR00672##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-(2,2,2-trifluoroethoxy)benzamide
Compound 322
(216) N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 21, but from 5-methyl-2-(2,2,2-trifluoroethoxy)benzoic acid (114.6 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (173.7 mg, 92.3% yield) as a white solid.
(217) 1H NMR (400 MHz, DMSO): δ 10.07 (s, 1H), 8.93 (d, J=5.6 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.68 (s, 1H), 7.61-7.56 (m, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.42-7.40 (m, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.94 (q, J=8.8 Hz, 1H), 2.34 (s, 3H); LC-HRMS (ESI) calcd for [M+H, C22H16F4N3O4]+: 462.1077, Found 462.1070.
Example 52
(218) ##STR00673##
2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide
Compound 39
(219) According to the synthetic procedure depicted in Scheme 2, 2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide can be prepares as follows:
(220) a) Methyl 2-(2-fluorobenzamido)isonicotinate: To a stirred solution of methyl 2-aminoisonicotinate (1.0 g, 6.6 mmol), 2-fluorobenzoic acid (1.0 g, 7.3 mmol) and N,N-diisopropylethylamine (2.5 g, 19.7 mmol) in dichloromethane (50 ml) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 6.8 g, 13.1 mmol). The solution was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=4/1) to 256.4 mg (14.2% yield) of methyl 2-(2-fluorobenzamido)isonicotinate as a white solid.
(221) b) 2-(2-Fluorobenzamido)isonicotinic acid: To a solution of methyl 2-(2-fluorobenzamido)isonicotinate (256.4 mg, 0.93 mmol) in tetrahydrofuran (5 mL) was added 0.5 M lithium hydroxide solution (5 mL). The solution was stirred at room temperature for 12 hr. After concentration, the remained concentrated solution was acidified to pH 1 by adding 1 N hydrochloric acid. A massive precipitation was observed. The product was harvested by filtration and washed with water, then finally dried in vacuo to afford 180.5 mg (74.6% yield) of 2-(2-fluorobenzamido)isonicotinic acid as a white solid.
(222) c) 2-Fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide: To a stirred solution of 2-(2-fluorobenzamido)isonicotinic acid (180.5 mg, 0.69 mmol), 2-furoic acid hydrazide (91.6 mg, 0.73 mmol) and N,N-diisopropylethylamine (267.5 mg, 2.07 mmol) in dichloromethane (10 ml) was added PyBop (468.4 mg, 0.90 mmol). The solution was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to 206.8 mg (81.4% yield) of 2-fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide as a white solid.
(223) d) 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide: 2-Fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide (206.8 mg, 0.56 mmol) was dissolved in phosphorus oxychloride (2 ml) and the mixture was stirred with heating at 80° C. for 5 hr. Phosphorus oxychloride was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) to give the title compound (82.5 mg, 42.1% yield) as a pale-yellow solid.
(224) .sup.1H NMR (400 MHz, DMSO): δ 11.20 (s, 1H), 8.86 (s, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 7.79 (d, J=4.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.64-7.59 (m, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.39-7.33 (m, 2H), 6.87-6.86 (m, 1H); LC-HRMS (ESI) calcd for [M+H, C.sub.18H.sub.12FN.sub.4O.sub.3].sup.+: 351.0893, Found 351.0898.
Example 53
(225) ##STR00674##
2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide
Compound 373
(226) According to the synthetic procedure depicted in Scheme 2, 2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide can be prepares as follows:
(227) a) Methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate: A mixture of 2-ethoxy-5-ethylbenzoic acid (1.4 g, 7.23 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (5 ml) was stirred with refluxing for 2 hr. The excess thionyl chloride was evaporated under reduced pressure to give acid chloride.
(228) This acid chloride was dissolved in dichloromethane (20 ml) and added dropwise to a solution of methyl 2-aminoisonicotinate (1.0 g, 6.6 mmol) and pyridine (0.69 ml, 8.54 mmol) in dichloromethane (50 ml) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 12 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=4/1) to afford 1.96 g (90.5% yield) of methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate as a pale-yellow solid.
(229) b) 2-(2-Ethoxy-5-ethylbenzamido)isonicotinic acid: By the reaction in the same manner as in Example 52 using methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate (1.96 g, 5.97 mmol), 1.38 g (73.5% yield) of 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid was obtained as a white solid.
(230) c) 2-Ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide: By the reaction in the same manner as in Example 52 using 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid (1.38 g, 4.39 mmol), 2-furoic acid hydrazide (0.58 g, 4.61 mmol), N,N-diisopropylethylamine (1.7 g, 13.17 mmol) and PyBop (2.97 g, 5.71 mmol), 1.52 g (82.0% yield) of 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide was obtained as a white solid.
(231) d) 2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide: By the reaction in the same manner as in Example 52 using 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide (1.52 g, 3.60 mmol), 0.76 g (52.2% yield) of the title compound was obtained as a white solid.
(232) .sup.1H NMR (400 MHz, DMSO): δ 10.94 (s, 1H), 8.94 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.77 (d, J=5.6 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.88-6.87 (m, 1H), 4.29 (q, J=6.8 Hz, 2H), 2.64 (q, J=7.6, Hz, 2H), 1.50 (t, J=6.8, 3H), 1.20 (t, J=7.6 Hz, 3H); LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.21N.sub.4O.sub.4].sup.+: 405.1563, Found 405.1545.
Example 54
(233) ##STR00675##
N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide
Compound 396
(234) N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 2-methoxy-5-(trifluoromethyl)benzoic acid (0.32 g, 1.44 mmol). 85.6 mg of the title compound was obtained as a white solid.
(235) .sup.1H NMR (400 MHz, DMSO): δ 10.92 (s, 1H), 8.89 (s, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 6.87-6.86 (m, 1H), 4.03 (s, 3H);
(236) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14F.sub.3N.sub.4O.sub.4].sup.+: 431.0967, Found 431.0960.
Example 55
(237) ##STR00676##
N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethoxy)benzamide
Compound 400
(238) N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 2-methoxy-5-(trifluoromethoxy)benzoic acid (0.34 g, 1.44 mmol). 105.3 mg of the title compound was obtained as a white solid.
(239) .sup.1H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 8.89 (s, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.15 (s, 1H), 7.81-7.77 (m, 2H), 7.63-7.60 (m, 1H), 7.54-7.53 (m, 1H), 7.37 (d, J=9.2 Hz, 1H), 6.88-6.87 (m, 1H), 4.01 (s, 3H);
(240) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14F.sub.3N.sub.4O.sub.5].sup.+: 447.0916, Found 447.0911.
Example 56
(241) ##STR00677##
5-Chloro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxybenzamide
Compound 372
(242) 5-Chloro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxybenzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 5-chloro-2-methoxybenzoic acid (0.27 g, 1.44 mmol). 127.0 mg of the title compound was obtained as a pale-yellow solid;
(243) .sup.1H NMR (400 MHz, DMSO): δ 10.83 (s, 1H), 8.61 (d, J=0.8 Hz, 1H), 8.14 (s, 1H), 7.80-7.77 (m, 2H), 7.63-7.61 (m, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 6.87-6.86 (m, 1H), 3.97 (s, 3H);
(244) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.14ClN.sub.4O.sub.4].sup.+: 397.0704, Found 397.0689.
Example 63
(245) ##STR00678##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(3-hydroxypropyl)-2-methoxybenzamide
Compound 483
(246) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(3-hydroxypropyl)-2-methoxybenzamide
(247) can be prepared as in example 1, but from 5-(3-hydroxypropyl)-2-methoxybenzoic acid (105.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (143.0 mg, 65.4% yield) as a yellow solid.
(248) .sup.1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.04 (d, J=6.0 Hz, 1H), 8.12 (s, 1H), 7.92-7.86 (m, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.66-7.56 (m, 1H), 7.47 (d, J=3.5 Hz, 1H), 7.44 (dd, J=8.5, 1.9 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.85 (dd, J=3.4, 1.6 Hz, 1H), 4.49 (t, J=5.0 Hz, 1H), 4.02 (s, 3H), 3.43 (dd, J=11.3, 6.1 Hz, 2H), 2.70-2.59 (m, 2H), 1.78-1.67 (m, 2H);
(249) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.21FN.sub.3O.sub.5].sup.+: 438.1460, Found 438.1461.
Example 64
(250) ##STR00679##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-methoxypropyl)benzamide
Compound 484
(251) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-methoxypropyl)benzamide can be prepared as in example 1, but from 2-methoxy-5-(3-methoxypropyl)benzoic acid (112.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (167.4 mg, 74.2% yield) as a yellow solid.
(252) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.52 (d, J=3.0 Hz, 1H), 9.34 (dd, J=7.3, 2.1 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 7.94 (ddd, J=8.5, 4.9, 2.2 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.37 (dd, J=8.4, 2.4 Hz, 1H), 7.31-7.25 (m, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.63 (dd, J=3.5, 1.7 Hz, 1H), 4.23 (t, J=6.2 Hz, 2H), 4.09 (s, 3H), 3.03 (s, 3H), 2.80 (t, J=7.5 Hz, 2H), 2.18-2.05 (m, 2H);
(253) LC-HRMS (ESI) calcd for [M+H, C.sub.24H.sub.23FN.sub.3O.sub.5].sup.+: 452.1616, Found 452.1618.
Example 65
(254) ##STR00680##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-(piperidin-1-yl)propyl)benzamide
Compound 495
(255) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-(piperidin-1-yl)propyl)benzamide can be prepared as in example 1, but from 2-methoxy-5-(3-(piperidin-1-yl)propyl) benzoic acid (138.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (68.6 mg, 27.2% yield) as a yellow solid.
(256) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.49 (d, J=3.0 Hz, 1H), 9.31 (dd, J=7.3, 1.8 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.93-7.83 (m, 1H), 7.68 (d, J=0.7 Hz, 1H), 7.42 (dd, J=8.4, 2.1 Hz, 1H), 7.30-7.20 (m, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.63 (dd, J=3.4, 1.7 Hz, 1H), 4.07 (s, 3H), 3.13-2.94 (m, 4H), 2.92-2.85 (m, 2H), 2.73 (t, J=7.4 Hz, 2H), 2.28-2.17 (m, 2H), 2.10-1.89 (m, 4H), 1.72-1.54 (m, 2H);
(257) LC-HRMS (ESI) calcd for [M+H, C.sub.28H.sub.30FN.sub.4O.sub.4].sup.+: 505.2246, Found 505.2241.
Example 66
(258) ##STR00681##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-morpholinopropyl)benzamide
Compound 496
(259) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-morpholinopropyl)benzamide can be prepared as in example 1, but from 2-methoxy-5-(3-morpholinopropyl)benzoic acid (139.6 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (105.8 mg, 41.8% yield) as a yellow solid.
(260) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.54 (s, 1H), 9.36 (d, J=5.4 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.68 (s, 1H), 7.36 (dd, J=8.4, 2.2 Hz, 1H), 7.32-7.26 (m, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.66-6.60 (m, 1H), 4.09 (s, 3H), 3.78-3.71 (m, 4H), 2.69 (t, J=7.6 Hz, 2H), 2.53-2.42 (m, 4H), 2.41-2.32 (m, 2H), 1.85 (dt, J=15.0, 7.6 Hz, 2H); LC-HRMS (ESI) calcd for [M+H, C.sub.27H.sub.28FN.sub.4O.sub.5].sup.+: 507.2038, Found 507.2033.
Example 67
(261) ##STR00682##
2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 35
(262) 2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.1 mg, 0.5 mmol) and 4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (113.2 mg, 64.8% yield) as a yellow solid.
(263) .sup.1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.13-8.04 (m, 3H), 8.01-7.95 (m, 2H), 7.75-7.68 (m, 1H), 7.65-7.56 (m, 1H), 7.43 (d, J=3.5 Hz, 1H), 7.41-7.32 (m, 2H), 6.83 (dd, J=3.4, 1.7 Hz, 1H);
(264) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.13FN.sub.3O.sub.3].sup.+: 350.0935, Found 350.0939.
Example 69
(265) ##STR00683##
2-ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)nicotinamide
Compound 485
(266) 2-ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)nicotinamide can be prepared as in example 1, but from 2-ethoxy-5-ethylnicotinic acid (97.6 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (137.2 mg, 65.0% yield) as a yellow solid.
(267) .sup.1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.20-9.08 (m, 1H), 8.32-8.19 (m, 2H), 8.14-8.07 (m, 1H), 7.94-7.81 (m, 1H), 7.67-7.57 (m, 1H), 7.50-7.40 (m, 1H), 6.89-6.80 (m, 1H), 4.63-4.42 (m, 2H), 2.72-2.61 (m, 2H), 1.54-1.38 (m, 3H), 1.30-1.12 (m, 3H);
(268) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.20FN.sub.4O.sub.4].sup.+: 423.1463, Found 423.1463.
Example 70
(269) ##STR00684##
5-chloro-N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxynicotinamide
Compound 486
(270) 5-chloro-N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxynicotinamide can be prepared as in example 1, but from 5-chloro-2-methoxynicotinic acid (93.8 mg, 0.5 mmol) and 2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl) aniline (123.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (102.3 mg, 49.2% yield) as a yellow solid.
(271) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.42 (s, 1H), 9.31 (dd, J=7.3, 2.1 Hz, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.31 (d, J=2.6 Hz, 1H), 8.13 (s, 1H), 8.02-7.96 (m, 1H), 7.93 (s, 1H), 7.33 (dd, J=10.3, 8.7 Hz, 1H), 4.23 (s, 3H);
(272) LC-HRMS (ESI) calcd for [M+H, C.sub.18H.sub.12ClFN.sub.5O.sub.4].sup.+: 416.0556, Found 416.0557.
Example 71
(273) ##STR00685##
N-(3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide
Compound 298
(274) N-(3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl) aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (87.6 mg, 50.2% yield) as a yellow solid.
(275) .sup.1H NMR (400 MHz, DMSO) δ 13.69 (s, 1H), 10.75 (s, 1H), 8.58 (s, 1H), 8.05-8.02 (m, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.3 Hz, 1H), 7.65-7.58 (m, 2H), 7.43-7.32 (m, 2H), 6.98 (t, J=2.0 Hz, 1H);
(276) LC-HRMS (ESI) calcd for [M+H, C.sub.18H.sub.13FN.sub.5O.sub.2].sup.+: 350.1048, Found 350.1042.
Example 72
(277) ##STR00686##
2-fluoro-N-(3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 15
(278) 2-fluoro-N-(3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) aniline (121.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (94.5 mg, 51.6% yield) as a yellow solid.
(279) .sup.1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.56 (s, 1H), 8.01-7.94 (m, 2H), 7.92 (d, J=3.3 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.66-7.56 (m, 2H), 7.43-7.30 (m, 3H);
(280) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.13FN.sub.3O.sub.2S].sup.+: 366.0707, Found 366.0701.
Example 73
(281) ##STR00687##
2-fluoro-N-(3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 20
(282) 2-fluoro-N-(3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl) aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (123.1 mg, 70.5% yield) as a yellow solid.
(283) .sup.1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.00-7.96 (m, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.4 Hz, 1H), 7.65-7.57 (m, 2H), 7.42-7.32 (m, 2H), 7.08 (d, J=1.0 Hz, 1H);
(284) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.13FN.sub.3O.sub.3].sup.+: 350.0935, Found 350.0938.
Example 74
(285) ##STR00688##
2-fluoro-N-(3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 22
(286) 2-fluoro-N-(3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl) aniline (115.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (108.5 mg, 61.2% yield) as a yellow solid.
(287) .sup.1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 8.49 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.79-7.68 (m, 2H), 7.65-7.56 (m, 2H), 7.42-7.29 (m, 2H), 5.33-5.19 (m, 1H), 3.98-3.81 (m, 2H), 2.41-2.26 (m, 2H), 2.13-1.91 (m, 2H);
(288) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.17FN.sub.3O.sub.3].sup.+: 354.1248, Found 354.1241.
Example 75
(289) ##STR00689##
N-(3-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide
Compound 289
(290) N-(3-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-ethyl-1,3,4-oxadiazol-2-yl) aniline (94.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (65.3 mg, 42.0% yield) as a yellow solid.
(291) .sup.1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.49 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.76-7.68 (m, 2H), 7.65-7.54 (m, 2H), 7.44-7.27 (m, 2H), 2.96 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.5 Hz, 3H);
(292) LC-HRMS (ESI) calcd for [M+H, C.sub.17H.sub.15FN.sub.3O.sub.2].sup.+: 312.1143, Found 312.1146.
Example 76
(293) ##STR00690##
2-fluoro-N-(2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 290
(294) 2-fluoro-N-(2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl) aniline (131.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (125.7 mg, 65.4% yield) as a yellow solid.
(295) .sup.1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.44 (s, 1H), 8.75 (d, J=0.5 Hz, 1H), 8.64 (d, J=6.0 Hz, 1H), 8.00 (ddd, J=8.5, 4.6, 2.2 Hz, 1H), 7.82-7.75 (m, 1H), 7.67-7.55 (m, 2H), 7.38 (dd, J=15.6, 8.0 Hz, 2H).
(296) LC-HRMS (ESI) calcd for [M+H, C.sub.18H.sub.11F.sub.2N.sub.4O.sub.2S].sup.+: 385.0565, Found 385.0565.
Example 77
(297) ##STR00691##
2-fluoro-N-(2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide
Compound 79
(298) 2-fluoro-N-(2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (118.6 mg, 64.6% yield) as a yellow solid.
(299) .sup.1H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 8.12 (s, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.94 (t, J=6.5 Hz, 1H), 7.77 (t, J=6.9 Hz, 1H), 7.63 (dd, J=13.4, 5.8 Hz, 1H), 7.52-7.44 (m, 2H), 7.43-7.29 (m, 2H), 6.85 (dd, J=3.5, 1.7 Hz, 1H).
(300) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.12F.sub.2N.sub.3O.sub.3].sup.+: 368.0841, Found 368.0849.
(301) Scheme 3 below shows the general synthesis followed to prepare some compounds according to the invention:
(302) ##STR00692##
(303) The following compounds were made according to this method:
Example 57
(304) ##STR00693##
N-(5-chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzamide
Compound 479
(305) According to the synthetic procedure depicted in Scheme 3, N-(5-chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzamide can be prepared as the following:
(306) A:
Methyl 2-fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl)benzoate
(307) To a solution of 4-fluoro-3-(methoxycarbonyl)benzoic acid (1.98 g, 10 mmol) in dichloromethane (20 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give acid chloride. This acid chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise to a suspension of furan-2-carbohydrazide (1.3 g, 10 mmol) and anhydrous sodium carbonate (1.1 g, 10 mmol) in tetrahydrofuran (10 mL) and water (10 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and at room temperature for 6 hr. A massive precipitation was observed. The product was harvested by filtration and washed with water, then finally dried in vacuo to afford 2.5 g (81.7% yield) of Methyl 2-fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl) benzoate as a white solid.
(308) B:
Methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate
(309) Methyl 2-fluoro-5-(2-(furan-2-carbonyl) hydrazine-1-carbonyl)benzoate (2.5 g, 8.2 mmol) was dissolved in phosphorus oxychloride (40 ml) and the mixture was stirred with heating at 100° C. for 5 hr. Phosphorus oxychloride was evaporated under reduced pressure and water was added to the residue. A massive precipitation was observed. The product was harvested by filtration and washed with water, then dried in vacuo to afford 1.8 g (76.4% yield) of Methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate.
(310) C:
2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid
(311) Methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate (1.8 g, 6.2 mmol) was dissolved in methanol (20 ml) and water (20 ml) were added LiOH (0.7 g, 31.2 mmol), and the mixture was stirred at room temperature for 8 hr. Thereafter, the reaction liquid was neutralized with 2N hydrochloric acid. The resulting white solid was filtered and washed with water, then finally dried in vacuo to afford 1.0 g (58.5% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzoic acid.
(312) D:
N-(5-chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
(313) 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137 mg, 0.5 mmol) in dichloromethane (10 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give acid chloride. This acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 5-chloro-2-fluoroaniline (72.8 mg, 0.5 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 12 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (106 mg, 52.8% yield) as a light yellow solid.
(314) .sup.1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.52-8.36 (m, 1H), 8.33-8.22 (m, 1H), 8.12 (s, 1H), 8.08-7.95 (m, 1H), 7.66 (t, J=9.2 Hz, 1H), 7.51 (d, J=3.1 Hz, 1H), 7.46-7.25 (m, 2H), 6.91-6.80 (m, 1H);
(315) LC-HRMS (ESI), calcd for [M+H, C.sub.19H.sub.11ClF.sub.2N.sub.3O.sub.3].sup.+: 402.0452, Found 402.0456.
Example 58
(316) ##STR00694##
N-(5-chloro-2-methoxyphenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 480
(317) N-(5-chloro-2-methoxyphenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzamide can be prepared as in example 57, but from 5-chloro-2-methoxyaniline (78.8 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (103.0 mg, 49.8% yield) as a yellow solid.
(318) .sup.1H NMR (400 MHz, DMSO) δ 9.87 (d, J=5.7 Hz, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.32-8.24 (m, 1H), 8.23-8.18 (m, 1H), 8.14-8.05 (m, 1H), 7.64 (t, J=9.6 Hz, 1H), 7.50 (d, J=3.4 Hz, 1H), 7.23 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.87-6.81 (m, 1H), 3.88 (s, 3H);
(319) LC-HRMS (ESI) calcd for [M+H, C.sub.20H.sub.14ClFN.sub.3O.sub.4].sup.+: 414.0651, Found 414.0658.
Example 59
(320) ##STR00695##
N-(2-fluorophenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 44
(321) N-(2-fluorophenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in example 57, but from 2-fluoroaniline (55.6 mg, 0.5 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzoic acid (128.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (85.7 mg, 49.1% yield) as a yellow solid.
(322) .sup.1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.65 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 8.11 (s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.50 (d, J=3.5 Hz, 1H), 7.38-7.19 (m, 3H), 6.85 (dd, J=3.4, 1.6 Hz, 1H);
(323) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.13FN.sub.3O.sub.3].sup.+: 350.0935, Found 350.0938.
Example 60
(324) ##STR00696##
N-(5-chloro-2-methoxypyridin-3-yl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 481
(325) N-(5-chloro-2-methoxypyridin-3-yl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in example 57, but from 5-chloro-2-methoxypyridin-3-amine (79.3 mg, 0.5 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (128.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (110 mg, 53.0% yield) as a yellow solid.
(326) .sup.1H NMR (400 MHz, DMSO) δ 9.99 (d, J=9.1 Hz, 1H), 8.52 (dd, J=7.0, 2.2 Hz, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.35-8.30 (m, 1H), 8.12 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.70 (dd, J=11.0, 8.8 Hz, 1H), 7.51 (d, J=3.4 Hz, 1H), 6.86 (dd, J=3.5, 1.7 Hz, 1H), 3.55 (s, 3H);
(327) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.13ClFN.sub.4O.sub.4].sup.+: 415.0604, Found 415.0609.
Example 61
(328) ##STR00697##
5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2-methoxypyridin-3-yl)-2-fluorobenzamide
Compound 482
(329) 5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2-methoxypyridin-3-yl)-2-fluorobenzamide can be prepared as in example 57, but from 5-chloro-2-methoxypyridin-3-amine (79.3 mg, 0.5 mmol) and 5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzoic acid (136.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (120 mg, 58.0% yield) as a yellow solid.
(330) .sup.1H NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 9.96 (d, J=8.5 Hz, 1H), 8.53 (d, J=5.9 Hz, 1H), 8.44-8.36 (m, 1H), 8.34-8.24 (m, 1H), 7.84 (s, 1H), 7.68 (t, J=9.8 Hz, 1H), 7.22-7.07 (m, 1H), 7.00-6.87 (m, 1H), 6.31 (s, 1H), 3.54 (s, 3H).
(331) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.14ClFN.sub.5O.sub.3].sup.+: 414.0764, Found 414.0767.
(332) Scheme 4 below shows the general synthesis followed to prepare some compounds according to the invention:
(333) ##STR00698##
(334) The following compounds were made according to this method:
Example 62
(335) ##STR00699##
2-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide
Compound 325
(336) According to the synthetic procedure depicted in Scheme 4, 2-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide can be prepared as the following:
(337) A:
N′-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide
(338) To a solution of 4-fluoro-3-nitrobenzoic acid (1.85 g, 10 mmol) in dichloromethane (20 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give acid chloride. This acid chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise to a suspension of 2-furoic acid hydrazide (1.3 g, 10 mmol) and sodium carbonate (1.1 g, 10 mmol) in tetrahydrofuran (10 mL) and water (10 mL) at 0° C. The mixture was stirred at 0° C. for 1 hr, and at room temperature for 6 hrs. A massive precipitation was observed. The product was harvested by filtration and washed with water, then finally dried in vacuo to afford 2.3 g (78.5% yield) of N′-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.
(339) B:
2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-thiadiazole
(340) N′-(4-fluoro-3-nitrobenzoyl) furan-2-carbohydrazide (2.3 g, 7.8 mmol), Lawesson's reagent (4.8 g, 11.8 mmol) was dissolved in toluene (40 ml) and the mixture was stirred at 110° C. for 12 hrs. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (Hexane/Ethyl acetate=10/1) to give the title compound (1.4 g, 61.2% yield) as a yellow solid.
(341) C:
2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl) aniline
(342) A mixture of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-thiadiazole (1.4 g, 4.8 mmol) and Raney-Ni (0.3 g) in methanol (30 ml) was stirred at 50° C. for 16 hrs under 2.0 Mpa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) to give the title compound (1.0 g, 79.6% yield) as a yellow solid.
(343) D:
2-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide
(344) 2-fluorobenzoic acid (140 mg, 1 mmol) in dichloromethane (10 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (2.6 ml, 30 mmol), and the mixture was stirred at room temperature for 4 hrs. The solvent was evaporated under reduced pressure to give acid chloride. This acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl) aniline (261.2 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred at this temperature for 12 hrs. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (215 mg, 56.1% yield) as a light yellow solid.
(345) .sup.1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.59 (d, J=5.8 Hz, 1H), 8.06 (s, 1H), 7.94-7.84 (m, 1H), 7.78 (t, J=7.1 Hz, 1H), 7.63 (dd, J=13.4, 6.2 Hz, 1H), 7.58-7.49 (m, 1H), 7.45-7.30 (m, 3H), 6.81 (d, J=1.6 Hz, 1H).
(346) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.12F.sub.2N.sub.3O.sub.2S].sup.+: 384.0613, Found 384.0610.
(347) Scheme 5 below shows the general synthesis followed to prepare some compounds according to the invention:
(348) ##STR00700##
(349) The following compounds were made according to this method:
Example 78
(350) ##STR00701##
(2-ethoxy-5-ethylbenzoyl) (2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid
Compound 497
(351) According to the synthetic procedures depicted in scheme 5, (2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid can be prepares as follows:
(352) A:
(353) Dibenzyl(2-ethoxy-5-ethylbenzoyl) (2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl) phosphoramidate: To a solution of 2-ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl) benzamide (FTEC-252) (0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) were added sodium hydride (60% dispersion in mineral oil) (48 mg, 1.2 mmol) and the mixture was stirred at 0° C. for 1 hr. Then dibenzyl phosphorochloridate (0.36 g, 1.2 mmol) was added to the mixture at 0° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred at this temperature for 12 hrs. The mixture was concentrated under vacuum and the residue was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (50 mg, 7.3% yield) as a yellow solid.
(354) B:
(355) (2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid: A mixture of dibenzyl (2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl) phosphoramidate (50 mg, 0.07 mmol), Et3N (0.3 g, 0.3 mmol) and Pd—C(5%) in ethanol (20 ml) was stirred at room temperature for 16 hrs under 2.0 Mpa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) to give the title compound (20 mg, 54.4% yield) as a solid
(356) 1H NMR (400 MHz, DMSO) δ 8.11-8.08 (m, 1H), 8.01-7.94 (m, 1H), 7.83-7.74 (m, 1H), 7.44-7.41 (m, 1H), 7.23-7.17 (m, 1H), 6.96 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.85-6.81 (m, 1H), 6.63-6.53 (m 1H), 3.86-3.73 (m, 2H), 2.46-2.38 (m, 2H), 1.36 (t, J=6.9 Hz, 3H), 1.05 (t, J=7.7 Hz, 3H).
(357) LC-HRMS (ESI) calcd for [M+H, C23H22FN3O7].sup.+: 502.1174, Found 502.1177.
Example 79
(358) ##STR00702##
N-(5-chloro-2-fluorophenyl)-2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 487
(359) N-(5-chloro-2-fluorophenyl)-2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in example 57, but from 5-chloro-2-fluoroaniline (72.8 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl) benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (105 mg, 52.3% yield) as a light yellow solid.
(360) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.78 (d, J=14.2 Hz, 1H), 8.59 (d, J=6.8 Hz, 1H), 8.42-8.30 (m, 2H), 7.73-7.70 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.31 (d, J=3.5 Hz, 1H), 7.11 (d, J=8.7 Hz, 2H), 6.66 (dd, J=3.5, 1.7 Hz, 1H).
(361) LC-HRMS (ESI) calcd for [M+H, C.sub.19H.sub.11ClF.sub.2N.sub.3O.sub.3].sup.+: 402.0452, Found 402.0457.
Example 80
(362) ##STR00703##
2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 488
(363) 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in example 57, but from 2-fluoro-5-(2-morpholinoethoxy)aniline (120.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (100 mg, 40.3% yield) as a light yellow solid.
(364) .sup.1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.39-8.33 (m, 1H), 8.32-8.23 (m, 1H), 8.14-8.09 (m, 1H), 7.70-7.60 (m, 1H), 7.58-7.48 (m, 2H), 7.24 (t, J=9.2 Hz, 1H), 6.92-6.78 (m, 2H), 4.14-4.05 (m, 2H), 3.67-3.50 (m, 4H), 2.76-2.64 (m, 2H), 2.50-2.43 (m, 4H). LC-HRMS (ESI) calcd for [M+H, C.sub.25H.sub.23F.sub.2N.sub.4O.sub.5].sup.+: 497.1631, Found 497.1638.
Example 81
(365) ##STR00704##
2-fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide
Compound 489
(366) 2-fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in example 1, but from 2-fluoro-5-(2-morpholinoethoxy)aniline (120.1 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (155 mg, 62.4% yield) as a light yellow solid.
(367) .sup.1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.26 (t, J=6.7 Hz, 1H), 8.13 (d, J=1.1 Hz, 1H), 7.95 (t, J=6.4 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.54-7.50 (m, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.23 (t, J=9.7 Hz, 1H), 6.86 (dd, J=3.5, 1.7 Hz, 1H), 6.82 (dt, J=8.9, 3.4 Hz, 1H), 4.08 (t, J=5.6 Hz, 2H), 3.70-3.44 (m, 4H), 2.69 (t, J=5.4 Hz, 2H), 2.49-2.43 (m, 4H).
(368) LC-HRMS (ESI) calcd for [M+H, C.sub.25H.sub.23F.sub.2N.sub.4O.sub.5].sup.+: 497.1631, Found 497.1638.
Example 82
(369) ##STR00705##
N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide
Compound 490
(370) N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide can be prepared as in example 1, but from 2-methoxy-5-(2-morpholinoethoxy)benzoic acid (140.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)aniline (123.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (115.3 mg, 45.3% yield) as a yellow solid.
(371) .sup.1H NMR (400 MHz, DMSO) δ 10.54 (d, J=2.0 Hz, 1H), 9.06 (d, J=5.6 Hz, 1H), 8.84 (s, 1H), 8.20 (s, 1H), 7.92-7.85 (m, 1H), 7.62 (dd, J=10.5, 8.8 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.26-7.18 (m, 2H), 4.11 (t, J=5.7 Hz, 2H), 4.00 (s, 3H), 3.63-3.53 (m, 4H), 2.70 (t, J=5.7 Hz, 2H), 2.50-2.44 (m, 4H).
(372) LC-HRMS (ESI) calcd for [M+H, C.sub.25H.sub.25FN.sub.5O.sub.6].sup.+: 510.1783, Found 510.1786.
Example 83
(373) ##STR00706##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin-1-yl)ethoxy)benzamide
Compound 491
(374) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin-1-yl)ethoxy)benzamide can be prepared as in example 1, but from 2-methoxy-5-(2-(piperidin-1-yl)ethoxy)benzoic acid (139.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (130.7 mg, 51.6% yield) as a yellow solid.
(375) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.60 (s, 1H), 9.33 (d, J=6.4 Hz, 1H), 8.00-7.90 (m, 1H), 7.88-7.79 (m, 1H), 7.72-7.62 (m, 1H), 7.33-7.26 (m, 2H), 7.18-7.08 (m, 1H), 7.06-6.98 (m, 1H), 6.68-6.59 (m, 1H), 4.66-4.42 (m, 2H), 4.06 (s, 3H), 3.36-3.24 (s, 2H), 3.23-2.70 (s, 4H), 2.04-1.77 (m, 4H), 1.74-1.46 (m, 2H).
(376) LC-HRMS (ESI) calcd for [M+H, C.sub.27H.sub.28FN.sub.4O.sub.5].sup.+: 507.2038, Found 507.2039.
Example 84
(377) ##STR00707##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-methoxyethoxy)benzamide
Compound 492
(378) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-methoxyethoxy)benzamide can be prepared as in example 1, but from 2-methoxy-5-(2-methoxyethoxy)benzoic acid (113.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (152.3 mg, 67.2% yield) as a yellow solid.
(379) .sup.1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.05 (d, J=5.8 Hz, 1H), 8.14-8.09 (m, 1H), 7.92-7.82 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.47 (d, J=3.5 Hz, 1H), 7.27-7.16 (m, 2H), 6.85 (dd, J=3.5, 1.7 Hz, 1H), 4.17-4.07 (m, 2H), 4.00 (s, 3H), 3.70-3.61 (m, 2H), 3.32 (s, 3H).
(380) LC-HRMS (ESI) calcd for [M+H, C.sub.23H.sub.21FN.sub.3O.sub.6].sup.+: 454.1409, Found 454.1414.
Example 85
(381) ##STR00708##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(2-hydroxyethoxy)-2-methoxybenzamide
Compound 493
(382) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(2-hydroxyethoxy)-2-methoxybenzamide can be prepared as in example 1, but from 5-(2-hydroxyethoxy)-2-methoxybenzoic acid (106.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (108.5 mg, 49.4% yield) as a yellow solid.
(383) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.64 (s, 1H), 9.35 (d, J=5.5 Hz, 1H), 7.99-7.92 (m, 1H), 7.88 (d, J=3.1 Hz, 1H), 7.70-7.66 (m, 1H), 7.33-7.27 (m, 2H), 7.17-7.11 (m, 1H), 7.06-7.00 (m, 1H), 6.65-6.61 (m, 1H), 4.22-4.11 (m, 2H), 4.08 (s, 3H), 4.02-3.94 (m, 2H).
(384) LC-HRMS (ESI) calcd for [M+H, C.sub.22H.sub.19FN.sub.3O.sub.6].sup.+: 440.1252, Found 440.1259.
Example 86
(385) ##STR00709##
N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide
Compound 494
(386) N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide can be prepared as in example 1, but from 2-methoxy-5-(2-morpholinoethoxy)benzoic acid (140.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=100/1) to give the title compound (145.5 mg, 57.2% yield) as a yellow solid.
(387) .sup.1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.04 (d, J=5.4 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 7.893-7.84 (m, 1H), 7.60 (dd, J=10.5, 8.7 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.47 (d, J=3.5 Hz, 1H), 7.30-7.18 (m, 2H), 6.85 (dd, J=3.5, 1.7 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.99 (s, 3H), 3.69-3.45 (m, 4H), 2.70 (t, J=5.7 Hz, 2H), 2.49-2.40 (m, 4H).
(388) LC-HRMS (ESI) calcd for [M+H, C.sub.26H.sub.26FN.sub.4O.sub.6].sup.+: 509.1831, Found 509.1834.
(389) Biological Methods
(390) Expression of Human ALCAT1 in Insect Cells
(391) The human ALCAT1 protein were expressed in Spodoptera frugiperda (Sf9) insect cells by using a Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's instruction. High-titer recombinant baculovirus expressing the human ALCAT1 protein was generated by several rounds of viral amplification. The Sf9 cells were typically infected with recombinant baculovirus for 3 days, harvested in ice-cold phosphate-buffered saline (PBS), and homogenized in 20 mm NaCl by going through French press. The total cell lysates were centrifuged at 10,000×g for 1 hours at 4° C. to eliminate the nucleus fraction, followed by ultracentrifugation at 100,000×g to pallet the membrane fraction. The membrane fraction was resuspended in enzymatic buffer that contain 10% glycerol, quantified for protein concentration, aliquoted, and stored at −80° C.
(392) In Vitro Acyltransferase Assays
(393) ALCAT1 enzymatic activity was determined by measuring the conversion of monolysocardiolipin (MLCL) to cardiolipin or lysophosphatidylglycerol (LPG) to phosphatidylglycerol (PG) in an enzymatic reaction mixture that contained 50 mm Tris/HCl, pH 7.0, 100 μm lysophospholipids, 25 μm [.sup.14C]acyl-CoA (50 mCi/mmol, American Radiolabeled Chemicals, Inc), and membrane fraction (0.5-2.5 μg) in a total volume of 200 μl. The reaction was incubated at room temperature for 30 min. The lipids were extracted will chloroform, dried, and separated by thin layer chromatography (TLC) with chloroform:hexane:methanol:acetic acid (50:30:10:5, v/v) or chloroform:methanol:water (65:25:4, v/v). After separation, TLC plates were exposed to a Phosphorlmager screen to visualize the radiolabeled products with a Molecular Dynamics Typhoon Scanner (Sunnyvale, Calif.). In some experiments, NBD-CoA was used at 100 μM to replace the [.sup.14C]acyl-CoA in the enzymatic reaction. All quantitative data were expressed as mean±S.E. Statistical analyses for differences between two groups were carried out using a Student's t test.
(394) Cell-Based Assay for ALCA T Inhibitor Compounds
(395) The assay was performed on the H9C2 vector cell line and H9C2 with stable overexpression of ALCAT1. Materials used in the protocol were CoA, LPG, compounds, chloroform, methanol, 0.9% KCl, 6-well-plates, 1.5 mL tubes, DMEM, FBS, P/S and PBS.
(396) Cells were seeded in 6-well-plates, 8×10.sup.5 cells/well, and cultured at 37° C. in 5% CO.sub.2 overnight. Cells were then pretreated with selected compounds (3 μM) for 1 hr and incubated with CoA (5 μM) and LPG (100 μM) with or w/o selected compound (3 μM) for a further 3 hrs.
(397) Cells were washed once with ice-cold PBS, collected in ice-cold PBS and centrifuged at 5000 rpm for 5 min at 4° C. 200 μL of chloroform: methanol (2:1) was added to the cell pellet, which was vortexed to suspend the cells and incubated at RT for 1 hr.
(398) 40 μL of 0.9% KCl was added and the sample was vortexed before centrifugation at 10000 rpm for 5 min at RT. The aqueous phase (upper layer) was discarded and the organic phase (lower layer) was loaded to a TLC plate (10 cm×20 cm), 40 μL/sample.
(399) The plates were developed in chloroform: methanol: water (65:25:4) for about 30 min and scanned using a Typhoon Scanner. The bands intensity was analysed using ImageJ and the inhibition activity of the tested compounds was calculated.
(400) Assay for ALCA T1 Inhibitors
(401) Compound inhibitors for ALCAT1 enzyme were analyzed by an in vitro enzymatic assay as detailed above. Compound inhibitors were added to the enzymatic mixture at 1-20 μM concentrations before the start of the acyltransferase reaction.
(402) Results for compounds of the invention are shown in the Table below, with % inhibition provided for tests with 10 μM and 1 μM concentrations of compounds. Where multiple measurements were taken this is indicated by a “/” between multiple values.
(403) TABLE-US-00004 % inh % inh Compound @ 10 μM @ 1 μM 1 48/49/79 59/63 3 48/89 — 5 39 — 7 3 — 9 87 47 10 2 — 11 9 — 15 69/20 20 16 — 58/85 18 2 — 19 2 — 20 77/26 13 21 85 — 23 89 — 24 2 — 25 56 — 27 98 — 28 51 — 36 1 — 37 76/76/87 — 42 70 23 46 43/68/75 10/21 48 2/2/28 — 51 — 43/57 52 — 59 53 90 47 55 100 81 56 2 — 57 75/89/94 — 58 45 — 62 11 2 64 55 15 71 93 51 73 66 15 74 21 4 75 36 16 77 21 37 78 — 42/59 79 — 89 80 — 22 81 — 20/36 82 3 23 83 43 36 84 — 5 85 3 10 87 62 29 98 2 11 100 7 3 113 94 96 114 48 36 115 53 51 118 100 95 477 68 63 119 95 92 120 100 94 122 100 100 478 62 57 123 100 90 124 100 92 125 97 92 126 100 83 127 100 85 128 100 100 130 — 50/57 132 — 26/39 133 — 19/17 135 — 56/62 136 — 28/23 137 — 37/48 139 — 50/48 140 — 29 141 67 65 143 17 13 144 92 73 145 38 9 150 92 72 168 100 100 169 93 74 170 27 20 171 100 79 172 26 6 174 100 96 175 100 90 176 100 73 177 1 3 178 — 27 179 41 17 181 68 34 182 — 33 183 — 100/100 184 — 100/100 186 100 92 188 100 93 189 100 92 190 100 80 191 100 82 192 — 89/93 193 90 92 195 88 70 196 97 68 197 97 80 200 100 98 207 — 86/87 208 — 97/98 209 100 100 210 97 97 211 — 95/97 212 — 26 213 — 56/64 214 — 67/76 215 — 100/100 216 — 100/100 217 — 69/68 218 — 99/98 219 — 99/98 220 — 96/94 221 — 100/100 222 — 100/97 223 — 94/90 224 — 91/97 225 — 92/97 226 — 100/99 227 — 85/89 228 — 100/99 229 — 97/97 230 — 94/89 232 — 61/61 233 — 68/65 234 — 46/42 235 — 12 236 — 7/8 237 — 35/46 238 — 23/23 240 — 12/6 248 — 30/50 271 — 83/84 273 — 97/96 274 — 77/82 275 — 98/99 277 — 23/23 278 — 97/100 280 — 94/100 287 — 5/33 288 — 48/59 289 — 6/38 290 — 24/31 292 — 14/12 293 — 13 295 — 37 296 — 55/73 297 — 75/83 304 — 98/96 305 — 100 306 — 100 312 — 98 321 — 94/92 331 — 12 332 — 30 333 — 18 334 — 35 336 — 66 337 — 66 338 — 65 340 — 72 341 — 73 342 — 41 343 — 35/100 344 — 33 345 — 24 346 — 86 347 — 94 279 — 97 300 — 96 313 — 94 314 — 95 315 — 93 316 — 94 319 — 96 323 — 96 317 — 96 320 — 96 318 — 98 302 — 97 281 — 100/97 405 — 98 416 — 98 322 — 94 39 — 92 373 — 98 396 — 96 400 — 96 480 — 96 44 — 26 325 — 63 35 5 16 298 — 15 22 8 20 497 — 90
Cell-Based Assay for ALCA T Inhibitors
(404) Compound inhibitors for ALCAT1 enzyme were analyzed by an in vitro cell-based assay as detailed above. Results are provided in the Table below:
(405) TABLE-US-00005 Compound % inh @ 3 μM Compound % inh @ 3 μM 279 7 125 18/0 118 9 200 26/31 219 22 226 37/83/47 168 27 184 57 216 45 183 62 300 31 313 19 314 36 221 38 222 85 210 24 209 37 208 36 319 12 323 14 317 52 320 17 318 36 302 20 281 65 304 31 305 34 306 30 312 4 321 75 405 52 416 45 322 26 373 3 396 45 400 50 497 75
(406) Some of the ALCAT1 inhibitors with high activity were also subject to IC.sub.50 analysis. IC.sub.50 is the drug concentration causing 50% inhibition of ALCAT1 enzyme activity. For the IC.sub.50 analysis, chemical inhibitors of ALCAT1 enzyme were added at various concentrations, ranging from 100, 33, 10, 3.3, 0.1, 0.003, 0.001 μM, respectively. IC.sub.50 values for each compound were analyzed in triplicates, and calculated by GraphPad software.
(407) % inhibition and IC.sub.50 values were determined for several compounds, as well as several reference compounds, using the assay described above. The results are summarised below.
(408) The following compounds provided IC.sub.50 values of <100 nM (≤50.1 μM):
(409) 192, 193, 120, 124, 279, 197, 123, 119, 125, 122, 118, 200, 218, 219, 211, 228, 225, 226, 184, 216, 128, 39, 183, 300, 215, 313, 314, 315, 221, 222, 210, 209, 208, 322, 316, 319, 323, 317, 320, 318, 302, 373, 281, 301, 304, 305, 306, 312, 321, 405, 396, 168, 27, 400, 416, 497.
(410) The following compounds provided IC.sub.50 values of <35 nM (<0.035 μM):
(411) 118, 200, 219, 184, 216, 128, 183, 300, 215, 314, 315, 221, 222, 209, 316, 323, 317, 320, 318, 281, 304, 305, 306, 312, 405 and 416.
(412) The following compound provided an IC.sub.50 value of <10 nM (<0.01 μM):
(413) 222.
(414) The following Table shows the IC.sub.50 results for some compounds of the invention:
(415) TABLE-US-00006 Compound IC.sub.50 (nM) 1 210 3 890 5 4100 23 1800 27 47 37 3900 39 93 40 1700 44 990 46 3800 52 750 55 130 57 2800 58 2400 59 2000 79 110 113 110 118 31 119 90 120 38 122 39 123 87 124 62 125 67 126 110 127 210 128 29 144 130 150 410 168 48 169 470 171 350 174 110 175 150 176 220 183 24 184 18 186 390 188 640 189 320 190 290 191 330 192 92 193 67 195 360 196 340 197 79 200 33 203 1900 207 190 208 76 209 25 210 66 211 96 215 26 216 19 218 67 219 34 220 120 221 31 222 8 223 150 224 190 225 100 226 60 227 160 228 72 229 170 230 410 271 780 273 120 274 630 275 200 278 120 279 60 280 120 281 24 286 120 297 290 300 30 301 100 302 36 304 20 305 21 306 19 312 33 313 64 314 29 315 28 316 21 317 19 318 24 319 46 320 34 321 38 322 61 323 26 337 760 341 500 346 180 354 610 364 120 373 38 393 140 396 78 400 62 405 19 416 19 497 72
(416) The disclosure of all references cited herein, inasmuch as it may be used by those skilled in the art to carry out the invention, is hereby specifically incorporated herein by cross-reference.