Journal of Medicinal Chemistry
Article
C2′H, C4′H), 6.43 (m, 1 H, C6′H), 6.51 (d, J = 2.02 Hz, 1 H, C4H), 6.73
(dd, J = 8.97, 2.27 Hz, 1 H, C2H), 6.95 (m, 1 H, C10H), 7.15 (m, 1 H,
C8H), 7.28 (m, 1 H, C5′H), 7.42 (d, J = 8.21 Hz, 1 H, C7H), 7.96 (d, J =
8.97 Hz, 1 H, C1H), 8.71 (m, 1 H, C10H). HRMS-EI, m/z
(C26H27N3O4): calcd [M + H]+ 446.2074, found 446.2070.
according to general procedure A using 26f (250 mg, 0.67 mmol), 2,4-
difluoroaniline (200 mg, 1.54 mmol), Cs2CO3 (350 mg, 1.07 mmol), X-
Phos (50 mg, 0.11 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol). The
reaction mixture was heated for 6 h at reflux temperature and purified by
flash chromatography (SiO2, dichloromethane/ethanol 95:5). Yield:
100 mg (31.9%), colorless oil. HPLC: tR = 12.4 min, purity 100%. 1H
3-[(2,4-Difluorophenyl)amino]-9-{[(4R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methoxy}dibenzo[b,e]oxepin-11(6H)-one (3f).
Compound 3f was prepared according to General Procedure A using
26b (200 mg, 0.53 mmol), 2,4-difluoroaniline (200 mg, 1.55 mmol),
Cs2CO3 (1.30 g, 3.99 mmol), X-Phos (100 mg, 0.21 mmol) and
Pd(OAc)2 (20 mg, 0.09 mmol). The reaction mixture was heated for 4 h
at reflux temperature and purified by flash chromatography (SiO2,
dichloromethane/ethanol 95:5). Yield: 90 mg (36.3%), yellow oil.
HPLC: tR = 8.90 min, purity 95.7%. 1H NMR (200 MHz, DMSO-d6): δ
(ppm) = 1.29 (s, 3 H, −CH3), 1.34 (s, 3 H, −CH3), 3.76 (m, 1 H,
C3propoxyH), 4.06 (m, 3 H, C3propoxyH, C1propoxyH2), 4.40 (m, 1 H,
C2propoxyH), 5.12 (s, 2 H, C6H2), 6.22 (m, 1 H, C4H), 6.60 (dd, J = 8.65,
2.08 Hz, 1 H, C2H), 7.15 (m, 2 H, C6′H, C3′H), 7.29 (d, J = 2.53 Hz, 1 H,
C5′), 7.38 (m, 1 H, C8H), 7.44 (m, 2 H, C10H, C7H), 7.98 (d, J = 8.84
Hz, 1 H, C1H), 8.70 (s, 1 H, NH). HRMS-EI, m/z (C26H23F2NO5):
calcd 467.1543, found 467.1563.
3-[(2,4-Difluorophenyl)amino]-9-{[(4S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methoxy}dibenzo [b,e]oxepin-11(6H)-one (3g).
Compound 3g was prepared according to general procedure A using
26c (300 mg, 0.79 mmol), 2,4-difluoroaniline (200 mg, 1.55 mmol),
Cs2CO3 (1.30 g, 3.99 mmol), X-Phos (100 mg, 0.21 mmol), and
Pd(OAc)2 (20 mg, 0.09 mmol). The reaction mixture was heated for 4 h
at reflux temperature and purified by flash chromatography (SiO2,
dichloromethane/ethanol 95:5). Yield: 120 mg (32.5%), yellow solid.
HPLC: tR = 8.85 min, purity 99.2%. 1H NMR (200 MHz, DMSO-d6): δ
(ppm) = 1.29 (s, 3 H, −CH3), 1.34 (s, 3 H, −CH3), 3.76 (m, 1 H,
C3propoxyH), 4.05 (m, 3 H, C3propoxyH, C1PropoxyH2), 4.41 (m, 1 H,
C2propoxyH), 5.12 (s, 2 H, C6H2), 6.24 (m, 1 H, C4H), 6.61 (dd, J = 9.09,
1.52 Hz, 1 H, C2H), 7.12 (m, 2 H, C6′H, C3′H), 7.38 (m, 4 H C5′H,
C8H, C10H, C7H), 7.98 (d, J = 8.97 Hz, 1 H, C1H), 8.71 (s, 1 H, NH).
HRMS-EI, m/z (C26H23F2NO5): calcd 467.1544, found 467.1564.
9-[2-(Diethylamino)ethoxy]3-[(2,4-difluorophenyl)amino]-
dibenzo[b,e]oxepin-11(6H)-one (3j). Compound 3j was prepared
according to general procedure A using 26d (250 mg, 0.69 mmol), 2,4-
difluoroaniline (200 mg, 1.55 mmol), Cs2CO3 (700 mg, 2.14 mmol), X-
Phos (100 mg, 0.21 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol). The
reaction mixture was heated for 3 h at reflux temperature and purified by
flash chromatography (SiO2, dichloromethane/ethanol 95:5). Yield: 80
mg (25.6%), yellow oil. HPLC: tR = 5.35 min, purity 97.3%. 1H NMR
(400 MHz, CDCl3): δ (ppm) = 1.04 (t, J = 7.07 Hz, 6 H,
2*C2ethylaminoH3), 2.64 (m, 4 H, 2*C1ethylaminoH2), 2.88 (m, 2 H,
C2ethoxyH2), 4.08 (t, J = 5.56 Hz, 2 H, C1ethoxyH2), 5.02 (s, 2 H, C6H2),
5.86 (s, 1 H, NH), 6.38 (s, 1 H, C4H), 6.55 (d, J = 8.84 Hz, 1 H, C2H),
6.82 (m, 2 H, C3′H, C5′H), 6.98 (m, 1 H, C6′H), 7.17 (d, J = 8.08 Hz, 1
H, C7H), 7.28 (m, 1 H, C8H), 7.37 (s, 1 H, C10H), 8.12 (d, J = 8.84 Hz, 1
H, C1H). HRMS-EI, m/z (C26H26F2N2O3): calcd 452.1911, found
452.1894.
NMR (400 MHz, DMSO-d6): δ (ppm) = 1.41 (m, 13 H, C1−6
,
cyclohexyl
C2ethoxyH2), 4.05 (t, J = 6.44 Hz, 2 H, C1ethoxyH2), 5.12 (s, 2 H, C6H2),
6.23 (s, 1 H, C4H), 6.62 (d, J = 8.84 Hz, 1 H, C2H), 7.12 (m, 2 H, C3′H,
C6′H), 7.27 (s, 1 H, C10H), 7.40 (m, 3 H, C4′H, C7H, C8H), 7.98 (d, J =
9.10 Hz, 1 H, C1H), 8.70 (s, 1 H, NH). HRMS-EI, m/z
(C26H26F2N2O3): calcd 463.1958, found 463.1940.
3-[(2,4-Difluorophenyl)amino]-9-(2-hydroxyethoxy)-
dibenzo[b,e]oxepin-11(6H)-one (3m). Compound 3m was pre-
pared according to general procedure A using 26g (250 mg, 0.72 mmol),
2,4-difluoroaniline (200 mg, 1.54 mmol), Cs2CO3 (700 mg, 2.14 mmol),
X-Phos (100 mg, 0.21 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol). The
reaction mixture was heated for 6 h at reflux temperature and purified by
flash chromatography (SiO2, dichloromethane/ethanol 95:5). Yield: 55
1
mg (19.2%), yellow oil. HPLC: tR = 7.40 min, purity 100%. H NMR
(400 MHz, DMSO-d6): δ (ppm) 3.73 (m, 2 H, C1ethoxyH2), 4.05 (t, J =
4.67 Hz, 2 H, C2ethoxyH2), 4.88 (t, J = 5.56 Hz, 1 H, OH), 5.13 (s, 2 H,
C6H2), 6.24 (s, 1 H, C4H), 6.62 (d, J = 8.84 Hz, 1 H, C2H), 7.13 (m, 2 H,
C3′H, C5′H), 7.30 (s, 1 H, C6′H), 7.40 (m, 3 H, C8H, C7H, C10H), 8.00
(d, J = 8.84 Hz, 1 H, C1H), 8.70 (s, 1 H, NH). HRMS-EI, m/z
(C22H17F2NO4): calcd 397.1125, found 397.1106.
3-[(2,4-Difluorophenyl)amino]-9-(2-hydroxypropoxy)-
dibenzo[b,e]oxepin-11(6H)-one (3n). Compound 3n was prepared
according to general procedure A using 26h (250 mg, 0.69 mmol), 2,4-
difluoroaniline (200 mg, 1.54 mmol), Cs2CO3 (700 mg, 2.14 mmol), X-
Phos (100 mg, 0.21 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol). The
reaction mixture was heated for 3 h at reflux temperature and purified by
flash chromatography (SiO2, dichloromethane/ethanol 95:5). Yield: 45
mg (15.9%), yellow oil. HPLC: tR = 7.92 min, purity 98.6%. 1H NMR
(400 MHz, CDCl3): δ (ppm) 2.07 (m, 2 H, C2propoxyH2), 3.87 (t, J = 5.81
Hz, 2 H, C3propoxyH2), 4.19 (t, J = 5.94 Hz, 2 H, C1propoxyH2), 5.10 (s, 2 H,
C6H2), 6.02 (s, 1 H, −NH), 6.46 (s, 1 H, C4H), 6.63 (d, J = 8.84 Hz, 1 H,
C2H), 6.91 (m, 2 H, C3′H, C5′H), 7.06 (m, 1 H, C6′H), 7.24 (m, 1 H,
C8H), 7.36 (m, 1 H, C7H), 7.47 (s, 1 H, C10H), 8.19 (d, J = 8.84 Hz, 1 H,
C1H). HRMS-EI, m/z (C23H19F2NO4): calcd 411.1281, found
411.1289.
2-({3-[(2,4-Difluorophenyl)amino]-11-oxo-6,11-
dihydrodibenzo[b,e]oxepin-9-yl}oxy)ethyl Acetate (3o). Com-
pound 3o was prepared according to general procedure A using 26g
(250 mg, 0.72 mmol), 2,4-difluoroaniline (200 mg, 1.54 mmol), Cs2CO3
(700 mg, 2.14 mmol), X-Phos (100 mg, 0.21 mmol), and Pd(OAc)2 (20
mg, 0.09 mmol). The reaction mixture was heated for 6 h at reflux
temperature and purified by flash chromatography (SiO2, dichloro-
methane/ethanol 95:5). Yield: 15 mg (4.7%), yellow oil. HPLC: tR =
8.18 min, purity 100%. 1H NMR (200 MHz, CDCl3): δ (ppm) 2.11 (s, 3
H, −CH3), 4.23 (m, 2 H, C1ethoxyH2), 4.43 (m, 2 H, C2ethoxyH2), 5.10 (s, 2
H, C6H2), 5.96 (s, 1 H, −NH), 6.45 (d, J = 2.27 Hz, 1 H, C4H), 6.63 (dd,
J = 8.91, 2.34 Hz, 1 H, C2H), 6.92 (m, 2 H, C3′H, C5′H), 7.07 (dd, J =
8.21, 2.78 Hz, 1 H, C8H), 7.29 (m, 1 H, C6′H), 7.38 (m, 1 H, C7H), 7.46
(d, J = 2.78 Hz, 1 H, C10H), 8.19 (d, J = 8.97 Hz, 1 H, C1H). HRMS-EI,
m/z (C24H19F2NO6): calcd 439.1230, found 439.1222.
3-[(2,4-Difluorophenyl)amino]-9-(2-tetrahydro-2H-pyran-4-
ylethoxy)dibenzo[b,e]oxepin-11(6H)-one (3k). Compound 3k was
prepared according to general procedure A using 26e (200 mg, 0.54
mmol), 2,4-difluoroaniline (200 mg, 1.54 mmol), Cs2CO3 (350 mg, 1.07
mmol), X-Phos (50 mg, 0.11 mmol), and Pd(OAc)2 (10 mg, 0.05
mmol). The reaction mixture was heated for 6 h at reflux temperature
and purified by flash chromatography (SiO2, dichloromethane/ethanol
95:5). Yield: 75 mg (29.9%), yellow solid. HPLC: tR = 9.27 min, purity
3-[(2,4-Difluorophenyl)amino]-10-(methoxy)dibenzo[b,e]-
oxepin-11(6H)-one (4a). Compound 4a was prepared according to
general procedure A using 24b (200 mg, 0.73 mmol), 2,4-difluoroaniline
(200 mg, 1.55 mmol), Cs2CO3 (700 mg, 2.14 mmol), X-Phos (100 mg,
0.21 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol). The reaction mixture
was heated for 3 h at reflux temperature and purified by flash
chromatography (SiO2, hexane/ethyl acetate 2:1). Yield: 70 mg
1
100%. H NMR (400 MHz, DMSO-d6): δ (ppm) = 1.21 (m, 2 H,
C2
H2), 1.65 (m, 5 H, C3/5tetrahydropyranH2), C4tetrahydropyranH), 3.26
ethoxy
(m, 2 H, C2tetrahydropyranH2), 3.81 (m, 2 H, C5tetrahydropyranH2), 4.06 (t, J =
5.94 Hz, 2 H, C1ethoxy H2), 5.12 (s, 2 H, C6H2), 6.24 (s, 1 H, C4H), 6.62
(d, J = 9.10 Hz, 1 H, C2H), 7.11 (m, 2 H, C3′H, C5′H), 7.29 (m, 1 H,
C6′H), 7.39 (m, 3 H, C8H, C7H, C1H), 7.99 (d, J = 9.10 Hz, 1 H, C10H),
8.70 (s, 1 H, NH). HRMS-EI, m/z (C27H25F2NO4): calcd 465.1751,
found 465.1755.
1
(26.1%), yellow solid. HPLC: tR = 7.88 min, purity 100%. H NMR
(200 MHz, DMSO-d6): δ (ppm) = 3.74 (s, 3 H, −OCH3), 5.07 (s, 2 H,
C6H2), 6.19 (m, 1 H, C4H), 6.56 (dd, J = 8.91, 1.96 Hz, 1 H, C2H), 7.08
(m, 3 H, C3′H, C5′H, C9H), 7.39 (m, 3 H, C7H, C6′H, C1H), 7.69 (d, J =
8.84 Hz, 1 H, C8H), 8.55 (s, 1 H, NH). HRMS-EI, m/z (C21H15F2NO3):
calcd 367.1020, found 367.1033.
9-[2-Cyclohexylethoxy]3-[(2,4-difluorophenyl)amino]-
dibenzo[b,e]oxepin-11(6H)-one (3l). Compound 3l was prepared
P
dx.doi.org/10.1021/jm401276h | J. Med. Chem. XXXX, XXX, XXX−XXX