Chromone-2-carboxamide MCHr1 Antagonists
2C (29 mg, 0.10 mmol) and 2,2-difluoro-1,3-(methylenedioxy)-
benzaldehyde (19 mg, 0.10 mmol) were processed in a manner
analogous to method F to provide the title compound 42 as a white
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 22 6581
2
7.10-7.15 (m, 1 H), 7.31 (d, J ) 8.7 Hz, 2 H), 7.44 (s, 1 H), 8.28
(dd, J ) 8.7, 6.2 Hz, 1 H), 9.55 (d, J ) 7.5 Hz, 1 H); MS (ESI,
+
MeOH/NH
method A (t
4
OH) m/z 411 [M + H] , 409 [M - H]; analytical HPLC
1
solid: H NMR (300 MHz, DMSO-d
1
6
) δ 1.58-1.71 (m, 2 H),
R
) 5.21 min, 100%), method B (t ) 5.31 min, 98.1%).
R
.76-1.85 (m, 2 H), 1.99-2.10 (m, 2 H), 2.84 (d, J ) 11.2 Hz, 2
N-[1-[(2-Fluorobenzyl)methyl]piperidin-4-yl]-7-fluoro-4-oxo-
4H-chromene-2-carboxamide (48). Compound 22C (19 mg, 0.058
mmol) and 2-fluorobenzaldehyde (11 mg, 0.087 mmol) were
processed in a manner analogous to method F to provide the title
compound 48 as the TFA salt after purification by preparative
H), 3.48-3.52 (m, 2 H), 3.74-3.82 (m, 1 H), 6.82 (s, 1 H), 7.14
(
2
dd, J ) 8.1, 1.4 Hz, 1 H), 7.32-7.37 (m, 2 H), 7.43 (td, J ) 8.7,
.7 Hz, 1 H), 7.61 (dd, J ) 9.5, 2.4 Hz, 1 H), 8.11 (dd, J ) 9.0,
.3 Hz, 1 H), 8.83 (d, J ) 7.8 Hz, 1 H); MS (APCI, MeOH/NH
6
4
-
+
1
OH) m/z 461 [M + H] , 459 [M - H].
reversed-phase HPLC (7 mg, 20% yield): H NMR (500 MHz,
N-{1-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]piperidin-4-yl}-
-fluoro-4-oxo-4H-chromene-2-carboxamide (43). Compound
2C (19 mg, 0.065 mmol) and 6-chloropiperonal (12 mg, 0.065
5
pyridine-d ) δ 2.23 (s, 6 H), 3.10 (s, J ) 11.5 Hz, 2 H), 3.74 (s, 2
7
2
H), 4.20-4.33 (m, 1 H), 7.19-7.25 (m, 1 H), 7.27 (t, J ) 7.5 Hz,
1 H), 7.33-7.37 (m, 2 H), 7.41-7.48 (m, 1 H), 7.54-7.60 (m, 1
mmol) were processed according to general method F to provide
the title compound 43 (14.5 mg, 39%) as the trifluoroacetic acid
salt after purification by preparative reversed-phase HPLC as
described in the general section The TFA salt was dissolved in
H), 7.66 (dd, J ) 9.2, 2.3 Hz, 1 H), 8.31 (dd, J ) 9.1, 6.2 Hz, 1
+
H); MS (APCI, MeOH/NH
4
OH) m/z 399 [M + H] , 397 [M -
H]; analytical HPLC method A (t
(t ) 5.27 min, 100%).
N-[1-[(3-Fluorobenzyl)methyl]piperidin-4-yl]-7-fluoro-4-oxo-
R
) 5.15 min, 97.3%), method B
R
dichloromethane, washed with 1 M K
concentrated to give the free base for elemental analysis: H NMR
300 MHz, DMSO-d ) δ 1.57-1.72 (m, 2 H), 1.76-1.86 (m, 2
2 3 2 4
CO , dried (Na SO ), and
1
4H-chromene-2-carboxamide (49). Compound 22C (30 mg, 0.103
mmol) and 3-fluorobenzaldehyde (19 mg, 0.155 mmol) were
processed in a manner analogous to method F to provide the title
(
6
H), 2.07-2.19 (m, 2 H), 2.85 (d, 2 H, J ) 11.5 Hz), 3.48 (s, 2 H),
compound 49 (28 mg, 68%): 1H NMR (300 MHz, DMSO-d
3
7
9
.74-3.88 (m, 1 H), 6.06 (s, 2 H), 6.83 (s, 1 H), 7.01 (s, 1 H),
6
) δ
.05 (s, 1 H), 7.43 (td, 1 H, J ) 8.7, 2.5 Hz), 7.61 (dd, 1 H, J )
1.66 (qd, J ) 11.9, 3.9 Hz, 2 H), 1.76-1.86 (m, 2 H), 2.02-2.12
(m, 2 H), 2.84 (d, J ) 11.9 Hz, 2 H), 3.52 (s, 2 H), 3.73-3.85 (m,
1 H), 6.82 (s, 1 H), 7.04-7.17 (m, 3 H), 7.33-7.46 (m, 2 H), 7.61
(dd, J ) 9.5, 2.4 Hz, 1 H), 8.11 (dd, J ) 8.8, 6.4 Hz, 1 H), 8.83
.5, 2.5 Hz), 8.12 (dd, 1 H, J ) 8.9, 6.4 Hz), 8.83 (d, 1 H, J ) 7.9
+
Hz); MS (ESI, MeOH/NH
H] ; Anal. (C23
4
OH) m/z 459 [M + H] , 457 [M -
5
+
2
H20ClFN O
2
‚H O) C, H, N.
N-[1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)methyl]piperidin-4-
yl]-7-fluoro-4-oxo-4H-chromene-2-carboxamide (44). Compound
(d, J ) 7.8 Hz, 1 H); MS (ESI, MeOH/NH
4
OH) m/z 399 [M +
H] , 397 [M - H]; analytical HPLC method A (t ) 5.24 min,
100%), method B (t ) 5.34 min, 100%).
+
R
22C (29 mg, 0.10 mmol) and 1,4-benzodioxan-6-carbaldehyde (17
R
mg, 0.10 mmol) were processed in a manner analogous to method
F to provide the title compound 44 as a white solid (17 mg, 31%):
N-[1-[(4-Fluorobenzyl)methyl]piperidin-4-yl]-7-fluoro-4-oxo-
4H-chromene-2-carboxamide (50). Compound 22C (19 mg, 0.058
mmol) and 4-fluorobenzaldehyde (11 mg, 0.087 mmol) were
processed in a manner analogous to method F to provide the title
compound as a TFA salt after purification by preparative reversed-
1
H NMR (300 MHz, DMSO-d ) δ 1.55-1.70 (m, 2 H), 1.75-1.83
6
(
3
4
m, 2 H), 1.95-2.04 (m, 2 H), 2.79-2.86 (m, 2 H), 3.36 (s, 2 H),
.72-3.82 (m, J ) 8.1, 4.1 Hz, 1 H), 4.20 (s, 4 H), 6.72-6.82 (m,
H), 7.43 (td, J ) 8.7, 2.4 Hz, 1 H), 7.61 (dd, J ) 9.5, 2.4 Hz, 1
1
phase HPLC (16 mg, 47%): H NMR (500 MHz, solvent) δ 2.26-
H), 8.11 (dd, J ) 8.8, 6.4 Hz, 1 H), 8.82 (d, J ) 7.8 Hz, 1 H); MS
2.35 (m, 4 H), 2.59-2.67 (m, 2 H), 3.27-3.33 (m, J ) 12.2 Hz,
2 H), 3.94 (s, 2 H), 4.35-4.42 (m, 1 H), 7.20 (t, J ) 8.7 Hz, 2 H),
+
(
APCI, MeOH/NH
analytical HPLC method A (t
5.32 min, 96.02%).
N-[1-[(3,4-Dimethoxybenzyl)methyl]piperidin-4-yl]-7-fluoro-
-oxo-4H-chromene-2-carboxamide (45). Compound 22C (22.5
4
OH) m/z 439 [M + H] , 437 [M - H];
R
) 5.23 min, 100%), method B (t
R
7.33-7.35 (m, 2 H), 7.60-7.66 (m, 3 H), 8.31 (dd, J ) 8.9, 6.4
+
)
Hz, 1 H); MS (APCI, MeOH/NH
+ Cl]; analytical HPLC method A (t
B (t ) 5.33 min, 100%).
4
OH) m/z 399 [M + H] , 434 [M
R
) 5.24 min, 100%), method
4
R
mg, 0.0681 mmol) and 3,4-dimethoxybenzaldehyde (19 mg, 0.102
mmol) were processed in a manner analogous to method F to
provide the title compound 45 (32 mg, 74%): H NMR (500 MHz,
N-[1-[(2-Fluoro-4-methoxybenzyl)methyl]piperidin-4-yl]-7-
fluoro-4-oxo-4H-chromene-2-carboxamide (51). Compound 22C
(29 mg, 0.10 mmol) and 2-fluoro-4-methoxybenzaldehyde (16 mg,
1
pyridine-d
2
4
5
) δ 1.86-1.95 (m, 2 H), 2.03-2.12 (m, 4 H), 2.92-
.98 (m, 2 H), 3.44 (s, 2 H), 3.72 (s, 3 H), 3.77-3.79 (m, 3 H),
.29 (m, 1 H), 6.44 (dd, J ) 9.3, 2.3 Hz, 1 H), 6.92-6.98 (m, 2
0.10 mmol) were processed in a manner analogous to method F to
1
provide the title compound as a white solid (25 mg, 58%):
NMR (300 MHz, DMSO-d
H
6
) δ 1.54-1.68 (m, 2 H), 1.75-1.83
H), 7.15 (td, J ) 8.5, 2.1 Hz, 1 H), 7.46 (s, 1 H), 8.29 (dd, J )
(m, 2 H), 1.99-2.10 (m, 2 H), 2.79-2.87 (m, 2 H), 3.46 (s, 2 H),
3.73 (m, 1 H), 3.76 (s, 3 H), 6.74-6.84 (m, 3 H), 7.28 (t, J ) 8.8
Hz, 1 H), 7.43 (td, J ) 8.7, 2.4 Hz, 1 H), 7.61 (dd, J ) 9.5, 2.4
8
NH
method A (t
.9, 6.4 Hz, 1 H), 9.65 (d, J ) 7.9 Hz, 1 H); MS (ESI, MeOH/
4
+
OH) m/z 441 [M + H] , 439 [M - H]; analytical HPLC
) 5.12 min, 100%), method B (t ) 5.21 min, 97.8%).
R
R
Hz, 1 H), 8.11 (dd, J ) 8.8, 6.4 Hz, 1 H), 8.82 (d, J ) 7.8 Hz, 1
+
N-[1-[(3-Methoxybenzyl)methyl]piperidin-4-yl]-7-fluoro-4-
oxo-4H-chromene-2-carboxamide (46). Compound 22C (30 mg,
H); MS (APCI, MeOH/NH
4
OH) m/z 429 [M + H] , 427 [M -
H]; analytical HPLC method A (t
(t ) 5.36 min, 95.1%).
N-[1-[(3-Fluoro-4-methoxybenzyl)methyl]piperidin-4-yl]-7-
R
) 5.29 min, 100%), method B
0.103 mmol) and 3-methoxybenzaldehyde (21 mg, 0.155 mmol)
R
were processed in a manner analogous to method F to provide the
title compound 46 (35 mg, 83%): 1H NMR (500 MHz, pyridine-
fluoro-4-oxo-4H-chromene-2-carboxamide (52). Compound 22C
d
5
) δ 1.81-1.90 (m, 2 H), 2.02-2.09 (m, 4 H), 2.88-2.93 (m, 2
H), 3.45 (s, 2 H), 3.68 (s, 3 H), 4.21-4.29 (m, 1 H), 6.45 (dd, J )
.4, 2.2 Hz, 1 H), 6.93 (dd, J ) 8.1, 2.5 Hz, 1 H), 7.00 (d, J ) 7.5
Hz, 1 H), 7.09 (s, 1 H), 7.14 (td, J ) 8.6, 2.5 Hz, 1 H), 7.29 (t, J
7.8 Hz, 1 H), 7.44 (s, 1 H), 8.28 (dd, J ) 8.9, 6.4 Hz, 1 H), 9.51
d, J ) 7.5 Hz, 1 H); MS (ESI, MeOH/NH OH) m/z 411 [M +
) 5.24 min, 100%), method
(29 mg, 0.10 mmol) and 3-fluoro-4-methoxybenzaldehyde (16 mg,
0.10 mmol) were processed in a manner analogous to method F to
1
9
provide the title compound as a white solid (22 mg, 51%):
NMR (300 MHz, DMSO-d
H
6
) δ 1.57-1.70 (m, 2 H), 1.80 (m, 2
)
(
H), 1.98-2.07 (m, 2 H), 2.79-2.86 (m, 2 H), 3.42 (s, 2 H), 3.72-
3.81 (m, 1 H), 3.82 (s, 3 H), 6.82 (s, 1 H), 7.03-7.15 (m, 3 H),
7.43 (td, J ) 8.7, 2.5 Hz, 1 H), 7.61 (dd, J ) 9.5, 2.4 Hz, 1 H),
4
+
H] ; analytical HPLC method A (t
B (t ) 5.33 min, 97.1%).
N-[1-[(4-Methoxybenzyl)methyl]piperidin-4-yl]-7-fluoro-4-
oxo-4H-chromene-2-carboxamide (47). Compound 22C and
R
R
8.11 (dd, J ) 9.0, 6.3 Hz, 1 H), 8.82 (d, J ) 8.1 Hz, 1 H); MS
+
(APCI, MeOH/NH
4
OH) m/z 429 [M + H] , 427 [M - H]; Anal.
22 2 2
(C23H F N O4) C, H, N.
3
-methoxybenzaldehyde were processed in a manner analogous to
N-[1-{4-[(4-Aminopiperidin-1-yl)methyl]phenyl}ethanonyl]-
7-fluoro-4-oxo-4H-chromene-2-carboxamide (53). Compound
22C (29 mg, 0.10 mmol) and 4-acetobenzaldehyde (15 mg, 0.10
1
method F to provide the title compound 47 as a solid: H NMR
500 MHz, pyridine-d ) δ 1.82-1.91 (m, 2 H), 2.01-2.10 (m, 4
H), 2.88-2.93 (m, 2 H), 3.41 (s, 2 H), 3.69 (s, 3 H), 4.24-4.30
m, 1 H), 6.43 (d, J ) 9.4 Hz, 1 H), 6.98 (d, J ) 8.4 Hz, 2 H),
(
5
mmol) were processed in a manner analogous to method F to
1
(
provide the title compound as a white solid (25 mg, 58%):
H