Journal of Medicinal Chemistry
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extracted with ethyl acetate. The combined ethyl acetate phase was
washed with brine, dried over sodium sulfate, and concentrated. The
residue was purified by chromatography (reverse phase, acetonitrile/
Step 5. (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopentyl-4,5-di-
hydro-1H-pyrazol-3-yl)-2-methoxynicotinamide (R-16a). The title
compound was prepared from R-10 (0.174 g, 0.605 mmol) and 2-
methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotina-
mide (0.202 g, 0.726 mmol) following general procedure A. R-16a was
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water) to obtain 19 as a solid (0.160 g, 42%). H NMR (DMSO-d6,
400 MHz) δ 8.15 (d, J = 8.05 Hz, 1 H), 7.75 (d, J = 7.69 Hz, 1 H),
7.73 (d, J = 6.59 Hz, 1 H), 7.45 (d, J = 2.20 Hz, 1 H), 7.24 (dd, J =
8.97, 2.01 Hz, 1 H), 4.94 (td, J = 7.59, 3.48 Hz, 1 H), 3.98 (s, 3 H),
3.51 (dd, J = 18.48, 11.53 Hz, 1 H), 3.24 (dd, J = 18.48, 11.53 Hz, 1
H), 2.43−2.48 (m, 1 H), 1.73−1.82 (m, 1 H), 1.21−1.64 (m, 6 H),
0.99−1.10 (m, 1 H). ES-MS m/z 439.0 (M + H).
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obtained as a yellow solid (0.035 g, 14%). H NMR (DMSO-d6, 400
MHz) δ 8.19 (d, J = 7.81 Hz, 1 H), 7.70 (d, J = 7.81 Hz, 1 H), 7.67 (d,
J = 3.12 Hz, 2 H), 7.56 (d, J = 8.78 Hz, 1 H), 7.21 (d, J = 1.95 Hz, 1
H), 7.10 (dd, J = 2.24, 8.69 Hz, 1 H), 4.86 (d, J = 11.71 Hz, 1 H), 4.01
(s, 3 H), 3.38−3.54 (dd, J = 4.00, 18.45 Hz, 1 H), 3.19 (dd, J = 4.00,
18.45 Hz, 1 H), 2.48−2.56 (m, 1 H), 2.41 (s, 3 H), 1.66−1.86 (m, 1
H), 1.48 (d, J = 8.59 Hz, 3 H), 1.18−1.40 (m, 3 H), 0.86−1.11 (m, 1
H). ES-MS m/z 404.3 (M + H). HPLC purity 100%, method 1.
Synthesis of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopen-
tyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxy-N-methylnicotina-
mide (R-16b). General Procedure D. To a solution of carboxylic acid
R-14c (0.10 g, 0.247 mmol) in DMF (0.5 mL) was added CDI (0.061
g, 0.370 mmol). The mixture was stirred for 20 min, and then a 2 M
solution of methylamine in THF (1.24 mL, 2.47 mmol) was added.
The reaction stirred overnight at RT. The reaction was diluted with
ethyl acetate and water, and the layers were separated. The aqueous
layer was washed an additional ethyl acetate twice. The combined
organic layers were washed with brine and dried over magnesium
sulfate, filtered, and concentrated to provide pure R-16b as a yellow
Step 2: (R)-6-[1-(3-Chloro-4-cyano-phenyl)-5-cyclopentyl-4,5-di-
hydro-1H-pyrazol-3-yl]-2-methoxy-nicotinic Acid (R-19). Separation
of the enantiomers of 19 (0.160 g, 0.337 mmol) using chiral HPLC
(SFC conditions): Chiralpak AD-H, 30 mm × 250 mm; mobile phase,
50% methanol/carbon dioxide; flow rate, 70 mL/min. This separation
provided R-19 as a single peak from the chiral HPLC. R-19 was
obtained as yellow solid (0.063 g, 39%): first eluting peak tR = 7.395
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min. H NMR (DMSO-d6, 500 MHz) δ 12.59−13.22 (m, 1 H), 8.15
(d, J = 7.8 Hz, 1 H), 7.75 (dd, J = 10.7, 8.3 Hz, 2 H), 7.47 (d, J = 2.2
Hz, 1 H), 7.25 (dd, J = 8.9, 2.1 Hz, 1 H), 4.95 (dt, J = 11.5, 3.9 Hz, 1
H), 3.98 (s, 3 H), 3.46−3.58 (m, 1 H), 3.25 (dd, J = 18.4, 3.8 Hz, 1
H), 2.43−2.48 (m, 1 H), 1.72−1.86 (m, 1 H), 1.19−1.67 (m, 6 H),
0.98−1.07 (m, 1 H). ES-MS m/z 425.0 (M + H).
Synthesis of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopen-
tyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinamide (R-
16a). Step 1: 6-Bromo-2-methoxy-nicotinic Acid. A solution of
2,2,6,6-tetramethylpiperidine (0.766 g, 5.32 mmol) in tetrahydrofuran
(5 mL) was cooled to −78 °C under nitrogen, then 2.5 M n-
butyllithium in hexanes (2.34 mL, 0.375 g, 5.85 mmol) was added and
the mixture was stirred at −78 °C for 30 min. To the reaction mixture
was added a solution of 2-bromo-6-methoxypyridine (1.00 g, 5.32
mmol) in tetrahydrofuran (5 mL) dropwise. The reaction was stirred
at −78 °C for 1 h. After this time, an excess of dry ice was added to the
reaction mixture and the reaction was allowed to warm to room
temperature for 3 h. To the mixture was added water and ethyl acetate,
and the layers were separated. The aqueous layer was acidified to pH
4. The aqueous layer was extracted 3 times with ethyl acetate. The
combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and concentrated to give an off-white
solid (0.530 g, 43%). 1H NMR (DMSO-d6, 500 MHz) δ 12.87−13.40
(m, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 3.90 (s, 3
H).
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solid (0.094 g, 92%). H NMR (DMSO-d6, 500 MHz) δ 8.27−8.22
(m, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.59 (d, J
= 8.8 Hz, 1 H), 7.24 (d, J = 1.7 Hz, 1 H), 7.16−7.06 (m, 1 H), 4.95−
4.82 (m, 1 H), 4.04 (s, 3 H), 3.57−3.43 (m, 1 H), 3.29−3.19 (m, 1 H),
2.83 (d, J = 4.6 Hz, 3 H), 2.51 (m, 1 H), 2.44 (s, 3 H), 1.83−1.72 (m,
1 H), 1.65−1.56 (m, 1 H), 1.55−1.46 (m, 2 H), 1.44−1.35 (m, 1 H),
1.34−1.22 (m, 2 H), 1.13−1.02 (m, 1 H). ES-MS m/z 418.2 (M + H).
HPLC purity 100%, method 1.
Synthesis of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopen-
tyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxy-N,N-dimethylnico-
tinamide (R-16c). This compound was prepared from carboxylic acid
R-14c (0.048 g, 0.12 mmol) and a 2 M solution of dimethylamine in
tetrahydrofuran (0.595 mL, 1.19 mmol) following general procedure
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D. R-16c was obtained as a yellow solid (0.036 g, 71%). H NMR
(DMSO-d6, 500 MHz) δ 7.66−7.76 (m, 2 H), 7.58 (d, J = 8.5 Hz, 1
H), 7.23 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 8.7, 2.1 Hz, 1 H), 4.67−4.95
(m, 1 H), 3.96 (s, 3 H), 3.48 (dd, J = 18.4, 11.6 Hz, 1 H), 3.22 (dd, J =
18.11.6 Hz, 1 H), 2.98 (s, 3 H), 2.81 (s, 3 H), 2.50−2.60 (m, 1 H),
2.44 (s, 3 H), 1.77 (d, J = 8.1 Hz, 1 H), 1.47−1.65 (m, 3 H), 1.22−
1.44 (m, 3 H), 1.08 (d, J = 9.3 Hz, 1 H). ES-MS m/z 432.3 (M + H).
HPLC purity 100%, method 1.
Step 2: 6-Bromo-2-methoxy-nicotinic Acid Methyl Ester. To
potassium carbonate (1.34 g, 9.48 mmol) in N,N-dimethylformamide
(10 mL) was added 6-bromo-2-methoxy-nicotinic acid (1.10 g, 4.74
mmol) and methyl iodide (0.895 g, 6.31 mmol). The reaction was
stirred for 16 h at room temperature. The reaction mixture was diluted
with water and ethyl acetate, and the layers were separated. The
aqueous layer was washed with ethyl acetate 2 times. The combined
organic layers were washed with brine and dried over magnesium
sulfate, filtered, and concentrated. The filtrate was concentrated and
purified by silica gel column chromatography, eluting with a gradient
of 5−10% ethyl acetate/heptane to obtain the title compound as a
Synthesis of (R)-6-(1-(5-Cyano-6-methylpyridin-2-yl)-5-cy-
clopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotina-
mide (R-16d). This compound was prepared from chloropyrazoline
R-11 (0.175 g, 0.606 mmol) and boronate 15a (0.202 g, 0.727 mmol)
following general procedure A. Purification by silica gel column
chromatography eluting with a gradient of methanol in dichloro-
methane (0−9%) with ammonium hydroxide gave amide R-16d as a
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yellow solid (0.034 g, 14%). H NMR (DMSO-d6, 500 MHz) δ 8.24
(d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1
H), 7.73 (d, J = 8.8 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 1 H), 5.01 (dt, J =
11.6, 4.6 Hz, 1 H), 4.04 (s, 3 H), 3.52 (dd, J = 18.7, 11.6 Hz, 1 H),
3.20 (dd, J = 18.5, 4.6 Hz, 1 H), 2.83 (d, J = 4.6 Hz, 1 H), 2.54 (s, 3
H), 1.71 (dd, J = 12.0, 4.1 Hz, 1 H), 1.58−1.65 (m, 1 H), 1.48−1.58
(m, 2 H), 1.28−1.47 (m, 3 H), 1.11−1.18 (m, 1 H). ES-MS m/z 405.3
(M + H). HPLC purity 97%, method 1.
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colorless oil (0.459 g, 40%). H NMR (DMSO-d6, 500 MHz) δ 8.06
(d, J = 7.81 Hz, 1 H), 7.36 (d, J = 7.81 Hz, 1 H), 3.93 (s, 3 H), 3.81 (s,
3 H).
Step 3: 6-Bromo-2-methoxy-nicotinamide. 6-Bromo-2-methoxy-
nicotinic acid methyl ester (0.45 g, 183 mmol) and ammonium
hydroxide (5 mL) were combined in a sealed tube and heated to 70 °C
for 3 h. The reaction was cooled to room temperature, filtered, and
rinsed with water to obtain the title compound as a white solid (0.278
g, 66%). 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (d, J = 7.81 Hz, 1 H),
7.59−7.89 (m, 2 H), 7.35 (d, J = 7.81 Hz, 1H), 3.96 (s, 3 H).
Step 4: 2-Methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
yl)-nicotinamide (15a). This compound was prepared from 6-bromo-
2-methoxy-nicotinamide (0.270 g, 1.17 mmol) by the general
procedure C. The title compound was isolated as a brown liquid
Synthesis of (R)-6-(1-(5-Cyano-6-methylpyridin-2-yl)-5-cy-
clopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxy-N-methyl-
nicotinamide (R-16e). This compound was prepared from carboxylic
acid R-14d (0.10 g, 0.247 mmol) and a 2 M solution of methylamine
in tetrahydrofuran (1.23 mL, 2.47 mmol) following general procedure
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D. R-16e was obtained as a yellow solid (0.097 g, 62%). H NMR
(DMSO-d6, 500 MHz) δ 8.24−8.29 (m, 1 H), 8.21 (d, J = 7.8 Hz, 1
H), 7.89 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.26 (d, J = 8.8
Hz, 1 H), 4.85−5.09 (m, 1 H), 4.04 (s, 3 H), 3.44−3.59 (m, 1 H),
3.17−3.33 (m, 1 H), 2.83 (m, 4 H), 2.54 (s, 3 H), 1.66−1.82 (m, 1 H),
1.59−1.66 (m, 1 H), 1.49−1.58 (m, 2 H), 1.26−1.47 (m, 3 H), 1.06−
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(0.325 g, 100%). H NMR (DMSO-d6, 500 MHz) δ 8.11 (d, J = 7.3
Hz, 1 H), 7.63 (d, J = 7.3 Hz, 1 H), 7.51 (br s Two H), 3.98 (s, 3 H),
1.16 (s, 12 H).
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dx.doi.org/10.1021/jm500206r | J. Med. Chem. 2014, 57, 4273−4288