Journal of Medicinal Chemistry
Article
2H), 3.04 (d, J = 6.8 Hz, 2H), 3.31 (dt, J = 2.0, 11.6 Hz, 2H), 3.68 (s,
3H), 3.92−3.98 (m, 2H), 6.51 (dd, J = 1.6, 6.8 Hz, 1H), 6.69 (s, 1H),
6.77 (s, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz,
1H). 13C NMR (150 MHz, CDCl3) δ 157.6, 153.9, 139.9, 139.0, 137.5,
136.7, 123.4, 121.2, 120.6, 120.3, 115.2, 112.6, 109.9, 68.0, 62.0, 55.9,
34.5, 31.6, 21.8, 19.7, 19.3, 14.4, 10.6, 3.6. HRMS calcd for
(C28H37N3O2) [M + H]+ 448.2959; found 448.2951.
N-(Cyclopropylmethyl)-2-ethyl-N-[(tetrahydro-2H-pyran-4-
yl)methyl]-7-(2,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-
3-amine (24p). Compound 24p was prepared according to the
procedure described for the synthesis of 24r using 23a (60 mg, 0.15
mmol), (2,4,5-trimethoxyphenyl)boronic acid (39 mg, 0.18 mmol),
Pd(PPh3)4 (35 mg, 0.031 mmol) and Ba(OH)2·8H2O (58 mg, 0.18
mmol) in DME (10 mL) and water (5 mL). The product was purified
by column chromatography on silica gel (n-hexane:EtOAc = 1:1) to
afford 24p (62 mg, 85%) as a yellow oil. 1H NMR (600 MHz, CDCl3)
δ −0.02−0.06 (m, 2H), 0.34−0.41 (m, 2H), 0.78−0.88 (m, 1H),
1.19−1.36 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H), 1.52−1.63 (m, 1H),
1.71−1.79 (m, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.86−2.91 (m, 2H),
3.02−3.07 (m, 2H), 3.27−3.34 (m, 2H), 3.77 (s, 3H), 3.86 (s, 3H),
3.90−3.96 (m, 2H), 3.96 (s, 3H), 6.67 (s, 1H), 6.68 (d, J = 7.0 Hz,
1H), 7.01 (dd, J = 7.0, 8.6 Hz, 1H), 7.22 (s, 1 H), 7.44 (d, J = 8.6 Hz,
1H). 13C NMR (150 MHz, CDCl3) δ 153.5, 152.3, 150.6, 142.9, 137.7,
137.2, 121.3, 120.8, 115.3, 114.5, 114.3, 112.4, 98.3, 68.0, 62.1, 61.9,
56.8, 56.4, 56.1, 34.4, 31.6, 19.8, 14.1, 10.6, 3.7. HRMS calcd for
(C28H37N3O4) [M + H]+ 480.2858; found 480.2857.
N-(Cyclopropylmethyl)-7-(2,6-dimethoxy-4-methylphenyl)-
2-ethyl-N-[(tetrahydro-2H-pyran-4-yl)methyl]pyrazolo[1,5-a]-
pyridin-3-amine (24m). Compound 24m was prepared according to
the procedure described for the synthesis of 24l using 34b (420 mg,
1.0 mmol), NaH (60%, 61 mg, 1.5 mmol), (bromomethyl)-
cyclopropane (117 μL, 1.2 mmol) in DMF (5 mL) and 4 M HCl/
EtOAc (40 mL) in EtOAc (20 mL) and tetrahydro-2H-4-
pyrancarbaldehyde (232 mg, 2.0 mmol), NaBH(OAc)3 (432 mg, 2.0
mmol) in THF (5 mL). The product was purified by column
chromatography on silica gel (n-hexane:EtOAc = 4:1) to afford 24m
(353 mg, 76%, 3 steps) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ
−0.01−0.03 (m, 2H), 0.34−0.40 (m, 2H), 0.80−0.90 (m, 1H), 1.23 (t,
J = 7.6 Hz, 3H), 1.20−1.34 (m, 2H), 1.56−1.62 (m, 1H), 1.74−1.80
(m, 2H), 2.45 (s, 3H), 2.77 (q, J = 7.6 Hz, 2H), 2.89 (d, J = 6.4 Hz,
2H), 3.06 (d, J = 6.8 Hz, 2H), 3.32 (dt, J = 2.0, 11.6 Hz, 2H), 3.71 (s,
6H), 3.92−3.98 (m, 2H), 6.53 (s, 2H), 6.60 (dd, J = 1.2, 6.8 Hz, 1H),
7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.2, 8.8 Hz, 1H). 13C
NMR (150 MHz, C5D5N) δ 158.4, 152.8, 140.9, 137.2, 134.8, 121.1,
120.8, 115.2, 113.2, 109.5, 105.0, 67.2, 61.5, 61.3, 55.1, 34.1, 31.3, 21.4,
19.5, 13.8, 10.4, 3.4. HRMS calcd for (C28H37N3O3) [M + H]+
464.2908; found 464.2908.
[4-(3-{(Cyclopropylmethyl)[(tetrahydro-2H-pyran-4-yl)-
methyl]amino}-2-ethylpyrazolo[1,5-a]pyridin-7-yl)-3,5-
dimethoxyphenyl]methanol (24q). Compound 24q was prepared
according to the procedure described for the synthesis of 24r using
23a (250 mg, 0.64 mmol), [4-(hydroxymethyl)-2,6-dimethoxyphenyl]-
boronic acid (407 mg, 1.9 mmol), Pd(PPh3)4 (111 mg, 0.096 mmol),
and Ba(OH)2·8H2O (303 mg, 0.96 mmol) in DME (13 mL) and
water (6.5 mL). The product was purified by column chromatography
on silica gel (n-hexane:EtOAc = 1:3) to afford 24q (300 mg, 98%) as a
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pale yellow solid. H NMR (400 MHz, CDCl3) δ −0.03−0.05 (m,
N-(Cyclopropylmethyl)-7-(2,4-dimethoxy-6-methylphenyl)-
2-ethyl-N-[(tetrahydro-2H-pyran-4-yl)methyl]pyrazolo[1,5-a]-
pyridin-3-amine (24n). Compound 24n was prepared according to
the procedure described for the synthesis of 24l using 34c (80 mg,
0.19 mmol), NaH (60%, 12 mg, 0.29 mmol), (bromomethyl)-
cyclopropane (22 mg, 0.23 mmol) in DMF (2 mL) and 4 M HCl/
EtOAc (2 mL) in EtOAc (1 mL) and tetrahydro-2H-4-pyrancarbalde-
hyde (66 mg, 0.58 mmol), NaBH(OAc)3 (123 mg, 0.58 mmol) in
THF (2 mL). The product was purified by column chromatography
on silica gel (n-hexane:EtOAc = 4:1) to afford 24n (70 mg, 78%, 3
steps) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ −0.05−0.00 (m,
2H), 0.31−0.36 (m, 2H), 0.77−0.87 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H),
1.22−1.32 (m, 2H), 1.56−1.64 (m, 1H), 1.72−1.80 (m, 2H), 2.00 (s,
3H), 2.72−2.79 (m, 2H), 2.87 (d, J = 6.4 Hz, 2H), 3.04 (d, J = 6.8 Hz,
2H), 3.27−3.35 (m, 2H), 3.67 (s, 3H), 3.85 (s, 3H), 3.90−3.96 (m,
2H), 6.43 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.49 (dd, J =
1.2, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8
Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 161.0, 158.9, 153.8, 140.2,
137.5, 136.6, 121.2, 120.6, 115.9, 115.2, 112.9, 106.8, 96.7, 68.0, 62.0,
55.9, 55.3, 34.5, 31.6, 31.6, 19.8, 19.7, 14.4, 10.6, 3.6. HRMS calcd for
(C28H37N3O3) [M + H]+ 464.2908; found 464.2913.
2H), 0.32−0.40 (m, 2H), 0.80−0.90 (m, 1H), 1.22 (t, J = 7.5 Hz, 3H),
1.22−1.35 (m, 2H), 1.53−1.66 (m, 1H), 1.72−1.81 (m, 2H), 1.96 (t, J
= 5.6 Hz, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.86−2.92 (m, 2H), 3.02−
3.09 (m, 2H), 3.28−3.38 (m, 2H), 3.74 (s, 6H), 3.90−4.00 (m, 2H),
4.76 (d, J = 5.6 Hz, 2H), 6.61 (dd, J = 1.3, 6.8 Hz, 1H), 6.72 (s, 2H),
7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.3, 8.8 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 158.8, 153.4, 144.4, 137.4, 134.0, 121.2,
120.6, 115.4, 113.3, 110.9, 102.7, 68.0, 65.2, 62.1, 62.0, 56.1, 34.5, 31.6,
19.6, 14.4, 10.6, 3.6. HRMS calcd for (C28H37N3O4) [M + H]+
480.2857; found 480.2848.
N - ( C y c l o p r o p y l m e t h y l ) - 7 - [ 2 , 6 - d i m e t h o x y - 4 -
(methoxymethyl)phenyl]-2-ethyl-N-[(tetrahydro-2H-pyran-4-
yl)methyl]pyrazolo[1,5-a]pyridin-3-amine (24r). To a solution of
23a (60 mg, 0.15 mmol) in DME (2 mL) and water (1 mL) were
added [2,6-dimethoxy-4-(methoxymethyl)phenyl]boronic acid (45
mg, 0.20 mmol), Pd(PPh3)4 (35 mg, 0.030 mmol), and Ba-
(OH)2·8H2O (72 mg, 0.23 mmol). The mixture was stirred at 90
°C for 4 h under a nitrogen stream and was then cooled and diluted
with water. It was subsequently filtered through a pad of Celite to
remove insoluble residue, and the filtrate was washed with EtOAc. The
mixture was extracted with EtOAc, and the organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (n-
hexane:EtOAc = 1:1) to afford 24r (40 mg, 54%) as a light-yellow
solid. 1H NMR (400 MHz, CDCl3) δ −0.02−0.04 (m, 2H), 0.34−0.38
(m, 2H), 0.80−0.90 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.24−1.34 (m,
2H), 1.54−1.64 (m, 1H), 1.74−1.80 (m, 2H), 2.77 (q, J = 7.6 Hz,
2H), 2.88 (d, J = 6.8 Hz, 2H), 3.05 (d, J = 7.2 Hz, 2H), 3.31 (t, J =
11.6 Hz, 2H), 3.49 (s, 3H), 3.73 (s, 6H), 3.90−4.00 (m, 2H), 4.53 (s,
2H), 6.59 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 2H), 7.00 (dd, J = 6.8, 8.8
Hz, 1H), 7.44 (dd, J = 1.2, 8.8 Hz, 1H). 13C NMR (150 MHz, CDCl3)
δ 158.7, 153.3, 141.4, 137.3, 134.0, 121.0, 120.4, 115.4, 113.1, 111.3,
103.6, 74.9, 68.0, 62.2, 62.0, 58.4, 56.1, 34.5, 31.6, 19.7, 14.3, 10.6, 3.6.
HRMS calcd for (C29H39N3O4) [M + H]+ 494.3013; found 494.3019.
N - ( C y c l o p r o p y l m e t h y l ) - 7 - [ 2 , 4 - d i m e t h o x y - 6 -
(methoxymethyl)phenyl]-2-ethyl-N-[(tetrahydro-2H-pyran-4-
yl)methyl]pyrazolo[1,5-a]pyridin-3-amine (24s). Compound 24s
was prepared according to the procedure described for the synthesis of
24r using 23a (60 mg, 0.15 mmol), [2,4-dimethoxy-6-
(methoxymethyl)phenyl]boronic acid (104 mg, 0.46 mmol), Pd-
(PPh3)4 (35 mg, 0.030 mmol) and Ba(OH)2·8H2O (72 mg, 0.23
mmol) in DME (10 mL) and water (5 mL). The product was purified
N-(Cyclopropylmethyl)-2-ethyl-N-[(tetrahydro-2H-pyran-4-
yl)methyl]-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-
3-amine (24o). Compound 24o was prepared according to the
procedure described for the synthesis of 24l using 34d (100 mg, 0.23
mmol), NaH (60%, 14 mg, 0.35 mmol), (bromomethyl)cyclopropane
(27 μL, 0.28 mmol) in DMF (2 mL) and 4 M HCl/EtOAc (2 mL) in
EtOAc (1 mL) and tetrahydro-2H-4-pyrancarbaldehyde (107 mg, 0.94
mmol), NaBH(OAc)3 (198 mg, 0.94 mmol) in THF (2 mL). The
product was purified by column chromatography on silica gel (n-
hexane:EtOAc = 3:1) to afford 24o (82 mg, 73%, 3 steps) as a pale
1
yellow solid. H NMR (400 MHz, CDCl3) δ −0.02−0.03 (m, 2H),
0.34−0.40 (m, 2H), 0.80−0.90 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H),
1.23−1.34 (m, 2H), 1.54−1.64 (m, 1H), 1.73−1.80 (m, 2H), 2.78 (q, J
= 7.6 Hz, 2H), 2.89 (d, J = 6.8 Hz, 2H), 3.05 (d, J = 6.8 Hz, 2H),
3.27−3.36 (m, 2H), 3.71 (s, 6H), 3.89 (s, 3H), 3.92−3.97 (m, 2H),
6.26 (s, 2H), 6.59 (dd, J = 1.6, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz,
1H), 7.43 (dd, J = 1.6, 8.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
162.2, 159.5, 153.2, 137.4, 134.1, 121.0, 120.4, 115.2, 113.4, 105.2,
91.4, 68.0, 62.2, 62.0, 56.0, 55.4, 34.5, 31.6, 19.7, 14.4, 10.6, 3.6. HRMS
calcd for (C28H37N3O4) [M + H]+ 480.2857; found 480.2862.
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dx.doi.org/10.1021/jm300259r | J. Med. Chem. 2012, 55, 5255−5269