Journal of Medicinal Chemistry
Article
compound (963 mg) as a white solid. The solid was triturated in hot
Et2O (25 mL) to give the title compound 9 as a white solid (519 mg,
69% yield): 1H NMR (500 MHz, CDCl3) δ 1.89−1.97 (m, 4H), 2.33−
2.40 (m, 1H), 3.27−3.33 (m, 2H), 3.38−3.44 (m, 2H), 5.62 (br s,
1H), 5.79 (br s, 1H), 8.32 (s, 2H); 13C NMR (126 MHz, CDCl3) δ
29.4, 42.4, 50.1, 128.6, 149.1, 151.7, 176.9; LC−MS (method A, ESI,
m/z) tR = 1.16 min, 274/276/278 (M + H)+; ESI-HRMS calcd for
C11H1435Cl2N3O (M + H)+ 274.0508, found 274.0509.
dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one (43) (70 mg,
0.23 mmol), 4-morpholinophenylboronic acid (60 mg, 0.29 mmol),
and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol)
in MeCN (3 mL), at ambient temperature, was added 0.5 M aqueous
sodium carbonate solution (650 μL, 0.326 mmol). The reaction
mixture was heated to 150 °C under argon in the microwave for 60
min. Once cooled, the reaction mixture was concentrated in vacuo and
then dry-loaded onto silica. Purification was accomplished by flash
chromatography on silica gel eluting with CH2Cl2/MeOH (98:2 to
96:5) to give the title compound 44 (19 mg, 19% yield) as a white
Preparation of Compounds in Table 3 Exemplified by
Compounds 26 and 38. 1-(3-Chloro-5-phenylpyridin-4-yl)-
piperidine-4-carboxamide (26).41 To a stirred suspension of 1-(3,5-
dichloropyridin-4-yl)piperidine-4-carboxamide (9) (100 mg, 0.365
mmol), phenylboronic acid (49 mg, 0.401 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) in MeCN (4
mL) was added 0.5 M aqueous sodium carbonate solution (1.0 mL,
0.50 mmol). The reaction was heated to 150 °C under microwave
irradiation for 30 min. Once cooled, the reaction was concentrated in
vacuo and azeotroped with toluene (2 × 50 mL) to give a gray, oily
solid. Purification was accomplished by flash chromatography on silica
gel eluting with CH2Cl2/MeOH (97/3) and by semipreparitive HPLC
(gemini column 250 × 10, 15 min gradient, MeCN/H2O 10:90 to
90:10) to give the title compound 26 as a white solid (41 mg, 36%
yield): 1H NMR (500 MHz, CDCl3) δ 1.73−1.80 (m, 4H), 2.12−2.20
(m, 1H), 2.62 (dt, J = 13.4, 7.1 Hz, 2H), 3.15−3.21 (m, 2H), 5.40 (s,
2H), 7.24−7.30 (m, 2H), 7.38−7.51 (m, 3H), 8.21 (s, 1H), 8.44 (s,
1H); 13C NMR (126 MHz, CDCl3) δ 29.1, 42.4, 50.9, 127.8, 128.3,
128.6, 129.3, 134.1, 137.6, 149.6, 150.7, 152.8, 176.8; LC−MS
(method A, ESI, m/z) tR = 0.99 min, 316/318 (M + H)+; ESI-HRMS
calcd for C17H1935ClN3O (M + H)+ 316.1211, found 316.1206.
1-(3-Chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)piperidine-4-
carboxamide (38). To a stirred suspension of 1-(3,5-dichloropyridin-
4-yl)piperidine-4-carboxamide (9) (70 mg, 0.26 mmol), 4-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (92 mg, 0.32
mmol), and tetrakis(triphenylphosphine)palladium(0) (15 mg, 5 mol
%) in MeCN (3 mL), at ambient temperature, was added 0.5 M
aqueous sodium carbonate solution (720 μL, 0.360 mmol). The
reaction was heated to 150 °C for 45 min under microwave irradiation.
Once cooled, the reaction was concentrated in vacuo and then dry-
loaded onto silica. Purification was accomplished by flash chromatog-
raphy on silica gel (CH2Cl2/EtOH 98:2 to 93:7) to yield the title
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solid: H NMR (500 MHz, CDCl3) δ 1.34−1.39 (m, 2H), 1.92−2.01
(m, 4H), 2.74−2.81 (m, 2H), 3.17 (dt, J = 13.0, 4.0 Hz, 2H), 3.21−
3.25 (m, 4H), 3.29 (t, J = 6.9 Hz, 2H), 3.87−3.90 (m, 4H), 5.93 (br s,
1H), 6.98 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz 2H), 8.17 (br s, 1H),
8.39 (br s, 1H); 13C NMR (126 MHz, CDCl3) δ 31.8, 32.5, 38.7, 41.8,
47.7, 49.1, 67.0, 115.4, 128.3, 128.9, 130.2, 134.0, 149.2, 150.8, 151.0,
152.9, 181.7; LC−MS (method B, ESI, m/z) tR = 2.20 min, 427/429
(M + H)+; ESI-HRMS calcd for C23H2835ClN4O2 (M + H)+ 427.1895,
found 427.1903.
8-(3,5-Dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decane-1,3-dione
(53). To a stirred suspension of 3,4,5-trichloropyridine (10) (215 mg,
1.18 mmol) and 2,8-diazaspiro[4,5]decan-1,3-dione (180 mg, 1.07
mmol) in NMP (4.5 mL), at ambient temperature, was added
triethylamine (450 μL, 3.20 mmol). The reaction mixture was heated
to 220 °C under microwave irradiation for 60 min. Once cooled, the
mixture was diluted with MeOH (20 mL) and placed on an SCX
column (10 g). Elution was carried out with CH2Cl2/MeOH followed
by 1 M methanolic ammonia. Concentration of the ammonia extract in
vacuo gave a light orange solid. Recrystallization from EtOAc gave 8-
(3,5-dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decane-1,3-dione (53)
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(206 mg, 62% yield) as a cream solid: H NMR (500 MHz, CDCl3)
δ 1.69 (d, J = 13.4 Hz, 2H), 2.28 (ddd, J = 13.4, 10.7, 4.1 Hz, 2H), 2.72
(s, 2H), 3.32 (ddd, J = 13.2, 10.7, 2.6 Hz, 2H), 3.48 (dt, J = 13.2, 4.1
Hz, 2H), 8.26 (br s, 1H), 8.37 (br s, 2H); LC−MS (method B, ESI,
m/z) tR = 2.43 min, 314/316/318 (M + H)+.
8-(3-Chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)-2,8-
diazaspiro[4.5]decan-1,3-dione (54). Ten microwave vials were
prepared as follows: To a stirred suspension of 8-(3,5-dichloropyr-
idin-4-yl)-2,8-diazaspiro[4.5]decane-1,3-dione (53) (300 mg, 0.764
mmol), 4-morpholinophenylboronic acid (222 mg, 0.963 mmol), and
tetrakis(triphenylphosphine)palladium (0) (100 mg, 0.0850 mmol) in
MeCN (12 mL) at ambient temperature was added 0.5 M aqueous
sodium carbonate solution (3 mL). The reaction was heated to 150 °C
by microwave for 60 min. Once cooled, the reaction mixtures from the
ten vials were combined, concentrated in vacuo, and dry-loaded onto
silica. Purification was accomplished by flash chromatography
(hexane/EtOAc 30:70) to obtain the title compound 54 (950 mg,
25% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.48−1.54
(m, 2H), 2.07−2.14 (m, 2H), 2.55 (s, 2H), 2.75 (t, J = 11.7 Hz, 2H),
3.18−3.23 (m, 2H), 3.23−3.27 (m, 4H), 3.88−3.92 (m, 4H), 6.97−
7.05 (m, 2H), 7.17−7.24 (m, 2H), 8.10 (s, 1H), 8.25 (s, 1H), 8.47 (s,
1H); 13C NMR (126 MHz, CDCl3) δ 33.3, 40.6, 44.2, 47.2, 48.7, 66.8,
115.2, 127.8, 130.0, 148.1, 150.0, 150.9, 153.0, 174.9, 181.4, (2 Cq not
observed); LC−MS (method B, ESI, m/z) tR = 2.20 min, 441/443 (M
+ H)+; ESI-HRMS calcd for C23H2635ClN4O3 (M + H)+ 441.1688,
found 441.1693.
Preparation of Compounds in Table 5 Exemplified by
Compounds 56, 59, and 60. 8-(3-Bromo-5-methylpyridin-4-yl)-
2,8-diazaspiro[4.5]decan-1-one (55). A solution of 3-bromo-4-
chloro-5-methylpyridine (300 mg, 1.45 mmol), triethylamine (610
μL, 4.36 mmol), and 2,8-diazaspiro[4.5]decan-1-one hydrochloride
(291 mg, 1.53 mmol) in NMP (4.4 mL) was heated to 220 °C under
microwave irradiation for 5 h at 220 °C. Once cooled, the reaction was
partitioned between EtOAc and sat. NaHCO3 (100 mL each), the
separated organic layer was extracted with EtOAc (2 × 75 mL), and
the combined organic extracts were washed with brine (75 mL), dried
over MgSO4, filtered, and concentrated in vacuo to give a crude yellow
solid. The solid was recrystallized in hot EtOAc, filtered, washed with
ether, and dried in vacuo to yield 8-(3-bromo-5-methylpyridin-4-yl)-
2,8-diazaspiro[4.5]decan-1-one (55) (44 mg, 9% yield) as an off white
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compound 38 (53 mg, 52% yield) as a pale orange/pink solid: H
NMR (500 MHz, DMSO-d6) δ 1.53−1.60 (m, 4H), 2.04−2.11 (m,
1H), 2.49−2.57 (m, 2H), 3.00−3.06 (m, 2H), 3.15−3.20 (m, 4H),
3.73−3.78 (m, 4H), 6.73 (br s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.18 (d,
J = 8.7 Hz, 3H), 8.13 (br s, 1H), 8.40 (br s, 1H); 13C NMR (126 MHz,
CDCl3) δ 29.2, 42.4, 48.9, 51.0, 67.0, 115.4, 128.3 130.1, 134.0, 147.9,
149.7, 150.9, 153.6, 176.9, (1 Cq not observed); LC−MS (method B,
ESI, m/z) tR = 1.96 min, 401/403 (M + H)+; ESI-HRMS calcd for
C21H2635ClN4O2 (M + H)+ 401.1739, found 401.1746.
Preparation of Compounds in Table 4 Exemplified by
Compounds 44 and 54. 8-(3,5-Dichloropyridin-4-yl)-2,8-diazaspiro-
[4.5]decan-1-one (43). To a stirred suspension of 3,4,5-trichloropyr-
idine (10) (509 mg, 2.79 mmol) and 2,8-diazaspiro[4,5]decan-1-one
hydrochloride (410 mg, 2.66 mmol) in NMP (14.6 mL), at ambient
temperature, was added triethylamine (1.10 mL, 7.89 mmol). The
reaction mixture was heated to 220 °C under microwave irradiation for
60 min. Once cooled, the reaction mixture was partitioned between
EtOAc and sat. NaHCO3, the separated aqueous layer was extracted
with EtOAc (2 × 100 mL), and the combined organic extracts were
washed with brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo to give a crude pale yellow oil. Purification was
accomplished by flash chromatography on silica gel eluting with
CH2Cl2/EtOH (97.5:2.5 to 97:3) to give 8-(3,5-dichloropyridin-4-yl)-
2,8-diazaspiro[4.5]decan-1-one (43) (422 mg, 53% yield) as a white
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solid: H NMR (500 MHz, CDCl3) δ 1.53 (br d, J = 13.1 Hz, 2H),
2.07−2.18 (m, 4H), 3.33 (dt, J = 11.9, 2.6 Hz, 2H), 3.37−3.45 (m,
4H), 6.66 (br s, 1H), 8.33 (br s, 2H); LC−MS (method B, ESI, m/z)
tR = 2.66 min, 300/302/304 (M + H)+.
8-(3-Chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)-2,8-
diazaspiro[4.5]decan-1-one (44). To a stirred suspension of 8-(3,5-
M
J. Med. Chem. XXXX, XXX, XXX−XXX