6714 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 18
Lavieri et al.
dissolved in methanol (40 mL) and glacial acetic acid (10 mL)
and treated with palladium on carbon (cat., 80 mg) under an
atmosphere of hydrogen. After about 36 h the reaction mix-
ture was filtered through Celite, concentrated under reduced
pressure, diluted with water, made alkaline with saturated
sodium bicarbonate, and extracted 8 times into dichloro-
methane to afford a white solid (1.37 g, 5.49 mmol, 11%).
1H NMR (400.1 MHz, DMSO-d6) δ (ppm): 8.67 (s, 1H), 7.20
(q, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 6.62 (d, J = 13 Hz,
1H), 6.52-6.46 (m, 1H), 4.57 (s, 2H), 3.20-3.09 (m, 3H),
2.91-2.82 (m, 2H), 2.46-2.36 (m, 2H), 1.48 (d, J = 14 Hz,
2H). 13C NMR (100.6 MHz, DMSO-d6) δ (ppm): 176.0, 164.3,
145.0, 130.1, 109.3, 103.1, 100.2, 58.8, 58.6, 42.1 (2C), 28.9 (2C).
HRMS (TOF, ESI) C13H17N3OF [M þ H]þ calculated
250.1356, found 250.1351. LC-MS: rt (min) = 1.394. LRMS
(ESI) m/z = 250.1.
8.04-7.92 (m, 4H), 7.64-7.56 (m, 2H), 7.11 (q, J = 8 Hz, 1H),
6.68-6.63 (m, 1H), 6.58-6.52 (m, 1H), 6.49-6.43 (m, 1H), 4.58
(s, 2H), 3.48 (q, J=6 Hz, 2H), 2.91-2.83 (m, 2H), 2.80-2.72 (m,
2H), 2.64-2.53 (m, 4H), 1.58 (d, J = 14 Hz, 2H). 13C NMR
(100.6 MHz, DMSO-d6) δ (ppm): 175.9, 166.2, 164.3, 161.9,
145.0, 134.1, 132.2, 130.3, 128.8, 127.8, 127.6, 127.5, 127.3,
126.7, 124.1, 109.3, 103.3, 100.3, 58.7, 58.1, 56.9, 49.4 (2C),
37.3, 28.2 (2C). HRMS (TOF, ESI) C26H28N4O2F [M þ H]þ
calculated 447.2196, found 447.2195. LC-MS: rt (min) = 2.287.
LRMS (ESI) m/z = 447.2. Analogues 22b-d were made follow-
ing the same protocol starting from 21a and were purified via
reversed-phase chromatography to greater than 95% purity
(as trifluoroacetate salts) as analyzed by ELSD and UV at both
214 and 254 nM.
N-(2-(1-(3-Fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-
8-yl)ethyl)-2-naphthamide Hydrochloride (22a HCl). N-(2-(1-(3-
3
8-(2-Aminoethyl)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]de-
can-4-one Dihydrochloride (21a). 1-(3-Fluorophenyl)-1,3,8-tri-
azaspiro[4.5]decan-4-one 20a (1370 mg, 5.49 mmol) and tert-
butyl (2-oxoethyl)carbamate (961 mg, 6.03 mmol) were com-
bined and dissolved in dichloromethane (25 mL) and methanol
(10 mL) and stirred for about 30 min at room temperature. After
about 30 min macroporous triacetoxyborohydride (3 g, 7.26
mmol) was added to the reaction, and after 14 h an additional
amount of tert-butyl (2-oxoethyl)carbamate (200 mg, 1.25 mmol)
was added to drive the reaction to completion. After about 24 h
the reaction mixture was filtered through Celite and concen-
trated under reduced pressure. The crude compound was chro-
matographed on an 80 g flash column eluting in a gradient of
0%-10% methanol in dichloromethane to afford a white solid
(1.64 g, 4.18 mmol, 76%). 1H NMR (400.1 MHz, DMSO-d6) δ
(ppm): 8.69 (s, 1H), 7.22 (q, J = 8 Hz, 1H), 6.72-6.63 (m, 2H),
6.60-6.49 (m, 2H), 4.58 (s, 2H), 2.83-2.75 (m, 2H), 2.74-2.65
(m, 2H), 2.61-2.48 (m, 2H), 2.42-2.35 (m, 2H), 1.91 (s, 2H),
1.55 (d, J = 13 Hz, 2H), 1.39 (s, 9H). 13C NMR (100.6 MHz,
DMSO-d6) δ (ppm): 175.8, 161.9, 155.6, 145.0, 130.4, 109.4,
103.2, 100.3, 77.5, 58.7, 58.1, 57.4, 49.3 (2C), 37.6, 28.3 (3C),
28.1 (2C). HRMS (TOF, ESI) C20H30N4O3F [M þ H]þ calcu-
lated 393.2302, found 393.2301. LC-MS: rt (min) = 1.966.
LRMS (ESI) m/z = 393.2. tert-Butyl (2-(1-(3-fluorophenyl)-4-
oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)carbamate (1.64 g,
4.18 mmol) was dissolved in dichloromethane (40 mL) and a
minimal amount of methanol added dropwise. Hydrochloric
acid was added (4 M in dioxane, 20 mL), and the reaction was
stirred for approximately 36 h at room temperature. The reac-
tion was concentrated under reduced pressure to afford a white
solid (1.34 g, 3.66 mmol, 88%). 1H NMR (400.1 MHz, DMSO-
d6) δ (ppm): 9.12 (s, 1H), 8.47 (s, 2H), 7.18 (q, J = 8 Hz, 1H),
7.07-7.02 (m, 1H), 6.79-6.72 (m, 1H), 6.57-6.50 (m, 1H), 4.63
(s, 2H), 3.72-3.56 (m, 4H), 3.45-3.38 (m, 4H), 3.10-3.00 (m,
2H), 1.90 (d, J = 15 Hz, 2H), 13C NMR (100.6 MHz, DMSO-d6)
δ (ppm): 174.4, 162.3, 144.4, 130.3, 109.8, 103.8, 100.2, 69.0,
56.5, 53.3, 49.1 (2C), 33.8, 25.6 (2C). HRMS (TOF, ESI)
C15H22N4OF [M þ H]þ calculated 293.1778, found 293.1776.
LC-MS: rt (min) = 1.405. LRMS (ESI) m/z = 293.1.
Fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)-2-
naphthamide 22a (1.25 mg, 2.80 mmol) was stirred in methanol
(30 mL) at room temperature and treated with hydrochloric acid
(4 M in dioxane, 4 mL). After about 25 min the compound was
dried under reduced pressure to afford a white solid (1.31 g, 2.72
mmol, 97%). 1H NMR (400.1 MHz, DMSO-d6) δ (ppm): 10.99
(s, 1H), 9.14 (t, J = 5 Hz, 1H), 9.11 (s, 1H), 8.60 (s, 1H),
8.06-7.97 (m, 4H), 7.65-7.57 (m, 2H), 7.21 (q, J = 8 Hz, 1H),
7.05-7.01 (m, 1H), 6.83-6.77 (m, 1H), 6.58-6.52 (m, 1H), 4.64
(s, 2H), 3.85-3.75 (m, 2H), 3.74-3.64 (m, 4H), 3.41-3.36 (m,
2H), 3.11-2.99 (m, 2H), 1.92 (d, J = 14 Hz, 2H). 13C NMR
(100.6 MHz, DMSO-d6) δ (ppm): 174.4, 166.6, 164.6, 162.2,
144.6, 134.3, 132.1, 131.2, 130.5, 128.9, 127.9, 127.8, 127.6,
126.8, 124.2, 109.9, 104.0, 100.3, 59.0, 56.6, 55.7, 48.7 (2C),
34.4, 25.7 (2C). HRMS (TOF, ESI) C26H28N4O2F [M þ H]þ
calculated 447.2196, found 447.2186. LC-MS: rt (min) = 2.264.
LRMS (ESI) m/z = 447.2.
8-(2-Aminoethyl)-1-(3-chlorophenyl)-1,3,8-triazaspiro[4.5]-
decan-4-one Dihydrochloride (21b). 1-(3-Chlorophenyl)-1,3,8-
triazaspiro[4.5]decan-4-one 20b (127 mg, 0.47 mmol) and tert-
butyl (2-oxoethyl)carbamate (83.8 mg, 0.51 mmol) were com-
bined and dissolved in dichloromethane (1.5 mL) and methanol
(0.05 mL) and stirred for about 30 min at room temperature.
After about 30 min macroporous triacetoxyborohydride (600
mg, 1.4 mmol) was added to the reaction, and after 14 h an
additional amount of tert-butyl (2-oxoethyl)carbamate (41.9
mg, 0.25 mmol) was added to drive the reaction to completion.
After about 24 h the reaction mixture was filtered through Celite
and concentrated under reduced pressure. The crude compound
was chromatographed on a 12 g flash column eluting in a
gradient of 0%-10% methanol in dichloromethane to afford
a white solid (72 mg, 0.18 mmol, 37%). 1H NMR (400.1 MHz,
MeOD) δ (ppm): 7.21 (t, J = 9 Hz, 1H), 6.95-6.90 (m, 2H),
6.86-6.78 (m, 1H), 4.69 (s, 2H), 3.23-3.02 (m, 4H), 2.81-2.67
(m, 4H), 1.97 (s, 2H), 1.78 (d, J = 14 Hz, 2H), 1.45 (s, 9H). 13C
NMR (100.6 MHz, MeOD) δ (ppm): 178.2, 158.5, 145.8, 136.2,
141.3, 119.5, 115.4, 114.2, 80.3, 60.4, 60.1, 58.4, 50.7 (2C), 38.1,
29.2 (2C). 28.7 (3C). HRMS (TOF, ESI) C20H30N4O3Cl [M þ
H]þ calculated 409.2006, found 409.1996. LC-MS: rt (min) =
1.984. LRMS (ESI) m/z = 409.2. tert-Butyl (2-(1-(3-chloro-
phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)carbamate
(72 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL)
and a minimal amount of methanol added dropwise. Hydro-
chloric acid was added (4 M in dioxane, 1.0 mL), and the re-
action was stirred for approximately 16 h at room temperature.
The reaction was concentrated under reduced pressure to afford
a white solid (60 mg, 0.16 mmol, 93%). 1H NMR (400.1 MHz,
MeOD) δ (ppm): 7.25 (t, J = 8 Hz, 1H), 7.20-7.15 (m, 1H),
6.88-6.81 (m, 2H), 4.74 (s, 2H), 3.96-3.86 (m, 2H), 3.73-3.65
(m, 2H), 3.51 (s, 4H), 3.20-3.10 (m, 2H), 2.05 (d, J = 15 Hz,
2H). 13C NMR (100.6 MHz, MeOD) δ (ppm): 176.9, 145.2, 135.6,
131.5, 119.9, 115.1, 114.4, 60.5, 58.4, 54.9, 51.2 (2C), 35.4, 27.8
(2C). HRMS (TOF, ESI) C15H22N4OCl [M þ H]þ calculated
N-(2-(1-(3-Fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-
8-yl)ethyl)-2-naphthamide (22a). 8-(2-Aminoethyl)-1-(3-fluoro-
phenyl)-1,3,8-triazaspiro[4.5]decan-4-one dihydrochloride 21a
(1.23 g, 3.37 mmol), 2-naphthoyl chloride (641 mg, 3.37 mmol),
and N,N-diisopropylethylamine (2.05 mL, 11.7 mmol) were all
dissolved in N,N-dimethylformamide (20 mL) at 0 ꢀC. The re-
action mixture was allowed to warm to room temperature and
stirred for about 12 h. The reaction mixture was diluted with
water and extracted into dichloromethane 5 times. The dichloro-
methane layer was then washed 3 times with a solution of lithium
chloride (3 M) and dried under reduced pressure. The reaction
mixture was chromatographed on an 80 g flash column eluting
in 0%-5% methanol in dichloromethane to afford a white solid
1
(1.25 g, 2.80 mmol, 83%). H NMR (400.1 MHz, DMSO-d6)
δ (ppm): 8.69 (s, 1H), 8.60 (t, J = 5 Hz, 1H), 8.45 (s, 1H),