J. H. Kim, G. Nam / Bioorg. Med. Chem. xxx (2016) xxx–xxx
7
reaction was confirmed by TLC (hexane–ethyl acetate = 1:2). After
4.1.8. 3-(3-Benzoyl-3-azabicyclo[3.1.0]hexane-6-carboxamido)
the reaction was completed, the reaction mixture was concen-
methyl-5-isobutyl-1-phenyl-1H-pyrazole (10d)
trated under reduced pressure to obtain 210 mg (99%) of the target
Compound 10d was synthesized in a manner similar to that of
1
compound 6. H NMR (300 MHz, CDCl
3
) 1.17 (s, 4H), 2.21(m, 4H),
10b using 9 and benzoyl chloride (125
l
L, 1.08 mmol) to obtain
), d 7.48–7.30 (m, 10H),
6.94 (t, J = 4.98 Hz, 1H), 6.13 (s, 1H), 4.45 (d, J = 5.1 Hz, 2H), 4.19
d, J = 12.4 Hz, 1H), 3.66 (dd, J = 3.06, 10.9 Hz, 1H), 3.55–3.47 (m,
1
3
.00 (s, 3H), 7.51 (m, 2H), 7.79 (m, 2H), 9.59 (br s, 1H), 10.29 (br
360 mg (83.2%). H NMR (300 MHz, CDCl
3
s, 1H), 14.8 (s, 2H).
(
4
.1.4. 3-[3-(3,3-Dimethylbutyl)-3-azabicyclo[3.1.0]hexane-6-
2H), 2.48 (d, J = 7.14 Hz, 2H), 2.10 (d, J = 10.2 Hz, 2H), 1.85–1.76
carboxamido]-2(N-methyl)propyl-1H-benzo[d]imidazol (7a)
Compound 6 (100.6 mg, 0.270 mmol) and a molecular sieve
were dried in vacuum and dissolved in 2 mL of methylene chloride.
Then, triethylamine (38
0
(m, 1H), 1.31 (t, J = 3.0 Hz, 1H), 0.85 (d, J = 6.6 Hz, 6H). 13C NMR
3
(75 MHz, CDCl ), d 170.6, 170.3, 149.2, 144.3, 139.7, 136.6, 130.0,
129.1, 128.3, 128.1, 127.0, 125.8, 104.8, 51.1, 47.6, 37.7, 35.1,
+
l
L, 0.270 mmol) was added dropwise at
L, 0.270 mmol)
28.4, 25.4, 25.1, 23.7, 22.4. HRMS [ESI ] m/z calcd for C27
[M+Na] : 466.2261. found: 466.2269.
30
H N
4
O
+
°C. After adding 3,3-dimethylbutyraldehyde (33
l
dropwise, the mixture was stirred at room temperature for 1 h.
Sodium triacetoxyborohydride (171 mg, 0.810 mmol) was added
and stirred for 2 h. The reaction mixture was diluted with methy-
lene chloride and extracted several times with saturated sodium
bicarbonate. The organic layer was dried with anhydrous magne-
sium sulfate, filtered, concentrated under reduced pressure and
4.1.9. 5-Isobutyl-1-phenyl-3-[3-(2-phenylacetyl)-3-azabicyclo
[3.1.0]hexane-6-carboxamido] methyl-1H-pyrazole (10e)
Compound 10e was synthesized in a manner similar to that
1
of 10d, with a yield of 82.1%. H NMR (300 MHz, CDCl
3
), d
7.51–7.22 (m, 10H), 6.67 (t, J = 4.98 Hz, 1H), 6.15 (s, 1H), 4.47
(d, J = 5.16 Hz, 2H), 3.85 (d, J = 12.3 Hz, 1H), 3.65–3.56 (m, 4H),
3.49 (td, J = 3.9, 12.3 Hz, 1H), 2.50 (d, J = 7.17 Hz, 2H), 2.16–
2.07 (m, 2H), 1.87–1.78 (m, 1H), 1.17 (t, J = 3.0 6 Hz, 1H), 0.88
separated by column chromatography (CH
obtain 63.1 mg (61%) of the target compound 7a. H NMR
300 MHz, CDCl ) d 11.9 (br, 1H), 7.60 (br, 2H), 7.25–7.19 (m,
H), 3.55 (t, J = 6.09 Hz, 2H), 3.23–3.17 (m, 5H), 2.86 (t,
J = 6.06 Hz, 2H), 2.52–2.43 (m, 4H), 2.29 (br, 1H), 2.08 (s, 2H),
2 2
Cl –MeOH = 15:1) to
1
(
3
1
3
2
3
(d, J = 6.6 Hz, 6H). C NMR (75 MHz, CDCl ), d 170.6, 170.2,
149.1, 144.4, 139.7, 134.4, 129.2, 128.9, 128.7, 128.2, 126.9,
125.8, 104.9, 49.0, 48.1, 42.3, 37.7, 35.1, 28.4, 26.5, 25.3, 24.1,
22.4.
1
3
2
.00 (br, 2H), 1.40 (t, J = 8.22 Hz, 2H), 0.94 (s, 9H) C NMR
(
75.5 MHz, CDCl ) d 174.4, 154.6, 139.4, 125.6, 121.7, 54.8, 51.5,
3
4
6.1, 42.3, 35.5, 29.8, 29.6, 29.3, 26.5, 25.7, 25.0, 20.4.
4
.1.10. 5-Isobutyl-1-phenyl-3-(3-benzenesulfonyl-3-azabicyclo
4
.1.5. 3-[4-(Trifluoromethyl)phenylethyl]-3-azabicyclo[3.1.0]
[3.1.0]hexane-6-carboxamido) methyl-1H-pyrazole (10f)
Compound 10f was prepared in a similar manner to that for 10d
using benzenesulfonyl chloride to obtain 70.4 mg (79.4%). H NMR
hexane-6-carboxamido-2-(N-methyl)propyl-1H-benzo[d]
imidazol (7b)
1
Compound 7b was synthesized in a manner similar to that of 7a
3
(300 MHz, CDCl ) d 7.79 (d, J = 8.01 Hz, 2H), 7.62–7.37 (m, 8H), 6.73
with a yield of 53.5 mg (40%). 1H NMR (300 MHz, CDCl
7
) d 7.64–
.56 (m, 4H), 7.35–7.30 (m, 2H), 7.25–7.22 (m, 2H), 3.55 (t,
J = 5.91 Hz, 2H), 3.23–3.20 (m, 4H), 2.99–2.97 (m, 1H), 2.90–2.84
m, 4H), 2.80–2.76 (m, 2H), 2.55 (d, J = 8.82 Hz, 2H), 2.22 (s, 1H),
(br, 1H), 6.15 (s, 1H), 4.46 (d, J = 5.07 Hz, 2H), 3.59 (d, J = 9.51 Hz,
2H), 3.09 (d, J = 9.3 Hz, 2H), 2.51 (d, J = 7.17 Hz, 2H), 2.01 (s, 2H),
1.89–1.75 (m, 1H), 1.52 (t, J = 2.88 Hz, 1H), 0.87 (d, J = 6.6 Hz,
3
1
3
(
3
6H). C NMR (75 MHz, CDCl ) d 170.5, 149.0, 144.4, 139.8, 136.1,
2
1
4
.13–2.10 (m, 3H), 2.01 (br, 1H). 13C NMR (75 MHz, CDCl
3
) d
132.9, 129.2, 129.1, 128.1, 127.5, 125.8, 104.8, 49.6, 37.8, 35.1,
28.4, 24.5, 24.3, 22.4.
74.3, 154.6, 144.6, 129.1, 128.9, 125.2, 125.1, 121.9, 55.9, 54.4,
6.9, 46.2, 35.5, 35.0, 26.3, 25.6, 24.9, 20.2.
4
.1.11. (3-(3,3-Dimethylbutyl)-3-azabicyclo[3.1.0]hexan-6-yl)
4
.1.6. 3-[3-(3,3-Dimethylbutyl)-3-azabicyclo[3.1.0]hexane-6-
methanamine (14)
carboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (10a)
Compound 10a was synthesized in a manner similar to that of
Compound 13 (170 mg, 0.808 mmol) was dissolved in DCM
(7.42 mL) and lithium aluminum hydride (1M in ether, 3.23 mL,
3.23 mmol) was added 0 °C, and the reaction mixture was refluxed
for 20 h. After the reaction mixture was cooled down to 0 °C and
diluted with dichloromethane, and sodium sulfate hydrate wad
added carefully. The reaction mixture was filtered by celite, and
7
a with a yield of 63.9%. 1H NMR (300 MHz, CDCl
3
), d 7.53–7.40
(
(
m, 5H), 6.24 (br, 1H), 6.16 (s, 1H), 4.50 (d, J = 5.07 Hz, 2H), 3.11
d, J = 9.03 Hz, 2H), 2.53 (d, J = 7.14 Hz, 2H), 2.42 (t, J = 8.40 Hz,
2
H), 2.36 (d, J = 8.79 Hz, 2H), 1.99 (s, 2H), 1.89–1.80 (m, 2H), 1.35
1
3
(
(
1
2
4
t, J = 8.40 Hz, 2H), 0.90 (s, 9H), 0.89 (d, J = 7.32 Hz, 6H). C NMR
75 MHz, CDCl ), d 172.5, 162.3, 149.4, 144.3, 139.8, 129.1, 128.0,
25.7, 104.8, 54.9, 51.5, 42.4, 37.8, 35.2, 29.8, 29.6, 28.4, 25.1,
residual solution was concentrated in vacuo to give compound
1
3
14 (130 mg, 82.0%).
3
H NMR (300 MHz, CDCl ) d 3.09 (d,
J = 8.79 Hz, 2H), 2.53 (d, J = 6.96 Hz, 2H), 2.44 (t, J = 8.04 Hz, 2H),
2.32 (d, J = 8.16 Hz, 2H), 1.50 (br, 2H), 1.39 (t, J = 8.31 Hz, 2H),
1.34–1.29 (m, 1H), 1.24 (br, 2H), (s, 9H).
+
+
3.8, 22.4. HRMS [ESI ] m/z calcd for
26 38 4
C H N O [M+H] :
23.3046, found: 423.3115.
4
.1.7. 3-(3-Benzyl-3-azabicyclo[3.1.0]hexane-6-carboxamido)
4.1.12. 3-{2-[3-(3,3-Dimethylbutyl)-3-azabicyclo[3.1.0]hexane-
6-yl]methyl}carbamoyl-5-isobutyl-1-phenyl-1H-pyrazole (15a)
Compound 15a was synthesized in a manner similar to that of 5
methyl-5-isobutyl-1-phenyl-1H-pyrazole (10b)
Compound 10b was synthesized in a manner similar to that of
a, with a yield of 75.7%. 1H NMR (300 MHz, CDCl
using 5-Isobutyl-1-phenylpyrazole-3-carboxylic acid to obtain
15
7
3
), d 7.53–7.40
1
(
m, 5H), 7.34–7.22 (m, 5H), 6.43 (br, 1H), 6.17 (s, 1H), 4.51 (d,
109 mg (84.2%). H NMR (300 MHz, CDCl
3
), d 7.48–7.34 (m, 5H),
J = 5.07 Hz, 2H), 3.61 (s, 2H), 3.02 (d, J = 8.97 Hz, 2H), 2.52 (d,
J = 7.14 Hz, 2H), 2.45 (d, J = 8.49 Hz, 2H), 1.99 (s, 2H), 1.95 (s, 1H),
1
7.01 (br, 1H), 6.71 (s, 1H), 3.23 (t, J = 6.09 Hz, 2H), 3.00 (d,
J = 8.73 Hz, 2H), 2.47 (d, J = 7.02 Hz, 2H), 2.34 (t, J = 8.13 Hz, 2H),
2.22 (d, J = 8.4 9 Hz, 2H), 1.84–1.75 (m, 1H), 1.37 (br, 1H), 1.30
.91–1.78 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). 13C NMR (75 MHz,
1
3
CDCl
3
), d 172.6, 149.5, 144.3, 139.9, 139.4, 129.1, 128.5, 128.2,
3
(br, 4H), 0.83 (br, 15H). C NMR (75 MHz, CDCl ), d 162.0, 146.8,
1
2
28.0, 126.9, 125.8, 104.8, 58.8, 54.3, 37.8, 35.2, 28.4, 25.2, 23.6,
2.4.
144.9, 139.4, 129.2, 128.6, 125.9, 106.5, 55.1, 51.6, 42.3, 41.4,
35.1, 29.7, 29.6, 28.2, 22.3, 21.6, 19.7.