Journal of Medicinal Chemistry
Article
The material was purified by trituration with 1:1 CH2Cl2/hexanes,
yielding 93 mg (77%) of the N-Boc intermediate as a white solid. LC-
MS: RT = 8.78 min, [M + H]+ = 481.9. The material was deprotected
as described for 37, yielding 86 mg (98%) of the title compound as a
2H), 3.26−3.16 (m, 1H), 3.04−2.92 (m, 1H). LC-MS: RT = 4.27 min,
[M + H]+ = 343.1. Purity >95% by HPLC method A, RT = 3.57 min.
Purity >95% by HPLC method B, RT = 3.75 min.
N-(3-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-
carboxamide Dihydrochloride (48). The compound was prepared as
described for 37 from 3-methoxyphenylisocyanate (24 mg, 0.16
mmol) and 11 (45 mg, 0.15 mmol). The material was purified by
HPLC (10−95% MeCN/0.1% TFA in H2O/0.1% TFA gradient),
yielding 78 mg (91%) of the N-Boc intermediate TFA salt as a white
solid. LC-MS: RT = 7.47 min, [M + H]+ = 442.9. The material was
deprotected as described for 37, yielding 57 mg (99%) of the title
1
white solid. H NMR (400 MHz, DMSO-d6) δ 9.67−9.58 (br, 1H),
9.54−9.42 (br, 1H), 9.37 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.42 (d, J =
5.2 Hz, 1H), 7.99−7.94 (m, 1H), 7.77 (dd, J = 8.6 and 5.2 Hz, 1H),
7.68 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 4.94−4.86 (m, 1H),
4.65 (dd, J = 10.0 and 7.6 Hz, 1H), 4.57 (dd, J = 10.0 and 7.2 Hz, 1H),
4.27−4.19 (m, 1H), 3.55−3.48 (m, 1H), 3.40−3.30 (m, 2H), 3.30−
3.20 (m, 1H), 3.08−2.96 (m, 1H). LC-MS: RT = 4.85 min, [M + H]+
= 381.6. Purity >95% by HPLC method A, RT = 4.68 min. Purity
>95% by HPLC method B, RT = 5.79 min.
1
compound as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.74−
9.65 (br, 1H), 9.61−9.49 (br, 1H), 8.90 (s, 1H), 8.65 (d, J = 2.8 Hz,
1H), 8.45 (d, J = 4.4 Hz, 1H), 8.06−8.00 (m, 1H), 7.82 (dd, J = 8.8
and 5.4 Hz, 1H), 7.17−7.11 (m, 2H), 7.06−7.00 (m, 1H), 6.54 (dt, J =
8.0 and 1.2 Hz, 1H), 4.90−4.83 (m, 1H), 4.68 (dd, J = 10.0 and 8.4
Hz, 1H), 4.55 (dd, J = 9.6 and 6.4 Hz, 1H), 4.23−4.16 (m, 1H), 3.70
(s, 3H), 3.54−3.46 (m, 1H), 3.38−3.28 (m, 2H), 3.27−3.17 (m, 1H),
3.06−2.93 (m, 1H). LC-MS: RT = 3.61 min, [M + H]+ = 343.0. Purity
>95% by HPLC method A, RT = 3.48 min. Purity >95% by HPLC
method B, RT = 4.06 min.
N-(4-Isopropylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-
carboxamide Dihydrochloride (46). The compound was prepared as
described for 37 from 4-isopropylphenylisocyanate (67 mg, 0.42
mmol) and 11 (122 mg, 0.42 mmol). The material was purified by
HPLC (10−90% MeCN/0.1% TFA in H2O/0.1% TFA gradient),
yielding 232 mg (98%) of the N-Boc intermediate TFA salt as a white
solid. LC-MS: RT = 8.89 min, [M + H]+ = 455.9. The material was
deprotected as described for 37, yielding 135 mg (78%) of the title
1
compound as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.70−
N-(2-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-
carboxamide Dihydrochloride (49). The compound was prepared as
described for 37 from 2-methoxyphenylisocyanate (38 mg, 0.26
mmol) and 11 (72 mg, 0.25 mmol). The material was purified by
HPLC (10−95% MeCN/0.1% TFA in H2O/0.1% TFA gradient),
yielding 125 mg (92%) of the N-Boc intermediate TFA salt as a white
solid. LC-MS: RT = 7.84 min, [M + H]+ = 443.2. The material was
deprotected as described for 37, yielding 91 mg (97%) of the title
9.60 (br, 1H), 9.56−9.44 (br, 1H), 8.80 (s, 1H), 8.64 (d, J = 2.8 Hz,
1H), 8.43 (d, J = 5.4 Hz, 1H), 8.04−7.98 (m, 1H), 7.80 (dd, J = 8.8
and 5.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H),
4.86−4.80 (m, 1H), 4.67 (dd, J = 10.0 and 8.4 Hz, 1H), 4.51 (dd, J =
9.6 and 6.8 Hz, 1H), 4.21−4.14 (m, 1H), 3.54−3.46 (m, 1H), 3.36−
3.27 (m, 2H), 3.26−3.16 (m, 1H), 3.04−2.91 (m, 1H), 2.80 (hept, J =
6.8 Hz, 1H), 1.15 (d, J = 6.8 Hz, 6H). LC-MS: RT = 4.94 min, [M +
H]+ = 355.6. Purity >95% by HPLC method A, RT = 4.88 min. Purity
>95% by HPLC method B, RT = 6.22 min.
1
compound as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.66−
9.55 (br, 1H), 9.54−9.40 (br, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.43 (d, J
= 4.8 Hz, 1H), 8.03 (s, 1H), 7.97−7.91 (m, 1H), 7.77 (dd, J = 8.2 and
5.4 Hz, 1H), 7.58 (dd, J = 8.0 and 1.6 Hz, 1H), 7.07−7.00 (m, 2H),
6.92−6.86 (m, 1H), 4.80−4.72 (m, 1H), 4.65−4.53 (m, 2H), 4.17−
4.10 (m, 1H), 3.79 (s, 3H), 3.52−3.44 (m, 1H), 3.38−3.20 (m, 3H),
3.07−2.94 (m, 1H). LC-MS: RT = 3.73 min, [M + H]+ = 343.2. Purity
>95% by HPLC method A, RT = 3.39 min. Purity >95% by HPLC
method B, RT = 4.09 min.
N-(4-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-
carboxamide Dihydrochloride (47). The compound was prepared as
described for 37 from 4-methoxyphenylisocyanate (76 mg, 0.51
mmol) and 11 (150 mg, 0.51 mmol). The material was purified by
HPLC (10−90% MeCN/0.1% TFA in H2O/0.1% TFA gradient),
yielding 251 mg (88%) of the N-Boc intermediate TFA salt as a white
solid. LC-MS: RT = 7.18 min, [M + H]+ = 443.2. The material was
deprotected as described for 37, yielding 187 mg (99%) of the title
N-(2,4-Dimethoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-
1-carboxamide Dihydrochloride (50). The compound was prepared
as described for 37 from 2,4-dimethoxyphenylisocyanate (46 mg, 0.26
mmol) and 11 (72 mg, 0.25 mmol). The material was purified by
HPLC (10−95% MeCN/0.1% TFA in H2O/0.1% TFA gradient),
yielding 122 mg (84%) of the N-Boc intermediate TFA salt as a white
solid. LC-MS: RT = 7.53 min, [M + H]+ = 473.2. The material was
deprotected as described for 37, yielding 89 mg (96%) of the title
1
compound as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.83−
9.73 (br, 1H), 9.69−9.58 (br, 1H), 8.79 (s, 1H), 8.70 (d, J = 2.4 Hz,
1H), 8.48 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 8.8 and 2.4 Hz, 1H), 7.88
(dd, J = 8.8 and 5.2 Hz, 1H), 7.33 (d, J = 6.8 Hz, 2H), 6.83 (d, J = 6.8
Hz, 2H), 4.88−4.82 (m, 1H), 4.73 (dd, J = 10.0 and 8.4 Hz, 1H), 4.54
(dd, J = 9.6 and 6.4 Hz, 1H), 4.24−4.16 (m, 1H), 3.70 (s, 3H), 3.54−
3.46 (m, 1H), 3.38−3.28 (m, 2H), 3.26−3.15 (m, 1H), 3.04−2.91 (m,
1H). LC-MS: RT = 3.40 min, [M + H]+ = 343.1. Purity >95% by
HPLC method A, RT = 5.09 min. Purity >95% by HPLC method B,
RT = 3.79 min.
1
compound as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.67−
9.58 (br, 1H), 9.53−9.41 (br, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.44 (d, J
= 5.2 Hz, 1H), 8.02−7.93 (m, 2H), 7.80 (dd, J = 8.8 and 5.2 Hz, 1H),
7.29 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.46 (dd, J = 8.8 and
2.8 Hz, 1H), 4.78−4.70 (m, 1H), 4.66 (appt t, J = 9.0 Hz, 1H), 4.50
(dd, J = 9.8 and 6.6 Hz, 1H), 4.17−4.07 (m, 1H), 3.76 (s, 3H), 3.74 (s,
3H), 3.52−3.44 (m, 1H), 3.38−3.26 (m, 2H), 3.26−3.16 (m, 1H),
3.04−2.92 (m, 1H). LC-MS: RT = 3.45 min, [M + H]+ = 373.1. Purity
>95% by HPLC method A, RT = 3.48 min. Purity >95% by HPLC
method B, RT = 4.11 min.
(R)-N-(4-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-
1-carboxamide Dihydrochloride ((R)-47). The compound was
prepared as described for compound 47 from (R)-11. 1H NMR
(400 MHz, DMSO-d6) δ 9.88−9.78 (br, 1H), 9.74−9.60 (br, 1H),
8.81 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.12
(dd, J = 8.8 and 2.4 Hz, 1H), 7.89 (dd, J = 8.8 and 5.2 Hz, 1H), 7.33
(d, J = 6.8 Hz, 2H), 6.82 (d, J = 6.8 Hz, 2H), 4.89−4.82 (m, 1H), 4.74
(dd, J = 10.0 and 8.4 Hz, 1H), 4.55 (dd, J = 9.6 and 6.4 Hz, 1H),
4.24−4.16 (m, 1H), 3.70 (s, 3H), 3.53−3.46 (m, 1H), 3.38−3.26 (m,
2H), 3.25−3.14 (m, 1H), 3.04−2.91 (m, 1H). LC-MS: RT = 3.67 min,
[M + H]+ = 343.1. Purity >95% by HPLC method A, RT = 3.13 min.
Purity >95% by HPLC method B, RT = 3.76 min.
(S)-N-(4-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-
1-carboxamide Dihydrochloride ((S)-47). The compound was
prepared as described for compound 47 from (S)-11. 1H NMR
(400 MHz, DMSO-d6) δ 9.70−9.62 (br, 1H), 9.58−9.46 (br, 1H),
8.74 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.06
(dd, J = 8.8 and 2.4 Hz, 1H), 7.84 (dd, J = 8.8 and 5.2 Hz, 1H), 7.32
(d, J = 6.8 Hz, 2H), 6.82 (d, J = 6.8 Hz, 2H), 4.86−4.80 (m, 1H), 4.69
(dd, J = 10.0 and 8.4 Hz, 1H), 4.51 (dd, J = 9.6 and 6.4 Hz, 1H),
4.22−4.14 (m, 1H), 3.70 (s, 3H), 3.53−3.44 (m, 1H), 3.36−3.27 (m,
N-(3-Chloro-4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)-
piperazine-1-carboxamide Dihydrochloride (51). The compound
was prepared as described for 37 from 3-chloro-4-methoxyphenyliso-
cyanate (76 mg, 0.42 mmol) and 11 (122 mg, 0.42 mmol). The
material was purified by HPLC (10−90% MeCN/0.1% TFA in H2O/
0.1% TFA gradient), yielding 166 mg (68%) of the N-Boc
intermediate TFA salt as a white solid. LC-MS: RT = 7.87 min, [M
+ H]+ = 477.8. The material was deprotected as described for 37,
1
yielding 119 mg (94%) of the title compound as a white solid. H
NMR (400 MHz, DMSO-d6) δ 9.65−9.56 (br, 1H), 9.50−9.38 (br,
1H), 8.92 (s, 1H), 8.62 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H),
8.02−7.95 (m, 1H), 7.78 (dd, J = 8.6 and 5.2 Hz, 1H), 7.57 (d, J = 2.4
Hz, 1H), 7.33 (dd, J = 9.0 and 2.4 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H),
4.86−4.79 (m, 1H), 4.64 (appt t, J = 9.0 Hz, 1H), 4.50 (dd, J = 10.2
3978
dx.doi.org/10.1021/jm5004599 | J. Med. Chem. 2014, 57, 3966−3983