Journal of Medicinal Chemistry
Article
1H), 8.01 (s, 1H), 7.41 (s, 2H), 7.37−7.27 (m, 4H), 7.26−7.20 (m,
1H), 5.67 (s, 1H), 4.48 (s, 2H), 3.88 (s, 2H), 3.83−3.74 (m, 2H),
3.61−3.50 (m, 6H), 2.46 (br s, 4H), 1.92−1.83 (m, 2H), 1.83−1.72
(m, 2H), 1.47−1.36 (m, 4H), 0.93 (s, 6H); 13C NMR (101 MHz,
MeOD-d4): δ 170.3, 164.8, 163.7, 158.5, 148.6 (br s), 146.1, 140.6,
136.4, 129.7 (2C), 128.4 (2C), 128.3, 126.0, 124.1, 83.2, 64.4, 54.4,
53.9, 51.8, 51.1, 46.0, 41.6, 39.3, 35.6, 29.3, 28.8 (br s); HRMS (ESI):
m/z: calcd for [C32H43N8O]+: 555.3560, found: 555.3554.
tert-Butyl 4-(4-((4,4-Dimethylpiperidin-1-yl)methyl)phenyl)-
2-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate (35). In-
termediate 35 was obtained following the general procedure for
Buchwald−Hartwig coupling (chromatography: DCM/MeOH =
100:5 to 100:8 to 100:12 to 100:20). Beige solid, 93% yield. 1H
NMR (400 MHz, CDCl3): δ 7.25 (br s, 2H), 6.84−6.76 (m, 2H),
6.54 (s, 1H), 3.85 (s, 2H), 3.57−3.50 (m, 4H), 3.50−3.42 (m, 2H),
3.34 (s, 2H), 2.39 (br s, 4H), 1.87−1.79 (m, 2H), 1.78−1.71 (m,
2H), 1.48 (s, 9H), 1.41 (br s, 4H), 0.92 (s, 6H); 13C NMR (101
MHz, CDCl3): δ 168.8, 154.5, 148.0, 130.6 (2C), 114.7 (2C), 80.0,
62.6, 55.0, 52.8 (2C), 51.9, 49.8 (2C), 39.5 (br s), 38.4, 35.4, 28.4
(2C), 28.4 (3C). Two carbons are missing due to overlapping or
broadening.
28.2 (2C). Three carbons are missing due to overlapping; HRMS
(ESI): m/z: calcd for [C33H44N7O]+: 554.3607, found: 554.3602.
4-(4-((4,4-Dimethylpiperidin-1-yl)methyl)phenyl)-9-(6-
(methylamino)pyrimidin-4-yl)-1,4,9-triazaspiro[5.5]undecan-
2-one (10). The corresponding chloropyrimidine batch was the same
as the one used for compound 9.
Compound 10 was obtained following the general procedure for
SNAr with chloropyrimidine derivatives (chromatography: DCM/
MeOH = 100:0 to 100:12 in 20 min, 100:12 for 10 min, 100:12 to
100:15 in 10 min, and 100:15 for 10 min). White solid (3% yield over
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two steps). Mp: 235−236 °C; H NMR (400 MHz, MeOD-d4): δ
7.99 (s, 1H), 7.37−7.27 (m, 2H), 7.02−6.94 (m, 2H), 5.65 (s, 1H),
3.90−3.84 (m, 4H), 3.61−3.53 (m, 2H), 3.52 (s, 2H), 2.93−2.69 (m,
7H), 1.97−1.88 (m, 2H), 1.86−1.77 (m, 2H), 1.57−1.47 (m, 4H),
0.99 (s, 6H); 13C NMR (101 MHz, MeOD-d4): δ 170.8, 165.4, 163.7,
158.3, 151.3, 133.3 (2C), 115.9 (2C), 82.2 (br s), 62.0, 54.4, 54.2,
52.2, 50.2, 41.7, 37.5, 35.7, 30.9 (br s), 29.1, 28.5. One carbon is
missing due to overlapping or broadening; HRMS (ESI): m/z: calcd
for [C27H40N7O]+: 478.3294, found: 478.3289.
tert-Butyl 4-(4-((4,4-Dimethylpiperidin-1-yl)methyl)phenyl)-
1-methyl-2-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate
(45). To a stirred solution of 35 (400 mg, 0.85 mmol) in dry THF
(4.2 mL), at 0 °C, under a nitrogen atmosphere, KOtBu (1.5 equiv,
0.13 mmol, 130 μL, 1 M in THF) was added. The reaction mixture
was stirred at 25 °C for 5 min, MeI (1.2 equiv, 1.02 mmol, 63 μL) was
added, and the solution was stirred for 2 h. The reaction was
concentrated under reduced pressure, and the crude residue was
purified by flash column chromatography (chromatography: DCM/
MeOH = 100:3 to 100:5 to 100:8) to afford the desired product as a
4-(4-((4,4-Dimethylpiperidin-1-yl)methyl)phenyl)-1,4,9-
triazaspiro[5.5]undecan-2-one hydrochloride (36). Intermedi-
ate 36 was obtained following the general procedure for Boc group
deprotection. After evaporation, the crude residue was triturated in
acetone, and the resulting precipitate was filtered, washed with
acetone, and dried to afford the desired product as a beige solid (50%
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yield over two steps from intermediate 33). H NMR (400 MHz,
MeOD-d4): δ 7.49−7.37 (m, 2H), 7.11−7.04 (m, 2H), 4.23 (s, 2H),
3.90 (s, 2H), 3.55 (s, 2H), 3.39−3.34 (m, 4H), 3.17−3.07 (m, 2H),
2.14−1.98 (m, 4H), 1.69−1.59 (m, 4H), 1.07 (br s, 6H). Two
protons are missing due to overlapping with the solvent residual peak;
LRMS (ESI) m/z calcd for [C22H35N4O]+: 371.3, found: 371.3.
9-(6-Chloropyrimidin-4-yl)-4-(4-((4,4-dimethylpiperidin-1-
yl)methyl)phenyl)-1,4,9-triazaspiro[5.5]undecan-2-one (37).
Intermediate 37 was obtained following the general procedure for
SNAr with 4,6-dichloropyrimidine. Instead of chromatography, after
evaporation of the crude mixture, the residue was triturated in water.
The obtained precipitate was filtered, washed with water, and dried to
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brown solid (222 mg, 54% yield). H NMR (400 MHz, CDCl3): δ
7.66−7.55 (m, 2H), 6.88−6.82 (m, 2H), 4.18 (br s, 2H), 4.08 (br s,
2H), 3.92 (s, 2H), 3.58 (br s, 2H), 3.34 (br s, 2H), 2.98 (s, 3H), 2.94
(br s, 2H), 2.79 (br s, 2H), 2.30 (br s, 2H), 2.10−1.98 (m, 2H), 1.74
(d, J = 13.7 Hz, 2H), 1.59−1.54 (m, 2H), 1.50 (s, 9H), 1.09−0.96
(m, 6H); 13C NMR (101 MHz, CDCl3): δ 166.6, 154.5, 149.7, 133.1
(2C), 114.2 (2C), 80.3, 60.1, 57.5, 51.8, 51.2, 48.4, 40.5 (br s), 34.9,
30.8, 28.4 (3C), 27.8, 27.0. Two carbons are missing due to
overlapping or broadening; LRMS (ESI) m/z calcd for
[C28H45N4O3]+: 485.3, found: 485.4.
9-(6-Chloropyrimidin-4-yl)-4-(4-((4,4-dimethylpiperidin-1-
yl)methyl)phenyl)-1-methyl-1,4,9-triazaspiro[5.5]undecan-2-
one (46). The corresponding amine was obtained following the
general procedure for Boc group deprotection. The impure desired
product was engaged in the next step without further purification.
The corresponding chloropyrimidine was obtained following the
general procedure for SNAr with 4,6-dichloropyrimidine. Instead of
chromatography, after evaporation of the crude mixture, the residue
was triturated in Et2O. The obtained precipitate was filtered, washed
with Et2O, and dried to afford the desired product as a brown solid
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afford the desired product as a brown solid (63% yield). H NMR
(400 MHz, MeOD-d4): δ 8.30 (s, 1H), 7.28−7.21 (m, 2H), 6.98−
6.92 (m, 2H), 6.90 (s, 1H), 4.01 (br s, 2H), 3.80 (s, 2H), 3.77−3.67
(m, 2H), 3.48 (s, 2H), 3.47 (s, 2H), 2.43 (br s, 4H), 2.02−1.92 (m,
2H), 1.87−1.78 (m, 2H), 1.47−1.35 (m, 4H), 0.93 (s, 6H). 13C NMR
(101 MHz, MeOD-d4): δ 171.1, 163.9, 160.8, 159.1, 150.3, 132.4
(2C), 129.1, 116.2 (2C), 103.0, 63.6, 55.0, 54.4, 52.9, 50.8, 41.6, 39.2,
35.8, 29.4. One carbon is missing due to overlapping or broadening;
LRMS (ESI) m/z calcd for [C26H36ClN6O]+: 483.3, found: 483.3.
9-(6-(Benzylamino)pyrimidin-4-yl)-4-(4-((4,4-dimethylpiper-
idin-1-yl)methyl)phenyl)-1,4,9-triazaspiro[5.5]undecan-2-one
(9). The corresponding chloropyrimidine was obtained following the
general procedure for SNAr with 4,6-dichloropyrimidine. Instead of
chromatography, after evaporation, the crude residue was triturated in
water, filtered, and washed once with water. The obtained sticky solid
was dissolved in MeOH and concentrated under reduced pressure to
afford the desired product, which was engaged in the next step
without further purification.
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(57% yield over two steps). H NMR (400 MHz, MeOD-d4): δ 8.31
(s, 1H), 7.33−7.23 (m, 2H), 7.02−6.94 (m, 2H), 6.91 (s, 1H), 4.48
(br s, 2H), 3.87 (s, 2H), 3.67 (s, 2H), 3.55 (s, 2H), 2.94 (s, 3H), 2.51
(br s, 4H), 2.23−2.10 (m, 2H), 1.94 (d, J = 12.9 Hz, 2H), 1.49−1.37
(m, 4H), 0.94 (s, 6H).13C NMR (101 MHz, MeOD-d4): δ 169.8,
163.9, 160.8, 159.1, 150.6, 133.0 (2C), 116.0 (2C), 103.1, 62.7, 59.6,
53.4, 53.3, 50.5, 42.0, 38.3, 31.5, 29.2, 27.9, 25.4. One carbon is
missing due to overlapping or broadening; LRMS (ESI) m/z calcd for
[C27H38ClN6O]+: 497.3, found: 497.3.
Compound 9 was obtained following the general procedure for
SNAr with chloropyrimidine derivatives (chromatography: DCM/
MeOH = 100:0 to 100:8 in 20 min, 100:8 for 10 min, and 100:8 to
100:10 in 10 min). The obtained impure product was triturated in
water, filtered, and washed once with water to afford the desired
product as a pale yellow solid (5% yield over two steps). Mp: 228−
231 °C; 1H NMR (400 MHz, MeOD-d4): δ 8.01 (s, 1H), 7.35−7.29
(m, 4H), 7.27−7.20 (m, 3H), 6.95−6.90 (m, 2H), 5.67 (s, 1H), 4.48
(s, 2H), 3.87−3.76 (m, 4H), 3.54−3.47 (m, 4H), 3.45 (s, 2H), 2.52−
2.38 (m, 4H), 1.92−1.84 (m, 2H), 1.81−1.73 (m, 2H), 1.46−1.37
(m, 4H), 0.93 (s, 6H); 13C NMR (101 MHz, DMSO-d6): δ 167.0,
163.2, 161.6, 157.4, 148.2, 140.2, 129.8, 128.2 (2C), 127.1 (2C),
126.6, 114.2, 81.5, 61.7, 52.6, 52.4, 51.3, 49.1, 43.6, 38.2 (br s), 34.3,
4-(4-((4,4-Dimethylpiperidin-1-yl)methyl)phenyl)-1-methyl-
9-(6-(methylamino)pyrimidin-4-yl)-1,4,9-triazaspiro[5.5]-
undecan-2-one (13). Compound 13 was obtained following the
general procedure for SNAr with chloropyrimidine derivatives
(chromatography: DCM/MeOH = 100:0 to 100:8 in 15 min and
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100:8 for 10 min). Yellow solid (85% yield). Mp: 110−113 °C; H
NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.39 (br s, 2H), 6.88−6.81
(m, 2H), 5.46 (s, 1H), 4.82−4.73 (m, 1H), 4.36 (d, J = 13.2 Hz, 2H),
3.91 (s, 2H), 3.67 (br s, 2H), 3.59 (s, 2H), 3.16−3.03 (m, 2H), 2.96
(s, 3H), 2.91 (d, J = 5.3 Hz, 3H), 2.59 (br s, 4H), 2.13 (td, J = 13.1,
5.2 Hz, 2H), 1.88 (d, J = 13.4 Hz, 2H), 1.55 (br s, 4H), 0.96; 13C
NMR (101 MHz, CDCl3): δ 167.0, 164.0, 162.4, 157.6, 148.5, 131.4
(2C), 125.9 (br s), 114.4 (2C), 80.1, 61.6, 57.6, 52.5, 52.4, 49.2, 40.9,
N
J. Med. Chem. XXXX, XXX, XXX−XXX