Journal of Medicinal Chemistry
Article
[C13H24N5]+, 250.2026; found, 250.2031. C13H23N5···C4H2F6O4
(249.36 + 228.05).
7.35 (s, 1H), 6.04 (d, J = 7.2 Hz, 1H), 3.56 (t, J = 6.8 Hz, 2H), 3.27
(m, 2H), 2.82 (t, J = 7.7 Hz, 2H), 2.02 (m, 2H), 0.96 (s, 9H). H
1
N2-Neopentyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine Bis-
(2,2,2-trifluoroacetate) 40. According to the general procedure, the
title compound was prepared in the microwave reactor (7 h, 120 °C, 2
bar, 3 min prestirring) from 27 (250 mg, 0.799 mmol), DIPEA (204
μL, 1.17 mmol), and 2,2-dimethylpropan-1-amine (282 μL, 2.39
mmol) in i-PrOH (2 mL). The crude product was purified by
automated flash chromatography [gradient 0−20 min: DCM/MeOH
100/0−95/5 (v/v), SF 10−4 g] to give a colorless sticky oil (120 mg,
41.4%). Rf = 0.4 (DCM/MeOH 90/10). Deprotection (110 mg,
0.303 mmol) in DCM (2 mL) and TFA (0.5 mL) followed by
preparative HPLC [column: Phenomenex Kinetex 5u XB-C18 250 ×
21.2 mm; gradient: 0−30 min: A/B 90/10−48/52 (v/v), flow 20
mL/min, tR = 10 min] afforded 40 as colorless hygroscopic foam (100
NMR (600 MHz, DMSO-d6, +10 μL TFA): δ (ppm) 11.89 (br, 3H),
8.98 (m, 1H), 8.81 (m, 1H), 8.13 (m, 1H), 7.67 (m, 1H), 7.43 (s,
1H), 6.02 (d, J = 7.0 Hz, 1H), 3.40 (m, 2H), 3.15 (m, 2H), 2.69 (t, J
= 7.5 Hz, 2H), 1.89 (m, 2H), 0.87 (s, 9H). 13C NMR (151 MHz,
DMSO-d6, +10 μL TFA, HSQC, HMBC): δ (ppm) 162.32 (quat.,
1C), 158.49 (q, J = 37.4 Hz, TFA), 154.26 (quat., 1C), 141.15,
133.89, 132.67 (quat., 1C), 115.63, 115.46 (q, J = 290.2 Hz, TFA),
97.19, 51.20, 39.20, 32.16 (quat., 1C), 27.11 (3C), 27.00, 21.41.
HRMS (ESI) m/z: [M + H]+ calcd for [C15H25N6]+, 289.2135;
found, 289.2136. C15H24N6···C4H2F6O4 (288.40 + 228.05).
N-Neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-
yl)pyrimidin-2-amine Bis(2,2,2-trifluoroacetate) 43. According to
the general procedure, the title compound was prepared in the
microwave reactor (7.5 h, 130 °C, 3 bar, 3 min prestirring) from 30
(200 mg, 0.418 mmol), DIPEA (220 μL, 1.26 mmol), and 2,2-
dimethylpropan-1-amine (150 μL, 1.27 mmol) in i-PrOH (3 mL).
The crude product was purified by automated flash chromatography
[gradient 0−20 min: DCM/MeOH 100/0−90/10 (v/v), SF 10−4 g]
to give a yellow sticky oil (160 mg, 72.7%). Rf = 0.3 (DCM/MeOH
90/10). Deprotection (75 mg, 0.14 mmol) in DCM (2 mL) and TFA
(0.4 mL) followed by preparative HPLC [column: Phenomenex
Kinetex 5u XB-C18 250 × 21.2 mm; gradient: 0−30 min: A/B (v/v)
95/5−33/67, flow 15 mL/min, tR = 13.5 min] afforded 43 as colorless
hygroscopic foam (30 mg, 41.1%). RP-HPLC (220 nm): 96.2% (k =
1.97). Ratio of configurational isomers evident in NMR performed in
DMSO-d6: ca. 1:1.1. 1H NMR (300 MHz, MeOH-d4): δ (ppm) 8.79
(s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 6.57 (m, 1H), 4.69 (m, 2H), 4.21
1
mg, 67.2%). RP-HPLC (220 nm): 99.9% (k = 1.76). H NMR (300
MHz, MeOH-d4): δ (ppm) 7.59 (d, J = 7.3 Hz, 1H), 6.06 (d, J = 7.3
Hz, 1H), 4.30 (m, 1H), 3.32 (m, 6H), 2.24 (m, 2H), 1.80 (m, 2H),
1
0.98 (s, 9H). H NMR (600 MHz, DMSO-d6): δ (ppm) 12.29 (br,
1H), 9.92 (d, J = 6.4 Hz, 1H), 8.81 (br, 1H), 8.63 (br, 1H), 8.41 (m,
1H), 7.71 (d, J = 7.1 Hz, 1H), 6.03 (d, J = 7.0 Hz, 1H), 4.13 (m, 1H),
3.32 (m, 2H), 3.22 (m, 2H), 3.06 (m, 2H), 2.03 (m, 2H), 1.66 (m,
2H), 0.90 (s, 9H). 13C NMR (151 MHz, DMSO-d6, HSQC, HMBC):
δ (ppm) 161.67 (quat., 1C), 158.66 (q, J = 47.3 Hz, TFA), 154.32
(quat., 1C), 141.54, 117.06 (q, J = 298.6 Hz, TFA), 97.12, 51.15,
45.20, 41.72 (2C), 32.19 (quat., 1C), 27.52 (2C), 27.12 (3C). HRMS
(ESI) m/z: [M + H]+ calcd for [C14H26N5]+, 264.2183; found,
264.2185. C14H25N5···C4H2F6O4 (263.39 + 228.05).
N4-[2-(1H-Imidazole-4-yl)ethyl]-N2-neopentylpyrimidine-2,4-dia-
mine Bis(2,2,2-trifluoroacetate) 41. According to the general
procedure, the title compound was prepared in the microwave
reactor (11 h, 130 °C, 4 bar, 3 min prestirring) from 28 (150 mg,
0.322 mmol), DIPEA (330 μL, 1.89 mmol), and 2,2-dimethylpropan-
1-amine (230 μL, 1.95 mmol) in i-PrOH (2 mL). The crude product
was purified by automated flash chromatography [gradient 0−20 min:
DCM/MeOH 100/0−90/10 (v/v), SF 10−4 g)] to give a colorless
sticky foam (65 mg, 40%). Rf = 0.4 (DCM/MeOH 90/10).
Deprotection (60 mg, 0.12 mmol) in DCM (2 mL) and TFA (0.5
mL) followed by preparative HPLC [Phenomenex Kinetex 5u XB-
C18 250 × 21.2 mm; gradient 0−30 min: A/B (v/v) 86.5/14.4−28.5/
71.5; flow: 20 mL/min; tR = 8 min] afforded 41 as colorless
hygroscopic foam (21 mg, 36.0%). RP-HPLC (220 nm): 99.0% (k =
1
(m, 2H), 3.34 (m, 2H), 2.94 (m, 2H), 0.99 (s, 9H). H NMR (600
MHz, DMSO-d6): δ (ppm) 13.96 (br, 2H), 8.86 (s, 1H), 8.47 (br,
1H), 7.97 (d, J = 7.3 Hz, 1H), 6.61 (m, 1H), 5.00−3.00 (1 proton
(NH+) presumably superimposed by H2O), 4.91 (m, 2H), 4.12 (m,
2H), 3.24 (m, 2H), 2.83 (m, 2H), 0.91 (s, 9H). 13C NMR (151 MHz,
DMSO-d6, HSQC, HMBC): δ (ppm) 161.79 (quat., 1C) 158.72 (q, J
= 32.3 Hz, TFA), 153.65 (quat., 1C), 143.82, 133.68, 125.76 (quat.,
1C), 124.13 (quat., 1C), 116.90 (q, J = 297.8 Hz, TFA), 94.47, 51.42,
42.96, 42.86, 40.04, 32.96 (quat., 1C), 27.09 (3C), 20.82, 20.76.
HRMS (ESI) m/z: [M + H]+ calcd for [C15H23N6]+, 287.1979;
found, 287.1982. C15H22N6···C4H2F6O4 (286.38 + 228.05).
N4-(2-{[(5-Methyl-1H-imidazole-4-yl)methyl]thio}ethyl)-N2-neo-
pentylpyrimidine-2,4-diamine Bis(2,2,2-trifluoroacetate) 44. The
title compound was prepared in the microwave reactor (4 h, 120 °C, 3
bar, 3 min prestirring) from 31 (110 mg, 0.388 mmol), DIPEA (132
μL, 0.758 mmol), and 2,2-dimethylpropan-1-amine (137 μL, 1.16
mmol) in i-PrOH (3 mL). After the solvent was removed under
reduced pressure and the residue was dissolved in DCM (5 mL), the
organic phase was washed with H2O (3 × 2 mL) and brine (5 mL),
and dried over MgSO4. The crude product was purified by
chromatography [DCM/MeOH 100/0−92.5/7.5 (v/v), SiO2 13 g]
and preparative HPLC [column: Phenomenex Kinetex 5u XB-C18
250 × 21.2 mm; gradient: 0−30 min: A/B 85.5/14.5−52.2/47.8 (v/
v), flow 15 mL/min, tR = 14.5 min] to yield 44 as colorless
hygroscopic foam (38 mg, 17.4%). RP-HPLC (220 nm): 98.9% (k =
1
2.02). H NMR (300 MHz, MeOH-d4): δ (ppm) 8.84 (s, 1H), 7.56
(d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 6.02 (d, J = 7.0 Hz, 1H), 3.80 (t, J =
6.5 Hz, 1H), 3.28 (m, 2H), 3.07 (t, J = 6.5 Hz, 1H), 0.97 (s, 9H). 1H
NMR (600 MHz, DMSO-d6, +10 μL TFA): δ (ppm) 11.98 (br, 3H),
9.00 (s, 1H), 8.89 (m, 1H), 8.24 (m, 1H), 7.67 (m, 1H), 7.44 (s, 1H),
6.00 (d, J = 6.9 Hz, 1H), 3.66 (m, 2H), 3.19 (m, 2H), 2.94 (m, 2H),
0.89 (s, 9H). 13C NMR (151 MHz, DMSO-d6, +10 μL TFA, HSQC,
HMBC): δ (ppm) 162.46 (quat., 1C), 158.49 (q, J = 37.4 Hz, TFA),
154.24 (quat., 1C), 141.33, 133.99, 130.64 (quat., 1C), 116.39,
115.42 (q, J = 291.6 Hz, TFA), 97.22, 51.24, 39.33, 32.12 (quat., 1C),
27.11 (3C), 23.60. HRMS (ESI) m/z: [M + H]+ calcd for
[C14H23N5]+, 275.1979; found, 275.1983. C14H22N5···C4H2F6O4
(274.37 + 228.05).
1
2.55). H NMR (300 MHz, MeOH-d4): δ (ppm) 8.75 (s, 1H), 7.56
N4-[3-(1H-Imidazole-4-yl)propyl]-N2-neopentylpyrimidine-2,4-di-
amine Bis(2,2,2-trifluoroacetate) 42. According to the general
procedure, the title compound was prepared in the microwave
reactor (10 h, 130 °C, 3 bar, 3 min prestirring) from 29 (140 mg,
0.292 mmol), DIPEA (300 μL, 1.72 mmol), and 2,2-dimethylpropan-
1-amine (206 μL, 1.75 mmol) in i-PrOH (2 mL). The crude product
was purified by automated flash chromatography [gradient 0−20 min:
DCM/MeOH 100/0−90/10 (v/v), SF 10−4 g)] to a colorless sticky
foam (100 mg, 64.9%). Rf = 0.45 (DCM/MeOH 90/10).
Deprotection (70 mg, 0.13 mmol) in DCM (2 mL) and TFA (0.5
mL) followed by preparative HPLC [Phenomenex Kinetex 5u XB-
C18 250 × 21.2 mm; gradient 0−30 min: A/B (v/v) 90/10−33/67,
flow: 20 mL/min; tR = 10.5 min] afforded 42 as hygroscopic foam (35
(d, J = 7.3 Hz, 1H), 6.05 (d, J = 7.2 Hz, 1H), 3.88 (s, 2H), 3.68 (t, J =
6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.33 (s, 3H), 0.96 (s, 9H). 1H
NMR (600 MHz, DMSO-d6): δ (ppm) 14.24 (br, 3H), 8.99 (m, 1H),
8.88 (s, 1H), 8.39 (m, 1H), 7.69 (d, J = 7.0 Hz, 1H), 6.05 (d, J = 7.0
Hz, 1H), 3.86 (s, 2H), 3.55 (m, 2H), 3.19 (m, 2H), 2.68 (t, J = 6.7
Hz, 2H), 2.24 (s, 3H), 0.98 (s, 9H). 13C NMR (151 MHz, DMSO-d6,
HSQC, HMBC): δ (ppm) 162.32 (quat., 1C), 158.59 (q, J = 31.4 Hz,
TFA), 154.29 (quat., 1C), 141.40, 133.03, 125.94 (quat., 1C), 125.71
(quat., 1C), 117, 07 (q, J = 299.9 Hz, TFA), 97.10, 51.22, 39.74,
32.11 (quat., 1C), 29.81, 27.07 (3C), 23.13, 8.57. HRMS (ESI) m/z:
[M + H]+ calcd for [C16H27N6S]+, 335.2012; found, 335.2017.
C16H26N6 S···C4H2F6O4 (334.49 + 228.05).
(R)-4-[3-(Methylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-
amine Bis(2,2,2-trifluoroacetate) 45.29 In an argon-flushed Schlenk
flask, 32 (480 mg, 1.37 mmol) was dissolved in anhydrous THF (10
1
mg, 51.4%). RP-HPLC (220 nm): 99.9% (k = 2.23). H NMR (300
MHz, MeOH-d4): δ (ppm) 8.82 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H),
L
J. Med. Chem. XXXX, XXX, XXX−XXX