Journal of Medicinal Chemistry
Article
(m, 3H), 6.76 (s, 1H), 4.48−4.34 (m, 1H), 3.80−3.73 (m, 4H),
3.73−3.65 (m, 4H), 3.65−3.59 (m, 1H), 3.59−3.50 (m, 1H), 3.37−
3.24 (m, 3H), 2.59 (dd, J = 13.1, 9.7 Hz, 1H), 1.91−1.82 (m, 4H),
1.14−0.98 (m, 1H), 0.65−0.46 (m, 2H), 0.37−0.21 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 164.71, 164.02, 159.56, 156.78, 139.83,
129.39, 128.49, 126.24, 90.22, 66.76, 59.06, 47.38, 44.54, 44.18, 39.30,
29.42, 23.16, 10.87, 3.51. HRMS [C24H31N5O2 + H]+: 422.2551
calculated, 422.2549 found.
irradiation. Column chromatography (40% → 60% EtOAc/pentane)
afforded the product (37 mg, 87 μmol, 87%). TLC: Rf = 0.4 (50%
EtOAc/pentane). H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H),
1
7.50−7.31 (m, 5H), 6.80 (s, 1H), 4.66 (d, J = 13.3 Hz, 1H), 4.59−
4.48 (m, 2H), 4.20−4.13 (m, 1H), 3.80 (td, J = 11.8, 2.8 Hz, 1H),
3.77−3.70 (m, 4H), 3.70−3.59 (m, 4H), 3.36−3.22 (m, 2H), 3.22−
3.12 (m, 1H), 2.97 (dd, J = 13.3, 10.6 Hz, 1H), 1.12−0.99 (m, 1H),
0.60−0.46 (m, 2H), 0.28 (q, J = 4.7 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 164.34, 163.92, 160.97, 156.85, 139.91, 128.62, 128.23,
126.51, 91.50, 78.26, 67.02, 66.67, 50.63, 44.47, 44.11, 43.99, 10.94,
3.53. HRMS [C23H29N5O3 + H]+: 424.2343 calculated, 424.2340
found.
( )-2-(2-Benzylpiperidin-1-yl)-N-(cyclopropylmethyl)-6-morpho-
linopyrimidine-4-carboxamide (64). The title compound was
prepared according to General Procedure A using 2-chloropyrimidine
31 (30 mg, 0.10 mmol, 1 equiv), ( )-2-benzylpiperidine hydro-
chloride (52 mg, 0.24 mmol, 2.4 equiv), and DiPEA (104 μL, 0.60
mmol, 6 equiv). Total heating time: 6 days at 120 °C. Column
chromatography (30% → 60% EtOAc/pentane) afforded the product
( )-N-(Cyclopropylmethyl)-6-morpholino-2-(3-phenylpiperazin-
1-yl)pyrimidine-4-carboxamide (68). A round-bottom flask was
charged with Cbz-protected amine 70 (56 mg, 0.10 mmol, 1 equiv)
and MeOH (0.5 mL). The solution was purged with N2 and Pd/C
(10% w/w, 50 mg, 50 μmol, 0.5 equiv) was added. The mixture was
purged with N2 and then with H2 and stirred for 2 h under a H2
atmosphere (balloon). The mixture was filtered through a plug of
Celite and washed with MeOH, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (1% → 4% MeOH/DCM) to afford the product (38
1
(12 mg, 27 μmol, 27%). TLC: Rf = 0.4 (50% EtOAc/pentane). H
NMR (600 MHz, CDCl3) δ 7.98 (t, J = 5.2 Hz, 1H), 7.26 (t, J = 7.4
Hz, 2H), 7.24−7.16 (m, 3H), 6.70 (s, 1H), 5.13−4.97 (m, 1H),
4.77−4.60 (m, 1H), 3.82−3.73 (m, 4H), 3.66 (br s, 4H), 3.40−3.21
(m, 2H), 3.07−2.98 (m, 1H), 2.95 (dd, J = 13.1, 10.0 Hz, 1H), 2.81
(dd, J = 13.1, 5.1 Hz, 1H), 1.85−1.73 (m, 2H), 1.73−1.67 (m, 2H),
1.57−1.46 (m, 2H), 1.13−1.04 (m, 1H), 0.63−0.53 (m, 2H), 0.31 (q,
J = 4.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 164.75, 163.97,
160.84, 156.81, 140.16, 129.26, 128.47, 126.16, 90.34, 66.78, 52.27,
44.53, 44.24, 39.47, 35.32, 26.29, 25.82, 19.30, 10.95, 3.65, 3.61.
HRMS [C25H33N5O2 + H]+: 436.2707 calculated, 436.2706 found.
( )-N-(Cyclopropylmethyl)-2-(2-(cyclohexylmethyl)piperidin-1-
yl)-6-morpholinopyrimidine-4-carboxamide (65). The title com-
pound was prepared according to General Procedure A using 2-
chloropyrimidine 31 (24 mg, 80 μmol, 1 equiv), DiPEA (70 μL, 0.4
mmol, 5 equiv), and ( )-2-(cyclohexylmethyl)piperidine (22 mg,
0.12 mmol, 1.5 equiv). Total heating time: 24 h at 160 °C with μW
irradiation. Column chromatography (10% → 60% EtOAc/pentane)
afforded the product (6 mg, 14 μmol, 17%). TLC: Rf = 0.6 (50%
1
mg, 90 μmol, 90%). TLC: Rf = 0.3 (2% MeOH/DCM). H NMR
(400 MHz, CDCl3) δ 7.94 (t, J = 5.9 Hz, 1H), 7.51−7.44 (m, 2H),
7.43−7.30 (m, 3H), 6.76 (s, 1H), 4.69 (d, J = 12.5 Hz, 2H), 3.88−
3.78 (m, 1H), 3.78−3.71 (m, 4H), 3.68−3.61 (m, 4H), 3.32−3.23
(m, 2H), 3.21 (d, J = 10.6 Hz, 1H), 3.13−2.94 (m, 2H), 2.90 (t, J =
11.7 Hz, 1H), 2.11 (br s, 1H), 1.09−1.00 (m, 1H), 0.57−0.47 (m,
2H), 0.30−0.24 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 164.51,
163.99, 161.01, 156.89, 142.01, 128.73, 127.97, 127.32, 91.05, 66.72,
60.57, 51.48, 46.27, 44.49, 44.26, 44.10, 10.97, 3.55. HRMS
[C23H30N6O2 + H]+: 423.2503 calculated, 423.2501 found.
( )-2-(4-Benzyl-3-phenylpiperazin-1-yl)-N-(cyclopropylmethyl)-
6-morpholinopyrimidine-4-carboxamide (69). A round-bottom
flask was charged with amine 68 (19 mg, 45 μmol, 1 equiv) in dry
CH3CN (0.5 mL). This was followed by DiPEA (16 μL, 90 μmol, 2
equiv) and benzyl bromide (6.4 μL, 54 μmol, 1.2 equiv). The reaction
was stirred for 4 h at rt after which the solvents were concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (1 → 5% MeOH/DCM) affording the product (17
1
EtOAc/pentane). H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 6.67
(s, 1H), 5.07−4.94 (m, 1H), 4.61 (dd, J = 13.8, 4.4 Hz, 1H), 3.81−
3.70 (m, 4H), 3.70−3.56 (m, 4H), 3.37−3.17 (m, 2H), 2.90 (td, J =
13.1, 2.5 Hz, 1H), 1.80 (dd, J = 25.9, 12.9 Hz, 2H), 1.73−1.59 (m,
8H), 1.56−1.38 (m, 3H), 1.24−1.10 (m, 4H), 1.10−1.00 (m, 1H),
0.99−0.86 (m, 2H), 0.62−0.47 (m, 2H), 0.27 (q, J = 4.8 Hz, 2H). 13C
NMR (126 MHz, CDCl3) δ 164.86, 164.07, 160.88, 156.90, 89.87,
66.82, 47.48, 44.55, 44.22, 38.83, 36.74, 34.55, 34.22, 33.47, 29.85,
28.23, 26.76, 26.48, 26.42, 25.94, 19.46, 10.90, 3.57, 3.54. HRMS
[C25H39N5O2 + H]+: 442.3177 calculated, 442.3174 found.
1
mg, 33 μmol, 74%). TLC: Rf = 0.5 (2% MeOH/DCM). H NMR
(400 MHz, CDCl3) δ 7.90 (t, J = 5.7 Hz, 1H), 7.57 (d, J = 7.2 Hz,
2H), 7.41 (t, J = 7.4 Hz, 2H), 7.36−7.27 (m, 5H), 7.25−7.18 (m,
1H), 6.74 (s, 1H), 4.70−4.54 (m, 2H), 3.83 (d, J = 13.4 Hz, 1H),
3.77−3.67 (m, 4H), 3.66−3.54 (m, 4H), 3.35 (dd, J = 10.6, 3.1 Hz,
1H), 3.32−3.18 (m, 2H), 3.08 (td, J = 12.7, 2.7 Hz, 1H), 3.03−2.92
(m, 2H), 2.87 (d, J = 13.4 Hz, 1H), 2.17 (td, J = 11.8, 3.0 Hz, 1H),
1.09−0.95 (m, 1H), 0.57−0.44 (m, 2H), 0.25 (q, J = 4.6 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 164.48, 164.02, 160.74, 156.91, 141.70,
138.93, 128.92, 128.87, 128.29, 128.20, 127.87, 127.00, 90.97, 67.34,
66.71, 59.23, 51.90, 51.73, 44.47, 44.36, 44.08, 10.92, 3.53, 3.51.
HRMS [C30H36N6O2 + H]+: 513.2973 calculated, 513.2973 found.
( )-Benzyl 4-(4-((Cyclopropylmethyl)carbamoyl)-6-morpholino-
pyrimidin-2-yl)-2-phenylpiperazine-1-carboxylate (70). The title
compound was prepared according to General Procedure A using
2-chloropyrimidine 31 (30 mg, 0.10 mmol, 1 equiv), amine 141 (45
mg, 0.12 mmol, 1.2 equiv), and DiPEA (70 μL, 0.40 mmol, 4 equiv).
Total heating time: 41 h at 120 °C. Column chromatography (40% →
70% EtOAc/pentane) afforded the product (56 mg, 0.1 mmol, 99%).
( )-N-(Cyclopropylmethyl)-2-(2-(4-methoxybenzyl)piperidin-1-
yl)-6-morpholinopyrimidine-4-carboxamide (66). The title com-
pound was prepared according to General Procedure A using 2-
chloropyrimidine 31 (30 mg, 0.10 mmol, 1 equiv), ( )-2-(4-
methoxybenzyl)piperidine (46 mg, 0.22 mmol, 2.2 equiv), and
DiPEA (70 μL, 0.40 mmol, 4 equiv). Total heating time: 28 h at 160
°C with μW irradiation. Purification by HPLC (C18 reverse phase,
5% → 90% CH3CN/H2O + 0.2% TFA, RT 9.3 min) afforded the
product (13 mg, 29 μmol, 29%). TLC: Rf = 0.3 (40% EtOAc/
1
pentane). H NMR (400 MHz, CDCl3) δ 7.98 (t, J = 5.8 Hz, 1H),
7.16−7.10 (m, 2H), 6.85−6.75 (m, 2H), 6.69 (s, 1H), 5.00 (dt, J =
10.4, 4.9 Hz, 1H), 4.67 (dd, J = 13.5, 3.7 Hz, 1H), 3.84−3.72 (m,
7H), 3.65 (t, J = 4.8 Hz, 4H), 3.40−3.21 (m, 2H), 3.00 (td, J = 13.2,
2.8 Hz, 1H), 2.90 (dd, J = 13.2, 10.0 Hz, 1H), 2.74 (dd, J = 13.2, 5.1
Hz, 1H), 1.85−1.71 (m, 2H), 1.65 (s, 2H), 1.59−1.42 (m, 2H),
1.15−1.01 (m, 1H), 0.64−0.50 (m, 2H), 0.36−0.25 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 164.78, 164.00, 160.88, 158.03, 156.84,
132.18, 130.15, 113.89, 90.31, 66.79, 55.40, 52.38, 44.54, 44.23, 39.47,
34.37, 26.18, 25.83, 19.29, 10.97, 3.65, 3.61. HRMS [C26H35N5O3 +
H]+: 466.2813 calculated, 466.2809 found.
1
TLC: Rf = 0.3 (50% EtOAc/pentane). H NMR (400 MHz, CDCl3)
δ 7.90 (t, J = 5.9 Hz, 1H), 7.45−7.19 (m, 10H), 6.77 (s, 1H), 5.47 (br
s, 1H), 5.31−5.12 (m, 2H), 5.04 (d, J = 13.8 Hz, 1H), 4.52−4.31 (m,
1H), 4.17 (d, J = 9.4 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 3.71−3.60 (m,
4H), 3.53 (d, J = 13.4 Hz, 1H), 3.29 (t, J = 6.5 Hz, 2H), 3.17 (d, J =
9.2 Hz, 2H), 1.13−0.97 (m, 1H), 0.61−0.46 (m, 2H), 0.34−0.21 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 164.36, 163.88, 160.76, 156.82,
155.79, 139.31, 136.59, 128.68, 128.65, 128.23, 128.03, 127.44,
127.04, 91.44, 67.65, 66.70, 45.36, 44.54, 44.13, 43.82, 39.89, 10.93,
3.53. HRMS [C31H36N6O4 + H]+: 557.2871 calculated, 557.2869
found.
(
) - N - ( C y c l o p r o p y l m e t h y l ) - 6 - m o r p h o l i n o - 2 - ( 2 -
phenylmorpholino)pyrimidine-4-carboxamide (67). The title com-
pound was prepared according to General Procedure A using 2-
chloropyrimidine 31 (30 mg, 0.10 mmol, 1 equiv), DiPEA (52 μL,
0.30 mmol, 3 equiv), and ( )-2-phenylmorpholine (21 μL, 0.13
mmol, 1.3 equiv). Total heating time: 4 h at 160 °C with μW
499
J. Med. Chem. 2021, 64, 481−515