Journal of Medicinal Chemistry
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4H), 2.42 (s, 3H), 2.41 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 173.0, 171.2, 171.1, 160.1, 158.9,
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)cyclopropanecarboxamide (7b). To a solution of 6a
(10.9 mg, 0.0302 mmol) and Et3N (21 μL, 15.3 mg, 0.151 mmol) in
CH2Cl2 (1 mL) was added cyclopropanecarbonyl chloride (14 μL,
15.8 mg, 0.1508 mmol), and the resulting solution was stirred at rt for
2 h. Solvent was removed under reduced pressure, and the residue was
purified by preparatory TLC (CH2Cl2/MeOH−NH3 (7 N), 20:1) to
157.0, 105.5, 77.0, 54.6, 54.3, 45.7, 43.1, 30.8, 9.0. HRMS (m/z): [M +
H]+ calcd for C18H26N7O3S, 420.1818; found, 420.1838.
N-(2-((4,6-Dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)pyrimidin-4-yl)propionamide (4c). To a solution of 2d (50 mg,
0.151 mmol) and Et3N (152 mg, 1.51 mmol) in 2 mL of anhydrous
dioxane was added propionyl chloride (140 mg, 1.51 mmol) dropwise.
The resulting mixture was stirred at rt for 12 h. Solvent was removed
under reduced pressure, and the residue was purified by preparatory
TLC (CHCl3/MeOH−NH3 (7 N), 10:1) to afford 59 mg (83%) of
4c. 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J = 5.7 Hz, 1H), 7.84 (s,
1H), 7.81 (d, J = 5.7 Hz, 1H), 3.92 (s, 4H), 2.48 (m, 4H), 2.44 (s,
6H), 2.40 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 173.0, 171.9, 170.7, 160.4, 159.1,
1
afford 7.9 mg (61%) of 7b. H NMR (500 MHz, CDCl3): δ 7.49 (m,
1H), 7.29 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.78 (d, J =
7.6 Hz, 1H), 3.88−3.95 (m, 10H), 2.48 (m, 4H), 2.36 (s, 3H), 1.05−
1.13 (m, 1H), 0.74−0.96 (m, 4H). HRMS (m/z): [M + H]+ calcd for
C21H28N5O3S, 430.1913; found, 430.1897.
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)cyclobutanecarboxamide (7c). 6a (10 mg, 0.028 mmol),
Et3N (19.5 μL, 14.2 mg, 0.14 mmol), and cyclobutanecarbonyl
chloride (9.6 μL, 10.0 mg, 0.084 mmol) in CH2Cl2 (1 mL) were
stirred at rt for 2 h. Solvent was removed under reduced pressure, and
the residue was purified by preparatory TLC (EtOAc/MeOH−NH3 (7
N), 20:1) to afford 4.1 mg (33%) of 7c. 1H NMR (500 MHz, CDCl3):
δ 7.50 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.94
(br s, 1H), 6.77 (d, J = 7.9 Hz, 1H), 3.90 (br s, 10H), 3.07 (m, 1H),
2.50 (m, 14H), 2.14−2.42 (m, 7H), 1.82−2.02 (m, 2H). HRMS (m/
z): [M + H]+ calcd for C22H30N5O3S, 444.2069; found, 444.2052.
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)cyclohexanecarboxamide (7d). 6a (10 mg, 0.028
mmol), Et3N (19.5 μL, 14.2 mg, 0.14 mmol), and cyclohexanecarbonyl
chloride (11.4 μL, 12.3 mg, 0.084 mmol) in CH2Cl2 (1 mL) were
stirred at rt for 3 h. Solvent was removed under reduced pressure, and
the residue was purified by preparatory TLC (EtOAc/MeOH−NH3 (7
N), 20:1) to afford 12 mg (91%) of 7d. 1H NMR (500 MHz, CDCl3):
δ 7.50 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.02
(s, 1H), 6.76 (d, J = 7.7 Hz, 1H), 3.90 (br s, 10H), 2.51 (m, 4H), 2.38
(s, 3H), 2.11−2.22 (m, 1H), 1.19−1.96 (m, 10H). MS (m/z): [M +
H]+ 472.0.
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)benzamide (7e). 6a (10 mg, 0.028 mmol), Et3N (19.5
μL, 14.2 mg, 0.14 mmol), and benzoyl chloride (9.8 μL, 11.8 mg,
0.084 mmol) in CH2Cl2 (1 mL) were stirred at rt for 3 h. Solvent was
removed under reduced pressure, and the residue was purified by
preparatory TLC (EtOAc/MeOH−NH3 (7 N), 20:1) to afford 8.6 mg
(66%) of 7e. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.7 Hz, 2H),
7.74 (br s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 6.4 Hz, 1H), 7.47
(t, J = 7.8 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J =
7.9 Hz, 1H), 3.87−3.93 (m, 10H), 2.50 (m, 4H), 2.37 (s, 3H). HRMS
(m/z): [M + H]+ calcd for C24H28N5O3S, 466.1913; found, 466.1919.
2-Amino-N-(3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)-
pyrimidin-5-yl)thio)phenyl)acetamide (7f). To a solution of 6a (20
mg, 0.0552 mmol) in THF (1 mL) were added Boc-glycine (9.7 mg,
0.0552 mmol) and DCC (12 mg, 0.058 mmol), and the resulting
solution was stirred at rt for 5 h. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by preparatory TLC (EtOAc/MeOH−NH3 (7 N), 20:1) to afford a
solid which was dissolved in 2 mL of CH2Cl2/TFA (4:1). The
resulting solution was stirred at rt for 1 h. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by
preparatory TLC (CH2Cl2/MeOH−NH3 (7 N), 15:1) to afford 13.9
mg (60%) of 7f. 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 7.38 (d, J
= 8.2 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.6
Hz, 1H), 3.86−3.97 (m, 10H), 3.52 (s, 2H), 2.58 (m, 4H), 2.41 (s,
3H). HRMS (m/z): [M + H]+ calcd for C19H27N6O3S, 419.1865;
found, 419.1862.
157.3, 108.7, 105.7, 55.0, 46.2, 43.5, 30.8, 23.9, 8.9. HRMS (m/z): [M
+ H]+ calcd for C18H26N7OS, 388.1920; found, 388.1921.
N-(2-((4,6-Dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)pyrimidin-4-yl)furan-2-carboxamide (4d). To a solution of 2d
(50 mg, 0.151 mmol) and Et3N (152 mg, 1.51 mmol) in 2 mL of
anhydrous dioxane was added 2-furoyl chloride (197 mg, 1.51 mmol)
dropwise. The resulting mixture was stirred at rt for 12 h. Solvent was
removed under reduced pressure, and the residue was purified by
preparatory TLC (CHCl3/MeOH−NH3 (7 N), 10:1) to afford 56 mg
(87%) of 4d. 1H NMR (600 MHz, CDCl3): δ 8.58 (br s, 1H), 8.40 (d,
J = 5.6 Hz, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.56−7.58 (m, 1H), 7.31 (d,
J = 3.5 Hz, 1H), 6.60 (dd, J = 3.5, 1.7 Hz, 1H), 3.90−3.97 (m, 4H),
2.49 (m, 4H), 2.46 (s, 6H), 2.36 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ 171.9, 170.9, 160.5, 159.1, 157.1, 156.3, 146.4, 145.4, 117.2,
113.0, 108.5, 106.0, 55.0, 46.3, 43.5, 23.9. HRMS (m/z): [M + H]+
calcd for C20H24N7O2S, 426.1712; found, 426.1727.
N-(2-((4,6-Dimethyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)pyrimidin-4-yl)cyclopropanecarboxamide (4e). To a solution of
2d (50 mg, 0.151 mmol) and Et3N (152 mg, 1.51 mmol) in 2 mL of
anhydrous dioxane was added cyclopropanecarbonyl chloride (158
mg, 1.51 mmol) dropwise. The resulting mixture was stirred at rt for
12 h. Solvent was removed under reduced pressure, and the residue
was purified by preparatory TLC (CHCl3/MeOH−NH3 (7 N), 10:1)
to afford 48 mg (79%) of 4e. 1H NMR (500 MHz, CDCl3): δ 8.35 (d,
J = 5.6 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J = 5.6 Hz, 1H), 3.92 (m, 4H),
2.49 (m, 4H), 2.45 (s, 6H), 2.36 (s, 3H), 1.54 (m, 1H), 1.10 (m, 2H),
0.93 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 173.1, 172.0, 170.6,
160.4, 159.0, 157.3, 108.8, 105.7, 55.0, 46.2, 43.5, 23.8, 16.0, 9.1.
HRMS (m/z): [M + H]+ calcd for C19H26N7OS, 400.1920; found,
400.1913.
3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)aniline (6a). A mixture of 5a (0.200 g, 0.549 mmol), 3-
aminothiophenol (70 μL, 0.082 g, 0.659 mmol), neocuproine (0.023 g,
0.110 mmol), CuI (0.021, 0.110 mmol), and K2CO3 (0.152 g, 1.10
mmol) in DMF (7 mL) was heated at 120 °C for 24 h. Solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (CH2Cl2/MeOH−NH3 (7 N), 200:1 to
1
40:1) to afford 0.133 g (67%) of 6a. H NMR (500 MHz, CDCl3): δ
6.97 (t, J = 8.0 Hz, 1H), 6.46−6.51 (m, 1H), 6.36−6.40 (m, 2H),
3.88−4.03 (m, 10H), 3.58 (br s, 2H), 2.52 (m, 4H), 2.38 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 171.8, 160.1, 146.9, 139.5, 129.6, 116.2,
112.2, 112.1, 81.1, 55.0, 54.6, 46.3, 43.8. HRMS (m/z): [M + H]+
calcd for C17H24N5O2S, 362.1651; found, 362.1649.
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)propionamide (7a). To a solution of 6a (10 mg, 0.027
mmol) and Et3N (50 μL, 36 mg, 0.36 mmol) in 1 mL of CH2Cl2 was
added propionyl chloride (22 μL, 24.4 mg, 0.27 mmol). The reaction
was stirred at rt for 12 h and then quenched by adding cold MeOH.
Solvent was evaporated under reduced pressure, and the residue was
purified by preparatory TLC (CH2Cl2/MeOH−NH3 (7 N), 20:1) to
afford 7.3 mg (65%) of 7a. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J =
7.5 Hz, 1H), 7.13 (m, 2H), 7.04 (s, 1H), 6.78 (d, J = 7.5 Hz, 1H), 3.93
(m, 4H), 3.90 (s, 6H), 2.55 (m, 4H), 2.36 (s, 3H), 2.33 (q, J = 7.2 Hz,
2H), 1.21 (t, J = 7.2 Hz, 3H). HRMS (m/z): [M + H]+ calcd for
C20H28N5O3S, 418.1913; found, 418.1910.
N-(3-((4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-
thio)phenyl)but-3-enamide (7g). To a solution of 6a (10 mg, 0.027
mmol) and Et3N (50 μL, 36 mg, 0.36 mmol) in 1 mL of CH2Cl2 was
added 3-butenoyl chloride (28.2 mg, 0.27 mmol). The reaction was
stirred at rt for 12 h and then quenched by adding cold MeOH.
Solvent was evaporated under reduced pressure, and the residue was
purified by preparatory TLC (CH2Cl2/MeOH−NH3 (7 N), 20:1) to
afford 8.3 mg (72%) of 7g. 1H NMR (500 MHz, CDCl3): δ 7.35 (d, J
= 8.1 Hz, 1H), 7.29 (br s, 1H), 7.10−7.19 (m, 2H), 6.79 (d, J = 7.5
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dx.doi.org/10.1021/jm401552y | J. Med. Chem. 2014, 57, 1208−1224