Journal of Medicinal Chemistry
Article
7.77−7.63 (m, 3H), 7.57 (dd, J = 8.7, 2.2 Hz, 1H), 7.40 (d, J = 8.7
Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.65−4.56 (m, 1H), 3.89 (t, J =
8.3 Hz, 2H), 3.59 (s, 2H), 3.09 (s, 3H), 2.86 (t, J = 8.3 Hz, 2H),
2.30 (d, J = 4.5 Hz, 3H), 1.47 (d, J = 6.7 Hz, 6H). 13C NMR (101
MHz, DMSO-d6) δ 174.94, 159.79, 158.83, 157.75, 150.05, 139.34,
138.04, 135.42, 133.08, 129.50, 129.30, 128.66, 126.30, 123.46,
120.56, 117.97, 116.53, 115.99, 115.13, 108.72, 53.81, 50.61, 35.40,
28.16, 26.52, 23.03, 17.14. HRMS-ESI: calcd for C28H29N7NaO3S
[M + Na]+ 566.1950, found: 566.1957.
NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.33 (s, 1H), 8.27 (s,
1H), 8.09 (d, J = 5.1 Hz, 1H), 8.08−7.99 (m, 2H), 7.98−7.90 (m,
1H), 7.85 (s, 1H), 7.68−7.57 (m, 2H), 4.68−4.56 (m, J = 6.5 Hz,
1H), 3.87 (t, J = 8.2 Hz, 2H), 3.14 (t, J = 8.2 Hz, 2H), 2.31 (s,
3H), 1.48 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ
161.28, 159.86, 158.88, 157.75, 139.35, 138.69, 136.11, 133.49,
129.57, 129.47, 127.00, 126.94, 126.81, 126.58, 126.26, 126.23,
125.38, 122.67, 120.65, 118.10, 117.87, 117.20, 117.02, 116.60,
115.49, 53.82, 49.65, 28.28, 23.00, 17.15. HRMS-ESI: calcd for
C27H25F4N6O [M + H]+ 525.2026, found: 525.2055.
1-(5-((4-(1-Isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-
amino)indolin-1-yl)ethan-1-one (11h). 21a and acetyl chloride
were used by the method of 11a to get 11h. White solid. Yield:
(5-((4-(1-Isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-
amino)indolin-1-yl) (3-(trifluoromethyl)phenyl)methanone (11m).
21a and 3-(trifluoromethyl) benzoyl chloride were used by the
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90%. H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.33 (s, 1H),
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8.26 (s, 1H), 8.08 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.76 (s, 1H),
7.49 (dd, J = 8.7, 2.2 Hz, 1H), 4.64 (p, J = 6.6 Hz, 1H), 4.08 (t, J =
8.4 Hz, 2H), 3.16 (t, J = 8.5 Hz, 2H), 2.31 (s, 3H), 2.14 (s, 3H),
1.49 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ
168.02, 159.86, 158.96, 157.71, 139.32, 137.28, 137.25, 132.36,
129.46, 120.68, 117.24, 116.33, 116.16, 115.63, 53.81, 48.67, 28.13,
24.25, 23.04, 17.15. HRMS-ESI: calcd for C21H25N6O [M + H]+
377.2090, found: 377.2083.
method of 11a to get 11m. White solid. Yield: 70%. H NMR (400
MHz, DMSO-d6) δ 9.34 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.08 (s,
1H), 8.06−8.00 (m, 1H), 7.97−7.85 (m, 3H), 7.83 (s, 1H), 7.73 (t,
J = 7.8 Hz, 1H), 7.62 (s, 1H), 4.62 (hept, J = 6.7 Hz, 1H), 4.01 (q,
J = 10.5, 8.8 Hz, 2H), 3.11 (t, J = 8.2 Hz, 2H), 2.31 (s, 3H), 1.47
(d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 166.12,
159.87, 158.90, 157.74, 139.33, 138.75, 138.30, 133.42, 131.44,
130.13, 129.45, 126.94, 125.74, 124.22, 123.04, 120.66, 117.37,
117.10, 116.55, 115.44, 53.83, 50.95, 28.64, 23.01, 17.15. HRMS-
ESI: calcd for C27H26F3N6O [M + H]+ 507.2120, found: 507.2151.
1-(5-((4-(1-Isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-
amino)indolin-1-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one
(11n). 21a and 2-(4-(trifluoromethoxy)phenyl)acetyl chloride were
Cyclopropyl(5-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-methylpyrimi-
din-2-yl)amino)indolin-1-yl)methanone (11i). 21a and cyclopropa-
necarbonyl chloride were used by the method of 11a to get 11i.
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White solid. Yield: 89%. H NMR (400 MHz, DMSO-d6) δ 9.25 (s,
1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 8.7 Hz,
1H), 7.77 (s, 1H), 7.48 (d, J = 9.1 Hz, 1H), 4.63 (hept, J = 6.6 Hz,
1H), 4.28 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.3 Hz, 2H), 2.31 (s,
3H), 1.92 (s, 1H), 1.48 (d, J = 6.7 Hz, 6H), 0.93−0.73 (m, 4H).
13C NMR (101 MHz, DMSO-d6) δ 170.65, 159.86, 158.96, 157.71,
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used by the method of 11a to get 11n. White solid. Yield: 67%. H
NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.32 (s, 1H), 8.26 (s,
1H), 8.07 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.53−
7.42 (m, 2H), 7.36−7.29 (m, 2H), 7.25 (d, J = 8.3 Hz, 1H), 4.63
(hept, J = 6.6 Hz, 1H), 4.19 (t, J = 8.4 Hz, 2H), 3.92 (s, 2H), 3.19
(t, J = 8.4 Hz, 2H), 2.31 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H). 13C
NMR (101 MHz, DMSO-d6) δ 168.00, 159.85, 158.93, 157.73,
148.72, 139.31, 138.72, 137.54, 137.20, 132.47, 130.37, 129.47,
129.44, 122.68, 121.87, 120.67, 119.36, 117.21, 116.39, 116.35,
115.56, 53.81, 48.18, 41.58, 28.19, 23.03, 17.15. HRMS-ESI: calcd
for C28H28F3N6O2 [M + H]+ 537.2226, found: 537.2230.
139.31, 137.48, 137.22, 132.36, 129.44, 120.68, 117.20, 116.34,
115.59, 53.81, 48.19, 28.10, 23.04, 17.16, 13.43, 8.00. HRMS-ESI:
calcd for C23H26N6NaO [M + Na]+ 425.2066, found: 425.2063.
(2,2-Difluorocyclopropyl)(5-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-
methylpyrimidin -2-yl)amino)indolin-1-yl)methanone (11j). 2,2-
Difluorocyclopropane-1-carboxylic acid (86 mg, 0.7 mmol, 1.2
equiv) was first activated with HATU (296 mg, 0.7 mmol, 1.2
equiv) and DIEA (214 μL, 1.3 mmol, 2.0 equiv) in N,N-
dimethylformamide for 30 min, and then 21a (213 mg, 0.64
mmol, 1.0 equiv) was added and allowed to react at room
temperature for 12 h. After the reaction was completed, the reaction
solution was extracted with dichloromethane and purified to obtain
11j. White solid. Yield: 40%. 1H NMR (400 MHz, DMSO-d6) δ
9.31 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.94 (d, J =
8.7 Hz, 1H), 7.81 (s, 1H), 7.53 (dd, J = 8.8, 2.2 Hz, 1H), 4.63
(hept, J = 6.6 Hz, 1H), 4.36 (td, J = 10.1, 7.0 Hz, 1H), 4.12 (td, J =
9.9, 6.9 Hz, 1H), 3.27−3.08 (m, 3H), 2.31 (s, 3H), 2.12−1.88 (m,
2H), 1.48 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ
161.16, 159.37, 158.40, 157.24, 138.82, 137.46, 136.21, 132.23,
128.98, 120.15, 116.72, 115.99, 115.88, 115.07, 53.32, 47.89, 27.53,
26.65, 22.54, 16.66. HRMS-ESI: calcd for C23H25F2N6O [M + H]+
439.2058, found: 439.2051.
2-(1,1-Dioxidothiomorpholino)-1-(5-((4-(1-isopropyl-1H-pyrazol-
4-yl)-5-methyl-pyrimidin-2-yl)amino)indolin-1-yl)ethan-1-one
(11o). 21a and 2-(1,1-dioxidothio-morpholino)acetic acid were used
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by the method of 11j to get 11o. White solid. Yield: 50%. H NMR
(400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H),
8.07 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H),
7.51 (dd, J = 8.8, 2.3 Hz, 1H), 4.66−4.54 (m, 1H), 4.16−4.07 (m,
2H), 3.55 (s, 2H), 3.21−3.06 (m, 10H), 2.31 (s, 3H), 1.49 (s, 3H),
1.47 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 167.48, 159.87,
158.93, 157.72, 139.32, 137.54, 137.21, 132.25, 129.46, 120.66,
117.19, 116.39, 116.32, 115.55, 59.11, 53.82, 51.18, 50.49, 47.25,
28.36, 23.05, 17.16. HRMS-ESI: calcd for C25H31N7NaO3S [M +
Na]+ 532.2107, found: 532.2210.
1-(5-((4-(1-Isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-
amino)indolin-1-yl)-3-morpholinopropan-1-one (11p). 21a and 3-
morpholinopropanoic acid were used by the method of 11j to get
((1S,2S)-2-Fluorocyclopropyl)(5-((4-(1-isopropyl-1H-pyrazol-4-
yl)-5-methylpyri-midin-2-yl)amino)indolin-1-yl)methanone (11k).
21a and (1S,2S)-2-fluorocyclopropanecarboxylic acid were used by
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11p. White solid. Yield: 50%. H NMR (400 MHz, DMSO-d6) δ
9.26 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.98 (d, J =
8.8 Hz, 1H), 7.77 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 4.62 (h, J = 6.6
Hz, 1H), 4.10 (t, J = 8.5 Hz, 2H), 3.61 (s, 4H), 3.44 (s, 2H), 3.16
(t, J = 8.3 Hz, 2H), 2.66 (s, 4H), 2.48 (s, 2H), 2.31 (s, 3H), 1.48
(d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 159.86,
158.94, 157.71, 139.32, 137.38, 137.23, 132.40, 129.44, 120.67,
117.21, 116.37, 116.30, 115.59, 66.21, 59.15, 58.04, 53.82, 53.55,
47.92, 28.14, 23.05, 17.16. HRMS-ESI: calcd for C26H34N7O2 [M +
H]+ 476.2774, found: 476.2773.
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the method of 11j to get 11k. White solid. Yield: 50%. H NMR
(400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H),
8.08 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.51 (d, J = 9.1
Hz, 1H), 5.14−4.89 (m, 1H), 4.63 (p, J = 6.7 Hz, 1H), 4.33 (q, J =
9.5 Hz, 1H), 4.20 (q, J = 9.3 Hz, 1H), 3.21 (s, 2H), 2.31 (s, 3H),
2.22 (p, J = 7.0 Hz, 1H), 1.73−1.58 (m, 1H), 1.48 (d, J = 6.6 Hz,
6H), 1.18−1.00 (m, 1H). 13C NMR (101 MHz, DMSO-d6)
δ163.40, 159.37, 158.44, 157.22, 138.81, 137.01, 136.73, 131.94,
128.97, 120.17, 116.72, 115.89, 115.74, 115.10, 72.98, 70.76, 53.31,
47.56, 27.55, 22.54, 21.67, 21.55, 16.66. HRMS-ESI: calcd for
C23H26FN6O [M + H]+ 421.2152, found: 421.2143.
(R)-5-((4-(1-Isopropyl-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-
amino)-1-prolylindoline (11q). (R)-Boc-pyrrolidine-2-carboxylic
acid and 21a were used by the method of 11j. Then, TFA-
mediated Boc was removed and further purified to get 11q. White
(2-Fluoro-5-(trifluoromethyl)phenyl)(5-((4-(1-isopropyl-1H-pyra-
zol-4-yl)-5-meth-ylpyrimidin-2-yl)amino)indolin-1-yl)methanone
(11l). 21a and 2-fluoro-5-(trifluoromethyl)benzoyl chloride were
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solid. Yield: 35%. H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H),
8.32 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H),
7.79 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 4.63 (p, J = 6.8 Hz, 1H),
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used by the method of 11a to get 11l. White solid. Yield: 70%. H
1981
J. Med. Chem. 2021, 64, 1966−1988