Journal of Medicinal Chemistry
Article
5.3 Hz, 1H), 4.15 (s, 3H), 3.69 (s, 4H), 3.63 (dd, J = 14.1, 7.0
Hz, 1H), 2.58 (s, 4H), 2.42 (d, J = 6.9 Hz, 2H), 1.57 (d, J = 7.0
Hz, 6H), 1.06 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
chloroform-d) δ 165.54, 164.02, 159.71, 158.28, 154.52, 153.10,
148.77, 143.77, 142.85, 128.68, 125.67, 124.25, 121.36, 119.53,
118.47, 117.60, 114.26, 111.72, 109.14, 52.75, 52.39, 49.61,
38.11, 27.19, 22.01, 11.90; HRMS (ESI) calcd for C29H33N9 [M
+ H]+ 508.2932, found 508.2935.
4-(7-((4-(3-Isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-
2-yl)amino)quinazolin-4-yl)-1-methylpiperazin-2-one (37f).
Compound 37f was prepared according to general procedure I
on a 0.6 mmol scale. Purification by column chromatography
(4% MeOH/DCM) yielded the title compound (230 mg, 0.45
mmol, 75% yield). White solid; mp 140−142 °C. HPLC
analysis: retention time, 4.552 min; peak area, 99.29%. 1H NMR
(400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.84 (s, 1H), 8.64 (d, J =
5.8 Hz, 2H), 8.58 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 8.00 (d, J =
9.2 Hz, 1H), 7.96−7.88 (m, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.64
(d, J = 5.3 Hz, 1H), 4.30 (s, 2H), 4.16 (s, 3H), 4.01 (d, J = 5.0
Hz, 2H), 3.63 (dt, J = 14.0, 7.0 Hz, 1H), 3.58−3.46 (m, 2H),
2.91 (s, 3H), 1.57 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz,
chloroform-d) δ 165.84, 165.46, 162.46, 159.63, 158.25, 154.25,
153.19, 148.75, 144.14, 142.91, 128.59, 125.17, 124.21, 121.38,
119.51, 118.96, 117.59, 114.14, 111.14, 109.19, 53.83, 47.51,
45.25, 38.11, 34.49, 27.20, 22.00; HRMS (ESI) calcd for
C28H29N9O [M + H]+ 508.2568, found 508.2575.
4-(1,4-Diazepan-1-yl)-N-(4-(3-isopropyl-2-methyl-2H-in-
dazol-5-yl)pyrimidin-2-yl)quinazolin-7-amine (37g). Com-
pound 37g was prepared according to general procedure I on
a 0.6 mmol scale. Purification by column chromatography (4%
MeOH/DCM) yielded the title compound (162 mg, 0.33
mmol, 55% yield). Pale yellow solid; mp 125−128 °C. HPLC
analysis: retention time, 5.582 min; peak area, 98.16%. 1H NMR
(300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.84 (s, 1H), 8.62 (d, J =
5.3 Hz, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.39 (s, 1H), 7.96−
8.09(m, 2H), 7.84 (dd, J = 9.3, 2.0 Hz, 1H), 7.66 (d, J = 9.1 Hz,
1H), 7.60 (d, J = 5.3 Hz, 1H), 4.15 (s, 3H), 3.86−4.03 (m, 4H),
3.58−3.68 (m, 1H), 3.03 (s, 2H), 2.72−2.85 (m, 2H), 1.92 (s,
2H), 1.56 (d, J = 7.0 Hz, 6H); 13C NMR (101 MHz, DMSO-d6)
δ 164.72, 161.87, 160.28, 159.23, 154.15, 153.82, 148.35,
144.21, 143.08, 128.42, 126.72, 124.17, 121.53, 119.48, 117.67,
113.63, 110.34, 109.09, 54.36, 49.77, 49.19, 48.74, 38.54, 30.83,
26.76, 22.20; HRMS (ESI) calcd for C28H31N9 [M + H]+
494.2775, found 494.2780.
N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-
yl)-4-(4-methyl-1,4-diazepan-1-yl)quinazolin-7-amine (37h).
Compound 37h was prepared according to general procedure I
on a 0.6 mmol scale. Purification by column chromatography
(4% MeOH/DCM) yielded the title compound (243 mg, 0.48
mmol, 80% yield). Pale yellow solid; mp 205−207 °C. HPLC
analysis: retention time, 6.590 min; peak area, 99.55%. 1H NMR
(300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.83 (s, 1H), 8.61 (d, J =
5.3 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.40 (s, 1H), 7.95−8.10
(m, 2H), 7.84 (dd, J = 9.3, 2.2 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H),
7.60 (d, J = 5.3 Hz, 1H), 4.15 (s, 3H), 4.11 (d, J = 5.6 Hz, 1H),
3.89−4.02 (m, 4H), 3.59−3.68 (m, 1H), 3.18 (d, J = 4.6 Hz,
1H), 2.79 (d, J = 2.7 Hz, 2H), 2.27 (s, 3H), 2.02 (s, 2H), 1.56 (d,
J = 7.0 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 164.72,
161.91, 160.28, 159.20, 154.07, 153.83, 148.36, 144.26, 143.05,
128.41, 126.82, 124.16, 121.52, 119.49, 117.81, 117.67, 113.61,
110.30, 109.07, 57.63, 57.56, 50.76, 50.23, 46.38, 38.51, 28.07,
26.77, 22.18; HRMS (ESI) calcd for C29H33N9 [M + H]+
508.2932, found 508.2934.
4-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(3-isopropyl-
2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)quinazolin-7-
amine (37i). Compound 37i was prepared according to general
procedure I on a 0.6 mmol scale. Purification by column
chromatography (4% MeOH/DCM) yielded the title com-
pound (145 mg, 0.29 mmol, 48.3% yield). Pale yellow solid; mp
291−294 °C. HPLC analysis: retention time, 4.987 min; peak
area, 98.15%. 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H),
8.83 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.37 (s, 1H),
8.04 (d, J = 6.1 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 9.0
Hz, 1H), 7.61 (d, J = 5.1 Hz, 1H), 5.05 (s, 1H), 4.15 (s, 4H),
3.56−3.76 (m, 3H), 2.92−3.09 (m, 2H), 1.87 (d, J = 8.8 Hz,
1H), 1.71 (d, J = 8.6 Hz, 1H), 1.56 (d, J = 6.8 Hz, 6H), 1.23 (s,
1H); 13C NMR (75 MHz, chloroform-d) δ 165.47, 159.72,
159.35, 158.22, 154.68, 152.75, 148.75, 143.47, 142.81, 128.75,
125.40, 124.29, 121.29, 119.51, 117.56, 114.13, 111.31, 109.03,
61.87, 59.69, 56.62, 51.35, 38.12, 36.64, 29.69, 27.18, 22.00;
HRMS (ESI) calcd for C28H29N9 [M + H]+ 492.2619, found
492.2620.
N7-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-
yl)-N4-(1-methylpiperidin-4-yl)quinazoline-4,7-diamine
(37j). Compound 37j was prepared according to general
procedure I on a 0.6 mmol scale. Purification by column
chromatography (4% MeOH/DCM) yielded the title com-
pound (185 mg, 0.36 mmol, 60% yield). Yellow solid; mp 170−
172 °C. HPLC analysis: retention time, 6.560 min; peak area,
97.43%. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.80
(s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 8.39
(s, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.00−8.10 (m, 1H), 7.79 (dd, J
= 9.1, 2.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 9.1 Hz,
1H), 7.61 (d, J = 5.3 Hz, 1H), 4.15 (s, 4H), 3.59−3.66 (m, 1H),
2.84 (d, J = 11.2 Hz, 2H), 2.20 (s, 3H), 2.01 (t, J = 11.0 Hz, 2H),
1.91 (d, J = 10.3 Hz, 2H), 1.62−1.73 (m, 2H), 1.55 (d, J = 7.0
Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 164.77, 160.30,
159.14, 158.84, 155.87, 151.18, 148.36, 144.71, 143.07, 128.47,
124.12, 123.67, 121.56, 119.48, 118.70, 117.65, 113.74, 109.81,
109.04, 55.09, 47.81, 46.39, 38.53, 31.73, 26.75, 22.18; HRMS
(ESI) calcd for C29H33N9 [M + H]+ 508.2932, found 508.2930.
N7-(4-(3-Isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-
yl)-N4-(2-methoxyethyl)quinazoline-4,7-diamine (37k).
Compound 37k was prepared according to general procedure
I on a 0.6 mmol scale. Purification by column chromatography
(4% MeOH/DCM) yielded the title compound (222 mg, 0.47
mmol, 78.3% yield). Yellow solid; mp 165−166 °C. HPLC
analysis: retention time, 4.627 min; peak area, 99.40%. 1H NMR
(300 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.80 (s, 1H), 8.61 (d, J =
5.3 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.40 (s, 1H), 8.09−8.18
(m, 2H), 8.05 (dd, J = 9.2, 1.5 Hz, 1H), 7.79 (dd, J = 9.0, 2.2 Hz,
1H), 7.66 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 5.4 Hz, 1H), 4.15 (s,
3H), 3.68−3.73 (m, 2H), 3.55−3.66 (m, 3H), 3.30 (s, 3H), 1.56
(d, J = 7.0 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 164.79,
160.29, 159.49, 159.17, 155.80, 151.08, 148.35, 144.76, 143.11,
128.45, 124.15, 123.47, 121.56, 119.47, 118.91, 117.66, 113.75,
109.84, 109.09, 70.72, 58.46, 40.59, 38.53, 26.75, 22.18; HRMS
(ESI) calcd for C26H28N8O [M + H]+ 469.2459, found
469.2466.
N7-(4-(3-Isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-
yl)-N4-(3-methoxypropyl)quinazoline-4,7-diamine (37l).
Compound 37l was prepared according to general procedure I
on a 0.6 mmol scale. Purification by column chromatography
(4% MeOH/DCM) yielded the title compound (198 mg, 0.41
mmol, 68.3% yield). White solid; mp 160−162 °C. HPLC
analysis: retention time, 4.844 min; peak area, 99.73%. 1H NMR
T
J. Med. Chem. XXXX, XXX, XXX−XXX