Journal of Medicinal Chemistry
Article
(s, 1 H), 8.35 (d, J = 7.3 Hz, 1 H), 8.12−8.21 (m, 6 H), 7.93 (d, J = 8.3
Hz, 2 H), 7.83 (d, J = 6.8 Hz, 1 H), 7.47 (td, J = 8.3, 6.3 Hz, 1 H),
7.30−7.36 (m, 2 H), 7.28 (d, J = 8.8 Hz, 1 H), 7.18 (td, J = 8.7, 2.2 Hz,
1 H), 5.25 (s, 2 H), 2.96 (br. s., 4 H), 2.35−2.43 (m, 4 H), 2.15 (s, 3
H). LCMS found 618.2 [M + H]+.
4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-
methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile
(83). Synthesized by general procedure D. Flash column chromatog-
raphy: 0−30% methanol in dichloromethane, isolated as a yellow solid
in 32% yield. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.14 (d, J =
8.8 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.8, 2.2 Hz, 1H),
7.80−7.82 (m, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.47 (s, 1H), 7.41 (d, J =
2 Hz, 1H), 7.36−7.39 (m, 1H), 7.23 (s, 1H), 7.19−7.20 (m, 1H), 7.17
(d, J = 2 Hz, 1H), 7.05 (dd, J = 8.0,2.4 Hz, 1H), 7.01 (d, J = 8.8 Hz,
1H), 5.19 (s, 2H), 3.36−3.40 (m, 4H), 2.56−2.62 (m, 4H), 2.33 (s,
3H), 1.81−1.85 (m, 2H). LCMS found 656.2 [M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-
morpholinophenyl)thieno[3,2-d]pyrimidin-4-amine (85). Synthe-
sized by general procedure E, isolated as a yellow solid in 12% yield.
1H NMR (500 MHz, DMSO-d6) δ ppm 9.68 (s, 1 H), 8.59 (s, 1 H),
8.01 (d, J = 2.4 Hz, 1 H), 7.94 (s, 1 H), 7.67 (dd, J = 8.8, 2.4 Hz, 1 H),
7.47 (m, 1 H), 7.40 (m, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.32 (m, 2 H),
7.25 (m, 2 H), 7.18 (td, J = 9.3, 2.4 Hz, 1 H), 7.08 (dd, J = 7.8, 2.4 Hz,
1 H), 5.25 (s, 2 H), 3.78 (m, 4 H), 3.23 (m, 4 H), LCMS found 547.0,
[M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methylpiper-
azin-1-yl)sulfonyl)phenyl)phthalazin-1-amine, Formate Salt (74).
Synthesized by general procedure B. Flash column chromatography:
3−10% methanol in dichloromethane, then prep HPLC 5−95%
1
acetonitrile in water, isolated as a dull yellow solid in 28% yield. H
NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1 H), 9.20 (s, 1 H), 8.70 (d, J
= 8.3 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.42 (dd, J = 8.5, 1.7 Hz, 1
H), 8.21 (d, J = 2.9 Hz, 1 H), 8.16−8.20 (m, 3 H), 7.91 (d, J = 8.3 Hz,
2 H), 7.84 (dd, J = 9.0, 2.7 Hz, 1 H), 7.48 (td, J = 8.3, 6.3 Hz, 1 H),
7.30−7.36 (m, 2 H), 7.27 (d, J = 9.3 Hz, 1 H), 7.18 (td, J = 8.7, 2.7 Hz,
1 H), 5.25 (s, 2 H), 2.96 (br. s., 4 H), 2.39 (t, J = 4.6 Hz, 4 H), 2.15 (s,
3 H). LCMS found 618.2 [M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-
diazepan-1-yl)sulfonyl)phenyl)phthalazin-1-amine, Formate Salt
(75). Synthesized by general procedure B. Flash column chromatog-
raphy: 5−10% methanol in dichloromethane, then prep HPLC 5−95%
acetonitrile in water, isolated as an orange solid in 29% yield. 1H NMR
(500 MHz, MeOH-d4) δ 8.94 (s, 1 H), 8.73 (s, 1 H), 8.25 (s, 2 H),
8.20 (dd, J = 8.5, 1.2 Hz, 1 H), 8.00−8.06 (m, 3 H), 7.95 (d, J = 8.3
Hz, 2 H), 7.88 (d, J = 2.4 Hz, 1 H), 7.59 (dd, J = 8.8, 2.4 Hz, 1 H),
7.38 (td, J = 8.1, 5.9 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.23 (d, J =
9.8 Hz, 1 H), 6.99−7.06 (m, 2 H), 5.18 (s, 2 H), 3.60−3.66 (m, 2 H),
3.47 (t, J = 6.6 Hz, 2 H), 3.22−3.28 (m, 4 H), 2.77 (s, 3 H), 2.14−2.21
(m, 2 H). LCMS found 632.2 [M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-
morpholinophenyl)thieno[2,3-d]pyrimidin-4-amine (86). Synthe-
sized by general procedure E, 39% yield. 1H NMR (500 MHz,
DMSO-d6) δ 9.64 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.05 (d, J = 2.93
Hz, 1H), 7.71 (dd, J = 2.44, 8.79 Hz, 1H), 7.44−7.50 (m, 1H), 7.13−
7.41 (m, 7H), 7.04 (dd, J = 1.95, 8.30 Hz, 1H), 5.25 (s, 2H), 3.78 (t, J
= 4.7 Hz, 4H), 3.21 (t, J = 4.7 Hz, 4H). LCMS found 547.0, [M + H]+.
N-(4-(Benzyloxy)-3-chlorophenyl)-6-(4-(morpholinosulfonyl)-
phenyl)thieno[3,2-d]pyrimidin-4-amine (87). Synthesized by general
1
procedure E, isolated as a yellow solid in 8% yield. H NMR (400
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methyl-1,4-
diazepan-1-yl)sulfonyl)phenyl)phthalazin-1-amine, Formate Salt
(76). Synthesized by general procedure B. Flash column chromatog-
raphy: 5−15% methanol in dichloromethane, then prep HPLC 5−95%
MHz, DMSO-d6) δ ppm 8.61 (s, 1 H), 9.83 (s, 1 H), 8.15 (m, 3 H),
7.98 (s, 1 H), 7.88 (d, J = 8.8 Hz, 2 H), 7.65 (m, 1 H), 7.49 (m, 2 H),
7.42 (t, J = 7.3 Hz, 2 H), 7.35 (m, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 5.23
(s, 2 H), 3.65 (m, 4 H), 2.94 (m, 4 H). LCMS found 593.0, [M + H]+.
N-(4-(Benzyloxy)-3-chlorophenyl)-6-(4-(morpholinosulfonyl)-
phenyl)thieno[2,3-d]pyrimidin-4-amine (88). Synthesized by general
1
acetonitrile in water, isolated as a light yellow solid in 29% yield. H
NMR (500 MHz, MeOH-d4) δ 8.99 (s, 1 H), 8.51 (d, J = 8.3 Hz, 1 H),
8.25 (s, 1 H), 8.17−8.22 (m, 2 H), 7.97 (s, 4 H), 7.91 (d, J = 2.9 Hz, 1
H), 7.58−7.63 (m, 1 H), 7.39 (td, J = 7.8, 5.9 Hz, 1 H), 7.29 (d, J = 7.8
Hz, 1 H), 7.24 (d, J = 9.3 Hz, 1 H), 7.00−7.08 (m, 2 H), 5.20 (s, 2 H),
3.54−3.59 (m, 2 H), 3.47 (t, J = 6.6 Hz, 2 H), 2.97−3.04 (m, 4 H),
2.60 (s, 3 H), 2.06 (quin, J = 6.3 Hz, 2 H). LCMS found 632.2 [M +
H]+.
4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(3-
morpholinophenyl)quinoline-3-carbonitrile (77). Synthesized by
general procedure D. Flash column chromatography: 0−30%
methanol in dichloromethane, isolated as a yellow solid in 20%
yield. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (br, s, 1H), 8.73 (s, 1H),
8.55 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.55
(d, J = 2.4 Hz, 1H), 7.45−7.50 (m, 1H), 7.37−7.41 (m, 1H), 7.30−
7.35 (m, 6H), 7.17−7.22 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.29 (s,
2H), 3.76−3.79 (m, 4H), 3.20−3.23 (m, 4H). LCMS found 565.0 [M
+ H]+.
1
procedure E, isolated as a yellow solid in 40% yield. H NMR (500
MHz, DMSO-d6) δ ppm 9.79 (s, 1 H), 8.52 (s, 1 H), 8.41 (s, 1 H),
8.03 (d, J = 2.0 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 2 H), 7.88 (d, J = 8.3 Hz,
2 H), 7.68 (dd, J = 8.8, 2.4 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 2 H), 7.42 (t,
J = 7.6 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.29 (d, J = 9.3 Hz, 1 H),
5.22 (s, 2 H), 3.65 (m, 4 H), 2.94 (m, 4 H). LCMS found 593.0, [M +
H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methylpiper-
azin-1-yl)sulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine (89). Syn-
thesized by general procedure E, isolated as a yellow solid in 36% yield.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.84 (s, 1 H), 8.62 (s, 1 H),
8.14 (m, 3 H), 7.99 (d, J = 2.2 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.66
(dd, J = 9.2, 2.6 Hz, 1 H), 7.47 (m, 1 H), 7.32 (m, 2 H), 7.26 (d, J =
8.8 Hz, 1 H), 7.19 (td, J = 8.8, 2.2 Hz, 1 H), 5.26 (s, 2 H), 2.95 (m, 4
H), 2.38 (m, 4 H), 2.14 (s, 3 H). LCMS found 624.1, [M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methylpiper-
azin-1-yl)sulfonyl)phenyl)thieno[2,3-d]pyrimidin-4-amine (90). Syn-
thesized by general procedure E, isolated as a yellow solid in 25% yield.
1H NMR (500 MHz, DMSO-d6) δ ppm 9.79 (s, 1 H), 8.52 (s, 1 H),
8.41 (s, 1 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 2 H), 7.87
(d, J = 8.3 Hz, 2 H), 7.69 (dd, J = 8.8, 2.4 Hz, 1 H), 7.47 (m, 1 H),
7.32 (m, 2 H), 7.28 (d, J = 8.8 Hz, 1 H), 7.18 (td, J = 8.5, 2.4 Hz, 1 H),
5.24 (s, 2 H), 2.95 (m, 4 H), 2.37 (m, 4 H), 2.14 (s, 3 H). LCMS
found 624.1, [M + H]+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methyl-1,4-
diazepan-1-yl)sulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine, For-
mic Acid Salt (91). Synthesized by general procedure E, isolated as a
pale yellow solid in 4% yield. The product was separated by silica
column chromatography (dichloromethane/methanol) and purified by
HPLC to obtain the formic acid salt. 1H NMR (500 MHz, DMSO-d6)
δ ppm 9.82 (s, 1 H), 8.61 (s, 1 H), 8.22 (s, 1 H), 8.06−8.13 (m, 3 H),
7.99 (d, J = 2.4 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.66 (dd, J = 9.0,
2.7 Hz, 1 H), 7.47 (td, J = 8.3, 6.3 Hz, 1 H), 7.29−7.36 (m, 2 H), 7.26
(d, J = 8.8 Hz, 1 H), 7.18 (td, J = 8.7, 2.2 Hz, 1 H), 5.26 (s, 2 H), 3.35
(dt, J = 5.1, 2.3 Hz, 2 H), 3.32 (t, J = 6.1 Hz, 2 H), 2.53−2.58 (m, 2
4 - ( ( 4 - ( B e n z y l o x y ) - 3 - c h l o r o p h e n y l ) a m i n o ) - 6 - ( 4 -
(morpholinosulfonyl)phenyl)quinoline-3-carbonitrile (80). Synthe-
sized by general procedure D. Flash column chromatography: 0−20%
1
ethyl acetate in hexanes, isolated as a yellow solid in 50% yield. H
NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.87 (s, 1H), 8.55 (s,
1H), 8.24 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 2H), 8.01 (d, J =
8.8, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.46−7.51 (m, 3H), 7.39 (t, J = 7.2
Hz, 2H), 7.29−7.34 (m, 3H), 5.22 (s, 2H), 3.60−3.63 (m, 4H), 2.87−
2.89 (m, 4H). LCMS found 611.1 [M + H]+.
4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-
methylpiperazin-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (81).
Synthesized by general procedure D. Flash column chromatography:
0−30% methanol in dichloromethane, isolated as a yellow solid in 16%
1
yield. H NMR (400 MHz, DMSO-d6) δ 10.01 (br, s, 1H), 8.89 (s,
1H), 8.59 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H),
8.05 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.55 (br, s, 1H),
7.45−7.70 (m, 1H), 7.31−7.35 (m 4H), 7.17−7.21 (m, 1H), 5.30 (s,
2H), 2.95 (br, s, 4H), 2.38 (br, 4H), 2.14 (s, 3H). LCMS found 642.1
[M + H]+.
M
J. Med. Chem. XXXX, XXX, XXX−XXX