Journal of Medicinal Chemistry
Article
THF (11 mL) and H2O (1 mL). The solution was sparged with N2 for
5 min before being heated in a microwave synthesizer for 40 min at
120 °C. NH3 in MeOH solution (7N, 2 mL, 14 mmol) was added to
the reaction mixture, which was left to stir at rt under N2 atmosphere
for 2.5 h. The reaction mixture was diluted with EtOAc and washed
twice with H2O, followed by a further wash with saturated brine
solution. The organic phase was separated and dried over MgSO4 and
filtered. The filtrate solvents were evaporated to a brown solid, which
was purified by automated flash chromatography using a solvent
system of 0 to 80% EtOAc in hexane to yield 197 mg of impure
product as a pale-brown gum. This was further purified by automated
flash chromatography on silica gel using a solvent system of 0 to 2.5%
MeOH in DCM to yield title compound (76 mg, 35%) as a colorless
to afford crude product that was purified by flash chromatography on
silica gel eluting with a gradient of 0 to 80% ethyl acetate in hexane
then o to 2.5% MeOH in DCM to afford the title compound (12 mg,
13%) as a yellow solid: LCMS (method A): tR = 2.56 min; m/z = 452
1
[M + H]+; H NMR (400 MHz, DMSO-d6) δ 1.17 (d, J = 6.5 Hz,
3H), 1.61 (dq, J = 5.9, 13.0 Hz, 1H), 2.32 (dq, J = 6.2, 13.6 Hz, 1H),
2.76−3.02 (m, 2H), 4.63 (q, J = 6.3 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H),
6.23 (dd, J = 2.2, 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.5
Hz, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.75 (dd, J = 2.2, 8.5 Hz, 1H), 8.00
(d, J = 2.2 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.55−9.80 (m, 2H); 13C
NMR (100.6 MHz, DMSO-d6) δ 19.4 (CH3), 20.3 (CH3), 24.5
(CH2), 30.9 (CH2), 48.8 (CH), 102.3 (CH), 106.5 (CH), 115.1 (C),
124.4 (CH), 126.1 (CH), 126.4 (CH), 127.0 (CH), 127.0 (C), 128.3
(CH), 128.6 (CH), 128.8 (CH), 129.1 (C), 130.2 (CH), 132.1 (C),
135.9 (C), 136.7 (CH), 137.7 (C), 146.0 (C), 156.2 (C), 159.2 (C),
159.7 (C), 168.6 (C); HRMS, calcd for C23H18N3O3SCl [M]+ found
451.0755 requires 451.0757; HPLC 100% (tR = 1.17 min).
N-Benzyl-2,4-dihydroxy-N-{4-[methyl(quinoxalin-6-ylmethyl)-
carbamoyl]phenyl}benzamide (35a). This compound was synthe-
sized by same procedure outlined for 29a. Thus, 34 (see SI) and N-
methyl-1-quinoxalin-6-ylmethanamine were reacted as described to
afford crude product that was purified by flash chromatography on
silica gel eluting with a gradient of 0 to 70% ethyl acetate in hexane to
afford the title compound (64 mg, 55%) as a colorless solid: LCMS
(method C): tR = 1.16 min; m/z = 519 [M + H]+; 1H NMR (400 MHz,
DMSO-d6) δ 2.91 (s, 3H), 4.81 (s, 2H), 5.09 (s, 2H), 6.05 (dd, J = 2.3,
8.5 Hz, 1H), 6.17 (d, J = 2.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 7.14
(d, J = 8.4 Hz, 2H), 7.18−7.38 (m, 7H), 7.72 (d, J = 7.4 Hz, 1H), 7.95
(s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.86−8.98 (m, 2H), 9.35 (s, 1H),
9.90 (s, 1H); 13C NMR (100.6 MHz, DMSO-d6, 353 K) δ 52.2
(CH2), 102.3 (CH), 106.0 (CH), 112.9 (C), 126.5 (CH), 126.6 (C,
broad), 126.7 (CH), 127.3 (CH), 127.8 (CH), 129.1 (CH), 129.2 (C,
broad), 129.9 (CH), 133.3 (C), 137.2 (C), 139.3 (C), 141.3 (C),
141.9 (C), 143.9 (C), 145.0 (CH), 145.3 (CH), 157.0 (C), 159.6 (C),
169.2 (C), 169.8 (C); HRMS, calcd for C31H26N4O4 [M]+ found
518.1957 requires 518.1954; HPLC 100% (tR = 0.91 min).
1
glass: LCMS (method A): tR = 2.53 min; m/z = 425 [M + H]+; H
NMR (400 MHz, DMSO-d6) δ 1.18 (d, J = 6.5 Hz, 3H), 1.55 (dq, J =
6.0, 13.4 Hz, 1H), 2.35 (dq, J = 6.6, 12.9 Hz, 1H), 2.44 (s, 3H), 2.69−
2.87 (m, 2H), 4.62 (q, J = 6.4 Hz, 1H), 6.11−6.26 (m, 2H), 6.92−7.08
(m, 2H), 7.22 (dd, J = 2.0, 8.3 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.57
(ddd, J = 1.2, 6.9, 8.1 Hz, 1H), 7.70 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H),
7.91 (d, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.23 (s, 1H), 9.62 (s, 1H), 9.75
(s, 1H); 13C NMR (100.6 MHz, DMSO-d6) δ 19.4 (CH3), 20.3
(CH3), 24.5 (CH2), 30.9 (CH2), 48.8 (CH), 102.3 (CH), 106.5
(CH), 115.1 (C), 124.4 (CH), 126.1 (CH), 126.4 (CH), 127.0 (CH),
127.0 (C), 128.3 (CH), 128.6 (CH), 128.8 (CH), 129.1 (C), 130.2
(CH), 132.1 (C), 135.9 (C), 136.7 (CH), 137.7 (C), 146.0 (C), 156.2
(C), 159.2 (C), 159.7 (C), 168.6 (C); HRMS, calcd for C27H24N2O3
[M]+ found 424.1728 requires 424.1787; HPLC 100% (tR = 1.06
min).
4-[(2S)-6-{2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-
1,2,3,4-tetrahydroquinoline-1-carbonyl]benzene-1,3-diol (33b).
This compound was synthesized by the same procedure outlined for
33a. Thus, 32 and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine were
reacted as described to afford crude product that was purified by PREP
HPLC at pH4 (methods in SI) to afford title compound (12 mg, 16%)
as a beige-colored solid: LCMS (method C): tR = 1.23 min; m/z = 435
1
[M + H]+; H NMR (399 MHz, DMSO-d6) δ 1.16 (d, J = 6.5 Hz,
3H), 1.58 (dq, J = 5.9, 13.2 Hz, 1H), 2.24−2.43 (m, 1H), 2.74−3.01
(m, 2H), 4.62 (q, J = 6.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 6.21 (dd, J
= 2.2, 8.4 Hz, 1H), 6.95 (d, J = 3.7 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H),
7.07 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 3.6 Hz, 1H), 7.75 (dd, J = 2.0, 8.5
Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H); 13C NMR (100.6 MHz, DMSO-d6)
δ 19.2 (CH3), 24.4 (CH2), 30.5 (CH2), 48.9 (CH), 100.8 (CH),
102.3 (CH), 106.7 (CH), 113.2 (C), 115.1 (C), 125.1 (CH), 125.8
(CH), 127.9 (CH), 128.5 (CH), 130.3 (CH), 131.8 (C), 132.7 (C),
140.4 (C), 152.1 (C), 154.0 (C), 155.9 (C), 157.1 (C), 159.8 (C),
168.6 (C); HRMS, calcd for C23H19N4O3Cl [M]+ found 434.1145
requires 434.1146; HPLC 99.5% (tR = 0.96 min).
N-Benzyl-2,4-dihydroxy-N-(4-{[(4-methoxyphenyl)methyl]-
(methyl)carbamoyl}phenyl)benzamide (35b). This compound was
synthesized by the same procedure outlined for 29a. Thus, 34 (see SI)
and [(4-methoxyphenyl)methyl](methyl)amine were reacted as
described to afford crude product that was purified by flash
chromatography on silica gel eluting with a gradient of 0 to 40%
ethyl acetate in hexane to afford the title compound (51 mg, 46%) as a
colorless solid: LCMS (method C): tR = 1.29 min; m/z = 497 [M +
1
H]+; H NMR (400 MHz, DMSO-d6) rotamers δ 2.67 and 2.83 (s,
3H), 3.74 (s, 3H), 4.25 (s, 1H), 4.54 (s, 1H), 5.07 (s, 2H), 6.06 (d, J =
7.4 Hz, 1H), 6.10 (d, J = 2.2 Hz, 1H), 6.78−6.99 (m, 4H), 7.10 (d, J =
7.8 Hz, 2H), 7.14−7.37 (m, 8H), 9.57 (s, 1H), 9.90 (s, 1H); 13C NMR
(100.6 MHz, DMSO-d6, 353 K) δ 52.2 (CH2), 54.8 (CH3), 102.3
(CH), 106.0 (CH), 112.9 (C), 113.8 (CH), 126.4 (CH), 126.5 (CH),
126.6 (CH), 127.3 (CH), 127.8 (CH), 128.3 (CH), 128.7 (C), 129.9
(CH), 133.7 (C), 137.2 (C), 143.7 (C), 157.0 (C), 158.3 (C), 159.6
(C), 169.2 (C), 169.9 (C); HRMS, calcd for C30H28N2O5 [M]+ found
496.2002 requires 496.1998; HPLC 98.5% (tR = 1.02 min).
4-[(2S)-6-(2-Chloro-5-methylpyrimidin-4-yl)-2-methyl-1,2,3,4-tet-
rahydroquinoline-1-carbonyl]benzene-1,3-diol (33c). This com-
pound was synthesized by the same procedure outlined for 33a.
Thus, 32 and 2,4-dichloro-5-methylpyrimidined were reacted as
described to afford crude product that was purified by flash
chromatography on silica gel eluting with a gradient of 0 to 45%
ethyl acetate in hexane to afford the title compound (47 mg, 43%) as a
pale yellow solid: LCMS (method C): tR = 1.28 min; m/z = 410 [M +
1
H]+; H NMR (400 MHz, DMSO-d6) δ 1.15 (d, J = 6.5 Hz, 3H),
N-Benzyl-N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-di-
hydroxybenzamid (37a). This compound was synthesized by the
same procedure outlined for 29a. Thus, 36 (see SI) and 2,4-dichloro-
5-methylpyrimidine were reacted as described to afford crude product
that was purified by flash chromatography on silica gel eluting with a
gradient of 0 to 40% ethyl acetate in hexane to afford the title
compound (37 mg, 44%) as a colorless solid: LCMS (method A): tR =
1.49−1.62 (m, 1H), 2.26−2.33 (m, 1H), 2.33−2.37 (m, 3H), 2.71−
2.88 (m, 2H), 4.60 (q, J = 6.4 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 6.20
(dd, J = 2.2, 8.4 Hz, 1H), 7.00 (dd, J = 2.1, 8.4 Hz, 2H), 7.29 (dd, J =
2.1, 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 9.62 (s, 1H), 9.68 (s, 1H);.
13C NMR (100.6 MHz, DMSO-d6) δ 16.2 (CH3), 19.3 (CH3), 24.3
(CH2), 30.5 (CH2), 48.9 (CH), 102.3 (CH), 106.6 (CH), 115.0 (C),
124.4 (CH), 126.2 (CH), 127.3 (C), 128.5 (CH), 130.3 (CH), 131.4
(C), 132.3 (C), 139.6 (C), 155.9 (C), 157.6 (C), 159.8 (C), 161.9
(CH), 166.5 (C), 168.6 (C);; HRMS, calcd for C22H20N3O3Cl [M]+
found 409.1193 requires 409.1193; HPLC 100% (tR = 1.08 min).
4-[(2S)-6-{2-chlorothieno[3,2-d]pyrimidin-4-yl}-2-methyl-1,2,3,4-
tetrahydroquinoline-1-carbonyl]benzene-1,3-diol (33d). This com-
pound was synthesized by the same procedure outlined for 33a. Thus,
32 and 2,4-dichlorothieno[3,2-d]pyrimidine were reacted as described
1
2.51 min; m/z = 446 [M + H]+; H NMR (399 MHz, DMSO-d6) δ
2.26 (s, 3H), 5.13 (s, 2H), 6.09−6.14 (m, 2H), 6.96 (d, J = 8.2 Hz,
1H), 7.16−7.28 (m, 3H), 7.30−7.43 (m, 4H), 7.46−7.59 (m, 2H),
8.66 (d, J = 0.6 Hz, 1H), 9.60 (s, 1H), 9.91 (s, 1H); 13C NMR (100.6
MHz, DMSO-d6) δ 16.0 (CH3), 52.2 (CH2), 102.3 (CH), 106.4
(CH), 114.2 (C), 126.5 (CH), 127.0 (CH), 127.4 (CH), 127.5 (C),
128.3 (CH), 129.2 (CH), 130.4 (CH), 133.3 (C), 137.7 (C), 144.7
(C), 156.2 (C), 157.5 (C), 159.8 (C), 162.0 (CH), 166.2 (C), 169.3
M
J. Med. Chem. XXXX, XXX, XXX−XXX