Journal of Medicinal Chemistry
Article
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1.41 min, [M + H]+ = 454.31. H NMR (400 MHz, DMSO-d6) δ
yl)benzoate (32). Method B was used to couple methyl 4-
((2S*,4R*)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-
yl)benzoate (57a) and 4-(methylsulfonyl)phenylboronic acid. LCMS
7.49−7.69 (m, 2H), 7.31−7.48 (m, 4H), 7.22 (d, J = 7.3 Hz, 1H), 7.10
(dd, J = 7.8, 7.8 Hz, 2H), 6.72 (d, J = 7.8 Hz 2H), 6.58 (t, J = 7.2 Hz,
1H), 6.07 (d, J = 8.1 Hz, 1H), 4.73 (m, 1H), 4.28 (m, 1H), 3.43 (s,
2H), 2.62 (m, 1H), 2.23−2.39 (m, 4H), 2.14 (s, 3H) 1.16−1.56 (m,
7H), 1.10 (d, J = 6.1 Hz, 3H).
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(method formate): retention time 1.04 min, [M − H]− = 491.43. H
NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.3 Hz, 2H), 7.70 (d, J =
8.3 Hz, 2H), 7.66 (dd, J = 2.0, 8.3 Hz, 1H), 7.62 (d, J = 9.0 Hz, 2H),
7.50 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 8.1 Hz,
1H), 6.89 (d, J = 8.8 Hz, 2H), 4.73 (m, 1H), 4.51 (m, 1H), 3.86 (s,
3H), 3.32 (s, 3H), 2.64 (m, 1H), 2.16 (s, 3H), 1.29 (m, 1H), 1.12 (d, J
= 6.4 Hz, 3H).
1-((2S*,4R*)-2-Methyl-4-(phenylamino)-6-(4-(piperidin-1-
ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone Hy-
drochloride (25). Method B was used starting from 1-((2S*,4R*)-
4-amino-2-methyl-6-(4-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroqui-
nolin-1(2H)-yl)ethanone (27) and phenylboronic acid; mp 100 °C.
4-((2S*,4R*)-1-Acetyl-2-methyl-4-(p-tolylamino)-1,2,3,4-tet-
rahydroquinolin-6-yl)benzoic Acid (33). Method B was used to
couple methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetra-
hydroquinolin-6-yl)benzoate (57a) and 4-tolylboronic acid. This was
followed by hydrolysis using method D. LCMS (method formate):
LCMS (method formate): retention time 1.40 min, [M + H]+
=
454.41. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (br s, 1H), 7.38−7.68
(m, 7H), 7.11 (dd, J = 7.8, 7.8 Hz, 2H), 6.72 (d, J = 7.8 Hz, 2H), 6.58
(t, J = 7.2 Hz, 1H), 6.07 (d, J = 7.8 Hz, 1H), 4.72 (m, 1H), 4.28 (m,
3H), 2.88 (br s, 2H), 2.64 (m, 1H), 2.15 (s, 3H), 1.50−1.91 (m, 6H),
1.15−1.45 (m, 3H), 1.11 (d, J = 6.4 Hz, 3H).
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retention time 0.73 min, [M + H]+ = 415.36. H NMR (400 MHz,
DMSO-d6) δ 11.90−13.70 (br s, 1H),7.99 (d, J = 8.3 Hz, 2H), 7.66 (d,
J = 8.3 Hz, 2H), 7.62 (dd, J = 1.8, 8.2 Hz, 1H), 7.53 (br s, 1H), 7.45
(d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H),
5.84 (d, J = 8.1 Hz, 1H), 4.71 (m, 1H), 4.25 (m, 1H), 2.62 (m, 1H),
2.16 (s, 3H), 2.08 (s, 3H), 1.21 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H).
4-((2S*,4R*)-1-Acetyl-4-((4-chlorophenyl)amino)-2-methyl-
1,2,3,4-tetrahydroquinolin-6-yl)benzoic Acid (34). Method B
was used to couple methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-methyl-
1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and (4-chlorophenyl)-
boronic acid. This was followed by hydrolysis using method D; mp 84
°C. LCMS (method formate): retention time 1.08 min, [M − H]− =
N-((2S*,4R*)-1-Acetyl-2-methyl-6-(4-(piperidin-1-ylmethyl)-
phenyl)-1,2,3,4-tetrahydroquinolin-4-yl)formamide (26). Meth-
od E was used starting from N-((2S*,4R*)-1-acetyl-6-(4-formylphen-
yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (58a) and
piperidine. LCMS (method formate): retention time 1.03 min, [M +
H]+ = 406.24. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.3 Hz,
1H), 8.31 (s, 1H), 7.56−7.63 (m, 3H), 7.35−7.46 (m, 4H), 4.79 (m,
1H), 4.69 (m, 1H), 3.46 (s, 2H), 2.44−2.54 (m, 3H), 2.34 (m, 2H),
2.09 (s, 3H), 1.45−1.56 (m, 4H), 1.40 (m, 2H), 1.28 (m, 1H), 1.08 (d,
J = 6.4 Hz, 3H).
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1-((2S*,4R*)-4-Amino-2-methyl-6-(4-(piperidin-1-ylmethyl)-
phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (27). Forma-
mide deprotection was carried out upon N-((2S*,4R*)-1-acetyl-2-
methyl-6-(4-(piperidin-1-ylmethyl)phenyl)-1,2,3,4-tetrahydroquinolin-
4-yl)formamide (26) using method A. LCMS (method formate):
433.15. H NMR (400 MHz, DMSO-d6) δ 12.76−13.15 (br s, 1H),
7.99 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.63 (m, 1H), 7.49
(m, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.30 (d, J
= 7.8 Hz, 1H), 4.71 (m, 1H), 4.30 (m, 1H), 2.62 (m, 1H), 2.15 (s,
3H), 1.23 (m, 1H), 1.10 (d, J = 6.1 Hz, 3H).
retention time 1.06 min, [M + H]+ = 378.32. H NMR (400 MHz,
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Methyl 4-((2S*,4R*)-1-Acetyl-4-((4-fluorophenyl)amino)-2-
methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (35). Method
B was used to couple methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-methyl-
1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and (4-fluorophenyl)-
boronic acid. LCMS (method formate): retention time 1.19 min, [M +
DMSO-d6) δ 7.78 (br s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.52 (dd, J =
1.7, 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H),
4.62 (m, 1H), 3.59 (dd, J = 4.1, 11.9 Hz, 1H), 3.35 (m, 2H), 2.45 (m,
1H), 2.34 (m, 4H), 2.05 (s, 3H), 1.51 (m, 4H), 1.40 (m, 2H), 1.09 (d,
J = 6.1 Hz, 3H), 1.05 (m, 1H). NH2 not observed.
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H]+ = 433.23. H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 8.16 Hz,
1-((2S,4R)-2-Methyl-4-(phenylamino)-6-(4-(piperidin-1-
ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (28)
and 1-((2R,4S)-2-Methyl-4-(phenylamino)-6-(4-(piperidin-1-
ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (29).
Compound 25 was dissolved in EtOH and separated in its two
enantiomers using column CHIRALPAK AD 250 mm × 4.6 mm 10
uM, eluting with hexane/EtOH 40/60 for 15 min at a concentration of
1 mg/mL to give 28 (retention time 4.7 min) and 29 (retention time
7.7 min).
2H), 7.55−7.63 (m, 5H), 7.26 (m, 1H), 6.94 (m, 2H), 6.65 (m, 2H),
4.93 (m, 1H), 4.21 (m, 1H), 3.94 (s, 3H), 2.70 (m, 1H), 2.26 (s, 3H),
1.28−1.43 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H).
4-((2S*,4R*)-1-Acetyl-4-((3-fluorophenyl)amino)-2-methyl-
1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile (36). Method E was
used starting from 1-((2S*,4R*)-4-amino-6-bromo-2-methyl-3,4-dihy-
droquinolin-1(2H)-yl)ethanone (55) and 4-(cyanophenyl)boronic
acid, then method B was used with (3-fluorophenyl)boronic acid;
mp 124 °C. LCMS (method formate): retention time 1.20 min, [M +
H]+ = 400.30. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.3 Hz,
2H), 7.75 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 2.0, 8.3 Hz, 1H), 7.46−
7.51 (m, 2H), 7.11 (dd, J = 7.6, 7.6 Hz, 1H), 6.51−6.61 (m, 2H), 6.40
(d, J = 8.1 Hz, 1H), 6.34 (ddd, J = 2.0, 7.6, 7.6 Hz, 1H), 4.70 (m, 1H),
4.32 (m, 1H), 2.62 (m, 1H), 2.15 (s, 3H), 1.23 (m, 1H), 1.10 (d, J =
6.4 Hz, 3H).
Methyl 4-((2S*,4R*)-1-Acetyl-4-((4-(tert-butyl)phenyl)-
amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate
(30). Method B was used to couple methyl 4-((2S*,4R*)-1-acetyl-4-
amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and 4-
(tert-butyl)phenylboronic acid; mp 144 °C. LCMS (method formate):
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retention time 1.43 min, [M + H]+ = 471.39. H NMR (400 MHz,
DMSO-d6) δ 8.00 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.63
(d, J = 8.1 Hz, 1H), 7.57 (br s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.13 (d, J
= 8.3 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 5.84 (d, J = 8.1 Hz, 1H), 4.71
(m, 1H), 4.28 (m, 1H), 3.86 (s, 3H), 2.62 (m, 1H), 2.15 (s, 3H), 1.29
(m, 1H), 1.22 (s, 9H), 1.10 (d, J = 6.1 Hz, 3H).
4-((2S*,4R*)-1-Acetyl-4-((3-methoxyphenyl)amino)-2-meth-
yl-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile (37). Method E
was used starting from 1-((2S*,4R*)-4-amino-6-bromo-2-methyl-3,4-
dihydroquinolin-1(2H)-yl)ethanone (55) and 4-(cyanophenyl)-
boronic acid, then method B was used with (3-methoxyphenyl)-
boronic acid; mp 104 °C. LCMS (method formate): retention time
1.17 min, [M + H]+ = 412.26. 1H NMR (400 MHz, DMSO-d6) δ 7.90
(d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.65 (dd, J = 2.0, 8.1 Hz,
1H), 7.53 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.01 (t, J = 8.1
Hz, 1H), 6.28−6.36 (m, 2H), 6.19 (dd, J = 2.0, 8.1 Hz, 1H), 6.06 (d, J
= 8.3 Hz, 1H), 4.70 (m, 1H), 4.32 (m, 1H), 3.31 (s, 3H), 2.62 (m,
1H), 2.13 (s, 3H), 1.24 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H).
4-((2S*,4R*)-1-Acetyl-4-((3-methoxyphenyl)amino)-2-meth-
yl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic Acid (38). Method B
was used starting from methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-
methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and (3-
methoxyphenyl)boronic acid. This was followed by hydrolysis using
4-((2S*,4R*)-1-Acetyl-2-methyl-4-((4-(methylsulfonyl)-
phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic Acid
(31). Method D was used to hydrolyze methyl 4-((2S*,4R*)-1-
acetyl-2-methyl-4-((4-(methylsulfonyl)phenyl)amino)-1,2,3,4-tetrahy-
droquinolin-6-yl)benzoate (32). LCMS (method formate): retention
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time 0.62 min, [M − H]− = 477.39. H NMR (400 MHz, DMSO-d6)
δ 12.00−13.65 (br s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59−7.69 (m,
5H), 7.49 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 8.1
Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.74 (m, 1H), 4.53 (m, 1H), 3.01
(m, 3H), 2.64 (m, 1H), 2.16 (s, 3H), 1.32 (m, 1H), 1.12 (d, J = 6.1
Hz, 3H).
Methyl 4-((2S*, 4R *)-1-Acetyl-2-methyl-4-((4-
(methylsulfonyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-
N
dx.doi.org/10.1021/jm5010539 | J. Med. Chem. XXXX, XXX, XXX−XXX