Journal of Medicinal Chemistry
Article
2
H), 8.10 (d, J = 8 Hz, 1H), 8.32 (d, J = 8 Hz, 1H), 8.83 (s, 1H).
4-((1-((1,5-Dimethyl-1H-pyrazol-4-yl)carbonyl)piperidin-4-yl)-
+
+
1
HRMS: m/z (ES ) = 371.13831 (MH ) for C H ClN O.
amino)quinolin-2(1H)-one (22). Yield: 19%. H NMR (300 MHz,
18
19
6
(
5-Chloro-1-methyl-1H-pyrazol-4-yl)(4-((5-fluoro-1H-indazol-3-
DMSO-d ): δ 1.50 (d, J = 11 Hz, 2H), 1.89−2.03 (m, 3H), 2.31 (s,
6
1
yl)amino)piperidin-1-yl)methanone (13). Yield: 34%. H NMR (300
MHz, DMSO): δ 1.37−1.53 (m, 2H), 2.09 (d, J = 9 Hz, 2H), 3.05 (br
s, 1H), 3.19−3.30 (m, 1H), 3.58−3.80 (m, 2H), 3.82 (s, 3H), 4.28 (br
s, 1H), 5.86 (d, J = 7 Hz, 1H), 7.12 (dt, J = 3, 9 Hz, 1H), 7.21−7.31
3H), 3.13−3.45 (m, 2H), 3.74 (s, 3H), 3.91−4.45 (m, 2H), 5.44 (s,
1H), 6.52 (d, J = 8 Hz, 1H), 7.08 (t, J = 7 Hz, 1H), 7.21 (d, J = 8 Hz,
1H), 7.39−7.47 (m, 2H), 7.85−8.05 (m, 1H), 10.75 (s, 1H). HRMS:
+
+
m/z (ES ) = 366.19225 (MH ) for C20H N O .
23 5 2
(
m, 1H), 7.49 (dd, J = 3, 9 Hz, 1H), 7.70 (s, 1H), 11.51 (s, 1H).
6-Fluoro-4-((1-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-
carbonyl)piperidin-4-yl)amino)quinolin-2(1H)-one (23). Yield: 38%.
+
+
HRMS: m/z (ES ) = 377.12945 (MH ) for C H ClFN O.
17
18
6
1
H NMR (300 MHz, DMSO-d ): δ 1.29−1.60 (m, 2H), 1.80−2.12
4
-((1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)piperidin-4-
6
1
yl)amino)-6-phenylpyridin-2(1H)-one (14). Yield: 33%. H NMR
300 MHz, DMSO-d ): δ 1.31−1.42 (m, 2H), 1.88−1.98 (m, 2H),
(m, 2H), 2.96 (t, J = 12 Hz, 1H), 3.22 (t, J = 12 Hz, 1H), 3.57 (d, J =
13 Hz, 1H), 3.72 (br s, 1H), 4.00 (s, 3H), 4.48 (d, J = 13 Hz, 1H),
5.49 (s, 1H), 6.51 (d, J = 8 Hz, 1H), 7.15−7.29 (m, 1H), 7.30−7.40
(m, 1H), 7.73 (s, 1H), 7.93 (d, J = 11 Hz, 1H), 10.85 (br s, 1H).
(
6
3
4
7
1
.05 (br s, 1H), 3.30−3.33 (m, 1H), 3.53 (br s, 2H), 3.82 (s, 3H),
.12−4.40 (m, 1H), 5.23 (s, 1H), 5.95 (s, 1H), 6.54 (d, J = 8 Hz, 1H),
.42−7.49 (m, 3H), 7.56−7.64 (m, 2H), 7.71 (s, 1H), 10.60 (br s,
+
+
HRMS: m/z (ES ) = 438.15605 (MH ) for C H F N O .
20 19
4
5
2
+
+
4
-((1-((4,5-Dimethylisoxazol-3-yl)carbonyl)piperidin-4-yl)amino)-
H). HRMS: m/z (ES ) = 412.15279 (MH ) for C H ClN O .
21
22
5
2
1
6
-fluoroquinolin-2(1H)-one (24). Yield: 33%. H NMR (300 MHz,
4
-((1-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)pyrrolidin-3-
1
DMSO-d ): δ 1.58 (m, 2H), 2.00 (s, 3H), 2.02−2.21 (m, 2H), 2.46 (s,
yl)amino)quinolin-2(1H)-one (15). Yield: 24%. H NMR (300 MHz,
6
3
5
(
H), 3.11 (m, 1H), 3.26−3.43 (m, 2H), 3.81 (m, 2H), 4.58 (m, 1H),
DMSO-d ): δ 2.09 (br s, 1H), 2.18−2.30 (m, 1H), 3.51−3.71 (m,
6
.59 (s, 1H), 6.61 (d, J = 8 Hz, 1H), 7.25−7.37 (m, 1H), 7.37−7.48
3
=
H), 3.79−3.86 (s, 3H), 3.91−4.07 (m, 1H), 4.19 (br s, 1H), 5.36 (d, J
+
m, 1H), 7.99 (d, J = 11 Hz, 1H). HRMS: m/z (ES ) = 385.1681
9 Hz, 1H), 6.79 (dd, J = 14, 6 Hz, 1H), 7.10 (t, J = 8 Hz, 1H), 7.21
+
(
MH ) for C H FN O .
(
dd, J = 8, 4 Hz, 1H), 7.44 (t, J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H),
20 21
4
3
+
4-((1-((1,5-Dimethyl-1H-1,2,3-triazol-4-yl)carbonyl)piperidin-4-
8.04 (dd, J = 12, 8 Hz, 1H), 10.85 (br s, 1H). HRMS: m/z (ES ) =
1
+
yl)amino)-6-fluoroquinolin-2(1H)-one (25). Yield: 35%. H NMR
300 MHz, DMSO-d ): δ 1.49−1.70 (m, 2H), 2.15 (s, 3H), 2.35−2.42
3
72.12198 (MH ) for C H ClN O .
18
18
5
2
(
6
4
-((1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)azetidin-3-
1
(m, 2H), 2.46 (s, 3H), 2.98−3.05 (m, 1H), 3.76 (br s, 1H), 3.96 (m,
yl)amino)quinolin-2(1H)-one (16). Yield: 20%. H NMR (300 MHz,
DMSO-d ): δ 3.82 (s, 3H), 4.10 (br s, 1H), 4.25 (d, J = 6 Hz, 1H),
2
7
(
H), 4.50 (d, J = 13 Hz, 1H), 5.51 (s, 1H), 6.39−6.67 (m, 1H), 7.15−
.45 (m, 2H), 7.81−8.05 (m, 1H), 10.84 (br s, 1H). HRMS: m/z
6
4.38 (br s, 2H), 4.73 (d, J = 7 Hz, 1H), 5.15 (s, 1H), 7.13 (t, J = 8 Hz,
1H), 7.23 (d, J = 8 Hz, 1H), 7.30 (d, J = 4 Hz, 1H), 7.39−7.52 (m,
1H), 7.88 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 10.90 (s, 1H). HRMS: m/z
+
+
ES ) = 385.17815 (MH ) for C H FN O .
19 21 6 2
4
-((1-((5-Chloro-1-ethyl-1H-pyrazol-4-yl)carbonyl)piperidin-4-yl)-
1
amino)-6-fluoroquinolin-2(1H)-one (26). Yield: 15%. H NMR (300
+
+
(
ES ) = 358.10808 (MH ) for C H ClN O .
17 16 5 2
MHz, DMSO-d ): δ 1.35 (t, J = 7 Hz, 3H), 1.41−1.62 (m, 2H), 1.98
6
4
-(((2S,4R)-1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)-2-
1
(br s, 2H), 2.95 (br s, 1H), 3.17 (br s, 1H), 3.75 (br s, 2H), 4.18 (q, J
methylpiperidin-4-yl)amino)quinolin-2(1H)-one (17). Yield: 27%. H
=
7
7 Hz, 2H), 4.42 (br s, 1H), 5.50 (s, 1H), 6.51 (d, J = 8 Hz, 1H),
NMR (300 MHz, DMSO-d ): δ 1.20−1.50 (m, 2H), 1.32 (d, J = 9 Hz,
6
.14−7.28 (m, 1H), 7.29−7.42 (m, 1H), 7.74 (s, 1H), 7.92 (d, J = 11
3H), 1.64−1.75 (m, 1H), 1.81−1.94 (m, 1H), 1.97−2.08 (m, 1H),
3.37−3.72 (m, 1H), 3.83 (s, 3H), 3.87−3.92 (m, 1H), 4.11−4.47 (m,
1H), 5.48 (s, 1H), 6.48 (d, J = 8 Hz, 1H), 7.08 (t, J = 7 Hz, 1H), 7.20
+
+
Hz, 1H), 10.85 (br s, 1H). HRMS: m/z (ES ) = 418.13689 (MH ) for
C H ClFN O .
2
0
21
5
2
4
-((1-((5-Chloro-1-isopropyl-1H-pyrazol-4-yl)carbonyl)piperidin-
(
d, J = 8 Hz, 1H), 7.42 (t, J = 7 Hz, 1H), 7.69 (s, 1H), 7.97 (d, J = 8
1
4
-yl)amino)quinolin-2(1H)-one (27). Yield: 25%. H NMR (300
+
Hz, 1H), 10.75 (br s, 1 H). HRMS: m/z (ES ) = 400.15462 (MH + 1)
for C H ClN O .
MHz, DMSO-d ): δ 1.41 (d, J = 7 Hz, 6H), 1.44−1.62 (m, 2H), 2.00
6
20
22
5
2
(d, J = 11 Hz, 2H), 2.95 (br s, 1H), 3.09−3.31 (m, 1H), 3.74 (d, J = 6
4
-(((2S,4S)-1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)-2-
methylpiperidin-4-yl)amino)quinolin-2(1H)-one (18). Yield: 14%.
H NMR (300 MHz, DMSO-d ): δ 0.76−0.89 (m, 2H), 1.22 (d, J
Hz, 2H), 4.43 (br s, 1H), 4.70 (qn, J = 7 Hz, 1H), 5.45 (s, 1H), 6.54
(
d, J = 8 Hz, 1H), 7.09 (t, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 7.36−
1
=
6
7.51 (m, 1H), 7.75 (s, 1H), 7.98 (d, J = 8 Hz, 1H), 10.76 (s, 1H).
7 Hz, 4H), 1.78−1.96 (m, 3H), 3.76 (br s, 1H), 3.83 (s, 3H), 4.25
+
+
HRMS: m/z (ES ) = 414.16933 (MH ) for C H ClFN O .
21
24
5
2
(
(
1
d, J = 7 Hz, 1H), 5.31 (s, 1H), 6.48 (d, J = 6 Hz, 1H),), 7.03−7.26
4
-((1-((4,5-Dimethyl-1,2-oxazol-3-yl)carbonyl)piperidin-4-yl)-
1
m, 2H), 7.37−7.47 (m, 1H), 7.72 (s, 1H), 8.04 (d, J = 9 Hz,
amino)-6,7-difluoroquinolin-2(1H)-one (28). Yield: 41%. H NMR
+
H),10.82 (s, 1H). HRMS: (ES ) m/z = 400.15391 (MH + 1) for
(300 MHz, DMSO-d ): δ 1.41−1.67 (m, 2H), 1.99 (s, 4H), 2.45 (s,
6
C H ClN O .
3H), 2.98−3.19 (m, 1H), 3.34 (t, J = 12 Hz, 2H), 3.80 (d, J = 14 Hz,
20
22
5
2
4
-(((1R,3r,5S)-8-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)-8-
2H), 4.56 (d, J = 14 Hz, 1H), 5.56 (s, 1H), 6.61 (d, J = 8 Hz, 1H),
azabicyclo[3.2.1]octan-3-yl)amino)-6-fluoroquinolin-2(1H)-one
7
.22 (dd, J = 12, 8 Hz, 1H), 8.23 (dd, J = 13, 9 Hz, 1H), 10.9 (s, 1H).
1
(19). Yield: 23%. H NMR (300 MHz, DMSO-d ): δ 1.60 (m, 1H),
+
+
6
HRMS: m/z (ES ) = 403.15779 (MH ) for C H F N O .
20 20 2 4 3
1
4
7
3
.83 (m, 1H), 1.87−2.14 (m, 6H), 3.83 (s, 3H), 3.96−4.10 (m, 1H),
.23 (m, 1H), 4.60 (m, 1H), 5.50 (s, 1H), 6.45 (d, J = 8 Hz, 1H),
.14−7.26 (m, 1H), 7.26−7.42 (m, 1H), 7.76 (s, 1H), 7.90 (dd, J = 11,
4
-((1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)piperidin-4-
yl)amino)-6,7-difluoro-1-methylquinolin-2(1H)-one (29). Yield: 72%.
1
H NMR (300 MHz, DMSO-d ): δ 1.37−1.59 (m, 2H), 1.88−2.10
6
+
+
Hz, 1H), 10.82 (s, 1H). HRMS: m/z (ES ) = 430.14482 (MH ) for
(
m, 2H), 2.96 (br s, 1H), 3.31 (br s, 1H), 3.41−3.55 (m, 3H), 3.63−
C H ClFN O .
21
21
5
2
3.96 (m, 5H), 4.41 (br s, 1H), 5.65 (s, 1H), 6.54 (d, J = 8 Hz, 1H),
7.54 (dd, J = 13, 7 Hz, 1H), 7.71 (s, 1H), 8.24 (dd, J = 13, 9 Hz, 1H).
4
-(((1R,3s,5S)-8-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)-8-
azabicyclo[3.2.1]octan-3-yl)amino)-6-fluoroquinolin-2(1H)-one
+
+
HRMS: m/z (ES ) = 436.13505 (MH ) for C H ClF N O .
20
20
2
5
2
1
(20). Yield: 27%. H NMR (300 MHz, DMSO-d ): δ 1.21 (d, J = 7 Hz,
6
4-((1-((4,5-Dimethylisoxazol-3-yl)carbonyl)piperidin-4-yl)amino)-
1
1
H), 2.02−2.28 (m, 6H), 3.81 (br s, 1H), 3.87−3.94 (m, 4H), 4.22 (br
6
(
,7-difluoro-1-methylquinolin-2(1H)-one (30). Yield: 32%. H NMR
s, 1H), 4.63 (br s, 1H), 5.29 (s, 1H), 6.46 (br s, 1H), 7.31 (dd, J = 9, 5
Hz, 1H), 7.43 (td, J = 9, 3 Hz, 1H), 7.82−7.94 (m, 2H), 11.00 (s, 1H).
HRMS: m/z (ES ) = 430.14419 (MH ) for C H ClFN O .
300 MHz, DMSO-d ): δ 1.37−1.61 (m, 2H), 1.92 (s, 3H), 1.95−2.14
6
(m, 2H), 2.38 (s, 3H), 2.92−3.11 (m, 1H), 3.20−3.29 (m, 1H), 3.46
(s, 3H), 3.64−3.89 (m, 2H), 4.38−4.60 (m, 1H), 5.66 (s, 1H), 6.46−
6.64 (m, 1H), 7.44−7.63 (m, 1H), 8.14−8.31 (m, 1H). HRMS: m/z
+
+
21
21
5
2
4
-((1-((1-Methyl-1H-pyrazol-4-yl)carbonyl)piperidin-4-yl)amino)-
1
+
+
quinolin-2(1H)-one (21). Yield: 11%. H NMR (300 MHz, DMSO-
d ): δ 1.50 (d, J = 12 Hz, 2H), 1.99 (d, J = 12 Hz, 2H), 3.14−3.19 (m,
(
ES ) = 417.17333 (MH ) for C H F N O .
21 22 2 4 3
6
4-(((2S,4R)-1-((5-Chloro-1-methyl-1H-pyrazol-4-yl)carbonyl)-2-
2
(
7
H), 3.6−3.75 (m, 2H), 3.82 (m, 1H), 3.86 (s, 3H), 5.45 (s, 1H), 6.54
d, J = 8 Hz, 1H), 7.09 (t, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 7.39−
.47 (m, 1H), 7.66 (s, 1H), 7.98 (d, J = 8 Hz, 1H), 8.07 (s, 1H), 10.77
methylpiperidin-4-yl)amino)-6,7-difluoroquinolin-2(1H)-one (31).
1
Yield: 23%. H NMR (300 MHz, DMSO-d ): δ 1.23−1.48 (m, 4H),
6
1.57−1.75 (m, 1H), 1.88 (s, 1H), 2.01 (br s, 1H), 3.17 (m, 1H), 3.83
(s, 3H), 3.91 (br s, 1H), 4.35 (br s, 1H), 4.91 (br s, 1H), 5.52 (s, 1H),
+
+
(
s, 1H). HRMS: m/z (ES ) = 352.16966 (MH ) for C H N O .
19
21
5
2
5
432
dx.doi.org/10.1021/jm5005978 | J. Med. Chem. 2014, 57, 5419−5434