Journal of Medicinal Chemistry
Article
Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.92 (ddd, J = 8.5, 2.5, 1.3 Hz, 1H),
(R)-1-(7,8-Difluoro-2,2-dimethylchroman-4-yl)-3-(3-methyliso-
1
6
6
3
.75 (dd, J = 2.5, 1.1 Hz, 1H), 5.08−4.99 (m, 1H), 2.22 (dd, J = 13.3,
quinolin-5-yl)urea (46). Prepared via general procedure B. H NMR
.1 Hz, 1H), 1.83 (dd, J = 13.3, 10.8 Hz, 1H), 1.45 (s, 3H), 1.33 (s,
(300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.68 (s, 1H), 8.28 (d, J = 7.6
6
+
23
H). MS (DCI/NH ) m/z 432 (M + H) ; [α]
+7.5° (c 0.45,
D
Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.57−7.51 (m, 1H),
7.17 (t, J = 7.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 13.0,
3
CH OH).
3
5
.7 Hz, 1H), 5.08−4.98 (m, 1H), 2.66 (s, 3H), 2.25 (dd, J = 13.4, 6.1
(
R)-1-(2,2-Diethyl-6-fluorochroman-4-yl)-3-(isoquinolin-5-yl)urea
1
(
40). Prepared via general procedure A. H NMR (300 MHz, DMSO-
d6) δ 9.29 (d, J = 0.8 Hz, 1H), 8.73 (s, 1H), 8.56 (d, J = 6.0 Hz, 1H),
.34 (dd, J = 7.7, 1.1 Hz, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 8.1
Hz, 1H), 1.85 (dd, J = 13.2, 11.2 Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H).
+
23
MS (DCI/NH ) m/z 398 (M + H) ; [α] +17.1° (c 0.68, CH OH).
3 D 3
8
(R)-1-(6,8-Difluoro-2,2-dimethylchroman-4-yl)-3-(3-methyliso-
1
quinolin-5-yl)urea (47). Prepared via general procedure B. H NMR
Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.09−7.14 (m, 1H), 6.98−7.05 (m,
(
1
300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.68 (s, 1H), 8.25 (dd, J = 7.6,
2
1
H), 6.81 (dd, J = 8.9, 4.9 Hz, 1H), 4.93−5.02 (m, 1H), 2.20 (dd, J =
3.4, 6.1 Hz, 1H), 1.52−1.77 (m, 5H), 0.85−0.94 (m, 6H). MS (DCI/
6
.0 Hz, 1H), 7.76−7.71 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.24−7.15
+
23
(m, 1H), 7.05−6.97 (m, 2H), 5.07−4.97 (m, 1H), 2.66 (s, 3H), 2.24
NH ) m/z 394 (M + H) ; [α] +34.1° (c 0.46, CH OH).
3
D
3
(
3
dd, J = 13.3, 6.2 Hz, 1H), 1.86 (dd, J = 13.3, 11.0 Hz, 1H), 1.45 (s,
Procedure for 3-Methylisoquinoline Urea Preparation (General
Procedure B). (R)-1-(2,2-Diethyl-6-fluorochroman-4-yl)-3-(3-methyl-
isoquinolin-5-yl)urea (41). A slurry of 3-methylisoquinolin-5-amine
+
23
H), 1.32 (s, 3H). MS (DCI/NH ) m/z 398 (M + H) ; [α] +24°
3
D
(c 0.50, CH
OH).
3
(
7.00 g, 44.2 mmol), DCM (140 mL), and pyridine (3.64 mL, 45.0
(R)-1-(8-Fluoro-2,2-dimethyl-7-(trifluoromethyl)chroman-4-yl)-3-
(
3-methylisoquinolin-5-yl)urea (48). Prepared via general procedure
mmol) was cooled to <5 °C, and phenyl chloroformate (5.65 mL, 45.0
1
B. H NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.73 (s, 1H), 8.25
mmol) was added dropwise, keeping the temperature ≤5 °C. The
6
(
7
dd, J = 7.6, 0.8 Hz, 1H), 7.78−7.70 (m, 2H), 7.58−7.49 (m, 1H),
slurry was stirred at <5 °C. After 10 min, i-Pr NEt (26.2 mL, 150
2
.36 (d, J = 8.3 Hz, 1H), 7.30−7.21 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H),
mmol) and (R)-7-fluoro-2,2-dimethylchroman-4-aminium (2S,3S)-3-
29
5.11 (dd, J = 16.7, 9.2 Hz, 1H), 2.66 (s, 3H), 2.27 (dd, J = 13.4, 6.2
Hz, 1H), 2.01−1.87 (m, 1H), 1.50 (s, 3H), 1.37 (s, 3H). MS (DCI/
carboxy-2,3-dihydroxypropanoate (14.0 g, 37.5 mmol) (or other
corresponding substituted chromanamine salts for subsequent
isoquinoline ureas prepared via this general procedure) were added,
and the mixture was heated to 35 °C. After 1 h, the reaction mixture
was concentrated, diluted with EtOAc (280 mL), and washed with
water (140 mL) and 2 N HCl saturated with NaCl (140 mL) were
added. The layers were separated, and the organic layer was washed
with 2 N HCl/NaCl (140 mL). The aqueous layers were back-
extracted with EtOAc (70 mL), and the combined organic layers were
washed with 2N NaOH (2 × 140 mL) and brine (70 mL), dried
+
23
NH ) m/z 448 (M + H) ; [α] +30.2° (c 0.58, MeOH).
3
D
(
R)-1-(7-Trifluoromethoxy-2,2-dimethylchroman-4-yl)-3-(3-meth-
ylisoquinolin-5-yl)urea (49). Prepared via general procedure B. H
1
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.65 (s, 1H), 8.29 (d, J =
6
7
1
8
2
(
+
.3 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.53 (t, J = 7.6 Hz,
H), 7.46 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.93 (dd, J =
.0, 0.8 Hz, 1H), 6.76 (br s, 1H), 5.06−4.99 (m, 1H), 2.65 (s, 3H),
.23 (dd, J = 12.9, 5.7 Hz, 1H), 1.79 (dd, J = 12.9, 10.9 Hz, 1H), 1.44
+
23
s, 3H), 1.32 (s, 3H). MS (DCI/NH ) m/z 444 (M + H) ; [α]
3
D
(
Na SO ) the final organic layer, concentrated, and FCC (EtOAc)
2 4
7.8° (c 0.5, CH OH).
1
3
gave methylisoquinoline urea 41 (12.8 g, 31.3 mmol, 84%). H NMR
300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.27 (dd, J = 7.7,
(
R)-1-(6-Fluoro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methyli-
(
1
6
soquinolin-5-yl)urea (50). Prepared via general procedure B.
H
1
(
1
.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.53 (t, J = 7.9 Hz 1H), 7.12
dd, J = 9.4, 3.2 Hz, 1H), 7.07−6.96 (m, 2H), 6.81 (dd, J = 8.9, 4.9 Hz,
H), 5.04−4.91 (m, 1H), 2.66 (s, 3H), 2.30−2.15 (m, 1H), 1.78−1.50
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.66 (s, 1H), 8.25 (d, J =
6
7
1
.5 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J = 9.5 Hz, 1H), 7.53 (t, J = 7.9 Hz,
H), 7.20−6.97 (m, 4H), 5.11−5.02 (m, 1H), 4.77−4.59 (m, 4H),
+
(
m, 5H), 0.96−0.77 (m, 6H). MS (DCI/NH ) m/z 407 (M + H) .
3
2.66 (s, 3H), 2.35 (dd, J = 13.5, 6.0 Hz, 1H), 1.99 (dd, J = 13.5, 2.0
(
R)-1-(2,2-Diethyl-8-fluorochroman-4-yl)-3-(3-methylisoquinolin-
+
23
Hz, 1H). MS (DCI/NH ) m/z 416 (M + H) ; [α] +8.1° (c 0.57,
1
3
D
5
-yl)urea (42). Prepared via general procedure B. H NMR (300 MHz,
CH OH).
3
DMSO-d ) δ 9.18 (s, 1H), 8.64 (s, 1H), 8.29 (dd, J = 7.7, 1.1 Hz, 1H),
6
(
R)-1-(7-Fluoro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methyli-
7
2
1
0
.78−7.68 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.13 (dd, J = 20.6, 9.4 Hz,
H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 (td, J = 8.0, 5.0 Hz, 1H), 5.03 (s,
H), 2.65 (s, 3H), 2.24 (dd, J = 13.6, 6.1 Hz, 1H), 1.85−1.53 (m, 5H),
1
soquinolin-5-yl)urea (51). Prepared via general procedure B.
H
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.27 (d, J =
6
7
.5 Hz, 1H), 7.77−7.69 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.45−7.36
+
.98−0.81 (m, 6H). MS (ESI) m/z 408 (M + H) .
(
(
(
m, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.86 (td, J = 8.5, 2.6 Hz, 1H), 6.79
dd, J = 10.4, 2.6 Hz, 1H), 5.03 (dd, J = 14.8, 9.0 Hz, 1H), 4.80−4.68
m, 2H), 4.64−4.53 (m, 2H), 2.65 (s, 3H), 2.36 (dd, J = 13.7, 5.8 Hz,
(
R)-1-(8-Fluoro-2,2-dipropylchroman-4-yl)-3-(3-methylisoquino-
1
lin-5-yl)urea (43). Prepared via general procedure B. H NMR (300
MHz, DMSO-d ) δ 9.18 (s, 1H), 8.63 (s, 1H), 8.28 (dd, J = 7.7, 1.1
+
23
6
1H), 2.08−1.96 (m, 1H). MS (ESI+) m/z 416 (M + H) ; [α] +3.7°
D
Hz, 1H), 7.78−7.68 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.13 (dd, J =
(
c 1.0, CH OH).
3
2
1
1
0.6, 9.4 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 (td, J = 8.0, 5.0 Hz,
(
R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methyli-
44
1
H), 5.07−4.93 (m, 1H), 2.65 (s, 3H), 2.23 (dd, J = 13.6, 6.1 Hz, 1H),
soquinolin-5-yl)urea (52). Prepared via general procedure B. H
.85−1.25 (m, 7H), 0.98−0.81 (m, 6H). MS (ESI) m/z 436 (M +
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.69−8.66 (br s, 1H),
6
+
H) .
8.26 (d, J = 6.9 Hz, 1H), 7.76−7.70 (m, 2H), 7.54 (d, J = 7.9 Hz, 1H),
7.37 (d, J = 0.9 Hz, 1H), 7.07 (dd, J = 8.3, 2.2 Hz, 2H), 7.00 (d, J = 2.1
Hz, 1H), 5.08−5.01 (m, 1H), 4.74−4.72 (m, 2H), 4.58−4.56 (m, 2H),
2.66 (s, 3H), 2.42−2.31 (m, 1H), 2.07−1.96 (m, 1H). MS (DCI/
(
R)-1-(7-Fluoro-2,2-dimethylchroman-4-yl)-3-(3-methylisoquino-
1
lin-5-yl)urea (44). Prepared via general procedure B. H NMR (300
MHz, DMSO-d ) δ 9.18 (s, 1H), 8.62 (s, 1H), 8.30 (dd, J = 7.7, 1.1
6
+
23
Hz, 1H), 7.76−7.69 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.40−7.34 (m,
NH ) m/z 432 (M + H) ; [α] +1.3° (c 0.55, CH OH).
3
D
3
1
H), 6.96 (d, J = 8.3 Hz, 1H), 6.76 (td, J = 8.5, 2.6 Hz, 1H), 6.62 (dd,
(
R)-1-(7-Cyclopropyl-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-
methylisoquinolin-5-yl)urea (53). Prepared via general procedure B.
J = 10.6, 2.6 Hz, 1H), 5.04−4.94 (m, 1H), 2.65 (s, 3H), 2.21 (dd, J =
1
1
3.3, 6.1 Hz, 1H), 1.79 (dd, J = 13.3, 10.7 Hz, 1H), 1.42 (s, 3H), 1.31
H NMR (300 MHz, DMSO) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.28 (dd, J
+
23
(
s, 3H). MS (DCI/NH ) m/z 380 (M + H) ; [α] +4.4° (c 0.45,
= 7.7, 0.9 Hz, 1H), 7.76−7.67 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.23
(d, J = 8.2 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.74 (dd, J = 8.0, 1.8 Hz,
1H), 6.58 (d, J = 1.7 Hz, 1H), 4.99 (dd, J = 14.3, 8.9 Hz, 1H), 4.76−
3
D
CH OH.
3
(
R)-1-(7-Trifluoromethyll-2,2-dimethylchroman-4-yl)-3-(3-meth-
1
ylisoquinolin-5-yl)urea (45). Prepared via general procedure B. H
4
.63 (m, 2H), 4.61−4.49 (m, 2H), 2.65 (s, 3H), 2.32 (dd, J = 13.6, 5.7
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.68 (s, 1H), 8.28 (dd, J
6
Hz, 1H), 2.02−1.91 (m, 1H), 1.91−1.82 (m, 1H), 0.96−0.87 (m, 2H),
+ 23
=
7.7, 1.1 Hz, 1H), 7.76−7.70 (m, 2H), 7.58−7.50 (m, 2H), 7.26 (dd,
J = 8.1, 1.9 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),
.14−5.04 (m, 1H), 2.66 (s, 3H), 2.23 (d, J = 6.2 Hz, 1H), 1.86 (dd, J
13.3, 11.1 Hz, 1H), 1.45 (s, 3H), 1.33 (s, 3H). MS (DCI/NH ) m/z
0
.69−0.61 (m, 2H). MS (ESI+) m/z 438 (M + H) ; [α] 0° (c 1.0,
3
D
CH OH).
5
(R)-1-(8-Fluoro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methyli-
1
=
soquinolin-5-yl)urea (54). Prepared via general procedure B. H
3
+
23
4
30 (M + H) ; [α] +2.4° (c 0.20, CH OH).
NMR (300 MHz, DMSO-d ) δ 9.19 (s, 1H), 8.68 (s, 1H), 8.27 (dd, J
D
3
6
H
dx.doi.org/10.1021/jm500916t | J. Med. Chem. XXXX, XXX, XXX−XXX