Journal of Medicinal Chemistry
Article
was purified by silica gel column chromatography (EtOAc:MeOH =
617). Compound 20b (0.07 g, 0.119 mmol) was treated with
trifluoroacetic acid (2 mL) in CH Cl (2 mL) according to procedure
B to furnish the TFA salt of 21b (0.1 g, 95%). H NMR (600 MHz,
1
9
:1) to yield compound 18b (0.71 g, 86%). H NMR (600 MHz,
2
2
1
CDCl ): δ 7.83 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 3.0 Hz, 1H), 7.23 (t, J =
3
7
5
9
.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 3.69 (t, J =
.4 Hz, 2H), 3.21 (s, 4H), 2.77 (s, 4H), 2.66 (t, J = 5.4 Hz, 2H), 1.66 (s,
H).
Procedure H. tert-Butyl 7-Chloro-6-(4-(2-oxoethyl)piperazin-
-yl)-1H-indole-1-carboxylate (19a). Into a stirring solution of
CD OD): δ 7.23 (d, J = 3.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.05 (d, J =
3
7.8 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 3.56 (s, 4H), 3.45−3.41 (m, 7H),
3.29 (m, 3H), 2.92−2.80 (m, 3H), 2.74−2.70 (m, 2H), 2.21−2.20 (m,
2
5
1H), 1.92 (m, 1H), 1.68−1.62 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). [α]
=
D
1
−
23.9 (c = 1.0 in CH OH). Anal. Calcd for C H ClN S·3CF COOH·
3 24 33 6 3
H O: C, 43.25; H, 4.60; N, 10.09. Found: C, 42.89; H, 4.69; N, 9.85.
oxalyl chloride (0.22 mL, 2.55 mmol) in CH Cl (8 mL) at −78 °C was
added DMSO (0.33 mL, 4.63 mmol). The reaction mixture was stirred
for 0.5 h, followed by addition of compound 18a (0.4 g, 1.16 mmol, in 5
mL of CH Cl ). The reaction mixture was stirred at the same
temperature for 0.5 h, followed by addition of Et N (0.97 mL, 6.95
mmol), and stirring was continued for another 1.5 h while allowing the
reaction mixture to reach room temperature. The reaction mixture was
2
2
2
tert-Butyl 5-Bromo-7-fluoro-1H-indole-1-carboxylate (22). 5-
Bromo-7-fluoro-1H-indole (0.48 g, 2.22 mmol) was reacted with
2
2
(Boc) O (0.53 g, 2.44 mmol) and DMAP (0.3 g, 2.44 mmol) in THF (5
2
3
mL) according to procedure D. The crude material was purified by silica
gel column chromatography (hexane:EtOAc = 19:1) to afford
1
compound 22 in quantitative yield. H NMR (600 MHz, CDCl ): δ
3
quenched by addition of a saturated solution of NaHCO at 0 °C and
3
7.64 (d, J = 3.6 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 10.8, 1.2
Hz, 1H), 6.52 (q, J = 1.8 Hz, 1H), 1.65 (s, 9H).
tert-Butyl 5-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)piperazin-1-
yl)-7-fluoro-1H-indole-1-carboxylate (23). A mixture of 22 (0.69 g,
extracted with CH Cl (3 × 25 mL). The combined organic layer was
2
2
dried using Na SO , and the solvent was removed under reduced
2
4
pressure. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 3:2) to afford compound 19a (0.21
g, 48%). H NMR (600 MHz, CDCl ): δ 9.76 (s, 1H), 7.44 (d, J = 3.6
Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.49 (d, J =
3
9
2
.196 mmol), 6 (0.94 g, 3.84 mmol), Pd(OAc) (0.04 g, 0.17 mmol),
2
1
3
BINAP (0.14 g, 0.22 mmol), and Cs CO (2.15 g, 6.59 mmol) in toluene
2 3
(10 mL) was heated at 110 °C for 15 h according to procedure G. The
.6 Hz, 1H), 3.29−3.24 (m, 4H), 3.20 (m, 4H), 2.76 (m, 2H), 1.64 (s,
crude residue was purified by column chromatography (hexane:EtOAc
H).
1
=
7:3) to afford compound 23 (0.61 g, 58%). H NMR (600 MHz,
tert-Butyl 5-Chloro-4-(4-(2-oxoethyl)piperazin-1-yl)-1H-indole-1-
CDCl ): δ 7.56 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.71 (dd, J =
3
carboxylate (19b). Alcohol 18b (0.2 g, 0.58 mmol) was oxidized with
oxalyl chloride (0.11 mL, 1.27 mmol), DMSO (0.16 mL, 2.32 mmol),
and Et N (0.48 mL, 3.47 mmol) in CH Cl (7 mL) using procedure H.
The crude residue was purified by column chromatography (hexane/
EtOAc, 3:2) to afford compound 19b (0.07 g, 32%). H NMR (600
MHz, CDCl ): δ 9.78 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 3.0
Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 4.2 Hz, 1H), 3.41 (s, 4H),
3
1
2.6, 2.4 Hz, 1H), 6.46 (q, J = 1.8 Hz, 1H), 3.80 (t, J = 6.0 Hz, 2H), 3.19
(t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.60 (t, J = 6.0 Hz, 2H), 1.63
3
2
2
(s, 9H), 0.91 (s, 9H), 0.08 (s, 6H).
tert-Butyl 7-Fluoro-5-(4-(2-hydroxyethyl)piperazin-1-yl)-1H-in-
1
dole-1-carboxylate (24). Compound 23 (0.35 g, 0.73 mmol) was
reacted with n-tetrabutylammonium fluoride (1.45 mL, 1.46 mmol, 1.0
M solution in THF) in THF (7 mL) according to procedure E. The
3
.28 (s, 2H), 2.73 (s, 4H), 1.66 (s, 9H).
crude product was purified by silica gel column chromatography
(
S)-tert-Butyl 6-(4-(2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
1
(
EtOAc:MeOH = 5:1) to give compound 24 (0.23 g, 85%). H NMR
thiazol-6-yl)(propyl)amino)ethyl)piperazin-1-yl)-7-chloro-1H-in-
dole-1-carboxylate (20a). Compound 19a (0.18 g, 0.46 mmol) was
(
600 MHz, CDCl ): δ 7.57 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H),
3
6
.71 (dd, J = 12.6, 2.4 Hz, 1H), 6.47 (q, J = 1.8 Hz, 1H), 3.67 (t, J = 6.0
reacted with (−)-pramipexole (0.09 g, 0.43 mmol) and NaBH(OAc)
3
Hz, 2H), 3.20 (t, J = 4.8 Hz, 4H), 2.82 (bs, 1H), 2.69 (t, J = 4.8 Hz, 4H),
(0.2 g, 0.93 mmol) in CH Cl (10 mL) according to procedure A. The
2 2
2
.62 (t, J = 6.0 Hz, 2H), 1.63 (s, 9H).
crude product was purified by silica gel column chromatography
1
tert-Butyl 7-Fluoro-5-(4-(2-oxoethyl)piperazin-1-yl)-1H-indole-1-
(
(
EtOAc:MeOH = 5:1) to afford compound 20a (0.14 g, 56%). H NMR
600 MHz, CDCl ): δ 7.43 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H),
.01 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 5.13 (bs, 2H), 3.24−
.15 (m, 4H), 3.07−3.03 (m, 1H), 2.77−2.66 (m, 8H), 2.57−2.46 (m,
H), 2.01−1.99 (m, 1H), 1.75−1.71 (m, 1H), 1.64 (s, 9H), 1.51−1.45
carboxylate (25). Alcohol 24 (0.15 g, 0.41 mmol) was oxidized using
SO ·py complex (0.33 g, 2.06 mmol), DMSO (2 mL), and Et N (0.40
3
3
3
7
3
6
mL, 2.89 mmol) in CH Cl (4 mL) according to procedure F. The crude
2
2
product was purified by silica gel column chromatography using ethyl
1
25
D
acetate as solvent to give aldehyde 25 (0.12 g, 84%). H NMR (600
(
m, 2H), 0.90 (t, J = 7.2 Hz, 3H). [α] = −35.3 (c = 1.0 in CH OH).
3
MHz, CDCl ): δ 9.75 (s, 1H), 7.57 (d, J = 3.6 Hz, 1H), 6.81−6.79 (m,
3
(
S)-tert-Butyl 4-(4-(2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
1
H), 6.71 (dd, J = 13.2, 1.8 Hz, 1H), 6.47 (q, J = 1.8 Hz, 1H), 3.27−3.19
thiazol-6-yl)(propyl)amino)ethyl)piperazin-1-yl)-5-chloro-1H-in-
dole-1-carboxylate (20b). Compound 19b (0.07 g, 0.18 mmol) was
(
m, 6H), 2.73−2.70 (m, 4H), 1.63 (s, 9H).
S)-tert-Butyl 5-(4-(2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propyl)amino)ethyl)piperazin-1-yl)-7-fluoro-1H-indole-
-carboxylate (26). Aldehyde 25 (0.12 g, 0.33 mmol) was reacted with
(
reacted with (−)-pramipexole (0.04 g, 0.18 mmol) and NaBH(OAc)
3
(
0.08 g, 0.37 mmol) in CH Cl (5 mL) according to procedure A. The
2 2
1
crude product was purified by silica gel column chromatography
1
(−)-pramipexole (0.06 g, 0.30 mmol) and NaBH(OAc) (0.14 g, 0.66
(
(
7
4
2
2
EtOAc:MeOH = 9:1) to afford compound 20b (0.07 g, 64%). H NMR
600 MHz, CDCl ): δ 7.84 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 3.0 Hz, 1H),
3
mmol) in CH Cl (7 mL) according to procedure A. The crude product
2
2
3
was purified by silica gel column chromatography (EtOAc:MeOH =
.26 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 5.36 (bs, 2H), 3.37 (s,
H), 3.09−3.05 (m, 1H), 2.80−2.67 (m, 8H), 2.61−2.47 (m, 6H),
.02−2.00 (m, 1H), 1.76−1.69 (m, 1H), 1.65 (s, 9H), 1.52−1.46 (m,
1
9
:1) to afford compound 26 (0.09 g, 51%). H NMR (600 MHz,
CDCl ): δ 7.56 (d, J = 3.0 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.70 (dd, J =
3
25
D
13.8, 1.8 Hz, 1H), 6.46 (q, J = 1.8 Hz, 1H), 5.11 (bs, 2H), 3.19 (t, J = 4.8
Hz, 4H), 3.07−3.03 (m, 1H), 2.76−2.66 (m, 8H), 2.58−2.46 (m, 6H),
2.01−1.99 (m, 1H), 1.76−1.69 (m, 1H), 1.63 (s, 9H), 1.51−1.45 (m,
H), 0.90 (t, J = 7.2 Hz, 3H). [α] = −33.8 (c = 1.0 in CH OH).
3
6
6
(
S)-N -(2-(4-(7-Chloro-1H-indol-6-yl)piperazin-1-yl)ethyl)-N -
propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (21a) (D-
16). Compound 20a (0.07 g, 0.13 mmol) was treated with
trifluoroacetic acid (2 mL) in CH Cl (2 mL) according to procedure
2
5
6
2H), 0.89 (t, J = 7.2 Hz, 3H). [α] = −36.4 (c = 1.0 in CH OH).
D
3
6
6
(S)-N -(2-(4-(7-Fluoro-1H-indol-5-yl)piperazin-1-yl)ethyl)-N -
2
2
1
B to furnish the TFA salt of 21a (0.11 g, 91%). H NMR (600 MHz,
CD OD): δ 7.44 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 3.0 Hz, 1H), 6.91 (d, J =
propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (27) (D-
6
15). Compound 26 (0.08 g, 0.14 mmol) was treated with trifluoro-
3
acetic acid (2 mL) in CH Cl (2 mL) according to procedure B to
8
3
1
.4 Hz, 1H), 6.44 (d, J = 3.0 Hz, 1H), 3.60 (m, 1H), 3.51−3.42 (m, 8H),
.29 (s, 4H), 2.97−2.89 (m, 3H), 2.78−2.66 (m, 3H), 2.24−2.22 (m,
H), 1.97−1.95 (m, 1H), 1.74−1.67 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).
2
2
1
furnish the TFA salt of 27 (0.11 g, 85%). H NMR (600 MHz, CD OD):
3
δ 7.21 (d, J = 3.0 Hz, 1H), 6.94 (s, 1H), 6.69 (d, J = 13.2 Hz, 1H), 6.41 (t,
J = 3.0 Hz, 1H), 3.57−3.53 (m, 1H), 3.30−3.16 (m, 7H), 3.09−2.85 (m,
9H), 2.76−2.69 (m, 2H), 2.16−2.15 (m, 1H), 1.96−1.89 (m, 1H),
25
[α] = −25.2 (c = 1.0 in CH OH). Anal. Calcd for C H ClN S·
D
3
24 33
6
4
CF COOH: C, 41.36; H, 4.01; N, 9.04. Found: C, 41.38; H, 4.34; N,
3
25
D
9
.16.
1.71−1.65 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). [α]
CH OH). Anal. Calcd for C24 S·3CF COOH·2H
H, 4.83; N, 10.07. Found: C, 42.95; H, 4.67; N, 9.62.
= −26.6 (c = 1.0 in
6
6
(
S)-N -(2-(4-(5-Chloro-1H-indol-4-yl)piperazin-1-yl)ethyl)-N -
3
H
33FN
6
3
2
O: C, 43.17;
propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (21b) (D-
M
J. Med. Chem. XXXX, XXX, XXX−XXX