Substituted Thiazolothiopurine Hsp90 Inhibitors
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5359
Acetic Acid 2-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-
purin-9-yl]-propyl Ester (22): white powder, 83% yield; 1H NMR
(CDCl3) δ 2.00 (s, 3H), 2.26 (m, 2H), 4.08 (t, J ) 5.9 Hz, 2H),
4.47 (t, J ) 7.0 Hz, 2H), 6.06 (s, 2H, NH2), 7.36 (d, J ) 7.8 Hz,
1H), 7.42 (t, J ) 7.8 Hz, 1H), 7.82 (d, J ) 7.8 Hz, 1H), 8.42 (s,
1H); HRMS, calcd for C17H15ClN6O2S2 [M + H]+ 435.0459, found
435.0454; HPLC >98% (tR ) 5.77 min).
OH), 7.55 (m, 2H), 7.64 (s, 2H, NH2), 7.93 (m, 1H), 8.26 (s, 1H);
HRMS, calcd for C14H11ClN6OS2 [M + H]+ 379.0197, found
379.0204; HPLC >96% (tR ) 5.01 min).
2-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-purin-9-yl]-
1
propan-1-ol (32): white powder, 81% yield; H NMR (CDCl3) δ
1.93 (m, 2H), 3.47 (m, 2H), 4.24 (m, 1H, OH), 4.52 (t, J ) 7.0
Hz, 2H), 5.78 (s, 2H, NH2), 7.39 (d, J ) 7.8 Hz, 1H), 7.42 (t, J )
7.8 Hz, 1H), 7.82 (d, J ) 7.8 Hz, 1H), 8.43 (s, 1H); HRMS, calcd
for C15H13ClN6OS2 [M + H]+ 393.0354, found 393.0359; HPLC
>99% (tR ) 5.13 min).
Acetic Acid 4-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-
purin-9-yl]-butyl Ester (23): white powder, 82% yield; 1H NMR
(CDCl3) δ 1.67 (m, 2H), 1.91(m, 2H), 1.96 (s, 3H), 4.04 (t, J )
6.4 Hz, 2H), 4.39 (t, J ) 7.3 Hz, 2H), 6.31 (s, 2H, NH2), 7.33 (d,
J ) 7.8 Hz, 1H), 7.42 (t, J ) 7.8 Hz, 1H), 7.82 (d, J ) 7.8 Hz,
1H), 8.41 (s, 1H); HRMS, calcd for C18H17ClN6O2S2 [M + H]+
449.0616, found 449.0624; HPLC >95% (tR ) 5.90 min).
{2-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-purin-9-
yl]-ethyl}-phosphonic Acid Diethyl Ester (24): white powder,
2-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-purin-9-yl]-
1
butan-1-ol (33): white powder, 76% yield; H NMR (CDCl3) δ
1.59 (m, 2H), 1.93 (m, 2H), 3.72 (t, J ) 6.1 Hz, 2H), 4.10 (m, 1H,
OH), 4.47 (t, J ) 7.0 Hz, 2H), 5.91 (s, 2H, NH2), 7.36 (d, J ) 7.8
Hz, 1H), 7.45 (t, J ) 7.8 Hz, 1H), 7.83 (d, J ) 7.8 Hz, 1H), 8.49
(s, 1H); HRMS, calcd for C16H15ClN6OS2 [M + H]+ 407.051, found
407.0512; HPLC >98% (tR ) 5.22 min).
1
85% yield; H NMR (CDCl3) δ 1.28 (t, J ) 7.1 Hz, 6H, 2CH3),
2.52 (m, 4H, 2CH2), 4.07 (m, 2H, CH2), 4.65 (m, 2H, CH2), 5.67
(bs, 2H, NH2), 7.38 (d, J ) 8.0 Hz, 1H), 7.43 (t, J ) 8.0 Hz, 1H),
7.83 (d, J ) 8.0 Hz, 1H), 8.53 (s, 1H); HRMS, calcd for C18H20-
ClN6O3PS2 [M + H]+ 499.0537, found 499.0536; HPLC >98%
(tR ) 5.67 min).
General Procedure for the Syntheses of Compounds 34-39.
To 79 or 80 (0.22 mmol) was added 1 mL of the appropriate amine.
The reaction mixture was stirred overnight at room temperature.
The excess amine was removed by rotoevaporation. The residue
was purified by flash chromatography (silica gel) (5% MeOH/CH2-
Cl2) to give 34-39.
5-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-purin-9-yl]-
1
pentanenitrile (25): white powder, 83% yield; H NMR (CDCl3)
8-(7-Chlorobenzothiazo-2-ylsulfanyl)-9-(2-morpholin-4-yl-eth-
yl)-9H-purin-6-ylamine (34): white powder, 83% yield; 1H NMR
(CDCl3) δ 2.48(t, J ) 4.46 Hz, 4H), 2.76 (t, J ) 5.8 Hz, 2H), 3.64
(t, J ) 4.4 Hz, 4H), 4.45 (t, J ) 5.8 Hz, 2H), 5.85 (bs, 2H, NH2),
7.35 (d, J ) 7.8 Hz, 1H), 7.44 (t, J ) 7.9 Hz, 1H), 7.84 (d, J ) 7.9
Hz, 1H), 8.42 (s, 1H); HRMS, calcd for C18H18ClN7OS2 [M - H]-
446.063, found 446.0629; HPLC >95% (tR ) 4.71 min).
9-(2-tert-Butylamino-ethyl)-8-(7-chlorobenzothiazole-2-ylsul-
δ1.71 (m, 2H), 2.05 (m, 2H), 2.42 (t, J ) 7.1 Hz, 2H), 4.41 (t,
J ) 5.2 Hz, 2H), 5.88 (bs, 2H), 7.36 (d, J ) 8.0 Hz, 1H), 7.44 (t,
J ) 8.0 Hz, 1H), 7.84 (d, J ) 8.0 Hz, 1H), 8.45 (s, 1H); HRMS,
calcd for C17H14ClN7S2 [M + H]+ 416.0513, found 416.0508;
HPLC >96% (tR ) 5.69 min).
8-(7-Bromothiazolo[5,4-b]pyridin-2-ylsulfanyl)-9-butyl-9H-
purine-6-ylamine (26): white powder, 81% yield; 1H NMR
(CDCl3) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.34 (m, 2H), 1.85 (m, 2H),
4.36 (t, J ) 7.3 Hz, 2H), 5.74 (s, 2H), 8.50 (s, 1H), 8.70(s, 1H),
9.20 (s, 1H); HRMS, calcd for C15H14BrN7S2 [M + H]+ 436.0008,
found 436.0014; HPLC >96% (tR ) 5.79 min).
1
fanyl)-9H-purin-6-ylamine (35): white powder, 30% yield; H
NMR (CDCl3) δ 0.96 (s, 9H), 3.00 (t, J ) 4.8 Hz, 2H), 4.46 (t,
J ) 4.9 Hz, 2H), 5.77 (s, 2H, NH2), 7.35 (d, J ) 7.8 Hz, 1H), 7.43
(t, J ) 7.8 Hz, 1H), 7.84 (d, J ) 7.8 Hz, 1H), 8.43 (s, 1H); HRMS,
calcd for C18H20ClN7S2 [M + H]+ 434.0983, found 434.0988;
HPLC >99% (tR ) 5.04 min).
{2-[6-Amino-8-(7-bromothiazole[4,5-c]pyridin-2-ylsulfanyl)-
purin-9-yl]ethyl}-phosphonic Acid Diethyl Ester (27): white
1
powder, 65% yield; H NMR (CDCl3) δ 1.28(t, J ) 7.1 Hz, 6H,
8-(7-Chlorobenzothiazol-2-ylsulfanyl)-9-[2-(2,2-dimethyl-pro-
2CH3), 2.52 (m, 2H, CH2), 4.07 (m, 4H, 2CH2), 4.65 (m, 2H, CH2),
5.71 (bs, 2H, NH2), 8.46 (s, 1H), 8.58(s, 1H), 9.25 (s, 1H); HRMS,
calcd for C17H19BrN7O3PS2 [M + H]+ 543.9984, found 543.9984;
HPLC >95% (tR ) 5.02 min).
pylamino)-ethyl]-9H-purin-6-ylamine (36): white powder, 31%
1
yield; H NMR (CDCl3) δ 0.82 (s, 9H), 2.31 (s, 2H), 3.05 (t, J )
4.8 Hz, 2H), 4.47 (t, J ) 4.9 Hz, 2H), 5.74 (s, 2H, NH2), 7.35 (d,
J ) 7.8 Hz, 1H), 7.43 (t, J ) 7.8 Hz, 1H), 7.84 (d, J ) 7.8 Hz,
1H), 8.44 (s, 1H); analysis (C18H22ClN7S2) C, H, N; HPLC >99%
(tR ) 5.31 min).
9-Butyl-8-(7-chlorothiazole[4,5-c]pyridin-2-ylsulfanyl)-9H-pu-
1
rin-6-ylamine (28): white powder, 86% yield; H NMR (CDCl3)
δ 0.94 (t, J ) 7.4 Hz, 3H), 1.38 (m, 2H), 1.86 (m, 2H), 4.35 (t,
J ) 7.4 Hz, 2H), 5.74 (s, 2H, NH2), 8.46 (s 1H), 8.49 (s, 1H), 9.10
(s, 1H); HRMS, calcd for C15H14ClN7S2 [M + H]+ 392.0513, found
392.0514; HPLC >96% (tR ) 5.90 min).
8-(7-Chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-
1
ethyl)-9H-purin-6-ylamine (37): white powder, 42% yield; H
NMR (CDCl3) δ 0.16 (m, 2H), 0.36 (m, 2H), 2.15 (m, 1H), 3.15
(t, J ) 4.8 Hz, 2H), 4.46 (t, J ) 4.9 Hz, 2H), 5.70 (s, 2H, NH2),
7.35 (d, J ) 7.8 Hz, 1H), 7.43 (t, J ) 7.8 Hz, 1H), 7.84 (d, J ) 7.8
Hz, 1H), 8.44 (s, 1H); HRMS calcd for C17H16ClN7S2 [M + H]+
418.067, found 418.0680; HPLC >99% (tR ) 4.95 min).
{2-[6-Amino-8-(7-chlorothiazolo[4,5-c]pyridinl-2-ylsulfanyl)-
purin-9-yl]-ethyl}-phosphonic Acid Diethyl Ester (29): white
1
powder, 81% yield; H NMR (CDCl3) δ 1.28 (t, J ) 7.1 Hz, 6H,
2CH3), 2.52 (m, 2H, CH2), 4.07 (m, 4H, 2CH2), 4.65 (m, 2H, CH2),
5.76 (bs, 2H, NH2), 8.46 (s, 1H), 8.52 (s, 1H), 9.08 (s, 1H); HRMS,
calcd for C17H19ClN7O3PS2 [M + H]+ 500.049, found 500.0488;
HPLC >96% (tR ) 4.97 min).
8-(7-Chlorobenzothiazol-2-ylsulfanyl)-9-(3-isopropylamino-
1
propyl)-9H-purin-6-ylamine (38): white powder, 45% yield; H
NMR (DMSO-d6) δ 1.29 (d, J ) 5.5 Hz, 6H), 2.28 (m, 1H), 2.80
(m, 2H), 3.40 (m, 2H), 4.52 (t, J ) 7.3 Hz, 2H), 7.37 (d, J ) 8.4
Hz, 1H), 7.42 (t, J ) 8.4 Hz, 1H), 7.93 (d, J ) 8.4 Hz, 1H), 8.28
(s, 1H); HRMS, calcd for C18H20ClN7S2 [M + H]+ 434.0983, found
434.0989; HPLC >96% (tR ) 4.81 min).
Acetic Acid 3-[6-Amino-8-(7-chlorothiazolo[4,5-c]pyridin-2-
ylsulfanyl)-purin-9-yl]-propyl Ester (30): white powder, 83%
yield; 1H NMR (CDCl3) δ 2.02 (s, 3H), 2.26 (m, 2H), 4.09 (t, J )
5.9 Hz, 2H), 4.47 (t, J ) 7.0 Hz, 2H), 5.75 (s, 2H, NH2), 8.45 (s,
1H), 8.50 (s, 1H), 9.09 (s, 1H); HRMS, calcd for C16H14ClN7O2S2
[M + H]+ 436.0412, found 436.0406; HPLC >95% (tR ) 5.06
min).
9-(3-tert-Butylamino-propyl)-8-(7-chlorobenzothiazol-2-ylsul-
1
fanyl)-9H-purin-6-ylamine (39): white powder, 45% yield; H
NMR (CDCl3) δ1.32 (s, 9H), 2.22 (m, 2H), 3.02 (t, J ) 7.3 Hz,
2H), 4.53 (t, J ) 7.3 Hz, 2H), 5.67 (bs, 2H), 7.47 (d, J ) 8.4 Hz,
1H), 7.54 (t, J ) 8.4 Hz, 1H), 7.86 (d, J ) 1.1 Hz, 1H), 8.34 (s,
1H); HRMS, calcd for C19H22ClN7S2 [M + H]+ 448.1139, found
448.1144; HPLC >99% (tR ) 5.00 min).
General Procedure for Alkylation of Adenines (40-48). To
a mixture of adenine (10 g, 74 mmol) and cesium carbonate (28.93
g, 88.8 mmol) in DMF (100 mL) was added alkyl halide (88.8
mmol) at room temperature. The reaction mixture was stirred at
room temperature or heated to 50 °C for 16 h and quenched with
General Procedure for the Syntheses of Compounds 31-33.
To 21-23 was added an excess of NH3 in MeOH at room
temperature. The mixture was stirred overnight at room temperature.
The excess of ammonia was removed by rotoevaporation. The
residue was purified by chromatography (silica gel) (5% MeOH/
CH2Cl2) to give 31-33.
2-[6-Amino-8-(7-chlorobenzothiazol-2-ylsulfanyl)-purin-9-yl]-
1
ethanol (31): white powder, 74% yield; H NMR (DMSO-d6) δ
3.58 (m, 2H), 4.33 (t, J ) 5.9 Hz, 2H), 5.04 (t, J ) 5.0 Hz, 1H,