Journal of Medicinal Chemistry
Article
Hz, 1H), 3.24 (s, 3H), 2.85−2.77 (m, 3H), 2.59 (dd, J = 16.2, 8.3 Hz,
PKS2194. Synthesized by following the general procedure for boc-
deprotection of PKS2188 (0.19 mmol, from previous step). After
completion of reaction (3 h), excess trifluoroacetic acid and
dichloromethane were evaporated. The crude paste was washed
1
H), 2.41−2.38 (m, 2H).
PKS2204. Synthesized by following the general procedure for O-
debenzylation. The reaction was not complete, and the isolated crude
was purified by HPLC to give 40 mg product (50% brsm; 16.0 mg
twice with diethyl ether to give the product as an off-white solid (yield
1
1
starting material was recovered). H NMR (500 MHz, DMSO-d ) δ
= 111 mg, 84% for three steps). H NMR (500 MHz, DMSO-d ) δ
6
6
1
7
2.34 (s, 1H), 8.27−8.24 (m, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.28−
.25 (m, 2H), 7.20−7.15 (m, 3H), 6.99 (t, J = 7.9 Hz, 1H), 6.93 (dd,
8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.87 (d, J = 7.8 Hz, 1H), 8.53 (t, J =
6.0 Hz, 1H), 8.39 (dd, J = 8.4, 1.8 Hz, 1H), 8.27 (b, 3H), 7.88 (dd, J
= 8.1, 1.5 Hz, 1H), 7.61 (dd, J = 7.2, 1.5 Hz, 1H), 7.58−7.54 (m, 2H),
7.40−7.31 (m, 5H), 5.13 (J = 12.5 Hz, 1H), 5.10 (d, J = 12.5 Hz,
1H), 4.97 (dd, J = 16.4, 6.1 Hz, 1H), 4.90 (dd, J = 16.4, 5.9 Hz, 1H),
4.62−4.58 (m, 1H), 4.27 (m, 1H), 3.66 (dd, J = 9.8, 6.0 Hz, 1H), 3.57
(dd, J = 9.8, 4.8 Hz, 1H), 3.30 (s, 3H), 3.04 (dd, J = 17.5, 3.9 Hz,
J = 8.2, 1.5 Hz, 1H), 6.80 (dd, J = 7.7, 1.5 Hz, 1H), 4.66−4.60 (m,
1
H), 4.43−4. 38 (m, 1H), 4.28 (d, J = 5.9 Hz, 2H), 3.78 (s, 3H), 3.72
(s, 3H), 3.56 (dd, J = 9.7, 5.8 Hz, 1H), 3.47 (dd, J = 9.7, 5.0 Hz, 1H),
3
2
.24 (s, 3H), 2.79 (t, J = 7.9 Hz, 2H), 2.68 (dd, J = 16.6, 5.9 Hz, 1H),
.48−2.39 (m, 3H).
+
PKS2211. Synthesized following the general procedure for HATU-
1H), 2.85−2.80 (m, 1H). LCMS calcd for C H N O [M + H] :
2
5
28
4
5
mediated coupling of O-tert-butyl hydroxylamine hydrochloride (6.6
mg, 0.0525 mmol) and PKS2204 (18.0 mg, 0.035 mmol). After
completion of reaction (1 h), the mixture was diluted with water and
extracted with ethyl acetate. The organic layer was evaporated and
purified by HPLC to give the product (11.0 mg, 54%). H NMR (500
MHz, DMSO-d ) δ 10.37 (s, 1H), 8.37 (t, J = 6.0 Hz, 1H), 8.20 (d, J
464.2. Found: 464.3.
PKS2198. Synthesized following the general procedure for HATU-
mediated coupling of 3-phenylpropanoic acid (26.4 mg, 0.176 mmol)
and PKS2194 (111 mg, 0.16 mmol). After completion of reaction (3
h), the mixture was precipitated with water. The precipitate was
1
1
filtered and dried to give the product (77 mg, 81%). H NMR (500
6
=
7.9 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.28−7.25 (m, 2H), 7.19−
MHz, DMSO-d ) δ 8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.43 (t, J = 6.1 Hz,
6
7
6
1
6
.15 (m, 3H), 6.98 (t, J = 7.9 Hz, 1H), 6.92 (dd, J = 8.1, 1.6 Hz, 1H),
.82 (d, J = 7.7 Hz, 1H), 4.67−4.63 (m, 1H), 4.40 (dt, J = 7.6, 5.3 Hz,
H), 4.31−4.24 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.59 (dd, J = 9.8,
.0 Hz, 1H), 3.49 (dd, J = 9.8, 4.6 Hz, 1H), 3.24 (s, 3H), 2.80−2.76
1H), 8.38 (dd, J = 8.3, 1.8 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.12 (d,
J = 7.8 Hz, 1H), 7.87 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (dd, J = 7.2, 1.5
Hz, 1H), 7.57−7.53 (m, 2H), 7.35−7.30 (m, 5H), 7.27−7.24 (m,
2H), 7.19−7.15 (m, 3H), 5.03 (s, 2H), 4.95 (dd, J = 16.4, 6.1 Hz,
1H), 4.90 (dd, J = 16.4, 5.9 Hz, 1H), 4.77 (td, J = 8.2, 5.7 Hz, 1H),
4.49 (dt, J = 7.8, 5.3 Hz, 1H), 3.62 (dd, J = 9.7, 5.8 Hz, 1H), 3.52 (dd,
J = 9.7, 5.0 Hz, 1H), 3.28 (s, 3H), 2.85−2.77 (m, 3H), 2.59 (dd, J =
16.2, 8.4 Hz, 1H), 2.42−2.38 (m, 2H).
(
m, 2H), 2.52−2.48 (m, 1H), 2.43−2.39 (m, 2H), 2.33 (dd, J = 14.9,
1
3
7
1
1
3
6
.8 Hz, 1H), 1.11 (s, 9H). C NMR (126 MHz, DMSO-d ) δ 172.0,
6
71.3, 169.7, 168.0, 152.6, 146.5, 141.7, 132.8, 128.8, 128.6, 126.3,
24.1, 120.3, 112.0, 81.0, 72.3, 60.4, 58.7, 56.1, 53.6, 50.1, 37.4, 37.2,
5.3, 31.4, 26.7. HRMS calcd for C H N O Na [M + Na] :
09.2895. Found: 609.2897.
PKS2175. Synthesized following the general procedure for HATU
+
PKS2202. Synthesized by following the general procedure for O-
debenzylation of PKS2198 (73 mg, 0.122 mmol). The mixture was
3
0
42
4
8
filtered through celite, evaporated, and purified by HPLC to give the
1
coupling of boc-β-methoxyalanine dicyclohexylamine (80 mg, 0.02
mmol) and quinolin-8-ylmethylamine dihydrochloride (46 mg, 0.2
mmol) in 2 mL dimethylformamide. (Note: the reaction mixture was
not soluble in dimethylformamide.) After completion of reaction (3 h),
water was added to the reaction mixture (reaction mixture turned
transparent) and extracted twice with chloroform. The combined
organic layer was washed with water followed by brine, dried over
anhydrous sodium sulfate, and evaporated. The crude product was
product (19 mg, 30%). H NMR (500 MHz, DMSO-d ) δ 12.34 (s,
6
1H), 8.26−8.23 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.28−7.25 (m,
2H), 7.21−7.15 (m, 3H), 6.81 (dd, J = 7.5, 1.5 Hz, 1H), 6.76 (dd, J =
7.5, 1.5 Hz, 1H), 6.40 (t, J = 7.4 Hz, 1H), 4.63 (td, J = 7.8, 5.8 Hz,
1H), 4.40 (dt, J = 7.7, 5.4 Hz, 1H), 4.08 (dd, J = 15.3, 6.1 Hz, 1H),
4.03 (dd, J = 15.3, 5.9 Hz, 1H), 3.56 (dd, J = 9.8, 5.8 Hz, 1H), 3.47
(dd, J = 9.8, 5.0 Hz, 1H), 3.24 (s, 3H), 3.22 (t, J = 5.5 Hz, 2H), 2.80
(t, J = 7.9 Hz, 2H), 2.70−2.65 (m, 3H), 2.48−2.39 (m, 3H), 1.79−
1.74 (m, 2H).
1
purified by HPLC to give 68.5 mg (95%) of pure product. H NMR
(
500 MHz, DMSO-d ) δ 8.96−8.94 (m, 1H), 8.46 (t, J = 6.2 Hz, 1H),
PKS2226. Synthesized following the general procedure for HATU-
mediated coupling of PKS2202 (19.0 mg, 0.037 mmol) and O-tert-
butyl hydroxylamine hydrochloride (5.1 mg, 0.041 mmol). The
6
8
7
6
3
.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.64 (d, J =
.1 Hz, 1H), 7.58 (dd, J = 8.3, 4.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H),
.96 (d, J = 8.1 Hz, 1H), 4.96−4.87 (m, 2H), 4.26−4.22 (m, 1H),
.54−3.53 (m, 2H), 3.27 (s, 3H), 1.39 (s, 9H).
1
product was purified by HPLC (17.9 mg, 83%) H NMR (500 MHz,
DMSO-d ) δ 10.40 (s, 1H), 8.41 (t, J = 6.1 Hz, 1H), 8.18 (d, J = 7.9
6
PKS2181. Synthesized by following the general procedure for boc-
Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.28−7.25 (m, 2H), 7.20−7.15 (m,
3H), 6.84 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.38 (t, J = 7.4
Hz, 1H), 5.24−5.20 (m, 1H), 4.67−4.62 (m, 1H), 4.40−4.37 (m,
1H), 4.10 (dd, J = 15.1, 6.3 Hz, 1H), 4.00 (dd, J = 15.1, 5.8 Hz, 1H),
3.60 (dd, J = 9.8, 5.9 Hz, 1H), 3.49 (dd, J = 9.8, 4.5 Hz, 1H), 3.24 (s,
3H), 3.22−3.21 (m, 2H), 2.80−2.76 (m, 2H), 2.66 (t, J = 6.4 Hz,
2H), 2.52−2.48 (m, 1H), 2.42−2.39 (m, 2H), 2.35 (dd, J = 14.8, 7.5
deprotection of PKS2175 (68.5 mg, 0.19 mmol). The crude was used
in the next step. H NMR (500 MHz, DMSO-d ) δ 8.98 (dd, J = 4.2,
1
8
1
=
3
1
6
.8 Hz, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.42 (dd, J = 8.2, 1.8 Hz, 1H),
.22 (b, 3H), 7.93 (dd, J = 8.1, 1.5 Hz, 1H), 7.67 (dd, J = 7.1, 1.5 Hz,
H), 7.62−7.58 (m, 2H), 5.02 (dd, J = 15.9, 5.9 Hz, 1H), 4.96 (dd, J
15.9, 5.7 Hz, 1H), 4.13−4.10 (m, 1H), 3.75−3.69 (m, 2H), 3.32 (s,
1
3
H).
Hz, 1H), 1.79−1.74 (m, 2H), 1.14 (s, 9H). C NMR (126 MHz,
PKS2188. Synthesized following the general procedure for HATU-
DMSO-d ) δ 171.5, 170.9, 169.5, 167.6, 142.5, 141.2, 128.3, 128.1,
6
mediated coupling of N-(tert-butoxycarbonyl)-L-aspartic acid 4-
benzyl ester (61.4 mg, 0.19 mmol) and PKS2181 (0.19 mmol, from
previous step). After completion of reaction (1 h), the reaction
mixture was diluted with water and extracted twice with ethyl acetate.
Ethyl acetate layer was dried over anhydrous Na SO and evaporated.
128.0, 126.5, 125.8, 121.3, 120.0, 114.6, 80.6, 71.7, 58.3, 53.1, 49.6,
41.3, 36.8, 34.8, 31.00, 27.2, 26.3, 21.3. HRMS calcd for
+
C H N O Na [M + Na] : 604.3106. Found: 604.3105.
3
1
43
5
6
PKS2220. Synthesized following the general procedure for HATU-
mediated coupling of PKS21059 (20.2 mg, 0.06 mmol) and
2
4
The crude was dried under high vacuum and used in the next step
PKS2181 (32.2 mg, 0.066 mmol). The product was purified be
1
1
without further purification. H NMR (500 MHz, DMSO-d ) δ 8.96
HPLC (yield = 21.6 mg, 62%). H NMR (500 MHz, DMSO-d ) δ
6
6
(
dd, J = 4.3, 1.8 Hz, 1H), 8.49 (t, J = 5.9 Hz, 1H), 8.43 (dd, J = 8.3,
10.36 (s, 1H), 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.57 (t, J = 6.1 Hz, 1H),
8.38 (dd, J = 8.3, 1.8 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.15 (d, J =
7.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.5 Hz 1H), 7.63 (dd, J = 7.4, 1.5 Hz,
1H), 7.59−7.54 (m, 2H), 7.28−7.25 (m, 2H), 7.20−7.17 (m, 3H),
4.98−4.89 (m, 2H), 4.71−4.67 (m, 1H), 4.50−4.46 (m, 1H), 3.66
(dd, J = 9.7, 5.8 Hz, 1H), 3.55 (dd, J = 9.7, 4.7 Hz, 1H), 3.29 (s, 3H),
2.80−2.77 (m, 2H), 2.55−2.51 (m, 1H), 2.43−2.40 (m, 2H), 2.35
1
7
6
.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H),
.63 (dd, J = 7.1, 1.5 Hz, 1H), 7.61−7.55 (m, 2H), 7.37−7.30 (m,
H), 5.09 (d, J = 12.7 Hz, 1H), 5.05 (d, J = 12.7 Hz, 1H), 4.96 (dd, J
16.4, 6.0 Hz, 1H), 4.89 (dd, J = 16.4, 5.9 Hz, 1H), 4.51−4.48 (m,
H), 4.43 (td, J = 8.5, 5.0 Hz, 1H), 3.63 (dd, J = 9.7, 5.5 Hz, 1H),
.52 (dd, J = 9.7, 5.1 Hz, 1H), 3.28 (s, 3H), 2.85−2.81 (m, 1H), 2.62
=
1
3
1
3
(dd, J = 16.2, 8.9 Hz, 1H), 1.38 (s, 9H).
(dd, J = 14.7, 7.7 Hz, 1H), 1.06 (s, 9H). C NMR (126 MHz,
N
J. Med. Chem. XXXX, XXX, XXX−XXX