662
L. Wang et al. / European Journal of Medicinal Chemistry 156 (2018) 652e665
(100 MHz, CD3OD)
d
160.5, 155.5, 149.6, 149.5, 143.8, 135.9, 132.3,
329.0395.
128.2, 124.0, 119.6, 111.9, 110.6, 95.5, 55.2, 55.1; HRMS-ESI(ꢂ) m/z
calcd for C18H16N2O5S [M ꢂ H]ꢂ 371.0707, found 371.0700.
4.1.43. 6-((30-fluoro-[1,10-biphenyl]-3-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13r)
4.1.37. 6-((30,50-dimethoxy-[1,10-biphenyl]-4-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13l)
Yield 60%. White solid, m. p. 178e180 ꢀC; 1H NMR (600 MHz,
DMSO‑d6)
1H), 7.64e7.57 (m, 4H), 7.53e7.50 (m, 1H), 7.23 (t, J ¼ 7.3 Hz, 1H),
4.84 (s, 1H); 13C NMR (150 MHz, DMSO‑d6)
163.1 (d,
d 11.95 (s, 1H), 10.37 (s, 1H), 7.97 (s, 1H), 7.92e7.90 (m,
Yield 58%. White solid, m. p. 220e222 ꢀC; 1H NMR (600 MHz,
CDCl3)
d
7.65 (d, J ¼ 7.7 Hz, 2H), 7.59 (d, J ¼ 7.3 Hz, 2H), 6.70 (s, 2H),
d
6.52 (s, 1H), 5.46 (s, 1H), 3.86 (s, 6H); 13C NMR (150 MHz, CDCl3)
JCF ¼ 243.6 Hz), 159.3, 153.1, 149.6, 141.4 (d, JCF ¼ 8.0 Hz), 141.1, 135.1,
133.8, 131.5 (d, JCF ¼ 8.4 Hz), 131.3, 129.5, 128.0, 123.4, 115.3 (d,
JCF ¼ 21.1 Hz), 114.2 (d, JCF ¼ 22.4 Hz), 96.8; HRMS-ESI(ꢂ) m/z calcd
for C16H11FN2O3S [M ꢂ H]ꢂ 329.0402, found 329.0396.
d
161.2, 158.6, 153.0, 151.5, 144.6, 141.4, 136.2, 129.3, 123.5, 105.5,
100.2, 96.0, 55.5; HRMS-ESI(ꢂ) m/z calcd for C18H16N2O5S [M ꢂ H]ꢂ
371.0707, found 371.0699.
4.1.38. 6-((40-fluoro-30-methyl-[1,10-biphenyl]-4-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13m)
4.1.44. 6-((40-chloro-[1,10-biphenyl]-3-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13s)
Yield 70%. White solid, m. p. 186e188 ꢀC; 1H NMR (600 MHz,
Yield 82%. White solid, m. p. 190e192 ꢀC; 1H NMR (600 MHz,
DMSO‑d6)
7.69e7.67 (m, 3H), 7.60e7.57 (m, 1H), 7.24 (t, J ¼ 9.1 Hz, 1H), 4.78 (s,
1H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO‑d6)
161.4 (d,
d
11.97 (s, 1H), 10.37 (s, 1H), 7.80 (d, J ¼ 8.2 Hz, 2H),
DMSO‑d6)
1H), 7.75 (d, J ¼ 8.5 Hz, 2H), 7.63e7.62 (m, 2H), 7.53 (d, J ¼ 8.5 Hz,
2H), 4.83 (s,1H); 13C NMR (150 MHz, DMSO‑d6)
159.3,153.2,149.6,
d 11.96 (s, 1H), 10.35 (s, 1H), 7.92 (s, 1H), 7.88e7.86 (m,
d
d
JCF ¼ 244.8 Hz), 159.2, 153.5, 149.5, 142.0, 136.3, 135.3, 130.8 (d,
JCF ¼ 5.3 Hz), 128.8, 126.7 (d, JCF ¼ 8.3 Hz), 125.7, 125.4 (d,
JCF ¼ 17.5 Hz), 116.0 (d, JCF ¼ 22.4 Hz), 96.3, 14.7; HRMS-ESI(ꢂ) m/z
calcd for C17H13FN2O3S [M ꢂ H]ꢂ 343.0558, found 343.0563.
141.2, 137.8, 134.8, 133.6, 133.5, 131.3, 129.5,129.4,129.2, 128.0, 96.8;
HRMS-ESI(ꢂ) m/z calcd for C16H11ClN2O3S [M ꢂ H]ꢂ 345.0106,
found 345.0109.
4.1.45. 6-((30-chloro-40-fluoro-[1,10-biphenyl]-3-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13t)
4.1.39. 6-((30-fluoro-40-methoxy-[1,10-biphenyl]-4-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13n)
Yield 70%. White solid, m. p. 185e187 ꢀC; 1H NMR (600 MHz,
Yield 61%. White solid, m. p. 205e207 ꢀC; 1H NMR (600 MHz,
DMSO‑d6)
(m, 1H), 7.77e7.74 (m, 1H), 7.65e7.61 (m, 2H), 7.53e7.50 (m, 1H),
4.82 (s, 1H); 13C NMR (150 MHz, DMSO‑d6)
159.3, 157.65 (d,
d 11.95 (s, 1H), 10.34 (s, 1H), 8.00e7.97 (m, 2H), 7.91e7.89
DMSO‑d6)
7.67e7.65 (m, 3H), 7.56e7.55 (m, 1H), 7.28e7.25 (m, 1H), 4.78 (s,
1H), 3.88 (s, 3H); 13C NMR (150 MHz, DMSO‑d6)
159.2, 153.6, 152.2
d
11.97 (s, 1H), 10.35 (s, 1H), 7.82 (d, J ¼ 8.3 Hz, 2H),
d
d
JCF ¼ 247.9 Hz), 154.8, 149.6, 140.1, 136.8, 135.1, 133.8, 131.3, 129.52,
129.46, 128.1 (d, JCF ¼ 7.4 Hz), 120.7 (d, JCF ¼ 17.8 Hz), 117.9 (d,
JCF ¼ 21.2 Hz), 96.7; HRMS-ESI(ꢂ) m/z calcd for C16H10ClFN2O3S
[M ꢂ H]ꢂ 363.0012, found 363.0015.
(d, JCF ¼ 243.8 Hz), 149.5, 147.8 (d, JCF ¼ 10.7 Hz), 141.3, 136.3, 131.9
(d, JCF ¼ 6.5 Hz), 128.5, 125.5, 123.6, 114.9, 114.7, 96.3, 56.6; HRMS-
ESI(ꢂ) m/z calcd for C17H13FN2O4S [M ꢂ H]ꢂ 359.0507, found
359.0510.
4.1.46. 3-Hydroxy-6-((4'-(trifluoromethyl)-[1,10-biphenyl]-2-yl)
thio)pyrimidine-2,4(1H,3H)-dione (13u)
4.1.40. 3-Hydroxy-6-((4'-(trifluoromethyl)-[1,10-biphenyl]-3-yl)
thio)pyrimidine-2,4(1H,3H)-dione (13o)
Yield 51%. White solid, m. p. 130e132 ꢀC; 1H NMR (600 MHz,
Yield 58%. White solid, m. p. 196e198 ꢀC; 1H NMR (600 MHz,
DMSO‑d6)
d
11.77 (s, 1H), 10.30 (s, 1H), 7.79 (d, J ¼ 8.1 Hz, 2H), 7.75
DMSO‑d6)
d 11.97 (s, 1H), 10.36 (s, 1H), 8.00 (s, 1H), 7.96e7.93 (m,
3H), 7.83 (d, J ¼ 8.2 Hz, 2H), 7.68e7.66 (m, 2H), 4.86 (s,1H); 13C NMR
(d, J ¼ 7.8 Hz, 1H), 7.68 (t, J ¼ 7.4 Hz, 1H), 7.61e7.58 (m, 3H), 7.55 (d,
J ¼ 7.5 Hz, 1H), 4.67 (s, 1H); HRMS-ESI(ꢂ) m/z calcd for
(150 MHz, DMSO‑d6) d 159.3, 153.0, 149.6, 143.0, 140.9, 135.5, 134.0,
C
17H11F3N2O3S [M ꢂ H]ꢂ 379.0370, found 379.0370.
131.4, 129.8, 128.9 (q, JCF ¼ 32.0 Hz), 128.3, 128.2, 126.3 (q,
JCF ¼ 3.7 Hz), 124.7 (q, JCF ¼ 271.9 Hz), 96.9; HRMS-ESI(ꢂ) m/z calcd
for C17H11F3N2O3S [M ꢂ H]ꢂ 379.0370, found 379.0363.
4.1.47. 6-((40-fluoro-[1,10-biphenyl]-2-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13v)
Yield 55%. White solid, m. p. 135e137 ꢀC; 1H NMR (600 MHz,
4.1.41. 3-Hydroxy-6-((3'-(trifluoromethyl)-[1,10-biphenyl]-3-yl)
thio)pyrimidine-2,4(1H,3H)-dione (13p)
DMSO‑d6)
d
11.75 (s, 1H), 10.28 (s, 1H), 7.71 (d, J ¼ 7.8 Hz,1H), 7.64 (t,
Yield 72%. White solid, m. p. 195e197 ꢀC; 1H NMR (600 MHz,
J ¼ 7.6 Hz, 1H), 7.54 (t, J ¼ 7.6 Hz, 1H), 7.50 (d, J ¼ 7.5 Hz, 1H),
7.40e7.38 (m, 2H), 7.26e7.23 (m, 2H), 4.64 (s, 1H); HRMS-ESI(ꢂ) m/
z calcd for C16H11FN2O3S [M ꢂ H]ꢂ 329.0402, found 329.0397.
DMSO‑d6)
d 11.96 (s, 1H), 10.36 (s, 1H), 8.05e8.04 (m, 3H), 7.96 (d,
J ¼ 7.7 Hz, 1H), 7.76 (d, J ¼ 7.7 Hz, 1H), 7.71 (t, J ¼ 7.7 Hz, 1H),
7.67e7.64 (m, 2H), 4.84 (s, 1H); 13C NMR (150 MHz, DMSO‑d6)
d
159.3, 153.2, 149.6, 140.9, 140.1, 135.3, 134.1, 131.5, 131.4, 130.6,
5. Biology
130.3 (q, JCF ¼ 31.5 Hz), 129.8, 128.1, 125.2 (q, JCF ¼ 3.8 Hz), 124.6 (q,
JCF ¼ 272.6 Hz), 123.9 (q, JCF ¼ 3.6 Hz), 96.8; HRMS-ESI(ꢂ) m/z calcd
for C17H11F3N2O3S [M ꢂ H]ꢂ 379.0370, found 379.0370.
5.1. Reagents
Biologicals. Recombinant HIV-1 reverse transcriptase (RT) was
expressed and purified as previously described [30]. P4R5 HIV
infection indicator cells were obtained from the NIH AIDS Reagent
Program, Division of AIDS, NIAID, NIH (p4R5. MAGI from Dr.
Nathaniel Landau). These cells express CD4, CXCR4 and CCR5 as
well as a b-galactosidase reporter gene under the control of an HIV
LTR promoter.
Chemicals. DNA and RNA oligonucleotides for the preparation of
RNA/DNA duplexes for assay of RNase H activity were purchased
from Trilink (San Diego, CA).
4.1.42. 6-((40-fluoro-[1,10-biphenyl]-3-yl)thio)-3-
hydroxypyrimidine-2,4(1H,3H)-dione (13q)
Yield 80%. White solid, m. p. 168e170 ꢀC; 1H NMR (600 MHz,
DMSO‑d6)
1H), 7.78e7.76 (m, 2H), 7.63e7.60 (m, 2H), 7.32e7.29 (m, 2H), 4.83
(s, 1H); 13C NMR (150 MHz, DMSO‑d6)
d
11.95 (s,1H),10.35 (s,1H), 7.90 (s,1H), 7.85 (d, J ¼ 6.9 Hz,
d
162.7 (d, JCF ¼ 245.2 Hz),
159.3, 153.3, 149.6, 141.5, 135.5 (d, JCF ¼ 3.0 Hz), 134.5, 133.6, 131.3,
129.5 (d, JCF ¼ 8.2 Hz), 129.4, 127.8, 116.3 (d, JCF ¼ 21.4 Hz), 96.7;
HRMS-ESI(ꢂ) m/z calcd for C16H11FN2O3S [M ꢂ H]ꢂ 329.0402, found