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L. Liu et al. / Bioorg. Med. Chem. 24 (2016) 2215–2234
8.74 (s, 1H), 8.17–8.25 (m, 1H), 7.27–7.39 (m, 1H), 7.13–7.24 (m,
1H), 7.00–7.10 (m, 1H), 3.19–3.30 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H).
(m, 2H), 9.00–9.05 (m, 1H), 8.71 (s, 1H), 8.19 (dd, J = 4.7, 1.9 Hz,
1H), 7.32 (td, J = 8.9, 5.6 Hz, 1H), 7.09–7.21 (m, 1H), 6.97–7.07
(m, 1H), 4.19 (br s, 1H), 3.09 (d, J = 7.0 Hz, 2H), 1.05–1.12
(m, 1H), 0.54–0.59 (m, 2H), 0.33–0.40 (m, 2H).
8.3.31. N-(3-((3-(9H-Purin-6-yl)pyridin-2-yl)amino)-2,4-difluo-
rophenyl)butane-2-sulfonamide (5i)
This compound was prepared from 14 and butane-2-sulfonyl
chloride according to the procedure described in Method B as an
amorphous solid (46 mg, 0.10 mmol, 34%). LCMS (ESI, pos. ion)
calcd for C20H19F2N7O2S: 459.1; found: 460.2 (M+1). 1H NMR
(400 MHz, DMSO-d6) d ppm 13.31–14.01 (m, 1H), 11.39 (br s,
1H), 9.52 (br s, 2H), 8.90 (s, 1H), 8.59 (s, 1H), 8.06 (d, J = 2.4 Hz,
1H), 7.18 (d, J = 5.7 Hz, 1H), 6.98–7.10 (m, 1H), 6.91 (dd, J = 4.7,
7.4 Hz, 1H), 2.87 (br s, 1H), 1.85 (d, J = 4.7 Hz, 1H), 1.25–1.47 (m,
1H), 1.17 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.1 Hz, 3H).
8.3.37. N-(3-Amino-2,4-difluorophenyl)cyclopentanesulfon-
amide (10m)
This material was prepared from 8 and cyclopentanesulfonyl
chloride according to the procedure described in Method A as
yellow oil (64.0 mg, 0.232 mmol, 17%). LCMS (ESI, pos. ion) calcd
for C11H14F2N2O2S: 276.1; found: 277.2 (M+1).
8.3.38. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)cyclopentanesulfonamide (5m)
This compound was prepared from 10m and 12 according to the
sequence described for 4b as an amorphous solid (59.0 mg,
0.125 mmol, 54%). LCMS (ESI, pos. ion) calcd for C21H19F2N7O2S:
471.1; found: 472.2 (M+1). 1H NMR (400 MHz, DMSO-d6) d ppm
11.44 (br s, 1H), 9.57 (br s, 2H), 8.96 (s, 1H), 8.64 (s, 1H), 8.12
(dd, J = 1.6, 4.6 Hz, 1H), 7.18–7.31 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H),
6.96 (dd, J = 4.7, 7.8 Hz, 1H), 3.48 (t, J = 7.7 Hz, 1H), 1.77–1.95 (m,
4H), 1.59 (d, J = 6.6 Hz, 2H), 1.50 (d, J = 6.8 Hz, 2H).
8.3.32. N-(3-Amino-2,4-difluorophenyl)pentane-2-sulfonamide
(10j)
This material was prepared from 8 and pentane-2-sulfonyl
chloride according to the procedure described in Method A as color-
less oil (30 mg, 0.11 mmol, 10%). LCMS (ESI, pos. ion) calcd for
C
11H16F2N2O2S: 278.0; found: 279.0 (M+1). 1H NMR (400 MHz,
CDCl3) d ppm 6.92 (td, J = 8.9, 5.4 Hz, 1H), 6.74–6.85 (m, 1H), 6.25
(br s, 1H), 3.81 (br s, 2H), 3.10 (ddd, J = 9.9, 6.6, 3.4 Hz, 1H), 1.96
(ddd, J = 9.9, 6.6, 2.7 Hz, 1H), 1.59–1.66 (m, 1H), 1.45–1.54 (m, 1H),
1.38 (d, J = 6.8 Hz, 3H), 1.24–1.35 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H).
8.3.39. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)tetrahydrofuran-3-sulfonamide (5n)
This compound was prepared from 14 and tetrahydrofuran-3-
sulfonyl chloride according to the procedure described in Method
B as an amorphous solid (39 mg, 0.082 mmol, 54%). LCMS (ESI,
pos. ion) calcd for C20H17F2N7O3S: 473.1; found: 474.0 (M+1). 1H
NMR (400 MHz, DMSO-d6) d ppm 11.60 (br s, 1H), 9.72 (br s, 1H),
9.09 (s, 1H), 8.78 (s, 1H), 8.26 (dd, J = 1.8, 4.7 Hz, 1H), 7.36 (dt,
J = 6.0, 8.6 Hz, 1H), 7.17–7.29 (m, 1H), 7.10 (dd, J = 4.7, 7.8 Hz,
1H), 4.02–4.09 (m, 1H), 3.95–4.02 (m, 2H), 3.83–3.94 (m, 1H),
3.67–3.82 (m, 1H), 2.16–2.34 (m, 2H).
8.3.33. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)pentane-2-sulfonamide (5j)
This compound was prepared from 10j and 12 according to the
sequence described for 4b as an amorphous solid (15 mg,
0.032 mmol, 49%). LCMS (ESI, pos. ion) calcd for C21H21F2N7O2S:
473.1; found: 474.0 (M+1). 1H NMR (300 MHz, DMSO-d6) d ppm
11. 53 (br s, 1H), 9.67 (br s, 2H), 9.03 (s, 1H), 8.72 (s, 1H), 8.19
(dd, J = 4.7, 1.9 Hz, 1H), 7.30 (td, J = 8.8, 5.8 Hz, 1H), 7.09–7.22
(m, 1H), 7.03 (dd, J = 7.9, 4.8 Hz, 1H), 2.96–3.16 (m, 1H),
1.80–1.96 (m, 1H), 1.35–1.52 (m, 2H), 1.21–1.33 (m, 4H), 0.86
(t, J = 7.2 Hz, 3H).
8.3.40. N-(3-Amino-2,4-difluorophenyl)cyclohexanesulfonamide
(10o)
This material was prepared from 8 and cyclohexanesulfonyl
chloride according to the procedure described in Method A as a
white solid (0.161 g, 0.555 mmol, 34%). LCMS (ESI, pos. ion) calcd
8.3.34. N-(3-Amino-2,4-difluorophenyl)cyclopropanesulfon-
amide (10k)
This material was prepared from 8 and cyclopropanesulfonyl
chloride according to the procedure described in Method A as
yellow solid (0.278 g, 1.15 mmol, 68%). LCMS (ESI, pos. ion) calcd
for C9H10F2N2O2S: 248.0; found: 249.2 (M+1). 1H NMR (400 MHz,
DMSO-d6) d ppm 9.33 (s, 1H), 6.87 (ddd, J = 2.0, 8.9, 10.7 Hz, 1H),
6.54 (dt, J = 5.5, 8.6 Hz, 1H), 5.31 (s, 2H), 2.52–2.67 (m, 1H),
0.90–0.97 (m, 2H), 0.81–0.89 (m, 2H).
for
C
12H16F2N2O2S: 290.1; found: 291.1 (M+1). 1H NMR
(400 MHz, DMSO-d6) d ppm 9.34 (br s, 1H), 6.78–6.94 (m, 1H),
6.53 (dt, J = 5.5, 8.7 Hz, 1H), 5.31 (s, 2H), 2.81–2.95 (m, 1H), 2.02–
2.16 (m, 2H), 1.72–1.82 (m, 2H), 1.61 (d, J = 11.8 Hz, 1H), 1.32–
1.48 (m, 2H), 1.17–1.31 (m, 2H), 1.09–1.15 (m, 1H).
8.3.41. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)cyclohexanesulfonamide (5o)
8.3.35. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)cyclopropanesulfonamide (5k)18a
This compound was prepared from 10o and 12 according to the
sequence described for 4b as an amorphous solid (0.117 g,
0.241 mmol, 53%). LCMS (ESI, pos. ion) calcd for C22H21F2N7O2S:
485.1; found: 486.2 (M+1). 1H NMR (400 MHz, DMSO-d6) d ppm
13.72–14.00 (m, 1H), 11.57 (br s, 1H), 9.52–9.85 (m, 2H), 9.03 (s,
1H), 8.73 (s, 1H), 8.20 (dd, J = 2.0, 4.8 Hz, 1H), 7.31 (dt, J = 5.7,
8.8 Hz, 1H), 7.13–7.23 (m, 1H), 7.04 (dd, J = 4.7, 7.9 Hz, 1H), 2.96
(t, J = 11.8 Hz, 1H), 2.11 (d, J = 11.6 Hz, 2H), 1.79 (d, J = 13.5 Hz,
2H), 1.55–1.70 (m, 1H), 1.34–1.49 (m, 2H), 1.18–1.32 (m, 2H),
1.13 (d, J = 11.7 Hz, 1H).
This compound was prepared from 10k and 12 according to the
sequence described for 4b as an amorphous solid (36 mg,
0.081 mmol, 16%). LCMS (ESI, pos. ion) calcd for C19H15F2N7O2S:
443.1; found: 444.2 (M+1). 1H NMR (400 MHz, DMSO-d6) d ppm
11.58 (br s, 1H), 9.66 (d, J = 6.2 Hz, 1H), 9.03 (s, 1H), 8.71 (s, 1H),
8.21 (dd, J = 1.8, 4.7 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 7.20 (t,
J = 9.3 Hz, 1H), 7.04 (dd, J = 4.8, 7.8 Hz, 1H), 2.65 (s, 1H), 0.94–
1.05 (m, 2H), 0.85–0.92 (m, 2H).
8.3.36. N-(3-(3-(9H-Purin-6-yl)pyridin-2-ylamino)-2,4-difluo-
rophenyl)cyclobutanesulfonamide (5l)18a
8.3.42. N-(3-((3-(9H-Purin-6-yl)pyridin-2-yl)amino)-2,4-difluo-
rophenyl)tetrahydro-2H-pyran-4-sulfonamide (5p)
This compound was prepared from 14 and cyclobutanesulfonyl
chloride according to the procedure described in Method B as an
amorphous solid (63.2 mg, 0.138 mmol, 46%). LCMS (ESI, pos. ion)
calcd for C20H17F2N7O2S: 457.1; found: 458.0 (M+1). 1H NMR
(500 MHz, DMSO-d6) d ppm 11.44–11.54 (m, 1H), 9.57–9.67
This compound was prepared from 14 and tetrahydro-2H-
pyran-4-sulfonyl chloride according to the procedure described
in Method B as an amorphous solid (21.7 mg, 0.045 mmol, 15%).
LCMS (ESI, pos. ion) calcd for C21H19F2N7O3S: 487.1; found: 488.0
(M+1). 1H NMR (500 MHz, DMSO-d6)
d ppm 9.69 (s, 1H),