4168 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Hartz et al.
(s, 1H), 6.89 (s, 1H), 4.25-4.20 (m, 1H), 2.30 (s, 3H), 1.40 (d, J=
5.9 Hz, 3H), 1.12-1.00 (m, 1H), 0.78-0.68 (m, 1H), 0.60-0.51
(m, 1H), 0.49-0.40 (m, 1H), 0.39-0.28 (m, 1H). HRMS (ESI)
m/e 363.0778 [(M+H)+, calcd for C17H17N4OCl2 363.0779].
HPLC method A: tR = 5.28 min, 99.7%; method B: tR=
3.48 min, >99%.
by column chromatography to afford 12z (59 mg, 24% yield) as
a colorless solid; mp 165-166 ꢀC; [R]25D -20.5 (c 0.288, CHCl3).
1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.32 (d, J=2.2 Hz,
1H), 7.19 (d, J=1.9 Hz, 1H), 6.88 (s, 1H), 4.32-4.22 (m, 1H),
2.27 (s, 3H), 1.44 (d, J=6.6 Hz, 3H), 1.16-1.05 (m, 1H), 0.82-
0.73 (m, 1H), 0.63-0.54 (m, 1H), 0.51-0.44 (m, 1H), 0.42-0.36
(m, 1H). HRMS (ESI) m/e 372.0429 [(M + H)+, calcd for
C16H17N3OCl3 372.0437]. HPLC method A: tR = 5.98 min,
>99%; method B: tR=3.74 min, >99%.
(R)-3,5-Dichloro-2-[6-chloro-4-(1-cyclopropylethyl)-3-oxo-
3,4-dihydropyrazin-2-ylamino]benzonitrile (12aa). Compound
12aa was prepared according to the procedure described for the
synthesis of 12e (method A) using (R)-3,5-dichloro-1-(1-cyclo-
propylethyl)pyrazin-2(1H)-one (10) (150 mg, 0.644 mmol) and
2-amino-3,5-dichlorobenzonitrile (120 mg, 0.644 mmol). The
product was purified by column chromatography to afford
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-[2,6-dichloro-4-(triflu-
oromethoxy)phenylamino]pyrazin-2(1H)-one (12u). Compound
12u was prepared according to the procedure described for the
synthesis of 12d (method B) using 2,6-dichloro-4-(trifluoro-
methoxy)aniline (295 mg, 1.20 mmol) and (R)-3,5-dichloro-
1-(1-cyclopropylethyl)pyrazin-2(1H)-one (10) (233 mg, 1.00
mmol). The product was purified by column chromatography
to afford 12u (182 mg, 41% yield) as a colorless solid; mp 125-
125.5 ꢀC; [R]25D -16.1 (c 0.304, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 7.76 (s, 1H), 7.33 (s, 2H), 6.95 (s, 1H), 4.34-4.24
(m, 1H), 1.47 (d, J=6.6 Hz, 3H), 1.16-1.07 (m, 1H), 0.82-0.75
(m, 1H), 0.66-0.58 (m, 1H), 0.57-0.47 (m, 1H), 0.45-0.38
(m, 1H). HRMS (ESI) m/e 442.0104 [(M + H)+, calcd
for C16H14N3O2Cl3F3 442.0104]. Anal. (C16H13N3O2Cl3F3)
C, H, N.
(S)-5-Chloro-1-(1-cyclopropylethyl)-3-[2,6-dichloro-4-(triflu-
oromethyl)phenylamino]pyrazin-2(1H)-one (12v). Compound
12v was prepared according to the procedure described for the
synthesis of 12d (method B) using 2,6-dichloro-4-(trifluoro-
methoxy)aniline (172 mg, 0.75 mmol) and (S)-3,5-dichloro-1-
(1-cyclopropylethyl)pyrazin-2(1H)-one (10) (174 mg, 0.75
mmol). The product was purified by column chromatography
12aa (60 mg, 24% yield) as a pale-yellow solid; mp 183.4-
D
1
184 ꢀC; [R]25 -21.5 (c 0.514, CHCl3). H NMR (400 MHz,
CDCl3) δ 8.04 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.61 (d, J=
2.3 Hz, 1H), 6.99 (s, 1H), 4.29-4.21 (m, 1H), 1.44 (d, J=6.8 Hz,
3H), 1.12-1.05 (m, 1H), 0.80-0.73 (m, 1H), 0.62-0.55 (m, 1H),
0.51-0.44 (m, 1H), 0.41-0.34 (m, 1H). HRMS (ESI) m/e
383.0244 [(M+H)+, calcd for C16H14N4OCl3 383.0233]. Anal.
(C16H13N4OCl3) C, H, N.
(R)-5-Chloro-3-(4-chloro-2-methoxy-5-methylphenylamino)-
1-(1-cyclopropylethyl)pyrazin-2(1H)-one (12ab). Compound 12ab
was prepared according to the procedure described for the
synthesis of 12e (method A) using (R)-3,5-dichloro-1-(1-cyclo-
propylethyl)pyrazin-2(1H)-one (10) (60 mg, 0.260 mmol) and
4-chloro-2-methoxy-5-methylaniline (45 mg, 0.260 mmol) with
DMF (1 mL) as the solvent. The product was purified by column
chromatography to afford 12ab (70 mg, 74% yield) as a brown
to afford 12v (149 mg, 47% yield) as a colorless solid; [R]25
D
+18.1 (c 0.306, CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.90 (s,
1H), 7.69 (s, 2H), 6.98 (s, 1H), 4.35-4.25 (m, 1H), 1.50 (d, J=6.9
Hz, 3H), 1.17-1.07 (m, 1H), 0.85-0.76 (m, 1H), 0.66-0.57 (m,
1H), 0.56-0.48 (m, 1H), 0.45-0.37 (m, 1H). HRMS (ESI) m/e
426.0161 [(M + H)+, calcd for C16H14N3OCl3F3 426.0155].
Anal. (C16H13N3OCl3F3) C, H, N.
solid; [R]25 -8.3 (c 0.400, CHCl3). 1H NMR (400 MHz,
D
CDCl3) δ 8.89 (s, 1H), 8.52 (s, 1H), 6.86 (s, 2H), 4.24-4.20
(m, 1H), 3.88 (s, 3H), 2.36 (s, 3H), 1.42 (d, J=6.8 Hz, 3H), 1.12-
1.05 (m, 1H), 0.77-0.71 (m, 1H), 0.58-0.51 (m, 1H), 0.48-0.42
(m, 1H), 0.36-0.31 (m, 1H). HRMS (ESI) m/e 368.0935
[(M+H)+, calcd for C17H20N3O2Cl2 368.0933]. HPLC method
A: tR=7.07 min, 97.2%; method B: tR=4.35 min, 97.8%.
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,4,5-trimethylpheny-
lamino)pyrazin-2(1H)-one (12ac). Compound 12ac was pre-
pared according to the procedure described for the synthesis
of 12e (method A) using (R)-3,5-dichloro-1-(1-cyclopropy-
lethyl)pyrazin-2(1H)-one (10) (70 mg, 0.300 mmol) and 2,4,5-
trimethylaniline (41 mg, 0.300 mmol) with DMF (1 mL) as the
solvent. The product was purified by column chromatography
to afford 12ac (41 mg, 41% yield) as a light-brown solid;
[R]25D -18.3 (c 0.371, CHCl3). 1H NMR (300 MHz, CDCl3) δ
8.16 (s, 1H), 8.02 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 4.27-4.19 (m,
1H), 2.27 (s, 6H), 2.20 (s, 3H), 1.42 (d, J=6.8 Hz, 3H), 1.12-1.04
(m, 1H), 0.77-0.71 (m, 1H), 0.58-0.54 (m, 1H), 0.51-0.42 (m,
1H), 0.37-0.31 (m, 1H). HRMS (ESI) m/e 332.1529 [(M+H)+,
calcd for C18H23N3OCl 332.1530]. Anal. (C18H22N3OCl) C,
H, N.
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-[2,6-dichloro-4-(difluoro-
methoxy)phenylamino]pyrazin-2(1H)-one (12w). Compound
12w was prepared according to the procedure described for the
synthesis of 12e (method A) using (R)-3,5-dichloro-1-(1-cyclo-
propylethyl)pyrazin-2(1H)-one (10) (124 mg, 0.535 mmol) and
2,6-dichloro-4-(difluoromethoxy)aniline (19) (122 mg, 0.535
mmol). The product was purified by column chromatography
to afford 12w (140 mg, 62% yield) as a pale-yellow solid; mp
163-164 ꢀC; [R]25 -12.3 (c 0.290, CHCl3). 1H NMR (400
D
MHz, CDCl3) δ 7.69 (s, 1H), 7.21 (s, 2H), 6.91 (s, 1H), 6.52
(t, J=72.6 Hz, 1H), 4.30-4.23 (m, 1H), 1.44 (d, J=6.9 Hz, 3H),
1.12 (m, 1H), 0.80-0.73 (m, 1H), 0.61-0.55 (m, 1H), 0.51-0.45
(m, 1H), 0.41-0.35 (m, 1H). HRMS (ESI) m/e 424.0205
[(M+H)+, calcd for C16H15N3O2Cl3F2 424.0198]. Anal. (C16-
H14N3O2Cl3F2) C, H, N.
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4 (methylsul-
fonyl)phenylamino)pyrazin-2(1H)-one (12y). Compound 12y
was prepared according to the procedure described for the
synthesis of 12x (method C) using (R)-3,5-dichloro-1-(1-cyclo-
propylethyl)pyrazin-2(1H)-one (10) (150 mg, 0.644 mmol) and
2,6-dichloro-4-(methylsulfonyl)aniline (155 mg, 0.644 mmol).
The residue was purified by column chromatography to give 12y
(181 mg, 64% yield) as a colorless solid; [R]25D -25.2 (c 0.529,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 2H), 7.28
(s, 1H), 7.02 (s, 1H), 4.41-4.22 (m, 1H), 3.15 (s, 3H), 1.49 (d,
J=6.8 Hz, 3H), 1.19-1.08 (m, 1H), 0.86-0.76 (m, 1H), 0.67-
0.58 (m, 1H), 0.57-0.48 (m, 1H), 0.46-0.35 (m, 1H). HRMS
(ESI) m/e 436.0052 [(M + H)+, calcd for C16H17N3O3Cl3S
436.0056]. Anal. (C16H16N3O3Cl3S) C, H, N.
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,4-dichloro-6-methyl-
phenylamino)pyrazin-2(1H)-one (12z). Compound 12z was pre-
pared according to the procedure described for the synthesis of
12e (method A) using (R)-3,5-dichloro-1-(1-cyclopropylethyl)
pyrazin-2(1H)-one (10) (150 mg, 0.644 mmol) and 2,4-dichloro-
6-methylaniline (125 mg, 0.709 mmol). The product was purified
(R)-5-Chloro-1-(1-cyclopropylethyl)-3-(4-ethoxy-2,5-dimethyl-
phenylamino)pyrazin-2(1H)-one (12ae). Compound 12ae was
prepared according to the procedure described for the synthesis
of 12e (method A) using (R)-3,5-dichloro-1-(1-cyclopropy-
lethyl)pyrazin-2(1H)-one (10) (60 mg, 0.260 mmol) and 4-
ethoxy-2,5-dimethylaniline (42 mg, 0.260 mmol) with DMF
(1 mL) as the solvent. The product was purified by column
chromatography to afford 12ae (60 mg, 65% yield) as a tan
solid; [R]25 -12.7 (c 0.521, benzene). 1H NMR (400 MHz,
D
CDCl3) δ 8.02 (s, 1H), 7.85 (s, 1H), 6.80 (s, 1H), 6.65 (s, 1H),
4.27-4.20 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H),
2.22 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.40 (t, J=6.9 Hz, 3H),
1.13-1.04 (m, 1H), 0.78-0.71 (m, 1H), 0.59-0.52 (m, 1H),
0.49-0.43 (m, 1H), 0.37-0.31 (m, 1H). HRMS (ESI) m/e
362.1640 [(M + H)+, calcd for C19H25N3O2Cl 362.1635]. Anal.
(C19H24N3O2Cl) C, H, N.