3002 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Young et al.
m eth yl)a ceta m id e (18). Compound 18 was prepared from
[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-
pyrazin-1-yl]acetic acid12 and 3-(tetrazol-1-yl)-2-aminometh-
ylpyridine 65 using a procedure similar to that described for
yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid12 and 2-[1,2,4]-
triazol-1-yl-benzylamine 59 using a procedure similar to that
described for the preparation of 6. 1H NMR (DMSO-d6, 400
MHz): δ 8.90 (s, 1H), 8.70 (d, J ) 4.8 Hz, 1H), 8.62 (m, 1H),
8.24 (s, 1H), 7.98 (t, J ) 6.9 Hz, 1H), 7.70 (d, J ) 8 Hz, 1H),
7.57-7.46 (m, 5H), 7.10 (m, 1H), 6.79 (d, A of AB, J ) 3.4 Hz,
1H), 6.72 (d, B of AB, J ) 3.4 Hz, 1H), 4.52 (s, 2H), 4.20 (m,
4H). HRMS ES: calculated for C22H20F2N8O2, 467.1750; found,
467.1747.
1
the preparation of 6. H NMR (CD3OD, 400 MHz): δ 9.59 (s,
1H), 8.79 (dd, J ) 4.8 Hz, J ) 1.5 Hz, 1H), 8.63 (d, J ) 4.8 Hz,
1H), 7.96 (m, 2H), 7.69 (d, J ) 7.9 Hz, 1H), 7.59 (m, 1H), 7.50
(m, 1H), 6.80 (s, 1H), 4.83 (s, 2H), 4.42 (s, 2H), 4.27 (t, J )
13.8 Hz, 2H). HRMS ES: calculated for C20H17ClF2N10O2,
503.1266; found, 503.1268.
N-(5-Ch lor o-2-[1,2,4]tr ia zol-1-yl-ben zyl)-2-[3-(2,2-d iflu -
or o-2-p yr id in -2-yl-et h yla m in o)-2-oxo-2H -p yr a zin -1-yl]-
a ceta m id e (25). Compound 25 was prepared from [3-(2,2-
difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]ace-
tic acid12 and 5-chloro-2-[1,2,4]triazol-1-yl-benzylamine 61
using a procedure similar to that described for the preparation
2-[6-Ch lor o-3-(2,2-d iflu or o-2-p yr id in -2-yl-e t h yla m i-
n o)-2-oxo-2H-p yr a zin -1-yl]-N-[2-(1H-tetr a zol-5-yl)ben zyl]-
a ceta m id e Tr iflu or oa cetic Acid Sa lt (19). Compound 19
was prepared from [6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-
ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid12 and 2-(1H-
tetrazol-5-yl)-benzylamine hydrochloride salt 67 using a pro-
cedure similar to that described for the preparation of 6. 1H
NMR (CD3OD, 400 MHz): δ 8.63 (d, J ) 4.6 Hz, 1H), 7.93 (m,
1H), 7.71 (m, 2H), 7.57 (m, 2H), 7.50 (m, 2H), 6.82 (s, 1H),
4.84 (s, 2H), 4.67 (s, 2H), 4.27 (t, J ) 13.9 Hz, 2H). HRMS ES:
calculated for C21H18ClF2N9O2, 502.1313; found, 502.1318.
1
of 6. H NMR (DMSO-d6, 400 MHz): δ 8.92 (s, 1H), 8.71 (m,
2H), 8.26 (s, 1H), 7.99 (m, 1H), 7.71 (d, J ) 7.9 Hz, 1H), 7.54
(m, 4H), 7.04 (t, J ) 6.6 Hz, 1H), 6.81 (d, A of AB, J ) 4.6 Hz,
1H), 6.74 (d, B of AB, J ) 4.6 Hz, 1H), 4.54 (s, 2H), 4.21 (m,
4H). HRMS ES: calculated for C22H19ClF2N8O2, 501.1361;
found, 501.1370.
2-[6-Ch lor o-3-(2,2-d iflu or o-2-p yr id in -2-yl-eth yla m in o)-
2-oxo-2H-p yr a zin -1-yl]-N-[2-(1-m eth yl-1H-tetr a zol-5-yl)-
ben zyl]a ceta m id e Tr iflu or oa cetic Acid Sa lt (20). Com-
pound 20 was prepared from [6-chloro-3-(2,2-difluoro-2-pyridin-
2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid12 and 2-(1-
methyl-1H-tetrazol-5-yl)-benzylamine hydrochloride salt 68
using a procedure similar to that described for the preparation
2-{3-[2,2-Diflu or o-2-(1-oxy-p yr id in -2-yl)et h yla m in o]-
2-oxo-2H -p yr a zin -1-yl}-N-(2-[1,2,4]t r ia zol-1-yl-b en zyl)-
a cet a m id e (26). Compound 26 was prepared from {3-[2,2-
difluoro-2-(1-oxy-pyridin-2-yl)ethylamino]-2-oxo-2H-pyrazin-1-
yl}acetic acid21 and 2-[1,2,4]triazol-1-yl-benzylamine 59 using
a procedure similar to that described for the preparation of 6.
1H NMR (DMSO-d6, 400 MHz): δ 8.89 (s, 1H), 8.60 (m, 1H),
8.35 (d, J ) 6.3 Hz, 1H), 8.24 (s, 1H), 7.60 (d, J ) 7.7 Hz, 1H),
7.54-7.40 (m, 5H), 7.37 (t, J ) 6.4 Hz, 1H), 7.25 (t, J ) 6.4
Hz, 1H), 6.73 (d, A of AB, J ) 4 Hz, 1H), 6.58 (d, B of AB, J )
4 Hz, 1H), 4.48 (m, 4H), 4.20 (d, J ) 5.5 Hz, 2H). HRMS ES:
calculated for C22H20F2N8O3, 483.1699; found, 483.1698.
1
of 6. H NMR (CD3OD, 400 MHz): δ 8.63 (m, 1H), 7.94 (td, J
) 7.8 Hz, J ) 1.7 Hz, 1H), 7.70 (d, J ) 8.0 Hz, 1H), 7.62 (m,
2H), 7.53-7.47 (m, 3H), 6.82 (s, 1H), 4.78 (s, 2H), 4.32-4.24
(m, 4H), 4.01 (s, 3H). HRMS ES: calculated for C22H20
ClF2N9O2: 516.1470; found, 516.1466.
-
2-[6-Ch lor o-3-(2,2-d iflu or o-2-p yr id in -2-yl-eth yla m in o)-
2-oxo-2H-p yr a zin -1-yl]-N-[2-(2-m eth yl-2H-tetr a zol-5-yl)-
ben zyl]a ceta m id e Tr iflu or oa cetic Acid Sa lt (21). Com-
pound 21 was prepared from [6-chloro-3-(2,2-difluoro-2-pyridin-
2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid12 and 2-(2-
methyl-2H-tetrazol-5-yl)benzylamine hydrochloride salt 69
using a procedure similar to that described for the preparation
N-(5-Ch lor o-2-[1,2,4]t r ia zol-1-yl-b en zyl)-2-{3-[2,2-d if-
lu or o-2-(1-oxy-pyr idin -2-yl)eth ylam in o]-2-oxo-2H-pyr azin -
1-yl}a ceta m id e (27). Compound 27 was prepared from {3-
[2,2-difluoro-2-(1-oxy-pyridin-2-yl)ethylamino]-2-oxo-2H-pyrazin-
1-yl}acetic acid21 and 5-chloro-2-[1,2,4]triazol-1-yl-benzylamine
61 using a procedure similar to that described for the prepara-
tion of 6. 1H NMR (CD3OD, 400 MHz): δ 8.77 (s, 1H), 8.36 (d,
J ) 6 Hz, 1H), 8.18 (s, 1H), 7.69 (dd, J ) 7.8 Hz, J ) 2.2 Hz,
1H), 7.61 (m, 1H), 7.58-7.42 (m, 4H), 6.61 (d, A of AB, J )
3.8 Hz, 1H), 6.60 (d, B of AB, J ) 3.8 Hz, 1H), 4.56 (t, J )
13.1 Hz, 2H), 4.48 (s, 2H), 4.30 (s, 2H). HRMS ES: calculated
for C22H19ClF2N8O3, 517.1310; found, 517.1303.
1
of 6. H NMR (CD3OD, 400 MHz): δ 8.64 (d, J ) 4.1 Hz, 1H),
8.02 (d, J ) 7.8 Hz, 1H), 7.94 (m, 1H), 7.70 (d, J ) 7.8 Hz,
1H), 7.56-7.42 (m, 4H), 6.83 (s, 1H), 4.83 (s, 2H), 4.76 (s, 2H),
4.43 (d, J ) 2 Hz, 3H), 4.28 (t, J ) 13.8 Hz, 2H). HRMS ES:
calculated for C22H20ClF2N9O2, 516.1470; found, 516.1465.
2-{6-Ch lor o-3-[2,2-d iflu or o-2-(1-oxy-p yr id in -2-yl)eth yl-
amino]-2-oxo-2H-pyrazin-1-yl}-N-(2-[1,2,4]triazol-1-yl-benzyl)-
a ceta m id e Tr iflu or oa cetic Acid Sa lt (22). Compound 22
was prepared from {6-chloro-3-[2,2-difluoro-2-(1-oxy-pyridin-
2-yl)ethylamino]-2-oxo-2H-pyrazin-1-yl}acetic acid21 and 2-[1,2,4]-
triazol-1-yl-benzylamine 59 using a procedure similar to that
described for the preparation of 6. 1H NMR (CDCl3, 400
MHz): δ 8.46 (s, 1H), 8.42 (t, J ) 4.2 Hz, 1H), 8.10 (s, 1H),
7.70 (dd, J ) 6.1 Hz, J ) 4.2 Hz, 1H), 7.63 (dd, J ) 7.5 Hz, J
) 2.3 Hz, 1H), 7.52-7.42 (m, 4H), 7.32 (dd, J ) 7.5 Hz, J )
2.3 Hz, 1H), 7.14 (t, J ) 6.5 Hz, 1H), 6.84 (s, 1H), 6.40 (m,
1H), 4.78 (s, 2H), 4.64 (td, J ) 13.8 Hz, J ) 5.9 Hz, 2H), 4.31
(d, J ) 6.3 Hz, 2H). HRMS ES: calculated for C22H19ClF2N8O3,
517.1309; found, 517.1306.
2-(6-Meth yl-2-oxo-3-p h en ylm eth a n esu lfon yla m in o-2H-
pyr idin -1-yl)-N-(2-[1,2,4]tr iazol-1-yl-ben zyl)acetam ide (28).
Compound 28 was prepared from (6-methyl-2-oxo-3-phenyl-
methanesulfonylamino-2H-pyridin-1-yl)aceticacid11 and 2-[1,2,4]-
triazol-1-yl-benzylamine 59 using a procedure similar to that
described for the preparation of 6. 1H NMR (CDCl3, 400
MHz): δ 8.35 (s, 1H), 8.09 (s, 1H), 7.60 (m, 1H), 7.48-7.39
(m, 3H), 7.36 (t, J ) 6.4 Hz, 1H), 7.31-7.21 (m, 6H), 6.03 (d,
J ) 7.5 Hz, 1H), 4.72 (s, 2H), 4.33 (d, J ) 6.4 Hz, 2H), 4.28 (s,
2H), 2.32 (s, 3H). HRMS ES: calculated for C24H24N6O4S,
493.1653; found, 493.1654.
N-(5-Ch lor o-2-[1,2,4]t r ia zol-1-yl-b en zyl)-2-(6-m et h yl-
2-oxo-3-p h en ylm eth a n esu lfon yla m in o-2H-p yr id in -1-yl)-
a ceta m id e (29). Compound 29 was prepared from (6-methyl-
2-oxo-3-phenylmethanesulfonylamino-2H-pyridin-1-yl)acetic
acid11 and 5-chloro-2-[1,2,4]triazol-1-yl-benzylamine 61 using
a procedure similar to that described for the preparation of 6.
1H NMR (CDCl3, 400 MHz): δ 8.36 (s, 1H), 8.10 (s, 1H), 8.02
(br s, 1H), 7.86 (br s, 1H), 7.60 (d, J ) 2.2 Hz, 1H), 7.48 (t, J
) 6.2 Hz, 1H), 7.33 (m, 1H), 7.21 (m, 5H), 6.04 (d, J ) 7.7 Hz,
1H), 4.63 (s, 2H), 4.30 (d, J ) 6.2 Hz, 2H), 4.27 (s, 2H), 2.37
(s, 3H). HRMS ES: calculated for C24H23ClN6O4S, 527.1263;
found, 527.1251.
2-{6-Ch lor o-3-[2,2-d iflu or o-2-(1-oxy-p yr id in -2-yl)eth yl-
a m in o]-2-oxo-2H-p yr a zin -1-yl}-N-(5-ch lor o-2-[1,2,4]tr ia -
zol-1-yl-ben zyl)a ceta m id e Tr iflu or oa cetic Acid Sa lt (23).
Compound 23 was prepared from {6-chloro-3-[2,2-difluoro-2-
(1-oxy-pyridin-2-yl)ethylamino]-2-oxo-2H-pyrazin-1-yl}acetic
acid21 and 5-chloro-2-[1,2,4]triazol-1-yl-benzylamine 61 using
a procedure similar to that described for the preparation of 6.
1H NMR (CD3OD, 400 MHz): δ 8.77 (s, 1H), 8.36 (d, J ) 6.2
Hz, 1H), 8.19 (s, 1H), 7.69 (dd, J ) 8 Hz, J ) 2.4 Hz, 1H),
7.59-7.43 (m, 5H), 6.69 (s, 1H), 4.79 (s, 2H), 4.55 (t, J ) 13
1-(2(R)-Am in o-3-ph en ylpr opion yl)pyr r olidin e-2(S)-car -
boxylic Acid 2-[1,2,4]Tr ia zol-1-yl-ben zyla m id e (30). A
solution of Boc-D-Phe-Pro-OH (60 mg, 0.16 mmol), 2-[1,2,4]-
triazol-1-yl-benzylamine 59 (37 mg, 0.21 mmol), 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.24
mmol), 1-hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol), and
Hz, 2H), 4.31 (s, 2H). HRMS ES: calculated for C22H18
Cl2F2N8O3, 551.0920; found, 551.0925.
-
2-[3-(2,2-Diflu or o-2-p yr id in -2-yl-eth yla m in o)-2-oxo-2H-
pyr azin -1-yl]-N-(2-[1,2,4]tr iazol-1-yl-ben zyl)acetam ide (24).
Compound 24 was prepared from [3-(2,2-difluoro-2-pyridin-2-