2714 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 14
Barrow et al.
The following examples were prepared essentially as de-
scribed above. Compounds that were not solid as the free base
were treated with 1 N etheral HCl in ethyl acetate and the
solvent removed in vacuo to give the mono- or di-HCl salt as
indicated by C,H,N analysis. Racemic compounds were re-
solved to give individual enantiomers (35&36, 37&38, 39&40)
by preparative chiral HPLC (Chiralpak AD, 70:30 0.1% di-
ethylamine in hexane:ethanol).
3.29-3.17 (m, 1H), 3.03-2.84 (m, 2H), 2.74-2.67 (m, 1H),
2.50-2.26 (m, 2H), 2.12-1.94 (m, 2H), 1.90-1.75 (m, 2H),
1.70-1.40 (m, 4H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-m et h oxym et h yl-2-oxo-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(2-
cya n op h en yl)p ip er id in -1-yl]p r op yl}a m id e h yd r och lo-
1
r id e (44): H NMR (CD3OD, 300 MHz) δ 7.79-7.67 (m, 2H),
7.55-7.41 (m, 2H), 7.33-7.13 (m, 3H), 5.44 (s, 1H), 4.35 (s,
2H), 3.66-3.50 (m, 3H), 3.42 (s, 3H), 3.39-3.23 (m, 2H), 3.20-
3.06 (m, 2H), 3.05-2.93 (m, 2H), 2.22-2.03 (m, 4H), 1.96-
1.85 (m, 2H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-1,6-d im eth yl-2-oxo-1,2,3,4-
tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(4-flu or o-
ph en yl)piper idin -1-yl]pr opyl}am ide (35): 1H NMR (CDCl3,
300 MHz) δ 7.55 (br s, 1H),7.35-6.95 (m, 7H), 5.45 (br s, 1H),
5.25 (br s, 1H), 3.60-3.44 (m, 1H), 3.30-3.15 (m, 1H), 3.15 (s,
3H), 3.10-2.95 (m, 1H), 2.85-2.65 (m, 1H), 2.60-2.30 (m, 3H),
(4R)-4-(3,4-Diflu or op h en yl)-2-oxo-1,2,3,4-t et r a h yd r o-
p yr im id in e-5-ca r boxylic a cid {3-[4-(4-flu or op h en yl)p ip -
er id in -1-yl]p r op yl}a m id e (45): 1H NMR (CD3OD, 300 MHz)
δ 7.29-6.97 (m, 7H), 5.43 (s, 1H), 3.23-3.18 (m, 2H), 2.99-
2.96 (m, 2H), 2.53-2.50 (m, 1H), 2.29-2.26 (m, 2H), 2.07-
1.99 (m, 2H), 1.77-1.64 (m, 6H). Anal. C,H,N.
2.18 (s, 3H), 1.80-1.30 (m, 8H); optical rotation [R]23 -97 (c
D
) 0.18, CDCl3). Anal. C,H,N.
(4S)-4-(3,4-Diflu or op h en yl)-1,6-d im eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic a cid {3-[4-(4-flu o-
r op h en yl)p ip er id in -1-yl]p r op yl}a m id e (36): 1H NMR
(CDCl3, 300 MHz) δ 7.55 (br s, 1H),7.35-6.95 (m, 7H), 5.45
(br s, 1H), 5.25 (br s, 1H), 3.60-3.44 (m, 1H), 3.30-3.15 (m,
1H), 3.15 (s, 3H), 3.10-2.95 (m, 1H), 2.85-2.65 (m, 1H), 2.60-
2.30 (m, 3H), 2.18 (s, 3H), 1.80-1.30 (m, 8H); optical rotation
(4R)-4-(3,4-Diflu or op h en yl)-6-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r b oxylic a cid {3-[4-(4-flu or o-
p h en yl)p ip er id in -1-yl]p r op yl}a m id e
h yd r och lor id e
(46): 1H NMR (CD3OD, 300 MHz) δ 7.31-7.04 (m, 7H), 5.37
(s, 1H), 3.54-3.40 (m, 2H), 3.05-2.93 (m, 4H), 2.18 (s, 3H),
2.01-1.87 (m, 4H). Anal. C,H,N.
[R]23 +88 (c ) 0.22, CDCl3). Anal. C,H,N.
D
(4R)-4-(3,4-Diflu or op h en yl)-2-oxo-6-t r iflu or om et h yl-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(4-
flu or op h en yl)p ip er id in -1-yl]p r op yl}a m id e h yd r och lo-
(4R)-4-(3,4-Diflu or oph en yl)-1,3,6-tr im eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic a cid {3-[4-(4-flu o-
r op h en yl)p ip er id in -1-yl]p r op yl}a m id e (37): 1H NMR (DM-
SO-d6, 300 MHz) δ 9.85 (br s, 1H), 8.05 (br s, 1H), 7.50-7.00
(m, 7H), 5.25 (s, 1H), 3.60-2.70 (m, 9H), 3.10 (s, 3H), 2.75 (s,
1
r id e (47): H NMR (CD3OD, 300 MHz) δ 7.35-7.21 (m, 7H),
5.38 (s, 1H), 3.60-3.57 (m, 2H), 3.20-2.91 (m, 6H), 2.19-1.82
(m, 6H). Anal. C,H,N.
3H), 2.15 (s, 3H), 2.10-1.70 (m, 6H); optical rotation [R]23
-30 (c ) 0.12, MeOH). Anal. C,H,N.
D
(4R)-4-(3,4-Diflu or op h en yl)-6-m et h oxym et h yl-2-oxo-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(4-
flu or op h en yl)p ip er id in -1-yl]p r op yl}a m id e (48): 1H NMR
(CDCl3, 300 MHz) δ 7.21-6.89 (m, 7H), 5.65 (s, 1H), 5.43 (s,
1H), 4.54-4.49 (d, 1H, J ) 13.92 Hz), 4.36-4.31 (d, 1H, J )
13.91 Hz), 3.42 (s, 3H), 3.36-3.17 (m, 1H), 2.96-2.93 (d, 1H,
J ) 10.25 Hz), 2.86-2.82 (d, 1H, J ) 10.74), 2.51-2.24 (m,
3H), 2.05-1.52 (m, 10H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-2-oxo-1,2,3,4-t et r a h yd r o-
p yr im id in e-5-ca r b oxylic a cid {3-[4-(2-cya n o-4-flu or o-
p h en yl)p ip er id in -1-yl]p r op yl}a m id e h yd r och lor id e (49):
1H NMR (CD3OD, 300 MHz) δ 7.61-7.46 (m, 3H), 7.31-7.20
(m, 3H), 5.43 (s, 1H), 3.42-3.39 (m, 1H), 3.26-2.87 (m, 5H),
2.13-1.83 (m, 6H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(2-cya n o-4-
flu or op h en yl)p ip er id in -1-yl]p r op yl}a m id e (50): 1H NMR
(CDCl3, 300 MHz) δ 7.45-7.36 (m, 3H), 7.22-7.03 (m, 3H),
6.93 (s, 1H), 5.55 (s, 1H), 5.47 (s, 1H), 4.77 (s, 1H), 3.51-3.40
(m, 1H), 3.28-3.15 (m, 1H), 3.04-2.87 (m, 2H), 2.83-2.75 (m,
1H), 2.45-2.29 (m, 2H), 2.13 (s, 3H), 2.10-1.96 (m, 2H), 1.94-
1.83 (m, 1H), 1.82-1.72 (m, 1H), 1.70-1.48 (m, 4H). Anal.
C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-t r iflu or om et h yl-2-oxo-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(2-
c y a n o -4-flu o r o p h e n y l)p ip e r id in -1-y l]p r o p y l}a m id e
(51): 1H NMR (CDCl3, 300 MHz) δ 7.39-7.07 (m, 8H), 5.74
(s, 1H), 5.55 (s, 1H), 3.41-3.29 (m, 1H), 3.28-3.17 (m, 1H),
3.03-2.86 (m, 2H), 2.74-2.67 (m, 1H), 2.50-2.28 (m, 2H),
2.12-1.94 (m, 2H), 1.90-1.72 (m, 2H), 1.70-1.41 (m, 4H).
Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-2-oxo-1,2,3,4-t et r a h yd r o-
p yr im id in e-5-ca r b oxylic a cid [3-(3′,4′,5′,6′-t et r a h yd r o-
2′H-[2,4′]bip yr id in yl-1′-yl)p r op yl]a m id e d ih yd r och lor id e
(52): 1H NMR (CD3OD, 300 MHz) δ 8.79-8.77 (m, 1H), 8.56-
8.53 (m, 1H), 8.00-7.92 (m, 2H), 7.31-7.19 (m, 3H), 5.44 (s,
1H), 4.28-4.23 (m, 1H), 3.70-3.64 (m, 1H), 3.50-3.05 (m, 6H),
2.38-1.85 (m, 6H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r b oxylic a cid [3-(3′,4′,5′,6′-t et -
r a h yd r o-2′H-[2,4′]bip yr id in yl-1′-yl)p r op yl]a m id e (53): 1H
NMR (CDCl3, 300 MHz) δ 8.97 (br s, 1H), 8.82 (d, 1H, J ) 4
Hz), 8.56 (br s, 1H), 7.63 (t, 1H, J ) 7 Hz), 7.25-7.04 (m, 5H),
6.26 (br s, 1H), 5.64 (d, 1H, J ) 5 Hz), 3.68-3.60 (m, 1H),
3.38-3.26 (m, 1H), 3.17-3.02 (m, 2H), 2.77-2.50 (m, 3H), 2.31
(4S)-4-(3,4-Diflu or oph en yl)-1,3,6-tr im eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic a cid {3-[4-(4-flu o-
r op h en yl)p ip er id in -1-yl]p r op yl}a m id e (38): 1H NMR (DM-
SO-d6, 300 MHz) δ 9.85 (br s, 1H), 8.05 (br s, 1H), 7.50-7.00
(m, 7H), 5.25 (s, 1H), 3.60-2.70 (m, 9H), 3.10 (s, 3H), 2.75 (s,
3H), 2.15 (s, 3H), 2.10-1.70 (m, 6H); optical rotation [R]23
+40 (c ) 0.1, MeOH). Anal. C,H,N.
D
(4R)-4-(3,4-Diflu or op h en yl)-1-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-cya n o-4-(4-
flu or op h en yl)p ip er id in -1-yl]p r op yl}a m id e h yd r och lo-
1
r id e (39): H NMR (CDCl3, 300 MHz) δ 7.46-7.40 (m, 2H),
7.20-7.11 (m, 5H), 6.95 (s, 1H), 5.95 (s, 1H), 5.43 (s, 1H), 5.26
(s, 1H), 3.31-3.27 (m, 2H), 2.97-2.90 (m, 2H), 2.45-2.38 (m,
4H), 2.01-1.89 (m, 4H); optical rotation [R]23D -16.80 (c ) 0.25,
CH3OH). Anal. C,H,N.
(4S)-4-(3,4-Diflu or op h en yl)-1-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-cya n o-4-(4-
flu or op h en yl)p ip er id in -1-yl]p r op yl}a m id e (40): 1H NMR
(CDCl3, 300 MHz) δ 7.46-7.40 (m, 2H), 7.20-7.11 (m, 5H),
6.95 (s, 1H), 5.95 (s, 1H), 5.43 (s, 1H), 5.26 (s, 1H), 3.31-3.27
(m, 2H), 2.97-2.90 (m, 2H), 2.45-2.38 (m, 4H), 2.01-1.89 (m,
4H); optical rotation [R]23 +39.84 (c ) 0.26, CH3OH). Anal.
D
C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-2-oxo-1,2,3,4-t et r a h yd r o-
p yr im id in e-5-ca r boxylic a cid {3-[4-(2-cya n op h en yl)p ip -
er id in -1-yl]p r op yl}a m id e (41): 1H NMR (CD3OD, 300 MHz)
δ 7.69-7.62 (m, 2H), 7.49-7.46 (m, 1H), 7.40-7.37 (m, 1H),
7.25-7.13 (m, 3H), 5.43 (s, 1H), 3.24-3.22 (m, 2H), 3.05-2.97
(m, 3H), 2.35-2.32 (m, 2H), 2.12-2.08 (m, 2H), 1.85-1.66 (m,
6H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-m eth yl-2-oxo-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r b oxylic a cid {3-[4-(2-cya n o-
p h en yl)p ip er id in -1-yl]p r op yl}a m id e (42): 1H NMR (CDCl3,
300 MHz) δ 7.65-7.52 (m, 2H), 7.34-7.25 (m, 2H), 7.22-7.00
(m, 5H), 5.47 (br s, 2H), 3.51-3.40 (m, 1H), 3.28-3.18 (m, 1H),
3.04-2.88 (m, 2H), 2.84-2.75 (m, 1H), 2.50-2.31 (m, 2H), 2.12
(s, 3H), 2.11-1.96 (m, 2H), 1.94-1.84 (m, 1H), 1.82-1.72 (m,
1H), 1.70-1.52 (m, 4H). Anal. C,H,N.
(4R)-4-(3,4-Diflu or op h en yl)-6-t r iflu or om et h yl-2-oxo-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid {3-[4-(2-
cya n op h en yl)p ip er id in -1-yl]p r op yl}a m id e (43): 1H NMR
(CDCl3, 300 MHz) δ 7.66-7.52 (m, 2H), 7.48 (br s, 1H), 7.34-
7.08 (m, 6H), 5.70 (br s, 1H), 5.56 (s, 1H), 3.40-3.30 (m, 1H),