5478 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 25
Ward et al.
(m, 4H), 3.41-3.30 (m, 4H), 1.69-1.51 (m, 3H), 1.50 (d, J )
8.0 Hz, 3H), 0.97-0.93 (m, 6H); MS (ESI) m/z 297 (M + H).
Anal. (C14H24N4O3) C, H, N.
1.47 (m, 3H), 0.95-0.88 (m, 6H); MS (ESI) m/z 441 (M + H).
Anal. (C20H26N4O3Cl2) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(1R-Cya n o-3-p h e-
n ylp r op ylca r ba m oyl)-3-m eth ylbu tyl}a m id e (20). Amide
20 was prepared by an appropriate modification of Method A.
1H NMR 400 MHz (CDCl3) δ 7.44 (d, J ) 8.5 Hz, 1H), 7.31 (t,
J ) 7.3 Hz, 2H), 7.23 (t, J ) 7.5 Hz, 1H), 7.19 (d, J ) 7.0 Hz,
2H), 4.77-4.69 (m, 2H), 4.33-4.27 (m, 1H), 3.70-3.68 (m, 4H),
3.38-3.35 (m, 4H), 2.86-2.77 (m, 2H), 2.19-2.11 (m, 2H),
1.74-1.64 (m, 2H), 1.55-1.48 (m, 1H), 0.95 (d, J ) 6.0 Hz,
3H), 0.92 (d, J ) 6.5 Hz, 3H); MS (ESI) m/z 387 (M + H). Anal.
(C21H30N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid {1S-[(1-Cya n o-1-m eth -
yl)eth ylca r ba m oyl]-3-m eth ylbu tyl}a m id e (21). Amide 21
was prepared by an appropriate modification of Method C. 1H
NMR 400 MHz (CDCl3) δ 7.91 (s, 1H), 5.82 (d, J ) 8.1 Hz,
1H), 4.32 (ddd, J ) 8.1, 8.1, 6.0 Hz, 1H), 3.69-3.60 (m, 4H),
3.38-3.30 (m, 4H), 1.70-1.50 (m, 9H), 0.95 (d, J ) 9.8 Hz,
3H), 0.92 (d, J ) 9.8 Hz, 3H); MS (ESI) m/z 311 (M + H). Anal.
(C15H26N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(2-Ben zyloxy-1R-
cya n o-eth ylca r ba m oyl)-3-m eth ylbu tyl]a m id e (22). Amide
22 was prepared by an appropriate modification of Method A.
1H NMR 400 MHz (CDCl3) δ 7.40-7.31 (m, 5H), 7.09 (d, J )
8.0 Hz, 1H), 5.03-4.99 (m, 1H), 4.72 (d, J ) 7.5 Hz, 1H), 4.65
(d, J ) 11.8 Hz, 1H), 4.60 (d, J ) 11.8 Hz, 1H), 4.34-4.29 (m,
1H), 3.74 (dd, J ) 10.0, 4.0 Hz, 1H), 3.67-3.63 (m, 5H), 3.37-
3.26 (m, 4H), 1.73-1.61 (m, 2H), 1.56-1.51 (m, 1H), 0.95 (t, J
) 5.5 Hz, 6H); MS (ESI) m/z 403 (M + H). Anal. (C21H30N4O4)
C, H, N.
Mor p h olin e-4-ca r b oxylic Acid {1S-[2-(2-Ch lor ob en z-
yloxy)-1R-cya n oet h ylca r b a m oyl]-3-m et h ylb u t yl}a m id e
(23). Amide 23 was prepared by Method A. 1H NMR 400 MHz
(CDCl3) δ 7.50 (dd, J ) 7.0, 2.0 Hz, 1H), 7.39 (dd, J ) 7.3, 1.8
Hz, 1H), 7.32-7.26 (m, 3H), 7.18 (d, J ) 8.5 Hz, 1H), 5.07-
5.03 (m, 1H), 4.75-4.69 (m, 3H), 4.37-4.31 (m, 1H), 3.84 (dd,
J ) 9.5, 4.0 Hz, 1H), 3.73 (dd, J ) 9.5, 4.5 Hz, 1H), 3.69-3.62
(m, 4H), 3.36-3.26 (m, 4H), 1.72-1.64 (m, 2H), 1.57-1.52 (m,
1H), 0.95 (d, J ) 6.0 Hz, 3H), 0.94 (d, J ) 5.5 Hz, 3H); MS
(ESI) m/z 437 (M + H). Anal. (C21H29N4O4Cl) C, H, N.
Mor p h olin e-4-ca r b oxylic Acid {1S-[2-(3-Ch lor ob en z-
yloxy)-1R-cya n oet h ylca r b a m oyl]-3-m et h ylb u t yl}a m id e
(24). Amide 24 was prepared by Method A. 1H NMR 400 MHz
(CDCl3) δ 7.68 (d, J ) 8.0 Hz, 1H), 7.35-7.21 (m, 4H), 5.06-
5.01 (m, 1H), 4.75 (d, J ) 7.5 Hz, 1H), 4.61 (d, J ) 19.5 Hz,
1H), 4.56 (d, J ) 19.5 Hz, 1H), 4.37-4.30 (m, 1H), 3.76-3.73
(m, 1H), 3.68-3.64 (m, 5H), 3.36-3.30 (m, 4H), 1.75-1.52 (m,
3H), 0.95 (t, J ) 6.3 Hz, 6H); MS (ESI) m/z 437 (M + H). Anal.
(C21H29N4O4Cl) C, H, N.
Mor p h olin e-4-ca r b oxylic Acid {1S-[2-(4-Ch lor ob en z-
yloxy)-1R-cya n o-eth ylca r ba m oyl]-3-m eth ylbu tyl}a m id e
(25). 25 was prepared by Method A. 1H NMR 400 MHz (CDCl3)
δ 7.34 (d, J ) 8.0 Hz, 2H), 7.31 (d, J ) 6.0 Hz, 1H), 7.29 (d, J
) 8.0 Hz, 2H), 5.04-5.00 (m, 1H), 4.78 (d, J ) 7.5 Hz, 1H),
4.60 (d, J ) 19.3 Hz, 1H), 4.54 (d, J ) 19.3 Hz, 1H), 4.36-
4.30 (m, 1H), 3.72 (dd, J ) 9.5, 4.0 Hz, 1H), 3.66-3.61 (m,
5H), 3.35-3.28 (m, 4H), 1.71-1.51 (m, 3H), 0.95 (t, J ) 6.5
Hz, 6H); MS (ESI) m/z 437 (M + H). Anal. (C21H29N4O4Cl) C,
H, N.
Mor p h olin e-4-ca r boxylic Acid [1R-(1S-Cya n o-3-p h e-
n yl-p r op ylca r ba m oyl)-3-m eth ylbu tyl}a m id e (26). 26 was
prepared by an appropriate modification of Method B.
1H NMR 400 MHz (CDCl3) δ 7.37 (d, J ) 8.1 Hz, 1H), 7.34-
7.19 (m, 5H), 4.76-4.70 (m, 2H), 4.29 (dt, J ) 8.7, 4.9 Hz, 1H),
3.74-3.65 (m, 4H), 3.41-3.32 (m, 4H), 2.87-2.75 (m 2H),
2.19-2.10 (m, 2H), 1.75-1.48 (m, 3H), 0.95 (d, J ) 6.5 Hz,
3H), 0.92 (d, J ) 6.5 Hz, 3H); MS (ESI) m/z 387 (M + H). Anal.
(C21H30N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(1S-Cya n obu tylca r -
ba m oyl)-3-m eth ylbu tyl]a m id e (13). Amide 13 was prepared
by an appropriate modification of Method C. 1H NMR 400 MHz
(CDCl3) δ 8.11 (d, J ) 8.1 Hz, 1H), 5.31 (d, J ) 7.8 Hz, 1H),
4.80 (q, J ) 8.0 Hz, 1H), 4.41 (q, J ) 7.8 Hz, 1H), 3.70-3.62
(m, 4H), 3.41-3.31 (m, 4H), 1.87-1.40 (m, 7H), 0.97-0.89 (m,
9H); MS (ESI) m/z 325 (M + H). Anal. (C16H28N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(1S-Cya n op en tyl-
ca r ba m oyl)-3-m eth ylbu tyl]a m id e (14). Amide 14 was pre-
1
pared by an appropriate modification of Method C. H NMR
400 MHz (CDCl3) δ 7.90 (d, J ) 8.1 Hz, 1H), 5.22 (d, J ) 7.8
Hz, 1H), 4.77 (q, J ) 8.1 Hz, 1H), 4.35 (dt, J ) 7.8, 5.9 Hz,
1H), 3.75-3.68 (m, 4H), 3.45-3.32 (m, 4H), 1.89-1.55 (m, 5H),
1.50-1.40 (m, 4H), 0.96-0.89 (m, 9H); MS (ESI) m/z 339 (M
+ H). Anal. (C17H30N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(1S-Cya n o-2-m eth -
yl-p r op ylca r ba m oyl)-3-m eth ylbu tyl]a m id e (15). Amide 15
was prepared by an appropriate modification of Method C. 1H
NMR 400 MHz (CDCl3) δ 8.10 (d, J ) 8.2 Hz, 1H), 5.20 (d, J
) 8.0 Hz, 1H), 4.75 (dd, J ) 8.5, 8.1 Hz, 1H), 4.45 (q, J ) 8.0
Hz, 1H), 3.80-3.65 (m, 4H), 3.40-3.29 (m, 4H), 2.01-1.96 (m,
1H), 1.72-1.53 (m, 3H), 1.00 (t, J ) 7.0 Hz, 6H), 0.97-0.91
(m, 6H); MS (ESI) m/z 325 (M + H). Anal. (C16H28N4O3) C, H,
N.
Mor p h olin e-4-ca r b oxylic Acid [1S-(1S-Cya n o-2,2-d i-
m eth ylpr opylcar bam oyl)-3-m eth ylbu tyl]am ide (16). Amide
16 was prepared by an appropriate modification of Method C.
1H NMR 400 MHz (CDCl3) δ 7.95 (d, J ) 8.2 Hz, 1H), 4.99 (d,
J ) 8.1 Hz, 1H), 4.75 (d, J ) 8.2 Hz, 1H), 4.45 (q, J ) 8.0 Hz,
1H), 3.80-3.60 (m, 4H), 3.45-3.35 (m, 4H), 1.80-1.55 (m, 3H),
1.10 (s, 9H), 0.93-0.91 (m, 6H); MS (ESI) m/z 339 (M + H).
Anal. (C17H30N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid {1S-[(Cya n o-p h en yl-S-
m eth yl)ca r ba m oyl]-3-m eth ylbu tyl}a m id e (m a jor isom er )
a n d Mor p h olin e-4-ca r boxylic Acid {1S-[(Cya n op h en yl-
R-m eth yl)ca r ba m oyl]-3-m eth ylbu tyl}a m id e (m in or iso-
m er ) (17). Amide 17 was prepared by an appropriate modi-
fication of Method A in which the phenylglycine residue
epimerized to an inseparable 2 to 1 ratio of diastereomers. 1H
NMR (major isomer) 400 MHz (CDCl3) δ 7.66 (d, J ) 8.0 Hz,
1H), 7.47-7.38 (m, 5H, overlapped with minor isomer), 6.06
(d, J ) 8.2 Hz, 1H), 4.77 (d, J ) 8.3 Hz, 1H), 4.44-4.37 (m,
1H, overlapped with minor isomer), 3.63-3.60 (m, 4H), 3.28-
3.24 (m, 4H), 1.76-1.69 (m, 2H, overlapped with minor
isomer), 1.63-1.52 (m, 1H, overlapped with minor isomer),
0.99-0.77 (m, 6H, overlapped with minor isomer); 1H NMR
(minor isomer) 400 MHz (CDCl3) δ 7.74 (d, J ) 8.4 Hz, 1H),
7.47-7.38 (m, 5H, overlapped with major isomer), 6.03 (d, J
) 8.4 Hz, 1H), 4.75 (d, J ) 8.5 Hz, 1H), 4.44-4.37 (m, 1H,
overlapped with major isomer), 3.70-3.66 (m, 4H), 3.34-3.31
(m, 4H), 1.76-1.69 (m, 2H, overlapped with major isomer),
1.63-1.52 (m, 1H, overlapped with major isomer), 0.99-0.77
(m, 6H, overlapped with major isomer); MS (ESI) m/z 359 (M
+ H). Anal. (C19H26N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid [1S-(1S-Cya n o-2-p h e-
n yleth ylca r ba m oyl)-3-m eth ylbu tyl]a m id e (18). Amide 18
was prepared by an appropriate modification of Method C. 1H
NMR 400 MHz (CDCl3) δ 8.32 (d, J ) 8.0 Hz, 1H), 7.33-7.18
(m, 5H), 5.32 (d, J ) 8.1 Hz, 1H), 4.95 (q, J ) 8.0 Hz, 1H),
4.32 (q, J ) 8.1 Hz, 1H), 3.69-3.61 (m, 4H), 3.39-3.30 (m,
4H), 3.15-3.05 (m, 2H), 1.80-1.60 (m, 3H), 0.95 (d, J ) 9.5
Hz, 3H), 0.92 (d, J ) 9.5 Hz, 3H); MS (ESI) m/z 373 (M + H).
Anal. (C20H28N4O3) C, H, N.
Mor p h olin e-4-ca r boxylic Acid {1S-[1S-Cya n o-2-(3,4-
d ich lor op h en yl)et h ylca r b a m oyl]-3-m et h ylb u t yl}a m id e
(19). Amide 19 was prepared by an appropriate modification
of Method C. 1H NMR 400 MHz (CDCl3) δ 7.45 (d, J ) 8.1 Hz,
1H), 7.41 (d, J ) 8.2 Hz, 1H), 7.36 (d, J ) 2.1 Hz), 7.13 (dd, J
) 8.2, 2.1 Hz, 1H), 5.04 (ddd, J ) 8.3, 7.0, 7.0 Hz, 1H), 4.61
(d, J ) 7.6 Hz, 1H), 4.21 (ddd, J ) 8.5, 8.5, 6.0 Hz, 1H), 3.72-
3.65 (m, 4H), 3.39-3.26 (m, 4H), 3.09-3.03 (m, 2H), 1.72-
Mor p h olin e-4-ca r boxylic Acid [1R-(1S-Cya n o-3-p h e-
n yl-pr opylcar bam oyl)-1,3-dim eth yl-bu tyl]-am ide an d m or -
p h olin e-4-ca r boxylic Acid [1S-(1S-Cya n o-3-p h en yl-p r o-
p ylca r ba m oyl)-1,3-d im eth yl-bu tyl]-a m id e (27). 27 was
prepared as an inseparable mixture of isomers by an appropri-
ate variation of Method B using (D,L)-N-Boc-R-methyl-leucine.