SERINE PROTEASE INHIBITORS

INHIBITEURS DE LA SERINE PROTEASE

English Abstract

The present invention relates to certain substituted oxadiazole, thiadiazole
and triazole peptoids which are useful as inhibitors of serine proteases.

French Abstract

La présente invention concerne certains peptoïdes d'oxadiazol, de thiadiazole et de triazole substitués utiles comme inhibiteurs de la sérine protéases.

Claims

We claim:
1. A compound of the formula:
<IMG>
wherein:
X is O and Y is N;
R1 is isopropyl, n-butyl, tert-butyl; alkyl substituted with one or more
carboxyl, carboalkoxy, amino, alkylamino or dialkylamino groups; alkyl fused
(C9-C10)aryl, alkyl fused arylcycloalkyl, alkyl(aryl)2 or .alpha.,.alpha.-
dialkyl-arylalkyl optionally
comprising 1-4 heteroatoms selected from O, S and N, and optionally
substituted with
halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,
alkyl,
alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or
haloalkylthio; aryl or arylalkyl substituted with alkyl, amino, alkylamino,
dialkylamino, aryl or aryloxy wherein the aryl or aryloxy is optionally
substituted
with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,
alkyl,
alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or
haloalkylthio; aryl or arylalkyl substituted with two more halo, cyano, nitro,
hydroxyl,
haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy,
alkynyl,
alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio,
haloalkylthio, arylcarboxamide, (C5-C6)aryl, or -O-(C5-C6)aryl wherein aryl is
optionally substituted with halo, cyano, vitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;
aryl or
arylalkyl comprising one or more heteroatoms selected from O, S and N; or
cycloalkyl or alkylcycloalkyl optionally comprising one or more heteroatoms
selected
from O, S and N;
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
113

alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -OC(O)-, -NHC(O)- or an amino acid selected from
proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the
sulfur
with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,
homophenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl,
alkenyl or
phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide,
arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or
threonine
optionally substituted with alkyl or aryl; histidine, methionine, valine,
norvaline,
norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,
ornithine and
lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from N, O and S; and
R4 is benzyl.
2. A compound of claim 1 wherein R4-A- is benzyloxycarbonyl.
3. A compound of claim 2 wherein R1 is arylalkyl.
4. A compound of claim 3 wherein R1 is 3,5-dimethylbenzyl.
114

5. The compound of claim 4: (Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-
dimethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
6. A compound of claim 3 wherein R1 is 3,5-dimethoxybenzyl.
7. The compound of claim 6: (Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-
dimethoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
8. A compound of claim 3 wherein R1 is 3,5-ditrifluoromethylbenzyl.
9. The compound of claim 8: (Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-
ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
10. A compound of claim 3 wherein R1 is 3-methylbenzyl.
11. The compound of claim 10:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-
methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
12. A compound of claim 3 wherein R1 is 4-phenylbenzyl.
13. The compound of claim 12:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4-
phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
14. A compound of claim 3 wherein R1 is 3-phenylbenzyl.
15. The compound of claim 14:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-
phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
16. A compound of claim 3 wherein R1 is 3-phenoxybenzyl.
17. The compound of claim 16:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-
phenoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
18. A compound of claim 3 wherein R1 is 3,5-diphenylbenzyl.
19. The compound of claim 18:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-
diphenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
20. A compound of claim 3 wherein R1 is 4-dimethylaminobenzyl.
115

21. The compound of claim 20:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4-
dimethylaminobenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
22. A compound of claim 2 wherein R1 is alkyl(aryl)2.
23. A compound of claim 22 wherein R1 is diphenylmethine.
24. The compound of claim 23:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(diphenylmethine)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
25. A compound of claim 2 wherein R1 is .alpha.,.alpha.-dialkyl-arylalkyl.
26. A compound of claim 25 wherein R1 is .alpha.,.alpha.-dimethyl-(3-
trifluoromethyl)benzyl.
27. The compound of claim 26:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(.alpha.,.alpha.-
dimethyl-[3-trifluoromethyl]benzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]-L-prolinamide.
28. A compound of claim 2 wherein R1 is alkyl fused (C9-C10)aryl.
29. A compound of claim 28 wherein R1 is 1-napthylmethylene.
30. The compound of claim 29:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(1-
napthylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
31. A compound of claim 28 wherein R1 is 2-napthylmethylene.
32. The compound of claim 31:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(2-
napthylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
33. A compound of claim 2 wherein R1 is alkyl fused arylcycloalkyl.
34. A compound of claim 33 wherein R1 is 3,4-methylenedioxybenzyl.
35. The compound of claim 34:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-
methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
36. A compound of claim 2 wherein R1 is arylalkyl comprising one or more
heteroatoms.
37. A compound of claim 36 wherein R1 is 3-pyridylmethylene.
116

38. The compound of claim 37:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-
pyridylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
39. A compound of claim 2 wherein R1 is alkylcycloalkyl comprising one or more
heteroatoms.
40. A compound of claim 39 wherein R1 is morpholino-N-ethylene.
41. The compound of claim 40:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(morpholino-N-ethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
42. A compound of claim 2 wherein R1 is alkyl substituted with dialkylamine.
43. A compound of claim 42 wherein R1 is dimethylamino-N-ethylene.
44. The compound of claim 43:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(dimethylamino-N-ethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]-L-prolinamide.
45. A compound of claim 2 wherein R1 is alkyl substituted with carboalkoxy.
46. A compound of claim 45 wherein R1 is carbomethoxyethylene.
47. The compound of claim 46:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(carbomethoxyethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
48. A compound of claim 2 wherein R1 is alkylcycloalkyl.
49. A compound of claim 48 wherein R1 is adamantylmethylene.
50. The compound of claim 49:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(adamantylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
51. A compound of claim 48 wherein R1 is cyclohexylmethylene.
52. The compound of claim 51:(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-
(cyclohexylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
53. A compound of the formula:
<IMG>

wherein:
X is O and Y is N;
R1 is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano,
nitro,
hydroxyl, haloalkyl, amino, alkylamino, dialkylamino, alkylenedioxy, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O-(C5-
C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; cycloalkyl,
cycloalkenyl,
alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C5-C12)aryl, (C5-
C12)arylalkyl,
(C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl-fused (C5-C12)-
arylcycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S,
and
optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide,
alkylthio or haloalkylthio.
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -C(O)-, -NHC(O)-, -S(O)2-, -NH-S(O)2-, -OC(O)-, -C- or
proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the
sulfur
with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, vitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,
homophenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl,
alkenyl or
phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino,
aminoalkyl,
118

dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide,
arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or
threonine
optionally substituted with alkyl or aryl; histidine, methionine, valine,
norvaline,
norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,
ornithine and
lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from N, O and S; and
R4 is H, alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5-
C12)aryl,
(C5 or C7-C12)arylalkyl, fused (C5-C12)aryl-cycloalkyl or fused alkyl (C5-
C12)aryl-
cycloalkyl optionally comprising one or more heteroatoms selected from N, O
and S,
and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, vitro,
hydroxyl,
haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or
haloalkylthio.
54. A compound of claim 53 wherein R1 is optionally substituted arylalkyl.
55. A compound of claim 54 wherein R1 is 3-trifluoromethylbenzyl.
56. A compound of claim 55 wherein -A- is -C(O)-.
57. A compound of claim 56 wherein R4 is pyridinyl.
58. The compound of claim 57:3-Pyridylcarbonyl-L-valyl-N-[1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
59. A compound of claim 55 wherein A is -OC(O)-.
60. A compound of claim 59 wherein R4 is methyl.
61. The compound of claim 60:Methyloxycarbonyl-L-valyl-N-[1-(3-[5-(3
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
62. A compound of claim 59 wherein R4 is isopropyl.
63. The compound of claim 63:Isopropyloxycarbonyl-L-valyl-N-[1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
119

64. A compound of claim 56 wherein R4 is 4-pyridinylmethylene.
65. The compound of claim 64:4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(3-
[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]-L-prolinamide.
66. A compound of claim 55 wherein A is -S(O)2-.
67. A compound of claim 66 wherein R4 is alkyl.
68. A compound of claim 67 wherein R4 is methyl.
69. The compound of claim 68: Methylsulfonyl-L-valyl-N-[1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
70. A compound of the formula:
<IMG>
wherein:
X is N and Y is O;
R1 is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano,
nitro,
hydroxyl, haloalkyl, amino, alkylamino, dialkylamino, alkylenedioxy, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, or -O-
(C5-
C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; cycloalkyl,
cycloalkenyl,
alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C5-C12)aryl, (C5-
C12)arylalkyl,
(C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl, or alkyl-fused (C5-C12)-
arylcycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S,
and
optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide,
alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
120

alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R o or RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and
R o
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -C(O)-, -NHC(O)-, -S(O)2-, -NH-S(O)2-, -OC(O)-, -C- or
an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine
optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally
substituted
with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,
alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,
alkylthio or
haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine,
indoline-2-
carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally
substituted with
alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan,
tyrosine,
serine or threonine optionally substituted with alkyl or aryl; histidine,
methionine,
valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine,
glutamine, ornithine and lysine optionally substituted at the side chain
nitrogen with
alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,
dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl,
cycloalkyl,
alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl
optionally
comprising 1 or more heteroatoms selected from N, O and S; and
R4 is H, alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5-
C12)aryl,
(C5-C12)arylalkyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-
cycloalkyl
optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally
substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl,
haloalkyl,
alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy,
alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or
haloalkylthio.
121

71. A compound of claim 70 wherein -A- is -OC(O)-.
72. A compound of claim 71 wherein R4- is benzyl.
73. A compound of claim 72 wherein R1 is alkyl fused aryl-cylcoalkyl.
74. A compound of claim 73 wherein R1 is 3,4-methylenedioxybenzyl.
75. The compound of claim 74:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3,4-
methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
76. A compound of claim 73 wherein R1 is alkyl.
77. A compound of claim 76 wherein R1 is methyl.
78. The compound of claim 77:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-methyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
79. A compound of claim 72 wherein R1 is dialkylamino.
80. A compound of claim 79 wherein R1 is dimethylamino.
81. The compound of claim 80:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-
dimethylamino-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropylj-L-
prolinamide.
82. A compound of claim 72 wherein R1 is arylalkyl.
83. A compound of claim 82 wherein R1 is 3-methylbenzyl.
84. A compound of claim 83:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
85. A compound of claim 83 wherein R2 and R3 are alkyl.
86. A compound of claim 85 wherein R2 and R3 are each methyl.
87. A compound of claim 86:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-1-methylethyl]-L-prolinamide.
88. A compound of claim 72 wherein R1 is benzyl optionally substituted with
haloalkyl.
89. A compound of claim 88 wherein R1 is benzyl optionally substituted with
trifluoromethyl.
90. A compound of claim 89:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[S-(3-
trifluoromethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
122

91. A compound of claim 72 wherein R1 is benzyl optionally substituted with
dialkylamino.
92. A compound of claim 91 wherein R1 is benzyl optionally substituted with
dimethylamino.
93. A compound of claim 92:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(4-
dimethylaminobenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
94. A compound of claim 72 wherein R1 is alkyl-fused aryl.
95. A compound of claim 94 wherein R1 is napthylmethylene.
96. A compound of claim 95:(Benzyloxycarbonyl)-L-valyl-N-[1-(2-(5-(1-
napthylmethylene)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
97. A compound of claim 70 wherein R1 is arylalkyl.
98. A compound of claim 97 wherein R1 is 3-methylbenzyl.
99. A compound of claim 98 wherein R4-A- is 3-pyridylcarbonyl.
100. The compound of claim 99:3-Pyridylcarbonyl-L-valyl-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
101. A compound of claim 98 wherein A is -OC(O)-.
102. A compound of claim 101 wherein R4 is methyl.
103. The compound of claim 102:Methyloxycarbonyl-L-valyl-N-[1-(2-[5-(3
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
104. A compound of claim 101 wherein R4 is isopropyl.
105. The compound of claim 104:Isopropyloxycarbonyl-L-valyl-N-(1-(2-[5-(3
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L
prolinamide.
106. A compound of claim 101 wherein R4- is 4-pyridylmethylene.
107. The compound of claim 106:4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-
(3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
108. A compound of claim 98 wherein A is -S(O)2-.
109. A compound of claim 108 wherein R4 is alkyl.
110. A compound of claim 109 wherein R4 is methyl.
123

111. The compound of claim 110: Methylsulfonyl-L-valyl-N-[1-(3-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
112. A compound of claim 108 wherein R4 is aryl.
113. A compound of claim 112 wherein R4 is phenyl.
114. The compound of claim 113: Phenylsulfonyl-L-valyl-N-[1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
115. A compound of claim 70 wherein A is -S(O)2-.
116. A compound of claim 115 wherein R4 is alkyl.
117. A compound of claim 116 wherein R4 is methyl.
118. A compound of claim 117 wherein R1 is .alpha.,.alpha.-dialkyl-arylalkyl.
119. A compound of claim 118 wherein R1 is .alpha.,.alpha.-dimethylbenzyl.
120. The compound of claim 119: Methylsulfonyl-L-valyl-N-[1-(3-[5-
(.alpha.,.alpha.-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide.
121. A compound of claim 117 wherein R1 is alkyl.
122. A compound of claim 121 wherein R1 is tert-butyl.
123. The compound of claim 122: Methylsulfonyl-L-valyl-N-[1-(3-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S}-methylpropyl]-L-prolinamide.
124. A compound of the formula:
<IMG>
124

wherein:
X and Y are independently O, S or N, wherein N is optionally substituted with
alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl,
arylalkyl or
arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S,
and
optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that
at least
one of X or Y is N;
R1 is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano,
nitro,
hydroxyl, haloalkyl, amino, alkylamino, dialkylamino, alkylenedioxy, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O-(C5-
C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; cycloalkyl,
cycloalkenyl,
alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C5-C12)aryl, (C5-
C12)arylalkyl,
(C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl-fused
(C5-C12)-arylcycloalkyl optionally comprising 1-4 heteroatoms selected from N,
O and S, and
optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide,
alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -
RCOOR', -RNR'R"R o or RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R
o
are independently H, alkyl, alkenyl, cycloalkyl or (CS-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
B is -S(O)2- or -C(O)-; and
R6 is of the formula:
125

<IMG>, <IMG> , <IMG>,
<IMG> , <IMG> , <IMG>
wherein:
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R o or RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and
R o
are independently H, alkyl, alkenyl, cycloalkyl or (CS-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio,
amino, alkylamino, dialkylamino, or aryl, arylalkyl, fused aryl, fused aryl-
cycloalkyl
or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N
and S,
and optionally substituted with halo or alkyl;
R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or cycloalkyl,
aryl,
arylalkyl, aryloxycarboxamide, arylalkyloxycarboxamide or fused arylcycloalkyl
126

optionally comprising 1 or more heteratoms selected from N, O and S and
optionally
substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,
carboxy,
alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,
arylcarboxamide,
arylalkylcarboxamide, alkylthio or haloalkylthio;
R15 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino, or aryl, arylalkyl, fused aryl-cycloalkyl, alkyl-
fused
aryl-cycloalkyl, alkyl-fused aryl, cycloalkyl or alkylcycloalkyl optionally
comprising 1 or
more heteroatoms selected from O, N, or S; and
W is O or S; or C or N is optionally substituted with alkyl, aryl.
125. A compound of claim 124 wherein R6 is of formula (I).
126. A compound of claim 125 wherein R14 is amino.
127. The compound of claim 126: (2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-
[3,2,1 ]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methybenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
128. A compound of claim 124 wherein R6 is of formula (II).
129. A compound of claim 128 wherein R13 is optionally substituted aryl or
arylalkyl optionally comprising a heteroatom.
130. A compound of claim 129 wherein R13 is optionally substituted phenyl or
benzyl.
131. A compound of claim 130 wherein R13 is phenyl or benzyl.
132. The compound of claim 131: 2-Oxo-5-phenyl-1,4-benzodiazepine-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
133. A compound of claim 130 wherein R13 is phenyl or benzyl substituted with
halo, haloalkyl or alkoxy.
134. The compound of claim 133:
2-Oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-Oxo-5-(4-trifluoromethylphenyl)-1,4 benzodiazepine-N-(1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide:
135. A compound of claim 130 or 131 wherein R14 is H, amino or
benzyloxycarbonylamino.
127

136. The compound of claim 135: 3-(R,S)-Amino-2-oxo-5-phenyl-1,4-
benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(R,S)-methylpropyl]acetamide.
137. A compound of claim 135 wherein R15 is H, halo or dialkylamino.
138. The compound of claim 137:
3-(R,S)-Amino-2-oxo-5-phenyl-1,4-(2'-chlorobenzodiazepine)-N-[1-
(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide; or
2-Oxo-5-phenyl-1,4-(2'-dimethylaminobenzodiazepine)-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
139. A compound of claim 137 wherein R13 is phenyl or benzyl substituted with
halo, haloalkyl or alkoxy.
140. The compound of claim 139:
(R,S)-3-Amino-2-oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-
[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide; (R,S)-3-amino-2-oxo-5-(2-chlorophenyl)-1,4-
(2'-chlorobenzodiazepine)-N-[1-(2-(5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;
(R,S)-3-benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-1,4-(2'-
chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]
carbonyl)-2-(R,S)-methylpropyl]acetamide; or
3-(R,S)-Amino-2-oxo-5-(2-chlorophenyl)-1,4-(2'-
chlorobenzodiazepine)-N-[1-(2-(5-(3-methylbenzyl}-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
141. A compound of claim 129 wherein R13 is pyridyl.
142. A compound of claim 141 wherein R14 is H, amino or
benzyloxycarbonylamino.
143. The compound of claim 142:
3-(R,S)-Amino-2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
or
2-Oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-(5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
144. A compound of claim 128 wherein R13 is piperidinyl.
128

145. A compound of claim 144: 2-Oxo-5-(4-piperidinyl)-1,4-benzodiazepine-N-[1-
(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl] acetamide.
146. A compound of claim 128 wherein R13 is alkyl.
147. A compound of claim 146 wherein R13 is methyl
148. A compound of claim 147 wherein R14 is H, amino or
benzyloxycarbonylamino.
149. A compound of claim 148: 3-(R,S)-Amino-2-oxo-5-methyl-1,4-
benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(R,S)-methylpropyl]acetamide.
150. A compound of claim 128 wherein R13 is fused aryl-cycloalkyl optionally
comprising one or more heteroatoms.
151. A compound of claim 150 wherein R13 is 3,4-methylenedioxyphenyl.
152. A compound of claim 151 wherein R14 is H, amino or
benzyloxycarbonylamino.
153. A compound of claim 152: 2-Oxo-5-(3,4-methylendioxyphenyl)-1,4-
benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(S)-methylpropyl]acetamide.
154. A compound of claim 124 wherein R6 is of formula (IV).
155. A compound of claim 154 wherein R13 is alkyl.
156. A compound of claim 155 wherein R13 is methyl.
157. A compound of claim 156 wherein R14 is H, amino or
benzyloxycarbonylamino.
158. A compound of claim 157: 3-(R,S)-Amino-2-oxo-5-methyl-1,4-(2',3'-
methylenedioxy)-benzodiazepine)-N-[1-(2-[5-(3-methybenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
159. A compound of claim 124 wherein R6 is of formula (VI).
160. A compound of claim 159 wherein W is S.
161. A compound of claim 160 wherein R15 is H, aryl or arylalkyl.
162. A compound of claim 161 wherein R15 is benzyl or phenyl.
163. A compound of claim 162 wherein R13 is alkyl.
164. A compound of claim 163 wherein R13 is methyl.
165. A compound of claim 164 wherein R14 is H, amino or
benzyloxycarbonylamino.
129

166. A compound of claim 165: 3-(R,S)-Amino-2-oxo-5-methyl-1,4-(1-
thiophenodiazepine)-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-
2-(S)-methylpropyl]acetamide.
167. A compound of the formula:
<IMG>
wherein
X and Y are independently O, S or N, wherein N is optionally substituted with
alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl,
arylalkyl or
arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S,
and
optionally subsituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that
at least
one of X or Y is N;
R1 is alkyl, alkenyl or alkynyl optionally substituted with 1 or more,
preferably
1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino,
alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or
-O-(C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl,
alkylcycloalkyl,
alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-
C12)aryl,
(C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl
fused
(C5-C12)aryl-cycolalkyl optionally comprising 1-4 heteroatoms selected from N,
O
and S, and optionally substituted with halo, cyano, nitro, hydroxyl,
haloalkyl, amino,
aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy,
carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R° or RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
130

heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
B is -S(O)2-, -C(O)-, -OC(O)- or -CH2-C(O)-; and
R6 is of formula (I)
<IMG>
wherein m and n are independently 0 or 1;
D is a direct bond or an amino acid selected from proline, isoleucine,
cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl,
alkenyl or
phenyl optionally substituted with halogen, cyano, nitro, haloalkyl, amino,
aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,
indoline-2-carboxylic acid tetrahydrosioquinoline-2-carboxylic acid optionally
substituted with alkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkoxyl, haloalkoxy, carbonyl, carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkythio; tryptophan,
valine,
norvaline, norleucine, octahydroindole-2-carboxylic acid; or lysine optionally
substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl,
alkoxyalkyl,
alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl or
alkoxycarbonylalkyl; or cycloalkyl, cycloalkylalkyl, fused aryl-cycloalkyl or
alkyl
fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from
N, O
and S;
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -OC(O)- or -C-; and
R14 is H, alkyl, alkenyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused
aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteratoms selected from N, O and S, and optionally substituted with alkyl,
halo,
131

alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,
haloalkoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or
haloalkylthio; or
R6 is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl.
168. A compound of claim 167 wherein R6 is of formula (I).
169. A compound of claim 168 wherein D is Val.
170. A compound of claim 169 wherein R4-A is Cbz.
171. The compound of claim 170: Benzyloxycarbonyl-L-(1,2,3,4-
tetrahydroisoquinoline)-3-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(R,S)-methylpropyl] amide.
172. A compound of claim 167 wherein R6 is aryl, arylalkyl, cycloalkyl or
cycloalkylalkyl.
173. A compound of claim 172 wherein R6 is arylalkyl.
174. A compound of claim 173 wherein R6-B- is benzyloxycarbonyl.
175. A compound of the formula:
<IMG>
wherein X and Y are independently O, S or N, wherein N is optionally
substituted
with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl,
arylalkyl
or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S,
and
optionally subsituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of
X or Y
is N;
R1 is alkyl, alkenyl or alkynyl optionally substituted with 1 or more,
preferably
1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino,
alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or
-O-(C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl,
alkylcycloalkyl,
alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-
C12)aryl,
(C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl
fused
(C5-C12)aryl-cycolalkyl optionally comprising 1-4 heteroatoms selected from N,
O
132

and S, and optionally substituted with halo, cyano, nitro, hydroxyl,
haloalkyl, amino,
aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy,
carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
-RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-
4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thin, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR',
RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl,
(C5-C12)aryl, (C5-C12)arylalkyl or (C5-Cl2)arylalkenyl optionally comprising 1-
4.
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R11, R12 and E together form a monocyclic or bicyclic ring comprising 5-10
atoms selected from C, N, S and O; said ring containing 1 or more keto groups;
and
optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, alkylthio, haloalkylthio; cycloalkyl, cycloalkylalkyl,
cycloalkylalkenyl, (C5-C12)aryl, (C5-C12)arylalkyl, ((C5-C12)arylalkyl)OC(O)NH-
or
133

(C5-C12)arylalkenyl optionally comprising one or more heteroatoms selected
from N,
S and non-peroxide O, and optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,
carboxyl, carboalkoxy, -C(O)O(alkyl), -C(O)(alkyl), alkylcarboxamide,
alkylthio or
haloalkylthio.
176. A compound of claim 175 wherein R11, R12 and E together form a ring
structure of formula (I) or (Ia):
<IMG> <IMG>
wherein A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -S(O)2-NH-, -OC(O)NH-,
-OC(O)- or -C-;
V1, V2, V3 and V4 are independently C or N;
where V3 is C; R13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy,
carboxyl, alkylthio, amino, alkylamino or dialkylamino; or aryl, arylalkyl,
cycloalkyl,
alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl
optionally
comprising 1 or more heteroatoms selected from O, N and S, and optionally
substituted with halo or alkyl; or R13 is absent;
R14 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl,
arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
optionally comprising 1 or more heteratoms selected from N, O and S, and
optionally
substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,
carboxy,
alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,
arylcarboxamide, alkylthio or haloalkylthio; and
W1, W2 and W3 are independently selected from N optionally substituted with
alkyl; C, S and O.
177. A compound of claim 176 wherein R11, R12 and E together form a ring
structure of formula (I).
178. A compound of claim 177 wherein R14-A is benzyloxycarboxamide, H2N- or
H.
134

179. A compound of claim 178 wherein R13 is H or halo.
180. A compound of claim 179 wherein V1, V2 and V3 are C.
181. A compound of claim 180 wherein V4 is N.
182. The compound of claim 181:
2-[(6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
(1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide.
183. The compound of claim 181:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(R)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; or
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide.
184. The compound of claim 181:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide;
2-(5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide.
185. A compound of claim 177 wherein R1 is (.alpha.,.alpha.)-disubstituted
arylalkyl or alkyl
fused aryl-cycloalkyl, wherein the aryl or fused aryl-cycloalkyl group is
optionally substituted.
135

186. A compound of claim 185 wherein R1 is (.alpha.,.alpha.)-dimethylbenzyl
optionally
substituted with alkyl, alkoxy or hydroxy.
187. A compound of claim 186 wherein R13 is H or halo.
188. A compound of claim 187 wherein R14-A- is benzyloxycarboxamide, H2N- or
H.
189. The compound of claim 188:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(.alpha.,.alpha.-dimethyl-3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(.alpha.,.alpha.-dimethyl-3,4-dihydroxybenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-
(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-[5-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide
2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(.alpha.,.alpha.
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl]-N-[1-(2-[5-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.
190. A compound of claim 185 wherein R1 is (.alpha.,.alpha.)-dimethyl-3,4-
methylenedioxybenzyl.
191. The compound of claim 190: 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl]-N-[1-(2-[5-(.alpha.,.alpha.-dimethyl-3,4-
methylenedioxybenzyl)-
1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.
136

192. A compound of claim 177 wherein R1 is alkyl.
193. A compound of claim 192 wherein R1 is methyl, isopropyl, isobutyl, n-
butyl
or tert-butyl.
194. A compound of claim 193 wherein R13 is H or halo.
195. A compound of claim 194 wherein R14-A- is benzyloxycarboxamide, H2N- or
H.
196. The compound of claim 195:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl)-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)2-
(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-isopropyl-1,3,4-oxadiazolyl)carbonyl)2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-[1-(2-[5-
tert-butyl-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl)carbonyl)-2-(R)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-
butyl-1,3,4-oxadiazolyl)carbonyl)-2-(R,S)-methylpropyl]acetamide;
137

2-[6-Oxo-2-phenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide.
197. A compound of claim 77 wherein A is -S(O)2- or -S(O)2-NH-.
198. A compound of claim 197 wherein R14 is alkyl.
199. A compound of claim 198 wherein R1 is aryl or arylalkyl optionally
substituted with alkyl.
200. The compound of claim 199: 2-[5-(Methylsulfonyl)amino-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl)carbonyl)2-(S)-methylpropyl]acetamide.
201. A compound of claim 180 wherein V4 is C.
202. A compound of claim 177 wherein V4 is N.
203. A compound of claim 180 wherein R1 is alkylcycloalkyl.
204. A compound of claim 203 wherein R1 is methylcyclopropyl.
205. A compound of claim 204 wherein R13 is H or halo.
206. A compound of claim 205 wherein R14-A- is benzyloxycarboxamide, H2N- or
H.
207. The compound of claim 206:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]N-[1-(2-[5-(1-
methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-
methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
or
2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-
methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
208. The compound of claim 177:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-
(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide;
138

2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(.alpha.,.alpha.-
dimethylbenzyl)-1,3,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]acetamide;
or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-
(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
209. A compound of claim 177 wherein R11, R12 and E form a ring of formula
(Ia).
210. A compound of claim 209 where W is S.
211. The compound of claim 210: 2-[5-Amino-6-oxo-2-thienyl-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
212. A compound of claim 177 wherein V2 is N.
213. A compound of claim 212 wherein V1 and V3 are C, and V4 is N.
214. A compound of claim 213 wherein R14-A is H or H2N-.
215. The compound of claim 214:
2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-{3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-
(.alpha.,.alpha.-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
216. A compound of claim 175 wherein R11, R12 and E form a ring of formula
(V):
<IMG>
wherein
W is S, SO, SO2 or C;
n is 0, 1 or 2;
139

R13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio,
amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,
alkylcycloalkyl, fused
aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms selected from O, N and S, and optionally substituted with halo or
alkyl;
R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
optionally comprising 1 or more heteratoms selected from N, O and S, and
optionally
substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,
carboxy,
alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,
arylcarboxamide, alkylthio or haloalkylthio; and
G is -NHC(O)-, -OC(O)NH-, -C(O)-, -S(O)2-NH- or a direct bond.
217. A compound of claim 216 wherein R14-G is H2N.
218. A compound of claim 217 wherein R13 is phenyl optionally substituted with
halo.
219. A compound of claim 217 wherein R14-G is arylalkyloxycarboxamide.
220. A compound of claim 219 wherein R14-G is benzyloxycarboxamide and R13 is
H.
221. A compound of claim 175 wherein R11, R12 and E form a ring of formulas
(VI)
or (VIa):
<IMG> <IMG>
wherein
R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused
aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from O, N and S, and optionally substituted with halo or alkyl; and
R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
optionally comprising 1 or more heteratoms selected from N, O and S, and
optionally
substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,
carboxy,
140

alkenyl, alkynyl, haloalkoxy, carboalkoxy, arylalkyloxycarbonyl,
alkylcarboxamide,
aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio.
222. A compound of claim 221 wherein R11,, R12 and E form a ring of formula
(VI).
223. A compound of claim 222 wherein R14 is a fused aryl-cycloalkyl or alkyl
fused aryl-cycloalkyl optionally comprising one or more heteroatoms.
224. A compound of claim 223 wherein R14 is 3,4-methylenedioxybenzyl or
3,4-ethylenedioxybenzyl.
225. The compound of claim 224:4- 1-(3,4-Methylenedioxybenzyl)-3-(R)-
benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.
226. A compound of claim 221 wherein R13 is aryl or arylalkyl optionally
comprising one or more heteroatoms.
227. A compound of claim 226 wherein R13 is benzyl or phenyl.
228. A compound of claim 227 wherein R14 is H
229. A compound of claim 226 wherein R13 is pyridyl.
230. The compound of claim 229:
2-(R,S)-[(Methylene-4-pyridyl)piperazine-2,5-dione]-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
231. A compound of claim 175 wherein R11, R12 and E form a ring of formula
(VIa).
232. A compound of claim 231 wherein R13 is aryl or arylalkyl.
233. A compound of claim 232 wherein R13 is phenyl or benzyl.
234. A compound of claim 231 wherein R14 is Cbz.
235. A compound of claim 231 wherein R14 is H.
236. A compound of claim 175 wherein R11, R12 and E form a ring of formula
(IX)
or (IXa):
<IMG> <IMG>
wherein
141

U, V, W and Y are independently or together N, C, C(O), N(R13) where R13 is
H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino,
dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-
cycloalkyl or
alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms
selected
from O, N and S, and optionally substituted with halo or alkyl; N(R14) where
R14 is H,
alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-
cycloalkyl or
alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms
selected from
N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino,
alkylamino,
dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,
alkylcarboxamide,
aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C(R16)(R17)
where R16
and R17 are independently or together H, alkyl, alkylthio, alkylthioalkyl;
-(CH2)m C(O)OR or -(CH2)m C(O)NRR' where m is 1 to 6 and R and R' are
independently or together H or alkyl; or aryl, arylalkyl, cycloalkyl,
alkylcycloalkyl,
fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one
or
more heteroatoms selected from N, S and non-peroxide O and optionally
substituted
with amino, alkylamino, dialkylamino, guanidine, carboalkoxy, keto, hydroxy,
alkyl,
haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine; or together
form a
cyclic ring structure comprising 4-8 atoms selected from C, N, O and S.
237. A compound of claim 236 wherein R11, R12 and E form a ring of formula
(IX).
238. A compound of claim 237 wherein U is C(O); V is N; W is N or N(R13); and
Y is C(R16)(R17).
239. A compound of claim 238 wherein W is NH.
240. A compound of claim 239 wherein R16 and R17 are H.
241. A compound of claim 239 wherein R16 and R17 are alkyl.
242. A compound of claim 239 wherein R16 is alkyl and R17 is H.
243. A compound of claim 242 wherein R16 is isopropyl.
244. A compound of claim 243 wherein R1 is benzyl or (a,a)-dimethylbenzyl
optionally substituted with alkyl, alkoxy or hydroxy.
245. A compound of claim 244:
4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(.alpha.,.alpha.-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide;
4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[ 1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
4-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(.alpha.,.alpha.-
142

dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
or
4-(R)-Isopropyl-2,5-imidazolidinedione-N-[ 1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
246. A compound of claim 238 wherein R1 is alkyl.
247. A compound of claim 246 wherein R1 is methyl, isopropyl, isobutyl, n-
butyl
or tert-butyl.
248. A compound of claim 247:
4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-
oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; or
4-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
249. A compound of claim 239 wherein R16 is optionally substituted aryl or
arylalkyl.
250. A compound of claim 249 wherein R16 is benzyl or phenyl optionally
substituted with dialkylamino, and R17 is H.
251. A compound of claim 250 of the formula:
[4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide; or
4-(R,S)-Phenyl-2,5-imidazolidinedione-N-[ 1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
252. A compound of claim 249 wherein R16 is benzyl or phenyl optionally
substituted with hydroxyl.
253. A compound of claim 238 wherein R16 is pyridinyl or methylene pyridinyl
254. A compound of claim 250 wherein R17 is succinimidyl.
255. The compound of claim 254: [4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]-
2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
256. A compound of claim 253 wherein R17 is H.
257. A compound of claim 253 wherein R17 is alkyl.
143

258. The compound of claim 257: [4-(R,S)-(2-Pyridyl)-4-(R,S)-methyl]-2,5-
imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.
259. A compound of claim 239 wherein R16 and R17 are phenyl or benzyl.
260. A compound of claim 259: 4,4-Diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide
or 4,4-biphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-
methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-
methylpropyl]acetamide.
261. A compound of claim 239 wherein R16 and R17 together form a cyclic ring
structure.
262. A compound of claim 261 wherein R16 and R17 together are
-CH2-(CH2)2-CH2-.
263. A compound of claim 261 wherein R16 and R17 together are
-CH2-(CH2)3-CH2-.
264. A compound of claim 239 wherein R16 is fused aryl.
265. A compound of claim 264 wherein R16 is indolyl.
266. A compound of claim 265:
4-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
4-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(.alpha.,.alpha.-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
267. A compound of claim 239 wherein R16 is -(CH2)m C(O)OR.
268. A compound of claim 267 wherein R is methyl.
269. A compound of claim 239 wherein R16 is -(CH2)m C(O)NRR'.
270. A compound of claim 269 wherein R and R' are methyl.
271. A compound of claim 238 wherein W is N(R13) where R13 is cycloalkyl or
cycloalkylalkyl optionally comprising 1 or more heteroatoms.
272. A compound of claim 271 wherein R13 is morpholinoalkyl.
273. A compound of claim 272 wherein R16 is aryl or arylalkyl.
274. A compound of claim 273 wherein R16 is benzyl or phenyl and R17 is H.
275. A compound of claim 274:
1-(N-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(R,S)-
144

methylpropyl]acetamide;
1-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-
(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(R,S)-
methylpropyl]acetamide; or
1-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(R,S)-
methylpropyl]acetamide.
276. A compound of claim 238 wherein W is N(R13) where R13 is alkyl.
277. A compound of claim 276 wherein R13 is methyl.
278. A compound of claim 238 wherein W is N(R13) and R13 is aryl or arylalkyl.
279. A compound of claim 278 wherein R13 is benzyl.
280. A compound of claim 279 wherein R16 and R17 are H.
281. A compound of claim 237 wherein U is C(R16)(R17); V is N; W is N or
N(R13);
and Y is C(O).
282. A compound of claim 281 wherein R16 is aryl or arylalkyl.
283. A compound of claim 282 wherein R16 is benzyl or phenyl.
284. A compound of claim 283 wherein R17 is H.
285. A compound of claim 284 wherein W is N(R13).
286. A compound of claim 285 wherein R13 is aryl or arylalkyl.
287. A compound of claim 286 wherein R13 is benzyl or phenyl.
288. A compound of claim 237 wherein U is C(O); V is N; W is NH or N(R13); and
Y is N(R13).
289. A compound of claim 288 wherein R13 is aryl or arylalkyl.
290. A compound of claim 289 wherein R13 is phenyl or benzyl.
291. A compound of claim 289 wherein W is NH.
292. A compound of claim 289 wherein W is N(R13) where R13 is alkyl.
293. The compound of claim 292: 5-(R,S)-Phenyl-1-methyl-2,4-
imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.
294. A compound of claim 263 wherein R11, R12 and E form a ring of formula
(IXa).
295. A compound of claim 294 wherein W is N(R13).
296. A compound of claim 295 wherein R13 is aryl or cycloalkyl optionally
comprising 1 or more heteroatoms.
145

297. A compound of claim 296 where R13 is piperidinyl.
298. A method of inhibiting one or more serine proteases comprising
administering
to a host in need of such inhibition an effective amount of a compound of
claims 1, 53, 70, 124, 167 or 175.
299. A method of claim 298 wherein the serine protease in elastase.
300. A method of claim 299 wherein the elastase is human neutrophil elastase.
301. A method of claim 298 wherein said compound is administered orally.
302. A pharmaceutical composition comprising one or more compounds of claims
1, 53, 70, 124, 167 or 175 and a pharmaceutically acceptable Garner.
146

Description

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/21636
SERINE PROTEASE INHIBITORS
The present invention relates to certain substituted oxadiazole, thiadiazole
and
triazole peptoids which are useful as inhibitors of serine proteases.
Background of the Invention
The serine proteases are a class of enzymes which includes elastase,
chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have in
common a
catalytic triad consisting of Serine-195, Histidine-57 and Aspartic acid-102
(chymotrypsin numbering system). Human neutrophil elastase (HNE) is a
proteolytic
enzyme secreted by polymorphonuclear leukocytes (PMNs) in response to a
variety of
inflammatory stimuli. This release of HNE and its extracellular proteolytic
activity
are highly regulated and are normal, beneficial functions of PMNs. The
degradative
capacity of HNE, under normal circumstances, is modulated by relatively high
plasma
concentrations of a,-proteinase inhibitor (a,-PI). However, stimulated PMNs
produce
a burst of active oxygen metabolites, some of which (hypochlorous acid for
example)
are capable of oxidizing a critical methionine residue in a,-PI. Oxidized a,-
PI has
been shown to have limited potency as an HNE inhibitor and it has been
proposed that
alteration of this protease/antiprotease balance permits HNE to perform its
degradative functions in localized and controlled environments.
Despite this balance of protease/antiprotease activity, there are several
human
disease states in which a breakdown of this control mechanism is implicated in
the
pathogenesis of the condition. Improper modulation of HNE activity has been
suggested as a contributing factor in adult respiratory distress syndrome,
septic shock
and multiple organ failure. A series of studies also have indicated the
involvement of
PMNs and neutrophil elastase in myocardial ischemia-reperfusion injury. Humans
with below-normal levels of a,-PI have an increased probability of developing
emphysema. HNE-mediated processes are implicated in other conditions such as
arkhritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis,
cystic fibrosis,
chronic bronchitis, atherosclerosis, Alzheimer's disease, organ
transplantation, corneal
ulcers, and invasion behavior of malignant tumors.
There is a need for effective inhibitors of HNE as therapeutic and as

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
prophylactic agents for the treatment and/or prevention of elastase-mediated
problems.
Summary of the Invention
The present invention provides compounds which are useful as serine protease
inhibitors, including human neutrophil elastase. These compounds are
characterized
by their relatively low molecular weight, high potency and selectivity with
respect to
HNE. Additionally, certain compounds of the invention have demonstrated oral
bioavailability as exhibited by their higher blood levels after oral dosing.
Oral
bioavailability allows oral dosing for use in chronic disease, with the
advantages of
self administration and decreased cost over other means of adminstration. The
compounds described herein can be used effectively to prevent, alleviate or
otherwise
treat disease states characterized by the degradation of connective tissue by
proteases
in humans.
1 S The present invention provides compounds comprising oxadiazole,
thiadiazole
or triazole ring structures, and can be generically described by the formula:
N -- X
... Y : i
wherein Z is a serine protease binding moiety, preferably an elastase binding
moiety,
and most preferably a human neutrophil elastase binding moiety. Specifically,
Z is a
carbonyl containing group, preferably an a-amino carbonyl containing group
where
the carbonyl carbon is covalently attached to the carbon of the heterocycle.
R, is alkyl, alkenyl or alkynyl optionally substituted with 1 or more,
preferably
1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino,
alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O-(CS-
C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl,
alkylcycloalkyl,
alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (CS
C,z)aryl,
{C5-C,z)arylalkyl, (CS-C,z)arylalkenyl, fused (CS-C,2)aryl-cycloalkyl or alkyl
fused
(CS-C,2)aryl-cycolalkyl optionally comprising 1-4 heteroatoms selected from N,
O and
S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl,
amino,
aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy,
carboxyl, carboalkoxy, alkylcarboxamide, (CS-C6)aryl, -O-(C5-C6)aryl,

CA 02272548 1999-OS-19
WO 98!24806 PCT/US97/21636
arylcarboxamide, alkylthio or haloalkylthio.
X and Y are independently O, S or N, wherein N is optionally substituted with
alkyl or alkenyl optionally substituted with I-3 halo atoms; (CS-C6)aryl,
arylaikyl or
arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S,
and
optionally subsituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio. Preferably, at
least
one of X or Y is N. It will be understood that where X or Y is a substituted
N, both X
and Y are N. Preferably, the compounds of the present invention comprise 1,2,4-
oxadiazole (i.e., X is O; Y is N) or 1,3,4 oxadiazole rings (i.e., X is N; Y
is O).
The compounds of the present invention may be conveniently categorized as
Groups I through VI.
In one preferred embodiment, the invention provides compounds of the
formula (Group I):
..~ -
RQ-p .N. ''R
= '~ : i R
v 3 N-X
0
._ ~ R
'I i
0
wherein X , Y and R, are described above;
Rz and R3 are independently or together H; alkyl or alkenyl optionally
substituted with I -3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -
RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (CS-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl, (CS-
C,z)aryl, (CS-C,2)arylalkyl or (CS C,Z)arylalkenyl optionally comprising 1-4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (CS-C6)aryl, -O-(CS-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
3

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/21636
According to several preferred embodiments, the benzene ring is substituted
with an
alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a
dialkylamino; preferably dimethylamino. In yet another embodiment, R, is a
fused
arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl
fused
aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R, is
an
' alkyl group, preferably (C,-Cg)alkyl, either straight chain or branched,
such as methyl,
ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention further provides compounds of the formula (Group II):
Rz~ ; R3 N_-X
~~~'J~~~ R
0
wherein
X, Y, R,, RZ and R3 are as described above;
B is -S(O)2 , -C(O)-, -OC(O)- or -CHzC(O)-;
R6 is
R, s
.R,s R13 ~ Rls
i
R13. ___~ /' R13
_~ ; ~ ~ N,i ~R~z _ R
z >
~w ~Ny~ ~ .N~ ~'R~3 ~ 1 , ~ ,R'
~- _ 1_ .N, /,-~ 3
R, 4 / i l ~~ R 14~ \\ ~ ~~ ~ ' , . ~' R' 4~' .~ ~ j
O O ,
(I) (II) (III)
O
R13
p R13 / Rls R13\
\ W / Rls
N'i sr R~z ' , v . ~ R~z N , . ~ R'z
~' N R'3 ~ ~ R~3 or r R.
N, / ~.,_,N. ~ ~ 3
R~4 ~~ R14/ ~~/ ~ R/
14
(IV) (V) (VI)
wherein
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -
RC'.OOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
S

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
are independently H, alkyl, alkenyl, cycloalkyl or (CS-C6)aryl; or cycloalkyl,
alkylcycioalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl, (CS-
C,2)aryl, (CS-C,Z)arylalkyl or (CS-C,z)arylalkenyl optionally comprising 1-4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (CS-C6)aryl, -O-(C5-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R,3 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising i or more
heteroatoms
selected from O, N and S, and optionally substituted with halo or alkyl;
R,4 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkyl fused aryl-
cycloalkyl or
aryloxycarboxamide optionally comprising 1 or more heteroatoms selected from
N, O
and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy,
alkylcarboxamide,
aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio or
haloalkylthio;
R,5 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from O, N and S; and
W is O or S; or C or N optionally substituted with H, alkyl or aryl.
In a preferred embodiment, X is N and Y is O. In another preferred
embodiment, X is O and Y is N. According to several preferred embodiments, R,3
is
an optionally substituted phenyl or benzyl; pyridyl, piperidinyl, alkyl or H
or a fused
ring system such as 3,4-methylenedioxybenzyl; R,4 is optionally substituted
amino or
an arylalkyloxycarboxamide such as benzyloxycarboxamide; and R,5 is H or halo.
Preferably, RZ is isopropyl and R3 is H.
In a preferred embodiment of the invention, R, is an optionally substituted
aryl
or arylalkyl group, such as a a,a-dimethylbenzyl, benzyl or phenyl group.
According
to several preferred embodiments, the benzene ring is substituted with an
alkyl, such
L

CA 02272548 1999-OS-19
WO 98/24806 PCT/ITS97/21636
as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino,
preferably dimethylamino. In yet another embodiment, R, is a fused arylalkyl
group
such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
such as 3,4-methylenedioxybenzyl. In another embodiment, R, is an alkyl group,
preferably (C,-Cg)alkyl, either straight chain or branched, such as methyl,
ethyl,
propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention also provides compounds of the formula (Group III):
R
Rs N __X
_BN; ~__~ ,R
Ii
O
wherein X, Y, R,, R2, R, and B are as described above; and
R6 is of formula (I):
(~ ~~ ~ ~~
N ,(~ )",
R~4
r
(I)
wheremis0orl;nis0orl;
D is a direct bond or an amino acid selected from, but not limited to,
proline,
isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur
with alkyl,
alkenyl or phenyl optionally substituted with halo, cyano, vitro, haloalkyl,
amino,
aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,
homo-
phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl,
alkenyl or
phenyl optionally substituted with halo, cyano, vitro, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide,
arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or
threonine
optionally substituted with alkyl or aryl; histidine methionine, valine,
norvaline,
norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,
ornithine and

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteratoms
selected from N, O and S;
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)z-, -OC(O)- or-C-; and
R,4 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl,
arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
optionally comprising 1 or more heteratoms selected from N, O and S, and
optionally
substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,
carboxy,
alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkyicarboxamide, aryl, arylalkyl,
arylcarboxamide, alkylthio or haloalkylthio.
Alternatively, R6 is of formula (II):
i
R8/--~, \~;. N _~\; .
V ,y __ _
O
(II)
where
W is S or O;
Rg is alkylamino, dialkylamino or amino;
R9 is H, alkyl or halo.
In a preferred embodiment, X is N and Y is O. In another preferred
embodiment, X is O and Y is N. According to one embodiment, where R6 is of
formula (I), m is 1, n is 0. In another embodiment, m and n are 1. Preferably,
R,4 is
benzyl, A is -OC(O)- and D is Val.
Preferably, RZ is isopropyl and R3 is H.
In a preferred embodiment of the invention, R, is an optionally substituted
aryl
or arylalkyl group, such as a a,a-dimethylbenzyl, benzyl or phenyl group.
According
to several preferred embodiments, the benzene ring is substituted with an
alkyl, such
as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino,
preferably dimethylamino. In yet another embodiment, R, is a fused arylalkyl
group

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97/21636
such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
such as 3,4-methylenedioxybenzyl. In another embodiment, R, is an alkyl group,
preferably (C,-C8)alkyl, either straight chain or branched, such as methyl,
ethyl,
propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
According to one embodiment, W is S; R8 is amino and R, is H.
In yet a further embodiment of the invention of Group (III) compounds, R6 is
aryl, arylalkyl, cycloalkyl or alkylcycloalkyl. According to one embodiment,
R6-B is
Cbz.
The present invention further provides compounds of the formula (Group IV):
Rvo O RZ Rs N-X
J~\v
R,4A-D-N. II ,<~ ' ~__
~y
O
wherein
X, Y, R,, RZ and R3 are as described above;
R,o is (CS C6)aryl, (CS-C6)aryialkyl, (CS-C6)arylalkenyl, cycloalkyl, fused
aryl-
cycloalkyl optionally comprising one or more heteroatoms selected from N, S
and
non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl,
amino,
aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio;
D is a direct bond, -C(O)-, or an amino acid selected from, but not limited
to,
proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the
sulfur
with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,
homo-
phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;
tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl,
alkenyl or
phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide,
arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or
threonine
optionally substituted with alkyl or aryl; histidine methionine, valine,
norvaline,
norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,
ornithine and
lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,

CA 02272548 1999-OS-19
WO 98/24806 PCT/ITS97/21636
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising I or more
heteratoms
selected from N, O and S;
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -NH-S(O)z-, -S(O)Z-NH-,
-OC(O)NH-, -OC(O)- or -C-; and R,4 is as described above.
In a preferred embodiment, X is N and Y is O. In another preferred
embodiment, X is O and Y is N. Preferably, D is Val, A is -OC(O)- and R,4 is
aryl or
arylalkyl such as benzyl. In a preferred embodiment, R,o is (CS-C6)aryl or (CS-
C6)arylalkyl, preferably benzyl, or a fused aryl-cycloalkyl such as an indanyl
group.
According to another preferred embodiment, D is -C(O)-, and R,4-A is pyrrole.
Preferably, Rz is isopropyl and R3 is H.
In a preferred embodiment of the invention, R, is an optionally substituted
aryl
or arylalkyl group, such as a a,a-dimethylbenzyl, benzyl or phenyl group.
According
1 S to several preferred embodiments, the benzene ring is substituted with an
alkyl, such
as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino,
preferably dimethylamino. In yet another embodiment, R, is a fused arylalkyl
group
such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
such as 3,4-methylenedioxybenzyl. In another embodiment, R, is an alkyl group,
preferably (C,-Cg)alkyl, either straight chain or branched, such as methyl,
ethyl,
propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention additionally provides compounds of the formula (Group
V):
R~z O Rz ,R3 N-X
~y~ Ri
R~~
R,z R,s
wherein
X, Y, R,, Rz, R3, R'Z and R'3 are as described above; and
R", R,2 and E together form a monocyclic or bicyclic ring comprising 5-10
atoms selected from C, N, S and O; said ring containing I or more keto groups;
and
optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
lu
_ ~___ _ __ _._._. _ __

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamido, alkylthio, haloalkylthio; cycloalkyl, alkylcycloalkyl,
alkenylcycloalkyl, (CS-C,z)aryl, (CS-C,z)arylalkyl, ((CS-C,Z)arylalkyl)OC(O)NH-
or
(CS-C,z)arylalkenyl optionally comprising one or more heteroatoms selected
from N,
S and non-peroxide O, and optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,
carboxyl, carboalkoxy, -C(O)O(alkyl), -C(O)(alkyl), alkylcarboxamido,
alkylthio or
haloalkylthio.
In a preferred embodiment, X is N and Y is O. In another preferred
embodiment, X is O and Y is N.
Preferably, Rz is isopropyl and R3 is H.
In a preferred embodiment of the invention, R, is an optionally substituted
aryl
or arylalkyl group, such as a a,a-dimethylbenzyl, benzyl or phenyl group.
According
to several preferred embodiments, the benzene ring is substituted with an
alkyl, such
as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino,
preferably dimethylamino. In yet another embodiment, R, is a fused arylalkyl
group
such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl
such as 3,4-methylenedioxybenzyl. In another embodiment, R, is an alkyl group,
preferably (C,-Cg)alkyl, either straight chain or branched, such as methyl,
ethyl,
propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
According to one embodiment of the invention, R", R,Z, and E together form a
ring structure of formulas (I) or (Ia):
R~s
3 ~ ~3
V ~ V
i 4\ / ~~ / 2
\W1
~, N
R,4A ~ \
O O
(I) (la)
wherein A is as described above for Group (IV);
V,, VZ, V3 and V, are independently or together C or N;
where V3 is C; R,3 is II, alkyl, halo, alkoxy, carboalkoxy, carboxyl,
alkylthio,

CA 02272548 1999-OS-19
WO 98/24806 PCT/ITS97/21636
amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,
alkylcycloalkyl, fused
aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms selected from O, N and S, and optionally substituted with halo or
alkyl;
R,4 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl,
arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-
cycloalkyl,
arylalkylxoxycarbonyl or arylalkylcarboxamide optionally comprising 1 or more
heteratoms selected from N, O and S, and optionally substituted with alkyl,
halo,
alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,
haloalkoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or
haloalkylthio; and
W,, WZ and W3 are independently selected from N optionally substituted with
alkyl; C, S and O.
According to one preferred embodiment, VQ is N; and V,, Vz and V, are C.
Preferably, R,3 is H or halo; R,4-A is CbzNH, amino or H; and R'z and R'3 are
H.
Preferably, R", R,z and E together form a ring of formula (I). In a particular
embodiment, R,3 is H or F; and R,4-A- is H or HZN-. Where R", R,Z and E
together
form a ring of formula (Ia), W, is preferably S, and WZ and W3 are C.
In another embodiment, R", R,2 and E together form a ring of formula (II)
R~s
Ri4A
(II)
wherein A, R,3 and R,4 are as described above;
Preferably, R'2 and R'3 are H. According to one embodiment, R,3 is
1-piperidinyl; and R,4-A is CbzNH. Alternatively, R,3 is H; and R,4-A is
amino,
alkylamino or dialkylamino. In another preferred embodiment, R,3 is halo; and
R,4-A
is CH3-O-C(O)-. In yet another embodiment, R,3 is H; and R,4-A is CbzNH.
According to another embodiment of the invention, R", R,z and E form a ring
of formula (III) or (IV):

CA 02272548 1999-OS-19
WO 98!24806 PCTIUS97/21636
O O
r,;; N; .A-- R13 .I \\N,.A- R,3
f.:.. ,.I. ,
:,
l N ~ /~.._ l _ N v
R ~ 1 Rls
14
O O
(III) (IV)
wherein
A is a direct bond, -C- or -C(O)-;
R,3, R,Q and R,5 are as defined above.
According to a particular embodiment, R", R,2 and E form a ring of formula
(III); and -A-R,3 is -C(O)phenyl; R,4 is H; and R'2 and R'3 are H.
In another embodiment, R", R,z and E form a ring of formula (IV}; and -A-
R,3 is -C(O)phenyl; R,5 is H; and R'z and R'3 and H.
In another embodiment of the invention, R", R,Z and E form a ring of formula
(V):
W ~ R,3
( )~
.N'
RlaG W
O
(V)
wherein
W is S, SO, SOz or C;
n is 0, 1 or 2;
R,3 and R,4 are defined above; and
G is -NHC(O)-, -OC(O)NH-, -C(O)-, -NHS(O)z or a direct bond.
According to one embodiment, n is 0 and W is S, where preferably R,4-G is H.
Preferably, R,3 is optionally substituted benzyl or phenyl.
In another embodiment, n is 1 and W is C. Preferably, R,4-G is an
arylalkyloxycarboxamide, for example, CbzNH-. In a preferred embodiment, R,3
is H
or phenyl substituted with halo. Preferably, R'Z and R'3 are H.
The invention further provides compounds wherein R", R,2 and E form a ring
of formulas (VI), (VIa), (VII) or (VIII): .,
1'

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
O Ris R« O R'm Rm
' I I
R R'
Ria ~~ ~ Ri3 Ria ~\N r,~i~- R~s _ ~~,% ~~ -~~:,.' R'is ~s - ~ ~N.--~ to
-. N ~~
i i ~ I
N~ ~N ,-N ' N~ , .N N~'
' Rya \Oi~ - ~ Ria
O
(VI) (VIa) (VII) (VIII)
wherein
R,3 is as defined above, or is CH=R,5 or R,5 where R,5 is pyridinyl, phenyl or
benzyl optionally substituted with halo, dialkylamino or -C(O)OCH3;
R,4 and R',4 are independently or together H, alkyl, alkenyl, CH3C(O)-; or
aryl,
arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused
aryl-
cycloalkyl, aryloxycarbonyl or arylalkyloxycarbonyl optionally comprising 1 or
more
heteratoms selected from N, O and S, and optionally substituted with alkyl,
halo,
alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,
haloalkoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or
haloalkylthio; and
R,6, R", R',6 and R'" are independently or together H, alkyl, alkenyl,
alkylthio,
alkylthioalkyl; or cycloalkyl, cycloalkenyl, alkylcycloalkyl,~aryl, arylalkyl
or
arylalkenyl optionally substituted with guanidine, carboalkoxy, hydroxyl,
haloalkyl,
alkylthio, alkylguanidine, dialkylguanidine or amidine.
Preferred compounds are of formula (VI) or (VIa) where R,3 is CH=R,5 or R,S;
and R,4 is H, alkyl, CH3C(O)-, Cbz or benzyl optionally substituted with
alkyl, halo or
alkylamino; or 3,4-methylenedioxybenzyi or 3,4-ethylenedioxybenzyl; and R'z
and R'3
are H. Preferably, R,3 is =CHR,S where R,5 is phenyl or benzyl optionally
substituted
with halo or -C(O)CH3.
In a further embodiment, R", R,2 and E form a ring of formula (IX) or (IXa):
,,,
i
/i
Y-U
/ ~ I
W V~' W N~_
w : , J . I.:..
O O
(IX) (IXa)
wherein
1''~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
U, V, W and Y are independently or together N, C, C(O), N(R,3) where R,3 is
H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino,
dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-
cycloalkyl or
alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms
selected
from O, N and S, and optionally substituted with halo or alkyl; N(R,4) where
R,4 is H,
alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-
cycloalkyl or
alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms
selected from
N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino,
alkylamino,
dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy,
alkylcarboxamide,
aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C{R,6)(R")
where R,6
and R" are independently or together H, alkyl, alkylthio, alkylthioalkyl; a
carboxylic
acid ester of the formula -(CHZ)mC(O)OR or an N-substituted alkylamide of the
formula -(CHZ)mC(O)NRR' where m is 1 to 6 and R and R' are independently or
together H or alkyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more
heteroatoms selected from N, S and non-peroxide O and optionally substituted
with
amino, alkylamino, dialkylamino, guanidine, carboalkoxy, keto, hydroxyl,
alkyl,
haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine; or together
form a
cyclic ring structure comprising 4-8 atoms selected from C, N, O and S.
In one preferred embodiment, U is C(R,6)(R"), V is N, W is N(R,4) and Y is
C(O), where preferably R'2 and R'3 are H; R,6 is phenyl or benzyl; R" is H;
and R,4 is
H or benzyl optionally substituted with alkyl, halo, or alkylamine.
In another preferred embodiment, U is C(O); V is N, W is N, N(R,3) or N(R,4);
and Y is C(R,6)(R"), where preferably R'z and R'3 are H; R,4 is H; R,6 is H,
alkyl,
optionally substituted aryl or arylalkyl, preferably benzyl or phenyl
optionally
substituted with dialkylamino or hydroxyl; pyridinyl, methylene pyridinyl;
fused aryl
such as an indolyl; or a carboxylic acid ester or N-substituted alkyl amide,
as defined
above; and R" is H, alkyl, succinimidyl, aryl or arylalkyl.
In yet another preferred embodiment, U is C(O), V is N, W is N , N(R,3) or
N(R,4); and Y is N(R,3), where preferably R'2 and R'3 are H; W is NH; R,3 is
arylalkyl;
and R,4 is H.
In a further embodiment, U is C(R,6}(R"); V is N; W is N or N(R,3); and Y is
C(O). Preferably, R,3 and R,6 are aryl; and R" is H.
1~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Where R", R,2 and E form a ring of formula (IXa); W is typically N(R,3)
where R,3 is aryl or cycloalkyl such as piperidinyl.
In another embodiment, R,6 and R" form a cyclic ring structure, such as a
cyclopentyl or cyclohexyl group.
The invention further provides compounds of the formula (Group VI):
O Rz.~ R3 N - X
R12
,.;
R
Y,
O
R, ,
wherein X, Y, R,, Rz and R3 are as described above, and R", R,z and E together
form a
ring of formula (X):
O
-' ~ ( )n '
I
O
(
where U and V are independently or together N, C, N(R,3) where R,3 is H,
alkyl,
alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or
aryl,
arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused
aryl-
cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and
S; or
C(R,6)(R") where R,6 and R" are as defined above; and
andnislor2.
The present invention further provides methods of synthesizing compounds of
formula (A):
O Rz R3 N-X
~I, ~/
,~, ~~~,~ R
O
(A)
wherein
Z' is defined below;
R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; -
alkyl-
C(O)OCH3; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl,
1 ~:

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97121636
alkylcycloalkyl, alkenylcycloalkyl, (CS-C,Z)aryl, (CS-C,z)arylalkyl, {CS-
C,2)arylalkenyl, fused (CS-C,2)aryl-cycloalkyl or fused (CS-C,z)aryl-
cyclalkylalkyl
optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally
substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl,
S dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
carboxyl,
carboalkoxy, alkylcarboxamide, (CS-C6)aryl, -O-(CS-C6)aryl, arylcarboxamide,
alkylthio or haloalkylthio;
X and Y are independently O, S or N, wherein N is optionally substituted with
alkyl or alkenyl optionally substituted with 1-3 halo atoms; (CS-C6)aryl,
arylalkyl or
arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S,
and
optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino,
aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; and
RZ and R3 are independently or together H; alkyl or alkenyl optionally
1 S substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -
RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl, (CS-
C,2)aryl, (CS-C,z)arylalkyl or (CS-C,z)arylalkenyl optionally comprising 1-4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (CS-Cb)aryl, -O-(CS-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
comprising the steps of:.
(a) reacting a compound of formula (B):
N~-1X
My.~~ R~
(B)
wherein M is Li or MgBr,

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97/21636
with an aldehyde of formula (C}:
where [PrG,] is a protecting group;
Ri R3
[PGri]NH~ CHO
(C)
{b) removing the protecting group from the resulting alcohol (D)
(c) coupling the alcohol obtained from step (b) with an acid of formula (E):
and
Z'-COOH (E)
(d) oxidizing the resulting product and further, if desired, removing the
protecting group to yield the final compound.
According to one emodiment, the protecting group [PGR,] is removed from
alcohol (D) by reacting the aldehyde of formula (C) with hydrochloric acid in
dioxane. The protecting group [PGr,] may be any suitable group, preferably
Boc.
According to another embodiment, the oxidation step of (d) is performed using
Dess Martin reagent.
In a further embodiment, the compound of formula (B) is synthesized by:
(e) treating an acid of the formula (R,)COOH with thionyl chloride or oxalyl
chloride;
(f) treating the resulting acid chloride with hydrazine to yield a hydrazide
of
the formula (R,)CONHNH2;
N-X
(F)
(g) reacting the hydrazide with triethyl orthoformate or trimethyl
orthoformate
and TsOH to yield a oxadiazole of the formula (F):
and
(h) treating the oxadiazole with butyllithium and further, is desired,
reacting
with MgBr~ OEt2 to yield the compound B.
In one embodiment, Z' is
1

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
H3C , CHi
'
\
~
R4--A. N
O
wherein
A is a direct bond, -C(O)-, -NH-C(O)-, -S{O)Z-, -NH-S(O)Z , -OC(O)-, -C- or
an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine
optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally
substituted
with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,
alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,
alkylthio or
haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine,
indoline-2-
carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally
substituted with
alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, arylcarboxamide, alkylthio or haioalkylthio; tryptophan,
tyrosine,
serine or threonine optionally substituted with alkyl or aryl; histidine,
methionine,
valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine,
giutamine, ornithine and lysine optionally substituted at the side chain
nitrogen with
alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,
dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl,
cycloalkyl,
alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl
optionally
comprising 1 or more heteroatoms selected from N, O and S; and
R4 is H, alkyl, alkenyl, or alkynyl; or cycloalkyl, alkylcycloalkyl, (CS-
C,2)aryl,
(CS-C,2)arylalkyl, fused {CS-C,Z)aryl-cycloalkyl or fused (C5-C,2)aryl-
cycloalkylalkyl
optionally comprising one or more heteroatoms selected from N, O and S, and
optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro,
hydroxyl,
haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or
haloalkylthio or is absent; or
\ ~1

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Z' may be
R,s
Rvs '! y
R13~' ~ ' Rls
Ri3 - i
N~' j_ R'z ~ .- R~z
.N_,, \~ ~_ N_...,G~---,R'3 ' 1 ) /~ ~R~
R14; ~~ ~,, y~_- R14 ~-' ~_; , R ,, ..-I ~ 'N ~y~= 3
O l4 ,
O
(I) (11) (III)
Ris
y ,O Ria ~ . R" ~ Ris
-/ ~ w-It
' J;
' /R~3 ~ i_. RZ R3 or N,',- f.~/R'z..R'
~~ : ~N W% ~,~ N ~, 3
R14 lO , ~~rJ R'4~' ~~ , R14ii/'
p p ,
(IV) (V) (VI)
wherein
R'z and R'3 are independently or together H; alkyl or alkenyl optionally
substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino,
dialkylamino,
alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -
RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R',
R" and R°
are independently H, alkyl, alkenyl, cycloalkyl or (CS-C6)aryl; or cycloalkyl,
alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-
aminoaryl, (CS-
C,2)aryl, (CS-C,Z)arylalkyl or (CS-C,2)arylalkenyl optionally comprising 1-4
heteroatoms selected from N, O and S, and optionally substituted with halo,
cyano,
keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,
alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (CS C6)aryl, -O-(CS-
C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio;
R, 3 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from O, N and S, and optionally substituted with halo or alkyl;
R,4 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl,
cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkyl fused aryl-
cycloalkyl or
~U

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
aryloxycarboxamide optionally comprising 1 or more heteroatoms selected from
N, O
and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy,
alkylcarboxamide,
aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio or
haloalkylthio;
and
R,5 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,
alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl,
fused aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from O, N and S.
In yet a further embodiment, Z' is:
f
(~.)~.
N ~-( )m
,.
Ria
(I)
wheremis0orl;nis0orl;
D is a direct bond or an amino acid selected from proline, isoleucine,
cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl,
alkenyl or
phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino,
aminoaikyl,
dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,
alkylcarboxamide,
arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-
phenylalanine,
dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-
carboxylic acid optionally substituted with alkyl, alkenyl or phenyl
optionally
substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
dialkylamino, alkyl,
alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,
alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine
optionally
substituted with alkyl or aryl; histidine methionine, valine, norvaline,
norleucine,
octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine
optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyi, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl
'i

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/2I636
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from N, O and S; and
A' is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -NH-S(O)2-, -OC(O)- or-C-.
In yet another embodiment, Z' is:
~~:~; , ,l,W .
i'_ .. . N --__ %~
R8 / ~,""
O
(II)
where
WisSorO;
R8 is alkylamino, dialkylamino or amino; and
R, is H, alkyl or halo; or
Z'is:
Rio
R~4 A~p__
wherein
R,o is (CS-C6)aryl, (CS-C6)arylalkyl, (CS-C6)arylalkenyl, cycioalkyl,
alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl
optionally
comprising one or more heteroatoriis selected from N, S and non-peroxide O,
and
optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, alkylthio or haloalkylthio.
In a preferred embodiment, Z' is:
Ri2
i
~E \
Ri ~ ,~ ,
R~2 R~s
wherein
R", R,z and E together form a monocyclic or bicyclic ring comprising 5-10

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97121636
atoms selected from C, N, S and O; said ring containing 1 or more keto groups;
and
optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,
carboalkoxy,
alkylcarboxamide, alkylthio, haloalkylthio or cycloalkyl, alkylcycloalkyl,
S alkenylcycloalkyl, (CS-C,2)aryl, (CS-C,Z)arylalkyl, ((CS-
C,Z)arylalkyl)OC(O)NH- or
(CS-C,2)arylalkenyl optionally comprising one or more heteroatoms selected
from N,
S and non-peroxide O, and optionally substituted with halo, cyano, nitro,
haloalkyl,
amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,
carboxyl, carboalkoxy, -C(O)O(alkyl), -C(O)(alkyl), alkylcarboxamide,
alkylthio or
haloalkylthio.
In a preferred embodiment, the invention provides a method of synthesizing a
compound of formula (G):
.N ,Ar H3C" .; CH3N-N
O ~ ~~ \~
II s~_
i
O O
(G)
wherein
T is H or NHZ;
R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; a
carboxylic acid ester such as -alkyl-C(O)OCH3; alkylamino, dialkylamino,
alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (CS-
C,z)aryl,
(CS-C,2)arylalkyl, (CS C,Z)arylalkenyl, fused (CS-C,z)aryl-cycloalkyl or fused
(CS-
C,z)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N,
O and
S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl,
amino,
aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,
haloalkoxy,
carboxyl, carboalkoxy, alkylcarboxamide, (CS-C6)aryl, -O-(CS-C6)aryl,
arylcarboxamide, alkylthio or haloalkylthio; and
Ar is an aryl or arylalkyl optionally substituted with H, alkyl, amino,
alkylamino, dialkylamino, halo or hydroxyl;
comprising the steps of:
(a) reacting a compound of formula (B):
N-N
~0
(B) ~,

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97/21636
wherein M is Li or MgBr;
with an aldehyde of formula (C):
..
(PGri]NH ~ 'CHO
(C)
where [PrG,] is a protecting group;
(b) removing the protecting group from the resulting alcohol (D)
(c) coupling the alcohol obtained from step (b) with an acid of formula (H):
,N. ;Ar
COON
0
(H)
wherein T' is H or [PGr2]NH, where [PGrz] is a protecting group;
(d) oxidizing the resulting product to yield a ketone of formula (J):
,N., Ar _
N-N
/!
O i
(J)
and further, when T' is [PGr2]NH,
(e) removing the protecting group [PGrz] to yield the compound of formula
(G). Preferably, [PGr2] is Cbz.
As used herein, the term "optionally substituted" means, when substituted,
mono to fully substituted.
As used herein, the term "independently" means that the substituents may be
the same or different.
As used herein, the term "alkyl" means C,-C,S, however, preferably C,-C8.
As used herein, the term "alkenyl" means C,-C,S, however, preferably C,-C8.
As used herein, the term "alkynyl" means C,-C, 5, however, preferably C,-C8.
It will be understood that alkyl, alkenyl and alkynyl groups, whether
substituted or unsubstituted, may be linear or branched.
As used herein, the term "aryl," unless otherwise stated, means aryl groups
preferably comprising 5 to 12 carbons, and more preferably 5 to 6 carbons.
Unless
otherwise indicated, the term includes both mono- and bi-cyclic fused ring
systems.
a~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
As used herein, where the term "arylalkyl" is defined by the general formula
(Cx-
CY)arylalkyl, x and y refer to the number of carbons making up the aryl group.
The
alkyl group is as defined above. The term include mono-substituted alkyl
groups
(e.g., benzyl), as well as di-substituted alkyl groups such as -alkyl(aryl)Z
(e.g., -
CH(phenyl)Z). The terms arylalkyl and alkyl fused arylcycloalkyl include (a,a)-
disubstituted groups such as, for example, (a,a)-disubstituted benzyl and
(a,a)-
disubstituted 3,4-methylenedioxybenzyl groups, wherein the a substituents are
preferably alkyl groups such as methyl, ethyl or propyl. Specific examples
include
(a,a)-dimethylbenzyl and (a,a)-dimethyl-3,4-methylenedioxybenzyl.
As used herein, the term "arylalkenyl" includes aryl groups where the alkenyl
group comprises 1-3 or more double bonds. Exemplary arylalkenyl groups include
=CH-CHz aryl and -CH=CH-aryl, where aryl is preferably phenyl.
As used herein, the term "cycloalkyl," unless otherwise stated, means
cycloalkyl groups preferably comprising 3 to 12 carbons, and more preferably 3
to 6
carbons. Unless otherwise indicated, the term includes both mono-, bi- and tri-
cyclic
fused ring systems.
As used herein, the term "Cbz" means benzyloxycarbonyl.
As used herein, the term "carboxamide" is synonymous with amide; i.e., a
group of the formula -NHC(O)-.
As used hererin, the term "oxycarboxamide" means a group of the formula
-O-C(O)NH-.
As used herein, the term "oxycarbonyl" means a group of the formula -OC(O)-
Pharmaceutically acceptable salts of the compounds described above are
within the scope of the invention.
Brief Description of the Drawings
Figure 1 is a schematic representation of the synthesis of compounds of Group
I.
Figure 2 is a schematic representation of the synthesis of compounds of Group
I.
Figure 3 is a schematic representation of the synthesis of compounds of Group
I.

CA 02272548 19'99-OS-19
WO 98/24806 PCT/ITS97/21636
Figure 4 is a schematic representation of the synthesis of compounds of Group
I.
Figure 5 is a schematic representation of the synthesis of compounds of Group
II.
Figure 6 is a schematic representation of the synthesis of compounds of Group
II.
Figure 7 is a schematic representation of the synthesis of compounds of Group
II.
Figure 8 is a schematic representation of the synthesis of compounds of Group
III.
Figure 9 is a schematic representation of the synthesis of compounds of Group
III.
Figure 10 is a schematic representation of the synthesis of compounds of
Group IV.
Figure I I is a schematic representation of the synthesis of compounds of
Group V.
Figure 12 is a schematic representation of the synthesis of compounds of
Group V.
Figure 13 is a schematic representation of the synthesis of compounds of
Group V.
Figure 14 is a schematic representation of the synthesis of compounds of
Group V.
Figure 1 S is a schematic representation of the synthesis of compounds of
Group V.
Figure 16 is a schematic representation of the synthesis of compounds of
Group V.
Figure 17 is a schematic representation of the synthesis of compounds of
Group V.
Figure 18 is a schematic representation of the synthesis of compounds of
Group V.
Figure 19 is a schematic representation of the synthesis of compounds of
Group V.
Figure 20 is a schematic representation of the synthesis of compounds of

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Group V .
Figure 21 is a schematic representation of the synthesis of compounds of
Group V.
Figure 22 is a schematic representation of the synthesis of compounds of
Group V.
Figure 23 shows the activity of certain compounds of Group I.
Figure 24 shows the activity of certain compounds of Group I.
Figure 25 shows the activity of certain compounds of Group I.
Figure 26 shows the activity of certain compounds of Group I.
Figure 27 shows the activity of certain compounds of Group I.
Figure 28 shows the activity of certain compounds of Group II and III.
Figure 29 shows the activity of certain compounds of Groups II, III and IV.
Figure 30 shows the activity of certain compounds of Group V.
Figure 31 shows the activity of certain compounds of Group V.
Figure 32 shows the activity of certain compounds of Group V.
Figure 33 shows the activity of certain compounds of Group V.
Figure 34 shows the activity of certain compounds of Group V.
Figure 35 shows the activity of certain compounds of Group V.
Figure 36 shows the activity of certain compounds of Group V.
Figure 37 shows the activity of certain compounds of Group V.
Figure 38 shows the activity of certain compounds of Group V.
Figure 39 is a schematic representation of the synthesis of certain compounds
of the invention.
Detailed Description
The compounds of the present invention have been found to be potent
inhibitors of the serine protease human neutrophil elastase (HNE). They are
reversible inhibitors that presumably form a transition state intermediate
with the
active site serine residue. The compounds are characterized by their low
molecular
weights, high selectivity with respect to HNE and stability regarding
physiological
conditions. Therefore, the compounds can be implemented to prevent, alleviate
and/or otherwise treat diseases which are mediated by the degradative effects
associated with the presence of HNE. Their usage is of particular importance
as they
a~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
relate to various human treatment in vivo but may also be used as a diagnostic
tool in
vitro.
The present invention provides, but is not limited to, specific embodiments
set
forth in the Examples as well as those set forth below.
__.___ _~__ . ___ __T_ _ ~_~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
/ \ / \
HOC
HC
N ; ~~~C CHI / r / O a , CHsN-N
N " N N ~ ~ ''~~N~~ / \
O
O O O O /
CE-2164
CE-215 ~ \ ~ CH3
_ H~C~ CHs
O ~hC CH3N-O \ / O N-N
N 'I / / / \
~N ~ O
°~~ I ~ p N ~ °
HC
\ / O ~ 1 ' O CE-2165 ~ 1 CH3
CE-2158 ~ CFA
O ~ ~ / \
HN~~ <~~C CHI O
N-N N~~ ~yC CH~N_N
i Nv ~~ O HN N~ / \
O O / ~ ~ O
O
CE-2159 .~. ~ CH3 O CE-2166
CHI
,C CH, N _ p ~ 1,
3
~N ~ ~~~ ,.~~, CF
~~ N H C, ; CH
O O > >
CE-2160 ~ ~ ~ ~ N ~yC ~CH3
\ N-N
~C CHI
aC O O ~ O
N CHI
N-N CE-2168
~N J O O ~ i \ /~. - CHI
O
O /
CE-2161 1 ~~C CH,
CHI O~ N N
/ ~ H
O '_ ( ~ O ~ O C a
U aC CHa ~ O
O ~Ii~N N~N N_N
O CE-2170
O CE-2 62 O /
~I3C CH3
3C
HsC CHI N CH3
H3C-~g__ N 3C CHIN-N ~ ~ ~ OI N O
N O~ ~ /N
II O ~ / \ O
O O
O O CE-2171
CE-2163 ' ~
FCC
~CH~
29

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
H,c cH,
o H,C
N cH, o
H,C ~ I ~ N O _ / OH'C ~~ N-N
O O O / I ~ H,C N N
CE-2172 ~ ~ N ~ ~ O
i~ O
O CE-2179
CF,
O \
I
OH,C CH, - / ; ,.
N N
N N I I ~ ~ I CH '~ Fs
O N~ ~ O ~ O
O O ,C CH, \
N N-O
E-2173 ~ ~ ~ I /
C O N ~N~ I i
C ~ ~ , N
H,C
O O CE-2180
~O
~//~11~ OH,C CH,
1
N ~ O
O O
CE-2174
CH ~ OH,C CH, \
N-O
O~j I/I\ ~ N / CF
O
CE-2181
CH,
N-N
O
O / _,~ ~ iCH~
w CH, N-O
I i
H,C ~~ H C ~ N
N CHI C>i21u1 O
\ O ~ N-N
I / ~ O ~ I ~ / CF,
O # O
CE-2177 O
OH,C ~a
I N ~ N
\ O ~ %-O
O O/ /
~N
CFr2178 ~ ~ / ~ ~ CE~2183 /
w CIi~
~O
O ~ ~ W
OH,C CH, \
I / CH,
~O
O
C&2184
3~

CA 02272548 1999-OS-19
WO 98/24806 PCTIUS97/21636
o ,c CH, I \
~~ cH, /
I) 0~.~ N ~' N O O CH,
N/~~ Ii O O / I / ~ OH,C CH, \
N N ~ N-N I
CE-2185 O / ~N~ ~ \ /
1 \ ~ o
CF, I O O
H,C CH, CH / CE-2191
N~ ~ CH,
\ O ~ ~ N-N
1VI / O
O ~ O
O
CE-2186 / 1
w CH,
H,C CH, \
I / ~ ~ ~ I-\ I /
O ~ ~CH,
O \ ~ ~..:~~ H,C CH, \ O O
I / N - C&2192
O I ~ N CF
O O
CE-21 B7
O
H,C, CH, ./:~.
\ O N~-N ~/ ~ \~ N-O I
I / U ~N y.~ ~ ~ / CF'
N
O O O
CH, CE~2193
OH,C ~ CH, \ H,C '
N I N O I
N~~ /. ~~~~CF
N '
I / O O
CE-2188
,C CH,
O N-N
N O O O
H,C CH, \ I \
\ ~-N~ I / I / CF ~ O
I ~ I N CE~2194 I \
/ O
O /
CE-2189
I
H
N ' H,C CH,
C ~ \ Ei N-N
N-N O I \
1 I \ I / o ~ o
O ~ CH, CE~2195 O / 1
O
1 : CH,
CE-2190
31

CA 02272548 1999-OS-19
WO 98124806 PCT/US97I2I636
I
/ Ctt
s
HsC CHl \ HOC CHI
HN O N-N I CHI O CHy
~N\~~ I O~ / ~C~\O~~ N CHI N_N
O tl O Ii O
CE-2196 O ~ O
O
CE~2202
CO 3Ii~C CH, \
I N-N
\ I \ ~ / CH
O ~ O O ~ ~ /N
CE-2197
O
HOC CHI \
HN O N O I
N~ I i~~CF
\ ~ O N
N-O ~ O
I ~~/~CF \ CE-2203
O /
~N ~ O
0
CH, CE-2198
O N O ~C C~ N-N
/ N\
O,
O O \
CE-2204 I
w C~ \ ~ /
O N
!
~~ N ~O
O ~ HOC CH3 \
CE-2200 I ~ ~ N N
/ CFA N~~ ~~~ ~~O\ / C
0 ~ ~O
O~O
CE.2205
N
O
N \ ~ OH~C CHs
HN~ ~~II N-N
~N~~ IO~
O O
CE-2206 I
CHI
3~-

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
H~C~ CHI ~ ~C CHI CHI
CHI
N CH H~CwO w N CHI
HOC O ~ ~ ' N-O ~ O
O O/ ~ / i O ~ O O
CE~2207 N
O / CE-2213 /
CHI
Cf~
OH~C CHI H C
HOC CHI H~C~ ~ N~ CHI
H)~~ O N-N O ~ ~ N-O
N.~~ / O ~ O O / ~ I i
O N
/ CE-2214 O /
CE-2208 ~ ~ CHs w CFA
O OH~C CHI /
O~O I~N,J~ / \ ~ ' CHI
N~~ N O O 'C CHl ~ ~O
N-O
HN ~ N ~ / ~ ~ ~ CE~2215
N
O O /
CE-2209 ~ , Cps CHI /O H C CH
O s
N-N
/ / H ~ / \
O
O O
HlC CHI CE-2216
'yi N-N 1.. CH)
O
O
CE~2210 /
N-~=! HOC
~CH~
\ I H~C~ CHI /
CI N. O N-N
i N / ~ w
O
N / \ I O CHI O O
N-N CE-2217
N~ I ~\
H1N ~ O
O O // HOC
CE-221 I
HOC CHI /
N-N
/
_ HOC CHI ~ O
O N-N O
N N~ ~ \
~ CE~2218
HN~ ~ ~ OI O
~~// O /
CE-2212 ~ 1 CHI
33

CA 02272548 1999-OS-19
WO 98/2480b PCTIUS97121636
N-O C
/ N Ii I -~ CFl
_ ~ N -N /
C&2219 O \
N ~ N_O HsC i lhC
O O~~ I N N / \ I O~C ~s N-N / I
O / ~ N~ I \ w
C&2220 ' ~ HzN ~ ~ O
O
CE-2226
N / ~ ~ OH~C CHa
N-O
N~~ I N
O
O C&2221
w
Ci
Fi~C ~ I OH'C ~' N-N
N / \ I OH~C CFh / N~ / \
N-N ~ ffiN # O
N~ IO\ w O O
O ~ O C&2228
C&2223
HyC
-N
\
O
HaC
C&2229
-N /
\ \ HOC
O
C
C&2224 ~ ~ N N
I \
\ O ~ O
O
C&2230
34

CA 02272548 1999-OS-19
WO 98/24806 PCTIUS97/21636
cc~..2a~s
H,c
H,c o
c
O~ ~ N-N / I
w I ~N~~ I O ~ w
O O O
C&2239
C&2233
fi~C
FhC
O
C
~ N-N / I N ,p,
N \ ~N~ / \ w \/LJ~~ O
p O
CE.2240
N, / , C&2234
I~I\
HOC
O
C
Me ~ N~ ~ I_\ / I
w
'~ ~ OMe ~C ~ O
C O
N OHy ~ N_N / I
N II I ~ ~ CE-2241
~N ~ ~~ O
p
(:&2233
s ~ ~,~
N/ ~ O~C ~ N_N
N~ I
~N ~ O
O C&2236 O 081242

CA 02272548 1999-OS-19
WO 98/24806 PCT/U597/21636
0
C
HN~ O~ ~ N-N / ~ -N /
~N~ ~ ~ w ~ y.
O O
O O
CE-2243 C~224g
HOC ~ FhC
O
N / ~ OFhC Cii~ N-N / ~ OMe
N
O
O O O
CE-2244 . HN O N-N
N~ I
O
O O
H,C C&2249
C~ N-N /
O
O
C 02245 -N
O ~ ~ CHI
O
CE-2250
HN~ O~ N-N
~N~ ~ ~
O
O O /
C&2?A6 ~ -N
O ~ ~' \ w CHI
O
N'
O C&2251
HN~ O~C ~ N-N
~N~
O
p ° /
v
C&2247 ~ C~ N-N
O
O
C&2252
3~

CA 02272548 1999-OS-19
WO 98/24806 PCT/ITS97/21636
\ / ~c.N_~
N~ ~ / O~C ~ N N I
N~ / ~ \
°
°
_/
OH I N O~C ~ N-N
N~ /
O
O \
° c~us° I /
H~ oH'c ~'
N-N
N
O
O F
C&2253 O ~ .1 I / O"'-\
w ~ I \ O~C ~ / O
N N I
N~ / ~ \
\ OH ~ ~ # O
I O
CE-2261
i0
H N _ O~C
N-N
N~ /
O
I /
~1
/
I N-N
N~ / ~ \ I
'°
C&Z257
37

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
F
F
O I N OFi~C Cfi~ N-N N OIi~C CHI
\ O~~ N~~ IO\ I / ~N I N~ / \
1i H p Fi~C CHI ~ O~CIi~
ONO-P0.690 O
ONO-PO-696
_ \ C Cfi~
I / N-N
I
0 0 ~C CHI I o ~ O
/ o
oNO-FO-691 oNO.FO.s97
P F
N O~C C~ \ O N O~C
N N I I N-N
~N N~ / \ / C~ \ ~ N~ I \
O O ti~C ~ I / ~ O ~ O
ONO-PO-698
nran_nn~o~
I N-N
/N~ O~~C.\/~ I \ \
N~ ~ \ / C ~N
O H' ~ OCH,
O
ONO-PC>'693 ONO-PO-699
F
/ O
N -N I
/ \ \ O
O It~C
ONO-P0.694 ONO-PO-700
F
F
O~C ~ N-N N OEhC Cfi~ / OH
~N N~ I \ .N I
O ~ O O ~ ~ HiN ~ O OH
ONO~PO-695 ONO-P0.701 O HsC
38

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/21636
C
H'C ~S ~ ~ ~ ~ Of~ ~ N-N
0 C~ i/ N V 'ti
0
ONO-P(~702 O O
C ONO-PO-708
F
O
C
I N OIi~C CIi~ N-N / I ~ N
N~ I ~ w w
~N ~ O ~ O 0
i O O
ONO-P0~709
ONO-PO-703
C O~C Clip
N-N ~C_S~ N ~C C~ /
I ~ II # N-N I
O CFi~ O 0 I ~ \
O O ~ O
ONO-PO-704
ONO-PO-710 O
_N
I N~ O~C ~ N-N / I
O N~ I ~
~N ~ ~ ~ .,.
ONO-PO-705 0
ONO-Y(J'711
-N
N
O
ONQ'PO-706
ONO-P0.712
O~C
N-N
N~~ I O~ ~ ~C ~ ~ N ~C ~ N N
ONO-PO-707 ~ 0 O ~ 0 ~Clh
ONO~PO-713 O Clh
3g

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
F
N-N
N~ I ~ CH,
N ~ O O
~N
C ~ N-N
N~ I ~
~~O ~C ~
ONO-PO-7l5
F
N-N
N~ I ~C~
O CFi~
O Clip
ONO-PO-T16 '
CI
N ~ ~ I O~C ~ N-N
N I ~ C
O O cal,
ONO-PO-717
N-N
O CHI
oNaFaTls
~J
~. __
ONO-PO-714

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
~c~cH,
0
o~c c~ I
N-N
N ~ ~ ~ O
O~C~ O~C ~ N-N ~ I
Cii~ HN
O ONO-PO-T19 N
O ~ O O
Ofi.
ONO~1P(~T24
-N / I
O Cti~
ONO-PO-720 ~ I \ O~C ~ N N
N
FI O~ ''~~CH~
O CHI
ONO-PO-725
N I
W I -N
gxN O -
H~C C~ O CHI
ONO-PO-72l CHI
ONO-PO-726
F
N ~ I N OH~C V Qil
N-N
I N~ I
O
ONO-PO-?22
ONO-PO-727
ONSC ~ N-N N
H~~~O
N
O O CHI
ONO~PO-728
ONO-P0.723

CA 02272548 1999-OS-19
WO 98124806 PCT/US97/21636
F
N O~C
N-N
N~ I ~
O
ONO-PO-729 ~O
ONO~PO-734
N O~C
N-N
N
O Cii~
O Cfi~
oNO.roa3o
ONO-PO-735
I N OIi~C CFi~ N-N
N~ I ~ ~ N HOC CEi,
O N-N
O O ~ ~ N
FilN
ONa-PO-73l ~ O O
ONO-PO-736
N aH~C~CH~
N-N
a c
N~~'~ '~~
a a
ONO.PO-732
ONO-PO-737
-N
O CEh
ONO.PO-733

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)z-, -NH-S(O)Z-, -OC(O)-, -C- or
an amino acid selected from, but not limited to, proline, isoleucine,
cyclohexylalanine,
cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl
optionally
substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,
dialkylamino, alkyl,
alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,
alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine,
dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-
carboxylic acid optionally substituted with alkyl, alkenyl or phenyl
optionally
substituted with halo, cyano, nitro, haloalkyl, amino, aminoaikyl,
dialkylamino, alkyl,
alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,
alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine
optionally
substituted with alkyl or aryl; histidine, methionine, valine, norvaline,
norleucine,
octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine
optionally substituted at the side chain nitrogen with alkyl, alkenyl,
alkynyl,
alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused
aryl-
cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more
heteroatoms
selected from N, O and S; and
R4 is H, alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5-
C,Z}aryl,
(CS-C,2)arylalkyl, fused (CS-C,2)aryl-cycloalkyl or fused alkyl (CS-C,z)aryl-
cycloalkyl
optionally comprising one or more heteroatoms selected from N, O and S, and
optionally substituted with alkyl, alkenyi, alkynyl, halo, cyano, nitro,
hydroxyl,
haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloaikoxy,
carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or
haloalkylthio or is absent.
In a preferred embodiment, X is N and Y is O. In another preferred
embodiment, X is O and Y is N. Preferably, R4-A is an arylalkyloxycarbonyl
such as
benzyloxycarbonyl; alkoxycarbonyl, arylsulfonyl, alkylsulfonyl or alkyl.
Preferably, Rz and R3 are alkyl such as methyl or isopropyl, or H. In one
preferred embodiment, RZ is isopropyl and R3 is H.
In a preferred embodiment of the invention, R, is an optionally substituted
aryl
or arylalkyl group, such as an a,a-dimethylbenzyl, benzyl or phenyl group.

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
The nomenclature for the above embodiments is as follows (although the
majority of the embodiments disclosed indicate the stereochemistry of the 2-
methylpropyl group having the (S)-configuration, it will be understood that
both the
{R)-configuration and the racemic (R,S) are within the scope of the
invention):
CE-2157 2-Oxo-5-(phenyl)-1,4-benzodiazepine-N-(1-(2-[S-(3-methylbenzyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2158 3-(S)-[(Benzyloxycarbonyl)amino-(5,6 phenyl-s-lactam]-N-[ 1-(3-[5-
(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2159 2-(R,S)-[(Methylene-4-pyridyl) piperazine-2,5-dioneJ-N-[ 1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2160 3-(R,S)-[(Benzyloxycarbonyl)amino-8-lactam]-N-[1-(3-[S-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2161 (Pyridyl-3-carbonyl)-L-valyl-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2162 4-[1-(2-N-Morpholino)ethyl-3-(R)-benzyl piperazine-2,5-dione]-N-[i-
(2-[5-(3-methylbenzyl}-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2163 Methylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2164 (Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide
CE-2165 N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N[1-{2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide
CE-2166 1-Phenyl-1,2,4-triazolidine-3,5-dione-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2168 Phenylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2170 1-(2-(S-[3-Methylbenzyl]-1,3,4-oxadiazolyl]-2-(S)-
[(benzyloxycarbonyl)amino]-3-methylbutan-1-one
CE-2171 (3-Pyridylcarbonyl)-L-valyl-N-[ 1-(3-[5-(3-trifluoromethylbenzyl)-
1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2172 Methylsulfonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2173 1-(3-Morpholinoethyl)-S-(R)-benzyl-2,4-imidazolidinedione-N-[1-(2-
W3

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2174 4-(R)-Isopropyl-2,S-imidazolidinedione-N-[1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl] acetamide
CE-2176 1-Benzyl-1,2,4-triazolidine-3,S-dione-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2177 (Benzyloxycarbonyl)-L-valyl-N-[ 1-(2-[5-(3,4-methylenedioxybenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2178 (Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-
1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2179 S-(R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2180 1-(N-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[ 1-(3-
[5-(3 trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-
methyipropyl]acetamide
CE-2181 1-(N-Morpholinoethyl)-S-(S)-benzyl-2,4-imidazolidinedione-N-[1-(3-
[5-(3 trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2182 5-{R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(3-[5-(3
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2183 Benzyloxycarbonyl-L-(1,2,3,4-tetrahydroisoquinoline)-3-N-[1-(2-[S-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]amide
CE-2184 1-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[ 1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2185 4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(3-[S-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-
prolinamide
CE-2186 4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2187 4-[1-(3,4-Ethylenedioxybenzyl)-3-(S)-benzyl-piperazine-2,5-dione-N-
[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2188 1-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[ I-{3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
CE-2189 1-Benzyl-2,4-imidazolidinedione-N-[ 1-{3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2190 [1-Benzyloxycarbonyl-5-(R)-benzylpiperazin-3-one]-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methyipropyl]acetamide
CE-2191 1-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2192 1-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[ 1-
(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2193 1-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[ 1-
(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2194 [4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2195 (Pyrrole-2-carbonyl)-N-{1-(R,S)-indanyl)glycyl-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide
CE-2196 (6-(R)-Benzylpiperazin-2-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2197 4-[1-(3,4-Methylenedioxybenzyl)-3-{R)-benzylpiperazine-2,5-dione]-
N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2198 4-(R,S)-Phenyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2200 [4-{R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-{3-
[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2202 Isopropyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazoiyl]carbonyl)-2-(S)-methylpropyl]-L-proiinamide
CE-2203 [4-(R)-(3-pyridylmethylene)]-2,5-imidazolidinedione-N-[1-(3-[5-(3
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2204 1-Benzyloxycarbonyl-(2-(R)-phenylpiperazin-5-one)-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2205 [4-(R)-(3-pyridylmethyl)]-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
~S

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
CE-2206 [4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]-2,5-imidazolidinedione-
N-[1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-{S)-
methylpropyl]acetamide
CE-2207 Isopropyloxycarbonyl-L-valyl-N-[1-(3-[5-(3- trifluoromethylbenzyl)-
1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2208 (2-{R)-Phenylpiperazin-S-one)-N-[1-{2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2209 [4-(R,S)-(4-pyridyl)-4-{R,S)-N-succinimidyl]-2,5-imidazolidinedione-
N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
i0 methylpropyl]acetamide
CE-2210 {N-Benzylcarbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl}-2-(S)-methylpropyl]amide
CE-2211 (R,S)-3-Amino-2-oxo-5-phenyl-1,4-(6-2'-chlorobenzodiazepine)-N-[1-
(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S}-propyl]acetamide
CE-2212 3-[1-(4-Piperidine)]-benzimidazolidin-2-one-N-[1-(2-[5-{3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2213 Methyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-{S)-methylpropyl]-L-prolinamide
CE-2214 Methyloxycarbonyl-L-valyl-N-[1-(3-[5-(3 trifluoromethylbenzyl)-
1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
CE-2215 1,4-Quinazolin-2-one-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2216 [4-(R,S)-(2-Pyridyl)-4-(R,S)-methyl]-2,5-imidazolidinedione-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2217 2-Oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2218 {R,S)-3-Amino-2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-{2-[5-(3-
methylpropyl}-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2219 1,4-Quinazolin-2-one-N-[ 1-(3-[S-(3-trifluoromethylbenzyl)-1,2,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2220 (2S,SS)-S-Amino-1,2,4,5,6,7-hexahydroazepino-[3.2.1]-indole-4-one-
carbonyl-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]amide
L

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/Z1636
CE-2221 (R,S)-3-Amino-2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(3-[5-{3-
methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2223 (R,S)-3-Amino-2-oxo-5-phenyl-1,4-(2'-chlorobenzodiazepine)-N-[1-
{2-[5-(3-methylbenzyl}-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2224 (R,S)-3-Amino-2-oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-
[5-{3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2225 (R,S)-3-Amino-2-oxo-5-methyl-1,4-(2',3'-methylenedioxy)
benzodiazepine)-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2226 (R,S)-3-Amino-2-oxo-5-methyl-1,4-benzodiazepine-N-[1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(R,S)-methylpropyl] acetamide
CE-2227 4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-{3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2228 3-(R,S)-Amino-quinolin-2-one-N-[1-(2-[5-{3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
CE-2229 (R,S)-3-Amino-2-oxo-5-(2-chlorophenyl)-1,4-(2'-
chlorobenzodiazepine)-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-
2-
(R,S)-methylpropyl]acetamide
CE-2230 {R,S)-3-Benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-1,4-(2'
chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-
2
(R,S)-methylpropyl]acetamide
CE-2231 4-Spirocyclopentane-2,5-imidazolidinedione-N-[ 1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2232 Benzyloxycarbonyl-L-valyl-N-(phenyl)glycyl-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide
CE-2233 2-Oxo-5-(4-piperidinyl)-1,4-benzodiazepine-N-[1-(2-[S-(3-
methyibenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2234 2-(2-Pyridyl)-benzimidazole-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide
CE-2235 (R,S)-3-Amino-2-oxo-5-methyl-1,4-(2',3'-dimethoxybenzodiazepine)-
N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
CE-2236 (R,S)-3-Amino-2-oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-[1-(2-

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2237 2-Oxo-5-(4-trifluoromethylphenyl)-1,4 benzodiazepine-N-[1-(2-[5-(3-
methylbenzyl}-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2238 2,5-Imidazolidinedione-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2239 4,4-Dimethyl-2,5-imidazolidinedione-N-[ 1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2240 4-(S)-(2-Isopropyl)-2,5-imidazolidinedione-N-[ 1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2241 4-Spirocyclohexane-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2242 2-Oxo-5-phenyl-1,4-(4'-methylbenzodiazepine)-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2243 4-(R)-{3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2244 2-Oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-(I-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2245 2-Oxo-5-methyl-1,4-(2-phenyl-1-thiophenodiazepine)-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide
CE-2246 4-(R)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S}-methylpropyl]acetamide
CE-2247 4-(R)-(2-N,N-Dimethylcarboxamido)-2,5-inudazolidinedione-N-[ 1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2248 2-Oxo-5-(3,4-methylendioxyphenyl)-1,4-benzodiazepine-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2249 4-(R)-(3-Carbomethoxy~ropyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2250 2-Oxo-S-(2-methoxyphenyl}-1,4-benzodiazepine-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2251 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-
(2-(5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2252 4,4-biphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methyibenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
~8

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/2i636
CE-2253 4-Spiro-(2-indanyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2254 2-[(4-Fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-jl-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2255 4-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2256 4-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-(5-(3,4-
methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2257 4-(R)-(2-Imidazolyl)-2,5-imidazolidinedione-N-[1-(2-(5-{3-
methylbenzyl)-i,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2258 2-Oxo-S-phenyl-1,4-(2'-dimethylaminobenzodiazepine)-N-[1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2259 4,4-biphenyl-2,5-imidazolidinedione-N-[I-(2-[5-(3,4-
methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S}-methylpropyl]acetamide
CE-2260 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
CE-2261 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-(1-
(2-[S-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
CE-2262 2-[5-Amino-6-oxo-2-thiophenyl-I,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S}-methylpropyl]acetamide
CE-2263 2-[5-Amino-6-oxo-2-{3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-690 2-[S-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-I-pyrimidinyl]-N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-
2-(S)-methylpropyl]acetamide
ONO-PO-691 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-(S-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-692 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-(a,a-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]
carbonyl)-
2-(S)-methylpropyl]acetamide
ONO-PO-693 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
~! 9

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide
ONO-PO-694 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-695 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[S-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-696 2-[S-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-697 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl]-N-[ 1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-698 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-
dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-699 2-[S-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[S-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-700 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-(1-(2-[5-(a,a-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-701 2-[5-Amino-6-oxo-2-{4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl] N-[1-(2-[5-(a,a-dimethyl-3,4-dihydroxybenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide
ONO-PO-702 2-[S-(Methylsulfonyl)amino-6-oxo-2-(4-fluorophenyl}-1,6-
dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-
2-
(S)-methylpropyl]acetamide
ONO-PO-703 2-(5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-704 2-[S-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
~b

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
pyrimidinyl]-N-[1-(2-[S-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-705 2-[S-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-I-
pyrimidinyl]-N-[I-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-706 2-[S-Amino-6-oxo-2-{4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ I -(2-[5-butyl-1,3,4-oxadiazolyl] carbonyl}-2-(S)-
methylpropyl]acetamide
ONO-PO-707 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methyipropyl]acetamide
ONO-PO-708 4-(S)-{2-Isobutyl}-2,5-imidazolidinedione-N-[1-(2-[5-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-709 4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[ 1-(2-[5-(a,a-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide
ONO-PO-710 Methylsulfonyl-L-valyl-N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
ONO-PO-711 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-( 1-
(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-712 2-[5-Amino-6-oxo-2-(3-pyridyl)-I,6-dihydro-1-pyrimidinyl] N-
[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-713 Methylsulfonyl-L-valyl-N-[I-(2-[S-(tert-butyl-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
ONO-PO-714 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[S-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(S)-
methylpropyl]acetamide
ONO-PO-715 2-[S-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-I-pyrimidinyi]-N-
[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-716 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyi]-N-[I-
(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
SJ

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
ONO-PO-717 2-Oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-718 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide
ONO-PO-719 4-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-720 4-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[S-(a,a-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S )-methylpropyl] acetamide
ONO-PO-721 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide
ONO-PO-722 2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-723 4-(R.)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-724 4-(R)-(3-Indolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(a,a-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-725 2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[S-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl)acetamide
ONO-PO-726 2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[S-{a,a-
dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-727 2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[ 1-
(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide
ONO-PO-728 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-729 2-[S-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrin~idinyl]-N-[1-
(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide
ONO-PO-730 2-j6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] N-[1-(2-[5-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-731 2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-j 1-(2-j5-a,a-
dimethylbenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-732 2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-
_ ~._.._~..._ _ . T __ _.___ __ _

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide
ONO-PO-733 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide
ONO-PO-734 2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[ 1-
(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
ONO-PO-735 2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-
methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
ONO-PO-736 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-
(2-j5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
ONO-PO-737 2-[6-Oxo-2-phenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-j5-tert-
butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide
The compounds of the present invention are not limited to use for inhibition
of
human elastase. Elastase is a member of the class of enzymes known as serine
proteases. This class also includes, for example, the enzymes chymotrypsin,
cathepsin G, trypsin and thrombin. These proteases have in common a catalytic
triad
consisting of Serine-195, Histidine-57 and Aspartic acid-102 (chymotrypsin
numbering system). The precise hydrogen bond network that exists between these
amino acid residues allows the Serine-195 hydroxyl to form a tetrahedral
intermediate
with the carbonyl of an amide substrate. The decomposition of this
intermediate
results in the release of a free amine and the acylated enzyme. In a
subsequent step,
this newly formed ester is hydrolyzed to give the native enzyme and the
carboxylic
acid. It is this carboxyl component that helps characterize the specificity
for the
enzyme. In the example in which the carboxyl component is a peptide, the alpha-
substituent of the amino acid is predominately responsible for the specificity
toward
the enzyme. Utilizing the well accepted subset nomenclature by Schechter and
Berger
(Biochem. Biophy. Res. Commun., 27:157 (1967) and Biochem. Biophys. Res.
Commun., 32:898 (1968)), the amino acid residues in the substrate that undergo
the
cleavage are defined as P,...Po toward the N-terminus and P,'...Pn' toward the
C-
terminus. Therefore, the scissile bond is between the P, and the P,' residue
of the
peptide subunits. A similar nomenclature is utilized for the amino acid
residues of the

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
enzyme that make up the binding pockets accommodating the subunits of the
substrate. The difference is that the binding pocket for the enzyme is
designated by
5,...5" instead of P,...Pn as for the substrate.
The characteristics for the P, residue defining serine proteinase specificity
is
well established. The proteinases may be segregated into three subclasses:
elastases,
chymases and tryptases based on these differences in the P, residues. The
elastases
prefer small aliphatic moieties such as valine whereas the chymases and
tryptases
prefer large aromatic hydrophobic and positively charged residues
respectively.
One additional proteinase that does not fall into one of these categories is
propyl endopeptidase. The P, residue defining the specificity is a proline.
This
enzyme has been implicated in the progression of memory loss in Alzheimer's
patients. Inhibitors consisting of a-keto heterocycles have recently been
shown to
inhibit propyl endopeptidase; Tsutsumi et al., J. Med. Chem., 37: 3492-3502
(1994).
By way of extension, a-keto heterocycles as defined herein allow for an
increased
binding in P' region of the enzyme.
Table 1. P, Characteristics for Proteinase Specificity
Proteinase ClassRepresentative Enzyme P, Characteristic
Elastases Human Neutrophil Elastasesmall aliphatic residues
Chymases alpha-Chymotrypsin, aromatic or large
Cathepsln G hydrophobic residues
Tryptases Thrombin, Trypsin, positively charged
residues
Urokinase, Plasma Kallikrein,
Plasminogen Activator,
Plasmin
Other Prolyl Endopeptidase proline
Since the P, residue predominately defines the specificity of the substrate,
the
present invention relates to P,-Pa modifications, specifically, certain alpha-
substituted
keto-heterocycles composed of 1,3,4 oxadiazoles, 1,2,4-oxadiazoles, 1,3,4-
thiadiazoles, 1,2,4-thiadiazoles, 1-substituted, and 4-substituted 1,2,4-
triazoles. By
altering the alpha-substituent and the substituent on the heterocycle, the
specificity of
these compounds can be directed toward the desired proteinase (e.g., small
aliphatic
groups for elastase).

CA 02272548 1999-OS-19
WO 98/24806 PCTJIJS97/21636
The efficacy of the compounds for the treatment of various diseases can be
determined by scientific methods which are known in the art. The following are
noted
as examples for HNE mediated conditions:
- for acute respiratory distress syndrome, the method according to human
neutrophil elastase (HNE) model (AARD, 141:227-677 ( 1990)); the endotoxin
induced
acute lung injury model in minipigs (HARD, 142:782-788 (1990));or the method
according to human polymorphonuyclear elastase-induced lung hemorrage model in
hamsters (European Patent Publication No. 0769498) may be used;
- in ischemia/reperfusion, the method according to the canine model of
reperfusion injury (J. Clin. Invest., 81: 624-629 (1988)) may be used.
The compounds of the present invention, salts thereof, and their intermediates
can be prepared or manufactured as described herein or by various processes
known to
be present in the chemical art (see also, WO 96/16080). For example, compounds
of
Group I may be synthesized according to the schemes set forth in Figures 1-2
(1,3,4
oxadiazoles) and Figures 3-4 (1,2,4 oxadiazoles). Figures 5-7 describe the
synthesis
of compounds of Group II. Figures 8-9 describe the synthesis of compounds of
Group
III; Figure 10 describes synthesis of Group IV compounds. The several classes
of
Group V compounds are described in Figures 11-22.
Alternatively, the compounds of the present invention may be prepared as
described in Figure 39. The 2-substituted 1,3,4-oxadiazole (3) may be prepared
via
formation of the acid chloride from an acid (1 ) utilizing, for example,
thionyl chloride
or oxalyl chloride, followed by treatment with hydrazine in a suitable solvent
to yield
the hydrazide (2). Reaction of (2) with triethyl orthoformate or trimethyl
orthoformate and TsOH gives the requisite 2-substituted 1,3,4-oxadiazole (3).
Formation of the compound (3') utilizing standard conditions (ie. butyllithium
at low temperature in a polar aprotic solvent, and further, if desired,
reacting with
MgBr~OEtz) followed by addition of the aldehyde (4) yields the alcohol (5).
Deprotection of the protected amine of (S) using hydrochloric acid in dioxane
gives the amino hydrochloride (6) which is then coupled to the acid (7) by
methods
available to one skilled in the art to give intermediate (8). Oxidation using
Dess-
Martin's Periodinane or other methods as described in Oxidation in Organic
Chemistry by Milos Hudlicky, ACS Monograph 186 (1990) yields the ketone (9).
The final step requires removal of the protecting group from the amine. This

CA 02272548 1999-OS-19
WO 98/24806 PCT/ETS97/21636
may be carried out by a number of methods. For example, one may utilize
aluminum
chloride, anisole and nitromethane in a suitable solvent such as
dichloromethane to
give the final compound (10). Compound (10) can then be treated with an
electrophile (e.g., methanesulfonyl chloride) with added base to give (14).
S The aldehyde (4) may be prepared via either of three methods described. The
Weinreb amide ( 12) is prepared from the amino acid ( 11 ) which is
subsequently
reduced to the aldehyde using diisobutylalluminum hydride (DIBAL).
Alternatively,
one may generate the ester of the amino acid (13) followed by reduction with
DIBAL
to afford the aldehyde (4). Further, one may generate the alcohol (13-1)
followed by
oxidation with S03-Py in DMSO.
The activity of the compounds is presented in Figures 23-38 as K; values (nM).
K; values were determined, unless otherwise indicated, essentially as
described in
WO 96/16080, incorporated herein by reference.
Although the compounds described herein and/or their its salts may be
administered as the pure chemicals, it is preferable to present the active
ingredient as a
pharmaceutical composition. The invention thus further provides the use of a
pharmaceutical composition comprising one or more compounds and/or a
pharmaceutically acceptable salt thereof, together with one or more
pharmaceutically
acceptable Garners thereof and, optionally, other therapeutic and/or
prophylactic
ingredients. The carriers) must be 'acceptable' in the sense of being
compatible with
the other ingredients of the composition and not deleterious to the recipient
thereof.
Pharmaceutical compositions include those suitable for oral or parenteral
(including intramuscular, subcutaneous and intravenous) administration. The
compositions may, where appropriate, be conveniently presented in discrete
unit
dosage forms and may be prepared by any of the methods well lrnown in the art
of
pharmacy. Such methods include the step of bringing into association the
active
compound with liquid Garners, solid matrices, semi-solid Garners, finely
divided solid
carriers or combination thereof, and then, if necessary, shaping the product
into the
desired delivery system.
Pharmaceutical compositions suitable for oral administration may be presented
as discrete unit dosage forms such as hard or soft gelatin capsules, cachets
or tablets
each containing a predetermined amount of the active ingredient; as a powder
or as
granules; as a solution, a suspension or as an emulsion. The active ingredient
may

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
also be presented as a bolus, electuary or paste. Tablets and capsules for
oral
administration may contain conventional excipients such as binding agents,
fillers,
lubricants, disintegrants, or wetting agents. The tablets may be coated
according to
methods well known in the art., e.g., with enteric coatings.
Oral liquid preparations may be in the form of, for example, aqueous or oily
suspension, solutions, emulsions, syrups or elixirs, or may be presented as a
dry
product for constitution with water or other suitable vehicle before use. Such
liquid
preparations may contain conventional additives such as suspending agents,
emulsifying agents, non-aqueous vehicles (which may include edible oils), or
preservative.
The compounds may also be formulated for parenteral administration (e.g., by
injection, for example, bolus injection or continuous infusion) and may be
presented
in unit dose form in ampules, pre-filled syringes, small bolus infusion
containers or in
mufti-does containers with an added preservative. The compositions may take
such
forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and
may
contain fornlulatory agents such as suspending, stabilizing and/or dispersing
agents.
Alternatively, the active ingredient may be in powder form, obtained by
aseptic
isolation of sterile solid or by lyophilization from solution, for
constitution with a
suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds may be formulated
as ointments, creams or lotions, or as the active ingredient of a transdermal
patch.
Suitable transdermal delivery systems are disclosed, for example, in Fisher et
al. (LJ.S.
Patent (No. 4,788,603) or Bawas et al. (U.S. Patent No. 4,931,279, 4,668,504
and
4,713,224). Ointments and creams may, for example, be formulated with an
aqueous
or oily base with the addition of suitable thickening and/or gelling agents.
Lotions
may be formulated with an aqueous or oily base and will in general also
contain one
or more emulsifying agents, stabilizing agents, dispersing agents, suspending
agents,
thickening agents, or coloring agents. The active ingredient can also be
delivered via
iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4383,529, or
4,051,842.
Compositions suitable for topical administration in the mouth include unit
dosage forms such as lozenges comprising active ingredient in a flavored base,
usually sucrose and acacia or tragacanth; pastilles comprising the active
ingredient in
S7

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent
gets,
and mouthwashes comprising the active ingredient in a suitable liquid carrier.
When desired, the above-described compositions can be adapted to provide
sustained release of the active ingredient employed, e.g., by combination
thereof with
certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic
polymer
gels or mixtures thereof.
The pharmaceutical compositions according to the invention may also contain
other adjuvants such as flavorings, coloring, antimicrobial agents, or
preservatives.
It will be further appreciated that the amount of the compound, or an active
salt or derivative thereof, required for use in treatment will vary not only
with the
particular salt selected but also with the route of administration, the nature
of the
condition being treated and the age and condition of the patient and will be
ultimately
at the discretion of the attendant physician or clinician.
In general, however, a suitable dose will be in the range of from about 0.5 to
about 100 mglkg/day, e.g., from about 1 to about 75 mg/kg of body weight per
day,
such as 3 to about 50 mg per kilogram body weight of the recipient per day,
preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of
15 to 60
mg/kg/day.
The compound is conveniently administered in unit dosage form; for example,
containing 0.5 to 1000 mg, conveniently 5 to 750 mg, most conveniently, 10 to
S00
mg of active ingredient per unit dosage form.
Ideally, the active ingredient should be administered to achieve peak plasma
concentrations of the active compound of from about 0.5 to about 75 uM, more
preferably, about 1 to 50 uM, most preferably, about 2 to about 30 pM. This
may be
achieved, for example, by the intravenous injection of a 0.05 to 5% solution
of the
active ingredient, optionally in saline, or orally administered as a bolus
containing
about 0.5-500 mg of the active ingredient. Desirable blood levels may be
maintained
by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent
infusions containing about 0.4-15 mg/kg of the active ingredient(s).
The desired dose may conveniently be presented in a single dose or as divided
doses administered at appropriate intervals, for example, as two, three, four
or more
sub-doses per day. The sub-dose itself may be further divided, e.g., into a
number of

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
discrete loosely spaced administrations; such as multiple inhalations from an
insufflator or by application of a plurality of drops into the eye.
While the invention has been described in connection with specific
embodiments thereof, it will be understood that it is capable of further
modifications
S and this application is intended to cover any variations, uses, or
adaptations of the
invention following, in general, the principles of the invention and including
such
departures from the present disclosure as come within known or customary
practice
within the art to which the invention pertains and as may be applied to the
essential
features hereinbefore set forth, and as follows in the scope of the appended
claims.
The following examples are given to illustrate the invention and are not
intended to be inclusive in any manner:
Examples
The following abbreviations are used below: TFA - trifluoroacetic acid; HOBT
- hydroxybenzotriazole; DIEA - diisopropylethylamine; NMM - 4-
methylmorpholine;
DMF - N,N-dimethylformamide; TEA - triethylamine; EDCI - 1-{3-
dimethylaminopropyl-3-ethylcarbodiimide; BOPCI - bis(2-oxo-3-
oxazolidinyl)phosphinic chloride; FMOC - 9-fluorenyl methoxycarhonyl; BTD -
bicyclic turned dipeptide (see, e.g., Tetrathedron, 49:3577-3592 (1993)); THF -
tetrahydrofuran
Example 1- (CE-2072) (Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide
To a mixture containing 0.79 g {5.94 mmol) of N chlorosuccinimide in 40 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.65
mL (8.85
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the dropwise addition of a solution
containing
(benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(3-methylbenzyl)-1,3,4
oxadiazolyl]hydroxymethyl)-2-(S~-methylpropyl]-L-prolinamide (0.90 g, 1.49
mmol)
in 17 mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at
-25°C
followed by the addition of 1.0 mL (?.17 mmol) of triethylamine. The cold bath
was

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
removed and the mixture allowed to warm to room temperature and maintained for
20
minutes. The reaction mixture was diluted with ethyl acetate and washed with
water.
The organic phase was dried over magnesium sulfate, filtered and the solvent
removed
under reduced pressure. The residue was purified by column chromatography on
silica gel with 70% ethyl acetate/hexane to give 0.90 g of material which was
further
purified via preparative HPLC to afford 665 mg (73.9%) of the title compound
as a
white solid. FAB MS [M+H] m/z; Calcd: 604, Found 604.
The intermediate (benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide was
prepared
as follows:
a. 3-(S) Amino-2-(R,S)-hydroxy-4-methyl pentanoic acid.
To a solution containing 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-
methylpentanenitriie (see example 1 of WO 96/16080) (15.2 g, 50.0 mmol) in 183
mL
of dioxane was added 183 mL of concentrated hydrochloric acid and 7.45 mL of
1 S anisole. The reaction mixture was heated to reflex overnight. The
hydrolysis reaction
was allowed to cool to room temperature and then concentrated in vacuo. The
resulting aqueous solution was extracted with ether (2X). The aqueous phase
was
placed on a Dowex 50X8-100 column (H+ form, preeluted with deionized water to
pH=7). The column was eluted with 2.0 N ammonium hydroxide and the pure
fractions concentrated to afford 5.53 g (75%) of 3-(S)-amino-2-(R,S)-hydroxy-4-
methylpentanoic acid as a pale yellow solid. FAB MS [M+H] m/z; Calcd: 148,
Found: 148.
b. 3-(S)-~(Benzyloxycarbonyl)aminoJ-2-(R,S)-hydroxy-4-methylpentanoic
acid.
To a solution under an atmosphere of nitrogen containing 1.0 g (6.8 mmol) of
3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 mL of 1 N NaOH and
10
mL of dioxane was added 1.43 g (8.4 mmol) of benzyl chloroformate. The pH was
maintained above pH 8 with 1 N NaOH as needed. The reaction mixture was
allowed
to stir at room temperature overnight. The reaction was diluted with water and
washed with ether. The aqueous layer was acidified with 1 N HC1 to pH =2 and
extracted with ether (2X). The combined organic layers were dried over
magnesium
sulfate, filtered and evaporated in vacuo to afford 1.75 g (92%) of 3-(S)-

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
[(benzyloxycarbonyl)amino]-2-(R, S)-hydroxy-4-methylpentanoic acid as a light
yellow viscous oil. FAB MS [M+H] m/z; Calcd: 282, Found: 282.
c. 3-(S)-((Benzyloxylcarbonyl)aminoJ-2-(R, S)-acetoxy-4-methyl
pentanoic acid.
To a solution of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,,S~-hydroxy-4-
methylpentanoic acid (1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added
acetic
anhydride (S.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The
reaction
was allowed to stir overnight and was diluted with ethyl acetate and washed
with
water (2X). The organic layer was dried over magnesium sulfate, filtered and
evaporated in vacuo to give a thick oil. The residue was purified by column
chromatography on silica gel with 1 S% methanol/dichloromethane to afford 1.56
g
(80%) of 3-(S)-[{benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoic
acid
as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.
d. 1-((3-Methylphenylacetyl)-2-(2-(R, S)-acetoxy)-3-(S)-
1 S ~(benzyloxycarbonyl)aminoJ-4-methylpentanoylJ hydrazine.
To a solution containing 3-(S)-[(benzyloxycarbonyl)amino]-2-(R, S)-acetoxy-
4-methylpentanoic acid (2.3 g, 7.11 mmol) in 40 mL of DMF under a nitrogen
atmosphere at 0°C was added 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09
mmol)
of EDCI. After stirnng for 30 minutes, 1.20 g {7.31 mmol) of 3-methylphenyl
acetic
hydrazide {prepared analogously to the monoacid hydrazides cited by Rabins et.
al. (J.
Org. Chem, 30:2486 (1965)) and 1.0 mL (9.10 mmol) of NMM were added. The
reaction was allowed to warm to room temperature and stir overnight. The
reaction
was diluted with ethyl acetate and washed with S% potassium hydrogen sulfate,
saturated sodium bicarbonate, brine and water. The organic phase was dried
over
2S magnesium sulfate, filtered and evaporated under reduced pressure. The
residue was
purified by column chromatography on silica gel with 10%
methanol/dichloromethane
to afford 2.31 g (89.0%) of the title compound as a white solid. FAB MS [M+H]
m/z;
Calcd: 470, Found: 470.
e. I-~2-(S-~3-Methylbenzyl)J-1,3,4-oxadiazolylJ-I-acetoxy-2-(S)-
~(benzyloxycarbonyl)aminoJaminoJ-3-methylbutane.
A solution containing 2.31 g (4.92 mmol) of 1-[(3-methylphenylacetyl)-2- (2-
(R,S)-acetoxy)-3-(S)-[(benzyloxycarbonyl)amino]-4-methyl pentanoyl]hydrazine
in 25
GI

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
mL of pyridine and 1.88 g (9.86 mmol) of toluene sulfonyl chloride was heated
at
reflux under a nitrogen atmosphere for 72 hours. The solvent was removed under
reduced pressure and the residue dissolved in ethyl acetate and washed with
water.
The organic phase was dried over magnesium sulfate, filtered and evaporated
under
S reduced pressure. The residue was purified by column chromatography on
silica gel
with S% ethyl acetate/hexane to afford i.41 g (63.5%) of the title compound.
FAB
MS [M+H] m/z; Caicd: 452, Found: 452.
f. 1-(2-(S-(3 MethylbenzylJ-1,3,4-oxadiazolyl)J-2-(S)-
((benzyloxycarbonyl)aminoJ-3-methylbutan-1-ol.
A solution containing 1.80 g (3.99 mmol) of 1-[2-(S-[3-methylbenzyl]-1,3,4-
oxadiazoiyl)]-1-acetoxy-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutane and
0.72
g (5.21 mmol) of potassium carbonate in 30 mL of methanol and 8 mL of water
was
allowed to stir at room temperature for 30 minutes. The solvent was removed
under
reduced pressure and the residue dissolved in ethyl acetate and washed with
water.
1 S The organic phase was dried over magnesium sulfate, filtered and
evaporated under
reduced pressure. The residue was purified by column chromatography on silica
gel
with 50% ethyl acetate/hexane to afford 1.46 g (89.3%) of the title compound.
FAB
MS [M+H] m/z; Calcd: 410, Found: 410.
g. 1-(2-(S-~3 MethylbenzylJ)-1,3,4-oxadiazolylJ-2-(S)-Amino-3-
methylbutan-I-of hydrochloride.
To a solution containing 1.31 g (3.20 mmol) of 1-[2-(5-[3-methylbenzyl])-
1,3,4-oxadiazolyl]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-of in 25
mL of
trifluoroacetic acid under a nitrogen atmosphere at 0°C was added 0.43
mL (3.94
mmol) of thioanisole. The reaction was allowed to warm to room temperature
overnight. The solvent was removed under reduced pressure and the residue
dissolved
in ether and cooled to -78°C under a nitrogen atmosphere. To this
solution was added
3 mL (3 mmol) of 1 N hydrochloric acid in ether. The resulting white solid was
allowed to settle and the ether decanted. Additional ether was added and
decanted
(3X). The solid was dried under vacuum to afford 0.92 g (92.2%) of the title
compound. FAB MS [M+H) m/z; Calcd: 276, Found: 276.
h. (Benzyloxycarbonyl)-L-valyl-N ~l -(2-~S-(3-methylbenzyl)-1, 3, 4-
oxadiazolylJhydroxylmethyl)-2-(S)-methylpropylJ-L prolinamide.

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21b3b
To a solution containing 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in 25 mL of
anhydrous dichloromethane under a nitrogen atmosphere at 0°C was added
0.90 g
(3.54 mmol) of BOPC1 and 0.60 g (3.44 mmol) of DIEA. After stirring for 30
minutes, 0.90 g (2.89 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-
(S~-
amino-3-methyl butan-1-of hydrochloride in 15 mL of dichloromethane and 0.6 mL
(3.94 mmol) of DIEA was added. The reaction was allowed to stir at 0°C
overnight.
The reaction was diluted with dichloromethane and washed with a saturated
sodium
bicarbonate solution. The organic phase was dried over magnesium sulfate,
filtered
and evaporated. The residue was purified by column chromatography on silica
gel
with 5% methanol/dichloromethane to afford 1.0 g (57.3%) of the title compound
as a
tan solid. FAB MS [M+H] m/z; Calcd: 606, Found: 606.
Example 2 - (CE-2074)(Benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(methyl)-1,3,4-
oxadiazoly]carbony)]-2-(,S')-methylpropyl]-L-prolinamide. Prepared similar to
Example 1. FAB MS [M+H] m/z; Calcd: 514, Found: 514.
Example 3 - (CE-2075)(Benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(3-
trifluoromethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(,S~-methylpropyl] L-
prolinamide. Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 658,
Found:658.
Example 4 - (CE-2100)(Benzyloxycarbonyl)-L-valyl-N [1-{2-[5-(4-Dimethylamino
benzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(f)-methylpropyl]-L-prolinamide.
Prepared
similar to Example 1. FAB MS [M+H] m/z; Calcd: 633, Found: 633.
Example S - (CE-2124)(Benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(1-napthylenyl)-
1,3,4-xadiazolyl]carbonyl)-2-(,S')-methylpropyl]-L-prolinamide. Prepared
similar to
Example 1. FAB MS [M+H] m/z; Calcd: 640, Found: 640.
Example 6 - (CE-2177)(Benzyloxycarbonyl)-L-valyl-N [1-(2-[5-(3,4-
methylenedioxybenzyl)- 1,3,4-oxadiazolyl] carbonyl)-2-(,S~-methylpropyl]-L-
prolinamide. Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 634,
3

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97121636
Found: 634.
Example 7 - (CE-2178)(Benzyloxycarbonyl)-L-valyl-N [ 1-(3-[5-(3,4-
methylenedioxybenzyl)- 1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyi]-L-
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;
Calcd: 634, Found: 634.
Example 8 - (CE-2052)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[5-(3,5-
dimethylbenzyl)-1,2,4-oxadiazolyl] carbonyl}-2-(,S~-methylpropyl]-L-
prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 618,
Found: 618.
Example 9 - (CE-2053)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[5-(3,5-
dimethoxybenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-
prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 650,
Found: 650.
Example 10 - (CE-2054)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[5-(3,5-
ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;
Calcd: 726, Found: 726.
Example 11- (CE-2055)(Benzyloxycarbonyl) L-valyl-N [1-(3-[S-(3-methyibenzyl)-
1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-prolinamide. Prepared
similar to
Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 604, Found: 604.
Example 12 - (CE-2057)(Benzyloxycarbonyl) L-valyl-N [ 1-(3-[5-
biphenylmethine)-
1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-prolinamide. Prepared
similar to
Example 1 of WO 96/16080. FAB MS [M+H] mlz; Calcd: 666, Found: 666.
Example 13 - {CE-2058)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[5-(4-phenyibenzyl)-
1,2,4-oxadiazolyl] carbonyl)-2-(,S~-methylpropyl]-L-prolinamide. Prepared
similar to

CA 02272548 1999-OS-19
WO 98124806 PCT/US97/21636
Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666, Found: 666.
Example 14 - (CE-2062)(Benzyloxycarbonyl)-L-valyl-N [1-{3-[S-(3-phenylbenzyl)-
1,2,4-oxadiazolyl] carbonyl)-2-(,S~-methylpropyl] L-prolinamide. Prepared
similar to
Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666, Found: 666.
Example 15 - (CE-2066)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[S-(3-phenoxybenzyl}-
1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-prolinamide. Prepared
similar to
Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 682, Found: 682.
Example 16 - {CE-2069)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[S-
cyclohexylmethylene)-1,2,4-oxadiazolyl] carbonyl)-2-(,S~-methylpropyl]-L-
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;
Calcd: 596, Found: 596.
1S
Example 17 - (CE-2073)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[S-(a,a-dimethyl-3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl] carbonyl}-2-(S')-methylpropyl]-L-
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;
Calcd: 686, Found: 686.
Example 18 - (CE-2077)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[S-(1-
napthylmethylene)-1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-
prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 640,
Found: 640.
2S
Example 19 - (CE-2078)(Benzyloxycarbonyl)-L-valyl-N [1-(3-[S-(3-pyridylmethyl)-
1,2,4-oxadiazolyl] carbonyl)-2-(,S~-methylpropyl]-L-prolinamide. Prepared
similar to
Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 591, Found: 591.
Example 20 - (CE-2096)(Benzyloxycarbonyl) L-valyl-N [1-(3-[S-(3,S-
diphenylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]-L-
prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 742,
~s

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97J21636
Found: 742.
Example 21- (CE-2115)(Benzyloxycarbonyl) L-valyl-N [1-(3-[5-(4-
dimethylaminobenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S}-methylpropyl]-L-
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;
Calcd: 633, Found: 633.
Example 22 - (CE-2089) 2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N [1-(3-[S-(3-trifluoromethylbenzyl)-
1,2,4-
oxadiazolyl]carbonyl)-(S~-2-methylpropyl]acetamide.
To a mixture containing 1.1 S g (8.60 mmol) of N chlorosuccinimide in 43 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.95
mL (12.9
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the dropwise addition of a solution
containing
2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro- 1-
pyrimidinyl]-N [1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-
oxadiazolyl]hydroxyrnethyl)-(~-2-methylpropyl]acetamide (1.52 g, 2.15 mmol) in
i5
mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at -
25°C
followed by the addition of 1.2 mL (8.60 mmol) of triethylamine. The cold bath
was
removed and the mixture allowed to warm to room temperature over 20 minutes.
The
reaction mixture was diluted with ethyl acetate and washed with water. The
organic
phase was dried over magnesium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography on silica gel
using a
gradient elution of 2 to 10% methanol/dichloromethane to afford 1.19 g of
material
which was further purified via preparative HPLC to afford 629 mg (41%) of the
title
compound as a white solid. FAB MS [M+H] m/z; Calcd: 707, Found: 707.
The intermediate 2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4- fluorophenyl)-
1,6-dihydro-1-pyrimidinyl]-N [I-(3-[5-(3-trifluoromethylbenzyl)- 1,2,4-
oxadiazolyl]hydroxymethyl)-(S~-2-methylpropyl]acetamide was prepared as
follows:
to a solution containing 1.35 g (3.7 mmol) of 1-[3-[5-(3-methylbenzyl)- 1,2,4-
oxadiazolyl]-2-(S~-amino-3-rnethylbutan-1-of hydrochloride and [5-
[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
pyrimidinyl]acetic acid (J. Med. Chem. 38:98-108 (1995)) in 10 mL of anhydrous
DMF was added I .0 mL (7.44 mmol) of TEA and 0.76 g (4.94 mmol) of HOBT. The
mixture was cooled to 0°C and 0.95 g (4.94 mmol) of EDC was added and
the
reaction mixture was allowed to stir overnight. An additional 1.0 mL (7.44
mmol) of
S TEA was added and the reaction again allowed to stir overnight. The reaction
was
diluted with dichloromethane and washed with a saturated ammonium chloride
solution (2X) and water. The organic phase was dried over magnesium sulfate,
filtered and evaporated under reduced pressure. The residue was purified by
column
chromatography on silica gel with 2% methanol/dichloromethane to afford 1.52 g
(87%) of the title compound. FAB MS [M+H] m/z; Calcd: 709, Found: 709.
Example 23 - (CE-2090) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N ]1-(3-[S-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-
2- (,S'}-
methylpropyl]acetamide.
To a mixture containing 0.41 g (0.56 mmol) of 2-[5-
[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl}-1,6-dihydro-1-pyrimidinyl]-
N [1-(3-[S-(3-trifluormethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-(,S~-2-
methylpropyl]
acetamide in 4 mL of trifluoracetic acid at room temperature under a nitrogen
atmosphere was added 87 mg {0.70 mmol) of thioanisole. The reaction mixture
was
allowed to stir for 3 days and concentrated in vacuo. The residue was purified
via
preparative HPLC to afford 269 mg (47%) of the title compound as a white
solid.
FAB MS [M+H] m/z; Calcd: 573, Found: 573.
Example 24 - (CE-2095) 2-[5-[{Benzyloxycarbonyl)amino]-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N [1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-(f}-2-methylpropyl]acetamide.
To a mixture containing 0.83 g (6.23 mrnol) of N chlorosuccinimide in 32 mL
of anlxydrous toluene at 0°C under a nitrogen atmosphere was added 0.7
mL (9.35
mmol) of dimethyi sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the dropwise addition of a solution
containing
2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro- 1-
pyrimidinyl]-N [1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S'}-
2-

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
methylpropyl] acetamide (1.02 g, 1.56 mmol) in 12 mL of anhydrous toluene. The
reaction was allowed to stir for 2 hours at -25°C followed by the
addition of 0.9 mL
(6.23 mmol) of triethylamine. The cold bath was removed and the mixture
allowed to
warm to room temperature over 20 minutes. The reaction mixture was diluted
with
ethyl acetate and washed with water. The organic phase was dried over
magnesium
sulfate, filtered and evaporated. The residue was purified by column
chromatography
on silica gel using 1 % methanol/dichloromethane to afford 1.37 g of material
which
was further purified via preparative HPLC to give 368 mg (36%) of the title
compound as a white solid. FAB MS [M+H] m/z; Calcd: 653, Found: 653.
The intermediate 2-[S-[(benzyloxycarbonyl)amino)-6-oxo-2-(4- fluorophenyl)-
1,6-dihydro-1-pyrimidinyl]-N [1-(2-[S-(3-methylbenzyl)-1,3,4- oxadiazolyl]
hydroxymethyl)-(S)-2-methylpropyl]acetamide was prepared as follows: to a
solution
containing 1.35 g (3.7 mmol) of 1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-
(S}-
amino-3-methyl butane hydrochloride and [5- [(benzyloxycarbonyl)amino]-6-oxo-2-
(4-fluorophenyl)-1,6-dihydro-1- pyrimidinyl]acetic acid (,l. Med. Chem., 38:98-
108
(1995)) in 10 mL of anhydrous DMF was added 0.73 mL (6.6 mmol) of NMM and
0.46 g (3.0 mmol) of HOBT. The mixture was cooled to 0°C and 0.50 g
(2.6 mmol)
of EDCI was added and the reaction mixture was allowed to stir for 2 days. The
reaction was diluted with dichloromethane and washed with a saturated ammonium
chloride solution (2X) and water. The organic phase was dried over magnesium
sulfate, filtered and evaporated under reduced pressure. The residue was
purified by
column chromatography on silica gel using a gradient elution of 2 to 5%
methanoU
dichloromethane to afford 1.02 g (77%) of the title compound. FAB MS [M+HJ
m/z;
Calcd: 655, Found: 655.
Example 25 - (CE-2101) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N [ 1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
To a mixture containing 0.219 g (0.335 mmol) of 2-[5-[(benzyloxycarbonyl)
amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]- N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(,S~-2- methylpropylyl]acetamide in
3 mL
of trifluoroacetic acid at room temperature under a nitrogen atmosphere was
added
(~ y

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
0.05 mL (0.402 mmol) of thioanisole. The reaction mixture was allowed to stir
for 3
days and concentrated in vacuo. The residue was purified via preoperative HPLC
to
afford 187 mg (88%) of the title compound as a white solid. FAB MS [M+H} m/z;
Calcd: 519, Found: S 19.
Example 26 - (CE-2164)(Pyrrole-2-carbonyl)-N (benzyl)glycyl-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl-2-(f~-methylpropyl]amide.
To a mixture containing 1.97 g ( 14.7 mmol) of N chlorosuccinimide on 60 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 1.54
mL {21.0
mmol) of dimethyl sulfide. The mixture was allowed to stir for 1 hr. The
reaction
was cooled to -25°C using a carbon tetrachloride/dry ice bath, followed
by the
dropwise addition of a solution contain (0.90 g, 1.49 mmol) of (pyrrole-2-
carbonyl)-
N (benzyl)glycyl-N ( 1-(2-(5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]hydroxymethyl)]-2-
(S')-methylpropyl]amide in 30 mL of anhydrous toluene. The reaction was
allowed to
stir for 1 hour at -25°C followed by the addition of 2.16 mL (15.5
mmol) of
triethylamine. The cold bath was removed and the mixture allowed to warm to
room
temperature over 20 minutes. The reaction mixture was diluted with ethyl
acetate and
washed with water. The organic phase was dried over magnesium sulfate,
filtered and
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with ethyl acetate/hexane (4:1 ). The material
was
further purified via preparative HPLC to afford 1.20 g (63.4%) of the title
compound
as a white solid. FAB MS [M+H] m/z; Calcd: S 14, Found: 514.
The intermediate (pyrrole-2-carbonyl)-N (benzyl)glycyl-N [1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-2-(,S~-methylpropyl]amide was
prepared by the following method:
a. (Pyrrole-2-carbonyl)-N (benryl)glycine-t-butyl ester.
To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in
75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0°C
was added
6.96 g (27.0 mmol) of BOPCI and 14.1 mL (81.0 mmol) of DIEA. After stirring
for
30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)gylcine-t-butyl ester was added
and the
reaction allowed to warm to room temperature overnight. The reaction was
diluted
with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated
sodium

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/21636
bicarbonate solution and brine. The organic phase was dried over magnesium
sulfate,
filtered and evaporated under reduced pressure. The residue was purified by
column
chromatography on silica gel using a gradient of 100% hexane to 60%
hexane/ethyl
acetate to afford 2.92 g (34.4%) of the title compound as a white solid. FAB
MS
[M+H] m/z Calcd: 315, Found: 315.
b. (Pyrrole-2-carbonyl) N (benzyl)glycine.
To a solution containing 2.85 g (9.01 mmol) of (Pyrrole-2-carbonyl)-N
(benzyl)glycine-t-butyl ester in SO mL of anhydrous dichloromethane cooled to
0°C
was added 25 mL of TFA dropwise. After 90 minutes an additional 25 mL of TFA
was added and allowed to stir for 30 minutes. The mixture was evaporated in
vacuo
to afford 2.19 g of (Pyrole-2-carbonyl)-N (benzyl)glycine as a tan solid. FAB
MS
[M+H] m/z; Calcd. 259, Found 259.
c. (Pyrrole-2-carbonyl)-N (benzyl)glycyl-N (1-(2-~5-(3-methylbenzyl)-
1,3,4- oxadiazolylJhydroxymethyl)J-(S)-2-methylpropylJamide.
1 S To a solution containing 1.90 g (7.35 mmol) of (Pylrole-2-carbonyl)-N
(benzyl)glycine in 75 mL of anhydrous DMF was added 2.4 mL (22.1 mmol) of
NMM and 1.29 g (9.56 mmol) of HOBT. The mixture was cooled to 0°C and
1.69 g
(8.82 mmol) of EDCI was added and the reaction mixture was allowed to stir.
After
30 minutes 2.17 g (6.99 mmol) of 1-[2-(S-[3-methylbenzyl])-1,3,4- oxadiazolyl]-
2-
(S)-amino-3-methyl butan-1-of hydrochloride in 25 mL of anhydrous DMF was
added
and the mixture was allowed to warm to room temperature overnight. The
reaction
was diluted with ethyl acetate and washed with 5% potassium hydrogen sulfate
and
water. The organic phase was dried over magnesium sulfate, filtered and
evaporated
under reduced pressure. The residue was purified by column chromatography on
silica gel using a gradient elution of 20 to 80% ethyl acetate/hexane to
afford 2.02 g
(56%) of the title compound. FAB MS [M+H] m/z Calcd: 516, Found: 516.
Example 27 - {CE-2097)(Pyrrole-2-carbonyl)-N (benzyl)glycyl-N [1-{3-[5-(3-
trifluoromethylbenzyl)]-1,2,4-oxadiazolyl]carbonyl)-(S)-methylpropyl]amide was
prepared in a similar manner to Example 25. FAB MS [M+H] m/z; Calcd: 568,
Found: 568.
n,~

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97/21636
Example 28 - (CE-2130)(2S,SS)-S-Amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1)-
indole-4-one-carbonyl-N [1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-
(R,S)-2-methylpropyl]amide.
To a solution containing 0.93 g (1.28 mmol) of (2S,SS)-Fmoc-S-amino-
1,2,4,5,6,7-hexahydroazepino [3,2,1 ] indole-4-one-carbonyl-N [ 1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amide in 4.5 mL
of
anhydrous DMF under an atmosphere of nitrogen was added 0.45 mL of
diethylamine. After stirring at room temperature for 1 S min the mixture was
concentrated under high vacuum. The residue was purified via preparative HPLC
to
afford 0.57 g {72%) of the title compound as a white solid. FAB MS [M+H] m/z;
Calcd: 502, Found 502.
The intermediate (2S,SS)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-
[3,2,1 )-indole-4-one-carbonyl-N [ 1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl)carbonyl)-(S)-2-methylpropyl)amide was prepared as follows:
a. (2S, SS)-Fmoc-S-amino-1, 2, 4, S, 6, 7-hexahydroazepino- j3, 2,1 J-indole-4-
one-carbonyl-N jl -(2- j5-(3-methylbenzyl)-1, 3) 4-oxadiazolylJhydroxymethyl)-
(S)-2-
methylpropylJamide.
To a solution containing 1.25 g (2.67 mmol) of (2S,SS)-Fmoc-5-amino-
1,2,4,5,6,7-hexahydroazepino [3,2,1] indole-4-one-carboxylic acid in 200 mL of
anhydrous dichloromethane and 1 mL of anhydrous DMF under a nitrogen
atmosphere at 0°C was added 0.71 g (2.80 mmol) of BOPC1 and 0.6 mL
(3.45 mmol)
of DIEA. After stirring for 1 hr 1.14 g (3.66 mmol) of 1-[2-(5-[3-
methylbenzyl])-
1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-of hydrochloride in 10 mL of
anhydous dichloromethane was added and the reaction mixture allowed to stir at
4°C
overnight. The reaction was diluted with dichloromethane and washed with
water.
The organic phase was dried over magnesium sulfate, filtered and evaporated
under
reduced pressure. The residue was purified by column chromatograph on silica
gel
using 3% methanol/dichloromethane to afford 1.30 g (67%) of the title compound
as
tan solid.
b. (2S, SS)-Fmoc-S-amino-1, 2, 4, 5, 6, 7-hexahydroazepino- j3) 2,1 J-indole-
4-one-carbonyl-N jl -(2- j5-(3-methylbenzyl)-1, 3, 4-oxadiazolylJcarbonyl)J-
(S)-2-
methylpropylJamide.
n~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
To a mixture containing 0.95 g (7.16 mmol) of N chlorosuccinimide in 150
mL of anhydrous toluene at 0°C under a nitrogen atmosphere was added
0.79 mL
(10.7 mmol) of dimethyl sulfide. The mixture was allowed to stir for 30
minutes.
The reaction was cooled to -25°C using a carbon tetrachloride/dry ice
bath, followed
by the dropwise addition of a solution containing 1.30 g (1.79 mmol) of (2S,
SS)-
Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N [1-
(2-
[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amide
in
mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at -
25°C
followed by the addition of 1.17 mL {8.4 mmol) of triethylamine. The cold bath
was
10 removed and the mixture was allowed to warm to room temperature over 30
minutes.
The reaction mixture was diluted with ethyl acetate and washed with water. The
organic phase was dried over magnesium sulfate. The residue was filtered,
concentrated under reduced pressure and purified by column chromatography on
silica
gel with 10% ethyl acetate/hexane to give 0.93 g (72%) as a tan foam.
Example 29 - (CE-2126) BTD-[1-(2-[S-(3-methylbenzyl}-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.
To a solution containing 0.41 g (0.59 mmol) of FMOC-BTD-[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazole]carbonyl)-2-(S)-methylpropyl]amide in 4.5 mL of
anhydrous DMF under an atmosphere of nitrogen was added 0.5 mL of
diethylamine.
After stirnng at room temperature for 30 min the mixture concentrated under
high
vaccum. The residue was purified via preparative HPLC to afford 0.23 g (66 %)
of
the title compound as a white solid. FAB MS [M+H] m/z; Calcd: 472, Found 472.
The intermediate Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide was prepared as follows:
a. (2S, SS)-Fmoc-BTD-(1-(2-~S-(3-methylbenryl)-1,3,4-
oxadiazolylJhydroxymethyl)-2-(S)-methylpropylJamide.
To a solution containing 1.25 g (2.85 mmol) of FMOC-BTD in 80 mL of
anhydrous dichloromethane and 2.5 mL of anhydrous DMF under a nitrogen
atmosphere at 0°C was added 0.76 g (2.99 mmol) of BOPC 1 and 0.6 mL
(3.45 mmol)
of DIEA. After stirring for 30 minutes and 1.14 g (3.66 mmol) of 1-[2-(5-(3-
methylbenzyl])-1,3,4-oxadiazolyl]-2-(,S~-amino-3-methylbutan-1-of
hydrochloride and
'7 a

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
0.6 mL of DIEA in 10 mL of anhydrous dichloromethane was added and the
reaction
mixture allowed to stir at 0°C overnight. The reaction was diluted with
dichloromethane and washed with water. The organic phase was dried over
magnesium sulfate, filtered and evaporated under reduced presure. The residue
was
purified by column chromatography on silica gel using 3%
methanol/dichloromethane
to afford 1.13 g (55%) of the title compound as a tan foam.
b. Fmoc-BTD-~1-(2-(5-(3-methylbenzyl)-1, 3, 4-oxadiazolylJcarbonyl)J-2-
(S)-methylpropylJamide.
To a mixture containing 0.81 g (6.09 rnmol) of N chlorosuccinimide in 110
mL of 1:1 anhydrous dichioromethane/toluene at 0°C under a nitrogen
atmosphere
was added 0.67 mL (9.1 mmol) of dimethyl sulfide. The mixture was allowed to
stir
for 30 minutes. The reaction was cooled to -25°C using a carbon
tetrachloride/dry ice
bath, followed by the dropwise addition of a solution containing 1.06 g ( 1.52
mmol)
of Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-
methylpropyl]amide in 10 mL of anhydrous toluene. The reaction was allowed to
stir
for 2 hours at -25°C followed by the addition of 1.0 mL (7.6 mmol) of
triethylamine.
The cold bath was removed and the mixture was allowed to warm to room
temperature over 40 minutes. The reaction mixture was diluted with ethyl
acetate and
washed with water. The organic phase was dried over magnesium sulfate. The
resulting mixture was filtered, concentrated under reduced pressure and
purified by
column chromatography on silica geI with 70% ethyl acetate/hexane to give 0.53
g of
the product as a yellow oil. The material was fiu~ther purified by preparative
HPLC to
afford 0.41 g (38.8%) of the title compound as a white solid.
Example 30 - (CE-2134)(R,S)-3-Amino-2-oxo-S-phenyl-1,4; benzodiazepine-N [1-
(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
To a solution containing 0.93 g (1.19 mmol) of (R,S)-FMOC-3-amino-2-oxo-
5-phenyl-1,4; benzodiazepine-N [1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide in 6.0 mL of anhydrous DMF
under an atmosphere of nitrogen was added 0.45 mL of diethylamine. After
stirring at
room temperature for 2.5 hr the mixture was concentrated under high vaccum.
The
residue was purified via preparative HPLC to afford 0.030 g (4.5 %) of the
title

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
compound as a white solid. FAB MS [M+H] m/z; Calcd: 565, Found 565.
The intermediate (R,S)-FMOC-3-amino-2-oxo-S-phenyl-1,4,-benzodiazepine-
N [1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared as follows:
a. (R,S)-FMOC 3-amino-2-oxo-S phenyl-1,4,-benzodiazepine-N jl-(2-j5-
(3-methylbenzyl)-l , 3, 4-oxadiazolylJhydroxymethyl)-2-(S)-
methylpropyllJacetamide.
To a solution containing 0.75 g (1.41 mmol) of (R,S)-FMOC-3-amino-N 1-
carboxymethyl-2-oxo-5-phenyl-1,4,-benzodiazepine in 30 mL of anhydrous
dichloromethane under a nitrogen atmosphere at 0°C was added 0.36 g
(1.41 mmol)
of BOPC1 and 0.25 mL (1.41 mmol) of DIEA. After stirring for I hr 0.48 g (1.55
mmol) of 1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methyl
butan-1-
ol hydrochloride and 0.49 mL (2.82 mmol) of DIEA in 10 mL of anhydous
dichloromethane was added and the reaction mixture allowed to stir at
4°C overnight.
The reaction was diluted with ethyl acetate and washed with water. The organic
1 S phase was dried over magnesium sulfate, filtered and evaporated under
reduced
pressure. The residue was purified by column chromatography on silica gel
using a
gradient of 2 to 6% methanol/dichloromethane to afford 1.00 g (89%) of the
title
compound as a yellow solid.
b. (R,S)-FMOC-3-amino-2-oxo-5 phenyl-1,4,-benzodiazepine-N jl-(2-j5-
(3-methylbenzyl)-1, 3, 4-oxadiazolylJcarbonyl)-2-(S)-methylpropylJacetamide.
To a mixture containing 0.71 g (7.6 mmol) of N chlorosuccinimide in 40 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.84
mL (11.4
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath followed by the dropwise addition of a solution
containing
1.50 g (1.90 mmol) of (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N
[ 1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-
methylpropyl]acetamide in 10 mL of anhydrous toluene. The reaction was allowed
to
stir for 2 hours at -25°C followed by the addition of 1.0 mL (7.6 mmol)
of
triethylamine. The cold bath was removed and the mixture was allowed to warm
to
room temperature over 1 hour. The reaction mixture was diluted with ethyl
acetate
and washed with water. The organic phase was dried over magnesium sulfate. The
residue was filtered, concentrated under reduced pressure to afford 0.94 g
(62%) of
J~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
material which was used without further purification. FAB MS [M+H] m/z; Calcd:
787, Found: 787.
Example 31 - (CE-2145)(Benzyloxycarbonyl)-L-valyl-2 L-(2,3-dihydro-1H indole)
N [1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]amide.
To a mixture containing 0.48 g (3.67 mmol) of N chlorosuccinimide in 30 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.40
mL (5.41
mmol) of dimethyl sulfide. After stirnng for 1 hr the reaction mixture was
cooled to -
25°C using a carbon tetrachloride/dry ice bath followed by the dropwise
addition of a
solution containing 0.95 g (1.90 mmol) of (benzyloxycarbonyl}-L-valyl-2-L-(2,3-
dihydro-1H indole)- N [1-(2-[5-(3-methylbenzyl}-1,3,4-
oxadiazolyl]hydroxymethyl)-
2-(S)-methylpropyl]amide in 20 mL of anhydrous toluene. The reaction was
allowed
to stir for 2 hours at -25°C followed by the addition of 0.50 mL (3.6
mmol) of
triethylamine. The cold bath was removed and the mixture was allowed to warm
to
room temperature. The reaction nuxture was diluted with dichloromethane and
1 S washed with 1 N HC 1 (2X}, saturated sodium bicarbonate (2X) and water.
The
organic phase was dried over magnesium sulfate. The mixture was filtered and
concentrated under reduced pressure to afford 0.61 g. The residue was purified
by
column chromatography on silica gel with SO% ethyl acetate/hexane to afford
0.27 g
of material which was further purified via preparative HPLC to afford 196 mg
(33.4%) of the title compound as a white solid. FAB MS [M+H] m/z Calcd: 652,
Found 652.
The intermediate (benzyloxycarbonyl)-L-valyl-2 L-(2,3-dihydro-1H indole)-
N [1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-
methylpropyl]amide was prepared by the following procedures:
a. 2 L-Methyl (2,3-dihydroindole)carbo~ylate.
To a suspension containing S.OOg (30.6 mmol) of 2-L-(2,3-
dihydroindole)carboxylic acid in 100 mL of anhydrous MeOH cooled to 0°C
was
added a slow stream of HC 1 gas over 20 minutes. The resulting homogeneous
solution was allowed to stir overnight warming to room temperature. The
mixture
was evaporated and the residue was crystallized from methanol/ether to afford,
after
drying, 5.58 g (85%) of 2-L-methyl (2,3-dihydroindole)carboxylate.
b. 2-Methyl ~(S)-1-(N ~benryloxycarbonylJ-L-valyl)-2, 3-dihydro-1 H

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
indoleJcarboxylate.
To a solution containing 3.00 g (14.0 mmol) of methyl (2,3-dihydroindole)-L-
2-carboxylate in 60 mL of anhydrous dichloromethane, under a nitrogen
atmosphere
at 0°C, 7.15 g (28.8 mmol) of BOPC1 and 7.72 nlL, (70.2 mmol) of DIEA
was added
S a solution of 7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous
dichloromethane and 3 mL of DMF. After stirring for 3 days at 5°C the
mixture was
diluted with ethyl acetate and washed with 1 N HC 1 (2X) and brine. The
mixture was
filtered and evaporated under reduced pressure. The residue was purified by
column
chromatography on silica gel using a gradient of 9:1 to 1:1 hexane/ethyl
acetate to
afford 4.85 g (87%) of the title compound as a white foam.
2-~(S)-1-(N ~BenryloxycarbonylJ-L-valyl)-2, 3-dihydro-1 H
indoleJcarboxylic acid.
To a solution containing 4.85 g (12.17 mmol) of 2-methyl [(S)-1-(N
[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H indole]carboxylate in 45 mL of THF
1 S and 15 mL of MeOH at 0°C was added 15.8 mL of 1 N LiOH dropwise.
After 30
minutes 1 N HC 1 was added to pH 2 and the mixture extracted with ethyl
acetate
(3X). The combined organic phases were dried over magnesium sulfate, filtered
and
evaporated under reduced presure to afford 4.51 g (93%) of the title compound
as a
white solid.
d. (Benzyloxycarbonyl)-L-valyl-2 L-(2, 3-dihydro-1 H indole)-N (1-(2-~5-
(3-methylbenzyl)-1, 3, 4-oxadiazolylJhydroxymethyl)-2-(S)-methylpropylJamide.
To a solution containing 1.09 g (3.96 mmol) of 1-[2-(5-[3-methylbenzyl])-
1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-of and 1.31 g (3.3 mmol) of 2-
[(S)-
1-(N [benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H indole]carboxylic acid in 30
mL
of anhydrous dichloromethane was added 1.21 mL (6.93 mmol) of DIEA and 0.49 g
(3.63 mmol) of HOBT. The mixture was cooled to 0°C and 0.70 g (3.63
mmol) of
EDCI was added and the reaction mixture was allowed to stir overnight. An
additional 1.0 mL (7.44 mmol) of TEA was added and the reaction again allowed
to
stir overnight. The reaction was diluted with dichlorornethane and washed with
1 N
HC 1 (2X), saturated sodium bicarbonate (2X) and water. The organic phase was
dried over magnesium sulfate, filtered and evaporated under reduced pressure.
The
residue was purified by column chromatography on silica gel with 80% ethyl

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
acetate/hexane to afford 0.66 g (30%) of the title compound.
Example 32 - (CE-2125)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H indole)-
N [ I-(3-[5-{3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(,S~-
methylpropyl]amide. Prepared in a similar manner as in Example 30. FAB MS
[M+H] m/z; Calcd: 706, Found: 706.
Example 33 - (CE-2143) Acetyl-2 L-(2,3-dihydro-1H indole)-N [1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-{f)-methylpropyl]amide.
Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd: 515,
Found: 51 S.
Example 34 - (CE-2165} N-Acetyl-2-(L)-(2,3-dihydro-1H indole)-N [1-(2-[S-{3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S~-methylpropyl]amide. Prepared
in a
similar manner as in Example 30. FAB MS [M+H] m/z; Calcd: 461; Found: 461.
Example 35 - (CE-2104)(Morpholino-N carbonyl)-L-valyl-N [ 1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(f)-methylpropyl]-L-prolinamide.
To a mixture containing 0.69 g (5.17 mmol) of N chlorosuccinimide in 60 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.60
mL (8.17
mmol} of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/ dry ice bath, followed by the addition of a solution containing
(morpholino-N carbonyl)-L-valyl-N [1-(2-[5-(3-methyl benzyl)-1,3,4-
oxadiazolyl]hydroxymethyl)-2-(S-)methyl propyl]-L-prolinamide (0.75 g, 1.28
mmol)
in 10 mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at
-25°C
followed by the addition of 1.1 mL (0.83 g, 7,89 mmol) of triethylamine. The
cold
bath was removed and the reaction was allowed to warm to room temperature over
20
minutes. The reaction was diluted with ethyl acetate and washed with water.
The
organic phase was dried over magnesium sulfate and filtered. The solvents were
evaporated in vacuo and the residue purified by column chromatography, 70%
ethyl
acetate/hexane on silica gel. Final purification was performed by preparative
HPLC
to afford 405 mg (54.3%) of the title compound as a white solid. FAB MS [M+H]
m/z; Calcd: 583, Found: 583.

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
The intermediate (Morpholino-N carbonyl)-L-valyl-N [1-(2-[5-(3-
methylbenzyl)-1, 3,4-oxadiazolyl]hydroxymethyll)-2-(,S')-methylpropyl]-L-
prolinamide
was prepared as follows:
a. (Morpholino-N carbonyl)-L-valyl-L proline-O-t-butyl ester.
To a solution containing L-valyl-L-proline-O-t-butyl-ester (1.80 g, 5.87 mmol)
in 80 mL of anhydrous methylene chloride and 1.5 mL (13.64 mmol) of N-methyl
morpholine under a nitrogen atmosphere at 0°C was added rnorpholine
carbonyl
chloride dropwise. The mixture was allowed to warm to room temperature
overnight.
The reaction was diluted with methylene chloride and washed with water. The
organic layer was dried over magnesium sulfate, filtered and evaporated. The
residue
was purified by column chromatography on silica gel with 10%
methanol/dichloromethane to afford 1.98 g (88%) of the title compound as a
white
solid. FAB MS [M+H] m/z; Calcd: 384, Found 384.
b. (Morpholino-N carbonyl) L-valyl L proline.
To a solution containing (morpholino-N carbonyl) L-valyl-L-proline-O-t-butyl
ester (2.0 g, 5.22 mmol) in 80 mL of anhydrous methylene chloride under a
nitrogen
atmosphere at 0°C was added trifluoroacetic acid (13 mL, 130 mmol). The
mixture
was allowed to warm to room temperature overnight and the solvents were
evaporated
in vacuo to give 2.26g of a viscous oil. The material was used without further
purification.
c. (Morpholino-N carbonyl)-L-valyl N ~1-(2-~5-(3-methylbenzyl)-1,3,4-
oxadiazolylJ hydroxymethyl)-2-(S)-methylpropylJ-L prolinamide.
To a solution containingn 0.95 g (2.90 mmol) of (morpholino-N carbonyl) L
valyl-Proline in 25 mL of anhydrous dichloromethane under a nitrogen
atmosphere at
0°C was added 0.80 g (3.14 mmol) of BOPCI and 1.5 mL (8.61 mmol) of
DIEA.
After 30 minutes, 0.75g (2.41 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-
oxadiazolyl]-
2-(S)-amino-3-methylbutan-1-of hydrochloride in 10 mL of dichloromethane and
1.1
mL (6.31 mmol) of DIEA were added. The reaction was allowed to stir at
0°C
overnight. The reaction was diluted with dichloromethane and washed with a
saturated NaHC03 solution. The organic phase was dried over magnesium sulfate
and
filtered. The mixture was concentrated in vacuo and the residue purified by
column
chromatography on silica gel using 6% methanol/dichloromethane to afford 0.77
g

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/Z1636
(54.84%) of the title compound as a white solid. FAB MS [M+H] m/z; Calcd: 585,
Found: 585.
Example 36 - (CE-2079) 3-(S~-(Benzyloxycarbonyl)amino)-F-lactam-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S')-methylpropyl]acetamide.
To a mixture containing 2.37 g (17.75 mmol) of N chlorosuccinimide in 100
mL of anhydrous toluene at 0°C under a nitrogen atmosphere was added i
.94 mL
(2.64 mmol) of dimethyl sulfide. The reaction was cooled to -25°C using
a carbon
tetrachlorideldry ice bath, followed by the dropwise addition of a solution
containing
2.5 g (4.44 mmol) of 3-(S)-[(benzyloxycarbonyl)amino]-e-lactam-N [1-(2-[5-(3-
methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-{,S~-methyl propyl]acetamide
in
mL of anhydrous toluene. Upon complete addition, the reaction was allowed to
stir at -25°C for 2 hours, followed by the addition of 3.0 mL (21.52
mmol) of
triethylamine. The cold bath was removed and the reaction warmed to room
15 temperature and stirred for 30 minutes. The reaction was diluted with ethyl
acetate
and washed with water. The organic phase was dried over magnesium sulfate.
Filtration, removal of solvent and column chromatography of the residue on
silica gel
with 5% methanol/dichloromethane afforded 1.8 g of a pale yellow solid.
Subsequent
preparative HPLC gave 950 mg (38.1%) of the title compound as a white solid.
FAB
20 MS [M+H] m/z; Calcd: 562, Found: 562.
The intermediate 3-(,5~-[(benzyloxycarbonyl)amino]-e-lactam-N [1-(2-[S-(3-
methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S~-methyl propyl]acetamide
was
prepared as follows:
a. 3-(S)-~(Benryloxycarbonyl)aminoJ- ~-lactam.
To a mixture containing 9.9 g (37.18 mmol) of Cbz-ornithine in 150 mL of
acetonitrile under a nitrogen atmosphere was added 78 mL (369.70 mmol) of
hexamethyldisilazane. The reaction was heated at reflux for 48 hours. The
reaction
mixture was cooled to room temperature and poured into 250 mL of cold
methanol.
The solvent was removed under reduced pressure. Chloroform was added and the
mixture filtered through a plug of celite. The filtrate was concentrated under
reduced
pressure and the residue dissolved in ethyl acetate. Hexane was added until
the
solution was slightly turbid and then allowed to stand overnight. The
resultant solid
~ '1

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97121636
was filtered and dried to afford 8.37 g (90.7%) of the title compound.
b. N (3-(S)-(Benryloxycarbonyl)aminoJ-e-lactam-t-butyl acetate.
To a solution containing I .0 g (4.03 mmol) of 3-(S)-
[(benzyloxylcarbonyl)amino]-e-lactam in 20 mL of anhydrous DMF under a
nitrogen
atmosphere was added 1.50 mL {10.16 mmol) ofbromo-t-butyl acetate and 1.17 g
(S.OS mmol) of silver oxide. The reaction was heated to 45°C for 5
hours, diluted
with acetonitrile and filtered through a pad of celite. The filtrate was
concentrated
under reduced pressure and the residue dissolved in ethyl acetate and washed
with
water. The organic phase was dried over magnesium sulfate. Filtration, removal
of
solvent and column chromatography of the residue on silica get with 60% ethyl
acetate/hexane afforded 1.18 g (80.79%) of the title compound. FAB MS [M+H]
m/z;
Calcd: 363, Found: 363.
c. N ~3-(S)-(Benzyloxycarbonyl)amino)-e-lactam-carboxymethane.
To a solution containing 0.55 g (1.52 mmol) of N-[3-(S)-(Benzyloxy
carbonyl)amino]-e-lactam-t-butyl acetate in 20 mL (15.58 mmol) of
trifluoroacetic
acid. The reaction was allowed to warm to room temperature overnight. The
solvent
was removed under reduced pressure. The residue was dissolved in ether acetate
and
washed with water. The organic phase was dried over magnesium sulfate.
Filtration
and removal of solvent afforded 0.50 of the title compound. FAB MS [M+H] m/z;
Calcd: 307, Found: 307.
d. 3-(S)-(Benzyloxycarbonyl)amino)-e-lactam-N ~l-(2-(5-(3
methylbenzyl)-I , 3, 4-oxadiazolylJhydroxymethyl)-2-(S)-
methylpropylJacetamide.
To a solution containing 2.72 g (8.88 mmoi) of N-[3-(S)-(Benzyloxycarbonyl)
amino]-e-lactam-carboxymethane in 80 mL of dichloromethane under a nitrogen
atmosphere at 0°C was added 2.37 g (9.31 mmol) of BOPCI and 1.60 mL
{9.91
mmol) of DIEA. The reacton was allowed to stir at 0°C for 30 minutes
followed by
the addition of 2.37 g (7.60 mmol) of I-[3-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]-2-
(S)-amino-3methyl butan-1-of hydrochloride in 20 mL of dichloromethane and
i.60
mL (9.19 mmol) of DIEA. The reaction was allowed to stir at 0°C
overnight. The
reaction was diluted with dichloromethane and washed with water. The organic
phase
was dried over magnesium sulfate. Filtration, removal of solvent and column
chromatography of the residue on silica get with 10% methanol/dichloromethane
_.._ __ ~..r.. _.~__._..

CA 02272548 1999-OS-19
WO 98/24$06 PCT/US97/21636
afforded 2.58 g (50.23%) of the title compound. FAB MS [M+H] m/z; Calcd: 564,
Found: 564.
Example 37 - (CE-2080) 3-(S (Amino)-F-lactam-N [1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolylJcarbonyl)-2-(S~-methylpropylJacetamide trifluoroacetic acid salt.
This compound was prepared via deprotection of 3-(,S~-
[benzyloxycarbonyl)amino)-e-lactam-N [1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S~-methyl propylJacetamide under standard conditions
to
one skilled in the art to afford the title compound. FAB MS [M+H] m/z; Calcd:
428,
Found:428.
Example 38 - (CE-2091) 3-(S~-[(4-Morpholino carbonyl-butanoyl)amino]-E-lactam-
N [1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,f)-
methylpropylJacetamide.
To a solution containing 0.089 g (0.475 mmol) of 4-morpholino carbonyl
butanoic acid in 10 mL of dichloromethane under a nitrogen atmosphere at
0°C was
added 0.127 g (0.498 mmol) of BOPCI and 0.09 mL (0.492 mmol) of DIEA. The
reaction was allowed to stir for 30 minutes followed by the additin of 0.22 g
(0.406
mmol) of 3-(S~-amino-e- lactam-N [1-(2-[5-(3-methyl benzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R,S~-methyl propyl]acetamide trifluoroacetic acid
salt. The
reaction was allowed to stir at 0°C overnight. The reaction was diluted
with
dichloromethane and washed with water. The organic phase was dried over
magnesium sulfate. Filtration, removal of solvent and purification via
preparative
HPLC afforded 0.044 g (18%) of the title compound. FAB MS [M+HJ m/z; Calcd:
597, Found: 597.
Example 39 - (CE-2087) 6-[4-FluorophenylJ-e-lactam-N [1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(f~-methylpropyl] acetamide.
To a mixture containing 0.70 g (5.24 mmol) and N chlorosuccinimide in 30
mL of anhydrous toluene at 0°C under a nitrogen atmosphere was added
0.60 mL
(8.17 mmol) of dirnethyl sulfide. The reaction was cooled to -25°C
using a carbon
tetrachloride/dry ice bath, followed by the dropwise addition of a solution
containing
~S I

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
0.67 g (1.32 mmol) of 6-[4-fluorophenyl]-e-lactam-N [1-(2-[S-(3-methyl benzyl}-
1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 15 mL of
anhydrous toluene. Upon complete addition, the reaction was allowed to stir at
-25°C
for 2 hours followed by the addition of 0.90 mL (6.46 mmol) of triethylamine.
The
S cold bath was removed and the reaction allowed to warm to room temperature
and
maintained for 20 min. The reaction was diluted with ethyl acetate and washed
with
water. The organic phase was dried over magnesium sulfate. Filtration, removal
of
solvent under reduced pressure and column chromotography of the residue on
silica
gel with 10% methanol/dichloromethane afforded 0.61 g of a pale yellow solid.
Subsequent preparative HPLC gave 338 mg (50.5%) of the title compound. FAB MS
[M+H] m/z; Caicd: 507, Found: 507.
The intermedite 6-[4-fluorophenyl]-F-lactam-N [1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared as
follows:
a. 6-(4-FluorophenylJ-6-carbo~ymethylene-2 piperidinone.
To a solution containing 2.15 g (8.11 mmol) of 6-[4-fluorophenyl]-1-
carbomethoxymethylene-2-piperidinone, prepared in a similar fashion to that
reported
by Compernolle (Tetrahedron, 49:3193 (1993)) in 70 mL of methanol and 20 mL of
water under a nitrogen atmosphere was added 0.55 g (13.11 mmol) of lithium
hydroxide. The reaction was allowed to stir at room temperature for 2 hours.
The
solvent was removed under reduced pressure. The residue was diluted with water
and
washed with ethyl acetate. The aqueous phase was acidified with 1 N
hydrochloric
acid and extracted with ethyl acetate. The organic phase was dried over
magnesium
sulfate. Filtration and removal of solvent afforded 2.0 g (98.2%) of the title
compound. FAB MS [M+H] m/z; Calcd: 252, Found: 252.
b. 6-~4-FI uorophenylJ- e-lactam-N ~1-(2-~S-(3-methyl benzyl)-1, 3, 4-
oxadiazolylJ hydroxymethyl)-2-(S)-methylpropylJacetamide.
To a solution containing 1.04 g (4.14 mmol) of 6-[4-fluorophenyl]-6-
carboxymethylene-2-piperidinone in 25 mL of anhydrous dichloromethane under a
nitrogen atmosphere at 0°C was added 1.10 g (4.32 mmol) of BOPCI and
0.80 mL
(4.59 mmol) of DIEA. After stirring for 30 minutes, a solution containing 1.1
g (3.53
mmol) of 1-(2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-
methylbutan-1-
~,Y

CA 02272548 1999-OS-19
WO 98/24806 PCTIUS97/21636
of hydrochloride in 10 mL of dichloromethane and 1.10 mL (6.31 mmol) of DIEA.
The reaction was allowed to stir at 0°C overnight. The reaction was
diluted with
dichloromethane and washed with a saturated sodium bicarbonate solution. The
organic phase was dried over magnesium sulfate. Filtration, removal of solvent
under
reduced pressure and column chromotography of the residue on silica gel with
10%
methanol/dichloromethane afforded 736 mg (41.0%) of the title compound. FAB MS
[M+H] m/z; Calcd: 509, Found: 509.
Example 40 - (CE-2121) 2-[2-(R,S~-Phenyl-4-oxothiazolidin-3-yl]-N [1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S~-methylpropyl] acetamide.
To a mixture containing 2.05 g (15.38 mmol) of N chlorosuccinimide in 250
mL of anhydrous toluene at 0°C under a nitrogen atmosphere was added
1.70 mL
(23.06 mmol) of dimethyl sulfide. The reaction was cooled to -2S°C
using a carbon
tetrachloride/dry ice bath, followed by the addition of 1.90 g {3.84 mmol) of
2-[2-
1S (R,S~-phenyl-4-oxothiazolidin-3-yl]-N [1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]hydroxymethyl)-2-{S)-methylpropyl]acetamide in 20 mL of anhydrous
toluene dropwise. The reaction was allowed to stir at -25 °C for 2
hours, followed by
the addition of 2.52 mL (18.07 mmol) of triethylamine. The cold bath was
removed
and the reaction allowed to warm to room temperature over 40 minutes. The
reaction
was diluted with ethyl acetate and washed with water. The organic phase was
dried
over magnesium sulfate. Filtration, removal of solvent and column
chromatography
of the residue on silica gel with 60 % ethyl acetate/hexane afforded 1.10 g of
a yellow
oil. This was further purified via preparative HPLC to give 0.45 g (24%) of
the title
compound as an off white solid. FAB MS [M+H] m/z; Calcd: 493, Found 493.
The intermediate 2-[2-(R,S~-phenyl-4-oxothiazolidin-3-yl]-N [1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl]hydroxyrnethyl)-2-(S)-methypropyl]acetamide
was
prepared as follows: to a solution containing 1.78 g (7.S 1 mmol) of 2-{2-
phenyl-4-
oxothiazolidin-3-yl) acetic acid, prepared according to Holmes (J. Org. Chem,
60:7328 (1995)), in 80 mL of dichloromethane under a nitrogen atmosphere at
0°C
was added 2.04 g (8.02 mmol) of BOPCI and 1.35 mL (7.76 mmol) of DIEA. After
stirring for 30 minutes, 2.0 g (6.41 mmol) of 1-[3-[S-(3-methylbenzyl)]-1,3,4-
oxadiazolyl]-2-(S')-amino-3-methyl-butan-1-of hydrochloride in SO mL of
~3

CA 02272548 1999-OS-19
WO 98/24806 PCTlIJS97/21636
dichloromethane and 1.35 mL (7.76 mmol) of DIEA was added. The reaction was
allowed to stir at 0°C overnight. The reaction mixture was diluted with
dichloromethane and washed with water. The organic phase was dried over
magnesium sulfate, filtered and concentrated under reduced pressure. Column
S chromatography of the residue on silica gel with 4% methanoUdichloromethane
afforded 2.30 g of a yellow foam. Subsequent preparative HPLC gave 1.9 g of
the
title compound. FAB MS [M+H] m/z; Calcd: 495, Found: 495.
Example 41 - (CE-2122) 2-[2-(R,,S~-Benzyl-4-oxothiazolidin-3-yl]-N [ 1-(2-[5-
(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S~-methylpropyl] acetamide was
prepared in a similar manner as in Example 39. FAB MS [M+H] m/z; Calcd: 507,
Found: 507.
Example 42 - (CE-2136) 2-[(2-(R,,S~-Benzyl-4-oxothiazolidin-3-yl oxide]-N [1-
(2-[5-
(3-methyl benzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(R,S,)-methylpropyl]
acetamide.
To a solution containing 1.31 g (2.59 mmol) of 2-[2-(R,S~-benzyl-4-
oxothiazolidin-3-yl)-N [ 1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-
2-(S'}-
methyl propyl]-acetamide in 15 mL of methanol under a nitrogen atmosphere was
added 0.5I mL (5.17 mmol) of 30% hydrogen peroxide. The reaction was allowed
to
stir at room temperature overnight and then partitioned between brine and
dichloromethane. The organic phase was dried over magnesium sulfate.
Filtration,
removal of solvent under reduced pressure and column chromotography of the
residue
on silica gel with 85% ethyl acetate/hexane afforded 0.73 g of a tan oil.
Subsequent
preparative HPLC gave 0.54 g (48%) of the title compound. FAB MS [M+H] m/z;
Calcd: 523, Found 523.
Example 43 - (CE-2137) 2-[2-(R,S~-Benzyl-4-oxothiazolidin-3-yl oxide]-N [1-(3-
[5-
(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(R,S,)-methylpropyl]
acetamide. Prepared in a similar manner as in Example 41. FAB MS [M+H] m/z;
Calcd: 577, Found 577.
Example 44 - (CE-2118) 2-[2-(R,f)-Phenyl-4-oxometathiazan-3y1]-N [1-(2-[S-(3-
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl] acetamide.
Prepared

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
in a similar manner as in Example 39. FAB MS [M+H] m/z; Calcd: 507, Found:
507.
Example 45 - (CE-2140){1-Benzoyl-3,8-quinazolinedione)-N [1-(2-[5-{3
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl] acetamide.
S To a mixture containing 1.70 g (2.74 mmol) of N chlorosuccinimide in 75 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 1.70
mL (23.15
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the addition of 1.90 g (3.27 mmol) of
( 1-
Benzoyl-3,8-quinazolinedione)-N [1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolyl]hydroxymethyl)-2-(S~-methyl propyl] acetamide in 10 mL of toluene
dropwise. The reaction was allowed to stir at -25°C for 2 hours,
followed by the
addition of 3.20 mL (22.96 mmol) of triethylamine. The cold bath was removed
and
the reaction allowed to warm to room temperature and maintained for 15
minutes.
The reaction was diluted with ethyl acetate and washed with water. The organic
phase
was dried over magnesium sulfate, filtered, and the solvent removed under
reduced
pressure. The residue was chromatographed on silica gel with 5%
methanol/dichloromethane to afford 1.37 g of a brown oil. This was further
purified
via preparative HPLC to give 450 mg (40.1 %) of the title compound. FAB MS
[M+H]m/z; Calcd: 580, Found: 580.
The intermediate (1-benzoyl-3,8-quinazolinedione)-N [1-(2-[S-(3-
methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(f~-methylpropyl]acetamide
was
prepared as follows:
a. 1-Benzoyl-3,8-quinazolinedione-2-t-butyl acetate.
To a solution containing 5.0 g (18.78 mmol) of 1-Benzoyl-3,8-
quinazolinidione prepared in a similar manner to that reported by Melnyk et
al.
(Tetrahedron Lett., 37:4145 {1996)), in 100 mL of DMF under a nitrogen
atmosphere
was added 4.30 mL (29.12 mmol) of bromo t-butylacetate and 5.4 g (23.30 mmol)
of
silver oxide. The reaction was heated to 50°C overnight, diluted with
ethyl acetate
and washed with water. The organic phase was dried over magnesium sulfate.
Filtration, removal of solvent under reduced pressure and column
chromatography of
the residue on silica gel with 40% ethyl acetate/hexane gave 5.25 g (73.49%)
of
product. FAB MS [M+H] m/z; Calcd: 381, Found: 381.
8s

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
b. 1-Benzoyl-2-carboxymethylene-3, 8-quinazolinedione.
To a solution containing 5.20 g (13.67 mmol) of 1-benzoyl-3,8-
quinazolinedione-2-t-butyl acetate in 300 mL of dichloromethane under a
nitrogen
atmosphere at 0°C was added 21.0 mL (211.44 mmol) of trifluroacetic
acid. The
S reaction was allowed to warm to room temperature overnight. The solvent was
removed under reduced pressure and the residue dissolved in ethyl acetate and
washed
with water. The organic phase was dried over magnesium sulfate. Filtration and
removal of solvent afforded 4.32 g (97.45%) of the title compound. FAB MS
[M+H]m/z; Calcd: 325, Found: 325.
c. (1-Benzoyl-3, 8-quinazolinedione)-N ~l -(2-(5-(3-methylbenzyl)-1, 3, 4-
oxadiazolylJ hydroxymethyl)-2-(S)-methylpropylJacetamide.
To a solution containing 1.80 g (5.55 mmol) of 1-benzoyl-2-
carboxymethylene-3,8-quinazolinedione in 100 mL of anhydrous dichloromethane
and 5 mL of DMF under a nitrogen atmosphere at 0°C was added 1.90 g
(7.46 mmol)
of BOPCI and 1.40 mL (8.05 mmol) of DIEA. After stirring for 30 minutes, a
solution containing 1.70 g (5.45 mmol) of 1-[2-(S-[3-methylbenzyl]}-1,3,4-
oxadiazolyl]-2-(S)-amino-3-methylbutan-1-of hydrochloride in 20 mL of
dichloromethane and 3.80 mL (21.84 mmol) of DIEA was added. The reaction was
allowed to stir at 0°C overnight, diluted with dichloromethane and
washed with water.
The organic phase was dried over magnesium sulfate. Filtration, removal of
solvent
under reduced pressure and column chromatography of the residue on silica gel
with
10% methanol/dichloromethane afforded 1.93 g (60.9%) of the title compound.
FAB
MS[M+H]m/z; Calcd: 582, Found: 582.
Example 46 - (CE-2138)(1-Benzoyl-3,6-piperazinedione)-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared
in a similar manner as in Example 44. FAB MS [M+H]m/z; Calcd: 532, Found: 532.
Example 47 - (CE-2147)(1-Phenyl-3,6-piperazinedione)-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared
in a similar manner as in Example 44. FAB MS [M+H]m/z; Calcd: 504, Found: 504.
__ _ __ . _ __ ~_ ___ __ . __ _T

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Example 48 - (CE-2148)(1-Phenyl-3,6-piperazinedione)-N [1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S)-
methylpropyl)acetamide.
Prepared in a similar manner as in Example 44. FAB MS [M+H] m/z; Calcd:558,
Found: 55 8.
Example 49 - (CE-2108) 3-[(Benzyioxycarbonyl)amino)-quinoline-2-one-N [1-(2-[5-
(3-methybenzyl)-1,3,4-oxadiazolyl) carbonyl)-2-(f)-methylpropyl)acetamide.
To a mixture containing 0.16 g (1.18 rnmol) of N chlorosuccinimide in 20 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.13
mL (1.77
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath followed by the addition of a solution containing
0.18 g
(0.30 mmol) of 3-((benzyloxycarbonyl)amino)-quinoline-2-one-N [ 1-(2-[S-(3-
methylbenzyl)-1,3,4-Oxadiazolyl)hydroxymethyl)-2-(S~-methylpropyl)acetamide in
20
mL of methylene chloride dropwise. The reaction was allowed to stir at -
25°C for 2
hours, followed by the addition of 0.19 mL (1.38 mmol) of triethylamine. The
cold
bath was removed and the reaction was allowed to warm to room temperature and
maintained for 30 minutes. The reaction was diluted with ethyl acetate and
washed
with water. The organic phase was dried over magnesium sulfate. Filtration,
removal
of solvent under reduced pressure and column chromatography of the residue on
silica
gel with 3% methanol/dichloromethane afforded 0.23 g of an oil. Further
purification
via preparative HPLC gave 100 mg of the title compound.
FAB MS (M+H} m/z; Calcd: 608, Found: 608
The intermediate 3-[(benzyloxycarbonyl)amino)-quinoline-2-one-N-[1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl)hydroxymethly)-2-(S~-methylpropyl)acetamide
was prepared as follows:
a. 3-((Benzyloxycarbonyl)aminoJ-quinoline-2-one.
To a solution containing 0.5 g (3.10 mmol) of 3-amino-quinoline-2-(1H)-one
described by Anderson, et. al. (J. Heterocyclic Chem., 30:1533 (1993)) in 40
mL of
dioxane under a nitrogen atmosphere was added 0.14 g (3.4 mmol) of sodium
hydroxide in 14 mL of water. The reaction mixture was cooled to 0°C,
followed by
the addition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of the
reaction
was maintained above 8.0 with additional 1 N sodium hydroxide. The reaction
was

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
allowed to warm to room temperature and stirred for 2 hours. The reaction was
diluted with methylene chloride and washed with water. The organic phase was
dried
over magnesium sulfate. Filtration, removal of solvent under reduced pressure
and
column chromatography of the residue on silica gel with 2%
methanol/dichloromethane afforded 0.32 g (35%) of product as a white solid.
FAB
MS [M+H} m/z; Calcd: 295, Found: 295
b. 3-((Benzyloxycarbonyl)aminoJ-quinoline-2-one-N t-butyl-acetate.
To a solution containing 0.30 g (1.02 mmol) of 3-
[(benzyloxycarbonyl)amino}-quinoline-2-one in 20 mL of DMF under a nitrogen
atmosphere was added 0.15 mL (1.02 mmol) of t-butyl bromoacetate and 0.24 g
(1.02
mmol) of silver oxide. The reaction was heated to 70°C and maintained
overnight.
The reaction mixture was diluted with acetonitrile and filtered through a pad
of celite.
The filtrate was concentrated under reduced pressure and the residue
partitioned
between ethyl acetate and water. The organic phase was dried over magnesium
1 S sulfate. Filtration, removal of solvent under reduced pressure and column
chromatography of the residue on silica gel with dichloromethane afforded 0.20
g
(48%) or product as a white solid. FAB MS [M+H] m/z; Calcd: 409, Found: 409.
c. 3-~(Benzyloxycarbonyl)aminoJ-1-carboxymethylene-quinoline-2-one.
To a solution containing 1.30 g (3.18 mmol) of 3-
[(benzyloxycarbonyl)amino]-quinoline-2-one-N t-butyl-acetate in 35 mL, of
dichloromethane under a nitrogen atmosphere at 0°C was added 2.45 mL
(31.84
mmol) of trifluoroacetic acid. The reaction was allowed to warm to room
temperature
overnight. The solvent was removed under reduced pressure to afford 1.09 g
(97%) of
the title compound. FAB MS [M+H] m/z; Calcd: 353, Found: 353
d. 3-((Benzyloxycarbonyl)aminoJ-quinoline-2-one-N ~l -(2-~S-(3-
methylbenzyl)-1,3,4-oxadiazolylJ hydroxymethyl)-2-(S)-methylpropylJacetamide.
To a solution containing 1.09 g (3.09 mm01) of 3-
[(benzyloxycarbonyl)amino]-1-carboxymethylene-quinoline-2-one in 50 mL of
anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphere at
0°C
was added 0.84 (3.31 mmol) of BOPCI and 1.10 mL (6.31 mmol) of DIEA. After
stirring for 30 minutes, 0.82 g (2.65 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-
oxadiazolyl]-2(S)-amino-3-methylbutan-1-of hydrochloride in 8 mL of
~S

CA 02272548 1999-OS-19
WO 98/24$06 PCT/LTS97/21636
dichloromethane and 0.56 mL {3.20 mm01) of DIEA was added. The reaction was
allowed to stir at 0°C overnight, diluted with dichloromethane and
washed with water.
The organic phase was dried over magnesium sulfate. Filtration, removal of
solvent
under reduced pressure and column chromatography of the residue on silica gel
with
5% methanol/dichloromethane afforded 0.37 g (30.3%) of product. FAB MS [M+H]
m/z; C;alcd: 610, Found: 610
Example 50 - (CE-2107) 3-[{Benzyloxycarbonyl)amino]-7-piperidinyl-quinoline-2-
one-N [1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(f)-
methylpropyl]acetamide. Prepared in a similar manner as shown in Example 48.
FAB MS [M+H] m/z; Calcd: 691, Found: 691
Example 51 - (CE-2117) 3-Carbomethoxy-4-fluoro-quinoline-2-one-N[1-(2-[5-(3-
methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S~-methylpropyl]acetamide.
Prepared
in a similar manner as shown in Example 48. FAB MS [M+H] m/z; Calcd: 535,
Found: 535
Example 52 - (CE-2113) 3-(Amino-quinoline-2-one)-IV[1-(2-[S-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl)-2-(f)-methylpropyl]acetamide.
To a solution containing 2.30 g (3.79 mmol) of 3-
[(benzyloxycarbonyl)amino]-quinoline-2-one-N [1-(2-[5-(3-methyl benzyl)-1,3,4-
oxadiazolyl]-carbonyl)-2-(S')-methyl propyl]acetamide in 60 mL of
trifluoroacetic acid
under a nitrogen atmosphere at 0°C was added 0.53 mL (4.54 mmol) of
thioanisole.
The reaction was allowed to warm to room temperature overnight. The solvent
was
removed under reduced pressure. Subsequent preparative HPLC afforded 0.61 g
(27%) of the title compound. FAB MS [M+H] m/z; Calcd: 474, Found: 474
Example 53 - (CE-2116) 3-[(4-Morpholino)aceto] amino-quinoline-2-one-lV[1-(2-
[S-
(3-methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S~-methylpropyl]acetamide.
To a solution containing 0.32 g (1.22 mmol) of 4-morphoiino acetic acid in 18
mL of dichloromethane under a nitrogen atmosphere at 0°C was added 0.33
g (1.30
mmol) of BOPCI and 0.22 mL (1.26 mmol) of DIEA. After stirring for 1.5 hours,
a
solution containing 0.61 g (1.04 mmol) of 3-(amino-quinoline-2-one)-N [1-(2-[5-
(3-
~S~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(f)-methypropyl]acetamide in 20 mL
of
dichloromethane was added followed by 0.22 mL ( 1.26 mmol) of DIEA. The
reaction
was allowed to stir at 0°C overnight, diluted with dichloromethane and
washed with
water. The organic phase was dried over magnesium sulfate. Filtration, removal
of
solvent under reduced pressure and preparative HPLC afforded 0.20 g (27%) of
the
title compound. FAB MS [M+H] m/z; Calcd: 602, Found: 602
Example 54 - (CE-2088) 3,4-Dihydro-quinoline-2-one-N[1-(2-[5-(3-methylbenzyl)-
1,3,4-oxadiazolyl]carbonyl}-2-N methylpropyl]acetamide from commercially
available 3,4-Dihydro-2(1H)-quinoline-2-one. Prepared in a similar manner as
shown
in Example 52. FAB MS [M+H] m/z; Calcd: 461, Found: 461
Example 55 - (CE-2099) 1-Acetyl-3-benzylidene piperazine-2,5-dione-N [1-(2-[5-
(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S~-methylpropyl]acetamide.
To a solution containing 0.55 g (4.15 mmol) of 1V chlorosuccinimide in 35 mL
of anhydrous toluene at 0°C under a nitrogen atmosphere was added 0.46
mL (6.22
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the addition of a solution containing
0.58 g
(1.04 mmol) of 1-acetyl-3-benzylidene piperazine-2,5-dione-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(,S~-methylpropyl]acetamide
in 8
mL of toluene. The reaction was allowed to stir at -25°C for 2h,
followed by the
addition of 0.68 mL (4.87 mmol) of triethylamine. The cold bath was removed
and
the reaction allowed to warm to room temperature and maintained for 40
minutes.
The reaction was partitioned between ethyl acetate and water. The organic
phase was
dried over magnesium sulfate. Filtration, removal of solvent under reduced
pressure
and column chromatography of the residue on silica gel 60% ethyl
acetate/hexane
gave 0.54 g of a brown oil which was further purified via preparative HPLC to
give
146 mg (25 %) of the title compound. FAB MS [M+H] m/z; Calcd: S 5 8, Found: S
S 8
The intermediate 1-acetyl-3-benzylidene piperazine-2,5-dione-N[1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S~-methylpropyl]acetamide
was
prepared as follows:
a. 1 Acetyl-3-benzylidene piperazine-2,5-dione-N t-butyl acetate.
GO

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
To a solution containing 6.36 g (26.00 mmol) of 1-Acetyl-3-benzylidene
piperazine-2,5-dione described by D. Villemn, et al. (Synthetic
Communications,
20:3325 (I990)), in 100 mL of DMF under a nitrogen atmosphere was added 9.62
mL
(65.10 mmol) of t-butyl bromoacetate and 7.55 g (32.60 mmol) of silver oxide.
The
reaction was heated to 45°C overnight. The reaction was filtered
through a plug of
celite and the filtrate concentrated under reduced pressure. The residue was
diluted
with ethyl acetate and washed with water. The organic phase was dried over
magnesium sulfate. Filtration, removal of solvent under reduced pressure and
column
chromatography of the residue on silica gel with 1 % methanol/dichloromethane
gave
5.37 g of a tan solid. Further purification via preparative HPLC gave 2.5 g
(27%) of
the title compound. FAB MS[M+H]m/z; Calcd: 359, Found: 359.
b. 1-Acetyl-3-benzylidene-4-carboxymethylene piperazine-2, 5-dione.
To a solution containing 2.50 g (6.98 mmol) of 1-acetyl-3-benzyiidene
piperazine-2,5-dione-N t-butyl acetate in 100 mL of dichloromethane under a
nitrogen
1 S atmosphere at 0°C was added 5.40 mL (69.80 mmol) of trifluoroacetic
acid. The
reaction was allowed to warm to room temperature overnight. The solvent was
removed under reduced pressure and the residue diluted with ethyl acetate and
washed
with a saturated sodium bicarbonate solution. The aqueous phase was acidified
with 1
N hydrochloric acid and extracted with ethyl acetate. The organic phase was
dried
over magnesium sulfate. Filtration and removal of solvent under reduced
pressure
gave 1.96 g (96%) of product as a tan solid. FAB MS [M+H] m/z; Calcd: 303,
Found: 303.
c. I Acetyl-3-benzylidene piperazine-2,5-dione-N (1-(2~5-(3-
methyl benzyl)-1, 3) 4-oxadiazolylJhydroxymethyl)-2-(S)-
methylpropylJacetamide.
To a solution containing 0.65 g (2.14 mmol) of 1-acetyl-3-benzylidene-4-
carboxymethylene-piperazine-2,5-dione in 40 mL of anhydrous dichloromethane
and
3 mL of DMF under a nitrogen atmosphere at 0°C was added 0.57 g (2.24
mmol of
BOPCI and 0.39 mL (2.21 mmol) of DIEA. After stirring for 30 minutes, a
solution
containing 0.57 g (1.83 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-
2-(S)-
amino-3-methylbutan-1-of hydrochloride in 10 mL of dichloromethane and 0.39 mL
(2.21 mmol) of DIEA. The reaction was allowed to stir at 0°C overnight,
diluted with
dichloromethane and washed with water. The organic phase was dried over
°~l

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97/21636
magnesium sulfate. Filtration, removal of solvent under reduced pressure and
column
chromatography of the residue on silica gel with 5% methanol/ dichloromethane
gave
0.13 g (58%) of product. FAB MS[M+H] m/z; Calcd: 560, Found: 560.
Example 56 - (CE-2105) 1-Acetyl-3-(4-fluorobenzylidene) piperazine-2,5-dione-N
[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z; Calcd:
576, Found: 576.
Example 57 - (CE-2111) 1-Acetyl-3-(4-dimethylamino benzylidene) piperazine-
2,5-
dione-N [ 1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide. Prepared in a similar manner as shown in Example 54.
FAB MS[M+H] m/z; Calcd: 601, Found: 601.
1 S Example 58 - (CE-2112) 1-Acetyl-3-(4-carbomethoxy benzylidene) piperazine-
2,5-
dione-N [1-(2-[S-(3-rnethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide. Prepared in a similar manner as shown in Example 54.
FAB MS[M+H] m/z; Calcd: 616, Found: 616.
Example 59 - (CE-2114) 1-Acetyl-3-[(4-pyridyl)methylene] piperazine-2,5-dione-
N
[1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z; Calcd:
559, Found: 559.
Example 60 - (CE-2144) 4-[ 1-Benzyl-3-(R)-benzyl-piperazine-2,5,-dione]-N [ 1-
(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 2.20 g (16.48 mmol) of N chlorosuccinimide in 100
mL of anhydrous toluene under a nitrogen atmosphere at 0°C was added
2.1 mL
(28.59 mmol) of dimethyl sulfide. The reaction was cooled to -25°C
using a carbon
tetrachloride/dry ice bath, followed by the addition of a solution containing
2.5 g
(4.10 mmol) of 4-[1-benzyl-3-(R)-benzyl piperazine-2,5, dione]-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in
1 S

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
mL of toluene. The reaction was allowed to stir at -25°C for 2 hours,
followed by the
addition of 4.0 mL (28.70 mmol) of triethylamine. The cold bath was removed
and
the reaction allowed to warm to room temperature and maintained for 30
minutes.
The reaction was diluted with ethyl acetate and washed with water. The organic
phase
was dried over magnesium sulfate. Filtration, removal of solvent under reduced
pressure, and column chromatography of the residue on silica gel with 5%
methanol/dichloromethane afforded 2.27 g of a light brown solid which was
further
purified via preparative HPLC to give 350 mg (14.4%) of the title compound.
FAB
MS [M+H]m/z; Calcd: 608, Found: 608.
The intermediate 4-[1-benzyl-3-(R)-benzyl piperazine-2,5,-dione]-N [1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide
was prepared as follows:
a. 1-Benzyl-3-(R)-benzyl piperazine-2, 5-dione-4-t-butyl acetate.
To a solution containing 7.0 g (23.78 mmol) of 1-benzyl-3-(R)-benzyl
piperazine-2,5-dione described by Steele, et al. (J. Biorg) Med. Chem. Lett.,
5:47
(1995)) in 125 mL of DMF under a nitrogen atmosphere was added 5.30 mL (35.89
mmol;) of t-butyl bromoacetate and 6.80 g (29.34 mmol) of silver oxide. The
reaction
was heated to 50°C overnight, diluted with ethyl acetate and washed
with water. The
organic phase was dried over magnesium sulfate. Filtration, removal of solvent
under
reduced pressure and column chromatography of the residue on silica gel with
SO%
ethyl acetate/hexane afforded 7.74 g (79.7%) of the title compound as a white
solid.
FAB MS[M+H]m/z; Calcd:409,Found::409.
b. 1-Benryl-3-(R)-benryl-4-carboxymethylene piperazine-2, S-dione.
To a solution containing 7.70 g (18.85 mmol) of 1-Benzyl-3-(R)-benzyl
piperazine-2,5-dione-4-t-butyl acetate in 300 mL of dichoromethane under a
nitrogen
atmosphere at 0°C was added 19.0 mL(191.30 mmol) of trifluroacetic
acid. The
reaction was allowed to warm to room temperature overnight. The solvent was
removed under reduced pressure and the residue dissolved in ethyl acetate and
washed
with water. The organic phase was dried over magnesium sulfate. Filtration and
removal of solvent under reduced pressure afforded 6.69 g of product. FAB
MS[M+H]m/z; Calcd:353,Found:353.
q3

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
c. 4-~1-Benryl-3(R)-benryl piperazine-2,5,-dioneJ-N fl-(2-~S-(3-
methylbenryl)-1, 3, 4-oxadiazolylJhydroxymethyl)-2-(S)-methylpropylJacetamide.
To a solution containing 2.0 g (5.68 mmol) of 1-Benzyl-3-(R)-benzyl-4-
carboxyrnethylene-piperazine-2,5-dione in 100 mL of dichloromethane and 2 mL
of
DMF under a nitrogen atmosphere at 0°C was added 2.0 g (7.86 mmol) of
BOPCI and
1.50 mL (8.62 mmol) of DIEA. After stirring for 30 minutes, a solution
containing
1.80 g (5.7 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-
3-
methylbutan-1-of hydrochloride in 10 mL of dichloromethane and 4.0 mL (22.99
mmol) of DIEA. The reaction was allowed to stir at 0°C overnight,
diluted with
dichloromethane and washed with water. The organic phase was dried over
magnesium sulfate. Filtration, removal of solvent under reduced pressure and
column
chromatography of the residue on silica gel with 7% methanol/ dichloromethane
afforded 2.69 g (77.7%) of product. FAB MS[M+H]m/z; Calcd:610, Found: 610.
Example 61 - (CE-2128) 4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N [1-(2-
[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 59. FAB MS(M+H]m/z;
Calcd:608, Found: 608.
Ezample 62 - (CE-2146) 4-[1-Benzyl-3-(R)-benzylpiperazine-2,5; dione]-N [1-(3-
[S-
(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;
Calcd:662, Found: 662.
Example 63 - (CE-2129) 4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N [1-(3-
[5-
(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl}-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H]xn/z;
Calcd:662, Found: 662.
Example 64 - (CE-2133) 4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N [1-(3-
(5-
(2-dimethylaminoethyl}-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;
~H

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97121636
Calcd:575, Found: 575.
Example 65 - (CE-2084) 4-[1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N [1-
(3-
[5-(3-trifluoromethylbenzyi)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide. Prepared in a similar manner as shown in Example 59.
FAB MS[M+H]m/z; Calcd:572, Found: 572.
Example 66 - (CE-2106) 4-jl-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N [1-
(2-
[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;
Calcd:518, Found: 518.
Example 67 - (CE-2162) 4-[1-(2-N-Morpholino ethyl)-3-(R)-benzyl piperazine-
2,5,-
dione]-N [1-(2-[S-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
1 S methylpropyl] acetamide. Prepared in a similar manner as shown in Example
59.
FAB MS[M+H]m/z; Calcd:631, Found: 631.
Example 68 - (CE-2149) 5-(R,S)-Phenyl-2,4-imidazolidinedione-N [1-(2-[5-(3-
metllylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 0.28 g (2.10 mmol) of N chlorosuccinimide in 50 mL
of anhydrous toluene under a nitrogen atmosphere at 0°C was added 0.23
mL (3.13
mmol) of dimethyl sulfide. The reaction was cooled to -25°C using a
carbon
tetrachloride/dry ice bath, followed by the addition of a solution containing
0.26 g
(0.52 mmol) of 5-(R,S)-phenyl-2,4-imidazolidinedione-N [1-(2-[5(3-
methylbenzyl)-
1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 10 mL of
toluene.
The reaction was allowed to stir at -25°C for 2 hours, followed by the
addition of
0.30 mL (2.15 mmol) of triethylamine. The cold bath was removed and the
reaction
allowed to warm to room temperature and maintained for 30 minutes. The
reaction
was diluted with ethyl acetate and washed with water. The organic phase was
dried
over magnesium sulfate. Filtration, removal of solvent under reduced pressure
and
column chromatography of the residue of silica gel with 10%
methanol/dichloromethane, followed by preparative HPLC gave 120 mg (47.2%) of
9~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
the title compound. FAB MS[M+H]m/z; Calcd:490, Found: 490.
The intermediate 5-(R,S)-phenyl-2,4-imidazolidinedione-N [1-{2-[5(3-
methylbenzyl)-I,3,4-oxadiazolyl]hydroxymethyl}-2-(S)-methylpropyl]acetamide
was
prepared as follows:
S a. (R)-N (Ethoxy carbonylmethyl)-N'-(1-methoxy carbonyl-2 phenyl)urea.
To a solution containing 18.45 g (91.49 mmol) of (R)-2-phenylglycine
methylester in 250 mL of ethyl acetate and 13.4 mL (96.12 mmol) of
triethylamine
under a nitrogen atmosphere at 0°C was added 10 mL (91.49 mmol) of
ethyl
isocyanatoacetate. After stirnng for lh, the reaction was diluted with ethyl
acetate
and washed with water. The organic phase was dried over magnesium sulfate.
Filtration and removal of solvent under reduced pressure afforded 29.28 g
(97.6%) of
product as a white solid. FAB MS[M+H]m/z; Calcd: 235, Found: 235.
b. (R)-S-Phenyl-3-carboxymethyl hydantoin.
A mixture containing 29.28 g (99.49 mmol) of (R)-N (ethoxy
carbonylmethyl)-N'-(1-methoxy carbonyl-2-phenyl)urea in 500 mL of concentrated
hydrochloric acid was heated to reflux overnight. The reaction mixture was
cooled to
room temperature and extracted with ethyl acetate. The organic phase was dried
over
magnesium sulfate. Filtration and removal of solvent under reduced pressure
afforded
14.01 g (60%) of the title compound. FAB MS [M+H] m/z; Calcd: 295, Found: 295.
c. 5-(R,S) phenyl-2,4-imidazolidinedione-N ~1-(2-(S(3-methylbenzyl)-
1, 3, 4-oxadiazolylJhydroxymethyl)-2-(S)-methylpropylJacetamide
To a solution containing 2.55 g (10.89 mmol) of (R)-S-phenyl-3-
carboxymethyl hydantoin in 100 mL of dichloromethane and 10 mL of DMF under a
nitrogen atmosphere at 0°C was added 2.30 g (12.00 mmol) of EDCI and
1.62 g
(11.99 mmol) of HOBT. After stirring 30 minutes, a solution containing 4.43 g
(14.21 mmol) of 1-[2-(S-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-
methylbutan-I-of hydrochloride in 20 mL of dichloromethane and 4.78 mL (43.50
mmol) of NMM. The reaction was allowed to warm to room temperature overnight,
diluted with dichloromethane and washed with water. The organic phase was
dried
over magnesium sulfate. Filtration, removal of solvent under reduced pressure
and
column chromatography of the residue on silica gel with 50%
acetone/dichloromethane afforded 1.90 g (35.5%) of the title compound. FAB MS
9w

CA 02272548 1999-OS-19
WO 98124806 PCT/US97/21636
[M+H] m/z; Calcd: 490, Found: 490.
Example 69 - {CE-2154) S-(S)-Benzyl-2,4-imidazolidinedione-N [1-(2-[5-(3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared
in a similar manner as shown in Example 67. FAB MS [M+H] m/z; Calcd: 504,
Found: 504.
Example 70 - (CE-2142) 5-(R)-Benzyl-2,4-imidazolidinedione-N [ 1-(2-[5-{3-
methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared
in a similar manner as shown in Example 67. FAB MS [M+H] m/z; Calcd: 504,
Found: 504.
Example 71 - (CE-2141 ) S-(R)-Benzyl-2,4-imidazolidinedione-N [ 1-(3-[ 5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 67. FAB MS [M+H] mlz; Calcd:
558, Found: 558.
Example 72 - (CE-2155) 5-(S)-Berizyl-2,4-imidazolidinedione-N [1-(3-[5-(3-
trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z; Calcd:
558, Found: 558.
Example 73 - (CE-2151) 1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N [1-(2-[5-
(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl)acetamide.
Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z; Calcd:
594, Found: 594.
Example 74 - {CE-2150) 1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N [1-(3-[5-
(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z; Calcd:
648, Found: 648.

CA 02272548 1999-OS-19
WO 98/24806 PCT/LTS97/21636
Example 75 - (ONO-PO-698) 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 410 mg (0.744 mmol, 77% purity) of Dess-Martin
Reagent (1,1,1-triacetoxy-1,1-dihydro-1,2,benziodoxol-3-( 1H)-one) in 4 mL of
dichloromethane was added dropwise a solution containing 410 mg (0.676 mmol)
of 2-
[5-benzyioxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-
N-
[ 1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-
methylpropyl]acetamide in
5 mL of dichloromethane. The reaction mixture was allowed to stir for 1 hour.
The
reaction was quenched by addition of water, extracted with ethyl acetate (x2).
The
extract was washed with water and a saturated sodium chloride solution. The
organic
phase was dried over anhydrous sodium sulfate, filtered and evaporated under
reduced
pressure. The residue was purified by column chromatography on silica gel
using a
elution of 33% ethyl acetate/hexane to afford 372 mg of the tittle compound.
APCI,
Pos, 40V [M+H] m/z; Calcd: 605, Found: 605.
The intermediate 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-
1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[S-tert-butyl-1,3,4-
oxadiazolyl]hydroxymethyl)-2-
(S)-methylpropyl]acetamide was prepared as follows: to a solution containing
265 mg
(1.01 mmol) of [1-[5-tent-butyl-1,3,4-oxadiazol-2-yl]-2-(S)-amino-1-hydroxy-3-
methylbutane hydrochloride and 336 mg (0.843 mmol) of 5-
[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]acetic acid (J. Med. Chem., 38:98-108 (1995)) in 2 mL of anhydrous
DMF
was added 155 mg (1.01 mmol) of HOBT and 231 mg (1.01 mmol) of EDCI. The
mixture was cooled to 0 °C and 0.11 mL (1.0 mmol) of NMM was added
dropwise and
the reaction mixture was allowed to stir for 3 hours. The reaction was
quenched by
addition of water and extracted with ethyl acetate (x3). The extract was
washed with
aqueous 10% citric acid solution, a saturated sodium hydrogencarbonate
solution and a
saturated sodium chloride solution. The organic phase was dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The residue
was
purified by column chromatography on silica gel using a gradient elution of 0
to 1
methanol/chloroform to afford 418 mg of the tittle compound. APCI, Pos, 40V
[M+H]
m/z; Calcd: 607, Found: 607.

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Example 80 - (ONO-PO-690) 2-[S-{Benzyloxycarbonyl)amino-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl] N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar
manner
to Example 75. APCI, Pos, 40V [M+H] m/z; Calcd: 667, Found: 667.
Example 81 - {ONO-PO-697) 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1 pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-
oxadiazolyi]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar
manner
to Example 75. El, Pos, [M+H] m/z; Calcd: 624, Found: 624.
Example 82 - (ONO-PO-716) 2-[6-oxo-2-{4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-
N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
was
prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H] m/z; Calcd:
454,
Found: 454.
Example 83 - (ONO-PO-722) 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrirnidinyl]-
N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI,
Neg,
40V [M-H] m/z; Calcd: 516, Found: S 16.
Example 84 - (ONO-PO-727) 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-
N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide
was
prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H] m/z; Calcd:
456,
Found: 456.
Example 85 - (ONO-PO-730) 2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-tent-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was
prepared in
a similar manner to Example 75. APCI, Neg, 40V [M-H] m/z; Calcd: 436, Found:
436.
Example 86 - (ONO-PO-731) 2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[S-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was
prepared in a similar manner to Example 75. APCI, Neg, 40V [M-H] m/z; Calcd:
498,
Found: 498.

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Example 87 - (ONO-PO-732) 2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[I-(2-
[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide was
prepared
in a similar manner to Example 75. APCI, Pos, 40V [M+H] rn/z; Calcd: 438,
Found:
438.
Example 88 - (ONO-PO-734) 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-
N-[ 1-(2-[5-(1-methylcyclopropyl)-I,3,4-oxadiazolyl]carbonyl)-2-{S)-
methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI,
Pos,
40V [M+H] m/z; Calcd: 454, Found: 454.
Example 89 - (ONO-PO-735) 2-[6-Oxo-2-phenyl-I,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-(1-methylcyciopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide
was prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H] mlz;
Calcd:
436, Found: 436.
Example 90 - (ONO-PO-737) 2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-
[5-tent-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide was
prepared
in a similar manner to Example 75. APCI, Pos, 40V [M+H] m/z; Calcd: 438,
Found:438.
Example 91 - (ONO-PO-696) 2-[5-Amino-6-oxo-2-(4-fluorophenyl}-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl)acetamide.
To a mixture containing 296 mg (0.49 mmol) of 2-[S-
(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl] N-
[ 1-
(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide and
0.32 mL
{2.9 mmol) of anisole in 8 mL of dichlorornethane at 0 ° C was added
dropwise a
solution containing 392 mg (2.9 mmol) of aluminum chloride in 4 mL of
nitromethane.
The reaction mixture was allowed to stir for 1.5 hours, quenched by addition
of ice
water, extracted with ethyl acetate (x3). The extract was washed with water
and a
saturated sodium chloride solution. The organic phase was dried over anhydrous
magnesium sulfate, filtered and evaporated under reduced pressure. The residue
was
~ a ~>
_~.~ ..___ .. T _

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
purified by column chromatography on silica gel using a elution of 66% ethyl
acetate/hexane to afford 175 mg of the tittle compound as a white solid. APCI,
Pos,
40V [M+H] m/z; Calcd: 471, Found: 471.
Example 92 - (ONO-PO-691) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl] N-[1-(2-[5-(a,a-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,
Pos,
[M+H] m/z; Calcd: 533, Found: 533.
Example 93 - (ONO-PO-692) 2-[5-Amino-6-oxo-2-{4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(a,a-dimethyl-3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-
(S)-methylpropyl]acetamide was prepared in a similar manner to Example 91.
FAB,
Pos, [M+H] m/z; Calcd: 547, Found: 547.
Example 94 - (ONO-PO-693) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-I-
pyrimidinyl]-N-[ 1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,
Pos,
[M+H] m/z; Calcd: 519, Found: 519.
Example 95 - (ONO-PO-694) 2-[5-Amino-6-oxo-2-{4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd: 491, Found: 491.
Example 96 - (ONO-PO-695) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V (M+H] m/z; Calcd: 492, Found: 492.
Example 97 - (ONO-PO-699) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,
Pos
[M+H] m/z; Calcd: 521, Found: 521.
10~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Example 98 - (ONO-PO-701) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-I,6-dihydro-1-
pyrimidinyl]-N-[ I-(2-[S-(a,a-dimethyl)-3,4-dihydroxybenzyl)-1,3,4-
oxadiazolyl]carbonyl}-2-(S)-methylpropyl]acetamide was prepared in a similar
manner
to Example 91. APCI, Pos, 40V [M+H] m/z; Calcd: 565, Found: 565.
Example 99 - (ONO-PO-703) 2-[S-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd: 505, Found: 505.
Example 100 - (ONO-PO-704) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-I,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolylJcarbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,
Pos
[M+H) m/z; Calcd: 429, Found: 429.
Example 101 - (ONO-PO-705). 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-I-
pyrimidinyl]-N-[ 1-{2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd: 457, Found: 457.
Example 102 - (ONO-PO-706) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ I-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropylJacetamide was prepared in a similar manner to Example 91. FAB,
Pos
[M+HJ m/z; Calcd: 471, Found: 471.
Example 103 - (ONO-PO-707) 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,
Pos
[M+H] m/z; Calcd: 453, Found: 453.
Example 104 - (ONO-PO-711) 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-a,a-dimethybenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
(off

methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB,Pos
[M+H]m/z; Calcd:515,Found:515.
Example 105 - (ONO-PO-712) 2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:454, Found:454.
Example 106 - (ONO-PO-714) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:469, Found:469.
Example 107 - (ONO-PO-715) 2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:516, Found:516.
Example 108 - (ONO-PO-718) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4- oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:471, Found:471.
Example 109 - (ONO-PO-721) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:533, Found:533.
Example 110 - (ONO-PO-728) 2-[5-Amino-6-oxo-2-phenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Neg,
40V [M+H] m/z; Calcd:449, Found:559.
103

CA 02272548 1999-OS-19
WO 98124806 PCT/US97/21636
Example lIl - (ONO-PO-729) 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-
pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:453, Found:453.
Example 112 - (ONO-PO-733) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-i-
pyrimidinyl]-N-[1-{2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:471, Found:471.
Example 113 - (ONO-PO-736) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-
methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI,
Pos,
40V [M+H] m/z; Calcd:453, Found:453.
Example 114 - (ONO-PO-700) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-
pyrimidinyl]-N-[ I -(2-[5-(a,a-dimethyl-3,4-methylenedioxybenzyl)-I ,3,4-
oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
To a mixture containing 66 mg (0.093 mmol) of 2-[5-
(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-
[1-
(2-[5-(a,a-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-
(S)-
methylpropyl]acetamide (the compound prepared in a similar manner to Example
75)
was added 2.5 mL of 30% hydrobromic acid in acetic acid solution. The reaction
mixture was allowed to stir for 1 hour, quenched by addition of ice water,
extracted with
ethyl acetate (x3). The extract was washed with water (x2) and a saturated
sodium
chloride solution. The organic phase was dried over anhyudrous sodium sulfate,
filterd
and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel using a gradient elution of 0 to 1 %
methanol/chloroform to
afford 41 mg of the title compound. El, Pos, [M+] m/z; Calcd:576, Found:576.
Example 115 - (ONO-PO-702) 2-[5-{Methylsulfonyl)amino-6-oxo-2-(4-fluorphenyl)-
1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[S-(3-methylbenzyl)-1,3,4-
oxadiazolyl]carbonyl)-2-
(S)-methylpropyl]acetamide

CA 02272548 1999-OS-19
WO 98/24806 PCT/L1S97121636
To a mixture containing 187 mg (0.36 mmol) of 2-[5-amino-6-oxo-2-(4-
fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-
oxadiazolylJcarbonyl)-2-(S)-methylpropyl]acetamide (the compound prepared in
Example 25) in 3.5 mL of pyridine at 0°C under an atmosphere of argon
was added
S 0.028 mL (0.36 mmol) of mesyl chloride. The reaction mixture was allowed to
stir for
17 hours at room temperature, 15 hours at 50 ° C and 1 hour at 70
° C. The reaction
mixture was quenched by addition of ice water, extracted with dichloromethane.
The
extract was washed with a saturated sodium chloride solution. The organic
phase was
dried over anhydrous sodium sulfate, filtered and evaporated under reduced
pressure.
The residue was purified by column chromatography on silica gel using a
gradient
elution of SO to 66% ethyl acetate/hexane to afford 60 mg of the tittle
compound. APCI,
Pos, 40V [M+H] m/z; Calcd: 597, Found: 597.
Example 110 - In Yitro Inhibition of Elastase
The following protocol was used to determine inhibitory activity of ONO-PO
series of compounds. The elastase used in the protocol was derived from human
sputum (HSE). A mother solution of the HSE enzyme was prepared from
commercially available HSE (875 U/mg protein, SE-563, Elastin Product Co.,
Inc,
Missouri, USA) by diluting with saline to 1,000 U/ml, which was further
diluted to 2
U/ml at 0°C prior to use.
A solution was prepared by mixing 100 p,l 0.2 M HEPES-NaOH buffer (pH
8.0), 40 p,l 2.5 M NaCI, 20 pl 1 % polyethyleneglycol 6000, 8 wl distilled
water, 10 ~1
of a DMSO solution of inhibitor and 2 ~1 solution of N-methoxysuccinyl-Ala-Ala-
Pro-Val-p-nitroaniline (at concentrations of 100, 200 and 400 p.M}. The
solution was
incubated for 10 minutes at 37°C. To this was added an enzyme solution
of HSE
(elastase derived from human sputum). The resulting mixture was subj ected to
the
following rate assay.
Optical density (SPECTRA MAX 250, Molecular Devices) at 405 nm due to
p-nitroaniline generated by the enzyme reaction was measured at 37°C in
order to
measure the reaction rate during the period that the production rate of p-
nitroaniline
remains linear. The rate, mO.D.lmin., was measured for 10 minutes at 30 second
intervals immediately after the addition of the enzyme solution. ICS°
values were
determined by log-logit method and converted to K; values by Dixson plot
method.
IeS

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
The values are presented in Table 1 below.
Table 1.
Compound Ki (nM) Compound K; (nM) Compound K; (nM)
ONO-PO-690 78.3 ONO-PO-710 2.39 ONO-PO-73023.5
ONO-PO-691 0.52 ONO-PO-711 2.55 ONO-PO-7314.02
ONO-PO-692 1.37 ONO-PO-712 16.6 ONO-PO-73262.2
ONO-PO-693 2.71 ONO-PO-713 12 ONO-PO-73311.8
ONO-PO-694 24.8 ONO-PO-714 15.3 ONO-PO-73443.8
ONO-PO-695 13.9 ONO-PO-715 3.54 ONO-PO-73526.4
ONO-PO-696 6.38 ONO-PO-716 44.3 ONO-PO-7366.43
ONO-PO-697 27.3 ONO-PO-717 57.8 ONO-PO-73736.3
ONO-PO-698 0.77 ONO-PO-718 26.2
ONO-PO-699 21.2 ONO-PO-719 836.3
ONO-PO-700 1.18 ONO-PO-720 25.9
ONO-PO-701 2.98 ONO-PO-721 13.5
ONO-PO-702 1.78 ONO-PO-722 3.35
ONO-PO-703 2.25 ONO-PO-723 163.1
ONO-PO-704 14.0 ONO-PO-724 14.4
ONO-PO-705 10.7 ONO-PO-725 4281.4
ONO-PO-706 6.76 ONO-PO-726 589.5
ONO-PO-707 3.59 ONO-PO-727 132.8
ONO-PO-708 729.9 ONO-PO-728 8.75
ONO-PO-709 25.7 ONO-PO-729 29.1
CE compounds were tested as described in WO 96/16080. Results are
presented in Table 2 below. As shown, the compounds of the invention are
potent
inhibitors of elastase, with certain compounds showing subnanomolar levels of
inhibitory activity.
Example 111 -'Blood Level Screening
The inhibitors were dissolved or suspended in polyethylene glycol (PEG),
PEG-400 or PEG:HZO:EtOH at a concentration of 10 mg/ml. Unfasted male Sprague-
Dawley rats were given an oral dose of this solution by gavage. Rats received
10 mg
inhibitor/kg body weight in a volume of 1 ml/kg. After 1, 3 or 6 hr., the rats
were
killed with an overdose of urethane (2.5 g/kg; i.p.} and the blood collected
in a
heparinized tube via cardiac puncture. Red blood cells were separated fi om
the
106

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
plasma by centrifugation.
Depending on the inhibitor, one of four organics (ethyl acetate, toluene,
isopropyl ether or methyl t-butyl ether) was used to extract the compound from
the
plasma. Inhibitor concentrations were measured by HPLC or LC/MS analysis. The
results are presented in Table 2 below. Certain compounds of the invention
demonstrate high levels of oral bioavailability as shown by their blood level
concentrations over time.
Example 112 - Extracellular Matrix (ECM) Assay Procedure
Forty-eight well plates on which extracellular matix had been established were
supplied to Cortech by Dr. Simon's group at the State University of New York
at
Stony Brook. Briefly, the plates were prepared as follows: R22 rat heart
smooth
muscle cells were seeded into wells at 2.5 X 104 cells/cm. The cells were fed
every 4
days with Eagle's Minimal Essential Media supplemented with fetal bovine
serum,
tryptose phosphate broth, cefotaxime and streptomycin. At confluence, daily
supplements of 50 ug/ml ascorbic acid were added for 8 to 10 days during the
synthesis of the ECM layer. [35S]sulfate and ['H]proline were also added to
the
culture media to incorporate radiolabel into the matrix. Cells were later
lysed with
25mM NH40H. Plates were washed three times with water and once with phosphate-
buffered saline containing 0.02% NaN3. Plates were stored at 4°C until
use.
Matrix degradation assays were performed as follows: 0.40 ml of Hanks
balance salt solution (HESS) containing 1 or 5 uM test inhibitor (final
concentration;
diluted from DMSO stock solution; <2% DMSO final concentration) was added to
the
wells. After 30 minutes, SO u1 of a polymorphoneucleocyte (PMN) suspension was
added resulting in 5 X 105 cells/well. PMN's were stimulated with opsonized
zymosan. Zymosan particles were washed and suspended in 0.5 ml human serum for
1 hr at 37°C, vortexing every 15 min. The particles were then washed
three times with
HBSS and added to wells at a ratio of 10 particles/PMN in a volume of 50 ul.
After a
4 hr incubation at 37°C, a 100 ul aliquot of the supernatant was
withdrawn for
scintillation counting. Following removal of the remaining supernatant, the
residual
ECM was solubilized with 0.5 ml 2M NaOH. The amount of tritium in this
solubilized ECM was accessed by scintillation. ECM degradation data are
expressed
as (soluble counts released / total ECM counts) - (basal counts released
without
I~~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
PMN's / total ECM counts). The results are presented in Table Z below.
Table 2.
HNE ECM Data Plasma
K; % Inhibition Levels
(~M)
CE # (nlVn luM 5uM lhr 3hr 6 hr
CE2048 0.2
CE2049 0.5
CE2050 1.84
CE2051 1.56
CE2052 0.37
CE2053 0.41
CE2054 0.29
CE2055 0.49 0.002
CE2056 0.98
CE205? 0.375
CE2058 0.564
CE2061 71600
CE2062 0.3
CE2064 0.44
CE2065 0.47
CE2066 0.98
CE2067 3.6
CE2068 800
CE2069 4.4
CE2072 0.025 64.8 74.55 0.277 0.115 0.061
CE2073 0.235
CE2074 1
CE2075 0.039
CE2076 1.5
CE2077 0.15
CE2078 1.05
CE2079 34
CE2080 62
CE2082 53
CE2083 73
CE2084 133
CE2087 20
CE2088 66 0.801 0.755
CE2089 1.5
CE2090 2.7
CE2091 270
CE2092 6.3
CE2093 0.26
CE2094 10
CE2095 0.21 60.43 55.63
CE2096 0.79
CE2097 115
CE2098 85
CE2099 1.9 0.042
I~ CE21000.069 57.63 56.56 0.064
~1~~

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
CE2101 0.64 44.582 51.18 1.238 1.369 1.042
CE2102 258
CE2103 12.4
CE2104 0.33
CE210S 0.72
CE2106 41
CE2107 17
CE2108 10.5
CE2109 126
CE2110 0.13
CE2111 20 0.69
CE2112 1.2
CE2113 39 1.835 0.909
CE2114 25
CE2115 1
CE2116 ?6
CE2117 586
CE2118 13.2
CE2119 7.7
CE2120 S 1
CE2121 28
CE2122 63
CE2123 1 S
CE2124 0.033
CE2125 0.4 0.011
CE2126 S 0.161
CE2127 34
CE2128 64
CE2129 300
CE2130 2.1 16.32 29.02 0.162
CE2131 265
CE2132 23.5
CE2133 33000
CE2134 2 21.71 25.724 5.02
CE213S 17.5 0 37
CE2136 104
CE2137 558
CE2138 294
CE2139 41
CE2140 204
CE2141 64 O.OOS
CE2142 8.7
CE2143 11.5
CE2144 9.3
CE214S 0.038
CE2146 67
CE2147 1600
CE2149 0.28 51.275 SS.9 0 0 0
CE21S1 59 14.25 -8.3
CE2152 0.24
CE2154 10 54.6 65.4
lay

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
CE21SS S7
CE2156 S 12
CE21S7 1.4 9.96 13.42 3.81
CE21S9 S2
CE2160 260
CE2.1610.082 2S SS
CE2162 10.6 0.025
CE2163 0.75 54.7 64 0.316
CE2164 17 0.034
CE216S 2.6 0.067
CE2166 145
CE2168 O.1S
CE2170 297
CE217I 0.64
CE2172 2.2 0.021
CE2173 6.S 35.9 47.1
CE2174 1 S.2 1.49 18.3 1.86 0.97
CE2176 52
CE2177 0.016 74.2 76.78 0.393 0.41 0
CE2178 0.29 34 0.185
CE2179 7.6 48.8 45.9 1.229 O.S99
CE2180 44
CE2181 46
CE2182 S4
CE2183 0.23
CE2184 8.2 30.5 32.4 0.57
CE218S 0.27
CE2186 0.037
CE2187 42
CE2189 99
CE2190 29
CE2191 85 29.35 30.5
CE2192 7.3 40.8 49.7
CE2193 36
CE2194 2.4 41 58.7 1.11 O.S53
CE219S 10.6
CE2196 96
CE2197 4.8
CE2198 3.1
CE2200 13.7
CE2202 0.12
CE2203 79 0.004
CE2204 7.4 0.48
CE220S 37 0.475
CE2206 8.7 47.4 62.3
CE2207 1.2 0
CE2208 40
CE2209 36.4 0
CE2210 22.7
CE2211 348
CE2212 I 124
Ilc

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
CE2213 0.14 0.19
CE2214 0.92 0
CE221 I 63 1.16 0.83 0.63
S
CE2216 4.1 32.1 37.15 0.77 0.47 0.25
CE2217 S.S 28.1 41.2 1.99 0.521
CE2218 1.6 30.5 33.15
CE2219 537
CE2220 S2
CE2221 34
CE2223 0.93 34.1 36.15
S
CE2224 1 43.25 66.8 1.843 1.943 1.961
CE222S 8.2 30.85 43.45
CE2226 10.3 27.55 52.25
CE2227 40 1.276 0.74 0.962
CE2228 40 0.714 1.393 0.409
CE2229 9.S 31.25 48.2
CE2230 2.6 37.7 37.8 0
CE2231 16 1.226 0.787 O.S31
CE2232 O.1S 0.44 0.44 0.26
CE2233 41.6 54.7 SS.4 0.07 0.065 0.036
CE2234 796 39.7 3S
CE223S 9.5 19.75 13.25
CE2236 7.1 31.9 31.75
CE2237 3 34.6 42.6 1.02 1.8 0.84
CE2238 162 10.1 18.8 2.573 1.739 1.028
CE2239 43 11.9 11.3 1.46 1.15 0.71
CE2240 30 16.8 13.5 1.12 O.S 0.29
CE2241 14 18.6 31.7 0.598 0.289 0.078
CE2242 27 29.4 40.7
CE2243 11 48 54.9 2.801 2.104 1.598
CE2244 78.5
CE224S 24 34.7 39.3
CE2246 18.5 -2.3 32.6 1.182 0.837 0.496
CE2247 62.4 13.3 21.2 1.017 O.S72 0.186
CE2248 3.1 39.4 63.2 1.65 1.58 1.22
CE2249 13 22.4 42.4 1.179 0.704 0.213
CE22S0 6.9 27.4 48.6
CE22S 0.43 54.1 74.5 1.63 1.11 0.73
1
CE22S2 1.9 45.4 65.2 0.114 0.188 0.1
CE22S3 11 31.9 45.9 0.282 0.246 0.163
CE22S4 2.4 57.2 58.4 1.751 1.575 2.316
CE22SS 18 20.7 42
CE2256 16 24 47.8 0.9 0.33 0.2
CE22S7 30 48.3 61.4
CE22S8 3.7 42.9 38.1 1.624 1.S 1.212
CE22S9 3.3 43 59.6 O.S97 0.846 O.S02
CE2260 0.39 68.3 59.7 3.532 3.053 1.894
CE2261 0.36
CE2262 0.42
CE2263 0.67

CA 02272548 1999-OS-19
WO 98/24806 PCT/US97/21636
Example 113 - Ex vivo inhibition of elastase
Sixty (60) minutes after the oral adminstration of an inhibitor with an
appropriate vehicle, a blood sample (0.9 ml) is collected through the
abdominal aorta
by a syringe containing 0.1 ml of a 3.8% sodium citrate solution.
The blood sample is processed as follows: 60 ~.1 of (final 0.1-1 mg/ml) a
suspended solution of opsonized zymosan in Hank's buffer is added to the
preincubated whole blood (540 ~1) for 5 minutes at 37 °C, and the
resulting mixture is
incubated for 30 minutes at the same termperature. The reaction is terminated
by
immersing the test tube into ice water. The reaction mixture is then
centrifuged at
3,000 rpm for 10 minutes at 4 °C. Twenty (20) ~,1 each of the resulting
supernatant
(the Sample) is measured for elastase activity.
The mixture consisting of the following components is incubated for 24 hours
at 37 °C, and then optical density is measured at 405 nm:
0.2 M tris-HCl buffer (pH 100
8.0) p,l
2.5 M NaCI 40
pl
Distilled water 36
~.1
SO mM solution of a substrate 4 ~.1
(*)
The Sample 20
~,I
*N-Methylsuccinyl-Ala-Ala-Pro-V
al-p-nitroanlide
A test sample mixed with 1-methyl-2-pyrrolidone instead of the substrate is
regarded as Substrate (-). A test sample mixed with saline instead of the
Sample is
regarded as Blank. The remaining elastase activity in the Sample is calculated
according to the following:
optical density of Substrate (+) - (optical density of Substrate (-) + optical
density of Blank)
as a total production of p-nitroaniline over 24 hours based on a standard
curve for the
amount of p-nitroaniline.
An average activity is calculated based on the test sample of S-6 animals. An
agent at 3, 10 or 30 mg/kg is orally given by a forced administration to a 24
hour
fasted animal at 60 minutes before the blood sampling. Optical density is
measured
by SPECTRA MAX 250 (Molecular Devices).
i L~-