AU734615B2 - Serine protease inhibitors - Google Patents
Serine protease inhibitors Download PDFInfo
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- AU734615B2 AU734615B2 AU55894/98A AU5589498A AU734615B2 AU 734615 B2 AU734615 B2 AU 734615B2 AU 55894/98 A AU55894/98 A AU 55894/98A AU 5589498 A AU5589498 A AU 5589498A AU 734615 B2 AU734615 B2 AU 734615B2
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- oxadiazolyl
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Description
WO 98/24806 PCT/US97/21636 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 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 ac-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 c,-PI have an increased probability of developing emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, 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 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.
The present invention provides compounds comprising oxadiazole, thiadiazole or triazole ring structures, and can be generically described by the formula:
N-X
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- C,)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (Cs-C 12 )aryl, (Cs-C 1 2 )arylalkyl, (Cs-C 2 )arylalkenyl, fused (C 5 -Ci2)aryl-cycloalkyl or alkyl fused
(C
5
-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, (C 5
-C
6 )aryl, -O-(Cs-C,)aryl, -3arylcarboxamide, alkylthio or haloalkylthio.
X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms;, (C 5
C
6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkly, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxyamide, 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 X is 0; Y is N) or 1,3,4 oxadiazole rings X is N; Y is 0).
The compounds of the present invention may be conveniently categorised as Groups I through VI.
In one preferred embodiment, the invention provides compounds selected from the group consisting of: (Benzyloxycarbonyl)-L-valyl-N-[1 d im ethyl be nzyl) 2,4-oxad iazolyl Icarbonyl)-2-( S)-methyl propyl L-pro Ii na m ide, (Benzyloxycarbonyl )-L-valyl-N-f 1 5-dimethoxybenzyl ,2 ,4oxadiazolyllcarbonyl )-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl valyl-N-[1 5-ditrifluoromethylbenzyl)-1 ,2 ,4-oxadiazolyl]carbonyl S)methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl-N-[1 m methyl benzyl)-1, 4-oxad iazol yl ]ca rbonyl )-2-(S)-methyl propyl ]-L-proI in nam ide, (Benzyloxycarbonyl )-L-valyl-N-[1 -(3-[5-(4-phenylbenzyl ,2,4oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinam ide, (Benzyloxycarbonyl valyl-N-[1 henyl benzyl ,2,4-oxad iazol yl]ca rbonyl 5)-m eth y Ipro pyl] 25 L-prolinamide, (Benzyloxycarbonyl )-L-valyl-N-[l1-(3-[5-(3-phenoxybenzyl ,2,4oxadiazolylicarbonyl )-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl 0 valyl-N-[1 5-di phenyl benzyl)-1 ,2,4-oxadiazolyl]carbonyl 0::.:methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[l1-(3-[5-(4o~oodimethylaminobenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-Lprolinamide, (Benzyloxycarbonyl)-L-valy-N-1 -(3-[5-(biphenylmethine)-1 2,4oxadiazolyl]carbonyl )-methylpropyl]-L-proli namide, (Benzyloxycarbonyl valyl-N-[1 -(3-[5(c,a-dimethyl-[3-trifluoromethyllbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)- 2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valy-N-[1 ~.L~napthylmethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, 66 T29/01 /01 ,cf1 0561 .speci2.3 -4- (Benzyloxycarbonyl )-L-valyl-N-[ 1 -(3-[5-(2-napthylmethylene)-1 ,2,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-proli nam ide, (Benzyloxycarbonyl valyl-N-[1 ethyl ened ioxybe nzyl)- 1, 2 ,4-oxad iazol y]ca rbo nyl S)methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl-N-[1 pyridylmethylene)-1 .2,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxyc-arbonyl )-L-valyl-N-[1 -(3-[5-(morph olIino-N -ethyl ene)-1, ,2,4oxad iazolyl ]carbonyl ethyl propyl L-prol inamni de, (Benzyloxyc-arbonyl valyt-N-[1 -(3-[5-(dimethylamino-N-ethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl-N-[1 (carbomethoxyethylene)-1 ,2,4-oxadiazolyl]carbonyl )-2-(S)-methyipropyl]-Lprolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(adamantylmethylene)-1 ,2,4oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, or (Benzyloxycarbonyl)-Lvalyl-N-[1 -(3-[5-(cyclohexylmethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]-L-prolinamide.
According to a second embodiment the present invention provides a compound selected from the group consisting of: 3-Pyridylcarbonyl-L-valyl-N-[1 [5-(3-trifluoromethylbenzy ,2 ,4-oxad iazolyl]carbonyl)-2-(S)-methylpropyl]-Lprolinamide, Methyl oxyca rbonyl -L-val yl-N 1 -(3-[5-(3-trifl uorom ethyl benzy ,2,4oxadiazolyllcarbonyl)-2-(S)-methylpropyl]-L-prolinamide, lsopropyloxycarbonyl-Lvalyl-N-[1 -(3-[5-(3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl methylpropyl]-L-prolinamide, 4-Pyri dyl m ethyl en eoxycarbonyl -L-val yl-N trifluoromethylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropy]-Lprolinamide, or Methylsulfonyl-L-valyl-N-[1 -(3-[5-(3-trifluoromethylbenzyl ,2,4iazol yl ]carbonyl -(S)-methylIpro pyl ]-L-prolIi namn i de.
According to a third embodiment the present invention provides a compound of the formula: 29/01 /01 dl 0561 .speci2,4 wherein: X is N and Y is 0; R, is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, alkylamino, dialkylamino, alkylenedioxy, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, or -0-(C 5
C
6 )aryl;, hydroxyl, amino, alkylamino or dialkylamino; cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C 5
-C
12 )aryl, (C 5
-C
12 )arylalkyl,
(C
5
-C
1 2)arylalkenyl, fused (C 5
-C
1 2 )aryl-cycloal kyl, or alkyl-fused (C 5
-C
1 2)arylcycloalkyl optionally comprising 1-4 heteroatomns selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkly, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5
-C
6 )aryl, -0-(C 5
-C
6 )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, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -ROOR', RCOOR', -RNR'R"RO or -RC(O)NR'R" where R is alkyl or alkenyl, and R" and RO are independently H, alkyl, alkenyl, cycloalkyl or (C 5
-C
6 )aryl; or cycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, 12 )aryl, (C 5
-C
12 )arylalkyl or (C 5
-C
12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, amninoalkyl, dialkylamino, amidine, 0. 0: alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy alkylcarboxamide, (C 5 -0 6 )aryl, -0-(C5-C6)aryl, 25 arylcarboxamide, alkylthio or haloalkythio; A is a direct bond, -S(0) 2 -NH-S(0) 2
-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, animoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;, tetrahydrosioquinoline-2carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally 29/01/01 ,Cf10561 -6substituted 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;I histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutami ne, ornithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dial kylam inoal kyl, 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, 0 and S; and
R
4 is H, alkyl, alkenyl, alkynyl;I or cycloalkyl, alkylcycloalkyl, (C 5
-C
12 )aryl,
(C
5 -Ci 2 )arylalkyl, fused (C 5
-C
1 2)aryl-cycloalkyl or alkyl fused (C 5
-C
1 2 )aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, 0 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.
Preferably the compound is: (Benzyloxycarbonyl)-L-valyl-N-[1 (,4-methylenedioxybenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- (Benzyloxycarbonyl)-L-valyl-N-[1 -(2-[5-methyl-1 ,3,4- )-methyl propyl]-L-prolinamide, (Benzyloxycarbonyl valIyl 1 imethyl am ino- 1, 3,4-oxad iazo lyl ]ca rbonyl)-2-(S)-methyl propyl] -Lprolinamide, (Benzyloxycarbonyl )-L-valyl-N-[1 -(2-[5-(3-methylbenzyl ,3,4oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl 1 -(2-[5-(3-methyl benzyl 1, 3,4-oxad iazolyl]carbonyl -methyl ethyl]-L- (Benzyloxycarbonyl )-L-valyl-N-[l1-(2-[5-(3-trifluoromethylbenzyl 3,4oxad iazolyl]carbonyl)-2-( S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl :valIyl 1 imethyl am ino benzyl 1, 3,4-oxadi azolyllca rbonyl methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl-N-[1 1napthylmethylene)-1 ,3,4-oxadiazolyl]carbonyl )-2-(S)-methylpropyl]-L-prolinamide, 3-Pyridylcarbonyl-L-valy-N-[1 ethylI benzyl) 1, 3,4-oxad iazolIyl ]carbon yl)- 2-(S )-methyl propyl]-L-prol inamide, Methyloxycarbonyl-L-valyl-N-[1 methyl benzyl)-1 ,3,4-oxadiazolyl]carbonyl S)-methylpropyl]-L-prol inamide, Isop ro pyl oxyca rbonyl-L-val yl- 1 -[5-(3-methyl benzyl)-1, 3,4- 4~ ,\\xadiazolyl]carbonyl )-methyl propyl]-L-prolinam ide, 29/01 /01 ,cfl 0561 .speci2,6 6a 4-Pyridylmethyleneoxycarbonyl-L-valy-N-[1 -(3-[5-(3-methylbenzyl ,3,4oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, Methylsulfonyl-L-valyi-N- [1 -(3-[5-(3-methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-Lprolinamide, Phenylsulfonyl-L-valyl-N-[1 -(2-[5-(3-methylbenzyl)-1 3Aoxad iazol yl ]carbonyl -(S)-methyl pro pyl rol inam ide, Methylsulfonyl-L-valyl-N- [1 ,ac-dimethylbenzyl ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-Lprolinamide, or Methylsulfonyl-L-valy-N-[1 -(3-[5-tert-butyl-1,3,4oxad iazol yl ]carbonyl ethyl propyl L-p rol inam ide.
The present invention further provides a compound of the formlua:.
R2 R3N-X 0 In a preferred embodiment, X is N and Y is 0. In another preferred embodiment, X is 0 and Y is N. According to several preferred embodiments, R 13 :15 is an optionally substituted phenyl or benzyl; pyridyl, piperidinyl, alkyl or H or a fused ring system such as 3,4-m ethyl ened ioxybenzyl; R 14 is optionally substituted amino or an arylalkyloxycarboxamide such as benzyloxycarboxamide; and R 15 is H or halo.
Preferably, R 2 is isopropyl and R 3 is H.
20 In a preferred embodiment of the invention, R, is an optionally substituted aryl or arylalkyl group, such as a ac,cx-dimethylbenzyI, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such 29/01 /01,cf 10561 .speci2,6 wherein: X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or aLkenyl optionally substituted with 1 -3 halo atoms; (Cs-C 6 )aryl, arylaLkyl or arylalkenyl optionally comprising 1-3 heteroatomnis selected from N, 0 and S, and optionally subsituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkcyla-mino, aLkyl, aLkenyl, aLkynyl, alkoxy, haloalkoxy, carboxyl, carboal-koxy, alklylcarboxamide, arylcarboxamide, atkylthio or haloalkylthio, provided that at least one of X or Y is N; R, is alkcyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, t0 hydroxyl, haloalkyl, amino, alleylamino, dia~kylamino, alkylenedioxy, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkcylcarboxamide, arylcarboxamide or 0(S
C
6 )aryl; hydr-oxyl, amino, alkylamino or dialicylamriino; cycloal-kyl, cycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkcylcyctoalkenyl, (Cs-C 12 )arYl, (CS-C 12 )arylatkyl,
(C
5
-C
12 )arylalkenyl, fused (C 5
-C
1 2 )aryl-cycloa~cyI or alkyl-fused (C 5
-C
12 arylcycloalcyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aniinoalkyl, dialkylamino, alkyl, alkenyl, alkcylenedioxy, alkynyl, atkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,
(CS-C
6 )aryl, -O-(Cs-C 6 )aryl, arylcarboxamide, alkylth-io or haloaLkylthio; 20
R
2 and R 3 are independently or together H; al-kyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, aLkylthio, amino, alkylamino, dialkylamino, alkcylguanidinyl, dialkylguanidinyl, guanidi'nyl, or amidylguanidine; -RCOR', RC0OR, -RNR'R"R* or -RC(0)NRWR" where R is atkIyl or al-kenyl, and R" and R* are independently HK alkcyl, alkenyl, cycloal-kyl or (C5-Q)aryt; or cycloalkyl, aLkylcycloalkyl, aLkenylcycloalkyl, alkyl-oxyaryl, a~kyl-thioaryl, alkyl-aminoaryl,
(C
5
-C
12 )arYl, (C 5
-C
12 )arylaLkyl or (C 5
-C
12 )arylal-kenyl optionally comprising 1-4 h eteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, :keto, nitro, hydroxyl, haloaLkyl, amino, aminoalklyl, dialkyla-mino, amidine, alkyamdine, dialkylamidine, alkyl, alkenyl, alkylencdioxy, atkyrnyl, alkoxy, 1( haloatkoxy, carboxyl, carboalkoxy, alkylcar-boxa-rnide. (C5-C 6 )aryl, -0-(CS-C 6 )arYl, arylcarboxarnide, alkylthio or haloalkyltli"o, B is -S(0) 2 or and is of the formula: 6b N N R .N R, ,1 0 0 0 RI R P, 1w R13 N"R'3 or N x N
N
RI R 1 1 4 R1 (V (VI) wherein:
R'
2 and R' 3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkcylthio, amino, alkylarmno, diaLkylamnino, alkylguani'dinyl, dialkylguanidinyl, guanidinyl, or arnidylguanidine; -RCOR', RCOOR', -RNRRP" R* or -RC(O)NR'R" where R is alkyl or alkenyl, and R" and R* are independently H, alkyl, atkenyl, cycloalkcyl or (CS-C 6 )aryl; or cycloalkyl, alkcylcycloalkyl, aLkenylcycloakyl, alkyl-oxyaryl, alkyl-thioaryl, alky-aminoaryl, io (Cs-Ct z)aryl, (C 5 -C 1 2 )arylaLkyl or (CS-C 12 )arylalkenyt optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloatkyl, amino, aminoialkyl, diatkylammi~no,amidine.
aLkylamidine, diaLkylamidine, alkyl, alkenyl, alkylenedioxy, atkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamnide, (CS-C6aryl, -O-(C 5
-C
6 )aryl, 15I arylcarboxamide. alkylthio or halo aikyl thio; R, 3 is I-I, alkyl, halo, atkoxy, carboaLkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino. dialkylamino, or aryl, arylalkcyl, fused aryl fused aryl-cycloaLkcyl or cycloalkyl optionally comprising I or more heteroatoms selected from 0, N a-nd S, and optionally substituted with halo or aLkyl; P1 4 is alkyl, alkenyl, amino, alkylamino, dialkylamino;, or cycloalkcyl, aryl, arylalkyl, aryloxycar-boxamide, arylalkyloxycarboxamide or fused arylcycloalkyl 7_7 LU- 6c -"NT «3 WO 98/24806 PCT/US97/21636 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,-C,)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): R2R 3 N-X R- B- Y R,
O
wherein X, Y, R 1
R
2
R
3 and B are as described above; and
R
6 is of formula Ii
R
14 A-D )m
(I)
where m is 0 or 1; n is 0 or 1; 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, 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 1 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 I or more heteratoms selected from N, O and S; A is a direct bond, or-C-; and is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; 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, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or R6 is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl.
Alternatively, R6 is of formula (II):
N
where WisSorO; R, 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 20 formula mis 1, n is 0. In another embodiment, m and n are 1. Preferably, is benzyl, A is and D is Val.
f *Preferably, R, is isopropyl and R, 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, ,iAL preferably dimethylamino. In yet another embodiment, R, is a fused arylalkyl group WO 98/24806 PCTJUS97/21636 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,-C,)alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, r-butyl, etc.
According to one embodiment, W is S; R, is amino and R, is H.
In yet a further embodiment of the invention of Group (III) compounds, R 6 is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl. According to one embodiment, R 6 -B is Cbz.
The present invention further provides compounds of the formula (Group IV): Ri O R 2 R 3
N-X
N II
R
4
A-DR
O
wherein X, Y, R 2 and R 3 are as described above; RIo is (C 5
-C
6 )aryl, (C 5
-C
6 )arylalkyl, (C 5
-C
6 )arylalkenyl, cycloalkyl, fused arylcycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide 0, 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, 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, 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,
I
WO 98/24806 PCT/US97/21636 alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, O and S; A is a direct bond, -S(O) 2 -NH-S(0) 2 -S(0) 2
-NH-,
-OC(0)NH-, or and Ri 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 and R, 4 is aryl or arylalkyl such as benzyl. In a preferred embodiment, R 0 i is (Cs-C 6 )aryl or (C 5
C
6 )arylalkyl, preferably benzyl, or a fused aryl-cycloalkyl such as an indanyl group.
According to another preferred embodiment, D is and RI 4 -A is pyrrole.
Preferably, R 2 is isopropyl and R 3 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,-Cs)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
12 R 2 R N-X
N-X
R,1 Y
R'
2
R'
3
O
wherein X, Y, R, R 3
R'
2 and R' 3 are as described above; and
R,
1 Ri 2 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and 0; said ring containing 1 or more keto groups; and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, )0 WO 98/24806 PCT/US97/21636 dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, alkylthio, haloalkylthio; cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (Cs-CI 2 )aryl, (C 5
-C
1 )arylalkyl, ((C 5
-C,
2 )arylalkyl)OC(O)NH- or
(C
5 -C,2)arylalkenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide 0, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, -C(0)O(alkyl), -C(0)(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, R 2 is isopropyl and R 3 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,-Cs)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,2, and E together form a ring structure of formulas or (Ia): v 4 y V 2 V4 W2 R4-A
R-A
0 0 (la) wherein A is as described above for Group (IV); VI, V 2
V
3 and V 4 are independently or together C or N; where V 3 is C; R 13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,
I\
WO 98/24806 PCT/US97/21636 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 W2 and W3 are independently selected from N optionally substituted with alkyl; C, S and 0.
According to one preferred embodiment, V 4 is N; and V 1
V
2 and V 3 are C.
Preferably, R 3 is H or halo; R 4 -A is CbzNH, amino or H; and R' 2 and R' 3 are H.
Preferably, R, 2 and E together form a ring of formula In a particular embodiment, R, 3 is H or F; and R, 4 is H or H 2 Where R 12 and E together form a ring of formula W, is preferably S, and W 2 and W 3 are C.
In another embodiment, R, 2 and E together form a ring of formula (II) R13
RI
4 -A i 0 (Ii) wherein A, RI 3 and R,4 are as described above; Preferably, R' 2 and R' 3 are H. According to one embodiment, RB 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, is halo; and Ri4-A is CH 3 In yet another embodiment, R 13 is H; and RI 4 -A is CbzNH.
According to another embodiment of the invention, R 1
R,
2 and E form a ring of formula (III) or (IV): WO 98/24806 PCT/US97/21636 0 0 A- R3
R
1 3 RI4R i R 1 5 if O
O
(III) (IV) wherein A is a direct bond, or R,3, R, 4 and R 15 are as defined above.
According to a particular embodiment, 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 2 and E form a ring of formula and -A-
R,
3 is -C(O)phenyl; R, 5 is H; and and R' 3 and H.
In another embodiment of the invention, R, 2 and E form a ring of formula W ,R,3
R
14
G
(V)
wherein W is S, SO, SO 2 or C; n is 0, 1 or 2;
R,
3 and R, 4 are defined above; and G is -OC(O)NH-, -NHS(O) 2 or a direct bond.
According to one embodiment, n is 0 and W is S, where preferably is H.
Preferably, R 13 is optionally substituted benzyl or phenyl.
In another embodiment, n is 1 and W is C. Preferably, RI 4 -G is an arylalkyloxycarboxamide, for example, CbzNH-. In a preferred embodiment, R 1 3 is H or phenyl substituted with halo. Preferably, R' and R' 3 are H.
The invention further provides compounds wherein R,2 and E form a ring of formulas (Via), (VII) or (VIII): WO 98/24806 PCTIUS97/21636 0R 1 7 0 R172 14 'R13 R 14
R
16 R'14~~-R N N1N N-
R
1 4
R
4
Y
00 0 0 (VI) (Via) (ViI) (Vill) wherein R 13 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)OCH 3
R
14 and R', 4 are independently or together H, alkyl, alkenyl, CH 3 or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused arylcycloalkyl, aryloxycarbonyl or arylalkyloxycarbonyl optionally comprising I or more heteratoms selected from N, 0 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
1 6
R
17
R',
6 and R' 1 7 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 13 is CH=R 15 or and R, 4 is H, alkyl, CH 3 Cbz or benzyl optionally substituted with alkyl, halo or alkylamino; or 3,4-methylenedioxybenzyl or 3,4-ethylenedioxybenzyl; and R! 2 and R' 3 are H. Preferably, RD 3 is =CHR 1 5 where R 15 is phenyl or benzyl optionally substituted with halo or -C(0)CH 3 In a further embodiment, R 1 1 R 12 and E form a ring of formula (IX) or (IXa): Y-u W V'1_ W ZN 00 (IX) (IXa) wherein WO 98/24806 PCT/US97/21636 U, V, W and Y are independently or together N, C, N(R,3) where R 13 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(RI 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 where R, 6 and are independently or together H, alkyl, alkylthio, alkylthioalkyl; a carboxylic acid ester of the formula -(CH 2 )mC(0)OR or an N-substituted alkylamide of the formula -(CH 2 )mC(0)NRR' where m is 1 to 6 and R and R' are independently or together H or alkyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylcycloalkyl 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 V is N, W is N(R, 4 and Y is where preferably R' 2 and R' 3 are H; is phenyl or benzyl; R, 7 is H; and R 14 is H or benzyl optionally substituted with alkyl, halo, or alkylamine.
In another preferred embodiment, U is V is N, W is N, N(R 3 or and Y is C(R, 6 where preferably R' 2 and R' 3 are H; R, 4 is H; Rs 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,7 is H, alkyl, succinimidyl, aryl or arylalkyl.
In yet another preferred embodiment, U is V is N, W is N N(R,3) or and Y is N(R, 3 where preferably R' 2 and R' 3 are H; W is NH; R 13 is arylalkyl; and R,4 is H.
In a further embodiment, U is C(R, 6
)(R
7 V is N; W is N or and Y is Preferably, Ri 3 and R, 6 are aryl; and R, is H.
WO 98/24806 PCT/US97/21636 Where R 12 and E form a ring of formula (IXa); W is typically N(R, 3 where Ri3 is aryl or cycloalkyl such as piperidinyl.
In another embodiment, R 16 and form a cyclic ring structure, such as a cyclopentyl or cyclohexyl group.
The invention further provides compounds of the formula (Group VI): E R O 22 R3 gN-X Rat wherein X, Y, R 2 and R 3 are as described above, and R,2 and E together form a ring of formula
O
U
0 o
(X)
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 arylcycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S; or
C(R,
6 7 where R,6 and R, are as defined above; and and n is 1 or 2.
The present invention further provides methods of synthesizing compounds of formula 0 2
R
3
N-X
0
(A)
wherein Z' is defined below; R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; -alkyl- C(0)OCH 3 alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, I1 WO 98/24806 WO 9824806PCTIUS97/21636 alkylcycloalkyl, alkenylcycloalkyl, (C 5 -C 12 )aryl, (C 5
-C
12 )arylalkyl, (C 5
C
12 )arylalkenyl, fused (C 5
-C
12 )aryl-cycloalkyl or fused (C 5
-C,
2 )aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5
-C
6 )aryl, -0-(C 5
-C
6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5
-C
6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatomns selected from N, 0 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
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"Ra or -RC(0)NR'R" where R is alkyl or alkenyl, and R" and R' are independently H, alkyl, alkenyl, cycloalkyl or (C 5
-C
6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl,
C
12 )aryl, (C 5
-C
12 )arylalkyl or (C 5
-C
12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, amninoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5
-C
6 )aryl, -0-(C 5
-C
6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; comprising the steps of:..
reacting a compound of formula
N-X
MNy R,
(B)
wherein M is Li or MgBr, WO 98/24806 PCT/US97/21636 with an aldehyde of formula R2
R
3 [PGr,)NH CHO
(C)
where [PrG,] is a protecting group; removing the protecting group from the resulting alcohol (D) coupling the alcohol obtained from step with an acid of formula Z'-COOH (E) and 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 by reacting the aldehyde of formula with hydrochloric acid in dioxane. The protecting group [PGr,] may be any suitable group, preferably Boc.
According to another embodiment, the oxidation step of is performed using Dess Martin reagent.
In a further embodiment, the compound of formula is synthesized by: treating an acid of the formula (R,)COOH with thionyl chloride or oxalyl chloride; treating the resulting acid chloride with hydrazine to yield a hydrazide of the formula (R,)CONHNH 2
(F)
reacting the hydrazide with triethyl orthoformate or trimethyl orthoformate and TsOH to yield a oxadiazole of the formula and treating the oxadiazole with butyllithium and further, is desired, reacting with MgBr* OEt 2 to yield the compound B.
In one embodiment, Z' is WO 98/24806 WO 9824806PCT/US97/21636
H
3 C CH 3 0 wherein A is a direct bond, -S(O) 2
-NH-S(O)
2 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-2carboxylic 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 I or more heteroatoms selected from N, 0 and S; and
R
4 is alkyl, alkenyl, or alkynyl; or cycloalkyl, alkylcycloalkyl, (C 5
-C
12 )aryl,
(C
5
-C
12 )arylalkyl, fused (C 5
-C
12 )aryl-cycloalkyl or fuised (C 5
-C,
2 )aryl-cycloalkylalkyI optionally comprising one or more heteroatoms selected from N, 0 and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamnino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or haloalkylthio or is absent; or WO 98/24806 WO 9824806PCTIUS97/21636 Z'may be 13 I S fl R I RR3 000 00
R
3 0 R 13 W 1
R
1 N" R 2 R' R.F or N2 N R 3 N- R 3N R' I R4 r R14 o '0 0 (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', RCOOR', -RNR'R"R 0 or -RC(O)NR!R" where R is alkyl or alkenyl, and R" and R* are independently H, alkyl, alkenyl, cycloalkyl or (C 5
-C
6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5
C
12 )aryl, (C 5
-C
12 )arylalkyl or (C 5
-C
12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 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, (C 5
-C
6 )aryl, -O-(C 5
-C
6 )aryl, arylcarboxamide, alkylthio or haloalkylthio;
R
13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamnino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from 0, 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 WO 98/24806 PCT/US97/21636 aryloxycarboxamide optionally comprising I or more heteroatoms selected from N, 0 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 arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising I or more heteroatoms selected from 0, N and S.
In yet a further embodiment, Z' is: where m is 0 or 1; n is 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 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-2carboxylic 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, onithine 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- WO 98/24806 WO 9824806PCTfUS97/21636 cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising I or more heteroatoms selected from N, 0 and S; and A' is a direct bond, -S(0) 2 -NH-S(0) 2 or-C-.
in yet another embodiment, Z' is:
R
9 R8 w where W is S or 0; R, is alkylamino, dialkylamino or amino; and R. is H, alkyl or halo; or Z' is:
R
14 D 1 wherein Rio is (C 5
-C
6 )arYl, (C 5
-C
6 )arylalkyl, (C 5
-C
6 )arylalkenyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatomfs selected from N, S and non-peroxide 0, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, amninoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio.
In a preferred embodiment, Z' is: R&12
R
11
R'
2
R!
3 wherein
R
1 2 and E together form a monocyclic or bicyclic ring comprising 5-10 WO 98/24806 WO 9824806PCTIUS97/21636 atoms selected from C, N, S and 0; 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, alkenylcycloalkyl, (C 5 -C 1 )aryl, (CS-C 12 )arylalkyl, ((C 5 -C 12 )arylalkyl)OC(O)NH- or
(C
5
-C
12 )arYlalkenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide 0, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamnino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, -C(O)0(alkyl), -C(0)(alkyl), alkylcarboxamide, alkylthio or haloalkylthio.
In a preferred embodiment, the invention provides a method of synthesizing a compound of formula N Ar H 3 C_ "CH 0 0
(G)
wherein T is H or NH 2 R, is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; a carboxylic acid ester such as -alkyl-C(0)0CH 3 alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5
-C
1 2 )aryl,
(C
5
-C
12 )arylalkyl, (C 5
-C
12 )aylalkenyl, fused (C 5
-C
12 )aryl-cycloalkyl or fused (C 5
C
1 2)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C,)aryl, -0-(C 5
-C
6 )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: reacting a compound of formula (B3):
N-N
M/ 0 R, 4D WO 98/24806 PCT/US97/21636 wherein M is Li or MgBr; with an aldehyde of formula [PGr,]NH 'CHO
(C)
where [PrGj] is a protecting group; removing the protecting group from the resulting alcohol (D) coupling the alcohol obtained from step with an acid of formula N. Ar o COOH
(H)
wherein T' is H or [PGr2]NH, where [PGr 2 is a protecting group; oxidizing the resulting product to yield a ketone of formula N ,Ar i0
N-N
0 0
(J)
and further, when T' is [PGr2]NH, removing the protecting group [PGr2] to yield the compound of formula Preferably, [PGr 2 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,-Cis, however, preferably Ci-Cs.
As used herein, the term "alkenyl" means however, preferably Ci-Cs.
As used herein, the term "alkynyl" means C 1
-C,
5 however, preferably Ci-Cs.
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^ 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 benzyl), as well as di-substituted alkyl groups such as -alkyl(aryl) 2 CH(phenyl),). The terms arylalkyl and alkyl fused arylcycloalkyl include disubstituted groups such as, for example, (a,a)-disubstituted benzyl and 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-CH
2 -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; 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 WO 98124806 PCT/US97/21636 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 Figure 5 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 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 810 is a schematic representation of the synthesis of compounds of Group
III.V.
Figure 9 I is a schematic representation of the synthesis of compounds of Group IIIGroup V.
Figure 10 is a schematic representation of the synthesis of compounds of Group V.
Figure 11 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 15 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 2018 is a schematic representation of the synthesis of compounds of 30 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 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 (FINE). 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 IHNE. Their usage is of particular importance as they 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.
HC CHN I N HN 0 N93420 cli N 0 0r* e CE-2165
CH
aCH 3 CE-2059 30C Nk, 1, p CE-159 CH CE-2166 6 H 0 03 CE2 160 N S-q N-N I I e3C CHS C 0 0 00 0 N-N N: aX CE-2170 N 0 CE-161 CH3 O -Nc N 0 CE216 H00 C- CH H0C-S- '7 N N
N-NN-N
0 y0 CE-2170 H oCH CH N CE-2163 F3C CE-2172 CEM2179 CE-2190 CE-2174 ,7HC CH, 0_ N 0N
CF,,P,
0\-2 N8
N-N
e g.
Se* 0 CE.2176 0CH, CII, I oC- 0 Z-0 HC CHR N 0 H 1 C 0O
CH,,
N NC 2C 00 SCE-2177 0 -0
H
1 C CHC CR, *1 CH) 001 0I N ILI, N i
N-N
N 000
IN
0 NE25 0 CE-21780 E2,8b/k 0 0i0 S N 0 N kI III II S lc i3 ''N CE&214 WO 98/24806 WO 9824806PCTIUS97/21636 0, N CE-2 191 CE-2196 r-N 0 ~CH3 CE-21 87 0 /N CE-2 193 CE-2 I1R9 CE-2 195 CE-2190
CH,
HMN JS~/S _N y N 0 0 0 CF-2196 CE-2202 CE-2197
I-I
N
0 0N- 0 N/l N aF 0 0 CE-2203
OCHI
HCN
IN-N
C-IrlN CE2198
S
*0eO
S
O
S
0
S
S
S
S
SOS
S
5
S
OOS 0 5505 0
S
5005
S
S
0
S
0eSO*S CE-2204 CEF200 CE22os CE-2206 -32- WO 98/24806 WO 9824806PCTfUS97/21636 HC 0 HC CHI0 CHI HC~~ 0
IIT
00 H IC
CH,
HN 0NN
N
II0 CE-2208
CHI
O~Q~
0 N' H,C CHI, 0 f N-0 HN N ~J 1 0 0 CE-2209
CF,
UN N H3C CH, II N-N 0 1 0 0 0 CE-22 10 H,C,0HC:
CHI
0 CE-2213 CE-2216 N H,C CHI N Ii0 0 0 0 CE-2217 CE-2211I CE.221 9 CE-2212 00 N0 Nv N N o o N 0 NZNSa N-0 ME2221 S0 S 0 S4 NyN' 0 N-N0 0 0 S.222 N' N-N IN m 00 CE-ms2 a usc N 0 N-N/ H2N 0 0 0 a N o N-N 00 M23 S 0 0O WO 98/24806 WO 9824806PCTIUS97/21636 C-2237 CE-2 Cz-M3 CE-2233 CF-2240 CR4241 CE-2235 N
N-N
0 CE-2236
C"IC
CB-2242 WO 98/24806 PCTIUS97/21636 CE-2243 CP-2248 0 01 0 0 CE-2249 CE-2244 CE-2250 CE-2251 CE-2247 CE-2252 WO 98/24806 PCT/US97/21636 c-2259 CE-22S4 ce-225 ce-6l
HN/'N
C-2257 WO 98/24806 PCTfUS97/21636 0 I I 00HN N~N /\kn C'H, ONO-PO0690 0 3 Nce aII 0 ONO-O-696
FF
N 0 N 0 N 0"j
N-N
H
2 N 0 o~
N.~L
0 0 eic CH 3 0I 0 ONO-PO-691 ONO-PO-697 F
F
N %C CH, N 0 N H C tCH 0- 0i N -N N 0 0 0 H
N
2 0) 0 0 0C 0 C ONO-PO-692 F ONO-PO-6998
F
N N H1,C cl,01 C u 3
H
3 C2CH Nj N 0 Ny 0 0 0 ONO-PO-693 ONO-PO-699 F
F
0 0 ONCf09 -NOFO7N N 0, 0e NC H 3 C CI N 0N N-N N 0% N-HN 0 N- I\ HN N 0 OH 0N-O-9 ONO-P0.7oi 0 WO 98/24806 WO 9824806PCTIUS97/21636
N
2 N Ir 0N 7 4 fi IF H 00 0 ONO-PO-703 ONO-PO-709
F
,C i NN N 0H 3 C Cl N HC CH HN
H,-S
1
N-N
ON-P-704 00 F ON-P-710 H CH% N 01%NT-N N l, 1 HN N CI N 0N) N-N
H
2 N0 Ci, H2N 0~L ONO-PO-705 0 N ONO-PO-711I ONO-PO-706 ONO-PO-712 ONO-PO-707 WO 98/24806 PCT[US97/21636 ONO-MO714 N 06 N9-N INN~C
CHS
ONO-PO-715
F
N 0E:
N-N
N 012 0 012H ONO-PO-7160 l Li N' 0 ~C 01 N C-K N-N ii 1 0 0 012 ONO-PO-717
F
~N 0
N-N
ONO-PO-719 0 CH, WO 98124806 CISI266 PCTIUS97/21636 CF6 ONO-PO-719 ONO-PO-724 ONO-PO-720
I-N
CH,
0 Cl! CHi, ONO-PO-725 ONO-PO-721 ONO-PO-726 ONO-PG-722 ONG-PO-727
-N
1 cIS7
ONO-PO-TIS
ONG-PO-723 WO 98/2406 PCTIUS97/21636 ONO-MO729 ONO-PO-74 ONO-PO-730
ONO-P(
ONO-PO-735 CH,
-N
0 04 2 I -N C, 731 0 c 1 ONO-PO-736 N-N N HC H u 1 0 N-N 0 Cu 3 N cl D-732 0 CH, F ONO-PO-737
ONO-P
ONO-PO-733 The nomenclature for the above embodiments is as follows (although the majority of the embodiments disclosed indicate the stereochemistry of the 2methyipropyl group having the (S)-configuration, it will be understood that both the (R)-coafiguration and the racemic (RS) are within the scope of the invention): CE-2157 2-Oxo-5-(phenyl)- 1,4-benzodiazepine-N-[ 1-(2-[5-(3-methylbenzyl- 1,3 ,4-oxadiazoly1]carbofl)-2-(S)-methylpropyl]acetaTide CE-2158 3-(S)-[(Benzyloxycarbonyl)alifo-(5,6 phenyl-s-lactam]-N-[ 1 -(34[5- (3-trifluoromethylbenzyl)-l ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ar-etamide CE-21 59 S)-[6-Methylene-4-pyridyl) piperazine-2,5-dione-N-[l1-(2-[5-(3methylbenzyl)-1I,3,4-oxadiazolyl]crboflyl)-2-(S)-nethylpropyl]acetalhide CE-2160 3-(R,,S)-[(Benzyloxycarbonyl)amiflo--lactam]-N-[( 3-[5 trifluoromethylbenzyl)-1,2,4-oxadi'azolyl]cabonyl)2-S)-methylprpyl]aceaflde CE-2161 (Pyridyl-3-carbonyl)-Lvalyl-N-[ I .2-[5-(3-methylbenzyl)- 1,3,4oxadiazolyllcarbonyl)-2(S)-methylpropyl]L-prolnalide CE-2 162 1-(2-N-Morpholino)ethyl-3-(R)-belzyI piperazine-2,5-dione]-N- I (2-[5-(3-methylbenzyl)-l ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl~acetamide CE-2163 Methylsulfony-L-vayl-N-[ 1 .2-[5-(3-methylbenzyl)- 1,3,4- S:.oxadiazoly1]carbonyl)-2-(S)-methylpropyl]L-rolilalhde :.CE-2164 (Pyrrole-2-carbonyl)-N-(benzy)glycyl4'[b-(2-[5-3-methylbelzyl)- 1Qi,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]mide .*CE-21 65 N-Acety1-2-(L)-(2,3-dihydro-IH-indole)-N[ I-(2-[5-(3-methylbenzyl)- ,3,4-oxadiazoly]carbony)-2-(S)-methylpropyl]am1de :CE-2 166 1 -Phenyl-1 ,2,4-tiazolidine-3,5-dione-N-[ 1-(2-[5-(3-methylbenzyl)- 1 ,3,4-oxadiazolyll .carboflyl)-2-(S)-methylpropyl]acetmide CE-2168 Phenylsulfonyl-L-valyl-N-( 1-(2-[5-(3-methylbenzyl)- 1,3,4- *:::oxadiazolyl]carbonyl)-2-(S)-methylpropyW]L-prolinanlide CE-2170 1 -[2-{5-[3-Methylbenzyl]-1I,3,4-oxadiazolyl]-2.{S)f(benzyloxycarbonyl)amiflo]-3-methylbutafll -one CE-21 71 (3-Pyridylcarbony)-L-valyl-N- I -(3-[5-(3-trifluoromethylbenzyl)- 6: 3i 1 ,2,4-oxadiazolyl]carbonyl)-2(S)-methylpropyl]-L-prolinaflide 0CE-2172 Methylsulfonyl-L-vatl-lN- I -(3-[5-(3-trifluoromethylbenzyl)- 1,2,4- 0 oxadiazolyl~cabonyl)-2-(S)-methylpropyl]L-prolinanide CE-2173 I -(3-Morpholinoethyl)-5-(R)-bel-2,4-imidazolidilediofle-N-[ 1 N -43- (5-(3-methylbenzyl)-1 ,3,4-oxadiazolyl]carbofly)2,S)-methylpropyl]acetamide CE-2174 4-(R)-1sopropyl-2,5-imildazolidifledione-N-l .{2-[5-(3-methylbenzyl)- 1 ,3,4-oxadiazoIy)carbonyl)2(S)methylpropylUaetamde CE-2176 1 -Benzyl-1I,2,4-triazolidine-3,5-diofle-N-[ I-(2-[5-(3-methylbenzyl)- 1 3 ,4-oxadiazolyl]carboflY)2(S)411ethy1propyl]actmide CE-21 77 (Benzyloxycarbonyl)-L-valyl-N{ ,4-methylenedioxybenzyl)- 1,3 ,4-oxadiazoly]carbofyl)2(S)methyIpropyl]LpIrlnmde CE-2178 (B enzyloxycarbonyl)-L-valyl-N4 1-(3-[5-(3,4-methylenedioxybenzyl)- 1,2,4-oxadiazolyl]Carbofy)2(S)IfethylpropylLproiamde.
CE-21 79 5-(R,,S)-Phenyl-1-methyl-2,4-ilidazolidifliofle-N-[ methylbenzyl)- 1,3,4-oxadiazolyl]carboflY)2(S)-methylprolrOPY1amide CE-21 80 1 (-opolnehl-5( 1 zl24iidz~iedoeN[-(3trifluoromethylbelzyl)- 1 ,2,4-oxadiazoyl]cabonl)-2-{RS) niethylpropyllacetamide CE-2181 I -(N-MorpholinoethYl)-5 -(S)-benzyl-2,4-imidazolidinedione-N-[ 1-(3trifluoromethylbcflzyl)-l ,2,4-oxadiazolyl]crbofl)-2{R,"S)methylpropyl]acetamide SCE-2182 5-R)Pey--ety-,-n dzoiiein -I .00 trifluoromethylbcflzyl) 4 ,2,4-oxadiazolyl]crbolY2-(S)-methy1propylacetainde .29. CE-21 83 BeflzytoxycarboflYIL-vaIyI(1,2,3,4-tetrahydroisoquiflOife)-3N4I 3 -methybenzy)l,3,4oxadazolylIaronyl)2-(RS)-metfiylpropyl]ide :::CE-2184 1-NMrhlnehl--S-ezl-,-mdzldndoeN[-2 a(5-(3-mcthylbeflzyl)4 ,3,4-oxadiazoly]carboyl)2S)mehylpropylacetamide CE-21 85 4-PyridylmethyleefloxycarboflH-valyl-N4 l-(3-t5-(3trifluoromethylbenzyl)-I ,2A4-oxadiazolyl]carbofl)2(S)-methylpropyl]L- ::prolinamide ;.CE-21 86 4-Pyridylmethyleneoxycarboflyl-Livalyi-N-[ 1-(2-[5-(3-methylbenzyl)- *1,3 4 -oxadiazolycarbofyl)2(S)methylpropyl]Lprolinmide CE-21 87 4-[1 -(3,4Ehlndoyezl 3t [1 -(3-[5-(3-trifluoromethylbeflzyl)-1I,2,4-oxadiazolylcarboflyl)-2-(S)- *CE-2 188 I -Bny--S-ezl25iiazldndoeN[-3[-3 \VAk//tnifluoromethylbenlzyl) I1,2,4-oxadiazolyl]carbony1)-2-S)-mlethylpropyt]acetamide -44- L LL CE-2189 1 -Benzyl-2,4-imidazolidifedioneN4 trifluoromethylbelzyl)-1I, 2 4 -OXadiaZOIlykeabony)2-S)-methylpropylacetalnide CE-2190 [1 -BenzyloxycarbolI5-(R)-beflzyIipipein-3-one]-N.{1 methylbenzyl)-1I, 3 ,4-oxadiazoly]carboflyl)2(S)methylpropyl]actami1de CE-21 91 I-ezl4()bezl25iiaoldndoeN[-(2-[5-(3methylbenzyl)-1 3 4 -oxadiazolyl]carboyl)2,S)-mehylpropy1]acetamide CE-2192 1-NMrhlnehl--F)phnl24iiaoiiein
-N-I
(2-[5-(3-methylbenzyl)-l ,3,4-oxadiazoy]carboyl)2S)-methylpropylactmide CE-2 193 I (-opoioty)5(S-hnl24iiaoiiein-- (3.{5-(3-trifluoromlethylbenzlY)l ,2,4-oxadiazolyl]carboflyl)-2-(RS)methylpropyl]acetamfide CE-2 194 4 -,S)(4-Dimethyni3fophel)]2,5-imidazohdinedioneN-[ [5-(3-methylbenzyl)-l 3 4 -oxadiazolyl]carbol)2-S)-methyIpropy]actanT-ide CE-2195 (Pyrrole-2-carboflyl)-N-l -(RS)-indanylglycy1-N-[I-(2-[5 methylbenzyl)-l 3 ,4-oxadiazo1y]CarboylYI2S)-mehylpropyl]amide CE-2196 (64R)Benzylpiperzin2-ofe)-N-[-(2-[5-(3-methylbenzyl)-1 ,3 ,4oxadiazol~carbony)2,S)-mthylprpyl]aetamide SCE-21 97 4-[l 3 4 EthyenedioxybefzlZ)3(R-benzylpi perazi ne2, 5 dione]methylpropyllacetanlide *0 CE-2198 4 -(RS)-phenfl12,5-imdazoidmnedone-N-l *:trfluoromethylbelzyl)-l 2 ,4-oxadiazolyI]car'oflyl)-2(S)methy1propylaceta1ilide see a CE-2200 [4(S-4Dmtymnpey)-,-mdzldndoeN[-3 [5-(3-trifluoromethylbeflzyl)-l ,2,4-oxadiazoy1]Carboflyl)-2-{S>methylpropyl]acetalide CE-2202 isopropyloxycarbonyhl-valyl-N-[l -(2-[5-(3-methylbenzyl)- 1,3,4- 0 CE-2203 4 3 -pyridylfehylefe)]2,5-inidazolidifledione-N-[ 1 0trifluoromethylbeflzyl 2 4 -oxadiazolyl~carboflyl)-2(S)-methylpropyl~acetamnide 3G CE-2204 1 -BenzyIoxycarbonyl-( 2 )phenylpiperazin-5-ofle)-N-{l methylbenzyl)- 1,3 4 -oxadiazolyI)carboflY)2(S)-methyIpropyl]acetam1ide CE-2205 4 3 -pyridymethyl)]-2,5-imidazolidinedione-N-[ RtAL/4 -methylbenzyI)
I,
3 4 -oxadiazolyU~cabofylY)2(S)-methylpropylacetmide 0- CE-2206 [4(,S-4prdl--I_)Nsccnmdl-,-mdzldndoe 1 (2.{5-(3-methylbel)-1I,3,4-oxadiazolyl]carbonyl)-2-(S)methyipropyllacetamide CE-2207 Isopropyloxycarbonyl-L-valyi-N-[ 1 trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carboflY)2(S)mehyIpropylLprlinlide CE-2208 (2-(R)-Phenylpiperazin-5-oflC)-N4 1 -(2-[5-(3-methylbenzyl)- 1,3,4oxadiazoly1)carbonl)-2-(R,S)flmCthy1propyl]acetamide CE-2209 [4(S-4prdl--R)Nsciiiy]25i-dzldndoe N-fl -(34[5-(3-trifluoromethybeflzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamnide CE-221 0 (N-BenzylamilocarboflI)-N-(belzyi)gIycyI-N-l -(2-[5-(3-methylbeflzyl 1 ,3,4-oxadiazolyI]carbol)2(S)-methylpropylamide CE-221 1 (RS)-3-Amino-2-oxo-5-phefl- 1 ,4-(6-2'-chlorobenzodiazepine)-N-[ I1- (2-[5-phenyl-1 ,3,4-oxadiazolylcarbofly1)-2{RS)-rOpyI~acetallde CE-2212 3-fl -(4-Piperidine)]-belzilidazolidin-2-ofle-N4 methylbenzyl)-1 ,3 ,4-oxadiazolylcrboIYl)-2-(S)-methYPrOPYl]ace~ni-fLrde CE-2213 Methyloxycarboflyl-L-vaIl-N4 I .{2-[5-(3-methylbenzyl)-1 ,3,4- *so: oxadiazolylIcarbony)2(S)fllethy1propyl]1I-prlnmde 006:6 00 CE-2214 Methyloxycarboflyl-L-valyI-N{ trifluoromethylbenzyl)- 0 I ,2,4-oxadiazoly1]carbofly1)-2-S)mthyIpropyl.L-prolinamide CE-221 5 1 ,4-Quinazolin-2-ofle-N-[ I-(2-[5-(3-methylbenzylD-1 ,3,4- CE-2216 [4P,)(-yiy)4(S-ehl-,-mdzldndoeN[-2 [5-(3-methylbenzyl)-l ,3,4-oxadiazolyl]carbofl)-2-(S)-ethyIpropyI]acetalide 0025 CE-2217 2-Oxo-5-(2-pyridyl)-1 ,4-benzodiazepine-N-[-(2-15-(3-mfethylbeflzyl)- 1,3 ,4-oxadiazoiyl]carboflyl)-2-(S)-methylpropylacetamide CE-221 8 (RS)-3-Amino-2-oxo-5-(2-pyridyl)-l ,4-benzodiazepine-N-[ :methyipropyl)- 1,3 ,4-oxadiazolyl]carbonl)-2-(RS)-methylpropy1acetmide CE-2219 1 ,4-Quinazolifl-2-ofle-N4 I -[5-(3-trifluoromethylbenzyl)- 1,2,4i 3 oxadiazolyl]carbony)-2-(S)methylpropylacetamndde S: CE-2220 (2S,5S)-5-Axnino-1I,2,4,5,6,7-hexahydroazepino-13 .2.1 ]-indole-4-one- 09carbonyl-N-[ 1 (3-[5-(3-methylbeIzy1)-1I,2,4-oxadiazolyl]carbonyl)-2-(RS)- K4 methyipropyllamide 5 -46- CE-222 1 (R,S)-3-Amino-2-oxo-5-pheflyl-l ,4-benzodiazepine-N-[ 1 methylbenzyl)-I ,2,4-oxadiazoly]carbonyl)2,S)meiylpropy1acetffiide CE-2223 (RS)-3-Amino-2-oxo-5phenl-1l,4-(2'-chlorobenzodiazepine)-N-[ 1 (2-[5-(3-methylbenzyl)-1I,3,4-oxadiazoly1]carbofly)-2-(RS)-methylpropyl~aCet3Ifldde CE.-2224 (RS)-3-Amino-2-oxo-5-(4-chloropheflyl)- 1 ,4-benzodiazepine-N-[ 1 [5-(3-methybenzyl)-1I,3,4-oxadiazolyl]Carbofyl)2,S)methy1propyIacetamide CE-2225 (RS)-3-Amino-2-oxo-5-methyl-l ,4-(2',3'-mcthylenedioxy) benzodiazepine)-N-I1-(2-[5-(3-mTethybeflzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-(RS)methylpropyllacetamlide CE-2226 (R,,S)-3-Amino-2-oxo-5-methyl-l ,4-benzodiazepinei-N-[ methylbenzyl)-l ,3,4-oxadiazolyl]carbofylY)-2-(RS)methylpropy]acetmide CE-2227 4-(S)-(2-Isabuty1)-2,5-imidazolidiflediofe-N-[ methylbenzyl)-1 ,3,4-oxadiazoly]carbofly)-()rnthylprop1]actamide CE-2228 3-(R,S)-Amino-2-oxo- 4 5 -dihydro-1 -benzoazepile-N-[l -(2-[5-(3-methylbefl~)l,3, 4 -oxadiazolyl~carboflY)2(R,S)-meU1thypmpy]aetamide CE-2229 (RS)-3-Amino-2-oxo-5-(2-chlorophelyl) 1 chooezdaein)N[ 2[-3-ehlezl-,3A4-oxadiazolyllcarbonyl)-2- (RS)-methylpropy]acetamlide CE-2230 (,S)-3-BenzyloxycarbonflYam lo-2oxo5(2-chlorophenyl)lA{4- 2 2D1 chlorobenzodiazepifle)-N-[l -(2-[5-(3-methylbeflzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2- (RS)-methylpropylacetaflide CE-2231 4.-Sprcyclopefltfle-2,5-imdazolidinedione-N[I :methylbenzyl)-l ,3,4-oxadiazolyl]carbofly)2(S)-methy1propyl]aetamide C&-2232 Benzyloxycarbofyl-LVa1y1-NPhefYI)glYCYl-N-[ methylbenzyl)-l ,3,4-oxadiazo1Y1IcarboflY)2-S)-mfiylpropy1]amide *:CE-2233 2-Oxo-5-(4-piperidil)-1I,4-benzodiazepine-N-[1-(2-[5-(3s.:methylbenzyl)-l ,3,4-oxadiazolyl1carboflyl)2(S)-meiy1propy1]acetamide *:CE-2234 2-(2-Pyridy1)-benziflidazole-N-[ I-(2-[5-(3-mcthylbenzyl)- 1,3,4oxadiazoly1]carbofl)2(S)-methylpropyllacetamnide CE-2235 (RS)-3-Amnifo-2-oxo-5-methyl-1I,4-(2',3'-dimethoxybenzodiazepifle)- -methylbenzyD- 1,3 ,4-oxadiazolyl]carbaflyl)-2-(RS)- *9 methylpropyl]acetamlide 7 >CE-2236 (RS)-3-Axnino-2-oxo-5-methyI-1I,4-( I-thiophenodiazepine)-N-[ I 42- 7 (5-(3-methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)-m~ethYlPropyl]acetamide CE-2237 2-Oxo-5-(4-trifluoromethylphelyl)- 1,4 benzodiazepine-N-( methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-mthylpropy]acetaxnide CE-2238 2,5-Imidazolidinedioiie-N-[ 1-(2-[5-(3-methylbenzyl)- 1,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropylaCetafldde CE-2239 4,4-Dimethyl-2,5-imidazolidinedione-N-[ I -(2-[5-(3-methylbenzyl)- 1 ,3,4-oxadiazoly]carbonyI)-2-(S)-mthylpropy]acetamlide CE-2240 4-(S)-(2-Isopropyl)-2,5-imidazolidinedione-N-[ 1 methylbenzyl)-1 ,3,4-oxadiazolyI]carbonyl)-2-(S)-methylpropyl]acetamfide, CE-224 1 4-Spirocyclohexane-2,5-imidazolidiledione-N-I methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaniide CE-2242 2-Oxo-5-phenyl-1 ,4-(4'-methylbenzodiazepine)-N-[1 methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaiide CE-2243 4-(R)-(3-Indoylmethyl)-2,5-iidazolidilediofle-N-(1 -(2-[5-(3-methylbenzyl)- 1 ,3,4-oxadiazoly]carbony)-2-(S)-ethylpropy1]acetoflhde CE-2244 2-Oxo-5-medhyl-1 -thiophcnodiazepine)-N-[ methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-mthylpropy]actamfide 08: CE-2245 2-Oxo-5-methyl- 1,4-(2-phenyl-1-thiophenodiazepine)-N-[1 :methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S-methylpropyl]acetamide CE-2246 4-(R)-(2IsobutyI)2,-iidazolidnedione-N-[k<2-[-3methylbenzyl)-1 ,3,4-oxcadiazoly11cgbanyl)-2-(S)-methy~prpy1]acetamide 0 CE-2247 N N-Dimethyla miflocarboflmethyl)-2,5-imidazolidinediofle-N-1 [5-(3-methylbenzy)-1,3,4-oxaaazo1Y1]caboyl)<S)methy1propy]acetaXfldC CE-2248 2-Oxo-5 ,4-methylendioxyphenyl)-1I,4-benzodiazepine-N-[ 1-(2- (3-methylbenzy)-1,3,4-oxadizoy]cabol)-2-S)methyppy1Jacetalde *:CE-2249 4-(R)-(2-methoxycarbonyethy)-2,5-imidazoidilediofle-N-[1 e0:methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)-methypropyl]acetamide 00:CE-2250 20xo5-(2methoxyphey)- 1,4-benzadiazepine-N-[ :methylbenzyl)- 1,3 ,4-oxadiazolylcarbanyD-2-(S)-mfethylpropyl]acetamide 30 CE-225 1 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-l1-pyridimyl)-N-[ 1- *(2-[5-{3-methylbenzyl)-1I,3,4-oxadiazoly]carboflyl)-2-(S)-m~ethylpropyI]acetamide 0. CE-2252 4,4-Diphenyl-2,5-imidazolidiledione-N-[ I-(2-[5-(3-mnethylbenzyl)- 13 ,34-oxadiazoy]crbofly1)-2(S)-mthylpropylIacet31fide C-48 CE-2253 4-pr-2idny)25iiao dndoeN[-(2-[5-(3methylbenzyl)-1 3 4 -Joxadiazolyllcarbonyl)2S)meylpropyl]aeamide CE-2254 2-6oo2-4F rohnl-,6-dihydro-1 -pyrimidinyU-N-[1 methylbenzyl)- I,3 4 -oxadiazolyl]carbol)2-S)-mefiylpropylaceItaide CE-2255 4 4 -Hydroxybeflzyl)2,5imdazoidinedioneN-[ 1 methylbenzyl)- l, 3 4 -oxadiazolyl]carbolY)2(S)-methy1propylUacetanide CE-2256 4 -(R)-(4-HydroxybenzlZY)2,5imidazoidndioneN[l methylenedioxybeflzyl) 4 3 4 -oxadiazoly]carbofyl)-2(S)mthylpropy]atmide CE-2257 4 -(R)-2-tmidazoIylmethyI-2,5imidazoidifedioneN-l CE-2258 2-Oxo-5-phel-1 ,4-(2'-dimethylamiflobeflzodiazepifl)N4 methylbenzyl)-l ,-xdaollcroy)2-S-ehlroy~ctmd CE-2259 4,-ihnl25iiaoidndoeN[-2[-34 methylenedioxybelzyl> ,,-xdazllcroy)--S-ehlroy~ctm CE-2260 2-[5-Amnino-6-oxo-2-phenfl-1l,6-dihydro-1-pynimdflyl]-N methylbenzyl)-l ,-xdaoy~croy)2S-ehypoy~ctmd CE-2261 2-5Aio6oo2(-loohnl-,-iyr- -pyridinyl]-N-[ I ege (2-[5-(3,4-methyeledioxybeflzyl)- ,3,4-oxadiazoIyl]carbofl)l2S)-
C
methylpropyl~acetamide CE-2262 2-[5-Am-ino-6oxo-2-thiophenl-1l,6-dihydro-lI-pyrimidinyll-N-[ 1-(2- *0C[5-(3-methylbenzyl)-l, 3 4 -oxadiazolyI~Carboflyl)2(S)-methylpropyUaetaiude CE-2263 2-5Aio6oo -3prdl-,6-dihydro-l -pyrimidinyl]-N-[ 1-(2- :[5-(3-methylbenl~y)-1 3 4 -oxadiazolyl]carbonyD)2-(S)methylprpyl]acew1mde ONO-PO-690 2-5(ezlxcrbnlaio6oo2-4furpey 1,6dihydro- I pyrimidiny1)-N-l -(2-[5-(aG-dimethylbenzyIl ,3 ,4-oxadiazoly]Carboflyl)- 2-(S)-methylpropyl]acetaifde *::ONO-PO-691 2-[5-Amiflo-6oxo-2(4-fluorophenyl)- 1,6-dihydro-1 :pyrimidinyl]-N-[l 2[5(~admthleny 1,3 ,4-oxadiazolyllcarboflyl)-2(S)- *:.:methylpropyl]acetamfide ONO-PO-692 2 -[5-Amliflo-6-oxo-2-(4-fluorophenyl)-1I,6-dihydro- 1- S:pyrimidinyl]-N-I 5-c~c-imtyl3meh 2bnyl 1 l,3,4-oxadiazolyl]carbofyl)- 00 2-(S)-methylpropy]aceami1de /sr ONO-PO-693 2-tS-Amino6oxo-2{4fluorophenyl 1 ,6-dihydro-1-* -49-
-IO
WO 98/24806 WO 9824806PCTIUS97/21636 pyrimidiny]-N-I(2-[S-(3-methylbelzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(R)methyipropyllacetamide ONO-PO-694 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[1 -(2-115-phenyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methyipropyllacetamide ONO-PO-695 2-15-Amino-6-oxo-2-(4-fluorophenyl)-1I,6-dihydro- 1pyrimidinyl]-N-[1 -(2-[5-(3-pyridyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide ONO-PO-696 2-[5-Amino-6-oxo-2-(4-fluoropheniyl)- 1,6-dihydro- 1pyrimidinyl]-N-[1 -(2-[5-tert-butyl- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetaxnide ONO-PO-697 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)- 1,6dihydro-1 -pyrimidinyl]-N-[ 1-(2-[5-phenyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)methyipropyllacetanaide ONO-PO-698 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluoropheflyl)- 1,6dihydro-1 -pyrriidinylll-N-[ 1-(2-[5-tert-butyl- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide ONO-PO-699 2-15-Amiino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro- 1pyrimidinyl]-N-[1 -(2-[5-(4-methoxyphenyl)-1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)methylpropyllacetaniide ONO-PO-700 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[1 -(2-jj5-(a,a-dimethyl-3 ,4-methylenedioxybenzyl)- 1,3,4oxadiazolyl]carbonyl)-2-(S)-methylp ropyllacetamide ONO-PO-701 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-1 pyriniidinyl]-N-[ 1-(2-[5-(a,a-dimethyl-3 ,4-dihydroxybenzyl)-1 ,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl~acetamlide ONO-PO-702 2-[5-(Methylsulfonyl)amino-6-oxo-2-(4-fluorophelyl)-1 ,6dihydro-1 -pyrixnidinyl] -(3-methylbenzyl)-1,3 ,4-oxadiazolyl]carbonyl)-2- (S)-methylpropyllacetaniide ONO-PO-703 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[ 1-(2-[5-benzyl- 1,3,4- oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetamide ONO-PO-704 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1I,6-dihydro-1 WO 98/24806 WO 9824806PCTIUS97/21636 pyrimidinyl]-N-[l1-(2-[5-methyl- 1,3,4-oxadiazoly1]carbony1)-2-(S)methylpropyl]acetamide ONO-PO-705 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro- 1pyrimidinyl]-N-[ 1 -(2-[5-isopropyl- 1 ,3, 4 -oxadiazolyl]carbonyl)-2-(S)methyipropyijacetamide ONO-PO-706 2-[5-Amino-6-oxo-2-(4-fluoropheny)- 1,6-dihydro- 1pyrimidinyl]-N-[ 1 -(2-[5-butyl- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)- ONO-PO-707 2-[5-Amino-6-oxo-2-phenyl-1 ,6-dihydro-l1-pyrimidinyl]-N-[ 1- (2-[5-tert-butyl- 1 3 4 -oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamnide ONO-PO-708 4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[ 1-(2-[5-tertbutyl- 1, 3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl~acetamide ONO-PO-709 4-(S)--(2-Isobuty1)-2,5-imidazolidinedione-N..[ 1 dimethylbenzyl)- 1, 3 4 -oxadiazolyl]carbony1)-2-(S)-methylpropy]acetnlde ONO-PO-710 Methylsulfonyl-L-valyl-N-[l1-(2-[5-(a,a-dimethylbenzyl)- 1,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide ONO-PO-71 1 2-[5-Ainino-6-oxo-2-phenyl- 1,6-dihydro-l1-pyrimidinyl]-N-[ 1- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide ONO-PO-712 2-[5-Amino-6-oxo-2-(3-pyridyl)-1 ,6-dihydro-l1-pyrimidinyl]-N- [1-(2-[5-tert-butyl-1 3 4 -oxadiazolyljcarbonyl)-2-(S)-meffiylpropyl~acetanide ONO-PO-713 Methylsulfonyl-L-valyl-N-[1 -(2-[5-(tert-butyl- 1,3,4oxadiazolyl]carbonyl)-2-(S)-niethylpropyl]-L-prolinaniide ONO-PO-714 2-{5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro- 1pyrimidinyl]-N-[ -methylcyclopropyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetaniide ONO-PO-715 2-[5-Aniino-6-oxo-2-(3-pyridyl)- 1,6-dihydro-l1-pyrimidinyl]-N- [1-(2-[5-(a,at-dimethylbenzyl)-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetamide ONO-PO-71 6 2-16-oxo-2-(4-.fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 (2-[5-(tert-butyl)-1 ,3 4 -oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetamide ONO-PO-71 7 2-Oxo-5-(4-chlorphenyl)- 1 ,4-benzodiazepine-N-[ I 2 butyl-1I,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide ONO-PO-71 8 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro-1I pyrimidinylJ-N-[ 1-(2-[5-Qtert-butyl)- 1,3,4-oxadiazolyl~carbonyl)-2-(R)methylpropyl]acetamide ONO-PO-719 4-(R)-Isopropyl-2,5-imidazolidinedione-N-[ 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaniide ONO-PO-720 4-(R)-isopropyi-2,5 -imidazoiidinedione-IN4[i dimethylbenzyl)-1 ,3,4-oxadiazolyl~carbonyl)-2-(S)-methylpropyl~acetamjde ONO-PO-721 2-(5-Anooxo-2-(4-fluoophenyl)- 1 ,6-dihydr>- I pyriniidinyl]-N-[ I-(2-15-(c-dimthylbenzyl)- I,3,4-oxadiazolyl]carbonyl)-2-()methylpropyl]acetamide ONO-PO-722 2-(6-Oxo-2-(4-fluorophenyl)-I ,6-dihydro- 1 -pyirnidinyl]-N-[ 1- ,3,4-oxadiazolylkmbonyl)-2-(S)-methylpropyflacetaniide ONO-PO-723 R)-(3-Indolylmethyl 5-imidazolidinedione-N-[1 I ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylprobpyllacetanide ONO-PO-724 4-(R)-(3-Indolymethyl 5-imidazolidi nedione-N-[1 ,adimnethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide T: ONO-PO-725 2-[6-Oxo-2-phenyl-1 ,6-dihydro-1 -pyridinylj-N-[ -Z butyl-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetamide ONO-PO-726 2-[6-Oxo-2-phenyl-1 ,6-dihydro-1 -pyridinyl]-N-[ dimethylbenzyl)-1,3,4-oxadiazolyljcarbonyl)-2-(S)-methylpropyl]acetamide ONO-PO-727 2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyr dinyl]-N-[l- 113,4-oxadiazolyl]carbonyl)-2-{R)-methylpropyl~acetamide ONO-PO-728 2-[5-Amiino-6-oxo-2-phenyl-l ,6-dihydro-lI-pyrimidinyl]-N-[l I-methylcyclopropyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaniide :ONO-PO-729 2-[5-Anmino-6-oxo-2-phenyl-I ,6-dihydro-1 -pyrimidinylj-N-[ 1- (2-(5-tert-butyl-1I,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpr-opyl]acetarnide ONO-PO-730 2-t6-Oxo-2-phenyl-1I,6-dihydro-1 -pyrimidinyl]-N-[ 1-(2-[5-tertbutyl- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaniide ONO-PO-73 1 2-[6-Oxo-2-phenyl-1I,6-dihydro-1 -pyriniidinyl]-N-[ I 0% dimethylbenzyl- 1,3 ,4-oxadiazolylilcarbonyl)-2-(S)-methylpropylacetamide ~/>ONO-PO-732 2-[6-Oxo-2-phenyl- 1,6-dihydro-1 -pyriniidinyl]-N-[ 1-(2-[5-:ert- -52- Lu 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-1pyrimidinyl]-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- -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-(1methylcyclopropyl)- 1, 3 4 -oxadiazolyijcarbony)-2-(S)-methylpropyl]acetamide ONO-PO-736 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1- (2-[5-tert-butyl-1, 3 4 -oxadiazolyl]carbonyl)-2-(RS)-methylpropyl]acetamide ONO-PO-737 2-[6-Oxo-2-phenyl)-1,6-dihydro-l -pyrimidinyl]-N-[1 butyl-1, 3 4 -oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetaide 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 alphasubstituent 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 toward the N-terminus and toward the Cterminus. Therefore, the scissile bond is between the P, and the residue of the peptide subunits. A similar nomenclature is utilized for the amino acid residues of the 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 instead of 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 Class Representative Enzyme P, Characteristic Elastases Human Neutrophil Elastase small aliphatic residues Chymases alpha-Chymotrypsin, aromatic or large Cathepsin 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 Pi-P,' modifications, specifically, certain alpha-substituted keto-heterocycles composed of 1,3,4 oxadiazoles, 1,2,4-oxadiazoles, 1,3,4thiadiazoles, 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 small aliphatic groups for elastase).
WO 98/24806 PCT/US97/21636 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 (AARD, 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 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 may be prepared via formation of the acid chloride from an acid utilizing, for example, thionyl chloride or oxalyl chloride, followed by treatment with hydrazine in a suitable solvent to yield the hydrazide Reaction of with triethyl orthoformate or trimethyl orthoformate and TsOH gives the requisite 2-substituted 1,3,4-oxadiazole Formation of the compound utilizing standard conditions (ie. butyllithium at low temperature in a polar aprotic solvent, and further, if desired, reacting with MgBr.OEt 2 followed by addition of the aldehyde yields the alcohol Deprotection of the protected amine of using hydrochloric acid in dioxane gives the amino hydrochloride which is then coupled to the acid by methods available to one skilled in the art to give intermediate 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 The final step requires removal of the protecting group from the amine. This r- WO 98/24806 PCT/US97/21636 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 Compound (10) can then be treated with an electrophile methanesulfonyl chloride) with added base to give (14).
The aldehyde 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 Further, one may generate the alcohol (13-1) followed by oxidation with S0 3 -Py in DMSO.
The activity of the compounds is presented in Figures 23-38 as K i values (nM).
KI values were determnnined, 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 carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) 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 known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, 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 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., 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 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 multi-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 formulatory 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, 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. (U.S.
Patent (No. 4,788,603) or Bawas et al. 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, 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 WO 98/24806 PCT/US97/21636 an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, 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, by combination thereof with certain hydrophilic polymer matrices, 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 mg/kg/day, 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 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 500 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 AM, more preferably, about 1 to 50 gM, most preferably, about 2 to about 30 gM. 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, into a number of 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 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-(3dimethylaminopropyl-3-ethylcarbodiimide; BOPCI bis(2-oxo-3oxazolidinyl)phosphinic chloride; FMOC 9-fluorenyl methoxycarbonyl; BTD bicyclic turned dipeptide (see, 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 o0C under a nitrogen atmosphere was added 0.65 mL (8.85 mmol) of dimethyl sulfide. The reaction was cooled to -25 0 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 followed by the addition of 1.0 mL (7.17 mmol) of triethylamine. The cold bath was WO 98/24806 PCT/US97/21636 removed and the mixture allowed to warm to room temperature and maintained for 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 of the title compound as a white solid. FAB MS m/z; Calcd: 604, Found 604.
The intermediate (benzyloxycarbonyl)-L-valyl-N-[1-( 2 -[5-(3-methylbenzyl)- 1,3,4-oxadiazolyl]hydroxymethyl)-2-()-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-4methylpentanenitrile (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 anisole. The reaction mixture was heated to reflux overnight. The hydrolysis reaction was allowed to cool to room temperature and then concentrated in vacuo. The resulting aqueous solution was extracted with ether The aqueous phase was placed on a Dowex 50X8-100 column (HI 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 of 3-(S)-amino-2-(R,S)-hydroxy-4methylpentanoic acid as a pale yellow solid. FAB MS m/z; Calcd: 148, Found: 148.
b. 3 -(S)-[(Benzyloxycarbonyl)amino]-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 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 The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 1.75 g of WO 98/24806 WO 9824806PCTIUS97/21636 [(benzyloxycarbonyl)amno]-2-(R5)-hydroxy-4-methylpentanoic acid as a light yellow viscous oil. FAB MIS mlz; Calcd: 282, Found: 282.
C. 3-(S)-[(Benzyloxylcarbonyl)amino]-2-(R,S)-acetoxy-4-,nethyI 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 (5.7 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 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 15% methanolldichloromethane to afford 1.56 g of 3 -(5}{[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy4methyI pentanoic acid as a light yellow viscous oil. FAB MIS rnlz; Calcd: 324, Found: 324.
d. J-[(3-Methylphenylacetyl) S) -acetoxy)-3-S)- [(benzyloxycarbonyl)amino]-4-methylpentanoyl] hydrazine.
To a solution containing 3 -(5)-[(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 0 C was added 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09 mmol) of EDCI. After stirring for 30 minutes, 1.20 g (7.31 rnmol) 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 10 mimol) of NMMv were added. The reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with ethyl acetate and washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate, brine 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 10% methanolldichloromethane to afford 2.31 g of the title compound as a white solid. FAB MS mlz; Calcd: 470, Found: 470.
e. J-[2-(S-[3-Methylbenzyl)]-J1,3, 4-oxadiazolyl]-)I -acetoxy-2-(S) [(benzyloxycarbonyl)amino]amino]-3-methylbutane.
A solution containing 2.31 g (4.92 nimol) of 1-[(3-methylphenylacetyl)-2- (2- (R,S)-acetoxy)-3-(S)-II(benzyloxycarbonyl)amino]-4-methy pentanoyl]hydrazine in 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 reduced pressure. The residue was purified by column chromatography on silica gel with 5% ethyl acetate/hexane to afford 1.41 g of the title compound. FAB MS m/z; Calcd: 452, Found: 452.
f. 1-[2-(5-[3-Methylbenzyl]-l,3,4-oxadiazolyl)]-2-(S)- [(benzyloxycarbonyl)amino]-3-methylbutan-l-ol.
A solution containing 1.80 g (3.99 mmol) of 1-[ 2 -(5-[3-methylbenzyl]-1,3,4oxadiazolyl)]-l-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.
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 of the title compound. FAB MS m/z; Calcd: 410, Found: 410.
g. 1-[2-(5-[3-Methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-Amino-3methylbutan-l-ol 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-l-ol 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 -78C 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 The solid was dried under vacuum to afford 0.92 g of the title compound. FAB MS m/z; Calcd: 276, Found: 276.
h. (Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-, 3,4oxadiazolyl]hydroxylmethyl)-2-(S)-methylpropyl]-L-prolinamide.
To a solution containing 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in 25 mL of anhydrous dichioromethane under a nitrogen atmosphere at 0 0 C was added 0.90 g (3.54 mmol) ofBOPCI and 0.60 g (3.44 nmol) of DIEA. After stirring for minutes, 0.90 g (2.89 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl-2{S)anino-3-methyl butan-I-ol hydrochloride in 15 mL of dichioromethane and 0.6 mL (3.94 nmol) of DIEA was added. The reaction was allowed to stir at 0 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% methanolldichloromethane to afford 1.0 g of the title compound as a tan solid. FAB MS m/z; Calcd: 606, Found: 606.
Example 2 (CE-2074)(Benzyloxycarbonyl)-L-valyl-N-[ 1 -(methyl)-1,3,4oxadiazoly]carbony)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example 1. FAB MS m/z Caled: 514, Found: 514.
Example 3 (CE-2075)(Benzyloxycarbonyl)-L-valy-N-[ 1 T: trifluoromethylbenzyl)- 1,3,4-oxadiazoly lcarbonyl)-2-(S)-methylpropyl]-Lprolinanide. Prepared similar to Example 1. FAB MS mlz; Calcd: 658, )0 Found: 658.
Example 4 (CE-2100)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(4-Dimethylamino benzyl)-1,3,4-oxadiazolyl]carbonyI)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example 1. FAB MS m/z; Calcd: 633, Found: 633.
Example 5 (CE-21 24)(BenzyloxycarbonyI)-L-valyl-N-[1 -napthylmethylene)- 1,3,4-xadiazolyl]carbony)-2-(S)-methylpropyl)-L-prolinarnide. Prepared similar to Example 1. FAB MS m/z; Calcd: 640, Found: 640.
Example 6 (CE-21 77)(Benzyoxycarbonyl)-L-valyl-N-[ 1 methylenedioxybenzyl)- 1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-Lprolinamide. Prepared similar to Example i. FAB MS m/z; Calcd: 634, -63- 0 WO 98/24806 PCT/US97/21636 Found: 634.
Example 7 (GE-2 178)(Benzyloxycarbonyl)-L-valyl-N-[ methylenedioxybenzyl)- 1 ,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L.
prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 634, Found: 634.
Example 8 (CE-2052)(Benzyloxycarbonyl)-L-valyl-N-[l1-(3-[5-(3,5dimethylbenzyl)- 1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinaniide.
Prepared similar to Example 1 of WO 96/16080. FABR MS mlz; Calcd: 618, Found: 618.
Example 9 (CE-2053)(Benzyloxycarbonyl)-L-valyl-N.{ dimethoxybenzyl)-1 ,2,4-oxadiazolyll carbonyl)-2-(S)-methylpropyl)-L-prolinamide.
Prepared similar to Example I of WO 96/16080. FABR MS m/z; Calcd: 650, Found: 650.
Example 10 (CE-2054)(Benzyloxycarbonyl)-L-valyl-N-[ ditrifluoromethylbenzyl)-1 ,2,4-oxadiazolyl] carbony1)-2-(S)-methylpropyl]-Lprolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 726, Found: 726.
Example 11- (CE- 2055)(Benzyloxycarbonyl)-L-valyl-N-[ 1-(3-[5-(3-methylbenzyl)- 1 ,2,4-oxadiazoly1] carbonyl)-2-(S)-methylpropyl]-L-prolinanuide. Prepared similar to Example 1 of WO 96/16080. FABR MS mlz; Calcd: 604, Found: 604.
Example 12 (CE-2057)(Benzyloxycarbonyl)-L-valyl-N..[ biphenylmethine)- 1 ,2,4-oxadiazolyl] carbonyl)- 2 -(S)-methylpropyl]-L-prolinanide. Prepared similar to Example 1 of WO 96/16080. FAR MS mlz; Calcd: 666, Found: 666.
Example 13 (CE-2058)(Benzyloxycarbony)-L-valyl-N-[ 1-(3-[5-(4-phenylbenzyl)- 1 2 4 -oxadiazolyl] carbonyl)- 2 -(S)-methylpropyl]-L-prolinamide. Prepared similar to WO 98/24806 WO 9824806PCTIUS97/21636 Example 1 of WO 96/16080. FAB MS mlz; Calcd: 666, Found: 666.
Example 14 (CE-2062)(Benzyloxycarbonyl)-L-valyl-N-[ 1-(3-Ij5-(3-phenylbenzy)- 1 ,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MIS m/z; Calcd: 666, Found: 666.
Example 15 (CE-2066)(Benzyloxycarbonyl)-L-valyl-N-[ 1-(3-[5-(3-phenoxybenzyl)- 1 ,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MIS mlz; Calcd: 682, Found: 682.
Example 16 (CE-2069)(Benzyloxycarbonyl)-L-valyl-N-[ cyclohexylmnethylene)-1I,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-Lprolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 596, Found: 596.
Example 17 (CE-2073)(Benzyloxycarbonyl)-L-valyl-N-[ I-(3-[5-(a,a-dimethyl-3trifluoromethylbenzyl)- 1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-Lprolinamide. Prepared similar to Example I of WO 96/16080. FAB MS mlz; Calcd: 686, Found: 686.
Example 18 (CE-2077)(Benzyloxycarbonyl)-L-valyl-N-[ 1napthylnethylene)- 1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 640, Found: 640.
Example 19 (CE-2078)(Benzyloxycarbonyl)-L-valyl-N-[ 1-(3-[5-(3-pyridylmethyl)- 1 ,2,4-oxadiazolyl] carbonyl)-2-(SI)-methylpropyl]-L-prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 591, Found: 591.
Example 20 (CE-2096)(Benzyloxycarbonyl)-L-valyl-N-[ diphenylbenzyl)- 1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
Prepared similar to Example 1 of WO 96/16080. FAB MS mlz; Calcd: 742, WO 98/24806 PCT/US97/21636 Found: 742.
Example 21 (CE-2115)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4dimethylaminobenzyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-Lprolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS m/z; Calcd: 633, Found: 633.
Example 22 (CE-2089) 2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.
To a mixture containing 1.15 g (8.60 mmol) of N-chlorosuccinimide in 43 mL of anhydrous toluene at OoC under a nitrogen atmosphere was added 0.95 mL (12.9 mmol) ofdimethyl sulfide. The reaction was cooled to -25 0 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- 1pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide (1.52 g, 2.15 mmol) in mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at -25 0
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 of the title compound as a white solid. FAB MS m/z; Calcd: 707, Found: 707.
The intermediate 2 -[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4- fluorophenyl)- 1,6-dihydro-1 -pyrimidinyl]-N-[1 -(3-[5-(3-trifluoromethylbenzyl)- 1,2,4oxadiazolyl]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)- 1,2,4oxadiazolyl]-2-(S)-amino-3-methylbutan- 1-ol hydrochloride and [(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-l pyrimidinyl]acetic acid Med. Chem. 38:98-108 (1995)) in 10 mL of anhydrous DMF was added 1.0 ml (7.44 mmol) of TEA and 0.76 g (4.94 mnol) of HOBT. The mixture was cooled to 0 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 nL (7.44 mmol) of TEA was added and the reaction again allowed to stir overnight. The reaction was diluted with dichioromethane 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 of the title compound. FAB MS mlz; Calcd: 709, Found: 709. Example 23 (CE-2090) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-1pyrimidinyl]-N-l -(3-[5-(3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolylcarbonyl)-2- methylpropyl]acetamide.
To a mixture containing 0.41 g (0.56 mmol) of [(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)- ,6-dihydro-l -pyrimidinyl]- -(3-[5-(3-trifluormethylbenzyl)-1 2,4-oxadiazolylcarbonyl)-(S)-2- methylpropyl] acetamide in 4 nl of trifluoracetic acid at room temperature under a nitrogen atmosphere was added 87 mg (0.70 mmol) of thioanisole. The reaction mixture was I allowed to stir for 3 days and concentrated in vacuo. The residue was purified via preparative HPLC to afford 269 mg of the title compound as a white solid.
FAB MS mlz; Caled: 573, Found: 573.
Example 24 (CE-2095) 2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4- 2S fluorophenyl)-1 ,6-dihydro-i -pyrimidinyl]-N-[I -(2-[5-(3-methylbenzyl)- 1,3,4oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.
To a mixture containing 0.83 g (6.23 mmol) of N-chlorosuccinimide in 32 mL of anhydrous toluene at 0 0 C under a nitrogen atmosphere was added 0.7 mL (9.35 mmol) of dimethyl sulfide. The reaction was cooled to -25 0 C using a carbon tetrachloride/dry ice bath, followed by the dropwise addition of a solution containing 6 -oxo- 2 4 -fluorophenyl)- ,6-dihydro- 1p~A 2 jyjmidinyl]-N..[ I-(2-[5-(3-methylbenzyl)- 1,3 ,4-oxadiazolyl]hydroxymethyl).(S)- 2- -67- ~~x
NTU
WO 98/24806 WO 9824806PCT/US97/21636 methyipropyl] acetaniide (1.02 g, 1.56 mmol) in 12 mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at -25 0 C followed by the addition of 0.9 mnL (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% methanolldichloromethane to afford 1.37 g of material which was fur-ther purified via preparative HPLC to give 368 mg of the title compound as a white solid. FAB MS mlz; Caled: 653, Found: 653.
The intermediate 2 -[5-[(benzyloxycarbonyl)axnino]-6-oxo.2-(4- fluorophenyl)- 1 ,6-dihydro-lI-pyrimidinyl]-N-[ 1-(2-[5-(3-methylbenzyl)- 1,3,4- oxadiazolyl] hydroxymethyl)-(S)-2-methylpropyl]acetwnide 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)amnino-3-methyl butane hydrochloride and [(benzyloxycarbonyl)amino]-6-oxo-2.
(4-fluorophenyl)-1,6-dihydro-1- pyrimidinyl]acetic acid Med. Chem., 38:98-108 (1995)) in 10 mL of anhydrous DMIF 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 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 colun chromatography on silica gel using a gradient elution of 2 to 5% methanol] dichloromethane to afford 1.02 g of the title compound. FAB MS mlz; Calcd: 655, Found: 655.
Example 25 (CE-2 101) 2 -[5-Anlino-6-oxo-2-(4-fluorophenyl) 1 ,6-dihydro- 1pyrimidinyl]-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 amino]-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro- 1-pyrimidinyl]- methylbenzyl)- 1,3,4-oxadiazolyllcarbonyl)-(S)-2- methylpropylyl]acetarnjde in 3 mL of trifluoroacetic acid at room temperature under a nitrogen atmosphere was added 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 of the title compound as a white solid. FAB MS m/z; Calcd: 519, Found: 519.
Example 26 (CE-21 6 4 )(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3methylbenzyl)-l, 3 4 -oxadiazolyl]carbonyl-2-(S)-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 0 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 0 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 The material was further purified via preparative HPLC to afford 1.20 g of the title compound as a white solid. FAB MS m/z; Calcd: 514, Found: 514.
The intermediate (pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3methylbenzyl)-1, 3 ,4-oxadiazolyl]hydroxymethyl)]-2-(S)-methylpropyl]amide was prepared by the following method: a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester.
To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in mL of anhydrous dichloromethane under a nitrogen atmosphere at o0C was added 6.96 g (27.0 mmol) of BOPCl 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 WO 98/24806 PCT/US97/21636 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 of the title compound as a white solid. FAB MS 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 50 mL of anhydrous dichloromethane cooled to 0 C was added 25 mL ofTFA 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/z; Calcd. 259, Found 259.
c. (Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)- 1,3,4- oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amide.
To a solution containing 1.90 g (7.35 mmol) of (Pyrrole-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 0OC and 1.69 g (8.82 mmol) ofEDCI was added and the reaction mixture was allowed to stir. After minutes 2.17 g (6.99 mmol) of 1-[2-(5-[3-methylbenzyl])-l,3,4- oxadiazolyl]-2- (S)-amino-3-methyl butan-1-ol 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 of the title compound. FAB MS m/z Calcd: 516, Found: 516.
Example 27 (CE-2097)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(3-[5-(3trifluoromethylbenzyl)]-1, 2 4 -oxadiazolyl]carbonyl)-(S)-methylpropyl]amide was prepared in a similar manner to Example 25. FAB MS m/z; Calcd: 568, Found: 568.
WO 98/24806 WO 9824806PCT/US97/21636 Example 28 (CE-2 130)(2S,5 S)-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)- (R,S)-2-methylpropyl]amide.
To a solution containing 0.93 g (1.28 inmol) of (2S,5S)-Fmoc-5-amino- 1,2,4,5 ,6,7-hexahydroazepino indole-4-one-carbonyl-N-[l1-(2-[5-(3methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amnide in 4.5 mL of anhydrous DUvI under an atmosphere of nitrogen was added 0.45 mL of diethylamine. After stirring at room temperature for 15 min the mixture was concentrated under high vacuum. The residue was purified via preparative HPILC to afford 0.57 g of the title compound as a white solid. FAB MIS mlz; Calcd: 502, Found 502.
The intermediate (2S,5 S)-Fmoc-5 -amino- 1,2 ,4 ,5,6 ,7-hexahydroazepino- [3,2,1 ]-indole-4-one-carbonyl-N-[ 1-(2-[5-(3-methylbenzyl)- 1,3,4oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amide was prepared as follows: a. (2S, SS) -Fmoc-S -amino-i ,24, 5,6, 7-hexahydroazepino-[3,2, l]-indole-4one-carbonyl -N-fl -(2-[S-(3-methylbenzyl)-l, 3, 4-oxadiazolyllhydroxymethyl)-(S)-2met hylpropyllamide.
To a solution containing 1.25 g (2.67 nmol) of (2S,5S)-Fmoc-5-amino- 1,2,4,5,6,7-hexahydroazepino indole-4-one-carboxylic acid in 200 mL of anhydrous dichloromethane and 1 mL of anhydrous DMF under a nitrogen atmosphere at 0 0 C was added 0.71 g (2.80 nimol) of BOPC1 and 0.6 mL (3.45 mmol) of DLEA. After stirring for 1 hr 1. 14 g (3.66 nmmol) of 1-[2-(5-[3-methylbenzyl])- 1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol 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 dichioromethane 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 of the title compound as tan solid.
b. (2S, SS)-Fmoc-S-amino-l,2, 4,S,6, 7-hexahydroazepino-[3, 2, l]-indole- 4-one-carbonyl-N-[1-(2-[S-(3-methylbenzyl)-l, 3,4-oxadiazolyl]carbonyl)]-(S)-2met hyipropyllamide.
WO 98/24806 PCT/US97/2 1636 To a mixture containing 0.95 g (7.16 minol) of N-chlorosuccinimide in 150 mL of anhydrous toluene at 0 0 C under a nitrogen atmosphere was added 0.79 rnL (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 ba th, followed by the dropwise addition of a solution containing 1.30 g (1.79 nimol) of (2S, -amino- 1 ,2,4,5,6,7-hexahydroazepino-[3 1 ]-indole-4-one-carbonyl-N-[ 1 [5-(3-methylbenzyl)- 1,3,4-oxadiazolyl]hydroxymethyl)]-(s)-2-methylpropyljamide in mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at followed by the addition of 1. 17 mL (8.4 mmnol) of triethylamine. The cold bath was 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 as a tan foamn.
Example 29 (CE-2126) BTD-[l-(2-[5-(3-methylbenzyl)-1,3,4oxadiazolyllcarbonyl)-2-(S)-methylpropyl]amide.
To a solution containing 0.41 g (0.59 mmol) of FMOC-BTD-[ 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 stirring 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 mlz; Calcd: 472, Found 472.
The intermediate Fmoc-BTD-[ 1-(2-15-(3-methylbenzyl)-1 ,3,4oxadiazolyllcarbonyl)-2-(S)-methylpropyl]amide was prepared as follows: a. (2S, SS)-Fmoc-BTD-[J-(2-[5-(3-methylbenzyl)-J,3,4oxadiazolyljhydroxymethyl)-2-(S)-methylpropyl]amide.
To a solution containing 1.25 g (2.85 mniol) of FMOC-BTD in 80 mL of anhydrous dichloromethane and 2.5 ml, of anhydrous DMIF under a nitrogen atmosphere at 0 0 C was added 0.76 g (2.99 mmol) of BOPC1 and 0.6 mL (3.45 mmol) of D1EA. After stirring for 30 minutes and 1. 14 g (3.66 mmol) of methylbenzyl])-1 ,3,4-oxadiazolyl]-2-(S)-amiino-3-methylbutan-l1-ol hydrochloride and 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% methanoldichloromethane to afford 1.13 g of the title compound as a tan foam.
b. Fmoc-BTD-[l-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)]-2- (S)-methylpropyl]amide.
To a mixture containing 0.81 g (6.09 mmol) of N-chlorosuccinimide in 110 mL of 1:1 anhydrous dichloromethane/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)-l,3,4-oxadiazolyl]hydroxymethyl)-2-(S)methylpropyl]amide in 10 mL of anhydrous toluene. The reaction was allowed to stir for 2 hours at -25C 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 ooo* 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 S column chromatography on silica gel with 70% ethyl acetate/hexane to give 0.53 g of the product as a yellow oil. The material was further purified by preparative HPLC to afford 0.41 g of the title compound as a white solid.
2: Example 30 (CE-2134)(R,S)-3-Amino-2-oxo-5-phenyl-l,4,-benzodiazepine-N-[1- (2-[5-(3-methylbenzyl)- ,3,4-oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide.
To a solution containing 0.93 g (1.19 mmol) of(R,S)-FMOC-3-amino-2-oxo- 5-phenyl- ,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4- S 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 -73- .i WO 98/24806 PCTIUS97/21636 compound as a white solid. FAB MS m/z; Caled: 565, Found 565.
The intermediate (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine- N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide was prepared as follows: a. (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1, 4, (3-methylbenzyl) 3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyll]acetamide.
To a solution containing 0.75 g (1.41 mmol) of(R,S)-FMOC-3-amino-N-1carboxymethyl-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) ofBOPC1 and 0.25 mL (1.41 mmol) of DIEA. After stirring for 1 hr 0.48 g (1.55 mmol) of 1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methy butan-1ol 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 0 C overnight.
The reaction 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 of 2 to 6% methanol/dichloromethane to afford 1.00 g of the title compound as a yellow solid.
b. (R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5- (3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 0.71 g (7.6 mmol) of N-chlorosuccinimide in 40 mL of anhydrous toluene at OC under a nitrogen atmosphere was added 0.84 mL (11.4 mmol) ofdimethyl sulfide. The reaction was cooled to -25 0 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 0 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 of ?4 WO 98/24806 PCT/US97/21636 material which was used without further purification. FAB MS 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 stirring for 1 hr the reaction mixture was cooled to 0 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-(2,3dihydro-1H-indole)- -(2-[5-(3-methylbenzyl)-l,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 0 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 mixture was diluted with dichloromethane and washed with 1 N HC1 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 50% ethyl acetate/hexane to afford 0.27 g of material which was further purified via preparative HPLC to afford 196 mg of the title compound as a white solid. FAB MS m/z Calcd: 652, Found 652.
The intermediate (benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-lH-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)carboxylate.
To a suspension containing 5.00g (30.6 mmol) of 2-L-(2,3dihydroindole)carboxylic acid in 100 mL of anhydrous MeOH cooled to 0°C was added a slow stream of HC1 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 of 2-L-methyl (2,3-dihydroindole)carboxylate.
b. 2-Methyl [(S)-l-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1 H- -7; WO 98/24806 PCT/US97/21636 indole]carboxylate.
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) ofBOPC1 and 7.72 mL (70.2 mmol) of DIEA was added 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 0 C the mixture was diluted with ethyl acetate and washed with 1 N HC1 (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 of the title compound as a white foam.
c. 2-[(S)-l-(N-[Benzyloxycarbonyl]-L-valyl)-2,3-dihydro-IHindole]carboxylic acid.
To a solution containing 4.85 g (12.17 mmol) of2-methyl [benzyloxycarbonyl]-L-valyl)-2,3-dihydro-lH-indole]carboxylate in 45 mL of THF and 15 mL ofMeOH at 0°C was added 15.8 mL of 1 N LiOH dropwise. After minutes 1 N HC1 was added to pH 2 and the mixture extracted with ethyl acetate The combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced presure to afford 4.51 g of the title compound as a white solid.
d. (Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-H-indole)-N-[l-(2-[5- (3-methylbenzyl)-l,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amide.
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- -ol and 1.31 g (3.3 mmol) of 1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-lH-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 dichloromethane and washed with 1 N HC1 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 WO 98/24806 PCT/US97/21636 acetate/hexane to afford 0.66 g of the title compound.
Example 32 (CE-2125)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-IH-indole)- N-[1 -(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/z; Calcd: 706, Found: 706.
Example 33 (CE-2143) Acetyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.
Prepared in a similar manner as in Example 30. FAB MS m/z; Calcd: 515, Found: 515.
Example 34 (CE-2165) N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N-[I-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]anide. Prepared in a similar manner as in Example 30. FAB MS m/z; Caled: 461; Found: 461.
Example 35 (CE-2104)(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
To a mixture containing 0.69 g (5.17 mmnol) of N-chlorosuccinimide in 60 mL of anhydrous toluene at OC under a nitrogen atmosphere was added 0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was cooled to -25 0 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)-1,3,4oxadiazolyl]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 0
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 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 of the title compound as a white solid. FAB MS [M+H] m/z; Calcd: 583, Found: 583.
WO 98/24806 PCT/US97/21636 The intermediate (Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3methylbenzyl)-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 o0C was added morpholine 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 methanol/dichloromethane to afford 1.98 g of the title compound as a white solid. FAB MS m/z; Caled: 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)-,3, 4oxadiazolyl] hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide.
To a solution containingn 0.95 g (2.90 mmol) of (morpholino-N-carbonyl)-Lvalyl-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 l-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]- 2 -(S)-amino-3-methylbutan- 1-ol 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 NaHCO 3 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 WO 98/24806 PCTIUS97/21636 (54.84%) of the title compound as a white solid. FAB MS m/z; Calcd: 585, Found: 585.
Example 36 (CE-2079) 3-(S)-(Benzyloxycarbonyl)amino)- -lactam-N-[1-(2-[5-(3methylbenzyl)-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 1.94 mL (2.64 mmol) of dimethyl sulfide. The reaction was cooled to -25 0 C using a carbon tetrachloride/dry ice bath, followed by the dropwise addition of a solution containing 2.5 g (4.44 mmol) of 3-(S)-[(benzyloxycarbonyl)amino]- -lactam-N-[1-(2-[5-(3methylbenzyl)-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 0 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 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 of the title compound as a white solid. FAB MS m/z; Calcd: 562, Found: 562.
The intermediate 3-(S)-[(benzyloxycarbonyl)amino]-e -lactam-N-[1-(2-[5-(3methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methyl propyl]acetamide was prepared as follows: a. 3-(S)-[(Benzyloxycarbonyl)amino]- e-lactam.
To a mixture containing 9.9 g (37.18 mmol) of Cbz-omithine 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 WO 98/24806 PCT/US97/21636 was filtered and dried to afford 8.37 g of the title compound.
b. N-[3-(S)-(Benzyloxycarbonyl)amino]- e-lactam-t-butyl acetate.
To a solution containing 1.0 g (4.03 mmol) of [(benzyloxylcarbonyl)amino]-e-lactam in 20 mL of anhydrous DMF under a nitrogen atmosphere was added 1.50 mL (10.16 mmol) of bromo-t-butyl acetate and 1.17 g (5.05 mmol) of silver oxide. The reaction was heated to 45 0 C for 5 hours, diluted with acetonitrile and filtered through a pad ofcelite. 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/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/z; Calcd: 307, Found: 307.
d. 3-(S)-[Benzyloxycarbonyl)amino)- e-lactam-N-[-(2-[5-(3methylbenzyl)-1, 3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 2.72 g (8.88 mmol) 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 1-[3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2- (S)-amino-3methyl butan-1-ol hydrochloride in 20 mL of dichloromethane and 1.60 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 afforded 2.58 g (50.23%) of the title compound. FAB MS [M+HI mlz; Calcd: 564, Found: 564.
Example 37 (CE-2080) 3-(S-(Amino)-L -lactam-N-[ l-(2-[5-(3-methylbenzyl)- 1,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyI]acetamide trifluoroacetic acid salt.
This compound was prepared via deprotection of [benzyloxycarbony)amino)- L -lactam-N-[I -methylbenzyl)-l ,3,4oxadiazolyl]carbonyl)-2-(S)-methyl propyl]acetamide under standard conditions to one skilled in the art to afford the title compound. FAB MS /ih; Caled: 428, Found: 428.
Example 38 (CE-2901) 3-(S)-[2-(4-Morpholino carbonyl)ethylcarbonylamino]-E-laCtam- 1-(2-[5-(3-methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide.
To a solution containing 0.089 g (0.475 mmol) of 4-morpholino 4-oxobutanoic acid in 10 nL of dichioromethane under a nitrogen atmosphere at 0 0 C was added 0.127 g (0.498 nmol) of BOPCI and 0.09 nL (0.492 mmol) of DIEA. The reaction was allowed to stir for 30 minutes followed by the additin of 0.22 g (0.406 *0 .0 nmol) of 3-(S)-amino-E- lactam-N-[1-(2-[5-(3-methyl benzyl)-l,3,4oxadiazolyl]carbonyl)-2- -methyl propyliacetamide trifluoroacetic acid salt. The 0 reaction was allowed to stir at 0 0 C overnight. The reaction was diluted with dichioromethane 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 of the title compound. FAB MS n/z; Calcd: 25 597, Found: 597.
000 Example 39 (CE-2087) 6-[4-Fluorophenyl]-£-lactam-N-[-(2-[5-(3-ethylbenzyl)- 1,3 ,4-oxadiazolyl~carbonyl)-2-(S)-methylpropyl acetamide.
To a mixture containing 0.70 g (5.24 mmol) and N-chlorosuccinimide in -:0033 mL of anhydrous toluene at 0 0 C under a nitrogen atmosphere was added 0.60 mL *jl (8.17 mxol) of dimethyl sulfide. The reaction was cooled to -25 0 C using a carbon -tetrachloride/dry ice bath, followed by the dropwise addition of a solution containing -81- WO 98/24806 PCT/US97/21636 0.67 g (1.32 mmol) of 6 4 -fluorophenyl]-e-lactam-N-[1-(2-[5-(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 for 2 hours followed by the addition of 0.90 mL (6.46 mmol) of triethylamine. The 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 of the title compound. FAB MS m/z; Calcd: 507, Found: 507.
The intermedite 6-[4-fluorophenyl]- E -lactam-N-[ 1 -(2-[5-(3-methylbenzyl)- 1, 3 ,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared as follows: a. 6 4 -Fluorophenyl]-6-carboxymethylene-2-piperidinone.
To a solution containing 2.15 g (8.11 mmol) of 6-[4-fluorophenyl]-1carbomethoxymethylene-2-piperidinone, prepared in a similar fashion to that reported by Compemolle (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 of the title compound. FAB MS m/z; Calcd: 252, Found: 252.
b. 6-[4-Fluorophenyl]- -lactam-N-[1-(2-[5-(3-methylbenzyl)-1, 3,4oxadiazolyl] hydroxymethyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 1.04 g (4.14 mmol) of 6-[4-fluorophenyl]-6carboxymethylene-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) ofDIEA. 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- WO 98/24806 PCTfUJS97/21636 ol 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 methanol/dichloromethane afforded 736 mg of the title compound. FAB MS m/z; Calcd: 509, Found: 509.
Example 40 (CE-2121) 2-[2-(R,S)-Phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3methylbenzyl)-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 -25 0 C using a carbon tetrachloride/dry ice bath, followed by the addition of 1.90 g (3.84 mmol) of 2-[2- (R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 20 mL of anhydrous toluene dropwise. The reaction was allowed to stir at -25 0 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 of the title compound as an off-white solid. FAB MS m/z; Calcd: 493, Found 493.
The intermediate 2-[2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methypropyl]acetamide was prepared as follows: to a solution containing 1.78 g (7.51 mmol) of 2-(2-phenyl-4oxothiazolidin-3-yl) acetic acid, prepared according to Holmes 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 BOPC1 and 1.35 mL (7.76 mmol) of DIEA. After stirring for 30 minutes, 2.0 g (6.41 mmol) of 1-[3-[5-(3-methylbenzyl)]-1,3,4oxadiazolyl]-2-(S)-amino-3-methyl-butan-l-ol hydrochloride in 50 mL of g3 dichioromethane and 1.35 rnL (7.76 mmol) of DIEA was added. The reaction was allowed to stir at 0 0 C overnight. The reaction mixture was diluted with dichioromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography of the residue on silica gel with 4% methanol/dichloromethane afforded 2.30 g of a yellow foam. Subsequent preparative HPLC gave 1.9 g of the title compound. FAB MS nl/z; Calcd: 495, Found: 495.
Example 41 (CE-2122) 2-[2-(RS)-Benzyl-4-oxothiazolidin-3-yl]-N-[R-(2-(5-(3methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] acetamide was prepared in a similar manner as in Example 39. FAB MS m/z; Calcd: 5.07, Found: 507.
Example 42 (CE-2 136) 2-[(2-(RS)-Benzyl-4-oxothiazolidifl-3-y oxide]-N-[ (3-methyl benzyl)-1 ,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]acetamlide.
To a solution containing 1.31 g (2.59 nimol) of 2-[2-(RAS-benzyl-4- 0:0 oxtizldn3y)N[-2[-3mtybny)134oaizlt carbonyl)-2-{S)methyl propyl]-acetamide in 15 mL of methanol under a nitrogen atmosphere was added 0.51 -mL (5.17 nimol) of 30% hydrogen peroxide. The reaction was allowed to 0*.20~ stir at room temperature overnight and then partitioned between brine and dicliloromethane. 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 of the title compound. FAB MS nilz; Calcd: 523, Found 523.
Example 43 (CE-2137) 2-[2-(R.S)-Benzyl-4-oxothiazolidin-3-yl 0 1 (3-trifluoromethylbenzyl)- I,2,4-oxadiazolyl] carbonyl)-2 )-methylpropyl] acetamide. Prepared in a similar manner as in Example 41. FAB MS mlz; .3.~Calcd: 577, Found 577.
Example 44 (CE-21 18) 2-jj2-(R,S)Phenyl-4-oxometathiazan-3yl]-N-[l-(2-[5-(3methylbenzyl)-1 ,3,4-oxadiazolyl] carbonyl)-2-(S)-rnethylpropyl] acetamide. Prepared -84in a similar manner as in Example 39. FAB MS rnlz; Calcd: 507, Found: 507.
Example 45 (CE-2 140X1 -Benoyl-3,8-phthalazi nediofle)-N-1 methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl)7-{S)-methylpropyl] acetamide.
To a mixture containing 1.70 g (2.74 mmol) Of KV-chlorosuccinimide in 75 mL.
of anhydrous toluene at 0 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 mniol) of (1- Benzoyl-3,8 -phthatazinedione)-N-[1 -(2-[5-(3-methylbenzyl ,3,4oxadiazolyl]hydroxymethyl)-2-(S)-meIthyl 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 triethylanine. The cold bath was removed and the reaction allowed to warmn 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 0:0 methanolldichloromethane to afford 1.37 g of a brown oil. This was further purified C* via preparative HPLC to give 450 mg of the title compound. FAB MS Calcd: 580, Found: 580.
The intermediate (l-benzoyl-3,8-phthalazilediofle)-N-1 methylbenzyl)-1 ,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl~acetamide was prepared as follows: a. I-Benzoyl-3,8-phthalaziflediofle-2-t-butyI acetate.
To a solution containing 5.0 g (18.78 mmol) of 1-Benzoyl-3,8- 2~ phthalazinedione prepared in a similar manner to that reported by Melnyk et al.
S(Tetrahedron Lett., 37:4145 (1996)), in 100 mL. of DMF under a nitrogen atmosphere was added 4.30 mL. (29.12 nimol) of bromo t-butylacetate and 5.4 g (23.30 mmol) of silver oxide. The reaction was heated to 50 0 C overnight, diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate.
3~ Filtration, removal of solvent under reduced pressure and column chromatography of se the residue on silica gel with 40% ethyl acetate/hexane gave 5.25 g (73.49%) of /.product. FAB MS m/z; Calcd: 381, Found: 381.
AL
b. 1-Benzoyl-2-carboxymethylene- 3 8- phthalazinedione.
To a solution containing 5.20 g (13.67 mmol) of I-benzoyl-3,8phthalazifedione-2-t-butyl acetate in 300 nL of dichloromethane under a nitrogen atmosphere at 0*C was added 21.0 mL (211.44 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 afforded 4.32 g (97.45%) of the title compound. FAB MS Calcd: 325, Found: 325.
c. (I-Benzoyl-3,8-phthalazinedione)-N-[-(2-5-(3-methybezyi)- 1,3,4oxadiazolyl] hydroxymethyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 1.80 g (5.55 mmol) of l-benzoyl-2carboxymethyene-3,8 -phthalazifedione in 100 mL of anhydrous dichioromethane and 5 nL of DMF under a nitrogen atmosphere at OOC was added 1.90 g (7.46 mmol) of BOPCI and 1.40 mL (8.05 nmol) of DIEA. After stirring for 30 minutes, a solution containing 1.70 g (5.45 mmol) of 1-[2-(5-[3-methylbenzyl])-1,3,4oxadiazolyl]-2-(S)-amino-3-methylbutan- 1 -1 hydrochloride in 20 rnL of dichloromethane and 3.80 mL (21.84 nmol) of DIEA was added. The reaction was allowed to stir at 000 overnight, diluted with dichloromethane and washed with water.
20 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 methanolldichloromethane afforded 1.93 g of the title compound. FAB MSIM+H]n/z; Calcd: 582, Found: 582.
Example 46 (CE-21 38)( i Benzoyl-perhydropyridazifle-3,6-diofe)-N[l methylbenzyl)-1,3,4-oxadiazolylI carbonyl)-2-(S)-methylpropyl]acetamide. Prepared in a similar manner as in Example 44. FAB MS [M+H]miz; Calcd: 532, Found: 532.
Example 47 (CE-2I47)(1 IPhenyI-perhydropyridazine-3,6-dione)-N-I-(2-[5-(3- O methylbenzyl)-l,3,4-oxadiazoly] carbonyl)-2-(S)-methylpropylacetamide. Prepared in a similar manner as in Example 44. FAB MS Calcd: 504, Found: 504.
-86- 3U 1+w ~X 4 d 00 4
S
S.
S
S.
S..
.4 0' 54 .4 0" 0/ 03 7 Example 48 (CE-2148)(1-Phenyi-perhydropyridazine-3,6-dione-N-[1 trifluoromethylbenzyl)-1,24-oxadiazolyl] carbonyl)-2-(S)-methylpopyl]acetamide.
Prepared in a similar manner as in Example 44. FAB MS ni/z Calcd:558, Found: 558.
Example 49 (CE-2108) 3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5- (3-methybenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 0.16 g (1.18 mmol) of N-chlorosuccinimide in 20 mL of anhydrous toluene at 0*C under a nitrogen atmosphere was added 0.13 mL (1.77 mmol) ofdimethyl sulfide. The reaction was cooled to -25C 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-[-(2-[5-(3methylbenzyl)-1,3,4-0xadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetanide in mL of methylene chloride dropwise. The reaction was allowedto stir at -25 0 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/z; Calcd 608, Found: 608 The intermediate 3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N- (3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethly)-2-(Se)-methylpropyl]acetamide was prepared as follows: a. 3-[(Benzyloxycarbonyl)amino-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. Heterocyclic Chem., 30:1533 (1993)) in 40 mL of dioxane under a nitrogen atmosphere was added 0.14 g (3.4 mmol) of sodium 30 hydroxide in 14 mL of water. The reaction mixture was cooled to OC, followed by 00 the addition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of the reaction was maintained above 8.0 with additional I N sodium hydroxide. The reaction was -87- ArT cZ> 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 of product as a white solid. FAB MS m/z; Calcd: 295, Found: 295 b. 3-[(Benzyloxycarbonyl)amino]-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 0 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 sulfate. Filtration, removal of solvent under reduced pressure and column chromatography of the residue on silica gel with dichloromethane afforded 0.20 g or product as a white solid. FAB MS m/z; Calcd: 409, Found: 409.
c. 3-[(Benzyloxycarbonyl)amino]-l-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) oftrifluoroacetic acid. The reaction was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure to afford 1.09 g of the title compound. FAB MS m/z; Calcd: 353, Found: 353 d. 3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl] hydroxymethyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 1.09 g (3.09 nmOl) of 3- [(benzyloxycarbonyl)amino]-l-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 l-[2-(5-[3-methylbenzyl])-1,3,4oxadiazolyl]-2(S)-amino- 3 -methylbutan-l-ol hydrochloride in 8 mL of 89 dichioromethane and 0.56 mL (3.20 mmOl) of DIEA was added. The reaction was allowed to stir at 0 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 of product. FAB MS [M+H] m/z; Caled: 610, Found: 610 Example 50 (CE-2 107) 3-[(Benzyloxycarbonyl)amino]-7-piperidiny-quinolie-2one-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 mlz; Calcd: 691, Found: 691 Example 51 (CE-2117) 3-Carbomethoxy-7-fluoro-quinoline-2-one-M methybenzyl)-1,3,4-oxadiazolyl]carbony1)-2-(S)-methylPropyl]acetanide. Prepared in a similar manner as shown in Example 48. FAB MS mlz; Calcd: 535, Found: 535 0:0 6ee: Example 52 (CE-2113) 3-(Amino-quinoline-2-one)-N[1-(2-5-(3-methylbenzyl)- I ,3,4-oxadiazolyl]caronyl)-2-(S)-methylpropy1Iacetamide.
*e o"Z0 To a solution containing 2.30 g (3.79 mmol) of 3- @0 [(benzyloxycarbonyl)amino]-quinoline-2-oneN[ [I-(2-[5-(3-methyl benzyl)-1,3,4oxadiazolyl]-carbonyl)-2-(S)-methyl propyljacetamide in 60 mL of trifluoroacetic acid under a nitrogen atmosphere at 0 0 C was added 0.53 nL (4.54 nmol) 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 of the title compound. FAB MS n/z; Calcd: 474, Found: 474 Example 53 (CE-2116) 3-[(4-Morpholino)aceto] amino-quinoline-2-one-N[1-( 2 i (3-methylbenzyl)-1 ,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 0.32 g (1.22 mmol) of 4-morpholino acetic acid in 18 mL of dichloromethane under a nitrogen atmosphere at 0 0 C was added 0.33 g (1.30 nimol) 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-[l-(2-[5-( 3 -89- 17 methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-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 of the title compound. FAB MS 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-S-methylpropyl]acetamide from commercially available 3,4-Dihydro-2(IH)-quinoline-2-one. Prepared in a similar manner as shown in Example 52. FAB MS m/z; Caled: 461, Found: 461 Example 55 (CE-2099) 1-Acetyl-3-benzylidene piperazine-2,5-dione-N-[1-(2-[5-(3methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 0.55 g (4.15 mmol) of N-chlorosuccinimide in 35 mL of anhydrous toluene at 0 0 C under a nitrogen atmosphere was added 0.46 mL (6.22 mmol) ofdimethyl sulfide. The reaction was cooled to -25 0 C using a carbon tetrachloride/dry ice bath, followed by the addition of a solution containing 0.58 g (1.04 mmol) of l-acetyl-3-benzylidene piperazine-2,5-dione-N-[1-(2-[5-(3- *:20 methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 8 S* mL of toluene. The reaction was allowed to stir at -25 0 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 S and column chromatography of the residue on silica gel 60% ethyl acetate/hexane gave 0.54 g ofa brown oil which was further purified via preparative HPLC to give 146 mg of the title compound. FAB MS m/z; Calcd: 558, Found: 558 sees*' The intermediate 1-acetyl-3-benzylidene piperazine-2,5-dione-N[ 30 methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was 0** S prepared as follows: Sa. I-Acetyl-3-benzylidene piperazine-2, S-dione-N-t-butyl acetate.
LI
WO 98/24806 PCT/US97/21636 To a solution containing 6.36 g (26.00 mmol) of 1-Acetyl-3-benzylidene described by D. Villemn, et al. (Synthetic Communications, 20:3325 (1990)), 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 45C 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 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-benzylidene acetate in 100 mL of dichloromethane under a nitrogen atmosphere at 0°C was added 5.40 mL (69.80 mmol) oftrifluoroacetic 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 of product as a tan solid. FAB MS m/z; Calcd: 303, Found: 303.
c. I-Acetyl-3-benzylidene piperazine-2,5-dione-N-[1-(2[5-(3methylbenzyl)-l, 3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.
To a solution containing 0.65 g (2.14 mmol) of 1-acetyl-3-benzylidene-4in 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 l-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)amino-3-methylbutan-l-ol 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 11 WO 98/24806 PCTIUS97/21636 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 of product. FAB MS[M+H] mlz; Calcd: 560, Found: 560.
Example 56 (CE-2 105) I1-Acetyl-3-(4-fluorobenzylidene) [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] mlz; Calcd: 576, Found: 576.
Example 57 (CE-2 11 1) 1 -Acetyl-3-(4-dimethylamino benzylidene) piperazine- dione-N-[ 1-(2-[5-(3-methylbenzyl)-1I,3,4-oxadiazolyl~carbonyl)-2-(S)methylpropyl]acetamide. Prepared in a similar manner as shown in Example 54.
FAB MS[M+H] mlz; Calcd: 601, Found: 601.
Example 58 (CE-2112) I -Acetyl-3-(4-carbomethoxy benzylidene) dione-N-[ 1-(2-[5-(3-methylbenzyl)-1I,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropylacetainide. Prepared in a similar manner as shown in Example 54.
FAB MS[M+H] m/z; Calcd: 616, Found: 616..
Example 59 (CE-21 14) 1-Acetyl-3-[(4-pyridyl)methylene] [1 -(2-[5-(3-methylbenzyl)-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 54. FAB MS[M+H] mlz; Calcd: 559, Found: 559.
Example 60 (CE-2 144) 1-Benzyl-3-(R)-benzyl-piperazine-2,5,-dione]-N-[ (3-methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaflide.
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 0 C was added 2.1 mL (28.59 nimol) of dimethyl sulfide. The reaction was cooled to -25 0 C using a carbon tetrachloride/dry ice bath, followed by the addition of a solution containing 2.5 g (4.10 mmol) of I-benzyl-3-(R)-benzyl piperazine-2,5,-dione]-N-[ methy lbenzyl)-1 ,3 ,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetanide in WO 98/24806 PCT/US97/21636 mL of toluene. The reaction was allowed to stir at -25 0 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 methanol/dichloromethane afforded 2.27 g of a light brown solid which was further purified via preparative HPLC to give 350 mg of the title compound. FAB MS Calcd: 608, Found: 608.
The intermediate 4-[1-benzyl-3-(R)-benzyl piperazine-2,5,-dione]-N-[1-(2-[5- (3-methylbenzyl)-l,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 described by Steele, et al. 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 0 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 ethyl acetate/hexane afforded 7.74 g of the title compound as a white solid.
FAB MS[M+H]m/z; Calcd:409,Found::409.
b. 1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-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.
WO 98/24806 WO 9824806PCTIUS97/21636 C. 4-[1-Benzyl-3(R)-benzyl piperazine-2, 5, methylbenzyl)-1, 3, 4-oxadiazolyljhydroxymethyl)-2-(S)-methylpropyllacetamide.
To a solution containing 2.0 g (5.68 mnnol) of l-Benzyl-3-(R)-benzyl-4in 100 niL of dichioromethane and 2 ml. of DMF under a nitrogen atmosphere at 0 0 C was added 2.0 g (7.86 inmol) 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)-aniino-3methylbutan-1-ol hydrochloride in 10 ml of dichioromethane and 4.0 mL. (22.99 mmol) of DIEA. The reaction was allowed to stir at 0 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! dichioromethane afforded 2.69 g of product. FAB MS[M+Hlmi/z; Calcd:610, Found: 610.
Example 61 (CE-2 128) 441 -Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[ (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.
Example 62 (CE-2 146) 441 -Benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[ (3-trifluoromethylbenzyl)-1I,2,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetam-ide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H~mz; Calcd:662, Found: 662.
Example 63 (CE-2 129) 4-[1 -Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[ 1-(34[5- (3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetaniide Prepared in a similar manner as shown in Example 59. FAB MS[M+Hlm/z; Calcd:662, Found: 662.
Example 64 (CE-2 133) I-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[ (2-dimethylaminoethyl)- 1,2,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyllacetamide.
Prepared in a similar manner as shown in Example 59. FAB MS[M+H~mz; WO 98/24806 PCT/US97/21636 Calcd:575, Found: 575.
Example 65 (CE-2084) 4-[1 -Methyl-3-(R,S)-phenylpiperazine-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]m/z; Calcd:572, Found: 572.
Example 66 (CE-2106) 4-[1-Methyl-3-(R,S)-phenylpiperazine-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:518, Found: 518.
Example 67 (CE-2162) 4-[1 -(2-N-Morpholino ethyl)-3-(R)-benzyl 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:631, Found: 631.
Example 68 (CE-2149) 5-(R,S)-Phenyl-2,4-imidazolidinedione-N-[ methylbenzyl)-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 0 C was added 0.23 mL (3.13 mmol) ofdimethyl sulfide. The reaction was cooled to -25 0 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 -25C 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 methanol/dichloromethane, followed by preparative HPLC gave 120 mg of 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(3methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared as follows: 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 stirring 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 of product as a white solid. FAB MS[M+H]m/z; Calcd: 235, Found: 235.
b. (R)-5-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 of the title compound. FAB MS m/z; Calcd: 295, Found: 295.
c. 5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)- 1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide To a solution containing 2.55 g (10.89 mmol) of (R)-5-phenyl-3carboxymethyl 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-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3methylbutan-l-ol 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 acetone/dichloromethane afforded 1.90 g of the title compound. FAB MS
%L
WO 98/24806 PTU9/13 PCT/US97/21636 mlz; Calcd: 490, Found: 490.
Example 69 (CE-2 154) 5-(S)-Benzyl-2,4-imidazolidinedione-N-[ methylbenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyllacetamide. Prepared in a similar manner as shown in Example 67. FAR MS mlz; Calcd: 504, Found: 504.
Example 70 (CE-2 142) 5-(R)-Benzyl-2,4-imidazolidinedione-N-[ 1 methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide. Prepared in a similar manner as shown in Example 67. FAB MS mlz; Calcd: 504, Found: 504.
Example 71 (CE-2 141) 5-(R)-Benzyl-2,4-imidazolidinedione-N-[ trifluoromethylbenzyl)-1I,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetaniide.
Prepared in a similar manner as shown in Example 67. FAR MS mlz; Calcd: 558, Found: 558.
Example 72 (CE-21 55) 5-(S)-Benzyl-2,4-imidazolidinedione-N-[ trifluoromethylbenzyl)- 1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyllacetamide.
Prepared in a similar manner as shown in Example 67. FAB MS ni/z; Calcd: 558, Found: 558.
Example 73 (CE-2 151) 1 -Benzyl-4-QI?)-benzyl-2,5-imidazolidinedione-N-[ (3-methylbenzyl)-1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-niethylpropyl]acetamide.
Prepared in a similar manner as shown in Example 67. FAR MS mlz; Calcd: 594, Found: 594.
Example 74 (CE-21 50) 1 -Benzyl-4-(,R)-benzyl-2,5-imidazolidinedione-N-[ (3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
Prepared in a similar manner as shown in Example 67. FAR MS mlz; Calcd: 648, Found: 648.
WO 98/24806 PCTIUS97/21636 Example 75 (ONO-PO-698) 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4fluorophenyl)-1,6-dihydro-1 -pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
To a mixture containing 410 mg (0.744 mmol, 77% purity) of Dess-Martin Reagent (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-benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-l -pyrimidinyl]-N- [1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 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 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/z; Calcd: 605, Found: 605.
The intermediate 2-[5-(Benzyloxycarbonyl)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 was prepared as follows: to a solution containing 265 mg (1.01 mmol) of [1-[5-tert-butyl-1,3,4-oxadiazol-2-yl]-2-(S)-amino-1-hydroxy-3methylbutane hydrochloride and 336 mg (0.843 mmol) of [(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1pyrimidinyl]acetic acid 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 EDC1. 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 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; Caled: 607, Found: 607.
WO 98/24806 WO 9824806PCTIUS97/21636 Example 80 (ONO-PO-690) 2-[5-{Benzyloxycarbonyl)amino-6-oxo-2-(4fluorophenyl)- l,6-dihydro-l -pyrimidinyl]-N-I-(2-[5-(a,a-dimethylbenzyl)-1 ,3 ,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI, Pos, 40V mlz; Calcd: 667, Found: 667.
Example 81 (ONO-PO-697) 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4fluorophenyl)-1 ,6-dihydro-1 -prinidinyl]-N-[ 1-(2-[5-phenyl-1 ,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. El, Pos, nilz; Calcd: 624, Found: 624.
Example 82 (ONO-PO-7 16) 2-[6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 -pyrimidinyl]- I-(2-[5-tert-butyl-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetaniide was prepared in a similar manner to Example 75. APCI, Neg, 40V mlz; Calcd: 454, Found: 454.
Example 83 (ONO-PO-722) 2-[6-oxo-2-(4-fluorophenyl)-l ,6-dihydro- 1-pyrixnidinyl]- N-[1-(2-[5-(a,a-dimethylbenzyl)-1 ,3,4-oxadiazolyljcarbonyl)-2-(S)methylpropyl]acetaxnide was prepared in a similar manner to Example 75. APGI, Neg, m/z; Calcd: 516, Found: 516.
Example 84 (ONO-PO-727) 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1 -pyrimidinyl]- N-[1 -(2-[5-tert-butyl-l1,3,4-oxadiazoly1]carbonyl)-2-(R)-methylpropyllacetamide was prepared in a similar manner to Example 75. APCI, Pos, 40V m/z; Calcd: 456, Found: 456.
Example 85 (ONO-PO-730) 2-[6-oxo-2-phenyl- 1,6-dihydro-l -pyrimiidinyl]-N-[ 1-(2- 1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI, Neg, 40V [M-1I] mlz; Calcd: 436, Found: 436.
Example 86 (ONO-PO-731) 2-[6-oxo-2-phenyl-l,6-dihydro-1-pyrimidinyl]-N-I1-(2- [5-(a,Gt-dimethylbenzyl)-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI, Neg, 40V m/z; Calcd: 498, Found: 498.
WO 98/24806 WO 9824806PCT/US97/21636 Example 87 (ONO-PO-732) 2-[6-oxo-2-phenyl-1 ,6-dihydro-l-pyriinidinyl]-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/z; Calcd: 438, Found: 438.
Example 88 (ONO-PO-734) 2-[6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 -pyrimidinyl]- N-[1 -methylcyclopropyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyllacetamide was prepared in a similar manner to Example 75. APCI, Pos, 40V nilz; Calcd: 454, Found: 454.
Example 89 (ONO-PO-73 5) 2-[6-Oxo-2-phenyl- 1,6-dihydro-1-pyrimidinyl]-N-[ 1-(2- I-methylcyclopropyl)-1I,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI, Pos, 40V mlz; Calcd: 436, Found: 436.
Example 90 (ONO-PO-737) 2-16-oxo-2-phenyl- 1,6-dihydro-1 -pyrimidinyl]-N-[l1-(2- [5-tert-butyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide was prepared in a similar manner to Example 75. APCI, Pos, 40V ni/z; Calcd: 438, Found:438.
Example 91 (ONO-PO-696) 2-[5-Amino-6-oxo-2-(4-fiuorophenyl)-1 ,6-dihydro-1pyrimidinyl]-N-[l -(2-[5-tert-butyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl~acetamide.
To a mixture containing 296 mg (0.49 mmnol) of (benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-l -pyrirnidinyl]-N-[1 (2-[5-tert-butyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl~acetamide and 0.32 mE (2.9 nimol) of anisole in 8 niL of dichioromethane at OoC was added dropwise a solution containing 392 mg (2.9 mmol) of aluminum chloride in 4 niL of nitromethane.
The reaction mixture was allowed to stir for 1.5 hours, quenched by addition of ice water, extracted with ethyl acetate 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 i' WO 98/24806 WO 9824806PCTIUS97/21636 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, nt/z; Calcd: 471, Found: 471.
Example 92 (ONO-PO-691) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1pyrim-idinyl]-N-[1 -(2-[5-(a,cz-dimethylbenzyl)-l ,3 ,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetaniide was prepared in a similar manner to Example 91. FAB, Pos, mlz; Calcd: 533, Found: 533.
Example 93 (ONO-PO-692) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-1 pyrimidinyl]-N-[1 -(2-15-(a,a-dimethyl-3-methylbenzyl)- 1,3,4-oxadiazolyl]carbonyl)-2- (S)-methylpropyl]acetaniide was prepared in a similar manner to Example 91. FAB, Pos, mlz; Calcd: 547, Found: 547.
Example 94 (ONO-PO-693) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1pyrimidinyl]-N-[l1-(2-[5-(3-methylbenzyl)-1I,3,4-oxadiazolyllcarbonyl)-2-(R)methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB, Pos, mlz; Calcd: 519, Found: 519.
Example 95 (ONO-PO-694) 2-jj5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1pyriniidinyl]-N-[ 1-(2-[5-phenyl-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI, Pos, m/z; Calcd: 491, Found: 491.
Example 96 (ONO-PO-695) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-l,6-dihydro-1pyrimidinyl]-N-[1 -(2-[5-(3-pyridyl)-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl~acetamide was prepared in a similar manner to Example 91. APCI, Pos, mlz; Caled: 492, Found: 492.
Example 97 (ONO-PO-699) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1pyrimidinyl)-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 mlz; Calcd: 521, Found: 521.
WO 98/24806 WO 9824806PCTIUS97/21636 Example 98 (ONO-PO-701) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[ [5-(a,a-dimethyl)-3 ,4-dihydroxybenzyl)- 1,3,4oxadiazolyl]carbonyl)-2-(S)-methylpropyI]acetamide was prepared in a similar manner to Example 91. APCI, Pos, 40V mlz; Calcd: 565, Found: 565.
Example 99 (ONO-PO-703) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-l pyrimidinyl]-N-[ I-(2-[5-benzyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI, Pos, 40V mlz; Calcd: 505, Found: 505.
Example 100 (ONO-PO-704) 2-[5-Arnino-6-oxo-2-(4-fluorophenyl)- l,6-clihydro-l pyrimidinyl]-N-[ 1-(2-[5-methyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methyipropyllacetamide was prepared in a similar manner to Example 91. FAB, Pos mlz; Calcd: 429, Found: 429.
Example 101 (ONO-PO-705) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro- 1pyfrmidinyl]-N-[ 1-(2-[5-isopropyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropylacetamide was prepared in a similar manner to Example 91. APCI, Pos, 40V nt/z; Calcd: 457, Found: 457.
Example 102 (ONO-PO-706) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1I,6-dihydro- 1pyrimidinyl]-N-[ 1-(2-[5-butyl-1 ,3,4-oxadiazolyl]carbonyl)-2 methylpropyl]acetamide was prepared in a similar manner to Example 91. FAB, Pos mlz; Calcd: 471, Found: 471.
Example 103 (ONO-PO-707) 2-[5-Axnino-6-oxo-2-phenyl-1,6-dihydro-1pyrimidinyl]-N-[ 1-(2-[5-tert-butyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamide was prepared in a simnilar manner to Example 91. FAB, Pos mlz; Calcd: 453, Found: 453.
Example 104 (ONO-PO-7 1) 2-15-Amino-6-oxo-2-phenyl-1I,6-dihydro-1 pyrimidinyl]-N-[l -(2-[S-c,a-dimethybenzyl- 1,3,4-oxadiazolyl]carbonyl)-2-(S)- (o~ WO 98/24806 WO 9824806PCTIUS97/21636 methyipropyllacetarnude was prepared in a similar manner to Example 91. FAB, Pos mlz; Caled: 515, Found: 515.
Example 105 (ONO-PO-7 12) 2-[5-Amino-6-oxo-2-(3-pyridyl)- 1,6-dihydro- 1pyrimidinyl]-N-[ 1-(2-[5-tert-butyl- 1,3,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI, Pos, m/z; Calcd:454, Found:454.
Example 106 (ONO-PO-7 14) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[1 1-methylcyclopropyl)-1 ,3 ,4-oxadiazolyllcarbonyl)-2-(S)methylpropyl]acetamide was prepared in a similar manner to Example 91. APCI, Pos, mlz; Caled: 469, Found: 469.
Example 107 (ONO-PO-7 15) 2-[5-Amino-6-oxo-2-(3-pyridyl)- 1,6-dihydro-l pyrim-idinyl]-N-I -(2-[5-(a,a-dimethylbenzyl)-l ,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyljacetaniide was prepared in a similar manner to Example 91. APCI, Pos, mlz; Calcd: 516, Found: 516.
Example 108 (ONO-PO-7 18) 2-15-Amidno-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-1 pyrimidinyl]-N-[ 1-(2-[5-tert-butyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(R)methylpropyllacetamide was prepared in a similar manner to Example 91. APCI, Pos, mlz; Calcd: 471, Found: 471.
Example 109 (ONO-PO-721) 2-[5-Aniino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-lpyrimidinyl]-N-[l -(2-15-(a,a-dimethylbenzyl)-1 ,3 ,4-oxadiazolyl]carbonyl)-2-(R)methylpropyl]acetamide was prepared in a similar manner to Example 91. AIPCI, Pos, nilz; Calcd: 533, Found: 533.
Example 110 (ONO-PO-728) 2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1pyrimidinyl]-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, mlz; Calcd:449, Found:559.
Example 111 (ONO-PO-729) 2-[5-Amidno-6-oxo-2-phenyl- l ,6-dihydro- I1pyrimidinyl]-N-[l -(2-[5-tert-butyl- I ,3,4-oxadiazolyl]carbonyl)-2{(R)methylpropyl]acetan-Lide was prepared in a similar manner to Example 9 1. APCI, Pos, rnz; Calcd:453, Found:453.
Example 112 (ONO-PO-733) 2-15-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro- 1pyrimaidinyllj-N-[ l .2-[5-tert-butyl-1I,3,4-oxadiazolyllcarbonyl)-2-(R,S)methylpropy]acetamide was prepared in a similar manner to Example 91. APCI, Pos, m/z; Calcd:47 1, Found:47 1.
Example 113 (ONO-PO-736) 2-15-Anino-6-oxo-2-phenyI-1 ,6-dihydro-1pyrimidinyl]-N-[l -(2-[5-tert-butyl-1,3,4-oxadiazolyl]Carboflyl)-2-(R,S>methyipropyllacetamide was prepared in a similar manner to Example 91. APCI. Pos, mlz; Calcd:453, Found:453.
Example 114 (ONO-PO-700) 2-[5-Amidno-6-oxo-2-(4-fluoropheflyl)- 1,6-dihydro- 1pyrixnidinyl]-N-[l a(-imethyl-3,4-methylenedioxybenzyl)-l ,3,4oxadiazolyllcarbonyl)2(S)-methylprOpylacetalide To a mixture containing 66 mg (0.093 nimol) of 20 (benzyloxycarbonyl)anio-6-x0- 2 4 -fluorophenyl)-l ,6-dihydro-l -pyrimidinyl]-N-[ 1- (2-[5-(a,cz-dimethyl-3 ,4-methylenedioxybelzyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]acetamfide (the compound prepared in a similar manner to Example was added 2.5 niL of 30% hydrobromic acid in acetic acid solution. The reaction mixture was allowed to stir for 1 hour, quenched by addition of ice water, extrcted with ethyl acetate 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% methaol/chloroform to afford 41 mg of the title compound. El, Pos, m/z; Calcd:576, Found:576.
0000 0 0000 0000 00 00 00 00 a b 0 0 00 00 0 1 *0 0 000 0 1,0 00 0 00 0 000 4 0000 so 0 00 0 0 00 0 00 00 0000 0 0 0 0 000000 a 0 000 0 i~z; -1 Example 115 (ONO-PO-702) 2-II5-(Methylsulfonyl)amlino-6-oxo-2-(4-fluorphenyl)- I ,6-dihydro- I -pyrimidinyl]-N-f I -(2-(5-(3-methylbenzyl)-1l,3,4-oxadiazolyl]carboflyl)-2- (S)-methylpropyllacetafLhide -104-
LU
WO 98/24806 PCT/US97/21636 To a mixture containing 187 mg (0.36 mmol) of 2-[5-amino-6-oxo-2-(4fluorophenyl)-l,6-dihydro-l-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4oxadiazolyl]carbonyl)-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 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 500C and 1 hour at 70oC. 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 50 to 66% ethyl acetate/hexane to afford 60 mg of the tittle compound. APCI, Pos, 40V m/z; Calcd: 597, Found: 597.
Example 110 In Vitro 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 1l 0.2 M HEPES-NaOH buffer (pH 40 gl 2.5 M NaCI, 20 p. 1% polyethyleneglycol 6000, 8 ul distilled water, 10 [l1 of a DMSO solution of inhibitor and 2 pl solution of N-methoxysuccinyl-Ala-Ala- Pro-Val-p-nitroaniline (at concentrations of 100, 200 and 400 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 subjected 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./min., was measured for 10 minutes at 30 second intervals immediately after the addition of the enzyme solution. ICo 0 values were determined by log-logit method and converted to K, values by Dixson plot method.
WO 98/24806 PCT/US97/21636 The values are presented in Table 1 below.
Table 1.
Compound Ki (nM) Compound KI. (nM) Compound K. (nM) ONO-PO-690 78.3 ONO-PO-710 2.39 ONO-PO-730 23.5 ONO-PO-691 0.52 ONO-PO-711 2.55 ONO-PO-731 4.02 ONO-PO-692 1.37 ONO-PO-712 16.6 ONO-PO-732 62.2 ONO-PO-693 2.71 ONO-PO-713 12 ONO-PO-733 11.8 ONO-PO-694 24.8 ONO-PO-714 15.3 ONO-PO-734 43.8 ONO-PO-695 13.9 ONO-PO-715 3.54 ONO-PO-735 26.4 ONO-PO-696 6.38 ONO-PO-716 44.3 ONO-PO-736 6.43 ONO-PO-697 27.3 ONO-PO-717 57.8 ONO-PO-737 36.3 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:H 2 0: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; and the blood collected in a heparinized tube via cardiac puncture. Red blood cells were separated from the 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. 3 5 S]sulfate and 3 H]proline were also added to the culture media to incorporate radiolabel into the matrix. Cells were later lysed with NH40H. Plates were washed three times with water and once with phosphatebuffered saline containing 0.02% NaN 3 Plates were stored at 4 0 C until use.
Matrix degradation assays were performed as follows: 0.40 ml of Hanks balance salt solution (HBSS) containing 1 or 5 uM test inhibitor (final concentration; diluted from DMSO stock solution; DMSO final concentration) was added to the wells. After 30 minutes, 50 ul 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 WO 98/24806 PCT/US97/21636 PMN's total ECM counts). The results are presented in Table 2 below.
Table 2.
HNE K ECM Data Inlubition Plasma Levels (tgM) CE (nM) luM 5uM lhr 3hr 6 hr CE2048 0.2 CE2049 CE2050 1.84 CE2051 1.56 CE2052 0.37 CE2053 0.41 CE2054 0.29 CE2055 0.49 0.002 CE2056 0.98 CE2057 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 CE2077 0.15 CE2078 1.05 CE2079 34 CE2080 62 CE2082 53 CE2083 73 CE2084 133 CE2087 CE2088 66 0.801 0.755 CE2089 CE2090 2.7 CE2091 270 CE2092 6.3 CE2093 0.26 CE2094 CE2095 0.21 60.43 55.63 CE2096 0.79 CE2097 115 CE2098 CE2099 1.9 0.042 CE2100 0.069 57.63 56.56 0.064 WO 98/24806 WO 9824806PCTIUS97/21636 CE2101 0.64 44.582 51.18 1.238 1.369 1.042 CE2102 258 CE2103 12.4 CE2104 CE2105 0.72 CE2106 41 CE2107 17 CE2108 10.5 CE2109 126 CE21 10 0.13 CE21I11 20 0.69 1 CE2112 1.2 CE2113 39 1.835 0.909 CE2114 CE2115 1 CE2116 76 CE2117 586 CE2118 13.2 CE2119 7.7 CE2120 51 CE2121 28 CE2122 63 CE2123 15 CE2124 0.033 CE2125 0.4 0.011 CE2126 5 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 CE2135 17.5 0 37 CE2136 104 CE2137 558 CE2138 294 CE2139 41 CE2140 20O4 CE2141 64 0.005 CE2142 8.7 CE2143 11.5 CE2144 9.3 CE2145 0.-038 CE2146 67 CE2147 1600 CE2149 0.28 51.275 55.9 0 0 0 CE2151 59 14.25 -8.3 CE2152 0.24 4 CE2154 105.66.
WO 98/24806 WO 9824806PCTIUS97/21636 CE2155 CE2156 512 CE2157 1.4 9.96 13.42 3.81 CE2159 52 CE2 160 260 CE2161 0.082 25 CE2162 10.6 0.025 CE2163 0.75 54.7 64 0.316 CE2164 17 0.034 CE2165 2.6 0.067 CE2166 145 CE2168 0.15 CE2170 297 CE2171 0.64 CE2172 2.2 0.021 CE2173 6.5 35.9 47.1 CE2174 15.2 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 0.599 CE2180 44 CE2181 46 CE2182 54 CE2183 0.23 CE2184 8.2 30.5 32.4 0.57 CE2185 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 0.553 CE2195 CE2196 96 CE2197 4.8 CE2198 3.1 CE2200 13.7 CE2202 0.12 CE2203 79 0.004 CE2204 7.4 0.48 CE2205 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 124 WO 98/24806 WO 9824806PCTIUS97/21636 CE2213 0.14 0.19 CE2214 0.92 0 CE2215 163 1.16 0.83 0.63 CE2216 .4.1 32.1 37.15 0.77 0.47 0.25 CE2217 5.5 28.1 41.2 1.99 0.521 CE2218 1.6 30.5 33.15 CE2219 537 CE2220 CE2221 34 CE2223 0.93 34.15 36.15 CE2224 1 43.25 66.8 1.843 1.943 1.961 CE2225 8.2 30.85 43.45 CE2226 10.3 27.55 52.25 CE2227 40 1.276 0.74 0.962 CE2228 40 0.7 14 1.393 0.409 CE2229 9.5 31.25 48.2 CE2230 2.6 37.7 37.8 0 CE2231 16 1.226 0.787 0.531 CE2232 0.15 0.44 0.44 0.26 CE2233 41.6 54.7 55.4 0.07 0.065 0.036 CE2234 796 39.7 CE2235 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 0.5 0.29 CE2241 14 18.6 31.7 0.598 0.289 0.078 CE2242 27 1 29.4 40.7 CE2243 11 48 54.9 2.801 2.104 1.598 CE2244 78.5 CE2245 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 0.572 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 CE2250 6.9 27.4 48.6 CE2251 0.43 54.1 74.5 1.63 1.11 0.73 CE2252 1.9 45.4 65.2 0.114 0.188 0.1 CE2253 11 31.9 45.9 0.282 0.246 0.163 CE2254 2.4 57.2 58.4 1.751 1.575 2.316 CE2255 18 20.7 1 42 CE2256 16 24 47.8 0.9 0.33 0.2 CE2257 30 48.3 61.4 CE2258 1 3.7 42.9 38.1 1.624 1.5 1.212 CE2259 3.3 43 59.6 0.597 0.846 0.502 CE2260 0.39 68.3 59.7 3.532 3.053 1.894 CE2261 0.36 CE2262 CE2263 0.67 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 [l1 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 pil) for 5 minutes at 37 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 Twenty (20) Ill 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 and then optical density is measured at 405 nm: 0.2 M tris-HCl buffer (pH 8.0) 100 pi MNaCl 40 pl Distilled water 36 gl mM solution of a substrate 4 pl The Sample 20 p.
*N-Methylsuccinyl-Ala-Ala-Pro-Val-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 5-6 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).
112a Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.
Se..
17/05/99, IpIOSS1.pI12a.doc,I 2
Claims (20)
1. A compound selected from the group consisting of: (Benzyloxycarbonyl )-L-valyl-N-[I -(3-[5-(3,5-dimethylbenzyl)-1 ,2,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(3,5-dimethoxybenzyl)-1 ,2,4-oxadiazoly]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(3,5-ditrifluoromethylbenzyl)-1 ,2,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- 1 -(3-[5-(3-methyl benzyl ,2 ,4-oxad iazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(4-phenylbenzyl)-1 ,2,4- oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(3-phenylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-1 -(3-15-(3-phenoxybenzyl)-1 ,2,4- oxad iazolyl ]carbonyl)-2-(S)-methyl pro pyl]-L-prol inam ide, (Benzyloxycarbonyl)-L-valyl- N-[1 5-diphenylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(4-dimethylaminobenzyl)-1 ,2,4- oxad iazol yl ]carbonyl)-2-(S)-methyl pro pyl]-L-prol i nam ide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(biphenylmethine)-1 4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prol inamide, (Benzyloxycarbonyl)-L-valyl-N-[1 ,a-dimethyl-[3- o trifl uorom ethyl] benzyl)-1, 2,4-oxad iazolyl]carbonyl)-2-(S)-methyl propyl ]-L-prol inam ide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(lI-napthylmethylene)-1 ,2,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(2-napthylmethylene)-1 ,2,4-oxad iazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valy-N-[1 -(3-[5-(3,4-methylenedioxybenzyl)-1 4- oxadiazolylcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(3-pyridylmethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prol inamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(3-[5-(morpho i no-N -ethylene)- 1, 2,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(3-[5-(dimethylamino-N-ethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 (carbomethoxyethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1I-(3-[5-(adamantyl methylene)-1 ,2,4- oxadiazolyilcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, or (Benzyloxycarbonyl)-L- IT V 03/04101 ,ct10561 .claims,1 113 -114- valyl-N-[1 -(3-[5-(cyclohexylmethylene)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]- L-prol inmide.
2. A compound selected from the group consisting of: 3- Pyridylcarbonyl-L-valyl-N-[1 -(3-[5-(3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)- 2-(S )-methyl propyl]-L-prol inamide, Methyloxycarbonyl-L-valyl-N-[1 trifluoromethylbenzyl)-1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, I sopropyloxycarbonyl-L-valyl-N-[1 -(3-[5-(3-trifluoromethylbenzyl ,2,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, 4- Pyridylmethyleneoxycarbonyl-L-valyl-N-[1 -(3-[5-(3-trifluoromethylbenzyl)-1 ,2,4- oxadiazolyllcarbonyl )-2-(S)-methylpropyl]-L-prolinamide, or Methylsulfonyl-L-valyl-N- [1 -(3-[5-(3-trifluoromethylbenzyl)-1 ,2,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]-L- prol inam ide.
3. A compound of the formula: 0 wherein: X Xis Nand YisO0; R, 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-(C 5 C 6 )aryl; hydroxyl, amino, alkylamino or dialkylamino; cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C 5 -C 1 2 )aryl, (C 5 -C 12 )arylalkyl, (C 5 C 1 2 )arlalkenyl, fused (C 5 -C 1 2 )aryl-cycloalkyl, or alkyl-fused (C 5 -C 1 2 )-arylcycloalkyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkly, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, 'SN OO0304/O 1, cf1056 1. clai ms,1 114 -115- carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )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, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dial kylguanidi nyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', RNR'R"RO or -RC(O)NR'R" where R is alkyl or alkenyl, and R" and RO are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -Ci 2 )aryl, (C 5 C 12 )arylalkyl or (C5-C 12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 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, (C 5 -C 6 )aryl, -0-(C 5 -C 6 )aryl, arylcarboxamide, alkylthio or haloal kythio; A is a direct bond, -S(0) 2 -NH-S(0) 2 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, animoalkyl, dial kylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; 0 phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; 9~...:tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, 9 dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine *995 optionally substituted with alkyl or aryl; histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysi ne optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dial kylam inoal kyl, 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, 0 and S; and R 4 is H, alkyl, alkenyl, alkynyl; or cycloalkyl, alkylcycloalkyl, (C 5 -C 1 2 )aryl, (C 5 -C 12 )arylalkyl, fused (C 5 -C 12 )aryl-cycloalkyl or alkyl fused (C 5 -C 12 )aryl-cycloalkyl *optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally 03/04/O1,cfl 0561. claims,1 115 -116- substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or haloalkylthio.
4. The compound of claim 3: (Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5- (3,4-methylenedioxybenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(2-[5-methyl-1 13,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl- N-[1 -(2-[5-dimethylamino-1 ,3,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(2-[5-(3-methylbenzyl)-1, 3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl )-L-valyl- N-[1 -(2-[5-(3-methylbenzyl ,3,4-oxadiazolyl]carbonyl)-1 -methyl ethyll]-L-prol inam ide, (Benzyloxycarbonyl)-L-valyl-N-[1 -(2-[5-(3-trifluoromethylbenzyl)-1 ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (Benzyloxycarbonyl)-L-valyl- N-[1 -(2-[5-(4.-dimethylaminobenzyl)-1 ,3,4-oxad iazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, (Benzyloxycarbonyl)-L-valy-N-[1 -(2-[5-(lI-napthylmethylene)-1 ,3,4- oxadiazolyllcarbonyl)-2-(S)-methylpropyl]-L-prolinam ide, 3-Pyridylcarbonyl-L-valyl-N- [1 ethyl benzyl)-1, ,3,4-oxad iazol yl ]carbonyl )-2-(S)-methyl propyl]-L- prolinamide, Methyloxycarbonyl-L-valyl-N-[1 -(2-[5-(3-methylbenzyl)-1 ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, lsopropyloxycarbonyl-L-valyl- I -(2-[5-(3-methyl benzyl ,3,4-oxad iazolyl]carbonyl)-2-(S)-methylpropyl]-L- .7 prolinamide, 4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1 -(3-[5-(3-methylbenzyl)-1 ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, Methylsulfonyl-L-valyl-N-[1 (3-[5-(3-methylbenzyl)-1, 3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, Phenylsulfonyl-L-valyl-N-t1 -(2-15-(3-methylbenzyl)-I ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, Methylsulfonyl-L-valyl-N-[1 ,c-dimethylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide, or Methylsulfonyl-L-valyl-N-[I -(3-[5-tert-butyl-1 ,3,4-oxadiazolyl]carbonyl)- 2-(S)-methylpropyl]-L-prol inamide. A compound of the formula: 0e 0 030*00 051cai 1 wherein: X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, 0 and S, and optionally subsituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoaLkyl, dialkylamnino, alkyl, alkenyl, alkcynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that at least one of X or Y is N; R, is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, io hydroxyl, haloalkyl, amino, alkylamino, dialkylamino, alkylenedioxy, alkoxy, haloalkoxy, carboxyl, carboallcoxy, alkylcarboxamide, arylcarboxamide or C 6 )aryl; hydroxyl, amino, alkylamnino or dialkylamino;_cycloalkyl, cycloalkenyl, alkylcycloalkyl, alcenylcycloalkyl, alcylcycloalkenyl, (Cs-C 1 2 )aryl, (C5-C 12 )arylallcyl, (C 5 -C 12 )arylalkenyl, fused (CS-C 12 )aryl-cycloalkyl or alkyl-flised (CS-C 12 arylcycloalicyl optionally comprising 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, nitro, hydroxyL, haloalkcyl, amino, aminoalkyl, diallcylamino, ailcyl, alcenyl, alcylenedioxy, alkcynyl,'alkoxy, haloalkoxy, carboxyl, carboalkcoxy, alkylcarboxamide, (CS-C 6 )aryl, -0-(C5-C: 6 )aryl, arylcarboxamide, alkylthio or haloalkylthio; ZQ.. R 2 and R 3 are independently or together H; alkyl or alkenyl optionally :::substituted with 1-3 halo, hydroxyl, thio, alkcylthio, amino, alkylamino, dialkcylamnino, :alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR!, :RCOOR!, -RNR'R"R 0 or -RC(O)NR'R" where R is alkyl or alkenyl, and R" and R* :::are independently HL alkyl, alkenyt, cycloalkyl or (C5-Q)aryl; or cycloalicyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkcyl-thioaryl, ailcyl-aminoaryl, 1 2 )arYl, (C 5 -C 12 )arylalkyl or (C 5 -C 12 )arylalkeny.1 optionally comprising 1-4 ::heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, *:keto, nitro, hydiroxyl, haloalkyl, amino, amninoalkyl, dialkylamino, amaidine, ::alkylamiddine, dialkylamnidifle, alkyl, alkenyl, alkyleniedioxy, alkynyl, alkoxy, haloaLkoxy, carboxyl, carboalkoxy, alicylcarboxarnide, (Cs-C 6 )aryl, -0-(CS-C 6 )ar-yl, .)arylcarboxamide, alkylthio or hatoalk-ylthio; B is -S(0) 2 Or and R 6 is of the formnula: CU -117- R13 13 -R 13 R4 N- y N R'3 R 1 R 14 R4 N 0 R13 0 IS R1 0RO R 13 N' R' R!2 or N N N N RI N 3R 14 NR,3 R) 4 y 4 0 0 0 (IV) MV (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, dialkcylamino, alkylguanidinyl, diallcylguanidinyl, guanidinyl, or axnidylguanidine; -RCOR', RCOOR!, -RNR!R"R 0 or -RC(O)NRR" where R is alkcyl or alikenyl, and and W 0 are independently H, alkyl, alkenyl, cycloalkcyl or (Cs-C6)aryl; or cycloalkyl, **alkcylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-amninoaryl, (CS-Ct 2 )arYl, (C 5 -C 12 )arylalkCyl or (C 5 -C1 2 )arylalkenyl optionally comprising 1-4 heteroatonis selected fr-om N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalcyl, diallcylamino,amiddine, :alkcylamidine, dialkylamidine, alkyl, ailcenyl, alkylenedioxy, alcynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, ailcylcarboxamide, (Cs-C 6 )aryl, -O-(CS-C 6 )aryl, *.arylcarboxamide, alkylthio or haloalkylthio; R 13 is H, alkyl, halo, atkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, ~::amino, alkylamino, diallcylamiflo, or aryl, arylalkyl, fused aryl fused aryl-cycloalkyl or cycloalkyl optionally comprising I or more heteroatoms selected from 0, N and S, and optionally substituted with halo or alkyl; R1 4 is H, alkyl, alkenyl, amino, alkcylamino, diaLkylamino; or cycloalkyl, aryl, arylalkyl, aryloxycarboxamide, arylatkyloxycarboxamide or fused arylcycloalkyl INC -119- optionally comprising 1 or more heteratoms selected from N, 0 and S and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylcarboxamide, arylalkylcarboxamide, alkylthio or haloalkylthio; R 15 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 0, N, or S; and W is 0 or S; or C or N is optionally substituted with alkyl, aryl.
6. The compound of claim 5: (2S,5S)-5-Amino-I ,2,4,5,6,7- hexahydroazepino-[3,2, I ]-indole-4-one-carbonyl-N-[l -(2-[5-(3-methybenzyl ,3,4- oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide; 2-Oxo-5-phenyl-I ,4- benzodiazepine-N-[I -(2-[5-(3-methylbenzyl 3, 4-oxadiazolyl]carbonyl)-2-(S)- methylpropyllacetamide; 2-Oxo-5-(4-chlorophenyl)-I ,4-benzodiazepine-N-[I butyl- 1, 3,4-oxad iazol yl ]carbonyl)-2-(S)-methyl pro pyl]acetam ide; 2-Oxo-5-(4-trifl uoromethylphenyl ,4-benzodiazepine-N-[I methylbenzyl)- 3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; R, ,4-benzodiazepine-N-[I -(2-[5-(3-methylbenzyl ,3,4- 20 oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide; I ,4-(2'-chlorobenzodiazepine)-N-[I -(2-[5-(3-methylbenzyl)- 3,4-oxadiazolyllcarbonyl 2-(R,S)-methylpropyl]acetamide; 2-Oxo-5-phenyl-1 ,4-(2'-dimethylaminobenzodiazepine)-N-[l methylbenzyl)- 3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; S)-3- Amino-2-oxo-5-(4-chlorophenyl ,4-benzodiazepine-N-[l -(2-[5-(3-methybenzyl)-1 ,3,4- oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide; S)-3-amino-2-oxo-5-(2- chlorophenyl)-l ,4-(2'-chlorobenzodiazepine)-N-[1 -(2-[5-(3-methylbenzyl)-l ,3,4- oxadiazolyl]carbonyl R, S)-methylpropyl]acetamide; S)-3-benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-I chlorobenzodiazepine)-N-[1 -(2-[5-(3-methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2- S)-methylpropyl]acetamide; S)-Amino-2-oxo-5-(2-chlorophenyl)-I ,4-(2'chlorobenzodiazepine)-N-[1 (2-[5-(3-methylbenzyl 3,4-oxadiazolyl]carbonyl-2-(R, 5)-methylpropyllacetamide; 3- p p. p. .p N 1~ 0< 03/0410011010561. claims.1 119 -120- S)-Ami no-2-oxo-5-(2-pyridyl )-1,4-benzodiazepine-N-[1 hyl benzyl 1, 3,4-oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide; 2-Oxo-5-(2-pyridyl)-1,4-benzodiazepi ne-N-[ 1 -(2-[5-(3-methyl benzyl ,3,4- oxad jazolyllcarbonyl )-2-(S)-methyl propyllacetam ide; 2-Oxo-5-(4-pi peridi nyl ,4- benzodiazepine-N-[1 -(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide; S)-Amino-2-oxo-5-methyl-1 ,4-benzodiazepine-N-[1 [5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R, S)-methylpropyl]acetamide; 2- Oxo-5-(3, 4-methylendioxyphenyl)-1 ,4-benzodiazepine-N-[1 -(2-[5-(3-methylbenzyl 1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; methyl-I 3'-methylenedioxy)-benzodiazepine)-N-[1 -(2-[5-(3-methybenzyl)-1, 3,4- oxadiazolyllcarbonyl R, S)-methylpropyl]acetamide; or 0 s o* .0.0* 0 3 -'N C N 03104101 ,cf10561.claims, 120 3-(R,S)-Axnino-2-oxo-5-methyl- 1 thiophenodiazepine)-N-[ I -(2-15-(3-methybenzyl)- 1,3 ,4.-oxadiazolyilcarbonyl)- 2-(S)-methylpropyl]aoetamide.
7. A compound of the formula: z R 3 N-X R? 6 -B-N R 0 wherein X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (CS-C 6 )aryl, arylalkyl or arylailcenyl optionally comprising 1-3 heteroatoms selected from N, 0 and S, and optionally subsituted with halo, cyano, ni tro, hydroxyl, haloalkyl, amino, aminoallcyl, io dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that at least one of X or Y is N; R, is alkcyl, alkenyl or alkynyl optionally substituted with I or more, preferably 1-3, halo, hydroxyl, cyano, nitro, haloallcyl, alcylamino, diallcylamino, alkoxy, haloalkoxy, carboxyl, carboallcoxy, alkylcarboxamide, arylcarboxamide or C, 6 )aryl; hydroxyl, amino, alkylamnino or dialkcylamino; or cycloatkyl, alkylcycloalkyl, *:.alkenylcycloalkyl, cycloalkenyl, ailcylcycloalkenyl, alkenylcycloalkenyl, (Cs-C 2 )aryl,- (C5-C12)arYlalkyl, (C 5 -Cu2)arylalkenyI, fused (C 5 -C 12 )aryt-cycloalkyl or alkyl fused 5 -C 12 )aryl-cycolalkyl. optionally comprising 1-4 heteroatomns selected from N, 0 :and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalicyl, ammno, aminoalkyl, diallcylamidno, alcyL alkenyl, alkcylenedioxy, alkynyl, atkoxy, haloalkoxy, :carboxyt, carboalkoxy, alkylcarboxamide, (C5-C 6 )aryt, -O-(C5-C6)aryl, arylcarboxamide, allcylthio or haloalkylthio; R 2 and R 3 are independently or together H; alkyl or alkenyl optionally .ofS substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkcylamino, dialkylamino, ::aikylguanidinyl, dialkcylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', RCOOR!, -RNR'R"R* or -RC(0)NRR" where R is alkcyl or alkenyl, and R" and R* are independently H, alkyl, alkenyl, cycloalkyl or (CS-C 6 )aryl; or cycloalkyl, alkylcycloalkyl, atkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (q5-C 12 )arYl, (C 5 -C 12 )arYlalkYl or (CS-C 12 )arylalkenyl optionally comprising 1-4 VI-121- heteroatoms selected from N, 0 and S, -and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, diallcylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkcenyl, alkylenedioxy, aLkynyl, alkoxy, haloalkoxy, carboxyl, carboatkoxy, alkylcarboxaniide, (Cs-C 6 )aryl, -0-(CS-C6)aryl, arylcarboxamide, alkylthio or haloallcylthio; B is -S(0) 2 or and R 6 is of formula (1) R 1 4 -A-D~ 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, aminoalcyl, diallcylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, allcylthio or haloalkylthio; phenylalanine, indoline-2-carboxylic acid teftrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialicylamnino, alkoxyl, haloalkoxy, carbonyl, carboalkoxy, alkcylcarboxamide, arylcarboxamide, allcylthio or haloalkythio; tryptophan, valine, norvaline, norleucine, octahydroindole-2-carboxyfic acid; or lysine optionally substituted at the side chain nitrogen with alkyL, alkenyl, alkcynyl, alkoxyalicyl, alkylthioalkyl, allcylaminoalcyl, dialkylaninoalcyl, carboxyalkyl. or alkoxycarbonylalkyl; or cycloalkyl, cycloalkylaicyl, fused aryl-cycloalkyl or alkcyl fused aryl-cycloalkyl optionally comprising I or more heteratoms selected from N, 0 00: and S; A is a direct bond, -S(0) 2 or and R 14 is H, alkyl, alkenyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising I or more heteratoms selected from N, 0 and S, and optionally substituted with alicyl, halo, -122- -123- alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio, or R 6 is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl.
8. The compound of claim 7: Benzyloxycarbonyl-L-valyl-(l 2,3,4- tetrahydroisoquinoline)-3-N-[l -(2-[5-(3-methylbenzyl )-1,3,4-oxadiazolyl] carbonyl S)-methylpropyl]amide.
9. A compound of the formula: R, 2 0 R 2 R3 y Rt wherein X and Y are independently 0, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (CS-C 6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatorns selected from N, 0 and S, and optionally subsituted with halo, cyano, nitro, hydroxyl, haloallcyL, amino, aminoalkyl, dialkylamdno, alkyl, alkenyl, ailcynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or allcylthio; provided that at least one of X or Y *is N; R, is alkyl, alkenyl or alkynyl optionally substituted with I or more, preferably 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkcylarnno, dialkylamino, alkoxy, Shaloatkoxy, carboxyl, carboalkoxy, alkcylcarboxamide, arylcarboxamide or 0Cs C 6 )aryt; hydroxyl, amnino, alkylamnino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkcylcycloalkenyl, alkcenylcycloalkenyl, (C5-C 12 )aryt, S S (Cs-C, 2 )arylatkyl, (C 5 -Cj 2 )arylatkeflyl, fused (C5-C12)aryl-cycloatkyl or alkyl fused (C 5 -C 12 )aryI-cycolalkyI optionally comprising 1-4 heteroatoms selected from N, 0 a nd S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alcenyl, alkylenedioxy, alkcynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (Cs-C, 6 )ar-yl, -O-{Cs-C 6 )aryl, arylcarboxamide, allcylthio or haloallcylthio; R 2 and R 3 are independently or together H; alkcyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alcylamino, dialkylamino, alcylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR!, RCOOR!, -RNR!R"R! or -RC(O)NR!R" where R is alkyl or alkenyl, and R" and R* are independently H, alkyl, alkenyl, cycloalcyl Or (C5-C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkcyl-thioar yl, alicyl-amninoaryl, 1 2 )arYt, (C5-C 12 )arylatkyl or (Cs-C, 2 )arylalkenyl optionally comprisfinig 1-4 heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoallcyl, dialkcylaniino, amidine, alkylamidine, dialkylamidine, alkyl, alcenyl, alkylenedioxy, allcynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alcylcarboxamide, (CS-Q)aryl, -0-(Cs-C 6 )aryl, arylcarboxamide, alkyithia or haloalkylthio; R' 2 and R! 3 are independently or together H; ailkyl or alcenyl optionally substituted with 1-3 halo, hydroxyl, tNo, alkylthio, amino, alkylamnino, dialkylamnino, aklguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR!, RCOOR!, -RNR!R"R! or -RC(0)NRTR" where R is alkyl. or alkenyl, and R" and R! are independently H, alkyl, alkenyl, cycloalcyl or (Cs-C 6 )aryl; or cycloalkyl, alkylcycloalkyl, atkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alcyl-aminoaryl, 5 -C12)arYl, (C 5 -C12)arYlalkcYl or (Cs-C 12 )arylalkenyl optionally comprising 1-4 :::heteroatoms selected from N, 0 and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyL, haloallcyl, amino, amninoallcyl, dialkylamino,amidine, ~:alkylam~idine, dialkylamidine, alkyl, atkenyl, alkylenedioxy, alkcynyl, alkoxy, ::haloatkoxy, carboxyl, carboalkoxy, alcylcarboxarnide, (C5-C 6 )aryl, -0-(Cs-C. 6 )aryl, arylcarboxamide, allkylthio or haloalkylthio; 5.:RR 1 R1 2 and E together form a monocyclic or bicyclic ring comprising 5-10 Satoms selected from C, N, S and 0; said ring containing I or more keto groups; and optionally substituted with halo, cyano, nitro, haloalkyl, amino, amninoaflcyl, dialkylamino, alkyl, alkenyl, alkynyl, atkoxy, haloalkoxy, carboxyl, carboatkoxy, alkylcarboxamide, alkylthio, haloalkylthio; cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, (CS-C 12 )arYl, (C 5 -C 12 )arylatkyl, ((C.5-C 12 )arylallcyl)OC(0)NH- or 124 (CS-C 12 )arylaikenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide 0, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialicylamino, alkyl, alkenyl, alkcytiyl, alkoxy, haloalkoxy, carboxyl, carboallcoxy, -C(O)O(allcyl), -C(O)(alkyl), alylcarboxainide, alkylthio or haloalkylthio. A compound of claim 9, wherein R, 1 R 12 and E form a ring structure of formula or (la): v 13W R 14 -A 1 A 00 (1a) wherein A is a direct bond, -S(O) 2 -OC(O)NH-, OC(O)- or to VI, V2, V 3 and V 4 are independently C or N; where V 3 is C; R 13 is K~ alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino or diallcylamino; or aryl, aryl alkyl, cycloalkyl, .:.alkylcycloalkyl, fused aryl-cycloallcyl or alkyl fused aryl-cycloalkcyl optionally :..comprising I or more heteroatoms selected from 0, N and S, and optionally substituted with halo or alkyl; or RD is absent; R 14 is H, alkyl. alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, ::cycloalkyl, alkylcycloalkyl, fused aryi-cycloallcyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, 0 and S, and optionally O:V* substituted with alkyl, halo, alkoxy, amino, alkylarnino, dialkcylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamiide, axyl, arylailcyl, Sarylcarboxamide, alkylthio or haloalkylthio; and W 1 W 2 and W 3 are independently selected from N optionally substituted with alkyl; C, SandO0.
11. A compound of claim 10, wherein R, RI 2 and E together form a ring structure of formula
12. A compound of claim 11, wherein R 14 -A is benzyloxycarboxamide, H 2 N- or H. -125 rIQ
13. A compound of claim 12, wherein R 13 is H or halo
14. A compound of claim 13, wherein VI, V 2 and V 3 are C. A compound of claim 14, wherein V 4 is N.
16. The compound of claim 2-[(6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro- I -pyrimidinyl]-N-[ I (3 -methylbenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-{S)-methylpropyl~acetamide; 2-[5-Amino-6-oxo-2-phenyl-1I,6-dihydro- 1-pyrimidinyl]-N-[ (3-methylbenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)2-(S )-methylpropyl]acetamide; t0 2-[5-Amino-6-oxo-2-(4-fluorophenyl )-1I,6-.dihydro- I-pyrimidinyl] -N- [1 -(2-[5-(3-pyridyl)- 1,3,4-oxadiazolyl]carbonyl)2-(S)- methyipropyijacetamnide; 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-I-pyrimidinyl 3-N- [1 -(2-[5-(3-methylbeazyl)- 1,3,4-oxadiazolyl]carbonyl)2-(R)- methyipropyllacetamide; 2.{5-Amino-6-oxo-2-(4-fluorophenyl)-1 ,6-dihydro-I-pyrimidinyl]-N- [I .{2-(5-phenyl-l13,4-oxadiazolyl]carbonyl)2(S)-methylpropyl]acetamidde; 2-[5-(Benzyloxycarbofl)amfiflo-6-oxo-2-(4-fluorophel)- 1,6- M.dihydro-lI-pyrimidinyl]-N-( I-(2-[5-phenyl- 1,3,4-oxadiazolyljcarbonyl)2-(S)- methylpropyl]acetamide; 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-lI-pyrimidinyl]-N- [1.-(2-[5-(4-methoxypheflyl)- 1,3 ,4-axadiazolyl]carbonyl)2-(S)- methylpropyl]acetaflide; *4606:2-[5-Amino-6-oxo-2-(4-fluorophelyl)- I ,6-dihydro- 1-pyiimidinyl]-N- (I -{2-[5-benzyl-l ,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetaflude; or 2-(5-Amno-6-oxo-2-4-fluorophenfl)- I ,6-dihydro- I -pyrimidinyl]-N- [1I -methylbenzyl)-l ,3 ,4-oxadiazolyllcarbonyl)2-(S)- methylpropyllacetamide.
17. A compound of claim 12, wherein R, is isubstituted arylalkyl or alkyl fused aryl-cycloalkyl, wherein the aryl or fused aryl-cycloalkyl group is optionally substituted. N -126- T-
18. A compound of claim 17, wherein R, is (ct,ca)-dimethylbenzyl optionally substituted with alkyl, alkoxy or hydroxy.
19. A compound of claim 18, wherein R 13 is H or halo. A compound of claim 19, wherein R 14 -A-benzyloxycarboxamide, H 2 N- or H.
21. The compound of claim -Aniino-6-oxo-2-(4-fluoropheflyl)- 1,6-dihydro- I-pyrimidinyl]-N- [I (2-[5-(c,a-dimnethylbenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)2-(S)- methyipropyllacetamide; to 2-[5-Amino-6-oxo-2-(4-fluorophely1)-1I,6-dihydro- 1-pyrimidinyl]-N- (I -{2-[5-(a,a-dimethyl-3 -methylbenzyl)-l ,3 ,4-oxadiazolyl]carbonyl)2-(S)- methyipropyllacetamide; 2-[5-Amifl0-6-oxo-2-(4-fluoropheflyI)-1 ,6-dihydro-1-pyrimidinyl]-N- [1 .{2-[5-(ct,a-dimethyl-3 ,4-dihydroxybenzyl)-1I,3,4-oxadiazolyllcarbonyl)2- (S)-methylpropyflacetaflide 2-[5-Amino-6-oxo-2-phely1- I ,6-dihydro-l -pyrimidinyl-N-[ I (oa-dimethylbelzYl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methyipropyllacetamide; 2-5Aio6oo2(-loohnl)16dhdolprmdnt- 1- 1,3,4-oxadiazolyl]carboflyl)-2-{R)- methylpropylla-etamide 2[6-Oxo2-(4-fluorophel)- ,6-dihydro-l -pyrxmidinyl]-N-[ 1 (a,cz-dimethylbeflzyl)-l ,3 ,4-oxadiazolylIcarboflyl)-2-(S)- methyipropyllacetamnide; 2-[6-Oxo-2-phenyl-l ,6-dihydro-l-pyrimidiny]-N-[-(2-[5-(L,- dimethylbenzyl}-l ,3 ,4-oxadiazoly)carbonly)-2(S)-methypropy1)acetamifde; or 24[5 (Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophelyl)- 1,6- dihydro-l1-pyrimlidinyl]-N4 1 -(2-[5-(aC-dimethylbeflzyl)- 1,3,4- :oxadiazolyI~carbony)2(S)-methylpropylactride. *::3022. A compound of claim 17, wherein R, is (cL,c)-dImethyl-3, 4 methylenedioxybenzyl
23. The compound of claim 22: 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6- dihydro- I -pyrimidinyll-N-( 1 -(2-[5-(cax-dimethyl-3 ,4-methylenedioxybenzyl)- 4. 1,3 ,4-oxadiazolyl1Carbonyl)2-(S)-mthylpropyl] acetarnide.
127- 24. A compound of claim 11, wherein R, is alkyl. A compound of claim 24, wherein R, is methyl, isopropyl, isobutyl, n-butyl or tert-butyl. 26. A compound of claim 25, wherein R 13 is H or halo. 27. A compound of claim 26, wherein R 14 is benzyloxycarboxamide, H 2 N- or H. 28. The compound of claim 27: 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1,6-dihydro-lI-pyrimidinyl]-N- [1 -(2-[5-tert-butyl- 1,3 ,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl~acetamnide; 2-[5-(Benzyloxycarbonyl)amino-6-oxo-2(4-fluorophenyl)- 1,6- dihydro- I -pyrimidinyll-N-[ I -(2-[5-tert-butyl- I ,3,4-oxadiazolyllcarbonyl)2- (S)-methylpropyl]acetamide; 2-[5-Amino-6-oxo-2-(4-fluoropheflyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- 1,3 ,4-oxadiazolyljcarbonyl)2-{S)-methylpropyl]acetamide; 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1I,6-dihydro- I-pyrimidinyl]-N- [1 -2-[5-isopropyl- 1,3 ,4-oxadiazolyllcarbonyl)2-(S)-methylpropyl]acetamide; 2-[5-Amino-6-oxo-2-(4-fluoropheflyl)- I ,6-dihydro-1 -pyrimidinyl]-N- I1 -butyl- 1 ,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; 2-[5-Arnino-6-oxo-2-phelyI- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 tert-butyl- 1,3 ,4-oxadiazolyl]Carbonyl)2-(S)-methylpropy]acetamfide; 2-[6-oxo-2-(4-fluorophefl)- 1,6-dihydro-lI-pyrimidinyl]-N-[ ::(ter-t-butyl)- I ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamiide; 2-[6-Oxo-2-(4-fluoropheflyl)- I,6-dihydro-l -pyrimidinyl]-N-[ tert-butyl- 1,3 ,4-oxadiazolyl]carbonl)-2-(R)-methylpropy1]acetaIfide; 2-[5-Ainino-6-oxo-2-pheflyl- 1,6-dihydro- 1-pyrimidinyl]-N-[ butyl-1I,3,4-oxadiazolyl~carbonyl)-2-(R)-methylpropy1]acetamide; 2.{6-Oxo-2-phenyt- 1,6-dihydro-lI -pyriinidinyl]-N-[ I 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)-mthylpropyl]acetarilide; ~2-[6-Oxo-2-pheflyl-1I,6-dihydro-l -pyrimi dinyl]-N-[ 1-(2-[5-tert-butyl- 1,3 ,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyllacetamide; -Amino-6-oxo-2-(4-fluorophenyl)- 1,6-ciihydro-lt -pyrimidinyl]-N-[ 1 1,3 ,4-oxadiazolyl]carbonyl)-2-(RS)-methylpropyljacetarmide; -Axino-6-oxo-2-phenyl- I ,6-dihydro- I -pyrimidinyl]-N-( 1 -tent- butyl- 1,3 ,4-oxadiazolylcarbonyl)-2-RS)-methylpropyt]aCetmiide; -128- 2-(6-Oxo-2-pheflyl)- I ,6-dihydro- I -pyrimidinyl] I 1 ,3,4-oxadiazoyl]carbolyl)-2-(,S-methypropyI]acetarlude; or 2-[5-Amino-6-oxo-2-(4-fluorophenyI)- 1,6-dihydro-I -pyrimidinyl]-N- (I -(2-[5-(tert-butyl)- 1,3,4-oxadiazolyl]carbonyl)-2-(R)- methylpropyl]acetanide. 29. A compound of claim 11, wherein A is -S(0) 2 or -S(O) 2 -NH-. A compound of claim 29, wherein R 14 is alkyl. 31. A compound of claim 30, wherein R, is aryl or arylalkyl optionally substituted with alkyl. 32. The compound of claim 31: 2-[5-(Methylsulfonyl)amino-6-oxo-2-(4- fluorophenyl)-1I,6-dihydro-lI-pyrimidinyl] 1-(2[5 -methylb enzyl)- 1,3,4- oxadiazolyl]carbonyl)2-()-methylpropyI]acetaflllde. 33. A compound of claim 14, wherein V 4 is C. 34. A compound of claim 11, wherein V 4 is N. A compound of claim 14, wherein R, is alkylcycloalkyl. 36. A compound of claim 35, wherein R, is methylcyclopropyl. 37. A compound of claim 36, wheren R13 is H or halo. 38. A compound of claim 37, wherein R 14 is benzyloxycarboxamide, H 2 N- or H. 39. The compound of claim 38: 2: 2-[5-Amino-6-oxo-2-(4-fl~uorophel)-j ,6-dihydro-l -pyrimidinyl]-N- [10-5(-ehlylpoy)134oaizllcroy)2() methylpropyl]acetamide; ~2-I5-Amino-6-oxo-2-pheflyl-1 ,6-dihydro-l-pyrimidinyl]-N-[ 1- methiylcyclopropyl)- 1,3,4-oxadiazoly]carbony)-2-(S)-methylpropy1]acetarflide; 2-[6-Oxo-2-(4-fluorophel)- 1 ,6-dihydro- I -pyrimidinyl]-N-[ 1 -(1I methylcyclopropyl)- 1 ,3,4-oxadiazolyl]carbofl)-2-(S)-methylpropylI acetalide; or 2-[6-Oxo-2-pheflyl- 1 ,6-dihydro- I -pyrimidinyl]-N-[ 1 1- methylcyclopropyl)-l ,3,4-oxadiazolyllcarbony)-2-(S) -methylpropylacetaflde. The compound of claim I I 2-[5-Amino-6-oxo-2-(4-fluoropheny1)-1,6-dihydro-I -pyridill-N- I (2-[5-(3-methylbenzyl)-l ,3,4-oxadiazolyl)carbonyl)-2-(S)- methylpropyllacetamide; L -129- ci. 2-[6-Oxo-2-phenyl- I ,6-dihydro- I -pyridinyl]-N-[ I -ert-butyl- 1,3 ,4-oxadiazolyl]carbo11yl)-2-(S)-methyIpropyI~acetamide; 2-[6-.Oxo-2-phcflyl- I ,6-dihydro- I -pyridinyl]-N-[ 1 dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetailide; or 2-[5-Amnino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- I -pyridinylil-N-[ I (24[5-(3 ,4-methylenedioxybenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyt]acetamide. 41. A compound of claim 11, wherein Ri 1 R 12 and E form a ring of formula (la). 42. A compound of claim 41, wherein W is S. 43. The compound of claim 42: 24[5-Axnino-6-oxo-2-thienyl-1I,6-dihydro- 1- pyrimidinyl]-N-[ 1 .2-[5-(3-methylbenzyl)- 1,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyllacetamide. 44. A compound of claim 11, wherein V 2 is N. 45. A compound of claim 44, wherein V, and V 3 are C, and V 4 is N. 46. A compound of claim 45, wherein R 14 -A is H or H 2 N-. 47. The compound of claim 46: [5-(3-methylbenzyl)- 1,3 ,4-oxadiazolylhjcarbonyl)-2-(S)- methylpropyllacetaflude; 2-5-Amino-6-ox0-2-(3-pyridyl)- 1,6-dihydro-l -pyrirnidinyl]-N-[I -(24(5- tert-butyl-l ,3,4-axadiazolyl]Carboflyl)-2-(S)-methylpropy1]acetamIde; or ~2-[5-Arnino-6-oxo-2-(3-pyridyl)- 1,6-dihydro-lI-pyriidinyl]-N-[ dimiethylbenzyl)-1 ,3,4-oxad~iazolyl]carbonyl)-2-(S)-methylpropyl]acetaflllde. 48. A compound of claim 9, wherein R, 1 R 12 and E form a ring of formula N R 1 4 -G isS O 0 rC n is 0, 1 or 2; -130- R 13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamidno, dialkylamino; or aryl, arylalkyl, cycloallcyl, alkylcycloalcyL 1 fused aryl-cycloalkyl or alkyl fused aryl-cycloalcyl optionally comprising I or more heteroatoms selected from 0, N and S, and optionally substituted with halo or alkyl; R 14 is H, ailkyl, alkenyl, amino, alkylamino, diallcylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkcyl fused aryl-cycloalkyl optionally comprising I or more heteratoms selected from N, 0 and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamnino, carboxy, alkenyl, alkcynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloallcylthio; and G is -OC(O)NH-, -S(0) 2 -NH- or a direct bond. 49. A compound of claim 9, wherein R, 1 R 12 and E form a ring of formulas (VI) or (Via): 906 0* S 0 0 66604 (vi) (Va) wherein R 13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkcylthio, amino, alkylam-ino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl- cycloaLkyl or alkyl fused aryl-cycloalkyl optionally comprising I or more heteroatoms selected from 0, N and S, and optionally substituted with halo or alkyl; and R 1 4 is H, alkyl, alcenyl, amino, alkylamnino, dialkylamino; or aryl, arylaikyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkcyl fused aryl-cycloalkyl optionally comprising I or more heteratoms selected from N, 0 and S, and optionally ubstituted with alkyl, halo, alkoxy, amino, alicylamino, dialkylamino, carboxy, -131- Z 3I
132- alkenyl, alkynyl, haloalkoxy, carboalkoxy, arylalkyloxycarbonyl, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio. The compound of claim 49: 4-[1 -(3,4-Ethylenedioxybenzyl)-3-(R)- benzylpiperazine-2,5-dione-N-[1 -(2-[5-(3-methylbenzyl ,3,4-oxadiazolyl]carbonyl)2- ethyl propyll]acetam ide; or S)-[6-(Methylene-4-pyridyl) N-[1 methylbenzyl)-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide. 51. A compound of claim 9, wherein R 11 R 12 and E form a ring of formula (IX) or (IXa): y-U W V (MC (IXa) 0 wherein *26 0). O3IO4IO1cf1O561.claims, 132 U, V, W and Y are independently or together N, C, N(R 13 where R 13 is H, ailkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, diallcylamino; or aryl, arylalkyl, cycloalcyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalcyl optionally comprising I or more heteroatoms selected from 0, N and S, and optionally substituted with halo or alkyl; N(R 14 where R 1 4 is H, alkyl, alkenyl, or aryl, arylalkyl, cycloallcyl, alkylcycloalkyl, fused aryl-cycloakl or alkyl fused aryl-cycloalcyl optionally comprising 1 or more heteratoms selected from N, 0 and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkcynyl, haloalkcoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C(R, 6 )(R 17 where R 16 and R 1 7 are independently or together H, alkyl, alkylthio, alkylthioalkyl; (CH 2 )mC(O)OR or -(CH 2 )mC(0)NRR' where m is I to 6 and R and R! are independently or together H or alkcyl; or aryl, arylalkyL, cycloalkyl, allcylcycloalkcyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide 0 and optionally substituted with amino, alcylamino, dialkylamino,_guanidine, carboalkoxy, keto, hydroxy, alkyl, haloalkyl, alkylthio, alcylguanidine, dialkylguanidine or amidine; or together form a cyclic ring structure comprising 4-8 atoms selected from C, N, 0 and S. 52. A compound of claim 5 1: 4-(S)-(2-lsobutyl)-2,5 -imidazolidinedione-N-[ 1 -(cz,a- di methylbenzyl)- 1,3 ,4-oxadi azolyl]carbonyl)2 -(S)-methylpropyll acetamnide; 4-(S)-(2-lsobutyl)-2 5 -LfldazolIidifledio ne-N-[ 1 methylbenzyl)- 1,3 ,4-oxadiazolyllcarbonyl)-2-(S)-methylpropyl]acetaiflide; 4-(R)-lsopropyl-2,5 -im idazolidifledione-N-[ 1 -Qxa- 133 N L/ <N 1 T -134 d im ethyl benzyl)-1, ,3,4-oxad iazolyl]carbonyl)-2-(S)-methyl propyl ]acetam ide; 4-(R)-Isopropyl-2,5-imidazolidinedione-N-[1 -(2-[5-(3-methylbenzyl)-1 ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; 4-(S)-(2-Isobutyl)-2, 5-imidazolidinedione-N-[1 -(2-[5-tert-butyl-1 ,3,4- oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; 4-(R)-Isopropyl-2,5-imidazolidinedione-N-[ 1 -(2-L5-tert-butyl-1 ,3,4- oxad iazolyl]carbonyl )-2-(S)-methylpropyl]acetamide; S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1 methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; S)-Phenyl-2, 5-imidazolidinedione-N-[ 1 -(3-[5-(3-trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl )-2-(S)-methylpropyl]acetamide; S)-(4-pyri dyl)-4-(R, S)-N -succi n imidyl 5-i midazol id ined ione-N 1 [5-(3-methylbenzyl ,3,4-oxadiazolyI]carbonyI)-2-(S)-methylpropyl]acetamide; S)-(2-Pyridyl)-4-(R, S)-methyl]-2, 5-imidazolidinedione-N-[1 methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; 4,4-Diphenyl-2, 5-imidazolidinedione-N-[1 -(2-[5-(3-methylbenzyl)-1 ,3,4- oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; 4,4-Diphenyl-2, imidazolidinedione-N-[1 -(2-15-(3,4-methylenedioxybenzyl ,3,4- oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide; .4-(R)-(3-Indolylmethyl)-2, 5-imidazolidinedione-N-[1 -(2-[5-tert-butyl-1 ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; 4-(R)-(3-Indolylmethyl)-2, 5-imidazolidinedione-N-[1 a- dm ethyl benzyl)-1, ,3,4-oxad iazolyl]carbonyl)-2 -(S)-methyl propyl ]acetam ide; 1 -(N-Morphol inoethyl)-5-( R)-benzyl-2,4-i midazolidinedione-N-[1 25 methyl benzy 1,3,4-oxad iazolyl ]carbonyl)2-(R, S)-methyl propyl ]acetam ide; 1 -(N-Morpholinoethyl)-5-(R, S)-phenyl-2, 4-imidazolidinedione-N-[1 0: methyl benzyl)-1, 3,4-oxad iazolyl]carbonyl)2-(R, S)-methyl propyl ]acetam ide; 0 0 0 -Morphol i noethyl)-5-(S)-benzyl -2,4-imni dazol idi nedione-N 1 m ethyl be nzyl)- 1, 3,4-oxad iazolyl ]carbonyl)2-(R, S)-mnethylIpropyl]acetam id e; or 0 30 S)-Phenyl-1 -methyl-2,4-im idazolidi nedione-N-[ 1 methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide. 53. 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 any one of claims 1 to 52. 03/04/0101c10561. claims, 134 -135- 54, A method of claim 53, wherein the serine protease is elastase. A method of claim 54, wherein the elastase is human neutrophil elastase. 56. A method of claim 53, wherein said compound is administered orally. 57. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 52 and a pharmaceutically acceptable carrier. 58. Use of a pharmaceutically effective amount of a compound of any one of claims 1 to 52 in the preparation of a medicament to inhibit one or more serine proteases. 59. Use of claim 58, wherein the serine protease is elastase. Use of claim 59, wherein the elastase is human neutrophil elastase. 61. A compound of any one of claims 1 to 52, substantially as herein described with reference to any one of the Examples and/or accompanying Figures. 62. A method of claim 53 of inhibiting one or more serine proteases which method is substantially as herein described with reference to any one of the Examples and/or accompanying Figures. 63. A pharmaceutical composition of claim 57, substantially as herein described with reference to any one of the Examples and/or accompanying Figures. DATED this 3 rd day of April ,2001. CORTECH, INC. By their Patent Attorneys: CALLI(AN LAWRIE 03/04/01,cf10561.claims, 135
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| US08/760,916 US5861380A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-keto and di-keto containing ring systems |
| US08/771,317 US5801148A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-proline analogs |
| US08/761313 | 1996-12-06 | ||
| US08/761,313 US5869455A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-N-substituted derivatives |
| US08/761,190 US5807829A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitor--tripeptoid analogs |
| US08/762,381 US5891852A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-cycloheptane derivatives |
| US08/761190 | 1996-12-06 | ||
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| US08/985201 | 1997-12-04 | ||
| US08/984,881 US6015791A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-cycloheptane derivatives |
| US08/985,201 US6150334A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-tripeptoid analogs |
| US08/984884 | 1997-12-04 | ||
| US08/984,884 US6001811A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors--N-substituted derivatives |
| US08/985056 | 1997-12-04 | ||
| US08/985,056 US5998379A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-proline analogs |
| US08/985298 | 1997-12-04 | ||
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| JP (1) | JP3220169B2 (en) |
| CN (1) | CN1247542A (en) |
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| EP3192872A1 (en) | 2003-08-26 | 2017-07-19 | The Regents of the University of Colorado, a body corporate | Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections |
| US7358368B2 (en) | 2003-11-04 | 2008-04-15 | Ajinomoto Co., Inc. | Azlactone compound and method for preparation thereof |
| AU2007253819B2 (en) | 2006-05-23 | 2011-02-17 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| TWI389899B (en) * | 2006-08-08 | 2013-03-21 | Msd Oss Bv | An orally active thrombin inhibitor |
| EP2117537A1 (en) | 2007-02-09 | 2009-11-18 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| JP5268120B2 (en) * | 2007-05-22 | 2013-08-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Benzimidazolone chymase inhibitor |
| US9938353B2 (en) | 2011-06-24 | 2018-04-10 | The Regents Of The University Of Colorado, A Body Corporate | Compositions, methods and uses for alpha-1 antitrypsin fusion molecules |
| CA2896951A1 (en) | 2012-01-10 | 2013-07-18 | The Regents Of The University Of Colorado, A Body Corporate | Compositions, methods and uses for alpha-1 antitrypsin fusion molecules |
| MX362192B (en) * | 2013-05-08 | 2019-01-08 | Kissei Pharmaceutical | a-SUBSTITUTED GLYCINEAMIDE DERIVATIVE. |
| US10160726B2 (en) * | 2014-08-06 | 2018-12-25 | Novartis Ag | Quinolone derivatives as antibacterials |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9216272D0 (en) * | 1991-08-15 | 1992-09-09 | Ici Plc | Substituted heterocycles |
| GB9307555D0 (en) * | 1992-04-16 | 1993-06-02 | Zeneca Ltd | Heterocyclic compounds |
| FR2694295B1 (en) * | 1992-07-28 | 1994-09-02 | Adir | New peptides derived from trifluoromethyl ketones, their preparation process and the pharmaceutical compositions containing them. |
| ATE186305T1 (en) * | 1994-06-02 | 1999-11-15 | Merrell Pharma Inc | PERFLUOROALKYLL KETONES, INHIBITORS OF ELASTASE AND PROCESS FOR THE PRODUCTION THEREOF |
| US5618792A (en) * | 1994-11-21 | 1997-04-08 | Cortech, Inc. | Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase |
-
1997
- 1997-12-05 RU RU99114606/04A patent/RU2217436C2/en not_active IP Right Cessation
- 1997-12-05 JP JP52565698A patent/JP3220169B2/en not_active Expired - Fee Related
- 1997-12-05 WO PCT/US1997/021636 patent/WO1998024806A2/en not_active Application Discontinuation
- 1997-12-05 TR TR2001/03270T patent/TR200103270T2/en unknown
- 1997-12-05 TR TR1999/01681T patent/TR199901681T2/en unknown
- 1997-12-05 AU AU55894/98A patent/AU734615B2/en not_active Ceased
- 1997-12-05 CA CA002272548A patent/CA2272548A1/en not_active Abandoned
- 1997-12-05 CN CN97180392A patent/CN1247542A/en active Pending
- 1997-12-05 HU HU0100669A patent/HUP0100669A3/en unknown
- 1997-12-05 EP EP97952232A patent/EP0954526A2/en not_active Withdrawn
- 1997-12-05 NZ NZ336046A patent/NZ336046A/en unknown
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1999
- 1999-06-04 NO NO992734A patent/NO992734L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001507679A (en) | 2001-06-12 |
| WO1998024806A2 (en) | 1998-06-11 |
| CA2272548A1 (en) | 1998-06-11 |
| RU2217436C2 (en) | 2003-11-27 |
| CN1247542A (en) | 2000-03-15 |
| NO992734D0 (en) | 1999-06-04 |
| TR200103270T2 (en) | 2003-03-21 |
| HUP0100669A2 (en) | 2001-08-28 |
| AU5589498A (en) | 1998-06-29 |
| NZ336046A (en) | 2000-10-27 |
| EP0954526A2 (en) | 1999-11-10 |
| HUP0100669A3 (en) | 2001-12-28 |
| JP3220169B2 (en) | 2001-10-22 |
| NO992734L (en) | 1999-08-02 |
| TR199901681T2 (en) | 2000-03-21 |
| WO1998024806B1 (en) | 1999-05-20 |
| WO1998024806A3 (en) | 1998-10-15 |
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