WO1998024806B1 - Substituted oxadiazole, thiadiazole and triazole serine protease inhibitors - Google Patents
Substituted oxadiazole, thiadiazole and triazole serine protease inhibitorsInfo
- Publication number
- WO1998024806B1 WO1998024806B1 PCT/US1997/021636 US9721636W WO9824806B1 WO 1998024806 B1 WO1998024806 B1 WO 1998024806B1 US 9721636 W US9721636 W US 9721636W WO 9824806 B1 WO9824806 B1 WO 9824806B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- aryl
- amino
- carbonyl
- Prior art date
Links
- 150000004866 oxadiazoles Chemical class 0.000 title abstract 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical class C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 title abstract 2
- 150000003852 triazoles Chemical class 0.000 title abstract 2
- 239000003001 serine protease inhibitor Substances 0.000 title 1
- 102000012479 Serine Proteases Human genes 0.000 claims abstract 5
- 108010022999 Serine Proteases Proteins 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims 327
- 125000000217 alkyl group Chemical group 0.000 claims 261
- -1 carboalkoxy Chemical group 0.000 claims 212
- 125000003118 aryl group Chemical group 0.000 claims 205
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 176
- 125000003342 alkenyl group Chemical group 0.000 claims 160
- 125000004663 dialkyl amino group Chemical group 0.000 claims 131
- 125000005843 halogen group Chemical group 0.000 claims 126
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 126
- 125000003710 aryl alkyl group Chemical group 0.000 claims 106
- 125000004414 alkyl thio group Chemical group 0.000 claims 99
- 125000003545 alkoxy group Chemical group 0.000 claims 89
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 86
- 229910052717 sulfur Inorganic materials 0.000 claims 86
- 125000000753 cycloalkyl group Chemical group 0.000 claims 85
- 125000005842 heteroatom Chemical group 0.000 claims 84
- 229910052760 oxygen Inorganic materials 0.000 claims 83
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims 81
- 125000004438 haloalkoxy group Chemical group 0.000 claims 78
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims 77
- 125000000304 alkynyl group Chemical group 0.000 claims 77
- 125000001188 haloalkyl group Chemical group 0.000 claims 73
- 125000003282 alkyl amino group Chemical group 0.000 claims 72
- 125000004093 cyano group Chemical group *C#N 0.000 claims 69
- 125000004995 haloalkylthio group Chemical group 0.000 claims 60
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 59
- 125000004103 aminoalkyl group Chemical group 0.000 claims 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 50
- 125000005018 aryl alkenyl group Chemical group 0.000 claims 42
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 38
- 125000005530 alkylenedioxy group Chemical group 0.000 claims 36
- 229910052757 nitrogen Inorganic materials 0.000 claims 36
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 23
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims 22
- 150000001409 amidines Chemical class 0.000 claims 21
- 125000000468 ketone group Chemical group 0.000 claims 21
- 229930194542 Keto Chemical group 0.000 claims 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 20
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims 19
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 19
- 150000001408 amides Chemical class 0.000 claims 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 11
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims 7
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 7
- 229910052799 carbon Inorganic materials 0.000 claims 6
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 5
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 5
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims 5
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical group C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 5
- 239000004472 Lysine Substances 0.000 claims 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Chemical group C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 5
- 235000018417 cysteine Nutrition 0.000 claims 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 5
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims 5
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims 5
- 229960000310 isoleucine Drugs 0.000 claims 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 5
- 229960003646 lysine Drugs 0.000 claims 5
- CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical compound C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 claims 5
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 5
- 239000011593 sulfur Substances 0.000 claims 5
- 239000004474 valine Substances 0.000 claims 5
- 239000005977 Ethylene Substances 0.000 claims 4
- 102000016387 Pancreatic elastase Human genes 0.000 claims 4
- 108010067372 Pancreatic elastase Proteins 0.000 claims 4
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims 4
- 229940024606 amino acid Drugs 0.000 claims 4
- 235000001014 amino acid Nutrition 0.000 claims 4
- 150000001413 amino acids Chemical class 0.000 claims 4
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims 4
- 229910052736 halogen Inorganic materials 0.000 claims 4
- 150000002978 peroxides Chemical class 0.000 claims 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical group OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims 3
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 claims 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Chemical group OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Chemical group CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims 3
- 239000004473 Threonine Chemical group 0.000 claims 3
- 229960001230 asparagine Drugs 0.000 claims 3
- 235000009582 asparagine Nutrition 0.000 claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims 3
- 229960002743 glutamine Drugs 0.000 claims 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical group OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 3
- 229930182817 methionine Chemical group 0.000 claims 3
- 229960003104 ornithine Drugs 0.000 claims 3
- YWIQQKOKNPPGDO-VURMDHGXSA-N phenyldehydroalanine Chemical compound OC(=O)C(/N)=C/C1=CC=CC=C1 YWIQQKOKNPPGDO-VURMDHGXSA-N 0.000 claims 3
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical group OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims 3
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 claims 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 2
- 125000005533 aryl carboxamido group Chemical group 0.000 claims 2
- 125000004104 aryloxy group Chemical group 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 125000004122 cyclic group Chemical group 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000000262 haloalkenyl group Chemical group 0.000 claims 2
- 150000002367 halogens Chemical group 0.000 claims 2
- 102000052502 human ELANE Human genes 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000005764 inhibitory process Effects 0.000 claims 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000003107 substituted aryl group Chemical group 0.000 claims 2
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 claims 1
- WGUXTQDCAZNJIF-UHFFFAOYSA-N 1-methyl-3,5-bis(trifluoromethyl)benzene Chemical group CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WGUXTQDCAZNJIF-UHFFFAOYSA-N 0.000 claims 1
- CQASWQMEHDUZSJ-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-1h-isoquinoline-2-carboxylic acid Chemical group C1C=CC=C2CN(C(=O)O)CCC21 CQASWQMEHDUZSJ-UHFFFAOYSA-N 0.000 claims 1
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 claims 1
- 125000006506 3-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims 1
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims 1
- 125000005596 alkyl carboxamido group Chemical group 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- XQAMLJAXMAXEPL-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound C1C(=O)NCC(=O)N1.C1C(=O)NCC(=O)N1 XQAMLJAXMAXEPL-UHFFFAOYSA-N 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 claims 1
- 108010043958 Peptoids Proteins 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 0 CC=C(**)C(N(C(*)(*)C(NCC*)=*)C(C(C=C*=C)=C)=*)=O Chemical compound CC=C(**)C(N(C(*)(*)C(NCC*)=*)C(C(C=C*=C)=C)=*)=O 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06052—Val-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
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Abstract
The present invention relates to certain substituted oxadiazole, thiadiazole and triazole peptoids which are useful as inhibitors of serine proteases.
Claims
AMENDED CLAIMS
[received by the International Bureau on 14 September 1998 (14.09.98); original claims 1-302 replaced by amended claims 1-331 (49 pages)]
1. A compound of the formula:
R4 - N R-
H I 3 N-X
O ■ O {j γ R,
O wherein:
X is O and Y is N;
Ri is isopropyl, n-butyl, tert-butyl; alkyl substituted with one or more carboxyl, carboalkoxy, amino. alkylamino or dialkvlamino groups; alkyl fused (Cc;-Cιo)aryl. alkyl fused arylcycloalkyl, alkyl(aryl)2 or .α-dialkyl-arylalkyl optionally comprising 1-4 heteroatoms selected from O, S and N, and optionally substituted with halo, cyano. nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide. alkylthio or haloalkylthio; aryl or arylalkyl substituted with alkyl, amino, alkylamino. dialkylamino. aryl or aryloxy wherein the aryl or aryloxy is optionally substituted with halo, cyano, nitro. hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino. alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy. carboxyl. carboalkoxy, alkylcarboxamide. (C5-C6)aryl, -O-(Cs-C6)aryl, arylcarboxamide. alkylthio or haloalkylthio; aryl or arylalkyl substituted with two more halo, cyano, nitro, hydroxyl, haloalkyl, amino. aminoalkyl, dialkylamino. alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio, arylcarboxamide, (C5-C6)aryl, or -O-(C5-C6)aryl wherein aryl is optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; aryl or arylalkyl comprising one or more heteroatoms selected from O, S and N; or cycloalkyl or alkylcycloalkyl optionally comprising one or more heteroatoms selected from O, S and N;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio. alkylthio. amino. alkylamino. dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR*, -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C]2)aryl, (Cs-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino. aminoalkyl, dialkylamino. amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy. alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -OC(O)-, -NHC(O)- or an amino acid selected from proline. isoleucine. cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro. haloalkyl, amino. aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine. homo-phenylalanine. dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl. alkenyl or phenyl optionally substituted with halo, cyano, nitro. haloalkyl. amino. aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine, methionine. valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl- cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S; and
R4 is benzyl. 2. A compound of claim 1 wherein R4-A- is benzyloxycarbonyl.
148
3. A compound of claim 2 wherein Ri is arylalkyl.
4. A compound of claim 3 wherein Ri is 3,5-dimethylbenzyl.
5. The compound of claim 4: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3,5- dimethylbenzyl)-1.2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
6. A compound of claim 3 wherein Ri is 3,5-dimethoxybenzyl.
7. The compound of claim 6: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3,5- dimethoxybenzyl)-1.2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
8. A compound of claim 3 wherein R\ is 3,5-ditrifluoromethylbenzyl.
9. The compound of claim 8: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3,5- ditrifluoromethylbenzyl)-1.2.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
10. A compound of claim 3 wherein R\ is 3-methylbenzyl.
11. The compound of claim 10: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3- methylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
12. A compound of claim 3 wherein Ri is 4-phenylbenzyl.
13. The compound of claim 12: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(4- phenylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
14. A compound of claim 3 wherein R\ is 3-phenylbenzyl.
15. The compound of claim 14: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3- phenylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
16. A compound of claim 3 wherein Ri is 3-phenoxybenzyl.
17. The compound of claim 16: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3- phenoxybenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
18. A compound of claim 3 wherein Ri is 3,5-diphenylbenzyl.
19. The compound of claim 18: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3,5- diphenylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
20. A compound of claim 3 wherein Ri is 4-dimethylaminobenzyl.
149
21. The compound of claim 20: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(4- dimethylaminobenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
22. A compound of claim 2 wherein R\ is alkyl(aryl)2.
23. A compound of claim 22 wherein R\ is diphenylmethine.
24. The compound of claim 23: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (diphenylmethine)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
25. A compound of claim 2 wherein R\ is α.α-dialkyl-arylalkyl.
26. A compound of claim 25 wherein
is α, -dimethyl-(3- trifluoromethyl)benzyl.
27. The compound of claim 26: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(α,α- dimethyl-[3-trifluoromethyl]benzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]-L-prolinamide.
28. A compound of claim 2 wherein Ri is alkyl fused (C9-Cιo)aryl.
29. A compound of claim 28 wherein R\ is 1-napthylmethylene.
30. The compound of claim 29: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(l- napthylmethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
31. A compound of claim 28 wherein Ri is 2-napthylmethylene.
32. The compound of claim 31 : (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(2- napthylmethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
33. A compound of claim 2 wherein R\ is alkyl fused arylcycloalkyl optionally comprising 1-4 heteroatoms.
34. A compound of claim 33 wherein Ri is 3.4-methylenedioxybenzyl.
35. The compound of claim 34: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3,4- methylenedioxybenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
36. A compound of claim 2 wherein
is arylalkyl comprising one or more heteroatoms.
37. A compound of claim 36 wherein Ri is 3-pyridylmethylene.
150
38. The compound of claim 37: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5-(3- pyridylmethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
39. A compound of claim 2 wherein R\ is alkylcycloalkyl comprising one or more heteroatoms.
40. A compound of claim 39 wherein R\ is morpholino-N-ethylene.
41. The compound of claim 40: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (moφholino-N-ethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
42. A compound of claim 2 wherein Ri is alkyl substituted with dialkylamino.
43. A compound of claim 42 wherein Ri is dimethylamino-N-ethylene.
44. The compound of claim 43: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (dimethylamino-N-ethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]-L-prolinamide.
45. A compound of claim 2 wherein R\ is alkyl substituted with carboalkoxy.
46. A compound of claim 45 wherein Ri is carbomethoxyethylene.
47. The compound of claim 46: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (carbomethoxyethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
48. A compound of claim 2 wherein Ri is alkylcycloalkyl.
49. A compound of claim 48 wherein R] is adamantylmethylene.
50. The compound of claim 49: (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (adamantylmethylene)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
51. A compound of claim 48 wherein R\ is cyclohexylmethylene.
52. The compound of claim 51 : (Benzyloxycarbonyl)-L-valyl-N-[l-(3-[5- (cyclohexylmethylene)-l,2.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
53. A compound of the formula:
R A ' N
H , N — X
O
0 £ Y R. o
wherein:
X is O and Y is N;
Ri 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-(C5-C6)aryl; hydroxyl, amino. alkylamino or dialkylamino; cycloalkyl, cycloalkenyl. alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl-fused (C5-Cι2)-arylcycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S. and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino. aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide. alkylthio or haloalkylthio.
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1 -3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Ci2)aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N. O and S. and optionally substituted with halo, cyano, keto, nitro. hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl. alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -C(O)-, -NHC(O)-, -S(O)2-, -NH-S(O)2-, -OC(O)-, - C- or proline. isoleucine, cyclohexylaianine, cysteine optionally substituted at the sulfur with alkyl. alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid
152
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 arylcycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S; and
R is H. alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5- Cι2)aryl, (C$ or C7-Cι2)arylalkyl, fused (C5-Cι2)aryl-cycloalkyl or fused alkyl (C5-Cι2)aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy. amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide. aryl. arylalkyl, arylcarboxamido, alkylthio or haloalkylthio.
54. A compound of claim 53 wherein R\ is optionally substituted arylalkyl.
55. A compound of claim 54 wherein R\ is 3-trifluoromethylbenzyl.
56. A compound of claim 55 wherein R4-A is pyridinyl-C(O)-.
57. The compound of claim 56: 3-Pyridylcarbonyl-L-valyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
58. A compound of claim 55 wherein R4-A- is methoxyphenylcarbonyl.
59. The compound of claim 58: Methoxyphenylcarbonyl-L-valyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
60. A compound of claim 55 wherein I t-A- is methyloxycarbonyl.
61. The compound of claim 60: Methyloxycarbonyl-L-valyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
62. A compound of claim 55 wherein R4 is isopropyl.
153
63. The compound of claim 62: Isopropyloxycarbonyl-L-valyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
64. A compound of claim 55 wherein R4-A is 4-pyridinylmethyleneoxycarbonyl.
65. The compound of claim 64: 4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[l-(3- [5-(3-trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]-L-prolinamide.
66. A compound of claim 55 wherein I pA is alkyl-S(O) -.
67. A compound of claim 66 wherein R*-A is H3C-S(O)2.-
68. The compound of claim 68: Methylsulfonyl-L-valyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)-l,2.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]- - prolinamide.
69. A compound of claim 53 wherein R4-A is morpholino-N-carbonyl.
70. A compound of the formula:
A ' Ν R
H 1 2 - Ν^X
O
O 0 Ν H H Y R|
O wherein:
X is Ν and Y is O;
Ri is alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, alkylamino. dialkylamino, alkylenedioxy, alkoxy, haloalkoxy, carboxyl, carboalkoxy. alkylcarboxamide, arylcarboxamide, or -O-(C5-C6)aryl; hydroxyl, amino. alkylamino or dialkylamino; cycloalkyl, cycloalkenyl, alkylcycloalkyl. alkenylcycloalkyl, alkylcycloalkenyl, (C5-Cι2)aryl, (C5-Ci2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι )aryl-cycloalkyl, or alkyl-fused (Cs-Cι2)-arylcycloalkyl optionally comprising 1-4 heteroatoms selected from Ν, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl. alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
154
R2 and R3 are independently or together H: alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio. alkylthio. amino, alkylamino, dialkylamino. alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR". -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R'. R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl. alkenylcycloalkyl, alkyl-oxyaryl. alkyl-thioaryl, alkyl-aminoaryl, (C5-Ci2)aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano. keto, nitro, hydroxyl, haloalkyl. amino. aminoalkyl, dialkylamino, amidine. alkylamidine, dialkylamidine. alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide. (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide. alkylthio or haloalkylthio;
A is a direct bond, -C(O)-, -NHC(O)-, -S(O)2-, -NH-S(O)2-, -OC(O)-, - C- or an amino acid selected from proline, isoleucine, cyclohexylaianine. cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide. arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine. dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino. aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide. arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine, methionine, valine, norvaline, norleucine. octahydroindole-2- carboxylic acid: asparagine, glutamine, ornithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl. dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N. O and S; and 4 is H. alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5- Cι2)aryl, (C5-Cι2)arylalkyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-
155
Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro. hydroxyl, haloalkyl, alkoxy, amino. alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio.
71. A compound of claim 70 wherein A is -OC(O)-.
72. A compound of claim 71 wherein R4 is benzyl.
73. A compound of claim 72 wherein R\ is alkyl fused aryl-cycloalkyl optionally comprising 1-4 heteroatoms.
74. A compound of claim 73 wherein Ri is 3.4-methylenedioxybenzyl.
75. The compound of claim 74: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(3,4- methylenedioxy benzyl)- 1,3.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
76. A compound of claim 72 wherein R\ is alkyl.
77. A compound of claim 76 wherein R\ is methyl.
78. The compound of claim 77 : (Benzy loxycarbony l)-L-valy 1-N- [ 1 -(2- [5 -methy 1- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
79. A compound of claim 72 wherein Ri is dialkylamino.
80. A compound of claim 79 wherein Ri is dimethylamino.
81. The compound of claim 80: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5- dimethylamino-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
82. A compound of claim 72 wherein R\ is optionally substituted arylalkyl.
83. A compound of claim 82 wherein Ri is 3-methylbenzyl.
84. A compound of claim 83: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(3- methylbenzyl)-1.3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
85. A compound of claim 83 wherein R and R3 are alkyl.
86. A compound of claim 85 wherein R2 and R are each methyl.
87. A compound of claim 86: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(3- methylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)- 1 -methylethyl]-L-prolinamide.
88. A compound of claim 72 wherein R\ is benzyl optionally substituted with haloalkyl.
156
89. A compound of claim 88 wherein Ri is benzyl optionally substituted with trifluoromethylbenzyl.
90. A compound of claim 89: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(3- trifluoromethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
91. A compound of claim 72 wherein Ri is benzyl optionally substituted with dialkylamino.
92. A compound of claim 91 wherein R\ is benzyl optionally substituted with dimethylamino.
93. A compound of claim 92: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(4- dimethylaminobenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
94. A compound of claim 72 wherein R\ is alkyl-fused aryl.
95. A compound of claim 94 wherein Ri is napthylmethylene.
96. A compound of claim 95: (Benzyloxycarbonyl)-L-valyl-N-[l-(2-[5-(l- napthylmethylene)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
97. A compound of claim 70 wherein Ri is optionally substituted arylalkyl.
98. A compound of claim 97 wherein R| is 3-methylbenzyl.
99. A compound of claim 98 wherein R_ -A- is 3-pyridylcarbonyl.
100. The compound of claim 99: 3-Pyridylcarbonyl-L-valyl-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
101. A compound of claim 98 wherein A is -OC(O)-.
102. A compound of claim 101 wherein R4 is methyl.
103. The compound of claim 102: Methyloxycarbonyl-L-valyl-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
104. A compound of claim 101 wherein R4 is isopropyl.
105. The compound of claim 104: Isopropyloxycarbonyl-L-valyl-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
106. A compound of claim 101 wherein R4- is 4-pyridylmethylene.
157
107. The compound of claim 106: 4-Pyridylmethyleneoxycarbonyl-L-valyl-N-[l- (3-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
108. A compound of claim 98 wherein A is -S(O)2-.
109. A compound of claim 108 wherein R is alkyl.
110. A compound of claim 109 wherein R is methyl.
1 11. The compound of claim 1 10: Methylsulfonyl-L-valyl-N-[l-(3-[5-(3- methylbenzyl)-l ,3.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
1 12. A compound of claim 108 wherein R is aryl.
1 13. A compound of claim 1 12 wherein R is phenyl.
1 14. The compound of claim 1 13: Phenylsulfonyl-L-valyl-N-[l-(2-[5-(3- methylbenzyl)-l ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
1 15. A compound of claim 70 wherein A is alkyl-S(O)2- or alkyl-OC(O)-, R2 is isopropyl and R3 is H.
116. A compound of claim 1 15 wherein A is H3C-S(0)2- or H3C-OC(O)-.
1 17. A compound of claim 1 16 wherein R\ is α,α-dialkyl-arylalkyl or α,α- dialkylalkyl fused arylcycloalkyl.
1 18. A compound of claim 1 17 wherein Ri is α,α-dimethylbenzyl or α, -dimethyl- 3 ,4-methylenedioxybenzy 1.
1 19. The compound of claim 1 18: Methylsulfonyl-L-valyl-N-[l-(3-[5-(α,α- dimethylbenzyl)-l,3.4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L- prolinamide.
120. A compound of claim 1 16 wherein Ri is alkyl.
121. A compound of claim 120 wherein Ri is tert-butyl.
122. The compound of claim 121 : Methylsulfonyl-L-valyl-N-[l-(3-[5-tert-butyl- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.
123. A compound of the formula:
O
158
wherein
X and Y are O, N. or S , provided that at least one of X or Y is N;
Ri is (C5-C!2)aryl, (C5-Cι2)arylalkyl or (C5-C[2)arylalkenyl, optionally comprising one or more heteroatoms selected from N. S and non-peroxide O; and optionally substituted with alkyl. halo, haloalkyl. amino, alkylamino or dialkylamino;
R2 and R3. are independently or together H or alkyl;
B is -S(0)2- or -C(O)-;
(IV) (V) (VI) wherein
R'2 and R'3 are independently or together H. alkyl. alkylthio, alkylthioalkyl; or cycloalkyl, cycloalkylalkyl, (C5-C6)aryl or (C5-C6)arylalkyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidinyl, dialkylguanidinyl or amidine;
Rι3 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio. amino. alkylamino. dialkylamino, or aryl, arylalkyl, fused aryl, fused aryl-cycloalkyl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
Rι4 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or cycloalkyl, aryl, arylalkyl, aryloxycarboxamide. arylalkyloxycarboxamide or
159
fused arylcycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino. carboxyl, alkenyl, alkynyl, haloalkoxy. carboalkoxy, alkylcarboxamide, aryl, arylcarboxamide, arylalkylcarboxamide, alkylthio or haloalkylthio;
R15 is H. alkyl. halo, alkoxy, carboalkoxy, carboxyl, alkylthio. amino, alkylamino, dialkylamino. or aryl, arylalkyl, fused aryl-cycloalkyl, fused aryl- cycloalkylalkyl, cycloalkyl or cycloalkylalkyl optionally comprising 1 or more heteroatoms selected from O, N. or S; and
W is C. O, S or N.
124. A compound of claim 123 wherein R^ is of formula (I).
125. A compound of claim 124 wherein Rι is arylalkylcarboxamide or amine.
126. The compound of claim 125 :
2S, 5S-5-Amino-l,2,4,5.6,7-hexahydroazepino-[3.2,l]-indole-4-one- carbonyl-N-[l-(2-[5-(3-methylbenzyl)-1.3,4-oxadiazolyl]carbonyl)-(Λ,S)-2- methylpropyl]amide;
2S, 5S-5-Amino-l,2,4,5,6,7-hexahydroazepino-[3,2,l]-indole-4-one- carbonyl-N-[l-(3-[5-(3-trifluoromethylbenzyl)-l,2,4-oxadiazolyl]carbonyl)- (Λ,5)-2-methylpropyl]amide; or
2S, 5S-5-Amino-l,2,4,5,6,7-hexahydroazepino-[3.2,l]-indole-4-one- carbonyl-N-[l-(3-[5-(3-methylbenzyl)-l,2.4-oxadiazolyl]carbonyl)-(/?,S)-2- methylpropyl]amide.
127. A compound of claim 123 wherein R is of formula (II).
128. A compound of claim 127 wherein Rπ is optionally substituted aryl or arylalkyl optionally comprising a heteroatom.
129. A compound of claim 128 wherein Rι4 and R] 5 are H.
130. The compound of claim 129:
2-Oxo-5-phenyl-l,4-benzodiazepine-Ν-[l-(2-[5-(3-methylbenzyl- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-Oxo-5-(2-pyridyl)-l,4-benzodiazepine-N-[l-(2-[5-(3-methylbenzyl- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
131. The compound of claim 128:
2-Oxo-5-(4-trifluoromethylphenyl)- 1 ,4-benzodiazepine-N-[ 1 -(2-[5-(3 - methylbenzyl-1.3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
160
2-Oxo-5-(2-methoxyphenyl)-l,4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
132. The compound of claim 128:
2-Oxo-5-(4-chlorophenyl)-l,4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylρropyl]acetamide.
133. The compound of claim 128:
2-Oxo-5-phenyl-l,4-(4'-methylbenzodiazepine)-N-[l-(2-[5-(3- methylbenzyl- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-Oxo-5-phenyl- 1 ,4-(2'-dimethylaminobenzodiazepine)-N-[l -(2-[5-(3- methylbenzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
134. A compound of claim 127 wherein R) is cycloalkyl optionally substituted with one or more heteroatoms.
135. The compound of claim 134:
2-Oxo-5-(4-piperidinyl)-l,4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
136. A compound of claim 127 wherein Rι is fused aryl-cycloalkyl optionally substituted with one or more heteroatoms.
137. The compound of claim 136:
2-Oxo-5-(3,4-methylenedioxyphenyl)-l,4-benzodiazepine-N-[l-(2-[5- (3-methylbenzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
138. The compound of claim 128:
(R,S)-3-Amino-2-oxo-5-phenyl-1.4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide; or
(R,S)-3-Amino-2-oxo-5-phenyl- 1 ,4-benzodiazepine-N-[l -(3-[5-(3- trifluoromethylbenzyl- 1 ,2,4-oxadiazolyl]carbonyl)-2-(R,S)- methylpropyljacetamide.
139. The compound of claim 128:
(R,S)-3-Amino-2-oxo-5-phenyl- 1 ,4-benzodiazepine-N-[l -(3-[5-(3- methylbenzyl)-l,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide; or
(R,S)-3-Amino-2-oxo-5-(2-pyridyl)-l,4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
140. The compound of claim 128:
161
(R,S)-3-Amino-2-oxo-5-(4-chlorophenyl)- 1 ,4-benzodiazepine-N-[ 1 -(2- [5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)- methy lpropy 1] acetamide .
141. The compound of claim 128:
(R,S)-3-Amino-2-oxo-5-phenyl-l,4-(2'-chlorobenzodiazepine)-N-[l- (2- [5 -phenyl- 1 ,3 ,4-oxadiazoly 1] carbony l)-2-(R, S)-propy 1] acetamide ; or
(R,S)-3-Amino-2-oxo-5-phenyl-l,4-(2'-chlorobenzodiazepine)-N-[l- (2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)- methy lpropyl] acetamide .
142. The compound of claim 128:
(R,S)-3-Benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-l,4-(2'- chlorobenzodiazepine)-N-[l-(2-[5-(3-methylbenzyl)- 1,3,4- oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide; or
(R,S)-3 -Amino-2-oxo-5 -(2-chlorophenyl)- 1 ,4-(2 ' - chlorobenzodiazepine)-N-[l-(2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
143. The compound of claim 128:
(R,S)-3-Amino-2-oxo-5-methyl-l,4-benzodiazepine-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
144. A compound of claim 123 wherein Re is of formula (IV).
145. A compound of claim 144 wherein Rι3 is alkyl or aryl and Rι is H or amino.
146. The compound of claim 145:
(R,S)-3 - Amino-2-oxo-5 -methyl- 1 ,4-(2 ' , 3 ' -methylenedioxy- benzodiazepine)-N-[l-(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)2- (R,S)-methylpropyl]acetamide.
147. A compound of claim 123 wherein R6 is of formula (VI).
148. A compound of claim 147 wherein W is S, Rι4 is H or amino, Rι3 is alkyl or aryl and R15 is aryl or arylalkyl.
149. The compound of claim 148:
2-Oxo-5-methyl-l,4-(2-phenyl-l-thiophenodiazepine)-N-[l-(2-[5-(3- methybenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
150. The compound of claim 148 :
2-Oxo-5-methyl- 1 ,4-( 1 -thiophenodiazepine)-N-[ 1 -(2-[5-(3- methybenzyl)-1.3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetarr.icε; or
(R,S)-3-Amino-2-oxo-5-methyl- 1 ,4-(2 -phenyl- 1 -thiophenodiazepine)- N-[ 1 -(2-[5-(3-methybenzyl)- 1 ,3.4-oxadiazolyI]carbonyl)-2-(R.S)- methylpropyljacetamide.
151. A compound of claim 123 wherein Rs is of formula (III).
152. A compound of claim 151 wherein R is amino or benzyloxvcarboxamide.
153. The compound of claim 152:
3-(5 -[(Benzyloxycarbonyl)amino-(5,6-phenyl-ε-lactam]-N-[ 1 -(3-[5- (3-trifIuoromethylbenzyl)- 1.2.4-oxadiazolyl]carbonyl)-2-(S)- methylpropyljacetamide; or
3-(S)-Amino-(5.6-phenyl-ε-lactam)-N-[ l -(3-[5-(3- trifluoromethylbenzy 1)- 1.2.4-oxadiazolyl]carbonyl)-2-(5)- methylpropyljacetamide.
154. A compound of claim 123 wherein Rf, is of formula (V).
155. A compound of claim 154 wherein R|4 is amino.
156. The compound of claim 155:
3-( ?.5 -Amino-quinolin-2-one-Ν-[ l -(2-[5-(3-methylbenzyl)- 1.3.4- oxadiazolyl]carbonyl)-2-(Λ..S')-methylprop\ ]acetamide.
157. The compound:
(R.S)-3-Armno-2-oxo-5-methyl- 1.4-(2'.3'-dιmethoxybenzodiazepιne )- N-[ l -(2-[5-(3-methybenzyl)-1.3.4-oxadιazolyl]carbonyl)-2-(R.S)- methylpropyl]acetamide.
158. A compound of the formula:
R,
R-, N — X
. - - N H
O wherein
X and Y are independently O. S or . wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1 -3 halo atoms: (Cs-Cήjaryl. arylalkyl or arylalkenyl optionally comprising 1 -3 heteroatoms selected from N. O and S. and optionally substituted with halo, cyano. nitro.
163
hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3 halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (Cs-Ci2)aryl, (C5-Cι2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (Cs-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano. nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R 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"R0 or -RC(0)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl. alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-Cβ)aryl, arylcarboxamide. alkylthio or haloalkylthio;
B is -S(O)2-, -C(O)-, -OC(O)- or -CH2-C(0)-; and
Rή is of the formula (I)
164
N ( )„
R,. A — D
(I) wherein m and n are independently 0 or 1 ;
D is a direct bond or an amino acid selected from proline, isoleucine, cyclohexylaianine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halogen, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino. alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide. arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, indoline-2-carboxylic acid tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl, haloalkenyl, alkynyl, halogen, cyano, nitro, haloalkyl, amino, aminoalkyl. dialkylamino, alkoxy, haloalkoxy, carbonyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, valine, norvaline, norleucine, octahydroindole-2- carboxylic acid; or lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl or alkoxycarbonylalkyl; or cycloalkyl, cycloalkylalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N. O and S; A is a direct bond, -C(O)-, -NH-C(O)-, -S(0)2-, -OC(O)- or -C-; and
Rι is H, alkyl, alkenyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino. alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or
Rό is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl.
159. A compound of claim 158 wherein R(, is of formula (I).
160. A compound of claim 159 wherein D is Val.
165
161. A compound of claim 160 wherein Rι is alkyl, aryl or arylalkyl optionally comprising a heteroatom, and A is -OC(O)-.
162. A compound of claim 161 wherein R] -A is benzyloxy carbonyl.
163. A compound of claim 162 wherein n and m are 1.
164. The compound of claim 163:
Benzyloxycarbonyl-Z,-valyl-(l,2,3,4-tetrahydroisoquinoline)-3-N-[l- (2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(i?,S)- methy lpropy 1] amide .
165. A compound of claim 162 wherein n is 0 and m is 1.
166. The compound of claim 7:
Benzyloxycarbonyl-Z,-valyl-2-i-(2,3-dihydro-lH-indole)-N-[l-(3-[5- (3-trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(5)- methylpropyl]amide; or
Benzyloxycarbonyl-I-valyl-2-Z.-(2,3 -dihydro- 1 H-indole)-N-[ 1 -(2-[5- (3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.
167. A compound of claim 159 wherein Rι -A is alkyl-C(O)- or alkyl-OC(O)-.
168. The compound of claim 167:
N-Acetyl-2-I-(2,3-dihydro-lH-indole)-N-[l-(2-[5-(3-methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide; or
N-Acetyl-2-i-(2,3-dihydro-lH-indole)-N-[l-(3-[5-(3- trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]amide.
169. A compound of claim 158 wherein R^ is aryl, arylalkyl, cycloalkyl or cycloalkylalkyl.
170. A compound of claim 169 wherein R6-B is benzyloxycarbonyl.
171. A compound of the formula:
io π R2 R.
R14 A — D — Ν . ,. ^ .
- ^ ^ R, o wherein X and Y are independently O, S or Ν, wherein Ν is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms;
(C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from Ν, O and S, and optionally substituted with halo, cyano, nitro,
166
hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio, provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (Cs-Ci2)arylalkyl, (C5-C]2)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio. alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C(2)aryl, (Cs-Ci2)arylalkyl or (C5-C]2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (Cs-C6)aryl, -0-(C5-C )aryl, arylcarboxamide, alkylthio or haloalkylthio;
Rio is (C5-C6)aryl, (C5-C6)arylalkyl, (C5-C6)arylalkenyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,
167
carboxyl, carboalkoxy. alkylcarboxamide, alkylthio or haloalkylthio; and optionally comprising 1 or more heteroatoms selected from N. S and O;
D is a direct bond, -C(O)- or an amino acid selected from proline. isoleucine, cyclohexylaianine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halogen, cyano, nitro, haloalkyl, amino. aminoalkyl, dialkylamino, alkyl. alkoxy. haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide. alkylthio or haloalkylthio; phenylalanine. indoline-2-carboxylic acid. tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl, haloalkenyl. alkynyl, halogen, cyano. nitro. haloalkyl. amino, aminoalkyl, dialkylamino. alkoxy, haloalkoxy, carbonyl. carboalkoxy, alkylcarboxamide. arylcarboxamide. alkylthio or haloalkylthio: tryptophan. valine. norvaline. norleucine. octahydroindole-2-carboxylic acid or lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl. alkylaminoalkvl. dialkylaminoalkyl. carboxvalkyl, alkoxycarbonylalkyl or cycloalkyl. alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N. O and S;
A is a direct bond. -C(O)-. -NH-C(O)-, -S(0)2-, -OC(0)NH-, -OC(O)- or -C-; and
Rι is H. alkyl. alkenyl; or aryl. arylalkyl, cycloalkyl. alkylcycloalkyl. fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N. O and S. and optionally substituted with alkyl, halo, alkoxy. amino. alkylamino. dialkylamino. carboxyl. alkenyl. alkynyl, haloalkoxy, carboalkoxy. alkylcarboxamido. aryl, arylalkyl, arylcarboxamido. alkylthio or haloalkylthio.
172. A compound of claim 171 wherein Rio is fused aryl-cycloalkyl.
173. A compound of claim 172 wherein Rio is indanyl and R)4 is pyrrolyl.
174. A compound of claim 173 wherein D is a direct bond.
175. The compound of claim 174 :
(Pyrrole-2-carbonyl)-N-[ 1 -(tf , )-indanyl]glycyl-N-[ 1 -(2-[5-(3- methylbenzyl)-l,3.4-oxadiazolyl]carbonyl)-2-(S)-methyipropyl]amide.
176. A compound of claim 171 wherein Rio is aryl or arylalkyl.
177. A compound of claim 176 wherein Rio and R are benzyl.
168
178. A compound of claim 177 wherein D is a direct bond.
179. The compound of claim 178:
(N-Benzylcarbonyl)-N-(benzyl)glycyl-N-[l-(2-[5-(3-methylbenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.
180. A compound of claim 176 wherein Rio is phenyl and Rι is benzyl.
181. A compound of claim 180 wherein D is Val.
182. The compound of claim 181 :
Benzyloxycarbonyl-L-valyl-N-(phenyl)glycyi-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide; or
Benzyloxycarbonyl-L-valyl-N-(phenyl)glycyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] amide .
183. A compound of claim 171 wherein Rio is cycloalkyl.
184. A compound of claim 183 wherein Rio is cyclohexyl and D is a direct bond.
185. A compound of claim 184 wherein R) is optionally substituted aryl.
186. The compound of claim 185:
3-Phenylpropionyl-N-(cyclohexyl)glycyl-N-[l-(3-[5-(3- trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] .
187. A compound of the formula:
R, H Y
R\ R\ O
wherein X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1 -3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy,
169
haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, (C5-C12)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(Cs-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1 -3 halo, hydroxyl. thio, alkylthio. amino, alkylamino. dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R'. R" and R° are independently H, alkyl. alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι )aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1 -4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro. hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl. arylcarboxamide. alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio. alkylthio, amino. alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl. alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Cι )arylalkyl or (C5-C[2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S. and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino. aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl. alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy,
170
carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
Rπ, Rι2 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and O; said ring containing 1 or more keto groups; and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio; cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, ((C5- Cι2)arylalkyl)OC(O)NH- or (C5-Cι2)arylalkenyl optionally comprising one or more heteroatoms selected from N. S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy. haloalkoxy, carboxyl. carboalkoxy, -C(O)O(alkyl), -C(0)(alkyl), alkylcarboxamide, alkylthio or haloalkylthio. A compound of the formula:
wherein X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl,
171
alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (Cs-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (Cs-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (Cs-C6)aryl, -0-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl
172
or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio; i, V2, V3 and V are independently C or N; where V3 is C; Rι is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino or 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, and optionally substituted with halo or alkyl; or Rj3 is absent;
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -S(O)2-NH-, -OC(O)NH-, -OC(O)- or -C-;
Rι4 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; and
Wi, W2 and W are independently selected from N optionally substituted with alkyl; C, S and O.
189. A compound of claim 188 of the formula:
190. A compound of claim 189 wherein R14-A is benzyloxycarboxamide, H2N- or H.
173
191. A compound of claim 190 wherein Rι3 is H or halo.
192. A compound of claim 191 wherein Vi, V2 and V3 are C.
193. A compound of claim 192 wherein V4 is N.
194. The compound of claim 193 :
2-[(6-oxo-2-(4-fluorophenyl)-l,6-dihydro-l-pyrimidinyl]-N-[l-(2-[5- (3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl-l ,6-dihydro- 1 -pyrimidinyl]-N-[l-(2-[5- (3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-Aιnino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- l-pyrimidinyl]-N- [ 1 -(2-[5-(3-pyridyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide.
195. The compound of claim 193 :
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l,6-dihydro-l-pyrimidinyl]-N- [l-(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R)- methylpropyljacetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-phenyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)- 1 ,6- dihydro-l-pyrimidinyl]-N-[l-(2-[5-phenyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide.
196. The compound of claim 193 :
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1.6-dihydro- 1 -pyrimidinyl]-N- [ 1 -(2-[5-(4-methoxyphenyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyljacetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-benzyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- l-pyrimidinyl]-N- [ 1 -(2-[5-(3-methylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyljacetamide.
197. A compound of claim 189 wherein Ri is α,α-disubstituted arylalkyl or alkyl fused aryl-cycloalkyl, wherein the aryl or fused aryl-cycloalkyl group is optionally substituted.
174
198. A compound of claim 197 wherein Ri is α,α-dimethylbenzyl optionally substituted with alkyl, alkoxy or hydroxyl.
199. A compound of claim 198 wherein Rj3 is H or halo.
200. A compound of claim 199 wherein R) -A- is benzyloxycarboxamide, H2N- or H.
201. The compound of claim 200:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-(α,α-dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide ;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- l-pyrimidinyl]-N- [l-(2-[5-(α,α-dimethyl-3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-(α,α-dimethyl-3,4-dihydroxybenzyl)-l,3,4-oxadiazolyl]carbonyl)-2- (S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- (α,α-dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 - (2-[5-(α,α-dimethylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(R)- methylpropy 1] acetamide
2-[6-Oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- (α,α-dimethylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyljacetamide;
2-[6-Oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-(α,α- dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-l,6- dihydro-l-pyrimidinyl]-N-[l-(2-[5-(α,α-dimethylbenzyl)-l,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
202. A compound of claim 189 wherein Ri is (α,α)-dimethyl-3,4- methy lenedioxybenzy 1.
203. The compound of claim 202: 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l,6- dihydro-l-pyrimidinyl]-N-[l-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
175
204. A compound of claim 202 wherein Rι is alkyl and A is -OC(0)NH-.
205. The compound of claim 204 wherein R is methyl.
206. A compound of claim 189 wherein Ri is alkyl.
207. A compound of claim 206 wherein Ri is methyl, isopropyl, isobutyl, w-butyl or tert-butyl.
208. A compound of claim 207 wherein Rι3 is H or halo.
209. A compound of claim 208 wherein Ru-A- is benzyloxycarboxamide, H2N- or H.
210. The compound of claim 209:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-tert-butyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)- 1 ,6- dihydro- l-pyrimidinyl]-N-[l-(2-[5-tert-butyl-l,3,4-oxadiazolyl]carbonyl)-2- (S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-methyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l, 6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-isopropyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-butyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylproρyl]acetamide;
2-[6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- (tert-butyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-(4-fluorophenyl)- 1.6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- tert-butyl-l,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-l,6-dihydro-l-pyrimidinyl]-N-[l-(2-[5-tert-butyl- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-tert-butyl- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 - (2-[5-tert-butyl-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-tert-butyl- 1 ,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-
176
[ 1 -(2-[5-(tert-butyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(R)- methylpropyljacetamide.
211. The compound of claim 209:
2-[5-Amino-6-oxo-2 -phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- tert-butyl-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[5-Amino-6-oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-tert- butyl-l,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[l -(2-[5-tert- butyl- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;
212. A compound of claim 209 wherein R!4 is alkyl and A is -OC(O)NH-.
213. A compound of claim 212 wherein Rt4 is methyl.
214. A compound of claim 189 wherein A is -S(O)2- or -S(O)2-NH-.
215. A compound of claim 214 wherein Rt4 is alkyl.
216. A compound of claim 215 wherein R] is aryl or arylalkyl optionally substituted with alkyl.
217. The compound of claim 216: 2-[5-(Methylsulfonyl)amino-6-oxo-2-(4- fluorophenyl)-l,6-dihydro-l-pyrimidinyl]-N-[l-(2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
218. A compound of claim 193 wherein Ri is alkylcycloalkyl.
219. A compound of claim 218 wherein Rj is methylcyclopropyl.
220. The compound of claim 219:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N- [l-(2-[5-(l-methylcyclopropyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide ;
2-[5-Amino-6-oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-( 1 - methylcyclopropyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-( 1 - methylcyclopropyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[6-Oxo-2-phenyl- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5-( 1 - memylcyclopropyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
221. A compound of claim 192 wherein V is C.
222. The compound of claim 221:
2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 -pyridinyl]-N-[ 1 -
177
(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide ;
2-[6-Oxo-2-phenyl-l, 6-dihydro- l-pyridinyl]-N-[l-(2-[5-tert-butyl- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
2-[6-Oxo-2-phenyl-l,6-dihydro-l-pyridinyl]-N-[l-(2-[5-(α,α- dimethylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[5-Amino-6-oxo-2-(4-fluorophenyl)-l,6-dihydro-l-pyridinyl]-N-[l- (2-[5-(3,4-methylenedioxybenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide .
223. A compound of claim 189 wherein V2 is N.
224. A compound of claim 223 wherein V) and V3 are C, and V4 is N.
225. A compound of claim 224 wherein Rι4-A is H or H2N-.
226. The compound of claim 225:
2-[5-Amino-6-oxo-2-(3-pyridyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2- [5-(3-methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide ;
2-[5-Amino-6-oxo-2-(3-pyridyl)- 1 ,6-dihydro- 1 -pyrimidinyl]-N-[ 1 -(2-[5- tert-butyl- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or 2- [5-Amino-6-oxo-2-(3 -pyridy 1)- 1 ,6-dihydro- 1 -pyrimidiny 1] -N- [ 1 -(2- [5 -(α,α- dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
227. A compound of claim 188 of the formula:
228. A compound of claim 227 where Wi is S.
229. The compound of claim 228: 2-[5-Amino-6-oxo-2-thienyl-l, 6-dihydro- 1- pyrimidinyl]-N-[l-(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide .
178
A compound of the formula:
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (Cs-Cι2)aryl, (C5-Cι2)arylalkyl, (Cs-Cι2)arylalkenyl, fused (Cs-Cι2)aryl-cycloalkyl or alkyl fused (C5-C[2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -0-(Cs-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (Cs-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-CI2)aryl, (C5-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N,
179
O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C] )aryl, (Cs-Ci2)arylalkyl or (C5-Cι )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
Rπ is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl; or R]3 is absent;
A is a direct bond, -C(O)-, -NH-C(O)-, -S(O)2-, -S(O)2-NH-, -OC(O)NH-, -OC(O)- or -C-;
Rι4 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio.
231. A compound of claim 230 wherein Ro is H, halo or piperidinyl.
232. A compound of claim 231 wherein Rι4 is arylalkyl.
180
233. A compound of claim 232 wherein R[4 is benzyl.
234. The compound of claim 233 :
3-[(Benzyloxycarbonyl)amino]-7-piperidinyl-quinoline-2-one-N-[l-(2- [5-(3-methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(5)- methylpropyljacetamide;
3-[(Benzyloxycarbonyl)amino]quinoline-2-one-N-[l-(2-[5-(3- methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
3-amino-quinoline-2-one-N-[l-(2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl)-2-(<S)-methylpropyl]acetamide.
235. The compound of claim 230:
3-[(4-Mo holino)aceto]amino-quinoline-2-one-N-[l-(2-[5-(3- methylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
236. A compound of the formula:
wherein X and Y are independently O, S or Ν, wherein Ν is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1 -3 heteroatoms selected from Ν, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of X or Y is Ν;
181
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1 -3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl or (Cs-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl,
182
haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, -C(O)- or -C-;
Rn is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl; or Rι3 is absent;
Rι is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; and
Ri5 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S. A compound of the formula:
wherein X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,
183
arylcarboxamide or alkylthio; provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O- (C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Ci2)aryl, (C5-Cι2)arylalkyl, (Cs-Ci2)arylalkenyl, fused (C5-C1 )aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (Cs-Cι2)aryl, (Cs-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R' are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (Cs-Cι2)aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N,
184
O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
W is S, SO, SO2 or C; n is 0, 1 or 2;
R13 is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
Rι4 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fiised aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; and
G is -NHC(O)-, -OC(O)NH-, -C(O)-, -S(O)2-NH- or a direct bond.
238. A compound of claim 237 wherein R14-G is benzyloxycarboxamide, H N- or H.
239. A compound of claim 238 wherein Rj3 is phenyl optionally substituted with halo.
240. A compound of claim 238 wherein Rι3 is H.
241. A compound of claim 240 wherein W is C.
242. The compound of claim 241 :
3-(5)-[(Benzyloxycarbonyl)amino]-ε-lactam-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(5)-methylpropyl]acetamide;
3 -(S)-(Amino)-ε-lactam-N- [ 1 -(2- [5-(3-methylbenzy 1)- 1,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
6-[4-Fluorophenyl]-ε-lactam-N-[l-(2-[5-(3-methylbenzyl)-l,3,4- oxadiazolyl]carbonyl)-2-(5 -methylpropyl]acetamide.
185
243. A compound of claim 239 wherein W is S.
244. The compound of claim 243 :
2-[2-(Λ,S)-Phenyl-4-oxometathiazan-3-yl]-N-[l-(2-[5-(3- methylbenzyl)- 1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
2-[2-(^S)-Phenyl-4-oxothiazolidin-3-yl]-N-[l-(2-[5-(3-methylbenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(5)-methylpropyl]acetamide.
245. A compound of the formula:
(C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from Ν, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of X or Y is Ν;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or
-O-(C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl, (C5-Ci2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl optionally comprising 1-4 heteroatoms selected from Ν, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl,
186
dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR*, -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (Cs-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-C12)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R1 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl; and
187
Ru is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, arylalkyloxycarbonyl, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio. 246. A compound of claim 245 of the formula:
247. A compound of claim 246 wherein Ru is fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms.
248. A compound of claim 247 wherein R!4 is 3,4-methylenedioxybenzyl or 3,4- ethy lenedioxy benzyl .
249. The compound of claim 248: 4-[l-(3,4-Methylenedioxybenzyl)-3-(R)- benzylpiperazine-2,5 -dione]-N- [ 1 -(2- [5 -(3 -methylbenzyl)- 1,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
250. A compound of claim 246 wherein R[3 is aryl or arylalkyl optionally comprising one or more heteroatoms.
251. A compound of claim 250 wherein R13 is benzyl or phenyl.
252. A compound of claim 251 wherein R is H
253. A compound of claim 250 wherein Rι3 is pyridyl.
254. The compound of claim 253 :
2-(R,S)-[(Methylene-4-pyridyl) piperazine-2,5-dione]-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
255. A compound of claim 245 of the formula:
188
256. A compound of claim 255 wherein Rπ is aryl or arylalkyl.
257. A compound of claim 256 wherein Rπ is phenyl or benzyl.
258. A compound of claim 255 wherein R is benzyloxy carbonyl.
259. A compound of claim 255 wherein R is H.
260. A compound of the formula:
wherein X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or alkylthio; provided that at least one of X or Y is N;
Ri is alkyl, alkenyl or alkynyl optionally substituted with 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or -O-(C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-Cι2)aryl, (Cs-Ci2)arylalkyl, (C5-Cι2)arylalkenyl, fused (C5-Cι2)aryl-cycloalkyl or alkyl fused (C5-Cι2)aryl-cycloalkyl 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,
189
carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Ci2)aryl, (C5-Ci2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R'2 and R'3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or -RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-Cι2)aryl, (C5-Cι2)arylalkyl or (C5-Cι2)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkyiamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, -O-(Cs-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
U, V, W and Y are independently or together N, C, C(O), N(Rι3) where R[3 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl; N(Ru) where Ru is H, alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl,
190
alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C(R16)(Rι7) where Ri6 and
are independently or together H, alkyl, alkylthio, alkylthioalkyl; -(CH2)mC(O)OR or -(CH2)mC(O)NRR* where m is 1 to 6 and R and R' are independently or together H or alkyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O and optionally substituted with amino, alkylamino, dialkylamino,_guanidine, carboalkoxy, keto, hydroxyl, alkyl, haloalkyl, alkylthio, alkylguanidinyl, dialkylguanidinyl or amidine; or together form a cyclic ring structure comprising 4-8 atoms selected from C, N, O and S. 261. A compound of claim 260 of the formula
262. A compound of claim 261 wherein U is C(O); V is N; W is N or N(R]3); and
Y is C(R,6)(Ri7).
263. A compound of claim 262 wherein W is NH.
264. A compound of claim 263 wherein Rι6 and R)7 are H.
265. A compound of claim 263 wherein Rι6 and
are alkyl.
266. A compound of claim 263 wherein Rι6 is alkyl and
is H.
267. A compound of claim 266 wherein Rι6 is isopropyl.
268. A compound of claim 267 wherein Ri is benzyl or (α,α)-dimethylbenzyl optionally substituted with alkyl, alkoxy or hydroxyl.
269. A compound of claim 268:
4-(S)-(2-Isobuty l)-2,5 -imidazolidinedione-N-[ 1 -(2- [5 -(α,α- dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N- [ 1 -(2- [5 -(3 - methylbenzyl)- 1 ,3 ,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;
191
4-(R)-Isopropyl-2,5-imidazolidinedione-N-[l-(2-[5-(α,α- dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
4-(R)-Isopropyl-2,5-imidazolidinedione-N-[l-(2-[5-(3-methylbenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
270. A compound of claim 263 wherein Ri is alkyl.
271. A compound of claim 270 wherein Rf is methyl, isopropyl, isobutyl, «-butyl or tert-butyl.
272. A compound of claim 271 :
4-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[l-(2-[5-tert-butyl- 1,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
4-(R)-Isopropyl-2.5-imidazolidinedione-N-[l-(2-[5-tert-butyl-l,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
273. A compound of claim 263 wherein R)6 is aryl or arylalkyl optionally substituted with amino, alkylamino or dialkylamino.
274. A compound of claim 273 wherein Rj6 is benzyl or phenyl optionally substituted with dialkylamino, and Rπ is H.
275. A compound of claim 274 of the formula:
[4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[l-(2- [5-(3-methylbenzyl)-l ,3,4-oxadiazolyl]carbonyl)-2-(S)- methy lpropy 1] acetamide ;
4-(R,S)-Phenyl-2,5-imidazolidinedione-N-[l-(3-[5-(3- trifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide; or
4-(R,S)-Phenyl-2,5-imidazoiidinedione-N-[l-(2-[5-(3-methylbenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
276. A compound of claim 263 wherein Rι6 is benzyl or phenyl optionally substituted with hydroxyl.
277. A compound of claim 263 wherein Rι6 is pyridinyl or methylene pyridinyl.
278. A compound of claim 277 wherein Rπ is succinimidyl.
279. The compound of claim 278: [4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]- 2,5-imidazolidinedione-N-[l -(2-[5-(3-methylbenzyl)-l ,3,4- oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
280. A compound of claim 277 wherein Rπ is H.
192
281. A compound of claim 277 wherein Rπ is alkyl.
282. The compound of claim 281 : [4-(R,S)-(2-Pyridyl)-4-(R,S)-methyl]-2,5- imidazolidinedione-N-[l-(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)- 2-(S)-methylpropyl]acetamide.
283. A compound of claim 262 wherein Rι6 and Rπ are phenyl or benzyl.
284. A compound of claim 283 : 4,4-Diphenyl-2,5-imidazolidinedione-N-[l -(2-[5- (3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide or 4,4-Diphenyl-2,5-imidazolidinedione-N-[l-(2-[5-(3,4- methylenedioxybenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyljacetamide.
285. A compound of claim 263 wherein Rι6 and R!7 together form a cyclic ring structure.
286. A compound of claim 285 wherein Rι6 and R)7 together are -CH2-(CH2)2-CH2-.
287. A compound of claim 285 wherein Rι6 and Rπ together are -CH2-(CH2)3-CH2-.
288. A compound of claim 263 wherein Rι6 is arylalkyl substituted with one nitrogen.
289. A compound of claim 288 wherein Rι6 is indolylmethylene.
290. A compound of claim 289:
4-(R)-(3-Indolemethylene)-2,5-imidazolidinedione-N-[l-(2-[5-tert- butyl-1 ,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide; or
4-(R)-(3-Indolemethylene)-2,5-imidazolidinedione-N-[l-(2-[5-( ,α- dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
291. A compound of claim 262 wherein Rt6 is -(CH2)mC(O)OR.
292. A compound of claim 291 wherein R is methyl.
293. A compound of claim 262 wherein R16 is -(CH2)mC(O)NRR'.
294. A compound of claim 293 wherein R and R' are methyl.
295. A compound of claim 262 wherein W is N(R]3) where Rι3 is cycloalkyl or alkylcycloalkyl optionally comprising 1 or more heteroatoms.
296. A compound of claim 295 wherein R)3 is morpholinoalkyl.
297. A compound of claim 296 wherein Ri6 is aryl or arylalkyl.
298. A compound of claim 297 wherein Rι6 is benzyl or phenyl and Rπ is H.
193
299. A compound of claim 298:
1 -(N-Mo holinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[ 1 -(2- [5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)- methylpropyl]acetamide; l-(N- oφholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[l- (2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)- methylpropyljacetamide; or
1 -(N-Moφholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[ 1 -(2- [5-(3-methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R,S)- methylpropyljacetamide.
300. A compound of claim 262 wherein W is N(R13) where Rπ is alkyl.
301. A compound of claim 300 wherein Rj3 is methyl.
302. A compound of claim 262 wherein W is N(Rι3) and Rπ is aryl or arylalkyl.
303. A compound of claim 302 wherein Rπ is benzyl.
304. A compound of claim 303 wherein Rι6 and Rπ are H.
305. A compound of claim 261 wherein U is C(Ri6)(Rπ); V is N; W is N or N(Rπ); and Y is C(O).
306. A compound of claim 305 wherein Rι6 is aryl or arylalkyl.
307. A compound of claim 306 wherein Rι6 is benzyl or phenyl.
308. A compound of claim 307 wherein Rπ is H.
309. A compound of claim 308 wherein W is N(Rι ).
310. A compound of claim 309 wherein Rπ is aryl or arylalkyl.
311. A compound of claim 310 wherein Rπ is benzyl or phenyl.
312. A compound of claim 261 wherein U is C(O); V is N; W is NH or N(Rπ); and Y is N(Rπ).
313. A compound of claim 312 wherein Rπ is aryl or arylalkyl.
314. A compound of claim 313 wherein Rπ is phenyl or benzyl.
315. A compound of claim 312 wherein W is NH.
316. The compound of claim 315: l-Phenyl-l,2,4-triazolidine-3,5-dione-N-[l-(2-[5-(3-methylbenzyl)- l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.
317. A compound of claim 312 wherein W is N(Rπ) where Rπ is alkyl.
194
318. A compound of claim 260 of the formula:
319. A compound of claim 318 wherein W is N(Rπ).
320. A compound of claim 319 wherein Rπ is aryl or cycloalkyl optionally comprising 1 or more heteroatoms.
321. A compound of claim 320 where Rπ is piperidinyl.
322. 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 claim 1, 53, 70, 123, 157, 158 or 171.
323. A method of claim 322 wherein the serine protease is elastase.
324. A method of claim 323 wherein the elastase is human neutrophil elastase.
325. A method of claim 322 wherein said compound is administered orally.
326. A pharmaceutical composition comprising one or more compounds of claim 1, 53, 70, 123, 157, 158 or 171 and a pharmaceutically acceptable carrier.
327. 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 claim 187, 188, 230, 236, 237, 245 or 260.
328. A method of claim 327 wherein the serine protease is elastase.
329. A method of claim 328 wherein the elastase is human neutrophil elastase.
330. A method of claim 327 wherein said compound is administered orally.
331. A pharmaceutical composition comprising one or more compounds of claim 187, 188, 230, 236, 237, 245 or 260 and a pharmaceutically acceptable carrier.
195
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52565698A JP3220169B2 (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitor |
| BR9713684-0A BR9713684A (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors |
| EP97952232A EP0954526A2 (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors |
| NZ336046A NZ336046A (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors containing substituted oxadiazole, thiadiazole and triazole peptide derivatives |
| CA002272548A CA2272548A1 (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors |
| AU55894/98A AU734615B2 (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors |
| HU0100669A HUP0100669A3 (en) | 1996-12-06 | 1997-12-05 | Peptide derivatives as serine protease inhibitors, their use and pharmaceutical compositions comprising thereof |
| NO992734A NO992734L (en) | 1996-12-06 | 1999-06-04 | Serine protease inhibitors |
Applications Claiming Priority (20)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/761,313 | 1996-12-06 | ||
| US08/760,916 US5861380A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-keto and di-keto containing ring systems |
| US08/762,381 | 1996-12-06 | ||
| US08/771,317 US5801148A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-proline analogs |
| US08/762,381 US5891852A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-cycloheptane derivatives |
| US08/761,190 US5807829A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitor--tripeptoid analogs |
| US08/761,313 US5869455A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-N-substituted derivatives |
| US08/771,317 | 1996-12-06 | ||
| US08/760,916 | 1996-12-06 | ||
| US08/761,190 | 1996-12-06 | ||
| US98529897A | 1997-12-04 | 1997-12-04 | |
| US08/985,056 US5998379A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-proline analogs |
| US08/984,884 US6001811A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors--N-substituted derivatives |
| US08/984,881 US6015791A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-cycloheptane derivatives |
| US08/984,884 | 1997-12-04 | ||
| US08/985,201 US6150334A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-tripeptoid analogs |
| US08/985,298 | 1997-12-04 | ||
| US08/985,056 | 1997-12-04 | ||
| US08/984,881 | 1997-12-04 | ||
| US08/985,201 | 1997-12-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO1998024806A2 WO1998024806A2 (en) | 1998-06-11 |
| WO1998024806A3 WO1998024806A3 (en) | 1998-10-15 |
| WO1998024806B1 true WO1998024806B1 (en) | 1999-05-20 |
Family
ID=27581319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/021636 WO1998024806A2 (en) | 1996-12-06 | 1997-12-05 | Substituted oxadiazole, thiadiazole and triazole serine protease inhibitors |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0954526A2 (en) |
| JP (1) | JP3220169B2 (en) |
| CN (1) | CN1247542A (en) |
| AU (1) | AU734615B2 (en) |
| CA (1) | CA2272548A1 (en) |
| HU (1) | HUP0100669A3 (en) |
| NO (1) | NO992734L (en) |
| NZ (1) | NZ336046A (en) |
| RU (1) | RU2217436C2 (en) |
| TR (2) | TR199901681T2 (en) |
| WO (1) | WO1998024806A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6004933A (en) * | 1997-04-25 | 1999-12-21 | Cortech Inc. | Cysteine protease inhibitors |
| US6656910B2 (en) * | 1997-12-04 | 2003-12-02 | Cortech, Inc. | Serine protease inhibitors |
| JP2003520185A (en) * | 1998-06-03 | 2003-07-02 | コーテック インコーポレーテッド | Α-Ketooxadiazoles as serine protease inhibitors |
| JP2003505008A (en) * | 1998-08-17 | 2003-02-12 | コーテック インコーポレーテッド | Serine protease inhibitors containing α-ketoheterocycles |
| FR2782997A1 (en) * | 1998-09-08 | 2000-03-10 | Hoechst Marion Roussel Inc | NOVEL BENZODIAZEPINONE DERIVATIVES, PREPARATION METHOD AND INTERMEDIATES THEREOF, MEDICAMENT APPLICATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME |
| AU3719100A (en) * | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Inhibitors of serine protease activity, methods and compositions for treatment of viral infections |
| AU3731400A (en) * | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Methods and compositions useful in inhibiting apoptosis |
| WO2000051625A1 (en) * | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses |
| US6489308B1 (en) * | 1999-03-05 | 2002-12-03 | Trustees Of University Of Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions |
| AU2941200A (en) * | 1999-03-12 | 2000-10-04 | Ono Pharmaceutical Co. Ltd. | 1,3,4-oxadiazole derivatives and process for producing the same |
| CA2375229A1 (en) * | 1999-06-17 | 2000-12-28 | Source Precision Medicine, Inc. | Method and compounds for inhibiting activity of serine elastases |
| US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
| AU6371900A (en) * | 1999-07-26 | 2001-02-13 | Du Pont Pharmaceuticals Company | Lactam inhibitors of hepatitis c virus ns3 protease |
| CN1399632A (en) * | 1999-09-27 | 2003-02-26 | 小野药品工业株式会社 | Pyrimidine derivatives, process for preparing the derivatives and drugs containing the same as active ingredient |
| US6797720B2 (en) | 1999-12-03 | 2004-09-28 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazoline derivative and an agent comprising its derivative as active ingredient |
| WO2001040263A1 (en) * | 1999-12-03 | 2001-06-07 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazolin-2-one derivatives and drugs containing these derivatives as the active ingredient |
| EP1253144A4 (en) * | 2000-02-03 | 2003-02-12 | Ono Pharmaceutical Co | 1,3,4-oxadiazole derivatives and process for producing the same |
| AU2001230570A1 (en) * | 2000-02-03 | 2001-08-14 | Ono Pharmaceutical Co. Ltd. | 1,3,4-oxadiazole derivatives and process for producing the same |
| JPWO2002014310A1 (en) * | 2000-08-10 | 2004-01-15 | 小野薬品工業株式会社 | 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl] -N- [1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl ) -2- (R, S) -Methylpropyl] acetamide hydrochloride compound |
| CA2421499A1 (en) * | 2000-09-08 | 2003-03-06 | Ono Pharmaceutical Co., Ltd. | Novel crystals of 1,3,4-oxadiazole derivative, process for producing the same and pharmaceutical agent containing the same as active ingredient |
| WO2002026229A1 (en) * | 2000-09-29 | 2002-04-04 | Ono Pharmaceutical Co., Ltd. | Airway mucus secretion inhibitors |
| WO2003006014A1 (en) * | 2001-07-10 | 2003-01-23 | Ono Pharmaceutical Co., Ltd. | Medicine comprising combination of five-membered heterocyclic compound and drug compensating for or enhancing its activity |
| JP4455056B2 (en) * | 2001-07-11 | 2010-04-21 | バーテックス ファーマシューティカルズ インコーポレイテッド | Cross-linked bicyclic serine protease inhibitor |
| IL148924A (en) * | 2002-03-26 | 2015-06-30 | Mor Research Applic Ltd | Use of agents that inhibit the activity of intracellular elastase in the preparation of a medicament for treating and/or preventing necrosis of cells and diseases associated therewith |
| PL2520654T3 (en) | 2003-08-26 | 2017-08-31 | 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 |
| US7951823B2 (en) | 2006-05-23 | 2011-05-31 | 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 |
| EP2152674B1 (en) | 2007-05-22 | 2011-08-03 | Boehringer Ingelheim International GmbH | Benzimidazolone chymase inhibitors |
| KR20140137347A (en) | 2012-01-10 | 2014-12-02 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | Compositions, methods and uses for alpha-1 antitrypsin fusion molecules |
| EP2995611B1 (en) * | 2013-05-08 | 2017-10-11 | Kissei Pharmaceutical Co., Ltd. | Alpha-substituted glycineamide derivative |
| JP2017523213A (en) * | 2014-08-06 | 2017-08-17 | ノバルティス アーゲー | Quinolone derivatives as antibacterial agents |
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. |
| NZ284766A (en) * | 1994-06-02 | 1998-06-26 | Merrell Pharma Inc | Perfluoro amino ketones; medicaments as elastase inhibitors |
| 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 HU HU0100669A patent/HUP0100669A3/en unknown
- 1997-12-05 EP EP97952232A patent/EP0954526A2/en not_active Withdrawn
- 1997-12-05 AU AU55894/98A patent/AU734615B2/en not_active Ceased
- 1997-12-05 WO PCT/US1997/021636 patent/WO1998024806A2/en not_active Application Discontinuation
- 1997-12-05 TR TR1999/01681T patent/TR199901681T2/en unknown
- 1997-12-05 TR TR2001/03270T patent/TR200103270T2/en unknown
- 1997-12-05 CA CA002272548A patent/CA2272548A1/en not_active Abandoned
- 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 CN CN97180392A patent/CN1247542A/en active Pending
- 1997-12-05 NZ NZ336046A patent/NZ336046A/en unknown
-
1999
- 1999-06-04 NO NO992734A patent/NO992734L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001507679A (en) | 2001-06-12 |
| AU734615B2 (en) | 2001-06-21 |
| TR200103270T2 (en) | 2003-03-21 |
| JP3220169B2 (en) | 2001-10-22 |
| HUP0100669A3 (en) | 2001-12-28 |
| WO1998024806A3 (en) | 1998-10-15 |
| HUP0100669A2 (en) | 2001-08-28 |
| NO992734L (en) | 1999-08-02 |
| TR199901681T2 (en) | 2000-03-21 |
| CA2272548A1 (en) | 1998-06-11 |
| EP0954526A2 (en) | 1999-11-10 |
| NO992734D0 (en) | 1999-06-04 |
| CN1247542A (en) | 2000-03-15 |
| AU5589498A (en) | 1998-06-29 |
| WO1998024806A2 (en) | 1998-06-11 |
| NZ336046A (en) | 2000-10-27 |
| RU2217436C2 (en) | 2003-11-27 |
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