OA10764A - Protease inhibitors - Google Patents

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Publication number
OA10764A
OA10764A OA9800049A OA9800049A OA10764A OA 10764 A OA10764 A OA 10764A OA 9800049 A OA9800049 A OA 9800049A OA 9800049 A OA9800049 A OA 9800049A OA 10764 A OA10764 A OA 10764A
Authority
OA
OAPI
Prior art keywords
leucinyl
benzyloxycarbonyl
amino
cbz
alkyl
Prior art date
Application number
OA9800049A
Other languages
English (en)
Inventor
Thomas Joseph Carr
Renee Louise Desjarlais
Timothy Francis Gallagher
Stacie Marie Halbert
Hye-Ja Oh
Scott Kevin Thompson
Daniel Frank Veber
Dennis Shinji Yamashita
Jack Hwekwo Yen
Original Assignee
Smithkline Beecham Corp
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Publication date
Application filed by Smithkline Beecham Corp filed Critical Smithkline Beecham Corp
Publication of OA10764A publication Critical patent/OA10764A/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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Claims (68)

  1. -207- We claim: 010764 A compound according to Formula I:
    rz -208
    010764 15 L = c2-6aIky!> Ar-co.6alkyl, Het-C().6alkyl, CH(R66)nr60r685CH(R66)Ar, CH(R66)OAr’, NR66R67; M = C(O), SO2; -209- 010764
    J = C(O), SO2; T = Ar, Het; V = C3-7cycloalkyl; W = H, -CN, -CF3, -NO2, -COR7, -CO2R6, -CONHR6, .-SO2NHR6,-NHSO2R6,-NHCOR7,-O-COR6,-SR6, NR’R6, NR’(C=NH)NHR5, Cl, Br, I, F; X = Y=:Z = N, O, S or CR4, provided that at least two of X, Y and Z are heteroatoms and at least one ofX, Y and Z is N, or one of X, Y and Z is C=N, C=C or N=N and the othertwo are CR4 or N, provided that X, Y and Z together comprise at least twoN; ~ indicates a single or double bond in the five-membered heterocycle;m = 0, 1,2;η = 1 to 6; ¢ = 0,1,2: Ar = phenyl, naphthyl, optionally substituted by one or more ofPh-CQ.galkyl, Het-Cg^alkyl, Ci.galkoxy, Ph-CQ^alkoxy, Het-C0.6alkoxy, OH, (CH2)j.6NR58R59, O(CH2)i.6NR58r59; Ar’ = phenyl or naphthyl, optionally substituted by one or more ofPh-CQ.^alkyl, Het-Co^alkyl, Cj.galkoxy, Ph-CQ.galkoxy, Het-C0-6alkoxy, OH, (CH2) j _6NR58R59, O(CH2)i.6NR58r595 or halogen; R’ = H, Ci-^alkyl, Ar-CQ.galkyl, Het-CQ.galkyl; Rl=H,Ci-6alkyl; = C4-6alkyl, C^alkenyl, benzyl; R3 = Ci-6alkyl, Ar-Co-6alkyl, Het-C0.6alkyl, R5CO-, R5SO2-, R5OC(O)-,r5nhco-; R4 = H, Ci-6alkyl, Ar-Co-6alkyl, Het-CQ.galkyl; -210- 010764 R 5 = Ar-0-6alkyl» Het-CQ.galkyl; R6 = H, C1 -6alkyl, CH2CF3, Ar-Co-6alkyl, Het-Cg.^alkyl; R7 = Ci-6alkyl, Ar-Co-6alkyl, Het-Co-6alkyl; R 8 = H; C2-6 alkenyl; C2-6alkynyl; Het; Ar; Ci-ôalkyl, optionally substituted by OR’, SR’, NR’2, CO2R’, CO2NR2, N(C=NH)NH2, Het orAr; R9 = H, Ci-6alkyl, Ar-Cg.^alkyl, Het-Cg^alkyl; Ræ = Ci-6alkyl, Ar-CQ.galkyl, Het-CQ.6alkyl; R^ = H, Cj-^alkyl, Ar-Cj.^alkyl, Het-CQ.galkyl, or R H NR12 = H, Ci.6alkyl, Ar-C0.6alkyl, Het-C0-6alkyl; R13 = H, Ci.^alkyl, Ar-C^alkyl, Het-C^alkyl; R14 = ^ N—R9R72,Ac; R15 = H, Cj^alkyl, C/j.galkenyl, C2_6alkynyl, Ar, Het, orCj.galkyl optionally substituted by OR9, NR92, CONr92, N(C=NH)NH-, Het or Ar; r!6 - C2-6aikyl, C2.galkenyl, C2_6alkynyl, Ar, Het, or C2.6alkyloptionally substituted by OR9, SR9, NR92, CO2R9,CONR92,N(C=NH)NH-, HetorAr; Ri9 = H, Cj.^alkyl, C2-6alkenyl, Cb.galkynyl, Ar, Het, or Cj.galkyl optionally substituted by OR9, SR9, NR92,CO2R9, CONR92, N(C=NH)NH-, Het or Ar; r17 = r72 = H, Ci-ôalkyl, R10, R10C(O)-, R10C(S)-, R10OC(O)-;r21 _ r26 _ C5_6alkyl; C2-6alkenyl; C3-1 icycloalkyl; T-C3-ôalkyl; V-Ci-6alkyl; T-C2-6alkenyl; T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR20, OR-^.NR^R27 or C i-4alkyl; R27 = R28Co, R28OCO; R28 = Ci-6alkyl; C3. 1 îcycloalkyl; Ar; Het; T-Cj-galkyl; T-(CH2)nCH(T)(CH2)n; optionally substituted by one ortwo halogens, SR2(9, OR20, Nr20r73( Ci-^alkyl; -21 Ι- ΟΙ 0764 r20 = R22 = R23 = R24 = R25 = R73 = Η, C 1_4alkyl, Ar-C0. 6alkyl, Het-Co.6alkyl; R29 =
    Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl-10 leucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl- leucinyl, Ν,Ν-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy- -212- 010764 benzoyl-, 2- or 3- benzyloxybenzoyl-, bipheny 1 acetyl,alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline 5 carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxybenzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl Cg-Cgalkyloxy carbonyl-amino acid-, 10 heteroaryl Cg-Cgalkyloxy carbonyl-amino acid-, y aryl Cq-C^alkyloxy carbonyl-amino acid-, heteroarylCg-C^alky loxy carbonyl-amino acid-, C j -Cgalkyloxycarbonyl-amino acid-; Cj-C^alkyl carbonyl, arylCq-C^alkyl carbonyl, heteroaryl CQ-Cgalkyl carbonyl, 15 aryl CQ-Cgalkyl carbonyl, heteroaryl Cq-Cgalkyl carbonyl, Cj-Cgalkyl sulfonyl, aryl Cg-Cgalkyl sulfonyl, heteroarylCq-Cgalkyl sulfonyl, aryl CQ-Cgalkyl sulfonyl, heteroarylCg-Cgalkyl sulfonyl; 20 R30 = -H, Ci-6alkyl; R31 =
    -213- 010764
    Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl- 5 leucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl- leucinyl, Ν,Ν-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, 10 alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz- norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinolinecarbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl,acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy 15 benzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl Cg-Cgalkyloxy carbonyl-amino acid-, heteroaryl C^-Cgalkyloxy carbonyl-amino acid-,aryl Cfj-Cgalkyloxy carbonyl-amino acid-, heteroaryl 20 Co-Cgalkyloxy carbonyl-amino acid-, C i -Cgalkyloxy carbonyl-amino acid-; Cj-C^alkyl carbonyl, aryl CQ-Cgalkylcarbonyl, heteroaryl Cg-Cgalkyl carbonyl, aryl CQ-Cgalkyl -214- 010764 carbonyl, heteroaryl CQ-C^alkyl carbonyl, Cj-Cgalkylsulfonyl, aryl Cg-C^alkyl sulfonyl, heteroaryl CQ-C^alkylsulfonyl, aryl CQ-C^alkyl sulfonyl, substituted heteroarylCQ-Cgalkyl sulfonyl; 5 R37 = OCH2Ar, OCH2Ci_(jalkyl, aryl substituted CQ-galkyl, heteroaryl substituted CQ-6alkyl,4-imidazole methylene; 2-, 3-, or 4-pyridylmethylneneoxy; 4-pyridy 1 methylene, 2- pyridyl sulfonyl, 4-pyridyl, aryl Cg-galkyloxy, heteroaryl substituted Cg-galkyloxy; 10 R33 = C t-6alkyi, -CH2Ph, -CH2CH2CO2R34; R34=s-H, Cpgalkyl; R35 = Ar, HetAr; R3^ = Aryl, heteroaryl, pyridyl, isoquinolinyl; R37= C pealkyl, -CH2Ph, -CH2CH2CO2R34; 15 R3^ = Cbz; Cpgalkyl or aryl substituted , I Cbz; Cj-^alkyl -CO; benzoyl; C j-^alkyl or arylsubstituted benzoyl; -215- 010764
    10 Cbz-leucinyl-; 2-, 3-, or 4-pyridy 1 methyloxycarbonyl-leucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, Ν,Ν-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl,alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz- -216- 010764 norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon- (t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinolinecarbonyl, biphenyl acetyl, alpha- isobuty 1-biphenyl acetyl,acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxybenzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl CQ-C^alkyloxy carbonyl-amino acid-, heteroaryl Cg-Cgalkyloxy carbonyl-amino acid-,aryl Cg-Cgalkyloxy carbonyl-amino acid-, heteroaryl CQ-C^alkyloxy carbonyl-amino acid-, C|- i Cgalkyloxy carbonyl-amino acid-; Cj-Cgalkyl carbonyl, aryl CQ-C^alkyl carbonyl, heteroaryl CQ-C^alkyl carbonyl,aryl CQ-Cgalkyl carbonyl, heteroaryl CQ-Cgalkyl carbonyl,CpCgalkyl sulfonyl, aryl Cg-C^alkyl sulfonyl, heteroarylCg-Cgalkyl sulfonyl, aryl Cg-C^alkyl sulfonyl, heteroarylCQ-C^alkyl sulfonyl; r40 - h an£j Cp^alkyl; R41 =HandC1-6alkyI; R42 = Cpgalkyl, aryl substituted Cp^alkyl and hetero arylsubstituted Cj-galkyl,; H when R43 is Cp^alkyl, aryl substitutedCj-galkyl; and heteroaryl substituted Cj-galkyl; R43 = Cj-galkyl, aryl substituted Cj-galkyl and hetero arylsubstituted Cj-^alkyl,; H when R42 is Cj-galkyl, aryl substitutedCj-^alkyt; and heteroaryl substituted Cj-galkyl; R44 = CH(R53)NR45R54, CH(R55)Ar, Cj^alkyl; R45 = r46 - R47 = R48 = R49 = R50 - R51 = H, C^alkyl,Ar-CQ.galkyl, Het-CQ.^alkyl; R52 = Ar, Het, CH(R56)Ar, CH(R56)OAr, N(R56)Ar, C^alkyl,CH(R56)NR46R57; r53 = C2_6alkyl, Ar-CQ.galkyl, Het-CQ.^alkyl, r53 and R4^ may be connected to form a pyrrolidine or piperidine ring; r54 = R57 = r47, R47C(O), R47C(S), R47OC(O); -217- 010764 r55 = R56 = r58 = r59 = h> Ci_6alkyl, Ar-C0.6alkyl, Het-C0, 6alkyl; R60 = r61 = R62 = R63 = R64 = H> c^alkyl, Ar-Co-6alkyl, or Het-Cg^alkyl; R65 = Cj.^alkyl, Ar, Het, CH(R69)Ar, CH(R69)OAr, N(R69)Ar,CH(R69)NR61r70; r66 = R69 = R71 = h, C^alkyl, (CH2)0-6-C3.6cycloalkyl, Ar-C0.6alkyl, Het-Cg.galkyl; R67 = C i.^alkyl, (CH2)o.6-C3-6cycloalkyl, Ar-Co^alkyl, Het-Co-galkyl; R66 and R^7 may be combined to form a i 3-7 membered monocyclic or 7-10-membered bicycliccarbocyclic or heterocyclic ring, optionally substituted with1-4 of Cj.^alkyl, Ph-CQ.galkyl, Het-CQ.galkyl, Cj.galkoxy, Ph-C0. 6alkoxy, Het-C0.6alkoxy, OH, (CH2)i_6NR58R59, O(CH2)16NR58r59. r68 = r70 = R62 R62C(O)j R62C(S)( R62OC(O), R62OC(O)NR59CH(R7 1)(CO); and pharmaceutically acceptable salts thereof.
  2. 2. A compound according to Claim 1 wherein:
  3. 3. A compound according to Claim 2 wherein A is Leu.
  4. 4. A compound according to Claim 2 wherein W is CN, NHR^, SR^, CONHR^ orCO2R6.
  5. 5. A compound according to Claim 2 wherein RHs H, methyl or isobutyl.
  6. 6. A compound according to Claim 2 wherein R2 is R^OC(O)-. -218- αΐ 0764
  7. 7. A compound according to Claim 2 selected from the group consisting of:(2S, l'S)- 2-(benzyloxycarbonyl)amino-N-[l’-(2-carboxythiazol-4-yl)-3’-methylbutyl]-4- methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[r-(2-carboxamidothiazol-4-yl)-3’-methylbutyl]- 4-methylpentanamide; 2S,rS)-2-(benzyloxycarbonyl)amino-N-[r-(2-carboethoxythiazol-4-yl)-3’-methylbutyl]-4- methylpentanamide; (2S,rS)-2-(benzyloxycarbonyl)amino-N-[r-(2-cyanothiazol-4-yl)-3-methylbutyl]-4- methylpentanamide; / (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-[2-(N’-benzylcarboxamido)thiazol-4-yl]-3 -methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-[2-[N’-(3-methylpropyl)carboxamido]thiazol- 4-yl)]-3’-methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-[2-[N’-(2-phenylethyl)carboxamido]thiazol-4-yl)]-3’-methylbutyl]-4-methylpentanamide; (2S,rS)-2-(benzyloxycarbonyl)amino-N-[r-(4-carboethoxythiazol-2-yl)-3’-methylbutyl]-4- methylpentanamide; (2S,rS)-2-(benzyloxycarbonyl)amino-N-[r-(4-carboxythÎazol-2-yl)-3’-methylbutyl]-4- methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(4-carboethoxythiadiazol-2-yl)-3-methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3 -methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbony l)amino-N-[ 1 ’-(4-carboethoxyoxadiazol-2-yl)-3 .methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[ 1 ’-(4-carboethoxythiazol-2-yl)-3’-methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzy loxycarbonyl)amino-N-[ 1 ’-(4-carboxamidooxadiazol-2-yl)-3-methylbutyl]-4-methylpentanamide; (2S,l’S)-2-(benzyloxycarbonyl)amino-N-[l’-(2-carboethoxythiazol-4-yl)-3’-methylbutyl]-3- phenylpropanamide; (2S, 1 ’S)-2-(benzy loxycarbonyl-L-leucinyl)amino-N-[ 1 ’-(2-carboethoxythiazol-4-yl)-3 - methylbutyl]-4-methylpentanamide; -219- 0 î 076 4 (2S,rS)-2-(benzyloxycarbonyI)amino-N-[r-(5-mercapto-l,2,4-oxadiazol-3-yl)-3’- methylbutyl]-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(2-mercaptothiazol-4-yl)-3’-methylbuty 1 ]-4- methylpentanamide; 5 (2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-methylpentanamide; (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(2-benzyloxycarbonylthiazol-4-yl)-3-methylbutyl]-4-methylpentanamide; (2S,rS)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3-tnethyH-(2-1G phenoxycarbonylthiazol-4-yl)butyl]pentanamide; i (2S, 1 ’S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3’-methyl-1 -(2-(2-methylpropyloxycarbonyl)thiazol-4-yl]butyl]pentanamide; (2R, 1 ’S)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(4-carboethoxythiazol-2-yl)ethyl]-4-methylpentanamide; 15 (2R, 1 TR)-2-(benzyloxycarbonyl)amino-N-[ 1 ’-(4-carboethoxythiazol-2-yl)ethy I ]-4- methylpentanamide; and (2S, 1 ’S)-N-[ 1 -(2-aminothiazol-4-yl)-3’-methylbutyl]-2-(benzyloxycarbonyl)amino-4-methylpentanamide. 20 8. A compound according to Claim 1 wherein: R12 O II
    ,s. ,s,
  8. 9. A compound according to Claim 8 wherein B is 25 N N -220- 16 17 9 \
  9. 10. A compound according to Claim 9 wherein R1 Us 13 and R^7 and R13 are H. 010764
  10. 11. A compo'und according to Claim 8 wherein E is absent. N-R9R·72
  11. 12. A compound according to Claim 8 in which R^ js i
  12. 13. A compound according to Claim 8 in which R^ or R1^ are i-Bu. 14. A compound according to Claim 8 which is:
  13. 15. A compound according to Claim 8 wherein R17 or R77 is R^OC(O)-.
  14. 16. A compound according to Claim 8 selected from the group consisting of:( 1 S)-N-[4- [(l-benzyloxycarbonylamino)-3-methyIbutyl]thiazol-2-ylcarbon,yl]-N’-(N- benzyloxycarbonyl-L-leucinyl)hydrazide; N-benzyloxycarbonyl-L-leucinyl-N-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide; and (lS)-N-[2-[(l-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N’-(N- benzyloxycarbonyl-L-leucinyl)hydrazide.
  15. 17. A compound according to Claim 1 wherein: O R' andQ = 24 ,22 R25 -N'Y ,21 26 ,23 -221- 010764
  16. 18. A compound according to Claim 17 wherein: R^l and are selected from the group consisting of:N-Cbz-leucinyl, N-Cbz-glycinyl, N-acetyl-leucinyl, N-Cbz-alanyl,
    r22 = r23 = r24= r25 = h< Z
  17. 19. A compound according to Claim 17 selected from the group consisting of:2,2-(N,N’-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;2,2’-(N,N’-bis-cyclohexylacetyl)carbohydrazide;2,2’-(N,N’-bis-4-methylpentanoyl)carbohydrazide;2,2’-(N,N’-bis-cyclopentylacetyl)carbohydrazide;2,2’-(N,N’-bis-benzyioxycarbonylglycinyl)carbohydrazide;2,2’-(N,N’-bis-acetyl-L-leucinyl)carbohydrazide;2,2’-(N,N’-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide; and2-(N-benzyloxycarbonyl-L-leucinyl)-2’-[N’-(4-methylpentanoyl)]carbohydrazide.
  18. 20. A compound according to Claim 1 wherein:
  19. 21. A compound according to Claim 20 wherein R^0 is selected from the groupconsisting of -Me and -CH2CH2Me2-
  20. 22. A compound according to Claim 20 wherein R^^ is selected from the groupconsisting of -Pr, -Bu, and -CH2CH2Me2·
  21. 23. A compound according to Claim l wherein R^4 is -r-Bu. -222- 010764
  22. 24. A compound according to Claim 20 selected from the group consisting of:bis-(Cbz-leuciny 1)-1,3-diamino-propan-2-one; bis-1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one; l-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one; l-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butyl ester)-amino-propan-2-one; l-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one; bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one; l-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-amino-propan-2-one; l-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one; l-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one; bis-1,3-(Cbz-leuciny l)-diamino-5-methy l-(S)-hexan-2-one; i-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one; and l-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-amino-propan-2-one.
  23. 25. A compound according to Claim 24 known as l-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one.
  24. 26. A compound according to Claim 1 wherein:
    II
    and Q=
  25. 27. A compound according to Claim 26 wherein: R35 is selected from the group consisting of Ph, Cl CN or pyridine.
  26. 28. A compound according to Claim 27 known as bis-1,3-(4-(3-chloro-2-cyano- phenoxy)-phenyl sulfonamido)-propan-2-one. -223- 0 î 0764
  27. 29. A compound according to Claim 27 known bis-l,3-(4-phenoxy-phenyîsulfonamido)-propan-2-one.
  28. 31. A compound according to Claim 30 wherein R36 is selected from the groupconsisting of: 10
  29. 32. A compound according to Claim 30 wherein R^ of said compound is Me. 15
  30. 33. A compound according to Claim 31 selected from the group consisting of:l-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)phenyl sulfonamido)-propan-2-one; 1 -(Cbz-leucinyl)- amino-3-(tosy l-amino)-propan-2-one; 20 l-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)propan-2-one; l-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;l-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)propan-2-one; andl-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one. -224- 010764
  31. 34. A compound according to Claim 33 known as l-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one.
  32. 35. A compound according to Claim 33 known as l-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one.
  33. 36. A compound according to Claim 33 known as l-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one.
  34. 37. A compound according to Claim 1 wherein:
  35. 38. A compound according to claim 37 wherein r43 is 2-dibenzofuranylsulfonyl.
  36. 39. A compound according to Claim 38 selected from the group consisting of:(S)-pheny lmethy 1 [ 1 - [ [ [3- [benzy loxycarbony 1-leuciny l-amino]-2-oxopropy 1]-1 - (benzyl)amino]carbonyl]-3-methylbutyl]carbamate; (S)-Phenylmethyl [l-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3- (benzyl)aminojcarbonyl]-3-methylbutyl]carbamate; (S)-Phenylmethyl [l-([[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4- pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate; l-i[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyI) benzamide; and (S)-Phenylmethyl [l-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-l-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate. -225- 010764
  37. 40. À compound according to Claim 39 known (S)-phenylmethyl [ l-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-l-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyljcarbamate.
  38. 41. A compound according to Claim 39 known as (S)-phenylmethyl [ l-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-l-(benzyl)amino]carbonyl]-3-methylbutyljcarbamate.
  39. 42. A compound according to Claim 1 wherein:
    43. A compound according to Claim 42 wherein: RA c 44 = CH(R53)NHR54; R45, R46, R48, R49, R50 and R51 are H; R4? is independently CH3, benzyl, 2-pyridinylmethoxy, 4- dimethylaminobenzyl ; J = C(O); R52 = Ar, CH(R10)Ar, CH(R10)OAr, N(R10)Ar, CH(R10)NR”R11; r53 - ethyl, i-Bu; r54 = R47t R47C(O), r47qc(O); R56 = H,CH3,i-Bu; R57 = R47, R47OC(O); Ar = phenyl or naphthyl, optionally substituted by one or more of Ph-CQ. galkyl, Het-CQ.galky 1, C j .^alkoxy, Ph-CQ.^alkoxy, Het-Cg. galkoxy, OH, (CH2)i.6NR58R59, O(CH2)1.6NR58R59; r58} r59 = h, Cj.^alkyl, Ar-Cg^alkyl; Het-CQ.galkyl.
  40. 44. A compound according to Claim 42 selected from the group consisting of: -226- 010764 2-[N-(N-benzyloxÿcarbonyl-L-leucinyl)]-2-[N’-(4- phenoxyphenylsulfonyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-alanyl)j-2’-[N-(N-benzyloxycarbonyl-L- leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(4-phenylbenzoyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(4-methoxybenzoyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(4-phenoxybenzoyl)]carbohydrazide; 2-(N-acetyl)-2’-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-acetyl-L-leuçinyl)]-2’-[N’-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide; 2-[N-(N-acetyl-L-alanyl)]-2’-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2-[N’-[4-(N,N- dimethylaminomethyl)benzoyl)]]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2-[N-[4-hydroxy-[3-(4- morpholinomethyl)]]benzoyl]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2-[N’-[4-(N,N- dimethylaminomethyI)benzyloxy]carbonyl-L-leucinyl]carbohydrazide; 2-(N-benzoyl)-2’-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-[3-(4- morpholinomethyl)benzoyl]]carbohydrazide; 2-[N-(3-benzyloxybenzoyl)]-2-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-[4-[3-(N-N-dimethylamino)-l- propyloxy]benzoyl]]carbohydrazide; 2-[N-(2-benzyloxybenzoyl)]-2’-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-[3-(4- pyridylmethoxy)benzoyl]]carbohydrazide; 2-[N-(4-benzyloxybenzoyl)]-2-[N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(3-benzyloxy-5- methoxy)benzoyl]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(3-benzyloxy-4,5- dimethoxy)benzoyl]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucÎnyl)]-2’-[N’-(3-benzyloxy-5- ethoxy)benzoyl]carbohydrazide; 2-[N-(N-benzyloxycarbonylglycinyl)]-2-[N’-(N-benzyloxycarbonyl-L- leucinyl)]carbohydrazide; -227- 010764 2-[N-(3-benzyloxybenzoyl)]-2’-[N-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(4-phenylphenylacetyl)]carbohydrazide; (2’S)-2-[N-(3-benzyloxybenzoyI)]-2’-[N’-(N-benzyloxycarbonyl-2- aminobutyryl)]carbohydrazide; 2,2’-[N,N’-[bis-(4-phenylphenylacetyl)]]carbohydrazÎde; (2TRS)'2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[2-(4-, phenylphenoxy)propionyl]carbohydrazide; 2-[N-(3-benzyloxybenzoyl)]-2’-[N’-(4-methylpentanoyl)]carbohydrazide; (2RS, 2TRS)-2,2’-[N,N’-[bis-[2-(4-phenylphenyl)-4-methylpentanoyl)]]]carbohydrazide; (2’RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-[2-(4-phenylphenyl)-4- methylpentanoyl).]]carbohydrazide; (2’RS)-2-[N-(3-benzyloxybenzoyl)]- 2’-[N’-[2-(4-phenylphenyl)-4- methylpentanoyl)]]carbohydrazide; 2-[N-(3-benzyloxybenzoyl)]-2’-[N’-(N-benzyloxycarbonyl-N-methyl-L- leucinyl)]carbohydrazide; 2-(N-(3-benzyloxybenzoyl)]-2’-[N’r[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]]carbohydrazide; 2-[N-[3-(4-pyridylmethoxy)benzoyl]]-2’-[N’-[N-(2-pyridinylmethoxycarbonyl)-L- leucinyl]]carbohydrazide; (2RS)-2-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]-2’-[N’-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-[2-(4-phenylphenyl)-4- methylpentanoyl)]]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyI)]-2’-[N’-[2-(4-phenylphenyl)-4- methylpentanoyl)]]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)b2’-[N’-[N-(4-phenylphenyl)-N-(2- methylpropyl)carbamoyl]]carbohydrazide; 2-[N-(3-benzyloxybenzoyl)l-2-[N’-(N-methyl-L-leucinyl)]carbohydrazide; and2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2’-[N’-(N-methyl-L-leucinyl)]carbohydrazide.
  41. 45. A compound according to Claim 1 wherein: -228- 010764 D = θ and Q= R63
  42. 46. A compound according to Claim 45 wherein G is:
  43. 47. A compound according to Claim 45 wherein r63 is H and R^4 is H.
  44. 48. A compound according to Claim 45 wherein R66 is i-butyl and R^9 is10 i-butyl.
  45. 49. A compound according to Claim 45 wherein R6^ is CH(r69)NR61r70
  46. 50. A compound according to Claim 49 wherein R^9 is i-butyl. 15
  47. 51. A compound according to Claim 50 wherein R^ Hs H.
  48. 52. A compound according to Claim 49 wherein R7^ is R^2OC(O), in which R62 is
  49. 53. A compound according to Claim 45 wherein R65 is Ar or CH(R69)Ar, in which Arin said R^5 group is -229- 010764
  50. 54. A compound according to Claim 45 wherein L is 5 CH(R4)NR’R6i CH(R4)Ar, NR4r5, CH(R4)OAr’, Ar, or Het.
  51. 55. A compound according to Claim 54 wherein R4 is i-butyl.
  52. 56. A compound according to Claim 45 wherein L is 10 CH(R66)NR60R68, CH(R66)Ar, NR66R67, CH(r66)0At’, Ar, or Het, in which Ar in said L group is
    15
  53. 57. A compound according to Claim 54 wherein L is Het, in which said Het is -230- 010764
  54. 58. A compound according to Claim 54 wherein L is NR^6r67
  55. 59. A compound according to Claim 54 wherein L is CH(R.66)r60r68 /
  56. 60. A compound according tô Claim 45 which is:
    O
  57. 61. A compound according to Claim 45 which is :
  58. 62. A compound according to Claim 45 selected from the group consisting of: (lS)-N-[2-[(l-benzyloxycarbonylamino)-3-methylbutylîthiazol-4-ylcarbonyl]-N- (4-phenoxyphenylsulfonyl)hydrazide; ( 1 S)-N-[4-[ 1 -(N-benzyloxycarbony l-L-leucinylamino)-3-methy lbuty 1 ] thiazol-2-ylcarbonyl]-N’-(N-benzyloxycarbonyl-L-leucinyl)hydrazide; (lS)-N-[2-[(l-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N- (4-phenylphenylacetyl)hydrazide; (lS)-N-[2-[(l-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N- [3-(4-pryidinylmethoxy)benzoyl]hydrazide; -231- 010764 N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(4-pyridinylmethoxycarbonyl)-L-leucÎnyl]-N-[2-[4-(l,2,3-thiadiazol-4- yl)phenyl]thiazol-4-ylcarbonyl]hydrazide; N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; (lS,2’RS)-N-[2-[(l-benzyloxycarbonylamïno)-3-methylbutyl]thiazol-4- ylcarbonyl]-N’-[2-(4-phenylphenylacetyl)-4-methylpentanoyI]hydrazide; N-[2-(3-behzyloxyphenyl)thÎazol-4-ylcarbonyl]-N’-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; (lRS)-N-[2-[l-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N-[N-(4- pyridinylmethoxycarbonyI)-L-Ieucinyl]hydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl)hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N’-[2-(4-phenylbenzyl)thiazol-4- ylcarbonyl]hydrazide; N-[2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-L-Ieucinyl)-N’-[2-[N-(2-methylpropyl)-N- phenyrâmino]thiazol-4-ylcarbonyl]hydrazide; N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyI]hydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N’-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyl]hydrazide; N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N-[N-(2- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N’-[N-(3- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; and -232- 010764 N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N’-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide.
  59. 63. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
  60. 64. A method of inhibiting a cysteine protease comprising administering to a patient in need thereof an effective amount of a compound according to Claim 1.
  61. 65. A method according to Claim 64 wherein said cysteine protease is cathepsin K. Z
  62. 66. A method of treating a disease characterized by bone loss comprisinginhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 1.
  63. 67. A method according to Claim 66 wherein said disease is osteoporosis.
  64. 68. A method according to Claim 66 wherein said disease is periodontitis.
  65. 69. A method according to Claim 66 wherein said disease is gingivitis. /
  66. 70. A method of treating a disease characterized by excessive cartilage or matrix dégradation comprising inhibiting said excessive cartilage or matrix dégradation by administering to a patient in need thereof an effective amount of a compound according to Claim 1.
  67. 71. A method according to Claim 70 wherein said disease is osteoarthritis.
  68. 72. A method according to Claim 70 wherein said disease is rheumatoid arthritis. !
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US1374796P 1996-03-20 1996-03-20
US1789296P 1996-05-17 1996-05-17
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Families Citing this family (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741818A (en) 1995-06-07 1998-04-21 University Of Saskatchewan Semicarbazones having CNS activity and pharmaceutical preparations containing same
US6586466B2 (en) 1995-10-30 2003-07-01 Smithkline Beecham Corporation Carbohydrazide-protease inhibitors
US20020128476A1 (en) * 1996-08-08 2002-09-12 Smithkline Beecham Corporation Inhibitors of cysteine protease
DZ2285A1 (fr) * 1996-08-08 2002-12-25 Smithkline Beecham Corp Inhibiteurs de protéase de la cystéine.
JP2000517319A (ja) * 1996-08-28 2000-12-26 スミスクライン・ビーチャム・コーポレイション システインプロテアーゼのインヒビター
NZ500590A (en) 1997-04-22 2001-11-30 Cocensys Inc Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
MA26487A1 (fr) * 1997-04-29 2004-12-20 Smithkline Beecham Corp Heterocyclecetohydrazides inhibiteurs de proteases, procede pour leur preparation et compositions pharmaceutiques les contenant .
IL132630A0 (en) * 1997-05-08 2001-03-19 Smithkline Beecham Corp Protease inhibitors
MA26618A1 (fr) * 1998-04-09 2004-12-20 Smithkline Beecham Corp Composes et compositions pharmaceutiques pour le traitement du paludisme
DZ2796A1 (fr) * 1998-05-21 2003-12-01 Smithkline Beecham Corp Composés à fonction bis-aminométhyl-carbonyle nouveaux, procédé pour leur préparation et compositions pharmaceutiques les contenant.
AU9110298A (en) * 1998-05-21 1999-12-06 Smithkline Beecham Corporation Protease inhibitors
AR018915A1 (es) * 1998-06-24 2001-12-12 Smithkline Beecham Corp Inhibidores de proteasas diacilhidrazinicos, composicion farmaceutica que la comprenden, usos de los mismos para la manufactura de un medicamento, unprocedimiento de fabricacion de dichos compuestos
JP2003527819A (ja) * 1998-08-14 2003-09-24 スミスクライン・ビーチャム・コーポレイション カテプシンｋの阻害方法
MXPA01002102A (es) 1998-09-03 2003-02-24 Kyowa Hakko Kogyo Kk Compuestos heterociclicos que contienen oxigeno.
EP1126833A4 (fr) * 1998-10-29 2004-09-08 Trega Biosciences Inc Derives oxadiazole, thiadiazole et triazole et bibliotheques combinatoires contenant ces derives
US6117870A (en) * 1998-11-12 2000-09-12 Fujirebio Kabushiki Kaisha Cyclic amide derivatives
ES2161594B1 (es) * 1998-12-17 2003-04-01 Servier Lab Nuevos derivados de la hidrazida, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen.
US20030144175A1 (en) * 1998-12-23 2003-07-31 Smithkline Beecham Corporation Protease inhibitors
US6562782B1 (en) 1999-05-10 2003-05-13 University Of Rochester Oligocycloalkanoid compounds and methods of use
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
WO2001034600A1 (fr) 1999-11-10 2001-05-17 Smithkline Beecham Corporation Inhibiteurs de protease
JP2003513971A (ja) 1999-11-10 2003-04-15 スミスクライン・ビーチャム・コーポレイション プロテア−ゼ阻害剤
AU2001243441B2 (en) 2000-03-21 2004-11-25 Smithkline Beecham Corporation Protease inhibitors
WO2002080920A1 (fr) * 2001-04-06 2002-10-17 Axys Pharmaceuticals, Inc. Arylacetamido-cetobenzoxazole comme inhibiteurs de la cysteine protease
US20040204368A1 (en) * 2001-05-31 2004-10-14 Kazuyuki Ohmoto Oxadiazole derivative compounds and drugs containing these compounds as the active ingredient
EP1465862A1 (fr) 2002-01-17 2004-10-13 SmithKline Beecham Corporation Derives de cetoamides a substitution cycloalkyle, utiles comme inhibiteurs de cathepsine k
WO2003095623A2 (fr) * 2002-05-10 2003-11-20 The Trustees Of Columbia University In The City Of New York Lignees cellulaires et systemes mis au point par genie genetique et destines a propager le virus varicelle-zona, et methodes d'utilisation associees
US7101880B2 (en) * 2002-06-24 2006-09-05 Schering Aktiengesellschaft Peptidic compounds as cysteine protease inhibitors
US7056947B2 (en) * 2002-07-05 2006-06-06 Georgia Tech Research Corp. Aza-peptide epoxides
US8013014B2 (en) 2002-07-05 2011-09-06 Georgia Tech Research Corporation Aza-peptide epoxides
US20060020001A1 (en) * 2002-12-23 2006-01-26 Allan Shepard Use of cathepsin k inhibitors for the treatment of glaucoma
US7384970B2 (en) * 2003-03-24 2008-06-10 Irm Llc Inhibitors of cathepsin S
US7109243B2 (en) * 2003-03-24 2006-09-19 Irm Llc Inhibitors of cathepsin S
EP1633702B1 (fr) * 2003-05-30 2008-07-02 Prozymex A/S Inhibiteurs de protease
US7173051B2 (en) * 2003-06-13 2007-02-06 Irm, Llc Inhibitors of cathepsin S
JP2007502831A (ja) * 2003-08-20 2007-02-15 ニトロメッド インコーポレーティッド ニトロソ化およびニトロシル化心血管化合物、組成物、ならびに使用方法
US7256207B2 (en) * 2003-08-20 2007-08-14 Irm Llc Inhibitors of cathepsin S
US20070238740A1 (en) * 2003-08-28 2007-10-11 Nitromed, Inc. Nitrosated And Nitrosylated Cardiovascular Compounds, Compositions And Methods Of Use
US20090131342A1 (en) * 2004-01-22 2009-05-21 Nitromed, Inc. Nitrosated and/or nitrosylated compounds, compositions and methods of use
GB0412553D0 (en) * 2004-06-04 2004-07-07 Univ Aberdeen Therapeutic agents for the treatment of bone conditions
WO2006041855A2 (fr) 2004-10-04 2006-04-20 Nitromed, Inc. Compositions et procedes faisant intervenir des composes apocynine et des donneurs d'oxyde nitrique
DK1836201T4 (da) * 2004-12-20 2013-11-11 Genentech Inc Pyrrolidininhibitorer af IAP.
AU2006206249A1 (en) * 2005-01-21 2006-07-27 Nicox S.A. Cardiovascular compounds comprising heterocyclic nitric oxide donor group compositions and methods of use
EP1858525A2 (fr) * 2005-02-16 2007-11-28 Nitromed, Inc. Sels donneurs d oxyde nitrique organique de composes antimicrobiens et composes et procedes d utilisation
JP2008531697A (ja) * 2005-02-28 2008-08-14 ニトロメッド インコーポレーティッド 酸化窒素増強基を含む心血管化合物、組成物および使用法
WO2006099058A2 (fr) * 2005-03-09 2006-09-21 Nitromed, Inc. Sels organiques d'antagonistes de l'angiotensine ii augmentant le taux de monoxyde d'azote endogene, compositions et procedes d'utilisation correspondants
WO2006127591A2 (fr) * 2005-05-23 2006-11-30 Nitromed, Inc. Sels renforçant l'oxyde nitrique organique de composes anti-inflammatoires non steroidiens, compositions et procedes d'utilisation
EP1915157A4 (fr) 2005-08-02 2010-09-01 Nicox Sa Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US20090054381A1 (en) * 2005-10-04 2009-02-26 Nitromed, Inc. Methods for treating respiratory disorders
US7838023B2 (en) * 2005-11-16 2010-11-23 Nitromed, Inc. Furoxan compounds, compositions and methods of use
TW200804288A (en) * 2005-12-12 2008-01-16 Astrazeneca Ab Alkylsulphonamide quinolines
US20090053328A1 (en) * 2005-12-20 2009-02-26 Nitromed, Inc. Nitric Oxide Enhancing Glutamic Acid Compounds, Compositions and Methods of Use
WO2007075542A2 (fr) * 2005-12-22 2007-07-05 Nitromed, Inc. Composes au pyruvate activateurs d'oxyde nitrique, compositions et procedes d'utilisation
AU2007243765A1 (en) 2006-03-29 2007-11-08 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
GB0705400D0 (en) 2007-03-21 2007-05-02 Univ Aberdeen Therapeutic compounds andm their use
WO2008134679A1 (fr) * 2007-04-30 2008-11-06 Genentech, Inc. Inhibiteurs de iap
AU2009203971A1 (en) * 2008-01-11 2009-07-16 Genentech, Inc. Inhibitors of IAP
JP2011529962A (ja) 2008-08-02 2011-12-15 ジェネンテック， インコーポレイテッド Ｉａｐのインヒビター
GB0817207D0 (en) 2008-09-19 2008-10-29 Pimco 2664 Ltd therapeutic apsac compounds and their use
GB0817208D0 (en) 2008-09-19 2008-10-29 Pimco 2664 Ltd Therapeutic apsap compounds and their use
WO2014170648A1 (fr) 2013-04-19 2014-10-23 Astrazeneca Ab Composé antagoniste du récepteur nk3 (nk3ra) utilisé dans une méthode pour traiter le syndrome des ovaires polykystiques (sopk)
GB201311361D0 (en) 2013-06-26 2013-08-14 Pimco 2664 Ltd Compounds and their therapeutic use
AU2015367528B2 (en) 2014-12-17 2020-05-14 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
CN105424646B (zh) * 2015-11-05 2018-09-14 湖北瑞昊安科医药科技发展有限公司 一种监控γ-氨基丁酸生物转化过程的系统和方法

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1051084A (fr) * 1964-06-25
US4038247A (en) * 1970-05-19 1977-07-26 Ciba-Geigy Corporation Stabilizing polyolefins with diacyl dihydrazides
US5142056A (en) * 1989-05-23 1992-08-25 Abbott Laboratories Retroviral protease inhibiting compounds
US5057525A (en) * 1981-10-01 1991-10-15 Janssen Pharmaceutica N.V. Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives
IT1195287B (it) * 1981-11-05 1988-10-12 Ausonia Farma Srl Derivato tiazolico,procedimento per la sua preparazione e relative composizioni farmaceutiche
US4518528A (en) * 1983-05-19 1985-05-21 Rasnick David W α Amino fluoro ketones
US4749792A (en) * 1984-09-26 1988-06-07 E. R. Squibb & Sons, Inc. Diamino ketones and alcohols as analgesic agents
US4638010A (en) * 1985-02-28 1987-01-20 E. R. Squibb & Sons, Inc. Ester substituted aminoalkanoylureido amino and imino acid and ester compounds
KR900006545B1 (ko) * 1986-03-14 1990-09-13 신텍스(미합중국) 인코포레이티드 트란스글루타미나제 억제제
US5374637A (en) * 1989-03-22 1994-12-20 Janssen Pharmaceutica N.V. N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives
US4994471A (en) * 1989-05-12 1991-02-19 Boc, Inc. N-aryl-N-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds
GB9019558D0 (en) * 1990-09-07 1990-10-24 Szelke Michael Enzyme inhibitors
EP0504938A3 (en) * 1991-03-22 1993-04-14 Suntory Limited Prophylactic and therapeutic agent for bone diseases comprising di- or tripeptide derivative as active ingredient
JP3190431B2 (ja) * 1991-07-01 2001-07-23 三菱化学株式会社 ケトン誘導体
JPH05140063A (ja) * 1991-11-19 1993-06-08 Suntory Ltd ジペプチド誘導体及びそれを有効成分とする骨疾患の予防及び治療剤
US5216168A (en) * 1992-04-01 1993-06-01 G. D. Searle & Co. 2- and 3- amino and azido derivatives of 1,5-iminosugars
US5206251A (en) * 1992-04-01 1993-04-27 G. D. Searle & Co. 2- and 3- amino and azido derivatives of 1,5-iminosugars
EP0650368A1 (fr) * 1992-06-24 1995-05-03 Cortex Pharmaceuticals, Inc. Emploi d'inhibiteurs de calpaine dans l'inhibition et le traitement d'etats medicaux associes a une activite de calpaine accrue
US5374623A (en) * 1992-08-20 1994-12-20 Prototek, Inc. Cysteine protease inhibitors effective for in vivo use
CA2111930A1 (fr) * 1992-12-25 1994-06-26 Ryoichi Ando Derives d'aminocetones
DK0603769T3 (da) * 1992-12-25 1999-06-14 Mitsubishi Chem Corp Alfa-aminoketonderivater
JPH06199850A (ja) * 1992-12-28 1994-07-19 Tanabe Seiyaku Co Ltd インドール含有ペプチド及びその製法
JP2848232B2 (ja) * 1993-02-19 1999-01-20 武田薬品工業株式会社 アルデヒド誘導体
EP0693124A1 (fr) * 1993-04-06 1996-01-24 Forsyth Dental Infirmary For Children Genes humains specifiques et apparentes aux osteoclastes
CA2120648C (fr) * 1993-04-22 2004-06-22 Neil H. Nodelman Nouveau systeme de catalyseur destine aux systemes rim contenant des additifs acides
CA2122227A1 (fr) * 1993-04-29 1994-10-30 Roland E. Dolle Analogues de peptides utilises comme inhibiteurs irreversibles de la protease de l'interleukine-1.beta.
US5866545A (en) 1993-08-13 1999-02-02 Merck & Co., Inc. Substituted ketone derivatives as inhibitors of interleukin-1β converting enzyme
US5501969A (en) * 1994-03-08 1996-03-26 Human Genome Sciences, Inc. Human osteoclast-derived cathepsin
AU2223595A (en) * 1994-04-13 1995-11-10 Takeda Chemical Industries Ltd. Aziridine derivatives, their production and use
US5585387A (en) * 1994-10-07 1996-12-17 Torcan Chemical Ltd. Prepration of cisapride
US6544767B1 (en) * 1994-10-27 2003-04-08 Axys Pharmaceuticals, Inc. Cathespin O2 protease
TW438591B (en) * 1995-06-07 2001-06-07 Arris Pharm Corp Reversible cysteine protease inhibitors
WO1997049668A1 (fr) * 1996-06-13 1997-12-31 Smithkline Beecham Corporation Inhibiteurs de cysteine protease
AU6333296A (en) * 1996-06-14 1998-01-07 Human Genome Sciences, Inc. Cathepsin k gene
US5861298A (en) * 1996-06-17 1999-01-19 Smithkline Beecham Corporation Cathepsin K gene
DZ2285A1 (fr) * 1996-08-08 2002-12-25 Smithkline Beecham Corp Inhibiteurs de protéase de la cystéine.
JP2000517319A (ja) * 1996-08-28 2000-12-26 スミスクライン・ビーチャム・コーポレイション システインプロテアーゼのインヒビター
US5830850A (en) * 1996-08-28 1998-11-03 Mount Sinai School Of Medicine Of The City Of New York Methods for the treatment of bone resorption disorders, including osteoporosis

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NO981938L (no) 1998-06-29
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WO1997016433A1 (fr) 1997-05-09
NO20006716L (no) 1998-06-29
KR19990067184A (ko) 1999-08-16
EA199800353A1 (ru) 1998-12-24
US6057362A (en) 2000-05-02
AU1118097A (en) 1997-05-22
NO20006718L (no) 1998-06-29
NO20006716D0 (no) 2000-12-29
US6331542B1 (en) 2001-12-18
HUP9900964A2 (hu) 1999-07-28
CN1341593A (zh) 2002-03-27
AP9801222A0 (en) 1998-06-30
CN1341590A (zh) 2002-03-27
NO20006717D0 (no) 2000-12-29
NO20006718D0 (no) 2000-12-29
BG102475A (en) 1999-04-30
EP0934291A4 (fr) 1999-08-11
SK56798A3 (en) 1998-12-02
US5998470A (en) 1999-12-07
PL326508A1 (en) 1998-09-28
TR199800767T2 (xx) 1998-07-21
NO981938D0 (no) 1998-04-29
NO20006717L (no) 1998-06-29
MX9803548A (es) 1998-09-30
HUP9900964A3 (en) 2001-02-28
EP0934291A1 (fr) 1999-08-11
CZ132798A3 (cs) 1999-02-17
US6232342B1 (en) 2001-05-15
US6284777B1 (en) 2001-09-04
CN1341592A (zh) 2002-03-27

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