Protease inhibitors

A compound according to Formula I:

• 72
• provided that at least two of X, Y and Z are heteroatoms and at least one of X, Y and Z is N, or one of X, Y and Z is C=N, C=C or N=N and the other two are CR4 or N, provided that X, Y and Z together comprise at least two N;
• indicates a single or double bond in the five-membered heterocycle;
• m=0, 1, 2;
• n=1 to 6;
• φ=0, 1, 2;
• Ar=phenyl, naphthyl, optionally substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NR58R59, O(CH2)1-6NR58R59;
• Ar′=phenyl or naphthyl, optionally substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NR58R59, O(CH2)1-6NR58R59, or halogen;
• R′=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R1=H, C1-6alkyl;
• R2=C4-6alkyl, C4-6alkenyl, benzyl;
• R3=C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl, R5CO—, R5SO2—, R5OC(O)—, R5NHCO—;
• R4=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R5=Ar-0-6alkyl, Het-C0-6alkyl;
• R6=H, C1-6alkyl, CH2CF3, Ar—C0-6alkyl, Het-C0-6alkyl;
• R7=C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R8═H;
• C2-6 alkenyl;
• C2-6alkynyl;
• Het;
• Ar;
• C1-6alkyl, optionally substituted by OR′, SR′, NR′2, CO2R′, CO2NR′2, N(C═NH)NH2, Het or Ar;
• R9=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R10=C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R11=H, C1-6alkyl, Ar—C1-6alkyl, Het-C0-6alkyl, or
• R17R9—
• 73
• R12=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R13=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R14
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• —R9R72, Ac;
• R15=H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C1-6alkyl optionally substituted by OR9, NR92, CONR92, N(C═NH)NH—, Het or Ar;
• R16=C2-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C2-6alkyl optionally substituted by OR9, SR9, NR92, CO2R9, CONR92, N(C═NH)NH—, Het or Ar;
• R19=H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C1-6alkyl optionally substituted by OR9, SR9, NR92, CO2R9, CONR92, N(C═NH)NH—, Het or Ar;
• R17=R72=H, C1-6alkyl, R10, R10C(O)—, R10C(S)—, R10OC(O)—;
• R21=R26 C5-6alkyl;
• C2-6alkenyl;
• C3-11cycloalkyl;
• T-C3-6alkyl;
• V-C1-6alkyl;
• T-C2-6alkenyl;
• T-(CH2)nCH(T)(CH2)n;
• optionally substituted by one or two halogens, SR20, OR20,NR20R27 or C1-4alkyl;
• R27=R28CO, R28OCO;
• R28=C1-6alkyl;
• C3-11cycloalkyl;
• Ar;
• Het;
• T-C1-6alkyl;
• T-(CH2)nCH(T)(CH2)n;
• optionally substituted by one or two halogens, SR20, OR20, NR2OR73, C1-6alkyl;
• R20=R22=R23=R24=R25=R73=H, C1-4alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R29=
• 75
• Cbz-leucinyl-;
• 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-;
• 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxybenzoyl-, 2- or 3-benzyloxybenzoyl-, biphenyl 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 carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3-benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-;
• 2-,3-, or 4-pyridylmethyloxycarbonyl-aminoacid-;
• aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-;
• C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl;
• R30=—H, C1-6 alkyl;
• R31=
• 76
• Cbz-leucinyl-;
• 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-;
• 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-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-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl;
• acetyl-leucinyl-, 6- or 8-quinoline carbonyl, biphenyl acetyl, alpha-isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3-benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-;
• 2-,3-, or 4-pyridylmethyloxycarbonyl-aminoacid-;
• aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-;
• C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, substituted heteroaryl C0-C6alkyl sulfonyl;
• R32=OCH2Ar, OCH2C1-6alkyl, aryl substituted C0-6alkyl, heteroaryl substituted C0-6alkyl,4-imidazole methylene;
• 2-, 3-, or 4-pyridylmethylneneoxy;
• 4-pyridyl methylene, 2-pyridyl sulfonyl, 4-pyridyl, aryl C0-6alkyloxy, heteroaryl substituted C0-6alkyloxy;
• R33=C1-6alkyl, —CH2Ph, —CH2CH2CO2R34;
• R34=—H, C1-6alkyl;
• R35=Ar, HetAr;
• R36=Aryl, heteroaryl, pyridyl, isoquinolinyl;
• R37=C1-6alkyl, —CH2Ph, —CH2CH2CO2R34;
• R38=Cbz;
• C1-6alkyl or aryl substituted Cbz;
• C1-6alkyl —CO;
• benzoyl;
• C1-6alkyl or aryl substituted benzoyl;
• R39=
• 77
• Cbz-leucinyl-;
• 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-;
• 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-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-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl;
• acetyl-leucinyl-, 6- or 8-quinoline carbonyl, biphenyl acetyl, alpha-isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3-benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-;
• 2-,3-, or 4-pyridylmethyloxycarbonyl-aminoacid-;
• aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-;
• C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl;
• R40=H and C1-6alkyl;
• R41=H and C1-6alkyl;
• R42=C1-6alkyl, aryl substituted C1-6alkyl and hetero aryl substituted C1-6alkyl,;
• H when R43 is C1-6alkyl, aryl substituted C1-6alkyl;
• and heteroaryl substituted C1-6alkyl;
• R43=C1-6alkyl, aryl substituted C1-6alkyl and hetero aryl substituted C1-6alkyl,;
• H when R42 is C1-6alkyl, aryl substituted C1-6alkyl;
• and heteroaryl substituted C1-6alkyl;
• R44=CH(R53)NR45R54, CH(R55)Ar, C5-6alkyl;
• R45=R46=R47=R48=R49=R50=R51=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R52=Ar, Het, CH(R56)Ar, CH(R56)OAr, N(R56)Ar, C1-6alkyl, CH(R56)NR46R57;
• R53=C2-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl,
• R53 and R45 may be connected to form a pyrrolidine or piperidine ring;
• R54=R57=R47, R47C(O), R47C(S), R47OC(O);
• R55=R56=R58=R59=H, C1-6alkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R60=R61=R62=R63=R64=H, C1-6alkyl, Ar—C0-6alkyl, or Het-C0-6alkyl;
• R65=C1-6alkyl, Ar, Het, CH(R69)Ar, CH(R69)OAr, N(R69)Ar, CH(R69)NR61R70;
• R66=R69=R71=H. C1-6alkyl, (CH2)0-6—C3-6cycloalkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R67=C1-6alkyl, (CH2)0-6—C3-6cycloalkyl, Ar—C0-6alkyl, Het-C0-6alkyl;
• R66 and R67 may be combined to form a 3-7 membered monocyclic or 7-10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 of C1-6alkyl, Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NR58R59, O(CH2)1-6NR58R59;
• R68=R70=R62, R62C(O), R62C(S), R62OC(O), R62OC(O)NR59CH(R71)(CO);
• and pharmaceutically acceptable salts thereof.