1-Acylamino-2-Hydroxy-3-Amino- -Arylalkanes as Renin Inhibitors

A compound of formula II:

• wherein
• R1 is hydrogen, halogen, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy, cyano-lower alkoxy, hydroxy-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy, or aryl;
• R2 is hydrogen, halogen, cyano, carbamoyl, lower alkyl, lower haloalkyl, cycloalkyl, halocycloalkyl, cycloalkyl-lower alkyl, halocycloalkyl-loweralkyl, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower haloalkoxy-lower alkyl, lower alkoxy-lower alkyl, lower haloalkoxy-lower alkyl, cycloalkoxy-lower alkyl, halocycloalkoxy-lower alkyl, hydroxy, lower alkanoyloxy-lower alkoxy, hydroxy-lower alkoxy, halo-(hydroxy)-lower alkoxy, lower alkanesulfonyl-(hydroxy)-lower alkoxy, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, lower alkoxycarbonyl-amino-lower alkyl, aminocarbonylamino-lower alkyl, lower alkylaminocarbonylamino-lower alkyl, di(lower alkyl)aminocarbonylamino-lower alkyl, aminosulfonylamino-lower alkyl, lower alkylaminosulfonylamino-lower alkyl, di(lower alkyl)aminosulfonylamino-lower alkyl, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, lower alkoxycarbonyl-amino-lower alkoxy, aminocarbonylamino-lower alkoxyl, lower alkylaminocarbonylamino-lower alkoxy, di(lower alkyl)aminocarbonylamino-lower alkoxy, aminosulfonylamino-lower alkoxy, lower alkylaminosulfonylamino-lower alkoxy, di(lower alkyl)aminosulfonylamino-lower alkoxy, oxo-lower alkoxy, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower halocycloalkoxy, cycloalkyl-lower alkoxy, halocycloalkyl-lower alkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, halocycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, lower haloalkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy, lower alkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, optionally N-oxidized pyridyl-lower alkoxy, thiazolylthio-lower alkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy, optionally N-oxidized pyridylthio-lower alkoxy, pyrimidinylthio-lower alkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl;
• R3 is hydrogen, halogen, cyano, carbamoyl, lower alkyl, lower haloalkyl, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkanesulfonyl-lower alkyl, optionally partially hydrogenated or N-oxidized pyridyl-lower alkyl, thiazolyl-thio-lower alkyl or thiazolinylthio-lower alkyl, imidazolylthio-lower alkyl, optionally N-oxidized pyridylthio-lower alkyl, pyrimidinylthio-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkanoyl-amino-lower alkyl, lower alkanesulfonylamino-lower alkyl, polyhalo-lower alkane-sulfonylamino-lower alkyl, pyrrolidino-lower alkyl, piperidino-lower alkyl, piperazino-lower alkyl, N′-lower alkylpiperazino-lower alkyl or N′-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl, thiomorpholino-lower alkyl, S-oxothiomorpholino-lower alkyl or S,S-dioxothio-morpholino-lower alkyl, cyano-lower alkyl, carboxy-lower alkyl, lower alkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-di-lower alkyl-carbamoyl-lower alkyl, cycloalkyl;
• phenyl or naphthyl that is unsubstituted or substituted with one to three groups independently selected from lower alkyl, lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl, trifluoromethoxy, and cyano;
• hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy, aryl, lower haloalkoxy, lower alkylthio-lower alkoxy, lower haloalkylthio-lower alkoxy, lower alkanesulfonyl-lower alkoxy, lower haloalkanesulfonyl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, heterocyclyl-lower alkoxy, optionally partially or fully hydrogenated heteroarylthio-lower alkoxy, such as thiazolylthio-lower alkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy, optionally N-oxidized pyridylthio-lower alkoxy, pyrimidinylthio-lower alkoxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, lower alkanesulfonylamino-lower alkoxy, polyhalo-lower alkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy, piperidino-lower alkoxy, piperazino-lower alkoxy, N′-lower alkylpiperazino-lower alkoxy or N′-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy, thiomorpholino-lower alkoxy, S-oxothiomorpholino-lower alkoxy or S,S-dioxothiomorpholino-lower alkoxy, cyano-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl;
• or
• R2 and R3 taken together with the atoms through which they are attached form a fused dioxolane, dioxane, benzene or cyclohexene ring, wherein said ring is substituted with up to 2 substituents independently selected from lower alkyl and lower alkoxy-lower alkyl;
• R4 is hydrogen, lower alkyl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, or cycloalkyl-lower alkoxy;
• or
• R3 and R4 taken together with the atoms through which they are attached form a fused dioxolane, dioxane, benzene or cyclohexene ring, wherein said ring is substituted with up to 2 substituents independently selected from lower alkyl and lower alkoxy-lower alkyl;
• provided that R3 does not form a ring with R2;
• X is methylene or hydroxymethylene;
• R5 is lower alkyl, lower haloalkyl, cycloalkyl, halocycloalkyl, lower alkyl-cycloalkyl, lower haloalkyl-cycloalkyl, cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl;
• R6 is amino, lower alkylamino, di-lower alkylamino, or lower alkanoylamino;
• R7 is hydrogen, lower alkyl, lower haloalkyl, cycloalkyl, lower alkoxy-lower alkyl, or lower haloalkoxy-lower alkyl;
• X1 is an amino-protecting group;
• X is hydrogen or together with X3 is a bivalent protecting group;
• X3 is hydrogen or a hydroxy-protecting group;
• and the enantiomers, diastereomers, and salts thereof.

A compound of formula III

• wherein
• R5 is lower alkyl or cycloalkyl;
• R7 is hydrogen, lower alkyl, lower haloalkyl, cycloalkyl, lower alkoxy-lower alkyl, or lower haloalkoxy-lower alkyl
• Q is carbonyl, thiocarbonyl, or sulfonyl;
• R8 is lower alkyl, lower haloalkyl, C8-C15alkyl, C8-C15haloalkyl, cycloalkyl, halocycloalkyl, lower alkyl-cycloalkyl, cycloalkyl-lower alkyl, halocycloalkyl-lower alkyl, lower alkoxy-loweralkyl, lower haloalkoxy-lower alkyl, cycloalkoxy-lower alkyl, cycloalkoxy-cycloalkyl, lower alkylthio-lower alkyl, lower haloalkylthio-lower alkyl, lower alkanesulfonyl-lower alkyl, lower haloalkanesulfonyl-lower alkyl, lower alkylthio-cycloalkyl, lower haloalkylthio-cycloalkyl, lower alkanesulfonyl-cycloalkyl, lower haloalkanesulfonyl-cycloalkyl, aryl, aryl-lower alkyl, aryl-lower hydroxyalkyl, arylcycloalkyl, aryloxy-lower alkyl, aryloxy cycloalkyl, arylthio-lower alkyl, arylsulfonyl-lower alkyl, arylthio-cycloalkyl, arylsulfonyl-cycloalkyl, lower alkanoyl-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkanoylamino-lower alkyl, N-mono-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, piperidino-lower alkyl, hydroxypiperidino-lower alkyl, lower alkoxypiperidino-lower alkyl, morpholino-lower alkyl, dimethylmorpholino-lower alkyl, thiomorpholino-lower alkyl, S,S-dioxothiomorpholino-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono-lower alkylcarbamoyl-lower alkyl, N,N-di-lower alkylcarbamoyl-lower alkyl, carboxy-(hydroxy)-lower alkyl, lower alkoxycarbonyl-(hydroxy)-lower alkyl, carbamoyl-(hydroxy)-lower alkyl, N-mono-lower alkylcarbamoyl-(hydroxy)-lower alkyl, N,N-di-lower alkylcarbamoyl-(hydroxy)-lower alkyl, 5- or 6-membered carboxycycloalkyl-lower alkyl, 5- or 6-membered lower alkoxycarbonyl-cycloalkyl-lower alkyl, 5- or 6-membered carbamoylcycloalkyl-lower alkyl, 5- or 6-membered N-mono-alkylcarbamoylcycloalkyl-lower alkyl, N,N-di-lower alkylcarbamoylcycloalkyl-lower alkyl, cyano-lower alkyl, sulfamoyl-lower alkyl, lower alkylsulfamoyl-lower alkyl, or di-lower alkylsulfamoyl-lower alkyl, imidazolyl-lower alkyl, oxopyrrolidinyl-lower alkyl, benzimidazolyl-lower alkyl, oxadiazolyl-lower alkyl, pyridyl-lower alkyl, oxopiperidinyl-lower alkyl or quinolinyl-lower alkyl, piperidin-4-yl-lower alkyl, or lower alkanoylpiperidin-4-yl-lower alkyl, wherein said aryl, imidazolyl, benzimidazolyl, oxadiazolyl, pyridyl, quinolinyl, aryloxy, arylthio and arylsulfonyl groups are optionally substituted with up to four groups independently selected from halo, cyano, nitro, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, optionally halogenated lower alkylthio, optionally halogenated lower alkanesulfonyl, and lower alkoxycarbonyl;
• or R8 is OR9 or NR9R10
• R9 is 1) hydrogen, lower alkyl, lower haloalkyl, lower alkenyl, (C8-C15)alkyl, (C8-C15)haloalkyl, cycloalkyl, halocycloalkyl, lower alkyl-cycloalkyl, cycloalkyl-lower alkyl, halocycloalkyl-lower alkyl, lower alkoxy-loweralkyl, lower haloalkoxy-lower alkyl, cycloalkoxy-lower alkyl, cycloalkoxy-cycloalkyl, lower alkylthio-lower alkyl, lower haloalkylthio-lower alkyl, lower alkanesulfonyl-lower alkyl, lower haloalkanesulfonyl-lower alkyl, lower alkylthio-cycloalkyl, lower haloalkylthio-cycloalkyl, lower alkanesulfonyl-cycloalkyl, lower haloalkanesulfonyl-cycloalkyl, aminocarbonyl-lower alkyl, lower alkyl-amonocarbonyl-lower alkyl, or di(lower alkyl)-amonocarbonyl-lower alkyl, or 2) aryl, aryl-lower alkyl, aryloxy-lower alkyl, arylthio-lower alkyl, or arylsulfonyl-lower alkyl
• wherein aryl is optionally substituted with up to four groups independently selected from halo, cyano, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, optionally halogenated lower alkylthio, and optionally halogenated lower alkanesulfonyl;
• R10 is 1) hydrogen, lower alkyl, lower haloalkyl, (C8-C15)alkyl, (C8-C15)haloalkyl, cycloalkyl, halocycloalkyl, cycloalkyl-lower alkyl, halocycloalkyl-lower alkyl, lower alkoxy-lower alkyl, lower haloalkoxy-lower alkyl, alkylthio-lower alkyl, lower haloalkylthio-lower alkyl, lower alkanesulfonyl-lower alkyl, or lower haloalkanesulfonyl-lower alkyl, or 2) aryl or aryl-lower alkyl
• wherein aryl is optionally substituted with up to four groups independently selected from halo, cyano, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, optionally halogenated lower alkylthio, and optionally halogenated lower alkanesulfonyl;
• or R9 and R10 taken together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring composed of carbon atoms and 0 or 1 N, O, or S atoms in addition to the nitrogen atom to which R9 and R10 are attached, said ring atoms being substituted with the appropriate number of hydrogen atoms and optionally substituted with up to four groups independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, lower alkanoyl, lower alkoxycarbonyl, aryl, aryl-lower alkyl, and oxo, such that substitution of one oxo group on a carbon atom forms a carbonyl group and substitution of one or two oxo groups on sulfur forms sulfoxide or sulfone groups respectively;
• wherein the aryl and arylalkyl groups are substituted with up to four groups independently selected from halo, cyano, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, optionally halogenated lower alkylthio, and optionally halogenated lower alkanesulfonyl;
• X1 is an amino-protecting group;
• X2 is hydrogen or together with X3 is a bivalent protecting group;
• X3 is hydrogen or a hydroxy-protecting group;
• and the enantiomers, diastereomers, and salts thereof;