3,4,5-Substituted piperidines as therapeutic compounds

Method for the inhibition of beta-secretase, cathepsin D, plasmepsin II and/or HIV-protease using a therapeutically effective amount of a compound of the general formula

• in which
• (A) R1 is heterocyclyl, optionally substituted with oxo or oxide, or as specified under (E) or (F), in particular azepanyl, benzo[1,3]dioxolyl, benzofuranyl, benzoimidazolyl, 4H-benzo[1,4]oxazinyl, benzoxazolyl, 4H-benzo[1,4]thiazinyl, 1H-quinolinyl, chromenyl, dihydrobenzo[e][1,4]diazepinyl, dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, dihydro-3H-benzo[1,4]oxazinyl, dihydrobenzo[d][1,3]oxazinyl, dihydro-2H-benzo[1,4]thiazinyl, dihydro-2H-1λ6-benzo[1,4]thiazinyl, dihydro-1H-quinazolinyl, 1a,7b-dihydro-1H-cyclopropa[c]chromenyl, dihydroimidazolyl, 1,3-dihydroindolyl, 2,3-dihydroindolyl, dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 1,1-dioxodihydro-2H-benzo[1,4]thiazinyl, indazolyl, indolyl, 3H-isobenzofuranyl, [1,5]naphthyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo[1,4]oxazinyl, 2-oxobenzoxazolyl, 3-oxo-4H-benzo[1,4]thiazinyl, 2-oxodihydrobenzo[e][1,4]diazepinyl, 2-oxodihydrobenzo[d][1,3]oxazinyl, 2-oxodihydro-1H-quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-1,3-dihydroindolyl, 1-oxo-3H-isobenzofuranyl, 2-oxopiperidinyl 2-oxo-1H-pyrido[2,3-b][1,4]oxazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo[e][1,4]diazepinyl, 4-oxo-3H-thieno[2,3-d]pyrimidinyl, 5-oxo-4H-[1,2,4]triazinyl, phthalazinyl, piperidinyl, pyrazolyl, 1H-pyrido[2,3-b][1,4]oxazinyl, pyridyl, 1H-pyrrolizinyl, 1H-pyrrolo[2,3-b]pyridyl, pyrrolyl, tetrahydrobenzo[e][1,4]diazepinyl, 3H-thieno[2,3-d]pyrimidinyl, tetrahydro-quinoxalinyl, 1,1a,2,7b-tetrahydrocyclopropa[c]chromenyl, tetrahydropyranyl, triazinyl, imidazo[1,5-a]pyridinyl, tetrahydroimidazo[1,5-a]pyridinyl or 1,1,3-trioxodihydro-2H-1λ6-benzo[1,4]thiazinyl;
• (B) R1 is aryl when R2 is tetrazolyl or imidazolyl which may be substituted by 1-3 halogen, hydroxyl, cyano, trifluoromethyl, C1-8-alkyl, halo-C1-8-alkyl, hydroxy-C1-8-alkyl, C1-8-alkoxy-C1-8-alkyl, cyano-C1-8-alkyl, carboxy-C1-8-alkyl, C1-8-alkanoyloxy-C1-8-alkyl, C1-8-alkoxycarbonyloxy-C1-8-alkyl, C1-8-alkoxycarbonyl, C1-8-alkoxy, C2-8-alkenyloxy-C1-8-alkyl, C1-8-alkoxy-C1-8-alkylamino-C1-8-alkyl, C1-8-alkoxy-C1-8-alkylsulfanyl-C1-8-alkyl, C1-8-alkoxy-C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkyl, C1-8-alkylsulfanyl-C1-8-alkoxy-C1-8-alkyl, C1-8-alkylsulfanyl-C1-8-alkyl, C1-8-alkylsulfonyl-C1-8-alkoxy-C1-8-alkyl, C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkoxy-C1-8-alkyl, C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkyl, optionally halogen-substituted C1-8-alkoxy-C1-8-alkoxy-C1-8-alkyl, or heterocyclyl-C0-8-alkoxy-C1-8-alkyl groups, or a C1-8-alkylenedioxy group, and/or by an L1-T1-L2-T2-L3-T3-L4-T4-L5-U radical;
• or
• (C) R1 is aryl when X is —O—CH—R11—CO—NR9—;
• or
• (D) R1 is aryl when Z is -alk-NR9— where alk denotes C1-8-alkylene, and n is 1;
• or
• (E) R1 is aryl which is substituted by 1-4 acetamidinyl-C1-8-alkoxy, acetamidinyl-C1-8-alkyl, acyl-C1-8-alkoxy-C1-8-alkyl, (N-acyl)-C1-8-alkoxy-C1-8-alkylamino, C1-8-alkoxy, C1-8-alkoxy-C1-8-alkoxy, C1-8-alkoxy-C1-8-alkoxy-C1-8-alkyl, C1-8-alkoxy-C1-8-alkyl, (N—C1-8-alkoxy)-C1-8-alkylaminocarbonyl-C1-8-alkoxy, (N—C1-8-alkoxy)-C1-8-alkylaminocarbonyl-C1-8-alkyl, C1-8-alkoxy-C1-8-alkylcarbamoyl, C1-8-alkoxy-C1-8-alkylcarbonyl, C1-8-alkoxy-C1-8-alkylcarbonylamino, 1-C1-8-alkoxy-C1-8-alkylimidazol-2-yl, 2-C1-8-alkoxy-C1-8-alkyl-4-oxoimidazol-1-yl, 1-C1-8-alkoxy-C1-8-alkyltetrazol-5-yl, 5-C1-8-alkoxy-C1-8-alkyltetrazol-1-yl, 6-alkoxyaminocarbonyl-C1-8-alkoxy, C1-8-alkoxyaminocarbonyl-C1-8-alkyl, C1-8-alkoxycarbonyl, C1-8-alkoxycarbonyl-C1-8-alkoxy, C1-8-alkoxycarbonyl-C1-8-alkyl, C1-8-alkoxycarbonylamino-C1-8-alkoxy, C1-8-alkoxycarbonylamino-C1-8-alkyl, C1-8-alkyl, (N—C1-8-alkyl)-C1-8-alkoxy-C1-8-alkylcarbamoyl, (N—C1-8-alkyl)-C1-8-alkoxy-C1-8-alkylcarbonylamino, (N—C1-8-alkyl)-C1-8-alkoxycarbonylamino, (N—C1-8-alkyl)-C0-8-alkylcarbonylamino-C1-8-alkoxy, (N—C1-8-alkyl)-C0-8-alkylcarbonylamino-C1-8-alkyl, (N—C1-8-alkyl)-C1-8-alkylsulphonylamino-C1-8-alkoxy, (N—C1-8-alkyl)-C1-8-alkylsulphonylamino-C1-8-alkyl, C1-8-alkylamidinyl, C1-8-alkylaminocarbonyl-C1-8-alkoxy, di-C1-8-alkylaminocarbonyl-C1-8-alkoxy, C1-8-alkylaminocarbonyl-C1-8-alkoxy-C1-8-alkyl, C1-8-alkylaminocarbonyl-C1-8-alkyl, C1-8-alkylaminocarbonylamino-C1-8-alkoxy, C1-8-alkylaminocarbonylamino-C1-8-alkyl, di-C1-8-alkylaminocarbonyl-C1-8-alkyl, C1-8-alkylamino-C2-8-alkoxy, di-C1-8-alkylamino-C2-8-alkoxy, C1-8-alkylamino-C1-8-alkyl, di-C1-8-alkylamino-C1-8-alkyl, C1-8-alkylcarbamoyl, di-C1-8-alkylcarbamoyl, C0-8-alkylcarbonyl, C0-8-alkylcarbonylamino-C1-8-alkoxy, C0-8-alkylcarbonylamino, C0-8-alkylcarbonylamino-C1-8-alkyl, C1-8-alkylcarbonyloxy-C1-8-alkoxy, C1-8-alkylcarbonyloxy-C1-8-alkyl, C1-8-alkylsulphonyl, C1-8-alkylsulphonyl-C1-8-alkoxy, C1-8-alkylsulphonyl-C1-8-alkyl, C1-8-alkylsulphonylamino-C1-8-alkoxy, C1-8-alkylsulphonylamino-C1-8-alkyl, carbamoyl, carbamoyl-C1-8-alkoxy, carbamoyl-C1-8-alkyl, carboxy-C1-8-alkoxy, carboxy-C1-8-alkoxy-C1-8-alkyl, carboxy-C1-8-alkyl, cyano, cyano-C1-8-alkoxy, cyano-C1-8-alkyl, C3-8-cycloalkylcarbonylamino-C1-8-alkoxy, C3-8-cycloalkylcarbonylamino-C1-8-alkyl, cyclopropyl-C1-8-alkyl, O,N-dimethylhydroxylamino-C1-8-alkyl, halo-C1-8-alkoxy, halo-C1-8-alkyl, halogen, hydroxy-C1-8-alkoxy-C1-8-alkoxy, hydroxy-C1-8-alkoxy-C1-8-alkyl, hydroxy-C1-8-alkyl, (N-hydroxy)-C1-8-alkylaminocarbonyl-C1-8-alkoxy, (N-hydroxy)-C1-8-alkylaminocarbonyl-C1-8-alkyl, (N-hydroxy)aminocarbonyl-C1-8-alkoxy, (N-hydroxy)aminocarbonyl-C1-8-alkyl, 2-oxooxazolidinyl-C1-8-alkoxy, 2-oxooxazolidinyl-C1-8-alkyl, O-methyloximyl-C1-8-alkyl or trifluoromethyl;
• or
• (F) R1 is aryl which is substituted by 1-4 3-acetamidomethylpyrrolidinyl 3-C1-8-alkoxy-C1-8-alkylpyrrolidinyl, 3,4-dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4,4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4-hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2-methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3-methyl[1,2,4]oxadiazol-5-ylalkoxy, 5-methyl[1,2,4]oxadiazol-3-ylalkoxy, 3-methyl[1,2,4]oxadiazol-5-ylalkyl, 5-methyl[1,2,4]oxadiazol-3-ylalkyl, 4-methylpiperazinyl, 5-methyltetrazol-1-ylalkoxy, 5-methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]oxadiazol-5-ylalkoxy, [1,2,4]oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo[1,3]oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2-oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2-oxotetrahydropyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, [1,2,4]triazol-1-ylalkoxy, [1,2,4]triazol-4-ylalkoxy, [1,2,4]triazol-1-ylalkyl, [1,2,4]triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5-ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4-ylalkyl or thiomorpholinyl;
• R2 is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, which radicals may be substituted by 1-3 halogen, hydroxyl, cyano, trifluoromethyl, C1-8-alkyl, halo-C1-8-alkyl, hydroxy-C1-8-alkyl, C1-8-alkoxy-C1-8-alkyl, cyano-C1-8-alkyl, carboxy-C1-8-alkyl, C1-8-alkanoyloxy-C1-8-alkyl, C1-8-alkoxycarbonyloxy-C1-8-alkyl, C1-8-alkoxycarbonyl, C1-8-alkoxy, C2-8-alkenyloxy-C1-8-alkyl, C1-8-alkoxy-C1-8-alkylamino-C1-8-alkyl, C1-8-alkoxy-C1-8-alkylsulfanyl-C1-8-alkyl, C1-8-alkoxy-C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkyl, C1-8-alkylsulfanyl-C1-8-alkoxy-C1-8-alkyl, C1-8-alkylsulfanyl-C1-8-alkyl, C1-8-alkylsulfonyl-C1-8-alkoxy-C1-8-alkyl, C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkoxy-C1-8-alkyl, C3-8-cycloalkyl-C0-8-alkoxy-C1-8-alkyl, optionally halogen-substituted C1-8-alkoxy-C1-8-alkoxy-C1-8-alkyl, heterocyclyl-C0-8-alkoxy-C1-8-alkyl groups or a C1-8-alkylenedioxy group, and/or by an L1-T1-L2-T2-L3-T3-L4-T4-L5-U radical;
• L1, L2, L3, L4 and L5 are each independently a bond, C1-8-alkylene, C2-8-alkenylene or C2-8-alkynylene, or are absent;
• T1, T2, T3 and T4 are each independently
• (a) a bond, or are absent, or are one of the groups
• (b) —CH(OH)—
• (c) —CH(OR6)—
• (d) —CH(NR5R6)—
• (e) —CO—
• (f) —CR7R8—
• (g) —O— oder —NR6—
• (h) —S(O)0-2—
• (l) —SO2NR6—
• (j) —NR6SO2—
• (k) —CONR6—
• (l) —NR6CO—
• (m) —O—CO—
• (n) —CO—O—
• (o) —O—CO—O—
• (p) —O—CO—NR6—
• (q) —N(R6)—CO—N(R6)—
• (r) —N(R6)—CO—O—
• (s) Pyrrolidinylen, Piperidinylen oder Piperazinylen
• (t) —C(R11)(R12),
• where the bonds starting from (b)-(t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two groups (b)-(f), three groups (g)-(h) and one group (i)-(t) is/are present;
• R3 is hydrogen, hydroxyl, C1-8-alkoxy or C1-8-alkenyloxy;
• R4 is optionally halogen- and/or hydroxy-substituted C1-8-alkyl, optionally halogen- and/or hydroxy-substituted C1-8-alkoxy-C1-8-alkyl, optionally N-mono- or N,N-di-C1-8-alkylated amino-C1-8-alkyl, optionally N-mono- or N,N-di-C1-8-alkylated or optionally hydroxy-substituted amino-C0-8-alkylcarbonyl-C1-8-alkyl, hydroxy-C0-8-alkylcarbonyl-C0-8-alkyl, C1-8-alkoxy-C0-8-alkylcarbonyl-C0-8-alkyl, optionally N—C1-8-alkylated C1-8-alkoxycarbonylamino-C1-8-alkyl, optionally N—C1-8-alkylated C1-8-alkoxy-C1-8-alkylamino-C1-8-alkyl, optionally N—C1-8-alkylated or optionally halogen-substituted C1-8-alkylcarbonylamino-C1-8-alkyl, cyano-C1-8-alkyl, optionally N—C1-8-alkylated or optionally halogen-substituted C3-8-cycloalkyl-C0-8-alkylcarbonylamino-C1-8-alkyl, optionally N—C1-8-alkylated hydroxy-C1-8-alkylamino-C1-8-alkyl, optionally N—C1-8-alkylated or optionally halogen-substituted heterocyclyl-C0-8-alkylcarbonylamino-C1-8-alkyl, C3-8-cycloalkyl-C0-8-alkyl, C3-8-cycloalkyloxy-C1-8-alkyl, heterocyclyl-C0-8-(optionally hydroxy-substituted)alkyl, optionally N—C1-8-alkylated heterocyclyl-C0-8-alkylamino-C0-8-alkylcarbonyl-C0-8-alkyl, C1-8-alkylsulphonyl-C1-8-alkyl, C2-8-alkinyl, heterocyclyl-C2-8-alkinyl, optionally N-mono- or N,N-di-C1-8-alkylated amino-C2-8-alkinyl, heterocyclylcarbonyl-C0-8-alkyl, heterocyclyloxy-C1-8-alkyl, optionally N-mono- or N,N-di-C1-8-alkylated amino, C1-8-alkylcarbonyl-C1-8-alkoxy, C1-8-alkylcarbonyloxy, aryl-C1-8-alkoxy, aryloxy, optionally N-mono- or N,N-di-C3-8-cycloalkyl-C1-C6-alkylated carbamoyl-C1-8-alkoxy, optionally N-mono- or N,N-di-C1-C6-alkylated carbamoyloxy, hydroxyl, hydroxy-C1-8-alkoxy, hydroxy-C1-8-alkoxy-C1-8-alkoxy, optionally halogen- and/or hydroxy-substituted C1-8-alkoxy, optionally halogen- and/or hydroxy-substituted C1-8-alkoxy-C1-8-alkoxy, optionally N-mono- or N,N-di-C1-8-alkylated amino-C1-8-alkoxy, optionally N-mono- or N,N-di-C1-8-alkylated or optionally hydroxy-substituted amino-C0-8-alkylcarbonyl-C1-8-alkoxy, hydroxy-C0-8-alkylcarbonyl-C0-8-alkoxy, C1-8-alkoxy-C0-8-alkylcarbonyl-C0-8-alkoxy, optionally N—C1-8-alkylated C1-8-alkoxycarbonylamino-C1-8-alkoxy, optionally N—C1-8-alkylated C1-8-alkoxy-C1-8-alkylamino-C1-8-alkoxy, optionally N-C1-8-alkylated or optionally halogen-substituted C1-8-alkylcarbonylamino-C1-8-alkoxy, cyano-C1-8-alkoxy, optionally N—C1-8-alkylated or optionally halogen-substituted C3-8-cycloalkyl-C0-8-alkylcarbonylamino-C1-8-alkoxy, optionally N—C1-8-alkylated hydroxy-C1-8-alkylamino-C1-8-alkoxy, optionally N—C1-8-alkylated or optionally halogen-substituted heterocyclyl-C0-8-alkylcarbonylamino-C1-8-alkoxy, C3-8-cycloalkyl-C0-8-alkoxy, C3-8-cycloalkyloxy-C1-8-alkoxy, heterocyclyl-C0-8-(optionally hydroxy-substituted)alkoxy, optionally N—C1-8-alkylated heterocyclyl-C0-8-alkylamino-C0-8-alkylcarbonyl-C0-8-alkoxy, C1-8-alkylsulphonyl-C1-8-alkoxy, C2-8-alkinyl-oxy, heterocyclyl-C2-8-alkinyl-oxy, optionally N-mono- or N,N-di-C1-8-alkylated amino-C2-8-alkinyl-oxy, heterocyclylcarbonyl-C0-8-alkoxy, heterocyclyloxy-C1-8-alkyoxy or oxo;
• R5 and R6 are each independently hydrogen, C1-8-alkyl, C2-8-alkenyl, aryl-C1-8-alkyl or acyl, or, together with the N atom to which they are bonded, are a 5- to 6-membered heterocyclic ring which may contain an additional N, O or S atom or an —SO— or —SO2— group, where the additional N atom may optionally be substituted by C1-8-alkyl radicals;
• R7 and R8, together with the carbon atom to which they are bonded, are a 3-8-membered ring which may contain one or two —O— or —S— atoms or —SO— or —SO2— groups;
• R9 is hydrogen, C1-8-alkyl, C1-8-alkoxy-C1-8-alkyl, acyl, aryl-C1-8-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-8-alkyl;
• R10 is carboxy-C1-8-alkyl, C1-8-alkoxycarbonyl-C1-8-alkyl, C1-8-alkyl or hydrogen;
• R11 is hydrogen, halogen, acyl, C2-8-alkenyl, C1-8-alkyl, or aryl-C1-8-alkyl;
• R12 is hydrogen, halogen or C1-8-alkyl;
• R11 and R12, together with the C-atom to which they are attached, may also be C3-8-cycloalkyl;
• U is hydrogen, C1-8-alkyl, cyano, trifluoromethyl, optionally substituted C3-12-cycloalkyl, aryl, or heterocyclyl;
• X is a bond, oxygen or sulphur or is >CR11R12, >CHOR9, —O—CO—, >CO, >C═NOR10, —O —CR11R12—, —O—CR11R12—CO—NR9—, —CO—NR9— or —NR9—, where a bond starting from a nitrogen, oxygen or sulphur atom leads to a saturated C atom of the Z group or to R1;
• W is oxygen or sulphur;
• Z is C1-8-alkylene, C2-8-alkenylene, hydroxyl substituted-C1-8-alkylene, —O—, —N—, —S—, —O-alk-, —NR9-alk, —S-alk-, -alk-O—, -alk-S— or-alk-NR9—, where alk denotes C1-8-alkylene;
• and where
• (a) if Z is —O— or —S—, X is —CR11R12—;
• and
• (b) if X is a bond, Z is C1-8-alkylene, C2-8-alkenylene, —NR9-alk-, -alk-NR9—, -alk-O— or -alk-S—;
• n is 1 or, when X is —O—CO—, is 0 or 1;
• m is 0 or 1;
• or pharmaceutically acceptable salt or prodrug thereof, or where one or more atoms are replaced by their stable, non-radioactive isotopes
• for the inhibition of beta-secretase, cathepsin D, plasmepsin II and/or HIV-protease.