Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors

• US 20070149584A9
• Filed: 07/11/2005
• Published: 06/28/2007
• Est. Priority Date: 07/09/2004
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Maillard, Michel, Jagodzinska, Barbara, Tung, Jay, Probst, Gary, John, Varghese, Aquino, Jose
• Granted Patent: US 7,385,085 B2
• Time in Patent Office: Days
• US Class Current: 514/378
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 251/54 of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 251/84 having doubly-bound carbon atoms of hydrazone groups being part of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 255/42 the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• CPC Class Codes: C07C 255/58 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 285/08 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings

Abstract

The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.

Claims

1. A compound of formula (I),

2. The compound according to claim 1, wherein R₁ is selected from —

CH₂-aryl, wherein the aryl ring is optionally substituted with at least one group independently selected from halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, and —

OH.

3. The compound according to claim 1, wherein R₁ is selected from 3-allyloxy-5-fluoro-benzyl, 3-benzyloxy-5-fluoro-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, 3-propyl-thiophen-2-yl-methyl, 3,5-difluoro-2-propylamino-benzyl, 2-ethylamino-3,5-difluoro-benzyl, 2-hydroxy-5-methyl-benzamide, 3-fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-fluoro-5-heptyloxy-benzyl, and 3-fluoro-5-hexyloxy-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.

4. The compound according to claim 1, wherein R₂ is selected from hydrogen, 3-Allyl-5-benzyl-2-oxo-imidazolidin-1-yl, 6-Benzyl-3,3-dimethyl-2-oxo-piperazin-1-yl, 3-Allyl-5-benzyl-2-oxo-pyrrolidin-1-yl, 5-Benzyl-3-isobutyl-2-oxo-imidazolidin-1-yl, 3-Benzyl-5-methyl-1,1-dioxo-1λ

⁶-[1,2,5]thiadiazolidin-2-yl, 3-Benzyl-1,1-dioxo-1λ

⁶-isothiazolidin-2-yl, 2-Benzyl-5-oxo-pyrrolidin-1-yl, 5-Benzyl-3-ethyl-2-oxo-pyrrolidin-1-yl, 3-Amino-5-benzyl-2-oxo-pyrrolidin-1-yl, 3-Acetylamino-5-benzyl-2-oxo-pyrrolidin-1-yl, 5-Benzyl-3-[1,3]dioxolan-4-ylmethyl-2-oxo-pyrrolidin-1-yl, 3-Benzyl-5-oxo-morpholin-4-yl, 2-Benzyl-6-oxo-piperazin-1-yl, 8-Benzyl-6-methyl-10-oxo-6,9-diaza-spiro[4.5]dec-9-yl, 5-Benzyl-3-furan-2-ylmethylene-2-oxo-pyrrolidin-1-yl, 3-acetylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-acetylamino-3-(cyclopropylmethyl)-2-oxo-pyrrolidin-1-yl, 3-(2-amino-5-carboxypentanoylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-(2-methoxy-acetylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-ethoxycarbonylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-ethylureido-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-hydroxypropionylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.

5. The compound according to claim 1, wherein R_C is selected from

6. The compound according to claim 5, wherein A₅ is selected from —

C(═

N—

OH)—

, —

C(═

N—

O—

CH₃)—

, —

C(═

N—

O—

CH₂CH₃)—

, —

C(═

N—

O—

CH₂CH₂OH)—

, —

C(═

N—

O—

CH₂CH₂NH₂)—

, —

C(═

N—

NHCH₃)—

, and —

C(═

N—

CN)—

, and A₁, A₂, A₃, and A₄ are —

CH₂—

.

7. The compound according to claim 1, wherein R_C is selected from 1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-amino-ethoxyimino)-cyclohexyl, 5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexyl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-yl, 1-(Acrylic acid methyl ester)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(Acrylamide)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohex-1-yl, 4-methoxyimino-1-(3-thiophen-3-yl-phenyl)-cyclohexyl, 1-(3-furan-3-yl-phenyl)-4-methoxyimino-cyclohexyl, 4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]-cyclohexyl, 4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrimidin-5-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexyl, 2-Acetyl-5-(3-tert-butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 1-(3-tert-Butyl-phenyl)-4-methylene-cyclohexyl, and ethyl 2-(4-(3-tert-butylphenyl)cyclohexylidene)acetate.

8. The compound according to claim 1, wherein R_X is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′

-Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phen-1-yl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, 6-tert-Butyl-pyrimidin-4-yl, 3-pyridin-4-yl-phenyl, 3-pyrimidin-5-yl-phenyl, and 3-pyrazol-1-yl-phenyl.

9. The compound according to claim 1, wherein R_X is 3-tert-Butyl-phen-1-yl.

10. The compound according to claim 1, wherein the formula (I) compound is selected from 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5difluorophenyl)butan-2-ol and 1-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.

21. A method of inhibiting production of A-beta, comprising:

administering to a patient a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 1.

11. A method of preventing or treating at least one condition that benefits from inhibition of at least one aspartyl-protease, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I),

or pharmaceutically acceptable salts thereof, wherein

R₁ is

wherein

n is 0 or 1;

q is 0 or 1;

r is 0, 1, or 2;

K is selected from

—

(CR_3aR_3b)—

,

—

O—

,

—

SO₂—

,

—

C(O)—

, and

—

CH(NR₅₅R₆₀)—

;

R₅₅ and R₆₀ are each independently selected from hydrogen and alkyl;

R_3a and R_3b are independently selected from

-hydrogen,

-halogen,

—

O-alkyl, and

-alkyl optionally substituted with at least one group independently selected from halogen, —

CN, —

CF₃, and —

OH;

W is selected from —

(CH₂)_1-4—

, —

O—

, —

S(O)_0-2—

, —

N(R₅₅)—

, and —

C(O)—

;

E is a bond or alkyl;

A is selected from

-aryl optionally substituted with at least one group independently selected from R₅₀,

-cycloalkyl optionally substituted with at least one group independently selected from R₅₀,

-heteroaryl optionally substituted with at least one group independently selected from R₅₀, and

-heterocycle optionally substituted with at least one group independently selected from R₅₀, wherein at least one atom of the heterocycle is optionally replaced with —

C(O)— and

—

S(O)_0-2—

;

wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from —

(CO)_0-1R₂₁₅, —

(CO)_0-1R₂₂₀, —

S(O)_0-2R₂₀₀, and —

N(R₂₀₀)—

S(O)_0-2R₂₀₀;

R₅₀ is independently selected from

—

OH,

-halogen,

—

OCF₃,

—

NO₂,

—

CN,

—

N(R)C(O)R,

—

CO₂—

R,

—

NH—

CO₂—

R,

—

O-(alkyl)-CO₂H,

—

NRR′

,

—

SR,

—

CH₂OH,

—

C(O)—

R₂₅,

—

C(O)NRR′

,

—

SO₂NRR′

,

—

S(O)_1-2R₂₅,

-alkyl optionally substituted with at least one group independently selected from —

CF₃, halogen, —

O-alkyl, —

OCF₃, —

NRR′

, —

OH, and —

CN,

-cycloalkyl optionally substituted with at least one group independently selected from —

CF₃, halogen, —

O-alkyl, —

OCF₃, —

NRR′

, —

OH, and —

CN,

—

O-alkyl optionally substituted with at least one group independently selected from —

CF₃, halogen, —

O-alkyl, —

OCF₃, —

NRR′

, —

OH, and —

CN,

—

O-benzyl optionally substituted with at least one group independently selected from —

H, —

OH, halogen, and alkyl,

—

O—

(CH₂)_0-2—

O—

(CH₂)_1-2—

O-alkyl, and

—

(CH₂)_0-2—

O—

(CH₂)_1-2—

OH;

R and R′

are each independently selected from hydrogen, alkyl, —

(CH₂)_0-2-aryl and —

(CH₂)_0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, —

O-alkyl, amino, monoalkylamino, and dialkylamino;

R₂₅ is selected from alkyl, —

(CH₂)_0-2-aryl and —

(CH₂)_0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, —

O-alkyl, amino, monoalkylamino, and dialkylamino;

L is selected from a bond, —

C(O)—

, —

S(O)_1-2—

, —

O—

, —

C(R₁₁₀)(R₁₁₂)O—

, —

OC(R₁₁₀)(R₁₁₂)—

, —

N(R₁₁₀)—

, —

C(O)N(R₁₁₀)—

, —

N(R₁₁₀)C(O)—

, —

C(R₁₁₀)(R′

)—

, —

C(OH)R₁₁₀—

, —

SO₂NR₁₁₀—

, —

N(R₁₁₀)SO₂—

, —

N(R₁₁₀)C(O)N(R₁₁₂)—

, —

N(R₁₁₀)C(S)N(R₁₁₂)—

, —

OCO₂—

, —

NCO₂—

, and —

OC(O)N(R₁₁₀)—

;

R₁₁₀ and R₁₁₂ are each independently selected from

-hydrogen and

-alkyl optionally substituted with at least one group independently selected from —

OH, —

O-alkyl, and halogen;

G is selected from

-alkyl (optionally substituted with at least one group independently selected from —

CO₂H, —

CO₂(alkyl), —

O-alkyl, —

OH, —

NRR′

, alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R₅₀), and heteroaryl (optionally substituted with at least one group independently selected from R₅₀);

—

(CH₂)_0-3-cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from —

CO₂H, —

CO₂—

(alkyl), —

O-alkyl, —

OH, —

NH₂, haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl) amino, aryl (optionally substituted with at least one group independently selected from R₅₀), and heteroaryl (optionally substituted with at least one group independently selected from R₅₀);

—

(CRR)_1-4-aryl wherein the aryl is optionally substituted with at least one group independently selected from R₅₀,

—

(CH₂)_1-4-heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R₅₀,

—

(CH₂)_0-4-heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R₅₀, and

—

C(R₁₀)(R₁₂)—

C(O)—

NH—

R₁₄;

R₁₀ and R₁₂ are each independently selected from

—

H,

-alkyl,

-(alkyl)_0-1-aryl,

-(alkyl)_0-1-heteroaryl,

-(alkyl)_0-1-heterocycle,

-aryl,

-heteroaryl,

-heterocycle,

—

(CH₂)_1-4—

OH,

—

(CH₂)_1-4-Z-(CH₂)_1-4-aryl, and

—

(CH₂)_1-4-Z-(CH₂)_1-4-heteroaryl,

wherein the heterocycle, aryl, and heteroaryl groups included within R₁₀ and R₁₂ are optionally substituted with at least one group independently selected from R₅₀;

Z is selected from —

O—

, —

S—

, and —

NR₁₆—

;

R₁₄ is;

—

H,

-alkyl,

-aryl,

-heteroaryl,

-heterocycle,

-(alkyl)-aryl,

-(alkyl)-heteroaryl,

-(alkyl)-, and

—

(CH₂)_0-2—

O—

(CH₂)_0-2—

OH;

wherein the heterocycle, aryl, and heteroaryl groups included within R₁₄ are optionally substituted with at least one group independently selected from R₅₀;

R₁₆ is selected from hydrogen and alkyl;

or

R₁ is selected from

alkyl;

wherein

X, Y, and Z are independently selected from —

C(H)_0-2—

, —

O—

, —

C(O)—

, —

NH—

, and —

N—

;

wherein at least one bond of the (IIf) ring may optionally be a double bond;

R₅₀, R_50a, and R_50b are independently selected from —

H, halogen, —

OH, —

SH, —

CN, —

C(O)-alkyl, —

NR₇R₈, —

NO₂, —

S(O)_0-2-alkyl, alkyl, alkoxy, —

O-benzyl (optionally substituted with at least one group independently selected from —

H, —

OH, and alkyl), —

C(O)—

NR₇R₈, alkyloxy, alkoxyalkoxyalkoxy, and cycloalkyl;

wherein the alkyl, alkoxy, and cycloalkyl groups within R₅₀, R_50a, and R_50b are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR₅R₆, CN, haloalkoxy, NR₇R₈, and alkoxy;

R₅ and R₆ are independently selected from —

H and alkyl, or

R₅ and R₆, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and

R₇ and R₈ are independently selected from —

H, alkyl optionally substituted with at least one group independently selected from —

OH, —

NH₂, and halogen, -cycloalkyl, and -alkyl-O-alkyl;

R₂ is selected from

—

H.

-alkyl optionally substituted with at least one group independently selected from R₂₀₀]

—

OH,

—

O-alkyl optionally substituted with at least one group independently selected from R₂₀₀,

—

O-aryl optionally substituted with at least one group independently selected from R₂₀₀, —

NH-alkyl optionally substituted with at least one group independently selected from R₂₀₀,

-heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —

(CR₂₄₅R₂₅₀)—

, —

O—

, —

C(O)—

, —

C(O)C(O)—

, —

N(R₂₀₀)_0-2—

, and —

S(O)_0-2—

, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R₂₀₀), —

NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —

(CR₂₄₅R₂₅₀)—

, —

O—

, —

C(O)—

, —

C(O)C(O)—

, —

N(R₂₀₀)_0-2—

, and —

S(O)_0-2—

, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R₂₀₀,

—

C(O)—

N(R₃₁₅)(R₃₂₀), wherein R₃₁₅ and R₃₂₀ are each independently selected from

—

H, alkyl, and aryl,

—

NH—

R₄₀₀,

—

R₄₀₀,

—

NH—

R₅₀₀,

—

R₅₀₀,

—

NH—

R₆₀₀,

—

R₆₀₀, and

—

R₇₀₀;

R₄₀₀ is

wherein R₄₀₅ is selected from —

H, —

N(R₅₁₅)₂ and O-alkyl;

R₅₀₀ is a heteroaryl selected from (IIa) and (IIb)

wherein

M₁ and M₄ are independently selected from

—

C(R₅₀₅)—

,

—

N—

,

—

N(R₅₁₅)—

,

—

S—

, and

—

O—

;

M₂ and M₃ are independently selected from

—

C(R₅₁₀)—

,

—

N(R₅₂₀)_0-1—

,

—

S—

, and

—

O—

;

M₅ is selected from —

C— and

—

N—

;

R₅₀₅ is independently selected from

—

H,

-alkyl,

-halogen,

—

NO₂,

—

CN,

R₂₀₀, and

-aryl;

R₅₁₀ is independently selected from

—

H,

-alkyl,

-halogen,

-amino,

—

CF₃,

R₂₀₀, and

-aryl;

R₅₁₅ is independently selected from

—

H,

-alkyl, and

-aryl;

R₅₂₀ is independently selected from

—

H,

-alkyl,

—

(CH₂)_0-2-aryl, and

—

C(Ph)₃;

R₆₀₀ is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from —

R₆₀₅;

R₆₀₅ is selected from —

H, -halogen, -alkyl, -aryl, —

CO₂-alkyl, —

NO₂, —

CN, —

NH₂, —

NR₂₂₀R₂₂₅, -thioalkyl, —

CF₃, —

OH, —

O-alkyl, and -heterocycloalkyl;

R₇₀₀ is aryl optionally substituted with at least one —

R₂₀₅;

R_C is selected from formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf)

wherein,

A₁ and A₂ are independently selected from —

(CH₂)_0-2—

, —

CH(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

NH—

, —

NR₂₂₀—

, —

C(═

N—

R₂₃₀)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

A₃, A₄, A₅, and A₆ are independently selected from —

CH₂—

, —

CH(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, —

NH—

, —

NR₂₂₀—

, —

N(CO)_0-1R₂₀₀—

, —

N(S(O₂)alkyl)-, —

C(═

N—

R₂₃₀)—

, —

C(═

N—

NH(alkyl))-, —

C(═

N—

N(alkyl)(alkyl))-, —

C(═

N—

O—

(CH₂)_1-4—

OH)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

R₂₃₀ is independently selected from —

H, —

OH, R₂₁₅ (optionally substituted with —

OH, —

NH₂, —

C(O)H, and —

CN), alkyl, cycloalkyl, alkoxy, -alkyl-OH, -alkyl-NH₂, -alkyl-C(O)H, —

O—

R₂₁₅ (optionally substituted with —

OH, —

NH₂, —

C(O)H, and —

CN), —

O-alkyl, —

O-alkyl-OH, —

O-alkyl-NH₂, —

O-alkyl-C(O)H, —

NH₂, —

NHR₂₁₅, —

N(R₂₁₅)₂, —

NR₂₃₅R₂₄₀, and —

CN;

wherein at least one carbon of the alkyl or cycloalkyl within R₂₃₀ is optionally independently replaced with —

C(O)—

or a heteroatom;

wherein the cycloalkyl and heterocylcoalkyl within formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf) may optionally contain at least one double bond;

wherein in formulae (IIIa), (IIIb), (IIIc), and (IIId), at least one of A₁, A₂, A₃, A₄, or A₅ is selected from —

C(═

N—

R₂₃₀)—

, —

C(═

N—

NH(alkyl))-, —

C(═

N—

N(alkyl)(alkyl))-, C(═

N—

O—

(CH₂)_1-4—

OH)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

wherein in formulae (IIIe) and (IIIf), when A₁, A₂, and A₆ are selected from —

(CH₂)_0-2—

, —

CH(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, —

NH—

, —

NR₂₂₀—

, —

N(CO)_0-1R₂₀₀—

, and —

N(S(O₂)alkyl)-, at least one carbon of the aryl ring group within (IIIe) and (IIIf) is optionally independently replaced with a group selected from —

N—

, —

NH—

, —

O—

, —

C(O)—

, and —

S(O)_0-2—

;

wherein each aryl or heteroaryl group attached directly or indirectly to R_C is optionally substituted with at least one group independently selected from R₂₀₀;

wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to R_C is optionally substituted with at least one group independently selected from R₂₁₀; and

R_X is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —

R_xa—

R_xb,

wherein R_xa and R_xb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

wherein each aryl or heteroaryl group of R_X is optionally substituted with at least one group independently selected from R₂₀₀;

wherein each cycloalkyl or heterocycloalkyl of R_X is optionally substituted with at least one group independently selected from R₂₁₀; and

wherein at least one carbon of the heteroaryl or heterocycloalkyl group of R_X is independently optionally replaced with a group independently selected from

—

NH—

,

—

N—

,

—

N(CO)_0-1R₂₁₅—

,

—

N(CO)_0-1R₂₂₀—

,

—

O—

,

—

C(O)—

,

—

S(O)_0-2—

, and

—

NS(O)_0-2R₂₀₀;

R₂₀₀ at each occurrence is independently selected from

-alkyl optionally substituted with at least one group independently selected from R₂₀₅,

—

OH,

—

NO₂,

-halogen,

—

CN,

—

(CH₂)_0-4—

C(O)H,

—

(CO)_0-1R₂₁₅,

—

(CO)_0-1R₂₂₀,

—

(CH₂)_0-4—

(CO)_0-1—

NR₂₂₀R₂₂₅,

—

(CH₂)_0-4—

(CO)_0-1—

NH(R₂₁₅),

—

(CH₂)_0-4—

C(O)-alkyl,

—

(CH₂)_0-4—

(CO)_0-1-cycloalkyl,

—

(CH₂)_0-4—

(CO)_0-1-heterocycloalkyl,

—

(CH₂)_0-4—

(CO)_0-1-aryl,

—

(CH₂)_0-4—

(CO)_0-1-heteroaryl,

—

(CH₂)_0-4—

C(O)—

O—

R₂₁₅,

—

(CH₂)_0-4—

SO₂—

NR₂₂₀R₂₂₅,

—

(CH₂)_0-4—

S(O)_0-2-alkyl,

—

(CH₂)_0-4—

S(O)_0-2-cycloalkyl,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

O—

R₂₁₅,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

SO₂—

R₂₂₀,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

N(R₂₁₅)₂,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

R₂₂₀,

—

(CH₂)_0-4—

O—

C(O)-alkyl,

—

(CH₂)_0-4—

O—

(R₂₁₅),

—

(CH₂)_0-4—

S—

(R₂₁₅),

—

(CH₂)_0-4—

O-alkyl optionally substituted with at least one halogen, and

-adamantane;

wherein each aryl and heteroaryl group included within R₂₀₀ is optionally substituted with at least one group independently selected from R₂₀₅, R₂₁₀, and alkyl (optionally substituted with at least one group independently selected from R₂₀₅ and R₂₁₀);

wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₀ is optionally substituted with at least one group independently selected from R₂₁₀;

R₂₀₅ at each occurrence is independently selected from

-alkyl,

-haloalkoxy,

—

(CH₂)_0-3-cycloalkyl,

-halogen,

—

(CH₂)_1-6—

OH,

—

O-aryl,

—

OH,

—

SH,

—

(CH₂)_0-4—

C(O)H,

—

(CH₂)_0-6—

CN,

—

(CH₂)_0-6—

C(O)—

NR₂₃₅R₂₄₀,

—

(CH₂)_0-6—

C(O)—

R₂₃₅,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

SO₂—

R₂₃₅,

—

OCF₃,

—

CF₃,

-alkoxy,

-alkoxycarbonyl, and

—

NR₂₃₅R₂₄₀;

R₂₁₀ at each occurrence is independently selected from

—

(CH₂)_0-4—

OH,

—

(CH₂)_0-4—

CN,

—

(CH₂)_0-4—

C(O)H,

-alkyl optionally substituted with at least one group independently selected from R₂₀₅,

-alkanoyl,

—

S-alkyl;

—

S(O)₂-alkyl,

-halogen,

-alkoxy,

-haloalkoxy,

—

NR₂₂₀R₂₂₅,

-cycloalkyl optionally substituted with at least one group independently selected from R₂₀₅,

-heterocycloalkyl,

-heteroaryl,

—

(CH₂)_0-4—

NR₂₃₅R₂₄₀,

—

(CH₂)_0-4—

NR₂₃₅(alkoxy),

—

(CH₂)_0-4—

S—

(R₂₁₅),

—

(CH₂)_0-4—

NR₂₃₅—

C(O)H,

—

(CH₂)_0-4—

NR₂₃₅—

C(O)-(alkoxy),

—

(CH₂)_0-4—

NR₂₃₅—

C(O)—

R₂₄₀,

—

C(O)—

NHR₂₁₅,

—

C(O)-alkyl,

—

C(O)—

NR₂₃₅R₂₄₀, and

—

S(O)₂—

NR₂₃₅R₂₄₀;

R₂₁₅ at each occurrence is independently selected from

-alkyl,

—

(CH₂)_0-2-aryl,

—

(CH₂)_0-2-cycloalkyl,

—

(CH₂)_0-2-heteroaryl,

—

(CH₂)_0-2-heterocycloalkyl, and

—

CO₂—

CH₂-aryl;

wherein the aryl group included within R₂₁₅ is optionally substituted with at least one group independently selected from R₂₀₅ and R₂₁₀, and

wherein the heterocycloalkyl and heteroaryl groups included within R₂₁₅ are optionally substituted with at least one group independently selected from R₂₁₀;

R₂₂₀ and R₂₂₅ at each occurrence are independently selected from

—

H,

-alkyl,

—

(CH₂)_0-4—

C(O)H,

-alkylhydroxyl,

-alkoxycarbonyl,

-alkylamino,

—

S(O)₂-alkyl,

-alkanoyl optionally substituted with at least one halogen,

—

C(O)—

NH₂,

—

C(O)—

NH(alkyl),

—

C(O)—

N(alkyl)(alkyl),

-haloalkyl,

—

(CH₂)_0-2-cycloalkyl,

-(alkyl)-O-(alkyl),

-aryl,

-heteroaryl, and

-heterocycloalkyl;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R₂₂₀ and R₂₂₅ are each optionally substituted with at least one group independently selected from R₂₇₀;

R₂₇₀ at each occurrence is independently selected from

—

R₂₀₅,

-alkyl optionally substituted with at least one group independently selected from R₂₀₅,

-aryl,

-halogen,

-alkoxy,

-haloalkoxy,

—

NR₂₃₅R₂₄₀,

—

OH,

—

CN,

-cycloalkyl optionally substituted with at least one group independently selected from R₂₀₅,

—

C(O)-alkyl,

—

S(O)₂—

NR₂₃₅R₂₄₀,

—

C(O)—

NR₂₃₅R₂₄₀,

—

S(O)₂-alkyl, and

—

(CH₂)_0-4—

C(O)H;

R₂₃₅ and R₂₄₀ at each occurrence are independently selected from

—

H,

—

OH,

—

CF₃,

—

OCH₃,

—

NHCH₃,

—

N(CH₃)₂,

—

(CH₂)_0-4—

C(O)(H or alkyl),

-alkyl,

-alkanoyl,

—

SO₂-alkyl, and

-aryl.

12. The method according to claim 11, wherein the at least one compound of formula (I) is selected from 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3, -difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.

13. A method of preventing or treating at least one condition associated with amyloidosis, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), or pharmaceutically acceptable salts thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

14. The method according to claim 11, wherein the aspartyl protease is beta-secretase and the condition is Alzheimer'"'"'s disease.

15. The method according to claim 11, wherein the aspartyl protease is beta-secretase and the condition is dementia.

16. A method of preventing or treating at least one condition associated with amyloidosis, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), further comprising a composition including beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11.

17. A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11.

18. A method of affecting beta-secretase-mediated cleavage of amyloid precursor protein in a patient, comprising administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11.

19. A method of inhibiting cleavage of amyloid precursor protein at a site between Met596 and Asp597 (numbered for the APP-695 amino acid isotype), or at a corresponding site of an isotype or mutant thereof, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11.

20. A method of inhibiting cleavage of amyloid precursor protein or mutant thereof at a site between amino acids, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11, and wherein the site between amino acids corresponds to between Met652 and Asp653 (numbered for the APP-751 isotype);

between Met671 and Asp672 (numbered for the APP-770 isotype);

between Leu596 and Asp597 of the APP-695 Swedish Mutation;

between Leu652 and Asp653 of the APP-751 Swedish Mutation;

or

between Leu671 and Asp672 of the APP-770 Swedish Mutation.

22. A method of preventing, delaying, halting, or reversing a disease characterized by A-beta deposits or plaques, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11.

23. The method in claim 22, wherein the A-beta deposits or plaques are in a human brain.

24. A method of interacting an inhibitor with beta-secretase, comprising:

administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_c are as defined in claim 11, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′

, and S2′

.

25. A method of modifying the pharmacokinetic parameters of a pharmaceutical composition comprising at least one compound of formula (I) wherein R₁, R₂ and R_C are as defined in claim 11, further comprising increasing at least one parameter selected from C_max, T_max, and half-life.

26. A method of treating a condition in a patient, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R₁, R₂, and R_c are defined as in claim 11.