Methods of treating amyloidosis using aryl-cyclopropyl derivative aspartyl protease inhibitors

• US 20070149525A1
• Filed: 10/12/2006
• Published: 06/28/2007
• Est. Priority Date: 10/12/2005
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Bowers, Simeon, Truong, Anh, Tung, Jay, Probst, Gary, Toth, Gergely, Hom, Roy
• Application Number:
  US11/546,347
• Publication Number:
  US 20070149525A1
• Time in Patent Office: Days
• US Class Current: 514/237.800
• 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 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/18 the ring system containing six carbon atoms
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 323/31 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 213/56 Amides
• 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 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/06 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 309/04 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/06 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 317/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 319/12 : not condensed with other rings
• CPC Class Codes: C07D 321/06 : 1,3-Dioxepines; Hydrogenated 1,3-dioxepines
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 491/08 : Bridged systems
• CPC Class Codes: C07D 498/18 : Bridged systems

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, alkyl, 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, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, 2-ethylamino-3,5-difluoro-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, 2-Hydroxy-5-methyl-benzamide, 3,5-Difluoro-4-hydroxy-benzyl, 3,5-Difluoro-benzyl, 3-Fluoro-4-hydroxy-benzyl, 3-Fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-Fluoro-5-heptyloxy-benzyl, 3-Fluoro-5-hexyloxy-benzyl, 3-Fluoro-5-hydroxy-benzyl, and 3-Fluoro-benzyl.

4. The compound according to claim 1, wherein R₂ is selected from —

C(O)—

CH₃ and —

C(O)—

CH₂F.

5. The compound according to claim 1, wherein R_C is selected from aryl and -heteroaryl, wherein each aryl or heteroaryl is optionally substituted with at least one R₂₀₁ group.

6. The compound according to claim 1, wherein the formula (I) compound is selected from

N-(4-(6-(4-tert-butylpyridin-2-yl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-(1H-pyrazol-1-yl)phenyl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-(1H-pyrazol-1-yl)phenyl)-3-oxa-bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-1,2,3-triazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2,2-dimethylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-((1H-pyrazol-1-yl)methyl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-methylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-mercaptophenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(5-neopentylpyridin-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-hydroxy-5-neopentyl-1,2-dihydropyridin-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-neopentylthiazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiazol-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-pyrazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-pyrazol-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-hydroxycyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

2-(3-(1H-pyrazol-1-yl)phenyl)-2-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)cyclopropanecarboxamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-bromophenyl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-neopentylisoxazol-5-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide,

N-(4-(1-(3-neopentylphenyl)cyclobutylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-(1H-pyrazol-1-yl)thiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(5-neopentylpyridin-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-tert-butylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(5-neopentylthiophen-2-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(bicyclo[2.2.1]heptan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(5-methylthiophen-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-cyclopentylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-cyclohexylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3′

,5′

-difluorobiphenyl-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4-(3,3-dimethylbut-1-ynyl)thiophen-2-yl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-(thiophen-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-neopentyl-1H-pyrazol-4-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-neopentyl-1H-1,2,3-triazol-4-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(6-(1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(2-benzyl-1-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-hydroxy-5-neopentylphenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-neopentyl-1H-pyrazol-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(1-tert-butyl-1H-pyrazol-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4-(3,3-dimethylbutyl)thiophen-2-yl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(5-tert-butylthiophen-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-((1H-pyrazol-1-yl)methyl)thiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydrofuran-3-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydrofuran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(5-methylthiophen-3-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(1,1,1-trifluoropropan-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(5-(1H-pyrazol-1-yl)pyridin-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(3-(3,6-dihydro-2H-pyran-2-yl)phenyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(3-(5,6-dihydro-2H-pyran-2-yl)phenyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-morpholinophenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,3-dioxepan-5-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2,6-difluoro-3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(4-neopentylthiazol-2-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydro-2H-pyran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,4-dioxan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-tert-butyl-1H-pyrazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(2-azabicyclo[2.2.1]heptan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-thiomorpholinophenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(1H-tetrazol-5-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-phenylacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(5-oxopyrrolidin-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-4-oxopentanamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-methoxyacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-ethoxyacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-5-oxohexanamide,

N-(4-(1-(3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2-methoxyethoxy)acetamide,

methyl 4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-5-oxohexanamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(2-methyltetrahydrofuran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(1H-imidazol-4-yl)acetamide,

N-(4-(1-(3-(1,4-oxazepan-4-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

4-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamoyl)butanoic acid,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(5-methylisoxazol-3-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2,5-dioxoimidazolidin-4-yl)acetamide,

N-(4-(1-(3-(1,1-difluoro-2-methylpropan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1,2-difluoro-2-methylpropyl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,3-dioxolan-4-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-(2-hydroxyethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-(hydroxymethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(3-oxomorpholino)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-isopropylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-ethylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

N-(4-(1-(5-tert-butyloxazol-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

or at least one pharmaceutically acceptable salt thereof.

7. 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 at least one pharmaceutically acceptable salt thereof;

wherein

R₁ is selected from

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,

—

S(O)_0-2-alkyl,

-alkyl,

-alkoxy,

—

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

H, —

OH, and alkyl,

—

C(O)—

NR₇R₈,

-alkoxyalkoxyalkoxy, and

-cycloalkyl;

wherein the alkyl, alkoxy, and cycloalkyl groups within R₅₀, R_50a, and R_50b are optionally substituted with at least one substituent independently selected from alkyl, halogen, —

OH, —

NR₅R₆, —

CN, haloalkoxy, 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;

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 —

C(O)—

CH₃, —

C(O)—

CH₂(halogen), —

C(O)—

CH(halogen)₂, —

S(O)₂—

CH₃, —

S(O)₂—

CH₂(halogen), and —

S(O)₂—

CH(halogen)₂;

A₁ and A₂ together with the atom to which they are attached form a 3 or 4 membered cycloalkyl, or a 6, 7 or 8 membered bicyclic ring, wherein one member of the cycloalkyl or bicyclic ring is optionally a heteroatom selected from —

O—

, —

S(O)_0-2—

, and —

N(R₁₃₆)—

, wherein the cycloalkyl or bicyclic ring is optionally substituted with 1, 2 or 3 R₂₀₁ groups; and

wherein the at least one carbon of the cycloalkyl or bicyclic ring is optionally replaced with —

C(O)—

; and

R₁₃₆ is independently selected from alkyl, —

(CH₂)_0-2-cycloalkyl, —

(CH₂)_0-2-(aryl), —

(CH₂)_0-2-(heteroaryl), and —

(CH₂)_0-2-(heterocycloalkyl);

R_C is selected from aryl, heteroaryl, —

R_Xa—

(CH₂)_0-2—

R_Xb;

wherein R_Xa is independently selected from aryl and heteroaryl and R_Xb is independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

wherein at least one carbon of each cycloalkyl may be optionally replaced with —

C(O)—

, —

O—

, —

NH—

, —

N(R₂₀), —

S—

, and —

S(O)₂—

wherein R₂₀ is selected from H, CN, alkyl, haloalkyl, and cycloalkyl;

wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl group within R_C is optionally substituted with at least one group independently selected from R₂₀₁; and

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

NH—

, —

N—

(R₂₀), —

N(CO)_0-1R₂₁₆—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, and —

NS(O)_0-2R₂₀₁;

wherein R₂₀₁ at each occurrence is independently selected from;

—

H,

-alkyl optionally substituted with at least one group independently selected from R₂₀₆,

—

OH,

—

NO₂,

—

NR₇R₈,

-halogen,

—

CN,

—

(CH₂)_0-4—

C(O)H,

—

(CO)_0-1—

R₂₁₆,

—

(CH₂)_0-4—

(CO)_0-1—

NR₇R₈,

—

(CH₂)_0-4—

C(O)_0-1-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—

CO₂—

H,

—

(CH₂)_0-4—

CO₂—

R₂₁₆,

—

(CH₂)_0-4—

SO₂—

NR₇R₈,

—

(CH₂)_0-4—

S(O)_0-2-alkyl,

—

(CH₂)_0-4—

S(O)_0-2-cycloalkyl,

—

(CH₂)_0-4—

O—

C(O)-alkyl,

—

(CH₂)_0-4—

O—

(R₂₁₆),

—

(CH₂)_0-4—

S—

(R₂₁₆), and

—

(CH₂)_0-4—

O-alkyl optionally substituted with at least one halogen;

wherein each aryl and heteroaryl group included within R₂₀₁ is optionally substituted with at least one group independently selected from

—

R₂₀₆,

—

R₂₁₆, and

-alkyl optionally substituted with at least one group independently selected from R₂₀₆ and R₂₁₆;

wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₁ is optionally substituted with at least one group independently selected from R₂₀₆;

R₂₀₆ at each occurrence is independently selected from

-alkyl,

-haloalkoxy,

—

(CH₂)_0-3-cycloalkyl,

-halogen,

—

(CH₂)_0-6—

OH,

-aryl,

—

O-aryl,

—

OH,

—

SH,

—

(CH₂)_0-4—

C(O)H,

—

(CH₂)_0-6—

CN,

—

(CH₂)_0-6—

C(O)—

NR₇R₈,

—

(CH₂)_0-6—

C(O)—

R₂₁₆,

—

(CH₂)_0-4—

N(H or R₂₁₆)—

SO₂—

R₂₁₆,

—

CF₃,

—

CN,

-alkoxy,

-alkoxycarbonyl, and

—

NR₇R₈;

R₂₁₆ at each occurrence is independently selected from

-alkyl,

—

(CH₂)_0-2-cycloalkyl,

—

(CH₂)_0-2-aryl,

—

(CH₂)_0-2-heteroaryl,

—

(CH₂)_0-2-heterocycloalkyl, and

—

CO₂—

CH₂-aryl.

8. The method according to claim 7, wherein the at least one compound of formula (I) is selected from:

N-(4-(6-(4-tert-butylpyridin-2-yl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-(1H-pyrazol-1-yl)phenyl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-(1H-pyrazol-1-yl)phenyl)-3-oxa-bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-1,2,3-triazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2,2-dimethylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-((1H-pyrazol-1-yl)methyl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-methylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-mercaptophenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(5-neopentylpyridin-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-hydroxy-5-neopentyl-1,2-dihydropyridin-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-neopentylthiazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiazol-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-pyrazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-neopentyl-1H-pyrazol-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-hydroxycyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

2-(3-(1H-pyrazol-1-yl)phenyl)-2-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)cyclopropanecarboxamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-(3-bromophenyl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-neopentylthiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-neopentylisoxazol-5-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide,

N-(4-(1-(3-neopentylphenyl)cyclobutylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-(1H-pyrazol-1-yl)thiophen-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(5-neopentylpyridin-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-tert-butylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(5-neopentylthiophen-2-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(5-methylthiophen-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-cyclopentylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-cyclohexylphenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3′

,5′

-difluorobiphenyl-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4-(3,3-dimethylbut-1-ynyl)thiophen-2-yl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-(thiophen-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-neopentyl-1H-pyrazol-4-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(6-(1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(2-benzyl-1-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-hydroxy-5-neopentylphenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(1-neopentyl-1H-pyrazol-3-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(1-tert-butyl-1H-pyrazol-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4-(3,3-dimethylbutyl)thiophen-2-yl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(5-tert-butylthiophen-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydrofuran-3-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydrofuran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(1,1,1-trifluoropropan-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(5-(1H-pyrazol-1-yl)pyridin-3-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(3-(3,6-dihydro-2H-pyran-2-yl)phenyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-morpholinophenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,3-dioxepan-5-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2,6-difluoro-3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(4-neopentylthiazol-2-yl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(tetrahydro-2H-pyran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,4-dioxan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(1-tert-butyl-1H-pyrazol-4-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide

N-(4-(1-(3-(2-azabicyclo[2.2.1]heptan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-thiomorpholinophenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(1H-tetrazol-5-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-phenylacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(5-oxopyrrolidin-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-4-oxopentanamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-methoxyacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-ethoxyacetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-5-oxohexanamide,

N-(4-(1-(3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2-methoxyethoxy)acetamide,

methyl 4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-5-oxohexanamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(2-methyltetrahydrofuran-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(1H-imidazol-4-yl)acetamide,

N-(4-(1-(3-(1,4-oxazepan-4-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

4-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamoyl)butanoic acid,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(5-methylisoxazol-3-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2,5-dioxoimidazolidin-4-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-5-oxopyrrolidine-2-carboxamide,

N-(4-(1-(3-(1,1-difluoro-2-methylpropan-2-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1,2-difluoro-2-methylpropyl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(3-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropylamino)butan-2-yl)acetamide,

N-(4-(1-(3-(1,3-dioxolan-4-yl)phenyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-isopropylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)phenyl)-2-ethylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

N-(4-(1-(5-tert-butyloxazol-2-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

or at least one pharmaceutically acceptable salt thereof.

9. 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 at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 7.

10. The method according to claim 7, wherein the aspartyl protease is beta-secretase and the condition is Alzheimer'"'"'s disease.

11. The method according to claim 7, wherein the aspartyl protease is beta-secretase and the condition is dementia.

12. 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, and wherein R₁, R₂ and R_C are as defined in claim 7.

13. A method of inhibiting beta-secretase activity in a host, the method comprising 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 7.

14. 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, A₁, A₂ and R_C are defined as in claim 7.

15. 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, A₁, A₂ and R_C are defined as in claim 7.

16. 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, A₁, A₂ and R_C are defined as in claim 7, and wherein said 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.

17. 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, A₁, A₂ and R_C are defined as in claim 7.

18. 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, A₁, A₂ and R_C are defined as in claim 7.

19. The method in claim 18, wherein the A-beta deposits or plaques are in a human brain.

20. 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, A₁, A₂ and R_C are defined as in claim 7, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′

, and S2′

.

21. 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 7, further comprising increasing at least one parameter chosen from C_max, T_max, and half-life.

22. 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 said patient, wherein R₁, R₂, A₁, A₂ and R_C are defined as in claim 7.