Methods of treatment of amyloidosis using ethanolcyclicamine aspartyl protease inhibitors

• US 20060074098A1
• Filed: 08/26/2005
• Published: 04/06/2006
• Est. Priority Date: 08/27/2004
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: John, Varghese, Fang, Lawrence, Hom, Roy
• Application Number:
  US11/211,484
• Publication Number:
  US 20060074098A1
• Time in Patent Office: Days
• US Class Current: 514/278
• 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: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 491/10 Spiro-condensed 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, 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, 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 —

NH—

C(O)—

CH₃, —

NH—

C(O)—

CH(halogen)₂, and —

NH—

C(O)CH₂(halogen).

5. The compound according to claim 1, wherein R_C is selected from 4-Butyl-4-hydroxy-piperidin-2-yl, (4,4-dimethyl-pentyl)-4-hydroxy-piperidin-2-yl, 4-Butyl-4-hydroxy-1-aza-spiro[5.5]undec-2-yl, 6-ethyl-1,2,3,4-tetrahydro-isoquinolin-3-yl, 4-oxo-piperidin-2-yl, 4-propyl-piperidin-2-yl, 2-piperidin-2-yl, 4-(4-ethyl-phenyl)-piperidin-2-yl, 5-Butyl-4-oxo-piperidin-2-yl, 5-(3-ethyl-phenyl)-4-oxo-piperidin-2-yl, and 2-(Decahydro-isoquinolin-3-yl.

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

N-[2-(4-Butyl-4-hydroxy-piperidin-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[4-(4,4-dimethyl-pentyl)-4-hydroxy-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(4-Butyl-4-hydroxy-1-aza-spiro[5.5]undec-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-(6-ethyl-1,2,3,4-tetrahydro-isoquinolin-3-yl)-2-hydroxy-ethyl]-acetamide, N-[1-Benzyl-2-hydroxy-2-(4-oxo-piperidin-2-yl)-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-2-(4-oxo-piperidin-2-yl)-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-2-(4-propyl-piperidin-2-yl)-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-2-piperidin-2-yl-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[4-(4-ethyl-phenyl)-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(5-Butyl-4-oxo-piperidin-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[5-(3-ethyl-phenyl)-4-oxo-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(Decahydro-isoquinolin-3-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, 7-(2-Acetylamino-1-hydroxy-3-phenyl-propyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester, N-(1-(6-(3-tert-butylcyclohexyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(3,3-dimethylbutyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(4,4-dimethylpentyl)piperidin-2-yl )-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-phenethylpiperidin-2-yl)propan-2-yl)acetamide, N-(1-(6-(3-tert-butylphenyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-(3-methoxyphenethyl )piperidin-2-yl)propan-2-yl)acetamide, methyl3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)benzoate, N-(1-(decahydroisoquinolin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(3-fluorophenethyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, 3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)-N,N-dipropylbenzamide, N-(3-(3,5-difluorophenyl)-1-(5-(3,3-dimethylbutyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-(2-(3-methoxycyclohexyl)ethyl)piperidin-2-yl)propan-2-yl)acetamide, N-(1-(6-(2-cyclohexylethyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, methyl 3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)benzoate, 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,

—

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,

—

(NH)C(O)—

CH₂(halogen), —

(NH)C(O)—

CH(halogen)₂,

U is selected from —

C(O)—

, —

C(═

S)—

, —

S(O)_0-2—

, —

C(═

N—

R₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, —

C(O)—

O—

, —

S(O)₂—

NR₂₀—

, and —

S(O)₂—

O—

;

U′

is selected from —

C(O)—

, —

C(═

N—

R₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, and —

C(O)—

O—

;

V is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —

[C(R₄)(R_4′

)]_1-3-D, and -(T)_0-1-R_N;

V′

is selected from -(T)_0-1-R_N′

;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′

are optionally substituted with at least one independently selected R_B groups;

wherein at least one carbon of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V and V′

are optionally replaced with —

N—

, —

O—

, —

NH—

, —

C(O)—

, —

C(S)—

, —

C(═

N—

H)—

, —

C(═

N—

OH)—

, —

C(═

N-alkyl)-, or —

C(═

N—

O-alkyl)-;

R_B at each occurrence is independently selected from halogen, —

OH, —

CF₃, —

OCF₃, —

O-aryl, —

CN, —

NR₁₀₁R′

₁₀₁, alkyl, alkoxy, —

(CH₂)_0-4—

(C(O))_0-1—

(O)_0-1-alkyl, —

C(O)—

OH, —

(CH₂)_0-3-cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;

wherein, the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups included within R_B are optionally substituted with 1 or 2 groups independently selected from —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, —

C₁-C₄ haloalkyl, —

C₁-C₄ haloalkoxy, halogen, —

OH, —

CN, and —

NR₁₀₁R′

₁₀₁;

R₁₀₁ and R′

₁₀₁ are independently selected from —

H, alkyl, —

(C(O))_0-1—

(O)_0-1-alkyl, —

C(O)—

OH, and aryl;

R₄ and R_4′

are independently selected from hydrogen, alkyl, —

OH, —

(CH₂)_0-3-cycloalkyl, —

(CH₂)_1-3OH, —

F, —

CF₃, —

OCF₃, —

O-aryl, alkoxy, —

C₃-C₇ cycloalkoxy, aryl, and heteroaryl, or

R₄ and R_4′

are taken together with the carbon to which they are attached to form a 3, 4, 5, 6, or 7 membered carbocylic ring wherein 1, 2, or 3 carbons of the ring are optionally replaced with —

O—

, —

N(H)—

, —

N(alkyl)-, —

N(aryl)-, —

C(O)—

, or —

S(O)_0-2;

D is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2 R_B groups; and

T is selected from —

NR₂₀— and

—

O—

;

R₂₀ is selected from —

H, —

CN, alkyl, haloalkyl, and cycloalkyl;

R₂₁ is selected from —

H, alkyl, haloalkyl, and cycloalkyl;

R_N is selected from —

OH, —

NH₂, —

NH(alkyl), —

NH(cycloalkyl), —

N(alkyl)(alkyl), —

N(alkyl)(cycloalkyl), —

N(cycloalkyl)(cycloalkyl), —

R′

₁₀₀, alkyl-R₁₀₀, —

(CRR′

)_0-6R₁₀₀, —

(CRR′

)_1-6—

O—

R′

₁₀₀, —

(CRR′

)_1-6—

S—

R′

₁₀₀, —

(CRR′

)_1-6—

C(O)—

R₁₀₀, —

(CRR′

)_1-6—

SO₂-R₁₀₀, —

(CRR′

)_1-6—

NR₁₀₀—

R′

₁₀₀, —

(CRR′

)_1-6—

P(O)(O-alkyl)₂, alkyl-O-alkyl-C(O)OH, and —

CH(R_E1)—

(CH₂)_0-3-E₁-E₂-E₃;

R_N′

is —

SO₂R′

₁₀₀;

R and R′

are independently selected from hydrogen, —

C₁-C₁₀ alkyl (optionally substituted with at least one group selected from —

OH), —

C₁-C₁₀ alkylaryl, and —

C₁-C₁₀ alkylheteroaryl;

R₁₀₀ and R′

₁₀₀ are independently selected from

-cycloalkyl,

-heterocycloalkyl,

-alkoxy,

-aryl,

-heteroaryl,

-aryl-W-aryl,

-aryl-W-heteroaryl,

-aryl-W-heterocycloalkyl,

-heteroaryl-W-aryl,

-heteroaryl-W-heteroaryl,

-heteroaryl-W-heterocycloalkyl,

-heterocycloalkyl-W-aryl,

-heterocycloalkyl-W-heteroaryl,

-heterocycloalkyl-W-heterocycloalkyl,

—

W—

R₁₀₂,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]—

(CH₂)_0-2-aryl,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]—

(CH₂)_0-2-heterocycloalkyl,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]—

(CH₂)_0-2-heteroaryl,

—

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, and wherein 1, 2, or 3 carbons of the alkyl group are optionally replaced with a group independently selected from —

C(O)—

, and —

NH—

,

-alkyl-O-alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups,

-alkyl-S-alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, and

-cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups;

wherein the ring portions included within R₁₀₀ and R′

₁₀₀ are optionally substituted with 1, 2, or 3 groups independently selected from —

OR, —

NO₂, halogen, —

CN, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

O—

P(O)(OR)(OR′

), —

(CH₂)_0-4—

C(O)—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

C(O)NR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

C(O)—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

C(O)—

(CH₂)_0-4-cycloalkyl, —

(CH₂)_0-4-R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

C(O)—

R₁₁₀, —

(CH₂)_0-4—

C(O)-R₁₂₀, —

(CH₂)_0-4—

C(O)—

R₁₃₀, —

(CH₂)_0-4—

C(O)—

R₁₄₀, —

(CH₂)_0-4—

C(O)—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO₂—

(CH₂)_0-4-cycloalkyl, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

C(O)-(alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R110)₂, —

(CH₂)_0-4—

O—

C(O)—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

C(O)OH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4-cycloalkyl, and —

(C₁-C₁₀)-alkyl;

R_E1 is selected from —

H, —

OH, —

NH₂, —

NH—

(CH₂)_0-3—

R_E2, —

NHR_E8, —

NR_E350C(O)R₅, —

C₁-C₄ alkyl-NHC(O)R_E5, —

(CH₂)_0-4R_E8, —

O—

(C₁-C₄ alkanoyl), —

C₆-C₁₀ aryloxy (optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

C₁-C₄ alkyl, —

CO₂H, —

C(O)—

C₁-C₄ alkoxy, and —

C₁-C₄ alkoxy), alkoxy, -aryl-(C₁-C₄ alkoxy), —

NR_E350CO₂R_E351, —

C₁-C₄ alkyl-NR_E350CO₂R₃₅₁, —

CN, —

CF₃, —

CF₂—

CF₃, —

C≡

CH, —

CH₂—

CH═

CH₂, —

(CH₂)_1-4—

R_E2, —

(CH₂)_1-4—

NH—

R_E2, —

O—

(CH₂)_0-3—

R_E2, —

S—

(CH₂)_0-3—

R_E2, —

(CH₂)_0-4—

NHC(O)—

(CH₂)_0-6-R_E352, and —

(CH₂)_0-4—

(R_E353)_0-1—

(CH₂)_0-4—

R_E354;

R_E2 is selected from —

SO₂—

(C₁-C₈ alkyl), —

SO—

(C₁-C₈ alkyl), —

S—

(C₁-C₈ alkyl), —

S—

C(O)-alkyl, —

SO₂—

NR_E3R_E4, —

C(O)—

C₁-C₂ alkyl, and —

C(O)—

NR_E4R_E10;

R_E3 and R_E4 are independently selected from —

H, —

C₁-C₃ alkyl, and —

C₃-C₆ cycloalkyl;

R_E10 is selected from alkyl, arylalkyl, alkanoyl, and arylalkanoyl;

R_E5 is selected from cycloalkyl, alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

NR_E6R_E7, C₁-C₄ alkoxy, —

C₅-C₆ heterocycloalkyl, —

C₅-C₆ heteroaryl, —

C₆-C₁₀ aryl, —

C₃-C₇ cycloalkyl C₁-C₄ alkyl, —

S—

C₁-C₄ alkyl, —

SO₂—

C₁-C₄ alkyl, —

CO₂H, —

C(O)NR_E6R_E7, —

CO₂—

C₁-C₄ alkyl, and —

C₆-C₁₀ aryloxy), heteroaryl (optionally substituted with 1, 2, or 3 groups independently selected from —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, halogen, —

C₁-C₄ haloalkyl, and —

OH), heterocycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, halogen, and —

C₂-C₄ alkanoyl), aryl (optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —

OH, —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, and —

C₁-C₄ haloalkyl), and —

NR_E6R_E7;

R_E6 and R_E7 are independently selected from —

H, alkyl, alkanoyl, aryl, —

SO₂—

C₁-C₄ alkyl, and aryl-C₁-C₄ alkyl;

R_E8 is selected from —

SO₂-heteroaryl, —

SO₂-aryl, —

SO₂-heterocycloalkyl, —

SO₂—

C₁-C₁₀ alkyl, —

C(O)NHR_E9, heterocycloalkyl, —

S-alkyl, and —

S—

C₂-C₄ alkanoyl;

R_E9 is selected from —

H, alkyl, and -aryl C₁-C₄ alkyl;

R_E350 is selected from —

H and alkyl;

R_E351 is selected from aryl-(C₁-C₄ alkyl), alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, -cyano, -heteroaryl, —

NR_E6R_E7, —

C(O)NR_E6R_E7, —

C₃-C₇ cycloalkyl, and —

C₁-C₄ alkoxy), heterocycloalkyl (optionally substituted with 1 or 2 groups independently selected from —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, halogen, —

C₂-C₄ alkanoyl, -aryl-(C₁-C₄ alkyl), and —

SO₂—

(C₁-C₄ alkyl)), heteroaryl (optionally substituted with 1, 2, or 3 groups independently selected from —

OH, —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, halogen, —

NH₂, —

NH(alkyl), and —

N(alkyl)(alkyl)), heteroarylalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, halogen, —

NH₂, —

NH(alkyl), and —

N(alkyl)(alkyl)), aryl, heterocycloalkyl, —

C₃-C₈ cycloalkyl, and cycloalkylalkyl;

wherein the aryl, heterocycloalkyl, —

C₃-C₈ cycloalkyl, and cycloalkylalkyl groups included within R_E351 are optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, —

CN, —

NO₂, alkyl, alkoxy, alkanoyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, —

C₁-C₆ thioalkoxy, —

C₁-C₆ thioalkoxy-alkyl, and alkoxyalkoxy;

R_E352 is selected from heterocycloalkyl, heteroaryl, aryl, cycloalkyl, —

S(O)_0-2-alkyl, —

CO₂H, —

C(O)NH₂, —

C(O)NH(alkyl), —

C(O)N(alkyl)(alkyl), —

CO₂-alkyl, —

NH—

S(O)_0-2-alkyl, —

N(alkyl)S(O)_0-2-alkyl, —

S(O)_0-2-heteroaryl, —

S(O)_0-2-aryl, —

NH(arylalkyl), ‘

N(alkyl)(arylalkyl), thioalkoxy, and alkoxy;

wherein each group included within R_E352 is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, —

NO₂, —

CN, alkoxycarbonyl, and aminocarbonyl;

R_E353 is selected from —

O—

, —

C(O)—

, —

NH—

, —

N(alkyl)-, —

NH—

S(O)_0-2—

, —

N(alkyl)-S(O)_0-2—

, —

S(O)_0-2—

NH—

, —

S(O)_0-2—

N(alkyl)-, —

NH—

C(S)—

, and —

N(alkyl)-C(S)—

;

R_E354 is selected from heteroaryl, aryl, arylalkyl, heterocycloalkyl, —

CO₂H, —

CO₂-alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)(alkyl), —

C(O)NH₂, —

C₁-C₈ alkyl, —

OH, aryloxy, alkoxy, arylalkoxy, —

NH₂, —

NH(alkyl), —

N(alkyl)(alkyl), and -alkyl-CO₂-alkyl;

wherein each group included within R_E354 is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkyl, alkoxy, —

CO₂H, —

CO₂-alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, —

NO₂, —

CN, alkoxycarbonyl, and aminocarbonyl;

E₁ is selected from —

NR_E11— and

—

C₁-C₆ alkyl (optionally substituted with 1, 2, or 3 groups selected from —

C₁-C₄ alkyl);

R_E11 is selected from —

H and alkyl;

or R_E1 and R_E11 combine to form —

(CH₂)_1-4—

;

E₂ is selected from a bond, —

SO₂—

, —

SO—

, —

S—

, and —

C(O)—

;

E₃ is selected from —

H, —

C₁-C₄ haloalkyl, —

C₅-C₆ heterocycloalkyl (containing at least one group independently selected from —

N—

, —

O—

, and —

S—

), —

C₆-C₁₀ aryl, —

OH, —

N(E_3a)(E_3b), —

C₁-C₁₀ alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy), —

C₃-C₈ cycloalkyl (optionally substituted with 1, 2, or 3 groups independently selected from —

C₁-C₃ alkyl and halogen), alkoxy, aryl (optionally substituted with at least one group independently selected from halogen, alkyl, alkoxy, —

CN and —

NO₂), and arylalkyl (optionally substituted with at least one group independently selected from halogen, alkyl, alkoxy, —

CN, and —

NO₂);

E_3a and E_3b are independently selected from —

H, —

C₁-C₁₀ alkyl (optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

C₁-C₄ alkoxy, —

C₃-C₈ cycloalkyl, and —

OH), —

C₂-C₆ alkyl, —

C₂-C₆ alkanoyl, -aryl, —

SO₂—

(C₁-C₄ alkyl), -aryl C₁-C₄ alkyl, and —

C₃-C₈ cycloalkyl C₁-C₄ alkyl;

or

E_3a, E_3b, and the nitrogen to which they are attached form a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrolidinyl;

wherein each ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl, alkoxy, alkoxyalkyl, and halogen;

W is selected from —

(CH₂)_0-4—

, —

O—

, —

S(O)_0-2—

, —

N(R₁₃₅)—

, —

CR(OH)—

, and —

C(O)—

;

R₁₀₂ and R₁₀₂′

are independently selected from hydrogen, and —

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, aryl, and —

R₁₁₀;

R₁₀₅ and R′

₁₀₅ are independently selected from

—

H,

—

R₁₁₀,

—

R₁₂₀,

-cycloalkyl,

—

(C₁-C₂ alkyl)-cycloalkyl,

-(alkyl)-O—

(C₁-C₃ alkyl), and

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

OH, amine, and halogen;

or

R₁₀₅ and R′

₁₀₅ together with the atom to which they are attached form a 3, 4, 5, 6, or 7 membered carbocyclic ring, wherein one member is optionally a heteroatom selected from —

O—

, —

S(O)_0-2—

, and —

N(R₁₃₅)—

;

wherein the carbocyclic ring is optionally substituted with 1, 2 or 3 R₁₄₀ groups; and

wherein the at least one carbon of the carbocylic ring is optionally replaced with —

C(O)—

;

R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups;

R₁₁₅ at each occurrence is independently selected from halogen, —

OH, —

C(O)—

O—

R₁₀₂, —

C₁-C₆ thioalkoxy, —

C(O)—

O-aryl, —

NR₁₀₅R′

₁₀₅, —

SO₂—

(C₁-C₈ alkyl), —

C(O)—

R₁₈₀, R₁₈₀, —

C(O)NR₁₀₅R′

₁₀₅, —

SO₂NR₁₀₅R′

₁₀₅, —

NH—

C(O)-(alkyl), —

NH—

C(O)—

OH, —

NH—

C(O)—

OR, —

NH—

C(O)—

O-aryl, —

O—

C(O)-(alkyl), —

O—

C(O)-amino, —

O—

C(O)-monoalkylamino, —

O—

C(O)-dialkylamino, —

O—

C(O)-aryl, —

O-(alkyl)-C(O)—

O—

H, —

NH—

SO₂-(alkyl), alkoxy, and haloalkoxy;

R₁₂₀ is heteroaryl, optionally substituted with 1 or 2 R₁₂₅ groups;

R₁₂₅ at each occurrence is independently selected from halogen, amino, monoalkylamino, dialkylamino, —

OH, —

CN, —

SO₂—

NH₂, —

SO₂—

NH-alkyl, —

SO₂—

N(alkyl)₂, —

SO₂—

(C₁-C₄ alkyl), —

C(O)—

NH₂, —

C(O)—

NH-alkyl, —

C(O)—

N(alkyl)₂, alkyl (optionally substituted with 1, 2, or 3 groups independently selected from C₁-C₃ alkyl, halogen, —

OH, —

SH, —

CN, —

CF₃, —

C₁-C₃ alkoxy, amino, monoalkylamino, and dialkylamino), and alkoxy (optionally substituted with 1, 2, or 3 halogen);

R₁₃₀ is heterocycloalkyl optionally substituted with 1 or 2 R₁₂₅ groups;

R₁₃₅ is independently selected from alkyl, cycloalkyl, —

(CH₂)_0-2-(aryl), —

(CH₂)_0-2-(heteroaryl), and —

(CH₂)_0-2-(heterocycloalkyl);

R₁₄₀ at each occurrence is independently selected from heterocycloalkyl (optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl, alkoxy, halogen, hydroxy, cyano, nitro, amino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, amino-alkyl, monoalkylamino-alkyl, dialkylaminoalkyl, and —

C(O)H);

R₁₅₀ is independently selected from

-hydrogen,

-cycloalkyl,

—

(C₁-C₂ alkyl)-cycloalkyl,

—

R₁₁₀,

—

R₁₂₀, and

-alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —

OH, —

NH₂, —

C₁-C₃ alkoxy, —

R₁₁₀, and halogen;

R₁₅₀′

is independently selected from

-cycloalkyl,

—

(C₁-C₃ alkyl)-cycloalkyl,

—

R₁₁₀,

—

R₁₂₀, and

-alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —

OH, —

NH₂, —

C₁-C₃ alkoxy, —

R₁₁₀, and halogen; and

R₁₈₀ is independently selected from

-morpholinyl,

-thiomorpholinyl,

-piperazinyl,

-piperidinyl,

-homomorpholinyl,

-homothiomorpholinyl,

-homothiomorpholinyl S-oxide,

-homothiomorpholinyl S,S-dioxide,

-pyrrolinyl, and

-pyrrolidinyl;

wherein each R₁₈₀ group is optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl, alkoxy, halogen, hydroxy, cyano, nitro, amino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl, monoalkylamino-alkyl, dialkylamino-alkyl, and —

C(O)H; and

wherein the at least one carbon of R₁₈₀ is optionally replaced with —

C(O)—

;

R_C is selected from formulae (IIIa), (IIIb), (IIIc), and (IIId)

wherein

A′

is —

NH—

;

ring a′

is a 5, 6, or 7 membered cycloalkyl ring;

ring b′

is a 5, 6, or 7 membered cycloalkyl ring;

ring c′

is a 5 or 6 membered aromatic ring or a 5, 6, or 7 membered cycloalkyl ring;

wherein at least one carbon of cycloalkyl rings a′

, b′ and

c′

of formulae (IIIa), (IIIb), (IIIc), and (IIId) is optionally replaced with a group independantly selected from —

C(O)—

, —

NH—

, —

N—

, —

N(R₂₀₀)—

, —

O—

, —

S(O)_0-2—

, and —

N(S(O)_0-2—

R₂₀₀)—

;

wherein at least one carbon of aromatic ring c′

of formula (IIId) is optionally replaced with a group independently selected from —

C(R₂₀₀)—

, —

O—

, —

S(O)_0-2—

, —

N—

, —

NH—

, —

N(S(O)_0-2—

R₂₀₀)—

, and —

N(R₂₀₀)—

;

wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl within R_C is optionally substituted with at least one group independently selected from R₂₀₀; and

wherein each cycloalkyl and heterocycloalkyl within formulae (IIIa), (IIIb), (IIIc), and (IIId) optionally contains at least one double bond;

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(Oyalkyl,

—

(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.

8. The method according to claim 7, wherein the at least one compound of formula (I) is selected from N-[2-(4-Butyl-4-hydroxy-piperidin-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[4-(4,4-dimethyl-pentyl)-4-hydroxy-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(4-Butyl-4-hydroxy-1-aza-spiro[5.5]undec-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-(6-ethyl-1,2,3,4-tetrahydro-isoquinolin-3-yl)-2-hydroxy-ethyl]-acetamide, N-[1-Benzyl-2-hydroxy-2-(4-oxo-piperidin-2-yl)-ethyl]-acetamide, N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-2-(4-oxo-piperidin-2-yl)-ethyl]-acetamide, N-[1-(3, 5-Difluoro-benzyl)-2-hydroxy-2-(4-propyl-piperidin-2-yl)-ethyl]-acetamide, N-[l-(3,5-Difluoro-benzyl)-2-hydroxy-2-piperidin-2-yl-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[4-(4-ethyl-phenyl)-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(5-Butyl-4-oxo-piperidin-2-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-[5-(3-ethyl-phenyl)-4-oxo-piperidin-2-yl]-2-hydroxy-ethyl}-acetamide, N-[2-(Decahydro-isoquinolin-3-yl)-1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl]-acetamide, 7-(2-Acetylamino-1-hydroxy-3-phenyl-propyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester, N-(1-(6-(3-tert-butylcyclohexyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(3,3-dimethylbutyl)piperidin-2-yl )-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(4,4-dimethylpentyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-phenethylpiperidin-2-yl)propan-2-yl)acetamide, N-(1-(6-(3-tert-butylphenyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-(3-methoxyphenethyl)piperidin-2-yl)propan-2-yl)acetamide, methyl 3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)benzoate, N-(1-(decahydroisoquinolin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-(6-(3-fluorophenethyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, 3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)-N,N-dipropylbenzamide, N-(3-(3,5-difluorophenyl)-1-(5-(3,3-dimethylbutyl)piperidin-2-yl)-1-hydroxypropan-2-yl)acetamide, N-(3-(3,5-difluorophenyl)-1-hydroxy-1-(6-(2-(3-methoxycyclohexyl)ethyl)piperidin-2-yl)propan-2-yl)acetamide, N-(1-(6-(2-cyclohexylethyl)piperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)acetamide, methyl 3-(2-(6-(2-acetamido-3-(3,5-difluorophenyl)-1-hydroxypropyl)piperidin-2-yl)ethyl)benzoate, 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, 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, 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, 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, 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, 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, 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, and R_C are defined as in claim 7.