Methods of treating amyloidosis using cyclopropyl derivative aspartyl protease inhibitors

• US 20070149569A1
• Filed: 10/12/2006
• Published: 06/28/2007
• Est. Priority Date: 10/12/2005
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Truong, Anh, Jagodzinska, Barbara, Tung, Jay, Tisdale, Eric, Neitz, R.
• Granted Patent: US 7,906,556 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• 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: 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 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/18 the ring system containing six carbon atoms
• CPC Class Codes: C07C 323/26 the carbon skeleton being saturated and containing rings
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• 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 295/108 to an acyclic saturated chain
• CPC Class Codes: C07D 295/182 Radicals derived from carboxylic acids

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 -alkyl optionally substituted with at least one R₂₀₁ group, and wherein at least one carbon within R_C is optionally replaced with —

O—

, —

S—

, or —

NH.

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

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(3,3-dimethylbutyl)cyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(hydroxymethyl)cyclopropanecarboxamide,

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

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

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

N-(4-(2-methyl-1-(2- (neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

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

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

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

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

N-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)-2-hydroxycyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-aminocyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

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

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

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

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

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

N-(4-(6-((2-(1H-pyrazol-1-yl)ethoxy)methyl)bicyclo[3.1 O]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

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

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

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

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

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

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

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

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

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

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

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

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

N₁-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-3-hydroxybutan-2-yl)—

N³, N³-diethyl-5-methylisophthalamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-methyl-2-propylcyclopropylamino)butan-2-yl)acetamide,

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

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-neopentylcyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-phenylcyclopropanecarboxamide,

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-methyl-N-phenylcyclopropanecarboxamide,

N-(4-(1-(2,6-difluorobenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

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

or at least one pharmaceutically acceptable salt thereof.

8. 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,

13 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)—

N R₇R₈,

-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), —

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 hydrogen, alkyl, —

(CH₂)_0-2-cycloalkyl, —

(CH₂)_0-2-(aryl), —

(CH₂)_0-2-(heteroaryl), and —

(CH₂)_0-2-(heterocycloalkyl);

R_C is selected from alkyl, heterocycloalkyl

—

R_Xa—

(CH₂)_0-2—

R_Xb;

wherein x′

is a 5 or 6 membered heterocycloalkyl ring, wherein at least one additional atom of x′

may be a heteroatom selected from —

O—

, —

S(O)_0-2—

, and —

N(R₁₃₆)—

;

wherein R_Xa is —

C(O)—

N(R₂₀)— and

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

or

wherein R₂₀ at each occurrence is independently selected from H, —

CN, alkyl, haloalkyl, and cycloalkyl;

wherein at least one carbon of each alkyl within R_C may be optionally replaced with —

C(O)—

, —

O—

, —

NH—

, —

N(R₂₀), —

S—

, and —

S(O)₂—

;

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

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(0)_0-2-alkyl,

—

(CH₂)_0-4—

S(0)_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.

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(3,3-dimethylbutyl)cyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(hydroxymethyl)cyclopropanecarboxamide,

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

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

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

N-(4-(2-methyl-1-(2-(neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

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

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

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

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

N-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)-2-hydroxycyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-aminocyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N¹-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-3-hydroxybutan-2-yl)—

N³, N³-diethyl-5-methylisophthalamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-methyl-2-propylcyclopropylamino)butan-2-yl)acetamide,

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

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-neopentylcyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-phenylcyclopropanecarboxamide,

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

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-methyl-N-phenylcyclopropanecarboxamide,

N-(4-(1-(2,6-difluorobenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

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

or at least one pharmaceutically acceptable salt thereof.

10. 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 8.

11. The method according to claim 8, wherein the aspartyl protease is beta-secretase and the condition is Alzheimer'"'"'s disease.

12. The method according to claim 8, wherein the aspartyl protease is beta-secretase and the condition is dementia.

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), 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 8.

14. 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 8.

15. 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 8.

16. 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 8.

17. 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 8, 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.

18. 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 8.

19. 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 8.

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

21. 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 8, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′

, and S2′

.

22. 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 8, further comprising increasing at least one parameter chosen from C_max, T_max, and half-life.

23. 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 8.