Methods of treatment of amyloidosis using spirocyclohexane aspartyl-protease inhibitors

US 20060014790A1
Filed: 01/21/2005
Published: 01/19/2006
Est. Priority Date: 01/21/2004
Status: Abandoned Application

First Claim

Patent Images

1. A method of preventing or treating conditions which benefit from inhibition of at least one aspartyl-protease, comprising:

administering to a host in need thereof a composition comprising a therapeutically effective amount of at least one selective compound of formula (I), or pharmaceutically acceptable salts thereof, wherein R₁is 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_50bare 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 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_50bare optionally substituted with at least one group independently selected from alkyl, halogen, —

OH, —

NR₅R₆, —

CN, haloalkoxy, —

NR₇R₈, and alkoxy;

R₅and R₆are independently selected from H or alkyl, or R₅and R₆, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and

R₇and R₈are independently selected from —

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

OH, —

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

R₂is selected from H and F;

R_cis selected from the following formula (IIIa), (IIIb), or (IIIc) structures wherein, A, B, and C are independently selected from —

CH₂—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, —

NH—

, —

NR₂₀₀, —

N(CO)_0-1R₂₀₀—

, and —

N(S(O₂)alkyl)-;

wherein (IIIa), (IIIb), and (IIIc) are each optionally substituted with at least one group independently selected from alkyl, alkoxy, —

OH, halogen, —

NH₂, —

NH(alkyl), —

N(alkyl)(alkyl), —

NH—

C(O)-alkyl, and —

NS(O₂)-alkyl;

R_xis selected from -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —

R_xa—

R_xb;

wherein R_Xaand R_Xbare independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

wherein each aryl or heteroaryl group within R_Cis optionally substituted with at least one group independently selected from R₂₀₀;

wherein each cycloalkyl or heterocycloalkyl within R_Cis optionally substituted with at least one group independently selected from R₂₁₀; and

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

NH—

, —

N—

, —

N(CO)_0-1R₂₁₅—

, —

N(CO)_0-1R₂₂₀—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, and —

NS(O)_0-2R₂₀₀;

R₂₀₀at 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—

NR₂₂₀R₂₂₅, —

(CH₂)_0-4—

CO—

NH(R₂₁₅), —

(CH₂)_0-4—

CO-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—

CO₂R₂₁₅, —

(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)—

CO₂R₂₁₅, —

(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—

NR₂₂₀R₂₂₅, —

(CH₂)_0-4—

O—

C(O)-alkyl, —

(CH₂)_0-4—

O—

(R₂₁₅), —

(CH₂)_0-4—

S—

(R₂₁₅), —

(CH₂)_0-4—

O-alkyl optionally substituted with at least one F, and -adamantane;

wherein each aryl and heteroaryl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₀₅, R₂₁₀, and alkyl (optionally substituted with at least one group independently selected from R₂₀₅and R₂₁₀);

wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₁₀;

R₂₀₅at each occurrence is independently selected from -alkyl, -haloalkoxy, —

(CH₂)_0-3-cycloalkyl, -halogen, —

(CH₂)_0-6—

OH, —

O-phenyl, —

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, —

CN, —

CF₃, -alkoxy, -alkoxycarbonyl, and —

NR₂₃₅R₂₄₀;

R₂₁₀at each occurrence is independently selected from —

OH, —

CN, —

(CH₂)_0-4—

C(O)H -alkyl optionally substituted with at least one group independently selected from R₂₀₅, -alkanoyl, —

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)_0-6—

OH, —

(CH₂)_0-6—

CN, —

(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, —

S(O)₂—

NR₂₃₅R₂₄₀, —

C(O)—

NR₂₃₅R₂₄₀, and —

S(O)_0-2-alkyl;

R₂₁₅at each occurrence is independently selected from -alkyl, —

(CH₂)_0-2-aryl, -cycloalkyl, —

(CH₂)_0-2-heteroaryl, and —

(CH₂)_0-2-heterocycloalkyl;

wherein the aryl group included within R₂₁₅is optionally substituted with at least one group independently selected from R₂₀₅or R₂₁₀;

wherein the heterocycloalkyl and heteroaryl groups included within R₂₁₅are optionally substituted with at least one group independently selected from R₂₁₀;

R₂₂₀and R₂₂₅at each occurrence are independently selected from —

H, -alkyl, —

(CH₂)_0-4—

C(O)H, -alkyl hydroxyl, -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 and heterocycloalkyl groups included within R₂₂₀and R₂₂₅are each optionally substituted with at least one group independently selected from R₂₇₀;

R₂₇₀at each occurrence is independently selected from —

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

CO—

NR₂₃₅R₂₄₀, —

S(O)₂-alkyl, and —

(CH₂)_0-4—

C(O)H;

R₂₃₅and R₂₄₀at each occurrence are independently selected from —

H, —

OH, —

CF₃, —

OCH₃, —

NH—

CH₃, —

N(CH₃)₂, —

(CH₂)_0-4—

C(O)(H or alkyl), -alkyl, -alkanoyl, —

SO₂-alkyl, and -phenyl.

View all claims

2 Assignments

Timeline View

Assignment View

0 Petitions

Accused Products

Abstract

The invention relates to acetyl 2-hydroxy-1,3-diaminospirocyclohexanes and derivatives thereof that are useful in 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.

Citations

82 Claims

1. A method of preventing or treating conditions which benefit from inhibition of at least one aspartyl-protease, comprising:
- administering to a host in need thereof a composition comprising a therapeutically effective amount of at least one selective compound of formula (I), or pharmaceutically acceptable salts thereof, wherein R₁is 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_50bare 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 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_50bare optionally substituted with at least one group independently selected from alkyl, halogen, —
  
  OH, —
  
  NR₅R₆, —
  
  CN, haloalkoxy, —
  
  NR₇R₈, and alkoxy;
  
  R₅and R₆are independently selected from H or alkyl, or R₅and R₆, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
  
  R₇and R₈are independently selected from —
  
  H, -alkyl optionally substituted with at least one group independently selected from —
  
  OH, —
  
  NH₂, and halogen, -cycloalkyl, and -alkyl-O-alkyl;
  
  R₂is selected from H and F;
  
  R_cis selected from the following formula (IIIa), (IIIb), or (IIIc) structures wherein, A, B, and C are independently selected from —
  
  CH₂—
  
  , —
  
  O—
  
  , —
  
  C(O)—
  
  , —
  
  S(O)_0-2—
  
  , —
  
  NH—
  
  , —
  
  NR₂₀₀, —
  
  N(CO)_0-1R₂₀₀—
  
  , and —
  
  N(S(O₂)alkyl)-;
  
  wherein (IIIa), (IIIb), and (IIIc) are each optionally substituted with at least one group independently selected from alkyl, alkoxy, —
  
  OH, halogen, —
  
  NH₂, —
  
  NH(alkyl), —
  
  N(alkyl)(alkyl), —
  
  NH—
  
  C(O)-alkyl, and —
  
  NS(O₂)-alkyl;
  
  R_xis selected from -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —
  
  R_xa—
  
  R_xb;
  
  wherein R_Xaand R_Xbare independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  
  wherein each aryl or heteroaryl group within R_Cis optionally substituted with at least one group independently selected from R₂₀₀;
  
  wherein each cycloalkyl or heterocycloalkyl within R_Cis optionally substituted with at least one group independently selected from R₂₁₀; and
  
  wherein at least one carbon of the heteroaryl or heterocycloalkyl group within R_Cis independently optionally replaced with a group selected from —
  
  NH—
  
  , —
  
  N—
  
  , —
  
  N(CO)_0-1R₂₁₅—
  
  , —
  
  N(CO)_0-1R₂₂₀—
  
  , —
  
  O—
  
  , —
  
  C(O)—
  
  , —
  
  S(O)_0-2—
  
  , and —
  
  NS(O)_0-2R₂₀₀;
  
  R₂₀₀at 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—
  
  NR₂₂₀R₂₂₅, —
  
  (CH₂)_0-4—
  
  CO—
  
  NH(R₂₁₅), —
  
  (CH₂)_0-4—
  
  CO-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—
  
  CO₂R₂₁₅, —
  
  (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)—
  
  CO₂R₂₁₅, —
  
  (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—
  
  NR₂₂₀R₂₂₅, —
  
  (CH₂)_0-4—
  
  O—
  
  C(O)-alkyl, —
  
  (CH₂)_0-4—
  
  O—
  
  (R₂₁₅), —
  
  (CH₂)_0-4—
  
  S—
  
  (R₂₁₅), —
  
  (CH₂)_0-4—
  
  O-alkyl optionally substituted with at least one F, and -adamantane;
  
  wherein each aryl and heteroaryl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₀₅, R₂₁₀, and alkyl (optionally substituted with at least one group independently selected from R₂₀₅and R₂₁₀);
  
  wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₁₀;
  
  R₂₀₅at each occurrence is independently selected from -alkyl, -haloalkoxy, —
  
  (CH₂)_0-3-cycloalkyl, -halogen, —
  
  (CH₂)_0-6—
  
  OH, —
  
  O-phenyl, —
  
  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, —
  
  CN, —
  
  CF₃, -alkoxy, -alkoxycarbonyl, and —
  
  NR₂₃₅R₂₄₀;
  
  R₂₁₀at each occurrence is independently selected from —
  
  OH, —
  
  CN, —
  
  (CH₂)_0-4—
  
  C(O)H -alkyl optionally substituted with at least one group independently selected from R₂₀₅, -alkanoyl, —
  
  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)_0-6—
  
  OH, —
  
  (CH₂)_0-6—
  
  CN, —
  
  (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, —
  
  S(O)₂—
  
  NR₂₃₅R₂₄₀, —
  
  C(O)—
  
  NR₂₃₅R₂₄₀, and —
  
  S(O)_0-2-alkyl;
  
  R₂₁₅at each occurrence is independently selected from -alkyl, —
  
  (CH₂)_0-2-aryl, -cycloalkyl, —
  
  (CH₂)_0-2-heteroaryl, and —
  
  (CH₂)_0-2-heterocycloalkyl;
  
  wherein the aryl group included within R₂₁₅is optionally substituted with at least one group independently selected from R₂₀₅or R₂₁₀;
  
  wherein the heterocycloalkyl and heteroaryl groups included within R₂₁₅are optionally substituted with at least one group independently selected from R₂₁₀;
  
  R₂₂₀and R₂₂₅at each occurrence are independently selected from —
  
  H, -alkyl, —
  
  (CH₂)_0-4—
  
  C(O)H, -alkyl hydroxyl, -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 and heterocycloalkyl groups included within R₂₂₀and R₂₂₅are each optionally substituted with at least one group independently selected from R₂₇₀;
  
  R₂₇₀at each occurrence is independently selected from —
  
  R₂₀₅, -alkyl optionally substituted with at least one group independently selected from R₂₀₅, -phenyl, -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, —
  
  CO—
  
  NR₂₃₅R₂₄₀, —
  
  S(O)₂-alkyl, and —
  
  (CH₂)_0-4—
  
  C(O)H;
  
  R₂₃₅and R₂₄₀at each occurrence are independently selected from —
  
  H, —
  
  OH, —
  
  CF₃, —
  
  OCH₃, —
  
  NH—
  
  CH₃, —
  
  N(CH₃)₂, —
  
  (CH₂)_0-4—
  
  C(O)(H or alkyl), -alkyl, -alkanoyl, —
  
  SO₂-alkyl, and -phenyl.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68)
- - 2. The method according to claim 1, wherein R₁is —
    - CH₂-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, and —
      
      OH.
  - 3. The method according to claim 1, wherein R₁is 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 method according to claim 1, wherein R₂is hydrogen.
  - 5. The method according to claim 1, wherein R_Cis selected from 4-(3-Ethyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-ethyl-benzene, 1-Cyclohexyl-3-isobutyl-benzene, 1-Cyclohexyl-3-isopropyl-benzene, 1-Cyclohexyl-3-(2,2-dimethyl-propyl)-benzene, 1-tert-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-ethynyl-benzene, 8-(3-Isopropyl-phenyl)-1,4-dioxa-spiro[4.5]decane, 4-(3-Isopropyl-phenyl)-cyclohexanone, 2-(3-Cyclohexyl-phenyl)-4-methyl-thiophene, 1-[5-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, 3-(3-Cyclohexyl-phenyl)-furan, 3-(3-Cyclohexyl-phenyl)-thiophene, 5-(3-Cyclohexyl-phenyl)-thiophene-2-carbaldehyde, 2-(3-Cyclohexyl-phenyl)-furan-3-carbaldehyde, N-(3′
    - -Cyclohexyl-biphenyl-3-yl)-acetamide, 4-(3-tert-Butyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-trifluoromethyl-benzene, 1-sec-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-pentyl-benzene, 1-Cyclohexyl-3-(3-methyl-butyl)-benzene, 1-Cyclohexyl-3-(1-ethyl-propyl)-benzene, 1-Cyclohexyl-3-cyclopentyl-benzene, 1-Cyclohexyl-3-pent-4-enyl-benzene, 3-(3-Cyclohexyl-phenyl)-propionic acid ethyl ester, 2-(3-Cyclohexyl-phenyl)-pyridine, 2-(3-Cyclohexyl-phenyl)-3-methyl-pyridine, 2-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-3-methyl-thiophene, 1-Cyclohexyl-3-(2-fluoro-benzyl)-phenylene, 1-Cyclohexyl-3-(4-fluoro-benzyl)-phenylene, 2-(3-Cyclohexyl-phenyl)-adamantane, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1,1-dioxide, 1-[4-(3-Isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1-oxide, 2,2,2-Trifluoro-1-[4-(3-isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-piperidine-1-carbaldehyde, 1-Cyclohexyl-3-cyclopropyl-benzene, 1-Bromo-3-tert-butyl-5-cyclohexyl-benzene, 4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-piperidine, 3-Bromo-5-(3-cyclohexyl-phenyl)-[1,2,4]thiadiazole, 2-(3-Cyclohexyl-phenyl)-1-methyl-1H-imidazole, 4-(3-Cyclohexyl-phenyl)-3,5-dimethyl-3H-pyrazole, 3-(3-Cyclohexyl-phenyl)-2,5-dimethyl-pyrazine, 3-(3-Cyclohexyl-phenyl)-pyrazine-2-carbonitrile, 4-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-isonicotinonitrile, 2-(3-Cyclohexyl-phenyl)-pyrazine, 3-(3-Cyclohexyl-phenyl)-6-methyl-pyridazine, 3-(3-Cyclohexyl-phenyl)-thiophene-2-carbonitrile, 2-Chloro-3-(3-cyclohexyl-phenyl)-thiophene, 1-[4-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, and 3-Cyclohexyl-benzonitrile.
  - 6. The method according to claim 1, wherein R_Xis selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
    - -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, and 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.
  - 7. The method according to claim 1, wherein the compound of formula (I) is selected from N-{1-(3,5-Difluoro-benzyl)-3-[4-(3-ethyl-phenyl)-tetrahydro-pyran-4-ylamino]-2-hydroxy-propyl}-acetamide, N-{2-Hydroxy-1-(4-hydroxy-benzyl)-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3-Fluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3-Fluoro-4-hydroxy-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[8-(3-isopropyl-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-4-oxo-cyclohexylamino]-propyl}-acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-tetrahydro-pyran-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1,1-dioxo-hexahydro-1|6-thiopyran-4-ylamino]-propyl}-acetamide, N-[3-[1-Acetyl-4-(3-isopropyl-phenyl)-piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1-methanesulfonyl-piperidin-4-ylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidin-4-ylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-3-[1-formyl-4-(3-isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-propyl}-acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxy-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxy-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-oxo-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(4-oxo-1-(3-(thiophen-3-yl)phenyl)cyclohexylamino)butan-2-yl)acetamide yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methoxyamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methoxyamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(4-(3-tert-butylphenyl)piperidin-4-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(hydroxyamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(hydroxyamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methylsulfanyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylamino)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-aminocyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-aminocyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, 4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-piperidine-1-carboxylic acid amide, N-(4-(1-(3-tert-butylphenyl)-4-(trifluoromethyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-[3-[4-Acetylamino-1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfinyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2 yl)acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxy-4-hydroxymethyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxy-4-hydroxymethyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, methyl 4-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-4-(3-tert-butylphenyl)cyclohexylcarbamate, methyl 4-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-4-(3-tert-butylphenyl)cyclohexylcarbamate, N-(4-(3-(3-tert-butylphenyl)-1-methylpiperidin-3-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfonamido)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfonylmethanamido)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfonamido)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfonylmethanamido)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-formamidocyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(hydroxymethyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, 1-(4-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-4-(3-tert-butylphenyl)cyclohexyl)-3-methylurea, 1-(4-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-4-(3-tert-butylphenyl)cyclohexyl)-3-methylurea, N-[3-[8-(3-Bromo-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-cyano-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-oxo-1-(3-thiophen-3-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-(4-(1-(3-tert-butylphenyl)-4-(methylsulfonyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.
  - 8. The method according to claim 1, wherein the host in need thereof is a cell.
  - 9. The method according to claim 1, wherein the host in need thereof is a warm-blooded animal.
  - 10. The method according to claim 1, wherein the host in need thereof is human.
  - 11. The method according to claim 1, wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.
  - 12. The method according to claim 1, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down'"'"'s syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism (FTDP).
  - 13. The method according to claim 1, wherein the condition is Alzheimer'"'"'s disease.
  - 14. The method according to claim 1, wherein the condition is dementia.
  - 15. A method of preventing or treating conditions associated with amyloidosis, comprising:
    - administering to a host in need thereof 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), wherein R₁, R₂, and R_Care defined as in claim 1, or pharmaceutically acceptable salt thereof.
  - 17. A method of preventing or treating the onset of dementia comprising:
    - administering to a patient a therapeutically effective amount of at least one compound of formula (I),
  - 18. A method of preventing or treating conditions associated with amyloidosis by administering to a host in need thereof an effective amount of at least one compound having the following structure:
  - 19. A method of preventing or treating Alzheimer'"'"'s disease by administering to a host in need thereof an effective amount of at least one compound having the following structure:
  - 20. A method of preventing or treating dementia by administering to a host in need thereof an effective amount of at least one compound having the following structure:
  - 21. A method of inhibiting beta-secretase activity in a cell, the method comprising the step of administering to the cell an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1.
  - 22. A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1.
  - 23. The method according to claim 22, wherein the host is a human.
  - 24. 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),
  - 25. 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),
  - 26. 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),
  - 27. 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),
  - 28. A method of preventing or treating deposition of A-beta, comprising:
    - administering a therapeutically effective amount of at least one compound of formula (I),
  - 29. 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),
  - 30. The method in claim 29, wherein the A-beta deposits or plaques are in a human brain.
  - 31. A method of preventing, delaying, halting, or reversing a condition associated with a pathological form of A-beta in a host comprising:
    - administering to a patient in need thereof an effective amount of at least one compound of formula (I),
  - 32. A method of inhibiting the activity of at least one aspartyl protease in a patient in need thereof, comprising:
    - administering a therapeutically effective amount of at least one compound of formula (I),
  - 33. The method according to claim 32 wherein the at least one aspartyl protease is beta-secretase.
  - 34. 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),
  - 35. A method of modifying the pharmacokinetic parameters of at least one compound of formula (I), wherein R₁, R₂, and R_Care defined as in claim 1, comprising increasing C_max, T_max, and half-life.
  - 36. A method of treating a condition in a patient, comprising:
    - administering a therapeutically effective amount of at least one compound of formula (I),
  - 37. The method according to claim 36, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down'"'"'s syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism (FTDP).
  - 38. The method according to claim 37, wherein the condition is Alzheimer'"'"'s disease.
  - 39. The method according to claim 38, wherein the condition is dementia.
  - 40. A method of prescribing a medication for preventing, delaying, halting, or reversing disorders, conditions or diseases associated with amyloidosis comprising:
    - identifying in a patient symptoms associated with disorders, conditions or diseases associated with amyloidosis; and
      
      prescribing at least one dosage form of at least one compound of formula (I),
  - 41. An article of manufacture, comprising:
    - (a) at least one dosage form of at least one compound of formula (I), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1;
      
      (b) a package insert providing that a dosage form comprising a compound of formula (I) should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (c) at least one container in which at least one dosage form of at least one compound of formula (I) is stored.
  - 42. A packaged pharmaceutical composition for treating conditions related to amyloidosis, comprising:
    - (a) a container which holds an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1;
      
      and (b) instructions for using the pharmaceutical composition.
  - 43. An article of manufacture, comprising:
    - (a) a therapeutically effective amount of at least one compound of formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1;
      
      (b) a package insert providing an oral dosage form should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (c) at least one container comprising;
      
      at least one oral dosage form of at least one compound of formula (I).
  - 44. An article of manufacture, comprising:
    - (a) at least one oral dosage form of at least one compound of formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_Care defined as in claim 1;
      
      in a dosage amount ranging from about 2 mg to about 1000 mg;
      
      associated with (b) a package insert providing that an oral dosage form comprising;
      
      a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (c) at least one container in which at least one oral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.
  - 45. An article of manufacture, comprising:
    - (a) at least one oral dosage form of at least one compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, in a dosage amount ranging from about 2 mg to about 1000 mg in combination with (b) at least one therapeutically active agent;
      
      associated with (c) a package insert providing that an oral dosage form comprising;
      
      a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with at least one therapeutically active agent should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (d) at least one container in which at least one dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with a therapeutically active agent is stored.
  - 46. The article of manufacture according to claim 45 wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.
  - 47. An article of manufacture, comprising:
    - (a) at least one parenteral dosage form of at least one compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL;
      
      associated with (b) a package insert providing that a parenteral dosage form comprising;
      
      a compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (c) at least one container in which at least one parenteral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL is stored.
  - 48. An article of manufacture comprising:
    - (a) a medicament comprising;
      
      an effective amount of at least one compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, in combination with active and/or inactive pharmaceutical agents;
      
      (b) a package insert providing that an effective amount of at least one compound of formula (I) should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis; and
      
      (c) a container in which a medicament comprising;
      
      an effective amount of at least one compound of formula (I) in combination with active and/or inactive pharmaceutical agents is stored.
  - 49. A kit comprising:
    - (a) at least one dosage form of at least one compound according to claim 1;
      
      and (b) at least one container in which at least one dosage form of at least one compound according to claim 1 is stored.
  - 50. A kit according to claim 49, further comprising a package insert:
    - a) containing information of the dosage amount and duration of exposure of a dosage form containing at least one compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, and b) providing that the dosage form should be administered to a patient in need of therapy for disorders, conditions or diseases associated with amyloidosis.
  - 51. The kit according to claim 49 further comprising:
    - at least one therapeutically active agent.
  - 52. The kit according to claim 49 wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.
  - 53. A method of producing A-beta-secretase complex comprising:
    - exposing beta-secretase to a compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, or a pharmaceutically acceptable salt thereof, in a reaction mixture under conditions suitable for the production of the complex.
  - 54. A manufacture of a medicament for preventing, delaying, halting, or reversing Alzheimer'"'"'s disease, comprising:
    - adding an effective amount of at least one compound of formula (I) wherein R₁, R₂, and R_Care defined as in claim 1, to a pharmaceutically acceptable carrier.
  - 55. A method of selecting a beta-secretase inhibitor comprising:
    - targeting the moieties of at least one formula (I) compound,
  - 56. The method according to claim 55, wherein R₁is —
    - CH₂-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, and —
      
      OH.
  - 57. The method according to claim 55, wherein R₁is 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.
  - 58. The method according to claim 55, wherein R₂is hydrogen.
  - 59. The method according to claim 55, wherein R_Cis selected from 4-(3-Ethyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-ethyl-benzene, 1-Cyclohexyl-3-isobutyl-benzene, 1-Cyclohexyl-3-isopropyl-benzene, 1-Cyclohexyl-3-(2,2-dimethyl-propyl)-benzene, 1-tert-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-ethynyl-benzene, 8-(3-Isopropyl-phenyl)-1,4-dioxa-spiro[4.5]decane, 4-(3-Isopropyl-phenyl)-cyclohexanone, 2-(3-Cyclohexyl-phenyl)-4-methyl-thiophene, 1-[5-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, 3-(3-Cyclohexyl-phenyl)-furan, 3-(3-Cyclohexyl-phenyl)-thiophene, 5-(3-Cyclohexyl-phenyl)-thiophene-2-carbaldehyde, 2-(3-Cyclohexyl-phenyl)-furan-3-carbaldehyde, N-(3′
    - -Cyclohexyl-biphenyl-3-yl)-acetamide, 4-(3-tert-Butyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-trifluoromethyl-benzene, 1-sec-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-pentyl-benzene, 1-Cyclohexyl-3-(3-methyl-butyl)-benzene, 1-Cyclohexyl-3-(1-ethyl-propyl)-benzene, 1-Cyclohexyl-3-cyclopentyl-benzene, 1-Cyclohexyl-3-pent-4-enyl-benzene, 3-(3-Cyclohexyl-phenyl)-propionic acid ethyl ester, 2-(3-Cyclohexyl-phenyl)-pyridine, 2-(3-Cyclohexyl-phenyl)-3-methyl-pyridine, 2-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-3-methyl-thiophene, 1-Cyclohexyl-3-(2-fluoro-benzyl)-phenylene, 1-Cyclohexyl-3-(4-fluoro-benzyl)-phenylene, 2-(3-Cyclohexyl-phenyl)-adamantane, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1,1-dioxide, 1-[4-(3-Isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1-oxide, 2,2,2-Trifluoro-1-[4-(3-isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-piperidine-1-carbaldehyde, 1-Cyclohexyl-3-cyclopropyl-benzene, 1-Bromo-3-tert-butyl-5-cyclohexyl-benzene, 4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-piperidine, 3-Bromo-5-(3-cyclohexyl-phenyl)-[1,2,4]thiadiazole, 2-(3-Cyclohexyl-phenyl)-1-methyl-1H-imidazole, 4-(3-Cyclohexyl-phenyl)-3,5-dimethyl-3H-pyrazole, 3-(3-Cyclohexyl-phenyl)-2,5-dimethyl-pyrazine, 3-(3-Cyclohexyl-phenyl)-pyrazine-2-carbonitrile, 4-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-isonicotinonitrile, 2-(3-Cyclohexyl-phenyl)-pyrazine, 3-(3-Cyclohexyl-phenyl)-6-methyl-pyridazine, 3-(3-Cyclohexyl-phenyl)-thiophene-2-carbonitrile, 2-Chloro-3-(3-cyclohexyl-phenyl)-thiophene, 1-[4-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, and 3-Cyclohexyl-benzonitrile.
  - 60. The method according to claim 55, wherein R_Xis selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
    - -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, and 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.
  - 61. The method according to claim 55, wherein the host in need thereof is a cell.
  - 62. The method according to claim 55, wherein the host in need thereof is a warm-blooded animal.
  - 63. The method according to claim 55, wherein the host in need thereof is human.
  - 64. The method according to claim 55, wherein the at least one compound of formula (I) is chosen from N-{1-(3,5-Difluoro-benzyl)-3-[4-(3-ethyl-phenyl)-tetrahydro-pyran-4-yl-amino]-2-hydroxy-propyl}-acetamide, N-{2-Hydroxy-1-(4-hydroxy-benzyl)-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3-Fluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3-Fluoro-4-hydroxy-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[8-(3-isopropyl-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-4-oxo-cyclohexylamino]-propyl}-acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-tetrahydro-pyran-4-yl-amino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1,1-dioxo-hexahydro-1|6-thiopyran-4-yl-amino]-propyl}-acetamide, N-[3-[1-Acetyl-4-(3-isopropyl-phenyl)-piperidin-4-yl-amino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1-methanesulfonyl-piperidin-4-yl-amino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-isopropyl-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl-amino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-3-[1-formyl-4-(3-isopropyl-phenyl)-piperidin-4-yl-amino]-2-hydroxy-propyl}-acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidin-4-yl-amino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-(4-(1-(3-tert-butylphenyl)-4-hydroxyl-cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-[3-[4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-piperidin-4-yl-amino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3-Fluoro-4-hydroxy-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-4-oxo-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(4-methoxy-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methyl-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxy-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[3-(3-tert-Butyl-phenyl)-8-oxa-bicyclo[3.2.1]oct-3-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-{1-(3-Fluoro-5-hydroxy-benzyl)-2-hydroxy-3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-oxo-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-(4-(1-(3-tert-butylphenyl)-4-hydroxyl-cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and N-[3-[4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, or a pharmaceutically acceptable salt thereof.
  - 65. The method according to claim 55, wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.
  - 66. The method according to claim 55, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down'"'"'s syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism (FTDP).
  - 67. The method according to claim 55, wherein the condition is Alzheimer'"'"'s disease.
  - 68. The method according to claim 55, wherein the condition is dementia.

16. A method of preventing or treating the onset of Alzheimer'"'"'s disease comprising:
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),

69. A method of preventing or treating conditions which benefit from inhibition of at least one aspartyl-protease, comprising:
- administering to a host in need thereof a composition comprising a therapeutically effective amount of at least one compound of formula (I), or pharmaceutically acceptable salts thereof, said compound having an F value of at least 10%, and wherein;
  
  R₁is 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_50bare 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 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_50bare optionally substituted with at least one group independently selected from alkyl, halogen, —
  
  OH, —
  
  NR₅R₆, —
  
  CN, haloalkoxy, —
  
  NR₇R₈, and alkoxy;
  
  R₅and R₆are independently selected from H or alkyl, or R₅and R₆, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
  
  R₇and R₈are independently selected from —
  
  H, -alkyl optionally substituted with at least one group independently selected from —
  
  OH, —
  
  NH₂, and halogen, -cycloalkyl, and -alkyl-O-alkyl;
  
  R₂is selected from H and F;
  
  R_cis selected from the following formula (IIIa), (IIIb), or (IIIc) structures wherein, A, B, and C are independently selected from —
  
  CH₂—
  
  , —
  
  O—
  
  , —
  
  C(O)—
  
  , —
  
  S(O)_0-2—
  
  , —
  
  NH—
  
  , —
  
  NR₂₀₀, —
  
  N(CO)_0-1R₂₀₀-, and —
  
  N(S(O₂)alkyl)-;
  
  wherein (IIIa), (IIIb), and (IIIc) are each optionally substituted with at least one group independently selected from alkyl, alkoxy, —
  
  OH, halogen, —
  
  NH₂, —
  
  NH(alkyl), —
  
  N(alkyl)(alkyl), —
  
  NH—
  
  C(O)-alkyl, and —
  
  NS(O₂)-alkyl;
  
  R_xis selected from -aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —
  
  R_xa—
  
  R_xb;
  
  wherein R_Xaand R_Xbare independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
  
  wherein each aryl or heteroaryl group within R_Cis optionally substituted with at least one group independently selected from R₂₀₀;
  
  wherein each cycloalkyl or heterocycloalkyl within R_Cis optionally substituted with at least one group independently selected from R₂₁₀; and
  
  wherein at least one carbon of the heteroaryl or heterocycloalkyl group within R_Cis independently optionally replaced with a group selected from —
  
  NH—
  
  , —
  
  N—
  
  , —
  
  N(CO)_0-1R₂₁₅—
  
  , —
  
  N(CO)_0-1R₂₂₀—
  
  , —
  
  O—
  
  , —
  
  C(O)—
  
  , —
  
  S(O)_0-2—
  
  , and —
  
  NS(O)_0-2R₂₀₀;
  
  R₂₀₀at 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—
  
  NR₂₂₀R₂₂₅, —
  
  (CH₂)_0-4—
  
  CO—
  
  NH(R₂₁₅), —
  
  (CH₂)_0-4—
  
  CO-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—
  
  CO₂R₂₁₅, —
  
  (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)—
  
  CO₂R₂₁₅, —
  
  (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—
  
  NR₂₂₀R₂₂₅, —
  
  (CH₂)_0-4—
  
  O—
  
  C(O)-alkyl, —
  
  (CH₂)_0-4—
  
  O—
  
  (R₂₁₅), —
  
  (CH₂)_0-4—
  
  S—
  
  (R₂₁₅), —
  
  (CH₂)_0-4—
  
  O-alkyl optionally substituted with at least one F, and -adamantane;
  
  wherein each aryl and heteroaryl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₀₅, R₂₁₀, and alkyl (optionally substituted with at least one group independently selected from R₂₀₅and R₂₁₀);
  
  wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₀is optionally substituted with at least one group independently selected from R₂₁₀;
  
  R₂₀₅at each occurrence is independently selected from -alkyl, -haloalkoxy, —
  
  (CH₂)_0-3-cycloalkyl, -halogen, —
  
  (CH₂)_0-6—
  
  OH, —
  
  O-phenyl, —
  
  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, -CN, —
  
  CF₃, -alkoxy, -alkoxycarbonyl, and —
  
  NR₂₃₅R₂₄₀;
  
  R₂₁₀at each occurrence is independently selected from —
  
  OH, —
  
  CN, —
  
  (CH₂)_0-4—
  
  C(O)H -alkyl optionally substituted with at least one group independently selected from R₂₀₅, -alkanoyl, —
  
  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)_0-6—
  
  OH, —
  
  (CH₂)_0-6—
  
  CN, —
  
  (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, —
  
  S(O)₂—
  
  NR₂₃₅R₂₄₀, —
  
  C(O)—
  
  NR₂₃₅R₂₄₀, and —
  
  S(O)_0-2-alkyl;
  
  R₂₁₅at each occurrence is independently selected from -alkyl, —
  
  (CH₂)_0-2-aryl, -cycloalkyl, —
  
  (CH₂)_0-2-heteroaryl, and —
  
  (CH₂)_0-2-heterocycloalkyl;
  
  wherein the aryl group included within R₂₁₅is optionally substituted with at least one group independently selected from R₂₀₅or R₂₁₀;
  
  wherein the heterocycloalkyl and heteroaryl groups included within R₂₁₅are optionally substituted with at least one group independently selected from R₂₁₀;
  
  R₂₂₀and R₂₂₅at 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 and heterocycloalkyl groups included within R₂₂₀and R₂₂₅are each optionally substituted with at least one group independently selected from R₂₇₀;
  
  R₂₇₀at each occurrence is independently selected from —
  
  R₂₀₅, -alkyl optionally substituted with at least one group independently selected from R₂₀₅, -phenyl, -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, —
  
  CO—
  
  NR₂₃₅R₂₄₀, —
  
  S(O)₂-alkyl, and —
  
  (CH₂)_0-4—
  
  C(O)H;
  
  R₂₃₅and R₂₄₀at each occurrence are independently selected from —
  
  H, —
  
  OH, —
  
  CF₃, —
  
  OCH₃, —
  
  NH—
  
  CH₃, —
  
  N(CH₃)₂, —
  
  (CH₂)_0-4—
  
  C(O)(H or alkyl), -alkyl, -alkanoyl, —
  
  SO₂-alkyl, and -phenyl.
- View Dependent Claims (70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82)
- - 70. The method according to claim 69, wherein R₁is —
    - CH₂-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, and —
      
      OH.
  - 71. The method according to claim 69, wherein R₁is 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.
  - 72. The method according to claim 69, wherein R₂is hydrogen.
  - 73. The method according to claim 69, wherein R_Cis selected from 4-(3-Ethyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-ethyl-benzene, 1-Cyclohexyl-3-isobutyl-benzene, 1-Cyclohexyl-3-isopropyl-benzene, 1-Cyclohexyl-3-(2,2-dimethyl-propyl)-benzene, 1-tert-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-ethynyl-benzene, 8-(3-Isopropyl-phenyl)-1,4-dioxa-spiro[4.5]decane, 4-(3-Isopropyl-phenyl)-cyclohexanone, 2-(3-Cyclohexyl-phenyl)-4-methyl-thiophene, 1-[5-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, 3-(3-Cyclohexyl-phenyl)-furan, 3-(3-Cyclohexyl-phenyl)-thiophene, 5-(3-Cyclohexyl-phenyl)-thiophene-2-carbaldehyde, 2-(3-Cyclohexyl-phenyl)-furan-3-carbaldehyde, N-(3′
    - -Cyclohexyl-biphenyl-3-yl)-acetamide, 4-(3-tert-Butyl-phenyl)-tetrahydro-pyran, 1-Cyclohexyl-3-trifluoromethyl-benzene, 1-sec-Butyl-3-cyclohexyl-benzene, 1-Cyclohexyl-3-pentyl-benzene, 1-Cyclohexyl-3-(3-methyl-butyl)-benzene, 1-Cyclohexyl-3-(1-ethyl-propyl)-benzene, 1-Cyclohexyl-3-cyclopentyl-benzene, 1-Cyclohexyl-3-pent-4-enyl-benzene, 3-(3-Cyclohexyl-phenyl)-propionic acid ethyl ester, 2-(3-Cyclohexyl-phenyl)-pyridine, 2-(3-Cyclohexyl-phenyl)-3-methyl-pyridine, 2-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-3-methyl-thiophene, 1-Cyclohexyl-3-(2-fluoro-benzyl)-phenylene, 1-Cyclohexyl-3-(4-fluoro-benzyl)-phenylene, 2-(3-Cyclohexyl-phenyl)-adamantane, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1,1-dioxide, 1-[4-(3-Isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-Isopropyl-phenyl)-tetrahydro-thiopyran 1-oxide, 2,2,2-Trifluoro-1-[4-(3-isopropyl-phenyl)-piperidin-1-yl]-ethanone, 4-(3-Isopropyl-phenyl)-piperidine-1-carbaldehyde, 1-Cyclohexyl-3-cyclopropyl-benzene, 1-Bromo-3-tert-butyl-5-cyclohexyl-benzene, 4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-piperidine, 4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-piperidine, 3-Bromo-5-(3-cyclohexyl-phenyl)-[1,2,4]thiadiazole, 2-(3-Cyclohexyl-phenyl)-1-methyl-1H-imidazole, 4-(3-Cyclohexyl-phenyl)-3,5-dimethyl-3H-pyrazole, 3-(3-Cyclohexyl-phenyl)-2,5-dimethyl-pyrazine, 3-(3-Cyclohexyl-phenyl)-pyrazine-2-carbonitrile, 4-(3-Cyclohexyl-phenyl)-thiazole, 2-(3-Cyclohexyl-phenyl)-isonicotinonitrile, 2-(3-Cyclohexyl-phenyl)-pyrazine, 3-(3-Cyclohexyl-phenyl)-6-methyl-pyridazine, 3-(3-Cyclohexyl-phenyl)-thiophene-2-carbonitrile, 2-Chloro-3-(3-cyclohexyl-phenyl)-thiophene, 1-[4-(3-Cyclohexyl-phenyl)-thiophen-2-yl]-ethanone, and 3-Cyclohexyl-benzonitrile.
  - 74. The method according to claim 69, wherein R_Xis selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
    - -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, and 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.
  - 75. The method according to claim 69, wherein the at least one compound of formula (I) is chosen from N-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, or a pharmaceutically acceptable salt thereof.
  - 76. The method according to claim 69, wherein the host in need thereof is a cell.
  - 77. The method according to claim 69, wherein the host in need thereof is a warm-blooded animal.
  - 78. The method according to claim 69, wherein the host in need thereof is human.
  - 79. The method according to claim 69, wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.
  - 80. The method according to claim 69, wherein the condition is selected from Alzheimer'"'"'s disease, Down'"'"'s syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down'"'"'s syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease, and frontotemporal dementias with parkinsonism (FTDP).
  - 81. The method according to claim 69, wherein the condition is Alzheimer'"'"'s disease.
  - 82. The method according to claim 69, wherein the condition is dementia.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
Original Assignee
Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
Inventors
Probst, Gary, Sealy, Jennifer, John, Varghese, Aquino, Jose, Tung, Jay S., Fang, Lawrence, Hom, Roy

Application Number

US11/038,790
Publication Number

US 20060014790A1
Time in Patent Office

Days
Field of Search
US Class Current

514/317
CPC Class Codes

A61K 31/165   having aromatic rings, e.g....

A61K 31/38   having sulfur as a ring het...

A61K 31/381   having five-membered rings

A61K 31/445   Non condensed piperidines, ...

A61P 25/00   Drugs for disorders of the ...

A61P 25/16   Anti-Parkinson drugs

A61P 25/28   for treating neurodegenerat...

A61P 43/00   Drugs for specific purposes...

Methods of treatment of amyloidosis using spirocyclohexane aspartyl-protease inhibitors

First Claim

2 Assignments

0 Petitions

Accused Products

Abstract

Citations

82 Claims

Specification

Solutions

Use Cases

Quick Links

Methods of treatment of amyloidosis using spirocyclohexane aspartyl-protease inhibitors

First Claim

2 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

Citations

82 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links