Substituted urea and carbamate, phenacyl-2-hydroxy-3-diaminoalkane, and benzamide-2-hydroxy-3-diaminoalkane aspartyl-protease inhibitors

• US 20050261273A1
• Filed: 03/09/2005
• Published: 11/24/2005
• Est. Priority Date: 03/09/2004
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Neitz, R. Jeffrey, Maillard, Michel, Tucker, John, Dressen, Darren, John, Varghese, Aquino, Jose, Shah, Neerav, Tung, Jay S., Hom, Roy
• Application Number:
  US11/075,292
• Publication Number:
  US 20050261273A1
• Time in Patent Office: Days
• US Class Current: 514/211.10
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• 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 233/40 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/10 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 235/74 of a saturated carbon skeleton
• CPC Class Codes: C07C 235/82 with 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
• CPC Class Codes: C07C 237/30 having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 239/16 having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 255/34 with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 271/20 : to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 271/22 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 275/14 : being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/26 : having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 311/03 : having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/05 : to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/07 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/30 : having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 323/59 : with acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 327/46 : having carbon atoms of thiocarboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/28 : 2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
• CPC Class Codes: C07D 209/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/18 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/56 : Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/94 : Oxygen atom, e.g. piperidine N-oxide
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/30 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 233/46 : with only hydrogen atoms attached to said nitrogen atoms
• CPC Class Codes: C07D 233/58 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/76 : with substituted hydrocarbon radicals attached to the third ring carbon atom
• CPC Class Codes: C07D 233/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 257/04 : Five-membered rings
• 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 261/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 : Nitrogen atoms
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 277/14 : Oxygen atoms
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/00 : Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 307/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/54 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/96 : spiro-condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 317/72 : spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 333/18 : by sulfur atoms
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/28 : Halogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 335/06 : Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/4006 : Esters of acyclic acids which can have further substituents on alkyl

Abstract

The invention relates to acetyl 2-hydroxy-1,3-diaminospirocyclohexanes and derivatives thereof that are useful in treating at least one disease, disorder, and condition associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and condition associated with abnormal deposition of A-beta protein.

Claims

1. A method of preventing or treating at least one condition which 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 selective 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;

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-RN;

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 group;

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))_0-1—

OH, and aryl;

R₄ and R_4′

are independently selected from hydrogen, —

OH, alkyl, —

(CH₂)_0-3-cycloalkyl, —

(CH₂)_0-3OH, fluorine, —

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 is 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-alikyl-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 independently selected from OH), —

C₁-C₁₀ alkylaryl, and —

C₁-C₁₀ alkylheteroaryl;

R₁₀₀ and R′

₁₀₀ are independently selected from

-alkoxy,

-heterocycloalkyl,

-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, 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, —

(CH_{2 )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)R_E5, —

C₁-C₄ alkyl-NHC(O)R_E5, —

(CH₂)_0-4R_E3, —

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_E350CO₂R_E351, —

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, —

NHS(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 R₃₅₂ 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)—

; and

E₃ is selected from —

H, —

C₁-C₄ haloalkyl, —

C₅-C₆ heterocycloalkyl, —

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 may optionally 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 carbocylic ring, wherein one member is optionally a heteroatom selected from —

O—

, —

S(O)_0-2—

, and —

N(R₁₃₅)—

, wherein the carbocylic 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

—

H,

-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 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); and

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

—

C(O)—

;

R_C is selected from formulas (IIIa), (IIIb), and (IIIc),

wherein,

A, B, and C are independently selected from

—

CH₂—

,

—

O—

,

—

C(O)—

,

—

S(O)_0-2—

,

—

NH—

,

—

N(R₂₀₀)—

,

—

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

R_xa—

R_xb;

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

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

wherein each cycloalkyl or heterocycloalkyl within R_C is 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_C is 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;

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—

C(O)—

NR₂₂₀R₂₂₅,

—

(CH₂)_0-4—

C(O)—

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—

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 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)_0-6—

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,

—

CN,

—

OCF₃,

—

CF₃,

-alkoxy,

-alkoxycarbonyl, and

—

NR₂₃₅R₂₄₀;

R₂₁₀ at 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,

-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)₂-alkyl;

R₂₁₅ at each occurrence is independently selected from

-alkyl,

—

(CH₂)_0-2-aryl,

—

(CH₂)_0-2-cycloalkyl,

—

(CH₂)_0-2-heteroaryl, and

—

(CH₂)_0-2-heterocycloalkyl;

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,

—

NH—

CH₃,

—

N(CH₃)₂,

—

(CH₂)_0-4—

C(O)—

(H or alkyl),

-alkyl,

-alkanoyl,

—

SO₂-alkyl, and

-aryl.

2. The method according to claim 1, wherein U is selected from —

C(O)—

, —

C(S)—

, —

S(O)_0-2—

, —

C(═

NR₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, —

C(O)—

O—

, —

S(O)₂—

NR₂₀—

, and —

S(O)₂—

O—

; and

V is -(T)_0-1-R_N, wherein R₂₀, R₂₁, T and R_N are defined as in claim 1.

3. The method according to claim 1, wherein U′

is selected from —

C(O)—

, —

C(═

NR₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, —

C(O)—

O—

, —

S(O)₂—

NR₂₀— and

S(O)₂—

O—

; and

V′

is -(T)_0-1-R_N′

, wherein R₂₀, R₂₁, T and R_N′

are defined as in claim 1.

4. The method according to claim 1, wherein U is selected from —

S(O)₂—

NR₂₀—

, and —

S(O)₂—

O—

, wherein R₂₀ is defined as in claim 1.

5. The method according to claim 1, wherein U is selected from —

C(O)—

NR₂₀—

, and —

C(O)—

O—

, wherein R₂₀ is defined as in claim 1.

6. The method according to claim 1, wherein R_N is

7. The method according to claim 1, wherein R_N is selected from alkyl, —

(CH₂)_0-2-aryl, —

C₂-C₆ alkyl, —

C₂-C₆ alkyl, —

C₃-C₇ cycloalkyl, and —

(CH₂)_0-2-heteroaryl.

8. The method according to claim 1, wherein U is selected from —

N(R₂₀)—

C(O)— and

—

O—

C(O)—

, and R₂₀ is defined as in claim 1.

9. The method according to claim 1, wherein U is —

C(O)— and

T is —

N(R₂₀)—

or —

O—

, and R₂₀ is defined as in claim 1.

10. The method according to claim 1, wherein U is —

C(O)— and

T is —

O.

11. The method according to claim 1, wherein U is —

C(O)— and

T is —

NH—

.

12. The method according to claim 1, wherein U is —

SO₂— and

V is -T_0-1-R_N, and R_N is defined as in claim 1.

13. The method according to claim 1, wherein U is selected from —

C(O)— and

—

S(O)_0-2—

, and V is —

[C(R₄)(R₄)]_1-3-D, and wherein R₄, R_4′

and D are defined as in claim 1.

14. The method according to claim 1, wherein

V is —

(CH₂)_1-3-aryl or —

(CH₂)_1-3-heteroaryl, wherein each ring is independently optionally substituted with 1 or 2 groups independently selected from halogen, —

OH, —

OCF₃, —

O-phenyl, —

CN, —

NR₁₀₁R′

₁₀₁, alkyl, alkoxy, —

(CH₂)_0-3(C₃-C₇ cycloalkyl), aryl, heteroaryl, and heterocycloalkyl, and

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

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, —

C₁-C₄ haloalkyl, —

C₁-C₄ haloalkoxy, halogen, —

OH, —

CN, and —

NR₁₀₁R′

₁₀₁, and wherein R₁₀₁ and R′

₁₀₁ are defined as in claim 1.

15. The method according to claim 1, wherein U is —

C(O)—

.

16. The method according to claim 1, wherein U is selected from —

C(O)— and

—

S(O)_0-2—

; and

V is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within V are optionally substituted with at least one independently selected R_B group, and wherein R_B is defined as in claim 1.

17. The method according to claim 1, wherein V is selected from aryl and heteroaryl,

wherein each ring is independently optionally substituted with 1 or 2 groups independently selected from halogen, —

OH, —

OCF₃, —

O-phenyl, —

CN, —

NR₁₀₁R′

₁₀₁, alkyl, alkoxy, —

(CH₂)_0-3(C₃-C₇ cycloalkyl), aryl, heteroaryl, and heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups 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, and wherein R₁₀₁ and R′

₁₀₁ are defined as in claim 1.

18. The method according to claim 1, wherein R₁ is —

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

OH.

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

2-((4-(1-(3-tert-butylphenyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamoyl)methoxy)acetic acid,

4-(4-(1-(3-tert-butylphenyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamoyl)-2,2-dimethylbutanoic acid,

4-[3-[1-(3-tert-Butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylcarbamoyl]-butyric acid,

N-(4-(1-(3-tert-butylphenyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-3-(N-methylmethan-2-ylsulfonamido)benzamide,

N-(4-(1-(3-tert-butylphenyl)cyclohexylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(methylsulfonamido)thiazole-4-carboxamide, and

Pentanedioic acid amide [3-[1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-amide.

20. The method according to claim 1, wherein the host is a cell.

21. The method according to claim 1, wherein the host is an animal.

22. The method according to claim 1, wherein the host is human.

23. 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.

24. 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 (MCl) 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).

25. The method according to claim 1, wherein the condition is Alzheimer'"'"'s disease.

26. The method according to claim 1, wherein the condition is dementia.

27. An article of manufacture, comprising:

(a) at least one dosage form of at least one compound of formula (I),

or apharmaceutically acceptable salt thereof, wherein R₁, R₂, and R_C are 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 at least one disorder, condition or disease 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.

28. A packaged pharmaceutical composition for treating at least one condition related to amyloidosis, comprising:

(a) a container which holds 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 defined as in claim 1;

and

(b) instructions for using the pharmaceutical composition.

29. An article of manufacture, comprising:

(a) 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 1;

(b) a package insert providing an oral dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and

(c) at least one container comprising;

at least one oral dosage form of the therapeutically effective amount at least one compound of formula (I).

30. An article of manufacture, comprising:

(a) at least one oral dosage form 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 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;

the 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 at least one disorder, condition or disease associated with amyloidosis; and

(c) at least one container in which at least one oral dosage form of the at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.

31. An article of manufacture, comprising:

(a) at least one oral dosage form 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 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;

the 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 at least one disorder, condition or disease associated with amyloidosis; and

(d) at least one container in which at least one dosage form of the 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.

32. The article of manufacture according to claim 31 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.

33. An article of manufacture, comprising:

(a) at least one parenteral dosage form 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 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 at least one disorder, condition or disease associated with amyloidosis; and

(c) at least one container in which at least one parenteral dosage form of the 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.

34. An article of manufacture comprising:

(a) a medicament comprising;

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 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 at least one disorder, condition or disease 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.

35. 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.

36. A kit according to claim 35, 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), or at least one pharmaceutically acceptable salt thereof, and

b) providing that the dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis.

37. A kit according to claim 36 further comprising:

at least one therapeutically active agent.

38. The kit according to claim 37 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.

41. A method of selecting a beta-secretase inhibitor comprising:

targeting at least one moiety of at least one formula (I) compound,

42. A method of preventing or treating at least one condition which benefits from inhibition of at least one aspartic-protease, comprising:

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

or a pharmaceutically acceptable salt thereof, wherein the inhibition is at least 10% for a dose of about 100 mg/kg or less, and wherein, wherein R₁, R₂, and R_C are defined as in claim 1.

39. A method of producing a beta-secretase complex comprising:

exposing beta-secretase to a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a reaction mixture under conditions suitable for the production of the complex.

40. 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), or a pharmaceutically acceptable salt thereof, to a pharmaceutically acceptable carrier.

43. A compound of formula (I),

44. A compound of formula (I),

45. A compound of formula (I)