Oxime derivative hydroxyethylamine aspartyl-protease inhibitors

• US 20060128715A1
• Filed: 07/11/2005
• Published: 06/15/2006
• Est. Priority Date: 07/09/2004
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Probst, Gary, Sealy, Jennifer, John, Varghese, Tung, Jay S., Hom, Roy
• Application Number:
  US11/177,348
• Publication Number:
  US 20060128715A1
• Time in Patent Office: Days
• US Class Current: 514/252.100
• 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 237/18 the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 251/54 of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 251/58 of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 251/84 having doubly-bound carbon atoms of hydrazone groups being part of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 255/31 having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 255/61 containing cyano groups and nitrogen atoms being part of imino groups bound to the same carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 207/335 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/53 Nitrogen atoms
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 239/18 with hetero atoms attached to said nitrogen atoms, except nitro radicals, e.g. hydrazine 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 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/72 spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 333/22 : Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings

Abstract

The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.

Claims

1. A compound of formula (I),

2. The compound according to claim 1, wherein R₁ is selected from —

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

OH.

3. The compound according to claim 1, wherein R₁ is selected from 3-Allyloxy-5-fluoro-benzyl, 3-Benzyloxy-5-fluoro-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, 3-propyl-thiophen-2-yl-methyl, 3,5-difluoro-2-propylamino-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, 2-ethylamino-3,5-difluoro-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 2-Hydroxy-5-methyl-benzamide, 3,5-Difluoro-4-hydroxy-benzyl, 3,5-Difluoro-benzyl, 3-Fluoro-4-hydroxy-benzyl, 3-Fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-Fluoro-5-heptyloxy-benzyl, 3-Fluoro-5-hexyloxy-benzyl, 3-Fluoro-5-hydroxy-benzyl, and 3-Fluoro-benzyl.

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

C(O)CH₃, —

C(O)—

CH(halogen)₂, and —

C(O)CH₂(halogen).

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

6. The compound according to claim 5, wherein A₅ is selected from —

C(═

N—

OH)—

, —

C(═

N—

O—

CH₃)—

, —

C(═

N—

O—

CH₂CH₃)—

, —

C(═

N—

O—

CH₂CH₂OH)—

, —

C(═

N—

O—

CH₂CH₂NH₂)—

, —

C(═

N—

NHCH₃)—

, and —

C(═

N—

CN)—

, and A₁, A₂, A₃, and A₄ are —

CH₂—

.

7. The compound according to claim 1, wherein R_C is selected from 1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-amino-ethoxyimino)-cyclohexyl, 5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexyl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-yl, 1-(Acrylic acid methyl ester)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(Acrylamide)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohex-1-yl, 4-methoxyimino-1-(3-thiophen-3-yl-phenyl)-cyclohexyl, 1-(3-furan-3-yl-phenyl)-4-methoxyimino-cyclohexyl, 4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]-cyclohexyl, 4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrimidin-5-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexyl, 2-Acetyl-5-(3-tert-butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 1-(3-tert-Butyl-phenyl)-4-methylene-cyclohexyl, and ethyl 2-(4-(3-tert-butylphenyl)cyclohexylidene)acetate.

8. The compound according to claim 1, wherein R_X is 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-phen-1-yl, 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, 6-tert-Butyl-pyridazin-4-yl, 6-tert-Butyl-pyrimidin-4-yl, 3-pyridin-4-yl-phenyl, 3-pyrimidin-5-yl-phenyl, and 3-pyrazol-1-yl-phenyl.

9. The compound according to claim 1, wherein R_X is 3-tert-Butyl-phen-1-yl.

10. The compound according to claim 1, wherein the formula (I) compound is selected from N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4methoxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, [4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-acetic acid methyl ester, 2-[4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-(N,N-di-R₂₁₅)-acetamide, 2-[4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-(N,N-dimethyl)-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl] acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-thiophen-3-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-3-[1-(3-furan-3-yl-phenyl)-4-methoxyimino-cyclohexylamino]-2-hydroxy-propyl}acetamide, N-(1-(3,5-Difluoro-benzyl)-2-hydroxy-3-{4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]-cyclohexylamino}-propyl)-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyrimidin-5-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[2-Acetyl-5-(3-tert-butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methylene-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, [4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-acetic acid ethyl ester, 4-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylcarbamoyl]-butyric acid, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2yl)methanesulfonamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-methyl-5-(3-thiophen-3-yl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-propyl}-acetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)methanesulfonamide, N-(1-(3,5-difluorophenyl)-4-(5-(3-(furan-3-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-(1H-pyrazol-1-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-3-hydroxy-1-phenylbutan-2yl)acetamide, N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(2-methyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-(4-(6-(3-tert-butylphenyl)-2-methyl-5,6,7,8-tetrahydroquinazolin-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide, N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-(thiophen-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-(4-neopentylthiophen-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and N-(1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-2-hydroxy-5-methylhexan-3-yl)acetamide.

11. A method of preventing or treating at least one condition that benefits from inhibition of at least one aspartyl-protease, comprising:

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

or pharmaceutically acceptable salts thereof;

wherein

R₁ is selected from

alkyl;

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 (lif) ring may optionally be a double bond;

R₅₀, R_50a, and R_50b are independently selected from

—

H,

-halogen,

—

OH,

—

SH,

—

CN,

—

C(O)-alkyl,

—

NR₇R₈,

—

NO₂,

—

S(O)_0-2-alkyl,

-alkyl,

-alkoxy,

—

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

H, —

OH, and alkyl,

—

C(O)—

NR₇R₈,

-alkyloxy,

-alkoxyalkoxyalkoxy, and

-cycloalkyl;

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

OH, —

NR₅R₆, —

CN, haloalkoxy, —

NR₇R₈, and alkoxy;

R₅ and R₆ are independently selected from —

H and alkyl, or

R₅ and R₆, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and

R₇ and R₈ are independently selected from

—

H,

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

OH, —

NH₂, and halogen,

-cycloalkyl, and

-alkyl-O-alkyl;

R₂ is selected from —

C(O)—

CH₃, —

C(O)—

CH₂(halogen), —

C(O)—

CH(halogen)₂,

 

and

U is selected from —

C(O)—

, —

C(═

S)—

, —

S(O)_0-2—

, —

C(═

N—

R₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, —

C(O)—

O—

, —

S(O)₂—

NR₂₀—

, and —

S(O)₂—

O—

;

U′

is selected from —

C(O)—

, —

C(═

N—

R₂₁)—

, —

C(═

N—

OR₂₁)—

, —

C(O)—

NR₂₀—

, and —

C(O)—

O—

;

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

[C(R₄)(R_4′

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

V′

is selected from -(T)_0-1-R_N′

;

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

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

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

are optionally replaced with —

N—

, —

O—

, —

NH—

, —

C(O)—

, —

C(S)—

, —

C(═

N—

H)—

, —

C(═

N—

OH)—

, —

C(═

N-alkyl)-, or —

C(═

N—

O-alkyl)-;

R_B at each occurrence is independently selected from halogen, —

OH, —

CF₃, —

OCF₃, —

O-aryl, —

CN, —

NR₁₀₁R′

₁₀₁, alkyl, alkoxy, —

(CH₂)_0-4—

(C(O))_0-1—

(O)_0-1-alkyl, —

C(O)—

OH, —

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

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

C₁-C₄ alkyl, —

C₁-C₄ alkoxy, —

C₁-C₄ haloalkyl, —

C₁-C₄ haloalkoxy, halogen, —

OH, —

CN, and —

NR₁₀₁R′

₁₀₁;

R₁₀₁ and R′

₁₀₁ are independently selected from —

H, alkyl, —

(C(O))_0-1—

(O)_0-1-alkyl, —

C(O)—

OH, and aryl;

R₄ and R_4′

are independently selected from hydrogen, alkyl, —

OH, —

(CH₂)_0-3-cycloalkyl, —

(CH₂)_1-3OH, —

F, —

CF₃, —

OCF₃, —

O-aryl, alkoxy, —

C₃-C₇ cycloalkoxy, aryl, and heteroaryl, or

R₄ and R_4′

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

O—

, —

N(H)—

, —

N(alkyl)-, —

N(aryl)-, —

C(O)—

, or —

S(O)_0-2;

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

T is selected from —

NR₂₀— and

—

O—

;

R₂₀ is selected from —

H, —

CN, alkyl, haloalkyl, and cycloalkyl;

R₂₁ is selected from —

H, alkyl, haloalkyl, and cycloalkyl;

R_N is selected from —

OH, —

NH₂, —

NH(alkyl), —

NH(cycloalkyl), —

N(alkyl)(alkyl), —

N(alkyl)(cycloalkyl), —

N(cycloalkyl)(cycloalkyl), -R′

₁₀₀, alkyl-R₁₀₀, —

(CRR′

)_0-6R₁₀₀, —

(CRR′

)_1-6—

O—

R′

₁₀₀, —

(CRR′

)_1-6—

S—

R′

₁₀₀, —

(CRR′

)_1-6—

C(O)—

R₁₀₀, —

(CRR′

)_1-6—

SO₂—

R₁₀₀, —

(CRR′

)_1-6—

NR₁₀₀—

R′

₁₀₀, —

(CRR′

)_1-6—

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

CH(R_E1)-(CH₂)_0-3-E₁-E₂-E₃;

R_N′

is —

SO₂R′

₁₀₀;

R and R′

are independently selected from hydrogen, —

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

OH), —

C₁-C₁₀ alkylaryl, and —

C₁-C₁₀ alkylheteroaryl;

R₁₀₀ and R₁₁₀₀ are independently selected from

-cycloalkyl,

-heterocycloalkyl,

-alkoxy,

-aryl,

-heteroaryl,

-aryl-W-aryl,

-aryl-W-heteroaryl,

-aryl-W-heterocycloalkyl,

-heteroaryl-W-aryl,

-heteroaryl-W-heteroaryl,

-heteroaryl-W-heterocycloalkyl,

-heterocycloalkyl-W-aryl,

-heterocycloalkyl-W-heteroaryl,

-heterocycloalkyl-W-heterocycloalkyl,

—

W—

R₁₀₂,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]-(CH₂)_0-2-aryl,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]-(CH₂)_0-2-heterocycloalkyl,

—

CH[(CH₂)_0-2—

O—

R₁₅₀]-(CH₂)_0-2-heteroaryl,

—

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

C(O)—

, and —

NH—

,

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

-alkyl-5-alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, and

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

wherein the ring portions included within R₁₀₀ and R′

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

OR, —

NO₂, halogen, —

CN, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

O—

P(═

O)(OR)(OR′

), —

(CH₂)_0-4—

C(O)—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

C(O)NR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

C(O)—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

C(O)—

(CH₂)_0-4-cycloalkyl, —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

C(O)—

R₁₁₀, —

(CH₂)_0-4—

C(O)—

R₁₂₀, —

(CH₂)_0-4—

C(O)—

R₁₃₀, —

(CH₂)_0-4—

C(O)—

R₁₄₀, —

(CH₂)_0-4—

C(O)—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO₂—

(CH₂)_0-4-cycloalkyl, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

C(O)—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

C(O)-(alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R₁₁₀)₂, —

(CH₂)_0-4—

O—

C(O)—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

C(O)OH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4-cycloalkyl, and —

(C₁-C₁₀)-alkyl;

R_E1 is selected from —

H, —

OH, —

NH₂, —

NH—

(CH₂)_0-3—

R_E2, —

NHR_E8, —

NR_E350C(O)R_E5, —

C₁-C₄ alkyl-NHC(O)R_E5, —

(CH₂)_0-4R_E8, —

O—

(C₁-C₄ alkanoyl), —

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

C₁-C₄ alkyl, —

CO₂H, —

C(O)—

C₁-C₄ alkoxy, and —

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

NR_E350CO₂R_E351, —

C₁-C₄ alkyl-N R_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, —

NH—

S(O)_0-2-alkyl, —

N(alkyl)S(O)_0-2-alkyl, —

S(O)_0-2-heteroaryl, —

S(O)_0-2-aryl, —

NH(arylalkyl), —

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

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

NO₂, —

CN, alkoxycarbonyl, and aminocarbonyl;

R_E353 is selected from —

O—

, —

C(O)—

, —

NH—

, —

N(alkyl)-, —

NH—

S(O)_0-2—

, —

N(alkyl)-S(O)_0-2—

, —

S(O)_0-2—

NH—

, —

S(O)_0-2—

N(alkyl)-, —

NH—

C(S)—

, and —

N(alkyl)-C(S)—

;

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

CO₂H, —

CO₂-alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)(alkyl), —

C(O)NH₂, —

C₁-C₈ alkyl, —

OH, aryloxy, alkoxy, arylalkoxy, —

NH₂, —

NH(alkyl), —

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

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

CO₂H, —

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

NO₂, —

CN, alkoxycarbonyl, and aminocarbonyl;

E₁ is selected from —

NR_E11— and

—

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

C₁-C₄ alkyl);

R_E11 is selected from —

H and alkyl;

or R_E1 and R_E11 combine to form —

(CH₂)_1-4—

;

E₂ is selected from a bond, —

SO₂—

, —

SO—

, —

S—

, and —

C(O)—

;

E₃ is selected from —

H, —

C₁-C₄ haloalkyl, —

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

N—

, —

O—

, and —

S—

), —

C₆-C₁₀ aryl, —

OH, —

N(E_3a)(E_3b), —

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

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

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

CN and —

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

CN, and —

NO₂);

E_3a and E_3b are independently selected from —

H, —

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

C₁-C₄ alkoxy, —

C₃-C₈ cycloalkyl, and —

OH), —

C₂-C₆ alkyl, —

C₂-C₆ alkanoyl, -aryl, —

SO₂—

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

C₃-C₈ cycloalkyl C₁-C₄ alkyl;

or

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

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

W is selected from —

(CH₂)_0-4—

, —

O—

, —

S(O)_0-2—

, —

N(R₁₃₅)—

, —

CR(OH)—

, and —

C(O)—

;

R₁₀₂ and R₁₀₂′

are independently selected from hydrogen, and —

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, aryl, and -R₁₁₀;

R₁₀₅ and R′

₁₀₅ are independently selected from

—

H,

-R₁₂₀,

-cycloalkyl,

—

(C₁-C₂ alkyl)-cycloalkyl,

-(alkyl)-O—

(C₁-C₃ alkyl), and

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

OH, amine, and halogen;

or

R₁₀₅ and R′

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

O—

, —

S(O)_0-2—

, and —

N(R₁₃₅)—

;

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

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

C(O)—

;

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

R₁₁₅ at each occurrence is independently selected from halogen, —

OH, —

C(O)—

O—

R₁₀₂, —

C₁-C₆ thioalkoxy, —

C(O)—

O-aryl, —

NR₁₀₅R′

₁₀₅, —

SO₂—

(C₁-C₈ alkyl), —

C(O)—

R₁₈₀, R₁₈₀, —

C(O)NR₁₀₅R′

₁₀₅, —

SO₂NR₁₀₅R′

₁₀₅, —

NH—

C(O)-(alkyl), —

NH—

C(O)—

OH, —

NH—

C(O)—

OR, —

NH—

C(O)—

O-aryl, —

O—

C(O)-(alkyl), —

O—

C(O)-amino, —

O—

C(O)-monoalkylamino, —

O—

C(O)-dialkylamino, —

O—

C(O)-aryl, —

O-(alkyl)-C(O)—

O—

H, —

NH—

SO₂—

(alkyl), alkoxy, and haloalkoxy;

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

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

OH, —

CN, —

SO₂—

NH₂, —

SO₂—

NH-alkyl, —

SO₂—

N(alkyl)₂, —

SO₂—

(C₁-C₄ alkyl), —

C(O)—

NH₂, —

C(O)—

NH-alkyl, —

C(O)—

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

OH, —

SH, —

CN, —

CF₃, —

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

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

R₁₃₅ is independently selected from alkyl, cycloalkyl, —

(CH₂)_0-2-(aryl), —

(CH₂)_0-2-(heteroaryl), and —

(CH₂)_0-2-(heterocycloalkyl);

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

C(O)H);

R₁₅₀ is independently selected from

-hydrogen,

-cycloalkyl,

—

(C₁-C₂ alkyl)-cycloalkyl,

-R₁₁₀,

-R₁₂₀, and

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

OH, —

NH₂, —

C₁-C₃ alkoxy, -R₁₁₀, and halogen;

R₁₅₀′

is independently selected from

-cycloalkyl,

—

(C₁-C₃ alkyl)-cycloalkyl,

-R₁₁₀,

-R₁₂₀, and

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

OH, —

NH₂, —

C₁-C₃ alkoxy, -R₁₁₀, and halogen; and

R₁₈₀ is independently selected from

-morpholinyl,

-thiomorpholinyl,

-piperazinyl,

-piperidinyl,

-homomorpholinyl,

-homothiomorpholinyl,

-homothiomorpholinyl S-oxide,

-homothiomorpholinyl S,S-dioxide,

-pyrrolinyl, and

-pyrrolidinyl;

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

C(O)H; and

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

C(O)—

;

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

wherein,

A₁ and A₂ are independently selected from —

(CH₂)_0-2—

, —

CH(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

NH—

, —

NR₂₂₀—

, —

C(═

N—

R₂₃₀)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

A₃, A₄, A₅, and A₆ are independently selected from —

CH₂—

, —

C H(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, —

NH—

, —

NR₂₂₀—

, —

N(CO)_0-1R₂₀₀—

, —

N(S(O₂)alkyl)-, —

C(═

N—

R₂₃₀)—

, —

C(═

N—

NH(alkyl))-, —

C(═

N—

N(alkyl)(alkyl))-, —

C(═

N-0 (CH₂)_1-4—

OH)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

R₂₃₀ is independently selected from —

H, —

OH, R₂₁₅ (optionally substituted with —

OH, —

NH₂, —

C(O)H, and —

CN), alkyl, cycloalkyl, alkoxy, -alkyl-OH, -alkyl-NH₂, -alkyl-C(O)H, —

O—

R₂₁₅ (optionally substituted with —

OH, —

NH₂, —

C(O)H, and —

CN), —

O-alkyl, —

O-alkyl-OH, —

O-alkyl-NH₂, —

O-alkyl-C(O)H, —

NH₂, —

NHR₂₁₅, —

N(R₂₁₅)₂, —

NR₂₃₅R₂₄₀, and —

CN;

wherein at least one carbon of the alkyl or cycloalkyl within R₂₃₀ is optionally independently replaced with —

C(O)—

or a heteroatom;

wherein the cycloalkyl and heterocylcoalkyl within formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf) may optionally contain at least one double bond;

wherein in formulae (IIIa), (IIIb), (IIIc), and (IIId), at least one of A₁, A₂, A₃, A₄, or A₅ is selected from —

C(═

N—

R₂₃₀)—

, —

C(═

N—

NH(alkyl))-, —

C(═

N—

N(alkyl)(alkyl))-, C(═

N—

O—

(CH₂)_1-4—

OH)—

, —

C(═

CH—

R₂₃₀)—

, —

C(═

N—

C(O)—

R₂₃₀)—

, and —

C(═

CH—

C(O)—

R₂₃₀)—

;

wherein in formulae (IIIe) and (IIIf), when A₁, A₂, and A₆ are selected from —

(CH₂)_0-2—

, —

CH(R₂₀₀)—

, —

C(R₂₀₀)₂—

, —

O—

, —

C(O)—

, —

S(O)_0-2—

, —

NH—

, —

NR₂₂₀—

, —

N(CO)_0-1R₂₀₀—

, and —

N(S(O₂)alkyl)-, at least one carbon of the aryl ring group within (IIIe) and (IIIf) is optionally independently replaced with a group selected from —

N—

, —

NH—

, —

O—

, —

C(O)—

, and —

S(O)_0-2—

;

wherein each aryl or heteroaryl group attached directly or indirectly to R_C is optionally substituted with at least one group independently selected from R₂₀₀;

wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to R_C is optionally substituted with at least one group independently selected from R₂₁₀; and

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 of R_X is optionally substituted with at least one group independently selected from R₂₀₀;

wherein each cycloalkyl or heterocycloalkyl of R_X is optionally substituted with at least one group independently selected from R₂₁₀; and

wherein at least one carbon of the heteroaryl or heterocycloalkyl group of R_X is independently optionally replaced with a group independently 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-(CO)_0-1—

NR₂₂₀R₂₂₅]

—

(CH₂)_0-4—

(CO)_0-1—

NH(R₂₁₅),

—

(CH₂)_0-4—

C(O)-alkyl,

—

(CH₂)_0-4—

(CO)_0-1-cycloalkyl,

—

(CH₂)_0-4—

(CO)_0-1-heterocycloalkyl,

—

(CH₂)_0-4—

(CO)_0-1-aryl,

—

(CH₂)_0-4—

(CO)_0-1-heteroaryl,

—

(CH₂)_0-4—

C(O)—

O—

R₂₁₅,

—

(CH₂)_0-4—

SO₂—

NR₂₂₀R₂₂₅,

—

(CH₂)_0-4—

S(O)_0-2-alkyl,

—

(CH₂)_0-4—

S(O)_0-2-cycloalkyl,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

O—

R₂₁₅,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

SO₂—

R₂₂₀,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

N(R₂₁₅)₂,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

C(O)—

R₂₂₀,

—

(CH₂)_0-4—

O—

C(O)-alkyl,

—

(CH₂)_0-4—

O—

(R₂₁₅),

—

(CH₂)_0-4—

S—

(R₂₁₅),

—

(CH₂)_0-4—

O-alkyl optionally substituted with at least one halogen, and

-adamantane;

wherein each aryl and heteroaryl group included within R₂₀₀ is optionally substituted with at least one group independently selected from R₂₀₅, R₂₁₀, and alkyl (optionally substituted with at least one group independently selected from R₂₀₅ and R₂₁₀);

wherein each cycloalkyl or heterocycloalkyl group included within R₂₀₀ is optionally substituted with at least one group independently selected from R₂₁₀;

R₂₀₅ at each occurrence is independently selected from

-alkyl,

-haloalkoxy,

—

(CH₂)_0-3-cycloalkyl,

-halogen,

—

(CH₂)_1-6—

OH,

—

O-aryl,

—

OH,

—

SH,

—

(CH₂)_0-4—

C(O)H,

—

(CH₂)_0-6—

CN,

—

(CH₂)_0-6—

C(O)—

NR₂₃₅R₂₄₀,

—

(CH₂)_0-6—

C(O)—

R₂₃₅,

—

(CH₂)_0-4—

N(H or R₂₁₅)—

SO₂—

R₂₃₅,

—

OCF₃,

—

CF₃,

-alkoxy,

-alkoxycarbonyl, and

—

NR₂₃₅R₂₄₀;

R₂₁₀ at each occurrence is independently selected from

—

(CH₂)_0-4—

OH,

—

(CH₂)_0-4—

CN,

—

(CH₂)_0-4—

C(O)H,

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

-alkanoyl,

—

S-alkyl;

—

S(O)₂-alkyl,

-halogen,

-alkoxy,

-haloalkoxy,

—

NR₂₂₀R₂₂₅,

-cycloalkyl optionally substituted with at least one group independently selected from R₂₀₅,

-heterocycloalkyl,

-heteroaryl,

—

(CH₂)_0-4—

NR₂₃₅R₂₄₀,

—

(CH₂)_0-4—

NR₂₃₅(alkoxy),

—

(CH₂)_0-4—

S—

(R₂₁₅),

—

(CH₂)_0-4—

NR₂₃₅—

C(O)H,

—

(CH₂)_0-4—

NR₂₃₅—

C(O)-(alkoxy),

—

(CH₂)_0-4—

NR₂₃₅—

C(O)—

R₂₄₀,

—

C(O)—

NHR₂₁₅,

—

C(O)-alkyl,

—

C(O)—

NR₂₃₅R₂₄₀, and

—

S(O)₂—

NR₂₃₅R₂₄₀;

R₂₁₅ at each occurrence is independently selected from

-alkyl,

—

(CH₂)_0-2-aryl,

—

(CH₂)_0-2-cycloalkyl,

—

(CH₂)_0-2-heteroaryl,

—

(CH₂)_0-2-heterocycloalkyl, and

—

CO₂—

CH₂-aryl;

wherein the aryl group included within R₂₁₅ is optionally substituted with at least one group independently selected from R₂₀₅ and R₂₁₀, and

wherein the heterocycloalkyl and heteroaryl groups included within R₂₁₅ are optionally substituted with at least one group independently selected from R₂₁₀;

R₂₂₀ and R₂₂₅ at each occurrence are independently selected from

—

H,

-alkyl,

—

(CH₂)_0-4—

C(O)H,

-alkylhydroxyl,

-alkoxycarbonyl,

-alkylamino,

—

S(O)₂-alkyl,

-alkanoyl optionally substituted with at least one halogen,

—

C(O)—

NH₂,

—

C(O)—

NH(alkyl),

—

C(O)—

N(alkyl)(alkyl),

-haloalkyl,

—

(CH₂)_0-2-cycloalkyl,

-(alkyl)-O-(alkyl),

-aryl,

-heteroaryl, and

-heterocycloalkyl;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R₂₂₀ and R₂₂₅ are each optionally substituted with at least one group independently selected from R₂₇₀;

R₂₇₀ at each occurrence is independently selected from

-R₂₀₅,

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

-aryl,

-halogen,

-alkoxy,

-haloalkoxy,

—

NR₂₃₅R₂₄₀,

—

OH,

—

CN,

-cycloalkyl optionally substituted with at least one group independently selected from R₂₀₅,

—

C(O)-alkyl,

—

S(O)₂—

NR₂₃₅R₂₄₀,

—

C(O)—

NR₂₃₅R₂₄₀,

—

S(O)₂-alkyl, and

—

(CH₂)_0-4—

C(O)H;

R₂₃₅ and R₂₄₀ at each occurrence are independently selected from

—

H,

—

OH,

—

CF₃,

—

OCH₃,

—

NHCH₃,

—

N(CH₃)₂,

—

(CH₂)_0-4—

C(O)(H or alkyl),

-alkyl,

-alkanoyl,

—

SO₂-alkyl, and

-aryl.

12. The method according to claim 11, wherein the at least one compound of formula (I) is selected from N-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, [4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-acetic acid methyl ester, 2-[4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-(N,N-di-R₂₁₅)-acetamide, 2-[4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-(N,N-dimethyl)-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl] acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-thiophen-3-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-3-[1-(3-furan-3-yl-phenyl)-4-methoxyimino-cyclohexylamino]-2-hydroxy-propyl}-acetamide, N-(1-(3,5-Difluoro-benzyl)-2-hydroxy-3-{4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]-cyclohexylamino}-propyl)-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyrimidin-5-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexylamino]-propyl}-acetamide, N-[3-[2-Acetyl-5-(3-tert-butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, N-[3-[1-(3-tert-Butyl-phenyl)-4-methylene-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide, [4-[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-cyclohexylidene]-acetic acid ethyl ester, 4-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylcarbamoyl]-butyric acid, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2yl)methanesulfonamide, N-{1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-methyl-5-(3-thiophen-3-yl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-propyl}-acetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)methanesulfonamide, N-(1-(3,5-difluorophenyl)-4-(5-(3-(furan-3-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-(1H-pyrazol-1-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-3-hydroxy-1-phenylbutan-2-yl)acetamide, N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(2-methyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-(4-(6-(3-tert-butylphenyl)-2-methyl-5,6,7,8-tetrahydroquinazolin-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide, N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-(thiophen-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-(4-neopentylthiophen-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)butan-2-yl)acetamide, N-(4-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-fluoroacetamide, N-(4-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and N-(1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-2-hydroxy-5-methylhexan-3-yl)acetamide.

13. A method of preventing or treating at least one condition associated with amyloidosis, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), or pharmaceutically acceptable salts thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

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

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

16. A method of preventing or treating at least one condition associated with amyloidosis, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), further comprising a composition including beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof, and wherein R₁, R₂ and R_C are as defined in claim 11.

17. 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 at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

18. A method of affecting beta-secretase-mediated cleavage of amyloid precursor protein in a patient, comprising administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

19. A method of inhibiting cleavage of amyloid precursor protein at a site between Met596 and Asp597 (numbered for the APP-695 amino acid isotype), or at a corresponding site of an isotype or mutant thereof, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

20. A method of inhibiting cleavage of amyloid precursor protein or mutant thereof at a site between amino acids, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11, and wherein the site between amino acids corresponds to

between Met652 and Asp653 (numbered for the APP-751 isotype);

between Met671 and Asp672 (numbered for the APP-770 isotype);

between Leu596 and Asp597 of the APP-695 Swedish Mutation;

between Leu652 and Asp653 of the APP-751 Swedish Mutation;

or

between Leu671 and Asp672 of the APP-770 Swedish Mutation.

21. A method of inhibiting production of A-beta, comprising:

administering to a patient a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

22. A method of preventing, delaying, halting, or reversing a disease characterized by A-beta deposits or plaques, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11.

23. The method in claim 22, wherein the A-beta deposits or plaques are in a human brain.

24. A method of interacting an inhibitor with beta-secretase, comprising:

administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R₁, R₂ and R_C are as defined in claim 11, wherein the at least one compound interacts with at least one of the following beta-secretase subsites;

S1, S1′

, and S2′

.

25. A method of modifying the pharmacokinetic parameters of a pharmaceutical composition comprising at least one compound of formula (I) wherein R₁, R₂ and R_C are as defined in claim 11, further comprising increasing at least one parameter selected from C_max, T_max, and half-life.

26. A method of treating a condition in a patient, comprising:

administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R₁, R₂, and R_C are defined as in claim 11.