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1. WO2006010095 - INHIBITEURS D'UNE ASPARTYL PROTEASE DE TYPE HYDROXYETHYLAMINE SUBSTITUEE PAR UN DERIVE D'OXIME

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS
What is claimed is:

1. A compound of formula (I),

Ri

OH H
(I)
or at least one pharmaceutically acceptable salt thereof, wherein
R1 is



wherein (Gfr 'nH
n is 0 or 1 ;
q is 0 or 1 ;
r is O, 1 , or 2;
K is selected from


-O-,
-SO2-,
-C(O)-, and
-CH(NR55R60)-;
R55 and R6oare each independently selected from hydrogen and alkyl;
R3a and R3b are independently selected from
-hydrogen,
-halogen,
-O-alkyl, and
-alkyl optionally substituted with at least one group
independently selected from halogen, -CN, -CF3, and - OH;

W is selected from -(CH2)I-4-, -O-, -S(O)0-2-, -N(R55)-, and -C(O)-;
E is a bond or alkyl;
A is selected from
-aryl optionally substituted with at least one group independently selected from R5o,
-cycloalkyl optionally substituted with at least one group independently selected from R50,
-heteroaryl optionally substituted with at least one group independently selected from R50, and
-heterocycle optionally substituted with at least one group independently selected from R50, wherein at least one atom of the heterocycle is optionally replaced with -C(O)- and -S(O)o-2-; wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from -(CO)0-I R215, -(CO)0-I R220, -S(O)0-2R2Oo, and -N(R2Oo)-S(O)0-2R200;
R50 is independently selected from
-OH,
-halogen,
-OCF3,
-NO2,
-CN,
-N(R)C(O)R,
-CO2-R,
-NH-CO2-R,
-O-(alkyl)-CO2H,
-NRR',
-SR,
-CH2OH,
-C(O)-R25,
-C(O)NRR',
-SO2NRR',

-alkyl optionally substituted with at least one group
independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-cycloalkyl optionally substituted with at least one group
independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-O-alkyl optionally substituted with at least one group
independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-O-benzyl optionally substituted with at least one group
independently selected from -H, -OH, halogen, and
alkyl,
-O-(CH2)0-2-O-(CH2)1-2-O-alkyl, and
-(CH2)o-2-O-(CH2)1-2-OH;
R and R' are each independently selected from hydrogen, alkyl, -(CH2)o-2-aryl and -(CH2)0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, -O-alkyl, amino, monoalkylamino, and dialkylamino; R25 is selected from alkyl, -(CH2)0-2-aryl and -(CH2)0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, -O-alkyl, amino, monoalkylamino, and dialkylamino;
selected from a bond, -C(O)-, -S(O)i.2-, -O-, -C(Ri I0)(Rn2)O-, -OC(Ri10)(Rii2)-, -N(R110)-, -C(O)N(R110)-, -N(R110)C(O)-, -C(R110)(R')-, -C(OH)R110-, -SO2NR110-, -N(R110)SO2-, -N(R110)C(O)N(R112)-, -N(R110)C(S)N(R112)-, -OCO2-, -NCO2-, and -OC(O)N(R110)-;
R110 and Ri12 are each independently selected from
-hydrogen and -alkyl optionally substituted with at least one group
independently selected from -OH, -O-alkyl, and halogen; G is selected from
-alkyl (optionally substituted with at least one group independently selected from -CO2H, -CO2(alkyl), -O-alkyl, -OH, -NRR', alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
-(CH2)o-3-cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from -CO2H, -CO2- (alkyl), -O-alkyl, -OH, -NH2, haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl) amino, aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
-(CRR)i-4-aryl wherein the aryl is optionally substituted with at least one group independently selected from R50,
-(CH2)i-4-heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R50,
-(CH2)o-4-heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R50, and
-C(Rio)(Ri2)-C(0)-NH-R14;
Rio and Ri2 are each independently selected from
-H1
-alkyl,
-(alkyl)o-raryl,
-(alkyl)o-rheteroaryl,
-(alkyl)o-i -heterocycle,
-aryl,
-heteroaryl, -heterocycle,
-(CH2)L4-OH,
-(CH2)i.4-Z-(CH2)1-4-aryl, and
-(CH2)i-4-Z-(CH2)i.4-heteroaryl,
wherein the heterocycle, aryl, and heteroaryl groups
included within R10 and Ri2 are optionally
substituted with at least one group independently
selected from R50;
Z is selected from -O-, -S-, and -NRi6-;
Ri4 is:
-H,
- alkyl,
-aryl,
-heteroaryl,
-heterocycle,
-(alkyl)-aryl,
-(alkyl)-heteroaryl;
-(alkyl)-, and
-(CH2)o-2-O-(CH2)o-2-OH;
wherein the heterocycle, aryl, and heteroaryl groups
included within Ri4 are optionally substituted with
at least one group independently selected from
R50;
R16 is selected from hydrogen and alkyl;
or
Ri is selected from




(Nd) t (Me) _ (Hf) ; and
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 (Mf) ring may optionally be a double bond;
R50, Rδoa. and R50b 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∞a, and R5Ob are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR5R6, CN, haloalkoxy, NR7R8, and alkoxy;
R5 and R6 are independently selected from -H and alkyl, or
R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
R7 and R8 are independently selected from -H, alkyl optionally substituted with at least one group independently selected from -OH, -NH2, and halogen, -cycloalkyl, and -alkyl-O-alkyl;
R2 is selected from
-H,
-alkyl optionally substituted with at least one group independently selected from R20O,
-OH, -O-alkyl optionally substituted with at least one group independently selected

-O-aryl optionally substituted with at least one group independently selected

-NH-alkyl optionally substituted with at least one group independently selected from R200,
-heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from -(CR245R250)-, -O- , -C(O)-, -C(O)C(O)-, -N(R2oo)o-2-, and -S(O)0-2-, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected

-NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from -(CR245R250)-, -O-, -C(O)-, -C(O)C(O)-, -N(R2oo)o-2-, and -S(O)o-2-, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected

-C(O)-N(R3-I5)(R32O), wherein R3i5 and R320 are each independently selected from -H, alkyl, and aryl,
-NH-R400,
-R400,
-NH-R500,
-R500,
-NH-R600,

R-ωo is



wherein R405 is selected from -H, -N(R515J2 and O-alkyl;

a heteroaryl selected from (Ma) and (lib)



(Ha) and (|lb) wherein
M1 and M4 are independently selected from
-C(R505)-,
-N-,
-N(R5I5)-,
-S-, and
-O-;
M2 and M3 are independently selected from



-S-, and
-O-;
M5 is selected from -C- and -N-;
R505 is independently selected from
-H,
-alkyl,
-halogen,
-NO2,
-CN,
R200, and
-aryl;
R510 is independently selected from
-H,
-alkyl,
-halogen, -amino,
-CF3,
R200, and
-aryl;
R515 is independently selected from
-H,
-alkyl, and
-aryl;
R520 is independently selected from
-H,
-alkyl,
-(CH2)o-2-aryl, and
-C(Ph)3;
R60O is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9,

10, 1 1 , 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from -Rβos;
R6o5 is selected from -H, -halogen, -alkyl, -aryl, -CO2-alkyl, -NO2, -CN, -NH2,

-NR220R225. -thioalkyl, -CF3, -OH, -O-alkyl, and -heterocycloalkyl;
R700 is aryl optionally substituted with at least one -R205;
elected from formula (Ilia), (1Mb), (UIc), (MId), (MIe), and (IHf)



(Ilia) (1Mb) (NIc) (Hid)


(Illθ) j and (MIf) - wherein,
A1 and A2 are independently selected from -(CH2)0-2-, -CH(R2Oo)-, -C(R2oo)2-, -NH-, -NR220-, -Cf=N-R230)-, -C(=CH-R23o)-, -C(=N-C(O)-R230)-, and

A3, A4, A5, and A6 are independently selected from -CH2-, -CH(R2oo)-> -C(R20O)2-, -O-, -C(O)-, -S(O)0-2-, -NH-, -NR220-, -N(CO)0-1R200-, -N(S(O2)alkyl)-, -Cf=N-R230)-, -C(=N-NH(alkyl))-, -C(=N-N(alkyl)(alkyl))-, -C(=N-0-(CH2)M-0H)-, -Cf=CH-R230)-, -C(=N-C(O)-R230)-, and

-Cf=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, -0-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(R215J2, -NR235R2^, 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 (Ilia), (MIb), (NIc), (IMd), (MIe), and (IMf) may optionally contain at least one double bond;
wherein in formulae (IMa), (MIb), (NIc), and (NId), 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 (MIe) and (MIf), when A1, A2, and A6 are selected from -(CH2)O-2-, -CH(R200)-, -C(R20O)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 (MIe) and (MIf) is optionally independently replaced with a group selected from -N-, -NH-, -O-, -C(O)-,

wherein each aryl or heteroaryl group attached directly or indirectly to Rc is optionally substituted with at least one group independently selected from R2oo;
wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to Rc optionally substituted with at least one group independently selected from R210; and Rx is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and -Rxa-Rχb, wherein Rxa and Rxb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each aryl or heteroaryl group of Rx is optionally substituted with at least one group independently selected from R2oo;
wherein each cycloalkyl or heterocycloalkyl of Rx is optionally substituted with at least one group independently selected from R2io; and
wherein at least one carbon of the heteroaryl or heterocycloalkyl group of Rx is independently optionally replaced with a group independently selected from
-NH-,
-N-,
-N(CO)0-I FW.


-O-,
-C(O)-,
-S(O)o-2-, and
-NS(O)0.2R200;
R20O at each occurrence is independently selected from
-alkyl optionally substituted with at least one group independently
selected from R205,
-OH,
-NO2,
-halogen,
-CN, -(CH2)(M-C(O)H,



-(CH2)θ-4-(CO)o-1-NR22θR225.
-(CH2)(M-(CO)0-I-NH(R215),
-(CH2)0-4-C(O)-alkyl,
-(CH2)o-4-(CO)0-i-cycloalkyl,
-(CH2)o-4-(CO)o-rheterocycloalkyl,
-(CH2)o-4-(CO)0-i-aryl,
-(CH2)o-4-(CO)0-i-heteroaryl,
-(CH2)O-4-C(O)-O-R215,
-(CH2)O-4-SO2-N R220R2251
-(CH2)o-4-S(O)o.2-alkyl.
-(CH2)0-4-S(O)o-2-cycloalkyl,
-(CH2)O-4-N(H or R2Is)-C(O)-O-R2I5,
-(CH2)O-4-N(H or R2i5)-SO2-R22o,
-(CH2)(M-N(H or R2is)-C(O)-N(R2i5)2,
-(CH2)M-N(H or R2Is)-C(O)-R220,
-(CH2)0-4-O-C(O)-alkyl,
-(CH2)O-4-O-(R215),


-(CH2)o-4-O-alkyl optionally substituted with at least one halogen, and
-adamantane;
wherein each aryl and heteroaryl group included within R2oo 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 R21O);
wherein each cycloalkyl or heterocycloalkyl group included within R2oo is optionally substituted with at least one group independently selected from

R210;
R2o5 at each occurrence is independently selected from -alkyl,
-haloalkoxy,
-(CH2)o-3-cycloalkyl,
-halogen,


-O-aryl,
-OH,
-SH,
-(CH2)O-4-C(O)H,
-(CH2)O-6-CN,
-(CH2)O-6-C(O)-NR235R240,
-(CH2)O-6-C(O)-R235,
-(CH2)O-4-N(H or R2i5)-SO2-R235)
-OCF3,
-CF3,
-alkoxy,
-alkoxycarbonyl, and
-N R235R240; R2io at each occurrence is independently selected from
-(CH2)O-4-OH,
-(CH2)O-4-CN,
-(CH2)O-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,

-cycloalkyl optionally substituted with at least one group independently selected from R2o5,
-heterocycloalkyl,
-heteroaryl,
-(CH2)O-4-NR235R240,
-(CH2)o-4-NR235(alkoxy),
-(CH2)0-4-S-(R215),
-(CH2)O-4-NR235-C(O)H,
-(CH2)o-4-NR235-C(O)-(alkoxy),
-(CH2)O-4-NR235-C(O)-R240,
-C(O)-NHR215,
-C(O)-alkyl,


-S(O)2-NR235R240;
R2I5 at each occurrence is independently selected from
-alkyl,
-(CH2)0.2-aryl,
-(CH2)o-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

R220 and R22S at each occurrence are independently selected from
-H,
-alkyl,
-(CH2)C-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)o-2-cycloalkyl,
-(alkyl)-O-(alkyl),
-aryl,
-heteroaryl, and
-heterocycloalkyl;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R22o and R225 are each optionally substituted with at least one group independently selected from R270;
each occurrence is independently selected from


-alkyl optionally substituted with at least one group independently selected from R205,
-aryl,
-halogen,
-alkoxy,
-haloalkoxy,


-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)O-4-C(O)H;
R235 and R240 at each occurrence are independently selected from
-H,
-OH,
-CF3,
-OCH3,
-NHCH3,


-(CH2)O-4-C(O)(H or alkyl),
-alkyl,
-alkanoyl,
-SO2-alkyl, and
-aryl.

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, CrC2 alkyl, CrC2 alkoxy, and -OH.

3. The compound according to claim 1 , wherein Ri 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, 2-ethylamino-3,5-difluoro-benzyl, 2-hydroxy-5-methyl-benzamide, 3-fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-fluoro-5-heptyloxy-benzyl, and 3-fluoro-5-hexyloxy-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, S-chloro-thiophen-2-yl-methyl, δ-chloro-S-ethyl-thiophen^-yl-methyl, 3,5-difluoro-2-hydroxy-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, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.

4. The compound according to claim 1 , wherein R2 is selected from hydrogen, 3-Allyl-5-benzyl-2-oxo-imidazolidin-1 -yl, 6-Benzyl-3,3-dimethyl-2-oxo-piperazin-1 -yl, 3-Allyl-5-benzyl-2-oxo-pyrrolidin-1 -yl, 5-Benzyl-3-isobutyl-2-oxo-imidazolidin-1-yl, 3-Benzyl-5-methyl-1 ,1-dioxo-1λ6-[1 ,2,5]thiadiazolidin-2-yl, 3-Benzyl-1 ,1 -dioxo-1λ6-isothiazolidin-2-yl, 2-Benzyl-5-oxo-pyrrolidin-1-yl, 5-Benzyl-3-ethyl-2-oxo-pyrrolidin-1 -yl, 3-Amino-5-benzyl-2-oxo-pyrrolidin-1 -yl, 3-Acetylamino-5-benzyl-2-oxo-pyrrolidin-1-yl, 5-BenzyI-3-[1 ,3]dioxolan-4-ylmethyl-2-oxo-pyrrolidin-1-yl, 3-Benzyl-5-oxo-morpholin-4-yl, 2-Benzyl-6-oxo-piperazin-1 -yl, 8-Benzyl-6-methyl-10-oxo-6,9-diaza-spiro[4.5]dec-9-yl, 5-Benzyl-3-furan-2-ylmethylene-2-oxo-pyrrolidin-1-yl, 3-acetylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1 -yl, 3-acetylamino-3-(cyclopropylmethyl)-2-oxo-pyrrolidin-1-yl, 3-(2-amino-5-carboxypentanoylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-(2-methoxy-acetylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1 -yl, 3-ethoxycarbonylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1 -yl, 3-ethylureido-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-hydroxypropionylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-Bromo-[1 ,2,4]thiadiazol-5-ylamino, [1 ,2,4]thiadiazol-5-ylamino, 4-Chloro-[1 ,2,5]thiadiazol-3-ylamino, [1 ,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1 ,3,4]thiadiazol-2-ylamino, [1 ,3,4]thiadiazol-2-ylamino, 5-Amino-[1 ,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1 ,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1 ,3,4]oxadiazol-2-ylamino, 5-Amino-[1 ,3,4]oxadiazol-2-ylamino, 1-trityl-1 H-[1 ,2,4]triazol-3-ylamino, 1 H-[1 ,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1 ,2,3]triazol-4-ylamino, 2-trityl-2H-[1 ,2,3]triazol-4-ylamino, 5-Bromo-2H-[1 ,2,3]triazol-4-ylamino, 2H-[1 ,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1 ,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.

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

(Hid)
wherein A5 is -C(=N-R23o) and Ai, A2, A3, A4, Rx and R23oare defined as in claim 1.

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 Rc 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-(1 H-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 Rx is selected from

3-(1 ,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1 H-pyrrol-2-yl)-phenyl, 3-(1 -hydroxy-1 -methyl-ethyl)-phenyl, 3-(1 -methyl-1 H-imidazol-2-yl)-phenyl, 3-(1 -methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1 H-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 Rx is 3-tert-Butyl-phen-1-yl.

10. The compound according to claim 1 , wherein the formula (I) compound is selected from 4-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyiminoJ-cyclohexylaminol^^S.S-difluoro-benzylJ-S-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(S-tert-Butyl-phenyO^.δ.βJ-tetrahydro-benzotclisoxazol-S-ylaminol^^S.S-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1 -(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N- phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazonoJ-cyclohexylaminol^^S.δ-difluoro-benzyO-S-hydroxy-N-phenyl-butyramide, 4-[1 -(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1 -(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1 H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1 ,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1 ,2,4]thiadiazol-5-ylamino)- butylamino]-cyclohexanone oxime, 3-[3-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1 ,2-dione, 3-[3-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1 ,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1 ,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1 -(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1 -(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.

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),



(D
or pharmaceutically acceptable salts thereof, wherein
Ri is



wherein
n is 0 or 1 ;
q is 0 or 1 ;
r is O, 1 , or 2;
K is selected from


-O-,
-SO2-, -C(O)-, and
-CH(NR55R60)-;
R55 and R6oare each independently selected from hydrogen and alkyl; R3a and R3b are independently selected from
-hydrogen,
-halogen,
-O-alkyl, and
-alkyl optionally substituted with at least one group
independently selected from halogen, -CN, -CF3, and - OH;
W is selected from -(CH2)i-4-, -O-, -S(O)0-2-, -N(R55)-, and -C(O)-;
E is a bond or alkyl;
A is selected from
-aryl optionally substituted with at least one group independently selected from R50,
-cycloalkyl optionally substituted with at least one group independently selected from R50,
-heteroaryl optionally substituted with at least one group independently selected from R50, and
-heterocycle optionally substituted with at least one group independently selected from R50, wherein at least one atom of the heterocycle is optionally replaced with -C(O)- and -S(O)o-2-; wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from -(CO)0-I R215, -(CO)0-I R220, -S(O)0-2R200, and -N(R200)-S(O)0-2R200;
R50 is independently selected from
-OH,
-halogen,
-OCF3,
-NO2,
-CN, -N(R)C(O)R,
-CO2-R,
-NH-CO2-R,
-O-(alkyl)-CO2H,
-NRR',
-SR,
-CH2OH,
-C(O)-R25,
-C(O)NRR',
-SO2NRR',
-S(O)I-2R25,
-alkyl optionally substituted with at least one group independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-cycloalkyl optionally substituted with at least one group independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-O-alkyl optionally substituted with at least one group independently selected from -CF3, halogen, -O- alkyl, -OCF3, -NRR1, -OH, and -CN,
-O-benzyl optionally substituted with at least one group independently selected from -H, -OH, halogen, and alkyl,
-O-(CH2)0-2-O-(CH2)1-2-O-alkyl, and
-(CH2)o-2-O-(CH2)1-2-OH;
R and R' are each independently selected from hydrogen, alkyl, -(CH2)o-2-aryl and -(CH2)0-2-cycloalkyl, wherein each aryl or cycloalkyl is optionally substituted with at least one group independently selected from halogen, hydroxy, alkyl, -O-alkyl, amino, monoalkylamino, and dialkylamino;

R25 is selected from alkyl, -(CH2)0-2-aryl and -(CH2)o-2-cycloalkyl,
wherein each aryl or cycloalkyl is optionally substituted
with at least one group independently selected from
halogen, hydroxy, alkyl, -O-alkyl, amino, monoalkylamino,
and dialkylamino;
L is selected from a bond, -C(O)-, -S(O)i-2-, -O-, -C(Rno)(Rii2)O-, -OC(RIIO)(RII2)-, -N(R110)-, -C(O)N(R110)-, -N(R110)C(O)-, -C(R110)(R')-, -C(OH)R110-, -SO2NR110-, -N(R110)SO2-, -N(R110)C(O)N(R112)-, -N(R110)C(S)N(R112)-, -OCO2-, -NCO2-, and -OC(O)N(R110)-;
R110 and Ri12 are each independently selected from
-hydrogen and
-alkyl optionally substituted with at least one group
independently selected from -OH, -O-alkyl, and halogen; G is selected from
-alkyl (optionally substituted with at least one group independently selected from -CO2H, -CO2(alkyl), -O-alkyl, -OH, -NRR', alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
-(CH2)0-3-cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from -CO2H, -CO2- (alkyl), -O-alkyl, -OH, -NH2, haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl) amino, aryl (optionally substituted with at least one group independently selected from R50), and heteroaryl (optionally substituted with at least one group independently selected from R50);
-(CRR^-aryl wherein the aryl is optionally substituted with at least one group independently selected from R50,
-(CH2)1-4-heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R50, -(CH2)o-4-heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R50, and -C(R10)(Ri2)-C(O)-NH-R14;
Rio and R12 are each independently selected from
-H,
-alkyl,
-(alkyl)o-raryl,
-(alkyl)0-i-heteroaryl,
-(alkyl)o-i -heterocycle,
-aryl,
-heteroaryl,
-heterocycle,
-(CH2)L4-OH,
-(CH2)1-4-Z-(CH2)i-4-aryl, and
-(CH2)1-4-Z-(CH2)1-4-heteroaryl,
wherein the heterocycle, aryl, and heteroaryl groups
included within R10 and Ri2 are optionally
substituted with at least one group independently
selected from R50;
Z is selected from -O-, -S-, and -NR16-;
R14 is:
-H,
- alkyl,
-aryl,
-heteroaryl,
-heterocycle,
-(alkyl)-aryl,
-(alkyl)-heteroaryl,
-(alkyl)-, and
-(CH2)O-2-O-(CH2)O-2-OH;

wherein the heterocycle, aryl, and heteroaryl groups
included within R14 are optionally substituted with
at least one group independently selected from


R16 is selected from hydrogen and alkyl;
or
Ri is selected from



(lid) f (Me) f (Hf) ; and
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 (Nf) ring may optionally be a double bond;
R50, Rδoa, and R50b 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)-NR7Rs, alkyloxy, alkoxyalkoxyalkoxy, and cycloalkyl;
wherein the alkyl, alkoxy, and cycloalkyl groups within R50, Rsoa, and R5Ob are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR5R6, CN, haloalkoxy, NR7R8, and alkoxy;

R5 and R6 are independently selected from -H and alkyl, or
R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
R7 and R8 are independently selected from -H, alkyl optionally substituted with at least one group independently selected from -OH, -NH2, and halogen, -cycloalkyl, and -alkyl-O-alkyl;
R2 is selected from
-H,
-alkyl optionally substituted with at least one group independently selected from R2Oo,
-OH,
-O-alkyl optionally substituted with at least one group independently selected from R2Oo,
-O-aryl optionally substituted with at least one group independently selected from R20O,
-NH-alkyl optionally substituted with at least one group independently selected

-heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from -(CR245R2So)-, -O- , -C(O)-,

-C(O)C(O)-, -N(R2Oo)o-2-, and -S(O)0-2-, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R2Oo),
-NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from -(CR245R25o)-, -O-, -C(O)-,

-C(O)C(O)-, -N(R200)O-2-, and -S(O)0-2-, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected

-C(O)-N(R3is)(R32o). wherein R315 and R32o are each independently selected from -H, alkyl, and aryl,


-Rsoo,

R400 is



wherein R405 is selected from -H, -N(R515J2 and O-alkyl; R500 is a heteroaryl selected from (Ma) and (Mb)



(Ma) and Cb)
wherein
Mi and M4 are independently selected from
-C(R5O5)-,
-N-,
-N(R5I5)-,
-S-, and
-O-;
M2 and M3 are independently selected from



-S-, and
-O-;
M5 is selected from -C- and -N-;
R5o5 is independently selected from -H,
-alkyl,
-halogen,
-NO2,
-CN,
R2oo> and
-aryl;
R510 is independently selected from
-H,
-alkyl,
-halogen,
-amino,
-CF3,


-aryl;
R515 is independently selected from
-H,
-alkyl, and
-aryl;
R520 is independently selected from
-H,
-alkyl,


-C(Ph)3;
R6Oo is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9,

10, 1 1 , 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from -Rβos;
R6o5 is selected from -H, -halogen, -alkyl, -aryl, -CO2-alkyl, -NO2, -CN, -NH2,

-NR22oR225, -thioalkyl, -CF3, -OH, -O-alkyl, and -heterocycloalkyl;
R700 is aryl optionally substituted with at least one -R205;
elected from formula (Ilia), (NIb), (lllc), (MId), (IHe), and (MIf)

Ia) (MIb) (MIc) (HId)



("Ie) , and (| l lf) ;
wherein,
A1 and A2 are independently selected from -(CH2)(K--. -CH(R2Oo)-, -C(R2oo)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-, -CH(R2Oo)-.
-C(R20O)2-, -O-, -C(O)-, -S(O)0-2-, -NH-, -NR220-, -N(CO)0-iR20o-, -N(S(O2)alkyl)-, -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)-;
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 (Ilia), (NIb), (MIc), (MId), (MIe), and (NIf) may optionally contain at least one double bond;

wherein in formulae (Ilia), (1Mb), (lllc), and (Mid), 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-R23o)-, -C(=N-C(0)-R23o)-, and -C(=CH-C(O)-R230)-;
wherein in formulae (NIe) and (MIf), when A1, A2, and A6 are selected from -(CH2)O-2-, -CH(R200)-, -C(R20O)2-, -O-, -C(O)-, -S(O)0-2-, -NH-, -NR220-, -N(CO)0-1 R200-, and -N(S(O2)alkyl)-, at least one carbon of the aryl ring group within (NIe) and (INf) 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 Rc is optionally substituted with at least one group independently selected from R200;
wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to Rc optionally substituted with at least one group independently selected from R210; and Rx is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and -Rxa-Rχb, wherein Rxa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each aryl or heteroaryl group of Rx is optionally substituted with at least one group independently selected from R200;
wherein each cycloalkyl or heterocycloalkyl of Rx 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 Rx 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)O-4-C(O)H,



-(CH2)o-4"(CO)o-1 -N R22θR225>
-(CH2)(M-(CO)O-I-NH(R2I5),
-(CH2)o-4-C(O)-alkyl,
-(CH2)0-4-(CO)o-i-cycloalkyl,
-(CH2)o-4-(CO)0-i-heterocycloalkyl,
-(CH2)o-4-(CO)0-i-aryl,
-(CH2)o-4-(CO)0-i-heteroaryl,
-(CH2)O-4-C(O)-O-R215,
-(CH2)o-4-SO2-NR22θR225.
-(CH2)o-4-S(O)o-2-alkyl,
-(CH2)o-4-S(O)o-2-cycloalkyl,
-(CH2)O-4-N(H or R2Is)-C(O)-O-R215,
-(CH2)O-4-N(H or R2is)-SO2-R22o,
-(CH2)O-4-N(H or R215)-C(O)-N(R215)2,
-(CH2)O-4-N(H or R215)-C(O)-R220,
-(CH2)0-4-O-C(O)-alkyl,
-(CH2)o-4-O-(R215),


-(CH2)0-4-O-alkyl optionally substituted with at least one halogen, and
-adamantane;
wherein each aryl and heteroaryl group included within R20O 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 R2o5 and R210);
wherein each cycloalkyl or heterocycloalkyl group included within R2oo 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)L6-OH,
-O-aryl,
-OH,
-SH,
-(CH2)O-4-C(O)H,
-(CH2)O-6-CN,
-(CH2)O-6-C(O)-NR235R240,
-(CH2)o-6-C(O)-R235,
-(CH2)O-4-N(H or R2i5)-SO2-R235,
-OCF3,
-CF3,
-alkoxy,
-alkoxycarbonyl, and
-N R235R240; R2io at each occurrence is independently selected from
-(CH2)O-4-OH,


-(CH2)M-C(O)H,
-alkyl optionally substituted with at least one group independently selected from R20s,
-alkanoyl,
-S-alkyl;

-S(O)2-alkyl,
-halogen,
-alkoxy,
-haloalkoxy,


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


-(CH2)o-4-NR235(alkoxy),


-(CH2)O-4-NR235-C(O)H,
-(CH2)O-4-NR235-C(O)-(BIkOXy),
-(CH2)O-4-NR235-C(O)-R240,
-C(O)-NHR215,
-C(O)-alkyl,
-C(O)-NR235R240, and
-S(O)2-NR235R240;
R2I5 at each occurrence is independently selected from
-alkyl,
-(CH2)o-2-aryl,
-(CH2)o-2-cycloalkyl,
-(CH2)o-2-heteroaryl,
-(CH2)0-2-heterocycloalkyl, and
-CO2-CH2-aryl;
wherein the aryl group included within R2i5 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 R2io; R220 and R225 at each occurrence are independently selected from
-H1
-alkyl,


-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)o-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;
each occurrence is independently selected from


-alkyl optionally substituted with at least one group independently selected from R205,
-aryl,
-halogen,
-alkoxy,
-haloalkoxy,
-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)o-4-C(O)H;
R235 and R240 at each occurrence are independently selected from
-H,
-OH,
-CF3,
-OCH3,
-NHCH3,
-N(CHa)2,
-(CH2)O-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 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1 -(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2- hydroxyimino-hexahydro-pyrimidin-S-ylaminol^-CS.δ-difluoro-benzyO-S-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyO^-methoxyimino-cyclohexylaminoJ^-CS.S-difluoro-benzyO-S-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazonoJ-cyclohexylaminoJ^-CS.S-difluoro-benzylJ-S-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N- phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1 H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenylj-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1 -yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1 ,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1 ,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1 ,2-dione, 3-[3-[1 -(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylaminoJ-I^S.δ-difluoro-benzylJ^-hydroxy-propylaminoj^-methoxy-cyclobut-3-ene-1 ,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1 ,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1 -(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.

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 Rc 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, wherein R1, R2 and Rc 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 Rc 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 Rc 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 Ri, R2 and Rc 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 Rc 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 Rc are as defined in claim 1.

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 Rc 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 R0 are as defined in claim 11 , and 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 Ri, R2 and Rc are as defined in claim 11 , further comprising increasing at least one parameter selected from Cmaχ, Tmax, 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 Rc are defined as in claim 11.