Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors

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.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
       
       or at least one pharmaceutically acceptable salt thereof, wherein
 R 1  is 
 
       
         
           
           
               
               
           
         
         
           wherein 
           n is 0 or 1; 
           q is 0 or 1; 
           r is 0, 1, or 2; 
           K is selected from
 —(CR 3a R 3b )—, 
 —O—, 
 —SO 2 —, 
 —C(O)—, and 
 —CH(NR 55 R 60 )—; 
 R 55  and R 60  are each independently selected from hydrogen and alkyl; 
 R 3a  and R 3b  are independently selected from
 hydrogen, 
 -halogen, 
 —O-alkyl, and 
 -alkyl optionally substituted with at least one group independently selected from halogen, —CN, —CF 3 , and —OH; 
 
 
           W is selected from —(CH 2 ) 1-4 —, —O—, —S(O) 0-2 —, —N(R 55 )—, and —C(O)—; 
           E is a bond or alkyl; 
           A is selected from
 -aryl optionally substituted with at least one group independently selected from R 50 , 
 -cycloalkyl optionally substituted with at least one group independently selected from R 50 , 
 -heteroaryl optionally substituted with at least one group independently selected from R 50 , and 
 -heterocycle optionally substituted with at least one group independently selected from R 50 , wherein at least one atom of the heterocycle is optionally replaced with —C(O)— and —S(O) 0-2 —; 
 wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from —(CO) 0-1 R 215 , —(CO) 0-1 R 220 , —S(O) 0-2 R 200 , and —N(R 200 )—S(O) 0-2 R 200 ;
 R 50  is independently selected from 
  —OH, 
  -halogen, 
  —OCF 3 , 
  —NO 2 , 
  —CN, 
  —N(R)C(O)R, 
  —CO 2 —R, 
  —NH—CO 2 —R, 
  —O-(alkyl)-CO 2 H, 
  —NRR′, 
  —SR, 
  —CH 2 OH, 
  —C(O)—R 25 , 
  —C(O)NRR′, 
  —SO 2 NRR′, 
  —S(O) 1-2 R 25 , 
  -alkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , —NRR′, —OH, and —CN, 
  -cycloalkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , NRR′, —OH, and —CN, 
  —O-alkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , —NRR′, —OH, and —CN, 
  —O-benzyl optionally substituted with at least one group independently selected from —H, —OH, halogen, and alkyl, 
  —O—(CH 2 ) 0-2 —O—(CH 2 ) 1-2 —O-alkyl, and 
  —(CH 2 ) 0-2 —O—(CH 2 ) 1-2 —OH; 
 R and R′ are each independently selected from hydrogen, alkyl, —(CH 2 ) 0-2 -aryl and —(CH 2 ) 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; 
 R 25  is selected from alkyl, —(CH 2 ) 0-2 -aryl and —(CH 2 ) 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; 
 
 
           L is selected from a bond, —C(O)—, —S(O) 1-2 —, —O—, —C(R 110 )(R 112 )O—, —OC(R 110 )(R 112 )—, —N(R 110 )—, —C(O)N(R 110 )—, —N(R 110 )C(O)—, —C(R 110 )(R′)—, —C(OH)R 110 —, —SO 2 NR 110 —, —N(R 110 )SO 2 —, —N(R 110 )C(O)N(R 112 )—, —N(R 110 )C(S)N(R 112 )—, —OCO 2 —, —NCO 2 —, and —OC(O)N(R 110 )—;
 R 110  and R 112  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 —CO 2 H, —CO 2 (alkyl), —O-alkyl, —OH, —NRR′, alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R 50 ), and heteroaryl (optionally substituted with at least one group independently selected from R 50 ); 
 —(CH 2 ) 0-3 -cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from —CO 2 H, —CO 2 -(alkyl), —O-alkyl, —OH, —NH 2 , haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl)amino, aryl (optionally substituted with at least one group independently selected from R 50 ), and heteroaryl (optionally substituted with at least one group independently selected from R 50 ); 
 —(CRR) 1-4 -aryl wherein the aryl is optionally substituted with at least one group independently selected from R 50 , 
 —(CH 2 ) 1-4 -heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R 50 , 
 —(CH 2 ) 0-4 -heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R 50 , and 
 —C(R 10 )(R 12 )—C(O)—NH—R 14 ;
 R 10  and R 12  are each independently selected from 
  —H, 
  -alkyl, 
  -(alkyl) 0-1 -aryl, 
  -(alkyl) 0-1 -heteroaryl, 
  -(alkyl) 0-1 , -heterocycle, 
  -aryl, 
  -heteroaryl, 
  -heterocycle, 
  —(CH 2 ) 1-4 —OH, 
  —(CH 2 ) 1-4 -Z-(CH 2 ) 1-4 -aryl, and 
  —(CH 2 ) 1-4 -Z-(CH 2 ) 1-4 -heteroaryl, 
  wherein the heterocycle, aryl, and heteroaryl groups included within R 10  and R 12  are optionally substituted with at least one group independently selected from R 50 ; 
 
 Z is selected from —O—, —S—, and —NR 16 —; 
 R 14  is:
  —H, 
  -alkyl, 
  -aryl, 
  -heteroaryl, 
  -heterocycle, 
  -(alkyl)-aryl, 
  -(alkyl)-heteroaryl, 
  -(alkyl)-, and 
  —(CH 2 ) 0-2 —O—(CH 2 ) 0-2 —OH; 
  wherein the heterocycle, aryl, and heteroaryl groups included within R 14  are optionally substituted with at least one group independently selected from R 50 ; 
 R 16  is selected from hydrogen and alkyl; 
 
 
         
         or 
         R 1  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 (IIf) ring may optionally be a double bond; 
 
           R 50 , R 50a , and R 50b  are independently selected from —H, halogen, —OH, —SH, —CN, —C(O)-alkyl, —NR 7 R 8 , —NO 2 , —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)—NR 7 R 8 , alkyloxy, alkoxyalkoxyalkoxy, and cycloalkyl;
 wherein the alkyl, alkoxy, and cycloalkyl groups within R 50 , R 50a , and R 50b  are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR 5 R 6 , CN, haloalkoxy, NR 7 R 8 , and alkoxy; 
 
           R 5  and R 6  are independently selected from —H and alkyl, or 
           R 5  and R 6 , and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and 
           R 7  and R 8  are independently selected from —H, alkyl optionally substituted with at least one group independently selected from —OH, —NH 2 , and halogen, -cycloalkyl, and -alkyl-O-alkyl; 
         
         R 2  is selected from
 —H, 
 -alkyl optionally substituted with at least one group independently selected from R 200 , 
 —OH, 
 —O-alkyl optionally substituted with at least one group independently selected from R 200 , 
 —O-aryl optionally substituted with at least one group independently selected from R 200 , 
 —NH-alkyl optionally substituted with at least one group independently selected from R 200 , 
 -heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —(CR 245 R 250 )—, —O—, —C(O)—, —C(O)C(O)—, —N(R 200 ) 0-2 —, and —S(O) 0-2 —, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R 200 ), 
 —NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —(CR 245 R 250 )—, —O—, —C(O)—, —C(O)C(O)—, —N(R 200 ) 0-2 —, and —S(O) 0-2 —, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R 200 , 
 —C(O)—N(R 315 )(R 320 ), wherein R 315  and R 320  are each independently selected from —H, alkyl, and aryl, 
 —NH—R 400 , 
 —R 400 , 
 —NH—R 500 , 
 —R 500 , 
 —NH—R 600 , 
 —R 600 , and 
 —R 700 ; 
 
         R 400  is 
       
       
         
           
           
               
               
           
         
         
           wherein R 405  is selected from —H, —N(R 515 ) 2  and O-alkyl; 
         
         R 500  is a heteroaryl selected from (IIa) and (IIb) 
       
       
         
           
           
               
               
           
         
         
           wherein 
           M 1  and M 4  are independently selected from
 —C(R 505 )—, 
 —N—, 
 —N(R 515 )—, 
 —S—, and 
 —O—; 
 
           M 2  and M 3  are independently selected from
 —C(R 510 )—, 
 —N(R 520 ) 0-1 —, 
 —S—, and 
 —O—; 
 
           M 5  is selected from —C— and —N—; 
           R 505  is independently selected from
 —H,
 -alkyl, 
 -halogen, 
 
 —NO 2 , 
 —CN, 
 R 200 , and 
 -aryl; 
 
           R 510  is independently selected from
 —H, 
 -alkyl, 
 -halogen, 
 -amino, 
 —CF 3 , 
 R 200 , and 
 -aryl; 
 
           R 515  is independently selected from
 —H, 
 -alkyl, and 
 -aryl; 
 
           R 520  is independently selected from
 —H, 
 -alkyl, 
 —(CH 2 ) 0-2 -aryl, and 
 —C(Ph) 3 ; 
 
           R 600  is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from —R 605 ; 
           R 605  is selected from —H, -halogen, -alkyl, -aryl, —CO 2 -alkyl, —NO 2 , —CN, —NH 2 , —NR 220 R 225 , -thioalkyl, —CF 3 , —OH, —O-alkyl, and -heterocycloalkyl; 
           R 700  is aryl optionally substituted with at least one —R 205 ; 
         
         R C  is selected from formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf) 
       
       
         
           
           
               
               
           
         
         
           wherein, 
           A 1  and A 2  are independently selected from —(CH 2 ) 0-2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —NH—, —NR 220 —, —C(═N—R 230 )—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           A 3 , A 4 , A 5 , and A 6  are independently selected from —CH 2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S(O) 0-2 —, —NH—, —NR 220 —, —N(CO) 0-1 R 200 —, —N(S(O 2 )alkyl)-, —C(═N—R 230 )—, —C(═N—NH(alkyl))-, —C(═N—N(alkyl)(alkyl))-, —C(═N—O—(CH 2 ) 1-4 —OH)—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           R 230  is independently selected from —H, —OH, R 215  (optionally substituted with —OH, —NH 2 , —C(O)H, and —CN), alkyl, cycloalkyl, alkoxy, -alkyl-OH, -alkyl-NH 2 , -alkyl-C(O)H, —O—R 215  (optionally substituted with —OH, —NH 2 , —C(O)H, and —CN), —O-alkyl, —O-alkyl-OH, —O-alkyl-NH 2 , —O-alkyl-C(O)H, —NH 2 , —NHR 215 , —N(R 215 ) 2 , —NR 235 R 240 , and —CN;
 wherein at least one carbon of the alkyl or cycloalkyl within R 230  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 A 1 , A 2 , A 3 , A 4 , or A 5  is selected from —C(═N—R 230 )—, —C(═N—NH(alkyl))-, —C(═N—N(alkyl)(alkyl))-, C(═N—O—(CH 2 ) 1-4 —OH)—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           wherein in formulae (IIIe) and (IIIf), when A 1 , A 2 , and A 6  are selected from —(CH 2 ) 0-2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S(O) 0-2 —, —NH—, —NR 220 —, —N(CO) 0-1 R 200 —, and —N(S(O 2 )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 R 200 ; 
           wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to R C  is optionally substituted with at least one group independently selected from R 210 ; 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 R 200 ; 
 wherein each cycloalkyl or heterocycloalkyl of R X  is optionally substituted with at least one group independently selected from R 210 ; 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) 0-1 R 215 —, 
 —N(CO) 0-1 R 220 —, 
 —O—, 
 —C(O)—, 
 —S(O) 0-2 —, and 
 —NS(O) 0-2 R 200 ; 
 
           R 200  at each occurrence is independently selected from
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 —OH, 
 —NO 2 , 
 -halogen, 
 —CN, 
 —(CH 2 ) 0-4 —C(O)H, 
 —(CO) 0-1 R 215 , 
 —(CO) 0-1 R 220 , 
 —(CH 2 ) 0-4 —(CO) 0-1 —NR 220 R 225 , 
 —(CH 2 ) 0-4 —(CO) 0-1 —NH(R 215 ), 
 —(CH 2 ) 0-4 —C(O)-alkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -cycloalkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -heterocycloalkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -aryl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -heteroaryl, 
 —(CH 2 ) 0-4 —C(O)—O—R 215 , 
 —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 , 
 —(CH 2 ) 0-4 —S(O) 0-2 -alkyl, 
 —(CH 2 ) 0-4 —S(O) 0-2 -cycloalkyl, 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—O—R 215 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 220 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—N(R 215 ) 2 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—R 220 , 
 —(CH 2 ) 0-4 —O—C(O)-alkyl, 
 —(CH 2 ) 0-4 —O—(R 215 ), 
 —(CH 2 ) 0-4 —S—(R 215 ), 
 —(CH 2 ) 0-4 —O-alkyl optionally substituted with at least one halogen, and 
 -adamantane; 
 wherein each aryl and heteroaryl group included within R 200  is optionally substituted with at least one group independently selected from R 205 , R 210 , and alkyl (optionally substituted with at least one group independently selected from R 205  and R 210 ); 
 wherein each cycloalkyl or heterocycloalkyl group included within R 200  is optionally substituted with at least one group independently selected from R 210 ; 
 
           R 205  at each occurrence is independently selected from
 -alkyl, 
 -haloalkoxy, 
 —(CH 2 ) 0-3 -cycloalkyl, 
 -halogen, 
 —(CH 2 ) 1-6 —OH, 
 —O-aryl, 
 —OH, 
 —SH, 
 —(CH 2 ) 0-4 —C(O)H, 
 —(CH 2 ) 0-6 —CN, 
 —(CH 2 ) 0-6 —C(O)—NR 235 R 240 , 
 —(CH 2 ) 0-6 —C(O)—R 235 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 235 , 
 —OCF 3 , 
 —CF 3 , 
 -alkoxy, 
 -alkoxycarbonyl, and 
 
           —NR 235 R 240 ; R 210  at each occurrence is independently selected from
 —(CH 2 ) 0-4 —OH, 
 —(CH 2 ) 0-4 —CN, 
 —(CH 2 ) 0-4 —C(O)H, 
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 -alkanoyl, 
 —S-alkyl; 
 —S(O) 2 -alkyl, 
 -halogen, 
 -alkoxy, 
 -haloalkoxy, 
 —NR 220 R 225 , 
 -cycloalkyl optionally substituted with at least one group independently selected from R 205 , 
 -heterocycloalkyl, 
 -heteroaryl, 
 —(CH 2 ) 0-4 —NR 235 R 240 , 
 —(CH 2 ) 0-4 —NR 235 (alkoxy), 
 —(CH 2 ) 0-4 —S—(R 215 ), 
 —(CH 2 ) 0-4 —NR 235 —C(O)H, 
 —(CH 2 ) 0-4 —NR 235 —C(O)-(alkoxy), 
 —(CH 2 ) 0-4 —NR 235 —C(O)—R 240 , 
 —C(O)—NHR 215 , 
 —C(O)-alkyl, 
 —C(O)—NR 235 R 240 , and 
 —S(O) 2 —NR 235 R 240 ; 
 
           R 215  at each occurrence is independently selected from
 -alkyl, 
 —(CH 2 ) 0-2 -aryl, 
 —(CH 2 ) 0-2 -cycloalkyl, 
 —(CH 2 ) 0-2 -heteroaryl, 
 —(CH 2 ) 0-2 -heterocycloalkyl, and 
 —CO 2 —CH 2 -aryl; 
 wherein the aryl group included within R 215  is optionally substituted with at least one group independently selected from R 205  and R 210 , and 
 
           wherein the heterocycloalkyl and heteroaryl groups included within R 215  are optionally substituted with at least one group independently selected from R 210 ; 
           R 220  and R 225  at each occurrence are independently selected from
 —H, 
 -alkyl, 
 —(CH 2 ) 0-4 —C(O)H, 
 -alkylhydroxyl, 
 -alkoxycarbonyl, 
 -alkylamino, 
 —S(O) 2 -alkyl, 
 -alkanoyl optionally substituted with at least one halogen, 
 —C(O)—NH 2 , 
 —C(O)—NH(alkyl), 
 —C(O)—N(alkyl)(alkyl), 
 -haloalkyl, 
 —(CH 2 ) 0-2 -cycloalkyl, 
 -(alkyl)-O-(alkyl), 
 -aryl, 
 -heteroaryl, and 
 -heterocycloalkyl; 
 wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R 220  and R 225  are each optionally substituted with at least one group independently selected from R 270 ; 
 
           R 270  at each occurrence is independently selected from
 —R 205 , 
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 -aryl, 
 -halogen, 
 -alkoxy, 
 -haloalkoxy, 
 —NR 235 R 240 , 
 —OH, 
 —CN, 
 cycloalkyl optionally substituted with at least one group independently selected from R 205 , 
 —C(O)-alkyl, 
 —S(O) 2 —NR 235 R 240 , 
 —C(O)—NR 235 R 240 , 
 —S(O) 2 -alkyl, and 
 —(CH 2 ) 0-4 —C(O)H; 
 
           R 235  and R 240  at each occurrence are independently selected from
 —H, 
 —OH, 
 —CF 3 , 
 —OCH 3 , 
 —NHCH 3 , 
 —N(CH 3 ) 2 , 
 —(CH 2 ) 0-4 —C(O)(H or alkyl), 
 -alkyl, 
 -alkanoyl, 
 —SO 2 -alkyl, and 
 -aryl. 
 
         
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is selected from —CH 2 -aryl, wherein the aryl ring is optionally substituted with at least one group independently selected from halogen, C 1 -C 2  alkyl, C 1 -C 2  alkoxy, and —OH. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  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, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-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 R 2  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-1λ 6 -([1,2,5]thiadiazolidin-2-yl, 3-Benzyl-1,1-dioxo-1λ 6 -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-Benzyl-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-1H-[1,2,4]triazol-3-ylamino, 1H-[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 R C  is selected from 
       
         
           
           
               
               
           
         
       
       wherein A 5  is —C(═N—R 230 ) and A 1 , A 2 , A 3 , A 4 , R X  and R 230  are defined as in  claim 1 . 
     
     
         6 . The compound according to  claim 5 , wherein A 5  is selected from —C(═N—OH)—, —C(═N—O—CH 3 )—, —C(═N—O—CH 2 CH 3 )—, —C(═N—O—CH 2 CH 2 OH)—, —C(═N—O—CH 2 CH 2 NH 2 )—, —C(═N—NHCH 3 )—, and —C(═N—CN)—, and A 1 , A 2 , A 3 , and A 4  are —CH 2 —. 
     
     
         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 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-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-(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-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-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-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-(1H-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),   
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein
 R 1  is 
 
       
         
           
           
               
               
           
         
         
           wherein 
           n is 0 or 1; 
           q is 0 or 1; 
           r is 0, 1, or 2; 
           K is selected from
 —(CR 3a R 3b )—, 
 —O—, 
 —SO 2 —, 
 —C(O)—, and 
 —CH(NR 55 R 60 )—; 
 R 55  and R 60  are each independently selected from hydrogen and alkyl; 
 R 3a  and R 3b  are independently selected from
 -hydrogen, 
 -halogen, 
 —O-alkyl, and 
 -alkyl optionally substituted with at least one group independently selected from halogen, —CN, —CF 3 , and —OH; 
 
 
           W is selected from —(CH 2 ) 1-4 —, —O—, —S(O) 0-2 —, —N(R 55 )—, and —C(O)—; 
           E is a bond or alkyl; 
           A is selected from
 -aryl optionally substituted with at least one group independently selected from R 50 , 
 -cycloalkyl optionally substituted with at least one group independently selected from R 50 , 
 -heteroaryl optionally substituted with at least one group independently selected from R 50 , and 
 -heterocycle optionally substituted with at least one group independently selected from R 50 , wherein at least one atom of the heterocycle is optionally replaced with —C(O)— and —S(O) 0-2 —; 
 wherein at least one heteroatom of the heteroaryl or heterocycle is optionally substituted with a group independently selected from —(CO) 0-1 R 215 , —(CO) 0-1 R 220 , —S(O) 0-2 R 200 , and —N(R 200 )—S(O) 0-2 R 200 ;
 R 50  is independently selected from 
  —OH, 
  -halogen, 
  —OCF 3 , 
  —NO 2 , 
  —CN, 
  —N(R)C(O)R, 
  —CO 2 —R, 
  —NH—CO 2 —R, 
  —O-(alkyl)-CO 2 H, 
  —NRR′, 
  —SR, 
  —CH 2 OH, 
  —C(O)—R 25 , 
  —C(O)NRR′, 
  —SO 2 NRR′, 
  —S(O) 1-2 R 25 , 
  -alkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , —NRR′, —OH, and —CN, 
  -cycloalkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , —NRR′, —OH, and —CN, 
  —O-alkyl optionally substituted with at least one group independently selected from —CF 3 , halogen, —O-alkyl, —OCF 3 , —NRR′, —OH, and —CN, 
  —O-benzyl optionally substituted with at least one group independently selected from —H, —OH, halogen, and alkyl, 
  —O—(CH 2 ) 0-2 —O—(CH 2 ) 1-2 —O-alkyl, and 
  —(CH 2 ) 0-2 —O—(CH 2 ) 1-2 —OH; 
 R and R′ are each independently selected from hydrogen, alkyl, —(CH 2 ) 0-2 -aryl and —(CH 2 ) 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; 
 R 25  is selected from alkyl, —(CH 2 ) 0-2 -aryl and —(CH 2 ) 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; 
 
 
           L is selected from a bond, —C(O)—, —S(O) 1-2 —, —O—, —C(R 110 )(R 112 )O—, —OC(R 110 )(R 112 )—, —N(R 110 )—, —C(O)N(R 110 )—, —N(R 110 )C(O)—, —C(R 110 )(R′)—, —C(OH)R 100 —, —SO 2 NR 110 —, —N(R 110 )SO 2 —, —N(R 110 )C(O)N(R 112 )—, —N(R 110 )C(S)N(R 112 )—, —OCO 2 —, —NCO 2 —, and —OC(O)N(R 110 )—;
 R 110  and R 112  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 —CO 2 H, —CO 2 (alkyl), —O-alkyl, —OH, —NRR′, alkyl, -haloalkyl, -alkyl-O-alkyl), aryl (optionally substituted with at least one group independently selected from R 50 ), and heteroaryl (optionally substituted with at least one group independently selected from R 50 ); 
 —(CH 2 ) 0-3 -cycloalkyl wherein cycloalkyl is optionally substituted with at least one group independently selected from —CO 2 H, —CO 2 -(alkyl), —O-alkyl, —OH, —NH 2 , haloalkyl, alkyl, -alkyl-O-alkyl, mono(alkyl)amino, di(alkyl)amino, aryl (optionally substituted with at least one group independently selected from R 50 ), and heteroaryl (optionally substituted with at least one group independently selected from R 50 ); 
 —(CRR) 1-4 -aryl wherein the aryl is optionally substituted with at least one group independently selected from R 50 , 
 —(CH 2 ) 1-4 -heteroaryl wherein the heteroaryl is optionally substituted with at least one group independently selected from R 50 , 
 —(CH 2 ) 0-4 -heterocycle, wherein the heterocycle is optionally substituted with at least one group independently selected from R 50 , and 
 —C(R 10 )(R 12 )—C(O)—NH—R 14 ;
 R 10  and R 12  are each independently selected from 
  —H, 
  -alkyl, 
  -(alkyl) 0-1 -aryl, 
  -(alkyl) 0-1 -heteroaryl, 
  -(alkyl) 0-1 -heterocycle, 
  -aryl, 
  -heteroaryl, 
  -heterocycle, 
  —(CH 2 ) 1-4 —OH, 
  —(CH 2 ) 1-4 -Z-(CH 2 ) 1-4 -aryl, and 
  —(CH 2 ) 1-4 -Z-(CH 2 ) 1-4 -heteroaryl, 
  wherein the heterocycle, aryl, and heteroaryl groups included within R 10  and R 12  are optionally substituted with at least one group independently selected from R 50 ; 
 Z is selected from —O—, —S—, and —NR 16 —; 
 R 14  is: 
  —H, 
  -alkyl, 
  -aryl, 
  -heteroaryl, 
  -heterocycle, 
  -(alkyl)-aryl, 
  -(alkyl)-heteroaryl, 
  -(alkyl)-, and 
  —(CH 2 ) 0-2 —O—(CH 2 ) 0-2 —OH; 
  wherein the heterocycle, aryl, and heteroaryl groups included within R 14  are optionally substituted with at least one group independently selected from R 50 ; 
 R 16  is selected from hydrogen and alkyl; 
 
 
         
         or 
         R 1  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 (IIf) ring may optionally be a double bond; 
 
           R 50 , R 50a , and R 50b  are independently selected from —H, halogen, —OH, —SH, —CN, —C(O)-alkyl, —NR 7 R 8 , —NO 2 , —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)—NR 7 R 8 , alkyloxy, alkoxyalkoxyalkoxy, and cycloalkyl;
 wherein the alkyl, alkoxy, and cycloalkyl groups within R 50 , R 50a , and R 50b  are optionally substituted with at least one group independently selected from alkyl, halogen, OH, NR 5 R 6 , CN, haloalkoxy, NR 7 R 8 , and alkoxy; 
 
           R 5  and R 6  are independently selected from —H and alkyl, or 
           R 5  and R 6 , and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and 
           R 7  and R 8  are independently selected from —H, alkyl optionally substituted with at least one group independently selected from —OH, —NH 2 , and halogen, -cycloalkyl, and -alkyl-O-alkyl; 
         
         R 2  is selected from
 —H, 
 -alkyl optionally substituted with at least one group independently selected from R 200 , 
 —OH, 
 —O-alkyl optionally substituted with at least one group independently selected from R 200 , 
 —O-aryl optionally substituted with at least one group independently selected from R 200 , 
 —NH-alkyl optionally substituted with at least one group independently selected from R 200 , 
 -heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —(CR 245 R 250 )—, —O—, —C(O)—, —C(O)C(O)—, —N(R 200 ) 0-2 —, and —S(O) 0-2 —, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R 200 ), 
 —NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —(CR 245 R 250 )—, —O—, —C(O)—, —C(O)C(O)—, —N(R 200 ) 0-2 —, and —S(O) 0-2 —, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R 200 , 
 —C(O)—N(R 315 )(R 320 ), wherein R 315  and R 320  are each independently selected from —H, alkyl, and aryl, 
 —NH—R 400 , 
 —R 400 , 
 —NH—R 500 , 
 —R 500 , 
 —NH—R 600 , 
 —R 600 , and 
 —R 700 ; 
 
         R 400  is 
       
       
         
           
           
               
               
           
         
         
           wherein R 405  is selected from —H, —N(R 515 ) 2  and O-alkyl; 
         
         R 500  is a heteroaryl selected from (IIa) and (IIb) 
       
       
         
           
           
               
               
           
         
         
           wherein 
           M 1  and M 4  are independently selected from
 —C(R 505 )—, 
 —N—, 
 —N(R 515 )—, 
 —S—, and 
 —O—; 
 
           M 2  and M 3  are independently selected from
 —C(R 510 )—, 
 —N(R 520 ) 0-1 —, 
 —S—, and 
 —O—; 
 
           M 5  is selected from —C— and —N—; 
           R 505  is independently selected from:
 H, 
 -alkyl, 
 -halogen, 
 —NO 2 , 
 —CN, 
 R 200 , and 
 -aryl; 
 
           R 510  is independently selected from
 —H, 
 -alkyl, 
 -halogen, 
 -amino, 
 —CF 3 , 
 R 200 , and 
 -aryl; 
 
           R 515  is independently selected from
 —H, 
 -alkyl; and 
 -aryl; 
 
           R 520  is independently selected from
 —H, 
 -alkyl, 
 —(CH 2 ) 0-2 -aryl, and 
 —C(Ph) 3 ; 
 
           R 600  is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from —R 605 ; 
           R 605  is selected from —H, -halogen, -alkyl, -aryl, —CO 2 -alkyl, —NO 2 , —CN, —NH 2 , —NR 220 R 225 , -thioalkyl, —CF 3 , —OH, —O-alkyl, and -heterocycloalkyl; 
           R 700  is aryl optionally substituted with at least one —R 205 ; 
         
         R C  is selected from formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf) 
       
       
         
           
           
               
               
           
         
         
           wherein, 
           A 1  and A 2  are independently selected from —(CH 2 ) 0-2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —NH—, —NR 220 —, —C(═N—R 230 )—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           A 3 , A 4 , A 5 , and A 6  are independently selected from —CH 2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S(O) 0-2 —, —NH—, —NR 220 —, —N(CO) 0-1 R 200 —, —N(S(O 2 )alkyl)-, —C(═N—R 230 )—, —C(═N—NH(alkyl))-, —C(═N—N(alkyl)(alkyl))-, —C(═N—O—(CH 2 ) 1-4 —OH)—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           R 230  is independently selected from —H, —OH, R 215  (optionally substituted with —OH, —NH 2 , —C(O)H, and —CN), alkyl, cycloalkyl, alkoxy, -alkyl-OH, -alkyl-NH 2 , -alkyl-C(O)H, —O—R 215  (optionally substituted with —OH, —NH 2 , —C(O)H, and —CN), —O-alkyl, —O-alkyl-OH, —O-alkyl-NH 2 , —O-alkyl-C(O)H, —NH 2 , —NHR 215 , —N(R 215 ) 2 , —NR 235 R 240 , and —CN;
 wherein at least one carbon of the alkyl or cycloalkyl within R 230  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 A 1 , A 2 , A 3 , A 4 , or A 5  is selected from —C(═N—R 230 )—, —C(═N—NH(alkyl))-, —C(═N—N(alkyl)(alkyl))-, C(═N—O—(CH 2 ) 1-4 —OH)—, —C(═CH—R 230 )—, —C(═N—C(O)—R 230 )—, and —C(═CH—C(O)—R 230 )—; 
           wherein in formulae (IIIe) and (IIIf), when A 1 , A 2 , and A 6  are selected from —(CH 2 ) 0-2 —, —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S(O) 0-2 —, —NH—, —NR 220 —, —N(CO) 0-1 R 200 —, and —N(S(O 2 )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 R 200 ; 
           wherein each cycloalkyl or heterocycloalkyl attached directly or indirectly to R C  is optionally substituted with at least one group independently selected from R 210 ; 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 R 200 ; 
 wherein each cycloalkyl or heterocycloalkyl of R X  is optionally substituted with at least one group independently selected from R 210 ; 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) 0-1 R 215 —, 
 —N(CO) 0-1 R 220 —, 
 —O—, 
 —C(O)—, 
 —S(O) 0-2 —, and 
 —NS(O) 0-2 R 200 ; 
 
           R 200  at each occurrence is independently selected from
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 —OH, 
 —NO 2 , 
 -halogen, 
 —CN, 
 —(CH 2 ) 0-4 —C(O)H, 
 —(CO) 0-1 R 215 , 
 —(CO) 0-1 R 220 , 
 —(CH 2 ) 0-4 —(CO) 0-1 —NR 220 R 225 , 
 —(CH 2 ) 0-4 —(CO) 0-1 —NH(R 215 ), 
 —(CH 2 ) 0-4 —C(O)-alkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -cycloalkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -heterocycloalkyl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -aryl, 
 —(CH 2 ) 0-4 —(CO) 0-1 -heteroaryl, 
 —(CH 2 ) 0-4 —C(O)—O—R 215 , 
 —(CH 2 ) 0-4 —S(O) 0-2 -alkyl, 
 —(CH 2 ) 0-4 —S(O) 0-2 -cycloalkyl, 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—O—R 215 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 220 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—N(R 215 ) 2 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—R 220 , 
 —(CH 2 ) 0-4 —O—C(O)-alkyl, 
 —(CH 2 ) 0-4 —O—(R 215 ), 
 —(CH 2 ) 0-4 —S—(R 215 ), 
 —(CH 2 ) 0-4 —O-alkyl optionally substituted with at least one halogen, and 
 -adamantane; 
 wherein each aryl and heteroaryl group included within R 200  is optionally substituted with at least one group independently selected from R 205 , R 210 , and alkyl (optionally substituted with at least one group independently selected from R 205  and R 210 ); 
 wherein each cycloalkyl or heterocycloalkyl group included within R 200  is optionally substituted with at least one group independently selected from R 210 ; 
 
           R 205  at each occurrence is independently selected from
 -alkyl, 
 -haloalkoxy, 
 —(CH 2 ) 0-3 -cycloalkyl, 
 -halogen, 
 —(CH 2 ) 1-6 —OH, 
 —O-aryl, 
 —OH, 
 —SH, 
 —(CH 2 ) 0-4 —C(O)H, 
 —(CH 2 ) 0-6 —CN, 
 —(CH 2 ) 0-6 —C(O)—NR 235 R 240 , 
 —(CH 2 ) 0-6 —C(O)—R 235 , 
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 235 , 
 —OCF 3 , 
 —CF 3 , 
 -alkoxy, 
 -alkoxycarbonyl, and 
 
           —NR 235 R 240 ; R 210  at each occurrence is independently selected from
 —(CH 2 ) 0-4 —OH, 
 —(CH 2 ) 0-4 —CN, 
 —(CH 2 ) 0-4 —C(O)H, 
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 -alkanoyl, 
 —S-alkyl; 
 —S(O) 2 -alkyl, 
 -halogen, 
 -alkoxy, 
 -haloalkoxy, 
 —NR 220 R 225 , 
 -cycloalkyl optionally substituted with at least one group independently selected from R 205 , 
 -heterocycloalkyl, 
 -heteroaryl, 
 —(CH 2 ) 0-4 —NR 235 R 240 , 
 —(CH 2 ) 0-4 —NR 235 (alkoxy), 
 —(CH 2 ) 0-4 —S—(R 215 ), 
 —(CH 2 ) 0-4 —NR 235 —C(O)H, 
 —(CH 2 ) 0-4 —NR 235 —C(O)-(alkoxy), 
 —(CH 2 ) 0-4 —NR 235 —C(O)—R 240 , 
 —C(O)—NHR 215 , 
 —C(O)-alkyl, 
 —C(O)—NR 235 R 240 , and 
 —S(O) 2 —NR 235 R 240 ; 
 
           R 215  at each occurrence is independently selected from
 -alkyl, 
 —(CH 2 ) 0-2 -aryl, 
 —(CH 2 ) 0-2 -cycloalkyl, 
 —(CH 2 ) 0-2 -heteroaryl, 
 —(CH 2 ) 0-2 -heterocycloalkyl, and 
 —CO 2 —CH 2 -aryl; 
 wherein the aryl group included within R 215  is optionally substituted with at least one group independently selected from R 205  and R 210 , and 
 
           wherein the heterocycloalkyl and heteroaryl groups included within R 215  are optionally substituted with at least one group independently selected from R 210 ; R 220  and R 225  at each occurrence are independently selected from
 —H, 
 -alkyl, 
 —(CH 2 ) 0-4 —C(O)H, 
 -alkylhydroxyl, 
 -alkoxycarbonyl, 
 -alkylamino, 
 —S(O) 2 -alkyl, 
 -alkanoyl optionally substituted with at least one halogen, 
 —C(O)—NH 2 , 
 —C(O)—NH(alkyl), 
 —C(O)—N(alkyl)(alkyl), 
 -haloalkyl, 
 —(CH 2 ) 0-2 -cycloalkyl, 
 -(alkyl)-O-(alkyl), 
 -aryl, 
 -heteroaryl, and 
 -heterocycloalkyl;
 wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups included within R 220  and R 225  are each optionally substituted with at least one group independently selected from R 270 ; 
 
 
           R 270  at each occurrence is independently selected from
 —R 205 , 
 -alkyl optionally substituted with at least one group independently selected from R 205 , 
 -aryl, 
 -halogen, 
 -alkoxy, 
 -haloalkoxy, 
 —NR 235 R 240 , 
 —OH, 
 —CN, 
 -cycloalkyl optionally substituted with at least one group independently selected from R 205 , 
 —C(O)-alkyl, 
 —S(O) 2 —NR 235 R 240 , 
 —C(O)—NR 235 R 240 , 
 —S(O) 2 -alkyl, and 
 —(CH 2 ) 0-4 —C(O)H; 
 
           R 235  and R 240  at each occurrence are independently selected from
 —H, 
 —OH, 
 —CF 3 , 
 —OCH 3 , 
 —NHCH 3 , 
 —N(CH 3 ) 2 , 
 —(CH 2 ) 0-4 —C(O)(H or alkyl), 
 -alkyl, 
 -alkanoyl, 
 —SO 2 -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, -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-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-(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-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-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-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-(1H-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. 
     
     
         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 R 1 , R 2  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, wherein R 1 , R 2  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 R 1 , R 2  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 R 1 , R 2  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 R 1 , R 2  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 R 1 , R 2  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 R 1 , R 2  and R c  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 R 1 , R 2  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 R 1 , R 2  and R C  are as defined in  claim 11 , and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S 1 , S 1 ′, and S 2 ′. 
     
     
         25 . A method of modifying the pharmacokinetic parameters of a pharmaceutical composition comprising at least one compound of formula (I) wherein R 1 , R 2  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 R 1 , R 2 , and R C  are defined as in  claim 11 .