Substituted hydroxyethylamine aspartyl protease inhibitors

Abstract

The invention relates to novel compounds and also to methods of treating at least one disease, disorder, or condition associated with amyloidosis using such compounds. 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 a pharmaceutically acceptable salt thereof, wherein  
     R 1  is selected from  
     
       
         
         
             
             
         
       
       wherein  
       X, Y, and Z are independently, selected from 
 —C(H) 0-2 —,  
 —O—,  
 —C(O)—,  
 —NH—, and  
 —N—,  
 wherein at least one bond of the (IIf) ring may optionally be a double bond;  
 
       L is selected from 
 —O—,  
 —SO 2 —,  
 —C(O)—,  
 —C(R 55 )(R 60 )—, and  
 —CH(NR 55 R 60 )—;  
 
       R 55  and R 60  are each independently selected from hydrogen and alkyl;  
       R 50 , R 50a , and R 50b  are independently selected from 
 —H,  
 -halogen,  
 —OH,  
 —C(O)H,  
 —C(O)CH 3 ,  
 —CH 2 OH,  
 —SH,  
 —S(O) 0-2 CH 3 ,  
 —CN,  
 —NO 2 ,  
 —NH 2 ,  
 —NHCH 3 ,  
 —N(CH 3 ) 2    
 —C 1 -C 2  alkyl,  
 —OCH 3 ,  
 —OCF 3 , and  
 —CF 3 ;  
 R 2  is selected from  
 
       —H, 
 wherein when R 1  is benzyl, and R C  is 6-Isopropyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not —H;  
 wherein, when R 1  is 3,5-difluorobenzyl, and R C  is 6-Ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not —H;  
 wherein when R 1  is 3,5-difluorobenzyl, and R C  is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R 2  is not —H;  
 
       —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 ;  
       -alkyl, 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 ) 0-1 —, 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 phenyl,  
 wherein when R 1  is 3,5-difluorobenzyl, and R C  is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R 2  is not methylcarbamoyl;  
 
       —O—C(O)—N(R 315 )(R 320 ),  
       —NH—R 400 ,  
       —R 400 ,  
       —NH—R 500 ,  
       —R 500    
       —NH—R 600 ,  
       —R 600 , and  
       —NH—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 III(a) and III(b),  
       
         
           
           
               
               
           
         
       
       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—,  
 —N(R 520 )—,  
 —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  
 phenyl;  
 
       R 510  is independently selected from 
 —H,  
 -alkyl,  
 -halogen,  
 -amino,  
 —CF 3 ,  
 —R 200 , and  
 -phenyl;  
 
       R 515  is independently selected from 
 —H,  
 -alkyl, and  
 -phenyl;  
 
       R 520  is independently selected from 
 —H,  
 -alkyl,  
 —(CH 2 ) 0-2 -phenyl, 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 -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—C(O)—, -nitro, —CN, -amino, —NR 220 R 225 , -thioalkyl, —CF 3 , —OH, —O-alkyl, and -heterocycloalkyl;  
       wherein when R 1  is 3,5-difluoro-benzyl, and R C  is 6-ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;  
       wherein when R 1  is 3,5-difluoro-benzyl, and R C  is 3-methoxy-benzyl, R 2  is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino; or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;  
       R 700  is aryl optionally substituted with at least one R 205 ;  
       R C  is selected from  
       —(CH 2 ) 0-3 -cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —R 205  and —CO 2 -(alkyl),  
       -alkyl optionally substituted with at least one group independently selected from R 205 ,  
       —(CR 245 R 250 ) 0-4 —R X , wherein at least one —(CR 245 R 256 )— is optionally replaced with a group independently selected from —O—, —N(R 215 )—, —C(O) 12 —, —C(O)N(R 215 )—, and —S(O) 0-2 —, and  
       -formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);  
       R X  is selected from  
       -hydrogen,  
       -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 attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is optionally substituted with at least one group independently selected from R 200 ;  
       wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is optionally substituted with at least one group independently selected from R 210  and —(CR 245 R 250 ) 0-4 —R 200 ;  
       wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is independently optionally replaced with a group selected from —O—, —C(O)—, —N(R 215 ) 0-1 —, and —S(O) 0-2 —;  
       wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is independently optionally substituted with a group 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 245  and R 250  at each occurrence are independently selected from  
 
       —H,  
       —(CH 2 ) 0-4 C(O)—OH,  
       —(CH 2 ) 0-4 C(O)—O-alkyl,  
       —(CH 2 ) 0-4 C(O)-alkyl,  
       -alkyl,  
       -hydroxyalkyl,  
       —O-alkyl,  
       -haloalkoxy,  
       —(CH 2 ) 0-4 -cycloalkyl,  
       —(CH 2 ) 0-4 -aryl,  
       —(CH 2 ) 0-4 -heteroaryl, and  
       —(CH 2 ) 0-4 -heterocycloalkyl; or  
       R 245  and R 250  are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,  
       wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond,  
       wherein the bicyclic ring system is optionally a fused or spiro ring system,  
       wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from 
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —C(═N—R 255 )—,  
 —N—,  
 —NR 220 —,  
 —N((CO) 0-1 R 200 )—, and  
 —N(SO 2 R 200 )—;  
 
       wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R 245  and R 250  are optionally substituted with at least one group independently selected from -halogen, -alkyl, —N(R 220 )(R 225 ), —CN, and —OH;  
       wherein the monocyclic and bicyclic groups included in R 245  and R 250  are optionally substituted with at least one group independently selected from halogen, —(CH 2 ) 0-2 —OH, —O-alkyl, alkyl, —(CH 2 ) 0-2 —S-alkyl, —CF 3 , aryl, —N(R 220 )(R 225 ), —CN, —(CH 2 ) 0-2 —NH 2 , —(CH 2 ) 0-2 —NH(alkyl), —NHOH, —NH—O—alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O 2 )-alkyl;  
       formula (IVa) is  
       
         
           
           
               
               
           
         
       
       wherein Q 1  is selected from (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, and —C(O)—;  
       Q 2  and Q 3  each are independently selected from (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S—, —S(O) 2 —, —NH—, and —N(R 7 )—;  
       Q 4  is selected from a bond, (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S—, —S(O) 2 —, —NH—, and —N(R 7 ); and  
       P 1 , P 2 , P 3 , and P 4  each are independently selected from —CH—, —C(R 200 )—, and —N—;  
       formula (IVb) is  
       
         
           
           
               
               
           
         
       
       wherein R 4  is selected from —H and -alkyl, and  
       P 1 , P 2 , P 3 , and P 4  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—;  
       formula (IVc) is  
       
         
           
           
               
               
           
         
       
       wherein R 4  is selected from —H and -alkyl; and  
       P 1 , P 2 , P 3 , and P 4  at each occurrence are independently selected from —CH—, —CR 200 —, and —N—;  
       formula (IVd) is  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1, 2, 3, 4, 5, or 6;  
       Y′ is selected from —H, —CN, —OH, —O-alkyl, —CO 2 H, —C(O)OR 215 , -amino, -aryl, and -heteroaryl; and  
       P 1  and P 2  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—, 
 or P 1  and P 2  are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,  
 
       P 3  and P 4  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—, 
 or P 3  and P 4  are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,  
 
       P 5  at each occurrence is independently selected from —CH—, —C(R 200 )—, and —N—, 
 wherein at least one bond in the monocyclic or bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally a double bond,  
 wherein the bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally a fused or spiro ring system,  
 wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally replaced by a group independently selected from 
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —C(═N—R 255 )—,  
 —N—,  
 —NR 220 —,  
 —N((CO) 0-1 R 200 )—, and  
 —N(SO 2 R 200 )—; and  
 
 
       P 5  at each occurrence is independently selected from —CH—, —C(R 200 )—, and —N—,  
       formula (IVe) is  
       
         
           
           
               
               
           
         
       
       wherein  
       U is selected from —CH 2 —CR 100 R 101 —, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —N(R 100 )—, —CH 2 —C(O)—, —CH 2 —O—, —C(O)—C(R 100 )(R 101 )—, —SO 2 —N(R 100 )—, —C(O)—N(R 55 )—, —N(R 55 )—C(O)—N(R 55 )—, —O—C(O)—O—, —N(R 55 )—C(O)—O—, and —C(O)—O—; 
 wherein R 100  and R 101  at each occurrence are independently selected from —H, -alkyl, -aryl, —C(O)-alkyl, —(CO) 0-1 R 215 , —(CO) 0-1 R 220 , and —S(O) 2 -alkyl;  
 formula (IVf) is  
                     
 
       wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, —N(R 5 )C(O)H, —C(O)H, —C(O)N(R 5 )(R 6 ), —NR 5 R 6 , R 280 , R 285 , -aryl, and -heteroaryl;  
       wherein R 280  and R 285 , and the carbon to which they are attached form a C 3 -C 7  spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, -halogen, —CF 3 , and —CN;  
       wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R 290  and R 295 ;  
       wherein R 290  and R 295  at each occurrence are independently selected from 
 -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —OH,  
 —NO 2 ,  
 -halogen,  
 —CO 2 H,  
 —CN,  
 —(CH 2 ) 0-4 —C(O)—NR 21 R 22 ,  
 —(CH 2 ) 0-4 —CO 2 R 20 ,  
 —(CH 2 ) 0-4 —SO 2 —NR 21 R 22 ,  
 —(CH 2 ) 0-4 —S(O)-(alkyl),  
 —(CH 2 ) 0-4 —S(O) 2 -(alkyl),  
 —(CH 2 ) 0-4 —S(O) 2 -(cycloalkyl),  
 —(CH 2 ) 0-4 —N(H or R 20 )—C(O)—O—R 20 ,  
 —(CH 2 ) 0-4 —N(H or R 20 )—C(O)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —N—C(S)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —N(H or R 20 )—CO—R 21 ,  
 —(CH 2 ) 0-4 —NR 21 R 22 ,  
 —(CH 2 ) 0-4 —R 11 ,  
 —(CH 2 ) 0-4 —O—C(O)-(alkyl),  
 —(CH 2 ) 0-4 —O—P(O)—(OR 5 ) 2 ,  
 —(CH 2 ) 0-4 —O—C(O)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—C(S)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—(R 20 )—CO 2 H,  
 —(CH 2 ) 0-4 —S—(R 20 ),  
 —(CH 2 ) 0-4 —O-(alkyl optionally substituted with at least one halogen),  
 -cycloalkyl,  
 —(CH 2 ) 0-4 —N(H or R 20 )—S(O) 2 —R 21 , and  
 —(CH 2 ) 0-4 -cycloalkyl;  
 formula (IVg) is  
                     
 
       wherein  
       a is 0 or 1;  
       b is 0 or 1;  
       S′ is selected from —C(O)— and —CO 2 —;  
       T′ is —(CH 2 ) 0-4 —;  
       U′ is —(CR 245 R 250 )—;  
       V′ is selected from -aryl- and -heteroaryl-;  
       W′ is selected from 
 -a bond,  
 -alkyl-substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —(CO) 0-1 —N(R 220 )—,  
 —(CH 2 ) 0-4 -(CO) 0-1 —,  
 —(CH 2 ) 0-4 —CO 2 —,  
 —(CH 2 ) 0-4 —SO 2 —N(R 220 )—,  
 —(CH 2 ) 0-4 —N(H or R 215 )—CO 2 —,  
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —,  
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—N(R 215 )—,  
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—,  
 —(CH 2 ) 0-4 —N(R 220 )—,  
 —(CH 2 ) 0-4 —O—, and  
 —(CH 2 ) 0-4 —S—;  
 
       X′ is selected from aryl and heteroaryl;  
       wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R 205 ;  
       wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R 200 ;  
       wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from 
 —(CO) 0-1 R 215 ,  
 —(CO) 0-1 R 220 , and  
 —S(O) 0-2 R 200 ;  
 
       R 21  and R 22  each independently are selected from 
 —H,  
 -alkyl optionally substituted with at least one group independently selected from —OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —R 17 , and —R 18 ,  
 —(CH 2 ) 0-4 —C(O)-(alkyl),  
 —(CH 2 ) 0-4 —C(O)-(cycloalkyl),  
 —(CH 2 ) 0-4 —C(O)—R 17 ,  
 —(CH 2 ) 0-4 —C(O)—R 18 ,  
 —(CH 2 ) 0-4 —C(O)—R 19 , and  
 —(CH 2 ) 0-4 —C(O)—R 11 ;  
 
       R 17  at each occurrence is aryl optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —NR 5 R 6 , —CN, —CF 3 , and —O-alkyl,  
 -halogen,  
 —O-alkyl optionally substituted with at least one group independently selected from halogen, —NR 21 R 22 , —OH, —CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —C(O)-(alkyl),  
 —S(O)—O—NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
 
       R 18  at each occurrence is heteroaryl optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 -halogen,  
 —O-alkyl optionally substituted with at least one group independently selected from -halogen, —NR 21 R 22 , —OH, and —CN,  
 -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —C(O)-(alkyl),  
 —S(O) 2 —NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
 
       R 19  at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —C(O)—, —S(O)—, and —S(O) 2 —, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 -halogen,  
 —O-alkyl optionally substituted with at least one group independently selected from -halogen, —OH, —CN, —NR 21 R 22 , and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —C(O)-(alkyl),  
 —S(O) 2 —NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
 
       R 11  at each occurrence is heterocycloalkyl 
 wherein at least one carbon of the heterocycloalkyl is optionally replaced with —C(O)—, —S(O)—, and —S(O) 2 —,  
 wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, and -halogen;  
 
       R 20  is selected from -alkyl, -cycloalkyl, —(CH 2 ) 0-2 —(R 17 ), and —(CH 2 ) 0-2 —(R 18 );  
       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 ,  
 —NH 2 ,  
 -halogen,  
 —CN,  
 —CF 3 ,  
 —OCF 3 ,  
 —(CH 2 ) 0-4 —C(O)H,  
 —(CO) 0-1 R 215 ,  
 —(CO) 0-1 R 220 ,  
 —(CH 2 ) 0-4 —C(O)—NR 220 R 225 ,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 —R 215 ,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 —R 220 ,  
 —(CH 2 ) 0-4 —C(O)-alkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -cycloalkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -heterocycloalkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -aryl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -heteroaryl,  
 —(CH 2 ) 0-4 —C(O)—O—R 215 ,  
 —(CH 2 ) 0-4 —S(O) 0-2 —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 )—S(O) 1-2 —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 —NR 220 R 225 ,  
 —(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 —C(O)H,  
 —(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 205 ,  
 —R 210 , and  
 -alkyl optionally substituted with at least one group independently selected from R 205  and R 210 ;  
 
 
       R 205  at each occurrence is independently selected from 
 -alkyl,  
 -heteroaryl,  
 -heterocycloalkyl,  
 -aryl,  
 -haloalkoxy,  
 —(CH 2 ) 0-3 -cycloalkyl,  
 -halogen,  
 —(CH 2 ) 0-6 —OH,  
 —O-phenyl,  
 —SH,  
 —(CH 2 ) 0-4 —C(O)CH 3    
 —(CH 2 ) 0-4 —C(O)H  
 —(CH 2 ) 0-4 —CO 2 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 ,  
 —CF 3 ,  
 —CN,  
 —OCF 3 ,  
 —C(O) 2 -benzyl,  
 —O-alkyl,  
 —C(O) 2 -alkyl, and  
 —NR 235 R 240 ;  
 
       R 210  at each occurrence is independently selected from 
 —OH,  
 —CN,  
 —(CH 2 ) 0-4 —C(O)H,  
 -alkyl wherein a carbon atom is optionally replaced with —C(O)—, and a carbon atom is optionally substituted with at least one group independently selected from R 205 ,  
 —S-alkyl,  
 -halogen,  
 —O-alkyl,  
 -haloalkoxy,  
 —NR 220 R 225 ,  
 -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 , and  
 —S(O) 2 -alkyl;  
 
       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, and  
 —(CH 2 ) 0-2 -heterocycloalkyl;  
 wherein the aryl groups included within R 215  are optionally substituted with at least one group independently selected from R 205  or R 210 ;  
 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,  
 —OH,  
 -alkyl,  
 —(CH 2 ) 0-4 —C(O)H,  
 -alkyl-OH,  
 —(CH 2 ) 0-4 —CO 2 -alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 -aminoalkyl,  
 —S(O) 2 -alkyl,  
 —(CH 2 ) 0-4 —C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —C(O)—NH 2 ,  
 —(CH 2 ) 0-4 —C(O)—NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —C(O)—N(alkyl)(alkyl),  
 -haloalkyl,  
 —(CH 2 ) 0-2 -cycloalkyl,  
 -alkyl-O-alkyl,  
 —O-alkyl,  
 -aryl,  
 -heteroaryl, and  
 -heterocycloalkyl;  
 wherein the aryl, heteroaryl 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 ,  
 -phenyl,  
 -halogen,  
 —O-alkyl,  
 -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 ,  
 —CO—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,  
 
       -alkyl, 
 —C(O)-alkyl,  
 —OH,  
 —CF 3 ,  
 —OCH 3 ,  
 —NH—CH 3 ,  
 —N(CH 3 ) 2 ,  
 —(CH 2 ) 0-4 —C(O)—(H or alkyl),  
 —SO 2 -alkyl, and  
 -phenyl;  
 
       R 255  is selected from -hydrogen, —OH, —N(R 220 )(R 225 ), and —O-alkyl;  
       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  is independently selected from 
 —H,  
 -alkyl optionally substituted with at least one group independently selected from —OH, amino, and halogen,  
 -cycloalkyl, and  
 -alkyl-O-alkyl.  
 
     
   
   
       2 . The compound according to  claim 1 , wherein R 1  is selected from —CH 2 -phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —C 1 -C 2  alkyl, —O-methyl, and —OH.  
   
   
       3 . The compound according to  claim 1 , wherein R 1  is selected from 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 C  is —C(R 245 )(R 250 )—R X wherein R 245  and R 250  are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one atom within the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from 
 —O—,    —C(O)—,    —S(O) 0-2 —,    —C(═N—R 255 )—,    —N—,    —NR 220 —,    —N((CO) 0-1 R 200 )—, and    —N(SO 2 R 200 )—; and    wherein the monocyclic or bicyclic groups included within R 245  and R 250  are optionally substituted with at least one group independently selected from halogen, —(CH 2 ) 0-2 —OH, —(CH 2 ) 0-2 —S-alkyl, —CF 3 , —O-alkyl, alkyl, aryl, —N(R 220 )(R 225 ), —CN, —(CH 2 ) 0-2 —NH 2 , —(CH 2 ) 0-2 —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O 2 )-alkyl; and wherein R X , R 220 , R 225 , R 255 , and R 200  are as defined in  claim 1 .    
   
   
       5 . The compound according to  claim 1 , wherein R C  is selected from formulae (Va), (Vb), (Vc), and (Vd),  
     
       
         
         
             
             
         
       
       wherein,  
       A, B, and C are independently selected from 
 —CH 2 —,  
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —N((CO) 0-1 R 200 )—,  
 —N(SO 2 R 200 )—,  
 —C(═N—R 255 )—, and  
 —N(R 220 )—;  
 
       A′ at each occurence is independently selected from —CH 2 — and —O—; 
 wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, —(CH 2 ) 0-2 —OH, —(CH 2 ) 0-2 —S-alkyl, —CF 3 , —CN, -halogen, —(CH 2 ) 0-2 —NH 2 , —(CH 2 ) 0-2 —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH—heteroaryl, —NH—C(O)-alkyl, and —NHS( 0-2 )-alkyl; and  
 
       R X , R 220 , R 255 , and R 200  are as defined in  claim 1 .  
     
   
   
       6 . The compound according to  claim 1 , wherein R C  is selected from formulae (VIa) and (VIb)  
     
       
         
         
             
             
         
       
     
     wherein at least one carbon of the heterocycloalkyl of formula (VIa) and the cycloalkyl of formula (VIb) is optionally replaced with a group independently selected from —O—, —SO 2 —, and —C(O)—, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group independently selected from R 205 , R 245 , and R 250 , wherein R 100 , R 200 , R 205 , R 245 , and R 250  are as defined in  claim 1 .  
   
   
       7 . The compound according to  claim 1 , wherein R C  is selected from 6-isobutyl-1,1-dioxo-1λ 6 -thiochroman-4-yl, 6-Isopropyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.  
   
   
       8 . The compound according to  claim 1 , wherein R 2  is selected from hydrogen, 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.  
   
   
       9 . The compound according to  claim 2 , 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-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, and 6-tert-Butyl-pyrimidin-4-yl.  
   
   
       10 . A method of preventing or treating at least one condition which benefits from inhibition of at least one aspartyl-protease, comprising: 
 administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I),                          or pharmaceutically acceptable salts thereof, wherein    R 1  is selected from                          wherein    X, Y, and Z are independently, selected from —C(H) 0-2 —, 
 —O—,  
 —C(O)—,  
 —NH—, and  
 —N—,  
 wherein at least one bond of the (IIf) ring may optionally be a double bond;  
   L is selected from 
 —O—,  
 —SO 2 —,  
 —C(O)—,  
 —C(R 55 )(R 60 )—, and  
 —CH(N R 55 R 60 )—;  
   R 55  and R 60  are each independently selected from hydrogen and alkyl;    R 50 , R 50a , and R 50b  are independently selected from 
 —H,  
 -halogen,  
 —OH,  
 —C(O)H,  
 —C(O)CH 3 ,  
 —CH 2 O,  
 —SH,  
 —S(O) 0-2 CH 3 ,  
 —CN,  
 —NO 2 ,  
 —NH 2 ,  
 —NHCH 3 ,  
 —N(CH 3 ) 2    
 —C 1 -C 2  alkyl,  
 —OCH 3 ,  
 —OCF 3 , and  
 —CF 3 ;  
 R 2  is selected from  
   —H, 
 wherein when R 1  is benzyl, and R C  is 6-Isopropyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not —H;  
 wherein, when R 1  is 3,5-difluorobenzyl, and R C  is 6-Ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not —H;  
 wherein when R 1  is 3,5-difluorobenzyl, and R C  is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R 2  is not —H;  
   —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 ;    -alkyl, 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 ) 0-1 —, 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 phenyl,  
 wherein when R 1  is 3,5-difluorobenzyl, and R C  is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R 2  is not methylcarbamoyl;  
   —O—C(O)—N(R 315 )(R 320 ),    —NH—R 400 ,    —R 400 ,    —NH—R 500 ,    —R 500      —NH—R 600 ,    —R 600 , and    —NH—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 III(a) and III(b),                          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—,  
 —N(R 520 )—,  
 —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  
 phenyl;  
   R 510  is independently selected from 
 —H,  
 -alkyl,  
 -halogen,  
 -amino,  
 —CF 3 ,  
 —R 200 , and  
 -phenyl;  
   R 515  is independently selected from 
 —H,  
 -alkyl, and  
 -phenyl;  
   R 520  is independently selected from 
 —H,  
 -alkyl,  
 —(CH 2 ) 0-2 -phenyl, 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 -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—C(O)—, -nitro, —CN, -amino, —NR 220 R 225 , -thioalkyl, —CF 3 , —OH, —O-alkyl, and -heterocycloalkyl;    wherein when R 1  is 3,5-difluoro-benzyl, and R C  is 6-ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, R 2  is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;    wherein when R 1  is 3,5-difluoro-benzyl, and R C  is 3-methoxy-benzyl, R 2  is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino; or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;    R 700  is aryl optionally substituted with at least one R 205 ;    R C  is selected from    —(CH 2 ) 0-3 -cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —R 205  and —CO 2 -(alkyl),    -alkyl optionally substituted with at least one group independently selected from R 205 ,    —(CR 245 R 250 ) 0-4 —R X , wherein at least one —(CR 245 R 250 )— is optionally replaced with a group independently selected from —O—, —N(R 215 )—, —C(O) 1-2 —, —C(O)N(R 215 )—, and —S(O) 0-2 —, and    -formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);    R X  is selected from    -hydrogen,    -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 attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is optionally substituted with at least one group independently selected from R 200 ;    wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is optionally substituted with at least one group independently selected from R 210  and —(CR 245 R 250 ) 0-4 —R 200 ;    wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is independently optionally replaced with a group selected from —O—, —C(O)—, —N(R 215 ) 0-1 —, and —S(O) 0-2 —;    wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR 245 R 250 ) 0-4 — is independently optionally substituted with a group 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 245  and R 250  at each occurrence are independently selected from  
   —H,    —(CH 2 ) 0-4 C(O)—OH,    —(CH 2 ) 0-4 C(O)—O-alkyl,    —(CH 2 ) 0-4 C(O)-alkyl,    -alkyl,    -hydroxyalkyl,    —O-alkyl,    -haloalkoxy,    —(CH 2 ) 0-4 -cycloalkyl,    —(CH 2 ) 0-4 -aryl,    —(CH 2 ) 0-4 -heteroaryl, and    —(CH 2 ) 0-4 -heterocycloalkyl; or    R 245  and R 250  are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,    wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond,    wherein the bicyclic ring system is optionally a fused or spiro ring system,    wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from 
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —C(═N—R 255 )—,  
 —N—,  
 —NR 220 —,  
 —N((CO) 0-1 R 200 )—, and  
 —N(SO 2 R 200 )—;  
   wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R 245  and R 250  are optionally substituted with at least one group independently selected from -halogen, -alkyl, —N(R 220 )(R 225 ), —CN, and —OH;    wherein the monocyclic and bicyclic groups included in R 245  and R 250  are optionally substituted with at least one group independently selected from halogen, —(CH 2 ) 0-2 —OH, —O-alkyl, alkyl, —(CH 2 ) 0-2 —S-alkyl, —CF 3 , aryl, N(R 220 )(R22 5 ), —CN, —(CH 2 ) 0-2 —NH 2 , —(CH 2 ) 0-2 —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH—C(O)-alkyl, and —NHS(O 2 )-alkyl;    formula (IVa) is                          wherein Q 1  is selected from (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, and —C(O)—;    Q 2  and Q 3  each are independently selected from (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S—, —S(O) 2 —, —NH—, and —N(R 7 )—;    Q 4  is selected from a bond, (—CH 2 —) 0-1 , —CH(R 200 )—, —C(R 200 ) 2 —, —O—, —C(O)—, —S—, —S(O) 2 —, —NH—, and —N(R 7 ); and    P 1 , P 2 , P 3 , and P 4  each are independently selected from —CH—, —C(R 200 )—, and —N—;    formula (IVb) is                          wherein R 4  is selected from —H and -alkyl, and    P 1 , P 2 , P 3 , and P 4  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—;    formula (IVc) is                          wherein R 4  is selected from —H and -alkyl; and    P 1 , P 2 , P 3 , and P 4  at each occurrence are independently selected from —CH—, —CR 200 —, and —N—;    formula (IVd) is                          wherein m is 0, 1, 2, 3, 4, 5, or 6;    Y′ is selected from —H, —CN, —OH, —O-alkyl, —CO 2 H, —C(O)OR 215 , -amino, -aryl, and -heteroaryl; and    P 1  and P 2  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—, 
 or P 1  and P 2  are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,  
   P 3  and P 4  at each occurrence are independently selected from —CH—, —C(R 200 )—, and —N—, 
 or P 3  and P 4  are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,  
   P 5  at each occurrence is independently selected from —CH—, —C(R 200 )—, and —N—, 
 wherein at least one bond in the monocyclic or bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally a double bond,  
 wherein the bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally a fused or spiro ring system,  
 wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P 1  and P 2  or P 3  and P 4  is optionally replaced by a group independently selected from 
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —C(═N—R 255 )—,  
 —N—,  
 —NR 220 —,  
 —N((CO) 0-1 R 200 )—, and  
 —N(SO 2 R 200 )—;  
 formula (IVe) is  
                     
 
   wherein    U is selected from —CH 2 —CR 100 R 101 —, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —N(R 100 )—, —CH 2 —C(O)—, —CH 2 —O—, —C(O)—C(R 100 )(R 101 )—, —SO 2 —N(R 100 )—, —C(O)—N(R 55 )—, —N(R 55 )—C(O)—N(R 55 )—, —O—C(O)—O—, —N(R 55 )—C(O)—O—, and —C(O)—O—; 
 wherein R 100  and R 101  at each occurrence are independently selected from —H, -alkyl, -aryl, —C(O)-alkyl, —(CO) 0-1 R 215 , —(CO) 0-1 R 220 , and —S(O) 2 -alkyl;  
 formula (IVf) is  
                     
   wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, —N(R 5 )C(O)H, —C(O)H, —C(O)N(R 5 )(R 6 ), —NR 5 R 6 , R 280 , R 285 , -aryl, and -heteroaryl;    wherein R 280  and R 285 , and the carbon to which they are attached form a C 3 -C 7  spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, -halogen, —CF 3 , and —CN;    wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R 290  and R 295 ;    wherein R 290  and R 295  at each occurrence are independently selected from 
 -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —OH,  
 —NO 2 ,  
 -halogen,  
 —CO 2 H,  
 —CN,  
 —(CH 2 ) 0-4 —C(O)—NR 21 R 22 ,  
 —(CH 2 ) 0-4 —CO 2 R 20 ,  
 —(CH 2 ) 0-4 —SO 2 —NR 21 R 22 ,  
 —(CH 2 ) 0-4 —S(O)-(alkyl),  
 —(CH 2 ) 0-4 —S(O) 2 -(alkyl),  
 —(CH 2 ) 0-4 —S(O) 2 -(cycloalkyl),  
 —(CH 2 ) 0-4 —N(H or R 20 )—C(O)—O—R 20 ,  
 —(CH 2 ) 0-4 —N(H or R 20 )—C(O)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —N—C(S)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —N(H or R 20 )—CO—R 21 ,  
 —(CH 2 ) 0-4 —NR 21 R 22 ,  
 —(CH 2 ) 0-4 —R 11 ,  
 —(CH 2 ) 0-4 —O—C(O)-(alkyl),  
 —(CH 2 ) 0-4 —O—P(O)—(OR 5 ) 2 ,  
 —(CH 2 ) 0-4 —O—C(O)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—C(S)—N(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—(R 20 ) 2 ,  
 —(CH 2 ) 0-4 —O—(R 2 O)—CO 2 H,  
 —(CH 2 ) 0-4 —S—(R 20 ),  
 —(CH 2 ) 0-4 —O-(alkyl optionally substituted with at least one halogen),  
 -cycloalkyl,  
 —(CH 2 ) 0-4 —N(H or R 20 )—S(O) 2 —R 21 , and  
 —(CH 2 ) 0-4 -cycloalkyl;  
 formula (IVg) is  
                     
   wherein    a is 0 or 1;    b is 0 or 1;    S′ is selected from —C(O)— and —CO 2 —;    T′ is —(CH 2 ) 0-4 —;    U′ is —(CR 245 R 250 )—;    V′ is selected from -aryl- and -heteroaryl-;    W′ is selected from 
 -a bond,  
 -alkyl-substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —(CO) 0-1 —N(R 220 )—,  
 —(CH 2 ) 0-4 —(CO) 0-1 —,  
 —(CH 2 ) 0-4 —CO 2 —,  
 —(CH 2 ) 0-4 —SO 2 —N(R 220 )—,  
 —(CH 2 ) 0-4 —N(H or R 215 )—CO 2 —,  
 —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —,  
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—N(R 215 )—,  
 —(CH 2 ) 0-4 —N(H or R 215 )—C(O)—,  
 —(CH 2 ) 0-4 —N(R 220 )—,  
 —(CH 2 ) 0-4 —O—, and  
 —(CH 2 ) 0-4 —S—;  
   X′ is selected from aryl and heteroaryl;    wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R 205 ;    wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R 200 ;    wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from 
 —(CO) 0-1 R 215 ,  
 —(CO) 0-1 R 220 , and  
 —S(O) 0-2 R 200 ;  
   R 21  and R 22  each independently are selected from 
 —H,  
 -alkyl optionally substituted with at least one group independently selected from —OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —R 17 , and —R 18 ,  
 —(CH 2 ) 0-4 —C(O)-(alkyl),  
 —(CH 2 ) 0-4 —C(O)-(cycloalkyl),  
 —(CH 2 ) 0-4 —C(O)—R 17 ,  
 —(CH 2 ) 0-4 —C(O)—R 18 ,  
 —(CH 2 ) 0-4 —C(O)—R 19 , and  
 —(CH 2 ) 0-4 —C(O)—R 11 ;  
   R 17  at each occurrence is aryl optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —NR 5 R 6 , —CN, —CF 3 , and —O-alkyl,  
   -halogen, 
 —O-alkyl optionally substituted with at least one group independently selected from halogen, —NR 21 R 22 , —OH, —CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —C(O)-(alkyl),  
 —S(O)—O—NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
   R 18  at each occurrence is heteroaryl optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 -halogen,  
 —O-alkyl optionally substituted with at least one group independently selected from -halogen, —NR 21 R 22 , —OH, and —CN,  
 -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 —C(O)-(alkyl),  
 —S(O) 2 —NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
   R 19  at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —C(O)—, —S(O)—, and —S(O) 2 —, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from 
 -alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 ,  
 -halogen,  
 —O-alkyl optionally substituted with at least one group independently selected from -halogen, —OH, —CN, —NR 21 R 22 , and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF 3 , —O-alkyl, and —NR 5 R 6 , —C(O)-(alkyl),  
 —S(O) 2 —NR 5 R 6 ,  
 —C(O)—NR 5 R 6 , and  
 —S(O) 2 -(alkyl);  
   R 11  at each occurrence is heterocycloalkyl 
 wherein at least one carbon of the heterocycloalkyl is optionally replaced with —C(O)—, —S(O)—, and —S(O) 2 —,  
   wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, and -halogen;    R 20  is selected from -alkyl, -cycloalkyl, —(CH 2 ) 0-2 —(R 17 ), and —(CH 2 ) 0-2 —(R 18 );    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 ,  
 —NH 2 ,  
 -halogen,  
 —CN,  
 —CF 3 ,  
 —OCF 3 ,  
 —(CH 2 ) 0-4 —C(O)H,  
 —(CO) 0-1 R 215 ,  
 —(CO) 0-1 R 220 ,  
 —(CH 2 ) 0-4 —C(O)—NR 220 R 225 ,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 —R 215 ,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 —R 220 ,  
 —(CH 2 ) 0-4 —C(O)-alkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -cycloalkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -heterocycloalkyl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -aryl,  
 —(CH 2 ) 0-4 —(C(O)) 0-1 -heteroaryl,  
 —(CH 2 ) 0-4 —C(O)—O—R 215 ,  
 —(CH 2 ) 0-4 —S(O) 0-2 —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 )—S(O) 1-2 —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 —NR 220 R 225 ,  
 —(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 —C(O)H,  
 —(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 205 ,  
 —R 210 , and  
 -alkyl optionally substituted with at least one group independently selected from R 205  and R 210 ;  
 
   R 205  at each occurrence is independently selected from 
 -alkyl,  
 -heteroaryl,  
 -heterocycloalkyl,  
 -aryl,  
 -haloalkoxy,  
 —(CH 2 ) 0-3 -cycloalkyl,  
 -halogen,  
 —(CH 2 ) 0-6 —OH,  
 —O-phenyl,  
 —SH,  
 —(CH 2 ) 0-4 —C(O)CH 3    
 —(CH 2 ) 0-4 —C(O)H  
 —(CH 2 ) 0-4 —CO 2 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 ,  
 —CF 3 ,  
 —CN,  
 —OCF 3 ,  
 —C(O) 2 -benzyl,  
 —O-alkyl,  
 —C(O) 2 -alkyl, and  
 —NR 235 R 240 ;  
   R 210  at each occurrence is independently selected from 
 —OH,  
 —CN,  
 —(CH 2 ) 0-4 —C(O)H,  
 -alkyl wherein a carbon atom is optionally replaced with —C(O)—, and a carbon atom is optionally substituted with at least one group independently selected from R 205 ,  
 —S-alkyl,  
 -halogen,  
 —O-alkyl,  
 -haloalkoxy,  
 —NR 220 R 225 ,  
 -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 , and  
 —S(O) 2 -alkyl;  
   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, and  
 —(CH 2 ) 0-2 -heterocycloalkyl;  
 wherein the aryl groups included within R 215  are optionally substituted with at least one group independently selected from R 205  or R 210 ;  
 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,  
 —OH,  
 -alkyl,  
 —(CH 2 ) 0-4 —C(O)H,  
 -alkyl-OH,  
 —(CH 2 ) 0-4 CO 2 -alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 -aminoalkyl,  
 —S(O) 2 -alkyl,  
 —(CH 2 ) 0-4 —C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —C(O)—NH 2 ,  
 —(CH 2 ) 0-4 —C(O)—NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R 205 ,  
 —(CH 2 ) 0-4 —C(O)—N(alkyl)(alkyl),  
 -haloalkyl,  
 —(CH 2 ) 0-2 -cycloalkyl,  
 -alkyl-O-alkyl,  
 —O-alkyl,  
 -aryl,  
 -heteroaryl, and  
 -heterocycloalkyl;  
 wherein the aryl, heteroaryl 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 ,  
 -phenyl,  
 -halogen,  
 —O-alkyl,  
 -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 ,  
 —CO—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,  
 -alkyl,  
 —C(O)-alkyl,  
 —OH,  
 —CF 3 ,  
 —OCH 3 ,  
 —NH—CH 3 ,  
 —N(CH 3 ) 2 ,  
 —(CH 2 ) 0-4 —C(O)—(H or alkyl),  
   —SO 2 -alkyl, and 
 -phenyl;  
   R 255  is selected from -hydrogen, —OH, —N(R 220 )(R 225 ), and —O-alkyl;    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  is independently selected from 
 —H,  
 -alkyl optionally substituted with at least one group independently selected from —OH, amino, and halogen,  
 -cycloalkyl, and  
 -alkyl-O-alkyl.  
   
   
   
       11 . The method according to  claim 10 , wherein R, is selected from —CH 2 -phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —C 1 -C 2  alkyl, —O-methyl, and —OH.  
   
   
       12 . The method according to  claim 10 , wherein R 1  is selected from 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, piperidin4-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.  
   
   
       13 . The method according to  claim 10 , wherein R C  is —C(R 245 )(R 250 )—R X , wherein R 245  and R 250  are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one atom within the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from 
 —O—,    —C(O)—,    —S(O) 0-2 —,    —C(═N—R 255 )—,    —N—,    —NR 220 —,    —N((CO) 0-1 R 200 )—, and    —N(SO 2 R 200 )—; and    wherein the monocyclic or bicyclic groups included within R 245  and R 250  are optionally substituted with at least one group independently selected from halogen, —OH, —O-alkyl, alkyl, aryl, —N(R 220 )(R 225 ), —CN, —NH 2 , —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH—C(O)-alkyl, and —NHS(O 2 )-alkyl; and wherein R X , R 220 , R 225 , R 255 , and R 200  are as defined in  claim 10 .    
   
   
       14 . The method according to  claim 10 , wherein R C  is selected from formulae (Va), (Vb), (Vc), and (Vd),  
     
       
         
         
             
             
         
       
       wherein,  
       A, B, and C are independently selected from 
 —CH 2 —,  
 —O—,  
 —C(O)—,  
 —S(O) 0-2 —,  
 —N((CO) 0-1 R 200 )—,  
 —N(SO 2 R 200 )—,  
 —C(═N—R 255 )—, and  
 —N(R 220 )—;  
 
       A′ at each occurence is independently selected from —CH 2 — and —O—; 
 wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, —(CH 2 ) 0-2 —OH, —(CH 2 ) 0-2 —S-alkyl, —CF 3 , —CN, -halogen, —(CH 2 ) 0-2 —NH 2 , —(CH 2 ) 0-2 —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O 2 )-alkyl; and  
 
       R X , R 220 , R 255 , and R 200  are as defined in  claim 10 .  
     
   
   
       15 . The method according to  claim 10 , wherein R C  is selected from formulae (VIa) and (VIb),  
     
       
         
         
             
             
         
       
       wherein at least one carbon of the heterocycloalkyl of formula (VIa) and the cycloalkyl of formula (VIb) is optionally replaced with a group independently selected from —O—, —SO 2 —, and —C(O)—, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group independently selected from R 205 , R 245 , and R 250 , wherein R 100 , R 200 , R 205 , R 245 , and R 250  are as defined in  claim 10 .  
     
   
   
       16 . The method according to  claim 10 , wherein R C  is selected from 6-isobutyl-1,1-dioxo-1λ 6 -thiochroman-4-yl, 6-Isopropyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ 6 -isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.  
   
   
       17 . The method according to  claim 10 , wherein R 2  is selected from hydrogen, 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.  
   
   
       18 . The method according to  claim 11 , 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-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, and 6-tert-Butyl-pyrimidin-4-yl.  
   
   
       19 . The method according to  claim 10 , wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.  
   
   
       20 . The method according to  claim 10 , wherein the condition is selected from Alzheimer's disease, Down's syndrome or Trisomy 21, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases, Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease, and frontotemporal dementias with parkinsonism.  
   
   
       21 . The method according to  claim 10 , wherein the condition is Alzheimer's disease.  
   
   
       22 . The method according to  claim 10 , wherein the condition is dementia.  
   
   
       23 . 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 beta-secretase inhibitor of formula (I),                          or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined in  claim 10 .    
   
   
       24 . 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 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 defined in  claim 10 .    
   
   
       25 . A method of preventing or treating the onset of dementia comprising: administering to a patient a therapeutically effective amount of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof to the patient, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       26 . A method of preventing or treating at least one condition associated with amyloidosis by administering to a host an effective amount of at least one compound of formula (I):  
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       27 . A method of preventing or treating Alzheimer's disease by administering to a host an effective amount of at least one compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       28 . A method of preventing or treating dementia by administering to a host an effective amount of at least one compound having the following structure:  
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       29 . A method of inhibiting beta-secretase activity in a cell, the method comprising the step of administering to the cell an effective amount of at least one compound of formula (l) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       30 . A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       31 . The method according to  claim 30 , wherein the host is a human.  
   
   
       32 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       33 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       34 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 , 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.  
 
   
   
       35 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       36 . A method of preventing or treating deposition of A-beta, comprising: administering a therapeutically effective amount of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       37 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       38 . The method in  claim 37 , wherein the A-beta deposits or plaques are in a human brain.  
   
   
       39 . A method of preventing, delaying, halting, or reversing a condition associated with a pathological form of A-beta in a host comprising: administering to a patient in need thereof an effective amount of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 .  
   
   
       40 . A method of inhibiting the activity of at least one aspartyl protease in a patient in need thereof, comprising: administering a therapeutically effective amount of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 , to the patient.  
   
   
       41 . The method according to  claim 40  wherein the at least one aspartyl protease is beta-secretase.  
   
   
       42 . 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 a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1 , wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′, and S2′.  
   
   
       43 . A method of treating at least one condition in a patient, comprising: administering a therapeutically effective amount of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a 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 1 .  
   
   
       44 . The method according to  claim 43 , wherein the condition is selected from Alzheimer's disease, Down's syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down's syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease, and frontotemporal dementias with parkinsonism (FTDP).  
   
   
       45 . The method according to  claim 44 , wherein the condition is Alzheimer's disease.  
   
   
       46 . The method according to  claim 44 , wherein the condition is dementia.  
   
   
       47 . A method of prescribing a medication for preventing, delaying, halting, or reversing at least one disorder, condition or disease associated with amyloidosis comprising: identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and prescribing at least one dosage form of at least one compound of formula (I),  
     
       
         
         
             
             
         
       
     
     or a 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 1 .  
   
   
       48 . An article of manufacture, comprising: 
 (a) at least one dosage form of at least one compound of formula (I),                          or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1;     (b) a package insert providing that a dosage form comprising a compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and    (c) at least one container in which at least one dosage form of at least one compound of formula (I) is stored.    
   
   
       49 . A packaged pharmaceutical composition for treating at least one condition related to amyloidosis, comprising: 
 (a) a container which holds an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in  claim 1;  and    (b) instructions for using the pharmaceutical composition.    
   
   
       50 . An article of manufacture, comprising: 
 (a) a therapeutically effective amount of at least one compound of formula (I)                          or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1;     (b) a package insert providing an oral dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and    (c) at least one container comprising: at least one oral dosage form of at least one compound of formula (I).    
   
   
       51 . An article of manufacture, comprising: 
 (a) at least one oral dosage form of at least one compound of formula (I)                          or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R C  are defined as in  claim 1;     in a dosage amount ranging from about 2 mg to about 1000 mg; associated with    (b) a package insert providing that an oral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and    (c) at least one container in which at least one oral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.    
   
   
       52 . An article of manufacture, comprising: 
 (a) at least one oral dosage form of at least one compound of formula (I)                          wherein R 1 , R 2 , and R C  are defined as in  claim 1 , in a dosage amount ranging from about 2 mg to about 1000 mg in combination with    (b) at least one therapeutically active agent; associated with    (c) a package insert providing that an oral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with at least one therapeutically active agent should be administered to a patient in need of therapy for at least one disorder, condition or diseases associated with amyloidosis; and    (d) at least one container in which at least one dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with a therapeutically active agent is stored.    
   
   
       53 . The article of manufacture according to  claim 52  wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.  
   
   
       54 . An article of manufacture, comprising: 
 (a) at least one parenteral dosage form of at least one compound of formula (I)                          wherein R 1 , R 2 , and R C  are defined as in  claim 1 , in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL; associated with    (b) a package insert providing that a parenteral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and    (c) at least one container in which at least one parenteral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL is stored.    
   
   
       55 . An article of manufacture comprising: 
 (a) a medicament comprising: an effective amount of at least one compound of formula (I)                          wherein R 1 , R 2 , and R C  are defined as in  claim 1 , in combination with active and/or inactive pharmaceutical agents;    (b) a package insert providing that an effective amount of at least one compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and    (c) a container in which a medicament comprising: an effective amount of at least one compound of formula (I) in combination with active and/or inactive pharmaceutical agents is stored.    
   
   
       56 . A kit comprising: 
 (a) at least one dosage form of at least one compound according to  claim 1;  and    (b) at least one container in which at least one dosage form of at least one compound according to  claim 1  is stored.    
   
   
       57 . A kit according to  claim 56 , further comprising a package insert: 
 a) containing information of the dosage amount and duration of exposure of a dosage form containing at least one compound of formula (I) as defined in  claim 1 , and    b) providing that the dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis.    
   
   
       58 . The kit according to  claim 57  further comprising: at least one therapeutically active agent.  
   
   
       59 . The kit according to  claim 58  wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.  
   
   
       60 . A method of producing A-beta-secretase complex comprising: exposing beta-secretase to a compound of formula (I) as defined in  claim 1 , or a pharmaceutically-acceptable salt thereof, in a reaction mixture under conditions suitable for the production of the complex.  
   
   
       61 . A manufacture of a medicament for preventing, delaying, halting, or reversing Alzheimer's disease, comprising: adding an effective amount of at least one compound of formula (I) as defined in  claim 1 , to a pharmaceutically acceptable carrier.