Substituted Aminoethers for the Treatment of Alzheimer's Disease

Abstract

The invention provides compounds of formula (I): useful in treating Alzheimer's disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts or esters thereof;
 wherein X is O, S, NR 20 , or NR 20 NR 20 ; 
 wherein each R 20  is H, C 1-6  alkyl or alkenyl, C 1-6  haloalkyl or C 4-7  cycloalkyl; 
 wherein R 1  is —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6  alkyl), or
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or 
 C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, and mono- or dialkylamino, or 
 aryl, heteroaryl, heterocyclyl, —C 1 -C 6  alkyl-aryl, —C 1 -C 6  alkyl-heteroaryl, or —C 1 -C 6  alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SK, —C≡N, —NR 105 R′ 105 , —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′, —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or
 C 1 -C 6  alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or 
 C 3 -C 7  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, —C 1 -C 6  alkyl and mono- or dialkylamino, or 
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino and —C 1 -C 3  alkyl, or 
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, C 1 -C 6  alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo; 
 
 
 R and R′ independently are hydrogen, C 1 -C 10  alkyl, C 1 -C 10  alkylaryl or C 1 -C 10  alkylheteroaryl; 
 wherein R C  is hydrogen, —(CR 245 R 250 ) 0-4 -aryl, —(CR 245 R 250 ) 0-4 -heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl, —(CR 245 R 250 ) 0-4 -aryl-heteroaryl, —(CR 245 R 250 ) 0-4 -aryl-heterocyclyl, —(CR 245 R 250 ) 0-4 -aryl-aryl, —(CR 245 R 250 ) 0-4 -heteroaryl-aryl, —(CR 245 R 250 ) 0-4 -heteroaryl-heterocyclyl, —(CR 245 R 250 ) 0-4 -heteroaryl-heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl-heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl-heterocyclyl, —(CR 245 R 250 ) 0-4 -heterocyclyl-aryl, —[C(R 255 )(R 260 )] 1-3 —CO—N—(R 255 ) 2 , —CH(aryl) 2 , —CH(heteroaryl) 2 , —CH(heterocyclyl) 2 , —CH(aryl)(heteroaryl), —(CH 2 ) 0-1 —CH((CH 2 ) 0-6 —OH)—(CH 2 ) 0-1 -aryl, —(CH 2 ) 0-1 —CH((CH 2 ) 0-6 —OH—(CH 2 ) 0-1 -heteroaryl, —CH(-aryl or -heteroaryl)-CO—O(C 1 -C 4  alkyl), —CH(—CH 2 —OH)—CH(OH)-phenyl-NO 2 , (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-OH; —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 , —(CH 2 ) 0-6 —C(═NR 235 )(NR 235 R 240 ), or
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —OC═ONR 235 R 240 , —S(═O) 0-2 (C 1 -C 6  alkyl), —SH, —NR 235 C═ONR 235 R 240 , —C═ONR 235 R 240 , and —S(═O) 2 NR 235 R 240 , or 
 —(CH 2 ) 0-3 —(C 3 -C 8 ) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —CO 2 H, and —CO 2 —(C 1 -C 4  alkyl), or 
 cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocyclyl wherein one, two or three carbons of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with a heteroatom independently selected from NH, NR 215 , O, or S(═O) 0-2 , and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group can be optionally substituted with one or two groups that are independently R 205 , ═O, —CO—NR 235 R 240 , or —SO 2 —(C 1 -C 4  alkyl), or 
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups, wherein 
 each aryl and heteroaryl is optionally substituted with 1, 2, or 3 R 200 , and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or 4 R 210 ; 
 
 R 200  at each occurrence is independently selected from —OH, —NO 2 , halogen, —CO 2 H, C≡N, —(CH 2 ) 0-4 —CO—NR 220 R 225 , —(CH 2 ) 0-4 —CO—(C 1 -C 12  alkyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkenyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkynyl), —(CH 2 ) 0-4 —CO—(C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —CO-aryl, —(CH 2 ) 0-4 —CO-heteroaryl, —(CH 2 ) 0-4 —CO-heterocyclyl, —(CH 2 ) 0-4 —CO—O—R 215 , —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 , —(CH 2 ) 0-4 —SO—(C 1 -C 6  alkyl), —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12  alkyl), —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —N(H or R 215 )—CO—O—R 215 , —(CH 2 ) 0-4 —N(H or R 215 )—CO—N(R 215 ) 2 , —(CH 2 ) 0-4 —N—CS—N(R 215 ) 2 , —(CH 2 ) 0-4 —N(—H or R 205 )—CO—R 220 , —(CH 2 ) 0-4 —NR 220 R 225 , —(CH 2 ) 0-4 —O—CO—(C 1 -C 6  alkyl), —(CH 2 ) 0-4 —O—P(O)—(OR 240 ) 2 , —(CH 2 ) 0-4 —O—CO—N(R 215 ) 2 , —(CH 2 ) 0-4 —O—CS—N(R 215 ) 2 , —(CH 2 ) 0-4 —O—(R 215 ), —(C 2 ) 0-4 —O—(R 215 )—COOH, —(CH 2 ) 0-4 —S—(R 215 ), —(CH 2 ) 0-4 —O—(C 1 -C 6  alkyl optionally substituted with 1, 2, 3, or 5 —F), C 3 -C 7  cycloalkyl, —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 220 , —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, or
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 R 205  groups, or 
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, each of which is optionally substituted with 1 or 2 R 205  groups, wherein 
 the aryl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or
 C 1 -C 6  alkyl substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein 
 
 the heterocyclyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 210 ; 
 
 R 205  at each occurrence is independently selected from C 1 -C 6  alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, NH 2 , NH(C 1 -C G  alkyl) or N—(C 1 -C 6  alkyl)(C 1 -C 6  alkyl); 
 R 210  at each occurrence is independently selected from halogen, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, —NR 220 R 225 , OH, C≡N, —CO—(C 1 -C 4  alkyl), —SO 2 —NR 235 R 240 , —CO—NR 235 R 240 , —SO 2 —(C 1 -C 4  alkyl), ═O, or
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 7  cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups; 
 
 R 215  at each occurrence is independently selected from C 1 -C 6  alkyl, —(CH 2 ) 0-2 -(aryl), C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, and —(CH 2 ) 0-2 -(heteroaryl), —(CH 2 ) 0-2 -(heterocyclyl), wherein
 the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein 
 the heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 R 210 ; 
 
 R 220  and R 225  at each occurrence are independently selected from —H, —C 3 -C 7  cycloalkyl, —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl), —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl), —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 1 -C 6  alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocyclyl, or
 —C 1 -C 10  alkyl optionally substituted with —OH, —NH 2  or halogen, wherein 
 the aryl, heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 R 270  groups 
 
 R 235  and R 240  at each occurrence are independently H, or C 1 -C 6  alkyl; 
 R 245  and R 250  at each occurrence are independently selected from —H, C 1 -C 4  alkyl, C 1 -C 4  alkylaryl, C 1 -C 4  alkylheteroaryl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and phenyl; or 
 R 245  and R 250  are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, where one carbon atom is optionally replaced by a heteroatom selected from —O—, —S—, —SO 2 —, and —NR 220 —; 
 R 255  and R 260  at each occurrence are independently selected from —H, —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6  alkyl), —(C 1 -C 4  alkyl)-aryl, —(C 1 -C 4  alkyl)-heteroaryl, —(C 1 -C 4  alkyl)-heterocyclyl, -aryl, -heteroaryl, -heterocyclyl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -aryl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heteroaryl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heterocyclyl, or
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups, wherein 
 each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or
 C 1 -C 6  alkyl substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein 
 
 each heterocyclyl is optionally substituted with 1, 2, 3, or 4 R 210 ; 
 
 R 265  at each occurrence is independently —O—, —S— or —N(C 1 -C 6  alkyl)-; 
 R 270  at each occurrence is independently R 205 , halogen C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, NR 235 R 240 , —OH, —C≡N, —CO—(C 1 -C 4  alkyl), —SO 2 —NR 235 R 240 , —CO—NR 235 R 240 , —SO 2 —(C 1 -C 4  alkyl), ═O, or
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups; 
 
 R n  is R′ 100 , —SO 2 R′ 100 , —(CRR′) 1-6 R′ 100 , —C(═O)—(CRR′) 0-6 R 100 , —C(═O)—(CRR′) 1-6 —O—R′ 100 , —C(═O)—(CRR′) 1-6 —S—R′ 100 , —C(═O)—(CRR′) 1-6 —C(═O)—R 100 , —C(═O)—(CRR′) 1-6 —SO 2 —R 100 ; —C(═O)—(CRR′) 1-6 NR 100 —R′ 100 ; or 
 
     
       
         
         
             
             
         
       
       R 4  is selected from the group consisting of H; NH 2 ; —NH—(CH 2 ) n6 —R 4-1 ; —NHR 8 ; —NR 50 C(O)R 5 ; C 1 -C 4  alkyl-NHC(O)R 5 ; —(CH 2 ) 0-4 R 8 ; —O—C 1 -C 4  alkanoyl; OH; C 6 -C 10  aryloxy optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 4  alkyl, —CO 2 H, —C(O)—C 1 -C 4  alkoxy, or C 1 -C 4  alkoxy; C 1 -C 6  alkoxy; aryl C 1 -C 4  alkoxy; —NR 50 CO 2 R 51 ; —C 1 -C 4  alkyl-NR 50 CO 2 R 51 ; —C≡N; —CF 3 ; —CF 2 —CF 3 ; —C≡CH; —CH 2 —CH═CH 2 ; —(CH 2 ) 1-4 —R 4-1 ; —(CH 2 ) 1-4 —NH—R 4-1 ; —O—(CH 2 ) n6 —R 4-1 ; —S—(CH 2 ) n6 —R 4-1 ; —(CH 2 ) 0-4 —NHC(O)—(CH 2 ) 0-6 —R 52 ; —(CH 2 ) 0-4 —R 53 —(CH 2 ) 0-4 —R 54 ;
 wherein 
 n 6  is 0, 1, 2, or 3; 
 n 7  is 0, 1, 2, or 3; 
 R 4-1  is selected from the group consisting of —SO 2 —(C 1 -C 8  alkyl), —SO—(C 1 -C 8  alkyl), —S—(C 1 -C 8  alkyl), —S—CO—(C 1 -C 6  alkyl), —SO 2 —NR 4-2 R 4-3 ; —CO—C 1 -C 2  alkyl; —CO—NR 4-3 R 4-4 ; 
 R 4-2  and R 4-3  are independently H, C 1 -C 3  alkyl, or C 3 -C 6  cycloalkyl; 
 R 4-4  is alkyl, arylalkyl, alkanoyl, or arylalkanoyl; 
 R 4-6  is —H or C 1 -C 6  alkyl; 
 R 5  is selected from the group consisting of C 3 -C 7  cycloalkyl; C 1 -C 6  alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR 6 R 7 , C 1 -C 4  alkoxy, C 5 -C 6  heterocycloalkyl, C 5 -C 6  heteroaryl, C 6 -C 10  aryl, C 3 -C 7  cycloalkyl C 1 -C 4  alkyl, —S—C 1 -C 4  alkyl, —SO 2 —C 1 -C 4  alkyl, —CO 2 H, —CONR 6 R 7 , —CO 2 —C 1 -C 4  alkyl, C 6 -C 10  aryloxy; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, C 1 -C 4  haloalkyl, or OH; heterocycloalkyl optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, or C 2 -C 4  alkanoyl; aryl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, or C 1 -C 4  haloalkyl; and —NR 6 R 7 ; wherein
 R 6  and R 7  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkanoyl, phenyl, —SO 2 —C 1 -C 4  alkyl, phenyl C 1 -C 4  alkyl; 
 
 R 8  is selected from the group consisting of —SO 2 -heteroaryl, —SO 2 -aryl, —SO 2 -heterocycloalkyl, —SO 2 —C 1 -C 10  alkyl, —C(O)NR 9 , heterocycloalkyl, —S—C 1 -C 6  alkyl, —S—C 2 -C 4  alkanoyl, wherein
 R 9  is aryl C 1 -C 4  alkyl, C 3 -C 6  alkyl, or H; 
 
 R 50  is H or C 1 -C 6  alkyl; 
 R 51  is selected from the group consisting of aryl C 1 -C 4  alkyl; C 1 -C 6  alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, heteroaryl, —NR 6 R 7 , —C(O)NR 6 R 7 , C 3 -C 7  cycloalkyl, or —C 1 -C 4  alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, C 2 -C 4  alkanoyl, aryl C 1 -C 4  alkyl, and —SO 2  C 1 -C 4  alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently OH, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, NH 2 , NH(C 1 -C 6  alkyl) or N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, NH 2 , NH(C 1 -C 6  alkyl) or N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl); aryl; heterocycloalkyl; C 3 -C 8  cycloalkyl; and cycloalkylalkyl; wherein the aryl; heterocycloalkyl, C 3 -C 8  cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO 2 , C 1 -C 5  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkanoyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxy, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 1 -C 6  thioalkoxy, C 1 -C 6  thioalkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkoxy C 1 -C 6  alkoxy; 
 R 52  is heterocycloalkyl, heteroaryl, aryl, cycloalkyl, —S(O) 0-2 —C 1 -C 6  alkyl, CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —CO 2 -alkyl, —NHS(O) 0-2 —C 1 -C 6  alkyl, —N(alkyl)S(O) 0-2 —C 1 -C 6  alkyl, —S(O) 0-2 -heteroaryl, —S(O) 0-2 -aryl, —NH (arylalkyl), —N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is optionally substituted with 1, 2, 3, 4, or groups that are independently alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, NO 2 , CN, alkoxycarbonyl, or aminocarbonyl; 
 R 53  is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O) 0-2 —, —N(alkyl)-S(O) 0-2 —, —S(O) 0-2 —NH—, —S(O) 0-2 —N(alkyl)-, —NH—C(S)—, or —N(alkyl)-C(S)—; 
 R 54  is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO 2 H, —CO 2 -alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH 2 , C 1 -C 8  alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH 2 , NH(alkyl), N(alkyl)(alkyl), or —C 1 -C 6  alkyl-CO 2 —C 1 -C 6  alkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, CO 2 H, —CO 2 -alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO 2 , CN, alkoxycarbonyl, or aminocarbonyl; 
 
       X′ is selected from the group consisting of —C 1 -C 6  alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; and —NR 4-6 —; or 
       R 4  and R 4-6  combine to form —(CH 2 ) n10 —, wherein
 n 10  is 1, 2, 3, or 4; 
 
       Z is selected from the group consisting of a bond; SO 2 ; SO; S; and C(O); 
       Y is selected from the group consisting of H; C 1 -C 4  haloalkyl; C 5 -C 6  heterocycloalkyl; C 6 -C 10  aryl; OH; —N(Y 1 ) (Y 2 ); C 1 -C 10  alkyl optionally substituted with 1 thru 3 substituents which can be the same or different and are selected from the group consisting of halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C 3 -C 8  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1 -C 3  alkyl, and halogen; alkoxy; aryl optionally substituted with halogen, alkyl, alkoxy, CN or NO 2 ; arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or NO 2 ; wherein
 Y 1  and Y 2  are the same or different and are H; C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1 -C 4  alkoxy, C 3 -C 8  cycloalkyl, and OH; C 2 -C 6  alkenyl; C 2 -C 6  alkanoyl; phenyl; —SO 2 —C 1 -C 4  alkyl; phenyl C 1 -C 4  alkyl; or C 3 -C 8  cycloalkyl C 1 -C 4  alkyl; or 
 
       Y 1 , Y 2  and the nitrogen to which they are attached form a ring selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or halogen; 
       R 100  and R′ 100  independently represent aryl, heteroaryl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH[(CH 2 ) 0-2 —O—R 150 ]—(CH 2 ) 0-2 -aryl, —CH[(CH 2 ) 0-2 —O—R 150 ]—(CH 2 ) 0-2 -heterocyclyl or —CH[(CH 2 ) 0-2 —O—R 150 ]—(CH 2 ) 0-2 -heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from
 —OR, —NO 2 , halogen, —C≡N, —OCF 3 , —CF 3 , —(CH 2 ) 0-4 —O—P(═O)(OR)(OR′), —(CH 2 ) 0-4 —CO—N 105 R′ 105 , —(CH 2 ) 0-4 —O—(CH 2 ) 0-4 —CONR 102 R 102 ′, —(CH 2 ) 0-4 —CO—(C 1 -C 12  alkyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkenyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkynyl), —(CH 2 ) 0-4 —CO—(CH 2 ) 0-4  (C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —R 110 , —(CH 2 ) 0-4 —R 120 , —(CH 2 ) 0-4 —R 130 , —(CH 2 ) 0-4 —CO—R 110 , —(CH 2 ) 0-4 —CO—R 120 , —(CH 2 ) 0-4 —CO—R 130 , —(CH 2 ) 0-4 —CO—R 140 , —(CH 2 ) 0-4 —CO—O—R 150 , —(CH 2 ) 0-4 —SO 2 —NR 105 R′ 105 , —(CH 2 ) 0-4 —SO—(C 1 -C 8  alkyl), —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12  alkyl), —(CH 2 ) 0-4 —SO 2 —(CH 2 ) 0-4 —(C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —N(R 150 )—CO—O—R 150 , —(CH 2 ) 0-4 —N(R 150 )—CO—N(R 150 ) 2 , —(CH 2 ) 0-4 —N(R 150 )—CS—N(R 150 ) 2 , —(CH 2 ) 0-4 —N(R 150 )—CO—R 105 , —(CH 2 ) 0-4 —NR 105 R′ 105 , —(CH 2 ) 0-4 —R 140 , —(CH 2 ) 0-4 —O—CO—(C 1 -C 6  alkyl), —(CH 2 ) 0-4 —O—P(O)—(O—R 110 ) 2 , —(CH 2 ) 0-4 —O—CO—N(R 150 ) 2 —(CH 2 ) 0-4 —O—CS—N(R 150 ) 2 , —(CH 2 ) 0-4 —O—(R 150 ), —(CH 2 ) 0-4 —O—R 150 ′—COOH, —(CH 2 ) 0-4 —S—(R 150 ), —(CH 2 ) 0-4 —N(R 150 )—SO 2 —R 105 , —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, (C 2 -C 10 ) alkenyl, or (C 2 -C 10 )alkynyl, or 
 
       R 100  is C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 R 115  groups, or 
       R 100  is —(C 1 -C 6  alkyl)-O—C 1 -C 6  alkyl) or —(C 1 -C 6  alkyl)-S—(C 1 -C 6  alkyl), each of which is optionally substituted with 1, 2, or 3 R 115  groups, or 
       R 100  is C 3 -C 8  cycloalkyl optionally substituted with 1, 2, or 3 R 115  groups; 
       W is —(CH 2 ) 0-4 —, —O—, —S(O) 0-2 —, —N(R 135 )—, —CR(OH)— or —C(O)—; 
       R 102  and R 102 ′ independently are hydrogen, or
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, aryl or —R 110 ; 
 
       R 105  and R′ 105  independently represent —H, —R 110 , —R 120 , C 3 -C 7  cycloalkyl, —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl), —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl), C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkyl chain with one double bond and one triple bond, or
 C 1 -C 6  alkyl optionally substituted with —OH or —NH 2 ; or, 
 C 1 -C 6  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, or 
 
       R 105  and R′ 105  together with the atom to which they are attached form a 3 to 7 membered carbocylic ring, where one member is optionally a heteroatom selected from —O—, —S(O) 0-2 —, —N(R 135 )—, the ring being optionally substituted with 1, 2 or three R 140  groups; 
       R 115  at each occurrence is independently halogen, —OH, —CO 2 R 102 , —C 1 -C 6  thioalkoxy, —CO 2 -phenyl, —NR 105 R′ 135 , —SO 2 —(C 1 -C 8  alkyl), —C(═O)R 108 , R 180 , —CONR 105 R′ 105 , —SO 2 NR 105 R′ 105 , —NH—CO—(C 1 -C 6  alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C 1 -C 6  alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C 1 -C 6  alkyl)-CO 2 H, —NH—SO 2 —(C 1 -C 6  alkyl), C 1 -C 6  alkoxy or C 1 -C 6  haloalkoxy; 
       R 135  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, —(CH 2 ) 0-2 -(aryl), —(CH 2 ) 0-2 -(heteroaryl), or —(CH 2 ) 0-2 -(heterocyclyl); 
       R 140  is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 ) alkyl, and ═O; 
       R 150  is hydrogen, C 3 -C 7  cycloalkyl, —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl), C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkyl with one double bond and one triple bond, —R 10 , —R 120 , or
 C 1 -C 6  alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3  alkoxy, R 110 , and halogen; 
 
       R 150 ′ is C 3 -C 7  cycloalkyl, —(C 1 -C 3  alkyl)-(C 3 -C 7  cycloalkyl), C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkyl with one double bond and one triple bond, —R 110 , —R 120 , or
 C 1 -C 6  alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3  alkoxy, R 110 , and halogen; 
 
       R 180  is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 ) alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, and ═O; 
       R 110  is aryl optionally substituted with 1 or 2 R 125  groups; 
       R 125  at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO 2 —NH 2 , —SO 2 —NH—C 1 -C 6  alkyl, —SO 2 —N(C 1 -C 6  alkyl) 2 , —SO 2 —(C 1 -C 4  alkyl), —CO—NH 2 , —CO—NH—C 1 -C 6  alkyl, or —CO—N(C 1 -C 6  alkyl) 2 , or
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently selected from C 1 -C 3  alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, and mono- and dialkylamino, or 
 C 1 -C 6  alkoxy optionally substituted with one, two or three of halogen; 
 
       R 120  is heteroaryl, which is optionally substituted with 1 or 2 R 125  groups; and 
       R 130  is heterocyclyl optionally substituted with 1 or 2 R 125  groups; 
       R 2  is selected from the group consisting of H; C 1 -C 6  alkyl, optionally substituted with 1, 2, or 3 substituents that are independently selected from the group consisting of C 1 -C 3  alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ; wherein
 R 1-a  and R 1-b  are —H or C 1 -C 6  alkyl; 
 —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6  alkenyl; C 2 -C 6  alkynyl; —CONR N-2 R N-3 ; —SO 2  NR N-2 R N-3 ; —CO 2 H; and —CO 2 —(C 1 -C 4  alkyl); 
 
       R 3  is selected from the group consisting of H; C 1 -C 6  alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 3  alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ; —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6  alkenyl; C 2 -C 6  alkynyl; —CO—NR N-2 R N-3 ; —SO 2 —NR N-2 R N-3 ; —CO 2 H; and —CO—O—(C 1 -C 4  alkyl);
 wherein
 R N-2  and R N-3  at each occurrence are independently selected from the group consisting of —C 1 -C 8  alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH 2 , phenyl and halogen; —C 3 -C 8  cycloalkyl; —(C 1 -C 2  alkyl)-(C 3 -C 8  cycloalkyl); —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl); —C 2 -C 6  alkenyl; —C 2 -C 6  alkynyl; —C 1 -C 6  alkyl chain with one double bond and one triple bond; aryl; heteroaryl; heterocycloalkyl; or 
 R N-2 , R N-3  and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, —CN, —NO 2 , —NH 2 , NH(C 1 -C 6  alkyl), N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl), —OH, —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl), C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 1 -C 6  thioalkoxy, and C 1 -C 6  thioalkoxy C 1 -C 6  alkyl; 
 
 
       or wherein, 
       R 2 , R 3  and the carbon to which they are attached form a carbocycle of three thru seven carbon atoms, wherein one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, or —NR N-2 —. 
     
   
   
       2 . A compound according to  claim 1 , wherein Rn is —C(═O)—(CRR′) 1-6 R 100 . 
   
   
       3 . A compound according to  claim 1 , wherein Rn is —C(═O)—(CRR′) 0-6 R 100 , where R 100  is not -heterocyclyl-W-aryl. 
   
   
       4 . A compound according to  claim 1 , wherein Rn is 
     
       
         
         
             
             
         
       
       wherein 
       X′ is C 1 -C 4  alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —, where R 4-6  is —H or C 1 -C 6  alkyl; 
       or 
       R 4  and R 4-6  combine to form —(CH 2 ) n10 —, wherein 
       n 10  is 1, 2, 3, or 4; 
       Z is selected from a bond; SO 2 ; SO; S; and C(O); 
       Y is selected from H; C 1 -C 4  haloalkyl; C 5 -C 6  heterocycloalkyl containing at least one N, O, or S; phenyl; OH; —N(Y 1 )(Y 2 ); C 1 -C 10  alkyl optionally substituted with 1 thru 3 substituents which can be the same or different and are selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C 3 -C 8  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1 -C 3  alkyl, and halogen; alkoxy; phenyl optionally substituted with halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, CN or NO 2 ; phenyl C 1 -C 4  alkyl optionally substituted with halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, CN or NO 2 ; wherein 
       Y 1  and Y 2  are the same or different and are H; C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1 -C 4  alkoxy, C 3 -C 8  cycloalkyl, and OH; C 2 -C 6  alkenyl; C 2 -C 6  alkanoyl; phenyl; —SO 2 —C 1 -C 4  alkyl; phenyl C 1 -C 4  alkyl; and C 3 -C 8  cycloalkyl C 1 -C 4  alkyl; or
 —N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or halogen. 
 
     
   
   
       5 . A compound according to  claim 1  wherein R 1  is (CH 2 ) n1 —(R 1-aryl ) where n 1  is zero or one and R 1-aryl  is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6  alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C 1 -C 3  alkyl, halogen, —OH, —SH, —NR 1-a R 1-b, —C≡N, —CF   3 , and C 1 -C 3  alkoxy; halogen; C 1 -C 6  alkoxy; —NR N-2 R N-3 ; and OH; wherein
 R 1-a  and R 1-b  are —H or C 1 -C 6  alkyl;   R N-2  and R N-3  at each occurrence are independently selected from the group consisting of —C 1 -C 8  alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH 2 , phenyl and halogen; —C 3 -C 8  cycloalkyl; —(C 1 -C 2  alkyl)-(C 3 -C 8  cycloalkyl); —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl); —C 2 -C 6  alkenyl; —C 2 -C 6  alkynyl; —C 1 -C 6  alkyl chain with one double bond and one triple bond; aryl; heteroaryl; heterocycloalkyl; or
 R N-2 , R N-3  and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, —CN, —NO 2 , —NH 2 , NH(C 1 -C 6  alkyl), N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl), —OH, —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl), C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 1 -C 6  thioalkoxy, and C 1 -C 6  thioalkoxy C 1 -C 6  alkyl. 
   
   
   
       6 . A compound according to  claim 5 , wherein R 1  is aryl, heteroaryl, heterocyclyl, —C 1 -C 6  alkyl-aryl, —C 1 -C 6  alkyl-heteroaryl, or —C 1 -C 6  alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NO 2 , —NR 105 R′ 105 , —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′ (where R 105 , R′ 105 , R and R′ are as defined above), —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or
 C 1 -C 6  alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or   C 3 -C 7  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, —C 1 -C 6  alkyl and mono- or dialkylamino, or   C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino and —C 1 -C 3  alkyl, or   C 2 -C 10  alkenyl or C 2 -C 10  alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, C 1 -C 6  alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo.   
   
   
       7 . A compound according to  claim 6 , wherein R 1  is
 —C 1 -C 6  alkyl-aryl, —C 1 -C 6  alkyl-heteroaryl, or —C 1 -C 6  alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NO 2 , —NR 105 R′ 105 , —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′ (where R 105 , R′ 10 , R and R′ are as defined above), —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or
 C 1 -C 6  alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or 
 C 3 -C 7  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, —C 1 -C 6  alkyl and mono- or dialkylamino, or 
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino and —C 1 -C 3  alkyl, or 
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, C 1 -C 6  alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo. 
   
   
   
       8 . A compound according to  claim 7 , wherein R 1  is
 —(CH 2 )-aryl, —(CH 2 )-heteroaryl, or —(CH 2 )-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NO 2 , —NR 105 R′ 105 , —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′ (where R 105 , R′ 105 , R and R′ are as defined above), —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or
 C 1 -C 6  alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or 
 C 3 -C 7  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, —C 1 -C 6  alkyl and mono- or dialkylamino, or 
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino and —C 1 -C 3  alkyl, or 
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, C 1 -C 6  alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo. 
   
   
   
       9 . A compound according to  claim 8 , wherein R 1  is
 —CH 2 -phenyl or —CH 2 -pyridinyl where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, C 1 -C 4  alkoxy, hydroxy, —NO 2 , and
 C 1 -C 4  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, SH, NH 2 , NH(C 1 -C 6  alkyl), N—(C 1 -C 6  alkyl)(C 1 -C 6  alkyl), C≡N, CF 3 . 
   
   
   
       10 . A compound according to  claim 9 , wherein R 1  is
 —CH 2 -phenyl or —CH 2 -pyridinyl where the phenyl or pyridinyl rings are each optionally substituted with 1 or 2 groups independently selected from halogen, C 1 -C 2  alkyl, C 1 -C 2  alkoxy, hydroxy, —CF 3 , and —NO 2 .   
   
   
       11 . A compound according to  claim 10 , wherein R 1  is —CH 2 -phenyl where the phenyl ring is optionally substituted with 2 groups independently selected from halogen, C 1 -C 2  alkyl, C 1 -C 2  alkoxy, hydroxy, and —NO 2 . 
   
   
       12 . A compound according to  claim 11 , wherein R 1  is benzyl, or 3,5-difluorobenzyl. 
   
   
       13 . A compound according to  claim 1 , wherein X is O. 
   
   
       14 . A compound according to  claim 1 , X is S. 
   
   
       15 . A compound according to  claim 1 , X is NR 20 . 
   
   
       16 . A compound according to  claim 1 , X is NR 20 NR 20 . 
   
   
       17 . A compound according to  claim 1  selected from the group consisting of: 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-bromo-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-cyano-N,N-dipropyl isophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N,N-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-ethynyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-ethyl-N,N-dipropylisophthalamide; 
     N 3 -{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N,N′-dipropylbenzene-1,3,5-tricarboxamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-[(dimethylamino)methyl]-N,N-dipropyl isophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)oxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)oxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]oxy}propyl)-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]oxy}propyl)-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-isopropylbenzyl)oxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-isopropylbenzyl)oxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-methoxybenzyl)oxy]propyl}-5-(1,3-oxazo-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-methoxybenzyl)oxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]oxy}propyl)-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]oxy}propyl)-5-methyl-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}oxy)propyl]-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}oxy)propyl]-5-methyl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3-isopropylphenyl)cyclopropyl]oxy}propyl)-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3 isopropylphenyl)cyclopropyl]oxy}propyl)-5-methyl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3 methoxyphenyl)cyclopropyl]oxy}propyl)-5-(1,3-oxazol-2-yl)-N,N-dipropyl isophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[-(3-methoxyphenyl)cyclopropyl]oxy}propyl)-5-methyl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3 ethylphenyl)cyclopropyl]oxy}propyl)-5-(1,3-oxazol-2-yl-N,N-dipropylisophthalamide; 
     N′-((1S)-2-amino-1-(3,5-difluorobenzyl)-3-{[1-(3 ethylphenyl)cyclopropyl]oxy}propyl)-5-methyl-N,N-dipropylisophthalamide; 
     N 4 -{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-6-(1,3-oxazol-2-yl)-N 2 ,N 2 -dipropylpyridine-2,4-dicarboxamide; 
     N 4 -{((1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-6-methyl-N 2 ,N 2 -dipropylpyridine-2,4-dicarboxamide; 
     N 2 -{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-6-(1,3-oxazol-2-yl)-N 4 , N 4 -dipropylpyridine-2,4-dicarboxamide; 
     N 2 -{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-6-methyl-N 4 ,N 4 -dipropylpyridine-2,4-dicarboxamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N-ethyl-5-(1,3-oxazol-2-yl)-N-propylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N-ethyl-5-methyl-N-propylisophthalamide; 
     N′-({(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N-butyl-N-methyl-5-(1,3-oxazo-2-yl)isophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-N-butyl-N,N-dimethylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)oxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(6-ethylpyridin-2-yl)methoxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(6-ethylpyridin-2-yl)methoxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(4-ethylpyridin-2-yl)methoxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(4-ethylpyridin-2-yl)methoxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(4-ethylpyrimidin-2-yl)methoxy]propyl}-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-{(1S)-2-amino-1-(3,5-difluorobenzyl)-3-[(4-ethylpyrimidin-2-yl)methoxy]propyl}-5-methyl-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-3-butoxy-1-(3,5-difluorobenzyl)propyl]-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-3-butoxy-1-(3,5-difluorobenzyl)propyl]-5-methyl-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-(3-methylbutoxy)propyl]-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-(3-methylbutoxy)propyl]-5-methyl-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-propoxypropyl]-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-propoxypropyl]-5-methyl-N,N-dipropylisophthalamide; 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-isobutoxypropyl]-5-(1,3-oxazol-2-yl)-N,N-dipropylisophthalamide; and 
     N′-[(1S)-2-amino-1-(3,5-difluorobenzyl)-3-isobutoxypropyl]-5-methyl-N,N-dipropylisophthalamide. 
   
   
       18 . A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound or salt according to  claim 1 . 
   
   
       19 . A method for making a compound according to  claim 1 . 
   
   
       20 . A pharmaceutical composition comprising a compound according to  claims 1  in combination with a physiologically acceptable carrier or excipient. 
   
   
       21 - 22 . (canceled)