Substituted amide beta secretase inhibitors

1. A compound having the structural formula

or a pharmaceutically acceptable salt thereof, wherein

R 1 is

R 2 is cycloalkyl;

R 3 is phenylene;

R 4 is hydrogen, —C(O)-alkyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaralkyl or heteroaryl;

R 7 is 1 to 4 moieties, each moiety being independently selected from hydrogen, —OH, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy and alkoxy, with the proviso that when R 7 is —OH, aralkoxy, heteroaralkoxy and alkoxy, R 7 is not attached to a ring carbon adjacent to a ring nitrogen;

R 6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —C(O)R 8 , —C(O)OR 11 , —S(O)R 8 , —S(O 2 )R 8 or —CN; with the proviso that when Y is O, R 6 cannot be —C(O)R 8 , —C(O)OR 11 , —S(O)R 8 , —S(O 2 )R 8 or —CN;

R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl or —N(R 9 )(R 10 );

R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, alkenyl and alkynyl;

or R 9 and R 10 together with the nitrogen to which they are attached, form a 3-7 membered heterocyclyl ring;

R 11 is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, alkenyl or alkynyl;

X is a bond connecting R 3 and R 4 , —O—, —S—, alkylene, -alkyleneNH—, -alkyleneNHC(O)—, -alkyleneNHSO 2 —, —NH—, —NHC(O)—, or —NHSO 2 —;

Y is O or (H, H);

m is 0, 1, 2, or 3; and

n is 1;

wherein each alkyl is optionally substituted with 1 to 3 moieties selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl) 2 , carboxy and —C(O)O-alkyl; and

wherein each arylene, heteroarylene, heterocyclylalkyl, heterocyclylene, cycloalkylene, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aralkoxy or heteroaralkoxy is optionally substituted with 1 to 4 moieties selected from the group consisting of —CF 3 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH 2 , —C(═NH)—NH 2 , —C(═NH)—NH(alkyl), Y 1 Y 2 N—, Y 1 Y 2 N-alkyl-, Y 1 Y 2 NC(O)—, Y 1 Y 2 NSO 2 — and —SO 2 NY 1 Y 2 , wherein Y 1 and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, —C(O)alkyl and aralkyl, with the proviso that cycloalkyl, cycloalkylene, heterocyclyl and heterocyclylene can be substituted with ═O.

2. The compound of claim 1 wherein R 3 is phenylene or halo-substituted phenylene.

3. The compound of claim 2 wherein R 3 is phenylene or fluoro substituted phenylene.

4. The compound of claim 1 wherein R 4 is hydrogen, —C(O)-alkyl, alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, alkoxyalkyl, heteroaralkyl, substituted heteroaryl, substituted heteroaralkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, substituted heterocyclyl, substituted heterocyclylalkyl or heteroaryl.

5. The compound of claim 4 wherein R 4 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, —C(O)Oethyl,

6. The compound of claim 1 wherein R 7 is hydrogen, alkyl substituted by a cycloalkyl group, alkyl substituted by an aryl or heteroaryl group.

7. The compound of claim 1 wherein R 6 is aralkyl or —S(O) 2 —R 8 .

8. The compound of claim 1 wherein R 6 is

9. The compound of claim 1 wherein X is a bond connecting R 3 and R 4 , O, alkylene, -alkylene-NHSO 2 — or -alkylene-NHC(O)—; Y is O and n is 1.

10. The compound of claim 1 wherein

R 1 is

n is 1;

R 2 is cycloalkyl;

R 3 is phenylene or halo-substituted phenylene;

R 4 is hydrogen, —C(O)-alkyl, alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, alkoxyalkyl, heteroaralkyl, substituted heteroaryl, substituted heteroaralkyl, heterocyclyl, heterocyclylalkyl, substituted heterocyclyl, substituted heterocyclylalkyl or heteroaryl;

R 7 is hydrogen, alkyl substituted by a cycloalkyl group, alkyl substituted by an aryl or heteroaryl group;

R 6 is aralkyl or —S(O) 2 R 8 ;

R 8 is

X is a bond connecting R 3 and R 4 , O, alkylene, -alkylene-NHSO 2 — or -alkylene-NHC(O)—; and

Y is O.

11. The compound of claim 10 wherein R 3 is

12. The compound of claim 10 wherein R 4 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, —C(O)Oethyl,

13. The compound of claim 10 wherein R 6 is

14. The compound of claim 10 wherein R 7 is hydrogen.

15. The compound of claim 10 wherein X is a bond connecting R 3 and R 4 , O, alkylene, -alkylene-NHSO 2 — or -alkylene-NHC(O)—; Y is O and n is 1.

16. A compound of claim 1 having the stereochemical structure

17. The compound of claim 1 , wherein R 2 is cyclopropyl.

18. The compound of claim 10 , wherein R 2 is cyclopropyl.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically effective carrier.