Inhibitors of beta-secretase

摘要

The present invention relates to compounds represented by Structural Formula (I):;
or a pharmaceutically acceptable salt thereof. Definitions for the variables are provided herein.

主权项

1. A compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:
each R0 is independently selected from —H, —CN, —NO2, halogen, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)2R5, —S(O)2NR12R13, —C(═O)OR5, —OC(═O)R5, —C(═S)OR5, —OC(═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═O)R5, —C(═S)R5, (C1-C6)alkyl, (C3-C4)cycloalkyl and (C3-C4)cycloalkyl(C1-C3)alkyl and wherein each (C1-C6)alkyl and (C1-C3)alkoxy represented by R0 are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy(C1-C6)alkyl, (C1-C3)alkoxy, and —NR6R7, or two R0 together with the ring carbon atom to which they are attached form a (C3-C6)cycloalkyl, optionally substituted with halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy(C1-C6)alkyl, (C1-C3)alkoxy, and —NR6R7; R1 is —H, —OH, —(C1-C4)alkoxy, (C1-C6)alkyl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, wherein each alkyl, aryl and heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halogen, —CN, —OH, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy; each R2 is independently selected from a) —H, halogen, —CN, —NO2, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)2R5, —S(O)2NR12R13, —C(═O)OR5, —OC(═O)R5, —C(═S)OR5, —OC(═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═O)R5, —C(═S)R5; and b) (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl, wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —CN, —NO2, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)2R5, —S(O)2NR12R13, —C(═O)OR5, —OC(═O)R5, —C(═S)OR5, —OC(═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═O)R5, —C(═S)R5, (C1-C6)alkyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, —(C1-C6)alkylene-NR11—SO2—(C1-C3)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, —(C1-C6)alkylene-NR11—C(═O)—(C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on the groups represented by R2 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R5 is selected from the group consisting of —H, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy(C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C3)alkyl and phenyl optionally substituted with halogen, —CN, —NO2, (C1-C3)alkyl, halo(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl; R6 is —H or (C1-C3)alkyl; R7 is —H, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl; Ring A is a 3-9 membered cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, —CN, —OR5, —NR6R7, —S(O)iR5, —NR11S(═O)2R5, —C(═O)OR5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, aryl, aryl(C1-C6)alkyl, heteroaryl and heteroaryl(C1-C6)alkyl, wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, aryl, aryl(C1-C6)alkyl, heteroaryl and heteroaryl(C1-C6)alkyl substituents on Ring A is optionally substituted with 1 to 5 substituents independently selected from the group consisting of (C1-C6)alkyl, halogen, —CN, —OH, —NR11SO2(C1-C3)alkyl, —NR11C(═O)—(C1-C3)alkyl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl, and wherein Ring A is optionally fused to a phenyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of (C1-C6)alkyl, halogen, —CN, —OH, —NR11SO2(C1-C3)alkyl, —NR11C(═O)—(C1-C3)alkyl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R11 is —H or (C1-C3)alkyl; R12 is —H or (C1-C3)alkyl; R13 is —H, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl; d is an integer from 1 to 6; i is 0, 1 or 2; and p is 1, 2, 3 or 4.