Benzenesulfonyl-chromane, thiochromane, tetrahydronaphthalene and related gamma secretase inhibitors

A compound of the formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is selected from the group consisting of —C(R1)2—, —O—, —S—, —S(O2)—, —NR1—, and —N(C(O)R1)—;
• The dotted line () represents an optional bond between Y and Z;
• Y is selected from the group consisting of N, CH and C, and when Y is N the optional bond is absent, when Y is CH the optional bond is absent, and when Y is C the optional bond is present;
• Z is selected from the group consisting of:
• CH, C, and N, provided that both Y and Z are not N, and when Z is N the optional bond is absent, when Z is CH the optional bond is absent, and when Z is C the optional bond is present;
• Q represents a 5 to 8 membered ring fused to Rings A1 and Q1, wherein Y and Z are as defined above and the remaining Q ring members are —CH2— groups;
• Q1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q1 ring comprising at least one heteroatom selected from the group consisting of N, S, S(O), and S(O)2, or Q1 is a 5 membered ring comprising an oxygen atom;
• or
• Q1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q1 ring comprising at least one heteroatom selected from the group consisting of N, S, S(O), and S(O)2, or Q1 is a 5 membered ring comprising an oxygen atom;
• and said Q1 ring being substituted with 1 to 3 substituents independently selected from the group consisting of:
• R3 substituents;
• Each R1 is independently selected from the group consisting of H and alkyl;
• R2 is selected from the group consisting of:
• H, and alkyl;
• Each R3 substituent is independently selected from the group consisting of:
• (1) alkyl, (2) alkoxyalkyl-, (3) hydroxyalkyl, (4) —OR2, (5) arylalkyl-, (6) ═O, (7) substituted arylalkyl-, (8) alkenyl, (9) heterocycloalkylalkyl-, (10) -alkyl-C(O)OH, (11) -alkyl-NR5R6, wherein R5 and R6 are each independently selected from the group consisting of:
• H and alkyl, (12) -alkyl-C(O)NR5R6, wherein R5 and R6 are as defined in (11), (13) arylalkenyl-, (14) -alkyl-C(O)OR7 wherein R7 is a C1 to C6 alkyl group, and (15) substituted arylalkenyl-, wherein said substituted arylalkenyl- is substituted with 1 to 3 substituents independently selected from the group consisting of:
• —OR5, —NR5R6,
• —CF3, —CN, —C(O)2R5, and —C(O)NR5R6, and wherein R5 and R6 are as defined in (11);
• or
• two R3 groups bound to the same carbon, taken together with the carbon to which they are bound, form a cycloalkyl ring or form a cycloalkenyl ring;
• Ar is selected from the group consisting of:
• (a) unsubstituted aryl, (b) aryl substituted with one or more L1 groups, (c) unsubstituted heteroaryl, and (d) substituted heteroaryl substituted with one or more L1 groups;
• each L1 is independently selected from the group consisting of:
• halogen, alkyl, —CN, —CF3, —O—(C1-C6)alkyl, —O-(halo(C1-C6)alkyl), —C(O)—O—(C1-C6)alkyl, -alkylene-OH, halo(C1-C6)alkyl, hydroxyalkoxy-, and alkoxyalkoxy-;
• and
• n is 0, 1, 2 or 3.