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

A compound having the formula (IF):

• or a pharmaceutically acceptable salt thereof,
• wherein Q is a cyclohexyl ring unsubstituted or substituted with one or more independently selected L3 groups;
• X is —O—;
• each L3 is independently selected from the group consisting of:
• —CN, ═O, R5, —OR5;
• ═N—R5 and —N(R5)2;
• R4 is H or alkyl;
• each R5 is independently selected from the group consisting of:
• (1) H, (2) (C1-C6)alkyl, (3) hydroxyl substituted alkyl, (4) R6, (5) R7, (6) —C(O)—(C1-C6)alkyl, (7) —C(O)—(C1-C6)haloalkyl, (8) —C(O)—R6, (9) —C(O)—R7, (10) —C(O)NH—(C1-C6)alkyl, (11) —C(O)N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, (12) —S(O)2—(C1-C6)alkyl, (13) —S(O)2—(C1-C6)haloalkyl, (14) —S(O)2—R6, (15) —S(O)2—R7, (16) —S(O)2—R8, (17) -alkylene-C(O)—(C1-C6)alkyl, (18) -alkylene-C(O)—(C1-C6)haloalkyl, (19) -alkylene-C(O)—R6, (20) -alkylene-C(O)—R7, (21) -alkylene-S(O)2—(C1-C6)alkyl, (22) -alkylene-S(O)2—(C1-C6)haloalkyl, (23) -alkylene-S(O)2—R6, (24) -alkylene-S(O)2—R7, (25) -alkylene-S(O)2—R8, (26) -alkylene-NHC(O)—(C1-C6)alkyl, (27) -alkylene-NHC(O)—(C1-C6)haloalkyl, (28) -alkylene-NHC(O)—R6, (29) -alkylene-NHC(O)—R7, (30) -alkylene-NHS(O)2—(C1-C6)alkyl, (31) -alkylene-NHS(O)2—(C1-C6)haloalkyl, (32) -alkylene-NHS(O)2—R6, (33) -alkylene-NHS(O)2—R7, (34) -alkylene-N(alkyl)C(O)—(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)—(C1-C6)haloalkyl, (36) -alkylene-N(alkyl)C(O)—R6, (37) -alkylene-N(alkyl)C(O)—R7, (38) -alkylene-N(alkyl)S(O)2—(C1-C6)alkyl, (39) -alkylene-N(alkyl)S(O)2—(C1-C6)haloalkyl, (40) -alkylene-N(alkyl)S(O)2—R6, (41) -alkylene-N(alkyl)S(O)2—R7, (42) -alkylene-C(O)—NH—(C1-C6)alkyl, (43) -alkylene-C(O)—NHR6, (44) -alkylene-C(O)—NHR7, (45) -alkylene-S(O)2NH—(C1-C6)alkyl, (46) -alkylene-S(O)2NH—R6, (47) -alkylene-S(O)2NH—R7, (48) -alkylene-C(O)—N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, (49) -alkylene-C(O)—N(alkyl)R6, (50) -alkylene-C(O)—N(alkyl)R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)—NH-alkyl, (56) -alkylene-OC(O)NH—R8, (57) -alkylene-CN, (58) —R8, (59) -alkylene-SH, (60) -alkylene-S(O)2—NH—R8, (61) -alkylene-S(O)2-alkylene-R6, (62) halo substituted alkylene, (63) —C(O)OR8, (64) —C(O)O(C1-C6)alkyl, (65) —C(O)R8, (66) —C(O)-alkylene-β-(C1-C6)alkyl, (67) —C(O)NH2, (68) -alkylene-O—(C1-C6)alkyl, (69) -alkylene-R8, (70) —S(O)2-halo(C1-C6)alkyl, (71) hydroxy substituted halo(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH—S(O)2—R8, (74) -alkylene-NH—C(O)—R8, (75) -alkylene-NH—C(O)O—(C1-C6)alkyl, (76) -alkylene-O—C(O)—(C1-C6)alkyl, (77) -alkylene-O—S(O)2—(C1-C6)alkyl, (78) -alkylene-R6, (79) -alkylene-R7, (80) -alkylene-NH—C(O)—NH—(C1-C6)alkyl, (81) -alkylene-N(S(O)2halo(C1-C6)alkyl)2 wherein each —S(O)2halo(C1-C6)alkyl moiety is independently selected, (82) -alkylene-N((C1-C6)alkyl)S(O)2R8, (83) -alkylene-OC(O)—N(alkyl)2 wherein each alkyl is independently selected, (84) -alkylene-NH—(C1-C6)alkyl, (85) —C(O)-alkylene-C(O)O—(C1-C6)alkyl, (86) —C(O)—C(O)—O—(C1-C6)alkyl, (87) —C(O)-alkylene-R6, (88) —C(O)—NH—R8, (89) —C(O)—NH—R6, (90) —C(O)—NH-alkylene-R6, (91) —C(O)-alkylene-NH—S(O)2-halo(C1-C6)alkyl, (92) —C(O)-alkylene-NH—C(O)—O—(C1-C6)alkyl, (93) —C(O)-alkylene-NH2, (94) —C(O)-alkylene-NH—S(O)2—R8, (95) —C(O)-alkylene-NH—S(O)2—(C1-C6)alkyl, (96) —C(O)-alkylene-NH—C(O)—(C1-C6)alkyl, (97) —C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2 wherein each —S(O)2(C1-C6)alkyl moiety is independently selected, (98) —C(O)-alkylene-NH—C(O)—NH—(C1-C6)alkyl, (99) -alkylene-O—R6, (100) -alkylene-R7, (101) —C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)—O—(C1-C6)alkyl, (104) haloalkyl, (105) halo, (106) -alkylene —C(O)—NH2, (107) ═N—O—(C1-C6)alkyl, (108) ═N—O-alkylene-R6, (109) ═N—O-alkenyl, (110) ═N—O—R6, (111) ═N—NH—S(O)2—R6, (112) alkenyl, (113)=R8, (114) -alkylene-O-alkylene-SK(C1-C6)alkyl)3 wherein each alkyl is independently selected, (115) -alkylene-S(O)2—N(alkylene-R6)2 wherein each alkylene-R6 moiety is independently selected, (116) -alkylene-S(O)2—NH2, (117) —O—C(O)—R9, (118) —O—C(O)—(C1-C6)alkyl, (119) —S(O)2NH((C1-C6)alkyl), (120) —S(O)2N((C1-C6)alkyl)2 wherein each alkyl is independently selected, (121) —S(O)2NHR8, (122) -alkylene-C(O)OH, (123) -alkylene-C(O)NH(halo(C1-C6)alkyl), (124) -alkylene-C(O)—NH-alkylene-R8, (125) -alkylene-C(O)—NH-alkylene-OH, (126) —C(O)O(haloC1-C6alkyl), (127) —C(O)OR6, (128) —C(O)OR7, (129) -alkylene-NHSO2N(alkyl)2 wherein each alkyl is independently selected, (130) -alkylene-NHSO2NHalkyl, (131) -alkylene-N(alkyl)-SO2N(alkyl)2 wherein each alkyl is independently selected, (132) -alkylene-N(alkyl)-SO2NHalkyl wherein each alkyl is independently selected, (133) -alkylene-O—SO2-alkyl, (134) -alkylene-NH—C(O)—N(alkyl)2 wherein each alkyl is independently selected, (135) -alkylene-NH—C(O)—NHalkyl, (136) -alkylene-N(alkyl)-C(O)—N-(alkyl)2 wherein each alkyl is independently selected, (137) -alkylene-N(alkyl)-C(O)—NHalkyl, (138) —CN, (139) -alkylene-P(O)(Oalkyl)2 wherein each alkyl is independently selected, (140) -alkylene-CH(OH)—P(O)(Oalkyl)2 wherein each alkyl is independently selected, (141) -alkylene-OC(O)N(C1-C6 alkyl)-R8, (142) -alkylene-S(O)2—N(C1-C6 alkyl)-R8, (143) -alkylene-N(C1-C6 alkyl)-S(O)2—R8, (144) -alkylene-N(C1-C6 alkyl)-C(O)—R8, (145) -alkylene-N(C1-C6 alkyl)-C(O)O—(C1-C6)alkyl wherein each alkyl is independently selected, (146) -alkylene-N(C1-C6 alkyl)-C(O)—NH—(C1-C6)alkyl wherein each alkyl is independently selected, (147) -alkylene-NH—C(O)—N(C1-C6 alkyl)2 wherein each alkyl is independently selected, (148) -alkylene-N(C1-C6 alkyl)-C(O)—N(C1-C6 alkyl)2 wherein each alkyl is independently selected, (149) —C(O)—N(C1-C6 alkyl)-R8, (150) —C(O)—N(C1-C6 alkyl)-R6, (151) —C(O)—N(C1-C6 alkyl)-alkylene-R6, (152) —C(O)-alkylene-N(C1-C6 alkyl)-S(O)2-halo(C1-C6)alkyl wherein each alkyl is independently selected, (153) —C(O)-alkylene-N(C1-C6 alkyl)-C(O)—O—(C1-C6)alkyl wherein each alkyl is independently selected, (154) —C(O)-alkylene-NH(C1-C6 alkyl), (155) —C(O)-alkylene-N(C1-C6 alkyl)2 wherein each alkyl is independently selected, (156) —C(O)-alkylene-N(C1-C6 alkyl)-S(O)2—R8, (157) —C(O)-alkylene-N(C1-C6 alkyl)-S(O)2—(C1-C6)alkyl, (158) —C(O)-alkylene-N(C1-C6 alkyl)-C(O)—(C1-C6)alkyl, (159) —C(O)-alkylene-N(C1-C6 alkyl)-C(O)—NH—(C1-C6)alkyl wherein each alkyl is independently selected, (160) —C(O)-alkylene-NH—C(O)—N((C1-C6)alkyl)2 wherein each alkyl is independently selected, (161) —C(O)-alkylene-N(C1-C6 alkyl)-C(O)—N((C1-C6)alkyl)2 wherein each alkyl is independently selected, (162) -alkylene-C(O)—N(C1-C6 alkyl)2 wherein each alkyl is independently selected, (163) ═N—N(C1-C6 alkyl)-S(O)2—R6, (164) —S(O)2N(C1-C6 alkyl)R8, (165) -alkylene-C(O)N(C1-C6 alkyl)(halo(C1-C6)alkyl) wherein each alkyl group is independently selected, (166) -alkylene-C(O)N(halo(C1-C6)alkyl)2 wherein each alkyl group is independently selected, (167) -alkylene-C(O)—N(C1-C6 alkyl)-alkylene-R8, (168) -alkylene-C(O)—N(C1-C6 alkyl)-alkylene-OH, and (169) —O—C(O)—R7;
• R6 is selected from the group consisting of:
• unsubstituted (C6-C14)aryl, (C6-C14)aryl substituted with one or more L1 groups, unsubstituted (C5-C14)heteroaryl, and (C5-C14)heteroaryl substituted with one or more L1 groups;
• R7 is selected from the group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl substituted with one or more L2 groups;
• R8 is selected from the group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or more L3 groups;
• Ar is unsubstituted phenyl or phenyl substituted with one or more L1 groups;
• R9 is a bridged multicyclic heterocycloalkyl ring wherein said R9 moiety is unsubstituted or said R9 moiety is substituted with one or more L2 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-;
• each L2 is independently selected from the group consisting of:
• (a) —OH, (b) alkyl, (c) alkyl substituted with one or more —OH groups, (d) halo, (e) haloalkyl, and (f) heterocycloalkyl;
• n is 0, 1, 2 or 3;
• and
• m is 1;
• and
• provided that for the substituent —OR5, the R5 moiety and the oxygen atom to which it is bound to does not form a —O—O— group;
• and
• provided that for the substituents —OR5, ═N—R5 and —NHR5, R5 is not —CH2OH, —CH2NH2, —CH2NHalkyl, —CH2NHaryl or —C(O)OH.