Spiropyrrolidine beta-secretase inhibitors for the treatment of alzheimer's disease

摘要

The present invention is directed to spiropyrrolidine compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.;

主权项

1. A compound of the formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from
(1) hydrogen(2) C1-6alkyl,(3) C2-6alkenyl,(4) —C3-9 cycloalkyl,(5) —C6-10aryl,(6) heteroaryl group having from 5 to 12 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,(7) a heterocyclic group having 4 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,wherein said alkyl, alkenyl, aryl, cycloalkyl, heterocyclic or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,(b) —OH,(c) —CN,(d) —C1-6 alkyl,(e) —C3-8 cycloalkyl,(f) —O—C1-6 alkyl,(g) —O—CH2—C6-10aryl,(h) —C6-10aryl,(i) heteroaryl group having from 5 to 12 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,(j) oxo,(k) a heterocyclic group having 4 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,(l) —O—CH2—C3-8 cycloalkyl,(m) —C(═O)—C1-6 alkyl, or(n) —NR5AR5B; R3 and R4 are each independently selected from:
(1) hydrogen,(2) OH,(3) —C1-6 alkyl,(4) —CN,(5) —C6-10 aryl, or(6) heteroaryl group having from 5 to 12 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,wherein said alkyl, aryl or heteroaryl R2 or R3 moiety is optionally substituted with one or more
(a) halo,(b) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen, and
(c) —O—C 1-6 alkyl; and R10 and R11 are each independently selected from:
(1) hydrogen,(2) —C1-6 alkyl,(3) hydroxyl,(4) —(CH2)m C6-10aryl(5) —C2-6alkenyl,(6) —O—C1-6alkyl,(7) halogen,(8) —SO2—C1-6alkyl,(9) —NR5AR5B,(10) —C3-8 cycloalkyl,(11) —C(═O)—(O)m—C1-6 alkyl,(12) —C(═O)—(O)m—C6-10 aryl,(13) —C(═O)—NH—C1-6 alkyl, and(14) —S(═O)2—C6-10 aryl,wherein said alkyl, cycloalkyl, alkenyl or aryl moiety is optionally substituted with one or more
(a) halo,(b) hydroxyl,(c) —C1-6 alkyl,(d) —NR5AR5B,(e) —O—C1-6 alkyl, and(f) —C6-10aryl,wherein said wherein said alky or aryl is optionally substituted with one or more halo;R5A and R5B are independently selected from the group consisting of(1) hydrogen,(2) —C1-6 alkyl,(3) —C(═O)—(O)m—C1-6 alkyl,(4) —C(═O)—(O)m—C6-10 aryl,(5) —SO2—C3-8 cycloalkyl,(6) —SO2—C1-6 alkyl,(4) —C(═O)—NR6AR6B, wherein R6A and R6B are selected from the group consisting ofwherein the alkyl, cycloalkyl or aryl moiety is optionally substituted with one or more
(a) halogen,(b) hydroxyl,(c) —O—C1-6 alkyl, or(d) —C(═O)—(O)m—C1-6 alkyl,or R6A and R6B are linked together with the nitrogen to which they are attached to form a 4-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur, and the ring is optionally substituted with one or more
(a) halogen,(b) hydroxyl,(c) C1-6 alkyl,(d) —O—C1-6 alkyl,(e) —C(═O)—(O)m—C1-6 alkyl, or(f) —SO2—C1-6 alkyl; and m is 0 or 1.