Bicyclic spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease
View Patent ↗The present invention is directed to bicyclic spiropiperidine 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.
1. A compound of formula (IA):
wherein:
R 1 is selected from the group consisting of
(1) hydrogen, and
(2) —C 1-10 alkyl;
R 2 is phenyl, wherein said phenyl R 2 moiety is optionally substituted with one or more moieties selected from the group consisting of:
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl,
(e) —C 3-12 cycloalkyl,
(f) —O—C 1-10 alkyl,
(g) —C 0-6 alkyl-aryl, and
(h) —C 0-6 alkyl-heteroaryl,
wherein said alkyl, cycloalkyl, aryl, and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(ii)-OH,
(iii) —CN,
(iv) —C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC 1-6 alkyl,
(vi) —C 2-6 alkenyl, or
(vii) —SO 2 C 1-3 alkyl;
Q is —CH 2 —;
R 3 is phenyl, wherein said phenyl R 3 moiety is optionally substituted with one or more moieties selected from the group consisting of:
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl,
(e) —C 2-10 alkenyl,
(f) —C 3-12 cycloalkyl,
(g) —C—C 3-12 cycloalkyl, and
(h) —O—C 1-10 alkyl,
wherein said alkyl, alkenyl, and cycloalkyl, moiety is optionally substituted with one or more
(i) halo,
(ii)-OH,
(iii) —CN,
(iv) —C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo,
(v) —OC 1-6 alkyl,
(vi) —C 2-6 alkenyl, or
(vii) —SO 2 C 1-3 alkyl;
R 4 is selected from the group consisting of hydrogen and —C 1-0 alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl.
3. A compound of claim 2 , wherein R 1 is selected from the group consisting of H, methyl, ethyl, n-propyl, and isopropyl.
4. A compound of claim 1 which is selected from the group consisting of
EX
Structure
4
5
6
7
8
9
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.