Piperidine and pyrrolidine beta-secretase inhibitors for the treatment of alzheimer's disease
View Patent ↗The present invention is directed to 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 (II):
wherein
n is 1;
R 1 is phenyl,
wherein said phenyl R 1 group is unsubstituted or substituted with one or more groups independently selected from the group consisting of:
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is optionally substituted with halogen,
(c) —OH,
(d) —CN,
(e) —O—C 1-10 alkyl,
(f) —C 3-12 cycloalkyl, and
(g) —NR A R B ;
wherein R A and R B are selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl, and
(iii) —C 1-10 alkyl-C 6-10 aryl;
X is selected from the group consisting of
Y is selected from the group consisting of
(1) —NR 5 R 6 ,
(2) —C(═O)—NR 5 R 6 ,
(4) halogen;
R 4 is selected from the group consisting of
(1) —C 1-10 alkyl;
R 7 is selected from the group consisting of
(1) hydrogen, and
(2) —C 1-10 alkyl;
R 5 and R 6 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
and
(4) —C 1-10 alkyl-C 3-12 cycloalkyl,
wherein said alkyl or cycloalkyl R 5 or R 6 group is optionally independently substituted
with one or more groups independently 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) heteroaryl, wherein said heteroaryl is optionally substituted with halogen;
(h) phenyl,
(i) —NR A R B , and
(j) —C(═O)—NR A R B , and
(k) —C(═O)—OH,
or R 5 and R 6 are joined together with the nitrogen atom to which they are attached to
form a 4-6 membered ring, which is optionally substituted with one or more groups independently selected from the group consisting of:
(a) —C 1-10 alkyl,
(b) —C 2-10 alkenyl, and
(c) —C 2-10 alkynyl,
wherein said alkyl, alkenyl and alkynyl is optionally substituted with one or more groups independently selected from the group consisting of:
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl, and
(v) —C 3-12 cycloalkyl,
R 10 is phenyl;
R 11 is selected from the group consisting of
(1) hydrogen, and
(2) —C 1-10 alkyl;
R 12 is selected from the group consisting of
(1) hydrogen, and
(2) —C 1-10 alkyl;
R 13 is selected from the group consisting of
(1) C(═O)—R 16 ,
wherein R 16 is selected from the group consisting of
(a) —C 1-10 alkyl,
(b) —C 3-12 cycloalkyl,
(c) —(CH 2 ) n -phenyl,
(d) —C 2-10 alkenyl,
(e) —C 2-10 alkynyl, or
(f) heteroaryl,
wherein said alkyl, alkenyl and alkynyl R 16 moiety is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl, or
(v) —C 3-12 cycloalkyl,
and said cycloalkyl, heteroaryl and phenyl R 16 moiety is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl,
(iii) —OH,
(iv) —CN,
(v) —C 3-12 cycloalkyl, or
(vi) —O—C 1-10 alkyl,
(vii) heteroaryl;
R 8 is C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R 9A , R 9B and R 9C are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) —C 1-10 alkyl,
(4) —OH,
(5) —CN,
(6) —C 3-12 cycloalkyl, and
(7) —O—C 1-10 alkyl;
R 17 is selected from the group consisting of
(1) hydrogen, and
(2) Cl;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
2. A compound of claim 1 , wherein R 1 is phenyl, optionally substituted with one or more halo.
3. A compound of claim 1 , wherein R 1 is phenyl.
4. A compound of claim 1 , wherein the compound of formula (II) is a compound of formula (IIA)
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
EX
Structure
50
51
52
6. A compound of claim 3 , wherein X is
7. A compound of claim 6 , wherein R 7 is C 1 -C 10 alkyl; and Y is
wherein R 8 is C 1-10 alkyl; R 9A is halogen; R 9B is H; and R 9B is H.
8. A compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
EX
Structure
49
9. A compound of claim 3 , wherein X is
10. A compound of claim 9 , wherein Y is NR 5 R 6 .
11. A compound of claim 10 , wherein R 5 and R 6 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-10 alkyl, and
(3) —C 1-10 alkyl-C 3-12 cycloalkyl,
wherein said alkyl or cycloalkyl R 5 or R 6 group is optionally substituted with one or more groups independently selected from the groups consisting of:
(a) halo,
(b) —OH,
(c) —C 1-10 alkyl, and
(d) —O—C 1-10 alkyl.
12. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
EX
Structure
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
13. A compound of claim 3 , wherein X is:
14. A compound of claim 13 , wherein R 10 is phenyl; and R 11 is —C 1 -C 10 alkyl.
15. A compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
EX
Structure
15
16
17
18
19
16. A compound of claim 3 , wherein X is:
17. A compound of claim 16 , wherein R 12 is selected from the group consisting of H and —C 1 -C 10 alkyl; and R 13 is —C(═O)—R 16 .
18. A compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
EX
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
21. A method for the manufacture of a medicament for treating Alzheimer's Disease, comprising combining a compound of any of the embodiments of claim 1 or a pharmaceutically acceptable salt thereof, with a pharmaceutical carrier or diluent.