2,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's Disease
View Patent ↗The present invention is directed to 2,4,6-substituted pyridyl derivative compounds 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 (I):
wherein:
X is
Y 1 is N and Y 2 and Y 3 are each CH;
A is selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl, and
(3) —C 2-10 alkenyl,
wherein said alkyl or alkenyl is unsubstituted or substituted with one or more
(a) halo,
(b) —C 3-12 cycloalkyl,
(c) —OH,
(d) —CN,
(e) —O—C 1-10 alkyl,
(f) phenyl, or
and said phenyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl,
(v) —C 1-10 alkyl, or
(vi) —C 3-12 cycloalkyl;
Q is —C 0-3 alkyl, wherein said alkyl is unsubstituted or substituted with one or more
(1) halo,
(2) —C 3-12 cycloalkyl,
(3) —OH,
(4) —CN,
(5) —O—C 1-10 alkyl, and
(6) —C 1-10 alkyl;
R 1 is (1) aryl selected from the group consisting of phenyl and napthyl,
(3) —C 1-10 alkyl, and
(4) C 3-8 cycloalkyl, said cycloalkyl optionally fused to a C 6-10 aryl group,
wherein said alkyl, cycloalkyl, or aryl is unsubstituted or substituted with one or more
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with halogen,
(c) —OH,
(d) —CN,
(e) —O—C 1-10 alkyl,
(f) —C 3-12 cycloalkyl, or
(g) —NR 8 R 9 ;
R 2 is selected from the group consisting of
(1) —OH, and
(2) —NR 8 R 9 , wherein R 8 and R 9 are selected from the group consisting of
(a) hydrogen,
(b) C 1-10 alkyl, and
(c) C 0-6 alkyl-C 6-10 aryl,
R 4 is selected from the group consisting of
(1)—C 1-10 alkyl, or
(2) —C 3-12 cycloalkyl,
wherein said alkyl and cycloalkyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —O—C 1-10 alkyl,
(e) —C 1-10 alkyl,
(f) —C 3-12 cycloalkyl,
(g) aryl selected from the group consisting of phenyl and napthyl, or
and said aryl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl,
(v) —C 3-12 cycloalkyl, or
(vi) —C 1-10 alkyl;
R 7 is selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) aryl selected from the group consisting of phenyl and naphthyl;
wherein said alkyl or aryl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —O—C 1-10 alkyl,
(e) —C 3-12 cycloalkyl,
(f) aryl selected from the group consisting of phenyl and napthyl, or
wherein said cycloalkyl, or aryl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl,
(v) —C 3-12 cycloalkyl, or
(vi) aryl selected from the group consisting of phenyl and napthyl;
R 5 and R 6 are independently selected from the group consisting of
(1) hydrogen,
(2)—C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl, and
(5) —C 1-10 alkyl-C 3-12 cycloalkyl,
wherein said alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl
(e) —C 3-12 cycloalkyl,
(f) —O—C 1-10 alkyl,
(h) phenyl, or
(i) —NR 8 R 9 ;
and n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof, or an individual enantiomer or diastereomer of said compound or said salt.
2. The compound of claim 1 wherein R 1 is phenyl and Q is CH 2 .
3. The compound of claim 1 wherein R 2 is —NR 8 R 9 .
4. The compound of claim 1 wherein A is C 1-6 alkyl.
5. The compound of claim 1 wherein R 4 and R 7 are C 1-10 alkyl.
6. The compound of claim 1 which is a compound of formula (II)
wherein A, X, Y 1 , Y 2 , Y 3 , Q, R 1 , R 2 , R 4 , R 5 , and R 7 , are as defined in claim 1 , and R 10 is selected from the group consisting of H and C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof, or an individual enantiomer or diastereomer of said compound or said salt.
7. The compound of claim 6 , wherein R 1 is phenyl and Q is CH 2 .
8. The compound of claim 6 , wherein R 2 is NR 8 R 9 .
9. The compound of claim 6 , wherein R 5 is hydrogen or C 1-10 alkyl,wherein said C 1-10 alkyl is substituted or unsubstituted with one or more:
(1) halo,
(2) —OH,
(3) —CN,
(4) phenyl,
(5) —OC 1-10 alkyl, or
(6) —NR 8 R 9 .
10. The compound of claim 9 , wherein R 5 is C 1-10 alkyl, wherein said C 1-10 alkyl is substituted or unsubstituted with one or more halo.
11. The compound of claim 1 which is selected from the group consisting of
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
27
28
31
32
33
34
35
36
37
38
51
53
54
55
56
57
58
59
60
61
63
64
66
67
68
71
74
78
79
80
81
82
83
85
87
90
and pharmaceutically acceptable salts thereof.
12. The pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.