Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of Alzheimer's disease
View Patent ↗The present invention is directed to macrocyclic aminopyridyl compounds represented by general 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:
Y is selected from the group consisting of
(1) hydrogen,
(2) —C 1-3 alkyl, wherein said alkyl is optionally substituted with one or more halogen,
(3) halogen, and
(4) cyano;
A is selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
R 2 is selected from the group consisting of:
(1) (R 5 —SO 2 )N(R 6 )—, wherein R 5 is
(a) —C 1-10 alkyl,
wherein said alkyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl, and
(v) —C 1-10 alkyl;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) —C 1-10 alkyl, and
(e) —C 6-10 aryl
wherein said alkyl, is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl,
R 3 is
wherein if the dotted line leading to Q 3 is absent, then Q 3 is selected from the group consisting of
(a) —CH 2 —
(c) —NR x —,
wherein R x is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(v) —C 3-8 cycloalkyl,
(vi) —C 0-6 alkylene-C 6-10 aryl, and
(viii) —CO 0-6 alkyl-C 3-8 cycloalkyl,
and if the dotted line leading to Q 3 represents a bond, then Q 3 is —CH— or —CH 2 —CH—,
if the dotted line leading to R y is absent, then R y is selected from the group consisting of
(a) hydrogen,
(b) —C 1-10 alkyl,
and if the dotted line leading to R y represents a bond, then R y is selected from the group consisting of
(a) ═CH—C 1-10 alkyl,
(b) ═CH—C 0-6 alkyl-C 6-10 aryl,
Q 4 is —CH 2 :
R 4 is —(CH 2 ) s -Q 2 -(CH 2 ) t , wherein Q 2 is selected from the group consisting of
(1) —O—
(2) —O—C(═O)—, and
(3) —C(═O)—O—,
m is 1;
n is 1;
r is 0;
s is 1; and
t is 0 or 1;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 wherein Y is hydrogen.
3. The compound of any of claims 1 - 2 wherein R 4 is —(CH 2 ) s -Q 2 —(CH 2 ) t , wherein Q 2 is selected from the group consisting of
(1) —O—, wherein s and t are 1, and
(2) —O—C(═O)—, wherein s is 1 and t is 0.
4. The compound of claim 1 wherein A is —CH 3 .
5. The compound of claim 1 wherein R 2 is (R 5 —SO 2 )N(R 6 )—, wherein R 5 is methyl and R 6 is —C 1-6 alkyl.
6. The compound of claim 1 wherein the dotted line leading to Q 3 is absent, and Q 3 is NR x , R x is hydrogen, and n is 1.
7. The compound of claim 1 , wherein the dotted line leading to R y is absent and R y is selected from the group consisting of hydrogen and —CH 3 .
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
9. A method for inhibition of β-secretase activity in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 .
10. The compound, or an individual enantiomer and/or diastereomer thereof, or a pharmaceutically acceptable salt of said compound or said individual enantiomer and/or diastereomer, said compound having a structure selected from the group consisting of:
Structure
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 and a pharmaceutically acceptable carrier.
12. A method for inhibition of β-secretase activity in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of claim 10 .