Macrocyclic 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 or prevention 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 prevention or treatment of such diseases in which the beta-secretase enzyme is involved
1. A compound of the formula I:
wherein:
R 1 is
R 4 —S(O) p N(R 5 )—,
wherein R 4 is independently selected from the group consisting of:
(a) —C 1-8 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(b) —NR 5 R 6 ,
(c) phenyl, and
(d) benzyl,
wherein R 5 and R 6 are independently selected from the group consisting of:
(a) hydrogen,
(b) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) phenyl, and
(d) benzyl,
and wherein p is independently 0, 1, or 2;
R 2 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, or —C 3-8 cycloalkyl which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) —S(O) p —C 1-6 alkyl,
(f) —CN,
(g) —CO 2 H,
(h) —CO 2 —C 1-6 alkyl,
(i) —CO—NR 5 R 6 ,
(j) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —CN,
(iii) halo,
(iv) —CF 3 ,
(v) —O—R 5 , and
(vi) —CO 2 R 5 ,
(3) phenyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —CN,
(c) halo,
(d) —CF 3 ,
(e) —O—R 5 , and
(f) —CO 2 R 5 ;
R 3 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, or —C 3-8 cycloalkyl which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl or pyridyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —CN,
(iii) halo,
(iv) —CF 3 ,
(v) —O—R 5 , and
(vi) —CO 2 R 5 ,
(f) —S(O) p N(R 5 )—C 1-6 alkyl, and
(g) —S(O) p N(R 5 )-phenyl,
(3) phenyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —CN,
(c) halo,
(d) —CF 3 ,
(e) —O—R 5 , and
(f) —CO 2 R 5 ;
X is selected from the group consisting of:
(1) —CH 2 —, and
(2) —O—;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula II:
3. The compound of claim 2 wherein:
R 1 is selected from:
(1) CH 3 —S(O) 2 N(CH 3 )—;
(2) CH 3 CH 2 —S(O) 2 N(CH 3 )—;
(3) (CH 3 ) 2 CH—S(O) 2 N(CH 3 )—;
(4) phenyl-S(O) 2 N(CH 3 )—; and
(5) (CH 3 ) 2 N—S(O) 2 N(CH 3 )—;
R 2 is —C 1-6 alkyl, unsubstituted or substituted with cyclopropyl or halo;
R 3 is —C 1-6 alkyl or —C 3-8 cycloalkyl; and
X is —CH 2 — or —O—;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 of the formula III:
5. The compound of claim 1 wherein:
R 1 is selected from:
(1) CH 3 —S(O) 2 N(CH 3 )—;
(2) CH 3 CH 2 —S(O) 2 N(CH 3 )—;
(3) (CH 3 ) 2 CH—S(O) 2 N(CH 3 )—;
(4) phenyl-S(O) 2 N(CH 3 )—; and
(5) (CH 3 ) 2 N—S(O) 2 N(CH 3 )—;
R 2 is —C 1-6 alkyl, unsubstituted or substituted with cyclopropyl or halo;
R 3 is —C 1-6 alkyl or —C 3-8 cycloalkyl; and
X is —CH 2 — or —O—;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 wherein:
R 1 is R 4 —S(O) 2 N(R 5 )—,
wherein R 4 is independently selected from the group consisting of:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(b) phenyl, and
(c) benzyl,
and wherein R 5 is independently selected from the group consisting of:
(a) hydrogen,
(b) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) phenyl, and
(d) benzyl.
7. The compound of claim 6 wherein R 1 is selected from:
(1) CH 3 —S(O) 2 N(CH 3 )—;
(2) CH 3 CH 2 —S(O) 2 N(CH 3 )—;
(3) (CH 3 ) 2 CH—S(O) 2 N(CH 3 )—; and
(4) phenyl-S(O) 2 N(CH 3 )—;
(5) (CH 3 ) 2 N—S(O) 2 N(CH 3 )—.
8. The compound of claim 7 wherein R 1 is CH 3 —S(O) 2 N(CH 3 )—.
9. The compound of claim 1 wherein R 2 is —C 1-6 alkyl, unsubstituted or substituted with cyclopropyl or halo.
10. The compound of claim 9 wherein R 2 is selected from:
(1) CH 3 —;
(2) CH 3 CH 2 —;
(3) (CH 3 ) 2 CH—;
(4) CH 3 CH 2 CH 2 —;
(5) (CH 3 ) 2 CHCH 2 —;
(6) CH 3 CH 2 CH 2 CH 2 —;
(7) CH 3 CH 2 CH 2 CH 2 CH 2 —;
(8) cyclopropyl-CH 2 —;
(9) CF 3 CH 2 —; and
(10) CH 2 FCH 2 —.
11. The compound of claim 1 wherein R 3 is —C 1-6 alkyl or —C 3-8 cycloalkyl.
12. The compound of claim 11 wherein R 3 is selected from:
(1) CH 3 —;
(2) CH 3 CH 2 —;
(3) (CH 3 ) 2 CH—;
(4) CH 3 CH 2 CH 2 —;
(5) (CH 3 ) 2 CHCH 2 —;
(6) CH 3 CH 2 CH 2 CH 2 —;
(7) CH 3 CH 2 CH 2 CH 2 CH 2 —; and
(8) bicyclo[2.2.1]heptyl-.
13. The compound of claim 12 wherein R 3 is (CH 3 ) 2 CHCH 2 —.
14. A compound of claim 1 which is selected from the group consisting of:
Ex
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or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
16. A compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.