Macrocyclic β-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 in 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 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 biphenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —C 3-6 cycloalkyl,
(iii) —O—C 1-6 alkyl,
(iv) halo,
(v) hydroxy,
(vi) —CF 3 ,
(vii) —OCF 3 ,
(viii) —NR 9 R 10 , and
(ix) —CN,
(f) —CO 2 R 9 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) benzyl, and
(iv) phenyl,
(g) —NR 9 R 10 , wherein R 10 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) benzyl, and
(iv) phenyl,
(h) —CONR 9 R 10 ,
(3) phenyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —C 1-6 alkyl-phenyl,
(c) —C 3-6 cycloalkyl,
(d) —O—C 1-6 alkyl,
(e) halo,
(f) hydroxy,
(g) —CF 3 ,
(h) —OCF 3 ,
(i) —NR 9 R 10 , and
(j) —CN;
R 2 is selected from the group consisting of:
(1) hydrogen,
(2) R 4 —S(O) p —,
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 p is independently 0, 1, or 2,
(3) R 4 —S(O) p N(R 5 )—,
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,
(4) —CN,
(5) —C 1-6 alkyl-CN,
(6) halogen,
wherein R 8a and R 8b are independently selected from the group consisting of:
(a) hydrogen,
(b) —CN,
(c) halo,
(d) —C 1-6 alkyl,
(e) —O—R 5 ,
(f) —S—R 5 ,
(g) —CO 2 R 5 , and
(h) tetrazolyl,
wherein n is 1, 2, 3 or 4;
R 3 is selected from the group consisting of:
(1) —CH(OH)—R 6 ,
(2) —C(O)R 6 ,
(3) —CH(R 6 )—NR 7 R 9 , and
(4) —C(O)—NR 7 R 9 ;
R 6 is independently selected from the group consisting of:
(1) hydrogen
(2) C 1-6 alkyl,
wherein Z is selected from the group consisting of —C(O)—, —CH(OH)—, and
and wherein q is 1 or 2;
R 7 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 biphenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —C 3-6 cycloalkyl,
(iii) —O—C 1-6 alkyl,
(iv) halo,
(v) hydroxy,
(vi) —CF 3 ,
(vii) —OCF 3 ,
(viii) —NR 9 R 10 , and
(ix) —CN,
(f) —CO 2 R 9 ,
(g) —NR 9 R 10 ,
(h) —CONR 9 R 10 ,
(3) —CHR 5 —CONR 9 R 10 ,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —C 1-6 alkyl-phenyl,
(c) —C 3-6 cycloalkyl,
(d) —O—C 1-6 alkyl,
(e) halo,
(f) hydroxy,
(g) —CF 3 ,
(h) —OCF 3 ,
(i) —NR 9 R 10 , and
(j) —CN;
m is independently 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R 1 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, 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 biphenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C 1-6 alkyl,
(ii) —C 3-6 cycloalkyl,
(iii) —O—C 1-6 alkyl,
(iv) halo,
(v) hydroxy,
(vi) —CF 3 ,
(vii) —OCF 3 ,
(viii) —NR 9 R 10 , and
(ix) —CN,
(f) —CO 2 R 9 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) benzyl, and
(iv) phenyl,
(g) —NR 9 R 10 , wherein R 10 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) benzyl, and
(iv) phenyl,
(h) —CONR 9 R 10 ,
(3) phenyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —C 1-6 alkyl-phenyl,
(c) —C 3-6 cycloalkyl,
(d) —O—C 1-6 alkyl,
(e) halo,
(f) hydroxy,
(g) —CF 3 ,
(h) —OCF 3 ,
(i) —NR 9 R 10 , and
(j) —CN.
3. The compound of claim 1 wherein R 1 is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) isopropyl,
(4) isobutyl, and
(5) phenyl.
4. The compound of claim 1 wherein R 2 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.
5. The compound of claim 1 wherein R 2 is
CH 3 —S(O) 2 N(CH 3 )—.
6. The compound of claim 1 wherein R 3 is selected from the group consisting of:
(1) —CH(OH)—R 6 ,
(2) —C(O)R 6 , and
(3) —CH(R 6 )—NR 7 R 9 .
7. The compound of claim 1 wherein R 6 is:
and wherein n is 2 or 3, and R 5 is hydrogen or methyl.
8. The compound of claim 1 wherein R 6 is:
wherein R 5 is hydrogen or methyl, and Z is selected from the group consisting of
—C(O)—, —CH(OH)—, and
9. The compound of claim 1 wherein R 3 is selected from the group consisting of:
(1) —CH 2 —OH, and
(2) —CH 2 —NH—CH(CH 2 CH 3 )—CO—NH—CH 2 CH(CH 3 ) 2 .
10. The compound of claim 1 wherein m is 1.
11. The compound of claim 1 wherein m is 2.
12. A compound which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.