Macrocyclic spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease

1. A compound of formula (I)

wherein X is selected from the group consisting of

(1) N, and

(2) CR 5 , wherein R 5 is selected from the group consisting of

(a) hydrogen,

(b) —C 1-6 alkyl,

(c) —C 3-7 cycloalkyl,

(d) —C 0-6 alkyl-aryl,

(e) —C 0-6 alkyl-heteroaryl,

(f) halo, and

(g) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, wherein said alkyl, cycloalkyl, aryl or heteroaryl R5 moiety is optionally substituted with one or more

(i) halo,

(ii) —C 1-6 alkyl,

(iii) —O—C 1-6 alkyl, and

(iv) —NO 2 ;

R 1 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl,

(5) —C 3-12 cycloalkyl, wherein one or two of the ring carbon atoms is optionally replaced by a —Si(C 1-6 alkyl) 2 -group,

(6) —C 3-12 cycloalkenyl,

(7) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen,

(8) aryl, and

(9) heteroaryl,

wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl R 1 moiety is optionally 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,

(g) —O—CH 2 -aryl,

(h) aryl,

(i) heteroaryl,

(j) —NR 6A R 6B , wherein R 6A and R 6B are selected from the group consisting of

(i) hydrogen, and

(ii) —C 1-6 alkyl,

(k) —NR 6A C(═O)R 6B ,

(l) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,

(m) —SO 2 C 1-3 alkyl,

(n) —SO 2 NR 6A R 6B ,

(o) —NR 6A SO 2 C 1-3 alkyl,

(p) —C(═O)—O—R 6A ,

(q) —C(═O)NR 6A R 6B ,

(r) —C(═O)R 6A , and

(s) —Si(C 1-6 alkyl) 3 ,

wherein said alkyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with one or more

(i) halo,

(ii) —C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen,

(iii) —O—C 1-6 alkyl, and

(iv) —NO 2 ;

R 2 is selected from the group consisting of

(1) —C 1-4 alkylene,

(3) —C 2-4 alkenylene,

(4) —C 2-4 alkynylene,

(5) —C 3-12 cycloalkylene, wherein one or two of the ring carbon atoms is optionally replaced by a —Si(C 1-6 alkyl) 2 - group,

(6) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,

(7) arylene, and

(8) heteroarylene,

wherein said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclic group, arylene

or heteroarylene R 2 moiety is optionally 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,

(g) —C 0-6 alkyl-aryl, wherein said aryl is optionally substituted with one or more halo,

(h) —C 0-6 alkyl-heteroaryl,

(i) —NC(═O)—NR 6A R 6B ,

(j) —NC(═O)—C 1-3 alkyl-NR 6A R 6B ,

(k) —N R 6A C(═O) R 6B ,

(l) —NR 6A R 6B ,

(m) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, and

(n) —Si(C 1-6 alkyl) 3 ,

and said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moiety is optionally substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —C 1-10 alkyl,

(v) —OC 1-10 alkyl,

(vi) —SO 2 C 1-3 alkyl,

(vii) —SO 2 NR 6A R 6B ,

(viii) —NR 6A SO 2 C 1-3 alkyl,

(ix) —C(═O)—O—R 6A , and

(x) —C(═O)NR 6A R 6B ;

R 3 is selected from the group consisting of

(1) —C 1-4 alkylene,

(2) —C 2-4 alkenylene,

(3) —C 2-4 alkynylene,

(4) —C 3-12 cycloalkylene, wherein one or two of the ring carbon atoms is optionally replaced by a —Si(C 1-6 alkyl) 2 - group,

(5) —C 0-4 alkylene-C 3-12 cycloalkenylene,

(6) —C 0-4 alkylene-phenylene, and

(7) C 0-4 alkylene-heteroarylene,

wherein said alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, phenylene or heteroarylene R 3 moiety is optionally substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 1-10 alkyl,

(e) —C 2-10 alkenyl,

(f) —C 3-12 cycloalkyl,

(g) —O—C 3-12 cycloalkyl,

(h) —O—C 1-10 alkyl,

(i) —O—C 3-12 heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,

(j) aryl,

(k) heteroaryl,

(l) —NR 6A R 6B , and

(m) —Si(C 1-6 alkyl) 3 ,

and said alkyl, alkenyl, cycloalkyl, heterocyclic, aryl and heteroaryl moiety is optionally substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —C 3-12 cycloalkyl,

(v) —C 1-10 alkyl,

(vi) —OC 1-10 alkyl,

(vii) —NR 6A R 6B ,

(viii) —C 2-6 alkenyl,

(ix) —C 1-6 haloalkyl,

(x) —SO 2 C 1-3 alkyl,

(xi) —SO 2 NR 6A R 6B , and

(xii) —CONR 6A R 6B ;

R 4 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-4 alkyl, and

(3) —C 2-4 alkenyl,

wherein said alkyl or alkenyl R 4 group is optionally substituted with one or more

(a) halo,

(b) —OH,

(c) —C 1-6 alkyl,

(d) —CN,

(e) —O—C 1-10 alkyl,

(f) —C(═O)—R 7 , wherein R 7 is selected from the group consisting of

(i) hydrogen,

(ii) OH,

(iii) —C 1-6 alkyl,

(iv) —OC 1-6 alkyl, and

(v) aryl;

(g) —NR 8 R 9 , wherein R 8 and R 9 are selected from the group consisting of

(i) hydrogen, and

(ii) —C 1-6 alkyl, and

(h) —S(O) n —C 1-6 alkyl, wherein n is 0, 1 or 2,

Y is selected from the group consisting of

(1) —O—,

(2) —NR 8 R 9 —,

(3) —S(O) p —, wherein p is 0, 1 or 2,

(4) —C(═O)—NR 8 R 9 —,

(5) —NR 8 R 9 —C(═O)—

(6) —C 1-5 alkylene, and

(7) —C 2-5 alkenylene,

wherein said alkylene or alkenylene Y moiety is optionally substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —C 3-12 cycloalkyl,

(v) —C 1-10 alkyl,

(vi) —OC 1-10 alkyl, and

(vii) —C 2-4 alkenyl;

and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein X is N.

3. A compound of claim 1 , wherein X is CR 5 .

4. A compound of claim 1 , wherein R 1 is selected from the group consisting of

(1) —C 1-10 alkyl, and

(2) —C 3-12 cycloalkyl,

wherein said alkyl or cycloalkyl R 1 moiety is optionally substituted with one or more

(a) halo,

(b) —OH, and

(c) —CN.

5. A compound of claim 1 , wherein R 2 is selected from the group consisting of optionally substituted —C 1-4 alkylene or phenylene.

6. A compound of claim 1 , wherein R 3 is selected from the group consisting of —C 1-4 alkylene or —C 0-4 alkylene-phenylene.

7. A compound of claim 1 , wherein R 4 is selected from the group consisting of hydrogen or methyl.

8. A compound of claim 1 , wherein Y is selected from the group consisting of

(1) —C 1-4 alkylene,

(2) —C(═O)NR 8 R 9 , or

(3) —NR 8 R 9 —C(═O)—.

9. A compound of claim 1 , wherein R 2 is C 1-4 alkylene, Y is C 1-5 alkylene or C 2-5 alkenylene, and R 3 is benzyl.

10. A compound of claim 1 , wherein R 2 is C 1-4 alkylene, Y is —C(═O)—NR 7 R 8 — or —NR 7 R 8 —(═O)— and R 3 is benzylene.

11. A compound of claim 1 , wherein R 2 is phenyl, Y is C 1-5 alkylene or C 2-5 alkenylene, and R 3 is C 1-4 alkylene or C 2-4 alkenylene.

12. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II)

wherein X, R 1 , R 2 , R 4 and Y are as defined in claim 1 , and pharmaceutically acceptable salts thereof.

13. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III)

wherein X, R 1 , R 3 , R 4 and Y are as defined in claim 1 , and pharmaceutically acceptable salts thereof.

14. A compound of claim 1 , which is selected from the group consisting of

1-(cyclohexylamino)-6,7,8,9,17,18-hexahydro-3H,5H,15H-16,18a-ethano-14,10-(metheno)imidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-8-methylene-6,7,8,13,15,16-hexahydro-3H,5H-14,16a-ethano-9,12-ethenoimidazo[1,5-a] [1,5] diazacyclotetradecin-3-one;

(7Z)-1-(cyclohexylamino)-8-methyl-6,13,15,16-tetrahydro-3H,5H-14,16a-ethano-9,12-ethenoimidazo[1,5-a][1,5]diazacyclotetradecin-3-one;

(8E)-1-(cyclohexylamino)-5,6,7,10,18,19-hexahydro-3H,16H-17,19a-ethano-15,11-(metheno)imidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-8-methyl-6,7,8,13,15,16-hexahydro-3H,5H-14,16a-ethano-9,12-ethenoimidazo[1,5-a][1,5]diazacyclotetradecin-3-one;

1-(cyclohexylamino)-5,6,7,8,9,10,18,19-octahydro-3H,16H-17,19a-ethano-15,11-(metheno)imidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-6,7,10,15,17,18-hexahydro-3H,5H-16,18a-ethano-11,14-ethenoimidazo[5,1-d][1,5,10]triazacyclohexadecine-3,8(9H)-dione;

1-(cyclohexylamino)-10,11,12,13,14,15,16,17,19,20-decahydro-3H,9H-18,20a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclooctadecin-3-one;

2-(cyclohexylamino)-3,5,21-triazahexacyclo[19.2.2.2 6,9 0.2 11,14 0.2 16,19 0.0 1,5 ]hentriaconta-2,6,8,11,13, 16,18,26,28,30-decaen-4-one;

2-(cyclohexylamino)-15-methyl-3,5,21-triazahexacyclo[19.2.2.2 6.9 0.2 11,14 0.2 16,19 0.2 1,5 ]hentriaconta-2,6,8,11,13,16,18,26,28,30-decaen-4-one;

1-(cyclohexylamino)-6,7,8,9,10,11,19,20-octahydro-3H,5H,17H-18,20a-ethano-16,12-(metheno)imidazo[1,5-a][1,5]diazacyclooctadecin-3-one;

1-(cyclohexylamino)-5,6,7,8,9,10,11,12,20,21-decahydro-3H,18H-19,21a-ethano-17,13-(metheno)imidazo[1,5-a][1,5]diazacyclononadecin-3-one;

1-(cyclohexylamino)-5,6,7,8,9,14,16,17-octahydro-3H-15,17a-ethano-10,13-ethenoimidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

1-(cyclohexylamino)-6,7,8,9,10,15,17,18-octahydro-3H,5H-16,18a-ethano-11,14-ethenoimidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-5,6,7,8,9,10,11,16,18,19-decahydro-3H-17,19a-ethano-12,15-ethenoimidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-6,7,8,9,10,11,12,17,19,20-decahydro-3H,5H-18,20a-ethano-13,16-ethenoimidazo[1,5-a][1,5]diazacyclooctadecin-3-one;

1-(cyclohexylamino)-10-methylene-6,7,8,9,10,15,17,18-octahydro-3H,5H-16,18a-ethano-11,14-ethenoimidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-10-methylene-5,6,7,8,9,10,18,19-octahydro-3H,16H-17,19a-ethano-15,11-(metheno)imidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-8-methylene-5,6,7,8,16,17-hexahydro-3H,14H-15,17a-ethano-13,9-(metheno)imidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

1-(cyclohexylamino)-8-methyl-5,6,16,17-tetrahydro-3H,14H-15,17a-ethano-13,9-(metheno)imidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

1-(cyclohexylamino)-10-methyl-6,7,8,9,10,15,17,18-octahydro-3H,5H-16,18a-ethano-11,14-ethenoimidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-10-methyl-5,6,7,8,9,10,18,19-octahydro-3H,16H-17,19a-ethano-15,11-(metheno)imidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-6,7,9,10,18,19-hexahydro-3H,16H-17,19a-ethano-15,11-(metheno)imidazo[5,1-d][1,5,10]triazacycloheptadecine-3,8(5H)-dione;

1-(cyclohexylamino)-10,11,12,13,15,16-hexahydro-3H,9H-14,16a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclotetradecin-3-one;

1-(cyclohexylamino)-10,11,12,13,14,15,17,18-octahydro-3H-16,18a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-10,11,12,13,14,15,17,18-octahydro-3H,9H-16,18a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-9,10,11,12,13,14,15,16,18,19-decahydro-3H-17,19a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-10,11,12,13,15,16-hexahydro-3H-14,16a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclotetradecin-3-one;

1-(cyclohexylamino)-11,12,13,14,16,17-hexahydro-3H,10H-15,17a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

1-(cyclohexylamino)-10,11,12,13,14,15,17,18-octahydro-3H-16,18a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclohexadecin-3-one;

1-(cyclohexylamino)-11,12,13,14,15,16,18,19-octahydro-3H,10H-17,19a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacycloheptadecin-3-one;

1-(cyclohexylamino)-10,11,12,13,14,15,16,17,19,20-decahydro-3H-18,20a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclooctadecin-3-one;

1-(cyclohexylamino)-11,12,13,14,15,16,17,18,20,21-decahydro-3H,10H-19,21a-ethano-9,5-(metheno)imidazo[1,5-a][1,5]diazacyclononadecin-3-one;

(16S,17aR)-1-(cyclohexylamino)-16-methyl-9,10,11,12,13,14,16,17-octahydro-3H-15,17a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

(18S,19aR)-1-(cyclohexylamino)-18-methyl-9,10,11,12,13,14,15,16,18,19-decahydro-3H-17,19a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclooctadecin-3-one;

1-(cyclohexylamino)-9-methylene-9,10,11,12,13,14,16,17-octahydro-3H-15,17a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

1-(cyclohexylamino)-9-methyl-9,10,11,12,13,14,16,17-octahydro-3H-15,17a-ethano-5,8-ethenoimidazo[1,5-a][1,5]diazacyclopentadecin-3-one;

or pharmaceutically acceptable salts thereof.

15. 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.

16. A pharmaceutical composition for the treatment of Alzheimer's Disease, comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. 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.