Benzenesulfonyl-chromane, thiochromane, tetrahydronaphthalene and related gamma secretase inhibitors
View Patent ↗This invention discloses novel gamma secretase inhibitors of the formula: R 2 and R 3 , or R 2 and R 4 , or R 3 and R 4 , together with the atoms to which they are bound, can form a fused cycloalkyl or fused heterocycloalkyl ring. The cycloalkyl ring or the heterocycloalkyl ring can be optionally substituted with one or more substitutents. One or more compounds of formula (I), or formulations comprising such compounds, may be useful, e.g. in treating Alzheimer's Disease.
1. A compound having the formula (IF):
or a pharmaceutically acceptable salt thereof,
wherein Q forms a heterocycloalkyl ring consisting of a tetrahydropyranyl or tetrahydrothiopyran ring unsubstituted or substituted with one or more independently selected L 3 groups;
X is O;
m is 1;
R 4 is hydrogen;
each L 3 is independently selected from the group consisting of: —CN, —R 5 , —OR 5 ; and —N(R 5 ) 2 ;
Each R 5 is independently selected from the group consisting of: (1) H, —S(O) 2 —(C 1 -C 6 )haloalkyl, —S(O) 2 unsubstituted cycloalkyl, —(C 1 -C 6 )alkylene-NHS(O) 2 —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene —NHS(O) 2 unsubstituted cycloalkyl, —(C 1 -C 6 )alkylene-(S(O) 2 —(C 1 -C 6 )alkyl, dihydroxyl- substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyleneC(O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene —NHC(O) 2 —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-unsubstituted and substituted heteroaryl, wherein the unsubstituted heteroaryl is benzothiazolyl, hydrothiazolyl, diazolyl, benzimidazolyl and the substituted heteroaryl is isoxazolyl substituted by hydroxyl, (C 1 -C 6 )alkyl, hydroxyl substituted (C 1 -C 6 )alkyl, —C(O)N(C 1 -C 6 )alkyl) 2 , —(C 1 -C 6 )alkylene-C(O)—(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-NHC(O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NHC(O)—(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-NHS(O) 2 —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-NHS(O) 2 —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-O—C(O)—NH—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—C(O)—NH-unsubstituted cycloalkyl, —(C 1 -C 6 )alkylene-CN, -unsubstituted cycloalkyl, —C(O)NH 2 , —C(O)—N(alkyl) 2 , —(C 1 -C 6 )alkylene-NH 2 , -hydroxyl substituted (C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-NH—C(O)-unsubstituted cyclopropyl, —(C 1 -C 6 )alkylene-O—C(O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—S(O) 2 —(C 1 -C 6 )alkyl, —CN, —(C 1 -C 6 )alkylene-NHS(O) 2 -unsubstituted heterocycloalkyl and —(C 1 -C 6 )alkylene-unsubstituted heterocycloalkyl;
Ar is unsubstituted phenyl, or phenyl substituted with one or more L 1 groups;
each L 1 is independently selected from the group consisting of halogen and —CF 3 ; and n is 0, 1, 2 or 3; and provided that for the substituent —OR 5 , the R 5 moiety and the oxygen atom to which it is bound to does not form a —O—O— group; and
provided that for the substituents —OR 5 , and —NHR 5 , R 5 is not —CH 2 OH, —CH 2 NH 2 , —CH 2 NHalkyl, —CH 2 NHaryl or —C(O)OH.
2. The compound of claim 1 wherein each L 3 as —N(R 5 ) 2 is the same or different —NHR 5 group, and each R 5 is independently selected from the group consisting of:
—S(O) 2 —(C 1 -C 6 )haloalkyl and —S(O) 2 unsubstituted cycloalkyl.
3. The compound of claim 1 wherein each L 3 is the same or different OR 5 group, and each R 5 is independently-selected from the group consisting of: H, and (C 1 -C 6 )alkyl.
4. The compound of claim 1 wherein each L 3 is the same or different R 5 group, and each R 5 is independently selected from the group consisting of: H, (C 1 -C 6 )alkyl, and —S(O) 2 —C 1 -C 6 )haloalkyl.
5. The compound of claim 1 wherein L 1 is halogen.
6. The compound of claim 1 wherein L 1 is halogen wherein each halogen is individually selected from the group consisting of Cl and F.
7. The compound of claim 1 wherein substituent Ar is phenyl substituted with an L 1 group wherein said L 1 group is halogen or (C 1 -C 6 )haloalkyl.
8. The compound of claim 1 wherein substituent Ar is phenyl substituted with an L 1 group wherein said L 1 group is Cl or —CF 3 .
9. The compound of claim 1 wherein n is 1 or 2.
10. The compound of claim 1 wherein n is 1.
11. The compound of claim 1 wherein n is 2.
12. The compound of claim 1 wherein L 1 is halogen wherein each halogen is independently selected from the group consisting of Cl and Br, and n is 2.
13. The compound of claim 1 wherein L 1 is F and n is 2.
14. The compound of claim 1 wherein n is 2, and L 1 is selected from the group consisting of Cl and F.
15. The compound of claim 1 wherein n is 2, L 1 is selected from the group consisting of Cl and F, and Ar as phenyl is substituted with Cl.
16. The compound of claim 1 wherein n is 2, L 1 is F, and Ar is phenyl substituted with Cl.
17. The compound of claim 1 wherein the compound of formula (IF) is a compound of formula (IF.1):
wherein L 1 is F, and Ar is phenyl substituted with Cl or —CF 3 .
18. The compound of claim 1 wherein Q is:
19. The compound of claim 1 wherein Q is:
20. The compound of claim 1 wherein Q is:
21. The compound of claim 20 wherein L 3 is a C 1 -C 6 alkyl group.
22. The compound of claim 17 wherein ring Q is:
23. The compound of claim 1 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is selected from the group consisting of: -alkylene-NHS(O) 2 —(C 1 -C 6 )alkyl, and -alkylene-NHS(O) 2 —(C 1 -C 6 )haloalkyl.
24. The compound of claim 23 wherein L 3 is selected from the group consisting of: —CH 2 NHS(O) 2 CH 2 CH 3 and —CH 2 NHS(O) 2 CF 3 .
25. The compound of claim 1 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is hydroxyl substituted alkyls.
26. The compound of claim 25 wherein L 3 is selected from the group consisting of: (—CH 2 CH(OH)CH 2 CH 3 ) and —CH 2 CH 2 CH(OH)CH 2 OH).
27. The compound of claim 1 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is -alkylene-S(O) 2 —(C 1 -C 6 )alkyl.
28. The compound of claim 27 wherein L 3 is —CH 2 CH 2 SO 2 CH 2 CH 3 or —CH 2 CH 2 SO 2 CH 3 .
29. The compound of claim 1 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is —(C 1 -C 6 )alkylene-C(O)—(C 1 -C 6 )alkyl.
30. The compound of claim 29 wherein L 3 is —CH 2 CH 2 —C(O)—CH 3 .
31. The compound of claim 17 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is selected from the group consisting of: —(C 1 -C 6 )alkylene-NHS(O) 2 —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkylene-NHS(O) 2 —(C 1 -C 6 )haloalkyl.
32. The compound of claim 31 wherein L 3 is selected from the group consisting of: —CH 2 NHS(O) 2 CH 2 CH 3 and —CH 2 NHS(O) 2 CF 3 .
33. The compound of claim 17 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is hydroxyl substituted alkyls.
34. The compound of claim 33 wherein L 3 is selected from the group consisting of: (—CH 2 CH(OH)CH 2 CH 3 ) and —CH 2 CH 2 CH(OH)CH 2 OH).
35. The compound of claim 17 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is —(C 1 -C 6 )alkylene-S(O) 2 —(C 1 -C 6 )alkyl.
36. The compound of claim 35 wherein L 3 is
—CH 2 CH 2 SO 2 CH 2 CH 3 or —CH 2 CH 2 SO 2 CH 3 .
37. The compound of claim 17 wherein Q is the substituted heterocycloalkyl ring:
wherein L 3 is —(C 1 -C 6 )alkylene-C(O)—(C 1 -C 6 )alkyl.
38. The compound of claim 37 wherein L 3 is —CH 2 CH 2 —C(O)—CH 3 .
39. The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of
41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
44. The compound of claim 1 or a pharmaceutically acceptable salt thereof in purified form.
45. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
46. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
47. The compound of claim 4 wherein the haloalkyl of —S(O) 2 —(C 1 -C 6 )haloalkyl is —CF 3 .
48. The compound of claim 23 wherein the haloalkyl of —alkylene-NHS(O) 2 —(C 1 -C 6 )haloalkyl is —CF 3 .