Benzenesulfonyl-chromane, thiochromane, tetrahydronaphthalene and related gamma secretase inhibitors
View Patent ↗Disclosed are novel gamma secretase inhibitors of the formula (I): or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein L 1 , n, X, Ar, Y, Z, Q, and Q 1 are as defined herein. Also disclosed are methods for inhibiting gamma secretase, methods for treating Alzheimer's disease, methods of treating one or more neurodegenerative diseases, and methods of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain) using the compounds of formula 1.0.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of —C(R 1 ) 2 —, —O—, —S—, —S(O 2 )—, —NR 1 —, and —N(C(O)R 1 )—;
The dotted line ( ) represents an optional bond between Y and Z;
Y is selected from the group consisting of N, CH and C, and when Y is N the optional bond is absent, when Y is CH the optional bond is absent, and when Y is C the optional bond is present;
Z is selected from the group consisting of: CH, C, and N, provided that both Y and Z are not N, and when Z is N the optional bond is absent, when Z is CH the optional bond is absent, and when Z is C the optional bond is present;
Q represents a 5 to 8 membered ring fused to Rings A 1 and Q 1 , wherein Y and Z are as defined above and the remaining Q ring members are —CH 2 — groups;
Q 1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q 1 ring comprising at least one heteroatom selected from the group consisting of N, S, S(O), and S(O) 2 , or Q 1 is a 5 membered ring comprising an oxygen atom; or
Q 1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q 1 ring comprising at least one heteroatom selected from the group consisting of N, S, S(O), and S(O) 2 , or Q 1 is a 5 membered ring comprising an oxygen atom; and said Q 1 ring being substituted with 1 to 3 substituents independently selected from the group consisting of: R 3 substituents;
Each R 1 is independently selected from the group consisting of H and alkyl;
R 2 is selected from the group consisting of: H, and alkyl;
Each R 3 substituent is independently selected from the group consisting of: (1) alkyl, (2) alkoxyalkyl-, (3) hydroxyalkyl, (4) —OR 2 , (5) arylalkyl-, (6) ═O, (7) substituted arylalkyl-, (8) alkenyl, (9) heterocycloalkylalkyl-, (10) -alkyl-C(O)OH, (11) -alkyl-NR 5 R 6 , wherein R 5 and R 6 are each independently selected from the group consisting of: H and alkyl, (12) -alkyl-C(O)NR 5 R 6 , wherein R 5 and R 6 are as defined in (11), (13) arylalkenyl-, (14) -alkyl-C(O)OR 7 wherein R 7 is a C 1 to C 6 alkyl group, and (15) substituted arylalkenyl-, wherein said substituted arylalkenyl- is substituted with 1 to 3 substituents independently selected from the group consisting of: —OR 5 , —NR 5 R 6 ,
—CF 3 , —CN, —C(O) 2 R 5 , and —C(O)NR 5 R 6 , and wherein R 5 and R 6 are as defined in (11); or
two R 3 groups bound to the same carbon, taken together with the carbon to which they are bound, form a cycloalkyl ring or form a cycloalkenyl ring;
Ar is selected from the group consisting of: (a) unsubstituted aryl, (b) aryl substituted with one or more L 1 groups, (c) unsubstituted heteroaryl, and (d) substituted heteroaryl substituted with one or more L 1 groups;
each L 1 is independently selected from the group consisting of: halogen, alkyl, —CN, —CF 3 , —O—(C 1 -C 6 )alkyl, —O-(halo(C 1 -C 6 )alkyl), —C(O)—O—(C 1 -C 6 )alkyl, -alkylene-OH, halo(C 1 -C 6 )alkyl, hydroxyalkoxy-, and alkoxyalkoxy-; and
n is 0, 1, 2 or 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CH, Z is CH, Q is a 6 membered ring, and Q 1 is a 6 membered ring comprising a nitrogen atom and a —S(O) 2 — group, or wherein Y is —CH, Q is a 6 membered ring, Q 1 is a 6 membered ring comprising a nitrogen atom and a —S(O) 2 — group, and said Q 1 ring is substituted with 1 to 3 substituents.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CH, Z is CH, Q is a 6 membered ring, or wherein Y is CH, Z is CH, Q is a 6 membered ring, Q 1 is a 5 membered ring comprising an oxygen atom and said Q 1 ring is substituted with 1 to 3 substituents.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CH, Z is CH, Q is a 6 membered ring, and Q 1 is a 5 membered ring comprising a nitrogen atom; or wherein Y is CH, Q is a 6 membered ring, Q 1 is a 5 membered ring comprising a nitrogen atom, and said Q 1 ring is substituted with 1 to 3 substituents.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is C, Z is C, the optional bond between Y and Z is present, Q is a 6 membered ring, and Q 1 is a 5 membered ring comprising a nitrogen atom; or wherein Y is C, Z is C, the optional bond between Y and Z is present, Q is a 6 membered ring, Q 1 is a 5 membered ring comprising a nitrogen atom, and said Q 1 ring is substituted with 1 to 3 substituents.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CH, Z is CH, Q is a 6 membered ring, and Q 1 is a 6 membered ring comprising a nitrogen atom or wherein Y is CH, Z is CH, Q is a 6 membered ring, Q 1 is a 6 membered ring comprising a nitrogen atom, and said Q 1 ring is substituted with 1 to 3 substituents.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is N, Z is CH, Q is a 6 membered ring, and Q 1 is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y, or wherein Y is N, Z is CH, Q is a 6 membered ring, Q1 Q 1 is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y, and said Q 1 ring is substituted with 1 to 3.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O, n is 2 and L 1 is F.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the group consisting of: phenyl, phenyl substituted with at least one Cl, phenyl substituted with a —CF 3 group, and phenyl substituted with a cyano group.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O, n is 2, L 1 is F, and Ar is selected from the group consisting of phenyl substituted with one —CF 3 , phenyl substituted with one —CN, and phenyl substituted with one Cl.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 3.
12. The compound of claim 1 wherein said compound is selected from the group consisting of the compounds of formulas:
or a pharmaceutically acceptable salt thereof.
13. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of one or more compounds of claim 1 or a pharmaceutically acceptable salt thereof, and an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA A inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors.
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of one or more compounds of claim 1 or a pharmaceutically acceptable salt thereof, and an effective amount of one or more BACE inhibitors.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of one or more compounds of claim 13 or a pharmaceutically acceptable salt thereof, and an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB 1 receptor inverse agonists or CB 1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA A inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of one or more compounds of claim 13 or a pharmaceutically acceptable salt thereof, and an effective amount of one or more BACE inhibitors.