3-fluoro-piperidines as NMDA/NR2B antagonists
View Patent ↗Compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for treating conditions such as, for example, Parkinson's disease, Alzheimer's disease, migraine, epilepsy and pain.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 5 or 6 membered heteroaromatic ring containing 1 or 2 nitrogen ring atoms, thiazolyl, or thiadiazolyl, wherein the NH is linked to a carbon ortho to a nitrogen on the HetAr ring;
HetAr is optionally substituted with 1 or 2 substituents, each substituent independently is C 1-4 alkyl, fluoro, chloro, bromo, or iodo;
A is a bond or —C 1-2 alkyl-; and
B is aryl(CH 2 ) 0-3 —O—C(O)—, indanyl(CH 2 ) 0-3 —O—C(O)—, aryl(CH 2 ) 1-3 —C(O)—, aryl-cyclopropyl-C(O)—, aryl(CH 2 ) 1-3 —NH—C(O)—, wherein any of the aryl is optionally substituted by 1-5 substitutents, each substituent independently is C 1-4 alkyl, fluoro, or chloro.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 6 membered heteroaromatic ring containing 1 nitrogen ring atom.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is thiazolyl.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is thiadiazolyl.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is 1,2,4 thiadiazolyl.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A is a bond.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A is methylene.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —C 2 alkyl-.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
B is aryl-cyclopropyl-C(O)—, wherein said aryl is optionally substituted as defined in claim 1 .
11. The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein said aryl is phenyl, optionally substituted as defined in claim 1 .
12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
B is aryl(CH 2 ) 0-3 —O—C(O)—, wherein said aryl is optionally substituted as defined in claim 1 .
13. The compound according to claim 1 , or a pharmaceutically acceptable salts thereof, wherein
B is aryl(CH 2 )—O—C(O)—, wherein said aryl is optionally substituted as defined in claim 1 .
14. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein said aryl is optionally substituted with C 1-4 alkyl.
15. The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein said aryl is 4-tolyl.
16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms;
A is methylene; and
B is aryl(CH 2 )—O—C(O)—, wherein said aryl is optionally substituted as defined in claim 1 .
17. The compound according to claim 16 , or a pharmaceutically acceptable salt thereof, wherein
said aryl is optionally substituted with C 1-4 alkyl.
18. The compound according to claim 17 , or a pharmaceutically acceptable salt thereof, wherein
said aryl is 4-tolyl.
19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms;
A is methylene; and
B is 4-tolyl(CH 2 )—O—C(O)—.
20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is thiadiazolyl;
A is methylene; and
B is aryl(CH 2 )—O—C(O)—, wherein said aryl is optionally substituted as defined in claim 1 .
21. The compound according to claim 1 , or pharmaceutically acceptable salts thereof, wherein
HetAr is 1,2,4-thiadiazolyl;
A is methylene; and
B is 4-tolyl(CH 2 )—O—C(O)—.
22. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
HetAr is a 6 membered heteraromatic ring containing 2 nitrogen ring atoms;
A is methylene; and
B is aryl-cyclopropyl-C(O)—.
23. The compound according to claim 1 , or pharmaceutically acceptable salts thereof, wherein
HetAr is a 6 membered heteroaromatic ring containing 2 nitrogen ring atoms; and
B is phenyl-cyclopropyl-C(O)—.
24. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
25. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
27. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
31. The compound according to claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising an inert carrier and a therapeutically effective amount of a compound according to claim 1 .