Therapeutic isoxazole compounds
The invention provides a compound of formula I: wherein A 1 , A 2 , A 3 , R 1 , X, Y, and B have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of monoamine oxidase B (MAO-B) enzyme function and are useful for improving cognitive function and for treating psychiatric disorders in animals.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is (C 1 -C 6 )alkyl substituted with one or more R h ;
each R h is fluoro;
A 1 is CR 2 ;
R 2 is H (hydrogen) or (C 1 -C 6 )alkyl;
X is —C(═O)—;
Y is —N(R 4 ) 2 where the two R 4 groups are taken together with the nitrogen to which they are attached to form a piperidinyl optionally substituted with one or more R d ;
each R d is independently halo, cyano, —(CH 2 ) n NR f R g , —C(O)NR f R g , —NR e C(O)R g , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, heterocycle, heterocycle(C 1 -C 6 )alkyl, or —NR e S(O) 2 (C 1 -C 6 )alkyl;
each n is independently an integer selected from 0, 1, and 2;
each R 5 is H (hydrogen);
each R e is independently hydrogen or (C 1 -C 6 )alkyl;
each R f and R g is independently hydrogen or (C 1 -C 6 )alkyl, or R f and R g are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic ring system, optionally comprising one or more additional heteroatom groups selected from O (oxygen), and NR c ; and
each R c is independently hydrogen or (C 1 -C 6 )alkyl.
2. The compound of claim 1 , wherein R 1 is CF 3 ; and R 2 is (C 1 -C 6 )alkyl.
3. The compound of claim 1 , wherein Y is —N(R 4 ) 2 where the two R 4 groups are taken together with the nitrogen to which they are attached to form a piperidinyl substituted with one or more R d .
4. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient or carrier.
20. A method for improving cognitive function in an animal in need of such treatment comprising administering to the animal an effective amount of a compound of claim 1 .