Fused heterocyclic indane carboxamide CGRP receptor antagonists
View Patent ↗The present invention is directed to fused heterocyclic indane carboxamide derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from C(R 4 ) or N;
Y is selected from C(R 5 ) or N;
R 2 is selected from hydrogen and C 1-4 alkyl;
R 1 is selected from the group consisting of: (1) C 1-6 alkyl, optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F, Cl, Br, hydroxy and C 1-4 alkoxy, (2) C 3-6 cycloalkyl, optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F, Cl, Br, hydroxy and C 1-4 alkoxy, and
wherein R 6 , R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of: hydrogen, methyl, F, Cl and Br;
R 3 is selected from the group consisting of:
(1) hydrogen;
(2) C 1-6 alkyl, optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F, amino, hydroxy and C 1-4 alkoxy, said C 1-4 alkoxy optionally substituted with hydroxy;
(3) C 3-6 cycloalkyl or a 5- or 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from S, O and N, said C 3-6 cycloalkyl and heterocyclyl optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and —CF 3 ; and
(4) phenyl;
R 4 is hydrogen or methyl; and
R 5 is hydrogen, F or CN.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1-hydroxy-1-methylethyl, 1-amino-1-methylethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl and 1-(2-hydroxyethoxy)-1-methylethyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: cyclopropyl, 1-(trifluoromethyl)cyclopropyl, cyclopentyl and tetrahydropyranyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl and 2,3-difluorophenyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
9. The compound of claim 1 having Formula Ia
or a pharmaceutically acceptable salt thereof, wherein:
R a and R b are both hydrogen or both F.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein X is CH.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1-hydroxy-1-methylethyl, 1-amino-1-methylethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl and 1-(2-hydroxyethoxy)-1-methylethyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are both hydrogen.
13. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein X is N.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1-hydroxy-1-methylethyl, 1-amino-1-methylethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl and 1-(2-hydroxyethoxy)-1-methylethyl.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are both hydrogen.
16. A compound of claim 1 , selected from one of the following tables:
R 1
R 2
R 3
X
H
CH
H
CH
H
H
CH
H
Me
CH
H
CH
H
CH
H
N
H
CH
H
CH
H
CH
H
CH
H
CH
H
CH
H
N
H
CH
H
N
H
N
H
CH
Me
N
Me
CH
R 1
R 2
R 3
X
Me
CH
Me
CH
Me
CH
or a pharmaceutically acceptable salt of any of the foregoing compounds.
17. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18. A method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 , wherein the headache is migraine headache.