Piperidinone carboxamide azaindane CGRP receptor antagonists
View Patent ↗The present invention is directed to piperidinone carboxamide azaindane 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 8 )═ or —N═, wherein R 8 is hydrogen, F or CN;
R 1 is selected from the group consisting of: C 1-4 alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy;
R 2 is selected from hydrogen and methyl;
when R 2 is hydrogen then
R 3 is selected from hydrogen, F or Cl;
R 4 is selected from hydrogen, F or Cl;
R 5 is hydrogen;
R 6 is selected from hydrogen or F; and
R 7 is selected from hydrogen, F or Cl;
except that at least two of R 3 , R 4 , R 6 and R 7 must be F or Cl unless R 3 is F in which case R 4 , R 6 and R 7 may all be hydrogen; and if R 4 is Cl then R 7 cannot be Cl;
when R 2 is methyl then
R 3 is selected from hydrogen, methyl, F, Cl, or Br;
R 4 is selected from hydrogen, methyl, F or Cl;
R 5 is selected from hydrogen or F;
R 6 is selected from hydrogen or F; and
R 7 is selected from hydrogen, methyl, F or Cl;
except that if R 5 is F then at least three of R 3 , R 4 , R 6 and R 7 must be F; and if R 4 is methyl or Cl then R 7 cannot be methyl or Cl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —N═.
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 —C(CN)═.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl, optionally substituted with 1 to 3 F or hydroxy, or both.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 2,2,2-trifluoroethyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein at least two of R 3 , R 4 , R 6 and R 7 are F or Cl, except that if R 4 is Cl then R 7 cannot be Cl.
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 if F and R 4 , R 6 and R 7 are hydrogen.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 5 is F and at least three of R 3 , R 4 , R 6 and R 7 are F.
13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen and if R 4 is methyl or Cl then R 7 cannot be methyl or Cl.
14. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, methyl, F or Cl; R 4 is selected from hydrogen, methyl, F or Cl; R 5 is hydrogen; R 6 is selected from hydrogen or F; and R 7 is selected from hydrogen, methyl, F or Cl; except that if R 4 is methyl or Cl then R 7 cannot be methyl or Cl.
15. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16. 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.
17. The method of claim 16 , wherein the headache is migraine headache.
18. The compound
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition which comprises an inert carrier and the compound of claim 18 , or a pharmaceutically acceptable salt thereof.
20. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 18 , or a pharmaceutically acceptable salt thereof.
21. The compound
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition which comprises an inert carrier and the compound of claim 21 , or a pharmaceutically acceptable salt thereof.
23. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 21 , or a pharmaceutically acceptable salt thereof.
24. The compound
or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition which comprises an inert carrier and the compound of claim 24 , or a pharmaceutically acceptable salt thereof.
26. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 24 , or a pharmaceutically acceptable salt thereof.
27. The compound
or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition which comprises an inert carrier and the compound of claim 27 , or a pharmaceutically acceptable salt thereof.
29. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 27 , or a pharmaceutically acceptable salt thereof.
30. A compound selected from the following group
R 2
Ar
H
2-fluorophenyl
Me
2-chlorophenyl
Me
3-methylphenyl
H
2,3-difluorophenyl
H
2,3,5-trifluorophenyl
H
2-chloro-6-fluorophenyl
H
2,6-dichlorophenyl
H
2,3-dichlorophenyl
H
2,3,6-trifluorophenyl
Me
2,3,5,6-tetrafluorophenyl
Me
3-fluoro-2-methylphenyl
or a pharmaceutically acceptable salt of any of the foregoing compounds.
31. A pharmaceutical composition which comprises an inert carrier and a compound of claim 30 , or a pharmaceutically acceptable salt thereof.
32. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of claim 30 , or a pharmaceutically acceptable salt thereof.
33. A compound selected from the following group:
R 1
Ar
cyclobutylmethyl
2,3-difluorophenyl
2-methylpropyl
2-fluorophenyl
cyclobutylmethyl
2-fluorophenyl
isopropyl
2-fluorophenyl
(2S)-3,3,3-trifluoro-2-hydroxypropyl
2,3-difluorophenyl
or a pharmaceutically acceptable salt of any of the foregoing compounds.
34. A pharmaceutical composition which comprises an inert carrier and the compound of claim 33 , or a pharmaceutically acceptable salt thereof.
35. A method of treating migraine in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of claim 33 , or a pharmaceutically acceptable salt thereof.