Substituted tetrazolo[1,5-A]pyrazine inhibitors of histamine receptors for the treatment of disease
The present invention relates to substituted tetrazolo[1,5-a]pyrazine compounds for Formula IX: as well as pharmaceutical compositions thereof, which may be useful as inhibitors of H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
1. A compound of structural Formula (IX)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a monocyclic 4- to 7-membered nonaromatic heterocycloalkyl, which may be optionally substituted with a substituent chosen from amino and lower alkyl; and
R 2 is chosen from monocyclic 5- to 7-membered nonaromatic heterocycloalkyl, phenyl and monocyclic 5- to 6-membered heteroaryl, any of which may be optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro.
2. The compound as recited in claim 1 , having structural Formula (X)
or a pharmaceutically acceptable salt thereof, wherein:
A is a monocylic 4- to 7-membered nonaromatic heterocycloalkyl which is attached through a ring nitrogen to the ocore and which may be optionally substituted with a substituent chosen from amino and lower alkyl; and
R 2 is chosen from phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, pyrazole, imidazoline, imidazolidine, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, thiadiazole, triazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, piperazine, pyridazine, pyrimidine, and pyrazine, any of which may be optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro.
3. The compound as recited in claim 2 , having structural Formula (XI)
or a pharmaceutically acceptable salt thereof, wherein:
X 8 is chosen from CH and N;
m and n are each an integer chosen from 1 and 2;
R 2 is chosen from phenyl, furan, thiophene, and thiazole, any of which may be optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro; and
R 24 is chosen from hydrogen, amino, and lower alkyl.
4. The compound as recited in claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophene, optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro.
5. The compound as recited in claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophene, optionally substituted with one to three halogen substituents.
6. The compound as recited in claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophene.
7. The compound as recited in claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
X 8 is CH;
m and n are each 1; and
R 24 is chosen from hydrogen, amino, and lower alkyl.
8. The compound as recited in claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 24 is amino.
9. The compound as recited in claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 24 is NHCH 3 .
10. The compound as recited in claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
X 8 is N;
m and n are each 2; and
R 24 is chosen from hydrogen and lower alkyl.
11. The compound as recited in claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 24 is chosen from hydrogen and methyl.
12. The compound as recited in claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 24 is methyl.
13. A compound as recited in claim 1 , chosen from:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound as recited in claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
15. A pharmaceutical composition as recited in claim 14 , wherein the compound is chosen from:
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
16. The compound
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.