Triazole derivatives which are SMO antagonists
View Patent ↗The present invention provides a method for the treatment or prevention of conditions which can be ameliorated by Smo antagonism, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I: or a pharmaceutically acceptable salt or solvate thereof; wherein: 2 of X, Y and Z represent nitrogen atoms, and the other represents an oxygen atom; R 1 and R 2 are taken together with the atom to which they are attached and represent a cyclobutyl ring, optionally substituted with 1-2 fluorine atoms, and R 3 represents hydrogen or a fluorine atom; or R 1 represents methyl, R 2 represents methyl or a fluorine atom and R 3 represents a fluorine atom.
1. A method for the treatment of a Hedgehog-expressing cancer selected from the group consisting of basal cell carcinoma, prostate cancer, pancreatic cancer, small cell lung cancer, gastrointestinal cancer, and medulloblastoma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein:
2 of X, Y and Z represent nitrogen atoms, and the other represents an oxygen atom;
R 1 and R 2 are taken together with the atom to which they are attached and represent a cyclobutyl ring, optionally substituted with 1-2 fluorine atoms, and R 3 represents hydrogen or a fluorine atom;
or
R 1 represents methyl,
R 2 represents methyl or a fluorine atom and
R 3 represents a fluorine atom.
2. The method of claim 1 wherein one of X and Y is O and the other is N, and Z is N.
3. The method of claim 1 wherein the compound is of structural formula II:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 wherein the compound is selected from:
5-(1,1-Difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo [2.2.2]oct-1-yl)-1,2,4-oxadiazole;
5-(3,3-Difluorocyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;
5-(1-Fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;
2-(1,1-Difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;
2-(3,3-Difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole 2-(1-Fluoro-1-methylethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 wherein the compound is:
5-(1,1-Difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the compound is:
5-(3,3-Difluorocyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 wherein the compound is:
5-(1-Fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 wherein the compound is:
2-(1,1-Difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 wherein an additional anti-cancer agent is administered either simultaneously, separately or sequentially.