N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as Wnt signaling modulators
The present invention relates to methods for modulating the Wnt signaling pathway using compounds of Formula (1), wherein A 1 , Y and Z all represent rings.
1. A method for treating a Wnt-mediated disorder in a subject suffering therefrom, comprising administering to the subject a compound of Formula (6),
or a pharmaceutically acceptable salt thereof; wherein:
X 1 , X 2 , X 3 and X 4 is selected from N and CR 7 ;
one of X 5 , X 6 , X 7 and X 8 is N and the others are CH;
X 9 is selected from N and CH;
Z is selected from phenyl, pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl, pyridazinyl or piperazinyl of Z is optionally substituted with an R 6 group;
R 1 , R 2 and R 3 are hydrogen;
m is 1;
R 4 is selected from hydrogen, halo, difluoromethyl, trifluoromethyl and methyl;
R 6 is selected from hydrogen, halo and —C(O)R 10 ; wherein R 10 is methyl; and
R 7 is selected from hydrogen, halo, cyano, methyl and trifluoromethyl;
and optionally in combination with a chemotherapeutic agent;
wherein said Wnt-mediated disorder is colorectal cancer, colorectal carcinoma, breast cancer, head and neck squamous cell carcinoma, pancreatic cancer, melanoma, or head and neck cancer.
2. The method of claim 1 , wherein said compound is 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein said compound is a fumaric acid salt.
4. The method of claim 1 , wherein said compound is N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetamide, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , wherein said compound is a fumaric acid salt.
6. The method of claim 1 , wherein said Wnt-mediated disorder is breast cancer.
7. The method of claim 1 , wherein said Wnt-mediated disorder is head and neck squamous cell carcinoma.
8. The method of claim 1 , wherein said Wnt-mediated disorder is melanoma.
9. The method of claim 1 , wherein said Wnt-mediated disorder is pancreatic cancer.
10. A combination comprising a therapeutically effective amount of a compound of Formula (6),
wherein:
X 1 , X 2 , X 3 and X 4 is selected from N and CR 7 ;
one of X 6 , X 6 , X 7 and X 8 is N and the others are CH;
X 9 is selected from N and CH;
Z is selected from phenyl, pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl, pyridazinyl or piperazinyl of Z is optionally substituted with an R 6 group;
R 1 , R 2 and R 3 are hydrogen;
m is 1;
R 4 is selected from hydrogen, halo, difluoromethyl, trifluoromethyl and methyl;
R 6 is selected from hydrogen, halo and —C(O)R 10 ; wherein R 10 is methyl; and
R 7 is selected from hydrogen, halo, cyano, methyl and trifluoromethyl;
or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.
11. The combination of claim 10 , wherein said compound is 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.
12. The combination of claim 11 , wherein said compound is fumaric acid salt.