N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators

Abstract

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 (1), 
       
         
           
           
               
               
           
         
         an N-oxide derivative or a pharmaceutically acceptable salt thereof, wherein: 
         ring E is an optionally substituted aryl or heteroaryl; 
         A 1  is a C 1-5 heterocycle, quinolinyl, or a heteroaryl selected from the group 
       
       
         
           
           
               
               
           
         
         wherein any heterocycle of A 1  is optionally substituted with -LC(O)R 10 ; 
         X 1 , X 2 , X 3  and X 4  are independently CR 7  or N; 
         Y is phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; 
         Z is aryl, C 1-5  heterocycle, or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S; 
         each Y and Z are optionally substituted with 1-3 R 6  groups; 
         R 1  and R 5  are independently H or C 1-6  alkyl; 
         R 2  and R 3  are H; 
         R 4  is hydrogen, halo, cyano, C 1-6 alkoxy, —C(O)CH 3 , or a C 1-6  alkyl optionally substituted with halo, alkoxy or amino; 
         R 6  is hydrogen, halo, C 1-6 alkoxy, C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which can be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; CN, -L-W, NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 , -L-C(O)NR 8 R 9 , OR 10 ; -L-S(O) 2 R 10  or -L-S(O) 2 NR 8 R9; 
         R 7  is H, halo, C 1-6  alkoxy, cyano, C 1-6  alkyl optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; NR 8 R 9 , -L-C(O)R 10 , -L-C(O)NR 8 R 9 , OR 10 ; -L-S(O) 2 R 10  or -L-S(O) 2 NR 8 R 9 ; 
         R 8  and R 9  are independently H, -L-W, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; or R 8  and R 9  together with the atoms to which they are attached may form a ring; 
         R 10  is H, L-W, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; 
         L is a bond or (CR 2 ) 1-4  wherein R is H or C 1-6  alkyl; 
         W is C 3-7 cycloalkyl, C 1-5 heterocycle, aryl or heteroaryl; 
         m is 0-4; 
         n is 0-3; and 
         p is 0-2; 
         and optionally in combination with a second therapeutic agent; 
         wherein said Wnt-mediated disorder is keloids, fibrosis, proteinuria, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, retinopathy, macular degeneration or a cell proliferative disorder associated with aberrant Wnt signaling activity. 
       
     
     
         2 . The method of  claim 1 , wherein ring E is phenyl, pyridyl or pyrimidinyl, each of which optionally substituted with R 7 . 
     
     
         3 . The method of  claim 2 , wherein R 7  is H, halo, cyano, C 1-6 alkoxy, —S(O) 2 R 10 , or an optionally halogenated C 1-6  alkyl. 
     
     
         4 . The method of  claim 1 , wherein said compound is of Formula (5): 
       
         
           
           
               
               
           
         
         an N-oxide derivative or a pharmaceutically acceptable salt thereof, wherein: 
         A 1  is piperazinyl substituted with —C(O)CH 3 , 
       
       
         
           
           
               
               
           
         
       
       or selected from: 
       
         
           
           
               
               
           
         
         ring E is phenyl or one of X 1 , X 2 , X 3  and X 4  is N and the others are CR 7 ; 
         one of X 5 , X 6 , X 7  and X 8  is N and the others are CR 11 ; 
         Z is a 6-membered heterocycle or a 6-membered heteroaryl, each containing 1-2 nitrogen heteroatoms and each of which is optionally substituted with 1-2 R 6  groups; 
         R 1 , R 2  and R 3  are H; 
         R 6  is hydrogen, cyano, C 1-6 alkoxy, —S(O) 2 R 10 , —C(O)NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 , C 1-6  alkyl optionally substituted with halo, C 2-6  alkenyl or C 2-6  alkynyl; 
         W is C 3-7 cycloalkyl; 
         R 7  and R 11  are independently H, halo, cyano, C 1-6 alkoxy, —S(O) 2 R 10 , or an optionally halogenated C 1-6  alkyl; 
         R 8  and R 9  are independently H, -L-W, or C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; 
         R 10  is C 1-6  alkyl or -L-W; and 
         m, n and p are independently 0-2. 
       
     
     
         5 . The method of  claim 4 , wherein A 1  is 
       
         
           
           
               
               
           
         
       
       and m is 0-1. 
     
     
         6 . The method of  claim 1 , wherein said compound is of Formula (6): 
       
         
           
           
               
               
           
         
         an N-oxide derivative or a pharmaceutically acceptable salt thereof; wherein: 
         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. 
       
     
     
         7 . The method of  claim 1 , wherein said compound is 2-(2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetamido)-5-(pyrazin-2-yl)pyridine 1-oxide, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 1 , wherein said compound is 2′,3-dimethyl-5-(2-oxo-2-(5-(pyrazin-2-yl)pyridin-2-ylamino)ethyl)-2,4′-bipyridine 1′-oxide, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . 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. 
     
     
         10 . The method of  claim 9 , wherein said compound is a fumaric acid salt. 
     
     
         11 . 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. 
     
     
         12 . The method of  claim 11 , wherein said compound is a fumaric acid salt. 
     
     
         13 . The method of  claim 1 , wherein said Wnt-mediated disorder is a cell proliferative disorder selected from the group of colorectal cancer, colorectal carcinoma, breast cancer, head and neck squamous cell carcinoma, esophageal cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, pancreatic cancer, leukemia, lymphoma, neuroblastoma, retinoblastoma, sarcoma, osteosarcoma, chondosarcoma, Ewing's sarcoma, rhabdomysarcoma, brain tumor, Wilm's tumor, basal cell carcinoma, melanoma, head and neck cancer, cervical cancer and prostate cancer. 
     
     
         14 . The method of  claim 13 , wherein said Wnt-mediated disorder is colorectal cancer or colorectal carcinoma. 
     
     
         15 . The method of  claim 13 , wherein said Wnt-mediated disorder is breast cancer. 
     
     
         16 . The method of  claim 13 , wherein said Wnt-mediated disorder is head and neck squamous cell carcinoma. 
     
     
         17 . The method of  claim 13 , wherein said Wnt-mediated disorder is pancreatic cancer. 
     
     
         18 . The method of  claim 13 , wherein said Wnt-mediated disorder is melanoma. 
     
     
         19 . The method of  claim 1 , wherein said Wnt-mediated disorder is fibrosis. 
     
     
         20 . The method of  claim 19 , wherein said fibrosis is skin fibrosis. 
     
     
         21 . A method for inhibiting Wnt signaling in a cell, comprising contacting the cell with an effective amount of a compound of Formula (1), or an N-oxide derivative or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A combination comprising a therapeutically effective amount of a compound of Formula (1), or an N-oxide derivative or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.