Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer

Abstract

The present invention relates to pyridine and pyrimidine based compounds, pharmaceutical compositions comprising these compounds and their potential use as therapeutic agents for the treatment and/or prevention of cancer.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X and Y are each independently CH, C(R 4 ) or N; 
         W is C(R 4 ); 
         Z is C(R 6 ) or N; 
         R 1  and R 2  are each independently hydrogen or C 1-6  alkyl; or R 1  and R 2  taken together with the carbon atom to which they are attached may form a 5- or 6-membered carbocycle or heterocycle, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         R 3  and R 4  are each independently a group selected from C 1-6  alkyl, C 1-6  alkoxy, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         when Z is N, R 5  is R 7 , —C(O)R 7 , —C(O)OR 7 —, —S(O) l R 7 , —C(O)N(R 7 )R 8 , —C(S)N(R 7 )R 8 —, —S(O) l N(R 7 )R 8  or heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         when Z is C(R 6 ), R 5  is H, CN, C(O)OH, —C(O)R 7 , —C(O)OR 7 —, —S(O) l R 7 , —N(R 6 )R 7 , —C(O)N(R 7 )R 8 , —C(S)N(R 7 )R 8 —, —S(O) l N(R 7 )R 8 , —N(R 7 )C(O)R 8 , —N(R 7 )S(O) l R 8  or a C 1-6  alkyl or heterocyclyl group which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         R 6  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, R 5 , (CH 2 ) m R 5  or —N(R 7 )R 8 ; 
         R 7  and R 8  are each independently hydrogen or a group selected from C 1-6  alkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O and S, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         or R 7  and R 8  may be linked so that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocycle which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
         each R a  is independently selected from halogen, trifluoromethyl, cyano, oxo, nitro, —OR b , —C(O)R b , —C(O)OR b , —OC(O)R b , —S(O) l R b , —N(R b )R c , —N(R b )C(O)R c , —C(O)N(R b )R c , —S(O) l N(R b )R c  and R d ; 
         R b  and R c  are each independently hydrogen or R d ; 
         R d  is selected from hydrocarbyl (e.g. C 1-6 alkyl), carbocyclyl, carbocyclyl-C 1-6 alkyl, and heterocyclyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6  alkyl, C 1-6  alkoxy; 
         l is 0, 1 or 2; and 
         m and n are each independently 1, 2 or 3; 
         or a pharmaceutically acceptable salt or N-oxide thereof. 
       
     
     
         2 . A compound according to  claim 1 , which is of the formula (II): 
       
         
           
           
               
               
           
         
         wherein T is a bond or —CH 2 —. 
       
     
     
         3 . A compound according to  claim 1 , wherein X and Y are each CH. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . A compound according to  claim 1 , wherein R 3  is a group selected from C 1-6  alkyl, aryl or heteroaryl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     
     
         7 . A compound according to  claim 6 , wherein R 3  is a group selected from C 1 -C 6  alkyl, phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl and thiophenyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     
     
         8 . A compound according to  claim 1 , wherein Z is C(R 6 ). 
     
     
         9 . A compound according to  claim 8 , wherein R 6  is hydrogen, methyl, or aniline. 
     
     
         10 . A compound according to  claim 1 , wherein R 5  is —C(O)NH 2 , CO 2 H, CN or heterocyclyl. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . A compound which is selected from any one of the following:
 4-(3-methylpyridin-4-yl)cyclohexanecarboxamide;   4-(3,5-dimethylpyridin-4-yl)cyclohexanecarboxamide;   1-(5-methylpyrimidin-4-yl)piperidine-4-carboxamide;   1-(5-phenylpyrimidin-4-yl)piperidine-4-carboxamide;   1-(3-(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide;   1-(3-(thiophen-2-yl)pyridin-4-yl)piperidine-4-carboxamide;   1-(3,5-diphenylpyridin-4-yl)piperidine-4-carboxamide;   1-(3-(3,5-dimethylisoxazol-4-yl)pyridin-4-yl)piperidine-4-carboxamide;   1-(3-(thiophen-3-yl)pyridin-4-yl)piperidine-4-carboxamide;   1-(3-cyclopropylpyridin-4-yl)piperidine-4-carboxamide;   1-(3-(1H-pyrazol-4-yl)pyridin-4-yl)piperidine-4-carboxamide;   1-(3-phenylpyridin-4-yl)piperidine-4-carboxamide;   1-(3,5-dio-tolylpyridin-4-yl)piperidine-4-carboxamide;   1-(5-(4-methoxyphenyl)pyrimidin-4-yl)piperidine-4-carboxamide;   1-(3,5-bis(4-methoxyphenyl)pyridin-4-yl)piperidine-4-carboxamide;   or a pharmaceutically acceptable salt or N-oxide thereof.   
     
     
         14 - 15 . (canceled) 
     
     
         16 . A compound of the formula (I) as defined in  claim 1  with the proviso that R 4  is not an optionally substituted imidazolyl group. 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical formulation comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         19 . (canceled) 
     
     
         20 . A method for the treatment, prevention or delaying the progression of cancer in a subject, which comprises administering a therapeutically effective amount of a compound of formula (I) as defined in  claim 1 .