4-piperidinyl compounds for use as tankyrase inhibitors

Abstract

The present invention provides for compounds of formula (I): wherein R 1 -R 4 and n are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.

What is claimed is: 
     
       1. A compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  is R 2  or R 2 —NHC(O)—; 
       R 2  is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halo, OH, CN, NO 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C(O)R a , COOR a , NR a R b , NHC(O)R a , and C(O)NR a R b ; 
       or 
       R 2  is a 5 membered heteroaryl having one to four heteroatoms selected from the group consisting of N, O, and S, or R 2  is a 6 membered heteroaryl having one or two N,
 said 5 and 6 membered heteroaryl rings being optionally substituted with one to three substituents each independently selected from the group consisting of: halo, oxo, OH, CN, NO 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C(O)R a , COOR a , NR a R b , NHC(O)R a , and C(O)NR a R b ; 
 
       or 
       R 2  is an 8-10 membered bicyclic heteroaryl having 3 or 4 heteroatoms selected from the group consisting of N, O, and S,
 said 8-10 membered heteroaryl being optionally substituted with one to three substituents each independently selected from the group consisting of: 
 (a) halo, 
 (b) oxo, 
 (c) OH, 
 (d) CN, 
 (e) NO 2 , 
 (f) C 1-6 alkyl optionally substituted with one hydroxy or one C 1-6  alkoxy, 
 (g) C 1-6  alkoxy, 
 (h) C 1-6  haloalkyl, 
 (i) C(O)R a , 
 (j) COOR a , 
 (k) NR a R b , 
 (l) NHC(O)R a , and 
 (m) C(O)NR a R b ; 
 
       R 3  is H and R 4  is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, OH, CN, NO 2 , C 1-6 alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C(O)R a , COOR a , NR a R b , NHC(O)R a , and C(O)NR a R b ; 
       or 
       R 3  and R 4  together with the atoms to which they are attached form optionally substituted indan-1-one, said indan-1-one is attached to the piperidine ring of formula (I) through spiro carbon 4 and is optionally substituted with one to three substituents each independently selected from the group consisting of: halo and C 1-6  alkoxy; 
       R a  is H or C 1-6  alkyl; 
       R b  is H or C 1-6  alkyl; and 
       n is 1 or 2; or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound according to  claim 1  having the following formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound according to  claim 1  wherein R 3  is H; or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound according to  claim 1  wherein R 4  is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound according to  claim 4  wherein R 4  is substituted phenyl; or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound according to  claim 5  wherein R 4  is phenyl substituted by one or two substituents each independently selected from the group consisting of halo, C 1-6  alkyl, and C 1-6  alkoxy; or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound according to  claim 1  wherein R 3  and R 4  together with the atoms to which they are attached form optionally substituted indan-1-one; or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound according to  claim 1  wherein n is 1; or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound according to  claim 1  wherein n is 2; or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound according to  claim 1  wherein R 1  is R 2 ; or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound according to  claim 1  wherein R 2  is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound according to  claim 1  wherein R 2  is an optionally substituted 5 or 6 membered heteroaryl; or a pharmaceutically acceptable salt thereof. 
     
     
       13. The compound according to  claim 1  wherein R 2  is an optionally substituted 8-10 membered bicyclic heteroaryl; or a pharmaceutically acceptable salt thereof. 
     
     
       14. The compound according to  claim 1  wherein R 2  is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each of (a)-(1) is optionally substituted with one or two substituents each independently selected from the group consisting of halo, OH, CN, NO 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C(O)R a , COOR a , NR a R b , NHC(O)R a , and C(O)NR a R b ; or a pharmaceutically acceptable salt thereof. 
     
     
       15. The compound according to  claim 1  which is: 
       2-Chloro-6-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-benzonitrile; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-{(R)-3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-Chloro-5-((3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)methyl)benzonitrile; 
       6-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-1-methyl-1,3a,5,7a-tetrahydro-pyrazolo[3,4-d]pyrimidin-4-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-4a,7a-dihydro-3H-thieno[3,2-d]pyrimidin-4-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-6-methyl-4a,7a-dihydro-3H-thieno[2,3-d]pyrimidin-4-one; 
       2-{3-[4-(4-Chloro-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-{3-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-{(S)-3-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-{(R)-3-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-{(R)-3-[4-(4-Methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-((3-(5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-2-oxopyrrolidin-1-yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; 
       (S)-2-((3-(5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-2-oxopyrrolidin-1-yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; 
       (R)-2-((3-(5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-2-oxopyrrolidin-1-yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one; 
       2-[4-(4-Methoxy-benzoyl)-2′-oxo-[1,3′]bipiperidinyl-1′-ylmethyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-[(S)-4-(4-Methoxy-benzoyl)-2′-oxo-[1,3′]bipiperidinyl-1′-ylmethyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 
       2-[(R)-4-(4-Methoxy-benzoyl)-2′-oxo-[1,3′]bipiperidinyl-1′-ylmethyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; 2-((3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)methyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-pyrimidin-4-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-6-methyl-3H-pyrimidin-4-one; 
       6-Ethyl-2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-pyrimidin-4-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-5-methyl-3H-pyrimidin-4-one; 
       2-{3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-5,6-dimethyl-3H-pyrimidin-4-one; 
       2-((3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)methyl)cyclohepta[d]imidazol-4(3H)-one; 
       2-{(R)-3-[4-(4-Methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; 
       2-{(S)-3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; 
       2-{(R)-3-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; 
       N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)-2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)-acetamide; 
       N-(5,6-Dihydro-thiazolo[2,3-c][1,2,4]triazol-3-yl)-2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamide; 
       N-(5,6-Dihydro-thiazolo[2,3-c][1,2,4]triazol-3-yl)-2-{(R)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamide; 
       N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetamide; 
       2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)-N-(1-methyl-1H-tetrazol-5-yl)acetamide; 
       N-(3,4-dihydro-2H-pyrano[2,3-d]pyridazin-5-yl)-2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetamide; or 
       N-Isoxazolo[5,4-b]pyridin-3-yl-2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamide; or a pharmaceutically acceptable salt thereof. 
     
     
       16. A compound which is 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one having the following formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       17. A compound which is 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one having the following formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       18. A compound which is 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one having the following formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       19. A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
       20. A method for the treatment of cancer comprising administration of an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a subject in need thereof. 
     
     
       21. A compound which is 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one having the following formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
       22. The compound of claim 1, wherein said compound is 2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.  
     
     
       23. The compound of claim 1, wherein said compound is 2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one; or a pharmaceutically acceptable salt thereof.  
     
     
       24. The compound of claim 1, wherein said compound is 2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; or a pharmaceutically acceptable salt thereof.  
     
     
       25. The compound of claim 1, wherein said compound is 2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; or a pharmaceutically acceptable salt thereof.  
     
     
       26. The pharmaceutical composition according to claim 19, comprising a compound selected from
 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; and   2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.    
     
     
       27. The pharmaceutical composition according to claim 26, comprising 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.  
     
     
       28. The pharmaceutical composition according to claim 26, comprising 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.  
     
     
       29. The pharmaceutical composition according to claim 26, comprising 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.  
     
     
       30. The pharmaceutical composition according to claim 26, comprising 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.  
     
     
       31. A method for treating polycystic kidney disease, comprising administration of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.  
     
     
       32. The method of claim 31, wherein said compound is selected from
 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one;   2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   2-{3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one; and   2-{3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one;   or a pharmaceutically acceptable salt thereof.    
     
     
       33. The method of claim 32, wherein said compound is 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.  
     
     
       34. The method of claim 32, wherein said compound is 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.  
     
     
       35. The method of claim 32, wherein said compound is 2-{(S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one, or a pharmaceutically acceptable salt thereof.  
     
     
       36. The method of claim 32, wherein said compound is 2-{(S)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3H-cycloheptaimidazol-4-one, or a pharmaceutically acceptable salt thereof.