Chromene derivatives and their analogs as wnt pathway antagonists

Abstract

Compounds of formula (IIc); wherein X 3 and X 4 independently from each other are N or CR 8 wherein R 8 may be same or different; Y 1 , Y 2 , Y 3 and Y 4 independently from each other are N or CR 9 wherein R 9 may be same or different and wherein up to 3 of the group Y 1 , Y 2 , Y 3 and Y 4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

1 - 16 . (canceled) 
     
     
         17 . Compound of formula (IIc) 
       
         
           
           
               
               
           
         
         wherein 
         X 3  and X 4  independently from each other are N or CR 8  wherein R 8  may be same or different; 
         Y 1 , Y 2 , Y 3  and Y 4  independently from each other are N or CR 9  wherein R 9  may be same or different and wherein up to 3 of the group Y 1 , Y 2 , Y 3  and Y 4  may be N; 
         R 1 ; R 2 ; R 3 ; R 4  and R 5  are selected from H, OH; halogen; CN; C 1 -C 6  alkyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; C 4 -C 15  heteroarylalkyl; C(O)R 1a ; C(O)OR 1a ; C(O)N(R 1a R 1b ); N(R 1a )S(O) 2 OR 1b ; N(R 1a R 1b ); N(R 1a )S(O) 2 N(R 1b R 1c ); N(R 1a )C(O)R 1b ; N(R 1a )S(O) 2 R 1b ; N(R 1a )S(O)R 1b ; N(R 1a )C(O)N(R 1b R 1c ); N(R 1a )C(O)OR 1b ; SR 1a ; S(O) 2 OR 1a ; S(O) 2 N(R 1a R 1b ); S(O)N(R 1a R 1b ); S(O) 2 R 1a ; S(O)R 1a ; OR 1a ; OC(O)R 1a ; and OC(O)N(R 1a R 1b ); and wherein alkyl; alkenyl, alkinyl, aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted by one or more groups R 10  which are same or different; optionally two adjacent substituents R 1 ; R 2 ; R 3 ; R 4  and R 5  form together a 5- to 7-membered heterocyclic ring optionally substituted by one or more groups R 10  which may be same or different; and wherein at least 3 of the group of R 1 ; R 2 ; R 3 ; R 4 ; and R 5  are not H; 
         R 1a ; R 1b ; and R 1c  are independently from each other selected from H; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; and C 4 -C 15  heteroarylalkyl; wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted with one or more R 10  which are same or different; 
         R 10  is selected from halogen; CN; OH, C 1 -C 6  alkyl; OR 10a ; C(O)R 10a ; C(O)OR 10a ; C(O)N(R 10a R 10b ); N(R 10a R 10b ); OC(O)R 10a ; N(R 10a )C(O)R 10b ; S(O) 2 N(R 10a R 10b ); S(O)N(R 10a R 10b ); S(O) 2 R 10a ; S(O)R 10a ; S(O) 2 OR 10a ; N(R 10a )S(O) 2 N(R 10b R 10c ); SR 10a ; N(R 10a )S(O) 2 R 10b ; N(R 10a )S(O)R 10b ; N(R 10a )C(O)N(R 10b R 10c ); and OC(O)N(R 10a R 10b ); wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 10a ; R 10b  and R 10C  are independently from each other selected from H; and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 6  is selected from CN; C(O)R 6a ; C(O)OR 6a ; C(O)N(R 6a R 6b ); C(NR 6a )N(R 6b R 6c ); CR 6a NOR 6b ; SR 6a ; S(O)R 6a ; S(O) 2 R 6a ; S(O) 2 OR 6a ; S(O) 2 N(R 6a R 6b ); and S(O)N(R 6a R 6b ); 
         R 6a ; R 6b ; and R 6c  are independently from each other selected from H; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; and C 4 -C 15  heteroarylalkyl which are optionally substituted with one or more R 11 , which are the same or different; 
         R 11  is selected from halogen; CN; OH; C 1 -C 6  alkyl; OR 11a ; C(O)R 11a ; C(O)OR 11a ; C(O)N(R 11a R 11b ); N(R 11a R 11b ); OC(O)R 11a ; N(R 11a )C(O)R 11b ; SR 11a ; S(O)R 11a ; S(O) 2 R 11a ; S(O) 2 OR 11a ; S(O) 2 N(R 11a R 11b ); S(O)N(R 11a R 11b ); N(R 11a )S(O) 2 N(R 11b R 11c ); N(R 11a )S(O) 2 R 11b ; N(R 11a )S(O)R 11b ; N(R 11a )C(O)N(R 11b R 11c ); and OC(O)N(R 11a R 11b ); wherein C 1 -C 6  alkyl is optionally substituted with one or more R 18  which are same or different; 
         R 18  is selected from halogen, CN, OH; OR 11a ; C(O)R 11a ; C(O)OR 11a ; C(O)N(R 11a R 11b ); N(R 11a R 11b ); OC(O)R 11a ; N(R 11a )C(O)R 11b ; SR 11a ; S(O)R 11a ; S(O) 2 R 11a ; S(O) 2 OR 11a ; S(O) 2 N(R 11a R 11b ); S(O)N(R 11a R 11b ); N(R 11a )S(O) 2 N(R 11b R 11c ); N(R 11a )S(O) 2 R 11b ; N(R 11a )S(O)R 11b ; N(R 11a )C(O)N(R 11b R 11c ); and OC(O)N(R 11a R 11b ); 
         R 11a ; R 11b ; and R 11c  are independently from each other selected from H; and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are the same or different; 
         R 7  is selected from H; OH; OR 7a ; OC(O)R 7a ; OC(O)N(R 7a R 7b ); N(R 7a R 7b ); N(R 7a )C(O)R 7b ; N(R 7a )C(O)N(R 7b R 7c ); N(R 7a )C(O)OR 7b ; N(R 7a )S(O) 2 OR 7b ; N(R 7a )S(O)R 7b ; N(R 7a )S(O) 2 R 7b ; N(R 7a )S(O) 2 N(R 7b R 7c ); 
         R 7a ; R 7b ; and R 7c  are independently from each other selected from H; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; and C 4 -C 15  heteroarylalkyl wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; heteroarylalkyl are optionally substituted with one or more R 12 , which are same or different; 
         R 12  is selected from halogen; CN; OH; C 1 -C 6  alkyl; OR 12a ; C(O)R 12a ; C(O)OR 12a ; C(O)N(R 12a R 12b ); N(R 12a R 12b ); OC(O)R 12a ; N(R 12a )C(O)R 12b ; S(O) 2 N(R 12a R 12b ); S(O)N(R 12a R 12b ); S(O) 2 R 12a ; S(O)R 12a ; S(O) 2 OR 12a ; N(R 12a )S(O) 2 N(R 12b R 12c ); SR 12a ; N(R 12a )S(O) 2 R 12b ; N(R 12a )S(O)R 12b ; N(R 12a )C(O)N(R 12b R 12c ); N(R 12a )C(O)OR 12b ; OC(O)N(R 12a R 12b ); and S(O) 2 N(R 11a )C(O)N(R 11b R 11c ); wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 12a ; R 12b  and R 12c  are independently from each other selected from H; and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 8  is selected from H; OH; CN, halogen, C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; C 4 -C 15  heteroarylalkyl; C(O)R 8a ; C(O)OR 8a ; C(O)N(R 8a R 8b ); C(NR 8a )N(R 8b R 8c ); C(R 8a )N(R 8b ); OR 8a ; OC(O)R 8a ; OC(O)N(R 8a R 8b ); SR 8a ; S(O)R 8a ; S(O) 2 R 8a ; S(O) 2 OR 8a ; S(O) 2 N(R 8a R 8b ); S(O)N(R 8a R 8b ); S(O) 2 N(R 8a )C(O)N(R 8b R 8c ); N(R 8a )S(O) 2 N(R 8b R 8c ); N(R 8a )S(O) 2 R 8b ; N(R 8a )S(O)R 8b ; N(R 8a )S(O) 2 OR 8b ; N(R 8a R 8b ); N(R 8a )C(O)R 8b ; N(R 8a )C(O)N(R 8b R 8c ); and N(R 8a )C(S)N(R 8b R 8c ); wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are/is optionally substituted by one or more R 16 , which are same or different; 
         R 8a  and R 8b ; and R 8c  are independently from each other selected from H; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; and C 4 -C 15  heteroarylalkyl which are optionally substituted with one or more R 16 , which are same or different; 
         R 16  is selected from halogen; CN; OH; C 1 -C 6  alkyl; OR 16a ; C(O)R 16a ; C(O)OR 16a ; C(O)N(R 16a R 16b ); N(R 16a R 16b ); OC(O)R 16a ; N(R 16a )C(O)R 16b ; S(O) 2 N(R 16a R 16b ); S(O)N(R 16a R 16b ); S(O) 2 R 16a ; S(O)R 16a ; S(O) 2 OR 16a ; N(R 16a )S(O) 2 N(R 16b R 16c ); SR 16a ; N(R 16a )S(O) 2 R 16b ; N(R 16a )S(O)R 16b ; N(R 16a )C(O)N(R 16b R 16c ); and OC(O)N(R 16a R 16b ); wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 16a  and R 16b  and R 16c  are independently from each other selected from H; and C 1 -C 6  alkyl; wherein C 1-6  alkyl is optionally substituted with one or more halogen which are the same or different; 
         R 9  is selected from H; OH; halogen; CN; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl; C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; C 4 -C 15  heteroarylalkyl; OR 9a ; C(O)R 9a ; C(O)OR 9a ; C(O)N(R 9a R 9b ); S(O) 2 N(R 9a R 9b ); S(O)N(R 9a R 9b ); S(O) 2 R 9a ; S(O)R 9a ; S(O) 2 OR 9a ; S(O) 2 N(R 9a )C(O)N(R 9b R 9c ); N(R 9a )S(O) 2 N(R 9b R 9c ); SR 9a ; OC(O)R 9a ; N(R 9a )C(O)R 9b ; N(R 9a )S(O) 2 R 9b ; N(R 9a )S(O)R 9b ; N(R 9a )C(O)N(R 9b R 9c ); N(R 9a )C(S)N(R 9b R 9c ); OC(O)N(R 9a R 9b ); C(NR 9a )N(R 9b R 9c ); N(R 9a )S(O) 2 OR 9b ; N(R 9a R 9b ); and C(R 9a )NR 9b ; wherein alkyl; cycloalkyl; heterocyclyl; alkenyl; alkinyl; aryl; heteroaryl; aralkyl; and heteroarylalkyl are optionally substituted by one or more R 13 , which are same or different; 
         R 9a ; R 9b ; and R 9c  are independently from each other selected from H; C 1 -C 6  alkyl; C 3 -C 7  cycloalkyl; C 3 -C 7  heterocyclyl; C 2 -C 6  alkenyl; C 2 -C 6  alkinyl C 3 -C 7  aryl; C 3 -C 7  heteroaryl; C 4 -C 15  aralkyl; and C 4 -C 15  heteroarylalkyl which are optionally substituted with one or more R 13 , which are same or different; 
         R 13  is selected from halogen; CN; OH; C 1 -C 6  alkyl; OR 13a ; C(O)R 13a ; C(O)OR 13a ; C(O)N(R 13a R 13b ); N(R 13a R 13b ); OC(O)R 13a ; N(R 13a )C(O)R 13b ; S(O) 2 N(R 13a R 13b ); S(O)N(R 13a R 13b ); S(O) 2 R 13a ; S(O) 2 OR 13a ; S(O)R 13a ; N(R 13a )S(O) 2 N(R 13b R 13c ); SR 13a ; N(R 13a )S(O) 2 R 13b ; N(R 13a )S(O)R 13b ; N(R 13a )C(O)N(R 13b R 13c ); and OC(O)N(R 13a R 13b ); wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         R 13a ; R 13b  and R 13c  are independently from each other selected from H; and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with one or more halogen which are same or different; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         18 . A compound according to  claim 17 , wherein at least one substituent R 9  is not H, and pharmaceutically acceptable salts thereof. 
     
     
         19 . A compound according to  claim 17 , wherein at least one member of the group X 3 , X 4 , Y 1 , Y 2 , Y 3  and Y 4  is N; and pharmaceutically acceptable salts thereof. 
     
     
         20 . A compound according to  claim 17 , wherein R 1 ; R 4 ; and R 5  are independently from each other selected from H; NH 2 ; NHCH 3 ; CH 2 OH; CH 2 OCH 3 ; CH 2 NH 2 ; CH 2 NHCH 3 ; OH; OCH 3 ; Br; F; and C 1 ; and R 2  and R 3  are independently from each other selected from H; NH 2 ; NHCH 3 ; CH 2 OH; CH 2 OCH 3 ; CH 2 NH 2 ; CH 2 NHCH 3 ; OH; OCH 3 ; Br; F; and Cl; or R 2  and R 3  are forming together OCH 2 O;
 and pharmaceutically acceptable salts thereof.   
     
     
         21 . A compound according to  claim 17 , wherein
 R 8  is selected from H; OH; OR 8a ; NH 2 ; NHR 8a ; N(R 8a R 8b ); CH 2 OH; CH 2 OR 16a ; CH 2 NH 2 ; CH 2 NHR 16a ; CH 2 N(R 16a R 16b ); C(O)NH 2 ; C(O)NHR 8a ; C(O)N(R 8a R 8b ); C(O)OH; and C(O)OR 8a ;   R 8a  and R 8b  are independently from each other selected from C 1 -C 6  alkyl which is optionally substituted with one or more halogen which are the same or different; OH, OR 16a , NH 2 ; NHR 16a , NR 16a R 16b ;   R 16a  and R 16b  are independently from each other selected from C 1 -C 6  alkyl; wherein C 1 -6 alkyl is optionally substituted with one or more halogen which are the same or different;   and R 9  is selected H; OH; OR 9a ; NH 2 ; NHR 9a ; N(R 9a R 9b ); CH 2 OH; CH 2 OR 13a ; CH 2 NH 2 ; CH 2 NHR 13a ; CH 2 N(R 13a R 13b ); C(O)NH 2 ; C(O)NHR 9a ; C(O)N(R 9a R 9b ); C(O)OH; and C(O)OR 9a ;   R 9a  and R 9b  are independently from each other selected from C 1 -C 6  alkyl which is optionally substituted with one or more halogen which are the same or different; OH, OR 13a , NH 2 ; NHR 13a , NR 13a R 13b ;   R 13a  and R 13b  are independently from each other selected from C 1 -C 6  alkyl; wherein C 1 -6 alkyl is optionally substituted with one or more halogen which are the same or different;   and pharmaceutically acceptable salts thereof.   
     
     
         22 . Method of using a compound according to  claim 17  for modulating the Wnt signalling pathway. 
     
     
         23 . Method for the treatment of a disorder or disease associated with an aberrant activation of Wnt signalling in a mammal by using a compound according to  claim 17 . 
     
     
         24 . The method according to  claim 23 , wherein the Wnt associated disorder or disease is a cell proliferative disorder, rheumatoid arthritis, increased bone density, aging or age-related disorders and/or diseases or Dupuytren disease (superficial fibromatosis). 
     
     
         25 . The method according to  claim 24 , wherein the cell proliferation disorder is cancer or a proliferative skin disorder. 
     
     
         26 . The method according to  claim 25 , wherein the cancer is member of the group multiple myeloma, colon cancer, breast cancer, gastritic cancer, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, uterine cancer, kidney cancer, leukaemia, gliomas, basal cell carcinoma, rhabdomyosarcoma, mesothelioma, osteosarcoma, medulloblastomas and other primary CNS malignant neuroectodermal tumors. 
     
     
         27 . A pharmaceutical composition containing a compound of  claim 17 . 
     
     
         28 . Method of using the compound according to  claim 17  in a kit. 
     
     
         29 . Method for the preparation of a medicament comprising the steps of:
 a) preparing at least one compound according to  claim 17 ; and   b) formulating a medicament containing at least said compound.   
     
     
         30 . Method of treating a mammal for the modulation of the Wnt signalling pathway, which method comprises administering to said mammal a therapeutically effective amount of a compound according to  claim 17 .