Substituted 2-indolinone as ptk inhibitors containing a zinc binding moiety

Abstract

The present invention relates to substituted 2-indolinone containing zinc-binding moiety based derivatives that have enhanced or unique properties as inhibitors of protein tyrosine kinase (PTK) receptors and their use in the treatment of PTK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

1 . A compound represented by formula I: 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein
 X 1  is N, CR 4 ; where R 4  is hydrogen or aliphatic; 
 L is absent or NH; 
 Cy is a aryl, substituted aryl, heteroaryl, substituted heteroaryl; 
 G is O or S; 
 B is a linker; 
 C is selected from: 
 
       
         
           
           
               
               
           
         
       
       where W is O or S; Y is absent, N, or CH; Z is N or CH; R 7  and R 9  are independently hydrogen, OR′ or aliphatic group, wherein R′ is hydrogen, aliphatic, substituted aliphatic or acyl; provided that if R 7  and R 9  are both present, one of R 7  or R 9  must be OR′ and if Y is absent, R 9  must be OR′; and R 8  is hydrogen, acyl, aliphatic, or substituted aliphatic; 
       
         
           
           
               
               
           
         
       
       where W is O or S; J is O, NH or NCH 3 ; and R 10  is hydrogen or lower alkyl; 
       
         
           
           
               
               
           
         
       
       where W is O or S; Y 1  and Z 1  are independently N, C or CH; 
       and 
       
         
           
           
               
               
           
         
       
       where Z, Y, and W are as previously defined; R 11  and R 12  are independently selected from hydrogen or aliphatic; R 1 , R 2  and R 3  are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , CN, N 3 , NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
 R 23  is hydrogen, acyl, aliphatic or substituted aliphatic. 
 
     
     
         2 . A compound according to  claim 1 , wherein B is a direct bond or straight or branched, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO 2 , N(R 8 ), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R 8  is hydrogen, acyl, aliphatic or substituted aliphatic. 
     
     
         3 . A compound according to  claim 1  represented by formula (II): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R 5  and R 6  are independently selected from hydrogen, CF 3 , aliphatic or substituted aliphatic; R 4 , R 20 , R 21 , R 22 , R 23 , G, B and C are as previously defined in  claim 1 . 
     
     
         4 . A compound according to  claim 1  represented by formula III: 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein B 1  is absent, O, S, SO, SO 2 , aryl, heteroaryl, heterocylic, N(R 8 ), CO; B 2  is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclic, N(R 8 ), CO, SO, or SO 2 ; B 3  is absent, O, N(R 8 ), CO, C 1 -C 6  alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclic; B 4  is absent, O, S, SO, SO 2 , N(R 8 ), CO; B 5  is absent, C 1 - C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, heterocyclic, heteroaryl or aryl; and R′, R 20 , R 21 , and R 22  are as previously defined in  claim 1 . 
     
     
         5 . A compound according to  claim 1  represented by formula (IV): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein n is 1-9; and R′, R 20 , R 21 , and R 22  are as previously defined in  claim 1 . 
     
     
         6 . A compound according to  claim 1  represented by formula (V): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein n is 1-9; and R 1 , R 2 , R 3 , R 20 , R 21 , and R 22  are as previously defined in  claim 1 . 
     
     
         7 . A compound according to  claim 1  represented by formula (VI): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein n is 1-6; m is 1 or 2; R′, R 20 , R 21 , and R 22  are as previously defined in  claim 1 . 
     
     
         8 . A compound according to  claim 1  represented by formula (VII): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein C is —C(O)NHOR′ or 
       
         
           
           
               
               
           
         
       
       R′, R 4 , R 5 , R 6 , R 20 , R 21 , R 22 , and R 23  are as previously defined  claim 1 . 
     
     
         9 . A compound according to  claim 1  represented by formula (VIII): 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein n is 0-7; R 24  is absent or selected from alkylene, alkenylene, and alkynylene; n is 0-7; G is Ar 1 , X 2 —Ar 1  or X 2 -alkyl-Ar 1 , where Ar 1  is independently selected Cy and X 2  is O, S or NH; Cy, R′, R 4 , R 5 , R 6 , R 20 , R 21 , R 22 , and R 23  are as previously defined in  claim 1 . 
     
     
         10 . A compound according to  claim 1  selected from the compounds delineated in Table A or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof: 
       
         
           
                 
                 
               
                   TABLE A 
                 
                     
                 
                   Compound 
                     
                 
                   No. 
                   Structure 
                 
                     
                 
                    1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   13 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   14 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   19 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   20 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   21 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   22 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   23 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   24 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   25 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   26 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   27 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   28 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   29 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A pharmaceutical composition comprising as an active ingredient a compound of  claim 1  and a pharmaceutical acceptable carrier. 
     
     
         12 . A method of treating a PTK related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 11 . 
     
     
         13 . The method of  claim 12 , wherein said PTK related disease or disorder is a cell proliferative disorder. 
     
     
         14 . The method of  claim 12 , wherein said PTK is selected from the group consisting of VEGF receptors and PDGF receptors. 
     
     
         15 . The method of  claim 14 , wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease and Burkitt's disease. 
     
     
         16 . The method of  claim 14 , wherein said PTK related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder. 
     
     
         17 . A method of treating an HDAC-mediated disease comprising administering to a subject in need thereof a pharmaceutical composition of  claim 11 . 
     
     
         18 . A method of treating PTK and HDAC mediated diseases comprising administering to a subject in need thereof a pharmaceutical composition of  claim 11 .