2-indolinone derivatives as modulators of protein kinase activity

Abstract

The present invention relates to novel imidazoly 2-indolinones and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.

What is claimed:  
     
         1 . An 2-indolinone having the chemical structure:  
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt or prodrug thereof, wherein: 
 A, B, D and E are independently selected from the group consisting of carbon and nitrogen wherein it is understood that, when A, B, D or E is nitrogen, R 6 , R 7 , R 8  or R 9 , respectively, does not exist;  
 G and J are selected from the group consisting of nitrogen and carbon such that, when G is nitrogen, J is carbon and when J is nitrogen, G is carbon, it being recognized that, when G or J is nitrogen, R 5  or. R 5′ , respectively, does not exist;  
 R 1  and R 3  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, hydroxy, alkoxy, C-carboxy, O-carboxy, C-amido, C-thioamido, sulfonyl and trihalomethylsulfonyl;  
 R 2  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and halo;  
 R 4 , R 5  and R 5′ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicylic, halo, hydroxy, nitro, cyano, alkoxy, aryloxy, C-carboxy, O-carboxy, carbonyl, S-sulfonamido, amino and NR 10 R 11  wherein 
 R 10  and R 11  are independently selected from the group consisting of alkyl, cycloalkyl, aryl, carbonyl, sulfonyl, tri-halomethanesulfonyl and, combined, a five-member or a six-member heteroalicyclic ring;  
 
 R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, N-trihalomethanesulfonamido, carbonyl, C-carboxy, O-carboxy, cyano, nitro, halo, cyanato, isocyanato, thiocyanato, isothiocyanato, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and —NR 10 R 11  with R 10  and R 11  as defined above; and,  
 R 6  and R 7  or R 7  and R 8  or R 1  and R 9 , combined, may form a five- or six-member aromatic, heteroaromatic, alicyclic or heteroalicyclic ring group.  
 
     
     
         2 . The compound, salt or prodrug of  claim 1 , wherein A, B, D and E are carbon.  
     
     
         3 . The compound, salt or prodrug of  claim 1 , wherein R 1 , R 2  and R 3  are hydrogen.  
     
     
         4 . The compound, salt or prodrug of  claim 1 , wherein: 
 R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of: 
 hydrogen;  
 unsubstituted lower alkyl;  
 lower alkyl substituted with a group selected from the group consisting of halo, C-carboxy and —NR 10 R 11 ;  
 unsubstituted lower alkoxy;  
 lower alkoxy substituted with a group selected from the group consisting of halo, C-carboxy and NR 10 R 11 ;  
 trihalomethyl;  
 unsubstituted alkenyl;  
 unsubstituted alkynyl;  
 unsubstituted aryl;  
 aryl substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halo groups, halo, unsubstituted lower alkoxy, C-carboxy, amino, S-sulfonamido or —NR 10 R 11 ;  
 unsubstituted heteroalicyclic;  
 heteroalicyclic substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halo groups, aldehyde, unsubstituted lower alkyl carbonyl, hydroxy, unsubstituted alkoxy, alkoxy substituted with one or more halo groups, C-carboxy, amino, S-sulfonamido or —NR 10 R 11 ;  
 unsubstituted aryloxy;  
 aryloxy substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, halo, hydroxy, amino, S-sulfonamido or —NR 10 R 11 ;  
 thiohydroxy;  
 unsubstituted thioalkoxy;  
 unsubstituted thioaryloxy;  
 thioaryloxy substituted with one or more groups independently selected from the group consisting of halo, hydroxy, amino, S-sulfonamido or —NR 10 R 11 ;  
 S-sulfonamido;  
 C-carboxy;  
 O-carboxy;  
 hydroxy;  
 cyano;  
 nitro;  
 halo;  
 C-amido;  
 N-amido;  
 amino; and,  
 —NR 10 R 11 .  
   
     
     
         5 . The compound, salt or prodrug of  claim 1 , wherein: 
 R 10  is hydrogen; and,    R 11  is unsubstituted lower alkyl.    
     
     
         6 . The compound, salt or prodrug of  claim 1 , wherein: 
 R 4 , R 5  and R 5′  are independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl, lower alkyl susbstituted on the carbon furthest from the point of attachment to the ring with a C-carboxy group, halo, hydroxy, unsubstituted lower alkoxy, O-carboxy, C-carboxy, amino, C-amido, N-amido, nitro, amino, S-sulfonamido and —NR 10 R 11 .    
     
     
         7 . The compound, salt or prodrug of  claim 2 , wherein R 1 , R 2  and R 3  are hydrogen.  
     
     
         8 . The compound, salt or prodrug of  claim 4 , wherein: 
 A, B, D and E are carbon; and,    R 1 , R 2  and R 3  are hydrogen.    
     
     
         9 . The compound, salt or prodrug of  claim 8 , wherein: 
 R 10  is hydrogen; and,    R 11  is unsubstitued lower alkyl.    
     
     
         10 . The compound, salt or prodrug of  claim 9 , wherein R 4  and R 5  and R 5′  are independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower alkyl substituted at the carbon furthest from the point of attachment to the ring with a C-carboxy group, trihalomethyl, halo, hydroxy, unsubstituted lower alkoxy, O-carboxy, C-carboxy, amino, C-amido, N-amido, nitro, S-sulfonamido and —NR 10 R 11 .  
     
     
         11 . The compound, salt or prodrug of  claim 9 , wherein: 
 G is nitrogen;    J is carbon; and,    R 4  and R 5′  are hydrogen.    
     
     
         12 . The compound, salt or prodrug of  claim 9 , wherein: 
 G is carbon;    J is nitrogen; and,    R 4  and R 5  are hydrogen.    
     
     
         13 . A method for the modulation of the catalytic activity of a protein kinase, comprising contacting said protein kinase with a compound, salt or prodrug of  claim 1 .  
     
     
         14 . The method of  claim 13 , wherein said protein kinase comprises a receptor protein tyrosine kinase.  
     
     
         15 . The method of  claim 14 , wherein said receptor protein tyrosine kinase is selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-LR, IRR, PDGFRα, PDGFRβ, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.  
     
     
         16 . The method of  claim 13 , wherein said protein kinase comprises a non-receptor protein tyrosine kinase.  
     
     
         17 . The method of  claim 16 , wherein said non-receptor protein tyrosine kinase is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.  
     
     
         18 . The method of  claim 13 , wherein said protein kinase comprises a serine-threonine protein kinase.  
     
     
         19 . The method of  claim 18 , wherein said serine-threonine protein kinase is selected from the group consisting of CDK2 and Raf.  
     
     
         20 . A pharmacological composition comprising: 
 a compound, salt of prodrug of  claim 1;  and,    a physiologically acceptable carrier or excipient.    
     
     
         21 . A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound, salt or prodrug of  claim 1  to said organism.  
     
     
         22 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a cellular tyrosine kinase related disorder and a serine-threonine kinase related disorder.  
     
     
         23 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder, and a flk related disorder.  
     
     
         24 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of squamous cell carcinoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer and small-cell lung cancer.  
     
     
         25 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of diabetes, autoimmune disorder, hyperproliferation disorder, inflammatory disorder, angiogenesis, restenosis, fibrosis, psoriasis, osteoarthritis and rheumatiod arthritis.  
     
     
         26 . The method of  claim 21  wherein said organism is a human.  
     
     
         27 . A method for synthesizing an imidazoyl-2-indolinone comprising the steps of: 
 binding a carbonylimidazole to a solid substrate;    reacting said solid substrate-bound carbonylimidazole with a 2-indolinone to form a solid substrate-bound imidazoyl-2-indolinone; and, releasing said imidazoly-2-indolinone from said solid substrate.    
     
     
         28 . The method of  claim 27  comprising using a resin as said solid substrate.  
     
     
         29 . The method of  claim 27  comprising using a 2-chlorotrityl resin as said solid substrate.  
     
     
         30 . The method of  claim 27  comprising washing said solid substrate-bound imidazoyl-2-indolinone with acetone, water, dichloromethane and methanol.