Novel 3-(substituted)-2-indolinones compounds and use thereof as inhibitors of protein kinase activity

Abstract

The present invention relates to novel 3-(substituted)-2-indolinones compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to e useful in the prevention and treatment of protein kinase related disorders such as cancer.

1 . A compound having the chemical structure:  
                   
       wherein: 
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, alkyl, halo and S-sulfonamido;  
 “A” is a ring selected from the group consisting of tetrahydrobenzene, naphthalene, tetrahydronaphthalene, tetrahydrofuran, pyrrolidine, pyridine, quinoline, indole, isatin, chromone, fluorene, carbazole, benzo[b]furan, thieno[b]thiophene and uracil;  
 said “A” ring is substituted with one or more groups independently selected from the group consisting of hydrogen, alkyl, trihalomethyl, 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, azido, nitro, halo, cyanato, isocyanato, thiocyanato, isothiocyanato, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and —NR 5 R 6 ;  
 R 1  and R 2  or R 2  and R 3  or R 3  and R 4  may combine to form a methylenedioxy or an ethylenedioxy group; and,  
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trihalomethanesulfonyl and, combined, a five-member or a six-member heteroalicyclic ring.  
 
     
     
         2 . The compound of    claim 1    wherein said “A” ring is selected from the group consisting of naphthalene, tetrahydronaphthalene, tetrahydrofuran, pyrrolidine, quinoline, isatin, chromone, fluorene, carbazole, benzo[b]furan, thieno[b]thiophene and uracil.  
     
     
         3 . The compound of    claim 1    wherein the “A” ring is substituted with a group selected from the group consisting of 
 hydrogen;  
 unsubstituted lower alkyl;  
 lower alkyl substituted with a group selected from the group consisting of unsubstituted aryl, halo, hydroxy, unsubstituted lower alkyl C-carboxy, and —NR 5 R 6 , unsubstituted lower alkoxy;  
 lower alkoxy substituted with a group selected from the group consisting of C-carboxy, —NR 5 R 6 , and halo;  
 halo;  
 nitro;  
 cyano;  
 hydroxy;  
 acetyl;  
 trihaloacetyl;  
 trihalomethyl;  
 unsubstituted aryl;  
 aryl substituted with one or more groups selected from the group consisting of halo, hydroxy, unsubstituted lower alkyl, unsubstituted lower alkoxy, hydroxy, cyano and nitro, unsubstituted lower aryloxy; and,  
 aryloxy substituted with one or more groups selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, halo, unsubstituted lower alkoxy, and unsubstituted aryl; unsubstituted lower alkyl C-carboxy, unsubstituted lower alkyl thioalkoxy, carboxylic acid, unsubstituted lower alkyl O-carboxy, 4-formylpiperazinyl, 4-formylmorpholinyl, N-pyrrolidinyl and —NR 5 R 6 .  
 
     
     
         4 . The compound of    claim 1    wherein R 5  and R 6  are independently selected from the group consisting of hydrogen and unsubstituted lower alkyl.  
     
     
         5 . A combinatorial library of 3-(substituted)-2-indolinone compounds, comprising compounds formed by reacting oxindoles with aldehydes, wherein: 
 said oxindole is selected from the group consisting of 5,7-dibromooxindole, 5-iodooxindole, 5-bromo-4-methyloxindole, 5-methylamino-sulfonyloxindole, 5-(4-trifluoromethylanilino-sulfonyl)-oxindole, 5-(morpholin-4-yl)-sulfonyloxindole, 5-(2-chloroethyl)oxindindole and 5,7-dibromo-4-methyloxindole; and,    said aldehyde is selected from the group consisting of benzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 2-formyl-5,6,7,8-tetrahydronaphthalene, 3-furaldehyde, furfural, 2-quinolinecarboxaldehyde, 3-quinolinecarboxaldehyde, 4-quinonlinecarboxaldehyde, 1-pyrrolidinecarboxaldehyde, 3-thiophenecarboxaldehyde, indole-3-carboxaldehyde, 2-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde, 3-thiophenecarboxaldehyde, pyrrole-2-carboxaldehyde, pyrrole-3-carboxaldehyde, 2-imidazolecarboxaldehyde, 4-imidazolecarboxaldehyde, pyrazole-3-carboxaldehyde, 2-formylbenzimidazole, 2-formyl-4,5,6,7-tetrahydroindole, benzo[b]furan-2-carboxaldehyde, thieno[b]thiophene-2-carboxaldehyde, isatin, chromone-3-carboxaldehyde, fluorene-2-carboxaldehyde, pyridine-2-carboxaldehyde, pyridine-3-carboxaldehyde, 1,2,3,6-tetrahydro benzaldehyde, 3-tetrahydrofurancarboxaldehyde, carbazole-3-carboxaldehyde, 5-formyluracil and 2-(trifluoroacetyl)thiophene wherein 
 said aldehyde may be unsubstituted, or substituted with one or more groups selected from the group consisting of: 
 unsubstituted lower alkyl;  
 lower alkyl substituted with a group selected from the group consisting of unsubstituted aryl, halo, hydroxy, unsubstituted lower alkyl C-carboxy, and —NR 5 R 6 , unsubstituted lower alkoxy;  
 lower alkoxy substituted with a group selected from the group consisting of C-carboxy, —NR 5 R 6 , and halo;  
 halo;  
 nitro;  
 cyano;  
 hydroxy;  
 acetyl;  
 trihaloacetyl;  
 trihalomethyl;  
 unsubstituted aryl;  
 aryl substituted with one or more groups selected from the group consisting of halo, hydroxy, unsubstituted lower alkyl, unsubstituted lower alkoxy, hydroxy, cyano and nitro, unsubstituted lower aryloxy; and,  
 aryloxy substituted with one or more groups selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, halo, unsubstituted lower alkoxy, and unsubstituted aryl; unsubstituted lower alkyl C-carboxy, unsubstituted lower alkyl thioalkoxy, carboxylic acid, unsubstituted lower alkyl O-carboxy, 4-formylpiperazinyl, 4-formylmorpholinyl, N-pyrrolidinyl and —NR 5 R 6 .  
 
   
     
     
         6 . A pharmacological composition, comprising: 
 said compound, salt or prodrug of    claim 1   ; and,    a pharmaceutically acceptable carrier.    
     
     
         7 . 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   .  
     
     
         8 . The method of    claim 7    wherein said protein kinase comprises a protein tyrosine kinase.  
     
     
         9 . The method of    claim 8    wherein said protein tyrosine kinase comprises a receptor tyrosine kinase.  
     
     
         10 . The method of    claim 9    wherein said receptor tyrosine kinase is selected from the group consisting of EGF, HER2, HER3, HER 4 , IR, IGF-1R, 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.  
     
     
         11 . The method of    claim 7    wherein said protein tyrosine kinase comprises a cellular tyrosine kinase.  
     
     
         12 . The method of    claim 11    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.  
     
     
         13 . The method of    claim 7    wherein said protein kinase comprises a serine-threonine protein kinase.  
     
     
         14 . The method of    claim 13    wherein said serine-threonine protein kinase is selected from the group consisting of CDK2 and Raf.  
     
     
         15 . A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound of    claim 1    to said organism.  
     
     
         16 . The method of    claim 15    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, a serine threonine kinase related disorder and a flk related disorder.  
     
     
         17 . The method of    claim 16    wherein said receptor tyrosine kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder and an IGFR related disorder.  
     
     
         18 . The method of    claim 15    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, lung carcinoma, small-cell lung cancer and glioma.  
     
     
         19 . The method of    claim 15    wherein said protein kinase related disorder is selected from the group consisting of autoimmune disorder, hyper-proliferation disorder, inflammatory disorder, diabetes, restenosis, fibrosis, psoriasis, angiogenesis, osteoarthritis and rheumatoid arthritis.  
     
     
         20 . The method of    claim 15    wherein said organism is a human.