3-(arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

1 . A compound represented by the general formula II:  
     
       
         
         
             
             
         
       
     
     wherein R 5  is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl; R 3  is selected from the group consisting of D, halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid; R 4  is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl; b is 0 or an integer from 1 to 3; a is 0 or an integer of from 1 to 5; the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof provided however said compound is not 
 3-Phenylaminomethylene-1,3-dihydro-indol-2-one,  
 3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,  
 3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,  
 3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid ethyl ester,  
 3-[(2-Ethyl-phenylamino)-methylene}-1,3-dihydro-indol-2-one,  
 3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,  
 3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one or  
 3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.  
 
   
   
       2 . A method for treating diseases related to unregulated tyrosine kinase signal transduction, wherein said disease is selected from the group consisting of carcinoma, sarcoma, leukemia, erythromblastoma, glioblastoma, meningioma, astrocytoma, melanoma, myoblastoma, brain cancer, bladder cancer, ovarian cancer, gastric cancer, pancreas cancer, colon cancer, blood cancer, lung cancer, bone cancer, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, surgical adhesions, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, glomerulopathies, psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .  
   
   
       3 . The method of  claim 2  wherein said disease is age-related macular degeneration.  
   
   
       4 . The method of  claim 2  wherein said disease is psoriasis.  
   
   
       5 . The method of  claim 2  wherein R is selected from the group consisting of fluoro, methyl, NR 2 (CR 7 R 8 ) d R 6  and (CR 7 R 8 ) c —R 6 , wherein R 6  is selected from the group consisting of diloweralkylamino, 3-fluoropyrrolidinyl, piperidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one, N-methylhomopiperazinyl, (dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2-(N-methyl-2-aminoethyl)-1,3-dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1-(3-aminopropyl)imidazole, histaminyl, N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R)-3-amino-1-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyranyl, ethanolamine and alkyl-substituted derivatives thereof.  
   
   
       6 . The method of  claim 5  wherein R 6  is selected from the group consisting of dimethylamino, diethylamino, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 3-pyridinyl, 4-pyridinyl, pyrrolidinyl, morpholinyl, piperazinyl, heptamethyleneiminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyranyl, N,N-diisopropylethylenediaminyl and 4-aminomethyltetrahydropyranyl.  
   
   
       7 . The method of  claim 6  where R 6  is unsubstituted or mono or di-methyl substituted morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl.  
   
   
       8 . The method of  claim 7  wherein R 6  is morpholinyl.