3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene)-2-indolinone derivatives as kinase inhibitors

Abstract

The present invention relates to certain 3-(4,5,6,7-tetrahydroindol-2-yl-methylidene)-2-indolinone derivatives that inhibit kinases, in particular Src kinase. Pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are also disclosed.

1 - 21 . (Cancelled)  
     
     
         22 . A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound of Formula (1):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Y is a methylene, ethylene, carbonyl or —COCH 2 —;  
 m is 0 or 1;  
 R 1  is —S(O) n R 5  (where n is 0, 1, or 2 and R 5  is alkyl or aralkyl) or —SO 2 NR 6 R 7  where R 6  and R 7  are independently hydrogen, alkyl, cycloalkyl, alkoxyalkyl, or hydroxyalkyl;  
 R 2  is hydrogen, alkyl, or hydroxyalkyl;  
 R 3  is alkyl or hydroxyalkyl; or  
 R 2  and R 3  together with the nitrogen atom to which they are attached form a heterocycloamino group;  
 R 4  is:  
 (a) hydrogen;  
 (b) —PO(OR 8 ) 2  where each R 8  is independently hydrogen or alkyl;  
 (c) —COR 9  where R 9  is alkyl; or  
 (d) —CHR 10 NR 11 R 12  where R 10  is hydrogen or alkyl, and R 11  and R 12  are independently hydrogen or alkyl or R 11  and R 12  together with the nitrogen atom to which they are attached form heterocycloamino; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         23 . The method of  claim 22  wherein said protein kinase is Src Kinase.  
     
     
         24 . A method for treating or preventing a protein kinase related disorder in a patient in need of such treatment comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound or salt of  claim 22  and a pharmaceutically acceptable carrier or excipient to said patient.  
     
     
         25 . The method of  claim 24  wherein the disorder is mediated by Src kinase.  
     
     
         26 . The method of  claim 25  wherein said Src kinase related disorder is a cancer selected from the group consisting of colon cancer, endometrial cancer, breast cancer, ovarian cancer, pancreatic cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, and bladder cancers.  
     
     
         27 . The method of claim  21 , wherein m is 1 and Y is ethylene.  
     
     
         28 . The method of claim  21 , wherein m is 1 and Y is —COCH 2 —.  
     
     
         29 . The method of  claim 22  or  23 , wherein R 4  is hydrogen.  
     
     
         30 . The method of  claim 24 , wherein R 1  is —SO 2 R 5  where R 5  is alkyl.  
     
     
         31 . The method of  claim 24 , wherein R 1  is —SO 2 NR 6 R 7  where R 6  is hydrogen or alkyl; and R 7  is alkyl, cycloalkyl or hydroxyalkyl.  
     
     
         32 . The method of  claim 25 , wherein R 2  and R 3  are independently alkyl.  
     
     
         33 . The method of  claim 25 , wherein R 2  is hydrogen or alkyl; and R 3  is hydroxyalkyl.  
     
     
         34 . The method of  claim 25 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form heterocycloamino optionally substituted with one, or two substituents independently selected from alkyl, alkoxycarbonyl, acyl, hydroxyalkylcarbonyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, or hydroxyalkyl.  
     
     
         35 . The method of  claim 29 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-ethyloxycarbonylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-formylpiperazin-1-yl, 4-hydroxymethylcarbonylpiperazin-1-yl, piperazin-1-yl, 4-ethoxycarbonylmethyl-piperazin-1-yl, 4-carboxymethylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or morpholin-4-yl.  
     
     
         36 . The method of  claim 26 , wherein R 2  and R 3  are independently alkyl.  
     
     
         37 . The method of  claim 26 , wherein R 2  is hydrogen or alkyl; and R 3  is hydroxyalkyl.  
     
     
         38 . The method of  claim 26 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, alkoxycarbonyl, acyl, hydroxyalkylcarbonyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, or hydroxyalkyl.  
     
     
         39 . The method of  claim 38 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-ethyloxycarbonylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-formylpiperazin-1-yl, 4-hydroxymethylcarbonylpiperazin-1-yl, piperazin-1-yl, 4-ethoxycarbonylmethyl-piperazin-1-yl, 4-carboxymethylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or morpholin-4-yl.  
     
     
         40 . The method of claim  21 , wherein R 2  and R 3  are independently alkyl.  
     
     
         41 . The method of claim  21 , wherein R 2  is hydrogen or alkyl; and R 3  is hydroxyalkyl.  
     
     
         42 . The method of claim  21 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, alkoxycarbonyl, acyl, hydroxyalkylcarbonyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxy, or hydroxyalkyl.  
     
     
         43 . The method of claim  21 , wherein R 2  and R 3  together with the nitrogen atom to which they are attached form 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-ethyloxycarbonylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-formylpiperazin-1-yl, 4-hydroxymethylcarbonylpiperazin-1-yl, piperazin-1-yl, 4-ethoxycarbonylmethyl-piperazin-1-yl, 4-carboxymethylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or morpholin-4-yl.  
     
     
         44 . The method of any one of claims  40 ,  41 ,  42 , or  43  wherein R 4  is hydrogen.  
     
     
         45 . The method of  claim 22 , wherein: 
 (a) R 4  is hydrogen;    (b) R 2  and R 3  are methyl;    (c) R 2  is methyl; and R 3  is 2-hydroxyethyl; or    (d) R 2  and R 3  together with the nitrogen atom to which they are attached form 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-ethyloxycarbonyl-piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-formylpiperazin-1-yl, 4-hydroxymethylcarbonylpiperazin-1-yl, piperazin-1-yl, 4-ethoxycarbonylmethylpiperazin-1-yl, 4-carboxymethylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, or morpholin-4-yl.