(2-oxindol-3-ylidenyl)acetic acid derivatives and their use as protein kinase inhibitors

Abstract

The present invention relates to (2-oxindol-3-ylidenyl)acetic acid derivatives which modulate the activity of protein kinases and are therefore useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.

What is claimed:  
     
         1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is selected from the group consisting of oxygen, sulfur and —NH—;  
 Y is selected from the group consisting of carbon and nitrogen, it being understood that, when Y is nitrogen, R 5  does not exist;  
 n is 0, 1, 2 or 3;  
 R 1  is selected from the group consisting of hydrogen and alkyl;  
 R 2  is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, trihaloalkyl, hydroxy, alkoxy, —C(O)R 16 , —NR 17 R 18 , and —(CH 2 ) r R 19 ;  
 R 3  and R 4  are independently selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, —NR 17 R 18 , —C(O)R 16 , aryl, 6-member ring heteroaryl, —S(O) 2 NR 17 R 18 , —NR 17 S(O) 2 R 18 , —NR 17 C(O)R 18 , and —NR 17 C(O)OR 18 ;  
 R 5  is selected from the group consisting of hydrogen, alkyl, halo, hydroxy, and alkoxy;  
 when n is 0 and X is oxygen or sulfur, R 6  is selected from the group consisting of hydrogen, alkyl, and aryl;  
 when n is 0 and X is nitrogen, R 6  is selected from the group consisting of hydrogen, alkyl, and aryl or R 6  combines with X to form a heteroalicyclic ring;  
 when n is 1, 2 or 3, R 6  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, —C(O)R 16 , and —NR 17 R 18 ;  
 R 7  is selected from the group consisting of  
                     
 wherein:  
 B 1 , B 2 , B 3 , B 4  and B 5  are carbon, or one of B 1 , B 2 , B 3 , B 4  or B 5  is nitrogen, the others being carbon, or  
 B 1  and B 2  or B 2  and B 3  or B 3  and B 4  are nitrogen, the others being carbon, or  
 B 1  and B 3  or B 2  and B 4  or B 5  are nitrogen, the othere being carbon, or  
 R 8 , R 11  and R 12  are independently selected from the group consisting of hydrogen, alkyl, trihalomethyl, hydroxy, alkoxy, halo, —C(O)R 16 , —(CH 2 ) r R 19 , and —NR 17 R 18 ;  
 R 9  and R 10  are independently selected from the group consisting of hydrogen, alkyl, trihalomethyl, hydroxy, alkoxy, halo, —C(O)R 16 , —(CH 2 ) r R 19 , and —NR 17 R 18 ; or  
 R 9  and R 10  may combine to form a —(CH 2 ) 3 — or a —(CH 2 ) 4 — group; it being understood that, when any of B 1 , B 2 , B 3 , B 4  or B 5  is nitrogen, R 8 , R 9 , R 10 , R 11  or R 12 , respectively, does not exist;  
 D 1  is selected from the group consisting of —NR 20 —, oxygen, or sulfur;  
 D 2 , D 3  and D 4  are independently selected from the group consisting of carbon and nitrogen, it being understood that, when D 2 , D 3  or D 4  is nitrogen, R 13 , R 14  or R 15 , respectively, does not exist;  
 R 15  is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, —(CH 2 ) s R 21 , and —C(O)R 16 ;  
 R 13  and R 14  are independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, —(CH 2 ) s R 21 , and —C(O)R 16 ; or  
 R 13  and R 14  may combine to form a —(CH 2 ) 4 — group;  
 R 16  is selected from the group consisting of hydrogen, hydroxy, alkoxy, and —NR 17 R 18 ;  
 R 17  and R 18  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl; or  
 R 17  and R 18  may combine to form a group selected from the group consisting of —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 2 O(CH 2 ) 2 —, and —(CH 2 ) 2 N(R 20 )(CH 2 ) 2 —;  
 R 19  is selected from the group consisting of hydroxy, alkoxy, —NR 17 R 18 , and —C(O)R 16 , wherein R 16 , R 17  and R 18  are defined as above;  
 R 20  is selected from the group consisting of hydrogen and alkyl;  
 R 21  is selected from the group consisting of hydroxy, alkoxy, —NR 17 R 18 , and —C(O)R 16 , wherein R 16 , R 17  and R 18  are defined as above; and,  
 r and s are independently 1, 2 or 3; or,  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound or salt of  claim 1 , wherein R 1  is hydrogen.  
     
     
         3 . The compound or salt of  claim 2 , wherein R 2  and R 5  are hydrogen.  
     
     
         4 . The compound or salt of  claim 3 , wherein R 7  is  
       
         
           
           
               
               
           
         
       
       where B 1 , B 2 , B 3 , B 4  and B 5  are carbon.  
     
     
         5 . The compound or salt of  claim 4 , wherein R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halo, trihalomethyl and —NR 17 R 18 .  
     
     
         6 . The compound or salt of  claim 3 , wherein R 7  is  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound or salt of  claim 6 , wherein: 
 D 1  is —NH—; and,    D 2 , D 3  and D 4  are carbon.    
     
     
         8 . The compound or salt of  claim 7 , wherein R 13  and R 15  are independently selected from the group consisting of hydrogen, lower alkyl and halo.  
     
     
         9 . The compound or salt of  claim 8 , wherein R 14  is selected from the group consisting of hydrogen and —(CH 2 ) s R 21 .  
     
     
         10 . The compound or salt of  claim 1 , wherein: 
 X is oxygen;    n is 0; and,    R 6  is selected from the group consisting of hydrogen and lower alkyl.    
     
     
         11 . The compound or salt of  claim 4 , wherein: 
 X is oxygen;    n is 0; and    R 6  is selected from the group consisting of hydrogen and lower alkyl.    
     
     
         12 . The compound or salt of  claim 7 , wherein: 
 X is oxygen;    n is 0; and    R 6  is selected from the group consisting of hydrogen and lower alkyl.    
     
     
         13 . The compound or salt of  claim 1 , wherein 
 X is —NH—;    n is 0;    R 6  is phenyl; and    R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, trihalomethyl, —(CH 2 ) s NR 17 R 18  and —NR 17 R 18 .    
     
     
         14 . The compound or salt of  claim 4 , wherein: 
 X is —NH—;    n is 0;    R 6  is phenyl; and    R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, trihalomethyl, —(CH 2 ) s NR 17 R 18  and —NR 17 R 18 .    
     
     
         15 . The compound of  claim 7 , wherein: 
 X is —NH—;    n is 0;    R 6  is phenyl; and    R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, trihalomethyl, —(CH 2 ) s NR 17 R 18  and —NR 17 R 18 .    
     
     
         16 . The compound or salt of  claim 1 , wherein: 
 X is —NH—,    n is 2, 3 or 4; and    R 6  is —NR 17 R 18 .    
     
     
         17 . The compound or salt of  claim 16 , wherein: 
 R 17  and R 18  are independently selected from the group consisting of hydrogen, lower alkyl and, combined to form —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 2 O(CH 2 ) 2 —, and —(CH 2 ) 2 N(CH 3 )(CH 2 ) 2 .    
     
     
         18 . The compound of  claim 7 , wherein: 
 X is —NH—,    n is 2, 3 or 4; and,    R 6  is —NR 17 R 18 .    
     
     
         19 . A pharmaceutical composition, comprising a compound or salt of  claim 1;  and a pharmaceutically acceptable carrier or excipient.  
     
     
         20 . A method for treating a protein kinase related disorder in an organism comprising administering to said organism a therapeutically effective amount of a compound or salt of  claim 1 .  
     
     
         21 . The method of  claim 20  wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder and a serine-threonine kinase related disorder.  
     
     
         22 . The method of  claim 20  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.  
     
     
         23 . The method of  claim 20  wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.  
     
     
         24 . The method of  claim 20  wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder.  
     
     
         25 . The method of  claim 20  wherein said organism is a human.