Methods of Inhibiting the Catalytic Activity of a Protein Kinase and of Treating a Protein Kinase Related Disorder

Abstract

The invention provides a method of inhibiting the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and also provides a method of treating a protein kinase related disorder comprising a step of administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein each substituent in formula (I) is same as defined in the description.

What is claimed is: 
     
         1 . A method of inhibiting the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, 
       wherein
 the inhibiting of catalytic activity occurs in non-colon cancer treatment activity; 
 X being selected from the group consisting of carbon and nitrogen; 
 R 1  and R 2  each being independently selected from the group consisting of hydrogen and alkyl; 
 R 3  being selected from the group consisting of alkyl, trifluoromethyl, aryl, aralkyl, and methyl, at least one of said alkyl, aryl, aralkyl, and methyl being optionally further substituted by halogen; 
 R 4  being selected from the group consisting of alkyl, cycloalkyl, heterocyclo alkyl, aryl, heteroaryl, —(CH 2 ) n (OCH 2 CH 2 ) r R 11 , —[CH 2 CH(OH)] r CH 2 NR 9 R 10  and —(CH 2 ) n NR 9 R 10 , at least one said alkyl, cylcoalkyl, heterocyclo alkyl, aryl and heteroaryl is optionally further substituted by the group consisting of aryl, hydroxyl, amino, carboxamido, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 when X is nitrogen, R 5  is absent, R 6 , R 7 , R 8  are each independently selected from the group consisting of hydrogen and halogen; 
 when X is carbon, R 5 , R 6 , R 7 , R 8  are each independently selected from the group consisting of hydrogen, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocyclo alkyl, aryl, heteroaryl, hydroxyl, cyano, nitro, —OR 9 , —O[CH 2 CH 2 O] r R 11 , —NR 9 R 10 , —(CH 2 ) n CO 2 R 9 , —(CH 2 ) n CONR 9 R 10 , —COR 9 , —NR 9 COR 10 , —SO 2 R 9  and —NHCO 2 R 10 , at least one of said aryl, heteroaryl, cycloalkyl and heterocyclo alkyl is optionally further substituted by the group consisting of alkyl, alkoxyl and halogen; 
 R 9  and R 10  each being independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclo alkyl and heteroaryl, at least one of said alkyl, cycloalkyl, aryl, heterocyclo alkyl and heteroaryl being optionally further substituted by the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 R 9  and R 10  being taken together with the attached atom to form 4 to 8 membered hetero rings, wherein said 4 to 8 membered hetero rings contain at least one heteroatom selected from the group consisting of N, O and S, and said 4 to 8 membered rings being optionally further substituted by the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 R 11  is selected from the group consisting of hydrogen and alkyl;
 n is an integer from 2 to 6; 
 z is an integer from 1 to 4; and 
 r is an integer from 1 to 6. 
 
 
     
     
         2 . The method according to  claim 1 , wherein said protein kinase is selected from the group consisting of receptor tyrosine kinase, non-receptor protein tyrosine kinase and serine-threonine protein kinase. 
     
     
         3 . The method according to  claim 1 , wherein R 1  and R 2  are hydrogen. 
     
     
         4 . The method according to  claim 1 , wherein said compound of formula (I) has the formula (IA): 
       
         
           
           
               
               
           
         
         wherein R 1  to R 8 , and X are defined as those in  claim 1 . 
       
     
     
         5 . The method according to  claim 1 , wherein said compound of formula (I) has the formula (IB): 
       
         
           
           
               
               
           
         
         wherein R 1  to R 8 , and X are defined as those in  claim 1 . 
       
     
     
         6 . The method according to  claim 1 , wherein said compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein said pharmaceutical composition comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         8 . The method according to  claim 1 , wherein said pharmaceutically acceptable salt is salt formed with the acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid and trifluoroacetic acid. 
     
     
         9 . A method of treating a protein kinase related disorder comprising a step of administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, 
       wherein
 said protein kinase related disorder is a non-colon cancer disorder; 
 X being selected from the group consisting of carbon and nitrogen; 
 R 1  and R 2  each being independently selected from the group consisting of hydrogen and alkyl; 
 R 3  being selected from the group consisting of alkyl, trifluoromethyl, aryl, aralkyl, and methyl, at least one of said alkyl, aryl, aralkyl, and methyl being optionally further substituted by halogen; 
 R 4  being selected from the group consisting of alkyl, cycloalkyl, heterocyclo alkyl, aryl, heteroaryl, —(CH 2 ) n (OCH 2 CH 2 ) r R 11 , —[CH 2 CH(OH)] r CH 2 NR 9 R 10  and —(CH 2 ) n NR 9 R 10 , at least one said alkyl, cylcoalkyl, heterocyclo alkyl, aryl and heteroaryl is optionally further substituted by the group consisting of aryl, hydroxyl, amino, carboxamido, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 when X is nitrogen, R 5  is absent, R 6 , R 7 , R 8  are each independently selected from the group consisting of hydrogen and halogen; 
 when X is carbon, R 5 , R 6 , R 7 , R 8  are each independently selected from the group consisting of hydrogen, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocyclo alkyl, aryl, heteroaryl, hydroxyl, cyano, nitro, —OR 9 , —O[CH 2 CH 2 O] r R 11 , —NR 9 R 10 , —(CH 2 ) n CO 2 R 9 , —(CH 2 ) n CONR 9 R 10 , —COR 9 , —NR 9 COR 10 , —SO 2 R 9  and —NHCO 2 R 10 , at least one of said aryl, heteroaryl, cycloalkyl and heterocyclo alkyl is optionally further substituted by the group consisting of alkyl, alkoxyl and halogen; 
 R 9  and R 10  each being independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclo alkyl and heteroaryl, at least one of said alkyl, cycloalkyl, aryl, heterocyclo alkyl and heteroaryl being optionally further substituted by the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 R 9  and R 10  being taken together with the attached atom to form 4 to 8 membered hetero rings, wherein said 4 to 8 membered hetero rings contain at least one heteroatom selected from the group consisting of N, O and S, and said 4 to 8 membered rings being optionally further substituted by the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclo alkyl, carboxyl, alkoxycarbonyl and —NR 9 R 10 ; 
 
       R 11  is selected from the group consisting of hydrogen and alkyl;
 n is an integer from 2 to 6; 
 z is an integer from 1 to 4; and 
 r is an integer from 1 to 6. 
 
     
     
         10 . The method according to  claim 9 , wherein said protein kinase related disorder is selected from the group consisting of the disorder related to VEGFR, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR, Ret, Flt1 and Flt3. 
     
     
         11 . The method according to  claim 10 , wherein said protein kinase related disorder is selected from the group consisting of the disorder related to VEGFR, PDGFR, c-Kit, Ret, Flt1 and Flt3. 
     
     
         12 . The method according to  claim 10 , wherein said protein kinase related disorder is selected from the group consisting of leukemia, diabetes, autoimmune diseases, hyperplasias, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular diseases, multiple angioblastoma, inflammatory diseases and fibrosis. 
     
     
         13 . The method according to  claim 12 , wherein said protein kinase related disorder is cancer selected from squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid adenocarcinoma, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, carcinosarcoma in urinary and genital system, gastrointestinal carcinoma, gliomas, colorectal cancer and ovarian cancer. 
     
     
         14 . The method according to  claim 9 , wherein R 1  and R 2  are hydrogen. 
     
     
         15 . The method according to  claim 9 , wherein said compound of formula (I) has the formula (IA): 
       
         
           
           
               
               
           
         
         wherein R 1  to R 8 , and X are defined as those in  claim 9 . 
       
     
     
         16 . The method according to  claim 9 , wherein said compound of formula (I) has the formula (IB): 
       
         
           
           
               
               
           
         
         wherein R 1  to R 8 , and X are defined as those in  claim 9 . 
       
     
     
         17 . The method according to  claim 9 , wherein said compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The method according to  claim 9 , wherein said pharmaceutical composition comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         19 . The method according to  claim 9 , wherein said pharmaceutically acceptable salt is salt formed with the acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid and trifluoroacetic acid.