Pyrimidine derivatives as kinase inhibitors and their therapeutical applications

Abstract

The present invention provides kinase inhibitors with anti-proliferative activity comprising substituted pyrimidine derivatives and pharmaceutically-acceptable formulations thereof. In addition, the invention provides methods for making novel compounds and methods for using the compounds.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         W is selected from the group consisting of: Cl, Br, I, CN, C 1 -C 4  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, CF 3 , CF 2 H, CFH 2 , C 2 -C 6  alkynyl, CON(R1)R2; 
         R1 and R2 represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl; 
         Ar represents heteroaryl or aryl, each of which is substituted with from 0 to 4 substituents independently chosen from the group consisting of:
 (1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro or alkoxycarbonyl; 
 (2) NR1; and 
 (3) groups of the formula (Ia): 
 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 4  represents hydrogen, C 1 -C 4  alkyl, or oxo; 
         X—R 3  is CH; or X—R 3  is O; or X is N, and R 3  represents hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 2 -C 6  alkanoyl, C 1 -C 6  alkoxycarbonyl, C 2 -C 6  alkanoyloxy, mono- and di-(C 3 -C 8  cycloalkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6  alkylsulfonyl, mono- and di-(C 1 -C 6  alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH or oxo; 
         R 5  and R 6  are independently selected from the comprising of: hydrogen, F, Cl, Br, CN, C 1 -C 4  alkyl, and C 1 -C 6  alkoxy; and 
         R 7 , R 8  and R 9  are independently selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  aryl or heteroaryl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 2 -C 6  alkanoyl, C 1 -C 6  alkoxycarbonyl, and C 2 -C 6  alkanoyloxy. 
       
     
     
         2 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . A compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . A method of treating an animal suffering from a cellular proliferative disorder comprising:
 a. Preparing, or causing to be prepared, the compound or pharmaceutically acceptable salt of  claim 1 ;   b. optionally, formulating, or causing to be formulated, the compound or pharmaceutically acceptable salt of step a with a pharmaceutically acceptable carrier; and   c. administering, or causing to be administered, the compound or pharmaceutically acceptable salt of step a or the formulation of step b to the animal suffering from the proliferative disorder.   
     
     
         10 . The method of  claim 9 , wherein the animal is a mammal. 
     
     
         11 . The method of  claim 10 , wherein the animal is a human. 
     
     
         12 . The method of  claim 9 , wherein the cellular proliferative disorder is a cancer, a precancerous state, a benign tumor, autoimmune disorder, transplant rejection, graft versus host disease, response to an infection, response to an environmental insult or a genetic disorder. 
     
     
         13 . The method of  claim 12 , wherein the cellular proliferative disorder is a cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is a skin cancer, breast cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer, nasopharyngeal cancer, lung cancer, esophageal cancer, gastric cancer, hepatic cancer, biliary cancer, pancreatic cancer, lymphoma, lung cancer, renal cancer, bladder cancer, esophageal cancers, myeloid leukemia, lymphocytic leukemia, myleoproliferative disorder, myelodysplastic syndrome, lymphoma, neuroendocrine cancer, sarcoma or brain tumor.