Axl kinase inhibitors and use of the same

Abstract

Tartrate salts of the compound of structure (I), , crystalline forms thereof, and therapeutic applications thereof for treating solid tumors (e.g., advanced solid tumor) or hematopoietic cancers. Also provided herein are methods for synthesizing the tartrate salts and the crystalline forms thereof.

1 . A tartrate salt of a compound of structure (I): 
       
         
           
           
               
               
           
         
       
       . 
     
     
         2 . The tartrate salt of  claim 1 , having a molar ratio of tartaric acid to the compound of structure (I) of about 1:1 to about 2:1. 
     
     
         3 . The tartrate salt of  claim 2 , having a molar ratio of tartaric acid to the compound of structure (I) of about 2:1. 
     
     
         4 . The tartrate salt of  claim 1 , wherein the tartrate salt is a salt of L-(+)-tartaric acid. 
     
     
         5 . A method of treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a tartrate salt of  claim 1 . 
     
     
         6 - 26 . (canceled) 
     
     
         27 . A method of treating cancer in a subject, comprising administering to the subject a compound of structure (I): 
       
         
           
           
               
               
           
         
       
        or a pharmaceutically acceptable salt or crystalline form thereof, wherein:
 the compound, or pharmaceutically acceptable salt or crystalline form thereof, is administered to the subject orally once daily at a dose from about 1.5 mg/m 2  to about 65 mg/m 2 , or at a dose of about 20 mg to about 100 mg, optionally about 25 mg to about 75 mg 
 the cancer is selected from the group consisting of EGFR+ non-small cell lung cancer; BRAF-, KRAS-, or NRAS-mutated colorectal carcinoma; persistent or recurrent ovarian carcinoma; BRAF-mutated melanoma, inflammatory breast cancer, and triple negative breast cancer; or 
 the subject has an advanced solid cancer or hematopoietic cancer, wherein the subject shows disease progression after a prior chemotherapy, an immunotherapy, or a combination thereof; or 
 treating ascites in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of structure (I), or a pharmaceutically acceptable salt thereof. 
 
     
     
         28 - 41 . (canceled) 
     
     
         42 . A compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
        and pharmaceutically acceptable salts thereof. 
     
     
         43 - 46 . (canceled) 
     
     
         47 . The method of  claim 27 , for treating ascites in a subject in need thereof, wherein the ascites is caused by a cancer. 
     
     
         48 - 53 . (canceled) 
     
     
         54 . The tartrate salt of  claim 2 , having a molar ratio of tartaric acid to the compound of structure (I) of about 1:1. 
     
     
         55 . The tartrate salt of  claim 54 , wherein the tartrate salt is a salt of L-(+)-tartaric acid. 
     
     
         56 . The tartrate salt of  claim 3 , wherein the tartrate salt is a salt of L-(+)-tartaric acid.