Csf-1r inhibitors for treatment of brain tumors

Abstract

The present invention provides a compound of formula I; wherein R 1 is an alkyl pyrazole or an alkyl carboxamide, and R 2 is a hydroxycycloalkyl; or a pharmaceutically acceptable salt thereof, and compositions containing these compounds, for use to treat a brain tumor, particularly glioblastoma. The invention provides effective treatment of a brain tumor and can be used by oral administration of a compound of Formula I as further described herein. The invention also provides a method to treat a subject having a brain tumor such as glioblastoma, wherein the method comprises administering to the subject an effective amount of a compound of Formula I. Gene signatures correlated with successful treatment using these methods are also disclosed.

1 - 24 . (canceled) 
     
     
         25 . A method to treat a brain tumor in a mammalian subject, comprising administering to the subject an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is an alkyl pyrazole or an alkyl carboxamide; and 
         R 2  is hydroxycyclohexyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 25 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R′ is Me or Et. 
     
     
         27 . The method of  claim 25 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 25 , wherein the brain tumor is a glioma. 
     
     
         29 . The method of  claim 28 , wherein the glioma is glioblastoma multiforme. 
     
     
         30 . The method of  claim 25 , wherein the brain tumor is a brain metastasis, astrocytoma, oligodendroglioma, ependymomas, or a mixed glioma. 
     
     
         31 . The method of  claim 25 , wherein the compound of formula (I) is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 31 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 31 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of  claim 31 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 31 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 25 , wherein the method further comprises administering to the subject an effective amount of an additional cancer therapeutic selected from bevacizumab with or without irinotecan, a nitrosourea, a platin, an alkylating agent, a tyrosine kinase inhibitor, Ukrain, and a cannabinoid. 
     
     
         37 . The method of  claim 25 , wherein the compound of Formula (I) is administered orally. 
     
     
         38 . The method of  claim 37 , wherein the amount of the compound of Formula (I) administered to the subject is between about 50 mg/kg per day and about 500 mg/kg per day. 
     
     
         39 . The method of  claim 25 , wherein the brain tumor is proneural glioblastoma. 
     
     
         40 . The method of  claim 25 , wherein the subject has an elevated level of PDGF or PDGFR signaling. 
     
     
         41 . The method of  claim 25 , wherein the subject is contemporaneously treated with an inhibitor of PDGFR. 
     
     
         42 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       where R′ is Methyl, Ethyl or Propyl. 
     
     
         43 . The compound of  claim 42 , wherein R′ is methyl. 
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 42 , and at least one pharmaceutically acceptable excipient.