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 of treating a mammalian subject having glioblastoma multiforme, comprising administering to the subject an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 25 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The method of  claim 25 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method of  claim 25 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         29 . The method of  claim 26 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         30 . The method of  claim 27 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         31 . The method of  claim 25 , wherein the method further comprises the step of:
 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.   
     
     
         32 . The method of  claim 25 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally. 
     
     
         33 . The method of  claim 25 , wherein the compound or pharmaceutically salt thereof is administered to the subject in an amount between about 10 mg/kg per day to about 500 mg/kg per day. 
     
     
         34 . The method of  claim 25 , wherein the compound or pharmaceutically salt thereof is administered to the subject in one or two oral doses per day. 
     
     
         35 . The method of  claim 25 , wherein the subject has an elevated level of PDGF or PDGFR signaling. 
     
     
         36 . The method of  claim 25 , wherein the subject is contemporaneously treated with an inhibitor of PDGFR.