Kinase inhibitors with improved cyp safety profile

Abstract

Compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases, with an improved safety profile due to low CYP3A4 inhibition, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.

1 . A compound having Formula I 
     
       
         
         
             
             
         
       
       or a therapeutically acceptable salt thereof, 
       wherein 
       R 1  is hydroxyalkyl; 
       R 2  is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; and 
       R 3  is hydrogen or alkyl. 
     
   
   
       2 . The compound of  claim 1  which is
 N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea;   N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-[4-(difluoromethoxy)phenyl]urea;   N-[4-(4-amino-7-{1-[(2S)-2-hydroxypropyl]-1H-pyrazol-4-yl}thieno[3,2-c]pyridin-3-yl)phenyl]-N′-(3-methylphenyl)urea;   N-(4-{4-amino-7-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(4-methoxyphenyl)urea; or   N-[4-(4-amino-7-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-4-yl}thieno[3,2-c]pyridin-3-yl)phenyl]-N′-(4-methoxyphenyl)urea.   
   
   
       3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein said compound does not inhibit CYP3A4. 
   
   
       4 . A composition comprising an excipient and a therapeutically effective amount of a compound of  claim 1 . 
   
   
       5 . A method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of  claim 1 .