Pyrrolotriazines as alk inhibitors

Abstract

This application provides compounds of the general formula (I) and/or a salt thereof, where X, R 1 and R 2 are as defined herein. Compositions and therapeutic uses are also described.

1 . A compound that is a single enantiomer selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and/or a salt thereof. 
     
     
         2 . The single enantiomer according to  claim 1  that is (3R,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol, and/or a salt thereof. 
     
     
         3 . A compound selected from the group consisting of:
 (±)-3,4-cis-1-(2-Methoxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   (±)-3,4-cis-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   (±)-2-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2, 1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   (±)-3,4-cis-4-{3-Methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   (±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;   (±)-2-(3,4-trans-3-fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   (±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   (±)-1-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-2-methyl-propan-2-ol;   (±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   (±)-[4-(3,3-Difluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;   (±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine;   (3R,4S)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   (3S,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   2-((3S,4S)-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   2-((3R,4R)-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   (3S,4S)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2, 1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   (3R,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol;   4-Bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester;   2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol;   and a salt thereof.   
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 1 , and/or a salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         5 . A method of inhibiting ALK kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 1 , and/or a salt thereof. 
     
     
         6 . A method of treating a ALK-positive disease/disorder in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 1 , and/or a salt thereof. 
     
     
         7 . A method of treating proliferative disease in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 1 , and/or a salt thereof. 
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 3 , and/or a salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         9 . A method of inhibiting ALK kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 3 , and/or a salt thereof. 
     
     
         10 . A method of treating a ALK-positive disease/disorder in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 3 , and/or a salt thereof. 
     
     
         11 . A method of treating proliferative disease in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 3 , and/or a salt thereof.