Fused ring derivative used as fgfr4 inhibitor

Abstract

A compound represented by formula I or a pharmaceutically acceptable salt thereof and a use thereof in preparing a drug for treating, stopping or preventing a disease or disorder mediated by FGFR4 activity.

1 - 50 . (canceled) 
     
     
         51 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 
       
         
           
                 
                 
               
                     
                 
                   1. 
                   N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl- 
                 
                     
                   6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- 
                 
                     
                   naphthyridine-1(2H)-carboxamide; 
                 
                   4. 
                   (R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2- 
                 
                     
                   yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4- 
                 
                     
                   dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
                 
                   8. 
                   (R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2- 
                 
                     
                   yl)-7-formyl-6-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8- 
                 
                     
                   naphthyridine-1(2H)-carboxamide; 
                 
                   16. 
                   N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl- 
                 
                     
                   6-((2-oxo-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8- 
                 
                     
                   naphthyridine-1(2H)-carboxamide; 
                 
                   79. 
                   N-(5-cyano-4-(((2R)-1-(methylsulfinyl)propan-2-yl)amino)pyridin- 
                 
                     
                   2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4- 
                 
                     
                   dihydro-1,8-naphthyridine-1(2H)-carboxamide; 
                 
                   82. 
                   N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7- 
                 
                     
                   formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- 
                 
                     
                   naphthyridine-1(2H)-carboxamide; or 
                 
                   83. 
                   N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-yl)amino)pyridin- 
                 
                     
                   2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4- 
                 
                     
                   dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         52 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         53 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is (R)—N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         54 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is (R)—N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         55 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((2-oxo-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         56 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is N-(5-cyano-4-(((2R)-1-(methylsulfinyl)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         57 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         58 . The compound or a pharmaceutically acceptable salt thereof according to  claim 51 , wherein, the compound is N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         59 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim  1 , and at least one pharmaceutically acceptable excipient. 
     
     
         60 . The pharmaceutical composition according to  claim 59 , wherein, the compound is (R)—N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         61 . The pharmaceutical composition according to  claim 59 , wherein, the compound is N-(5-cyano-4-(((2R)-1-(methylsulfinyl)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         62 . The pharmaceutical composition according to  claim 59 , wherein, the compound is N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         63 . The pharmaceutical composition according to  claim 59 , wherein, the compound is N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. 
     
     
         64 . A method for the treatment, prevention or precaution of diseases or conditions mediated by FGFR4 activity, wherein the said method comprises administering to a subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to  claim 51 , wherein the diseases mediated by FGFR4 activity are selected from one or more following diseases: liver cancer, head and neck cancer, esophageal cancer, stomach cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyoma and combinations thereof. 
     
     
         65 . The method according to  claim 64 , wherein, the compound is (R)—N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide.