Pyrazole compounds substituted with heteroaryl and pharmaceutical use thereof

Abstract

Pyrazole compounds substituted with heteroaryl or pharmaceutically acceptable salts thereof that have an SGLT1 inhibitory activity and are useful for a drug, pharmaceutical compositions comprising the same, and pharmaceutical use thereof are disclosed. Specifically, a compound of Formula [X]:wherein R1 is hydrogen or halogen, R2 is C1-6 alkyl or halo-C1-6 alkyl, Ring Het is substituted pyridyl or optionally substituted pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising it, and pharmaceutical use thereof is provided.

1 - 22 . (canceled) 
     
     
         23 : A compound of formula [8]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; and 
 A 7  is C 1-4  alkyl or benzyl. 
 
       
     
     
         24 : A compound of formula [10]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; 
 A 7  is C 1-4  alkyl or benzyl; and 
 ring Het is selected from the group consisting of
 (1) pyridyl substituted with R 3 ; and 
 (2) pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with R 4 , 
 wherein
 R 3  is cyano, halogen, or halo-C 1-3  alkyl; 
 R 4  is halogen, hydroxy, C 1-3  alkyl, halo-C 1-3  alkyl, C 1-3  alkoxy, or —N(R 5 )(R 6 ); and 
 R 5  and R 6  are each independently hydrogen or C 1-3  alkyl. 
 
 
 
       
     
     
         25 : A method of preparing a compound of formula [10]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; 
 A 7  is C 1-4  alkyl or benzyl; and 
 ring Het is selected from the group consisting of
 (1) pyridyl substituted with R 3 ; and 
 (2) pyrazinyl, pyrimidinyl, or pyridazinyl, optionally substituted with R 4 , 
 wherein
 R 3  is cyano, halogen, or halo-C 1-3  alkyl; 
 R 4  is halogen, hydroxy, C 1-3  alkyl, halo-C 1-3  alkyl, C 1-3  alkoxy, or —N(R 5 )(R 6 ); and 
 R 5  and R 6  are each independently hydrogen or C 1-3  alkyl, 
 
 
 
         the method comprising step e) reacting a compound of formula [8]: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; and 
 A 7  is C 1-4  alkyl or benzyl, 
 
         with a compound of formula [9]: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein ring Het is as defined for formula [10], 
         in a solvent in the presence of an acid. 
       
     
     
         26 : The method of  claim 25 , wherein
 the solvent of step e) is an ether solvent, an alcoholic solvent, or a hydrocarbon solvent;   the acid of step e) is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid; and   the reacting of step e) is carried out at a temperature of between about 20° C. and about 130° C.   
     
     
         27 : The method of  claim 25 , wherein the compound of formula [8] is obtained by step d) reacting a compound of formula [6]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; and 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl, 
 
         with a compound of formula [7]: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 A 7  is C 1-4  alkyl or benzyl, 
 
         in a solvent in the presence of a base. 
       
     
     
         28 : The method of  claim 27 , wherein
 the solvent of step d) is an ether solvent, an alcoholic solvent, a hydrocarbon solvent, a polar solvent, or a mixture of any of the foregoing;   the base of step d) is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazane, and sodium hydride; and   the reacting of step d) is carried out at a temperature of between about −78° C. and about 110° C.   
     
     
         29 : The method of  claim 27 , wherein the compound of formula [6] is obtained by step c) reacting a compound of formula [5]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; and 
 A 4  is n-butyl, 
 
         in a solvent in the presence of an acid. 
       
     
     
         30 : The method of  claim 29 , wherein
 the solvent of step c) is a ketone solvent, an alcoholic solvent, an ether solvent, a halogenated hydrocarbon, a polar solvent, water, or a mixture of any of the foregoing;   the acid of step c) is selected from the group consisting of hydrochloric acid and trifluoroacetic acid; and   the reacting of step c) is carried out at a temperature of between about 20° C. and about 50° C.   
     
     
         31 : The method of  claim 29 , wherein the compound of formula [5] is obtained by step b) reacting a compound of formula [3]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; 
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl; and 
 X IB  is a halogen, 
 
         with a compound of formula [4]: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 A 4  is n-butyl, 
 
         in a solvent in the presence of both a palladium catalyst and a base. 
       
     
     
         32 : The method of  claim 31 , wherein
 the solvent of step b) is an alcoholic solvent or a polar solvent;   the palladium catalyst of step b) is a mixture of palladium (II) acetate with either 1,1′-bis(diphenylphosphino)ferrocene or 1,3′-bis(diphenylphosphino)propane;   the base of step b) is an organic base; and   the reacting of step b) is carried out at a temperature of between about 80° C. and about 150° C.   
     
     
         33 : The method of  claim 31 , wherein the compound of formula [3] is obtained by step a) reacting a compound of formula [1]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 R 1  is hydrogen or halogen; and 
 X 1A  and X 1B  are each independently halogen, provided that X 1A  is more reactive than X 1B , 
 
         with a compound of formula [2]
   R 2 —OH  [2]
 
 
         or a salt thereof, wherein
 R 2  is C 1-6  alkyl or halo-C 1-6  alkyl, 
 
         in a solvent in the presence of a base. 
       
     
     
         34 : The method of  claim 33 , wherein
 the solvent of step a) is an ether solvent or a polar solvent;   the base of step a) is cesium carbonate or sodium hydride; and   the reacting of step a) is carried out at a temperature of between about 60° C. and about 170° C.