Substituted imidazo- and triazolopyrimidines, imidazo- and pyrazolopyrazines and imidazotriazines

Abstract

The invention relates to substituted imidazo- and triazolopyrimidines, imidazo- and pyrazolopyrazines and imidazotriazines and processes for their preparation, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, in particular of hematological disorders, preferably of leukopenias and neutropenias.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         A represents a group of the formula 
       
       
         
           
           
               
               
           
         
         where
 # 1  represents the point of attachment to the heterocycle substituted by R 1 , 
 # 2  represents the point of attachment to the carbon atom to which R 13  is attached, 
 # 3  represents the point of attachment to the carbon atom to which R 4  is attached, 
 
         m represents the number 1, 2, 3 or 4, 
         R 1  represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl or hydroxycarbonylmethyl, 
         R 2  represents phenyl,
 where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently of one another selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxymethyl, C 1 -C 4 -alkylaminomethyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylsulfonylamino, C 1 -C 4 -alkylaminosulfonyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl,
 where phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl may be substituted by 1 to 3 substituents, where the substituents are independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl, 
 
 
         R 4  represents hydrogen, chlorine or fluorine, 
         R 13  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the heterocycle, 
           n represents the number 0 or 1, 
           X represents NR 11 , S or O,
 where 
 R 11  represents hydrogen, C 1 -C 3 -alkyl or cyclopropyl, 
 
           Y represents NR 12 , S or O,
 where 
 R 12  represents hydrogen, C 1 -C 3 -alkyl or cyclopropyl, 
 
           R 3  represents 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 2-cyclopropylaminopyrimid-4-yl, 2-methylaminopyrimid-4-yl, 2-ethylaminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl,
 where 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 1,3-thiazol-5-yl are substituted by 1 to 3 substituents, where the substituents are independently of one another selected from the group consisting of halogen, cyano, nitro, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl, trifluoromethylcarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 3 -C 6 -cycloalkylcarbonyl,
 where alkyl, alkoxy, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and cycloalkylcarbonyl may be substituted by one substituent, where the substituent is selected from the group consisting of halogen, cyano, hydroxyl, amino, trifluoromethyl and C 3 -C 6 -cycloalkyl, 
 
 
           R 5  represents hydrogen, C 1 -C 3 -alkyl or cyclopropyl, 
           R 6  represents hydrogen or C 1 -C 3 -alkyl, 
           R 7  represents hydrogen, C 1 -C 3 -alkyl or cyclopropyl, 
           R 8  represents hydrogen or C 1 -C 3 -alkyl, 
           R 9  represents hydrogen, C 1 -C 3 -alkyl or cyclopropyl, 
           R 10  represents hydrogen or C 1 -C 3 -alkyl, 
         
         or one of its salts. 
       
     
     
         2 . The compound as claimed in  claim 1 , wherein
 A represents a group of the formula   
       
         
           
           
               
               
           
         
         R 4  represents hydrogen or chlorine, 
         R 13  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the heterocycle, 
           n represents the number 0, 
           X represents NR 11 ,
 where 
 R 11  represents hydrogen or methyl, 
 
           Y represents NR 2 ,
 where 
 R 12  represents hydrogen or methyl, 
 
           R 3  represents 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 2-cyclopropylaminopyrimid-4-yl, 2-methylaminopyrimid-4-yl, 2-ethylaminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl,
 where 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 1,3-thiazol-5-yl are substituted by 1 to 3 substituents, where the substituents are independently of one another selected from the group consisting of halogen, cyano, nitro, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl, trifluoromethylcarbonyl, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 3 -C 6 -cycloalkylcarbonyl,
 where alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and cycloalkylcarbonyl may be substituted by one substituent, where the substituent is selected from the group consisting of halogen, cyano, hydroxyl, amino, trifluoromethyl and C 3 -C 6 -cycloalkyl, 
 
 
           R 5  represents hydrogen or methyl, 
           R 6  represents hydrogen, 
           R 7  represents hydrogen or methyl, 
           R 8  represents hydrogen, 
           R 9  represents hydrogen, 
           R 10  represents hydrogen, 
         
         or one of its salts. 
       
     
     
         3 . The compound as claimed in  claim 1 , wherein
 m represents the number 1, 2 or 3,   R 1  represents C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or hydroxycarbonylmethyl,   R 2  represents phenyl,
 where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently of one another selected from the group consisting of chlorine, fluorine, trifluoromethyl and methyl, 
   R 4  represents hydrogen,   R 13  represents a group of the formula   
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the heterocycle, 
           n represents the number 0, 
           X represents NR 11 ,
 where 
 R 11  represents hydrogen, 
 
           Y represents NR 2 ,
 where 
 R 12  represents hydrogen, 
 
           R 3  represents 2-pyridyl,
 where 2-pyridyl is substituted by 1 or 2 substituents, where the substituents are independently of one another selected from the group consisting of cyano, nitro, amino, trifluoromethylcarbonyl, ethylcarbonyl and methylcarbonyl, 
 
           R 5  represents hydrogen, 
           R 6  represents hydrogen, 
           R 7  represents hydrogen, 
           R 8  represents hydrogen, 
           R 9  represents hydrogen, 
           R 10  represents hydrogen, 
         
         one of its salts. 
       
     
     
         4 . A process for preparing a compound of the formula (I), or one of its salts, its solvates or the solvates of its salts as claimed in  claim 1 , wherein
 [A] a compound of the formula   
       
         
           
           
               
               
           
         
         in which 
         A, m, X, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  have the meaning given in  claim 1 , 
         is reacted with a compound of the formula
   R 3 —X 1   (III),
 
 
         in which 
         R 3  has the meaning given in  claim 1 , and 
         X 1  represents halogen, 
         or 
         [B] a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, m, R 1 , R 4  and R 13  have the meaning given in  claim 1 , and 
         X 2  represents iodine, bromine, chlorine or trifluoromethanesulfonyl, 
         is reacted with a compound of the formula
   Q-R 2   (V),
 
 
         in which 
         R 2  has the meaning given in  claim 1 , and 
         Q represents —B(OH) 2 , a boronic acid ester, or —BF 3   − K + , 
         under Suzuki coupling conditions, 
         or 
         [C] a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, m, R 1 , R 2  and R 4  have the meaning given in  claim 1 , 
         is reacted with a compound of the formula
   H—R 13   (IX),
 
 
         in which 
         R 13  has the meaning given in  claim 1 . 
       
     
     
         5 . A pharmaceutical composition comprising a compound as claimed in  claim 1  and an inert non-toxic pharmaceutically acceptable auxiliary. 
     
     
         6 . A pharmaceutical composition comprising a compound as claimed in  claim 2  and an inert non-toxic pharmaceutically acceptable auxiliary. 
     
     
         7 . A pharmaceutical composition comprising a compound as claimed in  claim 3  and an inert non-toxic pharmaceutically acceptable auxiliary. 
     
     
         8 . A method for treating haematologic disorders comprising administering to a human or animal in need thereof a therapeutically effective amount of at least one compound as claimed in  claim 1 . 
     
     
         9 . A method for the ex vivo expansion of adult haematopoietic stem cells from bone marrow and/or from peripheral blood comprising adding to bone marrow and/or peripheral blood an effective amount of a compound as claimed in  claim 1 .