Tetrahydro-Pyrido-Pyrimidine Derivatives

Abstract

wherein Y, R1, R2 and m are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.

1 .- 20 . (canceled) 
     
     
         21 . A process or method for the manufacture of a tetrahydro-pyrido-pyrimidine derivative of the formula (I) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof, 
       
         
           
           
               
               
           
         
         wherein 
         Y is selected from O or NR 3 ; 
         R 1  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 
         or
 —C(O)—R 4  
 wherein 
 R 4  is selected from C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl-sulfonyl-C 1 -C 8 -alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C 1 -C 8 -alkyl, hydroxy, C 1 -C 8 -alkoxy, amino, N—C 1 -C 8 -alkyl-amino or N,N-di-C 1 -C 8 -alkyl-amino, 
 wherein ‘C 1 -C 8 -alkyl’ in N—C 1 -C 8 -alkyl-amino and N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy; 
 wherein ‘C 3 -C 12 -cycloalkyl’ in C 3 -C 12 -cycloalkyl and C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; 
 wherein ‘heterocyclyl’ is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; 
 wherein ‘heterocyclyl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; 
 wherein ‘heteroaryl’ is selected from 
 furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heteroaryl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; 
 
 
         R 2  is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; 
         R 3  is selected from H, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl; and 
         m is selected from 0 or 1. 
         comprising the steps of method A: 
         b) deprotecting the compound of formula (E), 
       
       
         
           
           
               
               
           
         
         wherein PG 2  represents a suitable protecting group and R 1 , Y and m are as defined for a compound of formula (I) 
         c) followed by reaction with 
         R 2 -Hal, 
         wherein R 2  is as defined for a compound of formula (I) and Hal represents halogen, under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst, in the presence of a base, in an organic solvent;
 and wherein compound of formula (E) is prepared comprising the step of 
 d) deprotecting PG 1  from the compound of formula (C), 
 
       
       
         
           
           
               
               
           
         
         
           wherein PG 1  represents a suitable protecting group, and the other substituents are as defined above, 
           e) followed by coupling reaction with 
           R 1 -Act 
           wherein when R 1  is —C(O)—R 4 , wherein R 4  is as defined for a compound of formula (I), and Act represents an activating group or a hydroxy group, the coupling reaction is an amide, urea or carbamic ester formation, or; 
           wherein when R 1  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl and Act represents halogen, the coupling reaction is carried out in the presence of an amine base or alternatively, the reaction is carried out under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst in the presence of a base;
 wherein the compound of formula (C) is prepared comprising the step of 
 a) coupling a compound of formula (A), 
 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein X represents halogen and PG 2  is as defined above; with a compound of formula (B), 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein the substituents are as defined above, 
             wherein when HY is OH and X represents halogen, the reaction takes place in the presence of a suitable base, or 
             wherein when HY is NR 3 H and X represents halogen: the reaction takes place in the presence of a suitable base, or 
             wherein when HY is NR 3 H and X represents hydroxy: a base promoted phosphonium coupling reaction is employed; 
           
         
         or, alternatively comprising the steps of a), d) and e) of method A as defined above, starting from a compound of formula (A) wherein PG 1  represents R 2 ; 
         or, alternatively comprising the steps of method B: 
         d) deprotecting the compound of formula (D), 
       
       
         
           
           
               
               
           
         
         wherein PG 1  represents a suitable protecting group, and the other substituents are as defined above 
         e) followed by coupling reaction with 
         R 1 -Act, 
         wherein when R 1  is —C(O)—R 4 , wherein R 4  is as defined for a compound of formula (I), and Act represents an activating group or a hydroxy group, the coupling reaction is an amide, urea or carbamic ester formation, or; 
         wherein when R 1  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl and Act represents halogen, the coupling reaction is carried out in the presence of an amine base or alternatively, the reaction is carried out under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst in the presence of a base;
 wherein compound of formula (D) is prepared comprising the step of 
 b) deprotecting PG 1  from the compound of formula (C), 
 
       
       
         
           
           
               
               
           
         
         
           wherein PG 1  represents a suitable protecting group, and the other substituents are as defined above, 
           c) followed by coupling reaction with 
           R 2 -Hal, 
           wherein R 2  is as defined for a compound of formula (I) and Hal represents halogen, under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst, in the presence of a base, in an organic solvent;
 wherein the compound of formula (C) is prepared as described above; 
 
         
         or, alternatively comprising the steps a), b) and c) of method B as defined above, starting from a compound of formula (B) wherein PG 1  represents R 1 , 
         and, if desired, transforming a compound of formula (I) into a different compound of formula (I), transforming a salt of an obtainable compound of formula (I) into the free compound or a different salt, transforming an obtainable free compound of formula (I) into a salt thereof, and/or separating an obtainable mixture of isomers of a compound of formula I into individual isomers.