Chromenone Derivatives

Abstract

The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , n and R 6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

1 . A compound of the Formula I: 
       
         
           
           
               
               
           
         
       
       in which:
 R 1  is (1-4C)alkyl optionally substituted by hydroxy; 
 R 2  is H or (1-4C)alkyl; or 
 R 1  and R 2  together form a 3 to 8 membered nitrogen containing heterocyclyl ring system, which optionally contains 1 or 2 further heteroatoms selected from oxygen, nitrogen and sulphur, wherein a ring sulphur atom is optionally oxidised to form the S oxide(s), said ring being optionally substituted by hydroxy; 
 R 3  and R 5  are independently selected from H, halogeno, (1-3C)alkoxy and cyano; 
 R 4  is H or fluoro; 
 n is 0 or 1, and when n is 1, the R 6  group is methyl; or a pharmaceutically-acceptable salt thereof. 
 
     
     
         2 . A compound of the Formula I according to  claim 1 , wherein:
 R 1  is (1-4C)alkyl optionally substituted by hydroxy;   R 2  is (1-4C)alkyl; or   R 1  and R 2  together form a 4 to 6 membered nitrogen containing heterocyclyl ring system, which optionally contains 1 further heteroatom selected from oxygen, nitrogen and sulphur, wherein a ring sulphur atom is optionally oxidised to form the S oxide(s), said ring being optionally substituted by hydroxy; or a pharmaceutically-acceptable salt thereof.   
     
     
         3 . A compound of the Formula I according to  claim 1 , wherein R 3  and R 5  are independently selected from H, fluoro, methoxy and cyano; or a pharmaceutically-acceptable salt thereof. 
     
     
         4 . A compound of the Formula I according to  claim 1 , wherein R 4  is H; or a pharmaceutically-acceptable salt thereof. 
     
     
         5 . A compound of the Formula I according to  claim 1 , wherein n is 0; or a pharmaceutically-acceptable salt thereof. 
     
     
         6 . A compound of the Formula I according to  claim 1 , wherein n is 1 and R 6  is methyl; or a pharmaceutically-acceptable salt thereof. 
     
     
         7 . A compound of the Formula I according to  claim 1 , wherein:
 R 1  is (1-4C)alkyl optionally substituted by hydroxy;   R 2  is (1-4C)alkyl; or   R 1  and R 2  together form a 4 to 6 membered nitrogen containing heterocyclyl ring system, which optionally contains 1 further heteroatom selected from oxygen, nitrogen and sulphur, wherein a ring sulphur atom is optionally oxidised to form the S oxide(s), said ring being optionally substituted by hydroxy;   R 3  and R 5  are independently selected from H or halogeno and R 4  is H;   n is 0 or 1, and when n is 1, the R 6  group is methyl; or a pharmaceutically-acceptable salt thereof.   
     
     
         8 . A compound of the Formula I according to  claim 1  wherein:
 R 1  is methyl, ethyl or 2-hydroxyethyl; 
 R 2  is methyl or ethyl; or 
 R 1  and R 2  together form a nitrogen containing heterocyclyl ring system, selected from azetidinyl, morpholinyl, 1-oxotetrahydro-1,4-thiazinyl and piperidinyl, said ring being optionally substituted by hydroxy; 
 R 3  and R 5  are independently selected from H or halogeno and R 4  is H; 
 n is 0 or 1, and when n is 1, the R 6  group is methyl; or a pharmaceutically-acceptable salt thereof. 
 
     
     
         9 . A compound of the Formula I according to  claim 1  wherein:
 R 1  is methyl or 2-hydroxyethyl; 
 R 2  is methyl; or 
 R 1  and R 2  together form a nitrogen containing heterocyclyl ring system, selected from azetidin-1-yl, morpholin-4-yl, 1-oxotetrahydro-1,4-thiazin-4-yl, piperidin-1-yl and 4-hydroxypiperidin-1-yl; 
 R 3  and R 5  are independently selected from H, fluoro, methoxy and cyano; 
 R 4  is H or fluoro; 
 n is 0 or 1, and when n is 1, the R 6  group is methyl; or a pharmaceutically-acceptable salt thereof. 
 
     
     
         10 . A compound of the Formula I according to  claim 1  selected from any one of the following:—
 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 
 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one; 
 8-[(2S)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; 
 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4H-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-[(2S)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-chromen-4-one; 
 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 
 8-[(2S)-1-(3-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide; 
 8-[(2R)-1-(3-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide; 
 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one; 
 8-[(2S)-1-(3-fluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; 
 8-[(2R)-1-(3-fluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4H-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-[(2S)-1-(3-fluorophenyl)pyrrolidin-2-yl]-2-morpholino-chromen-4-one; 
 6-(azetidine-1-carbonyl)-8-[(2R)-1-(3-fluorophenyl)pyrrolidin-2-yl]-2-morpholino-chromen-4-one; 
 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 
 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one; 
 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one; and 
 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide; or a pharmaceutically-acceptable salt thereof. 
 
     
     
         11 . A compound of the Formula I according to  claim 1  which is 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; or a pharmaceutically-acceptable salt thereof. 
     
     
         12 . A compound of the Formula I according to  claim 1  which is 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one. 
     
     
         13 . A pharmaceutically-acceptable salt of a compound of the Formula I according to  claim 1  which is 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one. 
     
     
         14 . A compound of the Formula I according to  claim 1  which is 8-[(2S)-1-(3,5-difluorophenyl)pyrrolidi n-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one; or a pharmaceutically-acceptable salt thereof. 
     
     
         15 . A compound of the Formula I according to  claim 1  which is 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methyl morpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one; or a pharmaceutically-acceptable salt thereof. 
     
     
         16 . A pharmaceutical composition, which comprises a compound of Formula I, or a pharmaceutically-acceptable salt thereof, according to  claim 1  in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method for the treatment or prevention of a warm blooded animal having tumours which are sensitive to inhibition of PI 3-kinase enzymes, which comprises administering to said animal an effective amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, according to  claim 1 .