Inhibitors of phosphatidylinositol 3-kinase gamma

Abstract

that inhibit phosphatidylinositol 3-kinase gamma (PI3Kδ) activity, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 X is C(O) or SO 2 ; 
 Y is selected from —CH 2 —, —CH═CH—, —C(CH 2 )—, —CH(CH 3 )—, —CH 2 CH 2 , —CH(OH)—, —N═CH— or —C(O)—; 
 R 1  is (3,3-dimethylbutan-2-yl) or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by cyclopropyl and 0, 1, 2 or 3 F; 
 R 2  is selected from CH 3 , NHR 4 , S 2 R 5  or (1-methyl-1H-pyrazol-5-yl)methyl; 
 R 3  is selected from 
 
       
       
         
           
           
               
               
           
         
         
           R 4  is C(O)CH 3  or SO 2 R 6 ; 
           R 5  is selected from (3-cyanophenyl)sulfamoyl, CH 3 , N(CH 3 ) 2 , NH 2 , NHCH 2 CF 3 , NH(oxetan-3-yl), NHC 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 0-3 F and 0-1 substituents independently selected from OCH 3 , cyclopropyl or NHC 3-4 cycloalkyl, wherein said cycloalkyl may be substituted by 0-2 F; 
           R 6  is selected from cyclopropyl, (1,3-dimethyl-1H-pyrazol-4-yl)methyl or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by 0-1 substituents independently selected from OCH 3 , NCH 3  or cyclopropyl; 
           R 7  is selected from H, Cl or CH 3 ; 
           R 8  is selected from —NH(C═O)CH 3 , 
         
       
       
         
           
           
               
               
           
         
         
           R 9  is selected from H, C or NH 2 ; 
           R 10  is selected from H or NH 2 ; 
           R 11  is selected from C(O)NH 2 , C(O)NHCH 3  or C(O)NHCH 2 phenyl; 
           R 12  is selected from CO 2 H, CO 2 CH 2 CH 3  or CO 2 NH(CH 2 ) 3 NH 2 ; 
           R 13  is selected from H or CH 3 ; 
           Y is selected from N or CH; or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         2 . A compound according to  claim 1  of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein
 R 1  is (3,3-dimethylbutan-2-yl) or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by cyclopropyl and 0, 1, 2 or 3 F; 
 R 2  is NHR 4  or SO 2 R 5 ; 
 R 7  is selected from H, Cl or CH 3 ; 
 R 4  is C(O)CH 3  or SO 2 R 6 ; 
 R 5  is selected from (3-cyanophenyl)sulfamoyl, CH 3 , N(CH 3 ) 2 , NH 2 , NHCH 2 CF 3 , NH(oxetan-3-yl), NHC 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 0-3 F and 0-1 substituents independently selected from OCH 3 , cyclopropyl or NHC 3-4 cycloalkyl, wherein said cycloalkyl may be substituted by 0-2 F; 
 R 6  is selected from cyclopropyl, (1,3-dimethyl-1H-pyrazol-4-yl)methyl or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by 0-1 substituents independently selected from OCH 3  or cyclopropyl; or a pharmaceutically-acceptable salt thereof. 
 
       
     
     
         3 . A compound according to  claim 1  wherein R 1  is iso-propyl or 1-cyclopropylethyl; or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound according to  claim 1  wherein
 R 2  is NHR 4 ; 
 R 4  is SO 2 R 6 ; 
 R 6  is CH 3 ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . A compound according to  claim 1  wherein
 R 2  is SO 2 R 5 ; 
 R 5  is CH 3  or NHCH 3 ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . A compound of the formula (I) according to  claim 1  selected from:
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 N-{4-Methyl-5-[7-(methylsulfonyl-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-5-yl]-1,3-thiazol-2-yl}acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-ylacetamide, 
 N-(5-{7-(Acetylamino)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{7-(Cyclobutylsulfamoyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-{4-Methyl-5-[7-(methylsulfamoyl)-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-5-yl]-1,3-thiazol-2-yl}acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylmethyl)sulfamoyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(cyclopropylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(ethylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(oxetan-3-ylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(3,3-difluorocyclobutyl)sulfamoyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(2-methoxyethyl)sulfamoyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-({[1-(fluoromethyl)cyclopropyl]methyl}sulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(2,2,2-trifluoroethyl)sulfamoyl]-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-{4-Methyl-5-[1-oxo-2-(propan-2-yl)-7-sulfamoyl-2,3-dihydro-1H-isoindol-5-yl]-1,3-thiazol-2-yl}acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylsulfonyl)amino]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(propylsulfonyl)amino]-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(ethylsulfonyl)amino]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{7-[(tert-Butylsulfonyl)amino]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(2-methoxyethyl)sulfonyl]amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide, 
 N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(cyclopropylmethyl)sulfonyl]amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide, 
 N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide, 
 N-(4-Chloro-5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 6-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2-[(1S)-1-cyclopropylethyl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 N-{5-[2-(2-Cyclopropylpropan-2-yl)-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide, 
 N-(5-{2-[(2S)-3,3-Dimethylbutan-2-yl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-{5-[2-tert-Butyl-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide, 
 N-(4-Methyl-5-{7-(methylsulfamoyl)-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, 
 N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
 N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, and pharmaceutically acceptable salts thereof. 
 
     
     
         7 . A compound according to  claim 1  which is N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A compound according to  claim 1  which is N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  and a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A method of treating asthma or chronic obstructive pulmonary disease in a patient suffering from said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as claimed in  claim 1 . 
     
     
         14 . A combination of a compound of formula (I) as claimed in  claim 1  and one or more agents independently selected from:
 a glucocorticoid receptor agonist (steroidal or non-steroidal); 
 a selective β 2  adrenoceptor agonist; 
 a selective inhibitor of PI3Kδ; 
 an antimuscarinic agent; 
 a p38 antagonist; and 
 a PDE4 antagonist. 
 
     
     
         15 . A method of treating, or reducing the risk of, cancer or CNS related disorders which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as claimed in  claim 1 .