Dual inhibitors of phosphatidylinositol 3-kinase delta & gamma

Abstract

There are disclosed certain novel compounds (including pharmaceutically acceptable salts thereof),that inhibit phosphatidylinositol 3-kinase gamma (PI3Kδ) and phosphatidylinositol 3-kinase gamma (PI3Kγ) 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 SO 2 NHR 5  or SO 2 R 6 ; 
         R 1  is selected from C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by cyclopropyl, 0, 1 or 2 CH 3  and 0, 1, 2 or 3 F; 
         R 2  is selected from H or CH 3 ; 
         R 3  is selected from H or C 1-3 alkyl; 
         R 4  is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by OC 1-3 alkyl; or 
         R 3  and R 4  taken together with the N atom and X form a 5, 6 or 7-membered cycloheteroalkyl ring containing 0 or 1 further heteroatoms selected from N or κ, wherein said cycloheteroalkyl ring is substituted by 0, 1 or 2 substituents independently selected from CH 3 , OH, CH 2 OH or CH 2 CH 2 OH; or 
         R 3  and R 4  taken together with the N atom and X are selected from 
       
       
         
           
           
               
               
           
         
         R 5  is selected from C 1-3 alkyl or (oxetan-3-yl); 
         R 6  is selected from C 1-3 alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein
 X is C(O); 
 Y is SO 2 NHR 5  or SO 2 R 6 ; 
 R 1  is selected from C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted by cyclopropyl, 0, 1 or 2 CH 3  and 0, 1, 2 or 3 F; 
 R 2  is CH 3 ; 
 R 3  and R 4  taken together with the N atom and X form a 5, 6 or 7-membered cycloheteroalkyl ring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkyl ring is substituted by 0, 1 or 2 substituents independently selected from CH 3 , OH, CH 2 OH or CH 2 CH 2 OH; 
 R 5  is selected from C 1-3 alkyl or (oxetan-3-yl); 
 R 6  is selected from C 1-3 alkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . A compound according to  claim 1  wherein
 Y is SO 2 R 6 ; 
 R 3  and R 4  taken together with the N atom and X form a 5-membered cycloheteroalkyl ring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkyl ring is substituted by 0 or 1 substituents independently selected from CH 3 , OH, or CH 2 OH; 
 R 6  is CH 3 ; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . A compound according to  claim 1  wherein
 R 1  is (1S)-1-cyclopropylethyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . A compound according to  claim 1  wherein
 R 1  is (2S)-1,1,1-trifluoropropan-2-yl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . A compound according to  claim 1  wherein
 R 3  and R 4  taken together with the N atom and X form 2-oxopyrrolidin-1-yl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         7 . A compound according to  claim 1  wherein
 R 1  is (1S)-1-cyclopropylethyl; 
 R 3  and R 4  taken together with the N atom and X form 2-oxopyrrolidin-1-yl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . A compound of the formula (I) according to  claim 1  selected from:
 N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}acetamide, 
 N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-N-methylacetamide, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxopiperidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[(6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 6-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, 
 5-(4-Methyl-2-{[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-H-isoindol-1-one, 
 5-(4-Methyl-2-{[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-1-one, 
 5-(4-Methyl-2-{[6-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-1-one, 
 N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-N-methylacetamide, 
 N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-2-methoxy-N-methylacetamide, 
 (2R)—N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-2-methoxy-N-methylpropanamide, 
 (2S)—N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-2-methoxy-N-methylpropanamide, 
 N-{6-[(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-2-ethoxy-N-methylacetamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(2-oxopiperidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(4-methyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[(8aS)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-(1,1-dioxido-1,2-thiazolidin-2-yl)pyridin-2-yl]amino}-4-methyl-1,3-thiazol-5-yl)-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 N-Methyl-6-(4-methyl-2-{[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 N-{6-[(5-{2-[(1S)—I-Cyclopropylethyl]-7-(ethylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)amino]pyridin-2-yl}-2-methoxy-N-methylacetamide, 
 N-Ethyl-6-(4-methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-(4-Methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-N-(propan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-(4-Methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-N-(propan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-(4-Methyl-2-{[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-N-(propan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-(4-Methyl-2-{[6-(2-oxopiperidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-(4-Methyl-2-{[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-N-(oxetan-3-yl)-3-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-tert-Butyl-N-methyl-6-(4-methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(2S)-3,3-Dimethylbutan-2-yl]-N-methyl-6-(4-methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxopiperazin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-one, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(2-oxopiperazin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(5S)-5-methyl-2-oxopiperazin-1-yl]pyridin-2-yl}amino)-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(3R)-3-methyl-2-oxopiperazin-1-yl]pyridin-2-yl)amino}-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(3S)-3-methyl-2-oxopiperazin-1-yl]pyridin-2-yl}amino)-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(5R)-5-methyl-2-oxopiperazin-1-yl]pyridin-2-yl}amino)-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(2R)-2-methyl-6-oxopiperazin-1-yl]pyridin-2-yl)amino}-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(2-{[6-(3,3-dimethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino}-4-methyl-1,3-thiazol-5-yl)-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(2-{[6-(5,5-dimethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino}-4-methyl-1,3-thiazol-5-yl)-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-[4-methyl-2-({6-[(2S)-2-methyl-6-oxopiperazin-1-yl]pyridin-2-yl)amino}-1,3-thiazol-5-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-ethyl-6-(4-methyl-2-{[6-(2-oxopiperazin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-(4-methyl-2-{[6-(2-oxopiperazin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-N-(propan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(2-oxo-1,4-diazepan-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-N-methyl-6-(4-methyl-2-{[6-(7-oxo-1,4-diazepan-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[(3R)-3-hydroxy-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[{2-({6-[(4R)-4-hydroxy-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[(2S)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[(2R)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(1S)-1-Cyclopropylethyl]-6-[2-({6-[4-(2-hydroxyethyl)-2-oxopiperazin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 6-[2-({6-[(3S)-3-Hydroxy-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-4-methyl-1,3-thiazol-5-yl]-3-oxo-N-(propan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(2S)-Butan-2-yl]-N-methyl-6-(4-methyl-2-{[6-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 2-[(2S)-Butan-2-yl]-N-methyl-6-(4-methyl-2-{[6-(3-oxomorpholin-4-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, 
 N-Methyl-6-(4-methyl-2-{[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]amino}-1,3-thiazol-5-yl)-3-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindole-4-sulfonamide, and pharmaceutically acceptable salts thereof. 
 
     
     
         9 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  and a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         10 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 8  and a pharmaceutically acceptable adjuvant, diluent or carrier.