Selective dual inhibitors of pi3 delta and gamma protein kinases

Abstract

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

1 - 26 . (canceled) 
     
     
         27 . A method of inhibiting a catalytic activity of a PI3 δ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method of inhibiting a catalytic activity of a PI3 γ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 
     
     
         29 . A method of inhibiting a catalytic activity of a PI3 δ kinase and PI3 γ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 27 , wherein the inhibition takes place in a subject suffering from a disease, disorder or condition selected from a proliferative disease, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis, cardiac disease, and any combination thereof. 
     
     
         31 . The method of  claim 28 , wherein the inhibition takes place in a subject suffering from a disease, disorder or condition selected from a proliferative disease, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis, cardiac disease, and any combination thereof. 
     
     
         32 . The method of  claim 29 , wherein the inhibition takes place in a subject suffering from a disease, disorder or condition selected from a proliferative disease, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis, cardiac disease, and any combination thereof. 
     
     
         33 . A method of treating a disease, disorder or condition that would benefit from inhibiting catalytic activity of a PI3 δ/γ kinase comprising administering to a subject in need thereof an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method for the treatment of a PI3K associated disease, disorder or condition comprising administering to a subject in need thereof an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 34 , further comprising administering an additional active agent selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and any mixture thereof. 
     
     
         36 . A compound selected from
 (S)-2-(1-(4-amino-3-(4-methoxy-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,   (S)-2-(1-(4-amino-3-(3-amino-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one,   
       and pharmaceutically acceptable salts thereof.