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 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. 
     
     
         28 . 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,   
       and pharmaceutically acceptable salts thereof. 
     
     
         29 . A compound selected from
 (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. 
     
     
         30 . A pharmaceutical composition comprising a compound according to  claim 27  and at least one pharmaceutically acceptable carrier. 
     
     
         31 . A pharmaceutical composition comprising a compound according to  claim 28  and at least one pharmaceutically acceptable carrier. 
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 29  and at least one pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 27 . 
     
     
         34 . A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 28 . 
     
     
         35 . A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 29 . 
     
     
         36 . A method of treating rheumatoid arthritis, psoriasis, lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 27 . 
     
     
         37 . A method of treating rheumatoid arthritis, psoriasis, lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 28 . 
     
     
         38 . A method of treating rheumatoid arthritis, psoriasis, lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 29 . 
     
     
         39 . A method of treating leukemia in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 27 . 
     
     
         40 . A method of treating leukemia in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 28 . 
     
     
         41 . A method of treating leukemia in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 29 . 
     
     
         42 . A method of treating chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), or indolent non-Hodgkin's lymphoma (I-NHL) disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 27 . 
     
     
         43 . A method of treating chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), or indolent non-Hodgkin's lymphoma (I-NHL) disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 28 . 
     
     
         44 . A method of treating chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), or indolent non-Hodgkin's lymphoma (I-NHL) disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 29 . 
     
     
         45 . A method for the treatment of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute or chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, osteoarthritis, allergic rhinitis, or lupus erythematosus in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 27 . 
     
     
         46 . A method for the treatment of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute or chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, osteoarthritis, allergic rhinitis, or lupus erythematosus in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 28 . 
     
     
         47 . A method for the treatment of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute or chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, osteoarthritis, allergic rhinitis, or lupus erythematosus in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of  claim 29 . 
     
     
         48 . The method of  claim 45 , 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 mixtures thereof. 
     
     
         49 . The method of  claim 46 , 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 mixtures thereof. 
     
     
         50 . The method of  claim 47 , 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 mixtures thereof.