Heterocyclic compounds and uses thereof

Abstract

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein.

1 - 38 . (canceled) 
     
     
         39 . A process for preparing Compound 49 of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising reacting Compound 8 of the formula: 
       
         
           
           
               
               
           
         
       
       with (2-methoxypyridin-4-yl)boronic acid of the formula: 
       
         
           
           
               
               
           
         
       
       or a pinacol ester thereof. 
     
     
         40 . The process of  claim 39 , comprising reacting Compound 8 with (2-methoxypyridin-4-yl)boronic acid. 
     
     
         41 . The process of  claim 39 , wherein the reaction between Compound 8 and (2-methoxypyridin-4-yl)boronic acid, or a pinacol ester thereof, occurs in the presence of PdCl 2 (dppf). 
     
     
         42 . The process of  claim 39 , wherein Compound 8 is prepared by a process comprising reacting Compound 1 of the formula: 
       
         
           
           
               
               
           
         
       
       with 2-amino-4-chloropyrimidine-5-carbonitrile of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The process of  claim 42 , wherein the reaction between Compound 1 and 2-amino-4-chloropyrimidine-5-carbonitrile occurs in the presence of triethylamine. 
     
     
         44 . The process of  claim 42 , wherein the reaction between Compound 1 and 2-amino-4-chloropyrimidine-5-carbonitrile occurs in the presence of a solvent of n-BuOH or NMP. 
     
     
         45 . A process for preparing Compound 359 of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising reacting Compound 329 of the formula: 
       
         
           
           
               
               
           
         
       
       with a pinacol ester of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The process of  claim 45 , wherein the reaction between Compound 329 and the pinacol ester occurs in the presence of PdCl 2 (Amphos) 2 . 
     
     
         47 . The process of  claim 45 , wherein Compound 329 is prepared by a process comprising reacting Compound 324 of the formula 
       
         
           
           
               
               
           
         
       
       with 4-amino-6-chloropyrimidine-5-carbonitrile of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         48 . The process of  claim 47 , wherein the reaction between Compound 324 and 4-amino-6-chloropyrimidine-5-carbonitrile occurs in the presence of Hunig's base. 
     
     
         49 . The process of  claim 47 , wherein the reaction between Compound 324 and 4-amino-6-chloropyrimidine-5-carbonitrile occurs in the presence of a solvent of n-BuOH. 
     
     
         50 . A method for inhibiting at least one of PI3K-δ and PI3K-γ, comprising contacting a cell expressing at least one of PI3K-δ and PI3K-γ with an effective amount of Compound 49 or Compound 359 of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         51 . The method of  claim 50 , wherein the cell is contacted in vitro. 
     
     
         52 . The method of  claim 50 , wherein the cell is contacted ex vivo. 
     
     
         53 . The method of  claim 50 , wherein a live cell is contacted. 
     
     
         54 . The method of  claim 53 , wherein the cell is a T-cell. 
     
     
         55 . The method of  claim 54 , wherein the cell is a T-cell from a patient suffering from a hematological cancer. 
     
     
         56 . The method of  claim 55 , wherein the hematological cancer is acute lymphocytic leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, NK cell leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK cell lymphoma, small non-cleaved cell lymphoma, Kaposi's Sarcoma, viral-induced cancers, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell leukemia/lymphoma, Hodgkin disease, non-Hodgkin lymphoma, mantle cell lymphoma, or T-cell lymphoma. 
     
     
         57 . The method of  claim 56 , wherein the hematological cancer is non-Hodgkin lymphoma. 
     
     
         58 . The method of  claim 56 , wherein the hematological cancer is multiple myeloma.