Inhibitors of mutant isocitrate dehydrogenases and compositions and methods thereof

Abstract

The invention provides novel chemical compounds useful for treating cancer, or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.

1 - 36 . (canceled) 
     
     
         37 . A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (I): 
       
         
           
           
               
               
           
         
         wherein,
 each of R A  and R B  is independently H or halogen, CN, CF 3 , alkylamine, alkoxy and alky group, or R A  and R B  join together to form a 5-membered aromatic ring along with the two carbons (—C═C—) of the pyrimidine ring that R A  and R B  are bonded to respectively; 
 R E  is a group comprising an electrophilic warhead, 
 
         or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof, in an amount effective to treat, prevent, or reduce one or more cancers, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. 
       
     
     
         38 . A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula of (II): 
       
         
           
           
               
               
           
         
         wherein,
 each of R A  and R B  is independently H or a halogen, CN, CF 3 , alkylamine, alkoxy and alky group, or R A  and R B  join together to form a 5-membered aromatic ring along with the two carbons (—C═C—) of the pyrimidine ring that R A  and R B  are bonded to respectively; 
 Z 1  and Z 2  is independently CH or N; 
 R 1  is H or a halogen atom; and 
 R 2  is a functional group that comprises an electrophilic group, 
 
         or a pharmaceutically acceptable form thereof, in an amount effective to treat, prevent, or reduce one or more cancers, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. 
       
     
     
         39 . A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (III): 
       
         
           
           
               
               
           
         
         wherein,
 each of R A  and R B  is independently H or halogen, CN, CF 3 , alkylamine, alkoxy and alky group, or R A  and R B  join together to form a 5-membered aromatic ring along with the two carbons (—C═C—) of the pyrimidine ring that R A  and R B  are bonded to respectively; 
 Z 1  and Z 2  is independently CH or N; 
 R 1  is H or a halogen atom; and 
 R 2  is a functional group that comprises an electrophilic group, 
 
         or a pharmaceutically acceptable form thereof, in an amount effective to treat, prevent, or reduce one or more cancers, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. 
       
     
     
         40 . The method of  claim 37 , wherein the one or more cancers comprise a blood cancer or a hematologic malignance. 
     
     
         41 . The method of  claim 40 , wherein the one or more cancers are selected from B-acute lymphoblastic leukemias, B-acute lymphoblastic leukemias, chronic myelomonocytic leukemia, cute myelogenous leukemia, lymphoma, myelodysplasia syndrome, myeloproliferative neoplasms and myeloproliferative neoplasms. 
     
     
         42 . The method of  claim 38 , wherein the one or more cancers comprise a blood cancer or a hematologic malignance. 
     
     
         43 . The method of  claim 42 , wherein the one or more cancers are selected from B-acute lymphoblastic leukemias, B-acute lymphoblastic leukemias, chronic myelomonocytic leukemia, cute myelogenous leukemia, lymphoma, myelodysplasia syndrome, myeloproliferative neoplasms and myeloproliferative neoplasms. 
     
     
         44 . The method of  claim 39 , wherein the one or more cancers comprise a blood cancer or a hematologic malignance. 
     
     
         45 . The method of  claim 44 , wherein the one or more cancers are selected from B-acute lymphoblastic leukemias, B-acute lymphoblastic leukemias, chronic myelomonocytic leukemia, cute myelogenous leukemia, lymphoma, myelodysplasia syndrome, myeloproliferative neoplasms and myeloproliferative neoplasms.