Combinations of lsd1 inhibitors for the treatment of hematological malignancies

Abstract

The instant invention relates to combinations of the compound of formula (I) or pharmaceutically acceptable salts thereof with other active pharmaceutical ingredients pharmaceutical compositions comprising them, and their use as medicaments, particularly for the treatment of hematological malignancies.

1 . A combination comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from a retinoic acid analogue, a nucleoside analogue, a DOT1L inhibitor, a HDAC inhibitor, a demethylating agent, an FLT3 inhibitor, a BCL2 inhibitor, an MDM2 inhibitor, a c-KIT inhibitor, a BET inhibitor, an anthracycline, arsenic trioxide, hydroxyurea and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from tretinoin, cytarabine, sapacitabine, clofarabine, elacytarabine, fludarabine, cytarabine ocfosfate, gemcitabine, 2-chloro-2-deoxyadenosine (also known as 2-CDA), troxacitabine, forodesine, nelarabine, pinometostat, EPZ-004777, SGC-0946, Belinostat, Panobinostat, Vorinostat, Ricolinostat, Entinostat, Mocetinostat, Abexinostat, Resminostat, Givinostat, Quisinostat, decitabine, azacitidine, guadecitabine, Quizartinib, Sorafenib, Sunitinib, Lestaurtinib, ABT-737, Navitoclax, Venetoclax, Obatoclax, Nutlin-3A, dasatinib, imatinib, JQ1, GSK1210151A, MS 436, GSK525762, OTX-015, CPI-203, GSK1324726A, daunorubicin, doxorubicin, idarubicin, arsenic trioxide, hydroxyurea, and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from tretinoin, cytarabine, pinometostat, EPZ-00477, Vorinostat, Ricolinostat, Entinostat, decitabine, azacitidine, Quizartinib, ABT-737, Nutlin-3A, dasatinib, JQ1, daunorubicin, arsenic trioxide, hydroxyurea, and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a retinoic acid analogue or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The combination according to  claim 4 , wherein the retinoic acid analogue is tretinoin or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a nucleoside analogue or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The combination according to  claim 6 , wherein the nucleoside analogue is cytarabine or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a DOT1L inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The combination according to  claim 8 , wherein the DOT1L inhibitor is pinometostat, EPZ-004777 or SGC-0946, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and an HDAC inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The combination according to  claim 10 , wherein the HDAC inhibitor is Belinostat, Panobinostat, Vorinostat, Ricolinostat, Entinostat, Mocetinostat, Abexinostat, Resminostat, Givinostat, Quisinostat, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a demethylating agent or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The combination according to  claim 12 , wherein the demethylating agent is decitabine or azacitidine, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and an FLT3 inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The combination according to  claim 14 , wherein the FLT3 inhibitor is Quizartinib, Sorafenib, Sunitinib and Lestaurtinib, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The combination according to  claim 16 , wherein the BCL2 inhibitor is ABT-737, Navitoclax, Venetoclax, Obatoclax, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a MDM2 inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The combination according to  claim 18 , wherein the MDM2 inhibitor is Nutlin-3A, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a c-KIT inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The combination according to  claim 20 , wherein the c-KIT inhibitor is dasatinib or imatinib, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a BET inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The combination according to  claim 22 , wherein the BET inhibitor is JQ1, GSK1210151A, MS 436, GSK525762, OTX-015, CPI-203, GSK1324726A, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The combination according to  claim 1 , comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and an anthracycline or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The combination according to  claim 24 , wherein the anthracycline is daunorubicin, idarubicin, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The combination according to  claim 25 , which further comprises cytarabine, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and arsenic trioxide. 
       
     
     
         28 . The combination according to  claim 1  comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and hydroxyurea. 
       
     
     
         29 . A pharmaceutical composition comprising a combination according to  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . A method for the treatment of a hematological malignancy in a patient in need thereof, which method comprises administering a therapeutically effective amount of a combination according to  claim 1  to said patient. 
     
     
         34 . A method for the treatment of a hematological malignancy in a patient in need thereof, which method comprises administering the pharmaceutical composition according to  claim 29  to said patient. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 33  or  34 , wherein the hematological malignancy is a myeloid hematological malignancy. 
     
     
         38 . The method of  claim 37 , wherein the myeloid hematological malignancy is acute myeloid leukemia. 
     
     
         39 . The method of  claim 37 , wherein the myeloid hematological malignancy is chronic myelogenus leukemia. 
     
     
         40 . The method of  claim 37 , wherein the myeloid hematological malignancy is myelodysplastic syndrome. 
     
     
         41 . The method of  claim 37 , wherein the myeloid hematological malignancy is a myeloproliferative disease. 
     
     
         42 . The method of  claim 41 , wherein the myeloproliferative disease is selected from the group consisting of myelofibrosis, acute biphenotypic leukemia, Polycythemia vera, Chronic eosinophilic leukemia/Hypereosinophilic syndrome, Essential thrombocytosis, and Chronic eosinophilic leukemia/Hypereosinophilic syndrome. 
     
     
         43 . The method of  claim 37 , wherein the myeloid hematological malignancy is a myeloid hematological malignancy with translocation or rearrangements involving MLL, AF9, AF4, AF10, AML1, ETO, CALM; or mutation in NPM1 or Notch1, or LSD1 overexpression. 
     
     
         44 . The method of  claim 33  or  34 , wherein the hematological malignancy is a lymphoid hematological malignancy. 
     
     
         45 . The method of  claim 44 , wherein the lymphoid hematological malignancy is acute lymphoblastic leukemia. 
     
     
         46 . The method of  claim 44 , wherein the lymphoid hematological malignancy is a lymphoid hematological malignancy with translocation or rearrangements involving MLL, AF9, AF4, AF10, AML1, ETO, CALM; or mutation in NPM1 or Notch1, or LSD1 overexpression. 
     
     
         47 . The method of  claim 33 , wherein the patient is a human being. 
     
     
         48 . (canceled)