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 (I), pharmaceutical compositions comprising them, and their use as medicaments, particularly for the treatment of hematological malignancies.

1 - 15 . (canceled) 
     
     
         16 . A combination 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 - 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 16  to said patient. 
     
     
         34 . A method for the treatment of a hematological malignancy in a patient in need thereof, which method comprises administering to said patient a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 34 , wherein the hematological malignancy is a myeloid hematological malignancy. 
     
     
         38 . The method of  claim 37 , wherein the myeloid hematological malignancy is selected from the group consisting of acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, a myeloproliferative disease, myelofibrosis, acute biphenotypic leukemia, polycythemia vera, essential thrombocytosis, and chronic eosinophilic leukemia/hypereosinophilic syndrome. 
     
     
         39 - 43 . (canceled) 
     
     
         44 . The method of  claim 34 , wherein the hematological malignancy is a lymphoid hematological malignancy. 
     
     
         45 . The the method of  claim 44 , wherein the lymphoid hematological malignancy is acute lymphoblastic leukemia. 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 34 , wherein the patient is a human being. 
     
     
         48 . (canceled) 
     
     
         49 . The combination according to  claim 16 , wherein the BCL2 inhibitor is Venetoclax or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The combination according to  claim 16 , comprising the compound of formula (I) as a dihydrochloride salt. 
     
     
         51 . The combination according to  claim 16 , further comprising one or more therapeutic agents selected from the group consisting of a retinoic acid analogue, a nucleoside analogue, a DOT1L inhibitor, a HDAC inhibitor, a demethylating agent, an FLT3 inhibitor, an MDM2 inhibitor, a c-KIT inhibitor, a BET inhibitor, an anthracycline, arsenic trioxide, hydroxyurea, and pharmaceutically acceptable salts thereof. 
     
     
         52 . The combination according to  claim 16 , further comprising one or more therapeutic agents selected from the group consisting of tretinoin, cytarabine, sapacitabine, clofarabine, elacytarabine, fludarabine, cytarabine ocfosfate, gemcitabine, 2-chloro-2-deoxyadenosine (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, 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. 
     
     
         53 . The combination according to  claim 16 , further comprising azacitidine or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method according to  claim 34 , wherein the BCL2 inhibitor is ABT-737, Navitoclax, Venetoclax, Obatoclax, or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method according to  claim 34 , wherein the BCL2 inhibitor is Venetoclax or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method according to  claim 34 , wherein the compound of formula (I) is administered as a dihydrochloride salt. 
     
     
         57 . The method according to  claim 34 , further comprising administering to the patient a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of a retinoic acid analogue, a nucleoside analogue, a DOT1L inhibitor, a HDAC inhibitor, a demethylating agent, an FLT3 inhibitor, an MDM2 inhibitor, a c-KIT inhibitor, a BET inhibitor, an anthracycline, arsenic trioxide, hydroxyurea, and pharmaceutically acceptable salts thereof. 
     
     
         58 . The method according to  claim 34 , further comprising administering to the patient a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of tretinoin, cytarabine, sapacitabine, clofarabine, elacytarabine, fludarabine, cytarabine ocfosfate, gemcitabine, 2-chloro-2-deoxyadenosine (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, 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. 
     
     
         59 . The method according to  claim 34 , further comprising administering to the patient a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof.