Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1

Abstract

The present invention relates to compounds of formula (I): in which Y, Y 1 , R 1 , R 2 , R 3 and R 4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.

We claim: 
     
         1 . A method for treating a patient having a leukemia selected from chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) comprising administering to said patient a therapeutically effective amount of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof and optionally a sequential or simultaneous administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 
     
     
         2 . The method of  claim 1  comprising administering to said patient a therapeutically effective amount of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1  comprising a sequential administration of a therapeutically effective amount of a compound of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof and a sequential administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 
     
     
         4 . The method of  claim 1  comprising administering to said patient a therapeutically effective amount of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof and a simultaneous administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 
     
     
         5 . The method of  claim 4  wherein (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide is dosed in the range of 90-130 mg/kg. 
     
     
         6 . The method of  claim 5  wherein nilotinib is dosed at 10-50 mg/kg. 
     
     
         7 . The method of  claim 6  wherein imatinib is dosed at 50-200 mg/kg. 
     
     
         8 . A compound selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising an amorphous dispersion of (R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide and 1 to 2 excipients selected from PVP VA64 and Pharmacoat® 603. 
     
     
         10 . The composition of  claim 9 , wherein the percentage of Pharmacoat® 603 is in the range of 30% to 45%, the percentage of PVP VA64 is in the range of 30% to 45% and the percentage of (R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide is in the range of 20% to 30%. 
     
     
         11 . The composition of  claim 10 , wherein the percentage of Pharmacoat® 603 is 37.5%, the percentage of PVP VA64 is 37.5% and the percentage of (R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide is 25%. 
     
     
         12 . A pharmaceutical composition comprising an amorphous dispersion of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 1 to 2 excipients selected from PVP VA64 and Pharmacoat® 603. 
     
     
         13 . The composition of  claim 12 , wherein the percentage of Pharmacoat® 603 is in the range of 30% to 45%, the percentage of PVP VA64 is in the range of 30% to 45% and the percentage of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)-nicotinamide is in the range of 20% to 30%. 
     
     
         14 . The composition of  claim 13 , wherein the percentage of Pharmacoat® 603 is 37.5%, the percentage of PVP VA64 is 37.5% and the percentage of (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide is 25%.