[1,2,4]Triazolo[4,3-B]Pyridazines For Use in the Treatment of Proliferative Diseases

Abstract

The invention concerns compounds of Formula (I)or pharmaceutically-acceptable salts thereof, wherein R1, R2 and n have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use as anti-proliferative and/or cell-killing agents.

1 .- 9 . (canceled) 
     
     
         10 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is the group 
       
       
         
           
           
               
               
           
         
       
       or the group 
       
         
           
           
               
               
           
         
         and—denotes the point of attachment; 
         R 2  is a C 1 -C 4 alkyl; and 
         n is 2 or 3. 
       
     
     
         11 . The method of  claim 10 , wherein R 1  is the group 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 10 , wherein R 1  is the group 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 10 , wherein R 1  is the group 
       
         
           
           
               
               
           
         
       
       and
 n is 2. 
 
     
     
         14 . The method of  claim 10 , wherein the compound of Formula (I) is selected from:
 4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-1,3-dimethylpiperazin-2-one;   1-(4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethanone;   4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-1,3-dimethylpiperazin-2-one; and   1-(4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-3,5-dimethylpiperazin-1-yl)ethanone.   
     
     
         15 . The method of  claim 10 , wherein the compound of Formula (I) is selected from:
 1-((3S,5R)-4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethanone;   (R)-4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-1,3-dimethylpiperazin-2-one; and   1-((3R,5S)-4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-3,5-dimethylpiperazin-1-yl)ethanone.   
     
     
         16 . The method of claim  1 , wherein the cancer is ovarian cancer, acute myeloid and mixed lineage leukemia, multiple myeloma, or diffuse large B-cell lymphoma. 
     
     
         17 . The method of claim  1 , wherein the cancer is ovarian cancer, multiple myeloma, or diffuse large B-cell lymphoma. 
     
     
         18 . The method of claim  1 , wherein the cancer is acute myeloid and mixed lineage leukemia. 
     
     
         19 . The method of claim  1 , wherein the cancer is ovarian cancer. 
     
     
         20 . A compound of Formula (IB) 
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound of Formula (IC) 
       
         
           
           
               
               
           
         
       
     
     
         22 . A compound of Formula (ID) 
       
         
           
           
               
               
           
         
       
     
     
         23 . A process of preparing a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is the group 
       
       
         
           
           
               
               
           
         
         or the group 
       
       
         
           
           
               
               
           
         
         and—denotes the point of attachment; 
         R 2  is a C 1 -C 4 alkyl; and 
         n is 2 or 3; 
         comprising reacting a compound of Formula (II) 
       
       
         
           
           
               
               
           
         
         with a compound of Formula (IIIa) or a compound of Formula (IIIb) 
       
       
         
           
           
               
               
           
         
         to form the compound of Formula (I). 
       
     
     
         24 . The process of  claim 23 , wherein the reacting comprises coupling the compound of Formula (II) with the compound of Formula (IIIa) or Formula (IIIb) in the presence of a trialkylphosphine and a diazene reagent. 
     
     
         25 . The process of  claim 24 , wherein the trialkylphosphine is tributylphosphine. 
     
     
         26 . The process of  claim 24 , wherein the diazene reagent is (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone. 
     
     
         27 . The process of  claim 23 , wherein the compound of Formula (II) is prepared by reacting a compound of Formula (IV) 
       
         
           
           
               
               
           
         
         with 4-(piperidin-4-yl)phenol. 
       
     
     
         28 . The process of  claim 27 , wherein reacting a compound of Formula (IV) with 4-(piperidin-4-yl)phenol is performed in the presence of a base. 
     
     
         29 . The process of  claim 27 , wherein the compound of Formula (IV) is prepared by reacting 3-chloro-6-hydrazinylpyridazine with tetramethoxymethane, tetraethoxymethane, a tetrapropoxymethane, or a tetrabutoxymethane.