Dimeric Smac Mimetics

Abstract

The invention provides small molecule mimics of the Smac peptide that are dimers or dimer-like compounds having two binding domains connected by a linker. These compounds are useful to promote apoptosis. The invention includes pharmaceutical compositions comprising such compounds and methods to use them to treat conditions including cancer and autoimmune disorders.

1 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof; and including any stereoisomeric forms thereof; 
         wherein each Y and Y′ independently represents an optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, SR, S(O)R, SO 2 R, SO 2 NR 2 , NR 2 , OC(O)R, NRC(O)R, NRCOOR, NRC(O)NR 2 , NRSO 2 R, CN, C(O)NR 2 , C(O)R, COOR, NO 2  or halo, wherein each R is independently H, C 1 -C 8  alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these each of which may be optionally substituted; 
       
       or is any other substituent suitable for an alkyl group;
 and wherein two Y or Y′ groups on the same or adjacent atoms can cyclize to form an optionally substituted 3-7 membered ring that can be saturated, unsaturated or aromatic, and which ring may include one or more heteroatoms selected from O, S and N as a ring member; 
 each of R 1a , R 1b , R 1a′  and R 1b′  is independently H, or C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted; or 
 R 1a  and R 1b , or R 1a′  and R 1b′  may be taken together with the carbon atom to which they are attached to form an optionally substituted 3-7 membered ring, optionally containing a heteroatom selected from N, O and S as a ring member; 
 each R 2  and R 2′  is independently H or optionally substituted C1-C8 alkyl; 
 each W and W′ is independently an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted C5-C6 aryl or heteroaryl ring; 
 each X and X′ is independently an optionally substituted C1-C8 alkyl, C1-C8 heteroalkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl, or an optionally substituted C 5 -C 20  ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S as a ring member, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′; 
 each Q and Q′ independently represents —O—, —S— or —NR 5 —, where each R 5  is independently H, or optionally substituted C1-C8 alkyl, or optionally substituted C1-C8 heteroalkyl; or one or both of Q and Q′ may be a bond when L comprises a ring; 
 each n and n′ is independently 0-3; 
 each m and m′ is independently 0-4; 
 each Z and Z′ independently represents an optionally substituted C1-C6 aminoalkyl group; and 
 L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14 alkynylene, C3-C8 cycloalkylene, C5-C21 cycloalkylalkylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21 arylalkenylene, C5-C21 arylalkynylene, C1-C14 heteroalkylene, C1-C14 heteroalkenylene, C1-C14 heteroalkynylene, C3-C8 heterocyclyl, C5-C21 heterocyclylalkylene, C5-C12 heteroarylene, C5-C21 heteroarylalkylene, C5-C21 heteroarylalkenylene, or C5-C21 heteroarylalkynylene linker, each of which may be optionally substituted. 
 
     
     
         2 . A compound selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2 , selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A compound of  claim 2  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A compound selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A compound of  claim 14  selected from the group consisting of the following compounds, including a free base form thereof, or any pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 16 , and at least one pharmaceutically acceptable excipient, and further comprising at least one additional therapeutic agent that is TRAIL. 
     
     
         23 . A method for reducing cell proliferation or inducing cell death, comprising contacting a cell with an effective amount of the compound according to  claim 16 , thereby reducing cell proliferation or inducing cell death.