Smac mimetic dimers and trimers useful as anti-cancer agents

Abstract

The invention provides small molecule mimics of the Smac peptide that are dimer-like or trimer-like compounds having two or three amide-containing 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 (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         wherein b is 0 or 1; 
         each Q, Q′ and Q″, if present, independently represents —O— or —NR 2 —, where each R 2  is independently H, optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl; or —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4  alkyl or C 1 -C 4  heteroalkyl; or one or more of Q, Q′ and Q″ may be a bond when L comprises a ring; 
         L represents an optionally substituted C1-C24 hydrocarbyl linker, optionally containing from 1-8 heteroatoms selected from N, O and S, which linker is 1-18 atoms in length when counted along the shortest path between Q and Q′, or Q and Q″, or Q′ and Q″; and 
         each D, D′ and D″, if present, is independently selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein each R a  and R b  is independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of these, each of which may be optionally substituted; or is optionally substituted phenyl; 
         each R 1  is independently H or optionally substituted C1-C8 alkyl; 
         each Z independently represents an optionally substituted C1-C6 aminoalkyl group; 
         each Y, where present, independently represents C1-C8 alkyl, ═O, OR, NR 2 , OC(O)R, NRC(O)R, NRSO 2 R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two Y groups can cyclize to form a 3-6 membered ring that can be saturated, unsaturated or aromatic, and which ring may include a heteroatom selected from O, S and N as a ring member and may be optionally substituted; 
         each W, where present, independently represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; 
         each X, where present, independently represents 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, provided that each X comprises at least one aryl or heteroaryl ring; 
         each n, where present, is independently 0-3; 
         each m, where present, is independently 0-4; and 
         each R 6 , where present, is independently H, C1-C8 alkyl, C5-C12 aryl or C5-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted; or is a C8-C14 bicyclic or tricyclic ring system comprising a 5- or 6-membered saturated or partially unsaturated ring fused to a C5-C6 aryl or C5-C6 heteroaryl ring, which ring system may be attached to nitrogen through any available position on the saturated or aromatic ring; 
         with the proviso that, when b is 0, D and D′ are not the same and both of the formula 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , having the formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         wherein each R a , R a′ , R b  and R b′  is independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of these, each of which may be optionally substituted; or is optionally substituted phenyl; 
         each Y and Y′ independently represents C1-C8 alkyl, ═O, OR, NR 2 , OC(O)R, NRC(O)R, NRSO 2 R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two Y or Y′ groups can cyclize to form a 3-6 membered ring that can be saturated, unsaturated or aromatic, and which ring may include a heteroatom selected from O, S and N as a ring member and may be optionally substituted; 
         each W and W′ independently represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; 
         each X and X′ independently represents 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′, provided that each X and X′ comprises at least one aryl or heteroaryl ring; 
         each Q and Q′ independently represents —O— or —NR 2 —, where each R 2  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 R 1  and R 1′  is independently H or optionally substituted C1-C8 alkyl; 
         each Z and Z′ independently represents an optionally substituted C1-C6 aminoalkyl group; and 
         L represents an optionally substituted C1-C24 hydrocarbyl linker, optionally containing from 1-8 heteroatoms selected from N, O and S, which linker is 1-18 atoms in length when counted along the shortest path between Q and Q′. 
       
     
     
         3 . The compound of  claim 1 , wherein:
 each n and n′ is 1, and each of m and m′ is 0 or 1, and wherein Y and Y′, if present, are the same;   each R 1  and R 1′  is H or methyl; and/or   each Z and Z′ is a 1-aminoalkyl group represented by the formula —CH(R 3 )NR 4   2 , where R 3  and each R 4  is independently H or C1-C4 alkyl.   
     
     
         4 . The compound of  claim 2 , having the formula (3A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         wherein Ra is H and Rb is R 5 ; 
         R 5  is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or phenyl, each of which may be optionally substituted; 
         each Y represents C1-C8 alkyl, ═O, OR, NR 2 , OC(O)R, NRC(O)R, NRSO 2 R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl; 
         W represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; 
         X represents 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, provided that each X comprises at least one aryl or heteroaryl ring; 
         Q represents —O— or —NR 2 —, where each R 2  is independently H, or optionally substituted C1-C8 alkyl, or optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises a ring; 
         m is 0-4; 
         p is 2-3; 
         Z represents an optionally substituted C1-C6 aminoalkyl group of the formula —CH(R 3 )NR 4   2 ; 
         R 3  is H, or an optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl, and R 3  can cyclize with R 4  on an adjacent nitrogen atom to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; 
         each R 4  is independently H, or an optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl, and the two R 4  groups on one nitrogen can cyclize to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; and 
         L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14 alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21 arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of one of these, each of which may be optionally substituted. 
       
     
     
         6 . The compound of  claim 4 , having the formula (4): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         wherein R 5  is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or phenyl, each of which may be optionally substituted; 
         each Y represents C1-C8 alkyl, ═O, OR, NR 2 , OC(O)R, NRC(O)R, NRSO 2 R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl; 
         W represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; 
         X represents 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, provided that each X comprises at least one aryl or heteroaryl ring; 
         Q represents —O— or —NR 2 —, where each R 2  is independently H, optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises a ring; 
         m is 0-4; 
         p is 2 or 3; 
         R 3  is H, or an optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl, and R 3  can cyclize with R 4  on an adjacent nitrogen atom to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; 
         each R 4  is independently H, or an optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl, and the two R 4  groups on one nitrogen can cyclize to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; and 
         L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14 alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21 arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of one of these, each of which may be optionally substituted. 
       
     
     
         6 . The compound of  claim 4 , having the formula (5): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         R5 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or phenyl, each of which may be optionally substituted; 
         each Y represents C1-C8 alkyl, ═O, OR, NR2, OC(O)R, NRC(O)R, NRSO2R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl; 
         W represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; X represents an optionally substituted C5-C20 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, provided that each X comprises at least one aryl or heteroaryl ring; 
         Q represents —O— or —NR2-, where each R2 is independently H, optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl; or Q may be a bond when L comprises a ring; 
         m is 0-4; 
         R3 is H, or an optionally substituted C1-C8 alkyl or optionally substituted C1-C8 heteroalkyl, and R3 can cyclize with R4 on an adjacent nitrogen atom to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; 
         each R4 is independently H, or an optionally substituted C1-C8 alkyl or C1-C8 heteroalkyl group, and the two R4 groups on one nitrogen can cyclize to form an optionally substituted azacyclic group having 5-10 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as a ring member; 
         L represents a C1-C14 alkylene, C1-C14 alkenylene, C1-C14 alkynylene, C5-C12 arylene, C5-C21 arylalkylene, C5-C21 arylalkenylene, or C5-C21 arylalkynylene linker, or a heteroform of one of these, each of which may be optionally substituted. 
       
     
     
         7 . The compound of  claim 2 , wherein:
 each X and X′ independently comprises an optionally substituted phenyl ring; or two phenyl rings, each of which may be optionally substituted; or a tetrahydronaphthyl, indanyl or fluorenyl ring system   each W and W′ represents —C(O)NR(CHR)p-, where p is 0-2, and each R independently represents H, C1-C4 alkyl or C1-C4 heteroalkyl;   each Q and Q′ is —NR2-, where each R2 is independently H or C1-C4 alkyl; and/or   at least one of Q and Q′ is a bond.   
     
     
         8 . The compound of  claim 2 , wherein:
 L comprises at least one optionally substituted carbocyclic, heterocyclic, aromatic or heteroaromatic ring that is part of or is fused to the linker which forms the shortest path between Q and Q′;   L comprises at least one triazole ring; or   L comprises a C1-C14 alkylene, C1-C14 heteroalkylene, C2-C14 alkenylene, C2-C14 heteroalkenylene, C2-C14 alkynylene, or a C2-C14 heteroalkynylene group, each of which may be optionally substituted.   
     
     
         9 . The compound of  claim 2  wherein:
 L is a C2-C14 alkynylene or a C2-C14 heteroalkynylene group or 
 L comprises at least one optionally substituted carbocyclic, heterocyclic, aromatic or heteroaromatic ring that is part of or is fused to the linker which forms the shortest path between Q and Q′, said aromatic or heteroaromatic ring is an optionally substituted 5- or 6-membered aromatic or heteroaromatic ring, wherein said optionally substituted 5- or 6-membered aromatic or heteroaromatic ring is selected from the group consisting of phenyl, pyridyl, pyrazinyl, triazinyl, pyrazolyl, and thiophenyl, each of which may be optionally substituted. 
 
     
     
         10 . The compound of  claim 2 , wherein R3 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; and/or
 each R4 is independently H or methyl.   
     
     
         11 . A compound selected from the group consisting of the compounds in Tables 3 and 4, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1 , further comprising at least one additional therapeutic agent selected from the group consisting of TRAIL, etoposide, a TRAIL receptor antibody, an Hsp90 inhibitor, TNF-α, and TNF-β. 
     
     
         13 . A method to treat cancer, inflammation, or an autoimmune disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         14 . A compound of formula (6): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate form thereof, 
         wherein Ra and Rb are independently H, or C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or a heteroform of one of these, each of which may be optionally substituted; 
         each Y independently represents C1-C8 alkyl, ═O, OR, NR2, OC(O)R, NRC(O)R, NRSO2R or COOR, wherein each R is independently H, C1-C8 alkyl or C1-C8 heteroalkyl, and wherein two Y groups can cyclize to form a 3-6 membered ring that can be saturated, unsaturated or aromatic, and which ring may include a heteroatom selected from O, S and N as a ring member and may be optionally substituted; 
         W represents an optionally substituted C1-C6 alkylene or C1-C6 heteroalkylene; 
         X represents an optionally substituted C5-C20 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, provided that each X comprises at least one aryl or heteroaryl ring; 
         n is 0-3; 
         m is 0-4; 
         R1 is H or optionally substituted C1-C8 alkyl; 
         U represents —OR8, —OC(O)R8, —OSO2R8, C═O, —OC(O)OR8, —COORS, —NR82, azido or halo, where each R8 is independently H, or C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C5-C12 aryl, C5-C21 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted; or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl or C5-C21 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted; and 
         Z is an optionally substituted C1-C6 aminoalkyl group wherein the amine may be in a protected or unprotected form.