Monomers capable of dimerizing in an aqueous solution, and methods of using same

Abstract

Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.

What is claimed is: 
     
         1 . A therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer represented by:
   X 1 —Y 1 —Z 1   (Formula I)
   and a second monomer represented by
   X 2 —Y 2 —Z 2   (Formula II),
 
   wherein
 X 1  is a first ligand moiety capable of binding to a first target biomolecule;
 Y 1  is absent or is a connector moiety covalently bound to X 1  and Z 1 ; 
 Z 1  is a first linker selected from the group consisting of: 
 
 a) 
   
       
         
           
           
               
               
           
         
         
           
             wherein 
             A 1  is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
             A 2 , independently for each occurrence, is (a) absent; or (b) selected from the group consisting of —N—, acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, provided that at least one of A 1  and A 2  is present; or 
             A 1  and A 2 , together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring; 
             A 3  is selected from the group consisting of —NHR′, —SH, or —OH; 
             W is CR′ or N; 
             R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
             m is 1-6; 
                represents a single or double bond; and 
             R 1  is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
             Q 1  is (a) absent; or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or 
             R 1  and Q 1  together with the atoms to which they are attached form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring; 
           
           b) 
         
       
       
         
           
           
               
               
           
         
         
           wherein
 BB, independently for each occurrence, is a 4-8 membered cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally substituted with one or more groups represented by R 2 , wherein the two substituents comprising —OH have a 1, 2 or 1,3 configuration; 
 each R 2  is independently selected from hydrogen, halogen, oxo, sulfonate, —NO 2 , —CN, —OH, —NH 2 , —SH, —COOH, —CON(R′) 2 , substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R 2  together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; 
 A 1 , independently for each occurrence, is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 R′ is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
 
           c) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein 
             BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, aryl, or heteroaryl moiety; 
             A 3 , independently for each occurrence, is selected from the group consisting of —NHR′, —OH, or —O—C 1-4 alkyl; 
             R 3  and R 4  are independently selected from the group consisting of H, C 1-4 alkyl, phenyl, or R 3  and R 4  taken together from a 3-6 membered ring; 
             R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or R 5  and R 6  taken together form phenyl or a 4-6 membered heterocycle; and 
             R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
           
           d) 
         
       
       
         
           
           
               
               
           
         
         
           wherein
 A 1  is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 A 3 , independently for each occurrence, is selected from the group consisting of —NHR′ or —OH; 
 AR is a fused phenyl or 4-7 membered aromatic or partially aromatic heterocyclic ring, wherein AR is optionally substituted by oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; —S—C 1-4 alkyl; halogen; —OH; —CN; —COOH; —CONHR′; wherein the two hydroxyl moieties are ortho to each other; 
 R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; CONHR′; and 
 R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
 
           e) 
         
       
       
         
           
           
               
               
           
         
         
           wherein
 Q 1  is selected from the group consisting of C 1-4 alkyl, alkylene, or a bond; C 1-6 cycloalkyl; a 5-6 membered heterocyclic ring; or phenyl; 
 Q 2 , independently for each occurrence, is selected from the group consisting of H, C 1-4 alkyl, alkylene, or a bond; C 1-6 cycloalkyl; a 5-6 membered heterocyclic ring; phenyl; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; 
 A 3 , independently for each occurrence, is selected from the group consisting of —NH 2  or —OH; 
 A 4 , independently for each occurrence, is selected from the group consisting of —NH—NH 2 ; —NHOH, —NH—OR″, or —OH; 
 R″ is selected from the group consisting of H or C 1-4 alkyl; and 
 
           f) 
         
       
       
         
           
           
               
               
           
         
         
           wherein
 A 5  is selected from the group consisting of —OH, —NH 2 , —SH, —NHR″′; 
 R′″ is selected from C 1-4 alkyl optionally substituted with hydroxyl; —NH 2 ; —OH; —O-phenyl; and C 1-4 alkoxy; 
 R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or R 5  and R 6  taken together may form a 5-6 membered ring; 
 
         
         wherein
 X 2  is a second ligand moiety capable of binding to a second target biomolecule; 
 Y 2  is absent or is a connector moiety covalently bound to X 2  and Z 2 ; and 
 Z 2  is a boronic acid or oxaborale moiety capable of binding with the Z 1  moiety of Formula I to form the multimer; and 
 pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof. 
 
       
     
     
         2 . A first monomer capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media, wherein the first monomer is represented by the formula:
   X 1 —Y 1 —Z 1   (Formula I)
   
       and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein
 X 1  is a first ligand moiety capable of binding to a first target biomolecule;
 Y 1  is absent or is a connector moiety covalently bound to X 1  and Z 1 ; 
 Z 1  is a first linker selected from the group consisting of: 
 
 a) 
 
       
         
           
           
               
               
           
         
         
           wherein 
           A 1  is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
           A 2 , independently for each occurrence, is (a) absent; or (b) selected from the group consisting of —N—, acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, provided that at least one of A 1  and A 2  is present; or 
           A 1  and A 2 , together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring; 
           A 3  is selected from the group consisting of —NHR′, —SH, or —OH; 
           W is CR′ or N; 
           R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
           m is 1-6; 
              represents a single or double bond; and 
           R 1  is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
           Q 1  is (a) absent; or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or 
           R 1  and Q 1  together with the atoms to which they are attached form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring; 
         
         b) 
       
       
         
           
           
               
               
           
         
         wherein
 BB, independently for each occurrence, is a 4-8 membered cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally substituted with one or more groups represented by R 2 , wherein the two substituents comprising —OH have a 1, 2 or 1,3 configuration; 
 each R 2  is independently selected from hydrogen, halogen, oxo, sulfonate, —NO 2 , —CN, —OH, —NH 2 , —SH, —COOH, —CON(R′) 2 , substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R 2  together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; 
 A 1 , independently for each occurrence, is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 R′ is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
 
         c) 
       
       
         
           
           
               
               
           
         
         
           wherein 
           BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, aryl, or heteroaryl moiety; 
           A 3 , independently for each occurrence, is selected from the group consisting of —NHR′, —OH, or —O—C 1-4 alkyl; 
           R 3  and R 4  are independently selected from the group consisting of H, C 1-4 alkyl, phenyl, or R 3  and R 4  taken together from a 3-6 membered ring; 
           R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or R 5  and R 6  taken together form phenyl or a 4-6 membered heterocycle; and 
           R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
         
         d) 
       
       
         
           
           
               
               
           
         
         wherein
 A 1  is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 A 3 , independently for each occurrence, is selected from the group consisting of —NHR′ or —OH; 
 AR is a fused phenyl or 4-7 membered aromatic or partially aromatic heterocyclic ring, wherein AR is optionally substituted by oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; —S—C 1-4 alkyl; halogen; —OH; —CN; —COOH; —CONHR′; wherein the two substituents comprising —OH are ortho to each other; 
 R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; CONHR′; and 
 R′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 , —NO 2 , —SH, or —OH; 
 
         e) 
       
       
         
           
           
               
               
           
         
         wherein
 Q 1  is selected from the group consisting of C 1-4 alkyl, alkylene, or a bond; C 1-6 cycloalkyl; a 5-6 membered heterocyclic ring; or phenyl; 
 Q 2 , independently for each occurrence, is selected from the group consisting of H, C 1-4 alkyl, alkylene, or a bond; C 1-6 cycloalkyl; a 5-6 membered heterocyclic ring; phenyl; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; 
 A 3 , independently for each occurrence, is selected from the group consisting of —NH 2  or —OH; 
 A 4 , independently for each occurrence, is selected from the group consisting of —NH—NH 2 ; —NHOH, —NH—OR″, or —OH; 
 R″ is selected from the group consisting of H or C 1-4 alkyl; and 
 
         f) 
       
       
         
           
           
               
               
           
         
         wherein
 A 5  is selected from the group consisting of —OH, —NH 2 , —SH, —NHR″′; 
 R′″ is selected from —NH 2 ; —OH; —O-phenyl; and C 1-4 alkoxy; 
 
         R 5  and R 6  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or R 5  and R 6  taken together may form a 5-6 membered ring; and 
         the second monomer has a boronic acid or oxaborole moiety capable of binding with the Z 1  moiety of Formula I to form the multimer. 
       
     
     
         3 . The first monomer of  claim 2 , wherein A 1  is selected from the group consisting of C 1 -C 3 alkylene optionally substituted with one, two, or three halogens, or —C(O)—. 
     
     
         4 - 8 . (canceled) 
     
     
         9 . The first monomer of  claim 2 , wherein Z 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein
 X is selected from O, S, CH, NR′, or when X is NR′, N may be covalently bonded to Y of formula I; 
 R′ is selected from the group consisting of H, C 1-4 alkyl; 
 R 5 , R 6 , and R 7  are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′; or a mono- or bicyclic heterocyclic optionally substituted with amino, halo, hydroxyl, oxo, or cyano; and 
 AA is a 5-6 membered heterocyclic ring optionally substituted by C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; —OH; —CN; —COOH; —CONHR′, or —S—C 1-4 alkyl. 
 
     
     
         10 . The first monomer of  claim 9 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The first monomer of  claim 9 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The first monomer of  claim 9 , wherein X is nitrogen. 
     
     
         13 . The first monomer of  claim 9 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The first monomer of  claim 14 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         17 - 20 . (canceled) 
     
     
         21 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         22 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         23 - 24 . (canceled) 
     
     
         25 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         26 . The first monomer of  claim 2 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The first monomer of  claim 2 , wherein the first monomer forms a biologically useful dimer with a second monomer in vivo. 
     
     
         28 . The first monomer of  claim 2 , wherein the second monomer is X 2 —Y 2 —Z 2  (Formula II), wherein Z 2  is the boronic acid or oxaborole moiety, and wherein
 X 2  is a second ligand moiety capable of binding to a second target biomolecule; and 
 Y 2  is absent or is a connector moiety covalently bound to X 2  and Z 2 . 
 
     
     
         29 . The first monomer of  claim 2 , wherein X 1  and X 2  are the same. 
     
     
         30 . The first monomer of  claim 2 , wherein X 1  and X 2  are different. 
     
     
         31 . The first monomer of  claim 2 , wherein the first target biomolecule and the second target biomolecule are different. 
     
     
         32 . The first monomer of  claim 2 , wherein the first target biomolecule and the second target biomolecule are the same. 
     
     
         33 . The first monomer of  claim 2 , wherein the apparent IC 50  of an essentially equimolar combination of the first monomer and the second monomer against the first target biomolecule and the second target biomolecule is at least about 3 to 10 fold lower than the lowest of the IC 50  of the second monomer against the second target biomolecule or the IC 50  of the first monomer against the first target biomolecule. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . The first monomer of  claim 2 , wherein the aqueous fluid has a physiologically acceptable pH. 
     
     
         37 . The first monomer of  claim 28 , wherein Z 2  of the second monomer is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 R 8  is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —COOH; or —CONHR′; 
 A 1  is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 Q is selected from the group consisting of substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 
 AA, independently for each occurrence, is phenyl, aryl, or a 5-7 membered heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, C 1-4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 2-4 alkenyl; C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —NR 2 ′″, wherein R′″ is independently selected from the group consisting of H and C 1-4 alkyl; —COOH; —CONHR′; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and 
 R′ is H or C 1-4 alkyl. 
 
     
     
         38 . The first monomer of  claim 37 , wherein R 8  and the substituent comprising boronic acid are ortho to each other, and wherein R 8  is —CH 2 NH 2 . 
     
     
         39 . The first monomer of  claim 37 , wherein Z 2  of the second monomer is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         40 . The first monomer of  claim 37 , wherein Z 2  of the second monomer is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         41 . The first monomer of  claim 27 , wherein Z 2  of the second monomer is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 R 8  is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —COOH; or —CONHR′; 
 AA, independently for each occurrence, is a 5-7 membered heterocyclic ring having one, two, or three heteroatoms, or phenyl, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 2-4 alkenyl, C 1-4 alkoxy; —S—C 1-4 alkyl; —CN; —NR 2 ′″, wherein R′″ is independently selected from the group consisting of H and C 1-4 alkyl; —COOH; —CONHR′; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and 
 R′ is H or C 1-4 alkyl. 
 
     
     
         42 . (canceled) 
     
     
         43 . The first monomer of  claim 27 , wherein the first monomer and the second monomer form a dimer. 
     
     
         44 . (canceled) 
     
     
         45 . The first monomer of  claim 2 , wherein the target biomolecule is a protein. 
     
     
         46 . (canceled) 
     
     
         47 . A method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof, comprising administering to the patient thereof an amount of the first monomer of  claim 1  and an amount of a boronic acid monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo. 
     
     
         48 . The method of  claim 47 , wherein the multimer is a dimer. 
     
     
         49 . (canceled) 
     
     
         50 . A method of modulating two or more target biomolecule domains substantially simultaneously comprising:
 contacting an aqueous composition comprising said biomolecule domains with a first monomer represented by:
   X 1 —Y 1 —Z 1   (Formula I)
 
   
       and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
 X 1  is a first ligand moiety capable of binding to a first target biomolecule domain; and 
 a second monomer represented by:
   X 2 —Y 2 —Z 2   (Formula II),
 
 
 
       wherein
 X 2  is a ligand moiety capable of binding to a second target biomolecule domain; 
 wherein upon contact with the aqueous composition, said first monomer and said second monomer forms a dimer that binds to the first target biomolecule domain and the second target biomolecule domain. 
 
     
     
         51 - 62 . (canceled)