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

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:

• X1—Y1—Z1 (Formula I)
• and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein
• X1 is a first ligand moiety capable of binding to a first target biomolecule;
• Y1 is absent or is a connector moiety covalently bound to X1 and Z1;
• Z1 is a first linker selected from the group consisting of:
• a)
• wherein
• A1 is (a) absent;
• or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
• A2, 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 A1 and A2 is present;
• or
• A1 and A2, together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;
• A3 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, —NH2, —NO2, —SH, or —OH;
• m is 1-6;
• represents a single or double bond;
• and
• R1 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, —NH2, —NO2, —SH, or —OH;
• Q1 is (a) absent;
• or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic;
• or
• R1 and Q1 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 R2, wherein the two substituents comprising —OH have a 1, 2 or 1,3 configuration;
• each R2 is independently selected from hydrogen, halogen, oxo, sulfonate, —NO2, —CN, —OH, —NH2, —SH, —COOH, —CON(R′)2, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R2 together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system;
• A1, 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, —NH2, —NO2, —SH, or —OH;
• c)
• wherein
• BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, aryl, or heteroaryl moiety;
• A3, independently for each occurrence, is selected from the group consisting of —NHR′, —OH, or —O—C1-4alkyl;
• R3 and R4 are independently selected from the group consisting of H, C1-4alkyl, phenyl, or R3 and R4 taken together from a 3-6 membered ring;
• R5 and R6 are independently selected from the group consisting of H, C1-4alkyl optionally substituted by hydroxyl, amino, halogen, or thio;
• C1-4alkoxy;
• halogen;
• —OH;
• —CN;
• —COOH;
• —CONHR′;
• or R5 and R6 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, —NH2, —NO2, —SH, or —OH;
• d)
• wherein
• A1 is (a) absent;
• or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
• A3, 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, C1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio;
• C1-4alkoxy;
• —S—C1-4alkyl;
• halogen;
• —OH;
• —CN;
• —COOH;
• —CONHR′;
• wherein the two substituents comprising —OH are ortho to each other;
• R5 and R6 are independently selected from the group consisting of H, C1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio;
• C1-4alkoxy;
• 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, —NH2, —NO2, —SH, or —OH;
• e)
• wherein
• Q1 is selected from the group consisting of C1-4alkyl, alkylene, or a bond;
• C1-6cycloalkyl;
• a 5-6 membered heterocyclic ring;
• or phenyl;
• Q2, independently for each occurrence, is selected from the group consisting of H, C1-4alkyl, alkylene, or a bond;
• C1-6cycloalkyl;
• a 5-6 membered heterocyclic ring;
• phenyl;
• substituted or unsubstituted aliphatic;
• substituted or unsubstituted heteroaliphatic;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• A3, independently for each occurrence, is selected from the group consisting of —NH2 or —OH;
• A4, independently for each occurrence, is selected from the group consisting of —NH—NH2;
• —NHOH, —NH—OR″, or —OH;
• R″ is selected from the group consisting of H or C1-4alkyl;
• and
• f)
• wherein
• A5 is selected from the group consisting of —OH, —NH2, —SH, —NHR″′;
• R′″ is selected from —NH2;
• —OH;
• —O-phenyl;
• and C1-4alkoxy;
• R5 and R6 are independently selected from the group consisting of H, C1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio;
• C1-4alkoxy;
• halogen;
• —OH;
• —CN;
• —COOH;
• —CONHR′;
• or R5 and R6 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 Z1 moiety of Formula I to form the multimer.

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:
• X1—Y1—Z1 (Formula I)
• and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
• X1 is a first ligand moiety capable of binding to a first target biomolecule domain;
• and
• a second monomer represented by:
• X2—Y2—Z2 (Formula II),
• wherein
• X2 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.