Large ring compounds

Abstract

To provide a novel and improved receptor molecule capable of exhibiting higher affinity and / or selectivity to a specific target sugar (for example, glucose).SOLUTION: The present invention relates to macrocyclic compounds that are capable of selectively binding to target sugars (e.g., glucose), making them particularly well suited for use in sugar sensing applications. The invention also relates to methods of preparing the compounds, compositions and devices containing them, and their use in the detection of target sugars.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to macrocyclic compounds capable of selectively binding to target sugars (e.g., glucose), which are particularly suitable for use in sugar-sensing applications. The invention also relates to methods for preparing the compounds, compositions and devices containing them, and their use in detecting target sugars. [Background technology]

[0002] The detection and subsequent monitoring of sugars, particularly glucose, has many practical applications in both medical and non-medical applications. For example, the reliable detection of glucose in an individual's bloodstream is the basis for the majority of currently available therapies for the treatment of diabetes, a disease that the World Health Organization (WHO) states affected approximately 422 million people in 2014 and is predicted to be the seventh leading cause of death by 2030.

[0003] However, diabetes is not the only practical application for detecting sugars; accurate determination of sugar levels in fermentation media, for example, in brewing processes and / or cell culture, is also highly desirable, where the ability to closely monitor the exact levels of sugars present during fermentation can be highly advantageous in fine-tuning both the yield and properties of the final product.

[0004] However, the detection and subsequent monitoring of sugars relies heavily on the provision of sugar receptor molecules (so-called "synthetic lectins") that can bind to and therefore detect sugars in the aqueous media they are typically found in. Historically, however, binding sugars in aqueous media has proven to be a very challenging task for synthetic chemists, and even natural carbohydrate-binding proteins known as lectins have struggled to exhibit binding affinities on the scale typically found in nature for such protein-substrate binding interactions.

[0005] Sugars are hydrophilic species and often carry hydromimetic hydroxyl groups that are well hydrated and significantly similar to water molecules. In this regard, successful binding requires that the receptor molecule be able to distinguish between the hydroxyl groups of the sugar and a series of water molecules that are typically present in much higher abundance than the target sugar. Furthermore, for binding to occur, water must be displaced from both the receptor molecule and the sugar, and therefore the energetic outcome is often difficult to predict, thereby making modeling and designing such receptor molecules challenging.

[0006] Furthermore, the ability to selectively target one sugar molecule over another presents significant challenges: for example, for specific sugar binding to occur, the receptor molecule must be able to distinguish between multiple sugar molecules that often have only very subtle structural differences (i.e., the configuration of a single asymmetric center).

[0007] Despite the above challenges, several successful synthetic sugar receptor molecules capable of selective sugar recognition in aqueous media have been reported (see, e.g., WO 2013 / 160701). However, to further advance the use of these synthetic sugar receptors in sugar detection applications such as those outlined above, there remains a need for new and improved receptor molecules that can exhibit higher affinity and / or selectivity for specific target sugars (e.g., glucose).

[0008] It is with the foregoing in mind that the present invention has been devised. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2013 / 160701 Summary of the Invention [Means for solving the problem]

[0010] According to one aspect of the present invention there is provided a compound as defined herein, or a salt, hydrate or solvate thereof.

[0011] According to a second aspect of the present invention there is provided a complex comprising a compound as defined herein, or a salt, hydrate or solvate thereof, in association with a target sugar.

[0012] According to a third aspect of the present invention there is provided a complex comprising a compound as defined herein, or a salt, hydrate or solvate thereof, in association with a displaceable reporter molecule.

[0013] According to a fourth aspect of the present invention there is provided a composition comprising a compound as defined herein, or a salt, hydrate or solvate thereof, and a transferable reporter molecule.

[0014] According to a fifth aspect of the present invention there is provided a saccharide detection device comprising a conjugate as defined herein, a composition as defined herein or a compound as defined herein.

[0015] According to another aspect of the present invention, there is provided a use of a conjugate as defined herein, a composition as defined herein, a saccharide detection device as defined herein, or a compound as defined herein for detecting a target sugar in an aqueous environment.

[0016] According to a further aspect of the present invention there is provided a kit comprising a compound as defined herein and a transferable reporter molecule.

[0017] According to a further aspect of the present invention there is provided a process for preparing a compound defined herein, or a salt, hydrate or solvate thereof.

[0018] According to yet a further aspect of the present invention there is provided a novel intermediate as defined herein suitable for use in any one of the synthetic methods described herein.

[0019] Features, including any suitable and preferred features, in relation to one aspect of the invention may be features, including any suitable and preferred features, in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0021] Throughout the description and claims of this specification, the terms "comprise" and "contain" and variations thereof mean "including, but not limited to," and they are not intended to (and do not) exclude other moieties, additives, ingredients, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification should be understood to contemplate the plural as well as the singular, unless the context otherwise requires.

[0022] It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where incompatible. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, can be combined in any combination, except where at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of the foregoing embodiments. The invention extends to any novel, or any novel combination of, features disclosed herein (including any accompanying claims, abstract, and drawings), or to any novel, or any novel combination of features of any method or process so disclosed.

[0023] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific for the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific for the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. Similar rules apply to other radicals, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0024] The term "alkenyl" will be understood to include both straight-chain and branched hydrocarbon groups containing one or more carbon-carbon double bonds. For example, reference to "(2-6C)alkenyl" will be understood to refer to an alkene group containing from 3 to 6 carbon atoms and may include, for example, hexenyl, pentenyl, butenyl, propenyl, and ethylenyl.

[0025] The term "alkynyl" will be understood to include both straight-chain and branched hydrocarbon groups containing one or more carbon-carbon triple bonds. Again, reference to "(2-6C)alkenyl" will be understood to refer to an alkyne group containing 3 to 6 carbon atoms, and can include, for example, hexynyl, pentynyl, butynyl, propynyl, and acetylenyl.

[0026] The term "(m-nC)" or "(m-nC) group" when used alone or as a prefix, refers to any group having m to n carbon atoms.

[0027] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1-6C)alkylene" means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, such as, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0028] "(3-8C)cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

[0029] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing 3 to 8 carbon atoms and at least one double bond, such as 3-cyclohexen-1-yl, or cyclooctenyl, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0030] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms, suitably 7 to 12 member atoms in the ring. Bicyclic heterocycles may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include oxidized sulfur heterocycles containing SO or SO groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for a heterocyclyl group bearing one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2 thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2 thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. Those skilled in the art will recognize that any heterocycle may be linked to another group through any suitable atom, such as through a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring linked through the ring nitrogen.

[0031] "Bridged ring system" means a ring system that shares two or more atoms. See, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0032] "Spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., the heterocycle is linked to an additional carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azospiro[3.5]nonane.

[0033] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0034] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, e.g., fused 5- and 6-membered rings or bicyclic structures formed from two fused 6-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to three heteroatoms, more typically up to two, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, will be fewer than five.

[0035] Heteroaryl includes furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H furo[3,2b]pyranyl, 5H pyrido[2,3d]o oxazinyl, 1H pyrazolo[4,3d]oxazolyl, 4H imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, imidazo[2,1b]thiazolyl, imidazo[1,2b][1,2,4]triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4 tetrahydro-1,8 naphthyridinyl, 1,2,3,4 tetrahydropyrido[2,3b]pyrazinyl, and 3,4 dihydro-2H-pyrido[3,2b][1,4]oxazinyl.

[0036] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0037] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0038] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a pyrazine ring fused to a five- or six-membered ring containing one or two ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a five- or six-membered ring containing one or two ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an isothiazole ring fused to a five- or six-membered ring containing one or two ring heteroatoms; a thiophene ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a furan ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms;

[0039] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indozolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0040] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0041] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like. In certain embodiments, aryl is phenyl.

[0042] The term "halo" refers to any suitable halogen and may be selected from fluoro, chloro, bromo, and iodo groups. Suitably, the term halo refers to a fluoro, chloro, or bromo group, and most suitably refers to a chloro group.

[0043] The term "optionally substituted" refers to either a group, structure, or molecule that is substituted or that is not substituted. 1 The term "one / any CH, CH, CH group or heteroatom (i.e., NH) within the group is optionally substituted" refers to the R 1 It suitably means that (any) one of the hydrogen radicals of the group is replaced by the relevant defined group.

[0044] The term "hydrophilic substituent" will be understood to refer to a substituent that has an affinity for water and tends to solvate. Thus, the term "hydrophilic substituent" can be understood to encompass any substituent that facilitates aqueous solubility for the compounds of the present invention.

[0045] The term "hydrophilic polymer" is understood to refer to any oligomer, polymer, and / or copolymer comprising at least three repeating units (suitably at least 10 repeating units), where one or more of the repeating units (monomers) comprises a polar functional group having an affinity for water. The term "hydrophilic polymer" will be understood to encompass linear, branched, and hyperbranched polymers. Suitably, the hydrophilic polymer is selected from polycarboxylic acids, polycarboxylates, polyhydroxys, polyesters, polyethers, polyamines, polyamides, polyphosphates, or polyoxyalkylenes. More suitably, it is a polycarboxylic acid, polycarboxylate, polyhydroxy, or polyether. Even more suitably, the hydrophilic polymer is polyethylene glycol, polyvinyl alcohol, polyacrylate, polyacrylamide, or polyvinylpyrrolidine. Most suitably, the hydrophilic polymer is polyethylene glycol or polyacrylamide.

[0046] It will be understood that the term "hydrophilic dendritric group" refers to any dendrimer, dendron, or branched molecule that contains one or more polar functional groups that have an affinity for water. That is, it will be understood that the term "hydrophilic dendritric group" encompasses any dendrimer, dendron, or branched molecule that facilitates water solubility of the compounds of the present invention. Furthermore, it will be readily understood that "dendrimer" is a term of art that refers to a dendritic molecular structure having a core or central point, interior layers (otherwise known as "generations") of one or more repeating building units attached to the core or central point, and an exterior (outermost) layer of building units that includes terminal functional groups at the termini of the dendrimer structure.

[0047] Where any substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups, or substituents selected from two or more of the specified groups.

[0048] The phrase "compounds of the invention" means compounds disclosed herein generally and specifically. Compounds of the Invention

[0049] According to one aspect of the present invention, there is provided a compound of formula (I), or a salt, hydrate, or solvate thereof, as shown below: [ka] During the ceremony, Bonds b1 and b2 are independently selected from a single bond or a double bond; R 1a , R 1b , R 2a and R 2bare independently selected from hydrogen, carbonyl, (1-8C)alkyl, (3-10C)cycloalkyl, aryl, heteroaryl, and heterocyclyl, each except hydrogen and carbonyl being optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, mercapto, and hydrophilic substituents; or R 1a and R 1b are linked to form a group of the formula: [ka] and / or R 2a and R 2b are linked to form a group of the formula: [ka] (In the formula, [ka] indicates the attachment point, Bonds b1 and b2 are as defined above, Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R1 and R2 are independently selected from (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; a and b are integers independently selected from 0 to 2; m and n are integers independently selected from 0 to 2; Z1 and Z2 are independently selected from hydrophilic substituents. C and D are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and groups of the formula: [ka] (In the formula, s, t, and v are integers independently selected from 1 or 2; [ka] indicates the attachment point) R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 (In the formula, L 1 is absent or is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo, Y 1 is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O),N(R b )C(O)N(R a ), N(R a )C(O)O,OC(O)N(R a ), S(O)2N(R a ), and N(R a )SO2, and R a and R b are each independently selected from hydrogen and (1-4C)alkyl; Q 1is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is optionally (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (y is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c , Si(R e )(R d )R c and (CH2) z NR d R c (z is 1, 2, or 3), and R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, and (3-6C)cycloalkyl, and R c and R d can be linked together with the attached nitrogen atom such that they form a 4- to 7-membered heterocyclic ring optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, or hydroxyl), or Two R groups and / or two R groups may together form a group of the formula: [ka] (In the formula, R x is hydrogen, and halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, sulfamoyl, mercapto, ureido, NR f R g , OR f , C(O)R f , C(O)OR f ,OC(O)R f , C(O)N(R g )R f and N(R g )C(O)R f and R is selected from (1-6C)alkyl optionally substituted with one or more substituents selected from f and R g is selected from hydrogen and (1-4C)alkyl; Dashed lines represent attachment points to C and / or D), W1, W2, W3 and W4 are CR h R i are independently selected from R h and R i is selected from hydrogen and (1-2C)alkyl; X1, X2, X3 and X4 are independently selected from the group of the following formulae: [ka] (In the formula, [ka] indicates the attachment point, W x is selected from O or NH, and Q is O, S and NR j Selected from R j is selected from hydrogen, (1-4C)alkyl, aryl, heteroaryl, and sulfonyl; Z3 and Z4 are independently selected from hydrophilic substituents; L is absent or a linker optionally bearing a hydrophilic substituent Z5; c and d are integers independently selected from 0 to 4; o and p are integers independently selected from 0 to 2; i) the compound of formula I is optionally attached to a transferable reporter molecule via one or more substituents associated with R1, R2, R3, R4, Z1, Z2, Z3, Z4 and / or Z5, and / or ii) The compound of formula I may comprise one or more substituents R 1a , R 1b , R 2a , R 2b , optionally attached to a substituent of formula A1 shown below at a position relative to R1, R2, R3, R4, Z1, Z2, Z3, Z4 and / or Z5, X 2a -L 2a -Z 2a (Formula A1) [In the formula, X 2a is absent or O, S, SO, SO2, N(R x2 ), C(O), C(O)O, OC(O), C(O)N(R x2 ), N(R x2 )C(O),N(R x2 )C(O)N(R x3 ), N(R x2 )C(O)O,OC(O)N(R x2 ), S(O)2N(R x2 ) and N(R x2 )SO2 and R x2 and R x3 are each independently selected from hydrogen and (1-4C)alkyl; L 2ais absent or selected from (1-20C)alkylene, (1-20C)alkyleneoxide, (1-20C)alkenyl, and (1-20C)alkynyl, each of which is optionally substituted by one or more substituents selected from (1-2C)alkyl, aryl, and oxo; Z 2a is carboxy, carbamoyl, sulfamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , ONR xc R xd , C(O)X a , C(Q z ) OR xf , N=C=O, NR xc C(O)CH2X b , C(O)N(R xe )NR Xc R Xd , S(O) y X a (y is 0, 1 or 2), SO2N(R xe )NR xc R xd , Si(R xg )(R xh )R xi , SSX c an amino acid and selected from the following formula: [ka] (In the formula, X a is a leaving group (e.g., halo or CF), X b is a halo (e.g., iodo), X c is aryl or heteroaryl optionally substituted with one or more substituents selected from halo, cyano, and nitro; R xc , R xd and R xe are each independently selected from hydrogen and (1-6C)alkyl; Rxf is selected from hydrogen or (1-6C) alkyl, or R xf is C(O)OR xf is a substituent that, taken together, forms an activated ester (e.g., a hydroxysuccinimide ester, a hydroxy-3-sulfo-succinimide ester, or a pentafluorophenyl ester); Q z is O or + NR Q1 R Q2 Selected from R Q1 and R Q2 are independently selected from hydrogen and methyl; R xg , R xh and R xi are each independently selected from (1-4C)alkyl, hydroxy, halo, and (1-4C)alkoxy); provided that the compound of Formula I contains at least one hydrophilic substituent (eg, Z1, Z2, Z3, Z4, or Z5).

[0050] The present inventors have surprisingly and advantageously discovered that the compounds of the present invention exhibit extremely high affinity for a specific target sugar (e.g., glucose) in aqueous media. Furthermore, it has also been discovered that the compounds of the present invention exhibit an unprecedented level of selectivity for a specific target sugar (e.g., glucose) over other structurally similar sugars (e.g., mannose).

[0051] In addition to the remarkable affinity and selectivity exhibited by the compounds of the present invention, the non-covalent interactions between the compounds of the present invention and target sugars, as opposed to covalent interactions, allow the compounds of the present invention to reversibly associate with specific target sugars. In light of the aforementioned challenges in the art related to the development of efficient and selective saccharide receptor molecules, particularly in biologically relevant aqueous media, the compounds of the present invention clearly represent a unique and highly useful class of compounds for use in saccharide-sensing applications.

[0052] Without being bound by theory, it is believed that one guiding principle in the design of compounds of the invention is complementarity. Suitably, both polar and nonpolar groups of compounds of the invention are positioned to provide favorable contact with the target sugar. For example, substituents C and D can make hydrophobic / CH-π contacts with the axial C-H group of the sugar, while spacer groups (e.g., bis-urea motifs) can form hydrogen-bonding interactions to the -O- and -OH units of the sugar. Furthermore, the bis-urea spacer groups of compounds of the invention also serve to maintain a well-defined "cavity" while keeping substituents C and D the correct distance apart for successful saccharide-binding interactions (i.e., 8-10 Å, suitably about 9 Å). For illustrative purposes only, Figure 1 shows both a schematic diagram of the key interactions that take place between a target sugar and compounds of the invention (Figures 1a and 1b), as well as a molecular model of the ground-state conformation of one particular compound of the invention with glucose (Figures 1c and 1d). In Figure 1c, ten intermolecular NH...O hydrogen bonds (with distances between 1.9 and 2.2 Å) can be seen, and Figure 1d further shows the close CH-π contacts formed between the saccharide and the compound of the invention.

[0053] The compounds of the present invention benefit from a high level of water solubility, which allows them to be easily dissolved and therefore suitable for use in various aqueous media (i.e., in the bloodstream or fermentation medium) where target sugars are typically present. Thus, in embodiments, the compounds of the present invention are water soluble. Suitably, the compounds of the present invention have a water solubility of at least about 1 μM. More suitably, the compounds of the present invention have a water solubility of at least about 100 μM. Even more suitably, the compounds of the present invention have a water solubility of at least about 500 μM. Even more suitably, the compounds of the present invention have a water solubility of at least about 1 mM. Most suitably, the compounds of the present invention have a water solubility of at least about 2 mM.

[0054] In another embodiment, the compounds of the present invention have a water solubility of 1 μM to 50 mM. Suitably, the compounds of the present invention have a water solubility of 1 μM to 20 mM. More suitably, the compounds of the present invention have a water solubility of 100 μM to 20 mM. Most suitably, the compounds of the present invention have a water solubility of 100 μM to 10 mM.

[0055] In a further embodiment, there is provided a compound of formula (I), or a salt, hydrate or solvate thereof, as shown below: [ka] During the ceremony, Bonds b1 and b2 are independently selected from a single bond or a double bond; R 1a , R 1b , R 2a and R 2b are independently selected from hydrogen, carbonyl, (1-8C)alkyl, (3-10C)cycloalkyl, aryl, heteroaryl, and heterocyclyl, each except hydrogen and carbonyl being optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, mercapto, and hydrophilic substituents; or R 1a and R 1b are linked to form a group of the formula: [ka] and / or R 2a and R 2b are linked to form a group of the formula: [ka] (In the formula, [ka] indicates the attachment point, Bonds b1 and b2 are as defined above, Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R1 and R2 are independently selected from (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; a and b are integers independently selected from 0 to 2; m and n are integers independently selected from 0 to 2; Z1 and Z2 are independently selected from hydrophilic substituents; C and D are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and groups of the formula: [ka] (In the formula, s, t, and v are integers independently selected from 1 or 2; [ka] indicates the attachment point), R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 (In the formula, L 1 is absent or is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo, Y 1is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O),N(R b )C(O)N(R a ), N(R a )C(O)O,OC(O)N(R a ), S(O)2N(R a ), and N(R a )SO2, and R a and R b are each independently selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is optionally (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (y is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c , Si(R e )(R d )R c and (CH2) z NR d R c (z is 1, 2, or 3), and Rc , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, and (3-6C)cycloalkyl, and R c and R d can be linked together with the attached nitrogen atom such that they form a 4- to 7-membered heterocyclic ring optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, or hydroxyl), or two R groups and / or two R groups together form a group of the formula: [ka] (In the formula, R x is hydrogen, and halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, sulfamoyl, mercapto, ureido, NR f R g , OR f , C(O)R f , C(O)OR f ,OC(O)R f , C(O)N(R g )R f and N(R g )C(O)R f and R is selected from (1-6C)alkyl optionally substituted with one or more substituents selected from f and R g is selected from hydrogen and (1-4C)alkyl; Dashed lines represent attachment points to C and / or D), W1, W2, W3 and W4 are CR h R i are independently selected from R h and R i is selected from hydrogen and (1-2C)alkyl; X1, X2, X3 and X4 are independently selected from the group of the following formulae: [ka] (In the formula, [ka] indicates the attachment point, W x is selected from O or NH, and Q is O, S and NR j Selected from R j is selected from hydrogen, (1-4C)alkyl, aryl, heteroaryl, and sulfonyl; Z3 and Z4 are independently selected from hydrophilic substituents; L is absent or a linker optionally bearing a hydrophilic substituent Z5; c and d are integers independently selected from 0 to 4, and o and p are integers independently selected from 0 to 2; the compound of formula I is optionally attached to a transferable reporter molecule via one or more substituents associated with R1, R2, R3, R4, Z1, Z2, Z3, Z4 and / or Z5; provided that the compound of Formula I contains at least one hydrophilic substituent (eg, Z1, Z2, Z3, Z4, or Z5).

[0056] Particular compounds of the invention include, for example, compounds of Formula I, or salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, each of bonds b1 and b2, rings A and B, C, D, R1, R2, R3, R4, W1, W2, W3, W4, X1, X2, X3, X4, Z1, Z2, Z3, Z4, Z5, L, a, b, c, d, m, n, o, p, and any associated substituents have any of the meanings defined above or in any of paragraphs (1) to (60) below; (1) Bonds b1 and b2 are single bonds, (2) Bonds b1 and b2 are double bonds, (3)R 1a , R 1b , R 2a and R2b are independently selected from (1-8C)alkyl, (3-10C)cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, cyano, hydroxyl, and hydrophilic substituents; or R 1a and R 1b are linked to form a group of the formula: [ka] and / or R 2a and R 2b are linked to form a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, Bonds b1 and b2 are as defined above, Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R1 and R2 are independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; a and b are integers independently selected from 0 to 2; m and n are integers independently selected from 0 to 2; Z1 and Z2 are independently selected from hydrophilic substituents; (4)R 1a , R 1b , R 2a and R 2bare independently selected from aryl and heteroaryl, each of which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)alkoxy, amino or hydroxyl; or R 1a and R 1b are linked to form a group of the formula: [ka] and / or R 2a and R 2b are linked to form a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, Bonds b1 and b2 are as defined above, Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R1 and R2 are independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; a and b are integers independently selected from 0 to 2; m and n are integers independently selected from 0 to 2; Z1 and Z2 are independently selected from hydrophilic substituents; (5)R 1a and R 1b are linked to form a group of the formula: [ka] and R 2a and R 2bare linked to form a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, Bonds b1 and b2 are as defined above, Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl; R1 and R2 are independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; a and b are integers independently selected from 0 to 2; m and n are integers independently selected from 0 to 2; Z1 and Z2 are independently selected from hydrophilic substituents; (6) Rings A and B are independently selected from aryl, heteroaryl, and heterocyclyl (e.g., pyrrolidinyl); (7) Rings A and B are independently selected from aryl and heteroaryl; (8) Rings A and B are aryl; (9) Rings A and B are independently selected from phenyl, pyridyl, naphthyl, and pyrrolidinyl; (10) Rings A and B are phenyl or pyrrolidinyl, preferably phenyl; (11) R1 and R2 are independently selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, and hydroxyl; (12) R1 and R2 are independently selected from (1-4C) alkyl, halo, amino, cyano, and hydroxyl; (13) C and D are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and groups of the formula: [ka] During the ceremony, [ka] indicates the attachment point, (14) C and D are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; (15) C and D are independently selected from aryl and heteroaryl; (16) C and D are independently selected from phenyl, naphthenyl, and anthracenyl; (17) C and D are phenyl; (18) C and D are anthracenyl; (19) R3 and R4 are independently selected from halo, (1-4C) alkyl, (1-4C) alkoxy, amino, nitro, (1-4C) alkylamino, (1-4C) dialkylamino, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (2-4C) alkenyl, (2-4C) alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-5C)alkylene; Y 1 is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O),N(R b )C(O)N(R a ), N(R a )C(O)O,OC(O)N(R a ), S(O)2N(R a ), and N(Ra )SO2, and R a and R b are each independently selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (y is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c , Si(R e )(R d )R c , and (CH2) z NR d R c (z is 1, 2, or 3), and R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, or (3-6C)cycloalkyl; Two R groups and / or two R groups may together form a group of the formula: [ka] During the ceremony, R x is hydrogen, and halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, sulfamoyl, mercapto, ureido, NR f R g , OR f , C(O)R f , C(O)OR f ,OC(O)R f , C(O)N(R g )R f and N(R g )C(O)R f and R is selected from (1-6C)alkyl optionally substituted with one or more substituents selected from f and R g is selected from hydrogen and (1-4C)alkyl; The dashed lines represent attachment points to C and / or D. (20) R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-5C)alkylene; Y 1 is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ) and N(R a )C(O), and R a is selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , and N(R d )C(O)R c and optionally further substituted by one or more substituents independently selected from R c and R d are each independently selected from hydrogen and (1-6C)alkyl, and Two R groups and / or two R groups may together form a group of the formula: [ka] During the ceremony, R x is hydrogen, and halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, sulfamoyl, mercapto, ureido, NR f R g , OR f , C(O)R f , C(O)OR f ,OC(O)R f , C(O)N(R g )R f and N(R g )C(O)R f and R is selected from (1-6C)alkyl optionally substituted with one or more substituents selected from f and R g is selected from hydrogen and (1-4C)alkyl; The dashed lines represent attachment points to C and / or D. (21) R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-5C)alkylene; Y1 is absent or selected from one of the following groups: O, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra) and N(Ra)C(O), where Ra is selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C)alkyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , and N(R d )C(O)R c and optionally further substituted by one or more substituents independently selected from R c and R d are each independently selected from hydrogen and (1-6C)alkyl, and Two R groups and / or two R groups may together form a group of the formula: [ka] During the ceremony, Rx represents hydrogen, and halo, (1-4C)haloalkyl, NR f R g , OR f , C(O)R f , C(O)OR f and C(O)N(R g )R f and R is selected from (1-6C)alkyl optionally substituted with one or more substituents selected from f and R g is selected from hydrogen and (1-4C)alkyl, and The dashed lines represent attachment points to C and / or D. (22) R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo, Y 1 is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O),N(R b )C(O)N(R a ), N(R a )C(O)O,OC(O)N(R a ), S(O)2N(R a ), and N(R a )SO2, and R a and R b are each independently selected from hydrogen and (1-4C)alkyl; Q 1is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is optionally (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c( y is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c , Si(R e )(R d )R c and (CH2) z NR d R c (z is 1, 2, or 3), and R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, and (3-6C)cycloalkyl, and R c and R d can be linked together with the attached nitrogen atom such that they form a 4- to 7-membered heterocyclic ring optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, and hydroxyl; (23)R 3およびR4 is independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-5C)alkylene; Y 1 is absent or contains the following groups: O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ) and N(R a )C(O), and R a is selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (y is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c , Si(Re )(R d )R c , and (CH2) z NR d R c (z is 1, 2, or 3), and R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, and (3-6C)cycloalkyl; (24) R3 and R4 are independently selected from halo, (1-4C) alkyl, (1-4C) alkoxy, amino, nitro, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-2C) alkylene; Y1 is absent or selected from one of the following groups: O, N(Ra), C(O), C(O)O, OC(O), C(O)N(Ra) and N(Ra)C(O), where Ra is selected from hydrogen and (1-4C)alkyl; Q 1 is hydrogen, (1-8C) alkyl, aryl, (3-10C) cycloalkyl, heteroaryl and heterocyclyl, and Q 1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , and N(R d )C(O)R c and optionally further substituted by one or more substituents independently selected from R c and Rd are each independently selected from hydrogen and (1-6C)alkyl; (25) R3 and R4 are independently selected from halo, (1-4C) alkyl, (1-4C) alkoxy, amino, nitro, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-2C) alkylene; Y is absent or selected from one of the following groups: O, N(Ra), C(O)O, and C(O)N(Ra), where Ra is selected from hydrogen and (1-4C)alkyl; and Q 1 is hydrogen, (1-8C) alkyl, aryl, and heteroaryl; Q 1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, NR c R d , OR c , C(O)R d , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , and N(R d )C(O)R c and optionally further substituted by one or more substituents independently selected from R c and R d are each independently selected from hydrogen and (1-6C)alkyl; (26) R3 and R4 are independently selected from halo, (1-4C) alkyl, (1-4C) alkoxy, amino, nitro, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, and groups of the formula: -L 1 -Y 1 -Q 1 During the ceremony, L 1 is absent or is (1-2C) alkylene; Y is absent or selected from one of the following groups: O, N(Ra), C(O)O, and C(O)N(Ra), where Ra is selected from hydrogen and (1-4C)alkyl; and Q 1 is hydrogen or (1-8C)alkyl, wherein the (1-8C)alkyl is selected from halo, amino, (1-4C)aminoalkyl, hydroxy, NR c R d , OR c , C(O)R d , C(O)OR c , and C(O)N(R d )R c and optionally further substituted with one or more substituents independently selected from R c and R d are each independently selected from hydrogen and (1-2C)alkyl; (27) R3 and R4 are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)haloalkyl, (1-4C)haloalkoxy, and cyano; (28) R3 and R4 are independently selected from (1-4C) alkyl, and (1-4C) alkoxy; (29) W1, W2, W3 and W4 are CR h R i are independently selected from R h and R i is selected from hydrogen and methyl; (30) W1, W2, W3, and W4 are each CH2; (31) X1, X2, X3 and X4 are independently selected from the group consisting of the following formulae: [ka] During the ceremony, [ka] denotes the attachment point, and Q is O, S and NRj Selected from R j is selected from hydrogen, (1-4C)alkyl, and aryl; (32) X1, X2, X3 and X4 are independently selected from the group consisting of the following formulae: [ka] During the ceremony, [ka] denotes the attachment point, and Q is selected from O and S; (33) X1, X2, X3 and X4 are groups of the following formula: [ka] During the ceremony, [ka] indicates the attachment point, (34) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic substituents, wherein the hydrophilic substituents comprise one or more hydrophilic functional groups selected from carboxylic acids, carboxylate ions, carboxylic esters, hydroxyls, amines, amides, ethers, ketones, and aldehyde groups, ureas, nitro groups, sulfates, sulfonates, phosphates, phosphonates, and combinations thereof; (35) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic substituents, wherein the hydrophilic substituents comprise one or more hydrophilic functional groups selected from carboxylic acids, carboxylate ions, carboxylic esters, hydroxyls, amines, amides, ethers, ketone groups, aldehyde groups, and combinations thereof; (36) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic substituents, wherein the hydrophilic substituents comprise one or more hydrophilic functional groups selected from carboxylic acid, carboxylate, hydroxyl, amine, and combinations thereof; (37) Z1, Z2, Z3, Z4, and Z5 are independently selected from a hydrophilic polymer (e.g., polyethylene glycol), a hydrophilic dendritic group, or C(O)OM1; M1 is hydrogen or a cation (e.g., Na, Li, NH4); (38) Z1, Z2, Z3, Z4, and Z5 are independently selected from a hydrophilic polymer (e.g., polyethylene glycol) or a hydrophilic dendritic group; (39) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic polymers (e.g., polyethylene glycol) or dendritic groups comprising building units of generations 1 to 5 and a terminal functional group T1, each building unit being independently selected from a group of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 are O, C(O), C(O)O, OC(O), C(O)N(R r ), N(R r )C(O),N(R s )C(O)N(R r ), N(R r )C(O)O,OC(O)N(R r ), S(O)2N(R r ), and N(R r )SO2 and R r and R s are each independently selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-4C)alkylene; V is absent or is a group of the formula: [ka] During the ceremony, V1, V2, V 3、 V4 and V5 are O, S and NR t and R is independently selected from (1-6C)alkylene optionally interrupted by one or more groups selected from t is selected from hydrogen and (1-2C)alkyl; # is L 2a to, or L 2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and Terminal functional groups T1 are NH2, OH, and C(O)OM x , C(O)OR u and C(O)NHR u Selected from R u is selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, hydroxy(1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, ethylene glycol, and polyethylene glycol; M x is a cation (e.g., Na, Li, NH4), (40) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic polymers (e.g., polyethylene glycol) or dendritic groups comprising building units of generations 1 to 5 and a terminal functional group T1, each building unit being independently selected from a group of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 are O, C(O), C(O)O, OC(O), C(O)N(R r ) and N(R r )C(O), and R r is selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-4C)alkylene; V is absent or is a group of the formula: [ka] During the ceremony, V1, V2, V 3、 V4 and V5 are O, S and NR tand R is independently selected from (1-6C)alkylene optionally interrupted by one or more groups selected from t is selected from hydrogen and (1-2C)alkyl; # is L 2a to, or L 2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and Terminal functional group T1 is OH, C(O)OM x , C(O)OR u and C(O)NHR u Selected from R u is selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, hydroxy(1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, ethylene glycol, and polyethylene glycol; M x is a cation (e.g., Na, Li, NH4), (41) Z1, Z2, Z3, Z4, and Z5 are independently selected from dendritic groups comprising building units of generations 1 to 4 and terminal functional groups T1, each of which is independently selected from groups of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 are O, C(O), C(O)O, OC(O), C(O)N(R r ) and N(R r )C(O), and R r is selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-4C)alkylene; V is absent or is a group of the formula: [ka] During the ceremony, V1, V2, V 3、 V4 and V5 are independently selected from (1-6C)alkylene, optionally interrupted by one or more groups selected from O and NRt; t is selected from hydrogen and (1-2C)alkyl; # is L 2a to, or L 2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and Terminal functional group T1 is OH, C(O)OM x , C(O)OR u and C(O)NHR u Selected from R u is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, and hydroxy(1-4C)alkyl; M x is a cation (e.g., Na, Li, NH4), (42) Z1, Z2, Z3, Z4, and Z5 are independently selected from hydrophilic polymers or dendritic groups comprising building units of generations 1 to 4 and a terminal functional group T1, each building unit being independently selected from a group of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 are O, C(O), C(O)O, and C(O)N(R r ) and R r is selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-4C)alkylene; V is absent or is a group of the formula: [ka] During the ceremony, V1, V2, and V3 are independently selected from (1-6C)alkylene optionally interrupted by one or more groups selected from oxygen atoms; # is L 2a to, or L 2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and Terminal functional group T1 is OH, C(O)OM x , C(O)OR u and C(O)NHR u Selected from R u is selected from hydrogen, (1-4C)alkoxy, and hydroxy(1-4C)alkyl; M x is a cation (e.g., Na, Li, NH4), (43) Z1, Z2, Z3, Z4, and Z5 are independently selected from dendritic groups comprising building units of generations 1 to 4 and terminal functional groups T1, each of which is independently selected from groups of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 are O, C(O)O, and C(O)N(R r ) and R r is selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-4C)alkylene; V is a group of the formula: [ka] During the ceremony, V1, V2, and V3 are independently selected from (1-6C)alkylene optionally interrupted by one or more groups selected from oxygen atoms; # is L 2a to, or L2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and The terminal functional groups T1 are OH and C(O)OM x Selected from M x is a cation (e.g., Na, Li, NH4), (44) Z1, Z2, Z3, Z4, and Z5 are independently selected from dendritic groups comprising building units of generations 1 to 3 and terminal functional groups T1, each building unit being independently selected from groups of formula A: -L 2 -L 2a -V- (Formula A) During the ceremony, L 2 is C(O)N(R r ) and R r is selected from hydrogen and (1-4C)alkyl; L 2a is a bond or (1-2C)alkylene; V is a group of the formula: [ka] During the ceremony, V1, V2, and V3 are independently selected from (1-4C)alkylene optionally interrupted by one or more groups selected from oxygen atoms; # is L 2a to, or L 2a If is a bond, then L 2 indicates the attachment point to [ka] indicates the point of attachment to either another group of Formula A or to the terminal functional group T1, and The terminal functional group T1 is C(O)OM x and M xis a cation (e.g., Na, Li, NH4), (45) L is absent or a linker of 8 to 12 atoms in length (e.g., 10 atoms in length), which optionally bears a hydrophilic substituent Z5; (46) L does not exist, (47) L is a linker of 8 to 12 atoms in length (e.g., 10 atoms in length), which optionally bears a hydrophilic substituent Z5; (48) L is absent or selected from the group of the following formulae: [ka] During the ceremony, [ka] indicates the attachment point, W5 and W6 are CR k R l are independently selected from R k and R l is selected from hydrogen and (1-2C)alkyl; X5 and X6 are independently selected from the group consisting of the following formulae: [ka] During the ceremony, [ka] denotes the attachment point, and Q2 is O, S and NR m Selected from R m is selected from hydrogen, (1-4C)alkyl, aryl, heteroaryl, and sulfonyl; Bond b3 is a single bond or a double bond, Ring E is selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R5 is selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; Z5 is a hydrophilic substituent as defined herein; q is an integer from 0 to 2, e is an integer from 0 to 2, (49) L is absent or is selected from the group of the following formulae: [ka] During the ceremony, [ka] indicates the attachment point, W5 and W6 are CH2; X5 and X6 are independently selected from the group consisting of the following formulae: [ka] During the ceremony, [ka] denotes the attachment point, and Q2 is selected from O or S; Bond b3 is a single bond or a double bond, Ring E is selected from aryl and heteroaryl, and R5 is selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; Z5 is a hydrophilic substituent as defined herein; q is an integer from 0 to 1, e is an integer from 0 to 1, (50) L is absent or selected from the group of the following formulae: [ka] During the ceremony, R5 is selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; Z5 is a hydrophilic substituent as defined herein; q is an integer from 0 to 1, e is an integer from 0 to 1, (51) L is absent or is selected from the group of the following formulae: [ka] During the ceremony, R5 is selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, and mercapto; Z5 is a hydrophilic substituent as defined herein, and q is 1, (52) c and d are integers independently selected from 0 to 4 (e.g., 0 to 3); (53) c and d are integers independently selected from 1 to 3; (54) One of c and d is 3, and the other is an integer selected from 0 to 3; (55) One of c and d is 3, and the other is an integer selected from 1 to 3; (56) Both c and d are 3, (57) a and b are integers independently selected from 0 to 1; (58) a and b are 0, (59) m, n, o, and p are integers independently selected from 0 to 1; (60) m and n are 1, and o and p are 0.

[0057] It will be readily understood that in the above paragraphs (39) to (44), the term "generation" refers to the number of layers of building units (e.g., groups of formula A) that make up the dendritic group. The term "generation" is a term commonly used in the art in the field of dendrimer chemistry and will be readily understood by those skilled in the art. For example, it will be understood that a first-generation dendritic group has one layer (generation) of building units, e.g., [[building units]]. A second-generation dendritic group has two layers of building units, e.g., if the building units have trifunctional branch points, the dendritic group may be [[building units][building units]3], and a third-generation dendritic group has three layers of building units, e.g., [[building units]3[building units]9]. In this regard, those skilled in the art will understand that when a dendritic group comprises first-generation building units of formula A, [ka] It will be readily understood that indicates the point of attachment of the terminal functional group T1. Furthermore, if the dendritic group comprises two generation building units of formula A, one skilled in the art will recognize that for the first generation building units of formula A, [ka] But for the attachment points of the second generation building units of formula A, and for the second generation building units of formula A, [ka] It will be understood that indicates the point of attachment of the terminal functional group T1.

[0058] For illustrative purposes only, below are provided schematic diagrams of both dendritic groups comprising first generation building units of formula A, and dendritic groups comprising second generation building units of formula A. In this schematic diagram, A corresponds to a building unit of formula A having a trifunctional branch point, as described hereinabove, and T1 corresponds to a terminal functional group T1, as described hereinabove. [ka]

[0059] In one embodiment, at least one of the integers m, n, o, or p is greater than or equal to 1. In this regard, it will be understood that at least one of Z1, Z2, Z3, Z4, or Z5 is present.

[0060] In another embodiment, the (transferable) reporter molecule is attached to the compound of formula I via one or more substituents R1, R2, R3, R4, Z1, Z2, Z3, Z4 or Z5. Suitably, the (transferable) reporter molecule is attached to the compound of formula I via one or more hydrophilic substituents Z1, Z2, Z3, Z4 or Z5. It will be appreciated that the (transferable) reporter molecule may be attached to one or more substituents R1, R2, R3, R4, Z1, Z2, Z3, Z4 or Z5 directly or via a suitable linker (e.g. a polyethylene glycol linker). Suitably, the (transferable) reporter molecule is attached to one or more substituents Z1, Z2, Z3, Z4 or Z5.

[0061] Suitably, the (transferable) reporter molecule is an aromatic molecule and / or a dye molecule. More suitably, the (transferable) reporter molecule is an aromatic molecule, most suitably a fluorescent aromatic molecule (e.g., fluoresceinamine or tetramethylrhodamine isothiocyanate).

[0062] Compounds of formula I, as defined above, may be prepared by adding one or more substituents R 1a , R 1b , R 2a, R 2b , R1, R2, R3, R 4、 Z1, Z2, Z3, Z4 and / or Z5 (e.g., one or more substituents R1 or R2 or one or more substituents R3 or R4) may optionally be attached at a position relative to Z1, Z2, Z3, Z4 and / or Z5 (e.g., one or more substituents R1 or R2 or one or more substituents R3 or R4). Thus, the substituents of formula A1 may be optionally attached at a position relative to one or more substituents R 1a , R 1b , R 2a , R 2b , R1, R2, R3, R 4、 Z1, Z2, Z3, Z4 and / or Z5 may be located in the position of one or more substituents R 1a , R 1b , R 2a , R 2b , R1, R2, R3, R 4、 It will be understood that Z1, Z2, Z3, Z4 and / or Z5 may be attached to Z. Suitably, when present, the substituents of formula A1 may be attached to one or more substituents R 1a , R 1b , R 2a , R 2b , R1, R2, R3, R 4、 Take place at Z1, Z2, Z3, Z4 and / or Z5.

[0063] In one embodiment, the compound of formula I may contain one or more substituents R 1a , R 1b , R 2a , R 2b may be optionally attached to a substituent of formula A1 at a position relative to R1, R2, R3 and / or R4 (e.g., one or more substituents R1 or R2 and / or one or more substituents R3 or R4), wherein the substituent of formula A1 is X 2a -L 2a -Z 2a (Formula A1) During the ceremony X 2a is absent or O, S, SO, SO2, N(R x2 ), C(O), C(O)O, OC(O), C(O)N(R x2 ) and N(Rx2 )C(O), and R x2 is selected from hydrogen and (1-4C)alkyl; L 2a is absent or selected from (1-20C)alkylene, (1-20C)alkyleneoxide, (1-20C)alkenyl, and (1-20C)alkynyl, each of which is optionally substituted by one or more substituents selected from (1-2C)alkyl, aryl, and oxo; Z 2a is carboxy, carbamoyl, sulfamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , ONR xc R xd , C(O)X a , C(O)OR xf , N=C=O, NR xc C(O)CH2X b , C(O)N(R xe )NR Xc R Xd , S(O) y X a (y is 0, 1 or 2), SO2N(R xe )NR xc R xd , Si(R xg )(R xh )R xi and an amino acid, During the ceremony, X a is hydrogen or a leaving group (e.g., halo or CF), X b is a halo (e.g., iodo), R xc , R xd and R xe are each independently selected from hydrogen and (1-6C)alkyl; R xf is selected from hydrogen and (1-6C) alkyl, or R xf is C(O)OR xfis a substituent that, taken together, forms an activated ester (e.g., a hydroxysuccinimide ester, a hydroxy-3-sulfo-succinimide ester, or a pentafluorophenyl ester); R xg , R xh and R xi are each independently selected from (1-4C)alkyl, hydroxy, halo, and (1-4C)alkoxy.

[0064] In another embodiment, the compound of formula I may further comprise one or more substituents R 1a , R 1b , R 2a , R 2b , optionally attached at positions relative to R1, R2, R3 and / or R4, the substituent of formula A1 is X 2a -L 2a -Z 2a (Formula A1) During the ceremony X 2a is absent or O, S, SO, SO2, N(R x2 ), C(O), C(O)O, OC(O), C(O)N(R x2 ) and N(R x2 )C(O), and R x2 is selected from hydrogen and (1-4C)alkyl; L 2a is absent or selected from (1-20C)alkylene, (1-20C)alkyleneoxide, (1-20C)alkenyl, and (1-20C)alkynyl, each of which is optionally substituted by one or more substituents selected from (1-2C)alkyl, aryl, and oxo; Z 2a is carboxy, carbamoyl, sulfamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , C(O)X a , C(O)OR xf, N=C=O, NR xc C(O)CH2X b and C(O)N(R xe )NR Xc R Xd is selected from During the ceremony, X a is hydrogen or a leaving group (e.g., halo or CF), X b is a halo (e.g., iodo), R xc , R xd and R xe are each independently selected from hydrogen and (1-6C)alkyl; R xf is selected from hydrogen and (1-6C) alkyl, or R xf is C(O)OR xf is a substituent that, taken together, forms an activated ester (e.g., a hydroxysuccinimide ester, a hydroxy-3-sulfo-succinimide ester, or a pentafluorophenyl ester); R xg , R xh and R xi are each independently selected from (1-4C)alkyl, hydroxy, halo, and (1-4C)alkoxy.

[0065] In a further embodiment, the compound of formula I has one or more substituents R 1a , R 1b , R 2a , R 2b , optionally attached at positions relative to R1, R2, R3 and / or R4, the substituent of formula A1 is X 2a -L 2a -Z 2a (Formula A1) During the ceremony X 2a is not present or O,N(R x2 ), C(O)O, OC(O), C(O)N(R x2 ) and N(R x2)C(O), and R x2 is selected from hydrogen and (1-4C)alkyl; L 2a is absent or selected from (1-20C)alkylene, (1-20C)alkyleneoxide, (1-20C)alkenyl, and (1-20C)alkynyl, each of which is optionally substituted by one or more substituents selected from (1-2C)alkyl, and oxo; Z 2a is carboxy, carbamoyl, sulfamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , C(O)OR xf and N=C=O; During the ceremony, R xc , and R xd are each independently selected from hydrogen and (1-6C)alkyl; R xf is selected from hydrogen and (1-6C) alkyl, or R xf is C(O)OR xf are substituents that, taken together, result in an activated ester (eg, a hydroxysuccinimide ester, a hydroxy-3-sulfo-succinimide ester, or a pentafluorophenyl ester).

[0066] In still further embodiments, the compound of formula I is a compound of formula A1, wherein the substituent of formula A1 is one or more substituents R 1a , R 1b , R 2a , R 2b , optionally attached at positions relative to R1, R2, R3 and / or R4, the substituent of formula A1 is X 2a -L 2a -Z 2a (Formula A1) During the ceremony X 2a is not present or O,N(R x2), C(O)O, and C(O)N(R x2 ) and R x2 is selected from hydrogen and (1-4C)alkyl; L 2a is absent or selected from (1-10C)alkylene, (1-10C)alkyleneoxide, (1-10C)alkenyl, and (1-10C)alkynyl, each of which is optionally substituted by one or more substituents selected from (1-2C)alkyl, and oxo; Z 2a is carboxy, carbamoyl, sulfamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , C(O)OR xf and N=C=O; During the ceremony, R xc , and R xd are each independently selected from hydrogen and (1-6C)alkyl; R xf is selected from hydrogen, (1-6C)alkyl, succinimide, 3-sulfo-succinimide, and pentafluorophenyl.

[0067] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group containing one, two or three heteroatoms selected from N, O or S.

[0068] Suitably, the heteroaryl is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0069] Suitably, the heterocyclyl group is a 4-, 5-, or 6-membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, O, or S. Most optimally, the heterocyclyl group is a 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms selected from N, O, or S [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl].

[0070] Suitably the aryl group is phenyl or anthracenyl, most suitably phenyl.

[0071] Suitably, bonds b1 and b2 are as defined in either one of paragraphs (1) or (2) above.

[0072] Appropriately, R 1a , R 1b , R 2a and R 2b is as defined in any one of paragraphs (3) to (5) above. Most appropriately, R 1a , R 1b , R 2a and R 2b is defined in paragraph (5) above.

[0073] Suitably, rings A and B are as defined in any one of paragraphs (6) to (10) above. Most suitably, rings A and B are phenyl.

[0074] Suitably, R1 and R2 are as defined in any one of paragraphs (11)-(12) above.

[0075] Suitably, C and D are as defined in any one of paragraphs (13) to (18) above. Most suitably, C and D are as defined in any one of paragraphs (17) to (18) above.

[0076] Suitably, R3 and R4 are as defined in any one of paragraphs (19) to (28) above. Most suitably, R3 and R4 are as defined in paragraph (28) above.

[0077] Suitably, W1, W2, W3 and W4 are as defined in either one of paragraphs (29) or (30) above.

[0078] Suitably, X1, X2, X3 and X4 are as defined in any one of paragraphs (31) to (33) above. Most suitably, X1, X2, X3 and X4 are as defined in paragraph (33) above.

[0079] Suitably, Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (34) to (44) above. Most suitably, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (44) above.

[0080] Suitably, L is as defined in any one of paragraphs (45) to (51) above.

[0081] Suitably, integers c and d are as defined in any one of paragraphs (52) to (56) above.

[0082] Suitably, the integers a and b are as defined in any one of paragraphs (57) to (58) above.

[0083] Suitably, the integers m, n, o and p are as defined in any one of paragraphs (59) to (60) above.

[0084] In certain groups of compounds of the invention, R 1a and R 1b is R 2a and R 2btogether to form rings A and B, respectively, i.e., the compound has structural formula Ia (a subdefinition of formula (I)) as shown below, or a salt, hydrate and / or solvate thereof: [ka] wherein each bond b1 and b2, R1, R2, R3, R4, Z1, Z2, Z3, Z4, a, b, c, d, m, n, o, p, L, C, D and rings A and B are as defined herein above.

[0085] In one embodiment of the compound of formula Ia, Bonds b1 and b2 are as defined in either paragraph (1) or (2) above; Rings A and B are defined in any one of paragraphs (6) to (10) above; R1 and R2 are defined in any one of paragraphs (11)-(12) above; C and D are as defined in any one of paragraphs (13) to (18) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; W1, W2, W3, and W4 are as defined in any one of paragraphs (29)-(30) above; X1, X2, X3 and X4 are defined in any one of paragraphs (31) to (33) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (34) to (44) above; L is as defined in any one of paragraphs (45) to (51) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0086] In another embodiment of the compound of formula Ia, Bonds b1 and b2 are as defined in paragraph (2) above; Rings A and B are as defined in paragraph (10) above; R1 and R2 are as defined in paragraph (12) above; C and D are as defined in either paragraph (17) or (18) above; R3 and R4 are as defined in paragraph (28) above; W1, W2, W3, and W4 are as defined in paragraph (30) above; X1, X2, X3 and X4 are as defined in paragraph (33) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (42) to (44) above; L is as defined in paragraph (51) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0087] In certain groups of compounds of the invention, R 1a and R 1b is R 2a and R 2b together form rings A and B, respectively, and Q is O, and W1, W2, W3, and W4 are CH2, i.e., the compound has the structural formula Ib (a subdefinition of formula (I)) shown below, or a salt, hydrate, and / or solvate thereof: [ka] wherein each bond b1 and b2, R1, R2, R3, R4, Z1, Z2, Z3, Z4, a, b, c, d, m, n, o, p, L, C, D and rings A and B are as defined herein above.

[0088] In one embodiment of the compound of formula Ib, Bonds b1 and b2 are as defined in either paragraph (1) or (2) above; Rings A and B are defined in any one of paragraphs (6) to (10) above; R1 and R2 are defined in any one of paragraphs (11)-(12) above; C and D are as defined in any one of paragraphs (13) to (18) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (34) to (44) above; L is as defined in any one of paragraphs (45) to (51) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0089] In another embodiment of the compound of formula Ib, Bonds b1 and b2 are as defined in paragraph (2) above; Rings A and B are as defined in paragraph (10) above; R1 and R2 are as defined in paragraph (12) above; C and D are as defined in either paragraph (17) or (18) above; R3 and R4 are as defined in paragraph (28) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (40) to (44) above; L is as defined in paragraph (51) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0090] In another particular group of compounds of the invention, R 1a and R 1b is R 2a and R 2b are linked together to form rings A and B, respectively, Q is O, W1, W2, W3, and W4 are CH2, and L is as shown below, i.e., the compound has the structural formula Ic (a subdefinition of formula (I)) as shown below, or a salt, hydrate, and / or solvate thereof, [ka] wherein each bond b1, b2 and b3, R1, R2, R3, R4, R5, Z1, Z2, Z3, Z4, Z5, a, b, c, d, e, m, n, o, p, q, C, D and rings A, B and E are as defined herein above.

[0091] In one embodiment of the compound of formula Ic, Bonds b1 and b2 are as defined in either paragraph (1) or (2) above; Rings A and B are defined in any one of paragraphs (6) to (10) above; R1 and R2 are defined in any one of paragraphs (11)-(12) above; C and D are as defined in any one of paragraphs (13) to (18) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (34) to (44) above; Bond b3, ring E, R5 and integers e and q は , as defined in any one of paragraphs (48) to (49) above, the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0092] In another embodiment of the compound of formula Ic, Bonds b1 and b2 are as defined in paragraph (2) above; Rings A and B are as defined in paragraph (10) above; R1 and R2 are as defined in paragraph (12) above; C and D are as defined in any one of paragraphs (17)-(18) above; R3 and R4 are as defined in paragraph (28) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (40) to (44) above; Bond b3, ring E, R5 and integers e and q は , as defined in paragraph (49) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0093] In yet another particular group of compounds of the invention, Q is O, W1, W2, W3 and W4 are CH2, and L is as shown below, rings A, B and E are phenyl, integers m and n are 1, and integers a, b and e are 0, i.e., the compound has structural formula Id (a subdefinition of formula (I)) as shown below, or a salt, hydrate and / or solvate thereof: [ka] wherein R3, R4, Z1, Z2, Z3, Z4, Z5, c, d, o, p, and rings C and D are each as defined hereinabove.

[0094] In one embodiment of the compound of formula Id, Rings C and D are defined in any one of paragraphs (13) to (18) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; Z1, Z2, Z3, Z4 and Z5 are as defined in any one of paragraphs (34) to (44) above; Integers c and d are as defined in any one of paragraphs (42) to (56) above, and The integers o and p are as defined in any one of paragraphs (59)-(60) above.

[0095] In another particular group of compounds of the invention, Q is O, W1, W2, W3 and W4 are CH2, and L is as shown below, rings A, B and E are phenyl, integers m and n are 1, and integers a, b and e are 0, i.e., the compound has structural formula Ie (a subdefinition of formula (I)) as shown below, or a salt, hydrate and / or solvate thereof: [ka] wherein each of Z1, Z2, Z3, Z4 and Z5 is as defined hereinabove; R 3a , R 3b , R 3c , R 4a , R 4b and R 4c are independently selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and the formula: -L 1a -Y 1a -Q 1a During the ceremony, L 1a is absent or is (1-2C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo; Y 1a is absent or O, S, SO, SO2, N(R n ), C(O), C(O)O, OC(O), C(O)N(R n ) and N(R n )C(O) and R n is selected from hydrogen and (1-4C)alkyl, and Q 1a is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl and heterocyclyl; Q 1ais (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR o R p , OR o , C(O)R o , C(O)OR o ,OC(O)R o , C(O)N(R p )R o , N(R p )C(O)R o , S(O) y1 R o (y1 is 0, 1 or 2), SO2N(R p )R o , N(R p )SO2R o , Si(R q )(R p )R o and (CH2) z1 NR o R p (z1 is 1, 2, or 3), and R o , R p and R q are each independently selected from hydrogen and (1-6C)alkyl.

[0096] In one embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are defined in any one of paragraphs (34) to (42) above; R 3a , R 3b , R 3c , R 4a , R 4b , and R 4c are independently selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, and groups of the formula: -L 1a -Y 1a -Q 1a During the ceremony, L 1a is absent or is (1-2C) alkylene; Y 1a is absent or O, S, SO, SO2, N(R l ), C(O), C(O)O, OC(O), C(O)N(R n ) and N(R n )C(O) and R n is selected from hydrogen and (1-4C)alkyl, and Q 1a is hydrogen, (1-8C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-10C) cycloalkyl, (3-10C) cycloalkenyl, heteroaryl or heterocyclyl, and Q 1a is optionally substituted with one or more substituents independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, and mercapto.

[0097] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (42) above; R 3a , R 3b , R 3c , R 4a , R 4b , and R 4c are independently selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, and (2-4C)alkynyl;

[0098] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (42) above; R 3a , R 3b , R 3c , R 4a , R 4b , and R 4c are independently selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, and (2-4C)alkynyl; However, R 3a , R 3b and R 3c cannot all become hydrogen.

[0099] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (42) above; R 3a , R 3b , R 3c , R 4a , R 4b , and R 4c are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, and (2-4C)alkynyl.

[0100] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (44) above; R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently selected from hydrogen and (1-4C)alkyl.

[0101] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (44) above; R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently selected from hydrogen, (1-4C)alkoxy, and (1-4C)alkyl.

[0102] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (44) above; R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently selected from (1-4C)alkoxy, and (1-4C)alkyl.

[0103] In another embodiment of the compound of formula Ie, Z1, Z2, Z3, Z4 and Z5 are as defined in paragraph (44) above; R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently (1-4C) alkyl (e.g., ethyl).

[0104] In still a further group of compounds of the invention, R 1a and R 1b is R 2a and R 2b are linked together to form rings A and B, respectively, and Q is O, L is absent, and W1, W2, W3, and W4 are CH2, i.e., the compound has the structural formula If (a subdefinition of formula (I)) shown below, or a salt, hydrate, and / or solvate thereof: [ka] wherein each bond b1 and b2, R1, R2, R3, R4, Z1, Z2, Z3, Z4, a, b, c, d, m, n, o, p, C, D and rings A and B are as defined herein above.

[0105] In one embodiment of the compound of formula If, Bonds b1 and b2 are as defined in either paragraph (1) or (2) above; Rings A and B are defined in any one of paragraphs (6) to (10) above; R1 and R2 are defined in any one of paragraphs (11)-(12) above; C and D are as defined in any one of paragraphs (13) to (18) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; Z1, Z2, Z3, and Z4 are defined in any one of paragraphs (34) to (44) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0106] In another embodiment of the compound of formula If, Bonds b1 and b2 are as defined in paragraph (2) above; Rings A and B are as defined in paragraph (10) above; R1 and R2 are as defined in paragraph (12) above; C and D are as defined in any one of paragraphs (17)-(18) above; R3 and R4 are as defined in paragraph (28) above; Z1, Z2, Z3, and Z4 are defined in any one of paragraphs (38) to (44) above; the integers c and d are as defined in any one of paragraphs (52) to (56) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (52)-(53) above.

[0107] In another particular group of compounds of the invention, Q is O, L is absent, W1, W2, W3 and W4 are CH2, rings A and B are phenyl and rings C and D are anthracenyl, i.e. the compound has structural formula Ig (subdefinition of formula (I)) as shown below, or a salt, hydrate and / or solvate thereof: [ka] wherein each of R1, R2, R3, R4, Z1, Z2, Z3, Z4, a, b, c, d, m, n, o, and p is as defined above.

[0108] In one embodiment of the compound of formula Ig, R1 and R2 are defined in any one of paragraphs (11)-(12) above; R3 and R4 are defined in any one of paragraphs (19) to (28) above; Z1, Z2, Z3, and Z4 are defined in any one of paragraphs (34) to (44) above; the integers c and d are as defined in paragraph (52) above; Integers a and b are as defined in any one of paragraphs (57)-(58) above, and The integers m, n, o, and p are as defined in any one of paragraphs (59)-(60) above.

[0109] Particular compounds of the present invention include the compounds exemplified in this application, or any of their salts, solvates or hydrates, and particularly any of the following formulae: i) [ka] ii) [ka] iii) [ka] iv) [ka] v) [ka] vi) [ka] vii) [ka] viii) [ka] ix) [ka] x) [ka] xi) [ka] xii) [ka] xiii) [ka] xiv) [ka] xv) [ka] xvi) [ka] xvii) [ka] xviii) [ka] xix) [ka] During the ceremony, Each of Z1, Z2 and Z5 is independently selected from one of the following groups: [ka] In the formula, each R z1 is independently selected from hydrogen or Na (i.e., the carboxy group is either a carboxylic acid or its sodium salt); Each of Z3 and Z4 is a group of the formula: [ka] Z 100 is a base of the formula: [ka] R1 and R2 are groups of the formula: [ka] R 3a and R 4a are independently selected from hydrogen or methoxy; During the ceremony, [ka] indicates the attachment point.

[0110] Particular compounds of the present invention include the compounds exemplified in this application, or any of their salts, solvates or hydrates, and particularly any of the following formulae: i) [ka] ii) [ka] iii) [ka] iv) [ka] v) [ka] vi) [ka] vii) [ka] viii) [ka] ix) [ka] x) [ka] xi) [ka] xii) [ka] xiii) [ka] During the ceremony, Each of Z1, Z2 and Z5 is independently selected from one of the following groups: [ka] Each of Z3 and Z4 is a group of the formula: [ka] Z 100 is a base of the formula: [ka] R 3a and R 4a are independently selected from hydrogen or methoxy; During the ceremony, [ka] indicates the attachment point.

[0111] More particular compounds of the present invention include the compounds exemplified in this application, or any of their salts, solvates or hydrates, and particularly any of the following formulae: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0112] Further particular compounds of the present invention include the compounds exemplified in this application, or any of their salts, solvates or hydrates, and particularly any of the following formulae: i) [ka] wherein each of Z1, Z2, and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, ii) [ka] wherein each of Z1 and Z2 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, iii) [ka] wherein each of Z3 and Z4 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, iv) [ka] wherein each of Z1, Z2, and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, or v) [ka] wherein each of Z2 and Z5 is a group of the formula: [ka] Z 100 is a base of the formula: [ka] During the ceremony, [ka] indicates the attachment point.

[0113] Still more particular compounds of the present invention include the compounds exemplified in this application, or any of the salts, solvates or hydrates thereof, and particularly any of the following formulae: i) [ka] wherein each of Z1, Z2, and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, ii) [ka] wherein each of Z1 and Z2 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, iii) [ka] wherein each of Z3 and Z4 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point.

[0114] Suitably, the compound of the invention is: [ka] wherein each of Z1, Z2, and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point.

[0115] In certain embodiments of the invention, the compound is not: [ka]

[0116] It will be readily understood that the solid and dashed lines used herein above in Formulas I, Ia, Ib, Ic, Id, Ie, If, and Ig are used for illustrative purposes only (i.e., to indicate the relative orientation of the compounds of the present invention) and do not refer to the absolute configuration (i.e., stereochemistry) of the compounds shown.

[0117] Suitable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with, for example, inorganic or organic acids such as, for example, hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, maleic acid, etc. Furthermore, suitable salts of compounds of the present invention that are sufficiently acidic are, for example, alkali metal salts such as, for example, sodium salts or potassium salts, alkaline earth metal salts such as, for example, calcium salts or magnesium salts, ammonium salts, or salts with organic bases that yield an acceptable cation, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0118] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the spatial arrangement of their atoms are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and can be described by the Cahn and Prelog R- and S-sequencing rules or by the way the molecule rotates the plane of polarized light and can be designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0119] The compounds of the present invention may have one or more asymmetric centers, and therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers, or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to encompass both individual enantiomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see, for example, the article in "Advanced Organic Chemistry," Chapter 4, 4th Edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical, diastereomeric, and geometric isomers capable of saccharide recognition, and mixtures thereof.

[0120] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T), C can be in any isotopic form, including 12C, 13C, and 14C, and O can be in any isotopic form, including 16O and 18O.

[0121] It is also understood that certain compounds of formula (I), and sub-formulas Ia to If, may exist in solvated forms, such as, for example, hydrated forms, as well as unsolvated forms, and it is understood that the present invention encompasses all such solvated forms that are capable of saccharide recognition.

[0122] It will also be appreciated that certain compounds of formula (I), and sub-formulas Ia to If, may exhibit polymorphism, and the present invention encompasses all such forms capable of saccharide recognition.

[0123] Compounds of formula (I) and subformulas Ia-Ig may exist in many different tautomeric forms, and references to compounds of formula (I) and subformulas Ia-If include all such forms. For the avoidance of doubt, if a compound exists in any of several tautomeric forms and only one is specifically described or shown, all others are encompassed by formula I. Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, nitro / acinitro. [ka]

[0124] Compounds of formula (I) and subformulas Ia-Ig containing an amine functional group can form N-oxides. Reference herein to a compound of formula I containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1989. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[0125] The present invention may relate to any compound, or particular group of compounds, defined herein by any preferred or suitable feature or otherwise with respect to a particular embodiment, but the present invention may also relate to any compound, or particular group of compounds, that specifically excludes said any preferred or suitable feature or particular embodiment.

[0126] Suitably, the present invention excludes any individual compound that does not have saccharide binding capacity as defined herein. immobilization

[0127] In one embodiment, the compound of the present invention is immobilized on or in a solid or semi-solid support.Those skilled in the art of organic and synthetic chemistry will understand that the term "solid or semi-solid support" refers to any suitable support on which the compound of the present invention can be immobilized or incorporated.Suitably, the solid and / or semi-solid support is selected from a polymer matrix (e.g., polystyrene beads) and / or a gel (e.g., hydrogel or sol-gel).More suitably, the solid support is a polymer matrix (e.g., polystyrene beads), and the semi-solid support is a gel (e.g., hydrogel or sol-gel).

[0128] In one embodiment, the polymeric matrix and / or gel comprises one or more homopolymers, copolymers and / or cross-linked polymers. Suitably, the polymeric matrix and / or gel comprises one or more polymers selected from polyethylene glycol, poloxamer, polyacrylamide, polyacrylate, polyalkylacrylate, polyvinylpyrrolidine, polyvinyl alcohol, polystyrene, polycarboxylic acid ether, polyurethane, polyallyamine, polyethyleneimine, polysaccharides, and mixtures and / or derivatives thereof.

[0129] In one embodiment, the polymer matrix and / or gel comprises one or more water-soluble polymers. Suitably, the polymer matrix and / or gel comprises one or more water-soluble polymers selected from polyethylene glycol, polyacrylamide, polyvinyl alcohol, and polycarboxylate. More suitably, the polymer matrix and / or gel comprises one or more water-soluble polymers selected from polyethylene glycol or polyacrylamide.

[0130] It will be appreciated that the compounds of the present invention may be attached (immobilized) to a solid or semi-solid support by any suitable means known in the art. Thus, attachment of the compounds of the present invention to a solid or semi-solid support may take the form of one or more covalent and / or non-covalent interactions.

[0131] In one embodiment, the compounds of the invention are chemically linked (covalently attached) to the polymeric matrix and / or gel. The compounds of the invention may be chemically linked to the polymeric matrix and / or gel at any suitable position on the compound, and the attachment may take the form of any suitable bond. Suitably, the compounds of the invention are provided with a substituent R 1 , R 2 , R 3 , R 4 , R 1 , Z 1 , Z 2 , Z 3 , Z 4 or Z 5 More suitably, the compounds of the present invention are chemically linked to the polymeric matrix and / or gel via one or more of the substituents associated with at least one of the substituents Z1, Z2, Z3, Z4 or Z5.

[0132] In one embodiment, the compound of the present invention is chemically linked (covalently bonded) to the polymer matrix and / or gel via a linker L2. Of course, the linker L2 may be any group capable of forming a covalent bond between the compound of the present invention and the polymer matrix and / or gel. The linker L2 may take the form of a bond (e.g., an amide bond) or may be in the form of a suitable cross-linker molecule used to link the compound of the present invention to the polymer matrix and / or gel. Those skilled in the art will be able to select a suitable cross-linker molecule for use in covalently bonding the compound of the present invention to the polymer matrix and / or gel.

[0133] In another embodiment, the compounds of the present invention are associated with and / or physically incorporated into the polymer matrix and / or gel through non-covalent interactions. Of course, any suitable non-covalent interaction can be utilized for the association between the compounds of the present invention and the polymer matrix and / or gel. Non-limiting examples of suitable non-covalent interactions include hydrogen bonding interactions, ionic interactions, hydrophobic interactions, van der Waals interactions, and combinations thereof. synthesis

[0134] The compounds of the present invention may be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further illustrated in the accompanying Examples.

[0135] In the description of synthetic methods provided herein, and in any reference synthetic methods used to prepare starting materials, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental time, and work-up procedure, can be selected by one of ordinary skill in the art.

[0136] It is understood by one skilled in the art of organic synthesis that the functions present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0137] It will be understood that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of particular starting materials, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the art will understand that when such protection is necessary, such protecting groups may be put in place and subsequently removed.

[0138] For examples of protecting groups, see one of the many general texts on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist appropriate for the removal of the protecting group in question, such method being chosen to effect removal of the protecting group with minimal disturbance of groups elsewhere in the molecule.

[0139] Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group for some of the reactions mentioned herein.

[0140] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The protection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups, or aroyl groups can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl, can be removed by hydrogenation over a catalyst, such as palladium on carbon, or by treatment with a Lewis acid, such as boron tris(trifluoroacetic acid). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0141] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, aroyl groups, for example, benzoyl, or arylmethyl groups, for example, benzyl. The protection conditions for the above protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl, or aroyl groups, can be removed by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example, lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation over a catalyst, for example, palladium on carbon.

[0142] Suitable protecting groups for carboxy groups are, for example, esterifying groups, such as methyl or ethyl groups, which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, a t-butyl group, which may be removed, for example, by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or, for example, a benzyl group, which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0143] Resins can also be used as protecting groups.

[0144] The methods used to synthesize compounds of formula (I) vary depending on the nature of rings A and B, C, D, R1, R2, R3, R4, W1, W2, W3, W4, X1, X2, X3, X4, Z1, Z2, Z3, Z4, Z5, L, a, b, c, d, m, n, o, p, and any substituents associated therewith. Suitable processes for their preparation are further illustrated in the accompanying Examples.

[0145] In certain embodiments, compounds of the present invention (ie, compounds of formula (I)) are prepared according to Method A or Method B shown below. Method A a compound of formula III, as shown below: [ka] wherein bonds b1 and b2, rings A and B, D, W1, W4, X1, X4, Z1, Z2, Z4, R1, R2, R4 and integers a, b, d, m, n and p are as defined herein above, and q 1 is an integer selected from 0 or 1, with a compound of formula IV [ka] wherein C, R3, Z3, c and o are as defined hereinabove; 1 is an integer from 0 to 1, and E1, E2, and E3 are each selected from groups of formula X1 shown below. [ka] During the ceremony, [ka] denotes the attachment point, and Y1 is O, S or NR j Selected from R j is defined herein. and thereafter, at will, as necessary. i) removing any protecting groups present; ii) converting a compound of formula (I) into another compound of formula (I), and / or iii) forming a salt, hydrate, or solvate thereof; Method B a compound of formula V, as shown below: [ka] wherein bonds b1 and b2, rings A and B, D, W1, W4, X1, X4, Z1, Z2, Z4, R1, R2, R4 and integers a, b, d, m, n and p are as defined herein above; and q 2is an integer selected from 0 or 1, and E4, E5 and E6 are each selected from the group of formula X2 shown below. [ka] During the ceremony, [ka] denotes the attachment point, and Y2 is O, S or NR j Selected from R j is defined herein. with a compound of formula VI. [ka] wherein C, R3, Z3 and integers c and o are as defined hereinabove; W 2 is an integer between 0 and 1. and thereafter, at will, as necessary. i) removing any protecting groups present; ii) converting a compound of formula (I) into another compound of formula (I), and / or iii) forming salts, hydrates, or solvates thereof;

[0146] Suitably, methods A and / or B described herein above are carried out in the presence of one or more of the following: - Bases - Templates - catalyst, and / or - Activator

[0147] In one embodiment, Method A and / or B is carried out in the presence of a base. Non-limiting examples of suitable bases include NaOH, KOH, potassium tert-butoxide, trimethylamine, diisopropylethylamine, diisopropylmethylamine, N-methylmorpholine, piperidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-dimethylpyridine, methylimidazole, 4-(dimethylamino)pyridine (DMAP), and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU). Suitably, the base is pyridine, 4-(dimethylamino)pyridine (DMAP) or methylimidazole. Most suitably, the base is pyridine.

[0148] In another embodiment, Methods A and / or B are carried out in the presence of a template. The term "template" is understood as a term in the art and refers to a molecule that can reversibly associate with one or more starting materials and / or intermediates and / or final products of a reaction, thereby serving to facilitate the production of one or more final products of the reaction. Non-limiting examples of suitable templates include octyl-β-glucoside, methyl-β-glucoside, octyl-β-galactoside, methyl-β-galactoside, octyl-β-mannoside, and methyl-β-mannoside. Suitably, the template is octyl-β-glucoside.

[0149] It will be understood that the template can be used in any suitable amount. Suitably, the molar ratio of template to compound of formula III or compound of formula V is 0.1:1 to 10:1. More suitably, the molar ratio of template to compound of formula III or compound of formula V is 0.5:1 to 5:1. Most suitably, the molar ratio of template to compound of formula III or compound of formula V is 0.5:1 to 2:1.

[0150] In certain embodiments, Method A and / or Method B are carried out in the presence of a base (eg, 4-dimethylaminopyridine) and a template (eg, octyl-β-glucoside).

[0151] In certain embodiments, Methods A and B may be carried out in the presence of one or both of a catalyst and / or an activator. The term "catalyst" will be understood to mean any suitable reagent that serves to accelerate the rate of reaction between compounds of Formulae III and IV and V and VI without undergoing any permanent chemical change, while the term "activator" will be understood to mean any suitable agent that reacts with one or more of the starting materials of the reaction to serve to accelerate the reactivity of said starting materials in the reaction.

[0152] Of course, any suitable reaction conditions can be used in Methods A and B defined hereinabove. Furthermore, it will be understood that the reaction conditions used in Methods A and B will vary according to the particular functional groups present. One of ordinary skill in the art will be able to select appropriate reaction conditions (e.g., temperature, pressure, reaction time, concentration, etc.) for use in either Method A or Method B.

[0153] In one embodiment, Methods A and / or B are carried out at a temperature of from -100°C to 200°C. Suitably, the process of the invention is carried out at a temperature of from 0°C to 150°C. More suitably, the process of the invention is carried out at a temperature of from 0°C to 100°C. Most suitably, the process of the invention is carried out at a temperature of from 0°C to 75°C.

[0154] In another embodiment, Method A and / or B is carried out in an organic solvent. The organic solvent can be used to dissolve the compounds of Formula III, IV, V, and VI, thereby facilitating the reaction therebetween. Therefore, it will be understood that the organic solvent selected will depend on the specific compound selected. Suitable organic solvents may include, but are not limited to, chloroform, dichloromethane, DMF, DMSO, acetonitrile, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 2-methyltetrahydrofuran (2M-THF), and mixtures thereof.

[0155] In certain embodiments, Method A and / or Method B are carried out in pyridine.

[0156] In another embodiment, Methods A and / or B are carried out under anhydrous conditions.

[0157] In a further embodiment, Methods A and B are carried out under an inert atmosphere (ie, nitrogren or argon).

[0158] The resulting compounds of the present invention (i.e., compounds of formula (I)) can be isolated and purified using techniques well known in the art. A non-limiting example of a suitable technique is chromatography, particularly high performance liquid chromatography (HPLC). Intermediates

[0159] In another aspect, the present invention provides novel intermediates, as defined herein, which are suitable for use in the synthetic methods described herein.

[0160] Thus, in certain aspects of the present invention, there is provided a compound of Formula III or Formula V, or a salt, solvate, ester, or hydrate thereof, as shown below: [ka] [ka] In the formula, each bond b1 and b2, rings A and B, D, W1, W4, X1, X4, Z1, Z2, Z4, R1, R2, R4, a, b, d, m, n, p, E4, E5, E6, q 1 and q 2 is as defined above.

[0161] It will be understood that the preferred and suitable substituents for each of rings A and B, D, W1, W4, X1, X4, Z1, Z2, Z4, R1, R2, R4, a, b, d, m, n, and p for compounds of formula III are similar to the preferred and suitable substituents for each of rings A and B, D, W1, W4, X1, X4, Z1, Z2, Z4, R1, R2, R4, a, b, d, m, n, and p for compounds of formula (I) described hereinabove.

[0162] In certain embodiments, the compounds of Formula III and / or Formula V may comprise one or more substituents R 1a , R 1b , R 2a , R 2b , R1, R2, R3, R4, Z1, Z2, Z3, Z4 and / or Z5 may be optionally attached to a substituent of formula A1 as defined hereinabove.

[0163] In certain embodiments, the present invention provides the following compound, or a salt, solvate, ester, or hydrate thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, R z is selected from -OCH2C(O)ONa, -OCH2C(O)OC(CH3)3 or -OCH2C(O)OCH3; R1 is a group of the formula: [ka] Z 1、 Each of Z2 and Z5 is a group of the formula: [ka] each Z 100 is a base of the formula: [ka] and Z 1a , Z 2a and Z 5a is selected from the following: [ka] During the ceremony, [ka] indicates the attachment point, or [ka] In the formula, Z 1’ , Z 2’、 and Z 5’ is a base of the formula: [ka]

[0164] In certain embodiments, the present invention provides the following compound, or a salt, solvate, ester, or hydrate thereof: [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, R z is selected from -OCH2C(O)ONa, -OCH2C(O)OC(CH3)3 or -OCH2C(O)OCH3, and Z 1、 Each of Z2 and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point, or [ka] In the formula, Z 1’ , Z 2’、 and Z 5’ is a base of the formula: [ka]

[0165] In another specific embodiment, the present invention provides the following compound, or a salt, solvate, ester, or hydrate thereof: [ka] During the ceremony, R z is selected from -OCH2C(O)ONa, -OCH2C(O)OC(CH3)3 or -OCH2C(O)OCH3, and Z 1、 Each of Z2 and Z5 is a group of the formula: [ka] During the ceremony, [ka] indicates the attachment point. sugar recognition

[0166] The compounds of the present invention can advantageously associate with one or more target sugars in an aqueous medium. It will be understood that the association between the compounds of the present invention and one or more target sugars can involve one or more covalent and / or non-covalent interactions therebetween. Suitably, the compounds of the present invention can associate with one or more target sugars solely through non-covalent interactions (e.g., C—P interactions, Van der Waal interactions, and polar interactions), advantageously making the compounds of the present invention suitable for use in reversible sugar binding and subsequent sequential sugar detection.

[0167] To measure the saccharide binding affinity of the compounds of the present invention, isothermal titration calorimetry (ITC) studies may be used, as described in the Examples section herein below. Of course, other suitable techniques known in the art may also be used to measure saccharide binding affinity. Non-limiting examples of other suitable techniques include fluorescence titration, UV-visible titration, and / or 1 H NMR titration is an example.

[0168] Although the saccharide binding affinity of compounds of Formula I changes with structural changes, as expected, compounds of the present invention have been found to exhibit saccharide (e.g., glucose) binding affinity in ITC studies as described in the Examples section herein below.

[0169] In general, compounds of the present invention exhibit activity at 10 M or higher in the ITC studies described in the Examples section herein below. -1 Suitably, the compounds of the present invention exhibit a binding affinity (Ka) for a target sugar (e.g., glucose) in water of 50M or greater. -1 More suitably, the compounds of the present invention exhibit a binding affinity (Ka) for a target sugar (e.g., glucose) in water of 100M or greater. -1 Even more suitably, the compounds of the present invention exhibit a binding affinity (Ka) for a target sugar (e.g., glucose) in water of 500M or greater. -1 Even more suitably, the compounds of the present invention exhibit a binding affinity (Ka) for a target sugar (e.g., glucose) in water of 1000M or greater. -1 Most suitably, the compounds of the present invention exhibit a binding affinity (Ka) for the target sugar (e.g., glucose) in water of 2000M or greater. -1 The binding affinity (Ka) for the target sugar (e.g., glucose) in water is shown.

[0170] In certain embodiments, the compounds of the present invention are -1 Above, most appropriately 10000M -1 The binding affinity (Ka) for the target sugar (e.g., glucose) in water is shown.

[0171] The compounds of the invention also advantageously exhibit selectivity for saccharides containing all-equatorial substituents over those containing at least one axial substituent (e.g., mannose). In certain embodiments, the compounds of the invention also exhibit selectivity for monosaccharides over disaccharides, trisaccharides, and oligosaccharides.

[0172] Suitably, the compounds of the invention have a high binding affinity (K a ) which exhibits a binding affinity (K) for saccharides containing at least one axial substituent (e.g., mannose). a ) is at least two times higher than the binding affinity (K a ) which exhibits a binding affinity (K) for saccharides containing at least one axial substituent (e.g., mannose). a Even more suitably, the compounds of the present invention have a binding affinity (K a ) which exhibits a binding affinity (K) for saccharides containing at least one axial substituent (e.g., mannose). a Even more suitably, the compounds of the present invention have a binding affinity (K a ) which exhibits a binding affinity (K) for saccharides containing at least one axial substituent (e.g., mannose). a ) is at least 100 times higher. Most suitably, the compounds of the present invention have a binding affinity (K a ) which exhibits a binding affinity (K) for saccharides containing at least one axial substituent (e.g., mannose). a ) is at least 500 times higher.

[0173] Furthermore, the compounds of the present invention advantageously exhibit selectivity for sugars containing all-equatorial substituents (e.g., glucose) over other commonly occurring small molecules. Non-limiting examples of such commonly occurring small molecules include purines and pyrimidines (e.g., cytidine, adenosine, guanosine, uridine, adenine, cytosine, thymine, uracil, uric acid, hypoxanthine, and xanthine), organic acids (e.g., glutaric acid and glutamic acid), and amino acids (e.g., histidine, phenylanaline, tryptophan, etc.). One problem commonly associated with sugar receptors known in the art is that they often exhibit some affinity for such small molecules, which, when present, effectively "poison" the receptor's affinity for the target sugar. Advantageously, the compounds of the present invention do not suffer from such "toxic" effects because they have little affinity for such small molecules. Complexes and Compositions

[0174] According to a further aspect of the present invention there is provided a conjugate comprising a compound of the invention as defined herein in association with a target sugar.

[0175] It will be understood that the preferred and suitable compounds of the invention with respect to the conjugates are analogous to the preferred and suitable compounds described above with respect to the compounds of the invention per se.

[0176] In one embodiment, the target sugar is a saccharide containing all-equatorial substituents. More suitably, the target sugar is a monosaccharide containing all-equatorial substituents. Most suitably, the target sugar is glucose (e.g., β-glucose).

[0177] In another aspect of the invention there is provided a complex comprising a compound of the invention as defined herein in association with a transferable reporter molecule.

[0178] In one embodiment, the complex comprises a compound of formula Ib, Ic or Id as defined herein in association with a transferable receptor molecule.

[0179] A displaceable reporter molecule is understood to be any compound that can associate (bind) with a compound of the invention in the absence of a target sugar (e.g., glucose), that can dissociate from a compound of the invention, and that is detectable upon exposure of the composition to the target sugar.

[0180] In one embodiment, the transferable reporter molecule is an aromatic molecule and / or a dye molecule. Suitably, the transferable reporter molecule is an aromatic molecule. More suitably, the transferable reporter molecule is a fluorescent aromatic molecule (e.g., fluoresceinamine or tetramethylrhodamine isothiocyanate).

[0181] Suitably, the mobile reporter molecule has an emission wavelength of from 300 nm to 1000 nm. More suitably, the mobile reporter molecule has an emission wavelength of from 300 nm to 800 nm. Even more suitably, the mobile reporter molecule has an emission wavelength of from 500 nm to 700 nm.

[0182] In certain embodiments, the transferable reporter molecule is attached to a saccharide (e.g., a glucoside). Suitably, the transferable reporter molecule is attached to the saccharide (e.g., a glucoside) via a linker (e.g., an alkyl linker).

[0183] According to a further aspect of the present invention there is provided a composition comprising a compound of the invention as defined hereinabove, or a salt, hydrate or solvate thereof, and a transferable reporter molecule capable of associating with said compound.

[0184] In one embodiment, there is provided a composition comprising a compound of formula Ib, Ic, or Id as defined herein above, or a salt, hydrate, or solvate thereof, and a transferable reporter molecule capable of associating with said compound.

[0185] Suitably, the transferable reporter molecule is an aromatic and / or dye molecule, most suitably an aromatic molecule, and most suitably a fluorescent aromatic molecule (eg fluoresceinamine or tetramethylrhodamine isothiocyanate).

[0186] In another embodiment, the composition of the invention comprises a diluent and / or carrier. Suitably, the diluent and / or carrier is a pharmaceutically acceptable diluent and / or carrier, for example suitable for veterinary and / or pharmaceutical use (i.e., administration to animals and / or humans).

[0187] According to a further aspect of the present invention there is provided a composition comprising a compound of the invention as defined herein, or a salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent and / or carrier.

[0188] Of course, the composition of the present invention can also contain one or more additional excipients.Additional excipients can be included to improve various properties of the formulation, such as formulation stability, biocompatibility and administration.Those skilled in the art can select suitable excipients based on conventional knowledge in the formulation field.

[0189] A non-limiting list of additional additives that may be added to the compositions of the present invention includes pH adjusters, surfactants, viscosity adjusters, tonicity adjusters, sterilizing agents, preservatives, lubricants, and solubility enhancers.

[0190] In another embodiment, the compositions of the present invention comprise one or more additional saccharide-detecting agents. Suitable saccharide-detecting agents for incorporation into the compositions of the present invention include known saccharide-binding compounds (e.g., boronic acid-based compounds) and / or saccharide-specific enzymes (e.g., glucose oxidase (GOx)).

[0191] The compositions of the invention may be obtained by any conventional procedure using conventional formulation excipients well known in the art. Uses, Devices and Kits

[0192] The present invention provides compounds that exhibit sugar (e.g., glucose) binding affinity in water. Furthermore, in certain embodiments, the compounds of the present invention exhibit selectivity for all-equitorial sugars over sugars containing one or more axial substituents.

[0193] Thus, the present invention provides a compound as defined herein (e.g., a compound of formula If or Ig), a conjugate as defined herein, a composition as defined herein, or a sugar detection device as defined herein for detecting a target sugar in an aqueous environment. Suitably, the target sugar is all-equitorial sugars, more suitably all-equitorial monosaccharides, and most suitably glucose (e.g., β-glucose).

[0194] In one embodiment, the aqueous environment is blood or plasma.

[0195] In another embodiment, the aqueous environment is a fermentation and / or cell culture medium.

[0196] In embodiments in which a transferable reporter molecule is used, it will be understood that the transferable reporter molecule is separated from the compound of the invention and then detected upon exposure of the composition or sugar detection device to a target sugar (e.g., glucose).

[0197] According to another aspect of the present invention, there is provided the use of a conjugate as defined herein, a composition as defined herein, a sugar detection device as defined herein, or a compound as defined herein (e.g., a compound of formula If or Ig) for the diagnosis of a condition resulting in or otherwise associated with abnormal and / or altered concentrations of a target sugar. Suitably, the target sugar is all-equitorial sugars, more suitably all-equitorial monosaccharides, and most suitably glucose (e.g., β-glucose).

[0198] In one embodiment, diagnosis of a condition resulting in or otherwise associated with abnormal and / or altered concentrations of a target sugar is performed in vivo.

[0199] In another embodiment, diagnosis of a condition resulting in or otherwise associated with abnormal and / or altered concentrations of a target sugar is performed in vitro or in a sample removed from the human and / or animal body (i.e., a blood sample).

[0200] In a further embodiment, the condition is diabetes.

[0201] According to another aspect of the present invention there is provided a sugar detection device comprising a composition as defined herein or a compound as defined herein.

[0202] Suitably, the device is in a form suitable for introduction into the human and / or animal body. More suitably, the device is in a form suitable for introduction into direct contact with the bloodstream of a human and / or animal patient. Non-limiting examples of devices suitable for introduction into the human and / or animal body include pellets, tablets, capsules, stents and / or chips.

[0203] In another embodiment, the device is configured to be compatible with introduction into fermentation and / or cell culture medium. Non-limiting examples of suitable devices for introduction into fermentation and / or cell culture medium include fiber optic cables and / or stents.

[0204] The excellent binding affinity and selectivity for glucose exhibited by certain compounds of the present invention make them particularly suitable for use in the glucose-responsive insulin-based system, which is well known to those skilled in the art and which is typically activated (e.g., switched on) by increased glucose concentrations.

[0205] Thus, in another aspect of the present invention, there is provided the use of a compound defined herein (e.g., of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig) in the glucose-responsive insulin-based system.

[0206] According to another aspect of the present invention, there is provided a conjugate comprising a compound defined herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig) covalently attached to insulin.

[0207] According to yet another aspect of the present invention, there is provided a kit comprising a compound defined herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig) and insulin.

[0208] In one embodiment, there is provided a kit comprising a compound of Formula Ib, Ic or Id as defined herein and insulin.

[0209] According to a further aspect of the invention there is provided a kit comprising a compound of the invention and a (transferable) reporter molecule.

[0210] In one embodiment, there is provided a kit comprising a compound of formula Ib, Ic or Id as defined herein and a (transferable) reporter molecule. Example [Brief explanation of the drawings]

[0211] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Figure 1] Figure 1 shows a schematic of the key interactions that take place between a target sugar and a compound of the invention (Figures 1a and 1b), as well as a molecular model of the ground-state conformation of one particular compound of the invention with glucose (Figures 1c and 1d). In Figure 1c, ten intermolecular NH...O hydrogen bonds (having distances between 1.9 and 2.2 Å) are visible, and Figure 1d further shows the close C-H contacts formed between the sugar and the compound of the invention. [Figure 2] Figure 2 shows a) a partial H NMR spectrum and b) a binding analysis curve of receptor 1 (0.25 mM) titrated with a mixed solution of D-glucose (9.6 mM) and receptor 1 (0.25 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum represents binding with slow exchange on the NMR timescale. The integral (indicated as ⋅) of the peak at 8.04 ppm relative to the region 8.22–7.21 ppm was plotted against the D-glucose concentration (mM). The calculated integral was overlaid with the observed value, yielding a Ka of 18,026 ± 208 M (1.04%). [Figure 3] Figure 3 shows the H NMR spectrum of receptor 1 (0.25 mM) titrated with a mixed solution of D-glucose (9.6 mM) and receptor 1 (0.25 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. [Figure 4]Figure 4 shows the H NMR spectra of a) α-D-glucose (5 mM) and b) α-D-glucose (5 mM) containing acceptor 1 (0.2 mM) at specific time intervals. The relative integrals of the α-H1 (5.22 ppm) and β-H2 (3.23 ppm) protons over time were calculated to determine whether acceptor 1 affects the rate of anomerization between α- and β-D-glucose. The rate of anomerization was found to be independent of acceptor 1 (see Table 2). [Figure 5] Figure 5 shows a plot of the relative integral of αH1:βH2 versus time (min). The similar slopes suggest that the receptor does not affect the rate of anomerization of D-glucose. [Figure 6] Figure 6 shows the ITC binding results for receptor 1 (0.13 mM) titrated with glucose (7.5 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the accompanying ITC software (Ka = 21,000 ± 2640 M), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 7] Figure 7 shows the ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in 10 mM PBS buffer (pH 7.4). A) shows a blank ITC run (adding sugar to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the included ITC software (Ka = 19,100 ± 1310 M-1), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 8]Figure 8 shows the ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in 10 mM PBS buffer (pH 6). A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the included ITC software (Ka = 19,800 ± 1290 M-1), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 9] Figure 9 shows the ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in 10 mM PBS buffer (pH 8). A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the included ITC software (Ka = 23,400 ± 1850 M-1), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 10] Figure 10 shows the ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in DMEM cell culture medium (no glucose, 10 kJ MWCO, 90% v / v) and 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to medium), B) shows an actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 5637 ± 118 M). [Figure 11]Figure 11 shows the ITC binding results of receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in 10 mM phosphate buffer (pH 7.4) supplemented with salts such as ferric nitrate (0.2 µM), calcium chloride (1.8 mM), magnesium sulfate (0.81 mM), potassium chloride (5.3 mM), sodium bicarbonate (44 mM), sodium chloride (110 mM), and basic sodium phosphate (0.9 mM). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 5164 ± 303 M). [Figure 12] Figure 12 shows the H NMR spectrum of receptor 1 (0.1 mM) dissolved in DO with 10 mM phosphate buffer (pH 7.4) at 298 K. Addition of MgSO (0.8 mM) and CaCl (1.8 mM), concentrations present in DMEM cell culture medium, to the free receptor showed a small change in the chemical shift (δ units in ppm) for proton s. Addition of two equivalents of D-glucose (0.2 mM) did not saturate the receptor. Addition of the same concentration of glucose to the free receptor in DO without added salt (top spectrum) saturates the receptor, suggesting that Ca and Mg inhibit binding. [Figure 13] Figure 13 shows ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (7 mM) in Leibovitz L-15 cell culture medium (no glucose, 10k MWCO, 90% v / v) and 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to medium), B) shows an actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 5214 ± 452 M). [Figure 14]Figure 14 shows ITC binding results for receptor 1 (0.06 mM) titrated with D-glucose (5 mM) in human serum (no glucose, 10k MWCO, 90% v / v) and 10 mM phosphate buffer (pH 8.5). A) shows a blank ITC run (sugar added to the medium), B) shows an actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 2477 ± 142 M). [Figure 15] Figure 15 shows a) the H NMR spectrum and b) the binding analysis curve of receptor 1 (0.07 mM) titrated with a mixed solution of D-methyl-β-glucoside (10 mM) and receptor 1 (0.07 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum represents binding with slow exchange on the NMR timescale. The integral (indicated as ⋅) of the peak at 8.31 ppm relative to the region 8.36–7.36 ppm was plotted against the guest concentration (mM). The calculated integral was overlaid with the observed value, yielding Ka = 7522 ± 414 M (5.51%). [Figure 16] Figure 16 shows the ITC binding results for receptor 1 (0.13 mM) titrated with methyl-β-D-glucoside (7 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the included ITC software (Ka = 9120 ± 542 M), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 17] Figure 17 shows ITC binding results for receptor 1 (0.06 mM) titrated with methyl-β-D-glucoside (7 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 7886 ± 1296 M). [Figure 18] Figure 18 shows the ITC binding results for receptor 1 (0.1 mM) titrated with D-glucuronic acid (5 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 5348 ± 189 M). [Figure 19] Figure 19 shows the H NMR spectrum of receptor 1 (0.1 mM) titrated with a mixed solution of D-gluconic acid (10 mM) and receptor 1 (0.1 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum indicates that no binding was observed, despite some peak broadening at high guest concentrations. [Figure 20] Figure 20 shows the ITC binding results for receptor 1 (0.06 mM) titrated with glucono-δ-lactone / gluconic acid (200 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to water), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 21] Figure 21 shows a) partial H NMR spectra and b) binding analysis curves of receptor 1 (0.05 mM) titrated with a mixed solution of D-galactose (250 mM) and receptor 1 (0.05 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectra indicate binding with fast / intermediate exchange on the NMR time scale. The change (in μm) in the chemical shift (Δδ ppm) of the peak at 7.63 ppm was plotted against increasing guest concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a Ka of 132 ± 13 M (10.2%). [Figure 22]Figure 22 shows acceptor 1 (0.06 mM) titrated with D-galactose (518 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering acceptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 23] Figure 23 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-galactose (75 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 182 ± 4.2 M). [Figure 24] Figure 24 shows a partial H NMR spectrum of receptor 1 (0.1 mM) titrated with a mixed solution of 2-deoxy-D-glucose (50 mM) and receptor 1 (0.1 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum indicates binding with an intermediate exchange rate on the NMR timescale (a rate between the fast and slow exchange rates between H and H species). The K could not be determined because the peaks of receptor 1 significantly broadened upon guest addition. [Figure 25] Figure 25 shows ITC binding results for receptor 1 (0.06 mM) titrated with 2-detoxoxy-D-glucose (7 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the accompanying ITC software (Ka = 657 ± 90 M), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 26]Figure 26 shows ITC binding results for receptor 1 (0.06 mM) titrated with 2-detoxyl-D-glucose (7 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 725 ± 41 M). [Figure 27] Figure 27 shows a) partial H NMR spectra and b) binding analysis curves of receptor 1 (0.11 mM) titrated with a mixed solution of D-mannose (250 mM) and receptor 1 (0.11 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectra indicate binding with fast / intermediate exchange on the NMR timescale. The change (in μm) in the chemical shift (Δδ ppm) of the peak at 7.63 ppm was plotted against increasing guest concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a Ka of 140 ± 2 M (1.31%). [Figure 28] Figure 28 shows acceptor 1 (0.06 mM) titrated with D-mannose (504 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering acceptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 29] Figure 29 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-mannose (75 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1XX), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 143 ± 1.5 M). [Figure 30]Figure 30 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-xylose (5 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 5804 ± 174 M). [Figure 31] Figure 31 shows the partial H NMR spectrum of receptor 1 (0.11 mM) titrated with a mixed solution of D-cellubiose (250 mM) and receptor 1 (0.11 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum represents slow exchange coupling on the NMR timescale. The integrals (indicated as ⋅) of the peak at 8.02 ppm relative to the region 8.36–7.36 ppm were used to calculate the K (M−1) for each addition time point (see Table 3). The average of these calculations was K = 31 ± 2.66 (9%). [Figure 32] Figure 32 shows ITC binding results for receptor 1 (0.06 mM) titrated with cellobiose (250 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows the actual run (sugar entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio and the goodness of fit calculated with the included ITC software (Ka = 36.6 ± 2.5 M), and D) shows the goodness of fit calculated using an Excel spreadsheet to support the results. [Figure 33] Figure 33 shows ITC binding results for receptor 1 (0.6 mM) titrated with D-cellobiose (250 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 30.9 ± 4.9 M). [Figure 34]Figure 34 shows a) partial H NMR spectra and b) binding analysis curves of receptor 1 (0.11 mM) titrated with a mixed solution of D-fructose (250 mM) and receptor 1 (0.11 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectrum indicates binding with fast / intermediate exchange on the NMR timescale. The change (in μm) in the chemical shift (Δδ ppm) of the peak at 7.63 ppm was plotted against increasing guest concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a Ka of 51 ± 3 M (5.46%). [Figure 35] Figure 35 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-fructose (75 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 60.3 ± 1.6 M). [Figure 36] Figure 36 shows a) partial H NMR spectra and b) binding analysis curves of receptor 1 (0.11 mM) titrated with a mixed solution of D-ribose (250 mM) and receptor 1 (0.11 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The spectra indicate binding with fast exchange on the NMR timescale. The change (in units of ⋅) in the chemical shift (Δδ ppm) of the peak at 7.83 ppm was plotted against increasing guest concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a Ka of 264 ± 10 M (3.96%). [Figure 37]Figure 37 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-ribose (75 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 216.5 ± 4.1 M). [Figure 38] Figure 38 shows a) partial H NMR spectra and b) binding analysis curves for receptor 1 (0.1 mM) titrated with a mixed solution of methyl α-D-glucoside (500 mM) and receptor 1 (0.1 mM) in DO buffered with 10 mM phosphate buffer (pH 7.4) at 298 K. The change (indicated as ·) in the chemical shift (Δδ ppm) of the peak at 7.63 ppm was plotted against increasing guest concentration (mM). The calculated Δδ values ​​are overlaid with the observed values, which effectively indicates that no binding occurs. [Figure 39] Figure 39 shows acceptor 1 (0.06 mM) titrated with methyl-α-D-glucoside (500 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering acceptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 40] Figure 40 shows the ITC binding results for receptor 1 (0.06 mM) titrated with methyl-α-D-glucoside (500 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 41] Figure 41 shows the ITC results for acceptor 1 (0.06 mM) titrated with N-acetyl-D-glucosamine (498 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering acceptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 42]Figure 42 shows the ITC binding results for receptor 1 (0.06 mM) titrated with N-acetyl-D-glucosamine (498 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 43] Figure 43 shows receptor 1 (0.06 mM) titrated with D-uracil (5 mM) in 10 mM PBS buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 44] Figure 44 shows receptor 1 (0.06 mM) titrated with uric acid (2.34 mM) in 10 mM PBS buffer (pH 7.4). A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 45] Figure 45 shows the ITC results of acceptor 1 (0.06 mM) titrated with maltose (500 mM) in HO. A) shows a blank ITC run (sugar added to water), B) shows an actual run (sugar entering acceptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 46] Figure 46 shows ITC binding results for receptor 1 (0.1 mM) titrated with D-mannitol (500 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 47] Figure 47 shows the ITC binding results for receptor 1 (0.06 mM) titrated with paracetamol (87 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to water), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 48] Figure 48 shows the ITC binding results for receptor 1 (0.06 mM) titrated with ascorbic acid (500 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to water), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 49] Figure 49 shows the ITC binding results for receptor 1 (0.06 mM) titrated with L-fucose (500 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to water), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 50] Figure 50 shows the ITC binding results for receptor 1 (0.06 mM) titrated with L-phenylalanine (82 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 51] Figure 51 shows ITC binding results for receptor 1 (0.1 mM) titrated with myo-inositol (5 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 7563 ± 313 M). [Figure 52] Figure 52 shows ITC binding results for receptor 1 (0.1 mM) titrated with adenosine (500 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 53]Figure 53 shows the ITC binding results of receptor 1 (0.1 mM) titrated with cytosine (20 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 54] Figure 54 shows ITC binding results for receptor 1 (0.06 mM) titrated with L-tryptophan (54 mM) in 10 mM phosphate buffer (pH 7.4). A) shows a blank ITC run (substrate added to medium), B) shows an actual run (substrate entering receptor 1), and C) shows the plotted change in enthalpy versus molar ratio. [Figure 55] Figure 55 shows a partial H NMR ROESY spectrum of receptor 1 (2 mM) with D-glucose (5 mM, 2.5 equivalents) in DO. Chemical exchange peaks (black, annotated) link the CH protons on β-D-glucose in the free and bound states. The chemical shifts of glucose protons accompanying signal transfer upon binding are listed in the table. Under these conditions, no signal from bound α-D-glucose was observed. [Figure 56] FIG. 56 shows the structures of substrates tested for affinity to receptor 1. [Figure 57] Figure 57 shows the partial H NMR spectrum (top) and binding analysis curve (bottom) of 90 (1 mM) titrated with a mixed solution of D-glucose (1 M) and 90 (1 mM) in DO at pH 7.4 and 298 K. The change in chemical shift (Δδ, ppm), indicated by ·, was plotted versus the D-glucose concentration (mM). The calculated value of Δδ was overlaid with the observed value, yielding a K = 5.1 ± 0.2 M (3.6%). [Figure 58]Figure 58 shows the partial H NMR spectrum (top) and binding analysis curve (bottom) of 90 (0.25 mM) titrated with a mixed solution of D-cellubiose (250 mM) and 90 (0.25 mM) in DO at pH 7.4 and 298 K. The change in chemical shift (Δδ, ppm), indicated by ·, was plotted against the D-cellubiose concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a Ka of 46 ± 0.4 M (0.89%). [Figure 59] Figure 59 shows the partial H NMR spectrum (top) and binding analysis curve (bottom) of 90 (0.2 mM) titrated with a mixed solution of D-cellotriose (15 mM) and 90 (0.2 mM) in DO at pH 7.4 and 298 K. The change in chemical shift (Δδ, ppm), indicated by ·, was plotted against the D-cellotriose concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a K = 949 ± 2.9 M (0.3%). [Figure 60] Figure 60 shows the partial H NMR spectrum of 90 (0.2 mM) measured in a mixed solution of D-cellotetraose (15 mM) and 90 (0.2 mM) in DO at pH 7.4 and 298 K. The K could not be determined because the spectrum indicates binding with an intermediate exchange rate. [Figure 61] Figure 61 shows the partial H NMR spectrum of 90 (0.2 mM) measured in a mixed solution of D-cellopentaose (15 mM) and 90 (0.2 mM) in DO at pH 7.4 and 298 K. The K could not be determined because the spectrum indicates binding with an intermediate exchange rate. [Figure 62] Figure 62 shows the partial H NMR spectrum (top) and binding analysis curve (bottom) of 90 (0.2 mM) titrated with a mixed solution of D-maltose (500 mM) and 90 (0.2 mM) in DO at pH 7.4 and 298 K. The change in chemical shift (Δδ, ppm), indicated by ·, was plotted against the D-maltose concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a K = 15 ± 1.8 M (11.8%). [Figure 63]Figure 63 shows the partial H NMR spectrum (top) and binding analysis curve (bottom) of 90 (0.2 mM) titrated with a mixed solution of D-maltotriose (500 mM) and 90 (0.2 mM) in DO at pH 7.4 and 298 K. The change in chemical shift (Δδ, ppm), indicated by ·, was plotted against the D-maltotriose concentration (mM). The calculated Δδ was overlaid with the observed value, yielding a K = 20 ± 0.7 M (3.3%). [Figure 64] Figure 64 shows the ITC binding results of 90 (0.2 mM) titrated with D-cellobiose (200 mM) in water at 298 K. A) shows a blank run (substrate added to water), B) shows the titration (substrate entering the acceptor), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 37.6 ± 2.5 M). [Figure 65] Figure 65 shows the ITC binding results of 90 (0.2 mM) titrated with D-cellotriose (15 mM) in water at 298 K. A) shows a blank run (substrate added to water), B) shows the titration (substrate entering the receptor), C) shows the plotted change in enthalpy versus molar ratio, and D) shows the goodness of fit calculated using an Excel spreadsheet (Ka = 955 ± 11 M). [Figure 66] Figure 66 shows a) an ITC titration of d-glucose (7.1 mM) into receptor 4 (0.40 mM) in 10 mM phosphate buffer at 298 K, and b) a magnified image of the injectate kcal mol-1 vs. molar ratio trace. The calculated Ka is 6490 M-1 + / - 72.6 M-1. [Figure 67] Figure 67 shows a) an ITC titration of d-glucose (7.1 mM) into acceptor 5 (0.46 mM) in 10 mM phosphate buffer at 298 K, and b) a magnified image of the injectate kcal mol-1 versus molar ratio trace. Calculated Ka at 10400 M-1 + / - 132 M-1. [Figure 68]Figure 68 shows the H NMR binding analysis curve generated after titrating a mixed solution of β-D-glucose (10 mM) and receptor 7 (127 μM) in 10 mM PB, 140 mM NaCl, DO to a solution of receptor 7 (127 μM) in 10 mM PB, 140 mM NaCl, DO. Ka calculated at 6886 M+ / -190 M. [Figure 69] Figure 69 shows a) an ITC titration of d-glucose (7.1 mM) into receptor 8 (0.42 mM) in 10 mM phosphate buffer at 298 K, and b) a magnified image of the injectate kcal mol-1 versus molar ratio trace. Ka calculated at 4210 M-1 + / - 73 M-1. [Figure 70] Figure 70 shows the H NMR binding analysis curve generated after titrating a mixed solution of β-D-glucose (10 mM) and receptor 9 (210 μM) in 10 mM PB, 140 mM NaCl, DO into a solution of receptor 9 (210 μM) in 10 mM PB, 140 mM NaCl, DO. [Figure 71] Figure 71 shows the H NMR binding analysis curve generated after titrating a mixed solution of β-D-glucose (100 mM) and receptor 10 (250 μM) in 10 mM PB, 140 mM NaCl, and DO into a solution of receptor 10 (250 μM) in 10 mM PB, 140 mM NaCl, and DO. [Figure 72] Figure 72 shows the H NMR binding analysis curve generated after titrating a mixed solution of β-D-glucose (10 mM) and receptor 13 (265 μM) in 10 mM PB, 140 mM NaCl, and DO into a solution of receptor 13 (265 μM) in 10 mM PB, 140 mM NaCl, and DO. [Figure 73] Figure 73 shows partial H NMR spectra of receptor 11 (50 μM) and receptor 11 (50 μM) in DO (pH 7.4, 10 mM PBsoln) titrated with D-glucose (10 mM) supplemented with 10 mM PBsoln. Assuming receptor saturation at approximately 1 mM, half-saturation occurs at 0.5 mM. Therefore, 1 / 0.5 mM = Ka approximately 2000 M. [Figure 74]Figure 74 shows: A) Circular dichroism (CD) spectra and B) binding analysis curves generated after titration of receptor 11 (70 μM) in aqueous solution (pH 7.4 containing 10 mM PBsoln) with D-glucose (10 mM) plus receptor 11 (70 μM) and 10 mM PBsoln. [Figure 75] Figure 75 shows a) an ITC titration of d-glucose (7.73 mM) into acceptor 13 (0.13 mM) in 10 mM phosphate buffer at 298 K, and b) a magnified image of the injectate kcal mol-1 versus molar ratio trace. Ka calculated at 1310 M-1 + / - 33 M-1. [Figure 76] Figure 76 shows a) an ITC titration of d-glucose (7.10 mM) into receptor 3 (0.29 mM) in 10 mM phosphate buffer at 298 K, and b) a magnified image of the injectate kcal mol-1 versus molar ratio trace. Calculated Ka at 5760 M-1 + / - 269 M-1. [Figure 77] Figure 77 shows the H NMR binding analysis curve generated after titrating a mixed solution of β-D-glucose (3.24 M) and receptor 2 (265 μM) in DO into a DO solution of receptor 12 (223 μM) at 298 K.

[0212] material and method Commercially available reagents were purchased from Sigma-Aldrich, Alfa-Aesar, or Acros Organics and used without further purification unless otherwise specified. All air- and water-sensitive manipulations were performed using standard vacuum line and Schlenk techniques or in a dry box containing a purified argon atmosphere. Solvents for air- and water-sensitive manipulations were obtained from the Anhydrous Engineering Solvent Purification System or were distilled and dried over activated molecular sieves.

[0213] Column chromatography was performed using silica gel 60 (Sigma-Aldrich) and appropriate eluents. TLC was performed using aluminum-backed TLC plates (Merck-Keiselgel 60 F254) and visualized using UV fluorescence and / or developed using ninhydrin, potassium permanagante, EtOH / H2SO4, vanillin, Pd(OAc)2 / H2O, or iodine.

[0214] HPLC chromatography was performed using a Waters 600 controller with a Waters 2998 photodiode array detector. For analytical purposes, an XSELECT CSH C18 5 μm (4.6 × 150 mm) column was used, and for preparative purposes, an XSELECT CSH Prep C18 5 μm OBD (19 × 250 mm) column was used, usually using an acetone-water solvent mixture.

[0215] 1 H and 13 C NMR spectra were recorded on a Varian VNMR 400 MHz, a Jeol Eclipse 400 MHz, a Varian VNMR 500 MHz, a Bruker cryogenically cooled 500 MHz, and a Varian VNMR cryogenically cooled S600 MHz spectrometer. All spectra were obtained at ambient temperature unless otherwise stated. 1 H and 13 C NMR chemical shifts are reported relative to tetramethylsilane as an internal standard and in CDCl3, unless otherwise stated, as the solvent. 1 H (residuals) and 13 C chemical shifts are secondary standard.

[0216] IR spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer with an ATR accessory and frequencies are reported in wavenumbers (cm -1ESI-LRMS (electrospray ionization low-resolution mass spectrometry) was performed on a VG Analytical Quattro, ESI-HRMS (electrospray ionization high-resolution mass spectrometry) on a Bruker Daltonics Apex IV, and MALDI-MS (matrix-assisted laser desorption / ionization) on an Applied Biosystems 4700. Elemental analysis was performed on a EuroVector EA3000 Elemental Analyser.

[0217] 1 H-NMR titrations were performed on a Varian VNMR cryogenically cooled S600 spectrometer. Sugar solutions in DO (99.9%) containing known concentrations of acceptor to be used in the experiments were prepared and, if necessary, equilibrated overnight before use. Aliquots were then added to NMR tubes containing known concentrations of acceptor solution (typically 100 μM to 400 μM). Thus, the acceptor concentration was kept constant and the carbohydrate concentration was increased. The sample tubes were shaken after each addition. 1 H-NMR spectra were obtained at 298K.

[0218] Isothermal titration (micro)calorimetry (ITC) experiments were performed on a MicroCal iTC200 microcalorimeter and / or a MicroCal VP-ITC. ITC experiments were performed at 298 K. Sugar solutions were prepared in HPLC-grade water and equilibrated overnight, if necessary. Sample cells were filled with known concentrations of acceptor solution in HPLC-grade water (typically 50 μM-200 μM). Aliquots (typically 1.0 μL) of carbohydrate solution were then added, and heat release was tracked as a function of time. Heats of dilution were measured by injecting the same carbohydrate solution into HPLC-grade water using identical conditions. After each addition, the heat of dilution was subtracted from the heat of binding using the MicroCal software program implemented in ORIGIN 7.0. This resulted in an XY matrix of heat versus total guest concentration. This matrix was then imported into a custom-written Excel program, and the data was fitted to a 1:1 binding model to obtain the Ka. ΔG can be derived from Ka, and ΔS can be derived from ΔH and ΔG using the general thermodynamic equation. This analytical method is compatible with K calculated using MicroCal software. a was used in conjunction with the goodness of fit to validate the results obtained. Synthesis procedure Bicyclic Receptor Synthesis Scheme 1 - Synthetic procedure used for the preparation of 1,3,5-triethyl-2,4,6-tris(isocyanatomethyl)benzene (compound 103) [ka] 1,3,5-triethyl-2,4,6-tris(aminomethyl)benzene (Compound 106) [ka]

[0219] Under an inert N2 atmosphere, 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene 104 (324 mg, 0.74 mmol) was dissolved in anhydrous DMF (4.5 mL) and NaN3 (157 mg, 2.42 mmol) was added. The reaction was heated to 60 °C for 16 h. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with water (3 × 20 mL), dried (MgSO4), and filtered. DMF (4 mL) was added to the filtrate and the solvent was removed in vacuo to a volume of approximately 4 mL. Conversion to trisazide 105 was achieved by 1 The reaction mixture was confirmed by H NMR (220 mg, 0.68 mmol, 92%). The resulting DMF solution was transferred to a degassed anhydrous solution of THF (22 mL) and PMe3 (1 M in THF, 4.1 mL) under an inert N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h, and degassed HO (5 mL) was added, and the reaction mixture was stirred for an additional 16 h. The solvent and excess PMe3 were then evaporated by bubbling N2 through the solution, and the crude residue was suspended in HO (ca. 10 mL). The suspension was then lyophilized to give 106 (148 mg, 0.61 mmol, 90%) as a white solid. 1 H NMR:(400MHz, (CDCl3):1.24(t, J=7.5Hz, 9H, C(1) H ), 2.83(q, J=7.5Hz, 6H, C(2) H ), 3.88(s, 6H, C(5) H 2), 13 C NMR:(100MHz, (CDCl3):δ 16.8( C (1)H2), 22.6( C (2)H), 39.7( C (5)H), 137.4( C 3), 140.4( C 4), LRMS:(ESI + ) Measured value [M+Na] + :272.2 1,3,5-triethyl-2,4,6-tris(isocyanatomethyl)benzene (Compound 103) [ka] Method A

[0220] A flask was charged with 106 (30 mg, 0.12 mmol) and NaHCO (20 mg, 0.24 mmol). CHCl (5 mL) and HO (5 mL) were added, and the mixture was cooled to 0 °C and stirred rapidly. Triphosgene (40 mg, 0.13 mmol) was added, and the reaction mixture was vigorously stirred at room temperature for 1 h. The reaction mixture was diluted with CHCl (20 mL) and brine (10 mL), the organic layer was separated, dried (MgSO), and the solvent was removed in vacuo to give 103 (50 mg, 0.166 mmol, 78%) as a colorless oil. Method B

[0221] Under an inert N2 atmosphere, a flask was charged with triphosgene (1.81 g, 6.1 mmol). Anhydrous toluene (70 mL) was added. A solution of 106 (500 mg, 2.0 mmol) in anhydrous toluene (40 mL) was added dropwise over 7 minutes. The reaction mixture was heated to reflux and stirred for an additional 75 minutes. The reaction mixture was cooled, and the solvent was removed under high vacuum. The residue was then redissolved in approximately 40 mL of toluene and filtered through cotton wool. The solvent was removed under high vacuum to give 103 (630 mg, 1.9 mmol, 95%) as an oil, which slowly crystallized to a pale yellow solid.

[0222] 1 H NMR:(400MHz, (CDCl3):1.26(t, J=7.6Hz, 9H, C(1) H ), 2.84(q, J=7.6Hz, 6H, C(2) H ), 4.49(s, 6H, C(5) H 2), 13 C NMR:(100MHz, (CDCl3):δ 16.1( C (1)H2), 22.8( C (2)H), 40.4( C(5 )H), 123.1( C 6), 132.4( C3 ), 143.1( C4 ), v max2973, 2933, 2875, 2243, 1495, 1453, 1335, 1042, 856, 577cm -1 ,LRMS:(ESI + ) Measured value [M+Na] + :350.1. HRMS:(ESI + )C 18 H 21 N3O3Na + Calculated value for: 350.1475, Found value [M+Na] + :350.1474. Fmoc-protected tert-butyl G2 linker (compound 84) [ka] Method A

[0223] Under an inert N2 atmosphere, Fmoc-aminobenzoic acid 67 (983 mg, 2.63 mmol), HBTU (996 mg, 2.63 mmol), and HOBt (355 mg, 2.63 mmol) were suspended in anhydrous THF (30 mL). DIPEA (1.2 mL, 6.57 mmol) was added, and the reaction was stirred at room temperature for 10 min. Second-generation dendritic amine 82 (3.1 g, 2.19 mmol) was then added, and the reaction was stirred for 24 h. The solvent was then removed in vacuo, and the crude residue was purified by flash column chromatography (3% MeOH:CHCl) to give 84 (3.49 g, 2.01 mmol, 92%) as an off-white solid. Method B

[0224] Under an inert N2 atmosphere, 67 (5 g, 15.3 mmol), HBTU (5.03 g, 15.3 mmol), and HOBt.HO (2.06 g, 15.3 mmol) were suspended in anhydrous THF (60 mL). DIPEA (7.2 mL, 38.3 mmol) was added, and the reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the crude residue was dissolved in ethyl acetate (100 mL) and then poured into water (300 mL). The precipitate was then filtered and air-dried to give the crude HOBt ester / tetramethylurea complex (1:1, 4.36 g, 7.19 mmol, Mw = 607.67 g). -1 ), which was used without further purification. The crude HOBt ester complex was then suspended in anhydrous THF (60 mL), and 82 (9.4 g, 6.54 mmol) and DIPEA (2.1 mL, 12.3 mmol) were added. The reaction mixture was stirred at room temperature for 24 h, and the solvent was removed in vacuo. The crude residue was then purified by flash column chromatography (5% MeOH:CHCl) to give 84 (9.02 g, 5.19 mmol, 86%) as an off-white solid.

[0225] 1 H NMR:(400MHz, (CDCl3):δ 1.43(s, 81H, C(26) H 3), 1.95(m, 18H, C(23) H 2), 2.11(t, J=7.2Hz, 6H, C(18) H 2), 2.17(m, 18H, C(22) H 2), 2.25(t, J=7.2Hz, 6H, C(19) H 2), 4.27(m, 3H, C(7) H and N H 2), 4.47(d, J=7.4Hz, 2H, C(8) H 2), 6.08(s, 3H, N H ), 6.76(d, J=8.4Hz, 1H, C(13) H ), 7.26~7.31(m, 2H, C(4) H ), 7.38(t, J=7.4Hz, 2H, C(3) H ), 7.57~7.69(m, 2H, C(5) H), 7.71(d, J=8.7Hz, 1H, C(2) H ), 7.75(d, J=7.6Hz, 3H, C(2) H ), 7.78(d, J=2.1Hz, 1H, C(15) H ), 8.54(s, 1H, N H ), 13 C NMR:(100MHz, (CDCl3):δ 28.0( C 26), 29.8( C 22), 29.9( C 23), 31.8( C 19), 32.2( C 18), 47.2( C7 ), 53.4( C17 ), 57.4( C 21), 67.3( C 8), 80.6( C 25)116.6( C 12), 119.9( C 2), 122.6( C 10), 124.6( C 14), 125.3( C 4), 126.0( C 15), 126.8( C 13), 127.0( C 5), 127.6( C 3), 141.3( C 1), 143.8( C 6), 145.3( C 11), 154.9( C 9), 166.6( C 16), 172.7( C 24), 173.1( C 20);v max 2977, 2963, 1752, 1723, 1689, 1637, 1535, 1367, 1242, 1151, 1098, 844cm -1 , HRMS:(ESI + ) Measured value [M+2Na] 2+ :921.0252.

[0226] Fmoc-aminobenzoic acid (67) was prepared according to the literature procedure described in Angew. Chem., 2008, 120, 6957.

[0227] Second-generation dendritic amine (82) was prepared according to literature procedures as described in Angew. Chem. Int. Ed., 2015, 54, 2057. Triamino G2MM tert-butyl-protected triethylbenzene half-acceptor (compound 108) [ka]

[0228] Under an inert N2 atmosphere, 84 (600 mg, 0.35 mmol) was dissolved in a solution of 103 (28 mg, 0.086 mmol) in anhydrous dichloromethane (5 mL). Anhydrous pyridine (40 μL) was added and the reaction was refluxed for 16 h, after which it was cooled to room temperature and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography (1:1, EtOAc:CHCl→4% MeOH:CHCl) to give 107 (400 mg, 0.072 mmol, 84%) as a white solid. Conversion to 107 was confirmed by limited NMR studies. * and confirmed by high-resolution mass spectrometry. (ESI + ): m / z[M+3Na] 3+ Calculated value 2869.6877, found value 1928.1169, [M+4Na] 4+ Calculated for 1451.8339, found 1451.8320. Under an inert N2 atmosphere, 107 (300 mg, 0.052 mmol) was dissolved in anhydrous dichloromethane (8 mL) and cooled to 0 °C. DBU (50 μL, 0.30 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (4% MeOH:CHCl) to give 108 (238 mg, 0.047 mmol, 91%) as a white solid. 1 H NMR:(400MHz, (CD3OD):δ 1.24(t, J=7.6Hz, C(1) H 3), 1.43(s, 243H, C(23) H 3), 1.94(m, 54H, C(20)H 2), 2.09(m, 18H, C(15) H 2), 2.18(m, 54H, C(19) H 2), 2.23(m, 18H, C(16) H 2), 2.86(m, 6H, C(2) H 2), 4.51(s, 6H, C(5) H 2), 7.21(dd, J=2.1, 8.4Hz, 3H, C(9) H ), 7.29(d, J=2.1Hz, 3H, C(11) H ), 7.4(d, J=8.4Hz, 3H, C(8) H ), 7.4(s, 9H, N H ), 7.91(s, 3H, N H ), 13 C NMR:(100MHz, (CDCl3):δ 17.0( C 1), 22.5( C 2), 28.5( C 23), 30.5( C 19), 30.7( C 20), 32.3( C 15), 32.6( C 16), 37.9( C 5), 58.9( C18 ), 59.4( C14 ), 81.6( C 22), 117.4( C 11), 118.9( C 9)124.5( C 8), 130.0( C 10), 132.9( C3 ), 133.8( C7 ), 141.4( C 12), 145.1( C 4), 157.9( C 6), 170.1( C 13), 174.4( C 21), 175.6( C 17), HRMS:(ESI + ) Measured value [M+3Na] 3+ :1706.0490. *Only limited NMR studies were possible due to the slow conformational exchange of 107, which results in very broad signals of low intensity. tert-Butyl-protected triethylbenzene acceptor (compound 1a) [ka] Method A

[0229] Under an inert N2 atmosphere, 108 (124 mg, 0.024 mmol) was dissolved in anhydrous dichloromethane (50 mL) and heated to reflux. A solution of 103 (8 mg, 0.024 mmol) in anhydrous dichloromethane (3 mL) was added, and the reaction was stirred at reflux for 3 days. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC and then lyophilized to give 1a (20 mg, 0.004 mmol, 15%) as a white solid. Method B

[0230] Under an inert N2 atmosphere, 108 (200 mg, 0.04 mmol), octyl glucoside (23 mg, 0.08 mmol), and 4-dimethylaminopyridine (14 mg, 0.12 mmol) were dissolved in anhydrous dichloromethane (35 mL). A solution of 103 (13 mg, 0.04 mmol) in anhydrous dichloromethane (5 mL) was added, and the reaction was stirred at reflux for 2 days. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC and then lyophilized to give 1a (85 mg, 0.016 mmol, 40%) as a white solid.

[0231] 1 H NMR:(400MHz, (CD3OD):δ 1.24(m, 18H C(1) H 3), 1.43(s, 243H, C(23) H 3), 1.95(m, 54H, C(20) H 2), 2.13(m, 18H, C(15) H 2), 2.20(m, 54H, C(19) H 2), 2.25(m, 18H, C(16) H 2), 2.74, 2.84(br m, 6H, C(2) H2), 4.40, 4.49(br s, 6H, C(5) H 2) 7.43 (s, 9H, N) H ), 7.63(d, J=8.7Hz, 3H, C(10) H ), 8.03(d, J=8.7Hz, 3H, C(11) H ), 8.07 (s, 3H, C(8)) H ), 13 C NMR: (100MHz, (CDCl3): δ 15.5, 15.6 ( C 1) 22.3, 22.5 C 2) 27.1 C 23), 29.1 C 19), 29.3 C 20), 30.8 C 15), 31.0 ( C 16), 37.5 C 5), 57.3 C 18), 58.1 C 14), 80.2 C 22), 120.3 C 11), 123.5 C 8) 124.1 C 10), 127.6 C 7), 129.4 C9 ), 132.0, 132.6 ( C 3) 135.0 ( C 12), 143.0, 143.2 ( C 4) 155.8, 156.6 ( C 6) 168.2 C 13), 173.0 ( C 21), 174.1 C 17) HRMS:(ESI) + ) Measured value [M+3Na] 3+ :1816.1093. Toryon Receptor (Receptor 1)

change

[0232] 1a (3.5 mg, 0.65 μmol) was dissolved in HPLC-grade dichloromethane (1.6 mL). Trifluoroacetic acid (0.4 mL) was added, and the reaction was stirred at room temperature for 16 h. The solvent was then removed under a stream of nitrogen, and the crude product was suspended in water and lyophilized. The resulting solid was suspended in water, neutralized to pH 7 with NaOH (aq), and then lyophilized to give receptor 1 (3.3 mg, 0.62 μmol, 95%) as a white solid. 1 H NMR:(400MHz, (D2O):δ 1.17(m, 18H C(1) H 3), 1.94(m, 54H, C(20) H 2), 2.12(m, 18H, C(15) H 2), 2.18(m, 54H, C(19) H 2), 2.31(m, 18H, C(16) H 2), 2.76(br m, 6H, C(2) H 2), 4.46(br s, 6H, C(5) H 2), 7.61(d, J=9.6Hz, 3H, C(10) H ), 7.82(br m, 6H, C(11) H , C(8) H ), 13 C NMR:(100MHz, (CDCl3):δ 18.0, 18.1( C 1), 25.0, 25.2( C 2), 32.6( C 15), 32.7( C 19), 32.9( C 16), 33.3( C 20), 40.1, 40.3( C 5), 60.7( C 18), 61.3( C 14), 120.0( C 11), 121.6( C 10), 122.8( C 8), 125.7( C 7), 130.0( C9 ), 134.7, 135.0( C 3), 135.6( C 12), 146.7, 146.9( C 4), 159.6, 159.9(C 6), 170.3( C 13), 177.8( C 17), 184.1( C 17). compound 8d [ka]

[0233] A Schlenk tube equipped with a magnetic stirrer was charged with 108 (200.0 mg, 0.04 mmol), DMAP (14.5 mg, 0.12 mmol), and n-octyl glucoside (23.2 mg, 0.08 mmol), added to a flask, and placed under nitrogen. Anhydrous DCM (40 mL) was added, and the reaction was concentrated to 34. o The mixture was warmed to 5°C. A solution of compound 5d (12.5 mg, 0.051 mmol) in toluene (ca. 85% purity) was added to the flask, and the reaction was stirred for 16 h. The solvent was completely removed, and the crude product was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge eluting with 10% acetone:water (1 CV), a gradient of 10 to 95% acetone:water (10 CV), and 95% acetone:water (2 CV). A white solid (67 mg, 0.012 mmol, 32%) was obtained. Compound 8e-receptor 2 [ka]

[0234] Method A: Compound 8d was dissolved in anhydrous DCM (volume: 6 mL) and TFA (1.74 mL, 22.67 mmol) at room temperature. The resulting yellow solution was stirred at room temperature for 2 hours. Volatiles were removed under vacuum to give a yellow solid. The solid was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge by loading the sample in 1:1 MeOH / HO + 0.1% formic acid. The resulting white solid was neutralized to pH 7 using 100 mM NaOH solution, and the resulting solution was concentrated to dryness under vacuum. A white crystalline solid (37 mg, 0.008 mmol, 74%) was obtained.

[0235] Method B: The solid obtained from compound 44 was dissolved in anhydrous CHCl (5.9 mL) and TFA (1.7 mL, 23 mmol) was added at room temperature. The resulting yellow solution was stirred at room temperature for 2 hours or until complete by TLC (baseline product in 60% EtOAc / CHCl). The solvent / TFA was removed in vacuo (rotary evaporator, then high vacuum) to give a yellow solid. The solid was purified by reverse-phase chromatography (loading the sample onto 1:1 MeOH / HO + 0.1% formic acid). Fraction 2-7 was collected and concentrated in vacuo. The resulting white solid was neutralized to pH 7 using 100 mM NaOH solution, and the resulting solution was concentrated in vacuo (rotary evaporator / cold finger with liquid N) to give compound 45 as a white crystalline solid (37 mg, 75%).

[0236] 1 H NMR: (500MHz, D2O, 298 K): δ 7.74(br d, J=7.1Hz, 3H, H9), 7.59(d, J=8.6Hz, 3H, H8), 7.48(s, 3H, NH), 7.40(s, 3H, H6), 7.01(s, 3H, H1), 4.40(br s, 6H, H 12 ), 3.93(br s, 6H, H3), 2.70(br s, 6H, H 15 ), 2.20(br s, 18H, H 20 ), 2.07(m, 72H, H 19 +H 24 ), 1.83(m, 54H, H23 ), 1.07(br t, 9H, H 16 ).

[0237] 13 C NMR (126MHz, D2O)δ 173.2, 166.0, 160.0, 149.4, 148.1, 135.5, 131.1, 128.9, 122.8, 121.6, 119.6, 118.0, 11 7.4, 114.5, 113.9, 49.5, 49.0, 48.9, 43.1, 33.8, 28.6, 22.0, 21.6, 21.2, 21.1, 13.5, 6.3. Compound 9-Receptor 3 [ka]

[0238] Triethylbenzene acceptor 1 (15.0 mg, 0.003 mol), HBTU (W: 2.6 mg, 0.006 mmol), and 5-(aminoacetamido)fluorescein (21.8 mg, 0.048 mmol) were dissolved in DMF (1.25 mL) and HO (1.25 mL). The reaction mixture was stirred in the dark at room temperature for 16 h and then concentrated under reduced pressure. The crude reaction mixture was neutralized with aqueous NaOH to approximately pH 7. The NaOH was then concentrated under reduced pressure. The product was purified by reverse-phase flash chromatography on a 12 g SNAP Ultra C18 cartridge eluting with 20% MeOH / HO + 0.1% formic acid over 1 CV, followed by 65% ​​MeOH / HO + 0.1% formic acid over 8 CV, 100% HO + 0.1% formic acid over 0.5 CV, and then 100% HO + 0.1% formic acid over 3 CV. The product containing fractions were combined, concentrated under reduced pressure, neutralized to approximately pH 7, and then lyophilized to give compound 9 as an orange powder. 1 H NMR: (400MHz, D2O, 298 K): δ 7.91-7.28(m, 15H, Ar), 7.25-6.89(m, 9H, Ar), 6.73-6.32(m, 12H, Ar), 4.52-4.04(m, 12H, H5), 4.02-3.81(m, 6H, H 22 ), 2.59-1.61(m, 156H, H1+15+16+19+20 ), 1.21-0.82(m, 18H, H1). Key Intermediates Compound A1 [ka]

[0239] 3,4-Diaminobenzoic acid (41.000 g, 0.269 mol) was mixed with saturated NaHCO3 (0.40 L) and acetonitrile (0.40 L) to give a brown slurry. Solid Fmoc-OSu (99.99 g, 0.296 mol) was then added portionwise over 5 min. The heterogeneous suspension was stirred at room temperature for 16 h and then acidified with 1 M HCl (aq). The solid was collected on a frit and washed with cold diethy ether (3 × 100 mL), hexane (3 × 100 mL), then MeOH (3 × 50 mL), and then dried under vacuum. Brown solid (101 g, 0.269 mol, 100%). This intermediate (10.000 g, 0.027 mol), HOBt (8.181 g, 0.053 mol), and HBTU (20.259 g, 0.053 mol) were dissolved in THF (300 mL) and DIPEA (18.610 mL, 0.107 mol). The heterogeneous slurry was stirred at room temperature for 90 minutes, after which the solvent was removed in vacuo to give a viscous oil. The oil was dissolved in EtOAc (80 mL) and added to a rapidly stirred mixture of water (200 mL) and EtOAc (40 mL). After approximately 2 minutes, a precipitate formed, and diethyl ether (100 mL) was added to the flask. After stirring for 10 minutes, the solid was collected by filtration, washed with water (3 × 10 mL) and diethyl ether (2 × 10 mL), and then dried under vacuum for 16 hours. 1H NMR: (500 MHz, DMSO-d) δ 8.94(s, 1H), 8.14(dd,J=17.7, 8.4Hz, 2H), 8.01-7.93(m, 1H), 7.90(d,J=7 .6Hz, 2H), 7.87-7.68(m, 6H), 7.68-7.61(m, 1H), 7.54(dt, J=11.5, 7.5Hz, 1 H), 7.42(t, J=7.4Hz, 2H), 7.34(t, J=7.6Hz, 2H), 6.89(d, J=8.6Hz, 1H), 6.4 6(s, 2H), 4.44(s, 2H), 4.31(s, 1H), 3.40(s, 7H), 3.03(s, 7H), 2.50(s, 4H). compound 2 [ka]

[0240] A 100 mL Schlenk tube was charged with compound A1 (2.750 g, 2.263 mmol), N,N-diisopropylethylamine (0.585 mL, 3.341 mmol), and anhydrous THF (10 mL). Solid 3-(2-aminoethyl)pentane-1,3,5-N-Boc-triamine* (0.800 g, mol: 1.911 mmol) was added, and the homogeneous solution / suspension was stirred. After 72 h, TLC (SiO2, 7:3 EtOAc:DCM) indicated complete consumption of the starting material and product formation. The solvent was removed in vacuo, and the crude residue was extracted with DCM (2 × 10 mL). The filtrate was concentrated to dryness, and the residue was purified by MPLC (12% → 100% DCM in EtOAc). Orange amorphous solid (1.154 g, 1.413 mmol, 74%). 1 H NMR: (400Hz, CDCl3)δ 7.00~7.82(m, 11H, ArH), 6.71(2H, d, J=8.13Hz, N H 2), 3.14(6H, q, J=7Hz, C H 2NH), 2.04(app.s, 6H, CC H 2), 1.40(27H,s,C(C H 3)3). MS:(ESI + )C 44 H 60N6O9Na + Calculated value for: 839.4314, Found value [M+Na] + :839.4318. *Carter, TS;Mooibroek, TJ;Stewart, PFN;Crump, MP;Galan, MC& Davis, APAngewandte Chemie International Edition, 2016, 55, 9311-9315. compound 3b [ka]

[0241] NaH (1.05 g, 26.3 mmol, 60% in mineral oil) was added to a Schlenk tube (100 mL) and placed under nitrogen. The mineral oil was removed by washing the solid with 3 x 25 mL of petroleum ether at 60-80 °C. The washed NaH was suspended in anhydrous DMF (10 mL) and cooled in an ice bath with vigorous stirring for approximately 10 min. Solid trifluoroacetamide (4.46 g, 39.46 mmol) was added portionwise under a countercurrent of nitrogen. The mixture was stirred for 5 min and then allowed to warm to room temperature. Once gas evolution had completely ceased (within 1 h), solid 1,3,5-tribromomethyl-2,4,6-trimethoxybenzene* (2.00 g, 4.39 mmol) was added portionwise under a countercurrent of nitrogen, and the resulting white suspension was stirred at room temperature. After approximately 18 h, the suspension was poured into 0.5 M HCl (150 mL), and the pale orange precipitate was collected on a frit. The solid was washed with water (2×10 mL) and then dried under vacuum overnight (approximately 10 -2 mbar). Off-white solid (2.44 g, 4.491 mol, 102%). The crude product was used without further purification and contained 2-3% DMF ( 1 quantified by H NMR spectroscopy). 1 H NMR:(400MHz, DMSO-d6)δ d.4.40(6H, 3 J HH =4.6Hz, ArC H 2NHC(O)CF3), s.3.70(9H, OCH 3). 13 C NMR:(400MHz, DMSO-d6)δ q.158.3( 2 J CF =37.1Hz, C (O)CF3), 137.3, 132.1(Ar), q.116.1( 1 J CF =287.9Hz, C F3), 62.5(NH C H2Ar), 32.1(O C H3). *Rosien, J.; Seichter, W.; Mazik, M., Organic and Biomolecular Chemistry, 2013, 11(38), 6569-6579. compound 3c [ka]

[0242] Prepared by a route similar to compound 3b using 1,3,5-tribromomethyl-2,4,6-trimethylbenzene: Off-white solid (4.86 g, 0.01 mol, 82%). 1 H NMR:(500MHz, CDCl3 / MeOH-d4)δs.4.47(6H, ArC H 2NHC(O)CF3), s.2.26(9H, OC H 3). 13 C NMR:(125MHz, CDCl3 / MeOH-d4)δq.157.6( 2 J CF =37.2Hz, C (O)CF3), 137.8, 131.1(Ar), q.115.9( 1 J CF =287.3Hz, C F3), 39.4 Ar C H2NHC(O)CF3), 16.0(Ar C H3). MS: (APCI - )493.9 compound 3d [ka]

[0243] Prepared by a route similar to compound 3b using 1,3,5-tris(bromomethyl)benzene (5.07 g, 0.014 mol). The crude product was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge (1 CV of 10% acetone:water, 10 CV of a gradient from 10 to 95% acetone:water, and 2 CV of 95% acetone:water). A white solid (2.16 g, 0.005 mol, 34%) was obtained. 1 H NMR: (400MHz, MeOH-d4)δ 7.07, (s, 3H, Ar H ), 4.35 (6H, 3 J HH =4.6Hz, ArC H 2N(O)HCF3). 13 C NMR:(125MHz, MeOH-d4)δ q.158.1( 2 J CF =36.9Hz, C (O)CF3), 138.1, 132.2(Ar), q.114.6( 1 J CF =286.9Hz, C F3), 125.9(Ar), 42.3, Ar C H2NHC(O)CF3). compound 4a [ka]

[0244] NaH (3.809 g, 0.095 mol, 60% in mineral oil) was added to a Schlenk tube (100 mL) and placed under nitrogen. The mineral oil was removed by washing the solid with 3 x 25 mL of petroleum ether at 60-80 °C. The washed NaH was suspended in anhydrous DMF (40 mL) and cooled in an ice bath with vigorous stirring for approximately 10 min. Solid trifluoroacetamide (16.147 g, 0.143 mol) was added portionwise under a countercurrent of nitrogen. The mixture was stirred for 5 min and then allowed to warm to room temperature. Once gas evolution had completely ceased (within 1 h), solid 1,3,5-tribromomethyl-2,4,6-trimethoxybenzene* (7.00 g, 0.016 mol) was added portionwise under a countercurrent of nitrogen, and the resulting white suspension was stirred at room temperature. After approximately 18 h, the suspension was poured into 0.5 M HCl (150 mL), and the pale orange precipitate was collected on a frit. The solid was washed with water (2×10 mL) and then dried under vacuum overnight (approximately 10 -2 mbar). An off-white solid (7.910 g, 0.015 mol, 93%) was obtained. The intermediate acetamide (4.90 g, 0.009 mol) was dissolved in methanol (38.6 mL) and water (38.6 mL). NaOH (1.05 g, 3.150 mol) was added, and the reaction mixture was stirred at 65 °C for approximately 18 h. Solid BocO (7.287 g, 0.033 mol) and triethylamine (2.534 mL, 0.026 mol) were added, and the reaction was stirred at ambient temperature for an additional 4 h. The reaction mixture was diluted with DCM (200 mL) and washed with saturated aqueous NaHCO (200 mL), 1 m NaOH (200 mL), and brine (100 mL). The organic phase was concentrated to dryness, and the resulting crude product was purified by MPLC (0 → 50% MeOH in DCM). Colorless solid (4.820g, 0.009mol, 96%). 1 H NMR:(400MHz, CDCl3)δ m.br 4.33(9H, ArC H 2NHCO2C(CH3)3), N H ), q.2.71(6H, 3 J HH =7.5Hz, ArC H 2CH3), s.1.44(27H, CO2C(C H3)3), t.1.19(9H, 3 J HH =7.5Hz, ArCH2C H 3). 13 C NMR:(125MHz, CDCl3)δ 155.5( C O2C(CH3)3), 143.9, 132.6(Ar), 79.7(CO2 C (CH3)3), 38.9 Ar C H2NHCO2C(CH3)3), 28.6(CO2C( C H3)3), 23.0(Ar C H2CH3), 16.7(ArCH2 C H3). *Rosien, J., Seichter, W., Mazik, M., Organic and Biomolecular Chemistry, 2013, 11(38), 6569-6579. compound 4b [ka]

[0245] Compound 3c (9.123 g, 0.013 mol) was dissolved in MeOH (125 mL) and NaOH (1.689 g, 0.042 mol) overnight at room temperature. Then, BOC anhydride (11.702 g, 0.054 mol) was added and stirred overnight. The solvent was removed in vacuo, and the crude product was partitioned between DCM and HO. The organic fractions were combined, washed with 0.5 M HCl (50 mL), dried over MgSO, and concentrated in vacuo to give an off-white solid. Purification was performed by MPLC (0→20% EtOAc in petrol). Colorless crystalline solid (5.62 g, 0.011 mol, 83%). 1 H NMR:(500MHz, CDCl3)δ d.4.33(9H, ArC H 2NHCO2C(CH3)3), N H ), s.2.37(9H, ArC H 3), s.1.44(27H, CO2C(C H 3)3). 13C NMR:(125MHz, CDCl3)δ 155.7( C O2C(CH3)3), 136.9, 133.5(Ar), 79.7(CO2 C (CH3)3), 40.0 Ar C H2NHCO2C(CH3)3), 28.5(CO2C( C H3)3), 16.0(Ar C H3). compound 4c [ka]

[0246] Prepared by a similar route to compound 4b using compound 3b (0.919 g, 1.69 mmol). Purified by MPLC (0→40% EtOAc in petroleum ether). Colorless crystalline solid (0.655 g, 1.15 mmol, 68%). 1 H NMR:(4500MHz, CDCl3)δ d 4.38(6H, 3 J HH =4.2Hz ArC H 2NHCO2C(CH3)3), s. 3.79(9H, OC H 3) 1.43(27H, CO2C(C H 3)3). compound 4d [ka]

[0247] Prepared in a similar manner to compound 4b using compound 3d (2.155 g, 0.005 mol) dissolved in MeOH (30 mL). Solid NaOH (0.599 g, 0.015 mol). Purified by MPLC (50% EtOAc in DCM) and then recrystallized from DCM / petrol. Colorless crystalline solid (0.88 g, 0.002 mmol, 40%). 1 H NMR:(400MHz, CDCl3)δ s.7.08(1H, Ar H )d.4.24(6H,3 J HH =6.6Hz, ArC H 2N(O)OC(C H 3)3), s.1.46(9H, C(C H 3)3). 13 C NMR:(125MHz, CDCl3)δ 155.7( C O2C(CH3)3), 136.8(Ar), 125.2(Ar), 78.9(CO2 C (CH3)3), 45.2(Ar C H2NHCO2C(CH3)3), 28.2(CO2C( C H3)3). compound 5a [ka]

[0248] Method A: A pre-dried 250 mL round-bottom flask equipped with a nitrogen inlet and reflux condenser and mounted in a heating block was charged with triphosgene (1.78 g, 6 mmol). The flask was placed under vacuum for 10 minutes (approximately 10 min). -2 The flask was heated to 300°C (1000°F) and refilled with nitrogen. Anhydrous toluene (150 mL) was added, resulting in a colorless, homogeneous solution. To this, a solution of 1,3,5-triaminomethyl-2,4,6-triethylbenzene (0.5 g, 2 mmol), previously dried with one azeotropic distillate of toluene (80 mL), in anhydrous toluene (20 mL) was added via syringe over 10 minutes. After the addition was complete, the temperature was raised to 125°C to reflux the reaction. After 75 minutes, the flask was cooled to room temperature and the solvent was removed in a rotary evaporator. The residue was extracted with toluene (3 x 10 mL), concentrated to dryness, and yielded a pale yellow oil that crystallized on standing. A pale yellow, crystalline solid (350 mg, 1.07 mmol, 54%) was obtained.

[0249] Method B: A pre-dried 200 mL Schlenk tube was charged with a magnetic stirrer and compound 4a (1.266 g, 2.25 mmol) and then placed under a nitrogen atmosphere. 2-Chloropyridine (1.7 mL, 20.21 mmol) and anhydrous DCM (70 mL) were added via syringe to give a colorless, homogeneous solution. Triflic anhydride (1.5 mL, 10.11 mmol) was added dropwise over 2 minutes at ambient temperature with stirring (400 rpm). The reaction was stirred for 30 minutes before a small aliquot (approximately 50 mL) of the reaction mixture was removed and analyzed by TLC (SiO, 50% EtO in petrol) to determine the starting material (R). f =0.24) and complete consumption of 5a (R f =0.5), revealing a conversion to 4,4'-dichloromethane (H NMR (δ 1.01-1.02) δ 1.01-1.02 ... 1 H NMR: (400 MHz, toluene-d6) δs 3.93 (6H, ArC H 2NCO), m.2.51-2.37(6H, ArC H 2CH3), m.0.96-0.86(9H, ArCH2 CH 3). 13 C NMR: (100 MHz, toluene-d6) 143.2, 132.6 (Ar), 124.0 (N C O), 40.4(Ar C H2NCO), 22.8(ArC H 2CH3), 16.0(ArCH2C H 3). compound 5b [ka]

[0250] Prepared by a route similar to compound 5a (Method B) using compound 4c (0.351 g, 0.616 mmol): Colorless crystalline solid (0.144 g, 0.432 mmol 70%). 1 H NMR: (400 MHz, toluene-d) δ d 3.90 (6H, ArC H 2NCO), s.3.40(9H, OC H 3). 13 C NMR: (125 MHz, toluene-d) δ 159.7 (Ar), 121.4 (N C O), 62.9(ArO C H3), 36.2(Ar C H2NCO). compound 5c [ka]

[0251] Prepared by a route similar to compound 5a (Method B) using compound 4b (0.300 g, 0.985 mmol): Colorless crystalline solid (0.198 g, 0.694 mmol, 71%). 1 H NMR: (500 MHz, toluene-d) δs 3.73 (6H, ArC H 2NCO), s.1.91(9H, C H 3). 13 C NMR: (125MHz, toluene-d)8)δ 135.9, 133.4(Ar), 124.4(ArCH)2N C O), 41.2(Ar C H2NCO), 15.1(Ar C H3). compound 5d [ka]

[0252] Prepared by a route similar to compound 5a (Method B) using compound 4d (0.250 g, 0.537 mmol): Colorless oil (0.062 g, 0.255 mmol, 48%). 1H NMR: (500 MHz, toluene-d) δs 6.56 (3H, Ar H ), s.3.64(6H, ArC H 2NCO). 13 C NMR: (125MHz, toluene-d8)δ 138.4(Ar), 124.2(Ar, ArCH2N C O), 45.7(Ar C H2NCO). compound 5e [ka]

[0253] A pre-dried round-bottom flask was charged with 1,3,5-triaminomethyl-2,4,6-triethylbenzenetristrifluoroacetate (0.535 g, 0.905 mmol). THF (9 mL) was added, followed by CS2 (1.100 mL, 18.100 mmol) and DCC (0.585 mg, 2.806 mmol). The reaction was stirred for 16 h and then concentrated in vacuo. The resulting residue was triturated with DCM, and the filtrate was purified by MPLC (5% EtOAc / DCM → 40%) to give a white solid (0.168 g, 0.447 mmol, 49%). 1 H NMR:(400MHz, CDCl3)δ s.4.74(6H, ArC H 2NCS), q.2.84(6H, J=7.6Hz, ArC H 2CH3), t.1.26(9H, J=7.6Hz, ArCH2C H 3). 13 C NMR: (100MHz, CDCl3)144.2, 132.4(Ar), 130.1(N C S), 42.9(Ar C H2NCS), 23.2(ArC H 2CH3), 15.8(ArCH2C H 3). compound 5f [ka]

[0254] A pre-dried round-bottom flask was charged with tris(2-aminotheyl)amine (5.000 g, 0.033 mol). THF (500 mL) was added, followed by CS2 (40.0 mL, 0.660 mol) and DCC (21.258 g, 0.102 mol). The reaction was stirred for 16 h and then filtered. The filtrate was then concentrated in vacuo. The resulting residue was triturated with DCM, and the filtrate was purified by MPLC (12% EtOAc / DCM → 30%) to give a yellow solid (3.340 g, 0.023 mmol, 71%). 1 H NMR:(500MHz, CDCl3)δ t.4.74(6H, J=6.2Hz, NCH2C H 2NCS), t.2.96(6H, J=6.2Hz, NC H 2CH2NCS). 13 C NMR: (125 MHz, CDCl3) 132.8 (N C S), 54.5(N C H2CH2NCS), 44.4(NCH2 C H2NCS). compound 6b [ka]

[0255] A pre-dried Schlenk tube was charged with compound 5b (18 mg, 0.053 mmol) and compound 84 (333 mg, 0.186 mmol) under a stream of nitrogen. Dry THF (3 mL) and anhydrous pyridine (0.024 mL, 0.053 mmol) were added. MoO2Cl2 flakes were added under a stream of nitrogen. The reaction was stirred for 16 h. The reaction mixture was concentrated to dryness, and the crude residue was purified by MPLC (2:3 EtOAc:DCM) to give a brown solid (174 mg, 0.030 mmol, 57%). 1 H NMR:(500MHz, CDCl3)δ m.7.77-7.07(33H, Ar H ), m.4.56-4.06(15H, ArCH 2j 、CO2C H 2C H )、s.3.66(9H、ArOC H 3)、m.2.31-1.80z(144H、NHC H 2C H 2C(O))、s.1.34(162H、CO2C(C H 3)3)、s.1.33(81H、CO2C(C H 3)3)。 13 C NMR:(125MHz、CDCl3)δ 173.1、173.0( C ONH)、172.7、172.7( C O2C(CH3)3)、172.6(Ar C ONHR)、166.6(NH C (O)NH)、158.4( C OCH3)、153.9( C O2CH2CH)、143.8( C NHFmoc)、143.6(Fmoc 4°)、141.3( C NHFmoc)、141.2(Fmoc 4°)、127.7(Fmoc Ar)、127.7、127.7( C CO2NHR)、127.1(Fmoc Ar)、127.0( C NHC(O)NH)、125.3、125.3( C H C HCNH)、124.5(Fmoc Ar)、120.0(Fmoc Ar)、119.9( C HCNHFmoc)、119.9( C CH2NHC(O)NH)、80.5、80.4(CO2 C (CH3)3)、67.3(CO2 C H2CH)、60.4(ArO C H3)、57.4、57.4( C (CH2CH2CO2)3)、57.4( C (CH2CH2CONH)3)、47.2(CO2CH2 C H)、39.2(Ar C H2NHC(O)NH)、32.2(CH2 C H2CO2C(CH3)3)、31.7(CH2C H2CONH), 29.8( C H2CH2CONH), 29.7( C H2CH2CO2C(CH3)3), 28.0(CO2C( C H3)3). compound 6c [ka]

[0256] A pre-dried Schlenk tube was charged with compound 84 (441 mg, 0.245 mmol) under a stream of nitrogen, and a solution of compound 5c (20 mg, 0.070 mmol) in THF (0.5 mL) was added. Dry THF (3.5 mL) and anhydrous pyridine (0.006 mL, 0.070 mmol) were added. The reaction was stirred at 50 °C for 16 h. The reaction mixture was concentrated to dryness, and the crude residue was purified by reverse-phase MPLC (70-95% acetone / HO) on a 120 g SNAP Ultra C18 cartridge to give a white solid (197 mg, 0.035 mmol, 50%). 1 H NMR: (400 MHz, methanol-d4) δ m. 7.86-7.03 (33H, Ar H ), m.4.48-4.04(15H, ArC H 2. CO2C H 2C H ), s.2.37(9H, ArC H 3), m.2.31-1.86z(144H, NHC H 2C H 2C(O)), s.1.40(243H, CO2C(C H 3)3). 13 C NMR: (125 MHz, methanol-d4) δ 175.6, 175.5( C ONH), 174.4( C O2C(CH3)3), 174.4(Ar C ONHR), 157.1(NH C (O)NH), 153.0( C O2CH2CH), 145.0( C NHFmoc), 142.6(Fmoc 4°), 134.4(C CH3), 131.2(Fmoc Ar), 128.9( C CO2NHR), 128.2( C NHC(O)NH), 126.3( C H C HCNH), 121.4(Fmoc Ar), 121.1( C HCNHFmoc), 121.1( C CH2NHC(O)NH), 81.6(CO2 C (CH3)3), 59.4, 58.8( C (CH2CH2CO2)3), 58.7( C (CH2CH2CONH)3), 40.1(Ar C H2NHC(O)NH), 30.7(CH2 C H2CO2C(CH3)3), 30.5(CH2 C H2CONH), 28.5( C H2CH2CONH, C H2CH2CO2C(CH3)3), 28.4(CO2C( C H3)3), 16.2(Ar C H3). compound 6d [ka]

[0257] A pre-dried Schlenk tube was charged with compound 84 (441 mg, 0.245 mmol) under a stream of nitrogen, and a solution of compound 5d (212 mg, 0.049 mmol) in THF (0.5 mL) was added. Dry THF (2.5 mL) and anhydrous pyridine (0.004 mL, 0.049 mmol) were added. The reaction was stirred for 32 h. The reaction mixture was concentrated to dryness, and the crude residue was purified by reverse-phase MPLC on a 120 g SNAP Ultra C18 cartridge (70-95% acetone / HO) to give a white solid (110 mg, 0.020 mmol, 40%). 1 H NMR: (500 MHz, methanol-d4) δ m. 8.03-7.06 (33H, Ar H ), m.4.55-4.17(15H, ArCH 2. CO2C H 2C H ), m.2.27-1.85 (144H, NHC) H 2C H 2C(O)), s.1.41(243H, CO2C(C) H 3)3). 13 C NMR: (125MHz, メタノール-d4)δ 175.5( C ONH), 174.4 ( C O2C(CH3)3), 174.4(Ar C ONHR), 157.3 (NH C (O)NH), 153.9 ( C O2CH2CH), 143.8 ( C NHFMoc), 143.6(Fmoc 4°), 141.1(Fmoc 4°), 129.0( C CO2NHR), 127.7(Fmoc Ar), 126.3( C H C HCNH), 124.4(Fmoc Ar), 122.0( CH CCH2NHC(O)NH), 120.9 ( C HCNHFmoc), 120.0(Fmoc Ar), 81.6(CO2 C (CH3)3), 58.7 ( C (CH2CH2CO2)3、 C (CH2CH2CONH)3), 40.7(CO2CH2C H ), 40.1 (Ar C H2NHC(O)NH), 30.7(CH2) C H2CO2C(CH3)3), 30.5(CH2) C H2CONH), 28.5 ( C H2CH2CONH, C H2CH2CO2C(CH3)3), 28.5(CO2C( C H3)3). Compounds 6h-1 and 6h-2 Compound 6h-1

change

[0258] A Schlenk flask was charged with a stir bar, compound 84 (0.933 g, 0.519 mmol), compound 5a (0.100 g, 0.305 mmol) was dissolved in anhydrous THF (6 mL), pyridine (0.147 mL, 1.833 mmol) was added, and the mixture was then cooled to 50°C. o The mixture was heated at RT for 5 h. Compound 11 (0.228 g, 0.397 mmol) in anhydrous THF (1 mL) was added in one portion, and the reaction was stirred for an additional 12 h. The reaction mixture was transferred to a RBF, washed with CHCl, and then concentrated in vacuo. The resulting crude residue was then purified by reverse-phase flash chromatography on a 120 g SNAP Ultra C18 cartridge eluting with 1 CV 85% acetone / HO, 10 CV 85–95% acetone / HO, 2 CV 95% acetone, affording the isolated peaks (fr17-29) 6H-1 (511 mg, 37%) and (fr8-15) 6H-2 (458 mg, 46%). Compound 6h-1

[0259] 1 H NMR: (400 MHz, (CD3OD): δ 8.02-7.46 (19H, br.m, ArH), 7.46-7.11 (14H, br.m, ArH), 4.60-4.30 (12H, br.m, NHCH2Ph ​​and FmoCh), 4.19 (3H, br.s, NHCH2Ph ​​and FmoCh), 3.71-3.55 (14H, m, PEG CH2), 3.33 (2H, m, PEG CH2), 2.85 (6H, br.s, CH)2), 2.35-1.86 (96H, m, dendrimer CH2), 1.42 (162H, s, CH3), 1.23 (9H, br.s, CH3). HRMS: (ESI + )C 244 H 352 N 21 O 57 Na3 2+ Calculated value for: 1520.8407, Found value [M+3Na] 3 +:1520.8395. Compound 6h-2

[0260] 1 H NMR: (400 MHz, (CD3OD): δ 8.01-7.51 (19H, br.m, ArH), 7.43-7.17 (14H, br.m, ArH), 4.54-4.25 (12H, br.m, NHCH2Ph ​​and FmoCh), 4.15 (3H, br.s, NHCH2Ph ​​and FmoCh), 3.69-3.47 (28H, m, PEG CH2), 3.26 (4H, m, PEG CH2), 2.82 (6H, br.s, CH)2), 2.33-1.80 (48H, m, dendrimer CH2), 1.42 (81H, s, CH3), 1.17 (9H, br.s, CH)3). compound 6i [ka]

[0261] Compound 5a (55.0 mg, 0.168 mmol) and compound 2 (480 mg, 0.588 mmol) were weighed into a dry Schlenk flask equipped with a stir bar. Anhydrous THF (3.3 mL) was added. The reaction mixture was stirred at 50°C for 20 hours, then transferred to a round-bottom flask and concentrated to dryness. The crude product was purified by MPLC on a 60 g C18 SNAP ULTRA cartridge eluting (3 CV 70% acetone / water, 10 CV 70-95% acetone / water, 3 CV 95% acetone) to produce the isolated peak (fr18-22). 273 mg of white solid, 59% yield. 1 H NMR: (400MHz, CD3OD)δ 7.05- 7.85(33H, m, ArH), 4.35(3H, s, Flu-C H ), 4.26(6H, s, Flu-CHC H 2O), 3.01(18H, m, H16), 2.71(6H, m, ArC H 2CH3), 1.93(18H, m, H15), 1.30(81H, s, t Bu), 1.06 (9H, t, J=7.00Hz, ArCH2C H 3).13 C NMR:(101MHz, CD3OD)δ 15.59(9C, ArCH2 C H3), 22.23(3C, Ar C H2C H 3), 27.31(27C, t Bu), 34.89(9C, C C H2CH2NH), 35.21(9C, CCH2 C HNH), no peak observed (1C, Flu-CH C H2), 51.32(1C, C (CH2CH2NHBoc)3), no peak observed (9C, t Bu), no peak observed (1C, Flu- C H), 119.60-127.47(60C, Ar), 141.28(9C, Boc C =O), 143.64 (1C, Fmoc) C =O), 156.89 (1C, Ar- C =O). compound 7b [ka]

[0262] To a stirred solution of 6b (0.170 g, 0.030 mmol) in DCM (5 mL) at 0 °C was added distilled DBU (0.006 mL, 0.040 mmol). The reaction was stirred at 0 °C for 2 h and then concentrated in vacuo. The resulting crude residue was then purified by reverse-phase flash chromatography eluting with a 120 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80–95% acetone / HO, 2 CV 95% acetone) to give an off-white solid (0.133 g, 0.026 mmol, 89%). 1 H NMR: (500 MHz, methanol-d4) δ m. 7.30-7.27 (3H, C H CNH(Ar)), m.7.22-7.15(6H, C H CHCNH, C H CNH2(Ar)), s.4.54(6H, ArC H2NH), s. 3.89 (9H, ArOC H 3), m. 2.25 - 1.91 (144H, NHC H 2C H 2C(O)), s. 1.43 (243H, CO2C(C H 3)3). 13 C NMR: (125 MHz, methanol - d4) δ 175.5, 175.4( C ONH), 174.4, 174.3( C O2C(CH3)3), 170.6, 170.0 (Ar C ONHR), 160.2 (NH C (O)NH), 157.9( C OCH3), 141.4, 140.7( C NH2), 134.7, 132.7( C CO2NHR), 129.9, 125.6( C NHC(O)NH), 124.4, 123.6, 120.7, 118.8( C H C HCNH), 117.2, 116.6( CH CNH2), 115.5( C CH2NHC(O)NH), 81.6 (CO2 C (CH3)3), 59.3 (ArO C H3), 58.7, 58.6( C (CH2CH2CO2)3), 54.8( C (CH2CH2CONH)3), 35.0, 35.0 (Ar C H2NHC(O)NH), 32.7, 32.5 (CH2 C H2CO2C(CH3)3), 32.2, 32.2 (CH2 C H2CONH), 30.7( C H2CH2CONH), 30.4,( C H2CH2CO2C(CH3)3), 28.5, 28.4 (CO2C( C H3)3). compound 7c

Chem.

[0263] Compound 6c (0.097 g, 0.017 mmol) was prepared in a manner similar to that for 7b. Purification by reverse-phase flash chromatography eluting with a 120 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80–95% acetone / HO, 2 CV 95% acetone) gave a white solid (0.072 g, 0.014 mmol, 85%). 1 H NMR: (500 MHz, methanol-d4) δ m. 7.42-7.30 (3H, C H CNH(Ar)m.7.31-7.29 C H CNH2(Ar)), m.7.23-7.19(3H, C H CHCNH(Ar)), m.4.54-4.48(6H, ArC H 2NH), s.2.49(6H, ArC H 3), s.(3H, ArC H 3), m.2.28-1.90(144H, NHC H 2C H 2C(O)), s.1.44(243H, CO2C(C H 3)3). 13 C NMR: (125 MHz, methanol-d4) δ 175.5 ( C ONH), 174.4, 174.3( C O2C(CH3)3), 170.1(Ar C ONHR), 158.1(NH C (O)NH), 141.3( C NH2), 135.4( C CO2NHR), 134.7( C NHC(O)NH), 130.0( C CH3), 124.4, 118.9( C H C HCNH), 117.4( C HCNH2), 111.4( C CH2NHC(O)NH), C (CH2CH2CONH)3), 81.6(CO2 C (CH3)3), 58.7( C (CH2CH2CO2) 3、 C(CH2CH2CONH)3), 40.3(Ar C H2NHC(O)NH), 32.5(CH2 C H2CO2C(CH3)3), 32.2(CH2 C H2CONH), 30.7( C H2CH2CONH), 30.5, ( C H2CH2CO2C(CH3)3), 28.4(CO2C( C H3)3), 16.3(Ar C H3). compound 7d [ka]

[0264] Compound 6d (0.110 g, 0.020 mmol) was prepared in a manner similar to that for 7b. Purification by reverse-phase flash chromatography eluting with a 120 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80–95% acetone / HO, 2 CV 95% acetone) gave a white solid (0.022 g, 0.004 mmol, 21%). 1 H NMR (500 MHz, methanol-d4) δ m 7.43-7.13 (12H, Ar), m 4.50-4.29 (6H, ArC H 2NH), m.2.34-1.86(144H, NHC H 2C H 2C(O)), s.1.43(243H, CO2C(C H 3)3). 13 C NMR: (HSQC) (125 MHz, methanol-d4) δ 175.5 ( C ONH), 174.4( C O2C(CH3)3), 174.4(Ar C ONHR), 157.3(NH C (O)NH), 141.2( C NH2), 135.4( C CO2NHR), 134.7( C NHC(O)NH), 126.3( C H CHCNH), 124.4, ( C HCHCNH), 122.0( CH CCH2NHC(O)NH), 118.9(CH C HCNH), 115.6( C HCNH2), 81.6(CO2 C (CH3)3), 58.7( C (CH2CH2CO2)3, C (CH2CH2CONH)3), 44.4(Ar C H2NHC(O)NH), 35.1(CH2 C H2CO2C(CH3)3), 34.6(CH2 C H2CONH), 30.4( C H2CH2CONH), 30.2, ( C H2CH2CO2C(CH3)3), 28.0(CO2C( C H3)3). compound 7e [ka]

[0265] Compound 13 (231 mg, 0.30 mmol) was dried azeotropically with toluene and then dissolved in anhydrous dichloromethane (1.5 mL) under an inert N2 atmosphere. Pyridine (41 uL, 0.51 mmol) was added, followed by a solution of compound 5a (8 mg, 0.086 mmol) in anhydrous dichloromethane (0.5 mL), and the reaction mixture was stirred at 34 °C until complete TLC. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (SiO2, 1:4 to 1:2 EtOAc:CHCl, then 5:95 MeOH:CHCl) to give the FMOC-protected intermediate. HRMS: (ESI+) C 150 H 192 N 12 NaO 30 3+ Calculated value for: 983.7859, Found value [M+3Na] 3+:983.7844. Under an inert N2 atmosphere, the FMOC-protected intermediate (140 mg, 0.053 mmol) was dissolved in anhydrous dichloromethane (9 mL) and cooled to 0 °C. DBU (50 μL, 0.34 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (SiO2, CHCl2 then 7.5% MeOH:CHCl2) to give compound 7e (95 mg, 0.048 mmol, 91%). 1 H NMR: (400MHz, CD3OD, 298K): δ 7.40(s, 3H, NH), 7.35(d, J=8.2Hz, 3H, H 11 ), 7.21(d, J=2.0Hz, 3H, H8), 7.10(dd, J=8.2, 2.0Hz, 3H, H 10 ), 4.52(s, 6H, H5), 2.94-2.87(m, 6H, H2), 2.30-2.25(m, 18H, H 16 ), 2.12-2.06(m, 18H, H 15 ), 1.45(s, 81H, H 19 ), 1.26(t, J=7.4Hz, 9H, H1), HRMS:(ESI+)C 105 H 164 N 12 O 24 2+ Calculated for: 989.1002, Found [M+2H] 2+ :989.1004. compound 11 [ka]

[0266] Compound 2 was prepared in a similar manner to compound A1 by treating compound A1 (3.308 g, 5.443 mmol) with additional HCl (3.308 g, 5.443 mmol) and dissolving it in S1 (volume: 22.680 mL). R3 (volume: 1.270 mL, 7.258 mmol) was added dropwise, followed by R2 (volume: 1.000 mL, 4.536 mmol), and the reaction was stirred until complete by TLC. TLC with 70% EtOAc / CHCl indicated the reaction was complete in 24 h (visualized by UV / weak ninhydrin staining). The reaction mixture was transferred to a RBF, washed with CHCl, and concentrated in vacuo to give a brown residue. The crude product was purified by flash column chromatography, eluting with 50% to 100% EtOAc / CHCl. Colorless amorphous (2.50g, 4.35mmol, 80%). 1 H NMR: (400MHz, CDCl3)δ 7.74(d, J=7.5Hz, 2H, Ar H ), 7.60(d, J=2.0Hz, 2H, Ar H ), 7.45(s, 1H, Ar H ), 7.38(t, J=7.5Hz, 2H, Ar H ), 7.26(d, J=9.6Hz, 2H, Ar H ), 7.05(s, 1H, Ar H ), 6.84(s, 1H Ar H ), 6.65(d, J=8.4Hz, 1H C(O)N H CH2), 4.49(s, 1H, Flu-C H 2), 4.18(s, 2H, Flu-OC H 2), 3.68-3.45 (m, 14H, OC H 2), 3.27(t, J=5.0Hz, 2H C(O)NHC H 2), 1.34(d, J=6.7Hz, 2H, N3C H 2). compound 12 [ka]

[0267] Compound A1 (2.000 g, 3.291 mmol) in 16.5 mL of DCM and DIPEA (0.917 mL, 5.266 mmol) was treated with propargylamine (0.422 mL, 6.583 mmol) for 72 h in a similar manner to compound 2. Purification was performed by column chromatography using ethyl acetate as the eluent. White solid (1.36 g, 3.290 mmol, 99%) was obtained. 1 H NMR: (400 MHz, methanol-d) δ 7.95 (d, J = 7.5 Hz, 2H, Ar H ), 7.89-7.80(m, 3H, Ar H ), 7.61(d, J=8.4Hz, 1H, Ar H ), 7.52(t, J=7.4Hz, 2H, Ar H ), 7.44(s, 2H), 6.87(d, J=8.4Hz, 1H, Ar H ), 4.45(s, 2H), 4.40(s, 1H, Flu-C H 2), 4.17(d, J=2.5Hz, 2H, Flu-OC H 2), 2.87(t, J=2.4Hz, 1H, CH2CC H ), 2.67(p, J=1.9Hz, 2H, C H 2CCH). compound 13 [ka]

[0268] A 50 mL RBF was charged with compound A1 (500 mg, 1.017 mmol), di-tert-butyl-4-amino-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate* (560 mg, 1.35 mmol) and anhydrous toluene (10 mL). The slurry was evaporated to dryness and the residue was redissolved in anhydrous pyridine (5 mL) and DCM (3 mL). The mixture was stirred for 50 minutes. oThe mixture was stirred at RT for 16 h at RT. The solvent was removed to give a viscous brown oil, which was partitioned between EtOAc and 1 M aq HCl. The organic phase was washed with water and then with brine. The combined organic fractions were concentrated, then absorbed onto silica gel and purified by flash chromatography (20 to 50% EtOAc:DCM): pink powder (467 mg, 0.612 mmol, 60%). 1 H NMR: (400MHz, CDCl3)δ 7.79(d, J=7.6Hz, 2H, Ar H ), 7.64(d, J=2.1Hz, 1H, Ar H ), 7.43(t, J=7.5Hz, 2H, Ar H ), 7.34(s, 3H, Ar H ), 6.78(d, J=9.0Hz, 1H, N H ), 6.60(s, 1H, Ar H ), 6.30(s, 1H, Ar H ), 4.56(s, 2H, Flu-C H 2O), 4.28(s, 1H, Flu-C H 2), 4.08(s, 2H), 2.30(dd, J=8.8, 6.7Hz, 6H, C H 2C(O)), 2.16-2.04(m, 6H, CC H 2), 1.44(s, 24H, C(C) H 3)3). *Newkome, George R.;Weis, Claus D.Organic Preparation and Procedures International, 1996, vol.28, #4 p.495~498 compound 14 [ka]

[0269] A Schlenk flash was charged under N with (3S,4S)-pyrrolidine-3,4-diol (100.0 mg, 0.970 mmol), di-tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl)-4-isocyanatoheptanedioate (385.4 mg, 0.873 mmol) and anhydrous DMF to give an orange solution. The solution was stirred for 16 h, then poured into water (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried, and concentrated to dryness. An off-white solid (430 mg, 0.79 mmol, 81%) was obtained. 1 H NMR: (400MHz, CDCl3)δ 4.65(s, 1H, C(O)N H ), 4.15-4.06(m, 2H, C H OH), 3.95(s, 2H, O H ), 3.52(dd, J=10.9, 4.2Hz, 2H, NC H 2), 3.21(d, J=10.8Hz, 2H, NC H 2), 2.17(dd, J=9.0, 6.7Hz, 6H, C H 2C(O), 2.02-1.82(m, 6H, CC H 2), 1.37(s, 27H, C(C) H 3)3). 13 C NMR:(125MHz, CDCl3)δ 176.8(s, N C (O)N), 168.1(s, C C O2C), 79.7(s, CO2 C (CH3)3), 75.7(s, C OH), 51.5(s, C H2N), 30.8(s, C H2C(O)), 29.8(s, C C H2), 28.1(s, CO2C( C H3)3). compound 15 [ka]

[0270] A Schlenk flash was charged with compound 14 (400.0 mg, 0.734 mmol), anhydrous DCM, and TEA (0.409 mL, 2.93 mmol), and neat methylsulfonyl chloride (0.125 mL, 1.62 mmol) was added dropwise. The orange solution was stirred overnight to give a cloudy orange solution. TLC (SiO2, 100% EtOAc) showed complete consumption of the starting material to a new product (Rf = 0.4). Water was added (10 mL), and the organic layer was separated, dried over MgSO4, and concentrated to dryness. An orange crystalline solid (428 mg, 0.611 mmol, 83%) was obtained. 1 H NMR: (400MHz, CDCl3)δ 5.42(s, 1H, C(O)N H ), 5.2(d, J=4.5, 2H, C H OS(O2)O), 3.77(dd, J=12.2, 4.5Hz, 2H, NC H 2), 3.65(d, J=12.2Hz, 2H, NC H 2), 3.11, (s, 1H, C H 3S(O)2O), 2.24(t, J=8.0Hz, 6H, C H 2C(O), 1.97(m, 6H, CC H 2), 1.42(s, 27H, C(C) H 3)3). 13 C NMR:(125MHz, CDCl3)δ 176.9(s, N C (O)N), 168.3(s, C C O2C), 79.8(s,CO2 C (CH3)3), 79.0(s, CH3S(O)2O C ),49.0( C H2N), 38.6(s, C H3S(O)2O), 30.5(s, C H2C(O)), 30.2(s, C C H2), 28.4(s, CO2C( C H3)3). Compound 15a [ka]

[0271] Compound 15 (428.0 mg, 0.611 mmol) was dissolved in dry DMF and solid NaN3 (119.2 mg, 1.833 mmol, 3.000 equiv.) was added in one portion. The orange suspension was stirred for 16 h at 100°C. o The mixture was heated to 50°C, giving a dark brown solution. It was partitioned between EtOAc and water, washed with 2 x 10 mL of 5% LiCl (aq), brine (1 x 10 mL), dried over MgSO4, and then concentrated to dryness with approximately 1 g of silica gel. The crude product absorbed on this silica was loaded onto a frit on a 1 cm x 2 cm plug of fresh silica and eluted with 50% EtOAc (approximately 20 mL). The colorless filtrate was evaporated to dryness. A colorless crystalline solid (256 mg, 0.43 mmol, 74%) was obtained. 1 H NMR: (400MHz, CDCl3)δ 5.21(s, 1H, C(O)N H ), 3.92(m, 2H, C H N3), 3.60(dd, J=10.9, 5.7Hz, 2H, NC H 2), 3.30(ds, J=10.9, 3.3Hz, 2H, NC H 2), 2.19(t, J=7.5Hz, 6H, C H 2C(O), 1.92(m, 6H, CC H 2), 1.37(s, 27H, C(C) H 3)3). 13 C NMR:(125MHz, CDCl3)δ 176.8(s, N C (O)N), 169.3(s, C C O2C), 79.8(s, CO2 C (CH3)3), 64.0(s, C N3), 48.5(s, C H2N), 30.3(s, C H2C(O), 29.9(s, C C H2), 28.3(s, CO2C( C H3)3). compound 16 [ka]

[0272] Compound 15a (200.0 mg, 0.336 mmol) was dissolved in EtOH (1.000 mL) and mixed with 10% Pd / C (25.0 mg, 0.235 mmol). The reaction flask was purged with nitrogen and then with hydrogen. The resulting mixture was stirred under a hydrogen atmosphere (delivered from a balloon) for 20 hours. The crude reaction mixture was filtered through Celite™ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO, MeCN:CH2Cl2 1:4 then MeOH:CH2Cl2 1:9) to give compound 16 (93 mg, 0.171 mmol, 51%). 1 H NMR:(400MHz, CDCl3, 298K):δ 4.59(s, 1H, NH), 3.63(dd, J=10.1, 5.3Hz, 2H, H8), 3.08(q, J=5.7, 5.0Hz, 2H, H9), 2.94(dd, J=10.3, 5.7Hz, 2H, H8), 2.17(t, J=7.8Hz, 6H, H4), 1.95-1.85(m, 6H, H5), 1.38(s, 27H, H1). 13 C NMR:(100MHz, CDCl3, 298 K):δ 173.18(C3), 155.63(C7), 80.57(C2), 58.37(C9), 56.74(C6), 52.03(C8), 30.53(C5), 29.91(C4), 28.13(C1), HRMS:(ESI + )C 27 H 50 N4NaO7 + Calculated value for: 565.3572, Found value [M+Na] + :565.3547. compound 200 -1,3,5-tris(bromomethyl)-2-bromo-4,6-dimethylbenzene [ka]

[0273] 2-Bromo-4,6-dimethylbenzene (5.000 g, 0.027 mol, 1.000 equiv.), paraformaldehyde (12.736 g, 0.424 mol, 15.700 equiv.), and AcOH / HBr 33% (70 mL) were added to a dry 200 mL round-bottom flask. ZnBr (15.211 g, 0.068 mol, 2.500 equiv.) was slowly added while stirring, and the mixture was heated to 90 °C. After 24 h, an additional portion of paraformaldehyde (12.736 g, 0.424 mol, 15.700 equiv.) and 2.7 g of ZnBr (12.736 g, 0.424 mol, 15.700 equiv.) were added. The yellow solution was heated for an additional 140 h. The reaction mixture was then cooled to room temperature, and the colorless crystals isolated by filtration were washed with AcOH (3 × 10 mL) and then with water until the pH of the filtrate was neutral. After drying under vacuum for 2 days, colorless crystals were obtained (7.50 g, 0.016 mol, 60%).

[0274] 1 H NMR (400MHz, CDCl3) δ 4.78(s, 4H, CH2), 4.54(s, 2H, CH2), 2.54(s, 6H, CH3). Compound 201 -1,3,5-tris(azidomethyl)-2-bromo-4,6-dimethylbenzene [ka]

[0275] 1,3,5-Tris(bromomethyl)-2-bromo-4,6-dimethylbenzene (1.326 g, 2.859 mmol) was dissolved in dry DMF (30.000 mL) under nitrogen and stirred with NaN (1.115 g, 17.154 mmol). oThe mixture was heated to 5°C and stirred overnight. The reaction was cooled and poured into water (100 mL), and the precipitate was extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with 5% LiCl (2 x 20 mL), then brine, dried (MgSO), and concentrated to dryness behind a blast shield to give a colorless oil that crystallized on standing (1.00 g, 2.856 mmol, 99%).

[0276] 1 H NMR (400MHz, CDCl3) δ 4.72(s, 4H, CH2), 4.55(s, 2H, CH2), 2.50(s, 6H, CH3). Compound 202- 1,3,5-Tris(aminomethyl)-2-bromo-4,6-dimethylbenzene trihydrochloride [ka]

[0277] 1,3,5-Tris(azidomethyl)-2-bromo-4,6-dimethylbenzene (0.600 g, 1.713 mmol, 1.000 equiv.) and triphenylphosphine (3.011 g, 11.48 mmol, 6.7) were dissolved in THF (12 mL) and water (0.375 mL, 20.78 mmol, 12.13 equiv.) was added. o The mixture was stirred at RT overnight at RT. The solvent was completely removed and treated with 0.5 M HCl (10 mL). It was extracted with EtOAc (2 x 10 mL), and the aqueous layer was saved, concentrated to near dryness, and added to rapidly stirred acetone (20 mL). The white precipitate was collected on a frit, washed with acetone (10 mL), and dried under vacuum. A colorless solid (0.65 g, 1.71 mmol, 99%) was obtained.

[0278] 1 H NMR (400MHz, D2O) δ 4.54 (s, 4H, CH2), 4.38 (s, 2H, CH2), 2.53 (s, 6H, CH3). compound 203-Di-tert-butyl((2-bromo-5-(((tert-butoxycarbonyl)amino)methyl)-4,6-dimethyl-1,3-phenylene)bis(methylene))dicarbamate [ka]

[0279] 1,3,5-Tris(aminomethyl)-2-bromo-4,6-dimethylbenzene trihydrochloride (0.68 g, 1.78 mmol), BOCO (2.33 g, 10.7 mmol), and triethylamine (1.5 mL, 10.7 mmol) were dissolved in MeOH (70 mL) and stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between EtOAc (50 mL) and 0.5 M citric acid. The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic fractions were combined, dried (MgSO), and concentrated to dryness to give a colorless oil (0.80 g, 1.4 mmol, 78%) that crystallized on standing.

[0280] 1 H NMR (400MHz, CDCl3) δ 4.77 (br.s, 2H, NH), 4.55 (d, J=5.7Hz, 4H, CH2), 4.36 (br.s, 3H, NH and CH2), 2.48 (s, 6H, CH3), 1.44 (s, 9H, CH3). compound 204 -1-Bromo-2,4,6-tris(isocyanatomethyl)-3,5-dimethylbenzene [ka]

[0281] Prepared by a similar route to compound 103 using compound 202 (0.20 g, 0.35 mmol) to give compound 204 as a pale pink crystalline solid (94 mg, 0.27 mmol, 77%).

[0282] 1H NMR (400MHz, CDCl3) δ 4.70 (s, 4H, CH2), 4.49 (s, 2H, CH2), 2.52 (s, 6H, CH3).

[0283] 13 C NMR (101MHz, CDCl3)δ 138.4(C), 135.1(C), 134.4(C), 129.1(C), 124.4(C), 45.6(CH2), 41.3(CH2), 16.7(CH3).

[0284] HRMS(ESI + )C 14 H 13 BrN3O3 + Calculated value: 350.0135, Measured value [M+H] + :350.0139. compound 205 [ka]

[0285] The Schlenk tube was dried under vacuum with a heat gun and cooled to room temperature. Compound 84 (628.4 mg, 0.350 mmol, 3.5 equiv) was added to the flask and dissolved in anhydrous toluene (5 mL). The solvent was removed over the line, and the reagents were azeotropically dried. The resulting residue was dried for 30 minutes before use. The solid was redissolved in anhydrous toluene (4 mL), and a solution of 1-bromo-2,4,6-tris(isocyanatomethyl)-3,5-dimethylbenzene (compound 204, 35.0 mg, 0.100 mmol, 1.0 equiv) in anhydrous toluene (1 mL) was added to the flask. Pyridine (0.048 mL, 0.600 mmol, 6.0 equiv) was added, and the reaction was heated to 34 °C for 24 hours (Note: This reaction became bright orange over time). TLC (5% MeOH / CHCl, UV and Seebach visualization) indicated the reaction was complete. The reaction was concentrated in vacuo and purified by reverse-phase flash chromatography (SNAP Ultra C18 120 g cartridge, acetone:water 70:30 to 100:0 in 12 CV). Fractions 6–11 contained excess 3-G2MM linker, which was collected, and fractions 15–18 contained compound 205 as an off-white foam (348 mg, 61%).

[0286] 1 H NMR (400 MHz, CD3OD) δ 8.09-7.49 (br.m, 19H, ArH), 7.51-7.10 (br.m, 14H, ArH), 4.74-4.54 (br.m, 4H, benzyl CH2 and FmocH), 4.51-4.05 (br.s, 11H, benzyl CH2 and FmocH), 2.50 (br.s, 6H, methyl CH3), 2.31-1.81 (m, 144H, dendrimer CH2), 1.41 (s, 243H, dendrimer CH3).

[0287] HRMS (nanospray ESI + )C 308 H 466 BrN 21 O 75 4+ Calculated value: 1435.8134, Measured value [M+4H] 4+ :1435.8147. compound 206 [ka]

[0288] Compound 205 (327.0 mg, 0.057 mmol, 1.000 equiv) was dissolved in anhydrous CHCl (2.9 mL) and cooled to 0 °C. DBU (0.051 mL, 0.342 mmol, 6.0 equiv) was added dropwise and the reaction was stirred for 2 h. The reaction mixture was then concentrated in vacuo and purified by reverse-phase flash chromatography (SNAP Ultra C18 60 g cartridge, acetone:water 70:30 to 100:0 over 12 CV) to give compound 206 as a pale pink solid (0.278 g, 97%).

[0289] 1 H NMR (400 MHz, CD3OD) δ 7.40 (dd, J = 8.3, 3.5 Hz, 3H, ArH), 7.30 (d, J = 2.1 Hz, 3H, ArH), 7.21 (dd, J = 8.3, 2.1 Hz, 3H, ArH), 4.73 (br.s, 4H, benzyl CH2), 4.52 (br.s, 2H, benzyl CH2), 2.60 (br.s, 6H, CH3), 2.31-2.14 (m, 72H, dendrimer CH2), 2.13-2.04 (m, 18H, dendrimer CH2), 2.00-1.88 (m, 54H, dendrimer CH2), 1.44 (s, 243H, dendrimer CH3).

[0290] 13C NMR(126MHz, CD3OD)δ 175.5(C), 174.4(C), 170.1(C), 158.1(C), 158.0(C), 141.4(C), 140.2(C), 137.1(C), 136.1(C), 132.8(C), 130.7(C), 130.0(C), 129.9(C ), 124.4(CH), 118.9(CH), 117.3(CH), 81.7(C), 59.4(C), 58.7(C), 32.5(CH2), 32.2(CH2), 30.7(CH2), 30.5(CH2), 28.5(CH3), 17.1(CH3),

[0291] HRMS (nanospray ESI + )C 263 H 435 BrN 21 O 69 3+ Calculated value: 1691.0137, Measured value [M+3H] 3+ :1691.0132. compound 207 [ka]

[0292] Compound 206 (270.0 mg, 0.053 mmol, 1.0 equiv) was dissolved in anhydrous pyridine (22.3 mL), and the reaction mixture was heated to 40 °C using a DrySyn thermostat with the external temperature of the thermal probe set at 40 °C. In a separate pear-shaped flask, TEB NCO (compound 103, 20.9 mg, 0.064 mmol, 1.2 equiv) was dissolved in anhydrous CHCl (2.3 mL). The TEB NCO solution was added via syringe pump at 0.85 mL / hr. Upon completion of the addition, the reaction was allowed to stand at 40 °C overnight. The reaction mixture was concentrated under vacuum on a liquid nitrogen cold-finger rotary evaporator to dryness. The resulting foam was coevaporated twice with toluene, and the resulting foam was purified by reverse-phase chromatography (loaded in MeCN, SNAP Ultra C18 60 g cartridge, eluted with acetone:water 70:30 to 100:0 over 12 CV). Fractions 3-6 contained compound 207 as a colorless foam (196 mg, 68%).

[0293] 1 H NMR (500 MHz, CD3OD) δ 8.20-7.83 (m, 4H, ArH), 7.73-7.56 (m, 5H, ArH), 7.44 (s, 5H, NH), 4.55-4.31 (m, 12H, benzyl CH2), 2.96-2.74 (m, 6H, ethyl CH2), 2.55 (s, 6H, methyl CH3), 2.36-1.80 (m, 144H, dendrimer CH2), 1.44 (s, 243H, dendrimer CH3), 1.25-1.16 (m, 9H, ethyl CH3).

[0294] 13C NMR(126MHz, CD3OD:δ 175.5, 175.4, 174.3, 169.5, 169.3, 158.3, 158.0, 157.9, 157.5, 144.4, 144. 4, 139.7, 136.9, 136.2, 135.2, 134.3, 134.1, 132.7, 132.0, 131.4, 130.7, 12 9.8, 125.9, 125.8, 125.1, 124.5, 122.6, 81.6, 59.5, 59.4, 58.8, 58.7, 43.5, 40.1, 38.9, 32.4, 32.2, 32.2, 30.7, 30.7, 30.4, 28.5, 23.6, 17.1, 16.9, 16.7,

[0295] HRMS (nanospray ESI + )C 281 H 455 BrN 24 O 72 Na 3+ Calculated value: 1808.0615, Measured value [M+2H+Na] 3+ :1808.0601. Compound 208-Receptor 4 [ka]

[0296] Compound 207 (196 mg, 0.036 mmol, 1.0 equiv) was dissolved in CHCl (9.0 mL) and TFA (2.4 mL) was added. The reaction was left at room temperature overnight and then added dropwise to 300 mL of HO to precipitate the acid. The suspension was centrifuged in 50 mL batches, then washed with HO and sonicated. The isolated solid was then dried under high vacuum to give compound 208 as a colorless solid (108 mg, 77%).

[0297] 1H NMR (500 MHz, DMSO-d) δ 12.04 (s, 27H, COOH), 8.23-7.66 (m, 6H, ArH), 7.59-7.41 (m, 3H, ArH), 7.41-7.16 (m, 6H, NH), 6.67-6.34 (m, 6H, NH), 4.45-4.20 (m, 12H, benzyl CH), 2.81 (s, 6H, ethyl CH), 2.47 (s, 6H, methyl CH), 2.28-1.75 (m, 144H, dendrimer CH), 1.20-1.08 (m, 9H, ethyl CH).

[0298] 13 C NMR (126MHz, DMSO-d6)δ 174.4, 172.4, 165.7, 158.5, 158.3, 156.0, 155.6, 154.8, 150.6, 142.9, 138.0, 135.4, 135.1, 134.7, 133. 9, 133.5, 133.1, 130.2, 129.7, 129.1, 122.9, 78.7, 57.4, 56.4, 30.8, 30.4, 29.0, 28.1, 22.4, 16.7, 16.2. compound 209 [ka]

[0299] Prepared in a manner similar to compound 2 by treating the HBTU-activated linker (compound A1, 14.3 g, 11.8 mmol, 1.0 equiv.) in CHCl (16.5 mL) and DIPEA (2.7 mL, 21 mmol, 1.8 equiv.) with propargylamine (1.6 mL, 25 mmol, 2.1 equiv.) for 72 h. Purification by column chromatography using ethyl acetate as eluent afforded compound 209 as a colorless solid (2.24 g, 5.4 mmol, 46%).

[0300] 1H NMR(400MHz, CD3OD)δ 7.87-7.60(m, 5H, ArH), 7.57-7.45(m, 1H, ArH), 7.45-7.23(m, 4H, ArH), 6.79(d, J=8.4Hz, 1H, ArH), 4.45(br.s, 2H, Fmoc CH2), 4.27(br.s, 1H, Fmoc CH), 4.11(d, J=2.5Hz, 2H, alkyne CH2), 2.56(p, J=2.5Hz, 1H, alkyne CH).

[0301] HRMS(ESI + )C 25 H 21 N3O3Na + Calculated value: 434.1475, Measured value [M+Na] + :434.1479. Compounds 210a and 210b Compound 210a [ka] Compound 210b [ka]

[0302] A Schlenk flask was charged with a stir bar, compound 84 (0.933 g, 0.519 mmol, 1.7 equiv.), and compound 5a (0.100 g, 0.305 mmol, 1.0 equiv.), dissolved in anhydrous THF (6 mL) and pyridine (0.147 mL, 1.833 mmol, 6.0 equiv.), and then cooled to 50°C. oThe mixture was heated at RT for 5 h. Compound 209 (0.189 g, 0.458 mmol, 1.5 equiv) was added in one portion, and the reaction was stirred for an additional 12 h. The reaction mixture was transferred to a RBF, washed with CHCl, and then concentrated in vacuo. The resulting crude residue was then purified by reverse-phase flash chromatography (loaded with MeCN) on a 120 g SNAP Ultra C18 cartridge eluting with 1 CV 85% acetone / HO, 10 CV 85-95% acetone / HO, and 2 CV 95% acetone to afford a colorless solid identified as compound 210b (fr18-24) (312 mg, 35%), a colorless solid identified as compound 210a (fr37-47) (524 mg, 40%), and a colorless solid identified as compound 108 (fr57-60) (354 mg, 20%).

[0303] 1 H NMR compound 210a (400 MHz, CDCl3) δ 8.06-7.54 (m, 19H, ArH), 7.48-7.11 (14H, m, ArH), 4.60-4.28 (m, 13H, benzyl CH2 and FmocH), 4.23-4.09 (m, 4H, benzyl CH2, FmocH and alkyne CH2), 2.84 (br.s, 6H, ethyl CH2), 2.61 (t, J = 2.5 Hz, 1H, alkyne CH), 2.31-1.87 (m, 96H, dendrimer CH2), 1.43 (s, 162H, dendrimer CH3), 1.20 (br.s, 9H, ethyl CH3).

[0304] HRMS Compound 210a (nanospray ESI + )C 239 H 342 N 18 O 54 Na2 2+ Calculated value: 2188.2210, Measured value [M+2Na] 2+ :2188.2224.

[0305] 1H NMR compound 210b (400 MHz, CDCl3) δ 8.01-7.51 (m, 19H, ArH), 7.47-7.07 (m, 14H, ArH), 4.61-4.27 (m, 13H, benzyl CH2 and FmocH), 4.21-4.08 (m, 4H, benzyl CH2, FmocH and alkyne CH2), 2.84 (br.s, 6H, ethyl CH2), 2.61 (t, J = 2.5 Hz, 2H, alkyne CH), 2.34-1.82 (m, 48H, dendrimer CH2), 1.44 (s, 81H, dendrimer CH3), 1.19 (br.s, 9H, ethyl CH3).

[0306] HRMS Compound 210b (nanospray ESI + )C 166 H 213 N 15 O 33 Na2 2+ Calculated value: 1495.7634, Measured value [M+2Na] 2+ :1495.7628. compound 211 [ka]

[0307] A RBF charged with compound 210a (0.524 g, 0.121 mmol, 1.0 equiv) was dissolved in anhydrous CHCl (6 mL) under nitrogen and cooled to 0 °C. DBU (0.108 mL, 0.726 mmol, 6.0 equiv) was added dropwise, and the reaction mixture was allowed to stand at 0 °C for 2 h. The reaction mixture was then concentrated in vacuo and purified by normal-phase flash chromatography on a SNAP KP-Sil 50 g cartridge (eluting with CHCl:MeOH 100:0 to 90:10 over 12 CV). This material was then purified by reverse-phase chromatography (loaded with MeCN) on a SNAP Ultra C18 60 g cartridge (eluting with acetone:water 75:25 to 100:0 over 12 CV) to give compound 211 as a colorless solid (0.200 g, 0.055 mmol, 45%).

[0308] 1 H NMR(500MHz, CD3OD)δ 7.69-7.54(m, 1H, ArH) 7.46-7.32(m, 3H, ArH), 7.33-7.26(m, 2H, ArH), 7.23-7.19(m, 2H, ArH), 7.17-7.12(m, 1H, ArH), 4.54-4.43(m, 6H, benzyl CH2) 4.11(d, J=2.5, 2H, alkyne CH2), 2.88 (m, 6H, ethyl CH2), 2.58 (t, J=2.5, 1H, alkyne CH), 2.32-2.03 (m, 60H, dendrimer CH2), 2.01-1.84 (m, 36H, dendrimer CH2), 1.43 (s, 162H, dendrimer CH3), 1.25 (m, 9H, ethyl CH3).

[0309] HRMS (nanospray ESI + )C 194 H 315 N 18 O 48 3+ Calculated value: 1222.4271, measured value [M+3H] 3+ :1222.4281. compound 212 [ka]

[0310] An RBF charged with compound 210b (0.312 g, 0.106 mmol, 1.0 equiv) was dissolved in anhydrous CHCl (5.3 mL) under nitrogen and cooled to 0 °C. DBU (0.095 mL, 0.635 mmol, 6.0 equiv) was added dropwise, and the reaction mixture was allowed to stand at 0 °C for 2 h. The reaction mixture was then concentrated in vacuo and purified by normal-phase flash chromatography on a SNAP KP-Sil 50 g cartridge (CHCl:MeOH 100:0 to 90:10 over 12 CV). This material was then purified by reverse-phase chromatography (loaded with MeCN) on a SNAP Ultra C18 60 g cartridge (acetone:water 75:25 to 100:0 over 12 CV) to give compound 212 as a colorless solid (0.130 g, 0.057 mmol, 54%).

[0311] 1 H NMR(500MHz, CD3OD)δ 7.71-7.50(m, 1H, ArH) 7.46-7.32(m, 3H, ArH), 7.31-7.22(m, 2H, ArH), 7.22-7.16(m, 1H , ArH), 7.16-7.06(m, 2H, ArH), 4.61-4.34(m, 6H, benzyl CH2) 4.11(br.s, 4H, alkyne CH2), 2. 88 (q, J = 7.5, 6H, ethyl CH2), 2.58 (t, J = 2.5, 2H, alkyne CH), 2.33-2.04 (m, 30H, dendrimer CH2), 2.02-1.86 (m, 18H, dendrimer CH2), 1.44 (s, 81H, dendrimer CH3), 1.24 (t, J = 7.5, 9H, ethyl CH3).

[0312] HRMS (nanospray ESI + )C 121 H 185 N 15 O 27 2+ Calculated value: 1140.6798, Measured value [M+2H] 2+ :1140.6805. compound 213 [ka]

[0313] Compound 211 (200.0 mg, 0.055 mmol, 1.0 equiv) was dissolved in anhydrous pyridine (22.9 mL) and the reaction was heated to 40 °C in a DrySyn with the external temperature of the heat probe set at 40 °C. In a separate pear-shaped flask, compound 5a (21.6 mg, 0.066 mmol, 1.2 equiv) was dissolved in anhydrous pyridine (22.9 mL). CH 2 Cl 2 (The compound 5a solution was dissolved in 2.3 mL of 5a. The compound 5a solution was added via syringe pump at 0.85 mL / h. Once the addition was complete, the reaction was left at 40 °C overnight. The reaction mixture was concentrated under vacuum on a liquid nitrogen cold finger rotary evaporator to dryness. The resulting foam was co-evaporated twice with toluene, and the resulting foam was purified by reverse-phase chromatography (loaded in MeCN, SNAP Ultra C18 60 g cartridge, eluted with acetone:water 70:30 to 100:0 over 12 CV). Fractions 5-9 contained compound 213 as a colorless foam (115 mg, 53%).

[0314] 1 H NMR (500 MHz, CD3OD) δ 8.07-7.94 (m, 6H, ArH), 7.68 (d, J = 8.4 Hz, 2H, ArH), 7.63 (d, J = 8.4 Hz, 1H, ArH), 7.46 (s, 1H, NH), 4.59-4.34 (m, 12H, benzyl CH2), 4.17 (d, J = 2.5 Hz, 2H, alkyne CH2), 3.00-2.85 (m, 6H, ethyl CH2). 2.85-2.74 (m, 6H, ethyl CH2), 2.63 (t, J = 2.5Hz, 1H, alkyne CH), 2.36-2.09 (m, 60H, dendrimer CH2), 1.97 (t, J = 8.2Hz, 36H, dendrimer CH2), 1.45 (s, 162H, dendrimer CH3), 1.26-1.18 (m, 18H, dendrimer CH3),

[0315] 13 C NMR(126MHz, CD3OD 175.5, 175.5, 174.4, 169.3, 169.0, 158.4, 158.3, 157.2, 157.2, 144.5, 144.5 , 144.4, 137.1, 136.9, 134.3, 134.2, 134.0, 133.8, 131.2, 130.1, 130.1, 129.4 ,126.1,125.9,125.5,125.3,122.7,122.3,81.6,80.8,72.2,59.4,58.8,58.7,38.9,38.8,38.8,38.7,32.4,32.2,30.7,30.4,28.4,23.6,16.8,16.7,16.6,

[0316] HRMS (nanospray ESI + )C 212 H 336 N 21 O 51 3+ Calculated value: 1331.4802, measured value [M+3H] 3+ :1331.4784. Compound 214-Receptor 5 [ka]

[0317] Compound 213 (111 mg, 0.028 mmol, 1.0 equiv) was dissolved in CHCl (7.0 mL) and TFA (1.9 mL) was added. The reaction was left at room temperature overnight and then added dropwise to 300 mL of HO to precipitate the acid. This suspension was centrifuged in 50 mL batches, then washed with HO and sonicated. The isolated solid was then dried under high vacuum to give compound 214 as a colorless solid (36 mg, 43%).

[0318] 1 H NMR (500 MHz, DMSO-d) δ 12.02 (s, 27H, COOH), 8.73 (s, 1H, NH), 8.19-7.67 (m, 6H, ArH), 7.64-7.12 (m, 9H, ArH and NH), 6.48 (s, 3H, NH), 6.39 (s, 3H, NH), 4.52-4.15 (m, 12H, benzyl CH), 4.11-3.93 (m, 2H, alkyne CH), 3.34 (s, 6H, NH), 3.09 (s, 1H, alkyne CH), 2.82 (s, 6H, ethyl CH), 2.66 (s, 6H, ethyl CH), 2.28-1.62 (m, 144H, dendrimer CH), 1.26-1.01 (m, 18H, ethyl CH).

[0319] 13C NMR (126MHz, DMSO-d6) δ174.9, 172.9, 166.0, 165.9, 156.4, 156.1, 155.0 , 142.8, 142.7, 135.5, 135.4, 133.9, 133.8, 133.4, 133.3, 129.2, 128.7, 128.4, 127.5, 124.6, 123.9, 123.6, 123.1, 119.9, 119.3, 82.1, 73.1, 57. 9, 56.8, 37.6, 37.2, 31.2, 30.8, 29.5, 28.9, 28.6, 22.8, 22.5, 16.8, 16.7. compound 215 [ka]

[0320] Compound 212 (130.0 mg, 0.057 mmol, 1.0 equiv) was dissolved in anhydrous pyridine (23.8 mL), and the reaction was heated to 40 °C in a DrySyn system with the external temperature of the heat probe set to 40 °C. In a separate pear-shaped flask, compound 5a (22.0 mg, 0.068 mmol, 1.2 equiv) was dissolved in anhydrous CHCl (2.4 mL). The compound 5a solution was added via syringe pump at 0.85 mL / h. Upon completion of the addition, the reaction was allowed to stand at 40 °C overnight. The reaction mixture was concentrated under vacuum on a liquid nitrogen cold-finger rotary evaporator and dried. The resulting foam was coevaporated twice with toluene, and the resulting foam was purified by reverse-phase chromatography (loaded in MeCN, SNAP Ultra C18 60 g cartridge, eluted with acetone:water 70:30 to 100:0 over 12 CV). Fractions 3-4 contained compound 215 as a colorless foam (33 mg, 23%).

[0321] 1H NMR(500MHz, CD3OD)δ 8.03(d, J=2.1Hz, 2H, ArH), 7.99-7.92(m, 4H, ArH), 7.66(dd,J=8.6, 2.1Hz, 1H, ArH), 7.61(dd, J=8.6 , 2.1Hz, 2H, ArH), 7.45(s, 1H, NH), 4.56-4.36(m, 12H, benzyl CH2), 4.15(d, J=2.5Hz, 4H, alkyne CH2), 2.97 -2.84 (m, 6H, ethyl CH2), 2.84-2.72 (m, 6H, ethyl CH2), 2.61 (t, J = 2.5 Hz, 2H, alkyne CH), 2.32-2.09 (m, 30H, dendrimer CH2), 2.01-1.88 (m, 18H, dendrimer CH2), 1.43 (s, 81H, dendrimer CH3), 1.28-1.13 (m, 18H, ethyl CH3).

[0322] 13 C NMR(126MHz, CD3OD 175.6, 175.5, 174.4, 169.4, 169.1, 158.4, 158.3, 157.3, 157.2, 144.5, 144.5, 14 4.5, 137.2, 136.9, 134.3, 134.2, 133.9, 133.8, 131.1, 130.1, 130.1, 129.3, 126. 1, 126.0, 125.5, 125.3, 122.7, 122.2, 81.7, 80.8, 72.1, 59.5, 58.8, 58.7, 38.9, 38.8, 38.7, 38.7, 32.4, 32.2, 32.2, 30.7, 30.4, 30.0, 28.4, 23.6, 16.7, 16.6, 16.5,

[0323] HRMS (nanospray ESI + )C 139 H 206 N 18 O 30 2+ Calculated value: 1304.2589, Measured value [M+2H] 2+ :1304.2606. Compound 216-Receptor 6 [ka]

[0324] Compound 215 (30 mg, 0.012 mmol, 1.0 equiv) was dissolved in CHCl (3.0 mL) and TFA (0.81 mL) was added. The reaction was left at room temperature overnight and then added dropwise to 300 mL of HO to precipitate the acid. This suspension was centrifuged in 50 mL batches, then washed with HO and sonicated. The isolated solid was then dried under high vacuum to give compound 216 as a colorless solid (17 mg, 67%).

[0325] 1 H NMR (500MHz, DMSO-d6)δ 12.03(s, 27H, COOH), 8.75(t, J=5.7Hz, 1H, NH), 8.21-7.93(m, 6H, ArH), 7.91-7.73(m, 4H, NH), 7.60-7.42(m, 3H, ArH), 7.38-7.21(m, 6H, ArH and NH), 6.46(s, 3H, NH), 6.37(s, 3H, NH), 4.52-4. 21 (m, 12H, benzyl CH2), 4.03 (d, J = 2.5Hz, 2H, alkyne CH2), 3.10 (t, J = 2.5Hz, 1H, alkyne CH), 2.83 (s, 6H, ethyl CH2), 2.69 (m, 6H, ethyl CH2), 2.18-1.72 (m, 144H, dendrimer CH2), 1.19-1.09 (m, 18H, ethyl CH2).

[0326] 13 C NMR (126MHz, DMSO-d6)δ 174.9, 172.9, 166.0, 165.9, 156.3, 156.1, 155.0, 149.3, 142.8, 142.8, 13 7.6, 135.5, 135.4, 133.9, 133.8, 133.3, 130.6, 129.2, 128.7, 128.3, 127. 5, 124.7, 124.6, 123.9, 123.7, 123.1, 120.4, 119.9, 119.3, 82.1, 73.1, 57.8, 56.8, 37.5, 37.3, 31.2, 30.8, 29.5, 28.9, 28.5, 22.8, 22.5, 16.8, 16.7. compound 217 [ka]

[0327] N-Boc-L-serine (5.00 g, 24.4 mmol, 1.0 equiv.) was dissolved in anhydrous DMF (50 mL) and cooled to 0 °C. NaH (2.05 g, 51.1 mmol, 2.1 equiv.) (60% dispersion in mineral oil) was added. After stirring at 0 °C for 30 min, 3-bromopropyne (2.52 mL, 26.7 mmol) (80% solution in toluene) was added dropwise. After stirring at 0 °C for 30 min, the ice bath was removed and stirring continued at ambient temperature overnight. After this time, the solution was dark brown. Aqueous sulfuric acid buffer (16 g NaSO, 2 mL HSO, made up to 150 mL with HO) was added slowly to the flask to avoid the exotherm that occurred during quenching. A precipitate formed and slowly dissolved to give an orange solution. Brine (150 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 150 mL). The combined organics were washed with HO (3 x 150 mL), dried over MgSO, filtered, and the resulting filtrate was concentrated under vacuum. Some DMF was transferred during this step. Before the organics were completely concentrated, silica gel was added and then concentrated to dryness. The silica was then washed with CHCl (500 mL) followed by 10% MeCN / CHCl (500 mL) to elute the desired compound or until fractions were free of product (PMA stain, 10% MeCN / CHCl, streaky dark spots 0.3-0.4 R f). The resulting filtrate was concentrated in vacuo to give the desired compound as a yellow gum after drying under high vacuum (4.9 g, 83%). (S)-2-[(tert-butoxycarbonyl)amino]-3-(prop-2-yn-1-yloxy)propanoic acid (2.1 g, 8.6 mmol, 1.0 equiv) was dissolved in CHCl (33.6 mL) and TFA (33.1 mL) was added. The reaction was stirred at room temperature until complete by TLC. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the TFA salt of O-(prop-2-yn-1-yl)serine, which was carried on directly to the next step. O-(prop-2-yn-1-yl)serine (2.22 g, 8.63 mmol, 1.0 equiv) was dissolved in acetone (14.4 mL) and HO (14.4 mL). Sodium carbonate (2.75 g, 25.9 mmol, 3.0 equiv) and Fmoc-OSu (3.06 g, 9.07 mmol, 1.05 equiv) were added, and the reaction was stirred overnight. The reaction mixture was acidified to pH 3 with HCl (3 M) and extracted with EtOAc (3 × 100 mL). The combined organic phase was dried over NaSO, and the resulting filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (eluted with 2.5% MeOH in CHCl) to afford N-(((9H-fluor-9-yl)methoxy)carbonyl)-O-(prop-2-yn-1-yl)serine as a white solid (2.83 g, 90%). The second-generation dendritic amine (compound 82, 600 mg, 0.417 mmol, 1.0 equiv) was dissolved in THF (3.6 mL). N-(((9H-Fluor-9-yl)methoxy)carbonyl)-O-(prop-2-yn-1-yl)serine (183 mg, 0.500 mmol, 1.2 equiv), COMU (0.21 g, 0.50 mmol, 1.2 equiv), K-Oxima (90 mg, 0.50 mmol, 1.2 equiv), and DIPEA (0.22 mL, 1.25 mmol, 3.0 equiv) were then added to the solution. The reaction was stirred overnight at room temperature. The reaction was concentrated in vacuo to remove the THF. The residue was redissolved in EtOAc (40 mL) and then washed sequentially with KHSO (100 mL), saturated NaHCO (100 mL), and brine (100 mL). The organic phase was dried over MgSO, filtered, and concentrated in vacuo to give a crude yellow oil.Purification by reverse-phase flash chromatography on a SNAP Ultra C18 120 g cartridge (eluted with acetone:water 78:22 for 3 CV and 91:9 for 4 CV) afforded the Fmoc-protected intermediate (fr10-13) as an off-white solid (602 mg, 81%). To a RBF dried under vacuum with a heat gun, the Fmoc-protected intermediate (1.2 g, 0.67 mmol, 1.0 equiv.) was added. Anhydrous CHCl (33.6 mL) was added, and the flask was cooled to 0 °C. DBU (0.20 mL, 1.3 mmol, 2.0 equiv.) was added dropwise, and the reaction was stirred until complete by TLC (5% MeOH / CHCl, stained with ninhydrin for visualization). The reaction flask was warmed to room temperature after 2 h. The reaction was concentrated in vacuo and the crude residue was purified by reverse-phase chromatography on a SNAP Ultra C18 120 g cartridge (eluting with acetone:water 75:25 to 100:0 over 12 CV). Fraction 5-18 contained compound 217 as a yellow foam (0.95 g, 91%).

[0328] 1 H NMR (400 MHz, CD3OD) δ 4.58 (br.s, 1H, NH), 4.30-4.15 (m, 2H, alkyne CH2), 3.72 (dd, J = 9.2, 5.4 Hz, 1H, serine CHH), 3.63 (dd, J = 9.2, 5.4 Hz, 1H, serine CHH), 3.48 (t, J = 5.4 Hz, 1H, serine CH), 2.90 (t, J = 2.4 Hz, 1H, alkyne CH), 2.29-1.90 (m, 48H, dendrimer CH2), 1.45 (s, 81H, dendrimer CH3).

[0329] HRMS(ESI + )C 82 H 142 N5O 23 Na 2+ Calculated value for: 793.9991, Measured value [M+H+Na] 2+ :793.9974. compound 218 [ka]

[0330] The RBF was dried under vacuum using a heat gun. Once cooled, compound 217 (0.45 g, 0.29 mmol, 1.0 equiv.) and HBTU-activated linker (0.21 g, 0.35 mmol, 1.2 equiv.) were added and suspended in anhydrous THF (1.44 mL). DIPEA (0.08 mL, 0.46 mmol, 1.6 equiv.) was then added, and the reaction was stirred overnight at room temperature. The reaction was initially heterogeneous but became a homogeneous (dark brown) solution after 16 h at room temperature. The reaction was concentrated under vacuum and purified by reverse-phase flash chromatography on a SNAP Ultra C18 120 g cartridge (eluting with acetone:water 66:34 for 3 CV, then 88:12 for 5 CV). Fr7-11 contained compound 218 as a yellow solid (441 mg, 80%).

[0331] 1 H NMR(400MHz, CD3OD)δ 7.80-7.42(m, 6H, ArH), 7.41-7.07(m, 4H, ArH), 6.72(d, J=8.5Hz, 1H, ArH), 4.47(d, J=5.3Hz, 1H, serine CH), 4.39(br.s, 2H, Fmoc CH2), 4.19(br.s, 1H, Fmoc CH), 4.17-4.07 (t, J = 2.4 Hz, 2H, alkyne CH2), 3.83 (dd, J = 9.6, 5.3 Hz, 1H, serine CHH), 3.75 (dd, J = 9.6, 5.3 Hz, 1H, serine CHH), 2.81 (t, J = 2.4 Hz, 1H, alkyne CH), 2.17-1.73 (m, 48H, dendrimer CH2), 1.32 (s, 81H, dendrimer CH3),

[0332] HRMS(ESI + )C 104 H 157 N7O 26 Na2 2+ Calculated value: 983.5497, Measured value [M+2Na] 2+ :983.5496. compound 219 [ka]

[0333] Compound 218 (0.64 mg, 0.33 mmol, 3.5 equiv) was concentrated into a pear-shaped flask and dried via azeotropic distillation with anhydrous toluene (5 mL), followed by drying under high vacuum for 30 min. CH 2 Cl 2 ( Compound 5a (31 mg, 0.095 mmol, 1.0 equiv.) and pyridine (0.046 mL, 0.57 mmol, 6.0 equiv.) were added, and the reaction was heated to 34 °C for 12 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography on a SNAP Ultra C18 120 g cartridge (acetone:water elution: 70:30 to 95:5 over 12 CV). Fraction 1-8 yielded compound 218, and fraction 11-14 contained compound 219 as an off-white solid (476 mg, 83%).

[0334] 1 H NMR (400 MHz, CD3OD) δ 7.93-7.36 (m, 19H, ArH), 7.34-7.05 (m, 14H, ArH), 4.49 (t, J = 5.0 Hz, 3H, serine CH), 4.38 (br.s, 6H, benzyl CH), 4.27 (br.s, 6H, Fmoc CH), 4.15 (t, J = 2.2 Hz, 6H, alkyne CH), 4.07 (s, 3H, Fmoc CH), 3.84 (dd, J = 9.6, 5.0 Hz, 3H, serine CHH), 3.76 (dd, J = 9.6, 5.0 Hz, 3H, serine CHH), 2.81 (t, J = 2.2 Hz, 1H, alkyne CH), 2.74 (br.s, 6H, ethyl CH), 2.22-1.71 (m, 144H, dendrimer CH), 1.32 (s, 243H, dendrimer CH), 1.09 (t, J = 7.4 Hz, 9H, ethyl CH).

[0335] HRMS (nanospray ESI + )C 330 H 496 N 24 O 814+ Calculated value: 1523.6382, Measured value [M+4H] 4+ :1523.6409. compound 220 [ka]

[0336] An RBF charged with compound 219 (0.451 g, 0.074 mmol, 1.0 equiv) was dissolved in anhydrous CHCl (3.7 mL) under nitrogen and cooled to 0 °C. DBU (0.066 mL, 0.444 mmol, 6.0 equiv) was added dropwise, and the reaction mixture was allowed to stand at 0 °C for 2 h. The reaction mixture was then concentrated in vacuo and purified by reverse-phase flash chromatography on a SNAP Ultra C18 60 g cartridge (acetone:water eluted from 70:30 to 100:0 over 12 CV). Fraction 3-7 contained compound 220 as a colorless solid (0.279 g, 69%).

[0337] 1 H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 8.3 Hz, 3H, ArH), 7.24 (d, J = 2.1 Hz, 3H, ArH), 7.15 (dd, J = 8.2, 2.1 Hz, 3H, ArH), 4.48 (t, J = 5.3 Hz, 3H, serine CH), 4.42 (br.s, 6H, benzyl CH), 4.25-4.10 (m, 6H, alkyne CH), 3.84 (dd, J = 9.6, 5.3 Hz, 3H, ArH). H, serine CHH), 3.76 (dd, J = 9.6, 5.3 Hz, 3H, serine CHH), 2.83 (t, J = 2.4 Hz, 3H, alkyne CH), 2.80 (q, J = 6.1 Hz, 6H, ethyl CH), 2.20-1.73 (m, 144 H, dendrimer CH), 1.34 (s, 243 H, dendrimer CH), 1.22-1.12 (m, 9H, ethyl CH).

[0338] 13C NMR(126MHz, CD3OD)δ 175.4, 174.4, 171.6, 170.4, 157.8, 145.1, 141.4, 133.9, 131.4, 130.5, 124.4, 119.0, 117.4, 8 1.7, 80.4, 77.0, 70.4, 59.4, 59.4, 58.7, 56.2, 39.3, 32.2, 32.1, 30.7, 30.5, 28.5, 23.9, 17.0,

[0339] HRMS (nanospray ESI + )C 285 H 466 N 24 O 75 4+ Calculated value: 1357.0870, Measured value [M+4H] 4+ :1357.0824. compound 221 [ka]

[0340] Compound 220 (265.0 mg, 0.049 mmol, 1.0 equiv.), DMAP (18 mg, 0.147 mmol, 3.0 equiv.), and n-octyl glucoside (29 mg, 0.098 mmol, 2.0 equiv.) were weighed into a round-bottom flask and anhydrous toluene was added, which was removed in situ under high vacuum. The procedure was repeated, and the resulting foam was dried for 30 min. The reagents were then dissolved in anhydrous CHCl (98 mL) and heated to 34 °C. Compound 5a (19.2 mg, 0.059 mmol, 1.2 equiv.) was weighed into a separate dry RBF and dissolved in anhydrous CHCl (9.8 mL). This solution was then injected into the reaction mixture at 1 mL / h. Upon completion, the reaction was left at 34 °C for an additional 24 h. The reaction mixture was cooled and concentrated under vacuum. The fraction was purified by reversed-phase flash chromatography on a SNAP Ultra C18 120 g column (eluting with acetone:water 70:30 to 100:0 over 12 CV). Fraction 1-8 was collected and purified by preparative HPLC (C18 20 x 150 mm, 5 μm, 20 mL / min, acetone:water 70:30 to 100:0 over 30 min). Analysis at this stage was difficult due to the presence of n-octyl glucose (110 mg, 39%). Mass spectrometry confirmed that the material obtained after preparative HPLC contained compound 221.

[0341] HRMS (nanospray ESI + )C 303 H 487 N 27 O 78 4+ Calculated value: 1438.6254, Measured value [M+4H] 4+ :1438.6232. Compound 222-Receptor 7 [ka]

[0342] Compound 221 (110 mg, 0.019 mmol, 1.0 equiv) was dissolved in CHCl (4.8 mL) and TFA (1.3 mL) was added. The reaction was left at room temperature overnight and then concentrated in vacuo. The residue was purified by reverse-phase flash chromatography on a SNAP Ultra C18 30 g column (eluting with MeOH:water + 0.1% formic acid 10:90 to 100:0 over 12 CV). Fractions 30-32 were collected and purified by preparative HPLC (C18 20 × 150 mm, 5 μm, 20 mL / min, MeOH:water + 0.1% formic acid 10:90 to 100:0 over 30 min) to give compound 222 as a colorless solid (30 mg, 37%).

[0343] 1 H NMR (400 MHz, CD3OD) δ 8.46 (s, 3H, NH), 8.17 (s, 3H, ArH), 8.02 (d, J = 8.5 Hz, 3H, ArH), 7.62 (d, J = 8.5 Hz, 3H, ArH), 4.65 (t, J = 5.4 Hz, 3H, serine CH), 4.53-4.33 (m, 12H, benzyl CH), 4.37-4.23 (m, 6H, alkyl CH). 4.10-3.84 (m, 6H, serine CH2), 2.98 (t, J=2.4Hz, 3H, alkyne CH2), 2.76 (s, 6H, ethyl CH2), 2.69 (s, 6H, ethyl CH2), 2.48-1.68 (s, 144H, dendrimer CH2), 1.41-1.00 (m, 18H, ethyl CH3),

[0344] 13 C NMR(126MHz, CD3OD)δ 182.8, 175.2, 175.0, 170.6, 170.0, 160.8, 157.4, 156.8, 144.2, 132.3, 131.9, 128 .3, 127.8, 124.4, 68.7, 58.3, 58.2, 54.7, 37.6, 31.6, 30.8, 30.6, 22.6, 22.3, 15.4. compound 223 [ka]

[0345] A pre-dried Schlenk tube was charged with compound 84 (441 mg, 0.245 mmol) under a stream of nitrogen, and a solution of compound 5c (20 mg, 0.070 mmol) in THF (0.5 mL) was added. Dry THF (3.5 mL) and anhydrous pyridine (0.006 mL, 0.070 mmol) were added. The reaction was stirred at 50 °C for 16 h. The reaction mixture was concentrated to dryness, and the crude residue was purified by reverse-phase MPLC on a 120 g SNAP Ultra C18 cartridge (70-95% acetone / HO) to give compound 223 (197 mg, 0.035 mmol, 50%) as a white solid.

[0346] HRMS (nanospray ESI + )C 309 H 469 N 21 O 75 4+ Calculated value: 1419.3407, Measured value [M+4H] 4+ :1419.3391. compound 224 [ka]

[0347] Prepared in a manner similar to 7b from compound 223 (0.097 g, 0.017 mmol). Purification by reverse-phase flash chromatography eluting with a 120 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80–95% acetone / HO, 2 CV 95% acetone) gave a white solid (0.072 g, 0.014 mmol, 85%).

[0348] 1 H NMR (500 MHz, methanol-d4) δ m. 7.42-7.30 (3H, C H CNH ( Ar))m.7.31-7.29 C H CNH 2( Ar)), m.7.23-7.19(3H, C H CHCNH(Ar)), m.4.54-4.48(6H, ArCH 2NH), s. 2.49 (6H, ArC H 3), s. (3H, ArC H 3), m. 2.28 - 1.90 (144H, NHC H 2C H 2C(O)), s. 1.44 (243H, CO2C(C H 3)3).

[0349] 13 C NMR (125 MHz, methanol - d4) δ 175.5( C ONH), 174.4, 174.3( C O2C(CH3)3), 170.1 (Ar C ONHR), 158.1 (NH C (O)NH), 141.3( C NH2), 135.4( C CO2NHR), 134.7( C NHC(O)NH), 130.0( C CH3), 124.4, 118.9( C H C HCNH), 117.4( C HCNH2), 111.4( C CH2NHC(O)NH), C (CH2CH2CONH)3), 81.6 (CO2 C (CH3)3), 58.7,( C (CH2CH2CO2)3), 40.3 (Ar C H2NHC(O)NH), 32.5 (CH2 C H2CO2C(CH3)3), 32.2 (CH2 C H2CONH), 30.7( C H2CH2CONH), 30.5,( C H2CH2CO2C(CH3)3), 28.4 (CO2C( C H3)3), 16.3 (Ar C H3). compound 225

Chem.

[0350] Compound 224 (200.0 mg, 0.040 mmol, 1.0 equiv) was dissolved in anhydrous pyridine (16.8 mL), and the reaction was heated to 40 °C in a DrySyn system with the external temperature of the heat probe set to 40 °C. In a separate pear-shaped flask, compound 5c (13.7 mg, 0.048 mmol, 1.2 equiv) was dissolved in anhydrous CHCl (1.7 mL). The compound 5c solution was added via syringe pump at 0.85 mL / h. Upon completion of the addition, the reaction was allowed to stand at 40 °C overnight. The reaction mixture was concentrated under vacuum on a liquid nitrogen cold-finger rotary evaporator and dried. The resulting foam was coevaporated twice with toluene, and the resulting foam was purified by reverse-phase chromatography (loaded in MeCN, SNAP Ultra C18 60 g cartridge, eluted with acetone:water 70:30 to 100:0 over 12 CV). Fractions 4-6 contained compound 225 as a colorless foam (127 mg, 60%).

[0351] 1 H NMR (500 MHz, CD3OD) δ 8.07 (s, 2H, NH), 7.95 (s, 3H, ArH), 7.89 (br.s, 3H, ArH), 7.66 (d, J = 8.6 Hz, 3H, ArH), 7.44 (s, 6H, NH), 4.51 (s, 6H, benzyl CH2), 4.45 (s, 1H, benzyl CH2), 2.49 (s, 9H, methyl CH3), 2.43 (s, 9H, methyl CH3), 2.32-1.91 (m, 144H, dendrimer CH2), 1.43 (s, 243H, dendrimer CH3).

[0352] 13 C NMR(126MHz, CD3OD)δ 175.5, 174.4, 169.4, 158.6, 157.6, 137.5, 137.4, 135.1, 134.7, 131.4, 129.9, 126 .0, 122.6, 81.6, 59.5, 58.8, 40.2, 40.0, 32.5, 32.2, 30.7, 30.5, 28.5, 16.7, 16.3.

[0353] HRMS (nanospray ESI + )C 279 H 450N 24 O 72 Na4 4+ Calculated value: 1345.7981, Measured value [M+4Na] 4+ :1345.7994. Compound 226-Receptor 8 [ka]

[0354] Compound 225 (120 mg, 0.023 mmol, 1.0 equiv) was dissolved in CHCl (5.8 mL) and TFA (1.5 mL) was added. The reaction was left at room temperature overnight and then added dropwise to 300 mL of HO to precipitate the acid. The suspension was centrifuged in 50 mL batches, then washed with HO and sonicated. The isolated solid was then dried under high vacuum to give compound 226 as a colorless solid (80 mg, 91%).

[0355] 1 H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 27H, COOH), 8.00 (s, 3H, ArH), 7.93 (d, J = 8.5 Hz, 3H, ArH), 7.78 (s, 3H, NH), 7.73 (s, 3H, NH), 7.54 (d, J = 8.5 Hz, 3H, ArH), 7.41 (s, 3H, NH), 7.27 (s, 9H, NH), 6.54 (s, 3H, NH), 6.44 (s, 3H, NH), 4.36 (s, 12H, benzyl CH), 2.42 (s, 9H, methyl CH), 2.35 (s, 9H, methyl CH), 2.25-1.71 (m, 144H, dendrimer CH).

[0356] 13 C NMR (126MHz, DMSO-d6)δ 174.9, 172.8, 166.0, 156.6, 155.2, 135.9, 129.4, 128.8, 124.8, 123.7, 119.7, 67.5, 57.9, 56.8, 31.2, 30.8, 29.5, 28.5, 16.3. compound 227 [ka]

[0357] A Schlenk tube equipped with a magnetic stirrer was charged with compound 108 (200 mg, 0.04 mmol, 1.0 equiv.), DMAP (14.5 mg, 0.12 mmol, 3.0 equiv.), and n-octyl glucoside (23.2 mg, 0.08 mmol, 2.0 equiv.), dissolved in anhydrous CHCl (40 mL), and then warmed to 34 °C. A solution of 1,3,5-triisocyanatobenzene (12.5 mg, 0.051 mmol) in toluene (purity approximately 85%) was added to the flask, and the reaction was allowed to stand for 16 h. The solvent was removed under vacuum, and the crude product was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge (acetone:water eluted from 70:30 to 100:0 over 12 CV) to give compound 227 as a white solid (67 mg, 0.012 mmol, 32%).

[0358] 1 H NMR (500 MHz, CD3OD) δ 8.11 (d, J = 8.6 Hz, 3H, ArH), 7.76-7.69 (m, 6H, ArH), 7.14 (s, 3H, ArH), 4.43 (s, 6H, benzyl CH2), 4.29 (s, 6H, benzyl CH2), 2.80-2.70 (m, 6H, ethyl CH2), 2.31-1.86 (m, 144H, dendrimer CH2), 1.43 (s, 243H, dendrimer CH3), 1.21 (t, J = 7.4 Hz, 9H, ethyl CH3).

[0359] HRMS(ESI + )C 279 H 450 N 24 O 72 Na4 4+ Calculated value: 1345.7981, Measured value [M+4Na] 4+ :1345.7985. compound 228 [ka]

[0360] A 50 mL flask equipped with a magnetic stirrer and a tap gas adapter was charged with compound 13 (89 mg, 0.045 mmol). Compound 13 was placed under vacuum for 5 minutes and then placed under nitrogen. Compound 13 was dissolved in dry pyridine (20 mL, 0.002 M) and the solution was heated to 40 °C. A solution of compound 103 (16 mg, 0.050 mmol) in dry dichloromethane (1.0 mL, 0.050 M) was added at a rate of 0.1 mL / h. The reaction was stirred at 40 °C for an additional 12 hours and then concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on a 60 g SNAP Ultra C18 cartridge eluting with 60% acetone / water for 1 CV, 60% to 100% acetone / water for 10 CV, and 100% acetone for 6 CV.

[0361] 1 H NMR(500MHz, CD3OD)δ 7.99(d, J=8.5, 3H, ArH), 7.95(d, J=2.1, 3H, ArH), 7.62(s, 3H, RNHCO), 7.53(dd, J=8.6, 2.1, 3H, ArH), 4.48(s, 6H, BnH), 4.41(s, 6H, BnH ), 2.85(q, J=7.5, 6H, CH2CH3), 2.75(q, J=7.5, 6H, CH2CH3), 2.28(t, J=8.0, 18H, CCH2CH2), 2.10(t, J=8.0, 18H, CCH2CH2), 1.45(s, 81H, t BuH), 1.21(t, J=7.4, 18H, CH2CH3).

[0362] 13C NMR (126 MHz, CD3OD) δ 208.96(C), 173.18(C), 168.38(C), 156.81(C), 155.83(C), 143.16(C), 14 3.10(C), 134.95(C), 132.69(C), 132.24(C), 129.85(C), 127.95(C), 123. 89(CH), 123.46(CH), 120.73(CH), 80.34(C), 58.34(C), 37.39(CH2), 29.42(CH2), 29.19(CH2), 26.98(CH3), 22.25(CH2), 15.25(CH3), 15.22(CH3).

[0363] HRMS (nanospray) C 123 H 185 N 15 O 27 Calculated value: 1152.6793, Measured value [M+2H] 2+ :1152.6798. Compound 229-Receptor 9 [ka]

[0364] A 10 mL flask equipped with a magnetic stirrer was charged with compound 228 (27 mg, 0.012 mmol). Compound 228 was dissolved in dichloromethane (2.9 mL, 0.004 M) and trifluoroacetic acid was added. The reaction was stirred for 12 hours at room temperature. The reaction mixture was added dropwise to rapidly stirred water (150 mL), which resulted in the formation of a white precipitate. The precipitate was centrifuged and dissolved in acetone. After transferring to a round-bottom flask, the acetone was removed under vacuum and the white solid was azeotroped with toluene.

[0365] 1H NMR (600MHz, D2O) δ 7.86 (s, 3H, ArH), 7.76 (d, J= 8.5, 3H, ArH), 7.52(d, J=8.5, 3H, ArH), 4.44(s, 12H, BnH), 2.84-2.64(m, 12H, CH2CH3), 2.29-2.16(m, 18H, CCH2CH2), 2.15-2.01(m, 18H, CCH2CH2), 1.24-1.10(m, 18H, CH2CH3).

[0366] 13 C NMR (126MHz, DMSO-d6)δ 174.50(C), 166.09(C), 155.49(C), 154.56(C), 142.30(C), 134.21(C), 132.81(C), 128.34(C), 128.20(C), 123 .05(CH), 122.59(CH), 119.33(CH), 57.10(C), 37.04(CH2), 29.06(CH2), 28.22(CH2), 21.04(CH2), 16.34(CH3). compound 230 [ka]

[0367] Compound 11 (1.384 g, 2.409 mmol) and compound 5a (0.200 g, 0.611 mmol) were placed in a round-bottom flask under nitrogen and dissolved in anhydrous DMF (21 mL). To this solution was added dry pyridine (0.147 mL, 1.833 mmol), followed by 30 min. o The mixture was heated to RT for 100°C for 100 h. The solvent was evaporated under vacuum to give a gum, and the crude product was purified by column chromatography by pre-adsorption onto silica gel (20 g) by dissolving it in a mixture of dichloromethane and methanol and removing the solvent under vacuum to give a free-flowing powder. This pre-adsorbed material was loaded onto an empty cartridge, lined with a 100 g SNAP HP Sil cartridge, and eluted with a gradient of dichloromethane with increasing concentrations of methanol to give recovered compound 11 (367 mg) and compound 230 (1.171 g, 93%).

[0368] 1 H NMR:(400MHz, (CD3OD):δ m.br.7.95-7.20(33H, ArH), s.4.40(6H, ArCH2NH), m.4.30-4.10(9H, FmocH), m.3.71-3.60(42H, C H 2C H 2O, and OC H 2CH2NH2), m.3.33(6H,OCH2C H 2N3), m.br.2.79(6H, ArC H 2CH3), s.br.1.19(9H, ArCH2C H 3). compound 231 [ka]

[0369] To a stirred suspension of compound 230 (1.171 g, 0.571 mmol) in DCM (5 mL) was added distilled DBU (0.426 mL, 2.854 mmol) at room temperature. After 10 min, the reaction mixture became a clear solution and, after stirring for a total of 2 h, was loaded directly onto a 50 g SNAP KP Sil flash chromatography column. Elution with a gradient of dichloromethane containing increasing concentrations of methanol afforded the desired product contaminated with a fluorenyl by-product. Partial evaporation of the product-containing fractions yielded a thick white slurry, from which the solid was isolated by centrifugation. The wet solid was resuspended in methanol, centrifuged again, and the solid was dried to give compound 231 as an off-white solid (0.344 g, 43%).

[0370] 1 H NMR (400MHz, CDCl3 / methanol-d4)δ m.7.12-6.85 (9H, ArH), s.4.32 (6H, ArC H 2NH), m.3.50-3.40 (42H, C H 2C H 2O, and OC H 2CH2N3), t.3.20(6H, OCH2CH 2N3), m.br.2.66(6H, CH2), s.br.1.09(9H, CH3). compound 232 [ka]

[0371] Compound 231 (226 mg, 163 mmol) was dissolved in dry DMSO (1 mL) and diluted with dry pyridine (70 mL). o C., and a solution of compound 5a (60 mg, 183 mmol) in dry DCM (2 mL) was added by syringe pump over 6 h, followed by 40 o The mixture was stirred at RT for an additional 60 h at RT. Evaporation of the solvent on a rotary evaporator gave an orange gum dissolved in methanol containing little water. This was loaded onto a Biotage 120 g reverse-phase column and eluted with a water / methanol gradient. The compound eluting at approximately 80% methanol was collected, evaporated, redissolved in methanol, and concentrated by evaporating the solvent. The hot solution (approximately 3 mL) was allowed to cool overnight to give the product (Compound 232) as a white crystalline mass (83 mg, 30%).

[0372] 1 H NMR (400MHz, D2O) δs.8.09 (3H, ArH), d.7.98 (3H, ArH), d.7.58 (3H, ArH), m.4.41-4.45 (12H, ArC H 2NH), m.3.5-3.7(42H, OC H 2C H 2), m.2.7-2.9(12H, ArC H 2CH3), m.1.20(18H, ArCH2C H 3).

[0373] HRMS:(ESI + )C 81 H 116 N 24 O 18 2+ [M+2H] 2+Calculated value: 856.4449, measured value: 856.4470. Compound 233-Receptor 10 [ka]

[0374] Compound 232 (22 mg, 0.013 mmol) was dissolved in a mixture of warm methanol (2 mL) and water (0.1 mL), and triphenylphosphine (26 mg, 0.099 mmol) was added under a nitrogen atmosphere. The reaction mixture was then heated for 60 min. o The mixture was heated at 25°C for 16 hours and then cooled to room temperature. The cloudy mixture was diluted with more methanol and water, followed by 40 μL of 1 M aqueous hydrogen chloride (until acidic). Additional water was added and extracted twice with DCM to remove triphenylphosphine-based compounds. The slightly cloudy aqueous layer was passed through a Bond Elut (500 mg) several times until the eluate became clear and TLC showed no product passing through. The mixture was then eluted with 6 mL of water, followed by 2 x 4 mL of 25% MeOH in water, then 4 x 4 mL of 50%, and then 2 x 4 mL of 75% MeOH in water. TLC showed that the product eluted in the 25% to 75% methanol fractions, which were combined and evaporated, then redissolved in water, and lyophilized to give compound 233 (19 mg, 89%) as an off-white solid.

[0375] 1 H NMR (400MHz, D2O) δs.7.88 (3H, ArH), d.7.71 (3H, ArH), d.7.43 (3H, ArH), s.br.4.20 (12H, ArC H 2NH), m.3.4-3.6(42H, OC H 2C H 2, and O.C. H 2CH2NH2), t.3.00(6H, OCH2C H 2NH2), m.2.48(12H, ArC H 2CH3), m.0.96(18H, ArCH2C H 3).

[0376] HRMS: (MALDI + )C 81 H 120 N 18 O 18 Na + [M+Na] + Calculated value: 1655.8920, measured value: 1655.8932. Hexacarboxylate macrocycle (compound H8-receptor 11) [ka] N-(4,5-dimethyl-2-nitrophenyl)acetamide (Compound H2) [ka]

[0377] 4,5-Dimethyl-2-nitroaniline (compound H1, 2 g, 12 mmol) was suspended in glacial acetic acid (24 mL) and heated to 90° C. Acetic acid (1.2 mL, 13 mmol) was added, and the mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature and poured into water (300 mL). The yellow precipitate was filtered, washed with water, and recrystallized from ethanol to give compound H2 (2.4 g, 11.6 mmol, 97%) as a yellow crystalline solid.

[0378] 1 H NMR:(400MHz, (CDCl3):δ 2.25(s, 6H, C(9, 10) H 3), 2.32(s, 3H, C(1) H 3), 7.93(s, 1H, C(8) H ), 8.51(s, 1H, C(5)H), 10.26(br s, 1H, N H ).

[0379] 13 C NMR:(100MHz, (CDCl3):δ 19.1( C 10), 20.5( C 9), 25.6( C 1), 122.6( C 8), 125.9( C 5), 132.3(C 7), 132.7( C 6), 134.1( C 3), 146.8( C 4), 168.9( C (2)O);ν max 3341, 2987, 2901, 1708, 1695, 1576, 1323, 1151, 759cm -1 .

[0380] HRMS:(ESI + ) Measured value [M+Na] + :231.0745. 4-Amino-5-nitrophthalic acid (compound H3) [ka]

[0381] Compound H2 (2 g, 9.6 mmol) and KMnO4 (6 g, 37.9 mmol) were suspended in water (50 mL) under an inert N2 atmosphere and stirred at reflux for 3 days. Additional KMnO4 (3 g, 19 mmol) was added midway through the reaction time. The resulting brown precipitate was filtered and washed with water. The yellow filtrate was acidified to pH 3 with 1 M HCl, extracted with EtOAc (3 x 100 mL), washed with brine (100 mL), and dried (MgSO4). The solvent was removed in vacuo to give compound H3 (0.77 g, 2.88 mmol, 60%) as a yellowish-orange solid.

[0382] 1 H NMR:(400MHz, (CDCl3):δ 7.25(s, 1H, C(6) H ), 7.63(br s, 2H, N H 2), 8.70(s, 1H, C(3) H ), 11.50(br s, 2H, C(7, 8)O2 H ).

[0383] 13 C NMR:(100MHz, (CDCl3):δ 117.7( C 4), 118.7( C 6), 129.3(C 3), 132.6( C 5), 141.5( C 2), 146.9( C 1), 167.8( C 7), 169.0( C 8);ν max 3486, 3364, 2972, 2901, 1712, 1681, 1626, 1502, 1252, 1057, 882cm -1 .

[0384] LRMS: (EI) Actual measurement value [M] + :226.1. Dimethyl 4-amino-5-nitrophthalate (Compound H4) [ka]

[0385] Compound H3 (0.8 g, 3.5 mmol) was dissolved in MeOH (30 mL) and concentrated H2SO4 (0.5 mL) was added. The reaction mixture was stirred at reflux for 3 hours, after which the solvent was removed in vacuo. The residue was dissolved in EtOAc (60 mL), washed with 5% NaHCO3 (60 mL), brine (60 mL), and dried (MgSO4). The solvent was removed in vacuo, and the crude solid was purified by flash column chromatography (100% CHCl2) to give compound H4 (0.72 g, 2.8 mmol, 80%) as an orange solid.

[0386] 1 H NMR:(400MHz, (CDCl3):δ 3.88(s, 3H, C(10) H 3), 3.92(s, 3H, C(9) H 3), 6.91(s, 1H, C(6) H ), 7.26(br s, 2H, N H 2), 8.74(s, 1H, C(3) H ).

[0387] 13 C NMR:(100MHz, (CDCl3):δ 52.5( C 9), 53.1(C 10), 116.9( C 4), 118.3( C 6), 129.7( C 3), 131.2( C 5), 140.7( C 2), 146.6( C 1), 164.7( C 7), 168.0( C 8);ν max 3486, 3342, 2987, 2901, 1736, 1697, 1621, 1502, 1435, 1339, 1250, 1027, 762cm -1 .

[0388] LRMS:(ESI + ) Measured value [M+Na] + :277.1. Dimethyl 4-amino-5-nitrophthalate (Compound H5) [ka]

[0389] A solution of compound H4 (0.1 g, 0.39 mmol) in MeOH (10 mL) was added to Pd / C (10 mg) under an inert N atmosphere. The reaction vessel was then purged with hydrogen (1 atm), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then filtered through Celite, washed with CHCl, and the filtrate was concentrated in vacuo. The crude product was then purified by flash column chromatography (5% MeOH:CHCl) to give compound H5 (81 mg, 0.36 mmol, 93%) as a light brown solid.

[0390] 1 H NMR:(400MHz, (CDCl3):δ 3.84(s, 6H, C(5) H 3), 7.02(s, 2H, C(2) H ).

[0391] 13 C NMR:(100MHz, (CDCl3):δ 52.4( C 5), 116.6( C2), 124.1( C 3), 1136.6( C 1), 168.4( C 4).

[0392] HRMS:(ESI + ) Measured value [M+Na] + :247.0685. Hexaester amino half-acceptor (compound H6) [ka]

[0393] Compound H5 (80 mg, 0.36 mmol) was dissolved in dry pyridine (10 mL) under an inert N atmosphere and heated to 40 °C. A solution of TEB isocyanate (compound 103, 20 mg, 0.06 mmol) in dry CHCl (2 mL) was added over 1 h, and the reaction was stirred at 40 °C for 16 h. The reaction mixture was concentrated in vacuo, and residual pyridine was azeotroped with toluene (3 × 30 mL). The crude product was then suspended in CHCl, filtered, and air-dried to give compound H6 (49 mg, 0.049 mmol, 82%) as a light brown solid.

[0394] 1 H NMR:(400MHz, ((CD3)2SO):δ 1.19(t, J=7.2Hz, 9H, C(1) H 3), 2.79(br q, 6H, C(2) H 2), 3.72, 3.73(s, 2×9H, C(14, 16) H 3), 4.36(s, 6H, C(5) H 2), 5.87(br s, 6H, N H 2), 6.51(br t, 3H, N H C(5)), 6.84(s, 3H, C(11) H ), 8.13(s, 3H, C(8) H ), 8.60(s, 3H, N H ).

[0395] 13 C NMR:(100MHz, ((CD3)2SO):δ 16.9(C 1), 22.8( C 2), 37.7( C 5), 52.2, 52.5( C 14 and C 16), 114.0( C 11), 117.3( C 9), 121.7( C 8), 126.9( C 7), 128.6( C 10), 133.2( C 4), 142.2( C 12), 143.4( C 4), 155.5( C 6), 167.3, 169.2( C 9).

[0396] HRMS:(ESI + ) Measured value [M+H] + :1000.4041. Hexaester hexaurea macrocycle (compound H7) [ka]

[0397] Method A: Under an inert N2 atmosphere, compound H5 (40 mg, 0.18 mmol) was dissolved in dry pyridine (100 mL) and heated to 40 °C. A solution of TEB isocyanate (compound 103, 38 mg, 0.12 mmol) in dry CHCl (2 mL) was added over 1 h, and the reaction was stirred at 40 °C for 16 h. The reaction mixture was concentrated in vacuo, and residual pyridine was azeotroped with toluene (3 × 30 mL). The crude product was then purified by reverse-phase HPLC (100% water → 100% acetonitrile) to give compound H7 (9.5 mg, 0.007 mmol, 12%) as a white solid.

[0398] Method B: Under an inert N2 atmosphere, compound H6 (20 mg, 0.02 mmol) was dissolved in dry pyridine (20 mL) and heated to 40 °C. A solution of TEB isocyanate (compound 103, 7.8 mg, 0.024 mmol) in dry CHCl (2 mL) was added, and the reaction was stirred at 40 °C for 16 h. The reaction mixture was concentrated in vacuo, and residual pyridine was azeotroped with toluene (3 × 30 mL). The crude product was then purified by reverse-phase HPLC (100% water → 100% acetonitrile) to give compound H7 (8 mg, 0.006 mmol, 31%) as a white solid.

[0399] 1 H NMR:(400MHz, (CD3OD):δ 1.22(t, J=7.4Hz, 18H, C(1) H 3), 2.79(q, J=7.4Hz, 12H, C(2) H 2), 3.86(s, 18H, C(11) H 3), 4.42(s, 12H, C(5) H 2), 8.34(s, 6H, C(8) H ).

[0400] 13 C NMR:(100MHz, (CD3OD):δ 15.3( C 1), 22.4( C 2), 37.5( C 5), 51.5( C 11), 121.6( C 8), 126.3( C 7), 131.6( C 3), 131.9( C 9), 143.2( C 4), 155.6( C 6), 168.1( C 10).

[0401] HRMS:(ESI + ) Measured value [M+H] + :1327.5635. Hexacarboxylate hexaurea macrocycle (compound H8-receptor 11) [ka]

[0402] Compound H7 (8 mg, 0.006 mmol) was dissolved in MeOH (4 mL), followed by the dropwise addition of NaOH (5 M, 1 mL). The solution was stirred at 40° C. for 1 hour, and the reaction was diluted with water (5 mL). MeOH was removed under vacuum, and the aqueous solution was neutralized to pH 7.4 using an acidic ion exchange resin, filtered, and lyophilized to give compound H8 (7.8 mg, 0.0056 mmol, 93%) as a white solid.

[0403] 1 H NMR:(600MHz, D2O):δ 1.19(t, J=7.4Hz, 18H, C(1) H 3), 2.75(br q, 12H, C(2) H 2), 4.47(s, 12H, C(5) H 2), 7.73(s, 6H, C(8) H ).

[0404] 13 C NMR: (100 MHz, DO): δ 15.4 ( C 1), 22.5( C 2), 37.6( C 5), 124.6( C 8), 128.3( C 7), 131.8( C 3), 134.9( C 9), 143.3( C 4), 157.4( C 6), 176.4( C 10). compound 234 [ka]

[0405] Compound 15 (2.000 g, 3.363 mmol) was dissolved in THF (145.0 mL) and mixed with triphenylphosphine (0.838 g, 3.195 mmol). The reaction was stirred at room temperature for 24 h. Water (75 mL) was added and the reaction was heated at 50 °C for 3 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated in vacuo, and the crude residue was purified by reverse-phase MPLC on a C18 SNAP Ultra 120 g cartridge eluting (40% acetone:water to 60% acetone:water) to give compound 234 as a white solid (1.510 g, 2.655 mmol, 79%).

[0406] 1 H NMR(400MHz, CD3OD)δ 4.57(s, 1H, N H ), 3.86(dt, J=5.8, 4.0Hz, 1H, NC H 2), 3.73(dd, J=11.2, 5.8Hz, 1H, NC H 2), 3.59(dd, J=10.6, 6.1Hz, 1H, NC H 2), 3.41-3.32(m, 2H, C H N3, C H NH2), 3.13(dd, J=10.6, 4.1Hz, 1H NC H 2), 2.22(m, 6H, C H 2C(O)), 1.95(m, 6H, CC H 2), 1.45(s, 27H, C(C H 3)3).

[0407] 13 C NMR(100MHz, CD3OD)δ 174.9(s, C C O2C), 157.8(s, N C (O)N), 81.7(s, CO2 C (CH3)3), 67.2(s, C NH2), 58.3( C N3), 56.8(s, C H2N), 52.5( C H2N), 31.2(s, C H2C(O)), 30.8(s, C C H2), 28.4(s, CO2C(C H3)3). compound 235 [ka]

[0408] Compound 234 (67 mg, 0.118 mmol) and compound 103 (11 mg, 0.034 mmol) were dissolved in DCM (1 mL) and stirred for 18 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase MPLC on a C18 SNAP Ultra 120 g cartridge eluting with 70% acetone:water to 100% acetone:water to give compound 235 as a white solid (60 mg, 0.030 mmol, 89%).

[0409] 1 H NMR (400MHz, CD3OD)δ 4.39(s, 6H, ArC H 2NH), 4.24(dt, J=6.7, 4.7Hz, 3H, C H NH), 4.05(dt, J=6.0, 4.5Hz, 3H, NC H 2), 3.68(dd, J=10.8, 6.7Hz, 3H, NC H 2), 3.61(dd, J=11.3, 6.0Hz, 3H, NC H 2), 3.32(m, 3H, C H N3), 3.17(dd, J=10.8, 4.6Hz, 3H NC H 2), 2.78(q, J=7.4Hz, 6H, ArC H 2CH3), 2.21(dd, J=9.3, 6.6Hz, 18H, C H 2C(O)), 1.94(dd, J=9.3, 6.6Hz, 18H, CC H 2), 1.44(s, 81H, C(C H 3)3), 1.18(t, J=7.4Hz, 9H, ArCH2C H 3).

[0410] 13 C NMR(100MHz, CD3OD)δ 174.9(s, C C O2C), 157.8, 152.4(s, NC (O)N), 137.5, 133.7(Ar), 81.8(s, CO2 C (CH3)3), 69.1(s, C HNH), 61.5( C N3), 58.5(s, C H2N), 51.0( C H2N), 39.3(ArC H 2NH), 31.2(s, C H2C(O), 30.9(s, C C H2), 28.4(s, CO2C( C H3)3), 22.2(s, Ar C H2CH3), 15.6(s, ArCH2 C H3). compound 236 [ka]

[0411] To a solution of compound 235 (100 mg, 0.049 mmol) in MeOH (15 mL) was added a slurry of Pd / C (30 mg) in DCM. The reaction was placed under a hydrogen atmosphere and stirred overnight. Filtration through Celite™ and concentration of the filtrate gave a white solid (91 mg, 0.047 mmol, 96%).

[0412] 1 H NMR(400MHz, CD3OD)δ 4.46-4.33(m, 6H, ArC H 2NH), 4.25(d, J=6.9Hz, 3H, C H NH), 3.88-3.74(m, 6H, NC H 2), 3.60(d, J=6.4Hz, 3H, NC H 2), 3.33-3.27(m, 3H, C H NH2), 3.20(dd, J=10.4, 7.0zHz, 3H, NC H 2), 2.78(q, J=8.2Hz, 6H, ArC H 2CH3), 2.30-2.14(m, 18H, C H 2C(O)), 2.04-1.85(m, 18H, CCH 2), 1.44(s, 81H, C(C H 3)3), 1.19(t, J=7.4Hz, 9H, ArCH2C H 3).

[0413] 13 C NMR(100MHz, CD3OD)δ 174.8(s, C C O2C), 157.9, 151.5(s, N C (O)N), 137.2, 132.0(Ar), 81.7(s, CO2 C (CH3)3), 68.1(s, C HNH), 67.5( C NH2), 58.2(s, C H2N), 54.8( C H2N), 43.6(ArC H 2NH), 31.2(s, C H2C(O)), 30.8(s, C C H2), 28.4(s, CO2C( C H3)3), 22.3(s, Ar C H2CH3), 16.9(s, ArCH2 C H3). compound 237 [ka]

[0414] A mixture of compound 236 (110 mg, 0.056 mmol), n-octyl glucoside (33 mg, 0.112 mmol), and DMAP (21 mg, 0.168 mmol) was azeotropically dried with toluene in a two-necked flask and then placed under N2. The residue was then dissolved in DCM (110 mL) and cooled to 0 °C. A solution of TEB NCO (compound 103, 18 mg, 0.056 mmol) in DCM (20 mL) was added. The reaction mixture was heated to 35 °C for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge eluting with 70% acetone:water to 100% acetone:water (46 mg, 0.020 mmol, 36%).

[0415] 1 H NMR(500MHz、CD3OD)δ 4.79-4.33(m、6H、ArC H 2NH)、4.31-4.10(m、6H、ArC H 2NH)、3.97-3.80(m、6H、C H NH)、3.73-3.37(m、9H、NC H 2)、2.96-2.56(m、9H、NC H 2、ArC H 2CH3)、2.35-2.20(m、24H、ArC H 2CH 3、 C H 2C(O))、2.10-1.87(m、18H、CC H 2)、1.48-1.40(m、81H、C(C H 3)3)、1.24-1.10(m、18H、ArCH2C H 3)。

[0416] 13 C NMR(125MHz、(CD3)2SO)δ 172.5(s、C C O2C)、157.6、155.4(s、N C (O)N)、141.6、133.9(Ar)、79.7(s、CO2 C (CH3)3)、56.2(NH C (CH2)3)、52.7(s、 C HNH)、50.2(s、 C H2N)、36.6(ArC H 2NH)、29.4(s、 C H2C(O))、29.3(s、C C H2)、27.8(s、CO2C( C H3)3)、22.0(s、Ar C H2CH3)、16.3(s、ArCH2 C H3)。

[0417] MS:(ESI+)C 117 H 195 N 18 O 27 2+Calculated for: 1141.7180, Found [M+2H] 2+ :1141.7196 Compound 238-Receptor 12 [ka]

[0418] Compound 237 (8 mg, 3.504 μmol) was dissolved in TFA (1.3 mL) and heated to 30°C with stirring for 20 hours. The reaction mixture was cooled, and pentane (25 mL) was added. The resulting suspension was centrifuged, and the supernatant was removed. The residual oil was dissolved in 0.2 mL of aqueous NaHCO3 solution (3.5 mL) and the solution was desalted through a 20 mL column of G-25 Sephadex. The resulting solution was lyophilized to give compound 238 as a white solid (6.5 mg, 3.290 mmol, 94%).

[0419] 1 H NMR (500MHz, D2O) δ 4.66-4.50(m, 3H, ArC H 2NH), 4.27-4.03(m, 9H, ArC H 2NH), 4.02-3.82(m, 3H, C H NH), 3.79-3.34(m, 12H, C H NH, NC H 2), 3.09-2.75(m, 6H, ArC H 2CH3), 2.75-2.27(m, 9H, NC H 2. ArC H 2CH3), 2.26-2.13(m, 18H, C H 2C(O)), 2.03-1.89(m, 18H, CC H 2), 1.23-1.09(m, 18H, ArCH2C H 3).

[0420] 13 C NMR(125MHz, D2O)δ 183.4(s, C C O2), 160.2, 159.7, 159.3(NH C (O)NH), 157.6(s, NHC (O)N), 144.9, 144.2, 144.1(Ar), 58.1(NH C (CH2)3), 58.0, 57.9(s, C HNH), 49.1, 48.4, 47.7(s, C H2N), 39.8, 38.8, 37.6 (ArC H 2NH), 32.2, 32.1(s, C H2C(O)), 31.7(s, C C H2), 23.5, 22.7, 22.1(s, Ar C H2CH3), 16.1, 15.9, 15.5(s, ArCH2 C H3).

[0421] MS: (ESI+)C 117 H 195 N 18 O 27 2+ Calculated for: 1141.7180, Found [M+2H] 2+ :1141.7196 compound 239 [ka]

[0422] A 1 L flask equipped with a side-arm gas adapter and a magnetic stirrer was dried under vacuum using a heat gun. The flask was cooled to room temperature and charged with G2 amine (compound 82, 2.50 g, 1.74 mmol) under a stream of nitrogen. THF (100 mL) and EtN (0.25 mL, 1.80 mmol) were added, and the flask was cooled to 0 °C in an ice bath. A solution of triphosgene (0.26 g, 1.00 mmol) in THF (25 mL) was added dropwise over 20 min. After 3 h, the solvent was removed under vacuum, and the resulting residue was dissolved in chloroform (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO) and concentrated under vacuum to give compound 239 as a white foam (2.50 g, 1.71 mmol, 98%).

[0423] 1H NMR (400 MHz, toluene-d) δ 2.26 (m, 18H, C H 2), 2.07(m, 30H, C H 2), 1.40(s, 81H, C H 3).

[0424] 13 C NMR (100 MHz, toluene-d) δ 173.3 (C C O2C), 172.4( C ONH), 123.7(N= C =O), 80.4( C (CH3)3), 58.2(NH C (CH2)3), 53.7( C (NCO)), 30.7( C H2), 30.5( C H2), 28.7( C H2), 28.5( C H3). compound 240 [ka]

[0425] A Schlenk tube was charged with (3S,4S)-pyrrolidine-3,4-diol (185.0 mg, 1.790 mmol), G2 NCO (2.500 g, 2.000 mmol), and anhydrous DMF (100 mL) under N2. The solution was stirred for 16 h, poured into 5% aqueous LiCl (700 mL), and extracted with EtOAc (300 mL). The organic layer was separated, dried, and concentrated to a gummy solid (2.760 g, 1.759 mmol, 88%).

[0426] 1 H NMR (400MHz, CDCl3)δ 6.24(s, 3H, C(O)N H ), 6.13(2H, s, O H ), 4.19(s, 1H, NC(O)N H ), 3.63(dd, J=11.5, 3.7Hz, 2H, C H OH), 3.54-3.37(m, 4H, NC H2), 2.17(dd, J=10.3, 6.4Hz, 24H, C H 2C(O)), 1.92(dd, J=9.9, 6.4Hz, 24H, CC H 2), 1.41(s, 81H, C(C H 3)3).

[0427] 13 C NMR(100MHz, CDCl3)δ 173.4( C (O)NH), 172.9(C C O2C), 162.6(s, N C (O)N), 80.8(s, CO2 C (CH3)3), 80.7(s, C OH), 57.4(s, C H2N), 30.1(s, C H2C(O)), 30.0(s, C H2C(O)NH), 29.9(s, C C H2), 29.9(C C H2), 28.2(s, CO2C( C H3)3). compound 241 [ka]

[0428] Compound 240 (1.851 g, 1.180 mmol) was dissolved in DCM (13.9 mL) and triethylamine (0.66 mL, 4.719 mmol) was added. The reaction was cooled to 0 °C and mesyl chloride (0.20 mL, 2.595 mmol) was added dropwise. The reaction was stirred at room temperature for 16 h and washed with 5% aqueous KHSO4, saturated aqueous NaHCO3, and brine. The organic layer was concentrated in vacuo to give compound 241 as a white foam (1.350 g, 0.783 mmol, 66%).

[0429] 1 H NMR (400MHz, CDCl3)δ 6.95(s, 1H, NC(O)N H ), 6.17(s, 3H, C(O)N H)、5.32 - 5.13 (m, 2H, C H OSO2), 3.94 - 3.56 (m, 4H, NC H 2), 3.13 (s, J = 1.6 Hz, 2H, SO2C H 3), 2.31 - 2.11 (m, 24H, C H 2C(O)), 2.04 - 1.86 (m, 24H, CC H 2), 1.41 (s, 81H, C(C H 3)3).

[0430] 13 C NMR (100 MHz, CDCl3) δ 173.3 ( C (O)NH), 172.7 (C C O2C), 156.3 (s, N C (O)N), 80.6 (s, CO2 C (CH3)3), 80.1 (s, C OSO2), 57.4 (s, C H2N), 38.6 (SO2 C H3), 29.9 (s, C H2C(O)), 29.9 (s, C H2C(O)NH), 29.8 (s, C C H2), 29.8 (C C H2), 28.1 (s, CO2C( C H3)3). compound 242

Chem.

[0431] NaN (0.131 g, 2.017 mmol) was added to a solution of compound 241 (1.160 g, 0.672 mmol) in DMF (3.4 mL) at 0 °C. The reaction was then heated at 100 °C for 16 h. The reaction was cooled, diluted with EtOAc (30 mL), and washed with water (30 mL), 5% aqueous LiCl (2 × 30 mL), and brine (30 mL). The organic layer was concentrated in vacuo, and the residue was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge eluting (70% acetone:water to 100% acetone:water) to give compound 242 as a white solid (788 mg, 0.487 mmol, 72%).

[0432] 1 H NMR(400MHz, CD3OD)δ 4.29-4.18(m, 2H, C H N3), 3.84-3.70(m, 2H, NC H 2), 3.55-3.44(m, 2H, NC H 2), 2.32-2.19 (m, 24H, C H 2C(O)), 2.06-1.98(m, 24H, CC H 2), 1.52(s, 81H, C(C H 3)3).

[0433] 13 C NMR(100MHz, CD3OD)δ 175.8( C (O)NH), 174.4(C C O2C), 158.1(s, N C (O)N), 81.7(s, CO2 C (CH3)3), 65.1(s, C H2N3), 62.2(NC(O)NH C (CH2)3), 61.5(NH C (CH2)3), 58z.8( C H2N), 30.7(s, C H2C(O)), 30.7(s, C H2C(O)NH), 30.5(s, C C H2), 30.5(C C H2), 28.4(s, CO2C( C H3)3). compound 243 [ka]

[0434] Compound 241 (300 mg, 0.185 mmol) was dissolved in THF (8.0 mL). Triphenylphosphine (46 mg, 0.176 mmol) was added and the reaction was stirred for 18 hours. Water (4.0 mL) was added and the reaction was heated at 50°C for 6 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge eluting (75% acetone:water to 100% acetone:water) to give compound 243 as a white solid (187 mg, 0.117 mmol, 66%).

[0435] 1 H NMR(400MHz, CD3OD)δ 3.92-3.72(m, J=5.8, 4.0Hz, 3H, NC H 2), 3.61(dd, J=10.7, 6.0Hz, 1H, C H N3), 3.41-3.32(m, 1H, C H NH2), 3.24-3.12(m, 1H NC H 2), 2.23-2.16(m, 24H, C H 2C(O)), 1.99-1.91(m, 24H, CC H 2), 1.45(s, 81H, C(C H 3)3).

[0436] 13 C NMR(100MHz, CDCl3)δ 173.3( C (O)NH), 172.7(C C O2C), 158.2(s, N C (O)N), 81.6(s, CO2 C (CH3)3), 58.7( C NH2), 58.6(s, C H2N), 58.4( C N3), 33.1(s, C H2C(O)), 32.3(s, CH2C(O)NH), 30.7(s, C C H2), 30.5(C C H2), 28.4(s, CO2C( C H3)3). compound 244 [ka]

[0437] Compound 7b (80 mg, 0.016 mmol) was azeotropically dried with toluene in a reaction flask and then redissolved in pyridine (8.0 mL). This was heated to 40 °C, and a solution of compound 5a (6.2 mg, 0.019 mmol) in DCM (0.7 mL) was added via syringe pump over 3 h. The reaction was then cooled to room temperature and stirred for an additional 16 h. The reaction was concentrated in vacuo, and the resulting crude residue was purified by reverse-phase flash chromatography on a 30 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80-95% acetone / HO, 2 CV 100% acetone) to give compound 244 as a white solid (55 mg, 0.010 mmol, 64%).

[0438] 1 H NMR (500 MHz, methanol-d4) δ z d.8.12(3H, J=2.1Hz, Ar), dd.7.56(3H, J=8.4, 2.1Hz, Ar), d.7.41(3H, J=8.4Hz), s.4.58(6H, ArC H 2NH), s.4.45(6H, ArC H 2NH), s.3.85(9H, ArOC H 3), m.2.82-2.72(6H, ArC H 2CH3), m.2.35-1.89(144H, NHC H 2C H 2C(O)), s.1.43(243H, CO2C(C H 3)3), t.1.20(9H, J=7.3Hz, ArCH2C H 3).

[0439] 13 C NMR (125 MHz, methanol-d4) δ 175.5 ( C ONH), 174.4( C O2C(CH3)3), 171.1(Ar C ONHR), 81.6(CO2 C (CH3)3), 59.3(ArO C H3), 58.7( C (CH2CH2CO2)3), 54.6( C (CH2CH2CONH)3), 44.2, 43.7(Ar C H2NHC(O)NH), 32.2(CH2 C H2CONH, C H2CH2CONH), 30.7(CH2 C H2CO2C(CH3)3), 30.5, ( C H2CH2CO2C(CH3)3), 28.5(CO2C( C H3)3), 16.9(ArCH2 C H3).

[0440] MS: (ESI+)C 282 H 456 N 24 O 75 3+ Calculated value for: 1795.0979, Found value [M+3H] 3+ :1795.0938. Compound 245-Receptor 13 [ka]

[0441] Compound 244 (8.5 mg, 0.002 mmol) was dissolved in DCM (0.5 mL) and formic acid (0.5 mL, 13.3 mmol) was added. After 24 h, the reaction mixture was added dropwise to stirring water (20 mL) and the white precipitate was collected by centrifugation. The supernatant was decanted, and the white solid was neutralized to pH 7 using 10 mM NaOH solution. The resulting solution was desalted on a 10 mL column of G-25 Sephadex. The resulting solution was lyophilized to give a white solid (1 mg, 0.32 μmol, 16%).

[0442] 1 H NMR (500MHz, CD2Cl2 / formic acid-d2, 1:1)δ 1 H NMR (500 MHz, methanol-d4) δ s. 8.18 (3H, Ar), s. 7.50 (6H, Ar), s. 4.48 (6H, ArC H 2NH), s.4.41(6H, ArC H 2NH), s.3.83(9H, ArOC H 3), m.2.69-2.60(6H, ArC H 2CH3), m.2.45-1.81(144H, NHC H 2C H 2C(O)), m.1.16-1.08(9H, ArCH2C H 3). compound 246 [ka]

[0443] Prepared in a manner similar to compound 244 from compound 7a (202.0 mg, 0.040 mmol) and 5c (11.4 mg, 0.040 mmol). Purification by reverse-phase flash chromatography eluting with a 120 g SNAP Ultra C18 cartridge (1 CV 80% acetone / HO, 10 CV 80–97% acetone / HO, 4 CV 97% acetone) gave compound 246 as a white solid (108.0 mg, 50.6%).

[0444] 1H NMR (500 MHz, methanol-d4) δ m. 8.08-7.58 (9H, Ar), m. 4.63-4.30 (12H, ArC H 2NH), m.2.95-2.60(9H ArC H 3), m.2.32-1.84(150H, NHC H 2C H 2C(O), ArC H 2CH3), s.1.43(243H, CO2C(C H 3)3), s.1.29(9H, ArCH2C H 3). Compound 247-Receptor 14 [ka]

[0445] Compound 246 (108 mg, 0.02 mmol) was dissolved in anhydrous DCM (volume: 20 mL) and TFA (4.8 mL, 60.0 mmol) at room temperature. The resulting yellow solution was stirred at room temperature for 12 hours. Volatiles were removed under vacuum to give a yellow solid. The solid was purified by reverse-phase MPLC on a C18 SNAP Ultra 60 g cartridge by loading the sample in 1:1 MeOH / HO + 0.1% formic acid. The resulting white solid was neutralized to pH 7 using 100 mM NaOH solution, and the resulting solution was concentrated to dryness under vacuum. A white crystalline solid (30 mg, 0.008 mmol, 40%) was obtained.

[0446] 1 H NMR (500 MHz, methanol-d4) δ m. 8.37-7.81 (9H, Ar), m. 4.57-4.22 (12H, ArC H 2NH), m.2.85-1.66(159H, ArC H 3. NHC H 2C H 2C(O), ArC H 2CH3), t.1.25(9H, J=9.2Hz, ArCH2C H 3). 2,3:4,5-Bis-O-(1-methylethylidene)-1-O-2-propynyl-L-arabinitol (Compound 248) [ka]

[0447] To a suspension of sodium hydride (500 mg of 60% by weight in oil, 12.9 mmol) in THF (20 mL) was added 2,3:4,5-bis-O-(1-methylethylidene)-L-arabinitol (2.00 g, 8.61 mmol). o The mixture was heated at RT for 30 min, then cooled in an ice bath, after which propargyl bromide (2.56 g, 17.2 mmol) was added. o After stirring at 5°C for 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional hour. Water was then carefully added and the organic solvent was evaporated. The residue was dissolved in a mixture of DCM and aqueous citric acid, and the organic layer was dried over sodium sulfate and evaporated to give 2.38 g of an orange oil. Silica gel chromatography eluting with a DCM to 10% diethyl ether gradient gave 1.47 g of a yellow oil. This material was loaded onto another silica gel column eluting with 15% EtOAc in petrol and evaporated to give 2,3:4,5-bis-O-(1-methylethylidene)-1-O-2-propynyl-L-arabinitol (1.26 g, 54%) as a colorless oil.

[0448] 1 H NMR(400MHz, CDCl3)δ m.4.23(2H, OC H 2CCH), m.4.15-4.02(3H), dd.3.95(1H), dd.3.82(1H), t.3.71(1H), dd.3.63(1H), t.2.42(1H, OCH2CC H ), s.1.405(3H), s.1.40(3H), s.1.37(3H), s.1.33(3H).

[0449] 13C NMR (400MHz, CDCl3)δ 109.97, 109.78, 79.60, 79.60, 77.84, 77.24, 74.76, 70.43, 67.77, 58.81, 27.16, 27.12, 26.85, 25.36. 1-O-2-Propynyl-L-arabinitol (Compound 249) [ka]

[0450] 2,3:4,5-Bis-O-(1-methylethylidene)-1-O-2-propynyl-L-arabinitol (1.26 g, 4.66 mmol) was dissolved in a mixture of TFA (4 mL) and water (2 mL). After 3 h, the solvent was evaporated, and the residue was dissolved in methanol with heating. After several evaporations and redissolutions in methanol, the residue was dissolved in a minimum amount of hot methanol and allowed to crystallize. The crystals were filtered and washed with slightly cold methanol to give 1-O-2-propynyl-L-arabinitol (135 mg, 15%) as white crystals.

[0451] 1 H NMR(400MHz, D2O)δ m.4.22(2H, OC H 2CCH), m.4.03(1H), dd.3.79(1H), m.3.73-3.59(4H), m.3.52(1H), t.2.86(1H, OCH2CC H ).

[0452] 13 C NMR (400MHz, D2O) δ 79.55, 76.07, 71.58, 70.97, 70.87, 68.51, 63.03, 58.24. compound 250 [ka]

[0453] Compound 233 (25 mg, 0.015 mmol), sodium ascorbate (11.6 mg, 0.058 mmol), and compound 249 (16.7 mg, 0.088 mmol) were dissolved in degassed THF (5 mL) and water (2 mL). To this was added a solution of copper sulfate (10.9 mg, 0.044 mmol) in water (0.5 mL). The bronze color rapidly turned brown and faded within a few seconds to give a colorless solution. After 1 min, the solution began to turn cloudy, and an orange solid formed over the next hour. The reaction mixture was evaporated to dryness and triturated in a mixture of DCM and methanol. The supernatant was loaded onto a normal-phase column and eluted with an increasing gradient (0–50%) of methanol in DCM; however, the solubility of the compounds prevented insufficient recovery of impurities. This impurity was purified by reverse phase chromatography eluting with a water-methanol gradient and lyophilized to give compound 250 (7 mg, 20%) as a white solid.

[0454] HRMS: (nanospray + )C 105 H 158 N 24 O 33 2+[ M+2H] 2+ Calculated value: 1142.0726, measured value: 1142.0708. Monocyclic Receptor Synthesis Scheme 2 - Synthetic procedure used for the preparation of anthracene diamine 37 [ka]

[0455] Tetrahydroxyanthracene (33) was prepared according to the literature procedure described in J. Org. Chem., 1989, 54, 1018. Tetra-tert-butyl-2,2',2'',2''''-((9,10-dimethylanthracene-2,3,6,7-tetrayl)tetrakis(oxy))tetraacetate (34) [ka]

[0456] Tetrahydroxyanthracene 33 (2.35 g, 8.7 mmol) was dissolved in anhydrous THF (500 mL) under an inert N atmosphere. KCO (4.9 g, 35.2 mmol) and tert-butyl bromoacetate (7 mL, 47.4 mmol) were added, and the reaction mixture was stirred at reflux for 16 h. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude residue was then dissolved in CHCl (500 mL), washed with water (150 mL), brine (200 mL), and dried (MgSO). The solvent was removed in vacuo, and the crude residue was purified by flash column chromatography (1% MeOH:CHCl) to give 34 (3.8 g, 5.2 mmol, 60%) as a yellow solid. 1 H NMR:(400MHz, (CDCl3):δ 1.49(s, 36H, 3×C(1) H 3), 2.85(s, 6H, 2×C(9) H 3), 4.76(s, 8H, C(4) H 2), 7.38(s, 4H, 4×C(6) H ), 13 C NMR:(100MHz, (CDCl3):δ 14.6( C (9)H3), 28.1( C (1)H3), 66.6( C (4)H2), 82.3( C (2)(CH3)3), 105.7( C (6)H), 124.3( C 8), 126.2( C 7), 147.2( C 5), 167.8(C(3)O);ν max 2987, 2901, 1750, 1453, 1369, 1145, 1066 cm -1 , HRMS:(ESI + ) Measured value [M+Na] + :749.3520. Tetra-tert-butyl-2,2',2'',2''''-((9,10-bis(bromomethyl)anthracene-2,3,6,7-tetrayl)tetrakis(oxy))tetraacetate (35) [ka] Under an inert N2 atmosphere, 34 (3 g, 4.1 mmol) was dissolved in anhydrous CHCl2 (500 mL). NBS (1.84 g, 10.3 mmol) and ABCN (50 mg, 5 mol%) were added, and the mixture was stirred under reflux for 1.5 h. The reaction mixture was then cooled to room temperature and diluted with CHCl2 (300 mL). The solution was washed with NaOH (300 mL, 1 M) and water (300 mL), and the solvent was removed in vacuo to give 35 (3.5 g, 4.0 mmol, 98%) as an orange solid. 1 H NMR:(400MHz, (CDCl3):δ 1.52(s, 36H, 3×C(1) H 3), 4.81(s, 8H, C(4) H 2), 5.22(s, 4H, 2×C(9) H 2), 7.38(s, 4H, 4×C(6) H ), 13 C NMR:(100MHz, (CDCl3):δ 28.1( C (1)H3), 29.7( C (9)H3), 66.4( C (4)H2), 82.6( C (2)(CH3)3), 104.2( C (6)H), 126.2( C 8), 126.4( C 7), 148.7( C 5), 167.4(C(3)O);ν max 2987, 2933, 1706, 1488, 1362, 1228, 1183, 1066cm -1 , HRMS:(ESI + ) Measured value [M+Na] + :905.1709, 907.1692. Tetra-tert-butyl-2,2',2'',2''''-((9,10-bis(azidomethyl)anthracene-2,3,6,7-tetrayl)tetrakis(oxy))tetraacetate (36) [ka]

[0457] Under an inert N2 atmosphere, 35 (3.5 g, 4.0 mmol) was dissolved in anhydrous MeCN (300 mL). NaN3 (1 g, 15.9 mmol) was added and the reaction was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude product was dissolved in CHCl2 (400 mL), washed with water (3 x 100 mL), and the solvent was removed in vacuo to give 36 (3.2 g, 3.9 mmol, 98%) as an orange solid. 1 H NMR:(400MHz, (CDCl3):δ 1.52(s, 36H, 3×C(1) H 3), 4.78(s, 8H, C(4) H 2), 5.08(s, 4H, 2×C(9) H 2), 7.40(s, 4H, 4×C(6) H ), 13 C NMR:(100MHz, (CDCl3):δ 28.1( C (1)H3), 46.9( C (9)H3), 66.4( C (4)H2), 82.6( C (2)(CH3)3), 104.6( C (6)H), 124.2( C 8), 126.8( C 7), 148.7( C 5), 167.5( C (3)O);ν max 2988, 2931, 2091, 1736, 1498, 1364, 1227, 1186, 1062cm -1 , HRMS:(ESI + ) Measured value [M+Na] + :831.3530. Tetra-tert-butyl-2,2',2'',2''''-((9,10-bis(aminomethyl)anthracene-2,3,6,7-tetrayl)tetrakis(oxy))tetraacetate (37) [ka]

[0458] Under an inert N2 atmosphere, 36 (100 g, 0.12 mmol) was dissolved in anhydrous, degassed THF (8 mL). PMe3 was added (2.5 mL, 2.5 mmol, 1 M in THF), and the mixture was stirred at room temperature for 3 h. Degassed water (2 mL) was added, and the reaction mixture was stirred for 1 h. The solvent was then evaporated under a stream of nitrogen, and the crude residue was dissolved in THF / HO (5:1, 3 mL). The solvent was then removed by lyophilization, affording 37 (90 mg, 0.12 mmol, 96%) as a light brown solid. 1 H NMR:(400MHz, (CDCl3):δ 1.50(s, 36H, 3×C(1) H 3), 4.58(s, 4H, 2×C(9) H 2), 4.77(s, 8H, C(4) H 2), 7.49(s, 4H, 4×C(6) H ), 13 C NMR:(100MHz, (CDCl3):δ 28.1( C (1)H3), 38.9( C (9)H2), 66.5( C (4)H2), 82.4( C (2)(CH3)3), 105.0( C (6)H), 125.8( C 8), 126.2( C 7), 148.0( C 5), 167.6( C (3)O););ν max 2982, 2926, 1729, 1497, 1358, 1222, 1144, 1069 cm -1 ;HRMS:(MALDI + ) Measured value [M+H] + :757.3909. Scheme 3 - Synthetic procedures used for the preparation of monocyclic receptor 40 [ka] Tetra-tert-butyl-2,2',2'',2''''-((9,10-bis(isocyanatomethyl)anthracene-2,3,6,7-tetrayl)tetrakis(oxy))tetraacetate (38) [ka]

[0459] Under an inert N2 atmosphere, a flask was charged with 37 (30 mg, 0.04 mmol) and NaHCO3 (12 mg, 0.14 mmol). CHCl2 (1 mL) and HO (1 mL) were added, and the mixture was cooled to 0 °C and stirred rapidly. Triphosgene (9.4 mg, 0.016 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with CHCl2 (10 mL), the organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo to give 38 (29 mg, 0.036 mmol, 91%) as an orange solid. 1 H NMR:(400MHz, (CDCl3):δ 1.51(s, 36H, 3×C(1) H 3), ), 4.78(s, 8H, C(4) H 2), 5.07(s, 4H, 2×C(9) H 2), 7.35(s, 4H, 4 × C(6) H ), 13 C NMR:(100MHz, (CDCl3):δ 28.0( C (1)H3), 39.83( C (9)H2), 66.6( C (4)H2), 82.7( C (2)(CH3)3), 104.4( C (6)H), 125.5( C 8), 126.0( C 7), 148.7( C 5), 167.3(C(3)O);ν max 2979, 2934, 2251, 1734, 1493, 1367, 1225, 1144, 1064cm -1 , HRMS:(ESI + ) Measured value [M+Na] + :831.3319. tert-Butyl-protected semi-acceptor (39) [ka]

[0460] Under an inert N atmosphere, 1,2-phenylenediamine (0.3 g, 2.70 mmol) was dissolved in dry, degassed CHCl (120 mL). A solution of 38 (55 mg, 0.068 mmol) in dry, degassed CHCl (50 mL) was added dropwise over 10 min, followed by stirring at room temperature for 30 min. The solvent was removed in vacuo, and the crude solid was purified by flash column chromatography (80:20 EtOAc:hexanes → 5:95 MeOH:CHCl → 10:90 MeOH:CHCl) to give 39 (53 mg, 0.052 mmol, 77%) as an orange-brown solid. 1 H NMR:(400MHz, ((CD3)2SO):δ 1.47(s, 36H, 3×C(1) H 3), ), 4.59(s, 4H, N(19) H 2), 4.87(s, 8H, C(4) H 2), 5.12(s, 4H, 2 × C(9) H 2), 6.50-6.57(m, 4H, C(13) H and N(18) H ), 6.66-6.70(m, 2H, C(15) H ), 6.77(t, J=7.6Hz, 2H, C(14) H ), 7.42-7.48(m, 4H, C(12) H and N(18) H ), 7.66(s, 4H, 4×C(6) H ), 13 C NMR:(100MHz, ((CD3)2SO):δ 28.2( C (1)H3), 36.7( C (9)H2), 66.8( C (4)H2), 82.9( C (2)(CH3)3), 105.2( C (6)H), 114.5( C 15), 118.9( C13), 122.8( C 11), 125.2, 125.5( C 12 and C 14), 125.8( C 8), 126.2( C 7), 148.3( C 5), 149.5( C 16), 154.2( C 10), 167.5( C (3)O), ν max 3315, 2973, 2901, 1733, 1622, 1494, 1393, 1225, 1146, 1057, 742cm -1 , HRMS:(ESI + ) Measured value [M + Na] + :1047.4689. tert-Butyl-protected tetraurea macrocycle (40) [ka]

[0461] Under an inert N atmosphere, 38 (40 mg, 0.049 mmol) was dissolved in dry, degassed CHCl (600 mL). To this was added a solution of 39 (50 mg, 0.049 mmol) in dry, degassed pyridine (60 mL) dropwise over 20 min. The reaction was stirred at room temperature for 16 h, after which the solvent was removed under reduced pressure. The crude residue was suspended in HPLC-grade water and lyophilized to give a fine crude solid. The product was then purified by reverse-phase HPLC and lyophilized to give 40 (50 mg, 0.027 mmol, 56%) as an off-white solid. 1 H NMR:(400MHz, ((CD3)2CO):δ 1.49(s, 36H, 3×C(1) H 3), ), 4.78(m, 16H, C(4) H 2), 5.12(m, 8H, C(9) H 2), 6.95(s, 4H, C(13) H ), 7.65(s, 8H, C(6) H ), 8.07(s, 4H, C(12) H ), 13C NMR:(100MHz, ((CD3)2CO):δ 27.3( C (1)H3), 36.0( C (9)H2), 66.0( C (4)H2), 81.6( C (2)(CH3)3), 105.3( C (6)H), 126.3( C 8), 126.9( C 7), 127.4( C 12), 132.2( C 13), 135.6( C 11), 147.8( C 5), 155.5( C 10), 167.9 (C(3)O); HRMS: (ESI + ) Measured value [M+Na] + :1856.8145, [M+2Na] 2+ :939.9019. Scheme 4 - Synthetic procedures used for the preparation of monocyclic receptor 89 [ka] [ka] 9,10-Bis(isocyanatomethyl)anthracene(55) [ka]

[0462] Under an inert N2 atmosphere, add anthracene-9,10-diyldimethanamine An-NH2 to the flask. *(20 mg, 0.085 mmol) and NaHCO3 (26 mg, excess) were charged. CHCl2 (1 mL) and HO (1 mL) were added, and the mixture was cooled to 0 °C and stirred rapidly. Triphosgene (20 mg, 0.068 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with CHCl2 (10 mL), the organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo to give 55 (22 mg, 0.076 mmol, 91%) as a yellow solid. 1 H NMR:(400MHz, (CDCl3):δ 5.38(s, 4H, C(5) H 2), 7.66(dd, J=6.9, 3.2Hz, 4H, C(1) H ), 8.35(dd, J=6.9, 3.2Hz, 4H, C(2) H ), 13 C NMR:(100MHz, (CDCl3):δ 39.0( C (5)H2), 124.1( C (1)H), 126.7( C( 8)H), 127.3( C 4), 129.3( C 3), 167.3;ν max 2921, 2234, 1620, 1491, 1448, 1324, 1185, 858, 751cm -1 , HRMS:(ESI + ) Measured value [M+Na] + :311.0785. *Prepared according to the synthetic procedure described in the literature procedure described in Org. Biomol. Chem., 2005, 3, 48. Diamino tert-butyl-protected anthracene half-acceptor (88) [ka]

[0463] Under an inert N2 atmosphere, 84 (350 mg, 0.195 mmol) was dissolved in anhydrous dichloromethane (10 mL). 55 (25 mg, 0.098 mmol) was added and the reaction was heated to reflux for 2 days. The reaction was cooled to room temperature and the solvent was removed in vacuo. The crude residue was purified by reverse-phase HPLC to give the Fmoc-protected product 86 (254 mg, 0.66 mmol, 67%) as a white solid. Conversion to 86 was confirmed by limited NMR investigation* and high-resolution mass spectrometry. (ESI+): [M+2Na] 2+ Calculated for 1963.1077, found 1963.1067. Under an inert N2 atmosphere, 86 was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0 °C. DBU (45 μl, 0.28 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (5% MeOH:CH2Cl2) to give 88 (215 mg, 0.063 mmol, 95%) as an off-white solid. 1 H NMR:(400MHz, (CD3OD):δ 1.43(s, 162H, C(23) H 3), 1.93(m, 36H, C(20) H 2), 2.08(m, 12H, C(15) H 2), 2.18(m, 48H, C(19, 16) H 2), 5.36(s, 4H, C(5) H 2), 7.18(dd, J=2.1, 8.3Hz, 2H, C(9) H ), 7.26(d, J=2.1Hz, 2H, C(11) H ), 7.41(d, J=8.3Hz, 2H, C(8) H ), 7.41(s, 6H, N H ), 7.60(dd, J=3.3, 6.9Hz, 4H, C(1) H ), 7.89(s, 2H, N H ), 8.47(dd, J=3.3, 6.9Hz, 4H, C(2) H ), 13 C NMR:(100MHz, (CDCl3):δ 27.1( C 23), 29.1( C 20), 29.3( C2...

Claims

1. 1. A compound of structural formula Id, as shown below, or a salt, hydrate, or solvate thereof: 【Chemistry 1】 During the ceremony, C and D are phenyl; R ３ and R ４ is independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl and (2-4C)alkynyl; Z １ ~Z ５ are independently selected from hydrophilic substituents, the hydrophilic substituents are independently selected from a hydrophilic substituent comprising one or more hydrophilic functional groups selected from carboxylic acid, carboxylate ion, carboxylic ester, hydroxyl, amine, amide, ether, ketone and aldehyde groups, nitro group, sulfate, sulfonate, phosphate, phosphonate, and combinations thereof; a hydrophilic polymer or a hydrophilic dendritic group; c and d are integers independently selected from 0 to 4, and o is 0, p is 1 or 2, o is 1 and p is 0, 1 or 2; or o is 2 and p is 0, 1 or 2; A compound of formula Id, or a salt, hydrate, or solvate thereof:

2. Z １ ~Z ５ are independently selected from a hydrophilic polymer or a hydrophilic dendritic group, said hydrophilic polymer being selected from the group consisting of polycarboxylic acids, polycarboxylates, polyhydroxys, polyesters, polyethers, polyamines, polyamides, polyphosphates and polyoxyalkylenes.

3. The compound of claim 2 , wherein the hydrophilic polymer is polyethylene glycol or polyacrylamide.

4. The compound of any one of claims 1 to 3, immobilized on or in a solid or semi-solid support.

5. 5. The immobilized compound of claim 4, wherein the solid or semi-solid support is a polymer matrix and / or a gel, such as a hydrogel.

6. The immobilized compound of claim 5 , wherein the compound is chemically linked to the polymer matrix and / or gel.

7. 6. The immobilized compound of claim 5, wherein the compound is physically incorporated within the polymer matrix and / or gel via non-covalent interactions.

8. The immobilization compound according to any one of claims 5 to 7, wherein the polymeric matrix and / or gel comprises one or more homopolymers, copolymers and / or cross-linked polymers.

9. 9. The immobilization compound according to any one of claims 5 to 8, wherein the polymeric matrix and / or gel comprises a polymer selected from the list consisting of polyethylene glycol, poloxamer, polyacrylamide, polyacrylate, polyalkylacrylate, polyvinylpyrrolidine, polyvinyl alcohol, polystyrene, polycarboxylic ethers, polyurethanes, polyallyamine, polyethyleneimine, polysaccharides, and mixtures thereof.

10. 10. The immobilization compound of claim 9, wherein the polymer is a polyurethane.

11. A saccharide detection device comprising the compound according to any one of claims 1 to 10.

12. A composition comprising a compound according to any one of claims 1 to 10 or a saccharide detection device according to claim 11 for detecting a target sugar in an aqueous environment.

13. The composition or saccharide detection device of claim 12 , wherein the target sugar is glucose.

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