Modified cyclodextrin compounds and methods for their use

Abstract

Disclosed herein are modified cyclodextrin compounds (e.g., compounds of Formula I, I-a, Lal, Lb, Lbl, Lc, or Lcl) and methods of their use (e.g. methods of sequestering bilirubin by administering said compounds).

Description

P090285WO MODIFIED CYCLODEXTRIN COMPOUNDS AND METHODS FOR THEIR USE RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. provisional application No.63 / 673,651, filed July 19, 2024, the entire content of which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0002] This disclosure is related to modified cyclodextrin compounds and methods for their use, e.g., methods of sequestering bilirubin in a human patient in need thereof. Therefore, this disclosure is related to the fields of medicine, pharmacy, genetics, chemistry, and biology. BACKGROUND

[0003] Cyclodextrins are a family of cyclic oligosaccharides that are naturally produced by some bacteria and are also synthesized industrially from starch. Some types are alpha, beta, and gamma cyclodextrins, which may differ in size and cavity diameter. Cyclodextrins can be substituted at their hydroxyl groups, to generate a wide range of modified cyclodextrin compounds with different chemical and biological properties. Improved cyclodextrins are needed. SUMMARY OF THE DISCLOSURE

[0004] In a first aspect, described herein are compounds of Formula I: R1R2L1br a pharmaceuO * * + L2ais a bond , wherein represents the connection to L2band represents the conne2- group;1P090285WO L1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene, wherein the C1-C6alkylene of L1band L2bare each optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2and C1-C3alkyl; and wherein: when L2ais a bond, then L2bis a bond, R2is -OH, and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3alkyl, - NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl; and O * when , then R1and R2are each independently: a 5- teroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10aryl; wherein the heteroaryl, heterocycloalkyl, and aryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1- C3alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl; 2P090285WO m is 3 or 4; and n is 2 or 3; and the sum of m and n is 5 or 6.

[0005] In other aspects, described herein are complexes comprising bilirubin and a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, wherein the bilirubin is at least partially retained within the cavity of the compound.

[0006] In other aspects, described herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0007] In other aspects, described herein are methods of treating or preventing a disease in a subject in need thereof, wherein the disease is caused by excess levels of bilirubin in the plasma of the subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0008] In other aspects, described herein are methods of sequestering bilirubin in the plasma of a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0009] In other aspects, described herein are methods of increasing bilirubin excretion from a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of 3P090285WO Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 compares predicted docking scores and association constants (Ka) determined experimentally by circular dichroism (left panel) and UV / Vis spectroscopy (right panel) for the binding of modified and unmodified β-cyclodextrin and γ-cyclodextrin compounds to bilirubin.

[0011] Figure 2A shows the methyl region of the 1D1H NMR spectra of free bilirubin and bilirubin in the presence of various concentrations of Compound 1. The spectra show an increasing downfield shift compared to the spectrum of free bilirubin with increasing concentrations of Compound 1. This indicates the formation of complexes between bilirubin and Compound 1.

[0012] Figure 2B shows the methyl region of the 1D1H NMR spectra of free bilirubin and bilirubin in the presence of various concentrations of the parent γ-cyclodextrin scaffold. The overlapping spectra indicate that no complexes were formed.

[0013] Figure 3 shows the result of structure simulations for the bilirubin:Compound 1 complex.

[0014] Figure 4 shows the bilirubin concentration in plasma of the treated rats as a function of time post-administration of the bilirubin dose.

[0015] Figure 5A shows the methyl region of the 1D1H NMR spectra of Compound 2, 8, or a mixture thereof alone (free Compound) and Compound 2, 8 or a mixture thereof in the presence of various concentrations of bilirubin. The spectra show an increasing downfield shift compared to the spectrum of free Compound with increasing concentrations of bilirubin. This indicates the formation of complexes between bilirubin and Compound 2, 8 or a mixture thereof.

[0016] Figure 5B illustrates the chemical shift as a function of the ratio of bilirubin to Compound 2, 8, or a mixture thereof. DETAILED DESCRIPTION

[0017] Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular methods, compositions, or materials disclosed 4P090285WO herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

[0018] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 2 to about 50” should be interpreted to include not only the explicitly recited values of 2 to 50, but also include all individual values and sub-ranges within the indicated range.

[0019] As used herein, the term “about” when used in the context of describing a number refers to that number plus or minus 10% of that number. The term “about” in a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0020] The term “increased” and “decreased” used herein may refer to a result comparing the detected or measured concentration or level or rate in a subject with the administration with the concentration or level or rate in the same without the administration (e.g., prior to the administration or treatment) or in a different subject with or without the administration.

[0021] In this disclosure, “comprises”, “comprising”, “containing”, and “having” and the like can mean “includes”, “including” and the like and are generally interpreted to be open ended terms. The terms “consisting of”, or “consists of” are closed terms and include only the components, structure, steps, or the like specifically listed in conjunction with such terms. “Consisting essentially of” or “consists essentially of” are generally closed terms with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the composition’s nature or characteristics would be permissible if present under the “consisting essentially of” language, even though not expressly recited in a list of items following such terminology. In this specification when using an open ended term like “comprising” or 5P090285WO “including”, it is understood that direct support should be afforded also to “consisting essentially of” language as well as “consisting of” language as if stated explicitly and vice versa.

[0022] As used herein, “subject” refers to a human. In some examples, the human subject may be an adult or pediatric patient (i.e., 18 years or younger). In some embodiments, the subject may be a human infant or neonate. In some aspects, the subject may be an infant (i.e., 0-6 months old). In some aspects, the subject may be a neonate (i.e., 0-4 weeks old). The subject may be less than 2 years old, less than 1 year old, less than 6 months old, less than 3 months old, less than 1 month old, less than 2 weeks old.

[0023] The terms “treat,” “treating,” or “treatment” as used herein, refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disease / disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, a delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” may also mean reducing the likelihood of a disease or condition occurring or recurring. ”Treatment” may also mean prolonging survival as compared to expected survival if not receiving treatment (i.e., a reduction in mortality as compared to no treatment or a patient receiving placebo). Those in need of treatment include those already with the disease, condition, or disorder as well as those prone to have the disease, condition or disorder or those in which the disease, condition or disorder is to be prevented.

[0024] As used herein, the term “therapeutically effective amount” means a quantity that leads to measurable and beneficial effects for the subject administered the substance, i.e., significant efficacy.

[0025] All atoms are understood to have their normal number of valences for bond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the atom’s oxidation state). On occasion a moiety can be defined, for example, as (A)aB, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

[0026] Where a substituent can vary in the number of atoms or groups of the same kind (e.g., alkyl groups can be C1, C2, C3, etc.), the number of repeated atoms or groups can be represented by a range (e.g., Cl-C6alkyl) which includes each and every number in the range and any and all sub ranges. For example, C1-C3 alkyl includes Cl, C2, C3, Cl-2, Cl-3, and C2-3 alkyl. 6P090285WO

[0027] As used herein, “Alkyl” refers to optionally substituted, linear and branched chain aliphatic groups. “C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5and C6straight chain (linear) saturated aliphatic hydrocarbon groups and C3,C4, C5and C6 branched saturated aliphatic hydrocarbon groups. Examples of alkyl include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6for straight chain, C3-C6for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0028] The term “Aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen. —O—(C1-C6) alkyl, (C1-C6) alkyl, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O)(C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, NH((C1-C6) alkyl), N((C1-C6) alkyl)2, —S(O) 2—(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and —S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0029] “Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. The term “halogen” also contemplates terms “halo” or “halide.”

[0030] “Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present disclosure.

[0031] “Heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 12 ring atoms, containing one or more ring heteroatoms selected from N, O, and S, the 7P090285WO remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, and S and may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl (e.g., 1-methyl-1H- imidazol-3-yl) isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, thiophen-2-yl, quinolinyl (e.g., 2,6‐ dimethylquinolinyl), benzopyranyl, benzodiazol‐1‐yl, e,g., 1H‐1,3‐benzodiazol‐1‐yl) isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2- c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6- naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3- b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4- b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H- 1λ2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3- b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5- a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. In some embodiments, a heteroaryl is selected from imidazolyl (e.g., 1- methyl-1H-imidazol-3-yl), quinolinyl (e.g., 2,6‐dimethylquinolinyl), benzodiazol‐1‐yl (e.g., 1,3‐ benzoxazol‐2‐yl), 1H‐1,3‐benzodiazol‐1‐yl), thiazolyl (e.g., 1,3‐thiazolyl), triazolyl, indolyl, and pyrrolo[2,3-b]pyridinyl.

[0032] “Heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, or a 7-12 membered bicyclic (fused, bridged, or spiro rings) ring system having one or more heteroatoms (such as O, N, or S), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group 8P090285WO consisting of nitrogen, oxygen and sulfur, unless specified otherwise. A heterocycloalkyl may be optionally substituted independently with one or more substituents described herein, e.g. oxo, Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4- dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofurran]-yl, 7′H-spiro[cyclohexane- 1,5′-furo[3,4-b]pyridin]-yl, 3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, pyrazolo[1,5‐a]pyrimidinyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, 2,5-dioxopyrrolyl and the like. In some embodiments, a heterocycloalkyl group described herein is pyrazolo[1,5‐a]pyrimidinyl or 5-dioxopyrrolyl. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl).

[0033] The terms “alkylene,” “arylene” and “heteroarylene” refer to divalent radicals derived from alkyl, aryl, or heteroaryl, respectively.

[0034] For the avoidance of doubt, any and all disclosures of a group which is “optionally substituted” should be read as disclosing both the unsubstituted group and the substituted group. For example, the group may be unsubstituted. Compounds

[0035] In some embodiments, the compounds of the disclosure (i.e., compounds of Formula I) are compounds of Formula I-a: 9P090285WO R1L1bO a pharmaceutically acceptable salt thereof, wherein:-T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3alkylene, wherein the C1-C6alkylene of L1bis optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2 and C1-C3 alkyl; and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3alkyl, - NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl.

[0036] In some embodiments, the compounds of the disclosure (i.e., compounds of Formula I) are compounds of Formula I-a1: 10P090285WO R1L1bO (I-a1), or a pharmaceutically acceptable salt thereof, wherein:L1bis a bond or a C1-C6 alkylene; R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, or a C6-C10 aryl, wherein the heteroaryl and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, C1-C3alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl.

[0037] In some embodiments, the compounds of the disclosure (i.e., compounds of Formula I) are compounds of Formula I-b: R1L1ba pharmaceutically acceptable salt thereof, wherein:, , T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3alkylene; wherein the C1-C6 alkylene of L1b, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2and C1-C3alkyl; and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected 11P090285WO from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl; wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3alkyl, - NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl.

[0038] In some embodiments, the compounds of the disclosure (i.e., compounds of Formula I) are compounds of Formula I-b1: R1L1bO (I-b1), or a pharmaceutically acceptable salt thereof, wherein: Le, or -T-Q-, wherein T is phenylene or a 5 or 6 membered heteroarylene comprising one to three heteroatoms independently selected from N and S, and Q is a bond, wherein the C1-C6 alkylene of L1bare each optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N and S of T are each optionally substituted with one or two substituents independently selected from -NH2 and C1-C3 alkyl; and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N and O, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted 12P090285WO with one to three substituents independently selected from halogen, oxo, hydroxy, and a C1-C3 alkyl.

[0039] In some embodiments, the compounds of the disclosure (i.e., compounds of Formula I) are compounds of Formula (I-c): R1R2L1bL2bO lly acL1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene; wherein the C1-C6alkylene of L1band L2bare each optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2or C1-C3alkyl; and R1and R2are each independently: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1- C3 alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl.

[0040] In some embodiments, the compounds of the disclosure (i.e., compounds of 13P090285WO Formula (I)) are compounds of Formula (I-c1): R1R2L1bL2bO O lly accL1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-; wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms, each of which are N, and Q is -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene; and R1and R2are each independently: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N; or a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, wherein the heterocycloalkyl and heteroaryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, and NRaRb, where Raand Rbare each independently H or C1-C3 alkyl.

[0041] In some embodiments of the compounds of the disclosure, L1bis a C1-C6alkylene and L2bis -T-Q-. In some embodiments of the compounds of the disclosure, L1bis -T- Q- and L2bis a C1-C6 alkylene. In some embodiments of the compounds of the disclosure, Q is - SO2-. In some embodiments of the compounds of the disclosure, L1bis a bond. In some embodiments of the compounds of the disclosure, L1bis a 5 or 6 membered heteroarylene comprising one to three heteroatoms independently selected from N and S, optionally substituted with one or two substituents independently from C1-C3alkyl. For example, in some embodiments L1bis a phenylene. In some embodiments of the compounds of the disclosure, L1bis a C1-C6 alkylene, wherein the alkylene is optionally substituted with one or two -NH2.

[0042] In some embodiments of the compounds of the disclosure, R1is a 5- to 12- membered heteroaryl comprising 1-3 heteroatoms, each of which are N, optionally substituted with one to three substituents selected from halogen and a C1-C3 alkyl. For example, in some 14P090285WO embodiments, R1is a 9- or 10-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, optionally substituted with one to three substituents independently selected from halogen and a C1-C3alkyl. For example, in some embodiments, R1is a pyrazolopyrimidine or a quinoline optionally substituted with one to three substituents independently selected from halogen and a C1-C3 alkyl. In some embodiments of the compounds of the disclosure, R1is a C6-C10 aryl, optionally substituted with one to three substituents independently selected from halogen, - NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl (e.g., Ra, Ra1, Rb, and Rb1are each H). For example, in some embodiments, R1is a C6-C10 aryl, optionally substituted with one to three substituents independently selected from halogen and hydroxy. In some embodiments of the compounds of the disclosure, when R1is halogen, the halogen is fluoro.

[0043] In some embodiments of the compounds or pharmaceutically acceptable salts thereof disclosed herein (e.g., compounds or pharmaceutically acceptable salts thereof of Formula I, I-c, or Ic-1), R1and R2are each independently a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N; or a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, where heterocycloalkyl and heteroaryl are each optionally substituted with one to three substituents independently selected from a C1-C3alkyl and -NH2. For example, in some embodiments of the compounds or pharmaceutically acceptable salts thereof disclosed herein (e.g., compounds or pharmaceutically acceptable salts thereof of Formula I, I-c, or Ic-1), R1is a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, and R2is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N. As another example, in some embodiments of the compounds or pharmaceutically acceptable salts thereof disclosed herein (e.g., compounds or pharmaceutically acceptable salts thereof of Formula I, I-c, or Ic-1), R1is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, and R2is a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N.

[0044] In some embodiments, a compound disclosed herein is selected from the compounds of Table C-1 and pharmaceutically acceptable salts thereof: Table C-1: Compounds of the disclosure 15P090285WO Cmd. Structure Cmd. Structure # # N N16P090285WO 9 F 10 Cl Cl17P090285WO 15 16 H OH HO O HN H O O O OH HO NH HO O HNHIn some embodiments, the compounds of Table C-1 and pharmaceutically acceptable salts thereof are selected from Compounds 1 to 8.

[0045] In some embodiments, a compound of the disclosure is a mixture of Compound 2 and Compound 8.

[0046] In some embodiments, a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof binds to (e.g., forms a complex with) bilirubin.

[0047] In some embodiments, the binding or complex formation of the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof and bilirubin increases bilirubin solubility.

[0048] In some embodiments, the administration of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 18P090285WO or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof is effective to increase bilirubin clearance from plasma. For example, the administration of the compound or the pharmaceutically acceptable salt thereof increases bilirubin clearance from plasma.

[0049] In some embodiments, the administration of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof is effective to increase excretion of bilirubin from the subject. For example, the administration of the compound or the pharmaceutically acceptable salt thereof increases excretion of bilirubin from the subject.

[0050] Disclosed herein, in certain embodiments, are compositions comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof. The composition may be a pharmaceutical composition. The composition may further comprise at least one pharmaceutically acceptable excipient.

[0051] Disclosed herein, in certain embodiments, are pharmaceutical compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0052] The excipient may comprise a tonicity adjusting agent, a preservative, a solubilizing agent, a buffer, a solution (e.g., an IV solution), or any combination thereof. The tonicity adjusting agent can be dextrose, glycerol, sodium chloride, glycerin, mannitol, or a combination thereof. The preservative can be an antioxidant, an antimicrobial, a chelating agent, or a combination thereof. The antioxidant can be ascorbic acid, acetylcysteine, a sulfurous acid salt (e.g., bisulfite, metabisulfite), a monothioglycerol, or a combination thereof. The antimicrobial can be a phenol, meta-cresol, benzyl alcohol, paraben, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts (e.g., acetate, borate, nitrate), or a combination thereof. The chelating agent can be calcium disodium ethylenediaminetetraacetic acid (EDTA), disodium EDTA, sodium EDTA, calcium versetamide sodium, calteridol, diethylenetriaminepenta acetic acid (DTPA), or a combination thereof. The solubilizing agent can be a surfactant or a co-solvent. The surfactant can be polyoxyethylene sorbitan monooleate 19P090285WO (Tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (Polysorbat 20, Tween® 20), lecithin, polyoxyethylene-polyoxypropylene copolymers (Pluronics), or a combination thereof. The co-solvent can be propylene glycol, glycerin, ethanol, polyethylene glycol (PEG), sorbitol, dimethylacetamide, Cremophor EL, or a combination there. The polyethylene glycol can be PEG 300, PEG 400, PEG 600, PEG 3350, or PEG 4000. The buffer can comprise sodium acetate, acetic acid, glacial acetic acid, ammonium acetate, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonic acid, benzoate sodium, benzoic acid, sodium bicarbonate, boric acid, sodium boric acid, sodium carbonate, citrate acid, sodium citrate, disodium citrate, trisodium citrate, diethanolamine, glucono delta lactone, glycine, glycine HCl, histidine, histidine HCl, hydrochloric acid, hydrobromic acid, lysine, maleic acid, meglumine, methanesulfonic acid, monoethanolamine, phosphate acid, monobasic potassium, dibasic potassium, monosodium phosphate, disodium phosphate, trisodium phosphate, sodium hydroxide, succinate sodium, sulfuric acid, tartarate sodium, tartaric acid, tromethamine (Tris), or a combination thereof. Methods of Treatment

[0053] In some aspects, described herein is a method of treating or preventing a disease in a subject. Some aspects include administering a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and / or a complex as described herein to the subject. The subject may be in need of treatment for a disease. The subject may be identified as in need of such treatment. The administration may treat a disease. The administration may prevent a disease. The administration may include an effective amount of the compound, pharmaceutically acceptable salt, composition and / or complex. The composition may include a compound or pharmaceutically acceptable salt thereof of the disclosure. Such compounds may include, or may consist of, a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C- 1, (e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof.

[0054] For the avoidance of doubt, any and all disclosures of methods of treatment or prevention provided herein should also be read as disclosing the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or a complex 20P090285WO comprising the same, for use in the described methods of treatment. The compound may include or consist of a compound of Formula I. The compound may include or consist of a compound of Formula I-a. The compound may include or consist of a compound of Formula I-a1. The compound may include or consist of a compound of Formula I-b. The compound may include or consist of a compound of Formula I-b1. The compound may include or consist of a compound of Formula I-c. The compound may include or consist of a compound of Formula I-c1. The compound may include or consist of a compound shown in a Table or figure herein, such as Table C-1. The compound may include or consist of Compound 2. The compound may include or consist of Compound 8. The compound may include or consist of a mixture thereof (e.g. a mixture of Compounds 2 and 8). The compound may include or consist of a salt thereof, such as a pharmaceutically acceptable salt.

[0055] In some aspects, described herein is a method of treating or preventing a disease in a subject in need thereof, wherein the disease is caused by excess levels of bilirubin in the plasma of the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a composition comprising the same.

[0056] In some embodiments of the methods disclosed herein, the disease is jaundice or hyperbilirubinemia. In some embodiments of the methods disclosed herein, the disease is kernicterus (bilirubin encephalopathy). Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolize or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, a bilirubin concentration of greater than 3 mg / dl is considered hyperbilirubinemia. Extremely high levels of unconjugated bilirubin in plasma enables bilirubin to cross the blood-brain-barrier to reach the brain and central nervous system to impart damage. This is termed kernicterus, or bilirubin encephalopathy. Further, unbound plasma bilirubin past a threshold exerts neurotoxic effects through triggering diversified metabolic cascades. It decreases oxygen consumption and increases neuronal apoptosis directly or indirectly through release of pro-inflammatory enzymes by glial cells. Primary targets affected 21P090285WO are the basal ganglia, brainstem and cerebellum due to differential tissue binding, bilirubin uptake and cell's higher sensitivity to injury. Thus, there exists a need for new methods to treat hyperbilirubinemia, e.g., by sequestering bilirubin in plasma to aid excretion. In some embodiments, the disease includes jaundice. In some embodiments, the disease includes hyperbilirubinemia.

[0057] Further provided herein, in some embodiments, is a method of increasing bilirubin excretion from a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0058] In some embodiments, described herein is a method of sequestering bilirubin in the plasma of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a or a pharmaceutical composition comprising the same.

[0059] In some embodiments of the methods disclosed herein, the administration of the effective amount of the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, normalizes the serum concentration of bilirubin in the subject; for example, the administration results in a serum concentration of total bilirubin of less than or equal to 1.2 mg / dL. The administration may reduce a bilirubin measurement in a blood sample, relative to a baseline measurement. The baseline measurement may be in a blood sample obtained before the administration or before a treatment. The administration may reduce a bilirubin measurement in a blood sample to be 3 mg / dl or less.

[0060] In some embodiments of the methods disclosed herein, the therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, is an amount suitable to 22P090285WO achieve the therapeutic effect described herein. In some embodiments, the therapeutically effective amount is at least about 50 mg / kg, at least about 100 mg / kg, at least about 200 mg / kg, at least about 300 mg / kg, at least about 400 mg / kg, at least about 500 mg / kg, at least about 600 mg / kg, at least about 700 mg / kg, at least about 800 mg / kg, at least about 900 mg / kg, at least about 1000 mg / kg, at least about 1100 mg / kg, at least about 1200 mg / kg, at least about 1300 mg / kg, at least about 1400 mg / kg, at least about 1500 mg / kg, at least about 1600 mg / kg, at least about 1700 mg / kg, at least about 1800 mg / kg, at least about 1900 mg / kg, at least about 2000 mg / kg, at least about 2100 mg / kg, at least about 2200 mg / kg, at least about 2300 mg / kg, at least about 2400 mg / kg, at least about 2500 mg / kg, at least about 3500 mg / kg, at least about 3500 mg / kg, at least about 4000 mg / kg, at least about 4500 mg / kg, at least about 5000 mg / kg, at least about 5500 mg / kg, at least about 6000 mg / kg, at least about 6500 mg / kg, at least about 7000 mg / kg, at least about 7500 mg / kg¸ or at least about 8000 mg / kg. In some embodiments, the therapeutically effective amount of a compound of the disclosure (e.g., a compound of Table C- 1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, is about 2000 mg / kg.

[0061] In some embodiments of the methods disclosed herein, the therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

[0062] In some embodiments of the methods disclosed herein, the human subject may be under 1, under 3, under 5 years old, or at least 5 (e.g., at least 10, at least 15, at least 20, at least 25, at least 30, at least 40) years old. In some embodiments of the methods disclosed herein, the subject is a neonate. In some embodiments of the methods disclosed herein, the subject is between 0 months to 6 months old.

[0063] In some embodiments of the methods disclosed herein, the subject is a human subject.

[0064] In some embodiments of the methods disclosed herein, the administration of the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8), or a pharmaceutically acceptable salt thereof, or a composition comprising the same, 23P090285WO increases bilirubin excretion levels to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%, 250%, 300%, 350%, 400%, 500%, 1000%, 2000%, 5000%, or more, than bilirubin excretion levels of the subject prior to the administration of a similar subject without the administration.

[0065] In some embodiments of the methods disclosed herein, the administration of the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8), or a pharmaceutically acceptable salt thereof, or a composition comprising the same, increases bilirubin excretion levels in a subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%, 250%, 300%, 350%, 400%, 500%, 1000%, 2000%, 5000%, or more, than bilirubin excretion levels of the subject prior to the administration.

[0066] In some embodiments of the methods disclosed herein, the administration of the compound of the disclosure (e.g., a compound of Formula I, I-a, I-a1, I-b, I-b1, I-c, or I-c1, or Table C-1, e.g., Compound 1 or Compound 2 or Compound 8 or a mixture of Compounds 2 and 8) or a pharmaceutically acceptable salt thereof, or a composition comprising the same, increases excretion of bilirubin for about 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 20 hours, 24 hours, or longer, post administration. General Synthetic Schemes General Synthetic Scheme 1 OH OH OH OThio OH N3O H

[0067] Activation of a β-cyclodextrin (“β-CD”) or a γ-cyclodextrin (“γ-CD”) by 24P090285WO reacting the β-cyclodextrin or the γ-cyclodextrin with a thioesterification reagent of formula XThio, wherein Thio is a sulfonyl-containing group (e.g., p-toluenesulfonyl or methanesulfonyl) and X is a leaving group, e.g., a halogen (e.g., chloride, bromide, or iodide) results in compound I-1. Compound I-1 is reacted with an azide (e.g., NaN3) to yield compound I-2. The azide of Compound I-2 is converted to amine (using e.g., PPh3 and NH3H2O) to yield the compound I-3. Compound I-3 is reacted with a reagent of formula R1-COOH, wherein R1is as defined in Formula I, I-a, I-a1, I-b, or I-b1, to yield a monosubstituted compound of the disclosure. 25P090285WO General Synthetic Scheme 2 OBn OH OBn O O O BnO O O BnOHHO O OHOHOOOHO O BnO OOBnO Bn H2Bn OR1NHOHea-cycoe s co ace w a eage wee s a eav g group, e.g., a halogen (e.g., chloride, bromide, or iodide), and PG is a protecting group, e.g. benzyl) in the presence of a strong base (e.g., NaH or triethylamine) to arrive at Intermediate 2- 26P090285WO 1. Intermediate 2-1 is partially deprotected using e.g., DIBAL-H to afford Intermediate 2-2. Intermediate 2-2 is reacted with a thionyl compound, e.g., SO2Cl, in the presence a strong base (e.g., NaH or triethylamine) to make Intermediate 2-3. Intermediate 2-3 is oxidized, using e.g., ruthenium-catalyzed oxidation, e.g., with NaIO4, to yield Intermediate 2-4. Azidation of Intermediate 2-4 (using, e.g., NaN3) yields Intermediate 2-5. The OH group of Intermediate 2-5 is reacted with methanesulfonic anhydride to make Intermediate 2-6. Intermediate 2-8 is made from Intermediate 2-6 via a Gabriel synthesis (i.e., reaction with a phthalimide salt, e.g., 2-potassioisoindole-1,3-dione, to make Intermediate 2-7 followed by liberation of the primary amine using e.g., hydrazine hydrate). Intermediate 2-8 is reacted with a compound R1-CO2H, wherein R1is as defined in Formula I, I-c, or I-c1, in the presence of a non-nucleophilic base (e.g., N,N-Diisopropylethylamine, DIEA) and a coupling reagent (e.g., 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HATU) to afford Intermediate 2-9. The azide of Intermediate 2-9 is reduced to an amine, e.g., via a palladium-catalyzed azide reduction, to yield Intermediate 2-10. Intermediate 2-10 is reacted with R2CO2H, wherein R2is as defined in Formula I, I-c, or I-c1, to arrive at a compound of Formula I, I-c, or I-c1. ENUMERATED EMBODIMENTS Embodiment 1. A compound selected from: Cmd Structure Cmd Structure27P090285WO 3 OH OH H H HO O O 4 HO O H O O H OHOOHH OH OHON H OOHH N H O H NEmbodiment 2. A compound having the following structure: OH H O H OH N (Compound 1),28P090285WO or a pharmaceutically acceptable salt thereof. Embodiment 3. A compound having one of the following structures: OH N H S O HO O O O 2), r a pharmaceutically acceptable saltEmbodiment 4. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of the preceding embodiments and at least one pharmaceutically acceptable excipient. Embodiment 5. A complex comprising bilirubin and a compound or a pharmaceutically acceptable salt thereof of any one of the preceding embodiments, wherein the bilirubin is at least partially retained within the cavity of the compound. Embodiment 6. A method of treating a disease caused by excess levels of bilirubin in a human subject, the method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-3 or a pharmaceutical composition of embodiment 4. Embodiment 7. The method of embodiment 6, wherein the disease is hyperbilirubinemia. 29P090285WO Embodiment 8. The method of embodiment 6, wherein the disease is jaundice. Embodiment 9. The method of embodiment 6, wherein the disease is kernicterus. Embodiment 10. A method of increasing bilirubin excretion from a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-3 or a pharmaceutical composition of embodiment 4. Embodiment 11. A method of sequestering bilirubin in the plasma of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-3 or a pharmaceutical composition of embodiment 4. Embodiment 12. The method of any one of embodiments 6-11, wherein the administration normalizes serum concentration of bilirubin. Embodiment 13. The method of embodiment 12, wherein the administration results in serum concentration of total bilirubin of less than or equal to 1.2 mg / dL. Embodiment 14. The method of any one of embodiments 6-13, wherein the compound or pharmaceutical composition is administered subcutaneously. EXAMPLES Example 1 -Preparation of N- {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐ yl]methyl}pyrazolo[1,5‐a]pyrimidine‐6‐carboxamide (Compound 1) 30P090285WOStep 1:

[0069] A mixture of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 5,10,15,20,25,30,35,40‐octakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (50 g, 38.57 mmol, 1 equiv) and 4Å molecular sieves (20 g) in pyridine (500 mL) was stirred for 16 h at RT. Then TsCl (8.09 g, 42.44 mmol, 1.1 equiv) was added and the mixture was stirred for 2 h at RT. The mixture was poured into acetone (1 L) and the precipitated solids were collected by filtration and washed with acetone (3 x 200 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: Water (0.1% NH3.H2O), Mobile phase B: EtOH, 3% to 30% B gradient in 20 min; detector, UV 254 nm, to afford [(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36 31P090285WO S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐yl]methyl 4‐methylbenzene‐1‐sulfonate (Intermediate 1-1) (13.5 g, 24 %) as a white solid. LCMS (ES): [M-H+]-= 1449.55. Step 2:

[0070] A mixture of [(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36 S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐yl]methyl 4‐methylbenzene‐1‐sulfonate (Intermediate 1-1) (13.5 g, 9.31 mmol, 1 equiv) and NaN3(1.81 g, 27.93 mmol, 3 equiv) in 10 / 1 DMF / H2O (150 mL) was stirred for 3 h at 100 °C. The mixture was allowed to cool to RT and was then poured into acetone (1 L). The precipitated solids were collected by filtration and washed with acetone (3 x 100 mL) to give (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (azidomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 1-2) (10.5 g) as a white solid. LCMS (ES): [M-H+]-= 1320.25. Step 3:

[0071] A mixture of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (azidomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 32P090285WO 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 1-2) (2 g, 1.51 mmol, 1 equiv) and PPh3 (1.19 g, 4.54 mmol, 3 equiv) in DMF (20 mL) was stirred for 16 h at RT then concentrated NH3.H2O (3 mL) was added and the mixture was stirred for 5 h at RT. Acetone was added and the precipitated solids were collected by filtration and purified by prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column21.2*250, 5um; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL / min mL / min; Gradient: 27% B to 36% B in 12 min; Wave Length: 254nm nm; RT1(min): 9) to afford (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (aminomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 1-3) (713 mg, 36%) as a white solid. LCMS (ES): [M-H+]+= 1294.60.1H NMR (400 MHz, DMSO-d6) δ 5.79 (dp, J = 27.9, 9.5, 8.2 Hz, 16H), 4.90 (q, J = 6.5, 4.2 Hz, 8H), 4.68 – 4.37 (m, 6H), 3.89 – 3.50 (m, 30H), 3.39 (d, J = 9.2 Hz, 7H), 3.32 (dd, J = 9.6, 4.5 Hz, 12H), 2.90 (d, J = 13.1 Hz, 1H), 2.69 (dd, J = 13.7, 6.2 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 102.49~102.05(m), 83.05, 81.62~81.22(m), 73.43~72.64(m), 60.32, 42.34~39.30(m). Step 4:

[0072] To a stirred mixture of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (aminomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 1-3) (2.5 g, 1.93 mmol, 1 equiv), pyrazolo[1,5-a] pyrimidine-5-carboxylic acid (0.47 g, 2.89 mmol, 1.5 equiv), DIEA (0.50 g, 3.86 mmol, 2 equiv) in DMF (30 mL) was added HATU (1.47 g, 3.86 mmol, 2 equiv) RT. The mixture was stirred for 16 h at RT. Acetone (120 mL) was added and the 33P090285WO precipitated solids were collected by filtration and purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: 10 mM NH4HCO3(aq.) +0.05% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 25% B in 8 min; Wave Length: 254nm nm; RT1(min): 7) to afford N- {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐ yl]methyl}pyrazolo[1,5‐a]pyrimidine‐6‐carboxamide (Compound 1) (187 mg, 7%) as a white solid. LCMS (ES): [M-H+]-= 1439.25.1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 7.3 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.88 (s, 1H), 6.09 – 5.48 (m, 16H), 5.10 – 4.72 (m, 8H), 4.53 (q, J = 27.9, 21.4 Hz, 6H), 4.24 (d, J = 5.6 Hz, 1H), 3.87 (q, J = 11.8, 9.3 Hz, 3H), 3.61 (d, J = 22.1 Hz, 35H), 3.26 (d, J = 11.4 Hz,H).13C NMR (101 MHz, DMSO-d6) δ 162.96, 149.59, 146.80~146.57(m), 137.34, 105.98, 102.12~101.77(m), 97.92, 81.60~81.13(m), 73.45~72.58(m), 70.15, 60.47~60.11(m). Example 2a -Preparation of Compound 2 34P090285WO Step 1:

[0073] To a mixture of NaH (711.04 g, 29.63 mol, 63 equiv, 60% purity in mineral oil) in DMSO (3.5 L) was added with beta-CD (320 g, 282.19 mmol, 1 equiv) in batches, and stirred for 1 h at room temperature under nitrogen atmosphere. To the resulting mixture was added (chloromethyl)benzene (3010.4 g, 23.70 mol, 84 equiv) dropwise in 0.5 h at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NH4Cl (3 L). The resulting mixture was extracted with EtOAc (2 x 3 L). The combined organic layers were washed with brine (2 x 2 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The mixture was precipitated with MeOH (3 L). The precipitated oil was collected by filtration and washed with MeOH (2 x 2 L). The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford Intermediate 2-1 (520 g, 61%) as a white oil. MALDI-TOF (m / z): 3050.98 [M+Na+] Step 2:

[0074] To a solution of Intermediate 2-1 (520 g, 171.9 mmol, 1 equiv) in Toluene (5.5 L) was added with DIBAl-H (1.5 M in Tol) (977.90 g, 6.88 mol, 40 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. Potassium sodium tartrate (2.5 L). The resulting mixture was extracted with EtOAc (2 x 3 L). The combined organic layers were washed with brine (2 x 2 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford Intermediate 2-2 (450 g, 92%) as a white oil. Q-TOF (m / z): 2868.25 [M+Na+]. 1H NMR (300 MHz, Chloroform-d) δ 7.26 – 6.79 (m, 95H), 5.49 (dd, J = 13.4, 3.8 Hz, 2H), 5.22 – 5.11 (m, 4H), 4.98 – 4.90 (m, 5H), 4.81 – 4.64 (m, 11H), 4.52 – 4.36 (m, 22H), 3.93 (ddt, J = 31.2, 13.0, 6.8 Hz, 28H), 3.72 – 3.42 (m, 15H), 2.41 (s, 2H). Step 3:

[0075] To a stirred solution of Intermediate 2-2 (150 g, 52.72 mmol, 1 equiv) in DCM (1.5 L) were added TEA (74.54 g, 738.07 mmol, 14 equiv) and SOCl2(37.63 g, 316.32 mmol, 6 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(1 36P090285WO L). The resulting mixture was extracted with DCM (2 x 1 L). The combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was slurries with MeOH (3 L) to afford Intermediate 2-3 (110 g, crude) as brown oil. Step 4:

[0076] To a stirred mixture of Intermediate 2-3 (110 g, 38.05 mmol, 1 equiv) and RuCl3.H2O (4.29 g, 18.5 mmol, 0.5 equiv) in DCM (1.1 L), ACN (1.1 L) and H2O (2.2 L) were added NaIO4 (28.76 g, 133.175 mmol, 6 equiv) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with DCM (4 L). The resulting mixture was washed with H2O (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford Intermediate 2-4 (62 g, 56%) as a white solid. Step 5:

[0077] A solution of Intermediate 2-4 (62 g, 21.33 mmol, 1 equiv) and NaN3(6.93 g, 106.65 mmol, 5 equiv) in DMF (650 mL) was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NaHCO3(800 mL). The resulting mixture was extracted with EtOAc (2 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous H2SO4. After filtration, the filtrate was concentrated under reduced pressure. The syrup obtained was dissolved in THF (650 mL) and H2SO4(17.2 mL), H2O (8.6 mL) were added. The solution was stirred at room temperature for 0.5 h. The mixture was neutralized to pH 8 with sat. NaHCO3(300 mL). The resulting mixture was extracted with EtOAc (2 x 2 L). The combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L), dried over anhydrous H2SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford Intermediate 2-5 (40 g, 65%) as a white solid. Q-TOF (m / z): 2893.2633 [M+Na+]. Step 6:

[0078] A solution of Intermediate 2-5 (21 g, 7.32 mmol, 1 equiv), TEA (3.70 g, 36.6 mmol, 5 equiv) and Methanesulfonic anhydride (3.83 g, 21.96 mmol, 3 equiv) in DCM (210 37P090285WO mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of NaHCO3 (300 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 300 mL). The combined organic layers were washed with brine (3x300 mL), dried over anhydrous H2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford Intermediate 2-6 (15.10 g, 70%) as a white solid. Q-TOF (m / z): 2966.28 [M+NH4+] Step 7:

[0079] A solution of Intermediate 2-6 (15.10 g, 5.12 mmol, 1 equiv) and 2- potassioisoindole-1,3-dione (2.84 g, 15.36 mmol, 3 equiv) in DMF (150 mL) was stirred for 16 h at 70 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous H2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford Intermediate 2-7 (10.29 g, 67%) as a white solid. Q-TOF (m / z): 3017.32 [M+NH4+] Step 8:

[0080] A solution of Intermediate 2-7 (10.29 g, 3.43 mmol, 1 equiv) and hydrazine hydrate (0.52 g, 10.29 mmol, 3 equiv) in THF (100 mL) was stirred for 16 h at 70 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous H2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford Intermediate 2-8 (5.02 g, 51%) as a white solid. Q-TOF (m / z): 2870.29 [M+H+] Step 9:

[0081] A solution of Intermediate 2-8 (5.02 g, 1.75 mmol, 1 equiv), 2-(pyrrolidine-1- sulfonyl)benzoic acid (0.54 g, 2.10 mmol, 1.2 equiv), DIEA (0.34 g, 2.63 mmol, 1.5 equiv) and HATU (1.00 g, 2.63 mmol, 1.5 equiv) in DMF (70 mL) was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous H2SO4. After filtration, the filtrate was concentrated under 38P090285WO reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford Intermediate 2-9 (4.20 g, 77%) as a white solid. Step 10:

[0082] A mixture of Intermediate 2-9 (4.20 g, 1.35 mmol, 1 equiv) and 10% Pd / C (6.3 g) in i-PrOH / DCM (v:v=2:1, 210 mL) was stirred for 4 d at 35oC under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH / CH2Cl2(v:v =1:1, 400 mL). The filtrate was concentrated under reduced pressure. This resulted in Intermediate 2-10 (1.65 g, 89%) as a white solid. The crude product was used in the next step directly without further purification. LCMS (m / z): 1370.90 [M+H+]. Step 11:

[0083] A solution of Intermediate 2-10 (1.65 g, 1.20 mmol, 1 equiv), 3-(2-ethyl-1,3- benzodiazol-1-yl)propanoic acid (0.31 g, 1.44 mmol, 1.2 equiv), DIEA (0.23 g, 1.80 mmol, 1.5 equiv) and HATU (0.68 g, 1.80 mmol, 1.5 equiv) in DMF (17 mL) was stirred for 16 h at room temperature under nitrogen atmosphere. Then the mixture was poured into MTBE / ACN (150 mL, v / v=1:1). The precipitated solids were collected by filtration and washed with MTBE / ACN (v / v=1:1) (3 x 50 mL). The crude product (1.4 g) was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep Shield RP18 OBD, 19*250mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 14% B to 23% B in 10 min; RT1(min): 9.25) to afford Compound 2 (186.2 mg, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.70 – 7.33 (m, 5H), 7.14 (p, J = 6.8 Hz, 2H), 6.11 – 5.41 (m, 14H), 5.17 – 4.68 (m, 7H), 4.68 – 4.23 (m, 7H), 4.07 – 3.50 (m, 27H), 3.40 – 2.41 (m, 23H), 1.63 (s, 4H), 1.40 – 1.19 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 170.26, 168.59, 156.46, 142.67, 137.80, 135.26, 134.85, 132.79, 129.61, 129.44, 129.35, 121.89, 121.55, 118.67, 110.44, 102.79, 102.65, 102.41, 102.24, 84.07, 83.82, 81.99, 81.75, 81.46, 73.39, 72.96, 72.58, 70.37, 70.13, 60.34, 47.80, 35.46, 25.40, 20.21, 11.99. Compound 8 can be made in a manner analogous to Compound 2. Example 2b -Alternative Preparation of Compound 2 39P090285WO OH H OBn OBn HO O H O H BnO O BnO O H OH O O HOO OHH OBn OBnOO O H OBnBnOO HO O HBn OBnHO OHBnO O HOBnBnO O HOHOHOBnOOBnONEt3NEt3M O DIEA F EA40P090285WO

[0084] To a mixture of NaH (711.0 g, 17.8 mol, 63 eq, 60% purity in mineral oil) in DMSO (6.4 L) was added (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5,10,15,20,25,30,35‐ heptakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (320 g, 282.2 mmol, 1 eq) in DMSO (3.2 L) in batches, and stirred for 1 h at room temperature under a nitrogen atmosphere. To the mixture was added benzyl chloride (3000 g, 23.70 mol, 84 eq) dropwise in 0.5 h at room temperature. The mixture was stirred for 16 h at room temperature. Then reaction saturated NH4Cl (aq., 3 L) was added. The mixture was extracted with EtOAc (2 x 3 L) and the combined organic layers were washed with brine (2 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. MeOH (3 L) was added to the residue and removed to give a thick syrup, which was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA to afford (1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R, 35R,36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐5,10,15,20,25,30,35‐ heptakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane (Intermediate 2b-1) (520 g, 61%) as a light brown oil. MALDI-TOF (m / z): 3048.048 [M+Na]+

[0085] To a solution of Intermediate 2b-1 (520 g, 0.17 mol, 1 eq) in Toluene (2.25 L) was added with DIBAL-H (1.5 M in toluene, 4.5 L, 6.80 mol, 40 eq) dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 2 h at 50 °C and was then allowed to cool down to room temperature.3N HCl (aq., 5 L) was added and the mixture was extracted with EtOAc (2 x 3 L). The combined organic layers were washed with sat. NaHCO3 (aq., 2 x 3 L) and the combined organic layers were washed with brine (2 x 3 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1 / 2 PE / EA to afford [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 41P090285WO 6S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐25‐(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methanol (Intermediate 2b-2) (255 g, 52%) as a white oil. Q-TOF (m / z): 2868.25 [M+Na]+1H NMR (300 MHz, Chloroform-d) δ 7.26 – 6.79 (m, 95H), 5.49 (dd, J = 13.4, 3.8 Hz, 2H), 5.22 – 5.11 (m, 4H), 4.98 – 4.90 (m, 5H), 4.81 – 4.64 (m, 11H), 4.52 – 4.36 (m, 22H), 3.93 (ddt, J = 31.2, 13.0, 6.8 Hz, 28H), 3.72 – 3.42 (m, 15H), 2.41 (s, 2H).

[0086] To a stirred solution of Intermediate 2b-2 (150 g, 52.7 mmol, 1 eq) in DCM (1.5 L) were added SOCl2 (37.6 g, 316.3 mmol, 6 eq) dropwise at room temperature. The mixture was stirred for an additional 3 h at room temperature and then saturated NaHCO3 (aq., 1 L) was added. The mixture was extracted with DCM (2 x 1 L) and the combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Addition of MeOH (3 L) gave a thick syrup that was separated from the MeOH supernatant. The MeOH portion was filtered and the syrup that was collected on the filter paper was dissolved in DCM and combined with the other portion to afford (1R,2R,4R,6R,7R,9R,11R,12R,14R,16R,17R,19R,20R,21S,22R,24R,26R,27R,29R,31R,3 2R,34R,41R,43R,44S,45S,46R,47S,48R,49S,50R,51S,52R,53S,54R)‐ 20,21,43,44,45,46,47,48,49,50,51,52,53,54‐tetradecakis(benzyloxy)‐6,11,16,26,31‐ pentakis[(benzyloxy)methyl]‐3,5,8,10,13,15,18,23,25,28,30,33,35,37,39,42‐hexadecaoxa‐ 38lambda4‐ thianonacyclo[17.16.7.22,34.24,7.29,12.214,17.224,27.229,32.022,41]tetrapentacontan‐38‐one (Intermediate 2b-3) (110 g, crude) as a thick brown oil.

[0087] To a stirred solution of Intermediate 2b-3 (110 g, 38.1 mmol, 1 eq) in DCM (1.1 L) and ACN (1.1 L) was added NaIO4(28.8 g, 133.2 mmol, 3.5 eq) in H2O (1.1 L) and RuCl3.H2O (4.3 g, 19.0 mmol, 0.5 eq) in H2O (1.1 L) at room temperature. The mixture was stirred for 16 h at room temperature and was then diluted with DCM (2 L). The mixture was washed with 3 x 1 L of H2O. The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was 42P090285WO purified by silica gel column chromatography, eluting with 2 / 1 PE / EA to afford (1R,2R,4R,6R,7R,9R,11R,12R,14R,16R,17R,19R,20R,21S,22R,24R,26R,27R,29R,31R,32R,34 R,41R,43R,44S,45S,46R,47S,48R,49S,50R,51S,52R,53S,54R)‐ 20,21,43,44,45,46,47,48,49,50,51,52,53,54‐tetradecakis(benzyloxy)‐6,11,16,26,31‐ pentakis[(benzyloxy)methyl]‐3,5,8,10,13,15,18,23,25,28,30,33,35,37,39,42‐hexadecaoxa‐ 38lambda6‐thianonacyclo[17.16.7.22,34.24,7.29,12.214,17.224,27.229,32.022,41]tetrapentacontane‐38,38‐ dione (Intermediate 2b-4) (62 g, 40% by 2 steps) as a white solid.

[0088] A solution of Intermediate 2b-4 (28 g, 9.63 mmol, 1 eq) and potassium phthalimide (5.34 g, 28.89 mmol, 3 eq) in DMF (300 mL) was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature and was them extracted with EtOAc (3 x 500 mL) and H2O (300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4 filtered and concentrated. The syrup obtained was dissolved in THF (300 mL) and H2SO4(7.8 mL) and H2O (3.9 mL) were added, and the solution was stirred for 0.5 h at room temperature. The pH of the mixture was adjusted to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (3 x 300 mL) and brine (2 x 300 mL), dried over anhydrous Na2SO4filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 2 / 1 PE / EA to afford Intermediate 2b-5 (17.5 g, 61%) as a white solid as a mixture of isomers, 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36R,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,38,39,40,41,42,43,44,45,46,47,48,49‐tridecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐37‐hydroxy‐25‐(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer A) and 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,46,47,48,49‐tridecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐45‐hydroxy‐20‐(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ 43P090285WO tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer B). MALDI (m / z): 2997.803 [M+Na]+

[0089] A solution of Intermediate 2b-5 (17.5 g, 5.88 mmol, 1 eq), TEA (2.97 g, 29.4 mmol, 5 eq) and Ms2O (3.07 g, 17.64 mmol, 3 eq) in DCM (180 mL) was stirred for 16 h at room temperature. Saturated NaHCO3(aq., 300 mL) was added at room temperature and the mixture was extracted with CH2Cl2(3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA to afford Intermediate 2b-6 as a white solid and as a mixture of isomers, [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,46,47,48,49‐tridecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐20‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐45‐hydroxy‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl methanesulfonate (Isomer A) and [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6R,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,38,39,40,41,42,43,44,45,46,47,48,49‐tridecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐25‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐37‐hydroxy‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl methanesulfonate (Isomer B).

[0090] A solution of Intermediate 2b-6 (13.5 g, 4.42 mmol, 1 eq) and NaN3 (1.44 g, 22.1 mmol, 5 eq) in DMF (135 mL) was stirred for 2 h at 100 °C. The mixture was allowed to cool down to room temperature and was then extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA to afford Intermediate 2b-7 (9.6 g, 72%) as a white solid and as a mixture of isomers, 2‐ 44P090285WO {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36R,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐25‐(azidomethyl)‐ 36,38,39,40,41,42,43,44,45,46,47,48,49‐tridecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐37‐hydroxy‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer A) and 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐20‐(azidomethyl)‐ 36,37,38,39,40,41,42,43,44,46,47,48,49‐tridecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐45‐hydroxy‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer B). MALDI (m / z): 3000.009 [M+H]+

[0091] A solution of Intermediate 2b-7 (7.5 g, 2.50 mmol, 1 eq) and PEt3 (1.77 g, 15.0 mmol, 6 eq) in THF (75 mL) was stirred for 2 h at 60 °C. The mixture was allowed to cool down to room temperature and then NH3.H2O (38 mL) and H2O (75 mL) were added. The mixture was stirred at room temperature for an additional 16 h. The mixture was extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30 / 1 / 1 DCM / MeOH / EA to afford 2‐ {[(1R,3R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,36 S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐25‐(aminomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Intermediate 2b-8) as a white solid.

[0092] A solution of Intermediate 2b-8 (4.25 g, 1.43 mmol, 1 eq), 2-(pyrrolidine-1- sulfonyl) benzoic acid (440 mg, 1.72 mmol, 1.2 eq), DIEA (280 mg, 2.15 mmol, 1.5 eq) and HATU (820 mg, 2.15 mmol, 1.5 eq) in DMF (50 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. The mixture was extracted with EtOAc (3 x 300 45P090285WO mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3 / 2 PE / EA to afford 2‐(pyrrolidine‐1‐ sulfonyl)‐N‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐20‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}benzamide (Intermediate 2b-9) (3.21 g, 70%) as a white solid. MALDI (m / z): 3234.115 [M+Na]+

[0093] A solution of Intermediate 2b-9 (2.94 g, 0.92 mmol, 1 eq) and hydrazine hydrate (140 mg, 2.76 mmol, 3 eq) in THF (30 mL) was stirred for 16 h at 70 °C. The mixture was allowed to cool down to room temperature and was then extracted with EtOAc (3 x 150 mL) and H2O (100 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1 / 1 PE / EA to afford N‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐20‐(aminomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Intermediate 2b-10) (1.83 g, 64%) as a white solid.

[0094] A mixture of Intermediate 2b-10 (1.74 g, 0.56 mmol, 1 eq), TFA (cat.) and 10% Pd / C (2.6 g) in DMF (30 mL) was stirred for 16 h at 35oC under a hydrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was filtered through celite and the filter cake was washed with 1 / 1 MeOH / CH2Cl2 ( 300 mL). The filtrate was concentrated under reduced pressure to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐20‐(aminomethyl)‐ 46P090285WO 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecahydroxy‐10,15,25,30,35‐ pentakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Intermediate 2b-11) (0.71 g) as a white solid. The crude product was used in the next step directly without further purification. LCMS (m / z): 1370.65 [M+H]+

[0095] A solution of Intermediate 2b-11 (650 mg, 0.47 mmol, 1 eq), 3-(2-ethyl-1,3- benzodiazol-1-yl)propanoic acid (120 mg, 0.56 mmol, 1.2 eq), DIEA (90 mg, 0.71 mmol, 1.5 eq) and HATU (270 mg, 0.71 mmol, 1.5 eq) in DMF (10 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. Then the mixture was poured into 1 / 1 MTBE / MeCN (100 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MTBE / MeCN (3 x 50 mL). The crude product (480 mg) was purified by prep-HPLC with the following conditions (Column: Xbridge Prep Shield RP18 OBD, 19*250mm, 5um; Mobile Phase A: Water (10 mM NH4HCO3+0.05% NH3H20), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 15 to 30% B in 10 min; RT1(min)) to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐20‐{[3‐(2‐ethyl‐1H‐1,3‐ benzodiazol‐1‐yl)propanamido]methyl}‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,25,30,35‐pentakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Compound 2) (219 mg, 29%) as a white solid. LCMS (m / z): 1571.80 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 5.5 Hz, 1H), 7.79 (dd, J = 10.7, 6.2 Hz, 2H), 7.56 (ddd, J = 31.2, 15.4, 7.5 Hz, 3H), 7.40 (dd, J = 17.8, 7.4 Hz, 2H), 7.12 (p, J = 7.2 Hz, 2H), 5.99 – 5.52 (m, 14H), 4.96 (d, J = 3.6 Hz, 1H), 4.91 – 4.65 (m, 6H), 4.59 – 4.41 (m, 5H), 4.31 (dtd, J = 21.4, 14.4, 6.8 Hz, 2H), 3.87 – 3.47 (m, 26H), 3.40 – 3.00 (m, 20H), 2.84 (q, J = 7.4 Hz, 2H), 2.70 – 2.52 (m, 2H), 1.62 (d, J = 5.9 Hz, 4H), 1.29 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 170.26, 168.60, 156.45,142.67, 137.81, 135.26, 134.82, 132.80, 129.62, 129.44, 129.35, 121.90, 121.55, 118.67, 110.45, 102.78, 102.64, 102.42, 102.25, 47P090285WO 84.08, 83.81, 81.98, 81.74, 81.44, 73.45, 72.95, 72.81, 72.56, 72.49, 70.12, 60.33, 47.80, 35.45, 25.40, 20.21, 11.99. Example 3 -Preparation of N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecahydroxy‐10,15,20,25,30,35‐ hexakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐ 1H‐pyrrolo[3,2‐b]pyridine‐3‐carboxamide (Compound 3) OH OH O O O HO O OHOO HO OHOH OHOOHOHO OH OH O OH OH

[0096] To a solution of commercially available (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (CAS: 29390-67-8) (1.3 g, 1.15 mmol, 1 eq) and 1H-pyrrolo[3,2-b] pyridine-3-carboxylic acid (279 mg, 1.72 mmol, 1.5 eq) in DMF (15 mL) was added DMAP (210 mg, 1.72 mmol, 1.5 eq) and EDCI (330 mg, 1.72 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction was then poured into MTBE (50 mL). The precipitated solids were collected by filtration and washed with MTBE (3 x 10 mL). The crude product (750 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column30*150 48P090285WO mm, 5μm; Mobile Phase A: Water(10 mM NH4HCO3 (aq.)+0.1% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 3% B to 20% B in 8 min) to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecahydroxy‐10,15,20,25,30,35‐ hexakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐1H‐ pyrrolo[3,2‐b]pyridine‐3‐carboxamide (Compound 3) (222 mg, 15%) as a yellow solid. LCMS: (ES, m / z): [M+H]+= 1278.751H NMR (400 MHz, Deuterium Oxide) δ 8.36 – 8.27 (m, 1H), 7.98 (s, 1H), 7.82 – 7.75 (m, 1H), 7.14 (dd, J = 8.3, 4.8 Hz, 1H), 5.06 – 4.87 (m, 6H), 4.78 (d, J = 3.7 Hz, 1H), 4.20 (d, J = 13.7 Hz, 1H), 3.96 – 3.66 (m, 20H), 3.60 – 3.19 (m, 20H), 2.71 (d, J = 12.4 Hz, 1H).13C NMR (101 MHz, Deuterium Oxide) δ 166.20, 143.70, 142.01, 133.03, 129.34, 120.70, 117.92, 108.39, 102.15, 101.84, 101.26, 83.66, 81.08, 80.95, 80.73, 80.38, 73.05, 72.78,72.03, 71.59, 70.88, 60.24, 59.61, 39.84. Example 4 -Preparation of 2‐(2‐ethyl‐1H‐1,3‐benzodiazol‐1‐yl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}acetamide (Compound 4) NH2OH H H HO O O O O O O N. ac ass . 49P090285WO

[0097] A solution of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (CAS: 29390-67-8) (1.5 g, 1.32 mmol, 1 eq), (2-ethyl-1,3-benzodiazol-1-yl)acetic acid (296 mg, 1.45 mmol, 1.1 eq), DIEA (256 mg, 1.98 mmol, 1.5 eq) and HATU (753 mg, 1.98 mmol, 1.5 eq) in DMF (15 mL) was stirred for 16 hours at room temperature. Then the mixture was poured into 1 / 1 MTBE / MeCN (150 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MTBE / MeCN (3 x 50 mL). The crude product (1.1 g) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH4HCO3 (aq.)+0.1% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 35% B in 8 min) to afford 2‐(2‐ethyl‐1H‐1,3‐benzodiazol‐1‐yl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}acetamide (Compound 4) (200 mg, 11%) as a white solid. LCMS (m / z):1320.80 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.5 Hz, 1H), 7.62 – 7.48 (m, 1H), 7.45 – 7.30 (m, 1H), 7.21 – 7.06 (m, 2H), 6.01 – 5.43 (m, 14H), 5.04 – 4.74 (m, 9H), 4.67 (d, J = 5.7 Hz, 1H), 4.49 (ddt, J = 20.2, 11.3, 7.5 Hz, 4H), 4.34 (d, J = 5.5 Hz, 1H), 3.99 – 3.46 (m, 28H), 3.45 – 3.34 (m, 13H), 2.78 (q, J = 7.4 Hz, 2H), 2.54 (s, 1H), 1.29 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 167.36, 157.20, 142.50, 136.21, 121.93, 121.61, 118.72, 110.08, 102.64, 102.47, 102.31, 84.03, 82.46, 82.10, 82.02, 81.78, 73.44, 72.86, 72.61, 72.49, 70.34, 60.81, 60.27, 45.62, 20.37, 11.90 50P090285WO Example 5 -Preparation of 3,5‐dibromo‐2‐hydroxy‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}benzamide (Compound 5) NH H2OH H HO O O O H OH OHOOHHO O O HOO OHHOOHHOOHOHOHBr r

[0098] A solution of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (CAS: 29390-67-8) (1.5 g, 1.32 mmol, 1 eq), 3,5-dibromo-2-hydroxybenzoic acid (464 mg, 1.58 mmol, 1.2 eq), DIEA (341 mg, 2.64 mmol, 2.0 eq) and HATU (753 mg, 1.98 mmol, 1.5 eq) in DMF (15 mL) was stirred for 16 h at room temperature. Then the mixture was poured into 1 / 1 MTBE / MeCN (150 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MTBE / MeCN (3 x 50 mL). The crude product (1.9 g) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS30*150 mm, 5m; Mobile Phase A: Water (10 mM NH4HCO3(aq.)+0.1% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 30% B in 9 min) to afford 3,5‐dibromo‐2‐hydroxy‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 51P090285WO 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}benzamide (Compound 5) (210 mg, 10%) as a white solid. LCMS (m / z): 1410.40 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.23 – 7.28 (m, 2H), 7.10 (s, 1H), 6.05 – 5.51 (m, 14H), 5.11 – 4.69 (m, 7H), 4.66 – 4.31 (m, 5H),4.2 (s, 1H) 4.01 – 3.41 (m, 28H), 3.28 (p, J = 5.1, 4.7 Hz, 13H), 2.88 (s, 1H), 1.24 (d, J = 6.8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 102.76, 102.51, 102.40, 82.12, 81.97, 81.84, 81.63, 73.46, 72.97, 72.85, 72.39, 60.30, 54.05. Example 6 -Preparation of N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐ yl]methyl}‐2,6‐dimethylquinoline‐4‐carboxamide (Compound 6). 52P090285WO OH H O O OH OH H H H O O H O OH O OHOOHO H H H HO OH HO O O OOHO O OHOOHO H HO OHOHO O HO HO O H H OH H N3O H OH(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 5,10,15,20,25,30,35,40‐octakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (500 g, 385.5 mmol, 1 eq) and 4Å molecular sieves (200 g) in pyridine (5 L) was stirred for 16 h at 25 °C. Then TsCl (80.9 g, 424.0 mmol, 1.1 eq) was added and the mixture was stirred for an additional 2 h at 25°C. The mixture was filtered, and acetone (12 L) was added to the filtrate. The precipitated solids were collected by filtration and washed with acetone (3 x 2 L) and then purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 3% to 20% EtOH in Water (0.1% NH3·H2O) in 45 min to afford [(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36 S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 53P090285WO 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐yl]methyl 4‐methylbenzene‐1‐sulfonate (Intermediate 6-1) (121 g, 83.4 mmol, 1 eq) and NaN3(10.8 g, 166.7 mmol, 2 eq) in 10 / 1 DMF / H2O (1320 mL) was stirred for 3 h at 100 °C. The mixture was allowed to cool down to room temperature and then poured into acetone (6 L). The precipitated solids were collected by filtration and washed with acetone (3 x 1 L) to give (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (azidomethyl)‐10,15,20,25,30,35,40‐ heptakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 6-2) (97 g, crude) as a white solid. LCMS (m / z): 1320.25 [M-H+].

[0100] A solution of Intermediate 6-2 (97 g, 73.4 mmol, 1 eq) and PPh3 (57.7 g, 220.1 mmol, 3 eq) in DMF (970 mL) was stirred for 16 h at room temperature. Then NH3·H2O (97 mL) was added and the mixture was stirred for an additional 5 h at room temperature. The mixture was poured into acetone (5 L) and the precipitated solids were collected by filtration and washed with acetone (3 x 1 L) to afford (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (aminomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 6-3) (66.6 g, 70%) as a white solid. LCMS (m / z): 1295.35 [M-H+].

[0101] To a stirred solution of Intermediate 6-3 (1.8 g, 1.4 mmol, 1 eq) in DMF was added 2,6-dimethylquinoline-4-carboxylic acid (420 mg, 2.1 mmol, 1.5 eq) dropwise at room temperature. Then DIEA (360 mg, 2.8 mmol, 2 eq) and HATU (1.1 g, 2.8 mmol, 2 eq) were added in portions at room temperature. The mixture was stirred for an additional 16 h at room temperature. Acetone was added and the solid was collected by filtration. The crude product (930 mg) was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD 54P090285WO C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mM NH4HCO3+0.05%NH3·H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 3% to 25% B in 8 min) to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐ yl]methyl}‐2,6‐dimethylquinoline‐4‐carboxamide (Compound 6) (230 mg, 11%) as a white solid. LCMS (m / z): 1479.90 [M+H]+1H NMR (400 MHz, DMSO) δ 8.59 (t, J = 5.3 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.56 (dd, J = 8.6, 2.0 Hz, 1H), 7.39 (s, 1H), 6.04 – 5.62 (m, 16H), 4.90 (dq, J = 10.0, 3.5 Hz, 8H), 4.61 – 4.43 (m, 7H), 3.98 – 3.39 (m, 38H), 3.35 – 3.22 (m, 8H), 2.65 (s, 3H), 2.47 (s, 3H), 0.98 – 0.90 (m, 2H).13C NMR (101 MHz, DMSO) δ 167.72, 157.86, 146.62, 142.17, 135.96, 132.04, 128.73, 124.59, 123.08, 120.10, 102.95, 102.21, 102.11, 84.20, 81.61, 81.45, 81.26, 80.96, 73.23, 72.99, 72.64, 72.54, 70.52, 60.38, 48.05, 25.06, 21.73,21.21. Example 7 -Preparation of 2‐amino‐4,5‐difluoro‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacont 55P090285WO an‐5‐yl]methyl}benzamide (Compound 7) OH H O OH OH OH H H O OH H O OH OOHOOHHOH H HO OH O O O OHOOHO O OOHO H HO HO OHOHO O OH OH HO OH H N3O H OH

[0102] A solution of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 5,10,15,20,25,30,35,40‐octakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (500 g, 385 mmol, 1 eq) and 4Å molecular sieve (200 g) in pyridine (5 L) was stirred for 16 h at 25 °C. To the above mixture was added TsCl (80.9 g, 424 mmol, 1.1 eq). The resulting mixture was stirred for an additional 2 h at 25°C and then filtered. Acetone (12 L) was added to the filtrate and the precipitated solids were collected by filtration and washed with acetone (3 x 2 L). The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase A: Water (0.1% NH4OH), mobile phase B: EtOH; 3% to 30%B in 20 min) to afford [(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36 S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 56P090285WO 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐yl]methyl 4‐methylbenzene‐1‐sulfonate (Intermediate 7-1) (121 g, 21 %) as a white solid. LCMS (m / z): 1449.55 [M-H]-

[0103] A solution of Intermediate 7-1 (121 g, 83.4 mmol, 1 eq) and NaN3(10.8 g, 167 mmol, 2 eq) in 10 / 1 DMF / H2O (1320 mL) was stirred for 3 h at 100 °C. The reaction was poured into acetone (6 L) and the precipitated solids were collected by filtration and washed with acetone (3 x 1 L) to give (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (azidomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 7-2) (97 g, crude) as a white solid. LCMS (m / z): 1320.25 [M-H]-

[0104] A solution of Intermediate 7-2 (97.0 g, 73.4 mmol, 1 eq) and PPh3 (57.7 g, 220.2 mmol, 3 eq) in DMF (970 mL) was stirred for 16 h at ambient temperature. NH4OH (97 mL) was added, and the mixture was stirred for an additional 5 h at room temperature. The reaction was poured into acetone (5 L) and the precipitated solids were collected by filtration and washed with acetone (3 x 1 L) to provide (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36S ,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐5‐ (aminomethyl)‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontane‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐hexadecol (Intermediate 7-3) (66.6 g, 70%) as a white solid. LCMS (m / z): 1294.60 [M+H]+57P090285WO1H NMR (400 MHz, DMSO-d6) δ 5.79 (dp, J = 27.9, 9.5, 8.2 Hz, 16H), 4.90 (q, J = 6.5, 4.2 Hz, 8H), 4.68 – 4.37 (m, 6H), 3.89 – 3.50 (m, 30H), 3.39 (d, J = 9.2 Hz, 7H), 3.32 (dd, J = 9.6, 4.5 Hz, 12H), 2.90 (d, J = 13.1 Hz, 1H), 2.69 (dd, J = 13.7, 6.2 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 102.49, 102.05, 83.05, 81.62, 81.47, 81.22, 73.43, 73.31, 73.13, 72.98, 72.64, 60.32, 42.34.

[0105] To a stirred solution of Intermediate 7-3 (3.0 g, 2.3 mmol, 1 eq), 2-amino-4,5- difluorobenzoic acid (600 mg, 3.5 mmol, 1.5 eq), DIEA (800 uL, 4.6 mmol, 2 eq) in DMF (30 mL) was added HATU (1.76 g, 4.6 mmol, 2 eq). The resulting mixture was stirred for 16 hours, and the addition of MTBE (100 mL) gave a precipitate. The crude product (2.14 g) was collected by filtration and purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mM NH4HCO3 (aq)+ 0.5% wt / wt NH4OH Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 3% to 32% B in 8 min) to afford 2‐amino‐4,5‐difluoro‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6S,38R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)‐ 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56‐ hexadecahydroxy‐10,15,20,25,30,35,40‐heptakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39‐ hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan‐5‐ yl]methyl}benzamide (Compound 7) (520 mg, 15%) as a white solid. LCMS (m / z): 1451.75 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 5.4 Hz, 1H), 7.58 (dd, J = 12.0, 9.0 Hz, 1H), 6.63 (dd, J = 13.2, 7.2 Hz, 1H), 6.50 (s, 2H), 6.05 – 5.59 (m, 15H), 5.04 – 4.79 (m, 8H), 4.64 – 4.30 (m, 7H), 3.79 (q, J = 12.1, 8.1 Hz, 3H), 3.71 – 3.34 (m, 36H), 3.28 (d, J = 13.9 Hz, 8H).13C NMR (101 MHz, DMSO-d6) 102.238, 81.591~81.264(m),73.310~72.598(m). Example 8 -Preparation of N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐25‐{[3‐(2‐ethyl‐1H‐1,3‐ benzodiazol‐1‐yl)propanamido]methyl}‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ 58P090285WO tetradecahydroxy‐10,15,20,30,35‐pentakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Compound 8) 59P090285WO OH H OBn OBn HO O H H O BnO O H OH O O BnO O HOO O O OHH OBnBnOH OBnBnO HO O HOBHO OHO BnO OnOOBnH BnO OBnO BnO O HOHO OH O BnOOO Bn O OBn3R R160P090285WO

[0106] To a mixture of NaH (711.0 g, 17.8 mol, 63 eq, 60% purity in mineral oil) in DMSO (6.4 L) was added (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,3 5R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5,10,15,20,25,30,35‐ heptakis(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (320 g, 282.2 mmol, 1 eq) in DMSO (3.2 L) in batches, and stirred for 1 h at room temperature under a nitrogen atmosphere. To the mixture was added benzyl chloride (3000 g, 23.70 mol, 84 eq) dropwise in 0.5 h at room temperature. The mixture was stirred for 16 h at room temperature. Then reaction saturated NH4Cl (aq., 3 L) was added. The mixture was extracted with EtOAc (2 x 3 L) and the combined organic layers were washed with brine (2 x 2 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. MeOH (3 L) was added to the residue and removed to give a thick syrup, which was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA to afford (1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R, 35R,36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐5,10,15,20,25,30,35‐ heptakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane (Intermediate 8- 1) (520 g, 61%) as a light brown oil. MALDI-TOF (m / z): 3048.048 [M+Na+]

[0107] To a solution of Intermediate 8-1 (520 g, 0.17 mol, 1 eq) in Toluene (2.25 L) was added with DIBAL-H (1.5 M in toluene, 4.5 L, 6.80 mol, 40 eq) dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 2 h at 50 °C and was then allowed to cool down to room temperature.3N HCl (aq., 5 L) was added and the mixture was extracted with EtOAc (2 x 3 L). The combined organic layers were washed with sat. NaHCO3 (aq., 2 x 3 L) and the combined organic layers were washed with brine (2 x 3 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1 / 2 PE / EA to afford [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 61P090285WO 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐25‐(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methanol (Intermediate 8-2) (255 g, 52%) as a white oil. Q-TOF (m / z): 2868.25 [M+Na+]1H NMR (300 MHz, Chloroform-d) δ 7.26 – 6.79 (m, 95H), 5.49 (dd, J = 13.4, 3.8 Hz, 2H), 5.22 – 5.11 (m, 4H), 4.98 – 4.90 (m, 5H), 4.81 – 4.64 (m, 11H), 4.52 – 4.36 (m, 22H), 3.93 (ddt, J = 31.2, 13.0, 6.8 Hz, 28H), 3.72 – 3.42 (m, 15H), 2.41 (s, 2H).

[0108] To a stirred solution of Intermediate 8-2 (150 g, 52.7 mmol, 1 eq) in DCM (1.5 L) were added SOCl2(37.6 g, 316.3 mmol, 6 eq) dropwise at room temperature. The mixture was stirred for an additional 3 h at room temperature and then saturated NaHCO3(aq., 1 L) was added. The mixture was extracted with DCM (2 x 1 L) and the combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Addition of MeOH (3 L) gave a thick syrup that was separated from the MeOH supernatant. The MeOH portion was filtered and the syrup that was collected on the filter paper was dissolved in DCM and combined with the other portion to afford (1R,2R,4R,6R,7R,9R,11R,12R,14R,16R,17R,19R,20R,21S,22R,24R,26R,27R,29R,31R,3 2R,34R,41R,43R,44S,45S,46R,47S,48R,49S,50R,51S,52R,53S,54R)‐ 20,21,43,44,45,46,47,48,49,50,51,52,53,54‐tetradecakis(benzyloxy)‐6,11,16,26,31‐ pentakis[(benzyloxy)methyl]‐3,5,8,10,13,15,18,23,25,28,30,33,35,37,39,42‐hexadecaoxa‐ 38lambda4‐ thianonacyclo[17.16.7.22,34.24,7.29,12.214,17.224,27.229,32.022,41]tetrapentacontan‐38‐one (Intermediate 8-3) (110 g, crude) as a thick brown oil.

[0109] To a stirred solution of Intermediate 8-3 (110 g, 38.1 mmol, 1 eq) in DCM (1.1 L) and MeCN (1.1 L) was added NaIO4 (28.8 g, 133.2 mmol, 3.5 eq) in H2O (1.1 L) and RuCl3.H2O (4.3 g, 19.0 mmol, 0.5 eq) in H2O (1.1 L) at room temperature. The mixture was stirred for 16 h at room temperature and was then diluted with DCM (2 L). The mixture was washed with 3 x 1 L of H2O. The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 2 / 1 PE / EA to afford (1R,2R,4R,6R,7R,9R,11R,12R,14R,16R,17R,19R,20R,21S,22R,24R,26R,27R,29R,31R,32R,34 R,41R,43R,44S,45S,46R,47S,48R,49S,50R,51S,52R,53S,54R)‐ 62P090285WO 20,21,43,44,45,46,47,48,49,50,51,52,53,54‐tetradecakis(benzyloxy)‐6,11,16,26,31‐ pentakis[(benzyloxy)methyl]‐3,5,8,10,13,15,18,23,25,28,30,33,35,37,39,42‐hexadecaoxa‐ 38lambda6‐thianonacyclo[17.16.7.22,34.24,7.29,12.214,17.224,27.229,32.022,41]tetrapentacontane‐38,38‐ dione (Intermediate 8-4) (62 g, 40% by 2 steps) as a white solid.

[0110] A solution of Intermediate 8-4 (28 g, 9.6 mmol, 1 eq) and potassium phthalimide (5.3 g, 28.9 mmol, 3 eq) in DMF (300 mL) was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature and was then extracted with EtOAc (3 x 500 mL) and H2O (300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The syrup obtained was dissolved in a mixture of THF (300 mL), H2SO4(7.8 mL) and H2O (3.9 mL) by stirring for 0.5 h at room temperature. The pH of the mixture was adjusted to pH 8 with saturated NaHCO3 (aq.) and then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (3 x 300 mL) and brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 2 / 1 PE / EA to afford Intermediate 8-5 (17.5 g, 61%) as a white solid and as a mixture of isomers, 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐25‐(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer A) and 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐20‐(hydroxymethyl)‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer B). MALDI (m / z): 2997.803 [M+Na+].

[0111] A solution of Intermediate 8-5 (17.5 g, 5.9 mmol, 1 eq), NEt3(3.0 g, 29.4 mmol, 5 eq) and Ms2O (3.1 g, 17.6 mmol, 3 eq) in DCM (180 mL) was stirred for 16 h at room temperature and then saturated NaHCO3 (aq.300 mL) was added. The mixture was extracted 63P090285WO with CH2Cl2 (3 x 300 mL) and the combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA to afford Intermedaite 8-6 (13.5 g, 75%) as a white solid and as a mixture of isomers, [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐20‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl methanesulfonate (Isomer A) and [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐25‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl methanesulfonate (Isomer B).

[0112] A solution of Intermediate 8-6 (13.5 g, 4.4 mmol, 1 eq) and NaN3(1.4 g, 22.1 mmol, 5 eq) in DMF (135 mL) was stirred for 2 h at 100 °C. The mixture was allowed to cool down to room temperature and was then extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3 / 1 PE / EA (3:1) to afford Intermediate 8-7 (9.6 g, 72%) as a white solid and as a mixture of isomers, 2‐ {[(1R,3R,5R,6R,8R,10R,11R,13S,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐ 25‐(azidomethyl)‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐ 10,15,20,30,35‐pentakis[(benzyloxy)methyl]‐16‐methyl‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer A) and 2‐ 64P090285WO {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐ 20‐(azidomethyl)‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐ 10,15,25,30,35‐pentakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2,3‐ dihydro‐1H‐isoindole‐1,3‐dione (Isomer B). MALDI (m / z): 3000.009 [M+H+].

[0113] A solution of Intermediate 8-7 (9.6 g, 3.2 mmol, 1 eq) and hydrazine hydrate (480 mg, 9.6 mmol, 3 eq) in THF (100 mL) was stirred for 16 h at 70 °C. The mixture was allowed to cool down to room temperature and was then extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 19 / 1 DCM / MeOH to afford Intermediate 8-8 (6.4 g, 70%) as a white solid and as a mixture of isomers, 1‐ [(1R,3R,5R,6R,8R,10R,11R,13S,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐25‐(azidomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐16‐methyl‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methanamine (Isomer A) and 1‐ [(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,3 6S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐20‐(azidomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methanamine (Isomer B). MALDI (m / z): 2892.627 [M+Na+]

[0114] A solution of Intermediate 8-8 (6.4 g, 2.2 mmol, 1 eq), 2-(pyrrolidine-1- sulfonyl)benzoic acid (680 mg, 2.7 mmol, 1.2 eq), DIEA (430 mg, 3.4 mmol, 1.5 eq) and HATU (1.3 g, 3.4 mmol, 1.5 eq) in DMF (60 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. The mixture was extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified 65P090285WO by silica gel column chromatography, eluted with 3 / 2 PE / EA (3:2) to afford Intermediate 8-9 (5.1 g, 73%) as a white solid and as a mixture of isomers, N‐ {[(1R,3R,5R,6R,8R,10R,11R,13S,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐25‐(azidomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,20,30,35‐ pentakis[(benzyloxy)methyl]‐16‐methyl‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Isomer A) and N‐ {[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)‐20‐(azidomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐10,15,25,30,35‐ pentakis[(benzyloxy)methyl]‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Isomer B).

[0115] A solution of Intermediate 8-9 (5.1 g, 1.6 mmol, 1 eq) and PEt3 (1.2 g, 9.8 mmol, 6 eq) in THF (60 mL) was stirred for 2 h at 60 °C. The mixture was allowed to cool down to room temperature and NH3·H2O (30 mL) and H2O (60 mL) were added. The mixture was stirred at room temperature for an additional 16 h and then extracted with EtOAc (3 x 300 mL) and H2O (200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 19 / 1 DCM / MeOH to afford N‐ {[(1R,3R,5R,6R,8R,10R,11R,13S,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R, 36S,37R,38S,39R,40S,41R,42S,43R,44R,45R,46S,47R,48S,49R)‐ 25‐(aminomethyl)‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecakis(benzyloxy)‐ 10,15,20,30,35‐pentakis[(benzyloxy)methyl]‐16‐methyl‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Intermediate 8-10) (2.9 g, 58%) as a white solid. MALDI (m / z): 3103.724 [M+Na+]

[0116] A mixture of Intermediate 8-10 (2.88 g, 0.93 mmol, 1 equiv), TFA (cat.) and 10% Pd / C (4.32 g) in DMF (40 mL) was stirred for 4 d at 35oC under a hydrogen atmosphere. The mixture was allowed to cool down to room temperature and then 66P090285WO filtered. The filter cake was washed with 1 / 1 MeOH / CH2Cl2 (400 mL). The filtrate was concentrated under reduced pressure to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13S,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐25‐(aminomethyl)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecahydroxy‐10,15,20,30,35‐ pentakis(hydroxymethyl)‐16‐methyl‐2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Intermediate 8-11) (1.13 g, 88%) as a white solid. The crude product was used in the next step directly without further purification. LCMS (m / z): 1370.75 [M+H+]

[0117] A solution of Intermediate 8-11 (1.13 g, 0.83 mmol, 1 eq), 3-(2-ethyl-1,3- benzodiazol-1-yl) propanoic acid (0.22 g, 1.0 mmol, 1.2 eq), DIEA (0.16 g, 1.25 mmol, 1.5 eq) and HATU (0.48 g, 1.25 mmol, 1.5 eq) in DMF (10 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. Then the mixture was poured into 1 / 1 MTBE / ACN (100 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MTBE / ACN (3 x 50 mL). The crude product (1.2 g) was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep Shield RP18 OBD, 19*250mm, 5um; Mobile Phase A: Water (10 mM NH4HCO3+0.05%NH3H20), Mobile Phase B: meCN; Flow rate: 25 mL / min; Gradient: 13% to 25% B in 10 min) to afford N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐25‐{[3‐(2‐ethyl‐1H‐1,3‐ benzodiazol‐1‐yl)propanamido]methyl}‐36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,30,35‐pentakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐2‐ (pyrrolidine‐1‐sulfonyl)benzamide (Compound 8) (203 mg, 16%) as a white solid. LCMS (m / z): 1571.80 [M+H+]

[0118] 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.78 (t, J = 7.5 Hz, 2H), 7.69 – 7.30 (m, 5H), 7.14 (p, J = 7.2 Hz, 2H), 6.10 – 5.41 (m, 14H), 5.07 – 4.16 (m, 14H), 3.66 (dp, J = 38.6, 13.4 Hz, 26H), 3.44-3.42 (m, 4H), 3.38 – 3.00 (m, 16H), 2.87 (q, J = 7.6 Hz, 2H), 2.62 (dp, J = 21.2, 7.3 Hz, 2H), 1.63 (d, J = 6.3 Hz, 4H), 1.31 (t, J = 7.4 Hz, 3H). 67P090285WO

[0119] 13C NMR (101 MHz, DMSO-d6) δ 170.20, 168.56, 156.47, 142.68, 137.81, 135.27, 134.81, 132.85, 129.59, 129.47, 129.31, 121.88, 121.55, 118.70, 110.46, 102.65, 102.47, 102.27, 84.16, 82.14, 81.67, 73.58, 73.37, 73.04, 72.90, 72.58, 70.38, 70.05, 60.29, 47.80, 35.45, 25.40, 20.23, 11.98. Example 9 -Preparation of 1‐(3‐chloro‐4‐fluorophenyl)‐5‐methyl‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐ 1H‐1,2,3‐triazole‐4‐carboxamide (Compound 9) HO O OH OH O O HO O OH OOHHO Cl F

[0120] To a solution of 3-chloro-4-fluorophenylboronic acid (20 g, 115 mmol, 1 eq), Cu(OAc)2 (2.1 g, 11.5 mmol, 0.1 eq) in 10 / 1 DMSO / H2O (220 mL), was added NaN3 (14.9 g, 230 mmol, 2.0 eq) and stirred for 2 hours at room temperature under an atmosphere of nitrogen. To this mixture was added ethyl acetoacetate (14.9 g, 115 mmol, 1 eq) and piperidine (1.95 g, 23 mmol, 0.2 eq) dropwise at ambient temperature. The resulting mixture was stirred for 16 hours. Saturated NaHCO3 (aq., 300 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with 2 / 1 PE / EA to afford ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1,2,3-triazole-4-carboxylate (Intermediate 9- 1) (3.9 g, 12%) as a light yellow oil. 68P090285WO LCMS: (ES, m / z): 283.95 [M+H]+1H NMR (300 MHz, Chloroform-d) δ 7.55 – 7.46 (m, 1H), 7.35 – 7.25 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.38 (m, J = 14.3 Hz, 3H).

[0121] To a solution of ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1,2,3-triazole-4- carboxylate Intermediate 9-1 (3.9 g, 13.8 mmol, 1 eq) in THF (40 mL) was added 1 M NaOH (8 mL). The resulting mixture was stirred for 16 hours at 30 °C under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and acidified to pH=5 with 1 N HCl (aq.). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-(3-chloro-4-fluorophenyl)-5-methyl-1,2,3- triazole-4-carboxylic acid (Intermediate 9-2) (2.3 g, 65%) as a light yellow solid, which was used in the next step without further purification. LCMS: (ES, m / z): 256.10 [M+H]+

[0122] A solution of Intermediate 9-2 (1.8 g, 7.06 mmol, 1 eq), (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R ,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (9-3) (7.2 g, 6.35 mmol, 0.9 eq), diisopropylethylamine (1.37 g, 10.59 mmol, 1.5 eq) and HATU (4.02 g, 10.59 mmol, 1.5 eq) in DMF (25 mL) was stirred for 16 hours at ambient temperature. The reaction mixture was poured into 1 / 1 MeCN / diethyl ether (200 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MeCN / diethyl ether (100 mL). The crude product (2.8 g) was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% to 35% B in 8 min) to afford 1‐(3‐chloro‐4‐ fluorophenyl)‐5‐methyl‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 69P090285WO 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐1H‐ 1,2,3‐triazole‐4‐carboxamide (Compound 9) (240 mg, 2%) as a white solid. LCMS: (ES, m / z): 1371.20 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.21 – 7.94 (m, 2H), 7.69 (d, J = 7.0 Hz, 2H), 6.02 – 5.49 (m, 14H), 5.10 – 4.70 (m, 7H), 4.45 (d, J = 28.8 Hz, 6H), 3.85 (t, J = 8.7 Hz, 3H), 3.64 (ddt, J = 34.1, 26.3, 13.0 Hz, 23H), 3.52 – 3.43 (m, 7H), 3.35 – 3.20 (m, 12H).13C NMR (101 MHz, DMSO-d6) δ 161.130, 157.090, 138.562, 167.487, 132.759, 128.356, 127.134, 127.053, 121.230, 121.040, 118.534, 118.312, 102.785-101.942 (m), 84.666, 81.968- 81.507 (m), 73.511-72.447 (m), 70.367, 60.267, 9.529. Example 10 -Preparation of 2‐(2‐chlorophenyl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐ 1,3‐thiazole‐4‐carboxamide (Compound 10) HO O H OH NH2H H OH O O Cl H O O HO

[0123] A solution of commercially available (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 70P090285WO 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (CAS: 29390-67-8) (1 g, 0.88 mmol, 1 eq), 2-(2-chlorophenyl)-1,3-thiazole-4-carboxylic acid (315 mg, 1.32 mmol, 1.5 eq), DIEA (171 mg, 1.32 mmol, 1.5 eq) and HATU (502 mg, 1.32 mmol, 1.5 eq) in DMF (10 mL) was stirred for 16 hours at room temperature. Then the mixture was poured into 1 / 1 MTBE / MeCN (100 mL). The precipitated solids were collected by filtration and washed with 1 / 1 MTBE / MeCN (3 x 50 mL). The crude product (1.48 g) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH4HCO3 (aq.)+0.1% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 30% B in 8 min) to afford 2‐(2‐chlorophenyl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐yl]methyl}‐1,3‐ thiazole‐4‐carboxamide (Compound 10) (220 mg, 17%) as a white solid. LCMS (m / z): 1355.60 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 8.44 – 8.41 (m, 2H), 8.29 (t, J = 6.0 Hz, 1H), 7.67 (dd, J = 7.6, 1.7 Hz, 1H), 7.53 (pd, J = 7.3, 1.8 Hz, 2H), 5.87 – 5.68 (m, 14H), 4.96 – 4.74 (m, 7H), 4.56 – 4.39 (m, 5H), 4.25 (t, J = 5.9 Hz, 1H), 3.99 (d, J = 6.8 Hz, 1H), 3.92 – 3.87 (m, 1H), 3.74 – 3.55 (m, 20H), 3.48 – 3.42 (m, 8H), 3.36 – 3.22 (m, 11H), 3.07 (d, J = 9.5 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 162.85, 160.85, 149.80, 132.07, 131.65, 131.36, 131.17, 131.08, 128.18, 125.88, 102.86, 102.54, 102.34, 101.85, 84.98, 82.24, 82.02, 81.88, 81.77, 81.25, 73.68, 73.51, 73.36, 73.17, 72.95, 72.84, 72.58, 72.53, 72.42, 72.33, 69.91, 60.61, 60.31, 60.01, 59.59. Example 11 -Preparation of 3‐(1,3‐benzoxazol‐2‐yl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R, 71P090285WO 36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}benzamide (Compound 11) O NH2HO OH H H HO O O O H OH OHOOHHO O O OHHOOHHOHO

[0124] A solution of (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R ,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐5‐(aminomethyl)‐ 10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane‐ 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐tetradecol (CAS: 29390-67-8) (1.0 g, 0.88 mmol, 1.0 eq), 3-(1,3-benzoxazol-2-yl)benzoic acid (232 mg, 0.97 mmol, 1.1 eq), DIEA (502 mg, 1.32 mmol, 1.5 eq) and HATU (170 mg, 1.32 mmol, 1.5 eq) in DMF (10 mL) was stirred for 16 hours at room temperature. Then the mixture was poured into 1 / 1 MTBE / MeCN (150 mL). The precipitated solids were collected by filtration and washed with 1 / 1MTBE / MeCN (3 x 50 mL). The crude product (870 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS30*150 mm, 5um; Mobile Phase A: Water (10 mM NH4HCO3 (aq.)+0.1% wt / wt NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 40% B in 9.5 min) to afford 3‐(1,3‐benzoxazol‐2‐yl)‐N‐ {[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,3 6R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)‐ 72P090285WO 36,37,38,39,40,41,42,43,44,45,46,47,48,49‐ tetradecahydroxy‐10,15,20,25,30,35‐hexakis(hydroxymethyl)‐ 2,4,7,9,12,14,17,19,22,24,27,29,32,34‐ tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan‐5‐ yl]methyl}benzamide (Compound 11) (200 mg, 17%) as a white solid. LCMS (m / z):1355.80 [M+H]+1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.85 (ddd, J = 7.2, 5.0, 2.6 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.46 (ddd, J = 6.4, 3.6, 1.8 Hz, 2H), 5.96 – 5.59 (m, 14H), 5.00 – 4.74 (m, 7H), 4.42 (ddt, J = 30.1, 12.5, 5.7 Hz, 7H), 3.91 (dd, J = 19.0, 9.5 Hz, 3H), 3.81 – 3.48 (m, 24H), 3.41 (dd, J = 14.7, 8.2 Hz, 9H), 3.29(dd, J = 14.7, 8.2 Hz, 5H).13C NMR (101 MHz, DMSO-d6) δ 166.04, 162.33, 150.76, 141.90, 135.89, 131.05, 131.05, 130.11, 129.76, 126.74, 126.23, 125.49, 120.401, 111.52, 102.76, 102.50, 101.98, 84.79, 82.09, 81.93, 81.49, 73.66, 73.54, 73.44, 72.88, 72.59, 72.47, 70.17, 60.43, 60.32, 59.74, 41.26. Example 12 - In vitro Screening of Experimental Binding Methods Circular Dichroism and UV Absorption Spectroscopy

[0125] All studies were performed in phosphate buffered saline buffer, pH 7.4 (diluted 10x from PBS, Gibco 70011-036). The control compounds, ^^^^-CD, β-CD, and heptakis-(6-deoxy- 6-amino)-β-cyclodextrin, were purchased from Cyclolab. DMSO (Sigma D8418) was used for the preparation of bilirubin stock solution. Bilirubin stock solution was always prepared freshly before measurements. For circular dichroism and UV absorption spectroscopy, 4.05 mM and 5 mM stock solutions were prepared, respectively. The stock solution was kept at room temperature in the dark and was used for a maximum of 1 hour after preparation. Cyclodextrin solubility was investigated first, and for the further studies the approximate saturated solution was used as the highest concentration. In all studies, two-fold dilution series were prepared from the cyclodextrins.

[0126] For circular dichroism spectroscopy, a Jasco J-720 spectropolarimeter equipped with a 1 cm cylindrical cuvette was used. Wavelength range was set to 550-400 nm. In 73P090285WO each measurement 800 µl of the cyclodextrin solution was first measured, then 10 µl of 4.05 mM stock solution of bilirubin was added making a 50 µM bilirubin concentration, and a second measurement was taken. The bilirubin spectra were calculated by correcting the second measurement with the first one. The calculation of the ellipticity change was based on that wavelength were a maximal ellipticity change was detected. The change was fitted with the onesite binding formula: ^^^^^^^^ ^^^^^^^^^^^^^^^ = ^^^^^^^^^^^^^^^^^^^^^+^^^^where X and Y denotes cyclodextrin concentration and ellipticity change, respectively. Bmaxis the calculated maximal change of ellipticity, Kdis the binding constant.

[0127] For UV absorption spectroscopy, the binding of bilirubin to cyclodextrins causes a slight change in its extinction coefficient or in special cases in the shape of the spectra as well, and the maximal spectral change at around the peak at 450 nm. All measurements were executed using a BMG LABTECH Spectrostar Nano plate reader. Wavelength range was set to 350-550 nm. Measurement was taken in 96-well no binding clean microplates (Greiner 655901). In each measurement a cyclodextrin solution series with and without bilirubin was prepared. All solution without bilirubin were prepared in 900 µl volume, then 10 µl 5 mM bilirubin stock solution was added to 490 µl of the cyclodextrin making a 100 µM bilirubin concentration. Absorbance measurements were taken using two parallel of 100-100 µl of the solutions with and without bilirubin. The bilirubin spectra were calculated by correcting the second measurement with the first one.

[0128] The calculation of the absorbance change was based on that wavelength were a maximal absorbance change was detected. To eliminate the pipetting errors the absorbance was corrected with the absorbance values where no change happens upon cyclodextrin binding (Isosbestic point). The absorbance change was fitted with the one site binding formula: ^^^^^^^^^^^^^^^^=^^^^^^^^^^^^^^^^^^^^^^^^^^^^+^^^^where X and Y denotes cyclodextrin concentration and ellipticity change, respectively. Bmax is the calculated maximal change of ellipticity, Kd is the binding constant. NMR Binding Measurement

[0129] All studies were performed in phosphate buffered saline buffer, pH 7.4 and 10% D2O. DMSO was used for the preparation of bilirubin stock solution. Bilirubin stock solution was always prepared freshly before measurements. For all NMR experiments, Bruker 74P090285WO Avance III 600 MHz spectrometer equipped with HFCN helium cryoprobe SampleJet was used. The probe and the SampleJet temperature were kept at 25˚C and 6˚C, respectively.

[0130] For evaluating the free state behavior,1H and1H T2-CPMG NMR experiments were performed with varying cyclodextrin sample concentration from 0.3 mM to 3.6 mM. For binding measurements, the cyclodextrin samples are titrated from 0.05 mM to 3 mM concentration while the bilirubin concentration is kept constant at 0.05 mM. For the assignment and conformational study of cyclodextrin / bilirubin complex, 1D1H and 2D COSY, HSQC- DEPT, HMBC, ROSESY NMR experiments were performed. A relatively high concentration (20 mM) of both cyclodextrin and bilirubin was used. To maintain high concentration of cyclodextrin and bilirubin concentration in the sample tube, 100% DMSO was used.

[0131] Association constants (Ka) of the binding between compounds of the disclosure and bilirubin were determined by circular dichroism (CiDi, De) and UV / Vis spectroscopy (DAbs), calculated using 1:1 mode. Order of magnitude increases in binding relative to unmodified cyclodextrins were observed. In addition, moderate-good correlations between predicted docking scores and experimental binding were observed (See Figure 1).

[0132] For Compound 1, binding was further confirmed via 1D1H NMR. The 1D1H NMR chemical shifts in bilirubin resonances confirm binding for Compound 1. See Figure 2A, which shows increasing shifts of the spectra away from the spectrum of free bilirubin as the concentration of Compound 1 is increased. The shifts indicate complexation between bilirubin and Compound 1. In contrast, no complexation was observed with the parent γ-cyclodextrin scaffold (Figure 2B).

[0133] The association constants for Compound 2 obtained in the circular dichroism, UV spectroscopy, and 1D1H NMR experiments are summarized in Table 1. Table 1 – In vitro experimental binding to bilirubin. Cmpd CiDi Ka(M-1) UV Ka(M-1) NMR Ka(M-1)75P090285WO Cmpd CiDi Ka(M-1) UV Ka(M-1) NMR Ka(M-1)Example 13 - Structure Determination for Bilirubin:Compound 1 Complex

[0134] To further elucidate the binding of Compound 1 and bilirubin, complex structure determination was carried out. A 2D ROESY NMR experiment established key intra- and inter-molecular cross-peaks. Molecular dynamics simulations determined conformers satisfying the nuclear Overhauser effect (NOE) distances and indicating cavity binding. It was found that the cavity-bound structure places one of the bilirubin pyrrolones partly embedded in cavity of Compound 1, and the other one pi-stacked against the pyrazolopyrimidine sidechain of Compound 1. See Figure 3. Example 14 - Plasma Compartment Retention of Bilirubin Following Co-Administration of Bilirubin with Compound 1 or γ-CD.

[0135] An in vivo study was conducted.5-6-week old Sprague-Dawley male rats were dosed with saline or test article (Compound 1 or γ-CD, 2000 mpk sc) followed 1 h later (timed for test article Cmax) by treatment with bilirubin, 30 mpk, iv. Compound 1 and γ-CD exhibited comparable Cmaxand overall exposure. However, while γ-CD had no effect relative to saline control, animals treated with Compound 1 showed a nearly 3-fold decreased distribution of bilirubin from the plasma compartment. See Table 2.

[0136] Figure 4 shows the bilirubin concentration in plasma of the treated rats as a function of time post administration of the bilirubin dose. Table 2 – Plasma concentration of bilirubin in rats treated with Compound 1. 76P090285WO Treatment Analyte Dose (mg / kg) Cmax(ng / mL) AUC0-inf(hr*ng / mL). . Example 15- Results of Expanded Compound Screening

[0138] The binding affinity of further cyclodextrin compounds was evaluated. The study identified a compound (Compound 2, 8, or a mixture thereof) having an average Ka of 1.2 x 106M-1as determined by1H NMR (measured in DMSO-d6). The average Kaof Compound 1 measured in DMSO-d6 was1000 M-1. The methyl region of the 1D1H NMR spectrum of a complex comprising bilirubin and Compound 2, 8, or a mixture theeof is shown in Figure 5A. Figure 5B illustrates the chemical shift as a function of the ratio of bilirubin and Compound 2, 8, or a mixture thereof. EQUIVALENTS

[0139] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. 77

Claims

1. P090285WO CLAIMS What is claimed is:

1. A compound of Formula I: R1R2L1bL2br a pha O * HN * + L2ais a bond , wherein represents the connection to L2ban d represents the conne 2- group; L1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene, wherein the C1-C6alkylene of L1band L2bare each independently optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each independently optionally substituted with one or two substituents independently selected from -NH2and C1-C3alkyl; and wherein: when L2ais a bond, then L2bis a bond, R2is -OH, and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10aryl, 78 P090285WO wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl; and O * HN when L2a+ is , then R1and R2are each independently: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10aryl; wherein the heteroaryl, heterocycloalkyl, and aryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1- C3 alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl; m is 3 or 4; and n is 2 or 3; and the sum of m and n is 5 or 6.

2. The compound of claim 1, wherein the compound is a compound of Formula I-a: R1L1ba pharmaceutically acceptable salt thereof, wherein: L is a bond, a C1-C6 alkylene, or -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms selected from N, O, and S, and 79 P090285WO Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene, wherein the C1-C6alkylene of L1bis optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2and C1-C3alkyl; and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3 alkyl, - NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl.

3. The compound of claim 1 or 2, wherein the compound is a compound of Formula I-a1: R1L1b(I-a1), or a pharmaceutically acceptable salt thereof, wherein: 1- 6 ylene; R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, or a C6-C10 aryl, wherein the heteroaryl and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, C1-C3alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl. 80 P090285WO 4. The compound or pharmaceutically acceptable salt thereof of claim 2 or 3, wherein L1bis a bond.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4, wherein R1is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, optionally substituted with one to three substituents independently selected from halogen and a C1-C3alkyl.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4, wherein R1is a 9- or 10-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, optionally substituted with one to three substituents independently selected from halogen and a C1-C3alkyl.

7. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4, wherein R1is a pyrazolopyrimidine or a quinoline optionally substituted with one to three substituents independently selected from halogen and a C1-C3alkyl.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-4, wherein R1is a C6-C10 aryl, optionally substituted with one to three substituents independently selected from halogen, -NRaRb, and -NH-C(O)-NRa1Rb1wherein Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl.

9. The compound or pharmaceutically acceptable salt thereof of claim 8, wherein Ra, Ra1, Rb, and Rb1are each independently H.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 2-9, wherein the halogen is fluoro.

11. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 81 P090285WO H2N F OH O H O OH HO F H H OHNH OH.

12. The compound of claim 1, wherein the compound is a compound of Formula I-b: R1L1ba pharmaceutically acceptable salt thereof, wherein: , 1- 6 y , -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene; wherein the C1-C6alkylene of L1bis optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently 82 P090285WO selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from C1-C3 alkyl.and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl; wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1-C3alkyl, - NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3 alkyl.

13. The compound of claim 1 or 12, wherein the compound is a compound of Formula I-b1: R1L1b(I-b1), or a pharmaceutically acceptable salt thereof, wherein: L , e, or -T-Q-, wherein T is phenylene or a 5 or 6 membered heteroarylene comprising one to three heteroatoms independently selected from N and S, and Q is a bond, wherein the C1-C6 alkylene of L1bare each optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms selected from N and S of T are each optionally substituted with one or two substituents independently selected from -NH2 and C1-C3 alkyl; and R1is: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N and O, 83 P090285WO a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1are each optionally substituted with one to three substituents selected from halogen, oxo, hydroxy, and a C1-C3alkyl.

14. The compound or pharmaceutically acceptable salt thereof of claim 12 or 13, wherein L1bis a bond.

15. The compound or pharmaceutically acceptable salt thereof of claim 12 or 13, wherein L1bis a 5 or 6 membered heteroarylene comprising 1-3 heteroatoms independently selected from N and S, optionally substituted with one or two substituents independently selected from C1-C3 alkyl.

16. The compound or pharmaceutically acceptable salt thereof of claim 12 or 13, wherein L1bis a C1-C6 alkylene, wherein the alkylene is optionally substituted with one or two -NH2.

17. The compound or pharmaceutically acceptable salt thereof of claim 12 or 13, wherein L1bis a phenylene.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 12-17, wherein R1is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N and O, optionally substituted with one to three substituents independently selected from C1-C3alkyl.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 12-17, wherein R1is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, optionally substituted with one to three substituents independently selected from C1-C3 alkyl.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 12-17, wherein R1is a C6-C10aryl, optionally substituted with one to three substituents independently selected from halogen and hydroxy. 84 P090285WO 21. The compound of claim 1, 12 or 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: Br Br OH H OH H OH HOHO OH 85 P090285WO NH2nd 22. The pharmaceutically acceptable salt of the compound of claim 1, 12 or 13, wherein the pharmaceutically acceptable salt is: N - N x H , wherein X- is an anion.

23. The pharmaceutically acceptable salt of claim 22, wherein X- is F-, Cl-, Br-, I-, NO3-, or NO2-.

24. The compound of claim 1, wherein the compound is a compound of Formula I-c: 86 P090285WO R1R2L1bL2bO O r a pharmaceutically acc L1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-, wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S, and Q is a bond, -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene; wherein the C1-C6alkylene of L1band L2bare each optionally substituted with one or two -NH2, and the phenylene and 5- or 6-membered heteroarylene comprising 1-3 heteroatoms independently selected from N, O, and S of T are each optionally substituted with one or two substituents independently selected from -NH2or C1-C3alkyl; and R1and R2are each independently: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms independently selected from N, O, and S, or a C6-C10 aryl, wherein the heteroaryl, heterocycloalkyl, and aryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, oxo, hydroxy, C1- C3 alkyl, -NRaRb, and -NH-C(O)-NRa1Rb1where Ra, Ra1, Rb, and Rb1are each independently H or a C1-C3alkyl.

25. The compound of claim 1 or 24, wherein the compound is a compound of Formula I-c1: 87 P090285WO R1R2L1bL2bO O lly ac L1band L2bare each independently a bond, a C1-C6 alkylene, or -T-Q-; wherein T is phenylene or a 5- or 6-membered heteroarylene comprising 1-3 heteroatoms, each of which are N, and Q is -SO2-, -CH2SO2-, -SO2CH2-, -NHSO2-, -SO2NH-, -C(O)-, or a C1-C3 alkylene; and R1and R2are each independently: a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N; or a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, wherein the heterocycloalkyl and heteroaryl of R1and R2are each optionally substituted with one to three substituents independently selected from halogen, C1-C3alkyl, and NRaRb, where Raand Rbare each independently H or C1-C3 alkyl.

26. The compound or pharmaceutically acceptable salt thereof of claim 23 or 25, wherein L1bis a C1-C6alkylene and L2bis -T-Q-.

27. The compound or pharmaceutically acceptable salt thereof of claim 23 or 25, wherein one of L1bis -T-Q- and L2bis a C1-C6 alkylene.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 23-27, wherein Q is -SO2-.

29. The compound or pharmaceutically acceptable salt thereof of one of claims 23-28, wherein R1and R2are each independently a 5- to 12-membered heteroaryl comprising 1- 3 heteroatoms, each of which are N; or a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, wherein the heterocycloalkyl and heteroaryl are 88 P090285WO each optionally substituted with one to three substituents independently selected from a C1-C3 alkyl and -NH2.

30. The compound or pharmaceutically acceptable salt thereof of one of claims 23-28, wherein R1is a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N, and R2is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N.

31. The compound or pharmaceutically acceptable salt thereof of one of claims 23-28, wherein R1is a 5- to 12-membered heteroaryl comprising 1-3 heteroatoms, each of which are N, and R2is a 4- to 12-membered heterocycloalkyl comprising 1-3 heteroatoms, each of which are N.

32. The compound of claim 1, 23, or 25, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: OH N H O OH HO O S H O O HO O ON N.

33. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of the preceding claims and at least one pharmaceutically acceptable excipient. 89 P090285WO 34. A complex comprising bilirubin and a compound or a pharmaceutically acceptable salt thereof of any one of claims 1-32, wherein the bilirubin is at least partially retained within the cavity of the compound.

35. A method of treating a disease caused by excess levels of bilirubin in a human subject, the method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1-32 or a pharmaceutical composition of claim 33.

36. The method of claim 35, wherein the disease is hyperbilirubinemia.

37. The method of claim 35, wherein the disease is jaundice.

38. The method of claim 35, wherein the disease is kernicterus.

39. A method of increasing bilirubin excretion from a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1-32 or a pharmaceutical composition of claim 33.

40. A method of sequestering bilirubin in the plasma of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1-32 or a pharmaceutical composition of claim 33.

41. The method of any one of claims 35-40, wherein the administration normalizes serum concentration of bilirubin.

42. The method of claim 41, wherein the administration results in serum concentration of total bilirubin of less than or equal to 1.2 mg / dL.

43. The method of any one of claims 35-42, wherein the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered subcutaneously. 90

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