Process for polyethylene glycol synthesis

Abstract

The present disclosure relates to a process for the synthesis of polyethylene glycol (PEG) derivatives.

Description

Attorney Docket No.56009-737.601 PROCESS FOR POLYETHYLENE GLYCOL SYNTHESIS CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 705,400 filed on October 9, 2024 and U.S. Provisional Application No.63 / 595,477 filed on November 2, 2023, which are hereby incorporated by reference in their entirety. FIELD OF THE DISCLOSURE

[0002] Disclosed herein methods of making polyethylene glycol derivates. BACKGROUND OF THE DISCLOSURE

[0003] Polyethylene glycol (‘PEG’) is a polyether compound derived from petroleum with a multitude of applications from medicine to biology. In medicinal chemistry, PEG often serves as a linker for heterobifunctional compounds joining two disparate units. Given that PEG is a symmetrical compound, challenges in selectively functionalizing the opposite PEG alcohols remain. These often result in poor downstream yields since impurities, such as di-functionalization PEG, are carried through multiple synthetic steps. Therefore, obtaining pure PEG analogs ready for process level and / or large scale synthesis remains a critical challenge.

[0004] The present disclosure relates to a process for the synthesis of polyethylene glycol (PEG) derivatives. SUMMARY OF THE DISCLOSURE

[0005] Provided herein is a process for the synthesis of a polyethylene glycol derivative of Formula (II), or a salt, solvate, or hydrate thereof, thereof:x (II), comprisingwith intermediate, wherein: n is an integer from 1-21; m is an integer from 0-6; and x is n + (m + 3).Attorney Docket No.56009-737.601 In some intermediatesynthesized by an oxidation.

[0007] In somesynthesized by a nucleophilicsubstitution reaction from.

[0008] In some embodiments, the process further comprises the synthesis of a compound of Formula (IV), or a salt thereof:x Formula (IV), wherein Z is a counterion;comprising the steps of reacting a compound of Formula , azodicarboxylate (DIAD) to obtain a compound ofFormula treating the compound of Formula (V) with hydrazine to obtain a compound of Formula (IV).

[0009] In some embodiments, the process further comprises the synthesis of a compound of Formula (VI), or a salt thereof or a metalx Formula (VI), wherein M is one or more metal ions; comprising the steps of reacting the compound of Formula (IV) with a metal salt.

[0010] In another aspect, provided herein is a compound having the structure of:Attorney Docket No.56009-737.601x , or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein x is 4-30, obtained by the process of described herein. In, solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein. Inor a salt, solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein. InO O O O O O O or a salt, solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein. InO O O O O O O O OH solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein. InO O O O O O O O O solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein.

[0016] In another aspect, provided herein is a composition comprising: NO2OH Ox, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein x is 4-30, and wherein the composition comprises less than about 10% of impurities as demonstrated by HPLC. In, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of impurities as demonstrated by HPLC.

[0018] In another aspect, provide herein is a compound having the structures of:Attorney Docket No.56009-737.601solvate, or hydrate thereof, or metal ion complex thereof, obtained by the process described herein. InO O O O O O O O O or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC. InO O O O O O O O OH or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC. InO O O O O O O or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC.

[0022] In another aspect, provided herein having the structure:wherein n is 1-21 and M is one or more metal ions.

[0023] In another aspect, provided herein having the structure:wherein x is 4-30 and M is one or more metal ions.

[0024] In another aspect, provided having the structure:x wherein x is 4-30 and M is one or more metal ions.

[0025] In another aspect, provided herein is a metal ion complex having the structure:Attorney Docket No.56009-737.601M , wherein M is one or more metal ions. InM , wherein M is one or more metal ions.Attorney Docket No.56009-737.601

[0027] In some embodiments, the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is manganese.

[0028] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. FIGURES

[0029] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing below.

[0030] FIG.1 Illustrates the MicroED structure of PEG-8-NHC metal ion complex with calcium. The top image illustrates the symmetric unit of PEG-8-NHC crystal structure. The bottom image illustrates molecular structure schematic of PEG-8-NHC.

[0031] FIG.2 Illustrates the MicroED structure of CPD-18 calcium metal ion complex. The top illustrates the structure model overlaid with the electrostatic potential map. The middle image illustrates the structure determined by MicroED. The bottom image illustrates molecular structure schematic of Calcium- CPD-18 complex. INCORPORATION BY REFERENCE

[0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE DISCLOSURE

[0033] Provided herein are methods of making polyethylene glycol derivates and compositions comprising said polyethylene glycol derivates. Synthesis of a compound of Formula (I)

[0034] In an aspect, provided herein is a process for the synthesis of a compound of Formula (I), or a salt, solvate, or hydrate thereof, or metal ion complex thereof:Attorney Docket No.56009-737.601 R OH OxFormula comprisingintermediatewherein: R is an optionally substituted aryl or optionally substituted alkyl; n is an integer from 1-21; m is an integer from 0-6; and x is 4-30.

[0035] In some embodiments, R is an optionally substituted C1-C6alkyl, which is optionally substituted with one, two, three or more substituents selected from alkyl, alkoxy, cyano, halogen, and nitro. In some embodiments, R is an optionally substituted C1-C4alkyl. In some embodiments, R is an optionally substituted C1-C3alkyl. In some embodiments, R is an methyl or ethyl. In some embodiments, R is ethyl. In some embodiments, R is methyl.

[0036] In some embodiments, R is an optionally substituted aryl. In some embodiments, the aryl is phenyl, which is optionally substituted with one, two, three, or more substituents selected from alkyl, alkoxyl, cyano, halogen, and nitro. In some embodiments, R is phenyl substituted with nitro.

[0037] In some embodiments, the compound of Formula (I) has the structure of Formula (II), or a salt, solvate, or hydrate thereof, or metal ion complex thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (III), or a salt, solvate, or hydrate thereof, or metal ion complex thereof.

[0038] In an aspect, provided herein is a process for the synthesis of a compound of Formula (II), or a salt, solvate, or hydrate thereof, or metalx (II), comprisingintermediate, wherein: n is an integer from 1-21;Attorney Docket No.56009-737.601 m is an integer from 0-6; and x is n + (m + 3).

[0039] In an aspect, provided herein is a process for the synthesis of a compound of Formula (III), or a salt, solvate, or hydrate thereof, or metalx Formula (III), comprisingintermediate (E), wherein: n is an integer from 1-21; m is an integer from 0-6; and x is n + (m + 3).In some embodiments, the process comprises (i) a first step and (ii) a second step.

[0040] In some embodiments, step (i) further comprises a metal ion complex purification. In some embodiments, step (ii) further comprises a metal ion complex purification. First step (i)

[0041] In some embodiments, first step comprises mixing intermediate C and intermediate D1, intermediate D, or intermediate E in a first solvent in the presence of a base. In some embodiments, first step comprises mixing intermediate C and intermediate D1 in a first solvent in the presence of a base. In some embodiments, first step comprises mixing intermediate C and intermediate D in a first solvent in the presence of a base. In some embodiments, first step comprises mixing intermediate C and intermediate E in a first solvent in the presence of a base.

[0042] In some embodiments, the base is added to the first solvent portion-wise.

[0043] In some embodiments, the base comprises a metal salt.

[0044] In some embodiments, the base is selected from sodium tert-butoxide (NaOtBu), potassium tert- butoxide (KOtBu), lithium tert-butoxide (LiOtBu), sodium hydride (NaH), potassium hydride (KH) methyl lithium (MeLi), butyl lithium (BuLi), hexyllithium (HxLi), lithium diisopropyl amine (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), and lithium tetramethylpiperidine (LiTMP), or combinations thereof. In some embodiments, the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and lithium tert-butoxide (LiOtBu). In some embodiments, the base is solid sodium tert-butoxide (NaOtBu). In some embodiments, the base is potassium tert-butoxide (KOtBu). In some embodiments, the base is lithium tert-butoxide (LiOtBu).Attorney Docket No.56009-737.601

[0045] In some embodiments, the first solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, isopropyl acetate, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the first solvent is selected from tetrahydrofuran and methyl tetrahydrofuran, or a combination thereof.

[0046] In some embodiments, 0.8 to 3.0 equivalents of the base are present in the first solvent. In some embodiments, 1.0 to 2.5 equivalents of the base are present in the first solvent. In some embodiments, 1.0 to 2.0 equivalents of the base are present in the first solvent. In some embodiments, 1.0 to 1.5 equivalents of the base are present in the first solvent.

[0047] In some embodiments, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents of the base is present in the first solvent. In some embodiments, 1.0 equivalents of the base are present in the first solvent. In some embodiments, 1.1 equivalents of the base are present in the first solvent. In some embodiments, 1.2 equivalents of the base are present in the first solvent. In some embodiments, 1.3 equivalents of the base are present in the first solvent. In some embodiments, 1.4 equivalents of the base are present in the first solvent. In some embodiments, 1.5 equivalents of the base are present in the first solvent.

[0048] In some embodiments, the first solvent is adjusted to a temperature of about -10 °C to about 40 °C prior to addition of the base. In some embodiments, the first solvent is adjusted to a temperature of about -10 °C to about 30 °C prior to addition of the base. In some embodiments, the first solvent is adjusted to a temperature of about -10 °C to about 20 °C prior to addition of the base. In some embodiments, the first solvent is adjusted to a temperature of about -10 °C to about 15 °C prior to addition of the base. In some embodiments, the first solvent is adjusted to a temperature of about -10 °C to about 10 °C prior to addition of the base. In some embodiments, the first solvent is adjusted to a temperature of about -5 °C to about 5 °C prior to addition of the base. Second step (ii)

[0049] In some embodiments, the second step comprises mixing the product from step (i) in a second solvent in the presence of an acid. In some embodiments, the produce from step (i) is a compound of Formula (I), or a salt, solvate, or hydrate thereof, or metal ion complex thereof. In some embodiments, the produce from step (i) is a compound of Formula (II), or a salt, solvate, or hydrate thereof, or metal ion complex thereof. In some embodiments, the product from step (i) is a compound of Formula (III), or a salt, solvate, or hydrate thereof, or metal ion complex thereof.

[0050] In some embodiments, the acid is added to the second solvent.

[0051] In some embodiments, the acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, and formic acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is phosphoric acid. In someAttorney Docket No.56009-737.601 embodiments, the acid is nitric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is formic acid.

[0052] In some embodiments, the second solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the second solvent is selected from tetrahydrofuran and methyl tetrahydrofuran, or combinations thereof. In some embodiments, the second solvent is tetrahydrofuran. In some embodiments, the second solvent is methyl tetrahydrofuran.

[0053] In some embodiments, the second solvent is adjusted to a temperature of about 50 °C to about 90 °C after addition of the acid. In some embodiments, the second solvent is adjusted to a temperature of about 60 °C to about 85 °C after addition of the acid. In some embodiments, the second solvent is adjusted to a temperature of about 70 °C to about 80 °C after addition of the acid.

[0054] In some embodiments, the second solvent further comprises water as a co-solvent.

[0055] In some embodiments, steps (i) and (ii) are repeated. In some embodiments the steps are repeated until a desirable compound linker length is obtained. In some embodiments, steps (i) and (ii) are repeated 1- 20 times. In some embodiments, steps (i) and (ii) are repeated 1-18 times. In some embodiments, steps (i) and (ii) are repeated 1-15 times. In some embodiments, steps (i) and (ii) are repeated 1-12 times. In some embodiments, steps (i) and (ii) are repeated 1-10 times. In some embodiments, steps (i) and (ii) are repeated 1-8 times. In some embodiments, steps (i) and (ii) are repeated 1-6 times. In some embodiments, steps (i) and (ii) are repeated 1-5 times. In some embodiments, steps (i) and (ii) are repeated 10 times. In some embodiments, steps (i) and (ii) are repeated 9 times. In some embodiments, steps (i) and (ii) are repeated 8 times. In some embodiments, steps (i) and (ii) are repeated 7 times. In some embodiments, steps (i) and (ii) are repeated 6 times. In some embodiments, steps (i) and (ii) are repeated 5 times. In some embodiments, steps (i) and (ii) are repeated 4 times. In some embodiments, steps (i) and (ii) are repeated 3 times. In some embodiments, steps (i) and (ii) are repeated 2 times. In some embodiments, steps (i) and (ii) are repeated once.

[0056] In some embodiments, the process is performed in a single reactor.

[0057] In some embodiments, the process further comprises purifying the compound of Formula (I), (II), or (III), wherein the purifying comprises formation of a complex with a metal ion followed by filtration.

[0058] In some embodiments, the metal ion is calcium, magnesium, or manganese. In some embodiments, the metal ion is magnesium or manganese. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese.

[0059] In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 20%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 30%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 40%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 45%. In some embodiments, the yield of theAttorney Docket No.56009-737.601 compound of Formula (I), (II), or (III) is at least 50%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 55%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 60%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 65%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 70%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 75%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 80%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 85%. In some embodiments, the yield of the compound of Formula (I), (II), or (III) is at least 90%.

[0060] In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 95.0%. In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 96.0%. In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 97.0%. In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 98.0%. In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 99.0%. In some embodiments, the purity of the compound of Formula (I), (II), or (III) is at least 99.9%.

[0061] In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 2% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 1.5% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 1% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 0.8% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 0.5% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 0.2% as determined by HPLC. In some embodiments, the level of Formula (I), (II), or (III) impurities is less than about 0.1% as determined by HPLC. In, In. someAttorney Docket No.56009-737.601someembodiments, the impurity is:

[0064] In some embodiments, the process further comprises the synthesis of a compound of Formula (IV), or a salt thereof:x Formula (IV), wherein Z is a counterion;comprising the steps of reacting a compound of Formula with a phthalimide, (DIAD) to obtain acompound of Formula treating the compound of Formula (V) with hydrazine to obtain a compound of Formula (IV).

[0065] In some embodiments, Z is a counter ion selected from Cl-, Br-, SO4-2, CO3-2, or PO4-3. In some embodiments, Z is Cl-. In some embodiments, Z is Br-. In some embodiments, Z is SO4-2.

[0066] In some embodiments, the purity of a compound of Formula (IV) is at least 80.0%. In some embodiments, the purity of a compound of Formula (IV) is at least 85.0%. In some embodiments, the purity of a compound of Formula (IV) is at least 90.0%. In some embodiments, the purity of Formula (IV) is at least 95.0%. In some embodiments, the purity of Formula (IV) is at least 96.0%. In some embodiments, the purity of Formula (IV) is at least 97.0%. In some embodiments, the purity of Formula (IV) is at least 98.0%. In some embodiments, the purity of Formula (IV) is at least 99.0%.

[0067] In some embodiments, the process further comprises the synthesis of a compound of Formula (VI), or a salt thereof or a metalx Formula (VI), wherein M is one or more metal ions;Attorney Docket No.56009-737.601 comprising the steps of reacting the compound of Formula (IV) with a metal salt.

[0068] In some embodiments, the process of synthesizing a compound of Formula (VI) comprises a solvent selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, isopropyl acetate, dimethylacetamide, toluene, and NMP, or combinations thereof. In some embodiments, the solvent is dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, or toluene or a combination thereof. In some embodiments, the solvent is dichloromethane or toluene, or a combination thereof.

[0069] In some embodiments, the formation of a compound of Formula (VI) is a purification step. In some embodiments, the purity of a compound of Formula (VI) is greater than the purity of a compound of Formula (VI).

[0070] In some embodiments, the purity of a compound of Formula (VI) is at least 90.0%. In some embodiments, the purity of Formula (VI) is at least 95.0%. In some embodiments, the purity of a compound of Formula (VI) is at least 96.0%. In some embodiments, the purity of a compound of Formula (VI) is at least 97.0%. In some embodiments, the purity of a compound of Formula (VI) is at least 98.0%. In some embodiments, the purity of a compound of Formula (VI) is at least 99.0%.

[0071] In some embodiments, the level of Formula (VI) impurities is less than about 2% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 1.5% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 1% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 0.8% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 0.5% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 0.2% as determined by HPLC. In some embodiments, the level of Formula (VI) impurities is less than about 0.1% as determined by HPLC.

[0072] In some embodiments, the metal ion forms a metal complex. In some embodiments, the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese. In some embodiments, the metal ion is calcium. Synthesis of Intermediate C

[0073] In some intermediate C, or a salt, solvate, hydrate, or metal ion complex thereof:synthesized by an oxidation reaction from intermediate B:Attorney Docket No.56009-737.601.

[0074] In some embodiments, the oxidation reaction comprises mixing intermediate B in a solvent in the presence of an oxidant.

[0075] In some embodiments, the oxidant is selected from oxone, hydrogen peroxide (H2O2), meta- chloroperozybenzoic acid (mCPBA), titanium dioxide and tert-butylhydroperoxide (TiO2 / TBHP), osmium tetroxide, sodium periodate, ruthenium tetroxide, ruthenium (III) chloride (RuCl3), hydrate, sodium hypochlorite (NaOCl), and sodium periodate (NaIO4), or combinations thereof. In some embodiments, the oxidant is RuCl3hydrate, or RuCl3hydrate and NaIO4. In some embodiments, the oxidant is RuCl3hydrate. In some embodiments, the oxidant is RuCl3hydrate and NaIO4. In some embodiments, the oxidant is NaIO4.

[0076] In some embodiments, the oxidation solvent is selected from dichloromethane, dichloroethane, acetonitrile, water, tetrahydrofuran, methyl tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone, nitrobenzene, and dichlorobenzene, or combinations thereof. In some embodiments, the oxidation solvent is selected from dichloromethane, acetonitrile, and water, or combinations thereof. In some embodiments, the oxidation solvent is dichloromethane. In some embodiments, the oxidation solvent is acetonitrile.

[0077] In some embodiments, intermediate C is purified by precipitation with heptane and filtration.

[0078] In some embodiments, the purity of intermediate C is at least 80.0%. In some embodiments, the purity of intermediate C is at least 85.0%. In some embodiments, the purity of intermediate C is at least 90.0%. In some embodiments, the purity of intermediate C is at least 95.0%. In some embodiments, the purity of intermediate C is at least 96.0%. In some embodiments, the purity of intermediate C is at least 97.0%. In some embodiments, the purity of intermediate C is at least 98.0%. In some embodiments, the purity of intermediate C is at least 99.0%.

[0079] In some embodiments, the level of intermediate C impurities is less than about 5% as determined by HPLC. In some embodiments, the level of intermediate C impurities is less than about 4% as determined by HPLC. In some embodiments, the level of intermediate C impurities is less than about 3% as determined by HPLC. In some embodiments, the level of intermediate C impurities is less than about 2% as determined by HPLC. In some embodiments, the level of intermediate C impurities is less than about 1% as determined by HPLC. In is selected from:, combination thereof.Attorney Docket No.56009-737.601

[0081] In some embodiments, the intermediate C impurity . some embodiments, the of intermediate C. In some embodiments, the intermediate C impurity is. Synthesis of Intermediate B

[0082] In some embodiments, intermediate B, or a salt, solvate, or hydrate thereof, or metal ion complex thereof: synthesized by a cyclization reaction from intermediate diol A:, y is 3-10.

[0083] In some embodiments, the cyclization reaction comprises mixing intermediate diol A in a third solvent in the presence of a third base and thionyl chloride.

[0084] In some embodiments, the third base is selected from triethyl amine, diisopropylethylamine, pyridine, DMAP, DABCO, and DBU. In some embodiments, the third base is triethyl amine. In some embodiments, the third base is diisopropylethylamine. In some embodiments, the third base is pyridine. In some embodiments, the third base is DMAP. In some embodiments, the third base is DABCO. In some embodiments, the third base is DBU.

[0085] In some embodiments, the third solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the third solvent is selected from dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, acetonitrile, dichloroethane, dichlorobenzene, cyclopentyl methyl ether, and methyl tert-butyl ether. In some embodiments, the third solvent is methyl tetrahydrofuran. In some embodiments, the third solvent is tetrahydrofuran. In some embodiments, the third solvent is acetonitrile. In some embodiments, the third solvent is dichloromethane. Synthesis of Intermediate DAttorney Docket No.56009-737.601

[0086] In some embodiments, intermediate D, or a salt, solvate, or hydrate thereof, or metal ion complex thereof:synthesized by a nucleophilic substitution reaction from.

[0087] In some embodiments, the nucleophilic substitution reaction comprises mixingin a fourth solvent in the presence of a fourth base.

[0088] In some embodiments, the fourth solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dimethylacetamide, and NMP, or combinations thereof. In some embodiments, the fourth solvent is selected from dimethylformamide, DMA, NMP, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, dioxane, DME, and DMSO. In some embodiments, the fourth solvent is selected from acetonitrile, tetrahydrofuran and methyl tetrahydrofuran, or combinations thereof. In some embodiments, the fourth solvent is tetrahydrofuran. In some embodiments, the fourth solvent is methyltetrahydrofuran. In some embodiments, the fourth solvent is acetonitrile.

[0089] In some embodiments, the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, DBU, DIPEA, triethyl amine, or pyridine. In some embodiments, the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate. In some embodiments, the fourth base is sodium carbonate. In some embodiments, the fourth base is potassium carbonate. In some embodiments, the fourth base is sodium bicarbonate. In some embodiments, the fourth base is potassium bicarbonate. In some embodiments, the fourth base is cesium carbonate. In some embodiments, the fourth base is DBU. In some embodiments, the fourth base is DIPEA. In some embodiments, the fourth base is triethyl amine. In some embodiments, the fourth base is pyridine.

[0090] In some embodiments, the process further comprises purifying intermediate D, wherein the purifying comprises formation of a complex with a metal ion followed by filtration.

[0091] In some embodiments, the metal ion is calcium, magnesium, or manganese. In some embodiments, the metal ion is magnesium or manganese. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is manganese.

[0092] In some embodiments, the purification further comprises a solvent selected from ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran, toluene, ACE, dichloromethane, ethanol, isopropyl alcohol, MTBE, and DME. In some embodiments, the purification further comprises a solvent selected from ethanol and tetrahydrofuran. In some embodiments, the purification further comprises ethanol. In some embodiments, the purification further comprises tetrahydrofuran.Attorney Docket No.56009-737.601

[0093] In some embodiments, the purity of intermediate D is above 80.0%. In some embodiments, the purity of intermediate D is above 85.0%. In some embodiments, the purity of intermediate D is above 90.0%. In some embodiments, the purity of intermediate D is above 95.0%. In some embodiments, the purity of intermediate D is above 96.0%. In some embodiments, the purity of intermediate D is above 97.0%. In some embodiments, the purity of intermediate D is above 98.0%. In some embodiments, the purity of intermediate D is above 99.0%. In some embodiments, the purity of intermediate D is above 99.9%.

[0094] In some embodiments, the level of intermediate D impurities is less than about 5% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 4% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 3% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 2% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 1% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 0.5% as determined by HPLC. In some embodiments, the level of intermediate D impurities is less than about 0.1% as determined by HPLC. In D from:, or combinations thereof. In D.impurity is selected from: . someAttorney Docket No.56009-737.601 D

[0097] In some embodiments, the polyethylene derivate of Formula (II) has the structure of Formula (IIa), (IIb), or (IIc),x Formula (IIc).

[0098] In some embodiments, n is 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or any integer therein. In some embodiments, n is 1-21. In some embodiments, n is 1-20. In some embodiments, n is 1-19. In some embodiments, n is 1-18. In some embodiments, n is 1-17. In some embodiments, n is 1-16. In some embodiments, n is 1-15. In some embodiments, n is 1-14. In some embodiments, n is 1-13. In some embodiments, n is 1-12. In some embodiments, n is 1-11. In some embodiments, n is 1-10. In some embodiments, n is 1-9. In some embodiments, n is 1-8. In some embodiments, n is 1-7. In some embodiments, n is 1-6. In some embodiments, n is 1-5. In some embodiments, n is 1-4. In some embodiments, n is 1-3. In some embodiments, n is 1-2. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, n is 21. In some embodiments, n is 20. In some embodiments, n is 19. In some embodiments, n is 18. In some embodiments, n is 17. In some embodiments, n is 16. In some embodiments, n is 15. In some embodiments, n is 14. In some embodiments, n is 13. In some embodiments, n is 12. In some embodiments, n is 11. In some embodiments, n is 10. In some embodiments, n is 9. In some embodiments, n is 8. In some embodiments, n is 7. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0099] In some embodiments, m is 0-6, 0-5, 0-4, 0-3, 0-2, or 0-1, or any integer therein. In some embodiments, m is 0-6. In some embodiments, m is 0-5. In some embodiments, m is 0-4. In some embodiments, m is 0-3. In some embodiments, m is 0-2. In some embodiments, m is 0-1. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 6. In some embodiments, m is 5. In some embodiments, m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 0.

[0100] In some embodiments, x is 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or any integerAttorney Docket No.56009-737.601 therein. In some embodiments, x is 1-30. In some embodiments, x is 1-29. In some embodiments, x is 1-28. In some embodiments, x is 1-27. In some embodiments, x is 1-26. In some embodiments, x is 1-25. In some embodiments, x is 1-24. In some embodiments, x is 1-23. In some embodiments, x is 1-22. In some embodiments, x is 1-21. In some embodiments, x is 1-20. In some embodiments, x is 1-19. In some embodiments, x is 1-18. In some embodiments, x is 1-17. In some embodiments, x is 1-16. In some embodiments, x is 1-15. In some embodiments, x is 1-14. In some embodiments, x is 1-13. In some embodiments, x is 1-12. In some embodiments, x is 1-11. In some embodiments, x is 1-10. In some embodiments, x is 1-9. In some embodiments, x is 1-8. In some embodiments, x is 1-7. In some embodiments, x is 1-6. In some embodiments, x is 1-5. In some embodiments, x is 1-4. In some embodiments, x is 1-3. In some embodiments, x is 1-2. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, x is 30. In some embodiments, x is 29. In some embodiments, x is 28. In some embodiments, x is 27. In some embodiments, x is 26. In some embodiments, x is 25. In some embodiments, x is 24. In some embodiments, x is 23. In some embodiments, x is 22. In some embodiments, x is 21. In some embodiments, x is 20. In some embodiments, x is 19. In some embodiments, x is 18. In some embodiments, x is 17. In some embodiments, x is 16. In some embodiments, x is 15. In some embodiments, x is 14. In some embodiments, x is 13. In some embodiments, x is 12. In some embodiments, x is 11. In some embodiments, x is 10. In some embodiments, x is 9. In some embodiments, x is 8. In some embodiments, x is 7. In some embodiments, x is 6. In some embodiments, x is 5. In some embodiments, x is 4. In some embodiments, x is 3. In some embodiments, x is 2. In some embodiments, x is 1.

[0101] In some embodiments, n is 1-6; and m is 1-4. In some embodiments, n is 4; and m is 0.

[0102] In some embodiments, n is 4; m is 0; and x is 7. In some embodiments, n is 5; m is 1; and x is 9. In some embodiments, n is 9; m is 1; and x is 13. In some embodiments, n is 9; m is 0; and x is 12. In some embodiments, n is 13; m is 1; and x is 17.

[0103] In some embodiments, y is 3-10. In some embodiments, y is 3-9. In some embodiments, y is 3-8. In some embodiments, y is 3-7. In some embodiments, y is 10. In some embodiments, y is 9. In some embodiments, y is 8. In some embodiments, y is 7. In some embodiments, y is 6. In some embodiments, y is 5. In some embodiments, y is 4. In some embodiments, y is 3. In, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, comprising mixing a compound with the structure:a compound with the structure:Attorney Docket No.56009-737.601.

[0105] In some embodiments, the process comprises a first step and a second step, wherein the first step comprises sodium tert-butoxide, comprises sulfuric acid.

[0106] In some embodiments, , or a salt, solvate, or hydrate thereof, or metal ion thereof is a two-step (ii): oxidizing the presence of RuCl3hydrate to form . In, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, isstep (i): mixing thepresence of K2CO3to form . Inis purified by a purification process comprising forming a metal ion complex with a manganese ion followed by filtration.

[0109] In another aspect, provided herein is a compound having the structure of Formula (II), or a salt, solvate, or hydrate thereof, orx , wherein x is 4-30,Attorney Docket No.56009-737.601 obtained by the process described herein.

[0110] In another aspect, provided herein is a compound having the structure of Formula (VI), or a salt thereof or ax , wherein x is 4-30 and M is one or more metal ions, obtained by the process described herein.

[0111] In some embodiments, x is 5, 9, 12, 13, 17, 21, 25, or 30. In some embodiments, x is 5, 9, 12, 13, 17, 21, or 25. Inobtained by the process described herein. InO O O O O O OH obtained by the process described herein. InO O O O O O O obtained by the process described herein. InO O O O O O O O OH obtained by the process described herein. InO O O O O O O O O obtained by the process described herein. Inobtained by the process described herein. Compositions and Metal Ion Complexes

[0118] In another aspect, provided herein is a composition comprising:Attorney Docket No.56009-737.601x , wherein x is 4-30, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of impurities as determined by HPLC.

[0119] In some embodiments, x is 5, 9, 12, 13, 17, 21, 25, or 30. In some embodiments, x is 5, 9, 12, 13, 17, 21, or 25. In, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC. InO O O O O O OH , or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC.O O O O O O O O O or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC.O O O O O O O O OH or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC., a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC. In, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as demonstrated by HPLC.Attorney Docket No.56009-737.601

[0126] In some embodiments, the composition comprises less than about 9% of the impurity. In some embodiments, the composition comprises less than about 8% of the impurity. In some embodiments, the composition comprises less than about 7% of the impurity. In some embodiments, the composition comprises less than about 6% of the impurity. In some embodiments, the composition comprises less than about 5% of the impurity. In some embodiments, the composition comprises less than about 4% of the impurity. In some embodiments, the composition comprises less than about 3% of the impurity. In some embodiments, the composition comprises less than about 2% of the impurity. In some embodiments, the composition comprises less than about 1% of the impurity. In some embodiments, the composition comprises less than about 0.5% of the impurity. In, combinations thereof. In. theimpurity is: . some. someAttorney Docket No.56009-737.601embodiments, the impurity is: some

[0129] In another aspect, provided herein having the structure:wherein: M is one or more metal ions; and n is 1-21.

[0130] In another aspect, provided herein having the structure:wherein: M is one or more metal ions; and x is 4-30.

[0131] In another aspect, provided having the structure:x wherein: M is one or more metal ions; and x is 4-30. Inwherein M is one or more metal ions.

[0133] In another aspect, provided herein is a metal ion complex having the structure:Attorney Docket No.56009-737.601 O2NOOO OOOO O OO O OH M wherein M is one or more metal ions. InO O O O O O O M wherein M is one or more metal ions.M wherein M is one or more metal ions.O O O O O O O O O M wherein M is one or more metal ions.

[0137] In another aspect,M , wherein M is one or more metal ions.

[0138] In anotherM , wherein M is one or more metal ions .

[0139] In another aspect, provided herein is a metal ion complex having the structure: O2NOM , wherein M is one or more metal ions .

[0140] In another aspect, provided herein is a metal ion complex having the structure:Attorney Docket No.56009-737.601M , wherein M is one or more metal ions. InO O O O O O O M , wherein M is one or more metal ions. InO O O O O O O O O M , wherein M is one or more metal ions.

[0143] In some embodiments, the metal ion forms a metal complex. In some embodiments, the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. In some embodiments, the metal ion is magnesium, calcium, or manganese. In some embodiments, the metal ion is magnesium. In some embodiments, the metal ion is calcium. In some embodiments, the metal ion is manganese.

[0144] In some embodiments, the purity of the metal ion complex is above 98.0%, above 99.0%, or above 99.9%. In some embodiments, the purity of the metal ion complex is above 98.0%. In some embodiments, the purity of the metal ion complex is above 99.0%. In some embodiments, the purity of the metal ion complex is above 99.9%.

[0145] In some embodiments, n is 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or any integer therein. In some embodiments, n is 1-21. In some embodiments, n is 1-20. In some embodiments, n is 1-19. In some embodiments, n is 1-18. In some embodiments, n is 1-17. In some embodiments, n is 1-16. In some embodiments, n is 1-15. In some embodiments, n is 1-14. In some embodiments, n is 1-13. In some embodiments, n is 1-12. In some embodiments, n is 1-11. In some embodiments, n is 1-10. In some embodiments, n is 1-9. In some embodiments, n is 1-8. In some embodiments, n is 1-7. In some embodiments, n is 1-6. In some embodiments, n is 1-5. In some embodiments, n is 1-4. In some embodiments, n is 1-3. In some embodiments, n is 1-2. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, n is 21. In some embodiments, n is 20. In some embodiments, n is 19. In some embodiments, n is 18. In some embodiments, n is 17. In some embodiments, n is 16. In some embodiments, n is 15. In some embodiments, n is 14. In some embodiments, n is 13. In some embodiments, n is 12. In some embodiments, n is 11. In some embodiments, n is 10. In some embodiments, n is 9. In some embodiments, n is 8. In some embodiments, n is 7. In some embodiments, n is 6. In some embodiments, n isAttorney Docket No.56009-737.601 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0146] In some embodiments, x is 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or any integer therein. In some embodiments, x is 1-30. In some embodiments, x is 1-29. In some embodiments, x is 1-28. In some embodiments, x is 1-27. In some embodiments, x is 1-26. In some embodiments, x is 1-25. In some embodiments, x is 1-24. In some embodiments, x is 1-23. In some embodiments, x is 1-22. In some embodiments, x is 1-21. In some embodiments, x is 1-20. In some embodiments, x is 1-19. In some embodiments, x is 1-18. In some embodiments, x is 1-17. In some embodiments, x is 1-16. In some embodiments, x is 1-15. In some embodiments, x is 1-14. In some embodiments, x is 1-13. In some embodiments, x is 1-12. In some embodiments, x is 1-11. In some embodiments, x is 1-10. In some embodiments, x is 1-9. In some embodiments, x is 1-8. In some embodiments, x is 1-7. In some embodiments, x is 1-6. In some embodiments, x is 1-5. In some embodiments, x is 1-4. In some embodiments, x is 1-3. In some embodiments, x is 1-2. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, x is 30. In some embodiments, x is 29. In some embodiments, x is 28. In some embodiments, x is 27. In some embodiments, x is 26. In some embodiments, x is 25. In some embodiments, x is 24. In some embodiments, x is 23. In some embodiments, x is 22. In some embodiments, x is 21. In some embodiments, x is 20. In some embodiments, x is 19. In some embodiments, x is 18. In some embodiments, x is 17. In some embodiments, x is 16. In some embodiments, x is 15. In some embodiments, x is 14. In some embodiments, x is 13. In some embodiments, x is 12. In some embodiments, x is 11. In some embodiments, x is 10. In some embodiments, x is 9. In some embodiments, x is 8. In some embodiments, x is 7. In some embodiments, x is 6. In some embodiments, x is 5. In some embodiments, x is 4. In some embodiments, x is 3. In some embodiments, x is 2. In some embodiments, x is 1.

[0147] The number of metal ion atoms (M) correlates to the number of oxygen atoms in the compound that can coordinate to a metal ion to form a metal ion complex. In some embodiments, the metal ion complex comprise one or more metal ions. In some embodiments, the metal ion complex comprises 1, 2, 3, 4, or 5 metal ions. In some embodiments, the metal ion complex comprises 1 or 2 metal ions. In some embodiments, the metal ion complex comprises 1 metal ion. In some embodiments, the metal ion complex comprises 2 metal ions. In some embodiments, the metal ion complex comprises 3 metal ions. Further Forms of the Compounds

[0148] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixturesAttorney Docket No.56009-737.601 thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography.

[0149] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H (D),3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability.

[0150] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more1H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

[0151] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0152] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed hereinAttorney Docket No.56009-737.601 include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0153] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0154] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.

[0155] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.Attorney Docket No.56009-737.601

[0156] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4alkyl)4, and the like.

[0157] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0158] In some embodiments, the compounds described herein exist as solvates. In some embodiments, the disclosure provides for methods of treating diseases by administering the compounds in the form of such solvates. In some embodiments, the disclosure provides for methods of treating diseases by administering a composition comprising the compounds in the form of such solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents.

[0159] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Definitions

[0160] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0161] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0162] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0163] When ranges of values are disclosed, and the notation “from n1… to n2” or “between n1… and n2” is used, where n1and n2are the numbers, then unless otherwise specified, this notation is intended toAttorney Docket No.56009-737.601 include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0164] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0165] “oxo” refers to =O.

[0166] “Carboxyl” refers to -COOH.

[0167] “Cyano” refers to -CN.

[0168] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl. In some embodiments, the alkyl is a C1-C6alkyl. In some embodiments, the alkyl is a C1-C5alkyl. In some embodiments, the alkyl is a C1-C4alkyl. In some embodiments, the alkyl is a C1-C3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0169] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (- CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy,Attorney Docket No.56009-737.601 carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0170] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” or “C2- C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0171] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0172] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0173] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system,Attorney Docket No.56009-737.601 which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0174] “Carbocycle” refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.

[0175] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis- decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturatedAttorney Docket No.56009-737.601 cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, - NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0176] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0177] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0178] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1- haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2- dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1- chloro,2-fluoroethane.

[0179] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0180] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0181] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl isAttorney Docket No.56009-737.601 substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0182] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0183] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2- C6heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4Attorney Docket No.56009-737.601 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo- 1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0184] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromaticAttorney Docket No.56009-737.601 ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0185] The term “linker” or “oligomeric backbone” refers to a chain of at least 10 contiguous atoms. In certain embodiments, the linker contains no more than 20 non-hydrogen atoms. The terms linker and oligomeric backbone can be used interchangeably. In some embodiments, the linker contains no more than 40 non-hydrogen atoms. In some embodiments, the linker contains no more than 60 non-hydrogen atoms. In certain embodiments, the linker contains atoms chosen from C, H, N, O, and S. In some embodiments, every non-hydrogen atom is chemically bonded either to 2 neighboring atoms in the linker, or one neighboring atom in the linker and a terminus of the linker. In some embodiments, the linker forms an amide bond with at least one of the two other groups to which it is attached. In certain embodiments, the linker forms an ester or ether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a thioester or thioether bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms a direct carbon-carbon bond with at least one of the two other groups to which it is attached. In some embodiments, the linker forms an amine or amide bond with at least one of the two other groups to which it is attached. In some embodiments, the linker comprises –(CH2OCH2)- units. In some embodiments, the linker comprises –(CH(CH3)OCH2)- units. In some embodiments, the linkerAttorney Docket No.56009-737.601 comprises -(CH2NRNCH2) units, for RN= C1-4alkyl. In some embodiments, the linker comprises an arylene, cycloalkylene, or heterocycloalkylene moiety.

[0186] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0187] As used herein, “optionally substituted” is a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted” or “optionally substituted” it is meant that the group is substituted with one or more substituents independently selected from C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6heteroalkyl, C3-C7carbocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 3-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), aryl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C6haloalkoxy), halo, cyano, hydroxy, C1-C6alkoxy, C1-C6alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., –CF3), halo(C1-C6)alkoxy (e.g., –OCF3), C1-C6alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0188] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0189] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid,Attorney Docket No.56009-737.601 glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0190] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0191] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0192] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. EXAMPLES

[0193] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which areAttorney Docket No.56009-737.601 encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art. Compound Synthesis

[0194] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Abbreviations

[0195] Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; ACE = acetone; AIBN = azobisisobutyronitrile; aq. = aqueous; AY = assay yield; Boc = tert-butyloxycarbonyl; Boc2O = di-tert-butyl dicarbonate; CD3OD = deuterated methanol; CDCl3= deuterated chloroform; DABCO = (1,4- diazabicyclo[2.2.2]octane); DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butyl aluminum hydride; DIEA = DIPEA = N,N- diisopropylethylamine; DMAc = N,N-dimethylacetamide; DMAB = dimethylamine borane; DMAP = 4- dimethylaminopyridine; DME = dimethylethane; DMF = N,N-dimethylformamide; DMSO-d6= deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EA = EtOAc = ethyl acetate; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; EtOH = ethanol; h = hour; HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = HOBt = 1- hydroxybenzotriazole; IMP = impurity; IPAc = isopropyl acetate; i-PrOH = isopropanol; KHMDS = Potassium bis(trimethylsilyl)amide; KOH = potassium hydroxide; LAH = lithium aluminium hydride; LCAP = liquid chromatography area purity; LiHMDS = Lithium bis(trimethylsilyl)amide; LiOtBu = t- BuOLi = lithium tert-butoxide; mCBPA = meta-chloroperoxybenzoic acid; MeCN = ACN = acetonitrile; MeOH = methanol; MeTHF = 2-MeTHF = 2-Methyltetrahydrofuran; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; Mol Wt = molar weight; n-BuLi = n-butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaIO4= sodium periodate; NaOMe = sodium methoxide; NaOtBu = t-BuONa = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMI = 1-methyl-1H- imidazole; NMM = N-Methylmorpholine; NMP = N-Methyl-2-pyrrolidone; P = product; PE = petroleum ether; PG = protecting group; HPLC = high-performance liquid chromatography; PyBop = (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; Q NMR = quantitative nuclear magnetic resonance analysis; RT = r.t. = room temperature; sat. = saturated; ss = saturated solution; SM = starting material; t-BuOH = tert-butanol; TBAB = tetrabutylammonium bromide; TBS = TBDMS = tert- butyldimethylsilyl; TBSCl = TBDMSCl = tert-butyldimethylchlorosilane; TBHP = tert-butyl hydroperoxide; TCHF = N’-tetramethylformamidinium hexafluorophosphate; TEA = Et3N = triethylamine;Attorney Docket No.56009-737.601 TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TPPO = tetraphenylphosphine oxide; TsCl = tosyl chloride; V = vol = volume. Analytical Methods

[0196] NMR Spectroscopy:1H and13C (1H decoupled) NMR spectroscopy data was collected on a Bruker BioSpin GmbH 300 MHz (1H 300 MHz;13C 75 MHz) equipped with Z116098-0773 (PA BBO 400S1 BBF-H-D-05-Z-SP) or Z825501-0039 (PA BBI 300S1 H-BB-D-05 Z) probe Chemical shifts are reported in parts per million (ppm) and coupling constants (J) are given in hertz. All data was recorded in CDCl3and referenced to residual CHCl3(δ 7.261H; 77.1613C), DMSO-d6and referenced to residual DMSO (δ 2.501H; 39.5213C). Multiplicities are denoted by singlet (s), doublet (d), doublet of doublets (dd), doublet of doublet Strand 2021 – S3 – of doublets (ddd), triplet (t), apparent triplet (app. t), doublet of triplets (dt), quartet (q), doublet of quartets (dq), triplet of quintets (tquin.), and multiplet (m). Broad peaks are denoted by (br).

[0197] QNMR for reaction solution

[0198] The formula is as follows:

[0199] WtStd= Weight of internal standard (mg)

[0200] N[H]Std= Theoretical [H] value of CH group at particular location in internal standard

[0201] MSpl= molecular weight of sample

[0202] n[H]Spl= Actual [H] value of CH at particular location in sample

[0203] WtSpl= Weight of sample (mg)

[0204] n[H]Std= Actual [H] value of CH at particular location in internal standard

[0205] MStd= molecular weight of internal standard

[0206] N[H]Spl = Theoretical [H] value of CH group at particular location in sample

[0207] P = purity of internal standard

[0208] Mass Spectrometry: HRMS data was obtained by 2 methods.

[0209] Method A by using an Q-TOF mass spectrometer (Agilent 1290 UPLC with 6546 Q-TOF) in positive mode between m / z 100-3200, employing lockmass correction according to the manufacturer’s instructions.

[0210] System: MPA: 0.1% FA in H2O and MPB: 0.1% FA in MeCN.

[0211] Capillary (kV): 4.0; Gas temperature (°C): 300; Drying Gas (L / min): 5; Sheath Gas (L / min): 11; Fragmentor (V): 150; Interface Type: ESI, Positive; Analyser Mode: Sensitivity; Scan Range: 100-3200 m / z.

[0212] Method B by using an ESI-TOF mass spectrometer (Agilent 1290 UPLC with 6230 TOF) in positive mode between m / z 50-1600, employing lockmass correction according to the manufacturer’s instructions.Attorney Docket No.56009-737.601

[0213] System: MPA: 0.04% NH4HO in H2O and MPB: MeCN: MeOH=1:1

[0214] Capillary (kV): 4.0; Gas temperature (°C): 350; Drying Gas (L / min): 5; Sheath Gas (L / min): 10; Fragmentor (V): 200; Interface Type: ESI, Positive; Analyser Mode: Sensitivity; Scan Range: 50-1600 m / z.

[0215] Ion Chromatography: Instrument: ICS-6000, Detection: Suppressed Conductivity, Anion Self- Regenerating Suppressor: ADRS 600, Collection Rate: 5.0 Hz, Cell Temperature: 35.0 °C, Suppressor: External Mode, Suppressor Current: External Mode, Suppressor Current: 75 mA, Column Temperature: 30.0 °C, Flow Rate: 1.0 mL / min, Run Time: 7 min, Injection Volume: 25 µL, Column: AS184*250 mm, Guard Column: AG184*50 mm, Eluent: 30 mM KOH in Water.

[0216] MicroED: Polarized-light microscope: Axio Scope 5 POL (Ziess), CryoEM: Talos F200C (200 kV, Thermo Fisher Scientific), Detector: Ceta-D (CMOS, Thermo Fisher Scientific), Data collection software: EPU-D (Version 1.4.0.125REL, Thermo Fisher Scientific), CryoEM grid: Holey Carbon EM grid (Cu200 mesh R2 / 2, QUANTIFOIL), Cryogenic sample holder: Model 698 (Gatan). Grid loading condition: cryo-transfer. Resolution: 0.90 Angstroms. Unit cell (a, b, c in Å, α, β, γ in deg): 13.39(3), 11.48(1), 13.75(2), 90, 97.16(16), 90; and space group: P21 / c(no.14). SYNTHESIS OF POLYETHYLENE GLYCOL DERIVATIVES

[0217] Example 1. First Generation PEG Derivate Synthesis

[0218] Scheme 1. Route of first generation PEG linkerAttorney Docket No.56009-737.601

[0219] The synthetic route for the first generation PEG-8 linker, comprises 10 linear steps and resulted in low overall yield of 4.6% due to low selectivity in tosylation step 5. The intermediates and Boc protected final product are difficult to purify due to poor crystallinity. Additionally, the synthesis uses hazardous and / or expensive reagents such as NaH and Ag2O. Therefore, the route is not suitable to process scale up. Subsequently a new route was developed.

[0220] Example 2: Synthesis of 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD-103)

[0221] Scheme 2. Steps a and b for the synthesis of CPD-103.CPD-101CPD-102 CPD-103

[0222] Tetraethylene glycol was a key raw material for the synthesis of intermediate 1,3,6,9,12-pentaoxa- 2-thiacyclotetradecane 2,2-dioxide (CPD-103). It is usually contaminated with the n-PEG-OH (n = 1, 2, 3, 5, 6…) analogues and these will generate potential impurities in the downstream chemistry. Tetraethylene was purified using a short distillation path prior to step a.

[0223] Step a: To a 3000 L reactor was charged with dichloromethane (10.00 V, V = L / kg to the limiting reagent) under nitrogen at ambient temperature and agitate at 25 ºC. Tetraethylene glycol (45.0 kg, 1.0 eq.) and N, N-diisopropylethylamine (143.5 kg, 4.8 eq.) were added at 25 °C The temperature was adjusted to 0 °C and thionyl chloride (55.3 kg, 2.0 eq.) in dichloromethane (5 V) solution was added over 12 hours. The reaction mixture was agitated for 1 hour at 0 °C.

[0224] Under nitrogen, deionized water (10 V) was added and the reaction mixture was agitated for 30 min at 0 °C. The temperature was adjusted to 25 °C and the reaction mixture was further agitated for 30 min. The organic layer was separated and was washed with 5% aq. citric acid (10 V) and then 10% brine (10 V). The organics were separated and transferred to a 500 L reactor under nitrogen and then concentrated under vacuum until a volume of 2-4 V was obtained. Acetonitrile (5 V) was added and the volume was reduced under vacuum to about 2-4 V. Next deionized water (4 V-8 V, to make the mixture to CH3CN: H2O=1: 2) was added and the mixture was stirred for 30 min at 25 °C. The mixture was pressure filtered through diatomite (22.50 kg) and the filter cake was washed with CH3CN: water =1: 2 (3 V). The resulting filtrate was collected and washed with n-heptane (2 x 10 V) at 25 ℃. The resulting MeCN / water layer (430.2 kg) which contained the desired product was used in the next step without further purification .

[0225] 1H NMR (300 MHz, Chloroform-d): δ 4.35 (ddd, J = 10.7, 5.8, 4.6 Hz, 2H), 4.10 (dt, J = 11.1, 4.8 Hz, 2H), 3.85 – 3.64 (m, 12H).

[0226] 13C NMR (75 MHz, Chloroform-d): δ 70.68, 70.46, 69.47, 61.74.

[0227] HRMS (m / z): [M + H]+Calcd for C8H17O6S = 241.0746, Found 241.0750.Attorney Docket No.56009-737.601

[0228] Step b: Under nitrogen, 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2-oxide (CPD-102) in acetonitrile / water (430.2 kg,) was added to a 3000 L reactor and dichloromethane (154.3 kg, 4 V) was added at 25 °C with agitation. Next, Ruthenium (III) chloride hydrate (292.5 g, 0.01 eq.) was added at 25 °C followed by addition of sodium periodate (60.0 kg, 2.3 eq.) portion wise at 30 °C. The reaction mixture was agitated for 4 hours. After consumption of intermediate CPD-102 (monitored by GC), the temperature was adjusted to 25 °C and the reaction mixture was further agitated for 30 min.

[0229] The crude product was filtered through diatomite (14.8 kg, 0.5 w / w) and the filter cake was washed with dichloromethane (397.2 kg, 10 V). The resulting filtrate was further filtered through a filter element (0.45 μm) and the organics were separated and washed with 5% sodium hydrogen sulfite solution (156.2 kg, 5 V). The organic phase was separated and the aqueous phase was extracted with dichloromethane (195.1 kg, 5 V). The combined organics were concentrated under vacuum to 2-4 V, ethyl acetate (5 V) was added, and the resulting mixture was concentrated to 2-4 V. This process was repeated once.

[0230] The crude product was diluted with n-heptane (4 V) and purified by a silica gel plug (2.4 w / w, 70.0 kg, 100~200 mesh) and eluted with 230.0 kg of ethyl acetate: n-heptane = 1: 2, 1538.6 kg of ethyl acetate: n-heptane = 2: 3, followed by 180 kg of ethyl acetate in sequence. The combined fractions containing product were concentrated under reduced pressure and the product was triturated in 5% ethyl acetate / n-heptane. The solids were vacuum dried for 12 hours at 30 °C to result in 18.3 kg of the desired product as an off-white solid. [Yield 31% over 2 steps]

[0231] 1H NMR (300 MHz, Chloroform-d): δ 4.52 – 4.44 (m, 4H), 3.90 – 3.81 (m, 4H), 3.71 – 3.62 (m, 8H).

[0232] 13C NMR (75 MHz, Chloroform-d): δ 72.21, 70.68, 70.61, 68.41.

[0233] HRMS (m / z): [M + H]+Calcd for C8H17O7S = 257.0695, Found 257.0697.

[0234] Step-b critical impurity: Triethylene glycol analogue of CPD-103

[0235] The major impurities include the dimer byproduct and can be removed by silica gel column purification in the downstream process. Table 1. Identified of Step-b impurities Impurity Structure O O CPD-103-1OSOO OAttorney Docket No.56009-737.601 OOS OOO O O CPD-103 dimer O O O O O SOO

[0236] Example 3. Second Generation Synthesis of 4-(4-nitrophenoxy)-3,6,9,12-tetraoxatetradecan- 1-ol (CPD-18) Route 1

[0237] Scheme 3. Step-1 of route 1.

[0238] Step 1: 4-Fluoronitrobenzene (290.0 g, 1.0 eq.) and K2CO3(556.0 g, 2.0 eq.) was added into ethylene glycol (2.9 L, 10 V) at ambient temperature. The mixture was stirred for 3 hours at 70 °C.

[0239] The reaction mixture was poured into ice water (8.7 L, 30 V) over 1 hour and the resulting mixture was slurried for 2 hours at 25 °C. The mixture was then filtrated and the solid was washed with H2O (1.4 L, 5 V). The filter cake was dissolved in dichloromethane (5.8 L, 20 V) and the organic phase was separated and concentrated (~2.17 L, 7.5 V) . n-Heptane (2.9 L, 10 V) was added at 25 °C over 0.5 hours with stirring. The mixture was slurried for 1 hour, filtrated and dried at 40 °C to give 297.0 g (yield: 79%) of the desired product as a white solid. Formation of dimer impurity (CPD-181A) was observed and was purged in the next steps.

[0240] Scheme 4. Step-2 and 3 of route 1. tBuONaStep-3 CPD-18

[0241] Step 2: 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD-103) (250 g, 1.0 eq.) and 2- (4-nitrophenoxy)ethan-1-ol (CPD-181) (232.5 g, 1.3 eq.) were added into THF (1.2 L, 5 V) with stirring under N2. Tert-BuONa (731.0 mL, 1.5 eq., 2 M in THF) was added at 10~20 °C over 4 hours. The mixtureAttorney Docket No.56009-737.601 was stirred at 10~20 °C for 1 hour and consumption of CPD-103 starting material was monitored by TLC. After completion of the reaction, H2O (1.5 L, 6 V) was added at 10~20 °C and the solution was concentrated.

[0242] Step 3: The mixture was washed with dichloromethane (3 x 1.2 L, 3 x 5 V) and 20% aqueous H2SO4(0.2 eq.). To the aqueous layer, 2-Me-THF (1.5 L, 6 V) and 20% H2SO4(125.0 mL, 0.5 V) were added and the mixture was stirred at 70-75 °C for 2 hours. (Reaction monitored by HPLC, CPD-18S <1%). The mixture was cooled to ambient temperature and the layers were separated. The aqueous phase was extracted with 2-Me-THF (2.5 L, 10 V). The combined organic phase was washed with 10% K2CO3(2 x 2.5 L, 2 x 10 V) and 20% NaCl solution (1.2 L, 5 V) and then concentrated to give crude CPD-18.

[0243] Purification: Crude CPD-18 (250.0 g.1.0 eq.) dissolved in THF (2.5 L, 10 V) was added MgCl2 (613.0 g, 5.0 eq. wt to crude) at 15-20 °C and the slurry was stirred for 18 hours at 25 °C. Next, the slurry was diluted with MTBE (2.5 L, 10 V) and stirred for 1 hour at 25 °C. The reaction mixture was filtered and the resulting solid was washed with a 1:1 mixture of THF: MTBE (1.2 L, 5 V) and dried at 40 °C for 3-6 hours (CPD-18 Mg complex purity by HPLC: 99.82%).

[0244] CPD-18-Mg complex (860 g) was dissolved in ice water (2.5 L, 10 vol) and extracted with dichloromethane (2.5 L, 10 V). The organic layer was concentrated and dried under vacuum at 40 °C to obtain CPD-18 (228.0 g, 65% yield over two steps).

[0245] Example 4. Second Generation Synthesis of 4-(4-nitrophenoxy)-3,6,9,12-tetraoxatetradecan- 1-ol (CPD-18) Route 2.

[0246] Scheme 5. Step-1 of route 2.

[0247] Step 1: 4-Fluoronitrobenzene (16.5 kg, 1.0 eq.) and K2CO3(32.3 kg, 2.0 eq.) was added to PEG-5 (33.6 kg, 1.2 eq.) in acetonitrile (130.3 kg, 10 V) and the mixture was heated to 80 °C and stirred for 12 hours. The mixture was filtered and washed with acetonitrile (39.6 kg, 3 V). The filtrate was diluted with n- heptane (57.0 kg, 5 V) and concentrated under reduced pressure to 2-3 V. The solvent was changed to n- heptane by addition of n-heptane (5 V) followed by concentrating under reduced pressure to 2-3 V. Then H2O (329.5 kg, 20 V) was added and the mixture was stirred for 2 hours at 25 °C. The mixture was filtered and the solids (CPD-18A) were washed with H2O (33.0 kg, 2 V). Sodium chloride (66.0 kg, 4 w / w) was added and the filtrate was extracted twice with 1:1 MTBE: IPAc (61.3 kg / 72.2 kg, 5 V / 5 V) andAttorney Docket No.56009-737.601 concentrated under reduced pressure. The solvent was changed to ethanol by addition of ethanol (10 V) followed by concentrating at 40 ºC under reduced pressure to 2-3 V twice to afford the crude product.

[0248] Purification: Crude CPD-18 was dissolved in ethanol (10 V) and anhydrous MnCl2(25.8 kg, 2.5 eq.) was added and the mixture was stirred for 30 minutes at ambient temperature. The mixture was seeded with pure CPD-18-Mn complex (147.0 g, 0.5 % w / w) and stirred at 20 ºC for 6 hours. The mixture was filtered and the solid was washed with ethanol (23.2 kg, 1 V) to yield CPD-18 (99.6% pure by HPLC).

[0249] The resulting mixture was diluted with ethanol (140.0 kg, 6 V) and anhydrous MnCl2 (20.55 kg, 2.00 eq.) was added followed by ethanol (46.1 kg, 2 V) as a rinse of the charging port. The mixture was stirred at 80 °C for 1 hour to obtain a clear solution and was then allowed to slowly cool down to 25 °C over 6 hours. The mixture was then stirred at 20 °C for an additional 6 hours. The mixture was filtered and the solid (CPD-18 complex, 100% pure by HPLC) was washed with ethanol (23.2 kg, 1 V) and added into H2O (294.5 kg, 10 V) followed by dichloromethane (390.0 kg, 10 V). The resulting mixture was stirred for 30 min and filtered. The filtrate was collected and the layers were separated. The aqueous layer was extracted with dichloromethane (372.3 kg, 10 V) and the combined organic layers were washed with water (146.0 kg, 5 V) and filtered. The solvent was changed to THF by the addition of THF (264.6 kg, 10 V) and the mixture was concentrated under reduced pressure at 40 ºC to 2-4 V to yield the desired product (61.5 kg THF solution containing 25.6 kg CPD-18, 60.7% yield) which was used in the next step without further purification.

[0250] CPD-18 Mn Complex

[0251] HRMS (m / z): [M + Na]+Calcd for C16H25NNaO8382.1478, Found 382.1459.

[0252] Ion Chromatography: 14 wt% of Cl- (1.0 eq. Cl-).

[0253] CPD-18 Ca Complex

[0254] HRMS (m / z): [M + Na]+Calcd for C16H25CaCl2O8Found 470.35.

[0255] The structure as determined by MicroED is shown in FIG.2.

[0256] CPD-18

[0257] 1H NMR (300 MHz, Chloroform-d): δ 8.23 – 8.14 (m, 2H), 7.04 – 6.95 (m, 2H), 4.29 – 4.20 (m, 2H), 3.94 – 3.87 (m, 2H), 3.76 – 3.64 (m, 13H), 3.62 – 3.57 (m, 2H), 3.06 (s, 2H).

[0258] 13C NMR (75 MHz, Chloroform-d) δ: 163.87, 141.51, 125.82, 114.62, 72.59, 70.83, 70.53, 70.50, 70.46, 70.19, 69.31, 68.14, 61.60.

[0259] HRMS (m / z): [M + Na]+Calcd for C16H25NNaO8= 382.1478, Found 382.1400.

[0260] CPD-18 synthesis via CPD-18S intermediate (Example 3) achieved successfully to synthesis CPD-18 and it was purified via MnCl2complex process to produce >99% pure CPD-18.

[0261] Updated CPD-18 synthesis (Example 4) via PEG-5-OH is more cost effective since CPD-103 starting material is not involved in the process and it is a single step to synthesize CPD-18. Purification via MnCl2complex is more effective over MgCl2complex to remove PEG analogue impurities in the higher range.Attorney Docket No.56009-737.601

[0262] (4-nitrophenoxy)-3,6,9,12-tetraoxatetradecan-1-ol (CMP-18) impurities

[0263] The three most significant impurities (CPD-182, CPD-183, and CPD-184) shown in Table 2 result from the poor quality of PEG-5 which contains trace PEG-2, 3 and 4.

[0264] Respective impurities were synthesized and identified by HPLC using RRT (trough relative retention time) markers for monitoring impurities trend. Table 2. CPD-18 process impurities Impurity No.Structure NameO2N 1 O O O O O O CPD-18-OAc O O2N 2 O O O O O O CPD-18-2MeTHP O O2N 3 O CPD-182 OOHO2N 4 O OH CPD-183 O O O2N 5 O O CPD-184 O OOH

[0265] Example 5. Screening of metal salts and solvents for purification of (4-nitrophenoxy)- 3,6,9,12-tetraoxatetradecan-1-ol (CPD-18) by metal complexation

[0266] Scheme 6. Metal complexation (5 eq) XCl2ComplexTHF (10 V) CPD-18 rt, 18 h (LCAP: 93.9%) 184:18 = 1.9:93.9

[0267] Experiments were performed by mixing 0.1 g of (4-nitrophenoxy)-3,6,9,12-tetraoxatetradecan-1- ol (CPD-18, CPD-18-4:18 = 1.9:93.9) with 5 equivalents of XCl2in 1 mL (10 V) of the solvent for 18 hours. The mixtures were filtered and the purity of the filter cake and the assay yield (AY) loss of CPD-18 in the mother liquid were assessed. The results are listed in Table 3.Attorney Docket No.56009-737.601 Table 3. Screening of metal chloride salts for complexation with CPD-18 LCAP of Clear so AY lost in Entry XCln(5 eq.)Solvent (10 V) Temp. Timelid solution? CPD-184: mother CPD-18 liquid 1 CoCl2THF r.t. 18 h No No 18 in solid - 2 MgCl2THF r.t. 18 h Yes - - 3 CaCl2THF r.t. 18 h No 1.5: 95.6 4.5 % 4 ZnCl2THF r.t. 18 h Yes - - 5 BaCl2THF r.t. 18 h No No 18 in solid - 6 CuCl2THF r.t. 18 h No No 18 in solid - 7 FeCl3THF r.t. 18 h Yes - - 8 NiCl2THF r.t. 18 h No No 18 in solid - 9 AlCl3THF r.t. 18 h Yes - - 10 MnCl2THF r.t. 18 h No 0.4: 99.6 6.03 % 11 InCl3 THF r.t. 18 h Yes - - LCAP: Liquid Chromatography Area Purity AY: Assay Yield

[0268] Experiments were performed by slurrying 0.1 g of CPD-18 complex with 5 equivalents of CaCl2in 1 mL (10 V) of the solvents for 2 days. The mixtures were filtered and the purity of filter cake and the assay yield (AY) loss of CPD-18 in the mother liquid were assessed. The results are listed in Table 4. Table 4. Screening of solvents for CPD-18 Ca complex LCAP of Entry Solvent (10 V) Temp. Time Clearsolid AY lost in solution?CPD-184: mother liquid CPD-18 1 EA r.t. 2 days No 1.3: 98.7 - 2 Isopropyl acetate r.t. 2 days No 1.4: 98.6 - 3 ACN r.t. 2 days No 1.3: 98.7 0.05 % 4 THF r.t. 2 days No 0.7: 99.3 0.91 % 5 2-MeTHF r.t. 2 days No 1.3: 98.7 0.8 % 6 TOL r.t. 2 days No 1.2: 98.8 - 7 ACE r.t. 2 days No 0.6: 99.4 0.13 % 8 DCM r.t. 2 days No 1.2: 98.8 0.09 % 9 EtOH r.t. 2 days Yes - - 10 IPA r.t. 2 days No 0.4: 99.6 2.3 % 11 MTBE r.t. 2 days No 1.3: 97.6 -Attorney Docket No.56009-737.601 12 DME r.t. 2 days Yes - - LCAP: Liquid Chromatography Area Purity AY: Assay Yield

[0269] Experiments were performed by slurrying 0.1 g of CPD-18 complex with 5 equivalents of MnCl2in 1 mL (10 V) of the solvents for 2 days. The mixtures were filtered and the purity of filter cake and the assay yield (AY) loss of CPD-18 in the mother liquid were assessed. The results are listed in Table 5. Table 5. Screening of solvents for CPD-18 Mn complex Entry Solvent (10 V) Temp. Time ClearLCAP of AY lost in solution?solid 184: 18 mother liquid 1 EA r.t. 18 h No 0.9: 99.1 0.1 % 2Isopropylacetate r.t. 18 h No 1.7: 98.3 -3 ACN r.t. 18 h No 0.1: 99.9 44.7 % 4 THF r.t. 18 h No 0.6: 99.4 22.9 % 5 2-MeTHF r.t. 18 h No 1.2: 98.8 0.54 % 6 TOL r.t. 18 h No 1.8: 93.6 - 7 ACE r.t. 18 h No 0.6: 99.4 7.46 % 8 DCM r.t. 18 h No 2.0: 98.0 0.13 % 9 EtOH r.t. 18 h No 0.4: 99.6 11.9 % 10 IPA r.t. 18 h No 0.8: 99.2 2.61 % 11 MTBE r.t. 18 h No 1.9: 93.8 0.14 % 12 DME r.t. 18 h No 0.6: 99.4 40.6 % LCAP: Liquid Chromatography Area Purity AY: Assay Yield

[0270] Experiments were performed by mixing 0.1 g of CPD-18 with different equivalents of MnCl2in 1 mL (10 V) of EtOH or THF for 18 h. The mixtures were filtered and the purity of filter cake and the assay yield (AY) loss of CPD-18 in the mother liquid were assessed. The results are listed in Table 6. Table 6. Screening of equivalents of MnCl2in EtOH and THF Clear LCAP of AY lost in EntryMnCl2(eq.)Solvent (10 V) Temp. Time solution? solid mother 184: 18 liquid 1 1 EtOH r.t. 18 h No 0.09: 99.9 32.2 % 2 2 EtOH r.t. 18 h No 0.03: 99.9 11.2 % 3 3 EtOH r.t. 18 h No 0.03: 99.9 9.1 %Attorney Docket No.56009-737.601 4 4 EtOH r.t. 18 h No 0.06: 99.9 8.9 % 5 5 EtOH r.t. 18 h No 0.1: 99.9 9.1% 6 1 THF r.t. 18 h No 0.3: 99.7 10.2 % 7 2 THF r.t. 18 h No 0.2: 99.8 10.8 % 8 3 THF r.t. 18 h No 0.2: 99.8 11.0 % 9 4 THF r.t. 18 h No 0.4: 99.6 12.2 % 10 5 THF r.t. 18 h No 0.5: 99.5 13.2 % LCAP: Liquid Chromatography Area Purity AY: Assay Yield

[0271] Example 6. Synthesis of 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol (CPD-110)

[0272] Scheme 7. Steps-4 and 5.CPD-18 OSOH3CPD-109CPD-110

[0273] Step 1: 14-(4-Nitrophenoxy)-3,6,9,12-tetraoxatetradecan-1-ol (CPD-18) in THF (21.0 kg, 1.0 eq.) was added to 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD-103) (18.1 kg, 1.2 eq.) under nitrogen at 25 ºC. The reaction mixture was cooled to 0 ºC and tert-BuONa (6.1 kg) was added portion wise. The resulting mixture was stirred at 25 ºC for 5 hours and then cooled to -5~0 °C. Water (210 L, 10 V) was added and the mixture was stirred for 30 min at 0~5 °C. The mixture was washed with isopropyl acetate (3 xAttorney Docket No.56009-737.601 178.8 kg, 3 x 10 V) and further washed with 2-Me-THF (2 x 180.7 kg, 2 x 10 V). The aqueous layer which contained the product was subjected to the next step reaction without further purification.

[0274] Step 2: To crude CPD-109 in aqueous solution was added 2-Me-THF (91.0 kg, 5 V). The reaction was cooled to 15 ºC and H2SO4(19.3 kg, 0.5 V) was added. The resulting mixture was heated to 70 °C and stirred for 2 hours. The reaction was cooled to 25 °C, added methyl tert-butyl ether (78.0 kg, 5 V) and the resulting mixture was stirred for 30 min. The layers were separated and the aqueous phase was washed twice with 1:12-Me-THF / methyl tert-butyl ether (90.7 kg / 78.0 kg, 5 V / 5 V) and was then extracted with dichloromethane (279.5 kg, 10 V). The organic phase was washed with aqueous 8 wt% sodium bicarbonate solution (228.8 kg, 10 V) followed by 10 wt% NaCl aqueous solution (233.8 kg, 10 V). The organic layer was filtered and concentrated to dryness at below 40 ºC to give CPD-110 (18.9 kg, 99.9% pure by HPLC, 59.6% yield) as a thick oil.

[0275] 1H NMR (300 MHz, Chloroform-d): δ 8.27 – 8.12 (m, 2H), 7.08 – 6.94 (m, 2H), 4.24 (dd, J = 5.7, 3.8 Hz, 2H), 3.90 (dd, J = 5.7, 3.8 Hz, 2H), 3.75 – 3.56 (m, 32H), 2.91 (s, 1H).

[0276] 13C NMR (75 MHz, Chloroform-d): δ 163.87, 141.50, 125.81, 114.59, 72.52, 70.86, 70.57, 70.51, 70.28, 69.33, 68.20, 61.62.

[0277] HRMS (m / z): [M + H]+Calcd for C24H41NNaO12= 558.2526, Found 558.2428.

[0278] Example 7. Optimization of 1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide (CPD- 103) ring opening

[0279] Different solvent combinations with tert-BuONa and tert-BuOLi were screened and the results were monitored by HPLC. The results are listed in Table 7. Impurities (CPD-187S and CPD-188S) are listed below.CPD-187STable 7. Screening of base and solvent combination Entry Solvent (10 V) Base (2 eq.) Temp. time ResultSM: 187S: 188S: P1 Toluene t-BuOLi 40 °C 16 h 0.3: 0.3: 2.0: 94.5 2 DCM t-BuOLi 40 °C 16 h 0.3: 0.6: 2.8: 92.9 3 THF t-BuOLi 40 °C 16 h 0.6: 0.16: 0.47: 79.3 4 2-MeTHF t-BuOLi 40 °C 16 h 0.5: 0.26: 0.88: 94.9 5 ACN t-BuOLi 40 °C 16 h 0.7: 1.7: 0.38: 94.3Attorney Docket No.56009-737.601 6 Toluene t-BuONa 0 °C 16 h 1.2: 0.5: 1.6: 89.5 7 DCM t-BuONa 0 °C 16 h 0.4: 0.09: 0.39: 92.6 8* DCM* t-BuONa 20~30 °C 16 h 0.7: 0.06: 0.04: 86.6 9 THF t-BuONa 0 °C 16 h 0.5: 0.08: 1.0: 74.5 10* THF* t-BuONa 20~30 °C 16 h 5.1: 0.05: 0.13: 78.6 11 2-MeTHF t-BuONa 0 °C 16 h 0.5: 0.17: 1.5: 77.4 12 ACN t-BuONa 0 °C 16 h 0.4: 0.24: 2.6: 83.6 * Base was dissolved into 10 V solvent and added into the mixture for 2 h. SM: Starting material P: Product

[0280] Different equivalents of tert-BuONa were screened and the reactions were monitored by HPLC. The results are listed in Table 8. Table 8. Investigation of base equivalents for CPD-103 ring opening. Entry Eq. of base BaseTemp.Time Result (LCAP Area%) (°C)(h) P: 188S: SM 0-15 5 79: 0.09: 20 1 0.9 eq. t-BuONa solid 25±5 16 80: 0.09: 18 0-15 5 75: 0.09: 24 2 1.0 eq. t-BuONa solid 25±5 16 77: 0.11: 22 31.0 eq. t-BuONa0-15 5 66: 0.05: 33 (2 M in THF)25±5 16 68: 0.05: 31 0-15 5 99: 0.19: 0.79 4 1.1 eq. t-BuONa solid 25±5 16 99: 0.21: 0.23 5 1.2 eq. t-BuONa solid 0-15 5 99: 0.41: 0 6 1.5 eq. t-BuONa solid 0-15 5 99: 0.86: 0 LCAP: Liquid Chromatography Area Purity P: Product SM: Starting material

[0281] Different equivalents of CPD-103 were explored with base tert-BuONa and the reactions were monitored by HPLC. The results are listed in Table 9. Table 9. Investigation CPD-103 equivalents for ring opening Entry Solventt-BuONaResult (LCAP Area%) (eq.) 103 (eq.) Temp. (°C) Time (h)P:188S:SM 2 91: 0.15: 8.5 1 THF (5V) 1.1 1.1 0-25 16 97: 0.19: 2.0 2 97: 0.1: 2.5 2 THF (5V) 1.1 1.2 0-25 16 99: 0.2: 0 2 96: 0.18: 3.6 3 THF (5V) 1.1 1.3 0-25 16 99: 0.21: 0.67 2 96: 0.15: 3.4 4 THF (5V) 1.1 1.5 0-25 16 97: 0.14: 2.3Attorney Docket No.56009-737.601 LCAP: Liquid Chromatography Area Purity P: Product SM: Starting material

[0282] Example 8. Screening of metal salts and solvents for purification of 26-(4-nitrophenoxy)- 3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol (CPD-110) by metal complexation

[0283] Experiments were performed by mixing 0.1 g of crude CPD-110 with 5 equivalents of XCl2in 1 mL (10 V) of the solvent for 18 hours. The mixtures were filtered and the purity of filter cake and the assay yield (AY) loss of CPD-110 in the mother liquid were assessed. The results are listed in Table 10.Table 10. Screening of metal chloride salts for complexation with CPD-110 Entry XCln SolventClear HPLC of Loss of (5 eq.)Temp. Timesolution? solid ML 1 FeCl3THF (10 V) 20 °C 2 days Yes - - 2 MgCl2THF (10 V) 20 °C 2 days Yes - - 2 Product 3 CaCl THF (10 V) 20 °C 2 days No <0.1 mainly mg / mL 4 BaCl2THF (10 V) 20 °C 2 days No No product >80mg / mL 5 CoCl2THF (10 V) 20 °C 2 days No No product >80mg / mL 6 NiCl2THF (10 V) 20 °C 2 days No No product >80mg / mL 7 CuCl2THF (10 V) 20 °C 2 days No No product >80mg / mL 8 ZnCl2THF (10 V) 20 °C 2 days Yes - - 9 AlCl3THF (10 V) 20 °C 2 days Yes - - 10 InCl3THF (10 V) 20 °C 2 days Yes - -

[0284] CaCl2equivalents screening: Experiments were performed by mixing 0.1 g of CPD-110 (98.5% purity by HPLC) with different equivalents of CaCl2in 1 mL (10 V) of the solvents for 18 h. Then filter the mixtures and test the purity of cake and assay loss of CPD-110 in the mother liquid. The result is listed in Table 11. Table 11. Screening of equivalents of CaCl2CaCl2Solvent Temp. Time ClearHPLC of Loss of solution?solid ML 1 1 eq. THF (10 V) 20 °C 3 days No 98.5% 19 mg / mL 22 eq. THF (10 V) 20 °C 3 days No 98.5% <0.1mg / mLAttorney Docket No.56009-737.601 3 3 eq. THF (10 V) 20 °C 3 days No 98.5%<0.1mg / mL44 eq. THF (10 V) 20 °C 3 days No 98.5% <0.1mg / mL55 eq. THF (10 V) 20 °C 3 days No 98.5% <0.1mg / mL6 0 eq. THF (10 V) 20 °C 3 days Yes 98.5% -

[0285] Solvent screening: Experiments were performed by mixing 0.1 g of CPD-110 (99.54% purity by HPLC) with 2.5 equivalents of CaCl2in 1 mL (10 V) of the solvents for 18 h. Then filter the mixtures and test the purity of cake and assay loss of CPD-110 in the mother liquid. The result is listed in Table 12. Table 12. Solvent screening CaClSolvent Clear 110: 188: 18 in Entry 2(4 eq.) (10 V)Temp. Time.solution? filter cake (LCAP) 1 CaCl2EA r.t. 18 h No 99.59: 0.15: 0.07 2 CaCl2EtOH r.t. 18 h Yes - 3 CaCl2DCM r.t. 18 h No 99.72: 0.14: 0.06 4 CaCl2MeCN r.t. 18 h No 99.63: 0.14: 0.07 5 CaCl2THF r.t. 18 h No 99.58: 0.15: 0.07 6 CaCl22MeTHF r.t. 18 h No 99.57: 0.15: 0.075 7 CaCl2IPA r.t. 18 h No 99.59: 0.14: 0.07 8 CaCl2IPAc r.t. 18 h No 99.52: 0.15: 0.08 9 CaCl2Toluene r.t. 18 h No 99.58: 0.15: 0.08 LCAP: Liquid Chromatography Area Purity

[0286] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol CaCl2complex (CPD-110 CaCl2complex)

[0287] 1H NMR (300 MHz, DMSO-d6): δ 8.28 – 8.15 (m, 2H), 7.28 – 7.14 (m, 2H), 4.90 (t, J = 5.3 Hz, 1H), 4.35 – 4.21 (m, 2H), 3.87 – 3.75 (m, 2H), 3.68 – 3.40 (m, 32H).

[0288] 13C NMR (75 MHz, DMSO-d6): δ 164.28, 141.15, 126.29, 115.59, 72.71, 70.36, 70.21, 70.18, 69.03, 68.75, 60.44.

[0289] HRMS (m / z): [M + Na]+Calcd for C24H41NNaO12= 558.2526, Found 558.2437.

[0290] Ion Chromatography: 20 wt% of Cl- (1.2 eq. of Cl-).

[0291] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol (CPD-110) impuritiesAttorney Docket No.56009-737.601

[0292] All the possible PEG analogue impurities such as CPD-186, CPD-187, CPD-188, CPD-110-OAc and CPD-110 dimer impurities have been synthesized and monitored in the reaction profile by HPLC. Examples are shown in Table 13. Table 13. CPD-110 process impurities No. Structure Name O2N 1 O O O OH CPD-187 O O O O O2N 2 O O O CPD-188 O O OOHO2N O O CPD-110 3 O O O O O O O O NO2dimer O2NCPD-110 4 O O O O O O O O OAc O O2N O O CPD-18 5 O O O O NOdimer 2

[0293] Example 9. Synthesis of 2-(26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl) isoindoline-1,3-dione (CPD-110-NH3)

[0294] Scheme 8. Synthesis of PEG-8-NHCAttorney Docket No.56009-737.601

[0295] 26-(4-nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol (100 g, 187 mmol, 1 eq.) was dissolved into THF (1000 mL, 10 V). PhtNH (33.0 g, 224 mmol, 1.2 eq.) and PPh3(98.0 g, 373 mmol, 2 eq.) were added and the result mixture was cooled to 5±5 °C. DIAD (75.5 g, 373 mmol, 2 eq.) was added dropwise and the resulting mixture was stirred for 1 h at 5±5 °C.20wt % NaCl aqueous solution (5 V) was added to the reaction mixture at 5±5 °C and stirred for 15 minutes at 20±5 °C. The organic layer was separated and concentrated under reduced pressure to give desired product (375 g, crude, assuming 100% yield) as a yellow semi-solid.

[0296] 1H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J = 9.3 Hz, 2H), 7.92 – 7.79 (m, 4H), 7.16 (d, J = 9.3 Hz, 2H), 4.31 – 4.20 (m, 2H), 3.82 – 3.70 (m, 4H), 3.67 – 3.38 (m, 30H).

[0297] 13C NMR (101 MHz, DMSO-d6) δ 168.22, 164.32, 141.27, 134.89, 132.00, 126.29, 123.49, 115.50, 70.43, 70.25, 70.21, 70.17, 70.10, 69.94, 69.08, 68.71, 67.40, 37.57.

[0298] HRMS (m / z): [M+H]+calculated for C32H45N2O13665.2916, found 665.3439.

[0299] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-aminium chloride

[0300] 2-(26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl) isoindoline-1,3-dione (375 g, 144 mmol, crude, 1 eq.) was dissolved into ethanol (620 mL, 5 V). Hydrazine hydrate (35.1 g, 433 mmol, 3 eq.80% aq.) was added at 20±5 °C, and the result mixture was warmed to 45 °C. The reaction mixture was stirred for 14 hours at 45 °C and was then cooled to 25±5 °C.2-Methyltetrahydrofuran (10 V) was added and the mixture was stirred for 30 minutes at 25±5 °C. The solid was filtered out and washed with 2-Attorney Docket No.56009-737.601 methyltetrahydrofuran (5.00 V). The filtrate was concentrated to remove EtOH. The residue was slurried with 2-methyltetrahydrofuran (10 V) and 1 M HCl (10 V) for 15 minutes at 25±5 °C. The solid was filtered out. The aqueous phase was washed with EA (10 V x 7) to give 675 g aqueous phase. NaCl, 225 g was added to the aqueous phase, and the result mixture was stirred to give a clear solution. The solution was extracted with DCM (10 V). The DCM solution was washed with 25 wt% NaCl aqueous solution (10 V). The organic phase was concentrated to 1~2 V to give the desired product (110 g) as a yellow DCM solution. The DCM solution was used for the next step without further purification.

[0301] 1H NMR (300 MHz, DMSO-d6) δ 8.20 (dd, J = 10.0, 2.9 Hz, 5H), 7.18 (d, J = 9.3 Hz, 2H), 4.35 – 4.19 (m, 2H), 3.81 – 3.77 (m, 2H), 3.66 – 3.48 (m, 30H), 2.95 (q, J = 5.6 Hz, 2H).

[0302] 13C NMR (101 MHz, DMSO-d6) δ 164.33, 141.27, 126.32, 115.55, 70.42, 70.26, 70.23, 70.21, 70.10, 70.08, 69.08, 68.73, 67.04, 66.82, 38.88.

[0303] HRMS (m / z): [M+H]+calculated for C24H43N2O11535.2867, found 535.2931.

[0304] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-aminium chloride calcium chloride complex (PEG-8-NHC)

[0305] 26-(4-Nitrophenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-aminium chloride salt (110 g, 150 mmol, 1 eq., DCM solution, containing 80 g free base) was added to DCM (1 L). CaCl2(41.5 g, 374 mmol, 2.5 eq.) was added and the resulting mixture was stirred for 18 h at 20±5 °C. Toluene (1 L) was added dropwise over 1 h, and the resulting mixture was stirred for 2 h at 20±5 °C. The mixture was filtered and the filter cake was washed with DCM: toluene=1:1 (10 V) under nitrogen. The filter cake was dried at 40±5 °C under vacuum for 18 hours to give PEG-8-NHC (133 g) as a white solid. (Yield: 76% for 3 steps, Purity: 99.5%, Ca2+: 10.4 %, Cl-: 22.8 %, the structure was confirmed by MicroED as shown in FIG.1.

[0306] 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 3H), 8.21 (d, J = 9.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 4.33 – 4.21 (m, 2H), 3.84 – 3.75 (m, 2H), 3.68 (t, J = 5.6 Hz, 2H), 3.62 – 3.51 (m, 28H), 2.90 (t, J = 5.6 Hz, 2H).

[0307] 13C NMR (101 MHz, DMSO-d6) δ 164.43, 141.33, 126.44, 115.74, 70.50, 70.31, 70.18, 70.15, 69.18, 68.89, 67.04, 38.82.

[0308] HRMS (m / z): [M+H]+calculated for C24H43N2O11535.2867, found 535.2926.

[0309] Example 10. Synthesis of 2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-ol

[0310] Scheme 9.Attorney Docket No.56009-737.601

[0311] Hexaethylene glycol monomethyl ether 45.0 g, 152 mmol, 1.0 eq.) was dissolved into THF (405 mL, 9 V).1,3,6,9,12-Pentaoxa-2lambda6-thiacyclotetradecane-2,2-dione (46.7 g, 182 mmol, 1.2 eq.) was added into the mixture at 20±5 °C. t-BuONa (21.9 g, 228 mmol, 1.5 eq.) was added into the mixture in batches at 20±5 °C. The resulting reaction mixture was stirred for 1 h at 20±5 °C. H2O (225 mL, 5 V) was added into the mixture to quench the reaction. The quenched mixture was concentrated to remove THF. The residue was washed with 2-MeTHF (225 mL, 5 V) 3 times.2-MeTHF (225 mL, 5 V) and H2SO4(45 mL, 1 V) were added into the aqueous phase at 20±5 °C, the result mixture was warmed to 80±5 °C and stirred for 4 h at 80±5 °C. The reaction mixture was cooled to 20±5 °C and separated. The aqueous phase was extracted with DCM (450 mL, 10 V) 3 times. The combined organic phase was washed with NaHCO3saturated solution (450 mL, 10 V), NaCl saturated solution (450 mL, 10 V) sequentially. The organic phase was concentrated under reduced pressure (P<-0.085MPa) to afford 62 g product (85% yield) as a yellow oil.

[0312] 1H NMR (400 MHz, Chloroform-d): δ 3.75 – 3.57 (m, 38H), 3.55 (dd, J = 6.0, 3.3 Hz, 2H), 3.38 (s, 3H), 3.18 (d, J = 2.3 Hz, 3H, OH+H2O).

[0313] 13C NMR (101 MHz, Chloroform-d): δ 72.67, 71.83, 70.49, 70.45, 70.41, 70.39, 70.13, 61.49, 61.47, 58.92.

[0314] HRMS (m / z): [M + H]+Calcd for C21H45O11473.2956, Found 473.3014.

[0315] Example 11. Synthesis of Polyethylene Glycol (PEG) Derivatives

[0316] The Following PEG derivative compounds are made by Examples 1-8.CPD-0150

[0318] 1H NMR (300 MHz, Chloroform-d): δ 8.19 (dd, J = 8.7, 1.5 Hz, 2H), 7.05 – 6.93 (m, 2H), 4.31 – 4.19 (m, 2H), 3.90 (dd, J = 5.6, 3.9 Hz, 2H), 3.82 – 3.44 (m, 43H), 2.98 (s, 2H).

[0319] 13C NMR (75 MHz, Chloroform-d): δ 163.86, 141.48, 125.80, 114.59, 72.56, 70.84, 70.55, 70.49, 70.24, 69.31, 68.19, 61.58.

[0320] HRMS (m / z): [M + H]+Calcd for C30H54NO15668.3493, Found 668.3487.Attorney Docket No.56009-737.601

[0321] 38-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontan-1-ol (CPD-CPD-0120

[0322] 1H NMR (300 MHz, Chloroform-d): δ 8.27 – 8.13 (m, 2H), 7.07 – 6.91 (m, 2H), 4.23 (dd, J = 5.7, 3.7 Hz, 2H), 3.90 (dd, J = 5.6, 3.8 Hz, 2H), 3.81 – 3.36 (m, 47H), 2.95 (s, 2H).

[0323] 13C NMR (75 MHz, Chloroform-d): δ 163.87, 141.52, 125.82, 114.60, 72.56, 70.87, 70.58, 70.52, 70.25, 69.34, 68.20, 61.62.

[0324] HRMS (m / z): [M + H]+Calcd for C32H58NO16= 712.3756, Found 712.3732.

[0325] 47-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45-pentadecaoxaheptatetracontan-CPD-0160

[0326] 1H NMR (300 MHz, Chloroform-d): δ 8.25 – 8.11 (m, 2H), 7.06 – 6.90 (m, 2H), 4.29 – 4.17 (m, 2H), 3.97 – 3.85 (m, 2H), 3.81 – 3.58 (m, 59H), 2.86 (s, 2H).

[0327] 13C NMR (75 MHz, Chloroform-d): δ 163.86, 141.54, 125.84, 114.60, 72.59, 70.88, 70.59, 70.52, 70.25, 69.35, 68.20, 61.63.

[0328] HRMS (m / z): [M + H]+Calcd for C38H70NO19= 844.4542, Found 844.4532.

[0329] 50-(4-nitrophenoxy)-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48-hexadecaoxapentacontan-1-CPD-0130

[0330] 1H NMR (300 MHz, Chloroform-d): δ 8.28 – 8.13 (m, 2H), 7.08 – 6.91 (m, 2H), 4.32 – 4.19 (m, 2H), 3.94 – 3.86 (m, 2H), 3.77 – 3.57 (m, 63H), 2.82 (s, 2H).

[0331] 13C NMR (75 MHz, Chloroform-d): δ 163.87, 141.54, 125.84, 114.60, 72.54, 70.89, 70.60, 70.53, 70.30, 69.35, 68.21, 61.66.

[0332] HRMS (m / z): [M + H]+Calcd for C40H74NO20= 888.4804, Found 888.4788.

[0333] Development of the synthetic route presents many advantages. Namely, the total number of synthetic steps is reduced to 4 steps from 10 steps; and overall yield is increased.Attorney Docket No.56009-737.601

[0334] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

Attorney Docket No.56009-737.601 CLAIMS WHAT IS CLAIMED IS:

1. A process for the synthesis of a compound of Formula (I), or a salt, solvate, or hydrate thereof, or metal ion complex thereof:Formula (I), comprising mixing intermediatewith intermediatewherein: R is an optionally substituted phenyl or optionally substituted C1-C6alkyl; n is an integer from 1-21; m is an integer from 0-6; and x is 4-30. 2 A process for the synthesis of a compound of Formula (II), or a salt, solvate, or hydrate thereof, or metal ion complex thereof:comprising mixing intermediatewherein: n is an integer from 1-21 m is an integer from 0-6; and x is n + (m + 3). 3 The process of claim 2, wherein the process comprises (i) a first step and (ii) a second step. 4 The process of claim 3, wherein the first step comprises mixing intermediate C and intermediate D in a first solvent in the presence of a base. 5 The process of claim 4, wherein the base comprises a metal salt.Attorney Docket No.56009-737.601 6. The process of claim 4 or 5, wherein the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), lithium tert-butoxide (LiOtBu), sodium hydride (NaH), potassium hydride (KH) methyl lithium (MeLi), butyl lithium (BuLi), hexyllithium (HxLi), lithium diisopropyl amine (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), and lithium tetramethylpiperidine (LiTMP), or combinations thereof. 7 The process of any one of claims 4-6, wherein the base is selected from sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and lithium tert-butoxide (LiOtBu). 8 The process of any one of claims 4-7, wherein the base is solid sodium tert-butoxide (NaOtBu). 9 The process of any one of claims 4-8, wherein 0.8 to 3.0 equivalents of the base is present in the first solvent. 10 The process of any one of claims 4-9, wherein 1.0 to 1.5 equivalents of the base is present in the first solvent. 11 The process of any one of claims 4-10, wherein 1.1 equivalents of the base is present in the first solvent. 12 The process of any one of claims 4-11, wherein the base is added to the first solvent portion-wise. 13 The process of any one of claims 4-12, wherein the first solvent is adjusted to a temperature of about -10 °C to about 40 °C prior to addition of the base. 14 The process of any one of claims 4-13, wherein the first solvent is adjusted to a temperature of about -10 °C to about 15 °C prior to addition of the base. 15 The process of any one of claims 4-14, the first solvent is adjusted to a temperature of about -5 °C to about 5 °C prior to addition of the base. 16 The process of any one of claims 4-15, wherein the first solvent is selected from toluene, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether, and diphenyl ether, or combinations thereof. 17 The process of any one of claims 4-16, wherein the first solvent is selected from tetrahydrofuran and methyl tetrahydrofuran, or a combination thereof. 18 The process of claim 3, wherein the second step comprises mixing the product from step (i) in a second solvent in the presence of an acid. 19 The process of claim 18, wherein the acid is added to the second solvent. 20 The process of claim 18 or 19, wherein the acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, and formic acid. 21 The process of any one of claims 18-20, wherein the acid is sulfuric acid. 22 The process of any one of claims 19-21, wherein the second solvent is adjusted to a temperature of about 50 °C to about 90 °C after addition of the acid.Attorney Docket No.56009-737.601 23. The process of any one of claims 19-22, wherein the second solvent is adjusted to a temperature of about 70 °C to about 80 °C after addition of the acid.

24. The process of any one of claims 18-23, wherein the second solvent is selected from toluene , ethyl acetate, dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether, and diphenyl ether, or combinations thereof.

25. The process of any one of claims 18-24, wherein the second solvent is selected from tetrahydrofuran and methyl tetrahydrofuran, or combinations thereof.

26. The process of any one of claims 18-25, wherein the second solvent is methyl tetrahydrofuran.

27. The process of any one of claims 18-26, wherein the second solvent further comprises water as a cosolvent.

28. The process of any one of claims 1-27, wherein steps (i) and (ii) are repeated 1-20 times.

29. The process of any one of claims 1-28, wherein the process is performed in a single reactor.

30. The process of any one of claims 1-29, wherein the process further comprises purification by metal ion complexation.

31. The process of claim 30, wherein the metal ion is calcium, magnesium, or manganese.

32. The process of claim 31, wherein the metal ion is calcium.

33. The process of any one of claims 1-32, wherein the yield of the compound of Formula (I) or (II) is at least 20%.

34. The process of any one of claims 1-32, wherein the yield of the compound of Formula (I) or (II) is at least 40%.

35. The process of any one of claims 1-32, wherein the yield of the compound of Formula (I) or (II) is at least 60%.

36. The process of any one of claims 1-32, wherein the purity of the compound of Formula (I) or (II) is at least 95.0%.

37. The process of any one of claims 1-32, wherein the purity of the compound of Formula (I) or (II) is at least 99.0%.

38. The process of any one of claims 1-32, wherein the purity of the compound of Formula (I) or (II) is at least 99.9%.

39. The process of any one of claims 1-38, wherein the level of Formula (I) or (II) impurities is less than about 2% as determined by HPLC.

40. The process of any one of claims 1-38, wherein the level of Formula (I) or (II) impurities is less than about 1% as determined by HPLC.

41. The process of any one of claims 1-38, wherein the level of Formula (I) or (II) impurities is less than about 0.2% as determined by HPLC.

42. The process of any one of claims 39-41, wherein the impurity is selected from:Attorney Docket No.56009-737.60143. The process of any one of claims 1-42, wherein intermediate C, or a salt, solvate, or hydrate thereof, or metal ion complex thereof: synthesized by an oxidation reaction from intermediate B:

44. The process of claim 43, wherein the oxidation reaction comprises mixing intermediate B in a solvent in the presence of an oxidant.

45. The process of claim 44, wherein the oxidant is selected from oxone, H2O2, mCPBA, TiO2 / TBHP, osmium tetroxide, sodium periodate, ruthenium tetroxide, RuCl3hydrate, NaOCl, and NaIO4, or combinations thereof.

46. The process of claim 44 or 45, wherein the oxidant is RuCl3hydrate, or RuCl3hydrate and NaIO4.

47. The process of any one of claims 43-46, wherein the oxidation solvent is selected from dichloromethane, dichloroethane, acetonitrile, water, tetrahydrofuran, methyl tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone, nitrobenzene, dichlorobenzene, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether, and diphenyl ether, or combinations thereof.

48. The process of any one of claims 43-46, wherein the oxidation solvent is selected from dichloromethane, acetonitrile, and water, or combinations thereof.

49. The process of any one of claims 43-48, wherein intermediate C is purified by precipitation with heptane and filtration.

50. The process of any one of claims 43-49, wherein the purity of intermediate C is at least 90.0%.

51. The process of any one of claims 43-49, wherein the purity of intermediate C is at least 95.0%.

52. The process of any one of claims 43-49, wherein the purity of intermediate C is at least 98.0%.Attorney Docket No.56009-737.601 53. The process of any one of claims 43-52, wherein the level of intermediate C impurities is less than about 4% as determined by HPLC.

54. The process of any one of claims 43-52, wherein the level of intermediate C impurities is less than about 2% as determined by HPLC.

55. The process of any one of claims 43-52, wherein the level of intermediate C impurities is less than about 1% as determined by HPLC.

56. The process of any one of claims 53-55, wherein the intermediate C impurity is selected from57. The process of any one of claims 43-56, wherein intermediate B:

58. The process of claim 57, wherein the cyclization reaction comprises mixing intermediate diol A in a third solvent in the presence of a third base and thionyl chloride.

59. The process of claim 58, wherein the third base is selected from triethyl amine, diisopropylethylamine, pyridine, DMAP, DABCO, and DBU.

60. The process of claim 58 or 59, wherein the third base is diisopropylethylamine.

61. The process of any one of claims 57-60, wherein the third solvent is selected from dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, acetonitrile, dichloroethane, dichlorobenzene, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl acetate, dimethylacetamide, NMP, cyclopentyl methyl ether, and diphenyl ether.

62. The process of any one of claims 57-60, wherein the third solvent is dichloromethane.

63. The process of any one of claims 2-62, wherein intermediate D, or a salt, solvate, or hydrate thereof, or metal ion complex thereof: NO2synthesized by a nucleophilic substitution reaction from.Attorney Docket No.56009-737.60164. The process of claim 63, wherein the nucleophilic substitution reaction comprises mixingin a fourth solvent in the presence of a fourth base.

65. The process of claim 64, wherein the fourth solvent is selected from dimethyl formamide, dimethyl amide, NMP, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran, dioxane, DME, and dimethyl sulfoxide.

66. The process of claim 64 or 65, wherein the fourth solvent is acetonitrile.

67. The process of any one of claims 64-66, wherein the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, DBU, DIPEA, triethyl amine, or pyridine.

68. The process of any one of claims 64-66, wherein the fourth base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate.

69. The process of any one of claims 64-68, wherein the process further comprises purifying intermediate D by metal ion complexation.

70. The process of claim 69, wherein the metal ion is calcium, magnesium, or manganese.

71. The process of claim 69, wherein the metal ion is manganese.

72. The process of any one of claims 69-71, wherein the purification further comprises a solvent selected from ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran, toluene, ACE, dichloromethane, ethanol, isopropyl alcohol, MTBE, and DME.

73. The process of any one of claims 69-71, wherein the purification further comprises a solvent selected from ethanol and tetrahydrofuran.

74. The process of any one of claims 63-73, wherein the purity of intermediate D is above 98.0%.

75. The process of any one of claims 63-73, wherein the purity of intermediate D is above 99.0%.

76. The process of any one of claims 63-73, wherein the purity of intermediate D is above 99.9%.

77. The process of any one of claims 63-76, wherein the level of intermediate D impurities is less than about 1% as determined by HPLC.

78. The process of any one of claims 63-76, wherein the level of intermediate D impurities is less than about 0.1% as determined by HPLC.

79. The process of any one of claims 63-78, wherein the intermediate D impurity is selected fromAttorney Docket No.56009-737.601combinations thereof.

80. The process of any one of claims 1-79, wherein n is 5 and m is 1.

81. The process of any one of claims 57-80, wherein y is 4.

82. The process of any one of claims 1-81, wherein the process further comprises the synthesis of a compound of Formula (IV), or a salt thereof:Formula (IV), wherein Z is a counterion; comprising the steps of reacting a compound of Formulaphthalimide, triphenyl phosphine (PPh3), and diisopropyl azodicarboxylate (DIAD) to obtain a compound of Formulatreating the compound of Formula (V) with hydrazine to obtain a compound of Formula (IV).

83. The process of any one of claims 1-82, wherein the process further comprises the synthesis of a compound of Formula (VI), or a salt thereof or a metal ion complex thereof:Formula (VI) wherein M is one or more metal ions; comprising the steps of reacting the compound of Formula (IV) with a metal salt.

84. A composition comprising:Attorney Docket No.56009-737.601, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein x is 4-30, and wherein the composition comprises less than about 10% of an impurity as determined by HPLC.

85. The composition of claim 84, wherein x is 5, 9, 12, 13, 17, 21, or 25.

86. A composition comprising:salt, solvate, or hydrate thereof, or metal ion thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC.

87. A composition comprising:or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC. 88 A composition comprising:or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC. 89 A composition comprising:or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC. 90 A composition comprising:or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein the composition comprises less than about 10% of an impurity as determined by HPLC. 91 The composition of any one of claims 84-90, wherein the composition comprises less than about 5% of the impurity. 92 The composition of any one of claims 84-90, wherein the composition comprises less than about 1% of the impurity. 93 The composition of any one of claims 84-90, wherein the impurity is selected from:Attorney Docket No.56009-737.601combinations thereof.

94. A compound having the structure of Formula (II), or a salt, solvate, or hydrate thereof, or metal ion complex thereof:, wherein x is 4-30, obtained by the process of any one of claims 1-83.

95. The compound of claim 94, or a salt, solvate, or hydrate thereof, or metal ion complex thereof, wherein x is 5, 9, 12, 13, 17, 21, or 25.

96. The compound of claim 94 or 95, wherein the compound is ,. 97 A metal ion complex having the structure:Attorney Docket No.56009-737.601wherein x is 4-30 and M is one or more metal ions.

98. The metal ion complex of claim 97, wherein x is 5, 9, 12, 13, 17, 21, or 25.

99. A metal ion complex having the structure:, wherein M is one or more metal ions. 100 The metal ion complex of claims 97-99, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. 101 The metal ion complex of claim 100, wherein the metal ion is calcium. 102 A metal ion complex having the structure:wherein n is 1-21 and M is one or more metal ions. 103 A metal ion complex having the structure:, wherein M is one or more metal ions.Attorney Docket No.56009-737.601 104. The metal ion complex of claim 102 or 103, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium.

105. The metal ion complex of claim 104, wherein the metal ion is manganese.

106. A metal ion complex having the structure:wherein x is 4-30 and M is one or more metal ions.

107. A metal ion complex having the structure: ,M , wherein M is one or more metal ions. 108 The metal ion complex of claim 106 or 107, wherein the metal ion is selected from iron, magnesium, calcium, barium, cobalt, nickel, copper, zinc, aluminum, manganese, and indium. 109 The metal ion complex of claim 108, wherein the metal ion is calcium. 110 The metal ion complex of any one of claims 97-109, wherein the purity of the metal ion complex is above 98.0%, 99.0%, or 99.9%.

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