Compounds and their pharmaceutical uses

Abstract

Compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein ring X is a 3- to 7-membered monocyclic ring, at least one of R1, R2, R3, and R4 is OR5 or CH2OR5, and the other R1, R2, R3, and R4 are each independently halogen, OH, OR5, CH2OR5, CO2H, OC=OR6, (C=O)R6, R6, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, H, or absent. Also provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a compound of formula (I).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 014,448, filed April 23, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Coronaviruses, members of the Coronaviridae and Coronavirinae subfamily, are enveloped viruses containing single-stranded, positive-sense RNA genomes 26–32 kilobases in length. Coronaviruses have been identified in several vertebrate hosts, including birds, bats, pigs, rodents, camels, and humans. Humans can acquire coronavirus infections from other mammalian hosts. Human coronavirus infections are one of the leading causes of harmful upper respiratory tract disease in humans. In addition to encoding structural proteins, most of the coronavirus genome is transcribed and translated into a polyprotein that encodes proteins essential for viral replication and gene expression. Functional polypeptides are released from the polyprotein by extensive proteolytic processing, one of the key steps in the coronavirus life cycle. Without proteolysis, the virus would not package. This is primarily accomplished by the 33.1 kDa main protease (MPro), also known as the 3C-like protease (3CLPro).

[0003] The central nervous system (CNS) includes the brain and spinal cord. The CNS is vulnerable to a variety of disorders that can be caused by a variety of factors, including genetics, trauma, infection, degeneration, structural defects and / or damage, tumors, impaired blood flow, and autoimmune diseases. Symptoms of CNS disorders vary depending on the area of ​​the nervous system involved and the cause of the disorder.

[0004] The development of effective treatments for CNS disorders has lagged behind other therapeutic areas due to the complexity of such disorders and the lack of efficient technologies for delivering therapeutic agents across the blood-brain barrier. Therefore, there is great interest in developing novel therapeutic approaches for CNS disorders. Summary of the Invention

[0005] The present disclosure is based, at least in part, on the development of various compounds having the structures set forth herein that exhibit inhibitory activity against D-amino acid oxidase and / or 3C-like protease (3CLPro). Certain compounds disclosed herein have also demonstrated therapeutic efficacy in animal models of central nervous system (CNS) disease (e.g., the MK801 mouse model). Accordingly, the compounds disclosed herein are expected to be effective in treating CNS disorders (e.g., those associated with DAAO) and / or alleviating viral infections caused by coronaviruses, such as SARS-CoV-2.

[0006] Thus, one aspect of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring X is a 3- to 7-membered monocyclic ring that can be aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; at least one of R1, R2, R3, and R4 is OR5 or CH2OR5, and the other R1, R2, R3, and R4 are each independently halogen, OH, OR5, CH2OR5, CO2H, OC=OR6, (C=O)R6, R6, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, H, or absent; R5 is of the formula: [ka] During the ceremony, m is independently 1, 2, 3, 4, 5, 6, or 7; n is independently 0, 1, 2, or 3; R6 is of the formula: [ka] , ring Y is a 3- to 7-membered monocyclic ring which can be aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; Each of L1 and L2 is independently N, O, S, CH2, C=O, C 2~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, -(W-(CH2) s )- and absent, wherein s is 0, 1, 2, 3, 4, or 5; and W is O, S, or N; R7 is aryl, heteroaryl, aralkyl, C 2~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, and H.

[0007] In some embodiments, the X ring is [ka] wherein R1, R2, R3, and R4 are each OR5, each m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0.

[0008] In some embodiments, the X ring is [ka] wherein R1, R2, R3, and R4 are each OR5 or CH2OR5, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0.

[0009] In some embodiments, the X ring is [ka] wherein R1, R2, and R3 are each OR5 or OC=OR6, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0 or 1.

[0010] In some embodiments, at least one of R1, R2, or R3 is O-C=OR6.

[0011] In some embodiments, the X ring is an aryl, heteroaryl, or cycloalkyl ring; R, R, R, and R are each OH, COH, OR, or (C=O)R; m is 0, 1, 2, 3, 4, 5, 6, or 7; and n is 0 or 1.

[0012] In some embodiments, the X ring is [ka] wherein R1, R2, R3, and R4 are each OH, CO2H, OR5, or (C=O)R6; m is 0, 1, 2, 3, 4, 5, 6, or 7; and n is 0 or 1.

[0013] In some embodiments, the X ring is [ka] wherein R1, R2, R3, and R4 are each OH, CO2H, or OR5; m is 0, 1, 2, 3, 4, 5, 6, or 7; and n is 1.

[0014] In some embodiments, the X ring is [ka] wherein R1, R2, R3, and R4 are each OH, OR5, or (C=O)R6, and at least one of R1, R2, or R3 and R4 is (C=O)R6, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0.

[0015] In some embodiments, the X ring is [ka] wherein R1 is OR5, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0 or 1.

[0016] In some embodiments, the X ring is [ka] wherein R1 is OR5, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0.

[0017] In some embodiments, the X ring is [ka] wherein R1 is OR5, m is 0, 1, 2, 3, 4, 5, 6, or 7, and n is 0.

[0018] In some embodiments, ring Y is [ka] is.

[0019] In some embodiments, R7 is [ka] , or non-existence.

[0020] In some embodiments, the compound is of formula (II): [ka] During the ceremony, R9~R 14 are each independently H, OH, NH2, halogen, C 1~3 Alkyl, or C 1~3 is an alkoxy, R8 is H, OH, NH2, halo, C 1~3 Alkyl, C 1~3 alkoxy, aryl, heteroaryl, or O(CO)R6; R 15 is H, alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or alkylheteroaryl; and o is 1, 2, 3, 4, or 5.

[0021] In some embodiments, R 14 Each of is OH.

[0022] In some embodiments, R6 is [ka] [ka] is.

[0023] In some embodiments, R 15 teeth, [ka] is.

[0024] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0025] In other aspects, the disclosure provides compositions comprising any of the compounds disclosed herein and a carrier.

[0026] In some embodiments, the composition is a pharmaceutical composition, a dietary supplement composition, a health food, or a medical food.

[0027] The invention also features a method of treating a coronavirus infection, comprising administering to a subject in need thereof an effective amount of a compound or composition disclosed herein.

[0028] In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus.

[0029] In some embodiments, the compound or composition is administered orally, by injection, by external use, or by inhalation.

[0030] In some embodiments, the composition is disposed in a medical device selected from the group consisting of an inhaler, a nebulizer, a nasal spray, and a vaporizing aerosol device for administration to a subject.

[0031] In some embodiments, the subject is a human subject.

[0032] In some embodiments, the subject is administered the composition continuously or at a frequency ranging from every 5 minutes to once every 3 months.

[0033] In some embodiments, any of the methods disclosed herein further comprises administering to the human subject one or more additional antiviral agents, hi some embodiments, the one or more additional antiviral agents comprise a viral entry inhibitor, a viral uncoating inhibitor, a viral reverse transcriptase inhibitor, a viral protein synthesis inhibitor, a viral protease inhibitor, a viral polymerase inhibitor, a viral integrase inhibitor, an interferon, or a combination thereof.

[0034] In some embodiments, the viral entry inhibitor is selected from the group consisting of maraviroc, enfuvirtide, ibalizumab, fostemsavir, plerixafor, epigallocatechin gallate, vicriviroc, aplaviroc, maraviroc, tromantadine, nitazoxanide, umifenovir, and podofilox.

[0035] In some embodiments, the viral uncoating inhibitor is selected from the group consisting of amantadine, rimantadine, and pleconaril.

[0036] In some embodiments, the viral reverse transcriptase inhibitor is selected from the group consisting of zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, travada, nevirapine, raltegravir, and tenofovir disoproxil.

[0037] In some embodiments, the viral protease inhibitor is selected from the group consisting of fosamprenavir, ritonavir, atazanavir, nelfinavir, indinavir, saquinavir, famciclovir, fomivirsen, lopinavir, ribavirin, darunavir, oseltamivir, and tipranavir.

[0038] In some embodiments, the viral polymerase inhibitor is selected from the group consisting of amatoxin, rifamycin, cytarabine, fidaxomicin, tagetitoxin, foscarnet sodium, idoxuridine, penciclovir, sofosbuvir, trifluridine, valacyclovir, valganciclovir, vidarabine, and remdesivir.

[0039] In some embodiments, the viral integrase inhibitor is selected from the group consisting of raltegarvir, elvitegravir, dolutegravir, bictegravir, and cabotegravir.

[0040] In some embodiments, the interferon is selected from the group consisting of type I interferon, type II interferon, type III interferon, and pegylated interferon alfa-2a.

[0041] In yet another aspect, the disclosure provides methods for inhibiting D-amino acid oxidase (DAAO) in a subject, comprising administering to a subject in need thereof an effective amount of any of the compounds or compositions disclosed herein. In some embodiments, the subject is a human having, suspected of having, or at risk for a central nervous system (CNS) disorder, metabolic disorder, or pain.

[0042] Exemplary CNS disorders include, but are not limited to, schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign amnesia, closed head injury, autism spectrum disorder, Asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disability, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal thoughts and / or behavior, bipolar disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, and stroke.

[0043] Exemplary metabolic disorders include, but are not limited to, obesity, hyperlipidemia, hypercholesterolemia, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetes.

[0044] Exemplary pain disorders include, but are not limited to, psychogenic pain, acute pain, chronic pain, chronic pain syndromes, neuropathic pain, nociceptive pain, and hyperalgesia. Psychogenic pain can be headache, muscle pain, back pain and stomach pain; neuropathic pain is selected from the group consisting of sciatica, carpal tunnel syndrome, diabetic neuropathy, post-herpetic neuralgia and central pain syndrome; nociceptive pain is selected from the group consisting of radicular pain, somatic pain and visceral pain.

[0045] In some embodiments, the methods disclosed herein may further include administering to the subject one or more additional pharmaceutical agents (e.g., those disclosed herein) for treating and / or reducing the risk of a CNS disorder.

[0046] Additionally, the present disclosure provides methods for preparing the compounds disclosed herein.

[0047] In some embodiments, the preparation methods disclosed herein include: (a) providing compounds of formula (Ia) and (Ib), [ka] In the formula, R 16 is a group selected from an alkyl group, an alkylsilyl group, or an arylsilyl group; (b) reacting a compound of formula (Ia) with a compound of formula (Ib) to form intermediate I; (c)R 16 deprotecting the group to form intermediate II; (d) deprotecting the cyclic acetal group and purifying the reaction mixture to obtain a compound disclosed herein.

[0048] In other embodiments, the preparation methods disclosed herein include: (a) providing compounds of formula (Ic) and (Id), [ka] wherein p=1, 2, 3, or 4, and each L3 is independently NH, O, S, —((CH2) s -W)- or absent, and R 17 is a group selected from a benzyl group, an allyl group, an ethoxylmethyl group, a methoxylmethyl group, an ethoxylethyl group, an alkylsilyl group, or an arylsilyl group; (b) reacting a compound of formula (Ic) with a compound of formula (Id) to conjugate formula (Id) with one or more of L3 of formula (Ic) to form intermediate III; (c)R 17 deprotecting the group to form intermediate IV; (d) deprotecting the cyclic acetal group and purifying the reaction mixture to obtain a compound disclosed herein.

[0049] Any of the preparation methods disclosed herein may further comprise, after step (c), the following step: (e) reacting intermediate II with Formula (Ic); and coupling intermediate II with one or more L3 of Formula (Ic) to produce intermediate V.

[0050] In some embodiments, the method further comprises the following steps after step (c): (e) reacting intermediate IV with Formula (Ia) to produce intermediate VI.

[0051] The present disclosure further provides a method for preparing compound (Ia), comprising: (a) providing a compound of formula (Ie); [ka] (b) reacting the compound of formula (Ie) with a strong organic base at −78° C. to 0° C. to produce intermediate VII; (c) reacting the first intermediate VII with an alkyl-protected oxalic acid to form intermediate VIII; (d) reacting the second intermediate VIII with a cycloling reagent to form intermediate IX; (e) deprotecting the alkyl group of the protected oxalic acid to obtain Formula (Ia).

[0052] In some embodiments, the strong organic base in step (b) is an alkali alkoxide, an alkyl lithium, an alkyl amide lithium, or an alkyl silyl amide lithium.

[0053] In some embodiments, the cycloring reagent in step (d) is hydrazine, hydrazine hydrate, hydroxylamine, or any acceptable salt thereof.

[0054] In some embodiments, L1, L2, and L3 are independently a moiety selected from the group consisting of N, O, S, CH2, C2H4, C3H6, OCH2, OC2H4, OC3H6, NCH3, NC2H5, and C=O. [Brief explanation of the drawings]

[0055] [Figure 1] FIG. 1 shows the effect of compound 66 on locomotion in MK-801-treated mice. [Figure 2] FIG. 1 shows the effect of Compound 66 on prepulse inhibition in MK-801-treated mice. [Figure 3] FIG. 1 shows the effect of Compound 74 on locomotion in MK-801-treated mice. [Figure 4] FIG. 1 shows the effect of Compound 74 on prepulse inhibition in MK-801-treated mice. [Figure 5] FIG. 1 shows the effect of Compound 121 on locomotion in MK-801-treated mice. [Figure 6] FIG. 1 shows the effect of Compound 121 on prepulse inhibition in MK-801-treated mice. [Figure 7] FIG. 1 shows the effect of compound 138 on locomotion in MK-801-treated mice. [Figure 8] FIG. 1 shows the effect of compound 138 on prepulse inhibition in MK-801-treated mice. DETAILED DESCRIPTION OF THE INVENTION

[0056] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as set forth therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in "Organic Chemistry," by Thomas Sorrell, "University Science Books," Sausalito, 1999; Smith and March, "March's Advanced Organic Chemistry," 5th Edition, Vol. 1, No. 1, pp. 111-115, 2002; and in "Organic Chemistry," by Smith and March, "March's Advanced Organic Chemistry," Vol. 1, pp. 111-115, 2002. th , John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary recitation of substituents described herein.

[0057] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0058] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 ” is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C4~5 , and C 5~6 is intended to encompass.

[0059] The term "aliphatic" includes both saturated and unsaturated straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As understood by those skilled in the art, "aliphatic" herein is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight-chain, branched, and cyclic alkyl groups. A similar rule applies to other generic terms, such as "alkenyl," "alkynyl," and the like. Furthermore, terms such as "alkyl," "alkenyl," and "alkynyl" encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to refer to those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 6 carbon atoms.

[0060] In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-4 carbon atoms. Thus, exemplary aliphatic groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH-cyclohexyl moieties, and the like, which may further bear one or more substituents. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0061] The term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms or a radical of a saturated carbocyclyl ring ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., a halogen such as F or -OH) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6 In certain embodiments, the alkyl group is a substituted C 1~10 Alkyl (e.g., substituted C 1~6 Alkyl or substituted C 1~3 alkyl, for example, —CF or —CHOH).

[0062] "Alkenyl" refers to a straight-chain or branched hydrocarbon group or a saturated carbocyclyl ring radical having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2~20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 In alkenyl groups, a C=C double bond where no stereochemistry is specified (e.g., -CH=CHCH3 or) can be an (E)- or a (Z)-double bond.

[0063] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group or saturated carbocyclyl ring having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2~20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0064] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the aforementioned C 3~6 Exemplary C groups include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptathenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the aforementioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or comprises a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocycle, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocycle; in such cases, the number of carbons refers to the number of carbons in the carbocyclyl system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0065] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3ー6 Examples of cycloalkyl groups include the aforementioned C 5~6 Includes cyclopropyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0066] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl or the heterocycle, or in which a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocycle; in such cases, the number of ring members continues to refer to the number of ring members in the heterocycle system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0067] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0068] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5- to 10-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0069] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi electrons shared in a ring arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl" includes, for example, anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0070] The divalent bridging groups alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are further referred to using the suffix ene, for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

[0071] "Aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, an aralkyl is an optionally substituted benzyl. In certain embodiments, an aralkyl is benzyl. In certain embodiments, an aralkyl is an optionally substituted phenethyl. In certain embodiments, an aralkyl is phenethyl. In some embodiments, aralkyl is a subset of heteroaryl and aryl, optionally linked by an alkyl group.

[0072] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared by the ring arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members of the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0073] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0074] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0075] An atom, moiety, or group described herein may be unsubstituted or substituted, unless expressly stated otherwise, where valence allows. The term "optionally substituted" refers to substituted or unsubstituted.

[0076] Unless otherwise specified, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present in the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates all such combinations in order to arrive at stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituents are sulfur atom substituents.

[0077] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(Rbb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa, -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14and 5-14 membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd is substituted with an X group - is a counterion, or Or two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc)2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with an X group - is the counterion, R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(Rff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(OR ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(ORee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents can join to form =O or =S, and X - is the counterion, R ee Each instance of 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with an R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contain 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, Rgg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2,-OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can join to form =O or =S, and X - is the counter ion.

[0078] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain two or more formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , -B4O7 2- , SO4 2- , S2O3 2-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0079] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0080] "Acyl" is -C(=O)R aa , -CHO, -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2, -C(=O)SR aa , or -C(=S)SR aa R refers to a moiety selected from the group consisting of aa and R bb is as defined herein.

[0081] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc)N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5R dd is substituted with an R aa , R bb , R cc , and R dd is as defined above.

[0082] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(Rcc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd and R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in "Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 30th ed., 1999, pp. 111-114, 1999, which is incorporated herein by reference. rd This includes those described in detail in "The Journal of the American Chemical Society, Vol. 1, No. 1, pp. 111-115, 1999."

[0083] For example, an amide group (e.g., —C(═O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0084] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethyl Silylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bu meoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrilebenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p′-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0085] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0086] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacylate 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, N-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl ... amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N′,N′-Dimethylaminomethylene)amine, N,N′-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). Exemplary oxygen atom substituents include, but are not limited to, -R, aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2 includes X - , R aa , R bb , and R cc is as defined herein.

[0087] In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are described in "Protecting Groups in Organic Synthesis," T.W. Greene and P.G.M. Wuts, 3, pp. 111-114, 1997, incorporated herein by reference. rdThis includes the detailed information in the "Publication of the American Civilizations of 1999, John Wiley & Sons, 1999" edition. Exemplary oxygen protecting groups include methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methyl- 1-ethoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy Diethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-Dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- Dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, thiazolyl Trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, Acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-Trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4- Methyl pentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate The alkyl esters include, but are not limited to, nitrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0088] The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio.

[0089] Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in "J. Pharmaceutical Sciences, 1977, 66, 1-19," which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts of 2-phenylpropionate, ... +(C 1~4 Alkyl)4 - Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0090] The term "solvate" refers to a form of a compound that is combined with a solvent, typically by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0091] It should also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0092] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way molecules rotate the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0093] The term "prodrug" refers to a compound having a cleavable group that becomes a compound described herein by solvolysis or under physiological conditions and is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, acid anhydride, or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds described herein can be used in combination with C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C 12Substituted aryl and C7-C 12 Aryl alkyl esters may be preferred.

[0094] The terms "inhibit," "inhibit," "inhibits," or "inhibitor" refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a particular biological process in a cell relative to a vehicle.

[0095] When a compound, pharmaceutical composition, method, use, or kit is said to "selectively," "specifically," or "competitively" bind to a first protein, the compound binds to the first protein with a higher binding affinity (e.g., about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more) than it binds to a second protein (or a protein that is different from the first protein). When a compound is said to "selectively," "specifically," or "competitively" modulate (e.g., increase or inhibit) the activity of a protein, the compound modulates the activity of the protein to a greater extent (e.g., about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold) than the activity of at least one protein that is different from the first protein.

[0096] The term "abnormal activity" refers to activity that deviates from normal activity. The term "increased activity" refers to activity that is higher than normal activity.

[0097] The terms "composition" and "formulation" are used interchangeably.

[0098] A "subject," "individual," or "patient" to whom administration is contemplated refers to a human (i.e., a male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly)) or a non-human animal. A "subject" can be a human, but also includes other mammals, particularly mammals useful as laboratory models of human disease, such as mice, rats, rabbits, dogs, and the like. A "patient" refers to a human subject in need of treatment for a disease. In certain embodiments, the subject is a human with or at risk for a central nervous system (CNS) disorder, obesity, diabetes, or hyperlipidemia.

[0099] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0100] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen) to delay or prevent the onset of disease. Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0101] The term "continuously" refers to uninterrupted administration for the period of time medically or therapeutically necessary, including, but not limited to, for example, infusion with or without a pump, respiratory therapy, inhalation therapy.

[0102] Alleviating the target disease / disorder includes delaying the onset or progression of the disease or reducing the severity of the disease. Alleviating the disease does not necessarily require a curative result. As used herein, "delaying" the onset of the target disease or disorder means postponing, hindering, slowing, delaying, stabilizing, and / or postponing the progression of the disease. This delay can be for various lengths of time, depending on the history of the disease and / or the individual being treated. A method of "delaying" or alleviating the onset of a disease, or a method of delaying the onset of a disease, is a method of reducing the likelihood of developing one or more symptoms of the disease within a given time frame and / or reducing the severity of symptoms within a specific time frame, compared to not using the method. Such comparisons are usually based on clinical studies using a sufficient number of subjects to produce statistically significant results.

[0103] "Onset" or "progression" of a disease refers to the initial symptoms and / or subsequent progression of the disease. Disease onset can be detected and assessed using standard clinical techniques well known in the art. However, onset also refers to progression, which may be undetectable. For purposes of this disclosure, onset or progression refers to the biological course of symptoms. "Onset" includes onset, recurrence, and onset. As used herein, "onset" or "onset" of a target disease or disorder includes initial onset and / or recurrence.

[0104] To achieve any of the intended therapeutic effects described herein, an effective amount of the compositions herein can be administered to a subject in need of treatment via a suitable route.

[0105] The terms "condition," "disease," and "disorder" are used interchangeably.

[0106] An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response, i.e., treat a condition. As will be understood by one of ordinary skill in the art, the effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single administration. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple administrations.

[0107] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent.

[0108] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0109] The term "neuropsychiatric disorder," which includes any neurological or psychiatric disorder or CNS (central nervous system) disorder, refers to a disorder with any behavioral or psychiatric symptom or syndrome caused by neurodegenerative or organic brain damage. Key features of neuropsychiatric disorders include the development of various psychiatric symptoms, cognitive impairment, neurological symptoms, or possible manifestations of early brain development. For example, neuropsychiatric disorders include, but are not limited to, schizophrenia, psychotic disorders, major depressive disorder, suicidal ideation and / or behavior, Alzheimer's disease, dementia, frontotemporal dementia, mild cognitive impairment, benign forgetting, closed head injury, autism spectrum disorder, Asperger's disorder, Fragile X syndrome, attention deficit hyperactivity disorder, attention deficit hyperactivity disorder combined with tic disorder, obsessive-compulsive disorder, tic disorder, Tourette's syndrome, childhood learning disabilities, premenstrual syndrome, depression, bipolar disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic pain, eating disorders, addiction disorders, personality disorders, Parkinson's disorder, Huntington's disorder, amyotrophic lateral sclerosis, bedwetting, stroke, Duchenne muscular dystrophy, blepharospasm, and non-epileptic seizures.

[0110] The term "neurological disorder" refers to any disorder of the nervous system, including disorders involving the central nervous system (brain, brainstem, spinal cord, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (portions of which are in both the central and peripheral nervous systems). Neurodegenerative disorders refer to a class of neurological disorders characterized by the loss of nerve cells, including, but not limited to, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), multiple system atrophy, and Huntington's disease. Examples of neurological disorders include, but are not limited to, headaches, stupor and coma, dementia, seizures, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmopathy, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junction. Further examples of neurological disorders include acquired epileptic aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, subarachnoid cisterns, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformations, Asperger's syndrome, ataxia-telangiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, chronic pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain injury, brain tumor (including glioblastoma multiforme) , spinal cord tumors, Brown-Séquard syndrome, Canavan disease, carpal tunnel syndrome (CTS), burning pain, central pain syndrome, central pontine myelinolysis, head injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic pain, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, chronic regional pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), cytomegalovirus infection, dancing eyes dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease,Demorcier's syndrome, Dejerine-Klumpke palsy, dementia, dermatomyositis, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, encephalocele, cerebrospinal angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry's disease, Fahr's syndrome, syncope, familial spastic paraplegia, febrile seizures, Fisher's syndrome, Friedreich's ataxia, frontotemporal dementia Dementia and other "tauopathies", Gaucher disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion body disease, globoid cell leukodystrophy, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, head trauma, headache, hemifacial spasms, hereditary spastic paraplegia, hereditary polyneuropathic ataxia, herpes zoster otorhinolaryngology, shingles, Hirayama syndrome, HIV-associated dementia and neuropathy (see also Neurological symptoms of AIDS). Holoprosencephaly, Huntington's disease and other polyglutamine repeat disorders, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborn syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Kuur-Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, learning disabilities, Leigh encephalopathy, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy syndrome Dementia with bodies, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis), Lumbar disc disease, Lyme disease - neurological sequelae, Machado-Joseph disease, Megacephaly, Megalencephaly, Melkerson-Rosenthal syndrome, Meniere's disease, Meningitis, Menkes disease, Metachromatic leukodystrophy, Microcephaly, Migraine, Miller-Fisher syndrome, Minor stroke, Mitochondrial myopathy, Moebius syndrome, Unilateral upper limb muscular atrophy, Motor neuron disease, Moyamoya disease, Mucopolysaccharidoses, Multi-infarct dementia, Multifocal motor neuropathy, Multiple sclerosis and other demyelinating disorders, Multiple system atrophy with orthostatic hypotension, Muscular dystrophy, Myasthenia gravis, Myeloablative diffuse sclerosisInfantile myoclonic encephalopathy, myoclonus, myopathy, congenital myotonia, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological manifestations of AIDS, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, subclinical spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus, optic neuritis, orthostatic hypotension, abuse syndrome, paresthesias, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders, seizures Seizures, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, painful neuropathy and neuropathic pain, persistent vegetative state, pervasive developmental disorder, photophobia, phytanic acid storage disease, Pick's disease, nerve compression, pituitary tumor, polymyositis, porencephaly, post-polio syndrome, post-herpetic neuralgia (PHN), post-infectious encephalomyelitis, orthostatic hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome Syndrome (Type I and Type II), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Refsum's disease, repetitive strain injury, repetitive strain injury, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, St. Vitus's chorea, Sandhoff's disease, Schilder's disease, schizophrenia, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal tumors, spinal muscular atrophy, stiff-person syndrome, stroke, Sturge-Weber syndrome , subacute sclerosing panencephalitis, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, Sydenham chorea, syncope, syringomyelia, tardive dyskinesia, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's 10 syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremors, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease (VHL), Wallenberg's syndrome, Werdnig-Hoffmann disease,These include West syndrome, whiplash syndrome, Williams syndrome, Wilson's disease, and Zellweger 15 syndrome.

[0111] The term "pain" encompasses psychogenic pain, acute pain, chronic pain, chronic pain syndromes, neuropathic pain, nociceptive pain, hyperalgesia and allodynia.

[0112] Psychogenic pain is physical pain that is caused, increased, or prolonged by mental, emotional, or behavioral factors. Headache, back pain, or stomach pain are some of the most common types of psychogenic pain. Psychogenic pain is selected from the group consisting of headache, muscle pain, back pain, and stomach pain.

[0113] Neuropathic pain is pain caused by injury or disease affecting the somatosensory nervous system. Neuropathic pain can be caused by disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Therefore, neuropathic pain can be classified as peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain. Neuropathic pain is selected from the group consisting of sciatica, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, and central pain syndrome.

[0114] Nociceptive pain is the most common type of pain experienced by people. It occurs when nociceptive nerve fibers are triggered by inflammation, chemicals, or physical events. Nociceptive pain is selected from the group consisting of radicular pain, somatic pain, and visceral pain.

[0115] The term "mental disorder" refers to mental disorders and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition and Fifth Edition (DSM-IV, DSM-V) published by the American Psychiatric Association, Washington, DC (1994, 2015). Mental disorders include anxiety disorders (e.g., acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and obsessive-compulsive disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder I and II, cyclothymic disorder, dysthymic disorder, and major depressive disorder), suicidal thoughts and / or behaviors, personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizophrenic personality disorder, and and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizophrenic disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence or abuse, amphetamine dependence or abuse, cannabis dependence or abuse, cocaine dependence or abuse, hallucinogen dependence or abuse, inhalant dependence or abuse, nicotine dependence or abuse, opioid dependence or abuse, phencyclidine dependence or abuse, and sedative dependence or abuse), adjustment disorder, autism, Asperger's disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory deterioration), and Tourette's disorder.

[0116] The term "metabolic disorder" refers to any disorder involving an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. Metabolic disorders are associated with either a deficiency or excess in metabolic pathways, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors that affect metabolism include, but are not limited to, endocrine (hormonal) control systems (e.g., the insulin pathway, enteroendocrine hormones including GLP-1, PYY, etc.), neural control systems (e.g., GLP-1 in the brain), and the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes), hyperglycemia, hyperlipidemia, hypercholesterolemia, hyperinsulinemia, insulin resistance, and obesity.

[0117] The term "health food" or "health supplement" refers to any type of liquid and solid / semi-solid material used to nourish humans and animals to improve basic behavioral functions, hyperactivity, anxiety, depression, suicidal thoughts and / or behaviors, sensorimotor gating, pain threshold, memory and / or cognitive function, body weight, or to facilitate the treatment of any of the target diseases described herein. The term "nutraceutical composition" refers to a composition that contains ingredients from food sources and provides additional health benefits in addition to the basic nutritional value found in foods. The term "medical food" refers to a food formulated to be consumed or administered enterally, including foods typically used under medical supervision for the specific dietary management of target diseases such as those described herein. A "medical food" composition refers to a composition (as opposed to a naturally occurring food used in its natural state) that is specifically formulated and processed for patients in need of treatment (e.g., a human patient suffering from a disease or who requires the use of a product as a primary active agent to alleviate a disease or condition through a specific dietary management).

[0118] (I) Active ingredient In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring X is a 3- to 7-membered monocyclic ring that is aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; at least one of R1, R2, R3, and R4 is OR5 or CH2OR5, and the other R1, R2, R3, and R4 are each independently halogen, OH, OR5, CH2OR5, CO2H, OC=OR6, (C=O)R6, R6, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, H, or absent; R5 is of the formula: [ka] , in the formula, m is independently 1, 2, 3, 4, 5, 6, or 7; n is independently 0, 1, 2, or 3; R6 is of the formula: [ka] wherein ring Y is a 3- to 7-membered monocyclic ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl; Each of L1 and L2 is independently N, O, S, CH2, C=O, C 2~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, -(W-(CH2) s )- and absent, s is 0, 1, 2, 3, 4, or 5, and W is O, S, or N; R7 is selected from the group consisting of aryl, heteroaryl, aralkyl, C2-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and H.

[0119] In some embodiments, the X ring is [ka] R1、 Each of R2, R3, and R4 is OR5. Alternatively, or in addition, each m is 0, 1, 2, 3, 4, 5, 6, or 7. In some examples, n is 0.

[0120] In some embodiments, the X ring is [ka] Each of R1, R2, R3, and R4 can independently be OR5. 2、 Each of R3 and R4 can independently be CH2OR5. In some embodiments, at least one of R1, R2, R3, and R4 can be OR5, and R1, R2, R 3、 and at least one of R4 can be CH2OR5. Alternatively, or in addition, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some examples, n is 0.

[0121] In some embodiments, the X ring is [ka] R1, R2, R3, and R4 can each be OH, CO2H, OR5, or (C=O)R6. In some examples, two of R1, R2, R3, and R4 are the same moiety. In other examples, R1, R2, R3, and R4 are different moieties. In some examples, at least one of R1, R2, R3, and R4 is OR5. In some examples, at least one of R1, R2, R3, and R4 is (C=O)R6. In some examples, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some examples, n is 0 or 1.

[0122] In some embodiments, the present disclosure provides a compound of formula (II): [ka] , in the formula, R9~R 14 are each independently H, OH, NH2, halogen, C 1~3 Alkyl, or C 1~3 is an alkoxy, R8 is H, OH, NH2, hydrogen, C 1~3 Alkyl, C 1~3 alkoxy, aryl, heteroaryl, or O(CO)R6; R 15 is H, alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, or alkylheteroaryl; o is 1, 2, 3, 4, or 5.

[0123] In some examples, the compound of formula (II) is a compound having R, R, and R 10 In some examples, R, R, and R may have at least one of -OH. 10 In some embodiments, at least two of R, R, and R are —OH. 10 In other embodiments, all of R, R, and R are —OH. 10 Two of them are -OH and the other is O(CO)R6.

[0124] In some instances, R 13 and R 14 In some embodiments, at least one of R 13 and R 14 Alternatively, or in addition, both of R 15 can be H. In other embodiments, R 15 can be aryl or heteroaryl. In still other embodiments, R 15 In yet other embodiments, R can be alkylaryl or alkylheteroaryl. 15 can be cycloalkyl.

[0125] Exemplary compounds of formula (I) are provided in Table 1 below. [Table 1-1] Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17

[0126] (II) Pharmaceutical compositions and kits containing the same One aspect of the present disclosure relates to compositions, e.g., pharmaceutical compositions, health foods such as dietary supplement compositions, and medical foods, comprising one or more compounds of Formula (I) and a carrier, e.g., a pharmaceutically acceptable carrier and / or an edible carrier. Such carriers can be naturally occurring or non-naturally occurring (synthetic) and can provide various benefits to the compounds of Formula (I) in the composition, such as improving the in vitro and / or in vivo stability of the compounds of Formula (I), enhancing the bioavailability of the compounds of Formula (I), increasing associated biological activity, and / or reducing side effects. Suitable carriers include, but are not limited to, diluents, fillers, salts, buffers, stabilizers, solubilizers, buffers, preservatives, or combinations thereof.

[0127] (A) Pharmaceutical Composition The compositions described herein, for example, pharmaceutical compositions comprising a pharmaceutically acceptable carrier, can be used to treat any of the target diseases described herein. Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Exemplary pharmaceutically acceptable carriers are described, inter alia, in U.S. Pat. No. 5,211,657. Such preparations may routinely contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts are conveniently used to prepare pharmaceutically acceptable salts and are not excluded from the scope of the present invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from suitable inorganic bases (e.g., sodium hydroxide, barium hydroxide, iron(II) hydroxide, iron(III) hydroxide, magnesium hydroxide, calcium hydroxide, aluminum hydroxide, ammonium hydroxide, potassium hydroxide, cesium hydroxide, or lithium hydroxide) or suitable organic bases (e.g., pyridine, methylamine, imidazole, benzimidazole, histidine, phosphazene bases, or hydroxides of organic cations such as quaternary ammonium hydroxides and phosphonium hydroxides). Pharmaceutically acceptable salts can also be prepared as alkali metal or alkaline earth salts, such as lithium, sodium, potassium, or calcium salts.

[0128] The pharmaceutical compositions described herein may be in the form of a lyophilized formulation or an aqueous solution and may contain pharmaceutically acceptable carriers, excipients, or stabilizers. Remington: The Science and Practice of Pharmacy 20 th Ed. (2000) Lippincott Williams and Wilkins, Ed. K.E. Hoover. Such carriers, excipients, or stabilizers may enhance one or more properties (e.g., biological activity, stability, bioavailability), as well as other pharmacokinetic and / or biological activities, of the active ingredients in the compositions described herein.

[0129] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, benzoate, sorbate, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; gelatin; The surfactant may include proteins such as immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, serine, alanine, or lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextran, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose, or sorbitol, salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or non-ionic surfactants such as TWEEN® (polysorbate), PLURONICS® (non-ionic surfactants), or polyethylene glycol (PEG).

[0130] In some embodiments, the pharmaceutical compositions described herein comprise a pulmonary-compatible excipient. Suitable such excipients include monochlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, chloropentafluoroethane, monochlorodifluoroethane, difluoroethane, tetrafluoroethane, heptafluoropropane, octafluorocyclobutane, purified water, ethanol, propylene glycol, glycerin, PEG (e.g., PEG 400, PEG 600, PEG 800, and PEG 1000), sorbitan trioleate, soy lecithin, lecithin, oleic acid, polysorbate 80, magnesium stearate, and sodium lauryl sulfate, methylparaben, propylparaben, and the like. Ingredients include, but are not limited to, ethanol, chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, thymol, ascorbic acid, sodium bisulfite, sodium metabisulfite, EDTA, sodium hydroxide, tromethamine, ammonia, HCl, H2SO4, HNO3, citric acid, CaCl2, CaCO3, sodium citrate, sodium chloride, disodium EDTA, saccharin, menthol, ascorbic acid, glycine, lysine, gelatin, povidone K25, silicon dioxide, titanium dioxide, zinc oxide, lactose, lactose monohydrate, lactose anhydrous, mannitol, and dextrose.

[0131] In other embodiments, the pharmaceutical compositions described herein can be formulated in a sustained-release form. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers, which are in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include, but are not limited to, polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0132] Pharmaceutical compositions used for in vivo administration must be sterile. This can be easily achieved, for example, by filtration through sterile filtration membranes. Therapeutic compositions are generally placed into a container with a sterile access port, for example, an infusion bag or vial with a stopper that can be pierced by a hypodermic injection needle, or a manually accessible sealed container.

[0133] The pharmaceutical compositions described herein may be in unit dosage form, such as a solid, solution or suspension, or suppository, for administration by inhalation or insufflation, by intrathecal, intrapulmonary or intracerebral routes, or orally, parenterally, or rectally.

[0134] To prepare solid compositions, the primary active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents (e.g., water), to form a solid preformulation composition containing a homogeneous mixture of a compound disclosed herein, or a non-toxic pharmaceutically acceptable salt thereof.

[0135] When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as powder mass, tablets, pills, capsules, etc. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 5 grams of any of the compounds disclosed herein (e.g., those listed in Table 1).

[0136] Suitable surfactants include, inter alia, non-ionic agents such as polyoxyethylene sorbitans (e.g., Tween® 20, 40, 60, 80, or 85) and other sorbitans (e.g., Span™ 20, 40, 60, 80, or 85). Compositions containing a surfactant conveniently contain 0.05 to 5% surfactant, and may contain 0.1 to 2.5%. It will be appreciated that other ingredients, such as mannitol or other pharmaceutically acceptable vehicles, may be added as required.

[0137] Suitable suspensions can be prepared using commercially available fat suspensions such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™, and Lipiphysan™. The active ingredient can be dissolved in a premixed suspension composition or in an emulsion formed upon mixing with oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water. It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the tonicity of the suspension. Suitable suspensions will typically contain up to 20% oil, e.g., 5-20%. Fat suspensions contain fat droplets of 0.1-1.0 μm, particularly 0.1-0.5 μm, and have a pH in the range of 5.5-8.0.

[0138] In some embodiments, the pharmaceutical compositions described herein comprise a liposome composition. Liposomes are artificially prepared spherical vesicle compositions consisting of lamellar phase lipid bilayers. Liposomes or lipid vesicles are typically composed of phosphatidylcholine-enriched phospholipids, but may also contain mixed lipid chains with surfactant properties, such as egg phosphatidylethanolamine. Preferably, the liposome composition is composed of one or more vesicle-forming lipids selected from dialiphatic chain lipids such as phospholipids, diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin or glycosphingolipids, steroid lipids, hydrophilic polymer-derivatized lipids, or mixtures thereof. Preferably, the vesicle-forming lipids include one or more phospholipids, one or more steroidal lipids, and one or more hydrophilic polymer-derivatized lipids. The one or more phospholipids that can be used in the liposome composition include phospholipids that form bilayer vesicle structures. Phospholipids that can be used include phosphatidylcholine (PC); phosphatidylethanolamine (PE); phospholipids such as phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylonositol (PI), sphingomyelin, phosphatidic acid (PA), lecithin; dipalmitoylphosphatidylcholine (DPPC), egg phosphatidylcholine (EPC), hydrogenated egg phosphatidylcholine (HEPC), partially hydrogenated egg phosphatidylcholine (PHEPC), disallylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), and phospholipids such as phospholipids of ... Phosphatidylcholine lipid derivatives include, but are not limited to, phosphatidylcholine (DPPC), soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), diarachidoylphosphatidylcholine, dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), diarachidoylphosphatidylethanolamine (DAPE), and dipalmitoylphosphatidylglycerol (DPPG).

[0139] Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In some embodiments, compositions comprise a particle size between 10 nm and 100 mm. Compositions, preferably in sterile, pharmaceutically acceptable solvents, can be nebulized by the use of gases. Nebulized solutions can be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, endotracheal tube, and / or intermittent positive pressure breathing machine (respirator). Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0140] In some embodiments, any of the pharmaceutical compositions herein may further comprise a second therapeutic agent based on the intended therapeutic use of the composition.

[0141] (B) Health food In some embodiments, the compositions described herein can be health foods, which can be any type of liquid and solid / semi-solid material used to nourish humans and animals, or to treat viral infections, or specifically coronavirus infections. Health foods can be foods (e.g., tea-based drinks, juices, soft drinks, coffee, milk, jellies, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream and yogurt)), food / nutritional supplements, or nutritional formulations.

[0142] The health foods described herein may contain one or more edible carriers, which provide one or more benefits to the compositions in the products described herein. Examples of edible carriers include starch, cyclodextrin, maltodextrin, methylcellulose, carbon methoxycellulose, xanthan gum, and aqueous solutions thereof. Other examples include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, materials known to those skilled in the art, and combinations thereof. In some embodiments, the health foods described herein may further contain neuroprotective foods such as fish oil, flaxseed oil, and / or benzoates.

[0143] In some embodiments, a dietary supplement is a nutraceutical composition, which refers to a composition that contains ingredients from food sources to provide additional health benefits in addition to the basic nutritional value found in foods. The nutraceutical compositions described herein include the compositions described herein and additional ingredients and supplements that promote health and / or enhance stability and bioactivity.

[0144] The action of the nutraceutical composition may be rapid and / or short-term, or may help achieve long-term health goals as described herein, such as improving health in human subjects with or at risk for viral infections. The nutraceutical composition may be included in edible materials, e.g., as a dietary supplement or pharmaceutical formulation. As a dietary supplement, additional nutrients such as vitamins, minerals, or amino acids may be included. The composition may also be a beverage or food, e.g., tea, soft drinks, juice, milk, coffee, cookies, cereal, chocolate, and snack bars. If desired, the composition may be sweetened by adding sweeteners such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolysate, high fructose corn syrup, cane sugar, beet sugar, pectin, or sucralose.

[0145] The dietary supplement compositions disclosed herein can be in the form of a solution. For example, dietary supplement formulations can be provided in a medium such as a buffer, solvent, diluent, inert carrier, oil, or cream. In some embodiments, the formulation is in an aqueous solution, optionally containing a non-aqueous cosolvent such as alcohol. The dietary supplement composition can also be in the form of a powder, paste, jelly, capsule, or tablet. Lactose and cornstarch are commonly used as capsule diluents or tablet carriers. Lubricants such as magnesium stearate are usually added to form tablets.

[0146] Health food can be formulated for suitable administration route, for example, oral administration.For oral administration, the composition can be prepared by conventional means, for example, in the form of tablet or capsule, using acceptable excipients such as binder (for example, pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), filler (for example, lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricant (for example, magnesium stearate, talc, or silica), disintegrant (for example, potato starch, or sodium starch glycolate), or wetting agent (for example, sodium lauryl sulfate).Tablet can be coated by methods well known in the art.Bar and other chewable preparations are also included.

[0147] In some embodiments, the health food may be in liquid form, and one or more edible carriers may be a solvent or dispersion medium, including, but not limited to, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), lipids (e.g., triglycerides, vegetable oils, liposomes), or combinations thereof. The appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size by dispersion in a carrier such as a liquid polyol or lipid, by using surfactants such as hydroxypropylcellulose, or a combination thereof. In many cases, it is recommended to include an isotonic agent, such as sugar, sodium chloride, or a combination thereof.

[0148] Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or they can be presented as dry products that are to be constituted with water or other suitable vehicles before use.In one embodiment, liquid preparations can be formulated for administration with fruit juice.Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl p-hydroxybenzoates, benzoates, or sorbates).

[0149] The health foods described herein may further include one or more second therapeutic agents, including those described herein.

[0150] (C) Medical Food The present disclosure also provides medical food compositions for use during viral infection or in improving the underlying condition at risk for viral infection. Medical foods are foods formulated to be consumed or administered enterally. Such foods are typically used under the supervision of a physician for the specific dietary management of a target disease, such as those described herein. In some cases, such medical food compositions are specially formulated and processed (as opposed to naturally occurring foods used in their natural state) for patients in need of treatment (e.g., human patients suffering from an illness or who require the use of a product as a primary active agent to alleviate a disease or condition through a specific dietary management). In some examples, the medical food compositions described herein are not simply one of those recommended by a physician as part of an overall diet to manage symptoms or reduce the risk of a disease or condition.

[0151] Any of the medical food compositions described herein, comprising one or more compounds of formula (I) or their salts and at least one carrier (e.g., as described herein), can be in the form of a liquid solution, powder, bar, wafer, suspension in a suitable liquid, or suitable emulsion, as detailed below. The at least one carrier, which can be either naturally occurring or synthetic (non-naturally occurring), will impart one or more benefits to the composition, such as stability, bioavailability, and / or bioactivity. Any of the carriers described herein can be used to prepare a medical food composition.

[0152] In some embodiments, the medical food composition may further comprise one or more additional ingredients selected from the group including, but not limited to, natural flavors, artificial flavors, major trace and ultratrace minerals, minerals, vitamins, oats, nuts, spices, milk, eggs, salt, wheat flour, lecithin, xanthan gum, and / or sweeteners. The medical food composition may be placed in a suitable container, which may further comprise at least an additional therapeutic agent, such as those described herein.

[0153] (D) Kit The present disclosure also provides kits for use in improving the underlying medical condition. Such kits can include one or more containers containing a composition described herein and, optionally, one or more of the second therapeutic agents described herein.

[0154] In some embodiments, the kit can include instructions for use according to any of the methods described herein. The included instructions can include, for example, instructions for administering the composition of Formula (I) and, optionally, instructions for administering a second therapeutic agent to ameliorate the medical condition of a viral infection or at risk of a viral infection. The kit can further include instructions for selecting individuals suitable for treatment based on identifying whether the individual has or is at risk of a disease. In yet other embodiments, the instructions include instructions for administering one or more agents of the present disclosure to an individual at risk of a viral infection.

[0155] The instructions for using the composition of formula (I) to achieve the intended therapeutic effect generally include information regarding the dosage, administration schedule, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., a multi-dose package), or sub-unit dose. The instructions provided in the kit of the present invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), although machine-readable instructions (e.g., instructions transmitted via a magnetic or optical storage disk, or a QR code) are also acceptable.

[0156] The label or package insert may indicate that the composition is used for its intended therapeutic utility. Instructions for practicing any of the methods described herein may be provided.

[0157] The kit of the present invention is contained in suitable packaging. Suitable packaging includes, but is not limited to, chambers, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), etc. Packages for use in combination with specific devices, such as inhalers, nebulizers, ventilators, nasal administration devices (e.g., sprayers), or infusion devices such as minipumps, are also contemplated. The kit may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). The container may also have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle).

[0158] Kits may optionally provide additional components such as buffers and instructional information. Typically, kits include a container and a label or package insert on or associated with the container. In some embodiments, the invention provides an article of manufacture comprising the contents of the above-described kit.

[0159] (III) Application of the composition of formula (I) The present disclosure provides pharmaceutical compositions and methods for treating and / or alleviating symptoms of certain disorders, diseases affecting a subject.

[0160] Viruses are small infectious agents that replicate only within the living cells of a host organism. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not within an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles, or virions, consisting of (i) genetic material, i.e., long molecules of DNA or RNA that code for the structure of the proteins on which the virus acts; (ii) a protein coat, or capsid, that surrounds and protects the genetic material; and, in some cases, (iii) a lipid outer envelope.

[0161] Antivirals are a class of drugs designed to treat viral infections. Because the human body can deal with the majority of viruses through its immune system, these drugs target certain specific toxicities and life-threatening diseases that the body cannot fight alone or struggles to counter. Researchers working on "rational drug design" strategies to develop antiviral drugs have attempted to attack viruses at any stage of their life cycle (e.g., before cell entry, entry inhibition, and uncoating inhibition) during the viral synthesis, assembly, and release phases.

[0162] Members of the Coronaviridae family include virus strains with different phylogenetic origins (www.thelancet.com, published online January 29, 2020, https: / / doi.org / 10.1016 / S0140-6736(20)30251-8), which cause varying degrees of mortality and morbidity. Therefore, treatment of coronavirus infections varies depending on the specific strain causing the infection. Currently, there are no approved antiviral drug treatments for any coronavirus. Given the conservation of key residues and their functional importance, 3CLPro is expected to be an important target for the design of ubiquitous anticoronavirus drugs for infectious diseases.

[0163] In some embodiments, the present disclosure provides compositions capable of effectively inhibiting 3C-like protease (3CLPro), and uses thereof in inhibiting 3CLPro, treating patients suffering from a viral infection, reducing viral load in its clinical outcome, and / or reducing morbidity or mortality. The methods include administering to a subject in need thereof an effective amount of a composition comprising: (1) one or more compounds of Formula (I) or pharmaceutically acceptable salts thereof; and (2) a pharmaceutically acceptable carrier; wherein in some embodiments, the effective amount is a prophylactically effective amount (e.g., an amount effective to inhibit viral 3CLPro in a subject in need thereof, or an amount effective to treat a subject suffering from a viral infection, reducing viral load in its clinical outcome, and / or reducing morbidity or mortality).

[0164] In some embodiments, the target viral infection treated by the methods disclosed herein is pneumonia caused by infection with the coronavirus genus, which may include novel coronavirus (2019-nCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV). In some embodiments, the target viral infection treated by the methods disclosed herein is caused by alphacoronavirus strains 229E and NL63, betacoronavirus strains OC43 and HKU1, and coronavirus strains caused by novel transmission from other mammals to humans that share protein homology and proteolytic function of 3CLPro.

[0165] In yet another aspect, the disclosure further provides a method for reducing an individual's risk of developing a pathological coronavirus infection with clinical sequelae, the method generally involving administering a therapeutically effective amount of a composition comprising a 3CLPro) inhibitor and a therapeutically effective amount of a composition herein.

[0166] Any of the compounds described herein (e.g., compounds of Formula (I)) can be used to treat diseases or disorders. In certain embodiments, provided herein are methods for improving basic behavioral function, weight loss, hyperactivity, anxiety, depression, suicidal thoughts and / or behaviors, sensorimotor gating, pain threshold, memory, and / or cognitive function in a subject in need of treatment. Such compounds can also be used to treat diseases or disorders associated with DAAO, such as central nervous system disorders (e.g., those described herein). The compounds can also be used to treat obesity disorders.

[0167] As used herein, the term "treating" refers to the application or administration of a composition comprising one or more active agents to a subject in need of treatment, e.g., a subject with a target disease or disorder, a symptom of a disease / disorder, or a predisposition to a disease / disorder, with the intent to cure, relieve, alleviate, relieve, alter, relieve, improve, ameliorate, or affect the disorder, symptom of a disease, or predisposition to a disease or disorder.

[0168] Alleviating the target disease / disorder includes delaying the onset or progression of the disease or reducing the severity of the disease. Alleviating the disease does not necessarily require a curative result. As used herein, "delaying" the onset of the target disease or disorder means postponing, hindering, slowing, delaying, stabilizing, and / or postponing the progression of the disease. This delay can be for various lengths of time, depending on the history of the disease and / or the individual being treated. A method of "delaying" or alleviating the onset of a disease, or a method of delaying the onset of a disease, is a method of reducing the likelihood of developing one or more symptoms of the disease within a given time frame and / or reducing the severity of symptoms within a specific time frame, compared to not using the method. Such comparisons are usually based on clinical studies using a sufficient number of subjects to produce statistically significant results.

[0169] "Onset" or "progression" of a disease refers to the initial symptoms and / or subsequent progression of the disease. Disease onset can be detected and assessed using standard clinical techniques well known in the art. However, onset also refers to progression, which may be undetectable. For purposes of this disclosure, onset or progression refers to the biological course of symptoms. "Onset" includes onset, recurrence, and onset. As used herein, "onset" or "onset" of a target disease or disorder includes initial onset and / or recurrence.

[0170] To achieve any of the intended therapeutic effects described herein, an effective amount of a compound described herein (e.g., a compound of Formula (I)) can be administered to a subject in need of treatment via an appropriate route.

[0171] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a mammal being evaluated for therapy and / or treated. The subject can be a human, but also includes other mammals, particularly mammals useful as laboratory models of human disease, such as mice, rats, rabbits, dogs, and the like.

[0172] A human subject in need of treatment may be a human patient who has, is at risk for, or is suspected of having a target disease / disorder, such as a CNS disorder, or an obesity-related disease, such as diabetes, hyperglycemia, hypercholesterolemia, or hyperlipidemia. A subject with a target disease or disorder can be identified by routine medical examination, such as clinical tests, organ function tests, and / or behavioral tests. A subject suspected of having any of such target diseases / disorders may exhibit one or more symptoms of the disease / disorder. A subject at risk for a disease / disorder may be a subject with one or more risk factors for the disease / disorder, such as genetic factors. In some cases, the human subject is a child who has, is suspected of having, or is at risk for childhood-related obesity or CNS disorders, such as attention-deficit / hyperactivity disorder (ADHD), autism, Asperger's syndrome, obsessive-compulsive disorder, depression, suicidal thoughts and / or behaviors, psychosis, chronic pain, and learning disabilities.

[0173] The methods and compositions described herein can be used to treat CNS disorders. Exemplary CNS disorders that can be treated by the methods and compositions described herein include schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign amnesia, closed head injury, autism spectrum disorder, Asperger's syndrome, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorders, childhood learning disabilities, premenstrual syndrome, depression, major depressive disorder, anhedonia, and suicidal thoughts and / or behaviors. , bipolar disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain including hyperalgesia and allodynia, diabetic polyneuropathy, and chronic pain syndromes.

[0174] Obesity-related diseases include diseases and disorders that lead to obesity and diseases and disorders that occur more frequently in obese patients.Obesity is a medical condition characterized by the accumulation of excess body fat to a degree that can adversely affect health.Obesity can be determined by body mass index (BMI), which is a measurement obtained by dividing a person's weight by the square of their height.For example, if a BMI is 30 kg / m 2 Exemplary diseases associated with obesity include, but are not limited to, eating disorders, anorexia nervosa, bulimia nervosa, stroke, coronary heart disease, heart attack, congestive heart failure, congenital heart disease, hypertension, diabetes mellitus, hyperlipidemia, hypercholesterolemia, nonalcoholic steatohepatitis, insulin resistance, hyperuricemia, hypothyroidism, osteoarthritis, gallstones, infertility (e.g., hypogonadism and hyperandrogenism), obesity hypoventilation syndrome, obstructive sleep apnea, chronic obstructive pulmonary disease, and asthma.

[0175] In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) four times a day to once every three months, inclusive. In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) four times a day, three times a day, twice a day, once a day, once every day, once every three days, once every week, once every other week, once a month, once every other month, or once every three months. In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) four times a day. In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) once every three months. In some embodiments, a human subject is administered a compound described herein (e.g., a compound of Formula (I)) once every month, once every two months, once every three months, once every four months, once every five months, or once every six months. In some embodiments, a human subject is treated concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents for treating and / or reducing the risk of a CNS disorder or obesity-related disease.

[0176] As used herein, "effective amount" refers to the amount of each active agent (e.g., a compound of Formula (I) described herein) required to confer a therapeutic effect on a subject, alone or in combination with one or more other active agents, such as one or more of the second therapeutic agents described herein. In some embodiments, the therapeutic effect is inhibiting DAAO activity in a subject (e.g., by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more). In some embodiments, the therapeutic effect is improving baseline behavioral function, weight loss, hyperactivity, anxiety, depression, suicidal thoughts and / or behaviors, sensorimotor gating, pain threshold, memory, and / or cognitive function. In some embodiments, the therapeutic effect is alleviating one or more symptoms associated with any of the CNS disorders described herein. Alternatively, or in addition, the therapeutic effect is maintaining or reducing the subject's weight.

[0177] The N-methyl-D-aspartate (NMDA) receptor is a subtype of glutamatergic receptor that plays an important role in cognition, memory, and neurotoxicity. Modulation of NMDA receptors has been suggested to be beneficial for the treatment of central nervous system disorders. D-amino acid oxidase (DAAO) is a peroxisomal enzyme that oxidizes D-amino acids to their corresponding imino acids. DAAO has been reported to be involved in the metabolism of D-amino acids, including D-serine, in the brain and in the regulation of glutamatergic neurotransmission. Therefore, DAAO is a target for treating central nervous system (CNS) disorders related to D-serine and / or glutamatergic neurotransmission. Furthermore, DAAO degrades D-serine to 3-hydroxypyruvate, a potential mediator of type 2 diabetes (Zhang, 2015). This suggests that DAAO inhibitors could be used to treat obesity, diabetes, and hyperlipidemia.

[0178] It will be clear to those skilled in the art how to determine whether the amount of the composition described herein achieves a therapeutic effect. As will be recognized by those skilled in the art, the effective amount will vary depending on individual patient parameters, including the specific condition being treated, the severity of the condition, age, physical condition, size, sex, and weight, the duration of treatment, the nature of concomitant therapy (if any), the specific route of administration, genetic factors, and similar factors within the knowledge and expertise of medical professionals. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. In general, it is preferable to use the maximum dose of each component or combination thereof, i.e., the highest safe dose according to sound medical judgment.

[0179] Empirical considerations such as half-life generally contribute to the determination of dosage. The frequency and / or route of administration can be determined and adjusted over the course of treatment, and is generally, but not necessarily, based on the treatment and / or suppression and / or improvement and / or delay of the target disease / disorder. Alternatively, a continuous sustained-release formulation of the composition described herein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0180] In general, for administration of any composition, an exemplary daily dosage can range from about 0.1 μg / kg to 3 μg / kg to 30 μg / kg to 300 μg / kg to 3 mg / kg, to 30 mg / kg to 100 mg / kg, or to 300 mg / kg to 1 gram / kg or more, depending on the factors mentioned above. For repeated administration over several days or more, depending on the condition, treatment is sustained until a desired suppression of symptoms occurs or until a therapeutic level sufficient to alleviate the target disease or disorder or its symptoms is achieved. An exemplary dosing regimen involves administering one or more initial doses at appropriate intervals over an appropriate period of time. If desired, multiple maintenance doses can be administered to the subject at appropriate intervals over a suitable period of time. However, other dosing regimens may be useful depending on the pharmacokinetic decay pattern the physician desires to achieve. For example, administration from 1 to 24 times daily or weekly is contemplated. In some embodiments, a dosing range of about 3 μg / mg to about 2 mg / kg (e.g., about 3 μg / mg, about 10 μg / mg, about 30 μg / mg, about 100 μg / mg, about 300 μg / mg, about 1 mg / kg, about 3 mg / kg, about 30 mg / kg, and about 300 mg / kg) can be used. In some embodiments, the dosing frequency can be given hourly, every 2 hours, 4 times a day, 3 times a day, twice a day, once a day, once every other day, once weekly, once every other week, once every 4 weeks, once every 2 months, once every 3 months, or only once continuously for as long as medically or therapeutically needed. Dosing regimens can vary over time.

[0181] In some embodiments, a normal weight adult patient can be administered a dose ranging from about 0.3 to 500.00 mg / kg / day (e.g., 0.5 to 400 mg / kg / day, 1 to 300 mg / kg / day, 5 to 300 mg / kg / day, or 10 to 200 mg / kg / day). The particular dosing regimen, i.e., dose, timing, and repetition, will vary depending on the particular individual and their medical history, as well as the characteristics of the individual drug (such as the drug's half-life and other considerations known in the art).

[0182] The composition (e.g., a pharmaceutical composition, a health food composition, a dietary supplement composition, or a medical food composition) can be administered to a subject using conventional methods known to those skilled in the medical field, depending on the type of viral infection or the site of the disease being treated. The composition can also be administered via other conventional routes, for example, orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0183] The composition can be administered via a pulmonary delivery system, i.e., the active pharmaceutical ingredient is administered to the lungs. The pulmonary delivery system can be an inhaler system. In some embodiments, the inhaler system is a pressurized metered dose inhaler, a dry powder inhaler, or a nebulizer. In some embodiments, the inhaler system includes a spacer.

[0184] In some embodiments, the pressurized metered dose inhaler comprises a propellant, a co-solvent, and / or a surfactant. In some embodiments, the propellant is selected from the group consisting of fluorinated hydrocarbons such as trichloromonofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, chloropentafluoroethane, monochlorodifluoroethane, difluoroethane, tetrafluoroethane, heptafluoropropane, and octafluorocyclobutane. In some embodiments, the co-solvent is selected from the group consisting of purified water, ethanol, propylene glycol, glycerin, PEG 400, PEG 600, PEG 800, and PEG 1000. In some embodiments, the surfactant or lubricant is selected from the group consisting of sorbitan trioleate, soybean lecithin, lecithin, oleic acid, polysorbate 80, magnesium stearate, and sodium lauryl sulfate. In some embodiments, the preservative or antioxidant is selected from the group consisting of methylparaben, propyparaben, chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, thymol, ascorbic acid, sodium bisulfite, sodium metabisulfite, sodium bisulfite, EDTA. In some embodiments, the pH or isotonicity adjuster is selected from the group consisting of sodium oxide, tromethamine, ammonia, HCl, H2SO4, HNO3, citric acid, CaCl2, CaCO3.

[0185] In some embodiments, the dry powder inhaler comprises a dispersant, hi some embodiments, the dispersant or carrier particles are selected from the group consisting of lactose, lactose monohydrate, lactose anhydrous, mannitol, and dextrose, having particle sizes of about 1-100 μm.

[0186] In some embodiments, the nebulizer may include a co-solvent, surfactant, lubricant, preservative, and / or antioxidant. In some embodiments, the co-solvent may be purified water, ethanol, propylene glycol, glycerin, PEG (e.g., PEG400, PEG600, PEG800, PEG1000), or a combination thereof.

[0187] In some embodiments, the surfactant or lubricant can be sorbitan trioleate, soy lecithin, lecithin, oleic acid, magnesium stearate, sodium lauryl sulfate, or a combination thereof.

[0188] In some embodiments, the preservative or antioxidant may be sodium benzoate, potassium benzoate, calcium benzoate, methylparaben, propyparaben, chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, thymol, ascorbic acid, sodium bisulfite, sodium metabisulfite, sodium bisulfite, EDTA, or a combination thereof.

[0189] In some embodiments, the nebulizer further comprises a pH or tonicity adjuster, which may be sodium oxide, tromethamine, ammonia, HCl, H2SO4, HNO3, citric acid, CaCl2, CaCO3, or a combination thereof.

[0190] Injectable compositions may contain a variety of carriers, such as vegetable oils, dimethylactamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol). For intravenous injection, water-soluble antibodies may be administered by infusion, whereby the pharmaceutical formulation, the compositions described herein, and a physiologically acceptable excipient are infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, or other suitable excipients. For intramuscular preparations, for example, a sterile formulation of a suitable soluble salt form of the compositions herein may be dissolved in a pharmaceutical excipient such as water for injection, 0.9% saline, or 5% glucose solution, and administered.

[0191] In one embodiment, the composition is administered via a site-specific or targeted local delivery technique. Examples of site-specific or targeted local delivery techniques include various implantable depot sources of the composition or local delivery catheters, such as injection catheters, indwelling catheters, or needle catheters, endotracheal tubes, endobronchial catheters, synthetic grafts, adventitial wraps, shunts and stents, or other implantable devices, site-specific carriers, direct injection, or direct application. See, for example, PCT Publication No. 00 / 53211 and U.S. Patent No. 5,981,568. The therapeutic effect of the target disease / disorder can be evaluated by methods well known in the art.

[0192] In some embodiments, the present invention relates to a method of treating a coronavirus infection, comprising administering to a subject in need thereof an effective amount of a compound or composition disclosed herein.

[0193] In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus. In some embodiments, the subject treated by the disclosed methods has COVID-19, a disease caused by SARS-CoV-2 infection.

[0194] In some embodiments, the composition is disposed in a medical device selected from the group consisting of an inhaler, a nebulizer, a nasal spray, and a vaporizing aerosol device for administration to a subject.

[0195] In some embodiments, the subject is a human subject, e.g., a human subject having or suspected of having an infection with a coronavirus. In some examples, the human subject has COVID-19 or is suspected of having COVID-19 (e.g., has one or more symptoms associated with COVID-19).

[0196] In some embodiments, the human subject is treated simultaneously with, prior to, or subsequent to one or more additional antiviral agents, hi some examples, the additional antiviral agents include viral entry inhibitors, viral uncoating inhibitors, viral reverse transcriptase inhibitors, viral protein synthesis inhibitors, viral protease inhibitors, viral polymerase inhibitors, viral integrase inhibitors, interferons, and / or combinations thereof.

[0197] Exemplary viral entry inhibitors include maraviroc, enfuvirtide, ibalizumab, fostemsavir, plerixafo, epigallocatechin gallate, vicriviroc, aplaviroc, maraviroc, tromantadine, nitazoxanide, umifenovir, and podofilox. Exemplary viral uncoating inhibitors include amantadine, rimantadine, and pleconaril. Exemplary viral reverse transcriptase inhibitors include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, truvada, nevirapine, raltegravir, and tenofovir disoproxil. Exemplary viral protease inhibitors include fosamprenavir, ritonavir, atazanavir, nelfinavir, indinavir, saquinavir, famciclovir, fomivirsen, lopinavir, ribavirin, darunavir, oseltamivir, and tipranavir. Exemplary viral polymerase inhibitors include amatoxin, rifamycin, cytarabine, fidaxomicin, tagetitoxin, foscarnet sodium, idoxuridine, penciclovir, sofosbuvir, trifluridine, valacyclovir, valganciclovir, vidarabine, and remdesivir. Exemplary viral integrase inhibitors include raltegarvir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Exemplary interferons include type I interferon, type II interferon, type III interferon, and pegylated interferon alpha-2a.

[0198] In some embodiments, the subject is administered the composition continuously or at a frequency ranging from every 5 minutes to once every 3 months.

[0199] Combination therapy can also include administration of the agents described herein (e.g., compounds of Formula (I) and anti-CNS disorder agents, anti-obesity agents, or antiviral agents) in further combination with other biologically active ingredients (e.g., therapeutically effective drugs) and non-drug therapies (e.g., surgery).

[0200] general technology The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are described in Molecular Cloning: A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press, Oligonucleotide Synthesis (MJ Gait, ed. 1984), Methods in Molecular Biology, Humana Press, Cell Biology: A Laboratory Notebook (JECellis, ed., 1989) Academic Press, Animal Cell Culture (RIFreshney, ed. 1987), Introuction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and DG Newell, eds. 1993-8) J. Wiley and Sons, Methods in Enzymology (Academic Press, Inc.), Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.): Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, eds., 1987), Current Protocols in Molecular Biology (FMAusubel, et al. eds. 1987), PCR: The Polymerase Chain Reaction, (Mullis, et al., eds. 1994), Current Protocols in Immunology (JEColigan et al., eds., (1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (C.A. Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: a practice approach (D. Catty., ed., IRL Press, 1988 - 1989), Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000), Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999), The Antibodies (M. Zanetti and J.D. Capra, eds. Harwood Academic Publishers, 1995), DNA Cloning: A practical Approach, Volumes I and II (D.N. Glover ed. 1985), Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. (1985)>>, Transcription and Translation (B.D. Hames & S.J. Higgins, eds. (1984>>, Animal Cell Culture (R.I.Freshney, ed. (1986>>, Immobilized Cells and Enzymes (lRL Press, (1986>>, and are fully described in the literature such as B. Perbal, A practical Guide To Molecular Cloning (1984), F.M. Ausubel et al. (eds.).

[0201] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. Accordingly, the specific embodiments provided herein are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference for the purpose or subject matter referenced herein.

[0202] (IV) Method of preparation Any of the compounds of formula (I) disclosed herein may be isolated from a suitable natural source and modified. Alternatively, such compounds may be chemically synthesized. The present invention provides a method for preparing a compound of formula (I), comprising: (a) providing compounds of formula (Ia) and (Ib), [ka] , where R 16 is a group selected from an alkyl group, an alkylsilyl group, or an arylsilyl group; (b) reacting a compound of formula (Ia) with a compound of formula (Ib) to form intermediate I; (c)R 16 deprotecting the group to form intermediate II; (d) deprotecting the cyclic acetal group and purifying the reaction mixture to obtain the compound of the invention.

[0203] In some embodiments, provided herein is a method for preparing a compound, comprising: (a) providing compounds of formula (Ic) and (Id), [ka] wherein p=1, 2, 3, or 4, and each L3 is independently NH, O, S, —((CH2) s -W)- or absent, and R 17is a group selected from a benzyl group, an allyl group, an ethoxylmethyl group, a methoxylmethyl group, an ethoxylethyl group, an alkylsilyl group, or an arylsilyl group; (b) reacting a compound of formula (Ic) with a compound of formula (Id) to conjugate formula (Id) with one or more of L3 of formula (Ic) to form intermediate III; (c)R 17 deprotecting the group to form intermediate IV; (d) deprotecting the cyclic acetal group and purifying the reaction mixture to obtain a compound of the invention.

[0204] In some embodiments, the method further comprises the following steps after step (c): (e) reacting intermediate II with Formula (Ic) and further comprising coupling intermediate II with one or more L3 of Formula (Ic) to produce intermediate V.

[0205] In some embodiments, the method further comprises the following steps after step (c): (e) reacting intermediate IV with Formula (Ia) to produce intermediate VI.

[0206] In some embodiments, the present invention provides a method for preparing compound (Ia), comprising: (a) providing a compound of formula (Ie); [ka] (b) reacting the compound of formula (Ie) with a strong organic base at −78° C. to 0° C. to produce a first intermediate VII; (c) reacting the first intermediate VII with an alkyl-protected oxalic acid to form a second intermediate VIII; (d) reacting the second intermediate VIII with a cycloling reagent to form a third intermediate IX; (e) deprotecting the alkyl group of the protected oxalic acid to obtain formula (Ia).

[0207] In some embodiments, the strong organic base in step (b) is an alkali alkoxide, an alkyl lithium, an alkyl amide lithium, or an alkyl silyl amide lithium.

[0208] In some embodiments, the cycloring reagent in step (d) is hydrazine, hydrazine hydrate, hydroxylamine, or any acceptable salt thereof. [Example]

[0209] In order that the described invention may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the methods and compositions provided herein and should not be construed in any way as limiting the scope thereof.

[0210] Example 1. Synthesis of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5) [ka]

[0211] Preparation of methyl 3,4,5-trihydroxybenzoate (1) To a solution of 3,4,5-trihydroxybenzoic acid (10.0 g, 58.8 mmol) in methanol (118.0 mL) was added sulfuric acid (3.1 mL, 58.8 mmol) at room temperature. The resulting mixture was heated to reflux for 6 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give methyl 3,4,5-trihydroxybenzoate (1) as a white solid (9.6 g, 89%). 1 H NMR (MeOD, 400MHz) δ7.03(s,2H),3.81(s,3H).

[0212] Preparation of methyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (2) To a solution of 3,4,5-trihydroxybenzoate (1, 10.0 g, 54.3 mmol) in acetonitrile (543.0 mL) were added potassium carbonate (15.0 g, 108.6 mmol) and α,α-dichlorodiphenylmethane (9.9 mL, 51.6 mmol). The mixture was stirred at 40 °C for 6 h. After the reaction was complete, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography using EtOAc / hexane (1:3) to give methyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (2) as a white solid (10.5 g, 55%). 1 H NMR (CDCl3,400MHz) δ7.57-7.55(m,4H),7.39-7.34(m,7H),7.20(s,1H),3.84(s,3H).

[0213] Preparation of methyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (3) To a solution of methyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (2, 10.0 g, 28.7 mmol) in methyl ethyl ketone (144.0 mL) were added potassium carbonate (7.9 g, 57.4 mmol) and allyl bromide (8.7 mL, 100.5 mmol). The mixture was stirred at 40 °C for 6 h. After the reaction was complete, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was removed in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:4) to give methyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (3) as a white solid (10.4 g, 93%). 1H NMR(CDCl3,400MHz) δ7.59-7.57(m,4H),7.37(d,J=5.2Hz,6H),7.32(s,1H),7.26(s,1H),6.09-6.02(m,1H ),5.40(d,J=17.2Hz,1H),5.28(d,J=10.5Hz,1H),4.70(d,J=5.4Hz,2H),3.85(s,3H).

[0214] Preparation of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (4) To a solution of methyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (3, 10.0 g, 28.7 mmol) in methanol / tetrahydrofuran (1:1, 102.0 mL) was added lithium hydroxide (1.2 g, 51.5 mmol). The resulting mixture was stirred at 40 °C for 6 h. The mixture was concentrated in vacuo. The resulting residue was acidified (pH = 5) by the dropwise addition of 10% hydrochloric acid. The solid was collected and purified by recrystallization from EtOAc / hexane (1:4) to give 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (4) as a white solid (9.0 g, 93%). 1 H NMR(CDCl3,400MHz) δ7.60-7.58(m,4H),7.38-7.37(m,7H),7.32(s,1H),6.11-6.01(m,1H),5.41(d,J=17.2Hz,1H),5.29(d,J=10.8Hz,1H),4.71(d,J=5.2Hz,2H).

[0215] Preparation of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5) To a stirred solution of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (4, 9.0 g, 24.0 mmol) in dichloromethane (120.0 mL) was added oxalyl chloride (6.2 mL, 72.1 mmol) and DMF (0.1 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5, 9.1 g, crude) as a yellow solid. 1 H NMR(CDCl3,400MHz) δ7.59-7.58(m,4H),7.42-7.39(m,8H),6.11-6.01(m,1H),5.44(dd,J=17.2,1.2Hz,1H),5.33(dd,J=10.4,0.9Hz,1H),4.73(d,J=5.4Hz,2H).

[0216] Example 2. Synthesis of 7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (9) [ka]

[0217] Preparation of tert-butyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (6) To a solution of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5, 30.0 g, 76.5 mmol) in tetrahydrofuran (300.0 mL) was added a solution of potassium tert-butoxide (10.3 g, 91.8 mmol) in tetrahydrofuran (100 mL) at 0 °C under N. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the residue was diluted with EtOAc, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was removed in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:8) to give compound 6 as a white solid (32 g, 97%). 1 H NMR(CDCl3,400MHz) δ7.60-7.57(m,4H),7.39-7.35(m,6H),7.29-7.28(d,J=1.2Hz,1H),7.22-7.21(d,J=1.2Hz ,1H),6.11-6.01(m,1H),5.42-5.38(dd,J=17.2,1.5Hz,1H),5.29-5.26(dd,J=10.5,1.3Hz 1H), 4.71-4.69(d,J=5.6Hz,2H),1.55(s,9H).

[0218] Preparation of tert-butyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (7) To a stirred solution of tert-butyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (6, 32.0 g, 74.3 mmol) in anhydrous tetrahydrofuran (766.0 mL) was added aniline (5.2 mL, 37.2 mmol) and tetrakis(triphenylphosphine)palladium (8.6 g, 7.43 mmol). The mixture was stirred at room temperature under N for 16 h. The mixture was filtered through a Celite bed, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:4) to give compound 7 (27 g, 93%) as a white solid. 1H NMR (CDCl3,400MHz) δ7.61-7.58(m,4H),7.40-7.38(m,7H),7.19-7.18(d,J=1.4Hz,1H),6.14(br,1H),1.58(s,9H).

[0219] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (8) A mixture of compound 7 (27 g, 69.2 mmol), 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]-dioxole-5-carboxylic acid (4, 27.2 g, 72.6 mmol), and 4-dimethylaminopyridine (0.84 g, 6.9 mmol) in dichloromethane (692.0 mL) was stirred at 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (14.6 g, 76.1 mmol) was added, and the mixture was stirred at 0 °C for 10 min and then allowed to warm to room temperature. After the reaction was complete, the mixture was extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:9) to give compound 8 (48.2 g, 93%) as a white solid. 1 H NMR(CDCl3,400MHz) δ7.64-7.61(m,4H),7.59-7.56(m,4H),7.54-7.53(d,J=1.5Hz,1H),7.50-7.49(d,J=1.5Hz,1H),7.47-7.45(m,2H),7.43-7.38(m,12H) ),6.16-6.06(m,1H),5.48-5.43(dd,J=17.2,1.4Hz,1H),5.34-5.31(dd,J=10.4,1.2Hz,1H),4.78-4.76(d,J=5.5Hz,2H),1.57(s,9H).

[0220] Preparation of 7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (9) To a stirred solution of compound 8 (28.2 g, 37.8 mmol) in anhydrous dichloromethane (377.6 mL) was added formic acid (377.6 mL) at 0 °C. After 10 min and stirring at room temperature for 4 h, the mixture was extracted three times with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / dichloromethane (3:7) to give compound 9 (16.0 g, 61%) as a white solid. 1 H NMR(CDCl3,400MHz) δ7.61-7.58(m,5H),7.56-7.53(m,4H),7.51-7.49(m,2H),7.46-7.45(d,J=1.5Hz,1H),7.41-7.37(m,12H),6.12-6 .03(m,1H),5.45-5.40(d,J=17.2,1.5Hz,1H),5.32-5.28(d,J=10.8,1.3Hz,1H),4.75-4.73(d,J=1.4Hz,5.5,2H).

[0221] Example 3. Synthesis of 3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid (14) [ka]

[0222] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (10) To a stirred solution of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5, 20.0 g, 26.8 mmol) in anhydrous tetrahydrofuran (267.8 mL) was added aniline (1.9 mL, 13.4 mmol) and tetrakis(triphenylphosphine)palladium (3.1 g, 2.7 mmol). The mixture was stirred at room temperature under N for 16 h. The mixture was filtered through a Celite bed, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:5) to give compound 10 as a white solid (17.5 g, 92%). 1 H NMR(CDCl3,400MHz) δ7.62-7.58(m,4H),7.58-7.54(m,4H),7.52-7.51(d,J=1.4Hz,1H),7.46(s,1H),7.45(s,1H),7.43-7.36(m,13H),5.67(br,1H),1.56(s,9H).

[0223] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (11) A mixture of compound 10 (17.5 g, 24.8 mmol), 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (4, 9.7 g, 26.0 mmol), and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) in dichloromethane (354.0 mL) was stirred at 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (9.7 g, 26.0 mmol) was added, and the mixture was stirred at 0 °C for 10 min and then allowed to warm to room temperature. After the reaction was complete, the mixture was extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:8) to give compound 11 (25.0 g, 95%) as a white solid. 1H NMR(CDCl3,400MHz) δ7.74-7.73(d,J=1.5Hz,1H),7.66-7.65(d,J=1.5Hz,1H),7.62-7.52(m,12H),7.52-7.51(d,J=1.4Hz,1H),7.48-7.47(d,J=1.4Hz,1H),7 .43-7.34(m,20H),6.13-6.03(m,1H),5.46-5.41(dd,J=17.2,1.4Hz,1H),5.32-5.29(dd,J=10.5,1.1Hz,1H),4.76-4.74(d,J=5.4Hz,2H).

[0224] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (12) To a stirred solution of compound 11 (25.0 g, 23.5 mmol) in anhydrous tetrahydrofuran (235.2 mL) was added aniline (1.6 mL, 11.8 mmol) and tetrakis(triphenylphosphine)palladium (2.7 g, 2.4 mmol). The mixture was stirred at room temperature under N for 16 h. The mixture was filtered through a Celite bed, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:4) to give compound 12 as a white solid (22.2 g, 91%). 1 H NMR(CDCl3,400MHz) δ7.75-7.74(d,J=1.6Hz,1H),7.67-7.66(d,J=1.5Hz,1H),7.62-7.55(m,12H) ,7.52-7.51(d,J=1.5Hz,1H),7.45-7.37(m,21H),5.50(br,1H),1.56(s,9H).

[0225] Preparation of 7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (13) A solution of compound 12 (250 mg, 0.24 mmol) in formic acid / chloroform (33% by volume, 7.2 mL) was stirred at 60° C. for 90 minutes. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 13 as an off-white solid (163 mg, 69%). 1 H NMR (CDCl3,400MHz) δ7.72(d,J=1.6Hz,1H),7.64(d,J=1.6Hz,1H),7.61-7.52(m,13H),7.49(dd,J=3.2,1.5Hz,2H),7.43-7.35(m,19H).

[0226] Preparation of 3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid (14) To flame-dried 10 wt% Pd / C solid (115 mg) was added anhydrous tetrahydrofuran (7.2 mL) and compound 13 (70 mg, 0.07 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 14 as an off-white solid (25 mg, 73%). 1 H NMR (MeOD, 400MHz) δ7.58-7.53(m,1H),7.48-7.44(m,1H),7.44-7.39(m,1H),7.31-7.11(m,3H).

[0227] Example 4. 3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (18) [ka]

[0228] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (15) A mixture of compound 12 (20.0 g, 19.6 mmol), compound 9 (13.5 g, 19.6 mmol), and 4-dimethylaminopyridine (0.24 g, 2.0 mmol) in dichloromethane (325.8 mL) was stirred at 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.1 g, 21.5 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes and then allowed to warm to room temperature. After the reaction was complete, the mixture was extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using dichloromethane / hexane (3:2) to give compound 15 (31.4 g, 95%) as a white solid. 1H NMR(CDCl3,400MHz) δ7.78-7.75(m,3H),7.70-7.67(m,3H),7.65-7.55(m,20H),7.55-7.54 (d,J=1.4Hz,1H),7.51-7.50(d,J=1.4Hz,1H),7.46(s,2H),7.44-7.37 (m,30H),6.15-6.06(m,1H),5.49-5.43(dd,J=17.2,1.4Hz,1H),5.35-5.31(dd,J=10.5,1.2Hz,1H),4.78-4.76(d,J=5.5Hz,2H),1.57(s,9H).

[0229] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (16) To a nitrogen-flushed solution of compound 15 (8.0 g, 4.72 mmol) and tetrakis(triphenylphosphine)palladium (551 mg, 2.36 mmol) in dry tetrahydrofuran (63 mL), aniline (0.22 mL, 2.36 mmol) was added and stirred at room temperature for 12 h. The mixture was extracted with dichloromethane, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / dichloromethane (5 / 95) to give compound 16 as an off-white solid (7.4 g, 95%). 1 H NMR (CD2Cl2, 400MHz) δ7.76-7.72(m,3H),7.68-7.65(m,3H),7.62-7.49(m,22H),7.45-7.35(m,32H),1.53(s,9H).

[0230] Preparation of 7-((7-((7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (17) A solution of compound 16 (450 mg, 0.27 mmol) in formic acid / chloroform (50% by volume, 5.4 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 17 as an off-white solid (252 mg, 58%). 1 H NMR (CDCl3,400MHz) δ7.75-7.71(m,3H),7.67-7.62(m,3H),7.60-7.52(m,21H),7.49(d,J=1.5Hz,2H),7.43-7.34(m,3H).

[0231] Preparation of 3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (18) To flame-dried 10 wt% Pd / C solid (70 mg) was added anhydrous tetrahydrofuran (7.8 mL) and compound 17 (124 mg, 0.08 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 18 as an off-white solid (58 mg, 96%). 1 H NMR (MeOD, 400MHz) δ7.62-7.55(m,2H),7.53-7.46(m,2H),7.44-7.10(m,6H).

[0232] Example 5. 3-((3-((3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (22) [ka]

[0233] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-((7-((7-(allyloxy))-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (19) To a mixture of compound 16 (850 mg, 0.51 mmol), compound 12 (372 mg, 0.54 mmol), and 4-dimethylaminopyridine (13 mg, 0.10 mmol) in dichloromethane (5.1 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.56 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 19 as an off-white solid (1033 mg, 86%). 1 H NMR (CDCl3,400MHz) δ7.76-7.32(m,84H),6.12-6.02(m,1H),5.48-5.37(m,1H),5.32-5.28(m,1H),4.76-4.71(m,2H),1.53(s,9H).

[0234] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-((7-((7-(hydroxy))-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (20) To a nitrogen-flushed solution of compound 19 (1.0 g, 0.43 mmol) and tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) in dry tetrahydrofuran (9 mL), aniline (0.03 mL, 0.26 mmol) was added and stirred at room temperature for 16 h. The mixture was extracted with dichloromethane, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 5 / 95 EtOAc / dichloromethane to give compound 20 as an off-white solid (899 mg, 92%). 1 H NMR (CDCl3,400MHz) δ7.76-7.28(m,84H),1.53(s,9H).

[0235] Preparation of 7-((7-((7-((7-((7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (21) A solution of compound 20 (250 mg, 0.27 mmol) in formic acid / chloroform (33% by volume, 6.5 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 21 as an off-white solid (142 mg, 58%). 1 H NMR (CDCl3,400MHz) δ7.75-7.51(m,38H),7.50-7.47(m,2H),7.42-7.33(m,44H).

[0236] Preparation of 3-((7-((7-((7-((7-((2,2-diphenyl-7-((3,4,5-trihydroxybenzoyl)oxy)benzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-4,5-dihydroxybenzoic acid (22) To flame-dried 10 wt% Pd / C solid (100 mg) was added anhydrous tetrahydrofuran (3.1 mL) and compound 21 (70 mg, 0.03 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 22 as an off-white solid (24 mg, 71%). 1 H NMR (MeOD, 400MHz) δ7.64-7.54(m,4H),7.53-7.46(m,4H),7.44-7.09(m,6H).

[0237] Example 6. 3-((3-((3-((3-((3-((1H-pyrrole-2-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (25) [ka]

[0238] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 1H-pyrrole-2-carboxylate (23) To a mixture of compound 16 (700 mg, 0.42 mmol), pyrrole-2-carboxylic acid (56 mg, 0.51 mmol), and 4-dimethylaminopyridine (145 mg, 1.18 mmol) in dichloromethane (4.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg, 0.51 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 23 as an off-white solid (600 mg, 81%). 1 H NMR (CDCl3,400MHz) δ7.78-7.31(m,60H),7.21-7.18(m,1H),7.10-7.07(m,1H),6.40-6.35(m,1H),1.53(s,9H).

[0239] Preparation of 7-((7-((7-((7-((7-((1H-pyrrole-2-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (24) A solution of compound 23 (400 mg, 0.23 mmol) in formic acid / chloroform (50% by volume, 4.6 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 24 as an off-white solid (200 mg, 52%). 1 H NMR (CDCl3,400MHz) δ9.49(s,1H),7.80-7.31(m,60H),7.21-7.18(m,1H),7.11-7.07(m,1H),6.39-6.34(m,1H).

[0240] Preparation of 3-((3-((3-((3-((3-((1H-pyrrole-2-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (25) To flame-dried 10 wt% Pd / C solid (94 mg) was added anhydrous tetrahydrofuran (5.9 mL) and compound 24 (100 mg, 0.06 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 25 as an off-white solid (29 mg, 57%). 1 H NMR (MeOD, 400MHz) δ7.62-7.10(m,11H),7.10-7.06(m,1H),6.33-6.27(m,1H).

[0241] Example 7. 3-((3-((3-((3-((3-((1H-pyrrole-2-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (28) [ka]

[0242] 6-(((6-(((6-(((6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2 Preparation of -diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 1H-pyrrole-2-carboxylate (26) To a mixture of compound 20 (350 mg, 0.15 mmol), pyrrole-2-carboxylic acid (18 mg, 0.16 mmol), and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) in dichloromethane (3.1 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg, 0.17 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 26 as an off-white solid (250 mg, 69%). 1 H NMR (CD2Cl2,400MHz) δ9.37(s,1H),7.78-7.32(m,84H),7.20-7.16(m,1H),7.12-7.10(m,1H),6.44-6.33(m,1H),1.52(s,9H).

[0243] Preparation of 7-((7-((7-((7-((7-((7-((7-((1H-pyrrole-2-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (27) A solution of compound 26 (205 mg, 0.09 mmol) in formic acid / chloroform (50% by volume, 10 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 27 as an off-white solid (78 mg, 39%). 1 H NMR (CDCl2,400MHz) δ9.91(s,1H),7.81-7.31(m,84H),7.22-7.17(m,1H),7.14-7.08(m,1H),6.40-6.32(m,1H).

[0244] Preparation of 3-((3-((3-((3-((3-((3-((3-((3-((1H-pyrrole-2-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (28) To flame-dried 10 wt% Pd / C solid (30 mg) was added anhydrous tetrahydrofuran (3.4 mL) and compound 27 (78 mg, 0.03 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 28 as an off-white solid (34 mg, 85%). 1 H NMR (MeOD, 400MHz) δ7.63-7.05(m,16H),6.32-6.28(m,1H).

[0245] Example 8. 3-((3-((3-((3-((3,4-dihydroxy-5-((3-phenethyl-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (34) [ka]

[0246] Preparation of ethyl (Z)-2-hydroxy-4-oxo-6-phenylhex-2-enoate (29) To a stirred solution of benzylacetone (30.0 g, 200.0 mmol) in dry methanol (300 mL) was added dimethyl oxalate (27.0 g, 230.0 mmol) and sodium methoxide (42.0 mL, 200.0 mmol) at 0 °C. The reaction was slowly warmed to room temperature and stirred for 16 h. The mixture was diluted with EtOAc (500 mL) and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography using EtOAc / petroleum ether (1:3) to give ethyl (Z)-2-hydroxy-4-oxo-6-phenylhex-2-enoate (29) as a yellow solid (13.0 g, 27%). ESI-MS, m / z = 235 [M+H] + .

[0247] Preparation of ethyl 3-phenethyl-1H-pyrazole-5-carboxylate (30) To a stirred solution of ethyl (Z)-2-hydroxy-4-oxo-6-phenylhex-2-enoate (29, 13.0 g, 56.0 mmol) in ethanol (56 mL) was added hydrazine (51 wt % aqueous solution) (10.0 mL, 213.9 mmol). The mixture was heated to reflux for 16 h. The reaction was concentrated in vacuo, and the residue was purified by flash chromatography using EtOAc / petroleum (2:3) to give ethyl 3-phenethyl-1H-pyrazole-5-carboxylate (30) as a yellow oil (6.0 g, 50%). ESI-MS, m / z = 231 [M+H]+ .

[0248] Preparation of 3-phenethyl-1H-pyrazole-5-carboxylic acid (31) To a stirred solution of ethyl 3-phenethyl-1H-pyrazole-5-carboxylate (30, 5.0 g, 20.0 mmol) in tetrahydrofuran (40 mL) was added a solution of lithium hydroxide (1.0 g, 100.0 mmol) in water (20 mL). The mixture was stirred at room temperature for 16 hours. Most of the tetrahydrofuran was evaporated in vacuo. The pH of the mixture was adjusted to 2 with 1N hydrochloric acid. The mixture was filtered, and the solid was collected. The solid was purified by preparative HPLC to give 3-phenethyl-1H-pyrazole-5-carboxylic acid (31) as a white solid (83.9 mg, 2%). 1 H NMR (400MHz, DMSO-d6) δ12.97(s,2H),7.30-7.17(m,5H),6.48(s,1H),2.92(s,4H). ESI-MS, m / z=217[M+H] + .

[0249] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (32) To a mixture of compound 16 (210 mg, 0.13 mmol), compound 31 (29 mg, 0.13 mmol), and 4-dimethylaminopyridine (3 mg, 0.03 mmol) in dichloromethane (2.5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (27 mg, 0.14 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 32 as an off-white solid (190 mg, 81%). 1 H NMR (CD2Cl2, 400MHz) δ7.80-7.10(m,65H) 6.81(s,1H),3.09-2.98(m,4H),1.53(s,9H).

[0250] Preparation of 7-((7-((7-((7-((7-((3-phenethyl-1H-pyrazole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (33) A solution of compound 32 (182 mg, 0.10 mmol) in formic acid / chloroform (33% by volume, 6.5 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 33 as an off-white solid (113 mg, 64%). 1H NMR (CD2Cl2, 400MHz) δ7.83-7.10(m,65H),6.83(s,1H).

[0251] Preparation of 3-((3-((3-((3-((3,4-dihydroxy-5-((3-phenethyl-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (34) To flame-dried 10 wt% Pd / C solid (32 mg) was added anhydrous tetrahydrofuran (3.5 mL) and compound 33 (63 mg, 0.04 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 34 as an off-white solid (13 mg, 38%). 1 H NMR(MeOD,400MHz) δ7.65-7.07(m,15H),6.81-6.74(m,1H),3.09-2.97(m,4H)

[0252] Example 9. 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(2-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (42) [ka]

[0253] Preparation of (E)-4-(naphthalen-1-yl)but-3-en-2-one (35) To a solution of 1-naphthaldehyde (1.0 g, 6.4 mmol) in acetone / water (1 / 1, 2.6 mL) was added aqueous sodium hydroxide (1 wt%, 1.6 mL) and stirred at 60 °C for 2 h. The crude product was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 35 as a yellow oil (1.1 g, 91%) without further purification. 1 H NMR(CDCl3,400MHz) δ8.38(d,J=16.0Hz,1H),8.18(d,J=8.4Hz,1H),7.90(t,J=8.0Hz,2H),7.7 8(d,J=7.2Hz,1H),7.63-7.45(m,3H),6.82(d,J=16.0Hz,1H),2.47(s,3H)

[0254] Preparation of 4-(naphthalen-1-yl)butan-2-one (36) To flame-dried 10 wt% Pd / C solid (308 mg) was added anhydrous tetrahydrofuran (29 mL) and compound 35 (1137 mg, 5.79 mmol). The mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was then filtered and evaporated in vacuo. The residue was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 90 / 5) to give compound 36 as a colorless oil (814 mg, 71%). 1 H NMR(CDCl3,400MHz) δ7.99(d,J=8.2Hz,1H),7.90-7.82(m,1H),7.73(d,J=8.1Hz,1H),7.57-7.45(m,2 H),7.44-7.30(m,2H),3.37(t,J=7.8Hz,2H),2.89(t,J=7.8Hz,2H),2.16(s,3H).

[0255] Preparation of ethyl (Z)-2-hydroxy-6-(naphthalen-1-yl)-4-oxohex-2-enoate (37) To a solution of compound 36 (807 mg, 4.07 mmol) in tetrahydrofuran (27 mL) at −78° C., lithium diisopropylamide solution (2 M in tetrahydrofuran / heptane / ethylbenzene, 2.2 mL, 4.48 mmol) was added dropwise over 10 min and stirred at −78° C. for 10 min. Diethyl oxalate (683 μL, 4.88 mmol) was added, and the mixture was allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 1 N hydrochloric acid at 0° C. The mixture was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (10 / 80 / 10) to give compound 37 as a pale yellow oil (1025 mg, 84%). 1 H NMR(CDCl3,400MHz) δ8.01(d,J=8.4Hz,1H),7.90-7.84(m,1H),7.74(d,J=8.1Hz,1H),7.58-7.46(m,2H),7.44-7.31(m,2H), 6.37(s,1H),4.35(q,J=7.2Hz,2H),3.45(t,J=7.8Hz,2H),2.96(t,J=7.8Hz,2H),1.37(t,J=7.2Hz,2H).

[0256] Preparation of ethyl 3-(2-(naphthalen-1-yl)ethyl)-1H-pyrazole-5-carboxylate (38) To a solution of compound 37 (1018 mg, 3.41 mmol) in tetrahydrofuran / ethanol (1 / 1, 11.4 mL) was added hydrazine hydrate (199 μL, 4.09 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using methanol / dichloromethane (10 / 90). The collected residue was precipitated with ethanol / hexane to give compound 38 as an off-white solid (658 mg, 84%). 1H NMR(CD2Cl2,400MHz) δ8.09-8.00(m,1H),7.91-7.84(m,1H),7.74(d,J=8.2Hz,1H),7.57-7.45(m,2H),7.38(dd,J=8.1,7.1Hz,1H),7. 32-7.27(m,1H),6.68(s,1H),4.36(q,J=7.1Hz,2H),3.49-3.37(m,2H),3.22-3.07(m,2H),1.37(t,J=7.1Hz,2H).

[0257] Preparation of 3-(2-(naphthalen-1-yl)ethyl)1H-pyrazole-5-carboxylic acid (39) To a solution of compound 38 (658 mg, 2.24 mmol) in ethanol (4.5 mL) was added aqueous sodium hydroxide (10 wt%, 4.5 mL) and stirred at 60° C. for 2 h. The mixture was cooled to 0° C., quenched with 1N hydrochloric acid, and extracted with EtOAc and water. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with ethanol and hexane to give compound 39 as an off-white solid (520 mg, 87%). 1 H NMR(MeOD,400MHz) δ8.14(d,J=8.4Hz,1H),7.96-7.88(m,1H),7.77(d,J=8.0Hz,2H),7.62-7.47(m, 2H),7.46-7.32(m,2H),6.57(s,1H),3.37(t,J=8.0Hz,2H),3.01(t,J=8.0,2H).

[0258] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-(2-naphthalen-1-yl)ethyl)-1H-pyrazole-5-carboxylate (40) To a mixture of compound 16 (350 mg, 0.21 mmol), compound 39 (62 mg, 0.23 mmol), and 4-dimethylaminopyridine (21 mg, 0.17 mmol) in dichloromethane (4.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (49 mg, 0.25 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 40 as an off-white solid (327 mg, 81%). 1 H NMR(CDCl3,400MHz) δ8.05(d,J=8.4Hz,1H),7.88(d,J=7.7Hz,1H),7.83-7.28(m,65H),6.88(s,1H),3,48(t,J=7.8Hz,2H),3.20(t,J=7.8Hz,2H),1.53(s,9H).

[0259] Preparation of 7-((7-((7-((7-((7-((3-(2-(naphthalen-1-yl)ethyl)-1H-pyrazole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (41) A solution of compound 40 (327 mg, 0.10 mmol) in formic acid / chloroform (33% by volume, 11.4 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 41 as an off-white solid (145 mg, 46%). 1 H NMR (CD2Cl2, 400MHz) δ8.05(d,J=8.3Hz,1H),7.89-7.84(m,1H),7.84-7.11(m,65H),6,89(s,1H).

[0260] Preparation of 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(2-(naphthalen-1-yl)ethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (42) To flame-dried 10 wt% Pd / C solid (129 mg) was added anhydrous tetrahydrofuran (7.6 mL) and compound 41 (140 mg, 0.08 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 42 as an off-white solid (40 mg, 51%). 1H NMR (MeOD, 400MHz) δ7.64-6.88(m,13H),6.86-6.74(m,1H),3.02-2.81(m,4H),2.81-2.67(m,4H),2.18-1.67(m,4H).

[0261] Example 10. 3-((3-((3-((3-((3-((3-((3-(4-fluorophenethyl)-1H-pyrazole-5-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (50) [ka]

[0262] Preparation of (E)-4-(4-fluorophenyl)but-3-en-2-one (43) To a solution of p-fluorobenzaldehyde (1.0 g, 8.06 mmol) in acetone / water (1 / 1, 3.2 mL) was added aqueous sodium hydroxide (1 wt%, 2.0 mL) and stirred at 60° C. for 2 h. The crude product was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 43 as a yellow oil (1.3 g, 98%) without further purification. 1 H NMR (CDCl3,400MHz) δ7.57-7.51(m,2H),7.48(d,J=16.3Hz,2H),7.14-7.05(m,2H),6.64(d,J=16.2Hz,2H),2.37(s,3H).

[0263] Preparation of 4-(4-fluorophenyl)butan-2-one (44) To flame-dried 10 wt% Pd / C solid (399 mg) was added anhydrous tetrahydrofuran (38 mL) and compound 43 (1230 mg, 7.49 mmol). The mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was then filtered and evaporated in vacuo. The residue was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 90 / 5) to give compound 44 as a colorless oil (950 mg, 76%). 1 H NMR (CDCl3,400MHz) δ7.21-7.05(m,2H),7.02-6.89(m,2H),2,86(t,J=7.4Hz,2H),2.73(t,J=7.4Hz,2H),2.13(s,3H).

[0264] Preparation of ethyl (Z)-6-(4-fluorophenyl)-2-hydroxy-4-oxohex-2-enoate (45) To a solution of compound 44 (750 mg, 4.51 mmol) in tetrahydrofuran (28 mL) at −78° C., lithium diisopropylamide solution (2 M in tetrahydrofuran / heptane / ethylbenzene, 2.7 mL, 5.41 mmol) was added dropwise over 10 min and stirred at −78° C. for 10 min. Diethyl oxalate (852 μL, 6.09 mmol) was added, and the mixture was allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 1 N hydrochloric acid at 0° C. The mixture was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (10 / 80 / 10) to give compound 45 as a pale yellow oil (904 mg, 75%). 1 H NMR(CDCl3,400MHz) δ7.20-7.11(m,2H),7.02-6.92(m,2H),6.34(s,1H),4.34(q,J=7.1Hz,2H),2.95(t,J=7.6Hz,2H),2.80(t,J=7.5Hz,2H),1.37(t,J=7.2Hz,3H).

[0265] Preparation of ethyl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (46) To a solution of compound 45 (26.0 g, 97.65 mmol) in ethanol (195 mL) was added hydrazine hydrate (5.2 mL, 107.41 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure and extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using methanol / dichloromethane (10 / 90). The collected residue was precipitated with ethanol / hexane to give compound 46 as an off-white solid (17.1 g, 67%). 1 H NMR (CDCl3,400MHz) δ7.16-7.07(m,2H),7.01-6.92(m,2H),6.59(s,1H),4.37(q,J=7.1Hz,2H),3.04-2.89(m,4H),1.38(t,J=7.1Hz,3H).

[0266] Preparation of 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylic acid (47) To a solution of compound 46 (17.1 g, 65.35 mmol) in ethanol / tetrahydrofuran (1 / 1, 131 mL) was added aqueous sodium hydroxide (10 wt%, 65 mL) and stirred at 60° C. for 2 h. The mixture was cooled to 0° C., quenched with 1N hydrochloric acid, and extracted with EtOAc and water. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with ethanol and hexane to give compound 47 as an off-white solid (13.2 g, 86%). 1 H NMR (MeOD, 400MHz) δ7.22-7.13(m,2H),7.02-6.93(m,2H),6.53(s,1H),3.00-2.90(m,4H).

[0267] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (48) To a mixture of compound 16 (600 mg, 0.36 mmol), compound 47 (102 mg, 0.43 mmol), and 4-dimethylaminopyridine (124 mg, 1.01 mmol) in dichloromethane (3.6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg, 0.43 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 48 as an off-white solid (450 mg, 66%). 1 H NMR (CDCl3,400MHz) δ7.79-7.32(m,60H),7.16-7.09(m,2H),7.02-6.94(m,2H),6.80(s,1H),3.07-2.92(m,4H),1.54(s,9H).

[0268] Preparation of 7-((7-((7-((7-((7-((3-(4-fluorophenethyl)-1H-pyrazole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (49) A solution of compound 48 (404 mg, 0.22 mmol) in formic acid / chloroform (50% by volume, 4.4 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 49 as an off-white solid (136 mg, 35%). 1 H NMR (CDCl3,400MHz) δ7.83-7.32(m,60H),7.16-7.10(m,2H),7.02-6.94(m,2H),6.82(s,1H),3.08-2.95(m,4H).

[0269] Preparation of 3-((3-((3-((3-((3-((3-((3-(4-fluorophenethyl)-1H-pyrazole-5-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (50) To flame-dried 10 wt% Pd / C solid (60 mg) was added anhydrous tetrahydrofuran (6.7 mL) and compound 49 (120 mg, 0.07 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (1:25) to give compound 50 as an off-white solid (39 mg, 59%). 1 H NMR (MeOD, 400MHz) δ7.65-7.09(m, 12H), 7.04-6.95(m, 2H), 6.81-6.74(m, 1H), 3.08-2.95(m, 4H).

[0270] Example 11. 3-((3-((3-((3-((3-((3-((3-(3,5-difluorophenethyl)-1H-pyrrole-5-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (58) [ka]

[0271] Preparation of (E)-4-(3,5-difluorophenyl)but-3-en-2-one (51) To a solution of 3,5-difluorobenzaldehyde (3.0 g, 21.11 mmol) in acetone / water (1 / 1, 8.4 mL) was added aqueous sodium hydroxide (1 wt%, 5.3 mL) and stirred at 60 °C for 2 h. The crude product was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 51 as a yellow oil (3.7 g, 96%) without further purification. 1H NMR (CDCl3,400MHz) δ7.39(d,J=16.2Hz,2H),7.10-7.01(m,2H),6.88-6.81(m,1H),6.68(d,J=16.2Hz,2H),2.38(s,3H).

[0272] Preparation of 4-(3,5-difluorophenyl)butan-2-one (52) To flame-dried 10 wt% Pd / C solid (1081 mg) was added anhydrous tetrahydrofuran (41 mL) and compound 51 (3700 mg, 20.31 mmol). The mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was then filtered and evaporated in vacuo. The residue was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 90 / 5) to give compound 52 as a colorless oil (1710 mg, 46%). 1 H NMR (CDCl3,400MHz) δ6.74-6.67(m,2H),6.67-6.58(m,1H),2.87(t,J=7.4Hz,2H),2.75(t,J=7.2Hz,2H),2.15(s,3H).

[0273] Preparation of ethyl (Z)-6-(3,5-difluorophenyl)-2-hydroxy-4-oxohex-2-enoate (53) To a solution of compound 52 (1700 mg, 9.23 mmol) in tetrahydrofuran (62 mL) at −78° C., lithium diisopropylamide solution (2 M in tetrahydrofuran / heptane / ethylbenzene, 5.1 mL, 10.15 mmol) was added dropwise over 10 min and stirred at −78° C. for 10 min. Diethyl oxalate (1550 μL, 6.09 mmol) was added, and the mixture was allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 1 N hydrochloric acid at 0° C. The mixture was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (10 / 80 / 10) to give compound 53 as a colorless oil (2161 mg, 82%). 1H NMR (CDCl3,400MHz) δ6.77-6.61(m,3H),6.35(s,1H),4.34(q,J=7.1Hz,2H),2.96(t,J=7.6Hz,2H),2.82(t,J=7.4Hz,2H),1.36(t,J=7.1Hz,3H).

[0274] Preparation of ethyl 3-(3,5-difluorophenethyl)-1H-pyrazole-5-carboxylate (54) To a solution of compound 53 (2.1 g, 7.46 mmol) in ethanol / tetrahydrofuran (3 / 1, 20 mL) was added hydrazine hydrate (416 μL, 8.58 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure and extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using methanol / dichloromethane (10 / 90). The collected residue was precipitated with ethanol / hexane to give compound 54 as an off-white solid (1.5 g, 73%). 1 H NMR (CDCl3,400MHz) δ6.77-6.61(m,3H),6.61(s,1H),4.38(q,J=7.1Hz,2H),3.08-2.94(m,4H),1.38(t,J=7.1Hz,3H).

[0275] Preparation of 3-(3,5-difluorophenethyl)-1H-pyrazole-5-carboxylic acid (55) To a solution of compound 54 (1.5 g, 5.42 mmol) in ethanol (11 mL) was added aqueous sodium hydroxide (10 wt%, 5.5 mL) and stirred at 60° C. for 2 h. The mixture was cooled to 0° C., quenched with 1N hydrochloric acid, and extracted with EtOAc and water. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with ethanol and hexane to give compound 55 as an off-white solid (1.1 g, 82%). 1 H NMR (CDCl3,400MHz) δ6.58-6.78(m,2H),6.78-6.70(m,1H),6.57(s,1H),2.99(s,4H).

[0276] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-(3,5-fluorophenethyl)-1H-pyrazole-5-carboxylate (56) To a mixture of compound 16 (400 mg, 0.24 mmol), compound 55 (67 mg, 0.27 mmol), and 4-dimethylaminopyridine (24 mg, 0.19 mmol) in dichloromethane (4.8 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56 mg, 0.29 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 56 as an off-white solid (368 mg, 81%). 1 H NMR (CDCl3,400MHz) δ7.80-7.30(m,60H),6.82(s,1H),6.74-6.61(m,3H),3.08-2.94(m,4H),1.53(s,9H).

[0277] Preparation of 7-((7-((7-((7-((7-((3-(3,5-difluorophenethyl)-1H-pyrazole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (57) A solution of compound 56 (362 mg, 0.22 mmol) in formic acid / chloroform (40% by volume, 12.8 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 57 as an off-white solid (239 mg, 68%). 1 H NMR (CDCl3,400MHz) δ7.84-7.30(m,60H),6.83(s,1H),6.75-6.60(m,3H),3.10-2.96(m,4H).

[0278] Preparation of 3-((3-((3-((3-((3-((3-((3-(3,5-difluorophenethyl)-1H-pyrazole-5-carbonyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (58) To flame-dried 10 wt% Pd / C solid (99 mg) was added anhydrous tetrahydrofuran (3.0 mL) and compound 57 (100 mg, 0.05 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification was carried out by flash chromatography. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 58 as an off-white solid (32 mg, 58%). 1 H NMR (MeOD, 400MHz) δ7.63-7.10(m,10H),6.91-6.72(m,4H),3.05(s,4H).

[0279] Example 12. 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (66) [ka]

[0280] Preparation of (E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-one (59) To a solution of 4-trifluoromethylbenzaldehyde (10.0 g, 57.43 mmol) in acetone / water (1 / 1, 23.0 mL) was added aqueous sodium hydroxide (1 wt%, 14.4 mL) and stirred at 60 °C for 2 h. The crude product was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 59 as a yellow oil (12.0 g, 98%) without further purification. 1 H NMR (CDCl3,400MHz) δ7.70-7.62(m,4H),7.52(d,J=16.3Hz,2H),6.77(d,J=16.3Hz,2H),2.41(s,3H).

[0281] Preparation of 4-(4-(trifluoromethyl)phenyl)butan-2-one (60) To flame-dried 10 wt% Pd / C solid (2969 mg) was added anhydrous tetrahydrofuran (279 mL) and compound 59 (12.0 mg, 55.79 mmol). The mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was then filtered and evaporated in vacuo. The residue was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 90 / 5) to give compound 60 as a colorless oil (4.1 g, 34%). 1 H NMR (CDCl3,400MHz) δ7.53(d,J=8.1Hz,2H),7.29(d,J=8.1Hz,2H),2.95(t,J=7.5Hz,2H),2.78(t,J=7.5Hz,2H),2.15(s,3H).

[0282] Preparation of ethyl (Z)-2-hydroxy-4-oxo-6-(4-(trifluoromethyl)phenyl)hex-2-enoate (61) To a solution of compound 60 (4140 mg, 19.15 mmol) in tetrahydrofuran (127 mL) at −78° C., lithium diisopropylamide solution (2 M in tetrahydrofuran / heptane / ethylbenzene, 10.5 mL, 21.06 mmol) was added dropwise over 10 min and stirred at −78° C. for 10 min. Diethyl oxalate (3215 μL, 22.98 mmol) was added, and the mixture was allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 1 N hydrochloric acid at 0° C. The mixture was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (10 / 80 / 10) to give compound 61 as a pale yellow oil (5500 mg, 91%). 1 H NMR(CDCl3,400MHz) δ7.60-7.49(m,2H),7.37-7.27(m,2H),6.35(s,1H),4.36(q,J=6.7Hz,2H),3.04(t,J=7.5Hz,2H),2.85(t,J=7.5Hz,2H),1.37(t,J=7.0Hz,3H).

[0283] Preparation of ethyl 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylate (62) To a solution of compound 61 (5500 mg, 17.39 mmol) in ethanol (29 mL) was added hydrazine hydrate (1012 μL, 8.58 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using methanol / dichloromethane (10 / 90). The collected residue was precipitated with ethanol / hexane to give compound 62 as an off-white solid (2780 mg, 51%). 1 H NMR (CDCl3,400MHz) δ7.53(d,J=8.1Hz,2H),7.29(d,J=8.1Hz,2H),6.61(s,1H),4.37(q,J=7.1Hz,2H),3.04(s,4H),1.37(t,J=7.1Hz,3H).

[0284] Preparation of 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylic acid (63) To a solution of compound 62 (2780 mg, 8.90 mmol) in ethanol / tetrahydrofuran (1 / 1, 36 mL) was added aqueous sodium hydroxide (10 wt%, 18.0 mL) and stirred at 60° C. for 2 h. The mixture was cooled to 0° C., quenched with 1N hydrochloric acid, and extracted with EtOAc and water. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with ethanol and hexane to give compound 63 as an off-white solid (1895 mg, 75%). 1 H NMR (MeOD, 400MHz) δ7.56(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),6.75(s,1H),3.10-2.98(m,4H).

[0285] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylate (64) To a mixture of compound 16 (4300 mg, 2.60 mmol), compound 63 (812 mg, 2.86 mmol), and 4-dimethylaminopyridine (349 mg, 2.86 mmol) in dichloromethane (52 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (604 mg, 3.12 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 64 as an off-white solid (3740 mg, 75%). 1 H NMR (CDCl3,400MHz) δ7.81-7.27(m,64H),6.83(s,1H),3.07(s,4H),1.53(s,9H).

[0286] Preparation of 7-((7-((7-((7-((2,2-diphenyl-7-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (65) A solution of compound 64 (3740 mg, 1.95 mmol) in formic acid / chloroform (40% by volume, 130 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 65 as an off-white solid (1300 mg, 36%). 1H NMR (MeOD, 400MHz) δ7.83-7.27 (m, 64H), 6.84 (s, 1H), 3.08 (s, 4H).

[0287] Preparation of 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (66) To flame-dried 10 wt% Pd / C solid (2920 mg) was added anhydrous tetrahydrofuran (38 mL) and compound 65 (3200 mg, 1.72 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was carried out. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 66 as an off-white solid (1150 mg, 64%). 1 H NMR (MeOD, 400MHz) δ7.64-7.09 (m, 14H), 6.82 (s, 1H), 3.09 (s, 4H).

[0288] Example 13. 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (74) [ka]

[0289] Preparation of (E)-4-(2-(trifluoromethyl)phenyl)but-3-en-2-one (67) To a solution of 4-trifluoromethylbenzaldehyde (10.0 g, 57.43 mmol) in acetone / water (1 / 1, 23.0 mL) was added aqueous sodium hydroxide (1 wt%, 14.4 mL) and stirred at 60° C. for 2 h. The crude product was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 67 as a yellow oil (8.3 g, 67%) without further purification. 1 H NMR(CDCl3,400MHz) δ7.88(dd,J=16.2,2.0Hz,1H),7.71(d,J=8.1Hz,2H),7.58(t,J=7.6Hz,1H),7.49(t,J=7.7Hz,1H),6.63(d,J=16.2Hz,1H),2.40(s,3H).

[0290] Preparation of 4-(2-(trifluoromethyl)phenyl)butan-2-one (68) To flame-dried 10 wt% Pd / C solid (1992 mg) was added anhydrous tetrahydrofuran (41 mL) and compound 67 (8020 mg, 37.44 mmol). The mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was then filtered and evaporated in vacuo. The residue was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 90 / 5) to give compound 68 as a pale yellow oil (4380 mg, 54%). 1 H NMR (CDCl3,400MHz) δ7.62(d,J=7.8Hz,1H),7.46(t,J=7.5Hz,1H),7.35-7.27(m,2H),3.07(t,J=7.8Hz,2H),2.75(t,J=7.8Hz,2H),2.16(s,3H).

[0291] Preparation of ethyl (Z)-2-hydroxy-4-oxo-6-(2-(trifluoromethyl)phenyl)hex-2-enoate (69) To a solution of compound 68 (4380 mg, 20.26 mmol) in tetrahydrofuran (135 mL) at −78° C., lithium diisopropylamide solution (2 M in tetrahydrofuran / heptane / ethylbenzene, 11.1 mL, 22.28 mmol) was added dropwise over 10 min and stirred at −78° C. for 10 min. Diethyl oxalate (3401 μL, 24.31 mmol) was added, and the mixture was allowed to warm to 0° C. and stirred for 1 h. The mixture was quenched with 1 N hydrochloric acid at 0° C. The mixture was extracted with EtOAc and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (10 / 80 / 10) to give compound 69 as a pale yellow oil (5560 mg, 87%). 1 H NMR(CDCl3,400MHz) δ7.67-7.59(m,1H),7.51-7.42(m,1H),7.36-7.27(m,2H),6.35(s,1H),4.35(q,J =7.1Hz,2H),3.15(t,J=7.8Hz,2H),2.82(t,J=7.8Hz,2H),1.37(t,J=7.1Hz,3H).

[0292] Preparation of ethyl 3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylate (70) To a solution of compound 69 (5560 mg, 17.58 mmol) in ethanol (29 mL) was added hydrazine hydrate (1023 μL, 21.1 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using methanol / dichloromethane (10 / 90). The collected residue was precipitated with ethanol / hexane to give compound 70 as an off-white solid (3790 mg, 69%). 1H NMR(MeOD,400MHz) δ7.66(d,J=7.7Hz,1H),7.53(t,J=7.5Hz,1H),7.43-7.32(m,2H),6.56(s,1H),4. 34(q,J=7.1Hz,2H),3.20-3.10(m,2H),3.05-2.91(m,2H),1.37(t,J=7.1Hz,3H).

[0293] Preparation of 3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylic acid (71) To a solution of compound 70 (3788 mg, 12.13 mmol) in ethanol / tetrahydrofuran (1 / 1, 49 mL) was added aqueous sodium hydroxide (10 wt%, 49 mL) and stirred at 60° C. for 2 h. The mixture was cooled to 0° C., quenched with 1N hydrochloric acid, and extracted with EtOAc and water. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with ethanol and hexane to give compound 71 as an off-white solid (3138 mg, 91%). 1 H NMR (MeOD, 400MHz) δ7.66(d,J=7.8Hz,1H),7.53(t,J=7.5Hz,1H),7.43-7.32(m,2H),6.57(s,1H),3.20-3.09(m,2H),3.04-2.93(m,2H).

[0294] Preparation of 6-(((6-(((6-(((6-(((6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl)oxy)oxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylate (72) To a mixture of compound 16 (4600 mg, 2.78 mmol), compound 71 (869 mg, 3.06 mmol), and 4-dimethylaminopyridine (373 mg, 3.06 mmol) in dichloromethane (56 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (646 mg, 3.33 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 72 as an off-white solid (4443 mg, 83%). 1 H NMR (CDCl3,400MHz) δ7.79-7.27(m,64H),6.87(s,1H),3.21-3.11(m,2H),3.08-2.99(m,2H),1.53(s,9H).

[0295] Preparation of 7-((7-((7-((7-((2,2-diphenyl-7-((3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (73) A solution of compound 72 (4443 mg, 2.31 mmol) in formic acid / chloroform (40% by volume, 154 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 73 as an off-white solid (1300 mg, 36%). 1H NMR (CDCl3,400MHz) δ7.84-7.27(m,64H),6.89(s,1H),3.25-3.13(m,2H),3.11-3.02(m,2H).

[0296] Preparation of 3-((3-((3-((3-((3,4-dihydroxy-5-((3-(2-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (74) To flame-dried 10 wt% Pd / C solid (2829 mg) was added anhydrous tetrahydrofuran (37 mL) and compound 73 (3100 mg, 1.66 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was carried out. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 74 as an off-white solid (1170 mg, 67%). 1 H NMR (MeOD, 400MHz) δ7.73-7.04(m,14H),6.89-6.73(m,1H),3.26-3.14(m,2H),3.11-3.00(m,2H).

[0297] Example 14. 3-((3-((3-((3-((3-(benzoyloxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (77) [ka]

[0298] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (75) To a mixture of compound 16 (400 mg, 0.24 mmol), sodium benzoate (37 mg, 0.25 mmol), and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (5 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 75 as an off-white solid (367 mg, 86%). 1 H NMR (CDCl3,400MHz) δ8.30-8.21(m,2H),7.82-7.30(m,63H),1.53(s,9H).

[0299] Preparation of 7-((7-((7-((7-((7-(benzoyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (76) A solution of compound 75 (350 mg, 0.20 mmol) in formic acid / chloroform (33% by volume, 13 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 76 as an off-white solid (212 mg, 63%). 1 H NMR (CDCl3,400MHz) δ8.28-8.21(m,2H),7.81-7.30(m,63H).

[0300] Preparation of 3-((3-((3-((3-((3-(benzoyloxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (77) To flame-dried 10 wt% Pd / C solid (80 mg) was added anhydrous tetrahydrofuran (5 mL) and compound 76 (80 mg, 0.05 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 77 as an off-white solid (40 mg, 97%). 1 H NMR (MeOD, 400MHz) δ8.26-8.18(m, 2H), 7.75-7.06(m, 13H).

[0301] Example 15. 3-((3-((3-((3-((3-(2-cyclohexylacetoxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (80) [ka]

[0302] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(2-cyclohexylacetoxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (78) To a mixture of compound 16 (500 mg, 0.30 mmol), cyclohexylacetic acid (47 mg, 0.33 mmol), and 4-dimethylaminopyridine (18 mg, 0.15 mmol) in dichloromethane (6 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg, 0.36 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 78 as an off-white solid (387 mg, 72%). 1 H NMR (CDCl3,400MHz) δ7.75-7.31(m,60H),2.50(d,J=7.0Hz,2H),2.03-1.84(m,3H),1.82-1.64(m,3H),1.53(s,9H),1.42-1.02(m,5H).

[0303] Preparation of 7-((7-((7-((7-((7-(2-cyclohexylacetoxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (79) A solution of compound 78 (387 mg, 0.22 mmol) in formic acid / chloroform (40% by volume, 15 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 79 as an off-white solid (214 mg, 57%). 1 H NMR (CDCl3,400MHz) δ7.76-7.32(m,60H),2.50(d,J=7.0Hz,2H),2.04-1.86(m,3H),1.82-1.64(m,3H),1.41-1.04(m,5H).

[0304] Preparation of 3-((3-((3-((3-((3-(2-cyclohexylacetoxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid (80) To flame-dried 10 wt% Pd / C solid (148 mg) was added anhydrous tetrahydrofuran (5 mL) and compound 79 (150 mg, 0.09 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 80 as an off-white solid (53 mg, 68%). 1 H NMR (MeOD, 400MHz) δ7.65-7.09(m,10H),2.56-2.46(m,2H),2.00-1.84(m,3H),1.82-1.64(m,3H),1.44-1.04(m,5H).

[0305] Example 16. Synthesis of 5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3-(benzoyloxy)-4,5-dihydroxybenzoate (85) [ka]

[0306] Preparation of 7-((7-((7-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (81) To a stirred solution of compound 15 (30.0 g, 17.7 mmol) in anhydrous dichloromethane (176.9 mL) was added formic acid (88.5 mL) at 0 °C. After 10 min and stirring at room temperature for 4 h, the mixture was extracted three times with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / dichloromethane (1:8) to give compound 81 (22.5 g, 78%) as a white solid. 1 H NMR(CDCl3,400MHz) δ7.74-7.71(m,3H),7.66-7.63(m,3H),7.61-7.53(m,21H),7.51-7.50 (d,J=1.5Hz,1H),7.50-7.49(d,J=1.5Hz,1H),7.47-7.46(d,J=1.5Hz,1 H),7.41-7.35(m,30H),6.12-6.02(m,1H),5.45-5.39(dd,J=17.2,1.5Hz,1H),5.31-5.28(dd,J=10.5,1.3Hz,1H),4.75-4.73(d,J=5.5Hz,2H).

[0307] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (82) To a mixture of compound 81 (6200 mg, 3.78 mmol), phenol (391 mg, 4.16 mmol), and 4-dimethylaminopyridine (370 mg, 3.03 mmol) in dichloromethane (76 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (879 mg, 4.54 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 82 as an off-white solid (5648 mg, 87%). 1 H NMR(CD2Cl2,400MHz) δ7.78-7.34(m,62H),7.31-7.21(m,1H),7.21-7.14(m,2H),6.17-6.03(m,1H),5.49-5.39(m,1H),5.32-5.27(m,1H),4.78-4.71(m,2H).

[0308] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (83) To a nitrogen-flushed solution of compound 82 (6100 mg, 3.56 mmol) and tetrakis(triphenylphosphine)palladium (415 mg, 0.36 mmol) in dry tetrahydrofuran (71 mL), aniline (0.20 mL, 2.13 mmol) was added and stirred at room temperature for 16 h. The mixture was extracted with dichloromethane, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / dichloromethane (5 / 95) to give compound 83 as an off-white solid (5270 mg, 89%). 1 H NMR (CDCl3,400MHz) δ7.76-7.31(m,62H),7.25-7.13(m,3H).

[0309] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzoyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (84) To a mixture of compound 83 (135 mg, 0.08 mmol), benzoic acid (11 mg, 0.09 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol) in dichloromethane (2 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 mg, 0.10 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 84 as an off-white solid (122 mg, 85%). 1H NMR (CD2Cl2, 400MHz) δ8.28-8.21(m,2H),7.82-7.35(m,65H),7.32-7.21(m,1H),7.20-7.15(m,2H).

[0310] Preparation of 5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3-(benzoyloxy)-4,5-dihydroxybenzoate (85) To flame-dried 10 wt% Pd / C solid (118 mg) was added anhydrous tetrahydrofuran (4 mL) and compound 84 (118 mg, 0.07 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification was carried out by flash chromatography. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 85 as an off-white solid (36 mg, 57%). 1 H NMR (MeOD, 400MHz) δ8.29-8.17(m,2H),7.74-7.66(m,1H),7.64-7.23(m,15H),7.23-7.16(m,2H).

[0311] Example 17. 6-(tert-Butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (89) [ka]

[0312] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (86) To a solution of compound 10 (2.5 g, 3.5 mmol) in methyl ethyl ketone (35.4 mL) were added potassium carbonate (1.5 g, 10.6 mmol) and benzyl bromide (1.3 mL, 10.6 mmol). The mixture was stirred at 40 °C for 6 hours. After the reaction was complete, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was removed in vacuo. The residue was purified by flash chromatography using EtOAc / hexane (1:8) to give compound 86 as a white solid (2.6 g, 92%). 1 H NMR (CDCl3,400MHz) δ7.61-7.55(m,9H),7.48-7.33(m,20H),5.29(s,2H),1.56(s,9H).

[0313] Preparation of 7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (87) To a stirred solution of compound 86 (2.5 g, 3.1 mmol) in anhydrous dichloromethane (31.4 mL) was added formic acid (31.4 mL) at 0 °C. After 10 min and stirring at room temperature for 4 h, the mixture was extracted three times with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / dichloromethane (10%) to give compound 87 (1.3 g, 60%) as a white solid. 1 H NMR (CDCl3,400MHz) δ7.60-7.53(m,10H),7.52-7.51(d,J=1.5Hz,1H),7.47-7.45(m,3H),7.41-7.32(m,15H),5.28(s,2H).

[0314] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (88) To a mixture of compound 12 (2800 mg, 2.74 mmol), compound 87 (2129 mg, 2.87 mmol), and 4-dimethylaminopyridine (33 mg, 0.27 mmol) in dichloromethane (27 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (583 mg, 3.01 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 88 as an off-white solid (4471 mg, 94%). 1H NMR (CDCl3,400MHz) δ7.76-7.29(m,65H),5.28(s,2H),1.54(s,9H).

[0315] Preparation of 7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (89) A solution of compound 88 (4470 mg, 2.56 mmol) in formic acid / chloroform (40% by volume, 171 mL) was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane, water, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% EtOAc / dichloromethane with an additional 0.5% formic acid. The collected residue was precipitated with dichloromethane / hexane to give compound 89 as an off-white solid (2679 mg, 62%). 1 H NMR (CDCl3,400MHz) δ7.76-7.29(m,65H),5.27(s,2H).

[0316] Example 18. 5-((5-((5-((5-(((3-(4-fluorophenethyl)-1H-pyrazol-5-yl)methoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (92) [ka]

[0317] Preparation of (3-(4-fluorophenethyl)-1H-pyrazol-5-yl)methanol (90) To a solution of compound 47 (500 mg, 2.13 mmol) in anhydrous tetrahydrofuran (21 mL) at −78° C., lithium aluminum hydride (2.4 M in tetrahydrofuran, 3.6 mL, 8.54 mmol) was added dropwise over 5 minutes, and the mixture was allowed to warm to room temperature and stirred for 2 days. The mixture was cooled to 0° C. and quenched with 1N hydrochloric acid to pH 1. Solid anhydrous magnesium sulfate was added until saturated and extracted with n-butanol. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 10% methanol / dichloromethane. The collected residue was precipitated with ethanol / hexane to give compound 90 as a pale yellow solid (380 mg, 81%). 1 H NMR (MeOD, 400MHz) δ7.24-7.16(m,2H),7.05-6.96(m,2H),6.43(s,1H),4.72(s,2H),3.11-2.97(m,4H).

[0318] Preparation of 6-(((3-(4-fluorophenethyl)-1H-pyrazol-5-yl)methoxy)carbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (91) To a mixture of compound 90 (389 mg, 0.23 mmol), compound 90 (61 mg, 0.28 mmol), and 4-dimethylaminopyridine (23 mg, 0.18 mmol) in dichloromethane (5 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 91 as an off-white solid (145 mg, 33%). 1 H NMR(CDCl3,400MHz) δ7.77-7.28(m,65H),7.17-7.08(m,2H),6.99-6.87(m,2H),6.36-6.17(m,1H),5.56-5.29(m,2H),5.29-5.24(m,2H),3.24-2.79(m,4H).

[0319] Preparation of 5-((5-((5-((5-(((3-(4-fluorophenethyl)-1H-pyrazol-5-yl)methoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3-(benzyloxy)-4,5-dihydroxybenzoate (92) To flame-dried 10 wt% Pd / C solid (50 mg) was added anhydrous tetrahydrofuran (4 mL) and compound 91 (80 mg, 0.04 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 92 as an off-white solid (40 mg, 97%). 1 H NMR (MeOD, 400MHz) δ7.64-6.85 (m, 14H), 6.19-6.09 (m, 1H), 5.29-5.20 (m, 2H), 2.99-2.84 (m, 4H).

[0320] Example 19. 5-((5-((5-((2,3-dihydroxy-5-((pyridin-3-yloxy)carbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate hydrochloride (94) [ka]

[0321] Preparation of 2,2-diphenyl-6-((pyridin-3-yloxy)carbonyl)benzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (93) To a mixture of compound 89 (400 mg, 0.24 mmol), 3-hydroxypyridine (25 mg, 0.26 mmol), and 4-dimethylaminopyridine (15 mg, 0.12 mmol) in dichloromethane (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg, 0.28 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using EtOAc / hexane / dichloromethane (5 / 45 / 50). The collected residue was precipitated with dichloromethane / hexane to give compound 93 as an off-white solid (286 mg, 68%). 1 H NMR (CDCl3,400MHz) δ8.57-8.46(m,2H),7.77-7.28(m,67H),5.28(s,2H).

[0322] Preparation of 5-((5-((5-((2,3-dihydroxy-5-((pyridin-3-yloxy)carbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (94) To flame-dried 10 wt% Pd / C solid (154 mg) was added anhydrous tetrahydrofuran (4 mL) and compound 93 (160 mg, 0.14 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 8 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification was carried out by flash chromatography. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 94 as an off-white solid (37 mg, 46%). 1H NMR (MeOD, 400MHz) δ8.58-8.38(m, 2H), 7.85-7.71(m, 1H), 7.65-7.19(m, 11H).

[0323] Example 20. Cyclohexyl 3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate (96) [ka]

[0324] Preparation of cyclohexyl 7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (95) To a mixture of compound 89 (4000 mg, 2.37 mmol), cyclohexanol (1186 mg, 11.84 mmol), and 4-dimethylaminopyridine (347 mg, 2.84 mmol) in dichloromethane (30 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1146 mg, 5.92 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 95 as an off-white solid (3787 mg, 90%). 1H NMR (CDCl3,400MHz) δ7.75-7.29(m,65H),5.28(s,2H),5.02-4.91(m,1H),1.96-1.81(m,2H),1.81-1.66(m,2H),1.55-1.22(m,6H).

[0325] Preparation of cyclohexyl 3-((3-((3-((3-((3-(benzyloxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4-hydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl))oxy)-4,5-dihydroxybenzoate (96) To flame-dried 10 wt% Pd / C solid (3075 mg) was added anhydrous tetrahydrofuran (38 mL) and compound 95 (3200 mg, 1.81 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 8 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was carried out. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 96 as an off-white solid (1030 mg, 66%). 1 H NMR (MeOD, 400MHz) δ7.62-7.10(m, 10H), 4.99-4.89(m, 1H), 1.99-1.34(m, 10H).

[0326] Example 21. 5-((5-((5-((5-(cyclopropoxycarbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (98) [ka]

[0327] Preparation of 6-(cyclopropoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (97) To a mixture of compound 89 (450 mg, 0.27 mmol), cyclopropanol (77 mg, 1.33 mmol), and 4-dimethylaminopyridine (38 mg, 0.32 mmol) in dichloromethane (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (129 mg, 0.67 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 97 as an off-white solid (343 mg, 75%). 1 H NMR (CDCl3,400MHz) δ7.78-7.29(m,65H),5.28(s,2H),0.83-0.67(m,4H).

[0328] Preparation of 5-((5-((5-((5-(cyclopropoxycarbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3-(benzyloxy)-4,5-dihydroxybenzoate (98) To flame-dried 10 wt% Pd / C solid (167 mg) was added anhydrous tetrahydrofuran (4 mL) and compound 97 (170 mg, 0.10 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 8 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 98 as an off-white solid (23 mg, 29%). 1 H NMR (MeOD, 400MHz) δ7.62-7.03(m, 10H), 4.37-4.20(m, 1H), 0.85-0.70(m, 4H).

[0329] Example 22. Cycloheptyl 3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate (100) [ka]

[0330] Preparation of cycloheptyl 7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (99) To a mixture of compound 89 (450 mg, 0.27 mmol), cyclopropanol (77 mg, 1.33 mmol), and 4-dimethylaminopyridine (38 mg, 0.32 mmol) in dichloromethane (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (129 mg, 0.67 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using hexane / dichloromethane (30 / 70). The collected residue was precipitated with dichloromethane / hexane to give compound 99 as an off-white solid (377 mg, 79%). 1 H NMR(CDCl3,400MHz) δ7.76-7.29(m,65H),5.28(s,2H),5.19-5.08(m,1H),2.00-1.90(m,2H),1.83-1.64(m,4H),1.62-1.56(m,4H),1.54-1.41(m,2H).

[0331] Preparation of cycloheptyl 3-((3-((3-((3-((3-(benzyloxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate (100) To flame-dried 10 wt% Pd / C solid (162 mg) was added anhydrous tetrahydrofuran (4 mL) and compound 99 (170 mg, 0.10 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 8 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C10 with acetonitrile / water (30%-40%) with additional 1% formic acid. 18Purification was performed by flash chromatography. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 100 as an off-white solid (60 mg, 72%). 1 H NMR (MeOD, 400MHz) δ7.67-7.04(m,10H),5.17-5.07(m,1H),2.08-1.93(m,2H),1.91-1.70(m,4H),1.70-1.45(m,6H).

[0332] Example 23. 5-(benzoyloxy)-1,3-phenylenebis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (103) [ka]

[0333] Preparation of 3,5-dihydroxyphenylbenzoate (101) To a mixture of phloroglucinol (500 mg, 3.97 mmol) in tetrahydrofuran (150 mL) at 0 °C, benzoyl chloride (557 mg, 3.97 mmol) and triethylamine (2.0 g, 19.82 mmol) were added, and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was extracted with ethyl acetate, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using ethyl acetate / hexane (20 / 80). The collected residue was precipitated with ethyl acetate / hexane to give compound 101 as an off-white solid (150 mg, 16%). 1 H NMR (acetone-d6, 400 MHz) δ 8.58 (s, 2H), 8.15-8.12 (m, 2H), 7.70-7.65 (m, 1H), 7.57-7.53 (m, 2H), 6.36-6.32 (m, 3H).

[0334] Preparation of 5-(benzoyloxy)-1,3-phenylenebis(7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (102) To a mixture of compound 89 (734 mg, 0.43 mmol), compound 101 (50 mg, 0.22 mmol), and 4-dimethylaminopyridine (53 mg, 0.43 mmol) in dichloromethane (7 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (83 mg, 0.43 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using dichloromethane. The collected residue was precipitated with dichloromethane / hexane to give compound 102 as an off-white solid (450 mg, 58%). 1 H NMR (CDCl3,400MHz) δ8.18-8.16(d,2H),7.73-7.28(m,135H),7.09-7.05(m,3H).

[0335] Preparation of 5-(benzoyloxy)-1,3-phenylenebis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (103) To flame-dried 10 wt% Pd / C solid (240 mg) was added anhydrous tetrahydrofuran (7 mL) and compound 102 (240 mg, 0.07 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C102 with acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 103 as an off-white solid (60 mg, 51%). 1 H NMR (MeOD, 400MHz) δ8.20-8.18(d,2H),7.69-7.67(d,1H),7.58-7.57(m,8H),7.50-7.46(m,6H),7.31-7.23(m,8H),7.17-7.15(m,3H).

[0336] Example 24. 5-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)-1,3-phenylenebis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (107) [ka]

[0337] Preparation of 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl chloride (104) To a stirred solution of compound 63 (820 mg, 2.88 mmol) in dichloromethane (15.00 mL) was added oxalyl chloride (0.74 mL, 8.65 mmol) and DMF (0.05 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl chloride (104, 864 mg, crude) as a yellow solid.

[0338] Preparation of 3,5-dihydroxyphenyl 3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carboxylate (105) To a mixture of phloroglucinol (300 mg, 2.38 mmol) and compound 104 (720 mg, 2.38 mmol) in tetrahydrofuran (120 mL) at 0 °C, triethylamine (1.2 g, 11.89 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was extracted with ethyl acetate, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by reverse phase C chromatography using acetonitrile / water (40%-50%). 18 Purification was carried out by flash chromatography. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate and evaporated to give compound 105 as an off-white solid (83 mg, 9%). 1 H NMR (acetone-d6, 400 MHz) δ 8.57 (br, 1H), 7.64-7.62 (m, 2H), 7.51-7.47 (m, 2H), 6.79 (s, 1H), 6.29-6.24 (m, 3H), 3.14-3.06 (m, 4H).

[0339] Preparation of 5-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy-1,3-phenylenebis(7-((7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (106) To a mixture of compound 89 (689 mg, 0.41 mmol), compound 105 (80 mg, 0.2 mmol), and 4-dimethylaminopyridine (49 mg, 0.41 mmol) in dichloromethane (6 mL) at 0 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 6 h. The mixture was extracted with dichloromethane, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using ethyl acetate / dichloromethane (0% to 5%). The collected residue was precipitated with dichloromethane / hexane to give compound 106 as an off-white solid (300 mg, 40%). 1 H NMR (CDCl3,400MHz) δ7.66-7.25(m,136H),7.06-7.09(m,3H),6.77(s,1H),5.26(s,4H),3.04(s,4H).

[0340] Preparation of 5-((3-(4-(trifluoromethyl)phenethyl)-1H-pyrazole-5-carbonyl)oxy)-1,3-phenylenebis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (107) To flame-dried 10 wt% Pd / C solid (200 mg) was added anhydrous tetrahydrofuran (5 mL) and compound 106 (200 mg, 0.05 mmol). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified using reversed-phase C106 with acetonitrile / water (30%-40%) with additional 1% formic acid. 18 Purification by flash chromatography was performed. The collected residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (1:25) to give compound 107 as an off-white solid (28 mg, 27%). 1 H NMR (MeOD, 400MHz) δ7.57(m,8H),7.50-7.47(m,7H),7.41-7.38(m,2H),7.30-7.23(m,8H),7.18-7.12(m,3H),6.80(s,1H),3.08(s,4H).

[0341] Example 25. Synthesis of 7-((7-((7-benzyloxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (111) [ka]

[0342] Preparation of methyl 7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (108) To a solution of compound 2 (40.0 g, 115 mmol) in methyl ethyl ketone (450 mL) were added potassium carbonate (29.4 g, 212 mmol) and benzyl bromide (25.2 mL, 212 mmol). The mixture was stirred at 55° C. for 3 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was diluted with DCM, extracted with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and precipitated with EtOAc and hexane to give compound 108 as a white solid (47.3 g, 97%). 1 H NMR (CDCl3,500MHz) δ7.61-7.54(m,4H),7.46-7.42(m,2H),7.41-7.30(m,10H),7.29-7.27(pseudo d,J=1.5Hz,1H),5.24(s,2H),3.86(s,3H).

[0343] Preparation of 7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (109) To a stirred solution of compound 108 (47.3 g, 111 mmol) in THF / MeOH (1 / 1, 260 mL) was added LiOH (水溶液) (3M, 75 mL) was added and stirred at 50° C. for 4 hours. The mixture was cooled to room temperature, diluted with EtOAc, and quenched with 1N hydrochloric acid to pH=2. The mixture was extracted with EtOAc / water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo and precipitated with EtOAc / hexane to give compound 109 (38.7 g, 85%) as a white solid. 1 H NMR (CDCl3,500MHz) δ7.62-7.56(m,4H),7.48-7.43(m,3H),7.43-7.31(m,10H),5.26(s,2H).

[0344] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (110) To a mixture of compound 109 (5.0 g, 12.2 mmol), compound 10 (8.5 g, 12.2 mmol), and 4-dimethylaminopyridine (150 mg, 1.2 mmol) in DCM (125 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.5 g, 13.4 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was extracted with DCM, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using DCM / hexane (60% to 75%). The collected residue was precipitated with DCM / hexane to give compound 110 as an off-white solid (6.8 g, 50%). 1 H NMR (CDCl3,400MHz) δ7.72 (pseudo d, J=1.4Hz, 1H), 7.65 (pseudo d, J=1.6Hz, 1H), 7.62-7.50 (m, 13H), 7.50-7.28 (m, 26H), 5.28 (s, 2H), 1.54 (s, 9H).

[0345] Preparation of 7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (111) To a stirred solution of compound 110 (28 g, 25 mmol) in anhydrous DCM (127 mL) was added formic acid (127 mL) at 0° C. and stirred at 50° C. for 4 h. The mixture was extracted three times with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / DCM (10%) to give compound 111 (19.4 g, 73%) as a white solid. 1 H NMR (CDCl3,400MHz) δ7.74 (pseudo d, J=1.5Hz, 1H), 7.66 (pseudo d, J=1.4Hz, 1H), 7.63-7.29 (m, 39H), 5.29 (s, 2H).

[0346] Example 26. Synthesis of 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (113) [ka]

[0347] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (112) To a mixture of compound 87 (2201 mg, 2.97 mmol), compound 10 (2000 mg, 2.83 mmol), and 4-dimethylaminopyridine (69 mg, 0.57 mmol) in DCM (28 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (658 mg, 3.40 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was extracted with DCM, water, and brine. The organic residue was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography using DCM / hexane (70 / 30). The collected residue was precipitated with DCM / hexane to give compound 112 as an off-white solid (3951 mg, 98%). 1 H NMR(CDCl3,400MHz) δ7.73 (pseudo dd, J=5.6, 1.5Hz, 2H), 7.65 (pseudo dd, J=4.7, 1.5Hz, 2H), 7.63-7.50 (m, 17H), 7.50-7.29 (m, 32H), 5.28 (s, 2H), 1.54 (s, 9H).

[0348] Preparation of 7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (113) To a stirred solution of compound 112 (4.0 g, 2.8 mmol) in anhydrous DCM (138 mL) was added formic acid (138 mL) at 0° C. and stirred at 50° C. for 4 hours. The mixture was extracted three times with water, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography using EtOAc / DCM (10%) to give compound 113 (2.0 g, 53%) as a white solid. 1 H NMR (CDCl3,400MHz) δ7.73 (pseudo dd, J=5.6, 1.5Hz, 2H), 7.65 (pseudo dd, J=4.7, 1.5Hz, 2H), 7.63-7.50 (m, 17H), 7.50-7.29 (m, 32H), 5.28 (s, 2H).

[0349] Example 27. Synthesis of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoate) (117) [ka]

[0350] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (114) To a slurry solution of α-D-(+)-xylose (1.0 g, 6.7 mmol) and compound 5 (11.8 g, 30.0 mmol) in anhydrous acetonitrile (33.0 mL) was added anhydrous pyridine (4.7 mL, 60.0 mmol) at 0 °C and stirred at room temperature for 16 h. The crude mixture was cooled to 0 °C, quenched with 1 N hydrochloric acid, and extracted with EtOAc and brine. The slurry organic layer was filtered, dried over anhydrous magnesium sulfate, and filtered again. The organic solution was evaporated in vacuo and purified by normal-phase flash chromatography using DCM / hexane (50%-70%) to give compound 114 (8.9 g, 85%) as a white foamy solid. 1 H NMR(CDCl3,500MHz) δ7.65-7.58(m,4H),7.58-7.46(m,12H),7.41-7.28(m,27H),7.23-7.20(m,2H),7.1 8-7.13(m,2H),7.11(pseudo d,J=1.4Hz,1H),6.63(d,J=3.7Hz,1H),6.12-5.92(m,4H),5 .90-5.78(m,1H),5.47-5.17(m,9H),5.13-5.07(m,1H),4.76-4.70(m,2H),4.69-4. 57(m,4H),4.48-4.42(m,2H),4.21(dd,J=11.2,5.8Hz,1H),3.90(t,J=11.0Hz,1H).

[0351] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (115) To a solution of compound 114 (8.9 g, 5.65 mmol) and tetrakis(triphenylphosphine)palladium (659 mg, 0.56 mmol) in dry tetrahydrofuran (113 mL) flushed with argon, aniline (1.56 mL, 16.95 mmol) was added and stirred at room temperature for 16 h. The mixture was extracted with DCM, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 0% to 10% EtOAc / DCM, followed by precipitation with approximately 10% DCM / hexane to give compound 115 as an off-white solid (7.4 g, 92%). 1 H NMR(CDCl3,400MHz) δ7.61-7.41(m,17H),7.40-7.26(m,23H),7.25-7.03(m,8H),6.54(d,J=3.5Hz,1H),6.05(t,J=9.9H z,1H),5.42(dd,J=10.2,3.5Hz,1H),5.39-5.32(m,1H),4.19-4.07(m,1H),3.85(t,J=11.0Hz,1H).

[0352] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (116) To a slurry solution of compound 115 (300 mg, 0.21 mmol), compound 109 (378 mg, 0.89 mmol), and 4-dimethylaminopyridine (16 mg, 0.13 mmol) in DCM (6.8 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (189 mg, 0.98 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using 60% to 80% DCM / hexane and precipitated with approximately 10% DCM / hexane to give compound 116 (505 mg, 78%) as an off-white solid.1 H NMR(CDCl3,400MHz) δ7.60-7.21(m,116H),6.66(d,J=3.7Hz,1H),6.07(t,J=9.9Hz,1H),5.44(dd,J=10.1,4.0Hz,1H),5.41-5 .33(m,1H),5.20(s,4H),5.17(s,2H),5.14(s,2H),4.15(dd,J=11.0,5.6Hz,1H),3.90(t,J=11.0Hz,1H).

[0353] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoate) (117) To a solution of compound 116 (505 mg, 0.17 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added dried 10 wt% Pd / C solid (513 mg). The mixture was stirred at room temperature under H2 (8 atm) for 16 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 117 as an off-white solid (150 mg, 66%). 1 H NMR(MeOD,400MHz) δ7.62-7.31(m,3H),7.31-7.13(m,11H),7.12-6.95(m,2H),6.75-6.62(m,1H),6.1 1(td,J=9.9,3.8Hz,1H),5.65-5.44(m,2H),4.33-4.17(m,1H),4.14-3.99(m,1H).

[0354] Example 28. Synthesis of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (119) [ka]

[0355] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (118) To a slurry solution of compound 115 (200 mg, 0.14 mmol), compound 87 (440 mg, 0.59 mmol), and 4-dimethylaminopyridine (10 mg, 0.08 mmol) in DCM (6.4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (126 mg, 0.65 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes (60% to 80%) and precipitated with approximately 10% DCM / hexanes to give compound 118 (500 mg, 82%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.71-7.12(m,164H),6.65(d,J=3.7Hz,1H),6.07(t,J=9.9Hz,1H),5.44(dd,J=10.3,4.0Hz,1H),5.4 2-5.33(m,1H),5.24-5.12(m,6H),5.06(s,2H),4.15(dd,J=11.0,5.3Hz,1H),3.90(t,J=11.0Hz,1H).

[0356] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (119) To a solution of compound 118 (505 mg, 0.12 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added dried 10 wt% Pd / C solid (100 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 119 as an off-white solid (145 mg, 63%). 1 H NMR(MeOD,400MHz) δ7.65-7.15(m,22H),7.15-6.94(m,2H),6.76-6.62(m,1H),6.19-6.07(m,1H),5.65-5.45(m,2H),4.33-4.17(m,1H),4.17-3.97(m,1H).

[0357] Example 29. Synthesis of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (121) [ka]

[0358] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-((7-((7-benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (120) To a slurry solution of compound 115 (170 mg, 0.12 mmol), compound 111 (533 mg, 0.50 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in DCM (7 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (107 mg, 0.55 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes = 60% to 80% and precipitated with DCM / hexanes (approximately 10%) to give compound 120 (530 mg, 79%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.75-7.11(m,212H),6.65(d,J=3.5Hz,1H),6.07(t,J=9.8Hz,1H),5.43(dd,J=10.3,3.8Hz,1H ),5.41-5.33(m,1H),5.26-5.18(m,6H),5.15(s,2H),4.21-4.10(m,1H),3.89(t,J=10.6Hz,1H).

[0359] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (121) To a solution of compound 120 (505 mg, 0.03 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added dried 10 wt% Pd / C solid (511 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 121 as an off-white solid (140 mg, 60%). 1 H NMR(MeOD,400MHz) δ7.64-7.18(m,30H),7.14-6.96(m,2H),6.77-6.62(m,1H),6.20-6.05(m,1H),5.67-5.45(m,2H),4.33-4.16(m,1H),4.16-3.99(m,1H).

[0360] Example 30 Synthesis of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (123) [ka]

[0361] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (122) To a slurry solution of compound 115 (140 mg, 0.10 mmol), compound 113 (571 mg, 0.42 mmol), and 4-dimethylaminopyridine (7 mg, 0.06 mmol) in DCM (7.1 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (88 mg, 0.46 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes (60% to 80%) and precipitated with approximately 10% DCM / hexanes to give compound 122 (560 mg, 83%) as an off-white solid. 1 H NMR(CDCl3,500MHz) δ7.77-7.11(m,260H),6.65(d,J=3.5Hz,1H),6.07(t,J=9.8Hz,1H),5.43(dd,J=10.2,3.7 Hz,1H),5.41-5.32(m,1H),5.28-5.18(m,8H),4.21-4.10(m,1H),3.89(t,J=10.5Hz,1H).

[0362] Preparation of (2R,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (123) To a solution of compound 122 (505 mg, 0.07 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added dried 10 wt% Pd / C solid (511 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 123 as an off-white solid (150 mg, 64%). 1 H NMR(MeOD,400MHz) δ7.71-7.17(m,38H),7.15-6.95(m,2H),6.77-6.64(m,1H),6.21-6.07(m,1H),5.64-5.45(m,2H),4.33-4.16(m,1H),4.16-4.01(m,1H).

[0363] Example 31 Synthesis of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (126) [ka]

[0364] Preparation of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (124) To a slurry solution of D-(+)-xylose (890 mg, 5.93 mmol) and compound 5 (10.0 g, 25.49 mmol) in anhydrous acetonitrile (29.6 mL) was added anhydrous pyridine (6.8 mL, 82.99 mmol) at 0 °C and stirred at room temperature for 16 h. The crude mixture was cooled to 0 °C, quenched with 1 N hydrochloric acid, and extracted with EtOAc and brine. The slurry organic layer was filtered, dried over anhydrous magnesium sulfate, and filtered again. The organic solution was evaporated in vacuo and purified by normal-phase flash chromatography using DCM / hexane (50%-70%) to give the crude intermediate (1100 mg). To a solution of the Ar(g) flash intermediate in THF (19.1 mL) was added tetrakis(triphenylphosphine)palladium (111 mg, 0.10 mmol) and aniline (0.22 mL, 2.36 mmol) and stirred at room temperature for 16 h. The mixture was extracted with DCM, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 5% to 12% EtOAc / DCM and precipitated with approximately 10% DCM / hexane to give compound 124 as an off-white solid (210 mg, 3%). 1 H NMR(CDCl3,400MHz) δ7.55-7.44(m,16H),7.38-7.26(m,25H),7.25-7.08(m,7H),6.07(d,J=6.0Hz,1H),5.71(t,J=7.4H z,1H),5.51(t,J=13.5Hz,1H),5.27-5.15(m,1H),4.28-4.18(m,1H),3.65(dd,J=11.7,7.6Hz,1H).

[0365] Preparation of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (125) To a slurry solution of compound 124 (100 mg, 0.07 mmol), compound 87 (230 mg, 0.31 mmol), and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (3.3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (66 mg, 0.31 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes (60% to 80%) and precipitated with approximately 10% DCM / hexanes to give compound 125 (243 mg, 80%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.70-7.16(m,164H),6.02(d,J=6.8Hz,1H),5.78(t,J=8.6Hz,1H),5.59( t,J=8.2Hz,1H),5.25-5.11(m,8H),4.42-4.32(m,1H),3.75-3.63(m,1H).

[0366] Preparation of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (126) To a solution of compound 125 (220 mg, 0.05 mmol) in anhydrous tetrahydrofuran (4.4 mL) was added dried 10 wt% Pd / C solid (228 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 126 as an off-white solid (64 mg, 63%). 1 H NMR(MeOD,400MHz) δ7.66-7.15(m,22H),7.15-6.95(m,2H),6.27-6.13(m,1H),6.04-5.84(m,1H) ,5.73-5.55(m,1H),5.52-5.34(m,1H),4.46-4.30(m,1H),3.97-3.83(m,1H).

[0367] Example 32 Synthesis of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (128) [ka]

[0368] Preparation of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(7-((7-((7-((7-benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (127) To a slurry solution of compound 124 (80 mg, 0.06 mmol), compound 111 (263 mg, 4.4 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol) in DCM (3.4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 4.8 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using 60% to 80% DCM / hexane and precipitated with approximately 10% DCM / hexane to give compound 127 (226 mg, 72%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.69-7.18(m,212H),6.02(d,J=7.1Hz,1H),5.78(t,J=8.8Hz,1H),5.59( t,J=8.1Hz,1H),5.26-5.13(m,8H),4.43-4.30(m,1H),3.73-3.63(m,1H).

[0369] Preparation of (2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayltetrakis(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (128) To a solution of compound 127 (210 mg, 0.04 mmol) in anhydrous tetrahydrofuran (4.2 mL) was added dried 10 wt% Pd / C solid (233 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 128 as an off-white solid (57 mg, 59%). 1 H NMR(MeOD,400MHz) δ7.65-7.16(m,30H),7.16-6.97(m,2H),6.25-6.11(m,1H),6.03-5.85(m,1H) ,5.72-5.56(m,1H),5.51-5.34(m,1H),4.46-4.28(m,1H),3.99-3.81(m,1H).

[0370] Example 33 Synthesis of (2S,3R,4R,5R)-5-(((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (132) [ka]

[0371] Preparation of (2R,3R,4R,5R)-5-(((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (129) and (2S,3R,4R,5R)-5-(((7-allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (130) To a slurry solution of α-D-(-)-ribose (230 mg, 1.5 mmol) and compound 5 (3.0 g, 7.7 mmol) in anhydrous acetonitrile (7.7 mL) was added anhydrous pyridine (1.8 mL, 21.5 mmol) at 0 °C and stirred at room temperature for 16 h. The crude mixture was cooled to 0 °C, quenched with 1 N hydrochloric acid, and extracted with EtOAc and brine. The slurry organic layer was filtered, dried over anhydrous magnesium sulfate, and filtered again. The organic solution was evaporated in vacuo and purified by normal-phase flash chromatography using DCM / hexanes (55%-80%) and EtOAc / DCM (1%-5%) to give compound 129 (1.1 g, 44%) as a white foamy solid. 1H NMR(CDCl3,400MHz) δ7.62-7.54(m,8H),7.54-7.44(m,8H),7.43-7.27(m,28H),7.19(pseudo d,J=8.8Hz,4H),6.37(d,J=6.0 Hz,1H),6.11-5.97(m,2H),5.95-5.68(m,3H),5.54(dd,J=6.1,3.4Hz,1H),5.50-5.45(m,1H),5.41 (dd,J=17.2,1.4Hz,1H),5.29-4.98(m,7H),4.69(pseudo d,J=5.2Hz,2H),4.53(pseudo d,J=5.4Hz,2H),4.42 -4.36(m,2H),4.34(pseudo d,J=5.5Hz,2H),4.25(dd,J=11.9,4.1Hz,1H),4.15(dd,J=12.0,7.5Hz,1H). In addition, Compound 130 (600 mg, 25%) was obtained as a white foamy solid. 1 H NMR(CDCl3,400MHz) δ7.54-7.43(m,16H),7.37-7.22(m,28H),7.22-7.04(m,4H),6.45(pseudo s,1H),6.05(pseudo s,1H),5.79-5.60(m, 4H), 5.53 (pseudo s, 1H), 5.47-5.34 (m, 1H), 5.21-4.91 (m, 8H), 4.40-4.16 (m, 9H), 4.02 (dd, J=11.2, 4.7Hz, 1H).

[0372] Preparation of (2R,3R,4R,5R)-5-(((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (131) To a solution of compound 129 (1.1 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium (77 mg, 0.07 mmol) in dry tetrahydrofuran (6.7 mL) flushed with argon, aniline (0.13 mL, 1.40 mmol) was added and stirred at room temperature for 16 h. The mixture was extracted with DCM, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 5 / 95 EtOAc / DCM and precipitated with approximately 10% DCM / hexane to give compound 131 as an off-white solid (855 mg, 91%). 1 H NMR(CDCl3,400MHz) δ7.59-7.46(m,16H),7.39-7.27(m,27H),7.23-7.10(m,5H),6.40(d,J=3.7Hz,1H),5.85(t,J =3.4Hz,1H),5.53(t,J=3.5Hz,1H),5.49-5.41(m,1H),4.23-4.16(m,1H),4.11-4.04(m,1H).

[0373] Preparation of (2S,3R,4R,5R)-5-(((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate) (132) To a solution of compound 130 (600 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium (44 mg, 0.04 mmol) in dry tetrahydrofuran (1.9 mL) flushed with argon, aniline (0.08 mL, 0.80 mmol) was added and stirred at room temperature for 16 h. The mixture was extracted with DCM, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and purified by flash chromatography using 5 / 95 EtOAc / DCM and precipitated with approximately 10% DCM / hexane to give compound 132 as an off-white solid (427 mg, 79%). 1H NMR(CDCl3,400MHz) δ7.56-7.46(m,16H),7.40-7.27(m,27H),7.25-7.04(m,5H),6.43(pseudo s,1H),6.01(pseudo s, 1H), 5.51 (pseudo s, 1H), 5.42-5.33 (m, 1H), 4.26 (t, J=10.2Hz, 1H), 3.99-3.87 (m, 1H).

[0374] Example 34 Synthesis of (2R,3R,4R,5R)-5-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoate) (134) [ka]

[0375] Preparation of (2R,3R,4R,5R)-5-(((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (133) To a slurry solution of compound 131 (200 mg, 0.14 mmol), compound 109 (246 mg, 0.58 mmol), and 4-dimethylaminopyridine (10.4 mg, 0.08 mmol) in DCM (4.5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (123 mg, 0.64 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes (60% to 80%) and precipitated with approximately 10% DCM / hexanes to give compound 133 (318 mg, 74%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.62-7.17(m,116H),6.39(d,J=6.0Hz,1H),6.04(pseudo s,1H),5.51(dd,J=5.9,3.4Hz ,1H),5.50-5.41(m,1H),5.25(s,2H),5.11(s,4H),5.08(s,2H),4.26-4.08(m,2H).

[0376] Preparation of (2R,3R,4R,5R)-5-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoate) (134) To a solution of compound 133 (300 mg, 0.10 mmol) in anhydrous tetrahydrofuran (6.0 mL) was added dried 10 wt% Pd / C solid (304 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 134 as an off-white solid (77 mg, 57%). 1 H NMR (MeOD, 500MHz) δ7.50-7.12(m,15H),7.08-6.96(m,1H),6.49-6.37(m,1H),6.24-6.05(m,1H),5.61-5.44(m,2H),4.39-4.18(m,2H).

[0377] Example 35 Synthesis of (2R,3R,4R,5R)-5-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (136) [ka]

[0378] Preparation of (2R,3R,4R,5R)-5-(((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (135) To a slurry solution of compound 131 (140 mg, 0.10 mmol), compound 87 (300 mg, 0.41 mmol), and 4-dimethylaminopyridine (7 mg, 0.06 mmol) in DCM (4.4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (86 mg, 0.45 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes = 60% to 80% and precipitated with DCM / hexanes (approximately 10%) to give compound 135 (295 mg, 69%) as an off-white solid. 1 H NMR(CDCl3,400MHz) δ7.74-7.04(m,164H),6.39(d,J=4.1Hz,1H),6.00(pseudo s,1H),5.57-5.43 (m,2H),5.25(s,2H),5.10(s,2H),5.03-4.81(m,4H),4.25-4.07(m,2H).

[0379] Preparation of (2R,3R,4R,5R)-5-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoate) (136) To a solution of compound 135 (280 mg, 0.07 mmol) in anhydrous tetrahydrofuran (5.6 mL) was added dried 10 wt% Pd / C solid (291 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 136 as an off-white solid (77 mg, 60%). 1 H NMR (MeOD, 500MHz) δ7.64-7.13(m,23H),7.10-7.00(m,1H),6.51-6.37(m,1H),6.24-6.00(m,1H),5.63-5.44(m,2H),4.41-4.16(m,2H).

[0380] Example 36 Synthesis of (2R,3R,4R,5R)-5-(((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (138) [ka]

[0381] (2R,3R,4R,5R)-5-(((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetra Preparation of hydrofuran-2,3,4-triyltris(7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (137) To a slurry solution of compound 131 (90 mg, 0.06 mmol), compound 111 (289 mg, 0.27 mmol), and 4-dimethylaminopyridine (6 mg, 0.08 mmol) in DCM (3.8 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0.32 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using 60% to 80% DCM / hexane and precipitated with approximately 10% DCM / hexane to give compound 137 (250 mg, 71%) as an off-white solid. 1 H NMR(CDCl3,500MHz) δ7.77-7.03(m,212H),6.39(pseudo-s,1H),6.00(pseudo-s,1H),5.57-5.40(m,2H),5.25(s,2H),5.17(s,2H),5.14-5.03(m,4H),4.27-4.07(m,2H).

[0382] Preparation of (2R,3R,4R,5R)-5-(((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (138) To a solution of compound 137 (225 mg, 0.04 mmol) in anhydrous tetrahydrofuran (4.5 mL) was added dried 10 wt% Pd / C solid (236 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 138 as an off-white solid (77 mg, 74%). 1 H NMR (MeOD, 400MHz) δ7.66-7.13(m,31H),7.11-7.01(m,1H),6.52-6.36(m,1H),6.26-6.02(m,1H),5.66-5.44(m,2H),4.44-4.16(m,2H).

[0383] Example 37 Synthesis of (2R,3R,4R,5R)-5-(((3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (140) [ka]

[0384] (2R,3R,4R,5R)-5-(((7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetra Preparation of hydrofuran-2,3,4-triyltris(7-((7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (139) To a slurry solution of compound 131 (70 mg, 0.05 mmol), compound 113 (292 mg, 0.21 mmol), and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in DCM (3.6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48 mg, 0.25 mmol) at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 12 h. The crude mixture was extracted with DCM / water and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using DCM / hexanes = 60% to 80% and precipitated with DCM / hexanes (approximately 10%) to give compound 139 (240 mg, 71%) as an off-white solid. 1 H NMR(CDCl3,500MHz) δ7.78-7.01(m,260H),6.40(pseudo-s,1H),6.00(pseudo-s,1H),5.59-5.40(m,2H),5.26(s,2H),5.21(s,2H),5.19-5.03(m,4H),4.31-4.03(m,2H).

[0385] Preparation of (2R,3R,4R,5R)-5-(((3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3-((3-((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoate) (140) To a solution of compound 139 (235 mg, 0.03 mmol) in anhydrous tetrahydrofuran (4.7 mL) was added dried 10 wt% Pd / C solid (238 mg). The mixture was stirred at room temperature under H2 (8 atm) for 24 h. The crude mixture was filtered, washed with tetrahydrofuran and EtOAc, and the combined filtrates were evaporated in vacuo. The residue was extracted with EtOAc, 1N hydrochloric acid, and brine. The organic residue was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / hexane (10%). The crude solid was purified by reversed-phase C chromatography using ACN / H2O = 25% to 40% with 1% formic acid as an additive. 18 Further purification was carried out by flash chromatography. The collected residue was extracted with EtOAc / brine. The organic layer was dried over magnesium sulfate, evaporated, and precipitated with EtOAc / n-pentane (ca. 10%) to give compound 140 as an off-white solid (65 mg, 59%). 1 H NMR (MeOD, 400MHz) δ7.68-7.13(m,39H),7.10-6.99(m,1H),6.50-6.37(m,1H),6.27-6.03(m,1H),5.64-5.47(m,2H),4.39-4.19(m,2H).

[0386] Example 38 Synthesis of (2S,3R,4R,5R)-5-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoate) (142) [ka]

[0387] Preparation of (2S,3R,4R,5R)-5-(((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydrofuran-2,3,4-triyltris(7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (141) To a slurry solution of compound 132 (150 mg, 0.11 mmol), compound 109 (184 mg, 0.43 mmol), and 4-dimethylaminopyridine (8 mg, 0.06 mmol) in DCM (3.3 mL) was added 1-ethyl-3-(3-dimethyl...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring X is 【Chemistry 1-1】 or 【Chemistry 1-2】 and R １ , R ２ , R ３ , and R ４ At least one of the following is OR ５ or CH ２ OR ５ and other R １ , R ２ , R ３ , and R ４ each independently represents a halogen, OH, OR ５ , C.H. ２ OR ５ , CO ２ H, OC=OR ６ , (C=O)R ６ , R ６ , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, H, or absent; OR 5 is selected from the following formulae: 【Chemistry 2-1】 【Chemistry 2-2】 R ６ is of the formula 【Transformation 3】 wherein ring Y is a 3- to 7-membered monocyclic ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl; L １ and L ２ each independently selected from N, O, S, CH ２ , C=O, C ２～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, -(W-(CH ２ ) ｓ )- and absent, s is 0, 1, 2, 3, 4, or 5, and W is O, S, or N; R ７ is aryl, heteroaryl, aralkyl, C ２～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, and H, or a pharmaceutically acceptable salt thereof.

2. R ６ but, 【Chemistry 16-1】 【Chemistry 16-2】 2. The compound of claim 1, wherein:

3. 3. The compound of claim 1 or 2, selected from the following compounds listed in Table 1, or a pharmaceutically acceptable salt thereof. Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17

4. A composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a carrier.

5. The composition of claim 4 , wherein the composition is a pharmaceutical composition, a dietary supplement composition, a health food, or a medical food.

6. A pharmaceutical composition for use in a method for treating a coronavirus infection in a subject, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition according to claim 4 or 5, [Chemistry 1-3] During the ceremony, Ring X is [Chemistry 1-4] or [Chemistry 1-5] or [Chemistry 1-6] and at least one of R 1 , R 2 , R 3 , and R 4 is OR 5 or CH 2 OR 5 , and the other R 1 , R 2 , R 3 , and R 4 are each independently halogen, OH, OR 5 , CH 2 OR 5 , CO 2 H, OC═OR 6 , (C═O)R 6 , R 6 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, H, or absent; OR 5 is selected from the following formulae: [Chemistry 2-3] 【Chemistry 2-4】 R 6 is of the formula: 【Chemistry 3-1】 wherein ring Y is a 3- to 7-membered monocyclic ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl; each of L 1 and L 2 is independently a moiety selected from the group consisting of N, O, S, CH 2 , C═O, C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, —(W—(CH 2 ) s )—, and absent, where s is 0, 1, 2, 3, 4, or 5, and W is O, S, or N; R 7 is selected from the group consisting of aryl, heteroaryl, aralkyl, C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, and H; Pharmaceutical compositions.

7. 7. The pharmaceutical composition of claim 6, wherein the coronavirus virus is selected from the group consisting of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus.

8. 8. The pharmaceutical composition of claim 6 or 7, wherein the compound or its pharmaceutically acceptable salt or composition is administered orally, by injection, by external use, or by inhalation.

9. 9. The pharmaceutical composition of any one of claims 6 to 8, wherein the compound or pharmaceutically acceptable salt thereof or composition is disposed in a medical device selected from the group consisting of an inhaler, a nebulizer, a nasal spray, and a vaporizing aerosol device for administration to the subject.

10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the subject is a human subject.

11. The pharmaceutical composition according to any one of claims 6 to 10, wherein the subject is administered the compound or a pharmaceutically acceptable salt thereof, or the composition, continuously or at a frequency ranging from every 5 minutes to once every 3 months.

12. The pharmaceutical composition of any one of claims 6 to 11, wherein the human subject is further treated with one or more additional antiviral agents.

13. 13. The pharmaceutical composition of claim 12, wherein the one or more additional antiviral agents comprise a viral entry inhibitor, a viral uncoating inhibitor, a viral reverse transcriptase inhibitor, a viral protein synthesis inhibitor, a viral protease inhibitor, a viral polymerase inhibitor, a viral integrase inhibitor, an interferon, or a combination thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the viral entry inhibitor is selected from the group consisting of maraviroc, enfuvirtide, ibalizumab, fostemsavir, plerixafor, epigallocatechin gallate, vicriviroc, aplaviroc, maraviroc, tromantadine, nitazoxanide, umifenovir, and podofilox.

15. 14. The pharmaceutical composition of claim 13, wherein the viral uncoating inhibitor is selected from the group consisting of amantadine, rimantadine, and pleconaril.

16. 14. The pharmaceutical composition of claim 13, wherein the viral reverse transcriptase inhibitor is selected from the group consisting of zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, travada, nevirapine, raltegravir, and tenofovir disoproxil.

17. 14. The pharmaceutical composition of claim 13, wherein the viral protease inhibitor is selected from the group consisting of fosamprenavir, ritonavir, atazanavir, nelfinavir, indinavir, saquinavir, famciclovir, fomivirsen, lopinavir, ribavirin, darunavir, oseltamivir, and tipranavir.

18. 14. The pharmaceutical composition of claim 13, wherein the viral polymerase inhibitor is selected from the group consisting of amatoxin, rifamycin, cytarabine, fidaxomicin, tagetitoxin, foscarnet sodium, idoxuridine, penciclovir, sofosbuvir, trifluridine, valacyclovir, valganciclovir, vidarabine, and remdesivir.

19. 14. The pharmaceutical composition of claim 13, wherein the viral integrase inhibitor is selected from the group consisting of raltegarvir, elvitegravir, dolutegravir, bictegravir, and cabotegravir.

20. 14. The pharmaceutical composition of claim 13, wherein the interferon is selected from the group consisting of type I interferon, type II interferon, type III interferon, and pegylated interferon alfa-2a.

21. A pharmaceutical composition for use in a method for inhibiting D-amino acid oxidase (DAAO) in a subject, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the composition of claim 4 or 5.

22. 22. The pharmaceutical composition of claim 21, wherein the subject is a human having, suspected of having, or at risk for a central nervous system (CNS) disorder, metabolic disorder, or pain.

23. The CNS disorder is selected from the group consisting of schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign amnesia, closed head injury, autism spectrum disorder, Asperger's syndrome, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disability, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal thoughts and / or behavior, bipolar disorder, and encephalopathy.

23. The pharmaceutical composition of claim 22, wherein the condition is selected from the group consisting of polarity disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, and stroke.

24. 23. The pharmaceutical composition of claim 22, wherein the metabolic disorder is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetes.

25. 23. The pharmaceutical composition of claim 22, wherein the pain is selected from the group consisting of psychogenic pain, acute pain, chronic pain, chronic pain syndromes, neuropathic pain, nociceptive pain, and hyperalgesia.

26. 26. The pharmaceutical composition of claim 25, wherein the psychogenic pain is selected from the group consisting of headache, muscle pain, back pain, and stomach pain, the neuropathic pain is selected from the group consisting of sciatica, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, and central pain syndrome, and the nociceptive pain is selected from the group consisting of radicular pain, somatic pain, and visceral pain.

27. 27. The pharmaceutical composition of any one of claims 22 to 26, wherein the human subject is further treated with one or more additional pharmaceutical agents for treating and / or reducing the risk of a CNS disorder.

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